]> OWL-DL An INO extension with an focus on human interaction networks Yongqun "Oliver" He (YH) 2014-06-27 Zuoshuang "Allen" Xiang The Human Interaction Network Ontology (HINO) is an INO extension for the domain of human interaction networks. It has currently incoporated Reactome reactions and pathways. Like INO, HINO aligns with BFO. HINO is developed by following the OBO Foundry principles. Vision Release: 1.0.69 HINO: Human Interaction Network Ontology ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43171018 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43171008 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004714 Reactome Database ID Release 43181813 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008321 Reactome Database ID Release 43170999 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0001609 Reactome Database ID Release 43189631 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0001634 Reactome Database ID Release 43189661 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 43194541 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004714 Reactome Database ID Release 43198204 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 43194590 Reactome, http://www.reactome.org Synapsin Converted from EntitySet in Reactome Reactome DB_ID: 380576 Reactome Database ID Release 43380576 Reactome, http://www.reactome.org ReactomeREACT_18217 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43187724 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4375371 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015078 Reactome Database ID Release 43912612 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4375371 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43166570 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004705 Reactome Database ID Release 43204980 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4374729 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 4374732 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004705 Reactome Database ID Release 43204944 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004705 Reactome Database ID Release 43217311 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43204987 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008233 Reactome Database ID Release 43205109 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43205085 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0043130 Reactome Database ID Release 43205028 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008656 Reactome Database ID Release 43205051 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43193934 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43193885 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43193924 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004888 Reactome Database ID Release 43194356 Reactome, http://www.reactome.org Neuronal EAATs Converted from EntitySet in Reactome Reactome DB_ID: 210358 Reactome Database ID Release 43210358 Reactome, http://www.reactome.org ReactomeREACT_14035 ACTIVATION GENE ONTOLOGYGO:0005089 Reactome Database ID Release 43194502 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004767 Reactome Database ID Release 43194342 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43162362 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43162362 Reactome, http://www.reactome.org Astrocytic EAATs Converted from EntitySet in Reactome Reactome DB_ID: 210416 Reactome Database ID Release 43210416 Reactome, http://www.reactome.org ReactomeREACT_14651 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43162417 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004714 Reactome Database ID Release 4374710 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 43109806 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43165724 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43165724 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43165724 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43165690 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43165724 Reactome, http://www.reactome.org SLC6A GABA transporters Converted from EntitySet in Reactome Reactome DB_ID: 444011 Reactome Database ID Release 43444011 Reactome, http://www.reactome.org ReactomeREACT_20690 ACTIVATION GENE ONTOLOGYGO:0004679 Reactome Database ID Release 43381847 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004679 Reactome Database ID Release 43381847 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43162381 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005096 Reactome Database ID Release 43381841 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43380940 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43165690 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 43109816 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 4374732 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 4374732 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4375371 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0043682 Reactome Database ID Release 43936774 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004008 Reactome Database ID Release 43936821 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004322 Reactome Database ID Release 431562617 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005391 Reactome Database ID Release 43936847 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008900 Reactome Database ID Release 43937300 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005388 Reactome Database ID Release 43418313 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005388 Reactome Database ID Release 43936864 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005232 Reactome Database ID Release 43975264 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004012 Reactome Database ID Release 43939743 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004012 Reactome Database ID Release 43939743 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004221 Reactome Database ID Release 432179310 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016934 Reactome Database ID Release 43975398 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0042800 Reactome Database ID Release 431214228 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004723 Reactome Database ID Release 432025922 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016888 Reactome Database ID Release 43912391 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004520 Reactome Database ID Release 43981785 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008296 Reactome Database ID Release 43981788 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000150 Reactome Database ID Release 43913192 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004714 Reactome Database ID Release 4374714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004714 Reactome Database ID Release 4374741 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015254 Reactome Database ID Release 43432053 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015250 Reactome Database ID Release 43432032 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015250 Reactome Database ID Release 43432057 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015250 Reactome Database ID Release 43432066 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015250 Reactome Database ID Release 43507874 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004691 Reactome Database ID Release 43163671 Reactome, http://www.reactome.org GPAM/GPAT2 Converted from EntitySet in Reactome Reactome DB_ID: 1500606 Reactome Database ID Release 431500606 Reactome, http://www.reactome.org ReactomeREACT_123626 ACTIVATION GENE ONTOLOGYGO:0015265 Reactome Database ID Release 43507887 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015250 Reactome Database ID Release 43432032 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000146 Reactome Database ID Release 432028706 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015265 Reactome Database ID Release 43507887 Reactome, http://www.reactome.org MA Converted from EntitySet in Reactome Matrix Reactome DB_ID: 175256 Reactome Database ID Release 43175256 Reactome, http://www.reactome.org ReactomeREACT_7306 ACTIVATION GENE ONTOLOGYGO:0005381 Reactome Database ID Release 43917887 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016723 Reactome Database ID Release 43917825 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015078 Reactome Database ID Release 43912612 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015232 Reactome Database ID Release 43917884 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015232 Reactome Database ID Release 43917815 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015232 Reactome Database ID Release 43917906 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004322 Reactome Database ID Release 43917848 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004322 Reactome Database ID Release 43917800 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015254 Reactome Database ID Release 43432069 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016722 Reactome Database ID Release 43917904 Reactome, http://www.reactome.org PSIP1 Converted from EntitySet in Reactome Reactome DB_ID: 180145 Reactome Database ID Release 43180145 Reactome, http://www.reactome.org ReactomeREACT_9327 ACTIVATION GENE ONTOLOGYGO:0015254 Reactome Database ID Release 43507883 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015254 Reactome Database ID Release 43507883 Reactome, http://www.reactome.org Collagen alpha-1(XVII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192838 Reactome Database ID Release 432192838 Reactome, http://www.reactome.org ReactomeREACT_121760 ACTIVATION GENE ONTOLOGYGO:0015347 Reactome Database ID Release 43879613 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015347 Reactome Database ID Release 43879621 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015347 Reactome Database ID Release 43879524 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015132 Reactome Database ID Release 43879550 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005253 Reactome Database ID Release 43432018 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005253 Reactome Database ID Release 43432018 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015250 Reactome Database ID Release 43507880 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015250 Reactome Database ID Release 43507880 Reactome, http://www.reactome.org Collagen alpha-1(XVII) ectodomains Converted from EntitySet in Reactome Reactome DB_ID: 2471908 Reactome Database ID Release 432471908 Reactome, http://www.reactome.org ReactomeREACT_152058 Collagen alpha-1(XVII) transmembrane regions Converted from EntitySet in Reactome Reactome DB_ID: 2471902 Reactome Database ID Release 432471902 Reactome, http://www.reactome.org ReactomeREACT_151915 NRG1 Converted from EntitySet in Reactome Neuregulin-1 Reactome DB_ID: 1233225 Reactome Database ID Release 431233225 Reactome, http://www.reactome.org ReactomeREACT_117244 Collagen type XVII sheddases Converted from EntitySet in Reactome Reactome DB_ID: 2484973 Reactome Database ID Release 432484973 Reactome, http://www.reactome.org ReactomeREACT_151582 PathwayStep6350 PathwayStep6354 PathwayStep6353 PathwayStep6352 PathwayStep6351 PathwayStep6358 PathwayStep6357 PathwayStep6356 PathwayStep6355 PathwayStep6348 PathwayStep6349 SREBP1A/1C/2 Converted from EntitySet in Reactome Reactome DB_ID: 1655730 Reactome Database ID Release 431655730 Reactome, http://www.reactome.org ReactomeREACT_148091 SREBF1A/1C/2 Sec24 Converted from EntitySet in Reactome Reactome DB_ID: 203974 Reactome Database ID Release 43203974 Reactome, http://www.reactome.org ReactomeREACT_12680 PathwayStep6361 PathwayStep6360 PathwayStep6363 PathwayStep6362 PathwayStep6365 PathwayStep6364 PathwayStep6367 PathwayStep6366 PathwayStep6369 PathwayStep6368 PathwayStep6359 SREBP1A/1C/2 cleaved by S1P Converted from EntitySet in Reactome Reactome DB_ID: 1655726 Reactome Database ID Release 431655726 Reactome, http://www.reactome.org ReactomeREACT_148635 SREBF1A/1C/2 cleaved by S1P SREBP1A/1C/2 Converted from EntitySet in Reactome Reactome DB_ID: 1655725 Reactome Database ID Release 431655725 Reactome, http://www.reactome.org ReactomeREACT_148217 SREBF1A/1C/2 PathwayStep6336 PathwayStep6335 PathwayStep6334 PathwayStep6333 PathwayStep6332 PathwayStep6331 PathwayStep6330 PathwayStep6328 PathwayStep6329 PathwayStep6326 PathwayStep6327 SREBP1A/1C/2 cleaved by S2P Converted from EntitySet in Reactome Reactome DB_ID: 1655732 Reactome Database ID Release 431655732 Reactome, http://www.reactome.org ReactomeREACT_148464 SREBF1A/1C/2 cleaved by S2P SREBP1A/1C Converted from EntitySet in Reactome Reactome DB_ID: 1655729 Reactome Database ID Release 431655729 Reactome, http://www.reactome.org ReactomeREACT_117166 SREBF1A/1C PathwayStep6345 PathwayStep6344 PathwayStep6347 PathwayStep6346 PathwayStep6341 PathwayStep6340 PathwayStep6343 PathwayStep6342 PathwayStep6337 PathwayStep6338 PathwayStep6339 PathwayStep6397 PathwayStep6398 PathwayStep6395 PathwayStep6396 PathwayStep6399 PathwayStep6390 PathwayStep6393 PathwayStep6394 PathwayStep6391 PathwayStep6392 StAR-related cholesterol-binding proteins Converted from EntitySet in Reactome Reactome DB_ID: 196094 Reactome Database ID Release 43196094 Reactome, http://www.reactome.org ReactomeREACT_10617 PathwayStep6379 PathwayStep6377 PathwayStep6378 PathwayStep6375 PathwayStep6376 PathwayStep6373 PathwayStep6374 PathwayStep6371 PathwayStep6372 PathwayStep6370 PathwayStep6388 PathwayStep6389 PathwayStep6384 PathwayStep6385 PathwayStep6386 PathwayStep6387 PathwayStep6380 PathwayStep6381 PathwayStep6382 SRD5A1 or 2 or 3 Converted from EntitySet in Reactome Reactome DB_ID: 469656 Reactome Database ID Release 43469656 Reactome, http://www.reactome.org ReactomeREACT_23017 Steroid 5-alpha-reductases PathwayStep6383 PathwayStep6305 PathwayStep6304 PathwayStep6307 PathwayStep6306 PathwayStep6309 PathwayStep6308 PathwayStep6310 PathwayStep6311 PathwayStep6312 PathwayStep6313 PathwayStep6314 PathwayStep1 PathwayStep2 PathwayStep3 PathwayStep4 PathwayStep6318 PathwayStep5 PathwayStep6317 PathwayStep6 PathwayStep7 PathwayStep6316 PathwayStep8 PathwayStep6315 PathwayStep9 PathwayStep6319 PathwayStep6320 PathwayStep6321 PathwayStep6324 PathwayStep6325 PathwayStep6322 PathwayStep6323 Alpha 2 delta subunits of VGCC Converted from EntitySet in Reactome Reactome DB_ID: 210460 Reactome Database ID Release 43210460 Reactome, http://www.reactome.org ReactomeREACT_13042 beta subunit of VGCC Converted from EntitySet in Reactome Reactome DB_ID: 210517 Reactome Database ID Release 43210517 Reactome, http://www.reactome.org ReactomeREACT_12898 PathwayStep6302 PathwayStep6303 PathwayStep6300 PathwayStep6301 ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 431604461 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431604467 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431604455 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431604459 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004115 Reactome Database ID Release 43418563 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43164372 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43391182 Reactome, http://www.reactome.org NR2 subunits Converted from EntitySet in Reactome Reactome DB_ID: 419565 Reactome Database ID Release 43419565 Reactome, http://www.reactome.org ReactomeREACT_20888 ACTIVATION GENE ONTOLOGYGO:0004016 Reactome Database ID Release 43392125 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43420871 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43380101 Reactome, http://www.reactome.org CaMKII delta/gamma subunits Converted from EntitySet in Reactome Reactome DB_ID: 432790 Reactome Database ID Release 43432790 Reactome, http://www.reactome.org ReactomeREACT_20840 CaMKII alpha/beta subunits Converted from EntitySet in Reactome Reactome DB_ID: 432795 Reactome Database ID Release 43432795 Reactome, http://www.reactome.org ReactomeREACT_21184 Phospho GluR2 Converted from EntitySet in Reactome Reactome DB_ID: 421005 Reactome Database ID Release 43421005 Reactome, http://www.reactome.org ReactomeREACT_18957 NR1 subunits Converted from EntitySet in Reactome Reactome DB_ID: 432156 Reactome Database ID Release 43432156 Reactome, http://www.reactome.org ReactomeREACT_20957 GRIP1/GRIP2 Converted from EntitySet in Reactome Reactome DB_ID: 416631 Reactome Database ID Release 43416631 Reactome, http://www.reactome.org ReactomeREACT_18837 AP2A Converted from EntitySet in Reactome Reactome DB_ID: 416640 Reactome Database ID Release 43416640 Reactome, http://www.reactome.org ReactomeREACT_19022 GluR2 Converted from EntitySet in Reactome Reactome DB_ID: 392225 Reactome Database ID Release 43392225 Reactome, http://www.reactome.org ReactomeREACT_18509 ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431250381 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431250352 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431250301 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431918088 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 43194541 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431671668 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 431250368 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 431251983 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 431370496 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431253294 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431977300 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005096 Reactome Database ID Release 43195221 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005089 Reactome Database ID Release 43194957 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016362 Reactome Database ID Release 43201455 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005160 Reactome Database ID Release 43201461 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43173534 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004675 Reactome Database ID Release 43201437 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43173531 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005160 Reactome Database ID Release 43170854 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005215 Reactome Database ID Release 43178174 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 43178169 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004675 Reactome Database ID Release 43171178 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43171170 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005026 Reactome Database ID Release 43170856 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43170860 Reactome, http://www.reactome.org Gelatin degradation by MMP1, 2, 3, 7, 8, 9, 12, 13 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Gelatin is formed when collagen becomes partly or completely uncoiled when compared with the regular triple helix structure of fibrillar collagen. In vivo, once collagens are initially cleaved into clasical 3/4 and 1/4 fragments (by collagenases) they rapidly denature at body temperature and are degraded by gelatinases and other nonspecific tissue proteinases (Chung et al. 2004) to a semi-solid colloid gel. MMP2 and MMP9 are the major gelatinases (Collier et al. 1988, Wilhelm et al. 1989) often referred to respectively as Gelatinase A and Gelatinase B (Murphy & Crabbe 1995). However many other MMPs have gelatinase activity, including MMP1 (Murphy et al. 1982, Isaksen & Fagerhol 2001, Chung et al. 2004), MMP3 (Chin et al. 1985, Isaksen & Fagerhol 2001), MMP7 (Isaksen & Fagerhol 2001), MMP8 (Isaksen & Fagerhol 2001) MMP10 (Sanches-Lopez et al. 1993), MMP12 (Chandler et al. 1996), MMP13 (Knäuper et al. 1993, Isaksen & Fagerhol 2001), MMP16 (Shofuda et al. 1997), MMP17 (Wang et al. 1999), MMP18 (Spinucci et al. 1988), MMP19 (Stracke et al. 2000) and MMP22 (Yang & Kurkinen 1998). Pubmed10551873 Pubmed10809722 Pubmed11577169 Pubmed15257288 Pubmed2551898 Pubmed2834383 Pubmed2845110 Pubmed2995374 Pubmed6285893 Pubmed7674939 Pubmed8463259 Pubmed8576151 Pubmed8920930 Pubmed9092507 Pubmed9651395 Reactome Database ID Release 431454757 Reactome, http://www.reactome.org ReactomeREACT_150344 Reviewed: Sorsa, Timo, 2012-10-08 Gelatin degradation by MMP19 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Gelatin is formed when collagen becomes partly or completely uncoiled when compared with the regular triple helix structure of fibrillar collagen. In vivo, once collagens are initially cleaved into clasical 3/4 and 1/4 fragments (by collagenases) they rapidly denature at body temperature and are degraded by gelatinases and other nonspecific tissue proteinases (Chung et al. 2004) to a semi-solid colloid gel. MMP2 and MMP9 are the major gelatinases (Collier et al. 1988, Wilhelm et al. 1989) often referred to respectively as Gelatinase A and Gelatinase B (Murphy & Crabbe 1995). However many other MMPs have gelatinase activity, including MMP1 (Murphy et al. 1982, Isaksen & Fagerhol 2001, Chung et al. 2004), MMP3 (Chin et al. 1985, Isaksen & Fagerhol 2001), MMP7 (Isaksen & Fagerhol 2001), MMP8 (Isaksen & Fagerhol 2001) MMP10 (Sanches-Lopez et al. 1993), MMP12 (Chandler et al. 1996), MMP13 (Knäuper et al. 1993, Isaksen & Fagerhol 2001), MMP16 (Shofuda et al. 1997), MMP17 (Wang et al. 1999), MMP18 (Spinucci et al. 1988), MMP19 (Stracke et al. 2000) and MMP22 (Yang & Kurkinen 1998). Pubmed10551873 Pubmed10809722 Pubmed11577169 Pubmed15257288 Pubmed2551898 Pubmed2834383 Pubmed2845110 Pubmed2995374 Pubmed6285893 Pubmed7674939 Pubmed8463259 Pubmed8576151 Pubmed8920930 Pubmed9092507 Pubmed9651395 Reactome Database ID Release 432537499 Reactome, http://www.reactome.org ReactomeREACT_150252 Reviewed: Sorsa, Timo, 2012-10-08 Lysosomal degradation of gap junction plaques Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-23 13:10:01 Internalized GJ plaques are degraded by lysosomes. Lysosomal degradation appears to be the most common pathway of GJ degradation. (Qin et al., 2003; Grinzberg and Gilula., 1979 ; Berthoud et al., 2004 ; and Leithe et al., 2006). Pubmed12767974 Pubmed15094346 Pubmed16162097 Pubmed437313 Reactome Database ID Release 43190829 Reactome, http://www.reactome.org ReactomeREACT_10083 Degradation of ubiquitinated SMAD2 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11158580 Pubmed22045334 Reactome Database ID Release 432176452 Reactome, http://www.reactome.org ReactomeREACT_121119 Reviewed: Huang, Tao, 2012-05-14 Ubiquitinated SMAD2 undergoes proteasome-dependent degradation. Therefore, SMURF2 decreases the level of SMAD2 in the cell, irrespective of TGF-beta signaling, and may regulate the competence of a cell to respond to TGF-beta signaling (Zhang et al. 2001). These findings are contradicted by a recent study of Smurf2 knockout mice, where Smad2 protein levels were found to be unaltered in the absence of Smurf2 (Tang et al. 2011). Degradation of ubiquitinated SMAD3 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed14701756 Pubmed15781469 Reactome Database ID Release 432187382 Reactome, http://www.reactome.org ReactomeREACT_121055 Reviewed: Huang, Tao, 2012-05-14 SMAD3, ubiquitinated by STUB1 (CHIP), is degraded in a proteasome-dependent manner. STUB1-mediated downregulation of SMAD3 level happens in the absence of TGF-beta stimulation. STUB1 may therefore keep the basal level of SMAD3 low in the absence of TGF-beta signaling (Li et al. 2004, Xin et al. 2005). Endostatin degradation by cathepsins As well as generating endostatin from collagen XVIII, cathepsins L and B quickly degrade it, as do cathepsins D and K. In contrast MMPs that produce endostatin do not cleave it further (Ferreras et al. 2000). Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed11119712 Reactome Database ID Release 432471621 Reactome, http://www.reactome.org ReactomeREACT_150386 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type XIX degradation Authored: Jupe, S, 2011-07-12 Collagen type XIX is a FACIT (fibril-associated collagens with interrupted triple helix) collagen family member (Inoguchi et al. 1995) with a large non-collagenous N terminal domain that can self-assemble into higher order structures that are stabilized by intermolecular disulfide cross-links. Collagen type XIX is the least abundant collagen so far purified, comprising ?10-6% of dry weight in human umbilical cord (Myers et al. 2003). It is found in the basement membrane (BM) of normal human tissues. In developing embryos it is transiently expressed in certain muscular tissues and brain areas. Due to this localized expression, it is thought to be involved in the formation of specialized BM zones (Sumiyoshi et al. 2001). Collagen XIX is lost early in the development of invasive tumours, prior to penetration and eventual dissolution of the epithelial BM (Amenta et al. 2003). The NC1 domain of type XIX collagen exerts antitumor activity (Ramont et al. 2007). Edited: Jupe, S, 2012-11-12 Pubmed11169848 Pubmed12579531 Pubmed12788917 Pubmed17308049 Pubmed7775380 Reactome Database ID Release 432172433 Reactome, http://www.reactome.org ReactomeREACT_150411 Reviewed: Sorsa, Timo, 2012-10-08 Degradation of TGF-beta receptor complex Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11163210 Pubmed11278251 Pubmed15496141 Reactome Database ID Release 432169046 Reactome, http://www.reactome.org ReactomeREACT_120808 Recruitment of SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) to the activated TGF-beta receptor complex by SMAD7 and subsequent ubiquitination of SMAD7 and/or TGFBR1 triggers degradation of SMAD7 and TGFBR1 through proteasome and lysosome-dependent routes, resulting in downregulation of signaling by TGF-beta receptors. Reviewed: Huang, Tao, 2012-05-14 Ubiquitin-dependent degradation of the Smad complex terminates BMP2 signalling Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 EC Number: 6.3.2.19 Pubmed10587642 Pubmed10587654 Pubmed11571290 Reactome Database ID Release 43201425 Reactome, http://www.reactome.org ReactomeREACT_12048 Reviewed: Heldin, CH, 2007--1-1- The nuclear R-SMAD:Co-SMAD complex recruits ubiquitin conjugating enzymes, such as UBE2D1 and UBE2D3, that ubiquitinate the complex and eventually lead to its proteasomal degradation. This provides an end point to the signaling pathway. ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432176453 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432187377 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432169049 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004221 Reactome Database ID Release 432179282 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033829 Reactome Database ID Release 431464793 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003836 Reactome Database ID Release 431499958 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003831 Reactome Database ID Release 431499956 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 432187410 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035251 Reactome Database ID Release 431464797 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046922 Reactome Database ID Release 431464800 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431980072 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 4369594 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003777 Reactome Database ID Release 43177492 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43445092 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43382059 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43469651 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43469653 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 43186820 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43469652 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43179862 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431524188 Reactome, http://www.reactome.org HSD17B7 17-beta-hydroxysteroid dehydrogenase 7 3-keto-steroid reductase Converted from EntitySet in Reactome Reactome DB_ID: 194649 Reactome Database ID Release 43194649 Reactome, http://www.reactome.org ReactomeREACT_10277 INSIG Converted from EntitySet in Reactome Reactome DB_ID: 1655749 Reactome Database ID Release 431655749 Reactome, http://www.reactome.org ReactomeREACT_148176 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431433444 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035004 Reactome Database ID Release 431433507 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43205279 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 431433373 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431433439 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431433452 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431433495 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 431433543 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432447206 Reactome, http://www.reactome.org Isopentenyl-diphosphate delta-isomerase Converted from EntitySet in Reactome Reactome DB_ID: 191292 Reactome Database ID Release 43191292 Reactome, http://www.reactome.org ReactomeREACT_9566 ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 43186837 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431250510 Reactome, http://www.reactome.org HMG1/Y Converted from EntitySet in Reactome Reactome DB_ID: 175404 Reactome Database ID Release 43175404 Reactome, http://www.reactome.org ReactomeREACT_6982 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431250198 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431306968 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431250482 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431810443 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431448700 Reactome, http://www.reactome.org Vpu protein Converted from EntitySet in Reactome Reactome DB_ID: 175427 Reactome Database ID Release 43175427 Reactome, http://www.reactome.org ReactomeREACT_7289 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431963566 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431963577 Reactome, http://www.reactome.org Hydroxymethyl glutaryl CoA reductase Converted from EntitySet in Reactome Reactome DB_ID: 191355 Reactome Database ID Release 43191355 Reactome, http://www.reactome.org ReactomeREACT_9696 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431562637 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43418860 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431918091 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431358788 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004843 Reactome Database ID Release 431358793 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198368 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431358794 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431358800 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431251945 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 431306978 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 431306960 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 431250480 Reactome, http://www.reactome.org Vif Converted from EntitySet in Reactome Reactome DB_ID: 175462 Reactome Database ID Release 43175462 Reactome, http://www.reactome.org ReactomeREACT_7417 Viral Infectivity Factor ACTIVATION GENE ONTOLOGYGO:0004707 Reactome Database ID Release 43198750 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 43198361 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004675 Reactome Database ID Release 43198709 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43169894 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004714 Reactome Database ID Release 43198300 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43187781 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004714 Reactome Database ID Release 43535705 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004714 Reactome Database ID Release 43167688 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43170980 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43187737 Reactome, http://www.reactome.org Vpr protein Converted from EntitySet in Reactome Reactome DB_ID: 175202 Reactome Database ID Release 43175202 Reactome, http://www.reactome.org ReactomeREACT_7721 PathwayStep6457 PathwayStep6456 PathwayStep6455 PathwayStep6454 PathwayStep6453 PathwayStep6452 PathwayStep6451 PathwayStep6450 PPARG Converted from EntitySet in Reactome PPARgamma Peroxisome proliferator-activated receptor gamma Reactome DB_ID: 442506 Reactome Database ID Release 43442506 Reactome, http://www.reactome.org ReactomeREACT_27620 PathwayStep6449 PathwayStep6447 PathwayStep6448 PathwayStep6466 PathwayStep6465 PathwayStep6468 PathwayStep6467 PathwayStep6462 PathwayStep6461 PathwayStep6464 PathwayStep6463 PathwayStep6460 PathwayStep6458 PathwayStep6459 PathwayStep6475 PathwayStep6474 PathwayStep6473 PathwayStep6472 PathwayStep6479 PathwayStep6478 PathwayStep6477 PathwayStep6476 PathwayStep6471 PathwayStep6470 Rev Converted from EntitySet in Reactome Reactome DB_ID: 175501 Reactome Database ID Release 43175501 Reactome, http://www.reactome.org ReactomeREACT_6998 PathwayStep6469 PathwayStep6484 PathwayStep6483 PathwayStep6486 PathwayStep6485 PathwayStep6488 PathwayStep6487 PathwayStep6489 PathwayStep6480 PathwayStep6482 PathwayStep6481 PathwayStep6492 PathwayStep6493 PathwayStep6490 p-CLOCK/p-NPAS2 Converted from EntitySet in Reactome Reactome DB_ID: 421319 Reactome Database ID Release 43421319 Reactome, http://www.reactome.org ReactomeREACT_25499 PathwayStep6491 PathwayStep6498 PathwayStep6499 PathwayStep6496 PathwayStep6497 PathwayStep6494 PathwayStep6495 SREBP1A/1C/2 cleaved by S2P Converted from EntitySet in Reactome Reactome DB_ID: 1655720 Reactome Database ID Release 431655720 Reactome, http://www.reactome.org ReactomeREACT_116863 SREBF1A/1C/2 cleaved by S2P acetylcholine receptor subunits Converted from EntitySet in Reactome Reactome DB_ID: 629580 Reactome Database ID Release 43629580 Reactome, http://www.reactome.org ReactomeREACT_23363 Delta, epsilon, gamma subunits of acetylcholine receptor Converted from EntitySet in Reactome Reactome DB_ID: 532618 Reactome Database ID Release 43532618 Reactome, http://www.reactome.org ReactomeREACT_22592 GluR3/GluR4 Converted from EntitySet in Reactome Reactome DB_ID: 416296 Reactome Database ID Release 43416296 Reactome, http://www.reactome.org ReactomeREACT_18453 GluR1 Converted from EntitySet in Reactome Reactome DB_ID: 416297 Reactome Database ID Release 43416297 Reactome, http://www.reactome.org ReactomeREACT_18574 PathwayStep6402 PathwayStep6401 PathwayStep6400 PathwayStep6408 PathwayStep6407 PathwayStep6409 CaMKII subunits alpha/beta Converted from EntitySet in Reactome Reactome DB_ID: 417005 Reactome Database ID Release 43417005 Reactome, http://www.reactome.org ReactomeREACT_19047 PathwayStep6404 PathwayStep6403 PathwayStep6406 CaMKII subunits delta/gamma Converted from EntitySet in Reactome Reactome DB_ID: 417015 Reactome Database ID Release 43417015 Reactome, http://www.reactome.org ReactomeREACT_18463 PathwayStep6405 PathwayStep6410 PathwayStep6411 PathwayStep6412 PathwayStep6413 PathwayStep6419 PathwayStep6418 PathwayStep6417 PathwayStep6416 PathwayStep6415 PathwayStep6414 PathwayStep6423 GluR2 Converted from EntitySet in Reactome Reactome DB_ID: 416308 Reactome Database ID Release 43416308 Reactome, http://www.reactome.org ReactomeREACT_18506 PathwayStep6424 PathwayStep6421 PathwayStep6422 GRIP1/GRIP2 Converted from EntitySet in Reactome Reactome DB_ID: 416636 Reactome Database ID Release 43416636 Reactome, http://www.reactome.org ReactomeREACT_18455 PathwayStep6420 PathwayStep6426 Gamma subunit of VGCC (Stargazin) Converted from EntitySet in Reactome Reactome DB_ID: 416845 Reactome Database ID Release 43416845 Reactome, http://www.reactome.org ReactomeREACT_18715 PathwayStep6425 PathwayStep6428 PathwayStep6427 PathwayStep6429 GluR3/GluR4 Converted from EntitySet in Reactome Reactome DB_ID: 399698 Reactome Database ID Release 43399698 Reactome, http://www.reactome.org ReactomeREACT_18491 PathwayStep6430 PathwayStep6431 PathwayStep6432 PathwayStep6433 PathwayStep6434 PathwayStep6435 PathwayStep6439 PathwayStep6438 PathwayStep6437 PathwayStep6436 Gamma subunit of VGCC (Stargazin) Converted from EntitySet in Reactome Reactome DB_ID: 416844 Reactome Database ID Release 43416844 Reactome, http://www.reactome.org ReactomeREACT_18956 PathwayStep6441 PathwayStep6442 PathwayStep6440 GluR1 Converted from EntitySet in Reactome Reactome DB_ID: 392227 Reactome Database ID Release 43392227 Reactome, http://www.reactome.org ReactomeREACT_18970 PathwayStep6445 PathwayStep6446 PathwayStep6443 PathwayStep6444 ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 4369594 Reactome, http://www.reactome.org IP3R subunits Converted from EntitySet in Reactome Reactome DB_ID: 418284 Reactome Database ID Release 43418284 Reactome, http://www.reactome.org ReactomeREACT_18905 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43141607 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4375819 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43187927 Reactome, http://www.reactome.org TRPC3/6/7 Converted from EntitySet in Reactome Reactome DB_ID: 426176 Reactome Database ID Release 43426176 Reactome, http://www.reactome.org ReactomeREACT_23108 ACTIVATION GENE ONTOLOGYGO:0004861 Reactome Database ID Release 43188223 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 43187909 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369222 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369254 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 43113757 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43188393 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 4376013 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 4369755 Reactome, http://www.reactome.org BK channel beta subunit Converted from EntitySet in Reactome Reactome DB_ID: 418469 Reactome Database ID Release 43418469 Reactome, http://www.reactome.org ReactomeREACT_24695 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43157883 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369222 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369254 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 4369262 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008080 Reactome Database ID Release 432468053 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43187957 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008080 Reactome Database ID Release 432468053 Reactome, http://www.reactome.org Na+/Ca2+ exchanger proteins Converted from EntitySet in Reactome Reactome DB_ID: 425675 Reactome Database ID Release 43425675 Reactome, http://www.reactome.org ReactomeREACT_20277 ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43187499 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43187571 Reactome, http://www.reactome.org PMCAs Converted from EntitySet in Reactome Plasma membrane Ca2+ ATPases Reactome DB_ID: 418306 Reactome Database ID Release 43418306 Reactome, http://www.reactome.org ReactomeREACT_24662 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 43174087 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369254 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369246 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369246 Reactome, http://www.reactome.org Sarco/endoplasmic reticulum Ca2+ ATPases (SERCAs) Converted from EntitySet in Reactome Reactome DB_ID: 427905 Reactome Database ID Release 43427905 Reactome, http://www.reactome.org ReactomeREACT_24286 ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 4369198 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369222 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431363330 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 431363267 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43174076 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 432529016 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 432311326 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 431638806 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43201699 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 432311326 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43164602 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004407 Reactome Database ID Release 432545204 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43174077 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43188394 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43174240 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008234 Reactome Database ID Release 432467764 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008234 Reactome Database ID Release 432467772 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004407 Reactome Database ID Release 432545204 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 4376014 Reactome, http://www.reactome.org Phosphodiesterases, dual (cAMP, cGMP) activity Converted from EntitySet in Reactome Reactome DB_ID: 418547 Reactome Database ID Release 43418547 Reactome, http://www.reactome.org ReactomeREACT_19805 ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 43170155 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369222 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 4369262 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 4369757 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 43170155 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43170129 Reactome, http://www.reactome.org cGKs Converted from EntitySet in Reactome Cyclic GMP-dependent protein kinases (PKGs) Reactome DB_ID: 418379 Reactome Database ID Release 43418379 Reactome, http://www.reactome.org ReactomeREACT_24186 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432430544 Reactome, http://www.reactome.org Guanylate cyclase soluble subunit beta Converted from EntitySet in Reactome Reactome DB_ID: 392013 Reactome Database ID Release 43392013 Reactome, http://www.reactome.org ReactomeREACT_24398 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432430544 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43164602 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 432311326 Reactome, http://www.reactome.org Guanylate cyclase soluble subunit alpha Converted from EntitySet in Reactome Reactome DB_ID: 392015 Reactome Database ID Release 43392015 Reactome, http://www.reactome.org ReactomeREACT_24752 ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43174240 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43164602 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 432311326 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 432214352 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432422918 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43174240 Reactome, http://www.reactome.org PP2A-56 kDa regulatory subunit B delta isoform Converted from EntitySet in Reactome Reactome DB_ID: 165966 Reactome Database ID Release 43165966 Reactome, http://www.reactome.org ReactomeREACT_3775 PP2A- 56 kDa regulatory subunit B gamma isoform Converted from EntitySet in Reactome Reactome DB_ID: 196237 Reactome Database ID Release 43196237 Reactome, http://www.reactome.org ReactomeREACT_10823 PathwayStep6194 PathwayStep6193 PathwayStep6196 PathwayStep6195 PathwayStep6190 PathwayStep6192 PP2A-subunit A Converted from EntitySet in Reactome Reactome DB_ID: 165990 Reactome Database ID Release 43165990 Reactome, http://www.reactome.org ReactomeREACT_3223 PathwayStep6191 PathwayStep6198 PathwayStep6197 PathwayStep6199 PP2A-catalytic subunit C Converted from EntitySet in Reactome Reactome DB_ID: 165977 Reactome Database ID Release 43165977 Reactome, http://www.reactome.org ReactomeREACT_3798 PP2A- 56 kDa regulatory subunit B beta isoform Converted from EntitySet in Reactome Reactome DB_ID: 196240 Reactome Database ID Release 43196240 Reactome, http://www.reactome.org ReactomeREACT_10740 PathwayStep6181 PathwayStep6180 PathwayStep6185 PathwayStep6184 PathwayStep6183 PathwayStep6182 PathwayStep6189 PathwayStep6188 PathwayStep6187 PathwayStep6186 PathwayStep6170 PathwayStep6172 PathwayStep6171 PathwayStep6174 PathwayStep6173 PathwayStep6176 PathwayStep6175 PathwayStep6178 PathwayStep6177 PathwayStep6179 VAPA/B Converted from EntitySet in Reactome Reactome DB_ID: 429670 Reactome Database ID Release 43429670 Reactome, http://www.reactome.org ReactomeREACT_20034 VAMP-associated proteins A, B PathwayStep6155 PathwayStep6156 PathwayStep6153 PathwayStep6154 PathwayStep6159 PathwayStep6157 PathwayStep6158 CYP(4) Converted from EntitySet in Reactome Reactome DB_ID: 2161805 Reactome Database ID Release 432161805 Reactome, http://www.reactome.org ReactomeREACT_150979 PathwayStep6151 CYP(5) Converted from EntitySet in Reactome Reactome DB_ID: 2161990 Reactome Database ID Release 432161990 Reactome, http://www.reactome.org ReactomeREACT_152220 PathwayStep6152 PathwayStep6150 PathwayStep6164 PathwayStep6165 PathwayStep6166 PathwayStep6167 PathwayStep6168 PathwayStep6169 PathwayStep6160 PathwayStep6161 PathwayStep6162 PathwayStep6163 PathwayStep6129 PathwayStep6128 PathwayStep6137 PathwayStep6138 PathwayStep6135 PathwayStep6136 PathwayStep6133 PathwayStep6134 PathwayStep6131 PathwayStep6132 PathwayStep6130 PathwayStep6139 PathwayStep6146 PathwayStep6147 PathwayStep6148 PathwayStep6149 PathwayStep6142 PathwayStep6143 PathwayStep6144 PathwayStep6145 PathwayStep6140 PathwayStep6141 PathwayStep6108 PathwayStep6109 PathwayStep6106 PathwayStep6107 PathwayStep6112 PathwayStep6111 PathwayStep6110 PathwayStep6116 PathwayStep6115 PathwayStep6114 PathwayStep6113 PathwayStep6117 PathwayStep6118 PathwayStep6119 CYP4F2/4F3 Converted from EntitySet in Reactome Reactome DB_ID: 2161611 Reactome Database ID Release 432161611 Reactome, http://www.reactome.org ReactomeREACT_125551 PathwayStep6121 PathwayStep6120 PathwayStep6123 PathwayStep6122 PathwayStep6125 PathwayStep6124 PathwayStep6127 PathwayStep6126 DPEP1/2 Converted from EntitySet in Reactome Reactome DB_ID: 2162149 Reactome Database ID Release 432162149 Reactome, http://www.reactome.org ReactomeREACT_121852 CYP(3) Converted from EntitySet in Reactome Reactome DB_ID: 2161816 Reactome Database ID Release 432161816 Reactome, http://www.reactome.org ReactomeREACT_151091 CYP(2) Converted from EntitySet in Reactome Reactome DB_ID: 2161767 Reactome Database ID Release 432161767 Reactome, http://www.reactome.org ReactomeREACT_150617 CYP(1) Converted from EntitySet in Reactome Reactome DB_ID: 2162028 Reactome Database ID Release 432162028 Reactome, http://www.reactome.org ReactomeREACT_150842 PathwayStep6103 PathwayStep6102 PathwayStep6105 PathwayStep6104 PathwayStep6101 PathwayStep6100 INPP5(2) Converted from EntitySet in Reactome Reactome DB_ID: 1806186 Reactome Database ID Release 431806186 Reactome, http://www.reactome.org ReactomeREACT_122778 INPP5(1) Converted from EntitySet in Reactome Reactome DB_ID: 1806201 Reactome Database ID Release 431806201 Reactome, http://www.reactome.org ReactomeREACT_124927 SYNJ/MTM(1) Converted from EntitySet in Reactome Reactome DB_ID: 1806223 Reactome Database ID Release 431806223 Reactome, http://www.reactome.org ReactomeREACT_121627 ACTIVATION GENE ONTOLOGYGO:0019107 Reactome Database ID Release 43167549 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43179412 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 432065175 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43451354 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43548975 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43374399 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004707 Reactome Database ID Release 43451334 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005319 Reactome Database ID Release 43383196 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017081 Reactome Database ID Release 43383183 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005319 Reactome Database ID Release 43383196 Reactome, http://www.reactome.org PIP5K1A/B Converted from EntitySet in Reactome Reactome DB_ID: 1806245 Reactome Database ID Release 431806245 Reactome, http://www.reactome.org ReactomeREACT_122220 SYNJ Converted from EntitySet in Reactome Reactome DB_ID: 1806173 Reactome Database ID Release 431806173 Reactome, http://www.reactome.org ReactomeREACT_121477 PI4K2A/2B Converted from EntitySet in Reactome Reactome DB_ID: 1806167 Reactome Database ID Release 431806167 Reactome, http://www.reactome.org ReactomeREACT_123875 ACTIVATION GENE ONTOLOGYGO:0003720 Reactome Database ID Release 43163075 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 43174087 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431250481 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43912432 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 43109965 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017108 Reactome Database ID Release 4369151 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 4369115 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 4368508 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 4368509 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003720 Reactome Database ID Release 43163075 Reactome, http://www.reactome.org MTM(3) Converted from EntitySet in Reactome Reactome DB_ID: 1806231 Reactome Database ID Release 431806231 Reactome, http://www.reactome.org ReactomeREACT_124850 MTM(2) Converted from EntitySet in Reactome Reactome DB_ID: 1806263 Reactome Database ID Release 431806263 Reactome, http://www.reactome.org ReactomeREACT_122454 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43174158 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 43174127 Reactome, http://www.reactome.org ELOVL5/ELOVL2 Converted from EntitySet in Reactome Reactome DB_ID: 2046072 Reactome Database ID Release 432046072 Reactome, http://www.reactome.org ReactomeREACT_123763 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43156714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43174240 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43174076 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43174240 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43174085 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015385 Reactome Database ID Release 43426008 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015385 Reactome Database ID Release 43426012 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015368 Reactome Database ID Release 43425819 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015385 Reactome Database ID Release 43425966 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008511 Reactome Database ID Release 43426140 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015379 Reactome Database ID Release 43426138 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015385 Reactome Database ID Release 43426009 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015378 Reactome Database ID Release 43426160 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008273 Reactome Database ID Release 43425670 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005452 Reactome Database ID Release 43425598 Reactome, http://www.reactome.org ADAM10/17 Converted from EntitySet in Reactome Reactome DB_ID: 1852617 Reactome Database ID Release 431852617 Reactome, http://www.reactome.org ReactomeREACT_119209 ACTIVATION GENE ONTOLOGYGO:0015321 Reactome Database ID Release 43427659 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015321 Reactome Database ID Release 43427604 Reactome, http://www.reactome.org DSL Converted from EntitySet in Reactome DLL/JAG NOTCH Ligand Reactome DB_ID: 157643 Reactome Database ID Release 43157643 Reactome, http://www.reactome.org ReactomeREACT_5356 ACTIVATION GENE ONTOLOGYGO:0015321 Reactome Database ID Release 43427647 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0055056 Reactome Database ID Release 43428783 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051119 Reactome Database ID Release 43428794 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0022857 Reactome Database ID Release 43429131 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0055056 Reactome Database ID Release 43429072 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015116 Reactome Database ID Release 43427619 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005254 Reactome Database ID Release 43429573 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005452 Reactome Database ID Release 43427634 Reactome, http://www.reactome.org PPP3CA/B Converted from EntitySet in Reactome Reactome DB_ID: 2025955 Reactome Database ID Release 432025955 Reactome, http://www.reactome.org ReactomeREACT_119401 ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43435364 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43435356 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005381 Reactome Database ID Release 43442424 Reactome, http://www.reactome.org Phosphorylated NFATC1/2/3 Converted from EntitySet in Reactome Reactome DB_ID: 2025924 Reactome Database ID Release 432025924 Reactome, http://www.reactome.org ReactomeREACT_120227 ACTIVATION GENE ONTOLOGYGO:0005381 Reactome Database ID Release 43904829 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005366 Reactome Database ID Release 43429037 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005381 Reactome Database ID Release 43435344 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015166 Reactome Database ID Release 43429661 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005367 Reactome Database ID Release 43429638 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005362 Reactome Database ID Release 43429602 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005412 Reactome Database ID Release 43429647 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43442423 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43442350 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43442355 Reactome, http://www.reactome.org SARA Converted from EntitySet in Reactome Reactome DB_ID: 171177 Reactome Database ID Release 43171177 Reactome, http://www.reactome.org ReactomeREACT_7209 Smad Anchor for Receptor Activation ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43442410 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43442404 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43437144 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43437131 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43437146 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43437132 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43437081 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008519 Reactome Database ID Release 43444399 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015204 Reactome Database ID Release 43444105 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015220 Reactome Database ID Release 43429656 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008504 Reactome Database ID Release 43444156 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43442407 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005375 Reactome Database ID Release 43437290 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015375 Reactome Database ID Release 43444119 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005298 Reactome Database ID Release 43444116 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015095 Reactome Database ID Release 43442665 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005334 Reactome Database ID Release 43444029 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015101 Reactome Database ID Release 43549240 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015101 Reactome Database ID Release 43549263 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015101 Reactome Database ID Release 43549240 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008519 Reactome Database ID Release 43444392 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008519 Reactome Database ID Release 43444392 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008519 Reactome Database ID Release 43444427 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008519 Reactome Database ID Release 43444427 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015101 Reactome Database ID Release 43549130 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015101 Reactome Database ID Release 43549130 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015101 Reactome Database ID Release 43549263 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005415 Reactome Database ID Release 43428766 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005415 Reactome Database ID Release 43428768 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008523 Reactome Database ID Release 43429612 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005415 Reactome Database ID Release 43428770 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015347 Reactome Database ID Release 43561058 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015143 Reactome Database ID Release 43561239 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015307 Reactome Database ID Release 43597631 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015301 Reactome Database ID Release 43561044 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008513 Reactome Database ID Release 43549225 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015226 Reactome Database ID Release 43549231 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005456 Reactome Database ID Release 43727806 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005337 Reactome Database ID Release 43428769 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005337 Reactome Database ID Release 43727764 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005337 Reactome Database ID Release 43727766 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005337 Reactome Database ID Release 43727766 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008521 Reactome Database ID Release 43727756 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005337 Reactome Database ID Release 43428771 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005337 Reactome Database ID Release 43428769 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005337 Reactome Database ID Release 43428771 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005337 Reactome Database ID Release 43727764 Reactome, http://www.reactome.org Nitric oxide synthase Converted from EntitySet in Reactome Reactome DB_ID: 419294 Reactome Database ID Release 43419294 Reactome, http://www.reactome.org ReactomeREACT_24417 G-protein gamma subunit Converted from EntitySet in Reactome Reactome DB_ID: 167442 Reactome Database ID Release 43167442 Reactome, http://www.reactome.org ReactomeREACT_17199 CCNB Converted from EntitySet in Reactome Cyclin B Reactome DB_ID: 157461 Reactome Database ID Release 43157461 Reactome, http://www.reactome.org ReactomeREACT_6593 G-protein beta subunit Converted from EntitySet in Reactome Reactome DB_ID: 167409 Reactome Database ID Release 43167409 Reactome, http://www.reactome.org ReactomeREACT_16094 PathwayStep6297 PathwayStep6296 PathwayStep6299 PathwayStep6298 RAB1 Converted from EntitySet in Reactome Reactome DB_ID: 2422388 Reactome Database ID Release 432422388 Reactome, http://www.reactome.org ReactomeREACT_148210 PathwayStep6291 PathwayStep6290 PathwayStep6293 PathwayStep6292 PathwayStep6295 PathwayStep6294 p-RAB1 Converted from EntitySet in Reactome Reactome DB_ID: 2422387 Reactome Database ID Release 432422387 Reactome, http://www.reactome.org ReactomeREACT_147910 NRG1/2/3/4 Converted from EntitySet in Reactome Neuregulins Reactome DB_ID: 1227957 Reactome Database ID Release 431227957 Reactome, http://www.reactome.org ReactomeREACT_117720 ACTIVATION GENE ONTOLOGYGO:0005548 Reactome Database ID Release 43382563 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005452 Reactome Database ID Release 43425449 Reactome, http://www.reactome.org SMURF1 Converted from EntitySet in Reactome Reactome DB_ID: 2160937 Reactome Database ID Release 432160937 Reactome, http://www.reactome.org ReactomeREACT_125400 ACTIVATION GENE ONTOLOGYGO:0005395 Reactome Database ID Release 431467465 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008559 Reactome Database ID Release 431467472 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0043225 Reactome Database ID Release 431454941 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015232 Reactome Database ID Release 431369020 Reactome, http://www.reactome.org EGF-like ligands Converted from EntitySet in Reactome EGF-like growth factors Reactome DB_ID: 1233230 Reactome Database ID Release 431233230 Reactome, http://www.reactome.org ReactomeREACT_117179 ACTIVATION GENE ONTOLOGYGO:0015232 Reactome Database ID Release 43382512 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017127 Reactome Database ID Release 431454926 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005324 Reactome Database ID Release 43382568 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008510 Reactome Database ID Release 43425592 Reactome, http://www.reactome.org PathwayStep6249 PathwayStep6250 PathwayStep6251 PI4KA/2A/2B Converted from EntitySet in Reactome Reactome DB_ID: 1806171 Reactome Database ID Release 431806171 Reactome, http://www.reactome.org ReactomeREACT_123495 PathwayStep6258 PathwayStep6259 PathwayStep6256 PathwayStep6257 PathwayStep6254 PathwayStep6255 PathwayStep6252 PathwayStep6253 PIP5K1A-C Converted from EntitySet in Reactome Reactome DB_ID: 1806157 Reactome Database ID Release 431806157 Reactome, http://www.reactome.org ReactomeREACT_125627 PathwayStep6260 OCRL/INPP5E Converted from EntitySet in Reactome Reactome DB_ID: 1806215 Reactome Database ID Release 431806215 Reactome, http://www.reactome.org ReactomeREACT_123349 PathwayStep6261 PathwayStep6262 PathwayStep6267 PathwayStep6268 PathwayStep6269 PathwayStep6263 PathwayStep6264 PathwayStep6265 PathwayStep6266 LPGAT Converted from EntitySet in Reactome Reactome DB_ID: 1524026 Reactome Database ID Release 431524026 Reactome, http://www.reactome.org ReactomeREACT_122535 PLD1-4/6 Converted from EntitySet in Reactome Reactome DB_ID: 1524126 Reactome Database ID Release 431524126 Reactome, http://www.reactome.org ReactomeREACT_124712 PathwayStep6272 PLA2(13) Converted from EntitySet in Reactome Reactome DB_ID: 1524143 Reactome Database ID Release 431524143 Reactome, http://www.reactome.org ReactomeREACT_121683 PathwayStep6273 PathwayStep6270 PathwayStep6271 PathwayStep6276 PathwayStep6277 PathwayStep6274 PathwayStep6275 PathwayStep6278 PathwayStep6279 PI4KA/2B Converted from EntitySet in Reactome Reactome DB_ID: 1806271 Reactome Database ID Release 431806271 Reactome, http://www.reactome.org ReactomeREACT_121877 PLA2(14) Converted from EntitySet in Reactome Reactome DB_ID: 1524142 Reactome Database ID Release 431524142 Reactome, http://www.reactome.org ReactomeREACT_124374 PathwayStep6280 PathwayStep6281 PathwayStep6282 PathwayStep6283 PathwayStep6284 PathwayStep6285 PathwayStep6286 PathwayStep6287 PathwayStep6288 PathwayStep6289 PathwayStep6209 PathwayStep6207 PathwayStep6208 PathwayStep6205 PathwayStep6206 PathwayStep6215 PathwayStep6214 PathwayStep6213 PathwayStep6212 PathwayStep6211 PathwayStep6210 CTL1-5 Converted from EntitySet in Reactome Reactome DB_ID: 444452 Reactome Database ID Release 43444452 Reactome, http://www.reactome.org ReactomeREACT_20955 LPSAT Converted from EntitySet in Reactome Reactome DB_ID: 1524037 Reactome Database ID Release 431524037 Reactome, http://www.reactome.org ReactomeREACT_124851 PathwayStep6216 PathwayStep6217 PathwayStep6218 PathwayStep6219 PathwayStep6224 PathwayStep6223 PathwayStep6226 PathwayStep6225 PathwayStep6220 PathwayStep6222 PathwayStep6221 LPCAT Converted from EntitySet in Reactome Reactome DB_ID: 1524029 Reactome Database ID Release 431524029 Reactome, http://www.reactome.org ReactomeREACT_124294 PathwayStep6229 PathwayStep6227 PathwayStep6228 PathwayStep6233 PathwayStep6232 PathwayStep6231 PathwayStep6230 PathwayStep6237 PathwayStep6236 PathwayStep6235 PathwayStep6234 LPEAT Converted from EntitySet in Reactome Reactome DB_ID: 1524035 Reactome Database ID Release 431524035 Reactome, http://www.reactome.org ReactomeREACT_124644 PathwayStep6238 PathwayStep6239 PathwayStep6242 PathwayStep6241 PathwayStep6244 PathwayStep6243 PathwayStep6246 PathwayStep6245 PathwayStep6248 PathwayStep6247 PathwayStep6240 PLD1/2 Converted from EntitySet in Reactome Reactome DB_ID: 1500639 Reactome Database ID Release 431500639 Reactome, http://www.reactome.org ReactomeREACT_123764 ACTIVATION GENE ONTOLOGYGO:0005338 Reactome Database ID Release 43744232 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005338 Reactome Database ID Release 43744232 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015349 Reactome Database ID Release 43879601 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015245 Reactome Database ID Release 43879525 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005464 Reactome Database ID Release 43742347 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046964 Reactome Database ID Release 43741439 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005457 Reactome Database ID Release 43742379 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005462 Reactome Database ID Release 43742364 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005462 Reactome Database ID Release 43741455 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005459 Reactome Database ID Release 43735696 Reactome, http://www.reactome.org PNPLA2/3 Converted from EntitySet in Reactome Reactome DB_ID: 1500579 Reactome Database ID Release 431500579 Reactome, http://www.reactome.org ReactomeREACT_121716 PathwayStep6200 PathwayStep6203 PathwayStep6204 PathwayStep6201 PathwayStep6202 Angiomotins AMOT proteins Converted from EntitySet in Reactome Reactome DB_ID: 2028605 Reactome Database ID Release 432028605 Reactome, http://www.reactome.org ReactomeREACT_119439 MOB1 Converted from EntitySet in Reactome Reactome DB_ID: 2028544 Reactome Database ID Release 432028544 Reactome, http://www.reactome.org ReactomeREACT_118992 p-MOB1 Converted from EntitySet in Reactome Reactome DB_ID: 2028620 Reactome Database ID Release 432028620 Reactome, http://www.reactome.org ReactomeREACT_119145 p-LATS Converted from EntitySet in Reactome Reactome DB_ID: 2028548 Reactome Database ID Release 432028548 Reactome, http://www.reactome.org ReactomeREACT_119771 ACTIVATION GENE ONTOLOGYGO:0034450 Reactome Database ID Release 43937010 Reactome, http://www.reactome.org LATS Converted from EntitySet in Reactome Reactome DB_ID: 2028571 Reactome Database ID Release 432028571 Reactome, http://www.reactome.org ReactomeREACT_118962 ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43975882 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43975856 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43975858 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43937015 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 431678988 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 431678966 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43975854 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43975855 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005096 Reactome Database ID Release 43392511 Reactome, http://www.reactome.org GCNTs Converted from EntitySet in Reactome Reactome DB_ID: 914009 Reactome Database ID Release 43914009 Reactome, http://www.reactome.org ReactomeREACT_117184 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 432130638 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016667 Reactome Database ID Release 432213238 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43350178 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 432130341 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 432130638 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43913994 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43445092 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 432213237 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004177 Reactome Database ID Release 431236946 Reactome, http://www.reactome.org Core 3 mucins Converted from EntitySet in Reactome Reactome DB_ID: 1462159 Reactome Database ID Release 431462159 Reactome, http://www.reactome.org ReactomeREACT_116641 ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43211500 Reactome, http://www.reactome.org p-YAP1 Converted from EntitySet in Reactome Reactome DB_ID: 2028622 Reactome Database ID Release 432028622 Reactome, http://www.reactome.org ReactomeREACT_119346 phospho-YAP1 ACTIVATION GENE ONTOLOGYGO:0016175 Reactome Database ID Release 431236969 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016787 Reactome Database ID Release 431236961 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0022857 Reactome Database ID Release 431236952 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015433 Reactome Database ID Release 431236953 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 431236936 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004177 Reactome Database ID Release 43983155 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 43983143 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015433 Reactome Database ID Release 43983154 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43983159 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43983139 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0043130 Reactome Database ID Release 43983149 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43983141 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 431168627 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431168626 Reactome, http://www.reactome.org GSK3B Converted from EntitySet in Reactome Reactome DB_ID: 195269 Reactome Database ID Release 43195269 Reactome, http://www.reactome.org ReactomeREACT_10578 p-T41,S45-beta catenin Converted from EntitySet in Reactome Reactome DB_ID: 195290 Reactome Database ID Release 43195290 Reactome, http://www.reactome.org ReactomeREACT_10405 pS45- beta-catenin Converted from EntitySet in Reactome Reactome DB_ID: 195309 Reactome Database ID Release 43195309 Reactome, http://www.reactome.org ReactomeREACT_10903 Core 4 mucins Converted from EntitySet in Reactome Reactome DB_ID: 1462144 Reactome Database ID Release 431462144 Reactome, http://www.reactome.org ReactomeREACT_117525 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431168628 Reactome, http://www.reactome.org B3GNTs Converted from EntitySet in Reactome Reactome DB_ID: 916814 Reactome Database ID Release 43916814 Reactome, http://www.reactome.org ReactomeREACT_117810 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431168625 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 432076231 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035004 Reactome Database ID Release 432045912 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005261 Reactome Database ID Release 43169682 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004629 Reactome Database ID Release 431112664 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431112660 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43983699 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 431112661 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431112665 Reactome, http://www.reactome.org DARPP-32 (for CDK5 phosphorylation) Converted from EntitySet in Reactome Reactome DB_ID: 180044 Reactome Database ID Release 43180044 Reactome, http://www.reactome.org ReactomeREACT_17935 PP2B catalytic subunit Converted from EntitySet in Reactome Reactome DB_ID: 201798 Reactome Database ID Release 43201798 Reactome, http://www.reactome.org ReactomeREACT_16008 ACTIVATION GENE ONTOLOGYGO:0005261 Reactome Database ID Release 432089928 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43983699 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43210261 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43389351 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43389351 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43374399 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43374399 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43389754 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43389761 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008195 Reactome Database ID Release 43390328 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43983708 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43983706 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43168546 Reactome, http://www.reactome.org FRAT1 or FRAT2 Converted from EntitySet in Reactome Reactome DB_ID: 1226058 Reactome Database ID Release 431226058 Reactome, http://www.reactome.org ReactomeREACT_76559 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43202514 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43203801 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43202486 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43202517 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43210261 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43202546 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198368 Reactome, http://www.reactome.org phospho-APC Converted from EntitySet in Reactome Reactome DB_ID: 195293 Reactome Database ID Release 43195293 Reactome, http://www.reactome.org ReactomeREACT_10531 ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 43389160 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004709 Reactome Database ID Release 43392534 Reactome, http://www.reactome.org p-S37,T41,S45-beta-catenin Converted from EntitySet in Reactome Reactome DB_ID: 195316 Reactome Database ID Release 43195316 Reactome, http://www.reactome.org ReactomeREACT_10398 p-S33,S37,T41,S45-beta-catenin Converted from EntitySet in Reactome Reactome DB_ID: 195274 Reactome Database ID Release 43195274 Reactome, http://www.reactome.org ReactomeREACT_10205 IGF1/2 Converted from EntitySet in Reactome Insulin-like Growth Factor Reactome DB_ID: 2404183 Reactome Database ID Release 432404183 Reactome, http://www.reactome.org ReactomeREACT_150718 ICAM 1-4 Converted from EntitySet in Reactome Reactome DB_ID: 198193 Reactome Database ID Release 43198193 Reactome, http://www.reactome.org ReactomeREACT_11859 T antigens Converted from EntitySet in Reactome Core 1 mucins Reactome DB_ID: 1462240 Reactome Database ID Release 431462240 Reactome, http://www.reactome.org ReactomeREACT_116451 Core 2 mucins Converted from EntitySet in Reactome Reactome DB_ID: 1462066 Reactome Database ID Release 431462066 Reactome, http://www.reactome.org ReactomeREACT_117746 Ubiquitinated AUF1 (isoform p37 or p40) Converted from EntitySet in Reactome Reactome DB_ID: 451208 Reactome Database ID Release 43451208 Reactome, http://www.reactome.org ReactomeREACT_25754 ACTIVATION GENE ONTOLOGYGO:0019787 Reactome Database ID Release 43688999 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0070536 Reactome Database ID Release 43688991 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431248666 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0070536 Reactome Database ID Release 43741421 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43174557 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43166837 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43977372 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43981517 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43173681 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43977368 Reactome, http://www.reactome.org TNRC6 (GW182) Converted from EntitySet in Reactome Reactome DB_ID: 427775 Reactome Database ID Release 43427775 Reactome, http://www.reactome.org ReactomeREACT_119619 Argonaute AGO1/2/3/4 Converted from EntitySet in Reactome Reactome DB_ID: 629636 Reactome Database ID Release 43629636 Reactome, http://www.reactome.org ReactomeREACT_23182 ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43933529 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43936407 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43936422 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004709 Reactome Database ID Release 43450188 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004708 Reactome Database ID Release 431250107 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004931 Reactome Database ID Release 43877259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43918226 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43918231 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43992767 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43933524 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43937019 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43166117 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43975176 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432206268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0034450 Reactome Database ID Release 431014250 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431014251 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43975129 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43975181 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43975140 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431014248 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43173748 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43166764 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43166764 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43173748 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43183125 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43937069 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43166287 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43173628 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43173630 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43937066 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43936958 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43937003 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43450295 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43937068 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432213014 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 432562582 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432569080 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43975169 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43936943 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43975177 Reactome, http://www.reactome.org Phospho-p38 MAPK alpha/beta Converted from EntitySet in Reactome Reactome DB_ID: 170997 Reactome Database ID Release 43170997 Reactome, http://www.reactome.org ReactomeREACT_12165 PathwayStep6054 PathwayStep6055 PathwayStep6056 PathwayStep6057 PathwayStep6058 PathwayStep6059 PathwayStep6050 PathwayStep6051 Core 8 mucins Converted from EntitySet in Reactome Reactome DB_ID: 1462115 Reactome Database ID Release 431462115 Reactome, http://www.reactome.org ReactomeREACT_117842 PathwayStep6052 PathwayStep6053 ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43450164 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43450826 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43451564 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008384 Reactome Database ID Release 43451612 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43208937 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004709 Reactome Database ID Release 43451651 Reactome, http://www.reactome.org PathwayStep6067 PathwayStep6068 PathwayStep6065 PathwayStep6066 PathwayStep6069 PathwayStep6060 PathwayStep6063 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43448682 Reactome, http://www.reactome.org PathwayStep6064 ACTIVATION GENE ONTOLOGYGO:0019785 Reactome Database ID Release 431678840 Reactome, http://www.reactome.org PathwayStep6061 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43446883 Reactome, http://www.reactome.org PathwayStep6062 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43446690 Reactome, http://www.reactome.org PathwayStep6076 PathwayStep6077 PathwayStep6078 Core 7 mucins Converted from EntitySet in Reactome Reactome DB_ID: 1462341 Reactome Database ID Release 431462341 Reactome, http://www.reactome.org ReactomeREACT_117615 PathwayStep6079 PathwayStep6072 PathwayStep6073 PathwayStep6074 PathwayStep6075 PathwayStep6070 PathwayStep6071 PathwayStep6089 PathwayStep6087 PathwayStep6088 PathwayStep6085 PathwayStep6086 PathwayStep6083 PathwayStep6084 PathwayStep6081 PathwayStep6082 PathwayStep6080 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43909727 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432396614 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432424478 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432396614 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432396614 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43909731 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43909723 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43909717 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 432424488 Reactome, http://www.reactome.org PathwayStep6091 PathwayStep6090 PathwayStep6093 PathwayStep6092 PathwayStep6095 PathwayStep6094 ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 432424479 Reactome, http://www.reactome.org PathwayStep6097 PathwayStep6096 PathwayStep6099 PathwayStep6098 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432396614 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 432424483 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0070536 Reactome Database ID Release 43936417 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0070536 Reactome Database ID Release 43741421 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008236 Reactome Database ID Release 431462008 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43990525 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432396010 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0006471 Reactome Database ID Release 431972395 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432396596 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432395432 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431169401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005487 Reactome Database ID Release 43450099 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431169401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431169401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431169401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431169401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431169401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431169396 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0043130 Reactome Database ID Release 431169400 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43997310 Reactome, http://www.reactome.org 'alpha-D-Glucose 6-phosphate' positively regulates 'glycogen (starch) synthase activity of glycogen synthase 1 tetramer, D form [muscle]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371573 Reactome, http://www.reactome.org ReactomeREACT_5917 'Calcium [cytosol]' positively regulates 'phosphorylase kinase activity of phosphorylase kinase complex, muscle form [cytosol]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371523 Reactome, http://www.reactome.org ReactomeREACT_5973 'Calcium [cytosol]' positively regulates 'phosphorylase kinase activity of phosphorylase kinase complex, liver form [cytosol]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371536 Reactome, http://www.reactome.org ReactomeREACT_6017 'Calcium [cytosol]' positively regulates 'phosphorylase kinase activity of phosphorylase kinase complex, muscle form [cytosol]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371523 Reactome, http://www.reactome.org ReactomeREACT_5973 'ADP' negatively regulates 'ketohexokinase activity of ketohexokinase' INHIBITION-COMPETITIVE Reactome Database ID Release 4370331 Reactome, http://www.reactome.org ReactomeREACT_6104 'Potassium [cytosol]' positively regulates 'ketohexokinase activity of Ketohexokinase [cytosol]' ACTIVATION Reactome Database ID Release 43167174 Reactome, http://www.reactome.org ReactomeREACT_6712 'Magnesium [cytosol]' is required for 'ribose-phosphate diphosphokinase activity of phosphoribosyl pyrophosphate synthetase 1 holoenzyme [cytosol]' ACTIVATION Reactome Database ID Release 43111208 Reactome, http://www.reactome.org ReactomeREACT_5957 'Orthophosphate [cytosol]' is required for 'ribose-phosphate diphosphokinase activity of phosphoribosyl pyrophosphate synthetase 1 holoenzyme [cytosol]' ACTIVATION Reactome Database ID Release 43111207 Reactome, http://www.reactome.org ReactomeREACT_6089 'ATP' positively regulates 'glutamate dehydrogenase (NAD(P)+) activity of glutamate dehydrogenase 1, homohexamer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370586 Reactome, http://www.reactome.org ReactomeREACT_5976 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43873928 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43873925 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43997306 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43909567 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43210262 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43392414 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43873923 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43873920 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43909727 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43210705 Reactome, http://www.reactome.org Core 5 mucins Converted from EntitySet in Reactome Reactome DB_ID: 1462179 Reactome Database ID Release 431462179 Reactome, http://www.reactome.org ReactomeREACT_116422 PathwayStep1909 PathwayStep1900 PathwayStep1902 PathwayStep1901 PathwayStep1904 PathwayStep1903 PathwayStep1906 PathwayStep1905 PathwayStep1908 PathwayStep1907 extended Core 6 mucins Converted from EntitySet in Reactome Reactome DB_ID: 1967037 Reactome Database ID Release 431967037 Reactome, http://www.reactome.org ReactomeREACT_117859 PathwayStep1918 PathwayStep1919 PathwayStep1916 PathwayStep1917 PathwayStep1914 PathwayStep1915 PathwayStep1912 PathwayStep1913 PathwayStep1910 DARPP-32 phosporylated on T34 Converted from EntitySet in Reactome Reactome DB_ID: 180075 Reactome Database ID Release 43180075 Reactome, http://www.reactome.org ReactomeREACT_15578 PathwayStep1911 DARPP-32 (and/or phosphorylated) Converted from EntitySet in Reactome Reactome DB_ID: 180056 Reactome Database ID Release 43180056 Reactome, http://www.reactome.org ReactomeREACT_17763 G-protein alpha (i/o/z/t) subunit Converted from EntitySet in Reactome Reactome DB_ID: 167413 Reactome Database ID Release 43167413 Reactome, http://www.reactome.org ReactomeREACT_16054 PathwayStep1927 PathwayStep1928 PathwayStep1929 PathwayStep1923 PathwayStep1924 PathwayStep1925 PathwayStep1926 PathwayStep1920 PathwayStep1921 PathwayStep1922 p-T75-DARPP32s Converted from EntitySet in Reactome Reactome DB_ID: 180026 Reactome Database ID Release 43180026 Reactome, http://www.reactome.org ReactomeREACT_16096 PathwayStep1936 PathwayStep1937 PathwayStep1934 PathwayStep1935 PathwayStep1938 Core 6 mucins Converted from EntitySet in Reactome Reactome DB_ID: 1462353 Reactome Database ID Release 431462353 Reactome, http://www.reactome.org ReactomeREACT_116558 PathwayStep1939 PathwayStep1932 PathwayStep1933 PathwayStep1930 Opioid peptide Converted from EntitySet in Reactome Reactome DB_ID: 167443 Reactome Database ID Release 43167443 Reactome, http://www.reactome.org ReactomeREACT_15976 PathwayStep1931 PathwayStep1945 PathwayStep1946 PathwayStep1947 PathwayStep1948 PathwayStep1949 PathwayStep1940 PathwayStep1941 PathwayStep1942 PathwayStep1943 PathwayStep1944 PathwayStep1962 PathwayStep1961 PathwayStep1960 PathwayStep1966 PathwayStep1965 PathwayStep1964 PathwayStep1963 PathwayStep1969 PathwayStep1968 PathwayStep1967 PathwayStep1951 PathwayStep1950 PathwayStep1953 PathwayStep1952 PathwayStep1955 PathwayStep1954 PathwayStep1957 PathwayStep1956 PathwayStep1959 PathwayStep1958 PathwayStep1988 PathwayStep1987 PathwayStep1986 PathwayStep1985 PathwayStep1984 PathwayStep1983 PathwayStep1982 PathwayStep1981 PathwayStep1989 PathwayStep1990 PathwayStep1991 UPF3 Converted from EntitySet in Reactome Reactome DB_ID: 927833 Reactome Database ID Release 43927833 Reactome, http://www.reactome.org ReactomeREACT_76801 PathwayStep1975 PathwayStep1974 PathwayStep1977 PathwayStep1976 PathwayStep1971 PathwayStep1970 PathwayStep1973 PathwayStep1972 PathwayStep1979 PathwayStep1978 PathwayStep1980 PathwayStep1992 PathwayStep1993 PathwayStep1994 PathwayStep1995 PathwayStep1996 PathwayStep1997 PathwayStep1998 PathwayStep1999 PathwayStep6000 PathwayStep6001 PathwayStep6002 PathwayStep6003 PathwayStep6004 PathwayStep6005 PathwayStep6006 PathwayStep6020 PathwayStep6026 PathwayStep6025 PathwayStep6028 PathwayStep6027 PathwayStep6022 PathwayStep6021 PathwayStep6024 PathwayStep6023 PathwayStep6018 PathwayStep6019 PathwayStep6017 PathwayStep6016 PathwayStep6015 PathwayStep6014 PathwayStep6013 PathwayStep6012 PathwayStep6011 PathwayStep6010 PathwayStep6009 PathwayStep6007 PathwayStep6008 PathwayStep6040 PathwayStep6042 PathwayStep6041 PathwayStep6044 PathwayStep6043 PathwayStep6046 PathwayStep6045 PathwayStep6048 PathwayStep6047 PathwayStep6049 PathwayStep6031 PathwayStep6030 PathwayStep6035 PathwayStep6034 PathwayStep6033 PathwayStep6032 PathwayStep6039 PathwayStep6038 PathwayStep6037 PathwayStep6036 PathwayStep6029 ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43201794 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004862 Reactome Database ID Release 43180061 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43180059 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008599 Reactome Database ID Release 43180074 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004691 Reactome Database ID Release 43177276 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004115 Reactome Database ID Release 43111961 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004691 Reactome Database ID Release 43177276 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43170678 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 432179412 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43201776 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005525 Reactome Database ID Release 43167404 Reactome, http://www.reactome.org Cyclin A Converted from EntitySet in Reactome Reactome DB_ID: 75202 Reactome Database ID Release 4375202 Reactome, http://www.reactome.org ReactomeREACT_5498 ACTIVATION GENE ONTOLOGYGO:0004930 Reactome Database ID Release 43111868 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004435 Reactome Database ID Release 43111871 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43167406 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43418573 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004629 Reactome Database ID Release 43398194 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 43392298 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008179 Reactome Database ID Release 43170682 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43111895 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004016 Reactome Database ID Release 43170668 Reactome, http://www.reactome.org Cyclin A:Cdk1 substrate proteins Converted from EntitySet in Reactome Reactome DB_ID: 187963 Reactome Database ID Release 43187963 Reactome, http://www.reactome.org ReactomeREACT_9368 ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43392856 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43392204 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004629 Reactome Database ID Release 43139838 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43380089 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43392134 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004697 Reactome Database ID Release 43804937 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005089 Reactome Database ID Release 43194957 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43139831 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43763959 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43427711 Reactome, http://www.reactome.org Prolyl 4-hydroxylase alpha subunits Converted from EntitySet in Reactome Reactome DB_ID: 1650813 Reactome Database ID Release 431650813 Reactome, http://www.reactome.org ReactomeREACT_123883 ST6GALNAC3/4 Converted from EntitySet in Reactome Reactome DB_ID: 981824 Reactome Database ID Release 43981824 Reactome, http://www.reactome.org ReactomeREACT_117643 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43421295 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 432272659 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43420391 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43420678 Reactome, http://www.reactome.org Cargo of TOMM40 Converted from EntitySet in Reactome Proteins Imported by TOMM40:TOMM70 Complex Reactome DB_ID: 1268006 Reactome Database ID Release 431268006 Reactome, http://www.reactome.org ReactomeREACT_119170 ACTIVATION GENE ONTOLOGYGO:0019797 Reactome Database ID Release 431980260 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008475 Reactome Database ID Release 431981145 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431250506 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004656 Reactome Database ID Release 431650804 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43174077 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028546 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028546 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028588 Reactome, http://www.reactome.org Cargo of TOMM40 Converted from EntitySet in Reactome Proteins Imported by TOMM40:TOMM70 Complex Reactome DB_ID: 1268010 Reactome Database ID Release 431268010 Reactome, http://www.reactome.org ReactomeREACT_119520 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432470476 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431549514 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432186756 Reactome, http://www.reactome.org 3,4-Hyp collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2022492 Reactome Database ID Release 432022492 Reactome, http://www.reactome.org ReactomeREACT_125206 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432404194 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432404197 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432445137 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431226002 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028573 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028681 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028573 Reactome, http://www.reactome.org E2F1/2/3 Activating E2F transcription factors Cell cycle promoting E2Fs Converted from EntitySet in Reactome Reactome DB_ID: 68640 Reactome Database ID Release 4368640 Reactome, http://www.reactome.org ReactomeREACT_4364 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028693 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028576 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028681 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028588 Reactome, http://www.reactome.org MCM8 Converted from EntitySet in Reactome Reactome DB_ID: 176959 Reactome Database ID Release 43176959 Reactome, http://www.reactome.org ReactomeREACT_7413 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028693 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028576 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 432179400 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 431505509 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43196226 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43196225 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43196224 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43195306 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028254 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432028552 Reactome, http://www.reactome.org PathwayStep1811 PathwayStep1812 PathwayStep1810 PathwayStep1815 PathwayStep1816 PathwayStep1813 PathwayStep1814 PathwayStep1819 PathwayStep1817 PathwayStep1818 Sialyl-2,3 T antigens Converted from EntitySet in Reactome Reactome DB_ID: 1463569 Reactome Database ID Release 431463569 Reactome, http://www.reactome.org ReactomeREACT_117157 PathwayStep1820 PathwayStep1821 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604694 Reactome, http://www.reactome.org PathwayStep1822 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org PathwayStep1823 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432127615 Reactome, http://www.reactome.org PathwayStep1824 PathwayStep1825 PathwayStep1826 PathwayStep1827 PathwayStep1828 PathwayStep1829 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604738 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604746 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432127618 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604738 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604758 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604764 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604695 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604363 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604352 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604691 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604720 Reactome, http://www.reactome.org Disialyl T antigens Converted from EntitySet in Reactome Reactome DB_ID: 1463507 Reactome Database ID Release 431463507 Reactome, http://www.reactome.org ReactomeREACT_116915 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 432228678 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431602460 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604366 Reactome, http://www.reactome.org ST3GAL1-4 Converted from EntitySet in Reactome Reactome DB_ID: 981491 Reactome Database ID Release 43981491 Reactome, http://www.reactome.org ReactomeREACT_116569 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604375 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604348 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604361 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004720 Reactome Database ID Release 432022088 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 432002398 Reactome, http://www.reactome.org PathwayStep1800 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432214315 Reactome, http://www.reactome.org PathwayStep1801 ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 432002398 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004720 Reactome Database ID Release 432022088 Reactome, http://www.reactome.org PathwayStep1806 PathwayStep1807 PathwayStep1808 PathwayStep1809 PathwayStep1802 PathwayStep1803 PathwayStep1804 PathwayStep1805 ACTIVATION GENE ONTOLOGYGO:0050211 Reactome Database ID Release 431981159 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003755 Reactome Database ID Release 432025776 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 432002457 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050211 Reactome Database ID Release 431981141 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033823 Reactome Database ID Release 431981156 Reactome, http://www.reactome.org Sialyl Tn antigens Converted from EntitySet in Reactome Reactome DB_ID: 1463504 Reactome Database ID Release 431463504 Reactome, http://www.reactome.org ReactomeREACT_117745 Sialyl-2,6 T antigens Converted from EntitySet in Reactome Reactome DB_ID: 1463568 Reactome Database ID Release 431463568 Reactome, http://www.reactome.org ReactomeREACT_116456 PathwayStep1897 PathwayStep1898 PathwayStep1899 PathwayStep1893 PathwayStep1894 PathwayStep1895 PathwayStep1896 PathwayStep1892 PathwayStep1891 PathwayStep1890 PathwayStep1884 PathwayStep1885 PathwayStep1882 PathwayStep1883 PathwayStep1888 PathwayStep1889 PathwayStep1886 PathwayStep1887 PathwayStep1881 PathwayStep1880 PathwayStep1871 PathwayStep1872 PathwayStep1873 PathwayStep1874 PathwayStep1875 PathwayStep1876 PathwayStep1877 PathwayStep1878 PathwayStep1879 PathwayStep1870 PathwayStep1869 PathwayStep1868 PathwayStep1867 PathwayStep1866 PathwayStep1865 PathwayStep1864 PathwayStep1863 PathwayStep1862 PathwayStep1861 PathwayStep1860 PathwayStep1858 PathwayStep1857 PathwayStep1859 PathwayStep1854 PathwayStep1853 PathwayStep1856 PathwayStep1855 PathwayStep1850 PathwayStep1852 PathwayStep1851 PathwayStep1849 PathwayStep1848 PathwayStep1847 PathwayStep1846 PathwayStep1841 PathwayStep1840 PathwayStep1845 PathwayStep1844 PathwayStep1843 PathwayStep1842 PathwayStep1836 PathwayStep1835 PathwayStep1838 PathwayStep1837 PathwayStep1839 PathwayStep1830 PathwayStep1832 PathwayStep1831 PathwayStep1834 PathwayStep1833 IN Converted from EntitySet in Reactome Integrase Reactome DB_ID: 175096 Reactome Database ID Release 43175096 Reactome, http://www.reactome.org ReactomeREACT_7665 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431605824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432473585 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431606370 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431605824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432473585 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604695 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604361 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431604716 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431605829 Reactome, http://www.reactome.org p6 protein Converted from EntitySet in Reactome Reactome DB_ID: 175430 Reactome Database ID Release 43175430 Reactome, http://www.reactome.org ReactomeREACT_7114 4-Hyp collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 1650767 Reactome Database ID Release 431650767 Reactome, http://www.reactome.org ReactomeREACT_122309 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432473472 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432471617 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470891 Reactome, http://www.reactome.org p-CRY1/2 Converted from EntitySet in Reactome Reactome DB_ID: 400287 Reactome Database ID Release 43400287 Reactome, http://www.reactome.org ReactomeREACT_26012 PER1/2 Converted from EntitySet in Reactome Reactome DB_ID: 400344 Reactome Database ID Release 43400344 Reactome, http://www.reactome.org ReactomeREACT_25978 CSNK1E/CSNK1D Casein kinase I delta or Casein kinase I epsilon Converted from EntitySet in Reactome Reactome DB_ID: 421289 Reactome Database ID Release 43421289 Reactome, http://www.reactome.org ReactomeREACT_26408 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432484879 Reactome, http://www.reactome.org CRY1/2 Converted from EntitySet in Reactome Reactome DB_ID: 400223 Reactome Database ID Release 43400223 Reactome, http://www.reactome.org ReactomeREACT_26101 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470517 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470432 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470844 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470793 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432168030 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470632 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470307 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470200 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432482187 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470317 Reactome, http://www.reactome.org CLOCK/NPAS2 Converted from EntitySet in Reactome Reactome DB_ID: 400343 Reactome Database ID Release 43400343 Reactome, http://www.reactome.org ReactomeREACT_26942 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432485156 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431606420 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432473585 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431605824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432470134 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431606399 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005089 Reactome Database ID Release 43416599 Reactome, http://www.reactome.org Spectrin alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 420046 Reactome Database ID Release 43420046 Reactome, http://www.reactome.org ReactomeREACT_18492 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43419883 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43419647 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43399948 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43399940 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005096 Reactome Database ID Release 43399929 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030676 Reactome Database ID Release 43399937 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43421150 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43419084 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43419084 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43419656 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005100 Reactome Database ID Release 43416593 Reactome, http://www.reactome.org Spectrin beta chain Converted from EntitySet in Reactome Reactome DB_ID: 420050 Reactome Database ID Release 43420050 Reactome, http://www.reactome.org ReactomeREACT_19912 ACTIVATION GENE ONTOLOGYGO:0004720 Reactome Database ID Release 432022088 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432159870 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005096 Reactome Database ID Release 43416583 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43419649 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432159870 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432159870 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432537497 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432537494 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005089 Reactome Database ID Release 43418851 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43418882 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43418875 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43374396 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004435 Reactome Database ID Release 43622376 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005089 Reactome Database ID Release 43418851 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43210268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005096 Reactome Database ID Release 43428516 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008233 Reactome Database ID Release 43428539 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005096 Reactome Database ID Release 43428514 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43399943 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43399949 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43208885 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43421150 Reactome, http://www.reactome.org Collagen propeptides and chains Converted from EntitySet in Reactome Reactome DB_ID: 1650800 Reactome Database ID Release 431650800 Reactome, http://www.reactome.org ReactomeREACT_121431 ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43391870 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43374399 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43376142 Reactome, http://www.reactome.org MEF2C/D Converted from EntitySet in Reactome Reactome DB_ID: 1605563 Reactome Database ID Release 431605563 Reactome, http://www.reactome.org ReactomeREACT_120255 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43210268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 43392052 Reactome, http://www.reactome.org p-PPARGC1A Converted from EntitySet in Reactome Reactome DB_ID: 1592227 Reactome Database ID Release 431592227 Reactome, http://www.reactome.org ReactomeREACT_119064 p-PGC-1alpha ACTIVATION GENE ONTOLOGYGO:0003828 Reactome Database ID Release 43422455 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004708 Reactome Database ID Release 43448952 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43445086 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43443820 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43201699 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43445074 Reactome, http://www.reactome.org p-CRY1/2 Converted from EntitySet in Reactome Reactome DB_ID: 400237 Reactome Database ID Release 43400237 Reactome, http://www.reactome.org ReactomeREACT_26910 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431181151 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199274 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 431181154 Reactome, http://www.reactome.org ub-p-CRY1/2 Converted from EntitySet in Reactome Reactome DB_ID: 517938 Reactome Database ID Release 43517938 Reactome, http://www.reactome.org ReactomeREACT_26499 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43448950 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43448950 Reactome, http://www.reactome.org ub-p-PER1/2 Converted from EntitySet in Reactome Reactome DB_ID: 517830 Reactome Database ID Release 43517830 Reactome, http://www.reactome.org ReactomeREACT_25524 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43376138 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 43428513 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43445070 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43210268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43445086 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43442283 Reactome, http://www.reactome.org p-PER1/2 Converted from EntitySet in Reactome Reactome DB_ID: 400346 Reactome Database ID Release 43400346 Reactome, http://www.reactome.org ReactomeREACT_25419 ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43445092 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43445094 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43111895 Reactome, http://www.reactome.org CSNK1E/CSNK1D Casein Kinase I delta or Casein kinase I epsilon Converted from EntitySet in Reactome Reactome DB_ID: 421304 Reactome Database ID Release 43421304 Reactome, http://www.reactome.org ReactomeREACT_25677 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43445086 Reactome, http://www.reactome.org p-PER1/2 Converted from EntitySet in Reactome Reactome DB_ID: 400230 Reactome Database ID Release 43400230 Reactome, http://www.reactome.org ReactomeREACT_26103 Precursor Cargo of TIMM23 PAM Converted from EntitySet in Reactome Precursors Imported to the Matrix by TIMM23 PAM Reactome DB_ID: 1299463 Reactome Database ID Release 431299463 Reactome, http://www.reactome.org ReactomeREACT_119489 Precursor Cargo of TIMM23 PAM Converted from EntitySet in Reactome Precursors Imported to the Matrix by TIMM23 PAM Reactome DB_ID: 1299468 Reactome Database ID Release 431299468 Reactome, http://www.reactome.org ReactomeREACT_119158 Cargo of TIMM23 PAM Converted from EntitySet in Reactome Proteins Imported to the Matrix by TIMM23 PAM Reactome DB_ID: 1299472 Reactome Database ID Release 431299472 Reactome, http://www.reactome.org ReactomeREACT_119739 ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43376375 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43376349 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43376370 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43432698 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431225901 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431181348 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005086 Reactome Database ID Release 43199989 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43351174 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005086 Reactome Database ID Release 43199989 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005096 Reactome Database ID Release 43200615 Reactome, http://www.reactome.org Cargo of TIMM23 PAM Converted from EntitySet in Reactome Proteins Imported to the Matrix by TIMM23 PAM Reactome DB_ID: 1299460 Reactome Database ID Release 431299460 Reactome, http://www.reactome.org ReactomeREACT_119139 Precursor Cargo of TIMM23 SORT Converted from EntitySet in Reactome Precursors Inserted into Mitochondrial Inner Membrane by TIMM23 SORT Reactome DB_ID: 1268004 Reactome Database ID Release 431268004 Reactome, http://www.reactome.org ReactomeREACT_118927 TIMM17 Converted from EntitySet in Reactome Reactome DB_ID: 1252220 Reactome Database ID Release 431252220 Reactome, http://www.reactome.org ReactomeREACT_120273 PathwayStep1703 PathwayStep1704 PathwayStep1705 PathwayStep1706 PathwayStep1707 PathwayStep1708 PathwayStep1709 PathwayStep1700 PathwayStep1701 PathwayStep1702 Cargo of TIMM23 SORT Converted from EntitySet in Reactome Proteins Inserted into Inner Membrane by TIMM23 SORT Reactome DB_ID: 1299464 Reactome Database ID Release 431299464 Reactome, http://www.reactome.org ReactomeREACT_119476 Precursor Cargo of TIMM23 SORT Converted from EntitySet in Reactome Precursors Inserted into Mitochondrial Inner Membrane by TIMM23 SORT Reactome DB_ID: 1299465 Reactome Database ID Release 431299465 Reactome, http://www.reactome.org ReactomeREACT_119606 Cargo of SAM50 Converted from EntitySet in Reactome Proteins Inserted into Mitochondrial Outer Membrane by SAM50 Complex Reactome DB_ID: 1268005 Reactome Database ID Release 431268005 Reactome, http://www.reactome.org ReactomeREACT_118988 Proteins Chaperoned by TIMM9:TIMM10 Converted from EntitySet in Reactome Reactome DB_ID: 1299466 Reactome Database ID Release 431299466 Reactome, http://www.reactome.org ReactomeREACT_119124 Cargo of TIMM22 Converted from EntitySet in Reactome Proteins Inserted into Inner Membrane by TIMM22 Reactome DB_ID: 1307800 Reactome Database ID Release 431307800 Reactome, http://www.reactome.org ReactomeREACT_119704 GRPEL1 or GRPEL2 Converted from EntitySet in Reactome Reactome DB_ID: 1252226 Reactome Database ID Release 431252226 Reactome, http://www.reactome.org ReactomeREACT_119792 Cargo of SAM50 Converted from EntitySet in Reactome Proteins Inserted into Mitochondrial Outer Membrane by SAM50 Complex Reactome DB_ID: 1268003 Reactome Database ID Release 431268003 Reactome, http://www.reactome.org ReactomeREACT_119573 Cargo of TIMM22 Converted from EntitySet in Reactome Proteins Inserted into Inner Membrane by TIMM22 Reactome DB_ID: 1307796 Reactome Database ID Release 431307796 Reactome, http://www.reactome.org ReactomeREACT_119317 Products of MIA40:ERV1 Converted from EntitySet in Reactome Reactome DB_ID: 1307799 Reactome Database ID Release 431307799 Reactome, http://www.reactome.org ReactomeREACT_119222 Proteins Chaperoned by TIMM9:TIMM10 Converted from EntitySet in Reactome Reactome DB_ID: 1955378 Reactome Database ID Release 431955378 Reactome, http://www.reactome.org ReactomeREACT_119695 Proteins Chaperoned by TIMM8:TIMM13 Converted from EntitySet in Reactome Reactome DB_ID: 1299467 Reactome Database ID Release 431299467 Reactome, http://www.reactome.org ReactomeREACT_119274 PathwayStep1771 PathwayStep1770 Substrates of MIA40:ERV1 Converted from EntitySet in Reactome Reactome DB_ID: 1307798 Reactome Database ID Release 431307798 Reactome, http://www.reactome.org ReactomeREACT_119002 PathwayStep1769 PathwayStep1763 PathwayStep1764 PathwayStep1761 PathwayStep1762 PathwayStep1767 PathwayStep1768 PathwayStep1765 PathwayStep1766 PathwayStep1760 PathwayStep1758 PathwayStep1759 PathwayStep1750 PathwayStep1751 PathwayStep1752 PathwayStep1753 PathwayStep1754 PathwayStep1755 PathwayStep1756 PathwayStep1757 PathwayStep1793 PathwayStep1792 PathwayStep1791 PathwayStep1790 PathwayStep1789 PathwayStep1787 PathwayStep1788 PathwayStep1785 PathwayStep1786 PathwayStep1783 PathwayStep1784 PathwayStep1780 PathwayStep1782 PathwayStep1781 PathwayStep1776 PathwayStep1777 PathwayStep1778 PathwayStep1779 PathwayStep1772 PathwayStep1773 PathwayStep1774 PathwayStep1775 PathwayStep1720 PathwayStep1724 PathwayStep1723 PathwayStep1722 PathwayStep1721 PathwayStep1728 PathwayStep1727 PathwayStep1726 PathwayStep1725 PathwayStep1729 PathwayStep1711 PathwayStep1710 PathwayStep1713 PathwayStep1712 PathwayStep1715 PathwayStep1714 PathwayStep1717 PathwayStep1716 PathwayStep1719 PathwayStep1718 PathwayStep1746 PathwayStep1745 PathwayStep1744 PathwayStep1743 PathwayStep1742 PathwayStep1741 PathwayStep1740 PathwayStep1749 PathwayStep1748 PathwayStep1747 PathwayStep1733 PathwayStep1732 PathwayStep1735 PathwayStep1734 PathwayStep1731 PathwayStep1730 PathwayStep1737 PathwayStep1736 PathwayStep1739 PathwayStep1738 SHC1 Converted from EntitySet in Reactome Reactome DB_ID: 2404191 Reactome Database ID Release 432404191 Reactome, http://www.reactome.org ReactomeREACT_150644 SHC1 Converted from EntitySet in Reactome Reactome DB_ID: 1433343 Reactome Database ID Release 431433343 Reactome, http://www.reactome.org ReactomeREACT_150482 p-SHC1 Converted from EntitySet in Reactome Reactome DB_ID: 2404184 Reactome Database ID Release 432404184 Reactome, http://www.reactome.org ReactomeREACT_151111 PathwayStep1797 ACTIVATION GENE ONTOLOGYGO:0005243 Reactome Database ID Release 43196375 Reactome, http://www.reactome.org PathwayStep1796 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43191651 Reactome, http://www.reactome.org PathwayStep1795 ACTIVATION GENE ONTOLOGYGO:0016887 Reactome Database ID Release 43917728 Reactome, http://www.reactome.org PathwayStep1794 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43377383 Reactome, http://www.reactome.org PathwayStep1799 PathwayStep1798 ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 431458493 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431445142 Reactome, http://www.reactome.org p-IRS1/2/4 Converted from EntitySet in Reactome Reactome DB_ID: 2445139 Reactome Database ID Release 432445139 Reactome, http://www.reactome.org ReactomeREACT_151506 IRS1/2/4 Converted from EntitySet in Reactome Reactome DB_ID: 2445131 Reactome Database ID Release 432445131 Reactome, http://www.reactome.org ReactomeREACT_152472 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431445142 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431454665 Reactome, http://www.reactome.org ACVR2A/B Activin receptor type IIA/IIB Converted from EntitySet in Reactome Reactome DB_ID: 1181136 Reactome Database ID Release 431181136 Reactome, http://www.reactome.org ReactomeREACT_111501 ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 431458467 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431445142 Reactome, http://www.reactome.org IRS1/4 Converted from EntitySet in Reactome Reactome DB_ID: 2428932 Reactome Database ID Release 432428932 Reactome, http://www.reactome.org ReactomeREACT_150840 ACTIVATION GENE ONTOLOGYGO:0000146 Reactome Database ID Release 431449617 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000146 Reactome Database ID Release 431449634 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202267 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000146 Reactome Database ID Release 431449576 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000146 Reactome Database ID Release 431449577 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202294 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202370 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43202295 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202226 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202191 Reactome, http://www.reactome.org SEC61 alpha Converted from EntitySet in Reactome Reactome DB_ID: 444590 Reactome Database ID Release 43444590 Reactome, http://www.reactome.org ReactomeREACT_21208 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202262 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202147 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202180 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004435 Reactome Database ID Release 43202664 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 43202288 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016314 Reactome Database ID Release 43202259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016314 Reactome Database ID Release 43199445 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43202370 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43202386 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43202439 Reactome, http://www.reactome.org 5-Gal-Hyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 1981152 Reactome Database ID Release 431981152 Reactome, http://www.reactome.org ReactomeREACT_125391 4-Hyp, 5-Hyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2022982 Reactome Database ID Release 432022982 Reactome, http://www.reactome.org ReactomeREACT_123686 Monomeric connexin protein Converted from EntitySet in Reactome Reactome DB_ID: 190703 Reactome Database ID Release 43190703 Reactome, http://www.reactome.org ReactomeREACT_9675 Vamp Converted from EntitySet in Reactome Reactome DB_ID: 432694 Reactome Database ID Release 43432694 Reactome, http://www.reactome.org ReactomeREACT_19693 Lysosome Cargo Converted from EntitySet in Reactome Reactome DB_ID: 432697 Reactome Database ID Release 43432697 Reactome, http://www.reactome.org ReactomeREACT_20347 AP-1 mu Converted from EntitySet in Reactome Reactome DB_ID: 432709 Reactome Database ID Release 43432709 Reactome, http://www.reactome.org ReactomeREACT_19756 AP-1 sigma Converted from EntitySet in Reactome Reactome DB_ID: 432689 Reactome Database ID Release 43432689 Reactome, http://www.reactome.org ReactomeREACT_19510 Lysosome Cargo Converted from EntitySet in Reactome Reactome DB_ID: 435030 Reactome Database ID Release 43435030 Reactome, http://www.reactome.org ReactomeREACT_20098 Lysosome Destined Cargo Converted from EntitySet in Reactome Reactome DB_ID: 432690 Reactome Database ID Release 43432690 Reactome, http://www.reactome.org ReactomeREACT_19909 PathwayStep1699 PathwayStep1696 PathwayStep1695 PathwayStep1698 PathwayStep1697 PathwayStep1690 PathwayStep1693 PathwayStep1694 PathwayStep1691 PathwayStep1692 Dab2 Converted from EntitySet in Reactome Reactome DB_ID: 196159 Reactome Database ID Release 43196159 Reactome, http://www.reactome.org ReactomeREACT_10228 PathwayStep1687 PathwayStep1686 Clathrin light chain Converted from EntitySet in Reactome Reactome DB_ID: 196168 Reactome Database ID Release 43196168 Reactome, http://www.reactome.org ReactomeREACT_10283 PathwayStep1685 PathwayStep1684 PathwayStep1689 PathwayStep1688 PathwayStep1680 PathwayStep1681 PathwayStep1682 PathwayStep1683 Clathrin heavy chain Converted from EntitySet in Reactome Reactome DB_ID: 196143 Reactome Database ID Release 43196143 Reactome, http://www.reactome.org ReactomeREACT_10779 ZO-1 Converted from EntitySet in Reactome Reactome DB_ID: 191618 Reactome Database ID Release 43191618 Reactome, http://www.reactome.org ReactomeREACT_10984 PathwayStep1674 PathwayStep1673 PathwayStep1676 PathwayStep1675 PathwayStep1678 PathwayStep1677 PathwayStep1679 Clathrin heavy chain 2 Converted from EntitySet in Reactome Reactome DB_ID: 196022 Reactome Database ID Release 43196022 Reactome, http://www.reactome.org ReactomeREACT_10743 Clathrin heavy chain 1 Converted from EntitySet in Reactome Reactome DB_ID: 196031 Reactome Database ID Release 43196031 Reactome, http://www.reactome.org ReactomeREACT_10216 Clathrin light chain B Converted from EntitySet in Reactome Reactome DB_ID: 196027 Reactome Database ID Release 43196027 Reactome, http://www.reactome.org ReactomeREACT_10623 Clathrin light chain A Converted from EntitySet in Reactome Reactome DB_ID: 196034 Reactome Database ID Release 43196034 Reactome, http://www.reactome.org ReactomeREACT_10616 Myosin VI Converted from EntitySet in Reactome Reactome DB_ID: 196165 Reactome Database ID Release 43196165 Reactome, http://www.reactome.org ReactomeREACT_10361 Dynamin-2 Converted from EntitySet in Reactome Reactome DB_ID: 196377 Reactome Database ID Release 43196377 Reactome, http://www.reactome.org ReactomeREACT_10720 Myosin VI Converted from EntitySet in Reactome Reactome DB_ID: 196048 Reactome Database ID Release 43196048 Reactome, http://www.reactome.org ReactomeREACT_10786 Dab2 Converted from EntitySet in Reactome Reactome DB_ID: 196036 Reactome Database ID Release 43196036 Reactome, http://www.reactome.org ReactomeREACT_10839 Cx26/Cx32 Converted from EntitySet in Reactome Reactome DB_ID: 191080 Reactome Database ID Release 43191080 Reactome, http://www.reactome.org ReactomeREACT_9706 Cx26/Cx32 Converted from EntitySet in Reactome Reactome DB_ID: 191076 Reactome Database ID Release 43191076 Reactome, http://www.reactome.org ReactomeREACT_9641 PathwayStep1627 PathwayStep1626 PathwayStep1629 PathwayStep1628 PathwayStep1623 PathwayStep1622 PathwayStep1625 PathwayStep1624 PathwayStep1621 PathwayStep1620 NAT1 substrate Converted from EntitySet in Reactome Reactome DB_ID: 174969 Reactome Database ID Release 43174969 Reactome, http://www.reactome.org ReactomeREACT_7517 PathwayStep1619 PathwayStep1618 PathwayStep1617 PathwayStep1616 PathwayStep1615 PathwayStep1614 PathwayStep1613 PathwayStep1612 PathwayStep1611 PathwayStep1610 PathwayStep1605 PathwayStep1604 PathwayStep1607 PathwayStep1606 N-centre functional group substrate Converted from EntitySet in Reactome Reactome DB_ID: 174932 Reactome Database ID Release 43174932 Reactome, http://www.reactome.org ReactomeREACT_7594 PathwayStep1609 PathwayStep1608 PathwayStep1601 PathwayStep1600 PathwayStep1603 PathwayStep1602 O-centre functional group substrate Converted from EntitySet in Reactome Reactome DB_ID: 174911 Reactome Database ID Release 43174911 Reactome, http://www.reactome.org ReactomeREACT_7481 O-glucuronide Converted from EntitySet in Reactome Reactome DB_ID: 174914 Reactome Database ID Release 43174914 Reactome, http://www.reactome.org ReactomeREACT_7769 N-glucuronide Converted from EntitySet in Reactome Reactome DB_ID: 174918 Reactome Database ID Release 43174918 Reactome, http://www.reactome.org ReactomeREACT_7580 PathwayStep1666 PathwayStep1667 PathwayStep1668 PathwayStep1669 PathwayStep1662 PathwayStep1663 PathwayStep1664 PathwayStep1665 electrophilic substrate glutathione conjugate Converted from EntitySet in Reactome Reactome DB_ID: 176048 Reactome Database ID Release 43176048 Reactome, http://www.reactome.org ReactomeREACT_7578 electrophilic substrate Converted from EntitySet in Reactome Reactome DB_ID: 176065 Reactome Database ID Release 43176065 Reactome, http://www.reactome.org ReactomeREACT_7023 PathwayStep1670 PathwayStep1672 PathwayStep1671 PathwayStep1657 PathwayStep1658 PathwayStep1655 PathwayStep1656 PathwayStep1653 PathwayStep1654 PathwayStep1651 PathwayStep1652 electrophilic substrate glutathione conjugate Converted from EntitySet in Reactome Reactome DB_ID: 176049 Reactome Database ID Release 43176049 Reactome, http://www.reactome.org ReactomeREACT_7730 PathwayStep1659 Electrophilic substrate Converted from EntitySet in Reactome Reactome DB_ID: 176070 Reactome Database ID Release 43176070 Reactome, http://www.reactome.org ReactomeREACT_7380 PathwayStep1661 PathwayStep1660 PathwayStep1640 PathwayStep1641 PathwayStep1642 PathwayStep1643 PathwayStep1644 PathwayStep1645 PathwayStep1646 PathwayStep1647 PathwayStep1648 NAT2 substrate Converted from EntitySet in Reactome Reactome DB_ID: 174971 Reactome Database ID Release 43174971 Reactome, http://www.reactome.org ReactomeREACT_7193 PathwayStep1649 NAT2 acetylated conjugate Converted from EntitySet in Reactome Reactome DB_ID: 174958 Reactome Database ID Release 43174958 Reactome, http://www.reactome.org ReactomeREACT_7422 NAT1 acetylated conjugate Converted from EntitySet in Reactome Reactome DB_ID: 174960 Reactome Database ID Release 43174960 Reactome, http://www.reactome.org ReactomeREACT_7900 PathwayStep1650 PathwayStep1631 PathwayStep1632 PathwayStep1630 PathwayStep1635 PathwayStep1636 PathwayStep1633 PathwayStep1634 PathwayStep1639 PathwayStep1637 PathwayStep1638 5-Hyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 1981142 Reactome Database ID Release 431981142 Reactome, http://www.reactome.org ReactomeREACT_122021 Collagen propeptides, chains Converted from EntitySet in Reactome Reactome DB_ID: 2265541 Reactome Database ID Release 432265541 Reactome, http://www.reactome.org ReactomeREACT_122528 ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432186782 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004095 Reactome Database ID Release 43201039 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432176488 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004095 Reactome Database ID Release 43201041 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015227 Reactome Database ID Release 43200567 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004679 Reactome Database ID Release 43200412 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43200992 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43380980 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003989 Reactome Database ID Release 4376186 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004652 Reactome Database ID Release 4372183 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016407 Reactome Database ID Release 43109690 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43164035 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003950 Reactome Database ID Release 432187313 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43208887 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43173531 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004707 Reactome Database ID Release 43164955 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43870515 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432186745 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432179275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004221 Reactome Database ID Release 43870516 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43113433 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 43113432 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43109879 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43109879 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43109879 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004819 Reactome Database ID Release 43379613 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004818 Reactome Database ID Release 43379596 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004821 Reactome Database ID Release 43379619 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004820 Reactome Database ID Release 43379594 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43113431 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004813 Reactome Database ID Release 43379647 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004814 Reactome Database ID Release 43379627 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004816 Reactome Database ID Release 43379562 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004815 Reactome Database ID Release 43379607 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004817 Reactome Database ID Release 43379638 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004831 Reactome Database ID Release 43379577 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004830 Reactome Database ID Release 43379671 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004829 Reactome Database ID Release 43379659 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004827 Reactome Database ID Release 43379604 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004828 Reactome Database ID Release 43379558 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004825 Reactome Database ID Release 43379606 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004826 Reactome Database ID Release 43379621 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004823 Reactome Database ID Release 43379569 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004824 Reactome Database ID Release 43379563 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004822 Reactome Database ID Release 43379599 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004820 Reactome Database ID Release 43379584 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004819 Reactome Database ID Release 43379668 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004816 Reactome Database ID Release 43379559 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004815 Reactome Database ID Release 43379660 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004817 Reactome Database ID Release 43379580 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004818 Reactome Database ID Release 43379658 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004832 Reactome Database ID Release 43379579 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004427 Reactome Database ID Release 4371731 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004813 Reactome Database ID Release 43379595 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004814 Reactome Database ID Release 43379676 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004821 Reactome Database ID Release 43379587 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004823 Reactome Database ID Release 43379674 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004822 Reactome Database ID Release 43379670 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004825 Reactome Database ID Release 43379661 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004824 Reactome Database ID Release 43379597 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004827 Reactome Database ID Release 43379652 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004826 Reactome Database ID Release 43379675 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004829 Reactome Database ID Release 43379620 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004828 Reactome Database ID Release 43379630 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004830 Reactome Database ID Release 43379643 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004832 Reactome Database ID Release 43379578 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004831 Reactome Database ID Release 43379616 Reactome, http://www.reactome.org ubiquitin Converted from EntitySet in Reactome Reactome DB_ID: 917706 Reactome Database ID Release 43917706 Reactome, http://www.reactome.org ReactomeREACT_27665 ACTIVATION GENE ONTOLOGYGO:0004535 Reactome Database ID Release 43429904 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004535 Reactome Database ID Release 43430048 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004535 Reactome Database ID Release 43429943 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004427 Reactome Database ID Release 43449939 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004534 Reactome Database ID Release 43429949 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016896 Reactome Database ID Release 43429920 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004532 Reactome Database ID Release 43430003 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000175 Reactome Database ID Release 43429969 Reactome, http://www.reactome.org CHMP2 Converted from EntitySet in Reactome Reactome DB_ID: 917705 Reactome Database ID Release 43917705 Reactome, http://www.reactome.org ReactomeREACT_27491 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43927781 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43376970 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004521 Reactome Database ID Release 43927876 Reactome, http://www.reactome.org RAB8A,10,13,14 Converted from EntitySet in Reactome Reactome DB_ID: 1445136 Reactome Database ID Release 431445136 Reactome, http://www.reactome.org ReactomeREACT_148229 ACTIVATION GENE ONTOLOGYGO:0004525 Reactome Database ID Release 43203909 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004525 Reactome Database ID Release 43203909 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004521 Reactome Database ID Release 432106608 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004525 Reactome Database ID Release 43203884 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004004 Reactome Database ID Release 431295753 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051033 Reactome Database ID Release 43209663 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003723 Reactome Database ID Release 43209653 Reactome, http://www.reactome.org CHMP4 Converted from EntitySet in Reactome Reactome DB_ID: 917714 Reactome Database ID Release 43917714 Reactome, http://www.reactome.org ReactomeREACT_27572 ZO-1 Converted from EntitySet in Reactome Reactome DB_ID: 191617 Reactome Database ID Release 43191617 Reactome, http://www.reactome.org ReactomeREACT_10267 ZO-1 Converted from EntitySet in Reactome Reactome DB_ID: 191646 Reactome Database ID Release 43191646 Reactome, http://www.reactome.org ReactomeREACT_10847 cis-EET Converted from EntitySet in Reactome Reactome DB_ID: 215062 Reactome Database ID Release 43215062 Reactome, http://www.reactome.org ReactomeREACT_14302 PathwayStep1572 PathwayStep1573 PathwayStep1570 PathwayStep1571 PathwayStep1566 PathwayStep1565 PathwayStep1564 PathwayStep1563 PathwayStep1569 PathwayStep1568 PathwayStep1567 PathwayStep1560 PathwayStep1561 PathwayStep1562 PathwayStep1553 PathwayStep1552 PathwayStep1555 PathwayStep1554 PathwayStep1557 PathwayStep1556 PathwayStep1559 PathwayStep1558 PathwayStep1594 PathwayStep1595 PathwayStep1592 PathwayStep1593 PathwayStep1590 PathwayStep1591 PathwayStep1589 PathwayStep1588 PathwayStep1587 PathwayStep1586 PathwayStep1585 PathwayStep1581 PathwayStep1582 PathwayStep1583 PathwayStep1584 PathwayStep1580 PathwayStep1579 PathwayStep1578 PathwayStep1575 PathwayStep1574 PathwayStep1577 PathwayStep1576 PathwayStep1596 PathwayStep1597 PathwayStep1598 PathwayStep1599 TCR chain alpha Converted from EntitySet in Reactome Reactome DB_ID: 198184 Reactome Database ID Release 43198184 Reactome, http://www.reactome.org ReactomeREACT_11948 TCR chain beta Converted from EntitySet in Reactome Reactome DB_ID: 198177 Reactome Database ID Release 43198177 Reactome, http://www.reactome.org ReactomeREACT_11527 HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2130476 Reactome Database ID Release 432130476 Reactome, http://www.reactome.org ReactomeREACT_122019 PathwayStep1502 PathwayStep1501 PathwayStep1504 PathwayStep1503 Ubiquitin-dependent degradation controls basal levels of R-Smad1/5/8 Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 EC Number: 6.3.2.19 Pubmed10458166 Pubmed11016919 Pubmed11158580 Reactome Database ID Release 43201445 Reactome, http://www.reactome.org ReactomeREACT_12038 Reviewed: Heldin, CH, 2007--1-1- SMAD2 is polyubiquitinated by SMURF2 and targeted for proteasome-mediated degradation. Insulin degradation At the beginning of this reaction, 1 molecule of 'insulin' is present. <br><br>This reaction takes place in the 'endosome' and is mediated by the 'insulysin activity of IDA (insulin degrading activity' of 'IDA (insulin degrading activity)'.<br> Pubmed3061785 Pubmed8682206 Pubmed9793760 Reactome Database ID Release 4374730 Reactome, http://www.reactome.org ReactomeREACT_1355 Gelatin degradation by MMP19 Authored: Jupe, S, 2012-10-29 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Gelatin forms when collagen becomes partly or completely uncoiled, as opposed to the regular triple helix structure of fibrillar collagen. In vivo, once collagens are initially cleaved into clasical 3/4 and 1/4 fragments (by collagenases) they rapidly denature at body temperature and are degraded by gelatinases and other nonspecific tissue proteinases (Chung et al. 2004) to a semi-solid colloid gel. MMP2 and MMP9 are the major gelatinases (Collier et al. 1988, Wilhelm et al. 1989) often referred to respectively as Gelatinase A and Gelatinase B (Murphy & Crabbe 1995). However many other MMPs have gelatinase activity, including MMP1 (Murphy et al. 1982, Isaksen & Fagerhol 2001, Chung et al. 2004), MMP3 (Chin et al. 1985, Isaksen & Fagerhol 2001), MMP7 (Isaksen & Fagerhol 2001), MMP8 (Isaksen & Fagerhol 2001) MMP10 (Sanches-Lopez et al. 1993), MMP12 (Chandler et al. 1996), MMP13 (Knäuper et al. 1993, Isaksen & Fagerhol 2001), MMP16 (Shofuda et al. 1997), MMP17 (Wang et al. 1999), MMP18 (Spinucci et al. 1988), MMP19 (Stracke et al. 2000) and MMP22 (Yang & Kurkinen 1998). Pubmed10551873 Pubmed10809722 Pubmed11577169 Pubmed15257288 Pubmed2551898 Pubmed2834383 Pubmed2845110 Pubmed2995374 Pubmed6285893 Pubmed7674939 Pubmed8463259 Pubmed8576151 Pubmed8920930 Pubmed9092507 Pubmed9651395 Reactome Database ID Release 432537524 Reactome, http://www.reactome.org ReactomeREACT_150387 Reviewed: Sorsa, Timo, 2012-10-08 PathwayStep1500 Endocytosis and degradation of apoA-I ApoA-I bound to CUBN:AMN on the cell surface is endocytosed, moved to lysosomes, and degraded (Kozyraki et al. 1999). It is not known whether the CUBN:AMN complex is also degraded or recycled to the cell surface. Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed10371504 Reactome Database ID Release 43264834 Reactome, http://www.reactome.org ReactomeREACT_13602 Reviewed: Jassal, B, 2008-06-13 14:05:49 Degradation of newly synthesized ApoB-48 Authored: D'Eustachio, P, 2007-04-30 14:19:38 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0044257 Newly synthesized apoB-48 that is not complexed with lipid is rapidly degraded (Dixon et al. 1991). The mechanism and site of this degradation (within the endoplasmic reticulum or in cytosolic proteasomes) is unclear. Pubmed1848237 Reactome Database ID Release 43174731 Reactome, http://www.reactome.org ReactomeREACT_6829 Ubiquitin-dependent degradation of the SMAD complex terminates TGF-beta signaling Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 EC Number: 6.3.2.19 Edited: Jassal, B, 2006-02-14 10:42:31 Pubmed10587642 Pubmed10587654 Reactome Database ID Release 43173545 Reactome, http://www.reactome.org ReactomeREACT_6857 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 The nuclear R-SMAD:Co-SMAD complex recruits ubiquitin conjugating enzymes, such as UBE2D1 and UBE2D3, that ubiquitinate the complex and eventually lead to its proteasomal degradation. This provides an end point to the signaling pathway. PathwayStep1509 Degradation of SMAD2/3:SMAD4 complex Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 NEDD4L-mediated ubiquitination of SMAD2/3 triggers degradation and ends transcriptional activity of SMAD2/3:SMAD4 complex. Pubmed19917253 Reactome Database ID Release 432176503 Reactome, http://www.reactome.org ReactomeREACT_121362 Reviewed: Huang, Tao, 2012-05-14 Degradation of ubiquitinated SKI/SKIL Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11389444 Pubmed17510063 Pubmed17591695 Reactome Database ID Release 432186767 Reactome, http://www.reactome.org ReactomeREACT_120982 Reviewed: Huang, Tao, 2012-05-14 SKI/SKIL ubiquitinated by RNF111 (Levy et al. 2007, Nagano et al. 2007) or SMURF2 (Bonni et al. 2001) are degraded in a proteasome dependent way, enabling transcription of SMAD2/3:SMAD4 target genes. Degradation of Ub-SMAD7 After ubiquitination by RNF111 (Arkadia), ubiquitinated SMAD7 is degraded in a proteasome dependent way. Therefore, RNF111 has a positive effect on trancription initiated by TGF-beta signaling. However, TGF-beta signaling ultimately results in a decrease of RNF111 mRNA level, enabling negative-feedback regulation of TGF-beta signal by SMAD7. <br>RNF111 may fine tune the duration of cellular response to TGF-beta signal. Initially, RNF111 may enable signal propagation by inhibiting negative regulators of TGF-beta signaling, SKI/SKIL and SMAD7. Subsequent negative regulation of RNF111 expression by TGF-beta may allow the signaling cascade to be turned off (Koinuma et al. 2003). Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed14657019 Reactome Database ID Release 432186780 Reactome, http://www.reactome.org ReactomeREACT_120751 Reviewed: Huang, Tao, 2012-05-14 PathwayStep1506 PathwayStep1505 PathwayStep1508 PathwayStep1507 PathwayStep1527 PathwayStep1528 PathwayStep1529 PathwayStep1520 PathwayStep1521 PathwayStep1522 PathwayStep1523 PathwayStep1524 PathwayStep1525 PathwayStep1526 PathwayStep1518 PathwayStep1519 PathwayStep1516 PathwayStep1517 PathwayStep1510 PathwayStep1511 PathwayStep1514 PathwayStep1515 3,4-Hyp 5-Hyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2022150 Reactome Database ID Release 432022150 Reactome, http://www.reactome.org ReactomeREACT_124895 PathwayStep1512 PathwayStep1513 PathwayStep1549 PathwayStep1545 PathwayStep1546 PathwayStep1547 PathwayStep1548 PathwayStep1541 PathwayStep1542 PathwayStep1543 PathwayStep1544 PathwayStep1551 PathwayStep1550 PathwayStep1538 PathwayStep1539 PathwayStep1536 PathwayStep1537 PathwayStep1534 PathwayStep1535 PathwayStep1532 PathwayStep1533 PathwayStep1530 PathwayStep1531 PathwayStep1540 4-Hyp Glu-Gal-Hyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2023673 Reactome Database ID Release 432023673 Reactome, http://www.reactome.org ReactomeREACT_123960 3,4-Hyp Glu-Gal-Hyl-collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2023662 Reactome Database ID Release 432023662 Reactome, http://www.reactome.org ReactomeREACT_122106 Ena/VASP proteins Converted from EntitySet in Reactome Reactome DB_ID: 430213 Reactome Database ID Release 43430213 Reactome, http://www.reactome.org ReactomeREACT_20983 HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2130597 Reactome Database ID Release 432130597 Reactome, http://www.reactome.org ReactomeREACT_125352 Ig Kappa Light Chain V Region Converted from EntitySet in Reactome Reactome DB_ID: 2038813 Reactome Database ID Release 432038813 Reactome, http://www.reactome.org ReactomeREACT_120059 Glu-Gal-Hyl-collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 1981108 Reactome Database ID Release 431981108 Reactome, http://www.reactome.org ReactomeREACT_123460 Lck/Csk Converted from EntitySet in Reactome Reactome DB_ID: 389743 Reactome Database ID Release 43389743 Reactome, http://www.reactome.org ReactomeREACT_20288 PD-1 ligands Converted from EntitySet in Reactome Reactome DB_ID: 388774 Reactome Database ID Release 43388774 Reactome, http://www.reactome.org ReactomeREACT_20259 PathwayStep1399 PathwayStep1398 Procollagen galactosyltransferases Converted from EntitySet in Reactome Reactome DB_ID: 1981151 Reactome Database ID Release 431981151 Reactome, http://www.reactome.org ReactomeREACT_123165 PathwayStep1497 PathwayStep1498 PathwayStep1499 PathwayStep1488 PathwayStep1489 PathwayStep1486 PathwayStep1487 chondroitin(1)-core proteins (GalNAc)1 (GlcA)1 (Gal)2 (Xyl)1 (Ser)1 Converted from EntitySet in Reactome Reactome DB_ID: 2064172 Reactome Database ID Release 432064172 Reactome, http://www.reactome.org ReactomeREACT_121656 GlcA-Gal-Gal-Xyl-CS proteins (GlcA)1 (Gal)2 (Xyl)1 (Ser)1 Converted from EntitySet in Reactome Reactome DB_ID: 2064233 Reactome Database ID Release 432064233 Reactome, http://www.reactome.org ReactomeREACT_124761 PathwayStep1492 PathwayStep1491 PathwayStep1490 PathwayStep1496 PathwayStep1495 PathwayStep1494 PathwayStep1493 PathwayStep1475 PathwayStep1476 PathwayStep1477 PathwayStep1478 PathwayStep1479 PathwayStep1481 PathwayStep1480 PathwayStep1483 PathwayStep1482 PathwayStep1485 PathwayStep1484 PathwayStep1469 PathwayStep1468 PathwayStep1467 PathwayStep1466 PathwayStep1465 PathwayStep1464 PathwayStep1473 PathwayStep1474 PathwayStep1471 PathwayStep1472 PathwayStep1470 HS core proteins Converted from EntitySet in Reactome Reactome DB_ID: 2090076 Reactome Database ID Release 432090076 Reactome, http://www.reactome.org ReactomeREACT_123905 PathwayStep1458 PathwayStep1457 PathwayStep1459 PathwayStep1454 PathwayStep1453 PathwayStep1456 PathwayStep1455 PathwayStep1460 PathwayStep1461 PathwayStep1462 PathwayStep1463 PathwayStep1445 PathwayStep1444 PathwayStep1443 PathwayStep1442 PathwayStep1449 PathwayStep1448 PathwayStep1447 PathwayStep1446 HS core proteins Converted from EntitySet in Reactome Reactome DB_ID: 2090039 Reactome Database ID Release 432090039 Reactome, http://www.reactome.org ReactomeREACT_124689 PathwayStep1451 PathwayStep1452 PathwayStep1450 PathwayStep1439 PathwayStep1432 PathwayStep1431 PathwayStep1434 PathwayStep1433 PathwayStep1436 PathwayStep1435 PathwayStep1438 PathwayStep1437 HS/HPIN-PGs Converted from EntitySet in Reactome Heparan sulfate/heparin-PGs Reactome DB_ID: 2090050 Reactome Database ID Release 432090050 Reactome, http://www.reactome.org ReactomeREACT_125265 PathwayStep1440 PathwayStep1441 HS/HPIN-PGs Converted from EntitySet in Reactome Heparan sulfate/heparin-PGs Reactome DB_ID: 2076639 Reactome Database ID Release 432076639 Reactome, http://www.reactome.org ReactomeREACT_124554 PathwayStep1430 PathwayStep1424 PathwayStep1425 PathwayStep1426 PathwayStep1427 PathwayStep1420 PathwayStep1421 PathwayStep1422 PathwayStep1423 PathwayStep1428 PathwayStep1429 HS(5)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076688 Reactome Database ID Release 432076688 Reactome, http://www.reactome.org ReactomeREACT_124912 PathwayStep1415 PathwayStep1416 PathwayStep1413 PathwayStep1414 PathwayStep1411 PathwayStep1412 PathwayStep1410 PathwayStep1419 PathwayStep1417 PathwayStep1418 PathwayStep1400 PathwayStep1401 PathwayStep1402 PathwayStep1403 PathwayStep1404 PathwayStep1405 PathwayStep1406 PathwayStep1407 PathwayStep1408 PathwayStep1409 HS(4)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076655 Reactome Database ID Release 432076655 Reactome, http://www.reactome.org ReactomeREACT_121810 3,4-Hyp 5-Gal-Hyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2023569 Reactome Database ID Release 432023569 Reactome, http://www.reactome.org ReactomeREACT_122229 Ig Lamda Light Chain V Region Converted from EntitySet in Reactome Reactome DB_ID: 2038855 Reactome Database ID Release 432038855 Reactome, http://www.reactome.org ReactomeREACT_120009 Ig Lambda C region Converted from EntitySet in Reactome Immunoglobulin Lambda C Region Reactome DB_ID: 2038869 Reactome Database ID Release 432038869 Reactome, http://www.reactome.org ReactomeREACT_120152 Ig Heavy Chain V Region Converted from EntitySet in Reactome Reactome DB_ID: 2038838 Reactome Database ID Release 432038838 Reactome, http://www.reactome.org ReactomeREACT_119113 PathwayStep1286 PathwayStep1287 PathwayStep1284 PathwayStep1285 PathwayStep1282 PathwayStep1283 PathwayStep1280 PathwayStep1281 PathwayStep1279 PathwayStep1278 PathwayStep1277 PathwayStep1290 PathwayStep1295 PathwayStep1296 PathwayStep1297 PathwayStep1298 PathwayStep1291 PathwayStep1292 PathwayStep1293 PathwayStep1294 PathwayStep1289 PathwayStep1288 PathwayStep1299 4-Hyp 5-Gal-Hyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2023566 Reactome Database ID Release 432023566 Reactome, http://www.reactome.org ReactomeREACT_121622 PathwayStep1367 PathwayStep1368 PathwayStep1365 PathwayStep1366 PathwayStep1369 PathwayStep1371 PathwayStep1370 PathwayStep1375 PathwayStep1374 PathwayStep1373 PathwayStep1372 PathwayStep1354 PathwayStep1355 PathwayStep1356 PathwayStep1357 PathwayStep1358 PathwayStep1359 PathwayStep1360 HS(1)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076647 Reactome Database ID Release 432076647 Reactome, http://www.reactome.org ReactomeREACT_122714 PathwayStep1362 PathwayStep1361 PathwayStep1364 PathwayStep1363 HS6STs Converted from EntitySet in Reactome Heparan sulfate 6-O-sulfotransferases Reactome DB_ID: 2076470 Reactome Database ID Release 432076470 Reactome, http://www.reactome.org ReactomeREACT_124907 PathwayStep1389 PathwayStep1387 PathwayStep1388 PathwayStep1397 PathwayStep1396 PathwayStep1395 PathwayStep1394 PathwayStep1393 PathwayStep1392 PathwayStep1391 PathwayStep1390 HS(3)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076690 Reactome Database ID Release 432076690 Reactome, http://www.reactome.org ReactomeREACT_125525 PathwayStep1376 PathwayStep1377 PathwayStep1378 PathwayStep1379 PathwayStep1384 PathwayStep1383 PathwayStep1386 PathwayStep1385 PathwayStep1380 PathwayStep1382 PathwayStep1381 HS(2)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076620 Reactome Database ID Release 432076620 Reactome, http://www.reactome.org ReactomeREACT_123027 PathwayStep1324 PathwayStep1323 PathwayStep1322 PathwayStep1321 PathwayStep1328 PathwayStep1327 PathwayStep1326 PathwayStep1325 PathwayStep1329 HS3STs Converted from EntitySet in Reactome Heparan sulfate glucosamine 3-O-sulfotransferases Reactome DB_ID: 2076438 Reactome Database ID Release 432076438 Reactome, http://www.reactome.org ReactomeREACT_123150 HS(5)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076461 Reactome Database ID Release 432076461 Reactome, http://www.reactome.org ReactomeREACT_123398 PathwayStep1330 PathwayStep1331 PathwayStep1311 PathwayStep1310 PathwayStep1313 PathwayStep1312 PathwayStep1315 PathwayStep1314 PathwayStep1317 PathwayStep1316 PathwayStep1319 PathwayStep1318 NAD(P)+ Converted from EntitySet in Reactome NAD+, NADP+ Reactome DB_ID: 517495 Reactome Database ID Release 43517495 Reactome, http://www.reactome.org ReactomeREACT_21812 pyridine nucleotides, oxidized a-ketoisocaproate, a-keto b-methylvalerate, a-ketoisovalerate Converted from EntitySet in Reactome Reactome DB_ID: 508187 Reactome Database ID Release 43508187 Reactome, http://www.reactome.org ReactomeREACT_21823 Leu, Ile, Val Converted from EntitySet in Reactome Leucine, Isoleucine, Valine Reactome DB_ID: 508182 Reactome Database ID Release 43508182 Reactome, http://www.reactome.org ReactomeREACT_21489 NAD(P)H Converted from EntitySet in Reactome NADH, NADPH Reactome DB_ID: 517496 Reactome Database ID Release 43517496 Reactome, http://www.reactome.org ReactomeREACT_21828 pyridine nucleotides, reduced PathwayStep1320 PathwayStep1349 a-ketoisocaproate, a-keto b-methylvalerate, a-ketoisovalerate Converted from EntitySet in Reactome Reactome DB_ID: 508181 Reactome Database ID Release 43508181 Reactome, http://www.reactome.org ReactomeREACT_21879 PathwayStep1348 Leu, Ile, Val Converted from EntitySet in Reactome Leucine, Isoleucine, Valine Reactome DB_ID: 508190 Reactome Database ID Release 43508190 Reactome, http://www.reactome.org ReactomeREACT_21643 PathwayStep1347 PathwayStep1346 PathwayStep1345 PathwayStep1344 PathwayStep1343 isovaleryl-CoA, a-methylbutyryl-CoA, isobutyryl-CoA Converted from EntitySet in Reactome Reactome DB_ID: 508261 Reactome Database ID Release 43508261 Reactome, http://www.reactome.org ReactomeREACT_21630 HS/HPIN-PGs Converted from EntitySet in Reactome Heparan sulfate/heparin-PGs Reactome DB_ID: 2076357 Reactome Database ID Release 432076357 Reactome, http://www.reactome.org ReactomeREACT_122772 PathwayStep1352 PathwayStep1353 PathwayStep1350 PathwayStep1351 PathwayStep1337 PathwayStep1336 PathwayStep1339 PathwayStep1338 PathwayStep1333 PathwayStep1332 PathwayStep1335 PathwayStep1334 PathwayStep1340 PathwayStep1341 PathwayStep1342 HS(4)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076491 Reactome Database ID Release 432076491 Reactome, http://www.reactome.org ReactomeREACT_123903 PathwayStep1307 PathwayStep1308 PathwayStep1309 PathwayStep1303 PathwayStep1304 PathwayStep1305 PathwayStep1306 PathwayStep1300 PathwayStep1301 PathwayStep1302 HS(3)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076297 Reactome Database ID Release 432076297 Reactome, http://www.reactome.org ReactomeREACT_123421 PathwayStep1189 PathwayStep1193 PathwayStep1192 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432023458 Reactome, http://www.reactome.org PathwayStep1195 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432023453 Reactome, http://www.reactome.org PathwayStep1194 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431888195 Reactome, http://www.reactome.org PathwayStep1197 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431839025 Reactome, http://www.reactome.org PathwayStep1196 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 431839104 Reactome, http://www.reactome.org PathwayStep1199 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 431839105 Reactome, http://www.reactome.org PathwayStep1198 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431839068 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 431839092 Reactome, http://www.reactome.org Alpha-2(I) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268630 Reactome Database ID Release 432268630 Reactome, http://www.reactome.org ReactomeREACT_123199 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431839099 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431839066 Reactome, http://www.reactome.org PathwayStep1191 PathwayStep1190 Alpha-1(I) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268679 Reactome Database ID Release 432268679 Reactome, http://www.reactome.org ReactomeREACT_125242 PathwayStep1178 PathwayStep1179 PathwayStep1184 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432012069 Reactome, http://www.reactome.org PathwayStep1183 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432038388 Reactome, http://www.reactome.org PathwayStep1182 PathwayStep1181 PathwayStep1188 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432012064 Reactome, http://www.reactome.org PathwayStep1187 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432029976 Reactome, http://www.reactome.org PathwayStep1186 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432012066 Reactome, http://www.reactome.org PathwayStep1185 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432033455 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432033450 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432029972 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432033451 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432033453 Reactome, http://www.reactome.org PathwayStep1180 PathwayStep1167 PathwayStep1168 PathwayStep1169 PathwayStep1175 ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 432394010 Reactome, http://www.reactome.org PathwayStep1174 ACTIVATION GENE ONTOLOGYGO:0097256 Reactome Database ID Release 432160501 Reactome, http://www.reactome.org PathwayStep1177 ACTIVATION GENE ONTOLOGYGO:0036141 Reactome Database ID Release 432160508 Reactome, http://www.reactome.org PathwayStep1176 ACTIVATION GENE ONTOLOGYGO:0001716 Reactome Database ID Release 432160498 Reactome, http://www.reactome.org PathwayStep1171 PathwayStep1170 PathwayStep1173 PathwayStep1172 ACTIVATION GENE ONTOLOGYGO:0016314 Reactome Database ID Release 432317396 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432038941 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 432077387 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 431986642 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431982083 Reactome, http://www.reactome.org Collagen alpha-4(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2090004 Reactome Database ID Release 432090004 Reactome, http://www.reactome.org ReactomeREACT_122448 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431982074 Reactome, http://www.reactome.org 'CEBPD [nucleoplasm]' positively regulates 'Expression of EBF1' ACTIVATION As inferred from mouse, CEBPD binds the promoter of the EBF1 gene and activates transcription. Pubmed17060461 Reactome Database ID Release 43977295 Reactome, http://www.reactome.org ReactomeREACT_28002 'CEBPB [nucleoplasm]' positively regulates 'Expression of EBF1' ACTIVATION As inferred from mouse, CEBPB binds the promoter of the EBF1 gene and activates transcription. Pubmed17060461 Reactome Database ID Release 43977290 Reactome, http://www.reactome.org ReactomeREACT_28017 'CEBPD [nucleoplasm]' positively regulates 'Expression of KLF5' ACTIVATION Pubmed16054042 Reactome Database ID Release 43390517 Reactome, http://www.reactome.org ReactomeREACT_28008 'CEBPB [nucleoplasm]' positively regulates 'Expression of KLF5' ACTIVATION Pubmed16054042 Reactome Database ID Release 43390520 Reactome, http://www.reactome.org ReactomeREACT_28031 'EGR2 (KROX2) [nucleoplasm]' positively regulates 'Expression of CEBPB' ACTIVATION As inferred from mouse, EGF2 (KROX20) together with KLF4 bind the promoter of the CEBPB gene and activate transcription. Pubmed16054051 Reactome Database ID Release 43977394 Reactome, http://www.reactome.org ReactomeREACT_28016 'KLF4 [nucleoplasm]' positively regulates 'Expression of CEBPB' ACTIVATION As inferred from mouse, KLF4 together with EGF2 (KROX20) bind the promoter of the CEBPB gene and activate transcription. Pubmed18396140 Reactome Database ID Release 43977399 Reactome, http://www.reactome.org ReactomeREACT_28000 'HNF1A [nucleoplasm]' positively regulates 'HNF1A-dependent synthesis of FOXA3' ACTIVATION Reactome Database ID Release 43211493 Reactome, http://www.reactome.org ReactomeREACT_14770 'HNF1A [nucleoplasm]' positively regulates 'HNF1A-dependent synthesis of HNF4G protein' ACTIVATION Reactome Database ID Release 43211496 Reactome, http://www.reactome.org ReactomeREACT_14763 PathwayStep1158 PathwayStep1159 PathwayStep1156 PathwayStep1157 PathwayStep1166 PathwayStep1165 PathwayStep1164 PathwayStep1163 PathwayStep1162 PathwayStep1161 PathwayStep1160 'HNF1A [nucleoplasm]' positively regulates 'HNF1A-dependent synthesis of the L isoform of PKLR protein' ACTIVATION Reactome Database ID Release 43211490 Reactome, http://www.reactome.org ReactomeREACT_14747 'HNF1A [nucleoplasm]' positively regulates 'HNF1A-dependent synthesis of HNF4A' ACTIVATION Reactome Database ID Release 43211494 Reactome, http://www.reactome.org ReactomeREACT_14728 Collagen alpha-3(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2090018 Reactome Database ID Release 432090018 Reactome, http://www.reactome.org ReactomeREACT_122936 ACTIVATION GENE ONTOLOGYGO:0008374 Reactome Database ID Release 43422079 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008374 Reactome Database ID Release 43422079 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265014 Reactome, http://www.reactome.org 'EBF1 [nucleoplasm]' positively regulates 'Expression of PPARG' ACTIVATION Pubmed17060461 Reactome Database ID Release 43390516 Reactome, http://www.reactome.org ReactomeREACT_27978 'CEBPD [nucleoplasm]' positively regulates 'Expression of PPARG' ACTIVATION Pubmed10862621 Reactome Database ID Release 43390512 Reactome, http://www.reactome.org ReactomeREACT_27989 Wnt/beta-Catenin Signaling Inhibits Expression of PPARG As inferred from mouse 3T3-L1 cells, Wnt-1 and Wnt-10b inhibit PPARG expression (Ross et al. 2000, Bennett et al. 2002) by activating COUP-TFII (NR2F2) which recruits the SMRT repressor complex to the PPARG gene (Okamura et al. 2009). INHIBITION Pubmed10937998 Pubmed12055200 Pubmed19307559 Reactome Database ID Release 43976231 Reactome, http://www.reactome.org ReactomeREACT_28033 NF-KappaB Inhibits Expression of PPARG As inferred from mouse, NF-kappaB inhibits expression of PPARG in pre-adipocytes (Chae and Kwak 2003). TNFalpha represses PPARG via NF-kappaB (Chae and Kwak 2003, Kurebayashi et al. 2001, Xing et al. 1997). INHIBITION Pubmed11456275 Pubmed14646597 Pubmed9202217 Reactome Database ID Release 43976211 Reactome, http://www.reactome.org ReactomeREACT_27984 TGF-beta Inhibits Expression of PPARG As inferred from mouse, TGF-beta inhibits expression of PPARG. INHIBITION Pubmed10791980 Pubmed7694071 Reactome Database ID Release 43976214 Reactome, http://www.reactome.org ReactomeREACT_28006 'G1/S-specific cyclin D3 [nucleoplasm]' positively regulates 'Expression of FABP4 (aP2)' ACTIVATION As inferred from mouse, CyclinD3 interacts with PPARG and enhances transcription. Binding of the two factors was tested on the FABP4 (aP2) promoter. Pubmed16260612 Reactome Database ID Release 43935998 Reactome, http://www.reactome.org ReactomeREACT_27987 'Cdk4 [nucleoplasm]' positively regulates 'Expression of FABP4 (aP2)' ACTIVATION As inferred from mouse, Cdk4 interacts with PPARG and enhances transcription. Binding of the two factors was tested on the FABP4 (aP2) promoter. Pubmed16213226 Reactome Database ID Release 43936001 Reactome, http://www.reactome.org ReactomeREACT_28027 'CEBPB [nucleoplasm]' positively regulates 'Expression of PPARG' ACTIVATION Pubmed11279134 Pubmed15110775 Pubmed7557387 Pubmed8754811 Pubmed9405372 Reactome Database ID Release 43390518 Reactome, http://www.reactome.org ReactomeREACT_27996 'Processed SREBF1 [nucleoplasm]' positively regulates 'Expression of PPARG' ACTIVATION As inferred from mouse, SREBP1 binds to the PPARG1 and PPARG2 promoters and activates transcription. Pubmed10409739 Reactome Database ID Release 43934638 Reactome, http://www.reactome.org ReactomeREACT_27977 'KLF5 [nucleoplasm]' positively regulates 'Expression of PPARG' ACTIVATION Pubmed16054042 Reactome Database ID Release 43390511 Reactome, http://www.reactome.org ReactomeREACT_28023 ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43381506 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43381438 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43381432 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43139890 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43381460 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158743 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43381447 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190331 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190387 Reactome, http://www.reactome.org Wnt/beta-Catenin Signaling Inhibits Expression of CEBPA in pre-adipocytes. As inferred from mouse 3T3-L1 cells, Wnt-1 and Wnt-10b inhibit expression of CEBPA through stabillization of beta-Catenin. Wnt-10b is probably the actual regulator in vivo. INHIBITION Pubmed10937998 Pubmed12055200 Reactome Database ID Release 43976198 Reactome, http://www.reactome.org ReactomeREACT_28011 TGF-beta Inhibits Expression of CEBPA As inferred from mouse, TGF-beta inhibits expression of CEPBA in preadipocytes. INHIBITION Pubmed10791980 Pubmed7694071 Reactome Database ID Release 43976237 Reactome, http://www.reactome.org ReactomeREACT_27999 'EBF1 [nucleoplasm]' positively regulates 'Expression of CEBPA' ACTIVATION Pubmed17060461 Reactome Database ID Release 43390510 Reactome, http://www.reactome.org ReactomeREACT_27990 The activation of expression of CEBPA by EBF1 is inferred from mouse where Ebf1 directly binds one site in the Cebpa promoter and activates transcription of the Cebpa gene. 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CEBPA' ACTIVATION Pubmed16380219 Pubmed18981473 Reactome Database ID Release 43560533 Reactome, http://www.reactome.org ReactomeREACT_28032 The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the CEBPA gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Cebpa gene (Lefterova et al. 2008). TNF-alpha Inhibits Expression of CEBPA As inferred from mouse, TNF-alpha inhibits expression of CEBPA in pre-adipocytes. INHIBITION Pubmed11456275 Pubmed7694071 Reactome Database ID Release 43976204 Reactome, http://www.reactome.org ReactomeREACT_28034 'CEBPA [nucleoplasm]' positively regulates 'Maintenance of PPARG Expression in Differentiated Adipocytes' ACTIVATION Activation of PPARG transcription by CEPBA is inferred from mouse. Pubmed11782441 Pubmed15110775 Pubmed17011499 Reactome Database ID Release 43390514 Reactome, http://www.reactome.org ReactomeREACT_28001 Collagen alpha-6(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2089999 Reactome Database ID Release 432089999 Reactome, http://www.reactome.org ReactomeREACT_122693 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' positively regulates 'Expression of Lipoprotein lipase (LPL)' ACTIVATION Pubmed16380219 Pubmed18981473 Reactome Database ID Release 43560526 Reactome, http://www.reactome.org ReactomeREACT_27976 The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the LPL gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Lpl gene (Lefterova et al. 2008). 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' positively regulates 'Expression of Phosphoenolpyruvate carboxykinase 1 (PEPCK-C)' ACTIVATION Pubmed16380219 Pubmed18981473 Reactome Database ID Release 43560521 Reactome, http://www.reactome.org ReactomeREACT_28004 The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the PEPCK-C gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Pepck-c gene (Leftovera et al. 2008). 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' positively regulates 'Expression of Perilipin (PLIN)' ACTIVATION Pubmed16380219 Pubmed18981473 Reactome Database ID Release 43560522 Reactome, http://www.reactome.org ReactomeREACT_28019 The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the Perilipin (PLIN) gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Perilipin gene (Leftovera et al. 2008). 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' positively regulates 'Expression of FABP4 (aP2)' ACTIVATION Pubmed15273253 Pubmed18039840 Pubmed18981473 Pubmed19115207 Pubmed20101261 Pubmed20194623 Reactome Database ID Release 43390515 Reactome, http://www.reactome.org ReactomeREACT_28026 The PPARG:RXRA heterodimer bound to fatty acids activates transcription of FABP4 (aP2). In mouse the Pparg:Rxra heterodimer directly binds the promoter of the Fabp4 gene (Grontveld et al. 2010, Ge et al. 2008, Lefterova et al. 2008) ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190431 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190407 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190417 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190379 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265205 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016788 Reactome Database ID Release 43434410 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016788 Reactome Database ID Release 43434412 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190428 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 431268235 Reactome, http://www.reactome.org 'HIF:CBP:p300 [nucleoplasm]' positively regulates 'Expression of VEGF (isoform 1)' ACTIVATION Pubmed8756616 Pubmed8917528 Reactome Database ID Release 431235080 Reactome, http://www.reactome.org ReactomeREACT_125704 The HIF heterodimer binds the promoter of the VEGF gene, recruits p300 and CBP, and enhances transcription. 'PPARG:RXRA:Corepressor Complex [nucleoplasm]' negatively regulates 'Expression of GLUT4' As inferred from mouse cells, PPARG:RXRA in the absence of fatty acid ligand binds the promoter of the GLUT4 gene and represses expression. After activation of PPARG:RXRA by fatty acid ligand the repression is relieved. INHIBITION Pubmed12777391 Reactome Database ID Release 431183062 Reactome, http://www.reactome.org ReactomeREACT_27998 'CEBPA [nucleoplasm]' positively regulates 'Expression of GLUT4' ACTIVATION As inferred from mouse cells, C/EBPalpha (CEBPA) binds the promoter of the GLUT4 gene and activates transcription. Pubmed16754198 Pubmed18408001 Pubmed2404278 Reactome Database ID Release 431183065 Reactome, http://www.reactome.org ReactomeREACT_27992 'IRF3 bound to IFN-beta promoter [nucleoplasm]' positively regulates 'Expression of IFN-beta' ACTIVATION Reactome Database ID Release 431028811 Reactome, http://www.reactome.org ReactomeREACT_27085 'HIF:CBP:p300 [nucleoplasm]' positively regulates 'Expression of Carbonic Anhydrase IX (CA9)' ACTIVATION Hypoxia-inducible factor binds the promoter of the CA9 gene and enhances transcription. Pubmed11156414 Pubmed15184875 Reactome Database ID Release 431235075 Reactome, http://www.reactome.org ReactomeREACT_125708 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' positively regulates 'Expression of Adiponectin' ACTIVATION Pubmed12829629 Reactome Database ID Release 431183084 Reactome, http://www.reactome.org ReactomeREACT_28010 The PPARG:RXRA heterodimer activated by a thiazolidinedione agonist binds the promoter of the Adiponectin gene and activates transcription. 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' negatively regulates 'Expression of Leptin' INHIBITION PPARG together with an agonist, the thiazolidinedione BRL49653, repress expression of the Ob (leptin) gene. Pubmed8770873 Reactome Database ID Release 431183067 Reactome, http://www.reactome.org ReactomeREACT_27991 'CEBPA [nucleoplasm]' positively regulates 'Expression of Adiponectin' ACTIVATION C/EBPalpha (CEBPA) binds the promoter of the Adiponectin gene and activates transcription. Pubmed15919796 Pubmed18931025 Reactome Database ID Release 431183063 Reactome, http://www.reactome.org ReactomeREACT_27980 'CEBPB [nucleoplasm]' positively regulates 'Expression of Adiponectin' ACTIVATION C/EBPbeta (CEBPB) binds the promoter of the Adiponectin gene and activates transcription. Pubmed15850785 Reactome Database ID Release 431183080 Reactome, http://www.reactome.org ReactomeREACT_27997 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431307960 Reactome, http://www.reactome.org 'CEBPA [nucleoplasm]' positively regulates 'Expression of Leptin' ACTIVATION C/EBPalpha (CEBPA) binds the promoter of the Ob gene encoding leptin and activates transcription. Pubmed12213831 Pubmed8643605 Reactome Database ID Release 431183091 Reactome, http://www.reactome.org ReactomeREACT_27985 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43191481 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431268287 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43192397 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190354 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431268282 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431268270 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431268269 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43190903 Reactome, http://www.reactome.org Collagen alpha-5(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2090001 Reactome Database ID Release 432090001 Reactome, http://www.reactome.org ReactomeREACT_125279 'HIF:CBP:p300 [nucleoplasm]' positively regulates 'Expression of Erythropoietin (EPO)' ACTIVATION Pubmed7836384 Pubmed8387214 Pubmed8663540 Pubmed8917528 Pubmed9027736 Reactome Database ID Release 431235078 Reactome, http://www.reactome.org ReactomeREACT_125700 The HIF heterodimer binds the promoter of the EPO gene and recruits p300 and CBP to enhance transcription of EPO. ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 431272492 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004707 Reactome Database ID Release 431268259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431270442 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 431295602 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43179862 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43934571 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43934611 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43210262 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431268208 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431982067 Reactome, http://www.reactome.org Alpha-1(II) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268717 Reactome Database ID Release 432268717 Reactome, http://www.reactome.org ReactomeREACT_122268 Alpha-1(III) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268698 Reactome Database ID Release 432268698 Reactome, http://www.reactome.org ReactomeREACT_125052 capped, methylated pre-mRNA:CBC Complex Reactome DB_ID: 71954 Reactome Database ID Release 4371954 Reactome, http://www.reactome.org ReactomeREACT_3634 has a Stoichiometric coefficient of 1 RNA Polymerase II (unphosphorylated):TFIIF complex Reactome DB_ID: 71307 Reactome Database ID Release 4371307 Reactome, http://www.reactome.org ReactomeREACT_2692 has a Stoichiometric coefficient of 1 snRNP Sm core complex Reactome DB_ID: 71910 Reactome Database ID Release 4371910 Reactome, http://www.reactome.org ReactomeREACT_4149 has a Stoichiometric coefficient of 1 D4S-PGs Converted from EntitySet in Reactome Dermatan 4-sulfate proteoglycans Reactome DB_ID: 2065235 Reactome Database ID Release 432065235 Reactome, http://www.reactome.org ReactomeREACT_124564 Spliceosomal E Complex Reactome DB_ID: 72057 Reactome Database ID Release 4372057 Reactome, http://www.reactome.org ReactomeREACT_4545 has a Stoichiometric coefficient of 1 U2 snRNP Reactome DB_ID: 71980 Reactome Database ID Release 4371980 Reactome, http://www.reactome.org ReactomeREACT_3715 has a Stoichiometric coefficient of 1 SF3B Reactome DB_ID: 71976 Reactome Database ID Release 4371976 Reactome, http://www.reactome.org ReactomeREACT_3752 Splicing Factor 3B has a Stoichiometric coefficient of 1 RNA Polymerase II holoenzyme complex (unphosphorylated) Reactome DB_ID: 113401 Reactome Database ID Release 43113401 Reactome, http://www.reactome.org ReactomeREACT_4217 has a Stoichiometric coefficient of 1 mRNA (N6-adenosine)-methyltransferase Reactome DB_ID: 72093 Reactome Database ID Release 4372093 Reactome, http://www.reactome.org ReactomeREACT_3236 has a Stoichiometric coefficient of 1 capped, methylated pre-mRNP:CBC complex Reactome DB_ID: 71955 Reactome Database ID Release 4371955 Reactome, http://www.reactome.org ReactomeREACT_2736 has a Stoichiometric coefficient of 1 U1 snRNP Reactome DB_ID: 71917 Reactome Database ID Release 4371917 Reactome, http://www.reactome.org ReactomeREACT_2910 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of RGL1' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989822 Reactome, http://www.reactome.org ReactomeREACT_118016 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of SULT2A1' ACTIVATION Pubmed15635043 Pubmed20110263 Reactome Database ID Release 431989782 Reactome, http://www.reactome.org ReactomeREACT_117998 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of TIAM2' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989804 Reactome, http://www.reactome.org ReactomeREACT_117986 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of TNFRSF21' ACTIVATION Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989790 Reactome, http://www.reactome.org ReactomeREACT_117910 A to I edited RNA:Editosome (ADAR2) complex Reactome DB_ID: 77611 Reactome Database ID Release 4377611 Reactome, http://www.reactome.org ReactomeREACT_3344 has a Stoichiometric coefficient of 1 'NR1D1 (REV-ERBA):heme:Corepressor [nucleoplasm]' negatively regulates 'Expression of NPAS2' INHIBITION Pubmed20817722 Reactome Database ID Release 431368161 Reactome, http://www.reactome.org ReactomeREACT_118009 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of NPAS2' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989795 Reactome, http://www.reactome.org ReactomeREACT_117935 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of PEX11A' ACTIVATION Pubmed14729975 Pubmed19710929 Reactome Database ID Release 431989800 Reactome, http://www.reactome.org ReactomeREACT_118038 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of PLIN2' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989806 Reactome, http://www.reactome.org ReactomeREACT_117937 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of PPARA' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989805 Reactome, http://www.reactome.org ReactomeREACT_118060 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of PPARA' ACTIVATION As inferred from mouse, BMAL1:CLOCK heterodimers bind E-boxes in the second intron of the PPARA gene and activate transcription of PPARA. Pubmed15500444 Reactome Database ID Release 43879833 Reactome, http://www.reactome.org ReactomeREACT_27103 Pol II transcription complex with (ser5) phosphorylated CTD containing extruded transcript to +30 Reactome DB_ID: 157174 Reactome Database ID Release 43157174 Reactome, http://www.reactome.org ReactomeREACT_2595 has a Stoichiometric coefficient of 1 Editosome (ADAR2) complex Reactome DB_ID: 77610 Reactome Database ID Release 4377610 Reactome, http://www.reactome.org ReactomeREACT_5072 has a Stoichiometric coefficient of 1 A to I edited RNA:Editosome (ADAR1) complex Reactome DB_ID: 75089 Reactome Database ID Release 4375089 Reactome, http://www.reactome.org ReactomeREACT_4604 has a Stoichiometric coefficient of 1 Editosome (ADAR1) complex Reactome DB_ID: 75087 Reactome Database ID Release 4375087 Reactome, http://www.reactome.org ReactomeREACT_3053 has a Stoichiometric coefficient of 1 ADAR2 homodimer Reactome DB_ID: 111235 Reactome Database ID Release 43111235 Reactome, http://www.reactome.org ReactomeREACT_3351 has a Stoichiometric coefficient of 2 C to U edited ApoB RNA:Editosome complex Reactome DB_ID: 83676 Reactome Database ID Release 4383676 Reactome, http://www.reactome.org ReactomeREACT_5264 has a Stoichiometric coefficient of 1 ADAR1 homodimer Reactome DB_ID: 111236 Reactome Database ID Release 43111236 Reactome, http://www.reactome.org ReactomeREACT_4700 has a Stoichiometric coefficient of 2 Stem-looped mRNA:ACF complex Reactome DB_ID: 77605 Reactome Database ID Release 4377605 Reactome, http://www.reactome.org ReactomeREACT_4484 has a Stoichiometric coefficient of 1 Editosome for C to U editing Reactome DB_ID: 77606 Reactome Database ID Release 4377606 Reactome, http://www.reactome.org ReactomeREACT_2389 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of HMGCS2' ACTIVATION Pubmed12505311 Pubmed19710929 Reactome Database ID Release 431989792 Reactome, http://www.reactome.org ReactomeREACT_117936 p-IFNGR1:pJAK1:IFNGR2:p-JAK2 Reactome DB_ID: 873826 Reactome Database ID Release 43873826 Reactome, http://www.reactome.org ReactomeREACT_26458 has a Stoichiometric coefficient of 2 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ME1' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989821 Reactome, http://www.reactome.org ReactomeREACT_117976 p-IFNGR1:p-JAK1 Reactome DB_ID: 873805 Reactome Database ID Release 43873805 Reactome, http://www.reactome.org ReactomeREACT_26783 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of GLIPR1' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989810 Reactome, http://www.reactome.org ReactomeREACT_117941 IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2:SOCS-1/-3 Reactome DB_ID: 873821 Reactome Database ID Release 43873821 Reactome, http://www.reactome.org ReactomeREACT_26775 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of GRHL1' ACTIVATION Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989826 Reactome, http://www.reactome.org ReactomeREACT_118004 IFNG:p-IFNGR1:p-JAK1:IFNGR2:p-JAK2 Reactome DB_ID: 873814 Reactome Database ID Release 43873814 Reactome, http://www.reactome.org ReactomeREACT_25650 has a Stoichiometric coefficient of 1 C4S-PG Converted from EntitySet in Reactome Reactome DB_ID: 2065134 Reactome Database ID Release 432065134 Reactome, http://www.reactome.org ReactomeREACT_122214 chondroitin 4-sulfate proteoglycans 'ROR-alpha:Coactivator [nucleoplasm]' positively regulates 'Expression of NPAS2' ACTIVATION As inferred from mouse, ROR-alpha binds the promoter of the NPAS2 gene and enhances transcription. Pubmed20817722 Reactome Database ID Release 431368165 Reactome, http://www.reactome.org ReactomeREACT_117942 RNA Pol II with phosphorylated CTD: CE complex Reactome DB_ID: 77053 Reactome Database ID Release 4377053 Reactome, http://www.reactome.org ReactomeREACT_2371 has a Stoichiometric coefficient of 1 RNA Pol II with phosphorylated CTD: CE complex with activated GT Reactome DB_ID: 77056 Reactome Database ID Release 4377056 Reactome, http://www.reactome.org ReactomeREACT_3171 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of FABP1' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989803 Reactome, http://www.reactome.org ReactomeREACT_117999 p-STAT1 homodimer IFNG-activated factor (GAF) Reactome DB_ID: 873824 Reactome Database ID Release 43873824 Reactome, http://www.reactome.org ReactomeREACT_26144 has a Stoichiometric coefficient of 2 GAF bound to GAS promoter element Reactome DB_ID: 1031710 Reactome Database ID Release 431031710 Reactome, http://www.reactome.org ReactomeREACT_25470 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of FHL2' ACTIVATION Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989797 Reactome, http://www.reactome.org ReactomeREACT_117959 p-STAT1 dimer bound to p-IFNGR1 Reactome DB_ID: 909556 Reactome Database ID Release 43909556 Reactome, http://www.reactome.org ReactomeREACT_25936 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of G0S2' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989807 Reactome, http://www.reactome.org ReactomeREACT_118002 p-STAT1:p-STAT1 dimer IFNG-activated factor (GAF) Reactome DB_ID: 873827 Reactome Database ID Release 43873827 Reactome, http://www.reactome.org ReactomeREACT_26637 has a Stoichiometric coefficient of 2 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of FADS1' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989811 Reactome, http://www.reactome.org ReactomeREACT_117985 STAT1 bound to p-IFNGR1 Reactome DB_ID: 873828 Reactome Database ID Release 43873828 Reactome, http://www.reactome.org ReactomeREACT_26587 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of FATP1 (SLC27A1)' ACTIVATION Pubmed12118000 Pubmed9353271 Reactome Database ID Release 431989799 Reactome, http://www.reactome.org ReactomeREACT_117957 p-STAT1(Y701) bound to p-IFNGR1 Reactome DB_ID: 873817 Reactome Database ID Release 43873817 Reactome, http://www.reactome.org ReactomeREACT_26108 has a Stoichiometric coefficient of 1 ABLIM Converted from EntitySet in Reactome Reactome DB_ID: 418808 Reactome Database ID Release 43418808 Reactome, http://www.reactome.org ReactomeREACT_22492 Rho GEFs DOCK and Trio Converted from EntitySet in Reactome Reactome DB_ID: 418807 Reactome Database ID Release 43418807 Reactome, http://www.reactome.org ReactomeREACT_22958 CstF Cleavage Stimulation Factor Reactome DB_ID: 72006 Reactome Database ID Release 4372006 Reactome, http://www.reactome.org ReactomeREACT_3503 has a Stoichiometric coefficient of 1 UNC-5 receptors Converted from EntitySet in Reactome Reactome DB_ID: 373650 Reactome Database ID Release 43373650 Reactome, http://www.reactome.org ReactomeREACT_22907 CF II Reactome DB_ID: 72020 Reactome Database ID Release 4372020 Reactome, http://www.reactome.org ReactomeREACT_3772 has a Stoichiometric coefficient of 1 Cleavage and Polyadenylation Complex Reactome DB_ID: 72021 Reactome Database ID Release 4372021 Reactome, http://www.reactome.org ReactomeREACT_3144 has a Stoichiometric coefficient of 1 Spliceosomal Intermediate C Complex Reactome DB_ID: 72074 Reactome Database ID Release 4372074 Reactome, http://www.reactome.org ReactomeREACT_5473 has a Stoichiometric coefficient of 1 hnRNP proteins Reactome DB_ID: 188950 Reactome Database ID Release 43188950 Reactome, http://www.reactome.org ReactomeREACT_9269 has a Stoichiometric coefficient of 1 Spliceosomal Active C Complex Reactome DB_ID: 72022 Reactome Database ID Release 4372022 Reactome, http://www.reactome.org ReactomeREACT_2680 has a Stoichiometric coefficient of 1 Spliceosomal active C complex with lariat containing, 5'-end cleaved pre-mRNP:CBC complex Reactome DB_ID: 77505 Reactome Database ID Release 4377505 Reactome, http://www.reactome.org ReactomeREACT_5191 has a Stoichiometric coefficient of 1 lariat containing 5'-end cleaved mRNA:CBC complex Reactome DB_ID: 77474 Reactome Database ID Release 4377474 Reactome, http://www.reactome.org ReactomeREACT_4898 has a Stoichiometric coefficient of 1 pre-EJC complex Reactome DB_ID: 159631 Reactome Database ID Release 43159631 Reactome, http://www.reactome.org ReactomeREACT_4882 has a Stoichiometric coefficient of 1 Magoh-Y14 complex Reactome DB_ID: 156657 Reactome Database ID Release 43156657 Reactome, http://www.reactome.org ReactomeREACT_5524 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CYP4A11' ACTIVATION Pubmed12505311 Pubmed19710929 Reactome Database ID Release 431989801 Reactome, http://www.reactome.org ReactomeREACT_117965 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CYP7A1' ACTIVATION Pubmed10777541 Reactome Database ID Release 431989813 Reactome, http://www.reactome.org ReactomeREACT_118040 D2,4,4(S)3-PGs Converted from EntitySet in Reactome Dermatan sulfate proteoglycans Reactome DB_ID: 2065132 Reactome Database ID Release 432065132 Reactome, http://www.reactome.org ReactomeREACT_122418 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CPT1A' ACTIVATION Pubmed12505311 Pubmed19710929 Reactome Database ID Release 431989798 Reactome, http://www.reactome.org ReactomeREACT_117960 'ROR-alpha:Coactivator [nucleoplasm]' positively regulates 'Expression of CPT1A' ACTIVATION As inferred from mouse, ROR-alpha binds the promoter of the CPT1A gene and, together with coactivators EP300 and PGC-1alpha, enhances transcription. Pubmed15199055 Reactome Database ID Release 431801583 Reactome, http://www.reactome.org ReactomeREACT_117962 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CPT2' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989793 Reactome, http://www.reactome.org ReactomeREACT_117950 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CYP1A1' ACTIVATION Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989817 Reactome, http://www.reactome.org ReactomeREACT_117931 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of APOA2' ACTIVATION Pubmed17604218 Pubmed19710929 Reactome Database ID Release 431989786 Reactome, http://www.reactome.org ReactomeREACT_118055 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of APOA5' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989791 Reactome, http://www.reactome.org ReactomeREACT_117967 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CD36 (platelet glycoprotein IV, FAT)' ACTIVATION Pubmed17084382 Pubmed20110263 Reactome Database ID Release 431989789 Reactome, http://www.reactome.org ReactomeREACT_118045 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CD36 (platelet glycoprotein IV, FAT)' ACTIVATION Pubmed16380219 Pubmed18981473 Reactome Database ID Release 43560540 Reactome, http://www.reactome.org ReactomeREACT_27983 The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the Platelet glycoprotein IV (CD36, PAS IV, GPIV) gene. In mouse the Pparg:Rxra heterodimer binds the promoter of the Platelet glycoprotein IV gene (Lefterova et al. 2008). Src/Fyn Converted from EntitySet in Reactome Reactome DB_ID: 418805 Reactome Database ID Release 43418805 Reactome, http://www.reactome.org ReactomeREACT_22877 Spliceosomal A Complex Reactome DB_ID: 72068 Reactome Database ID Release 4372068 Reactome, http://www.reactome.org ReactomeREACT_4512 has a Stoichiometric coefficient of 1 U4:U5:U6 trisnRNP complex Reactome DB_ID: 77506 Reactome Database ID Release 4377506 Reactome, http://www.reactome.org ReactomeREACT_5066 has a Stoichiometric coefficient of 1 T-type VDCC Converted from EntitySet in Reactome Reactome DB_ID: 525821 Reactome Database ID Release 43525821 Reactome, http://www.reactome.org ReactomeREACT_21473 SF3A Reactome DB_ID: 71967 Reactome Database ID Release 4371967 Reactome, http://www.reactome.org ReactomeREACT_5131 has a Stoichiometric coefficient of 1 U6 snRNP Reactome DB_ID: 71982 Reactome Database ID Release 4371982 Reactome, http://www.reactome.org ReactomeREACT_4620 has a Stoichiometric coefficient of 1 U4 snRNP Reactome DB_ID: 71891 Reactome Database ID Release 4371891 Reactome, http://www.reactome.org ReactomeREACT_4877 has a Stoichiometric coefficient of 1 D2,4,4(S)3-PGs Converted from EntitySet in Reactome Dermatan sulfate proteoglycans Reactome DB_ID: 2065087 Reactome Database ID Release 432065087 Reactome, http://www.reactome.org ReactomeREACT_124493 U5 snRNP Reactome DB_ID: 71981 Reactome Database ID Release 4371981 Reactome, http://www.reactome.org ReactomeREACT_2482 has a Stoichiometric coefficient of 1 U4 snRNP:U6 snRNP complex Reactome DB_ID: 71983 Reactome Database ID Release 4371983 Reactome, http://www.reactome.org ReactomeREACT_5672 has a Stoichiometric coefficient of 1 CF I Reactome DB_ID: 72015 Reactome Database ID Release 4372015 Reactome, http://www.reactome.org ReactomeREACT_4896 has a Stoichiometric coefficient of 1 Spliceosomal B Complex Reactome DB_ID: 72069 Reactome Database ID Release 4372069 Reactome, http://www.reactome.org ReactomeREACT_3078 has a Stoichiometric coefficient of 1 CPSF Cleavage and polyadenylation specificity factor Reactome DB_ID: 71995 Reactome Database ID Release 4371995 Reactome, http://www.reactome.org ReactomeREACT_4530 has a Stoichiometric coefficient of 1 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of APOA1' ACTIVATION Pubmed17604218 Pubmed9748239 Reactome Database ID Release 431989818 Reactome, http://www.reactome.org ReactomeREACT_118021 'PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ANGPTL4' ACTIVATION Pubmed19934321 Reactome Database ID Release 43560539 Reactome, http://www.reactome.org ReactomeREACT_28024 The PPARG:RXRA heterodimer bound to fatty acids activates transcription of the ANGPTL4 gene. The PPARG:RXRA heterodimer binds the promoter of the ANGPTL4 gene. 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ANKRD1' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989812 Reactome, http://www.reactome.org ReactomeREACT_118036 D2,4(S)2-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2065226 Reactome Database ID Release 432065226 Reactome, http://www.reactome.org ReactomeREACT_122798 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of AGT' ACTIVATION Pubmed15067378 Reactome Database ID Release 431989825 Reactome, http://www.reactome.org ReactomeREACT_117956 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ANGPTL4' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989823 Reactome, http://www.reactome.org ReactomeREACT_117920 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ACSL1' ACTIVATION Pubmed16428347 Pubmed19710929 Pubmed9353271 Reactome Database ID Release 431989815 Reactome, http://www.reactome.org ReactomeREACT_117955 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ACSL1' ACTIVATION Pubmed19710929 Pubmed9353271 Reactome Database ID Release 431989787 Reactome, http://www.reactome.org ReactomeREACT_117969 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ACADM' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989794 Reactome, http://www.reactome.org ReactomeREACT_118052 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ACOX1' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989796 Reactome, http://www.reactome.org ReactomeREACT_117979 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ABCB4' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989788 Reactome, http://www.reactome.org ReactomeREACT_117947 L-type VDCC Converted from EntitySet in Reactome Reactome DB_ID: 525825 Reactome Database ID Release 43525825 Reactome, http://www.reactome.org ReactomeREACT_21787 alpha 2-8 polysialyltransferases Converted from EntitySet in Reactome Reactome DB_ID: 422438 Reactome Database ID Release 43422438 Reactome, http://www.reactome.org ReactomeREACT_18945 thymidine, (deoxy)uridine Converted from EntitySet in Reactome Reactome DB_ID: 500415 Reactome Database ID Release 43500415 Reactome, http://www.reactome.org ReactomeREACT_21581 thymidine monophosphate, uridine 2', 3', 5' monophosphates, deoxyuridine 3', 5' monophosphate Converted from EntitySet in Reactome Reactome DB_ID: 500414 Reactome Database ID Release 43500414 Reactome, http://www.reactome.org ReactomeREACT_21840 (deoxy)cytidine, thymidine, (deoxy)uridine Converted from EntitySet in Reactome Reactome DB_ID: 500346 Reactome Database ID Release 43500346 Reactome, http://www.reactome.org ReactomeREACT_21909 D2,4,4(S)3-PGs Converted from EntitySet in Reactome Dermatan sulfate proteoglycans Reactome DB_ID: 2065138 Reactome Database ID Release 432065138 Reactome, http://www.reactome.org ReactomeREACT_124659 GDNF family ligands (GFLs) Converted from EntitySet in Reactome Reactome DB_ID: 434920 Reactome Database ID Release 43434920 Reactome, http://www.reactome.org ReactomeREACT_20000 GFRalpha Converted from EntitySet in Reactome Reactome DB_ID: 434924 Reactome Database ID Release 43434924 Reactome, http://www.reactome.org ReactomeREACT_19467 D4S-PGs Converted from EntitySet in Reactome Dermatan 4-sulfate proteoglycans Reactome DB_ID: 2065207 Reactome Database ID Release 432065207 Reactome, http://www.reactome.org ReactomeREACT_123502 Covalent CE:GMP intermediate complex Reactome DB_ID: 111343 Reactome Database ID Release 43111343 Reactome, http://www.reactome.org ReactomeREACT_2774 has a Stoichiometric coefficient of 1 Capping complex (intermediate) Reactome DB_ID: 77065 Reactome Database ID Release 4377065 Reactome, http://www.reactome.org ReactomeREACT_3580 has a Stoichiometric coefficient of 1 Capping complex (with freed 5'- GMP) Reactome DB_ID: 77067 Reactome Database ID Release 4377067 Reactome, http://www.reactome.org ReactomeREACT_4741 has a Stoichiometric coefficient of 1 Capping complex (GpppN..) Reactome DB_ID: 77066 Reactome Database ID Release 4377066 Reactome, http://www.reactome.org ReactomeREACT_2312 has a Stoichiometric coefficient of 1 RNA Polymerase II (phosphorylated):TFIIF:capped pre-mRNA Reactome DB_ID: 113405 Reactome Database ID Release 43113405 Reactome, http://www.reactome.org ReactomeREACT_3935 has a Stoichiometric coefficient of 1 mRNA capping factors Reactome DB_ID: 113403 Reactome Database ID Release 43113403 Reactome, http://www.reactome.org ReactomeREACT_4925 has a Stoichiometric coefficient of 1 capped pre-mRNA:CBC:RNA Pol II (phosphorylated) complex Reactome DB_ID: 77089 Reactome Database ID Release 4377089 Reactome, http://www.reactome.org ReactomeREACT_3243 has a Stoichiometric coefficient of 1 Cap Binding Complex (CBC) Reactome DB_ID: 77088 Reactome Database ID Release 4377088 Reactome, http://www.reactome.org ReactomeREACT_3884 has a Stoichiometric coefficient of 1 Plexin-A (2 and 4) Converted from EntitySet in Reactome Reactome DB_ID: 416718 Reactome Database ID Release 43416718 Reactome, http://www.reactome.org ReactomeREACT_20091 C6S-PG Converted from EntitySet in Reactome Reactome DB_ID: 2065083 Reactome Database ID Release 432065083 Reactome, http://www.reactome.org ReactomeREACT_121851 chondroitin 6-sulfate proteoglycans D2,4(S)2-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2065202 Reactome Database ID Release 432065202 Reactome, http://www.reactome.org ReactomeREACT_122425 Fes phosphorylated CRMP's 1-5 Converted from EntitySet in Reactome Reactome DB_ID: 399829 Reactome Database ID Release 43399829 Reactome, http://www.reactome.org ReactomeREACT_20192 CSE-PG C4,6(S)2-PG Converted from EntitySet in Reactome Reactome DB_ID: 2065112 Reactome Database ID Release 432065112 Reactome, http://www.reactome.org ReactomeREACT_124482 chondroitin 4,6-disulfate proteoglycans chondroitin E proteoglycans PathwayStep1221 PathwayStep1220 ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431225930 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431225927 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 431225931 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431248647 Reactome, http://www.reactome.org HLA-E:CD94:NKG2C:DAP12 Reactome DB_ID: 2326822 Reactome Database ID Release 432326822 Reactome, http://www.reactome.org ReactomeREACT_148264 has a Stoichiometric coefficient of 1 NKG2D dimer Reactome DB_ID: 210233 Reactome Database ID Release 43210233 Reactome, http://www.reactome.org ReactomeREACT_148030 has a Stoichiometric coefficient of 2 CD94:NKG2C:HLA-E Reactome DB_ID: 2326867 Reactome Database ID Release 432326867 Reactome, http://www.reactome.org ReactomeREACT_148009 has a Stoichiometric coefficient of 1 CD94:NKG2C Reactome DB_ID: 2326783 Reactome Database ID Release 432326783 Reactome, http://www.reactome.org ReactomeREACT_148046 has a Stoichiometric coefficient of 1 DAP12 dimer:MDL-1 Reactome DB_ID: 210234 Reactome Database ID Release 43210234 Reactome, http://www.reactome.org ReactomeREACT_148533 has a Stoichiometric coefficient of 1 HLA-Bw4:KIR3DS1:DAP12 dimer:KIR3DS1:HLA-Bw4 Reactome DB_ID: 2272705 Reactome Database ID Release 432272705 Reactome, http://www.reactome.org ReactomeREACT_147965 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 (d)NDP (deoxy)nucleotide diphosphates Converted from EntitySet in Reactome Reactome DB_ID: 482803 Reactome Database ID Release 43482803 Reactome, http://www.reactome.org ReactomeREACT_21808 Cdk5 phosphorylated CRMP's 1-5 Converted from EntitySet in Reactome Reactome DB_ID: 399827 Reactome Database ID Release 43399827 Reactome, http://www.reactome.org ReactomeREACT_20320 KIR3DS1:HLA-Bw4 Reactome DB_ID: 2272751 Reactome Database ID Release 432272751 Reactome, http://www.reactome.org ReactomeREACT_148492 has a Stoichiometric coefficient of 1 PathwayStep1219 KIR2DS5:DAP12 dimer:KIR2DS5 Reactome DB_ID: 2272749 Reactome Database ID Release 432272749 Reactome, http://www.reactome.org ReactomeREACT_148570 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 HLA-C Cw4/Cw3:KIR2DS4:DAP12 dimer:KIR2DS4:HLA-C Cw3/Cw4 Reactome DB_ID: 2272757 Reactome Database ID Release 432272757 Reactome, http://www.reactome.org ReactomeREACT_148211 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 (d)NTP (deoxy)nucleotide triphosphates Converted from EntitySet in Reactome Reactome DB_ID: 482625 Reactome Database ID Release 43482625 Reactome, http://www.reactome.org ReactomeREACT_21786 HLA-C Cw3/HLA-C Cw4 Converted from EntitySet in Reactome Reactome DB_ID: 2272698 Reactome Database ID Release 432272698 Reactome, http://www.reactome.org ReactomeREACT_148591 KIR2DS4:HLA-C Cw4/HLA-C Cw3 Reactome DB_ID: 2272706 Reactome Database ID Release 432272706 Reactome, http://www.reactome.org ReactomeREACT_148272 has a Stoichiometric coefficient of 1 PathwayStep1215 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431225932 Reactome, http://www.reactome.org (d)NDP (deoxy)nucleotide diphosphates Converted from EntitySet in Reactome Reactome DB_ID: 482627 Reactome Database ID Release 43482627 Reactome, http://www.reactome.org ReactomeREACT_21492 GSK3beta phosphorylated CRMP's 1-5 Converted from EntitySet in Reactome Reactome DB_ID: 399832 Reactome Database ID Release 43399832 Reactome, http://www.reactome.org ReactomeREACT_19941 PathwayStep1216 ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431225929 Reactome, http://www.reactome.org PathwayStep1217 ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 431226011 Reactome, http://www.reactome.org PathwayStep1218 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431247843 Reactome, http://www.reactome.org PathwayStep1211 PathwayStep1212 PathwayStep1213 ACTIVATION GENE ONTOLOGYGO:0015036 Reactome Database ID Release 43265095 Reactome, http://www.reactome.org PathwayStep1214 ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43265064 Reactome, http://www.reactome.org PathwayStep1232 PathwayStep1231 PathwayStep1230 KIR2DS1 oligomer:HLA-C (Cw4) Reactome DB_ID: 2272773 Reactome Database ID Release 432272773 Reactome, http://www.reactome.org ReactomeREACT_148177 has a Stoichiometric coefficient of 1 DAP12:KIR2DS1:HLA-Cw4 Reactome DB_ID: 2272727 Reactome Database ID Release 432272727 Reactome, http://www.reactome.org ReactomeREACT_148039 has a Stoichiometric coefficient of 1 KIR2DS2:HLA-C1 (Cw3) Reactome DB_ID: 2272718 Reactome Database ID Release 432272718 Reactome, http://www.reactome.org ReactomeREACT_148175 has a Stoichiometric coefficient of 1 HLA-C1:KIR2DS2:DAP12 dimer:KIR2DS2:HLA-C1 Reactome DB_ID: 210244 Reactome Database ID Release 43210244 Reactome, http://www.reactome.org ReactomeREACT_148637 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 dADP, dGDP, dCDP, dUDP Converted from EntitySet in Reactome Reactome DB_ID: 499939 Reactome Database ID Release 43499939 Reactome, http://www.reactome.org ReactomeREACT_21608 STING:p-S172-TBK1:IRF3 Reactome DB_ID: 2396004 Reactome Database ID Release 432396004 Reactome, http://www.reactome.org ReactomeREACT_148605 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 STING:TBK1:IRF3 Reactome DB_ID: 1834956 Reactome Database ID Release 431834956 Reactome, http://www.reactome.org ReactomeREACT_148249 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 HSP-90 Converted from EntitySet in Reactome Reactome DB_ID: 419619 Reactome Database ID Release 43419619 Reactome, http://www.reactome.org ReactomeREACT_19960 STING:p-S172-TBK1 Reactome DB_ID: 2396005 Reactome Database ID Release 432396005 Reactome, http://www.reactome.org ReactomeREACT_148607 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 dADP, dGDP, dCDP, dUDP Converted from EntitySet in Reactome Reactome DB_ID: 499933 Reactome Database ID Release 43499933 Reactome, http://www.reactome.org ReactomeREACT_21937 dsDNA:IFI16 Reactome DB_ID: 1834947 Reactome Database ID Release 431834947 Reactome, http://www.reactome.org ReactomeREACT_148075 has a Stoichiometric coefficient of 1 ADP, GDP, CDP, UDP Converted from EntitySet in Reactome Reactome DB_ID: 499944 Reactome Database ID Release 43499944 Reactome, http://www.reactome.org ReactomeREACT_21992 viral dsRNA:TLR3:TRIF:RIP1 Reactome DB_ID: 177649 Reactome Database ID Release 43177649 Reactome, http://www.reactome.org ReactomeREACT_7715 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 STING:c-di-GMP Reactome DB_ID: 2395983 Reactome Database ID Release 432395983 Reactome, http://www.reactome.org ReactomeREACT_147998 has a Stoichiometric coefficient of 1 STING:STING Reactome DB_ID: 2395989 Reactome Database ID Release 432395989 Reactome, http://www.reactome.org ReactomeREACT_148482 has a Stoichiometric coefficient of 2 PathwayStep1228 PathwayStep1229 PathwayStep1226 ADP, GDP, CDP, UDP Converted from EntitySet in Reactome Reactome DB_ID: 499930 Reactome Database ID Release 43499930 Reactome, http://www.reactome.org ReactomeREACT_22084 PathwayStep1227 CRMP's 1-5 Converted from EntitySet in Reactome Reactome DB_ID: 399825 Reactome Database ID Release 43399825 Reactome, http://www.reactome.org ReactomeREACT_20445 PathwayStep1224 PathwayStep1225 PathwayStep1222 PathwayStep1223 ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43381428 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43381458 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43381179 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004521 Reactome Database ID Release 43381180 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43381048 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 43381068 Reactome, http://www.reactome.org CS/DS core proteins Converted from EntitySet in Reactome Reactome DB_ID: 2065248 Reactome Database ID Release 432065248 Reactome, http://www.reactome.org ReactomeREACT_124137 p-5Y-LAT:PLCG1:GADS:p-Y113,Y128,Y145-SLP-76 Reactome DB_ID: 2424460 Reactome Database ID Release 432424460 Reactome, http://www.reactome.org ReactomeREACT_147980 has a Stoichiometric coefficient of 1 GADS:p-Y113,Y128,Y145-SLP-76 Reactome DB_ID: 2424466 Reactome Database ID Release 432424466 Reactome, http://www.reactome.org ReactomeREACT_148093 has a Stoichiometric coefficient of 1 (d)ADP, (d)CDP ADP, dADP, CDP, dCDP Converted from EntitySet in Reactome Reactome DB_ID: 500060 Reactome Database ID Release 43500060 Reactome, http://www.reactome.org ReactomeREACT_21795 (d)AMP, (d)CMP AMP, dAMP, CMP, dCMP Converted from EntitySet in Reactome Reactome DB_ID: 500062 Reactome Database ID Release 43500062 Reactome, http://www.reactome.org ReactomeREACT_21705 p-5Y-LAT:GRB2:SOS1 Reactome DB_ID: 2424468 Reactome Database ID Release 432424468 Reactome, http://www.reactome.org ReactomeREACT_148348 has a Stoichiometric coefficient of 1 p-5Y-LAT:p-3Y-PLCG1:GADS:p-3Y-SLP-76:p-2Y-BTK:VAV Reactome DB_ID: 2424467 Reactome Database ID Release 432424467 Reactome, http://www.reactome.org ReactomeREACT_148036 has a Stoichiometric coefficient of 1 p-SYK/p-BTK Converted from EntitySet in Reactome Reactome DB_ID: 2424473 Reactome Database ID Release 432424473 Reactome, http://www.reactome.org ReactomeREACT_148438 p-5Y-LAT:PLCG1:GADS:p-3Y-SLP-76:BTK:VAV Reactome DB_ID: 2424461 Reactome Database ID Release 432424461 Reactome, http://www.reactome.org ReactomeREACT_148541 has a Stoichiometric coefficient of 1 p-5Y-LAT:PLCG1:GADS:p-3Y-SLP-76:p-2Y-BTK:VAV Reactome DB_ID: 2424457 Reactome Database ID Release 432424457 Reactome, http://www.reactome.org ReactomeREACT_148538 has a Stoichiometric coefficient of 1 (d)GDP Converted from EntitySet in Reactome Reactome DB_ID: 500077 Reactome Database ID Release 43500077 Reactome, http://www.reactome.org ReactomeREACT_22011 p-5Y-LAT:PLCG1:GADS:SLP76 Reactome DB_ID: 2424464 Reactome Database ID Release 432424464 Reactome, http://www.reactome.org ReactomeREACT_148283 has a Stoichiometric coefficient of 1 GADS:SLP76 Reactome DB_ID: 2424463 Reactome Database ID Release 432424463 Reactome, http://www.reactome.org ReactomeREACT_147999 has a Stoichiometric coefficient of 1 p-5Y-LAT:PLCG1 Reactome DB_ID: 2396571 Reactome Database ID Release 432396571 Reactome, http://www.reactome.org ReactomeREACT_148415 has a Stoichiometric coefficient of 1 (d)GMP Converted from EntitySet in Reactome Reactome DB_ID: 500071 Reactome Database ID Release 43500071 Reactome, http://www.reactome.org ReactomeREACT_21986 DAP12 Receptors:p-DAP12:p-6Y-SYK:PI3K Reactome DB_ID: 2424456 Reactome Database ID Release 432424456 Reactome, http://www.reactome.org ReactomeREACT_148439 has a Stoichiometric coefficient of 1 dUMP, TMP Converted from EntitySet in Reactome Reactome DB_ID: 499997 Reactome Database ID Release 43499997 Reactome, http://www.reactome.org ReactomeREACT_21666 dUDP, TDP Converted from EntitySet in Reactome Reactome DB_ID: 499999 Reactome Database ID Release 43499999 Reactome, http://www.reactome.org ReactomeREACT_21449 (d)CMP, UMP Converted from EntitySet in Reactome Reactome DB_ID: 500009 Reactome Database ID Release 43500009 Reactome, http://www.reactome.org ReactomeREACT_21486 (d)CDP, UDP Converted from EntitySet in Reactome Reactome DB_ID: 500006 Reactome Database ID Release 43500006 Reactome, http://www.reactome.org ReactomeREACT_21784 Phosphorylated Plexin-A Converted from EntitySet in Reactome Reactome DB_ID: 419620 Reactome Database ID Release 43419620 Reactome, http://www.reactome.org ReactomeREACT_20115 PAK Converted from EntitySet in Reactome Reactome DB_ID: 390765 Reactome Database ID Release 43390765 Reactome, http://www.reactome.org ReactomeREACT_19640 Phosphorylated PAK Converted from EntitySet in Reactome Reactome DB_ID: 399836 Reactome Database ID Release 43399836 Reactome, http://www.reactome.org ReactomeREACT_19490 ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43381524 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43381433 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43381417 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43381434 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265205 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43264894 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004181 Reactome Database ID Release 43265196 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265209 Reactome, http://www.reactome.org PathwayStep1210 ACTIVATION GENE ONTOLOGYGO:0005385 Reactome Database ID Release 43264972 Reactome, http://www.reactome.org CLM7:DAP12 Reactome DB_ID: 2426564 Reactome Database ID Release 432426564 Reactome, http://www.reactome.org ReactomeREACT_147946 has a Stoichiometric coefficient of 1 DAP12 receptors:DAP12 dimer Reactome DB_ID: 2395430 Reactome Database ID Release 432395430 Reactome, http://www.reactome.org ReactomeREACT_147923 has a Stoichiometric coefficient of 1 DAP12 receptors:p-Y91,Y102-DAP12 dimer Reactome DB_ID: 2395423 Reactome Database ID Release 432395423 Reactome, http://www.reactome.org ReactomeREACT_148548 has a Stoichiometric coefficient of 1 p-Y91,Y102-DAP12 dimer Reactome DB_ID: 2395437 Reactome Database ID Release 432395437 Reactome, http://www.reactome.org ReactomeREACT_148214 has a Stoichiometric coefficient of 2 DAP12 receptors:p-DAP12:SYK Reactome DB_ID: 210250 Reactome Database ID Release 43210250 Reactome, http://www.reactome.org ReactomeREACT_148179 has a Stoichiometric coefficient of 1 DAP12 Receptors:p-DAP12:p-6Y-SYK Reactome DB_ID: 2395411 Reactome Database ID Release 432395411 Reactome, http://www.reactome.org ReactomeREACT_148137 has a Stoichiometric coefficient of 1 DAP12:NKp44 Reactome DB_ID: 210241 Reactome Database ID Release 43210241 Reactome, http://www.reactome.org ReactomeREACT_148302 has a Stoichiometric coefficient of 1 DAP12:NKG2D Reactome DB_ID: 210232 Reactome Database ID Release 43210232 Reactome, http://www.reactome.org ReactomeREACT_148626 has a Stoichiometric coefficient of 1 PathwayStep1208 SIGLEC14/15/16:DAP12 dimer Reactome DB_ID: 2326835 Reactome Database ID Release 432326835 Reactome, http://www.reactome.org ReactomeREACT_148587 has a Stoichiometric coefficient of 1 PathwayStep1209 DAP12 dimer:TRIM1 Reactome DB_ID: 210248 Reactome Database ID Release 43210248 Reactome, http://www.reactome.org ReactomeREACT_148539 has a Stoichiometric coefficient of 1 IREM2:DAP12 Reactome DB_ID: 2426557 Reactome Database ID Release 432426557 Reactome, http://www.reactome.org ReactomeREACT_148241 has a Stoichiometric coefficient of 1 (d)ADP Converted from EntitySet in Reactome Reactome DB_ID: 500087 Reactome Database ID Release 43500087 Reactome, http://www.reactome.org ReactomeREACT_21649 Plexin-A (1-4) Converted from EntitySet in Reactome Reactome DB_ID: 399833 Reactome Database ID Release 43399833 Reactome, http://www.reactome.org ReactomeREACT_19575 PathwayStep1202 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43380995 Reactome, http://www.reactome.org PathwayStep1203 PathwayStep1200 PathwayStep1201 PathwayStep1206 ACTIVATION GENE ONTOLOGYGO:0003777 Reactome Database ID Release 43265176 Reactome, http://www.reactome.org PathwayStep1207 ACTIVATION GENE ONTOLOGYGO:0000146 Reactome Database ID Release 43265192 Reactome, http://www.reactome.org PathwayStep1204 ACTIVATION GENE ONTOLOGYGO:0005515 Reactome Database ID Release 43265183 Reactome, http://www.reactome.org PathwayStep1205 ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43387385 Reactome, http://www.reactome.org ISGF3 alpha Reactome DB_ID: 909693 Reactome Database ID Release 43909693 Reactome, http://www.reactome.org ReactomeREACT_25471 has a Stoichiometric coefficient of 1 p-STAT2:p-STAT1 ISGF3 Interferon-stimulated gene factor 3 Reactome DB_ID: 913527 Reactome Database ID Release 43913527 Reactome, http://www.reactome.org ReactomeREACT_25406 has a Stoichiometric coefficient of 1 p-STAT2:p-STAT1:IRF9 ISGF3 Interferon-stimulated gene factor 3 Reactome DB_ID: 909698 Reactome Database ID Release 43909698 Reactome, http://www.reactome.org ReactomeREACT_25831 has a Stoichiometric coefficient of 1 p-STAT2:p-STAT1:IRF9 p-STAT2:p-STAT1 Reactome DB_ID: 909702 Reactome Database ID Release 43909702 Reactome, http://www.reactome.org ReactomeREACT_27063 STAT2:1 hetero dimer has a Stoichiometric coefficient of 1 p-STAT2:p-STAT1:p-IFNAR1:p-TYK2 Reactome DB_ID: 909712 Reactome Database ID Release 43909712 Reactome, http://www.reactome.org ReactomeREACT_25563 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:p-JAK1:STAT2:p-IFNAR1:p-TYK2:p-STAT2:p-STAT1 Reactome DB_ID: 909711 Reactome Database ID Release 43909711 Reactome, http://www.reactome.org ReactomeREACT_26770 has a Stoichiometric coefficient of 1 p-STAT2:p-IFNAR1:p-TYK2 Reactome DB_ID: 909709 Reactome Database ID Release 43909709 Reactome, http://www.reactome.org ReactomeREACT_26779 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:p-JAK1:STAT2:p-IFNAR1:p-TYK2:p-STAT2 Reactome DB_ID: 909697 Reactome Database ID Release 43909697 Reactome, http://www.reactome.org ReactomeREACT_26908 has a Stoichiometric coefficient of 1 PathwayStep1262 STAT2:p-IFNAR1:p-TYK2 Reactome DB_ID: 909701 Reactome Database ID Release 43909701 Reactome, http://www.reactome.org ReactomeREACT_26919 has a Stoichiometric coefficient of 1 PathwayStep1263 PathwayStep1264 PathwayStep1265 PathwayStep1260 PathwayStep1261 PathwayStep1259 PathwayStep1256 Export Receptor bound mature mRNA Complex Reactome DB_ID: 113815 Reactome Database ID Release 43113815 Reactome, http://www.reactome.org ReactomeREACT_2624 has a Stoichiometric coefficient of 1 PathwayStep1255 TAP:3'-polyadenylated, capped mRNA complex Reactome DB_ID: 159100 Reactome Database ID Release 43159100 Reactome, http://www.reactome.org ReactomeREACT_4136 has a Stoichiometric coefficient of 1 PathwayStep1258 3'-polyadenylated, capped mRNA complex Reactome DB_ID: 156769 Reactome Database ID Release 43156769 Reactome, http://www.reactome.org ReactomeREACT_5827 has a Stoichiometric coefficient of 1 PathwayStep1257 mRNA 3'-end cleavage factor Reactome DB_ID: 72075 Reactome Database ID Release 4372075 Reactome, http://www.reactome.org ReactomeREACT_2642 has a Stoichiometric coefficient of 1 3' end cleaved, ligated exon containing complex Reactome DB_ID: 72177 Reactome Database ID Release 4372177 Reactome, http://www.reactome.org ReactomeREACT_3092 has a Stoichiometric coefficient of 1 post exon ligation complex Reactome DB_ID: 156556 Reactome Database ID Release 43156556 Reactome, http://www.reactome.org ReactomeREACT_5793 has a Stoichiometric coefficient of 1 ATAC C Complex with lariat containing 5'-end cleaved mRNA Reactome DB_ID: 77475 Reactome Database ID Release 4377475 Reactome, http://www.reactome.org ReactomeREACT_5134 has a Stoichiometric coefficient of 1 ATAC C Complex Reactome DB_ID: 77473 Reactome Database ID Release 4377473 Reactome, http://www.reactome.org ReactomeREACT_4626 has a Stoichiometric coefficient of 1 ATAC B Complex Reactome DB_ID: 77470 Reactome Database ID Release 4377470 Reactome, http://www.reactome.org ReactomeREACT_5095 has a Stoichiometric coefficient of 1 U6 ATAC snRNP Reactome DB_ID: 77467 Reactome Database ID Release 4377467 Reactome, http://www.reactome.org ReactomeREACT_3135 has a Stoichiometric coefficient of 1 p-IFNAR1:p-TYK2 Reactome DB_ID: 909694 Reactome Database ID Release 43909694 Reactome, http://www.reactome.org ReactomeREACT_25412 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:p-JAK1:STAT2:p-IFNAR1:p-TYK2:STAT2 Reactome DB_ID: 909696 Reactome Database ID Release 43909696 Reactome, http://www.reactome.org ReactomeREACT_25990 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:p-JAK1:STAT2 Reactome DB_ID: 909692 Reactome Database ID Release 43909692 Reactome, http://www.reactome.org ReactomeREACT_26892 has a Stoichiometric coefficient of 1 IFNAR1:p-TYK2 Reactome DB_ID: 909707 Reactome Database ID Release 43909707 Reactome, http://www.reactome.org ReactomeREACT_25907 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:p-JAK1:STAT2:p-IFNAR1:p-TYK2 Reactome DB_ID: 909704 Reactome Database ID Release 43909704 Reactome, http://www.reactome.org ReactomeREACT_26083 has a Stoichiometric coefficient of 1 IFNAR2:p-JAK1:STAT2 Reactome DB_ID: 909715 Reactome Database ID Release 43909715 Reactome, http://www.reactome.org ReactomeREACT_26198 has a Stoichiometric coefficient of 1 IFNAR1:TYK2 Reactome DB_ID: 909708 Reactome Database ID Release 43909708 Reactome, http://www.reactome.org ReactomeREACT_25562 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:JAK1:STAT2 Reactome DB_ID: 918195 Reactome Database ID Release 43918195 Reactome, http://www.reactome.org ReactomeREACT_26015 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:p-JAK1:STAT2:IFNAR1:p-TYK2 Reactome DB_ID: 909705 Reactome Database ID Release 43909705 Reactome, http://www.reactome.org ReactomeREACT_26001 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:JAK1:STAT2:IFNAR1:TYK2 Reactome DB_ID: 909703 Reactome Database ID Release 43909703 Reactome, http://www.reactome.org ReactomeREACT_25725 has a Stoichiometric coefficient of 1 PathwayStep1275 PathwayStep1276 PathwayStep1273 PathwayStep1274 PathwayStep1271 PathwayStep1272 PathwayStep1270 U4 ATAC snRNP Reactome DB_ID: 77465 Reactome Database ID Release 4377465 Reactome, http://www.reactome.org ReactomeREACT_5266 has a Stoichiometric coefficient of 1 PathwayStep1269 ATAC A Complex Reactome DB_ID: 77463 Reactome Database ID Release 4377463 Reactome, http://www.reactome.org ReactomeREACT_4037 has a Stoichiometric coefficient of 1 PathwayStep1268 U12 snRNP Reactome DB_ID: 77472 Reactome Database ID Release 4377472 Reactome, http://www.reactome.org ReactomeREACT_3595 has a Stoichiometric coefficient of 1 PathwayStep1267 U4 ATAC snRNP:U6 ATAC snRNP Reactome DB_ID: 77468 Reactome Database ID Release 4377468 Reactome, http://www.reactome.org ReactomeREACT_5116 has a Stoichiometric coefficient of 1 PathwayStep1266 U4 ATAC:U5:U6 ATAC Complex Reactome DB_ID: 77469 Reactome Database ID Release 4377469 Reactome, http://www.reactome.org ReactomeREACT_4539 has a Stoichiometric coefficient of 1 EJC complex Reactome DB_ID: 159638 Reactome Database ID Release 43159638 Reactome, http://www.reactome.org ReactomeREACT_4104 has a Stoichiometric coefficient of 1 Ligated exon containing complex Reactome DB_ID: 72157 Reactome Database ID Release 4372157 Reactome, http://www.reactome.org ReactomeREACT_5472 has a Stoichiometric coefficient of 1 U11 snRNP Reactome DB_ID: 77462 Reactome Database ID Release 4377462 Reactome, http://www.reactome.org ReactomeREACT_5751 has a Stoichiometric coefficient of 1 intron-containing complex Reactome DB_ID: 72159 Reactome Database ID Release 4372159 Reactome, http://www.reactome.org ReactomeREACT_3239 has a Stoichiometric coefficient of 1 p-5Y-LAT:GADS:p-3Y-SLP-76:p-2Y-BTK:VAV Reactome DB_ID: 2424459 Reactome Database ID Release 432424459 Reactome, http://www.reactome.org ReactomeREACT_148222 has a Stoichiometric coefficient of 1 p-5Y-LAT:PLCG1:GADS:p-3Y-SLP-76:BTK:p-VAV Reactome DB_ID: 2424469 Reactome Database ID Release 432424469 Reactome, http://www.reactome.org ReactomeREACT_147977 has a Stoichiometric coefficient of 1 IFNAR2:JAK1:STAT2 Reactome DB_ID: 918193 Reactome Database ID Release 43918193 Reactome, http://www.reactome.org ReactomeREACT_25438 has a Stoichiometric coefficient of 1 Exon Junction Complex Reactome DB_ID: 156656 Reactome Database ID Release 43156656 Reactome, http://www.reactome.org ReactomeREACT_2984 has a Stoichiometric coefficient of 1 IFNGR2:p-JAK2 Reactome DB_ID: 873819 Reactome Database ID Release 43873819 Reactome, http://www.reactome.org ReactomeREACT_25489 has a Stoichiometric coefficient of 1 IFNGR complex with p-JAK2 Reactome DB_ID: 873830 Reactome Database ID Release 43873830 Reactome, http://www.reactome.org ReactomeREACT_26400 has a Stoichiometric coefficient of 2 IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2 Reactome DB_ID: 873811 Reactome Database ID Release 43873811 Reactome, http://www.reactome.org ReactomeREACT_26738 has a Stoichiometric coefficient of 1 IFNG:IFNGR complex IFNG:IFNGR1:JAK1:IFNGR2:JAK2 Reactome DB_ID: 873829 Reactome Database ID Release 43873829 Reactome, http://www.reactome.org ReactomeREACT_25865 has a Stoichiometric coefficient of 1 IFNGR1:p-JAK1 Reactome DB_ID: 873807 Reactome Database ID Release 43873807 Reactome, http://www.reactome.org ReactomeREACT_26557 has a Stoichiometric coefficient of 1 IFNGR complex with p-JAK Reactome DB_ID: 873800 Reactome Database ID Release 43873800 Reactome, http://www.reactome.org ReactomeREACT_26394 has a Stoichiometric coefficient of 2 IFNG:IFNGR1:p-JAK1:IFNGR2:p-JAK2 Reactome DB_ID: 873820 Reactome Database ID Release 43873820 Reactome, http://www.reactome.org ReactomeREACT_26286 has a Stoichiometric coefficient of 1 PathwayStep1240 IFNG homodimer Reactome DB_ID: 873823 Reactome Database ID Release 43873823 Reactome, http://www.reactome.org ReactomeREACT_26955 has a Stoichiometric coefficient of 2 PathwayStep1241 IFNGR2:JAK2 Reactome DB_ID: 873808 Reactome Database ID Release 43873808 Reactome, http://www.reactome.org ReactomeREACT_26988 has a Stoichiometric coefficient of 1 PathwayStep1242 IFNGR1:JAK1 Reactome DB_ID: 873803 Reactome Database ID Release 43873803 Reactome, http://www.reactome.org ReactomeREACT_25538 has a Stoichiometric coefficient of 1 PathwayStep1243 PathwayStep1234 PathwayStep1233 PathwayStep1236 Capped Intronless Histone pre-mRNA:CBC complex Reactome DB_ID: 110758 Reactome Database ID Release 43110758 Reactome, http://www.reactome.org ReactomeREACT_3840 has a Stoichiometric coefficient of 1 PathwayStep1235 Mature Intronless Transcript Derived mRNA:eIF4E Complex Reactome DB_ID: 113818 Reactome Database ID Release 43113818 Reactome, http://www.reactome.org ReactomeREACT_3252 has a Stoichiometric coefficient of 1 PathwayStep1238 PathwayStep1237 PathwayStep1239 Mature Intronless Transcript Derived Histone mRNA:TAP:Aly/Ref Complex Reactome DB_ID: 158480 Reactome Database ID Release 43158480 Reactome, http://www.reactome.org ReactomeREACT_4560 has a Stoichiometric coefficient of 1 Mature Intronless Transcript Derived Histone mRNA:TAP:Aly/Ref complex Reactome DB_ID: 158479 Reactome Database ID Release 43158479 Reactome, http://www.reactome.org ReactomeREACT_5697 has a Stoichiometric coefficient of 1 Mature intronless transcript derived Histone pre-mRNA:CBC complex Reactome DB_ID: 156959 Reactome Database ID Release 43156959 Reactome, http://www.reactome.org ReactomeREACT_5592 has a Stoichiometric coefficient of 1 Mature intronless transcript derived Histone mRNA:SLBP:eIF4E Complex Reactome DB_ID: 141614 Reactome Database ID Release 43141614 Reactome, http://www.reactome.org ReactomeREACT_2270 has a Stoichiometric coefficient of 1 Mature intronless derived mRNA:TAP:Aly/Ref complex Reactome DB_ID: 158442 Reactome Database ID Release 43158442 Reactome, http://www.reactome.org ReactomeREACT_4662 has a Stoichiometric coefficient of 1 Nucleoplasmic mature intronless derived mRNA:TAP:Aly/Ref complex Reactome DB_ID: 158446 Reactome Database ID Release 43158446 Reactome, http://www.reactome.org ReactomeREACT_4247 has a Stoichiometric coefficient of 1 Mature intronless derived mRNA complex Reactome DB_ID: 112167 Reactome Database ID Release 43112167 Reactome, http://www.reactome.org ReactomeREACT_4047 has a Stoichiometric coefficient of 1 Mature SLBP independent Histone mRNA:eIF4E complex Reactome DB_ID: 158501 Reactome Database ID Release 43158501 Reactome, http://www.reactome.org ReactomeREACT_3452 has a Stoichiometric coefficient of 1 p-IFNAR1:p-TYK2:SOCS-1/SOCS-3 Reactome DB_ID: 912684 Reactome Database ID Release 43912684 Reactome, http://www.reactome.org ReactomeREACT_25659 has a Stoichiometric coefficient of 1 p-TYK2:p-IFNAR1:SOCS-1/SOCS-3:IFNA/B:IFNAR2:p-JAK1:STAT2 Reactome DB_ID: 912681 Reactome Database ID Release 43912681 Reactome, http://www.reactome.org ReactomeREACT_26646 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:p-JAK1:STAT2:IFNAR1:TYK2 Reactome DB_ID: 997300 Reactome Database ID Release 43997300 Reactome, http://www.reactome.org ReactomeREACT_26140 has a Stoichiometric coefficient of 1 IFNAR2c:UBP43 Reactome DB_ID: 912690 Reactome Database ID Release 43912690 Reactome, http://www.reactome.org ReactomeREACT_26598 has a Stoichiometric coefficient of 1 p-STAT2:STAT1:p-IFNAR1:p-TYK2 Reactome DB_ID: 997302 Reactome Database ID Release 43997302 Reactome, http://www.reactome.org ReactomeREACT_26277 has a Stoichiometric coefficient of 1 IFNA/B:IFNAR2:p-JAK1:STAT2:p-IFNAR1:p-TYK2:p-STAT2:STAT1 Reactome DB_ID: 997304 Reactome Database ID Release 43997304 Reactome, http://www.reactome.org ReactomeREACT_26740 has a Stoichiometric coefficient of 1 IFNGR1:JAK1:INFG2:JAK2 Reactome DB_ID: 873810 Reactome Database ID Release 43873810 Reactome, http://www.reactome.org ReactomeREACT_25803 has a Stoichiometric coefficient of 2 p-STAT2:STAT1 Reactome DB_ID: 997303 Reactome Database ID Release 43997303 Reactome, http://www.reactome.org ReactomeREACT_26603 has a Stoichiometric coefficient of 1 PathwayStep1250 PathwayStep1253 PathwayStep1254 PathwayStep1251 ISGF3 bound to ISRE promotor elements Reactome DB_ID: 1015697 Reactome Database ID Release 431015697 Reactome, http://www.reactome.org ReactomeREACT_25455 has a Stoichiometric coefficient of 1 PathwayStep1252 AAF IFNA-activated-factor (AAF) Reactome DB_ID: 913526 Reactome Database ID Release 43913526 Reactome, http://www.reactome.org ReactomeREACT_26749 has a Stoichiometric coefficient of 2 p-STAT1:p-STAT1 PathwayStep1247 Mature intronless transcript derived Histone mRNA:SLBP:TAP:Aly/Ref complex Reactome DB_ID: 159047 Reactome Database ID Release 43159047 Reactome, http://www.reactome.org ReactomeREACT_3824 has a Stoichiometric coefficient of 1 PathwayStep1246 Mature Intronless transcript derived Histone mRNA:SLBP:CBP80:CBP20 Reactome DB_ID: 111682 Reactome Database ID Release 43111682 Reactome, http://www.reactome.org ReactomeREACT_3802 has a Stoichiometric coefficient of 1 PathwayStep1245 PathwayStep1244 Mature intronless transcript derived Histone mRNA:SLBP:TAP:Aly/Ref complex Reactome DB_ID: 159045 Reactome Database ID Release 43159045 Reactome, http://www.reactome.org ReactomeREACT_2791 has a Stoichiometric coefficient of 1 PathwayStep1249 PathwayStep1248 AAF IFNA-activated-factor (AAF) Reactome DB_ID: 913524 Reactome Database ID Release 43913524 Reactome, http://www.reactome.org ReactomeREACT_26275 has a Stoichiometric coefficient of 2 p-STAT1 homodimer Nuclear Pore Complex (NPC) Reactome DB_ID: 157689 Reactome Database ID Release 43157689 Reactome, http://www.reactome.org ReactomeREACT_5542 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 16 has a Stoichiometric coefficient of 32 has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 8 Nup62 Complex Reactome DB_ID: 157712 Reactome Database ID Release 43157712 Reactome, http://www.reactome.org ReactomeREACT_4349 has a Stoichiometric coefficient of 16 has a Stoichiometric coefficient of 32 has a Stoichiometric coefficient of 51 (d)NTP (deoxy)nucleotide diphosphates Converted from EntitySet in Reactome Reactome DB_ID: 482807 Reactome Database ID Release 43482807 Reactome, http://www.reactome.org ReactomeREACT_21642 Nup107 Complex Reactome DB_ID: 157700 Reactome Database ID Release 43157700 Reactome, http://www.reactome.org ReactomeREACT_5570 has a Stoichiometric coefficient of 16 has a Stoichiometric coefficient of 32 has a Stoichiometric coefficient of 8 Cap Binding Complex (CBC) Reactome DB_ID: 162460 Reactome Database ID Release 43162460 Reactome, http://www.reactome.org ReactomeREACT_3506 has a Stoichiometric coefficient of 1 Export Receptor bound mature mRNA Complex Reactome DB_ID: 159259 Reactome Database ID Release 43159259 Reactome, http://www.reactome.org ReactomeREACT_2455 has a Stoichiometric coefficient of 1 Mature mRNP Complex Reactome DB_ID: 159329 Reactome Database ID Release 43159329 Reactome, http://www.reactome.org ReactomeREACT_4851 has a Stoichiometric coefficient of 1 Magoh-Y14 complex Reactome DB_ID: 162463 Reactome Database ID Release 43162463 Reactome, http://www.reactome.org ReactomeREACT_4361 has a Stoichiometric coefficient of 1 deoxycytidine, thymidine, deoxyuridine Converted from EntitySet in Reactome Reactome DB_ID: 500822 Reactome Database ID Release 43500822 Reactome, http://www.reactome.org ReactomeREACT_22085 CMP, UMP Converted from EntitySet in Reactome Reactome DB_ID: 500761 Reactome Database ID Release 43500761 Reactome, http://www.reactome.org ReactomeREACT_21421 PathwayStep1046 cytidine, uridine Converted from EntitySet in Reactome Reactome DB_ID: 500759 Reactome Database ID Release 43500759 Reactome, http://www.reactome.org ReactomeREACT_21676 PathwayStep1047 PathwayStep1048 PathwayStep1049 dCMP, TMP, dUMP Converted from EntitySet in Reactome Reactome DB_ID: 500823 Reactome Database ID Release 43500823 Reactome, http://www.reactome.org ReactomeREACT_21746 PathwayStep1054 PathwayStep1053 PathwayStep1056 PathwayStep1055 PathwayStep1050 PathwayStep1052 PathwayStep1051 (d)CMP Converted from EntitySet in Reactome Reactome DB_ID: 500828 Reactome Database ID Release 43500828 Reactome, http://www.reactome.org ReactomeREACT_21917 TMP, (d)UMP, uridine 2' monophosphate, uridine 3' monophosphate Converted from EntitySet in Reactome Reactome DB_ID: 500420 Reactome Database ID Release 43500420 Reactome, http://www.reactome.org ReactomeREACT_21437 PathwayStep1039 PathwayStep1037 PathwayStep1038 PathwayStep1035 (deoxy)cytidine Converted from EntitySet in Reactome Reactome DB_ID: 500829 Reactome Database ID Release 43500829 Reactome, http://www.reactome.org ReactomeREACT_21803 PathwayStep1036 thymidine, uridine, deoxyuridine Converted from EntitySet in Reactome Reactome DB_ID: 500421 Reactome Database ID Release 43500421 Reactome, http://www.reactome.org ReactomeREACT_21654 PathwayStep1045 PathwayStep1044 PathwayStep1043 PathwayStep1042 PathwayStep1041 PathwayStep1040 PathwayStep1068 PathwayStep1069 CMP, TMP. UMP Converted from EntitySet in Reactome Reactome DB_ID: 500316 Reactome Database ID Release 43500316 Reactome, http://www.reactome.org ReactomeREACT_21710 cytidine, thymidine, uridine Converted from EntitySet in Reactome Reactome DB_ID: 500318 Reactome Database ID Release 43500318 Reactome, http://www.reactome.org ReactomeREACT_21647 Alpha-2(I) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2029425 Reactome Database ID Release 432029425 Reactome, http://www.reactome.org ReactomeREACT_122548 Alpha-1(I) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025670 Reactome Database ID Release 432025670 Reactome, http://www.reactome.org ReactomeREACT_125106 (d)CMP, TMP, (d)UMP Converted from EntitySet in Reactome Reactome DB_ID: 500347 Reactome Database ID Release 43500347 Reactome, http://www.reactome.org ReactomeREACT_21862 Alpha-2(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025671 Reactome Database ID Release 432025671 Reactome, http://www.reactome.org ReactomeREACT_124204 Alpha-1(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025676 Reactome Database ID Release 432025676 Reactome, http://www.reactome.org ReactomeREACT_122880 Alpha-1(III) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025675 Reactome Database ID Release 432025675 Reactome, http://www.reactome.org ReactomeREACT_123016 Alpha-1(II) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025677 Reactome Database ID Release 432025677 Reactome, http://www.reactome.org ReactomeREACT_125563 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43182636 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43176203 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003689 Reactome Database ID Release 43176122 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369254 Reactome, http://www.reactome.org PathwayStep1070 PathwayStep1072 PathwayStep1071 PathwayStep1074 ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43182511 Reactome, http://www.reactome.org PathwayStep1073 ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 431363267 Reactome, http://www.reactome.org PathwayStep1076 ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43182511 Reactome, http://www.reactome.org PathwayStep1075 ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43182511 Reactome, http://www.reactome.org PathwayStep1078 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369222 Reactome, http://www.reactome.org PathwayStep1077 ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 431362272 Reactome, http://www.reactome.org PathwayStep1059 PathwayStep1057 PathwayStep1058 Alpha-1(V) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025761 Reactome Database ID Release 432025761 Reactome, http://www.reactome.org ReactomeREACT_124319 Alpha-3(V) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025755 Reactome Database ID Release 432025755 Reactome, http://www.reactome.org ReactomeREACT_124902 Alpha-2(V) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025767 Reactome Database ID Release 432025767 Reactome, http://www.reactome.org ReactomeREACT_124955 Alpha-2(VI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025747 Reactome Database ID Release 432025747 Reactome, http://www.reactome.org ReactomeREACT_121800 Alpha-1(VI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025746 Reactome Database ID Release 432025746 Reactome, http://www.reactome.org ReactomeREACT_121454 Alpha-5(VI) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025750 Reactome Database ID Release 432025750 Reactome, http://www.reactome.org ReactomeREACT_123642 Alpha-3(VI) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025753 Reactome Database ID Release 432025753 Reactome, http://www.reactome.org ReactomeREACT_124121 Alpha-3(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025668 Reactome Database ID Release 432025668 Reactome, http://www.reactome.org ReactomeREACT_124991 Alpha-4(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025678 Reactome Database ID Release 432025678 Reactome, http://www.reactome.org ReactomeREACT_122315 Alpha-6(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025666 Reactome Database ID Release 432025666 Reactome, http://www.reactome.org ReactomeREACT_124305 Alpha-5(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025681 Reactome Database ID Release 432025681 Reactome, http://www.reactome.org ReactomeREACT_124279 PathwayStep1063 PathwayStep1062 PathwayStep1061 PathwayStep1060 PathwayStep1067 PathwayStep1066 PathwayStep1065 PathwayStep1064 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of DNAJC3 (p58IPK)' ACTIVATION Pubmed14559994 Reactome Database ID Release 431791251 Reactome, http://www.reactome.org ReactomeREACT_118032 'eIF2-alpha (phosphorylated at Ser52) [cytosol]' positively regulates 'Translation and translocation of ATF4 ' ACTIVATION Pubmed15314157 Reactome Database ID Release 43420845 Reactome, http://www.reactome.org ReactomeREACT_19112 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of WFS1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791205 Reactome, http://www.reactome.org ReactomeREACT_117971 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of WIPI1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791235 Reactome, http://www.reactome.org ReactomeREACT_118014 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of YIF1A' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791234 Reactome, http://www.reactome.org ReactomeREACT_117948 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of ZBTB17' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791188 Reactome, http://www.reactome.org ReactomeREACT_118025 PathwayStep1097 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org PathwayStep1098 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org PathwayStep1099 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432176397 Reactome, http://www.reactome.org PathwayStep1093 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org PathwayStep1094 ACTIVATION GENE ONTOLOGYGO:0004861 Reactome Database ID Release 43188223 Reactome, http://www.reactome.org PathwayStep1095 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org PathwayStep1096 ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43349467 Reactome, http://www.reactome.org 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of TPP1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791238 Reactome, http://www.reactome.org ReactomeREACT_118019 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of TATDN2' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791248 Reactome, http://www.reactome.org ReactomeREACT_118003 PathwayStep1090 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of Talin-1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791219 Reactome, http://www.reactome.org ReactomeREACT_117953 PathwayStep1091 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of TSPYL2' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791233 Reactome, http://www.reactome.org ReactomeREACT_118024 PathwayStep1092 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43418854 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org 'DP-1:E2F1 complex [nucleoplasm]' positively regulates 'Transactivation of NOXA by E2F1' ACTIVATION Reactome Database ID Release 43159039 Reactome, http://www.reactome.org ReactomeREACT_6130 'Krueppel-like factor 4' positively regulates 'Synthesis of Preproghrelin' ACTIVATION Pubmed19327128 Reactome Database ID Release 43434462 Reactome, http://www.reactome.org ReactomeREACT_20490 The KLF4 transcription factor binds to the promoter of the preproghrelin gene and activates its transcription. 'p53 ser-15 phosphorylated [nucleoplasm]' positively regulates 'Transactivation of NOXA by p53' ACTIVATION Reactome Database ID Release 43159038 Reactome, http://www.reactome.org ReactomeREACT_6033 'ATF4 [nucleoplasm]' positively regulates 'Expression of IL-8' ACTIVATION Pubmed16912112 Pubmed16931790 Reactome Database ID Release 431791243 Reactome, http://www.reactome.org ReactomeREACT_117912 'KSRP:mRNA Degradation Complex [cytosol]' negatively regulates 'Expression of IL-8' INHIBITION KSRP binds an AU-rich element in the mRNA encoding IL-8 and destabilizes the mRNA. Pubmed15514971 Reactome Database ID Release 43517803 Reactome, http://www.reactome.org ReactomeREACT_117977 PathwayStep1079 PathwayStep1088 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org PathwayStep1089 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org PathwayStep1086 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43143490 Reactome, http://www.reactome.org PathwayStep1087 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43176203 Reactome, http://www.reactome.org PathwayStep1084 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org PathwayStep1085 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4375808 Reactome, http://www.reactome.org PathwayStep1082 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369603 Reactome, http://www.reactome.org PathwayStep1083 'ATF4 [nucleoplasm]' positively regulates 'Expression of IGFBP1' ACTIVATION Pubmed16687408 Reactome Database ID Release 431791203 Reactome, http://www.reactome.org ReactomeREACT_117926 PathwayStep1080 dsDNA:DAI:pS-172-TBK1 Reactome DB_ID: 1606333 Reactome Database ID Release 431606333 Reactome, http://www.reactome.org ReactomeREACT_119373 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 'ATF4 [nucleoplasm]' positively regulates 'Expression of HERPUD' ACTIVATION Pubmed14742429 Reactome Database ID Release 431791199 Reactome, http://www.reactome.org ReactomeREACT_117964 PathwayStep1081 'ATF4 [nucleoplasm]' positively regulates 'Expression of CCL2' ACTIVATION Pubmed16931790 Reactome Database ID Release 431791200 Reactome, http://www.reactome.org ReactomeREACT_117907 dsDNA:DAI:RIP1:RIP3 Reactome DB_ID: 1810470 Reactome Database ID Release 431810470 Reactome, http://www.reactome.org ReactomeREACT_116701 has a Stoichiometric coefficient of 1 'ATF4 [nucleoplasm]' positively regulates 'Expression of Asparagine Synthetase' ACTIVATION Pubmed18840095 Reactome Database ID Release 431791230 Reactome, http://www.reactome.org ReactomeREACT_118054 dsDNA:DAI:pS-172-TBK:IRF3 Reactome DB_ID: 1606328 Reactome Database ID Release 431606328 Reactome, http://www.reactome.org ReactomeREACT_118875 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 'ATF4 [nucleoplasm]' positively regulates 'Expression of ATF3' ACTIVATION Pubmed20022965 Reactome Database ID Release 43420835 Reactome, http://www.reactome.org ReactomeREACT_19115 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4375808 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4369607 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 4369594 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43351940 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43351837 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43351848 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of SSR1 (Trap alpha)' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791224 Reactome, http://www.reactome.org ReactomeREACT_117961 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of SULT1A3' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791194 Reactome, http://www.reactome.org ReactomeREACT_118000 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of SRPR (SRP Receptor subunit alpha)' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791198 Reactome, http://www.reactome.org ReactomeREACT_117968 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of SRPRB (SRP Receptor subunit beta)' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791232 Reactome, http://www.reactome.org ReactomeREACT_117954 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of Sec31A' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791254 Reactome, http://www.reactome.org ReactomeREACT_117911 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of SYVN1 (HRD1)' ACTIVATION Pubmed18664523 Reactome Database ID Release 431791215 Reactome, http://www.reactome.org ReactomeREACT_118043 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of Sec12' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791217 Reactome, http://www.reactome.org ReactomeREACT_118061 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43211667 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43211762 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 4369594 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43211202 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43211202 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004536 Reactome Database ID Release 43353596 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43352254 Reactome, http://www.reactome.org 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of SHC1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791246 Reactome, http://www.reactome.org ReactomeREACT_118046 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of SERP1 (RAMP4)' ACTIVATION Pubmed14559994 Reactome Database ID Release 431791190 Reactome, http://www.reactome.org ReactomeREACT_118023 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of PPP2R5B' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791193 Reactome, http://www.reactome.org ReactomeREACT_118012 Alpha-1(VII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2025748 Reactome Database ID Release 432025748 Reactome, http://www.reactome.org ReactomeREACT_122648 Alpha-6(VI) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025773 Reactome Database ID Release 432025773 Reactome, http://www.reactome.org ReactomeREACT_122293 Alpha-1(VIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2173307 Reactome Database ID Release 432173307 Reactome, http://www.reactome.org ReactomeREACT_125194 Alpha-1(X) chains Converted from EntitySet in Reactome Reactome DB_ID: 2173282 Reactome Database ID Release 432173282 Reactome, http://www.reactome.org ReactomeREACT_123278 Alpha-1(XI) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2179231 Reactome Database ID Release 432179231 Reactome, http://www.reactome.org ReactomeREACT_124458 Alpha-2(XI) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2179214 Reactome Database ID Release 432179214 Reactome, http://www.reactome.org ReactomeREACT_124059 Alpha-1(XII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179233 Reactome Database ID Release 432179233 Reactome, http://www.reactome.org ReactomeREACT_121930 Alpha-2(VIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179354 Reactome Database ID Release 432179354 Reactome, http://www.reactome.org ReactomeREACT_121540 Alpha-1(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2173303 Reactome Database ID Release 432173303 Reactome, http://www.reactome.org ReactomeREACT_122699 Alpha-2(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2173301 Reactome Database ID Release 432173301 Reactome, http://www.reactome.org ReactomeREACT_125325 Alpha-3(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2173285 Reactome Database ID Release 432173285 Reactome, http://www.reactome.org ReactomeREACT_124343 Alpha-1(XIV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179251 Reactome Database ID Release 432179251 Reactome, http://www.reactome.org ReactomeREACT_122079 Alpha-1(XIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179237 Reactome Database ID Release 432179237 Reactome, http://www.reactome.org ReactomeREACT_123142 Alpha-1(XXII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179261 Reactome Database ID Release 432179261 Reactome, http://www.reactome.org ReactomeREACT_122171 Alpha-1(XXIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179266 Reactome Database ID Release 432179266 Reactome, http://www.reactome.org ReactomeREACT_122378 Alpha-1(XX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179247 Reactome Database ID Release 432179247 Reactome, http://www.reactome.org ReactomeREACT_123051 Alpha-1(XXI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179265 Reactome Database ID Release 432179265 Reactome, http://www.reactome.org ReactomeREACT_124748 Collagen alpha-1(XVIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179240 Reactome Database ID Release 432179240 Reactome, http://www.reactome.org ReactomeREACT_123876 Alpha-1(XIX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179252 Reactome Database ID Release 432179252 Reactome, http://www.reactome.org ReactomeREACT_122133 Alpha-1(XVI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179239 Reactome Database ID Release 432179239 Reactome, http://www.reactome.org ReactomeREACT_122172 Alpha-1(XVII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179250 Reactome Database ID Release 432179250 Reactome, http://www.reactome.org ReactomeREACT_125582 Alpha-1(XV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179253 Reactome Database ID Release 432179253 Reactome, http://www.reactome.org ReactomeREACT_124570 Alpha-1(XXIV) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2179260 Reactome Database ID Release 432179260 Reactome, http://www.reactome.org ReactomeREACT_121690 Alpha-1(XXVII) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2179267 Reactome Database ID Release 432179267 Reactome, http://www.reactome.org ReactomeREACT_123023 Alpha-1(XXVIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179255 Reactome Database ID Release 432179255 Reactome, http://www.reactome.org ReactomeREACT_124569 Collagen alpha-2(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2090017 Reactome Database ID Release 432090017 Reactome, http://www.reactome.org ReactomeREACT_123479 Alpha-1(XXV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179269 Reactome Database ID Release 432179269 Reactome, http://www.reactome.org ReactomeREACT_125622 Alpha-1(XXVI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2179262 Reactome Database ID Release 432179262 Reactome, http://www.reactome.org ReactomeREACT_122472 Collagen alpha-1(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2090015 Reactome Database ID Release 432090015 Reactome, http://www.reactome.org ReactomeREACT_123370 Defensins that bind Lipid II:Lipid II Reactome DB_ID: 1471328 Reactome Database ID Release 431471328 Reactome, http://www.reactome.org ReactomeREACT_116494 has a Stoichiometric coefficient of 1 dsDNA:DAI Reactome DB_ID: 1591233 Reactome Database ID Release 431591233 Reactome, http://www.reactome.org ReactomeREACT_116520 has a Stoichiometric coefficient of 1 Beta defensins 4A,103:CCR2 Reactome DB_ID: 1973966 Reactome Database ID Release 431973966 Reactome, http://www.reactome.org ReactomeREACT_117628 has a Stoichiometric coefficient of 1 Beta defensin 103:TLR1:TLR2 Reactome DB_ID: 1974673 Reactome Database ID Release 431974673 Reactome, http://www.reactome.org ReactomeREACT_116671 has a Stoichiometric coefficient of 1 DAI:DAI Reactome DB_ID: 1591226 Reactome Database ID Release 431591226 Reactome, http://www.reactome.org ReactomeREACT_117422 has a Stoichiometric coefficient of 2 Alpha-defensin pore complex Reactome DB_ID: 1471355 Reactome Database ID Release 431471355 Reactome, http://www.reactome.org ReactomeREACT_117144 has a Stoichiometric coefficient of 6 Beta-defensins:anionic phospholipids Reactome DB_ID: 1471372 Reactome Database ID Release 431471372 Reactome, http://www.reactome.org ReactomeREACT_116741 has a Stoichiometric coefficient of 1 Beta-defensins 1,4A,103:CCR6 Reactome DB_ID: 1471343 Reactome Database ID Release 431471343 Reactome, http://www.reactome.org ReactomeREACT_117668 has a Stoichiometric coefficient of 1 HNP1-3:gp120 Reactome DB_ID: 1471336 Reactome Database ID Release 431471336 Reactome, http://www.reactome.org ReactomeREACT_116690 has a Stoichiometric coefficient of 1 Defensins alpha 1-3:CD4 Reactome DB_ID: 1471352 Reactome Database ID Release 431471352 Reactome, http://www.reactome.org ReactomeREACT_117378 has a Stoichiometric coefficient of 1 chondroitin(2)-core proteins (GlcA)1 (GalNAc)1 (GlcA)1 (Gal)2 (Xyl)1 (Ser)1 Converted from EntitySet in Reactome Reactome DB_ID: 2064050 Reactome Database ID Release 432064050 Reactome, http://www.reactome.org ReactomeREACT_121869 Defensin-6 dimer Reactome DB_ID: 1461977 Reactome Database ID Release 431461977 Reactome, http://www.reactome.org ReactomeREACT_116706 has a Stoichiometric coefficient of 2 Alpha-defensin dimers:anionic phospholipids Reactome DB_ID: 1471345 Reactome Database ID Release 431471345 Reactome, http://www.reactome.org ReactomeREACT_117299 has a Stoichiometric coefficient of 1 Defensin alpha 2 dimer Reactome DB_ID: 1462050 Reactome Database ID Release 431462050 Reactome, http://www.reactome.org ReactomeREACT_117453 has a Stoichiometric coefficient of 2 Defensin alpha 3 dimer Reactome DB_ID: 1462029 Reactome Database ID Release 431462029 Reactome, http://www.reactome.org ReactomeREACT_116757 has a Stoichiometric coefficient of 2 Defensin alpha 4 dimer Reactome DB_ID: 1467211 Reactome Database ID Release 431467211 Reactome, http://www.reactome.org ReactomeREACT_117775 has a Stoichiometric coefficient of 2 Defensin-5 dimer Reactome DB_ID: 1461970 Reactome Database ID Release 431461970 Reactome, http://www.reactome.org ReactomeREACT_116241 has a Stoichiometric coefficient of 2 dsRNA:RIG-I/MDA5:K48 Ub-IPS-1 Reactome DB_ID: 983461 Reactome Database ID Release 43983461 Reactome, http://www.reactome.org ReactomeREACT_25887 has a Stoichiometric coefficient of 1 K-48-polyubiquitinated IPS-1 Reactome DB_ID: 983463 Reactome Database ID Release 43983463 Reactome, http://www.reactome.org ReactomeREACT_26963 has a Stoichiometric coefficient of 1 Alpha-defensin dimers Converted from EntitySet in Reactome Reactome DB_ID: 1471331 Reactome Database ID Release 431471331 Reactome, http://www.reactome.org ReactomeREACT_117820 Defensin alpha 1 dimer Reactome DB_ID: 1462057 Reactome Database ID Release 431462057 Reactome, http://www.reactome.org ReactomeREACT_116776 has a Stoichiometric coefficient of 2 CSGALNACT Converted from EntitySet in Reactome Reactome DB_ID: 1971496 Reactome Database ID Release 431971496 Reactome, http://www.reactome.org ReactomeREACT_125395 chondroitin(3)-core proteins Converted from EntitySet in Reactome Reactome DB_ID: 2064075 Reactome Database ID Release 432064075 Reactome, http://www.reactome.org ReactomeREACT_122176 dsRNA:RIG-I/MDA5:K48 Ub-IPS-1:PCBP2:AIP4 Reactome DB_ID: 983459 Reactome Database ID Release 43983459 Reactome, http://www.reactome.org ReactomeREACT_26024 has a Stoichiometric coefficient of 1 TAX1BP1:TNFAIP3:TBK1/IKKi Reactome DB_ID: 937333 Reactome Database ID Release 43937333 Reactome, http://www.reactome.org ReactomeREACT_25569 has a Stoichiometric coefficient of 1 dsRNA:RIG-I/MDA5:IPS-1:PCBP2 Reactome DB_ID: 983462 Reactome Database ID Release 43983462 Reactome, http://www.reactome.org ReactomeREACT_25961 has a Stoichiometric coefficient of 1 K48-polyubiquitin TRAF3 Reactome DB_ID: 936556 Reactome Database ID Release 43936556 Reactome, http://www.reactome.org ReactomeREACT_26176 has a Stoichiometric coefficient of 1 TAX1BP1:TNFAIP3 Reactome DB_ID: 937339 Reactome Database ID Release 43937339 Reactome, http://www.reactome.org ReactomeREACT_26309 has a Stoichiometric coefficient of 1 dsRNA:RIG-I/MDA5:IPS-1:ATG5-ATG12 Reactome DB_ID: 936400 Reactome Database ID Release 43936400 Reactome, http://www.reactome.org ReactomeREACT_26782 has a Stoichiometric coefficient of 1 dsRNA:RIG-1/MDA5:IPS-1:TRAF3 Reactome DB_ID: 936558 Reactome Database ID Release 43936558 Reactome, http://www.reactome.org ReactomeREACT_25597 has a Stoichiometric coefficient of 1 IPS-1:ATG5-ATG12 conjugate Reactome DB_ID: 936373 Reactome Database ID Release 43936373 Reactome, http://www.reactome.org ReactomeREACT_25931 has a Stoichiometric coefficient of 1 ATG5-ATG12 conjugate Reactome DB_ID: 936428 Reactome Database ID Release 43936428 Reactome, http://www.reactome.org ReactomeREACT_26651 has a Stoichiometric coefficient of 1 ISGylated IRF3 Reactome DB_ID: 1169389 Reactome Database ID Release 431169389 Reactome, http://www.reactome.org ReactomeREACT_27520 has a Stoichiometric coefficient of 1 CS GlcA tranferases Converted from EntitySet in Reactome Reactome DB_ID: 1971467 Reactome Database ID Release 431971467 Reactome, http://www.reactome.org ReactomeREACT_124292 C4S-PG Converted from EntitySet in Reactome Reactome DB_ID: 2064226 Reactome Database ID Release 432064226 Reactome, http://www.reactome.org ReactomeREACT_124101 chondroitin 4-sulfate proteoglycans CS GalNAc tranferases Converted from EntitySet in Reactome Reactome DB_ID: 1971425 Reactome Database ID Release 431971425 Reactome, http://www.reactome.org ReactomeREACT_124285 Ankyrins Converted from EntitySet in Reactome Reactome DB_ID: 392740 Reactome Database ID Release 43392740 Reactome, http://www.reactome.org ReactomeREACT_22717 Potassium channel subunits Converted from EntitySet in Reactome Reactome DB_ID: 443640 Reactome Database ID Release 43443640 Reactome, http://www.reactome.org ReactomeREACT_23018 Sodium channel beta subunit Converted from EntitySet in Reactome Reactome DB_ID: 443638 Reactome Database ID Release 43443638 Reactome, http://www.reactome.org ReactomeREACT_22663 Sodium channel alpha subunit Converted from EntitySet in Reactome Reactome DB_ID: 443637 Reactome Database ID Release 43443637 Reactome, http://www.reactome.org ReactomeREACT_22593 CHST9,11,12,13 Converted from EntitySet in Reactome Reactome DB_ID: 1971481 Reactome Database ID Release 431971481 Reactome, http://www.reactome.org ReactomeREACT_125490 alpha/beta catenin Converted from EntitySet in Reactome Reactome DB_ID: 448856 Reactome Database ID Release 43448856 Reactome, http://www.reactome.org ReactomeREACT_21756 Promyogenic cadherins Converted from EntitySet in Reactome Reactome DB_ID: 375081 Reactome Database ID Release 43375081 Reactome, http://www.reactome.org ReactomeREACT_21576 synapse-associated proteins (SAP) Converted from EntitySet in Reactome Reactome DB_ID: 376003 Reactome Database ID Release 43376003 Reactome, http://www.reactome.org ReactomeREACT_23280 C6S-PG Converted from EntitySet in Reactome Reactome DB_ID: 2064219 Reactome Database ID Release 432064219 Reactome, http://www.reactome.org ReactomeREACT_121500 chondroitin 6-sulfate proteoglycans CSE-PG C4,6(S)2-PG Converted from EntitySet in Reactome Reactome DB_ID: 2064101 Reactome Database ID Release 432064101 Reactome, http://www.reactome.org ReactomeREACT_123649 chondroitin 4,6-disulfate proteoglycans chondroitin E proteoglycans CHST3,7 Converted from EntitySet in Reactome Reactome DB_ID: 2018661 Reactome Database ID Release 432018661 Reactome, http://www.reactome.org ReactomeREACT_125232 'NR1D1 (REV-ERBA):heme:Corepressor [nucleoplasm]' negatively regulates 'Expression of ELOVL3' As inferred from mouse, REV-ERBA (NR1D1) binds the promoter of the ELOVL3 gene and represses transcription, possibly by recruiting corepressors. INHIBITION Pubmed17003504 Reactome Database ID Release 431368187 Reactome, http://www.reactome.org ReactomeREACT_120364 MDP:NLRP1:ATP Reactome DB_ID: 879207 Reactome Database ID Release 43879207 Reactome, http://www.reactome.org ReactomeREACT_76210 has a Stoichiometric coefficient of 1 'p-T69,T71-ATF2 [nucleoplasm]' positively regulates 'Expression of PPARGC1A (PGC-1alpha)' ACTIVATION As inferred from mouse, phosphorylated ATF2 binds the PGC-1alpha promoter and enhances expression (Cao et al. 2004, Akimoto et al. 2005, Wright et al. 2007, Akimoto et al. 2008). Intracellular calcium acting via p38 MAPK is believed to activate (phosphorylate) ATF2. Pubmed15024092 Pubmed15767263 Pubmed17488713 Pubmed18434626 Reactome Database ID Release 431606710 Reactome, http://www.reactome.org ReactomeREACT_120337 IPAF elicitors:NLRC4 Reactome DB_ID: 877394 Reactome Database ID Release 43877394 Reactome, http://www.reactome.org ReactomeREACT_76033 has a Stoichiometric coefficient of 1 'NR1D1 (REV-ERBA):heme:Corepressor [nucleoplasm]' negatively regulates 'Expression of PPARGC1A (PGC-1alpha)' INHIBITION NR1D1 (REV-ERBA) binds heme and the promoter of the PGC-1alpha (PPARGC1A) gene. The REV-ERBA:heme complex recruits the corepressors NCoR and HDAC3 and represses transcription. Pubmed19710360 Reactome Database ID Release 431368172 Reactome, http://www.reactome.org ReactomeREACT_120342 C4S-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2063982 Reactome Database ID Release 432063982 Reactome, http://www.reactome.org ReactomeREACT_121630 chondroitin 4-sulfate proteoglycans 'p-S133-CREB1 [nucleoplasm]' positively regulates 'Expression of PPARGC1A (PGC-1alpha)' ACTIVATION As inferred from mouse, phosphorylated CREB enhances expression of PPARGC1A (PGC-1alpha). Pubmed12764228 Pubmed19233136 Reactome Database ID Release 431605556 Reactome, http://www.reactome.org ReactomeREACT_120325 'MEF2C/D:PPARGC1A [nucleoplasm]' positively regulates 'Expression of PPARGC1A (PGC-1alpha)' ACTIVATION As inferred from mouse, MEF2C or MEF2D with PGC-1alpha activate expression of PGC-1alpha (Handschin et al. 2003). Pubmed12764228 Reactome Database ID Release 431605584 Reactome, http://www.reactome.org ReactomeREACT_120341 dsDNA:AIM2 oligomer:ASC Reactome DB_ID: 874098 Reactome Database ID Release 43874098 Reactome, http://www.reactome.org ReactomeREACT_76330 has a Stoichiometric coefficient of 1 'p-PPARGC1A [nucleoplasm]' positively regulates 'Expression of PPARGC1A (PGC-1alpha)' ACTIVATION PGC-1alpha (PPARGC1A) enhances expression of its own gene in mouse (Jager et al.2007) and in rat hepatocytes (Lin et al. 2003) Pubmed12807885 Pubmed17609368 Reactome Database ID Release 431605575 Reactome, http://www.reactome.org ReactomeREACT_120333 dsDNA:AIM2 oligomer:ASC:Procaspase-1 Reactome DB_ID: 874100 Reactome Database ID Release 43874100 Reactome, http://www.reactome.org ReactomeREACT_76706 has a Stoichiometric coefficient of 1 'HIF1A [nucleoplasm]' positively regulates 'Expression of RORA (ROR-alpha)' ACTIVATION HIF1A binds the RORA promoter and enhances transcription. Pubmed15270719 Reactome Database ID Release 431480021 Reactome, http://www.reactome.org ReactomeREACT_120353 IPAF elicitors:NLRC4:Procaspase-1 Reactome DB_ID: 874083 Reactome Database ID Release 43874083 Reactome, http://www.reactome.org ReactomeREACT_76296 has a Stoichiometric coefficient of 1 'ROR-alpha:Coactivator [nucleoplasm]' positively regulates 'Expression of SREBF1 (SREBP1)' ACTIVATION As inferred from mouse, RORA (ROR-alpha) enhances expression of SREBP1 (SREBF1). Pubmed18441015 Reactome Database ID Release 431368163 Reactome, http://www.reactome.org ReactomeREACT_120324 dsDNA:AIM2 Reactome DB_ID: 874096 Reactome Database ID Release 43874096 Reactome, http://www.reactome.org ReactomeREACT_76737 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43352254 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43352254 Reactome, http://www.reactome.org C6S-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2064078 Reactome Database ID Release 432064078 Reactome, http://www.reactome.org ReactomeREACT_123050 chondroitin 6-sulfate proteoglycans ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43500678 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43500676 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43500673 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43500681 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43500670 Reactome, http://www.reactome.org 'ROR-alpha:Coactivator [nucleoplasm]' positively regulates 'Expression of NR1D1 (REV-ERBA)' ACTIVATION Pubmed12377782 RORA binds the NR1D1 (REV-ERBA) promoter and activates transcription. Reactome Database ID Release 431480011 Reactome, http://www.reactome.org ReactomeREACT_111923 Profilin Converted from EntitySet in Reactome Reactome DB_ID: 203077 Reactome Database ID Release 43203077 Reactome, http://www.reactome.org ReactomeREACT_20193 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43202816 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org Bcl-2/Bcl-X(L):NLRP1 Reactome DB_ID: 879218 Reactome Database ID Release 43879218 Reactome, http://www.reactome.org ReactomeREACT_76081 has a Stoichiometric coefficient of 1 'HNF1B [nucleoplasm]' positively regulates 'HNF1B-dependent synthesis of HNF6 protein' ACTIVATION Reactome Database ID Release 43210760 Reactome, http://www.reactome.org ReactomeREACT_14706 inosine, deoxyinosine Converted from EntitySet in Reactome Reactome DB_ID: 500172 Reactome Database ID Release 43500172 Reactome, http://www.reactome.org ReactomeREACT_21661 Pyrin trimer:ASC Reactome DB_ID: 877352 Reactome Database ID Release 43877352 Reactome, http://www.reactome.org ReactomeREACT_76773 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PSTPIP1 trimer:Pyrin trimer Reactome DB_ID: 879197 Reactome Database ID Release 43879197 Reactome, http://www.reactome.org ReactomeREACT_76648 has a Stoichiometric coefficient of 1 PSTPIP1 trimer Reactome DB_ID: 879213 Reactome Database ID Release 43879213 Reactome, http://www.reactome.org ReactomeREACT_76772 has a Stoichiometric coefficient of 3 (d)AMP Converted from EntitySet in Reactome Reactome DB_ID: 500088 Reactome Database ID Release 43500088 Reactome, http://www.reactome.org ReactomeREACT_22019 Robo1/ Robo2 Converted from EntitySet in Reactome Reactome DB_ID: 428477 Reactome Database ID Release 43428477 Reactome, http://www.reactome.org ReactomeREACT_19642 Ena/Vasp proteins Converted from EntitySet in Reactome Reactome DB_ID: 428478 Reactome Database ID Release 43428478 Reactome, http://www.reactome.org ReactomeREACT_20297 MDP:NLRP1 Reactome DB_ID: 877370 Reactome Database ID Release 43877370 Reactome, http://www.reactome.org ReactomeREACT_75983 has a Stoichiometric coefficient of 1 'BMAL2:CLOCK [nucleoplasm]' positively regulates 'Expression of PAI-1' ACTIVATION BMAL2 (ARNTL2, CLIF) forms a heterodimer with CLOCK, binds E-boxes in the PAI-1 promoter and activates transcription of the PAI-1 gene. BMAL2 shows constitutive rather than circadian expression. Pubmed11018023 Pubmed12738229 Reactome Database ID Release 43879829 Reactome, http://www.reactome.org ReactomeREACT_27127 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of NAMPT (NamPRT, PBEF, Visfatin)' ACTIVATION As inferred from mouse, the BMAL1:CLOCK heterodimer binds an E-box element in the promoter of the NAMPT gene and enhances transcription. Reactome Database ID Release 431368960 Reactome, http://www.reactome.org ReactomeREACT_117973 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of NOCTURNIN' ACTIVATION Pubmed18587630 Reactome Database ID Release 43549581 Reactome, http://www.reactome.org ReactomeREACT_27087 The phosphorylated BMAL1:CLOCK heterodimer binds an E-box element in the promoter of the NOCTURNIN gene and activates transcription of NOCTURNIN. NPAS2 is predicted to act redundantly with CLOCK. 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of PAI-1' ACTIVATION Pubmed12406875 Pubmed12738229 Pubmed16857194 Reactome Database ID Release 43549564 Reactome, http://www.reactome.org ReactomeREACT_27106 The phosphorylated BMAL1:CLOCK heterodimer binds an E-box in the promoter of the PAI-1 gene and activate transcription of PAI-1. NPAS2 is predicted to act redundantly with CLOCK. NLRP3 elicitor proteins:NLRP3 Reactome DB_ID: 1306879 Reactome Database ID Release 431306879 Reactome, http://www.reactome.org ReactomeREACT_76263 has a Stoichiometric coefficient of 1 Glucocorticoids enhance rhythmic transcription of PER2 ACTIVATION As inferred from mouse, glucocorticoids bind the glucocorticoid receptor at the promoter of the PER2 gene and enhance rhythmic transcription. Reactome Database ID Release 43879832 Reactome, http://www.reactome.org ReactomeREACT_27129 NLRP3 elicitors:NLRP3 Converted from EntitySet in Reactome Reactome DB_ID: 1306878 Reactome Database ID Release 431306878 Reactome, http://www.reactome.org ReactomeREACT_76877 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of PERIOD-2' ACTIVATION As inferred from mouse, the phosphorylated BMAL1:CLOCK heterodimer binds a noncanonical E-box in the promoter of the PER2 gene and activates transcription of PER2. NPAS2 is predicted to act redundantly with CLOCK. Pubmed18317514 Reactome Database ID Release 43549551 Reactome, http://www.reactome.org ReactomeREACT_27083 NLRP3 elicitors:NLRP3 oligomer:ASC Reactome DB_ID: 877381 Reactome Database ID Release 43877381 Reactome, http://www.reactome.org ReactomeREACT_76555 has a Stoichiometric coefficient of 1 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of CRYPTOCHROME-1' ACTIVATION Pubmed18317514 Reactome Database ID Release 43549578 Reactome, http://www.reactome.org ReactomeREACT_27077 The phosphorylated BMAL1:CLOCK heterodimer binds an E-box in the promoter of the CRY1 gene and activates transcription of CRY1. NPAS2 is predicted to act redundantly with CLOCK. NLRP3 elicitors:NLRP3 oligomer:ASC:Procaspase-1 Reactome DB_ID: 925458 Reactome Database ID Release 43925458 Reactome, http://www.reactome.org ReactomeREACT_76472 has a Stoichiometric coefficient of 1 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of PERIOD-1' ACTIVATION Pubmed10857746 Pubmed16474406 Pubmed17994337 Reactome Database ID Release 43549572 Reactome, http://www.reactome.org ReactomeREACT_27081 The phosphorylated BMAL1:CLOCK heterodimer binds E-boxes in the promoter of the PER1 gene and activates transcription of PER1. NPAS2 is predicted to act redundantly with CLOCK. Pyrin trimer Reactome DB_ID: 879202 Reactome Database ID Release 43879202 Reactome, http://www.reactome.org ReactomeREACT_76209 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43139951 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43202938 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43350320 Reactome, http://www.reactome.org CSE-PGs C4,6(S)2-PG Converted from EntitySet in Reactome Reactome DB_ID: 2064081 Reactome Database ID Release 432064081 Reactome, http://www.reactome.org ReactomeREACT_124950 chondroitin 4,6-disulfate proteoglycans chondroitin E proteoglycans ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43139951 Reactome, http://www.reactome.org TRPC4/5 Converted from EntitySet in Reactome Reactome DB_ID: 622368 Reactome Database ID Release 43622368 Reactome, http://www.reactome.org ReactomeREACT_22850 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43202938 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43202938 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43202938 Reactome, http://www.reactome.org NLRP3:SUGT1:HSP90 Reactome DB_ID: 874086 Reactome Database ID Release 43874086 Reactome, http://www.reactome.org ReactomeREACT_76613 has a Stoichiometric coefficient of 1 SUGT1:HSP90 Reactome DB_ID: 874112 Reactome Database ID Release 43874112 Reactome, http://www.reactome.org ReactomeREACT_76594 has a Stoichiometric coefficient of 1 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of NR1D1 (REV-ERBA)' ACTIVATION Activation of NR1D1 (REV-ERBA) expression by phosphorylated BMAL1:CLOCK is inferred from mouse. NPAS2 is predicted to act redundantly with CLOCK. Reactome Database ID Release 43549554 Reactome, http://www.reactome.org ReactomeREACT_27130 Oxidized thioredoxin:TXNIP Reactome DB_ID: 1250249 Reactome Database ID Release 431250249 Reactome, http://www.reactome.org ReactomeREACT_76193 has a Stoichiometric coefficient of 1 'NR1D1 (REV-ERBA):heme:Corepressor [nucleoplasm]' negatively regulates 'Expression of NR1D1 (REV-ERBA)' INHIBITION NR1D1 (REV-ERBA) binds its own promoter and represses its own expression. Pubmed8622974 Reactome Database ID Release 431480006 Reactome, http://www.reactome.org ReactomeREACT_111904 Thioredoxin:TXNIP Reactome DB_ID: 1250277 Reactome Database ID Release 431250277 Reactome, http://www.reactome.org ReactomeREACT_76548 has a Stoichiometric coefficient of 1 NLRP3 elicitor small molecules:NLRP3 Reactome DB_ID: 877226 Reactome Database ID Release 43877226 Reactome, http://www.reactome.org ReactomeREACT_76557 has a Stoichiometric coefficient of 1 TXNIP:NLRP3 Reactome DB_ID: 1250285 Reactome Database ID Release 431250285 Reactome, http://www.reactome.org ReactomeREACT_76813 has a Stoichiometric coefficient of 1 'NR1D1 (REV-ERBA):heme:Corepressor [nucleoplasm]' negatively regulates 'Expression of CLOCK' INHIBITION Pubmed21479263 Reactome Database ID Release 431368175 Reactome, http://www.reactome.org ReactomeREACT_120315 ATP:P2X7 oligomer Reactome DB_ID: 877257 Reactome Database ID Release 43877257 Reactome, http://www.reactome.org ReactomeREACT_76503 has a Stoichiometric coefficient of 3 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of AVP' ACTIVATION As inferred from mouse, BMAL1:CLOCK heterodimers bind an E-box enhancer in the AVP promoter and activate transcription of AVP. Pubmed12130638 Reactome Database ID Release 43879834 Reactome, http://www.reactome.org ReactomeREACT_27102 ATP:P2X7 oligomer:Pannexin-1 Reactome DB_ID: 877242 Reactome Database ID Release 43877242 Reactome, http://www.reactome.org ReactomeREACT_76478 has a Stoichiometric coefficient of 1 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of DBP' ACTIVATION As inferred from mouse, BMAL1:CLOCK heterodimers bind E-boxes in the promoter of the DBP gene and activate transcription of DBP. Reactome Database ID Release 43879819 Reactome, http://www.reactome.org ReactomeREACT_27096 PAMP:NOD oligomer:RIP2:CARD9 Reactome DB_ID: 741403 Reactome Database ID Release 43741403 Reactome, http://www.reactome.org ReactomeREACT_76094 has a Stoichiometric coefficient of 1 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of DEC1 (BHLHE40, BHLHB2)' ACTIVATION BMAL1:CLOCK heterodimers bind E-boxes in the promoter of the DEC1 (BHLHE40, BHLHB2) gene and activate transcription of DEC1. Pubmed14672706 Reactome Database ID Release 43879830 Reactome, http://www.reactome.org ReactomeREACT_27090 ATP:P2X7 Reactome DB_ID: 877166 Reactome Database ID Release 43877166 Reactome, http://www.reactome.org ReactomeREACT_76271 has a Stoichiometric coefficient of 1 D4S-PGs Converted from EntitySet in Reactome Dermatan 4-sulfate proteoglycans Reactome DB_ID: 2065135 Reactome Database ID Release 432065135 Reactome, http://www.reactome.org ReactomeREACT_124915 NOTCH1 positively regulates HEY1 transcription ACTIVATION Pubmed15107403 Reactome Database ID Release 431980081 Reactome, http://www.reactome.org ReactomeREACT_120335 'ROR-alpha:Coactivator [nucleoplasm]' positively regulates 'Expression of BMAL1 (ARNTL).' ACTIVATION Activation of BMAL1 expression by ROR-alpha is inferred from mouse. In mouse Rora together with coactivators Ep300 and Ppargc1a bind the promoter of Bmal1 and activate transcription. Pubmed15135064 Pubmed15821743 Pubmed16267379 Reactome Database ID Release 43400375 Reactome, http://www.reactome.org ReactomeREACT_27076 'NR1D1 (REV-ERBA):heme:Corepressor [nucleoplasm]' negatively regulates 'Expression of BMAL1 (ARNTL).' INHIBITION NR1D1 (REV-ERBA) binds to the same site in the promoter of the BMAL1 (ARNTL) gene as ROR-alpha. Whereas ROR-alpha activates transcription of BMAL1, REV-ERBA bound to heme recruits corepressors (NCoR and HDAC3) and inhibits transcription of BMAL1. Both REV-ERBA and ROR-alpha genes are targets of BMAL1:CLOCK/NPAS2 transactivation and they show alternating patterns of maximum protein levels, thus they give BMAL1 transcription circadian expression. Pubmed15761026 Pubmed16484495 Pubmed18006707 Pubmed18037887 Reactome Database ID Release 43421342 Reactome, http://www.reactome.org ReactomeREACT_27094 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43140204 Reactome, http://www.reactome.org PathwayStep1100 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43204205 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43204205 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43266291 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43140204 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43202853 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43114327 Reactome, http://www.reactome.org p90rsk Converted from EntitySet in Reactome Reactome DB_ID: 446849 Reactome Database ID Release 43446849 Reactome, http://www.reactome.org ReactomeREACT_23173 Ribosomal protein S6 kinase ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43202853 Reactome, http://www.reactome.org CAP Adenylyl cyclase-associated proteins Converted from EntitySet in Reactome Reactome DB_ID: 428868 Reactome Database ID Release 43428868 Reactome, http://www.reactome.org ReactomeREACT_20173 CLASP Converted from EntitySet in Reactome Reactome DB_ID: 428867 Reactome Database ID Release 43428867 Reactome, http://www.reactome.org ReactomeREACT_20461 G, dG Converted from EntitySet in Reactome Reactome DB_ID: 500245 Reactome Database ID Release 43500245 Reactome, http://www.reactome.org ReactomeREACT_21463 guanosine, deoxyguanosine 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' regulates 'Expression of DEC2 (BHLHE41, BHLHB3)' As inferred from mouse, the BMAL1:CLOCK heterodimer binds E-box elements in the promoter of the DEC2 (BHLHE41, BHLHB3) gene and activates transcription of DEC2. Reactome Database ID Release 43879843 Reactome, http://www.reactome.org ReactomeREACT_27123 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of DEC2 (BHLHE41, BHLHB3)' ACTIVATION As inferred from mouse, BMAL1:CLOCK heterodimers bind E-box elements in the promoter of the DEC2 gene and activate transcription of DEC2. Reactome Database ID Release 43893505 Reactome, http://www.reactome.org ReactomeREACT_27097 'p-BMAL1:p-CLOCK/NPAS2:DNA [nucleoplasm]' positively regulates 'Expression of FACTOR VII (F7)' ACTIVATION Activation of FACTOR VII expression by phosphorylated BMAL1:CLOCK is inferred from mouse. NPAS2 is predicted to act redundantly with CLOCK. Reactome Database ID Release 43549592 Reactome, http://www.reactome.org ReactomeREACT_27098 ribose 1-phosphate, deoxyribose 1-phosphate Converted from EntitySet in Reactome Reactome DB_ID: 500244 Reactome Database ID Release 43500244 Reactome, http://www.reactome.org ReactomeREACT_21637 'DP-1:E2F1 complex [nucleoplasm]' positively regulates 'Activation of E2F target genes at G1/S' ACTIVATION Reactome Database ID Release 43539112 Reactome, http://www.reactome.org ReactomeREACT_23404 Positive regulation of mHes1 transcription by mNICD1 chimeric enhancer complex ACTIVATION Reactome Database ID Release 432065279 Reactome, http://www.reactome.org ReactomeREACT_120360 'p53 ser-15 phosphorylated [nucleoplasm]' positively regulates 'Transcritional activation of p21 by p53 after DNA damage' ACTIVATION Reactome Database ID Release 43188380 Reactome, http://www.reactome.org ReactomeREACT_9386 'Myc/Max heterodimer [nucleoplasm]' positively regulates 'Activation of Cdc25A by c-myc' ACTIVATION Reactome Database ID Release 43188376 Reactome, http://www.reactome.org ReactomeREACT_9383 'p53 ser-15 phosphorylated [nucleoplasm]' positively regulates 'Transactivation of PUMA by p53' ACTIVATION Reactome Database ID Release 43159040 Reactome, http://www.reactome.org ReactomeREACT_5986 D2,4(S)2-PG Converted from EntitySet in Reactome Reactome DB_ID: 2065145 Reactome Database ID Release 432065145 Reactome, http://www.reactome.org ReactomeREACT_125480 'DP-1:E2F1 complex [nucleoplasm]' positively regulates 'Transactivation of PUMA by E2F1' ACTIVATION Reactome Database ID Release 43159042 Reactome, http://www.reactome.org ReactomeREACT_5935 dA, dG Converted from EntitySet in Reactome Reactome DB_ID: 500201 Reactome Database ID Release 43500201 Reactome, http://www.reactome.org ReactomeREACT_21606 deoxyadenosine, deoxyguanosine dAMP, dGMP Converted from EntitySet in Reactome Reactome DB_ID: 500199 Reactome Database ID Release 43500199 Reactome, http://www.reactome.org ReactomeREACT_21901 PathwayStep1111 PathwayStep1110 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399993 Reactome, http://www.reactome.org PathwayStep1107 ACTIVATION GENE ONTOLOGYGO:0005215 Reactome Database ID Release 432169020 Reactome, http://www.reactome.org PathwayStep1108 ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43139951 Reactome, http://www.reactome.org PathwayStep1105 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43140427 Reactome, http://www.reactome.org Abl tyrosine kinases Converted from EntitySet in Reactome Reactome DB_ID: 376002 Reactome Database ID Release 43376002 Reactome, http://www.reactome.org ReactomeREACT_19619 PathwayStep1106 ACTIVATION GENE ONTOLOGYGO:0019107 Reactome Database ID Release 43141353 Reactome, http://www.reactome.org SOS Converted from EntitySet in Reactome Reactome DB_ID: 167215 Reactome Database ID Release 43167215 Reactome, http://www.reactome.org ReactomeREACT_20305 PathwayStep1103 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43139902 Reactome, http://www.reactome.org PathwayStep1104 ACTIVATION GENE ONTOLOGYGO:0008597 Reactome Database ID Release 43140203 Reactome, http://www.reactome.org PathwayStep1101 PathwayStep1102 dAMP, dGMP, dIMP Converted from EntitySet in Reactome Reactome DB_ID: 500222 Reactome Database ID Release 43500222 Reactome, http://www.reactome.org ReactomeREACT_21509 PAK Converted from EntitySet in Reactome Reactome DB_ID: 428475 Reactome Database ID Release 43428475 Reactome, http://www.reactome.org ReactomeREACT_19955 NOTCH1 positively regulates HES5 transcription ACTIVATION Pubmed20972443 Reactome Database ID Release 431980080 Reactome, http://www.reactome.org ReactomeREACT_120334 SrGAP Converted from EntitySet in Reactome Reactome DB_ID: 428474 Reactome Database ID Release 43428474 Reactome, http://www.reactome.org ReactomeREACT_19581 NOTCH stimulates MYC expression ACTIVATION Reactome Database ID Release 431980079 Reactome, http://www.reactome.org ReactomeREACT_120351 dA, dG, dI Converted from EntitySet in Reactome Reactome DB_ID: 500224 Reactome Database ID Release 43500224 Reactome, http://www.reactome.org ReactomeREACT_22062 deoxyadenosine, deoxyguanosine, deoxyinosine NOTCH1 stimulates HES1 transcription ACTIVATION Reactome Database ID Release 431980075 Reactome, http://www.reactome.org ReactomeREACT_120340 PathwayStep1109 Stimulation of beta-casein transcription by ERBB4:STAT5A ACTIVATION Pubmed15534001 Pubmed18653779 Reactome Database ID Release 431254289 Reactome, http://www.reactome.org ReactomeREACT_117934 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432243940 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399974 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198624 Reactome, http://www.reactome.org IPS-1:TRAF2/TRAF6 Reactome DB_ID: 933465 Reactome Database ID Release 43933465 Reactome, http://www.reactome.org ReactomeREACT_25924 has a Stoichiometric coefficient of 1 PathwayStep1120 dsRNA:RIG-I/MDA5:IPS-1:TRAF2/TRAF6 Reactome DB_ID: 933467 Reactome Database ID Release 43933467 Reactome, http://www.reactome.org ReactomeREACT_26067 has a Stoichiometric coefficient of 1 PathwayStep1121 PathwayStep1122 dsRNA:RIG-I/MDA5:IPS-1:TRAF2/TRAF6:MEKK1 Reactome DB_ID: 933482 Reactome Database ID Release 43933482 Reactome, http://www.reactome.org ReactomeREACT_26122 has a Stoichiometric coefficient of 1 dsRNA:RIG-I/MDA5:IPS-1:TRAF2/TRAF6:TANK:TBK1/IKKi:IRF7 Reactome DB_ID: 933470 Reactome Database ID Release 43933470 Reactome, http://www.reactome.org ReactomeREACT_26674 has a Stoichiometric coefficient of 1 dsRNA:RIG-I/MDA5:IPS-1:TRAF2/TRAF6:TANK:TBK1/IKKi Reactome DB_ID: 933479 Reactome Database ID Release 43933479 Reactome, http://www.reactome.org ReactomeREACT_25493 has a Stoichiometric coefficient of 1 dsRNA:RIG-I/MDA5:IPS-1:TRAF2/TRAF6:TANK Reactome DB_ID: 933472 Reactome Database ID Release 43933472 Reactome, http://www.reactome.org ReactomeREACT_27050 has a Stoichiometric coefficient of 1 p-IRF3 dimer:PIN1 Reactome DB_ID: 936444 Reactome Database ID Release 43936444 Reactome, http://www.reactome.org ReactomeREACT_26699 has a Stoichiometric coefficient of 1 p-IRF3:p-IRF3 Reactome DB_ID: 936446 Reactome Database ID Release 43936446 Reactome, http://www.reactome.org ReactomeREACT_26064 has a Stoichiometric coefficient of 2 RNF125:E2 enzyme (UBE2K, UbcH5a-c):K48-polyubiquitin Reactome DB_ID: 936388 Reactome Database ID Release 43936388 Reactome, http://www.reactome.org ReactomeREACT_25756 has a Stoichiometric coefficient of 1 K48-Ub RIG-I/MDA5 Reactome DB_ID: 983460 Reactome Database ID Release 43983460 Reactome, http://www.reactome.org ReactomeREACT_25791 has a Stoichiometric coefficient of 1 (d)A, (d)G, (d)I Converted from EntitySet in Reactome Reactome DB_ID: 500124 Reactome Database ID Release 43500124 Reactome, http://www.reactome.org ReactomeREACT_21465 purine nucleosides (d)AMP, (d)GMP, (d)IMP Converted from EntitySet in Reactome Reactome DB_ID: 500125 Reactome Database ID Release 43500125 Reactome, http://www.reactome.org ReactomeREACT_21575 purine nucleotide monophosphates (deoxy)guanosine, (deoxy)inosine Converted from EntitySet in Reactome Reactome DB_ID: 500118 Reactome Database ID Release 43500118 Reactome, http://www.reactome.org ReactomeREACT_21894 dsRNA:RIG-I/MDA5:TRAF2/TRAF6:IPS-1:RIP-1/FADD:Casp-8/10 prodomain:IKK complex Reactome DB_ID: 933478 Reactome Database ID Release 43933478 Reactome, http://www.reactome.org ReactomeREACT_27017 has a Stoichiometric coefficient of 1 PathwayStep1113 PathwayStep1112 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399974 Reactome, http://www.reactome.org PathwayStep1115 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399974 Reactome, http://www.reactome.org PathwayStep1114 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399974 Reactome, http://www.reactome.org (d)GMP, (d)IMP Converted from EntitySet in Reactome Reactome DB_ID: 500120 Reactome Database ID Release 43500120 Reactome, http://www.reactome.org ReactomeREACT_21512 PathwayStep1117 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399974 Reactome, http://www.reactome.org PathwayStep1116 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399974 Reactome, http://www.reactome.org PathwayStep1119 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399974 Reactome, http://www.reactome.org PathwayStep1118 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 432399974 Reactome, http://www.reactome.org 'NKX2-2 [nucleoplasm]' positively regulates 'MAFA-, NKX2-2-, PAX6-, and PDX1-dependent synthesis of insulin precursor protein' ACTIVATION Reactome Database ID Release 43211292 Reactome, http://www.reactome.org ReactomeREACT_14752 PathwayStep1132 'PDX1 [nucleoplasm]' positively regulates 'MAFA-, NKX2-2-, PAX6-, and PDX1-dependent synthesis of insulin precursor protein' ACTIVATION Reactome Database ID Release 43211290 Reactome, http://www.reactome.org ReactomeREACT_14717 PathwayStep1133 'PAX6 [nucleoplasm]' positively regulates 'MAFA-, NKX2-2-, PAX6-, and PDX1-dependent synthesis of insulin precursor protein' ACTIVATION Reactome Database ID Release 43211287 Reactome, http://www.reactome.org ReactomeREACT_14725 PathwayStep1130 IPS-1:RIP-1/FADD:procaspase-8/10 Reactome DB_ID: 933475 Reactome Database ID Release 43933475 Reactome, http://www.reactome.org ReactomeREACT_26518 has a Stoichiometric coefficient of 1 'Forkhead box protein O1A [nucleoplasm]' negatively regulates 'FOXOA2-, MAFA-, and PAX6-dependent synthesis of PDX1 protein' INHIBITION Reactome Database ID Release 43211284 Reactome, http://www.reactome.org ReactomeREACT_14774 PathwayStep1131 'NEUROD1 [nucleoplasm]' positively regulates 'NEUROD1- and PDX1-dependent synthesis of glucokinase (GCK) protein' ACTIVATION Reactome Database ID Release 43633895 Reactome, http://www.reactome.org ReactomeREACT_23411 dsRNA:RIG-I/MDA5:IPS-1:RIP-1/FADD:procaspase-8/10 dimer Reactome DB_ID: 933483 Reactome Database ID Release 43933483 Reactome, http://www.reactome.org ReactomeREACT_26858 has a Stoichiometric coefficient of 1 'PDX1 [nucleoplasm]' positively regulates 'PDX1-dependent synthesis of NKX6-1 protein' ACTIVATION Reactome Database ID Release 43211357 Reactome, http://www.reactome.org ReactomeREACT_14767 FADD:procaspase-8/10 Reactome DB_ID: 933481 Reactome Database ID Release 43933481 Reactome, http://www.reactome.org ReactomeREACT_26671 has a Stoichiometric coefficient of 1 'PDX1 [nucleoplasm]' positively regulates 'PDX1-dependent synthesis of IAPP protein' ACTIVATION Reactome Database ID Release 43211304 Reactome, http://www.reactome.org ReactomeREACT_14756 FADD:procaspase-8/10 dimer Reactome DB_ID: 933474 Reactome Database ID Release 43933474 Reactome, http://www.reactome.org ReactomeREACT_26662 has a Stoichiometric coefficient of 1 'MAFA [nucleoplasm]' positively regulates 'MAFA-, NKX2-2-, PAX6-, and PDX1-dependent synthesis of insulin precursor protein' ACTIVATION Reactome Database ID Release 43211358 Reactome, http://www.reactome.org ReactomeREACT_14736 IPS-1:RIP-1/FADD:procaspase-8/10 dimer Reactome DB_ID: 933477 Reactome Database ID Release 43933477 Reactome, http://www.reactome.org ReactomeREACT_26951 has a Stoichiometric coefficient of 1 dsRNA:RIG-I/MDA5:TRAF2/TRAF6:IPS-1:RIP-1/FADD:Casp-8/10 prodomain Reactome DB_ID: 933473 Reactome Database ID Release 43933473 Reactome, http://www.reactome.org ReactomeREACT_26324 has a Stoichiometric coefficient of 1 procaspase-8/10 dimer Reactome DB_ID: 933469 Reactome Database ID Release 43933469 Reactome, http://www.reactome.org ReactomeREACT_25479 has a Stoichiometric coefficient of 2 'HNF1A [nucleoplasm]' positively regulates 'HNF1A-dependent synthesis of GLUT2 protein' ACTIVATION Reactome Database ID Release 43211497 Reactome, http://www.reactome.org ReactomeREACT_14720 FADD:Casp-8/10 prodomain Reactome DB_ID: 933480 Reactome Database ID Release 43933480 Reactome, http://www.reactome.org ReactomeREACT_25809 has a Stoichiometric coefficient of 1 'PDX1 [nucleoplasm]' positively regulates 'NEUROD1- and PDX1-dependent synthesis of glucokinase (GCK) protein' ACTIVATION Reactome Database ID Release 43633894 Reactome, http://www.reactome.org ReactomeREACT_23410 IPS-1:RIP-1/FADD:Casp-8/10 prodomain Reactome DB_ID: 933466 Reactome Database ID Release 43933466 Reactome, http://www.reactome.org ReactomeREACT_26433 has a Stoichiometric coefficient of 1 IPS-1:RIP-1/FADD Reactome DB_ID: 918293 Reactome Database ID Release 43918293 Reactome, http://www.reactome.org ReactomeREACT_26264 has a Stoichiometric coefficient of 1 AMP, dAMP, GMP, IMP Converted from EntitySet in Reactome Reactome DB_ID: 500101 Reactome Database ID Release 43500101 Reactome, http://www.reactome.org ReactomeREACT_21632 dsRNA:RIG-I/MDA5:IPS-1:RIP-1/FADD:Procasp-8/10 Reactome DB_ID: 933468 Reactome Database ID Release 43933468 Reactome, http://www.reactome.org ReactomeREACT_26650 has a Stoichiometric coefficient of 1 adenosine, deoxyadenosine, guanosine, inosine Converted from EntitySet in Reactome Reactome DB_ID: 500104 Reactome Database ID Release 43500104 Reactome, http://www.reactome.org ReactomeREACT_21681 PathwayStep1126 PathwayStep1125 PathwayStep1124 PathwayStep1123 PathwayStep1129 GMP, IMP Converted from EntitySet in Reactome Reactome DB_ID: 500260 Reactome Database ID Release 43500260 Reactome, http://www.reactome.org ReactomeREACT_21428 PathwayStep1128 guanine, hypoxanthine Converted from EntitySet in Reactome Reactome DB_ID: 500259 Reactome Database ID Release 43500259 Reactome, http://www.reactome.org ReactomeREACT_21911 PathwayStep1127 'HNF6 [nucleoplasm]' positively regulates 'HNF6-dependent synthesis of NEUROG3 protein during morphogenesis' ACTIVATION Reactome Database ID Release 43210852 Reactome, http://www.reactome.org ReactomeREACT_14741 PathwayStep1141 PathwayStep1142 'RBPJ [nucleoplasm]' positively regulates 'RBPJ- and NOTCH1-dependent synthesis of HES1 protein during morphogenesis' ACTIVATION Reactome Database ID Release 43210840 Reactome, http://www.reactome.org ReactomeREACT_14719 PathwayStep1143 'NOTCH1 intracellular domain [nucleoplasm]' positively regulates 'RBPJ- and NOTCH1-dependent synthesis of HES1 protein during morphogenesis' ACTIVATION Reactome Database ID Release 43210855 Reactome, http://www.reactome.org ReactomeREACT_14734 PathwayStep1144 PathwayStep1140 'FOXOA2 [nucleoplasm]' positively regulates 'FOXOA2-, MAFA-, and PAX6-dependent synthesis of PDX1 protein' ACTIVATION Reactome Database ID Release 43211277 Reactome, http://www.reactome.org ReactomeREACT_14713 dsRNA:RIG-I/MDA5:IPS-1:RIP-1/FADD Reactome DB_ID: 918291 Reactome Database ID Release 43918291 Reactome, http://www.reactome.org ReactomeREACT_26077 has a Stoichiometric coefficient of 1 'MAFA [nucleoplasm]' positively regulates 'FOXOA2-, MAFA-, and PAX6-dependent synthesis of PDX1 protein' ACTIVATION Reactome Database ID Release 43211282 Reactome, http://www.reactome.org ReactomeREACT_14722 IRF3 bound to IFN-beta promoter Reactome DB_ID: 1027359 Reactome Database ID Release 431027359 Reactome, http://www.reactome.org ReactomeREACT_25617 has a Stoichiometric coefficient of 1 IRF3-P dimer:CBP/p300 Reactome DB_ID: 1027364 Reactome Database ID Release 431027364 Reactome, http://www.reactome.org ReactomeREACT_26303 has a Stoichiometric coefficient of 1 'PAX6 [nucleoplasm]' positively regulates 'FOXOA2-, MAFA-, and PAX6-dependent synthesis of PDX1 protein' ACTIVATION Reactome Database ID Release 43211575 Reactome, http://www.reactome.org ReactomeREACT_14742 IRF3-P:IRF7-P Reactome DB_ID: 1027367 Reactome Database ID Release 431027367 Reactome, http://www.reactome.org ReactomeREACT_26957 has a Stoichiometric coefficient of 1 'NEUROG3 [nucleoplasm]' positively regulates 'NEUROG3-dependent synthesis of NEUROD1' ACTIVATION Reactome Database ID Release 43210926 Reactome, http://www.reactome.org ReactomeREACT_14753 dsRNA:RIG-1/MDA5:IPS-1:Ub-TRAF3:TBK1/IKKi:IRF3/IRF7 Reactome DB_ID: 918199 Reactome Database ID Release 43918199 Reactome, http://www.reactome.org ReactomeREACT_25519 has a Stoichiometric coefficient of 1 'NEUROG3 [nucleoplasm]' positively regulates 'NEUROG3-dependent synthesis of PAX4 protein' ACTIVATION Reactome Database ID Release 43633898 Reactome, http://www.reactome.org ReactomeREACT_23406 dsRNA:RIG-1/MDA5:IPS-1:Ub-TRAF3:TBK1/IKKi Reactome DB_ID: 918196 Reactome Database ID Release 43918196 Reactome, http://www.reactome.org ReactomeREACT_26022 has a Stoichiometric coefficient of 1 'NEUROG3 [nucleoplasm]' positively regulates 'NEUROG3-dependent synthesis of INSM1' ACTIVATION Reactome Database ID Release 43210929 Reactome, http://www.reactome.org ReactomeREACT_14737 TBK1/IKKi:SIKE1 Reactome DB_ID: 918197 Reactome Database ID Release 43918197 Reactome, http://www.reactome.org ReactomeREACT_25799 has a Stoichiometric coefficient of 1 'NEUROG3 [nucleoplasm]' positively regulates 'NEUROG3-dependent synthesis of NKX2-2' ACTIVATION Reactome Database ID Release 43210927 Reactome, http://www.reactome.org ReactomeREACT_14740 dsRNA:RIG-1/MDA5:IPS-1:Ub-TRAF3 Reactome DB_ID: 918200 Reactome Database ID Release 43918200 Reactome, http://www.reactome.org ReactomeREACT_26564 has a Stoichiometric coefficient of 1 thymidine, deoxyuridine Converted from EntitySet in Reactome Reactome DB_ID: 500444 Reactome Database ID Release 43500444 Reactome, http://www.reactome.org ReactomeREACT_21955 dsRNA:RIG-I/MDA5:NLRC5 Reactome DB_ID: 937325 Reactome Database ID Release 43937325 Reactome, http://www.reactome.org ReactomeREACT_26732 has a Stoichiometric coefficient of 1 thymine, uracil Converted from EntitySet in Reactome Reactome DB_ID: 500438 Reactome Database ID Release 43500438 Reactome, http://www.reactome.org ReactomeREACT_22075 dsRNA:RIG-I/MDA5:IPS-1 Reactome DB_ID: 918201 Reactome Database ID Release 43918201 Reactome, http://www.reactome.org ReactomeREACT_26220 has a Stoichiometric coefficient of 1 IPS-1:NLRX1 Reactome DB_ID: 936561 Reactome Database ID Release 43936561 Reactome, http://www.reactome.org ReactomeREACT_26115 has a Stoichiometric coefficient of 1 (deoxy)uridine Converted from EntitySet in Reactome Reactome DB_ID: 500430 Reactome Database ID Release 43500430 Reactome, http://www.reactome.org ReactomeREACT_21686 PathwayStep1139 PathwayStep1138 DCC/Neogenin Converted from EntitySet in Reactome Reactome DB_ID: 593676 Reactome Database ID Release 43593676 Reactome, http://www.reactome.org ReactomeREACT_22539 PathwayStep1135 DCC/UNC5A Converted from EntitySet in Reactome Reactome DB_ID: 593684 Reactome Database ID Release 43593684 Reactome, http://www.reactome.org ReactomeREACT_23092 PathwayStep1134 PathwayStep1137 RGD Converted from EntitySet in Reactome Reactome DB_ID: 374581 Reactome Database ID Release 43374581 Reactome, http://www.reactome.org ReactomeREACT_22662 Repulsive guidance molecules PathwayStep1136 'FGF10 [extracellular region]' positively regulates 'HNF1B- and FGF10-dependent synthesis of PTF1A protein' ACTIVATION Reactome Database ID Release 43210759 Reactome, http://www.reactome.org ReactomeREACT_14750 PathwayStep1154 'HNF1B [nucleoplasm]' positively regulates 'HNF1B- and FGF10-dependent synthesis of PTF1A protein' ACTIVATION Reactome Database ID Release 43210776 Reactome, http://www.reactome.org ReactomeREACT_14708 PathwayStep1155 PathwayStep1152 PathwayStep1153 PathwayStep1150 PathwayStep1151 'HES1 [nucleoplasm]' negatively regulates 'HNF6-dependent synthesis of NEUROG3 protein during morphogenesis' INHIBITION Reactome Database ID Release 43210847 Reactome, http://www.reactome.org ReactomeREACT_14712 MDA5:DAK Reactome DB_ID: 918203 Reactome Database ID Release 43918203 Reactome, http://www.reactome.org ReactomeREACT_25465 has a Stoichiometric coefficient of 1 'HNF6 [nucleoplasm]' positively regulates 'HNF6-dependent synthesis of ONECUT3 protein during morphogenesis' ACTIVATION Reactome Database ID Release 43210849 Reactome, http://www.reactome.org ReactomeREACT_14772 Ub-RIG-I K-63-linked polyubiquitin RIG-I Reactome DB_ID: 918191 Reactome Database ID Release 43918191 Reactome, http://www.reactome.org ReactomeREACT_26331 has a Stoichiometric coefficient of 1 'HNF6 [nucleoplasm]' positively regulates 'HNF6-dependent synthesis of HNF1B protein' ACTIVATION Reactome Database ID Release 43210841 Reactome, http://www.reactome.org ReactomeREACT_14702 dsRNA:RIG-I/MDA5 Converted from EntitySet in Reactome Reactome DB_ID: 918192 Reactome Database ID Release 43918192 Reactome, http://www.reactome.org ReactomeREACT_25628 'PDX1 [nucleoplasm]' positively regulates 'PDX1-dependent synthesis of NKX6-1 protein' ACTIVATION Reactome Database ID Release 43210761 Reactome, http://www.reactome.org ReactomeREACT_14760 dsRNA:MDA5 Reactome DB_ID: 913727 Reactome Database ID Release 43913727 Reactome, http://www.reactome.org ReactomeREACT_26245 has a Stoichiometric coefficient of 1 'PDX1 [nucleoplasm]' positively regulates 'PDX1-dependent synthesis of NR5A2 protein' ACTIVATION Reactome Database ID Release 43210790 Reactome, http://www.reactome.org ReactomeREACT_14710 ISG15:RIG-I conjugate Reactome DB_ID: 936557 Reactome Database ID Release 43936557 Reactome, http://www.reactome.org ReactomeREACT_26209 has a Stoichiometric coefficient of 1 'HNF6 [nucleoplasm]' positively regulates 'HNF6- and FGF10-dependent synthesis of PDX1 protein' ACTIVATION Reactome Database ID Release 43210763 Reactome, http://www.reactome.org ReactomeREACT_14733 'FGF10 [extracellular region]' positively regulates 'HNF6- and FGF10-dependent synthesis of PDX1 protein' ACTIVATION Reactome Database ID Release 43210779 Reactome, http://www.reactome.org ReactomeREACT_14768 dsRNA:Ub-RIG-I:TRIM25 Reactome DB_ID: 918190 Reactome Database ID Release 43918190 Reactome, http://www.reactome.org ReactomeREACT_26009 has a Stoichiometric coefficient of 2 'HNF6 [nucleoplasm]' positively regulates 'HNF6-dependent synthesis of ONECUT3 protein during early pancreas specification' ACTIVATION Reactome Database ID Release 43210781 Reactome, http://www.reactome.org ReactomeREACT_14724 ISG15:UBEIL/UbcH8:CEB1 Reactome DB_ID: 936560 Reactome Database ID Release 43936560 Reactome, http://www.reactome.org ReactomeREACT_26934 has a Stoichiometric coefficient of 1 F-actin capping protein fragment TRTK12:S100B homodimer Reactome DB_ID: 879368 Reactome Database ID Release 43879368 Reactome, http://www.reactome.org ReactomeREACT_26773 has a Stoichiometric coefficient of 1 AGER ligands:AGER:ERK Reactome DB_ID: 879427 Reactome Database ID Release 43879427 Reactome, http://www.reactome.org ReactomeREACT_26296 has a Stoichiometric coefficient of 1 AGE adducts:Peptide:AGER-1,2,3 Reactome DB_ID: 879489 Reactome Database ID Release 43879489 Reactome, http://www.reactome.org ReactomeREACT_26619 has a Stoichiometric coefficient of 1 dsRNA bound to RIG-I Reactome DB_ID: 168906 Reactome Database ID Release 43168906 Reactome, http://www.reactome.org ReactomeREACT_25966 has a Stoichiometric coefficient of 2 PathwayStep1149 PathwayStep1148 Slit (1-3) Converted from EntitySet in Reactome Reactome DB_ID: 390366 Reactome Database ID Release 43390366 Reactome, http://www.reactome.org ReactomeREACT_22560 PathwayStep1147 PathwayStep1146 PathwayStep1145 adenosine, deoxyadenosine Converted from EntitySet in Reactome Reactome DB_ID: 500173 Reactome Database ID Release 43500173 Reactome, http://www.reactome.org ReactomeREACT_21870 (d)GDP + ADP <=> (d)GMP + ATP [GUK1] Cytosolic guanylate kinase 1 (GUK1) catalyzes the reversible reactions of GDP and dGDP with ADP to form GMP and dGMP respectively and ATP. While native gel electrophoretic studies of whole cell extracts suggested the existence of multiple human enzymes with guanylate kinase activity (Jamil et al. 1975), only one has been purified and biochemically characterized (Agarwal et al. 1978; Brady et al. 1996). The enzyme is of clinical importance as it is a target of antitumor drugs and antiviral drugs such as acyclovir (Miller and Miller 1980). EC Number: 2.7.4.8 Pubmed177353 Pubmed211390 Pubmed6248551 Pubmed8663313 Reactome Database ID Release 43110133 Reactome, http://www.reactome.org ReactomeREACT_1256 (d)CMP or UMP + ATP <=> (d)CDP or UDP + ADP [CMPK1] Cytosolic UMP-CMP kinase (CMPK1) catalyzes the reversible reaction of CMP, dCMP, or UMP and ATP to form CDP, dCDP, or UDP and ADP (Liou et al. 2002; Scott and Wright 1979). EC Number: 2.7.4.4 Pubmed11912132 Pubmed40615 Reactome Database ID Release 4373548 Reactome, http://www.reactome.org ReactomeREACT_1618 (d)CDP or UDP + ADP <=> (d)CMP or UMP + ATP [CMPK1] Cytosolic UMP-CMP kinase (CMPK1) catalyzes the reversible reaction of CDP, dCDP, or UDP and ADP to form CMP, dCMP, or UMP and ATP (Liou et al. 2002; Scott and Wright 1979). EC Number: 2.7.4.4 Pubmed11912132 Pubmed40615 Reactome Database ID Release 4375125 Reactome, http://www.reactome.org ReactomeREACT_247 phosphorylation of dUMP or TMP to dUDP or TDP Cytosolic deoxythymidylate kinase (DTYMK) catalyzes the reversible reaction of either dUMP or TMP with ATP to form dUDP or TDP. The active form of the enzyme is a homodimer (Lee and Cheng 1977). EC Number: 2.7.4.4 Pubmed18469 Reactome Database ID Release 4373635 Reactome, http://www.reactome.org ReactomeREACT_273 dUMP or TMP + ATP <=> dUDP or TDP + ADP [DTYMK] dUDP or TDP + ADP <=> dUMP or TMP + ATP [DTYMK] Cytosolic deoxythymidylate kinase (DTYMK) catalyzes the reversible reaction of either dUDP or TDP with ADP to form dUMP or TMP. The active form of the enzyme is a homodimer (Lee and Cheng 1977). EC Number: 2.7.4.4 Pubmed18469 Reactome Database ID Release 4375126 Reactome, http://www.reactome.org ReactomeREACT_636 UTP + glutamine + ATP + H2O => CTP + glutamate + ADP + orthophosphate [CTPS] Cytosolic CTP synthase 1 (CTPS) catalyzes the reaction of UTP, glutamine, ATP and water to form CTP, glutamate, ADP, and orthophosphate (Han et al. 2005). The active form of the enzyme is a tetramer (Kursala et al. 2006). Both CTPS and a second human gene product, CPTS2, have CTP synthase activity in various test systems; their relative contributions to CTP metabolism in the body is not clear. EC Number: 6.3.4.2 Pubmed16179339 Pubmed16820675 Reactome Database ID Release 4373647 Reactome, http://www.reactome.org ReactomeREACT_574 amination of uridine 5'-triphosphate (UTP) to form cytidine 5'-triphosphate (CTP) ADP + ADP <=> AMP + ATP [AK2] EC Number: 2.7.4.3 Mitochondrial adenylate kinase 2 (AK2) catalyzes the reaction of two molecules of ADP to form AMP and ATP (Hamade et al. 1982). Localization of AK2 specifically to the mitochondrial intermembrane space is inferred from studies of the homologous rat enzyme (Criss 1970). Pubmed5484814 Pubmed6182143 Reactome Database ID Release 43110144 Reactome, http://www.reactome.org ReactomeREACT_2031 has a Stoichiometric coefficient of 2 (d)AMP or (d)CMP + ATP <=> (d)ADP or (d)CDP + ADP [AK5] Cytosolic adenylate kinase 5 [AK5] catalyzes the reactions of (d)AMP and (d)CMP with ATP to form (d)ADP and (d)CDP, respectively, and ADP. In the body AK5 expression was observed only in brain of nine tissues tested by Northern blotting (Van Rompay et al. 1999). AK5 is inferred to occur as a dimer from unpublished crystallographic data obtained for the catalytically active carboxyterminal third of the protein (PDB 2BWJ). Pubmed10215863 Reactome Database ID Release 43110138 Reactome, http://www.reactome.org ReactomeREACT_271 (d)ADP or (d)CDP + ADP <=> (d)AMP or (d)CMP + ATP [AK5] Cytosolic adenylate kinase 5 [AK5] catalyzes the reactions of (d)ADP and (d)CDP with ADP to form (d)AMP and (d)CMP, respectively, and ATP. In the body AK5 expression was observed only in brain of nine tissues tested by Northern blotting (Van Rompay et al. 1999). AK5 is inferred to occur as a dimer from unpublished crystallographic data obtained for the catalytically active carboxyterminal third of the protein (PDB 2BWJ). Pubmed10215863 Reactome Database ID Release 43110137 Reactome, http://www.reactome.org ReactomeREACT_1716 (d)GMP + ATP <=> (d)GDP + ADP [GUK1] Cytosolic guanylate kinase 1 (GUK1) catalyzes the reversible reactions of GMP and dGMP with ATP to form GDP and dGDP respectively and ADP. While native gel electrophoretic studies of whole cell extracts suggested the existence of multiple human enzymes with guanylate kinase activity (Jamil et al. 1975), only one has been purified and biochemically characterized (Agarwal et al. 1978; Brady et al. 1996). The enzyme is of clinical importance as it is a target of antitumor drugs and antiviral drugs such as acyclovir (Miller and Miller 1980). EC Number: 2.7.4.8 Pubmed177353 Pubmed211390 Pubmed6248551 Pubmed8663313 Reactome Database ID Release 4373788 Reactome, http://www.reactome.org ReactomeREACT_1606 Purine nucleotide Converted from EntitySet in Reactome Reactome DB_ID: 170037 Reactome Database ID Release 43170037 Reactome, http://www.reactome.org ReactomeREACT_6384 (d)NDP + ATP <=> (d)NTP + ADP [NME1,2,3] Authored: D'Eustachio, P, 2010-02-05 Cytosolic nucleoside diphosphate kinases catalyze the reversible reaction of ribonucleoside and deoxyribonucleoside 5'-diphosphates with ATP to form the corresponding nucleoside 5'-triphosphates and ADP. These kinases are ubiquitously expressed enzymes with broad substrate specificities (Berg and Joklik 1954; Parks and Agarwal 1973). Three human cytosolic nucleoside diphosphate kinase proteins, NME1, 2, and 3, have been characterized biochemically (Gilles et al. 1991; Schaertl et al. 1998; Erent et al. 2001; Chen et al. 2003). All are catalytically active as hexamers: homohexamers of NME1, 2, and 3 have been described, as have heterohexamers containing all possible combinations of NME1 and 2 (Gilles et al. 1991; Erent et al. 2001).<p>While cytosolic nucleoside diphosphate kinases can efficiently use several nucleotide triphosphates as a phosphate donor, the high concentrations of ATP relative to other nucleoside triphosphates in vivo makes it the likely major phosphate donor in these reactions and only reactions with ATP as the phosphate donor are annotated. All of these phosphorylation reactions are freely reversible in vitro (Parks and Agarwal 1973; Schaertl et al. 1998), but the high ratio of ATP to ADP concentrations in the cytosol should favor the conversion of (d)NDP and ATP to (d)NTP and ADP. EC Number: 2.7.4.6 Edited: D'Eustachio, P, 2010-02-05 ISBN0121227022 Pubmed11277919 Pubmed12972261 Pubmed13211603 Pubmed1851158 Pubmed9488696 Reactome Database ID Release 43482619 Reactome, http://www.reactome.org ReactomeREACT_21416 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 regeneration of active (reduced) Thioredoxin Cytosolic thioredoxin reductase catalyzes the reaction of thioredoxin, oxidized and NADPH + H+ to form thioredoxin, reduced and NADP+ (Urig et al. 2006). EC Number: 1.8.1.9 Pubmed16750198 Reactome Database ID Release 4373646 Reactome, http://www.reactome.org ReactomeREACT_1609 thioredoxin, oxidized + NADPH + H+ => thioredoxin, reduced + NADP+ thioredoxin, reduced (cytosol) <=> thioredoxin, reduced (nucleus) In this reaction, 1 molecule of 'Thioredoxin' is translocated from cytosol to nucleoplasm.<br><br>This movement of the molecule occurs through the 'nuclear pore'.<br> Reactome Database ID Release 43111805 Reactome, http://www.reactome.org ReactomeREACT_711 glutathione (oxidized) + NADPH + H+ => 2 glutathione (reduced) + NADP+ Cytosolic glutathione reductase catalyzes the reaction of glutathione (oxidized) and NADPH + H+ to form two molecules of glutathione (reduced) and NADP+ (Loos et al. 1976). EC Number: 1.8.1.7 Pubmed947404 Reactome Database ID Release 4371682 Reactome, http://www.reactome.org ReactomeREACT_2220 has a Stoichiometric coefficient of 2 thioredoxin, oxidized (nucleus) <=> thioredoxin, oxidized (cytosol) In this reaction, 1 molecule of 'thioredoxin, oxidized' is translocated from nucleoplasm to cytosol.<br><br>This movement of the molecule occurs through the 'nuclear pore'.<br> Reactome Database ID Release 43111806 Reactome, http://www.reactome.org ReactomeREACT_1678 NDP + reduced thioredoxin => dNDP + oxidized thioredoxin + H2O Deoxyribonucleotides needed for DNA repair are synthesized de novo by the reduction of ribonucleoside 5'-diphosphates. This reaction is catalyzed by a nuclear form of ribonucleotide reductase active throughout the cell cycle. The reducing equivalents needed for these reactions can be provided directly by thioredoxin. EC Number: 1.17.4.1 Reactome Database ID Release 43111804 Reactome, http://www.reactome.org ReactomeREACT_642 Reduction of nuclear ribonucleoside 5'-diphosphates to deoxyribonucleoside 5'-diphosphates (thioredoxin) glutaredoxin (oxidized) + glutathione (reduced) => glutaredoxin (reduced) + glutathione (oxidized) Cytosolic glutaredoxin (oxidized) and glutathione (reduced) react to form glutaredoxin (reduced) and glutathione (oxidized) (Padilla et al. 1995). Pubmed7851394 Reactome Database ID Release 43111746 Reactome, http://www.reactome.org ReactomeREACT_1461 NDP + reduced glutaredoxin => dNDP + oxidized glutaredoxin + H2O Cytosolic ribonucleotide reductase catalyzes the reduction of adenine, guanine, cytidine, and uridine ribonucleoside 5'-diphosphates to form the corresponding deoxyribonucleoside 5'-diphosphates, coupled to the oxidation of glutaredoxin (Eklund et al. 2001). Ribonucleotide reductase is a tetramer of two large and two small subunits (Shao et al. 2004; Zhou et al. 2005). The overall activity of the enzyme is regulated allosterically: ATP binding is stimulatory while dATP binding is inhibitory (Reichard et al. 2000).<p>The reducing equivalents needed for ribonucleotide reductase activity can be provided by either of two small proteins, glutaredoxin and thioredoxin (Holmgren 1989; Sun et al. 1998). Both are re-reduced with NADPH as the donor of reducing equivalents, and so are active in catalytic amounts. The relative contributions of glutaredoxin and thioredoxin in vivo are unknown. Pubmed10884394 Pubmed11796141 Pubmed14729598 Pubmed16373698 Pubmed2668278 Pubmed9677297 Reactome Database ID Release 43111742 Reactome, http://www.reactome.org ReactomeREACT_375 Reduction of cytosolic ribonucleoside 5'-diphosphates to deoxyribonucleoside 5'-diphosphates (glutaredoxin) NDP + reduced thioredoxin => dNDP + oxidized thioredoxin + H2O Cytosolic ribonucleotide reductase catalyzes the reduction of adenine, guanine, cytidine, and uridine ribonucleoside 5'-diphosphates to form the corresponding deoxyribonucleoside 5'-diphosphates, coupled to the oxidation of thioredoxin (Holmgren 1989; Eklund et al. 2001). Ribonucleotide reductase is a tetramer of two large and two small subunits (Shao et al. 2004; Zhou et al. 2005). The overall activity of the enzyme is regulated allosterically: ATP binding is stimulatory while dATP binding is inhibitory (Reichard et al. 2000).<p>The reducing equivalents needed for ribonucleotide reductase activity can be provided by either of two small proteins, glutaredoxin and thioredoxin (Holmgren 1989; Sun et al. 1998). Both are re-reduced with NADPH as the donor of reducing equivalents, and so are active in catalytic amounts. The relative contributions of glutaredoxin and thioredoxin in vivo are unknown. Pubmed10884394 Pubmed11796141 Pubmed14729598 Pubmed16373698 Pubmed2668278 Pubmed9677297 Reactome Database ID Release 43111751 Reactome, http://www.reactome.org ReactomeREACT_2182 Reduction of cytosolic ribonucleoside 5'-diphosphates to deoxyribonucleoside 5'-diphosphates (thioredoxin) UTP + glutamine + ATP + H2O => CTP + glutamate + ADP + orthophosphate [CTPS2] Cytosolic CTP synthase 2 (CTPS) catalyzes the reaction of UTP, glutamine, ATP and water to form CTP, glutamate, ADP, and orthophosphate (Han et al. 2005; van Kuilenberg et al. 2000). Unpublished X-ray crystallographic data suggest that the enzyme is a tetramer (PDB 3IHL). Both CTPS2 and a second human gene product, CPTS, have CTP synthase activity in various test systems; their relative contributions to CTP metabolism in the body is not clear. EC Number: 6.3.4.2 Pubmed10899599 Pubmed16179339 Reactome Database ID Release 43504054 Reactome, http://www.reactome.org ReactomeREACT_21305 amination of uridine 5'-triphosphate (UTP) to form cytidine 5'-triphosphate (CTP) uridine 5'-diphosphate (cytosolic) <=> uridine 5'-diphosphate (nuclear) In this reaction, 1 molecule of 'uridine 5'-diphosphate' is translocated from cytosol to nucleoplasm.<br><br>This movement of the molecule occurs through the 'nuclear pore'.<br> Reactome Database ID Release 43111815 Reactome, http://www.reactome.org ReactomeREACT_409 ITP + H2O => IMP + PPi Authored: D'Eustachio, P, 2012-10-05 Cytosolic ITPA dimer catalyzes the reaction of ITP and water to form IMP and PPi (pyrophosphate). Mg++ is required for enzymatic activity. The hydrolysis of ITP is thought to prevent its incorporation into mRNA, which would lead to aberrant protein synthesis (Lin et al. 2001; Abolhassani et al. 2010). Edited: D'Eustachio, P, 2012-10-05 ITPA hydrolyses ITP to IMP Pubmed11278832 Pubmed20081199 Reactome Database ID Release 432509827 Reactome, http://www.reactome.org ReactomeREACT_150277 Reviewed: Ito, Riyoko, 2012-10-05 dITP + H2O => dIMP + PPi Authored: D'Eustachio, P, 2012-10-05 Cytosolic ITPA dimer catalyzes the reaction of dITP and water to form dIMP and PPi (pyrophosphate). Mg++ is required for enzymatic activity. The hydrolysis of dITP is thought to prevent its incorporation into DNA, which would be mutagenic (Lin et al. 2001; Abolhassani et al. 2010). Edited: D'Eustachio, P, 2012-10-05 ITPA hydrolyses dITP to dIMP Pubmed11278832 Pubmed20081199 Reactome Database ID Release 432509838 Reactome, http://www.reactome.org ReactomeREACT_150247 Reviewed: Ito, Riyoko, 2012-10-05 XTP + H2O => XMP + PPi Authored: D'Eustachio, P, 2012-10-05 Cytosolic ITPA dimer catalyzes the reaction of XTP and water to form XMP and PPi (pyrophosphate). Mg++ is required for enzymatic activity. The hydrolysis of XTP is thought to prevent its incorporation into mRNA, which would lead to aberrant protein synthesis (Lin et al. 2001; Abolhassani et al. 2010). Edited: D'Eustachio, P, 2012-10-05 ITPA hydrolyses XTP to XMP Pubmed11278832 Pubmed20081199 Reactome Database ID Release 432509831 Reactome, http://www.reactome.org ReactomeREACT_150195 Reviewed: Ito, Riyoko, 2012-10-05 (d)NTP + ADP <=> (d)NDP + ATP [NME4] Authored: D'Eustachio, P, 2010-02-05 EC Number: 2.7.4.6 Edited: D'Eustachio, P, 2010-02-05 Nucleoside diphosphate kinase NME4 associated with the inner mitochondrial membrane (Tokarska-Schlattner et al. 2008) catalyzes the reversible reaction of ribonucleoside and deoxyribonucleoside 5'-diphosphates with ADP to form the corresponding nucleoside 5'-diphosphates and ATP. The active form of the enzyme is a hexamer of NME4 polypeptides whose amino-terminal 33 residues, a mitochondrial translocation signal, have been removed (Milon et al. 2000). The substrate specificity of NME4 has not been examined in detail, but is inferred to be broad like that of the homologous NME1, 2, and 3 kinases (Schaertl et al. 1998). Pubmed10799505 Pubmed18635542 Pubmed9488696 Reactome Database ID Release 43482812 Reactome, http://www.reactome.org ReactomeREACT_21292 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 adenosine 5'-diphosphate (cytosolic) <=> adenosine 5'-diphosphate (nuclear) In this reaction, 1 molecule of 'ADP' is translocated from cytosol to nucleoplasm.<br><br>This movement of the molecule occurs through the 'nuclear pore'.<br> Reactome Database ID Release 43111787 Reactome, http://www.reactome.org ReactomeREACT_1380 cytidine 5'-diphosphate (cytosolic) <=> cytidine 5'-diphosphate (nuclear) In this reaction, 1 molecule of 'cytidine 5'-diphosphate' is translocated from cytosol to nucleoplasm.<br><br>This movement of the molecule occurs through the 'nuclear pore'.<br> Reactome Database ID Release 43111811 Reactome, http://www.reactome.org ReactomeREACT_1048 guanosine 5'-diphosphate (cytosolic) <=> guanosine 5'-diphosphate (nuclear) In this reaction, 1 molecule of 'GDP' is translocated from cytosol to nucleoplasm.<br><br>This movement of the molecule occurs through the 'nuclear pore'.<br> Reactome Database ID Release 43111812 Reactome, http://www.reactome.org ReactomeREACT_844 (d)NTP + ADP <=> (d)NDP + ATP [NME1,2,3] Authored: D'Eustachio, P, 2010-02-05 Cytosolic nucleoside diphosphate kinases catalyze the reversible reaction of ribonucleoside and deoxyribonucleoside 5'-diphosphates with ADP to form the corresponding nucleoside 5'-diphosphates and ATP. These kinases are ubiquitously expressed enzymes with broad substrate specificities (Berg and Joklik 1954; Parks and Agarwal 1973). Three human cytosolic nucleoside diphosphate kinase proteins, NME1, 2, and 3, have been characterized biochemically (Gilles et al. 1991; Schaertl et al. 1998; Erent et al. 2001; Chen et al. 2003). All are catalytically active as hexamers: homohexamers of NME1, 2, and 3 have been described, as have heterohexamers containing all possible combinations of NME1 and 2 (Gilles et al. 1991; Erent et al. 2001).<p>While the high ratio of ATP to ADP concentrations in the cytosol normally favors the conversion of (d)NDP and ATP to (d)NTP and ADP, the reversibility of the reactions and the overlapping substrate specificities of the enzymes suggest that this group of reverse reactions can buffer the intracellular nucleotide pool and regulate the relative concentrations of individual nucleoside di- and tri-phosphates in the pool. EC Number: 2.7.4.6 Edited: D'Eustachio, P, 2010-02-05 ISBN0121227022 Pubmed11277919 Pubmed12972261 Pubmed13211603 Pubmed1851158 Pubmed9488696 Reactome Database ID Release 43482621 Reactome, http://www.reactome.org ReactomeREACT_21273 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 (d)NDP + ATP <=> (d)NTP + ADP [NME4] Authored: D'Eustachio, P, 2010-02-05 EC Number: 2.7.4.6 Edited: D'Eustachio, P, 2010-02-05 Nucleoside diphosphate kinase NME4 associated with the inner mitochondrial membrane (Tokarska-Schlattner et al. 2008) catalyzes the reversible reaction of ribonucleoside and deoxyribonucleoside 5'-diphosphates with ATP to form the corresponding nucleoside 5'-triphosphates and ADP. The active form of the enzyme is a hexamer of NME4 polypeptides whose amino-terminal 33 residues, a mitochondrial translocation signal, have been removed (Milon et al. 2000). The substrate specificity of NME4 has not been examined in detail but is inferred to be broad like that of the homologous NME1, 2, and 3 kinases (Schaertl et al. 1998). Pubmed10799505 Pubmed18635542 Pubmed9488696 Reactome Database ID Release 43482804 Reactome, http://www.reactome.org ReactomeREACT_21362 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 PP1 catalytic subunit Converted from EntitySet in Reactome Reactome DB_ID: 163538 Reactome Database ID Release 43163538 Reactome, http://www.reactome.org ReactomeREACT_3514 ACC1 ACACA ACC1 isoforms Converted from EntitySet in Reactome Reactome DB_ID: 200558 Reactome Database ID Release 43200558 Reactome, http://www.reactome.org ReactomeREACT_11704 Corepressors of PPARalpha Converted from EntitySet in Reactome Reactome DB_ID: 400207 Reactome Database ID Release 43400207 Reactome, http://www.reactome.org ReactomeREACT_19786 SREBP1A/2 Converted from EntitySet in Reactome Reactome DB_ID: 1655734 Reactome Database ID Release 431655734 Reactome, http://www.reactome.org ReactomeREACT_116516 SREBF1A/2 Wnt-1 or Wnt-10b Converted from EntitySet in Reactome Reactome DB_ID: 976184 Reactome Database ID Release 43976184 Reactome, http://www.reactome.org ReactomeREACT_27326 GPAM or GPAT2 Converted from EntitySet in Reactome Reactome DB_ID: 549113 Reactome Database ID Release 43549113 Reactome, http://www.reactome.org ReactomeREACT_22523 AGPAT Converted from EntitySet in Reactome LPAAT Reactome DB_ID: 1500583 Reactome Database ID Release 431500583 Reactome, http://www.reactome.org ReactomeREACT_119867 lipins Converted from EntitySet in Reactome LPIN1 or 2 or 3 Reactome DB_ID: 549151 Reactome Database ID Release 43549151 Reactome, http://www.reactome.org ReactomeREACT_22496 NR5A2 Converted from EntitySet in Reactome Reactome DB_ID: 210772 Reactome Database ID Release 43210772 Reactome, http://www.reactome.org ReactomeREACT_14385 PathwayStep1018 PathwayStep1017 PathwayStep1019 PathwayStep1014 PathwayStep1013 PathwayStep1016 PathwayStep1015 TCF2 Converted from EntitySet in Reactome HNF1B Reactome DB_ID: 210762 Reactome Database ID Release 43210762 Reactome, http://www.reactome.org ReactomeREACT_14001 Thiamin transport across the plasma membrane Authored: D'Eustachio, P, 2007-07-11 18:15:46 Pubmed10391221 Pubmed10391222 Pubmed10391223 Pubmed14615284 Pubmed16371350 Pubmed16705148 Pubmed16790503 Reactome Database ID Release 43199626 Reactome, http://www.reactome.org ReactomeREACT_11081 Two transport proteins, SLC19A2 (THTR1) and SLC19A3 (THTR2), associated with the plasma membrane, are each able to mediate the transport of extracellular thiamin into the cytosol. In the body, both transporters are widely distributed, and both are abundant in kidney and intestinal epithelia, consistent with their involvement in thiamin uptake under physiological conditions (Ashokkumar et al. 2006; Said et al. 2004; Subramanian et al. 2006 - J Biol Chem). The observation that mutations in SLC19A2 (THTR1) cause a progressive disorder that can be partially reversed by treatment with high doses of thiamin likewise suggests a role for this protein in thiamin uptake under normal conditions (Diaz et al. 1999; Fleming et al. 1999; Labay et al. 1999).<p>Two features of this transport process remain incompletely understood, however. First, mutations in SLC19A3 cause a progressive disorder that is responsive to biotin treatment (Zhou et al. 2005), although studies of cultured cells indicate that the protein has no affinity for biotin (Subramanian et al. 2006 - Am J Physiol). Also, studies to date provide little information about the mechanism by which thiamin, once taken up by epithelial cells in the intestine and kidney, is released from these cells into the blood. thiamin [extracellular] => thiamin [cytosol] Reduction of dehydroascorbate to ascorbate Authored: D'Eustachio, P, 2007-07-05 13:27:27 Cytosolic omega class glutathione transferases (GSTO1 and GSTO2) catalyze the reaction of dehydroascorbate (DHA) and glutathione (GSH) to form ascorbate and oxidized glutathione (GSSG). The GSTO enzymes occur as homodimers (Board et al. 2000), and while both have dehydroascorbate reductase activity in vitro, that of GSTO2 is much greater than that of GSTO1 (Schmuck et al. 2005). Polymorphisms affecting the activities of the two enzymes have been described (Whitbread et al. 2005). EC Number: 1.8.5.1 Pubmed10783391 Pubmed15970797 Pubmed16399380 Reactome Database ID Release 43198813 Reactome, http://www.reactome.org ReactomeREACT_11095 dehydroascorbate (DHA) + 2 glutathione (GSH) => ascorbate + oxidized glutathione (GSSG) has a Stoichiometric coefficient of 2 ferric CYB5A + NADH + H+ => ferrous CYPB5A + NAD+ Authored: D'Eustachio, P, 2007-07-05 13:27:27 Cytochrome b5 reductase (CYB5R3) catalyzes the reduction of cytosolic ferric CYB5A to ferrous CYPB5A, coupled to the conversion of NADH + H+ to NAD+ (Shirabe et al. 1995). CYB5R3 is associated with the outer mitochondrial membrane via a myristoyl group added post-translationally to glycine residue 2 of the protein (Borgese et al. 1993). EC Number: 1.6.2.2 Pubmed7668255 Pubmed8513896 Reactome Database ID Release 43198824 Reactome, http://www.reactome.org ReactomeREACT_11182 Reduction of ferric cytochrome B5A to ferrous cytochrome B5A Reduction of semidehydroascorbate to ascorbate Authored: D'Eustachio, P, 2007-07-05 13:27:27 Pubmed17222174 Pubmed7668255 Reactome Database ID Release 43198845 Reactome, http://www.reactome.org ReactomeREACT_11100 The reduction of cytosolic semidehydroascorbate to ascorbate is catalyzed by cytochrome B5 (CYB5A) associated with the mitochondrial outer membrane. In the course of the reaction, the heme iron of the cytochrome is oxidized (Linster and Van Schaftingen 2007; Shirabe et al. 1995). Ascorbate transport across the plasma membrane Authored: D'Eustachio, P, 2007-07-05 13:27:27 Pubmed10471399 Pubmed10556483 Pubmed10556521 Pubmed11396616 Reactome Database ID Release 43198870 Reactome, http://www.reactome.org ReactomeREACT_11120 The plasma membrane-associated transport proteins SVCT1 and SVCT2 are each capable of mediating the uptake of one molecule of ascorbate and two sodium ions from the extracellular space to the cytosol (Daruwala et al. 1999; Rajan et al. 1999; Wang et al. 1999). In the body SVCT2 is expressed in most tissues, while SVCT1 is largely confined to epithelial cells (Liang et al. 2001). SVCT2 may mediate fetal uptake of ascorbate from the maternal circulation (Rajan et al. 1999). The transporters responsible for its uptake from the small intestine and for its release from enterocytes into the circulation have not been identified, although both SVCT1 and 2 are expressed in intestinal cells. ascorbate [extracellular] + 2 Na+ [extracellular] => ascorbate [cytosol] + 2 Na+ [cytosol] has a Stoichiometric coefficient of 2 Dehydroascorbate transport across the plasma membrane Authored: D'Eustachio, P, 2007-07-05 13:27:27 Pubmed10862609 Pubmed9228080 Reactome Database ID Release 43198818 Reactome, http://www.reactome.org ReactomeREACT_11168 The uptake of extracellular dehydroascorbate into the cytosol is mediated by GLUT1 and GLUT3 associated with the plasma membrane (Rumsey et al. 1997, 2000). This process may play a significant role in ascorbate utilization in the central nervous system (Agus et al. 1997). The process is efficiently competitively inhibited by glucose, leading to the suggestion that inhibited dehydroascorbate uptake may contribute to the pathology of diabetes (Liang et al. 2001; Rumsey et al. 2000). dehydroascorbate [extracellular] => dehydroascorbate [cytosol] Mitochondrial NUDT9 hydrolyses ADP-ribose to R5P and AMP ADP-ribose + H2O => AMP + D-ribose 5-phosphate (mitochondrial) Authored: D'Eustachio, P, 2012-07-06 EC Number: 3.6.1.13 Edited: D'Eustachio, P, 2012-07-06 Mitochondrial NUDT9 (ADP-ribose pyrophosphatase) catalyzes the hydrolysis of ADP-ribose to form AMP and D-ribose 5-phosphate. The active enzyme is the longer of two isoforms generated by alternative splicing and is a monomer complexed with two magnesium ions (Perraud et al. 2003; Shen et al. 2003). Pubmed12427752 Pubmed12948489 Reactome Database ID Release 432393954 Reactome, http://www.reactome.org ReactomeREACT_150155 Reviewed: Ito, Riyoko, 2012-10-05 Cytosolic NUDT5 hydrolyses ADP-ribose to R5P and AMP ADP-ribose + H2O => AMP + D-ribose 5-phosphate (cytosolic) Authored: D'Eustachio, P, 2012-07-06 Cytosolic NUDT5 dimer (ADP-ribose pyrophosphatase) catalyzes the hydrolysis of ADP-ribose to form AMP and D-ribose 5-phosphate. Each NUDT5 subunit is associated with three magnesium ions (Zha et al. 2006, 2008). NUDT5 also catalyzes the hydrolysis of 8-oxo-dGTP but with a strongly alkaline pH optimum (Ito et al. 2011) so the physiological relevance of this reaction is unclear and it is not annotated here. EC Number: 3.6.1.13 Edited: D'Eustachio, P, 2012-07-06 Pubmed17052728 Pubmed18462755 Pubmed21389046 Reactome Database ID Release 432393939 Reactome, http://www.reactome.org ReactomeREACT_150191 Reviewed: Ito, Riyoko, 2012-10-05 PathwayStep1020 PathwayStep1021 PathwayStep1022 PathwayStep1023 ThDP + ATP <-> ThTP + ADP Authored: Jassal, B, 2010-11-09 EC Number: 2.7.4.15 Edited: Jassal, B, 2010-11-09 Pubmed6311826 Reactome Database ID Release 43997381 Reactome, http://www.reactome.org ReactomeREACT_25070 Reviewed: D'Eustachio, P, 2010-11-05 Thiamin triphosphate (ThTP) is believed to be synthesized from thiamin diphosphate (ThDP), catalyzed by ThDP kinase, an enzyme that remains poorly characterized (Nishino et al, 1983). Thiamin is pyrophosphorylated Cytosolic thiamin pyrophosphokinase (TPK) catalyzes the reaction of thiamin and ATP to form thiamin pyrophosphate (TPP) (thiamin diphosphate) and ADP. TPP is an active cofactor for transketolase, pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, enzymes involved in glycolysis and energy production. The gene encoding the human enzyme has been cloned and its protein product has been shown to have TPK activity (Nosaka et al. 2001; Zhao et al. 2001). Its homodomeric structure and association with Mg++ are inferred from properties of the homologous yeast enzyme (Baker et al. 2001). EC Number: 2.7.6.2 Pubmed11342111 Pubmed11342117 Pubmed11435118 Reactome Database ID Release 43196761 Reactome, http://www.reactome.org ReactomeREACT_11233 PathwayStep1029 PathwayStep1028 PathwayStep1027 phospho-MEF2 proteins Converted from EntitySet in Reactome Reactome DB_ID: 448866 Reactome Database ID Release 43448866 Reactome, http://www.reactome.org ReactomeREACT_21928 PathwayStep1026 PathwayStep1025 MEF2 proteins Converted from EntitySet in Reactome Reactome DB_ID: 448868 Reactome Database ID Release 43448868 Reactome, http://www.reactome.org ReactomeREACT_21665 PathwayStep1024 8-oxo-GDP + H2O => 8-oxo-GMP + Pi Authored: D'Eustachio, P, 2012-07-06 Edited: D'Eustachio, P, 2012-07-06 NUDT18 (MTH3) catalyzes the reaction of 8-oxo-GDP and water to form 8-oxo-GMP and Pi (orthophosphate) (Takagi et al. 2012). The subcellular location of NUDT18 has not been established but is assumed to be cytosolic like NUDT1. NUDT18 hydrolyses 8-oxo-GDP to 8-oxo-GMP Pubmed22556419 Reactome Database ID Release 432395873 Reactome, http://www.reactome.org ReactomeREACT_150251 Reviewed: Ito, Riyoko, 2012-10-05 NUDT18 hydrolyses 8-oxo-dGDP to 8-oxo-dGMP 8-oxo-dGDP + H2O => 8-oxo-dGMP + Pi (NUDT18) Authored: D'Eustachio, P, 2012-07-06 Edited: D'Eustachio, P, 2012-07-06 NUDT18 (MTH3) catalyzes the reaction of 8-oxo-dGDP and water to form 8-oxo-dGMP and Pi (orthophosphate) (Takagi et al. 2012). The subcellular location of NUDT18 has not been established but is assumed to be cytosolic like NUDT1. Pubmed22556419 Reactome Database ID Release 432395879 Reactome, http://www.reactome.org ReactomeREACT_150427 Reviewed: Ito, Riyoko, 2012-10-05 NUDT1 hydrolyses 2-OH-ATP to 2-OH-AMP 2-hydroxy-ATP + H2O => 2-hydroxy-AMP + PPi Authored: D'Eustachio, P, 2012-07-06 Edited: D'Eustachio, P, 2012-07-06 NUDT1 (MTH1) catalyzes the reaction of 2-hydroxy-ATP and water to form 2-hydroxy-AMP and PPi (pyrophosphate). Four NUDT1 proteins have been identified, encoded by a single gene with alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been shown to catalyze hydrolysis of 2-hydroxy-dATP (Fujikawa et al. 2001). The active enzyme is a monomer associated with a magnesium ion (Mishima et al. 2004). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well, but have not been experimentally characterized. The p18 isoform is predominantly cytosolic (Kang et al. 1995). Pubmed11139615 Pubmed15133035 Pubmed7782328 Reactome Database ID Release 432395872 Reactome, http://www.reactome.org ReactomeREACT_150136 Reviewed: Ito, Riyoko, 2012-10-05 NUDT1 hydrolyses 2-OH-dATP to 2-OH-dAMP 2-hydroxy-dATP + H2O => 2-hydroxy-dAMP + PPi Authored: D'Eustachio, P, 2012-07-06 Edited: D'Eustachio, P, 2012-07-06 NUDT1 (MTH1) catalyzes the reaction of 2-hydroxy-dATP and water to form 2-hydroxy-dAMP and PPi (pyrophosphate). Four NUDT1 proteins have been identified, encoded by a single gene with alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been shown to catalyze hydrolysis of 2-hydroxy-dATP (Fujikawa et al. 1993; Sakai et al. 2002). The active enzyme is a monomer associated with a magnesium ion (Mishima et al. 2004). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well but have not been experimentally characterized. The p18 isoform is predominantly cytosolic (Kang et al. 1995). Its expression prevents the accumulation of modified adenosine bases in DNA in mutant mouse cells lacking endogenous NUDT1 activity (Yoshimura et al. 2003). Together, these data support the hypothesis that by cleaving 2-hydroxy-dATP and thus preventing its incorporation into DNA, NUDT1 provides a physiologically important defense against mutagenesis due to oxidative stress. Pubmed10373420 Pubmed10536140 Pubmed11756418 Pubmed12857738 Pubmed15133035 Pubmed7782328 Reactome Database ID Release 432395818 Reactome, http://www.reactome.org ReactomeREACT_150363 Reviewed: Ito, Riyoko, 2012-10-05 NUDT1 hydrolyses 8-oxo-dGTP to 8-oxo-dGMP 8-oxo-dGTP + H2O => 8-oxo-dGMP + PPi (NUDT1) Authored: D'Eustachio, P, 2012-07-06 Edited: D'Eustachio, P, 2012-07-06 NUDT1 (MTH1) catalyzes the reaction of 8-oxo-dGTP and water to form 8-oxo-dGMP and PPi (pyrophosphate). Four NUDT1 proteins have been identified, encoded by a single gene with alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been biochemically (Sakumi et al. 1993; Takagi et al. 2012) and structurally (Mishima et al. 2004) characterized and shown to catalyze hydrolysis of 8-oxo-dGTP. The active enzyme is a monomer associated with a magnesium ion (Mishima et al. 2004). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well but have not been experimentally characterized. The p18 isoform is predominantly cytosolic (Kang et al. 1995). Its expression prevents the accumulation of oxo-guanine bases in DNA in mutant mouse cells lacking endogenous NUDT1 activity (Yoshimura et al. 2003). Together, these data support the hypothesis that by cleaving 8-oxo-dGTP and thus preventing its incorporation into DNA NUDT1 provides a physiologically important defense against mutagenesis due to oxidative stress. Pubmed10536140 Pubmed12857738 Pubmed15133035 Pubmed22556419 Pubmed7782328 Pubmed8226881 Reactome Database ID Release 432395849 Reactome, http://www.reactome.org ReactomeREACT_150178 Reviewed: Ito, Riyoko, 2012-10-05 NUDT15 hydrolyses 8-oxo-dGDP to 8-oxo-dGMP 8-oxo-dGDP + H2O => 8-oxo-dGMP + Pi (NUDT15) Authored: D'Eustachio, P, 2012-07-06 EC Number: 3.6.1.6 Edited: D'Eustachio, P, 2012-07-06 NUDT15 (MTH2) catalyzes the reaction of 8-oxo-dGDP and water to form 8-oxo-dGMP and Pi (orthophosphate) (Takagi et al. 2012). The subcellular location of NUDT15 has not been established but is assumed to be cytosolic like NUDT1. Pubmed22556419 Reactome Database ID Release 432395876 Reactome, http://www.reactome.org ReactomeREACT_150452 Reviewed: Ito, Riyoko, 2012-10-05 NUDT15 hydrolyses 8-oxo-dGTP to 8-oxo-dGMP 8-oxo-dGTP + H2O => 8-oxo-dGMP + PPi (NUDT15) Authored: D'Eustachio, P, 2012-07-06 Edited: D'Eustachio, P, 2012-07-06 NUDT15 (MTH2) catalyzes the reaction of 8-oxo-dGTP and water to form 8-oxo-dGMP and PPi (pyrophosphate). Cai et al. (2003) first identified this activity in studies of the homologous mouse protein; the activity of the human NUDT15 protein has since been confirmed experimentally (Takagi et al. 2012). Pubmed12767940 Pubmed22556419 Reactome Database ID Release 432395869 Reactome, http://www.reactome.org ReactomeREACT_150375 Reviewed: Ito, Riyoko, 2012-10-05 PathwayStep1033 PathwayStep1034 PathwayStep1031 PathwayStep1032 dIDP + H2O => dIMP + Pi Authored: D'Eustachio, P, 2012-10-05 Edited: D'Eustachio, P, 2012-10-05 NUDT16 dimer catalyzes the reaction of dIDP and water to form dIMP and Pi (orthophosphate). Mg++ is required for enzymatic activity. The protein is mostly located in the nucleus and concentrated in the nucleolus, where it can also mediate the decapping of U8 small nucleolar RNA (Iyama et al. 2010; Peculis et al. 2007). NUDT16 hydrolyses dIDP to dIMP Pubmed17567574 Pubmed20385596 Reactome Database ID Release 432509793 Reactome, http://www.reactome.org ReactomeREACT_150234 Reviewed: Ito, Riyoko, 2012-10-05 PathwayStep1030 NUDT18 hydrolyses 8-OH-dADP to 8-OH-dAMP 8-hydroxy-dADP + H2O => 8-hydroxy-dAMP + Pi Authored: D'Eustachio, P, 2012-07-06 Edited: D'Eustachio, P, 2012-07-06 NUDT18 (MTH3) catalyzes the reaction of 8-hydroxy-dADP and water to form 8-hydroxy-dAMP and Pi (orthophosphate) (Takagi et al. 2012). The subcellular location of NUDT18 has not been established but is assumed to be cytosolic like NUDT1. Pubmed22556419 Reactome Database ID Release 432395965 Reactome, http://www.reactome.org ReactomeREACT_150166 Reviewed: Ito, Riyoko, 2012-10-05 IDP + H2O => IMP + Pi Authored: D'Eustachio, P, 2012-10-05 Edited: D'Eustachio, P, 2012-10-05 NUDT16 dimer catalyzes the reaction of IDP and water to form IMP and Pi (orthophosphate). Mg++ is required for enzymatic activity. The protein is mostly located in the nucleus and concentrated in the nucleolus, where it can also mediate the decapping of U8 small nucleolar RNA (Iyama et al. 2010; Peculis et al. 2007). NUDT16 hydrolyses IDP to IMP Pubmed17567574 Pubmed20385596 Reactome Database ID Release 432509816 Reactome, http://www.reactome.org ReactomeREACT_150396 Reviewed: Ito, Riyoko, 2012-10-05 phospho-E2A Converted from EntitySet in Reactome Reactome DB_ID: 448853 Reactome Database ID Release 43448853 Reactome, http://www.reactome.org ReactomeREACT_21834 phospho-E12/E47 Myod Converted from EntitySet in Reactome Myod family/myogenic bHLH proteins Reactome DB_ID: 448854 Reactome Database ID Release 43448854 Reactome, http://www.reactome.org ReactomeREACT_22068 Ligands of GPR119 Converted from EntitySet in Reactome Reactome DB_ID: 400529 Reactome Database ID Release 43400529 Reactome, http://www.reactome.org ReactomeREACT_24785 Adenylation of phosphopantetheine Authored: Jassal, B, 2007-04-24 08:38:46 EC Number: 2.7.7.3 Pubmed11994049 Pubmed14514684 Reactome Database ID Release 43196754 Reactome, http://www.reactome.org ReactomeREACT_11222 The adenylate transferase activity of bifunctional coenzyme A synthase catalyzes the reaction of pantetheine phosphate and ATP to form dephospho-Coenzyme A and orthophosphate (Daugherty et al. 2002). The enzyme is associated with the mitochondrial outer membrane (Zhyvoloup et al. 2003). Phosphorylation of dephospho-CoA to produce CoA Authored: Jassal, B, 2007-04-24 08:38:46 EC Number: 2.7.1.24 Pubmed11994049 Pubmed14514684 Reactome Database ID Release 43196773 Reactome, http://www.reactome.org ReactomeREACT_11093 The kinase activity of CoA synthase catalyzes the reaction of Dephospho-CoA and ATP to form Coenzyme A and ADP. The enzyme is located in the mitochondrial outer membrane (Daugherty et al. 2002; Zhyvoloup et al. 2003). Fatty acid ligands of GPR120 Converted from EntitySet in Reactome Reactome DB_ID: 400551 Reactome Database ID Release 43400551 Reactome, http://www.reactome.org ReactomeREACT_21560 n-Oleoylethanolamide Reactome DB_ID: 400552 Reactome Database ID Release 43400552 Reactome, http://www.reactome.org ReactomeREACT_24438 E2A Converted from EntitySet in Reactome E12/E47 E2 alpha Reactome DB_ID: 448859 Reactome Database ID Release 43448859 Reactome, http://www.reactome.org ReactomeREACT_21923 Pyridoxamine is phosphorylated Authored: Stephan, R, 2010-09-16 EC Number: 2.7.1.35 Edited: Jassal, B, 2010-09-20 Pubmed10987144 Pubmed15249053 Pyridoxal kinase (PDXK) catalyzes the ATP-dependent phosphorylation of pyridoxamine (Lee et al, 2000; di Salvo et al, 2004). Reactome Database ID Release 43964958 Reactome, http://www.reactome.org ReactomeREACT_25323 Reviewed: D'Eustachio, P, 2010-11-08 PLP results from phosphorylation of pyridoxal Authored: Stephan, R, 2010-09-16 EC Number: 2.7.1.35 Edited: Jassal, B, 2010-09-20 Pubmed10987144 Pubmed15249053 Pyridoxal kinase (PDXK) catalyzes the ATP-dependent phosphorylation of pyridoxal (Lee et al, 2000; di Salvo et al, 2004). Reactome Database ID Release 43964970 Reactome, http://www.reactome.org ReactomeREACT_25295 Reviewed: D'Eustachio, P, 2010-11-08 Ligands of FFAR1 (GPR40) Converted from EntitySet in Reactome Reactome DB_ID: 1998756 Reactome Database ID Release 431998756 Reactome, http://www.reactome.org ReactomeREACT_117649 Phosphopantetheine conjugation of the ACP domain of FAS Authored: D'Eustachio, P, 2007-07-09 22:03:12 CoA-SH + FAS apoenzyme => adenosine 3',5'-bisphosphate + FAS holoenzyme Cytosolic AASDHPPT (alpha-aminoadipic semialdehyde dehydrogenase-phosphopantetheinyl transferase) catalyzes the transfer of a phosphopantetheine moiety from coenzyme A to serine 2156 within the ACP domain of FAS (fatty acyl synthase). Only a single human enzyme with phosphopantetheinyl transferase activity has been identified, and its broad substrate specificity suggests that it may be responsible as well for the postranslational modification of enzymes of lysine catabolism (Joshi et al. 2003; Praphanphoj et al. 2001). EC Number: 2.7.8.7 Pubmed11286508 Pubmed12815048 Reactome Database ID Release 43199202 Reactome, http://www.reactome.org ReactomeREACT_11175 CoA transport across the inner mitochondrial membrane Authored: D'Eustachio, P, 2007-07-09 22:03:12 Pubmed11158296 Pubmed17242360 Reactome Database ID Release 43199216 Reactome, http://www.reactome.org ReactomeREACT_11209 SLC25A16, associated with the inner mitochondrial membrane, mediates the transport of CoA (coenzyme A) into the mitochondrial matrix. Evidence for this event is indirect. The protein has the sequence motifs expected for a transport protein, and yeast cells deficient in its homologue, Leu5p, fail to accumulate mitochondrial CoA and can be rescued by expression of SLC25A16. At the same time, neither the yeast nor the human protein has been shown directly to function as a transporter (Prohl et al. 2001; Leonardi et al. 2007). Biotin transport across the plasma membrane Authored: D'Eustachio, P, 2007-07-09 22:03:12 Pubmed10329687 Pubmed10334869 Reactome Database ID Release 43199219 Reactome, http://www.reactome.org ReactomeREACT_11142 The plasma membrane-associated transport protein SLC5A6 (SMVT) mediates the uptake of one molecule of biotin and two sodium ions from the extracellular space to the cytosol. Limited Northern blotting studies suggest that SLC5A6 is widely expressed, and abundant in placenta and small intestine. SLC5A6 may thus play a central role in biotin uptake. SLC5A6 also mediates the uptake of pantothenate and lipoate (Prasad et al. 1999; Wang et al. 1999). biotin [extracellular] + 2 Na+ [extracellular] => biotin [cytosol] + 2 Na+ [cytosol] has a Stoichiometric coefficient of 2 PLP from oxidation of pyridoxine phosphate Authored: Stephan, R, 2010-09-18 EC Number: 1.4.3.5 Edited: Jassal, B, 2010-09-20 PNPO is able to oxidise pyridoxine phosphate to the PLP cofactor (Kang et al, 2004). Pubmed15182361 Reactome Database ID Release 43965019 Reactome, http://www.reactome.org ReactomeREACT_25348 Reviewed: D'Eustachio, P, 2010-11-08 PLP from oxidation of pyridoxamine phosphate Authored: Stephan, R, 2010-09-18 EC Number: 1.4.3.5 Edited: Jassal, B, 2010-09-20 PNPO is able to oxidise pyridoxamine phosphate to the PLP cofactor (Kang et al, 2004). Pubmed15182361 Reactome Database ID Release 43965079 Reactome, http://www.reactome.org ReactomeREACT_25127 Reviewed: D'Eustachio, P, 2010-11-08 Pyridoxine is phosphorylated Authored: Stephan, R, 2010-09-16 EC Number: 2.7.1.35 Edited: Jassal, B, 2010-09-20 Pubmed10987144 Pubmed15249053 Pyridoxal kinase (PDXK) catalyzes the ATP-dependent phosphorylation of pyridoxine(Lee et al, 2000; di Salvo et al, 2004). Reactome Database ID Release 43964962 Reactome, http://www.reactome.org ReactomeREACT_25109 Reviewed: D'Eustachio, P, 2010-11-08 phospho-p38 alpha/beta/gamma MAPK Converted from EntitySet in Reactome Reactome DB_ID: 448858 Reactome Database ID Release 43448858 Reactome, http://www.reactome.org ReactomeREACT_21534 PathwayStep1000 PathwayStep1001 PathwayStep1005 PathwayStep1004 PathwayStep1003 PathwayStep1002 PathwayStep1009 PathwayStep1008 p38 MAPK alpha/beta/gamma Converted from EntitySet in Reactome Reactome DB_ID: 448855 Reactome Database ID Release 43448855 Reactome, http://www.reactome.org ReactomeREACT_21979 PathwayStep1007 Phospho-p38 MAPK alpha/beta/gamma Converted from EntitySet in Reactome Reactome DB_ID: 448861 Reactome Database ID Release 43448861 Reactome, http://www.reactome.org ReactomeREACT_21724 PathwayStep1006 Adrenaline and Noradrenaline Converted from EntitySet in Reactome Reactome DB_ID: 400049 Reactome Database ID Release 43400049 Reactome, http://www.reactome.org ReactomeREACT_19090 Ligands of FFAR1 (GPR40) Converted from EntitySet in Reactome Reactome DB_ID: 400427 Reactome Database ID Release 43400427 Reactome, http://www.reactome.org ReactomeREACT_20176 Thiamin triphosphate can be hydrolysed back to thiamin diphosphate Authored: Stephan, R, 2010-09-16 EC Number: 3.6.1.28 Edited: Jassal, B, 2010-09-20 Pubmed11827967 Reactome Database ID Release 43965067 Reactome, http://www.reactome.org ReactomeREACT_25137 Reviewed: D'Eustachio, P, 2010-11-05 Thiamin triphosphate (ThTP) can transfer phosphate to a few proteins. Animal tissues contain a membrane-associated as well as a soluble thiamine triphosphatase that can dephosphorylate ThTP. Only the soluble enzyme was characterized in calf (Lakaye et al, 2002). FMN is futher phosphorylated to FAD EC Number: 2.7.7.2 FMN can be phosphorylated and adenylated to produce the second cofactor from riboflavin origins, FAD (flavin adenine dinucleotide). The enzyme responsible , FMN adenylyltransferase (FAD synthase), is cytosolic and transfers a phosphate and an adenyl group from ATP to form FAD. Pubmed16643857 Reactome Database ID Release 43196929 Reactome, http://www.reactome.org ReactomeREACT_11128 Riboflavin is phosphorylated to FMN EC Number: 2.7.1.26 Phosphorylation of riboflavin results in the formation of the first cofactor, FMN (flavin mononucleotide). This reaction is catalyzed by riboflavin kinase, a cytosolic enzyme existing as a monomer. It utilizes either zinc or magnesium ions in the reaction. Pubmed12623014 Reactome Database ID Release 43196964 Reactome, http://www.reactome.org ReactomeREACT_11232 FMN can be hydrolyzed back to riboflavin Cytosolic TRAP (tartrate-resistant acid phosphatase type 5) catalyzes the hydrolysis of FMN to yield riboflavin and orthophosphate. EC Number: 3.1.3.2 Pubmed2775236 Reactome Database ID Release 43196950 Reactome, http://www.reactome.org ReactomeREACT_11171 FAD can be hydrolyzed back to FMN EC Number: 3.6.1.9 Phosphatase action on FAD can reform FMN. The enzyme performing the reaction is nucleotide pyrophosphatase and it exists as a homodimer on the plasma membrane. Pubmed8001561 Reactome Database ID Release 43196955 Reactome, http://www.reactome.org ReactomeREACT_11150 Pantothenate is phosphorylated [PANK2] Authored: Jassal, B, 2007-04-24 08:38:46 EC Number: 2.7.1.33 Pantothenate kinase 2 catalyzes the reaction of ATP and pantothenate to form ADP and phosphopantothenate. While pantothenate kinase 2 co-purifies with mitocondria, its precise location within the mitochondrion has not been established (Hortnagel et al. 2003; Johnson et al. 2004). Recent work by Leonardi et al. (2007) supports a model in which the enzyme is located in the intermembrane space, hence freely accessible to small molecules from the cytosol.Pantothenate is phosphorylated by pantothenate kinase (PANK). Deficiencies in PANK2 cause a progressive neurodegenerative disorder associated with iron accumulation in the brain, but the relationship between disease symptoms and pantothenate metabolism remains unclear (Zhou et al. 2001; Zhang et al. 2006). Pubmed11479594 Pubmed12554685 Pubmed15105273 Pubmed16272150 Pubmed17242360 Reactome Database ID Release 43196857 Reactome, http://www.reactome.org ReactomeREACT_11197 Pantothenate transport across the plasma membrane Authored: D'Eustachio, P, 2007-07-09 22:03:12 Pubmed10329687 Pubmed10334869 Reactome Database ID Release 43199206 Reactome, http://www.reactome.org ReactomeREACT_11072 The plasma membrane-associated transport protein SLC5A6 (SMVT) mediates the uptake of one molecule of pantothenate and two sodium ions from the extracellular space to the cytosol. Limited Northern blotting studies suggest that SLC5A6 is widely expressed, and abundant in placenta and small intestine. SLC5A6 may thus play a central role in pantothenate uptake. SLC5A6 also mediates the uptake of biotin and lipoate (Prasad et al. 1999; Wang et al. 1999). has a Stoichiometric coefficient of 2 pantothenate [extracellular] + 2 Na+ [extracellular] => pantothenate [cytosol] + 2 Na+ [cytosol] Condensation of phosphopantothenate with cysteine Authored: Jassal, B, 2007-04-24 08:38:46 EC Number: 6.3.2.5 Pubmed11923312 Pubmed12906824 Reactome Database ID Release 43196753 Reactome, http://www.reactome.org ReactomeREACT_11112 The conjugation of cysteine and 4'- phosphopantothenate to form 4-phosphopantothenoylcysteine, coupled to the conversion of ATP to AMP and pyrophosphate, is catalyzed by cytosolic phosphopantothenate-cysteine ligase (Phosphopantothenoylcysteine synthase, PPC synthase). Mammalian PPC synthase prefers ATP to CTP, unlike the E. coli ortholog (Daughtery et al. 2002; Manoj et al. 2003). Pantothenate is phosphorylated [PANK1;3;4] Authored: D'Eustachio, P, 2007-07-09 22:03:12 Cytosolic pantothenate kinases catalyze the reaction of ATP and pantothenate to form ADP and phosphopantothenate. This enzymatic activity has been demonstrated in crude cell extracts for two isoforms of mouse pantothenate kinase 1 (Rock et al. 2002) and for their human homologues (Ramaswamy and 2004). Two additional human genes, PANK3 and PANK4, encode closely related proteins but pantothenate kinase activity has not been demonstrated experimentally for them (Leonardi et al. 2005; Zhou et al. 2001). EC Number: 2.7.1.33 Pubmed11479594 Pubmed12095677 Pubmed14523052 Pubmed15893380 Reactome Database ID Release 43199203 Reactome, http://www.reactome.org ReactomeREACT_11129 pantothenate + ATP => phosphopanthothenate + ADP Phosphopantothenoylcysteine is decarboxylated Authored: Jassal, B, 2007-04-24 08:38:46 EC Number: 4.1.1.36 Pubmed11923312 Pubmed15581364 Reactome Database ID Release 43196840 Reactome, http://www.reactome.org ReactomeREACT_11231 The decarboxylation of phosphopantothenoylcysteine is carried out by phosphopantothenoylcysteine decarboxylase (PPCDC). PPCDC is cytosolic and exists as a homotrimer, binding one FMN cofactor per subunit. While a second isoform has been inferred from large-scale sequnceing studies, it lacks the protein's FMN-binding domain and would thus appear to be nonfunctional if it is expressed. PathwayStep1011 PathwayStep1012 PathwayStep1010 Folate is reduced to dihydrofolate (DHF) Cytosolic dihydrofolate reductase catalyzes the reaction of folate, NADPH, and H+ to form dihydrofolate and NADP+ (Chen et al. 1984; Davies et al. 1990). Pubmed2248959 Pubmed6323448 Reactome Database ID Release 43197963 Reactome, http://www.reactome.org ReactomeREACT_11204 Extracellular 5-methyltetrahydrofolate import across the plasma membrane Pubmed10347183 Pubmed7852378 Reactome Database ID Release 43200652 Reactome, http://www.reactome.org ReactomeREACT_11162 SLC19A1 protein, associated with the plasma membrane, mediates the uptake of extracellular 5-methyltetrahydrofolate and other reduced folates (Williams and Flintoff 1995; Ferguson and Flintoff 1999). EGF-CFC Coreceptor CRIPTO and CRYPTIC Converted from EntitySet in Reactome Reactome DB_ID: 1181334 Reactome Database ID Release 431181334 Reactome, http://www.reactome.org ReactomeREACT_111846 Cytosolic folate export across the plasma membrane Pubmed17129779 Pubmed8662720 Reactome Database ID Release 43200646 Reactome, http://www.reactome.org ReactomeREACT_11104 SLC46A1 protein in the plasma membrane mediates the reversible transport of folate between the extracellular space and the cytosol. Retention of folate within the cell is dependent on polyglutamate addition (Qiu et al. 2006; Chen et al. 1996). Extracellular folate import across the plasma membrane Pubmed17129779 Pubmed8662720 Reactome Database ID Release 43200729 Reactome, http://www.reactome.org ReactomeREACT_11190 SLC46A1 protein in the plasma membrane mediates the reversible transport of folate between the extracellular space and the cytosol. Retention of folate within the cell is dependent on polyglutamate addition. Although the SLC46A1 gene is expressed in several tissues in the body, this transporter appears to be primarily needed for absorption of dietary folate from the intestinal lumen (Qiu et al. 2006; Chen et al. 1996). FURIN and PACE4 Converted from EntitySet in Reactome Reactome DB_ID: 1181135 Reactome Database ID Release 431181135 Reactome, http://www.reactome.org ReactomeREACT_111765 LEFTY Converted from EntitySet in Reactome LEFTY1 and LEFTY2 Reactome DB_ID: 1181332 Reactome Database ID Release 431181332 Reactome, http://www.reactome.org ReactomeREACT_111534 Mitochondrial tetrahydrofolate export across the inner mitochondrial membrane Pubmed10978331 Pubmed8662720 Reactome Database ID Release 43200720 Reactome, http://www.reactome.org ReactomeREACT_11219 SLC25A32 protein in the inner mitochondrial membrane mediates the reversible transport of tetrahydrofolate between the cytosol and the mitochondrial matrix. Retention of tetrahydrofolate within the mitochondrial matrix is dependent on mitochondrial polyglutamate addition (Titus and Moran 2000; Chen et al. 1996). Conversion of mitochondrial THF to THF-polyglutamate EC Number: 6.3.2.17 Mitochondrial folylpolyglutamate synthase catalyzes the reaction of THF-glutamate(n), L-glutamate, and ATP to form THF-glutamate(n+1), ADP, and orthophosphate. (The first glutamate residue is attached to the glutamate moiety of THF itself; for convenience the process is annotated here as if it proceeded in a single concerted step.) The extent of conjugation is variable, but the commonest mitochondrial form of THF has six added glutamate residues. Although its properties as a donor of one-carbon units are not affected by glutamate addition, THF that lacks added glutamate residues cannot be retained in the mitochondrial matrix so this reaction is needed for normal THF function under physiological conditions. The mitochondrial and cytosolic forms of folylpolyglutamate synthase are encoded by the same gene - alternative splicing generates mRNA with or without an initial exon encoding a mitochondrial targeting sequence (Garrow et al. 1992; Chen et al. 1996). Pubmed1409616 Pubmed8662720 Reactome Database ID Release 43200682 Reactome, http://www.reactome.org ReactomeREACT_11134 has a Stoichiometric coefficient of 6 Conversion of cytosolic 5-methyltetrahydrofolate (5-methylTHF) to 5-methylTHF-polyglutamate Cytosolic folylpolyglutamate synthase catalyzes the reaction of 5-methylTHF-glutamate(n), L-glutamate, and ATP to form 5-methylTHF-glutamate(n+1), ADP, and orthophosphate. (The first glutamate residue is attached to the glutamate moiety of 5-methylTHF itself; for convenience the process is annotated here as if it proceeded in a single concerted step.) The extent of conjugation is variable, but the commonest cytosolic form of 5-methylTHF has five added glutamate residues. Although its properties as a donor of one-carbon units are not affected by glutamate addition, 5-methylTHF that lacks added glutamate residues cannot be retained in the cytosol so this reaction is needed for normal 5-methylTHF function under physiological conditions (Garrow et al. 1992; Chen et al. 1996). EC Number: 6.3.2.17 Pubmed1409616 Pubmed8662720 Reactome Database ID Release 43200681 Reactome, http://www.reactome.org ReactomeREACT_11098 has a Stoichiometric coefficient of 5 Cytosolic tetrahydrofolate import across the inner mitochondrial membrane Pubmed10978331 Pubmed8662720 Reactome Database ID Release 43200680 Reactome, http://www.reactome.org ReactomeREACT_11143 SLC25A32 protein in the inner mitochondrial membrane mediates the reversible transport of tetrahydrofolate between the cytosol and the mitochondrial matrix. Retention of tetrahydrofolate within the mitochondrial matrix is dependent on mitochondrial polyglutamate addition (Titus and Moran 2000; Chen et al. 1996). DHF is reduced to tetrahydrofolate (THF) Cytosolic dihydrofolate reductase catalyzes the reaction of dihydrofolate, NADPH, and H+ to form tetrahydrofolate (THF) and NADP+ (Chen et al. 1984; Davies et al. 1990). Pubmed2248959 Pubmed6323448 Reactome Database ID Release 43197972 Reactome, http://www.reactome.org ReactomeREACT_11170 Conversion of cytosolic THF to THF-polyglutamate Cytosolic folylpolyglutamate synthase catalyzes the reaction of THF-glutamate(n), L-glutamate, and ATP to form THF-glutamate(n+1), ADP, and orthophosphate. (The first glutamate residue is attached to the glutamate moiety of THF itself; for convenience the process is annotated here as if it proceeded in a single concerted step.) The extent of conjugation is variable, but the commonest cytosolic form of THF has five added glutamate residues. Although its properties as a donor of one-carbon units are not affected by glutamate addition, THF that lacks added glutamate residues cannot be retained in the cytosol so this reaction is needed for normal THF function under physiological conditions (Garrow et al. 1992; Chen et al. 1996). EC Number: 6.3.2.17 Pubmed1409616 Pubmed8662720 Reactome Database ID Release 43197958 Reactome, http://www.reactome.org ReactomeREACT_11083 has a Stoichiometric coefficient of 5 2-amino 3-carboxymuconate semialdehyde transforms non-enzymatically to quinolinate Cytosolic 2-amino 3-carboxymuconate semialdehyde reacts non-enzymatically to form quinolinate and water (Fukuoka et al. 1998). Pubmed9473669 Reactome Database ID Release 43197187 Reactome, http://www.reactome.org ReactomeREACT_11211 HNF-4-alpha Converted from EntitySet in Reactome HNF4A (pancreas-specific) Hepatocyte nuclear factor 4-alpha Reactome DB_ID: 211468 Reactome Database ID Release 43211468 Reactome, http://www.reactome.org ReactomeREACT_14480 Transcription factor 14 Nicotinate D-ribonucleotide + ATP => deamino-NAD+ + pyrophosphate [NMNAT1] EC Number: 2.7.7.1 NMNAT1 catalyzes the reaction of nicotinate D-ribonucleotide and ATP to form deamino-NAD+ (nicotinate adenine dinucleotide) and pyrophosphate (Schweiger et al. 2001). The active form of the enzyme in vitro is a hexamer (Zhou et al. 2002), and its activity is substantially greater in the presence of Zn++ than of Mg++ (Sorci et al. 2007). The predicted amino acid sequence of the enzyme contains a nuclear localization domain and the protein is observed to localize to the nucleus (Schweiger et al. 2001; Berger et al. 2005). Pubmed11248244 Pubmed11788603 Pubmed16118205 Pubmed17402747 Reactome Database ID Release 43200512 Reactome, http://www.reactome.org ReactomeREACT_11237 A phospho-ribosyl group is added to quinolinate EC Number: 2.4.2.19 Pubmed9473669 Reactome Database ID Release 43197268 Reactome, http://www.reactome.org ReactomeREACT_11092 The enzyme, nicotinate nucleotide pyrophosphorylase, is specific for quinolinate. Its activity is strictly dependent on Mg2+ ions being present. A phosphoribosyl group is transferred to quinolinate to form nicotinate D-ribonucleotide. This reaction represents another rate-limiting step of the pathway from tryptophan to NAD+. HNF1A Converted from EntitySet in Reactome Reactome DB_ID: 211495 Reactome Database ID Release 43211495 Reactome, http://www.reactome.org ReactomeREACT_14443 Deamination of nicotinamide to nicotinate EC Number: 3.5.1.19 Nicotinamide deaminase deaminates nicotinamide to nicotinate. There is no literature on the human enzyme but there is evidence showing a marked nicotinamide deaminase activity when red blood cells are infected with <i>Plasmodium falciparum</i> (Zerez C. et al, 1990). What is not clear is whether this activity is stimulated by the parasite or encoded by its genome. Pubmed2183889 Reactome Database ID Release 43197201 Reactome, http://www.reactome.org ReactomeREACT_11136 Condensation of nicotinamide to nicotinamide D-ribonucleotide (NMN) EC Number: 2.4.2.12 Nicotinamide phosphoribosyltransferase (NamPRT) catalyzes the condensation of nicotinamide with 5- phosphoribosyl-1-pyrophosphate to yield nicotinamide D-ribonucleotide (NMN), an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway. Pubmed8289818 Reactome Database ID Release 43197250 Reactome, http://www.reactome.org ReactomeREACT_11225 A phosphoribosyl group is added to nicotinate to form nicotinate mononucleotide (NaMN) Cytosolic nicotinate phosphoribosyltransferase (NaPRT) catalyzes the Mg++-dependent reaction of nicotinate and phosphoribosyl pyrophosphate to form nicotinate mononucleotide (NaMN, nicotinate D-ribonucleotide) and pyrophosphate. The active form of the enzyme is a homodimer (Preiss and Handler 1958; Niedel and Dietrich 1973; Hara et al. 2007). EC Number: 2.4.2.11 Pubmed13563527 Pubmed17604275 Pubmed4349867 Reactome Database ID Release 43197186 Reactome, http://www.reactome.org ReactomeREACT_11132 Nicotinate D-ribonucleotide + ATP => deamino-NAD+ + pyrophosphate [NMNAT2] EC Number: 2.7.7.1 NMNAT2 catalyzes the reaction of nicotinate D-ribonucleotide and ATP to form deamino-NAD+ (nicotinate adenine dinucleotide) and pyrophosphate (Sorci et al. 2007). The active form of the enzyme is a monomer in vitro (Raffaelli et al. 2002). Although the predicted amino acid sequence of the enzyme lacks an obvious signal sequence or transmembrane domain (Yalowitz et al. 2004), recombinant FLAG-tagged protein expressed in HeLa cells localizes predominantly to the Golgi apparatus (Berger et al. 2005). Its localization within the Golgi apparatus is unknown and the annotation here is based on the plausible but speculative assumption that the enzyme is associated with the Gogi membrane and accessible from the cytosol. Immunostaining studies indicate that the protein is abundant in Islets of Langerhans and in several regions of the brain (Yalowitz et al. 2004). Pubmed12359228 Pubmed14516279 Pubmed16118205 Pubmed17402747 Reactome Database ID Release 43197235 Reactome, http://www.reactome.org ReactomeREACT_11116 Nicotinate D-ribonucleotide + ATP => deamino-NAD+ + pyrophosphate [NMNAT3] EC Number: 2.7.7.1 NMNAT3 catalyzes the reaction of nicotinate D-ribonucleotide and ATP to form deamino-NAD+ (nicotinate adenine dinucleotide) and pyrophosphate (Sorci et al. 2007). The active form of the enzyme is a tetramer in vitro (Zhang et al. 2003). Recombinant FLAG-tagged protein expressed in HeLa cells localizes both to the cytosol and to mitochondria (Berger et al. 2005). The cytosolic protein is annotated here. Pubmed12574164 Pubmed16118205 Pubmed17402747 Reactome Database ID Release 43200474 Reactome, http://www.reactome.org ReactomeREACT_11196 Amidation of deamino-NAD+ to NAD+ EC Number: 6.3.5.1 NAD synthase catalyzes the final step in the biosynthesis of NAD+, both in the de novo synthesis and in the salvage pathways. The enzyme makes use of glutamine as an amide donor in the reaction. NAD synthase exists as a homohexamer in the cytosol. There are two forms of NAD synthase in humans, NADsyn1 and NADsyn2. The major difference between the two forms is that NADsyn1 appears to be glutamine-dependent whereas NADsyn2 is strictly ammonia-dependent. Pubmed12547821 Reactome Database ID Release 43197271 Reactome, http://www.reactome.org ReactomeREACT_11135 NAD+ is phosphorylated to NADP+ EC Number: 2.7.1.23 NAD+ kinase catalyzes the transfer of a phosphate group from ATP to NAD+, forming NADP+. This is the only way to generate NADP+ in all living organisms. The enzyme requires a divalent metal to be effective. Zn2+ is the best metal for this purpose. Pubmed11594753 Reactome Database ID Release 43197198 Reactome, http://www.reactome.org ReactomeREACT_11234 PAX6 Converted from EntitySet in Reactome Reactome DB_ID: 211276 Reactome Database ID Release 43211276 Reactome, http://www.reactome.org ReactomeREACT_14342 THF polyglutamate + formate + ATP => 10-formylTHF polyglutamate + ADP + orthophosphate EC Number: 6.3.4.3 Pubmed3053686 Pubmed3871768 Reactome Database ID Release 43200711 Reactome, http://www.reactome.org ReactomeREACT_11109 The formate-tetrahydrofolate ligase activity of the trifunctional MTHFD1 enzyme catalyzes the reaction of THF polyglutamate, formate, and ATP to form 10-formylTHF polyglutamate, ADP, and orthophosphate. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985). RBPJ Converted from EntitySet in Reactome J kappa-recombination signal-binding protein Reactome DB_ID: 210850 Reactome Database ID Release 43210850 Reactome, http://www.reactome.org ReactomeREACT_14564 Recombining binding protein suppressor of hairless 5,10-methenylTHF polyglutamate + NADPH + H+ <=> 5,10-methyleneTHF polyglutamate + NADP+ Pubmed3053686 Pubmed3871768 Reactome Database ID Release 43200718 Reactome, http://www.reactome.org ReactomeREACT_11187 The methylenetetrahydrofolate dehydrogenase activity of the trifunctional MTHFD1 enzyme catalyzes the reversible reaction of 5,10-methenylTHF polyglutamate, NADPH, and H+ to form 5,10-methyleneTHF polyglutamate and NADP+. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985). 10-formylTHF polyglutamate <=> 5,10-methenylTHF polyglutamate + H2O EC Number: 3.5.4.9 Pubmed3053686 Pubmed3871768 Reactome Database ID Release 43200661 Reactome, http://www.reactome.org ReactomeREACT_11205 The methenyltetrahydrofolate cyclohydrolase activity of the trifunctional MTHFD1 enzyme catalyzes the reversible reaction of 10-formylTHF polyglutamate to form 5,10-methenylTHF polyglutamate and H2O. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985). 5,10-methyleneTHF polyglutamate + NADPH + H+ => 5-methylTHF polyglutamate + NADP+ Cytosolic MTHFR dimer catalyzes the reaction of 5,10-methyleneTHF polyglutamate, NADPH, and H+ to form 5-methylTHF polyglutamate and NADP+. The specificity and importance of this reaction in vivo have been established through the study of patients deficient in the enzyme (Goyette et al. 1995). EC Number: 1.5.1.20 Pubmed7726158 Reactome Database ID Release 43200676 Reactome, http://www.reactome.org ReactomeREACT_11102 Tetrahydrofolate polyglutamate (THF polyglutamate) + serine <=> 5,10-methyleneTHF polyglutamate + glycine Cytosolic serine hydroxymethyltransferase catalyzes the reversible reaction of tetrahydrofolate polyglutamate (THF polyglutamate) and serine to form 5,10-methyleneTHF polyglutamate and glycine. The active form of the enzyme is a tetramer (Renwick et al. 1998). In the body, this reaction is a major source of 5,10-methyleneTHF, which in turn is a critical precursor in the synthesis of dTMP. EC Number: 2.1.2.1 Pubmed9753690 Reactome Database ID Release 43200735 Reactome, http://www.reactome.org ReactomeREACT_11159 PAX4 Converted from EntitySet in Reactome Reactome DB_ID: 210889 Reactome Database ID Release 43210889 Reactome, http://www.reactome.org ReactomeREACT_14111 5,10-methyleneTHF polyglutamate + glycine <=> tetrahydrofolate polyglutamate (THF polyglutamate) + serine Cytosolic serine hydroxymethyltransferase catalyzes the reversible reaction of 5,10-methyleneTHF polyglutamate and glycine to form tetrahydrofolate polyglutamate (THF polyglutamate) and serine. The active form of the enzyme is a tetramer (Renwick et al. 1998). EC Number: 2.1.2.1 Pubmed9753690 Reactome Database ID Release 43200651 Reactome, http://www.reactome.org ReactomeREACT_11108 5,10-methyleneTHF polyglutamate + NADP+ <=> 5,10-methenylTHF polyglutamate + NADPH + H+ Pubmed3053686 Pubmed3871768 Reactome Database ID Release 43200644 Reactome, http://www.reactome.org ReactomeREACT_11192 The methylenetetrahydrofolate dehydrogenase activity of the trifunctional MTHFD1 enzyme catalyzes the reversible reaction of 5,10-methyleneTHF polyglutamate and NADP+ to form 5,10-methenylTHF polyglutamate, NADPH, and H+. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985). 5,10-methenylTHF polyglutamate + H2O <=> 10-formylTHF polyglutamate EC Number: 3.5.4.9 Pubmed3053686 Pubmed3871768 Reactome Database ID Release 43200740 Reactome, http://www.reactome.org ReactomeREACT_11074 The methenyltetrahydrofolate cyclohydrolase activity of the trifunctional MTHFD1 enzyme catalyzes the reversible reaction of 5,10-methenylTHF polyglutamate and H2O to form 10-formylTHF polyglutamate. MTHFD1 is cytosolic and occurs as a dimer. The human enzyme has been identified and partially characterized biochemically (Hum et al. 1988); additional reaction details can be inferred from the properties of the well-studied homologous rabbit enzyme (Villar et al. 1985). Cyclisation of GTP to precursor Z Authored: Stephan, R, 2010-09-01 Edited: Jassal, B, 2010-09-08 GTP cyclizes in a reaction involving radicals of S-adenosylmethionine, catalyzed by the iron-sulfur cluster dimeric MOCS1. The intermediate result is called precursor Z (Hanzelmann et al, 2002; Hanzelmann et al, 2004). Pubmed11891227 Pubmed15180982 Reactome Database ID Release 43947535 Reactome, http://www.reactome.org ReactomeREACT_25068 Reviewed: D'Eustachio, P, 2010-11-05 NFS1 transfers sulfur from cysteine onto MOCS3 Authored: Stephan, R, 2010-09-02 EC Number: 2.8.1.7 Edited: Jassal, B, 2010-09-08 In order to get a sulfur atom for subsequent sulfuration reactions, cysteine is first desulfurated by NFS1 which transfers it onto a cysteine of MOCS3, yielding a protein persulfide (Marelja et al, 2008). Pubmed18650437 Reactome Database ID Release 43947514 Reactome, http://www.reactome.org ReactomeREACT_24937 Reviewed: D'Eustachio, P, 2010-11-05 16/17/18-HETE Converted from EntitySet in Reactome Reactome DB_ID: 2161639 Reactome Database ID Release 432161639 Reactome, http://www.reactome.org ReactomeREACT_152524 8,9/11,12/14,15-EET Converted from EntitySet in Reactome Reactome DB_ID: 2161753 Reactome Database ID Release 432161753 Reactome, http://www.reactome.org ReactomeREACT_151174 (S)-Malate <=> Fumarate + H2O Authored: D'Eustachio, P, 2009-12-26 EC Number: 4.2.1.2 Mitochondrial fumarate hydratase catalyzes the reversible reaction of malate to form fumarate and water (Bourgeron et al. 1994). Unpublished crystallographic data indicate that the protein is a tetramer (PDB 3E04). Pubmed8200987 Reactome Database ID Release 43451033 Reactome, http://www.reactome.org ReactomeREACT_21360 (S)-Malate + NAD+ <=> Oxaloacetate + NADH + H+ EC Number: 1.1.1.37 Mitochondrial malate dehydrogenase catalyzes the reversible reaction of malate and NAD+ to form oxaloacetate and NADH + H+ (Luo et al. 2006). This reaction is highly endergonic but is pulled in the direction annotated here when the TCA cycle is operating. Unpublished crystallographic data indicate that the protein is a dimer (PDB 3E04). Pubmed16740313 Reactome Database ID Release 4370979 Reactome, http://www.reactome.org ReactomeREACT_2172 (S)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2 Authored: D'Eustachio, P, 2010-06-25 EC Number: 1.1.99.2 Edited: D'Eustachio, P, 2010-06-25 L2HDGH associated with the mitochondrial inner membrane catalyzes the FAD-dependent reaction of (S)-2-hydroxyglutarate to form 2-oxoglutarate (Rzem et al. 2006). L2HDGH mutations are associated with high levels of (S)-2-hydroxyglutarate in vivo and variable neurological symptoms (Rzem et al. 2004; Topcu et al. 2004). Pubmed15385440 Pubmed15548604 Pubmed16005139 Reactome Database ID Release 43880050 Reactome, http://www.reactome.org ReactomeREACT_24926 Reviewed: Jassal, B, 2010-11-09 Reviewed: Rush, MG, 2011-01-31 (R)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2 Authored: D'Eustachio, P, 2010-06-25 D2HDGH associated with the mitochondrial inner membrane catalyzes the FAD-dependent reaction of (R)-2-hydroxyglutarate to form 2-oxoglutarate (Achouri et al. 2004). D2HDGH mutations are associated with high levels of (R)-2-hydroxyglutarate in vivo and variable neurological symptoms (Struys et al. 2005; Wanders and Mooyer 1995)). Edited: D'Eustachio, P, 2010-06-25 Pubmed15070399 Pubmed16435184 Pubmed7564244 Reactome Database ID Release 43880007 Reactome, http://www.reactome.org ReactomeREACT_25270 Reviewed: Jassal, B, 2010-11-09 Reviewed: Rush, MG, 2011-01-31 Fumarate + H2O <=> (S)-Malate EC Number: 4.2.1.2 Mitochondrial fumarate hydratase catalyzes the reversible reaction of fumarate and water to form malate, the seventh step of the TCA cycle (Bourgeron et al. 1994). Unpublished crystallographic data indicate that the protein is a tetramer (PDB 3E04). Pubmed8200987 Reactome Database ID Release 4370982 Reactome, http://www.reactome.org ReactomeREACT_1656 Transfer of electrons through the succinate dehydrogenase complex Authored: Jassal, B, 2005-06-10 10:46:07 EC Number: 1.3.5.1 GENE ONTOLOGYGO:0006121 Pubmed8682198 Reactome Database ID Release 43163213 Reactome, http://www.reactome.org ReactomeREACT_6360 This event is deduced on the basis of bovine experimental data.<br>Complex II (succinate dehydrogenase) transfers electrons from the TCA cycle to ubiquinone. The 6th step in the TCA cycle is where succinate is dehydrogenated to fumarate with subsequent reduction of FAD to FADH<sub>2</sub>. FADH<sub>2</sub> provides the electrons for the transport chain. Succinate dehydrogenase belongs to subclass 1 of the SQR family (succinate:quinone reductase) (classified by Hagerhall, C and Hederstedt, L [1996]).<br>It consists of 4 subunits (referred to as A, B, C and D), all nuclear-encoded and is located on the matrix side of the inner mitochondrial membrane. Subunits A and B are hydrophilic whereas subunits C and D are integral proteins of the inner membrane. SQRs usually contain 3 Fe-S clusters bound by the B subunit. Succinate dehydrogenase contains one [2Fe-2S] cluster, one [4Fe-4S] cluster and one [3Fe-4S] cluster. Additionally, the A subunit has a covalently-bound FAD group. Reduced complex II has this FAD converted to FADH<sub>2</sub>. The electrons from complex II are transferred to ubiquinone (also called Q, Coenzyme Q or CoQ), a small mobile carrier of electrons located within the inner membrane. Ubiquinone is reduced to ubiquinol during this process. (R)-2-hydroxyglutarate + succinate semialdehyde <=> 2-oxoglutarate + 4-hydroxybutyrate ADHFE1 catalyzes the reversible reaction of (R)-2-hydroxyglutarate and succinate semialdehyde to form 2-oxoglutarate and 4-hydroxybutyrate (Struys et al. 2005). The localization of human ADHFE1 to the mitochondrial matrix is inferred from the location determined experimentally for its rat homolog (Kaufman et al. 1988). Authored: D'Eustachio, P, 2010-06-25 EC Number: 1.1.99.24 Edited: D'Eustachio, P, 2010-06-25 Pubmed16435184 Pubmed3182820 Reactome Database ID Release 43880002 Reactome, http://www.reactome.org ReactomeREACT_25041 Reviewed: Jassal, B, 2010-11-09 Reviewed: Rush, MG, 2011-01-31 2-oxoglutarate + 4-hydroxybutyrate <=> (R)-2-hydroxyglutarate + succinate semialdehyde ADHFE1 catalyzes the reversible reaction of 2-oxoglutarate and 4-hydroxybutyrate to form (R)-2-hydroxyglutarate and succinate semialdehyde (Struys et al. 2005). The localization of human ADHFE1 to the mitochondrial matrix is inferred from the location determined experimentally for its rat homolog (Kaufman et al. 1988). Authored: D'Eustachio, P, 2010-06-25 EC Number: 1.1.99.24 Edited: D'Eustachio, P, 2010-06-25 Pubmed16435184 Pubmed3182820 Reactome Database ID Release 43880033 Reactome, http://www.reactome.org ReactomeREACT_25102 Reviewed: Jassal, B, 2010-11-09 Reviewed: Rush, MG, 2011-01-31 2-oxoglutarate + NADPH + H+ => (R)-2-hydroxyglutarate + NADP+ [mutant IDH1] Authored: D'Eustachio, P, 2010-06-25 Edited: D'Eustachio, P, 2010-06-25 Mutant forms of IDH1 in which the arginine residue at position 132 has been replaced by histidine, cystine, leucine, or serine catalyze the reaction of 2-oxoglutarate and NADPH + H+ to form (R)-2-hydroxyglutarate and NADP+. Like normal IDH1, the mutant enzyme forms a dimer located in the cytosol (Dang et al. 2009).<p>Such mutations occur frequently as a somatic event in human glioblastomas (Parsons et al. 2008). Cells expressing the mutant protein accumulate elevated levels of 2-hydroxyglutarate, probably in the cytosol as IDH1 is a cytosolic enzyme. The fate of the 2-hydroxyglutarate is unclear, but the high frequency with which the mutation is found in surveys of primary tumors is consistent with the possibility that it is advantageous to the tumor cells (Dang et al. 2009). Pubmed19935646 Reactome Database ID Release 43880053 Reactome, http://www.reactome.org ReactomeREACT_25008 Reviewed: Jassal, B, 2010-11-09 Reviewed: Rush, MG, 2011-01-31 NADH enters the respiratory chain at Complex I Authored: Jassal, B, 2005-05-10 13:13:07 Complex I (NADH:ubiquinone oxidoreductase or NADH dehydrogenase) utilizes NADH formed from glycolysis and the TCA cycle to pump protons out of the mitochondrial matrix. It is the largest enzyme complex in the electron transport chain, containing 45 subunits. Seven subunits (ND1-6, ND4L) are encoded by mitochondrial DNA (Loeffen et al [1998]), the remainder are encoded in the nucleus. The enzyme has a FMN prosthetic group and 8 Iron-Sulfur (Fe-S) clusters. The electrons from NADH oxidation pass through the flavin (FMN) and Fe-S clusters to ubiquinone (CoQ). This electron transfer is coupled with the translocation of protons from the mitochondrial matrix to the intermembrane space. For each electron transferred, 2 protons can be pumped out of the matrix. As there are 2 electrons transferred, 4 protons can be pumped out.<br>Complex I is made up of 3 sub-complexes - Iron-Sulfur protein fraction (IP), Flavoprotein fraction (FP) and the Hydrophobic protein fraction (HP), probably arranged in an L-shaped structure with the IP and FP fractions protruding into the mitochondrial matrix and the HP arm lying within the inner mitochondrial membrane. The overall reaction can be summed as below:<br><b>NADH</b> + <b>Ubiquinone</b> + <b>5H<sup>+</sup></b><sub>matrix</sub><b> -></b> <b>NAD<sup>+</sup></b> + <b>Ubiquinol</b> + <b>4H<sup>+</sup></b><sub>memb. space</sub><br><br>The electrons from complex I are transferred to ubiquinone (Coenzyme Q, CoQ), a small mobile carrier of electrons located within the inner membrane. Ubiquinone is reduced to ubiquinol during this process. EC Number: 1.6.5.3 GENE ONTOLOGYGO:0006120 Pubmed11695836 Pubmed12231006 Pubmed12837546 Pubmed14741580 Pubmed15250827 Pubmed9878551 Reactome Database ID Release 43163217 Reactome, http://www.reactome.org ReactomeREACT_6310 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 5 EET(1) Converted from EntitySet in Reactome Reactome DB_ID: 2161818 Reactome Database ID Release 432161818 Reactome, http://www.reactome.org ReactomeREACT_150812 DHET(1) Converted from EntitySet in Reactome Reactome DB_ID: 2161883 Reactome Database ID Release 432161883 Reactome, http://www.reactome.org ReactomeREACT_150571 Vamp Converted from EntitySet in Reactome Reactome DB_ID: 432673 Reactome Database ID Release 43432673 Reactome, http://www.reactome.org ReactomeREACT_20239 Golgi-associated Vesicle Destined Cargo Converted from EntitySet in Reactome Reactome DB_ID: 432674 Reactome Database ID Release 43432674 Reactome, http://www.reactome.org ReactomeREACT_19733 ISL-1 Enhances Transcription of the GIP Gene ACTIVATION Pubmed19074620 Reactome Database ID Release 43400479 Reactome, http://www.reactome.org ReactomeREACT_24899 PAX6 Enhances Transcription of the GIP Gene ACTIVATION Pubmed19074620 Reactome Database ID Release 43400474 Reactome, http://www.reactome.org ReactomeREACT_24897 'ChREBP:MLX [nucleoplasm]' positively regulates 'Transcriptional activation of pyruvate kinase gene by ChREBP:MLX' ACTIVATION Reactome Database ID Release 43164418 Reactome, http://www.reactome.org ReactomeREACT_6086 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of TRIB3' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989816 Reactome, http://www.reactome.org ReactomeREACT_117983 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of UGT1A9' ACTIVATION Pubmed12582161 Reactome Database ID Release 431989819 Reactome, http://www.reactome.org ReactomeREACT_117987 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of TXNRD1' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989824 Reactome, http://www.reactome.org ReactomeREACT_118034 PAX6 Enhances Transcription of the GCG gene ACTIVATION Pubmed19074620 Reactome Database ID Release 43400535 Reactome, http://www.reactome.org ReactomeREACT_24901 'hTCF-4:Beta-catenin [nucleoplasm]' positively regulates 'Synthesis of Preproglucagon in Intestinal L Cells' ACTIVATION Beta-catenin:TCF-4 bound at the promoter of the GCG gene recruits RNA polymerase II. This regulation is inferred from experiments in mouse and rat cells. Pubmed15525634 Pubmed18258680 Reactome Database ID Release 43391470 Reactome, http://www.reactome.org ReactomeREACT_24889 GATA-4 Enhances Transcription of GIP Gene ACTIVATION Pubmed19074620 Reactome Database ID Release 43400525 Reactome, http://www.reactome.org ReactomeREACT_24908 CDX-2 Enhances Transcription of the GCG Gene ACTIVATION Pubmed18258680 Pubmed19074620 Reactome Database ID Release 43400473 Reactome, http://www.reactome.org ReactomeREACT_24906 'ATF6-alpha (aa 1-379) [nucleoplasm]' positively regulates 'Expression of CHOP (DDIT3, GADD153)' ACTIVATION Pubmed10958673 Reactome Database ID Release 431791221 Reactome, http://www.reactome.org ReactomeREACT_118039 'ATF4 [nucleoplasm]' positively regulates 'Expression of CHOP (DDIT3, GADD153)' ACTIVATION As inferred from rat Pubmed10085237 Pubmed12083523 Pubmed14630918 Reactome Database ID Release 431791227 Reactome, http://www.reactome.org ReactomeREACT_117921 'ChREBP:MLX [nucleoplasm]' positively regulates 'Transcriptional activation of GP-acyl transferase gene by ChREBP:MLX' ACTIVATION Reactome Database ID Release 43164416 Reactome, http://www.reactome.org ReactomeREACT_5932 'ChREBP:MLX [nucleoplasm]' positively regulates 'Transcriptional activation of Acetyl-CoA carboxylase by ChREBP:MLX' ACTIVATION Reactome Database ID Release 43164419 Reactome, http://www.reactome.org ReactomeREACT_5925 'ChREBP:MLX [nucleoplasm]' positively regulates 'Transcriptional activation of FAS monomer gene by ChREBP:MLX' ACTIVATION Reactome Database ID Release 43164420 Reactome, http://www.reactome.org ReactomeREACT_6072 'ChREBP:MLX [nucleoplasm]' positively regulates 'Transcriptional activation of Citrate lyase monomer gene by ChREBP:MLX' ACTIVATION Reactome Database ID Release 43164421 Reactome, http://www.reactome.org ReactomeREACT_6057 'NF-Y [nucleoplasm]' positively regulates 'Expression of CHOP (DDIT3, GADD153)' ACTIVATION Pubmed10958673 Reactome Database ID Release 431791208 Reactome, http://www.reactome.org ReactomeREACT_117919 'ATF4 [nucleoplasm]' positively regulates 'Expression of BIP (78 kDa Glucose-regulated protein, GRP78, HSPA5)' ACTIVATION Pubmed12871976 Reactome Database ID Release 431791222 Reactome, http://www.reactome.org ReactomeREACT_117988 'ATF6-alpha (aa 1-379) [nucleoplasm]' positively regulates 'Expression of BIP (78 kDa Glucose-regulated protein, GRP78, HSPA5)' ACTIVATION Pubmed10856300 Pubmed11163209 Pubmed14973138 Pubmed9837962 Reactome Database ID Release 43420838 Reactome, http://www.reactome.org ReactomeREACT_19098 'NF-Y [nucleoplasm]' positively regulates 'Expression of BIP (78 kDa Glucose-regulated protein, GRP78, HSPA5)' ACTIVATION Pubmed10866666 Reactome Database ID Release 431791245 Reactome, http://www.reactome.org ReactomeREACT_117944 'ATF6-alpha (aa 1-379) [nucleoplasm]' positively regulates 'Expression of Calreticulin' ACTIVATION Pubmed9837962 Reactome Database ID Release 431791247 Reactome, http://www.reactome.org ReactomeREACT_118049 IP6K1/2 Converted from EntitySet in Reactome Reactome DB_ID: 2023924 Reactome Database ID Release 432023924 Reactome, http://www.reactome.org ReactomeREACT_151275 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of CXXC1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791192 Reactome, http://www.reactome.org ReactomeREACT_117913 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of ATP6VOD1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791242 Reactome, http://www.reactome.org ReactomeREACT_117990 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of ADD1 (Adducin alpha)' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791249 Reactome, http://www.reactome.org ReactomeREACT_117989 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of CTDSP2' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791226 Reactome, http://www.reactome.org ReactomeREACT_118028 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of C19orf10' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791220 Reactome, http://www.reactome.org ReactomeREACT_117984 'ATF6-alpha (aa 1-379) [nucleoplasm]' positively regulates 'Expression of Xbp1(S)' ACTIVATION Pubmed10958673 Reactome Database ID Release 431791228 Reactome, http://www.reactome.org ReactomeREACT_118059 'ATF6-alpha (aa 1-379) [nucleoplasm]' positively regulates 'Expression of HSP90B1 (Endoplasmin)' ACTIVATION Pubmed9837962 Reactome Database ID Release 431791191 Reactome, http://www.reactome.org ReactomeREACT_118029 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of ACADVL' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791189 Reactome, http://www.reactome.org ReactomeREACT_117991 'NF-Y [nucleoplasm]' positively regulates 'Expression of Xbp1(S)' ACTIVATION Pubmed10958673 Reactome Database ID Release 43420839 Reactome, http://www.reactome.org ReactomeREACT_19109 The N-terminal fragment of ATF6-alpha contains a bZIP domain and binds the sequence CCACG in ER Stress Response Elements (ERSEs). ATF6-alpha binds ERSEs together with the heterotrimeric transcription factor NF-Y, which binds the sequence CCAAT in the ERSEs, and together the two factors activate transcription of ER stress-responsive genes. Evidence from overexpression and knockdowns indicates that ATF6-alpha is a potent activator but its homolog ATF6-beta is not and ATF6-beta may actually reduce expression of ER stress proteins. 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of Cullin-7' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791241 Reactome, http://www.reactome.org ReactomeREACT_118030 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of DCTN1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791204 Reactome, http://www.reactome.org ReactomeREACT_117929 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of GFPT1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791213 Reactome, http://www.reactome.org ReactomeREACT_117909 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of ARFGAP1 (GAP)' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791196 Reactome, http://www.reactome.org ReactomeREACT_118026 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of FKBP14' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791201 Reactome, http://www.reactome.org ReactomeREACT_118013 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of EXTL3' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791240 Reactome, http://www.reactome.org ReactomeREACT_117994 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of EDEM' ACTIVATION Pubmed14559994 Pubmed16461360 Reactome Database ID Release 431791197 Reactome, http://www.reactome.org ReactomeREACT_117951 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of DNAJB9' ACTIVATION Pubmed14559994 Pubmed16539657 Reactome Database ID Release 431791214 Reactome, http://www.reactome.org ReactomeREACT_117928 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of DNAJB11' ACTIVATION Pubmed14559994 Reactome Database ID Release 431791206 Reactome, http://www.reactome.org ReactomeREACT_118047 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of DDX11' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791229 Reactome, http://www.reactome.org ReactomeREACT_117933 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of GOSR2' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791231 Reactome, http://www.reactome.org ReactomeREACT_117952 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of HDGF' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791207 Reactome, http://www.reactome.org ReactomeREACT_117915 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of GSK3A' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791210 Reactome, http://www.reactome.org ReactomeREACT_118031 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of HYOU1' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791255 Reactome, http://www.reactome.org ReactomeREACT_117916 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of KDELR3' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791202 Reactome, http://www.reactome.org ReactomeREACT_118053 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of KLHDC3' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791216 Reactome, http://www.reactome.org ReactomeREACT_117975 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of LMNA' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791218 Reactome, http://www.reactome.org ReactomeREACT_118018 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of PDIA5' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791225 Reactome, http://www.reactome.org ReactomeREACT_117978 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of PDIA6 (Protein disulfide-isomerase A6)' ACTIVATION Pubmed14559994 Reactome Database ID Release 431791223 Reactome, http://www.reactome.org ReactomeREACT_118008 'XBP1(S) [nucleoplasm]' positively regulates 'Expression of PLA2G4B' ACTIVATION Pubmed16539657 Reactome Database ID Release 431791244 Reactome, http://www.reactome.org ReactomeREACT_118015 HSPG Converted from EntitySet in Reactome Reactome DB_ID: 174740 Reactome Database ID Release 43174740 Reactome, http://www.reactome.org ReactomeREACT_7848 heparan sulfate proteoglycans ABCG1 ATP-binding cassette sub-family G member 1 Converted from EntitySet in Reactome Reactome DB_ID: 194269 Reactome Database ID Release 43194269 Reactome, http://www.reactome.org ReactomeREACT_14613 PLTP Converted from EntitySet in Reactome Phospholipid transfer protein Reactome DB_ID: 194227 Reactome Database ID Release 43194227 Reactome, http://www.reactome.org ReactomeREACT_14647 AMP + ATP <=> ADP + ADP [AK2] EC Number: 2.7.4.3 Mitochondrial adenylate kinase 2 (AK2) catalyzes the reaction of AMP and ATP to form two molecules of ADP (Hamade et al. 1982). Localization of AK2 specifically to the mitochondrial intermembrane space is inferred from studies of the homologous rat enzyme (Criss 1970). Pubmed5484814 Pubmed6182143 Reactome Database ID Release 43110145 Reactome, http://www.reactome.org ReactomeREACT_390 has a Stoichiometric coefficient of 2 (d)ADP + ADP <=> (d)AMP + ATP [AK1] Cytosolic adenylate kinase 1 (AK1) catalyzes the reversible reactions of ADP and dADP with ADP to form AMP and dAMP respectively, plus ATP (Tsuboi 1978; Matsuura et al. 1989). EC Number: 2.7.4.3 Pubmed211388 Pubmed2542324 Reactome Database ID Release 43110141 Reactome, http://www.reactome.org ReactomeREACT_763 (d)AMP + ATP <=> (d)ADP + ADP [AK1] Cytosolic adenylate kinase 1 (AK1) catalyzes the reversible reactions of AMP and dAMP with ATP to form ADP and dADP respectively, plus ADP (Tsuboi 1978; Matsuura et al. 1989). EC Number: 2.7.4.3 Pubmed211388 Pubmed2542324 Reactome Database ID Release 4374220 Reactome, http://www.reactome.org ReactomeREACT_643 (R)-3-aminoisobutyric acid + pyruvate => 2-methyl-3-oxopropanoate + alanine Authored: D'Eustachio, P, 2010-07-07 EC Number: 2.6.1.40 Edited: D'Eustachio, P, 2010-07-07 Mitochondrial AGXT2 tetramer catalyzes the reaction of (R)-3-aminoisobutyric acid and pyruvate to form 2-methyl-3-oxopropanoate and alanine. While the human mitochondrial AGXT2 enzyme has been characterized experimentally in other respects (Rodionov et al. 2010), its ability to catalyze this transamination reaction is inferred from the properties of its rat homologue. Pubmed20018850 Reactome Database ID Release 43909780 Reactome, http://www.reactome.org ReactomeREACT_25332 Reviewed: Jassal, B, 2010-11-09 conversion of 3-Ureidoiosbutyrate to 3-Aminoisobutyrate Authored: Jassal, B, 2003-06-17 09:00:25 Cytosolic UPB1 (beta-ureidopropionase) catalyzes the reaction of 3-ureidoisobutyrate and H2O to form (R)-3-aminoisobutyrate, CO2, and NH3 (Tamaki et al. 2000; van Kuilenburg et al. 2004). EC Number: 3.5.1.6 Edited: D'Eustachio, P, 2003-07-18 15:39:00 Pubmed10989446 Pubmed15385443 Reactome Database ID Release 4373620 Reactome, http://www.reactome.org ReactomeREACT_902 beta-ureidoisobutyrate + H2O => 3-aminoisobutyrate + NH4+ + CO2 Mitochondrial uptake of (R)-3-aminoisobutyric acid Authored: D'Eustachio, P, 2010-07-07 Edited: D'Eustachio, P, 2010-07-07 Pubmed10989446 Reactome Database ID Release 43909755 Reactome, http://www.reactome.org ReactomeREACT_25053 Reviewed: Jassal, B, 2010-11-09 The mitochondrial uptake of cytosolic (R)-3-aminoisobutyric acid in human cells is inferred from the corresponding process known to occur in rat (Tamaki et al. 2000). reduction of thymine to form 5,6-Dihydrothymine Cytosolic dihydropyrimidine dehydrogenase catalyzes the reaction of thymine and NADPH + H+ to form 5,6-dihydrothymine and NADP+. The mechanism of the human reaction is inferred from that of the well-characterized pig enzyme (Yokota et al. 1994). EC Number: 1.3.1.2 Pubmed8083224 Reactome Database ID Release 4373616 Reactome, http://www.reactome.org ReactomeREACT_1067 thymine + NADPH + H+ => 5,6-dihydrothymine + NADP+ 5,6-dihydrothymine + H2O => beta-ureidoisobutyrate Cytosolic dihydropyrimidinase tetramer catalyzes the reaction of 5,6-dihydrothymine and water to yield 3-ureidoisobutyrate (Hamajima et al. 1998). EC Number: 3.5.2.2 Pubmed9718352 Reactome Database ID Release 4373618 Reactome, http://www.reactome.org ReactomeREACT_1977 conversion of 5,6-Dihydrothymine to 3-Ureidoisobutyrate Mitochondrial uptake of beta-alanine Authored: D'Eustachio, P, 2010-07-07 Edited: D'Eustachio, P, 2010-07-07 Pubmed10989446 Reactome Database ID Release 43909765 Reactome, http://www.reactome.org ReactomeREACT_25324 Reviewed: Jassal, B, 2010-11-09 The mitochondrial uptake of cytosolic beta-alanine in human cells is inferred from the corresponding process known to occur in rat (Tamaki et al. 2000). beta-alanine + pyruvate => 3-oxopropanoate + alanine Authored: D'Eustachio, P, 2010-07-07 EC Number: 2.6.1.18 Edited: D'Eustachio, P, 2010-07-07 Mitochondrial AGXT2 tetramer catalyzes the reaction of beta-alanine and pyruvate to form 3-oxopropanoate and alanine. While the human mitochondrial AGXT2 enzyme has been characterized experimentally in other respects (Rodionov et al. 2010), its ability to catalyze this transamination reaction is inferred from the properties of its rat homologue. Pubmed20018850 Reactome Database ID Release 43909776 Reactome, http://www.reactome.org ReactomeREACT_25226 Reviewed: Jassal, B, 2010-11-09 IP6K1/3 Converted from EntitySet in Reactome Reactome DB_ID: 2023977 Reactome Database ID Release 432023977 Reactome, http://www.reactome.org ReactomeREACT_151004 PPIP5K1/2 Converted from EntitySet in Reactome Reactome DB_ID: 2023997 Reactome Database ID Release 432023997 Reactome, http://www.reactome.org ReactomeREACT_152423 INPP5A/B Converted from EntitySet in Reactome Reactome DB_ID: 2024026 Reactome Database ID Release 432024026 Reactome, http://www.reactome.org ReactomeREACT_152071 INPP5(4) Converted from EntitySet in Reactome Reactome DB_ID: 2024044 Reactome Database ID Release 432024044 Reactome, http://www.reactome.org ReactomeREACT_151616 INPP4A/B Converted from EntitySet in Reactome Reactome DB_ID: 1806281 Reactome Database ID Release 431806281 Reactome, http://www.reactome.org ReactomeREACT_121439 NAD(P)+ Converted from EntitySet in Reactome NAD+, NADP+ Reactome DB_ID: 428218 Reactome Database ID Release 43428218 Reactome, http://www.reactome.org ReactomeREACT_20200 pyridine nucleotides, oxidized (2'-deoxy)adenosine + H2O => (2'-deoxy)inosine + NH3 [ADA] Cytosolic adenosine deaminase (ADA) catalyzes the hydrolysis of 2'deoxyadenosine and adenosine to yield deoxyinosine and inosine, respectively, plus ammonia (Akeson et al. 1988). Unpublished crystallographic data (PDB 3IAR) indicate that the human enzyme is a monomer. EC Number: 3.5.4.4 Pubmed3182793 Reactome Database ID Release 4374241 Reactome, http://www.reactome.org ReactomeREACT_2135 Vamp Converted from EntitySet in Reactome Reactome DB_ID: 432668 Reactome Database ID Release 43432668 Reactome, http://www.reactome.org ReactomeREACT_19572 guanine or hypoxanthine + PRPP => GMP or IMP + PPi [HPRT1] Cytosolic hypoxanthine-guanine phosphoribosyltransferase (HPRT1) tetramer catalyzes the reactions of guanine or hypoxanthine with PRPP to form GMP ir IMP and pyrophosphate (Holden and Kelley 1978; Jolly et al. 1983). EC Number: 2.4.2.8 Pubmed6300847 Reactome Database ID Release 4374215 Reactome, http://www.reactome.org ReactomeREACT_1444 AMP + H2O => IMP + NH3 [AMPD] Cytosolic AMP deaminase (AMPD) catalyzes the hydrolysis of AMP to yield IMP and ammonia. Three isoforms of AMPD, E, L, and M, have been identified that differ in their expression patterns in the body. All occur as tetramers and all have qualitatively the same catalytic activity, however (Bausch-Jurken et al. 1992; Mahnke-Zizelman et al. 1998). EC Number: 3.5.4.6 Pubmed1429593 Pubmed9857047 Reactome Database ID Release 4376590 Reactome, http://www.reactome.org ReactomeREACT_700 dA, dG, or dI + ATP => dAMP, dGMP, or dIMP + ADP [DGUOK] Mitochondrial deoxyguanosine kinase (DGUOK) catalyzes the reactions of deoxyadenosine, deoxyguanosine, and deoxyinosine with ATP to form the corresponding nucleotide monophosphates and ADP (Park and Ives 1988; Johansson and Karlson 1996). Crystallographic studies of the human enzyme have confirmed its dimeric structure and allowed identification of key amino acid residues responsible for its substrate specificity (Johansson et al. 2001). Pubmed11427893 Pubmed2845866 Pubmed8692979 Reactome Database ID Release 4374207 Reactome, http://www.reactome.org ReactomeREACT_2223 deoxyadenosine or deoxyguanosine + ATP => dAMP or dGMP + ADP [DCK] Cytosolic deoxycytidine kinase (DCK) catalyzes the reactions of deoxyadenosine and deoxyguanosine with ATP to form the corresponding nucleotide monophosphates and AMP, The enzyme is a dimer (Bohman and Eriksson 1988; Datta et al. 1989). While the enzyme can be found in nuclei of cultured cells expressing high levels of a tagged recombinant protein, its normal location appears to be cytosolic (Hatzis et al. 1998). Pubmed2539852 Pubmed2844225 Pubmed9804782 Reactome Database ID Release 43109671 Reactome, http://www.reactome.org ReactomeREACT_1332 (2'-deoxy)adenosine + ATP => (d)AMP + ADP [ADK] Cytosolic adenosine linase (ADK) catalyzes the reactions of adenosine and deoxyadenosine with ATP to yield the corresponding nucleotide monophosphates and ADP (Andres and Fox 1979). The enzyme is substantially more active on adenosine than deoxyadenosine in vitro (Hurley at al. 1985) though studies of cultured cells suggest that both reactions may be physiologically relevant (Hershfield et al. 1982). The enzyme is a monomer complexed with magnesium (Mathews et al. 1998). EC Number: 2.7.1.20 Pubmed227870 Pubmed2999129 Pubmed6281270 Pubmed9843365 Reactome Database ID Release 43109624 Reactome, http://www.reactome.org ReactomeREACT_1728 Adenine + PRPP => AMP + PPi Cytosolic APRT dimer catalyzes the reaction of adenine and 5-phospho-alpha-D-ribose 1-diphosphate to form AMP and pyrophosphate (Holden et al. 1979). EC Number: 2.4.2.7 Pubmed457664 Reactome Database ID Release 4374213 Reactome, http://www.reactome.org ReactomeREACT_165 hypoxanthine + (deoxy)ribose 1-phosphate <=> (deoxy)inosine + orthophosphate [NP] Cytosolic nucleoside phosphorylase (NP) trimer catalyzes the reversible reaction of hypoxanthine with ribose 1-phosphate or deoxyribose 1-phosphate to form inosine or deoxyinosine and orthophosphate (Ealick et al. 1990; Wiginton et al. 1980). While NP is active with either ribose 1-phosphate or deoxyribose 1-phosphate in vitro, levels of deoxyribose 1-phosphate are normally low in vivo, limiting the extent of this reaction. NP deficiency in vivo is associated with defects in purine nucleotide salvage and leads to immunodeficiency (Williams et al. 1987). EC Number: 2.4.2.1 Pubmed2104852 Pubmed3029074 Pubmed6771276 Reactome Database ID Release 43112033 Reactome, http://www.reactome.org ReactomeREACT_1636 guanine + (deoxy)ribose 1-phosphate <=> (deoxy)guanosine + orthophosphate [NP] Cytosolic nucleoside phosphorylase (NP) trimer catalyzes the reversible reaction of guanine with ribose 1-phosphate or deoxyribose 1-phosphate to form guanosine or deoxyguanosine and orthophosphate (Ealick et al. 1990; Wiginton et al. 1980). While NP is active with either ribose 1-phosphate or deoxyribose 1-phosphate in vitro, levels of deoxyribose 1-phosphate are normally low in vivo, limiting the extent of this reaction. NP deficiency in vivo is associated with defects in purine nucleotide salvage and leads to immunodeficiency (Williams et al. 1987). EC Number: 2.4.2.1 Pubmed2104852 Pubmed3029074 Pubmed6771276 Reactome Database ID Release 43112034 Reactome, http://www.reactome.org ReactomeREACT_1040 N6-methyl-AMP + H2O => IMP + methylamine Authored: D'Eustachio, P, 2012-03-14 Cytosolic ADAL (Adenosine DeAminase-Like) catalyzes the reaction of N6-methyl-AMP and water to form IMP and methylamine. The active form of the enzyme is a protein monomer complexed with a zinc ion (Murakami et al. 2011). Deamination of N6-methyl-AMP to form IMP EC Number: 3.5.4.4 Edited: D'Eustachio, P, 2012-03-16 Pubmed21755941 Reactome Database ID Release 432161187 Reactome, http://www.reactome.org ReactomeREACT_120992 Reviewed: Jassal, B, 2012-03-16 Adenylosuccinate => AMP + Fumarate Authored: D'Eustachio, P, 2004-02-13 16:27:00 EC Number: 4.3.2.2 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed10958654 Pubmed8366112 Reactome Database ID Release 4373828 Reactome, http://www.reactome.org ReactomeREACT_1042 The irreversible conversion of adenylosuccinate to adenosine 5'-monophosphate and fumarate is catalyzed by adenylosuccinate lyase. The active form of this enzyme is a cytosolic tetramer (Stone et al. 1993). The enzyme also catalyzes the conversion of 5'-phosphoribosyl-5-aminoimidazole-4-N-succinocarboxamide (SAICAR) to 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) and fumarate. Humans lacking the enzyme accumulate dephosphorylated forms of both substrates, indicating that the enzyme mediates both reactions in vivo as well (Race et al. 2000). adenylosuccinate => adenosine 5'-monophosphate + fumarate IMP + L-Aspartate + GTP => Adenylosuccinate + GDP + Pi [ADSS] Authored: D'Eustachio, P, 2004-02-19 09:47:00 EC Number: 6.3.4.4 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed15786719 Pubmed1592113 Reactome Database ID Release 43111524 Reactome, http://www.reactome.org ReactomeREACT_1719 Two isoforms of adenylosuccinate synthetase, ADSS and ADSSL1, catalyze the reaction of IMP, aspartate, and GTP to form adenylosuccinate, GDP, and orthophosphate (Powell et al. 1992; Sun et al. 2005). ADSS is a homotetramer (unpublished crystallographic data - PDB 2V40) and ADSSL1 is inferred to be a tetramer likewise. inosine 5'-monophosphate + L-aspartate + GTP => adenylosuccinate + guanosine 5'-diphosphate + orthophosphate AIR + CO2 => CAIR 5'-phosphoribosyl-5-aminoimidazole (AIR) + CO2 <=> 5'-phosphoribosyl-5-aminoimidazole-4-carboxylate (CAIR) Authored: D'Eustachio, P, 2004-02-13 11:42:00 EC Number: 4.1.1.21 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed17224163 Pubmed18388293 Pubmed2183217 Reactome Database ID Release 4373806 Reactome, http://www.reactome.org ReactomeREACT_589 The reversible carboxylation of 5'-phosphoribosyl-5-aminoimidazole (AIR) to form 5'-phosphoribosyl-5-aminoimidazole-4-carboxylate (CAIR) is catalyzed by the phosphoribosylaminoimidazole carboxylase domain of the bifunctional protein "phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase" (PAICS) (Schild et al. 1990). The enzyme is an octamer (Li et al. 2007); it may associate in the cytosol with other enzymes of de novo IMP biosynthesis under some metabolic conditions (An et al. 2008). FGAM + ATP => AIR + ADP + Pi 5'-phosphoribosylformylglycinamidine (FGAM) + ATP => 5'-phosphoribosyl-5-aminoimidazole (AIR) + ADP + orthophosphate Authored: D'Eustachio, P, 2004-02-12 17:35:00 EC Number: 6.3.3.1 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed11381136 Pubmed18388293 Pubmed2147474 Reactome Database ID Release 4373810 Reactome, http://www.reactome.org ReactomeREACT_1917 The irreversible synthesis of cytosolic 5'-phosphoribosyl-5-aminoimidazole (AIR) from 5'-phosphoribosylformylglycinamidine (FGAM), accompanied by the conversion of ATP to ADP and orthophosphate, is catalyzed by the phosphoribosylaminoimidazole synthetase domain of the trifunctional protein, "phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase" (GART) (Aimi et al. 1990). The active form of the protein is cytosolic and may co-localize with other enzymes of de novo IMP biosynthesis under some metabolic conditions (Gooljarsingh et al. 2001; An et al. 2008). SAICAR => AICAR + Fumarate 5'-phosphoribosyl-5-aminoimidazole-4-N-succinocarboxamide (SAICAR) <=> 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) + fumarate Authored: D'Eustachio, P, 2004-02-12 14:16:00 EC Number: 4.3.2.2 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed10958654 Pubmed18388293 Pubmed8366112 Reactome Database ID Release 4373800 Reactome, http://www.reactome.org ReactomeREACT_1463 The reversible conversion of 5'-phosphoribosyl-5-aminoimidazole-4-N-succinocarboxamide (SAICAR) to 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) and fumarate is catalyzed by adenylosuccinate lyase. The active form of this enzyme is a cytosolic tetramer (Stone et al. 1993), and fluoresence microscopy of cultured human cells suggests that it may associate with other enzymes of de novo IMP biosynthesis under some metabolic conditions (An et al. 2008). The enzyme also catalyzes the conversion of adenylosuccinate to adenosine 5'-monophosphate and fumarate. Humans lacking the enzyme accumulate dephosphorylated forms of both substrates, indicating that the enzyme mediates both reactions in vivo as well (Race et al. 2000). CAIR + Aspartate + ATP => SAICAR + ADP + Pi 5'-phosphoribosyl-5-aminoimidazole-4-carboxylate (CAIR) + L-aspartate + ATP => 5'-phosphoribosyl-5-aminoimidazole-4-N-succinocarboxamide (SAICAR) + ADP + orthophosphate Authored: D'Eustachio, P, 2004-02-13 12:25:00 EC Number: 6.3.2.6 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed17224163 Pubmed18388293 Pubmed2183217 Reactome Database ID Release 4373805 Reactome, http://www.reactome.org ReactomeREACT_108 The conversion of 5'-phosphoribosyl-5-aminoimidazole-4-carboxylate (CAIR) and aspartate to 5'-phosphoribosyl-5-aminoimidazole-4-N-succinocarboxamide (SAICAR), accompanied by the conversion of ATP to ADP and orthophosphate, is catalyzed by the phosphoribosylaminoimidazole succinocarboxamide synthetase domain of the bifunctional protein "phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase" (PAICS) (Schild et al. 1990). The enzyme is an octamer (Li et al. 2007); it may associate in the cytosol with other enzymes of de novo IMP biosynthesis under some metabolic conditions (An et al. 2008). FAICAR => IMP + H2O 5'-phosphoribosyl-5-formaminoimidazole-4-carboxamide (FAICAR) <=> inosine 5'-monophosphate + H2O Authored: Jassal, B, 2003-06-26 04:06:16 EC Number: 3.5.4.10 Pubmed11096114 Pubmed18388293 Pubmed8567683 Reactome Database ID Release 4373797 Reactome, http://www.reactome.org ReactomeREACT_263 The reversible synthesis of inosine 5'-monophosphate from 5'-phosphoribosyl-5-formaminoimidazole-4-carboxamide (FAICAR) is catalyzed by the IMP cyclohydrolase activity of the bifunctional 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase enzyme. This cytosolic protein occurs primarily as a dimer (Rayl et al. 1996; Vergis et al. 2001) and may further associate with other enzymes of de novo IMP biosynthesis under some metabolic conditions (An et al. 2008). AICAR + 10-Formyl-THF => FAICAR + THF 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) + 10-formyltetrahydrofolate => 5'-phosphoribosyl-5-formaminoimidazole-4-carboxamide (FAICAR) + tetrahydrofolate Authored: D'Eustachio, P, 2004-02-12 14:16:00 EC Number: 2.1.2.3 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed11096114 Pubmed18388293 Pubmed8567683 Reactome Database ID Release 4373798 Reactome, http://www.reactome.org ReactomeREACT_812 The irreversible transfer of a formyl group to 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), to yield 5'-phosphoribosyl-5-formaminoimidazole-4-carboxamide (FAICAR), is catalyzed by the phosphoribosylaminoimidazolecarboxamide formyltransferase activity of the bifunctional 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase enzyme. This cytosolic protein occurs primarily as a dimer (Rayl et al. 1996; Vergis et al. 2001) and may further associate with other enzymes of de novo IMP biosynthesis under some metabolic conditions (An et al. 2008). XMP + L-Glutamine + ATP + H2O => GMP + L-Glutamate + AMP + pyrophosphate Authored: D'Eustachio, P, 2004-02-23 15:33:00 Cytosolic GMP synthase (GMPS) catalyzes the reaction of xanthosine 5'-monophosphate (XMP), ATP, glutamine and water to form guanosine 5'-monophosphate (GMP), AMP, glutamate and pyrophosphate. GMPS is a monomer (Hirst et al. 1994; Nakamura and Lou 1995). EC Number: 6.3.4.1 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed7706277 Pubmed8089153 Reactome Database ID Release 4373792 Reactome, http://www.reactome.org ReactomeREACT_628 xanthosine 5'-monophosphate (XMP) + L-glutamine + ATP + H2O => guanosine 5'-monophosphate (GMP) + L-glutamate + adenosine 5'-monophosphate (AMP) + pyrophosphate IMP + H2O + NAD+ => XMP + NADH + H+ [IMPDH1,2] Authored: D'Eustachio, P, 2004-02-23 10:40:00 EC Number: 1.1.1.205 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed7903306 Reactome Database ID Release 4373794 Reactome, http://www.reactome.org ReactomeREACT_1488 Two human isoenzymes, IMP dehydrogenase 1 and 2 (IMPDH1,2) catalyze the irreversible dehydrogenation of inosine 5'-monophosphate (IMP) to form xanthosine 5'-monophosphate (XMP). The active forms of both isoenzymes are homotetramers, and they are nearly identical in their catalytic efficiencies and their susceptibility to inhibition by XMP (Carr et al. 1993; Colby et al. 1999; Hager et al. 1995). Both enzymes occur as homotetramers (Colby et al. 1999 - IMPDH2; unpubliched data in PDB 1JCN IMPDH1). A variety of experiments suggest that IMPDH1 and 2 have distinct functions in vivo. While IMPDH1 is expressed at constant levels, IMPDH2 is expressed at elevated levels in tumor cells and in mitotic normal cells. In humans, heterozygosity for mutant forms of IMPDH1 is associated with a form of retinitis pigmentosa (Bowne et al. 2002). In laboratory mice, mutations that disrupt the homologue of IMPDH1 have no obvious effect at the level of the whole organism, while ones that disrupt IMPDH2 are lethal (Gu et al. 2003).<P>This reaction is the rate limiting step in the synthesis of guanosine 5'-monophosphate (GMP) from IMP, and GMP competitively inhibits the well-characterized bacterial IMP dehydrogenase enzyme. Evidence for an inhibitory effect of GMP on the human isoenzymes has not been reported. Rather, they appear to be inhibited by XMP; in addition, transcription of one or both IMP dehydrogenase mRNAs may be inhibited by high cellular GMP concentrations (Glesne et al. 1991). inosine 5'-monophosphate (IMP) + NAD+ + H2O => xanthosine 5'-monophosphate (XMP) + NADH + H+ AP-1 mu Converted from EntitySet in Reactome Reactome DB_ID: 350815 Reactome Database ID Release 43350815 Reactome, http://www.reactome.org ReactomeREACT_15185 TrXA3/B3 Converted from EntitySet in Reactome Reactome DB_ID: 2161985 Reactome Database ID Release 432161985 Reactome, http://www.reactome.org ReactomeREACT_152004 HXA3/B3 Converted from EntitySet in Reactome Reactome DB_ID: 2162031 Reactome Database ID Release 432162031 Reactome, http://www.reactome.org ReactomeREACT_152458 FGAR + L-Glutamine + ATP + H2O => FGAM + L-Glutamate + ADP + Pi 5'-phosphoribosylformylglycinamide (FGAR) + L-glutamine + ATP + H2O => 5'-phosphoribosylformylglycinamidine (FGAM) + L-glutamate + adenosine 5'-diphosphate + orthophosphate Authored: D'Eustachio, P, 2004-02-13 10:19:00 EC Number: 6.3.5.3 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed18388293 Pubmed8110788 Reactome Database ID Release 4373812 Reactome, http://www.reactome.org ReactomeREACT_1427 The irreversible transfer of an amino group from L-glutamine to 5'-phosphoribosylformylglycinamide (FGAR), forming 5'-phosphoribosylformylglycinamidine (FGAM) and glutamate, accompanied by the conversion of ATP to ADP and orthophosphate, is catalyzed by phosphoribosylformylglycinamidine synthetase. The human enzyme has been purified and characterized biochemically (Barnes et al. 1994). Fluoresence microscopy studies of cultured human cells have shown that the enzyme is cytosolic and suggest that it may co-localize with other enzymes of de novo IMP biosynthesis under some metabolic conditions (An et al. 2008). GAR + 10-Formyl-THF => FGAR + THF 5-phosphoribosylglycinamide (GAR) + 10-formyl-tetrahydrofolate => 5'-phosphoribosylformylglycinamide (FGAR) + tetrahydrofolate Authored: D'Eustachio, P, 2004-02-12 16:37:00 EC Number: 2.1.2.2 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed11381136 Pubmed12450384 Pubmed18388293 Pubmed2147474 Reactome Database ID Release 4373813 Reactome, http://www.reactome.org ReactomeREACT_1509 The irreversible transfer of a formyl group to cytosolic 5-phosphoribosylglycinamide (GAR) to form 5'-phosphoribosylformylglycinamide (FGAR) is catalyzed by the phosphoribosylglycinamide formyltransferase domain of the trifunctional protein, "phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase" (GART) (Aimi et al. 1990; Zhang et al. 2002). Fluoresence microscopy studies of cultured human cells have shown that GART is cytosolic and suggest that it may co-localize with other enzymes of de novo IMP biosynthesis under some metabolic conditions (Gooljarsingh et al. 2001; An et al. 2008). 5-Phosphoribosylamine + Glycine + ATP => GAR + ADP + Pi 5-phosphoribosylamine + glycine + ATP => 5-phosphoribosylglycinamide (GAR) + ADP + orthophosphate Authored: D'Eustachio, P, 2004-02-12 15:28:00 EC Number: 6.3.4.13 Edited: D'Eustachio, P, Jassal, B, 0000-00-00 00:00:00 Pubmed11381136 Pubmed18388293 Pubmed2147474 Reactome Database ID Release 4373814 Reactome, http://www.reactome.org ReactomeREACT_285 The synthesis of cytosolic 5-phosphoribosylglycinamide from 5-phosphoribosylamine and glycine, accompanied by the conversion of ATP to ADP and orthophosphate, is catalyzed by the phosphoribosylglycinamide synthetase domain of the trifunctional protein, "phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase" (GART) (Aimi et al. 1990). The active form of the protein is cytosolic (Gooljarsingh et al. 2001; An et al. 2008). PRPP + H2O + L-Glutamine => 5-Phosphoribosylamine + L-Glutamate + PPi 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) + H2O + L-glutamine <=> 5-phosphoribosylamine + L-glutamate +pyrophosphate Authored: Jassal, B, 2003-06-26 04:06:16 Cytosolic PPAT (phosphoribosyl pyrophosphate amidotransferase) catalyzes the reaction of 5-phospho-alpha-D-ribose 1-diphosphate (PRPP), water, and L-glutamine to form 5-phosphoribosylamine, L-glutamate, and pyrophosphate. This event is the committed step in de novo purine synthesis. The reaction itself is reversible, but it is pulled strongly in the direction of 5'-phosphoribosylamine synthesis by the irreversible hydrolysis of the pyrophosphate that is also formed in the reaction. Fluoresence microscopy studies of cultured human cells have shown that PPAT is cytosolic and suggest that it may co-localize with other enzymes of de novo IMP biosynthesis under some metabolic conditions (An et al. 2008). The PPAT enzyme is inferred to be an iron-sulfur protein, like its well-characterized B. subtilis homologue, because incubation of purified enzyme with molecular oxygen or chelating agents inactivates it, and activity can be restored by incubation with ferrous iron and inorganic sulfide. The stoichiometry of the iron-sulfur moiety and its role in enzyme activity remain unknown (Itakura and Holmes 1979). The fully active form of the enzyme is a dimer, which can associate further to form a tetramer with sharply reduced activity (Holmes et al. 1973b; Iwahana et al. 1993). Interaction of the enzyme with inosine 5'-monophosphate (IMP), guanosine 5'-monophosphate (GMP), and adenosine 5'-monophosphate (AMP), end products of de novo purine biosynthesis, favors tetramer formation, while interaction with 5-phospho-alpha-D-ribose 1-diphosphate (PRPP), a required substrate, favors formation of the active dimer. Kinetic studies suggest that the enzyme's binding site for GMP and IMP is separate from its AMP binding site (Holmes et al. 1973a). EC Number: 2.4.2.14 Edited: Jassal, B, D'Eustachio, P, 0000-00-00 00:00:00 Pubmed18388293 Pubmed4348202 Pubmed4726295 Pubmed762062 Pubmed8380692 Reactome Database ID Release 4373815 Reactome, http://www.reactome.org ReactomeREACT_740 Dissociation of phosphoribosyl pyrophosphate amidotransferase tetramer PRPP stimulates the dissociation of phosphoribosyl pyrophosphate amidotransferase tetramers to form dimers (Holmes et al. 1973a,b). Pubmed4348202 Pubmed4726295 Reactome Database ID Release 43111289 Reactome, http://www.reactome.org ReactomeREACT_534 has a Stoichiometric coefficient of 2 Formation of phosphoribosyl pyrophosphate amidotransferase tetramer Cytosolic AMP, GMP, and IMP stimulate the association of phosphoribosyl pyrophosphate amidotransferase (PPAT) dimers to form tetramers (Holmes et al. 1973a,b). Pubmed4348202 Pubmed4726295 Reactome Database ID Release 43111285 Reactome, http://www.reactome.org ReactomeREACT_201 has a Stoichiometric coefficient of 2 Protons are translocated from the intermembrane space to the matrix In this reaction, 1 molecule of 'H+' is translocated from mitochondrial intermembrane space to mitochondrial matrix.<br><br>This reaction takes place in the 'mitochondrial inner membrane' and is mediated by the 'hydrogen ion transporter activity' of 'UCP dimer'. Reactome Database ID Release 43170026 Reactome, http://www.reactome.org ReactomeREACT_6312 The proton is delivered to the matrix side At the beginning of this reaction, 1 molecule of 'Fatty Acid "head-in"' is present. At the end of this reaction, 1 molecule of 'H+', and 1 molecule of 'Fatty Acid anion "head-in"' are present.<br><br> This reaction takes place in the 'mitochondrial inner membrane'.<br> Pubmed11709078 Pubmed8576230 Reactome Database ID Release 43166223 Reactome, http://www.reactome.org ReactomeREACT_6302 FA spontaneously flip-flops back to the matrix side At the beginning of this reaction, 1 molecule of 'Fatty Acid "head-out"' is present. At the end of this reaction, 1 molecule of 'Fatty Acid "head-in"' is present.<br><br> This reaction takes place in the 'mitochondrial inner membrane'.<br> Pubmed11709078 Pubmed8576230 Reactome Database ID Release 43166215 Reactome, http://www.reactome.org ReactomeREACT_6151 FA anion picks up a proton At the beginning of this reaction, 1 molecule of 'H+', and 1 molecule of 'Fatty Acid anion "head-out"' are present. At the end of this reaction, 1 molecule of 'Fatty Acid "head-out"' is present.<br><br> This reaction takes place in the 'mitochondrial inner membrane'.<br> Pubmed11709078 Pubmed8576230 Reactome Database ID Release 43166219 Reactome, http://www.reactome.org ReactomeREACT_6205 LXA4/B4 Converted from EntitySet in Reactome Reactome DB_ID: 2161856 Reactome Database ID Release 432161856 Reactome, http://www.reactome.org ReactomeREACT_152343 15epi-LXA4/B4 Converted from EntitySet in Reactome Reactome DB_ID: 2161609 Reactome Database ID Release 432161609 Reactome, http://www.reactome.org ReactomeREACT_152095 AP-1 sigma Converted from EntitySet in Reactome Reactome DB_ID: 350807 Reactome Database ID Release 43350807 Reactome, http://www.reactome.org ReactomeREACT_15259 Golgi-associated Vesicle Destined Cargo Converted from EntitySet in Reactome Reactome DB_ID: 435032 Reactome Database ID Release 43435032 Reactome, http://www.reactome.org ReactomeREACT_20220 FA anion diffuses laterally to UCP A FA anion diffuses laterally within the membrane towards UCP. The membrane potential drives the FA anion to an energy well halfway up on UCP. The electric field created by the redox-linked proton ejection drives the head group to the energy well. Pubmed11709078 Pubmed8576230 Reactome Database ID Release 43166220 Reactome, http://www.reactome.org ReactomeREACT_6165 Enzyme-bound ATP is released Authored: Jassal, B, 2005-06-30 14:42:50 GENE ONTOLOGYGO:0042776 In the last step, the beta subunit is converted to the open form and ATP is released. Passage of protons through the Fo part causes a ring of approximately 10 subunits to rotate. This rotation in turn drives the rotation of the gamma subunits, which forms part of one of the stalks. The gamma subunit moves between the three beta subunits which are held in place by the second stalk which can be regarded as a stator. The polypeptide called OSCP connects the stator stalk to the assembly of alpha and beta subunits. It is this step that is coupled to proton translocation as energy is required to break the strong bond between ATP and the protein.<br><br> Pubmed4517936 Reactome Database ID Release 43164834 Reactome, http://www.reactome.org ReactomeREACT_1985 has a Stoichiometric coefficient of 3 The FA anion diffuses away laterally from UCP At the beginning of this reaction, 1 molecule of 'FA anion:UCP dimer "head-out" complex' is present. At the end of this reaction, 1 molecule of 'UCP dimer', and 1 molecule of 'Fatty Acid anion "head-out"' are present.<br><br> This reaction takes place in the 'mitochondrial inner membrane'.<br> Reactome Database ID Release 43166387 Reactome, http://www.reactome.org ReactomeREACT_6218 FA anion flip-flops to the opposite surface Pubmed11709078 Pubmed8576230 Reactome Database ID Release 43166214 Reactome, http://www.reactome.org ReactomeREACT_6188 The FA anion which was facing the matrix side of the inner mitochondrial membrane now flip-flops over to the intermembrane space-side of the membrane. Electron transfer from reduced cytochrome c to molecular oxygen Authored: Jassal, B, 2005-06-28 15:06:45 Complex IV (cytochrome oxidase) contains the hemeprotein cytochrome a and a3. It also contains copper atoms which undergo a transition from Cu+ to Cu2+ during the transfer of electrons through the complex to molecular oxygen. A bimetallic centre containing a copper atom and a heme-linked iron protein binds oxygen after 4 electrons have been picked up. Water, the final product of oxygen reduction, is then released. Oxygen is the final electron acceptor in the respiratory chain. The overall reaction can be summed as below:<br><b>4Cyt c</b><sub>(red.)</sub> + <b>12H<sup>+</sup></b><sub>in</sub> + <b>O<sub>2</sub></b> -> <b>4Cyt c</b><sub>(ox.)</sub> + <b>2H<sub>2</sub>O</b> + <b>8H<sup>+</sup></b><sub>out</sub><br><br>Four protons are taken up from the matrix side of the membrane to form the water (scalar protons). Wikstrom (1977) suggests 4 protons are additionally transferred out from the matrix to the intermembrane space. EC Number: 1.9.3.1 GENE ONTOLOGYGO:0006123 Pubmed11340051 Pubmed15223 Pubmed7979252 Reactome Database ID Release 43163214 Reactome, http://www.reactome.org ReactomeREACT_6149 has a Stoichiometric coefficient of 12 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 Electron transfer from ubiquinol to cytochrome c of complex III Authored: Jassal, B, 2005-06-14 09:46:56 GENE ONTOLOGYGO:0006122 Pubmed186667 Pubmed239860 Reactome Database ID Release 43164651 Reactome, http://www.reactome.org ReactomeREACT_6300 The <b><i>Protonmotive Q cycle</i></b> is the mechanism by which complex III transfers electrons from ubiquinol to cytochrome c, linking this process to translocation of protons across the membrane. This cycle is complicated by the fact that both ubiquinol is oxidised and ubiquinone is reduced during this process. Through a complex series of electron transfers, Complex III consumes two molecules of ubiquinol (QH2) and two molecules of oxidized cytochrome c, generates one molecule of ubiquinone (Q) and two molecules of reduced cytochrome c, regenerates one molecule of ubiquinol (QH2), and mediates the translocation of two protons from the mitochondrial matrix to the mitochondrial intermembrane space.<br><br>The overall reaction can be summed up as below:<br><b>2QH<sub>2</sub></b> + <b>2cyt c</b><sub>(ox.)</sub> + <b>Q</b> + <b>2H<sup>+</sup></b><sub>matrix</sub> -> <b>2Q</b> + <b>2cyt c</b><sub>(red.)</sub> + <b>QH<sub>2</sub></b> + <b>4H<sup>+</sup></b><sub>memb. space</sub> has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 ATP is synthesized from ADP and Pi by ATPase Authored: Jassal, B, 2005-06-30 14:42:50 EC Number: 3.6.3.14 GENE ONTOLOGYGO:0006754 In the tight configuration, the beta subunit catalyzes the reaction of ADP + Pi to ATP + water. ATP is still tightly bound to the subunit at this stage. Pubmed4517936 Reactome Database ID Release 43164832 Reactome, http://www.reactome.org ReactomeREACT_190 ADP and Pi bind to ATPase Authored: Jassal, B, 2005-06-30 14:42:50 GENE ONTOLOGYGO:0006754 Pubmed4517936 Reactome Database ID Release 43164840 Reactome, http://www.reactome.org ReactomeREACT_991 The beta subunit has 3 conformations; <i>tight</i>, <i>open</i> and <i>loose</i>. ADP and Pi bind to the subunit in the loose form. On binding, this subunit is converted to the tight configuration. NAD(P)H Converted from EntitySet in Reactome NADH, NADPH Reactome DB_ID: 428206 Reactome Database ID Release 43428206 Reactome, http://www.reactome.org ReactomeREACT_20158 pyridine nucleotides, reduced Transfer of electrons from ETF to ubiquinone by ETF-QO EC Number: 1.5.5.1 ETF-ubiquinone oxidoreductase (ETF-QO), catalyzes the re-oxidation of reduced ETF, with ubiquinone as the electron acceptor. Reactome Database ID Release 43169270 Reactome, http://www.reactome.org ReactomeREACT_6169 Reducing equivalents from beta-oxidation of fatty acids transfer to ETF Electron transfer flavoprotein, ETF, a 63kDa heterodimer composed of alpha and beta subunit, binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reducing equivalents from the beta-oxidation of fatty acyl CoAs are transferred to ETF, reducing the ETF-bound FAD to FADH<sub>2</sub>. Reactome Database ID Release 43169260 Reactome, http://www.reactome.org ReactomeREACT_6154 TMP, (d)UMP, uridine 2' monophosphate, or uridine 3'-monophosphate + H2O => thymidine, deoxyuridine, or uridine + orthophosphate [NT5M] 5'3'-Nucleotidase, mitochondrial (NT5M) is the major nucleotidase of human mitochondria, catalyzing the hydrolysis of TMP, uridine 2'-, 3'-, and 5'-monophosphates, and dUMP to yield the corresponding (deoxy)nucleosides and orthophosphate. It may play a central role in "substrate cycles" to regulate mitochondrial deoxynucleotide levels, especially in non-dividing cells (Rampazzo et al. 2000; Gallinaro et al. 2002). The active form of the enzyme is a homodimer, with an absolute requirement for Mg++ (Rampazzo et al. 2000; Rinaldo-Matthis et al. 2002). EC Number: 3.1.3.5 Pubmed10899995 Pubmed12124385 Pubmed12352955 Reactome Database ID Release 43109514 Reactome, http://www.reactome.org ReactomeREACT_1389 TMP, uridine 2', 3', or 5' monophosphates, or deoxyuridine 3' or 5' monophosphates + H2O => thymidine or (deoxy)uridine + orthophosphate [NT5C] Cytosolic 5'3'-nucleotidase (NT5C) catalyzes the hydrolysis of uridine 2', 3', and 5' monophosphates, dexoyuridine 3' and 5' monophosphates, and thymidine monophosphate to yield the corresponding (deoxy)nucleosides and orthophosphate. The active form of the enzyme is a homodimer, with an absolute requirement for Mg++ (Hoglund and Reichard 1990; Rampazzo et al. 2000). This enzyme appears to play a central role in the "substrate cycles" that regulate cytosolic deoxynucleotide levels (Gazziola et al. 2001). EC Number: 3.1.3.5 Pubmed10681516 Pubmed11083867 Pubmed2157703 Reactome Database ID Release 43109480 Reactome, http://www.reactome.org ReactomeREACT_1172 (d)CMP, TMP, or (d)UMP + H2O => (deoxy)cytidine, thymidine, or (deoxy)uridine + orthophosphate [NT5C1A] Cytosolic 5'-nucleotidase IA (NT5C1A) catalyzes the hydrolysis of (deoxy)cytidine monophosphate, thymidine monophosphate and (deoxy)uridine monophosphate to the corresponding nucleosides plus orthophosphate. The enzyme is allosterically activated by ADP (Hunsucker et al. 2001). The human enzyme is inferred to be a homotetramer with one Mg++ ion bound per subunit based on its similarity to the pigeon heart enzyme (Bianchi and Spychala 2003; Sala-Newby et al. 1999; Skladanowski and Newby 1990). EC Number: 3.1.3.5 Pubmed10364222 Pubmed11133996 Pubmed12947102 Pubmed2344353 Reactome Database ID Release 43109380 Reactome, http://www.reactome.org ReactomeREACT_982 (d)CMP, TMP, or (d)UMP + H2O => (deoxy)cytidine, thymidine, or (deoxy)uridine + orthophosphate [NT5C3] Cytosolic 5'-nucleotidase 3 (NT5C3) catalyzes the hydrolysis of pyrimidine nucleoside monophosphates (d)CMP, TMP, and (d)UMP to nucleosides plus orthophosphate. While the enzyme appears to be present in many tissues, it is especially abundant in erythrocytes, where it may function to remove excess pyrimidine nucleotides generated by nucleic acid breakdown, while sparing purine nucleotides needed for red cell energy metabolism. Deficiencies in the enzyme are associated with a form of hemolytic anemia and its inactivation by heavy metals may be responsible for some hematological abnormalities associated with lead poisoning (Marinaki et al. 2001; Rees et al. 2003). The active form of the enzyme is a monomer. It has an absolute requirement for Mg++, and is inactive against purine nucleotides (Amici et al. 1997; Amici and Magni 2002). EC Number: 3.1.3.5 Pubmed11369620 Pubmed11795870 Pubmed12580951 Pubmed9428647 Reactome Database ID Release 43109449 Reactome, http://www.reactome.org ReactomeREACT_358 CMP or TMP or UMP + H2O => cytidine, thymidine, or uridine + orthophosphate [NT5E] 5'-nucleotidase (NT5E) associated with the plasma membrane catalyzes the reactions of extracellular CMP, TMP, or UMP with H2O to yield the corresponding nucleoside and orthophosphate. The active enzyme is a glycolipid-anchored dimer (Misumi et al. 1990; Thompson et al. 1987; Zimmerman 1992) EC Number: 3.1.3.5 Reactome Database ID Release 43109291 Reactome, http://www.reactome.org ReactomeREACT_1236 reduction of uracil to form dihydrouracil Cytosolic dihydropyrimidine dehydrogenase catalyzes the reaction of uracil and NADPH + H+ to form 5,6-dihydrouracil and NADP+. The mechanism of the human reaction is inferred from that of the well-characterized pig enzyme (Yokota et al. 1994). EC Number: 1.3.1.2 Pubmed8083224 Reactome Database ID Release 4373585 Reactome, http://www.reactome.org ReactomeREACT_546 uracil + NADPH + H+ => 5,6-dihydrouracil + NADP+ 5,6-dihydrouracil + H2O => beta-ureidopropionate Cytosolic dihydropyrimidinase tetramer catalyzes the reaction of 5,6-dihydrouracil and water to form 3-ureidopropionate (Hamajima et al. 1998). EC Number: 3.5.2.2 Pubmed9718352 Reactome Database ID Release 4373589 Reactome, http://www.reactome.org ReactomeREACT_2169 conversion of 5,6-dihydrouracil to 3-ureidopropionate (deoxy)uridine + orthophosphate <=> uracil + (deoxy)ribose 1-phosphate [UPP] Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) catalyzes the reversible reactions of uridine or deoxyuridine with orthophosphate to yield uracil and ribose 1-phosphate or deoxyribose 1-phosphate (Watanabe and Uchida 1995; Johansson, 2003). The active form of UPP1 is a dimer (Rooslid et al. 2009). EC Number: 2.4.2.3 Pubmed12849978 Pubmed19291308 Pubmed7488099 Reactome Database ID Release 4374376 Reactome, http://www.reactome.org ReactomeREACT_1812 thymidine or deoxyuridine + orthophosphate <=> thymine or uracil + 2-deoxy-D-ribose 1-phosphate [TYMP] Cytosolic thymidine phosphorylase (TYMP) catalyzes the reversible reactions of thymidine or deoxyuridine with orthophosphate to form thymine or uracil and 2-deoxy-D-ribose 1-phosphate. The active form of the enzyme is a homodimer (Desgranges et al. 1981; Norman et al. 2004; Usuki et al. 1992). EC Number: 2.4.2 Pubmed14725767 Pubmed1590793 Pubmed7284378 Reactome Database ID Release 43112265 Reactome, http://www.reactome.org ReactomeREACT_2153 conversion of 3-ureidopropionate to beta-alanine Authored: Jassal, B, 2003-06-17 09:00:25 Cytosolic 3-ureidopropionase catalyzes the reaction of 3-ureidopropionate and water to form beta-alanine, CO2, and NH3 (van Kuilenberg et al. 2004). EC Number: 3.5.1.6 Edited: D'Eustachio, P, 2003-07-18 15:39:00 Pubmed15385443 Reactome Database ID Release 4373591 Reactome, http://www.reactome.org ReactomeREACT_2183 beta-ureidopropionate + H2O => beta-alanine + NH4+ + CO2 Golgi-associated Vesicle Cargo Converted from EntitySet in Reactome Reactome DB_ID: 432672 Reactome Database ID Release 43432672 Reactome, http://www.reactome.org ReactomeREACT_19951 conversion of dUMP to dTMP Cytosolic thymidylate synthase catalyzes the reaction of dUMP and N5,N10-methylene tetrahydrofolate to form TMP and dihydrofolate (Davisson et al. 1989). The enzyme is a homodimer (Phan et al. 2001). EC Number: 2.1.1.45 Pubmed11278511 Pubmed2656695 Reactome Database ID Release 4373605 Reactome, http://www.reactome.org ReactomeREACT_1679 dUMP + N5,N10-methylene tetrahydrofolate => TMP + dihydrofolate Golgi-associated Vesicle Cargo Converted from EntitySet in Reactome Reactome DB_ID: 435029 Reactome Database ID Release 43435029 Reactome, http://www.reactome.org ReactomeREACT_19886 dUTP + H2O => dUMP + pyrophosphate Deoxyuridine triphosphatase (DUT) catalyzes the hydrolysis of dUTP to form dUMP and pyrophosphate. Two isoforms of DUT are expressed, generated by alternative splicing. The major one, annotated here, is localized to the nucleoplasm (Ladner et al. 1996). The enzyme is a homotrimer (Mol et al. 1996). In the cell, this reaction depletes the supply of dUTP, preventing its incorporation into DNA, while generating dUMP, the immediate precursor of thymidine nucleotides. EC Number: 3.6.1.23 Pubmed8631816 Pubmed8805593 Reactome Database ID Release 4373666 Reactome, http://www.reactome.org ReactomeREACT_150 hydrolysis of 2'-deoxyuridine 5'-triphosphate to form 2'-deoxyuridine 5'-phosphate thymine or uracil + 2-deoxy-D-ribose 1-phosphate <=> thymidine or deoxyuridine + orthophosphate [TYMP] Cytosolic thymidine phosphorylase (TYMP) catalyzes the reversible reactions of thymine or uracil with 2-deoxy-D-ribose 1-phosphate to form thymidine or deoxyuridine and orthiophosphate. The active form of the enzyme is a homodimer (Desgranges et al. 1981; Norman et al. 2004; Usuki et al. 1992). EC Number: 2.4.2 Pubmed14725767 Pubmed1590793 Pubmed7284378 Reactome Database ID Release 43112266 Reactome, http://www.reactome.org ReactomeREACT_966 uracil + (deoxy)ribose 1-phosphate <=> (deoxy)uridine + orthophosphate [UPP] Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) catalyzes the reversible reactions of uracil with ribose 1-phosphate or deoxyribose 1-phosphate to yield uridine or deoxyuridine and orthophosphate (Watanabe and Uchida 1995; Johansson, 2003). The active form of UPP1 is a dimer (Rooslid et al. 2009). EC Number: 2.4.2.3 Pubmed12849978 Pubmed19291308 Pubmed7488099 Reactome Database ID Release 4374372 Reactome, http://www.reactome.org ReactomeREACT_2200 cytidine or uridine + ATP => CMP or UMP + ADP [UCK1] Cytosolic uridine-cytidine kinase 1 (UCK1) catalyzes the reactions of cytidine or uridine with ATP to form CMP or UMP and ADP (Greenberg et al. 1977; Van Rompay et al. 2001). Unpublished crystallographic data show the enzyme to be a tetramer (PDB - 2JEO). Pubmed11306702 Pubmed195585 Reactome Database ID Release 4373599 Reactome, http://www.reactome.org ReactomeREACT_2062 cytidine or uridine + ATP => CMP or UMP + ADP [UCK2] Cytosolic uridine-cytidine kinase 2 (UCK2) catalyzes the reactions of cytidine or uridine with ATP to form CMP or UMP and ADP (Greenberg et al. 1977; Van Rompay et al. 2001). Crystallographic data show the enzyme to be a tetramer (Suzuki et al. 2004). When it is expressed as a fusion construct with green fluorescent protein, the protein localizes primarily to the cytosol of transfected CHO cells (Van Rompay et al. 2003). Pubmed11306702 Pubmed14609716 Pubmed15130468 Pubmed195585 Reactome Database ID Release 43109903 Reactome, http://www.reactome.org ReactomeREACT_2162 phosphorylation of 2'-Deoxythymidine to dTMP Cytosolic thymidine kinase 1 (TK1) catalyzes the reaction of thymidine and ATP to form TMP (thymidine 5'-monophosphate) and ADP. TK1 has been purified from human spleen and from cultured cells. The enzyme is active as a homotetramer, and phosphorylates thymidine and deoxyuridine using ATP as a phosphate donor in vitro (Sherley and Kelly 1988a; Munch-Petersen et al. 1991; Birringer et al. 2005). Divalent cations are required for enzyme activity (Mg++ is preferred) (Lee and Cheng 1986), and ATP stabilizes the tetrameric form of the enzyme (Munch-Petersen et al. 1993). In cells, enzyme activity is high during S phase of the cell cycle and low otherwise, correlated with intracellular levels of thymidine kinase 1 protein (Sherley and Kelly 1988b), and consistent with a requirement for TMP synthesis in normal cells only as part of DNA replication. Pubmed1063125 Pubmed15733844 Pubmed2026611 Pubmed3335503 Pubmed3372530 Pubmed8340387 Reactome Database ID Release 4373632 Reactome, http://www.reactome.org ReactomeREACT_437 thymidine + ATP => TMP (deoxythymidine 5'-monophosphate) + ADP [TK1] deoxycytidine, thymidine, or deoxyuridine + ATP => dCMP, TMP, or dUMP + ADP [TK2] Mitochondrial thymidine kinase 2 (TK2) catalyzes the reactions of deoxycytidine, thymidine, and deoxyuridine with ATP to form the corresponding deoxynucleotide monophosphates and ADP. The enzyme has been purified from human spleen and is active as a monomer (Munch-Petersen et al. 1991). The enzyme requires divalent cations for activity (Mg++ is preferred) but the nature of the association between the metal ion and the enzyme polypeptide is unclear (Lee and Cheng 1976). The mitochondrial localization of the enzyme has been established experimentally for rats and cattle (Jansson et al. 1992); its mitochondrial localization in humans is inferred from these results and the presence of a mitochondrial localization motif at the amino terminus of the open reading frame of a cloned human cDNA that is missing from the mature catalytically active protein (Wang et al. 1999). Pubmed1063125 Pubmed1597187 Pubmed2026611 Pubmed9989599 Reactome Database ID Release 43109759 Reactome, http://www.reactome.org ReactomeREACT_1691 (2'-deoxy)cytidine + ATP => (d)CMP + ADP [DCK] Cytosolic deoxycytidine kinase (DCK) catalyzes the reactions of cytidine or deoxycytidine with ATP to form CMP or dCMP and ADP. The enzyme is a homodimer (Sabini et al. 2003). Although a chimeric deoxycytidine kinase - green fluorescent protein expressed at high levels in cultured cells localized to nuclei, endogenous protein is primarily cytosolic (Hatzis et al. 1998). Despite its name, the enzyme has a broad substrate specificity, acting on cytidine, deoxycytidine, deoxyguanosine, and deoxyadenosine (Bohman and Eriksson 1988; Datta et al. 1989a, b; Sarup et al. 1989; Usova and Eriksson 2002). While ATP functions efficiently as a phosphate donor, other nucleoside triphosphates, notably UTP, function efficiently as phosphate donors in vitro and may function in this way in vivo as well (Shewach et al. 1992). Pubmed12429345 Pubmed12808445 Pubmed1406603 Pubmed1996353 Pubmed2539852 Pubmed2542307 Pubmed2548513 Pubmed2844225 Pubmed9804782 Reactome Database ID Release 4373598 Reactome, http://www.reactome.org ReactomeREACT_1547 phosphorylation of 2'-Deoxycytidine to 2'-Deoxycytidine 5'-phosphate deamination of 2'-Deoxycytidine to 2'-Deoxyuridine (deoxy)cytidine + H2O => (deoxy)uridine + NH4+ [CDA] Cytosolic cytidine deaminase catalyzes the hydrolysis of cytidine or dexoycytidine to form uridine or deoxyuridine and ammonia (Laliberte and Momparler 1994). The active form of the enzyme is a tetramer (Chung et al. 2005). EC Number: 3.5.4.5 Pubmed15689149 Pubmed7923172 Reactome Database ID Release 4373608 Reactome, http://www.reactome.org ReactomeREACT_376 Lysosome Destined Cargo Converted from EntitySet in Reactome Reactome DB_ID: 435031 Reactome Database ID Release 43435031 Reactome, http://www.reactome.org ReactomeREACT_20462 AP-1 mu Converted from EntitySet in Reactome Reactome DB_ID: 351192 Reactome Database ID Release 43351192 Reactome, http://www.reactome.org ReactomeREACT_14887 2 H2O2 => O2 + 2 H2O Authored: D'Eustachio, P, 2003-09-15 12:36:00 EC Number: 1.11.1.6 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Hydrogen peroxide is generated in the course of peroxisomal fatty acid oxidation and purine catabolism, and is rapidly converted to water and molecular oxygen by the enzyme catalase. This enzyme is widely distributed in the body, but is especially abundant in liver, kidney, and red blood cells. Pubmed10656833 Pubmed1999334 Reactome Database ID Release 4376031 Reactome, http://www.reactome.org ReactomeREACT_615 has a Stoichiometric coefficient of 2 2 glutathione, reduced + H2O2 => glutathione, oxidized + 2 H2O Cytosolic glutathione peroxidase (GPX1) tetramer catalyzes the reaction of reduced glutathione and hydrogen peroxide to form reduced glutathione and water (Chu et al. 1993). EC Number: 1.11.1.9 Pubmed8428933 Reactome Database ID Release 4371676 Reactome, http://www.reactome.org ReactomeREACT_2037 has a Stoichiometric coefficient of 2 Xanthine + H2O + O2 => Urate + H2O2 Cytosolic xanthine dehydrogenase (XDH) catalyzes the reaction of xanthine with H2O to form urate and H2O2. The active form of the enzyme is a dimer (Saksela and Raivio 1996; Yamaguchi et al. 2007). EC Number: 1.17.3.2 Pubmed17301077 Pubmed8670112 Reactome Database ID Release 4374258 Reactome, http://www.reactome.org ReactomeREACT_624 AP-1 sigma Converted from EntitySet in Reactome Reactome DB_ID: 351180 Reactome Database ID Release 43351180 Reactome, http://www.reactome.org ReactomeREACT_15200 dCMP + H2O => dUMP + NH4+ Cytosolic deoxycytidylate deaminase (DCTD) catalyzes the hydrolysis of dCMP (2'-deoxyuridine 5'-monophosphate) to yield dUMP (2'-deoxyuridine 5'-monophosphate) and ammonia. The active enzyme is a homohexamer (Maley et al. 1993; Weiner et al. 1993; unpublished crystallography data - PDB 2W4L). EC Number: 3.5.4.12 Pubmed7685356 Pubmed8448179 Reactome Database ID Release 4373596 Reactome, http://www.reactome.org ReactomeREACT_879 deamination of dCMP to form dUMP phosphoribosylation of orotate to form oritidine 5'-phosphate (OMP) Authored: Jassal, B, 2003-06-17 09:00:25 EC Number: 2.4.2.10 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed18184586 Pubmed6893554 Pubmed8631878 Pubmed9042911 Reactome Database ID Release 4373567 Reactome, http://www.reactome.org ReactomeREACT_33 The synthesis of orotidine 5'-monophosphate (OMP) from orotate and 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) is catalyzed by the orotate phosphoribosyltransferase activity of the bifunctional "uridine monophosphate synthetase (orotate phosphoribosyl transferase and orotidine 5'-decarboxylase)" protein. The reaction itself is freely reversible, but is pulled in the forward direction in vivo by the irreversible hydrolysis of pyrophosphate. While purified human protein has not been characterized in detail, the close similarity of the human gene to that encoding the well-studied hamster protein, and the demonstration that mutations in the human gene are associated with failure to convert orotate to UMP in vivo, provide convincing evidence that the human uridine monophosphate synthetase protein indeed catalyzes these two reactions (McClard et al. 1980; Suchi et al. 1997). The active form of the human protein is a dimer (Yablonski et al. 1996; Wittmann et al. 2008). orotate + 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) <=> orotidine 5'-monophosphate (OMP) + pyrophosphate orotidine 5'-monophosphate => uridine 5'-monophosphate + CO2 Authored: Jassal, B, 2003-06-17 09:00:25 EC Number: 4.1.1.23 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed18184586 Pubmed6893554 Pubmed8631878 Pubmed9042911 Reactome Database ID Release 4373564 Reactome, http://www.reactome.org ReactomeREACT_225 The decarboxylation of orotidine 5'-monophosphate (OMP) to form uridine 5'-monophosphate (UMP) is catalyzed by the orotidine 5'-phosphate decarboxylase activity of the bifunctional "uridine monophosphate synthetase (orotate phosphoribosyl transferase and orotidine 5'-decarboxylase)" protein. While purified human protein has not been characterized in detail, the close similarity of the human gene to that encoding the well-studied hamster protein, and the demonstration that mutations in the human gene are associated with failure to convert orotate to UMP in vivo, provide convincing evidence that the human uridine monophosphate synthetase protein indeed catalyzes these two reactions (McClard et al. 1980; Suchi et al. 1997). The active form of the human protein is a dimer (Yablonski et al. 1996; Wittmann et al. 2008). decarboxylation of Orotidine 5'-phosphate to form Uridine 5'-phosphate N-carbamoyl L-aspartate + H+ <=> (S)-dihydroorotate + H2O Authored: Jassal, B, 2003-06-17 09:00:25 EC Number: 3.5.2.3 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed8619816 Reactome Database ID Release 4373571 Reactome, http://www.reactome.org ReactomeREACT_744 The synthesis of dihydroorotate from N-carbamoyl L-aspartate is catalyzed by the dihydroorotase activity of cytosolic trifunctional CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) protein. This activity has not been directly demonstrated in experimental studies of the purified human protein, but has been inferred from the behavior of the purified hamster protein and the high degree of sequence similarity between the cloned hamster and human genes (Iwahana et al. 1996). Also on the basis of this similarity, the active human protein is annotated as a hexamer (Lee et al. 1985). condensation of N-Carbamoyl-L-aspartate to form (S)-Dihydroorotate (ring closure) oxidation of (S)-Dihydroorotate to form Orotate (S)-dihydroorotate + ubiquinone => orotate + ubiquinol Authored: Jassal, B, 2003-06-17 09:00:25 Dihydroorotate dehydrogenase catalyzes the oxidation of dihydroorotate to orotate (orotic acid). The enzyme is located in the inner mitochondrial membrane oriented so that cytosolic dihydroorotate molecules have access to it, and orotate is released into the cytosol. The reducing equivalents generated by the reaction are transferred by ubiquinone (Coenzyme Q) to the electron transport chain within the inner mitochondrial membrane. There is no evidence for the involvement of NAD+ as an acceptor of reducing equivalents in this reaction in mammalian cells (Jones 1980). In contrast, the reaction catalyzed by the enzyme isolated from the anaerobic bacterium Clostridium oroticum requires NAD+ as a cofactor but also proceeds strongly in the direction of dihydroorotate synthesis consistent with the greater electronegativity of NAD+ (Lieberman and Kornberg 1953).<P>Early studies of purified rat liver enzyme by Forman and Kennedy suggested the presence of flavin mononucleotide and iron-sulfur complexes as cofactors. More recent work by Bader, Beuneu, and their colleagues with recombinant human protein expressed in insect cells has confirmed the presence of flavin mononucleotide, at a stoichiometry of one molecule per molecule of apoenzyme but suggests that iron-sulfur complexes, if indeed they are involved in the oxidation and electron transport process, are not an integral part of the dihydroorotate dehydrogenase holoenzyme. EC Number: 1.3.5.2 EC Number: 1.3.99.11 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10889450 Pubmed13115431 Pubmed165196 Pubmed6105839 Pubmed9693067 Reactome Database ID Release 4373569 Reactome, http://www.reactome.org ReactomeREACT_669 bicarbonate and glutamine combine to form carbamoyl phosphate Authored: Jassal, B, 2003-06-17 09:00:25 EC Number: 6.3.5.5 Edited: D'Eustachio, P, 0000-00-00 00:00:00 L-glutamine + 2 ATP + HCO3- + H2O => carbamoyl phosphate + L-glutamate + 2 ADP + orthophosphate Pubmed4684686 Pubmed8619816 Reactome Database ID Release 4373577 Reactome, http://www.reactome.org ReactomeREACT_478 The synthesis of carbamoyl phosphate from glutamine, bicarbonate, and ATP is catalyzed by the carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity of cytosolic trifunctional CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) protein (Ito and Uchino 1973; Iwahana et al. 1996). The purified human protein is active in several different oligomerization states, as is its Syrian hamster homologue. The most abundant form of the latter is a hexamer, and the active human protein is annotated as a hexamer by inference (Ito and Uchino 1973; Lee et al. 1985). has a Stoichiometric coefficient of 2 carbamoyl phosphate and L-aspartate combine to form N-Carbamoyl-L-aspartate Authored: Jassal, B, 2003-06-17 09:00:25 EC Number: 2.1.3.2 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed2995985 Pubmed4684686 Pubmed8619816 Reactome Database ID Release 4373573 Reactome, http://www.reactome.org ReactomeREACT_1965 The synthesis of N-carbamoyl L-aspartate from carbamoyl phosphate and L-aspartate is catalyzed by the aspartate carbamoyltansferase activity of cytosolic trifunctional CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) protein (Ito and Uchino 1973; Iwahana et al. 1996). The purified human protein is active in several different oligomerization states as is its Syrian hamster homologue. The most abundant form of the latter is a hexamer, and the active human protein is annotated as a hexamer by inference (Ito and Uchino 1973; Lee et al. 1985). carbamoyl phosphate + L-aspartate <=> N-carbamoyl L-aspartate + orthophosphate AMP, dAMP, GMP, or IMP + H2O => adenosine, deoxyadenosine, guanosine, or inosine + orthophosphate [NT5E] 5'-nucleotidase (NT5E) associated with the plasma membrane catalyzes the reactions of extracellular AMP, dAMP, GMP, or IMP with H2O to yield the corresponding nucleoside and orthophosphate. The active enzyme is a glycolipid-anchored dimer (Misumi et al. 1990; Thompson et al. 1987; Zimmerman 1992) EC Number: 3.1.3.5 Pubmed1637327 Pubmed2129526 Pubmed3036115 Reactome Database ID Release 43109278 Reactome, http://www.reactome.org ReactomeREACT_849 GMP + NADPH + H+ => IMP + NADP+ + NH4+ [GMPR,GMPR2] Authored: D'Eustachio, P, 2010-02-17 Cytosolic GMP reductase (GMPR) catalyzes the reaction of GMP and NADPH + H+ to yield IMP and NADP+ + NH4+ (Spector et al. 1979; Deng et al. 2002). Two GMPR proteins have been identified, GMPR and GMPR2. Both proteins form homotetramers (GMPR - unpublished crstallographic data PDB 2BLE; GMPR2 - Li et al. 2006). EC Number: 1.7.1.7 Edited: D'Eustachio, P, 2010-02-18 Pubmed12009299 Pubmed16359702 Pubmed218932 Reactome Database ID Release 43514604 Reactome, http://www.reactome.org ReactomeREACT_21383 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 (deoxy)guanosine + orthophosphate <=> guanine + (deoxy)ribose 1-phosphate [NP] Cytosolic nucleoside phosphorylase (NP) trimer catalyzes the reversible reaction of guanosine or deoxyguanosine with orthophosphate to form guanine and ribose 1-phosphate or deoxyribose 1-phosphate (Ealick et al. 1990; Wiginton et al. 1980). While NP is active with either nuckeotide in vitro, levels of deoxyguanosine are normally low in vivo, limiting the extent of this reaction. NP deficiency in vivo is associated with defects in purine nucleotide salvage and leads to immunodeficiency (Williams et al. 1987). EC Number: 2.4.2.1 Pubmed2104852 Pubmed3029074 Pubmed6771276 Reactome Database ID Release 4374249 Reactome, http://www.reactome.org ReactomeREACT_758 (deoxy)inosine + orthophosphate <=> hypoxanthine + (deoxy)ribose 1-phosphate [NP] Cytosolic nucleoside phosphorylase (NP) trimer catalyzes the reversible reaction of inosine or deoxyinosine with orthophosphate to form hypoxanthine and ribose 1-phosphate or deoxyribose 1-phosphate (Ealick et al. 1990; Wiginton et al. 1980). While NP is active with either nuckeotide in vitro, levels of deoxyinosine are normally low in vivo, limiting the extent of this reaction. NP deficiency in vivo is associated with defects in purine nucleotide salvage and leads to immunodeficiency (Williams et al. 1987). EC Number: 2.4.2.1 Pubmed2104852 Pubmed3029074 Pubmed6771276 Reactome Database ID Release 4374242 Reactome, http://www.reactome.org ReactomeREACT_1518 Guanine + H2O => Xanthine + NH3 Cytosolic guanine deaminase (GDA) catalyzes the reaction of guanine and water to form xanthine and ammonia (Yuan et al. 1999). The active enzyme is a homodimer (Murphy et al. 2009). EC Number: 3.5.4.3 Pubmed10075721 Pubmed19470646 Reactome Database ID Release 4374255 Reactome, http://www.reactome.org ReactomeREACT_1442 Hypoxanthine + H2O + O2 => Xanthine + H2O2 Cytosolic xanthine dehydrogenase (XDH) catalyzes the reaction of hypoxanthine with H2O and oxygen to form xanthine and H2O2. The active form of the enzyme is a dimer (Saksela and Raivio 1996; Yamaguchi et al. 2007). EC Number: 1.17.3.2 Pubmed17301077 Pubmed8670112 Reactome Database ID Release 4374247 Reactome, http://www.reactome.org ReactomeREACT_401 (d)GMP or (d)IMP + H2O => (2'-deoxy)guanosine or (2'-deoxy)inosine + orthophosphate [NT5C2] Cytosolic purine 5'-nucleotidase (NT5C2) catalyzes the hydrolysis of GMP, dGMP, IMP, and dIMP to yield the corresponding nucleosides and orthophosphate (Bianchi and Spychala 2003; Spychala et al. 1988). The active form of the enzyme is a tetramer and has an absolute requirement for magnesium ions (Spychala et al. 1988; Wallden et al. 2007). Consistent with the biochemicalproperties of purified enzyme, cultured cells overexpressing the enzyme from a recombinant DNA clone showed enhanced activity against inosine and guanosine monophosphates, but not adenosine monophosphate (Gazziola et al. 2001; Sala-Newby et al. 2000). EC Number: 3.1.3.5 Pubmed10766785 Pubmed11083867 Pubmed12947102 Pubmed17405878 Pubmed2848805 Reactome Database ID Release 4374248 Reactome, http://www.reactome.org ReactomeREACT_1336 AMP + H2O => adenosine + orthophosphate [NT5C1B] 5'-nucleotidase cytosolic IB catalyzes the hydrolysis of AMP to yield adenosine and orthophosphate. The human enzyme has been identified as the product of a recombinant DNA clone, but its biochemical properties are largely inferred from those of the better studied mouse and rat enzymes (Sala-Newby and Newby 2001; Sala-Newby et al. 2003). EC Number: 3.1.3.5 Pubmed11690631 Pubmed12750059 Reactome Database ID Release 43109415 Reactome, http://www.reactome.org ReactomeREACT_1556 (2'-deoxy)purine nucleoside 5'-monophosphate + H2O => (2'-deoxy)purine nucleoside + orthophosphate [NT5C1A] (d)AMP, (d)GMP, or (d)IMP + H2O => (deoxy)adenosine, (deoxy)guanosine, or (deoxy)inosine + orthophosphate [NT5C1A] Cytosolic 5'-nucleotidase IA catalyzes the hydrolysis of purine ribo- and deoxyribonucleoside monophosphates to nucleosides plus orthophosphate. The enzyme is allosterically activated by ADP (Hunsucker et al. 2001). The human enzyme is inferred to be a homotetramer with one Mg++ ion bound per subunit, based on its similarity to the pigeon heart enzyme (Bianchi and Spychala 2003; Sala-Newby et al. 1999; Skladanowski and Newby 1990). EC Number: 3.1.3.5 Pubmed10364222 Pubmed11133996 Pubmed12947102 Pubmed2344353 Reactome Database ID Release 43109387 Reactome, http://www.reactome.org ReactomeREACT_2012 (d)GMP or (d)IMP + H2O => (d)G or (d)I + orthophosphate [NT5C] Cytosolic 5'3'-nucleotidase (NT5C) catalyzes the hydrolysis of deoxy- and ribo- guanosine and inosine nucleoside monophosphates to yield the corresponding nucleosides and orthophosphate. The active form of the enzyme is a homodimer, with an absolute requirement for Mg++ (Hoglund and Reichard 1990; Rampazzo et al. 2000). This enzyme appears to play a central role in the "substrate cycles" that regulate cytosolic deoxynucleotide levels (Gazziola et al. 2001). EC Number: 3.1.3.5 Pubmed10681516 Pubmed11083867 Pubmed2157703 Reactome Database ID Release 43109470 Reactome, http://www.reactome.org ReactomeREACT_1972 PathwayStep803 PathwayStep804 PathwayStep801 NOTCH3:DSL DLL/JAG:NOTCH3 NOTCH3:DLL/JAG NTM-NEC3-Notch ligand complex Reactome DB_ID: 157638 Reactome Database ID Release 43157638 Reactome, http://www.reactome.org ReactomeREACT_2798 has a Stoichiometric coefficient of 1 PathwayStep802 HER4 Converted from EntitySet in Reactome ERBB4 Reactome DB_ID: 1233235 Reactome Database ID Release 431233235 Reactome, http://www.reactome.org ReactomeREACT_116255 NOTCH3 fragment:DSL NOTCH3 fragment:DLL/JAG Notch 3 ligand-bound fragment-Notch ligand complex Reactome DB_ID: 157650 Reactome Database ID Release 43157650 Reactome, http://www.reactome.org ReactomeREACT_2424 has a Stoichiometric coefficient of 1 Phosphorylated ERBB2:ERBB4 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963592 Reactome Database ID Release 431963592 Reactome, http://www.reactome.org ReactomeREACT_117434 PathwayStep800 NOTCH3 NTM-NEC 3 heterodimer Reactome DB_ID: 157048 Reactome Database ID Release 43157048 Reactome, http://www.reactome.org ReactomeREACT_4341 has a Stoichiometric coefficient of 1 Phosphorylated ERBB2 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963588 Reactome Database ID Release 431963588 Reactome, http://www.reactome.org ReactomeREACT_116377 NOTCH4 NTM-NEC 4 heterodimer Reactome DB_ID: 157053 Reactome Database ID Release 43157053 Reactome, http://www.reactome.org ReactomeREACT_3481 has a Stoichiometric coefficient of 1 NOTCH4:DSL DLL/JAG:NOTCH4 NOTCH4:DLL/JAG NTM-NEC4-Notch ligand complex Reactome DB_ID: 157653 Reactome Database ID Release 43157653 Reactome, http://www.reactome.org ReactomeREACT_2938 has a Stoichiometric coefficient of 1 OCT1 substrates Converted from EntitySet in Reactome Reactome DB_ID: 549264 Reactome Database ID Release 43549264 Reactome, http://www.reactome.org ReactomeREACT_23354 STAT family members Converted from EntitySet in Reactome Reactome DB_ID: 380756 Reactome Database ID Release 43380756 Reactome, http://www.reactome.org ReactomeREACT_17706 NOTCH4 fragment:DSL NOTCH4 fragment:DLL/JAG Notch 4 ligand-bound fragment-Notch ligand complex Reactome DB_ID: 157627 Reactome Database ID Release 43157627 Reactome, http://www.reactome.org ReactomeREACT_5162 has a Stoichiometric coefficient of 1 VEGF Converted from EntitySet in Reactome Reactome DB_ID: 195361 Reactome Database ID Release 43195361 Reactome, http://www.reactome.org ReactomeREACT_12955 PIP3:Phosphorylated PKB complex Reactome DB_ID: 162387 Reactome Database ID Release 43162387 Reactome, http://www.reactome.org ReactomeREACT_3373 has a Stoichiometric coefficient of 1 Collagens Converted from EntitySet in Reactome Reactome DB_ID: 375078 Reactome Database ID Release 43375078 Reactome, http://www.reactome.org ReactomeREACT_18161 TGFB1:TGFBR2:p-TGFBR1:Smad7:SMURF1 Reactome DB_ID: 2169037 Reactome Database ID Release 432169037 Reactome, http://www.reactome.org ReactomeREACT_124822 has a Stoichiometric coefficient of 1 Collagen alpha 3-6(VI) Converted from EntitySet in Reactome Reactome DB_ID: 381921 Reactome Database ID Release 43381921 Reactome, http://www.reactome.org ReactomeREACT_17362 PathwayStep809 Smad7:SMURF1 Reactome DB_ID: 2169017 Reactome Database ID Release 432169017 Reactome, http://www.reactome.org ReactomeREACT_123773 has a Stoichiometric coefficient of 1 Phosphorylated p-Y877-ERBB2 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963580 Reactome Database ID Release 431963580 Reactome, http://www.reactome.org ReactomeREACT_116234 PathwayStep808 TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-Smad7 Reactome DB_ID: 2176395 Reactome Database ID Release 432176395 Reactome, http://www.reactome.org ReactomeREACT_121713 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Phosphorylated p-6Y-ERBB2 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963585 Reactome Database ID Release 431963585 Reactome, http://www.reactome.org ReactomeREACT_116794 PathwayStep807 ERBB2 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963573 Reactome Database ID Release 431963573 Reactome, http://www.reactome.org ReactomeREACT_116379 PathwayStep806 p-Y877-ERBB2 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963584 Reactome Database ID Release 431963584 Reactome, http://www.reactome.org ReactomeREACT_117823 PathwayStep805 PathwayStep812 NRGs/EGF-like ligands:p-ERBB4cyt2 Reactome DB_ID: 1250309 Reactome Database ID Release 431250309 Reactome, http://www.reactome.org ReactomeREACT_117424 has a Stoichiometric coefficient of 1 PathwayStep813 p-ERBB4jmAcyt2 homodimer Phosphorylated ERBB4jmAcyt2 homodimer Reactome DB_ID: 1250293 Reactome Database ID Release 431250293 Reactome, http://www.reactome.org ReactomeREACT_117567 has a Stoichiometric coefficient of 2 PathwayStep814 PathwayStep815 Rho GTPases Converted from EntitySet in Reactome Reactome DB_ID: 194897 Reactome Database ID Release 43194897 Reactome, http://www.reactome.org ReactomeREACT_10506 ERBB4jmAcyt1m80 dimer Reactome DB_ID: 1251972 Reactome Database ID Release 431251972 Reactome, http://www.reactome.org ReactomeREACT_117903 has a Stoichiometric coefficient of 2 GAP proteins Converted from EntitySet in Reactome Reactome DB_ID: 194904 Reactome Database ID Release 43194904 Reactome, http://www.reactome.org ReactomeREACT_10748 ERBB4m80 Converted from EntitySet in Reactome ERBB4jmA membrane-bound cleavage product of 80 kDa Reactome DB_ID: 1251960 Reactome Database ID Release 431251960 Reactome, http://www.reactome.org ReactomeREACT_116769 SMURF Converted from EntitySet in Reactome Reactome DB_ID: 173533 Reactome Database ID Release 43173533 Reactome, http://www.reactome.org ReactomeREACT_7705 PathwayStep810 NRGs/EGF-like ligands:P-ERBB4jmAcyt1 Reactome DB_ID: 1251957 Reactome Database ID Release 431251957 Reactome, http://www.reactome.org ReactomeREACT_117052 has a Stoichiometric coefficient of 1 Rac Converted from EntitySet in Reactome Reactome DB_ID: 195337 Reactome Database ID Release 43195337 Reactome, http://www.reactome.org ReactomeREACT_10725 PathwayStep811 p-ERBB4jmAcyt1 Phosphorylated ERBB4jmAcyt1 homodimer Reactome DB_ID: 1251953 Reactome Database ID Release 431251953 Reactome, http://www.reactome.org ReactomeREACT_117274 has a Stoichiometric coefficient of 2 ERBB4 homodimers Converted from EntitySet in Reactome Reactome DB_ID: 1250221 Reactome Database ID Release 431250221 Reactome, http://www.reactome.org ReactomeREACT_117065 ERBB4jmAcyt1ECD dimer Reactome DB_ID: 1251994 Reactome Database ID Release 431251994 Reactome, http://www.reactome.org ReactomeREACT_117370 has a Stoichiometric coefficient of 2 p-ERBB4 homodimers Converted from EntitySet in Reactome Phosphorylated ERBB4 homodimers Reactome DB_ID: 1250341 Reactome Database ID Release 431250341 Reactome, http://www.reactome.org ReactomeREACT_117418 NRGs/EGF-like ligands:ERBB4jmAcyt1ECD Reactome DB_ID: 1251990 Reactome Database ID Release 431251990 Reactome, http://www.reactome.org ReactomeREACT_116500 has a Stoichiometric coefficient of 1 Prolactin receptor ligands Converted from EntitySet in Reactome Reactome DB_ID: 1172021 Reactome Database ID Release 431172021 Reactome, http://www.reactome.org ReactomeREACT_111382 ERBB4jmAcyt2m80 dimer Reactome DB_ID: 1251981 Reactome Database ID Release 431251981 Reactome, http://www.reactome.org ReactomeREACT_116533 has a Stoichiometric coefficient of 2 OCT2 substrates Converted from EntitySet in Reactome Reactome DB_ID: 549237 Reactome Database ID Release 43549237 Reactome, http://www.reactome.org ReactomeREACT_22491 ERBB4/ERBB4m80/ERBB4s80 Converted from EntitySet in Reactome ERBB4 ubiqutination targets Reactome DB_ID: 1253281 Reactome Database ID Release 431253281 Reactome, http://www.reactome.org ReactomeREACT_116511 ERBB4_ECD Converted from EntitySet in Reactome ERBB4 extracellular domain Reactome DB_ID: 1251970 Reactome Database ID Release 431251970 Reactome, http://www.reactome.org ReactomeREACT_117885 Rho GTPases Converted from EntitySet in Reactome Reactome DB_ID: 194906 Reactome Database ID Release 43194906 Reactome, http://www.reactome.org ReactomeREACT_10871 PathwayStep817 Rac Converted from EntitySet in Reactome Reactome DB_ID: 195340 Reactome Database ID Release 43195340 Reactome, http://www.reactome.org ReactomeREACT_10395 PathwayStep816 OCT2 substrates Converted from EntitySet in Reactome Reactome DB_ID: 549266 Reactome Database ID Release 43549266 Reactome, http://www.reactome.org ReactomeREACT_23290 effector proteins Reactome DB_ID: 194872 Reactome Database ID Release 43194872 Reactome, http://www.reactome.org ReactomeREACT_10469 PathwayStep819 PathwayStep818 OCT1 substrates Converted from EntitySet in Reactome Reactome DB_ID: 549250 Reactome Database ID Release 43549250 Reactome, http://www.reactome.org ReactomeREACT_22807 cAMP phosphodiesterases Converted from EntitySet in Reactome Reactome DB_ID: 418562 Reactome Database ID Release 43418562 Reactome, http://www.reactome.org ReactomeREACT_19678 Uso1 homodimer Reactome DB_ID: 2422974 Reactome Database ID Release 432422974 Reactome, http://www.reactome.org ReactomeREACT_148357 has a Stoichiometric coefficient of 2 GPCRs that activate Gs Converted from EntitySet in Reactome Reactome DB_ID: 790204 Reactome Database ID Release 43790204 Reactome, http://www.reactome.org ReactomeREACT_22805 Grasp65:Gm130:p115:RAB1:GTP Gorasp1:Golga2:Uso1:RAB1:GTP Reactome DB_ID: 2422980 Reactome Database ID Release 432422980 Reactome, http://www.reactome.org ReactomeREACT_147990 has a Stoichiometric coefficient of 1 Ligands of GPCRs that activate Gs Converted from EntitySet in Reactome Reactome DB_ID: 790205 Reactome Database ID Release 43790205 Reactome, http://www.reactome.org ReactomeREACT_22668 Uso1 homodimer Reactome DB_ID: 2422979 Reactome Database ID Release 432422979 Reactome, http://www.reactome.org ReactomeREACT_148287 has a Stoichiometric coefficient of 2 GPRC6A ligands Converted from EntitySet in Reactome Reactome DB_ID: 420706 Reactome Database ID Release 43420706 Reactome, http://www.reactome.org ReactomeREACT_18638 RAB1:GTP Reactome DB_ID: 2311340 Reactome Database ID Release 432311340 Reactome, http://www.reactome.org ReactomeREACT_148443 has a Stoichiometric coefficient of 1 Metabotropic glutamate receptors Converted from EntitySet in Reactome Reactome DB_ID: 420516 Reactome Database ID Release 43420516 Reactome, http://www.reactome.org ReactomeREACT_18886 ERBB4jmAcyt2ECD dimer Reactome DB_ID: 1251961 Reactome Database ID Release 431251961 Reactome, http://www.reactome.org ReactomeREACT_117574 has a Stoichiometric coefficient of 2 Adam17 Reactome DB_ID: 1251982 Reactome Database ID Release 431251982 Reactome, http://www.reactome.org ReactomeREACT_117031 has a Stoichiometric coefficient of 1 NRGs/EGF-like ligands:ERBB4jmAcyt2ECD Reactome DB_ID: 1251973 Reactome Database ID Release 431251973 Reactome, http://www.reactome.org ReactomeREACT_117123 has a Stoichiometric coefficient of 1 FPRL1 ligands Converted from EntitySet in Reactome Reactome DB_ID: 444472 Reactome Database ID Release 43444472 Reactome, http://www.reactome.org ReactomeREACT_21182 Photon Reactome DB_ID: 419777 Reactome Database ID Release 43419777 Reactome, http://www.reactome.org ReactomeREACT_18935 CXCR1 ligands Converted from EntitySet in Reactome Reactome DB_ID: 373823 Reactome Database ID Release 43373823 Reactome, http://www.reactome.org ReactomeREACT_15254 p-S217,277,376-Grasp65:p-S37-Gm130:p-RAB1:GTP Reactome DB_ID: 2422975 Reactome Database ID Release 432422975 Reactome, http://www.reactome.org ReactomeREACT_148372 has a Stoichiometric coefficient of 1 p-S217,277,376-Gorasp1:p-S37-Golga2:p-RAB1:GTP CXCR2 ligands Converted from EntitySet in Reactome Reactome DB_ID: 373814 Reactome Database ID Release 43373814 Reactome, http://www.reactome.org ReactomeREACT_15250 CCNB:p-T161-CDK1 Reactome DB_ID: 2311324 Reactome Database ID Release 432311324 Reactome, http://www.reactome.org ReactomeREACT_148199 has a Stoichiometric coefficient of 1 SMURF/NEDD4L Converted from EntitySet in Reactome Reactome DB_ID: 2176415 Reactome Database ID Release 432176415 Reactome, http://www.reactome.org ReactomeREACT_124598 IP receptor:Prostacyclin Reactome DB_ID: 391929 Reactome Database ID Release 43391929 Reactome, http://www.reactome.org ReactomeREACT_17421 has a Stoichiometric coefficient of 1 Opioid ligands Converted from EntitySet in Reactome Reactome DB_ID: 374370 Reactome Database ID Release 43374370 Reactome, http://www.reactome.org ReactomeREACT_14899 LTA4 is hydrolysed to 6t-/6t,12epi-LTB4 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Non-enzymatic hydrolysis of the leukotriene A4 (LTA4) epoxide bond creates 6-trans leukotriene B4 (6t-LTB4) and 6-trans,12-epi leukotriene B4 (6t,12epi-LTB4) stereoisomers (Mansour & Agha 1999, Sirois et al. 1985). Pubmed10741385 Pubmed2998743 Reactome Database ID Release 432161962 Reactome, http://www.reactome.org ReactomeREACT_150455 Reviewed: Rush, MG, 2012-11-10 LTA4 is converted to EXA4 by ALOX15 Analogous to arachidonate 5-lipoxygenase (ALOX5) biosynthesis of leukotriene A4 (LTA4), arachidonate 15-lipoxygenase (ALOX15) can form an epoxide across C-14 and C-15 to form 14,15-LTA4 aka eoxin A4 (EXA4) (Feltenmark et al. 2008, Claesson et al. 2008). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed18184802 Pubmed18647347 Reactome Database ID Release 432162019 Reactome, http://www.reactome.org ReactomeREACT_150189 Reviewed: Rush, MG, 2012-11-10 EXA4 is converted to EXC4 by LTC4S Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 In addition to its role converting leukotriene A4 (LTA4) into leukotriene C4 (LTC4), the enzyme leukotriene C4 synthase (LTC4S) analogously converts eoxin A4 (EXA4), with reduced glutathione (GSH), to eoxin C4 (EXC4) (Feltenmark et al. 2008, Claesson et al. 2008). Pubmed18184802 Pubmed18647347 Reactome Database ID Release 432161768 Reactome, http://www.reactome.org ReactomeREACT_150273 Reviewed: Rush, MG, 2012-11-10 LTA4 is converted to LTC4 by LTC4S Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 4.4.1.20 Edited: Jassal, B, 2008-04-21 14:30:22 LTA4 conjugates with glutathione to form LTC4 Leukotriene A4 conjugates with reduced glutathione (GSH) to produce leukotriene C4 (LTC4). This conjugation is mediated by the homodimeric, perinuclear membrane-bound enzyme leukotriene C4 synthase (LTC4S) (Lam et al. 1994, Welsch et al. 1994). LTC4S differs from cytosolic and microsomal GSH-S-transferases by having a very narrow substrate specificity and the inability to conjugate xenobiotics. Pubmed7937884 Pubmed8052639 Reactome Database ID Release 43266050 Reactome, http://www.reactome.org ReactomeREACT_15413 Reviewed: Rush, MG, 2012-11-10 Guanylate cyclase, soluble Reactome DB_ID: 392012 Reactome Database ID Release 43392012 Reactome, http://www.reactome.org ReactomeREACT_24123 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ABCC1 mediates LTC4 export from the cell Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-04-21 14:30:22 LTC4 is exported from the cytosol by ABCC1 On formation, leukotriene C4 (LTC4) is exported to the extracellular region by the ABCC1 transporter (Sjolinder et al. 1999, Lam et al. 1989) and processed further by cleavage reactions. Pubmed10064732 Pubmed2753893 Reactome Database ID Release 43266070 Reactome, http://www.reactome.org ReactomeREACT_15474 Reviewed: Rush, MG, 2012-11-10 G-protein alpha (s):GTP Reactome DB_ID: 164358 Reactome Database ID Release 43164358 Reactome, http://www.reactome.org ReactomeREACT_5470 has a Stoichiometric coefficient of 1 LTC4 is converted to LTD4 by GGT1/5 Authored: Jassal, B, 2008-10-01 13:18:42 Cleavage of the gamma-glutamyl bond of LTC4 forms LTD4 EC Number: 2.3.2.2 Edited: Jassal, B, 2008-04-21 14:30:22 Pubmed21447318 Pubmed6122208 Reactome Database ID Release 43266046 Reactome, http://www.reactome.org ReactomeREACT_15356 Reviewed: Rush, MG, 2012-11-10 The reversible conversion of leukotriene C4 (LTC4) to leukotriene D4 (LTD4) is catalysed by gamma-glutamyl transferases 1 (GGT1) and 5 (GGT5). GGTs are present on the outer surface of plasma membranes and are a heterodimer of a heavy and a light chain. Its action involves the cleavage of the gamma-glutamyl peptide bond of glutathione conjugates, releasing glutamate (Anderson et al. 1982, Wickham et al. 2011). Heterotrimeric G-protein Gs (active) Reactome DB_ID: 392844 Reactome Database ID Release 43392844 Reactome, http://www.reactome.org ReactomeREACT_23174 has a Stoichiometric coefficient of 1 Further cleavage of LTD4 forms LTE4 Another outer surface membrane-bound, homodimeric enzyme, dipeptidase, existing in two forms DPEP1 (Adachi et al. 1989) and DPEP2 (Lee et al. 1983, Raulf et al. 1987), further hydrolyses leukotriene D4 (LTD4) to leukotriene E4 (LTE4), cleaving a glycine residue in the process. Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 3.4.13 Edited: Jassal, B, 2008-04-21 14:30:22 LTD4 is converted to LTE4 by DPEP1/2 Pubmed2768222 Pubmed3563417 Pubmed6293969 Reactome Database ID Release 43266012 Reactome, http://www.reactome.org ReactomeREACT_15395 Reviewed: Rush, MG, 2012-11-10 Prostacyclin:prostacyclin receptor:G-protein Gs (active) Reactome DB_ID: 392865 Reactome Database ID Release 43392865 Reactome, http://www.reactome.org ReactomeREACT_24753 has a Stoichiometric coefficient of 1 Prostacyclin:prostacyclin receptor:Gs (inactive) Reactome DB_ID: 392864 Reactome Database ID Release 43392864 Reactome, http://www.reactome.org ReactomeREACT_24060 has a Stoichiometric coefficient of 1 20cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed2836406 Reactome Database ID Release 432161792 Reactome, http://www.reactome.org ReactomeREACT_150394 Reviewed: Rush, MG, 2012-11-10 The cytochrome P450s 4F2 (CYP4F2) and F3 (CYP4F3) oxidise 20-aldehyde leukotriene B4 (20cho-LTB4) to form 20-carboxy leukotriene B4 (20cooh-LTB4) (Soberman et al. 1988). G-protein beta-gamma complex Reactome DB_ID: 167434 Reactome Database ID Release 43167434 Reactome, http://www.reactome.org ReactomeREACT_15674 has a Stoichiometric coefficient of 1 20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH An aldehyde dehydrogenase (ALDH) yet to be cloned in humans has been observed to oxidise 20-aldehyde leukotriene B4 (20cho-LTB4) to form 20-carboxy leukotriene B4 (20cooh-LTB4) (Sutyak et al. 1989). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed2549038 Reactome Database ID Release 432161979 Reactome, http://www.reactome.org ReactomeREACT_150283 Reviewed: Rush, MG, 2012-11-10 G-protein alpha (s):GDP Reactome DB_ID: 164333 Reactome Database ID Release 43164333 Reactome, http://www.reactome.org ReactomeREACT_5073 has a Stoichiometric coefficient of 1 20cooh-LTB4 is converted to 18cooh-LTB4 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Once omega-oxidation has occurred, 20-carboxy leukotriene B4 (20cooh-LTB4) can be further metabolized by beta-oxidation at its omega end into 18-carboxy-LTB4 (18cooh-LTB4) (Berry et al. 2003, Wheelan et al. 1999). The actual human enzyme or enzymes involved have yet to be identified. Pubmed12709426 Pubmed9862787 Reactome Database ID Release 432161790 Reactome, http://www.reactome.org ReactomeREACT_150160 Reviewed: Rush, MG, 2012-11-10 Heterotrimeric G-protein Gs (inactive) Reactome DB_ID: 391179 Reactome Database ID Release 43391179 Reactome, http://www.reactome.org ReactomeREACT_18222 has a Stoichiometric coefficient of 1 GPCRs that activate Gz Converted from EntitySet in Reactome Reactome DB_ID: 791494 Reactome Database ID Release 43791494 Reactome, http://www.reactome.org ReactomeREACT_23295 Phosphodiesterases, cyclic AMP-selective Converted from EntitySet in Reactome Reactome DB_ID: 418543 Reactome Database ID Release 43418543 Reactome, http://www.reactome.org ReactomeREACT_19661 GPCRs that activate Gi Converted from EntitySet in Reactome Reactome DB_ID: 790904 Reactome Database ID Release 43790904 Reactome, http://www.reactome.org ReactomeREACT_23196 Ligands of GPCRs that activate Gi Converted from EntitySet in Reactome Reactome DB_ID: 790906 Reactome Database ID Release 43790906 Reactome, http://www.reactome.org ReactomeREACT_22460 Guanylate cyclase:NO Reactome DB_ID: 392141 Reactome Database ID Release 43392141 Reactome, http://www.reactome.org ReactomeREACT_24768 has a Stoichiometric coefficient of 1 Ligands of GPCRs that activate Gz Converted from EntitySet in Reactome Reactome DB_ID: 791495 Reactome Database ID Release 43791495 Reactome, http://www.reactome.org ReactomeREACT_22598 Activated cGMP-dependent protein kinase (PKGs) Reactome DB_ID: 418378 Reactome Database ID Release 43418378 Reactome, http://www.reactome.org ReactomeREACT_24034 has a Stoichiometric coefficient of 1 5S-HETE is oxidised to 5-oxoETE by 5-HEDH Authored: Williams, MG, 2012-02-24 Current literature suggests that 5S-hydroxy-eicosatetraenoic acid (5S-HETE) itself does not appear to play a significant role in biological signalling. However, it can be further oxidised by a 5-hydroxy-eicosatetraenoic acid dehydrogenase (5-HEDH) to form the bioactive 5-oxo-eicosatetraenoic acid (5-oxoETE, also known as 5-KETE. While the gene has not yet been cloned, the biophysical properties of the human enzyme have been well characterised (Powell et al. 1992). Edited: Williams, MG, 2012-02-24 Pubmed1326548 Reactome Database ID Release 432161776 Reactome, http://www.reactome.org ReactomeREACT_150143 Reviewed: Rush, MG, 2012-11-10 BoNT Light chain Type G Reactome DB_ID: 190050 Reactome Database ID Release 43190050 Reactome, http://www.reactome.org ReactomeREACT_11979 has a Stoichiometric coefficient of 1 5S-HpETE is reduced to 5S-HETE by GPX1/2/4 Authored: Williams, MG, 2012-02-24 EC Number: 1.11.1.9 Edited: Williams, MG, 2012-02-24 Glutathione peroxidase 1 (GPX1) (Bryant et al. 1982, Sutherland et al. 2001), 2 (GPX2) (Chu et al. 1993), and 4 (Bryant et al. 1982, Sutherland et al. 2001) reduce 5-hydroperoxyeicosatetraenoic acid (5-HpETE) to 5-hydroxyeicosatetraenoic acid (5-HETE) in the presence of glutathione (GSH). This reaction is inferred from the event in rabbit involving the protein GPX1 (Chiba et al. 1999). Pubmed10549853 Pubmed11115402 Pubmed6816802 Pubmed8428933 Reactome Database ID Release 432161946 Reactome, http://www.reactome.org ReactomeREACT_150133 Reviewed: Rush, MG, 2012-11-10 has a Stoichiometric coefficient of 2 BoNT Light chain Type F Reactome DB_ID: 190025 Reactome Database ID Release 43190025 Reactome, http://www.reactome.org ReactomeREACT_11908 has a Stoichiometric coefficient of 1 EXD4 is converted to EXE4 by DPEP Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 In an analogous reaction to the formation of leukotriene E4 (LTE4), eoxin D4 (EXD4) is converted to eoxin E4 (EXE4) by a dipeptidase (DPEP) (Feltenmark et al. 2008, Claesson et al. 2008) which has not yet been identified. Pubmed18184802 Pubmed18647347 Reactome Database ID Release 432161868 Reactome, http://www.reactome.org ReactomeREACT_150428 Reviewed: Rush, MG, 2012-11-10 BoNT Light chain Type E Reactome DB_ID: 190051 Reactome Database ID Release 43190051 Reactome, http://www.reactome.org ReactomeREACT_11499 has a Stoichiometric coefficient of 1 EXC4 is converted to EXD4 by GGT Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 In an analogous reaction to the formation of leukotriene D4 (LTD4), eoxin C4 (EXC4) is converted to eoxin D4 (EXD4) by a class of gamma-glutamyltransferase (GGT) (Feltenmark et al. 2008, Claesson et al. 2008) which has not yet been identified. Pubmed18184802 Pubmed18647347 Reactome Database ID Release 432161945 Reactome, http://www.reactome.org ReactomeREACT_150192 Reviewed: Rush, MG, 2012-11-10 BoNT Light chain Type D Reactome DB_ID: 190052 Reactome Database ID Release 43190052 Reactome, http://www.reactome.org ReactomeREACT_11601 has a Stoichiometric coefficient of 1 Arachidonic acid is oxidised to 15R-HETE by Acetyl-PTGS2 Aspirin acetylates the cyclooxygenase, prostaglandin G/H synthase 2 (PTGS2) aka COX2. The acetylated PTGS2 triggers the formation of 15R-hydroxyeicosatetraenoic acid (15R-HETE) from arachidonic acid (Claria & Serhan 1995). Authored: Williams, MG, 2012-02-24 EC Number: 1.13.11.33 Edited: Williams, MG, 2012-02-24 Pubmed7568157 Reactome Database ID Release 432161951 Reactome, http://www.reactome.org ReactomeREACT_150372 Reviewed: Rush, MG, 2012-11-10 15S-HETE is oxidised to 15-oxoETE by 15-HEDH A 15-hydroxy-eicosatetraenoic acid dehydrogenase (15-HEDH) oxidises 15S-hydroxyeicosatetraenoic acid (15S-HETE) to 15-oxo-eicosatetraenoic acid (15-oxoETE) (Gulliksson et al. 2007). The actual human 15-HEDH has yet to be cloned. Authored: Williams, MG, 2012-02-24 EC Number: 1.1.1.232 Edited: Williams, MG, 2012-02-24 Pubmed17662651 Reactome Database ID Release 432161789 Reactome, http://www.reactome.org ReactomeREACT_150245 Reviewed: Rush, MG, 2012-11-10 15S-HpETE is reduced to 15S-HETE by GPX1/2/4 Authored: Williams, MG, 2012-02-24 EC Number: 1.11.1.9 Edited: Williams, MG, 2012-02-24 Glutathione peroxidases (GPXs) in human platelets (either GPX1, GPX2, or GPX4 are present in the cytosol) are involved in reducing 15S-hydroperoxyeicosatetraenoic acid (15S-HpETE) to 15S-hydroxyeicosatetraenoic acid (15S-HETE) (Hill et al. 1989). Pubmed2501828 Reactome Database ID Release 432161791 Reactome, http://www.reactome.org ReactomeREACT_150230 Reviewed: Rush, MG, 2012-11-10 has a Stoichiometric coefficient of 2 Arachidonic acid is oxidised to 15S-HpETE by ALOX15/15B Arachidonate 15-lipoxygenase (ALOX15) (Gulliksson et al. 2007, Kuhn et al. 1993, Izumi et al. 1991) and arachidonate 15-lipoxygenase B (ALOX15B) (Tang et al. 2002, Wecksler et al. 2008) are lipid peroxidising enzymes mainly expressed in airway epithelial cells, eosinophils, reticulocytes and in macrophages. They insert molecular oxygen at C-6 from the omega-end of arachidonic acid with formation of the unstable intermediate 15S-hydroperoxyeicosatetraenoic acid (15S-HpETE) which can be further converted, enzymatically or non-enzymatically, to 15S-hydroxyeicosatetraenoic acid (15S-HETE). Authored: Williams, MG, 2012-02-24 EC Number: 1.13.11.33 Edited: Williams, MG, 2012-02-24 Pubmed11839751 Pubmed1662607 Pubmed17662651 Pubmed18570379 Pubmed8334154 Reactome Database ID Release 432162002 Reactome, http://www.reactome.org ReactomeREACT_150130 Reviewed: Rush, MG, 2012-11-10 BoNT Reactome DB_ID: 194804 Reactome Database ID Release 43194804 Reactome, http://www.reactome.org ReactomeREACT_11848 has a Stoichiometric coefficient of 1 internalized BoNT BoNT Activated BoNT bound to membrane receptor Reactome DB_ID: 181495 Reactome Database ID Release 43181495 Reactome, http://www.reactome.org ReactomeREACT_11898 has a Stoichiometric coefficient of 1 12R-HpETE is reduced to 12R-HETE by GPX1/2/4 Authored: Williams, MG, 2012-02-24 EC Number: 1.11.1.9 Edited: Williams, MG, 2012-02-24 Glutathione peroxidase 1 (GPX1) (Bryant et al. 1982, Sutherland et al. 2001), 2 (GPX2) (Chu et al. 1993), and 4 (Bryant et al. 1982, Sutherland et al. 2001) are involved in converting 12R-hydroperoxy-eicosatetraenoic acid (12R-HpETE) to 12R-hydro-eicosatetraenoic acid (12R-HETE). Pubmed11115402 Pubmed6816802 Pubmed8428933 Reactome Database ID Release 432161959 Reactome, http://www.reactome.org ReactomeREACT_150334 Reviewed: Rush, MG, 2012-11-10 has a Stoichiometric coefficient of 2 Arachidonic acid is oxidised to 12R-HpETE by ALOX12B Authored: Williams, MG, 2012-02-24 EC Number: 1.13.11.31 Edited: Williams, MG, 2012-02-24 Pubmed9618483 Reactome Database ID Release 432161950 Reactome, http://www.reactome.org ReactomeREACT_150226 Reviewed: Rush, MG, 2012-11-10 The arachidonate 12-lipoxygenase, 12R-type (ALOX12B) oxidises arachidonic acid to 12R-hydroperoxy-eicosatetraenoic acid (12R-HpETE) (Boeglin et al. 1998). BoNT Light chain Type C Reactome DB_ID: 190030 Reactome Database ID Release 43190030 Reactome, http://www.reactome.org ReactomeREACT_11988 has a Stoichiometric coefficient of 1 BoNT Light chain Type B Reactome DB_ID: 190026 Reactome Database ID Release 43190026 Reactome, http://www.reactome.org ReactomeREACT_11358 has a Stoichiometric coefficient of 1 BoNT Light chain Type A Reactome DB_ID: 190035 Reactome Database ID Release 43190035 Reactome, http://www.reactome.org ReactomeREACT_11911 has a Stoichiometric coefficient of 1 BoNT Light Chain Converted from EntitySet in Reactome Reactome DB_ID: 168796 Reactome Database ID Release 43168796 Reactome, http://www.reactome.org ReactomeREACT_11588 Golgi cisternae Reactome DB_ID: 2314558 Reactome Database ID Release 432314558 Reactome, http://www.reactome.org ReactomeREACT_148019 ER to Golgi transport vesicle fused with cis-Golgi Reactome DB_ID: 2314561 Reactome Database ID Release 432314561 Reactome, http://www.reactome.org ReactomeREACT_148231 ER to Golgi transport vesicle Reactome DB_ID: 2314559 Reactome Database ID Release 432314559 Reactome, http://www.reactome.org ReactomeREACT_148289 phospho-G2/M transition protein Reactome DB_ID: 157604 Reactome Database ID Release 43157604 Reactome, http://www.reactome.org ReactomeREACT_3843 Cyclin A2:Cdk2 phosphorylated G2/M transition protein Reactome DB_ID: 617371 Reactome Database ID Release 43617371 Reactome, http://www.reactome.org ReactomeREACT_22726 phospho-G2/M transition protein Reactome DB_ID: 69753 Reactome Database ID Release 4369753 Reactome, http://www.reactome.org ReactomeREACT_4658 G2/M transition protein Reactome DB_ID: 157449 Reactome Database ID Release 43157449 Reactome, http://www.reactome.org ReactomeREACT_2998 phosphorylated nuclear Cyclin B1:Cdc2 substrates Reactome DB_ID: 182620 Reactome Database ID Release 43182620 Reactome, http://www.reactome.org ReactomeREACT_8297 nuclear Cyclin B1:Cdc2 substrates Reactome DB_ID: 170150 Reactome Database ID Release 43170150 Reactome, http://www.reactome.org ReactomeREACT_6526 CRS kinase Converted from EntitySet in Reactome Reactome DB_ID: 170106 Reactome Database ID Release 43170106 Reactome, http://www.reactome.org ReactomeREACT_6373 Arachidonic acid is converted to 12-oxoETE by ALOX12 Arachidonate 12-lipoxygenase, 12S-type (ALOX12) catalyses the formation of 12-oxo-eicosatetraenoic acid (12-oxoETE) from arachidonic acid. This conversion has been observed when normal human epidermis is exposed to arachidonic acid and with the purified recombinant enzyme in vitro (Anton & Vila 2000). Authored: Williams, MG, 2012-02-24 EC Number: 1.13.11.31 Edited: Williams, MG, 2012-02-24 Pubmed10692117 Reactome Database ID Release 432161948 Reactome, http://www.reactome.org ReactomeREACT_150327 Reviewed: Rush, MG, 2012-11-10 BoNT Light chain Type E Reactome DB_ID: 190044 Reactome Database ID Release 43190044 Reactome, http://www.reactome.org ReactomeREACT_11754 has a Stoichiometric coefficient of 1 12S-HpETE is reduced to 12S-HETE by GPX1/2/4 Authored: Williams, MG, 2012-02-24 EC Number: 1.11.1.9 Edited: Williams, MG, 2012-02-24 Glutathione peroxidase 1 (GPX1) (Bryant et al. 1982, Sutherland et al. 2001), 2 (GPX2) (Chu et al. 1993), and 4 (Bryant et al. 1982, Sutherland et al. 2001) are involved in converting 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE) to 12S-hydro-eicosatetraenoic acid (12S-HETE). GPXs are selenoenzymes that are responsible for reducing the cellular peroxide. Cellular GPXs compete with hepoxilins A3 (HXA3) synthase for 12S-HpETE as substrate either to produce 12S-HETE or to convert to HXA3, respectively. Pubmed11115402 Pubmed6816802 Pubmed8428933 Reactome Database ID Release 432161999 Reactome, http://www.reactome.org ReactomeREACT_150391 Reviewed: Rush, MG, 2012-11-10 has a Stoichiometric coefficient of 2 BoNT Light chain Type D Reactome DB_ID: 190037 Reactome Database ID Release 43190037 Reactome, http://www.reactome.org ReactomeREACT_11695 has a Stoichiometric coefficient of 1 15S-HpETE is oxidised to LXA4/B4 by ALOX5 Arachidonate 5-lipoxygenase (ALOX5) (Ueda et al. 1987) converts 15S-hydroperoxy-eicosatetraenoic acid (15S-HpETE) into lipoxin A4 (LXA4) and B4 (LXB4) (Serhan et al. 1984A, Serhan et al. 1984B). One of the reaction intermediates of this process might be 5S,6S-epoxy-15S-hydroxy-7E,9E,11Z,13E-eicosatetraenoic acid (5,6-Ep-15S-HETE) (Puustinen et al. 1986). However, its generation from LTA4 is unclear but it can be hydrolysed to form the lipoxins. Authored: Williams, MG, 2012-02-24 EC Number: 1.13.11 Edited: Williams, MG, 2012-02-24 Pubmed3579953 Pubmed3770188 Pubmed6089195 Pubmed6422933 Reactome Database ID Release 432161917 Reactome, http://www.reactome.org ReactomeREACT_150156 Reviewed: Rush, MG, 2012-11-10 BoNT Light chain Type G Reactome DB_ID: 190021 Reactome Database ID Release 43190021 Reactome, http://www.reactome.org ReactomeREACT_11495 has a Stoichiometric coefficient of 1 LTA4 is converted to LXA4/B4 by ALOX12 Arachidonate 12-lipoxygenase, 12S-type (ALOX12) catalyses the conversion of leukotriene A4 (LTA4) into the lipoxins LXA4, which has its third hydroxyl positioned at C-6 and LXB4, which has it positioned at C-14 (Romano et al. 1993, Serhan & Sheppard 1990). One of the reaction intermediates of this process might be 5S,6S-epoxy-15S-hydroxy-7E,9E,11Z,13E-eicosatetraenoic acid (5,6-Ep-15S-HETE) (Puustinen et al. 1986). However, its generation from LTA4 is unclear but it can be hydrolysed to form the lipoxins. Authored: Williams, MG, 2012-02-24 EC Number: 1.13.11 Edited: Williams, MG, 2012-02-24 Pubmed2155925 Pubmed3770188 Pubmed8250832 Reactome Database ID Release 432161775 Reactome, http://www.reactome.org ReactomeREACT_150303 Reviewed: Rush, MG, 2012-11-10 BoNT Light chain Type F Reactome DB_ID: 190034 Reactome Database ID Release 43190034 Reactome, http://www.reactome.org ReactomeREACT_11315 has a Stoichiometric coefficient of 1 LXA4 is oxidised to 15k-LXA4 by HPGD 15-hydroxyprostaglandin dehydrogenase (HPGD) converted lipoxin A4 (LXA4) to 15-oxo lipoxin A4 aka 15-keto-LXA4 (15k-LXA4) (Clish et al. 2000). Authored: Williams, MG, 2012-02-24 EC Number: 1.1.1.141 Edited: Williams, MG, 2012-02-24 Pubmed10837478 Reactome Database ID Release 432161779 Reactome, http://www.reactome.org ReactomeREACT_150285 Reviewed: Rush, MG, 2012-11-10 BoNT bound to membrane receptor Reactome DB_ID: 181532 Reactome Database ID Release 43181532 Reactome, http://www.reactome.org ReactomeREACT_11594 has a Stoichiometric coefficient of 1 NRG1/2:p-10Y-ERBB3:p-Y,877-ERBB2 Reactome DB_ID: 1248749 Reactome Database ID Release 431248749 Reactome, http://www.reactome.org ReactomeREACT_116662 has a Stoichiometric coefficient of 1 15R-HETE is converted to 15epi-LXA4/B4 by ALOX5 Arachidonate 5-lipoxygenase (ALOX5) converts 15R-hydro-eicosatetraenoic acid (15R-HETE) to the epi-lipoxins, 15epi-lipoxin A4 (15epi-LXA4) and 15epi-lipoxin B4 (15epi-LXB4) (Claria & Serhan 1995). These epi-lipoxins have altered stereochemistry at the C-15 hydroxyl but similar biological potency. Authored: Williams, MG, 2012-02-24 EC Number: 1.13.11 Edited: Williams, MG, 2012-02-24 Pubmed7568157 Reactome Database ID Release 432161907 Reactome, http://www.reactome.org ReactomeREACT_150272 Reviewed: Rush, MG, 2012-11-10 Gangliosides:Synaptotagmin Reactome DB_ID: 168789 Reactome Database ID Release 43168789 Reactome, http://www.reactome.org ReactomeREACT_11647 has a Stoichiometric coefficient of 1 Shc1:Phosphorylated ERBB2:ERBB3 heterodimers Reactome DB_ID: 1248755 Reactome Database ID Release 431248755 Reactome, http://www.reactome.org ReactomeREACT_116337 has a Stoichiometric coefficient of 1 Arachidonic acid is converted to HXA3/B3 by ALOX12 Arachidonate 12-lipoxygenase, 12S-type (ALOX12) converts arachidonic acid to both hepoxilin A3 (HXA3) and B3 (HXB3). They both incorporate an epoxide across the C-11 and C-12 double bond, as well as an additional hydroxyl moiety with HXA3 having a C-8 hydroxyl, whereas the HXB3 hydroxyl occurs at C-10 (Sutherland et al. 2001, Nigam et al. 2004). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed11115402 Pubmed15123652 Reactome Database ID Release 432161794 Reactome, http://www.reactome.org ReactomeREACT_150129 Reviewed: Rush, MG, 2012-11-10 15k-LXA4 is reduced to dhk-LXA4 by PTGR1 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Prostaglandin reductase 1 (PTGR1) aka LTB4DH, a 15-oxoprostaglandin 13-reductase (Yokomizo et al. 1996), metabolises 15-oxo lipoxin A4 aka 15-keto-LXA4 (15k-LXA4) to produce 13,14-dihydro-15-keto-Lipoxin A4 (dhk-LXA4). This reaction has been inferred from a reaction in pig (Clish et al. 2000). Pubmed10837478 Pubmed8576264 Reactome Database ID Release 432161844 Reactome, http://www.reactome.org ReactomeREACT_150208 Reviewed: Rush, MG, 2012-11-10 HXA3/B3 is hydrolysed to TrXA3/B3 by HXEH Authored: Williams, MG, 2012-02-24 EC Number: 3.3.2.7 Edited: Williams, MG, 2012-02-24 Pubmed2722835 Pubmed6406490 Pubmed8829479 Pubmed9540966 Reactome Database ID Release 432161949 Reactome, http://www.reactome.org ReactomeREACT_150426 Reviewed: Rush, MG, 2012-11-10 The epoxy moiety of hepoxilin A3 (HXA3) and B3 (HXB3) is labile and can be hydrolysed either by a hepoxilin specific epoxide hydrolase (HXEH) or in acidic aqueous solution to form the corresponding diol metabolites trioxilin A3 (TrXA3) and B3 (TrXB3) (Anton et al. 1995, Anton et al. 1998, Pace-Asciak et al. 1983, Pace-Asciak & Lee 1989). BoNT Light chain Type A Reactome DB_ID: 190046 Reactome Database ID Release 43190046 Reactome, http://www.reactome.org ReactomeREACT_11890 has a Stoichiometric coefficient of 1 BoNT Light Chain Converted from EntitySet in Reactome Reactome DB_ID: 181498 Reactome Database ID Release 43181498 Reactome, http://www.reactome.org ReactomeREACT_11337 BoNT Light chain Type C Reactome DB_ID: 190045 Reactome Database ID Release 43190045 Reactome, http://www.reactome.org ReactomeREACT_11680 has a Stoichiometric coefficient of 1 BoNT Light chain Type B Reactome DB_ID: 190022 Reactome Database ID Release 43190022 Reactome, http://www.reactome.org ReactomeREACT_11923 has a Stoichiometric coefficient of 1 ligated C-strand Okazaki fragment Reactome DB_ID: 176395 Reactome Database ID Release 43176395 Reactome, http://www.reactome.org ReactomeREACT_8082 C-strand Okazaki fragment minus Flap Reactome DB_ID: 176397 Reactome Database ID Release 43176397 Reactome, http://www.reactome.org ReactomeREACT_8740 Elastin Reactome DB_ID: 2161232 Reactome Database ID Release 432161232 Reactome, http://www.reactome.org ReactomeREACT_151987 Stacked Golgi cisternae Reactome DB_ID: 2314571 Reactome Database ID Release 432314571 Reactome, http://www.reactome.org ReactomeREACT_148001 TGFB1:TGFBR2:TGFBR1 Reactome DB_ID: 2167873 Reactome Database ID Release 432167873 Reactome, http://www.reactome.org ReactomeREACT_125329 TGF-beta 1:type II receptor:type I receptor complex has a Stoichiometric coefficient of 1 TGFB1:p-TGFBR:Smad7 Reactome DB_ID: 2167878 Reactome Database ID Release 432167878 Reactome, http://www.reactome.org ReactomeREACT_125031 TGFB1:TGFBR2:p-TGFBR1:Smad7 has a Stoichiometric coefficient of 1 Unknown Phosphatase Reactome DB_ID: 2529006 Reactome Database ID Release 432529006 Reactome, http://www.reactome.org ReactomeREACT_150933 GADD34:PP1CC Reactome DB_ID: 2162160 Reactome Database ID Release 432162160 Reactome, http://www.reactome.org ReactomeREACT_124572 has a Stoichiometric coefficient of 1 Dynein Reactome DB_ID: 377734 Reactome Database ID Release 43377734 Reactome, http://www.reactome.org ReactomeREACT_15191 TGFB1:p-TGFBR:Smad7:GADD34:PP1CC:SARA Reactome DB_ID: 2167871 Reactome Database ID Release 432167871 Reactome, http://www.reactome.org ReactomeREACT_124168 has a Stoichiometric coefficient of 1 Condensed prometaphase chromosomes Reactome DB_ID: 2520884 Reactome Database ID Release 432520884 Reactome, http://www.reactome.org ReactomeREACT_150762 Ca(4)CaM Active Calmodulin Reactome DB_ID: 74294 Reactome Database ID Release 4374294 Reactome, http://www.reactome.org ReactomeREACT_3178 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Condensed prophase chromosomes Reactome DB_ID: 2520882 Reactome Database ID Release 432520882 Reactome, http://www.reactome.org ReactomeREACT_151302 PPP3CA/B:Fe3+:Zn2+ Calcineurin beta catalytic subunit:Fe3+:Zn2+ Reactome DB_ID: 2025949 Reactome Database ID Release 432025949 Reactome, http://www.reactome.org ReactomeREACT_119469 has a Stoichiometric coefficient of 1 C-strand Okazaki fragment Reactome DB_ID: 176398 Reactome Database ID Release 43176398 Reactome, http://www.reactome.org ReactomeREACT_8833 PPP3R1:PPP3CA/B Calcineurin alpha regulatory subunit:Calcineurin beta catalytic subunit Reactome DB_ID: 2025977 Reactome Database ID Release 432025977 Reactome, http://www.reactome.org ReactomeREACT_119672 has a Stoichiometric coefficient of 1 Chromatin Converted from EntitySet in Reactome Reactome DB_ID: 2537690 Reactome Database ID Release 432537690 Reactome, http://www.reactome.org ReactomeREACT_152305 Arachidonic acid is oxidised to 12S-HpETE by ALOX12/15 Arachidonate 12-lipoxygenase, 12S-type (ALOX12) (Funk et al. 1990, Izumi et al. 1990) and arachidonate 15-lipoxygenase (ALOX15) (Kuhn et al. 1993, Sigal et al. 1990) convert arachidonic acid into 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE). Authored: Williams, MG, 2012-02-24 EC Number: 1.13.11.31 Edited: Williams, MG, 2012-02-24 Pubmed2217179 Pubmed2318885 Pubmed2377602 Pubmed8334154 Reactome Database ID Release 432161964 Reactome, http://www.reactome.org ReactomeREACT_150433 Reviewed: Rush, MG, 2012-11-10 TGFBR1 homodimer Reactome DB_ID: 170864 Reactome Database ID Release 43170864 Reactome, http://www.reactome.org ReactomeREACT_7737 Type I receptor dimer has a Stoichiometric coefficient of 2 “CERT” dissociates from the endoplasmic reticulum Authored: D'Eustachio, P, 2009-08-20 CERT:PPM1L:VAPA/B [ER] => CERT [cytosol] + PPM1L:VAPA/B [ER] Edited: D'Eustachio, P, 2009-08-20 Pubmed16895911 Reactome Database ID Release 43429694 Reactome, http://www.reactome.org ReactomeREACT_19306 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 “CERT” (ceramide transfer protein) can dissociate from its complex in the endoplasmic reticulum membrane with VAPA or VAPB (VAMP-associated proteins A or B) and PPM1L (protein phosphatase 1-like) and is released into the cytosol (Kawano et al. 2006). Single-Stranded Oligodeoxyribonucleotide (12 to 34 nucleotides) Reactome DB_ID: 912367 Reactome Database ID Release 43912367 Reactome, http://www.reactome.org ReactomeREACT_27694 CERT [ER] + ceramide [ER] => CERT:ceramide [ER] Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 Pubmed14685229 Pubmed16895911 Pubmed18165232 Pubmed18184806 Reactome Database ID Release 43429699 Reactome, http://www.reactome.org ReactomeREACT_19228 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 “CERT” (ceramide transfer protein), an isoform of COL4A3BP, mediates the translocation of ceramides from the endoplasmic reticulum (ER) membrane to the membrane of the Golgi apparatus. Immunoprecipitation experiments suggest that “CERT” is associated with the ER membrane as part of a complex with PPM1L (protein phosphatase 1-like) (Saito et al. 2008) and VAPA or VAPB (VAMP-associated proteins A or B) (Kawano et al. 2006). The carboxyterminal “START” domain of “CERT” protein specifically binds ceramides (Hanada et al. 2003; Kudo et al. 2008). “CERT” protein binds ceramide associated with the endoplasmic reticulum membrane Calcineurin:Phosphorylated NFATC1/2/3 Reactome DB_ID: 2025899 Reactome Database ID Release 432025899 Reactome, http://www.reactome.org ReactomeREACT_119836 has a Stoichiometric coefficient of 1 CERT + ATP => monophospho-CERT + ADP Authored: D'Eustachio, P, 2009-08-20 Cytosolic PRKD1 (protein kinase D1) catalyzes the phosphorylation of serine residue 132 of “CERT” (ceramide transfer protein) (Fugmann et al. 2007). EC Number: 2.7.11 Edited: D'Eustachio, P, 2009-08-20 Pubmed17591919 Reactome Database ID Release 43429698 Reactome, http://www.reactome.org ReactomeREACT_19152 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 PPP3R1:PPP3CA/B:Calmodulin:Ca2+ Calcineurin alpha regulatory:beta catalytic:Calmodulin Reactome DB_ID: 2025947 Reactome Database ID Release 432025947 Reactome, http://www.reactome.org ReactomeREACT_119482 has a Stoichiometric coefficient of 1 3-ketosphinganine + NADPH + H+ => sphinganine + NADP+ Authored: D'Eustachio, P, 2009-08-20 EC Number: 1.1.1.102 Edited: D'Eustachio, P, 2009-08-20 KDSR (3-ketodihydrosphingosine reductase) enzyme associated with the cytosolic face of the endoplasmic reticulum membrane catalyzes the reduction of 3-ketosphinganine by NADPH to form sphinganine (dihydrosphingosine) (Kihara and Igarashi 2004). Pubmed15328338 Reactome Database ID Release 43428123 Reactome, http://www.reactome.org ReactomeREACT_19162 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 PPP3CA/B:Calmodulin Calcineurin beta catalytic subunit:Active Calmodulin Reactome DB_ID: 2026003 Reactome Database ID Release 432026003 Reactome, http://www.reactome.org ReactomeREACT_119246 has a Stoichiometric coefficient of 1 EET(1) is hydrolysed to DHET(1) by EPHX2 Authored: Williams, MG, 2012-02-24 EC Number: 3.3.2.10 Edited: Williams, MG, 2012-02-24 Epoxide hydrolase 2 (EPHX2) hydrolyses 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids ("EET(1)") to their corresponding dihydroxyeicosatrienoic acids ("DHET(1)") (Werner et al. 2002; Gomez et al. 2004). The majority of the EET biological activities are diminished by this hydrolysis. Pubmed12468260 Pubmed15096040 Reactome Database ID Release 432161961 Reactome, http://www.reactome.org ReactomeREACT_150274 Reviewed: Rush, MG, 2012-11-10 Arachidonic acid is epoxidated to 8,9/11,12/14,15-EET by CYP(5) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed15258110 Pubmed7625847 Pubmed8631948 Pubmed9866708 Reactome Database ID Release 432161899 Reactome, http://www.reactome.org ReactomeREACT_150190 Reviewed: Rush, MG, 2012-11-10 Several cytochrome P450s (CYPs) convert arachidonic acid to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (8,9-, 11,12-, 14,15-EETs). The CYPs and their references are as follows: CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004); CYP2C8, CYP2C9 (Rifkind et al. 1995); CYP2C19 (Bylund et al. 1998, Rifkind et al. 1995); CYP2J2 (Wu et al. 1996). BoNT Light chain Type E Reactome DB_ID: 190047 Reactome Database ID Release 43190047 Reactome, http://www.reactome.org ReactomeREACT_11278 has a Stoichiometric coefficient of 1 Arachidonic acid is epoxidated to 5,6-EET by CYP(4) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed15258110 Pubmed8631948 Reactome Database ID Release 432161890 Reactome, http://www.reactome.org ReactomeREACT_150442 Reviewed: Rush, MG, 2012-11-10 Several cytochrome P450s (CYPs) convert arachidonic acid to 5,6-epoxyeicosatrienoic acid (5,6-EET). The CYPs and their references are as follows: CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004); CYP2J2 (Wu et al. 1996). BoNT Light chain Type A Reactome DB_ID: 190017 Reactome Database ID Release 43190017 Reactome, http://www.reactome.org ReactomeREACT_11247 has a Stoichiometric coefficient of 1 Arachidonic acid is hydroxylated to 20-HETE by CYP(3) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed12432928 Pubmed14660610 Pubmed15258110 Pubmed15611369 Pubmed9618440 Reactome Database ID Release 432161940 Reactome, http://www.reactome.org ReactomeREACT_150406 Reviewed: Rush, MG, 2012-11-10 Several cytochrome P450s (CYPs) convert arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). The CYPs and their references are as follows: CYP4A11 (Gainer et al. 2005, Powell 1998); CYP4F2 (Powell et al. 1998, Kikuta et al. 2002); CYP2U1 (Chuang et al. 2004); CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004). BoNT Light chain Types A,C and E Converted from EntitySet in Reactome Reactome DB_ID: 181583 Reactome Database ID Release 43181583 Reactome, http://www.reactome.org ReactomeREACT_11662 BoNT Light chain Type G Reactome DB_ID: 190032 Reactome Database ID Release 43190032 Reactome, http://www.reactome.org ReactomeREACT_11643 has a Stoichiometric coefficient of 1 BoNT Light chain Type F Reactome DB_ID: 190042 Reactome Database ID Release 43190042 Reactome, http://www.reactome.org ReactomeREACT_11984 has a Stoichiometric coefficient of 1 BoNT Light chain Type D Reactome DB_ID: 190038 Reactome Database ID Release 43190038 Reactome, http://www.reactome.org ReactomeREACT_11845 has a Stoichiometric coefficient of 1 BoNT Light chain Type B Reactome DB_ID: 190016 Reactome Database ID Release 43190016 Reactome, http://www.reactome.org ReactomeREACT_11746 has a Stoichiometric coefficient of 1 BoNT Light chain Types B,D,F,G Converted from EntitySet in Reactome Reactome DB_ID: 181504 Reactome Database ID Release 43181504 Reactome, http://www.reactome.org ReactomeREACT_11940 BoNT with Heavy chain N-terminal inserted into endosomal membrane Reactome DB_ID: 181582 Reactome Database ID Release 43181582 Reactome, http://www.reactome.org ReactomeREACT_11623 has a Stoichiometric coefficient of 1 BoNT with conformational change in Heavy chain N-terminal Reactome DB_ID: 181477 Reactome Database ID Release 43181477 Reactome, http://www.reactome.org ReactomeREACT_11938 has a Stoichiometric coefficient of 1 SLCO3A1 substrates Converted from EntitySet in Reactome Reactome DB_ID: 879563 Reactome Database ID Release 43879563 Reactome, http://www.reactome.org ReactomeREACT_24849 SLCO3A1 substrates Converted from EntitySet in Reactome Reactome DB_ID: 879529 Reactome Database ID Release 43879529 Reactome, http://www.reactome.org ReactomeREACT_24656 adherens junction-associated proteins Converted from EntitySet in Reactome Reactome DB_ID: 451386 Reactome Database ID Release 43451386 Reactome, http://www.reactome.org ReactomeREACT_24771 Arachidonic acid is hydroxylated to 16/17/18-HETE by CYP(1) Authored: Williams, MG, 2012-02-24 Cytochrome P450s 1A1 (CYP1A1), 1A2 (CYP1A2), and 1B1 (CYP1B1) convert arachidonic acid to 16-, 17-, and 18-hydroxyeicosatetraenoic acids (16-, 17-, and 18-HETEs) (Choudhary et al. 2004). Edited: Williams, MG, 2012-02-24 Pubmed15258110 Reactome Database ID Release 432161795 Reactome, http://www.reactome.org ReactomeREACT_150287 Reviewed: Rush, MG, 2012-11-10 Fringe-modified NOTCH1 Glu,Sia-Gal-GlcNAc-Fuc-NOTCH1 Reactome DB_ID: 1911516 Reactome Database ID Release 431911516 Reactome, http://www.reactome.org ReactomeREACT_120034 has a Stoichiometric coefficient of 1 Podocin oligomer Reactome DB_ID: 451771 Reactome Database ID Release 43451771 Reactome, http://www.reactome.org ReactomeREACT_24198 Arachidonic acid is hydroxylated to 19-HETE by CYP(2) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed14660610 Pubmed15258110 Pubmed15611369 Pubmed9435160 Reactome Database ID Release 432161814 Reactome, http://www.reactome.org ReactomeREACT_150441 Reviewed: Rush, MG, 2012-11-10 Several cytochrome P450s (CYPs) convert arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE). The CYPs and their references are as follows: CYP2C8 (Bylund et al. 1998); CYP2C9 (Bylund et al. 1998); CYP2C19 (Bylund et al. 1998); CYP4A11 (Gainer et al. 2005); CYP2U1 (Chuang et al. 2004); CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004). NOTCH1/Fringe-modified NOTCH1 Converted from EntitySet in Reactome Reactome DB_ID: 1911555 Reactome Database ID Release 431911555 Reactome, http://www.reactome.org ReactomeREACT_118918 SP-D oligomer Reactome DB_ID: 391097 Reactome Database ID Release 43391097 Reactome, http://www.reactome.org ReactomeREACT_24701 SP-A oligomer Reactome DB_ID: 391092 Reactome Database ID Release 43391092 Reactome, http://www.reactome.org ReactomeREACT_24070 DLL4:NOTCH1 Reactome DB_ID: 1911559 Reactome Database ID Release 431911559 Reactome, http://www.reactome.org ReactomeREACT_119247 has a Stoichiometric coefficient of 1 Pulmonory surfactant proteins A and D Converted from EntitySet in Reactome Reactome DB_ID: 391108 Reactome Database ID Release 43391108 Reactome, http://www.reactome.org ReactomeREACT_24725 NOTCH1:Ub-DSL Reactome DB_ID: 1911537 Reactome Database ID Release 431911537 Reactome, http://www.reactome.org ReactomeREACT_119851 Ub-DLL/JAG:NOTCH1 has a Stoichiometric coefficient of 1 Keratin 5/14 Reactome DB_ID: 446069 Reactome Database ID Release 43446069 Reactome, http://www.reactome.org ReactomeREACT_20869 PPP3R1:Ca2+ Calcineurin alpha regulatory subunit:Calcium Reactome DB_ID: 2025950 Reactome Database ID Release 432025950 Reactome, http://www.reactome.org ReactomeREACT_119808 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 F-actin Reactome DB_ID: 201877 Reactome Database ID Release 43201877 Reactome, http://www.reactome.org ReactomeREACT_20433 DLL1:NOTCH1 Reactome DB_ID: 1911557 Reactome Database ID Release 431911557 Reactome, http://www.reactome.org ReactomeREACT_119369 has a Stoichiometric coefficient of 1 Beta-catenin/gamma catenin Converted from EntitySet in Reactome Reactome DB_ID: 418993 Reactome Database ID Release 43418993 Reactome, http://www.reactome.org ReactomeREACT_19976 NOTCH1:DSL Converted from EntitySet in Reactome DLL/JAG:NOTCH1 NTM-NEC1-Notch ligand complex Reactome DB_ID: 157655 Reactome Database ID Release 43157655 Reactome, http://www.reactome.org ReactomeREACT_5547 palmitoyl-CoA + serine => 3-ketosphinganine + CoASH + CO2 Authored: D'Eustachio, P, 2009-08-20 EC Number: 2.3.1.50 Edited: D'Eustachio, P, 2009-08-20 Pubmed10722674 Pubmed11242114 Pubmed17023427 Pubmed17331073 Pubmed9363775 Reactome Database ID Release 43428127 Reactome, http://www.reactome.org ReactomeREACT_19401 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SPTLC (serine palmitoyltransferase) enzyme complexes associated with the endoplasmic reticulum membrane catalyze the reaction of palmitoyl-CoA and serine to form 3-ketosphinganine. SPTLC2 and SPTLC3 polypeptides exhibit enzyme activity when either is complexed with SPTLC1. SPTLC1 and 2 are abundant and widely expressed in human tissues, while SPTLC3 is expressed only in a smaller group of tissues and at variable levels. Results of studies in which siRNA was used to reduce levels of the three endogenous mRNAs differentially suggest that SPTLC2 and 3 both encode active serine palmitoyltransferases (Hornemann et al. 2006). Neither human nor mouse SPTLC1 has detectable enzyme activity, but the protein has an essential function, as mutations that disrupt it are associated with hereditary neuropathy (Dawkins et al. 2001). Studies of mouse and hamster proteins support the hypothesis that heterodimerization with SPTLC1 stabilizes SPTLC2 (or 3) and mediates its localization to the endoplasmic reticulum membrane (Hanada et al. 2000; Weiss and Stoffel 1997). Analyses of complexes extracted from human placenta, and of cultured human cells over-expressing various SPTLC constructs, suggest that these heterodimers may associate into larger complexes (Hanada et al. 2000; Weiss and Stoffel 1997; Hornemann et al. 2006, 2007). NOTCH1 fragment:Ub-DSL Reactome DB_ID: 1911540 Reactome Database ID Release 431911540 Reactome, http://www.reactome.org ReactomeREACT_119550 Ub-DLL/JAG:NOTCH1 fragment has a Stoichiometric coefficient of 1 multiphospho-CERT:PPM1L:VAPA/B + 3 H2O => CERT:PPM1L:VAPA/B + 3 orthophosphate Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 PPM1L (protein phosphatase 1-like) catalyzes the dephosphorylation of multiphospho-“CERT” (ceramide transfer protein) that is complexed with it in the endoplasmic reticulum membrane (Saito et al. 2008). Pubmed18165232 Reactome Database ID Release 43429730 Reactome, http://www.reactome.org ReactomeREACT_19304 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 has a Stoichiometric coefficient of 3 NOTCH1 fragment:DSL NOTCH1 fragment:DLL/JAG Reactome DB_ID: 157658 Reactome Database ID Release 43157658 Reactome, http://www.reactome.org ReactomeREACT_3700 has a Stoichiometric coefficient of 1 serine-type endopeptidases involved in novel PDGF processing Converted from EntitySet in Reactome Reactome DB_ID: 381937 Reactome Database ID Release 43381937 Reactome, http://www.reactome.org ReactomeREACT_17837 JAG1:NOTCH1 Reactome DB_ID: 157008 Reactome Database ID Release 43157008 Reactome, http://www.reactome.org ReactomeREACT_118991 has a Stoichiometric coefficient of 1 Extracellular matrix ligands Converted from EntitySet in Reactome Reactome DB_ID: 381946 Reactome Database ID Release 43381946 Reactome, http://www.reactome.org ReactomeREACT_17129 phosphatidylcholine + ceramide <=> sphingomyelin + diacylglycerol [SGMS1] Authored: D'Eustachio, P, 2009-08-20 EC Number: 2.7.8.27 Edited: D'Eustachio, P, 2009-08-20 Pubmed14685263 Pubmed14976195 Pubmed17449912 Pubmed4339164 Pubmed4817756 Reactome Database ID Release 43429798 Reactome, http://www.reactome.org ReactomeREACT_19414 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SGMS1 (sphingomyelin synthase 1) associated with the membrane of the Golgi apparatus catalyzes the reversible reaction of phosphatidylcholine and ceramide to form sphingomyelin and diacylglycerol. Phosphatidylcholine was identified as the source of the phosphocholine moiety donated to ceramide in this reaction, in studies of the mouse enzyme in the 1970s (Diringer et al. 1972; Ullman and Radin 1974). SGMS1 is widely expressed in the body and studies of cultured cells indicate that this reaction provides the major source of cellular sphingomyelin (Yamaoka et al. 2004; Huitema et al. 2004; Tafesse et al. 2007). JAG2:NOTCH1 NTM-NEC1-Jagged2 complex Reactome DB_ID: 157140 Reactome Database ID Release 43157140 Reactome, http://www.reactome.org ReactomeREACT_118972 has a Stoichiometric coefficient of 1 dihydroceramide + NADPH + H+ + O2 => phytoceramide + NADP+ + H2O Authored: D'Eustachio, P, 2009-08-20 DEGS2 (sphingolipid C4-hydroxylase 2 / “degenerative spermatocyte homolog 2”) enzyme associated with the cytosolic face of the endoplasmic reticulum catalyzes the hydroxylation of dihydroceramide to form phytoceramide (Mizutani et al. 2004). Sequence similarity to the bifunctional mouse DEGS2 enzyme suggests that human DEGS2 protein might also catalyze the C4-dehydrogenation of dihydroceramide, but this hypothesis has not been tested experimentally. Edited: D'Eustachio, P, 2009-08-20 Pubmed15063729 Reactome Database ID Release 43428260 Reactome, http://www.reactome.org ReactomeREACT_19258 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 BoNT Light chain Type F Reactome DB_ID: 190048 Reactome Database ID Release 43190048 Reactome, http://www.reactome.org ReactomeREACT_11730 has a Stoichiometric coefficient of 1 dihydroceramide + NAD(P)H + H+ + O2 => ceramide + NAD(P)+ + H2O Authored: D'Eustachio, P, 2009-08-20 DEGS1 (sphingolipid delta(4)-desaturase 1 / “degenerative spermatocyte homolog 1”) enzyme associated with the cytosolic face of the endoplasmic reticulum catalyzes the desaturation of dihydroceramide to form ceramide (Cadena et al. 1997; Ternes et al. 2002). The stoichiometry and cofactor requirements of the reaction are inferred from those observed in studies of ceramide synthesis in vitro catalyzed by rat liver microsomes (Michel et al. 1997). DEGS1 may also catalyze the 4-hydroxylation of dihydroceramide to form 4-hydroxysphinganine, but with low efficiency. Edited: D'Eustachio, P, 2009-08-20 Pubmed11937514 Pubmed9188692 Pubmed9312549 Reactome Database ID Release 43428259 Reactome, http://www.reactome.org ReactomeREACT_19261 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 BoNT Light chain Type E Reactome DB_ID: 190027 Reactome Database ID Release 43190027 Reactome, http://www.reactome.org ReactomeREACT_11852 has a Stoichiometric coefficient of 1 multiphospho-CERT + PPM1L:VAPA/B => multiphospho-CERT:PPM1L:VAPA/B Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 Multiphospho-CERT retains its affinity for VAPA or VAPB (VAMP-associated proteins A or B) and PPM1L (protein phosphatase 1-like) in the endoplasmic reticulum membrane, and can associate with them to form a membrane-associated complex (Saito et al. 2008). Pubmed18165232 Reactome Database ID Release 43429732 Reactome, http://www.reactome.org ReactomeREACT_19257 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 Gangliosides:Synaptogamin Reactome DB_ID: 194813 Reactome Database ID Release 43194813 Reactome, http://www.reactome.org ReactomeREACT_11246 has a Stoichiometric coefficient of 1 monophospho-CERT + 2 ATP => multiphospho-CERT + 2 ADP Authored: D'Eustachio, P, 2009-08-20 Cytosolic CSNK1G2 (casein kinase 1, gamma 2) catalyzes the phosphorylation of multiple serine and threonine residues of “CERT” (ceramide transfer protein) already phosphorylated on serine-132 (Tomishige et al. 2009). This reaction has the effect of inhibiting ceramide transport from the endoplasmic reticulum to the Golgi apparatus as multiphospho-CERT is unable to bind ceramides or associate with the Golgi membrane. EC Number: 2.7.11 Edited: D'Eustachio, P, 2009-08-20 Pubmed19005213 Reactome Database ID Release 43429714 Reactome, http://www.reactome.org ReactomeREACT_19156 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 has a Stoichiometric coefficient of 2 BoNT Light chain Type G Reactome DB_ID: 190028 Reactome Database ID Release 43190028 Reactome, http://www.reactome.org ReactomeREACT_11485 has a Stoichiometric coefficient of 1 BoNT Light chain Type B Reactome DB_ID: 190043 Reactome Database ID Release 43190043 Reactome, http://www.reactome.org ReactomeREACT_11446 has a Stoichiometric coefficient of 1 BoNT Light chain Type A Reactome DB_ID: 190036 Reactome Database ID Release 43190036 Reactome, http://www.reactome.org ReactomeREACT_11578 has a Stoichiometric coefficient of 1 BoNT Light chain Type D Reactome DB_ID: 190029 Reactome Database ID Release 43190029 Reactome, http://www.reactome.org ReactomeREACT_11931 has a Stoichiometric coefficient of 1 BoNT Light chain Type C Reactome DB_ID: 190024 Reactome Database ID Release 43190024 Reactome, http://www.reactome.org ReactomeREACT_11489 has a Stoichiometric coefficient of 1 BoNT Light Chain Converted from EntitySet in Reactome Reactome DB_ID: 181475 Reactome Database ID Release 43181475 Reactome, http://www.reactome.org ReactomeREACT_11482 BoNT Activated BoNT bound to invaginated membrane Reactome DB_ID: 194799 Reactome Database ID Release 43194799 Reactome, http://www.reactome.org ReactomeREACT_11561 has a Stoichiometric coefficient of 1 Cleaved classical PDGF peptides Converted from EntitySet in Reactome Reactome DB_ID: 389066 Reactome Database ID Release 43389066 Reactome, http://www.reactome.org ReactomeREACT_17262 NgR homomultimer Reactome DB_ID: 194455 Reactome Database ID Release 43194455 Reactome, http://www.reactome.org ReactomeREACT_14489 Procaspase2/3 Converted from EntitySet in Reactome Reactome DB_ID: 204948 Reactome Database ID Release 43204948 Reactome, http://www.reactome.org ReactomeREACT_14024 CERT:ceramide [ER] => ceramide [Golgi] + CERT [ER] Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 Pubmed14685229 Pubmed16571669 Pubmed16895911 Pubmed18165232 Reactome Database ID Release 43429683 Reactome, http://www.reactome.org ReactomeREACT_19225 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 “CERT” (ceramide transfer protein), associated with the cytosolic face of the endoplasmic reticulum (ER) in a complex with VAPA or VAPB (VAMP-associated proteins A or B) (Kawano et al. 2006) and PPM1L (protein phosphatase 1-like) (Saito et al. 2008), can bridge the gap between the ER and the Golgi apparatus via its PH domain and transfer a molecule of ceramide extracted from the ER membrane to the Golgi (Hanada et al. 2003; Saito et al. 2008). “CERT”-mediated ceramide transfer is positively regulated by OSBP (oxysterol binding protein), by an unknown mechanism (Perry and Ridgway 2006). “CERT” protein releases its bound ceramide into the membrane of the Golgi apparatus Dynamin-1/2/3 Converted from EntitySet in Reactome Reactome DB_ID: 446847 Reactome Database ID Release 43446847 Reactome, http://www.reactome.org ReactomeREACT_22651 ceramide + H2O <=> stearate + sphingosine [endoplasmic reticulum] ACER1 (alkaline ceramidase 1), associated with the endoplasmic reticulum membrane, catalyzes the reversible hydrolysis of ceramide to yield a free fatty acid (annotated here as stearate) and sphingosine (Sun et al. 2008). Authored: D'Eustachio, P, 2009-08-20 EC Number: 3.5.1.23 Edited: D'Eustachio, P, 2009-08-20 Pubmed17713573 Reactome Database ID Release 43428231 Reactome, http://www.reactome.org ReactomeREACT_19174 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 ADAM10:Zn++ ADAM 10 metalloprotease (Zn cofactor) Reactome DB_ID: 157186 Reactome Database ID Release 43157186 Reactome, http://www.reactome.org ReactomeREACT_3937 has a Stoichiometric coefficient of 1 Guanine nucleotide exchange factor Reactome DB_ID: 204704 Reactome Database ID Release 43204704 Reactome, http://www.reactome.org ReactomeREACT_12202 ceramide + H2O => stearate + sphingosine [Golgi] ACER2 (alkaline ceramidase 2), associated with the membrane of the Golgi apparatus, catalyzes the hydrolysis of ceramide to yield a free fatty acid (annotated here as stearate) and sphingosine. ACER2 mRNA is widely expressed in the body, although only at low levels except in placenta (Xu et al. 2006). Authored: D'Eustachio, P, 2009-08-20 EC Number: 3.5.1.23 Edited: D'Eustachio, P, 2009-08-20 Pubmed16940153 Reactome Database ID Release 43428205 Reactome, http://www.reactome.org ReactomeREACT_19413 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 NOTCH2 fragment:DSL NOTCH2 fragment:DLL/JAG Notch 2 ligand-bound fragment-Notch ligand complex Reactome DB_ID: 157630 Reactome Database ID Release 43157630 Reactome, http://www.reactome.org ReactomeREACT_4751 has a Stoichiometric coefficient of 1 protein tyrosine phosphatase Reactome DB_ID: 74731 Reactome Database ID Release 4374731 Reactome, http://www.reactome.org ReactomeREACT_3980 NOTCH2 NTM-NEC 2 heterodimer Reactome DB_ID: 157005 Reactome Database ID Release 43157005 Reactome, http://www.reactome.org ReactomeREACT_5316 has a Stoichiometric coefficient of 1 Unmethylated CpG DNA Reactome DB_ID: 167913 Reactome Database ID Release 43167913 Reactome, http://www.reactome.org ReactomeREACT_9187 DLL/JAG:NOTCH2 Reactome DB_ID: 2262789 Reactome Database ID Release 432262789 Reactome, http://www.reactome.org ReactomeREACT_124187 has a Stoichiometric coefficient of 1 GEF Converted from EntitySet in Reactome Reactome DB_ID: 194849 Reactome Database ID Release 43194849 Reactome, http://www.reactome.org ReactomeREACT_10196 ADAM10/17:Zn++ Reactome DB_ID: 1852620 Reactome Database ID Release 431852620 Reactome, http://www.reactome.org ReactomeREACT_119102 has a Stoichiometric coefficient of 1 IDA Reactome DB_ID: 74819 Reactome Database ID Release 4374819 Reactome, http://www.reactome.org ReactomeREACT_2385 NOTCH1 fragment Reactome DB_ID: 2193050 Reactome Database ID Release 432193050 Reactome, http://www.reactome.org ReactomeREACT_125002 has a Stoichiometric coefficient of 1 GABA B receptor G-protein beta-gamma complex Reactome DB_ID: 1013017 Reactome Database ID Release 431013017 Reactome, http://www.reactome.org ReactomeREACT_26464 has a Stoichiometric coefficient of 1 Kir4.2:Kir5.1 heterotetramer Reactome DB_ID: 975367 Reactome Database ID Release 43975367 Reactome, http://www.reactome.org ReactomeREACT_25550 has a Stoichiometric coefficient of 2 14-3-3 beta, zeta Converted from EntitySet in Reactome Reactome DB_ID: 914001 Reactome Database ID Release 43914001 Reactome, http://www.reactome.org ReactomeREACT_24076 PKA catalytic subunits Converted from EntitySet in Reactome Protein Kinase A, catalytic subunits Reactome DB_ID: 913999 Reactome Database ID Release 43913999 Reactome, http://www.reactome.org ReactomeREACT_24515 cAMP-dependent protein kinase catalytic subunits phytoceramide + H2O => stearate + phytosphingosine ACER3 (alkaline ceramidase 3) catalyzes the hydrolysis of phytoceramide to yield a free fatty acid (annotated here as stearate) and phytosphingosine. ACER3 mRNA is widely expressed in the body, although most abundant in placenta. Immunofluoresence studies of cultured cells over-expressing GFP-tagged protein suggest its localization to membranes of the endoplasmic reticulum (annotated here) and also the Golgi apparatus (Mao et al. 2001). Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 Pubmed11356846 Reactome Database ID Release 43428262 Reactome, http://www.reactome.org ReactomeREACT_19134 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 phosphatidylcholine + ceramide <=> sphingomyelin + diacylglycerol [SGMS2] Authored: D'Eustachio, P, 2009-08-20 EC Number: 2.7.8.27 Edited: D'Eustachio, P, 2009-08-20 Pubmed14685263 Pubmed17449912 Pubmed17982138 Pubmed19233134 Pubmed4339164 Pubmed4817756 Reactome Database ID Release 43429786 Reactome, http://www.reactome.org ReactomeREACT_19278 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SGMS2 (sphingomyelin synthase 2) catalyzes the reversible reaction of phosphatidylcholine and ceramide to form sphingomyelin and diacylglycerol. Most SGMS2 actitiy is associated with the plasma membrane, although active enzyme is also present in the Golgi apparatus (Tafesse et al. 2007; Villani et al. 2008; Ding et al. 2008). Phosphatidylcholine was identified as the source of the phosphocholine moiety donated to ceramide in this reaction, in studies of the mouse enzyme in the 1970s (Diringer et al. 1972; Ullman and Radin 1974). Palmitoylation of at least two cysteine residues near the carboxy terminus of SGMS2 appears to be required for association of the protein with the plasma membrane (Tani and Kuge 2009). SGMS2 is widely expressed in the body and while studies of cultured cells indicate that this is a minor source of cellular sphingomyelin, blockage of SGMS2 activity inhibits cell growth (Huitema et al. 2004; Tafesse et al. 2007). sphinganine + stearyl-CoA => dihydroceramide + CoASH Authored: D'Eustachio, P, 2009-08-20 EC Number: 2.3.1.24 Edited: D'Eustachio, P, 2009-08-20 LASS (“longevity assurance homolog”, also known as ceramide synthase, CerS) enzymes associated with the endoplasmic reticulum membrane catalyze the reaction of sphinganine (dihydrosphingosine) and a long-chain fatty acyl CoA such as stearyl-CoA to form a dihydroceramide and CoASH (Pewzner-Jung et al. 2006). Six human LASS genes have been identified; they differ in the identities of the fatty acyl CoAs that they use most efficiently as substrates (Lahiri and Futerman 2005; Laviad et al. 2008). Pubmed16100120 Pubmed16793762 Pubmed18165233 Reactome Database ID Release 43428185 Reactome, http://www.reactome.org ReactomeREACT_19234 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 sphinganine (dihydrosphingosine) +ATP => sphinganine 1-phosphate + ADP Authored: D'Eustachio, P, 2009-08-20 EC Number: 2.7.1.91 Edited: D'Eustachio, P, 2009-08-20 Pubmed10751414 Pubmed10802064 Pubmed10947957 Reactome Database ID Release 43428214 Reactome, http://www.reactome.org ReactomeREACT_19412 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SPHK1 and 2 (sphingosine kinases 1 and 2) each catalyze the reaction of sphinganine (dihydrosphingosine) and ATP to form dihydrosphingosine 1-phosphate and ADP. Both enzymes are found in the cytosol (although they are also present in membrane-associated forms). Both enzymes also catalyze the phosphorylation of sphingosine (Liu et al. 2000; Nava et al. 2000; Pitson et al. 2000). Class I MHC HC:B2M Reactome DB_ID: 1236928 Reactome Database ID Release 431236928 Reactome, http://www.reactome.org ReactomeREACT_111753 has a Stoichiometric coefficient of 1 IRAP in complex with MHC class I Reactome DB_ID: 1236916 Reactome Database ID Release 431236916 Reactome, http://www.reactome.org ReactomeREACT_111797 has a Stoichiometric coefficient of 1 G-protein beta-gamma subunits Reactome DB_ID: 1013019 Reactome Database ID Release 431013019 Reactome, http://www.reactome.org ReactomeREACT_25932 has a Stoichiometric coefficient of 1 Class I MHC:B2M Reactome DB_ID: 1236930 Reactome Database ID Release 431236930 Reactome, http://www.reactome.org ReactomeREACT_111780 has a Stoichiometric coefficient of 1 sphinganine 1-phosphate + H2O => sphinganine + orthophosphate Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 Pubmed12411432 Pubmed12815058 Reactome Database ID Release 43428664 Reactome, http://www.reactome.org ReactomeREACT_19369 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SGPP1 and 2 (sphingosine-1-phosphate phosphatase 1 and 2) enzymes associated with the endoplasmic reticulum membrane catalyze the hydrolysis of cytosolic sphinganine 1-phosphate to form sphinganine (dihydrosphingosine) and orthophosphate (Johnson et al. 2003; Ogawa et al. 2003). GABA(A)-rho homopentamer Reactome DB_ID: 975448 Reactome Database ID Release 43975448 Reactome, http://www.reactome.org ReactomeREACT_26162 has a Stoichiometric coefficient of 5 Antigen peptide bound class I MHC Reactome DB_ID: 1236934 Reactome Database ID Release 431236934 Reactome, http://www.reactome.org ReactomeREACT_111468 has a Stoichiometric coefficient of 1 sphinganine 1-phosphate => phosphoethanolamine + hexadecanal Authored: D'Eustachio, P, 2009-08-20 EC Number: 4.1.2.27 Edited: D'Eustachio, P, 2009-08-20 Pubmed11018465 Pubmed18558101 Reactome Database ID Release 43428681 Reactome, http://www.reactome.org ReactomeREACT_19349 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SGPL1 (sphingosine-1-phosphate lyase 1), associated with the endoplasmic reticulum membrane, catalyzes the cleavage of cytosolic sphinganine (dihydrosphingosine) 1-phosphate to form phosphoethanolamine and hexadecanal (Van Veldhoven et al. 2000; Fyrst and Saba 2008). Small conductance Ca2+ activated potassium channel Reactome DB_ID: 1297362 Reactome Database ID Release 431297362 Reactome, http://www.reactome.org ReactomeREACT_76180 has a Stoichiometric coefficient of 4 MR:soluble antigen Reactome DB_ID: 1236923 Reactome Database ID Release 431236923 Reactome, http://www.reactome.org ReactomeREACT_111745 has a Stoichiometric coefficient of 1 sphingosine +ATP => sphingosine 1-phosphate + ADP Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 Pubmed10751414 Pubmed10802064 Pubmed10947957 Reactome Database ID Release 43428273 Reactome, http://www.reactome.org ReactomeREACT_19352 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SPHK1 and 2 (sphingosine kinases 1 and 2) catalyze the reaction of sphingosine and ATP to form sphingosine 1-phosphate and ADP. Both enzymes are found in the cytosol (although they are also present in membrane-associated forms). Both enzymes also catalyze the phosphorylation of sphinganine (dihydrosphingosine) (Liu et al. 2000; Nava et al. 2000; Pitson et al. 2000). HCN channels Converted from EntitySet in Reactome Reactome DB_ID: 1297434 Reactome Database ID Release 431297434 Reactome, http://www.reactome.org ReactomeREACT_76601 MR:soluble antigen Reactome DB_ID: 1236926 Reactome Database ID Release 431236926 Reactome, http://www.reactome.org ReactomeREACT_111329 has a Stoichiometric coefficient of 1 sphingosine 1-phosphate + H2O => sphingosine + orthophosphate [cytosolic - PPAP] Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 PPAP2A, B, and C (phosphatidate phosphohydrolase type 2A, B, and C) enzymes associated with the plasma membrane catalyze the hydrolysis of cytosolic sphingosine 1-phosphate to form sphingosine and orthophosphate (Roberts et al 1998). Pubmed9705349 Reactome Database ID Release 43428696 Reactome, http://www.reactome.org ReactomeREACT_19185 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 HCN channel Homomer of subunit HCN1 Reactome DB_ID: 977551 Reactome Database ID Release 43977551 Reactome, http://www.reactome.org ReactomeREACT_76819 has a Stoichiometric coefficient of 4 MR:soluble antigen Reactome DB_ID: 1236929 Reactome Database ID Release 431236929 Reactome, http://www.reactome.org ReactomeREACT_111589 has a Stoichiometric coefficient of 1 sphingosine 1-phosphate + H2O => sphingosine + orthophosphate [cytosolic - SGPP] Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 Pubmed12411432 Pubmed12815058 Reactome Database ID Release 43428701 Reactome, http://www.reactome.org ReactomeREACT_19392 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SGPP1 and 2 (sphingosine-1-phosphate phosphatase 1 and 2) enzymes associated with the endoplasmic reticulum membrane catalyze the hydrolysis of cytosolic sphingosine 1-phosphate to form sphingosine and orthophosphate (Johnson et al. 2003; Ogawa et al. 2003). HCN channel Homomer of subunit HCN3 Reactome DB_ID: 977550 Reactome Database ID Release 43977550 Reactome, http://www.reactome.org ReactomeREACT_76575 has a Stoichiometric coefficient of 4 MHC II alpha beta heterodimer Reactome DB_ID: 2213186 Reactome Database ID Release 432213186 Reactome, http://www.reactome.org ReactomeREACT_123107 has a Stoichiometric coefficient of 1 sphingosine 1-phosphate + H2O => sphingosine + orthophosphate [extracellular] Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 PPAP2A (phosphatidate phosphohydrolase type 2A) enzyme associated with the plasma membrane catalyzes the hydrolysis of extracellular sphingosine 1-phosphate to form sphingosine and orthophosphate (Roberts et al 1998). Pubmed9705349 Reactome Database ID Release 43428690 Reactome, http://www.reactome.org ReactomeREACT_19309 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 HCN channel Homomer of subunit HCN4 Reactome DB_ID: 977547 Reactome Database ID Release 43977547 Reactome, http://www.reactome.org ReactomeREACT_76444 has a Stoichiometric coefficient of 4 Invariant chain trimer Reactome DB_ID: 2130599 Reactome Database ID Release 432130599 Reactome, http://www.reactome.org ReactomeREACT_124051 has a Stoichiometric coefficient of 3 HCN channel Homomer of subunt HCN2 Reactome DB_ID: 977546 Reactome Database ID Release 43977546 Reactome, http://www.reactome.org ReactomeREACT_76203 has a Stoichiometric coefficient of 4 alpha beta dimer:Ii trimer:calnexin Reactome DB_ID: 2213212 Reactome Database ID Release 432213212 Reactome, http://www.reactome.org ReactomeREACT_123467 has a Stoichiometric coefficient of 1 HCN channel bound to cAMP Reactome DB_ID: 1297435 Reactome Database ID Release 431297435 Reactome, http://www.reactome.org ReactomeREACT_76050 has a Stoichiometric coefficient of 1 sphingosine 1-phosphate => phosphoethanolamine + hexadec-2-enal Authored: D'Eustachio, P, 2009-08-20 EC Number: 4.1.2.27 Edited: D'Eustachio, P, 2009-08-20 Pubmed11018465 Pubmed18558101 Reactome Database ID Release 43428676 Reactome, http://www.reactome.org ReactomeREACT_19379 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 SGPL1 (sphingosine-1-phosphate lyase 1), associated with the endoplasmic reticulum membrane, catalyzes the cleavage of cytosolic sphingosine 1-phosphate to form phosphoethanolamine and hexadec-2-enal (Van Veldhoven et al. 2000; Fyrst and Saba 2008). (Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GTP) Reactome DB_ID: 170683 Reactome Database ID Release 43170683 Reactome, http://www.reactome.org ReactomeREACT_15996 has a Stoichiometric coefficient of 1 G alpha-olf:GTP Reactome DB_ID: 170661 Reactome Database ID Release 43170661 Reactome, http://www.reactome.org ReactomeREACT_16015 has a Stoichiometric coefficient of 1 G-protein alpha (i):GTP:Adenylate cyclase Reactome DB_ID: 396910 Reactome Database ID Release 43396910 Reactome, http://www.reactome.org ReactomeREACT_19914 has a Stoichiometric coefficient of 1 Neu5Ac is cleaved from GM3 by NEU1 and 4 to form a globoside (lysosomal lumen) Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.18 Edited: Jassal, B, 2011-09-21 Pubmed15213228 Pubmed1756715 Pubmed3136930 Pubmed8591035 Pubmed8985184 Reactome Database ID Release 431605724 Reactome, http://www.reactome.org ReactomeREACT_116118 Reviewed: Stephan, R, 2011-10-31 Sialidases (NEU, neuraminidases) hydrolyze sialic acids (N-acetylneuramic acid, Neu5Ac, NANA) to produce asialo compounds, a step in the degradation process of glycoproteins and gangliosides. NEU1 and NEU4 hydrolyse NANA in the lysosomal lumen. NEU1 is active in a multienzyme complex comprising cathepsin A protective protein (CTSA) and beta-galactosidase (Bonten et al. 1996, Rudenko et al. 1995). Defects in NEU1 are the cause of Sialidosis (MIM:256550) (Bonten et al. 1996). CTSA is thought to exert a protective function necessary for stability and activity of these enzymes (Galjart et al. 1988). Defects in CTSA are the cause of galactosialidosis (GSL, MIM:256540) (Zhou et al. 1991). NEU4 is also a lysosmal sialidase which, unlike NEU1, doesn't require association with other proteins for enzymatic activity. Isoform 2 is thought to be the lysosomal sialidase (Seyrantepe et al. 2004). Hexosaminidase A cleaves GalNAc from GM2 to form GM3 Authored: Jassal, B, 2011-09-21 Beta-hexosaminidase A (bHEXA) cleaves the terminal N-acetyl galactosamine from GM2 ganglioside to form GM3 ganglioside (Lemieux et al. 2006). There are two major forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988). Only form A is active towards GM2 ganglioside (Conzelmann & Sandhoff 1979). Defects in the two subunits cause lysosomal storage diseases marked by the accumulation of GM2 ganglioside in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991). EC Number: 3.2.1.52 Edited: Jassal, B, 2011-09-21 Pubmed16698036 Pubmed1720305 Pubmed2970528 Pubmed2971395 Pubmed527942 Reactome Database ID Release 431605595 Reactome, http://www.reactome.org ReactomeREACT_115984 Reviewed: Stephan, R, 2011-10-31 TLR7/8/9 Converted from EntitySet in Reactome Reactome DB_ID: 1679009 Reactome Database ID Release 431679009 Reactome, http://www.reactome.org ReactomeREACT_119993 Ganglioside GM2 activator presents GM2 to hexosaminidase for cleavage Authored: Jassal, B, 2011-09-21 Edited: Jassal, B, 2011-09-21 Pubmed12909021 Pubmed1915858 Reactome Database ID Release 431605717 Reactome, http://www.reactome.org ReactomeREACT_115670 Reviewed: Stephan, R, 2011-10-31 The Ganglioside GM2 activator protein (GM2A) is a small lysosomal lipid transfer protein that extracts a single GM2 molecule from membranes and presents it in a soluble form to beta-hexosaminidase A for cleavage (Wright et al. 2003). Defects in GM2A are the cause of GM2-gangliosidosis type AB (GM2GAB) (MIM:272750), also known as Tay-Sachs disease AB variant (Schroeder et al. 1991). Beta-galactosidase hydrolyses GM1 to GM2 Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.23 Edited: Jassal, B, 2011-09-21 Gangliosides are glycosphingolipids in which oligosaccharide chains containing N-acetylneuraminic acid (NeuNAc) are attached to a ceramide. The prototypical ganglioside GM1 can be hydrolysed to the GM2 ganglioside by beta-galactosidase (GLB1), cleaving off the terminal galactose (Asp et al. 1969). Defects in GLB1 causes the lysosomal storage diseases GM1-gangliosidosis (Yoshida et al. 1991) and Morquio syndrome B (Oshima et al. 1991). Pubmed1907800 Pubmed1928092 Pubmed5822067 Reactome Database ID Release 431605624 Reactome, http://www.reactome.org ReactomeREACT_115930 Reviewed: Stephan, R, 2011-10-31 Nonameric complex Reactome DB_ID: 2130379 Reactome Database ID Release 432130379 Reactome, http://www.reactome.org ReactomeREACT_124657 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Invariant chain trimer Reactome DB_ID: 2130697 Reactome Database ID Release 432130697 Reactome, http://www.reactome.org ReactomeREACT_121536 has a Stoichiometric coefficient of 3 Nonameric complex Reactome DB_ID: 2130477 Reactome Database ID Release 432130477 Reactome, http://www.reactome.org ReactomeREACT_122768 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Nonameric complex in COPII vesicle Reactome DB_ID: 2213211 Reactome Database ID Release 432213211 Reactome, http://www.reactome.org ReactomeREACT_123192 has a Stoichiometric coefficient of 1 Alpha-galactosidase A removes a terminal galactose from alpha-D-galactoside oligomers Alpha-galactosidase A (GLA) (Bishop et al. 1986) removes the terminal galactose residue from glycolipids or glycoproteins resulting in galactose and an alcohol. An example is the Fabry disease substrate globotriaosylceramide (Gb3Cer) which is hydrolysed to form galactose and lactosylceramide. GLA functions as a homodimer (Garman & Garboczi 2004) and defects in this enzyme lead to Fabry disease (FD) (MIM:301500), a rare X-linked sphingolipidosis disease where glycolipids such as GB3 accumulate in many tissues (Garman & Garboczi 2004, Eng et al. 1993). Multiple mutations in GLA can cause the disease symptoms of Fabry disease (Shabeer et al. 2006). Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.22 Edited: Jassal, B, 2011-09-21 Pubmed15003450 Pubmed16595074 Pubmed3014515 Pubmed7504405 Reactome Database ID Release 431605736 Reactome, http://www.reactome.org ReactomeREACT_115752 Reviewed: Stephan, R, 2011-10-31 (Gi alpha1:GDP:Adenylate cyclase):(G alpha-olf:GDP) Reactome DB_ID: 170656 Reactome Database ID Release 43170656 Reactome, http://www.reactome.org ReactomeREACT_15896 has a Stoichiometric coefficient of 1 Invariant chain trimer Reactome DB_ID: 2214377 Reactome Database ID Release 432214377 Reactome, http://www.reactome.org ReactomeREACT_124877 has a Stoichiometric coefficient of 3 SUMF1 mediates the oxidation of cysteine to formylglycine, producing active arylsulfatases Authored: Jassal, B, 2011-09-28 EC Number: 1 Edited: Jassal, B, 2011-09-28 Pubmed12757705 Pubmed12757706 Pubmed14563551 Pubmed15657036 Pubmed16368756 Pubmed8681943 Pubmed9699462 Reactome Database ID Release 431614362 Reactome, http://www.reactome.org ReactomeREACT_121125 Reviewed: D'Eustachio, P, 2012-05-14 The sulfatase-modifying factor 1 (SUMF1, also called C-alpha-formylglycine-generating enzyme, FGE) (Preusser-Kunze et al. 2005, Cosma et al. 2003, Landgrebe et al. 2003) oxidises the critical cysteine residue in arylsulfatases to an active site 3-oxoalanine residue thus confering sulfatase activity (Roeser et al. 2006). Defects in SUMF1 cause multiple sulfatase deficiency (MSD) (MIM:272200), an impairment of arylsulfatase activity due to defective post-translational modification of the cysteine residue (Cosma et al. 2003, Dierks et al, 2003). This post-translational modification is thought to be highly conserved in eukaryotes (Selmer et al. 1996, von Figura et al. 1998). SUMF1 is active as either a monomer or a homodimer. A monomer is described in this reaction. GABA B receptor G-protein beta-gamma and Kir3 channel complex Reactome DB_ID: 1013011 Reactome Database ID Release 431013011 Reactome, http://www.reactome.org ReactomeREACT_26489 has a Stoichiometric coefficient of 1 MHC II alpha/beta dimer Reactome DB_ID: 2214375 Reactome Database ID Release 432214375 Reactome, http://www.reactome.org ReactomeREACT_124905 has a Stoichiometric coefficient of 1 Beta-galactosidase can also hydrolyse globosides to form cerebrosides Authored: Jassal, B, 2011-09-21 Beta-galactosidase can hydrolyse a galactose moeity from globosides to form cerebrosides. Here, lactosylceramide is hydrolysed to glucosylceramide (Asp et al. 1969). EC Number: 3.2.1.23 Edited: Jassal, B, 2011-09-21 Pubmed5822067 Reactome Database ID Release 431606312 Reactome, http://www.reactome.org ReactomeREACT_115597 Reviewed: Stephan, R, 2011-10-31 (Gi alpha1:GTP:Adenylate cyclase):(G alpha-olf:GDP) Reactome DB_ID: 170659 Reactome Database ID Release 43170659 Reactome, http://www.reactome.org ReactomeREACT_15853 has a Stoichiometric coefficient of 1 MHC II alpha/beta dimer Reactome DB_ID: 2213181 Reactome Database ID Release 432213181 Reactome, http://www.reactome.org ReactomeREACT_123329 has a Stoichiometric coefficient of 1 Rap1 GTPase-activating proteins Converted from EntitySet in Reactome Reactome DB_ID: 392497 Reactome Database ID Release 43392497 Reactome, http://www.reactome.org ReactomeREACT_24585 Both hexosaminidase A and B can cleave GalNAc from globoside Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.52 Edited: Jassal, B, 2011-09-21 Pubmed12662933 Pubmed2965147 Pubmed2971395 Reactome Database ID Release 431605632 Reactome, http://www.reactome.org ReactomeREACT_115753 Reviewed: Stephan, R, 2011-10-31 There are two major forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988, Mahuran et al. 1988). Both are able to cleave GalNAc from globoside (a glycosphingolipid with more than one sugar attached as the side chain). Here, globoside is cleaved to form Gb3Cer (a globotriaosylceramide) (Mark et al. 2003). G alpha-olf:GDP complex Reactome DB_ID: 170669 Reactome Database ID Release 43170669 Reactome, http://www.reactome.org ReactomeREACT_17352 has a Stoichiometric coefficient of 1 Nonameric complex Reactome DB_ID: 2214394 Reactome Database ID Release 432214394 Reactome, http://www.reactome.org ReactomeREACT_122724 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Kir3 heterotetramer Reactome DB_ID: 975303 Reactome Database ID Release 43975303 Reactome, http://www.reactome.org ReactomeREACT_25668 has a Stoichiometric coefficient of 4 Kir4.1:Kir5.1 heterotetramer Reactome DB_ID: 975299 Reactome Database ID Release 43975299 Reactome, http://www.reactome.org ReactomeREACT_26620 has a Stoichiometric coefficient of 2 Active ARSA translocates to the lysosome Activated arylsulfatase A (ARSA) translocates to lysosomes by an unknown mechanism (see review von Figura et al. 1998). Authored: Jassal, B, 2012-05-15 Edited: Jassal, B, 2012-05-15 Pubmed9699462 Reactome Database ID Release 432248891 Reactome, http://www.reactome.org ReactomeREACT_121176 Reviewed: D'Eustachio, P, 2012-05-15 Kir heterotetramers Converted from EntitySet in Reactome Reactome DB_ID: 975294 Reactome Database ID Release 43975294 Reactome, http://www.reactome.org ReactomeREACT_26226 Nonameric complex Reactome DB_ID: 2130491 Reactome Database ID Release 432130491 Reactome, http://www.reactome.org ReactomeREACT_122861 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Kir2.1:Kirx.x heterotetramer Reactome DB_ID: 975359 Reactome Database ID Release 43975359 Reactome, http://www.reactome.org ReactomeREACT_26700 has a Stoichiometric coefficient of 2 Invariant chain trimer Reactome DB_ID: 2130720 Reactome Database ID Release 432130720 Reactome, http://www.reactome.org ReactomeREACT_123410 has a Stoichiometric coefficient of 3 unidentified caspase acting on Occludin Reactome DB_ID: 500677 Reactome Database ID Release 43500677 Reactome, http://www.reactome.org ReactomeREACT_21584 Sphingomyelin phosphodiesterase 2 and 3 (SMPD2 and 3) hydrolyse sphingomyelin to ceramide (plasma membrane) Authored: Jassal, B, 2011-09-21 EC Number: 3.1.4.12 Edited: Jassal, B, 2011-09-21 Pubmed10823942 Pubmed12566438 Pubmed9520418 Reactome Database ID Release 431606273 Reactome, http://www.reactome.org ReactomeREACT_115857 Reviewed: Stephan, R, 2011-10-31 The mammalian brain-specific, Mg2+-dependent, neutral sphingomyelin phosphodiesterases 2 (Tomiuk et al. 1998, Hofmann et al. 2000) and 3 (Marchesini et al. 2003) (SMPD2 and 3) hydrolyse sphingomyelin (SPHM) to ceramide (CERA) at the plasma membrane. unidentified caspase Reactome DB_ID: 351835 Reactome Database ID Release 43351835 Reactome, http://www.reactome.org ReactomeREACT_14138 Sphingomyelin phosphodiesterase (SMPD1) hydrolyses sphingomyelin to ceramide (lysosome) Authored: Jassal, B, 2011-09-21 EC Number: 3.1.4.12 Edited: Jassal, B, 2011-09-21 Pubmed1718266 Pubmed1740330 Pubmed1840600 Pubmed19405096 Reactome Database ID Release 431605797 Reactome, http://www.reactome.org ReactomeREACT_116148 Reviewed: Stephan, R, 2011-10-31 Sphingomyelin phosphodiesterase (SMPD1), also called acid sphingomyelinase (ASM), is a lysosomal phosphodiesterase that hydrolyses sphingomyelin to ceramide and phosphocholine (Schuchman et al. 1991, Schuchman et al. 1992). Defects in SMPD1 are the cause of two types of Niemann-Pick disease. Type A (NPDA, Niemann-Pick disease classical infantile form) (MIM:257200) (Ferlinz et al. 1991) and type B (NPDB, Niemann-Pick disease visceral form) (MIM:607616) (Rodriguez-Pascau et al. 2009). DFF40 homodimer/homooligomer Converted from EntitySet in Reactome Reactome DB_ID: 353623 Reactome Database ID Release 43353623 Reactome, http://www.reactome.org ReactomeREACT_14397 Glucosylceramidase cleaves the glucosidic bond of glucocerebroside to form ceramide Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.45 Edited: Jassal, B, 2011-09-21 Human glucosylceramidase (GBA) hydrolyses the glucosidic bond of glucocerebrosides to form ceramide (Dinur et al. 1986). GBA requires a low weight, non-enzymatic protein (one of the sphingolipids activator proteins) called Saposin-C (SAP-C) which acts with GBA to form an activated complex (Salvioli et al. 2000). Defects in GBA are the cause of Gaucher disease (GD) (MIM:230800), the most common glycolipid storage disorder, characterized by storage of glucocerebroside in the liver, spleen, and marrow (Beutler & Gelbart 1996). Pubmed10781797 Pubmed3456607 Pubmed8889578 Reactome Database ID Release 431605591 Reactome, http://www.reactome.org ReactomeREACT_115656 Reviewed: Stephan, R, 2011-10-31 DFF40 homooligomer Reactome DB_ID: 350274 Reactome Database ID Release 43350274 Reactome, http://www.reactome.org ReactomeREACT_14056 Sphingomyelin phosphodiesterase 4 (SMPD4) hydrolyses sphingomyelin to ceramide (ER membrane) Authored: Jassal, B, 2011-09-21 EC Number: 3.1.4.12 ER membrane-bound sphingomyelin phosphodiesterase 4 (SMPD4) hydrolyses sphingomyelin to ceramide (Krut et al. 2006). Edited: Jassal, B, 2011-09-21 Pubmed16517606 Reactome Database ID Release 431606288 Reactome, http://www.reactome.org ReactomeREACT_116064 Reviewed: Stephan, R, 2011-10-31 Galactocerebrosidase cleaves the galactosyl bond of galactocerebroside to form ceramide Authored: Jassal, B, 2011-09-23 EC Number: 3.2.1.46 Edited: Jassal, B, 2011-09-23 Galactocerebrosidase (GALC) hydrolyses the galactosyl moiety from galactocerebroside (also called galactosylceramide, GalCer) to form ceramide (Sakai et al. 1994). Defects in GALC are the cause of leukodystrophy globoid cell (GLD) (MIM:245200), also called Krabbe disease (Wenger et al. 1997). Pubmed7852280 Pubmed9338580 Reactome Database ID Release 431606564 Reactome, http://www.reactome.org ReactomeREACT_115737 Reviewed: Stephan, R, 2011-10-31 Arylsulfatase A hydrolyses sulfate from sulfatide to form cerebroside Arylsulfatase A (ARSA) (Stein et al. 1989) hydrolyses a sulfatide (a cerebroside 3-sulfate) to form a cerebroside and sulfate. ARSA is present in the lysosomal lumen and comprises two chains, component B and C linked by disulphide bonds (Fujii et al. 1992). The conversion to 3-oxoalanine (formylglycine, FGly) of a cysteine residue is critical for catalytic activity in all eukaryotes (Chruszcz et al. 2003, Lukatela et al. 1998).<br>Defects in ARSA are a cause of leukodystrophy metachromatic (MLD) (MIM:250100), characterized by lysosomal storage of cerebroside-3-sulfate in neural and non-neural tissues (Gieselmann et al. 1991, Polten et al. 1991). Arylsulfatase A activity is reduced in multiple sulfatase deficiency (MSD) (MIM:272200), a disorder characterized by decreased activity of sulfatases. The defect is due to the lack of post-translational modification of the critical cysteine needed for activity (Schmidt et al. 1995). Authored: Jassal, B, 2011-09-27 EC Number: 3.1.6.8 Edited: Jassal, B, 2011-09-27 Pubmed12888274 Pubmed1352993 Pubmed1670590 Pubmed1678251 Pubmed2562955 Pubmed7628016 Pubmed9521684 Reactome Database ID Release 431606807 Reactome, http://www.reactome.org ReactomeREACT_115556 Reviewed: Stephan, R, 2011-10-31 14-3-3 proteins Reactome DB_ID: 75004 Reactome Database ID Release 4375004 Reactome, http://www.reactome.org ReactomeREACT_2548 Persistent single-stranded DNA Reactome DB_ID: 176104 Reactome Database ID Release 43176104 Reactome, http://www.reactome.org ReactomeREACT_7801 DFF cleaved DNA fragments Reactome DB_ID: 211242 Reactome Database ID Release 43211242 Reactome, http://www.reactome.org ReactomeREACT_14049 Ubiquitin ligase Reactome DB_ID: 69593 Reactome Database ID Release 4369593 Reactome, http://www.reactome.org ReactomeREACT_4282 polyubiquitin chain Reactome DB_ID: 211771 Reactome Database ID Release 43211771 Reactome, http://www.reactome.org ReactomeREACT_13970 Chk1/Ckk2(Cds1) Reactome DB_ID: 75807 Reactome Database ID Release 4375807 Reactome, http://www.reactome.org ReactomeREACT_5826 AP-1 Clathrin coated nonameric complex Reactome DB_ID: 2130552 Reactome Database ID Release 432130552 Reactome, http://www.reactome.org ReactomeREACT_123325 has a Stoichiometric coefficient of 1 TREK homodimers Reactome DB_ID: 1299260 Reactome Database ID Release 431299260 Reactome, http://www.reactome.org ReactomeREACT_76233 has a Stoichiometric coefficient of 2 Clathrin Reactome DB_ID: 2130469 Reactome Database ID Release 432130469 Reactome, http://www.reactome.org ReactomeREACT_121943 has a Stoichiometric coefficient of 3 TASK Converted from EntitySet in Reactome Reactome DB_ID: 1299270 Reactome Database ID Release 431299270 Reactome, http://www.reactome.org ReactomeREACT_76290 AP-1 Complex Reactome DB_ID: 2130687 Reactome Database ID Release 432130687 Reactome, http://www.reactome.org ReactomeREACT_124440 has a Stoichiometric coefficient of 1 TASK 1 homomer Reactome DB_ID: 1299268 Reactome Database ID Release 431299268 Reactome, http://www.reactome.org ReactomeREACT_76680 has a Stoichiometric coefficient of 2 TGN-lysosome vesicle with nonameric complex Reactome DB_ID: 2213234 Reactome Database ID Release 432213234 Reactome, http://www.reactome.org ReactomeREACT_125234 has a Stoichiometric coefficient of 1 MHC II alpha/beta dimer Reactome DB_ID: 2213184 Reactome Database ID Release 432213184 Reactome, http://www.reactome.org ReactomeREACT_121486 has a Stoichiometric coefficient of 1 TRESK homodimer Reactome DB_ID: 1299256 Reactome Database ID Release 431299256 Reactome, http://www.reactome.org ReactomeREACT_76459 has a Stoichiometric coefficient of 2 Invariant chain trimer Reactome DB_ID: 2130656 Reactome Database ID Release 432130656 Reactome, http://www.reactome.org ReactomeREACT_122688 has a Stoichiometric coefficient of 3 THIK1 homodimers Reactome DB_ID: 1299264 Reactome Database ID Release 431299264 Reactome, http://www.reactome.org ReactomeREACT_76759 has a Stoichiometric coefficient of 2 BoNT Activated BoNT Reactome DB_ID: 181486 Reactome Database ID Release 43181486 Reactome, http://www.reactome.org ReactomeREACT_11835 has a Stoichiometric coefficient of 1 Glucosylceramidase 2 cleaves the glucosidic bond of glucocerebroside to form ceramide (plasma membrane) Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.45 Edited: Jassal, B, 2011-09-21 Human glucosylceramidase 2 (GBA2) hydrolyses the glucosidic bond of glucocerebrosides to form ceramide at the plasma membrane (Matern et al. 2001, Boot et al. 2007). Pubmed11489889 Pubmed17105727 Reactome Database ID Release 431861788 Reactome, http://www.reactome.org ReactomeREACT_115724 Reviewed: Stephan, R, 2011-10-31 TASK1/3 heterodimer Reactome DB_ID: 1299266 Reactome Database ID Release 431299266 Reactome, http://www.reactome.org ReactomeREACT_76906 has a Stoichiometric coefficient of 1 Nonameric complex Reactome DB_ID: 2130532 Reactome Database ID Release 432130532 Reactome, http://www.reactome.org ReactomeREACT_123017 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Glucosylceramidase 3 cleaves the glucosidic bond of glucocerebroside to form ceramide (cytosol) Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.45 Edited: Jassal, B, 2011-09-21 Human glucosylceramidase 3 (GBA3) hydrolyses the glucosidic bond of glucocerebrosides to form ceramide in the cytosol. GBA3 may be involved in the intestinal absorption and metabolism of dietary flavonoid glycosides (Berrin et al. 2002, Nemeth et al. 2003). Pubmed11784319 Pubmed12594539 Reactome Database ID Release 431861789 Reactome, http://www.reactome.org ReactomeREACT_115663 Reviewed: Stephan, R, 2011-10-31 TALK 1and 2 Converted from EntitySet in Reactome Reactome DB_ID: 1299271 Reactome Database ID Release 431299271 Reactome, http://www.reactome.org ReactomeREACT_76406 MHC II alpha/beta dimer Reactome DB_ID: 2213179 Reactome Database ID Release 432213179 Reactome, http://www.reactome.org ReactomeREACT_125607 has a Stoichiometric coefficient of 1 Acid ceramidase hydrolyses ceramide into sphingosine and free fatty acid (lysosome) Acid ceramidase (ASAH1) is a lysosomal enzyme that catalyses the hydrolysis of ceramide to sphingosine and free fatty acid. It functions as a heterodimer of one alpha and one beta subunit (Bernardo et al. 1995). Defects in ASAH1 are the cause of Farber lipogranulomatosis (FL) (MIM:228000), also called Farber disease (FD) (Zhang et al. 2000, Koch et al. 1996). Authored: Jassal, B, 2011-09-23 EC Number: 3.5.1.23 Edited: Jassal, B, 2011-09-23 Pubmed10993717 Pubmed7744740 Pubmed8955159 Reactome Database ID Release 431606602 Reactome, http://www.reactome.org ReactomeREACT_115911 Reviewed: Stephan, R, 2011-10-31 TALK1 homomer Reactome DB_ID: 1299275 Reactome Database ID Release 431299275 Reactome, http://www.reactome.org ReactomeREACT_76683 has a Stoichiometric coefficient of 2 Invariant chain trimer Reactome DB_ID: 2130584 Reactome Database ID Release 432130584 Reactome, http://www.reactome.org ReactomeREACT_122487 has a Stoichiometric coefficient of 3 Ectonucleotide pyrophosphatase/phosphodiesterase 7 (ENPP7) hydrolyses sphingomyelin Authored: Jassal, B, 2011-10-10 EC Number: 3.1.4.12 Edited: Jassal, B, 2011-10-10 Membrane-bound ectonucleotide pyrophosphatase/phosphodiesterase 7 (ENPP7) mediates the hydrolysis of sphingomyelin to ceramide and choline phosphate (Duan et al. 2003, Wu et al. 2005). Pubmed12885774 Pubmed15458386 Reactome Database ID Release 431640164 Reactome, http://www.reactome.org ReactomeREACT_115560 Reviewed: Stephan, R, 2011-10-31 TALK 2 homomer Reactome DB_ID: 1299272 Reactome Database ID Release 431299272 Reactome, http://www.reactome.org ReactomeREACT_76899 has a Stoichiometric coefficient of 2 MHC class II alpha/beta/Ii nonamer Reactome DB_ID: 2130431 Reactome Database ID Release 432130431 Reactome, http://www.reactome.org ReactomeREACT_122095 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 RNA primer:origin duplex with DNA damage Reactome DB_ID: 113499 Reactome Database ID Release 43113499 Reactome, http://www.reactome.org ReactomeREACT_3748 Galactosylceramide sulfotransferase (GAL3ST1) mediates the sulfation of membrane glycolipids Authored: Jassal, B, 2011-10-07 EC Number: 2.8.2.11 Edited: Jassal, B, 2011-10-07 Galactosylceramide sulfotransferase (GAL3ST1) (Honke et al. 1997) catalyses the transfer of sulfate from the sulfate donor PAPS to glycosphingolipids. A good substrate for this enzyme is galactosylceramide (GalCer) (Honke et al. 1996). Pubmed8830034 Pubmed9030544 Reactome Database ID Release 431638098 Reactome, http://www.reactome.org ReactomeREACT_115577 Reviewed: Stephan, R, 2011-10-31 glycogen synthase kinase-3 beta Reactome DB_ID: 75818 Reactome Database ID Release 4375818 Reactome, http://www.reactome.org ReactomeREACT_3846 Ceramide kinase (CERK) mediates the phosphorylation of ceramide Authored: Jassal, B, 2011-10-10 Ceramide kinase (CERK) mediates the phosphorylation of ceramide (CERA) to the lipid second messenger, ceramide 1-phosphate (C1P) (Sugiura et al. 2002). EC Number: 2.7.1.138 Edited: Jassal, B, 2011-10-10 Pubmed11956206 Reactome Database ID Release 431638845 Reactome, http://www.reactome.org ReactomeREACT_116045 Reviewed: Stephan, R, 2011-10-31 Cyclin E/A Converted from EntitySet in Reactome Reactome DB_ID: 187495 Reactome Database ID Release 43187495 Reactome, http://www.reactome.org ReactomeREACT_9300 Ceramide glucosyltransferase (UGCG) catalyses the transfer of glucose to ceramide Authored: Jassal, B, 2011-10-07 Ceramide glucosyltransferase (UGCG) catalyses the first glycosylation step in glycosphingolipid biosynthesis by the transfer of glucose to ceramide (Ichikawa et al. 1996). EC Number: 2.4.1.80 Edited: Jassal, B, 2011-10-07 Pubmed8643456 Reactome Database ID Release 431638104 Reactome, http://www.reactome.org ReactomeREACT_115635 Reviewed: Stephan, R, 2011-10-31 Lymphoid-expressed Fc-gamma receptors Converted from EntitySet in Reactome Reactome DB_ID: 200284 Reactome Database ID Release 43200284 Reactome, http://www.reactome.org ReactomeREACT_11814 PPP2R3B/PPP2R2A Converted from EntitySet in Reactome PP2A regulatory subunit B alpha/B" beta Reactome DB_ID: 1363263 Reactome Database ID Release 431363263 Reactome, http://www.reactome.org ReactomeREACT_111891 Steryl sulfatase hydrolyses sulfate from steroid sulfates Authored: Jassal, B, 2011-09-27 EC Number: 3.1.6.2 Edited: Jassal, B, 2011-09-27 Pubmed1539590 Pubmed1606923 Pubmed2668275 Pubmed2953589 Pubmed6417417 Pubmed9252398 Reactome Database ID Release 431606839 Reactome, http://www.reactome.org ReactomeREACT_115686 Reviewed: Stephan, R, 2011-10-31 Steryl sulfatase (formerly arylsulfatase C, ARSC) hydrolyses sulfate from steroid sulfates (Noel et al. 1983, Vaccaro et al. 1987, Suzuki et al. 1992). It is located on the ER membrane (Stein et al. 1989) and functions as a homodimer, using calcium as a cofactor. Defects in STS are the cause of ichthyosis X-linked (IXL) (MIM:308100), a keratinisation disorder (Basler et al. 1992, Alperin & Shapiro 1997). Neutral ceramidase hydrolyses ceramide into sphingosine and free fatty acid (plasma membrane) Authored: Jassal, B, 2011-09-23 EC Number: 3.5.1.23 Edited: Jassal, B, 2011-09-23 Neutral ceramidase (ASAH2) is an enzyme localised to the plasma membrane that catalyses the hydrolysis of ceramide to sphingosine and free fatty acid (Hwang et al. 2005, Galadari et al. 2006). Pubmed15845354 Pubmed16229686 Reactome Database ID Release 431606583 Reactome, http://www.reactome.org ReactomeREACT_115894 Reviewed: Stephan, R, 2011-10-31 Kinetochore Complex Reactome DB_ID: 141398 Reactome Database ID Release 43141398 Reactome, http://www.reactome.org ReactomeREACT_5901 Neu5Ac is cleaved from GM3 by NEU3 to form globoside (plasma membrane) Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.18 Edited: Jassal, B, 2011-09-21 Pubmed10861246 Reactome Database ID Release 431605768 Reactome, http://www.reactome.org ReactomeREACT_115699 Reviewed: Stephan, R, 2011-10-31 Sialidase-3 (NEU3) cleaves Neu5Ac from GM3 in the plasma membrane. NEU3 is thought to play a role in modulating the ganglioside content of the lipid bilayer (Monti et al. 2000). Neu5Ac is cleaved from GM3 by NEU2 to form a globoside (cytosol) Authored: Jassal, B, 2011-09-21 EC Number: 3.2.1.18 Edited: Jassal, B, 2011-09-21 Pubmed10191093 Reactome Database ID Release 431605723 Reactome, http://www.reactome.org ReactomeREACT_115906 Reviewed: Stephan, R, 2011-10-31 Sialidase-2 (NEU2) hydrolyses Neu5Ac from GM3 in the cytosol (Monti et al. 1999). Potassium transport channels (Kir 1.1 and Kir 4.1/5.1) Converted from EntitySet in Reactome Reactome DB_ID: 1299206 Reactome Database ID Release 431299206 Reactome, http://www.reactome.org ReactomeREACT_76764 G2/M transition proteins Reactome DB_ID: 617374 Reactome Database ID Release 43617374 Reactome, http://www.reactome.org ReactomeREACT_22572 G2/M transition proteins Reactome DB_ID: 617370 Reactome Database ID Release 43617370 Reactome, http://www.reactome.org ReactomeREACT_23060 Cyclin A1:Cdk2 phosphorylated G2/M transition protein Reactome DB_ID: 617372 Reactome Database ID Release 43617372 Reactome, http://www.reactome.org ReactomeREACT_23084 Sister Chromosomal Arm Reactome DB_ID: 1638790 Reactome Database ID Release 431638790 Reactome, http://www.reactome.org ReactomeREACT_150847 Sister Centromere Reactome DB_ID: 1638792 Reactome Database ID Release 431638792 Reactome, http://www.reactome.org ReactomeREACT_151483 KIR 1.1 homotetramer Reactome DB_ID: 1299205 Reactome Database ID Release 431299205 Reactome, http://www.reactome.org ReactomeREACT_76458 has a Stoichiometric coefficient of 4 Clathrin-coated vesicle Reactome DB_ID: 2130671 Reactome Database ID Release 432130671 Reactome, http://www.reactome.org ReactomeREACT_125198 has a Stoichiometric coefficient of 1 Kir 4.1/5.1 heterotetramer Reactome DB_ID: 1299207 Reactome Database ID Release 431299207 Reactome, http://www.reactome.org ReactomeREACT_76752 has a Stoichiometric coefficient of 2 Adaptor protein 2 complex Reactome DB_ID: 2130637 Reactome Database ID Release 432130637 Reactome, http://www.reactome.org ReactomeREACT_125487 has a Stoichiometric coefficient of 1 Clathrin coated MHC class II alpha/beta/Ii nonamer Reactome DB_ID: 2130309 Reactome Database ID Release 432130309 Reactome, http://www.reactome.org ReactomeREACT_123856 has a Stoichiometric coefficient of 1 Clathrin coated MHC class II alpha/beta/Ii nonamer Reactome DB_ID: 2130331 Reactome Database ID Release 432130331 Reactome, http://www.reactome.org ReactomeREACT_121490 has a Stoichiometric coefficient of 1 MHC class II alpha/beta/Ii nonamer Reactome DB_ID: 2130467 Reactome Database ID Release 432130467 Reactome, http://www.reactome.org ReactomeREACT_123439 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Invariant chain trimer Reactome DB_ID: 2130505 Reactome Database ID Release 432130505 Reactome, http://www.reactome.org ReactomeREACT_123751 has a Stoichiometric coefficient of 3 TWIK1 dimers Reactome DB_ID: 1299252 Reactome Database ID Release 431299252 Reactome, http://www.reactome.org ReactomeREACT_76783 has a Stoichiometric coefficient of 2 TWIK2 dimers Reactome DB_ID: 1299250 Reactome Database ID Release 431299250 Reactome, http://www.reactome.org ReactomeREACT_76488 has a Stoichiometric coefficient of 2 TWIK channels Converted from EntitySet in Reactome Reactome DB_ID: 1299255 Reactome Database ID Release 431299255 Reactome, http://www.reactome.org ReactomeREACT_76670 KCNK7 homodimers Reactome DB_ID: 1299253 Reactome Database ID Release 431299253 Reactome, http://www.reactome.org ReactomeREACT_76388 has a Stoichiometric coefficient of 2 Dissociation of Gi/o Heterotrimeric G-protein Complex Authored: May, B, 2009-05-27 03:41:50 Edited: May, B, 2009-05-27 03:41:50 Exchange of GDP for GTP by the alpha subunit of the heterotrimeric G-protein complex causes the complex to dissociate into the G alpha:GTP complex and the beta-gamma complex. Both complexes have effector functions. Pubmed14514350 Pubmed16373322 Pubmed17095603 Pubmed17900700 Pubmed18162464 Pubmed19258039 Pubmed7641683 Pubmed8997178 Reactome Database ID Release 43400037 Reactome, http://www.reactome.org ReactomeREACT_18349 Reviewed: D'Eustachio, P, 2009-06-02 00:48:17 kir2x heteroteramer Reactome DB_ID: 1299200 Reactome Database ID Release 431299200 Reactome, http://www.reactome.org ReactomeREACT_76901 has a Stoichiometric coefficient of 4 Invariant chain trimer Reactome DB_ID: 2130372 Reactome Database ID Release 432130372 Reactome, http://www.reactome.org ReactomeREACT_124799 has a Stoichiometric coefficient of 3 Octamer of Voltage gated K+ channels Reactome DB_ID: 1297370 Reactome Database ID Release 431297370 Reactome, http://www.reactome.org ReactomeREACT_76615 has a Stoichiometric coefficient of 4 MHC class II alpha/beta dimer Reactome DB_ID: 2213178 Reactome Database ID Release 432213178 Reactome, http://www.reactome.org ReactomeREACT_122410 has a Stoichiometric coefficient of 1 Binding of Adrenaline or Noradrenaline by Alpha-2A/2C Adrenergic Receptors Authored: May, B, 2009-05-27 03:41:50 Edited: May, B, 2009-05-27 03:41:38 Pubmed14514350 Pubmed17900700 Pubmed18162464 Pubmed7641683 Pubmed8277227 Pubmed8778232 Pubmed8997178 Pubmed9760042 Reactome Database ID Release 43400071 Reactome, http://www.reactome.org ReactomeREACT_18370 Reviewed: D'Eustachio, P, 2009-06-02 00:48:17 The pancreatic beta cell contains Alpha2A and Alpha2C Adrenergic Receptors. These are G-protein coupled receptors that can bind either adrenaline or noradrenaline. ATP sensitive K+ channels-inwardly rectifying (SUR1) Reactome DB_ID: 1297378 Reactome Database ID Release 431297378 Reactome, http://www.reactome.org ReactomeREACT_76659 has a Stoichiometric coefficient of 4 Clathrin Reactome DB_ID: 2130407 Reactome Database ID Release 432130407 Reactome, http://www.reactome.org ReactomeREACT_122140 has a Stoichiometric coefficient of 3 Activation of Gi/o Heterotrimeric G Proteins by Alpha Adrenergic Receptors Alpha-2A/2C Authored: May, B, 2009-05-27 03:41:50 Edited: May, B, 2009-05-27 03:41:18 In the pancreatic beta cell, alpha2 adrenergic receptors are coupled to Gi and Go heterotrimeric G-proteins. Binding of adrenaline or noradrenaline by the alpha2 adrenergic receptor acts through protein-protein interaction to stimulate the Gi alpha subunit or Go alpha subunit in heterotrimeric G-protein complexes to exchange GDP for GTP. The particular G alpha subunits have been identified in mice as Gi alpha1, Gi alpha 2, and Go alpha2. Pubmed14514350 Pubmed16352729 Pubmed16371464 Pubmed1645720 Pubmed17900700 Pubmed18162464 Pubmed1849000 Pubmed7641683 Pubmed8099279 Pubmed8662784 Pubmed8997178 Pubmed9760042 Reactome Database ID Release 43400092 Reactome, http://www.reactome.org ReactomeREACT_18311 Reviewed: D'Eustachio, P, 2009-06-02 00:48:17 ATP sensitive K+ channels-inwardly rectifying (SUR2) Reactome DB_ID: 1369001 Reactome Database ID Release 431369001 Reactome, http://www.reactome.org ReactomeREACT_111451 has a Stoichiometric coefficient of 4 MHC class II alpha/beta/Ii nonamer Reactome DB_ID: 2130425 Reactome Database ID Release 432130425 Reactome, http://www.reactome.org ReactomeREACT_122041 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Closing (Inhibition) of L-type Calcium Channels in Pancreatic Beta Cells Authored: May, B, 2009-05-27 03:41:50 Closing (inhibition) of the L-type calcium channels in the plasma membrane prevents the flow of calcium ions across the membrane. Edited: May, B, 2009-05-27 03:41:50 Pubmed14514350 Pubmed17900700 Pubmed7641683 Pubmed8997178 Reactome Database ID Release 43400046 Reactome, http://www.reactome.org ReactomeREACT_18280 Reviewed: D'Eustachio, P, 2009-06-02 00:48:17 Opening of Potassium Channels in Pancreatic Beta Cells in Response to Epinephrine ATP-sensitive Potassium channels open and allow an inward rectifying current of potassium ions to flow, reestablishing the resting potential of the cell. Authored: May, B, 2009-05-27 03:41:50 Edited: May, B, 2009-05-27 03:41:50 Pubmed14514350 Pubmed17900700 Pubmed7641683 Pubmed8997178 Reactome Database ID Release 43400063 Reactome, http://www.reactome.org ReactomeREACT_18430 Reviewed: D'Eustachio, P, 2009-06-02 00:48:17 Inhibition of Adenylate Cyclase by G-beta:G-gamma Adenylyl cyclases V and VI are the particular adenylyl cyclases present in beta cells of the human pancreas. The G-protein beta-gamma complex interacts with adenylyl cyclases via protein-protein interactions with the C1 and C2 cytoplasmic loops of adenylyl cyclase. The interaction may produce either stimulation or inhibition of the adenylyl cyclase depending on the particular adenylyl cyclase. In the case of adenylyl cyclases V and VI the interaction inhibits cyclase activity. Authored: May, B, 2009-05-27 03:41:50 Edited: May, B, 2009-05-27 03:41:50 Pubmed10449730 Pubmed14514350 Pubmed17900700 Pubmed7641683 Pubmed8099279 Pubmed8997178 Pubmed9707174 Pubmed9920805 Reactome Database ID Release 43400097 Reactome, http://www.reactome.org ReactomeREACT_18261 Reviewed: D'Eustachio, P, 2009-06-02 00:48:17 Binding of Acetylcholine by Muscarinic Acetylcholine Receptor M3 Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 Intrapancreatic parasympathetic (vagal) nerve endings release acetylcholine during preabsorptive and absorptive phases of feeding. The acetylcholine binds Muscarinic Acetylcholine Receptor M3 on pancreatic islet beta cells (inferred from experiments with knockout mice). Pubmed11588141 Pubmed16753580 Pubmed17900700 Pubmed17919190 Reactome Database ID Release 43400012 Reactome, http://www.reactome.org ReactomeREACT_18428 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 Orai1 dimer Reactome DB_ID: 434696 Reactome Database ID Release 43434696 Reactome, http://www.reactome.org ReactomeREACT_24301 has a Stoichiometric coefficient of 2 Activation of Gq by Muscarinic Acetylcholine Receptor M3 Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 Pubmed11588141 Pubmed12194018 Pubmed16753580 Pubmed16871065 Pubmed17900700 Pubmed17919190 Pubmed18383439 Pubmed8190105 Reactome Database ID Release 43399995 Reactome, http://www.reactome.org ReactomeREACT_18309 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 The binding of acetylcholine to the Muscarinic Acetylcholine Receptor M3 activates the heterotrimeric G protein, Gq, associated with the M3 receptor. Activation occurs through protein-protein interaction and results in the alpha subunit of Gq exchanging GDP for GTP (i.e releasing GDP and binding GTP). The 3 subunits of the G protein then dissociate into an alpha:GTP complex and a beta:gamma complex. Dissociation of Gq alpha:GTP Complex from G beta:G gamma Complex Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 In the non-activated state heterotrimeric G proteins exist at membranes as heterotrimeric complexes of alpha, beta, and gamma subunits, with the alpha subunit bound to GDP. Upon activation by a receptor coupled to the heterotrimer, exchange of GDP for GTP by the Gq alpha subunit causes the alpha subunit to lose affinity for the beta and gamma subunits. The alpha subunit with bound GTP then dissociates from the beta and gamma subunits. Pubmed15448129 Pubmed16242307 Pubmed16339447 Pubmed17095603 Pubmed17962409 Pubmed19212142 Reactome Database ID Release 43400027 Reactome, http://www.reactome.org ReactomeREACT_18316 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 IRAK1/ IRAK2 Converted from EntitySet in Reactome Reactome DB_ID: 937026 Reactome Database ID Release 43937026 Reactome, http://www.reactome.org ReactomeREACT_26527 Activation of Phospholipase C Beta by Gq alpha Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 Pubmed11588141 Pubmed17900700 Pubmed1846707 Reactome Database ID Release 43400023 Reactome, http://www.reactome.org ReactomeREACT_18418 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 The Gq alpha:GTP complex activates Phospholipase C beta-1 through protein interaction (inferred from homologues in Bos taurus). The activation by Gq alpha is insensitive to pertussis toxin whilst activation of PLC beta by the G beta-gamma complex is sensitive to pertussis toxin. Hydrolysis of 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate by Activated Phospholipase C Beta-1 Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 Phospholipase C beta-1 associated with the G(q) complex in the plasma membrane catalyzes the hydrolysis of 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate to yield D-myo-Inositol 1,4,5-trisphosphate and 1,2-Diacylglycerol. Pubmed11588141 Pubmed2841328 Reactome Database ID Release 43399998 Reactome, http://www.reactome.org ReactomeREACT_18383 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 Phosphorylation of MARCKS by Protein kinase C, alpha type Authored: May, B, 2009-05-28 03:44:04 EC Number: 2.7.11 Edited: May, B, 2009-05-28 03:44:04 One of the known targets of PKC-alpha is the Myristoylated Alanine-rich C Kinase Substrate (MARCKS). MARCKS is phosphorylated at 4 serine residues and is believed to affect trafficking of insulin granules, increasing insulin secretion. Pubmed11588141 Pubmed1527003 Pubmed17081983 Pubmed7989336 Pubmed8132675 Pubmed9808756 Reactome Database ID Release 43399978 Reactome, http://www.reactome.org ReactomeREACT_18263 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 has a Stoichiometric coefficient of 4 BK channel Reactome DB_ID: 418473 Reactome Database ID Release 43418473 Reactome, http://www.reactome.org ReactomeREACT_24118 has a Stoichiometric coefficient of 4 Activation of Protein kinase C, alpha type by Diacylglycerol Authored: May, B, 2009-05-28 03:44:04 Diacylglycerol, produced by PLC beta-mediated PIP2 hydrolysis in G alpha (q) signalling, remains in the plasma membrane and binds Protein Kinase C alpha (PKC-alpha), causing PKC-alpha to translocate from the cytosol to the plasma membrane. PKC-alpha is thereby activated and phosphorylates target proteins. Edited: May, B, 2009-05-28 03:44:04 Pubmed11588141 Reactome Database ID Release 43400015 Reactome, http://www.reactome.org ReactomeREACT_18303 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 BK channel, phophorylated Reactome DB_ID: 418495 Reactome Database ID Release 43418495 Reactome, http://www.reactome.org ReactomeREACT_24816 has a Stoichiometric coefficient of 4 IRAK1, IRAK2 Converted from EntitySet in Reactome Reactome DB_ID: 937023 Reactome Database ID Release 43937023 Reactome, http://www.reactome.org ReactomeREACT_26678 IRAG:IP3 receptor type 1 Reactome DB_ID: 418425 Reactome Database ID Release 43418425 Reactome, http://www.reactome.org ReactomeREACT_24389 has a Stoichiometric coefficient of 1 Phosphorylated IRAG:IP3 receptor type 1 Reactome DB_ID: 418432 Reactome Database ID Release 43418432 Reactome, http://www.reactome.org ReactomeREACT_24181 has a Stoichiometric coefficient of 1 IP3 receptor Reactome DB_ID: 418292 Reactome Database ID Release 43418292 Reactome, http://www.reactome.org ReactomeREACT_18961 has a Stoichiometric coefficient of 4 DAG-activated TRPC3/6/7 Reactome DB_ID: 426179 Reactome Database ID Release 43426179 Reactome, http://www.reactome.org ReactomeREACT_24061 has a Stoichiometric coefficient of 1 P2X1 purinoreceptor bound to ATP Reactome DB_ID: 139848 Reactome Database ID Release 43139848 Reactome, http://www.reactome.org ReactomeREACT_3044 has a Stoichiometric coefficient of 1 IP3 receptor bound to IP3 and Ca++ Reactome DB_ID: 139839 Reactome Database ID Release 43139839 Reactome, http://www.reactome.org ReactomeREACT_4346 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PDE6 Phosphodiesterase 6 Reactome DB_ID: 74055 Reactome Database ID Release 4374055 Reactome, http://www.reactome.org ReactomeREACT_24605 cGMP-PDE has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-Pellino-1,2,(3) Converted from EntitySet in Reactome Reactome DB_ID: 450819 Reactome Database ID Release 43450819 Reactome, http://www.reactome.org ReactomeREACT_22733 MHC class I HC:Calnexin/BiP:Erp57 Reactome DB_ID: 983119 Reactome Database ID Release 43983119 Reactome, http://www.reactome.org ReactomeREACT_76380 has a Stoichiometric coefficient of 1 LDL Reactome DB_ID: 171131 Reactome Database ID Release 43171131 Reactome, http://www.reactome.org ReactomeREACT_7774 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1500 has a Stoichiometric coefficient of 170 has a Stoichiometric coefficient of 670 has a Stoichiometric coefficient of 690 low-density lipoprotein complex hp-IRAK1/p-IRAK2 Converted from EntitySet in Reactome Reactome DB_ID: 1017213 Reactome Database ID Release 431017213 Reactome, http://www.reactome.org ReactomeREACT_25614 monoglucosylated MHC class I HC:Calnexin/BiP Reactome DB_ID: 983116 Reactome Database ID Release 43983116 Reactome, http://www.reactome.org ReactomeREACT_76535 has a Stoichiometric coefficient of 1 LDL:LRP8 Reactome DB_ID: 432119 Reactome Database ID Release 43432119 Reactome, http://www.reactome.org ReactomeREACT_24595 has a Stoichiometric coefficient of 1 monoglucosylated MHC class I HC (Glc)1(Man)9(GlcNAc)2-MHC class I heavy chain Reactome DB_ID: 983120 Reactome Database ID Release 43983120 Reactome, http://www.reactome.org ReactomeREACT_76509 has a Stoichiometric coefficient of 1 LDL:p-LRP8:FGR Reactome DB_ID: 432132 Reactome Database ID Release 43432132 Reactome, http://www.reactome.org ReactomeREACT_24077 has a Stoichiometric coefficient of 1 K48-polyubiquitinated substrate Reactome DB_ID: 983123 Reactome Database ID Release 43983123 Reactome, http://www.reactome.org ReactomeREACT_75986 has a Stoichiometric coefficient of 1 LDL:p-LRP8 Reactome DB_ID: 432133 Reactome Database ID Release 43432133 Reactome, http://www.reactome.org ReactomeREACT_24274 has a Stoichiometric coefficient of 1 Antigen peptide bound class I MHC:BAP31 oligomer Reactome DB_ID: 983132 Reactome Database ID Release 43983132 Reactome, http://www.reactome.org ReactomeREACT_76793 has a Stoichiometric coefficient of 1 PP2A Reactome DB_ID: 196206 Reactome Database ID Release 43196206 Reactome, http://www.reactome.org ReactomeREACT_10628 has a Stoichiometric coefficient of 1 MHC:B2M peptide loading complex Reactome DB_ID: 983121 Reactome Database ID Release 43983121 Reactome, http://www.reactome.org ReactomeREACT_76716 has a Stoichiometric coefficient of 1 p-PECAM:PP2A Reactome DB_ID: 432144 Reactome Database ID Release 43432144 Reactome, http://www.reactome.org ReactomeREACT_24470 has a Stoichiometric coefficient of 1 TAP Reactome DB_ID: 983113 Reactome Database ID Release 43983113 Reactome, http://www.reactome.org ReactomeREACT_76417 TAP1:TAP2 heterodimer Transporter associated with antigen processing (TAP) has a Stoichiometric coefficient of 1 PECAM-1:SHP-1 complex Reactome DB_ID: 210221 Reactome Database ID Release 43210221 Reactome, http://www.reactome.org ReactomeREACT_13228 has a Stoichiometric coefficient of 1 MHC HC:B2M:Erp57 Reactome DB_ID: 983136 Reactome Database ID Release 43983136 Reactome, http://www.reactome.org ReactomeREACT_76399 has a Stoichiometric coefficient of 1 PECAM-1:SHP-2 complex Reactome DB_ID: 210219 Reactome Database ID Release 43210219 Reactome, http://www.reactome.org ReactomeREACT_13041 has a Stoichiometric coefficient of 1 STIM1 Dimer Reactome DB_ID: 1168370 Reactome Database ID Release 431168370 Reactome, http://www.reactome.org ReactomeREACT_27372 has a Stoichiometric coefficient of 2 CRAC channel Reactome DB_ID: 434679 Reactome Database ID Release 43434679 Reactome, http://www.reactome.org ReactomeREACT_24443 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 GRIK4 heteromer with GRIK1/2/3 Reactome DB_ID: 450206 Reactome Database ID Release 43450206 Reactome, http://www.reactome.org ReactomeREACT_22030 has a Stoichiometric coefficient of 2 Peptide bound class I MHC Reactome DB_ID: 983127 Reactome Database ID Release 43983127 Reactome, http://www.reactome.org ReactomeREACT_75955 has a Stoichiometric coefficient of 1 GRIK4 interacting proteins Reactome DB_ID: 450889 Reactome Database ID Release 43450889 Reactome, http://www.reactome.org ReactomeREACT_21998 has a Stoichiometric coefficient of 1 Antigen peptide bound class I MHC Reactome DB_ID: 983114 Reactome Database ID Release 43983114 Reactome, http://www.reactome.org ReactomeREACT_76083 has a Stoichiometric coefficient of 1 GRIK5 heteromer with GRIk1/2/3 Reactome DB_ID: 450205 Reactome Database ID Release 43450205 Reactome, http://www.reactome.org ReactomeREACT_21502 has a Stoichiometric coefficient of 2 Kainate receptor-glutamate complex Reactome DB_ID: 451281 Reactome Database ID Release 43451281 Reactome, http://www.reactome.org ReactomeREACT_22077 has a Stoichiometric coefficient of 1 Gamma-aminobutyric acid alpha2-gephrin complex Reactome DB_ID: 975532 Reactome Database ID Release 43975532 Reactome, http://www.reactome.org ReactomeREACT_26413 has a Stoichiometric coefficient of 1 Antigen peptide bound class I MHC Reactome DB_ID: 983416 Reactome Database ID Release 43983416 Reactome, http://www.reactome.org ReactomeREACT_76542 has a Stoichiometric coefficient of 1 GPIb-IX-V complex Reactome DB_ID: 114668 Reactome Database ID Release 43114668 Reactome, http://www.reactome.org ReactomeREACT_3007 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 GABA(A) heteropentamer Reactome DB_ID: 975268 Reactome Database ID Release 43975268 Reactome, http://www.reactome.org ReactomeREACT_26202 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 monoglucosylated MHC class I HC (Glc)1(Man)9(GlcNAc)2-MHC class I heavy chain Reactome DB_ID: 983419 Reactome Database ID Release 43983419 Reactome, http://www.reactome.org ReactomeREACT_76454 has a Stoichiometric coefficient of 1 GABAB receptor:GABA Reactome DB_ID: 420698 Reactome Database ID Release 43420698 Reactome, http://www.reactome.org ReactomeREACT_18601 has a Stoichiometric coefficient of 1 Antigen peptide bound class I MHC Reactome DB_ID: 198904 Reactome Database ID Release 43198904 Reactome, http://www.reactome.org ReactomeREACT_11766 has a Stoichiometric coefficient of 1 GPVI:FceRI gamma:FYN:LYN:Collagen I Reactome DB_ID: 434812 Reactome Database ID Release 43434812 Reactome, http://www.reactome.org ReactomeREACT_20373 has a Stoichiometric coefficient of 1 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Release of the SLBP independent Histone mRNA from the NPC' ACTIVATION Reactome Database ID Release 43159057 Reactome, http://www.reactome.org ReactomeREACT_6122 GABAB receptor Reactome DB_ID: 420748 Reactome Database ID Release 43420748 Reactome, http://www.reactome.org ReactomeREACT_18843 has a Stoichiometric coefficient of 1 monoglucosylated MHC class I HC (Glc)1(Man)9(GlcNAc)2-MHC class I heavy chain Reactome DB_ID: 983420 Reactome Database ID Release 43983420 Reactome, http://www.reactome.org ReactomeREACT_76623 has a Stoichiometric coefficient of 1 Collagen IV:vWF complex Reactome DB_ID: 114596 Reactome Database ID Release 43114596 Reactome, http://www.reactome.org ReactomeREACT_2576 has a Stoichiometric coefficient of 1 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Transport of the mature SLBP independent Histone mRNA through the NPC' ACTIVATION Reactome Database ID Release 43159053 Reactome, http://www.reactome.org ReactomeREACT_6007 GRIK3 homomer glutamate complex Reactome DB_ID: 500705 Reactome Database ID Release 43500705 Reactome, http://www.reactome.org ReactomeREACT_21898 has a Stoichiometric coefficient of 1 COPII vesicle with MHC class I Reactome DB_ID: 983418 Reactome Database ID Release 43983418 Reactome, http://www.reactome.org ReactomeREACT_76797 has a Stoichiometric coefficient of 1 GPVI:FceRI gamma:FYN:LYN Reactome DB_ID: 432297 Reactome Database ID Release 43432297 Reactome, http://www.reactome.org ReactomeREACT_20322 has a Stoichiometric coefficient of 1 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Docking of Mature Histone mRNA complex:TAP at the NPC' ACTIVATION Reactome Database ID Release 43159067 Reactome, http://www.reactome.org ReactomeREACT_6106 COPII vesicle with MHC class I Reactome DB_ID: 983414 Reactome Database ID Release 43983414 Reactome, http://www.reactome.org ReactomeREACT_76571 has a Stoichiometric coefficient of 1 Collagen I Converted from EntitySet in Reactome Reactome DB_ID: 114501 Reactome Database ID Release 43114501 Reactome, http://www.reactome.org ReactomeREACT_2739 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Release of the Mature intronless transcript derived Histone mRNA:SLBP:eIF4E Complex' ACTIVATION Reactome Database ID Release 43159060 Reactome, http://www.reactome.org ReactomeREACT_5944 Kainate receptor-glutamate-Gprotein complex Reactome DB_ID: 500703 Reactome Database ID Release 43500703 Reactome, http://www.reactome.org ReactomeREACT_21842 has a Stoichiometric coefficient of 1 Antigen peptide bound class I MHC Reactome DB_ID: 983412 Reactome Database ID Release 43983412 Reactome, http://www.reactome.org ReactomeREACT_76258 has a Stoichiometric coefficient of 1 FceRI gamma dimer Reactome DB_ID: 210223 Reactome Database ID Release 43210223 Reactome, http://www.reactome.org ReactomeREACT_20921 has a Stoichiometric coefficient of 2 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Transport of the mature replication dependent histone mRNA:SLBP complex' ACTIVATION Reactome Database ID Release 43159051 Reactome, http://www.reactome.org ReactomeREACT_5916 G-protein beta-gamma:PLC beta 1/2/3 Reactome DB_ID: 398037 Reactome Database ID Release 43398037 Reactome, http://www.reactome.org ReactomeREACT_19982 has a Stoichiometric coefficient of 1 Sar1p-GTP Reactome DB_ID: 983415 Reactome Database ID Release 43983415 Reactome, http://www.reactome.org ReactomeREACT_76523 has a Stoichiometric coefficient of 1 GP VI : FceRI gamma dimer Reactome DB_ID: 114575 Reactome Database ID Release 43114575 Reactome, http://www.reactome.org ReactomeREACT_5147 has a Stoichiometric coefficient of 1 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Docking of Mature Replication Dependent Histone mRNA with the NPC' ACTIVATION Reactome Database ID Release 43159066 Reactome, http://www.reactome.org ReactomeREACT_6067 Integrin alpha2beta1 Reactome DB_ID: 114561 Reactome Database ID Release 43114561 Reactome, http://www.reactome.org ReactomeREACT_2290 has a Stoichiometric coefficient of 1 Integrin alpha2beta1:Collagen I:Mg++ Reactome DB_ID: 114562 Reactome Database ID Release 43114562 Reactome, http://www.reactome.org ReactomeREACT_5070 has a Stoichiometric coefficient of 1 Sar1p:GTP:Sec23p:Sec24p:Ag bound MHC class I Reactome DB_ID: 983413 Reactome Database ID Release 43983413 Reactome, http://www.reactome.org ReactomeREACT_76191 has a Stoichiometric coefficient of 1 Procollagen type I Reactome DB_ID: 114594 Reactome Database ID Release 43114594 Reactome, http://www.reactome.org ReactomeREACT_2604 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Docking of the TAP:EJC Complex with the NPC' ACTIVATION Reactome Database ID Release 43159293 Reactome, http://www.reactome.org ReactomeREACT_6111 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Transport of the export-competent complex through the NPC' ACTIVATION Reactome Database ID Release 43159295 Reactome, http://www.reactome.org ReactomeREACT_6100 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Disassembly of the mRNP by the RNA helicase Dbp5' ACTIVATION Reactome Database ID Release 43159294 Reactome, http://www.reactome.org ReactomeREACT_5940 Beta-2-microglobulin:class I MHC heavy chain Complex Reactome DB_ID: 167755 Reactome Database ID Release 43167755 Reactome, http://www.reactome.org ReactomeREACT_11450 has a Stoichiometric coefficient of 1 GRIK1 and 2 heterotetramer Reactome DB_ID: 450210 Reactome Database ID Release 43450210 Reactome, http://www.reactome.org ReactomeREACT_21700 has a Stoichiometric coefficient of 2 Ag peptide bound class I MHC Reactome DB_ID: 1236931 Reactome Database ID Release 431236931 Reactome, http://www.reactome.org ReactomeREACT_111834 has a Stoichiometric coefficient of 1 GRIK1 homomer Reactome DB_ID: 450209 Reactome Database ID Release 43450209 Reactome, http://www.reactome.org ReactomeREACT_21810 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Class I MHC HC:B2M:Erp57 Reactome DB_ID: 1236922 Reactome Database ID Release 431236922 Reactome, http://www.reactome.org ReactomeREACT_111545 has a Stoichiometric coefficient of 1 GRIK 3 homomer Reactome DB_ID: 450196 Reactome Database ID Release 43450196 Reactome, http://www.reactome.org ReactomeREACT_22081 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Class I MHC peptide loading complex Reactome DB_ID: 1236932 Reactome Database ID Release 431236932 Reactome, http://www.reactome.org ReactomeREACT_111292 has a Stoichiometric coefficient of 1 GRIK2 interacting proteins Reactome DB_ID: 450890 Reactome Database ID Release 43450890 Reactome, http://www.reactome.org ReactomeREACT_21432 has a Stoichiometric coefficient of 1 TAP Reactome DB_ID: 1236915 Reactome Database ID Release 431236915 Reactome, http://www.reactome.org ReactomeREACT_111811 TAP1:TAP2 heterodimer Transporter associated with antigen processing (TAP) has a Stoichiometric coefficient of 1 GRIK 2 homomer Reactome DB_ID: 450191 Reactome Database ID Release 43450191 Reactome, http://www.reactome.org ReactomeREACT_21798 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 K48-polyubiquitinated partially digested Ag Reactome DB_ID: 1236918 Reactome Database ID Release 431236918 Reactome, http://www.reactome.org ReactomeREACT_111624 has a Stoichiometric coefficient of 1 kaiante Receptors Converted from EntitySet in Reactome Reactome DB_ID: 450885 Reactome Database ID Release 43450885 Reactome, http://www.reactome.org ReactomeREACT_21711 Translocon Reactome DB_ID: 1236927 Reactome Database ID Release 431236927 Reactome, http://www.reactome.org ReactomeREACT_111416 has a Stoichiometric coefficient of 1 flavocytochrome b558 catalytic core Reactome DB_ID: 1996225 Reactome Database ID Release 431996225 Reactome, http://www.reactome.org ReactomeREACT_119948 has a Stoichiometric coefficient of 1 NOX2 complex Reactome DB_ID: 1996217 Reactome Database ID Release 431996217 Reactome, http://www.reactome.org ReactomeREACT_119115 has a Stoichiometric coefficient of 1 alphaVbeta5 Reactome DB_ID: 1236906 Reactome Database ID Release 431236906 Reactome, http://www.reactome.org ReactomeREACT_111396 has a Stoichiometric coefficient of 1 Particulate Ag:DC receptors Reactome DB_ID: 1236920 Reactome Database ID Release 431236920 Reactome, http://www.reactome.org ReactomeREACT_111282 has a Stoichiometric coefficient of 1 PathwayStep4110 PathwayStep4111 PathwayStep4112 PathwayStep4113 PathwayStep4114 Glutathione is taken up by the bacterium Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Glutathione is taken up by the bacterium by an ABC transporter called the oligopeptide importer. OppA determines substrate specificity (Dasgupta et al. 2010). Pubmed20808924 Reactome Database ID Release 431500817 Reactome, http://www.reactome.org ReactomeREACT_120818 Reviewed: Warner, D, 2012-04-30 Glutathione scavenges nitrosyl Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Glutathione (GSH) scavenges nitrosyl, yielding S-nitrosoglutathione (GSNO). Both GSH and GSNO are effective against <i>Mtb</i> (Venketaraman et al. 2005). Pubmed15731094 Reactome Database ID Release 431222384 Reactome, http://www.reactome.org ReactomeREACT_121323 Reviewed: Warner, D, 2012-04-30 Peroxynitrite oxidizes methionine residues Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Peroxynitrite oxidizes methionine residues (Pryor et al. 1994). Pubmed7972029 Reactome Database ID Release 431222411 Reactome, http://www.reactome.org ReactomeREACT_121170 Reviewed: Warner, D, 2012-04-30 PathwayStep4105 PathwayStep4104 Peroxynitrite is reduced by AhpE Authored: Schmidt, EE, 2006-02-06 10:50:16 EC Number: 1.11.1.15 Edited: Jassal, B, 2011-02-28 Pubmed19737009 Reactome Database ID Release 431500804 Reactome, http://www.reactome.org ReactomeREACT_120759 Reviewed: Warner, D, 2012-04-30 The peroxiredoxin AhpE participates in reducing peroxynitrite to nitrite, but how it is recycled back to the reduced form is still unknown (Hugo et al. 2009). PathwayStep4107 Peroxynitrite is reduced to nitrite by AhpC AhpC is an unusual peroxiredoxin - it has three cysteine residues that participate in the reduction of toxic peroxynitrite to nitrite. In a second step, another thioredoxin or the reductase chain AhpD/DlaT/Lpd is needed for reactivation (Guimaraes et al. 2005). Authored: Stephan, R, 2011-01-10 EC Number: 1.11.1.15 Edited: Jassal, B, 2011-02-28 Pubmed15886207 Reactome Database ID Release 431222431 Reactome, http://www.reactome.org ReactomeREACT_120880 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 PathwayStep4106 Nitric oxide is oxidized to nitrate Authored: Stephan, R, 2011-01-10 EC Number: 1.14.12.17 Edited: Jassal, B, 2011-02-28 Heme proteins, especially the truncated globin GlbN in <i>Mtb</i> possess oxygen-dependent nitric oxide dioxygenase activity, where the heme that is oxidized to ferriheme in the process will need to be reduced in a second step to activate the protein again. The responsible heme protein reductase is unknown (Ouellet et al. 2002, Pathania et al. 2002). Pubmed11959913 Pubmed12207698 Reactome Database ID Release 431222723 Reactome, http://www.reactome.org ReactomeREACT_121052 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 PathwayStep4109 Nitrogen dioxide is reduced to NO by F420 Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed19325122 Reactome Database ID Release 431500761 Reactome, http://www.reactome.org ReactomeREACT_120941 Reviewed: Warner, D, 2012-04-30 The archaeal cofactor F420 reduces toxic nitrogen dioxide that can be produced when NO and oxygen combine. F420 itself is reduced by the enzyme Fgd (Purwantini & Mukhopadyay 2008). PathwayStep4108 Cathelicidin LL-37 localizes to bacterial cell wall Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 In macrophages, LL-37 expression is stimulated by contact with <i>Mtb</i> and it localizes to the cell wall (Rivas-Santiago et al. 2008). Pubmed18160480 Reactome Database ID Release 431222685 Reactome, http://www.reactome.org ReactomeREACT_121346 Reviewed: Warner, D, 2012-04-30 NRAMP1 transports divalent metal ions across phagosomal membranes of macrophages Authored: Jassal, B, 2009-09-07 Edited: Jassal, B, 2009-08-21 Natural resistance-associated macrophage proteins (NRAMPs) regulates macrophage activation for antimicrobial activity against intracellular pathogens. They do this by mediating metal ion transport across macrophage membranes and the subsequent use of these ions in the control of free radical formation.<br>The human gene SLC11A1 encodes NRAMP1 (Kishi F, 2004; Kishi F and Nobumoto M, 1995) which can utilize the protonmotive force to mediate divalent iron (Fe2+), zinc (Zn2+) and manganese (Mn2+) influx to or efflux from phagosomes. Pubmed7980580 Pubmed8537108 Reactome Database ID Release 43435171 Reactome, http://www.reactome.org ReactomeREACT_20522 Reviewed: He, L, 2009-11-12 has a Stoichiometric coefficient of 2 Lactoferrin scavenges iron ions Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Lactoferrin is secreted from many tissues to collect stray iron ions that can catalyze unwanted reactions, and to starve microorganisms of this important metal. One molecule of lactoferrin can load two ferric (Fe(3+)) ions together with two carbonate (CO3(2-)) anions (Haridas et al. 1995). Pubmed15299793 Reactome Database ID Release 431222491 Reactome, http://www.reactome.org ReactomeREACT_121328 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 PathwayStep4120 PathwayStep4121 PathwayStep4124 PathwayStep4125 PathwayStep4122 PathwayStep4123 Nitric oxide oxidizes to nitrosyl Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Production of nitrosyl from nitric oxide is much faster when catalyzed by metal ions than via NO2 or N2O3. An alternative mechanism is by reaction with superoxide which is less probable in macrophages because they downregulate pathways leading to superoxide when NO is produced (Kharitonov et al. 1995, Clancy et al. 1994). Pubmed7499306 Pubmed8170969 Reactome Database ID Release 431222512 Reactome, http://www.reactome.org ReactomeREACT_121318 Reviewed: Warner, D, 2012-04-30 PB1-F2 binds to the mitochondrial adenine nucleotide translocator 3 ANT3, inducing apoptosis GENE ONTOLOGYGO:0046732 Influenza A virus induces apoptosis in a variety of ways including binding of viral PB1-F2 to host mitochondrial adenine nucleotide translocator 3 (ANT3). Pubmed11726970 Pubmed15163724 Reactome Database ID Release 43168878 Reactome, http://www.reactome.org ReactomeREACT_6243 PathwayStep4118 Hydroperoxyl enters the bacterium Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed10922044 Pubmed11970850 Pubmed15155722 Pubmed16847086 Reactome Database ID Release 431222342 Reactome, http://www.reactome.org ReactomeREACT_120718 Reviewed: Warner, D, 2012-04-30 Superoxide can enter the bacterium when acidic conditions apply. Together with a proton it forms the hydroperoxyl radical (Nathan & Shiloh 2000, Zahrt & Deretic 2002, Warner & Mizrahi 2006, Spagnolo et al, 2004). PathwayStep4117 Protonation of superoxide Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed11849539 Reactome Database ID Release 431222353 Reactome, http://www.reactome.org ReactomeREACT_121026 Reviewed: Warner, D, 2012-04-30 Superoxide gets protonated (Korshunov & Imlay 2002). PathwayStep4116 Peroxynitrite enters the bacterium Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Peroxynitrite can rapidly permeate biological membranes (Marla et al. 1997, Venugopal et al. 2011). Pubmed21238944 Pubmed9405597 Reactome Database ID Release 431470073 Reactome, http://www.reactome.org ReactomeREACT_121225 Reviewed: Warner, D, 2012-04-30 PathwayStep4115 Superoxide and nitric oxide react to peroxynitrite Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Nitric oxide and superoxide rapidly combine to form peroxynitrite (Pryor & Squadrito 1995). Pubmed7762673 Reactome Database ID Release 431222407 Reactome, http://www.reactome.org ReactomeREACT_121222 Reviewed: Warner, D, 2012-04-30 Nitric oxide enters the bacterium Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 NO enters the bacterium (Clancy et al. 1994). Pubmed8170969 Reactome Database ID Release 431222662 Reactome, http://www.reactome.org ReactomeREACT_121171 Reviewed: Warner, D, 2012-04-30 Nitric oxide diffuses into the phagosome Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Nitric oxide diffuses into the phagosome (Clancy et al. 1994). Although NO has been shown to be critical for control of <i>Mtb</i> infection in mice, it's role in human infection is less clear. Instead, the generation of antimicrobial defence molecules including cathelicidin in a vitamin D-dependent pathway is much better established (Fabri et al. 2011, Martineau et al. 2011). Pubmed21998409 Pubmed22025704 Pubmed8170969 Reactome Database ID Release 431222686 Reactome, http://www.reactome.org ReactomeREACT_120750 Reviewed: Warner, D, 2012-04-30 Intraphagosomal pH is lowered to 5 by V-ATPase Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0090383 Pubmed17662945 Reactome Database ID Release 431222516 Reactome, http://www.reactome.org ReactomeREACT_121163 Reviewed: Warner, D, 2012-04-30 The function of V-type proton pumping ATPases is basically the same as that of F-type ATPases, except that V-ATPases cannot synthesize ATP from the proton motive force, the reverse reaction of pumping. When pumping, ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons into the phagosome (Adachi et al. 2007). has a Stoichiometric coefficient of 3 PathwayStep4119 NOX2 generates superoxide from oxygen Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Macrophage NOX2 is a membrane complex that generates superoxide anions by reduction of oxygen with NADPH (Babior 1999, Dinauer et al. 1991). Pubmed10029572 Pubmed1763037 Reactome Database ID Release 431222376 Reactome, http://www.reactome.org ReactomeREACT_121023 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 PathwayStep4133 PathwayStep4134 PathwayStep4135 PathwayStep4136 PathwayStep4130 PathwayStep4131 PathwayStep4132 H2O2 gets scavenged by unsaturated lipid Authored: Stephan, R, 2011-01-10 Due to their abundance in Mycobacteria, lipids fulfill a buffering role in the tolerance of antioxidants. Lipid production is triggered by oxidative stress. The peroxidated lipid can be reduced by AhpC (Chauhan & Mande 2001). Edited: Jassal, B, 2011-02-28 Pubmed11171096 Reactome Database ID Release 431222341 Reactome, http://www.reactome.org ReactomeREACT_121370 Reviewed: Warner, D, 2012-04-30 Lpd reactivates dlaT Authored: Stephan, R, 2011-01-10 EC Number: 1.8.1.4 Edited: Jassal, B, 2011-02-28 Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from Lpd, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011). Pubmed11799204 Reactome Database ID Release 431222412 Reactome, http://www.reactome.org ReactomeREACT_120779 Reviewed: Warner, D, 2012-04-30 DlaT reactivates AhpD Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from Lpd, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011). Pubmed11799204 Reactome Database ID Release 431222690 Reactome, http://www.reactome.org ReactomeREACT_121040 Reviewed: Warner, D, 2012-04-30 AhpD reactivates AhpC Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from Lpd, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011). Pubmed21238944 Reactome Database ID Release 431222655 Reactome, http://www.reactome.org ReactomeREACT_121243 Reviewed: Warner, D, 2012-04-30 AhpC reduces peroxidated lipids Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed11171096 Reactome Database ID Release 431222526 Reactome, http://www.reactome.org ReactomeREACT_121359 Reduction of peroxidated lipids depends on reduced AhpC, the only alkyl hydoperoxidase in <i>Mtb</i> (Chauhan & Mande 2001). Reviewed: Warner, D, 2012-04-30 Fgd1 reactivates F420 Authored: Stephan, R, 2011-01-10 EC Number: 1.1 Edited: Jassal, B, 2011-02-28 Pubmed18434308 Reactome Database ID Release 431500781 Reactome, http://www.reactome.org ReactomeREACT_120793 Reviewed: Warner, D, 2012-04-30 The enzyme in <i>Mtb</i> known to reduce F420 is the glucose-6-phosphate dehydrogenase Fgd1 (Bashiri et al. 2008). TrxA/B1 reactivates Tpx Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed14871480 Reactome Database ID Release 431222644 Reactome, http://www.reactome.org ReactomeREACT_121268 Reviewed: Warner, D, 2012-04-30 The Tpx peroxiredoxin is reactivated by either TrxA or TrxB1 (Jaeger et al. 2006). TrxB reactivates TrxA Authored: Stephan, R, 2011-01-10 EC Number: 1.8.1.9 Edited: Jassal, B, 2011-02-28 Pubmed14871480 Reactome Database ID Release 431222485 Reactome, http://www.reactome.org ReactomeREACT_121244 Reviewed: Warner, D, 2012-04-30 TrxB is an NADPH-dependent thioredoxin reductase that reactivates TrxA (Jaeger et al. 2006). TrxA reactivates AhpC Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed14871480 Reactome Database ID Release 431222417 Reactome, http://www.reactome.org ReactomeREACT_120911 Reviewed: Warner, D, 2012-04-30 The peroxiredoxin AhpC can be alternatively reactivated by TrxA (Jaeger et al. 2004). PathwayStep4127 PathwayStep4126 PathwayStep4129 PathwayStep4128 Carboxymycobactin gets secreted Authored: Stephan, R, 2011-01-10 Carboxymycobactin is the more polar siderophore of <i>Mtb</i> and it is localized, after its secretion, in the phagosomal lumen. The transporters for export and secretion of this molecule are still unknown (Madigan et al. 2012). Edited: Jassal, B, 2011-02-28 Pubmed22232695 Reactome Database ID Release 431222738 Reactome, http://www.reactome.org ReactomeREACT_121354 Reviewed: Warner, D, 2012-04-30 PathwayStep4146 PathwayStep4147 PathwayStep4144 PathwayStep4145 PathwayStep4142 PathwayStep4143 PathwayStep2000 PathwayStep4140 PathwayStep2001 PathwayStep4141 PathwayStep2002 Mycothiol scavenges nitrosyl Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Nitrosyl is scavenged by mycothiol (MSH), which is functionally analogous to glutathione, which mycobacteria do not possess (Miller et al. 2007). Pubmed17638697 Reactome Database ID Release 431222594 Reactome, http://www.reactome.org ReactomeREACT_121129 Reviewed: Warner, D, 2012-04-30 Peroxynitrite is reduced to nitrite by Tpx Authored: Stephan, R, 2011-01-10 EC Number: 1.11.1.15 Edited: Jassal, B, 2011-02-28 Pubmed14871480 Pubmed16884737 Reactome Database ID Release 431222755 Reactome, http://www.reactome.org ReactomeREACT_121400 Reviewed: Warner, D, 2012-04-30 Tpx, like AhpC, is a peroxiredoxin with alkylhydroperoxidase, peroxidase, and peroxynitritase activities. Peroxynitrite is detoxified to nitrite (Jaeger et al. 2006, Rho et al. 2006). has a Stoichiometric coefficient of 2 MsrA/B reduces peptide-methionine S/R-sulfoxides Authored: Stephan, R, 2011-01-10 EC Number: 1.8.4.11 Edited: Jassal, B, 2011-02-28 MsrA and MsrB are enzymes that can both reduce the S- and R-stereoisomers of (peptidyl-) methionine sulfoxide. The exact nature of the accompanying thioredoxin is not settled, but it is predicted to be TrxA. The whole methionine-MsrA/B-thioredoxin-and-reductase system is an important part of NO detoxification in <i>Mtb</i> (St John et al. 2001, Lee et al. 2009). Pubmed11481433 Pubmed19040639 Reactome Database ID Release 431222363 Reactome, http://www.reactome.org ReactomeREACT_121257 Reviewed: Warner, D, 2012-04-30 MscR reduces nitrosomycothiol to ammonia Authored: Stephan, R, 2011-01-10 EC Number: 1.2.1 Edited: Jassal, B, 2011-02-28 MscR is an alcohol dehydrogenase that can probably reduce nitrosomycothiol with the help of NADH/H+ reducing equivalents to the sulfinamide which then presumably decomposes to the thione and ammonia (Vogt et al. 2003). Pubmed12809551 Reactome Database ID Release 431222583 Reactome, http://www.reactome.org ReactomeREACT_121395 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 SodB gets secreted Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed12675804 Reactome Database ID Release 431222523 Reactome, http://www.reactome.org ReactomeREACT_121173 Reviewed: Warner, D, 2012-04-30 Superoxide dismutase SodB is secreted via the Sec transport complex (Braunstein et al. 2003). Nitrosoglutathione gets cleaved to Cys(NO)-Gly Authored: Stephan, R, 2011-01-10 EC Number: 2.3.2.2 Edited: Jassal, B, 2011-02-28 Most gamma-glutamyl transpeptidases (GGT) cleave both glutathione and glutathione conjugates. Mtb GGT cleaves nitrosoglutathione )GSNO) to Cys(NO)-Gly, thus making it soluble for transport into the cytosol (Dayaram et al. 2006). Pubmed16452418 Reactome Database ID Release 431222712 Reactome, http://www.reactome.org ReactomeREACT_120883 Reviewed: Warner, D, 2012-04-30 SodC reduces superoxide to H2O2 Authored: Stephan, R, 2011-01-10 Copper-containing superoxide dismutase is localized in the plasma membrane of the bacterium where it catalyzes the reduction of superoxide (Wu et al. 1998). EC Number: 1.15.1.1 Edited: Jassal, B, 2011-02-28 Pubmed9849904 Reactome Database ID Release 431222469 Reactome, http://www.reactome.org ReactomeREACT_121151 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 SodB reduces superoxide to H2O2 Authored: Stephan, R, 2011-01-10 EC Number: 1.15.1.1 Edited: Jassal, B, 2011-02-28 Iron-containing superoxide dismutase is localized both within and without the bacterium where it catalyzes the reduction of superoxide (Zhang et al. 1991). Pubmed1904126 Reactome Database ID Release 431222462 Reactome, http://www.reactome.org ReactomeREACT_120864 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 KatG reduces H2O2 Another important antioxidant activity is the KatG catalase/peroxidase which also activates the anti-tuberculosis drug isoniazid (Nagy et al. 1997). Authored: Stephan, R, 2011-01-10 EC Number: 1.11.1.6 Edited: Jassal, B, 2011-02-28 Pubmed9395452 Reactome Database ID Release 431222704 Reactome, http://www.reactome.org ReactomeREACT_121262 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 PathwayStep4139 AhpC reduces H2O2 Authored: Stephan, R, 2011-01-10 EC Number: 1.11.1.7 Edited: Jassal, B, 2011-02-28 Pubmed11799204 Reactome Database ID Release 431222346 Reactome, http://www.reactome.org ReactomeREACT_121090 Reviewed: Warner, D, 2012-04-30 The versatile AhpC reduces hydrogen peroxide to water (Bryk et al. 2002). has a Stoichiometric coefficient of 2 PathwayStep4138 PathwayStep4137 DHC dimer Reactome DB_ID: 2029144 Reactome Database ID Release 432029144 Reactome, http://www.reactome.org ReactomeREACT_125239 has a Stoichiometric coefficient of 2 Dynein complex Reactome DB_ID: 2029145 Reactome Database ID Release 432029145 Reactome, http://www.reactome.org ReactomeREACT_125562 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 RILP dimer Reactome DB_ID: 2213233 Reactome Database ID Release 432213233 Reactome, http://www.reactome.org ReactomeREACT_125134 has a Stoichiometric coefficient of 2 RAB7:RILP:ORP1L complex Reactome DB_ID: 2213215 Reactome Database ID Release 432213215 Reactome, http://www.reactome.org ReactomeREACT_124801 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Dynein:Dynactin:microtubule Reactome DB_ID: 2029135 Reactome Database ID Release 432029135 Reactome, http://www.reactome.org ReactomeREACT_125410 has a Stoichiometric coefficient of 1 RAB7A:GTP Reactome DB_ID: 2213222 Reactome Database ID Release 432213222 Reactome, http://www.reactome.org ReactomeREACT_125196 has a Stoichiometric coefficient of 1 HLA-DO Reactome DB_ID: 2213224 Reactome Database ID Release 432213224 Reactome, http://www.reactome.org ReactomeREACT_122622 has a Stoichiometric coefficient of 1 HLA-DM:HLA-DO Reactome DB_ID: 2213213 Reactome Database ID Release 432213213 Reactome, http://www.reactome.org ReactomeREACT_122605 has a Stoichiometric coefficient of 1 peptide loaded MHC class II Reactome DB_ID: 2213223 Reactome Database ID Release 432213223 Reactome, http://www.reactome.org ReactomeREACT_123504 has a Stoichiometric coefficient of 1 peptide free MHC II:HLA-DM Reactome DB_ID: 2213227 Reactome Database ID Release 432213227 Reactome, http://www.reactome.org ReactomeREACT_122875 has a Stoichiometric coefficient of 1 IRAK1/ IRAK2 Converted from EntitySet in Reactome Reactome DB_ID: 975179 Reactome Database ID Release 43975179 Reactome, http://www.reactome.org ReactomeREACT_26099 Dimerisation of CREB Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 CREB readily dimerizes. Edited: Jassal, B, 2008-11-06 10:17:49 Reactome Database ID Release 43111916 Reactome, http://www.reactome.org ReactomeREACT_15415 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 has a Stoichiometric coefficient of 2 PKA catalytic subunit translocates to the nucleus Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Reactome Database ID Release 43111924 Reactome, http://www.reactome.org ReactomeREACT_1031 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 When cAMP level rises, the PKA catalytic subunit (C subunit) released from the holoenzyme enters the nucleus by passive diffusion whereas termination of signaling to the nucleus involves an active mechanism. In the nucleus, the C subunit binds to the heat-stable protein kinase inhibitor (PKI), and this binding not only inactivates the C subunit but also by conformational change unveils a nuclear export signal in PKI which leads to export of the C-PKI complex from the nucleus. PKA phosphorylates CREB Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 2.7.11 Edited: Jassal, B, 2008-11-06 10:17:49 Reactome Database ID Release 43111919 Reactome, http://www.reactome.org ReactomeREACT_15377 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 cAMP-dependent protein kinase A (PKA) phosphorylates in vitro CREB at a specific residue, serine 133; Phosphorylation of Ser133 is required for signal-induced transcription in vivo. DAG stimulates protein kinase C-delta Diacylglycerol (DAG) positively regulates the autophosphorylation of protein kinase C-delta (PKC-delta), which stimulates ERK1/2 and triggers neurite outgrowth. DAG also stimulates the translocation of PKC from the cytosol to the plasma membrane. PKC-delta contributes to growth factor specificity and response to neuronal cells by promoting cell-type-specific differences in growth factor signalling. DAG can also activate PKC-epsilon in the same manner. EC Number: 2.7.11.13 Reactome Database ID Release 43198314 Reactome, http://www.reactome.org ReactomeREACT_12062 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 3 Adenylate cyclase produces cAMP Adenylate cyclase is responsive to calcium and calmodulin and produces cAMP. One important physiological role for Calmodulin is the regulation of adenylylcyclases. Four of the ten known adenylylcyclases are calcium sensitive, in particular type 8 (AC8). Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed10075700 Pubmed16613843 Reactome Database ID Release 43111930 Reactome, http://www.reactome.org ReactomeREACT_1963 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Active PLC-gamma1 dissociates from EGFR Authored: Jassal, B, 2008-02-13 11:13:12 Once activated PLC-gamma1 dissociates from EGFR, it can hydrolyze PIP2. Pubmed10579907 Reactome Database ID Release 43212713 Reactome, http://www.reactome.org ReactomeREACT_12407 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Active PLCG1 hydrolyses PIP2 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 3.1.4.11 Edited: Jassal, B, 2006-10-10 09:20:18 Inositol 1,4,5-triphosphate (IP3) is a second messenger produced by phospholipase C (PLC) metabolism of phosphoinositol 4,5-bisphosphate (PIP2) (Canossa et al. 2001). Reactome Database ID Release 43167686 Reactome, http://www.reactome.org ReactomeREACT_12078 Reviewed: Greene, LA, 2007-11-08 15:39:37 Phospholipase C-gamma1 binds to the activated EGF receptor Authored: Jassal, B, 2008-02-13 11:13:12 Inactive phospholipase C-gamma1 (PLCG1) binds to activated epidermal growth factor receptor (EGFR). Pubmed2153914 Pubmed2472219 Reactome Database ID Release 43212706 Reactome, http://www.reactome.org ReactomeREACT_12401 Reviewed: Heldin, CH, 2008-02-12 09:44:02 EGFR activates PLC-gamma1 by phosphorylation Authored: Jassal, B, 2008-02-13 11:13:12 EC Number: 2.7.10 EGFR phosphorylates PLC-gamma1, thus activating it. Pubmed1689311 Pubmed2472219 Reactome Database ID Release 43212710 Reactome, http://www.reactome.org ReactomeREACT_12569 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 4 Phosphorylation of EGFR by SRC kinase Authored: Castagnoli, L, 2006-10-10 13:09:34 Besides autophosphorylation, EGFR can become tyrosine-phosphorylated by the action of the proto-oncogene tyrosine-protein kinase, c-src. This Src homology 2 (SH2) domain-containing protein is one of many such proteins which bind to phosphorylated sites on EGFR to affect signal transmission into the cell. EC Number: 2.7.10 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed8845374 Reactome Database ID Release 43177937 Reactome, http://www.reactome.org ReactomeREACT_9401 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 has a Stoichiometric coefficient of 12 HLA-DM Reactome DB_ID: 2213217 Reactome Database ID Release 432213217 Reactome, http://www.reactome.org ReactomeREACT_121865 has a Stoichiometric coefficient of 1 HLA-DM/HLA-DO Converted from EntitySet in Reactome Reactome DB_ID: 2213230 Reactome Database ID Release 432213230 Reactome, http://www.reactome.org ReactomeREACT_124165 MHC II:CLIP Reactome DB_ID: 2130574 Reactome Database ID Release 432130574 Reactome, http://www.reactome.org ReactomeREACT_122680 has a Stoichiometric coefficient of 1 lip10 trimer Reactome DB_ID: 2213183 Reactome Database ID Release 432213183 Reactome, http://www.reactome.org ReactomeREACT_122465 has a Stoichiometric coefficient of 3 MHC II:lip10 nonamer Reactome DB_ID: 2130723 Reactome Database ID Release 432130723 Reactome, http://www.reactome.org ReactomeREACT_124281 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 lip22 trimer Reactome DB_ID: 2213190 Reactome Database ID Release 432213190 Reactome, http://www.reactome.org ReactomeREACT_123068 has a Stoichiometric coefficient of 3 MHC II:lip22 nonamer Reactome DB_ID: 2130680 Reactome Database ID Release 432130680 Reactome, http://www.reactome.org ReactomeREACT_123870 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Invariant chain trimer Reactome DB_ID: 2130371 Reactome Database ID Release 432130371 Reactome, http://www.reactome.org ReactomeREACT_123274 has a Stoichiometric coefficient of 3 MHC class II alpha/beta dimer Reactome DB_ID: 2213187 Reactome Database ID Release 432213187 Reactome, http://www.reactome.org ReactomeREACT_123728 has a Stoichiometric coefficient of 1 Nonameric complex Reactome DB_ID: 2130531 Reactome Database ID Release 432130531 Reactome, http://www.reactome.org ReactomeREACT_121584 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 UBE2D1/2/3 Converted from EntitySet in Reactome Reactome DB_ID: 1234120 Reactome Database ID Release 431234120 Reactome, http://www.reactome.org ReactomeREACT_125348 UbcH5a/b/c Pro-EGF is cleaved to form mature EGF Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 3.4.24 Ligands of the epidermal growth factor receptor (EGFR) are shed from the plasma membrane by metalloproteases. Identification of the sheddases for EGFR ligands using mouse embryonic cells lacking candidate sheddases (a disintegrin and metalloprotease; ADAM) has revealed that ADAM10, -12 and -17 are the sheddases of the EGFR ligands in response to various shedding stimulants such as GPCR agonists, growth factors, cytokines, osmotic stress, wounding and phorbol ester. Among the EGFR ligands, heparin-binding EGF-like growth factor (HB-EGF), EGF and TGF-alpha are the best characterized. Reactome Database ID Release 43177946 Reactome, http://www.reactome.org ReactomeREACT_9423 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 EGFR binds EGF ligand Authored: Castagnoli, L, 2006-10-10 13:09:34 Pubmed8639530 Reactome Database ID Release 43177942 Reactome, http://www.reactome.org ReactomeREACT_9481 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 The prototypic receptor tyrosine kinase (RTK) EGFR is composed of 3 major domains; an extracellular domain linked via a single membrane-spanning domain to a cytoplasmic domain. EGF binds to the extracellular domain from where the signal is transmitted to the cytoplasmic domain. EGFR dimerization Authored: Castagnoli, L, 2006-10-10 13:09:34 EGF and other growth factors induce oligomerization of their specific receptors. Inactive EGFR monomers are in equilibrium with active EGFR dimers and binding of the EGF ligand stabilizes the active dimeric form. Pubmed8639530 Reactome Database ID Release 43177922 Reactome, http://www.reactome.org ReactomeREACT_9397 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 has a Stoichiometric coefficient of 2 EGFR autophosphorylation Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 2.7.10 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed1688559 Pubmed2022652 Pubmed2543678 Reactome Database ID Release 43177934 Reactome, http://www.reactome.org ReactomeREACT_9388 Reviewed: Muthuswamy, S, 2007-02-16 20:08:05 The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Dimerization of EGFR activates its intrinsic protein kinase activity and results in autophosphorylation of 6 tyrosine residues in the cytoplasmic tail of EGFR. Tyrosine autophosphorylation is crucial for normal receptor signalling. Five of these tyrosine residues (Y992, Y1068, Y1086, Y1148 and Y1173) serve as specific binding sites for cytosolic target proteins involved in signal transmission, while the tyrosine residue Y1045 is involved in recruitment of CBL ubiquitin ligase and downregulation of EGFR signaling through degradation of activated EGFR. has a Stoichiometric coefficient of 12 Loaded mycobactin gets imported Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed19948799 Reactome Database ID Release 431222597 Reactome, http://www.reactome.org ReactomeREACT_120927 Reviewed: Warner, D, 2012-04-30 The ABC-type transporter IrtA, probably complexed with IrtB and ViuB (Rv2895c), specifically transports iron-loaded mycobactin into the cytosol (Ryndak et al. 2009). Iron is reduced and separates from mycobactin Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed18461140 Reactome Database ID Release 431222399 Reactome, http://www.reactome.org ReactomeREACT_121393 Reviewed: Warner, D, 2012-04-30 The IrtA transporter has a flavin reductase domain very much like Fre from E.coli that can probably act as ferrisiderophore reductase to relieve incoming loaded mycobactin from its Fe3+ by reducing it to Fe2+. Furthermore Rv2895c, which co-precipitates with IrtB and therefore is probably part of the transporter complex, has such a domain as well (Farhana et al. 2008). has a Stoichiometric coefficient of 2 BfrA stores iron <i>Mtb</i> bacterioferritin BfrA oxidises Fe2+ to Fe3+, migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Reddy et al. 2012). Authored: Stephan, R, 2011-01-10 EC Number: 1.16.3.1 Edited: Jassal, B, 2011-09-05 Pubmed22101841 Reactome Database ID Release 431562604 Reactome, http://www.reactome.org ReactomeREACT_120963 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 IRF3/ IRF7 Converted from EntitySet in Reactome Reactome DB_ID: 450317 Reactome Database ID Release 43450317 Reactome, http://www.reactome.org ReactomeREACT_21735 BfrB stores iron <i>Mtb</i> bacterioferritin BfrB oxidises Fe2+ to Fe3+, migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Harrison & Arrosio 1996, Khare et al. 2011). Authored: Stephan, R, 2011-01-10 EC Number: 1.16.3.1 Edited: Jassal, B, 2011-09-05 Pubmed21494619 Pubmed8695634 Reactome Database ID Release 431562603 Reactome, http://www.reactome.org ReactomeREACT_120810 Reviewed: Warner, D, 2012-04-30 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 phosphorylated IRF3/IRF7 Converted from EntitySet in Reactome Reactome DB_ID: 450240 Reactome Database ID Release 43450240 Reactome, http://www.reactome.org ReactomeREACT_21760 Mycobactin is exported Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0015891 Mycobactin is the lipophilic siderophore of <i>Mtb</i>. After export into the periplasmic space, it localizes to the bacterium's cell wall. The responsible transporter activity is still unknown (Madigan et al. 2012). Pubmed22232695 Reactome Database ID Release 431222722 Reactome, http://www.reactome.org ReactomeREACT_121078 Reviewed: Warner, D, 2012-04-30 Carboxymycobactin and mycobactin exchange their iron load Authored: Stephan, R, 2011-01-10 Carboxymycobactin and mycobactin exchange their iron loads. This interplay between polar and nonpolar siderophore is unique to <i>Mtb</i>. However, mycobactin can gather iron from nonpolar regions of the host cell by itself too (Madigan et al. 2012). Edited: Jassal, B, 2011-02-28 Pubmed22232695 Reactome Database ID Release 431222325 Reactome, http://www.reactome.org ReactomeREACT_120837 Reviewed: Warner, D, 2012-04-30 activated TBK1/IKK epsilon Converted from EntitySet in Reactome Reactome DB_ID: 450251 Reactome Database ID Release 43450251 Reactome, http://www.reactome.org ReactomeREACT_21446 IKK related kinases TBK1/IKK epsilon Converted from EntitySet in Reactome Reactome DB_ID: 450329 Reactome Database ID Release 43450329 Reactome, http://www.reactome.org ReactomeREACT_21591 Nectin-like 5 bound to CD96 Reactome DB_ID: 198194 Reactome Database ID Release 43198194 Reactome, http://www.reactome.org ReactomeREACT_11952 has a Stoichiometric coefficient of 1 PathwayStep4103 TCR interacting with antigen-bearing MHC Class I Reactome DB_ID: 198897 Reactome Database ID Release 43198897 Reactome, http://www.reactome.org ReactomeREACT_11723 has a Stoichiometric coefficient of 1 PathwayStep4102 CD8 Reactome DB_ID: 198899 Reactome Database ID Release 43198899 Reactome, http://www.reactome.org ReactomeREACT_11597 has a Stoichiometric coefficient of 1 PathwayStep4101 T-cell receptor complex with CD8 Reactome DB_ID: 198898 Reactome Database ID Release 43198898 Reactome, http://www.reactome.org ReactomeREACT_11534 has a Stoichiometric coefficient of 1 PathwayStep4100 peptide loaded MHC class II Reactome DB_ID: 2213232 Reactome Database ID Release 432213232 Reactome, http://www.reactome.org ReactomeREACT_124034 has a Stoichiometric coefficient of 1 Ligand interacting with NKG2D Reactome DB_ID: 198915 Reactome Database ID Release 43198915 Reactome, http://www.reactome.org ReactomeREACT_11751 has a Stoichiometric coefficient of 1 NKG2D complexed with DAP10 Reactome DB_ID: 198920 Reactome Database ID Release 43198920 Reactome, http://www.reactome.org ReactomeREACT_11468 has a Stoichiometric coefficient of 2 HLA-C group 1 interacting with KIR2DL2/3 Reactome DB_ID: 198909 Reactome Database ID Release 43198909 Reactome, http://www.reactome.org ReactomeREACT_11577 has a Stoichiometric coefficient of 1 HLA-C Cw4 (group 2) Reactome DB_ID: 198911 Reactome Database ID Release 43198911 Reactome, http://www.reactome.org ReactomeREACT_11388 has a Stoichiometric coefficient of 1 p-RAF binds 14-3-3 beta/alpha Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Inactive Raf-1 is associated in the cytoplasm with 14-3-3. 14-3-3 binds to Raf-1 via the Ser259 phosphorylation site (S1). This interaction stabilises the inactive conformation of Raf-1 in which the Ras-binding Cysteine-rich domain (CRD) is obscured. The Raf-1 molecule contains an additional p21ras-binding domain (RBD), a second serine phosphorylation site at S621 (S2) and two tyrosine phosphorylation sites (at 340, Y1 and 341, Y2). Pubmed9069260 Reactome Database ID Release 43109804 Reactome, http://www.reactome.org ReactomeREACT_2158 Transient dissociation of 14-3-3 upon Ras binding Activated p21ras (the GTP-bound form) is associated with the plasma membrane. Inactive Raf-1 is associated in the cytoplasm with 14-3-3. 14-3-3 binds to Raf-1 via the Ser259 phosphorylation site (S1). This interaction stabilises the inactive conformation of Raf-1 in which the Ras-binding Cysteine-rich domain (CRD) is obscured. The Raf-1 molecule contains an additional p21ras-binding domain (RBD), a second serine phosphorylation site at S621 (S2) and two tyrosine phosphorylation sites (at 340, Y1 and 341, Y2).<br>Raf-1 binds activated p21ras via the RBD. This displaces 14-3-3 from Ser259 and unmasks the CRD. Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Pubmed9069260 Reactome Database ID Release 43109803 Reactome, http://www.reactome.org ReactomeREACT_359 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Kinesins:Dynactin:microtubule Reactome DB_ID: 2213219 Reactome Database ID Release 432213219 Reactome, http://www.reactome.org ReactomeREACT_121653 has a Stoichiometric coefficient of 1 CaMK IV phosphorylates CREB Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 2.7.11.17 Edited: Jassal, B, 2008-11-06 10:17:49 Reactome Database ID Release 43111912 Reactome, http://www.reactome.org ReactomeREACT_15427 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The cAMP-responsive element binding protein (CREB), a key regulator of gene expression, is activated by phosphorylation on Ser-133. Several different protein kinases possess the capability of driving this phosphorylation, making it a point of potential convergence for multiple intracellular signaling cascades. Work in neurons has indicated that physiologic synaptic stimulation recruits a fast calmodulin kinase IV (CaMKIV)-dependent pathway that dominates early signaling to CREB. Calmodulin activates Cam-PDE 1 Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Increased Ca2+ levels, acting via calmodulin, can activate PDE which can then act upon cAMP. Pubmed15272012 Pubmed18335582 Reactome Database ID Release 43111956 Reactome, http://www.reactome.org ReactomeREACT_15450 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 cAMP hydrolysis by Cam-PDE 1 Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Phosphodiesterases (PDEs) hydrolyze cAMP and cGMP, inactivating these second messengers. Pubmed17726023 Reactome Database ID Release 43111955 Reactome, http://www.reactome.org ReactomeREACT_827 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Inhibition of GRK2 by calmodulin Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 GRK2 is a Serine/Threonine kinase. G-protein-coupled receptor kinases (GRKs) are important regulators of G-protein-coupled receptor function. Binding of calmodulin to GRK2 results in inhibition of the kinase activity. This inhibition is almost completely abolished when GRK2 is phosphorylated by PKC. Pubmed11042191 Pubmed8910504 Pubmed9753452 Reactome Database ID Release 43111966 Reactome, http://www.reactome.org ReactomeREACT_15422 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PKC phosphorylates GRK2 Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 GRK2 is phosphorylated at serine 29 in vitro and in vivo by the alpha, gamma and delta isoforms of PKC. PKC-mediated phosphorylation at Ser29 increases GRK2 kinase activity towards GPCR substrates, contributing to GPCR desensitization. Phosphorylation at Ser29, which falls within the calmodulin-binding region of GRK2, abolishes the inhibitory effect of calmodulin on GRK2 kinase activity. Pubmed11042191 Reactome Database ID Release 43111970 Reactome, http://www.reactome.org ReactomeREACT_15534 GRB2 binds SOS1 Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Orlic-Milacic, Marija, 2011-08-25 Edited: Schmidt, EE, 0000-00-00 00:00:00 In the cytoplasm of unstimulated cells, SOS1 is found in a complex with GRB2. The interaction occurs between the carboxy terminal domain of SOS1 and the Src homology 3 (SH3) domains of GRB2. Pubmed8479541 Reactome Database ID Release 43109813 Reactome, http://www.reactome.org ReactomeREACT_2257 Reviewed: Heldin, CH, 2008-02-12 09:44:02 GRB2:SOS1 complex binds to EGF:EGFR complex Authored: Castagnoli, L, 2006-10-10 13:09:34 Cytoplasmic target proteins containing the SH2 domain can bind to activated EGFR. One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 tyrosine autophosphorylation sites on the receptor. Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed7518560 Pubmed7527043 Reactome Database ID Release 43177943 Reactome, http://www.reactome.org ReactomeREACT_12392 Reviewed: Heldin, CH, 2008-02-12 09:44:02 SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:GRB2:SOS1) Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed8493579 Reactome Database ID Release 43177938 Reactome, http://www.reactome.org ReactomeREACT_12386 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The guanine nucleotide exchange factor SOS1 interacts with EGFR through the adaptor protein, GRB2. Upon formation of this complex, SOS activates RAS by promoting GDP release and GTP binding. Long chain fatty acids Converted from EntitySet in Reactome Reactome DB_ID: 879559 Reactome Database ID Release 43879559 Reactome, http://www.reactome.org ReactomeREACT_24406 UDP-sugar substrates of SLC35D2 Converted from EntitySet in Reactome Reactome DB_ID: 744234 Reactome Database ID Release 43744234 Reactome, http://www.reactome.org ReactomeREACT_23127 PathwayStep890 PathwayStep4197 UDP-sugar substrates of SLC35D2 Converted from EntitySet in Reactome Reactome DB_ID: 744229 Reactome Database ID Release 43744229 Reactome, http://www.reactome.org ReactomeREACT_23247 PathwayStep891 PathwayStep4198 PathwayStep4195 PathwayStep4196 PathwayStep894 PathwayStep895 PathwayStep892 PathwayStep4199 PathwayStep893 PathwayStep898 PathwayStep899 PathwayStep4190 PathwayStep896 PathwayStep897 PathwayStep4193 PathwayStep4194 PathwayStep4191 PathwayStep4192 UDP-Gal transporter substrates Converted from EntitySet in Reactome Reactome DB_ID: 735691 Reactome Database ID Release 43735691 Reactome, http://www.reactome.org ReactomeREACT_22450 UDP-Gal transporter substrates Converted from EntitySet in Reactome Reactome DB_ID: 735692 Reactome Database ID Release 43735692 Reactome, http://www.reactome.org ReactomeREACT_22484 ligands of SLC29A4 Converted from EntitySet in Reactome Reactome DB_ID: 727774 Reactome Database ID Release 43727774 Reactome, http://www.reactome.org ReactomeREACT_23205 PathwayStep880 PathwayStep881 PathwayStep882 PathwayStep883 PathwayStep884 PathwayStep885 PathwayStep886 PathwayStep887 PathwayStep888 PathwayStep889 ligands of SLC29A3 Converted from EntitySet in Reactome Reactome DB_ID: 727746 Reactome Database ID Release 43727746 Reactome, http://www.reactome.org ReactomeREACT_22952 ligands of SLC29A4 Converted from EntitySet in Reactome Reactome DB_ID: 727737 Reactome Database ID Release 43727737 Reactome, http://www.reactome.org ReactomeREACT_23305 ligands of SLC29A3 Converted from EntitySet in Reactome Reactome DB_ID: 727782 Reactome Database ID Release 43727782 Reactome, http://www.reactome.org ReactomeREACT_22517 PathwayStep872 PathwayStep873 PathwayStep870 PathwayStep871 PathwayStep878 PathwayStep879 PathwayStep876 PathwayStep877 PathwayStep874 PathwayStep875 ligands of SLC29A1 Converted from EntitySet in Reactome Reactome DB_ID: 179745 Reactome Database ID Release 43179745 Reactome, http://www.reactome.org ReactomeREACT_8580 ligands of SLC29A2 Converted from EntitySet in Reactome Reactome DB_ID: 179742 Reactome Database ID Release 43179742 Reactome, http://www.reactome.org ReactomeREACT_8574 ligands of SLC29A2 Converted from EntitySet in Reactome Reactome DB_ID: 179747 Reactome Database ID Release 43179747 Reactome, http://www.reactome.org ReactomeREACT_8842 PathwayStep860 PathwayStep861 PathwayStep862 PathwayStep867 PathwayStep868 PathwayStep869 PathwayStep863 PathwayStep864 PathwayStep865 PathwayStep866 ligands of SLC28A3 Converted from EntitySet in Reactome Reactome DB_ID: 179737 Reactome Database ID Release 43179737 Reactome, http://www.reactome.org ReactomeREACT_8379 vRNP Export through the nuclear pore GENE ONTOLOGYGO:0046796 Pubmed11124902 Pubmed11231581 Pubmed11289803 Pubmed11451485 Pubmed11932251 Pubmed15574331 Pubmed16608852 Pubmed17081640 Pubmed8113738 Pubmed9837918 Reactome Database ID Release 43168880 Reactome, http://www.reactome.org ReactomeREACT_6136 Viral RNP, bound by M1 and NEP/NS2 interacting with CRM1, are shuttled through the nuclear pore into the cytoplasm (Martin, 1991; O'Neill, 1998; Buolo, 2006). This mechanism may resemble export of HIV-1 ribonucleoprotein, where the HIV-1 Rev export protein interacts with CRM1 (Askjaer, 1998). A number of cofactors are implicated in CRM1-mediated export, including the small GTPase Ran, Ran-binding proteins 1 and 3, and a guanine nucleotide exchange factor (Nilsson, 2001; Nemergut, 2002; Petosa, 2004). Ternary CRM1-cofactor-cargo complexes likely interact transiently with nuclear pore proteins (nucleoporins) as they traverse the pore (reviewed in Suntharalingam, 2003). RanGTP is hydrolyzed to RanGDP in the cytoplasm, an activity that can be stimulated by NEP/NS2 (Akarsu, 2003). Influenza infection activates Raf/MEK/ERK signaling, which is necessary for NEP/NS2-mediated export of viral RNP (Pleschka, 2001; Marjuki, 2006). Influenza vRNP complexes released into the cytoplasm do not re-enter the nucleus, as they are thought to remain bound by M1, preventing re-import (Martin, 1991). It has been suggested that M1 binding of zinc cations could distinguish M1 bound to the vRNP from polymerized, matrix M1 present in nascent virions (Elster, 1994). ligands of SLC28A1 Converted from EntitySet in Reactome Reactome DB_ID: 179739 Reactome Database ID Release 43179739 Reactome, http://www.reactome.org ReactomeREACT_8051 Entry of M2 into the endoplasmic reticulum Authored: Steel, J, 2007-04-30 20:49:24 Pubmed8460475 Reactome Database ID Release 43195733 Reactome, http://www.reactome.org ReactomeREACT_10095 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The integral membrane protein M2 is synthesized on membrane-bound ribosomes and subsequently transported across the ER, where it is folded and assembled into a tetramer. ligands of SLC28A1 Converted from EntitySet in Reactome Reactome DB_ID: 179738 Reactome Database ID Release 43179738 Reactome, http://www.reactome.org ReactomeREACT_8344 PathwayStep4148 Assembly of M2 tetramers Authored: Steel, J, 2007-04-30 20:49:24 Pubmed10508393 Pubmed11087364 Reactome Database ID Release 43188544 Reactome, http://www.reactome.org ReactomeREACT_10123 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The M2 from influenza A virus is a 97-residue protein with a single transmembrane helix that associates to form a tetramer in the endoplasmic reticulum (Salom et al, 2000). A 15-20-residue segment C-terminal to the membrane-spanning region has been postulated to aid in the stabilization of the tetrameric assembly (Kochendoerfer et al 1999). has a Stoichiometric coefficient of 4 PathwayStep4149 Entry of NA into the endoplasmic reticulum Authored: Steel, J, 2007-04-30 20:49:24 Pubmed8460475 Reactome Database ID Release 43195734 Reactome, http://www.reactome.org ReactomeREACT_10062 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The integral membrane protein NA is synthesized on membrane-bound ribosomes and subsequently transported across the ER where it is folded and glycosylated. Subsequently NA is assembled into a tetramer. vitamins transported by SMVT Converted from EntitySet in Reactome Reactome DB_ID: 429627 Reactome Database ID Release 43429627 Reactome, http://www.reactome.org ReactomeREACT_22987 Binding of M1 to vRNP Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 M1 protein binds to viral RNP through its C-terminal domain (Baudin, 2001). The influenza M1 protein accumulates in the infected cell nucleus through a nuclear localization signal (NLS) RKLKR (residues 101-105) in its N-terminus (Ye, 1999). A host cell protein, HSP70, is thought to inhibit M1 binding at nonpermissive temperatures (Hirayama et al., 2004). Pubmed10438836 Pubmed10644350 Pubmed11222100 Pubmed11531417 Pubmed12490406 Pubmed14722281 Reactome Database ID Release 43192746 Reactome, http://www.reactome.org ReactomeREACT_9407 Reviewed: Squires, B, 2007-02-12 19:39:22 Binding of NEP/NS2 to vRNP:M1 Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 GENE ONTOLOGYGO:0046796 Pubmed7503702 Pubmed8356796 Reactome Database ID Release 43168893 Reactome, http://www.reactome.org ReactomeREACT_6303 Reviewed: Squires, B, 2007-02-12 19:39:22 Structural characterization of NEP/NS2 suggests that acidic residues in the C-terminus of NEP/NS2 bind to M1, with Trp78 critical for interaction (Ward, 1995; Yasuda, 1993; Akarsu, 2003). Binding of vRNP:M1:NEP complex to CRM1 export receptor GENE ONTOLOGYGO:0046796 Pubmed11118210 Pubmed11119609 Pubmed11289803 Pubmed11451485 Reactome Database ID Release 43168857 Reactome, http://www.reactome.org ReactomeREACT_6194 Virus NEP/NS2 interacts with human CRM1 (hCRM1), possibly dependent on a nuclear export signal (NES) motif in the NEP/NS2 N-terminal region (O'Neill, 1998; Neumann, 2000). The CRM1/exportin-1 pathway is a cellular mechanism for nuclear export, with CRM1 interacting with the Ran small GTPase and a cargo molecule's leucine-rich NES (Fukuda, 1997; Petosa, 2004). Leptomycin B, which specifically inhibits hCRM1, blocks export of viral RNP (Elton, 2001; Ma, 2001; Watanabe, 2001). Thus, NEP/NS2 interaction with cellular nuclear export machinery is essential for nuclear export of vRNP complexes and influenza virus release. A role for NP protein interaction with export machinery has also been proposed (Elton, 2001). ligands of SLC29A1 Converted from EntitySet in Reactome Reactome DB_ID: 179746 Reactome Database ID Release 43179746 Reactome, http://www.reactome.org ReactomeREACT_8358 unidentified caspase acting on ZO-2 Reactome DB_ID: 500674 Reactome Database ID Release 43500674 Reactome, http://www.reactome.org ReactomeREACT_22003 ligands of SLC28A2 Converted from EntitySet in Reactome Reactome DB_ID: 179741 Reactome Database ID Release 43179741 Reactome, http://www.reactome.org ReactomeREACT_8955 unidentified caspase acting on ZO-1 Reactome DB_ID: 500671 Reactome Database ID Release 43500671 Reactome, http://www.reactome.org ReactomeREACT_22050 ligands of SLC28A2 Converted from EntitySet in Reactome Reactome DB_ID: 179740 Reactome Database ID Release 43179740 Reactome, http://www.reactome.org ReactomeREACT_8398 unidentified caspase acting on Plakophilin 1 Reactome DB_ID: 500682 Reactome Database ID Release 43500682 Reactome, http://www.reactome.org ReactomeREACT_21872 ligands of SLC28A3 Converted from EntitySet in Reactome Reactome DB_ID: 179743 Reactome Database ID Release 43179743 Reactome, http://www.reactome.org ReactomeREACT_8767 unidentified caspase acting on Desmoplakin Reactome DB_ID: 500669 Reactome Database ID Release 43500669 Reactome, http://www.reactome.org ReactomeREACT_21697 PathwayStep855 PathwayStep854 PathwayStep853 PathwayStep852 PathwayStep859 PathwayStep4150 PathwayStep858 PathwayStep857 PathwayStep856 PathwayStep4154 PathwayStep4153 PathwayStep4152 PathwayStep4151 PathwayStep851 PathwayStep4158 Assembly of NA tetramers Authored: Steel, J, 2007-04-30 20:49:24 Pubmed7541844 Pubmed9400974 Reactome Database ID Release 43169847 Reactome, http://www.reactome.org ReactomeREACT_6231 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Tetramerisation of the NA occurs in the ER following an initial dimerisation step. Tetramerisation is believed to be dependant on glycosylation of the NA molecules has a Stoichiometric coefficient of 4 PathwayStep850 PathwayStep4157 Glycosylation of NA Authored: Steel, J, 2007-04-30 20:49:24 Glycosylation of NA occurs within the endoplasmic reticulum and is believed to be neccessary for proper tetramerization of the NA dimers. Sugar residues become attached to four of the five potential glycosylation sites in the head of N1 neuraminidase (Hausman et al., 1997). Pubmed15331729 Pubmed6700587 Pubmed7541844 Pubmed9400974 Reactome Database ID Release 43169919 Reactome, http://www.reactome.org ReactomeREACT_6181 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 PathwayStep4156 PathwayStep4155 Entry of HA into the endoplasmic reticulum Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019060 Pubmed8460475 Reactome Database ID Release 43168884 Reactome, http://www.reactome.org ReactomeREACT_6309 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The integral membrane protein HA is synthesized on membrane-bound ribosomes and subsequently transported across the endoplasmic reticulum, where it is folded, glycosylated, and assembled into a trimer. PathwayStep4159 OAT2/4 sulfate conjugate substrates Converted from EntitySet in Reactome Reactome DB_ID: 561071 Reactome Database ID Release 43561071 Reactome, http://www.reactome.org ReactomeREACT_22525 OAT1-3 substrates Converted from EntitySet in Reactome Reactome DB_ID: 561078 Reactome Database ID Release 43561078 Reactome, http://www.reactome.org ReactomeREACT_22453 PathwayStep849 vitamins transported by SMVT Converted from EntitySet in Reactome Reactome DB_ID: 429605 Reactome Database ID Release 43429605 Reactome, http://www.reactome.org ReactomeREACT_23003 XL765 Reactome DB_ID: 2399863 Reactome Database ID Release 432399863 Reactome, http://www.reactome.org ReactomeREACT_148300 BEZ235 NVP-BEZ235 Reactome DB_ID: 2399744 Reactome Database ID Release 432399744 Reactome, http://www.reactome.org ReactomeREACT_148216 PI3K inhibitors Converted from EntitySet in Reactome Reactome DB_ID: 2399811 Reactome Database ID Release 432399811 Reactome, http://www.reactome.org ReactomeREACT_148311 BKM120 NVP-BKM120 Reactome DB_ID: 2399771 Reactome Database ID Release 432399771 Reactome, http://www.reactome.org ReactomeREACT_148266 OAT2/4 sulfate conjugate substrates Converted from EntitySet in Reactome Reactome DB_ID: 561062 Reactome Database ID Release 43561062 Reactome, http://www.reactome.org ReactomeREACT_23389 BGT226 NVP-BGT226 Reactome DB_ID: 2399772 Reactome Database ID Release 432399772 Reactome, http://www.reactome.org ReactomeREACT_147911 AKT/AKT1 E17K mutant Converted from EntitySet in Reactome Reactome DB_ID: 2400013 Reactome Database ID Release 432400013 Reactome, http://www.reactome.org ReactomeREACT_147936 PathwayStep842 GUSB substrates Converted from EntitySet in Reactome Reactome DB_ID: 2318407 Reactome Database ID Release 432318407 Reactome, http://www.reactome.org ReactomeREACT_148006 PathwayStep841 HYAL1 substrates Converted from EntitySet in Reactome Reactome DB_ID: 2318601 Reactome Database ID Release 432318601 Reactome, http://www.reactome.org ReactomeREACT_148345 PathwayStep844 microtubules Reactome DB_ID: 140523 Reactome Database ID Release 43140523 Reactome, http://www.reactome.org ReactomeREACT_4405 PathwayStep843 PathwayStep846 PathwayStep845 XL147 Reactome DB_ID: 2399886 Reactome Database ID Release 432399886 Reactome, http://www.reactome.org ReactomeREACT_148615 PathwayStep848 PathwayStep4161 GSK1059615 Reactome DB_ID: 2399768 Reactome Database ID Release 432399768 Reactome, http://www.reactome.org ReactomeREACT_148511 PathwayStep847 PathwayStep4160 PathwayStep4163 PathwayStep4162 PathwayStep4165 PathwayStep4164 PathwayStep4167 PathwayStep4166 PathwayStep840 PathwayStep4169 PathwayStep4168 RNP association Authored: Marsh, G, 2007-04-30 20:49:40 GENE ONTOLOGYGO:0019072 Pubmed13174769 Pubmed1833874 Reactome Database ID Release 43168895 Reactome, http://www.reactome.org ReactomeREACT_6336 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The random incorporation model as its name suggests proposes that there is no selection at all on which vRNPs are packaged. It is assumed that each vRNP has equal probability of being packaged, and that if enough vRNPS are packaged a particular percentage of budding virions will receive at least one copy of each genome segment. This model is supported by evidence that infectious virions may possess more than eight vRNPs assuring the presence of a full complement of eight vRNPs in a significant percentage of virus particles. Mathematical analysis of packaging suggested that twelve RNA segments would need to be packaged in order to obtain approximately 10% of virus particles that are fully infectious (Enami, 1991), a number that is compatible with experimental data (Donald, 1954). Due to the low amount of RNA per virion (estimated at 1-2% w/w), enumeration of the precise number of RNAs packaged in a virion is difficult. Association with M1 at cell membrane As influenza viruses bud from the plasma membrane of infected cells, complete virions are not seen inside cells. In polarized epithelial cells, assembly and budding of influenza occurs from the apical plasma membrane (Schmitt, 2004). For efficient assembly, all virion components must accumulate at the budding site, and it is believed that the viral glycoprotein accumulation determines the site of virus assembly and budding (Nayak, 2004). M1 is thought to be the bridge between the envelope glycoproteins and the RNPs for assembly (Schmitt, 2004). M2 is also required, because if it is not present RNPs are not packaged into budding virions (McCown, 2005), however it role is not known. Authored: Marsh, G, 2007-04-30 20:49:40 Pubmed15298170 Pubmed15567494 Pubmed15731254 Reactome Database ID Release 43195926 Reactome, http://www.reactome.org ReactomeREACT_10077 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 157 has a Stoichiometric coefficient of 2992 has a Stoichiometric coefficient of 37 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 has a Stoichiometric coefficient of 976 Membrane fusion Authored: Marsh, G, 2007-04-30 20:49:40 GENE ONTOLOGYGO:0046766 Reactome Database ID Release 43168860 Reactome, http://www.reactome.org ReactomeREACT_6193 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The final step in the budding process is the fusion of the lipid membrane surrounding the virion core, producing an extracellular enveloped virus particle. Neuraminidase enzymatic release from sialic acid Authored: Marsh, G, 2007-04-30 20:49:40 EC Number: 3.2.1.18 GENE ONTOLOGYGO:0019076 Pubmed10580059 Pubmed15011946 Pubmed4472498 Pubmed7815489 Pubmed978183 Reactome Database ID Release 43168870 Reactome, http://www.reactome.org ReactomeREACT_6348 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The release of influenza virus particles after seperation of the virus and infected cell membrane is an active process. During the budding process, HA on the surface of the newly budding virion binds to cell surface molecules containing sialic acid residues as seen during attachment. The NA glycoproteins neuraminidase activity is essential to cleave the link between the HA and sialic acid on the surface of the host cell from which the budding virus is emeging from. Thus the NA mediated cleavage of sialic acid residues terminally linked to glycoproteins and glycolipids is the final step in releasing the virus particle from the host cell. This essential role of NA in release of virus particle has been demonstrated with the use of NA inhibitors (Palese, 1976; Luo, 1999; Garman, 2004), ts NA mutant viruses (Palese, 1974) and with viruses lacking NA activity (Liu, 1995). In all cases, viruses remain bound to the cell surface in clumps in the absence of NA enzymatic activity, resulting in loss of infectivity. Addition of exogenous sialidase results in virus release and recovery of infectivity. The sialidase activity of the NA is also important for removing sialic acid from the HA on virus particles, if this is not removed, virus particles aggregate. Binding of NS1 to cleavage and host polyadenylation specificity factor (CPSF) GENE ONTOLOGYGO:0046778 Influenza virus's non-structural protein (NS1) binds to the host cell's cleavage and host polyadenylation specificity factor (CPSF), inhibiting the ability of CPSF to bind to pre-mRNAs and thus preventing efficient 3' end processing and export of host cell mRNAs out of the nucleus. Pubmed11421366 Pubmed12667806 Pubmed9651582 Pubmed9986787 Reactome Database ID Release 43168859 Reactome, http://www.reactome.org ReactomeREACT_6168 Binding of NS1 to poly(A)-binding protein II (PABII) GENE ONTOLOGYGO:0046778 Pubmed10205180 Reactome Database ID Release 43168883 Reactome, http://www.reactome.org ReactomeREACT_6287 The influenza virus non-structural protein 1 (NS1) binds to the host cell's poly(A)-binding protein II (PABII) thus preventing PABII from properly extending the poly-A tail of pre-mRNA within the host cell nucleus. These pre-mRNAs are then prevented from exiting the nucleus. ORCTL2 substrates Converted from EntitySet in Reactome Reactome DB_ID: 597604 Reactome Database ID Release 43597604 Reactome, http://www.reactome.org ReactomeREACT_23364 Binding of NS1 to dsRNA GENE ONTOLOGYGO:0030683 Pubmed14645582 Reactome Database ID Release 43168891 Reactome, http://www.reactome.org ReactomeREACT_6339 The ability of viral non-structural protein 1 (NS1) to sequester dsRNA is believed to be one of the primary mechanisms by which NS1 prevents activation of downstream anti-viral signaling pathways. Binding of NS1 to PKR At the beginning of this reaction, 1 molecule of 'NS1 Homodimer', and 1 molecule of 'PKR human' are present. At the end of this reaction, 1 molecule of 'NS1 Homodimer:PKR Complex' is present.<br><br> <br> GENE ONTOLOGYGO:0030683 Reactome Database ID Release 43168896 Reactome, http://www.reactome.org ReactomeREACT_6186 OAT1-3 substrates Converted from EntitySet in Reactome Reactome DB_ID: 561049 Reactome Database ID Release 43561049 Reactome, http://www.reactome.org ReactomeREACT_23252 ORCTL2 substrates Converted from EntitySet in Reactome Reactome DB_ID: 597623 Reactome Database ID Release 43597623 Reactome, http://www.reactome.org ReactomeREACT_22882 PathwayStep838 PathwayStep839 Accumulation of M1 at the inner leaflet of the lipid bilayer Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019068 Pubmed10775599 Pubmed10954572 Pubmed8918911 Pubmed9060654 Pubmed9971805 Reactome Database ID Release 43168894 Reactome, http://www.reactome.org ReactomeREACT_6137 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 There is evidence for the association of M1 with lipid rafts in influenza infected cells, whereas M1 expressed alone remains soluble (Ali et al., 2000; Zhang and Lamb, 1996), suggesting association of M1 with other viral proteins in targetting to the cell membrane. Coexpression of HA and NA together with M1 has been shown to promote raft association of M1. This association requires the TMD and cytoplasmic tails of HA and NA (Ali et al, 2000; Zhang et al, 2000). This is consistent with M1 becoming associated with HA and NA during their passage through the exocytic pathway to raft domains in the apical membrane. alternatively M1 may use the cytoskeleton to reach the virus assembly site, as M1 interacts with cytoskeletal components (Alvalos et al., 1997). The M1 interaction depends on the presence of RNP and is most likely mediated by direct binding of F-actin by NP (Digard et al., 1999). PathwayStep837 PathwayStep4172 PathwayStep836 PathwayStep4171 PathwayStep835 PathwayStep4170 PathwayStep834 PathwayStep833 PathwayStep832 PathwayStep831 PathwayStep830 PathwayStep4179 NA activation of TGF-beta GENE ONTOLOGYGO:0046732 Influenza A virus induces apoptosis in a variety of ways including by activation of host TGF-beta by viral neuraminidase (NA). Pubmed10823850 Pubmed8970987 Pubmed9934696 Reactome Database ID Release 43168865 Reactome, http://www.reactome.org ReactomeREACT_6229 PathwayStep4178 PathwayStep4177 PathwayStep4176 PathwayStep4175 PathwayStep4174 PathwayStep4173 Budding of vesicle with the HA trimer, NA tetramer and M2 tetramer from the endoplasmic reticulum into the cytosol Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019060 Pubmed0 Reactome Database ID Release 43168869 Reactome, http://www.reactome.org ReactomeREACT_6225 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Viral proteins are packaged into a golgi apparatus bound transport vesicle. Fusion of vesicle containing the HA trimer, NA tetramer and M2 tetramer to the Golgi apparatus Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019060 Once the tranport vesicle arrives at the golgi apparatus, it docks and dumps its contents into the golgi lumen. Pubmed0 Reactome Database ID Release 43168871 Reactome, http://www.reactome.org ReactomeREACT_6273 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Glycosylation and Folding of HA Authored: Steel, J, 2007-04-30 20:49:24 Pubmed10679029 Pubmed10764645 Pubmed12535523 Pubmed1321156 Pubmed1331514 Pubmed2178922 Pubmed3359486 Pubmed7541532 Pubmed8302866 Pubmed8497042 Pubmed8534914 Pubmed9348279 Reactome Database ID Release 43169921 Reactome, http://www.reactome.org ReactomeREACT_6177 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The ectodomain of HA is translocated into the ER lumen, where it undergoes a series of folding events mediated by the formation of disulfide bonds and glycosylation reactions. The formation of a discrete intermediate species of highly folded monomeric protein preceeds trimerisation. The folding process is efficient and rapid, with greater than 90% of the protein trafficked to the golgi apparatus; and mature HA0 subunits appearing in a matter of a few minutes. Calnexin and calreticulin have been identified as cellular lectins which interact transiently with newly synthesized HA by attaching to partially trimmed N-linked oligosaccharides (Herbert et al., 1997), facilitating correct folding of the HA molecule. Trimerization of HA Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019082 Pubmed2380242 Pubmed2429970 Pubmed2450677 Pubmed2645296 Pubmed3359486 Pubmed3757030 Pubmed7729412 Pubmed8460475 Reactome Database ID Release 43168875 Reactome, http://www.reactome.org ReactomeREACT_6141 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Trimerisation of the fully folded and fully oxidised HA monomer is thought to occur in the endoplasmic reticulum and ERGIC compartment, following dissociation of HA from calnexin. Trimerisation is generally thought to be the final step in HA maturation occurring in the endoplasmic reticulum before transport to the Golgi apparatus, although Yewdell et al (1988) provide data suggesing that trimerisation may occur within the Golgi. has a Stoichiometric coefficient of 3 OCT3 substrates Converted from EntitySet in Reactome Reactome DB_ID: 549326 Reactome Database ID Release 43549326 Reactome, http://www.reactome.org ReactomeREACT_22507 Association of HA into rafts Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019068 Influenza virus buds preferentially from lipid rafts (Scheiffele et al, 1999). NA protein individually accumulates at, and is selectively incorporated into rafts (Kundu et al., 1996). The signals for raft association lie within the transmembranse domain (TMD), (Barman et al., 2001, Barman et al., 2004), and raft association of NA has been shown to be essential for efficient virus replication. This is believed to be due to a requirement for a concentration of NA at specific areas of the plasma membrane to support a level of NA incorporation into budding particles sufficient to allow for efficient virus release (Barman et al., 2004). Pubmed11451488 Pubmed14561897 Pubmed15113907 Pubmed15567494 Pubmed8709291 Pubmed9312009 Pubmed9890962 Reactome Database ID Release 43168862 Reactome, http://www.reactome.org ReactomeREACT_6146 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Association of NP into rafts Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019068 Pubmed12359424 Pubmed15522099 Pubmed9060654 Reactome Database ID Release 43168882 Reactome, http://www.reactome.org ReactomeREACT_6271 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 There is evidence that NP alone is intrinsically targeted to the apical plasma membrane and associates with lipid rafts in a cholesterol-dependent manner, which suggests that RNPs could reach the assembly site independently of the other viral components. Palmitoylation of cysteine residues on HA in the cis-Golgi network Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019082 Pubmed1297175 Pubmed1433532 Pubmed16227287 Pubmed1664239 Pubmed1871979 Pubmed1901916 Pubmed2371783 Pubmed8262238 Pubmed8627657 Pubmed8761467 Pubmed9791024 Reactome Database ID Release 43168858 Reactome, http://www.reactome.org ReactomeREACT_6187 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The hemagglutinin of influenza virus is palmitoylated with long-chain fatty acids.<br>Palmitoylation of HA is believed to occur in the cis golgi network (Veit 1993), shortly after trimerisation of the molecule, and before cleavage of the HA into HA1 and HA2. HA is palmitoylated through thioester linkages at three cysteine residues located in the cytoplasmic domain and at the carboxy-terminal end of the transmembrane region. Lack of acylation has no obvious influence on the biological activities of HA. Palmitoylation of cysteine residues on M2 in the cis-golgi network Authored: Steel, J, 2007-04-30 20:49:24 Palmitoylation of influenza A M2 occurs in the ER, or cis golgi network, following tetramerisation. The palmitoylation reaction proceeds via a labile thioester type bond at a specific residue of M2 (Sugrue et al., 1990). Pubmed2045796 Pubmed2219738 Reactome Database ID Release 43195739 Reactome, http://www.reactome.org ReactomeREACT_10133 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 OCT3 substrates Converted from EntitySet in Reactome Reactome DB_ID: 549255 Reactome Database ID Release 43549255 Reactome, http://www.reactome.org ReactomeREACT_22750 PathwayStep827 PathwayStep828 PathwayStep829 PathwayStep824 PathwayStep4181 PathwayStep823 PathwayStep4180 PathwayStep826 PathwayStep4183 PathwayStep825 PathwayStep4182 PathwayStep820 PathwayStep822 PathwayStep821 PathwayStep4189 PathwayStep4188 Transport of processed viral proteins to the cell membrane Authored: Steel, J, 2007-04-30 20:49:24 Once processed, the viral proteins are transported from the golgi apparatus to the plasma membrane. Pubmed10890900 Reactome Database ID Release 43195730 Reactome, http://www.reactome.org ReactomeREACT_10039 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Association of NA into rafts Authored: Steel, J, 2007-04-30 20:49:24 Influenza virus buds preferentially from lipid rafts (Scheiffele et al, 1999). NA protein individually accumulates at, and is selectively incorporated into rafts (Kundu et al., 1996). The signals for raft association lie within the transmembranse domain (TMD), (Barman et al., 2001, Barman et al., 2004), and raft association of NA has been shown to be essential for efficient virus replication. This is believed to be due to a requirement for a concentration of NA at specific areas of the plasma membrane to support a level of NA incorporation into budding particles sufficient to allow for efficient virus release (Barman et al., 2004). Pubmed11451488 Pubmed15113907 Pubmed15567494 Pubmed8709291 Pubmed9890962 Reactome Database ID Release 43195726 Reactome, http://www.reactome.org ReactomeREACT_9947 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 PathwayStep4185 PathwayStep4184 PathwayStep4187 PathwayStep4186 Activated FGFR1 fusion mutants Converted from EntitySet in Reactome Reactome DB_ID: 1839058 Reactome Database ID Release 431839058 Reactome, http://www.reactome.org ReactomeREACT_125233 Processing of Proglucagon to Glucagon-like Peptide-1 Authored: May, B, 2009-05-18 21:31:59 EC Number: 3.4.21 Edited: May, B, 2009-09-09 In secretory granules of intestinal L cells, proglucagon is proteolytically cleaved by prohormone convertase 1 (PC1) at two sites to yield GLP-1 (7-36) or GLP-1 (7-37). In humans almost all circulating GLP-1 is GLP-1 (7-36) amidated at the C-terminus. Experiments in knockout mice have shown that PC1 is necessary for cleavage. Carboxypeptidase E and peptidylglycine alpha-amidating monooxygenase may be involved in trimming and amidating the C-terminus. Pubmed12651102 Reactome Database ID Release 43381798 Reactome, http://www.reactome.org ReactomeREACT_23895 Reviewed: Bloom, SR, 2010-06-24 Talin:RIAM complex Reactome DB_ID: 354176 Reactome Database ID Release 43354176 Reactome, http://www.reactome.org ReactomeREACT_15897 has a Stoichiometric coefficient of 1 Overexpressed FGFR1 Converted from EntitySet in Reactome Reactome DB_ID: 1982056 Reactome Database ID Release 431982056 Reactome, http://www.reactome.org ReactomeREACT_123099 Secretion of Glucagon-like Peptide 1 from Intestinal L Cells Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-09-09 Pubmed11564718 Pubmed12540594 Pubmed12810581 Pubmed14719035 Pubmed15619630 Pubmed16219666 Pubmed17065399 Pubmed17681422 Pubmed18519800 Pubmed19001044 Reactome Database ID Release 43383313 Reactome, http://www.reactome.org ReactomeREACT_24006 Reviewed: Bloom, SR, 2010-06-24 Secretion of GLP-1 from intestinal L-cells is dependent on a rise in cytosolic calcium which, in turn, is stimulated by glucose (requires the GLUT2 glucose transporter), fatty acids (especially monounsaturated fatty acids, requires the GPR120 and GPR40 receptors), insulin, leptin, gastrin-releasing peptide, cholinergic transmitters (requires M1 and M2 muscarinic receptors), amino acids (requires mitogen activated protein kinase pathway), beta-adrenergic transmitters, and peptidergic transmitters. The exact mechanisms controlling secretion have not been elucidated. Rap1-GTP:PIP2:RIAM RIAM bound to Rap1-GTP Reactome DB_ID: 354110 Reactome Database ID Release 43354110 Reactome, http://www.reactome.org ReactomeREACT_18055 has a Stoichiometric coefficient of 1 FGFR1b FGR1_HUMAN Fibroblast growth factor receptor 1b Reactome DB_ID: 189878 Reactome Database ID Release 43189878 Reactome, http://www.reactome.org ReactomeREACT_9784 Processing of preproGLP-1 to proGLP-1 Authored: May, B, 2009-05-18 21:31:59 EC Number: 3.4.21 Edited: May, B, 2009-09-09 Reactome Database ID Release 43400459 Reactome, http://www.reactome.org ReactomeREACT_23907 Reviewed: Bloom, SR, 2010-06-24 The GCG (Proglucagon) mRNA is translated by ribosomes at the outer surface of the rough endoplasmic reticulum. The nascent peptide enters the endoplasmic reticulum through the translocon complex and the signal peptide is cleaved by the signal peptidase. Integrin alphaIIb beta3 Reactome DB_ID: 114514 Reactome Database ID Release 43114514 Reactome, http://www.reactome.org ReactomeREACT_4958 has a Stoichiometric coefficient of 1 PAPP-A and PAPP-A2 Converted from EntitySet in Reactome Reactome DB_ID: 381483 Reactome Database ID Release 43381483 Reactome, http://www.reactome.org ReactomeREACT_17786 Transit of Proglucagon from the ER Lumen to Secretory Granules Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-09-09 Proglucagon transits from the lumen of the endoplasmic reticulum to secretory granules. Pubmed3900195 Reactome Database ID Release 43421416 Reactome, http://www.reactome.org ReactomeREACT_23848 Reviewed: Bloom, SR, 2010-06-24 Integrin alphaIIb beta3:p(Y530)-SRC:CSK Reactome DB_ID: 377608 Reactome Database ID Release 43377608 Reactome, http://www.reactome.org ReactomeREACT_15817 has a Stoichiometric coefficient of 1 PathwayStep902 Activation of Epac2 by cAMP Authored: May, B, 2009-05-28 03:42:50 Each molecule of Epac2 binds 2 molecules of cAMP. Epac2 binds cAMP less tightly than PKA binds cAMP so it is believed that Epac2 binds cAMP after PKA is saturated. The binding of cAMP by Epac2 activates the guanyl nucleotide exchange activity of Epac2. Epac2 has also been shown to directly bind the SUR1 subunits of ATP-gated potassium channels (KATP channels) in beta cells so Epac2 may regulate potassium transport.<br>Epac2 interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis of insulin. Epac2 also interacts with the ryanodine-sensitive calcium channel on the ER membrane and may cause release of calcium from the ER into the cytosol. Edited: May, B, 2009-05-28 03:42:50 Pubmed11071853 Pubmed12401793 Pubmed12496249 Pubmed15569269 Pubmed16613879 Pubmed16973695 Pubmed17306374 Pubmed18202100 Reactome Database ID Release 43381608 Reactome, http://www.reactome.org ReactomeREACT_18272 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 has a Stoichiometric coefficient of 2 PIP3:PDK1:AKT:p(T410)-PKC zeta Reactome DB_ID: 437184 Reactome Database ID Release 43437184 Reactome, http://www.reactome.org ReactomeREACT_20994 has a Stoichiometric coefficient of 1 PathwayStep903 Exchange of GDP for GTP by Rap1A Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 Epac1 and Epac2 are activated by binding cAMP and positively regulate the exchange of GDP for GTP by the small GTPase Rap1A. The downstream effects of Rap1A:GTP in beta cells are uncertain but may involve increasing the number of "restless newcomer" secretory granules near the plasma membrane and thereby increasing secretion of insulin.<br> Other effects of Rap1A :GTP may include regulating beta cell proliferation through activation of the Raf/MEK/ERK mitogenic cascade and activation of the PI3 Kinase/PDK/PKC cell growth pathway. Pubmed15569269 Pubmed15995848 Pubmed16973695 Pubmed17306374 Reactome Database ID Release 43381727 Reactome, http://www.reactome.org ReactomeREACT_18379 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 PIP3:PDK1:AKT:PKC zeta Reactome DB_ID: 437191 Reactome Database ID Release 43437191 Reactome, http://www.reactome.org ReactomeREACT_21150 has a Stoichiometric coefficient of 1 PathwayStep900 Rap1-GTP Reactome DB_ID: 354126 Reactome Database ID Release 43354126 Reactome, http://www.reactome.org ReactomeREACT_16044 has a Stoichiometric coefficient of 1 PathwayStep901 Activation of Epac1 by cAMP Authored: May, B, 2009-05-28 03:42:50 Each molecule of Epac1 binds 1 molecule of cAMP. Epac1 binds cAMP less tightly than PKA binds cAMP so it is believed that Epac1 binds cAMP after PKA is saturated. The binding of cAMP by Epac1 activates the guanyl nucleotide exchange activity of Epac1. Epac1 has also been shown to bind the SUR1 subunit of ATP-gated potassium channels (KATP channels) in beta cells so Epac1 may participate in direct regulation of potassium transport.<br>Epac1 also interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis of insulin. Edited: May, B, 2009-05-28 03:42:50 Pubmed11071853 Pubmed12401793 Pubmed12496249 Pubmed15569269 Pubmed16613879 Pubmed16973695 Pubmed17306374 Pubmed18202100 Reactome Database ID Release 43381668 Reactome, http://www.reactome.org ReactomeREACT_18315 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 Rap1-GDP Reactome DB_ID: 354074 Reactome Database ID Release 43354074 Reactome, http://www.reactome.org ReactomeREACT_15771 has a Stoichiometric coefficient of 1 Transit of ProGIP from the ER Lumen to Secretory Granules Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-09-09 ProGIP transits from the lumen of the endoplasmic reticulum to secretory granules. Pubmed10366038 Reactome Database ID Release 43421426 Reactome, http://www.reactome.org ReactomeREACT_23843 Reviewed: Bloom, SR, 2010-06-24 Proteolytic Cleavage of Glucagon-like Peptide-1 (GLP-1) Authored: May, B, 2009-05-18 21:31:59 Dipeptidyl Peptidase IV (DPP4) cleaves 2 amino acids from the N-terminus of GLP-1, inactivating it. DPP4 determines the half life of GLP-1 in the bloodstream. It is unknown if the soluble form of DPP4, the membrane-bound form, or both catalyze the cleavage of GLP-1. EC Number: 3.4.21 Edited: May, B, 2009-09-09 Pubmed14719797 Pubmed15584901 Pubmed7883856 Pubmed8100523 Pubmed8798518 Reactome Database ID Release 43400495 Reactome, http://www.reactome.org ReactomeREACT_23859 Reviewed: Bloom, SR, 2010-06-24 Processing of preproGIP to proGIP Authored: May, B, 2009-05-18 21:31:59 EC Number: 3.4.21 Edited: May, B, 2009-09-09 Pubmed2890159 Reactome Database ID Release 43400496 Reactome, http://www.reactome.org ReactomeREACT_23888 Reviewed: Bloom, SR, 2010-06-24 The GIP mRNA is translated by ribosomes at the outer surface of the rough endoplasmic reticulum. The nascent peptide enters the endoplasmic reticulum through the translocon complex and the signal peptide is cleaved by the signal peptidase. T3/T4 hormones Converted from EntitySet in Reactome Reactome DB_ID: 879603 Reactome Database ID Release 43879603 Reactome, http://www.reactome.org ReactomeREACT_24702 Double-stranded DNA and chromatin Converted from EntitySet in Reactome Reactome DB_ID: 977589 Reactome Database ID Release 43977589 Reactome, http://www.reactome.org ReactomeREACT_76370 PathwayStep907 T3/T4 hormones Converted from EntitySet in Reactome Reactome DB_ID: 879628 Reactome Database ID Release 43879628 Reactome, http://www.reactome.org ReactomeREACT_24262 PathwayStep906 ABri/ADan amyloid fibril Reactome DB_ID: 976871 Reactome Database ID Release 43976871 Reactome, http://www.reactome.org ReactomeREACT_76070 PathwayStep905 Alpha-synuclein fibril Reactome DB_ID: 1247852 Reactome Database ID Release 431247852 Reactome, http://www.reactome.org ReactomeREACT_76428 PathwayStep904 Variant fibrinogen alpha chain fibril Reactome DB_ID: 976911 Reactome Database ID Release 43976911 Reactome, http://www.reactome.org ReactomeREACT_76110 Inactive SRC (pY530):CSK Reactome DB_ID: 377606 Reactome Database ID Release 43377606 Reactome, http://www.reactome.org ReactomeREACT_15710 has a Stoichiometric coefficient of 1 Variant cystatin-C fibril Reactome DB_ID: 976935 Reactome Database ID Release 43976935 Reactome, http://www.reactome.org ReactomeREACT_76112 Integrin alphaIIb beta3:p(Y530)-SRC:CSK:Talin:RIAM complex Reactome DB_ID: 354130 Reactome Database ID Release 43354130 Reactome, http://www.reactome.org ReactomeREACT_16075 has a Stoichiometric coefficient of 1 Long chain fatty acids Converted from EntitySet in Reactome Reactome DB_ID: 879544 Reactome Database ID Release 43879544 Reactome, http://www.reactome.org ReactomeREACT_24650 Gelsolin amyloid fibril Reactome DB_ID: 976919 Reactome Database ID Release 43976919 Reactome, http://www.reactome.org ReactomeREACT_76655 PathwayStep909 Variant lysozyme C fibril Reactome DB_ID: 976860 Reactome Database ID Release 43976860 Reactome, http://www.reactome.org ReactomeREACT_76507 PathwayStep908 PIK3R1 mutants Converted from EntitySet in Reactome Reactome DB_ID: 2399557 Reactome Database ID Release 432399557 Reactome, http://www.reactome.org ReactomeREACT_147976 ADP-ATP translocase maintains a high ADP:ATP ratio in the matrix A family of antiport, ATP-ADP translocases, preferentially export ATP from the matrix while importing ADP from the cytosol, thereby maintaining a high ADP:ATP ratio in the matrix. When there are increased energy demands on the body, such as under heavy exercise, cytosolic ADP rises and is exchanged with mitochondrial matrix ATP via the transmembrane ADP:ATP translocase. Increased ADP causes the proton-motive force to be discharged and protons enter via ATPase, thereby regenerating the ATP pool.<br>There are 3 isoforms of translocases in humans; isoform 1 is the heart/skeletal muscle form, isoform 2 is the fibroblast form and isoform 3 is the liver form. All isoforms exist as homodimers. The translocase can adopt 2 different conformations, called the CATR (carboxyatractyloside) and BA (bongkrekic acid) conformations. Amongst the endogenous nucleotides, only ADP and ATP can trigger the rapid conversion between the CATR and BA conformations.<br>The reaction can be summed as below:<br><b>ADP</b><sub>out</sub> + <b>ATP</b><sub>in</sub> <-> <b>ADP</b><sub>in</sub> + <b>ATP</b><sub>out</sub><br> Authored: Jassal, B, 2005-06-30 14:42:50 Pubmed2648994 Pubmed5840415 Pubmed5857365 Pubmed9587671 Reactome Database ID Release 43163215 Reactome, http://www.reactome.org ReactomeREACT_9011 HLA-E Reactome DB_ID: 198912 Reactome Database ID Release 43198912 Reactome, http://www.reactome.org ReactomeREACT_11603 has a Stoichiometric coefficient of 1 Integrin alphaIIb beta3:Active (p-Y419)-SRC Reactome DB_ID: 377614 Reactome Database ID Release 43377614 Reactome, http://www.reactome.org ReactomeREACT_17534 has a Stoichiometric coefficient of 1 PIK3CA mutants Converted from EntitySet in Reactome Reactome DB_ID: 2394008 Reactome Database ID Release 432394008 Reactome, http://www.reactome.org ReactomeREACT_148447 Closing of Inward Rectifying, ATP-sensitive Potassium Channels (KATP channels) ATP-sensitive potassium channels (KATP channels) bind ATP and close. The KATP channels in the beta cell are inward rectifying (allowing potassium ions to pass out the cell) and are partially responsible for maintaining the resting potential of the cell, about -70 mV. Closure of the KATP channels causes a depolarization (a reduction in the voltage differential) across the plasma membrane. Authored: May, B, 2008-04-15 08:41:29 Edited: D'Eustachio, P, 2009-03-06 11:49:32 Edited: May, B, 2009-02-12 22:40:35 Pubmed10194514 Pubmed10206966 Pubmed10866047 Pubmed10868950 Pubmed11078440 Pubmed16332676 Pubmed16513675 Pubmed16556766 Pubmed17021801 Pubmed17380317 Pubmed17919183 Pubmed18346985 Pubmed18596924 Pubmed19587354 Reactome Database ID Release 43265682 Reactome, http://www.reactome.org ReactomeREACT_16883 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 has a Stoichiometric coefficient of 4 HLA-E interacting with NKG2A-CD94 heterdimer Reactome DB_ID: 198914 Reactome Database ID Release 43198914 Reactome, http://www.reactome.org ReactomeREACT_11770 has a Stoichiometric coefficient of 1 Talin:RIAM complex:ECM ligands:2X(Integrin alphaIIb beta3:Active (p-Y419)-SRC) Reactome DB_ID: 377622 Reactome Database ID Release 43377622 Reactome, http://www.reactome.org ReactomeREACT_16022 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activator:PI3K/PI3K mutants Converted from EntitySet in Reactome Reactome DB_ID: 2400011 Reactome Database ID Release 432400011 Reactome, http://www.reactome.org ReactomeREACT_148475 Calcium Influx through Voltage-gated Calcium Channels Authored: May, B, 2008-04-15 08:41:29 Edited: D'Eustachio, P, 2009-03-06 11:49:32 Edited: May, B, 2009-02-12 22:40:35 Pubmed10424882 Pubmed11815460 Pubmed11815462 Pubmed11815463 Pubmed1309948 Pubmed15000528 Pubmed15504896 Pubmed15585596 Pubmed16513675 Pubmed16868246 Pubmed17660294 Reactome Database ID Release 43265645 Reactome, http://www.reactome.org ReactomeREACT_16913 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 Voltage-gated calcium channels respond to a change in voltage across the plasma membrane by opening and allowing free movement of calcium ions. In an unstimulated cell the concentration of calcium ions outside the cells is higher than inside due to calcium transporters so channel opening results in an influx of calcium into the cytosol. In the cytosol the calcium ions cause an immediate exocytosis of the readily releasable pool of docked insulin granules as well as a migration of reserve granules toward the plasma membrane where they will be released during the second, sustained phase of insulin secretion.<br>Mouse and human beta cells are known to contain L type channels Cav1.2 and Cav1.3, both of which have been shown to physically associate with docked insulin granules via Syntaxin1A. Cav1.2 and Cav1.3 predominate in the initial rapid release of insulin. Human beta cells also contain the P/Q type channel Cav2.1 and the R type channel Cav2.3. Cav2.3 is involved in regulating the second, sustained phase of insulin release but signaling and regulatory differences between the two phases of secretion are not fully characterized. Human cells also exhibit T-type (brief burst) calcium currents but the responsible channel has not been identified. E-cadherin bound to KLRG1 Reactome DB_ID: 198192 Reactome Database ID Release 43198192 Reactome, http://www.reactome.org ReactomeREACT_11260 has a Stoichiometric coefficient of 1 Integrin alphaIIb beta3:SRC Reactome DB_ID: 1215929 Reactome Database ID Release 431215929 Reactome, http://www.reactome.org ReactomeREACT_27818 has a Stoichiometric coefficient of 1 PTEN Mutants Converted from EntitySet in Reactome Reactome DB_ID: 2317393 Reactome Database ID Release 432317393 Reactome, http://www.reactome.org ReactomeREACT_148130 PathwayStep910 IP3 binds to the IP3 receptor, opening the endoplasmic reticulum Ca2+ channel Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43169680 Reactome, http://www.reactome.org ReactomeREACT_12008 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening. has a Stoichiometric coefficient of 4 CRTAM bound to NECL2 Reactome DB_ID: 198195 Reactome Database ID Release 43198195 Reactome, http://www.reactome.org ReactomeREACT_11356 has a Stoichiometric coefficient of 1 Talin:RIAM complex:ECM ligands: 2X(Integrin alphaIIb beta3:SRC) Reactome DB_ID: 377620 Reactome Database ID Release 43377620 Reactome, http://www.reactome.org ReactomeREACT_18152 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep911 Processing of proGIP to GIP Authored: May, B, 2009-05-18 21:31:59 EC Number: 3.4.21 Edited: May, B, 2009-09-09 Prohormone Convertase 1/3 in secretory granules cleaves Glucose Insulinotropic Polypeptide at Arg51 and Arg93, liberating the mature 42 amino acid GIP molecule. Reactome Database ID Release 43400492 Reactome, http://www.reactome.org ReactomeREACT_23880 Reviewed: Bloom, SR, 2010-06-24 Integrin alphaIIb beta3:Inactive (p-Y530)-SRC Reactome DB_ID: 377612 Reactome Database ID Release 43377612 Reactome, http://www.reactome.org ReactomeREACT_15668 has a Stoichiometric coefficient of 1 PGT substrates Converted from EntitySet in Reactome Reactome DB_ID: 879566 Reactome Database ID Release 43879566 Reactome, http://www.reactome.org ReactomeREACT_24713 PathwayStep912 Secretion of Glucose-dependent Insulinotropic Polypeptide from Intestinal K Cells Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-09-09 GIP is secreted by intestinal K-cells in response to glucose, amino acids, and fats. In mice fatty acids act to increase GIP secretion by binding the G-protein coupled receptors GPR40 and GPR119 present on intestinal K-cells. The stimulation is dependent on adenyl cyclase and intracellular calcium but the exact mechanism is unknown. Pubmed16219666 Pubmed18202141 Pubmed18519800 Reactome Database ID Release 43400509 Reactome, http://www.reactome.org ReactomeREACT_23868 Reviewed: Bloom, SR, 2010-06-24 LILR-interacting MHC Class I molecules Reactome DB_ID: 199592 Reactome Database ID Release 43199592 Reactome, http://www.reactome.org ReactomeREACT_11528 has a Stoichiometric coefficient of 1 Talin:RIAM complex:ECM ligands: 2X(Integrin alphaIIb beta3:Inactive (p-Y530)-SRC) Reactome DB_ID: 377616 Reactome Database ID Release 43377616 Reactome, http://www.reactome.org ReactomeREACT_17147 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR mutants Converted from EntitySet in Reactome Reactome DB_ID: 1982043 Reactome Database ID Release 431982043 Reactome, http://www.reactome.org ReactomeREACT_123533 PathwayStep913 Proteolytic Cleavage of Glucose-dependent Insulinotropic Polypeptide (GIP) Authored: May, B, 2009-05-18 21:31:59 Dipeptidyl Peptidase IV (DPP4) cleaves 2 amino acids from the N-terminus of GIP, inactivating it. DPP4 determines the half life of GIP in the bloodstream. It is unknown if the soluble form of DPP4, the membrane-bound form, or both catalyze the cleavage of GIP. EC Number: 3.4.21 Edited: May, B, 2009-09-09 Pubmed15584901 Pubmed8100523 Reactome Database ID Release 43400513 Reactome, http://www.reactome.org ReactomeREACT_23981 Reviewed: Bloom, SR, 2010-06-24 MHC Class I interacting with LILRs Reactome DB_ID: 198896 Reactome Database ID Release 43198896 Reactome, http://www.reactome.org ReactomeREACT_11656 has a Stoichiometric coefficient of 1 Talin:RIAM complex:ECM ligands: 2X(Integrin alphaIIb beta3:p(Y530)-SRC:CSK) Reactome DB_ID: 377619 Reactome Database ID Release 43377619 Reactome, http://www.reactome.org ReactomeREACT_18137 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep914 Transport of Extracellular Glucose to the Cytosol by GLUT1 and GLUT2 Authored: May, B, 2010-01-29 Edited: May, B, 2010-01-30 Edited: May, B, 2010-05-30 Human pancreatic beta cells express glucose transporters 1 and (GLUT1, GLUT2), which are responsible for uptake of glucose from the extracellular medium into the cytosol. (Rodent pancreatic beta cells express only Glut2.) Pubmed11780755 Pubmed17380317 Pubmed7589840 Pubmed7593639 Pubmed7929812 Pubmed8027028 Pubmed8457197 Pubmed8987985 Pubmed9751501 Reactome Database ID Release 43499981 Reactome, http://www.reactome.org ReactomeREACT_21415 Reviewed: D'Eustachio, P, 2010-04-23 L-selectin interacting with known ligands Reactome DB_ID: 198924 Reactome Database ID Release 43198924 Reactome, http://www.reactome.org ReactomeREACT_11760 has a Stoichiometric coefficient of 1 Focal complex Reactome DB_ID: 354137 Reactome Database ID Release 43354137 Reactome, http://www.reactome.org ReactomeREACT_16114 has a Stoichiometric coefficient of 1 fibrin monomer Reactome DB_ID: 140586 Reactome Database ID Release 43140586 Reactome, http://www.reactome.org ReactomeREACT_5594 has a Stoichiometric coefficient of 2 Release of calcium from intracellular stores by IP3 receptor activation Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2006-10-10 09:20:18 IP3 promotes the release of intracellular calcium. Reactome Database ID Release 43169683 Reactome, http://www.reactome.org ReactomeREACT_12074 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 Exocytosis of Insulin Authored: May, B, 2008-05-13 13:18:27 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Exocytosis of insulin-zinc granules occurs by the calcium-dependent fusion of the membrane of the secretory granule with the plasma membrane. In general, exocytosis proceeds by formation of a "SNARE pair", a complex between a SNARE-type protein on the granule and a SNARE-type protein on the plasma membrane. (The interaction is between coiled coil domains on each SNARE-type protein.)<p>In the particular case of insulin granules in beta cells, the SNARE protein on the granule is Synaptobrevin2/VAMP2 and the SNARE protein on the plasma membrane is Syntaxin1A in a complex with SNAP-25. Unc18-1 binds Syntaxin1A and thereby prevents association with Synaptobrevin2 until dissociation of Unc18-1. Syntaxin 4 is also involved and binds filamentous actin but its exact role is unknown.<br>Insulin exocytosis occurs in two phases: 1) a rapid release of about 100 of the 1000 docked granules within the first 5 minutes of glucose stimulation and 2) a subsequent slow release over 30 minutes or more due to migration of internal granules to the plasma membrane. Data from knockout mice show that Syntaxin 1A is involved in rapid release but not slow release, whereas Syntaxin 4 is involved in both types of release.<p>Calcium dependence of membrane fusion is conferred by Synaptotagmin V, which binds calcium ions and associates with the Syntaxin1A-Synaptobrevin2 pair. The exact mechanism of Synaptotagmin's action is unknown. The migration of internal granules to the plasma membrane during slow release is also calcium dependent.<p>Microscopically, exocytosis is seen to occur as a "kiss and run" process in which the membrane of the secretory granule fuses transiently with the plasma membrane to form a small pore of about 4 nm between the interior of the granule and the exterior of the cell. Only a portion of the insulin in a granule is secreted after which the pore closes and the vesicle is recaptured back into the cell. Dynamin-1 and NSF may play a role in recapture but the mechanism is not fully known.<p>The major effect of adrenaline and noradrenaline on insulin secretion is the inhibition of exocytosis of pre-existing insulin secretory granules. The inhibition occurs at a "distal site", that is, the effect is most pronounced on granules already near the cytosolic face of the plasma membrane. The effect is caused by the Gi/o alpha:GTP complex but the exact mechanism by which Gi/o alpha:GTP inhibits exocytosis is unknown. Pubmed11815450 Pubmed11815463 Pubmed11873862 Pubmed12403834 Pubmed12684222 Pubmed12887316 Pubmed14514350 Pubmed15572341 Pubmed16443778 Pubmed16714477 Pubmed17900700 Pubmed18162464 Pubmed7641683 Pubmed8997178 Pubmed9914469 Reactome Database ID Release 43265166 Reactome, http://www.reactome.org ReactomeREACT_15326 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 has a Stoichiometric coefficient of 3 SLCO2B1 substrates Converted from EntitySet in Reactome Reactome DB_ID: 879553 Reactome Database ID Release 43879553 Reactome, http://www.reactome.org ReactomeREACT_24278 GP369 Reactome DB_ID: 2067712 Reactome Database ID Release 432067712 Reactome, http://www.reactome.org ReactomeREACT_123879 PathwayStep916 FGFR3 mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 2077412 Reactome Database ID Release 432077412 Reactome, http://www.reactome.org ReactomeREACT_122888 PathwayStep915 SLCO2B1 substrates Converted from EntitySet in Reactome Reactome DB_ID: 879654 Reactome Database ID Release 43879654 Reactome, http://www.reactome.org ReactomeREACT_24748 PathwayStep918 PathwayStep917 FGFR2b mutant-binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 2065925 Reactome Database ID Release 432065925 Reactome, http://www.reactome.org ReactomeREACT_122122 FP-1039 Reactome DB_ID: 2077408 Reactome Database ID Release 432077408 Reactome, http://www.reactome.org ReactomeREACT_125228 PathwayStep919 PGT substrates Converted from EntitySet in Reactome Reactome DB_ID: 879614 Reactome Database ID Release 43879614 Reactome, http://www.reactome.org ReactomeREACT_24629 FGFR2c mutant binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 2065982 Reactome Database ID Release 432065982 Reactome, http://www.reactome.org ReactomeREACT_125523 Talin:RIAM complex: ECM ligands:Integrin alphaIIb beta3:Active (p-Y419)- SRC:FADK1 Reactome DB_ID: 354103 Reactome Database ID Release 43354103 Reactome, http://www.reactome.org ReactomeREACT_15808 has a Stoichiometric coefficient of 1 FGFR2 point mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 2077401 Reactome Database ID Release 432077401 Reactome, http://www.reactome.org ReactomeREACT_123065 PathwayStep924 PathwayStep925 PathwayStep922 GP VI : phosphorylated Fc Epsilon R1 gamma complex Reactome DB_ID: 114598 Reactome Database ID Release 43114598 Reactome, http://www.reactome.org ReactomeREACT_4277 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep923 GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN Reactome DB_ID: 434820 Reactome Database ID Release 43434820 Reactome, http://www.reactome.org ReactomeREACT_19515 has a Stoichiometric coefficient of 1 Medin amyloid fibril Reactome DB_ID: 977096 Reactome Database ID Release 43977096 Reactome, http://www.reactome.org ReactomeREACT_76835 PathwayStep920 GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen I:p-SYK(Y348) Reactome DB_ID: 453171 Reactome Database ID Release 43453171 Reactome, http://www.reactome.org ReactomeREACT_24781 has a Stoichiometric coefficient of 1 Human insulin analogue amyloid fibrils Reactome DB_ID: 977219 Reactome Database ID Release 43977219 Reactome, http://www.reactome.org ReactomeREACT_76199 PathwayStep921 GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen I:SYK Reactome DB_ID: 434911 Reactome Database ID Release 43434911 Reactome, http://www.reactome.org ReactomeREACT_19516 has a Stoichiometric coefficient of 1 p-SYK(Y348):p-Vav family Reactome DB_ID: 437934 Reactome Database ID Release 43437934 Reactome, http://www.reactome.org ReactomeREACT_24454 has a Stoichiometric coefficient of 1 p-SYK(Y348):Vav family Reactome DB_ID: 437941 Reactome Database ID Release 43437941 Reactome, http://www.reactome.org ReactomeREACT_24120 has a Stoichiometric coefficient of 1 Prolactin amyloid fibril Reactome DB_ID: 976974 Reactome Database ID Release 43976974 Reactome, http://www.reactome.org ReactomeREACT_76143 Anions transported by Aquaporin-6 Converted from EntitySet in Reactome Reactome DB_ID: 879865 Reactome Database ID Release 43879865 Reactome, http://www.reactome.org ReactomeREACT_24249 Anions transported by Aquaporin-6 Converted from EntitySet in Reactome Reactome DB_ID: 879874 Reactome Database ID Release 43879874 Reactome, http://www.reactome.org ReactomeREACT_24681 Amyloid fibril main peptide chains Converted from EntitySet in Reactome Reactome DB_ID: 977144 Reactome Database ID Release 43977144 Reactome, http://www.reactome.org ReactomeREACT_76011 VAV1 Rho/Rac effectors:GDP Reactome DB_ID: 114543 Reactome Database ID Release 43114543 Reactome, http://www.reactome.org ReactomeREACT_4113 has a Stoichiometric coefficient of 1 Localized amyloid fibril main peptide chains Converted from EntitySet in Reactome Reactome DB_ID: 976963 Reactome Database ID Release 43976963 Reactome, http://www.reactome.org ReactomeREACT_76467 VAV1 Rho/Rac effectors:GTP Reactome DB_ID: 114539 Reactome Database ID Release 43114539 Reactome, http://www.reactome.org ReactomeREACT_4042 has a Stoichiometric coefficient of 1 Systemic amyloid fibril monomers Converted from EntitySet in Reactome Reactome DB_ID: 977105 Reactome Database ID Release 43977105 Reactome, http://www.reactome.org ReactomeREACT_76016 VAV2 Rho/Rac effectors:GDP Reactome DB_ID: 442278 Reactome Database ID Release 43442278 Reactome, http://www.reactome.org ReactomeREACT_24745 has a Stoichiometric coefficient of 1 Variant apolipoprotein AII Reactome DB_ID: 976870 Reactome Database ID Release 43976870 Reactome, http://www.reactome.org ReactomeREACT_75975 VAV2 Rho/Rac effectors:GTP Reactome DB_ID: 442290 Reactome Database ID Release 43442290 Reactome, http://www.reactome.org ReactomeREACT_24831 has a Stoichiometric coefficient of 1 Islet amyloid polypeptide fibril Reactome DB_ID: 976981 Reactome Database ID Release 43976981 Reactome, http://www.reactome.org ReactomeREACT_75940 PathwayStep929 Atrial natriuretic factor amyloid fibril Reactome DB_ID: 976987 Reactome Database ID Release 43976987 Reactome, http://www.reactome.org ReactomeREACT_76140 PathwayStep928 Beta amyloid fibril Reactome DB_ID: 976748 Reactome Database ID Release 43976748 Reactome, http://www.reactome.org ReactomeREACT_75967 PathwayStep927 Calcitonin amyloid fibril Reactome DB_ID: 976978 Reactome Database ID Release 43976978 Reactome, http://www.reactome.org ReactomeREACT_76552 PathwayStep926 PathwayStep933 p-SLP-76:VAV Reactome DB_ID: 430155 Reactome Database ID Release 43430155 Reactome, http://www.reactome.org ReactomeREACT_20942 has a Stoichiometric coefficient of 1 PathwayStep934 VAV3 Rho/Rac effectors:GTP Reactome DB_ID: 442315 Reactome Database ID Release 43442315 Reactome, http://www.reactome.org ReactomeREACT_24491 has a Stoichiometric coefficient of 1 PathwayStep935 Binding of fatty acid ligands by Free fatty acid receptor 1 (GPR40) Authored: May, B, 2009-06-08 Edited: May, B, 2009-06-08 Free fatty acid receptor 1 (FFAR1), also known as GPR40, is a G-protein coupled receptor located in the plasma membrane of pancreatic beta cells. FFAR1/GPR40 binds medium and long chain free fatty acids (free fatty acids having more than 12 carbon groups). Pubmed12496284 Pubmed12565875 Pubmed12629551 Pubmed16289108 Pubmed17101212 Pubmed18606873 Pubmed19401434 Pubmed19758793 Reactome Database ID Release 43400434 Reactome, http://www.reactome.org ReactomeREACT_19366 Reviewed: Kebede, M, 2009-09-09 Reviewed: Madiraju, MS, 2009-10-02 Reviewed: Poitout, V, 2009-09-09 VAV3 Rho/Rac effectors:GDP Reactome DB_ID: 442313 Reactome Database ID Release 43442313 Reactome, http://www.reactome.org ReactomeREACT_24607 has a Stoichiometric coefficient of 1 PathwayStep936 Activation of Gq by Fatty Acid Receptor 1: Fatty Acid Complex Authored: May, B, 2009-06-08 Edited: May, B, 2009-06-08 FFAR1 (GPR40) is a G-protein coupled receptor. Based on studies with inhibitors of G proteins such as pertussis toxin FFAR1 is believed to signal through Gq/11. Binding of free fatty acids by FFAR1 activates the heterotrimeric Gq complex, which then activates Phospholipase C. From experiments in knockout mice it is estimated that signaling through FFAR1 is responsible for about 50% of the augmentation of insulin secretion produced by free fatty acids. The rest of the augmentation is due to metabolism of the free fatty acids within the pancreatic beta cell. Pubmed12496284 Pubmed15914509 Pubmed16081037 Pubmed17101212 Pubmed17130640 Pubmed17395749 Pubmed18606873 Pubmed18827341 Pubmed19398560 Reactome Database ID Release 43416530 Reactome, http://www.reactome.org ReactomeREACT_19346 Reviewed: Kebede, M, 2009-09-09 Reviewed: Madiraju, MS, 2009-10-02 Reviewed: Poitout, V, 2009-09-09 Transthyretin fibril Reactome DB_ID: 976929 Reactome Database ID Release 43976929 Reactome, http://www.reactome.org ReactomeREACT_76820 Binding of Glucagon-like Peptide-1 by Glucagon-like Peptide-1 Receptor Authored: May, B, 2008-11-19 21:15:12 Edited: Jassal, B, 2009-05-11 13:30:54 Glucagon-like Peptide-1 is synthesized in intestinal L-cells in response to the presence of glucose and fatty acids absorbed from the intestine. Most GLP-1 is the GLP-1 (7-36) amidated form; some GLP-1 is the GLP-1 (7-37) form. GLP-1 circulates to the pancreas where it binds the Glucagon-like Peptide-1 Receptor (GLP-1R), a G-protein coupled receptor located on the plasma membrane of beta cells. GLP-1R is a seven-pass transmembrane protein and a member of the B family of GPCRs, which have N-terminal extracellular domains of 100-150 amino acids. GLP-1 interacts with the extracellular N-terminal region of GLP-1R. Pubmed12034449 Pubmed15569269 Pubmed17306374 Pubmed17444618 Pubmed18287102 Pubmed19861722 Pubmed7589461 Pubmed8138058 Pubmed8404634 Pubmed8405712 Reactome Database ID Release 43381612 Reactome, http://www.reactome.org ReactomeREACT_18260 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 PI3K gamma Reactome DB_ID: 392291 Reactome Database ID Release 43392291 Reactome, http://www.reactome.org ReactomeREACT_20417 has a Stoichiometric coefficient of 1 PathwayStep930 Activation of G(s) by GLP-1R Authored: May, B, 2009-05-28 03:42:50 Edited: May, B, 2009-05-28 03:42:50 GLP-1R that has bound GLP-1 activates the alpha subunit of the heterotrimeric G-protein G(s) by protein-protein interaction between intracellular loop 3 of GLP-1R and G(s). The activation causes exchange of GDP for GTP by the alpha subunit of G(s). Pubmed15569269 Pubmed17306374 Pubmed17900700 Pubmed19859570 Pubmed8405712 Reactome Database ID Release 43381706 Reactome, http://www.reactome.org ReactomeREACT_18411 Reviewed: Calamita, G, 2010-07-15 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 PI3K beta Reactome DB_ID: 437110 Reactome Database ID Release 43437110 Reactome, http://www.reactome.org ReactomeREACT_21094 has a Stoichiometric coefficient of 1 Variant apolipoprotein AII fibril Reactome DB_ID: 976916 Reactome Database ID Release 43976916 Reactome, http://www.reactome.org ReactomeREACT_76843 PathwayStep931 Rearrangement of the heterotrimeric G(s) complex Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 Pubmed15569269 Pubmed17095603 Pubmed17306374 Pubmed17900700 Pubmed18577758 Pubmed8405712 Reactome Database ID Release 43422320 Reactome, http://www.reactome.org ReactomeREACT_18433 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 The binding of GTP by G(s) alpha causes the heterotrimeric G-protein complex to reorientate, exposing previously bound faces of the G(s) alpha:GTP complex and the G-beta: G-gamma complex. Unlike the case with Gi/o heterotrimers, Gs heterotrimers are not observed to significantly dissociate in living cells. VAV family:PIP2 Reactome DB_ID: 434632 Reactome Database ID Release 43434632 Reactome, http://www.reactome.org ReactomeREACT_20899 has a Stoichiometric coefficient of 1 Variant apolipoprotein AI fibril Reactome DB_ID: 976893 Reactome Database ID Release 43976893 Reactome, http://www.reactome.org ReactomeREACT_76067 PathwayStep932 Activation of Adenylyl Cyclase by G(s):GTP Authored: May, B, 2009-05-28 03:42:50 By analogy with adenylyl cyclases I and II, adenylyl cyclase VIII is activated by G(s) alpha:GTP by protein-protein interaction between G(s) alpha and the C2 region of adenylyl cyclase VIII, forming a complex. Adenylyl cyclase VIII is present in beta cells of rat and is activated by both G(s) alpha:GTP and calcium:calmodulin, thus integrating signals from both GLP-1 via G(s) alpha and glucose via calcium. Human beta cells contain adenylyl cyclases V and VI, which are also activated by G(s) alpha:GTP, and may contain additional adenylyl cyclases. Edited: May, B, 2009-05-28 03:42:50 Pubmed13680124 Pubmed15569269 Pubmed17306374 Pubmed17900700 Pubmed9417641 Pubmed9920805 Reactome Database ID Release 43381704 Reactome, http://www.reactome.org ReactomeREACT_18332 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 VAV family:PIP3 Reactome DB_ID: 434635 Reactome Database ID Release 43434635 Reactome, http://www.reactome.org ReactomeREACT_20699 has a Stoichiometric coefficient of 1 Production of Cyclic AMP by Activated Adenylyl Cyclase Activated adenylyl cyclase catalyzes the conversion of one molecule of ATP to one molecule of 3',5'-cyclic AMP (cAMP) and one molecule of pyrophosphate. Authored: May, B, 2009-05-28 03:44:04 EC Number: 4.6.1.1 Edited: May, B, 2009-05-28 03:44:04 Pubmed10318832 Pubmed13680124 Pubmed15569269 Pubmed17306374 Pubmed7589461 Pubmed9417641 Reactome Database ID Release 43381607 Reactome, http://www.reactome.org ReactomeREACT_18321 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 cAMP induces dissociation of active PKA catalytic subunits from the PKA:AKAP79:IQGAP1 Complex Authored: Gopinathrao, G, 2005-05-18 22:14:39 Edited: May, B, 2009-05-28 03:44:04 Pubmed12180908 Pubmed12938160 Pubmed15569269 Pubmed17306374 Reactome Database ID Release 43381707 Reactome, http://www.reactome.org ReactomeREACT_18397 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 The inactive Protein Kinase A (PKA) complex contains 2 regulatory subunits and 2 catalytic subunits. Binding of the regulatory subunits to the catalytic subunits maintains inactivity. In humans there are 3 different catalytic subunits and 4 different regulatory subunits. The particular subunits present in the beta cells of the pancreas are unknown. In beta cells PKA is associated with AKAP79 and IQGAP1, which are believed to tether PKA to the inner surface of the plasma membrane.<br> Activation by cAMP occurs when each regulatory subunit binds 2 molecules of cAMP, causing dissociation of the catalytic subunits. The active catalytic subunits are thereby released to phosphorylate their target proteins.<br>Prolonged exposure to increased cAMP levels results in translocation of the active catalytic subunits to the nucleus, where they regulate the PDX-1 and CREB transcription factors and cause increased transcription of the insulin gene. has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Closing of Potassium voltage-gated channels by PKA Authored: May, B, 2009-05-28 03:42:50 Edited: May, B, 2009-05-28 03:42:50 Protein kinase A acts to antagonize voltage-gated potassium channels (Kv channels) by increasing the polarizing voltage required to open them. Maintenance of the Kv channels in the closed state prolongs depolarization and insulin secretion. The exact mechanism of the interaction between PKA and the Kv channels is unknown. Pubmed12475787 Pubmed14988243 Pubmed15569269 Pubmed15955806 Pubmed17306374 Reactome Database ID Release 43381713 Reactome, http://www.reactome.org ReactomeREACT_18269 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 Opening of ER calcium channels by activated PKA Activated Protein Kinase A promotes the release of calcium from the endoplasmic reticulum into the cytosol. This may be due to phosphorylation of ER calcium channels by PKA, however this has not been demonstrated. Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 Pubmed10318832 Pubmed12410638 Pubmed12475787 Pubmed15569269 Pubmed17306374 Pubmed8830891 Pubmed9488697 Reactome Database ID Release 43381644 Reactome, http://www.reactome.org ReactomeREACT_18395 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 Kerato-epithelin amyloid fibril Reactome DB_ID: 977188 Reactome Database ID Release 43977188 Reactome, http://www.reactome.org ReactomeREACT_76641 PDK1:AKT:PIP3 Reactome DB_ID: 198360 Reactome Database ID Release 43198360 Reactome, http://www.reactome.org ReactomeREACT_13226 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Lactoferrin amyloid fibril Lactotransferrin amyloid fibril Reactome DB_ID: 977101 Reactome Database ID Release 43977101 Reactome, http://www.reactome.org ReactomeREACT_76269 Semenogelin-1 amyloid fibril Reactome DB_ID: 977079 Reactome Database ID Release 43977079 Reactome, http://www.reactome.org ReactomeREACT_76248 PI3K alpha, beta, gamma Converted from EntitySet in Reactome Reactome DB_ID: 437157 Reactome Database ID Release 43437157 Reactome, http://www.reactome.org ReactomeREACT_20768 Odontogenic ameloblast-associated protein amyloid fibrils Reactome DB_ID: 977087 Reactome Database ID Release 43977087 Reactome, http://www.reactome.org ReactomeREACT_76241 PI3K alpha Reactome DB_ID: 198379 Reactome Database ID Release 43198379 Reactome, http://www.reactome.org ReactomeREACT_12697 has a Stoichiometric coefficient of 1 Systemic amyloid fibril main peptide chains Converted from EntitySet in Reactome Reactome DB_ID: 976760 Reactome Database ID Release 43976760 Reactome, http://www.reactome.org ReactomeREACT_76661 PathwayStep938 Amyloid protein A fibril Reactome DB_ID: 976898 Reactome Database ID Release 43976898 Reactome, http://www.reactome.org ReactomeREACT_76687 PathwayStep937 Apolipoprotein A-IV fibril Reactome DB_ID: 976889 Reactome Database ID Release 43976889 Reactome, http://www.reactome.org ReactomeREACT_76453 Beta2-microglobulin fibril Reactome DB_ID: 976945 Reactome Database ID Release 43976945 Reactome, http://www.reactome.org ReactomeREACT_76492 PathwayStep939 G-protein alpha (13):GTP Reactome DB_ID: 398056 Reactome Database ID Release 43398056 Reactome, http://www.reactome.org ReactomeREACT_18118 has a Stoichiometric coefficient of 1 Superoxide reacts rapidly with NO to form peroxynitrite (ONOO-) Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 Pubmed10906340 Pubmed11373284 Reactome Database ID Release 431497878 Reactome, http://www.reactome.org ReactomeREACT_111092 Reviewed: D'Eustachio, P, 2011-08-23 Superoxide (O2.-) formed from an uncoupled eNOS action, together with nitric oxide (NO) formed from a coupled eNOS action, readily react together to fom peroxynitrite (ONOO-) (Jourd'heuil et al. 2001, Reiter et al. 2000). Activated thrombin (factor IIa) Reactome DB_ID: 156786 Reactome Database ID Release 43156786 Reactome, http://www.reactome.org ReactomeREACT_3298 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 Uncoupled eNOS favours the formation of superoxide Authored: Jassal, B, 2011-08-17 BH2 may compete with BH4 to bind eNOS, uncoupling eNOS leading to the formation of superoxide rather than nitric oxide. BH2, the oxidised form of BH4, cannot contribute electrons to heme in the reductase domain of eNOS, thereby uncoupling it from arginine oxidation and producing superoxide from oxygen instead (Vasquez-Vivar et al. 2002). Edited: Jassal, B, 2011-08-17 Pubmed11879202 Reactome Database ID Release 431497810 Reactome, http://www.reactome.org ReactomeREACT_111249 Reviewed: D'Eustachio, P, 2011-08-23 Thrombin-activated PAR:Gq (inactive) Reactome DB_ID: 397803 Reactome Database ID Release 43397803 Reactome, http://www.reactome.org ReactomeREACT_17676 has a Stoichiometric coefficient of 1 NO biosynthesis Authored: Hemish, J, 2007-10-19 18:00:42 EC Number: 1.14.13.39 Nitric oxide (NO) is produced from L-arginine by the family of nitric oxide synthases (NOS) enzymes, forming the free radical NO and citrulline as byproduct. The cofactor tetrahydrobiopterin (BH4) is an essential requirement for the delivery of an electron to the intermediate in the catalytic cycle of NOS. Pubmed15467163 Pubmed7526779 Pubmed8782602 Pubmed9173876 Reactome Database ID Release 43202127 Reactome, http://www.reactome.org ReactomeREACT_12443 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 has a Stoichiometric coefficient of 2 Thrombin-activated PAR:Gq (active) Reactome DB_ID: 397802 Reactome Database ID Release 43397802 Reactome, http://www.reactome.org ReactomeREACT_17562 has a Stoichiometric coefficient of 1 The cofactor BH4 is required for electron transfer in the eNOS catalytic cycle Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 Pubmed15476407 Pubmed19583767 Reactome Database ID Release 431497784 Reactome, http://www.reactome.org ReactomeREACT_111175 Reviewed: D'Eustachio, P, 2011-08-23 The cofactor tetrahydrobiopterin (BH4) ensures endothelial nitric oxide synthase (eNOS) couples electron transfer to L-arginine oxidation (Berka et al. 2004). During catalysis, electrons derived from NADPH transfer to the flavins FAD and FMN in the reductase domain of eNOS and then on to the ferric heme in the oxygenase domain of eNOS. BH4 can donate an electron to intermediates in this electron transfer and is oxidised in the process, forming the BH3 radical. This radical can be reduced back to BH4 by iron, completing the cycle and forming ferrous iron again. Heme reduction enables O2 binding and L-arginine oxidation to occur within the oxygenase domain (Stuehr et al. 2009). AKT1 phosphorylates eNOS Authored: Hemish, J, 2007-10-19 18:00:42 HSP90 serves as a scaffold to promote productive interaction between AKT1 and eNOS. Due to the proximity of these proteins once complexed with HSP90, AKT1 phosphorylates eNOS at Ser1177. When Ser1177 is phosphorylated, the level of NO production is elevated two- to three-fold above basal level. <br><br> Pubmed10376602 Pubmed10376603 Pubmed10469573 Reactome Database ID Release 43202111 Reactome, http://www.reactome.org ReactomeREACT_12415 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 AKT1 binds eNOS complex via HSP90 AKT1 is recruited to the M domain of HSP90. Authored: Hemish, J, 2007-10-19 18:00:42 Pubmed11988487 Pubmed12799359 Reactome Database ID Release 43202137 Reactome, http://www.reactome.org ReactomeREACT_12382 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 Caveolin-1 dissociates from eNOS:CaM:HSP90 complex Authored: Hemish, J, 2007-10-19 18:00:42 HSP90 facilitates the CaM-induced displacement of caveolin from eNOS. Pubmed10781589 Reactome Database ID Release 43202144 Reactome, http://www.reactome.org ReactomeREACT_12459 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 Lipid-OH Reactome DB_ID: 1222348 Reactome Database ID Release 431222348 Reactome, http://www.reactome.org ReactomeREACT_124444 eNOS:Caveolin-1 complex binds to CaM Authored: Hemish, J, 2007-10-19 18:00:42 Caveolin inhibition of eNOS is relieved by calmodulin, which causes dissociation of eNOS from caveolin. Pubmed12842859 Pubmed9188442 Reactome Database ID Release 43202110 Reactome, http://www.reactome.org ReactomeREACT_12620 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 has a Stoichiometric coefficient of 2 G-protein G12/G13 (active) Converted from EntitySet in Reactome Reactome DB_ID: 398080 Reactome Database ID Release 43398080 Reactome, http://www.reactome.org ReactomeREACT_17446 Lipid-OOH Reactome DB_ID: 1222300 Reactome Database ID Release 431222300 Reactome, http://www.reactome.org ReactomeREACT_125320 HSP90 binds eNOS:Caveolin-1:CaM complex Authored: Hemish, J, 2007-10-19 18:00:42 HSP90 interacts with the amino terminus of eNOS (amino acids 442-600) and facilitates displacement of caveolin by calmodulin (CaM). Pubmed11988487 Pubmed12482742 Pubmed9580552 Reactome Database ID Release 43202129 Reactome, http://www.reactome.org ReactomeREACT_12426 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 Thrombin activated PAR:G12/13 (active) Reactome DB_ID: 397884 Reactome Database ID Release 43397884 Reactome, http://www.reactome.org ReactomeREACT_17549 has a Stoichiometric coefficient of 1 Unsaturated lipid Reactome DB_ID: 1222455 Reactome Database ID Release 431222455 Reactome, http://www.reactome.org ReactomeREACT_123804 Amino Acid Reactome DB_ID: 2103117 Reactome Database ID Release 432103117 Reactome, http://www.reactome.org ReactomeREACT_122542 eNOS associates with Caveolin-1 Authored: Hemish, J, 2007-10-19 18:00:42 Caveolin-1 is the primary negative regulatory protein for eNOS. Caveolin-1 binding to eNOS compromises its ability to bind Calmodulin (CaM), thereby inhibiting enzyme activity. The major binding region of caveolin-1 for eNOS is within amino acids 60-101 and to a lesser extent, amino acids 135-178. Pubmed11498544 Pubmed8798458 Pubmed9325253 Pubmed9712842 Reactome Database ID Release 43203712 Reactome, http://www.reactome.org ReactomeREACT_12499 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 Peptide-Methionine (R)-Sulfoxide Reactome DB_ID: 1641509 Reactome Database ID Release 431641509 Reactome, http://www.reactome.org ReactomeREACT_121596 Heterotrimeric G-protein G12 (inactive) Reactome DB_ID: 114551 Reactome Database ID Release 43114551 Reactome, http://www.reactome.org ReactomeREACT_5832 has a Stoichiometric coefficient of 1 Peptide methionine sulfoxide Converted from EntitySet in Reactome Reactome DB_ID: 2201256 Reactome Database ID Release 432201256 Reactome, http://www.reactome.org ReactomeREACT_124321 G-protein G12/G13 (inactive) Converted from EntitySet in Reactome Reactome DB_ID: 398082 Reactome Database ID Release 43398082 Reactome, http://www.reactome.org ReactomeREACT_17117 Peptide-Methionine (S)-Sulfoxide Reactome DB_ID: 1222452 Reactome Database ID Release 431222452 Reactome, http://www.reactome.org ReactomeREACT_125514 Thrombin activated PAR:G12/13 (inactive) Reactome DB_ID: 397883 Reactome Database ID Release 43397883 Reactome, http://www.reactome.org ReactomeREACT_18059 has a Stoichiometric coefficient of 1 G-protein alpha (12):GDP Reactome DB_ID: 114550 Reactome Database ID Release 43114550 Reactome, http://www.reactome.org ReactomeREACT_2575 has a Stoichiometric coefficient of 1 Activated FGFR Converted from EntitySet in Reactome Reactome DB_ID: 190352 Reactome Database ID Release 43190352 Reactome, http://www.reactome.org ReactomeREACT_9678 unidentified protein tyrosine kinase Reactome DB_ID: 163338 Reactome Database ID Release 43163338 Reactome, http://www.reactome.org ReactomeREACT_4938 G-betagamma Reactome DB_ID: 111865 Reactome Database ID Release 43111865 Reactome, http://www.reactome.org ReactomeREACT_5052 PTPS is phosphorylated by cGMP-dependant protein kinase II 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) requires phosphorylation on Ser-19 for enzyme activity (Scherer-Oppliger et al. 1999). Authored: Jassal, B, 2011-08-17 EC Number: 2.7.11.12 Edited: Jassal, B, 2011-08-17 Pubmed10531334 Reactome Database ID Release 431475422 Reactome, http://www.reactome.org ReactomeREACT_111245 Reviewed: D'Eustachio, P, 2011-08-23 has a Stoichiometric coefficient of 6 Activated PAR1:Beta-arrestin-1 Reactome DB_ID: 418080 Reactome Database ID Release 43418080 Reactome, http://www.reactome.org ReactomeREACT_24414 has a Stoichiometric coefficient of 1 GCH1 reduces GTP to dihydroneopterin triphosphate Authored: Jassal, B, 2011-08-17 EC Number: 3.5.4.16 Edited: Jassal, B, 2011-08-17 Pubmed7663943 Pubmed8068008 Reactome Database ID Release 431474146 Reactome, http://www.reactome.org ReactomeREACT_111143 Reviewed: D'Eustachio, P, 2011-08-23 The first and rate-limiting enzyme in tetrahydrobiopterin de novo biosynthesis is GTP cyclohydrolase I (GCH1, GTPCHI). Three different isoforms are produced but only isoform 1 is functionally active (Gütlich et al. 1994). GCH1 is functional as a homodecamer. First, a monomer of GCH1 forms a dimer. Then five dimers arrange into a ring-like structure to form the homodecamer (Nar et al. 1995). Activated PAR1:Beta-arrestin-2 Reactome DB_ID: 418167 Reactome Database ID Release 43418167 Reactome, http://www.reactome.org ReactomeREACT_24025 has a Stoichiometric coefficient of 1 G-protein alpha (12):GTP Reactome DB_ID: 114525 Reactome Database ID Release 43114525 Reactome, http://www.reactome.org ReactomeREACT_5043 has a Stoichiometric coefficient of 1 Localized amyloid fibril monomers Converted from EntitySet in Reactome Reactome DB_ID: 977181 Reactome Database ID Release 43977181 Reactome, http://www.reactome.org ReactomeREACT_76860 G-protein alpha (12/13):GTP Converted from EntitySet in Reactome Reactome DB_ID: 418572 Reactome Database ID Release 43418572 Reactome, http://www.reactome.org ReactomeREACT_20092 eNOS:Caveolin-1:NOSTRIN complex binds dynamin-2 NOSTRIN binds to dynamin via its SH3 domain. Pubmed16234328 Pubmed16722822 Reactome Database ID Release 43203662 Reactome, http://www.reactome.org ReactomeREACT_12512 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 eNOS:Caveolin-1 complex binds to Nostrin Authored: Hemish, J, 2007-10-19 18:00:42 Pubmed12446846 Pubmed16807357 Reactome Database ID Release 43203716 Reactome, http://www.reactome.org ReactomeREACT_12427 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 eNOS interacts with the SH3 domain of NOSTRIN (positions 434-506). Caveolin-1 also binds directly to NOSTRIN (residues 323-434), thus allowing formation of a ternary complex. Heterotrimeric G-protein G12 (active) Reactome DB_ID: 114547 Reactome Database ID Release 43114547 Reactome, http://www.reactome.org ReactomeREACT_5245 has a Stoichiometric coefficient of 1 NOSTRIN mediated translocation of eNOS from plasma membrane NOSTRIN translocates eNOS from the plasma membrane to intracellular vesicular structures. NOSTRIN internalization of eNOS is proposed to occur via vesicle fission and caveolar transport through cooperation with dynamin and N-WASP. Pubmed16807357 Reactome Database ID Release 43203625 Reactome, http://www.reactome.org ReactomeREACT_12634 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 eNOS:Caveolin-1:NOSTRIN:dynamin-2 complex binds N-WASP NOSTRIN interacts with the actin nucleation promoting factor N-WASP by means of its SH3 domain. Pubmed16234328 Pubmed16722822 Pubmed16807357 Reactome Database ID Release 43203565 Reactome, http://www.reactome.org ReactomeREACT_12611 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 IPI-504 Reactome DB_ID: 1217514 Reactome Database ID Release 431217514 Reactome, http://www.reactome.org ReactomeREACT_117607 retaspimycin hydrochloride depalmitoylation of eNOS Authored: Hemish, J, 2007-10-19 18:00:42 EC Number: 3.1.2.22 Increases in intracellular calcium and calmodulin stimulate depalmitoylation of eNOS by acyl protein thioesterase 1, which displaces eNOS from the membrane. This might be a mechanism to downregulate NO production following intense stimuli. Pubmed10551886 Reactome Database ID Release 43203613 Reactome, http://www.reactome.org ReactomeREACT_12463 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 has a Stoichiometric coefficient of 4 Benzoquinoid ansamycins Converted from EntitySet in Reactome Reactome DB_ID: 1217511 Reactome Database ID Release 431217511 Reactome, http://www.reactome.org ReactomeREACT_117275 depalmitoylated eNOS translocates from plasma membrane Authored: Hemish, J, 2007-10-19 18:00:42 Once depalmitoylated, it's proposed that eNOS is displaced from the plasma membrane and redistributed to other intracellular membranes, including the Golgi, where re-palmitoylation occurs. The mechanism of transport from the plasma membrane is still unknown. Pubmed10559837 Reactome Database ID Release 43202132 Reactome, http://www.reactome.org ReactomeREACT_12488 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 Irreversible EGFR TKIs Converted from EntitySet in Reactome Covalent EGFR tyrosine kinase inhibitors Irreversible anti-EGFR tyrosine kinase inhibitors Reactome DB_ID: 1216522 Reactome Database ID Release 431216522 Reactome, http://www.reactome.org ReactomeREACT_116254 eNOS binds NOSIP NOSIP (eNOS interacting protein) binds to the carboxyl-terminal region of the eNOS oxygenase domain. Note that the eNOS binding sites for caveolin and NOSIP overlap. Pubmed11149895 Reactome Database ID Release 43203553 Reactome, http://www.reactome.org ReactomeREACT_12589 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 Reversible EGFR TKIs Converted from EntitySet in Reactome Non-covalent EGFR tyrosine kinase inhibitors Reactome DB_ID: 1216523 Reactome Database ID Release 431216523 Reactome, http://www.reactome.org ReactomeREACT_117456 Reversible anti-EGFR tyrosine kinase inhibitors eNOS:NOSIP translocation from caveolae to intracellular compartments NOSIP promotes translocation of eNOS from the plasma membrane to intracellular sites, thereby uncoupling eNOS from plasma membrane caveolae and inhibiting NO synthesis. eNOS appears to be shifted to intracellular sites that colocalize with Golgi and/or cytoskeletal marker proteins. Pubmed11149895 Pubmed12446846 Reactome Database ID Release 43203680 Reactome, http://www.reactome.org ReactomeREACT_12590 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 GPVI:phosphorylated Fc Epsilon R1 gamma:FYN:LYN:Collagen I Reactome DB_ID: 434822 Reactome Database ID Release 43434822 Reactome, http://www.reactome.org ReactomeREACT_19828 has a Stoichiometric coefficient of 1 B7-1 homodimer/ B7-2 Converted from EntitySet in Reactome Reactome DB_ID: 388762 Reactome Database ID Release 43388762 Reactome, http://www.reactome.org ReactomeREACT_20199 Activated PAR1:Beta-arrestin-1:Activated Src:Activated ERK Reactome DB_ID: 418210 Reactome Database ID Release 43418210 Reactome, http://www.reactome.org ReactomeREACT_24392 has a Stoichiometric coefficient of 1 FGFR1 FGR1_HUMAN Phosphorylated Fibroblast growth factor receptor 1b Reactome DB_ID: 190424 Reactome Database ID Release 43190424 Reactome, http://www.reactome.org ReactomeREACT_9550 Activated PAR1:Beta-arrestin-1:Activated Src:ERK Reactome DB_ID: 418144 Reactome Database ID Release 43418144 Reactome, http://www.reactome.org ReactomeREACT_24357 has a Stoichiometric coefficient of 1 p-EGFR mutants dimer Converted from EntitySet in Reactome Reactome DB_ID: 1500866 Reactome Database ID Release 431500866 Reactome, http://www.reactome.org ReactomeREACT_117763 Activated PAR1:Beta-arrestin-2:Src:ERK Reactome DB_ID: 418179 Reactome Database ID Release 43418179 Reactome, http://www.reactome.org ReactomeREACT_24842 has a Stoichiometric coefficient of 1 Ligand-responsive EGFR mutants Converted from EntitySet in Reactome Reactome DB_ID: 1182966 Reactome Database ID Release 431182966 Reactome, http://www.reactome.org ReactomeREACT_117041 Activated PAR1:Beta-arrestin-1:Src:ERK Reactome DB_ID: 418103 Reactome Database ID Release 43418103 Reactome, http://www.reactome.org ReactomeREACT_24135 has a Stoichiometric coefficient of 1 Amyloid fibril monomers Converted from EntitySet in Reactome Reactome DB_ID: 977175 Reactome Database ID Release 43977175 Reactome, http://www.reactome.org ReactomeREACT_76278 C225 Cetuximab Erbitux (Bristol-Myers Squibb, New York, NY) Reactome DB_ID: 1248673 Reactome Database ID Release 431248673 Reactome, http://www.reactome.org ReactomeREACT_116480 monoubiquitinated N-myristoyl GAG (P12494) protein Reactome DB_ID: 184437 Reactome Database ID Release 43184437 Reactome, http://www.reactome.org ReactomeREACT_117034 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG (P12493) protein Reactome DB_ID: 184354 Reactome Database ID Release 43184354 Reactome, http://www.reactome.org ReactomeREACT_117162 has a Stoichiometric coefficient of 1 Activation of PP2A by Xylulose-5-phosphate Authored: Gopinathrao, G, 2005-05-14 18:58:58 Pubmed12110366 Pubmed12684532 Pubmed12721358 Reactome Database ID Release 43163769 Reactome, http://www.reactome.org ReactomeREACT_2177 Xylulose-5-phosphate binds to Protein phosphatase 2A (PP2A), activating it. This regulatory step may be the crucial physiological link explaining the coordinately increased rates of glycolysis and lipogenesis generally observed in individuals consuming high-carbohydrate diets. monoubiquitinated N-myristoyl GAG (P20889) protein Reactome DB_ID: 184266 Reactome Database ID Release 43184266 Reactome, http://www.reactome.org ReactomeREACT_117008 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG (P20873) protein Reactome DB_ID: 184464 Reactome Database ID Release 43184464 Reactome, http://www.reactome.org ReactomeREACT_117541 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG (P18800) protein Reactome DB_ID: 184367 Reactome Database ID Release 43184367 Reactome, http://www.reactome.org ReactomeREACT_117102 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG (P12495) protein Reactome DB_ID: 184306 Reactome Database ID Release 43184306 Reactome, http://www.reactome.org ReactomeREACT_116748 has a Stoichiometric coefficient of 1 cAMP induces dissociation of inactive PKA tetramers Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed16407073 Reactome Database ID Release 43111925 Reactome, http://www.reactome.org ReactomeREACT_1532 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The four protein kinase A (PKA) regulatory subunit isoforms differ in their tissue specificity and functional characteristics. The specific isoform activated in response to glucagon signalling is not known. The PKA kinase is a tetramer of two regulatory and two catalytic. The regulatory subunits block the catalytic subunits. Binding of cAMP to the regulatory subunit leads to the dissociation of the tetramer into two active dimers made up of a regulatory and a catalytic subunit. has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Jaks:IL6RB Reactome DB_ID: 1067642 Reactome Database ID Release 431067642 Reactome, http://www.reactome.org ReactomeREACT_27889 has a Stoichiometric coefficient of 1 Activated Adenylate cyclase catalyses cAMP synthesis Activated adenylate cyclase associated with the plasma membrane catalyzes the reaction of cytosolic ATP to form 3',5'-cyclicAMP and pyrophosphate. EC Number: 4.6.1.1 Edited: Jupe, S, 2009-09-09 Reactome Database ID Release 43164377 Reactome, http://www.reactome.org ReactomeREACT_1292 monoubiquitinated N-myristoyl GAG (Q70622) protein Reactome DB_ID: 184381 Reactome Database ID Release 43184381 Reactome, http://www.reactome.org ReactomeREACT_117473 has a Stoichiometric coefficient of 1 G alpha (s) activates adenylate cyclase Authored: Jupe, S, 2009-03-09 10:38:40 Edited: May, B, 2009-08-11 G(s)-alpha:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it. Pubmed9417641 Reactome Database ID Release 43163617 Reactome, http://www.reactome.org ReactomeREACT_2219 Reviewed: Akkerman, JW, 2009-06-03 monoubiquitinated N-myristoyl GAG (P35962) protein Reactome DB_ID: 184276 Reactome Database ID Release 43184276 Reactome, http://www.reactome.org ReactomeREACT_117272 has a Stoichiometric coefficient of 1 Glucagon:GCGR mediates GTP-GDP exchange Authored: Gopinathrao, G, 2005-08-12 11:14:59 Edited: D'Eustachio, P, 2010-05-26 Reactome Database ID Release 43825631 Reactome, http://www.reactome.org ReactomeREACT_22110 Reviewed: D'Eustachio, P, 2010-05-25 The G(s)alpha G-beta G-gamma complex bound to glucagon, in the plasma membrane, releases a molecule of bound GDP, binds a molecule of GTP, and dissociates to yield a G(s)alpha:GTP complex and a G-beta:G-gamma dimer. monoubiquitinated N-myristoyl GAG (P24736) protein Reactome DB_ID: 184311 Reactome Database ID Release 43184311 Reactome, http://www.reactome.org ReactomeREACT_117126 has a Stoichiometric coefficient of 1 Nuclear transport of pChREBP (Thr 666) protein ChREBP (Carbohydrate Response Element Binding Protein) doubly phosphorylated at threonine 666 and serine 196 is inactive and is localized to the cytosol. Removal of the phosphate residue at serine 196 allows ChREBP to translocate between the cytosol and the nucleoplasm. Reactome Database ID Release 43163670 Reactome, http://www.reactome.org ReactomeREACT_548 Phosphorylation of pChREBP (Thr 666) at Ser(196) by PKA Authored: Gopinathrao, G, 2005-05-12 21:32:40 EC Number: 2.7.11.11 Phosphorylation of ChREBP (Carbohydrate Response Element Binding Protein) at serine 196 by PKA inhibits its nuclear translocation. This reaction has been studied in detail using mouse proteins (Kawaguchi et al. 2001); the human version of the reaction is inferred from these studies. Reactome Database ID Release 43163676 Reactome, http://www.reactome.org ReactomeREACT_483 PhosphoChREBP (Thr 666) is exported to cytosol Authored: Gopinathrao, G, 2005-05-19 19:11:43 ChREBP (Carbohydrate Response Element Binding Protein) doubly phosphorylated at threonine 666 and serine 196 is inactive and is localized to the cytosol. Removal of the phosphate residue at serine 196 allows ChREBP to translocate between the cytosol and the nucleoplasm. Reactome Database ID Release 43164423 Reactome, http://www.reactome.org ReactomeREACT_1310 Heterotrimeric G-protein Gi (inactive) Reactome DB_ID: 392165 Reactome Database ID Release 43392165 Reactome, http://www.reactome.org ReactomeREACT_20935 has a Stoichiometric coefficient of 1 Phosphorylation of ChREBP at Thr(666) by PKA Authored: Gopinathrao, G, 2005-05-12 21:32:40 EC Number: 2.7.11.11 In its active (unphosphorylated) form, ChREBP (Carbohydrate Response Element Binding Protein) binds so-called ChRE (Carbohydrate Response Element) DNA sequence motifs found upstream of several genes involved in glucose utilization and lipid synthesis, activating transcription of these genes. Phosphorylation of ChREBP at threonine residue 666 by PKA (protein kinase A) blocks this binding activity, and thus has the effect of down-regulating expression of the target genes. ChREBP phosphorylation can be reversed by the action of protein phosphatase 2A (PP2A). Reactome Database ID Release 43163672 Reactome, http://www.reactome.org ReactomeREACT_304 G-protein alpha (i):GDP Reactome DB_ID: 392164 Reactome Database ID Release 43392164 Reactome, http://www.reactome.org ReactomeREACT_19806 has a Stoichiometric coefficient of 1 HIV-1 template DNA:30 nt transcript hybrid Reactome DB_ID: 167131 Reactome Database ID Release 43167131 Reactome, http://www.reactome.org ReactomeREACT_6431 ADP:P2Y purinoceptor 12:G-protein Gi (active) Reactome DB_ID: 392194 Reactome Database ID Release 43392194 Reactome, http://www.reactome.org ReactomeREACT_20967 has a Stoichiometric coefficient of 1 ADP:P2Y purinoceptor 12:G-protein Gi (inactive) Reactome DB_ID: 392184 Reactome Database ID Release 43392184 Reactome, http://www.reactome.org ReactomeREACT_21024 has a Stoichiometric coefficient of 1 G-protein alpha (i): GTP Reactome DB_ID: 392161 Reactome Database ID Release 43392161 Reactome, http://www.reactome.org ReactomeREACT_19580 has a Stoichiometric coefficient of 1 Heterotrimeric G-protein Gi (active) Reactome DB_ID: 392168 Reactome Database ID Release 43392168 Reactome, http://www.reactome.org ReactomeREACT_20744 has a Stoichiometric coefficient of 1 Elongating HIV-1 transcript prior to separation Reactome DB_ID: 167145 Reactome Database ID Release 43167145 Reactome, http://www.reactome.org ReactomeREACT_6418 G-protein alpha (q/11):GDP Reactome DB_ID: 114556 Reactome Database ID Release 43114556 Reactome, http://www.reactome.org ReactomeREACT_3769 has a Stoichiometric coefficient of 1 Elongating HIV-1 transcript in processive Pol II mediated elongation Reactome DB_ID: 167069 Reactome Database ID Release 43167069 Reactome, http://www.reactome.org ReactomeREACT_6500 Glucagon binds to Glucagon receptor Authored: Gopinathrao, G, 2005-05-03 20:30:53 Edited: Jassal, B, 2009-05-11 13:30:54 Glucagon (Thomsen J et al, 1972) is an important peptide hormone produced by the pancreas. It is released when the glucose level in the blood is low (hypoglycemia), causing the liver to convert stored glycogen into glucose and release it into the bloodstream. The action of glucagon is thus opposite to that of insulin. Glucagon, together with glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), are peptide hormones encoded by a single common prohormone precursor, proglucagon.The glucagon receptor (Lok S et al, 1994) plays a central role in regulating the level of blood glucose by controlling the rate of hepatic glucose production and insulin secretion. The activity of this receptor is mediated by coupling to Gs and q, which stimulate adenylyl cyclase and a phosphatidylinositol-calcium second messenger system respectively. Pubmed11946536 Pubmed15464082 Pubmed2826231 Pubmed8144028 Reactome Database ID Release 43163625 Reactome, http://www.reactome.org ReactomeREACT_156 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Heterotrimeric G-protein Gq/11 (inactive) Reactome DB_ID: 114557 Reactome Database ID Release 43114557 Reactome, http://www.reactome.org ReactomeREACT_5130 has a Stoichiometric coefficient of 1 HIV-1 template:capped HIV-1 transcript hybrid Reactome DB_ID: 167074 Reactome Database ID Release 43167074 Reactome, http://www.reactome.org ReactomeREACT_6586 ADP:P2Y purinoceptor 1:G-protein Gq (active) Reactome DB_ID: 418575 Reactome Database ID Release 43418575 Reactome, http://www.reactome.org ReactomeREACT_20825 has a Stoichiometric coefficient of 1 capped HIV-1 pre-mRNA Reactome DB_ID: 167079 Reactome Database ID Release 43167079 Reactome, http://www.reactome.org ReactomeREACT_6370 ADP:P2Y purinoceptor 1:G-protein Gq (inactive) Reactome DB_ID: 418578 Reactome Database ID Release 43418578 Reactome, http://www.reactome.org ReactomeREACT_21114 has a Stoichiometric coefficient of 1 minus sssDNA containing deaminated C residues Reactome DB_ID: 180629 Reactome Database ID Release 43180629 Reactome, http://www.reactome.org ReactomeREACT_9532 Rev-multimer Reactome DB_ID: 165543 Reactome Database ID Release 43165543 Reactome, http://www.reactome.org ReactomeREACT_6511 Rev-multimer Reactome DB_ID: 165542 Reactome Database ID Release 43165542 Reactome, http://www.reactome.org ReactomeREACT_6379 Elongating HIV-1 transcript prior to cleavage Reactome DB_ID: 167142 Reactome Database ID Release 43167142 Reactome, http://www.reactome.org ReactomeREACT_6397 Lipid Raft Reactome DB_ID: 167540 Reactome Database ID Release 43167540 Reactome, http://www.reactome.org ReactomeREACT_11624 PathwayStep2097 PathwayStep2096 PathwayStep2095 monoubiquitinated N-myristoyl GAG (P03349) protein Reactome DB_ID: 184421 Reactome Database ID Release 43184421 Reactome, http://www.reactome.org ReactomeREACT_117386 has a Stoichiometric coefficient of 1 PathwayStep2094 monoubiquitinated N-myristoyl GAG (P04591) protein Reactome DB_ID: 184475 Reactome Database ID Release 43184475 Reactome, http://www.reactome.org ReactomeREACT_116878 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG (P03350) protein Reactome DB_ID: 184287 Reactome Database ID Release 43184287 Reactome, http://www.reactome.org ReactomeREACT_117062 has a Stoichiometric coefficient of 1 PathwayStep2099 monoubiquitinated N-myristoyl GAG (P04593) protein Reactome DB_ID: 184300 Reactome Database ID Release 43184300 Reactome, http://www.reactome.org ReactomeREACT_116492 has a Stoichiometric coefficient of 1 PathwayStep2098 monoubiquitinated N-myristoyl GAG (P04592) protein Reactome DB_ID: 184431 Reactome Database ID Release 43184431 Reactome, http://www.reactome.org ReactomeREACT_117697 has a Stoichiometric coefficient of 1 Dephosphorylation of pChREBP (Ser 196) by PP2A At the beginning of this reaction, 1 molecule of 'pChREBP (Ser 196, Thr 666)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'pChREBP (Thr 666)' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.<br> EC Number: 3.1.3.4 Reactome Database ID Release 43163689 Reactome, http://www.reactome.org ReactomeREACT_1416 monoubiquitinated N-myristoyl GAG (P05887) protein Reactome DB_ID: 184446 Reactome Database ID Release 43184446 Reactome, http://www.reactome.org ReactomeREACT_117103 has a Stoichiometric coefficient of 1 Phosphorylation of ChREBP at Serine 568 by AMPK Authored: Gopinathrao, G, 2005-05-12 21:32:40 In the nucleus, activated AMPK phosphorylates serine residue 568 of ChREBP (Carbohydrate Response Element Binding Protein). Phosphorylated ChREBP does not bind to ChRE chromosomal DNA sequence elements and thus loses its ability to promote transcription of genes involved in glycolysis and lipogenesis. Reactome Database ID Release 43163691 Reactome, http://www.reactome.org ReactomeREACT_349 monoubiquitinated N-myristoyl GAG (P04594) protein Reactome DB_ID: 184296 Reactome Database ID Release 43184296 Reactome, http://www.reactome.org ReactomeREACT_116739 has a Stoichiometric coefficient of 1 Dephosphorylation of pChREBP (Thr 666) by PP2A At the beginning of this reaction, 1 molecule of 'pChREBP (Thr 666)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'ChREBP protein' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.<br> EC Number: 3.1.3.4 Reactome Database ID Release 43163688 Reactome, http://www.reactome.org ReactomeREACT_382 monoubiquitinated N-myristoyl GAG (P05889) protein Reactome DB_ID: 184341 Reactome Database ID Release 43184341 Reactome, http://www.reactome.org ReactomeREACT_116774 has a Stoichiometric coefficient of 1 Dephosphorylation of pChREBP (Ser 568) by PP2A At the beginning of this reaction, 1 molecule of 'pChREBP(Ser 568)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'ChREBP protein' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.<br> EC Number: 3.1.3.4 Reactome Database ID Release 43164056 Reactome, http://www.reactome.org ReactomeREACT_814 monoubiquitinated N-myristoyl GAG (P05888) protein Reactome DB_ID: 184359 Reactome Database ID Release 43184359 Reactome, http://www.reactome.org ReactomeREACT_116209 has a Stoichiometric coefficient of 1 PathwayStep2093 N-myristoylation of eNOS A glycine residue (Gly2) at the N-terminus of eNOS is myristoylated, providing membrane localization. Authored: Hemish, J, 2007-10-19 18:00:42 Pubmed7512951 Reactome Database ID Release 43203611 Reactome, http://www.reactome.org ReactomeREACT_12474 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 G-protein alpha (q/11): GTP Reactome DB_ID: 114534 Reactome Database ID Release 43114534 Reactome, http://www.reactome.org ReactomeREACT_5863 has a Stoichiometric coefficient of 1 PathwayStep2092 Formation of ChREBP:MLX heterodimer At the beginning of this reaction, 1 molecule of 'ChREBP protein', and 1 molecule of 'MLX protein' are present. At the end of this reaction, 1 molecule of 'ChREBP:MLX' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43163666 Reactome, http://www.reactome.org ReactomeREACT_129 monoubiquitinated N-myristoyl GAG (P05890) protein Reactome DB_ID: 184281 Reactome Database ID Release 43184281 Reactome, http://www.reactome.org ReactomeREACT_116290 has a Stoichiometric coefficient of 1 TP receptor:Thromboxane A2 Reactome DB_ID: 391925 Reactome Database ID Release 43391925 Reactome, http://www.reactome.org ReactomeREACT_18599 has a Stoichiometric coefficient of 1 PathwayStep2091 eNOS translocation from Golgi to Caveolae Palymitoylated, myristoylated eNOS forms a dimer and is transported from the Golgi to the plasma membrane. Transport is thought to be mediated by intracellular vesicles, but the details remain unknown. Pubmed11208594 Pubmed16722822 Reactome Database ID Release 43203700 Reactome, http://www.reactome.org ReactomeREACT_12492 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 has a Stoichiometric coefficient of 2 PathwayStep2090 palmitoylation of eNOS Authored: Hemish, J, 2007-10-19 18:00:42 DHHC-21 is a Golgi-localized acyl transferase that palmitoylates eNOS, which targets eNOS to plasmalemmal caveolae. Localization to this microdomain is likely to optimize eNOS activation and the extracellular release of nitric oxide. Pubmed16864653 Pubmed8626455 Pubmed8692835 Reactome Database ID Release 43203567 Reactome, http://www.reactome.org ReactomeREACT_12530 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 Heterotrimeric G-protein Gq (active) Reactome DB_ID: 114554 Reactome Database ID Release 43114554 Reactome, http://www.reactome.org ReactomeREACT_5824 has a Stoichiometric coefficient of 1 TP receptor:Thromboxane A2:G-protein G13 (inactive) Reactome DB_ID: 428905 Reactome Database ID Release 43428905 Reactome, http://www.reactome.org ReactomeREACT_20823 has a Stoichiometric coefficient of 1 G-protein alpha (13):GDP Reactome DB_ID: 398057 Reactome Database ID Release 43398057 Reactome, http://www.reactome.org ReactomeREACT_17165 has a Stoichiometric coefficient of 1 Host Derived Lipid Bilayer Membrane Rich In Sphingolipids And Cholesterol Reactome DB_ID: 189135 Reactome Database ID Release 43189135 Reactome, http://www.reactome.org ReactomeREACT_9219 Heterotrimeric G-protein G13 (inactive) Reactome DB_ID: 398072 Reactome Database ID Release 43398072 Reactome, http://www.reactome.org ReactomeREACT_17830 has a Stoichiometric coefficient of 1 Host Derived Lipid Bilayer Membrane Rich In Sphingolipids And Cholesterol Reactome DB_ID: 169703 Reactome Database ID Release 43169703 Reactome, http://www.reactome.org ReactomeREACT_9200 TP receptor:Thromboxane A2:G-protein Gq (inactive) Reactome DB_ID: 428764 Reactome Database ID Release 43428764 Reactome, http://www.reactome.org ReactomeREACT_20867 has a Stoichiometric coefficient of 1 Mature intronless transcript derived mRNA with m7G cap removed Reactome DB_ID: 193039 Reactome Database ID Release 43193039 Reactome, http://www.reactome.org ReactomeREACT_9723 Host Derived Lipid Bilayer Membrane Rich In Sphingolipids And Cholesterol Reactome DB_ID: 189136 Reactome Database ID Release 43189136 Reactome, http://www.reactome.org ReactomeREACT_9323 Heterotrimeric G-protein G13 (active) Reactome DB_ID: 398074 Reactome Database ID Release 43398074 Reactome, http://www.reactome.org ReactomeREACT_17395 has a Stoichiometric coefficient of 1 Influenza cRNA (complete) Reactome DB_ID: 192638 Reactome Database ID Release 43192638 Reactome, http://www.reactome.org ReactomeREACT_9879 AMP binds to gamma subunit of AMP kinase heterotrimer At the beginning of this reaction, 1 molecule of 'AMPK heterotrimer (inactive)', and 1 molecule of 'AMP' are present. At the end of this reaction, 1 molecule of 'AMPK heterotrimer:AMP' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed10698692 Reactome Database ID Release 43163664 Reactome, http://www.reactome.org ReactomeREACT_627 TP receptor:Thromboxane A2:G-protein G13 (active) Reactome DB_ID: 428907 Reactome Database ID Release 43428907 Reactome, http://www.reactome.org ReactomeREACT_20781 has a Stoichiometric coefficient of 1 Influenza H1N1 cRNA (extending) Reactome DB_ID: 193303 Reactome Database ID Release 43193303 Reactome, http://www.reactome.org ReactomeREACT_9876 LKB1 phosphorylates the alpha subunit of AMPK heterotrimer Authored: Gopinathrao, G, 2005-05-12 21:32:40 LKB1 phosphorylates threonine residue 172 of the alpha subunit of the AMPK heterotrimer, activating it. LKB1, a serine/threonine kinase, was first identified as the gene whose mutation is associated with the Peutz-Jeghers familial cancer syndrome. This disease phenotype is consistent with the hypothesis that the interaction between LKB1 and AMPK normally plays a key role in the negative regulation of cell growth (Hardie 2004). Pubmed15509864 Reactome Database ID Release 43164151 Reactome, http://www.reactome.org ReactomeREACT_1325 TP receptor:Thromboxane A2:G-protein Gq (active) Reactome DB_ID: 428904 Reactome Database ID Release 43428904 Reactome, http://www.reactome.org ReactomeREACT_20944 has a Stoichiometric coefficient of 1 Lipid Raft Reactome DB_ID: 195731 Reactome Database ID Release 43195731 Reactome, http://www.reactome.org ReactomeREACT_10332 Lipid Raft Reactome DB_ID: 195764 Reactome Database ID Release 43195764 Reactome, http://www.reactome.org ReactomeREACT_10385 Peptide-Methionine Reactome DB_ID: 1222500 Reactome Database ID Release 431222500 Reactome, http://www.reactome.org ReactomeREACT_122769 Viral dsRNA (-) Stranded Reactome DB_ID: 167931 Reactome Database ID Release 43167931 Reactome, http://www.reactome.org ReactomeREACT_6589 isocitrate + NADP+ => alpha-ketoglutarate + CO2 + NADPH + H+ [IDH2] Authored: D'Eustachio, P, 2009-12-26 EC Number: 1.1.1.42 Mitochondrial isocitrate dehydrogenase IDH2 catalyzes the irreversible reaction of isocitrate and NADP+ to form alpha ketoglutarate, CO2, and NADPH + H+ (Hartong et al. 2008). The structure of the active human enzyme has not been determined experimentally, but is inferred to be a homodimer with one Mn++ bound to each subunit based on detailed studies of the homologous pig enzyme (Ceccarelli et al. 2002). NADP-specific IDH2 was the first isocitrate dehydrogenase isoenzyme to be characterized in biochemical studies of the mammalian TCA cycle (Ochoa 1948). Later work with yeast revealed the existence of both NADP-specific (IDH2-homologous) and NAD-specific (IDH3-homologous) enzymes and demonstrated the ADP-dependence of the latter (Kornberg and Pricer 1951), consistent with the now widely accepted view that IDH3 mediates the conversion of isocitrate to alpha-ketoglutarate in the TCA cycle. The physiological function of IDH2 is thus unclear. The recent observation that individuals homozygous for IDH3 mutations that sharply reduce its activity do not show symptoms of deficient energy metabolism in most tissues raises the possibility that the IDH2 reaction may play an accessory role in the TCA cycle (Hartong et al. 2008). Pubmed12207025 Pubmed14832224 Pubmed18806796 Pubmed18914071 Reactome Database ID Release 43450984 Reactome, http://www.reactome.org ReactomeREACT_21355 isocitrate + NAD+ => alpha-ketoglutarate + CO2 + NADH + H+ [IDH3] EC Number: 1.1.1.41 Mitochondrial isocitrate dehydrogenase IDH3 catalyzes the irreversible reaction of isocitrate and NAD+ to form alpha ketoglutarate, CO2, and NADH + H+. The enzyme is a heteromer containing four polypeptide chains, two IDH3A, one IDH3B, and one IDH3G, and two Mn++ (Dange and Colman 2010). It is activated by ADP (Soundar et al. 2003, 2006; Bzymek and Colman 2007). This is the first of four oxidation reactions in the citric acid cycle, and the first decarboxylation. Pubmed14555658 Pubmed16737955 Pubmed17432878 Pubmed20435888 Reactome Database ID Release 4370967 Reactome, http://www.reactome.org ReactomeREACT_1068 alpha-ketoglutarate + CoASH + NAD+ => succinyl-CoA + CO2 + NADH + H+ EC Number: 1.2.1.52 Oxidative decarboxylation of alpha-ketoglutarate to succinyl CoA by alpha-ketoglutarate dehydrogenase Pubmed11752427 Pubmed15946682 Pubmed2188967 Pubmed9727038 Reactome Database ID Release 4371401 Reactome, http://www.reactome.org ReactomeREACT_66 The mitochondrial alpha-ketoglutarate dehydrogenase complex catalyzes the reaction of alpha-ketoglutarate, CoASH, and NAD+ to form succinyl-CoA, CO2, and NADH. The enzyme complex contains multiple copies of three different proteins, E1 (OGDH), E2 (DLST), and E3 (DLD), each with distinct catalytic activities (Reed and Hackert 1990; Zhou et al 2001). The reaction starts with the oxidative decarboxylation of alpha ketoglutarate catalyzed by E1alpha and beta (alpha ketoglutarate dehydrogenase). Lipoamide cofactor associated with E1 is reduced at the same time. Next, the succinyl group derived from alpha ketoglutarate is transferred to coenzyme A in two steps catalyzed E2 (dihydrolipolyl transacetylase). Finally, the oxidized form of lipoamide is regenerated and electrons are transferred to NAD+ in two steps catalyzed by E3 (dihydrolipoyl dehydrogenase). The biochemical details of this reaction have been worked out with alpha ketoglutarate dehydrogenase complex and subunits purified from bovine tissue (McCartney et al. 1998). While all of the human proteins are known as predicted protein products of cloned genes, direct experimental evidence for their functions is available only for E3 (DLD) (Brautigam et al. 2005). NADPH + NAD+ + H+ [cytosol] => NADP+ + NADH + H+ [mitochondrial matrix] Authored: D'Eustachio, P, 2009-12-26 NNT (nicotinamide nucleotide transhydrogenase) associated with the inner mitochondrial membrane catalyzes the reaction of mitochondrial NADPH and NAD+ to form NADP+ and NADH. The reaction is coupled to the translocation of a proton across the inner mitochondrial membrane into the mitochondrial matrix (White et al, 2000). The active form of NNT is inferred to be a homodimer based on the known structure of its bovine homolog (Yamaguchi and Hatefi 1991). Pubmed10673423 Pubmed2005110 Reactome Database ID Release 43450971 Reactome, http://www.reactome.org ReactomeREACT_21342 Acetyl-CoA + H2O + Oxaloacetate => Citrate + CoA EC Number: 2.3.3.1 Mitochondrial citrate synthase dimer catalyzes the irreversible reaction of acetyl-CoA, water, and oxaloacetate to form citrate and coenzyme A. This reaction is the entry point of two-carbon units into the citric acid cycle. The reaction is subject to allosteric regulation. The gene encoding the human enzyme has been cloned (Goldenthal et al. 1998), but the enzyme has not been characterized in detail - its properties are inferred from those of the well-studied homologous pig enzyme (e.g., Morgunov and Srere 1998). Pubmed9792662 Pubmed9809442 Reactome Database ID Release 4370975 Reactome, http://www.reactome.org ReactomeREACT_1282 isocitrate <=> citrate Authored: D'Eustachio, P, 2009-12-26 EC Number: 4.2.1.3 Mitochondrial aconitase reversibly converts isocitrate to citrate via a cis-aconitate intermediate. Mitochondrial aconitase activity has been demonstrated in diverse human tissue extracts (Slaughter et al. 1975) and a protein homologous to the well-characterized porcine enzyme has been purified from human tissues (Baldwin et al. 1991). Pubmed1052766 Pubmed1946331 Reactome Database ID Release 43450975 Reactome, http://www.reactome.org ReactomeREACT_21262 citrate <=> isocitrate EC Number: 4.2.1.3 Mitochondrial aconitase reversibly converts citrate to isocitrate via a cis-aconitate intermediate. Mitochondrial aconitase activity has been demonstrated in diverse human tissue extracts (Slaughter et al. 1975) and a protein homologous to the well-characterized porcine enzyme has been purified from human tissues (Baldwin et al. 1991). Pubmed1052766 Pubmed1946331 Reactome Database ID Release 4370971 Reactome, http://www.reactome.org ReactomeREACT_1898 PathwayStep2081 monoubiquitinated N-myristoyl GAG (P03347) protein Reactome DB_ID: 184419 Reactome Database ID Release 43184419 Reactome, http://www.reactome.org ReactomeREACT_116336 has a Stoichiometric coefficient of 1 PathwayStep2082 monoubiquitinated N-myristoyl GAG (P03348) protein Reactome DB_ID: 184366 Reactome Database ID Release 43184366 Reactome, http://www.reactome.org ReactomeREACT_116557 has a Stoichiometric coefficient of 1 PathwayStep2080 GDP + Orthophosphate + Succinyl-CoA <=> GTP + Succinate + CoA EC Number: 6.2.1.4 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Mitochondrial succinate CoA ligase (ADP-forming) catalyzes the reversible conversion of succinyl CoA to succinate plus Coenzyme A, coupled to the conversion of ADP and orthophosphate to ATP. The enzyme is a heterodimer containing SUCLG1 and SUCLA2 monomers.<p>The enzyme catalyzing the reaction in vertebrates is a heterodimer that occurs in two isoforms. The enzymes have been purified from pigeon and rat tissue and characterized in detail. Both isoforms, an alpha:betaA heterodimer and an alpha:betaG heterodimer, catalyze the reversible conversion of succinyl CoA to succinate plus Coenzyme A. The alpha:betaA heterodimer couples this conversion to the synthesis of ATP from ADP and orthophosphate, while the alpha:betaG heterodimer couples it to the synthesis of GTP from GDP and orthophosphate (Johnson et al. 1998a,b; Lambeth et al. 2004). Consistent with these results in model systems, patients homozygous for a mutant allele of the gene encoding the ADP enzyme beta subunit, SUCLA2, are deficient in succinyl CoA ligase activity (Elpeleg et al. 2005).<p>Both isoforms are found in vivo, and appear to be expressed at different levels in various tissues. Their relative contributions to the flux of carbon atoms through the TCA cycle are unknown. Genetic and biochemical data suggest that the alpha:betaA isoform may be required to catalyze the reverse reaction, conversion of succinate, Coenzyme A, and ATP to succinyl CoA, ADP, and orthophosphate for heme biosynthesis (Furuyama and Sassa 2000). Pubmed10727444 Pubmed13181903 Pubmed15234968 Pubmed17668387 Pubmed9765290 Pubmed9765291 Reactome Database ID Release 4371775 Reactome, http://www.reactome.org ReactomeREACT_337 monoubiquitinated N-myristoyl GAG (Q70622) protein Reactome DB_ID: 184298 Reactome Database ID Release 43184298 Reactome, http://www.reactome.org ReactomeREACT_116897 has a Stoichiometric coefficient of 1 TRAF6:hp-IRAK1:Pellino Reactome DB_ID: 937020 Reactome Database ID Release 43937020 Reactome, http://www.reactome.org ReactomeREACT_26423 has a Stoichiometric coefficient of 1 ADP + Orthophosphate + Succinyl-CoA <=> ATP + Succinate + CoA EC Number: 6.2.1.5 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Mitochondrial succinate CoA ligase (ADP-forming) catalyzes the reversible conversion of succinyl CoA to succinate plus Coenzyme A, coupled to the conversion of ADP and orthophosphate to ATP. The enzyme is a heterodimer containing SUCLG1 and SUCLA2 monomers.<p>The enzyme catalyzing the reaction in vertebrates is a heterodimer that occurs in two isoforms. The enzymes have been purified from pigeon and rat tissue and characterized in detail. Both isoforms, an alpha:betaA heterodimer and an alpha:betaG heterodimer, catalyze the reversible conversion of succinyl CoA to succinate plus Coenzyme A. The alpha:betaA heterodimer couples this conversion to the synthesis of ATP from ADP and orthophosphate, while the alpha:betaG heterodimer couples it to the synthesis of GTP from GDP and orthophosphate (Johnson et al. 1998a,b; Lambeth et al. 2004). Consistent with these results in model systems, patients homozygous for a mutant allele of the gene encoding the ADP enzyme beta subunit, SUCLA2, are deficient in succinyl CoA ligase activity (Elpeleg et al. 2005).<p>Both isoforms are found in vivo, and appear to be expressed at different levels in various tissues. Their relative contributions to the flux of carbon atoms through the TCA cycle are unknown. Genetic and biochemical data suggest that the alpha:betaA isoform may be required to catalyze the reverse reaction, conversion of succinate, Coenzyme A, and ATP to succinyl CoA, ADP, and orthophosphate for heme biosynthesis (Furuyama and Sassa 2000). Pubmed10727444 Pubmed13181903 Pubmed15234968 Pubmed15877282 Pubmed9765290 Pubmed9765291 Reactome Database ID Release 4370997 Reactome, http://www.reactome.org ReactomeREACT_629 ESCRT-I Reactome DB_ID: 184398 Reactome Database ID Release 43184398 Reactome, http://www.reactome.org ReactomeREACT_27580 has a Stoichiometric coefficient of 1 p-Pellino:hp-IRAK1:TRAF6 Reactome DB_ID: 937040 Reactome Database ID Release 43937040 Reactome, http://www.reactome.org ReactomeREACT_26368 has a Stoichiometric coefficient of 1 Succinate <=> Fumarate (with FAD redox reaction on enzyme) EC Number: 1.3.5.1 Pubmed16143825 Reactome Database ID Release 4370994 Reactome, http://www.reactome.org ReactomeREACT_1667 The succinate dehydrogenase complex, associated with the inner mitochondrial membrane, catalyzes the dehydrogenation of succinate to fumarate, reducing the FAD cofactor bound to the enzyme. This redox potential is then used in the electron transfer chain to drive a proton motive force to generate ATP. monoubiquitinated N-myristoyl GAG polyprotein:ESCRT-I Reactome DB_ID: 184477 Reactome Database ID Release 43184477 Reactome, http://www.reactome.org ReactomeREACT_117139 has a Stoichiometric coefficient of 1 K63-linked polyUb p-IRAK1:TRAF6 Reactome DB_ID: 937043 Reactome Database ID Release 43937043 Reactome, http://www.reactome.org ReactomeREACT_25933 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG polyprotein Converted from EntitySet in Reactome Reactome DB_ID: 184406 Reactome Database ID Release 43184406 Reactome, http://www.reactome.org ReactomeREACT_116700 Poly-K6-Ub-hp-IRAK1 Reactome DB_ID: 451565 Reactome Database ID Release 43451565 Reactome, http://www.reactome.org ReactomeREACT_23323 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep2089 monoubiquitinated N-myristoyl GAG (P20873) protein Reactome DB_ID: 184434 Reactome Database ID Release 43184434 Reactome, http://www.reactome.org ReactomeREACT_116274 has a Stoichiometric coefficient of 1 TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88 :activated TLR5 or 10 Reactome DB_ID: 975869 Reactome Database ID Release 43975869 Reactome, http://www.reactome.org ReactomeREACT_27677 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 8 monoubiquitinated N-myristoyl GAG (P20889) protein Reactome DB_ID: 184314 Reactome Database ID Release 43184314 Reactome, http://www.reactome.org ReactomeREACT_116929 has a Stoichiometric coefficient of 1 hp-IRAK1/or p-IRAK2:TRAF6 Converted from EntitySet in Reactome Reactome DB_ID: 937058 Reactome Database ID Release 43937058 Reactome, http://www.reactome.org ReactomeREACT_26897 PathwayStep2087 monoubiquitinated N-myristoyl GAG (P24736) protein Reactome DB_ID: 184263 Reactome Database ID Release 43184263 Reactome, http://www.reactome.org ReactomeREACT_117437 has a Stoichiometric coefficient of 1 TRAF6:hp-IRAK1 Reactome DB_ID: 937036 Reactome Database ID Release 43937036 Reactome, http://www.reactome.org ReactomeREACT_25583 has a Stoichiometric coefficient of 1 PathwayStep2088 monoubiquitinated N-myristoyl GAG (P35962) protein Reactome DB_ID: 184410 Reactome Database ID Release 43184410 Reactome, http://www.reactome.org ReactomeREACT_116959 has a Stoichiometric coefficient of 1 TRAF6:p-IRAK2 Reactome DB_ID: 936961 Reactome Database ID Release 43936961 Reactome, http://www.reactome.org ReactomeREACT_26255 has a Stoichiometric coefficient of 1 PathwayStep2085 PathwayStep2086 PathwayStep4300 PathwayStep2083 hp-IRAK1:activated IRAK4:MyD88oligomer:activated TLR5 or 10 Reactome DB_ID: 975877 Reactome Database ID Release 43975877 Reactome, http://www.reactome.org ReactomeREACT_27391 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PathwayStep4301 PathwayStep2084 hp-IRAK1 or p-IRAK2 : pIRAK4:MyD88:activated TLR5/10 Reactome DB_ID: 975881 Reactome Database ID Release 43975881 Reactome, http://www.reactome.org ReactomeREACT_27498 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PathwayStep2069 monoubiquitinated N-myristoyl GAG (P18800) protein Reactome DB_ID: 184389 Reactome Database ID Release 43184389 Reactome, http://www.reactome.org ReactomeREACT_117743 has a Stoichiometric coefficient of 1 PathwayStep2070 monoubiquitinated N-myristoyl GAG (P12494) protein Reactome DB_ID: 184424 Reactome Database ID Release 43184424 Reactome, http://www.reactome.org ReactomeREACT_116192 has a Stoichiometric coefficient of 1 PathwayStep2071 monoubiquitinated N-myristoyl GAG (P12495) protein Reactome DB_ID: 184493 Reactome Database ID Release 43184493 Reactome, http://www.reactome.org ReactomeREACT_116882 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG (P05890) protein Reactome DB_ID: 184489 Reactome Database ID Release 43184489 Reactome, http://www.reactome.org ReactomeREACT_117757 has a Stoichiometric coefficient of 1 TLR4:MD2:LPS:CD14 Reactome DB_ID: 2201299 Reactome Database ID Release 432201299 Reactome, http://www.reactome.org ReactomeREACT_124771 has a Stoichiometric coefficient of 2 monoubiquitinated N-myristoyl GAG (P12493) protein Reactome DB_ID: 184273 Reactome Database ID Release 43184273 Reactome, http://www.reactome.org ReactomeREACT_116818 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG (P05888) protein Reactome DB_ID: 184423 Reactome Database ID Release 43184423 Reactome, http://www.reactome.org ReactomeREACT_117050 has a Stoichiometric coefficient of 1 viral dsRNA :TLR3 Reactome DB_ID: 167985 Reactome Database ID Release 43167985 Reactome, http://www.reactome.org ReactomeREACT_7159 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 monoubiquitinated N-myristoyl GAG (P05889) protein Reactome DB_ID: 184445 Reactome Database ID Release 43184445 Reactome, http://www.reactome.org ReactomeREACT_117603 has a Stoichiometric coefficient of 1 TRAM:TLR4:MD2:LPS:CD14 Reactome DB_ID: 166163 Reactome Database ID Release 43166163 Reactome, http://www.reactome.org ReactomeREACT_7083 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep2076 monoubiquitinated N-myristoyl GAG (P04594) protein Reactome DB_ID: 184348 Reactome Database ID Release 43184348 Reactome, http://www.reactome.org ReactomeREACT_116740 has a Stoichiometric coefficient of 1 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex Reactome DB_ID: 937008 Reactome Database ID Release 43937008 Reactome, http://www.reactome.org ReactomeREACT_26622 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep2077 monoubiquitinated N-myristoyl GAG (P05887) protein Reactome DB_ID: 184346 Reactome Database ID Release 43184346 Reactome, http://www.reactome.org ReactomeREACT_117802 has a Stoichiometric coefficient of 1 MEKK1:activated TRAF6 Reactome DB_ID: 166867 Reactome Database ID Release 43166867 Reactome, http://www.reactome.org ReactomeREACT_7633 has a Stoichiometric coefficient of 1 PathwayStep2078 K63-poly-Ub TRAF6 K6 polyubiquitinated TRAF6 Reactome DB_ID: 936980 Reactome Database ID Release 43936980 Reactome, http://www.reactome.org ReactomeREACT_25539 has a Stoichiometric coefficient of 1 PathwayStep2079 monoubiquitinated N-myristoyl GAG (P04593) protein Reactome DB_ID: 184457 Reactome Database ID Release 43184457 Reactome, http://www.reactome.org ReactomeREACT_117850 has a Stoichiometric coefficient of 1 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex Reactome DB_ID: 936953 Reactome Database ID Release 43936953 Reactome, http://www.reactome.org ReactomeREACT_27027 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep2072 p-IRAK2:oligo-TRAF6 Reactome DB_ID: 936990 Reactome Database ID Release 43936990 Reactome, http://www.reactome.org ReactomeREACT_25874 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep2073 p-IRAK2:K63-linked pUb oligo-TRAF6 Reactome DB_ID: 936988 Reactome Database ID Release 43936988 Reactome, http://www.reactome.org ReactomeREACT_26930 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep2074 PathwayStep2075 TRAF6:K63-linked polyUb p-IRAK1:IKK complex Reactome DB_ID: 937038 Reactome Database ID Release 43937038 Reactome, http://www.reactome.org ReactomeREACT_26014 has a Stoichiometric coefficient of 1 PathwayStep2059 PathwayStep2058 Ub-Smad7 Reactome DB_ID: 2186779 Reactome Database ID Release 432186779 Reactome, http://www.reactome.org ReactomeREACT_125606 has a Stoichiometric coefficient of 1 DHNTP is dephosphorylated by PTPS to PTHP 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) (Takikawa et al. 1986) catalyses the second step in BH4 biosynthesis, the dephosphorylation of DHNTP to 6-pyruvoyl-tetrahydropterin (PTHP). PTPS is believed to function as a homohexamer (Nar et al. 1994, Bürgisser et al. 1994) and has a requirement for Zn2+ (one Zn2+ ion bound per subunit) and Mg2+ ions for activity (Bürgisser et al. 1995). The phosphorylation of Ser-19 is an essential modification for enzyme activity (Scherer-Oppliger et al. 1999). Authored: Jassal, B, 2011-08-17 EC Number: 4.2.3.12 Edited: Jassal, B, 2011-08-17 Pubmed10531334 Pubmed3536512 Pubmed7563095 Pubmed8137809 Pubmed8307017 Reactome Database ID Release 431474184 Reactome, http://www.reactome.org ReactomeREACT_111082 Reviewed: D'Eustachio, P, 2011-08-23 PTHP is reduced to BH4 by sepiapterin reductase (SPR) Authored: Jassal, B, 2011-08-17 EC Number: 1.1.1.153 Edited: Jassal, B, 2011-08-17 Pubmed1883349 Reactome Database ID Release 431475414 Reactome, http://www.reactome.org ReactomeREACT_111093 Reviewed: D'Eustachio, P, 2011-08-23 Sepiapterin reductase (SPR) (Ichinose et al. 1991) reduces DHNTP to tetrahydrobiopterin (BH4). has a Stoichiometric coefficient of 2 Sepiapterin reductase (SPR) is phosphorylated by Ca2+/calmodulin-dependent protein kinase II Authored: Jassal, B, 2011-08-17 EC Number: 2.7.11.12 Edited: Jassal, B, 2011-08-17 Pubmed11825621 Pubmed8137944 Reactome Database ID Release 431497853 Reactome, http://www.reactome.org ReactomeREACT_111129 Reviewed: D'Eustachio, P, 2011-08-23 To become active, sepiapterin reductase (SPR) must first be phosphorylated (serine 213 in humans) by Ca2+/calmodulin-dependent protein kinase II (Fujimoto et al. 2002, Katoh et al. 1994). has a Stoichiometric coefficient of 2 Peroxynitrite can oxidise BH4 to the BH3 radical Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 Peroxynitrite can oxidise BH4 to the BH3 radical, further reducing BH4 availability to couple eNOS activity and compounding the production of superoxide through uncoupled eNOS activity (Kuzkaya et al. 2003). Pubmed12692136 Reactome Database ID Release 431497866 Reactome, http://www.reactome.org ReactomeREACT_111062 Reviewed: D'Eustachio, P, 2011-08-23 BH4 is oxidised to the BH3 radical during the eNOS catalytic cycle Authored: Jassal, B, 2011-08-17 BH4 donates an electron to the eNOS catalytic cycle and is oxidised to the BH3 radical (BH3.-) (Berka et al. 2004). Edited: Jassal, B, 2011-08-17 Pubmed15476407 Reactome Database ID Release 431497824 Reactome, http://www.reactome.org ReactomeREACT_111060 Reviewed: D'Eustachio, P, 2011-08-23 Ferrous iron reduces the BH3 radical back to BH4 Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 Heme iron from the oxygenase domain of eNOS can reduce the BH3 radical back to BH4, with itself being oxidised from the ferrous (Fe2+) back to the ferric (Fe3+) form (Berka et al. 2004). Pubmed15476407 Reactome Database ID Release 431497883 Reactome, http://www.reactome.org ReactomeREACT_111125 Reviewed: D'Eustachio, P, 2011-08-23 Lactoferrin (loaded) Reactome DB_ID: 1470056 Reactome Database ID Release 431470056 Reactome, http://www.reactome.org ReactomeREACT_123248 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TLR10 homodimer bound to ligand Reactome DB_ID: 188116 Reactome Database ID Release 43188116 Reactome, http://www.reactome.org ReactomeREACT_9231 has a Stoichiometric coefficient of 1 Ascorbate can reduce the BH3 radical back to BH4 Ascorbate (vitamin C) can reduce the BH3 radical back to BH4, thereby maintaining BH4 levels (Baker et al. 2001, Patel et al. 2002, Kuzkaya et al. 2003). Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 Pubmed11243424 Pubmed11827745 Pubmed12692136 Reactome Database ID Release 431497855 Reactome, http://www.reactome.org ReactomeREACT_111191 Reviewed: D'Eustachio, P, 2011-08-23 monoubiquitinated N-myristoyl GAG polyprotein Converted from EntitySet in Reactome Reactome DB_ID: 184265 Reactome Database ID Release 43184265 Reactome, http://www.reactome.org ReactomeREACT_117519 TLR10 homodimer Reactome DB_ID: 188112 Reactome Database ID Release 43188112 Reactome, http://www.reactome.org ReactomeREACT_9273 has a Stoichiometric coefficient of 2 The BH3 radical can decay to dihydrobiopterin (BH2) Authored: Jassal, B, 2011-08-17 BH4 oxidation results in the radical BH3. which decays to 7,8-dihydrobiopterin (BH2) (Milstien & Katusic, 1999). Edited: Jassal, B, 2011-08-17 Pubmed10512739 Reactome Database ID Release 431497863 Reactome, http://www.reactome.org ReactomeREACT_111165 Reviewed: D'Eustachio, P, 2011-08-23 monoubiquitinated N-myristoyl GAG (P03347) protein Reactome DB_ID: 184470 Reactome Database ID Release 43184470 Reactome, http://www.reactome.org ReactomeREACT_116507 has a Stoichiometric coefficient of 1 Activated TLR5 or TLR10 homodimer Converted from EntitySet in Reactome Reactome DB_ID: 975862 Reactome Database ID Release 43975862 Reactome, http://www.reactome.org ReactomeREACT_27376 BH2 binding can lead to eNOS uncoupling Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 Pubmed11879202 Reactome Database ID Release 431497796 Reactome, http://www.reactome.org ReactomeREACT_111106 Reviewed: D'Eustachio, P, 2011-08-23 The oxidation product of BH4, 7,8-dihydrobiopterin (BH2), can compete with BH4 for binding to eNOS. This can lead to the uncoupling of eNOS and can result in the formation of reactive oxygen species (Vasquez-Vivar et al. 2002). monoubiquitinated N-myristoyl GAG (P03348) protein Reactome DB_ID: 184454 Reactome Database ID Release 43184454 Reactome, http://www.reactome.org ReactomeREACT_117785 has a Stoichiometric coefficient of 1 TLR5 homodimer:bacterial flagellin Reactome DB_ID: 188027 Reactome Database ID Release 43188027 Reactome, http://www.reactome.org ReactomeREACT_9374 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 GCHFR binds to GCH1 and negatively regulates its activity Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 High levels of the end product, BH4, negatively regulates GCH1. It does this via GTP cyclohydrolase 1 feedback regulatory protein (GCHFR). BH4-dependant GCHFR in the form of a homopentamer complexes with the decameric GCH1 enzyme in the ratio 2:1 to inactivate it. L-phenylalanine reverses this inhibition. These regulatory steps control the biosynthesis of BH4. (Swick & Kapatos 2006, Chavan et al. 2006, Harada et al. 1993). Pubmed16696853 Pubmed16778797 Pubmed8502995 Reactome Database ID Release 431474158 Reactome, http://www.reactome.org ReactomeREACT_111115 Reviewed: D'Eustachio, P, 2011-08-23 has a Stoichiometric coefficient of 2 monoubiquitinated N-myristoyl GAG (P03349) protein Reactome DB_ID: 184376 Reactome Database ID Release 43184376 Reactome, http://www.reactome.org ReactomeREACT_116289 has a Stoichiometric coefficient of 1 MyD88 complexed with the activated TLR5 or 10 receptor Reactome DB_ID: 975860 Reactome Database ID Release 43975860 Reactome, http://www.reactome.org ReactomeREACT_27814 has a Stoichiometric coefficient of 1 PathwayStep2060 monoubiquitinated N-myristoyl GAG (P03350) protein Reactome DB_ID: 184282 Reactome Database ID Release 43184282 Reactome, http://www.reactome.org ReactomeREACT_116786 has a Stoichiometric coefficient of 1 MYD88 homodimer Reactome DB_ID: 937078 Reactome Database ID Release 43937078 Reactome, http://www.reactome.org ReactomeREACT_25870 has a Stoichiometric coefficient of 2 monoubiquitinated N-myristoyl GAG (P04591) protein Reactome DB_ID: 184369 Reactome Database ID Release 43184369 Reactome, http://www.reactome.org ReactomeREACT_116777 has a Stoichiometric coefficient of 1 monoubiquitinated N-myristoyl GAG (P04592) protein Reactome DB_ID: 184355 Reactome Database ID Release 43184355 Reactome, http://www.reactome.org ReactomeREACT_116762 has a Stoichiometric coefficient of 1 PathwayStep2063 PathwayStep2064 PathwayStep2061 PathwayStep2062 PathwayStep2067 C-ter TLR7 dimer C-terminus TLR7 dimer Reactome DB_ID: 1678924 Reactome Database ID Release 431678924 Reactome, http://www.reactome.org ReactomeREACT_120221 has a Stoichiometric coefficient of 2 PathwayStep2068 C-ter-TLR9 dimer C-terminus Toll like receptor 9 (TLR9) dimer Reactome DB_ID: 1678956 Reactome Database ID Release 431678956 Reactome, http://www.reactome.org ReactomeREACT_119600 has a Stoichiometric coefficient of 2 PathwayStep2065 Plcg1:P-ERBB2:P-EGFR Reactome DB_ID: 1251930 Reactome Database ID Release 431251930 Reactome, http://www.reactome.org ReactomeREACT_117740 has a Stoichiometric coefficient of 1 Cathepsin L1 Reactome DB_ID: 1678983 Reactome Database ID Release 431678983 Reactome, http://www.reactome.org ReactomeREACT_119492 has a Stoichiometric coefficient of 1 PathwayStep2066 P-Plcg1:P-ERBB2:P-EGFR Reactome DB_ID: 1251931 Reactome Database ID Release 431251931 Reactome, http://www.reactome.org ReactomeREACT_116683 has a Stoichiometric coefficient of 1 N-ter TLR9 dimer Reactome DB_ID: 1679007 Reactome Database ID Release 431679007 Reactome, http://www.reactome.org ReactomeREACT_119555 has a Stoichiometric coefficient of 2 PathwayStep2048 PathwayStep2047 PathwayStep2049 Salvage - BH2 is reduced to BH4 by DHFR Authored: Jassal, B, 2011-08-17 EC Number: 1.5.1.3 Edited: Jassal, B, 2011-08-17 In the second salvage step, dihydrofolate reductase (DHFR) can regenerate BH4 from BH2, a process which increases the BH4:BH2 ratio providing BH4 for coupled eNOS production of NO. In mice cell lines, DHFR inhibition or knockdown diminishes the BH4:BH2 ratio and exacerbates eNOS uncoupling (Crabtree et al. 2009). Pubmed19666465 Reactome Database ID Release 431497794 Reactome, http://www.reactome.org ReactomeREACT_111041 Reviewed: D'Eustachio, P, 2011-08-23 Salvage - Sepiapterin is reduced to BH2 Authored: Jassal, B, 2011-08-17 EC Number: 1.1.1.153 Edited: Jassal, B, 2011-08-17 In the first of two salvage steps to maintain BH4 levels in the cell, sepiapterin is taken up by the cell and reduced by sepiapterin reductase (SRP) to form BH2 (Sawabe et al. 2008). Pubmed18511317 Reactome Database ID Release 431497869 Reactome, http://www.reactome.org ReactomeREACT_111234 Reviewed: D'Eustachio, P, 2011-08-23 IL6:sIL6R:Tyrosine phosphorylated IL6RB:Activated JAKs Reactome DB_ID: 1112570 Reactome Database ID Release 431112570 Reactome, http://www.reactome.org ReactomeREACT_27784 has a Stoichiometric coefficient of 1 Tyrosine phosphorylated IL6RB:Activated JAKs Reactome DB_ID: 1112563 Reactome Database ID Release 431112563 Reactome, http://www.reactome.org ReactomeREACT_27630 has a Stoichiometric coefficient of 1 (S)-Lactate + NAD+ <=> Pyruvate + NADH + H+ Cytosolic lactate dehydrogenase catalyzes the freely reversible reaction of lactate and NAD+ to form pyruvate and NADH + H+. In liver parenchymal cells, this reaction allows lactate from red blood cells and exercising muscle to be converted to pyruvate which in turn is typically used for gluconeogenesis which also consumes the NADH from the reaction.<p>Lactate dehydrogenase is active as a tetramer. Two isoforms of lactate dehydrogenase, A and B, are widely expressed in human tissues, and all five tetramers - A4, A3B, A2B2, AB3, and B4 - are found. A third isoform, C, and its tetramer, C4, are found in testis. EC Number: 1.1.1.27 Pubmed11276087 Pubmed11377399 Pubmed3435492 Reactome Database ID Release 4370510 Reactome, http://www.reactome.org ReactomeREACT_1010 lactate + H+ [extracellular] <=> lactate + H+ [cytosol] Authored: D'Eustachio, P, 2008-07-17 18:53:09 Edited: D'Eustachio, P, 2008-07-17 18:53:09 Pubmed15917240 Reactome Database ID Release 43373867 Reactome, http://www.reactome.org ReactomeREACT_14855 The membrane-associated MCT:basigin complex mediates the reversible uptake of extracellular lactate and H+ (Wilson et al. 2005). lactate + H+ [cytosol] <=> lactate + H+ [extracellular] Authored: D'Eustachio, P, 2008-07-17 18:53:09 Edited: D'Eustachio, P, 2008-07-17 18:53:09 Pubmed15917240 Reactome Database ID Release 43373875 Reactome, http://www.reactome.org ReactomeREACT_14839 The membrane-associated MCT:basigin complex mediates the reversible export of cytosolic lactate and H+ (Wilson et al. 2005). Pyruvate + NADH + H+ <=> (S)-Lactate + NAD+ Cytosolic lactate dehydrogenase catalyzes the reversible reaction of pyruvate and NADH + H+ to form lactate and NAD+. In the body under anaerobic conditions such as are found in red blood cells or rapidly exercising skeletal muscle, this reaction regenerates NAD+, allowing the continuation of glycolysis.<p>Lactate dehydrogenase is active as a tetramer. Two isoforms of lactate dehydrogenase, A and B, are widely expressed in human tissues, and all five tetramers - A4, A3B, A2B2, AB3, and B4 - are found. A third isoform, C, and its tetramer, C4, are found in testis. EC Number: 1.1.1.27 Pubmed11276087 Pubmed11377399 Pubmed3435492 Reactome Database ID Release 4371849 Reactome, http://www.reactome.org ReactomeREACT_178 Inactivation of PDC by phosphorylation of PDC E1 alpha component Authored: Gopinathrao, G, 2007-11-26 20:29:38 EC Number: 2.7.11.2 PDK-catalyzed phosphorylation (inactivation) of PDC E1 alpha subunit Pubmed11485553 Pubmed11486000 Pubmed15491150 Pubmed7499431 Pubmed8798399 Pubmed9405293 Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the pyruvate dehydrogenase complex, inactivating it. Pyruvate negatively regulates this reaction, and NADH and acetyl CoA positively regulate it (Bao et al. 2004). Four PDK isoforms have been identified and shown to catalyze the phosphorylation of E1 alpha in vitro (Gudi et al. 1995; Kolobova et al. 2001; Rowles et al. 1996). They differ in their expression patterns and quantitative responses to regulatory small molecules. All four isoforms catalyze the phosphorylation of serine residues 293 ("site 1") and 300 ("site 2"); PDK1 also catalyzes the phosphorylation of serine 232 ("site 3"). Phosphorylation of a single site in a single E1 alpha subunit is sufficient for enzyme inactivation (Bowker-Kinley et al. 1998; Gudi et al. 1995; Kolobova et al. 2001; Korotchkina and Patel, 2001). Reactome Database ID Release 43203946 Reactome, http://www.reactome.org ReactomeREACT_12462 Reviewed: D'Eustachio, P, 2008-01-11 20:49:08 has a Stoichiometric coefficient of 2 phospho-ERK-2 dimer Reactome DB_ID: 109855 Reactome Database ID Release 43109855 Reactome, http://www.reactome.org ReactomeREACT_3688 has a Stoichiometric coefficient of 2 IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10 Reactome DB_ID: 975868 Reactome Database ID Release 43975868 Reactome, http://www.reactome.org ReactomeREACT_27973 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Activation of PDC by dephosphorylation of phospho-E1 alpha component Authored: Gopinathrao, G, 2007-11-26 20:29:38 EC Number: 3.1.3.43 PDP-catalyzed dephosphorylation (activation) of phospho E1 alpha subunit Pubmed15855260 Pubmed17532339 Pubmed9395502 Pubmed9651365 Pyruvate dehydrogenase phosphatase (PDP) in the mitochondrial matrix catalyzes the hydrolytic removal of phosphate groups from phosphoserine residues in the E1 alpha subunit of the pyruvate dehydrogenase complex. The active form of PDP is a heterodimer of a catalytic subunit and a regulatory one. Two isoforms of the catalytic subunit have been identified and biochemically characterized (Huang et al. 1998) and mutations in PDP1 have been associated with PDP deficiency in vivo (Maj et al. 2005). The properties of the human regulatory subunit have been deduced from those of its bovine homologue (Lawson et al. 1997). The activity of PDP1 is greatly enhanced through Ca2+ -dependent binding of the catalytic subunit (PDP1c) to the L2 (inner lipoyl) domain of dihydrolipoyl acetyltransferase (E2), which is also integrated in the pyruvate dehydrogenase complex. PDP activity requires Mg2+ (Huang et al. 1998). Reactome Database ID Release 43204169 Reactome, http://www.reactome.org ReactomeREACT_12543 Reviewed: D'Eustachio, P, 2008-01-11 20:49:08 has a Stoichiometric coefficient of 2 phospho-ERK-2 dimer Reactome DB_ID: 109856 Reactome Database ID Release 43109856 Reactome, http://www.reactome.org ReactomeREACT_5046 has a Stoichiometric coefficient of 2 p-IRAK1:p-IRAK4:oligo-MyD88l:activated TLR5 or 10 Reactome DB_ID: 975872 Reactome Database ID Release 43975872 Reactome, http://www.reactome.org ReactomeREACT_27502 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PYR + H+ (cytosol) => PYR + H+ (mitochondrial matrix) Authored: D'Eustachio, P, 2008-06-20 15:07:05 Cytosolic PYR is transported to the mitochondrial matrix by MPC1:MPC2 Edited: D'Eustachio, P, 2008-09-12 21:47:19 Pubmed11945601 Pubmed22628558 Pubmed4822737 Pyruvate (PYR) and a proton are transported from the cytosol into the mitochondrial matrix, mediated by a complex of MCP1 and MCP2 in the inner mitochondrial membrane. Studies of pyruvate uptake in rat indicate that it is specific, saturable, and competitively inhibitable, indicating a specific role for a membrane transport protein (Papa et al. 1971; Halestrap and Denton 1974), and the stoichiometry of the human reaction is inferred from this work. MCP1 and MCP2 have been identified as essential components of the transporter based on the observation that expression of both proteins (but not either one alone) restored mitochondrial pyruvate uptake in mutant budding yeast. The proteins form a multimeric complex; its stoichiometry is unknown (Bricker et al. 2012). Reactome Database ID Release 43372342 Reactome, http://www.reactome.org ReactomeREACT_14833 Reviewed: Harris, RA, 2008-09-10 18:47:12 Reviewed: Jassal, B, 2012-10-12 MEK2:ERK-2 Reactome DB_ID: 109849 Reactome Database ID Release 43109849 Reactome, http://www.reactome.org ReactomeREACT_5435 has a Stoichiometric coefficient of 1 IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR5/10 Reactome DB_ID: 975859 Reactome Database ID Release 43975859 Reactome, http://www.reactome.org ReactomeREACT_27414 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 pyruvate + CoASH + NAD+ => acetylCoA + CO2 + NADH + H+ Authored: Birney, E, Schmidt, EE, 2003-01-28 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Oxidative decarboxylation of pyruvate to acetyl CoA by pyruvate dehydrogenase Pubmed10679936 Pubmed11752427 Pubmed15138885 Pubmed15946682 Pubmed16049940 Pubmed2188967 Reactome Database ID Release 4371397 Reactome, http://www.reactome.org ReactomeREACT_983 The mitochondrial pyruvate dehydrogenase complex catalyzes the reaction of pyruvate, CoASH, and NAD+ to form acetylCoA, CO2, and NADH. The enzyme complex contains multiple copies of three different proteins, E1 alpha, E1 beta, E2, and E3, each with distinct catalytic activities (Reed and Hackert 1990; Zhou et al 2001). The reaction starts with the oxidative decarboxylation of pyruvate catalyzed by E1 alpha and beta (pyruvate dehydrogenase). Lipoamide cofactor associated with E1 is reduced at the same time. Next, the acetyl group derived from pyruvate is transferred to coenzyme A in two steps catalyzed by E2 (dihydrolipolyl transacetylase). Finally, the oxidized form of lipoamide is regenerated and electrons are transferred to NAD+ in two steps catalyzed by E3 (dihydrolipoyl dehydrogenase). The biochemical details of this reaction have been worked out with pyruvate dehydrogenase complex and subunits purified from bovine tissue and other non-human sources. Direct evidence for the roles of the corresponding human proteins comes from studies of patients expressing mutant forms of E1 alpha (Lissens et al. 2000), E1 beta (Brown et al. 2004), E2 (Head et al. 2005), and E3 (Brautigam et al. 2005). phospho-ERK-2:MEK2 Reactome DB_ID: 109854 Reactome Database ID Release 43109854 Reactome, http://www.reactome.org ReactomeREACT_3199 has a Stoichiometric coefficient of 1 p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR5 or 10 Reactome DB_ID: 975867 Reactome Database ID Release 43975867 Reactome, http://www.reactome.org ReactomeREACT_27632 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 p-2S-cJUN:p-2S,2T-cFOS AP-1(cJun:cFos) phosphorylated Reactome DB_ID: 450327 Reactome Database ID Release 43450327 Reactome, http://www.reactome.org ReactomeREACT_21707 has a Stoichiometric coefficient of 1 Rnf111:Smad7 Reactome DB_ID: 2186774 Reactome Database ID Release 432186774 Reactome, http://www.reactome.org ReactomeREACT_122741 has a Stoichiometric coefficient of 1 Phospho-ERK dimer Converted from EntitySet in Reactome Reactome DB_ID: 198701 Reactome Database ID Release 43198701 Reactome, http://www.reactome.org ReactomeREACT_12827 pp-IRAK1:p-IRAK4:oligo-MyD88 :activated TLR5 or 10 complex Reactome DB_ID: 975883 Reactome Database ID Release 43975883 Reactome, http://www.reactome.org ReactomeREACT_27453 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 p-2S-cJUN:p-2T-ATF2 AP-1 heterodimer phosphorylated Reactome DB_ID: 450262 Reactome Database ID Release 43450262 Reactome, http://www.reactome.org ReactomeREACT_21429 has a Stoichiometric coefficient of 1 PathwayStep2050 PathwayStep2051 oligo-MyD88:activated TLR5 or 10 Reactome DB_ID: 975864 Reactome Database ID Release 43975864 Reactome, http://www.reactome.org ReactomeREACT_27690 has a Stoichiometric coefficient of 1 PathwayStep2052 PathwayStep2053 PathwayStep2054 p-S,2T-IRAK4:oligo-MyD88:activated TLR5 or 10 Reactome DB_ID: 975870 Reactome Database ID Release 43975870 Reactome, http://www.reactome.org ReactomeREACT_27900 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PathwayStep2055 IL6:sIL6R Reactome DB_ID: 1067687 Reactome Database ID Release 431067687 Reactome, http://www.reactome.org ReactomeREACT_27493 has a Stoichiometric coefficient of 1 IRAK1 or IRAK2 :p-IRAK4:MyD88 oligomer:activated TLR5 or 10 Reactome DB_ID: 975875 Reactome Database ID Release 43975875 Reactome, http://www.reactome.org ReactomeREACT_27359 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PathwayStep2056 MyD88 oligomer Reactome DB_ID: 937013 Reactome Database ID Release 43937013 Reactome, http://www.reactome.org ReactomeREACT_25612 has a Stoichiometric coefficient of 6 PathwayStep2057 IRAK4:oligo-MyD88:activated TLR5 or 10 Reactome DB_ID: 975876 Reactome Database ID Release 43975876 Reactome, http://www.reactome.org ReactomeREACT_27378 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 phospho-p38 MAPK : MAPKAPK2 or MaPKAPK3 Reactome DB_ID: 450213 Reactome Database ID Release 43450213 Reactome, http://www.reactome.org ReactomeREACT_21530 has a Stoichiometric coefficient of 1 KIR2DS1 complexed with DAP12 Reactome DB_ID: 199586 Reactome Database ID Release 43199586 Reactome, http://www.reactome.org ReactomeREACT_11752 has a Stoichiometric coefficient of 1 phospho-p38 MAPK : phospho MAPKAPK2 or phospho MaPKAPK3 Reactome DB_ID: 450254 Reactome Database ID Release 43450254 Reactome, http://www.reactome.org ReactomeREACT_21539 has a Stoichiometric coefficient of 1 phospho-p38 MAPK : phospho MAPKAPK2 or phospho MaPKAPK3 Reactome DB_ID: 450241 Reactome Database ID Release 43450241 Reactome, http://www.reactome.org ReactomeREACT_21519 has a Stoichiometric coefficient of 1 PathwayStep2038 PathwayStep2039 PathwayStep2036 PathwayStep2037 PathwayStep2046 PathwayStep2045 PathwayStep2044 KIR2DS2 complexed with DAP12 Reactome DB_ID: 199584 Reactome Database ID Release 43199584 Reactome, http://www.reactome.org ReactomeREACT_11717 has a Stoichiometric coefficient of 1 PathwayStep2043 HLA-C group 2 interacting with KIR2DS1 Reactome DB_ID: 199585 Reactome Database ID Release 43199585 Reactome, http://www.reactome.org ReactomeREACT_11864 has a Stoichiometric coefficient of 1 PathwayStep2042 PathwayStep2041 PathwayStep2040 IL6:IL6RA:Tyrosine phosphorylated IL6RB:Activated JAKs Converted from EntitySet in Reactome Reactome DB_ID: 1112584 Reactome Database ID Release 431112584 Reactome, http://www.reactome.org ReactomeREACT_27564 ATP-bound Gp96 dimer:CNPY3:TLR7/8/9 Reactome DB_ID: 1679076 Reactome Database ID Release 431679076 Reactome, http://www.reactome.org ReactomeREACT_119946 has a Stoichiometric coefficient of 2 Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs Reactome DB_ID: 1112594 Reactome Database ID Release 431112594 Reactome, http://www.reactome.org ReactomeREACT_27710 has a Stoichiometric coefficient of 2 Apo-GP96 dimer Reactome DB_ID: 1678941 Reactome Database ID Release 431678941 Reactome, http://www.reactome.org ReactomeREACT_119705 has a Stoichiometric coefficient of 2 IL6:IL6RA Reactome DB_ID: 1067638 Reactome Database ID Release 431067638 Reactome, http://www.reactome.org ReactomeREACT_27964 has a Stoichiometric coefficient of 1 FL-TLR7 dimer Reactome DB_ID: 1678995 Reactome Database ID Release 431678995 Reactome, http://www.reactome.org ReactomeREACT_119314 full-length TLR7 dimer has a Stoichiometric coefficient of 2 IL6:IL6RA:Tyrosine phosphorylated IL6RB:Activated JAKs Reactome DB_ID: 1112585 Reactome Database ID Release 431112585 Reactome, http://www.reactome.org ReactomeREACT_27518 has a Stoichiometric coefficient of 1 folded FL-TLR7/8/9 Converted from EntitySet in Reactome Reactome DB_ID: 1679066 Reactome Database ID Release 431679066 Reactome, http://www.reactome.org ReactomeREACT_119319 phospho-ERK-1:MEK1 Reactome DB_ID: 109843 Reactome Database ID Release 43109843 Reactome, http://www.reactome.org ReactomeREACT_2796 has a Stoichiometric coefficient of 1 p(S7)-Rap1 GTPase-activating protein 2:14-3-3beta, zeta Reactome DB_ID: 913992 Reactome Database ID Release 43913992 Reactome, http://www.reactome.org ReactomeREACT_24434 has a Stoichiometric coefficient of 1 MEK1:ERK-1 Reactome DB_ID: 109838 Reactome Database ID Release 43109838 Reactome, http://www.reactome.org ReactomeREACT_5539 has a Stoichiometric coefficient of 1 HLA-C group 1 interacting with KIR2DS2 Reactome DB_ID: 199588 Reactome Database ID Release 43199588 Reactome, http://www.reactome.org ReactomeREACT_11521 has a Stoichiometric coefficient of 1 IL6:Tyrosine phosphorylated hexameric IL-6 receptor:Activated JAKs:p-SHP2 Reactome DB_ID: 1112753 Reactome Database ID Release 431112753 Reactome, http://www.reactome.org ReactomeREACT_27855 has a Stoichiometric coefficient of 1 Rap1-GTP:Raf1 Reactome DB_ID: 430243 Reactome Database ID Release 43430243 Reactome, http://www.reactome.org ReactomeREACT_24874 has a Stoichiometric coefficient of 1 phospho-ERK-1 dimer Reactome DB_ID: 109844 Reactome Database ID Release 43109844 Reactome, http://www.reactome.org ReactomeREACT_3932 has a Stoichiometric coefficient of 2 Rap1 cAMP-GEFs:cAMP Reactome DB_ID: 392837 Reactome Database ID Release 43392837 Reactome, http://www.reactome.org ReactomeREACT_24050 has a Stoichiometric coefficient of 1 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex Reactome DB_ID: 937060 Reactome Database ID Release 43937060 Reactome, http://www.reactome.org ReactomeREACT_24862 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 p-IRAK2:K63-linked pUb oligo-TRAF6 Reactome DB_ID: 937064 Reactome Database ID Release 43937064 Reactome, http://www.reactome.org ReactomeREACT_24859 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 MDP:NOD2 Reactome DB_ID: 168414 Reactome Database ID Release 43168414 Reactome, http://www.reactome.org ReactomeREACT_22502 has a Stoichiometric coefficient of 1 pUb-TRAF6:TAB1:TAB2/TAB3:free polyubiquitin chain : phospho-TAK1 Reactome DB_ID: 847073 Reactome Database ID Release 43847073 Reactome, http://www.reactome.org ReactomeREACT_23131 has a Stoichiometric coefficient of 2 PathwayStep2029 PathwayStep2025 PathwayStep2026 PathwayStep2027 PathwayStep2028 PathwayStep2033 intracellular TLR:UNC93B1 Reactome DB_ID: 1678926 Reactome Database ID Release 431678926 Reactome, http://www.reactome.org ReactomeREACT_119522 has a Stoichiometric coefficient of 1 PathwayStep2032 FL-TLR9 dimer Reactome DB_ID: 1678978 Reactome Database ID Release 431678978 Reactome, http://www.reactome.org ReactomeREACT_119090 full-length TLR9 dimer has a Stoichiometric coefficient of 2 PathwayStep2035 FL-TLR8 dimer Reactome DB_ID: 1678913 Reactome Database ID Release 431678913 Reactome, http://www.reactome.org ReactomeREACT_119172 has a Stoichiometric coefficient of 2 PathwayStep2034 PathwayStep2031 PathwayStep2030 p38 MAPK : MAPKAPK2 or MAPKAPK3 Reactome DB_ID: 450269 Reactome Database ID Release 43450269 Reactome, http://www.reactome.org ReactomeREACT_22059 has a Stoichiometric coefficient of 1 MKK3-P:MKK6-P Reactome DB_ID: 450343 Reactome Database ID Release 43450343 Reactome, http://www.reactome.org ReactomeREACT_21457 has a Stoichiometric coefficient of 1 TLR8 dimer Reactome DB_ID: 188165 Reactome Database ID Release 43188165 Reactome, http://www.reactome.org ReactomeREACT_119029 full length TLR8 has a Stoichiometric coefficient of 2 MKK3-P:MKK6-P Reactome DB_ID: 167984 Reactome Database ID Release 43167984 Reactome, http://www.reactome.org ReactomeREACT_21595 has a Stoichiometric coefficient of 1 FL-TLR9 dimer Reactome DB_ID: 1679073 Reactome Database ID Release 431679073 Reactome, http://www.reactome.org ReactomeREACT_120181 full-length TLR9 dimer has a Stoichiometric coefficient of 2 MKK3:MKK6 Reactome DB_ID: 167916 Reactome Database ID Release 43167916 Reactome, http://www.reactome.org ReactomeREACT_21767 has a Stoichiometric coefficient of 1 FL-TLR7 dimer Reactome DB_ID: 188168 Reactome Database ID Release 43188168 Reactome, http://www.reactome.org ReactomeREACT_119775 has a Stoichiometric coefficient of 2 NFkB Complex Reactome DB_ID: 177673 Reactome Database ID Release 43177673 Reactome, http://www.reactome.org ReactomeREACT_7143 has a Stoichiometric coefficient of 1 FL-TLR9:FL-TLR9 Reactome DB_ID: 1679083 Reactome Database ID Release 431679083 Reactome, http://www.reactome.org ReactomeREACT_120168 full-length TLR9 dimer has a Stoichiometric coefficient of 2 NFkB Complex Reactome DB_ID: 168155 Reactome Database ID Release 43168155 Reactome, http://www.reactome.org ReactomeREACT_7108 has a Stoichiometric coefficient of 1 FL-TLR8 dimer Reactome DB_ID: 1678996 Reactome Database ID Release 431678996 Reactome, http://www.reactome.org ReactomeREACT_119111 has a Stoichiometric coefficient of 2 IkBs:NFkB Reactome DB_ID: 168130 Reactome Database ID Release 43168130 Reactome, http://www.reactome.org ReactomeREACT_7272 has a Stoichiometric coefficient of 1 FL-TLR7 dimer Reactome DB_ID: 1679085 Reactome Database ID Release 431679085 Reactome, http://www.reactome.org ReactomeREACT_120018 full-length TLR7 dimer has a Stoichiometric coefficient of 2 intracellular TLR:UNC93B1 Reactome DB_ID: 1679067 Reactome Database ID Release 431679067 Reactome, http://www.reactome.org ReactomeREACT_119414 has a Stoichiometric coefficient of 1 TAK1 complex Reactome DB_ID: 446878 Reactome Database ID Release 43446878 Reactome, http://www.reactome.org ReactomeREACT_22633 TAK1:TAB1:TAB2/3 has a Stoichiometric coefficient of 1 CD226 bound to nectin-like 5 Reactome DB_ID: 198197 Reactome Database ID Release 43198197 Reactome, http://www.reactome.org ReactomeREACT_11602 has a Stoichiometric coefficient of 1 hp-IRAK1:K6 poly-Ub oligo-TRAF6 Reactome DB_ID: 450144 Reactome Database ID Release 43450144 Reactome, http://www.reactome.org ReactomeREACT_23272 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CD226 bound to Nectin 2 Reactome DB_ID: 198190 Reactome Database ID Release 43198190 Reactome, http://www.reactome.org ReactomeREACT_11703 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 hp-IRAK1:K6-polyUb TRAF6 Reactome DB_ID: 450147 Reactome Database ID Release 43450147 Reactome, http://www.reactome.org ReactomeREACT_22716 has a Stoichiometric coefficient of 1 CD200 bound to CD200R Reactome DB_ID: 198191 Reactome Database ID Release 43198191 Reactome, http://www.reactome.org ReactomeREACT_11641 has a Stoichiometric coefficient of 1 K63-poly-Ub TRAF6 K6 polyubiquitinated TRAF6 Reactome DB_ID: 450156 Reactome Database ID Release 43450156 Reactome, http://www.reactome.org ReactomeREACT_23147 has a Stoichiometric coefficient of 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex Reactome DB_ID: 706477 Reactome Database ID Release 43706477 Reactome, http://www.reactome.org ReactomeREACT_23399 has a Stoichiometric coefficient of 1 PathwayStep2016 PathwayStep2017 PathwayStep2014 PathwayStep2015 PathwayStep2018 PathwayStep2019 PathwayStep2020 PathwayStep2024 Talin:RIAM complex:ECM ligands: alphaIIb beta3:Active (p-Y419)-SRC:p(Y397)-FADK1 Reactome DB_ID: 354135 Reactome Database ID Release 43354135 Reactome, http://www.reactome.org ReactomeREACT_15915 has a Stoichiometric coefficient of 1 PathwayStep2023 Talin:RIAM complex:ECM ligands: Integrin alphaIIb beta3:Active (p-Y419)-SRC:p(Y397,407,576,577,861,925)-FADK1 Reactome DB_ID: 354080 Reactome Database ID Release 43354080 Reactome, http://www.reactome.org ReactomeREACT_15973 has a Stoichiometric coefficient of 1 PathwayStep2022 PathwayStep2021 HLA-C Cw3 (group 1) Reactome DB_ID: 199562 Reactome Database ID Release 43199562 Reactome, http://www.reactome.org ReactomeREACT_11404 has a Stoichiometric coefficient of 1 FADK1 bound p130Cas complex Reactome DB_ID: 372688 Reactome Database ID Release 43372688 Reactome, http://www.reactome.org ReactomeREACT_15888 has a Stoichiometric coefficient of 1 MHC Class I molecules interacting with CD160 Converted from EntitySet in Reactome Reactome DB_ID: 199614 Reactome Database ID Release 43199614 Reactome, http://www.reactome.org ReactomeREACT_11830 Phosphorylated p130Cas in complex with FADK1 Reactome DB_ID: 372646 Reactome Database ID Release 43372646 Reactome, http://www.reactome.org ReactomeREACT_18088 has a Stoichiometric coefficient of 1 PAMP:NOD oligomer:K63-Ub-RIP2 Reactome DB_ID: 706482 Reactome Database ID Release 43706482 Reactome, http://www.reactome.org ReactomeREACT_23177 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 Antigen-bound Ig G Antibody Reactome DB_ID: 199174 Reactome Database ID Release 43199174 Reactome, http://www.reactome.org ReactomeREACT_11894 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 GRB2 bound to pFADK1 in Focal adhesion Reactome DB_ID: 354113 Reactome Database ID Release 43354113 Reactome, http://www.reactome.org ReactomeREACT_18065 has a Stoichiometric coefficient of 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO Reactome DB_ID: 706480 Reactome Database ID Release 43706480 Reactome, http://www.reactome.org ReactomeREACT_22571 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 MHC Class I interacting with CD160 Reactome DB_ID: 198906 Reactome Database ID Release 43198906 Reactome, http://www.reactome.org ReactomeREACT_11275 has a Stoichiometric coefficient of 1 SOS bound to Grb2:pFADK1 Reactome DB_ID: 354168 Reactome Database ID Release 43354168 Reactome, http://www.reactome.org ReactomeREACT_15655 has a Stoichiometric coefficient of 1 NOD1:iE-DAP oligomer Reactome DB_ID: 622306 Reactome Database ID Release 43622306 Reactome, http://www.reactome.org ReactomeREACT_23297 has a Stoichiometric coefficient of 6 Ig Kappa Immunoglobulin Kappa Light Chain Reactome DB_ID: 983670 Reactome Database ID Release 43983670 Reactome, http://www.reactome.org ReactomeREACT_26350 has a Stoichiometric coefficient of 1 Integrin alphaIIb beta 3:p(Y530)-SRC:CSK:Talin:RIAM complex:SHC Reactome DB_ID: 432098 Reactome Database ID Release 43432098 Reactome, http://www.reactome.org ReactomeREACT_24611 has a Stoichiometric coefficient of 1 PAMP:NOD oligomer Converted from EntitySet in Reactome Reactome DB_ID: 708346 Reactome Database ID Release 43708346 Reactome, http://www.reactome.org ReactomeREACT_22620 Ig Antibody Light Chain Converted from EntitySet in Reactome Reactome DB_ID: 197021 Reactome Database ID Release 43197021 Reactome, http://www.reactome.org ReactomeREACT_10330 Integrin alpha IIb beta 3:p(Y530)-SRC:CSK:Talin:RIAM complex:p(Y317)-SHC Reactome DB_ID: 443900 Reactome Database ID Release 43443900 Reactome, http://www.reactome.org ReactomeREACT_23140 has a Stoichiometric coefficient of 1 MDP:NOD2 oligomer Reactome DB_ID: 708350 Reactome Database ID Release 43708350 Reactome, http://www.reactome.org ReactomeREACT_23163 has a Stoichiometric coefficient of 6 Antigen-bound antibody bound to lymphoid Fc gamma receptors Reactome DB_ID: 198877 Reactome Database ID Release 43198877 Reactome, http://www.reactome.org ReactomeREACT_11822 has a Stoichiometric coefficient of 1 Crk bound to p130Cas:FADK1 Reactome DB_ID: 372652 Reactome Database ID Release 43372652 Reactome, http://www.reactome.org ReactomeREACT_15949 has a Stoichiometric coefficient of 1 NOD1:iE-DAP Reactome DB_ID: 168408 Reactome Database ID Release 43168408 Reactome, http://www.reactome.org ReactomeREACT_22558 has a Stoichiometric coefficient of 1 Ig Lambda Immunoglobulin Lambda Light Chain Reactome DB_ID: 983672 Reactome Database ID Release 43983672 Reactome, http://www.reactome.org ReactomeREACT_25751 has a Stoichiometric coefficient of 1 Integrin alpha IIb p(T779)-beta 3 Reactome DB_ID: 432105 Reactome Database ID Release 43432105 Reactome, http://www.reactome.org ReactomeREACT_24465 has a Stoichiometric coefficient of 1 CD40 complexed with CD40L Reactome DB_ID: 199402 Reactome Database ID Release 43199402 Reactome, http://www.reactome.org ReactomeREACT_11386 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 C3d complexed with antigen Reactome DB_ID: 199000 Reactome Database ID Release 43199000 Reactome, http://www.reactome.org ReactomeREACT_11562 has a Stoichiometric coefficient of 1 PathwayStep2003 PathwayStep2004 PathwayStep2005 PathwayStep2006 PathwayStep2007 PathwayStep2008 PathwayStep2009 PathwayStep2011 Complex of CD19, CD81, CD225 and CD21 Reactome DB_ID: 198931 Reactome Database ID Release 43198931 Reactome, http://www.reactome.org ReactomeREACT_11777 has a Stoichiometric coefficient of 1 PathwayStep2010 PathwayStep2013 PathwayStep2012 BoNT Light chain Type C1 Reactome DB_ID: 190018 Reactome Database ID Release 43190018 Reactome, http://www.reactome.org ReactomeREACT_11290 has a Stoichiometric coefficient of 1 HLA Bw4 interacting with KIR3DL1 Reactome DB_ID: 199565 Reactome Database ID Release 43199565 Reactome, http://www.reactome.org ReactomeREACT_11950 has a Stoichiometric coefficient of 1 HLA-Bw4 Reactome DB_ID: 199567 Reactome Database ID Release 43199567 Reactome, http://www.reactome.org ReactomeREACT_11642 has a Stoichiometric coefficient of 1 HLA-C group 2 interacting with KIR2DL1 Reactome DB_ID: 199560 Reactome Database ID Release 43199560 Reactome, http://www.reactome.org ReactomeREACT_11338 has a Stoichiometric coefficient of 1 Complex of CD19, CD81, CD225 and CD21 with C3d-bound Antigen Reactome DB_ID: 198991 Reactome Database ID Release 43198991 Reactome, http://www.reactome.org ReactomeREACT_11584 has a Stoichiometric coefficient of 1 hp-IRAK1:K6-poly-Ub oligo-TRAF6:Activated TAK1 complex Reactome DB_ID: 450186 Reactome Database ID Release 43450186 Reactome, http://www.reactome.org ReactomeREACT_23314 has a Stoichiometric coefficient of 1 HLA-G interacting with KIR2DL4 Reactome DB_ID: 199578 Reactome Database ID Release 43199578 Reactome, http://www.reactome.org ReactomeREACT_11741 has a Stoichiometric coefficient of 1 Activated TAK complexes Converted from EntitySet in Reactome Reactome DB_ID: 772536 Reactome Database ID Release 43772536 Reactome, http://www.reactome.org ReactomeREACT_23279 HLA-G Reactome DB_ID: 199581 Reactome Database ID Release 43199581 Reactome, http://www.reactome.org ReactomeREACT_11699 has a Stoichiometric coefficient of 1 Activated IKK Complex Reactome DB_ID: 177663 Reactome Database ID Release 43177663 Reactome, http://www.reactome.org ReactomeREACT_7826 has a Stoichiometric coefficient of 1 HLA-A3 interacting with KIR3DL2 Reactome DB_ID: 199573 Reactome Database ID Release 43199573 Reactome, http://www.reactome.org ReactomeREACT_11887 has a Stoichiometric coefficient of 1 IKK complex IKKA:IKKB:NEMO Inhibitor of KappaB kinase (IKK) Complex Reactome DB_ID: 168113 Reactome Database ID Release 43168113 Reactome, http://www.reactome.org ReactomeREACT_7693 has a Stoichiometric coefficient of 1 HLA-A3 Reactome DB_ID: 199571 Reactome Database ID Release 43199571 Reactome, http://www.reactome.org ReactomeREACT_11726 has a Stoichiometric coefficient of 1 ERBB4s80:Tab2:Ncor1 Reactome DB_ID: 1253302 Reactome Database ID Release 431253302 Reactome, http://www.reactome.org ReactomeREACT_117340 has a Stoichiometric coefficient of 1 Tab2:Ncor1 Reactome DB_ID: 1253314 Reactome Database ID Release 431253314 Reactome, http://www.reactome.org ReactomeREACT_116735 has a Stoichiometric coefficient of 1 ERBB4s80 Converted from EntitySet in Reactome Reactome DB_ID: 1252016 Reactome Database ID Release 431252016 Reactome, http://www.reactome.org ReactomeREACT_117313 ERBB4jmAcyt1s80 dimer Reactome DB_ID: 1252015 Reactome Database ID Release 431252015 Reactome, http://www.reactome.org ReactomeREACT_117651 has a Stoichiometric coefficient of 2 PathwayStep4254 PathwayStep4255 PathwayStep4256 PathwayStep4257 PathwayStep4250 PathwayStep2111 PathwayStep4251 PathwayStep2112 PathwayStep4252 PathwayStep4253 PathwayStep2110 PathwayStep2105 PathwayStep2104 PathwayStep2103 PathwayStep2102 PathwayStep4248 PathwayStep2109 PathwayStep4247 PathwayStep2108 PathwayStep2107 PathwayStep4249 PathwayStep2106 PathwayStep4260 RT Reactome DB_ID: 175052 Reactome Database ID Release 43175052 Reactome, http://www.reactome.org ReactomeREACT_8280 Reverse Transcriptase heterodimer has a Stoichiometric coefficient of 1 Virion with exposed coreceptor binding sites Reactome DB_ID: 173648 Reactome Database ID Release 43173648 Reactome, http://www.reactome.org ReactomeREACT_8974 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CD4:Env gp120 with exposed coreceptor binding site Reactome DB_ID: 171289 Reactome Database ID Release 43171289 Reactome, http://www.reactome.org ReactomeREACT_8048 has a Stoichiometric coefficient of 1 Virion with CD4 bound to gp120 Reactome DB_ID: 173650 Reactome Database ID Release 43173650 Reactome, http://www.reactome.org ReactomeREACT_8731 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CD4:gp120:gp41 membrane complex Reactome DB_ID: 171281 Reactome Database ID Release 43171281 Reactome, http://www.reactome.org ReactomeREACT_8675 has a Stoichiometric coefficient of 1 PathwayStep4267 PathwayStep4268 PathwayStep4265 PathwayStep4266 PathwayStep4263 PathwayStep2120 PathwayStep4264 PathwayStep2121 PathwayStep4261 PathwayStep2122 PathwayStep4262 PathwayStep2123 PathwayStep2114 PathwayStep2113 PathwayStep2116 PathwayStep2115 PathwayStep2118 PathwayStep2117 PathwayStep4259 PathwayStep4258 PathwayStep2119 Trimeric gp120:gp41 oligomer Reactome DB_ID: 171283 Reactome Database ID Release 43171283 Reactome, http://www.reactome.org ReactomeREACT_8546 has a Stoichiometric coefficient of 1 HIV-1 RNA homodimer Reactome DB_ID: 173112 Reactome Database ID Release 43173112 Reactome, http://www.reactome.org ReactomeREACT_8979 has a Stoichiometric coefficient of 2 Mature infectious virion Reactome DB_ID: 175514 Reactome Database ID Release 43175514 Reactome, http://www.reactome.org ReactomeREACT_8805 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ERBB4jmAcyt2s80 dimer Reactome DB_ID: 1252014 Reactome Database ID Release 431252014 Reactome, http://www.reactome.org ReactomeREACT_116932 has a Stoichiometric coefficient of 2 gp41 homotrimer Reactome DB_ID: 173660 Reactome Database ID Release 43173660 Reactome, http://www.reactome.org ReactomeREACT_8421 has a Stoichiometric coefficient of 3 gp120 homotrimer Reactome DB_ID: 173652 Reactome Database ID Release 43173652 Reactome, http://www.reactome.org ReactomeREACT_8666 has a Stoichiometric coefficient of 3 PathwayStep4230 PathwayStep4231 PathwayStep4232 PathwayStep4233 PathwayStep4234 PathwayStep4235 PathwayStep4226 PathwayStep4225 PathwayStep4228 PathwayStep4227 PathwayStep4229 PathwayStep4241 PathwayStep4242 PathwayStep2100 PathwayStep4240 PathwayStep2101 PathwayStep4245 PathwayStep4246 PathwayStep4243 PathwayStep4244 PathwayStep4239 PathwayStep4238 PathwayStep4237 PathwayStep4236 PathwayStep4211 PathwayStep4210 PathwayStep4213 PathwayStep4212 PathwayStep4207 PathwayStep4208 PathwayStep4209 PathwayStep4203 PathwayStep4204 PathwayStep4205 PathwayStep4206 PathwayStep4224 PathwayStep4223 PathwayStep4222 PathwayStep4221 PathwayStep4220 PathwayStep4218 PathwayStep4219 PathwayStep4216 PathwayStep4217 PathwayStep4214 PathwayStep4215 K-63 polyubiquitinated TRAF3 Reactome DB_ID: 936402 Reactome Database ID Release 43936402 Reactome, http://www.reactome.org ReactomeREACT_26596 has a Stoichiometric coefficient of 1 K63-poly-Ub-TRAF3:TRIF:activated TLR3/TLR4 Reactome DB_ID: 2213008 Reactome Database ID Release 432213008 Reactome, http://www.reactome.org ReactomeREACT_124855 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TRAF3:TRIF:activated TLR3/TLR4 Reactome DB_ID: 2201339 Reactome Database ID Release 432201339 Reactome, http://www.reactome.org ReactomeREACT_124037 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 SARM:TRIF:activated TLR3/TLR4 Reactome DB_ID: 2559578 Reactome Database ID Release 432559578 Reactome, http://www.reactome.org ReactomeREACT_151758 has a Stoichiometric coefficient of 1 PathwayStep4202 TRIF:activated TLR3/TLR4 Converted from EntitySet in Reactome Reactome DB_ID: 2201340 Reactome Database ID Release 432201340 Reactome, http://www.reactome.org ReactomeREACT_124095 PathwayStep4201 viral dsRNA:TLR3:TRIF Reactome DB_ID: 168907 Reactome Database ID Release 43168907 Reactome, http://www.reactome.org ReactomeREACT_7381 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep4200 TRIF:TRAM:TLR4:MD2:LPS:CD14 Reactome DB_ID: 166172 Reactome Database ID Release 43166172 Reactome, http://www.reactome.org ReactomeREACT_7861 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TLR4:MD2 Reactome DB_ID: 2201291 Reactome Database ID Release 432201291 Reactome, http://www.reactome.org ReactomeREACT_125521 has a Stoichiometric coefficient of 1 activated TLR3/4:TRIF:K63-poly-Ub-TRAF3:p-TBK1/p-IKKE:IRF3/IRF7 Reactome DB_ID: 937070 Reactome Database ID Release 43937070 Reactome, http://www.reactome.org ReactomeREACT_27000 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 activated TLR3/4:TRIF:K63-poly-Ub-TRAF3:p-TBK1/p-IKK epsilon Reactome DB_ID: 936970 Reactome Database ID Release 43936970 Reactome, http://www.reactome.org ReactomeREACT_26959 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ADP:P2Y purinoceptor 12 Reactome DB_ID: 392179 Reactome Database ID Release 43392179 Reactome, http://www.reactome.org ReactomeREACT_20705 has a Stoichiometric coefficient of 1 Basic L-amino acids Converted from EntitySet in Reactome Reactome DB_ID: 420746 Reactome Database ID Release 43420746 Reactome, http://www.reactome.org ReactomeREACT_18523 Sweet taste stimuli Converted from EntitySet in Reactome Reactome DB_ID: 444679 Reactome Database ID Release 43444679 Reactome, http://www.reactome.org ReactomeREACT_21919 GpIb-IX-V:vWF:Collagen IV Reactome DB_ID: 435464 Reactome Database ID Release 43435464 Reactome, http://www.reactome.org ReactomeREACT_20048 has a Stoichiometric coefficient of 1 14-3-3zeta dimer Reactome DB_ID: 206751 Reactome Database ID Release 43206751 Reactome, http://www.reactome.org ReactomeREACT_24853 has a Stoichiometric coefficient of 2 GPIb-IX-V:vWF Reactome DB_ID: 429541 Reactome Database ID Release 43429541 Reactome, http://www.reactome.org ReactomeREACT_24749 has a Stoichiometric coefficient of 1 GPIb-IX-V:vWF:14-3-3-zeta Reactome DB_ID: 429544 Reactome Database ID Release 43429544 Reactome, http://www.reactome.org ReactomeREACT_24215 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 GPIb-IX-V:vWF:filamin-A Reactome DB_ID: 430104 Reactome Database ID Release 43430104 Reactome, http://www.reactome.org ReactomeREACT_24471 has a Stoichiometric coefficient of 1 GPIb-IX-V:vWF:14-3-3-zeta:p85 Reactome DB_ID: 443399 Reactome Database ID Release 43443399 Reactome, http://www.reactome.org ReactomeREACT_24633 has a Stoichiometric coefficient of 1 Active c-Src:Raf1 Reactome DB_ID: 443443 Reactome Database ID Release 43443443 Reactome, http://www.reactome.org ReactomeREACT_24303 has a Stoichiometric coefficient of 1 14-3-3-zeta:Raf1 Reactome DB_ID: 443827 Reactome Database ID Release 43443827 Reactome, http://www.reactome.org ReactomeREACT_24804 has a Stoichiometric coefficient of 1 PathwayStep999 PathwayStep997 PathwayStep998 PathwayStep995 GPIb Reactome DB_ID: 114667 Reactome Database ID Release 43114667 Reactome, http://www.reactome.org ReactomeREACT_4769 has a Stoichiometric coefficient of 1 PathwayStep996 PathwayStep993 PathwayStep994 PathwayStep991 PathwayStep992 PathwayStep990 Carboxylate ligands of FFAR2 Converted from EntitySet in Reactome Reactome DB_ID: 444210 Reactome Database ID Release 43444210 Reactome, http://www.reactome.org ReactomeREACT_21562 Carboxylate ligands of FFAR3 Converted from EntitySet in Reactome Reactome DB_ID: 444074 Reactome Database ID Release 43444074 Reactome, http://www.reactome.org ReactomeREACT_21727 Bile acids Converted from EntitySet in Reactome Reactome DB_ID: 444840 Reactome Database ID Release 43444840 Reactome, http://www.reactome.org ReactomeREACT_22061 PathwayStep988 PathwayStep989 PathwayStep984 PathwayStep985 PathwayStep986 PathwayStep987 PathwayStep980 PathwayStep981 PathwayStep982 PathwayStep983 HIV-1 template DNA:11 nucleotide transcript hybrid Reactome DB_ID: 167112 Reactome Database ID Release 43167112 Reactome, http://www.reactome.org ReactomeREACT_6513 Heparan sulphate Converted from EntitySet in Reactome Reactome DB_ID: 381932 Reactome Database ID Release 43381932 Reactome, http://www.reactome.org ReactomeREACT_17070 HIV-1 template DNA:4-9 nucleotide transcript hybrid Reactome DB_ID: 167470 Reactome Database ID Release 43167470 Reactome, http://www.reactome.org ReactomeREACT_6414 HIV-1 template DNA:9 nucleotide transcript hybrid Reactome DB_ID: 167105 Reactome Database ID Release 43167105 Reactome, http://www.reactome.org ReactomeREACT_6694 PathwayStep959 PathwayStep950 PathwayStep4299 PathwayStep4298 PathwayStep4297 PathwayStep4296 PathwayStep4295 PathwayStep4294 PathwayStep958 PathwayStep4293 PathwayStep957 PathwayStep4292 PathwayStep956 PathwayStep4291 PathwayStep955 PathwayStep4290 PathwayStep954 PathwayStep953 PathwayStep952 PathwayStep951 viral minus strand DNA (ful-length) Reactome DB_ID: 175411 Reactome Database ID Release 43175411 Reactome, http://www.reactome.org ReactomeREACT_7761 aminophospholipid Converted from EntitySet in Reactome Reactome DB_ID: 947588 Reactome Database ID Release 43947588 Reactome, http://www.reactome.org ReactomeREACT_26709 viral minus strand DNA with sticky 3' end Reactome DB_ID: 177533 Reactome Database ID Release 43177533 Reactome, http://www.reactome.org ReactomeREACT_8391 viral minus strand DNA after ligation Reactome DB_ID: 175013 Reactome Database ID Release 43175013 Reactome, http://www.reactome.org ReactomeREACT_9289 viral plus strand DNA (full-length) Reactome DB_ID: 175036 Reactome Database ID Release 43175036 Reactome, http://www.reactome.org ReactomeREACT_7783 PathwayStep948 PathwayStep949 aminophospholipid Converted from EntitySet in Reactome Reactome DB_ID: 947594 Reactome Database ID Release 43947594 Reactome, http://www.reactome.org ReactomeREACT_26259 PathwayStep945 viral plus strand DNA after ligation Reactome DB_ID: 174981 Reactome Database ID Release 43174981 Reactome, http://www.reactome.org ReactomeREACT_9129 PathwayStep944 HIV-1 template DNA opened from -10 to +2, with first nucleotide base-paired at 5'-end Reactome DB_ID: 167138 Reactome Database ID Release 43167138 Reactome, http://www.reactome.org ReactomeREACT_6668 PathwayStep947 HIV-1 template DNA hybrid with phosphodiester-PPi intermediate Reactome DB_ID: 167109 Reactome Database ID Release 43167109 Reactome, http://www.reactome.org ReactomeREACT_6420 PathwayStep946 HIV-1 template DNA with first transcript dinucleotide, opened to +8 position Reactome DB_ID: 167096 Reactome Database ID Release 43167096 Reactome, http://www.reactome.org ReactomeREACT_6558 PathwayStep941 HIV-1 template DNA:3 nucleotide transcript hybrid Reactome DB_ID: 167114 Reactome Database ID Release 43167114 Reactome, http://www.reactome.org ReactomeREACT_6544 PathwayStep940 HIV-1 template DNA:4 nucleotide transcript hybrid Reactome DB_ID: 167122 Reactome Database ID Release 43167122 Reactome, http://www.reactome.org ReactomeREACT_6657 PathwayStep943 HIV-1 template DNA containing promoter with transcript of 2 or 3 nucleotides Reactome DB_ID: 167475 Reactome Database ID Release 43167475 Reactome, http://www.reactome.org ReactomeREACT_6665 PathwayStep942 minus strand DNA (extending) Reactome DB_ID: 173767 Reactome Database ID Release 43173767 Reactome, http://www.reactome.org ReactomeREACT_9369 viral minus strand DNA (initial) Reactome DB_ID: 173832 Reactome Database ID Release 43173832 Reactome, http://www.reactome.org ReactomeREACT_9263 minus sssDNA Reactome DB_ID: 173823 Reactome Database ID Release 43173823 Reactome, http://www.reactome.org ReactomeREACT_9333 Multimeric capsid coat Reactome DB_ID: 175314 Reactome Database ID Release 43175314 Reactome, http://www.reactome.org ReactomeREACT_8190 Multimeric matrix layer Reactome DB_ID: 175338 Reactome Database ID Release 43175338 Reactome, http://www.reactome.org ReactomeREACT_8606 Cannabinoids Converted from EntitySet in Reactome Reactome DB_ID: 444560 Reactome Database ID Release 43444560 Reactome, http://www.reactome.org ReactomeREACT_20797 PathwayStep4269 ATP:UTP Converted from EntitySet in Reactome Reactome DB_ID: 511955 Reactome Database ID Release 43511955 Reactome, http://www.reactome.org ReactomeREACT_21720 PathwayStep4275 PathwayStep4274 PathwayStep4273 PathwayStep4272 PathwayStep972 PathwayStep4279 PathwayStep971 PathwayStep4278 PathwayStep970 PathwayStep4277 PathwayStep4276 viral plus strand DNA (full-length) Reactome DB_ID: 173762 Reactome Database ID Release 43173762 Reactome, http://www.reactome.org ReactomeREACT_9229 PathwayStep976 viral plus strand DNA with sticky 3' end Reactome DB_ID: 177540 Reactome Database ID Release 43177540 Reactome, http://www.reactome.org ReactomeREACT_8159 PathwayStep975 viral second strand DNA with plus sssDNA (discontinuous) Reactome DB_ID: 188559 Reactome Database ID Release 43188559 Reactome, http://www.reactome.org ReactomeREACT_9196 PathwayStep974 viral minus strand DNA (full-length) Reactome DB_ID: 173821 Reactome Database ID Release 43173821 Reactome, http://www.reactome.org ReactomeREACT_9281 PathwayStep973 viral second strand DNA (plus sss) Reactome DB_ID: 173826 Reactome Database ID Release 43173826 Reactome, http://www.reactome.org ReactomeREACT_9285 PathwayStep4271 viral second strand DNA with plus sssDNA (extending) Reactome DB_ID: 173833 Reactome Database ID Release 43173833 Reactome, http://www.reactome.org ReactomeREACT_9216 PathwayStep979 PathwayStep4270 PathwayStep978 PathwayStep977 Activated MAPK kinases ERK1/2, JNK, p38 Converted from EntitySet in Reactome Reactome DB_ID: 450307 Reactome Database ID Release 43450307 Reactome, http://www.reactome.org ReactomeREACT_21930 K63-polyubiquitin Lys-63 polyubiquitin Reactome DB_ID: 450152 Reactome Database ID Release 43450152 Reactome, http://www.reactome.org ReactomeREACT_21645 BoNT F cleaved VAMP/Synaptobrevin Converted from EntitySet in Reactome Reactome DB_ID: 194801 Reactome Database ID Release 43194801 Reactome, http://www.reactome.org ReactomeREACT_11808 BoNT D cleaved VAMP/Synaptobrevin Converted from EntitySet in Reactome Reactome DB_ID: 194798 Reactome Database ID Release 43194798 Reactome, http://www.reactome.org ReactomeREACT_11414 Cysteinyl leukotrienes Converted from EntitySet in Reactome Reactome DB_ID: 416372 Reactome Database ID Release 43416372 Reactome, http://www.reactome.org ReactomeREACT_18959 Syntaxin fragment Converted from EntitySet in Reactome Reactome DB_ID: 181508 Reactome Database ID Release 43181508 Reactome, http://www.reactome.org ReactomeREACT_11762 Syntaxins Converted from EntitySet in Reactome Reactome DB_ID: 181547 Reactome Database ID Release 43181547 Reactome, http://www.reactome.org ReactomeREACT_11590 PathwayStep4284 PathwayStep4283 PathwayStep4286 PathwayStep4285 PathwayStep4288 PathwayStep4287 PathwayStep961 PathwayStep960 PathwayStep4289 tRNA-Lysine3 Reactome DB_ID: 177833 Reactome Database ID Release 43177833 Reactome, http://www.reactome.org ReactomeREACT_8828 PathwayStep963 Multimeric capsid coat Reactome DB_ID: 173644 Reactome Database ID Release 43173644 Reactome, http://www.reactome.org ReactomeREACT_8810 PathwayStep962 CCR5/CXCR4 Converted from EntitySet in Reactome Reactome DB_ID: 175536 Reactome Database ID Release 43175536 Reactome, http://www.reactome.org ReactomeREACT_8732 PathwayStep965 tRNA-Lysine3 Reactome DB_ID: 173782 Reactome Database ID Release 43173782 Reactome, http://www.reactome.org ReactomeREACT_8477 PathwayStep964 PathwayStep967 PathwayStep4280 PathwayStep966 PathwayStep969 PathwayStep4282 Multimeric matrix layer Reactome DB_ID: 173641 Reactome Database ID Release 43173641 Reactome, http://www.reactome.org ReactomeREACT_8178 PathwayStep968 PathwayStep4281 Exogenous Particulate antigen (Ag) Reactome DB_ID: 1236714 Reactome Database ID Release 431236714 Reactome, http://www.reactome.org ReactomeREACT_111741 Exogenous Particulate antigen (Ag) Reactome DB_ID: 1236726 Reactome Database ID Release 431236726 Reactome, http://www.reactome.org ReactomeREACT_111430 oligopeptide fragment Reactome DB_ID: 983034 Reactome Database ID Release 43983034 Reactome, http://www.reactome.org ReactomeREACT_75996 factor IXa Reactome DB_ID: 140896 Reactome Database ID Release 43140896 Reactome, http://www.reactome.org ReactomeREACT_3075 has a Stoichiometric coefficient of 1 BAP31 oligomer Reactome DB_ID: 983323 Reactome Database ID Release 43983323 Reactome, http://www.reactome.org ReactomeREACT_76550 factor VIIa Reactome DB_ID: 140733 Reactome Database ID Release 43140733 Reactome, http://www.reactome.org ReactomeREACT_3035 has a Stoichiometric coefficient of 1 precursor peptide fragment (>16 aa) Reactome DB_ID: 983036 Reactome Database ID Release 43983036 Reactome, http://www.reactome.org ReactomeREACT_76778 factor Xa Reactome DB_ID: 140649 Reactome Database ID Release 43140649 Reactome, http://www.reactome.org ReactomeREACT_3099 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 20 oligopeptide fragment (8-16aa) Reactome DB_ID: 983032 Reactome Database ID Release 43983032 Reactome, http://www.reactome.org ReactomeREACT_76829 TFPI:TF:F7a:factor Xa Reactome DB_ID: 140833 Reactome Database ID Release 43140833 Reactome, http://www.reactome.org ReactomeREACT_2685 has a Stoichiometric coefficient of 1 DC receptors recognizing apoptotic cells Converted from EntitySet in Reactome Reactome DB_ID: 1236904 Reactome Database ID Release 431236904 Reactome, http://www.reactome.org ReactomeREACT_111621 kininogen:C1q binding protein tetramer Reactome DB_ID: 158172 Reactome Database ID Release 43158172 Reactome, http://www.reactome.org ReactomeREACT_4804 has a Stoichiometric coefficient of 1 high molecular weight kininogen:C1q binding protein tetramer Antigen peptide Reactome DB_ID: 983324 Reactome Database ID Release 43983324 Reactome, http://www.reactome.org ReactomeREACT_76651 C1q binding protein tetramer Reactome DB_ID: 158318 Reactome Database ID Release 43158318 Reactome, http://www.reactome.org ReactomeREACT_2937 has a Stoichiometric coefficient of 4 Collagen alpha-1(XXIII) ectodomains Converted from EntitySet in Reactome Reactome DB_ID: 2473516 Reactome Database ID Release 432473516 Reactome, http://www.reactome.org ReactomeREACT_151913 Antigen peptide Reactome DB_ID: 983326 Reactome Database ID Release 43983326 Reactome, http://www.reactome.org ReactomeREACT_76481 Antigen peptide Reactome DB_ID: 983033 Reactome Database ID Release 43983033 Reactome, http://www.reactome.org ReactomeREACT_76532 prekallikrein:kininogen:C1q binding protein tetramer Reactome DB_ID: 158404 Reactome Database ID Release 43158404 Reactome, http://www.reactome.org ReactomeREACT_3461 has a Stoichiometric coefficient of 1 prekallikrein:high molecular weight kininogen:C1q binding protein tetramer DC receptors recognizing apoptotic cells Converted from EntitySet in Reactome Reactome DB_ID: 1236899 Reactome Database ID Release 431236899 Reactome, http://www.reactome.org ReactomeREACT_111806 factor Xa Reactome DB_ID: 140689 Reactome Database ID Release 43140689 Reactome, http://www.reactome.org ReactomeREACT_5349 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 20 factor VIIa Reactome DB_ID: 140751 Reactome Database ID Release 43140751 Reactome, http://www.reactome.org ReactomeREACT_2419 has a Stoichiometric coefficient of 1 TF:F7a Reactome DB_ID: 140734 Reactome Database ID Release 43140734 Reactome, http://www.reactome.org ReactomeREACT_4532 has a Stoichiometric coefficient of 1 tissue factor:factor VIIa complex MR/other probable receptors Converted from EntitySet in Reactome Reactome DB_ID: 1236909 Reactome Database ID Release 431236909 Reactome, http://www.reactome.org ReactomeREACT_111538 Collagen alpha-1(XXV) ectodomains Converted from EntitySet in Reactome Reactome DB_ID: 2473549 Reactome Database ID Release 432473549 Reactome, http://www.reactome.org ReactomeREACT_151692 partially digested Ag Reactome DB_ID: 1236713 Reactome Database ID Release 431236713 Reactome, http://www.reactome.org ReactomeREACT_111816 GPIb:GPIX:GPV complex Reactome DB_ID: 158331 Reactome Database ID Release 43158331 Reactome, http://www.reactome.org ReactomeREACT_2987 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 platelet glycoprotein Ib-IX-V complex Exogenous Particulate antigen (Ag) Reactome DB_ID: 1236716 Reactome Database ID Release 431236716 Reactome, http://www.reactome.org ReactomeREACT_111541 factor XIIa Reactome DB_ID: 158306 Reactome Database ID Release 43158306 Reactome, http://www.reactome.org ReactomeREACT_4236 has a Stoichiometric coefficient of 1 oligopeptide fragment Reactome DB_ID: 1236721 Reactome Database ID Release 431236721 Reactome, http://www.reactome.org ReactomeREACT_111723 activated kininogen Reactome DB_ID: 158400 Reactome Database ID Release 43158400 Reactome, http://www.reactome.org ReactomeREACT_5305 activated high molecular weight kininogen has a Stoichiometric coefficient of 1 partially digested Ag Reactome DB_ID: 1236718 Reactome Database ID Release 431236718 Reactome, http://www.reactome.org ReactomeREACT_111466 activated kininogen:C1q binding protein tetramer Reactome DB_ID: 158257 Reactome Database ID Release 43158257 Reactome, http://www.reactome.org ReactomeREACT_3121 has a Stoichiometric coefficient of 1 precursor peptide fragment (>16 aa) Reactome DB_ID: 1236722 Reactome Database ID Release 431236722 Reactome, http://www.reactome.org ReactomeREACT_111434 Exogenous soluble antigen Reactome DB_ID: 1236715 Reactome Database ID Release 431236715 Reactome, http://www.reactome.org ReactomeREACT_111291 Exogenous soluble antigen Reactome DB_ID: 1236720 Reactome Database ID Release 431236720 Reactome, http://www.reactome.org ReactomeREACT_111338 factor XI Reactome DB_ID: 158234 Reactome Database ID Release 43158234 Reactome, http://www.reactome.org ReactomeREACT_4915 has a Stoichiometric coefficient of 2 plasma thromboplastin antecedent Antigen peptide Reactome DB_ID: 1236727 Reactome Database ID Release 431236727 Reactome, http://www.reactome.org ReactomeREACT_111433 GPIb heterodimer Reactome DB_ID: 158368 Reactome Database ID Release 43158368 Reactome, http://www.reactome.org ReactomeREACT_5614 has a Stoichiometric coefficient of 1 platelet glycoprotein Ib heterodimer prolylcarboxypeptidase dimer Reactome DB_ID: 158176 Reactome Database ID Release 43158176 Reactome, http://www.reactome.org ReactomeREACT_5699 has a Stoichiometric coefficient of 2 Plasma kallikrein Reactome DB_ID: 158140 Reactome Database ID Release 43158140 Reactome, http://www.reactome.org ReactomeREACT_4124 has a Stoichiometric coefficient of 1 Exogenous soluble antigen Reactome DB_ID: 1236723 Reactome Database ID Release 431236723 Reactome, http://www.reactome.org ReactomeREACT_111490 kallikrein:kininogen:C1q binding protein tetramer Reactome DB_ID: 158197 Reactome Database ID Release 43158197 Reactome, http://www.reactome.org ReactomeREACT_4714 has a Stoichiometric coefficient of 1 kallikrein:high molecular weight kininogen:C1q binding protein tetramer MR/other probable receptors Converted from EntitySet in Reactome Reactome DB_ID: 1236913 Reactome Database ID Release 431236913 Reactome, http://www.reactome.org ReactomeREACT_111715 kallikrein Reactome DB_ID: 158243 Reactome Database ID Release 43158243 Reactome, http://www.reactome.org ReactomeREACT_5025 has a Stoichiometric coefficient of 1 LILR-binding HLA Class I Converted from EntitySet in Reactome Reactome DB_ID: 199591 Reactome Database ID Release 43199591 Reactome, http://www.reactome.org ReactomeREACT_11395 MHC class II epitopes Reactome DB_ID: 2213228 Reactome Database ID Release 432213228 Reactome, http://www.reactome.org ReactomeREACT_122727 factor VIIIa Reactome DB_ID: 158374 Reactome Database ID Release 43158374 Reactome, http://www.reactome.org ReactomeREACT_4317 has a Stoichiometric coefficient of 1 MHC class II epitopes Reactome DB_ID: 2213226 Reactome Database ID Release 432213226 Reactome, http://www.reactome.org ReactomeREACT_125085 unfolded antigen Reactome DB_ID: 2213225 Reactome Database ID Release 432213225 Reactome, http://www.reactome.org ReactomeREACT_124109 Antigen Reactome DB_ID: 2213221 Reactome Database ID Release 432213221 Reactome, http://www.reactome.org ReactomeREACT_122664 factor VIII:von Willebrand factor multimer Reactome DB_ID: 158363 Reactome Database ID Release 43158363 Reactome, http://www.reactome.org ReactomeREACT_3248 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 50 Exogenous soluble antigen Reactome DB_ID: 1236719 Reactome Database ID Release 431236719 Reactome, http://www.reactome.org ReactomeREACT_111524 factor VIII Reactome DB_ID: 158350 Reactome Database ID Release 43158350 Reactome, http://www.reactome.org ReactomeREACT_4493 has a Stoichiometric coefficient of 1 Exogenous soluble antigen Reactome DB_ID: 1236724 Reactome Database ID Release 431236724 Reactome, http://www.reactome.org ReactomeREACT_111799 factor VIIIa:factor IXa Reactome DB_ID: 158392 Reactome Database ID Release 43158392 Reactome, http://www.reactome.org ReactomeREACT_3217 has a Stoichiometric coefficient of 1 MR/other probable receptors Converted from EntitySet in Reactome Reactome DB_ID: 1236911 Reactome Database ID Release 431236911 Reactome, http://www.reactome.org ReactomeREACT_111733 factor VIIIa Reactome DB_ID: 158307 Reactome Database ID Release 43158307 Reactome, http://www.reactome.org ReactomeREACT_4190 has a Stoichiometric coefficient of 1 intracellular TLR3/7/8/9 Converted from EntitySet in Reactome Reactome DB_ID: 1679054 Reactome Database ID Release 431679054 Reactome, http://www.reactome.org ReactomeREACT_120129 factor XI Reactome DB_ID: 158143 Reactome Database ID Release 43158143 Reactome, http://www.reactome.org ReactomeREACT_5214 has a Stoichiometric coefficient of 2 plasma thromboplastin antecedent TLR3/7/8/9 Converted from EntitySet in Reactome Reactome DB_ID: 1679038 Reactome Database ID Release 431679038 Reactome, http://www.reactome.org ReactomeREACT_119544 factor XIa:GPIb:GPIX:GPV complex Reactome DB_ID: 158130 Reactome Database ID Release 43158130 Reactome, http://www.reactome.org ReactomeREACT_4765 has a Stoichiometric coefficient of 1 factor XIa Reactome DB_ID: 158390 Reactome Database ID Release 43158390 Reactome, http://www.reactome.org ReactomeREACT_2333 has a Stoichiometric coefficient of 2 PKA catalytic subunits, PKG type I Converted from EntitySet in Reactome Reactome DB_ID: 913988 Reactome Database ID Release 43913988 Reactome, http://www.reactome.org ReactomeREACT_24087 von Willibrand factor multimer Reactome DB_ID: 158136 Reactome Database ID Release 43158136 Reactome, http://www.reactome.org ReactomeREACT_5706 has a Stoichiometric coefficient of 50 factor XI:GPIb:GPIX:GPV complex Reactome DB_ID: 158162 Reactome Database ID Release 43158162 Reactome, http://www.reactome.org ReactomeREACT_5726 has a Stoichiometric coefficient of 1 Viral dsRNA (-) Stranded Reactome DB_ID: 433905 Reactome Database ID Release 43433905 Reactome, http://www.reactome.org ReactomeREACT_21794 Viral dsRNA (-) Stranded Reactome DB_ID: 434118 Reactome Database ID Release 43434118 Reactome, http://www.reactome.org ReactomeREACT_21871 TRIF:activated TLR3/TLR4 Converted from EntitySet in Reactome Reactome DB_ID: 2569052 Reactome Database ID Release 432569052 Reactome, http://www.reactome.org ReactomeREACT_151807 PS is decarboxylated to PE by PISD At the inner mitochondrial (IM) membrane, phosphatidylserine decarboxylase proenzyme (heterodimer of two chains from the same protein) (PISD) decarboxylates phosphatidylserine (PS) to phosphatidylethanolamine (PE). This event has been inferred from rats and limited data for a human PISD (Forbes et al. 2007). Authored: Williams, MG, 2011-09-14 EC Number: 4.1.1.65 Edited: Williams, MG, 2011-08-12 Pubmed17478478 Reactome Database ID Release 431483212 Reactome, http://www.reactome.org ReactomeREACT_121085 Cathepsins B, K, L, S Converted from EntitySet in Reactome Reactome DB_ID: 1678971 Reactome Database ID Release 431678971 Reactome, http://www.reactome.org ReactomeREACT_119745 factor XIII Reactome DB_ID: 140608 Reactome Database ID Release 43140608 Reactome, http://www.reactome.org ReactomeREACT_4285 has a Stoichiometric coefficient of 2 Legumain/Cathepsins Converted from EntitySet in Reactome Reactome DB_ID: 1678911 Reactome Database ID Release 431678911 Reactome, http://www.reactome.org ReactomeREACT_119541 fibrin multimer Reactome DB_ID: 139933 Reactome Database ID Release 43139933 Reactome, http://www.reactome.org ReactomeREACT_4444 has a Stoichiometric coefficient of 3 K63-polyubiquitin Lys-63 polyubiquitin Reactome DB_ID: 936967 Reactome Database ID Release 43936967 Reactome, http://www.reactome.org ReactomeREACT_27048 factor Va Reactome DB_ID: 140661 Reactome Database ID Release 43140661 Reactome, http://www.reactome.org ReactomeREACT_4837 has a Stoichiometric coefficient of 1 Ligand recognized by TLR10 Reactome DB_ID: 168948 Reactome Database ID Release 43168948 Reactome, http://www.reactome.org ReactomeREACT_9270 Va:Xa complex (prothrombinase) Reactome DB_ID: 140662 Reactome Database ID Release 43140662 Reactome, http://www.reactome.org ReactomeREACT_5441 has a Stoichiometric coefficient of 1 PE is hydrolyzed to 2-acyl LPE by PLA2G4C At the endoplasmic reticulum (ER) membrane, phosphatidylethanolamine (PE) is hydrolyzed, and has one of its acyl chains cleaved off by membrane-associated phospholipase A2 gamma 2A, PLA2G2A, to form 2-acyl lysophosphatidylethanolamine (LPE) (Yamashita et al. 2005, Ghomashchi et al. 2010, Yamashita et al. 2009). Cytosolic phospholipase A2 enzymes show not only PLA2 hydrolyzing activity to form the 1-acyl lysophospholipid but also have a degree of PLA1 activity, producing a 2-acyl lysophospholipid. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.32 Edited: Williams, MG, 2011-08-12 Pubmed15944408 Pubmed19501189 Pubmed20705608 Reactome Database ID Release 431482892 Reactome, http://www.reactome.org ReactomeREACT_121074 factor XIIa:C1Inh Reactome DB_ID: 158141 Reactome Database ID Release 43158141 Reactome, http://www.reactome.org ReactomeREACT_2283 has a Stoichiometric coefficient of 1 PE is hydrolyzed to 2-acyl LPE by PLA2[4] At the endoplasmic reticulum (ER) membrane, phosphatidylethanolamine (PE) is hydrolyzed, and has one of its acyl chains cleaved off by cytosolic phospholipase A2 alpha/delta/epsilon/zeta (PLA2G4A/D/E/F) (Ghomashchi et al. 2010). This produces 2-acyl lysophosphatidylethanolamine (LPE). Cytosolic phospholipase A2 enzymes show not only PLA2 hydrolyzing activity to form the 1-acyl lysophospholipid but also have a degree of PLA1 activity, producing a 2-acyl lysophospholipid. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.32 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482828 Reactome, http://www.reactome.org ReactomeREACT_121405 factor Va Reactome DB_ID: 140692 Reactome Database ID Release 43140692 Reactome, http://www.reactome.org ReactomeREACT_2497 has a Stoichiometric coefficient of 1 PE is hydrolyzed to 1-acyl LPE by PLA2[16] At the plasma membrane, phosphatidylethanolamine (PE) is hydrolyzed, removing one of its acyl groups, to 1-acyl phosphatidylethanolamine (LPE) by secretory phospholipase A2 proteins (Singer et al. 2002, Ishizaki et al. 1999). These include: Group IB (PLA2G1B) (Grataroli et al. 1982); Group IIA (PLA2G2A) (Seilhamer et al. 1989); Group IID (PLA2G2D) (Ishizaki et al. 1999); Group IIE (PLA2G2E) (Suzuki et al. 2000); Group IIF (PLA2G2F) (Valentin et al. 2000); Group III (PLA2G3) (Murakami et al. 2003, Murakami et al. 2005); Calcium-dependent Group V (PLA2G5) (Chen et al. 1994); Group X (PLA2G10) (Cupillard et al. 1997, Pan et al. 2002); and Group XIIA (PLA2G12A) (Gelb et al. 2000, Murakami et al. 2003). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10455175 Pubmed10681567 Pubmed11031251 Pubmed11112443 Pubmed12161451 Pubmed12359733 Pubmed12522102 Pubmed15863501 Pubmed2925608 Pubmed7060561 Pubmed8300559 Pubmed9188469 Reactome Database ID Release 431602398 Reactome, http://www.reactome.org ReactomeREACT_120742 Alpha2-macroglobulin Reactome DB_ID: 158255 Reactome Database ID Release 43158255 Reactome, http://www.reactome.org ReactomeREACT_3449 has a Stoichiometric coefficient of 4 2-acyl LPE is acylated to PE by LPEAT At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferases acylate 2-acyl lysophosphatidylethanolamine (LPE) to form phosphatidylethanolamine (PE). The lysophospholipid acyltransferases involved are: lysophospholipid acyltransferase 1 (MBOAT1) aka LPEAT1 (Gijon et al. 2008, Hishikawa et al. 2008); lysophospholipid acyltransferase LPCAT4 (LPCAT4) aka LPEAT2 (Cao et al. 2008, Ye et al. 2005); lysophospholipid acyltransferase 2 (MBOAT2) aka LPCAT4 (Hishikawa et al. 2008, Gijon et al. 2008); lysophospholipid acyltransferase 5 (LPCAT3) (Hishikawa et al. 2008, Zhao et al. 2008, Gijon et al. 2008, Jain et al. 2009, Kazachkov et al. 2008). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.52 Edited: Williams, MG, 2011-08-12 Pubmed18195019 Pubmed18287005 Pubmed18458083 Pubmed18772128 Pubmed18781350 Pubmed19351971 Reactome Database ID Release 431482646 Reactome, http://www.reactome.org ReactomeREACT_121016 kallikrein:alpha2-macroglobulin Reactome DB_ID: 158334 Reactome Database ID Release 43158334 Reactome, http://www.reactome.org ReactomeREACT_4115 has a Stoichiometric coefficient of 1 PE is hydrolyzed to 1-acyl LPE by PLA2[2] At the endoplasmic reticulum (ER) membrane, phosphatidylethanolamine (PE) is hydrolyzed, and has one of its acyl chains cleaved off, by phospholipase A2 to form 1-acyl lysophosphatidylethanolamine (LPE). The phospholipases are either cytosolic phospholipase A2 alpha/beta/delta/epsilon/zeta (PLA2G(4A/B/D/E/F) (Ghosh et al. 2006, Yamashita et al. 2009, Yamashita et al. 1999, Ghomashchi et al. 2010), 85 kDa calcium-independent phospholipase A2 (PLA2G6) (Larsson et al. 1998, Ma et al. 1999, Larsson Forsell et al. 1999), group XVI phospholipase A2 (PLA2G16) (Duncan et al. 2008), or Phospholipase B-like 1 (PLBD1) (Xu et al. 2009). PLBD1 acts as a phospholipase A2 but in addition has the propensity to hydrolyze the lysophospholipid formed in its initial reaction. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10092647 Pubmed10336645 Pubmed15944408 Pubmed16617059 Pubmed18614531 Pubmed19019078 Pubmed19501189 Pubmed20705608 Pubmed9417066 Reactome Database ID Release 431482884 Reactome, http://www.reactome.org ReactomeREACT_121252 factor IXa Reactome DB_ID: 158367 Reactome Database ID Release 43158367 Reactome, http://www.reactome.org ReactomeREACT_2936 has a Stoichiometric coefficient of 1 PE transports from the mitochondrial membrane to the ER Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed1898727 Pubmed2332429 Reactome Database ID Release 431483077 Reactome, http://www.reactome.org ReactomeREACT_121235 Transport of phosphatidylethanolamine (PE) occurs via membrane contact sites between the mitochondrial membrane and the endoplasmic reticulum (ER) membrane. The event is inferred from rats (Vance 1990, Vance 1991). kallikrein:C1Inh Reactome DB_ID: 158423 Reactome Database ID Release 43158423 Reactome, http://www.reactome.org ReactomeREACT_5874 has a Stoichiometric coefficient of 1 1-acyl LPE is acylated to PE by LPEAT At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferases acylate 1-acyl lysophosphatidylethanolamine (LPE) to form phosphatidylethanolamine (PE). The lysophospholipid acyltransferases involved are: lysophospholipid acyltransferase 1 (MBOAT1) aka LPEAT1 (Gijon et al. 2008, Hishikawa et al. 2008); lysophospholipid acyltransferase LPCAT4 (LPCAT4) aka LPEAT2 (Cao et al. 2008, Ye et al., 2005); lysophospholipid acyltransferase 2 (MBOAT2) aka LPCAT4 (Hishikawa et al. 2008, Gijon et al. 2008); lysophospholipid acyltransferase 5 (LPCAT3) (Hishikawa et al. 2008, Zhao et al. 2008, Gijon et al. 2008, Jain et al. 2009, Kazachkov et al. 2008). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.51 Edited: Williams, MG, 2011-08-12 Pubmed18195019 Pubmed18287005 Pubmed18458083 Pubmed18772128 Pubmed18781350 Pubmed19351971 Reactome Database ID Release 431482667 Reactome, http://www.reactome.org ReactomeREACT_120891 PE is hydrolyzed to 1-acyl LPE by PLA2[3] At the endoplasmic reticulum (ER) membrane, phosphatidylethanolamine (PE) is hydrolyzed, and has one of its acyl chains cleaved off, by membrane-associated phospholipase A2 gamma 2A, (PLA2G2A) or by calcium-independent phospholipase A2-gamma (PNPLA8), to form 1-acyl lysophosphatidylethanolamine (LPE) (Murakami et al. 2005, Kramer et al. 1989, Singer et al. 2002). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed12359733 Pubmed15695510 Pubmed2925633 Reactome Database ID Release 431482887 Reactome, http://www.reactome.org ReactomeREACT_121258 1-acyl LPE is hydrolyzed to GPETA by PLA2G4C At the endoplasmic reticulum (ER) membrane, membrane-bound cytosolic phospholipase A2 gamma (PLA2G4C) hydrolyzes 1-acyl lysophosphatidylethanolamine (LPE) to produce glycerophosphoethanolamine (GPETA) (Yamashita et al. 2005, Yamashita et al. 2009). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.5 Edited: Williams, MG, 2011-08-12 Pubmed15944408 Pubmed19501189 Reactome Database ID Release 431482571 Reactome, http://www.reactome.org ReactomeREACT_120895 thrombin:cleaved antithrombin III Reactome DB_ID: 140874 Reactome Database ID Release 43140874 Reactome, http://www.reactome.org ReactomeREACT_4175 has a Stoichiometric coefficient of 1 cleaved antithrombin III Reactome DB_ID: 140821 Reactome Database ID Release 43140821 Reactome, http://www.reactome.org ReactomeREACT_3619 has a Stoichiometric coefficient of 1 activated thrombin:thrombomodulin Reactome DB_ID: 141038 Reactome Database ID Release 43141038 Reactome, http://www.reactome.org ReactomeREACT_5904 has a Stoichiometric coefficient of 1 factor XIII cleaved tetramer Reactome DB_ID: 140789 Reactome Database ID Release 43140789 Reactome, http://www.reactome.org ReactomeREACT_2648 has a Stoichiometric coefficient of 2 antithrombin III:heparin Reactome DB_ID: 140799 Reactome Database ID Release 43140799 Reactome, http://www.reactome.org ReactomeREACT_2653 has a Stoichiometric coefficient of 1 factor XIIIa Reactome DB_ID: 140849 Reactome Database ID Release 43140849 Reactome, http://www.reactome.org ReactomeREACT_4387 activated factor XIII has a Stoichiometric coefficient of 2 activated thrombin (factor IIa) Reactome DB_ID: 140811 Reactome Database ID Release 43140811 Reactome, http://www.reactome.org ReactomeREACT_5334 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 thrombin:antithrombin III:heparin Reactome DB_ID: 140812 Reactome Database ID Release 43140812 Reactome, http://www.reactome.org ReactomeREACT_2423 has a Stoichiometric coefficient of 1 cleaved antithrombin III Reactome DB_ID: 140822 Reactome Database ID Release 43140822 Reactome, http://www.reactome.org ReactomeREACT_5877 has a Stoichiometric coefficient of 1 thrombin:cleaved antithrombin III:heparin Reactome DB_ID: 140871 Reactome Database ID Release 43140871 Reactome, http://www.reactome.org ReactomeREACT_2621 has a Stoichiometric coefficient of 1 fibrin multimer, crosslinked:tissue plasminogen activator (two-chain) Reactome DB_ID: 158745 Reactome Database ID Release 43158745 Reactome, http://www.reactome.org ReactomeREACT_3996 has a Stoichiometric coefficient of 1 tissue plasminogen activator (two-chain) Reactome DB_ID: 158760 Reactome Database ID Release 43158760 Reactome, http://www.reactome.org ReactomeREACT_4671 has a Stoichiometric coefficient of 1 activated protein C Reactome DB_ID: 141024 Reactome Database ID Release 43141024 Reactome, http://www.reactome.org ReactomeREACT_5044 has a Stoichiometric coefficient of 1 factor Vi Reactome DB_ID: 141055 Reactome Database ID Release 43141055 Reactome, http://www.reactome.org ReactomeREACT_4020 has a Stoichiometric coefficient of 1 phosphorylated IRF3 and/or IRF7 dimer Converted from EntitySet in Reactome Reactome DB_ID: 450256 Reactome Database ID Release 43450256 Reactome, http://www.reactome.org ReactomeREACT_21500 activated protein C Reactome DB_ID: 141050 Reactome Database ID Release 43141050 Reactome, http://www.reactome.org ReactomeREACT_2599 has a Stoichiometric coefficient of 1 p-2S-IRF7:p-2S-IRF7 Reactome DB_ID: 450344 Reactome Database ID Release 43450344 Reactome, http://www.reactome.org ReactomeREACT_21965 has a Stoichiometric coefficient of 2 protein C Reactome DB_ID: 141043 Reactome Database ID Release 43141043 Reactome, http://www.reactome.org ReactomeREACT_4912 has a Stoichiometric coefficient of 1 p-T,4S-IRF3:p-T,4S-IRF3 IRF3:IRF3 phosphorylated Reactome DB_ID: 166272 Reactome Database ID Release 43166272 Reactome, http://www.reactome.org ReactomeREACT_7146 has a Stoichiometric coefficient of 2 Plasmin Reactome DB_ID: 158770 Reactome Database ID Release 43158770 Reactome, http://www.reactome.org ReactomeREACT_4641 has a Stoichiometric coefficient of 1 phosphorylated IRF3 and/or IRF7 dimer Converted from EntitySet in Reactome Reactome DB_ID: 450349 Reactome Database ID Release 43450349 Reactome, http://www.reactome.org ReactomeREACT_21689 fibrin multimer, crosslinked:tissue plasminogen activator (one-chain):plasminogen Reactome DB_ID: 158777 Reactome Database ID Release 43158777 Reactome, http://www.reactome.org ReactomeREACT_3214 has a Stoichiometric coefficient of 1 p-T,4S-IRF3:p-T,4S-IRF3 Reactome DB_ID: 177675 Reactome Database ID Release 43177675 Reactome, http://www.reactome.org ReactomeREACT_7444 has a Stoichiometric coefficient of 2 fibrin multimer, crosslinked:tissue plasminogen activator (one-chain) Reactome DB_ID: 158764 Reactome Database ID Release 43158764 Reactome, http://www.reactome.org ReactomeREACT_4365 has a Stoichiometric coefficient of 1 RIP1:TRIF:activated TLR3/TLR4 Reactome DB_ID: 168912 Reactome Database ID Release 43168912 Reactome, http://www.reactome.org ReactomeREACT_7698 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 histidine-rich glycoprotein:plasminogen Reactome DB_ID: 158703 Reactome Database ID Release 43158703 Reactome, http://www.reactome.org ReactomeREACT_5514 has a Stoichiometric coefficient of 1 c-IAP1:UBE2D Reactome DB_ID: 2569051 Reactome Database ID Release 432569051 Reactome, http://www.reactome.org ReactomeREACT_152059 has a Stoichiometric coefficient of 1 PAI-2:urokinase plasminogen activator (two-chain):uPAR Reactome DB_ID: 159009 Reactome Database ID Release 43159009 Reactome, http://www.reactome.org ReactomeREACT_4630 has a Stoichiometric coefficient of 1 RIP1 ubiqutin ligases Converted from EntitySet in Reactome Reactome DB_ID: 2569050 Reactome Database ID Release 432569050 Reactome, http://www.reactome.org ReactomeREACT_151711 K63-linked polyUb - RIP1 Reactome DB_ID: 937021 Reactome Database ID Release 43937021 Reactome, http://www.reactome.org ReactomeREACT_26236 has a Stoichiometric coefficient of 1 activated TLR4/TLR3:TRIF:K63-pUb-RIP1 Reactome DB_ID: 937016 Reactome Database ID Release 43937016 Reactome, http://www.reactome.org ReactomeREACT_25755 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen Reactome DB_ID: 158786 Reactome Database ID Release 43158786 Reactome, http://www.reactome.org ReactomeREACT_3415 has a Stoichiometric coefficient of 1 activated TLR3/TLR4:TRIF:RIP1:FADD Reactome DB_ID: 2562577 Reactome Database ID Release 432562577 Reactome, http://www.reactome.org ReactomeREACT_150943 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 urokinase plasminogen activator (two-chain):uPAR Reactome DB_ID: 158969 Reactome Database ID Release 43158969 Reactome, http://www.reactome.org ReactomeREACT_5050 has a Stoichiometric coefficient of 1 active caspase-8 Reactome DB_ID: 2562550 Reactome Database ID Release 432562550 Reactome, http://www.reactome.org ReactomeREACT_151128 has a Stoichiometric coefficient of 2 plasminogen:histidine-rich glycoprotein Reactome DB_ID: 158961 Reactome Database ID Release 43158961 Reactome, http://www.reactome.org ReactomeREACT_5880 has a Stoichiometric coefficient of 1 activated TLR4/TLR3:TRIF:K63-pUb-RIP1:IKKcomplex Reactome DB_ID: 937030 Reactome Database ID Release 43937030 Reactome, http://www.reactome.org ReactomeREACT_26016 has a Stoichiometric coefficient of 1 PAI-1:urokinase plasminogen activator (two-chain):uPAR Reactome DB_ID: 159013 Reactome Database ID Release 43159013 Reactome, http://www.reactome.org ReactomeREACT_4824 has a Stoichiometric coefficient of 1 activated TLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8 Reactome DB_ID: 2562542 Reactome Database ID Release 432562542 Reactome, http://www.reactome.org ReactomeREACT_152273 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 urokinase plasminogen activator (two-chain) Reactome DB_ID: 158928 Reactome Database ID Release 43158928 Reactome, http://www.reactome.org ReactomeREACT_4096 has a Stoichiometric coefficient of 1 c-IAP2:UBE2D Reactome DB_ID: 2569049 Reactome Database ID Release 432569049 Reactome, http://www.reactome.org ReactomeREACT_150761 has a Stoichiometric coefficient of 1 fibrin multimer, crosslinked:tissue plasminogen activator (one-chain):plasminogen activator inhibitor 1 Reactome DB_ID: 158791 Reactome Database ID Release 43158791 Reactome, http://www.reactome.org ReactomeREACT_5096 has a Stoichiometric coefficient of 1 TRAF6 E3/E2 ubiquitin ligase complex Reactome DB_ID: 1248657 Reactome Database ID Release 431248657 Reactome, http://www.reactome.org ReactomeREACT_76422 has a Stoichiometric coefficient of 1 fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen activator inhibitor 1 Reactome DB_ID: 158789 Reactome Database ID Release 43158789 Reactome, http://www.reactome.org ReactomeREACT_4783 has a Stoichiometric coefficient of 1 urokinase plasminogen activator (one-chain):uPAR Reactome DB_ID: 158926 Reactome Database ID Release 43158926 Reactome, http://www.reactome.org ReactomeREACT_4234 has a Stoichiometric coefficient of 1 UBE2D1,2,3:Ubiquitin E2 Conjugating Enzymes UbcH5a/b/c:Ubiquitin Complex Reactome DB_ID: 1234116 Reactome Database ID Release 431234116 Reactome, http://www.reactome.org ReactomeREACT_124997 UbcH5a/b/c:Ubiquitin has a Stoichiometric coefficient of 1 alpha-2-antiplasmin:plasmin Reactome DB_ID: 158878 Reactome Database ID Release 43158878 Reactome, http://www.reactome.org ReactomeREACT_5642 has a Stoichiometric coefficient of 1 RIP3:TRIF:activated TLR3/4 Reactome DB_ID: 2569054 Reactome Database ID Release 432569054 Reactome, http://www.reactome.org ReactomeREACT_152149 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 RIP3:TRIF:activated TLR3/TLR4 Converted from EntitySet in Reactome Reactome DB_ID: 2569055 Reactome Database ID Release 432569055 Reactome, http://www.reactome.org ReactomeREACT_150814 RIP3:RIP1:TRIF:activated TLR3/4 Reactome DB_ID: 2569053 Reactome Database ID Release 432569053 Reactome, http://www.reactome.org ReactomeREACT_151344 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 activated TLR4/TLR3:TRIF:K63-pUb-TRAF6:free K63-linked pUb:activated TAK1 complex Reactome DB_ID: 936946 Reactome Database ID Release 43936946 Reactome, http://www.reactome.org ReactomeREACT_26039 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TLR7 or TLR8 Converted from EntitySet in Reactome Reactome DB_ID: 188166 Reactome Database ID Release 43188166 Reactome, http://www.reactome.org ReactomeREACT_9168 C-ter TLR7 dimer C-terminus TLR7 dimer Reactome DB_ID: 1679575 Reactome Database ID Release 431679575 Reactome, http://www.reactome.org ReactomeREACT_117622 has a Stoichiometric coefficient of 2 TLR8 dimer Reactome DB_ID: 1679576 Reactome Database ID Release 431679576 Reactome, http://www.reactome.org ReactomeREACT_116968 full length TLR8 has a Stoichiometric coefficient of 2 activated TLR4/TLR3:TRIF:TRAF6 Reactome DB_ID: 936976 Reactome Database ID Release 43936976 Reactome, http://www.reactome.org ReactomeREACT_25948 has a Stoichiometric coefficient of 1 activated TLR4/TLR3:TRIF:K63-pUb-TRAF6 Reactome DB_ID: 936965 Reactome Database ID Release 43936965 Reactome, http://www.reactome.org ReactomeREACT_25867 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TAB1 : TAB2/TAB3 : TAK1 Reactome DB_ID: 450277 Reactome Database ID Release 43450277 Reactome, http://www.reactome.org ReactomeREACT_21619 has a Stoichiometric coefficient of 1 activated TLR4/TLR3:TRIF:K63-pUb-TRAF6:free K63-linked pUb:TAK1complex Reactome DB_ID: 936954 Reactome Database ID Release 43936954 Reactome, http://www.reactome.org ReactomeREACT_26036 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CDP-DAG is converted to PGP by PGS1 At the inner mitochondrial (IM) membrane, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase (PGS1) converts cytidine diphosphate-diacylglycerol (CDP-DAG) and glycerol-3-phosphate (G3P) to phosphatidylglycerophosphate (PGP) and cytidine monophosphate (CMP). This event is inferred from rats. The enzyme PGS1 has been characterized in humans (Ota et al. 2004). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.8.5 Edited: Williams, MG, 2011-08-12 Pubmed14702039 Reactome Database ID Release 431482939 Reactome, http://www.reactome.org ReactomeREACT_121076 CD4:Env gp120/gp41insertion complex:CCR5/CXCR4 Reactome DB_ID: 171285 Reactome Database ID Release 43171285 Reactome, http://www.reactome.org ReactomeREACT_8356 has a Stoichiometric coefficient of 1 MyD88 complexed with the activated TLR receptor Reactome DB_ID: 975124 Reactome Database ID Release 43975124 Reactome, http://www.reactome.org ReactomeREACT_25822 has a Stoichiometric coefficient of 1 PA is converted to CDP-DAG by CDS2 At the inner mitochondrial (IM) membrane, phosphatidate cytidylyltransferase 2 (CDS2) converts phosphatidic acid (PA) and cytidine triphosphate (CTP) into cytidine diphosphate-diacylglycerol (CDP-DAG). Both ER and mitochondrial membranes have the capability to synthesise cytidine diphosphate-diacylglycerol (CDP-DAG) with phosphatidate cytidylyltransferase 1 and 2 (CDS1 and CDS2) (Lykidis et al. 1997, Schlame & Haldar 1993). However, transport of CDP-DAG between organelles cannot be ruled out (Stuhne-Sekalec et al. 1986). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.7.41 Edited: Williams, MG, 2011-08-12 Pubmed3718705 Pubmed8380172 Pubmed9407135 Reactome Database ID Release 431483165 Reactome, http://www.reactome.org ReactomeREACT_121008 C-ter-TLR9 dimer C-terminus Toll like receptor 9 (TLR9) dimer Reactome DB_ID: 1679581 Reactome Database ID Release 431679581 Reactome, http://www.reactome.org ReactomeREACT_116183 has a Stoichiometric coefficient of 2 PG is hydrolyzed to 1-acyl LPG by PLA2[1] At the endoplasmic reticulum (ER) membrane, phosphatidylglycerol (PG) is hydrolyzed, and has one of its acyl chains cleaved off, by cytosolic phospholipase A2 alpha/beta/delta/zeta (PLA2G4A/B/D/F) (Ghomashchi et al. 2010) to form 1-acyl lysophosphatidylglycerol (LPG). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482900 Reactome, http://www.reactome.org ReactomeREACT_121013 Env oligomer with gp41(inserted)/gp120(released) Reactome DB_ID: 171295 Reactome Database ID Release 43171295 Reactome, http://www.reactome.org ReactomeREACT_8679 has a Stoichiometric coefficient of 1 oligo-MyD88:activated TLR7-9 Reactome DB_ID: 975114 Reactome Database ID Release 43975114 Reactome, http://www.reactome.org ReactomeREACT_26395 has a Stoichiometric coefficient of 1 PGP is dephosphorylated to PG by an unknown phosphatase At the inner mitochondrial (IM) membrane, phosphatidylglycerophosphate (PGP) is dephosphorylated to phosphatidylglycerol (PG) by an as yet to be identified phosphatase. This phosphatase is principally localized in the mitochondria of chicken liver (Kiyasu et al. 1963). The identity of the human PGP phosphatase remains elusive and could be a NagD domain-containing protein (Lykidis 2007). Activity of rat liver mitochondrial PGP phosphatase has been demonstrated (MacDonald & McMurray 1980). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed14033231 Pubmed17512056 Pubmed6251897 Reactome Database ID Release 431483197 Reactome, http://www.reactome.org ReactomeREACT_121379 CD4:Env gp120/gp41 insertion complex Reactome DB_ID: 171276 Reactome Database ID Release 43171276 Reactome, http://www.reactome.org ReactomeREACT_8377 has a Stoichiometric coefficient of 1 MYD88 homodimer Reactome DB_ID: 975152 Reactome Database ID Release 43975152 Reactome, http://www.reactome.org ReactomeREACT_26418 has a Stoichiometric coefficient of 2 Virion with gp41 forming hairpin structure Reactome DB_ID: 173649 Reactome Database ID Release 43173649 Reactome, http://www.reactome.org ReactomeREACT_8661 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 IRAK4:oligo-MyD88:activated TLR 7/8 or 9 Reactome DB_ID: 975183 Reactome Database ID Release 43975183 Reactome, http://www.reactome.org ReactomeREACT_25785 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 gp41 homotrimer with fusion peptide inserted into membrane Reactome DB_ID: 173643 Reactome Database ID Release 43173643 Reactome, http://www.reactome.org ReactomeREACT_8602 has a Stoichiometric coefficient of 3 MyD88 oligomer Reactome DB_ID: 975141 Reactome Database ID Release 43975141 Reactome, http://www.reactome.org ReactomeREACT_27009 has a Stoichiometric coefficient of 6 CD4:Env gp120/gp41 hairpin complex Reactome DB_ID: 171294 Reactome Database ID Release 43171294 Reactome, http://www.reactome.org ReactomeREACT_8303 has a Stoichiometric coefficient of 1 IRAK1/or IRAK2 :p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 Reactome DB_ID: 975113 Reactome Database ID Release 43975113 Reactome, http://www.reactome.org ReactomeREACT_27033 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 CD4:Env gp120/gp41 hairpin complex:CCR5/CXCR4 Reactome DB_ID: 171297 Reactome Database ID Release 43171297 Reactome, http://www.reactome.org ReactomeREACT_8249 has a Stoichiometric coefficient of 1 p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptor Reactome DB_ID: 975159 Reactome Database ID Release 43975159 Reactome, http://www.reactome.org ReactomeREACT_26627 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 C-ter TLR9 dimer:unmethylated CpG DNA Reactome DB_ID: 1679087 Reactome Database ID Release 431679087 Reactome, http://www.reactome.org ReactomeREACT_116565 has a Stoichiometric coefficient of 1 CD4:Env gp120/gp41 fusion peptide complex Reactome DB_ID: 171280 Reactome Database ID Release 43171280 Reactome, http://www.reactome.org ReactomeREACT_8147 has a Stoichiometric coefficient of 1 TLR7 or TLR8:recognized ligand Reactome DB_ID: 188132 Reactome Database ID Release 43188132 Reactome, http://www.reactome.org ReactomeREACT_9279 has a Stoichiometric coefficient of 1 Env oligomer with gp41(fusion peptide)/gp120(released) Reactome DB_ID: 171302 Reactome Database ID Release 43171302 Reactome, http://www.reactome.org ReactomeREACT_8473 has a Stoichiometric coefficient of 1 Activated TLR7-9 homodimers Converted from EntitySet in Reactome Reactome DB_ID: 975158 Reactome Database ID Release 43975158 Reactome, http://www.reactome.org ReactomeREACT_26986 1-acyl LPI is acylated to PI by MBOAT7 At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferase 7 (MBOAT7) aka LPIAT acylates 1-acyl lysophosphatidylinositol (LPI) to form phosphatidylinositol (PI) (Gijon et al. 2008, Lee et al. 2008). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.51 Edited: Williams, MG, 2011-08-12 Pubmed18094042 Pubmed18772128 Reactome Database ID Release 431482598 Reactome, http://www.reactome.org ReactomeREACT_120739 gp41 homotrimer with exposed fusion peptide Reactome DB_ID: 173640 Reactome Database ID Release 43173640 Reactome, http://www.reactome.org ReactomeREACT_8823 has a Stoichiometric coefficient of 3 PI is hydrolyzed to 2-acyl LPI by PLA2[13] At the endoplasmic reticulum (ER) membrane, phosphatidylinositol (PI) is hydrolyzed, and has one of its acyl chains cleaved off, by cytosolic phospholipase A2 delta/epsilon (PLA2G4D/E) Ghomashchi et al. 2010). This produces 2-acyl lysophosphatidylinositol (LPI). Cytosolic phospholipase A2 enzymes show not only PLA2 hydrolyzing activity to form the 1-acyl lysophospholipid but also have a degree of PLA1 activity, producing a 2-acyl lysophospholipid. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.32 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482932 Reactome, http://www.reactome.org ReactomeREACT_121093 Virion with gp41 fusion peptide in insertion complex Reactome DB_ID: 173656 Reactome Database ID Release 43173656 Reactome, http://www.reactome.org ReactomeREACT_8875 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Smooth muscle/non-muscle myosin 2 regulatory light chains Converted from EntitySet in Reactome Reactome DB_ID: 420895 Reactome Database ID Release 43420895 Reactome, http://www.reactome.org ReactomeREACT_20357 2-acyl LPI is acylated to PI by MBOAT7 At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferase 7 (MBOAT7) aka LPIAT acylates 2-acyl lysophosphatidylinositol (LPI) to form phosphatidylinositol (PI) (Gijon et al. 2008, Lee et al. 2008). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.52 Edited: Williams, MG, 2011-08-12 Pubmed18094042 Pubmed18772128 Reactome Database ID Release 431482626 Reactome, http://www.reactome.org ReactomeREACT_121046 PI is hydrolyzed to 1-acyl LPI by PLA2[15] At the plasma membrane, phosphatidylinositol (PI) is hydrolyzed, removing one of its acyl groups, to 1-acyl lysophosphatidylinositol (LPI) by secretory phospholipase A2 proteins (Singer et al. 2002, Ishizaki et al. 1999). These include: Group IB (PLA2G1B) (Grataroli et al. 1982); Group IIA (PLA2G2A) (Seilhamer et al. 1989); Group IID (PLA2G2D) (Ishizaki et al. 1999); Group IIE (PLA2G2E) (Suzuki et al. 2000); Group IIF (PLA2G2F) (Valentin et al. 2000); Calcium-dependent Group V (PLA2G5) (Chen et al. 1994); Group X (PLA2G10) (Cupillard et al. 1997, Pan et al. 2002); and Group XIIA (PLA2G12A) (Gelb et al. 2000, Murakami et al. 2003). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10455175 Pubmed10681567 Pubmed11031251 Pubmed11112443 Pubmed12161451 Pubmed12359733 Pubmed12522102 Pubmed2925608 Pubmed7060561 Pubmed8300559 Pubmed9188469 Reactome Database ID Release 431602377 Reactome, http://www.reactome.org ReactomeREACT_120930 LARG and PDZ-RhoGEF Converted from EntitySet in Reactome Reactome DB_ID: 416544 Reactome Database ID Release 43416544 Reactome, http://www.reactome.org ReactomeREACT_20012 PC is transphosphatidylated to PG by PLD1-4/6 Authored: Williams, MG, 2011-09-14 EC Number: 3.1.4.4 Edited: Williams, MG, 2011-08-12 In the endoplasmic reticulum (ER) membrane, phospholipase D1-4,6 (PLD1-4,6) transphosphatidylates phosphatidylcholine (PC) with glycerol to displace choline (Cho) and form phosphatidylglycerol (PG). This reaction is inferred from rats, but PLD enzymes are present in humans (Hammond et al. 1995, Steed et al. 1998, Cao et al. 1997). Pubmed8530346 Pubmed9140189 Pubmed9761774 Reactome Database ID Release 431483142 Reactome, http://www.reactome.org ReactomeREACT_121402 PA transports from the outer to the inner mitochondrial membrane Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Phosphatidic acid (PA) transport within the mitochondrion occurs as free diffusion through the aqueous phase and not mediated by phospholipid transfer proteins. This event is inferred from rats (Chakraborty et al. 1999, Wojtczak et al. 1990). Pubmed10514455 Pubmed2344448 Reactome Database ID Release 431483099 Reactome, http://www.reactome.org ReactomeREACT_120748 CD4:Env gp120 (second conformation change) complex Reactome DB_ID: 171298 Reactome Database ID Release 43171298 Reactome, http://www.reactome.org ReactomeREACT_8874 has a Stoichiometric coefficient of 1 hp-IRAK1 or p-IRAK2 bound to the pIRAK4:MyD88:activated TLR7/8 or 9 complex Reactome DB_ID: 975178 Reactome Database ID Release 43975178 Reactome, http://www.reactome.org ReactomeREACT_25476 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PG and CDP-DAG are converted to CL by CRLS1 At the inner mitochondrial membrane (IM), cardiolipin synthase (CRLS1) converts phosphatidylglycerol (PG) and cytidine diphosphate-diacylglycerol (CDP-DAG) into cardiolipin (CL) (Lu et al. 2006, Houtkooper et al. 2006). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed16547353 Pubmed16678169 Reactome Database ID Release 431483063 Reactome, http://www.reactome.org ReactomeREACT_121330 CCR5/CXCR4:CD4:Env gp120 (second conformation change) complex Reactome DB_ID: 171293 Reactome Database ID Release 43171293 Reactome, http://www.reactome.org ReactomeREACT_8786 has a Stoichiometric coefficient of 1 p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 Reactome DB_ID: 975107 Reactome Database ID Release 43975107 Reactome, http://www.reactome.org ReactomeREACT_26344 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PG is hydrolyzed to 1-acyl LPG by PLA2[16] At the plasma membrane, phosphatidylglycerol (PG) is hydrolyzed, removing one of its acyl groups, to 1-acyl lysophosphatidylglycerol (LPG) by secretory phospholipase A2 proteins (Singer et al. 2002, Ishizaki et al. 1999). These include: Group IB (PLA2G1B) (Grataroli et al. 1982); Group IIA (PLA2G2A) (Seilhamer et al. 1989); Group IID (PLA2G2D) (Ishizaki et al. 1999); Group IIE (PLA2G2E) (Suzuki et al. 2000); Group IIF (PLA2G2F) (Valentin et al. 2000); Group III (PLA2G3) (Murakami et al. 2003, Murakami et al. 2005); Calcium-dependent Group V (PLA2G5) (Chen et al. 1994); Group X (PLA2G10) (Cupillard et al. 1997, Pan et al. 2002); and Group XIIA (PLA2G12A) (Gelb et al. 2000, Murakami et al. 2003). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10455175 Pubmed10681567 Pubmed11031251 Pubmed11112443 Pubmed12161451 Pubmed12359733 Pubmed12522102 Pubmed15863501 Pubmed2925608 Pubmed7060561 Pubmed8300559 Pubmed9188469 Reactome Database ID Release 431602368 Reactome, http://www.reactome.org ReactomeREACT_121220 pp-IRAK1:p-IRAK4:oligo-MyD88:activated TLR 7/8 or 9 complex Reactome DB_ID: 975161 Reactome Database ID Release 43975161 Reactome, http://www.reactome.org ReactomeREACT_25729 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 2-acyl LPG is acylated to PG by CRLS1 (IM) At the inner mitochondrial membrane (IM), cardiolipin synthase (CRLS1) acylates 2-acyl lysophosphatidylglycerol (LPG) to form phosphatidylglycerol (PG) (Nie et al. 2010). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.52 Edited: Williams, MG, 2011-08-12 Pubmed20025994 Reactome Database ID Release 431482546 Reactome, http://www.reactome.org ReactomeREACT_121169 p-IRAK1:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 complex Reactome DB_ID: 975130 Reactome Database ID Release 43975130 Reactome, http://www.reactome.org ReactomeREACT_25811 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 CD4:Env gp120/gp41 fusion peptide complex:CCR5 Reactome DB_ID: 171284 Reactome Database ID Release 43171284 Reactome, http://www.reactome.org ReactomeREACT_8410 has a Stoichiometric coefficient of 1 TRAF6:hp-IRAK1:Pellino Reactome DB_ID: 975143 Reactome Database ID Release 43975143 Reactome, http://www.reactome.org ReactomeREACT_26018 has a Stoichiometric coefficient of 1 phospho-Spt5 Converted from EntitySet in Reactome Reactome DB_ID: 350776 Reactome Database ID Release 43350776 Reactome, http://www.reactome.org ReactomeREACT_14075 Smooth muscle/non-muscle myosin 2 heavy chains Converted from EntitySet in Reactome Reactome DB_ID: 419183 Reactome Database ID Release 43419183 Reactome, http://www.reactome.org ReactomeREACT_20201 Virion with fusogenically activated gp41 Reactome DB_ID: 173639 Reactome Database ID Release 43173639 Reactome, http://www.reactome.org ReactomeREACT_8472 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TRAF6:hp-IRAK1 Reactome DB_ID: 975150 Reactome Database ID Release 43975150 Reactome, http://www.reactome.org ReactomeREACT_26576 has a Stoichiometric coefficient of 1 gp120 homotrimer after second conformation change Reactome DB_ID: 173651 Reactome Database ID Release 43173651 Reactome, http://www.reactome.org ReactomeREACT_8293 has a Stoichiometric coefficient of 3 hp-IRAK1/or p-IRAK2 :TRAF6 Reactome DB_ID: 975126 Reactome Database ID Release 43975126 Reactome, http://www.reactome.org ReactomeREACT_26363 has a Stoichiometric coefficient of 1 Env oligomer with gp120(second conformation change) Reactome DB_ID: 171303 Reactome Database ID Release 43171303 Reactome, http://www.reactome.org ReactomeREACT_8918 has a Stoichiometric coefficient of 1 TRAF6:hp-IRAK1/or p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR7/8 or 9 Reactome DB_ID: 975182 Reactome Database ID Release 43975182 Reactome, http://www.reactome.org ReactomeREACT_26553 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 IRAK1:p-S,2T-IRAK4 :oligo-MyD88:activated TLR 7/8 or 9 Reactome DB_ID: 975132 Reactome Database ID Release 43975132 Reactome, http://www.reactome.org ReactomeREACT_26100 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 p-IRAK2:p-IRAK4:oligo-MyD88:activated TLR 7/8 or9 Reactome DB_ID: 975133 Reactome Database ID Release 43975133 Reactome, http://www.reactome.org ReactomeREACT_26505 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Phosphorylated smooth muscle/non-muscle myosin 2 regulatory light chains Converted from EntitySet in Reactome Reactome DB_ID: 421613 Reactome Database ID Release 43421613 Reactome, http://www.reactome.org ReactomeREACT_20108 1-acyl LPG is acylated to PG by LPGAT At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferases acylate 1-acyl lysophosphatidylglycerol (LPG) to form phosphatidylglycerol (PG). The lysophospholipid acyltransferases involved are: lysophosphatidylcholine acyltransferase 1 (LPCAT1) (Nakanishi et al. 2006, Chen et al. 2006), lysophospholipid acyltransferase LPCAT4 (LPCAT4) aka LPEAT2 (Cao et al. 2008, Ye et al. 2005); or acyl-CoA:lysophosphatidylglycerol acyltransferase (LPGAT1) (Yang et al. 2004). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.51 Edited: Williams, MG, 2011-08-12 Pubmed15485873 Pubmed16243729 Pubmed16704971 Pubmed16864775 Pubmed18458083 Reactome Database ID Release 431482539 Reactome, http://www.reactome.org ReactomeREACT_121156 Virion with CD4:gp120 bound to CCR5/CXCR4 Reactome DB_ID: 173663 Reactome Database ID Release 43173663 Reactome, http://www.reactome.org ReactomeREACT_8665 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PG is hydrolyzed to 2-acyl LPG by PLA2[14] At the endoplasmic reticulum (ER) membrane, phosphatidylglycerol (PG) is hydrolyzed, and has one of its acyl chains cleaved off, by cytosolic phospholipase A2 delta/zeta (PLA2G4D/F) (Ghomashchi et al. 2010) to form 2-acyl lysophosphatidylglycerol (LPG). Cytosolic phospholipase A2 enzymes show not only PLA2 hydrolyzing activity to form the 1-acyl lysophospholipid but also have a degree of PLA1 activity, producing a 2-acyl lysophospholipid. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.32 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482920 Reactome, http://www.reactome.org ReactomeREACT_121221 CD4:Env gp120:CCR5/CXCR4:complex Reactome DB_ID: 171278 Reactome Database ID Release 43171278 Reactome, http://www.reactome.org ReactomeREACT_8881 has a Stoichiometric coefficient of 1 LIM Kinases Converted from EntitySet in Reactome Reactome DB_ID: 419708 Reactome Database ID Release 43419708 Reactome, http://www.reactome.org ReactomeREACT_20207 Env oligomer with gp120(exposed) Reactome DB_ID: 171290 Reactome Database ID Release 43171290 Reactome, http://www.reactome.org ReactomeREACT_8589 has a Stoichiometric coefficient of 1 IRAK2:p-S,2T-IRAK4:oligo-MyD88:activated TLR 7/8 or9 Reactome DB_ID: 975146 Reactome Database ID Release 43975146 Reactome, http://www.reactome.org ReactomeREACT_25986 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PG is hydrolyzed to 1-acyl LPG by PLA2G2A At the endoplasmic reticulum (ER) membrane, phosphatidylglycerol (PG) is hydrolyzed, and has one of its acyl chains cleaved off, by membrane-associated phospholipase A2 gamma 2A, PLA2G2A (Singer et al. 2002), to form 1-acyl lysophosphatidylglycerol (LPG). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed12359733 Reactome Database ID Release 431482907 Reactome, http://www.reactome.org ReactomeREACT_121060 gp120 homotrimer with exposed coreceptor binding sites Reactome DB_ID: 173662 Reactome Database ID Release 43173662 Reactome, http://www.reactome.org ReactomeREACT_8959 has a Stoichiometric coefficient of 3 1-acyl LPG is acylated to PG by CRLS1 (IM) At the inner mitochondrial (IR) membrane, cardiolipin synthase (CRLS1) acylates 1-acyl lysophosphatidylglycerol (LPG) to form phosphatidylglycerol (PG) (Nie et al. 2010). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.51 Edited: Williams, MG, 2011-08-12 Pubmed20025994 Reactome Database ID Release 431482689 Reactome, http://www.reactome.org ReactomeREACT_121361 LIM Kinases, phosphorylated Converted from EntitySet in Reactome Reactome DB_ID: 419709 Reactome Database ID Release 43419709 Reactome, http://www.reactome.org ReactomeREACT_19576 PG is hydrolysed to 2-acyl LPG by PLA2G4B (IM) At the inner mitochondrial (IR) membrane, phosphatidylglycerol (PG) is hydrolysed, and has one of its acyl chains cleaved off, by phospholipase A2 beta (PLA2G4B) (Ghomashchi et al. 2010) to form 2-acyl lysophosphatidylglycerol (LPG). Phospholipase A2 enzymes show not only PLA2 hydrolysing activity to form the 1-acyl lysophospholipid but also have a degree of PLA1 activity, producing a 2-acyl lysophospholipid. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.32 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482847 Reactome, http://www.reactome.org ReactomeREACT_120924 2-acyl LPG is acylated to PG by LPGAT At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferases acylate 2-acyl lysophosphatidylglycerol (LPG) to form phosphatidylglycerol (PG). The lysophospholipid acyltransferases involved are: lysophosphatidylcholine acyltransferase 1 (LPCAT1) (Nakanishi et al. 2006, Chen et al. 2006), lysophospholipid acyltransferase LPCAT4 (LPCAT4) aka LPEAT2 (Cao et al. 2008, Ye et al. 2005); or acyl-CoA:lysophosphatidylglycerol acyltransferase (LPGAT1) (Yang et al. 2004). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.52 Edited: Williams, MG, 2011-08-12 Pubmed15485873 Pubmed16243729 Pubmed16704971 Pubmed16864775 Pubmed18458083 Reactome Database ID Release 431482635 Reactome, http://www.reactome.org ReactomeREACT_121363 Virion with gp41 exposed Reactome DB_ID: 173665 Reactome Database ID Release 43173665 Reactome, http://www.reactome.org ReactomeREACT_8727 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PG is hydrolyzed to 1-acyl LPG by PLA2G4B (IM) At the inner mitochondrial membrane (IM), phosphatidylglycerol (PG) is hydrolyzed, and has one of its acyl chains cleaved off, by phospholipase A2 beta (PLA2G4B) to form 1-acyl lysophosphatidylglycerol (LPG) (Ghomashchi et al. 2010, Singer et al. 2002). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed12359733 Pubmed20705608 Reactome Database ID Release 431482745 Reactome, http://www.reactome.org ReactomeREACT_120887 Fibulins Converted from EntitySet in Reactome Reactome DB_ID: 2395327 Reactome Database ID Release 432395327 Reactome, http://www.reactome.org ReactomeREACT_151718 RTC with extensive RNase-H digestion Reactome DB_ID: 173789 Reactome Database ID Release 43173789 Reactome, http://www.reactome.org ReactomeREACT_9290 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex Reactome DB_ID: 975099 Reactome Database ID Release 43975099 Reactome, http://www.reactome.org ReactomeREACT_26866 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 RTC with minus strand DNA synthesis initiated from 3'-end Reactome DB_ID: 173786 Reactome Database ID Release 43173786 Reactome, http://www.reactome.org ReactomeREACT_9302 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 K63-linked-polyUb-TRAF6 Reactome DB_ID: 450227 Reactome Database ID Release 43450227 Reactome, http://www.reactome.org ReactomeREACT_21962 has a Stoichiometric coefficient of 1 RTC with extending minus strand DNA Reactome DB_ID: 173764 Reactome Database ID Release 43173764 Reactome, http://www.reactome.org ReactomeREACT_9298 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 minus sssDNA primer for minus strand DNA extension Reactome DB_ID: 173766 Reactome Database ID Release 43173766 Reactome, http://www.reactome.org ReactomeREACT_9197 has a Stoichiometric coefficient of 1 TAK1 complex Reactome DB_ID: 975128 Reactome Database ID Release 43975128 Reactome, http://www.reactome.org ReactomeREACT_25425 TAK1:TAB1:TAB2/3 has a Stoichiometric coefficient of 1 MLCL is hydrolyzed to DLCL by PLA2G4A (IM) At the inner mitochondrial membrane (IM), the phospholipase A2 group IV alpha (PLA2G4A) protein hydrolyzes monolysocardiolipin (MLCL) and produces dilysocardiolipin (DLCL) (Buckland et al. 1998, Sharp et al. 1994). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed8083230 Pubmed9487141 Reactome Database ID Release 431482759 Reactome, http://www.reactome.org ReactomeREACT_121167 minus sssDNA:tRNA primer generated by RNAse-H Reactome DB_ID: 173825 Reactome Database ID Release 43173825 Reactome, http://www.reactome.org ReactomeREACT_9280 has a Stoichiometric coefficient of 1 TRAF6:p-IRAK2 Reactome DB_ID: 975108 Reactome Database ID Release 43975108 Reactome, http://www.reactome.org ReactomeREACT_26288 has a Stoichiometric coefficient of 1 CL transports from the ER to the IM Authored: Williams, MG, 2011-09-14 Cardiolipin (CL) transports via membrane contact sites between the endoplasmic reticulum (ER) and the inner mitochondria membranes (IM) (Osman et al. 2011, Vance 1990, Gaigg et al. 1995, Zhao et al. 2009, Simbeni et al. 1991, Ardail et al. 1993, Shiao et al., 1995). Edited: Williams, MG, 2011-08-12 Pubmed19075029 Pubmed2037561 Pubmed21220505 Pubmed2332429 Pubmed7696296 Pubmed7744750 Pubmed8245031 Reactome Database ID Release 431482857 Reactome, http://www.reactome.org ReactomeREACT_121106 RTC with degraded RNA template and minus sssDNA Reactome DB_ID: 173773 Reactome Database ID Release 43173773 Reactome, http://www.reactome.org ReactomeREACT_9203 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TRAF6:K63-linked polyUb p-IRAK1:IKK complex Reactome DB_ID: 975121 Reactome Database ID Release 43975121 Reactome, http://www.reactome.org ReactomeREACT_25723 has a Stoichiometric coefficient of 1 minus sssDNA primer transferred to 3'- end of viral RNA template Reactome DB_ID: 173784 Reactome Database ID Release 43173784 Reactome, http://www.reactome.org ReactomeREACT_9258 has a Stoichiometric coefficient of 1 p-IRAK2:K63-linked pUb oligo-TRAF6 Reactome DB_ID: 975164 Reactome Database ID Release 43975164 Reactome, http://www.reactome.org ReactomeREACT_26097 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 RTC with minus sssDNA transferred to 3'-end of viral RNA template Reactome DB_ID: 173779 Reactome Database ID Release 43173779 Reactome, http://www.reactome.org ReactomeREACT_9360 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-IRAK2:oligo-TRAF6 Reactome DB_ID: 975137 Reactome Database ID Release 43975137 Reactome, http://www.reactome.org ReactomeREACT_26729 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-Pellino:hp-IRAK1:TRAF6 Reactome DB_ID: 975166 Reactome Database ID Release 43975166 Reactome, http://www.reactome.org ReactomeREACT_26952 has a Stoichiometric coefficient of 1 nicked minus sssDNA:RNA template:tRNA primer Reactome DB_ID: 182864 Reactome Database ID Release 43182864 Reactome, http://www.reactome.org ReactomeREACT_9355 has a Stoichiometric coefficient of 1 K63-poly-Ub-p-3S,3T-IRAK1 Reactome DB_ID: 975112 Reactome Database ID Release 43975112 Reactome, http://www.reactome.org ReactomeREACT_25636 has a Stoichiometric coefficient of 1 K63-linked poly-Ub-p-3S,3T-IRAK1:TRAF6 Reactome DB_ID: 975172 Reactome Database ID Release 43975172 Reactome, http://www.reactome.org ReactomeREACT_25541 has a Stoichiometric coefficient of 1 Cleaved collagen type IV alpha1.alpha1.alpha2 network Reactome DB_ID: 2564681 Reactome Database ID Release 432564681 Reactome, http://www.reactome.org ReactomeREACT_150525 Cleaved collagen type IV networks Converted from EntitySet in Reactome Reactome DB_ID: 2564684 Reactome Database ID Release 432564684 Reactome, http://www.reactome.org ReactomeREACT_150603 Cleaved collagen type IV alpha1.alpha2.alpha5.alpha6 network Reactome DB_ID: 2564682 Reactome Database ID Release 432564682 Reactome, http://www.reactome.org ReactomeREACT_152346 Cleaved collagen type IV alpha3.alpha4.alpha5 network Reactome DB_ID: 2564685 Reactome Database ID Release 432564685 Reactome, http://www.reactome.org ReactomeREACT_152375 Cleaved collagen type I fibril Reactome DB_ID: 2467150 Reactome Database ID Release 432467150 Reactome, http://www.reactome.org ReactomeREACT_152264 proMMP10 activators Converted from EntitySet in Reactome Reactome DB_ID: 2127633 Reactome Database ID Release 432127633 Reactome, http://www.reactome.org ReactomeREACT_119130 Cleaved collagen type III fibril Reactome DB_ID: 2468104 Reactome Database ID Release 432468104 Reactome, http://www.reactome.org ReactomeREACT_151381 Cleaved collagen type II fibril Reactome DB_ID: 2468059 Reactome Database ID Release 432468059 Reactome, http://www.reactome.org ReactomeREACT_151955 CL and 1-acyl LPE are converted to MLCL and PE by TAZ (IM) (Reversible) At the inner mitochondrial membrane (IM), tafazzin (TAZ) converts cardiolipin (CL) and 1-acyl lysophosphatidylethanolamine (LPE) to monolysocardiolipin (MLCL) and phosphatidylethanolamine (PE) (Xu et al. 2003, Xu et al. 2006, Malhotra et al. 2009). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.51 Edited: Williams, MG, 2011-08-12 Pubmed14551214 Pubmed17082194 Pubmed19416660 Reactome Database ID Release 431482894 Reactome, http://www.reactome.org ReactomeREACT_121114 MLCL is acylated to CL by HADH (IM) At the inner mitochondrial membrane (IM), the trifunctional enzyme HADH (3-hydroxyacyl-CoA dehydrogenase), an octamer of four alpha (HADHA) and four beta (HADHB) subunits, acylates monolysocardiolipin (MLCL) to cardiolipin (CL) (Taylor & Hatch 2009). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed19737925 Reactome Database ID Release 431482775 Reactome, http://www.reactome.org ReactomeREACT_120775 proMMP9 activating proteases Converted from EntitySet in Reactome Reactome DB_ID: 1604717 Reactome Database ID Release 431604717 Reactome, http://www.reactome.org ReactomeREACT_119770 MLCL transports from the IM to the ER Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Monolysocardiolipin (MLCL) transports via membrane contact sites between the endoplasmic reticulum (ER) and the inner mitochondria membranes (IM) (Cao et al. 2004, Zhao et al. 2009, Taylor & Hatch 2009). Pubmed15152008 Pubmed19075029 Pubmed19737925 Reactome Database ID Release 431482773 Reactome, http://www.reactome.org ReactomeREACT_120921 Trypsin, plasmin Converted from EntitySet in Reactome Reactome DB_ID: 1604696 Reactome Database ID Release 431604696 Reactome, http://www.reactome.org ReactomeREACT_119137 MLCL is acylated to CL by LCLAT1 (ER) At the endoplasmic reticulum (ER) membrane, lysocardiolipin acyltransferase 1 (LCLAT1) aka ALCAT1 acylates monolysocardiolipin (MLCL) to cardiolipin (CL) (Cao et al. 2004, Zhao et al. 2009). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed15152008 Pubmed19075029 Reactome Database ID Release 431482861 Reactome, http://www.reactome.org ReactomeREACT_121307 CL is hydrolyzed to MLCL by PLA2G6 (IM) At the inner mitochondrial membrane (IM), calcium-independent phospholipase A2 gamma (PLA2G6) hydrolyzes, removing one of the acyl chains, cardiolipin (CL) to form monolysocardiolipin (MLCL). This reaction is inferred from rats. PLA2G6 has also been characterized in humans (Larsson et al. 1998, Ma et al. 1999, Larsson Forsell et al. 1999). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10092647 Pubmed10336645 Pubmed9417066 Reactome Database ID Release 431482778 Reactome, http://www.reactome.org ReactomeREACT_120786 minus sssDNA:RNA template:tRNA primer Reactome DB_ID: 173812 Reactome Database ID Release 43173812 Reactome, http://www.reactome.org ReactomeREACT_9186 has a Stoichiometric coefficient of 1 LTBP1, LTBP3 Converted from EntitySet in Reactome Reactome DB_ID: 2395372 Reactome Database ID Release 432395372 Reactome, http://www.reactome.org ReactomeREACT_152016 MLCL and PC are converted to CL and 1-acyl LPC by TAZ (IM) (Reversible) At the inner mitochondrial membrane (IM), tafazzin (TAZ) converts monolysocardiolipin (MLCL) and phosphatidylcholine (PC) to cardiolipin (CL) and 1-acyl lysophosphatidylcholine (LPC) (Xu et al. 2003, Xu et al. 2006, Malhotra et al. 2009). Although this reaction is reversible, the net effect of the phospholipase A and acyltransferase reactions drives it towards the formation of LPC and CL. Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed14551214 Pubmed17082194 Pubmed19416660 Reactome Database ID Release 431482781 Reactome, http://www.reactome.org ReactomeREACT_121265 RTC with nicked minus sssDNA:tRNA primer:RNA template Reactome DB_ID: 182804 Reactome Database ID Release 43182804 Reactome, http://www.reactome.org ReactomeREACT_9226 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CL and 1-acyl LPC are converted to MLCL and PC by TAZ (IM) (Reversible) At the inner mitochondrial membrane (IM), tafazzin (TAZ) converts cardiolipin (CL) and 1-acyl lysophosphatidylcholine (LPC) to monolysocardiolipin (MLCL) and phosphatidylcholine (PC) (Xu et al. 2003, Xu et al. 2006, Malhotra et al. 2009). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.23 Edited: Williams, MG, 2011-08-12 Pubmed14551214 Pubmed17082194 Pubmed19416660 Reactome Database ID Release 431482794 Reactome, http://www.reactome.org ReactomeREACT_121044 MLCL and PE are converted to CL and 1-acyl LPE by TAZ (IM) (Reversible) At the inner mitochondrial membrane (IM), tafazzin (TAZ) converts monolysocardiolipin (MLCL) and phosphatidylethanolamine (PE) to cardiolipin (CL) and 1-acyl lysophosphatidylethanolamine (LPE) (Xu et al. 2003, Xu et al. 2006, Malhotra et al. 2009). Although this reaction is reversible, the net effect of the phospholipase A and acyltransferase reactions drives it towards the formation of LPE and CL. Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed14551214 Pubmed17082194 Pubmed19416660 Reactome Database ID Release 431482850 Reactome, http://www.reactome.org ReactomeREACT_120929 RTC with minus sssDNA:tRNA primer:RNA template Reactome DB_ID: 173774 Reactome Database ID Release 43173774 Reactome, http://www.reactome.org ReactomeREACT_9297 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 RNA template:tRNA primer Reactome DB_ID: 173798 Reactome Database ID Release 43173798 Reactome, http://www.reactome.org ReactomeREACT_9253 has a Stoichiometric coefficient of 1 BMP2,4,7,10,GF5 Converted from EntitySet in Reactome Reactome DB_ID: 2396226 Reactome Database ID Release 432396226 Reactome, http://www.reactome.org ReactomeREACT_150604 RTC with tRNA primer:RNA template Reactome DB_ID: 173801 Reactome Database ID Release 43173801 Reactome, http://www.reactome.org ReactomeREACT_9371 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 LPS:GPI-anchored CD14 Reactome DB_ID: 166034 Reactome Database ID Release 43166034 Reactome, http://www.reactome.org ReactomeREACT_7567 has a Stoichiometric coefficient of 1 ACF Converted from EntitySet in Reactome Reactome DB_ID: 350790 Reactome Database ID Release 43350790 Reactome, http://www.reactome.org ReactomeREACT_14019 RTC (Reverse Transcription Complex) with RNA template Reactome DB_ID: 173814 Reactome Database ID Release 43173814 Reactome, http://www.reactome.org ReactomeREACT_9085 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 LBP:bacterial LPS Reactome DB_ID: 166013 Reactome Database ID Release 43166013 Reactome, http://www.reactome.org ReactomeREACT_7556 has a Stoichiometric coefficient of 1 uncoated viral complex Reactome DB_ID: 173653 Reactome Database ID Release 43173653 Reactome, http://www.reactome.org ReactomeREACT_9366 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 EEA1:EEA1 Reactome DB_ID: 187897 Reactome Database ID Release 43187897 Reactome, http://www.reactome.org ReactomeREACT_9336 has a Stoichiometric coefficient of 2 Encapsidated viral core Reactome DB_ID: 188943 Reactome Database ID Release 43188943 Reactome, http://www.reactome.org ReactomeREACT_9259 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 N-ter TLR9 dimer:unmethylated CpG DNA Reactome DB_ID: 1679094 Reactome Database ID Release 431679094 Reactome, http://www.reactome.org ReactomeREACT_119250 has a Stoichiometric coefficient of 1 RT Reactome DB_ID: 173772 Reactome Database ID Release 43173772 Reactome, http://www.reactome.org ReactomeREACT_8803 Reverse Transcriptase heterodimer has a Stoichiometric coefficient of 1 N-ter TLR9 dimer Reactome DB_ID: 1679574 Reactome Database ID Release 431679574 Reactome, http://www.reactome.org ReactomeREACT_119168 has a Stoichiometric coefficient of 2 PI4P is dephosphorylated to PI by SACM1L at the Golgi membrane At the Golgi membrane, phosphatidylinositide phosphatase SAC1 (SACM1L) efficiently dephosphorylates phosphatidylinositol 4-phosphate (PI4P), and to a lesser extent phosphatidylinositol 3-phosphate (PI3P), to phosphatidylinositol (PI). No significant activity of this enzyme towards phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) was detected (Rohde et al. 2003). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed14527956 Reactome Database ID Release 431676133 Reactome, http://www.reactome.org ReactomeREACT_120917 Reviewed: Wakelam, Michael, 2012-05-14 HIV-1 RNA homodimer Reactome DB_ID: 174985 Reactome Database ID Release 43174985 Reactome, http://www.reactome.org ReactomeREACT_8245 has a Stoichiometric coefficient of 2 K63-linked polyUb-IRF7 Reactome DB_ID: 975154 Reactome Database ID Release 43975154 Reactome, http://www.reactome.org ReactomeREACT_25774 has a Stoichiometric coefficient of 1 K63-linked poly-Ub-IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9. Reactome DB_ID: 975174 Reactome Database ID Release 43975174 Reactome, http://www.reactome.org ReactomeREACT_26203 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 Reactome DB_ID: 975131 Reactome Database ID Release 43975131 Reactome, http://www.reactome.org ReactomeREACT_25804 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 Reactome DB_ID: 975148 Reactome Database ID Release 43975148 Reactome, http://www.reactome.org ReactomeREACT_26628 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex Reactome DB_ID: 975171 Reactome Database ID Release 43975171 Reactome, http://www.reactome.org ReactomeREACT_27039 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Collagen type XV multimer Reactome DB_ID: 2168022 Reactome Database ID Release 432168022 Reactome, http://www.reactome.org ReactomeREACT_151788 DLCL transports from the IM to the ER Authored: Williams, MG, 2011-09-14 Dilysocardiolipin (DLCL) transports via membrane contact sites between the endoplasmic reticulum (ER) and the inner mitochondria membranes (IM) (Zhao et al. 2009, Buckland et al. 1998). Edited: Williams, MG, 2011-08-12 Pubmed19075029 Pubmed9487141 Reactome Database ID Release 431482860 Reactome, http://www.reactome.org ReactomeREACT_120764 Cleaved collagen type XI fibril Reactome DB_ID: 2470603 Reactome Database ID Release 432470603 Reactome, http://www.reactome.org ReactomeREACT_150565 Cleaved collagen type X fibril Reactome DB_ID: 2470532 Reactome Database ID Release 432470532 Reactome, http://www.reactome.org ReactomeREACT_151538 Collagen type X fibril Reactome DB_ID: 2167968 Reactome Database ID Release 432167968 Reactome, http://www.reactome.org ReactomeREACT_150698 Cleaved collagen type VIII fibril Reactome DB_ID: 2470314 Reactome Database ID Release 432470314 Reactome, http://www.reactome.org ReactomeREACT_151193 Collagen type VIII fibril Reactome DB_ID: 2168017 Reactome Database ID Release 432168017 Reactome, http://www.reactome.org ReactomeREACT_151360 Cleaved collagen type VII fibril Reactome DB_ID: 2470309 Reactome Database ID Release 432470309 Reactome, http://www.reactome.org ReactomeREACT_151813 Cleaved collagen type VI fibril Reactome DB_ID: 2470223 Reactome Database ID Release 432470223 Reactome, http://www.reactome.org ReactomeREACT_151369 PI4KB binds to ARF1/3:GTP at the Golgi membrane At the Golgi membrane, ADP-ribosylation factor 1 and 3 (ARF1 and ARF3) complexed to GTP bind to phosphatidylinositol 4-kinase beta (PI4KB) and activate it (Haynes et al. 2007, Wong et al. 1997, Godi et al. 1999). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed10559940 Pubmed17555535 Pubmed9148941 Reactome Database ID Release 431676152 Reactome, http://www.reactome.org ReactomeREACT_121296 Reviewed: Wakelam, Michael, 2012-05-14 LTBPs Converted from EntitySet in Reactome Reactome DB_ID: 2396175 Reactome Database ID Release 432396175 Reactome, http://www.reactome.org ReactomeREACT_151267 Collagen type VI fibril Reactome DB_ID: 1637827 Reactome Database ID Release 431637827 Reactome, http://www.reactome.org ReactomeREACT_152217 PI is phosphorylated to PI4P by PI4KB at the Golgi membrane At the Golgi membrane, activated phosphatidylinositol 4-kinase beta (PI4KB) complexed to ADP-ribosylation factor 1/3 (ARF1/3) phosphorylates phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P) (Suzuki et al. 1997). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.67 Edited: Williams, MG, 2011-08-12 Pubmed9405935 Reactome Database ID Release 431675883 Reactome, http://www.reactome.org ReactomeREACT_121005 Reviewed: Wakelam, Michael, 2012-05-14 Cleaved collagen type V fibril Reactome DB_ID: 2470128 Reactome Database ID Release 432470128 Reactome, http://www.reactome.org ReactomeREACT_150493 PI4P is dephosphorylated to PI by SACM1L at the ER membrane At the endoplasmic reticulum (ER) membrane, transmembrane protein phosphatidylinositide phosphatase SAC1 (SACM1L) efficiently dephosphorylates phosphatidylinositol 4-phosphate (PI4P), and to a lesser extent phosphatidylinositol 3-phosphate (PI3P), to phosphatidylinositol (PI). No significant activity of this enzyme towards phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) was detected (Rohde et al. 2003). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed14527956 Reactome Database ID Release 431676124 Reactome, http://www.reactome.org ReactomeREACT_121134 Reviewed: Wakelam, Michael, 2012-05-14 Elastic fibre-asociated proteins Converted from EntitySet in Reactome Reactome DB_ID: 2161378 Reactome Database ID Release 432161378 Reactome, http://www.reactome.org ReactomeREACT_150721 PI is phosphorylated to PI4P by PI4KA/2A/2B at the Golgi membrane At the Golgi membrane, phosphatidylinositol 4-kinase alpha (PI4KA) (Gehrmann et al. 1999, Godi et al. 1999), or phosphatidylinositol 4-kinase type 2-alpha/beta (PI4K2A/B) (Balla et al. 2002, Minogue et al. 2001, Wei et al. 2002) phosphorylate phosphatidylinositol (PI) to produce phosphatidylinositol 4-phosphate (PI4P). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.67 Edited: Williams, MG, 2011-08-12 Pubmed10101268 Pubmed10559940 Pubmed11279162 Pubmed11923287 Pubmed12324459 Reactome Database ID Release 431676185 Reactome, http://www.reactome.org ReactomeREACT_120925 Reviewed: Wakelam, Michael, 2012-05-14 PG is converted to BMP Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed10101262 Pubmed17558022 Pubmed21136156 Pubmed650089 Reactome Database ID Release 431483209 Reactome, http://www.reactome.org ReactomeREACT_121203 The biosynthetic pathway of lysobisphosphatidic acid, also known as bis(monoacylglycerol) hydrogen phosphate (BMP), is still not fully understood with the <I>in vivo</I> enzymes responsible yet to be fully identified. It appears to involve multiple steps including hydrolysis of phosphatidylglycerol (PG) by a phospholipase A2, acylation, and a reorientation of the phosphoryl ester (Poorthuis & Hostetler 1978, Heravi & Waite 1999, Hullin-Matsuda et al. 2007, Gallala & Sandhoff 2010). Viral core surrounded by Matrix layer Reactome DB_ID: 173664 Reactome Database ID Release 43173664 Reactome, http://www.reactome.org ReactomeREACT_8910 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PI is phosphorylated to PI4P by PI4KA/2B at the ER membrane At the endoplasmic reticulum (ER) membrane, phosphatidylinositol 4-kinase alpha (PI4KA) (Wong et al. 1997, Gehrmann et al. 1999) or phosphatidylinositol 4-kinase type 2-beta (PI4K2B) (Wei et al. 2002) phosphorylate phosphatidylinositol (PI) to produce phosphatidylinositol 4-phosphate (PI4P). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.67 Edited: Williams, MG, 2011-08-12 Pubmed10101268 Pubmed12324459 Pubmed9148941 Reactome Database ID Release 431675813 Reactome, http://www.reactome.org ReactomeREACT_121159 Reviewed: Wakelam, Michael, 2012-05-14 DLCL is acylated to MLCL by LCLAT1 (ER) At the endoplasmic reticulum (ER) membrane, lysocardiolipin acyltransferase 1 (LCLAT1) aka ALCAT1 acylates dilysocardiolipin (DLCL) to produce monolysocardiolipin (MLCL) (Zhao et al. 2009). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed19075029 Reactome Database ID Release 431482867 Reactome, http://www.reactome.org ReactomeREACT_121279 Env oligomer with gp41 hairpin structure formation Reactome DB_ID: 173661 Reactome Database ID Release 43173661 Reactome, http://www.reactome.org ReactomeREACT_8224 has a Stoichiometric coefficient of 1 PG transports from the ER membrane to the late endosome membrane Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Lysobisphosphatidic acid, also known as bis(monoacylglycerol) hydrogen phosphate (BMP), is enriched in late endosomes and not found in the endoplasmic reticulum (ER) or mitochondria where phosphatidylglycerol (PG) is synthesised. Late endosomes form membrane contact sites with the ER, providing a means for PG to enter the late endosome and be converted to BMP (Levine 2004, Eden et al. 2010, Kobayashi et al. 1998, Hullin-Matsuda et al. 2007, Kobayashi et al. 1999). Pubmed10559883 Pubmed15350976 Pubmed17558022 Pubmed20118922 Pubmed9515966 Reactome Database ID Release 431483218 Reactome, http://www.reactome.org ReactomeREACT_121205 gp41 homotrimer with hairpin structure formation Reactome DB_ID: 173645 Reactome Database ID Release 43173645 Reactome, http://www.reactome.org ReactomeREACT_8273 has a Stoichiometric coefficient of 3 LPS:secreted CD14 Reactome DB_ID: 166026 Reactome Database ID Release 43166026 Reactome, http://www.reactome.org ReactomeREACT_7211 has a Stoichiometric coefficient of 1 LPS:CD14 Converted from EntitySet in Reactome Reactome DB_ID: 166043 Reactome Database ID Release 43166043 Reactome, http://www.reactome.org ReactomeREACT_7856 viral DNA with 3' sticky ends Reactome DB_ID: 177535 Reactome Database ID Release 43177535 Reactome, http://www.reactome.org ReactomeREACT_8181 has a Stoichiometric coefficient of 1 TLR4:MD2 Reactome DB_ID: 166050 Reactome Database ID Release 43166050 Reactome, http://www.reactome.org ReactomeREACT_7105 has a Stoichiometric coefficient of 1 provirus Integrated provirus Reactome DB_ID: 175486 Reactome Database ID Release 43175486 Reactome, http://www.reactome.org ReactomeREACT_7455 has a Stoichiometric coefficient of 1 TLR4:MD2:LPS:CD14 Reactome DB_ID: 166850 Reactome Database ID Release 43166850 Reactome, http://www.reactome.org ReactomeREACT_7465 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 linear duplex viral DNA Reactome DB_ID: 175124 Reactome Database ID Release 43175124 Reactome, http://www.reactome.org ReactomeREACT_7750 has a Stoichiometric coefficient of 1 RP105:MD1 Reactome DB_ID: 166154 Reactome Database ID Release 43166154 Reactome, http://www.reactome.org ReactomeREACT_7670 has a Stoichiometric coefficient of 1 PE is methylated to PC by PEMT At the endoplasmic reticulum (ER) membrane, phosphatidylethanolamine N-methyltransferase (PEMT) methylates phosphatidylethanolamine (PE) and produces phosphatidylcholine (PC) (Vance & Ridgway 1998, Shields et al. 2001, Guan et al. 1999). Authored: Williams, MG, 2011-09-14 EC Number: 2.1.1.17 Edited: Williams, MG, 2011-08-12 Pubmed10100195 Pubmed11420179 Pubmed3057511 Reactome Database ID Release 431483174 Reactome, http://www.reactome.org ReactomeREACT_121126 has a Stoichiometric coefficient of 3 1-LTR form of circular viral DNA Reactome DB_ID: 175558 Reactome Database ID Release 43175558 Reactome, http://www.reactome.org ReactomeREACT_9361 has a Stoichiometric coefficient of 1 LPS:CD14:CR3 Reactome DB_ID: 2559438 Reactome Database ID Release 432559438 Reactome, http://www.reactome.org ReactomeREACT_151313 has a Stoichiometric coefficient of 1 Acetylcholine clearance from synaptic cleft AcCho is hydrolyzed to Cho and acetate by ACHE Acetylcholinesterase (ACHE) oligomers (comprising monomers, dimers and tetramers), anchored to the extracellular side of the plasma membrane, hydrolyze acetylcholine (AcCho) to form choline (Cho) and acetate (Weinstock & Groner 2008, Velan et al. 1991, Kryger et al. 2000).<br><br>Acetylcholine from the synaptic cleft is degraded into inactive molecules, Cho and acetate by ACHE, which is located in the synaptic cleft (Weinstock & Groner 2008). Authored: Mahajan, SS, 2008-01-14 16:01:52 EC Number: 3.1.1.7 Edited: Mahajan, SS, 2008-11-18 00:03:09 Pubmed11053835 Pubmed1748670 Pubmed18457821 Reactome Database ID Release 43372519 Reactome, http://www.reactome.org ReactomeREACT_14816 Reviewed: Restituito, S, 2008-11-27 12:38:49 Ku proteins bound to viral DNA Reactome DB_ID: 175247 Reactome Database ID Release 43175247 Reactome, http://www.reactome.org ReactomeREACT_7016 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 MAL:PI(4,5)P2 Reactome DB_ID: 2559415 Reactome Database ID Release 432559415 Reactome, http://www.reactome.org ReactomeREACT_151450 has a Stoichiometric coefficient of 1 CTL1-5 can mediate the uptake of choline Authored: Jassal, B, 2009-10-23 Cho transports from the extracellular space to the cytosol Choline (Cho) transports from the extracellular space through the plasma membrane via the choline transporter-like proteins (SLC44A1-5 also known as CTL1-5) to the cytosol (Okuda & Haga 2000, Traiffort et al. 2005, O'Regan et al. 2000).<br><br>CTL1 is broadly expressed on leukocytes and endothelial cells (Wille et al. 2001). CTL2 is highly expressed in human inner ear and is the target of antibody-induced hearing loss (Nair et al. 2004). Edited: Jassal, B, 2009-08-21 Pubmed10677542 Pubmed11068039 Pubmed11698453 Pubmed14973250 Pubmed15715662 Reactome Database ID Release 43444433 Reactome, http://www.reactome.org ReactomeREACT_20598 Reviewed: He, L, 2009-11-12 viral DNA:Ku proteins:XRCC4:DNA ligase IV complex Reactome DB_ID: 175440 Reactome Database ID Release 43175440 Reactome, http://www.reactome.org ReactomeREACT_9308 has a Stoichiometric coefficient of 1 Activated TLR1:2 or TLR 2:6 heterodimers or TLR4 homodimer Converted from EntitySet in Reactome Reactome DB_ID: 181230 Reactome Database ID Release 43181230 Reactome, http://www.reactome.org ReactomeREACT_8654 F-actin capping protein alpha protein fragment TRTK-12 Converted from EntitySet in Reactome Reactome DB_ID: 879446 Reactome Database ID Release 43879446 Reactome, http://www.reactome.org ReactomeREACT_26814 Cho is phosphorylated to PCho by CHK dimer Authored: Williams, MG, 2011-09-14 EC Number: 2.7.1.32 Edited: Williams, MG, 2011-08-12 In the cytosol, choline kinase alpha subunit (CHKA) homodimer, choline kinase beta subunit (CHKB) dimer, or CHKA:CHKB heterodimer phosphorylates choline (Cho) to produce phosphocholine (PCho) (Malito et al. 2006, Gallego-Ortega et al. 2009). Pubmed17007874 Pubmed19915674 Reactome Database ID Release 431483004 Reactome, http://www.reactome.org ReactomeREACT_121281 2-LTR form of circular viral DNA Reactome DB_ID: 175242 Reactome Database ID Release 43175242 Reactome, http://www.reactome.org ReactomeREACT_9104 has a Stoichiometric coefficient of 1 TLR1:TLR2:TLR1/2 ligand:CD14 Reactome DB_ID: 181226 Reactome Database ID Release 43181226 Reactome, http://www.reactome.org ReactomeREACT_8364 has a Stoichiometric coefficient of 1 PCho is dephosphorylated to Cho by PHOSPHO1 Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 In the cytosol, the phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1) dephosphorylates phosphocholine (PCho) to choline (Cho) (Roberts et al. 2004). Pubmed15175005 Reactome Database ID Release 431483159 Reactome, http://www.reactome.org ReactomeREACT_121364 Autointegrated viral DNA as an inverted circle Reactome DB_ID: 175415 Reactome Database ID Release 43175415 Reactome, http://www.reactome.org ReactomeREACT_7515 has a Stoichiometric coefficient of 1 TLR1:TLR2 ligand:CD14 Reactome DB_ID: 2559462 Reactome Database ID Release 432559462 Reactome, http://www.reactome.org ReactomeREACT_152304 has a Stoichiometric coefficient of 1 Synthesis of o-acetylcholine Authored: Mahajan, SS, 2008-01-14 16:01:52 Cho is acetylated to AcCho by CHAT EC Number: 2.3.1.6 In the cytosol, choline O-acetyltransferase (CHAT) acetylates choline (Cho) to produce acetylcholine (AcCho) (Toussaint 1992).<br><br>AcCho is synthesised in the cytoplasm of cholinergic neurons from acetyl-CoA and Cho by CHAT enzyme. Pubmed1339386 Reactome Database ID Release 43264622 Reactome, http://www.reactome.org ReactomeREACT_15484 Autointegrated viral DNA as smaller circles Reactome DB_ID: 175037 Reactome Database ID Release 43175037 Reactome, http://www.reactome.org ReactomeREACT_7557 has a Stoichiometric coefficient of 1 PCho and CTP are condensed to CDP-Cho by PCYT1 dimer At the endoplasmic reticulum (ER) membrane, active membrane-bound choline-phosphate cytidylyltransferase A (PCYT1A) or B (PCYT1B) homodimer condenses phosphocholine (PCho) and cytidine triphosphate (CTP) to produce CDP-choline (CDP-Cho) (Lykidis et al. 1998). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.7.15 Edited: Williams, MG, 2011-08-12 Pubmed9593753 Reactome Database ID Release 431483081 Reactome, http://www.reactome.org ReactomeREACT_121282 HIV-1 closed pre-initiation complex Reactome DB_ID: 167125 Reactome Database ID Release 43167125 Reactome, http://www.reactome.org ReactomeREACT_6553 has a Stoichiometric coefficient of 1 CDP-Cho and DAG are converted to PC by CEPT1 at the ER membrane At the endoplasmic reticulum (ER) membrane, choline/ethanolaminephosphotransferase (CEPT1) converts CDP-choline (CDP-Cho) and diacylglycerol (DAG) to phosphatidylcholine (PC) and cytidine monophosphate (CMP) (Wright et al. 2002, Henneberry et al. 1999, Henneberry et al. 2002, Henneberry et al. 2000). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.8.2 Edited: Williams, MG, 2011-08-12 Pubmed10191259 Pubmed10893425 Pubmed12216837 Pubmed12221122 Reactome Database ID Release 431482961 Reactome, http://www.reactome.org ReactomeREACT_120896 Profibrillins Converted from EntitySet in Reactome Reactome DB_ID: 2159860 Reactome Database ID Release 432159860 Reactome, http://www.reactome.org ReactomeREACT_150866 MMP1-3, 7-9, 12, 13 Converted from EntitySet in Reactome Reactome DB_ID: 2537512 Reactome Database ID Release 432537512 Reactome, http://www.reactome.org ReactomeREACT_151110 Cleaved collagen type XV multimer Reactome DB_ID: 2484960 Reactome Database ID Release 432484960 Reactome, http://www.reactome.org ReactomeREACT_151893 Fibrillin C-term fragments Converted from EntitySet in Reactome Reactome DB_ID: 2159858 Reactome Database ID Release 432159858 Reactome, http://www.reactome.org ReactomeREACT_151567 Collagen type XVIII multimer Reactome DB_ID: 2172281 Reactome Database ID Release 432172281 Reactome, http://www.reactome.org ReactomeREACT_150706 Cleaved collagen type XVIII multimer Reactome DB_ID: 2470858 Reactome Database ID Release 432470858 Reactome, http://www.reactome.org ReactomeREACT_151434 GPETA is hydrolyzed to ETA and G3P by GPCPD1 Authored: Williams, MG, 2011-09-14 EC Number: 3.1.4.46 Edited: Williams, MG, 2011-08-12 In the cytosol, glycerophosphocholine phosphodiesterase (GPCPD1, also known as GDE5) hydrolyzes glycerophosphoethanolamine (GPETA) to produce ethanolamine (ETA) and glycerol-3-phosphate (G3P). This event has been inferred from mice. GPCPD1 has also been characterized in humans (Ota et al. 2004). Pubmed14702039 Reactome Database ID Release 431483107 Reactome, http://www.reactome.org ReactomeREACT_121308 AGER-1, 2, 3 Converted from EntitySet in Reactome Reactome DB_ID: 879379 Reactome Database ID Release 43879379 Reactome, http://www.reactome.org ReactomeREACT_25689 Endostatin-releasing proteases Converted from EntitySet in Reactome Reactome DB_ID: 2470862 Reactome Database ID Release 432470862 Reactome, http://www.reactome.org ReactomeREACT_151175 2-acyl LPE is hydrolyzed to GPETA by PLA2G4C At the endoplasmic reticulum (ER) membrane, membrane-bound cytosolic phospholipase A2 gamma (PLA2G4C) hydrolyzes 2-acyl lysophosphatidylethanolamine (LPE) to produce glycerophosphoethanolamine (GPETA) (Yamashita et al. 2005, Yamashita et al. 2009). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.5 Edited: Williams, MG, 2011-08-12 Pubmed15944408 Pubmed19501189 Reactome Database ID Release 431482545 Reactome, http://www.reactome.org ReactomeREACT_121022 Endostatin-degrading cathepsins Converted from EntitySet in Reactome Reactome DB_ID: 2471626 Reactome Database ID Release 432471626 Reactome, http://www.reactome.org ReactomeREACT_150853 Fibrillin peptides Converted from EntitySet in Reactome Reactome DB_ID: 2159821 Reactome Database ID Release 432159821 Reactome, http://www.reactome.org ReactomeREACT_152164 Cleaved collagen fibrils Converted from EntitySet in Reactome Reactome DB_ID: 2537527 Reactome Database ID Release 432537527 Reactome, http://www.reactome.org ReactomeREACT_151068 Fibrillin-1 Reactome DB_ID: 2159874 Reactome Database ID Release 432159874 Reactome, http://www.reactome.org ReactomeREACT_152353 Fibrillins Converted from EntitySet in Reactome Reactome DB_ID: 2159839 Reactome Database ID Release 432159839 Reactome, http://www.reactome.org ReactomeREACT_152243 Fibrillin-2 Reactome DB_ID: 2159861 Reactome Database ID Release 432159861 Reactome, http://www.reactome.org ReactomeREACT_151675 Fibrillin-3 Reactome DB_ID: 2159866 Reactome Database ID Release 432159866 Reactome, http://www.reactome.org ReactomeREACT_151535 PorB Homotrimer Reactome DB_ID: 180817 Reactome Database ID Release 43180817 Reactome, http://www.reactome.org ReactomeREACT_8553 has a Stoichiometric coefficient of 3 TLR1:TLR2 Reactome DB_ID: 168946 Reactome Database ID Release 43168946 Reactome, http://www.reactome.org ReactomeREACT_8486 has a Stoichiometric coefficient of 1 RTC without viral RNA template Reactome DB_ID: 173824 Reactome Database ID Release 43173824 Reactome, http://www.reactome.org ReactomeREACT_9260 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TLR6:TLR2 Reactome DB_ID: 168949 Reactome Database ID Release 43168949 Reactome, http://www.reactome.org ReactomeREACT_8554 has a Stoichiometric coefficient of 1 RTC with annealed complementary PBS seqments in +sssDNA and -strand DNA Reactome DB_ID: 173792 Reactome Database ID Release 43173792 Reactome, http://www.reactome.org ReactomeREACT_9090 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 MAL:activated TLR2/4 Reactome DB_ID: 2559411 Reactome Database ID Release 432559411 Reactome, http://www.reactome.org ReactomeREACT_152404 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TLR6:TLR2:ligand:CD14:CD36 Reactome DB_ID: 181410 Reactome Database ID Release 43181410 Reactome, http://www.reactome.org ReactomeREACT_8969 has a Stoichiometric coefficient of 1 TLR6/2 ligand:CD14:CD36 Reactome DB_ID: 2559461 Reactome Database ID Release 432559461 Reactome, http://www.reactome.org ReactomeREACT_150804 has a Stoichiometric coefficient of 1 PC is hydrolyzed to 1-acyl LPC by PLA2[5] At the endoplasmic reticulum (ER) membrane, phosphatidylcholine (PC) is hydrolyzed and has one of its acyl chains cleaved off by a phospholipase A2 to form 1-acyl lysophosphatidylcholine (LPC). The phospholipases are either cytosolic phospholipase A2 alpha/beta/delta/zeta (PLA2G4A/B/D/F) (Ghomashchi et al. 2010, Clarke et al. 1991, Sharp et al. 1994, Song et al. 1999, Chiba et al. 2004), 85 kDa calcium-independent phospholipase A2 (PLA2G6) (Larsson et al. 1998, Ma et al. 1999, Larsson Forsell et al. 1999), group XVI phospholipase A2 (PLA2G16) (Duncan et al. 2008), or Phospholipase B-like 1 (PLBD1) (Xu et al. 2009). PLBD1 acts as a phospholipase A2 but in addition has the propensity to hydrolyze the lysophospholipid formed in its initial reaction. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10085124 Pubmed10092647 Pubmed10336645 Pubmed10358058 Pubmed14709560 Pubmed15944408 Pubmed18614531 Pubmed19019078 Pubmed1904318 Pubmed19501189 Pubmed20705608 Pubmed8083230 Pubmed9417066 Pubmed9705332 Reactome Database ID Release 431482856 Reactome, http://www.reactome.org ReactomeREACT_120953 linear duplex viral DNA Reactome DB_ID: 175420 Reactome Database ID Release 43175420 Reactome, http://www.reactome.org ReactomeREACT_9244 has a Stoichiometric coefficient of 1 MyD88:Mal complexed with the activated TLR Reactome DB_ID: 166062 Reactome Database ID Release 43166062 Reactome, http://www.reactome.org ReactomeREACT_7694 has a Stoichiometric coefficient of 1 PC is hydrolyzed to 1-acyl LPC by PLA2[6] At the endoplasmic reticulum (ER) membrane, phosphatidylcholine (PC) is hydrolyzed, and has one of its acyl chains cleaved off, by a membrane-associated phospholipase A2 to form 1-acyl lysophosphatidylcholine (LPC). The phospholipases are either phospholipase A2 group II alpha (PLA2G2A) (Seihamer et al. 1989, Singer et al. 2002), cytosolic phospholipase A2 group IV gamma (PLA2G4C) (Yamashita et al. 2005, Pickard et al. 1999, Ghomashchi et al. 2010, Yamashita et al. 2009), or calcium-independent phospholipase A2-gamma (PNPLA8) (Murakami et al. 2005, Underwood et al. 1998). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10085124 Pubmed12359733 Pubmed15695510 Pubmed15944408 Pubmed19501189 Pubmed20705608 Pubmed2925608 Pubmed9705332 Reactome Database ID Release 431482816 Reactome, http://www.reactome.org ReactomeREACT_121263 PIC (PreIntegration Complex) Reactome DB_ID: 175143 Reactome Database ID Release 43175143 Reactome, http://www.reactome.org ReactomeREACT_9179 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 oligo-MyD88:Mal:activated TLR Reactome DB_ID: 937033 Reactome Database ID Release 43937033 Reactome, http://www.reactome.org ReactomeREACT_26196 has a Stoichiometric coefficient of 1 E2 enzymes UbcH8/UBE1L Converted from EntitySet in Reactome Reactome DB_ID: 936554 Reactome Database ID Release 43936554 Reactome, http://www.reactome.org ReactomeREACT_26406 PC:PITPNB is transported from the Golgi membrane to the ER membrane Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed18636990 Pubmed20332109 Reactome Database ID Release 431483211 Reactome, http://www.reactome.org ReactomeREACT_121375 Reviewed: Wakelam, Michael, 2012-05-14 The complex between phosphatidylcholine (PC) and phosphatidylinositol transfer protein beta isoform (PITPNB) transports from the Golgi membrane to the ER membrane (Carvou et al. 2010, Shadan et al. 2008). RTC with duplex DNA containing discontinuous plus strand flap Reactome DB_ID: 188560 Reactome Database ID Release 43188560 Reactome, http://www.reactome.org ReactomeREACT_9261 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 MAL:BTK:activated TLR2/4 Reactome DB_ID: 2201331 Reactome Database ID Release 432201331 Reactome, http://www.reactome.org ReactomeREACT_124673 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PC is exchanged with PI by PITPNB At the ER membrane, phosphatidylcholine (PC) is exchanged for phosphatidylinositol (PI) within the phosphatidylinositol transfer protein beta isoform (PITPNB) complex (Tilley et al. 2004, Yolder et al. 2001, Carvou et al. 2010, Schouten et al. 2002, Vordtriede et al. 2005, Shadan et al. 2008). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed11104777 Pubmed11980708 Pubmed14962392 Pubmed16274224 Pubmed18636990 Pubmed20332109 Reactome Database ID Release 431483219 Reactome, http://www.reactome.org ReactomeREACT_121312 Reviewed: Wakelam, Michael, 2012-05-14 RTC with integration competent viral DNA Reactome DB_ID: 175254 Reactome Database ID Release 43175254 Reactome, http://www.reactome.org ReactomeREACT_9124 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 activated TLR2/4:p-4Y-MAL:BTK Reactome DB_ID: 2201325 Reactome Database ID Release 432201325 Reactome, http://www.reactome.org ReactomeREACT_125282 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PC is hydrolyzed to 2-acyl LPC by PLA2G4C At the endoplasmic reticulum (ER) membrane, phosphatidylcholine (PC) is hydrolyzed, and has one of its acyl chains cleaved off, by membrane-associated phospholipase A2 gamma 4C, PLA2G4C (Yamashita et al. 2005, Ghomashchi et al. 2010, Yamashita et al. 2009), to form 2-acyl lysophosphatidylcholine (LPC). Cytosolic phospholipase A2 enzymes show not only PLA2 hydrolysing activity to form the 1-acyl lysophospholipid but also have a degree of PLA1 activity, producing a 2-acyl lysophospholipid. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.32 Edited: Williams, MG, 2011-08-12 Pubmed15944408 Pubmed19501189 Pubmed20705608 Reactome Database ID Release 431482827 Reactome, http://www.reactome.org ReactomeREACT_121088 IN bound to sticky 3' ends of viral DNA in PIC Reactome DB_ID: 177526 Reactome Database ID Release 43177526 Reactome, http://www.reactome.org ReactomeREACT_8354 has a Stoichiometric coefficient of 1 IN bound to sticky 3' ends of viral DNA Reactome DB_ID: 177528 Reactome Database ID Release 43177528 Reactome, http://www.reactome.org ReactomeREACT_8401 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 1-acyl LPC is acylated to PC by LPCAT At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferases acylate 1-acyl lysophosphatidylcholine (LPC) to form phosphatidylcholine (PC). The lysophospholipid acyltransferases involved are: lysophosphatidylcholine acyltransferase 1 (LPCAT1) (Nakanishi et al. 2006, Chen et al. 2006); lysophosphatidylcholine acyltransferase 2 (LPCAT2) (Shindou et al. 2006); lysophospholipid acyltransferase 5 (LPCAT3) (Hishikawa et al. 2008, Zhao et al. 2008, Gijon et al. 2008, Jain et al. 2009, Kazachkov et al. 2008); lysophospholipid acyltransferase LPCAT4 (LPCAT4) aka LPEAT2 (Cao et al. 2008, Ye et al. 2005); or lysophospholipid acyltransferase 2 (MBOAT2) aka LPCAT4 (Hishikawa et al. 2008, Gijon et al. 2008). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.51 Edited: Williams, MG, 2011-08-12 Pubmed16243729 Pubmed16704971 Pubmed16864775 Pubmed17182612 Pubmed18195019 Pubmed18458083 Pubmed18772128 Reactome Database ID Release 431482547 Reactome, http://www.reactome.org ReactomeREACT_120746 viral DNA bound with Integrase in PIC Reactome DB_ID: 177532 Reactome Database ID Release 43177532 Reactome, http://www.reactome.org ReactomeREACT_9078 has a Stoichiometric coefficient of 1 PC is hydrolysed to 2-acyl LPC by PLA2[7] At the endoplasmic reticulum (ER) membrane, phosphatidylcholine (PC) is hydrolysed, and has one of its acyl chains cleaved off, by cytosolic phospholipase A2 alpha/beta/delta/epsilon/zeta (PLA2G4A/B/D/E/F) (Ghomashchi et al. 2010). This produces 2-acyl lysophosphatidylcholine (LPC). Cytosolic phospholipase A2 enzymes show not only PLA2 hydrolysing activity to form the 1-acyl lysophospholipid but also have a degree of PLA1 activity, producing a 2-acyl lysophospholipid. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.32 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482862 Reactome, http://www.reactome.org ReactomeREACT_120738 viral DNA bound with Integrase Reactome DB_ID: 177545 Reactome Database ID Release 43177545 Reactome, http://www.reactome.org ReactomeREACT_9348 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Fibronectin matrix Reactome DB_ID: 2327729 Reactome Database ID Release 432327729 Reactome, http://www.reactome.org ReactomeREACT_152362 MFAP2, MFAP5 Converted from EntitySet in Reactome Reactome DB_ID: 2396477 Reactome Database ID Release 432396477 Reactome, http://www.reactome.org ReactomeREACT_151008 RTC with extending second-strand DNA Reactome DB_ID: 182880 Reactome Database ID Release 43182880 Reactome, http://www.reactome.org ReactomeREACT_9199 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Emilin-2 polymer Reactome DB_ID: 2161398 Reactome Database ID Release 432161398 Reactome, http://www.reactome.org ReactomeREACT_150473 PI is exchanged with PC by PITPNB At the Golgi membrane, phosphatidylinositol (PI) is exchanged for phosphatidylcholine (PC) within the phosphatidylinositol transfer protein beta isoform (PITPNB) complex (Tilley et al. 2004, Yolder et al. 2001, Carvou et al. 2010, Schouten et al. 2002, Vordtriede et al. 2005, Shadan et al. 2008). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed11104777 Pubmed11980708 Pubmed14962392 Pubmed16274224 Pubmed18636990 Pubmed20332109 Reactome Database ID Release 431483087 Reactome, http://www.reactome.org ReactomeREACT_121231 Reviewed: Wakelam, Michael, 2012-05-14 Emilin-3 polymer Reactome DB_ID: 2161347 Reactome Database ID Release 432161347 Reactome, http://www.reactome.org ReactomeREACT_151713 PI:PITPNB is transported from the ER membrane to the Golgi membrane Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed18636990 Pubmed20332109 Reactome Database ID Release 431483229 Reactome, http://www.reactome.org ReactomeREACT_121349 Reviewed: Wakelam, Michael, 2012-05-14 The phosphatidylinositol transfer protein beta isoform (PITPNB) bound to phosphatidylinositol (PI) complex transports from the endoplasmic reticulum (ER) membrane to the Golgi membrane (Carvou et al. 2010, Shadan et al. 2008). FBLN1, FBLN2 Converted from EntitySet in Reactome Reactome DB_ID: 2537674 Reactome Database ID Release 432537674 Reactome, http://www.reactome.org ReactomeREACT_152060 Emilins Converted from EntitySet in Reactome Reactome DB_ID: 2161303 Reactome Database ID Release 432161303 Reactome, http://www.reactome.org ReactomeREACT_151297 CDP-Cho and DAG are converted to PC by CHPT1 at the Golgi membrane At the Golgi membrane, cholinephosphotransferase 1 (CHPT1) converts CDP-choline (CDP-Cho) and diacylglycerol (DAG) to phosphatidylcholine (PC) and cytidine monophosphate (CMP) (Wright et al. 2002, Henneberry et al. 1999, Henneberry et al. 2002, Henneberry et al. 2000). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.8.2 Edited: Williams, MG, 2011-08-12 Pubmed10191259 Pubmed10893425 Pubmed12216837 Pubmed12221122 Reactome Database ID Release 431482973 Reactome, http://www.reactome.org ReactomeREACT_120834 RIG-I E3 ubiquitin ligases Converted from EntitySet in Reactome Reactome DB_ID: 936435 Reactome Database ID Release 43936435 Reactome, http://www.reactome.org ReactomeREACT_25644 Emilin-1 polymer Reactome DB_ID: 2161354 Reactome Database ID Release 432161354 Reactome, http://www.reactome.org ReactomeREACT_151615 Unidentified protease Reactome DB_ID: 428470 Reactome Database ID Release 43428470 Reactome, http://www.reactome.org ReactomeREACT_19522 unknown protein Reactome DB_ID: 555063 Reactome Database ID Release 43555063 Reactome, http://www.reactome.org ReactomeREACT_22919 Polysialic acid Reactome DB_ID: 422427 Reactome Database ID Release 43422427 Reactome, http://www.reactome.org ReactomeREACT_18892 T- and L-type VDCC Converted from EntitySet in Reactome Reactome DB_ID: 525824 Reactome Database ID Release 43525824 Reactome, http://www.reactome.org ReactomeREACT_21538 Na+/K+ channel subunits Converted from EntitySet in Reactome Reactome DB_ID: 443633 Reactome Database ID Release 43443633 Reactome, http://www.reactome.org ReactomeREACT_23061 HIV-1 transcription complex containing 4-9 nucleotide long transcript Reactome DB_ID: 167471 Reactome Database ID Release 43167471 Reactome, http://www.reactome.org ReactomeREACT_6563 has a Stoichiometric coefficient of 1 IRAK2:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR Reactome DB_ID: 937028 Reactome Database ID Release 43937028 Reactome, http://www.reactome.org ReactomeREACT_26069 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 HIV-1 transcription complex containing 11 nucleotide long transcript Reactome DB_ID: 167132 Reactome Database ID Release 43167132 Reactome, http://www.reactome.org ReactomeREACT_6664 has a Stoichiometric coefficient of 1 p-IRAK2:p-IRAK4:oligo-MyD88:Mal:activated TLR Reactome DB_ID: 937055 Reactome Database ID Release 43937055 Reactome, http://www.reactome.org ReactomeREACT_26900 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 HIV-1 transcription complex containing transcript to +30 Reactome DB_ID: 167120 Reactome Database ID Release 43167120 Reactome, http://www.reactome.org ReactomeREACT_6514 has a Stoichiometric coefficient of 1 IRAK1:p-S,2T-IRAK4 :oligo-MyD88:Mal:activated TLR Reactome DB_ID: 937018 Reactome Database ID Release 43937018 Reactome, http://www.reactome.org ReactomeREACT_26684 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 HIV-1 transcription complex containing extruded transcript to +30 Reactome DB_ID: 167102 Reactome Database ID Release 43167102 Reactome, http://www.reactome.org ReactomeREACT_6516 has a Stoichiometric coefficient of 1 p-IRAK1:p-IRAK4:oligo-MyD88:Mal:activated TLR Reactome DB_ID: 166118 Reactome Database ID Release 43166118 Reactome, http://www.reactome.org ReactomeREACT_7256 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 IRAK4:oligo-MyD88:Mal:activated TLR Reactome DB_ID: 166080 Reactome Database ID Release 43166080 Reactome, http://www.reactome.org ReactomeREACT_7025 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR receptor Reactome DB_ID: 937048 Reactome Database ID Release 43937048 Reactome, http://www.reactome.org ReactomeREACT_26813 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 HIV-1 transcription complex containing 9 nucleotide long transcript Reactome DB_ID: 167100 Reactome Database ID Release 43167100 Reactome, http://www.reactome.org ReactomeREACT_6561 has a Stoichiometric coefficient of 1 IRAK1/or IRAK2:p-IRAK4:MyD88 oligomer:Mal:activated TLR Reactome DB_ID: 166100 Reactome Database ID Release 43166100 Reactome, http://www.reactome.org ReactomeREACT_7005 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PC is converted to PS by PTDSS1 At the endoplasmic reticulum (ER) membrane, phosphatidylserine synthase 1 (PTDSS1) converts phosphatidylcholine (PC) into phosphatidylserine (PS) by facilitating the exchange of L-Serine (L-Ser) with the choline (Cho) head group (Saito et al. 1998, Tomohiro et al. 2009). Authored: Williams, MG, 2011-09-14 EC Number: 2 Edited: Williams, MG, 2011-08-12 Pubmed19014349 Pubmed9642289 Reactome Database ID Release 431483186 Reactome, http://www.reactome.org ReactomeREACT_120730 HIV-1 capped pre-mRNA:CBC:RNA Pol II (phosphorylated) complex Reactome DB_ID: 167080 Reactome Database ID Release 43167080 Reactome, http://www.reactome.org ReactomeREACT_6374 has a Stoichiometric coefficient of 1 PE is converted to PS by PTDSS2 At the endoplasmic reticulum (ER) membrane, phosphatidylserine synthase 2 (PTDSS2) converts phosphatidylethanolamine (PE) into phosphatidylserine (PS) by facilitating the exchange of L-Serine (L-Ser) with the ethanolamine (ETA) head group (Saito et al. 1998, Tomohiro et al. 2009). Authored: Williams, MG, 2011-09-14 EC Number: 2 Edited: Williams, MG, 2011-08-12 Pubmed19014349 Pubmed9642289 Reactome Database ID Release 431483089 Reactome, http://www.reactome.org ReactomeREACT_121084 1-acyl LPC is hydrolyzed to GPCho by PLA2G4C At the endoplasmic reticulum (ER) membrane, 1-acyl lysophosphatidylcholine (LPC) is hydrolyzed to glycerophosphocholine (GPCho) by membrane-bound cytosolic phospholipase A2 gamma (PLA2G4C) (Yamashita et al. 2005, Ghomashchi et al. 2010, Yamashita et al. 2009). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.5 Edited: Williams, MG, 2011-08-12 Pubmed15944408 Pubmed19501189 Pubmed20705608 Reactome Database ID Release 431482696 Reactome, http://www.reactome.org ReactomeREACT_121033 HIV-1 transcription complex with (ser5) phosphorylated CTD containing extruded transcript to +30 Reactome DB_ID: 167127 Reactome Database ID Release 43167127 Reactome, http://www.reactome.org ReactomeREACT_6638 has a Stoichiometric coefficient of 1 pp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLR Reactome DB_ID: 166281 Reactome Database ID Release 43166281 Reactome, http://www.reactome.org ReactomeREACT_7283 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 2-acyl LPC is hydrolyzed to GPCho by PLA2[8] At the endoplasmic reticulum (ER) membrane, 2-acyl lysophosphatidylcholine (LPC) is hydrolyzed to glycerophosphocholine (GPCho) by cytosolic phospholipase A2 alpha/beta/delta/epsilon/zeta (PLA2G4A/B/D/E/F) (Yamashita et al. 2005, Ghomashchi et al. 2010, Yamashita et al. 2009, Sharp et al. 1994) or by Phospholipase B1-like (PLBD1) (Xu et al. 2009). PLBD1 also acts as a phospholipase A2 but in addition has the propensity to hydrolyze the lysophospholipid formed in its initial reaction. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.5 Edited: Williams, MG, 2011-08-12 Pubmed15944408 Pubmed19019078 Pubmed19501189 Pubmed20705608 Pubmed8083230 Reactome Database ID Release 431482612 Reactome, http://www.reactome.org ReactomeREACT_121224 RNA Pol II with phosphorylated CTD: CE complex Reactome DB_ID: 167107 Reactome Database ID Release 43167107 Reactome, http://www.reactome.org ReactomeREACT_6521 has a Stoichiometric coefficient of 1 p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:Mal:activated TLR Reactome DB_ID: 166360 Reactome Database ID Release 43166360 Reactome, http://www.reactome.org ReactomeREACT_7712 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 2-acyl LPC is hydrolyzed to GPCho by PLA2G4C At the endoplasmic reticulum (ER) membrane, 2-acyl lysophosphatidylcholine (LPC) is hydrolyzed to glycerophosphocholine (GPCho) by membrane-bound cytosolic phospholipase A2 gamma (PLA2G4C) (Yamashita et al. 2005, Ghomashchi et al. 2010, Yamashita et al. 2009). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.5 Edited: Williams, MG, 2011-08-12 Pubmed15944408 Pubmed19501189 Pubmed20705608 Reactome Database ID Release 431482629 Reactome, http://www.reactome.org ReactomeREACT_120840 RNA Pol II with phosphorylated CTD: CE complex with activated GT Reactome DB_ID: 167123 Reactome Database ID Release 43167123 Reactome, http://www.reactome.org ReactomeREACT_6659 has a Stoichiometric coefficient of 1 TRAF6:hp-IRAK1:p-IRAK4:oligo-MyD88 :Mal:activated TLR Reactome DB_ID: 937053 Reactome Database ID Release 43937053 Reactome, http://www.reactome.org ReactomeREACT_25704 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 p38 MAPK Converted from EntitySet in Reactome Reactome DB_ID: 1250102 Reactome Database ID Release 431250102 Reactome, http://www.reactome.org ReactomeREACT_75997 GPCho is hydrolyzed to Cho and G3P by GPCPD1 Authored: Williams, MG, 2011-09-14 EC Number: 3.1.4.46 Edited: Williams, MG, 2011-08-12 In the cytosol, glycerophosphocholine phosphodiesterase (GPCPD1, also known as GDE5) hydrolyzes glycerophosphocholine (GPCho) to produce choline (Cho) and glycerol-3-phosphate (G3P). This event has been inferred from mice. GPCPD1 has also been characterized in humans (Ota et al. 2004). Pubmed14702039 Reactome Database ID Release 431483116 Reactome, http://www.reactome.org ReactomeREACT_121190 CE:Pol II CTD:Spt5 complex Reactome DB_ID: 167139 Reactome Database ID Release 43167139 Reactome, http://www.reactome.org ReactomeREACT_6491 has a Stoichiometric coefficient of 1 FoxO3a-binding Element DNA Containing a FoxO3a-binding Element Reactome DB_ID: 1535904 Reactome Database ID Release 431535904 Reactome, http://www.reactome.org ReactomeREACT_111770 PC is hydrolyzed to 1-acyl LPC by PLA2[16] At the plasma membrane, phosphatidylcholine (PC) is hydrolyzed, removing one of its acyl groups, to 1-acyl lysophosphatidylcholine (LPC) by secretory phospholipase A2 proteins (Singer et al. 2002, Ishizaki et al. 1999). These include: Group IB (PLA2G1B) (Grataroli et al. 1982); Group IIA (PLA2G2A) (Seilhamer et al. 1989); Group IID (PLA2G2D) (Ishizaki et al. 1999); Group IIE (PLA2G2E) (Suzuki et al. 2000); Group IIF (PLA2G2F) (Valentin et al. 2000); Group III (PLA2G3) (Murakami et al. 2003, Murakami et al. 2005); Calcium-dependent Group V (PLA2G5) (Chen et al. 1994); Group X (PLA2G10) (Cupillard et al. 1997, Pan et al. 2002); and Group XIIA (PLA2G12A) (Gelb et al. 2000, Murakami et al. 2003). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10455175 Pubmed10681567 Pubmed11031251 Pubmed11112443 Pubmed12161451 Pubmed12359733 Pubmed12522102 Pubmed15863501 Pubmed2925608 Pubmed7060561 Pubmed8300559 Pubmed9188469 Reactome Database ID Release 431602417 Reactome, http://www.reactome.org ReactomeREACT_120974 Phospho-p38 MAPK Converted from EntitySet in Reactome Reactome DB_ID: 1250100 Reactome Database ID Release 431250100 Reactome, http://www.reactome.org ReactomeREACT_76698 Coatomer:Arf1-GTP:GAP Lattice Reactome DB_ID: 200455 Reactome Database ID Release 43200455 Reactome, http://www.reactome.org ReactomeREACT_11353 2-acyl LPC is acylated to PC by LPCAT At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferases acylate 2-acyl lysophosphatidylcholine (LPC) to form phosphatidylcholine (PC). The lysophospholipid acyltransferases involved are: lysophosphatidylcholine acyltransferase 1 (LPCAT1) (Nakanishi et al. 2006, Chen et al. 2006); lysophosphatidylcholine acyltransferase 2 (LPCAT2) (Shindou et al. 2006); lysophospholipid acyltransferase 5 (LPCAT3) (Hishikawa et al. 2008, Zhao et al. 2008, Gijon et al. 2008, Jain et al. 2009, Kazachkov et al. 2008); lysophospholipid acyltransferase LPCAT4 (LPCAT4) aka LPEAT2 (Cao et al. 2008, Ye et al. 2005); or lysophospholipid acyltransferase 2 (MBOAT2) aka LPCAT4 (Hishikawa et al. 2008, Gijon et al. 2008). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.52 Edited: Williams, MG, 2011-08-12 Pubmed16243729 Pubmed16704971 Pubmed16864775 Pubmed17182612 Pubmed18195019 Pubmed18458083 Pubmed18772128 Reactome Database ID Release 431482533 Reactome, http://www.reactome.org ReactomeREACT_120871 Coatomer:GAP Lattice Reactome DB_ID: 200531 Reactome Database ID Release 43200531 Reactome, http://www.reactome.org ReactomeREACT_11478 1-acyl LPC is hydrolyzed to GPCho by PLA2[8] At the endoplasmic reticulum (ER) membrane, 1-acyl lysophosphatidylcholine (LPC) is hydrolyzed to glycerophosphocholine (GPCho) by cytosolic phospholipase A2 alpha/beta/delta/epsilon/zeta (PLA2G4A/B/D/E/F) (Yamashita et al. 2005, Ghomashchi et al. 2010, Yamashita et al. 2009, Sharp et al. 1994) or by Phospholipase B1-like (PLBD1) (Xu et al. 2009). PLBD1 also acts as a phospholipase A2 but in addition has the propensity to hydrolyze the lysophospholipid formed in its initial reaction. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.5 Edited: Williams, MG, 2011-08-12 Pubmed15944408 Pubmed19019078 Pubmed19501189 Pubmed20705608 Pubmed8083230 Reactome Database ID Release 431482685 Reactome, http://www.reactome.org ReactomeREACT_120985 Coatomer:GAP Lattice Reactome DB_ID: 200465 Reactome Database ID Release 43200465 Reactome, http://www.reactome.org ReactomeREACT_11929 PC is hydrolyzed to 1-acyl LPC by PLB1 At the plasma membrane, phosphatidylcholine (PC) is hydrolyzed, removing one of its acyl groups, to 1-acyl lysophosphatidylcholine (LPC) by membrane-associated phospholipase B1 (PLB1) (Maury et al. 2002, Gassama-Diagne et al. 1992). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed12150957 Pubmed1618844 Reactome Database ID Release 431602399 Reactome, http://www.reactome.org ReactomeREACT_120933 unidentified protein tyrosine kinase Reactome DB_ID: 445025 Reactome Database ID Release 43445025 Reactome, http://www.reactome.org ReactomeREACT_22532 NLRP3 elicitor proteins Converted from EntitySet in Reactome Reactome DB_ID: 1306880 Reactome Database ID Release 431306880 Reactome, http://www.reactome.org ReactomeREACT_76223 phospho-E proteins Converted from EntitySet in Reactome Reactome DB_ID: 448867 Reactome Database ID Release 43448867 Reactome, http://www.reactome.org ReactomeREACT_21977 Cleaved collagen alpha-1(XXV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2473554 Reactome Database ID Release 432473554 Reactome, http://www.reactome.org ReactomeREACT_150688 Coatomer:Arf1-GDP:GAP Lattice Reactome DB_ID: 200457 Reactome Database ID Release 43200457 Reactome, http://www.reactome.org ReactomeREACT_11944 Golgi-associated vesicle interacting proteins Converted from EntitySet in Reactome Reactome DB_ID: 434351 Reactome Database ID Release 43434351 Reactome, http://www.reactome.org ReactomeREACT_20153 Clathrin light chain Converted from EntitySet in Reactome Reactome DB_ID: 196030 Reactome Database ID Release 43196030 Reactome, http://www.reactome.org ReactomeREACT_10527 Clathrin heavy chain Converted from EntitySet in Reactome Reactome DB_ID: 196032 Reactome Database ID Release 43196032 Reactome, http://www.reactome.org ReactomeREACT_10738 HIV-1 promoter:TFIID complex Reactome DB_ID: 167094 Reactome Database ID Release 43167094 Reactome, http://www.reactome.org ReactomeREACT_6369 has a Stoichiometric coefficient of 1 HIV-1 open pre-initiation complex Reactome DB_ID: 167137 Reactome Database ID Release 43167137 Reactome, http://www.reactome.org ReactomeREACT_6605 has a Stoichiometric coefficient of 1 HIV-1 promoter:TFIID:TFIIA:TFIIB:Pol II:TFIIF complex* Reactome DB_ID: 167093 Reactome Database ID Release 43167093 Reactome, http://www.reactome.org ReactomeREACT_6371 has a Stoichiometric coefficient of 1 HIV-1 promoter:TFIID:TFIIA:TFIIB complex Reactome DB_ID: 167104 Reactome Database ID Release 43167104 Reactome, http://www.reactome.org ReactomeREACT_6531 has a Stoichiometric coefficient of 1 PI is hydrolyzed to 1-acyl LPI by PLA2[12] At the endoplasmic reticulum (ER) membrane, phosphatidylinositol (PI) is hydrolyzed, and has one of its acyl chains cleaved off, by membrane-associated phospholipase A2 gamma 2A (PLA2G2A) (Singer et al. 2002) or by cytosolic phospholipase A2 gamma (PLA2G4C) (Ghomashchi et al. 2010), to form 1-acyl lysophosphatidylinositol (LPI). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed12359733 Pubmed20705608 Reactome Database ID Release 431482868 Reactome, http://www.reactome.org ReactomeREACT_120824 HIV-1 transcription complex containing 4 nucleotide long transcript Reactome DB_ID: 167124 Reactome Database ID Release 43167124 Reactome, http://www.reactome.org ReactomeREACT_6640 has a Stoichiometric coefficient of 1 HIV-1 Promoter Escape Complex Reactome DB_ID: 167472 Reactome Database ID Release 43167472 Reactome, http://www.reactome.org ReactomeREACT_6417 has a Stoichiometric coefficient of 1 CDP-DAG is converted to PI by CDIPT At the endoplasmic reticulum (ER) membrane, CDP-diacylglycerol-inositol 3-phosphatidyltransferase (CDIPT) converts cytidine diphosphate-diacylglycerol (CDP-DAG) and inositol (Ins) into phosphatidylinositol (PI) and cytidine monophosphate (CMP) (Lykidis et al. 1997). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.8.11 Edited: Williams, MG, 2011-08-12 Pubmed9407135 Reactome Database ID Release 431482976 Reactome, http://www.reactome.org ReactomeREACT_121059 HIV-1 transcription complex Reactome DB_ID: 167101 Reactome Database ID Release 43167101 Reactome, http://www.reactome.org ReactomeREACT_6433 has a Stoichiometric coefficient of 1 PI is hydrolyzed to 1-acyl LPI by PLA2[11] At the endoplasmic reticulum (ER) membrane, phosphatidylinositol (PI) is hydrolyzed, and has one of its acyl chains cleaved off, by a phospholipase A2 to form 1-acyl lysophosphatidylinositol (LPI). The phospholipases are either cytosolic phospholipase A2 alpha/beta/zeta (PLA2G4A/D/F) (Ghomashchi et al. 2010), group XVI phospholipase A2 (PLA2G16) (Duncan et al. 2008), or Phospholipase B-like 1 (PLBD1) (Xu et al. 2009). PLBD1 also acts as a phospholipase A2 but in addition has the propensity to hydrolyze the lysophospholipid formed in its initial reaction. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed18614531 Pubmed19019078 Pubmed20705608 Reactome Database ID Release 431482825 Reactome, http://www.reactome.org ReactomeREACT_120796 HIV-1 transcription complex containing 3 nucleotide long transcript Reactome DB_ID: 167119 Reactome Database ID Release 43167119 Reactome, http://www.reactome.org ReactomeREACT_6450 has a Stoichiometric coefficient of 1 PS is hydrolyzed to 1-acyl LPS by PLA2[15] At the plasma membrane, phosphatidylserine (PS) is hydrolyzed, removing one of its acyl groups, to 1-acyl lysophosphatidylserine (LPS) by secretory phospholipase A2 proteins (Singer et al. 2002, Ishizaki et al. 1999). These include: Group IB (PLA2G1B) (Grataroli et al. 1982); Group IIA (PLA2G2A) (Seilhamer et al. 1989); Group IID (PLA2G2D) (Ishizaki et al. 1999); Group IIE (PLA2G2E) (Suzuki et al. 2000); Group IIF (PLA2G2F) (Valentin et al. 2000); Calcium-dependent Group V (PLA2G5) (Chen et al. 1994); Group X (PLA2G10) (Cupillard et al. 1997, Pan et al. 2002); and Group XIIA (PLA2G12A) (Gelb et al. 2000, Murakami et al. 2003). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10455175 Pubmed10681567 Pubmed11031251 Pubmed11112443 Pubmed12161451 Pubmed12359733 Pubmed12522102 Pubmed2925608 Pubmed7060561 Pubmed8300559 Pubmed9188469 Reactome Database ID Release 431602374 Reactome, http://www.reactome.org ReactomeREACT_120937 HIV-1 initiation complex Reactome DB_ID: 167129 Reactome Database ID Release 43167129 Reactome, http://www.reactome.org ReactomeREACT_6518 has a Stoichiometric coefficient of 1 PA is converted to CDP-DAG by CDS1 At the endoplasmic reticulum (ER) membrane, phosphatidate cytidylyltransferase 1 (CDS1) converts phosphatidic acid (PA) and cytidine triphosphate (CTP) into cytidine diphosphate-diacylglycerol (CDP-DAG). Both ER and mitochondrial membranes have the capability to synthesize cytidine diphosphate-diacylglycerol (CDP-DAG) with phosphatidate cytidylyltransferase 1 and 2 (CDS1 and CDS2) (Lykidis et al. 1997). However, transport of CDP-DAG between organelles cannot be ruled out (Stuhne-Sekalec et al. 1986). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.7.41 Edited: Williams, MG, 2011-08-12 Pubmed3718705 Pubmed9407135 Reactome Database ID Release 431483121 Reactome, http://www.reactome.org ReactomeREACT_121066 HIV-1 initiation complex with phosphodiester-PPi intermediate Reactome DB_ID: 167106 Reactome Database ID Release 43167106 Reactome, http://www.reactome.org ReactomeREACT_6680 has a Stoichiometric coefficient of 1 Antigen Reactome DB_ID: 173548 Reactome Database ID Release 43173548 Reactome, http://www.reactome.org ReactomeREACT_8485 2-acyl LPS is acylated to PS by LPSAT At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferases acylate 2-acyl lysophosphatidylserine (LPS) to form phosphatidylserine (PS). The lysophospholipid acyltransferases involved are: lysophospholipid acyltransferase 5 (LPCAT3) (Gijon et al. 2008, Hishikawa et al. 2008); lysophospholipid acyltransferase LPCAT4 (LPCAT4) aka LPEAT2 (Cao et al. 2008); or lysophospholipid acyltransferase 1 (MBOAT1) aka LPEAT1 (Hishikawa et al. 2008, Gijon et al. 2008). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.52 Edited: Williams, MG, 2011-08-12 Pubmed18287005 Pubmed18458083 Pubmed18772128 Reactome Database ID Release 431482691 Reactome, http://www.reactome.org ReactomeREACT_121340 Antigen Reactome DB_ID: 983667 Reactome Database ID Release 43983667 Reactome, http://www.reactome.org ReactomeREACT_119525 PS is hydrolyzed to 2-acyl LPS by PLA2[10] At the endoplasmic reticulum (ER) membrane, phosphatidylserine (PS) is hydrolyzed, and has one of its acyl chains cleaved off, by cytosolic phospholipase A2 alpha/delta/zeta (PLA2G4A/D/F) (Ghomashchi et al. 2010). This produces 2-acyl lysophosphatidylserine (LPS). Cytosolic phospholipase A2 enzymes show not only PLA2 hydrolyzing activity to form the 1-acyl lysophospholipid but also have a degree of PLA1 activity, producing a 2-acyl lysophospholipid. Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482897 Reactome, http://www.reactome.org ReactomeREACT_120780 Bcl-2/Bcl-X(L) Converted from EntitySet in Reactome Reactome DB_ID: 879209 Reactome Database ID Release 43879209 Reactome, http://www.reactome.org ReactomeREACT_76436 F-actin Reactome DB_ID: 196174 Reactome Database ID Release 43196174 Reactome, http://www.reactome.org ReactomeREACT_10550 1-acyl LPS is acylated to PS by LPSAT At the endoplasmic reticulum (ER) membrane, lysophospholipid acyltransferases acylate 1-acyl lysophosphatidylserine (LPS) to form phosphatidylserine (PS). The lysophospholipid acyltransferases involved are: lysophospholipid acyltransferase 5 (LPCAT3) (Gijon et al. 2008, Hishikawa et al. 2008); lysophospholipid acyltransferase LPCAT4 (LPCAT4) aka LPEAT2 (Cao et al. 2008); or lysophospholipid acyltransferase 1 (MBOAT1) aka LPEAT1 (Hishikawa et al. 2008, Gijon et al. 2008). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.51 Edited: Williams, MG, 2011-08-12 Pubmed18287005 Pubmed18458083 Pubmed18772128 Reactome Database ID Release 431482636 Reactome, http://www.reactome.org ReactomeREACT_121140 f-actin (ADP) Reactome DB_ID: 202998 Reactome Database ID Release 43202998 Reactome, http://www.reactome.org ReactomeREACT_148010 PS is hydrolyzed to 1-acyl LPS by PLA2G2A At the endoplasmic reticulum (ER) membrane, phosphatidylserine (PS) is hydrolyzed, and has one of its acyl chains cleaved off, by membrane-associated phospholipase A2 gamma 2A, PLA2G2A, to form 1-acyl lysophosphatidylserine (LPS) (Singer et al. 2002). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed12359733 Reactome Database ID Release 431482776 Reactome, http://www.reactome.org ReactomeREACT_121105 Dynamin Converted from EntitySet in Reactome Reactome DB_ID: 196042 Reactome Database ID Release 43196042 Reactome, http://www.reactome.org ReactomeREACT_10614 PS is hydrolyzed to 1-acyl LPS by PLA2[9] At the endoplasmic reticulum (ER) membrane, phosphatidylserine (PS) is hydrolyzed, and has one of its acyl chains cleaved off, by cytosolic phospholipase A2 alpha/beta/delta/epsilon/zeta (PLA2G4A,B,D/E/F) (Ghomashchi et al. 2010), or by group XVI phospholipase A2 (PLA2G16) (Duncan et al. 2008). This produces 1-acyl lysophosphatidylserine (LPS). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed18614531 Pubmed20705608 Reactome Database ID Release 431482771 Reactome, http://www.reactome.org ReactomeREACT_120765 Dynamin Converted from EntitySet in Reactome Reactome DB_ID: 196149 Reactome Database ID Release 43196149 Reactome, http://www.reactome.org ReactomeREACT_10654 Flagellin Converted from EntitySet in Reactome Reactome DB_ID: 874031 Reactome Database ID Release 43874031 Reactome, http://www.reactome.org ReactomeREACT_76632 F-actin Reactome DB_ID: 196015 Reactome Database ID Release 43196015 Reactome, http://www.reactome.org ReactomeREACT_10136 K48-polyubiquitin Lys-48 polyubiquitin Reactome DB_ID: 912740 Reactome Database ID Release 43912740 Reactome, http://www.reactome.org ReactomeREACT_24769 antigenic substrate Reactome DB_ID: 983035 Reactome Database ID Release 43983035 Reactome, http://www.reactome.org ReactomeREACT_76858 misfolded or infective protein E3 ligases in proteasomal degradation Converted from EntitySet in Reactome Reactome DB_ID: 976075 Reactome Database ID Release 43976075 Reactome, http://www.reactome.org ReactomeREACT_76724 Irreversible anti-EGFRplus TKIs Converted from EntitySet in Reactome Irreversible anti-EGFRplus tyrosine kinase inhibitors Reactome DB_ID: 1216531 Reactome Database ID Release 431216531 Reactome, http://www.reactome.org ReactomeREACT_117904 Irreversible EGFR-specific TKIs Converted from EntitySet in Reactome Irreversible EGFR-specific tyrosine kinase inhibitors Reactome DB_ID: 1216530 Reactome Database ID Release 431216530 Reactome, http://www.reactome.org ReactomeREACT_117861 Pro-defensins Converted from EntitySet in Reactome Reactome DB_ID: 1467213 Reactome Database ID Release 431467213 Reactome, http://www.reactome.org ReactomeREACT_117359 Reversible EGFR-specific TKIs Converted from EntitySet in Reactome Reactome DB_ID: 1176053 Reactome Database ID Release 431176053 Reactome, http://www.reactome.org ReactomeREACT_117604 Reversible EGFR-specific tyrosine kinase inhibitors Reversible anti-EGFRplus TKIs Converted from EntitySet in Reactome Reactome DB_ID: 1216525 Reactome Database ID Release 431216525 Reactome, http://www.reactome.org ReactomeREACT_116892 Reversible anti-EGFRplus tyrosine kinase inhibitors Divalent metals transported by NRAMP1 Converted from EntitySet in Reactome Reactome DB_ID: 445829 Reactome Database ID Release 43445829 Reactome, http://www.reactome.org ReactomeREACT_21144 Divalent metals transported by NRAMP1 Converted from EntitySet in Reactome Reactome DB_ID: 445832 Reactome Database ID Release 43445832 Reactome, http://www.reactome.org ReactomeREACT_20962 PA is hydrolyzed to 1-acyl LPA by PLA2[15] At the plasma membrane, phosphatidic acid (PA) is hydrolyzed, removing one of its acyl groups, to 1-acyl lysophosphatidic acid (LPA) by secretory phospholipase A2 proteins (Singer et al. 2002, Ishizaki et al. 1999). These include: Group IB (PLA2G1B) (Grataroli et al. 1982); Group IIA (PLA2G2A) (Seilhamer et al. 1989); Group IID (PLA2G2D) (Ishizaki et al. 1999); Group IIE (PLA2G2E) (Suzuki et al. 2000); Group IIF (PLA2G2F) (Valentin et al. 2000); Calcium-dependent Group V (PLA2G5) (Chen et al. 1994); Group X (PLA2G10) (Cupillard et al. 1997, Pan et al. 2002); and Group XIIA (PLA2G12A) (Gelb et al. 2000, Murakami et al. 2003). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed10455175 Pubmed10681567 Pubmed11031251 Pubmed11112443 Pubmed12161451 Pubmed12359733 Pubmed12522102 Pubmed2925608 Pubmed7060561 Pubmed8300559 Pubmed9188469 Reactome Database ID Release 431602446 Reactome, http://www.reactome.org ReactomeREACT_121397 PC is hydrolyzed to PA and choline by PLD1/2 Authored: Williams, MG, 2011-09-14 EC Number: 3.1.4.4 Edited: Williams, MG, 2011-08-12 Phosphatidylcholine (PC) is hydrolyzed to phosphatidic acid (PA) and choline (Cho) by the enzymes phospholipase D1/2 (PLD1/2), at the endoplasmic reticulum (ER) membrane (Lopez et al. 1998, Hammond et al. 1995). Pubmed8530346 Pubmed9582313 Reactome Database ID Release 431483182 Reactome, http://www.reactome.org ReactomeREACT_121350 DAG is acylated to TAG by DGAT1/2 At the endoplasmic reticulum (ER) membrane, diacylglycerol (DAG) is acylated and forms triacylglycerol (TAG) by the action of diacylglycerol O-acyltransferase 1 (DGAT1) tetramer or by diacylglycerol O-acyltransferase 2 (DGAT2) (Wakimoto et al. 2003, Oelkers et al. 1998, Cases et al. 2001). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.20 Edited: Williams, MG, 2011-08-12 Pubmed11481335 Pubmed14521909 Pubmed9756920 Reactome Database ID Release 431482889 Reactome, http://www.reactome.org ReactomeREACT_121007 TAG is hydrolyzed to DAG by PNPLA2/3 At the endoplasmic reticulum (ER) membrane, triacylglycerol (TAG) is hydrolyzed, removing one of its acyl groups to form diacylglycerol (DAG) by patatin-like phospholipase domain-containing protein 2/3 (PNPLA2/3) (He et al. 2010, Jenkins et al. 2004, Basantani et al. 2011). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.3 Edited: Williams, MG, 2011-08-12 Pubmed15364929 Pubmed20034933 Pubmed21068004 Reactome Database ID Release 431482777 Reactome, http://www.reactome.org ReactomeREACT_121195 G3P is acylated to 1-acyl LPA by GPAM/GPAT2 (OM) Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.15 Edited: Williams, MG, 2011-08-12 Glycerol-3-phosphate (G3P) is acylated to 1-acyl lysophosphatidic acid (LPA) by the enzymes glycerol-3-phosphate acyltransferase 1 (GPAT, also known as GPAM) and glycerol-3-phosphate acyltransferase 2 (GPAT2), at the outer mitochondrial (OM) membrane (Shindou & Shimizu 2009, Chen et al. 2008, Takeuchi & Reue 2009). Pubmed18238778 Pubmed18718904 Pubmed19336658 Reactome Database ID Release 431482695 Reactome, http://www.reactome.org ReactomeREACT_121291 PA is hydrolysed to 1-acyl LPA by PLA2G2A At the endoplasmic reticulum (ER) membrane, phosphatidic acid (PA) is hydrolyzed, and has one of its acyl chains cleaved off, by membrane-associated phospholipase A2 gamma 2A (PLA2G2A), to form 1-acyl lysophosphatidic acid (LPA) (Singer et al. 2002). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed12359733 Reactome Database ID Release 431482679 Reactome, http://www.reactome.org ReactomeREACT_121385 PA is hydrolyzed to 1-acyl LPA by PLA2[1] (OM) At the outer mitochondrial (OM) membrane, phosphatidic acid (PA) is hydrolyzed, and has one of its acyl chains cleaved off, by phospholipase A2 alpha/beta/delta/zeta (PLA2G4A/B/D/F) to form 1-acyl lysophosphatidic acid (LPA) (Ghomashchi et al. 2010). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482604 Reactome, http://www.reactome.org ReactomeREACT_121387 1-acyl LPA is acylated to PA by AGPAT5 (OM) At the outer mitochondrial (OM) membrane, 1-acyl lysophosphatidic acid (LPA) is acylated to phosphatidic acid (PA) by the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferases epsilon (AGPAT5) (Prasad et al. 2011). Authored: Williams, MG, 2011-09-14 EC Number: 2.3.1.51 Edited: Williams, MG, 2011-08-12 Pubmed21173190 Reactome Database ID Release 431482548 Reactome, http://www.reactome.org ReactomeREACT_121245 Pre-pro-defensins Converted from EntitySet in Reactome Reactome DB_ID: 1467262 Reactome Database ID Release 431467262 Reactome, http://www.reactome.org ReactomeREACT_116948 PA is hydrolysed to 1-acyl LPA by PLA2[1] At the endoplasmic reticulum (ER) membrane, phosphatidic acid (PA) is hydrolyzed, and has one of its acyl chains cleaved off, by phospholipase A2 alpha/beta/delta/zeta (PLA2G4A/B/D/F) to form 1-acyl lysophosphatidic acid (LPA) (Ghomashchi et al. 2010). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.4 Edited: Williams, MG, 2011-08-12 Pubmed20705608 Reactome Database ID Release 431482656 Reactome, http://www.reactome.org ReactomeREACT_120842 DHAP is converted to 1-acyl GO3P by GNPAT Authored: Williams, MG, 2011-09-14 Dihydroxyacetone phosphate (DHAP) is converted to 1-acyl glycerone 3-phosphate (GO3P) by the enzyme dihydroxyacetone phosphate acyltransferase (GNPAT) (de Vet et al. 1999, Ofman et al. 1994). This reaction step links Glycerolipid metabolism to Ether lipid metabolism. EC Number: 2.3.1.42 Edited: Williams, MG, 2011-08-12 Pubmed10553003 Pubmed8186247 Reactome Database ID Release 431483002 Reactome, http://www.reactome.org ReactomeREACT_121344 HIV-1 Polymerase II (phosphorylated):TFIIF:capped pre-mRNA Reactome DB_ID: 167088 Reactome Database ID Release 43167088 Reactome, http://www.reactome.org ReactomeREACT_6503 has a Stoichiometric coefficient of 1 RNA Pol II (hypophosphorylated):capped pre-mRNA complex Reactome DB_ID: 167086 Reactome Database ID Release 43167086 Reactome, http://www.reactome.org ReactomeREACT_6382 has a Stoichiometric coefficient of 1 RNA Pol II (hypophosphorylated) complex bound to DSIF protein Reactome DB_ID: 167070 Reactome Database ID Release 43167070 Reactome, http://www.reactome.org ReactomeREACT_6426 has a Stoichiometric coefficient of 1 RDH11 reduces RBP2:atRAL to RBP2:atROL Although the enzyme catalysing retinal reduction in human enterocytes is not identified, the best candidate is retinol dehydrogenase 11 (RDH11, RalR1). It is expressed in the intestine, has a basic pH optimum, and localises to the ER membrane where LRAT catalyses the next step in the pathway. However, RDH11 catalyses retinal reduction to retinol <i>in vitro</i> and uses NADPH as cofactor (Fierce et al. 2008). Authored: Stephan, R, 2010-09-19 EC Number: 1.1.1 Edited: Jassal, B, 2010-10-01 Pubmed18295589 Reactome Database ID Release 43975629 Reactome, http://www.reactome.org ReactomeREACT_25000 Reviewed: D'Eustachio, P, 2010-11-09 BCMO1:Fe2+ oxidises betaC to atRAL As long as vitamin A is needed, beta-carotene-monooxygenase (BCMO1) catalyses the cleavage of carotenes, resulting mainly in retinal (Fierce et al. 2008). Authored: Stephan, R, 2010-09-19 EC Number: 1.14.99.36 Edited: Jassal, B, 2010-10-01 Oxidation of beta-carotene to all-trans-retinal Pubmed18295589 Reactome Database ID Release 43975635 Reactome, http://www.reactome.org ReactomeREACT_25117 Reviewed: D'Eustachio, P, 2010-11-09 has a Stoichiometric coefficient of 2 phospho-NELF complex Reactome DB_ID: 170709 Reactome Database ID Release 43170709 Reactome, http://www.reactome.org ReactomeREACT_6596 has a Stoichiometric coefficient of 1 atROL binds to RBP2 to form RBP2:atROL Authored: Stephan, R, 2010-09-19 Edited: Jassal, B, 2010-10-01 In enterocytes, the dominant retinol-binding protein is RBP2 (CRBPII) which is abundant and binds retinol faster than the cell membrane. So, even though lipophilic retinol can easily enter the cell membrane of bowel enterocytes, it is collected by the abundancy of RBP2 into the enterocyte cytosol where it is further processed (Inagami & Ong 1997). Membrane retinol binds to cytosolic RBP2 Pubmed1542003 Reactome Database ID Release 43975633 Reactome, http://www.reactome.org ReactomeREACT_25146 Reviewed: D'Eustachio, P, 2010-11-09 Tat-containing early elongation complex with hyperphosphorylated Pol II CTD and phospho-NELF Reactome DB_ID: 170707 Reactome Database ID Release 43170707 Reactome, http://www.reactome.org ReactomeREACT_6495 has a Stoichiometric coefficient of 1 PLB1 hydrolyses RPALM to atROL Authored: Stephan, R, 2010-09-19 Cleavage of retinyl palmitate by PLB1 EC Number: 3.1.1.21 Edited: Jassal, B, 2010-10-01 Part of retinol ester hydrolase activity in the small intestine is associated with the brush border membrane but the protein having it is not identified. It is thought to be phospholipase B (Rigtrup et al. 1994). Pubmed8017323 Reactome Database ID Release 43975594 Reactome, http://www.reactome.org ReactomeREACT_25063 Reviewed: D'Eustachio, P, 2010-11-09 Tat-containing early elongation complex with hyperphosphorylated Pol II CTD Reactome DB_ID: 167182 Reactome Database ID Release 43167182 Reactome, http://www.reactome.org ReactomeREACT_6536 has a Stoichiometric coefficient of 1 1,25-dihydroxyvitamin D3 is deactivated Authored: Jassal, B, 2008-10-01 13:18:42 Calcitriol (1,25(OH)2-D3) is biologically inactivated through a series of reactions beginning with 24-hydroxylation and is most likely a mechanism of elimination. 24-Hydroxylation of the vitamin D metabolites is largely regulated inversely to 1-hydroxylation, the initial step towards activation. Edited: Jassal, B, 2008-06-02 10:50:11 Pubmed8506296 Reactome Database ID Release 43209765 Reactome, http://www.reactome.org ReactomeREACT_13667 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Tat:P-TEFb(Cyclin T1:Cdk9) complex Reactome DB_ID: 167237 Reactome Database ID Release 43167237 Reactome, http://www.reactome.org ReactomeREACT_6496 has a Stoichiometric coefficient of 1 Further hydroxylation of calcidiol in kidney to form calcitriol Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.13.13 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed11856765 Pubmed12855575 Reactome Database ID Release 43209868 Reactome, http://www.reactome.org ReactomeREACT_13628 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The second step in vitamin D3 activation requires further hydroxylation of 25-hydroxyvitamin D3 (calcidiol) to 1alpha-25-dihydroxyvitamin D3 (calcitriol). This conversion is mediated by 25-hydroxyvitamin D-1alpha hydroxylase (CYP27B1). P-TEFb(Cyclin T1:Cdk9) complex Reactome DB_ID: 167183 Reactome Database ID Release 43167183 Reactome, http://www.reactome.org ReactomeREACT_6577 has a Stoichiometric coefficient of 1 Vitamin D3 translocates to the cytosol and binds to IDBP Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-06-02 10:50:11 Once out of the lysosome, calcidiol binds to intracellular vitamin D binding protein (IDBP) which facilitates the localization of vitamin D metabolites in the cell. IDBPs are related to the hsc-70 family of heat shock proteins and demonstrate a high nucleotide homology to that family. No IDBP protein has been documented yet so IDBP has not been annotated. Pubmed3037489 Reactome Database ID Release 43209766 Reactome, http://www.reactome.org ReactomeREACT_13792 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Aborted HIV-1 early elongation complex Reactome DB_ID: 167467 Reactome Database ID Release 43167467 Reactome, http://www.reactome.org ReactomeREACT_6695 has a Stoichiometric coefficient of 1 K63-ubiquitin Converted from EntitySet in Reactome Reactome DB_ID: 450143 Reactome Database ID Release 43450143 Reactome, http://www.reactome.org ReactomeREACT_21627 Legumain degrades DBP Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 3.4.22 Edited: Jassal, B, 2008-06-02 10:50:11 Mammalian legumain (asparagine-specific endoprotease) is a subfamily of cysteine proteases with no homology to other known proteases and is found in a wide range of organisms from parasites to plants and animals. Legumain requires acidic conditions for its degradative activity and has strict specificity for cleavage with an asparagine residue in the P1 site. Cubilin, once released from the complex, cycles back to the cell surface. Calcidiol also becomes available for further processing. Pubmed11085925 Pubmed9821970 Reactome Database ID Release 43350158 Reactome, http://www.reactome.org ReactomeREACT_13664 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 DSIF:NELF:early elongation complex Reactome DB_ID: 167078 Reactome Database ID Release 43167078 Reactome, http://www.reactome.org ReactomeREACT_6594 has a Stoichiometric coefficient of 1 DBP:Calcidiol translocates into lysosomes Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-06-02 10:50:11 Pubmed11085925 Pubmed9821970 Reactome Database ID Release 43209760 Reactome, http://www.reactome.org ReactomeREACT_13530 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The internalized complex enters the lysosome where it can be acted upon the protease legumain. HIV-1 elongation complex containing Tat Reactome DB_ID: 167185 Reactome Database ID Release 43167185 Reactome, http://www.reactome.org ReactomeREACT_6611 has a Stoichiometric coefficient of 1 HIV-1 Tat-containing processive elongation complex Reactome DB_ID: 167184 Reactome Database ID Release 43167184 Reactome, http://www.reactome.org ReactomeREACT_6452 has a Stoichiometric coefficient of 1 Tat-containing early elongation complex with hyperphosphorylated Pol II CTD ( phospho-NELF phospho DSIF) Reactome DB_ID: 170710 Reactome Database ID Release 43170710 Reactome, http://www.reactome.org ReactomeREACT_6633 has a Stoichiometric coefficient of 1 phospho-DSIF complex Reactome DB_ID: 170705 Reactome Database ID Release 43170705 Reactome, http://www.reactome.org ReactomeREACT_6628 has a Stoichiometric coefficient of 1 LRAT esterifies RBP2:atROL to atREs Authored: Stephan, R, 2010-09-19 EC Number: 2.3.1.135 Edited: Jassal, B, 2010-10-01 Pubmed16939223 Pubmed9920938 Reactome Database ID Release 43975608 Reactome, http://www.reactome.org ReactomeREACT_25108 Reviewed: D'Eustachio, P, 2010-11-09 Transfer of a fatty acyl residue from lecithin is the main way to esterify all-trans-retinol (atROL). Lecithin is a generic name for yellow-brown fatty substances in animals and tissues. It can be composed of phosphatidylcholines, phosphatidylethanolamines, and phosphatidylinositols. Fatty acyl transfer is catalyzed by Lecithin retinol acyltransferase (LRAT) and takes place near the endoplasmic reticulum membrane. The main fatty acyl moieties that are are substrates for LRAT are palmitoyl, oleoyl, stearoyl and linoleoyl groups present in the A1 position of membrane phosphatidylcholine molecules. LRAT esterifies atROL with these acyl groups to form all-trans-retinyl esters (atREs). The aim is not storage but transport via chylomicrons (Ruiz et al. 1999). P-TEFb(Cyclin T1:Cdk9)-containing elongation complex with separated and uncleaved transcript Reactome DB_ID: 167199 Reactome Database ID Release 43167199 Reactome, http://www.reactome.org ReactomeREACT_6686 has a Stoichiometric coefficient of 1 Tat-containing elongation complex prior to separation Reactome DB_ID: 167193 Reactome Database ID Release 43167193 Reactome, http://www.reactome.org ReactomeREACT_6548 has a Stoichiometric coefficient of 1 Early elongation complex with separated aborted transcript Reactome DB_ID: 170736 Reactome Database ID Release 43170736 Reactome, http://www.reactome.org ReactomeREACT_6590 has a Stoichiometric coefficient of 1 TRAF2 and TRAF6 Converted from EntitySet in Reactome Reactome DB_ID: 918188 Reactome Database ID Release 43918188 Reactome, http://www.reactome.org ReactomeREACT_26063 DSIF:NELF:early elongation complex after limited nucleotide addition Reactome DB_ID: 170726 Reactome Database ID Release 43170726 Reactome, http://www.reactome.org ReactomeREACT_6432 has a Stoichiometric coefficient of 1 HIV-1 arrested processive elongation complex Reactome DB_ID: 167286 Reactome Database ID Release 43167286 Reactome, http://www.reactome.org ReactomeREACT_6609 has a Stoichiometric coefficient of 1 HIV-1 processive elongation complex Reactome DB_ID: 167081 Reactome Database ID Release 43167081 Reactome, http://www.reactome.org ReactomeREACT_6579 has a Stoichiometric coefficient of 1 RIG-I/MDA5 Converted from EntitySet in Reactome Reactome DB_ID: 936436 Reactome Database ID Release 43936436 Reactome, http://www.reactome.org ReactomeREACT_25428 E2 enzyme (UBE2K, UbcH5a-c) Converted from EntitySet in Reactome Reactome DB_ID: 936441 Reactome Database ID Release 43936441 Reactome, http://www.reactome.org ReactomeREACT_26340 HIV-1 aborted elongation complex after arrest Reactome DB_ID: 167482 Reactome Database ID Release 43167482 Reactome, http://www.reactome.org ReactomeREACT_6471 has a Stoichiometric coefficient of 1 HIV-1 early elongation complex with hyperphosphorylated Pol II CTD Reactome DB_ID: 167075 Reactome Database ID Release 43167075 Reactome, http://www.reactome.org ReactomeREACT_6467 has a Stoichiometric coefficient of 1 HIV-1 elongation complex Reactome DB_ID: 167082 Reactome Database ID Release 43167082 Reactome, http://www.reactome.org ReactomeREACT_6501 has a Stoichiometric coefficient of 1 HIV-1 paused processive elongation complex Reactome DB_ID: 167283 Reactome Database ID Release 43167283 Reactome, http://www.reactome.org ReactomeREACT_6459 has a Stoichiometric coefficient of 1 HIV-1 Tat-containing arrested processive elongation complex Reactome DB_ID: 167091 Reactome Database ID Release 43167091 Reactome, http://www.reactome.org ReactomeREACT_6532 has a Stoichiometric coefficient of 1 PETA and CTP are condensed to CDP-ETA by PCY2 At the endoplasmic reticulum (ER) membrane, active membrane-bound ethanolamine-phosphate cytidylyltransferase (PCY2) dimer condenses phosphoethanolamine (PETA) and cytidine triphosphate (CTP) to produce CDP-ethanolamine (CDP-ETA) (Zhu et al. 2008, Nakashima et al. 1997). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.7.14 Edited: Williams, MG, 2011-08-12 Pubmed18583706 Pubmed9083101 Reactome Database ID Release 431483190 Reactome, http://www.reactome.org ReactomeREACT_120845 Rev multimer-bound HIV-1 mRNA Reactome DB_ID: 165532 Reactome Database ID Release 43165532 Reactome, http://www.reactome.org ReactomeREACT_6517 has a Stoichiometric coefficient of 1 PETA is dephosphorylated to ETA by PHOSPHO1 Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 In the cytosol, phosphoethanolamine (PETA) is dephosphorylated to ethanolamine (ETA) by phosphoethanolamine/phosphocholine phosphatase (PHOSPHO1) (Roberts et al. 2004). Pubmed15175005 Reactome Database ID Release 431483096 Reactome, http://www.reactome.org ReactomeREACT_120854 Rev-bound HIV-1 mRNA Reactome DB_ID: 165535 Reactome Database ID Release 43165535 Reactome, http://www.reactome.org ReactomeREACT_6419 has a Stoichiometric coefficient of 1 Collagen type XVII sheddases Converted from EntitySet in Reactome Reactome DB_ID: 2473494 Reactome Database ID Release 432473494 Reactome, http://www.reactome.org ReactomeREACT_150624 ETA is phosphorylated to PETA by CHK/ETNK Authored: Williams, MG, 2011-09-14 EC Number: 2.7.1.82 Edited: Williams, MG, 2011-08-12 In the cytosol, ethanolamine (ETA) is phosphorylated to phosphoethanolamine (PETA) by choline kinase (CHK) dimer or by ethanolamine kinase 1/2 (ETNK1/2) (Lykidis et al. 2001, Gallego-Ortega et al. 2009). CHK dimer consists of either choline kinase alpha subunit (CHKA) or beta subunit (CHKB) homodimer, or of CHKA:CHKB heterodimer. Pubmed11044454 Pubmed19915674 Reactome Database ID Release 431483222 Reactome, http://www.reactome.org ReactomeREACT_121273 HIV-1 Tat-containing paused processive elongation complex Reactome DB_ID: 167071 Reactome Database ID Release 43167071 Reactome, http://www.reactome.org ReactomeREACT_6389 has a Stoichiometric coefficient of 1 2-MAG is hydrolyzed to fatty acid and glycerol by MGLL At the endoplasmic reticulum (ER) membrane, monoglyceride lipase (MGLL) hydrolyzes 2-monoacylglycerol (2-MAG) to form a fatty acid and glycerol (Dinh et al. 2004, Zvonok et al. 2008, Bertrand et al. 2010, Labar et al. 2010). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.23 Edited: Williams, MG, 2011-08-12 Pubmed15272052 Pubmed18452279 Pubmed19957260 Pubmed19962385 Reactome Database ID Release 431482543 Reactome, http://www.reactome.org ReactomeREACT_120753 HIV-1 Tat-containing aborted elongation complex after arrest Reactome DB_ID: 167460 Reactome Database ID Release 43167460 Reactome, http://www.reactome.org ReactomeREACT_6602 has a Stoichiometric coefficient of 1 Collagen alpha-1(XXIII) transmembrane regions Converted from EntitySet in Reactome Reactome DB_ID: 2473515 Reactome Database ID Release 432473515 Reactome, http://www.reactome.org ReactomeREACT_152509 PS transports from the ER membrane to the IM membrane Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed1898727 Pubmed2332429 Reactome Database ID Release 431483170 Reactome, http://www.reactome.org ReactomeREACT_121037 Transport of phosphatidylserine (PS) occurs via membrane contact sites between the endoplasmic reticulum (ER) membrane and the inner mitochondrial (IM) membrane. This event has been inferred from rats (Vance 1990, Vance 1991). CDP-ETA and DAG are converted to PE by CEPT1/EPT1 At the endoplasmic reticulum (ER) membrane, choline/ethanolaminephosphotransferase 1 (CEPT1) or ethanolaminephosphotransferase 1 (EPT1) converts CDP- ethanolamine (CDP-ETA) and diacylglycerol (DAG) to phosphatidylethanolamine (PE) and cytidine monophosphate (CMP) (Horibata et al. 2007, Wright et al. 2002, Henneberry et al. 1999, Henneberry et al. 2002, Henneberry et al. 2000). Authored: Williams, MG, 2011-09-14 EC Number: 2.7.8.1 Edited: Williams, MG, 2011-08-12 Pubmed10191259 Pubmed10893425 Pubmed12216837 Pubmed12221122 Pubmed17132865 Reactome Database ID Release 431482962 Reactome, http://www.reactome.org ReactomeREACT_121214 PA is dephosphorylated to DAG by LPIN At the endoplasmic reticulum (ER) membrane, phosphatidate phosphatase 1-3 (LPIN) dephosphorylates phosphatidic acid (PA) to form diacylglycerol (DAG) (Grimsey et al. 2008, Donkor et al. 2007). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.3.4 Edited: Williams, MG, 2011-08-12 Pubmed17158099 Pubmed18694939 Reactome Database ID Release 431483203 Reactome, http://www.reactome.org ReactomeREACT_120792 Rev multimer-bound HIV-1 mRNA:CRM1 complex Reactome DB_ID: 180873 Reactome Database ID Release 43180873 Reactome, http://www.reactome.org ReactomeREACT_8117 has a Stoichiometric coefficient of 1 Casp-8/10 prodomain Caspase-8/10 prodomains Converted from EntitySet in Reactome Reactome DB_ID: 933462 Reactome Database ID Release 43933462 Reactome, http://www.reactome.org ReactomeREACT_27032 2-MAG and DAG are transacylated to TAG by PNPLA2/3 At the endoplasmic reticulum (ER) membrane, a 2-monoacylglycerol (2-MAG) molecule and a diacylglycerol (DAG) molecule are transacylated by patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3). This forms triacylglycerol (TAG) and glycerol (Jenkins et al. 2004). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed15364929 Reactome Database ID Release 431482647 Reactome, http://www.reactome.org ReactomeREACT_120776 2-MAG is transacylated to DAG by PNPLA2/3 At the endoplasmic reticulum (ER) membrane, two 2-monoacylglycerol (2-MAG) molecules are transacylated by patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3) to form diacylglycerol (DAG) and glycerol (Jenkins et al. 2004). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 Pubmed15364929 Reactome Database ID Release 431482654 Reactome, http://www.reactome.org ReactomeREACT_121144 has a Stoichiometric coefficient of 2 procaspase-8/10 Converted from EntitySet in Reactome Reactome DB_ID: 933463 Reactome Database ID Release 43933463 Reactome, http://www.reactome.org ReactomeREACT_26572 procaspase-8 and procaspase-10 DAG is hydrolyzed to 2-MAG by PNPLA2/3 At the endoplasmic reticulum (ER) membrane, patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3) hydrolyze diacylglycerol (DAG), removing an acyl group to form 2-monoacylglycerol (2-MAG) (He et al. 2010, Jenkins et al. 2004, Basantani et al. 2011). Authored: Williams, MG, 2011-09-14 EC Number: 3.1.1.34 Edited: Williams, MG, 2011-08-12 Pubmed15364929 Pubmed20034933 Pubmed21068004 Reactome Database ID Release 431482811 Reactome, http://www.reactome.org ReactomeREACT_121017 Ran-GDP Reactome DB_ID: 180701 Reactome Database ID Release 43180701 Reactome, http://www.reactome.org ReactomeREACT_9732 has a Stoichiometric coefficient of 1 Rev multimer-bound HIV-1 mRNA:Crm1:Ran:GTP Reactome DB_ID: 165537 Reactome Database ID Release 43165537 Reactome, http://www.reactome.org ReactomeREACT_6601 has a Stoichiometric coefficient of 1 Rev multimer-bound HIV-1 mRNA Reactome DB_ID: 165547 Reactome Database ID Release 43165547 Reactome, http://www.reactome.org ReactomeREACT_6606 has a Stoichiometric coefficient of 1 Rev-bound HIV-1 mRNA Reactome DB_ID: 165551 Reactome Database ID Release 43165551 Reactome, http://www.reactome.org ReactomeREACT_6643 has a Stoichiometric coefficient of 1 Rev multimer-bound HIV-1 mRNA:Crm1:Ran:GTP:NPC Reactome DB_ID: 165531 Reactome Database ID Release 43165531 Reactome, http://www.reactome.org ReactomeREACT_6537 has a Stoichiometric coefficient of 1 Rev multimer-bound HIV-1 mRNA:Crm1:Ran:GTP Reactome DB_ID: 165552 Reactome Database ID Release 43165552 Reactome, http://www.reactome.org ReactomeREACT_6428 has a Stoichiometric coefficient of 1 (GlcNAc)2 (Man)8 glycans Converted from EntitySet in Reactome Reactome DB_ID: 964831 Reactome Database ID Release 43964831 Reactome, http://www.reactome.org ReactomeREACT_26078 TPO:Thrombopoietin receptor Reactome DB_ID: 443940 Reactome Database ID Release 43443940 Reactome, http://www.reactome.org ReactomeREACT_24575 has a Stoichiometric coefficient of 1 CalDAG-GEFs:DAG:Ca2+ Reactome DB_ID: 392841 Reactome Database ID Release 43392841 Reactome, http://www.reactome.org ReactomeREACT_24405 has a Stoichiometric coefficient of 1 Protein kinase C, novel isoforms:DAG Reactome DB_ID: 426071 Reactome Database ID Release 43426071 Reactome, http://www.reactome.org ReactomeREACT_23271 has a Stoichiometric coefficient of 1 Activated conventional protein kinase C Converted from EntitySet in Reactome Reactome DB_ID: 139830 Reactome Database ID Release 43139830 Reactome, http://www.reactome.org ReactomeREACT_4434 Talin:RIAM:ECM ligands:2X (Integrin alphaIIb beta3:Active (p-Y419)-SRC):SYK Reactome DB_ID: 429424 Reactome Database ID Release 43429424 Reactome, http://www.reactome.org ReactomeREACT_24734 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Talin:RIAM:ECM ligands:2X(Integrin alphaIIb beta3:Active (p-Y419)-SRC):p(Y)-SYK Reactome DB_ID: 429434 Reactome Database ID Release 43429434 Reactome, http://www.reactome.org ReactomeREACT_24653 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Alpha-2 adrenoceptor:Catecholamine Reactome DB_ID: 390700 Reactome Database ID Release 43390700 Reactome, http://www.reactome.org ReactomeREACT_17529 has a Stoichiometric coefficient of 1 GP1b-IX-V complex:activated thrombin (factor IIa) Reactome DB_ID: 429532 Reactome Database ID Release 43429532 Reactome, http://www.reactome.org ReactomeREACT_24330 has a Stoichiometric coefficient of 1 Activated PKC alpha Reactome DB_ID: 139828 Reactome Database ID Release 43139828 Reactome, http://www.reactome.org ReactomeREACT_4815 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated PKC beta Reactome DB_ID: 139829 Reactome Database ID Release 43139829 Reactome, http://www.reactome.org ReactomeREACT_4856 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 dNTP Converted from EntitySet in Reactome Reactome DB_ID: 173818 Reactome Database ID Release 43173818 Reactome, http://www.reactome.org ReactomeREACT_9307 PDGF dimer Converted from EntitySet in Reactome Reactome DB_ID: 184202 Reactome Database ID Release 43184202 Reactome, http://www.reactome.org ReactomeREACT_8926 Hepatocyte growth factor Reactome DB_ID: 141763 Reactome Database ID Release 43141763 Reactome, http://www.reactome.org ReactomeREACT_5871 has a Stoichiometric coefficient of 1 PDGF A homodimer Reactome DB_ID: 184203 Reactome Database ID Release 43184203 Reactome, http://www.reactome.org ReactomeREACT_8457 has a Stoichiometric coefficient of 2 PDGF AB heterodimer Reactome DB_ID: 184196 Reactome Database ID Release 43184196 Reactome, http://www.reactome.org ReactomeREACT_8811 has a Stoichiometric coefficient of 1 PDGF B homodimer Reactome DB_ID: 184206 Reactome Database ID Release 43184206 Reactome, http://www.reactome.org ReactomeREACT_8056 has a Stoichiometric coefficient of 2 Insulin-like growth factor Reactome DB_ID: 139880 Reactome Database ID Release 43139880 Reactome, http://www.reactome.org ReactomeREACT_3524 has a Stoichiometric coefficient of 1 Thrombospondin-1 trimer Reactome DB_ID: 265405 Reactome Database ID Release 43265405 Reactome, http://www.reactome.org ReactomeREACT_13859 has a Stoichiometric coefficient of 3 Alpha IIb Beta 3 Integrin Reactome DB_ID: 114513 Reactome Database ID Release 43114513 Reactome, http://www.reactome.org ReactomeREACT_4179 has a Stoichiometric coefficient of 1 TF:F7 Reactome DB_ID: 140775 Reactome Database ID Release 43140775 Reactome, http://www.reactome.org ReactomeREACT_4908 has a Stoichiometric coefficient of 1 tissue factor:factor VII complex factor X Reactome DB_ID: 140739 Reactome Database ID Release 43140739 Reactome, http://www.reactome.org ReactomeREACT_3749 has a Stoichiometric coefficient of 1 Activated PKC gamma Reactome DB_ID: 426343 Reactome Database ID Release 43426343 Reactome, http://www.reactome.org ReactomeREACT_19612 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PDGF dimer Converted from EntitySet in Reactome Reactome DB_ID: 184197 Reactome Database ID Release 43184197 Reactome, http://www.reactome.org ReactomeREACT_8756 PDGF A homodimer Reactome DB_ID: 184195 Reactome Database ID Release 43184195 Reactome, http://www.reactome.org ReactomeREACT_8850 has a Stoichiometric coefficient of 2 fibrinogen Reactome DB_ID: 114617 Reactome Database ID Release 43114617 Reactome, http://www.reactome.org ReactomeREACT_4520 has a Stoichiometric coefficient of 2 Hepatocyte growth factor Reactome DB_ID: 141765 Reactome Database ID Release 43141765 Reactome, http://www.reactome.org ReactomeREACT_5221 has a Stoichiometric coefficient of 1 Insulin-like growth factor Reactome DB_ID: 139879 Reactome Database ID Release 43139879 Reactome, http://www.reactome.org ReactomeREACT_4048 has a Stoichiometric coefficient of 1 Thrombospondin-1 trimer Reactome DB_ID: 549142 Reactome Database ID Release 43549142 Reactome, http://www.reactome.org ReactomeREACT_23242 has a Stoichiometric coefficient of 3 PDGF AB heterodimer Reactome DB_ID: 184198 Reactome Database ID Release 43184198 Reactome, http://www.reactome.org ReactomeREACT_8244 has a Stoichiometric coefficient of 1 PDGF B homodimer Reactome DB_ID: 184204 Reactome Database ID Release 43184204 Reactome, http://www.reactome.org ReactomeREACT_8592 has a Stoichiometric coefficient of 2 Fibrinogen Reactome DB_ID: 114618 Reactome Database ID Release 43114618 Reactome, http://www.reactome.org ReactomeREACT_4095 has a Stoichiometric coefficient of 2 ramiprilat Reactome DB_ID: 2065405 Reactome Database ID Release 432065405 Reactome, http://www.reactome.org ReactomeREACT_148411 Collagen type IV alpha1.alpha1.alpha2 network Reactome DB_ID: 2214294 Reactome Database ID Release 432214294 Reactome, http://www.reactome.org ReactomeREACT_152302 Collagen type IV networks Converted from EntitySet in Reactome Reactome DB_ID: 2564668 Reactome Database ID Release 432564668 Reactome, http://www.reactome.org ReactomeREACT_151427 PI3P is phosphorylated to PI(3,5)P2 by PIP5K1A/B at the plasma membrane At the plasma membrane, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A) and beta (PIP5K1B) phosphorylate phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (Tolias et al. 1998). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.150 Edited: Williams, MG, 2011-08-12 Pubmed9660759 Reactome Database ID Release 431676134 Reactome, http://www.reactome.org ReactomeREACT_121174 Reviewed: Wakelam, Michael, 2012-05-14 Collagen type X network Reactome DB_ID: 2214298 Reactome Database ID Release 432214298 Reactome, http://www.reactome.org ReactomeREACT_150710 Collagen type VIII network Reactome DB_ID: 2214297 Reactome Database ID Release 432214297 Reactome, http://www.reactome.org ReactomeREACT_151970 Collagen type VI network Collagen type VI beaded filament Reactome DB_ID: 2214296 Reactome Database ID Release 432214296 Reactome, http://www.reactome.org ReactomeREACT_150922 Cytosolic Hydroxylation of Asparagine Residue in HIF alpha Authored: May, B, 2011-03-18 EC Number: 1.14.11 Edited: May, B, 2011-03-18 HIF1AN (FIH, FIH-1) catalyzes the hydroxylation of an asparagine residue on each of HIF1A and HIF2A (Hewitson et al. 2002, Lando et al. 2002, Metzen et al. 2003, Lancaster et al. 2004). The reaction requires molecular oxygen as a substrate and is therefore inhibited by hypoxia. Pubmed12042299 Pubmed12080085 Pubmed12615973 Pubmed15239670 Reactome Database ID Release 431234164 Reactome, http://www.reactome.org ReactomeREACT_121198 Reviewed: Rantanen, Krista, 2012-05-19 Dual-specific AKAPs:PKA tetramer Reactome DB_ID: 992693 Reactome Database ID Release 43992693 Reactome, http://www.reactome.org ReactomeREACT_25534 has a Stoichiometric coefficient of 1 Collagen networks Converted from EntitySet in Reactome Reactome DB_ID: 2214293 Reactome Database ID Release 432214293 Reactome, http://www.reactome.org ReactomeREACT_151923 Cytosolic Hydroxylation of Proline Residues on EPAS1 (HIF2A) Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate EPAS1 (HIF2A) at proline-405 and proline-531 (Hirsila et al. 2003, Percy et al. 2008, Furlow et al. 2009). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008). Pubmed12615973 Pubmed12788921 Pubmed18184961 Pubmed18337469 Pubmed19208626 Reactome Database ID Release 431234179 Reactome, http://www.reactome.org ReactomeREACT_120822 Reviewed: Rantanen, Krista, 2012-05-19 has a Stoichiometric coefficient of 2 PKA tetramer Reactome DB_ID: 111922 Reactome Database ID Release 43111922 Reactome, http://www.reactome.org ReactomeREACT_5749 has a Stoichiometric coefficient of 2 Network forming tropocollagens Converted from EntitySet in Reactome Reactome DB_ID: 2213198 Reactome Database ID Release 432213198 Reactome, http://www.reactome.org ReactomeREACT_150924 p53:MYB:SIN3A Reactome DB_ID: 992748 Reactome Database ID Release 43992748 Reactome, http://www.reactome.org ReactomeREACT_26185 has a Stoichiometric coefficient of 1 Collagen type XXVII fibril Reactome DB_ID: 2193157 Reactome Database ID Release 432193157 Reactome, http://www.reactome.org ReactomeREACT_152232 Smad7:SMURF2 binds phosphorylated TGFBR1 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11163210 Reactome Database ID Release 432169043 Reactome, http://www.reactome.org ReactomeREACT_121135 Reviewed: Huang, Tao, 2012-05-14 Smad7 recruits SMURF2 to TGF-beta (TGFB1)-activated TGF-beta receptor complex. In this study, recombinant mouse Smad7 and recombinant human SMURF2, TGFBR2 and TGFBR1 were exogenously expressed in COS1 cells (Kavsak et al. 2000). Mitofusin complex Reactome DB_ID: 992739 Reactome Database ID Release 43992739 Reactome, http://www.reactome.org ReactomeREACT_25928 has a Stoichiometric coefficient of 2 Nuclear Hydroxylation of Proline Residues on EPAS1 (HIF2A) Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus hydroxylate HIF2A (EPAS1) at proline-405 and proline-531 (Hirsila et al. 2003, Percy et al. 2008, Furlow et al. 2009). The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to be cytosolic. Pubmed12615973 Pubmed12788921 Pubmed18184961 Pubmed19208626 Reactome Database ID Release 431234166 Reactome, http://www.reactome.org ReactomeREACT_120885 Reviewed: Rantanen, Krista, 2012-05-19 has a Stoichiometric coefficient of 2 Nuclear Hydroxylation of Proline Residues on HIF1A Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus (Metzen et al. 2003) hydroxylate HIF1A at proline-402 and proline-564 (Buick and McKnight 2001, Jaakkola et al. 2001, Ivan et al. 2001, Ivan et al. 2002, Berra et al. 2003, Hirsila et al. 2003, Appelhoff et al. 2004, Tuckerman et al. 2004, Fedulova et al. 2007, Tian et al. 2011). The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to occur in the cytosol. Pubmed11292861 Pubmed11292862 Pubmed11598268 Pubmed12351678 Pubmed12615973 Pubmed12788921 Pubmed12912907 Pubmed15247232 Pubmed15474027 Pubmed17434750 Pubmed21335549 Reactome Database ID Release 431234181 Reactome, http://www.reactome.org ReactomeREACT_120973 Reviewed: Rantanen, Krista, 2012-05-19 has a Stoichiometric coefficient of 2 Cytosolic Hydroxylation of Proline Residues on HIF1A Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate HIF1A at proline-402 and proline-564 (Bruick and McKnight 2001, Jaakkola et al. 2001, Ivan et al. 2001, Ivan et al. 2002, Berra et al. 2003, Hirsila et al. 2003, Appelhoff et al. 2004, Tuckerman et al. 2004, Fedulova et al. 2007, Tian et al. 2011). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008). Pubmed11292861 Pubmed11292862 Pubmed11598268 Pubmed12351678 Pubmed12615973 Pubmed12788921 Pubmed12912907 Pubmed15247232 Pubmed15474027 Pubmed17434750 Pubmed18337469 Pubmed21335549 Reactome Database ID Release 431234177 Reactome, http://www.reactome.org ReactomeREACT_120825 Reviewed: Rantanen, Krista, 2012-05-19 has a Stoichiometric coefficient of 2 Cytosolic Hydroxylation of Proline Residues on HIF3A Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate HIF3A at proline-492 (Hirsila et al. 2003, Maynard et al. 2003). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008). Pubmed12538644 Pubmed12615973 Pubmed12788921 Pubmed18337469 Reactome Database ID Release 431234173 Reactome, http://www.reactome.org ReactomeREACT_121242 Reviewed: Rantanen, Krista, 2012-05-19 Nuclear VHL:EloB/C:CUL2:RBX1 Complex Binds HIF-alpha Hydroxylated at Proline Residues Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 Pubmed10823831 Pubmed10878807 Pubmed10944113 Pubmed11024059 Pubmed11292861 Pubmed11292862 Pubmed11358837 Pubmed11454738 Pubmed11504942 Pubmed12101228 Pubmed12821933 Pubmed9122164 Reactome Database ID Release 431234169 Reactome, http://www.reactome.org ReactomeREACT_120876 Reviewed: Rantanen, Krista, 2012-05-19 The VHL component of the VHL:ElonginB:ElonginC:CUL2:RBX1 binds HIF-alpha that have hydroxylated proline residues (Cockman et al. 2000, Ohh et al. 2000, Tanimoto et al. 2000, Jaakkola et al. 2001, Ivan et al. 2001, Yu et al. 2001, Bonicalzi et al. 2001). The VHL:HIF-alpha complex is predominantly nuclear (Lewis and Roberts 2003) however binding and degradation of HIF-alpha can also occur in the cytosol (Berra et al. 2001). Nuclear Hydroxylation of Proline Residues on HIF3A Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus (Metzen et al. 2003) hydroxylate HIF3A at proline-492 (Hirsila et al. 2003, Maynard et al. 2003). Note that proline-492 of the reference isoform is proline-490 in isoform 2, the protein cited by Maynard et al. 2003. The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to occur in the cytosol. Pubmed12538644 Pubmed12615973 Pubmed12788921 Reactome Database ID Release 431234165 Reactome, http://www.reactome.org ReactomeREACT_120945 Reviewed: Rantanen, Krista, 2012-05-19 Collagen type IV alpha1.alpha2.alpha5.alpha6 network Reactome DB_ID: 2564665 Reactome Database ID Release 432564665 Reactome, http://www.reactome.org ReactomeREACT_151072 Cytosolic VHL:EloB/C:CUL2:RBX1 Complex Binds HIF-alpha Hydroxylated at Proline Residues Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 Pubmed10823831 Pubmed10878807 Pubmed10944113 Pubmed11292861 Pubmed11292862 Pubmed11358837 Pubmed11454738 Pubmed11504942 Pubmed12821933 Reactome Database ID Release 431234183 Reactome, http://www.reactome.org ReactomeREACT_120795 Reviewed: Rantanen, Krista, 2012-05-19 VHL within the VHL:ElonginB:ElonginC:CUL2:RBX1 Complex binds HIF-alpha subunits that have hydroxylated proline residues (Cockman et al. 2000, Ohh et al. 2000, Tanimoto et al. 2000, Jaakkola et al. 2001, Ivan et al. 2001, Yu et al. 2001). VHL constitutively shuttles between the cytosol and nucleoplasm (Lewis and Roberts 2003) and though the VHL:HIF-alpha complex is predominantly nuclear, binding and degradation can occur in both the cytosol and the nucleus (Berra et al. 2001). PI(3,5)P2 is dephosphorylated to PI3P by FIG4 at the early endosome membrane At the early endosome membrane, the PAS complex, consisting of FYVE finger-containing phosphoinositide kinase (PIKFYVE), yeast VAC14 homologue (VAC14), and polyphosphoinositide phosphatase aka SAC3 (FIG4), binds to the membrane via PIKFYVE's FYVE finger. The FIG4 phosphatase component dephosphorylates phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 3-phosphate (PI3P) (Sbrissa et al. 2007, Sbrissa et al. 2008). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed17556371 Pubmed18950639 Reactome Database ID Release 431676174 Reactome, http://www.reactome.org ReactomeREACT_121095 Reviewed: Wakelam, Michael, 2012-05-14 Collagen type IV alpha3.alpha4.alpha5 network Reactome DB_ID: 2564669 Reactome Database ID Release 432564669 Reactome, http://www.reactome.org ReactomeREACT_151163 PI3P is phosphorylated to PI(3,5)P2 by PIKFYVE at the early endosome membrane At the early endosome membrane, the PAS complex, consisting of FYVE finger-containing phosphoinositide kinase (PIKFYVE), yeast VAC14 homologue (VAC14), and polyphosphoinositide phosphatase aka SAC3 (FIG4), binds to the membrane via PIKFYVE's FYVE finger (Sbrissa et al. 2002, Cao et al. 2007). The PIKFYVE kinase component phosphorylates phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol 3,5-bisphosphate PI(3,5)P2 (Sbrissa et al. 1999). The PAS complex is present in the cytosol and is recruited to the membrane (Sbrissa et al. 2007). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.150 Edited: Williams, MG, 2011-08-12 Pubmed10419465 Pubmed11706043 Pubmed17556371 Pubmed17651088 Reactome Database ID Release 431676168 Reactome, http://www.reactome.org ReactomeREACT_120970 Reviewed: Wakelam, Michael, 2012-05-14 SLC7A9:SLC3A2 heterodimer Reactome DB_ID: 390758 Reactome Database ID Release 43390758 Reactome, http://www.reactome.org ReactomeREACT_17909 has a Stoichiometric coefficient of 1 Collagen type VII fibril Reactome DB_ID: 2214333 Reactome Database ID Release 432214333 Reactome, http://www.reactome.org ReactomeREACT_151190 PI(3,4)P2 is dephosphorylated to PI3P by INPP4A/B at the early endosome membrane At the early endosome membrane, type I (INPP4A) (Norris et al. 1995, Ivetac et al. 2005) and type II inositol-3,4-bisphosphate 4-phosphatase (INPP4B) (Norris et al. 1997) colocalise with early and recycling endosomes through their C2 domains which bind to the phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) present in these membranes. It is here that phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) is dephosphorylated by INPP4A/B to phosphatidylinositol 3-phosphate (PI3P). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.66 Edited: Williams, MG, 2011-08-12 Pubmed15716355 Pubmed7608176 Pubmed9295334 Reactome Database ID Release 431676162 Reactome, http://www.reactome.org ReactomeREACT_120915 Reviewed: Wakelam, Michael, 2012-05-14 Basigin:CD98hc complex Reactome DB_ID: 375086 Reactome Database ID Release 43375086 Reactome, http://www.reactome.org ReactomeREACT_17413 has a Stoichiometric coefficient of 1 PI(3,4)P2 is transported from the plasma membrane to the early endosome membrane Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 In mice, phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) translocates from the plasma membrane to the early endosome membrane (Watt et al. 2004). A similar event has also been detected in cells from <I>Chlorocebus sabaeus</I> (Green Monkey) (Ivetac et al. 2005). In humans this event is inferred from the other two occurrences. Pubmed14604433 Pubmed15716355 Reactome Database ID Release 431675834 Reactome, http://www.reactome.org ReactomeREACT_121188 Reviewed: Wakelam, Michael, 2012-05-14 RAD51B:RAD51C Reactome DB_ID: 983240 Reactome Database ID Release 43983240 Reactome, http://www.reactome.org ReactomeREACT_26032 has a Stoichiometric coefficient of 1 PI4P is dephosphorylated to PI by SYNJ at the plasma membrane At the plasma membrane, synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 aka Synaptojanin-1 (SYNJ1) (Guo et al. 1999, Mani et al. 2007, Johenning et al. 2004) and -2 (SYNJ2) (Malecz et al. 2000) dephosphorylate phosphatidylinositol 4-phosphate (PI4P) phosphatidylinositol (PI). The SAC1 domains of SYNJ1 and SYNJ2 demonstrate 4-phosphatase activity. Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed10224048 Pubmed11084340 Pubmed15080793 Pubmed18093523 Reactome Database ID Release 431675988 Reactome, http://www.reactome.org ReactomeREACT_120720 Reviewed: Wakelam, Michael, 2012-05-14 RAD51B:RAD51C:Single-stranded DNA Reactome DB_ID: 983270 Reactome Database ID Release 43983270 Reactome, http://www.reactome.org ReactomeREACT_25469 has a Stoichiometric coefficient of 1 PI is phosphorylated to PI4P by PI4K2A/B at the plasma membrane At the plasma membrane, phosphatidylinositol 4-kinase type 2-alpha (PI4K2A) (Balla et al. 2002, Minogue et al. 2001) and beta (PI4K2B) (Balla et al. 2002, Wei et al. 2002) phosphorylate phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.67 Edited: Williams, MG, 2011-08-12 Pubmed11279162 Pubmed11923287 Pubmed12324459 Reactome Database ID Release 431675780 Reactome, http://www.reactome.org ReactomeREACT_121154 Reviewed: Wakelam, Michael, 2012-05-14 PI5P is phosphorylated to PI(4,5)P2 by PIP4K2A/B at the plasma membrane At the plasma membrane, phosphatidylinositol-5-phosphate 4-kinase type-2 alpha (PIP4K2A) and beta (PIP4K2B) homodimers and heterodimers (Clarke et al. 2010) phosphorylate phosphatidylinositol 5-phosphate (PI5P) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP4K2A (Rameh et al. 1997, Clarke et al. 2008) and PIP4K2B (Rameh et al. 1997). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.149 Edited: Williams, MG, 2011-08-12 Pubmed18753295 Pubmed19896968 Pubmed9367159 Reactome Database ID Release 431675776 Reactome, http://www.reactome.org ReactomeREACT_121229 Reviewed: Wakelam, Michael, 2012-05-14 PI(3,5)P2 is dephosphorylated to PI5P by SYNJ/MTM[1] at the plasma membrane At the plasma membrane, synaptojanin-1 aka Synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 (SYNJ1) (Guo et al. 1999), -2 (SYNJ2) and some myotubularins (MTMs) dephosphorylate phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 5-phosphate (PI5P). The MTMs involved are: myotubularin (MTM1) (Cao et al. 2007, Tronchere et al. 2004, Schaletzky et al. 2003, Laporte et al. 2002) and myotubularin-related proteins 1 (MTMR1) (Tronchere et al. 2004), 3 (MTMR3) (Walker et al. 2001, Lorenzo et al. 2005), 6 (MTMR6) (Schaletzky et al. 2003, Choudhury et al. 2006), and 14 (MTMR14) (Tosch et al. 2006). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed10224048 Pubmed11676921 Pubmed12118066 Pubmed12646134 Pubmed14660569 Pubmed15840652 Pubmed16914545 Pubmed17008356 Pubmed17651088 Reactome Database ID Release 431676203 Reactome, http://www.reactome.org ReactomeREACT_120865 Reviewed: Wakelam, Michael, 2012-05-14 SLC7A7:SLC3A2 heterodimer Reactome DB_ID: 379424 Reactome Database ID Release 43379424 Reactome, http://www.reactome.org ReactomeREACT_17357 has a Stoichiometric coefficient of 1 PI(3,5)P2 is dephosphorylated to PI3P by SYNJ at the plasma membrane At the plasma membrane, synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 aka synaptojanin-1 (SYNJ1) (Guo et al. 1999, Mani et al. 2007) and -2 (SYNJ2) (Malecz et al. 2000) dephosphorylate phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 3-phosphate (PI3P). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed10224048 Pubmed11084340 Pubmed18093523 Reactome Database ID Release 431675836 Reactome, http://www.reactome.org ReactomeREACT_121103 Reviewed: Wakelam, Michael, 2012-05-14 SLC7A8:SLC3A2 heterodimer Reactome DB_ID: 352162 Reactome Database ID Release 43352162 Reactome, http://www.reactome.org ReactomeREACT_14666 has a Stoichiometric coefficient of 1 Collagen type I fibril with lysino-5-ketonorleucine cross-links Reactome DB_ID: 2396205 Reactome Database ID Release 432396205 Reactome, http://www.reactome.org ReactomeREACT_151384 Collagen type I fibril with deH-HLNL Reactome DB_ID: 2396378 Reactome Database ID Release 432396378 Reactome, http://www.reactome.org ReactomeREACT_152250 Collagen type I fibril with lysyl-pyridinoline cross-links Reactome DB_ID: 2396105 Reactome Database ID Release 432396105 Reactome, http://www.reactome.org ReactomeREACT_152278 PI(3,5)P2 is dephosphorylated to PI5P by MTM[2] at the early endosome membrane At the early endosome membrane, myotubularin (MTM1), myotubularin-related protein 2 (MTMR2) and myotubularin-related protein 4 (MTMR4) dephosphorylate phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 5-phosphate (PI5P).<br><br>The following lists the above proteins with their corresponding literature references: MTM1 (Cao et al. 2007, Cao et al. 2008), MTMR2 (Cao et al. 2008), and MTMR4 (Lorenzo et al. 2006). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed16787938 Pubmed17651088 Pubmed18524850 Reactome Database ID Release 431676105 Reactome, http://www.reactome.org ReactomeREACT_120861 Reviewed: Wakelam, Michael, 2012-05-14 Collagen type I fibril with hydroxylysino-5-ketonorleucine crosslinks Reactome DB_ID: 2396311 Reactome Database ID Release 432396311 Reactome, http://www.reactome.org ReactomeREACT_150716 PI is phosphorylated to PI3P by PIK3C2A/3 at the early endosome membrane At the early endosome membrane, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) aka VPS34 binds to phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4). The PIK3C3:PIK3R4 complex and phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A) phosphorylate phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI3P).<br><br>The following lists the above proteins with their corresponding literature references: PIK3C3:PIK3R4 complex (Panaretou et al. 1997, Volinia et al. 1995, Cao et al. 2007) and PIK3C2A (Arcaro et al. 2000, Domin et al. 2000). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.137 Edited: Williams, MG, 2011-08-12 Pubmed10766823 Pubmed10805725 Pubmed17651088 Pubmed7628435 Pubmed8999962 Reactome Database ID Release 431675939 Reactome, http://www.reactome.org ReactomeREACT_120935 Reviewed: Wakelam, Michael, 2012-05-14 Collagen type I fibril with free hydroxylysines Reactome DB_ID: 2428940 Reactome Database ID Release 432428940 Reactome, http://www.reactome.org ReactomeREACT_150919 Collagen type I fibril with allysines Reactome DB_ID: 2228714 Reactome Database ID Release 432228714 Reactome, http://www.reactome.org ReactomeREACT_151048 IRF2:promoters of INF alpha, INF beta Converted from EntitySet in Reactome Reactome DB_ID: 1018386 Reactome Database ID Release 431018386 Reactome, http://www.reactome.org ReactomeREACT_26555 Collagen type I fibril with dehydro-lysinonorleucine Reactome DB_ID: 2396093 Reactome Database ID Release 432396093 Reactome, http://www.reactome.org ReactomeREACT_151316 IRF3-P:IRF7-P Reactome DB_ID: 1027365 Reactome Database ID Release 431027365 Reactome, http://www.reactome.org ReactomeREACT_26495 has a Stoichiometric coefficient of 1 Collagen type I fibril with hydroxyallysines Reactome DB_ID: 2396055 Reactome Database ID Release 432396055 Reactome, http://www.reactome.org ReactomeREACT_152418 VAF (virus-activated factor) Reactome DB_ID: 1027360 Reactome Database ID Release 431027360 Reactome, http://www.reactome.org ReactomeREACT_25426 has a Stoichiometric coefficient of 1 PI3P is phosphorylated to PI(3,5)P2 by PIKFYVE at the late endosome membrane At the late endosome membrane, the PAS complex, consisting of FYVE finger-containing phosphoinositide kinase (PIKFYVE), yeast VAC14 homologue (VAC14), and polyphosphoinositide phosphatase aka SAC3 (FIG4), binds to the membrane via PIKFYVE's FYVE finger (Sbrissa et al. 2002, Cao et al. 2007). The PIKFYVE kinase component phosphorylates phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol 3,5-bisphosphate PI(3,5)P2 (Sbrissa et al. 1999). The PAS complex is present in the cytosol and is recruited to the membrane (Sbrissa et al. 2007). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.150 Edited: Williams, MG, 2011-08-12 Pubmed10419465 Pubmed11706043 Pubmed17556371 Pubmed17651088 Reactome Database ID Release 431675910 Reactome, http://www.reactome.org ReactomeREACT_120833 Reviewed: Wakelam, Michael, 2012-05-14 MASP-2 dimer Reactome DB_ID: 166694 Reactome Database ID Release 43166694 Reactome, http://www.reactome.org ReactomeREACT_8392 has a Stoichiometric coefficient of 2 CBP/p300:pIRF7:pIRF7 Reactome DB_ID: 933471 Reactome Database ID Release 43933471 Reactome, http://www.reactome.org ReactomeREACT_25574 has a Stoichiometric coefficient of 1 Collagen type I fibril with hydroxylysyl-pyridinoline cross-links Reactome DB_ID: 2396360 Reactome Database ID Release 432396360 Reactome, http://www.reactome.org ReactomeREACT_150702 Presence of PI(3,5)P2 stimulates the maturation of the early endosome into the late endosome Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed11285266 Pubmed16448788 Pubmed16510848 Reactome Database ID Release 431676041 Reactome, http://www.reactome.org ReactomeREACT_121247 Reviewed: Wakelam, Michael, 2012-05-14 The presence of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) in the early endosome membrane stimulates the vesicle maturation into the late endosome (Cabezas et al. 2006, Ikonomov et al. 2006, Ikonomov et al. 2001). MBL-II:MASP-2 dimer:MASP-1 dimer complex Reactome DB_ID: 166710 Reactome Database ID Release 43166710 Reactome, http://www.reactome.org ReactomeREACT_8380 has a Stoichiometric coefficient of 1 p-2S-IRF7:p-2S-IRF7 Reactome DB_ID: 450306 Reactome Database ID Release 43450306 Reactome, http://www.reactome.org ReactomeREACT_21640 has a Stoichiometric coefficient of 2 Collagen type I fibril with lysyl-pyrrole cross-links Reactome DB_ID: 2396231 Reactome Database ID Release 432396231 Reactome, http://www.reactome.org ReactomeREACT_151252 PI(3,5)P2 is dephosphorylated to PI5P by MTM[3] at the late endosome membrane At the late endosome membrane, myotubularin (MTM1), myotubularin-related protein 2 (MTMR2), myotubularin-related protein 4 (MTMR4), and myotubularin-related protein 7 (MTMR7) dephosphorylate phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 5-phosphate (PI5P).<br><br>The following lists the above proteins with their corresponding literature references: MTM1 (Cao et al. 2007, Cao et al. 2008, Tsujita et al. 2004, Tronchere et al. 2004), MTMR2 (Cao et al. 2008), MTMR4 (Lorenzo et al. 2006), and MTMR7 (Mochizuki & Majerus 2003, Lorenzo et al. 2006). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed12890864 Pubmed14660569 Pubmed14722070 Pubmed16787938 Pubmed17651088 Pubmed18524850 Reactome Database ID Release 431676065 Reactome, http://www.reactome.org ReactomeREACT_121325 Reviewed: Wakelam, Michael, 2012-05-14 MBL subunit Reactome DB_ID: 166675 Reactome Database ID Release 43166675 Reactome, http://www.reactome.org ReactomeREACT_8787 has a Stoichiometric coefficient of 3 VAF/pIRF7:CBP/p300 bound to type I IFN gene promoter Reactome DB_ID: 1027368 Reactome Database ID Release 431027368 Reactome, http://www.reactome.org ReactomeREACT_26244 has a Stoichiometric coefficient of 1 Collagen type I fibril with hydroxylysyl-pyrrole cross-links Reactome DB_ID: 2396116 Reactome Database ID Release 432396116 Reactome, http://www.reactome.org ReactomeREACT_151927 PI(3,5)P2 is dephosphorylated to PI3P by FIG4 at the late endosome membrane At the late endosome membrane, the PAS complex, consisting of FYVE finger-containing phosphoinositide kinase (PIKFYVE), yeast VAC14 homologue (VAC14), and polyphosphoinositide phosphatase aka SAC3 (FIG4), binds to the membrane via PIKFYVE's FYVE finger. The FIG4 phosphatase component dephosphorylates phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 3-phosphate (PI3P) (Sbrissa et al. 2007, Sbrissa et al. 2008). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed17556371 Pubmed18950639 Reactome Database ID Release 431676020 Reactome, http://www.reactome.org ReactomeREACT_121182 Reviewed: Wakelam, Michael, 2012-05-14 MBL-II tetramer Reactome DB_ID: 166684 Reactome Database ID Release 43166684 Reactome, http://www.reactome.org ReactomeREACT_8964 has a Stoichiometric coefficient of 4 VAF/pIRF7:CBP/p300 Converted from EntitySet in Reactome Reactome DB_ID: 1027361 Reactome Database ID Release 431027361 Reactome, http://www.reactome.org ReactomeREACT_25775 PI is phosphorylated to PI4P by PI4K2A/B at the early endosome membrane At the early endosome membrane, phosphatidylinositol 4-kinase type 2-alpha/beta (PI4K2A/B) (Balla et al. 2002) phosphorylates phosphatidylinositol (PI) to produce phosphatidylinositol 4-phosphate (PI4P). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.67 Edited: Williams, MG, 2011-08-12 Pubmed11923287 Reactome Database ID Release 431675974 Reactome, http://www.reactome.org ReactomeREACT_120766 Reviewed: Wakelam, Michael, 2012-05-14 IRF-1:IFN-alpha promoter Reactome DB_ID: 994039 Reactome Database ID Release 43994039 Reactome, http://www.reactome.org ReactomeREACT_25701 has a Stoichiometric coefficient of 1 PI3P is dephosphorylated to PI by MTM[2] at the early endosome membrane At the early endosome membrane, myotubularin (MTM1), myotubularin-related protein 2 (MTMR2), and myotubularin-related protein 4 (MTMR4) dephosphorylate phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol (PI).<br><br>The following lists the above proteins with their corresponding literature references: MTM1 (Cao et al. 2007, Cao et al. 2008, Kim et al. 2002), MTMR2 (Cao et al. 2008, Kim et al. 2002), and MTMR4 (Lorenzo et al. 2006, Zhao et al. 2001). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.64 Edited: Williams, MG, 2011-08-12 Pubmed11302699 Pubmed11733541 Pubmed16787938 Pubmed17651088 Pubmed18524850 Reactome Database ID Release 431676141 Reactome, http://www.reactome.org ReactomeREACT_121390 Reviewed: Wakelam, Michael, 2012-05-14 IRF1:Promoter region of IFN beta Reactome DB_ID: 1008252 Reactome Database ID Release 431008252 Reactome, http://www.reactome.org ReactomeREACT_25698 has a Stoichiometric coefficient of 1 PI(3,5)P2 transports from the early endosome membrane to the Golgi membrane Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) translocates from the early endosome membrane to the Golgi membrane (Rutherford et al. 2006). Pubmed16954148 Reactome Database ID Release 431675896 Reactome, http://www.reactome.org ReactomeREACT_121360 Reviewed: Wakelam, Michael, 2012-05-14 TRAF6:p-IRAK2 :p-IRAK4:oligo-MyD88 :Mal:activated TLR Reactome DB_ID: 2262774 Reactome Database ID Release 432262774 Reactome, http://www.reactome.org ReactomeREACT_124060 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PI4P is phosphorylated to PI(3,4)P2 by PIK3C2A at the early endosome membrane At the early endosome membrane, phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A) (Kraq et al. 2010, Arcaro et al. 2000) phosphorylates phosphatidylinositol 4-phosphate (PI4P) to phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.154 Edited: Williams, MG, 2011-08-12 Pubmed10805725 Pubmed21081650 Reactome Database ID Release 431676206 Reactome, http://www.reactome.org ReactomeREACT_121403 Reviewed: Wakelam, Michael, 2012-05-14 IRF1:Promotors of IFN alpha, IFN beta Converted from EntitySet in Reactome Reactome DB_ID: 1008247 Reactome Database ID Release 431008247 Reactome, http://www.reactome.org ReactomeREACT_26239 Procollagen C-linked trimers Converted from EntitySet in Reactome Reactome DB_ID: 2025682 Reactome Database ID Release 432025682 Reactome, http://www.reactome.org ReactomeREACT_125358 Basigin:Mannose-carrying cell recognition molecules Reactome DB_ID: 375090 Reactome Database ID Release 43375090 Reactome, http://www.reactome.org ReactomeREACT_18084 has a Stoichiometric coefficient of 1 Collagen type XXVIII chains Converted from EntitySet in Reactome Reactome DB_ID: 2179270 Reactome Database ID Release 432179270 Reactome, http://www.reactome.org ReactomeREACT_122532 JAK2 phosphorylation of IRS-1/2 Authored: Jupe, S, 2010-10-14 EC Number: 2.7.10.2 Edited: Jupe, S, 2011-06-10 GH has short term effects that mimic the actions of insulin in tissues that have been deprived of GH, including increased amino acid transport, glucose transport, and lipogenesis (Davidson 1987). GH and insulin have overlapping signaling pathways (Dominici et al. 2005). GH stimulates tyrosyl phosphorylation of insulin receptor substrate-1 (IRS-1) (Souza et al. 1994, Thirone et al. 1999), and IRS-2 (Argetsinger et al. 1996, Thirone et al. 1999), although more modestly than insulin or IGF-1. Tyrosyl phosphorylation of IRS-1 and IRS-2 in response to insulin provides binding sites for specific proteins containing SH2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3K), tyrosine phosphatase SHP2, and Grb2. This is one of several mechanisms proposed to explain the stimulatory effect of GH on the PI3-kinase/Akt pathway (Jin et al. 2008). GH promotes the binding of the 85-kDa regulatory subunit of PI3K to IRS-1 and IRS-2 in cultured cells (Ridderstrale et al. 1995, Argetsinger et al. 1995, 1996). Studies using truncated or mutated GHRs suggest that tyrosyl phosphorylation of IRS-1, IRS-2, and Shc is dependent on JAK2 activation (Argetsinger et al. 1995, 1996, VanderKuur et al. 1995). Despite a strong correlation between JAK2 activation and IRS phosphorylation it is not clear whether there is a direct association. JAK2 has been reported to interact directly with IRS in response to angiotensin II (Velloso et al. 1996) but also reported to interact indirectly via SH2B in response to leptin (Duan et al.2004). Pubmed15316008 Pubmed16112592 Pubmed18499741 Pubmed3301316 Pubmed7527025 Pubmed7535773 Pubmed7782332 Pubmed7876077 Pubmed8901609 Pubmed8910607 Pubmed9886807 Reactome Database ID Release 431168423 Reactome, http://www.reactome.org ReactomeREACT_111190 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 has a Stoichiometric coefficient of 2 Sodium/potassium-transporting ATPase beta subunit Reactome DB_ID: 375085 Reactome Database ID Release 43375085 Reactome, http://www.reactome.org ReactomeREACT_17537 has a Stoichiometric coefficient of 1 Collagen type XXVII propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2179268 Reactome Database ID Release 432179268 Reactome, http://www.reactome.org ReactomeREACT_124690 Integrin alpha3beta1 Reactome DB_ID: 204444 Reactome Database ID Release 43204444 Reactome, http://www.reactome.org ReactomeREACT_14560 has a Stoichiometric coefficient of 1 Basigin-binding integrins Converted from EntitySet in Reactome Reactome DB_ID: 204466 Reactome Database ID Release 43204466 Reactome, http://www.reactome.org ReactomeREACT_14484 Collagens and tropocollagens Converted from EntitySet in Reactome Reactome DB_ID: 2187524 Reactome Database ID Release 432187524 Reactome, http://www.reactome.org ReactomeREACT_123435 Basigin bound to integrins Reactome DB_ID: 204472 Reactome Database ID Release 43204472 Reactome, http://www.reactome.org ReactomeREACT_14081 has a Stoichiometric coefficient of 1 Non-fibrillar collagens Converted from EntitySet in Reactome Reactome DB_ID: 2187520 Reactome Database ID Release 432187520 Reactome, http://www.reactome.org ReactomeREACT_124505 Integrin alpha6beta1 Reactome DB_ID: 204443 Reactome Database ID Release 43204443 Reactome, http://www.reactome.org ReactomeREACT_14516 has a Stoichiometric coefficient of 1 Fibrillar procollagen triple helices Converted from EntitySet in Reactome Reactome DB_ID: 2268722 Reactome Database ID Release 432268722 Reactome, http://www.reactome.org ReactomeREACT_122953 Collagen and procollagen triple helices Converted from EntitySet in Reactome Reactome DB_ID: 2187523 Reactome Database ID Release 432187523 Reactome, http://www.reactome.org ReactomeREACT_125033 JAK2 binds STAT1/3 Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 JAK2 is believed to bind STAT1 and STAT3 directly in response to GH, as opposed to STAT5 which binds to phosphorylated tyrosine residues in the distal portion of the GHR cytoplasmic region (Smit et al. 1996). When associated with the prolactin receptor JAK2 is able to bind STAT1, STAT3 and STAT5 (DaSilva et al. 1996). Smit et al. identified mouse GHR residues Y341 (human Y332) and Y346 (not conserved in human) as required for STAT1, 3, and maximal STAT5 activation. Pubmed8732683 Pubmed8737372 Reactome Database ID Release 431168768 Reactome, http://www.reactome.org ReactomeREACT_111047 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 Non-fibrillar collagens Converted from EntitySet in Reactome Reactome DB_ID: 2192793 Reactome Database ID Release 432192793 Reactome, http://www.reactome.org ReactomeREACT_123200 JAK2 phosphorylates STAT1/STAT3 Authored: Jupe, S, 2010-10-14 EC Number: 2.7.10.2 Edited: Jupe, S, 2011-06-10 GH stimulated tyrosyl phosphorylation of Stats 1, 3, and 5 in CHO cells expressing GHR constructs that bind JAK2 but not in CHO cells expressing GHR constructs that do not bind JAK2 (Smit et al. 1996). STAT5 phosphorylation was greatly reduced in GHR mutants with the distal region of the cytoplasmic tail removed and by mutation of distal GHR tyrosine residues to phenylalanine but this had no effect on STAT1/STAT3 phosphorylation, suggesting that the latter interact with JAK2 directly. Reactome Database ID Release 431168767 Reactome, http://www.reactome.org ReactomeREACT_111207 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 has a Stoichiometric coefficient of 2 Fibrillar procollagens Converted from EntitySet in Reactome Reactome DB_ID: 2182022 Reactome Database ID Release 432182022 Reactome, http://www.reactome.org ReactomeREACT_125182 Growth hormone receptor binds Lyn Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 Pubmed12218045 Pubmed12734187 Pubmed18488018 Reactome Database ID Release 431168456 Reactome, http://www.reactome.org ReactomeREACT_111139 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 There is accumulating evidence that GH signalling utilises a Src family tyrosine kinase independently of JAK2, and that this is linked to activation of extracellular regulated kinases (ERKs) 1 and 2 (p44/42 MAPK). The relative strengths of these signaling pathways probably depends on cell type and may be mediated by conformational changes that are a consequence of ligand binding (Rowlinson et al. 2007). In NIH-3T3 cells GH activated c-Src, which in turn activated ERK1/2 via a pathway involving the activation of the Ras-like small GTPases RalA and RalB, leading to Elk-1 mediated transcription (Zhu et al. 2002). JAK2 and c-Src were both found to activate the Ras-like small GTPases Rap1 and Rap2 which inhibit RalA mediated activation of ERK1/2 (Ling et al. 2003). Src kinase inhibition was found to block ERK activation by GH. The major contributing kinase was identified as Lyn, which was found to co-immunoprecipitate with GHR and bind to the proximal 150 residues of the cytoplasmic domain (Rowlinson et al. 2007). Collagens and tropocollagens Converted from EntitySet in Reactome Reactome DB_ID: 2192795 Reactome Database ID Release 432192795 Reactome, http://www.reactome.org ReactomeREACT_125632 Lyn activates ERK Authored: Jupe, S, 2010-10-14 EC Number: 2.7.10.2 Edited: Jupe, S, 2011-06-10 Pubmed12845332 Pubmed18488018 Pubmed20664532 Reactome Database ID Release 431168459 Reactome, http://www.reactome.org ReactomeREACT_111235 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 The activation of Lyn by GHR is thought to indirectly activate ERK. Mutations of GHR predicted to disable a conformational change brought about by GH binding impaired ERK signaling but not JAK2/STAT5 signaling. ERK signaling was demonstrated to involve the Src family kinase Lyn (Rowlinson et al. 2008) and suggested to involve Src kinase dependent activation of Phospholipase C gamma and thereby Ras, similar to a mechanism proposed by Bivona et al. (2003). ERK activation mechanisms involving Src kinases and PLCgamma have been reported for the erythropoietin, thrombopoietin and prolactin receptors (Brooks & Waters 2010). has a Stoichiometric coefficient of 4 STAT5 tyrosine phosphorylation Authored: Jupe, S, 2010-10-14 EC Number: 2.7.10 Edited: Jupe, S, 2011-06-10 Pubmed8197455 Pubmed8732683 Pubmed9121492 Reactome Database ID Release 431168394 Reactome, http://www.reactome.org ReactomeREACT_111218 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 Stat5 tyrosine phosphorylation was seen in response to GH in CHO cells expressing mouse GHR forms capable of binding JAK2 (Smit et al. 1996). Similar results were obtained using the porcine receptor (Wang et al. 1996). Thus Jak2 phosphorylates Stat5, the phosphorylated monomers form dimers and translocate to the nucleus (Darnell et al. 1994). has a Stoichiometric coefficient of 2 Phosphorylated STAT5 is released Authored: Jupe, S, 2010-10-14 Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believed to occur following release of the phosphorylated monomers from the receptor complex and is typically represented in this manner (e.g. Turkson & Jove 2000). Edited: Jupe, S, 2011-06-10 Pubmed11426647 Pubmed9030599 Reactome Database ID Release 431168894 Reactome, http://www.reactome.org ReactomeREACT_111224 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 JAK2 phosphorylation of GHR Activated JAK2 phosphorylates multiple tyrosine residues on GHR (Argetsinger et al. 1993, VanderKuur et al. 1994) including Y332 (VanderKuur 1995), Y487, Y534, Y566, and Y627 (Wang et al. 1996). Wang et al. using the porcine receptor found that phosphorylation at any of the positions they examined (all conserved in humans) was sufficient for STAT5 phosphorylation. While STAT5 activation requires phosphorylation of the distal region of GHR, this has no effect on STAT1 or STAT3 activation (Yi et al. 1996) suggesting different mechanisms. Mutation of Y332 to F in a truncated form of GHR with only the first 54 residues of the cytoplasmic domain had no effect on JAK2 activation or cell proliferation presumed to be mediated by ERK (Wang et al. 1995) so the significance of phosphorylation at this position is unclear. SHP2 binds to Y595 of rat GHR (identical numbering in humans) and to a lesser extent Y487; mutation of these residues impairs the association (Stofega et al. 2000). SOCS3 binds to rat GHR Y333 (equivalent of human Y332), Y338 (not conserved in humans) (Ram & Waxman 1999) and Y487 (Hansen et al. 1999). SOCS-1 has been implicated as a direct inhibitor of JAK kinases (Yasukawa et al. 1999). This reaction represents the phosphorylation of all GHR tyrosines known to be phosphorylated by JAK2. Authored: Jupe, S, 2010-10-14 EC Number: 2.7.10 Edited: Jupe, S, 2011-06-10 Pubmed10064597 Pubmed10551777 Pubmed10976913 Pubmed3349036 Pubmed7535764 Pubmed7545168 Pubmed7691587 Pubmed8063815 Pubmed8343952 Pubmed8923468 Pubmed9121492 Reactome Database ID Release 43982807 Reactome, http://www.reactome.org ReactomeREACT_111147 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 has a Stoichiometric coefficient of 10 STAT5 association with GHR Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 JAK2 is required for GH-mediated phosphorylation of STATs 1,3,5A and 5B (Smit et al.1996). Some STAT activation may be mediated by direct association of JAK and STAT but maximal activation requires binding of STATs to phosphorylated tyrosines of the receptor (Smit et al. 1996, Lichanska & Waters 2006). Studies using mouse GHR truncated at K391, equivalent to human K380, suggest that STAT5 signaling is mediated by distal tyrosines, with 70% of the signaling lost if the receptor is truncated at P569, equivalent to human P558 (Rowland et al. 2005). Wang et al. (1996) using the porcine receptor found that phosphorylation at any one of the positions Y487, Y534, Y566 or Y627 (numbering identical in humans) was sufficient to allow STAT5 phosphorylation. Smit et al. (1996) identified mouse residues Y341 (human Y332) and Y346 (not conserved in human) as required for STAT1, 3, and maximal STAT5 activation. Pubmed15601831 Pubmed18219216 Pubmed8732683 Pubmed9121492 Reactome Database ID Release 431168393 Reactome, http://www.reactome.org ReactomeREACT_111212 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 SOCS binding to GHR Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 Pubmed10064597 Pubmed10551777 Pubmed15690087 Pubmed17666591 Reactome Database ID Release 431168809 Reactome, http://www.reactome.org ReactomeREACT_111220 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 Suppressor of Cytokine Signaling (SOCS) proteins inhibit the GH signal; SOCS2 null mice exhibit giantism (Greenhalgh et al. 2005). Suppressor of Cytokine Signaling (SOCS)1-3, and the realted Cytokine-inducible SH2-containing protein (CIS) all bind tyrosine-phosphorylated GHR; SOCS1 can also binds GHR in the absence of tyrosine phosphorylation (Ram & Waxman 1999, Hansen et al. 1999). SOCS3 binding has been mapped to phosphorylated tyrosines Y338, Y333 (Ram & Waxman 1999), and Y487 (Hansen et al. 1999) in the membrane proximal region of the receptor while SOCS2 and CIS bind to residues Y487 and Y595 (Uyttendaele et al. 2007). SOCS2/3/CIS may compete with STAT5 for GHR binding at these sites but in the case of SOCS3 also appears to act by inhibiting JAK2 directly (Yasukawa et al. 1999). Caveolin-1 bound to Basigin Reactome DB_ID: 204550 Reactome Database ID Release 43204550 Reactome, http://www.reactome.org ReactomeREACT_13130 has a Stoichiometric coefficient of 1 Basigin bound to CyPA Reactome DB_ID: 204480 Reactome Database ID Release 43204480 Reactome, http://www.reactome.org ReactomeREACT_12714 has a Stoichiometric coefficient of 1 Basigin bound to CD43 Reactome DB_ID: 204467 Reactome Database ID Release 43204467 Reactome, http://www.reactome.org ReactomeREACT_18170 has a Stoichiometric coefficient of 1 Basigin:MMP1 Reactome DB_ID: 375089 Reactome Database ID Release 43375089 Reactome, http://www.reactome.org ReactomeREACT_17528 has a Stoichiometric coefficient of 1 Tropocollagens Converted from EntitySet in Reactome Reactome DB_ID: 2060921 Reactome Database ID Release 432060921 Reactome, http://www.reactome.org ReactomeREACT_121559 SLC7A5:SLC3A2 heterodimer Reactome DB_ID: 352221 Reactome Database ID Release 43352221 Reactome, http://www.reactome.org ReactomeREACT_14214 has a Stoichiometric coefficient of 1 Fibrillar procollagens -N Converted from EntitySet in Reactome Reactome DB_ID: 2268931 Reactome Database ID Release 432268931 Reactome, http://www.reactome.org ReactomeREACT_122457 SLC7A11:SLC3A2 heterodimer Reactome DB_ID: 378505 Reactome Database ID Release 43378505 Reactome, http://www.reactome.org ReactomeREACT_16127 has a Stoichiometric coefficient of 1 Fibril forming tropocollagens Converted from EntitySet in Reactome Reactome DB_ID: 2089977 Reactome Database ID Release 432089977 Reactome, http://www.reactome.org ReactomeREACT_151583 SOCS binding to JAK2 Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 Pubmed10064597 Pubmed10421843 Pubmed10585430 Pubmed10829066 Pubmed15601820 Pubmed16037128 Reactome Database ID Release 431168813 Reactome, http://www.reactome.org ReactomeREACT_111198 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 SOCS1 can bind JAK2 and inhibit JAK kinase activity (Yasukawa et al. 1999). SOCS3 also inhibits JAK2 kinase activity (Sasaki et al. 1999) while all of SOCS1 -3 and CIS inhibit GHR signaling (Ram & Waxman 1999, Nicholson et al. 2000). This is not thought to be simply the outcome of binding competition between SOCS and STAT5, but a direct action of SOCS on JAK2 (Ram & Waxman 1999). Although SOCS are known to be ubiquitin ligases (Kamura et al. 2004), ubiquitin ligase activity on JAK2 or GHR has not been demonstrated and a role for SOCS in the ubiquitination of these proteins has been questioned (Flores-Morales et al. 2006). An alternative model suggested by the observation that SOCS3 strongly inhibits JAK2 only in the presence of GHR proposes that SOCS serve as an inhibitory 'bridge' by binding simultaneously to GHR and JAK2 (Ram & Waxman 1999). SLC7A10:SLC3A2 heterodimer Reactome DB_ID: 376183 Reactome Database ID Release 43376183 Reactome, http://www.reactome.org ReactomeREACT_15256 has a Stoichiometric coefficient of 1 Procollagen C-proteinases Converted from EntitySet in Reactome Reactome DB_ID: 2002397 Reactome Database ID Release 432002397 Reactome, http://www.reactome.org ReactomeREACT_122145 PTP1B binds the GH receptor complex Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 PTP1B has been shown to associate with GH-dependent phosphorylated GHR and induce its dephosphorylation (Pasquali et al. 2003). It can also dephosphorylate JAK2 (Gu et al. 2003). Both have the effect of reducing JAK signaling. Pubmed12748279 Pubmed12907755 Reactome Database ID Release 431168445 Reactome, http://www.reactome.org ReactomeREACT_111219 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 CD98hc complex Converted from EntitySet in Reactome Reactome DB_ID: 375088 Reactome Database ID Release 43375088 Reactome, http://www.reactome.org ReactomeREACT_18154 Collagen type I fibril Reactome DB_ID: 1474201 Reactome Database ID Release 431474201 Reactome, http://www.reactome.org ReactomeREACT_150867 Collagen fibrils Converted from EntitySet in Reactome Reactome DB_ID: 2127450 Reactome Database ID Release 432127450 Reactome, http://www.reactome.org ReactomeREACT_150722 Collagen type III fibril Reactome DB_ID: 1474212 Reactome Database ID Release 431474212 Reactome, http://www.reactome.org ReactomeREACT_151594 Collagen type II fibril Reactome DB_ID: 1474209 Reactome Database ID Release 431474209 Reactome, http://www.reactome.org ReactomeREACT_152451 SLC7A6:SLC3A2 heterodimer Reactome DB_ID: 379421 Reactome Database ID Release 43379421 Reactome, http://www.reactome.org ReactomeREACT_17753 has a Stoichiometric coefficient of 1 Collagen type XI fibril Reactome DB_ID: 2168008 Reactome Database ID Release 432168008 Reactome, http://www.reactome.org ReactomeREACT_152212 Metalloprotease cleavage of GHR Approximately half of circulating GH is bound to Growth Hormone Binding Protein ((GHBP) Herington et al. 1986), a soluble fragment of the Growth Hormone Receptor (Baumann et al. 1986) formed when the extracellular region is proteolytically cleaved (Leung et al. 1987). This cleavage is mediated by metalloproteases such as TACE (ADAM17, Zhang et al. 2000). The membrane-bound remnant is subsequently degraded by the gamma-secretase complex (Cowan et al. 2005). Authored: Jupe, S, 2010-10-14 EC Number: 3.4.24 Edited: Jupe, S, 2011-06-10 Pubmed11108241 Pubmed15743767 Pubmed16037128 Pubmed2825030 Pubmed3711337 Pubmed3940261 Reactome Database ID Release 431168777 Reactome, http://www.reactome.org ReactomeREACT_111197 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 Collagen type V fibril Reactome DB_ID: 1609685 Reactome Database ID Release 431609685 Reactome, http://www.reactome.org ReactomeREACT_150691 GHBP binds GH Authored: Herington, AC, 2011-06-13 Edited: Jupe, S, 2011-06-10 GHBP is the ectodomain of GHR, cleaved from membrane-bound GHR in man and rabbits, while in rodents it is derived from an alternatively spliced mRNA. GHBP circulates in nanomolar concentrations, sufficient to complex approximately 50% of plasma GH (Baumann et al. 1988). GHBP can compete for GHR binding, inhibiting GHR signaling (Lim et al. 1990), and generates 'unproductive' heterodimers with GHR at the cell surface (Ross et al. 1997), but GHBP can also increase GH biological activity by prolonging its half-life (Baumann et al. 1987). The net effect of GHBP may depend on the relative concentrations of circulating GH and GHBP (Lim et al. 1990, Barnard & Waters 1997), the overall effect is postulated to be stabilization of GH signaling (Veldhuis et al. 1993). GHBP appears to be positively linked to GH action. It has been suggested that plasma GHBP levels reflect tissue concentrations of GHR, but this remains to be proven. Pubmed2387255 Pubmed2825030 Pubmed3342762 Pubmed3818897 Pubmed8432866 Pubmed9058373 Pubmed9135564 Reactome Database ID Release 431362485 Reactome, http://www.reactome.org ReactomeREACT_111114 Reviewed: Waters, MJ, 2011-06-23 GHBP binds GHR Authored: Herington, AC, 2011-06-13 Edited: Jupe, S, 2011-06-10 GHBP, the ectodomain of GHR cleaved from membrane-bound GHR can form a heterodimer with GHR. This is not capable of signaling and may be a negative regulatory influence. GHBP can also inhibit signaling by competing with the full length receptor for GH binding. Pubmed9058373 Reactome Database ID Release 431362465 Reactome, http://www.reactome.org ReactomeREACT_111073 Reviewed: Waters, MJ, 2011-06-23 GHR internalization Authored: Jupe, S, 2010-10-14 Cell surface levels of GHR are the primary determinant of GH responsiveness. This is modulated partly by endocytosis and lysosomal degradation. This downregulation is strongly inhibited by the association of JAK2 with the receptor, and by GH if JAK2 is prevented from signaling, but markedly enhanced by GH if JAK2 is kinase active. GH down-regulation also requires GHR tyrosine phosphorylation (Deng et al. 2007) and is believed to be mediated by GHR ubiquitination and proteasomal degradation. Edited: Jupe, S, 2011-06-10 Pubmed17488973 Reactome Database ID Release 431168789 Reactome, http://www.reactome.org ReactomeREACT_111213 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 PTP1B dephosphorylates GHR Authored: Jupe, S, 2010-10-14 EC Number: 3.1.3.48 Edited: Jupe, S, 2011-06-10 PTP1B induces the dephosphorylation of GHR (Pasquali et al. 2003). Pubmed12907755 Reactome Database ID Release 431169192 Reactome, http://www.reactome.org ReactomeREACT_111061 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 has a Stoichiometric coefficient of 4 PTP1B dephosphorylates JAK2 Authored: Jupe, S, 2010-10-14 EC Number: 3.1.3.48 Edited: Jupe, S, 2011-06-10 PTP1B dephosphorylates JAK2 (Gu et al. 2003), limiting ligand-dependent signaling. Pubmed12748279 Reactome Database ID Release 431169210 Reactome, http://www.reactome.org ReactomeREACT_111128 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 has a Stoichiometric coefficient of 2 SHP1 (PTPN6) binds JAK2 in the receptor complex Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 Pubmed9111009 Reactome Database ID Release 431168839 Reactome, http://www.reactome.org ReactomeREACT_111226 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 SHP1 binds GH-activated JAK2 and controls the duration of GH-dependent JAK2 phosphorylation in the liver, consequently hepatic GH signaling is prolonged in mice lacking SHP1 (Hackett et al. 1999). SHP1 (PTPN6) dephosphorylates JAK2 Authored: Jupe, S, 2010-10-14 EC Number: 3.1.3.48 Edited: Jupe, S, 2011-06-10 Pubmed9111009 Reactome Database ID Release 431169188 Reactome, http://www.reactome.org ReactomeREACT_111048 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 SHP1 (PTPN6) dephosphorylates GH-activated JAK2, limiting the duration of signaling (Hackett et al. 1999). has a Stoichiometric coefficient of 2 PI is phosphorylated to PI5P by PIP5K1A/B at the plasma membrane At the plasma membrane, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A) and beta (PIP5K1B) phosphorylate phosphatidylinositol (PI) to produce phosphatidylinositol 5-phosphate (PI5P) (Tolias et al. 1998). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed9660759 Reactome Database ID Release 431675810 Reactome, http://www.reactome.org ReactomeREACT_120747 Reviewed: Wakelam, Michael, 2012-05-14 PI3P is dephosphorylated to PI by SYNJ/MTM[1] at the plasma membrane At the plasma membrane, synaptojanin-1 aka Synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 (SYNJ1) (Guo et al. 1999), -2 (SYNJ2) and some myotubularins (MTMs) dephosphorylate phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol (PI). The MTMs involved are: myotubularin (MTM1) (Cao et al. 2007, Tronchere et al. 2004, Schaletzky et al. 2003, Laporte et al. 2002, Kim et al. 2002) and myotubularin-related proteins 1 (MTMR1) (Kim et al. 2002, Tronchere et al. 2004), 3 (MTMR3) (Kim et al. 2002, Zhao et al. 2001, Walker et al. 2001, Lorenzo et al. 2005), 6 (MTMR6) (Schaletzky et al. 2003, Kim et al. 2002, Choudhury et al. 2006), and 14 (MTMR14) (Tosch et al. 2006). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.64 Edited: Williams, MG, 2011-08-12 Pubmed10224048 Pubmed11302699 Pubmed11676921 Pubmed11733541 Pubmed12118066 Pubmed12646134 Pubmed14660569 Pubmed15840652 Pubmed16914545 Pubmed17008356 Pubmed17651088 Reactome Database ID Release 431675994 Reactome, http://www.reactome.org ReactomeREACT_121287 Reviewed: Wakelam, Michael, 2012-05-14 PI(3,4,5)P3 is dephosphorylated to PI (4,5)P2 by PTEN at the plasma membrane At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Maehama & Dixon 1998, Myers et al. 1998, Das et al. 2003). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.67 Edited: Williams, MG, 2011-08-12 Pubmed12808147 Pubmed9593664 Pubmed9811831 Reactome Database ID Release 431676191 Reactome, http://www.reactome.org ReactomeREACT_121053 Reviewed: Wakelam, Michael, 2012-05-14 PI(4,5)P2 is phosphorylated to PI(3,4,5)P3 by PIK3C[1] at the plasma membrane At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits. These complexes phosphorylate phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) (Stephens et al. 1997). The PI(4,5)P2 3-kinase complexes involved are: PI(4,5)P2 3-kinase catalytic subunit alpha isoform (PIK3CA) bound to PI 3-kinase regulatory subunit alpha/beta/gamma (PIK3R1/2/3); beta (PIK3CB) bound to PIK3R1/2/3; delta (PIK3CD) bound to PIK3R1/2/3; and gamma (PIK3CG) bound to PI 3-kinase regulatory subunit 5 (PIK3R5) or 6 (PIK3R6).<br><br>The following lists the above proteins with their corresponding literature references: PIK3CA:PIK3R1, PIK3CA:PIK3R2, PIK3CA:PIK3R3 (Dey et al. 1998, Vanhaesebroeck et al. 1997, Meier et al. 2004); PIK3CB:PIK3R1, PIK3CB:PIK3R2, PIK3CB:PIK3R3 (Meier et al. 2004); PIK3CD:PIK3R1, PIK3CD:PIK3R2, PIK3CD:PIK3R3 (Vanhaesebroeck et al. 1997, Meier et al. 2004); and PIK3CG:PIK3R5, PIK3CG:PIK3R6 (Voigt et al. 2006, Suire et al. 2005, Stoyanov et al. 1995). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.153 Edited: Williams, MG, 2011-08-12 Pubmed15135396 Pubmed15797027 Pubmed16476736 Pubmed7624799 Pubmed9094719 Pubmed9113989 Pubmed9524259 Reactome Database ID Release 431676048 Reactome, http://www.reactome.org ReactomeREACT_121297 Reviewed: Wakelam, Michael, 2012-05-14 Basigin bound to MCTs Reactome DB_ID: 204396 Reactome Database ID Release 43204396 Reactome, http://www.reactome.org ReactomeREACT_15052 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PI(3,4,5)P3 is dephosphorylated to PI(3,4)P2 by INPP5[2] at the plasma membrane At the plasma membrane, phosphatidylinositol 5-phosphatases dephosphorylate phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). The phosphatidylinositol 5-phosphatases involved are: inositol polyphosphate 5-phosphatase K (INPP5K) aka SKIP (Ijuin et al. 2000, Gurung et al. 2003), phosphatidylinositol 4,5-bisphosphate 5-phosphatase A (INPP5J) aka PIPP (Gurung et al. 2003, Mochizuki & Takenawa 1999), phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 (INPP5D) aka SHIP1 (Drayer et al. 1995, Kavanaugh et al. 1996, Dunant et al. 2000), and phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 (INPPL1) aka SHIP2 (Habib et al. 1998, Wisniewski et al. 1999, Pesesse et al. 2001). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed10194451 Pubmed10593988 Pubmed10753883 Pubmed10822173 Pubmed11349134 Pubmed12536145 Pubmed8723348 Pubmed8769125 Pubmed9660833 Reactome Database ID Release 431675949 Reactome, http://www.reactome.org ReactomeREACT_120976 Reviewed: Wakelam, Michael, 2012-05-14 PI(3,4)P2 is phosphorylated to PI(3,4,5)P3 by PIP5K1A-C at the plasma membrane At the plasma membrane, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A), beta (PIP5K1B), and gamma (PIP5K1C) phosphorylate phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) to produce phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). This is a minor reaction, however, and its physiological role is uncertain.<br><br>The following lists the above proteins with their corresponding literature references: PIP5K1A (Zhang et al. 1997, Tolias et al. 1998), PIP5K1B (Zhang et al. 1997, Tolias et al. 1998), and PIP5K1C (Wenk et al. 2001, Di Paolo et al. 2002, Krauss et al. 2003). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed11604140 Pubmed12422219 Pubmed12847086 Pubmed9211928 Pubmed9660759 Reactome Database ID Release 431675773 Reactome, http://www.reactome.org ReactomeREACT_121089 Reviewed: Wakelam, Michael, 2012-05-14 PI(3,4)P2 is dephosphorylated to PI4P by PTEN at the plasma membrane At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) to phosphatidylinositol 4-phosphate (PI4P) (Myers et al. 1998, Das et al. 2003). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed12808147 Pubmed9811831 Reactome Database ID Release 431676149 Reactome, http://www.reactome.org ReactomeREACT_120852 Reviewed: Wakelam, Michael, 2012-05-14 MCT3 homodimer Reactome DB_ID: 374006 Reactome Database ID Release 43374006 Reactome, http://www.reactome.org ReactomeREACT_14875 has a Stoichiometric coefficient of 2 PI4P is phosphorylated to PI(3,4)P2 by PI3K3C[2] at the plasma membrane At the plasma membrane, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) 3-kinase catalytic subunits form complexes with regulatory subunits. These complexes along with phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunits alpha (PIK3C2A), beta (PIK3C2B), and gamma (PIK3C2G) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). The PI(4,5)P2 3-kinase complexes involved are: PI(4,5)P2 3-kinase catalytic subunit alpha isoform (PIK3CA) bound to PI 3-kinase regulatory subunit alpha/beta/gamma (PIK3R1/2/3); beta (PIK3CB) bound to PIK3R1/2/3; delta (PIK3CD) bound to PIK3R1/2/3; and gamma (PIK3CG) bound to PI 3-kinase regulatory subunit 5 (PIK3R5) or 6 (PIK3R6).<br><br>The following lists the above proteins with their corresponding literature references: PIK3C2A (Arcaro et al. 2000); PIK3C2B (Arcaro et al. 2000, Arcaro et al. 1998); PIK3C2G (Misawa et al. 1998, Ono et al. 1998); PIK3CA:PIK3R1, PIK3CA:PIK3R2, PIK3CA:PIK3R3 (Vanhaesebroeck et al. 1997); PIK3CB:PIK3R1, PIK3CB:PIK3R2, PIK3CB:PIK3R3 (Meier et al. 2004, Guo et al. 1997); PIK3CD:PIK3R1, PIK3CD:PIK3R2, PIK3CD:PIK3R3 (Vanhaesebroeck et al. 1997); and PIK3CG:PIK3R5, PIK3CG:PIK3R6 (Suire et al. 2005, Stoyanov et al. 1995). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.154 Edited: Williams, MG, 2011-08-12 Pubmed10805725 Pubmed15135396 Pubmed15797027 Pubmed7624799 Pubmed9113989 Pubmed9286278 Pubmed9514948 Pubmed9516481 Pubmed9830063 Reactome Database ID Release 431676109 Reactome, http://www.reactome.org ReactomeREACT_121261 Reviewed: Wakelam, Michael, 2012-05-14 MCT4 homodimer Reactome DB_ID: 374004 Reactome Database ID Release 43374004 Reactome, http://www.reactome.org ReactomeREACT_15228 has a Stoichiometric coefficient of 2 PI(3,4)P2 is dephosphorylated to PI3P by INPP4A/B at the plasma membrane At the plasma membrane, type I and type II inositol-3,4-bisphosphate 4-phosphatase (INPP4A) (Norris et al. 1995, Ivetac et al. 2005) and (INPP4B) (Norris et al. 1997) dephosphorylate phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) to phosphatidylinositol 3-phosphate (PI3P). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.66 Edited: Williams, MG, 2011-08-12 Pubmed15716355 Pubmed7608176 Pubmed9295334 Reactome Database ID Release 431676164 Reactome, http://www.reactome.org ReactomeREACT_121165 Reviewed: Wakelam, Michael, 2012-05-14 Monocarboxylate Transporter Homodimers Converted from EntitySet in Reactome Reactome DB_ID: 204393 Reactome Database ID Release 43204393 Reactome, http://www.reactome.org ReactomeREACT_15026 Collagen type XXIV fibril Reactome DB_ID: 2193154 Reactome Database ID Release 432193154 Reactome, http://www.reactome.org ReactomeREACT_152145 PI3P is phosphorylated to PI(3,4)P2 by PIP4K2/5K1 at the plasma membrane At the plasma membrane, phosphatidylinositol-5-phosphate 4-kinase type-2 alpha (PIP4K2A) and beta (PIP4K2B) homodimers and heterodimers (Clarke et al. 2010), along with phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A), beta (PIP5K1B), and gamma (PIP5K1C) phosphorylate phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP4K2A (Zhang et al. 1997, Rameh et al. 1997, Clarke et al. 2008), PIP4K2B (Zhang et al. 1997, Rameh et al. 1997), PIP5K1A (Zhang et al. 1997, Tolias et al. 1998), PIP5K1B (Zhang et al. 1997, Tolias et al. 1998), and PIP5K1C (Wenk et al. 2001, Di Paolo et al. 2002). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed11604140 Pubmed12422219 Pubmed18753295 Pubmed19896968 Pubmed9211928 Pubmed9367159 Pubmed9660759 Reactome Database ID Release 431676145 Reactome, http://www.reactome.org ReactomeREACT_121352 Reviewed: Wakelam, Michael, 2012-05-14 MCT1 homodimer Reactome DB_ID: 374001 Reactome Database ID Release 43374001 Reactome, http://www.reactome.org ReactomeREACT_15207 has a Stoichiometric coefficient of 2 Phosphorylated STAT1, STAT3 form dimers Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed16868551 Pubmed8140422 Pubmed9630226 Reactome Database ID Release 431112538 Reactome, http://www.reactome.org ReactomeREACT_27311 Reviewed: Rose-John, S, 2011-02-11 STATs can form dimers in the unphosphorylated state but only phosphorylated dimers are in the correct conformation to to bind consensus DNA sequences of target genes in the nucleus (Riech & Liu 2006). has a Stoichiometric coefficient of 3 Phosphorylated STATs are released Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Following phosphorylation, STATs are released from the receptor. Pubmed8140422 Reactome Database ID Release 431112604 Reactome, http://www.reactome.org ReactomeREACT_27182 Reviewed: Rose-John, S, 2011-02-11 Serine phosphorylation of STATs Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 In addition to tyrosine phosphorylation, STAT1 and STAT3 undergo serine phosphorylation at serine-727, contributing to maximal transcriptional activity (Wen & Darnell 1997, Shen et al. 2004). Though several candidates exist including Protein kinase C delta (Jain et al. 1999), the kinase responsible for IL-6 regulation of Stat serine phosphorylation has yet to be identified (Jain et al. 1999, Abe et al. 2001, Chung et al. 1997) and the significance of serine phosphorylation is unclear (Decker & Kovarik 2000); STAT3 modifed by serine phosphorylation augments oxidative phosphorylation in mitochondria and supported cellular transformation by oncogenic Ras (Reich 2009). Pubmed10446219 Pubmed10851062 Pubmed11429693 Pubmed14673173 Pubmed19797267 Pubmed9153303 Pubmed9343414 Reactome Database ID Release 431112727 Reactome, http://www.reactome.org ReactomeREACT_27262 Reviewed: Rose-John, S, 2011-02-11 has a Stoichiometric coefficient of 2 SOCS3 binds gp130 Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed10064597 Pubmed10777583 Pubmed11527983 Pubmed12403768 Pubmed12754505 Pubmed9419338 Pubmed9789053 Pubmed9889194 Reactome Database ID Release 431112755 Reactome, http://www.reactome.org ReactomeREACT_27241 Reviewed: Rose-John, S, 2011-02-11 Suppressor of cytokine signaling protein 3 (SOCS3) binds to the same gp130 phosphotyrosine (Tyr-759) as SHP2 (Schmitz et al. 2000) though they appear to suppress IL-6 signaling by independent mechanisms (Lehmann et al. 2003).<br>Members of the SOCS family (CIS and SOCS1-7) have an N-terminal SH2 domain preceded by an extended SH2 domain (ESS) and kinase inhibitory region (KIR) (Hilton et al. 1998). The related SOCS1 associates with JAKs via its KIR and SH2 domains (Narazaki et al. 1998, Yasukawa et al. 1999) leading to inhibition of JAK signaling and kinase activity. SOCS3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS1 and SOCS3 inhibit signaling in different ways (Nicholson et al. 1999), but it is possible that SOCS3's inhibitory actions require binding to both activated receptor gp130 Tyr-759 and the associated JAK for maximal inhibition (Greenhalgh & Hilton 2001). Socs3 deficiency results in prolonged STAT1/3 activation after IL-6 but not interferon-gamma stimulation suggesting that SOCS3 has a role in preventing IFN-gamma-like responses in cells stimulated by IL-6 (Croker et al. 2003). SHP2 is phosphorylated Authored: Ray, K, 2010-12-13 EC Number: 2.7.10.2 Edited: Jupe, S, 2010-12-10 Pubmed10409724 Pubmed11684012 Pubmed9285712 Pubmed9794795 Reactome Database ID Release 431112703 Reactome, http://www.reactome.org ReactomeREACT_27185 Reviewed: Rose-John, S, 2011-02-11 SHP2 is tyrosine-phosphorylated in a JAK1-dependent manner (Schaper et al. 1998, Lehmann et al. 2003, Fischer, 2004). Cells lacking JAK1 showed drastically reduced SHP2 phosphorylation following IL-6 treatment, but it is not entirely clear whether JAK1 directly phosphorylates SHP2 or alternatively is required for gp130 activation, which indirectly leads to SHP2 phosphorylation (Schaper et al, 1998). SHP2 tyrosine phosphorylation at Y546 or Y584 (usually described as Y542 or Y580 in literature references where numbering is based on a short isoform) relieves the PTP domain from the N-SH2 domain-mediated inhibition (Lu et al. 2001). Studies using catalytically-inactive SHP2 (Symes et al. 1997) suggest that it may dephosphorylate gp130 and/or associated signaling factors such as JAKs and STATs, limiting acute phase gene expression (Kim and Baumann, 1999). There is a consensus that SHP2 is involved in IL-6-induced activation of the MAPK pathway, but the molecular details are unclear. has a Stoichiometric coefficient of 2 SHP2 binds gp130 phosphotyrosine-759 Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Following IL-6 stimulation, SHP2 is recruited to gp130 phosphotyrosine-759 and is subsequently tyrosine-phosphorylated in a JAK1-dependent manner (Schaper et al. 1998, Lehmann et al. 2003, Fischer, 2004). Mutation of Tyr-759 impairs SHP2 recruitment and phosphorylation (Schaper et al. 1998). <br>There is a consensus that SHP2 is involved in IL-6-induced activation of the MAPK pathway but the molecular details are uncertain, in particular it is not clear whether the phosphatase activity of SHP2 is required. Two pathways have been linked with activation of ERK. One proposed mechanism is that SHP2 acts as an adaptor for Grb2-Sos recruitment (Fukada et al. 1996, Kim & Baumann 1999). Kim & Baumann demonstrate IL-6 induced SHP2 recruitment to p-Tyr-759 of gp130 but note that relatively little of the SHP2 remains associated with gp130, suggesting that SHP2 dissociates from the receptors when phosphorylated. This seems inconsistent with a Grb2-Sos recruitment role for SHP2, though it is possible that only low levels or transient recruitment are required. Kim & Baumann demonstrated that IL-6 induced ERK activation was not inhibited in cells transfected with a phosphatase inactive mutant of SHP2, whereas an SHP2 mutant missing the Grb2 interaction region significantly suppressed ERK activation. This suggests that phosphatase activity is not required for ERK activation while SHP-2 interaction with Grb2 is important. However, overexpression studies can generate artefactual interactions and this interpretation has been questioned (Dance et al. 2008). SHP2 and the adaptor protein Gab1 have been reported to couple gp130 signalling to Erk activation. In this proposal phosphorylated SHP2 dissociates from gp130 and becomes associated with membrane associated Gab1 in a complex with PI3-kinase (Takahashi-Tezuka et al. 1998, Eulenfeld & Schaper 2009). SHP2 interaction is suggested to induce a conformational change in Gab1 that permits Gab1-PI3-kinase activation and enhancement of IL-6-induced Erk pathway activation. However this is speculative, the role of SHP2 phosphatase function is unclear. Other possible mechanisms are outlined by Dance et al. (2008), extrapolated from growth factor receptor mechanisms but with unknown relevance to IL-6/gp130. Pubmed10409724 Pubmed12403768 Pubmed14611646 Pubmed17993263 Pubmed19050043 Pubmed7871433 Pubmed8934572 Pubmed9285712 Pubmed9632795 Pubmed9794795 Reactome Database ID Release 431112708 Reactome, http://www.reactome.org ReactomeREACT_27260 Reviewed: Rose-John, S, 2011-02-11 STAT1/3 dimers translocate to the nucleus Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 In untreated cells both STAT1 and STAT3 are distributed diffusely in the cytoplasm and the nucleus. A few minutes after IL-6 treatment both are preferentially located in the nucleus. This translocation is transient; after 2 h the distribution is comparable to that of untreated cells (Zhang et al. 1995). The mechanism by which STATs enter the nucleus is likely to be mediated by importins via nuclear pore complexes (NPCs) (Reich & Liu, 2006). Pubmed16868551 Pubmed7701321 Reactome Database ID Release 431112587 Reactome, http://www.reactome.org ReactomeREACT_27303 Reviewed: Rose-John, S, 2011-02-11 Activated C1S Reactome DB_ID: 173610 Reactome Database ID Release 43173610 Reactome, http://www.reactome.org ReactomeREACT_8340 has a Stoichiometric coefficient of 1 Activated C1S:activated C1R tetramer Reactome DB_ID: 173614 Reactome Database ID Release 43173614 Reactome, http://www.reactome.org ReactomeREACT_8696 has a Stoichiometric coefficient of 2 C1 complement factor (with activated C1R and C1S) Reactome DB_ID: 173615 Reactome Database ID Release 43173615 Reactome, http://www.reactome.org ReactomeREACT_8287 has a Stoichiometric coefficient of 1 C4 activator Converted from EntitySet in Reactome Reactome DB_ID: 166763 Reactome Database ID Release 43166763 Reactome, http://www.reactome.org ReactomeREACT_8154 Cell surface:C4b Reactome DB_ID: 981716 Reactome Database ID Release 43981716 Reactome, http://www.reactome.org ReactomeREACT_25739 has a Stoichiometric coefficient of 1 C4A-derived C4b Reactome DB_ID: 981643 Reactome Database ID Release 43981643 Reactome, http://www.reactome.org ReactomeREACT_26686 has a Stoichiometric coefficient of 1 C4B-derived C4b Reactome DB_ID: 981722 Reactome Database ID Release 43981722 Reactome, http://www.reactome.org ReactomeREACT_25695 has a Stoichiometric coefficient of 1 C4B Complement factor 4B Reactome DB_ID: 981727 Reactome Database ID Release 43981727 Reactome, http://www.reactome.org ReactomeREACT_26317 has a Stoichiometric coefficient of 1 C4b Converted from EntitySet in Reactome Reactome DB_ID: 981700 Reactome Database ID Release 43981700 Reactome, http://www.reactome.org ReactomeREACT_26471 Complement Factor 4 Converted from EntitySet in Reactome Reactome DB_ID: 981697 Reactome Database ID Release 43981697 Reactome, http://www.reactome.org ReactomeREACT_26761 C4A Complement factor 4A Reactome DB_ID: 166732 Reactome Database ID Release 43166732 Reactome, http://www.reactome.org ReactomeREACT_8206 has a Stoichiometric coefficient of 1 IL7RA associates with JAK1 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2011-05-06 IL7RA has the small juxta-membrane "Box1" motif, conserved throughout the type I cytokine receptor family (Murakami et al. 1991). This is believed to be the site of JAK1 binding (Tanner et al. 1995); deletion of Box1 eliminates JAK1 phosphorylation (Jiang et al. 2004). Studies with T-cell lines expressing mutant IL-4/IL-7 chimeric receptors revealed that loss of Box1 results in rapid cell death, while Y449F mutation causes cell cycle arrest that precedes cell death (Jiang et al. 2004). Mice expressing a knock-in mutation (IL-7R alpha Y449F) displayed defective homeostatic proliferation of naive CD4 and CD8 T-cells (Osbourne et al. 2007). The Y449 site is thus of particular interest because two critical IL-7 signaling pathways, the JAK/STAT pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway may originate from this site (Pallard et al. 1999). Pubmed10367898 Pubmed15226449 Pubmed15996891 Pubmed1662392 Pubmed17325202 Pubmed7896787 Pubmed9287175 Reactome Database ID Release 431264832 Reactome, http://www.reactome.org ReactomeREACT_116023 Reviewed: Puck, J, 2011-11-03 SHP2 binds c-Cbl upon IL-6 stimulation Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed18519587 Reactome Database ID Release 431112690 Reactome, http://www.reactome.org ReactomeREACT_27220 Reviewed: Rose-John, S, 2011-02-11 SHP2 binds CBL in response to IL-6 stimulation in 293T cells and contributes to the ubiquitination of gp130 (Tanaka et al. 2008).<br> IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in its K63-linked polyubiquitination. This stimulation-dependent ubiquitination was mediated by CBL, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner. IL-6 induced a rapid translocation of gp130 from the cell surface to endosomal compartments. The vesicular sorting molecule Hrs contributed to the lysosomal degradation of gp130 by directly recognizing its ubiquitinated form. Deficiency of either Hrs or CBL suppressed gp130 degradation, leading to a prolonged and amplified IL-6 signal. PPBSF is a complex of IL7 and HGFbeta Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2011-05-06 Pubmed11564764 Pubmed12184921 Reactome Database ID Release 431266684 Reactome, http://www.reactome.org ReactomeREACT_116110 Reviewed: Puck, J, 2011-11-03 The pre-pro-B cell growth-stimulating factor (PPBSF) is a self-assembling complex of IL7 and a variant beta-chain of hepatocyte growth factor (HGFbeta) (Lai & Goldschneider 2001). This 55 kDa heterodimer, unlike monomeric IL7, selectively stimulates proliferation and differentiation of pre-pro-B cells in a long-term bone marrow culture system and up-regulates IL7R alpha chain expression on pre-pro-B cell surface. It has been postulated that PPBSF is the active form of IL7 that normally induces IL7R-lo pre-pro-B cells to proliferate and differentiate into IL7R-hi pro-B cells, which then proliferate and differentiate into pre-B-cells on stimulation with monomeric IL7 (Wei et al. 2002). Interleukin-7:IL7RA:JAK1 binds Gc:JAK3 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2011-05-06 Pubmed8128231 Pubmed8266077 Reactome Database ID Release 43449958 Reactome, http://www.reactome.org ReactomeREACT_115695 Reviewed: Puck, J, 2011-11-03 Studies using chemical crosslinking and monoclonal antibodies specific for the IL-2 receptor gamma chain (Gc) demonstrated that Gc participates in the functional high-affinity interleukin-7 receptor complex (Noguchi et al. 1993, Kondo et al. 1994). <br><br>The membrane-associated Gc chain interacts with the intermediate 1:1 IL7:IL7R complex, forming the active ternary complex, which binds IL7 with a 3-fold higher affinity (Kd =80 pM). Interleukin-7 binds IL7RA:JAK1 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2011-05-06 Interleukin-7 receptor alpha chain (IL7R) binds interleukin-7 (IL7), forming a stable 1:1 IL7:IL7R complex, with a dissociation constant (Kd) of approximately 200 pM (Goodwin et al. 1990, Park et al. 1990). The full-length IL7R is a 439-residue single-pass transmembrane glycoprotein consisting of three domains: a 219-residue extracellular domain (ECD), a 25-residue transmembrane domain and a 195-residue cytoplasmic domain. The ECD belongs to the cytokine receptor homology class 1 (CRH1) family, consisting of two fibronectin type III (FNIII) domains with three potential disulfide bonds in the N-terminal FNIII domain and a WSXWS primary sequence motif in the C-terminal domain (Bazan, 1990). Recruitment of kinases to the cytoplasmic tail of IL7R is required for signal transduction because the intracellular portion of IL7R does not contain intrinsic tyrosine kinase activity. IL7 interacts directly with the extracellular region of IL7R and this leads to the recruitment of the Interleukin receptor common gamma chain (Gc, IL2R) and formation of a receptor complex. IL7 binds glycosylated IL7R 300-fold more tightly than unglycosylated. It is thought that IL7 interacts with both IL7R and Gc in the final complex (McElroy et al. 2007). Pubmed19141282 Pubmed2317865 Pubmed2324686 Reactome Database ID Release 43449978 Reactome, http://www.reactome.org ReactomeREACT_115823 Reviewed: Puck, J, 2011-11-03 p(Y449)-IL7RA mediates STAT5 activation Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2011-05-06 Multiple observations support a role for IL7-stimulated JAK/STAT signaling. IL7 induces rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, with concomitant tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7RA was shown to directly induce the activation of JAKs and STATs 1, 5, and 3 by van der Plas et al. (1996). In primary human T cells and NK cells, IL7 induced activation of STAT5a, STAT5b and to a lesser extent STAT1 and STAT3 (Yu et al. 1998). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).<br><br> In human thymocytes, IL7 activates STAT5. It is thought that phosphorylated Y449 in the cytoplasmic domain of the IL7RA is a docking site for STAT5 (Pallard et al. 1999). STAT5 can be activated in COS 7 cells when co transfected with JAK3 (Lin et al. 1996), though this does not demonstrate that JAK3 phosphorylates STAT5 proteins in response to IL7 in vivo (Lin & Leonard, 2000); it is not clear which JAK kinase phosphorylates STAT5 in vivo. T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that Tyr449 is a key residue regulating IL7 mediated STAT5 activation. STAT3 is critical for early B cell differentiation, but the details of its involvement are unclear (Chou et al 2006). Pubmed10367898 Pubmed10851055 Pubmed16825489 Pubmed17325202 Pubmed7481769 Pubmed7489741 Pubmed8631883 Pubmed8709637 Pubmed9590172 Pubmed9715265 Reactome Database ID Release 431295540 Reactome, http://www.reactome.org ReactomeREACT_115766 Reviewed: Puck, J, 2011-11-03 has a Stoichiometric coefficient of 2 IL7RA is phosphorylated on Y449 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10.2 Edited: Jupe, S, 2011-05-06 IL7 receptor signaling is presumed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor. Extending this model to IL7 suggests a similar series of events that bring JAK1 and JAK3 into proximity within a complex IL7:IL7RA:JAK1:Gc:JAK3. Cytoplasmic domains of the IL7 receptor chains orient so that their associated kinases (Janus and possibly phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). <br><br>Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and for activation of the JAK/STAT5 and PI3K/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). Phosphorylated Tyr449 is believed to be a docking site for STAT5 and possibly PI3K, which are then activated by JAKs (Lin et al. 1995, Jiang et al. 2004). T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine. It is thought that JAK1 phosphorylates IL7RA (Jiang et al. 2004). Pubmed10367898 Pubmed15226449 Pubmed15996891 Pubmed17325202 Pubmed7719938 Reactome Database ID Release 431295519 Reactome, http://www.reactome.org ReactomeREACT_115749 Reviewed: Puck, J, 2011-11-03 Growth hormone forms dimers and oligomers Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms. The peptide is encoded by 2 genes, GH1 and GH2, both give rise to multiple variant forms. Post-translational modification including oligomerization increases the variation (Baumann 2009). Approximately 14% of circulating human Growth Hormone (GH) is in dimer or oligomer form, this number varying from 0 to 100% (Kublickas et al. 2006). The biological activity of these oligomeric forms is variably diminished when compared to the monomer (Baumann 2009). Pubmed19467614 Reactome Database ID Release 43982765 Reactome, http://www.reactome.org ReactomeREACT_111071 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 p85 binds p(Y449)-IL7RA Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2011-05-06 Pubmed10367898 Pubmed15123689 Pubmed18523275 Pubmed19543225 Pubmed7520779 Pubmed7522165 Reactome Database ID Release 431295516 Reactome, http://www.reactome.org ReactomeREACT_115826 Reviewed: Puck, J, 2011-11-03 The p85 subunit of PI3K binds to phosphorylated Tyr-449 on IL7RA; Y449F substitution inhibits PI3K-dependent proliferation of IL7-stimulated murine B-lineage cells (Venkitaraman & Cowling 1994).<br><br>Stimulation of human lymphocyte precursor cells with IL-7 induced tyrosine phosphorylation of the p85 subunit of PI3-kinase (PI3K) and activation of PI3K kinase activity (Dadi et al. 1994). It is thought that, depending on species differences and stage of lymphocyte development, IL7 induced PI3K pathway can promote signals that are important for survival and proliferation of both T cells and B cells. <br><br>Activation of PI3K leads to the generation of membrane associated PIP3 and membrane recruitment of AKT/PKB, the key downstream target of PI3K. AKT mediates phosphorylation of downstream substrates involved in regulation of cell survival and proliferation. IL7 induced activation of PI3K/AKT in human thymocytes has been reported (Pallard et al. 1999; Johnson et al. 2008). In mouse thymocytes IL7 stimulation resulted in the inactivation of BAD by serine phosphorylation; the PI3K/AKT pathway has been implicated in BAD phosphorylation. These results suggest that IL7 signaling via AKT inactivates the pro-apoptotic protein BAD promoting T cell survival (Li et al. 2004). <br><br>Rochman et al. (2009) suggest that IL7 promotes lymphocyte survival by activating the pro-survival PI3K/AKT signaling pathway and by increasing the expression of survival factors such as BCL2 and myeloid cell leukemia sequence 1 (MCL-1) while iinhibiting the expression of pro-apoptotic factors BAX and BAD. Growth hormone receptor dimerizes Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 Pubmed16116438 Pubmed16820415 Pubmed1948064 Pubmed8343952 Reactome Database ID Release 43982775 Reactome, http://www.reactome.org ReactomeREACT_111208 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 The growth hormone receptor forms dimers (Cunningham et al. 1991) that subsequently signal via JAK2 (Argetsinger et al. 1993). Early studies suggested that dimerization occured following ligand binding, but it is now generally accepted that dimerization is independent of ligand binding and involves the transmembrane and juxtamembrane domains (van den Eijnden et al. 2006, Brown et al. 2005). has a Stoichiometric coefficient of 2 Growth hormone receptor binds JAK2 Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 JAKs bind to the box1 motif (residues 297-305) of the Growth Hormone Receptor (GHR) (Argetsinger et al. 1993), a proline-rich region just inside the cell membrane. Binding is mediated largely by the JAK N-terminal FERM domain (Frank et al. 1995, He et al. 2003). JAK 2 binding enhances the stability of GHR (He et al. 2005). Pubmed12920237 Pubmed16081639 Pubmed7956946 Pubmed8343952 Reactome Database ID Release 43982792 Reactome, http://www.reactome.org ReactomeREACT_111052 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 Complement factor 3 Reactome DB_ID: 166822 Reactome Database ID Release 43166822 Reactome, http://www.reactome.org ReactomeREACT_8213 has a Stoichiometric coefficient of 1 Cell surface:C4b:C2a Reactome DB_ID: 166784 Reactome Database ID Release 43166784 Reactome, http://www.reactome.org ReactomeREACT_8917 has a Stoichiometric coefficient of 1 Cell surface:C3b:Factor B complex Reactome DB_ID: 173737 Reactome Database ID Release 43173737 Reactome, http://www.reactome.org ReactomeREACT_8205 has a Stoichiometric coefficient of 1 Surface-associated C3bBb Cell surface:C3b:Factor Bb Reactome DB_ID: 173749 Reactome Database ID Release 43173749 Reactome, http://www.reactome.org ReactomeREACT_8668 has a Stoichiometric coefficient of 1 Cell surface:C3b:Factor Bb:Properdin Reactome DB_ID: 173752 Reactome Database ID Release 43173752 Reactome, http://www.reactome.org ReactomeREACT_8531 has a Stoichiometric coefficient of 1 C3bBb3b C3b:Factor Bb:C3b:Properdin complex C5 convertase Reactome DB_ID: 174554 Reactome Database ID Release 43174554 Reactome, http://www.reactome.org ReactomeREACT_8784 has a Stoichiometric coefficient of 1 C3bB Alternative pathway C3-convertase C3(H2O):Factor B Reactome DB_ID: 182529 Reactome Database ID Release 43182529 Reactome, http://www.reactome.org ReactomeREACT_8649 has a Stoichiometric coefficient of 1 iC3Bb C3(H2O):Factor Bb Initial C3 convertase Reactome DB_ID: 182451 Reactome Database ID Release 43182451 Reactome, http://www.reactome.org ReactomeREACT_8857 has a Stoichiometric coefficient of 1 C3b Reactome DB_ID: 166832 Reactome Database ID Release 43166832 Reactome, http://www.reactome.org ReactomeREACT_8621 has a Stoichiometric coefficient of 1 Cell surface:C3b Reactome DB_ID: 981542 Reactome Database ID Release 43981542 Reactome, http://www.reactome.org ReactomeREACT_26114 has a Stoichiometric coefficient of 1 Growth hormone binds the growth hormone receptor Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 Pubmed1549776 Pubmed19927328 Reactome Database ID Release 43982778 Reactome, http://www.reactome.org ReactomeREACT_111053 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 The growth hormone receptor (GHR) belongs to the superfamily of transmembrane proteins that includes the prolactin receptor and a number of class 1 cytokine receptors. It exists in two forms, full-length membrane-bound receptor with a single transmembrane region, and growth hormone binding protein (GHBP), a shorter soluble form corresponding to the extracellular domain of the full-length receptor. In rodents GHBP is encoded by a specific mRNA variant while in humans it results from proteolytic cleavage of the membrane receptor by a metalloprotease. The classical view is that growth hormone sequentially binds 2 molecules of GHR inducing dimerization, but it is now widely accepted that GHR dimers exist prior to ligand binding (Poger & Mark 2010). GH:GHR:JAK2 complex undergoes a conformational change Authored: Jupe, S, 2010-10-14 Classical models of GHR activation suggest that GH binds sequentially to two GHR molecules, leading to receptor dimerization and activation. More recently, evidence from FRET, BRET, Co-IP (Brown et al. 2005) and molecular simulations (Poger & Mark 2010) suggest that dimerization occurs before ligand binding, and that activation is a consequence of conformational changes caused by ligand binding, namely a relative rotation of the receptor dimer so that the catalytic domains of JAK2 molecules bound to the cytoplasmic tails are brought into close proximity and are consequently able to phosphorylate each other (Rowlinson et al. 2008). Realignment of the receptor subunits and consequent JAK2 activation is supported by crystal structures of the related erythropoietin receptor (Livnah et al. 1999); similar proposals have been made for many receptors, including the prolactin and erythropoietin receptors (Brooks & Waters 2010). Edited: Jupe, S, 2011-06-10 Pubmed16116438 Pubmed18488018 Pubmed19927328 Pubmed20664532 Pubmed9974392 Reactome Database ID Release 43982768 Reactome, http://www.reactome.org ReactomeREACT_111166 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 iC3 C3(H2O) Complement factor 3(H2O) Reactome DB_ID: 182450 Reactome Database ID Release 43182450 Reactome, http://www.reactome.org ReactomeREACT_8268 has a Stoichiometric coefficient of 1 SHP1 and SHP2 dephosphorylate Y628 of IL3RB Authored: Ray, KP, 2010-05-17 EC Number: 3.1.3.48 Edited: Jupe, S, 2010-08-06 Pubmed9162089 Reactome Database ID Release 43914036 Reactome, http://www.reactome.org ReactomeREACT_23816 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 Synthetic phosphopeptides based on Bc were dephosphorylated by SHP1 and SHP2, peptides phosphorylated at Y628 were the best substrate followed by those phosphorylated at Y766. SHP1 and SHP2 bind the common beta chain Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed7522233 Pubmed7528537 Pubmed7889566 Pubmed8943354 Pubmed8995399 Pubmed9162089 Reactome Database ID Release 43909738 Reactome, http://www.reactome.org ReactomeREACT_24014 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The common beta chain (Bc) has at least at least one direct binding site for SHP-1/SHP-2 (PTPN6/PTPN11). The SH2 domains of SHP1 and SHP2 associate with Y628 of Bc following IL-3 stimulation (Pei et al. 1994, Bone et al. 1997). SHPs act as regulators of signaling. SHP1 is thought to be a negative regulator of growth that terminates signals. Binding of SHP1 to EpoR leads to SHP1 activation and dephosphorylation of JAK2, terminating proliferative signals (Klingmuller et al. 1995). SHP1 has also been shown to interact directly and dephosphorylate JAK2 (Jiao et al. 1996). Although SHP-2 competes for the same binding site, it is thought to be a positive modulator. SHP2 associates with JAK1/2 and is phosphorylated at Y304 by these kinases, creating a GRB2 recognition motif (Yin et al. 1997). IL-3 induces the phosphorylation of SHP2 and its association with Grb2 (Welham et al. 1994). SHP2 could thereby act as an adaptor between Bc and Grb2 leading to activation of the ras/mitogen-activated protein kinase pathway. SHP2 can also associate with the p85 subunit of phosphatidylinositol 3-kinase (Welham et al. 1994) so SHP2 may also regulate this pathway. IL3 stimulation induces Vav binding to Tec kinase Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 IL3 stimulation induces rapid and transient tyrosine-phosphorylation of Vav and the binding of Vav to Tec kinase through Tec homology domains. (Machide et al. 1995). Vav1 and Tec were seen to associate into a complex with the activated prolactin receptor (Kline et al. 2001). These reports were interpreted as Tec enhancing Vav GEF activity, but it has been suggested that Vav might contribute to Tec activation in T cell signaling (Reynolds et al. 2002). Tec kinases generally require PI3K-dependent membrane translocation and phosphorylation of the kinase domain, often by an Src family kinase, for activation (Takesono et al. 2002). Pubmed11328862 Pubmed11994416 Pubmed12118060 Pubmed7651724 Reactome Database ID Release 43879914 Reactome, http://www.reactome.org ReactomeREACT_23914 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 CBL binds VAV Authored: Ray, KP, 2010-05-17 Cbl and Vav interact in thymocytes and peripheral T cells (Marengere et al. 1997). Cbl phosphorylated at Y700 binds Vav1 in 293T cells, leading to Vav ubiquitinylation and proteolytic degradation. Edited: Jupe, S, 2010-08-06 Pubmed12881521 Pubmed9200440 Reactome Database ID Release 43912727 Reactome, http://www.reactome.org ReactomeREACT_23989 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 CBL binds B-cell linker protein Authored: Ray, KP, 2010-05-17 Cbl binds B-cell linker protein, a molecular scaffold bridging Syk to downstream signaling pathways by recruiting signaling molecules, such as Btk, phospholipase C gamma 2, Vav, and Grb2 to the cell membrane to form a signalosome complex. Cbl is believed to negatively regulate signaling from this complex. Consistent with this, Cbl inactivation reverses a number of critical defects in early B cell differentiation seen in BLNK-deficient mice (Song et al. 2007). Edited: Jupe, S, 2010-08-06 Pubmed17202354 Reactome Database ID Release 43912724 Reactome, http://www.reactome.org ReactomeREACT_23998 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 Collagen type I fibre Reactome DB_ID: 2214305 Reactome Database ID Release 432214305 Reactome, http://www.reactome.org ReactomeREACT_151903 MBL-II:Activated MASP-1 dimer:Activated MASP-2 dimer complex Reactome DB_ID: 166713 Reactome Database ID Release 43166713 Reactome, http://www.reactome.org ReactomeREACT_8440 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 BHC complex:REST:REST DNA binding sites Reactome DB_ID: 996764 Reactome Database ID Release 43996764 Reactome, http://www.reactome.org ReactomeREACT_25596 has a Stoichiometric coefficient of 1 Collagen type II fibre Reactome DB_ID: 2214299 Reactome Database ID Release 432214299 Reactome, http://www.reactome.org ReactomeREACT_151036 Activated MBL bound to mannose-based carbohydrates on bacterial surfaces Reactome DB_ID: 166724 Reactome Database ID Release 43166724 Reactome, http://www.reactome.org ReactomeREACT_8515 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 ZFPM proteins:GATA proteins Reactome DB_ID: 996751 Reactome Database ID Release 43996751 Reactome, http://www.reactome.org ReactomeREACT_25675 has a Stoichiometric coefficient of 1 Collagen type I fibril with histidino-hydroxylysinoleucine cross-links Reactome DB_ID: 2399500 Reactome Database ID Release 432399500 Reactome, http://www.reactome.org ReactomeREACT_151084 MBL bound to mannose-based carbohydrates on bacterial surfaces Reactome DB_ID: 166719 Reactome Database ID Release 43166719 Reactome, http://www.reactome.org ReactomeREACT_8711 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Collagen fibres Converted from EntitySet in Reactome Reactome DB_ID: 2214304 Reactome Database ID Release 432214304 Reactome, http://www.reactome.org ReactomeREACT_151881 MASP-1 dimer Reactome DB_ID: 166693 Reactome Database ID Release 43166693 Reactome, http://www.reactome.org ReactomeREACT_8419 has a Stoichiometric coefficient of 2 Collagen type XI fibre Reactome DB_ID: 2214303 Reactome Database ID Release 432214303 Reactome, http://www.reactome.org ReactomeREACT_151368 Collagen type III fibre Reactome DB_ID: 2214307 Reactome Database ID Release 432214307 Reactome, http://www.reactome.org ReactomeREACT_152488 Collagen type V fibre Reactome DB_ID: 2214302 Reactome Database ID Release 432214302 Reactome, http://www.reactome.org ReactomeREACT_152391 Activated MASP-2 dimer Reactome DB_ID: 166702 Reactome Database ID Release 43166702 Reactome, http://www.reactome.org ReactomeREACT_8498 has a Stoichiometric coefficient of 1 Activated MASP-1 dimer Reactome DB_ID: 182687 Reactome Database ID Release 43182687 Reactome, http://www.reactome.org ReactomeREACT_8695 has a Stoichiometric coefficient of 1 IRF2:Promoter region of INF beta Reactome DB_ID: 1018384 Reactome Database ID Release 431018384 Reactome, http://www.reactome.org ReactomeREACT_26266 has a Stoichiometric coefficient of 1 Antigen: antibody: C1 complex Reactome DB_ID: 173582 Reactome Database ID Release 43173582 Reactome, http://www.reactome.org ReactomeREACT_8034 has a Stoichiometric coefficient of 1 IRF2:Promoter region of INF alpha Reactome DB_ID: 994019 Reactome Database ID Release 43994019 Reactome, http://www.reactome.org ReactomeREACT_26427 has a Stoichiometric coefficient of 1 CP CAPZ Capping protein F-actin capping protein Reactome DB_ID: 879384 Reactome Database ID Release 43879384 Reactome, http://www.reactome.org ReactomeREACT_26977 has a Stoichiometric coefficient of 1 HP1alpha:Histone H3 methylated at K9 Reactome DB_ID: 994100 Reactome Database ID Release 43994100 Reactome, http://www.reactome.org ReactomeREACT_27026 has a Stoichiometric coefficient of 1 Collagen type XII, XIV fibrils Converted from EntitySet in Reactome Reactome DB_ID: 2220797 Reactome Database ID Release 432220797 Reactome, http://www.reactome.org ReactomeREACT_150658 C1Q subunit (C1QA:C1QB:C1QC heterotrimer) Reactome DB_ID: 173588 Reactome Database ID Release 43173588 Reactome, http://www.reactome.org ReactomeREACT_8328 has a Stoichiometric coefficient of 1 F-actin capping protein:f-actin Reactome DB_ID: 994173 Reactome Database ID Release 43994173 Reactome, http://www.reactome.org ReactomeREACT_26552 has a Stoichiometric coefficient of 1 Collagen type I, II fibrils Converted from EntitySet in Reactome Reactome DB_ID: 2220802 Reactome Database ID Release 432220802 Reactome, http://www.reactome.org ReactomeREACT_150821 C1S:C1R tetramer Reactome DB_ID: 173585 Reactome Database ID Release 43173585 Reactome, http://www.reactome.org ReactomeREACT_8438 has a Stoichiometric coefficient of 2 LRRC16A:F-actin capping protein Reactome DB_ID: 994154 Reactome Database ID Release 43994154 Reactome, http://www.reactome.org ReactomeREACT_26939 has a Stoichiometric coefficient of 1 Collagen type XXVII fibre Reactome DB_ID: 2214301 Reactome Database ID Release 432214301 Reactome, http://www.reactome.org ReactomeREACT_151680 C1 complement factor Reactome DB_ID: 173584 Reactome Database ID Release 43173584 Reactome, http://www.reactome.org ReactomeREACT_8815 has a Stoichiometric coefficient of 1 REST:REST DNA binding sites Reactome DB_ID: 996761 Reactome Database ID Release 43996761 Reactome, http://www.reactome.org ReactomeREACT_25691 has a Stoichiometric coefficient of 1 Collagen type XXIV fibre Reactome DB_ID: 2214306 Reactome Database ID Release 432214306 Reactome, http://www.reactome.org ReactomeREACT_150582 C1Q Reactome DB_ID: 173579 Reactome Database ID Release 43173579 Reactome, http://www.reactome.org ReactomeREACT_8220 has a Stoichiometric coefficient of 6 BHC complex Reactome DB_ID: 996752 Reactome Database ID Release 43996752 Reactome, http://www.reactome.org ReactomeREACT_26743 has a Stoichiometric coefficient of 1 JAKs associate with IL6RB (gp130) Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed10861237 Pubmed11468294 Pubmed11557047 Pubmed12773095 Pubmed7537214 Pubmed8134389 Pubmed8272873 Pubmed9590172 Reactome Database ID Release 431067646 Reactome, http://www.reactome.org ReactomeREACT_27152 Reviewed: Rose-John, S, 2011-02-11 The tyrosine kinases JAK1, JAK2 and Tyk2 associate with the cytoplasmic domain of the interleukin-6 receptor beta subunit gp130 (Stahl et al. 1994), via interactions with the membrane proximal Box1/Box2 region, motifs conserved amongst many cytokine receptors. This region of gp130 is sufficient for JAK activation (Narazaki et al. 1994). The interbox region is also involved in JAK binding (Haan et al. 2000). This is a strong and stable assocation considered to be constitutive (Heinrich et al. 2003). The N-terminal region of JAK1 contains a FERM domain that is crucial for receptor association (Haan et al. 2001, Hilkens et al. 2001). IL-6 induces rapid phosphorylation and activation of JAK1, JAK2 and Tyk2 in cells (Guschin et al. 1995), but experiments in JAK1 deficient cell lines (Guschin et al. 1995) and JAK1 -/- mice (Rodig et al. 1998) where IL-6-induced responses (gp130 phosphorylation and actvation of Stat1 and Stat3) were greatly impaired, suggest that JAK1 is the key kinase for signal transduction. One possible model is that JAK1 associates with gp130 and triggers downstream events, but requires either JAK2 or Tyk2 for efficient activation or ligand-induced dimerization of the receptor complex. p-S585-IL3RB binds 14-3-3 proteins Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10477722 Pubmed10949031 Reactome Database ID Release 43912757 Reactome, http://www.reactome.org ReactomeREACT_23870 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The common beta chain (Bc), binds 14-3-3 zeta at a site that requires phosphorylation of Serine 585 (Stomski et al. 1999). Bc modifications that prevent Ser-585 phosphorylation do not recruit 14-3-3 zeta (Guthridge et al. 2000). 14-3-3 zeta binding allows recruitment of PI3K Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Immunoprecipitation and kinase activity experiments demonstrated that Ser-585 phosphorylation of the common beta chain (Bc) was required for activation of PI3K activity in response to IL-3 and co-precipitation of Bc, 14-3-3 zeta and the p85 subunit of Class 1A PI3 kinases (Guthridge et al. 2000). Subsequent experiments confirmed that Ser-585 phosphorylation and PI3K activation are required to promote cell survival in response to GM-CSF, but not for proliferation responses, and that this mechanism is independent of Bc tyrosine phosphorylation (Guthridge et al. 2004). This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors; the other involves Bc tyrosine-593 phosphorylation-mediated recruitment of SHC1, GRB2 and GAB2. Pubmed10949031 Pubmed12920017 Reactome Database ID Release 43914182 Reactome, http://www.reactome.org ReactomeREACT_23861 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 SHP2 can recruit GRB2 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed7522233 Pubmed7523381 Pubmed7559570 Reactome Database ID Release 43914022 Reactome, http://www.reactome.org ReactomeREACT_23965 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 SHP2 can associate with GRB2 (Stein-Gerlach et al. 1995). IL-3 induces the phosphorylation of SHP2 and its association with GRB2 (Welham et al. 1994). SHP2 may act as a scaffold protein to recruit other signaling molecules, e.g. SHP2 was reported to link GRB2 to the receptor tyrosine kinase c-kit (Tauchi et al. 1994). IL3RB is phosphorylated on Ser-585 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.11.11 Edited: Jupe, S, 2010-08-06 GM-CSF and IL-3 application lead to Ser-585 phosphorylation of the Common beta chain (Bc) shared with the IL-3 and IL-5 receptors (Stomski et al. 1999, Guthridge et al. 2000). PKA was identified as capable of phosphorylating Bc at S585 (Guthridge et al. 2000). Pubmed10477722 Pubmed10949031 Reactome Database ID Release 43913451 Reactome, http://www.reactome.org ReactomeREACT_23999 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 IL6:sIL6R binds to JAKs:IL6RB (gp130) Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed16707558 Pubmed2261637 Pubmed2788034 Reactome Database ID Release 431067651 Reactome, http://www.reactome.org ReactomeREACT_27309 Reviewed: Rose-John, S, 2011-02-11 The complex of IL6 and the soluble, short form of the IL6 receptor binds to surface expressed IL6RB (gp130), a process known as trans signaling (Rose-John et al. 2006). Interleukin-6 binds to IL-6 receptor alpha subunit Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Interleukin-6 site I interacts with the non-sigaling but ligand specific IL-6R alpha chain. Pubmed2788034 Reactome Database ID Release 431067667 Reactome, http://www.reactome.org ReactomeREACT_27186 Reviewed: Rose-John, S, 2011-02-11 Assembly of a hexameric IL-6 receptor Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed12829785 Pubmed16741736 Reactome Database ID Release 431067659 Reactome, http://www.reactome.org ReactomeREACT_27222 Reviewed: Rose-John, S, 2011-02-11 There are three contact sites between IL-6, IL-6R and gp130, named site I, II and III. Site I and II correspond to the respective sites of the growth hormone receptor complex whereas site III is only found in receptor complexes with at least three subunits. Various models of the IL-6 receptor complex have been proposed (Scheller & Rose-John 2006), but crystallographic data suggests the assembly of a hexameric complex containing two IL-6, two IL-6RA and two gp130 subunits. The quaternary structures of other IL-6/IL-12 family signaling complexes suggest they have a similar topology (Boulanger et al. 2003). has a Stoichiometric coefficient of 2 IL6:IL6RA binds JAKs:IL6RB (gp130) Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed2788034 Reactome Database ID Release 431067688 Reactome, http://www.reactome.org ReactomeREACT_27227 Reviewed: Rose-John, S, 2011-02-11 The complex of IL-6 bound to the IL-6 receptor alpha subunit binds the IL-6 receptor beta subunit gp130. Site II of IL-6 within the binary complex interacts with the cytokine binding-homology region of gp130. Subsequently, site III of IL-6 interacts with the gp130 immunoglobulin-like activation domain. IL6:sIL6R binds sgp130 Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed11121117 Reactome Database ID Release 431067676 Reactome, http://www.reactome.org ReactomeREACT_27205 Reviewed: Rose-John, S, 2011-02-11 Soluble gp130 binds to circulating IL6:sIL6R, preventing binding to gp130 on the plasma membrane, thereby specifically inhibiting IL-6 trans-signaling (Jostock et al. 2001). This protein is to enter clinical development for the treatment of inflammatory diseases. It can be anticipated that less beneficial activities of IL-6 will be blocked by soluble gp130 than by global blockade of IL-6 with neutralizing monoclonal antibodies to IL-6 or IL-6R Interleukin-6 binds to soluble IL-6 receptor Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed16707558 Pubmed2788034 Reactome Database ID Release 431067640 Reactome, http://www.reactome.org ReactomeREACT_27133 Reviewed: Rose-John, S, 2011-02-11 The short, soluble form of Interleukin-6 receptor alpha (sIL6R), like the longer membrane-associated form IL6RA, binds circulating Interleukin-6 (IL-6). sIL6R is generated by limited proteolysis of the longer membrane associated form and by translation of an alternatively spliced mRNA. The IL-6:sIL6R dimer can associate with the IL6 receptor signaling beta subunit gp130 and stimulate cells that do not express IL6RA, a process termed trans-signaling. Gp130 is widely expressed in many cell types that do not express IL6RA (Rose-John et al. 2006). Collagen type XVII fibril Reactome DB_ID: 2172656 Reactome Database ID Release 432172656 Reactome, http://www.reactome.org ReactomeREACT_151611 IgG Ig G Antibody Reactome DB_ID: 182629 Reactome Database ID Release 43182629 Reactome, http://www.reactome.org ReactomeREACT_8295 has a Stoichiometric coefficient of 2 Endostatin releasing proteases Converted from EntitySet in Reactome Reactome DB_ID: 2228675 Reactome Database ID Release 432228675 Reactome, http://www.reactome.org ReactomeREACT_150741 Antigen-antibody complex Reactome DB_ID: 173552 Reactome Database ID Release 43173552 Reactome, http://www.reactome.org ReactomeREACT_8124 has a Stoichiometric coefficient of 1 proMMP1 initial activators Converted from EntitySet in Reactome Reactome DB_ID: 1602468 Reactome Database ID Release 431602468 Reactome, http://www.reactome.org ReactomeREACT_120008 Antigen: antibody: C1 (activated C1R) complex Reactome DB_ID: 173619 Reactome Database ID Release 43173619 Reactome, http://www.reactome.org ReactomeREACT_8973 has a Stoichiometric coefficient of 1 proMMP3 initial activators Converted from EntitySet in Reactome Reactome DB_ID: 1604721 Reactome Database ID Release 431604721 Reactome, http://www.reactome.org ReactomeREACT_119611 IgG Heavy Chain Ig gamma heavy chain Reactome DB_ID: 1591203 Reactome Database ID Release 431591203 Reactome, http://www.reactome.org ReactomeREACT_111781 has a Stoichiometric coefficient of 1 MMP7 initial activators Converted from EntitySet in Reactome Reactome DB_ID: 1604762 Reactome Database ID Release 431604762 Reactome, http://www.reactome.org ReactomeREACT_119838 proMMP8 initial activators Converted from EntitySet in Reactome Reactome DB_ID: 2127623 Reactome Database ID Release 432127623 Reactome, http://www.reactome.org ReactomeREACT_119119 C1 complement factor (with activated C1R) Reactome DB_ID: 173617 Reactome Database ID Release 43173617 Reactome, http://www.reactome.org ReactomeREACT_8044 has a Stoichiometric coefficient of 1 C1S:activated C1R tetramer Reactome DB_ID: 173613 Reactome Database ID Release 43173613 Reactome, http://www.reactome.org ReactomeREACT_8336 has a Stoichiometric coefficient of 2 Activated C1R Reactome DB_ID: 173604 Reactome Database ID Release 43173604 Reactome, http://www.reactome.org ReactomeREACT_8067 has a Stoichiometric coefficient of 1 C-reactive protein pentamer:phosphocholine:C1Q Reactome DB_ID: 976769 Reactome Database ID Release 43976769 Reactome, http://www.reactome.org ReactomeREACT_25403 has a Stoichiometric coefficient of 1 C-reactive protein pentamer:phosphocholine Reactome DB_ID: 976722 Reactome Database ID Release 43976722 Reactome, http://www.reactome.org ReactomeREACT_26090 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 5 C-reactive protein homopentamer Reactome DB_ID: 976808 Reactome Database ID Release 43976808 Reactome, http://www.reactome.org ReactomeREACT_25462 has a Stoichiometric coefficient of 10 has a Stoichiometric coefficient of 5 Antigen: antibody: C1 (activated C1R and C1S) complex Reactome DB_ID: 173618 Reactome Database ID Release 43173618 Reactome, http://www.reactome.org ReactomeREACT_8066 has a Stoichiometric coefficient of 1 JAK activation Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed11287676 Pubmed11742534 Pubmed18178840 Pubmed7531704 Pubmed8134389 Pubmed8272873 Pubmed8986719 Pubmed9382798 Reactome Database ID Release 431112514 Reactome, http://www.reactome.org ReactomeREACT_27288 Reviewed: Rose-John, S, 2011-02-11 The molecular mechanism of Jak activation upon cytokine stimulation is not understood in detail (Haan et al. 2008). Cytokine-induced receptor aggregation and the resulting close proximity of Jaks bound to the beta receptor subunit is believed to trigger trans-phosphorylation of Jak tyrosines in their kinase activation loop, confering kinase activity. This active state is believed to be maintained by further autocatalytic tyrosine phosphorylations. For JAK1 the activation loop tyrosine residues are predicted by homology with models of JAK2 (Lindauer et al. 2001) to be Tyr-1034/1035. Mutation of Tyr-1034 abolishes JAK1 kinase activity (Liu et al. 1997). Evidence supporting JAK1 transphosphorylation includes JAK1 mutant cell lines, which cannot activate Tyk2 after stimulation with interferon alpha/beta (Velazquez et al. 1995) and the observation that IL-2 cannot activate JAK1 in the absence of JAK3 (Oakes et al. 1996). The receptor is not merely a docking site for JAKs as certain gp130 residues are required for JAK1 activation, but not essential for JAK1 binding (Haan et al. 2002). has a Stoichiometric coefficient of 12 Phosphorylation of gp130 Activated JAKs are believed to be responsible for phosphorylating the cytoplasmic region of gp130 (Wang & Fuller 1994, Reich & Liu 2006) creating docking sites for adaptor and downstream signaling molecules, in particular the STAT factors STAT1 and STAT3. Several phosphotyrosine residues of gp130 are docking sites for STAT factors (Stahl et al. 1995, Gerhartz et al. 1996), Tyr-759 phosphorylation allows recruitment of the phosphatase SHP2. Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed16868551 Pubmed7812050 Pubmed7871433 Pubmed8662591 Reactome Database ID Release 431112510 Reactome, http://www.reactome.org ReactomeREACT_27189 Reviewed: Rose-John, S, 2011-02-11 has a Stoichiometric coefficient of 20 STATs bind gp130 phosphotyrosines Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Pubmed8662591 Pubmed8662795 Reactome Database ID Release 431112565 Reactome, http://www.reactome.org ReactomeREACT_27225 Reviewed: Rose-John, S, 2011-02-11 STAT1 binds to gp130 via phosphotyrosine residues 905 and 915, these located within two YXPD recognition motifs. STAT3 can also be recruited to these sites as well as two additional sites around Y767 and Y814, these having less restricted sequence recognition requirements (YXXQ) (Gerhartz et al. 1996). Subsequent to receptor binding, these STAT factors are phosphorylated on a single tyrosine residue by JAKs (Hemmann et al. 1996). Tyrosine phosphorylation of STATs by IL6 receptor Authored: Ray, K, 2010-12-13 EC Number: 2.7.10.2 Edited: Jupe, S, 2010-12-10 IL-6 activates the tyrosine phosphorylation of STATs (Akira et al. 1994, Zhong et al. 1994) by JAKs (Hemmann et al. 1996) at a site that is essential for dimerization. For STAT1 this is tyrosine-701, for STAT3 tyrosine-705 (Kaptein et al. 1996, Shuai et al. 1994). Tyrosine phosphorylation leads to homo- or heterodimerization and translocation to the nucleus (Zhong et al. 1994), where the dimers bind to enhancers of interleukin-6- inducible genes e.g. acute phase protein genes, resulting in transcriptional activation. Pubmed7510216 Pubmed7512451 Pubmed8140422 Pubmed8626374 Pubmed8662795 Reactome Database ID Release 431112602 Reactome, http://www.reactome.org ReactomeREACT_27203 Reviewed: Rose-John, S, 2011-02-11 has a Stoichiometric coefficient of 2 CR1:C3bBb, C4bC2a complexes Converted from EntitySet in Reactome Reactome DB_ID: 981676 Reactome Database ID Release 43981676 Reactome, http://www.reactome.org ReactomeREACT_120030 C4bC2a, C3bBb Converted from EntitySet in Reactome Reactome DB_ID: 977357 Reactome Database ID Release 43977357 Reactome, http://www.reactome.org ReactomeREACT_119171 class I MHC complex Reactome DB_ID: 182294 Reactome Database ID Release 43182294 Reactome, http://www.reactome.org ReactomeREACT_11978 has a Stoichiometric coefficient of 1 CR1:C4bC2a Reactome DB_ID: 981651 Reactome Database ID Release 43981651 Reactome, http://www.reactome.org ReactomeREACT_120159 has a Stoichiometric coefficient of 1 Nef:class I MHC complex:AP-1:PACS-1 Complex Reactome DB_ID: 182254 Reactome Database ID Release 43182254 Reactome, http://www.reactome.org ReactomeREACT_11657 has a Stoichiometric coefficient of 1 CR1:C3bBb Reactome DB_ID: 981686 Reactome Database ID Release 43981686 Reactome, http://www.reactome.org ReactomeREACT_119312 has a Stoichiometric coefficient of 1 Arf1:Nef:endosomal CD4 Reactome DB_ID: 200867 Reactome Database ID Release 43200867 Reactome, http://www.reactome.org ReactomeREACT_11580 has a Stoichiometric coefficient of 1 MCP, CR1:C4b:C3b complexes Converted from EntitySet in Reactome Reactome DB_ID: 981661 Reactome Database ID Release 43981661 Reactome, http://www.reactome.org ReactomeREACT_120251 Internalized CD4:Nef:Clathrin-Coated Pit Adapter Protein:v-ATPase Reactome DB_ID: 167554 Reactome Database ID Release 43167554 Reactome, http://www.reactome.org ReactomeREACT_11967 has a Stoichiometric coefficient of 1 MCP:C3b Reactome DB_ID: 981623 Reactome Database ID Release 43981623 Reactome, http://www.reactome.org ReactomeREACT_119903 has a Stoichiometric coefficient of 1 CD8:Nef:AP-2 Complex:v-ATPase Complex Reactome DB_ID: 182158 Reactome Database ID Release 43182158 Reactome, http://www.reactome.org ReactomeREACT_11369 has a Stoichiometric coefficient of 1 CD8:Nef Complex Reactome DB_ID: 182194 Reactome Database ID Release 43182194 Reactome, http://www.reactome.org ReactomeREACT_11411 has a Stoichiometric coefficient of 1 CD4:Nef Complex Reactome DB_ID: 167596 Reactome Database ID Release 43167596 Reactome, http://www.reactome.org ReactomeREACT_11987 has a Stoichiometric coefficient of 1 CR1:C3b Reactome DB_ID: 981635 Reactome Database ID Release 43981635 Reactome, http://www.reactome.org ReactomeREACT_119014 has a Stoichiometric coefficient of 1 20oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed2836406 Reactome Database ID Release 432161745 Reactome, http://www.reactome.org ReactomeREACT_150304 Reviewed: Rush, MG, 2012-11-10 The cytochrome P450s 4F2 (CYP4F2) and F3 (CYP4F3) oxidise the omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20oh-LTB4) to form 20-aldehyde leukotriene B4 (20cho-LTB4) (Soberman et al. 1988). has a Stoichiometric coefficient of 2 CD4:Lck Complex Reactome DB_ID: 167529 Reactome Database ID Release 43167529 Reactome, http://www.reactome.org ReactomeREACT_11737 has a Stoichiometric coefficient of 1 CR1:C4b Reactome DB_ID: 981675 Reactome Database ID Release 43981675 Reactome, http://www.reactome.org ReactomeREACT_119535 has a Stoichiometric coefficient of 1 CD4:Nef:AP-2 Complex:v-ATPase Complex Reactome DB_ID: 167544 Reactome Database ID Release 43167544 Reactome, http://www.reactome.org ReactomeREACT_11339 has a Stoichiometric coefficient of 1 MCP:C4b Reactome DB_ID: 981669 Reactome Database ID Release 43981669 Reactome, http://www.reactome.org ReactomeREACT_119237 has a Stoichiometric coefficient of 1 AP-2 Complex Reactome DB_ID: 167712 Reactome Database ID Release 43167712 Reactome, http://www.reactome.org ReactomeREACT_11732 has a Stoichiometric coefficient of 1 C4b, C3b Converted from EntitySet in Reactome Reactome DB_ID: 977600 Reactome Database ID Release 43977600 Reactome, http://www.reactome.org ReactomeREACT_119260 5S-HpETE is dehydrated to LTA4 by ALOX5 Authored: Jassal, B, 2008-10-01 13:18:42 Dehydration of 5-HpETE to leukotriene A4 EC Number: 1.13.11.34 Edited: Jassal, B, 2008-04-21 14:30:22 In the second step of the formation of leukotriene A4 (LTA4) from arachidonic acid, arachidonate 5-lipoxygenase (ALOX5) converts 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) to an allylic epoxide, leukotriene A4 (LTA4) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986). Pubmed3006030 Pubmed3118366 Pubmed3164719 Reactome Database ID Release 43266051 Reactome, http://www.reactome.org ReactomeREACT_15453 Reviewed: Rush, MG, 2012-11-10 LTA4 is hydrolyzed to LTB4 Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 3.3.2.6 Edited: Jassal, B, 2008-04-21 14:30:22 LTA4 is hydolysed to LTB4 by LTA4H Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that catalyzes the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) to the dihydroxy acid leukotriene B4 (LTB4) (Radmark et al. 1984, McGee & Fitzpatrick 1985). Pubmed2995393 Pubmed6490615 Reactome Database ID Release 43266072 Reactome, http://www.reactome.org ReactomeREACT_15478 Reviewed: Rush, MG, 2012-11-10 LTB4 is oxidised to 12-oxoLTB4 by PTGR1 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Prostaglandin reductase 1 (PTGR1) aka LTB4DH metabolizes eicosanoids by catalysing the oxidation of leukotriene B4 (LTB4) to form 12-oxo-Leukotriene B4 (12-oxoLTB4) aka 12-Keto-LTB4. The gene was originally cloned as leukotriene B4 12-hydroxydehydrogenase (LTB4DH) but was later discovered to have dual functionality as a prostaglandin reductase (Yokomizo et al. 1996). This reaction has been inferred from a reaction in pigs (Yokomizo et al. 1993, Ensor et al. 1998). Pubmed8394361 Pubmed8576264 Pubmed9461497 Reactome Database ID Release 432161567 Reactome, http://www.reactome.org ReactomeREACT_150449 Reviewed: Rush, MG, 2012-11-10 IgG C region Converted from EntitySet in Reactome Ig gamma C region Reactome DB_ID: 1584646 Reactome Database ID Release 431584646 Reactome, http://www.reactome.org ReactomeREACT_111460 Collagen alpha-1(XVIII) chain endostatin-like fragments Converted from EntitySet in Reactome Reactome DB_ID: 2470878 Reactome Database ID Release 432470878 Reactome, http://www.reactome.org ReactomeREACT_151787 LTB4 is hydroxylated to 20oh-LTB4 by CYP4F2/4F3 Authored: Jassal, B, 2008-05-19 12:57:01 CYP4F2 omega-hydroxylates leukotriene B4, thus inactivating it EC Number: 1.14.13.30 Edited: Jassal, B, 2008-05-19 12:57:01 Leukotriene B4 (LTB4) is formed from arachidonic acid and is a potent inflammatory mediator. LTB4's activity is terminated by formation of its omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20oh-LTB4), catalysed by CYP4F2 primarily in human liver (Jin et al. 1998) and also by CYP4F3 (Kikuta et al. 1998). Pubmed9539102 Pubmed9799565 Reactome Database ID Release 43211873 Reactome, http://www.reactome.org ReactomeREACT_13738 Reviewed: Rush, MG, 2012-11-10 TXB2 is converted to 11dh-TXB2 by TXDH Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed3461463 Pubmed3823488 Pubmed8200461 Reactome Database ID Release 432161732 Reactome, http://www.reactome.org ReactomeREACT_150346 Reviewed: Rush, MG, 2012-11-10 Thromboxane B2 (TXB2) undergoes dehydrogenation at C-11 to form 11-dehydro-thromboxane B2 (11dh-TXB2). The enzyme responsible for catalysis has been termed 11-dehydroxythromboxane B2 dehydrogenase (TXDH) (Kumlin & Granström 1986, Catella et al. 1986, Westlund et al. 1994). The human TXDH isoform has not been cloned but 11dh-TXB2 has been detected in various experiments. Nef:class I MHC complex:Ap-1:PACS-1 Complex Reactome DB_ID: 182373 Reactome Database ID Release 43182373 Reactome, http://www.reactome.org ReactomeREACT_11308 has a Stoichiometric coefficient of 1 PGH2 is degraded to 12S-HHT and MDA by TBXAS1 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed11297515 Reactome Database ID Release 432161613 Reactome, http://www.reactome.org ReactomeREACT_150343 Reviewed: Rush, MG, 2012-11-10 Thromboxane synthase (TBXAS1) aka CYP5A1 facilitates rearrangement of the PGH2 endoperoxide bridge by a complementary mechanism to prostacyclin synthase, interacting with the C-9 oxygen to promote endoperoxide bond cleavage. The C-11 oxygen radical initiates intramolecular rearrangement, resulting in either the formation of thromboxane A2 (TXA2) or 12-hydroxyheptadecatrienoic acid (12S-HHT) and malonaldehyde (MDA) (Wang et al. 2001). ALOX5 is phosphorylated by MAPKAP2 Arachidonate 5-lipoxygenase (ALOX5) catalyzes the first step in leukotriene biosynthesis and has a key role in inflammatory processes. ALOX5 is phosphorylated by MAPKAPK2; MAPKAPK2 is stimulated by arachidonic acid. Authored: Jupe, S, 2009-07-14 EC Number: 2.7.11 Edited: Jupe, S, 2010-05-06 Pubmed10779545 Pubmed11844797 Reactome Database ID Release 43429016 Reactome, http://www.reactome.org ReactomeREACT_22105 Reviewed: Rush, MG, 2012-11-10 Oxidation of arachidonic acid to 5-HpETE Arachidonate 5-lipoxygenase (ALOX5) catalyzes the formation of leukotriene A4 (LTA4) from arachidonic acid in a two-step process. First, arachidonic acid AA is oxidized to form 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986). Arachidonic acid is oxidised to 5S-HpETE by ALOX5 Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.13.11.34 Edited: Jassal, B, 2008-04-21 14:30:22 Pubmed3006030 Pubmed3118366 Pubmed3164719 Reactome Database ID Release 43265296 Reactome, http://www.reactome.org ReactomeREACT_15337 Reviewed: Rush, MG, 2012-11-10 TXA2 is hydrolysed to TXB2 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed1059088 Pubmed11297515 Reactome Database ID Release 43443894 Reactome, http://www.reactome.org ReactomeREACT_150183 Reviewed: Rush, MG, 2012-11-10 Thromboxane A2 (TXA2) contains an unstable ether linkage that is rapidly hydrolysed under aqueous conditions to form the biologically inert thromboxane B2 (TXB2) (Wang et al. 2001, Hamberg et al. 1975), which is excreted. Thromboxane A2 degenerates to thromboxane B2 Fyn:Nef Complex Reactome DB_ID: 200911 Reactome Database ID Release 43200911 Reactome, http://www.reactome.org ReactomeREACT_11637 has a Stoichiometric coefficient of 1 DAF:C3 convertase complexes Converted from EntitySet in Reactome Reactome DB_ID: 981657 Reactome Database ID Release 43981657 Reactome, http://www.reactome.org ReactomeREACT_119393 C4B-derived C4c Reactome DB_ID: 981709 Reactome Database ID Release 43981709 Reactome, http://www.reactome.org ReactomeREACT_119428 has a Stoichiometric coefficient of 1 C4A-derived C4c Reactome DB_ID: 981502 Reactome Database ID Release 43981502 Reactome, http://www.reactome.org ReactomeREACT_119576 has a Stoichiometric coefficient of 1 C4c Converted from EntitySet in Reactome Reactome DB_ID: 981715 Reactome Database ID Release 43981715 Reactome, http://www.reactome.org ReactomeREACT_119729 Factor I:MCP, CR1:C4b, C3b complexes Reactome DB_ID: 977599 Reactome Database ID Release 43977599 Reactome, http://www.reactome.org ReactomeREACT_120091 has a Stoichiometric coefficient of 1 AP-1 Complex Reactome DB_ID: 167717 Reactome Database ID Release 43167717 Reactome, http://www.reactome.org ReactomeREACT_11249 has a Stoichiometric coefficient of 1 Nef:class I MHC complex Reactome DB_ID: 182256 Reactome Database ID Release 43182256 Reactome, http://www.reactome.org ReactomeREACT_11813 has a Stoichiometric coefficient of 1 class I MHC complex Reactome DB_ID: 182275 Reactome Database ID Release 43182275 Reactome, http://www.reactome.org ReactomeREACT_11465 has a Stoichiometric coefficient of 1 CD28:Nef:Clathrin-coated Pit Adapter Protein Reactome DB_ID: 167631 Reactome Database ID Release 43167631 Reactome, http://www.reactome.org ReactomeREACT_11442 has a Stoichiometric coefficient of 1 C4b-binding protein Reactome DB_ID: 981649 Reactome Database ID Release 43981649 Reactome, http://www.reactome.org ReactomeREACT_120080 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 7 CD28:Nef:Clathrin-coated Pit Adapter Protein Complex Reactome DB_ID: 167636 Reactome Database ID Release 43167636 Reactome, http://www.reactome.org ReactomeREACT_11677 has a Stoichiometric coefficient of 1 DAF:C3b Reactome DB_ID: 981684 Reactome Database ID Release 43981684 Reactome, http://www.reactome.org ReactomeREACT_119929 has a Stoichiometric coefficient of 1 Nef:CD28 Complex Reactome DB_ID: 167629 Reactome Database ID Release 43167629 Reactome, http://www.reactome.org ReactomeREACT_11853 has a Stoichiometric coefficient of 1 DAF:C4b Reactome DB_ID: 981639 Reactome Database ID Release 43981639 Reactome, http://www.reactome.org ReactomeREACT_119228 has a Stoichiometric coefficient of 1 DOCK2:ELMO1:RAC1:Nef Complex Reactome DB_ID: 200937 Reactome Database ID Release 43200937 Reactome, http://www.reactome.org ReactomeREACT_11827 has a Stoichiometric coefficient of 1 DAF:C4bC2a Reactome DB_ID: 981620 Reactome Database ID Release 43981620 Reactome, http://www.reactome.org ReactomeREACT_119816 has a Stoichiometric coefficient of 1 Lck:Nef Reactome DB_ID: 200922 Reactome Database ID Release 43200922 Reactome, http://www.reactome.org ReactomeREACT_11930 has a Stoichiometric coefficient of 1 DAF:C3bBb Reactome DB_ID: 981652 Reactome Database ID Release 43981652 Reactome, http://www.reactome.org ReactomeREACT_120189 has a Stoichiometric coefficient of 1 Nef:T cell Receptor zeta:Lipid Raft: Pak 2 Complex Reactome DB_ID: 167576 Reactome Database ID Release 43167576 Reactome, http://www.reactome.org ReactomeREACT_11396 has a Stoichiometric coefficient of 1 Hck-1:Nef Reactome DB_ID: 200872 Reactome Database ID Release 43200872 Reactome, http://www.reactome.org ReactomeREACT_11973 has a Stoichiometric coefficient of 1 C5b:C6:C7 complex Reactome DB_ID: 173708 Reactome Database ID Release 43173708 Reactome, http://www.reactome.org ReactomeREACT_8454 has a Stoichiometric coefficient of 1 C5b:C6 complex Reactome DB_ID: 173711 Reactome Database ID Release 43173711 Reactome, http://www.reactome.org ReactomeREACT_8500 has a Stoichiometric coefficient of 1 PGH2 is isomerised to PGD2 by PTGDS Authored: Williams, MG, 2012-02-24 EC Number: 5.3.99.2 Edited: Williams, MG, 2012-02-24 Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, PTDGS promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Zhou et al. 2010). Pubmed20667974 Reactome Database ID Release 432161620 Reactome, http://www.reactome.org ReactomeREACT_150378 Reviewed: Rush, MG, 2012-11-10 RTC with minus sssDNA containing deaminated C residues:tRNA primer:RNA template Reactome DB_ID: 180731 Reactome Database ID Release 43180731 Reactome, http://www.reactome.org ReactomeREACT_9776 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 C8 Reactome DB_ID: 173713 Reactome Database ID Release 43173713 Reactome, http://www.reactome.org ReactomeREACT_8563 has a Stoichiometric coefficient of 1 PGA2 is dehydrated to 15d-PGA2 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed10200320 Reactome Database ID Release 432161668 Reactome, http://www.reactome.org ReactomeREACT_150290 Reviewed: Rush, MG, 2012-11-10 The non-enzymatic dehydration of prostaglandin A2 (PGA2) into 15-deoxy prostaglandin A2 (15d-PGA2) which occurs in mice (Petrova et al. 1999) is inferred in humans. APOBEC3G:RTC with deaminated minus sssDNA:tRNA primer:RNA template Reactome DB_ID: 180744 Reactome Database ID Release 43180744 Reactome, http://www.reactome.org ReactomeREACT_9785 has a Stoichiometric coefficient of 1 C5b:C6:C7 complex Reactome DB_ID: 173719 Reactome Database ID Release 43173719 Reactome, http://www.reactome.org ReactomeREACT_8333 has a Stoichiometric coefficient of 1 Vif:APOBEC3G complex Reactome DB_ID: 180543 Reactome Database ID Release 43180543 Reactome, http://www.reactome.org ReactomeREACT_9662 has a Stoichiometric coefficient of 1 Membrane Attack Complex Reactome DB_ID: 173728 Reactome Database ID Release 43173728 Reactome, http://www.reactome.org ReactomeREACT_8325 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 12 PGH2 is isomerised to PGD2 by HPGDS Authored: Williams, MG, 2012-02-24 EC Number: 5.3.99.2 Edited: Williams, MG, 2012-02-24 Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, HPGDS with GSH promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Jowsey et al. 2001, Inoue et al. 2003). Pubmed11672424 Pubmed12627223 Reactome Database ID Release 432161701 Reactome, http://www.reactome.org ReactomeREACT_150171 Reviewed: Rush, MG, 2012-11-10 minus sssDNA containing deaminated C residues:RNA template:tRNA primer Reactome DB_ID: 180727 Reactome Database ID Release 43180727 Reactome, http://www.reactome.org ReactomeREACT_9668 has a Stoichiometric coefficient of 1 C5b:C6:C7:C8 complex Reactome DB_ID: 173722 Reactome Database ID Release 43173722 Reactome, http://www.reactome.org ReactomeREACT_8352 has a Stoichiometric coefficient of 1 Collagen alpha-1(XIII) chain N-term transmembrane regions Converted from EntitySet in Reactome Reactome DB_ID: 2471887 Reactome Database ID Release 432471887 Reactome, http://www.reactome.org ReactomeREACT_151383 APOBEC3G:Vif:Cul5:SCF complex Reactome DB_ID: 180549 Reactome Database ID Release 43180549 Reactome, http://www.reactome.org ReactomeREACT_9643 has a Stoichiometric coefficient of 1 C4b:C2a:C3b Reactome DB_ID: 173635 Reactome Database ID Release 43173635 Reactome, http://www.reactome.org ReactomeREACT_8556 has a Stoichiometric coefficient of 1 Cul5-SCF complex Reactome DB_ID: 180596 Reactome Database ID Release 43180596 Reactome, http://www.reactome.org ReactomeREACT_9690 has a Stoichiometric coefficient of 1 C3 convertases Converted from EntitySet in Reactome Reactome DB_ID: 173750 Reactome Database ID Release 43173750 Reactome, http://www.reactome.org ReactomeREACT_8751 Vif:Cul5:SCF complex Reactome DB_ID: 180539 Reactome Database ID Release 43180539 Reactome, http://www.reactome.org ReactomeREACT_9902 has a Stoichiometric coefficient of 1 C5 convertases Converted from EntitySet in Reactome Reactome DB_ID: 173759 Reactome Database ID Release 43173759 Reactome, http://www.reactome.org ReactomeREACT_8864 multi-ubiquitinated APOBEC3G:Vif:Cul5:SCF complex Reactome DB_ID: 180577 Reactome Database ID Release 43180577 Reactome, http://www.reactome.org ReactomeREACT_9570 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Complement factor 5 Reactome DB_ID: 173676 Reactome Database ID Release 43173676 Reactome, http://www.reactome.org ReactomeREACT_8215 has a Stoichiometric coefficient of 1 Rev:importin-beta:B23:Ran-GTP complex Reactome DB_ID: 180712 Reactome Database ID Release 43180712 Reactome, http://www.reactome.org ReactomeREACT_9842 has a Stoichiometric coefficient of 1 C5b Reactome DB_ID: 173671 Reactome Database ID Release 43173671 Reactome, http://www.reactome.org ReactomeREACT_8814 has a Stoichiometric coefficient of 1 PGH2 is reduced to PGF2a by FAM213B Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TXN) are the proteins involved in the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Moriuchi et al. 2008, Yoshikawa et al. 2011). This reaction has been inferred from an event in mice. An additional way of achieving this reaction involves the protein aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS. Pubmed18006499 Pubmed20950588 Reactome Database ID Release 432161612 Reactome, http://www.reactome.org ReactomeREACT_150194 Reviewed: Rush, MG, 2012-11-10 APOBEC3G:HIV-1PIC Reactome DB_ID: 180618 Reactome Database ID Release 43180618 Reactome, http://www.reactome.org ReactomeREACT_9691 has a Stoichiometric coefficient of 1 PGH2 is isomerised to PGE2 by PTGES Authored: Williams, MG, 2012-02-24 EC Number: 5.3.99.3 Edited: Williams, MG, 2012-02-24 Prostaglandin E synthase (PTGES) requires glutathione (GSH) as an essential cofactor for its enzymatic activity, and together they isomerise prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2) (Jegerschold et al. 2008). After PGH2 has been produced by the prostaglandin G/H synthases (PTGS1 and 2) on the lumenal side of the endoplasmic reticulum, it diffuses through the membrane to the active site of PTGES located on the cytoplasmic side. Pubmed18682561 Reactome Database ID Release 432161660 Reactome, http://www.reactome.org ReactomeREACT_150407 Reviewed: Rush, MG, 2012-11-10 APOBEC3G:RTC with minus sssDNA:tRNA primer:RNA template Reactome DB_ID: 180616 Reactome Database ID Release 43180616 Reactome, http://www.reactome.org ReactomeREACT_9745 has a Stoichiometric coefficient of 1 Prostaglandin E synthase isomerizes PGH2 to PGE2 Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 5.3.99.3 Prostaglandin E2 (PGE2) is the most abundant prostanoid in the body and is a major mediator of inflammation in diseases such as osteoarthritis and rheumatoid arthritis. The product of arachidonic acid, prostaglandin H2 (PGH2) serves as the substrate for the isomerization to PGE2. The conversion is carried out by prostaglandin E synthase (PGES), of which there are three forms. Two are membrane-bound enzymes and are designated as mPGES-1 (functionally linked with COX-2) and mPGES-2 (golgi membrane-associated, functionally coupled with both COX-1 and COX-2). The other is cytosolic (cPGES, PTGES3) and functionally linked to COX-1 to produce PGE2 immediately. In this reaction, cPGES is used for conversion of PGH2 to PGE2. Pubmed10922363 Reactome Database ID Release 43265295 Reactome, http://www.reactome.org ReactomeREACT_15459 Reviewed: Rush, MG, 2012-11-10 PGE2 is converted to PGF2a by CBR1 Authored: Williams, MG, 2012-02-24 Carbonyl reductase (CBR1) aka prostaglandin 9-keto reductase inactivates prostaglandin E2 (PGE2) by converting it to prostaglandin F2alpha (PGF2a) (Wermuth 1981, Miura et al. 2008). EC Number: 1.1.1.189 Edited: Williams, MG, 2012-02-24 Pubmed18493841 Pubmed7005231 Reactome Database ID Release 432161651 Reactome, http://www.reactome.org ReactomeREACT_150185 Reviewed: Rush, MG, 2012-11-10 PGE2 is dehydrated to PGA2 Authored: Williams, MG, 2012-02-24 Cyclopentenone prostaglandins comprise a family of molecules that are formed by dehydration of hydroxyl moieties in prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Dehydration of PGE2 leads to prostaglandin A2 (PGA2) (Hamberg & Samuelsson B 1966, Amin 1989). Edited: Williams, MG, 2012-02-24 Pubmed2717650 Pubmed5903721 Reactome Database ID Release 432161659 Reactome, http://www.reactome.org ReactomeREACT_150333 Reviewed: Rush, MG, 2012-11-10 PGA2 is isomerised to PGC2 Authored: Williams, MG, 2012-02-24 Dehydration in the cyclopentane ring of prostaglandin E2 (PGE2) yields prostaglandin A2 (PGA2) followed by isomerization of the double bond to yield the unstable compound prostaglandin C2 (PGC2) (Straus & Glass, 2001). Edited: Williams, MG, 2012-02-24 Pubmed11301410 Reactome Database ID Release 432161666 Reactome, http://www.reactome.org ReactomeREACT_150179 Reviewed: Rush, MG, 2012-11-10 PGC2 is isomerised to PGB2 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Isomerization of the double bond in prostaglandin A2 (PGA2) forms prostaglandin C2 (PGC2). This is an unstable compound which undergoes a second isomerization to yield prostaglandin B2 (PGB2) (Straus & Glass, 2001). Pubmed11301410 Reactome Database ID Release 432161735 Reactome, http://www.reactome.org ReactomeREACT_150271 Reviewed: Rush, MG, 2012-11-10 Factor H:Host cell surface Reactome DB_ID: 1006173 Reactome Database ID Release 431006173 Reactome, http://www.reactome.org ReactomeREACT_119254 has a Stoichiometric coefficient of 1 Host cell surface Reactome DB_ID: 1006146 Reactome Database ID Release 431006146 Reactome, http://www.reactome.org ReactomeREACT_119096 has a Stoichiometric coefficient of 1 Factor H:C3b Reactome DB_ID: 976755 Reactome Database ID Release 43976755 Reactome, http://www.reactome.org ReactomeREACT_120113 has a Stoichiometric coefficient of 1 Importin beta-1:Rev multimer complex Reactome DB_ID: 180707 Reactome Database ID Release 43180707 Reactome, http://www.reactome.org ReactomeREACT_9841 has a Stoichiometric coefficient of 1 Complement factor I:Factor H:C3b Reactome DB_ID: 976770 Reactome Database ID Release 43976770 Reactome, http://www.reactome.org ReactomeREACT_119450 has a Stoichiometric coefficient of 1 Vpr:importin-alpha complex Reactome DB_ID: 180623 Reactome Database ID Release 43180623 Reactome, http://www.reactome.org ReactomeREACT_8944 has a Stoichiometric coefficient of 1 Complement factor I C3B/C4B inactivator Reactome DB_ID: 976749 Reactome Database ID Release 43976749 Reactome, http://www.reactome.org ReactomeREACT_119465 has a Stoichiometric coefficient of 1 PGH2 is isomerised to TXA2 by TBXAS1 Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 5.3.99.5 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed11465543 Pubmed7925341 Reactome Database ID Release 4376500 Reactome, http://www.reactome.org ReactomeREACT_1377 Reviewed: Rush, MG, 2012-11-10 Thromboxane synthase (CYP5A1) mediates the isomerization of prostaglandin H2 to thromboxane A2 Thromboxane synthase (TBXAS1) aka CYP5A1 mediates the isomerization of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2) (Miyata et al. 2001, Chevalier et al. 2001). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. PIC anchored to the NPC Reactome DB_ID: 180610 Reactome Database ID Release 43180610 Reactome, http://www.reactome.org ReactomeREACT_8912 has a Stoichiometric coefficient of 1 Cell surface:FH,FHR3:C3bBb Reactome DB_ID: 977373 Reactome Database ID Release 43977373 Reactome, http://www.reactome.org ReactomeREACT_118983 has a Stoichiometric coefficient of 1 PGI2 is hydrolysed to 6k-PGF1a Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed15115769 Reactome Database ID Release 432161619 Reactome, http://www.reactome.org ReactomeREACT_150142 Reviewed: Rush, MG, 2012-11-10 The ring in prostaglandin I2 (PGI2) aka prostacyclin is highly labile and rapidly hydolyses to form the stable but biologically inactive 6-keto-prostaglandin F1alpha (6k-PGF1a) (Wada et al. 2004). PGI2 and 6k-PGF1a are often used interchangeably in the literature. Cell surface:FH,FHR3:C3b Reactome DB_ID: 977596 Reactome Database ID Release 43977596 Reactome, http://www.reactome.org ReactomeREACT_119386 has a Stoichiometric coefficient of 1 Importin beta-1:Rev multimer complex Reactome DB_ID: 180713 Reactome Database ID Release 43180713 Reactome, http://www.reactome.org ReactomeREACT_9823 has a Stoichiometric coefficient of 1 Rev:Importin-beta:B23 Reactome DB_ID: 180711 Reactome Database ID Release 43180711 Reactome, http://www.reactome.org ReactomeREACT_9742 has a Stoichiometric coefficient of 1 iC3b Reactome DB_ID: 977380 Reactome Database ID Release 43977380 Reactome, http://www.reactome.org ReactomeREACT_119218 has a Stoichiometric coefficient of 1 nucleoporin-associated Rev:Importin-beta:B23 complex Reactome DB_ID: 180720 Reactome Database ID Release 43180720 Reactome, http://www.reactome.org ReactomeREACT_9793 has a Stoichiometric coefficient of 1 Complement factor I:Cell surface:FH,FHR3:C3b Reactome DB_ID: 977365 Reactome Database ID Release 43977365 Reactome, http://www.reactome.org ReactomeREACT_119579 has a Stoichiometric coefficient of 1 Rev:Importin-beta:B23 Reactome DB_ID: 180724 Reactome Database ID Release 43180724 Reactome, http://www.reactome.org ReactomeREACT_9868 has a Stoichiometric coefficient of 1 iC3b Reactome DB_ID: 976805 Reactome Database ID Release 43976805 Reactome, http://www.reactome.org ReactomeREACT_120169 has a Stoichiometric coefficient of 1 Delta12-PGJ2 is dehydrated to 15d-PGJ2 15-Deoxy-delta(12,14)-PDJ2 (15d-PGJ2) is a dehydration product of delta-12-prostaglandin J2 (delta12-PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed11907120 Reactome Database ID Release 432161588 Reactome, http://www.reactome.org ReactomeREACT_150262 Reviewed: Rush, MG, 2012-11-10 Ran GTPase:GDP Reactome DB_ID: 165549 Reactome Database ID Release 43165549 Reactome, http://www.reactome.org ReactomeREACT_6416 has a Stoichiometric coefficient of 1 Collagen alpha-1(XIII) ectodomains Converted from EntitySet in Reactome Reactome DB_ID: 2471850 Reactome Database ID Release 432471850 Reactome, http://www.reactome.org ReactomeREACT_152330 PGD2 is dehydrated to 15d-PGD2 15-Deoxy-delta 12,14-prostaglandins D2 (15d-PGD2) is a dehydrated form of prostaglandin D2 (PGD2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed11907120 Reactome Database ID Release 432161673 Reactome, http://www.reactome.org ReactomeREACT_150400 Reviewed: Rush, MG, 2012-11-10 ANT1:Vpr complex Reactome DB_ID: 180906 Reactome Database ID Release 43180906 Reactome, http://www.reactome.org ReactomeREACT_8897 has a Stoichiometric coefficient of 1 PGD2 is dehydrated to PGJ2 Analogous to prostaglandin E2 (PGE2), dehydration of the prostaglandin D2 (PGD2) prostane ring forms prostaglandin J2 (PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed11907120 Reactome Database ID Release 432161733 Reactome, http://www.reactome.org ReactomeREACT_150141 Reviewed: Rush, MG, 2012-11-10 Crm1:Ran GTPase:GTP Reactome DB_ID: 165556 Reactome Database ID Release 43165556 Reactome, http://www.reactome.org ReactomeREACT_6618 has a Stoichiometric coefficient of 1 PGJ2 is isomerised to delta12-PGJ2 Authored: Williams, MG, 2012-02-24 Delta-12-prostaglandin J2 (delta12-PGJ2) is an isomerisation product of prostaglandin J2 (PGJ2) (Monneret et al. 2002). Edited: Williams, MG, 2012-02-24 Pubmed11907120 Reactome Database ID Release 432161563 Reactome, http://www.reactome.org ReactomeREACT_150384 Reviewed: Rush, MG, 2012-11-10 RanBP1:Ran-GTP:CRM1:Rev-bound mRNA complex Reactome DB_ID: 180718 Reactome Database ID Release 43180718 Reactome, http://www.reactome.org ReactomeREACT_8366 has a Stoichiometric coefficient of 1 15k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1 Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Prostaglandin reductase 1 (PTGR1) aka LTB4DH is a 13-prostaglandin reductase which metabolises eicosanoids by catalysing NADH/NADPH-dependant double bond reduction in 15-keto-prostaglandin E2 (15k-PGE2) and F2alpha (15k-PGF2a) to produce 13,14-dihydro-15-keto-prostaglandin E2 (dhk-PGE2) and F2alpha (dhk-PGF2a) respectively (Yokomizo 1996). This has been inferred from the reaction event in mice involving prostaglandin reductase 2 (Ptgr2) (Chou et al. 2007). Pubmed17449869 Pubmed8576264 Reactome Database ID Release 432161692 Reactome, http://www.reactome.org ReactomeREACT_150174 Reviewed: Rush, MG, 2012-11-10 PGH2 is isomerised to PGI2 by PTGIS Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 5.3.99.4 Edited: Jassal, B, 2008-05-19 12:57:01 Prostacyclin synthase (CYP8A1) mediates the isomerization of prostaglandin H2 to prostaglandin I2 Prostacyclin synthase (PTGIS) aka CYP8A1 mediates the isomerisation of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2) aka prostacyclin (Wada et al. 2004). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. Pubmed15115769 Reactome Database ID Release 4376496 Reactome, http://www.reactome.org ReactomeREACT_1841 Reviewed: Rush, MG, 2012-11-10 PGD2 is reduced to 11-epi-PGF2a by AKRIC3 Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is the enzyme involved in NADPH-dependent prostaglandin D2 11-keto reductase activity of reducing prostaglandin D2 (PGD2) to 11-epi-Prostaglandin F2alpha (11-epi-PGF2a) (Liston & Roberts 1985, Koda et al. 2004). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed15047184 Pubmed3862115 Reactome Database ID Release 432161614 Reactome, http://www.reactome.org ReactomeREACT_150443 Reviewed: Rush, MG, 2012-11-10 PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD 15-Hydroxyprostaglandin dehydrogenase (HPGD) oxidises prostaglandins D2 (PGD2), E2 (PGE2), and F2alpha (PGF2a) to 15-keto-prostaglandin D2 (15k-PGD2), E2 (15k-PGE2), and F2alpha (15k-PGF2a) respectively (Cho et al. 2006). This reaction is inferred from rabbits (Bergholte & Okita 1986). Authored: Williams, MG, 2012-02-24 EC Number: 1.1.1.141 Edited: Williams, MG, 2012-02-24 Pubmed16828555 Pubmed3954355 Reactome Database ID Release 432161662 Reactome, http://www.reactome.org ReactomeREACT_150186 Reviewed: Rush, MG, 2012-11-10 Hydrolysis of phosphatidylcholine Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Once bound to the membrane, cPLA2 hydrolyzes phosphatidylcholine to produce arachidonic acid (AA), a precursor to inflammatory mediators. While several phospholipases can catalyze this reaction in cells overexpressing the enzymes, PLA2G4A is the major enzyme that catalyzes this reaction in vivo (Reed et al. 2011). At the same time, possible physiological roles have been described for soluble phospholipases (sPLA) in the mobilization of arachidonic acid in some cell types or under some physiological conditions (Murakami et al. 2011). Here, the major role of PLA2G4A has been annotated. Pubmed21247147 Pubmed21746768 Reactome Database ID Release 43111883 Reactome, http://www.reactome.org ReactomeREACT_15331 Reviewed: Rush, MG, 2012-11-10 Desaturation of tetracosatetraenoyl-CoA to tetracosapentaenoyl-CoA Authored: Garapati, P V, 2012-01-11 EC Number: 1.14.19.3 Edited: Garapati, P V, 2012-01-11 Pubmed11988075 Pubmed1834642 Reactome Database ID Release 432046097 Reactome, http://www.reactome.org ReactomeREACT_120926 Tetracosatetraenoyl-CoA is further desaturated by delta 6-desaturase (FADS2) to tetracosapentaenoyl-CoA (TPA-CoA, 6,9,12,15,18-24:5(n-6)). has a Stoichiometric coefficient of 2 Translocation of tetracosapentaenoyl-CoA to peroxisomes Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 Prior to this reaction all the enzymes involved in the desaturation and elongation of linoleic acid are located in the ER, but for this last step tetracosapentaenoyl-CoA must be transferred to the peroxisomes for partial beta-oxidation to docosapentaenoyl-CoA (DPA-CoA, 4,7,10,13,16-22:5(n-6)) (Su et al. 2001). Pubmed11500517 Pubmed12897190 Pubmed9684854 Reactome Database ID Release 432046093 Reactome, http://www.reactome.org ReactomeREACT_121197 Peroxisomal beta-oxidation of tetracosapentaenoyl-CoA to Docosapentaenoyl-CoA Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 One cycle of peroxisomal beta-oxidation shortens C24:5(n-6) to C22:5(n-6), releasing one molecules of acetyl-CoA. Peroxisomal acyl-coenzyme A oxidase 1 (AOX), D-bifunctional protein (DBP/MFE2), and either peroxisomal 3-oxoacyl-CoA thiolase (Th) or SCPx thiolase (SCPx) enzymes have been proposed to be responsible for this partial beta-oxidation (Infante & Huszagh 1998, Su et al. 2001). Pubmed11500517 Pubmed9684854 Reactome Database ID Release 432046101 Reactome, http://www.reactome.org ReactomeREACT_120819 Translocation of DPA to the ER Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 Pubmed11500517 Pubmed20480548 Reactome Database ID Release 432066782 Reactome, http://www.reactome.org ReactomeREACT_120783 The resulted free DPA is transported back to ER, where it is incorporated into membrane lipids. Collagen type XVI chains Converted from EntitySet in Reactome Reactome DB_ID: 2179244 Reactome Database ID Release 432179244 Reactome, http://www.reactome.org ReactomeREACT_124800 TAB2/3 Converted from EntitySet in Reactome Reactome DB_ID: 975101 Reactome Database ID Release 43975101 Reactome, http://www.reactome.org ReactomeREACT_26800 Endostatin-XV Converted from EntitySet in Reactome Reactome DB_ID: 2484944 Reactome Database ID Release 432484944 Reactome, http://www.reactome.org ReactomeREACT_152254 Collagen type XII chains Converted from EntitySet in Reactome Reactome DB_ID: 2179235 Reactome Database ID Release 432179235 Reactome, http://www.reactome.org ReactomeREACT_124510 MMP9,13 Converted from EntitySet in Reactome Reactome DB_ID: 2470800 Reactome Database ID Release 432470800 Reactome, http://www.reactome.org ReactomeREACT_151640 Collagen type XIII chains Converted from EntitySet in Reactome Reactome DB_ID: 2179238 Reactome Database ID Release 432179238 Reactome, http://www.reactome.org ReactomeREACT_122946 Collagen type XIV chains Converted from EntitySet in Reactome Reactome DB_ID: 2179249 Reactome Database ID Release 432179249 Reactome, http://www.reactome.org ReactomeREACT_121814 Collagen type XV chains Converted from EntitySet in Reactome Reactome DB_ID: 2179248 Reactome Database ID Release 432179248 Reactome, http://www.reactome.org ReactomeREACT_122828 Collagen type VIII chains Converted from EntitySet in Reactome Reactome DB_ID: 2173302 Reactome Database ID Release 432173302 Reactome, http://www.reactome.org ReactomeREACT_125200 Desaturation of dihomo-gamma-lenolenoyl-CoA to arachidonoyl-CoA Authored: Garapati, P V, 2012-01-11 DGL-CoA (8,11,14-eicosatrienoyl-CoA) undergoes desaturation by delta 5-desaturase (D5-desaturase) forming arachidonoyl-CoA (AA-CoA, 5,8,11,14-Eicosatetraenoic acid). D5-desaturase has 62% sequence identity with D6-desaturase but desaturates a different carbon atom, adding a double bond at position C5 in arachidonoyl-CoA (AA-CoA). AA can be metabolized by variety of oxygenases (including cyclo-oxygenase and lipoxygenase systems) to form a family of varying products known as eicosanoids, prostaglandins, leukotrines and thromboxanes thus playing important role in inflamation response. Edited: Garapati, P V, 2012-01-11 Pubmed10601301 Pubmed10769175 Reactome Database ID Release 432046092 Reactome, http://www.reactome.org ReactomeREACT_121064 has a Stoichiometric coefficient of 2 Collagen type IX chains Converted from EntitySet in Reactome Reactome DB_ID: 2173288 Reactome Database ID Release 432173288 Reactome, http://www.reactome.org ReactomeREACT_125430 Elongation of gamma-lenolenoyl-CoA to dihomo-gamma-lenolenoyl-CoA Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 Gamma-linolenoyl-CoA (6,9,12-20:3(n-6)) is rapidly elongated to dihomo-gamma-linolenoyl-CoA (DGL-CoA; 8,11,14-20:3(n-6)) by the action of C18-PUFA-specific elongase 5 (ELOVL5). Two carbon atoms are added during this reaction. DGL-CoA later undergoes desaturation to form arachidonic acid (AA, 5,8,11,14-20:4(n-6)). <br>Depending on the cell type, DGL-CoA can also be metabolized by cyclooxygenases and lipoxygenases to produce anti-inflammatory eicosanoids (prostaglandins of series 1 (PGE1) and 15-hydroxyeico- satrienoic acid (15-HETrE)). GLA and these two oxidative metabolites exert clinical effects in a variety of diseases, including suppression of chronic inflammation, vasodilation and lowering of blood pressure, inhibition of platelet aggregation and thrombosis. (Fan et al. 2001, Fan & Chapkin 1998, Kapoor & Huang. 2006) ISBN1-893997-17-0 Pubmed10970790 Pubmed17168669 Pubmed8609415 Pubmed9732298 Reactome Database ID Release 432046094 Reactome, http://www.reactome.org ReactomeREACT_120909 has a Stoichiometric coefficient of 2 Collagen type X chains Converted from EntitySet in Reactome Reactome DB_ID: 2173283 Reactome Database ID Release 432173283 Reactome, http://www.reactome.org ReactomeREACT_121660 Elongation of docosatetraenoyl-CoA to tetracosatetraenoyl-CoA Authored: Garapati, P V, 2012-01-11 Docosatetraenoyl-CoA is elongated to tetracosatetraenoyl-CoA (TTA-CoA, 9,12,15,18-tetracosatetraenoic acid, 9,12,15,18-24:4(n-6)) by the elongase enzyme ELOVL2. Edited: Garapati, P V, 2012-01-11 Pubmed14636670 Pubmed5411545 Pubmed9704073 Reactome Database ID Release 432046095 Reactome, http://www.reactome.org ReactomeREACT_120858 has a Stoichiometric coefficient of 2 Collagen type XI chains Converted from EntitySet in Reactome Reactome DB_ID: 2179232 Reactome Database ID Release 432179232 Reactome, http://www.reactome.org ReactomeREACT_123074 Elongation of arachidonyl-CoA to docosatetraenoyl-CoA Arachidonyl-CoA undergoes a two-carbon chain elongation on the carboxyl end to form docosatetraenoyl-CoA (DTA-CoA/Adrenic acid/7,10,13,16-docosatetraenoic acid (7,10,13,16-22:4(n-6)). This reaction is catalyzed by the enzymes ELOVL5 or ELOVL2. Malanoyl-CoA provides the additional two carbons required for elongation. Docosatetraenoyl-CoA is further metabolized by cyclooxygenases (COX), lipoxygenases (LO) and cytochrome P450s (CYP450s) to dihomo (DH) eicosanoids (Kopf et al. 2010, Leonard et al. 2004). Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 Pubmed10970790 Pubmed14636670 Pubmed20038752 Reactome Database ID Release 432046083 Reactome, http://www.reactome.org ReactomeREACT_121099 arachidonoyl-CoA + malonyl-CoA => 3-oxo-(7,10,13,16)-docosatetraenoyl-CoA + CO2 + CoASH [ELOVL5] has a Stoichiometric coefficient of 2 hp-IRAK1/p-IRAK2 Converted from EntitySet in Reactome Reactome DB_ID: 1014260 Reactome Database ID Release 431014260 Reactome, http://www.reactome.org ReactomeREACT_25997 Desaturation of Linoleoyl-CoA to gamma-linolenoyl-CoA Authored: Garapati, P V, 2012-01-11 EC Number: 1.14.19.3 Edited: Garapati, P V, 2012-01-11 Pubmed11988075 Pubmed12562861 Pubmed12713571 Pubmed8386433 Reactome Database ID Release 432046096 Reactome, http://www.reactome.org ReactomeREACT_121304 The first major step in the metabolism of linoleic acid (LA) is desaturation of delta 9,12-octadecadienoyl CoA/linoleoyl CoA (LA-CoA) to delta 6,9,12-octodecatrienoyl CoA/gamma-lenoleoyl CoA (GLA-CoA). This step is catalyzed by delta-6-destaurase (fatty acid desaturase-2, FADS2) which introduces a cis-double bond between carbons 6 and 7. This is the rate limiting step in LA metabolism (Horrobin 1993). has a Stoichiometric coefficient of 2 Collagen type VII chains Converted from EntitySet in Reactome Reactome DB_ID: 2025769 Reactome Database ID Release 432025769 Reactome, http://www.reactome.org ReactomeREACT_123212 PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol Authored: D'Eustachio, P, 2012-06-04 PGH2 moves from the endoplasmic reticulum to the cytosol. The mechanism of this movement has not been determined and could could simply be diffusion through the ER membrane. Reactome Database ID Release 432299725 Reactome, http://www.reactome.org ReactomeREACT_150408 Reviewed: Rush, MG, 2012-11-10 PGH2 is reduced to PGF2a by AKR1C3 Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is responsible for the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Suzuki-Yamamoto et al. 1999, Komoto et al. 2004, Komoto et al. 2006). There is an additional way of achieving this reaction involving the prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TRX). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Pubmed10622721 Pubmed14979715 Pubmed16475787 Reactome Database ID Release 432161549 Reactome, http://www.reactome.org ReactomeREACT_150241 Reviewed: Rush, MG, 2012-11-10 PGG2 is reduced to PGH2 by PTGS1 Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.11.1.7 Edited: Jassal, B, 2008-05-19 12:57:01 Peroxidative reduction of PGG2 to PGH2 Prostaglandin G/H synthase 1 (PTGS1) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994). Pubmed1380156 Pubmed4514999 Pubmed7947975 Pubmed9139685 Reactome Database ID Release 43140359 Reactome, http://www.reactome.org ReactomeREACT_810 Reviewed: Rush, MG, 2012-11-10 has a Stoichiometric coefficient of 2 PGG2 is reduced to PGH2 by PTGS2 Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.11.1.7 Edited: Jassal, B, 2008-05-19 12:57:01 Peroxidative reduction of PGG2 to PGH2 Prostaglandin G/H synthase 2 (PTGS2) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994). Pubmed1380156 Pubmed4514999 Pubmed7947975 Pubmed9139685 Reactome Database ID Release 432309773 Reactome, http://www.reactome.org ReactomeREACT_147811 Reviewed: Rush, MG, 2012-11-10 has a Stoichiometric coefficient of 2 Collagen type XXV chains Converted from EntitySet in Reactome Reactome DB_ID: 2179257 Reactome Database ID Release 432179257 Reactome, http://www.reactome.org ReactomeREACT_124970 Collagen type XXVI chains Converted from EntitySet in Reactome Reactome DB_ID: 2179259 Reactome Database ID Release 432179259 Reactome, http://www.reactome.org ReactomeREACT_123743 Collagen type XXIII chains Converted from EntitySet in Reactome Reactome DB_ID: 2179256 Reactome Database ID Release 432179256 Reactome, http://www.reactome.org ReactomeREACT_121887 Collagen type XXIV Converted from EntitySet in Reactome Reactome DB_ID: 2179263 Reactome Database ID Release 432179263 Reactome, http://www.reactome.org ReactomeREACT_124478 Collagen type XXI chains Converted from EntitySet in Reactome Reactome DB_ID: 2179258 Reactome Database ID Release 432179258 Reactome, http://www.reactome.org ReactomeREACT_125260 Arachidonic acid oxidised to PGG2 Arachidonic acid is oxidised to PGG2 by PTGS2 Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.99.1 Edited: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-28 09:06:10 Prostaglandin G/H synthase PTGS2 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973). Pubmed4521806 Pubmed4776443 Reactome Database ID Release 432309787 Reactome, http://www.reactome.org ReactomeREACT_147758 Reviewed: Rush, MG, 2012-11-10 has a Stoichiometric coefficient of 2 Collagen type XXII chains Converted from EntitySet in Reactome Reactome DB_ID: 2179271 Reactome Database ID Release 432179271 Reactome, http://www.reactome.org ReactomeREACT_125176 Arachidonic acid oxidised to PGG2 Arachidonic acid is oxidised to PGG2 by PTGS1 Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.99.1 Edited: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-28 09:06:10 Prostaglandin G/H synthase PTGS1 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973). Pubmed4521806 Pubmed4776443 Reactome Database ID Release 43140355 Reactome, http://www.reactome.org ReactomeREACT_528 Reviewed: Rush, MG, 2012-11-10 has a Stoichiometric coefficient of 2 Collagen type XIX chains Converted from EntitySet in Reactome Reactome DB_ID: 2179243 Reactome Database ID Release 432179243 Reactome, http://www.reactome.org ReactomeREACT_123045 Aspirin acetylates PTGS2 Aspirin (acetylsalicylate) reacts spontaneously with one subunit of PTGS2 dimer (Dong et al. 2011) to acetylate serine residue 516 (Lecomte et al. 1994). The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2, but acquires the ability to convert it to 15R-HETE. Authored: D'Eustachio, P, 2012-06-07 Edited: D'Eustachio, P, 2012-06-07 Pubmed21467029 Pubmed8175750 Reactome Database ID Release 432314686 Reactome, http://www.reactome.org ReactomeREACT_150446 Reviewed: Rush, MG, 2012-11-10 Collagen type XX chains Converted from EntitySet in Reactome Reactome DB_ID: 2179246 Reactome Database ID Release 432179246 Reactome, http://www.reactome.org ReactomeREACT_121613 Aspirin acetylates PTGS1 Aspirin (acetylsalicylate) reacts spontaneously with one subunit of PTGS1 dimer to acetylate serine residue 516. The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2. The identity of the acetylated residue is inferred from data for the humann PTGS2 enzyme (Lecomte et al. 1994) and the ovine PGHS1 enzyme (Loll et al. 1995). Authored: D'Eustachio, P, 2012-06-07 Edited: D'Eustachio, P, 2012-06-07 Pubmed7552725 Pubmed8175750 Reactome Database ID Release 432314678 Reactome, http://www.reactome.org ReactomeREACT_150159 Reviewed: Rush, MG, 2012-11-10 Collagen type XVII chains Converted from EntitySet in Reactome Reactome DB_ID: 2179245 Reactome Database ID Release 432179245 Reactome, http://www.reactome.org ReactomeREACT_124531 PTGS2 dimer binds celecoxib Authored: D'Eustachio, P, 2012-06-05 Edited: D'Eustachio, P, 2012-06-05 Pubmed10966456 Pubmed21467029 Pubmed8901870 Reactome Database ID Release 432309779 Reactome, http://www.reactome.org ReactomeREACT_150255 Reviewed: Rush, MG, 2012-11-10 While closely similar, PTGS1 and 2 differ sufficiently in the structures of their active sites so that the latter enzyme selectively binds and is inhibited by celecoxib (Luong et al. 1996; Smith et al. 2000; Dong et al. 2011). Collagen type XVIII chains Converted from EntitySet in Reactome Reactome DB_ID: 2179241 Reactome Database ID Release 432179241 Reactome, http://www.reactome.org ReactomeREACT_123159 Arachidonate diffuses across the ER membrane Arachidonate released by phospholipases diffuses within the membrane and out of the membrane into the ER lumen and cytosol. The relatively low level of arachidonate in the cytoplasm is probably due to reesterification into complex lipids by acyl transferases. Authored: Jupe, S, 2009-07-14 Pubmed6146314 Pubmed6810878 Reactome Database ID Release 43428990 Reactome, http://www.reactome.org ReactomeREACT_150225 Reviewed: Rush, MG, 2012-11-10 PI(3,5)P2 transports from the late endosome membrane to the Golgi membrane Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) translocates from the late endosome membrane to the Golgi membrane (Rutherford et al. 2006). Pubmed16954148 Reactome Database ID Release 431676161 Reactome, http://www.reactome.org ReactomeREACT_121241 Reviewed: Wakelam, Michael, 2012-05-14 Ribonucleoprotein (RNP) Complex Reactome DB_ID: 189149 Reactome Database ID Release 43189149 Reactome, http://www.reactome.org ReactomeREACT_9162 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1000 has a Stoichiometric coefficient of 45 PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMO Reactome DB_ID: 741418 Reactome Database ID Release 43741418 Reactome, http://www.reactome.org ReactomeREACT_76201 has a Stoichiometric coefficient of 1 Activation of alpha-linolenic acid to alpha-linolenoyl-CoA Authored: Garapati, P V, 2012-01-11 EC Number: 6.2.1.3 Edited: Garapati, P V, 2012-01-11 ISBN978-0-12-417762-8 In the first step the precursor apha-linolenic (9,12,15-18:3(n-3)) acid is activated to a high energy form known as alpha-linolenoyl-CoA (9Z,12Z,15Z-octadecatrienoyl-CoA) by the iron enzyme long-chain-fatty-acid-CoA-ligase (acyl-CoA synthetase 1, ACSL1) and coenzyme A. Pubmed7061494 Reactome Database ID Release 432046085 Reactome, http://www.reactome.org ReactomeREACT_121179 Influenza A Viral Envelope Reactome DB_ID: 189144 Reactome Database ID Release 43189144 Reactome, http://www.reactome.org ReactomeREACT_9248 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO Reactome DB_ID: 741389 Reactome Database ID Release 43741389 Reactome, http://www.reactome.org ReactomeREACT_76247 has a Stoichiometric coefficient of 1 Desaturation of alpha-linoleoyl-CoA to Stearidonoyl-CoA Alpha-linoloyl-CoA is converted to Stearidonoyl-CoA (SDA, 6,9,12,15-18:3(n-3)) by delta-6-destaurase (fatty acid desaturase-2, FADS2). FADS2 uses the cytochrome b5 system to add a double bond at position 6. This is the rate limiting step in alpha-linolenic acid (ALA) metabolism (Horrobin 1993). Authored: Garapati, P V, 2012-01-11 EC Number: 1.14.19.3 Edited: Garapati, P V, 2012-01-11 Pubmed11988075 Pubmed12562861 Pubmed12713571 Pubmed1346092 Pubmed19056654 Pubmed8386433 Reactome Database ID Release 432046084 Reactome, http://www.reactome.org ReactomeREACT_121240 has a Stoichiometric coefficient of 2 Cleaved Trimeric palmitylated HA Reactome DB_ID: 203482 Reactome Database ID Release 43203482 Reactome, http://www.reactome.org ReactomeREACT_12200 has a Stoichiometric coefficient of 3 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex Reactome DB_ID: 706478 Reactome Database ID Release 43706478 Reactome, http://www.reactome.org ReactomeREACT_76707 has a Stoichiometric coefficient of 1 Elongation of stearidonoyl-CoA to eicosatetraenoyl-CoA Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 Pubmed10899997 Pubmed12716664 Pubmed14636670 Reactome Database ID Release 432046088 Reactome, http://www.reactome.org ReactomeREACT_120806 SDA-CoA (6,9,12,15-18:4(n-3)) is rapidly elongated by two carbon atoms to 8,11,14,17-eicosatetraenoyl-CoA (8,11,14,17-20:4(n-3), ETA-CoA). The NADPH-consuming enzyme long-chain fatty acyl elongase (ELOVL5) mediates this reaction which and adds malonyl-CoA to the SDA-CoA and releases carbon dioxide and free CoA (Leonard et al. 2004). has a Stoichiometric coefficient of 2 palmitylated M2 Tetramer Reactome DB_ID: 203489 Reactome Database ID Release 43203489 Reactome, http://www.reactome.org ReactomeREACT_12175 has a Stoichiometric coefficient of 4 NOD1:iE-DAP:Long prodomain caspases Reactome DB_ID: 622417 Reactome Database ID Release 43622417 Reactome, http://www.reactome.org ReactomeREACT_76886 has a Stoichiometric coefficient of 1 Desaturation of eicosatetraenoyl-CoA to eicosapentaenoyl-CoA Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 Eicosatetraenoyl-CoA (ETA-CoA) is desaturated by an additional carbon-carbon bond to form 5Z,8Z,11Z,14Z,17Z-eicosapentaenoyl-CoA (EPA-CoA, 5,8,11,14,17-20:5(n-3)). Delta-5-desaturase is required for this conversion. EPA-CoA has health benefits due to its anti-inflammatory actions. It is a precursor for the anti-inflammatory series-3 prostaglandins (PG), the series-5 leukotrienes (LT) and the series-3 thromboxanes (TA), which are anti-atherogenic and anti-thrombogenic (Ross et al. 2009). Pubmed10601301 Pubmed19422375 Pubmed8096621 Reactome Database ID Release 432046089 Reactome, http://www.reactome.org ReactomeREACT_121259 has a Stoichiometric coefficient of 2 Gycosylated NA Tetramer Reactome DB_ID: 203488 Reactome Database ID Release 43203488 Reactome, http://www.reactome.org ReactomeREACT_12178 has a Stoichiometric coefficient of 4 Elongation of eicosapentaenoyl-CoA to docosapentaenoyl-CoA Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 Eicosapentaenoyl-CoA (EPA-CoA) is transformed to docosapentaenoyl-CoA (DPA-CoA/clupanodonic acid; 7,10,13,16,19-22:5(n-3)) by addition of two carbon atoms from malanoyl-CoA. This reaction is catalyzed by the enzymes ELOVL5/2 (Leonard et al. 2004). DPA is quite high in seal oil and may act as an anti-atherogenic factor. DPA has 10-fold greater endothelial cell migration ability than EPA, which is important in wound-healing processes. DPA may act as a precursor for production of the DPA-related D-series of resolvins or neuroprotectins (Kaur et al. 2011). Pubmed12323085 Pubmed12323090 Pubmed14636670 Pubmed20655949 Pubmed8832760 Reactome Database ID Release 432046100 Reactome, http://www.reactome.org ReactomeREACT_121058 has a Stoichiometric coefficient of 2 Clathrin Reactome DB_ID: 177482 Reactome Database ID Release 43177482 Reactome, http://www.reactome.org ReactomeREACT_9338 has a Stoichiometric coefficient of 3 Elongation of docosapentaenoyl-CoA to tetracosapentaenoyl-CoA Authored: Garapati, P V, 2012-01-11 Docosapentaenoyl-CoA is elongated to tetracosapentaenoyl-CoA (9,12,15,18,21-24:5(n-3)) by the enzyme ELOVL2. Edited: Garapati, P V, 2012-01-11 Pubmed14636670 Pubmed1834642 Reactome Database ID Release 432046090 Reactome, http://www.reactome.org ReactomeREACT_121024 has a Stoichiometric coefficient of 2 C4-binding protein:C4b Reactome DB_ID: 981642 Reactome Database ID Release 43981642 Reactome, http://www.reactome.org ReactomeREACT_118966 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 7 C4b-binding protein:Factor I Reactome DB_ID: 981633 Reactome Database ID Release 43981633 Reactome, http://www.reactome.org ReactomeREACT_119445 has a Stoichiometric coefficient of 1 Gycosylated NA Tetramer Reactome DB_ID: 196475 Reactome Database ID Release 43196475 Reactome, http://www.reactome.org ReactomeREACT_10712 has a Stoichiometric coefficient of 4 C4 binding protein:C4bC2a Reactome DB_ID: 981663 Reactome Database ID Release 43981663 Reactome, http://www.reactome.org ReactomeREACT_120190 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 7 palmitylated M2 Tetramer Reactome DB_ID: 196494 Reactome Database ID Release 43196494 Reactome, http://www.reactome.org ReactomeREACT_10486 has a Stoichiometric coefficient of 4 C4 binding protein:protein S Reactome DB_ID: 981655 Reactome Database ID Release 43981655 Reactome, http://www.reactome.org ReactomeREACT_119894 has a Stoichiometric coefficient of 1 Sialic Acid Bound Influenza A Viral Particle Reactome DB_ID: 188954 Reactome Database ID Release 43188954 Reactome, http://www.reactome.org ReactomeREACT_9232 has a Stoichiometric coefficient of 1 PAMP:NOD oligomer:RIP2 Reactome DB_ID: 168409 Reactome Database ID Release 43168409 Reactome, http://www.reactome.org ReactomeREACT_76636 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 Influenza A Viral Particle Reactome DB_ID: 189171 Reactome Database ID Release 43189171 Reactome, http://www.reactome.org ReactomeREACT_9077 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 PAMP:NOD oligomer:RIP2:NEMO Reactome DB_ID: 688994 Reactome Database ID Release 43688994 Reactome, http://www.reactome.org ReactomeREACT_76490 has a Stoichiometric coefficient of 1 Ligands of GPCRs that activate G12/13 Converted from EntitySet in Reactome Reactome DB_ID: 791498 Reactome Database ID Release 43791498 Reactome, http://www.reactome.org ReactomeREACT_22781 GPCRs that activate G12/13 Converted from EntitySet in Reactome Reactome DB_ID: 791500 Reactome Database ID Release 43791500 Reactome, http://www.reactome.org ReactomeREACT_23262 VWF multimer Reactome DB_ID: 216029 Reactome Database ID Release 43216029 Reactome, http://www.reactome.org ReactomeREACT_14638 Activin Response Element DNA Containing an Activin Response Element Reactome DB_ID: 1225892 Reactome Database ID Release 431225892 Reactome, http://www.reactome.org ReactomeREACT_111540 Prolyl 3-hydroxylases Converted from EntitySet in Reactome Reactome DB_ID: 1980236 Reactome Database ID Release 431980236 Reactome, http://www.reactome.org ReactomeREACT_121762 Lysyl hydroxylase procollagen substrates Converted from EntitySet in Reactome Reactome DB_ID: 2023012 Reactome Database ID Release 432023012 Reactome, http://www.reactome.org ReactomeREACT_122001 Lysyl hydroxylated collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2022990 Reactome Database ID Release 432022990 Reactome, http://www.reactome.org ReactomeREACT_122551 Cleaved collagen alpha-1(XVI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2470818 Reactome Database ID Release 432470818 Reactome, http://www.reactome.org ReactomeREACT_151672 PI is phosphorylated to PI5P by PIKFYVE at the late endosome membrane At the late endosome membrane, the PAS complex, consisting of FYVE finger-containing phosphoinositide kinase (PIKFYVE), yeast VAC14 homologue (VAC14), and polyphosphoinositide phosphatase aka SAC3 (FIG4), binds to the membrane via PIKFYVE's FYVE finger. The PIKFYVE kinase component phosphorylates phosphatidylinositol (PI) to phosphatidylinositol 5-phosphate (PI5P) (Sbrissa et al. 1999, Sbrissa et al. 2002). The PAS complex is present in the cytosol and is recruited to the membrane. Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed10419465 Pubmed12270933 Reactome Database ID Release 431675866 Reactome, http://www.reactome.org ReactomeREACT_120944 Reviewed: Wakelam, Michael, 2012-05-14 CD14 Converted from EntitySet in Reactome Reactome DB_ID: 166029 Reactome Database ID Release 43166029 Reactome, http://www.reactome.org ReactomeREACT_7012 Protein kinase C conventional and novel isoforms Converted from EntitySet in Reactome Reactome DB_ID: 804920 Reactome Database ID Release 43804920 Reactome, http://www.reactome.org ReactomeREACT_23183 Ligands of GPCRs that activate Gq/11 Converted from EntitySet in Reactome Reactome DB_ID: 791492 Reactome Database ID Release 43791492 Reactome, http://www.reactome.org ReactomeREACT_23264 PI3P is dephosphorylated to PI by MTM[3] at the late endosome membrane At the late endosome membrane, myotubularin (MTM1), myotubularin-related protein 2 (MTMR2), myotubularin-related protein 4 (MTMR4), and myotubularin-related protein 7 (MTMR7) dephosphorylate phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol (PI).<br><br>The following lists the above proteins with their corresponding literature references: MTM1 (Cao et al. 2007, Cao et al. 2008, Tsujita et al. 2004, Tronchere et al. 2004, Kim et al. 2002); MTMR2 (Cao et al. 2008, Kim et al. 2002); MTMR4 (Lorenzo et al. 2006); and MTMR7 (Mochizuki & Majerus 2003, Lorenzo et al. 2006). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.64 Edited: Williams, MG, 2011-08-12 Pubmed11733541 Pubmed12890864 Pubmed14660569 Pubmed14722070 Pubmed16787938 Pubmed17651088 Pubmed18524850 Reactome Database ID Release 431675795 Reactome, http://www.reactome.org ReactomeREACT_120958 Reviewed: Wakelam, Michael, 2012-05-14 GPCRs that activate Gq/11 Converted from EntitySet in Reactome Reactome DB_ID: 791493 Reactome Database ID Release 43791493 Reactome, http://www.reactome.org ReactomeREACT_22567 PI is phosphorylated to PI3P by PIK3C2A/3 at the late endosome membrane At the late endosome membrane, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) aka VPS34 binds to phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4). The PIK3C3:PIK3R4 complex and phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A) phosphorylate phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI3P).<br><br>The following lists the above proteins with their corresponding literature references: PIK3C3:PIK3R4 (Panaretou et al. 1997, Volinia et al. 1995, Cao et al. 2007) and PIK3C2A (Arcaro et al. 2000, Domin et al. 2000). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.137 Edited: Williams, MG, 2011-08-12 Pubmed10766823 Pubmed10805725 Pubmed17651088 Pubmed7628435 Pubmed8999962 Reactome Database ID Release 431676024 Reactome, http://www.reactome.org ReactomeREACT_120760 Reviewed: Wakelam, Michael, 2012-05-14 Formation of DHA-CoA catalysed by 3-ketoacyl-CoA thiolase Authored: Garapati, P V, 2012-01-11 EC Number: 2.8.3.8 Edited: Garapati, P V, 2012-01-11 Pubmed11734571 Pubmed8656081 Reactome Database ID Release 432066788 Reactome, http://www.reactome.org ReactomeREACT_121028 The final step in the beta-oxidation process is the thiolytic cleavage of 1-(3-oxo-6Z,9Z,12Z,15Z,18Z,21Z-tetracosahexaenoyl)-CoA to form docosahexaenoyl-CoA (DHA-CoA). This step is catalysed by both sterol carrier protein X (SCPx) and the classic 3-ketoacyl-CoA thiolase (this reaction) (Ferdinandusse et al. 2001). Vpu:beta-TrCP1:Skp1 complex Reactome DB_ID: 180567 Reactome Database ID Release 43180567 Reactome, http://www.reactome.org ReactomeREACT_9101 has a Stoichiometric coefficient of 1 Conversion of DHA-CoA to docosahexaenoic acid (DHA) Authored: Garapati, P V, 2012-01-11 DHA-CoA preferentially moves back to the ER, perhaps as a free fatty acid. This conversion is usually catalysed by acyl-CoA thioesterases (ACOTs). No specific acyl-CoA thioesterase enzyme has been identified for the peroxisomal metabolism of DHA-CoA, but the peroxisomal ACOT8 has a wide substrate specificity and is likely to be responsible (Ferdinandusse et al. 2003, Hunt & Alexson. 2008). EC Number: 3.1.2.1 Edited: Garapati, P V, 2012-01-11 Pubmed12897190 Pubmed18538142 Reactome Database ID Release 432066779 Reactome, http://www.reactome.org ReactomeREACT_120988 Cleaved HA Influenza A Viral Particle Reactome DB_ID: 169239 Reactome Database ID Release 43169239 Reactome, http://www.reactome.org ReactomeREACT_9239 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 Dehydrogenation of 3-hydroxy tetracosahexaenoyl-CoA 3-hydroxy tetracosahexaenoyl-CoA undergoes dehydrogenation to form 1-(3-oxo-6Z,9Z,12Z,15Z,18Z,21Z-tetracosahexaenoyl)-CoA, catalysed by DBP. DBP is a bifunctional enzyme, involved in the hydration of a variety of trans-2,3-dehydroacyl-CoA's but also mediating dehydrogenation of a variety of 3-hydroxyacyl-CoA's (Jiang et al. 1997). Authored: Garapati, P V, 2012-01-11 EC Number: 4.2.1.74 Edited: Garapati, P V, 2012-01-11 Pubmed11734571 Pubmed8656081 Pubmed9089413 Reactome Database ID Release 432066780 Reactome, http://www.reactome.org ReactomeREACT_120744 CD4:Vpu:beta-TrCP_1:Skp1 complex Reactome DB_ID: 180592 Reactome Database ID Release 43180592 Reactome, http://www.reactome.org ReactomeREACT_9120 has a Stoichiometric coefficient of 1 Formation of DHA-CoA catalysed by sterol carrier protein X (SCPx) Authored: Garapati, P V, 2012-01-11 EC Number: 2.3.1.154 Edited: Garapati, P V, 2012-01-11 Pubmed11734571 Pubmed8656081 Reactome Database ID Release 432066781 Reactome, http://www.reactome.org ReactomeREACT_121001 The final step in the beta-oxidation process is the thiolytic cleavage of 1-(3-oxo-6Z,9Z,12Z,15Z,18Z,21Z-tetracosahexaenoyl)-CoA to form docosahexaenoyl-CoA (DHA-CoA). This step is catalysed by both sterol carrier protein X (SCPx) (this reaction) and the classic 3-ketoacyl-CoA thiolase (Ferdinandusse et al. 2001). multiubiquitinated CD4:Vpu:beta-TrCP_1:Skp1 complex Reactome DB_ID: 180530 Reactome Database ID Release 43180530 Reactome, http://www.reactome.org ReactomeREACT_9344 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Cleaved Trimeric palmitylated HA Reactome DB_ID: 203481 Reactome Database ID Release 43203481 Reactome, http://www.reactome.org ReactomeREACT_12168 has a Stoichiometric coefficient of 3 Retranslocation of DHA back to ER Authored: Garapati, P V, 2012-01-11 DHA is transported back to the ER, where it is incorporated into membrane lipids instead of being further beta-oxidized in the peroxisome (Ferdinandusse et al. 2003). Edited: Garapati, P V, 2012-01-11 Pubmed12897190 Pubmed18538142 Reactome Database ID Release 432066785 Reactome, http://www.reactome.org ReactomeREACT_121071 Ribonucleoprotein (RNP) Complex Reactome DB_ID: 169237 Reactome Database ID Release 43169237 Reactome, http://www.reactome.org ReactomeREACT_9135 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1000 has a Stoichiometric coefficient of 45 Activation of linoleic acid to linoleoyl-CoA Authored: Garapati, P V, 2012-01-11 EC Number: 6.2.1.3 Edited: Garapati, P V, 2012-01-11 ISBN978-0-12-417762-8 Pubmed18024425 Pubmed20480548 Pubmed7061494 Reactome Database ID Release 432046098 Reactome, http://www.reactome.org ReactomeREACT_121204 The dietary essential fatty acid (EFA) linoleic acid (LA) is activated to a high energy form known as linoleoyl-CoA by the action of long-chain acyl-CoA synthetases (ACSLs). Thioesterification of long-chain fatty acids into their acyl-CoA derivatives is considered to be the first committed step in fatty acid metabolism. Formation of acyl-CoA allows an otherwise non-reactive fatty acid to participate in biosynthetic or catabolic pathways. This acyl CoA form is converted to its longer-chain polyunsaturated products by a series of desaturation and elongation reactions (Ellis et al. 2010, Watkins 2008). Influenza A Viral Envelope Reactome DB_ID: 169245 Reactome Database ID Release 43169245 Reactome, http://www.reactome.org ReactomeREACT_9110 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 CD4:Vpu complex Reactome DB_ID: 180601 Reactome Database ID Release 43180601 Reactome, http://www.reactome.org ReactomeREACT_9255 has a Stoichiometric coefficient of 1 CD4:Vpu:beta-TrCP_1 Reactome DB_ID: 180532 Reactome Database ID Release 43180532 Reactome, http://www.reactome.org ReactomeREACT_9238 has a Stoichiometric coefficient of 1 Internalized CD8:Nef:Clathrin-Coated Pit Adapter Protein:v-ATPase Reactome DB_ID: 182230 Reactome Database ID Release 43182230 Reactome, http://www.reactome.org ReactomeREACT_11305 has a Stoichiometric coefficient of 1 Collagen type IV chains Converted from EntitySet in Reactome Reactome DB_ID: 2025674 Reactome Database ID Release 432025674 Reactome, http://www.reactome.org ReactomeREACT_125368 Collagen type V propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025765 Reactome Database ID Release 432025765 Reactome, http://www.reactome.org ReactomeREACT_122361 Collagen type II propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025673 Reactome Database ID Release 432025673 Reactome, http://www.reactome.org ReactomeREACT_121942 Collagen type III propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025672 Reactome Database ID Release 432025672 Reactome, http://www.reactome.org ReactomeREACT_125526 Collagen type VI propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025757 Reactome Database ID Release 432025757 Reactome, http://www.reactome.org ReactomeREACT_122917 Alpha-3-6(VI) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025754 Reactome Database ID Release 432025754 Reactome, http://www.reactome.org ReactomeREACT_121816 Collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025683 Reactome Database ID Release 432025683 Reactome, http://www.reactome.org ReactomeREACT_124110 Hydration of delta2-tetracosaheptaenoyl-CoA to 3-hydroxy tetracosahexaenoyl-CoA Authored: Garapati, P V, 2012-01-11 Delta2-THA-CoA is hydrated to 3-hydroxyacyl-CoA intermediate 1-(3-hydroxy-6Z,9Z,12Z,15Z,18Z,21Z-tetracosahexaenoyl)-CoA by HSD17B4/DBP (d-bifunctional protein) dimer. EC Number: 4.2.1.74 Edited: Garapati, P V, 2012-01-11 Pubmed11500517 Pubmed11734571 Pubmed8656081 Pubmed9089413 Reactome Database ID Release 432066778 Reactome, http://www.reactome.org ReactomeREACT_121210 Collagen type I propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2025667 Reactome Database ID Release 432025667 Reactome, http://www.reactome.org ReactomeREACT_125535 Oxidation of tetracosapentaenoyl-CoA to delta2-tetracosaheptaenoyl-CoA Authored: Garapati, P V, 2012-01-11 EC Number: 1.3.3.6 Edited: Garapati, P V, 2012-01-11 Pubmed11500517 Pubmed11734571 Pubmed8656081 Reactome Database ID Release 432066787 Reactome, http://www.reactome.org ReactomeREACT_120938 Retroconversion of C24:6(n-3) to docosahexaenoic acid (22:6(n-3) involves the initial oxidation of tetracosahexaenoyl-CoA to an intermediate 1-(2E,6Z,9Z,12Z,15Z,18Z,21Z-tetracosaheptaenoyl)-CoA (delta2-THA-CoA). This step is catalysed by the peroxisomal enzyme Straight-chain acyl-CoA oxidase (SCOX) (Ferdinandusse et al. 2001). Galactosyl-hydroxylysyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2023001 Reactome Database ID Release 432023001 Reactome, http://www.reactome.org ReactomeREACT_124357 Translocation of tetracosahexaenoyl-CoA to peroxisomes Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 Pubmed11500517 Pubmed12324224 Pubmed12897190 Pubmed8656081 Pubmed8663162 Reactome Database ID Release 432046087 Reactome, http://www.reactome.org ReactomeREACT_120799 The 24-carbon tetracosahexaenoyl-CoA (6,9,12,15,18,21-24:6(n-3) is transported to peroxisomes to undergo a putative single cycle of peroxisomal beta-oxidation, producing Docosahexaenoic Acid (DHA) (Sprecher 2002, Luthria et al. 1996). Glucosyl-galactosyl-hydroxylysyl collagen propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2023658 Reactome Database ID Release 432023658 Reactome, http://www.reactome.org ReactomeREACT_124228 Desaturation of tetracosapentaenoyl-CoA to tetracosahexaenoyl-CoA Authored: Garapati, P V, 2012-01-11 EC Number: 1.14.19.3 Edited: Garapati, P V, 2012-01-11 Reactome Database ID Release 432046099 Reactome, http://www.reactome.org ReactomeREACT_121219 Tetracosapentaenoyl-CoA (9,12,15,18,21-24:5(n-3)) is further converted by delta 6-desaturase (FADS2) to tetracosahexaenoyl-CoA (6,9,12,15,18,21-24:6(n-3)). has a Stoichiometric coefficient of 2 FH, FHR-3 Converted from EntitySet in Reactome Reactome DB_ID: 2109537 Reactome Database ID Release 432109537 Reactome, http://www.reactome.org ReactomeREACT_119141 Biogenic amines transported by VMAT1/2 Converted from EntitySet in Reactome Reactome DB_ID: 444152 Reactome Database ID Release 43444152 Reactome, http://www.reactome.org ReactomeREACT_21050 Biogenic amines transported by VMAT1/2 Converted from EntitySet in Reactome Reactome DB_ID: 444154 Reactome Database ID Release 43444154 Reactome, http://www.reactome.org ReactomeREACT_20722 Influenza A Viral Envelope with a fusion competent HA2 Reactome DB_ID: 189147 Reactome Database ID Release 43189147 Reactome, http://www.reactome.org ReactomeREACT_9291 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 Influenza A Viral Particle With A Fusion Competent HA2 Reactome DB_ID: 189182 Reactome Database ID Release 43189182 Reactome, http://www.reactome.org ReactomeREACT_9163 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 Influenza A Viral Envelope With An Inter-Membrane Spanning HA2 Reactome DB_ID: 189172 Reactome Database ID Release 43189172 Reactome, http://www.reactome.org ReactomeREACT_9331 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 Membrane Spanning Cleaved Trimeric palmitylated HA Reactome DB_ID: 203485 Reactome Database ID Release 43203485 Reactome, http://www.reactome.org ReactomeREACT_12295 has a Stoichiometric coefficient of 3 Fusion Competent Cleaved Trimeric palmitylated HA Reactome DB_ID: 203487 Reactome Database ID Release 43203487 Reactome, http://www.reactome.org ReactomeREACT_12237 has a Stoichiometric coefficient of 3 Influenza A Viral Particle Docked At The Endocytic Vesicle Membrane Reactome DB_ID: 189138 Reactome Database ID Release 43189138 Reactome, http://www.reactome.org ReactomeREACT_9257 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 Acidified Influenza A Viral Particle Docked At The Endocytic Vesicle Membrane With An Open Pore Reactome DB_ID: 189177 Reactome Database ID Release 43189177 Reactome, http://www.reactome.org ReactomeREACT_9103 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 Influenza A Viral Envelope Inserted Into The Endocytic Vesicle Membrane Reactome DB_ID: 189157 Reactome Database ID Release 43189157 Reactome, http://www.reactome.org ReactomeREACT_9160 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 Influenza A Viral Particle Docked At The Endocytic Vesicle Membrane With An Open Pore Reactome DB_ID: 189181 Reactome Database ID Release 43189181 Reactome, http://www.reactome.org ReactomeREACT_9315 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 Influenza A Viral Envelope Fused With The Endocytic Vesicle Membrane By An Inter-Membrane Spanning HA2 Reactome DB_ID: 189164 Reactome Database ID Release 43189164 Reactome, http://www.reactome.org ReactomeREACT_9088 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 hexoses transported by SGLT4 Converted from EntitySet in Reactome Reactome DB_ID: 429628 Reactome Database ID Release 43429628 Reactome, http://www.reactome.org ReactomeREACT_19903 Inositols transported by SMIT2 Converted from EntitySet in Reactome Reactome DB_ID: 429648 Reactome Database ID Release 43429648 Reactome, http://www.reactome.org ReactomeREACT_19739 Inositols transported by SMIT2 Converted from EntitySet in Reactome Reactome DB_ID: 429652 Reactome Database ID Release 43429652 Reactome, http://www.reactome.org ReactomeREACT_19525 compounds transported by GLUT9 Converted from EntitySet in Reactome Reactome DB_ID: 429148 Reactome Database ID Release 43429148 Reactome, http://www.reactome.org ReactomeREACT_19915 hexoses transported by SGLT4 Converted from EntitySet in Reactome Reactome DB_ID: 429620 Reactome Database ID Release 43429620 Reactome, http://www.reactome.org ReactomeREACT_19933 Glycosylated NA Tetramer Reactome DB_ID: 195796 Reactome Database ID Release 43195796 Reactome, http://www.reactome.org ReactomeREACT_10972 has a Stoichiometric coefficient of 4 Post Fusion Cleaved Trimeric palmitylated HA Reactome DB_ID: 203484 Reactome Database ID Release 43203484 Reactome, http://www.reactome.org ReactomeREACT_12116 has a Stoichiometric coefficient of 3 M2 Tetramer Reactome DB_ID: 195794 Reactome Database ID Release 43195794 Reactome, http://www.reactome.org ReactomeREACT_10281 has a Stoichiometric coefficient of 4 Long prodomain caspases Converted from EntitySet in Reactome Reactome DB_ID: 622416 Reactome Database ID Release 43622416 Reactome, http://www.reactome.org ReactomeREACT_76682 MCP, CR1 Converted from EntitySet in Reactome Reactome DB_ID: 977360 Reactome Database ID Release 43977360 Reactome, http://www.reactome.org ReactomeREACT_119720 C4d Converted from EntitySet in Reactome Reactome DB_ID: 981702 Reactome Database ID Release 43981702 Reactome, http://www.reactome.org ReactomeREACT_119059 PathwayStep4009 PathwayStep4006 PathwayStep4005 PathwayStep4008 PathwayStep4007 vRNP:M1:NEP:NP Reactome DB_ID: 192768 Reactome Database ID Release 43192768 Reactome, http://www.reactome.org ReactomeREACT_9710 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Crm1:Ran GTPase:GDP Reactome DB_ID: 165538 Reactome Database ID Release 43165538 Reactome, http://www.reactome.org ReactomeREACT_6660 has a Stoichiometric coefficient of 1 Glycosylated NA Tetramer Reactome DB_ID: 195775 Reactome Database ID Release 43195775 Reactome, http://www.reactome.org ReactomeREACT_10567 has a Stoichiometric coefficient of 4 M2 Tetramer Reactome DB_ID: 195797 Reactome Database ID Release 43195797 Reactome, http://www.reactome.org ReactomeREACT_10501 has a Stoichiometric coefficient of 4 Glycosylated and folded HA trimer Reactome DB_ID: 195787 Reactome Database ID Release 43195787 Reactome, http://www.reactome.org ReactomeREACT_10717 has a Stoichiometric coefficient of 3 Glycosylated and folded HA trimer Reactome DB_ID: 195803 Reactome Database ID Release 43195803 Reactome, http://www.reactome.org ReactomeREACT_10412 has a Stoichiometric coefficient of 3 Glycosylated and folded HA trimer Reactome DB_ID: 195819 Reactome Database ID Release 43195819 Reactome, http://www.reactome.org ReactomeREACT_10554 has a Stoichiometric coefficient of 3 M2 Tetramer Reactome DB_ID: 195727 Reactome Database ID Release 43195727 Reactome, http://www.reactome.org ReactomeREACT_10683 has a Stoichiometric coefficient of 4 Glycosylated NA Tetramer Reactome DB_ID: 195724 Reactome Database ID Release 43195724 Reactome, http://www.reactome.org ReactomeREACT_10176 has a Stoichiometric coefficient of 4 Glycosylated, palmitylated and folded HA trimer Reactome DB_ID: 195725 Reactome Database ID Release 43195725 Reactome, http://www.reactome.org ReactomeREACT_10197 has a Stoichiometric coefficient of 3 palmitylated M2 Tetramer Reactome DB_ID: 195761 Reactome Database ID Release 43195761 Reactome, http://www.reactome.org ReactomeREACT_10582 has a Stoichiometric coefficient of 4 PathwayStep4012 PathwayStep4013 PathwayStep4014 PathwayStep4015 PathwayStep4010 PathwayStep4011 PathwayStep4019 PathwayStep4018 PathwayStep4017 PathwayStep4016 NP:Lipid Raft Reactome DB_ID: 195766 Reactome Database ID Release 43195766 Reactome, http://www.reactome.org ReactomeREACT_10830 has a Stoichiometric coefficient of 1 Gycosylated NA Tetramer:Lipid Raft Reactome DB_ID: 195736 Reactome Database ID Release 43195736 Reactome, http://www.reactome.org ReactomeREACT_10954 has a Stoichiometric coefficient of 1 NP:Lipid Raft Reactome DB_ID: 195737 Reactome Database ID Release 43195737 Reactome, http://www.reactome.org ReactomeREACT_10315 has a Stoichiometric coefficient of 1 Glycosylated, palmitylated and folded HA trimer:Lipid Raft Complex Reactome DB_ID: 195723 Reactome Database ID Release 43195723 Reactome, http://www.reactome.org ReactomeREACT_10369 has a Stoichiometric coefficient of 1 Gycosylated NA Tetramer Reactome DB_ID: 195728 Reactome Database ID Release 43195728 Reactome, http://www.reactome.org ReactomeREACT_10841 has a Stoichiometric coefficient of 4 Glycosylated, palmitylated and folded HA trimer:Lipid Raft Complex Reactome DB_ID: 195755 Reactome Database ID Release 43195755 Reactome, http://www.reactome.org ReactomeREACT_10581 has a Stoichiometric coefficient of 1 Gycosylated NA Tetramer:Lipid Raft Reactome DB_ID: 195735 Reactome Database ID Release 43195735 Reactome, http://www.reactome.org ReactomeREACT_10662 has a Stoichiometric coefficient of 1 Segment 5 RNP Reactome DB_ID: 195951 Reactome Database ID Release 43195951 Reactome, http://www.reactome.org ReactomeREACT_10746 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Segment 4 RNP Reactome DB_ID: 195942 Reactome Database ID Release 43195942 Reactome, http://www.reactome.org ReactomeREACT_10933 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Glycosylated, palmitylated and folded HA trimer Reactome DB_ID: 195738 Reactome Database ID Release 43195738 Reactome, http://www.reactome.org ReactomeREACT_10978 has a Stoichiometric coefficient of 3 palmitylated M2 Tetramer Reactome DB_ID: 195732 Reactome Database ID Release 43195732 Reactome, http://www.reactome.org ReactomeREACT_10389 has a Stoichiometric coefficient of 4 PathwayStep4025 PathwayStep4026 PathwayStep4023 PathwayStep4024 PathwayStep4021 PathwayStep4022 PathwayStep4020 Ribonucleoprotein (RNP) Complex Reactome DB_ID: 188846 Reactome Database ID Release 43188846 Reactome, http://www.reactome.org ReactomeREACT_9223 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1000 has a Stoichiometric coefficient of 45 RNP Complex:Karyopherin alpha Reactome DB_ID: 188845 Reactome Database ID Release 43188845 Reactome, http://www.reactome.org ReactomeREACT_9151 has a Stoichiometric coefficient of 1 Viral Polymerase Reactome DB_ID: 192720 Reactome Database ID Release 43192720 Reactome, http://www.reactome.org ReactomeREACT_9586 Viral RNA dependent RNA polymerase has a Stoichiometric coefficient of 1 RNP Complex:Karyopherin alpha Reactome DB_ID: 188871 Reactome Database ID Release 43188871 Reactome, http://www.reactome.org ReactomeREACT_9328 has a Stoichiometric coefficient of 1 Ribonucleoprotein (RNP) Complex Reactome DB_ID: 188849 Reactome Database ID Release 43188849 Reactome, http://www.reactome.org ReactomeREACT_9227 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1000 has a Stoichiometric coefficient of 45 RNP:Karyopherin alpha:Karyopherin beta complex Reactome DB_ID: 188844 Reactome Database ID Release 43188844 Reactome, http://www.reactome.org ReactomeREACT_9341 has a Stoichiometric coefficient of 1 RNP:Karyopherin alpha:Karyopherin beta complex Reactome DB_ID: 188853 Reactome Database ID Release 43188853 Reactome, http://www.reactome.org ReactomeREACT_9158 has a Stoichiometric coefficient of 1 vRNA (Genomic):NP Complex Reactome DB_ID: 193302 Reactome Database ID Release 43193302 Reactome, http://www.reactome.org ReactomeREACT_9729 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 vRNA Transcription Complex Reactome DB_ID: 192703 Reactome Database ID Release 43192703 Reactome, http://www.reactome.org ReactomeREACT_9896 has a Stoichiometric coefficient of 1 vRNA:polymerase:host mRNA complex Initiated vRNA Transcription Complex Reactome DB_ID: 192756 Reactome Database ID Release 43192756 Reactome, http://www.reactome.org ReactomeREACT_9684 has a Stoichiometric coefficient of 1 Elongated vRNA-mRNA Complex Reactome DB_ID: 192700 Reactome Database ID Release 43192700 Reactome, http://www.reactome.org ReactomeREACT_9568 has a Stoichiometric coefficient of 1 PI3P is dephosphorylated to PI by SACM1L at the Golgi membrane At the Golgi membrane, phosphatidylinositide phosphatase SAC1 (SACM1L) dephosphorylates phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol (PI) but not as efficiently as phosphatidylinositol 4-phosphate (PI4P) dephosphorylation. No significant activity of this enzyme towards phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) was detected (Rohde et al. 2003). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.64 Edited: Williams, MG, 2011-08-12 Pubmed14527956 Reactome Database ID Release 431676114 Reactome, http://www.reactome.org ReactomeREACT_121034 Reviewed: Wakelam, Michael, 2012-05-14 PI is phosphorylated to PI3P by PIK3C2A/3 at the Golgi membrane At the Golgi membrane, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) aka VPS34 is bound to phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4). This PIK3C3:PIK2R4 complex and phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A) phosphorylate phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI3P).<br><br>The following lists the above proteins with their corresponding literature references: PIK3C3:PIK2R4 (Panaretou et al. 1997, Volinia et al. 1995) and PIK3C2A (Arcaro et al. 2000, Domin et al. 2000). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.137 Edited: Williams, MG, 2011-08-12 Pubmed10766823 Pubmed10805725 Pubmed7628435 Pubmed8999962 Reactome Database ID Release 431675961 Reactome, http://www.reactome.org ReactomeREACT_121404 Reviewed: Wakelam, Michael, 2012-05-14 C4a Converted from EntitySet in Reactome Reactome DB_ID: 981725 Reactome Database ID Release 43981725 Reactome, http://www.reactome.org ReactomeREACT_25991 PI(4,5)P2 is dephosphorylated to PI4P by SYNJ/INPP5[1] at the plasma membrane At the plasma membrane, Synaptojanin-1 (SYNJ1) and -2 (SYNJ2), inositol polyphosphate 5-phosphatase K (INPP5K) aka SKIP, phosphatidylinositol 4,5-bisphosphate 5-phosphatase A (INPP5J) aka PIPP dephosphorylate phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to form phosphatidylinositol 4-phosphate (PI4P). SYNJ1/2 both have an N-terminal Sac1-like domain, a central 5-phosphatase domain and a C-terminal proline-rich segment, with this latter part being the most divergent part of the protein sequence.<br><br>The following lists the above proteins with their corresponding literature references: SYNJ1 (Johenning et al. 2004, Haffner et al. 1997, Guo et al. 1999, Mani et al. 2007), SYNJ2 (Malecz et al. 2000), INPP5K (Injuin et al. 2000, Gurung et al. 2003), and INPP5J (Gurung et al. 2003, Mochizuki & Takenawa 1999). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.36 Edited: Williams, MG, 2011-08-12 Pubmed10224048 Pubmed10593988 Pubmed10753883 Pubmed11084340 Pubmed12536145 Pubmed15080793 Pubmed18093523 Pubmed9428629 Reactome Database ID Release 431676177 Reactome, http://www.reactome.org ReactomeREACT_121166 Reviewed: Wakelam, Michael, 2012-05-14 PI4P is phosphorylated to PI(4,5)P2 by PIP5K1A-C at the plasma membrane At the plasma membrane, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A), beta (PIP5K1B), and gamma (PIP5K1C) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to produce phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP5K1A (Halstead et al. 2006, Zhang et al. 1997), PIP5K1B (Zhang et al. 1997), and PIP5K1C (Di Paolo et al. 2002).<br><br>This reaction is of particular interest because its regulation by small GTPases of the RHO and ARF families, not yet annotated here, ties the process of phosphatidylinositol phosphate biosynthesis to regulation of the actin cytoskeleton and vesicular trafficking, and hence to diverse aspects of cell motility and signalling (Oude Weernink et al., 2004, 2007). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.68 Edited: Williams, MG, 2011-08-12 Pubmed12422219 Pubmed15464023 Pubmed16979564 Pubmed17245604 Pubmed9211928 Reactome Database ID Release 431676082 Reactome, http://www.reactome.org ReactomeREACT_120952 Reviewed: Wakelam, Michael, 2012-05-14 PI4P transports from the Golgi membrane to the plasma membrane Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Phosphatidylinositol 4-phosphate (PI4P) translocates from the Golgi membrane to the plasma membrane via a secretory vesicle mechanism (Szentpetery et al. 2010, Godi et al. 2004, Hammond et al. 2009). Pubmed15107860 Pubmed19508231 Pubmed20404150 Reactome Database ID Release 431675815 Reactome, http://www.reactome.org ReactomeREACT_121199 Reviewed: Wakelam, Michael, 2012-05-14 vRNP Reactome DB_ID: 192774 Reactome Database ID Release 43192774 Reactome, http://www.reactome.org ReactomeREACT_9584 has a Stoichiometric coefficient of 1 PI(4,5)P2 is dephosphorylated to PI4P by OCRL/INPP5E at the Golgi membrane At the Golgi membrane, phosphatidylinositol 4-phosphate (PI4P) inositol polyphosphate 5-phosphatase OCRL-1 (OCRL) (Choudhury et al. 2009, Suchy et al. 1995, Zhang et al. 1995) and 72 kDa inositol polyphosphate 5-phosphatase (INPP5E) (Bilas et al. 2009) dephosphorylate phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to form phosphatidylinositol 4-phosphate (PI4P). INPP5E is located in the Golgi membrane, mediated by its N-terminal proline-rich domain (Kong et al. 2000). Authored: Williams, MG, 2011-10-18 EC Number: 3.1.3.36 Edited: Williams, MG, 2011-08-12 Pubmed10764818 Pubmed10806194 Pubmed19211563 Pubmed19668216 Pubmed7761412 Pubmed8634694 Reactome Database ID Release 431675824 Reactome, http://www.reactome.org ReactomeREACT_120928 Reviewed: Wakelam, Michael, 2012-05-14 Viral Proteins Reactome DB_ID: 192631 Reactome Database ID Release 43192631 Reactome, http://www.reactome.org ReactomeREACT_9572 has a Stoichiometric coefficient of 1 viral antigens PI(3,4)P2 is dephosphorylated to PI4P by TPTE2 at the Golgi membrane At the Golgi membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (TPTE2) aka TPIP dephosphorylates phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) to produce phosphatidylinositol 4-phosphate (PI4P) (Tapparel et al. 2000, Walker et al. 2001). The transmembrane phosphatase TPTE2 gamma isoform colocalises in the Golgi and the endoplasmic reticulum (Tapparel et al. 2000). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed11716755 Pubmed14659893 Reactome Database ID Release 431676204 Reactome, http://www.reactome.org ReactomeREACT_121091 Reviewed: Wakelam, Michael, 2012-05-14 Viral Proteins Reactome DB_ID: 2168084 Reactome Database ID Release 432168084 Reactome, http://www.reactome.org ReactomeREACT_122241 has a Stoichiometric coefficient of 1 viral antigens PI4P is phosphorylated to PI(3,4)P2 by PIK3C2A/G at the Golgi membrane At the Golgi membrane, phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A) (Domin et al. 2000, Arcaro et al. 2000) and phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunit gamma (PIK3C2G) (Ono et al. 1998, Rozycka et al. 1998, Misawa et al. 1998) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). PIK3C2G phosphorylates phosphatidylinositol (PI) and PI4P but not phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.154 Edited: Williams, MG, 2011-08-12 Pubmed10766823 Pubmed10805725 Pubmed9516481 Pubmed9878262 Reactome Database ID Release 431675928 Reactome, http://www.reactome.org ReactomeREACT_121057 Reviewed: Wakelam, Michael, 2012-05-14 Initiated cRNA-vRNA Complex Reactome DB_ID: 192650 Reactome Database ID Release 43192650 Reactome, http://www.reactome.org ReactomeREACT_9672 has a Stoichiometric coefficient of 1 PI(3,5)P2 is dephosphorylated to PI3P by FIG4 at the Golgi membrane At the Golgi membrane, the PAS complex, consisting of FYVE finger-containing phosphoinositide kinase (PIKFYVE), yeast VAC14 homologue (VAC14), and polyphosphoinositide phosphatase aka SAC3 (FIG4), binds to the membrane via PIKFYVE's FYVE finger. The FIG4 phosphatase component dephosphorylates phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 3-phosphate (PI3P) (Sbrissa et al. 2007, Sbrissa et al. 2008). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 Pubmed17556371 Pubmed18950639 Reactome Database ID Release 431676005 Reactome, http://www.reactome.org ReactomeREACT_120990 Reviewed: Wakelam, Michael, 2012-05-14 cRNP Reactome DB_ID: 192682 Reactome Database ID Release 43192682 Reactome, http://www.reactome.org ReactomeREACT_9556 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PI3P is phosphorylated to PI(3,5)P2 by PIKFYVE at the Golgi membrane At the Golgi membrane, the PAS complex, consisting of FYVE finger-containing phosphoinositide kinase (PIKFYVE), yeast VAC14 homologue (VAC14), and polyphosphoinositide phosphatase aka SAC3 (FIG4), binds to the membrane via PIKFYVE's FYVE finger (Sbrissa et al. 2002). The PIKFYVE kinase component phosphorylates phosphatidylinositol 3-phosphate (PI3P) to phosphatidylinositol 3,5-bisphosphate PI(3,5)P2 (Sbrissa et al. 1999, McEwen et al. 1999). The PAS complex is present in the cytosol and is recruited to the membrane (Sbrissa et al. 2007). VAC14 acts as a scaffolding protein via its C-terminal domain (Sbrissa et al. 2008). Authored: Williams, MG, 2011-10-18 EC Number: 2.7.1.150 Edited: Williams, MG, 2011-08-12 Pubmed10419465 Pubmed10567352 Pubmed11706043 Pubmed17556371 Pubmed18950639 Reactome Database ID Release 431675921 Reactome, http://www.reactome.org ReactomeREACT_121228 Reviewed: Wakelam, Michael, 2012-05-14 Initiated vRNA-cRNA Complex Reactome DB_ID: 192901 Reactome Database ID Release 43192901 Reactome, http://www.reactome.org ReactomeREACT_9685 has a Stoichiometric coefficient of 1 vRNP Export Complex Reactome DB_ID: 192667 Reactome Database ID Release 43192667 Reactome, http://www.reactome.org ReactomeREACT_9906 has a Stoichiometric coefficient of 1 Ran GTPase:GTP Reactome DB_ID: 165530 Reactome Database ID Release 43165530 Reactome, http://www.reactome.org ReactomeREACT_6698 has a Stoichiometric coefficient of 1 vRNP:M1 for Export Reactome DB_ID: 192906 Reactome Database ID Release 43192906 Reactome, http://www.reactome.org ReactomeREACT_9769 has a Stoichiometric coefficient of 1 vRNP:M1:NEP Reactome DB_ID: 192767 Reactome Database ID Release 43192767 Reactome, http://www.reactome.org ReactomeREACT_9569 has a Stoichiometric coefficient of 1 vRNP destined for Export Reactome DB_ID: 192922 Reactome Database ID Release 43192922 Reactome, http://www.reactome.org ReactomeREACT_9574 has a Stoichiometric coefficient of 1 PathwayStep4000 PathwayStep4003 PathwayStep4004 PathwayStep4001 PathwayStep4002 PathwayStep4059 PathwayStep4058 PathwayStep4057 PathwayStep4056 PathwayStep4055 PathwayStep4054 PathwayStep4053 PathwayStep4052 PathwayStep4051 PathwayStep4050 Integrin MAC-1 Integrin alphaMbeta2 Reactome DB_ID: 202755 Reactome Database ID Release 43202755 Reactome, http://www.reactome.org ReactomeREACT_12291 has a Stoichiometric coefficient of 1 JAM-B bound to JAM-C Reactome DB_ID: 202761 Reactome Database ID Release 43202761 Reactome, http://www.reactome.org ReactomeREACT_12255 has a Stoichiometric coefficient of 1 Integrin alphaMbeta2:JAM3 Reactome DB_ID: 202754 Reactome Database ID Release 43202754 Reactome, http://www.reactome.org ReactomeREACT_12228 has a Stoichiometric coefficient of 1 VLA-4: JAM-B Reactome DB_ID: 202759 Reactome Database ID Release 43202759 Reactome, http://www.reactome.org ReactomeREACT_12179 has a Stoichiometric coefficient of 1 VLA-4 Integrin alpha4beta1 (VLA-4) Reactome DB_ID: 198201 Reactome Database ID Release 43198201 Reactome, http://www.reactome.org ReactomeREACT_11798 has a Stoichiometric coefficient of 1 Integrin CD11a-CD18 (LFA-1) Integrin alphaLbeta2 (LFA-1) Reactome DB_ID: 198196 Reactome Database ID Release 43198196 Reactome, http://www.reactome.org ReactomeREACT_11837 has a Stoichiometric coefficient of 1 JAM-A Homodimer Reactome DB_ID: 202763 Reactome Database ID Release 43202763 Reactome, http://www.reactome.org ReactomeREACT_12319 has a Stoichiometric coefficient of 2 Integrin alphaXbeta2 Reactome DB_ID: 202766 Reactome Database ID Release 43202766 Reactome, http://www.reactome.org ReactomeREACT_12091 has a Stoichiometric coefficient of 1 LFA-1:JAM-A Reactome DB_ID: 202749 Reactome Database ID Release 43202749 Reactome, http://www.reactome.org ReactomeREACT_12182 has a Stoichiometric coefficient of 1 Integrin alphaXbeta2:AMICA1 Reactome DB_ID: 202765 Reactome Database ID Release 43202765 Reactome, http://www.reactome.org ReactomeREACT_12224 has a Stoichiometric coefficient of 1 Tyrosine kinase inhibitors of overexpressed FGFR1 Converted from EntitySet in Reactome Reactome DB_ID: 2023441 Reactome Database ID Release 432023441 Reactome, http://www.reactome.org ReactomeREACT_123778 PathwayStep4049 PathwayStep4068 PathwayStep4067 PathwayStep4069 PathwayStep4064 PathwayStep4063 PathwayStep4066 PathwayStep4065 PathwayStep4060 PathwayStep4062 PathwayStep4061 PathwayStep4033 PathwayStep4032 PathwayStep4031 PathwayStep4030 PathwayStep4037 PathwayStep4036 PathwayStep4035 PathwayStep4034 AKT inhibitors Converted from EntitySet in Reactome Reactome DB_ID: 2399923 Reactome Database ID Release 432399923 Reactome, http://www.reactome.org ReactomeREACT_148563 PathwayStep4029 PathwayStep4027 PathwayStep4028 PathwayStep4042 PathwayStep4041 PathwayStep4044 PathwayStep4043 PathwayStep4046 PathwayStep4045 PathwayStep4048 PathwayStep4047 PathwayStep4040 Tyrosine kinase inhibitors of FGFR3 mutants Converted from EntitySet in Reactome Reactome DB_ID: 2077416 Reactome Database ID Release 432077416 Reactome, http://www.reactome.org ReactomeREACT_121428 Tyrosine kinase inhibitors of overexpressed FGFR2 Converted from EntitySet in Reactome Reactome DB_ID: 2029965 Reactome Database ID Release 432029965 Reactome, http://www.reactome.org ReactomeREACT_123364 PathwayStep4038 Tyrosine kinase inhibitors of FGFR1 fusion mutants Converted from EntitySet in Reactome Reactome DB_ID: 2045079 Reactome Database ID Release 432045079 Reactome, http://www.reactome.org ReactomeREACT_123740 PathwayStep4039 Tyrosine kinase inhibitors of FGFR2 mutants Converted from EntitySet in Reactome Reactome DB_ID: 2077403 Reactome Database ID Release 432077403 Reactome, http://www.reactome.org ReactomeREACT_124314 NEDD4L binds Smad7 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 In a yeast two-hybrid screen of a HeLa cDNA library using full-length mouse Smad7, NEDD4L was identified as a Smad7 interacting protein. The interaction was confirmed by co-transfection of COS7 cells with recombinant mouse Smad7 and recombinant human NEDD4L (Kuratomi et al. 2005). Pubmed15496141 Reactome Database ID Release 432176430 Reactome, http://www.reactome.org ReactomeREACT_121357 Reviewed: Huang, Tao, 2012-05-14 Plcg1 binds P-ERBB2:P-EGFR Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Mouse phospholipase C gamma 1 is phosphorylated by human recombinant ERBB2 exogenously expressed in mouse fibroblasts. Pubmed1672440 Reactome Database ID Release 431251923 Reactome, http://www.reactome.org ReactomeREACT_115990 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 PathwayStep4094 PathwayStep4095 PathwayStep4092 PathwayStep4093 PathwayStep4090 Tie2:Grb7 complex Reactome DB_ID: 204799 Reactome Database ID Release 43204799 Reactome, http://www.reactome.org ReactomeREACT_18058 has a Stoichiometric coefficient of 1 PathwayStep4091 Degradation multiubiquitinated Cyclin A Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-03-07 23:53:31 Following multiubiquitination, Cyclin A is targeted for destruction by the 26S proteasome. GENE ONTOLOGYGO:0043161 Pubmed11285280 Reactome Database ID Release 43174255 Reactome, http://www.reactome.org ReactomeREACT_6937 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 4 PECAM-1:PECAM-1 Reactome DB_ID: 210238 Reactome Database ID Release 43210238 Reactome, http://www.reactome.org ReactomeREACT_13059 has a Stoichiometric coefficient of 2 Tie2 and Grb14 complex Reactome DB_ID: 204809 Reactome Database ID Release 43204809 Reactome, http://www.reactome.org ReactomeREACT_18185 has a Stoichiometric coefficient of 1 Association of Cyclin A with the APC/C Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Cyclin A is believed to be recognized by the APC/C:Cdc20 complex through its D-box sequence, which is 10-20 residues longer than the D-box of cyclin B (Geley et al., 2001). Edited: Matthews, L, 2006-03-07 23:49:09 Pubmed10679238 Pubmed11285280 Reactome Database ID Release 43174171 Reactome, http://www.reactome.org ReactomeREACT_6830 Reviewed: Peters, JM, 2006-03-27 22:55:09 Ubiquitination of Cyclin A by APC/C:Cdc20 complex Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 6.3.2.19 Edited: Matthews, L, 2006-02-17 05:46:22 GENE ONTOLOGYGO:0042787 Pubmed11285280 Pubmed16413484 Rape et al. have recently demonstrated that the order in which APC/C targeted proteins are degraded is determined by the processivity of multiubiquitination of these substrates. Processive substrates acquire a polyubiquitin chain upon binding to the APC/C once and are degraded. Distributive substrates bind, dissociate and reassociate with the APC/C multiple times before acquiring an ubiquitin chain of sufficient length to insure degradation. In addition, distributive substrates that dissociate from the APC/C with short ubiquitin chains are targeted for deubiquitination (Rape et al., 2006). Paradoxically, although the multiubiquitination of cyclin A is distributive and later substrates of APC-Cdc20 such as Securin are processive (Rape et al., 2006), Cyclin A is degraded prior to Securin and Cyclin B. The mechanisms insuring this order have not yet be determined. Reactome Database ID Release 43174104 Reactome, http://www.reactome.org ReactomeREACT_6824 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 4 Formation of HIF-alpha:ARNT (HIF-1beta) Heterodimer Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 HIF-alpha (HIF1A, HIF2A (EPAS1), HIF3A) forms a heterodimer with ARNT (HIF1-beta) (Wang et al. 1995, Jiang et al. 1996, Tian et al. 1997, Gu et al. 1998, Erbel et al. 2003). Pubmed14668441 Pubmed7539918 Pubmed8663540 Pubmed9000051 Pubmed9840812 Reactome Database ID Release 431234171 Reactome, http://www.reactome.org ReactomeREACT_121202 Reviewed: Rantanen, Krista, 2012-05-19 Formation of HIF:CBP:p300 Complex at Promoters Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 HIF (heterodimer of HIF-alpha and HIF-beta) recruits p300 and CBP to the promoters of target genes (Kallio et al. 1998, Ebert and Bunn 1998, Ema et al. 1999, Gu et al. 2001, Dames et al. 2002, Freedman et al. 2002). Pubmed10202154 Pubmed11063749 Pubmed11959977 Pubmed11959990 Pubmed17804822 Pubmed9632793 Pubmed9822602 Reactome Database ID Release 431234167 Reactome, http://www.reactome.org ReactomeREACT_121196 Reviewed: Rantanen, Krista, 2012-05-19 PathwayStep4098 Destruction of Ubiquitinated HIF-alpha by the Proteasome Authored: May, B, 2011-03-18 Destruction of ubiquitinated HIF-alpha can occur in both the cytosol and nucleus (Berra et al. 2001). Upon reoxygenation of hypoxic cells HIF-alpha is ubiquitinated in the nucleus and transported to the cytosol in a complex with VHL:ElonginB:ElonginC:CUL2:RBX1 where it is destroyed (Groulx and Lee 2002, Jaakkola et al. 2001, Ivan et al. 2001) Edited: May, B, 2011-03-18 Pubmed11292861 Pubmed11292862 Pubmed11454738 Pubmed12101228 Reactome Database ID Release 431234159 Reactome, http://www.reactome.org ReactomeREACT_120788 Reviewed: Rantanen, Krista, 2012-05-19 PathwayStep4099 Translocation of HIF-alpha from Cytosol to Nucleus Authored: May, B, 2011-03-18 Edited: May, B, 2011-03-18 HIF-alpha is translocated into the nucleus (Kallio et al. 1998, Depping et al. 2008, Chachami et al. 2009). Importin 4 and importin 7 (Chachami et al. 2009) as well as the importin alpha/beta pathway (Depping et al. 2008) appear to be capable of interacting with HIF-alpha. During hypoxia HIF-alpha accumulates in the nucleus where it associates with CBP and p300 (Kallio et al. 1998). Pubmed18187047 Pubmed19788888 Pubmed9822602 Reactome Database ID Release 431234161 Reactome, http://www.reactome.org ReactomeREACT_120857 Reviewed: Rantanen, Krista, 2012-05-19 PathwayStep4096 Nuclear Ubiquitination of HIF-alpha Authored: May, B, 2011-03-09 EC Number: 6.3.2.19 Edited: May, B, 2011-03-09 Pubmed10535940 Pubmed10878807 Pubmed10973499 Pubmed11454738 Pubmed12101228 Pubmed12538644 Pubmed9891082 Reactome Database ID Release 431234172 Reactome, http://www.reactome.org ReactomeREACT_121374 Reviewed: Rantanen, Krista, 2012-05-19 VHL is an E3 ubiquitin ligase that conjugates ubiquitin to hydroxylated HIF-alpha (Iwai et al. 1999, Kamura et al. 2000, Ohh et al. 2000, Groulx and Lee 2002, Maynard et al. 2003). VHL is predominantly cytosolic and shuttles between the cytosol and the nucleus (Lee et al. 1999, Groulx and Lee 2002). Ubiquitination and degradation of HIF-alpha can occur in both the cytosol and the nucleus (Berra et al. 2001). Upon return to normoxia from hypoxia most ubiquitinated HIF-alpha is nuclear (Groulx and Lee 2002). PathwayStep4097 Nuclear Export of Ubiquitinated HIF-alpha:VHL:EloB/C:CUL2:RBX1 Complex Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-18 Pubmed12101228 Pubmed9891082 Reactome Database ID Release 431234175 Reactome, http://www.reactome.org ReactomeREACT_121002 Reviewed: Rantanen, Krista, 2012-05-19 When hypoxic cells return to normoxia, HIF-alpha is ubiquitinated in the nucleus and exported to the cytosol (Groulx and Lee 2002). The shuttling of VHL between the nucleus and cytosol is required (Groulx and Lee 2002, Lee et al. 1999). Cytosolic Ubiquitination of HIF-alpha Authored: May, B, 2011-03-09 EC Number: 6.3.2.19 Edited: May, B, 2011-03-09 Pubmed10535940 Pubmed10878807 Pubmed10973499 Pubmed11454738 Pubmed12101228 Pubmed12538644 Pubmed9891082 Reactome Database ID Release 431234163 Reactome, http://www.reactome.org ReactomeREACT_120954 Reviewed: Rantanen, Krista, 2012-05-19 VHL is an E3 ubiquitin ligase that conjugates ubiquitin to hydroxylated HIF-alpha (Iwai et al. 1999, Kamura et al. 2000, Ohh et al. 2000, Groulx and Lee 2002, Maynard et al. 2003). VHL is predominantly cytosolic and shuttles between the cytosol and the nucleus (Lee et al. 1999, Groulx and Lee 2002). Ubiquitination and degradation of HIF-alpha can occur in both the cytosol and the nucleus (Berra et al. 2001). ABCA7-dependent phospholipids Converted from EntitySet in Reactome Reactome DB_ID: 382530 Reactome Database ID Release 43382530 Reactome, http://www.reactome.org ReactomeREACT_16108 ABCA7-dependent phospholipids Converted from EntitySet in Reactome Reactome DB_ID: 382526 Reactome Database ID Release 43382526 Reactome, http://www.reactome.org ReactomeREACT_15647 Integrin alphaVbeta3 Reactome DB_ID: 210216 Reactome Database ID Release 43210216 Reactome, http://www.reactome.org ReactomeREACT_13287 has a Stoichiometric coefficient of 1 Integrin alphaVbeta3:PECAM-1 Reactome DB_ID: 210229 Reactome Database ID Release 43210229 Reactome, http://www.reactome.org ReactomeREACT_13361 has a Stoichiometric coefficient of 1 p-PECAM1:p-PECAM1 Reactome DB_ID: 211539 Reactome Database ID Release 43211539 Reactome, http://www.reactome.org ReactomeREACT_12801 has a Stoichiometric coefficient of 2 PECAM-1:SHIP1 complex Reactome DB_ID: 210218 Reactome Database ID Release 43210218 Reactome, http://www.reactome.org ReactomeREACT_13027 has a Stoichiometric coefficient of 1 PECAM-1:PLC gamma1 complex Reactome DB_ID: 210240 Reactome Database ID Release 43210240 Reactome, http://www.reactome.org ReactomeREACT_13045 has a Stoichiometric coefficient of 1 CyP60 complexed with Basigin Reactome DB_ID: 204498 Reactome Database ID Release 43204498 Reactome, http://www.reactome.org ReactomeREACT_12835 has a Stoichiometric coefficient of 1 Basigin homodimer Reactome DB_ID: 204594 Reactome Database ID Release 43204594 Reactome, http://www.reactome.org ReactomeREACT_13277 has a Stoichiometric coefficient of 2 Grb2 bound to Tie2 Reactome DB_ID: 204865 Reactome Database ID Release 43204865 Reactome, http://www.reactome.org ReactomeREACT_12659 has a Stoichiometric coefficient of 1 p85 bound to Tie2 Reactome DB_ID: 204834 Reactome Database ID Release 43204834 Reactome, http://www.reactome.org ReactomeREACT_13298 has a Stoichiometric coefficient of 1 IDUA substrates Converted from EntitySet in Reactome Reactome DB_ID: 2206286 Reactome Database ID Release 432206286 Reactome, http://www.reactome.org ReactomeREACT_148224 IDS substrates Converted from EntitySet in Reactome Reactome DB_ID: 2262742 Reactome Database ID Release 432262742 Reactome, http://www.reactome.org ReactomeREACT_148391 SGSH substrates Converted from EntitySet in Reactome Reactome DB_ID: 2263453 Reactome Database ID Release 432263453 Reactome, http://www.reactome.org ReactomeREACT_148098 NAGLU substrates Converted from EntitySet in Reactome Reactome DB_ID: 2263502 Reactome Database ID Release 432263502 Reactome, http://www.reactome.org ReactomeREACT_148043 HGSNAT substrates Converted from EntitySet in Reactome Reactome DB_ID: 2263501 Reactome Database ID Release 432263501 Reactome, http://www.reactome.org ReactomeREACT_147961 GLB1 substrates Converted from EntitySet in Reactome Reactome DB_ID: 2265533 Reactome Database ID Release 432265533 Reactome, http://www.reactome.org ReactomeREACT_148613 p21 RAS:GTP Reactome DB_ID: 109783 Reactome Database ID Release 43109783 Reactome, http://www.reactome.org ReactomeREACT_4782 has a Stoichiometric coefficient of 1 ARSB substrates Converted from EntitySet in Reactome Reactome DB_ID: 2282886 Reactome Database ID Release 432282886 Reactome, http://www.reactome.org ReactomeREACT_148427 pTie2:SHC1 complex Reactome DB_ID: 204857 Reactome Database ID Release 43204857 Reactome, http://www.reactome.org ReactomeREACT_12988 has a Stoichiometric coefficient of 1 SOS-1 bound to Tie2:Grb2 Reactome DB_ID: 210970 Reactome Database ID Release 43210970 Reactome, http://www.reactome.org ReactomeREACT_13320 has a Stoichiometric coefficient of 1 p21 RAS:GDP Reactome DB_ID: 109796 Reactome Database ID Release 43109796 Reactome, http://www.reactome.org ReactomeREACT_2657 has a Stoichiometric coefficient of 1 Tie2 and Ang4 complex Reactome DB_ID: 204789 Reactome Database ID Release 43204789 Reactome, http://www.reactome.org ReactomeREACT_12703 has a Stoichiometric coefficient of 1 pTie2 and SHP2 complex Reactome DB_ID: 204767 Reactome Database ID Release 43204767 Reactome, http://www.reactome.org ReactomeREACT_17975 has a Stoichiometric coefficient of 1 Tie2 and Dok-2 complex Reactome DB_ID: 204788 Reactome Database ID Release 43204788 Reactome, http://www.reactome.org ReactomeREACT_13019 has a Stoichiometric coefficient of 1 Complex of Tie2:Ang2 Reactome DB_ID: 204810 Reactome Database ID Release 43204810 Reactome, http://www.reactome.org ReactomeREACT_12895 has a Stoichiometric coefficient of 1 FN1 dimer Fibronectin dimer Reactome DB_ID: 266103 Reactome Database ID Release 43266103 Reactome, http://www.reactome.org ReactomeREACT_14040 has a Stoichiometric coefficient of 2 PathwayStep4072 PathwayStep4073 PathwayStep4070 PathwayStep4071 PathwayStep4076 PathwayStep4077 PathwayStep4074 PathwayStep4075 PathwayStep4078 PathwayStep4079 hexoses transported by GLUT7/11 Converted from EntitySet in Reactome Reactome DB_ID: 428802 Reactome Database ID Release 43428802 Reactome, http://www.reactome.org ReactomeREACT_20174 compounds transported by GLUT9 Converted from EntitySet in Reactome Reactome DB_ID: 429078 Reactome Database ID Release 43429078 Reactome, http://www.reactome.org ReactomeREACT_19454 hexoses transported by GLUT7/11 Converted from EntitySet in Reactome Reactome DB_ID: 428819 Reactome Database ID Release 43428819 Reactome, http://www.reactome.org ReactomeREACT_19505 PI3K Reactome DB_ID: 74693 Reactome Database ID Release 4374693 Reactome, http://www.reactome.org ReactomeREACT_4240 has a Stoichiometric coefficient of 1 Complex of Tie2:Ang-1 Reactome DB_ID: 204807 Reactome Database ID Release 43204807 Reactome, http://www.reactome.org ReactomeREACT_12688 has a Stoichiometric coefficient of 1 Tie2/Ang1 dimer Reactome DB_ID: 210862 Reactome Database ID Release 43210862 Reactome, http://www.reactome.org ReactomeREACT_13336 has a Stoichiometric coefficient of 2 Phosphorylated Tie2 in Tie2/Akt dimer Reactome DB_ID: 210859 Reactome Database ID Release 43210859 Reactome, http://www.reactome.org ReactomeREACT_13046 has a Stoichiometric coefficient of 2 pTie2:Ang-1 Reactome DB_ID: 204783 Reactome Database ID Release 43204783 Reactome, http://www.reactome.org ReactomeREACT_13342 has a Stoichiometric coefficient of 1 Integrin alpha5beta1:Fibronectin Reactome DB_ID: 202708 Reactome Database ID Release 43202708 Reactome, http://www.reactome.org ReactomeREACT_12353 has a Stoichiometric coefficient of 1 CXADR bound to JAML Reactome DB_ID: 198198 Reactome Database ID Release 43198198 Reactome, http://www.reactome.org ReactomeREACT_11619 has a Stoichiometric coefficient of 1 OLR1 bound to oxidized LDL Reactome DB_ID: 203127 Reactome Database ID Release 43203127 Reactome, http://www.reactome.org ReactomeREACT_12181 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TREM-1 bound to its ligand Reactome DB_ID: 203154 Reactome Database ID Release 43203154 Reactome, http://www.reactome.org ReactomeREACT_12367 has a Stoichiometric coefficient of 1 PathwayStep4080 PathwayStep4081 PathwayStep4082 PathwayStep4083 PathwayStep4084 PathwayStep4085 PathwayStep4086 PathwayStep4087 PathwayStep4088 PathwayStep4089 CD58 bound to CD2 Reactome DB_ID: 202794 Reactome Database ID Release 43202794 Reactome, http://www.reactome.org ReactomeREACT_12230 has a Stoichiometric coefficient of 1 Integrin alpha5beta1 Reactome DB_ID: 202730 Reactome Database ID Release 43202730 Reactome, http://www.reactome.org ReactomeREACT_12335 has a Stoichiometric coefficient of 1 CD47 bound to its ligand Reactome DB_ID: 202787 Reactome Database ID Release 43202787 Reactome, http://www.reactome.org ReactomeREACT_12217 has a Stoichiometric coefficient of 1 CD48 bound to CD244 Reactome DB_ID: 202790 Reactome Database ID Release 43202790 Reactome, http://www.reactome.org ReactomeREACT_12345 has a Stoichiometric coefficient of 1 JAM-C homodimer Reactome DB_ID: 202782 Reactome Database ID Release 43202782 Reactome, http://www.reactome.org ReactomeREACT_12100 has a Stoichiometric coefficient of 2 PECAM-1 bound to CD177 Reactome DB_ID: 202785 Reactome Database ID Release 43202785 Reactome, http://www.reactome.org ReactomeREACT_12173 has a Stoichiometric coefficient of 1 P-selectin bound to its ligand Reactome DB_ID: 202776 Reactome Database ID Release 43202776 Reactome, http://www.reactome.org ReactomeREACT_12193 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 JAM-B homodimer Reactome DB_ID: 202780 Reactome Database ID Release 43202780 Reactome, http://www.reactome.org ReactomeREACT_12209 has a Stoichiometric coefficient of 2 MERTK bound to its ligand Reactome DB_ID: 202770 Reactome Database ID Release 43202770 Reactome, http://www.reactome.org ReactomeREACT_12164 has a Stoichiometric coefficient of 1 CD84 Homodimer Reactome DB_ID: 202774 Reactome Database ID Release 43202774 Reactome, http://www.reactome.org ReactomeREACT_12135 has a Stoichiometric coefficient of 1 PathwayStep4629 PathwayStep4627 PathwayStep4628 PathwayStep4625 PathwayStep4626 PathwayStep4623 PathwayStep4624 PathwayStep4621 PathwayStep4622 PathwayStep4631 PathwayStep4630 JAK1 phosphorylates Y338, Y392 and Y510 of IL2RB Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 Following stimulation by IL2, the IL2R beta chain become phosphorylated on multiple tyrosine residues. These phosphotyrosine residues recruit position-specific signaling or adaptor proteins, leading to the activation of downstream signaling pathways. Although multiple kinases are involved in the phosphorylation of IL-2R beta, JAK1-dependent phosphorylation of tyrosines 338, 392 and 510 is known to be involved in STAT protein binding (Gaffen et al. 1996). Phospho-tyrosine 338 has also been shown to participate in recruitment and subsequent phosphorylation of the adaptor Shc (Friedmann et al. 1996). N.B. Numbering in the literature is based on the mature peptide, with the 26 residue signal peptide removed. Positions given in this reaction refer to the canonical Uniprot sequence, e.g. 338 is equivalent to 364 of the canonical sequence P14784. Pubmed11356007 Pubmed8700888 Pubmed9793823 Reactome Database ID Release 43452122 Reactome, http://www.reactome.org ReactomeREACT_27196 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 has a Stoichiometric coefficient of 3 Phosphorylation of IL2RB Y338 enables SHC recruitment Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Phosphorylation of IL2RB Y338 creates a binding site for the accessory protein SHC, which then becomes tyrosine phosphorylated and recruits the Grb2/Sos and Grb2:Gab2 complexes. Pubmed7499411 Pubmed8643566 Pubmed8700888 Reactome Database ID Release 43452091 Reactome, http://www.reactome.org ReactomeREACT_27317 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Phosphorylation of IL2RB Y338, Y392 or Y510 enables STAT recruitment Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Mutation analysis has shown that Y338, Y392 and Y510 are involved in IL-2-induced STAT protein binding. Phospho-tyrosines 338, 392 and 510 can each promote STAT5 activation (Gaffen et al. 1996), though Y510 appears to be the primary site for STAT5 binding (Gesbert et al. 1998). STAT3 may also be recruited to phospho-tyrosines on IL2RB and studies have shown defective IL-2 responses in STAT3-/- T cells, thereby supporting a functional role for STAT3 downstream of IL-2 signaling (Akaishi et al. 1998). Pubmed7568001 Pubmed8631883 Pubmed8700888 Pubmed8702919 Pubmed9793823 Pubmed9846704 Reactome Database ID Release 43452108 Reactome, http://www.reactome.org ReactomeREACT_27183 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 SHC1 bound to IL2 receptor is phosphorylated Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 Following IL2 stimulation of IL2R, Shc is known to be tyrosine phosphorylated (Zhu et al. 1994). The identity of the kinase is uncertain (Gesbert et al. 1998); JAK1 may be responsible but this has not been demonstrated, another candidate is Lck.<br><br>Following IL-3 treatment, Shc becomes tyrosyl phoshorylated at 3 sites, Y427 (Salcini et al. 1994), Y349 and Y350 (Gotoh et al. 1996). Y427 mediates the subsequent association with Grb2 (Salcini et al. 1994).<br><br>Numbering here refers to Uniprot P29353 where the p66 isoform has been selected as the canonical form. Literature references used here refer to the p52 isoform which lacks the first 110 residues, so Y427 is referred to as Y317 in Salcini et al. 1994, Y349 and Y350 as Y239 and Y240 in Gotoh et al. 1996. Pubmed2000405 Pubmed8119884 Pubmed8294403 Pubmed9793823 Reactome Database ID Release 43452100 Reactome, http://www.reactome.org ReactomeREACT_27150 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 PathwayStep4636 SOS1 activates H-Ras Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed17496910 Pubmed8493579 Reactome Database ID Release 43508236 Reactome, http://www.reactome.org ReactomeREACT_23928 Recruitment of Sos1 to the receptor complex brings it into contact with membrane-associated Ras-GDP. Interactions with Ras modulate Sos1 activity in a two-step manner (McKay & Morrison, 2007). Sos1 acts as a guanine exchange factor for Ras (Chardin et al. 1993), activating the Ras-Raf-MAPK pathway. Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 PathwayStep4637 Phosphorylated SHC1 recruits SHIP Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10194451 Pubmed10207047 Pubmed10570274 Pubmed7898932 Pubmed9058724 Pubmed9083021 Pubmed9099679 Pubmed9108392 Pubmed9852043 Reactome Database ID Release 43913374 Reactome, http://www.reactome.org ReactomeREACT_23874 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 SHIP dephosphorylates PIP3 and may limit the magnitude or duration of signaling events that are dependent upon PIP3-mediated membrane recruitment of plextrin homology (PH) domain signalling proteins such as PI3K and Akt (Aman et al. 1998). The PTB domain of SHC1 binds to phosphorylated tyrosine residues on SHIP. Mutations that inactivate the PTB domain prevent this binding and substitution of F for Y917 and Y1020 on SHIP prevents creation of the phosphotyrosine motifs that are recognized by the SHC1 PTB domain, blocking the interaction (Lamkin et al. 1997). A functional SHIP SH2 domain is also reported as a requirement for association of SHIP with Shc (Liu et al. 1997). GRB2 stabilizes the SHC1/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on SHC1, forming a ternary complex of SHC1:GRB2:SHIP described as inducible by IL-3, IL-5 or GM-CSF by many authors (Jucker et al. 1997, Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999). has a Stoichiometric coefficient of 4 PathwayStep4638 PathwayStep4639 PathwayStep4632 Phosphorylated SHC1 recruits GRB2:GAB2 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Phosphorylated Shc recruits Grb2 and Gab2, probably by binding to Grb2 in the Grb2:Gab2 complex. Gab2 associates with Grb2, Shc, Shp2 and the p85 subunit of PI3K (Gu et al. 1998). The association of Grb2 with Gab2 has been suggested to be constitutive (Gu et al. 2000, Kong et al. 2003, Harkiolaki et al. 2009), so Gab2 may be recruited to Shc1 with Grb2. Alternatively, Gab2 has been suggested to associate constitutively with Shc (Kong et al 2003). In either case, the result is a complex of Shc:Grb2:Gab2. Gab2 binding to p85 (Gu et al. 1998) links Shc1 to PI3K activity and subsequent activation of kinases such as Akt (Gu et al. 2000). Pubmed10982827 Pubmed12464621 Pubmed19523899 Pubmed8084588 Pubmed9885561 Reactome Database ID Release 43453104 Reactome, http://www.reactome.org ReactomeREACT_23856 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 has a Stoichiometric coefficient of 4 PathwayStep4633 SHC1 mediates cytokine-induced phosphorylation of GAB2 Authored: Ray, KP, 2010-05-17 Binding of Gab2 to tyrosine phosphorylated Shc promotes the phosphorylation of Gab2 by an unknown kinase. Gab2 becomes tyrosine phosphorylated in response to IL-2 (Brockdorff et al. 2001) and IL-3 (Gu et al. 1998). Chimeric receptors were used to demonstrate that Shc is sufficient for Gab2 tyrosine phosphorylation. In response to IL-3, Grb2 was also required, reflecting that Gab2 is recruited to the activated cytokine receptor complex as a complex of Gab2:Grb2 (Gu et al. 2000). Edited: Jupe, S, 2010-08-06 Pubmed10982827 Pubmed11340297 Pubmed9885561 Reactome Database ID Release 43912527 Reactome, http://www.reactome.org ReactomeREACT_23782 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 has a Stoichiometric coefficient of 4 PathwayStep4634 Gab2 binds the p85 subunit of Class 1A PI3 kinases Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10455108 Pubmed10982827 Pubmed9774657 Pubmed9885561 Reactome Database ID Release 43508247 Reactome, http://www.reactome.org ReactomeREACT_24024 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Shc promotes Gab2 tyrosine phosphorylation via Grb2 (Gu et al. 2000). This promotes binding of Gab2 to p85alpha, a component of Class 1A PI3Ks (Gu et al. 1998). JAK1 may also be involved in PI3K recruitment (Migone et al. 1998). Binding of p85 activates PI3K kinase activity, with consequent effects on many processes including Akt activation. This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors, the other is mediated by Serine-585 phosphorylation of the common beta chain. has a Stoichiometric coefficient of 4 PathwayStep4635 Phosphorylated SHC recruits GRB2:SOS1 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed1465135 Pubmed8119884 Pubmed8294403 Reactome Database ID Release 43453111 Reactome, http://www.reactome.org ReactomeREACT_23828 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Shc is tyrosine phosphorylated by an unidentified kinase, creating a docking site for the SH2 domain of Grb2 (Zhu et al. 1994). Grb2 is an adaptor protein believed to be constitutively associated with the guanine nucleotide exchange protein Sos1 (often abbreviated to Sos). Recruitment of the Grb2:Sos1 complex leads to activation of the Ras pathway (Ravichandran & Burakoff 1994) and consequently activation of the MAPK pathway. has a Stoichiometric coefficient of 4 PathwayStep4640 PTEN Truncation Mutants Converted from EntitySet in Reactome Reactome DB_ID: 2318581 Reactome Database ID Release 432318581 Reactome, http://www.reactome.org ReactomeREACT_148434 PathwayStep4642 PathwayStep4641 SREBP1A/1C/2 Dimerizes Authored: May, B, 2012-01-23 Edited: May, B, 2012-01-23 Pubmed11283257 Reactome Database ID Release 432065549 Reactome, http://www.reactome.org ReactomeREACT_147718 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 Dimerizes The N-terminal domains of SREBPs (SREBP1A/1C/2, SREBFs) dimerize via interaction of their helix-loop-helix leucine zipper domains (Nagoshi and Yoneda 2001). has a Stoichiometric coefficient of 2 SREBP1A/1C/2 Binds Importin beta-1 Authored: May, B, 2012-01-23 Edited: May, B, 2012-01-23 Pubmed10397761 Reactome Database ID Release 432065550 Reactome, http://www.reactome.org ReactomeREACT_147765 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 Binds Importin beta-1 SREBP1A/1C/2 (SREBF1A/1C/2) dimer binds Importin beta-1 via the helix-loop-helix leucine zipper domain of SREBP1A/1C/2 (Nagoshi et al. 1999). S2P Cleaves SREBP1A/1C/2 Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed10805775 Pubmed8156598 Pubmed8674110 Pubmed9659902 Reactome Database ID Release 431655851 Reactome, http://www.reactome.org ReactomeREACT_147876 Reviewed: Liang, Guosheng, 2012-08-25 S2P Cleaves SREBF1A/1C/2 S2P(MBTPS2), a membrane-bound protease in the Golgi, cleaves within the transmembrane region of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2 into the cytosol. PathwayStep4645 PathwayStep4646 PathwayStep4643 PathwayStep4644 PathwayStep4649 PathwayStep4647 PathwayStep4648 PathwayStep4653 PathwayStep4652 PathwayStep4651 PathwayStep4650 SREBP1A/1C Binds the FASN Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed10759542 Pubmed12177166 Pubmed17449569 Pubmed18559965 Pubmed18682402 Pubmed7592729 Pubmed9748295 Reactome Database ID Release 432426148 Reactome, http://www.reactome.org ReactomeREACT_147842 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C Binds the FASN Promoter SREBP1A (SREBF1A) or SREBP1C, together with NF-Y and SP1, bind and transactivate the promoter of the FASN gene (Bennett et al. 1995, Pai et al. 1998, Xiong et al. 2000, Amemiya-Kudo et al. 2002, Shin et al. 2007, Choi et al. 2008, Rome et al. 2008). NF-Y is required for response to cholesterol (Xiong et al. 2000). SREBP1A activates FASN more strongly than does SREBP1C or SREBP2 (Pai et al. 1998, Amemiya-Kudo et al. 2002). SREBP1A/1C Binds the GPAM Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed22634312 Reactome Database ID Release 432426158 Reactome, http://www.reactome.org ReactomeREACT_147903 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C Binds the GPAM Promoter SREBP1A (SREBF1A) or SREBP1C bind and transactivate promoter II of the GPAM gene (Harada et al. 2012). Promoter II is active in lipogenic tissues. As inferred from mouse, NF-Y also binds the GPAM promoter with SREBP1A/1C. SREBP1A/1C/2 Binds the TM7SF2 Promoter Authored: May, B, 2012-01-23 Edited: May, B, 2012-01-23 Formation of SREBF:NF-Y:TM7SF2 gene complex Formation of SREBP:NF-Y:TM7SF2 gene complex Pubmed18559965 Pubmed18654640 Pubmed20138239 Reactome Database ID Release 432065966 Reactome, http://www.reactome.org ReactomeREACT_147699 Reviewed: Liang, Guosheng, 2012-08-25 SREBP2 (SREBF2) binds and transactivates an unusual sterol regulatory element in the promoter of the TM7SF2 gene (Schiavoni et al. 2010). NF-Y binds the promoter and is important for activation by SREBP2. SREBP1A and SREBP1C can also bind the TM7SF2 promoter (Reed et al. 2008, Rome et al. 2008). PTEN Phosphatase Domain Missense Mutants Converted from EntitySet in Reactome Reactome DB_ID: 2317372 Reactome Database ID Release 432317372 Reactome, http://www.reactome.org ReactomeREACT_147971 SREBP1A/1C Binds the ACACB Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed12764144 Reactome Database ID Release 432426153 Reactome, http://www.reactome.org ReactomeREACT_147803 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C Binds the ACACB Promoter SREBP1A (SREBF1A) or SREBP1C, together with SP1, bind and transactivate promoter II of the ACACB gene in human HepG2 cells (Oh et al. 2003). SREBF1A/1C Binds the ACACA Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18559965 Pubmed9300785 Reactome Database ID Release 432426160 Reactome, http://www.reactome.org ReactomeREACT_147714 Reviewed: Liang, Guosheng, 2012-08-25 SREBP1A (SREBF1A) or SREBP1C bind two sites in the promoter of the ACACA gene (Magana et al. 1997, Rome et al. 2008). Each site is required for activation of transcription. SREBP1A/1C/2 Binds the ACACA Promoter PIK3R1 nSH2 domain mutants Converted from EntitySet in Reactome Reactome DB_ID: 2399722 Reactome Database ID Release 432399722 Reactome, http://www.reactome.org ReactomeREACT_148497 SREBP1A/1C/2 Dissociates from Importin beta-1 Authored: May, B, 2012-01-23 Edited: May, B, 2012-01-23 Pubmed10397761 Reactome Database ID Release 432065539 Reactome, http://www.reactome.org ReactomeREACT_147724 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 Dissociates from Importin beta-1 SREBP1A/1C/2 (SREBF1A/1C/2) dimer dissociates from Importin beta-1 in response to Ran-GTP in the nucleoplasm (Nagoshi et al. 1999). SREBP1A/1C/2 Transits to the Nucleus Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed10397761 Pubmed11283257 Pubmed14645851 Pubmed15550381 Pubmed8156598 Pubmed8674110 Pubmed9634703 Reactome Database ID Release 431655831 Reactome, http://www.reactome.org ReactomeREACT_147887 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 Transits to the Nucleus The N-terminal domain of SREBP1A/1C/2 (SREBF1A/1C/2) dimerizes and is imported from the cytosol into the nucleus by importin-beta (Nagoshi et al. 1999, Nagoshi and Yoned 2001, Lee et al. 2003). In the nucleus the dimers bind DNA (Parraga et al. 1998) and activate transcription (Datta and Osborne 2005). PathwayStep4654 PathwayStep4655 PathwayStep4656 PathwayStep4657 PathwayStep4658 PathwayStep4659 PathwayStep4660 PathwayStep4662 PathwayStep4661 PathwayStep4664 PathwayStep4663 SREBP1A/2 Binds the SQLE Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed12083769 Pubmed18559965 Reactome Database ID Release 432426151 Reactome, http://www.reactome.org ReactomeREACT_147752 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the SQLE Promoter SREBP1A (SREBF1A) or SREBP2 binds and transactivates the promoter of the SQLE gene (Reed et al. 2008). The promoter also contains a consensus binding site for NF-Y (Nagai et al. 2002). SREBP1A/1C/2 Binds the FDFT1 Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18559965 Pubmed18654640 Pubmed9604010 Pubmed9748295 Reactome Database ID Release 432426146 Reactome, http://www.reactome.org ReactomeREACT_147835 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 Binds the FDFT1 Promoter SREBP1A/1C/2 (SREBF1A/1C/2), together with NF-Y and SP1, bind and transactivate the promoter of the FDFT1 gene (Inoue et al. 1998, Pai et al. 1998, Reed et al. 2008, Rome et al. 2008). SREBP2 activates FDFT1 more strongly than does SREBP1A (Pai et al. 1998). SREBP1A/1C/2 Binds the HMGCS1 Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed12177166 Pubmed18654640 Pubmed9604010 Pubmed9748295 Reactome Database ID Release 432426150 Reactome, http://www.reactome.org ReactomeREACT_147710 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 Binds the HMGCS1 Promoter SREBP1A/1C/2 (SREBF1A/1C/2), together with NF-Y, bind and transactivate the promoter of the HMGCS1 gene (Maeda et al. 1998, Pai et al. 1998, Amemiya-Kudo et al. 2002, Reed et al. 2008). SREBP1A and SREBP2 activate HMGCS1 equally (Pai et al. 1998). SREBP1A/1C/2 Binds the FDPS Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed12177166 Pubmed18559965 Pubmed18654640 Pubmed20450493 Pubmed8798690 Pubmed9748295 Reactome Database ID Release 432426147 Reactome, http://www.reactome.org ReactomeREACT_147735 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 Binds the FDPS Promoter SREBP1A/1C/2 (SREBF1A/1C/2), together with NF-Y, bind and transactivate the promoter of the FDPS gene (Ericsson et al. 1996, Pai et al. 1998, Amemiya-Kudo et al. 2002, Reed et al. 2008, Rome et al. 2008, Ishimoto et al. 2010). The binding of NF-Y synergistically enhances the binding of SREBP1 (Ericsson et al. 1996). SREBP1A activates FDPS more strongly than does SREBP2 or SREBP1C (Amemiya-Kudo et al. 2002). SREBP1A/1C/2 Binds the ELOVL6 Promoter As inferred from mouse, SREBP1A/1C/2 (SREBF1A/1C/2) binds and transactivates the promoter of the ELOVL6 gene. Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Reactome Database ID Release 432426149 Reactome, http://www.reactome.org ReactomeREACT_147877 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 Binds the ELOVL6 Promoter Expression of Acetyl CoA Carboxylase 2 (ACACB, ACC2) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed9099716 Reactome Database ID Release 431655830 Reactome, http://www.reactome.org ReactomeREACT_147743 Reviewed: Liang, Guosheng, 2012-08-25 The ACACB gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Diphosphomevalonate Decarboxylase (MVD) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed8626466 Reactome Database ID Release 431655836 Reactome, http://www.reactome.org ReactomeREACT_147863 Reviewed: Liang, Guosheng, 2012-08-25 The MVD gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of 7-Dehydrocholesterol Reductase (DHCR7) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed9634533 Reactome Database ID Release 431655827 Reactome, http://www.reactome.org ReactomeREACT_147864 Reviewed: Liang, Guosheng, 2012-08-25 The DHCR7 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Acetyl CoA Carboxylase 1 (ACACA, ACC1) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed7732023 Reactome Database ID Release 431655845 Reactome, http://www.reactome.org ReactomeREACT_147816 Reviewed: Liang, Guosheng, 2012-08-25 The ACACA gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of ELOVL6 Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed20937905 Reactome Database ID Release 431655835 Reactome, http://www.reactome.org ReactomeREACT_147888 Reviewed: Liang, Guosheng, 2012-08-25 The ELOVL6 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SREBP1A/2 Binds the MVD Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18559965 Reactome Database ID Release 432426144 Reactome, http://www.reactome.org ReactomeREACT_147898 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the MVD Promoter SREBP1A (SREBF1A) or SREBP2 binds and transactivates the promoter of the MVD gene (Rome et al. 2008). SREBP1A/2 Binds the LSS Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18559965 Pubmed9748295 Reactome Database ID Release 432426154 Reactome, http://www.reactome.org ReactomeREACT_147766 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the LSS Promoter SREBP1A (SREBF1A) or SREBP2 binds and transactivates the promoter of the LSS gene (Pai et al. 1998, Rome et al. 2008). SREBP1A and SREBP2 activate LSS equally (Pai et al. 1998). SREBP1A/2 Binds the SC5DL Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18559965 Pubmed18654640 Reactome Database ID Release 432426164 Reactome, http://www.reactome.org ReactomeREACT_147859 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the SC5DL Promoter SREBP1A (SREBF1A) or SREBP2, together with NF-Y, bind and transactivate the promoter of the SC5DL gene (Reed et al. 2008, Rome et al. 2008). SREBP1A/2 Binds the HMGCR Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18559965 Pubmed18654640 Pubmed8647822 Pubmed9748295 Reactome Database ID Release 432426162 Reactome, http://www.reactome.org ReactomeREACT_147894 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the HMGCR Promoter SREBP1A (SREBF1A) or SREBP2, together with NF-Y, bind and transactivate the promoter of the HMGCR gene (Vallett et al. 1996, Pai et al. 1998, Reed et al. 2008, Rome et al. 2008). SREBP2 activates HMGCR slightly more than does SREBP1A (Pai et al. 1998). SREBP1A/2 binds 2 main sites and 2 auxiliary sites in the HMGCR promoter (Vallett et al. 1996). SREBP1A/2 Binds the CYP51A1 Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18559965 Pubmed18654640 Pubmed9748295 Reactome Database ID Release 432426163 Reactome, http://www.reactome.org ReactomeREACT_147786 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the CYP51A1 Promoter SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the CYP51A1 gene (Pai et al. 1998, Reed et al. 2008, Rome et al. 2008). SREBP1A and SREBP2 activate CYP51A1 equally (Pai et al. 1998). PIK3R1 iSH2 domain mutants Converted from EntitySet in Reactome Reactome DB_ID: 2399665 Reactome Database ID Release 432399665 Reactome, http://www.reactome.org ReactomeREACT_148063 SREBP1A/2 Binds the DHCR7 Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18654640 Reactome Database ID Release 432426155 Reactome, http://www.reactome.org ReactomeREACT_147715 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the DHCR7 Promoter SREBP1A (SREBF1A) and SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the DHCR7 gene (Reed et al. 2008). SREBP1A/2 Binds the GGPS1 Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18654640 Reactome Database ID Release 432426161 Reactome, http://www.reactome.org ReactomeREACT_147815 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the GGPS1 Promoter SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the GGPS1 gene (Reed et al. 2008). SREBP1A/2 Binds the IDI1 Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18654640 Reactome Database ID Release 432426152 Reactome, http://www.reactome.org ReactomeREACT_147783 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the IDI1 Promoter SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the IDI1 gene (Reed et al. 2008). SREBP1A/2 Binds the MVK Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18654640 Reactome Database ID Release 432426157 Reactome, http://www.reactome.org ReactomeREACT_147804 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the MVK Promoter SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the MVK gene (Reed et al. 2008). SREBP1A/2 Binds the PMVK Promoter Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed18654640 Reactome Database ID Release 432426156 Reactome, http://www.reactome.org ReactomeREACT_147861 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/2 Binds the PMVK Promoter SREBP1A (SREBF1A) or SREBP2, together with NF-Y and SP1, bind and transactivate the promoter of the PMVK gene (Reed et al. 2008). PathwayStep4602 PathwayStep4601 PathwayStep4600 PathwayStep4606 PathwayStep4605 PathwayStep4604 PathwayStep4603 4-cholesten-7alpha-ol-3-one is reduced to 5beta-cholestan-7alpha-ol-3-one 4-Cholesten-7alpha-ol-3-one, NADPH, and H+ react to form 5beta-cholestan-7alpha-ol-3-one and NADP+. This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). AKR1D1 is localized to the cytosol, and in the course of the reaction its steroid substrate moves from the endoplasmic reticulum membrane to the cytosol. It is unclear whether this translocation results simply from its increased hydrophilicity or is mediated by the enzyme or another transport protein (Russell 2003). 4-cholesten-7alpha-ol-3-one + NADPH + H+ => 5beta-cholestan-7alpha-ol-3-one + NADP+ Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12543708 Pubmed7508385 Reactome Database ID Release 43192033 Reactome, http://www.reactome.org ReactomeREACT_9972 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4609 4-cholesten-7alpha, 12alpha-diol-3-one is reduced to 5beta-cholesten-7alpha, 12alpha-diol-3-one 4-Cholesten-7alpha, 12alpha-diol-3-one and NADPH + H+ react to form 5beta-cholesten-7alpha,12alpha-diol-3-one + NADP+. This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). AKR1D1 is localized to the cytosol, and in the course of the reaction its steroid substrate moves from the endoplasmic reticulum membrane to the cytosol. It is unclear whether this translocation results simply from its increased hydrophilicity or is mediated by the enzyme or another transport protein (Russell 2003). 4-cholesten-7alpha, 12alpha-diol-3-one + NADPH + H+ => 5beta-cholesten-7alpha,12alpha-diol-3-one + NADP+ Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12543708 Pubmed7508385 Reactome Database ID Release 43192067 Reactome, http://www.reactome.org ReactomeREACT_10048 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4608 4-Cholesten-7alpha-ol-3-one is 12alpha-hydroxylated to 7-alpha,12-alpha-dihydroxycholest-4-en-3-one 7-Alpha-hydroxycholest-4-en-3-one, NADPH + H+, and O2 form 7-alpha,12-alpha-dihydroxycholest-4-en-3-one + NADP+ + H2O. This reaction is catalyzed by sterol 12alpha hydroxylase (CYP8B1), an enzyme associated with the endoplasmic reticulum membrane. While the human gene has been cloned (Gafvels et al. 1999), its protein product has not been characterized, and the enzymatic properties of human CYP8B1 protein are inferred from those of its well-characterized rabbit homolog (Ishida et al. 1992). 7-alpha-hydroxycholest-4-en-3-one + NADPH + H+ + O2 => 7-alpha,12-alpha-dihydroxycholest-4-en-3-one + NADP+ + H2O Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.14.13.95 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10051404 Pubmed1400444 Reactome Database ID Release 43192157 Reactome, http://www.reactome.org ReactomeREACT_10071 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep4607 7alpha-hydroxycholesterol is oxidized and isomerized to 4-cholesten-7alpha-ol-3-one 7alpha-hydroxycholesterol and NAD+ react to form 4-cholesten-7alpha-ol-3-one, NADH, and H+, in a reaction catalyzed by HSD3B7 (3 beta-hydroxysteroid dehydrogenase type 7) in the endoplasmic reticulum membrane. Its function in vivo has been confirmed in studies of patients with defects in bile acid synthesis (Schwarz et al. 2000). Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 1.1.1.145 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed11067870 Pubmed12679481 Reactome Database ID Release 43192097 Reactome, http://www.reactome.org ReactomeREACT_10067 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Cholesterol is hydroxylated to 7alpha-hydroxycholesterol by CYP7A1 Authored: Jassal, B, 2008-05-19 12:57:01 Cholesterol + NADPH + H+ + O2 => 7-alpha-hydroxycholesterol + NADP+ + H2O Cholesterol, NADPH + H+, and O2 form 7alpha-cholesterol (5-cholesten-3beta, 7alpha-diol), NADP+,and H2O, in a reaction catalyzed by CYP7A1 (cholesterol 7alpha-hydroylase) in the endoplasmic reticulum membrane. In the body, this enzyme is expressed only in liver, and its expression is tightly regulated at the level of transcription to determine the overall rate of bile acid and bile salt production (Russell 2003; Pullinger et al. 2002). EC Number: 1.14.13.17 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12093894 Pubmed12543708 Pubmed2384150 Reactome Database ID Release 43192051 Reactome, http://www.reactome.org ReactomeREACT_10052 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Expression of TM7SF2 Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed20138239 Reactome Database ID Release 431655833 Reactome, http://www.reactome.org ReactomeREACT_147728 Reviewed: Liang, Guosheng, 2012-08-25 The TM7SF2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Squalene Monooxygenase (SQLE) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed8626488 Reactome Database ID Release 431655844 Reactome, http://www.reactome.org ReactomeREACT_147725 Reviewed: Liang, Guosheng, 2012-08-25 The SQLE gene is transcribed to yield mRNA and the mRNA is translated to yield protein. 5beta-cholestan-3alpha, 7alpha, 12alpha-triol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-3alpha,7alpha,12alpha-triol is translocated from the cytosol to the mitochondrial matrix. The transporter that mediates its passage across the inner mitochondrial membrane is unknown: the StAR protein that performs this function for cholesterol at the start of steroid hormone biosynthesis is excluded as StAR is not expressed in liver. Other members of the START family of transporters are candidates, however (Russell 2003). Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12543708 Reactome Database ID Release 43192010 Reactome, http://www.reactome.org ReactomeREACT_10097 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5Beta-cholesten-7alpha, 12alpha-diol-3-one is reduced to 5beta-cholestan-3alpha, 7alpha, 12alpha-triol 5Beta-cholesten-7alpha, 12alpha-diol-3-one + NADPH + H+ => 5beta-cholestan-3alpha, 7alpha, 12alpha-triol + NAPDP+ 5Beta-cholesten-7alpha,12alpha-diol-3-one and NADPH + H+ form 5beta-cholestan-3alpha,7alpha,12alpha-triol and NAPDP+. The reaction is catalyzed by 3alpha-hydroxysteroid dehydrogenase (AKR1C4), a cytosolic enzyme belonging to the aldo-keto reductase family (Dufort et al. 2001). Biochemical studies with rat proteins raise the possibility that other related enzymes may also carry out this reaction in vivo (Russell 2003). Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed11158055 Pubmed12543708 Reactome Database ID Release 43192036 Reactome, http://www.reactome.org ReactomeREACT_10120 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5beta-cholestan-7alpha-ol-3-one is reduced to 5beta-cholestan-3alpha, 7alpha-diol 5Beta-cholesten-7alpha-ol-3-one and NADPH + H+ form 5beta-cholestan-3alpha,7alpha-diol and NAPDP+. The reaction is catalyzed by 3alpha-hydroxysteroid dehydrogenase (AKR1C4), a cytosolic enzyme belonging to the aldo-keto reductase family (Dufort et al. 2001). Biochemical studies with rat proteins raise the possibility that other related enzymes may also carry out this reaction in vivo (Russell 2003). 5beta-cholestan-7alpha-ol-3-one+ NADPH + H+ => 5beta-cholestan-3alpha, 7alpha-diol + NADP+ Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed11158055 Pubmed12543708 Reactome Database ID Release 43192160 Reactome, http://www.reactome.org ReactomeREACT_10068 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4611 PathwayStep4610 PathwayStep4613 PathwayStep4612 PathwayStep4615 PathwayStep4614 PathwayStep4617 PathwayStep4616 PathwayStep4619 Expression of Glycerol-3-phosphate Acyltransferase (GPAM, GPAT) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed20719759 Reactome Database ID Release 431655837 Reactome, http://www.reactome.org ReactomeREACT_147810 Reviewed: Liang, Guosheng, 2012-08-25 The GPAM gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PathwayStep4618 Expression of Geranylgeranyl Pyrophosphate Synthase (GGPS1) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed18726356 Reactome Database ID Release 431655832 Reactome, http://www.reactome.org ReactomeREACT_147826 Reviewed: Liang, Guosheng, 2012-08-25 The GGPS1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Lanosterol Demethylase (CYP51A1) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed8619637 Reactome Database ID Release 431655847 Reactome, http://www.reactome.org ReactomeREACT_147899 Reviewed: Liang, Guosheng, 2012-08-25 The CYP51A1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Isopentenyl-diphosphate Delta-isomerase 1 (IDI1) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed8020941 Reactome Database ID Release 431655823 Reactome, http://www.reactome.org ReactomeREACT_147880 Reviewed: Liang, Guosheng, 2012-08-25 The IDI1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Fatty Acid Synthase (FASN) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed7567999 Reactome Database ID Release 431655843 Reactome, http://www.reactome.org ReactomeREACT_115784 Reviewed: Liang, Guosheng, 2012-08-25 The FASN gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Farnesyl Diphosphate Synthase (FDPS) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed1968462 Reactome Database ID Release 431655824 Reactome, http://www.reactome.org ReactomeREACT_147807 Reviewed: Liang, Guosheng, 2012-08-25 The FDPS gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Lanosterol Synthase (LSS) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed17925399 Reactome Database ID Release 431655828 Reactome, http://www.reactome.org ReactomeREACT_147844 Reviewed: Liang, Guosheng, 2012-08-25 The LSS gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Lathosterol Oxidase (SC5D, SC5DL) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed8976377 Reactome Database ID Release 431655852 Reactome, http://www.reactome.org ReactomeREACT_147875 Reviewed: Liang, Guosheng, 2012-08-25 The SC5D gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Mevalonate Kinase (MVK) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed1377680 Reactome Database ID Release 431655846 Reactome, http://www.reactome.org ReactomeREACT_147902 Reviewed: Liang, Guosheng, 2012-08-25 The MVK gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Phosphomevalonate Kinase (PMVK) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed8663599 Reactome Database ID Release 431655839 Reactome, http://www.reactome.org ReactomeREACT_147771 Reviewed: Liang, Guosheng, 2012-08-25 The PMVK gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PathwayStep4620 Translocation of STAT1 dimer to nucleus Authored: Garapati, P V, 2010-06-08 Edited: Garapati, P V, 2010-07-07 Pubmed10982844 Pubmed12915721 Pubmed7510216 Reactome Database ID Release 43873917 Reactome, http://www.reactome.org ReactomeREACT_25379 Released GAF complex translocates to the nucleus and binds to the gamma-activated sequence (GAS) element present in the promoters of IFNG-regulated genes and induces the transcription of IFNG-responsive genes. Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Phoshorylation of STAT1 by JAK kinases Authored: Garapati, P V, 2010-06-08 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 Pubmed12040185 Pubmed7657660 Pubmed7690989 Pubmed8631301 Reactome Database ID Release 43873922 Reactome, http://www.reactome.org ReactomeREACT_24993 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 STAT1 pair recruited to the receptor complex is phosphorylated near the C-terminus at residue Y701, probably by JAK2. This phosphorylation enables the STAT1 homodimer formation which is further phosphorylated on residue S727. has a Stoichiometric coefficient of 2 Binding of STAT1 to p-IFNGR1 Authored: Garapati, P V, 2010-06-08 Edited: Garapati, P V, 2010-07-07 Pubmed12040185 Pubmed7796299 Pubmed8156998 Reactome Database ID Release 43873921 Reactome, http://www.reactome.org ReactomeREACT_25056 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The phosphorylated tyrosine residue 440 in the 440YDKPH444 motif on IFNGR1 chain serves as a docking site and recruits STAT1, an SH2 domain-containing transcription factor to the functional receptor unit. has a Stoichiometric coefficient of 2 Release of STAT1 dimer from active receptor unit Authored: Garapati, P V, 2010-06-08 Edited: Garapati, P V, 2010-07-07 Pubmed12915721 Pubmed18591661 Pubmed7510216 Reactome Database ID Release 43873927 Reactome, http://www.reactome.org ReactomeREACT_24944 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The phosphorylated STAT1 on IFNGR1 chains homodimerize through reciprocal SH2-phosphotyrosine interactions to form p-STAT1 homodimer called gamma-activated-factor (GAF). This phosphorylated STAT1 homodimer disassociates from the receptor complex and translocates to the nucleus. Phosphorylation of STAT1 at Ser727 Authored: Garapati, P V, 2010-06-08 EC Number: 2.7.11 Edited: Garapati, P V, 2010-07-07 Kinases like Protein kinase C delta (PKC-delta) and Calcium/calmodulin-dependent protein kinase II (CaMK II ) can phosphorylate STAT1 at serine 727 (S727). This phosphorylation is not required for STAT1 homodimer formation, nuclear translocation and DNA binding. However, it is essential for the full transcriptional activation of STAT1. Pubmed11972023 Pubmed15322115 Reactome Database ID Release 43909552 Reactome, http://www.reactome.org ReactomeREACT_25369 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 has a Stoichiometric coefficient of 2 Interaction of IFNG with IFNGR Authored: Garapati, P V, 2010-06-08 Edited: Garapati, P V, 2010-07-07 Pubmed10986460 Pubmed12438563 Pubmed1396683 Pubmed16467876 Pubmed7615558 Pubmed7617032 Pubmed7673114 Pubmed8550631 Reactome Database ID Release 43873926 Reactome, http://www.reactome.org ReactomeREACT_25347 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The IFNG receptor complex is a pre-assembled entity, as constitutive interactions are seen between IFNGR1 and IFNGR2, and between two IFNGR2 chains in the absence of ligand IFNG. JAK1 and JAK2 constitutively associate with the intracellular domains of the subunits of the IFNG receptor complex, providing it with tyrosine kinase activity. In unstimulated cells JAK1 preferentially associates with IFNGR1 and while JAK2 associates with IFNGR2 chains. JAK1 enhances the interaction between IFNGR1 and IFNGR2 chains, and thus has a major role in the pre-assembly of the IFNGR complex, in contrast the kinase activity of JAK2 is required to observe any signaling by IFNG.<br>IFNG binds directly to both the receptor chains IFNGR1 and IFNGR2. IFNGR1 is a high affinity receptor and binds directly to IFNG whereas IFNGR2 binds to IFNG in presence of IFNGR1. According to Krause et al. model IFNG binds to IFNGR1 chains first and then IFNGR2 chains interact with the IFNGR1:IFNG:IFNGR1 complex. Phosphorylation of JAK2 Authored: Garapati, P V, 2010-06-08 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 IFN-gamma binding to the receptor complex, induces JAK2 autophosphorylation and activation. Like all protein tyrosine kinases (PTKs) JAK2 activity also depends on the phosphorylation of tandem tyrosine residues within the activation loop that results in the removal of the activation loop from the active site. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity. Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only tyrosine 1007 is represented in the reaction. Pubmed15143187 Pubmed15530433 Pubmed20304997 Pubmed9111318 Reactome Database ID Release 43873919 Reactome, http://www.reactome.org ReactomeREACT_25139 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 has a Stoichiometric coefficient of 2 Transphosphorylation of JAK1 Authored: Garapati, P V, 2010-06-08 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 Pubmed14525967 Pubmed8631301 Reactome Database ID Release 43873918 Reactome, http://www.reactome.org ReactomeREACT_24928 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The initial phosphorylation of JAK1 and JAK2 is mediated by JAK2. Autophosphorylated JAK2 may transphopshorylate JAK1 bound to IFNGR1 chain. Tyrosine 1033 in the activation loop of the JAK1 kinase domain may be the target for transphosphorylation (phosphorylation site mentioned here is based on sequence similarity with all the other JAK kinases). has a Stoichiometric coefficient of 2 Phosphorylation of IFNGR1 by JAK kinases Authored: Garapati, P V, 2010-06-08 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 Pubmed14525967 Pubmed16237089 Pubmed7514165 Pubmed9143700 Reactome Database ID Release 43873924 Reactome, http://www.reactome.org ReactomeREACT_24933 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The phosphorylated active JAK1 kinase inturn phosphorylates tyrosine residue 440 on each of the IFNGR1 chains to form two adjacent docking sites for the latent STAT1 SH2 domains. has a Stoichiometric coefficient of 2 Dephosphorylation of STAT1 by SHP2 Authored: Garapati, P V, 2010-07-07 EC Number: 3.1.3.48 Edited: Garapati, P V, 2010-07-07 Pubmed10022928 Pubmed18508557 Reactome Database ID Release 43997309 Reactome, http://www.reactome.org ReactomeREACT_24939 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 SHP2 negatively regulates the IFN-induced JAK-STAT pathway by dephosphorylating STAT1 on Y701. Dephosphorylation of JAK1 by SHP1 Authored: Garapati, P V, 2010-07-07 EC Number: 3.1.3.48 Edited: Garapati, P V, 2010-07-07 Pubmed18508557 Pubmed8943354 Reactome Database ID Release 43997314 Reactome, http://www.reactome.org ReactomeREACT_25289 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 SHP1 directly associates with and dephosphorylates JAK1/2. Dephosphorylation of TYK2 by PTP1B Authored: Garapati, P V, 2010-07-07 EC Number: 3.1.3.48 Edited: Garapati, P V, 2010-07-07 Pubmed11694501 Reactome Database ID Release 43997311 Reactome, http://www.reactome.org ReactomeREACT_25329 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 TYK2 bears the substrate recognition motif for PTP1B, and on IFN stimulation PTP1B interacts with and dephosphorylates TYK2. UBP43 binds IFNAR2 and prevents JAK1 interaction Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Pubmed16710296 Reactome Database ID Release 43912685 Reactome, http://www.reactome.org ReactomeREACT_24958 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 UBP43, a type I IFN-inducible cysteine protease acts as a negative regulator of type I IFN signaling. UBP43 binds directly to IFNAR2 and blocks JAK-receptor interaction leading to inhibition of downstream phosphorylation and other signaling events. Inhibition of JAK kinase activity by SOCS1/3 Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Reactome Database ID Release 43912680 Reactome, http://www.reactome.org ReactomeREACT_25065 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 SOCS1/3 are the major negative regulators of IFNA/B signaling. They inhibit JAKs catalytic activity directly through their kinase inhibitory region (KIR) and turn off downstream IFNA/B signaling. SOCS1 may also prevent IFN signaling by targeting the signaling machinery to ubiquitin-proteasomal degradation pathway. Expression of IFN-induced genes Around 300 IFN-induced genes have been identified from different oligonucleotide microarray studies in melanoma (WM9) and fibrosarcoma (HT1080) cell lines as well as from human dendritic cells treated with IFN. Only the proteins which are well studied and their function characterized are represented here. Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Pubmed11092454 Pubmed11337497 Pubmed11404376 Pubmed12029096 Pubmed12766484 Pubmed14769151 Pubmed15047845 Pubmed16009940 Pubmed1730654 Pubmed2211721 Pubmed6162102 Pubmed6548414 Pubmed9096384 Pubmed9861020 Reactome Database ID Release 431015702 Reactome, http://www.reactome.org ReactomeREACT_25192 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 ISGF3 binds the ISRE promoter elements in IFN-stimulated genes Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). These ISGs are mainly implicated in anti-viral, anti-angiogenic, immunomodulatory, cell cycle inhibitory effects and apoptotic functions. All IFNA/B-stimulated genes have a conserved region of about 15bp in their promoter called the Interferon Stimulation Response Element (ISRE). The transcription factor ISGF3 binds to this ISRE and induce the transcription of these genes by IFN. Pubmed12766484 Pubmed18575461 Pubmed7540766 Pubmed9861020 Reactome Database ID Release 431015699 Reactome, http://www.reactome.org ReactomeREACT_24942 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Formation of p-STAT1 homodimer Authored: Garapati, P V, 2010-07-07 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 Pubmed17351669 Pubmed7510216 Reactome Database ID Release 43909718 Reactome, http://www.reactome.org ReactomeREACT_25105 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Under certain conditions type I IFNs, IFNA/B are able to activate genes through a second STAT-based signaling cascade enabling the formation of p-STAT1:p-STAT1 homodimers called IFNA-activated-factor (AAF). has a Stoichiometric coefficient of 2 Translocation of p-STAT1:p-STAT1 dimer to nucleus Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 IFNA-activated-factor (AAF) translocates to nucleus and then promotes the expression of a distinct set of gamma activated sequence (GAS)-driven genes like IRF1. IRF1, in turn, induces the transcription of ISG15, ISG54 and IFI6 genes. This second pathway of STAT1 homodimer formation is primarily activated by IFNG and is likely to account for some of the functional overlap between type I and type II IFNs. Pubmed7510216 Reactome Database ID Release 43913529 Reactome, http://www.reactome.org ReactomeREACT_25256 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Interaction of IRF9 with p-STAT2:p-STAT1 Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Pubmed7537377 Pubmed8621447 Pubmed9242679 Reactome Database ID Release 43909725 Reactome, http://www.reactome.org ReactomeREACT_25284 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The phosphorylated STAT2:STAT1 heterodimer associates with interferon-regulating factor 9 (IRF9) to form the interferon-stimulated gene factor 3 (ISGF3) complex. Translocation of ISGF3 complex to nucleus Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Pubmed17351669 Reactome Database ID Release 43909721 Reactome, http://www.reactome.org ReactomeREACT_25169 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The resultant ISGF3 trimeric complex then migrates to the nucleus and binds to interferon-stimulated response elements (ISREs). IRF9 is the DNA binding part of this ISGF3 complex. These ISREs are present in the promoters of a subset of ISGs (interferon stimulated genes), such as promyelocytic leukemia (PML), ISG15 ubiquitin-like modifier (ISG15), interferon-induced protein with tetratricopeptide repeats 2 (ISG54) and interferon alpha-inducible protein 6 (IFI6) to elicit an antiviral response. Ubiquitination of PAK-2p34 Authored: Jakobi, R, 2008-02-05 11:04:14 EC Number: 6.3.2.19 Edited: Matthews, L, 2008-02-03 20:50:13 Edited: Matthews, L, 2008-05-23 07:04:34 PAK-2p34 is ubiquitinated prior to degradation (Jakobi et al., 2003). Here, ubiquitination of PAK-2p34 is described as occurring in the cytosol. However, to date it is not known whether this occurs in the nucleus or in the cytoplasm. Evidence for this reaction comes from experiments using both human and rabbit proteins. Pubmed12853446 Reactome Database ID Release 43211734 Reactome, http://www.reactome.org ReactomeREACT_13600 Reviewed: Chang, E, 2008-05-21 00:05:41 Competitive inhibition of translation initiation by ISGylated 4EHP Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 Eukaryotic translation initiation factor 4F (eIF4F) is a protein complex that mediates recruitment of ribosomes to mRNA (Gingras et al. 1999). eIF4F contains complex of cap-binding protein eIF4E, scaffold protein eIF4G, and RNA helicase eIF4A. There are three eIF4E-family members in mammals termed eIF4E-1 (eIF4E), eIF4E2 (4EHP), and eIF4E3, of which both eIF4E and eIF4E3 are able to bind to eIF4G to facilitate translation initiation. However, 4EHP does not interact with eIF4G and thus cannot function in ribosome recruitment. 4EHP competes with eIF4E or eIF4E3 for binding to the RNA 5? cap structure and prevents translation initiation. ISGylated 4EHP has a much higher cap structure binding activity, suggesting a regulatory function of ISGylation in protein translation during immune responses (Okumura et al. 2007, Joshi et al. 2004). Pubmed10872469 Pubmed15153109 Pubmed17289916 Reactome Database ID Release 431678842 Reactome, http://www.reactome.org ReactomeREACT_115968 Reviewed: Zhang, DE, 2011--0-2- Nuclear translocation of catalytic domain of Mst3 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Edited: Matthews, L, 2008-06-02 08:04:50 Proteolytic cleavage of the COOH-terminal domain of Mst3 by caspases promotes nuclear translocation of the catalytic domain (Huang et al., 2002). Pubmed12107159 Reactome Database ID Release 43351947 Reactome, http://www.reactome.org ReactomeREACT_13406 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 ISGylation of protein translation regulator 4EHP 4EHP is a member of eukaryotic translation initiation factor 4E (eIF4E) family that acts as an mRNA 5' cap structure-binding protein and suppresses translation. 4EHP is one of the targets of ISG15 and ISGylated 4EHP has a much higher cap structure-binding activity. Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 Pubmed17289916 Reactome Database ID Release 431678843 Reactome, http://www.reactome.org ReactomeREACT_115679 Reviewed: Zhang, DE, 2011--0-2- Mitochondrial recruitment of Drp1 Adenoviral expression of the BAP31 cleavage product, p20 causes early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and recruitment of Drp1 to the mitochondria (Breckenridge et al., 2003) . Drp1 mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network . Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Edited: Matthews, L, 2008-06-03 01:13:58 Pubmed12668660 Reactome Database ID Release 43351948 Reactome, http://www.reactome.org ReactomeREACT_13560 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Translocation of active caspase-8 to the mitochondrial membrane Active caspase 8 associates with the membranes during apoptosis caused by multiple stimuli (Chandra et al., 2004). OMM-localized active caspase 8 can activate cytosolic caspase 3 and ER-localized BAP31 (Chandra et al., 2004) . Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Edited: Matthews, L, 2008-05-27 07:43:39 Pubmed15254227 Reactome Database ID Release 43351863 Reactome, http://www.reactome.org ReactomeREACT_13713 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Monoubiquitination of N-myristoyl GAG (P12493) protein Authored: Garapati, P V, 2011-01-18 Cytosolic N-myristoyl Gag polyprotein is conjugated with a single molecule of ubiquitin. Conjugation is typically to one of two lysine residues in the p6 domain of Gag but can be to lysine residues in the MA, CA, NC, and SP2 domains of the protein. The specific host cell E2 and E3 proteins that mediate Gag ubiquitination have not been identified. The same studies that first identified the p6 ubiquitination sites in Gag also called the biological significance of Gag ubiquitination into question by demonstrating that Gag proteins in which the p6 ubiquitination sites had been removed by mutagenesis could still assemble efficiently into infectious viral particles (Ott et al. 1998, 2000). More recent work, however, has identified additional ubiquitination sites throughout the C-terminal region of the Gag polyprotein, and when all of these sites are removed by mutagenesis, both viral assembly involving the mutant Gag polyprotein and infectivity of the resulting viral particles are sharply reduced (Gottwein et al. 2006). Note: Reactions directly involving interactions of human host proteins with foreign ones are highlighted in red. Edited: Garapati, P V, 2011-01-18 Pubmed11112487 Pubmed16775314 Pubmed9525617 Reactome Database ID Release 431169307 Reactome, http://www.reactome.org ReactomeREACT_115813 Reviewed: Zhang, DE, 2011--0-2- Partial autophosphorylation of PAK-2 at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197 Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-08 00:29:01 Edited: Matthews, L, 2008-06-02 07:41:19 Inactive PAK-2 can be partially autophosphorylated in the regulatory region without being activated (Gatti et al. 1999). Pubmed10075701 Pubmed16204230 Reactome Database ID Release 43211583 Reactome, http://www.reactome.org ReactomeREACT_13431 Reviewed: Chang, E, 2008-05-21 00:05:41 has a Stoichiometric coefficient of 5 Proteolytic PAK-2p34 fragment translocates to the nucleus Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-03 20:50:13 Edited: Matthews, L, 2008-05-18 16:50:19 Pubmed12853446 Reactome Database ID Release 43211712 Reactome, http://www.reactome.org ReactomeREACT_13409 Reviewed: Chang, E, 2008-05-21 00:05:41 The subcellular localization of PAK-2 is controlled by nuclear localization and nuclear export signal motifs (Jakobi et al.,2003). The regulatory domain contains a nuclear export signal motif that prevents the nuclear accumulation of full-length PAK-2. The activating proteolytic cleavage disrupts the nuclear export signal in PAK-2 and removes most its regulatory domain. The resulting activated PAK-2p34 fragment contains a nuclear localization signal and translocates to and is retained in the nucleus (Jakobi et al.,2003). Autophosphorylation of PAK-2p34 in the activation loop Activation of PAK-2p34 coincides with autophosphorylation of Thr 402 in the the catalytic domain (Walter et al., 1998). Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-03 20:50:13 Edited: Matthews, L, 2008-05-28 22:54:51 Pubmed9786869 Reactome Database ID Release 43211650 Reactome, http://www.reactome.org ReactomeREACT_13820 Reviewed: Chang, E, 2008-05-21 00:05:41 Cleavage of PAK-2 at 212 Authored: Jakobi, R, 2008-02-05 11:04:14 EC Number: 3.4.22 Edited: Matthews, L, 2008-02-03 20:50:13 Edited: Matthews, L, 2008-05-23 07:02:49 Pubmed12853446 Pubmed9786869 Reactome Database ID Release 43211651 Reactome, http://www.reactome.org ReactomeREACT_13747 Reviewed: Chang, E, 2008-05-21 00:05:41 p21-activated protein kinase (PAK-2), also known as gamma-PAK, is cleaved by caspase-3 during apoptosis and plays a role in regulating cell death. Cleavage produces two peptides; 1-212 containing most of the regulatory domain and 213-524 containing 34 amino acids of the regulatory domain as well as the catalytic domain (Walter et al., 1998). Proteolytic cleavage of PAK by caspase-3 creates the constitutively active PAK-2p34 fragment (Jakobi et al., 2003). Evidence for this reaction comes from experiments using both human and rabbit proteins. mRNA Transcript Targeted by HuR Phosphorylated on Ser221 and Ser318 Reactome DB_ID: 517622 Reactome Database ID Release 43517622 Reactome, http://www.reactome.org ReactomeREACT_26577 mRNA Transcript Targeted by HuR with Unknown Phosphorylation Reactome DB_ID: 450613 Reactome Database ID Release 43450613 Reactome, http://www.reactome.org ReactomeREACT_27075 mRNA Transcript Targeted by BRF1 Reactome DB_ID: 450523 Reactome Database ID Release 43450523 Reactome, http://www.reactome.org ReactomeREACT_26387 mRNA Transcript Targeted by AUF1(hnRNP D0) Reactome DB_ID: 450444 Reactome Database ID Release 43450444 Reactome, http://www.reactome.org ReactomeREACT_27038 mRNA Transcript Targeted by KSRP Reactome DB_ID: 450386 Reactome Database ID Release 43450386 Reactome, http://www.reactome.org ReactomeREACT_27068 mRNA Transcript Targeted by Tristetraproline Reactome DB_ID: 450597 Reactome Database ID Release 43450597 Reactome, http://www.reactome.org ReactomeREACT_26157 RNA (exact match) RNA exactly complementary to guide RNA Reactome DB_ID: 426523 Reactome Database ID Release 43426523 Reactome, http://www.reactome.org ReactomeREACT_119046 siRNA Reactome DB_ID: 426446 Reactome Database ID Release 43426446 Reactome, http://www.reactome.org ReactomeREACT_119919 siRNA (single-stranded) 21-24 nucleotides RNA (inexact match) RNA inexactly complementary to guide RNA Reactome DB_ID: 426515 Reactome Database ID Release 43426515 Reactome, http://www.reactome.org ReactomeREACT_119968 Cleaved RNA with 5' Phosphate and 3' Hydroxyl Reactome DB_ID: 426511 Reactome Database ID Release 43426511 Reactome, http://www.reactome.org ReactomeREACT_119521 Association of HMGB1/HMGB2 with chromatin Authored: Matthews, L, 2008-05-08 00:37:34 Edited: Matthews, L, 2008-04-25 14:06:16 Pubmed18239742 Pubmed9671700 Pubmed9784391 Reactome Database ID Release 43266204 Reactome, http://www.reactome.org ReactomeREACT_13513 Reviewed: Widlak, P, 2008-04-25 14:11:44 The major HMG-box-containing chromatin proteins HMGB1 and HMGB2 stimulate DNA cleavage by DFF40/CAD (Liu et al., 1998; Toh et al., 1998; Widlak et al., 2000). Changes in DNA conformation following HMG-box binding makes the substrate more accessible to cleavage by DFF40/CAD nuclease and thus may contribute to preferential linker DNA cleavage during apoptosis (Kalinowska-Herok and Widlak., 2008). Cleavage of DNA by DFF40 Authored: Matthews, L, 2008-01-29 12:03:24 Edited: Matthews, L, 2008-01-29 12:04:16 Edited: Matthews, L, 2008-05-02 11:33:14 Pubmed10713148 Pubmed18283539 Reactome Database ID Release 43211247 Reactome, http://www.reactome.org ReactomeREACT_13702 Reviewed: Widlak, P, 2008-05-07 23:54:18 The DFF40 cleaves DNA substrates to generate fragments possessing ends with 5’-phosphate and 3’-hydroxyl groups, and generates exclusively double strand breaks (primarily blunt ends). It has some sequence preferences on naked DNA substrates and prefers purine/pyrimidine blocks with rotational symmetry (Widlak et al., 2000). DFF is both a deoxyribonucleotide-specific and a double-strand-specific endonuclease (Hanus et al., 2008). ISGylation of host protein filamin B Authored: Garapati, P V, 2011-01-18 EC Number: 6.3.2.19 Edited: Garapati, P V, 2011-01-18 ISG15 negatively regulates the scaffold protein filamin B. In response to type I IFNs, filamin B recruits RAC1, MEKK1, and MKK4, enhancing their sequential activation and thereby promoting JNK activation and apoptosis. ISGylation of filamin B leads to the disassociation of RAC1, MEKK1, and MKK4 from the scaffold, preventing type I IFN dependent JNK activation and apoptosis. It has been suggested that this inhibition of apoptosis may protect uninfected bystander cells from IFN-mediated apoptosis (Jeon et al, 2009). Pubmed12582176 Pubmed16009940 Pubmed19270716 Pubmed20153823 Pubmed20946978 Reactome Database ID Release 431169398 Reactome, http://www.reactome.org ReactomeREACT_115658 Reviewed: Zhang, DE, 2011--0-2- ISGylation of protein phosphatase 1 beta (PP2CB) Authored: Garapati, P V, 2011-01-18 EC Number: 6.3.2.19 Edited: Garapati, P V, 2011-01-18 Protein phosphatase 1 beta (PPM1B/PP2CB) is a target for ISG15. PP2CB dephosphorylates TAK1 and suppresses TAK1/TAB1-mediated IkB alpha degradation and thereby controls the NF-kB signaling pathway, which plays a critical role in innate and adaptive immunity and cancer. ISGylation of PP2CB may block the suppressive function of the phosphatase against TAK1/TAB1 mediated NF-kB activation. Pubmed16872604 Pubmed20153823 Pubmed20946978 Reactome Database ID Release 431169405 Reactome, http://www.reactome.org ReactomeREACT_115843 Reviewed: Zhang, DE, 2011--0-2- ISGylation of E2 conjugating enzymes Authored: Garapati, P V, 2011-01-18 EC Number: 6.3.2.19 Edited: Garapati, P V, 2011-01-18 Pubmed16112642 Pubmed16122702 Pubmed16428300 Pubmed20153823 Reactome Database ID Release 431169402 Reactome, http://www.reactome.org ReactomeREACT_115543 Reviewed: Zhang, DE, 2011--0-2- Ubiquitin conjugating E2 enzymes UBC13 and UBCH6 are targets for ISGylation. This suppresses the ubiquitin-conjugating activity of both UBC13 and UBCH6. This modification may play an important role in the control of signal transduction pathways, such as the NF-kB pathway, which are associated with K63-linked polyubiquitination (Takeuchi et al, 2005). Interaction of ISG15 with NEDD4 and inhibition of Ebola virus budding Authored: Garapati, P V, 2011-01-18 Ebola virus VP40 virus-like particles (VLPs) requires the interaction of overlapping L-domains in the VP40 protein with host NEDD4 protein for efficient budding. Mono-ubiquitination of VP40 mediated by the NEDD4 E3 ligase is thought to be required for virus budding and release. ISG15 interacts with NEDD4 and inhibits the transfer of ubiquitin from the E2 enzyme to NEDD4. This prevents NEDD4-mediated ubiquitination of Ebola virus VP40 which is required for virion release. Edited: Garapati, P V, 2011-01-18 Pubmed11095724 Pubmed12525615 Pubmed18287095 Pubmed18305167 Pubmed20153823 Reactome Database ID Release 431169399 Reactome, http://www.reactome.org ReactomeREACT_115975 Reviewed: Zhang, DE, 2011--0-2- mRNA Transcript Targeted by HuR Phosphorylated on Ser158 and Ser318. Reactome DB_ID: 450605 Reactome Database ID Release 43450605 Reactome, http://www.reactome.org ReactomeREACT_26315 ISGylation of viral protein NS1 Authored: Garapati, P V, 2011-01-18 EC Number: 6.3.2.19 Edited: Garapati, P V, 2011-01-18 Pubmed20133869 Pubmed20219937 Pubmed20385878 Reactome Database ID Release 431169395 Reactome, http://www.reactome.org ReactomeREACT_115965 Reviewed: Zhang, DE, 2011--0-2- Some viral proteins are also targeted for ISGylation. The well studied viral protein ISGylation is the modification of the influenza A viral protein NS1, which functions as an IFN antagonist during viral infection. Studies identified seven lysine residues in NS1 as potential ISGylation sites among which K41 (Zhao et al. 2010), K126 and K217 (Tang et al. 2010) were found to be critical. ISGylation at these sites disrupts NS1 association with importin-alpha, a protein required for the nuclear import of NS1. Translocation of Influenza A virus nonstructural protein 1 (NS1A) into the nucleus Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 GENE ONTOLOGYGO:0046796 Influenza A virus nonstructural protein 1 (NS1A) is a multifunctional protein that exists as a dimer and is involved in the inhibition of host cell antiviral pre-mRNA processing and counteracts host cell antiviral responses. Unlike most other RNA viruses, influenza viruses replicate in the nucleus of the host cells. NS1A protein carries two nuclear localization signal (NLS) elements and these sequence elements are recognized by importin-alpha/beta. In the cytoplasm NS1A binds to importin-alpha/beta and these protein complexes are then translocated into the nucleus through the nuclear pore complex (NPC). Note:Reactions directly involving interactions of human host proteins with foreign ones are highlighted in red. Pubmed15702989 Pubmed17376915 Pubmed7559393 Reactome Database ID Release 431176059 Reactome, http://www.reactome.org ReactomeREACT_115827 Reviewed: Zhang, DE, 2011--0-2- ISGylation of IRF3 Authored: Garapati, P V, 2011-01-18 EC Number: 6.3.2.19 Edited: Garapati, P V, 2011-01-18 Pubmed16914094 Pubmed20153823 Pubmed20308324 Reactome Database ID Release 431169394 Reactome, http://www.reactome.org ReactomeREACT_115934 Reviewed: Zhang, DE, 2011--0-2- The transcription factor IRF3 is a target for ISGylation. Conjugation of ISG15 positively regulates IRF3 and thereby promotes induction of type I interferons. ISGylation of IRF3 prevents the binding of PIN1, a protein that promotes IRF3 ubiquitination and subsequent degradation. ISGylation of host proteins Authored: Garapati, P V, 2011-01-18 EC Number: 6.3.2.19 Edited: Garapati, P V, 2011-01-18 Many host proteins are targets for ISGylation including constitutively expressed proteins involved in various cellular pathways such as immunity, RNA splicing, chromatin remodeling/polymerase II transcription, stress responses and translation. Many ISG15 target proteins are IFN alpha/beta-induced antiviral proteins such as PKR, MxA, IRF3, and RIG-I, also included are several key regulators of signal transduction such as PLC gamma1, JAK1, STAT1 and ERK1. The contribution of most of these modified proteins to antiviral activity is unclear because the fate of the vast majority of ISGylated target proteins is unknown. Pubmed12582176 Pubmed16009940 Pubmed16139798 Reactome Database ID Release 431169406 Reactome, http://www.reactome.org ReactomeREACT_115890 Reviewed: Zhang, DE, 2011--0-2- Interaction of E3 ligase with ISG15:E2 complex Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 Pubmed16352599 Pubmed16407192 Pubmed16815975 Pubmed17289916 Reactome Database ID Release 431169403 Reactome, http://www.reactome.org ReactomeREACT_116157 Reviewed: Zhang, DE, 2011--0-2- Ubiquitin ligase HERC5/CEB1 appears to be the predominant E3 ligase for ISGylation; EFP and HHARI/ARIH1 have also been reported as ISG15 E3 ligases. The E3 ligase recognizes specific target substrates and mediates the transfer of ISG15 from E2 to the substrate. Transfer of ISG15 from E1 to E2 (UBCH8) Activated ISG15 linked to UBE1L is transferred to the E2 conjugating enzyme UBCH8. Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 Pubmed11157743 Pubmed15131269 Pubmed15485925 Pubmed18583345 Reactome Database ID Release 431169404 Reactome, http://www.reactome.org ReactomeREACT_115873 Reviewed: Zhang, DE, 2011--0-2- Activation of ISG15 by UBE1L E1 ligase Authored: Garapati, P V, 2011-01-18 EC Number: 6.3.2.19 Edited: Garapati, P V, 2011-01-18 Pubmed18583345 Pubmed19073728 Reactome Database ID Release 431169397 Reactome, http://www.reactome.org ReactomeREACT_116132 Reviewed: Zhang, DE, 2011--0-2- Ubiquitin ligase UBE1L is the ISG15 activating enzyme. UBE1L activates ISG15 in an ATP-dependent process that links UBE1L to ISG15 via a thioester bond. Arginine 153 (R153) in human ISG15 is identified as the key residue for ISG15 and UBE1L's interaction. duplex siRNA Reactome DB_ID: 426472 Reactome Database ID Release 43426472 Reactome, http://www.reactome.org ReactomeREACT_120073 siRNA (double-stranded) 21-24 nucleotides duplex miRNA Reactome DB_ID: 203896 Reactome Database ID Release 43203896 Reactome, http://www.reactome.org ReactomeREACT_12809 mature miRNA (double-stranded), 21-24 nucleotides pre-microRNA Reactome DB_ID: 203932 Reactome Database ID Release 43203932 Reactome, http://www.reactome.org ReactomeREACT_12796 pre-microRNA with 3' overhang Reactome DB_ID: 203866 Reactome Database ID Release 43203866 Reactome, http://www.reactome.org ReactomeREACT_12820 pri-microRNA Reactome DB_ID: 203828 Reactome Database ID Release 43203828 Reactome, http://www.reactome.org ReactomeREACT_12806 primary microRNA mRNA with premature termination codon not preceding exon junction Reactome DB_ID: 927733 Reactome Database ID Release 43927733 Reactome, http://www.reactome.org ReactomeREACT_76844 5' Fragment of Cleaved mRNA Reactome DB_ID: 927835 Reactome Database ID Release 43927835 Reactome, http://www.reactome.org ReactomeREACT_75951 3' Fragment of Cleaved mRNA Reactome DB_ID: 927738 Reactome Database ID Release 43927738 Reactome, http://www.reactome.org ReactomeREACT_76581 mRNA with premature termination codon preceding exon junction Reactome DB_ID: 927796 Reactome Database ID Release 43927796 Reactome, http://www.reactome.org ReactomeREACT_76257 GAF binds the GAS promoter elements in the IFNG-regulated genes Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 GAF transcription factor translocated into nucleus binds to defined DNA sequence called GAS (gamma activated sequence) elements in the promoters of IFN-gamma responsive elements and initiate transcription. Pubmed1281555 Pubmed1898761 Pubmed1901265 Pubmed9143706 Reactome Database ID Release 431031713 Reactome, http://www.reactome.org ReactomeREACT_25118 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Expression of IFNG-stimulated genes Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 IFN-gamma stimulates gene expression of about 200 genes which include the primary response genes like IRFs, Fc-gamma receptor (FCGR), GBPs (guanylate-binding proteins) and also major histocompatibility complex (MHC) class I and class II molecules, proteins involved in antigen presentation, antiviral proteins like PKR, OAS proteins etc. A wonderful list of most of the IFN-gamma inducible proteins with corresponding literature are mentioned in the review article and the supplementary document by Boehm et al 1997. Pubmed1508672 Pubmed18362138 Pubmed7530745 Pubmed8176225 Pubmed8483949 Pubmed8530158 Pubmed9143706 Reactome Database ID Release 431031716 Reactome, http://www.reactome.org ReactomeREACT_25082 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 PIAS1 binds p-STAT1 dimer Authored: Garapati, P V, 2010-06-08 Edited: Garapati, P V, 2010-07-07 PIAS1 protein interacts directly with phoshorylated STAT1 dimers and inhibit the transcriptional activity of STAT1 by blocking the DNA-binding domain of STAT1. It has also been suggested that PIAS proteins might regulate transcription by promoting small ubiquitin-related modifier (SUMO1) conjugation of STAT1. The significance of STAT1 sumoylation in regulating STAT1 activity is controversial and needs to be clarified. Pubmed10805787 Pubmed12855578 Pubmed18031232 Reactome Database ID Release 43877281 Reactome, http://www.reactome.org ReactomeREACT_25331 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Dephosphorylation of p-STAT1 dimer by nuclear isoform of TCPTP Authored: Garapati, P V, 2010-07-07 EC Number: 3.1.3.48 Edited: Garapati, P V, 2010-07-07 Pubmed11909529 Pubmed12138178 Reactome Database ID Release 43997326 Reactome, http://www.reactome.org ReactomeREACT_25185 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The nuclear isoform of T cell protein tyrosine phosphatase (TC-PTP) referred as TC45 (or TC-PTPa) dephosphorylates p-STAT1 dimer in the nucleus. It can also dephosphorylate p-JAK1/3 in IFNG stimulated cells. has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Double-stranded RNA Reactome DB_ID: 426463 Reactome Database ID Release 43426463 Reactome, http://www.reactome.org ReactomeREACT_120109 SOCS-1 and SOCS-3 binds to p-JAK2 Authored: Garapati, P V, 2010-06-08 Edited: Garapati, P V, 2010-07-07 Pubmed10064597 Pubmed10421843 Reactome Database ID Release 43877269 Reactome, http://www.reactome.org ReactomeREACT_25158 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 SOCS-1 and SOCS-3 coprecipitates with JAK kinases upon IFNG stimulation and are able to inhibit the JAK-STAT pathway, although with different affinity and kinetics. SOCS1 and SOCS3 binds to phosphorylated JAK1/2 and prevent the tyrosine kinase activity of JAKs through their kinase inhibitory region (KIR), thereby inhibiting downstream IFNG signaling. SOCS1 may also prevent IFNG signaling by targeting the signaling machinery to ubiquitin-proteasomal degradation pathway. miRNA Reactome DB_ID: 426443 Reactome Database ID Release 43426443 Reactome, http://www.reactome.org ReactomeREACT_119942 mature miRNA (single-stranded), 21-24 nucleotides Dephosphorylation of JAKs by PTPs Authored: Garapati, P V, 2010-06-08 EC Number: 3.1.3.48 Edited: Garapati, P V, 2010-07-07 Protein tyrosine phosphatases (PTPs) SHP1 and SHP2 down regulate the IFNG signaling by dephosphorylating the tyrosine residues critical to the activation of JAK kinases. PTP1B interacts directly with JAK2 but not JAK1 and dephosphorylate the tyrosine Y1007 on JAK2. Pubmed8943354 Reactome Database ID Release 43877308 Reactome, http://www.reactome.org ReactomeREACT_25190 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 has a Stoichiometric coefficient of 2 phosphofructokinase, M4 complex Reactome DB_ID: 71483 Reactome Database ID Release 4371483 Reactome, http://www.reactome.org ReactomeREACT_5899 has a Stoichiometric coefficient of 4 phosphofructokinase, ML3 complex Reactome DB_ID: 70461 Reactome Database ID Release 4370461 Reactome, http://www.reactome.org ReactomeREACT_5684 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 phosphofructokinase, PL3 complex Reactome DB_ID: 179515 Reactome Database ID Release 43179515 Reactome, http://www.reactome.org ReactomeREACT_8578 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 phosphofructokinase, P2L2 complex Reactome DB_ID: 179516 Reactome Database ID Release 43179516 Reactome, http://www.reactome.org ReactomeREACT_8936 has a Stoichiometric coefficient of 2 phosphofructokinase, P3L complex Reactome DB_ID: 179514 Reactome Database ID Release 43179514 Reactome, http://www.reactome.org ReactomeREACT_8836 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 phosphofructokinase, P4 complex Reactome DB_ID: 71453 Reactome Database ID Release 4371453 Reactome, http://www.reactome.org ReactomeREACT_4228 has a Stoichiometric coefficient of 4 Dissociation of the COP1-p53 complex ATM-dependent phosphorylation of COP1 on Ser(387) results in disruption of the COP1-p53 complex (Dornan et al., 2006) Authored: Matthews, L, 2008-06-12 21:09:06 Edited: Matthews, L, 2009-11-09 Pubmed16931761 Reactome Database ID Release 43264435 Reactome, http://www.reactome.org ReactomeREACT_20554 Reviewed: Dixit, VM, 2009-11-17 Translocation of COP1 from the nucleus to the cytoplasm Authored: Matthews, L, 2008-06-12 21:09:06 Edited: Matthews, L, 2009-11-09 Ionizing radiation results in an ATM-dependent movement of COP1 from the nucleus to the cytoplasm (Dornan et al., 2006). Pubmed16931761 Reactome Database ID Release 43264418 Reactome, http://www.reactome.org ReactomeREACT_20527 Reviewed: Dixit, VM, 2009-11-17 Phosphorylation of MDM2 at serine-395 by ATM kinase At the beginning of this reaction, 1 molecule of 'Mdm2' is present. At the end of this reaction, 1 molecule of 'phospho-MDM2' is present.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'kinase activity' of 'phospho-ATM (Ser 1981)'.<br> Pubmed11331603 Reactome Database ID Release 4369491 Reactome, http://www.reactome.org ReactomeREACT_988 Reviewed: Sanchez, Y, 2008-05-07 22:09:03 Phosphorylation of COP1 at Ser-387 by ATM ATM phosphorylates COP1 on Ser387 in response to DNA damage (Dornan et al., 2006). Authored: Matthews, L, 2008-06-12 21:09:06 Edited: Matthews, L, 2009-10-21 Pubmed16931761 Reactome Database ID Release 43349444 Reactome, http://www.reactome.org ReactomeREACT_20543 Reviewed: Dixit, VM, 2009-11-17 p62:MEKK3 binds to TRAF6 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Pubmed14661019 Pubmed19903815 Reactome Database ID Release 43507719 Reactome, http://www.reactome.org ReactomeREACT_22171 Reviewed: Pinteaux, E, 2010-05-17 p62, MEKK3 and TRAF6 co-localize in cytoplasmic aggregates that are thought to be centres for organizing TRAF6-regulated NF-kappaB signaling and the assembly of polyubiquinated proteins sorting to sequestosomes and proteasomes. p62/Sequestosome-1 is a scaffold protein involved in the regulation of autophagy, trafficking of proteins to the proteasome and activation of NF-kB. p62 binds the basic region of MEKK3. MEKK3 is known to bind TRAF6 in response to IL1B (Huang et al. 2004). Recently p62 was shown to be required for the association of MEKK3 with TRAF6. RNA knockdown of p62 inhibited IL1B and MEKK3 activation of NF-kB. IL1B stimulation resulted in dissociation of MEKK3 from p62:TRAF6 (Nakamura et al. 2010). Autoubiquitination of phospho-COP1(Ser-387 ) ATM phosphorylation promotes autoubiquitination of COP1 in vitro (Dornan et al., 2006). The number of ubiquitin molecules shown in this reaction is set arbitrarily at 4. Authored: Matthews, L, 2008-06-12 21:09:06 EC Number: 6.3.2.19 Edited: Matthews, L, 2008-04-30 12:41:30 Pubmed16931761 Reactome Database ID Release 43264444 Reactome, http://www.reactome.org ReactomeREACT_20581 Reviewed: Dixit, VM, 2009-11-17 has a Stoichiometric coefficient of 4 Proteasome mediated degradation of COP1 Authored: Matthews, L, 2008-06-12 21:09:06 Autoubiquitinated COP1 is degraded by the proteasome. The number of ubiquitin molecules shown in this reaction is arbitrarily set at 4. (Dornan et al., 2006). Edited: Matthews, L, 2009-11-09 Pubmed16931761 Reactome Database ID Release 43264458 Reactome, http://www.reactome.org ReactomeREACT_20637 Reviewed: Dixit, VM, 2009-11-17 has a Stoichiometric coefficient of 4 IRAK4-activated IRAK1 autophosphorylates A series of sequential phosphorylation events lead to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the upstream adapters MyD88 and Tollip. The significance of these phosphorylation events is not clear; the kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), so IRAK1 is believed to act primarily as an adaptor for TRAF6 (Conze et al. 2008). Authored: Ray, KP, 2010-05-17 EC Number: 2.7.11 Edited: Jupe, S, 2010-05-17 Pubmed10217414 Pubmed11923871 Pubmed14625308 Pubmed17337443 Pubmed18347055 Reactome Database ID Release 43446701 Reactome, http://www.reactome.org ReactomeREACT_22162 Reviewed: Pinteaux, E, 2010-05-17 has a Stoichiometric coefficient of 4 IRAK4 phosphorylates IRAK1 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.11 Edited: Jupe, S, 2010-05-17 MyD88 recruits unphosphorylated IRAK1 to the signaling complex. IRAK1 is then rapidly activated and autophosphorylates in a region that is outside the kinase domain (Cao et al. 1996). Several pieces of evidence suggest that IRAK4 triggers IRAK1 activation by phosphorylating its kinase activation loop, leading to IRAK1 autophosphorylation (Suzuki et al. 2002): in vitro kinase assays indicate that IRAK1 can be a direct substrate of IRAK4 (Li et al. 2002); IRAK1 phosphorylation by IRAK4 is independent of and precedes IRAK1 activation and autophosphorylation; IRAK1 autophosphorylation is partially inhibited in cells overexpressing a kinase-inactive IRAK4 protein (Li et al. 2002). Pubmed11923871 Pubmed11960013 Pubmed12297423 Pubmed8599092 Reactome Database ID Release 43446694 Reactome, http://www.reactome.org ReactomeREACT_22125 Reviewed: Pinteaux, E, 2010-05-17 has a Stoichiometric coefficient of 2 Hyperphosphorylated IRAK1 associates with TRAF6 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Hyperphosphorylated IRAK1, still within the receptor complex, binds TRAF6 through multiple regions including the death domain, the undefined domain and the C-terminal C1 domain (Li et al. 2001). The C-terminal region of IRAK-1 contains three potential TRAF6-binding sites; mutation of the amino acids (Glu544, Glu587, Glu706) in these sites to alanine greatly reduces activation of NFkappaB (Ye et al. 2002). Pubmed11287640 Pubmed12140561 Pubmed18070982 Pubmed8837778 Reactome Database ID Release 43446862 Reactome, http://www.reactome.org ReactomeREACT_22311 Reviewed: Pinteaux, E, 2010-05-17 IRAK2 is phosphorylated downstream of IRAK4 following IL1 receptor activation Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 IRAK2 has been implicated in IL1R and TLR signaling by the observation that IRAK2 can associate with MyD88 and Mal (Muzio et al. 1997). Like IRAK1, IRAK2 is activated downstream of IRAK4 (Kawagoe et al. 2008). It has been suggested that IRAK1 activates IRAK2 (Wesche et al. 1999) but IRAK2 phosphorylation is observed in IRAK1–/– mouse macrophages while IRAK4 deficiency abrogates IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1. IL6 production in response to IL1beta is impaired in embryonic fibroblasts from IRAK1 or IRAK2 knockout mice and abrogated in IRAK1/2 dual knockouts (Kawagoe et al. 2007) suggesting that IRAK1 and IRAK2 are both involved in IL1R signaling downstream of IRAK4. Pubmed12150927 Pubmed17878161 Pubmed18438411 Pubmed9374458 Reactome Database ID Release 43446684 Reactome, http://www.reactome.org ReactomeREACT_22435 Reviewed: Pinteaux, E, 2010-05-17 Phosphorylation of p53 at ser-15 by ATM kinase In response to DNA damage due to ionizing radiation, the serine at position 15 of the p53 tumor suppressor protein is rapidly phosphorylated by the ATM kinase. This serves to stabilize the p53 protein. A rise in the levels of the p53 protein induce the expression of the p21 cyclin-dependent kinase inhibitor. This prevents the normal progression from G1 to S phase, thus providing a check on replication of damaged DNA. Pubmed9733514 Pubmed9733515 Pubmed9843217 Reactome Database ID Release 4369511 Reactome, http://www.reactome.org ReactomeREACT_1756 Reviewed: Sanchez, Y, 2008-05-07 22:09:03 The Interleukin 1 receptor complex binds Tollip Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Pubmed10854325 Pubmed17113392 Reactome Database ID Release 43446868 Reactome, http://www.reactome.org ReactomeREACT_22120 Reviewed: Pinteaux, E, 2010-05-17 Toll-interacting protein (TOLLIP) binds to IRAK1 and IL-1RAP within the receptor complex. TOLLIP has the capacity to act as an ubiquitin-binding receptor for ubiquitinated IL1R1, linking IL1R to endosomal degradation. SMURF2 ubiquitinates Smad7 and phosphorylated TGFBR1 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed11163210 Reactome Database ID Release 432176393 Reactome, http://www.reactome.org ReactomeREACT_120905 Reviewed: Huang, Tao, 2012-05-14 When recombinant mouse Smad7 and recombinant human SMURF2, TGFBR2 and TGFBR1 are exogenously expressed in HEK293 cells, SMURF2 (recruited to the activated TGF-beta receptor complex through interaction with Smad7) ubiquitinates Smad7 and may also ubiquitinate TGFBR1. Experimental findings on ubiquitination of TGFBR1 by SMURF2 were inconclusive (Kavsak et al. 2000). has a Stoichiometric coefficient of 2 IL1R1:IL1:IL1RAP:MYD88 homodimer binds IRAK4 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 MYD88 is a cytoplasmic adaptor protein that is recruited to the intracellular region of the IL1 receptor complex following IL1 stimulation. MYD88 binds to the complex of the two receptor chains and subsequently to IL-1 receptor-associated kinase 4 (IRAK4). This complex is the minimum required for signaling (Brikos et al. 2007). Pubmed12538665 Pubmed17507369 Reactome Database ID Release 43446648 Reactome, http://www.reactome.org ReactomeREACT_22326 Reviewed: Pinteaux, E, 2010-05-17 Rnf111 binds SKI/SKIL in complex with SMAD2/3:SMAD4 upon TGF-beta stimulation Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed17591695 Reactome Database ID Release 432186736 Reactome, http://www.reactome.org ReactomeREACT_120868 Recombinant mouse Rnf111 (Arkadia) binds to the complex of endogenous human Smad2/3 and recombinant human SKI/SKIL in response to TGF-beta or activin stimulation (Levy et al. 2007). Reviewed: Huang, Tao, 2012-05-14 IRAK1 binds to MYD88 within the IL1R complex Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 MYD88 recruits unphosphorylated, inactive IRAK1 to the IL1 receptor complex. Pubmed8599092 Pubmed9430229 Reactome Database ID Release 43446692 Reactome, http://www.reactome.org ReactomeREACT_22379 Reviewed: Pinteaux, E, 2010-05-17 UNC5A binds NRAGE Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed12598531 Pubmed15573119 Pubmed17449433 Reactome Database ID Release 43374699 Reactome, http://www.reactome.org ReactomeREACT_22178 Reviewed: Cooper, HM, 2010-02-16 The neurotrophin receptor-interacting melanoma-associated antigen (MAGE) homologue, NRAGE, known to be a regulator of apoptosis, has been identified as a specific binding partner of UNC5H1. NRAGE utilizes two mechanisms to induce UNC5H1mediated apoptosis in cells: first, through the degradation of the caspase inhibitor X-chromosome-linked inhibitor of apoptosis protein (XIAP), and second, through the activation of the proapoptotic c-JUN N-terminal kinase (JNK) signaling pathway. IRAK4 is activated by autophosphorylation Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346. Pubmed17141195 Reactome Database ID Release 43446634 Reactome, http://www.reactome.org ReactomeREACT_22405 Reviewed: Pinteaux, E, 2010-05-17 has a Stoichiometric coefficient of 3 ALDOB tetramer Reactome DB_ID: 70340 Reactome Database ID Release 4370340 Reactome, http://www.reactome.org ReactomeREACT_3153 fructose-bisphosphate aldolase B tetramer has a Stoichiometric coefficient of 4 fructose-bisphosphate aldolase C, class I holoenzyme Reactome DB_ID: 70456 Reactome Database ID Release 4370456 Reactome, http://www.reactome.org ReactomeREACT_3278 has a Stoichiometric coefficient of 4 IL1R1:IL1:IL1RAP binds MYD88 homodimer Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 MYD88 is a cytoplasmic adaptor protein that is recruited to the intracellular region of the IL1 receptor complex following IL1 stimulation. MYD88 binds to the complex of the two receptor chains and subsequently to IL-1 receptor-associated kinase 4 (IRAK4). This complex is the minimum required for signaling (Brikos et al. 2007). Pubmed17507369 Pubmed9430229 Reactome Database ID Release 43450133 Reactome, http://www.reactome.org ReactomeREACT_22154 Reviewed: Pinteaux, E, 2010-05-17 aldolase tetramer Converted from EntitySet in Reactome Reactome DB_ID: 179508 Reactome Database ID Release 43179508 Reactome, http://www.reactome.org ReactomeREACT_8134 fructose bisphosphate aldolase tetramer fructose-bisphosphate aldolase A, class I holoenzyme Reactome DB_ID: 71493 Reactome Database ID Release 4371493 Reactome, http://www.reactome.org ReactomeREACT_4935 has a Stoichiometric coefficient of 4 PFKFB1 dimer 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 homodimer PF2K-Pase1 homodimer Reactome DB_ID: 71786 Reactome Database ID Release 4371786 Reactome, http://www.reactome.org ReactomeREACT_2587 has a Stoichiometric coefficient of 2 PFKFB dimers 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform homodimers Converted from EntitySet in Reactome Reactome DB_ID: 372870 Reactome Database ID Release 43372870 Reactome, http://www.reactome.org ReactomeREACT_14920 PP2A-ABdeltaC complex Reactome DB_ID: 165961 Reactome Database ID Release 43165961 Reactome, http://www.reactome.org ReactomeREACT_5648 has a Stoichiometric coefficient of 1 PFKFB3 dimer 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 homodimer Reactome DB_ID: 71795 Reactome Database ID Release 4371795 Reactome, http://www.reactome.org ReactomeREACT_2880 has a Stoichiometric coefficient of 2 PFKFB2 dimer 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 homodimer Reactome DB_ID: 71791 Reactome Database ID Release 4371791 Reactome, http://www.reactome.org ReactomeREACT_2573 has a Stoichiometric coefficient of 2 Caspase cleavage of DCC Authored: Garapati, P V, 2008-07-16 14:42:16 DCC exerts its pro-apoptotic effect when netrin ligand is absent. When unbound to its ligand, DCC is cleaved roughly in the middle of its intracellular domain (aspartic acid residue 1290) by caspase-3 (Mehlen et al. 1998). The cleavage releases DCC's inhibitory C-terminal domain and exposes the addiction/dependence domain (ADD), which is sufficient for cell death induction. EC Number: 3.4.22 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11248093 Pubmed15310786 Pubmed16158190 Pubmed9796814 Reactome Database ID Release 43373705 Reactome, http://www.reactome.org ReactomeREACT_22440 Reviewed: Cooper, HM, 2010-02-16 DCC interacts with DIP13alpha Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11248093 Pubmed12011067 Reactome Database ID Release 43373717 Reactome, http://www.reactome.org ReactomeREACT_22288 Reviewed: Cooper, HM, 2010-02-16 The ADD domain of DCC binds DCC-interacting 13alpha (DIP13alpha), which serves as an adaptor mediating the DCC apoptotic signal. The DIP13alpha protein has a pleckstrin homology domain and a phosphotyrosine binding domain. It interacts with the ADD region on the DCC cytoplasmic domain that is available after the caspase cleavage. This interaction is required for the induction of apoptosis. Caspase-9 binds DCC:DIP13alpha complex Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11248093 Pubmed12011067 Reactome Database ID Release 43373700 Reactome, http://www.reactome.org ReactomeREACT_22246 Reviewed: Cooper, HM, 2010-02-16 The ADD domain of DCC complexed with DIP13alpha interacts with the initiator caspase-9, leading to caspase activation and caspase-dependent cell death. DIP13alpha appears to function as a required adaptor to mediate DCC-caspase-9 interaction. Activation of caspase-3 Authored: Garapati, P V, 2008-07-16 14:42:16 EC Number: 3.4.22 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed12011067 Pubmed15573119 Reactome Database ID Release 43418845 Reactome, http://www.reactome.org ReactomeREACT_22412 Reviewed: Cooper, HM, 2010-02-16 The DCC-caspase activating complex activates caspase-3 through caspase-9. Caspase cleavage of UNC5B Authored: Garapati, P V, 2008-07-16 14:42:16 EC Number: 3.4.22 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11387206 Pubmed15573119 Reactome Database ID Release 43418852 Reactome, http://www.reactome.org ReactomeREACT_22343 Reviewed: Cooper, HM, 2010-02-16 The UNC5H family of netrin-1 receptors also contain death domains in their intracellular regions and function as dependence receptors. The cleavage site sequence DITD(S) found in UNC5H2 appears to be a classic caspase DXXD site and is conserved in UNC5H1 and UNC5H3 (DVAD(S) and DIID(S), respectively). UNC5H2, like DCC, is cleaved at Asp412 by caspase-3 or an unknown protease, but in contrast to DCC this results in the release of the death domain from the C-terminal region (Llambi et al. 2001). DAPK binds UNC5B Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed15729359 Pubmed16756490 Reactome Database ID Release 43418849 Reactome, http://www.reactome.org ReactomeREACT_22314 Reviewed: Cooper, HM, 2010-02-16 The released fragment of Unc5B with death domain interacts with a death domain containing serine/threonine kinase protein, death associated protein kinase (DAPK). DAPK mediates UNC5H2 induced cell death through a wide spectrum of apoptotic signals via its serine threonine kinase activity. Caspase cleavage of UNC5A Authored: Garapati, P V, 2008-07-16 14:42:16 EC Number: 3.4.22 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11387206 Pubmed15573119 Reactome Database ID Release 43418846 Reactome, http://www.reactome.org ReactomeREACT_22184 Reviewed: Cooper, HM, 2010-02-16 The UNC5H netrin1 receptors also contain death domains in their intracellular regions and function as dependence receptors. The cleavage site sequence DITD(S) found in UNC5H2 appears to be a classic caspase DXXD site and is conserved in UNC5H1 and UNC5H3 (DVAD(S) and DIID(S), respectively). IL1 receptor antagonist protein binds Interleukin 1 receptors Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Pubmed1828071 Pubmed2139180 Reactome Database ID Release 43445757 Reactome, http://www.reactome.org ReactomeREACT_22331 Reviewed: Pinteaux, E, 2010-05-17 The interleukin 1 receptor antagonist protein (ILRAP or IL1RN) is a member of the IL1 family that binds to IL1R1 (and with much lower affinity IL1R2) but does not elicit a signaling response. By competing with IL1 for IL1R1 binding ILRAP acts as a natural antagonist, inhibiting the biological actions of both agonist forms of IL1 (IL1 alpha and IL1 beta). Interleukin-1 receptor type 1: Interleukin 1 binds Interleukin-1 receptor accessory protein, membrane associated isoform Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Interleukin receptor 1 type 1 when bound to interleukin 1 binds interleukin 1 receptor accessory protein, essential for eliciting a signaling cascade. Pubmed7775431 Pubmed9371760 Reactome Database ID Release 43445752 Reactome, http://www.reactome.org ReactomeREACT_22382 Reviewed: Pinteaux, E, 2010-05-17 Interleukin-1 receptor type 2 binds Interleukin 1 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Interleukin-1 receptor type 2 (IL1R2) binds Interleukin-1 but does not participate in any signaling processes. IL1R2 is thought to be a decoy receptor, removing or neutralizing Interleukin-1 that could otherwise stimulate the type 1 receptor. Pubmed7848516 Pubmed8327496 Pubmed8332913 Reactome Database ID Release 43446130 Reactome, http://www.reactome.org ReactomeREACT_22253 Reviewed: Pinteaux, E, 2010-05-17 Interleukin-1 receptor type 1 binds Interleukin 1 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Interleukin-1 receptor type 1 (IL1R1) is the receptor responsible for transmitting the inflammatory effects of Interleukin-1 (IL1). Pubmed8327496 Reactome Database ID Release 43445753 Reactome, http://www.reactome.org ReactomeREACT_22375 Reviewed: Pinteaux, E, 2010-05-17 Interleukin-1 family are secreted Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 IL-1 Beta lacks signal sequences for compartmentation within the Golgi and classical secretory vesicles, so release of the mature form to extracellular compartments requires nonclassical mechanisms of secretion which are poorly understood. Three models with distinct mechanisms have been proposed to date (see Qu et al. 2007). Pubmed17641058 Reactome Database ID Release 43449058 Reactome, http://www.reactome.org ReactomeREACT_23994 Reviewed: Pinteaux, E, 2010-09-06 Interleukin-1 family precursors are cleaved by caspase-1 Authored: Ray, KP, 2010-05-17 EC Number: 3.4.22 Edited: Jupe, S, 2010-08-06 Pro-interleukin-1 beta (pro-IL1B) is the primary substrate of caspase-1. IL1B production and processing is stimulated when pathogen-associated molecular patterns (PAMPs) such as bacterial LPS are detected by cells of the innate immune system, and in response to pro-inflammatory cytokines such as TNF. Detection of PAMPs by Toll receptors leads to rapid IL1 transcription/translation and subsequent processing by caspase-1 in macrophages and monocytes. Processing is triggered by the activation of members of the NLR family and their associated inflammasome complexes. IL1B lacks a signal peptide to direct it to the Golgi for subsequent secretion, so the mode of secretion is uncertain. Once secreted, IL1B binds membrane-bound IL1 receptors, followed by recruitment of the IL1 receptor accessory protein to form a high affinity receptor complex. Ligand induced receptor activation induces the intracellular association of a number of cytosolic adapter proteins triggering intracellular signal transduction. This series of steps facilitates the induction of nuclear factor-kappa B (NFkB) and mitogen-activated protein kinase (MAPK) activity, leading to downstream transcription of additional inflammatory cytokines, including IL1B itself. A calpain-like potease has been reported to be important for the processing of pro- IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology. Pubmed12752666 Pubmed1574116 Pubmed8999548 Pubmed9121587 Reactome Database ID Release 43448703 Reactome, http://www.reactome.org ReactomeREACT_23804 Reviewed: Pinteaux, E, 2010-09-06 Proteasome mediated degradation of PAK-2p34 Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-03 20:50:13 Proteolytically activated PAK-2p34, but not full-length PAK-2, is degraded rapidly by the proteasome (Jakobi et al., 2003). Here, degradation of PAK-2p34 is described as occurring in the cytosol. However, to date it is not known whether this occurs in the nucleus or in the cytoplasm. Pubmed12853446 Reactome Database ID Release 43211715 Reactome, http://www.reactome.org ReactomeREACT_13413 Reviewed: Chang, E, 2008-05-21 00:05:41 Caspase-1 active tetramer formation Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed8044845 Reactome Database ID Release 43448702 Reactome, http://www.reactome.org ReactomeREACT_24001 Reviewed: Pinteaux, E, 2010-09-06 Two p10/p20 dimers associate to form the active tetramer has a Stoichiometric coefficient of 2 Bcl-XL interacting BH3-only proteins Converted from EntitySet in Reactome Reactome DB_ID: 508161 Reactome Database ID Release 43508161 Reactome, http://www.reactome.org ReactomeREACT_21650 Formation of caspase-1 p10/p20 dimer Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed8044845 Reactome Database ID Release 43448673 Reactome, http://www.reactome.org ReactomeREACT_23893 Reviewed: Pinteaux, E, 2010-09-06 The p10 and p20 subunits first dimerize, then two dimers associate to give the active tetramer. Interaction of PAK-2p34 with RGH10/ PS-GAP results in accumulation of PAK-2p34 in the perinuclear region Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-08 00:32:18 Edited: Matthews, L, 2008-05-23 07:17:49 Following caspase mediated cleavage, PAK-2p34 translocates to the nucleus (Jakobi et al., 2003). The interaction with PS-GAP changes the localization of PAK-2p34 from the nucleus to the perinuclear region (Koeppel et al.,2004). Pubmed12853446 Pubmed15471851 Reactome Database ID Release 43211731 Reactome, http://www.reactome.org ReactomeREACT_13712 Reviewed: Chang, E, 2008-05-21 00:05:41 Caspase-1 precursor is cleaved releasing p10 and p20 subunits Authored: Ray, KP, 2010-05-17 Caspase 1 is expressed as a precursor that is cleaved to generate the p10 and p20 subunits that subsequently form the active tetramer. Edited: Jupe, S, 2010-08-06 Pubmed8044845 Reactome Database ID Release 43448678 Reactome, http://www.reactome.org ReactomeREACT_23881 Reviewed: Pinteaux, E, 2010-09-06 Bcl-2 interacting BH-3 only proteins Converted from EntitySet in Reactome Reactome DB_ID: 508157 Reactome Database ID Release 43508157 Reactome, http://www.reactome.org ReactomeREACT_21617 Rho GTPase-activating protein 10 (RHG10) interacts with caspase-activated PAK-2p34 Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-03 20:50:13 Edited: Matthews, L, 2008-05-28 22:59:08 Murine PS-GAP interacts specifically with caspase-activated PAK-2p34, but not active or inactive full-length PAK-2, through a region between the GAP and SH3 domains (Koeppel et al.,2004). Evidence for this reaction comes from experiments using both mouse and rabbit proteins. Pubmed15471851 Reactome Database ID Release 43211716 Reactome, http://www.reactome.org ReactomeREACT_13630 Reviewed: Chang, E, 2008-05-21 00:05:41 Regulation of protein ISGylation by ISG15 deconjugating enzyme USP18 Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 Pubmed11788588 Pubmed16710296 Pubmed17692280 Pubmed20181693 Reactome Database ID Release 431678841 Reactome, http://www.reactome.org ReactomeREACT_115684 Reviewed: Zhang, DE, 2011--0-2- Ubiquitin specific protease 18 (USP18/UBP43) is the major ISG15 deconjugating enzyme. It removes ISG15 from ISGylated proteins. ISG15-specific protease activity of this enzyme is crucial for proper cellular balance of ISG15-conjugated proteins. However, it is not required for processing pre-ISG15 to the mature form. Furthermore, USP18 inhibits type I interferon signaling independent of its ISG15 deconjugating enzyme activity. Several viral proteins were also reported with de-ISGylation activity. PFKFB4 dimer 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 homodimer Reactome DB_ID: 71799 Reactome Database ID Release 4371799 Reactome, http://www.reactome.org ReactomeREACT_3550 has a Stoichiometric coefficient of 2 phosphofructokinase tetramer Converted from EntitySet in Reactome Reactome DB_ID: 179517 Reactome Database ID Release 43179517 Reactome, http://www.reactome.org ReactomeREACT_8683 phosphofructokinase, L4 complex Reactome DB_ID: 70465 Reactome Database ID Release 4370465 Reactome, http://www.reactome.org ReactomeREACT_2915 has a Stoichiometric coefficient of 4 phosphofructokinase, M2L2 complex Reactome DB_ID: 70463 Reactome Database ID Release 4370463 Reactome, http://www.reactome.org ReactomeREACT_5456 has a Stoichiometric coefficient of 2 phosphofructokinase, M3L complex Reactome DB_ID: 71475 Reactome Database ID Release 4371475 Reactome, http://www.reactome.org ReactomeREACT_5445 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Recruitment of the 9-1-1 complex to DNA Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 GENE ONTOLOGYGO:0006260 Pubmed10777662 Pubmed12237462 Pubmed12578958 Pubmed14500360 Pubmed14605214 Pubmed14624239 Pubmed15210332 Pubmed8943031 Reactome Database ID Release 43176264 Reactome, http://www.reactome.org ReactomeREACT_6729 Recruitment of the Rad9-Hus1-Rad1 complex to DNA The 9-1-1 complex is a heterotrimeric ring-shaped structure that is loaded onto DNA by the Rad17-RFC complex. In vitro studies indicate that loading is preferred onto DNA substrates containing ssDNA gaps that presumably resemble structures found upon replication fork stalling and DNA polymerase/helicase uncoupling. The Rad17-RFC and 9-1-1 complexes are structurally similar to the RFC (replication factor C) clamp loader and PCNA sliding clamp, respectively, and similar mechanisms are thought to be used during loading of the 9-1-1 complex and PCNA. Upon loading, the 9-1-1 complex can recruit Chk1 onto sites of replication fork uncoupling or DNA damage.<p>The purified Rad17 and Rad9-Hus1-Rad1 (9-1-1) complexes can form a stable co-complex in the presence of ATP, using Rad17-Rad9 interactions. From computer modeling studies, the Rad17 subunit of the complex is also proposed to interact with the C-terminus of Rad1, p36 with the C-terminus of Hus1, and p38 with the C-terminus of Rad9. A major known function of the 9-1-1 complex is to recruit Chk1 to stalled replication forks for activation by ATR. However, the presence of the 9-1-1 complex also alters the ability of Rad17 to become phosphorylated, perhaps suggesting that 9-1-1 may regulate the recruiment of additional ATR substrates. The 9-1-1 complex has also been found to interact with base excision repair factors human DNA polymerase beta, flap endonuclease FEN1, and the S. pombe MutY homolog (SpMYH), indicating that 9-1-1 also plays a direct role in DNA repair. Loading of claspin onto DNA during replication origin firing Authored: Borowiec, JA, 2006-02-25 17:40:15 Claspin is loaded onto DNA replication origins during replication initiation. Studies in Xenopus egg extracts indicate claspin loading requires the presence of Cdc45, a factor that promotes the initial unwinding of the origin DNA in the presence of Cdk2. This step is followed by RPA binding which is a prerequisite for recruitment of PCNA and DNA polymerases alpha and delta. As RPA is not required for claspin binding, it is postulated that claspin binds at the time of initial origin unwinding but prior to the initiation of DNA synthesis. Claspin would then continue to associate with replication fork machinery where it can serve as a checkpoint sensor protein. Even though associated with the replication fork, claspin is not an essential DNA replication factor.<p>Studies of Xenopus claspin indicate that it can physically associate with cognate Cdc45, DNA polymerase epsilon, RPA, RFC, and Rad17-RFC on chromatin. Studies of purified human claspin indicate that it binds with high affinity to branched (or forked) DNA structures that resemble stalled replication forks. Electron microscopy of these complexes indicates that claspin binds as a ring-like structure near the branch. The protein is hypothesized to encircle the DNA at these sites. Edited: D'Eustachio, P, 2006-02-25 17:41:28 GENE ONTOLOGYGO:0006260 Pubmed11090622 Pubmed12545175 Pubmed12620222 Pubmed15226314 Pubmed15279790 Pubmed16148040 Reactome Database ID Release 43176318 Reactome, http://www.reactome.org ReactomeREACT_6738 Binding of ATR-ATRIP to the RPA-ssDNA complex ATR kinase activity is stimulated upon binding of the ATR-ATRIP complex to an RPA-ssDNA complex. ATR can subsequently phosphorylate and activate the checkpoint kinase Chk1, allowing further amplification of the checkpoint signal. The ATR and Chk1 kinases then modify a variety of factors that can lead to stabilization of stalled DNA replication forks, inhibition of origin firing, inhibition of cell cycle progression, mobilization of DNA repair factors, and induction of apoptosis. This checkpoint signaling mechanism is highly conserved in eukaryotes, and homologues of ATR and ATRIP are found in such organisms as S. cerevisiae (Mec1 and Ddc2, respectively), S. pombe (rad3 and rad26, respectively), and X. laevis (Xatr and Xatrip, respectively).<p>The ATR (ATM- and rad3-related) kinase is an essential checkpoint factor in human cells. In response to replication stress (i.e., stresses that cause replication fork stalling) or ultraviolet radiation, ATR becomes active and phosphorylates numerous factors involved in the checkpoint response including the checkpoint kinase Chk1. ATR is invariably associated with ATRIP (ATR-interacting protein) in human cells. Depletion of ATRIP by siRNA causes a loss of ATR protein without affecting ATR mRNA levels indicating that complex formation stabilizes the ATR protein. ATRIP is also a substrate for the ATR kinase, but modification of ATRIP does not significantly regulate the recruitment of ATR-ATRIP to sites of damage, the activation of Chk1, or the modification of p53.<p>While the ATR-ATRIP complex binds only poorly to RPA complexed with ssDNA lengths of 30 or 50 nt, binding is significantly enhanced in the presence of a 75 nt ssDNA molecule. Complex formation is primarily mediated by physical interaction between ATRIP and RPA. Multiple elements within the ATRIP molecule can bind to the RPA-ssDNA complex, including residues 1-107 (highest affinity), 218-390, and 390-791 (lowest affinity). Although the full-length ATRIP is unable to bind ssDNA, an internal region (108-390) can weakly bind ssDNA when present in rabbit reticulocyte lysates. ATR can bind to the ssDNA directly independent of RPA, but this binding is inhibited by ATRIP. Upon binding, the ATR kinase becomes activated and can directly phosphorylate substrates such as Rad17. Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 GENE ONTOLOGYGO:0006260 Pubmed10559981 Pubmed10950868 Pubmed12015327 Pubmed12791985 Pubmed15371427 Pubmed15451423 Pubmed15743907 Pubmed16327781 Pubmed16407120 Pubmed8019001 Reactome Database ID Release 43176250 Reactome, http://www.reactome.org ReactomeREACT_6939 Recruitment of Rad17-RFC complex to DNA Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 GENE ONTOLOGYGO:0006260 Pubmed12578958 Pubmed14605214 Pubmed14624239 Pubmed15279787 Reactome Database ID Release 43176101 Reactome, http://www.reactome.org ReactomeREACT_6798 The Rad17-RFC complex is involved in an early stage of the genotoxic stress response. The major function of the protein complex is to load the Rad9-Hus1-Rad1 (9-1-1) complex onto DNA at sites of damage and/or stalled replication forks. This reaction is conceptually similar to the loading of the PCNA sliding clamp onto DNA by RFC. The association of the Rad17-RFC complex with ssDNA or gapped or primed DNA is significantly stimulated by RPA, but not by the heterologous E. coli SSB. Loading of the human 9-1-1 complex onto such DNA templates is also strongly stimulated by cognate RPA, but not yeast RPA. Although Rad17 and Rad9 are substrates of the ATR kinase activity, loading of the Rad17 and 9-1-1 complexes onto DNA occurs independent of ATR.<p>The Rad17-RFC complex is a heteropentamer structurally similar to RFC. The complex contains the four smaller RFC subunits (Rfc2 [p37], Rfc3 [p36], Rfc4 [p40], and Rfc5 [p38]) and the 75 kDa Rad17 subunit in place of the Rfc1 [p140] subunit. The Rad17 complex contains a weak ATPase that is slightly stimulated by primed DNA. Along with binding the 9-1-1 complex and RPA, the Rad17-RFC complex interacts with human MCM7 protein. Each of these interactions is critical for Chk1 activation.<p>The Rad17 subunit is conserved evolutionarily with the protein showing 49% identity at the amino acid level with the S. pombe rad17 protein. Targeted deletion of the N-terminal region of mouse Rad17 leads to embryonic lethality, strongly suggesting that human Rad17 is also essential for long-term viability.<p>Rad17-RFC complex associates with DNA substrates containing ssDNA regions including gapped or primed DNA in an ATP-independent reaction. Loading of the Rad9-Hus1-Rad1 (9-1-1) complex occurs preferentially on DNA substrates containing a 5' recessed end. This contrasts with the loading of PCNA by RFC which preferentially occurs on DNA with 3' recessed ends. Stalling of DNA replication fork and RPA binding Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 GENE ONTOLOGYGO:0006260 Pubmed10051570 Pubmed10373362 Pubmed10473346 Pubmed12142537 Pubmed12791985 Pubmed15833913 Pubmed16387650 Pubmed8196638 Pubmed9242902 Reactome Database ID Release 43176175 Reactome, http://www.reactome.org ReactomeREACT_6936 When a DNA replication fork encounters DNA lesions (e.g., cyclobutane pyrimidine dimers or alkylated bases) stalling of the replicative DNA polymerase may occur. This can lead to dissociation or 'uncoupling' of the DNA polymerase from the DNA helicase and generation of long regions of persistent ssDNA. Uncoupling can also occur in response to other genotoxic stresses such as reduced dNTP pools caused by hydroxyurea treatment which inhibits cellular ribonucleotide diphosphate reductase. The exposed ssDNA is bound by the single-stranded DNA binding protein RPA. The persistent nature of this RPA-ssDNA complex (as opposed to a more-transient complex found at an active replication fork) allows it to serve as a signal for replication stress that can be recognized by the ATR-ATRIP and Rad17-Rfc2-5 complexes.<p>RPA associates with ssDNA in distinct complexes that can be distinguished by the length of ssDNA occluded by each RPA molecule. These complexes reflect the progressive association of distinct DNA-binding domains present in the RPA heterotrimeric structure. Binding is coupled to significant conformational changes within RPA that are observable at the microscopic level. Presumably, the different conformations of free and ssDNA-bound RPA allow the protein to selectively interact with factors such as ATR-ATRIP when bound to DNA. IL2RB associates with JAK1 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Janus Kinase 1 (JAK1) constitutively associates with IL-2R beta. Pubmed7514277 Pubmed7973658 Pubmed7973659 Pubmed9553136 Reactome Database ID Release 43451900 Reactome, http://www.reactome.org ReactomeREACT_27175 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Myt-1 mediated phosphorylation of Cyclin B:Cdc2 complexes Myt1, which localizes preferentially to the endoplasmic reticulum and Golgi complex, phosphorylates Cdc2 on threonine 14 ( Liu et al., 1997). Pubmed9001210 Pubmed9268380 Reactome Database ID Release 43170055 Reactome, http://www.reactome.org ReactomeREACT_6217 TPL2 phosphorylates MEK1, SEK1 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.11.25 Edited: Jupe, S, 2010-05-17 Pubmed17709378 Pubmed8131746 Reactome Database ID Release 43451649 Reactome, http://www.reactome.org ReactomeREACT_22271 Reviewed: Pinteaux, E, 2010-05-17 Tpl2 (also known as Cot) is constitutively bound to NFKB p105 (p105) which inhibits its MEK kinase activity in resting cells. Proteolysis of p105 frees Tpl2 from p105 and allows subsequent phosphorylation and activation of MEK1. Tpl2 can also activate SEK1. Phosphorylation of Tpl-2 is believed to play a role in its activation (Cho et al, 2005; Robinson et al. 2007). <br>Positions of phosphorylations represented here are inferred from general experimental data (Zheng & Guan, 1994). has a Stoichiometric coefficient of 2 Wee1-mediated phosphorylation of Cyclin B1:phospho-Cdc2 complexes Pubmed1384126 Reactome Database ID Release 43170070 Reactome, http://www.reactome.org ReactomeREACT_6178 Wee1, a nuclear kinase, phosphorylates cyclin B1:Cdc2 on tyrosine 15 inactivating the complex. Interleukin-2 receptor alpha binds interleukin-2 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed15178252 Pubmed1526987 Pubmed16293754 Pubmed1631559 Pubmed16477002 Pubmed21119631 Pubmed2983318 Reactome Database ID Release 43450054 Reactome, http://www.reactome.org ReactomeREACT_27273 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 The interleukin-2 receptor is a heterotrimer composed of interleukin-2 receptor alpha (IL2RA), beta (IL2RB) and gamma (IL2RG) subunits. Individually, IL2RA and IL2RB have low affinity for interleukin-2 (IL2); IL2RG has very low affinity. The IL2RA chain has a short cytoplasmic domain and consequently does not transmit an intracellular signal, but it binds IL-2 with high affinity and is required in vivo for detection of physiological IL-2 levels (Kd for IL-2RB/G = 10-9 M versus 10-11 M for IL-2RA/B/G, Takeshita et al. 1992). The crystal structure of the trimeric complex bound to IL2 suggests that the initiating event is the binding of IL2 to IL2R alpha (Wang et al. 2005). This captures IL2 at the cell surface and allows the recruitment of the beta and gamma subunits, which then participate in signal transduction. IL-2R alpha chains are expressed at much greater levels than the other receptor chains, usually 10-1000-fold higher compared with IL-2R beta or gamma (~1,000 sites/cell), which are usually expressed in equal numbers (Smith & Cantrell 1985). Recent single cell analysis methods have found that as the density of IL-2R alpha chains varies 1,000-fold from 100 to 100,000 sites/cell, the equilibrium dissociation constant of IL-2 binding varies to the same extent, from 100 pM to 100 fM, with the consequence that as the density of IL-2R alpha chains increases there is a marked improvement in IL-2 binding efficiency and thus signaling (Feinerman O et al. 2010). IL-2 binding to IL-2Ralpha is rapid on and rapid off. Phosphorylation of Wee1 kinase by Chk1 Authored: Matthews, L, 2003-08-08 02:54:00 Phosphorylation of Wee1 by Chk1 stimulates Wee1 kinase activity. Reactome Database ID Release 4375028 Reactome, http://www.reactome.org ReactomeREACT_264 IL2RG associates with JAK3 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 IL-2 receptor gamma chain (IL2RG) associates with Janus Kinase 3 (JAK3). The carboxyl terminal region of IL2RG has been shown to be important for this asociation (Miyazaki et al. 1994, Zhu et al. 1998). Pubmed7514277 Pubmed7973658 Pubmed7973659 Pubmed9192665 Pubmed9553136 Reactome Database ID Release 43451895 Reactome, http://www.reactome.org ReactomeREACT_27167 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Retention of phospho-Cdc25C:14-3-3 complexes within the cytoplasm Authored: Matthews, L, 2003-08-05 01:10:00 Cdc25C is phosphorylated by Chk1 at ser-216 (Blasina et al.,1999 ) resulting in both inhibition of the Cdc25 phosphatase activity and creation of a 14-3-3 docking site (Peng et al., 1997). Association of 14-3-3 protein is believed to exclude Cdc25C from the nucleus via cytoplasmic retention of the Cdc25C:14-3-3 complex. Pubmed10330186 Pubmed9278512 Pubmed9889122 Reactome Database ID Release 4375022 Reactome, http://www.reactome.org ReactomeREACT_100 Interleukin-2: IL2 receptor alpha:beta binds IL2 receptor gamma subunit Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed15178252 Pubmed16293754 Pubmed16477002 Reactome Database ID Release 43450063 Reactome, http://www.reactome.org ReactomeREACT_27145 Recruitment of the IL-2R gamma chain forms a very stable quaternary complex, capable of signaling. The IL-2 gamma chain further retards IL-2 dissociation so that the rate of IL-2 dissociation from the complex is three times slower than the rate of internalization of the complex (t1/2 55= 45 min vs. 15 min). Therefore, the complex continues to signal as long as it remains on the cell surface. Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Association of phospho-Cdc25C(Ser 216) with 14-3-3 proteins Association of Cdc25C with 14-3-3 proteins with phospho-Cdc25C (Ser216) is believed to result in retention of this complex within the cytoplasm ( Dalal et al., 1999) Authored: Matthews, L, 2003-08-05 01:10:00 Pubmed10330186 Pubmed11313932 Reactome Database ID Release 4375016 Reactome, http://www.reactome.org ReactomeREACT_205 Interleukin-2 receptor alpha:IL2 binds Interleukin-2 receptor beta Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed15178252 Pubmed16477002 Reactome Database ID Release 43450027 Reactome, http://www.reactome.org ReactomeREACT_27278 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 The crystal structure of the assembled IL2:IL2 receptor complex and experiments using isothermal titration calorimetry suggest that the complex of IL2 with IL2R alpha is likely to preferentially associate with IL2R bet (Rickert et al. 2004, Stauber et al. 2006). Binding of IL-2/IL-2R alpha to IL-2R beta significantly slows the dissociation of IL-2. However, the trimeric complex of IL-2:IL-2R alpha:IL-2R beta is incapable of signaling without participation of the gamma chain. Within the IL-2R complex JAK3 phosphorylates JAK1 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 Pubmed10825200 Pubmed10889465 Pubmed11750878 Pubmed7481768 Pubmed7568005 Pubmed7659163 Pubmed8022485 Pubmed8777722 Pubmed9382798 Pubmed9590172 Reactome Database ID Release 43451942 Reactome, http://www.reactome.org ReactomeREACT_27274 Receptor activation involves JAK1 and JAK3 as T-cells from mice lacking either kinase are unable to respond to cytokines that utilize the Common gamma chain (Rodig et al. 1998, Park et al. 1995). Naturally occurring JAK3 mutations prevent binding to the IL-2 receptor, leading to severe immunodeficiency due to a lack of IL2R signaling (Macchi et al. 1995, Russell et al. 1995). Mechanistic models of receptor activation suggest that assembly of the quaternary receptor and the consequent proximity of JAK1 and JAK3, bound to the cytoplasmic domains of the beta and gamma chains, is the trigger for JAK activation (Ellery et al. 2000). JAK3 is thought to activate JAK1, as JAK3 does not require tyrosine phosphorylation to activate its kinase activity (Liu et al. 1997), and JAK3 has been demonstrated to phosphorylate JAK1 in response to IL-2 (Kawahara et al. 1995). JAK3 also becomes phosphorylated in response to IL-2 (Johnston et al. 1994), either by JAK1 trans-activation or by an indirect mechanism. The activated JAKs then phosphorylate critical tyrosine residues within IL2RB. Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 The SCF betaTrCP complex binds p-NFkB p105 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 IKK-mediated NFkB p105 phosphorylation generates a binding site for betaTrCP, the receptor subunit of the SCF-type beta-TrCP ubiquitin E3 ligase complex. Pubmed12482991 Pubmed14673179 Reactome Database ID Release 43451609 Reactome, http://www.reactome.org ReactomeREACT_22353 Reviewed: Pinteaux, E, 2010-05-17 NFKB p105, TPL2 (COT) and ABIN2 form a stable complex Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Pubmed12667451 Pubmed12832462 Pubmed15169888 Pubmed15699325 Pubmed9950430 Reactome Database ID Release 43451634 Reactome, http://www.reactome.org ReactomeREACT_22206 Reviewed: Pinteaux, E, 2010-05-17 The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with Tpl2 via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho & Tsichlis 2005). <br><br>A20-binding inhibitor of NFkappaB2 (ABIN-2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.<br> Beta-TrCP ubiquitinates then dissociates from p-NFKB p105 Authored: Ray, KP, 2010-05-17 Beta-TrCP ubiquitinates p105 at several lysine residues within the C-terminal region 660-968. The level of ubiquitination is variable; in this reaction p105 is represented with 3 ubiquitinated lysine residues. Removal of all lysines within this region abolishes subsequent p105 degradation. EC Number: 6.3.2.19 Edited: Jupe, S, 2010-05-17 Pubmed14673179 Reactome Database ID Release 43451617 Reactome, http://www.reactome.org ReactomeREACT_22407 Reviewed: Pinteaux, E, 2010-05-17 phosphoglycerate kinase 1 complex Reactome DB_ID: 70484 Reactome Database ID Release 4370484 Reactome, http://www.reactome.org ReactomeREACT_5354 has a Stoichiometric coefficient of 1 glyceraldehyde-3-phosphate dehydrogenase, testis-specific, tetramer Reactome DB_ID: 372869 Reactome Database ID Release 43372869 Reactome, http://www.reactome.org ReactomeREACT_15272 has a Stoichiometric coefficient of 4 phosphoglycerate mutase 1 dimer Reactome DB_ID: 71443 Reactome Database ID Release 4371443 Reactome, http://www.reactome.org ReactomeREACT_3282 bisphosphoglycerate phosphatase 1 dimer has a Stoichiometric coefficient of 2 phosphoglycerate mutase dimer Converted from EntitySet in Reactome Reactome DB_ID: 179494 Reactome Database ID Release 43179494 Reactome, http://www.reactome.org ReactomeREACT_8764 triosephosphate isomerase dimer Reactome DB_ID: 70452 Reactome Database ID Release 4370452 Reactome, http://www.reactome.org ReactomeREACT_4820 has a Stoichiometric coefficient of 2 glyceraldehyde-3-phosphate dehydrogenase tetramer Reactome DB_ID: 70447 Reactome Database ID Release 4370447 Reactome, http://www.reactome.org ReactomeREACT_5815 has a Stoichiometric coefficient of 4 glyceraldehyde-3-phosphate dehydrogenase tetramer Converted from EntitySet in Reactome Reactome DB_ID: 372871 Reactome Database ID Release 43372871 Reactome, http://www.reactome.org ReactomeREACT_15048 Phosphorylation of Cdc25C at Ser216 Authored: Sanchez, Y, 2004-02-10 21:59:11 Cdc25C is negatively regulated by phosphorylation on Ser 216, the 14-3-3-binding site. This is an important regulatory mechanism used by cells to block mitotic entry under normal conditions and after DNA damage (Bulavin et al., 2003). Edited: Matthews, L, 2004-03-22 22:00:00 Pubmed12766774 Reactome Database ID Release 4375809 Reactome, http://www.reactome.org ReactomeREACT_128 Reviewed: Manfredi, J, 0000-00-00 00:00:00 Phosphorylation and activation of Chk1 by ATM At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'Chk1' are present. At the end of this reaction, 1 molecule of 'phospho-Chk1', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'phospho-ATM (Ser 1981)'.<br> Reactome Database ID Release 4369889 Reactome, http://www.reactome.org ReactomeREACT_302 Phosphorylation of Cdc25A at Ser-123 by Chk1 Detection of DNA damage caused by ionizing radiation results in the phosphorylation of Cdc25A at Ser-123 by Chk1, inhibiting Cdc25A. Pubmed12399544 Reactome Database ID Release 4369604 Reactome, http://www.reactome.org ReactomeREACT_845 Recruitment and activation of Chk1 Authored: Borowiec, JA, 2006-02-25 17:40:15 Chk1 is a checkpoint kinase activated during genotoxic stress. Like ATR, Chk1 is essential for viability in mammals. Targeted gene disruption in mice shows that loss of Chk1 causes peri-implantation embryonic lethality. Even though ATR-ATRIP not bound to ssDNA can phosphorylate Chk1, Chk1 activation is greatly enhanced when recruited to stalled replication forks by physical interaction with a modified form of claspin and the Rad9-Hus1-Rad1 sliding clamp. Activation of Chk1 occurs following phosphorylation of two sites (serine 317 and serine 345). Mutational analysis indicates that modification of both sites is essential for maximal kinase activity, while phosphorylation of only a single site causes only weak activation of Chk1. Following phosphorylation, Chk1 can diffuse away from the complex to further amplify the checkpoint signal. ATR appears to be the primary kinase activating Chk1 as conditions that activate ATR (ultraviolet irradiation or treatment with hydroxyurea) also activate Chk1. Stresses that activate ATM, e.g., ionizing irradiation, do not cause significant Chk1 activation. While the ATR and ATM pathways are distinct, there is interplay between the two. For example, double-strand DNA breaks can be processed in an ATM-dependent manner to generate structures that can cause ATR and hence Chk1 activation. The ATR and ATM pathways also have mechanistic similarities. Analogous to the Chk1 kinase existing downstream of ATR, the Chk2 checkpoint kinase is modified and activated by ATM. Although having distinct structures, Chk1 and Chk2 also have overlapping targets with some substrate sites phosphorylatable by both kinases (e.g., serine 20 of p53). EC Number: 2.7.11 Edited: D'Eustachio, P, 2006-02-25 17:41:28 GENE ONTOLOGYGO:0006260 Pubmed10859163 Pubmed10859164 Pubmed11090622 Pubmed11390642 Pubmed12766152 Pubmed12781359 Pubmed15190204 Pubmed15272308 Pubmed15279789 Pubmed16360315 Pubmed16431910 Reactome Database ID Release 43176116 Reactome, http://www.reactome.org ReactomeREACT_6869 Phosphorylation and activation of CHK2 by ATM At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'Chk2' are present. At the end of this reaction, 1 molecule of 'phospho-Chk2', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'phospho-ATM (Ser 1981)'.<br> Pubmed10973490 Pubmed12773400 Reactome Database ID Release 4369891 Reactome, http://www.reactome.org ReactomeREACT_1603 Phosphorylation of Cdc25A at Ser-123 by Chk2 Detection of DNA damage caused by ionizing radiation results in the phosphorylation of Cdc25A at Ser-123 by Chk2. Reactome Database ID Release 4369608 Reactome, http://www.reactome.org ReactomeREACT_43 IRAK1 and 4 interact with Pellino1,2 and 3 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 IRAK1 and 4 interact with Pellino-1 (Jiang et al. 2003), 2 (Strellow et al. 2003) and 3 (Butler et al. 2005, 2007). Pellinos may act as scaffolding proteins, bringing signaling complexes into proximity. They are E3 ubiquitin ligases capable of ubiquitinating IRAK1, believed to mediate IL-1-stimulated formation of K63-polyubiquitinated IRAK1 in cells.<br><br>Though not clearly demonstrated and therefore not shown here, the current models of IRAK1 involvement suggest it would be within a complex including TRAF6. Pubmed12496252 Pubmed12860405 Pubmed15917247 Pubmed17675297 Pubmed17997719 Reactome Database ID Release 43450690 Reactome, http://www.reactome.org ReactomeREACT_22286 Reviewed: Pinteaux, E, 2010-05-17 has a Stoichiometric coefficient of 2 Phosphorylation of Cdc25A at Ser-123 in response to DNA damage Authored: O'Connell, M, Walworth, N, 2003-06-05 08:03:09 Chk1 directly phosphorylates Cdc25A at Ser-123. Chk1 phosphorylation is required for cells to delay cell cycle progression in response to double-strand DNA breaks (Zhao et al., 2002). Edited: Matthews, L, 2003-09-10 06:00:00 Pubmed12399544 Reactome Database ID Release 4369591 Reactome, http://www.reactome.org ReactomeREACT_1680 Reviewed: Manfredi, J, 0000-00-00 00:00:00 TAK1 is activated within the TAK1 complex Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Pubmed10702308 Pubmed14633987 Pubmed15327770 Reactome Database ID Release 43450187 Reactome, http://www.reactome.org ReactomeREACT_22176 Reviewed: Pinteaux, E, 2010-05-17 The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). Proteolytic degradation of ubiquitinated-Cdc25A At the beginning of this reaction, 1 molecule of 'Ubiquitinated Phospho-Cdc25A' is present. At the end of this reaction, 1 molecule of 'Amino Acid' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of '26S proteasome'.<br> Reactome Database ID Release 4369600 Reactome, http://www.reactome.org ReactomeREACT_873 Polyubiquitinated TRAF6 interacts with TAK1 complex Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Pubmed10882101 Pubmed15327770 Pubmed19675569 Reactome Database ID Release 43446870 Reactome, http://www.reactome.org ReactomeREACT_22322 Reviewed: Pinteaux, E, 2010-05-17 TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism. Ubiquitination of phosphorylated Cdc25A At the beginning of this reaction, 1 molecule of 'ubiquitin', and 1 molecule of 'phospho-Cdc25A' are present. At the end of this reaction, 1 molecule of 'Ubiquitinated Phospho-Cdc25A' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'Ubiquitin ligase'.<br> EC Number: 6.3.2.19 Reactome Database ID Release 4369598 Reactome, http://www.reactome.org ReactomeREACT_93 TRAF6 auto-ubiquitinates with Lys63-linked polyubiquitin chains Authored: Ray, KP, 2010-05-17 EC Number: 6.3.2.19 Edited: Jupe, S, 2010-05-17 Pubmed17135271 Reactome Database ID Release 43446877 Reactome, http://www.reactome.org ReactomeREACT_22430 Reviewed: Pinteaux, E, 2010-05-17 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. has a Stoichiometric coefficient of 3 The IKKB complex phosphorylates NFkB p105 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.11.10 Edited: Jupe, S, 2010-05-17 NFkappaB p105 protein (p105) is a precursor of the NFkappaB p50 subunit and an inhibitor of NFkappaB. The IkappaB kinase (IKK) complex phosphorylates p105 on S927 within the PEST region. TNF-alpha-induced p105 proteolysis additionally requires the phosphorylation of S932. Purified IKK (IKK1) or IKKB (IKK2) can phosphorylate both these regulatory serines in vitro. Pubmed12482991 Reactome Database ID Release 43451603 Reactome, http://www.reactome.org ReactomeREACT_22418 Reviewed: Pinteaux, E, 2010-05-17 has a Stoichiometric coefficient of 2 NEMO binds polyubiquitinated IRAK1 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008). Pubmed16547522 Pubmed16603398 Pubmed18180283 Pubmed19022706 Reactome Database ID Release 43451561 Reactome, http://www.reactome.org ReactomeREACT_22256 Reviewed: Pinteaux, E, 2010-05-17 Inactivation of Cyclin E:Cdk2 complexes by p27/p21 During G1, the activity of cyclin-dependent kinases (CDKs) is kept in check by the CDK inhibitors (CKIs) p27 and p21, thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF(Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2. Edited: Matthews, L, 2006-10-02 07:13:54 Pubmed10323868 Pubmed16262255 Pubmed16600864 Reactome Database ID Release 4369562 Reactome, http://www.reactome.org ReactomeREACT_334 Pellino ubiquitinates IRAK1 Authored: Ray, KP, 2010-05-17 EC Number: 6.3.2.19 Edited: Jupe, S, 2010-05-17 IL1 induces the poly-ubiquitination and degradation of IRAK1. This was believed to be K48-linked polyubiquitination, targeting IRAK1 for proteolysis by the proteasome, but recently IL-1R signaling has been shown to lead to K63-linked polyubiquitination of IRAK1 (Windheim et al. 2008; Conze et al. 2008), and demonstrated to have a role in the activation of NF-kappaB. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al. 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al. 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. <br>Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13–Uev1a to catalyze K63-linked ubiquitylation (Ordureau et al. 2008). Pubmed16884718 Pubmed17997719 Pubmed18180283 Pubmed18326498 Pubmed18347055 Pubmed19022706 Reactome Database ID Release 43451418 Reactome, http://www.reactome.org ReactomeREACT_22381 Reviewed: Pinteaux, E, 2010-05-17 has a Stoichiometric coefficient of 2 IRAK1 and 4 can phosphorylate Pellino-1 and 2. Authored: Ray, KP, 2010-05-17 EC Number: 2.7.11 Edited: Jupe, S, 2010-05-17 IRAK1 and 4 can phosphorylate Pellino-1 and -2 and probably -3. Phosphorylation enhances the E3 ligase activity of Pellino-1 in conjunction with several different E2-conjugating enzymes (Ubc13-Uev1a, UbcH4, or UbcH5a/5b). Phosphorylation at any of several different sites or a combination of other sites leads to full activation of Pellino-1 E3 ubiquitin ligase activity.<br><br>Though not shown here, the current models of IRAK1 involvement suggest it is part of a complex that includes TRAF6. Pubmed12860405 Pubmed19264966 Reactome Database ID Release 43450827 Reactome, http://www.reactome.org ReactomeREACT_22325 Reviewed: Pinteaux, E, 2010-05-17 IRAK1 induces oligomerisation of TRAF6 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Pubmed10908665 Pubmed12566447 Pubmed17063183 Pubmed18070982 Reactome Database ID Release 43450173 Reactome, http://www.reactome.org ReactomeREACT_22416 Reviewed: Pinteaux, E, 2010-05-17 TRAF6 oligomerization is induced by IRAK1. The TRAF6 oligomer consists of more than two molecules of TRAF6; thermodynamic data for TRAF2 strongly suggests that it is functionally a trimer (Rawlings et al. 2006). TRAF6 is represented here as a trimer, though the extent and significance of TRAF6 oligomerization is unclear. Oligomerisation may be assisted by TIFA (TRAF-interacting protein with a FHA domain; Takatsuna et al. 2003). has a Stoichiometric coefficient of 2 phosphoglycerate mutase 2 dimer Reactome DB_ID: 70488 Reactome Database ID Release 4370488 Reactome, http://www.reactome.org ReactomeREACT_2970 bisphosphoglycerate phosphatase 2 dimer has a Stoichiometric coefficient of 2 TRAF6 binding leads to IRAK1:TRAF6 release Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 MyD88 and Tollip only bind to non-phosphorylated IRAK1 [Wesche et al. 1997) so hyper-phosphorylated IRAK1 is predisposed to release from the receptor complex, a key step in this signaling cascade. It is believed that the interaction of IRAK1 with TRAF6 enables the release of IRAK1:TRAF6 from the receptor (Gottipati et al. 2007). Though released from the receptor complex, IRAK1:TRAF6 remains associated with the membrane, perhaps due to subsequent interaction with the TAK1 complex (Dong et al. 2006). Pubmed16831874 Pubmed17890055 Pubmed9430229 Reactome Database ID Release 43446894 Reactome, http://www.reactome.org ReactomeREACT_22209 Reviewed: Pinteaux, E, 2010-05-17 enolase dimer Converted from EntitySet in Reactome Reactome DB_ID: 179497 Reactome Database ID Release 43179497 Reactome, http://www.reactome.org ReactomeREACT_8680 enolase 1 dimer, (alpha) Reactome DB_ID: 71438 Reactome Database ID Release 4371438 Reactome, http://www.reactome.org ReactomeREACT_3125 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 SLC7A9:SLC3A1 heterodimer Reactome DB_ID: 379438 Reactome Database ID Release 43379438 Reactome, http://www.reactome.org ReactomeREACT_17730 has a Stoichiometric coefficient of 1 Di-peptides Reactome DB_ID: 427971 Reactome Database ID Release 43427971 Reactome, http://www.reactome.org ReactomeREACT_19476 has a Stoichiometric coefficient of 2 Tri-peptides Reactome DB_ID: 428046 Reactome Database ID Release 43428046 Reactome, http://www.reactome.org ReactomeREACT_19446 has a Stoichiometric coefficient of 3 Di-peptides Reactome DB_ID: 427981 Reactome Database ID Release 43427981 Reactome, http://www.reactome.org ReactomeREACT_19695 has a Stoichiometric coefficient of 2 Di-peptides/tri-peptides Converted from EntitySet in Reactome Reactome DB_ID: 428026 Reactome Database ID Release 43428026 Reactome, http://www.reactome.org ReactomeREACT_20481 Tri-peptides Reactome DB_ID: 427999 Reactome Database ID Release 43427999 Reactome, http://www.reactome.org ReactomeREACT_20221 has a Stoichiometric coefficient of 3 Di-peptides Reactome DB_ID: 427956 Reactome Database ID Release 43427956 Reactome, http://www.reactome.org ReactomeREACT_19989 has a Stoichiometric coefficient of 2 Di-peptides/tri-peptides Converted from EntitySet in Reactome Reactome DB_ID: 428037 Reactome Database ID Release 43428037 Reactome, http://www.reactome.org ReactomeREACT_20441 BH3 only proteins associate with and inactivate anti-apoptotic BCL-XL Authored: Matthews, L, 2010-02-08 BH3-only proteins (tBid, BIM, PUMA, BAD, NOXA) associate with and inactivate anti-apoptotic protein Bcl-XL( Yi et al., 2003; Puthalakath et al., 1999; Nakano and Vousden, 2001; Wang et al., 1999; Oda et al., 2000). The interactions of NOXA with Bcl-XL are inferred from experiments performed in mice (Oda et al., 2000). Edited: Matthews, L, 2010-02-08 Pubmed10195903 Pubmed10198631 Pubmed10807576 Pubmed11463392 Pubmed12624108 Reactome Database ID Release 43508162 Reactome, http://www.reactome.org ReactomeREACT_21278 tBID binds to inactive BAX protein At the beginning of this reaction, 1 molecule of 'tBID-p15', and 1 molecule of 'Inactive Bax alpha protein' are present. At the end of this reaction, 1 molecule of 'tBID bound to inactive BAX' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Reactome Database ID Release 43168849 Reactome, http://www.reactome.org ReactomeREACT_6160 BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 Authored: Matthews, L, 2010-02-04 Bcl-2 interacts with tBid, BIM, PUMA, NOXA, BAD Pubmed10198631 Pubmed10807576 Pubmed11463392 Pubmed12624108 Pubmed7834748 Reactome Database ID Release 43508163 Reactome, http://www.reactome.org ReactomeREACT_21389 Sequestration of tBID by BCL-2 At the beginning of this reaction, 1 molecule of 'Bcl-2 protein', and 1 molecule of 'tBID' are present. At the end of this reaction, 1 molecule of 'tBID:BCL-2' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> Pubmed12624108 Reactome Database ID Release 43114352 Reactome, http://www.reactome.org ReactomeREACT_784 Phosphorylation of DLC2 by MAPK-8 At the beginning of this reaction, 1 molecule of 'BMF sequestered to dynein (DLC2)' is present. At the end of this reaction, 1 molecule of 'phospho-dynein(DLC2) on microtubules', and 1 molecule of 'BMF' are present.<br><br> This reaction takes place on the 'plasma membrane' and is mediated by the 'kinase activity' of 'Mitogen-activated protein kinase 8 '.<br> Pubmed12591950 Reactome Database ID Release 43139908 Reactome, http://www.reactome.org ReactomeREACT_1981 Translocation of BMF to mitochondria GENE ONTOLOGYGO:0001844 In this reaction, 1 molecule of 'BMF' is translocated from cytosol to mitochondrial outer membrane.<br><br>This reaction takes place in the 'cytosol'.<br> Reactome Database ID Release 43139909 Reactome, http://www.reactome.org ReactomeREACT_600 TGFB1:TGFBR2:p-TGFBR1:Smad7:NEDD4L Reactome DB_ID: 2176429 Reactome Database ID Release 432176429 Reactome, http://www.reactome.org ReactomeREACT_125541 has a Stoichiometric coefficient of 1 tBID binds to inactive BAK protein Pubmed10950869 Reactome Database ID Release 43168848 Reactome, http://www.reactome.org ReactomeREACT_6153 tBID binds to its mitochondrial partner BAK to release cytochrome c. It has been observed in mouse systems that the activated tBID results in an allosteric activation of BAK. Activated BAX induces intramembranous oligomerization leading to a pore for cytochrome c efflux. Oligomerization of BAX at the mitochondrial membrane At the beginning of this reaction, 2 molecules of 'Activated BAX inserted into mitochondrial membrane' is present. At the end of this reaction, 1 molecule of 'Activated BAX' is present.<br><br> This reaction takes place in the 'mitochondrial envelope'.<br> Pubmed11136736 Reactome Database ID Release 43114275 Reactome, http://www.reactome.org ReactomeREACT_341 has a Stoichiometric coefficient of 2 Translocation of activated BAX to the mitochondria At the beginning of this reaction, 1 molecule of 'Activated BAX' is present. At the end of this reaction, 1 molecule of 'Activated BAX inserted into mitochondrial membrane' is present.<br><br> This reaction takes place in the 'cytosol'.<br> GENE ONTOLOGYGO:0001844 Pubmed11136736 Pubmed12176904 Pubmed12624108 Reactome Database ID Release 43114264 Reactome, http://www.reactome.org ReactomeREACT_1286 tBID activates BAX protein Authored: Gopinathrao, G, 2005-04-27 17:36:27 During certain types of apoptosis, activated tBID (p15) induces a change in conformation of Bax which leads to the unmasking of its NH2-terminal domain. This change in confirmation usually results in the release of cytochrome c from mitochondria. Pubmed10085289 Pubmed10629050 Reactome Database ID Release 43139917 Reactome, http://www.reactome.org ReactomeREACT_1506 Kinesins:microtubule Reactome DB_ID: 983245 Reactome Database ID Release 43983245 Reactome, http://www.reactome.org ReactomeREACT_26291 has a Stoichiometric coefficient of 1 pL1:p90rsk Reactome DB_ID: 445012 Reactome Database ID Release 43445012 Reactome, http://www.reactome.org ReactomeREACT_23259 has a Stoichiometric coefficient of 1 Nodal Bound to Nodal Receptor (human/mouse chimera) Reactome DB_ID: 1181338 Reactome Database ID Release 431181338 Reactome, http://www.reactome.org ReactomeREACT_111798 has a Stoichiometric coefficient of 2 Tight Junction Complex:Pard6a:RHOA Reactome DB_ID: 2161142 Reactome Database ID Release 432161142 Reactome, http://www.reactome.org ReactomeREACT_122604 has a Stoichiometric coefficient of 1 Tight Junction Complex:TGFB1:TGFBR2:TGFBR1:Pard6a:RHOA Reactome DB_ID: 2161159 Reactome Database ID Release 432161159 Reactome, http://www.reactome.org ReactomeREACT_123915 has a Stoichiometric coefficient of 1 p-NICD1:FBXW7:SKP1:CUL1:RBX1 Reactome DB_ID: 2064852 Reactome Database ID Release 432064852 Reactome, http://www.reactome.org ReactomeREACT_118998 has a Stoichiometric coefficient of 1 TPO:TPOR Reactome DB_ID: 443935 Reactome Database ID Release 43443935 Reactome, http://www.reactome.org ReactomeREACT_24648 has a Stoichiometric coefficient of 1 Ub,p-NICD1 Reactome DB_ID: 2064879 Reactome Database ID Release 432064879 Reactome, http://www.reactome.org ReactomeREACT_119175 has a Stoichiometric coefficient of 1 FBXW7:SKP1:CUL1:RBX1 Reactome DB_ID: 1604469 Reactome Database ID Release 431604469 Reactome, http://www.reactome.org ReactomeREACT_119709 has a Stoichiometric coefficient of 1 Release of SMAC from mitochondria At the beginning of this reaction, 1 molecule of 'Smac protein, mitochondrial precursor' is present. At the end of this reaction, 1 molecule of 'SMAC' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> Pubmed12660240 Pubmed12941691 Reactome Database ID Release 43114307 Reactome, http://www.reactome.org ReactomeREACT_1101 Cytochrome C Binds to Apaf-1 At the beginning of this reaction, 1 molecule of 'Cytochrome c', and 1 molecule of 'Apaf-1' are present. At the end of this reaction, 1 molecule of 'Apaf-1:Cytochrome C' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Pubmed9267021 Reactome Database ID Release 43114254 Reactome, http://www.reactome.org ReactomeREACT_1640 Cytochrome C:Apaf-1 binds Procaspase-9 Apaf-1 and Caspase-9 form a complex in the presence of dATP and cytochrome c (Li et al.,1997). Authored: Alnemri, E, 2004-02-17 00:23:30 Pubmed9390557 Reactome Database ID Release 43114256 Reactome, http://www.reactome.org ReactomeREACT_39 Cleavage of Procaspase-9 to Caspase-9 Authored: Alnemri, E, 2004-02-17 00:23:30 Caspase-9 is activated in an ATP-dependent manner following association with Apaf-1 and cytochrome c (Li et al., 1997) EC Number: 3.4.22 Pubmed9390557 Reactome Database ID Release 43114259 Reactome, http://www.reactome.org ReactomeREACT_2116 tBID activates BAK protein Authored: Gopinathrao, G, 2004-08-18 11:49:08 Pubmed10950869 Reactome Database ID Release 43139895 Reactome, http://www.reactome.org ReactomeREACT_1424 Reviewed: Vaux, D, 0000-00-00 00:00:00 tBID binds to its mitochondrial partner BAK to release cytochrome c. It has been observed in mouse systems that the activated tBID results in an allosteric activation of BAK. Activated BAX induces intramembranous oligomerization leading to a pore for cytochrome c efflux. Oligomerization of BAK at the mitochondrial membrane At the beginning of this reaction, 2 molecules of 'Activated BAK protein' is present. At the end of this reaction, 1 molecule of 'Active oligomeric BAK' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> Pubmed12721291 Reactome Database ID Release 43114263 Reactome, http://www.reactome.org ReactomeREACT_507 has a Stoichiometric coefficient of 2 Release of Cytochrome c from mitochondria In this reaction, 1 molecule of 'Cytochrome c' is translocated from mitochondrial intermembrane space to cytosol.<br><br>This reaction takes place in the 'mitochondrial outer membrane'.<br> Pubmed12660240 Pubmed12941691 Reactome Database ID Release 43114284 Reactome, http://www.reactome.org ReactomeREACT_535 Cleavage of Procaspase-7 by the apoptosome Authored: Alnemri, E, 2004-02-17 00:23:30 Caspases-3 and -7 are directly cleaved downstream of caspase-9 in the cytochrome c/Apaf-1-inducible caspase cascade (Slee et al., 1999). EC Number: 3.4.22 Pubmed9922454 Reactome Database ID Release 43114261 Reactome, http://www.reactome.org ReactomeREACT_2165 Cleavage of  Procaspase-3 by the apoptosome Authored: Alnemri, E, 2004-02-17 00:23:30 Caspases-3 and -7 are directly cleaved downstream of caspase-9 in the cytochrome c/Apaf-1-inducible caspase cascade (Slee et al., 1999). EC Number: 3.4.22 Pubmed10206961 Pubmed9390557 Pubmed9922454 Reactome Database ID Release 43114252 Reactome, http://www.reactome.org ReactomeREACT_1460 SMAC binds XIAP:Caspase-3 At the beginning of this reaction, 1 molecule of 'SMAC', and 1 molecule of 'XIAP:Caspase-3' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-3' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Pubmed11257231 Pubmed14960576 Pubmed9230442 Reactome Database ID Release 43114306 Reactome, http://www.reactome.org ReactomeREACT_1090 Smad7:NEDD4L Reactome DB_ID: 2176424 Reactome Database ID Release 432176424 Reactome, http://www.reactome.org ReactomeREACT_124621 has a Stoichiometric coefficient of 1 TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-Smad7 Reactome DB_ID: 2176425 Reactome Database ID Release 432176425 Reactome, http://www.reactome.org ReactomeREACT_121518 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 sucrase-isomaltase dimer Reactome DB_ID: 189082 Reactome Database ID Release 43189082 Reactome, http://www.reactome.org ReactomeREACT_9659 has a Stoichiometric coefficient of 2 Tyrosine phosphorylated growth hormone receptor:CIS/SOCS1-3 Reactome DB_ID: 1169193 Reactome Database ID Release 431169193 Reactome, http://www.reactome.org ReactomeREACT_111340 has a Stoichiometric coefficient of 1 PARD3:p-S345-Pard6a:PRKCZ Reactome DB_ID: 2161136 Reactome Database ID Release 432161136 Reactome, http://www.reactome.org ReactomeREACT_121936 has a Stoichiometric coefficient of 1 Tight Junction Complex:p-Pard6a:RHOA Reactome DB_ID: 2161140 Reactome Database ID Release 432161140 Reactome, http://www.reactome.org ReactomeREACT_122686 has a Stoichiometric coefficient of 1 lactase-phlorizin hydrolase dimer Reactome DB_ID: 189026 Reactome Database ID Release 43189026 Reactome, http://www.reactome.org ReactomeREACT_9833 has a Stoichiometric coefficient of 2 maltase-glucoamylase dimer Reactome DB_ID: 189009 Reactome Database ID Release 43189009 Reactome, http://www.reactome.org ReactomeREACT_9877 has a Stoichiometric coefficient of 2 sucrase-isomaltase Reactome DB_ID: 189115 Reactome Database ID Release 43189115 Reactome, http://www.reactome.org ReactomeREACT_9632 has a Stoichiometric coefficient of 1 Dissociation of Caspase-3 from SMAC:XIAP:Caspase-3 At the beginning of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-3' is present. At the end of this reaction, 1 molecule of 'Active caspase-3', and 1 molecule of 'SMAC:XIAP' are present.<br><br> This reaction takes place in the 'cytosol'.<br> Authored: Alnemri, E, 2004-02-17 00:23:30 Reactome Database ID Release 43114419 Reactome, http://www.reactome.org ReactomeREACT_1300 Dissociation of Caspase-7 from SMAC:XIAP:Caspase-7 At the beginning of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-7' is present. At the end of this reaction, 1 molecule of 'SMAC:XIAP', and 1 molecule of 'Active Caspase-7' are present.<br><br> This reaction takes place in the 'cytosol'.<br> Authored: Alnemri, E, 2004-02-17 00:23:30 Pubmed11257231 Reactome Database ID Release 43114392 Reactome, http://www.reactome.org ReactomeREACT_2102 SMAC binds XIAP:Caspase-7 At the beginning of this reaction, 1 molecule of 'XIAP:Caspase-7', and 1 molecule of 'SMAC' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-7' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Pubmed11257231 Pubmed14960576 Pubmed9230442 Reactome Database ID Release 43114354 Reactome, http://www.reactome.org ReactomeREACT_2091 SMAC binds XIAP:Caspase-9 At the beginning of this reaction, 1 molecule of 'SMAC', and 1 molecule of 'XIAP:Caspase-9' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-9' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Pubmed11084335 Pubmed14960576 Reactome Database ID Release 43114361 Reactome, http://www.reactome.org ReactomeREACT_1312 Caspase mediated cleavage of alpha-II-Fodrin Apoptosis induced caspases cleave cortical actin network components including fodrin and components of the focal adhesion complex components which links membrane proteins and cortical actin filaments to the extracellular matrix (Janicke et al.,1998). Cleavage of these proteins results in disruption of the cortical cytoskeleton and may contribute to membrane blebbing (see Fischer et al., 2003). The full length 240 kDa alpha-fodrin protein can be cleaved at several sites within its sequence by activated caspases to yield amino-terminal 150 kDa, carboxy-terminal 120 kDa and 35 kDa major products. Cleavage of alpha-II fodrin leads to membrane malfunction and cell shrinkage (Janicke et al., 1998). Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Pubmed12655297 Pubmed9624143 Reactome Database ID Release 43202967 Reactome, http://www.reactome.org ReactomeREACT_12024 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 Caspase-mediated cleavage of GAS2 Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 Cleavage of Gas2 during apoptosis is associated with changes of the microfilament system but does not interfere with its ability to bind F-actin (Brancolini et al., 1995). EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Pubmed10564664 Pubmed7489707 Reactome Database ID Release 43201639 Reactome, http://www.reactome.org ReactomeREACT_12004 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 Dissociation of Caspase-9 from SMAC:XIAP:Caspase-9 At the beginning of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-9' is present. At the end of this reaction, 1 molecule of 'Cleaved Caspase-9', and 1 molecule of 'SMAC:XIAP' are present.<br><br> This reaction takes place in the 'cytosol'.<br> Authored: Alnemri, E, 2004-02-17 00:23:30 Reactome Database ID Release 43114440 Reactome, http://www.reactome.org ReactomeREACT_1035 Caspase-mediated cleavage of alpha adducin Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Pubmed10823823 Reactome Database ID Release 43201608 Reactome, http://www.reactome.org ReactomeREACT_12044 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 The cortical actin cytoskeletal network is lost during apoptosis. During apoptosis, increased phosphorylation of the actin capping protein alpha-adducin leads to its dissociation from the cytoskeleton. The caspase-3-mediated cleavage cleavage of alpha adducin at Asp-Asp-Ser-Asp(633)-Ala prevents its reassociation (van de Water et al, 2000). Caspase-mediated cleavage of vimentin at DSVD (85) Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-05-18 16:53:19 Pubmed10469173 Pubmed11423904 Reactome Database ID Release 43201628 Reactome, http://www.reactome.org ReactomeREACT_13428 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Vimentin is cleaved by several caspases during apoptosis (Morishima et al., 1999, Byun et al., 2001). This cleavage disrupts the cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Caspase-6 recognizes and cleaves C terminal side of Asp-429. Vimentin is cleaved at Asp85 by caspases-3 and -7 (Byun et al., 2001). This clevage generates a pro-apoptotic amino-terminal cleavage product (amino acids 1-85) that amplifies the cell death signal (Byun et al., 2001). Caspase mediated cleavage of HIP-55 Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-11-11 23:40:56 HIP-55 is an actin binding SH3 domain protein that is cleaved by caspase-3. Cleavage results in dissociation of the actin-binding domain from the SH3 domain and may alter cell signaling to and from the actin cytoskeleton. In addition, this cleavage may be involved in the the alteration in cell morphology that occur during apoptosis (Chen et al., 2001). Pubmed11689006 Reactome Database ID Release 43202966 Reactome, http://www.reactome.org ReactomeREACT_12025 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 TGFB1:TGFBR2:TGFBR1 Reactome DB_ID: 170840 Reactome Database ID Release 43170840 Reactome, http://www.reactome.org ReactomeREACT_7425 TGF-beta 1:type II receptor:type I receptor complex has a Stoichiometric coefficient of 1 Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-Pard6a:RHOA Reactome DB_ID: 2161166 Reactome Database ID Release 432161166 Reactome, http://www.reactome.org ReactomeREACT_121836 has a Stoichiometric coefficient of 1 PARD3:Pard6a:PRKCZ Reactome DB_ID: 2161137 Reactome Database ID Release 432161137 Reactome, http://www.reactome.org ReactomeREACT_124445 has a Stoichiometric coefficient of 1 GLUT1:ATP Reactome DB_ID: 450089 Reactome Database ID Release 43450089 Reactome, http://www.reactome.org ReactomeREACT_21995 has a Stoichiometric coefficient of 1 GLUT4 tetramer Reactome DB_ID: 70384 Reactome Database ID Release 4370384 Reactome, http://www.reactome.org ReactomeREACT_2699 has a Stoichiometric coefficient of 4 GCK1:GKRP complex Reactome DB_ID: 170804 Reactome Database ID Release 43170804 Reactome, http://www.reactome.org ReactomeREACT_7241 glucokinase:glucokinase regulatory protein complex has a Stoichiometric coefficient of 1 GCK1:GKRP complex Reactome DB_ID: 170827 Reactome Database ID Release 43170827 Reactome, http://www.reactome.org ReactomeREACT_7407 glucokinase:glucokinase regulatory protein complex has a Stoichiometric coefficient of 1 pPF2K-Pase complex Reactome DB_ID: 163745 Reactome Database ID Release 43163745 Reactome, http://www.reactome.org ReactomeREACT_3400 has a Stoichiometric coefficient of 2 phosphoPFKFB1 dimer glucose 6-phosphate isomerase dimer Reactome DB_ID: 70469 Reactome Database ID Release 4370469 Reactome, http://www.reactome.org ReactomeREACT_2403 has a Stoichiometric coefficient of 2 Caspase mediated cleavage of vimentin at IDVD (259) Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-05-18 15:54:39 Pubmed10469173 Pubmed11423904 Reactome Database ID Release 43350319 Reactome, http://www.reactome.org ReactomeREACT_13489 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Vimentin is cleaved by several caspases during apoptosis (Morishima et al., 1999, Byun et al., 2001). This clevage disrupts the cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Asp259 is recognized and cleaved by caspase-6 (Byun et al., 2001). Caspase-mediated cleavage of vimentin at TNLD (429) Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-05-18 15:44:16 Pubmed10469173 Pubmed11423904 Reactome Database ID Release 43350318 Reactome, http://www.reactome.org ReactomeREACT_13519 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Vimentin is cleaved by several caspases during apoptosis (Morishima et al., 1999, Byun et al., 2001). This clevage disrupts the cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Caspase-6 recognizes and cleaves C terminal side of Asp-429. Caspase-mediated cleavage of gelsolin Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Gelsolin is cleaved by caspase-3 generating a constitutively <br>active fragment that can depolymerize F-actin contributing to actin cytoskeletal collapse (Kothakota et al., 1997) Pubmed9323209 Pubmed9930654 Reactome Database ID Release 43201622 Reactome, http://www.reactome.org ReactomeREACT_13795 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of plectin-1 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-05-08 00:38:35 Edited: Matthews, L, 2008-06-03 01:13:58 Plectin is a major cross-linking protein of the three main cytoplasmic filament systems. Caspase-8 mediated cleavage of plectin 1 appears to contribute to disruption of the microfilament system during the early stages of apoptosis (Stegh et al., 2000). Pubmed10891503 Reactome Database ID Release 43201637 Reactome, http://www.reactome.org ReactomeREACT_13522 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of Tau Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Caspase-3 cleaves Tau at position 421 in vitro producing an N-terminal fragment that functions as an apoptotic effector (Fasulo et al., 2000). EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-05-08 00:37:34 Pubmed10899937 Reactome Database ID Release 43201629 Reactome, http://www.reactome.org ReactomeREACT_13414 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of E-Cadherin Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Pubmed11076937 Reactome Database ID Release 43202939 Reactome, http://www.reactome.org ReactomeREACT_12072 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 The cleavage of E-cadherin at both the intracellular and extracellular domains likely contributes to the disruption of cadherin-mediated cell-cell contacts in apoptotic cells. Loss of cell contact is necessary for cell rounding and exit from the epithelium (Steinhusen et al., 2001). Caspase mediated cleavage of beta-catenin Apoptosis-induced cleavage of beta-catenin by caspase 3 results in reduced alpha catenin binding, relocalization to the cytoplasm and a reduction in cell-cell contact. In addition, the resulting proteolytic fragments have reduced transcription factor activity (Steinhusen et al., 2000 ). Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Pubmed10748026 Reactome Database ID Release 43202969 Reactome, http://www.reactome.org ReactomeREACT_12022 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of Desmoglein 3 Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 In epithelial cells, desmosomes are anchoring junctions that mediate strong cell-cell contacts. Desmosomal proteins are proteolytically targeted during apoptosis (Weiske et al., 2001). Desmogleins are a major component of the desmosome are specifically cleaved after onset of apoptosis. Cleavage of desmosomal proteins results in the disruption of the structure of desmosomes and contributes to cell rounding and disassembly of the intermediate filament network (Weiske et al., 2001). The cytosolic fragment has implications for the autoimmune disease, Pemphigus vulgaris (Tong et al. 2006). Pubmed11500511 Pubmed17254312 Reactome Database ID Release 43201631 Reactome, http://www.reactome.org ReactomeREACT_12082 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of Desmoglein 2 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2008-05-18 15:44:16 In apoptotic cells, intercellular contacts are disrupted through the activity of caspases. Apoptotic cleavage of Dsg2,the most widespread desmosomal cadherin, is mediated by caspase 3 in epithelial cells (Cirillo et al., 2008). Pubmed17559062 Reactome Database ID Release 43351877 Reactome, http://www.reactome.org ReactomeREACT_13598 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of Desmoglein 1 Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 Caspase mediated cleavage of desmoglein 1 leads to decreased expression at the cell surface and re-localization of its C terminus diffusely throughout the cytoplasm. Cleavage is thought to contribute to the dismantling of desmosomes during keratinocyte apoptosis (Dusek et al., 2006). EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Edited: Matthews, L, 2008-05-28 22:59:08 Pubmed16286477 Reactome Database ID Release 43202917 Reactome, http://www.reactome.org ReactomeREACT_11997 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 GLUT2 tetramer Reactome DB_ID: 70422 Reactome Database ID Release 4370422 Reactome, http://www.reactome.org ReactomeREACT_8747 has a Stoichiometric coefficient of 4 GLUT tetramers Converted from EntitySet in Reactome GLUT1, GLUT2, GLUT3, GLUT4 Reactome DB_ID: 450100 Reactome Database ID Release 43450100 Reactome, http://www.reactome.org ReactomeREACT_21900 GLUT1 tetramer Reactome DB_ID: 70400 Reactome Database ID Release 4370400 Reactome, http://www.reactome.org ReactomeREACT_2722 has a Stoichiometric coefficient of 4 GLUT3 tetramer Reactome DB_ID: 70408 Reactome Database ID Release 4370408 Reactome, http://www.reactome.org ReactomeREACT_4043 has a Stoichiometric coefficient of 4 Caspase-mediated cleavage of FADK 1 Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 FAK is a tyrosine kinase that localizes to focal adhesions and associates temporally and spatially with integrins (see references in Fischer et al., 2003 ). FAK is cleaved by caspases including caspase-7 (Wen et al., 1997). Caspases also cleave fodrin and components of the focal adhesion complex which links cortical actin filaments and membrane proteins to the extracellular matrix. Cleavage of these proteins is thought to promote cell shrinkage and cell detachment and disrupt antiapoptotic integrin signaling (see Fischer et al., 2003). Pubmed12655297 Pubmed9325343 Reactome Database ID Release 43201634 Reactome, http://www.reactome.org ReactomeREACT_12021 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 PAK1 dimer (inactive/autoinhibited) Reactome DB_ID: 445002 Reactome Database ID Release 43445002 Reactome, http://www.reactome.org ReactomeREACT_23136 has a Stoichiometric coefficient of 2 p-STAT1 Converted from EntitySet in Reactome Reactome DB_ID: 909687 Reactome Database ID Release 43909687 Reactome, http://www.reactome.org ReactomeREACT_26719 Caspase mediated cleavage of C-IAP1 Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Pubmed11106668 Reactome Database ID Release 43202960 Reactome, http://www.reactome.org ReactomeREACT_12045 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 c-IAP1 is cleaved by caspase-3 producing a proapoptotic C-terminal fragment. Caspase mediated cleavage of APC Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 Cleavage of APC by caspase 3 and release of the amino-terminal fragment (1-760) are required for the APC mediated acceleration of apoptosis-associated caspase activity (Qian et al., 2007). EC Number: 3.4.22 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Pubmed10200466 Pubmed17297457 Pubmed9973322 Reactome Database ID Release 43202947 Reactome, http://www.reactome.org ReactomeREACT_12012 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 pL1:CK-II Reactome DB_ID: 392745 Reactome Database ID Release 43392745 Reactome, http://www.reactome.org ReactomeREACT_22634 has a Stoichiometric coefficient of 1 Caspase-mediated cleavage of Lamin B1 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Caspases initiate the destruction of the nucleus cleavage of lamins leads to  disassembly of the nuclear lamina. Lamin B is cleaved by active caspase 6 (Orth et al., 1996) (Rao et al., 1996). EC Number: 3.4.22 Edited: Matthews, L, 2008-04-13 23:06:00 Edited: Matthews, L, 2008-06-02 08:00:47 Pubmed8663580 Pubmed8978814 Reactome Database ID Release 43264871 Reactome, http://www.reactome.org ReactomeREACT_13484 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 pPAK1:Rac1-GTP Reactome DB_ID: 445001 Reactome Database ID Release 43445001 Reactome, http://www.reactome.org ReactomeREACT_23376 has a Stoichiometric coefficient of 1 OAS proteins Converted from EntitySet in Reactome Reactome DB_ID: 1015696 Reactome Database ID Release 431015696 Reactome, http://www.reactome.org ReactomeREACT_26755 Caspase-mediated cleavage of Lamin A Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Caspases initiate the destruction of the nucleus cleavage of lamins leads to <br>disassembly of the nuclear lamina. Lamin A is cleaved by active caspase 6 (Orth et al., 1996). EC Number: 3.4.22 Edited: Matthews, L, 2008-04-13 23:06:00 Edited: Matthews, L, 2008-06-02 07:41:19 Pubmed8655646 Pubmed8663580 Reactome Database ID Release 43264865 Reactome, http://www.reactome.org ReactomeREACT_13476 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of occludin Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 EC Number: 3.4.22 Edited: Matthews, L, 2008-06-02 07:49:06 Following iinduction of apoptosis in epithelial cells, tight junction are disrupted. Tight junction proteins, including the the transmembrane protein occludin and the cytoplasmic adaptor proteins ZO-1 and ZO-2 are fragmented by caspase cleavage (Bojarski et al., 2004). Pubmed15054114 Reactome Database ID Release 43351876 Reactome, http://www.reactome.org ReactomeREACT_13549 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of Z0-2 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Cleavage of the C-terminal cytoplasmic domain of occludin during apoptosis generates a fragment that can longer associate with the cytoplasmic adapter proteins ZO-1, -2 and -3 and, as a consequence, with the actin cytoskeleton (Bojarski et al., 2003) . Cleavage of ZO-1 and ZO-2 further disrupts tight junction structure and function . Notably, claudins, which are associated with ZO-1, ZO-2 and ZO-3, completely lose their linkage to the actin cytoskeleton and other ZO-1-, ZO-2-, ZO-3-interacting proteins.(Bojarski et al., 2003) . EC Number: 3.4.22 Edited: Matthews, L, 2008-05-20 07:53:59 Pubmed15054114 Reactome Database ID Release 43351871 Reactome, http://www.reactome.org ReactomeREACT_13813 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of Z0-1 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Cleavage of the C-terminal cytoplasmic domain of occludin during apoptosis generates a fragment that can longer associate with the cytoplasmic adapter proteins ZO-1, -2 and -3 and, as a consequence, with the actin cytoskeleton (Bojarski et al., 2003) . Cleavage of ZO-1 and ZO-2 further disrupts tight junction structure and function . Notably, claudins, which are associated with ZO-1, ZO-2 and ZO-3, completely lose their linkage to the actin cytoskeleton and other ZO-1-, ZO-2-, ZO-3-interacting proteins.(Bojarski et al., 2003) . EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-06-03 01:13:58 Pubmed15054114 Reactome Database ID Release 43351913 Reactome, http://www.reactome.org ReactomeREACT_13587 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of plakophilin-1 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Desmosomes represent one of the anchoring junctions mediating strong cell-cell contacts.Desmosomal plaque proteins including the head domain of plakophilin provide interaction sites for cytokeratin filaments (see references in Weiske et al.,2001). Proteolytic fragmentation of these proteins prevents binding of intermediate filaments and in consequence results in remodeling of the intermediate filament cytoskeleton (Weiske et al., 2001).Cleaved Plakophilin-1 appears to be is impaired in supporting the formation and maintenance of desmosomes during apoptosis (Weiske et al., 2001). EC Number: 3.4.22 Edited: Matthews, L, 2008-06-03 00:29:28 Pubmed11500511 Reactome Database ID Release 43201595 Reactome, http://www.reactome.org ReactomeREACT_13418 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Caspase-mediated cleavage of Desmoplakin Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Cleavage of desmosomal proteins including desmoplakin contributes to cell rounding and disintegration of the intermediate filament system (Weiske et al., 2001). EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-05-18 16:53:19 Pubmed11500511 Reactome Database ID Release 43201636 Reactome, http://www.reactome.org ReactomeREACT_13605 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 L1:CNTN1 Reactome DB_ID: 443653 Reactome Database ID Release 43443653 Reactome, http://www.reactome.org ReactomeREACT_23027 has a Stoichiometric coefficient of 1 L1:ALCAM Reactome DB_ID: 443658 Reactome Database ID Release 43443658 Reactome, http://www.reactome.org ReactomeREACT_23036 has a Stoichiometric coefficient of 1 L1:RanBPM Reactome DB_ID: 374585 Reactome Database ID Release 43374585 Reactome, http://www.reactome.org ReactomeREACT_23100 has a Stoichiometric coefficient of 1 L1:Neurocan Reactome DB_ID: 443646 Reactome Database ID Release 43443646 Reactome, http://www.reactome.org ReactomeREACT_23328 has a Stoichiometric coefficient of 1 L1:HNK-1 Reactome DB_ID: 443641 Reactome Database ID Release 43443641 Reactome, http://www.reactome.org ReactomeREACT_23380 has a Stoichiometric coefficient of 1 L1:Laminin Reactome DB_ID: 443666 Reactome Database ID Release 43443666 Reactome, http://www.reactome.org ReactomeREACT_23226 has a Stoichiometric coefficient of 1 L1:Axonin-1 Reactome DB_ID: 374577 Reactome Database ID Release 43374577 Reactome, http://www.reactome.org ReactomeREACT_23324 has a Stoichiometric coefficient of 1 Caspase-mediated cleavage of MST3 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Caspase-mediated cleavage of Mst3 activates its intrinsic kinase activity. Proteolytic removal of the COOH-terminal domain promotes nuclear translocation of its kinase domain. Ectopic expression of COOH-terminal truncated Mst3 results in DNA fragmentation and morphological changes characteristic of apoptosis (Huang et al., 2002). EC Number: 3.4.22 Edited: Matthews, L, 2008-05-27 07:43:39 Pubmed12107159 Reactome Database ID Release 43351901 Reactome, http://www.reactome.org ReactomeREACT_13468 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 CHL1:Hsc70 Reactome DB_ID: 445018 Reactome Database ID Release 43445018 Reactome, http://www.reactome.org ReactomeREACT_22887 has a Stoichiometric coefficient of 1 Caspase-mediated cleavage of MASK Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 EC Number: 3.4.22 Edited: Matthews, L, 2008-05-27 07:43:39 MASK is cleaved in vitro by caspase 3 . C-terminally truncated forms of MASK can both induce apoptosis upon overexpression in mammalian cells (Dan et al., 2002). Pubmed11741893 Reactome Database ID Release 43350651 Reactome, http://www.reactome.org ReactomeREACT_13636 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 CHL1:Ankyrin-G Reactome DB_ID: 447021 Reactome Database ID Release 43447021 Reactome, http://www.reactome.org ReactomeREACT_23311 has a Stoichiometric coefficient of 1 Tyr phos L1:EPHB2 Reactome DB_ID: 443816 Reactome Database ID Release 43443816 Reactome, http://www.reactome.org ReactomeREACT_23011 has a Stoichiometric coefficient of 1 Caspase-mediated cleavage of claspin Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Claspin is cleaved by caspase-7 during the initiation of apoptosis following DNA damage (Clarke et al., 2005). Claspin is cleaved at a single aspartate residue into a large N-terminal fragment and a smaller C-terminal fragment that contain different functional domains. Only the large N-terminal fragment retains Chk1 binding activity. The smaller C-terminal fragment associates with DNA and inhibits the DNA-dependent phosphorylation of Chk1 associated with its activation indicating that cleavage of Claspin by caspase-7 inactivates the Chk1 signaling pathway (Clarke et al., 2005). EC Number: 3.4.22 Edited: Matthews, L, 2008-06-02 08:00:47 Pubmed16123041 Reactome Database ID Release 43351936 Reactome, http://www.reactome.org ReactomeREACT_13652 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 L1:HSA Reactome DB_ID: 443648 Reactome Database ID Release 43443648 Reactome, http://www.reactome.org ReactomeREACT_22674 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 5 Caspase-mediated cleavage of farnesyltransferase/geranyl- geranyltransferase subunit alpha Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2007-10-09 13:44:38 Edited: Matthews, L, 2007-11-11 23:40:56 Farnesyltransferase/geranyl-geranyltransferase catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. This enzyme complex consists of a heterodimer of an alpha and a beta subunit. The alpha subunit is thought to function in the formation of a stable complex with the substrate. This alpha subnit is cleaved by caspase 3. Expression of the cleavage product (60-379) induces cell death (Kim et al., 2001). Pubmed11313965 Reactome Database ID Release 43201640 Reactome, http://www.reactome.org ReactomeREACT_12014 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 Recruited STAT5 is phosphorylated Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 Pubmed10851055 Pubmed12407017 Pubmed7568001 Pubmed8631883 Reactome Database ID Release 43452097 Reactome, http://www.reactome.org ReactomeREACT_27154 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 STAT5 alpha and beta are recruited to the receptor complex and phosphorylated. JAK3 is believed to be responsible for the tyrosine phosphorylation of STAT5 in response to IL-2; it is not clear whether JAK1 is also involved (Lin & Leonard, 2000). Tyr-694 of STAT5a and Tyr-699 of STAT5b are required for IL-2 induced STAT5 activation (Lin et al. 1996). STAT5a and STAT5b are also known to be serine phophorylated in lymphocytes activated by IL-2 but the funtion of this is unclear (Xue et al. 2002). CDK5:CABLES:ABL Reactome DB_ID: 1013836 Reactome Database ID Release 431013836 Reactome, http://www.reactome.org ReactomeREACT_26864 has a Stoichiometric coefficient of 1 Caspase-mediated cleavage of Rock-1 Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing (Sebbagh et al., 2001). Cleavage and activation of ROCK-1 by caspase-3 plays has also been shown to play a crucial role in in cardiac myocyte apoptosis (Chang et al., 2006). EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-02-08 00:35:06 Pubmed11283607 Pubmed16983089 Reactome Database ID Release 43201611 Reactome, http://www.reactome.org ReactomeREACT_12531 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 The SHC1:SHIP1 complex is stabilized by GRB2 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Grb2 stabilizes the Shc/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on Shc. This forms a ternary complex of SHC1:GRB2:SHIP described as an outcome of IL-3, IL-5 or GM-CSF stimulation (Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999). Pubmed10194451 Pubmed10207047 Pubmed7898932 Pubmed9108392 Reactome Database ID Release 43913424 Reactome, http://www.reactome.org ReactomeREACT_23911 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 has a Stoichiometric coefficient of 4 CDK2:CABLES1:Wee-1 Reactome DB_ID: 1013858 Reactome Database ID Release 431013858 Reactome, http://www.reactome.org ReactomeREACT_25979 has a Stoichiometric coefficient of 1 Mx GTPases Converted from EntitySet in Reactome Reactome DB_ID: 1015693 Reactome Database ID Release 431015693 Reactome, http://www.reactome.org ReactomeREACT_25553 Caspase-mediated cleavage of Etk Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Cleavage of Etk by caspase-3 stimulates its kinase activity. Overexpression of the fragment induces apoptosis (Wu et al.,2001). EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Edited: Matthews, L, 2008-06-02 08:04:50 Pubmed11278797 Reactome Database ID Release 43351849 Reactome, http://www.reactome.org ReactomeREACT_13417 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Kinesin-1 Reactome DB_ID: 983227 Reactome Database ID Release 43983227 Reactome, http://www.reactome.org ReactomeREACT_26141 has a Stoichiometric coefficient of 2 Caspase mediated cleavage of BAP31 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Caspase-8 mediated cleavage of BAP31 at the ER produces a pro-apoptotic p20 fragment that remains at the ER (Breckenridgeet al., 2003). Cleavage stimulates Ca2+-dependent mitochondrial fission, enhancing the release of cytochrome C (Breckenridgeet al., 2003). EC Number: 3.4.22 Edited: Matthews, L, 2008-06-02 07:41:19 Pubmed12668660 Reactome Database ID Release 43351894 Reactome, http://www.reactome.org ReactomeREACT_13554 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Kinesin-2 Reactome DB_ID: 984619 Reactome Database ID Release 43984619 Reactome, http://www.reactome.org ReactomeREACT_26940 has a Stoichiometric coefficient of 1 Caspase 3-mediated cleavage of PKC delta Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 Caspase mediated cleavage produces a constitutively active kinase that induces apoptosis (Ghayur et al.,1996). EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Pubmed8976194 Reactome Database ID Release 43212552 Reactome, http://www.reactome.org ReactomeREACT_12471 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 NF-E2:Promoter region of beta-globin Reactome DB_ID: 1008206 Reactome Database ID Release 431008206 Reactome, http://www.reactome.org ReactomeREACT_27022 has a Stoichiometric coefficient of 1 C-terminal EH domain containing proteins:Rabenosyn-5 Reactome DB_ID: 1011577 Reactome Database ID Release 431011577 Reactome, http://www.reactome.org ReactomeREACT_26657 has a Stoichiometric coefficient of 1 Caspase-mediated cleavage of Acinus Acinus induces apoptotic chromatin condensation after cleavage and activation by CASP3 (Sahara et al., 1999). Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Pubmed10490026 Reactome Database ID Release 43201630 Reactome, http://www.reactome.org ReactomeREACT_12450 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 Rabenosyn-5:VPS-45 Reactome DB_ID: 1011605 Reactome Database ID Release 431011605 Reactome, http://www.reactome.org ReactomeREACT_26968 has a Stoichiometric coefficient of 1 Caspase-mediated cleavage of PKC theta Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 Cleavage of PKCtheta by Caspase-3 induces nuclear fragmentation and lethality (Datta et al., 1997) EC Number: 3.4.22 Edited: Matthews, L, 2007-09-03 07:38:20 Pubmed9252332 Pubmed9431985 Reactome Database ID Release 43201603 Reactome, http://www.reactome.org ReactomeREACT_12638 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 DOCK-GEFs:RAC1, CDC42 Reactome DB_ID: 1012969 Reactome Database ID Release 431012969 Reactome, http://www.reactome.org ReactomeREACT_25414 has a Stoichiometric coefficient of 1 SH2B family:p(Y813)-JAK2 Reactome DB_ID: 997243 Reactome Database ID Release 43997243 Reactome, http://www.reactome.org ReactomeREACT_26825 has a Stoichiometric coefficient of 1 NF-E2 Reactome DB_ID: 1008229 Reactome Database ID Release 431008229 Reactome, http://www.reactome.org ReactomeREACT_26613 has a Stoichiometric coefficient of 1 STAT5 dimers translocate to the nucleus and bind to specific DNA sequences Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10594041 Pubmed15601831 Pubmed16231422 Pubmed16469768 Pubmed21084450 Pubmed8896456 Reactome Database ID Release 43507937 Reactome, http://www.reactome.org ReactomeREACT_23774 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Reviewed: Waters, MJ, 2011-06-23 STAT5A and STAT5B dimers bind to similar core gamma-interferon activated sequence (GAS) motifs (Soldaini et al., 2000). STAT5a/b also form homo- and hetero-tetramers with distinct or expanded DNA-binding properties. Genes that are regulated by STAT5 include IL2RA (John et al. 1996), TNFSF11 (RANKL), Connexin-26 (GJB2) and Cyclin D1 (Hennighausen & Robinson, 2005). A comprehensive listing of hepatic STAT5b regulated genes is available from microarray/STAT5b knockout mice (Clodfelter et al. 2006), and similarly for STAT5-dependent genes regulated by the GH receptor (Rowland et al. 2005, Barclay et al. 2011). Syk binds IL2RB Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed7600304 Reactome Database ID Release 43508292 Reactome, http://www.reactome.org ReactomeREACT_27313 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Syk binds to the serine-rich (aa 267 to 322) S region of IL2RB and becomes activated upon IL-2 stimulation (Minami et al. 1995).<br>Syk is shown here binding with the IL2:IL2RB trimer:p-JAK1:JAK3 complex but it may become associated at an earlier stage of receptor activation. Phosphorylated STAT5 is released Authored: Ray, KP, 2010-05-17 Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believe to occur following the release of phosphorylated monomers (e.g. Turkson & Jove 2000). Edited: Jupe, S, 2010-08-06 Pubmed11426647 Pubmed9030599 Reactome Database ID Release 43919404 Reactome, http://www.reactome.org ReactomeREACT_27314 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Neurofascin:Ankyrin-G complex Reactome DB_ID: 373676 Reactome Database ID Release 43373676 Reactome, http://www.reactome.org ReactomeREACT_22462 has a Stoichiometric coefficient of 1 Phosphorylated STAT5a/b form dimers Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10485657 Pubmed10851055 Pubmed17934481 Pubmed7796299 Pubmed8702919 Pubmed9398404 Pubmed9528750 Pubmed9630227 Reactome Database ID Release 43452102 Reactome, http://www.reactome.org ReactomeREACT_23827 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 The STAT5a and STAT5b forms are encoded by 2 closely-related genes. They are thought to be present largely as monomers in unstimulated cells but rapidly form homo- and hetero-dimers upon stimulation (Cella et al. 1998). Tyrosine phosphorylation of STAT monomers allows dimers to form through reciprocal phosphotyrosine-SH2 interactions. The dimers translocate to the nucleus and bind to STAT-specific DNA-response elements of target genes to induce gene transcription (Baker et al.2007). STAT5a/b homo- and hetero-tetramers have also been shown to occur downstream of IL-2 and may have a distinct or expanded target repertoire from STAT5a/b dimers. Although STAT5a and STAT5b are highly homologous at the DNA and protein levels, each has unique funcions, as demonstrated by studies comparing mice lacking one isoform or the other. However, it is also known that STAT5a and STAT5b share a number of functions and that the phenotype of mice lacking both STAT5a and STAT5b is more severe than those lacking either one individually, which suggest that there may be some redundancy or that they cooperate in order to achieve the full spectrum of STAT5-dependent activities (Moriggl et al. 1999, Teglund et al. 1998). has a Stoichiometric coefficient of 3 Trans neurofascin dimer:ankyrin-G Reactome DB_ID: 443672 Reactome Database ID Release 43443672 Reactome, http://www.reactome.org ReactomeREACT_22613 has a Stoichiometric coefficient of 1 Pyk2 is activated following IL2 stimulation Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed15888917 Pubmed19207108 Pubmed9512511 Reactome Database ID Release 43508451 Reactome, http://www.reactome.org ReactomeREACT_27136 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 The proline rich tyrosine kinase 2 (PYK2) is a nonreceptor protein tyrosine kinase that is structurally related to FAK and thought to be important for leukocyte activation (Ostergaard & Lysechko, 2005). PYK2 tyrosine phosphorlation is known to occur downstream of IL-2 stimulation in human peripheral T lymphocytes. This phosphorylation can be prevented by blocking IL-2 mediated JAK activity. Although the function of Pyk2 within the IL-2 signaling pathways remains uncertain, a dominant negative mutant of Pyk2 inhibited IL-2-induced cell proliferation without affecting Stat5 activation which suggests that Pyk2 does indeed influence IL-2 driven immune cell responses. CHL1:alpha1beta1/alpha2beta1 integrins Reactome DB_ID: 445009 Reactome Database ID Release 43445009 Reactome, http://www.reactome.org ReactomeREACT_22459 has a Stoichiometric coefficient of 1 The common beta chain IL3RB binds JAK2 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 JAK2 associates with IL3 reecptor beta chain (IL3RB) better known as the cytokine recetpor common beta chain (Bc). This association was not found to be dependent upon, or influenced by, the presence of GM-CSF or the GM-CSF receptor alpha chain, suggesting that JAK2 and Bc may be constitutively associated (Quelle et al. 1994). Pubmed8007942 Reactome Database ID Release 43879937 Reactome, http://www.reactome.org ReactomeREACT_23962 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 CHL1:CNTN6 Reactome DB_ID: 443670 Reactome Database ID Release 43443670 Reactome, http://www.reactome.org ReactomeREACT_23145 has a Stoichiometric coefficient of 1 SYK is a substrate for JAK1 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 Pubmed10825200 Reactome Database ID Release 43508282 Reactome, http://www.reactome.org ReactomeREACT_27233 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Studies have shown that coexpression of Syk with catalytically active Jak1 results in Syk phosphorylation whereas coexpression of Syk with catalytically active Jak3 does not, suggesting that IL-2 driven phosphorylation of Syk is driven by Jak1 (Zhou et al. 2000). CHL1:NP-1 Reactome DB_ID: 445017 Reactome Database ID Release 43445017 Reactome, http://www.reactome.org ReactomeREACT_22777 has a Stoichiometric coefficient of 1 Pyk2 associates with Jak3 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed15888917 Pubmed9512511 Reactome Database ID Release 43508513 Reactome, http://www.reactome.org ReactomeREACT_27192 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 The proline-rich tyrosine kinase 2 (PYK2) is a nonreceptor protein tyrosine kinase that is structurally related to FAK and thought to be important for leukocyte activation (Ostergaard & Lysechko 2005).<br>Coimmunoprecipitation experiments have demonstrated a physical association of Jak3 and Pyk2. A dominant interfering mutant of Pyk2 inhibited IL-2-induced cell proliferation without affecting Stat5 activation. Collectively, these results suggest that Pyk2 is a component of the Jak-mediated IL-2 signaling pathway, but a role has not been firmly established. Integrins alpha1beta1, alpha2beta1 Converted from EntitySet in Reactome Reactome DB_ID: 444996 Reactome Database ID Release 43444996 Reactome, http://www.reactome.org ReactomeREACT_22630 p-Y172-VAV2/p-Y173-VAV3 Converted from EntitySet in Reactome Reactome DB_ID: 2424465 Reactome Database ID Release 432424465 Reactome, http://www.reactome.org ReactomeREACT_147969 Cleaved fragments of DFF45 dissociate from DFF40 Authored: Matthews, L, 2008-01-29 12:03:24 Edited: Matthews, L, 2008-05-02 11:33:14 Following caspase-3 cleavage, the fragments of DFF45 dissociate from DFF40, the active component of DFF (Liu et al. 1998). Pubmed9108473 Reactome Database ID Release 43211207 Reactome, http://www.reactome.org ReactomeREACT_13689 Reviewed: Widlak, P, 2008-05-07 23:54:18 has a Stoichiometric coefficient of 2 GM-CSF receptor alpha subunit binds GM-CSF Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed2555171 Pubmed9211889 Reactome Database ID Release 43913360 Reactome, http://www.reactome.org ReactomeREACT_23919 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The GM-CSF receptor alpha subunit has a single transmembrane domain, a glycosylated extracellular domain and a short (54 amino acids) cytoplasmic tail, containing no tyrosine kinase domain (Gearing et al. 1989). It binds GM-CSF with a relatively low affinity, and is not capable of signaling. The cytoplasmic domain of the alpha chain appears to be critical for GM-CSF signaling (Matsuguchi et al. 1997). Kinesin-5 homotetramer Reactome DB_ID: 984691 Reactome Database ID Release 43984691 Reactome, http://www.reactome.org ReactomeREACT_26711 has a Stoichiometric coefficient of 4 Cleavage of DFF45 (224) by caspase-3 Authored: Matthews, L, 2008-01-29 12:03:24 Caspase-3 cleaves DFF45 between residues 224,225. EC Number: 3.4.22 Edited: Matthews, L, 2008-01-27 14:01:04 Edited: Matthews, L, 2008-05-02 11:33:14 Pubmed9108473 Reactome Database ID Release 43211186 Reactome, http://www.reactome.org ReactomeREACT_12404 Reviewed: Widlak, P, 2008-05-07 23:54:18 Caspase 3-mediated cleavage of DFF45 (117) Authored: Matthews, L, 2008-01-29 12:03:24 Caspase-3 cleaves the DFF45 subunit of the DFF45:DFF40 complex at two sites to generate an active DNA fragmentation factor. One site of cleavage is between residues 117,118 (Liu et al., 1997) . EC Number: 3.4.22 Edited: Matthews, L, 2008-02-12 15:38:34 Edited: Matthews, L, 2008-05-02 11:33:14 Pubmed9108473 Pubmed9422506 Reactome Database ID Release 43211190 Reactome, http://www.reactome.org ReactomeREACT_12544 Reviewed: Widlak, P, 2008-05-07 23:54:18 Interleukin-5 is a homodimer Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Human IL-5 is a disulphide-linked homodimer with 115 amino-acid residues in each chain. Pubmed8483502 Reactome Database ID Release 43913446 Reactome, http://www.reactome.org ReactomeREACT_23864 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 has a Stoichiometric coefficient of 2 NFASC:pNFASC Reactome DB_ID: 445011 Reactome Database ID Release 43445011 Reactome, http://www.reactome.org ReactomeREACT_22522 has a Stoichiometric coefficient of 1 KIF4A homodimer Reactome DB_ID: 984684 Reactome Database ID Release 43984684 Reactome, http://www.reactome.org ReactomeREACT_26882 has a Stoichiometric coefficient of 2 Translocation of caspase-3 to the nucleus Active caspase-3 is translocated from the cytoplasm to the nucleus during progression through apoptosis (Kamada et al., 2005). Authored: Matthews, L, 2008-01-29 18:57:00 Edited: Matthews, L, 2008-01-27 14:01:04 Edited: Matthews, L, 2008-06-02 08:00:47 Pubmed15569692 Reactome Database ID Release 43211219 Reactome, http://www.reactome.org ReactomeREACT_13508 Reviewed: Widlak, P, 2008-05-07 23:54:18 GM-CSF receptor alpha:GM-CSF binds Bc Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed1702217 Pubmed1833064 Pubmed18692472 Pubmed19436055 Reactome Database ID Release 43913371 Reactome, http://www.reactome.org ReactomeREACT_23875 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The alpha subunit of the GM-CSF receptor binds GM-CSF with relatively low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of GM-CSF with the alpha chain to form a binary complex. This binary complex is then able to bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008). KIF4B homodimer Reactome DB_ID: 984621 Reactome Database ID Release 43984621 Reactome, http://www.reactome.org ReactomeREACT_26801 has a Stoichiometric coefficient of 2 Neurofascin:Syntenin-1 complex Reactome DB_ID: 373693 Reactome Database ID Release 43373693 Reactome, http://www.reactome.org ReactomeREACT_23202 has a Stoichiometric coefficient of 1 pNFASC:Doublecortin Reactome DB_ID: 443664 Reactome Database ID Release 43443664 Reactome, http://www.reactome.org ReactomeREACT_23013 has a Stoichiometric coefficient of 1 VAV2/VAV3 Converted from EntitySet in Reactome Reactome DB_ID: 2424458 Reactome Database ID Release 432424458 Reactome, http://www.reactome.org ReactomeREACT_148397 Association of DFF40 with chromatin Authored: Matthews, L, 2008-01-29 12:03:24 Direct interactions between the histone H1 C-terminal domain and DFF40/CAD possibly target the nuclease to chromatin linker DNA promoting the linker DNA cleavage during the terminal stages of apoptosis (Widlak et al., 2005). Noteworthy, it has been reported that DFF40/DFF45 complexes could also associate with chromatin and be activated with caspase-3 in DNA-bound state (Korn et al., 2005). Edited: Matthews, L, 2008-01-29 12:04:16 Edited: Matthews, L, 2008-05-02 11:31:29 Pubmed10318789 Pubmed15572351 Pubmed15910001 Reactome Database ID Release 43211239 Reactome, http://www.reactome.org ReactomeREACT_13514 Reviewed: Widlak, P, 2008-05-07 23:54:18 Neurofascin:CNTN1:CASPR complex Reactome DB_ID: 373682 Reactome Database ID Release 43373682 Reactome, http://www.reactome.org ReactomeREACT_22948 has a Stoichiometric coefficient of 1 Homodimerization of DFF40 Authored: Matthews, L, 2008-01-29 12:03:24 Edited: Matthews, L, 2008-05-02 11:33:14 Following its release from DFF45, DFF40 forms homodimers, which are the basic structures of the enzymatically active nuclease (Woo et al., 2004). Following dimerization, DFF40 can further oligomerize forming units containing at least 4 monomers (Liu et al., 1999; Widlak et al., 2003). Pubmed10318789 Pubmed12748178 Pubmed15149602 Reactome Database ID Release 43211193 Reactome, http://www.reactome.org ReactomeREACT_13708 Reviewed: Widlak, P, 2008-05-07 23:54:18 has a Stoichiometric coefficient of 2 Contactin1:CASPR complex Reactome DB_ID: 373655 Reactome Database ID Release 43373655 Reactome, http://www.reactome.org ReactomeREACT_23146 has a Stoichiometric coefficient of 1 KIF3A dimer Reactome DB_ID: 984646 Reactome Database ID Release 43984646 Reactome, http://www.reactome.org ReactomeREACT_25964 has a Stoichiometric coefficient of 2 KIF3B dimer Reactome DB_ID: 984756 Reactome Database ID Release 43984756 Reactome, http://www.reactome.org ReactomeREACT_26887 has a Stoichiometric coefficient of 2 Kinesin-3 dimers Converted from EntitySet in Reactome Reactome DB_ID: 984608 Reactome Database ID Release 43984608 Reactome, http://www.reactome.org ReactomeREACT_26306 Translocation of DFF to the nucleus Authored: Matthews, L, 2008-01-29 12:03:24 DFF associated with alpha-importin:beta-importin is translocated to the nucleus (Neimanis et al., 2007) Edited: Matthews, L, 2008-05-08 00:39:36 Pubmed17938174 Reactome Database ID Release 43211206 Reactome, http://www.reactome.org ReactomeREACT_13544 Reviewed: Widlak, P, 2008-05-07 23:54:18 Kinesin-10 KIF22 homodimer Reactome DB_ID: 984651 Reactome Database ID Release 43984651 Reactome, http://www.reactome.org ReactomeREACT_26993 has a Stoichiometric coefficient of 2 Association of DFF with alpha:beta importin Authored: Matthews, L, 2008-01-29 12:03:24 Edited: Matthews, L, 2008-05-02 11:33:14 Pubmed17938174 Reactome Database ID Release 43211191 Reactome, http://www.reactome.org ReactomeREACT_13756 Reviewed: Widlak, P, 2008-05-07 23:54:18 The translocation of the DFF complex from the cytoplasm to the nucleus is mediated by the importin alfa/beta heterodimer. Both DFF40 and DFF45 possess NLS at their C-termini that interact directly with the importin alfa/beta heterodimer. However, DFF complex binds more tightly compared with the individual subunits and C-termini of both subunits are required for DFF nuclear import (Neimanis et al., 2007). Kinesin-4 homodimers Converted from EntitySet in Reactome Reactome DB_ID: 984704 Reactome Database ID Release 43984704 Reactome, http://www.reactome.org ReactomeREACT_25427 Association of DFF40 with DFF45 Authored: Matthews, L, 2008-01-29 12:03:24 DNA Fragmentation Factor (DFF), is a heterodimer of 40 kDa (DFF40) and 45 kDa (DFF45) subunits (Liu et al., 1997). DFF45 (ICAD) appears to act as a chaperone for DFF40 (CAD) during its synthesis, remaining complexed with it to inhibit its DNase activity (Enari et al., 1998). The complex could exist as: a DFF40:DFF45 heterodimer, a (DFF40:DFF45)2 heterotetramer or a (DFF40:DFF40:DFF45:DFF45) heterotetramer (Lechardeur et al., 2005). Edited: Matthews, L, 2008-01-27 14:01:04 Edited: Matthews, L, 2008-05-02 11:33:14 Pubmed16204257 Pubmed9108473 Pubmed9422506 Reactome Database ID Release 43211224 Reactome, http://www.reactome.org ReactomeREACT_13679 Reviewed: Widlak, P, 2008-05-07 23:54:18 has a Stoichiometric coefficient of 2 KIF5B dimer Reactome DB_ID: 984749 Reactome Database ID Release 43984749 Reactome, http://www.reactome.org ReactomeREACT_25845 has a Stoichiometric coefficient of 2 Cleavage of Satb1 Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Cleaved Satb1 dissociates from chromatin and may function in high molecular weight DNA fragmentation (Galande et al., 2001). EC Number: 3.4.22 Edited: Matthews, L, 2008-04-13 23:06:00 Edited: Matthews, L, 2008-06-02 08:04:50 Pubmed11463840 Reactome Database ID Release 43352268 Reactome, http://www.reactome.org ReactomeREACT_22225 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 KIF5C dimer Reactome DB_ID: 984596 Reactome Database ID Release 43984596 Reactome, http://www.reactome.org ReactomeREACT_25911 has a Stoichiometric coefficient of 2 The receptor is activated Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed1396555 Pubmed1400495 Pubmed18692472 Pubmed2681215 Pubmed7567993 Pubmed7612228 Pubmed8007942 Pubmed8223433 Pubmed8647804 Pubmed8649415 Pubmed9057626 Pubmed9422786 Pubmed9766809 Reactome Database ID Release 43879942 Reactome, http://www.reactome.org ReactomeREACT_23912 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 Upon ligand binding to the alpha subunit, the alpha and Bc subunits asociate, forming a high affinity receptor. Subsequent signaling may require a disulfide-linked association between the alpha and beta chains (Stomski et al. 1996). While the formation of a 1:1:1 complex of interleukin:alpha subunit:common beta subunit represents a high-affinity binding complex, receptor activation involves the formation of higher order multimeric structures. The stoichiometry of endogenous active receptor complexes is not clear, but studies using dominant-negative, chimeric, and mutant receptors and modeling studies all suggest that a minimum of two Bc subunits are required for receptor activation and signaling (Guthridge et al. 1998, Hansen et al. 2008).<br><br> The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One such site is Y766, numbered according to the Uniprot canonical sequence. Note that in many publications this position is numbered as 750, referring to the mature sequence with signal peptide removed. These phosphorylations are mediated by receptor-associated kinases with JAK2 as the most likely candidate (Quelle et al. 1994, Guthridge et al. 1998). Specific phosphorylations appear to mediate association with different signaling components (Sato et al. 1993), e.g. substitution of F for Y766 prevents Shc phosphorylation (Inhorn et al. 1995) but not JAK2 phosphorylation. Modeling and structural data suggest that the active receptor is at least a dimer of ligand:alpha subunit:common beta subunit complexes (Bagley et al. 1997, Guthridge et al. 1998, Hansen et al. 2008). This fits a model of receptor activation whereby dimerization leads to Jak2 activation by transphosphorylation of the activation sites (Ihle et al. 1995, Guthridge et al. 1998, Hansen et al. 2008), leading to Bc activation by phosphorylation. The active receptors are represented here as dimers of ligand:alpha subunit:common beta subunit complexes. has a Stoichiometric coefficient of 2 NrCAM:Ankyrin-G Reactome DB_ID: 447023 Reactome Database ID Release 43447023 Reactome, http://www.reactome.org ReactomeREACT_23219 has a Stoichiometric coefficient of 1 JAK2 is phosphorylated, activated Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10.2 Edited: Jupe, S, 2010-08-06 JAK2 is tyrosine phosphorylated in response to IL-3 (Silvennoinen et al. 1993), GM-CSF (Quelle et al. 1994) and IL-5 (Cornelis et al. 1995) leading to kinase activity. Although structures of JAK kinase domains exist (e.g. Lucet et al. 2006) no complete structures of Janus kinases (JAKs) are available and the activation mechanism is poorly understood. Activation is believed to be a consequence of conformational changes, propagated from conformational changes in the common beta chain (Bc) following alpha-beta dimerization. This is believed to result in a trans-activation event whereby JAKs bound to activated, dimerized receptors phosphorylate and thereby activate each other (Quelle et al. 1994, Hou et al. 2002). This model is similar to IL2R activation of JAK1/3. In addition to the observed activation of JAK2 following stimulation with IL-3, IL-5 or GM-CSF, other supporting observations include: phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006) and autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the critical Y1007 phosphorylation is represented for this reaction.<br><br>Constitutive activation of JAK2 resulting from the V617F mutation is present in over 95% of Polycythemia Vera patients (Dusa et al. 2010). F595 is indispensible for constitutive activation by V617F, but not for JAK2 activation, suggesting that this is not part of the cytokine-induced mechansim of JAK2 activation. Pubmed12479803 Pubmed15143187 Pubmed15143188 Pubmed16174768 Pubmed20304997 Pubmed20585391 Pubmed7542592 Pubmed8007942 Pubmed8378315 Pubmed9111318 Reactome Database ID Release 43879910 Reactome, http://www.reactome.org ReactomeREACT_23935 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 has a Stoichiometric coefficient of 6 NrCAM:Axonin-1 Reactome DB_ID: 445006 Reactome Database ID Release 43445006 Reactome, http://www.reactome.org ReactomeREACT_23383 has a Stoichiometric coefficient of 1 STAT5 is recruited by JAK2 Activated JAK2 binds to unphosphorylated STAT5; cytokine treatment of cells leads to JAK2 activation and promotes binding of JAK2 to unphosphorylated STAT5.<br><br><br>STAT5 proteins are considered the main targets of IL-3, IL-5 and GM-CSF signaling (Mui et al. 1995a, Mui et al. 1995b, Ihle, 2001), but other members of this family including STAT3 and STAT1 (Chin et al. 1996) can be involved, the STAT family member activated appears to depend on the cell line used in the study, rather than the cytokine (Reddy et al. 2000). IL-5 and GM-CSF increase STAT3 and 5 signaling (Caldenhoven et al. 1995, Stout et al. 2004). <br><br><br>Unphosphorylated STATs are cytoplasmic; tyrosine phosphorylation facilitates dimerization and translocation to the nucleus where they act as transcription factors. STATs were originally described as ligand-induced transcription factors in interferon-treated cells, subsequently they were shown to be critical in many signal transduction pathways associated with cytokines and neurokines including several interleukins, the interferons, erythropoietin, prolactin, growth hormone, oncostatin M (OSM), and ciliary neurotrophic factor (Darnell 1997, Reddy et al. 2000). JAK-STAT signaling is widely accepted as a primary signaling route for receptors that share the common beta subunit (Bc). <br>The role of the receptor itself in STAT5 binding is somewhat controversial because while STAT proteins can be recruited to tyrosine phosphorylated receptors via their SH2 domains (Greenlund et al. 1995, Li et al. 1997) binding of STAT5 to Bc has not been formally demonstrated (Guthridge et al. 1998), though tyrosine-phosphorylated peptides of Bc have been demonstrated to associate with STAT5, and anti-Bc or phosphotyrosine antibodies inhibited GM-CSF induced STAT5 DNA binding activity (Sakurai et al. 2000). Binding of JAK2 to STAT5 can occur in vitro when no receptor is present (Flores-Morales et al. 1998). STAT5 activation was seen when all six conserved cytoplasmic tyrosines in Bc were mutated to P (Okuda et al. 1997), but a C-terminal deletion mutant of Bc while able to activate JAK2 was unable to activate STAT5 (Smith et al. 1997). These observations suggest that JAK2 activation is a critical step in STAT signaling from Bc-containing receptors, but other factors may be required. It is not clear whether Bc is directly involved or not in STAT5 activation, but the specificity for particular STAT members is believed to be determined by STAT docking sites present on the receptor molecules, not JAK kinase preference (Reddy et al. 2000). Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10851052 Pubmed11122381 Pubmed11458499 Pubmed15528381 Pubmed7539031 Pubmed7592760 Pubmed7720707 Pubmed7796299 Pubmed8614832 Pubmed9034328 Pubmed9121453 Pubmed9287210 Pubmed9389692 Pubmed9630227 Pubmed9685210 Pubmed9766809 Reactome Database ID Release 43879930 Reactome, http://www.reactome.org ReactomeREACT_23884 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 has a Stoichiometric coefficient of 3 NrCAM:SAP members Reactome DB_ID: 376023 Reactome Database ID Release 43376023 Reactome, http://www.reactome.org ReactomeREACT_23321 has a Stoichiometric coefficient of 1 NrCAM:NP-2 Reactome DB_ID: 549047 Reactome Database ID Release 43549047 Reactome, http://www.reactome.org ReactomeREACT_22473 has a Stoichiometric coefficient of 1 Interleukin-5 receptor alpha subunit binds Interleukin-5 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed1833065 Pubmed8496674 Pubmed9516124 Reactome Database ID Release 43913456 Reactome, http://www.reactome.org ReactomeREACT_23969 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The Interleukin-5 receptor alpha subunit (IL5Ra) has a single transmembrane domain, a glycosylated extracellular domain and a short (58 amino acids) cytoplasmic tail, containing no tyrosine kinase domain. It binds IL-5 with a relatively low affinity and is not capable of signaling by itself. The alpha subunit has alternatively spliced soluble forms that are capable of binding IL-5 and act as natural antagonists of IL-5 signaling. The cytoplasmic domain of the alpha chain appears to be critical for IL-5 signaling (Takaki et al. 1993). IL5R alpha chain was found to be constitutively associated with JAK2 (Ogata et al. 1998); the same study found that JAK1 was constitutively associated with Bc, though the consensus is that JAK2 is associated with Bc. CDO:BOC Reactome DB_ID: 375094 Reactome Database ID Release 43375094 Reactome, http://www.reactome.org ReactomeREACT_21552 has a Stoichiometric coefficient of 1 Interleukin-5:Interleukin-5 receptor alpha binds IL3RB:JAK2 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed1833065 Pubmed18692472 Pubmed2065657 Reactome Database ID Release 43913370 Reactome, http://www.reactome.org ReactomeREACT_23992 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The alpha subunit of the IL5 receptor binds IL-5 with relatively low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of ligand with the alpha chain to form a binary complex. This binary complex may bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008). Interleukin-3 receptor alpha subunit binds Interleukin-3 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed1833064 Reactome Database ID Release 43450074 Reactome, http://www.reactome.org ReactomeREACT_23939 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The Interleukin-3 receptor alpha subunit (IL3Ra) has a single transmembrane domain, a glycosylated extracellular domain and a short (53 amino acids) cytoplasmic tail, containing no tyrosine kinase domain (Kitamura et al. 1991). It binds interleukin-3 with low affinity, and is not capable of signaling by itself. Interleukin-3 receptor alpha: Interleukin-3 binds IL3RB:JAK2 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10477686 Pubmed1833064 Pubmed18692472 Pubmed8649415 Reactome Database ID Release 43450031 Reactome, http://www.reactome.org ReactomeREACT_23772 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The alpha subunit of the IL3 receptor binds IL 3 with low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of ligand with the alpha chain to form a binary complex. This binary complex is then able to bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008). Covalent linkage of the receptor subunits is required for receptor signalling (Stomski et al. 1996). p-STAT1 Converted from EntitySet in Reactome Reactome DB_ID: 909689 Reactome Database ID Release 43909689 Reactome, http://www.reactome.org ReactomeREACT_26279 Recruitment of SHC1 is mediated by Y593 of the common beta chain Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10982827 Pubmed8647804 Reactome Database ID Release 43879934 Reactome, http://www.reactome.org ReactomeREACT_23857 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 Upon receptor activation, Shc is recruited to the receptor complex, where it becomes tyrosine phosphorylated. The recruitment of Shc is mediated by Y593 (Y577 in the mature peptide) of the common beta chain (Bc), which binds the PTB domain of Shc (Pratt et al. 1996). Phosphorylated Shc interacts with Grb2 within a Grb2:Gab2 complex, promoting tyrosine phosphorylation of Gab2. The p85 subunit of PI3Kinases associates with phosphorylated Gab, and this induces activation of the catalytic p110 PI3K subunit leading to activation of Akt kinase, thereby regulating cell survival and/or proliferation. has a Stoichiometric coefficient of 3 MCAK dimer Reactome DB_ID: 990513 Reactome Database ID Release 43990513 Reactome, http://www.reactome.org ReactomeREACT_26054 has a Stoichiometric coefficient of 2 Tyrosine kinases phosphorylate the receptor Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 Phosphorylation of the receptor common beta chain (Bc) creates binding sites for proteins that trigger subsequent signaling cascades (Pawson & Scott, 1997). The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One site is Y766 (numbered as Y750 by Sakamaki et al. 1992 and many other publications). Phosphorylation of Bc in response to GM-CSF/IL3 is observed at low temperatures (4 degrees C) that prevent the phosphorylation of other proteins, suggesting that the kinase responsible is likely to be physically associated with the receptor complex prior to stimulation (Miyajima et al. 1993). JAK2 is activated in response to IL-3, IL-5 and GM-CSF but signaling via JAK/STAT is not dependent on Bc tyrosine phosphorylation (Okuda et al. 1997). Based on these observations and the role of JAK1/3 in IL-2 signaling, JAK2 is believed to be the most likely candidate responsible for the phosphorylation of Bc (Guthridge et al. 1998). To represent the possible phosphorylation of Bc by kinases other than JAK2, this reaction includes receptor complexes with both active and inactive JAK2. Phosphorylation is represented only where this is necesssary for subsequent signaling; phosphorylation at other positions is probable. Pubmed1396555 Pubmed1400495 Pubmed2681215 Pubmed8400249 Pubmed8647804 Pubmed9389692 Pubmed9405336 Pubmed9766809 Reactome Database ID Release 43879907 Reactome, http://www.reactome.org ReactomeREACT_23953 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 has a Stoichiometric coefficient of 12 Kinesin-14 Reactome DB_ID: 1015869 Reactome Database ID Release 431015869 Reactome, http://www.reactome.org ReactomeREACT_26798 has a Stoichiometric coefficient of 2 p-STAT5 is released from the receptor complex Authored: Ray, KP, 2010-05-17 Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believe to occur following the release of phosphorylated monomers (e.g. Turkson & Jove 2000). Edited: Jupe, S, 2010-08-06 Pubmed11426647 Pubmed9030599 Reactome Database ID Release 43921155 Reactome, http://www.reactome.org ReactomeREACT_23896 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 has a Stoichiometric coefficient of 3 STAT1 Converted from EntitySet in Reactome Reactome DB_ID: 380755 Reactome Database ID Release 43380755 Reactome, http://www.reactome.org ReactomeREACT_17621 STAT1 alpha/beta Activation of STAT5a/b by JAK2 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 JAK2 phosphorylates STAT5; phosphorylated STAT5 dimerizes and translocates to the nucleus (Darnell et al., 1994), binds DNA and activates target genes including c-fos, pim-1, oncostatin M, and Id-1 (Mui et al. 1996). STAT5 activation is believed to be the primary signaling mechanism for Bc (Ihle, 2001). Pubmed11458499 Pubmed8197455 Pubmed8665850 Pubmed9685210 Reactome Database ID Release 43879909 Reactome, http://www.reactome.org ReactomeREACT_23842 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 has a Stoichiometric coefficient of 6 Centralspindlin Reactome DB_ID: 984587 Reactome Database ID Release 43984587 Reactome, http://www.reactome.org ReactomeREACT_25726 has a Stoichiometric coefficient of 2 CENP-E dimer Reactome DB_ID: 984773 Reactome Database ID Release 43984773 Reactome, http://www.reactome.org ReactomeREACT_26478 has a Stoichiometric coefficient of 2 KIF18A dimer Reactome DB_ID: 984631 Reactome Database ID Release 43984631 Reactome, http://www.reactome.org ReactomeREACT_26936 has a Stoichiometric coefficient of 2 KIF9 dimer Reactome DB_ID: 984777 Reactome Database ID Release 43984777 Reactome, http://www.reactome.org ReactomeREACT_26592 has a Stoichiometric coefficient of 2 KIF15 dimer Reactome DB_ID: 984823 Reactome Database ID Release 43984823 Reactome, http://www.reactome.org ReactomeREACT_26477 has a Stoichiometric coefficient of 2 Kinesin-13 dimers Converted from EntitySet in Reactome Reactome DB_ID: 990485 Reactome Database ID Release 43990485 Reactome, http://www.reactome.org ReactomeREACT_25940 KIF2A dimer Reactome DB_ID: 990480 Reactome Database ID Release 43990480 Reactome, http://www.reactome.org ReactomeREACT_27040 has a Stoichiometric coefficient of 2 KIF2B dimer Reactome DB_ID: 990505 Reactome Database ID Release 43990505 Reactome, http://www.reactome.org ReactomeREACT_26862 has a Stoichiometric coefficient of 2 CBL binds CRK Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed8626543 Pubmed8649859 Reactome Database ID Release 43912790 Reactome, http://www.reactome.org ReactomeREACT_23925 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The Crk adapter protein family is comprised of Crk-I and Crk-II, alternatively spliced products of a single gene with differing biological functions, and Crk-L, a distinct Crk-like gene product. Cbl is the dominant phosphoprotein associated with Crk in activated lymphocytes. In vitro binding indicates that the Crk SH2 domain binds Y774 of Cbl (Reedquist et al. 1996), leaving the SH3 domain of Crk free to interact with other SH3 domain-associated proteins. CBL:CRKL binds RAPGEF1 Authored: Ray, KP, 2010-05-17 Cbl has been identified in ternary complexes with CRKL and C3G (RAPGEF1)(Reedquist et al. 1996) a Rap1 GEF, suggesting a role for Cbl in linking cytokine stimulation to Rap1 activation. Consistent with this, stimulation of NB-4 promyelocytic cells by IFN-gamma causes tyrosine phosphorylation and association of Cbl with CRKL followed by activation of Rap1 (Alsayed et al. 2000) and tyrosine phosphorylation of Cbl and its association with CRKL correlated with an increase in Rap 1 activity in anergic T cells (Boussiotis et al. 1997). Edited: Jupe, S, 2010-08-06 Pubmed10657627 Pubmed8626543 Pubmed9311917 Reactome Database ID Release 43912734 Reactome, http://www.reactome.org ReactomeREACT_23785 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 CBL is tyrosine phosphorylated Authored: Ray, KP, 2010-05-17 Cbl is tyrosine phosphorylated following stimulation with IL-3 (Anderson et al. 1997) and GM-CSF (Odai et al. 1995). Cbl may be phosphorylated prior to this IL-3 stimulated tyrosyl phosphorylation (Park et al. 1998). The kinase responsible for Cbl phosphorylation may be dependent on cell type; Fyn is demonstrated to have the ability to phosphorylate Cbl (Hunter et al. 1999), other candidates include Hck, Lyn (Hunter et al. 1999) and Syk (Park et al. 1998).<br><br> Tyrosines 700, 731 and 774 are the major sites of Cbl phosphorylation by non-receptor protein tyrosine kinases, with none showing any particular specificity for sites (Tsygankov et al. 2001). Fyn was observed to be constitutively associated with Cbl in lysates of several different cell types including the interleukin-3-dependent murine myeloid cell line 32Dcl3, and the prolactin-dependent rat thymoma cell line Nb2. Cbl phosphorylation at Y731 is postulated to provide an additional interaction between Cbl and the SH2 domain of p85-PI3K (Hunter et al. 1999). Cbl-p85 association increases in activated cells (Panchamoorthy et al. 1996). Expression of a Cbl Y731F mutant which abolishes binding of Cbl to p85 markedly increased levels of p85-PI3K (Dufour et al. 2008). Cbl-p85 binding negatively regulates PI3K activity (Fang et al. 2001); Cbl phosphorylation increased PI3K ubiquitination and proteasome degradation (Dufour et al. 2008). Cbl association with members of the Crk family is mediated by phosphorylation of Y700 and Y774 (Andoniou et al. 1996), binding with Vav is mediated by Y770 (Marengere et al 1997). EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 Pubmed11607840 Pubmed18374639 Pubmed7537740 Pubmed8649859 Pubmed8995358 Pubmed9200440 Pubmed9525940 Pubmed9590251 Pubmed9890970 Reactome Database ID Release 43912629 Reactome, http://www.reactome.org ReactomeREACT_23845 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 has a Stoichiometric coefficient of 3 CBL ubiquitinates PI3K Authored: Ray, KP, 2010-05-17 Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl-B targets PI3K for ubiquitination and degradation in T cells (Fang et al. 2000). Similarly, Cbl activation by tyrosine phosphorylation increases PI3K ubiquitination and proteasomal degradation (Dufour et al. 2008). Edited: Jupe, S, 2010-08-06 Pubmed11087752 Pubmed11994499 Pubmed18374639 Reactome Database ID Release 43912627 Reactome, http://www.reactome.org ReactomeREACT_23869 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 SHC1 bound to the common beta chain becomes tyrosine phosphorylated Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10 Edited: Jupe, S, 2010-08-06 IL-3, IL-5 and GM-CSF all induce tyrosine phosphorylation of Shc (Dorsch et al. 1994). Three sites are known to mediate specific downstream associations; tyrosine Y427 (Salcini et al. 1994) mediates the subsequent association of Shc with Grb2 (Salcini et al. 1994). The identity of the kinase is unknown. Y349 and Y350 phosphorylation is not required for Ras-MAPK signaling but are involved in IL-3-induced cell survival (Gotoh et al. 1996).<br>Residue numbering used here refers to Uniprot P29353 where the p66 isoform has been selected as the canonical form. Literature references given here refer to the p52 isoform which lacks the first 110 residues, so Y427 is referred to as Y317 in Salcini et al. 1994, Y349 and Y350 as Y239 and Y240 in Gotoh et al. 1996. Pubmed7513165 Pubmed8084588 Pubmed8947042 Reactome Database ID Release 43879925 Reactome, http://www.reactome.org ReactomeREACT_23971 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 CBL, GRB2, FYN and PI3K p85 subunit are constitutively associated Authored: Ray, KP, 2010-05-17 Cbl is constitutively associated with Grb2 in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain can bind the adaptor protein CRKL.<br><br> Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). <br>Cbl also associates with Fyn (Anderson et al. 1997) and the related kinases Hck and Lyn (Hunter et al. 1999). Binding studies indicate that this binding is independent of the phosphorylation state of Cbl; The association of Fyn with Cbl has been described as constitutive (Hunter et al. 1999).<br><br> Cbl further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this is also described as constitutive and is mediated by the SH3 domain of p85 (Hunter et al. 1997). Edited: Jupe, S, 2010-08-06 Pubmed7537740 Pubmed7629144 Pubmed8621719 Pubmed8995358 Pubmed9259313 Pubmed9590251 Pubmed9890970 Reactome Database ID Release 43879917 Reactome, http://www.reactome.org ReactomeREACT_23799 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 Nck:Robo1:Slit2:Glypican Reactome DB_ID: 428486 Reactome Database ID Release 43428486 Reactome, http://www.reactome.org ReactomeREACT_20473 has a Stoichiometric coefficient of 1 Robo1:Slit2:KIAA1688 Reactome DB_ID: 428491 Reactome Database ID Release 43428491 Reactome, http://www.reactome.org ReactomeREACT_19688 has a Stoichiometric coefficient of 1 Robo1:Slit2:SrGAP Reactome DB_ID: 376031 Reactome Database ID Release 43376031 Reactome, http://www.reactome.org ReactomeREACT_19732 has a Stoichiometric coefficient of 1 Glypican-1:Slit2:Robo1:Ena/Vasp:Profilin Reactome DB_ID: 428492 Reactome Database ID Release 43428492 Reactome, http://www.reactome.org ReactomeREACT_19848 has a Stoichiometric coefficient of 1 Glypican-1:Slit2:Robo1:Ena/Vasp proteins Reactome DB_ID: 376032 Reactome Database ID Release 43376032 Reactome, http://www.reactome.org ReactomeREACT_19985 has a Stoichiometric coefficient of 1 Robo1:Slit2:Glypican-1 Reactome DB_ID: 390371 Reactome Database ID Release 43390371 Reactome, http://www.reactome.org ReactomeREACT_19858 has a Stoichiometric coefficient of 1 Slit2:Glypican-1 Reactome DB_ID: 428489 Reactome Database ID Release 43428489 Reactome, http://www.reactome.org ReactomeREACT_19697 has a Stoichiometric coefficient of 1 phytanoyl-CoA + 2-oxoglutarate + O2 => 2-hydroxyphytanoyl-CoA + succinate + CO2 Authored: D'Eustachio, P, 2009-01-10 20:36:15 EC Number: 1.14.11.18 Edited: D'Eustachio, P, 2009-01-10 20:36:15 Peroxisomal phytanoyl-CoA dioxygenase catalyzes the reaction of phytanoyl-CoA, 2-oxoglutarate, and O2 to form 2-hydroxyphytanoyl-CoA, succinate, and CO2. The mature form of the enzyme lacks the first 30 amino acid residues of the full-length polypeptide and is complexed with Fe++. Mutations in this enzyme are the commonest cause of Refsum disease (Mukherji et al. 2001; McDonough et al. 2005). Pubmed11555634 Pubmed16186124 Reactome Database ID Release 43389639 Reactome, http://www.reactome.org ReactomeREACT_17021 Reviewed: Jassal, B, 2009-02-27 15:21:18 Abl:Robo1:Slit2:Glypican-1 Reactome DB_ID: 428873 Reactome Database ID Release 43428873 Reactome, http://www.reactome.org ReactomeREACT_19950 has a Stoichiometric coefficient of 1 phytanate + CoA-SH + ATP => phytanoyl-CoA + AMP + pyrophosphate Authored: D'Eustachio, P, 2009-01-10 20:36:15 EC Number: 6.2.1.24 Edited: D'Eustachio, P, 2009-01-10 20:36:15 Pubmed10198260 Reactome Database ID Release 43389622 Reactome, http://www.reactome.org ReactomeREACT_17000 Reviewed: Jassal, B, 2009-02-27 15:21:18 VLCS (very long chain acyl-CoA synthetase), associated with the inner surface of the peroxisomal membrane, cayalyzes the reaction of phytanate, CoA-SH, and ATP to form phytanoyl-CoA, AMP, and pyrophosphate (Steinberg et al. 1999). SOS:PAK:Nck:Robo1:Slit2:Glypican Reactome DB_ID: 428481 Reactome Database ID Release 43428481 Reactome, http://www.reactome.org ReactomeREACT_20383 has a Stoichiometric coefficient of 1 PMP34-mediated exchange of cytosolic ATP for peroxisomal AMP Authored: D'Eustachio, P, 2009-01-10 20:36:15 Edited: D'Eustachio, P, 2009-01-10 20:36:15 Pubmed12445829 Pubmed16756494 Pubmed9874197 Reactome Database ID Release 43389652 Reactome, http://www.reactome.org ReactomeREACT_16948 Reviewed: Jassal, B, 2009-02-27 15:21:18 The peroxisomal membrane transport protein PMP34 mediates the exchange of adenine nucleotides between the cytosol and the peroxisomal matrix. The localization of PMP34 has been established by immunofluoresence studies (Wylin et al. 1998). The cloned human protein restores adenine nucleotide transport in yeast whose endogenous peroxisomal transporter has been disrupted, and has adenine nucleotide transport activity in reconstituted lipid vesicles in vitro (Visser et al. 2002), consistent with its hypothesized role in vivo (Wanders and Waterham 2006). Pak:Nck:Robo1:Slit2:Glypican Reactome DB_ID: 428482 Reactome Database ID Release 43428482 Reactome, http://www.reactome.org ReactomeREACT_19485 has a Stoichiometric coefficient of 1 Expression of Farnesyldiphosphate Farnesyltransferase (FDFT1, Squalene Synthase) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed7685352 Reactome Database ID Release 431655850 Reactome, http://www.reactome.org ReactomeREACT_115945 Reviewed: Kersten, S, 2009-06-08 Reviewed: Liang, Guosheng, 2012-08-25 The FDFT1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. GBP Converted from EntitySet in Reactome Interferon-induced guanylate-binding proteins Reactome DB_ID: 1031695 Reactome Database ID Release 431031695 Reactome, http://www.reactome.org ReactomeREACT_26189 guanylate-binding proteins Expression of Hydroxymethylglutaryl coenzyme A synthase (HMGCS1) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed12177166 Pubmed19088433 Reactome Database ID Release 431655848 Reactome, http://www.reactome.org ReactomeREACT_115739 Reviewed: Kersten, S, 2009-06-08 Reviewed: Liang, Guosheng, 2012-08-25 The HMGCS1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase (HMGCR) Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Pubmed8647822 Reactome Database ID Release 431655826 Reactome, http://www.reactome.org ReactomeREACT_115997 Reviewed: Kersten, S, 2009-06-08 Reviewed: Liang, Guosheng, 2012-08-25 The HMGCR gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of ALAS1 Authored: May, B, 2011-08-20 Edited: May, B, 2011-08-20 Expression of 5-aminolevulinate synthase 1 Pubmed11267664 Pubmed18719978 Reactome Database ID Release 431592238 Reactome, http://www.reactome.org ReactomeREACT_115949 Reviewed: Kersten, S, 2009-06-08 The ALSA1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Recruitment of Corepressors by PPARA:RXRA Heterodimer Authored: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-06-08 In the absence of activating ligands of PPAR-alpha, the PPAR-alpha:RXR-alpha heterodimers recruit corepressors NCoR1, NCoR2(SMRT), and histone deacetylases (HDACs) to genes regulated by PPAR-alpha. The corepressors maintain chromatin at the gene in an inactive conformation and prevent expression of the gene. Pubmed10529898 Pubmed11330046 Pubmed16476485 Pubmed16503871 Pubmed18288277 Pubmed18292238 Reactome Database ID Release 43400183 Reactome, http://www.reactome.org ReactomeREACT_19283 Reviewed: Kersten, S, 2009-06-08 Activation of PPARA by Fatty Acid Ligands Authored: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-06-08 PPAR-alpha is activated by binding polyunsaturated fatty acids especially those having 18-22 carbon groups and 2-6 double bonds. These ligands bind the C-terminal region of PPAR-alpha and include linoleic acid, linolenic acids, arachidonic acid, and eicosapentaenoic acid. The fibrate drugs are also agonists of PPAR-alpha.<br>Binding of a ligand causes a conformational change in PPAR-alpha so that it recruits coactivators. By analogy with the closely related receptor PPAR-gamma, PPAR-alpha probably binds TBL1 and TBLR1, which are responsible for recruiting the 19S proteasome to degrade corepressors during the exchange of corepressors for coactivators. The coactivators belong to the CBP-SRC-HAT complex (CBP/p300, SRC1, SRC2, SRC3, CARM1, SWI/SNF, BAF60C, PRIC320, and PRIC285), the ASC complex (PRIP/ASC2, PIMT), and the TRAP-DRIP-ARC-MEDIATOR complex (TRAP130, PBP/TRAP220). The coactivators contain LXXLL motifs (Nuclear Receptor Boxes) that interact with the AF-2 region in nuclear receptors such as PPAR-alpha. Pubmed10529898 Pubmed11226238 Pubmed11330046 Pubmed14980219 Pubmed16476485 Pubmed16503871 Pubmed17007889 Pubmed17306620 Pubmed18288277 Pubmed19289416 Pubmed9171241 Reactome Database ID Release 43400143 Reactome, http://www.reactome.org ReactomeREACT_19175 Reviewed: Kersten, S, 2009-06-08 Formation of PPARA:RXRA Heterodimer at Promoters of Target Genes Authored: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-06-08 Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a type II nuclear receptor (its subcellular location is independent of ligand binding) related to PPAR-beta/delta and PPAR-gamma. PPAR-alpha is expressed highly in the liver where if functions to control lipid metabolism, especially fatty acid oxidation. <br>PPAR-alpha forms heterodimers with Retinoid X receptor alpha (RXR-alpha). The heterodimers bind peroxisome proliferator receptor elements (PPREs) in and around genes regulated by PPAR-alpha. Pubmed10529898 Pubmed11330046 Pubmed16476485 Pubmed16503871 Pubmed18288277 Pubmed8386511 Reactome Database ID Release 43400204 Reactome, http://www.reactome.org ReactomeREACT_19370 Reviewed: Kersten, S, 2009-06-08 PathwayStep4599 PathwayStep4592 pL1:Shootin-1:F-actin Reactome DB_ID: 443668 Reactome Database ID Release 43443668 Reactome, http://www.reactome.org ReactomeREACT_22531 has a Stoichiometric coefficient of 1 PathwayStep4591 pL1:ERM:F-actin Reactome DB_ID: 443655 Reactome Database ID Release 43443655 Reactome, http://www.reactome.org ReactomeREACT_22519 has a Stoichiometric coefficient of 1 PathwayStep4594 L1:AP-2 Clathrin complex Reactome DB_ID: 392743 Reactome Database ID Release 43392743 Reactome, http://www.reactome.org ReactomeREACT_22867 has a Stoichiometric coefficient of 1 PathwayStep4593 L1:clathrin-coated vesicle Reactome DB_ID: 555064 Reactome Database ID Release 43555064 Reactome, http://www.reactome.org ReactomeREACT_22698 has a Stoichiometric coefficient of 1 PathwayStep4596 Robo1:Slit2:Glypican-1 Reactome DB_ID: 428499 Reactome Database ID Release 43428499 Reactome, http://www.reactome.org ReactomeREACT_20056 has a Stoichiometric coefficient of 1 PathwayStep4595 Abl:pRobo1:slit2:Glypican-1 Reactome DB_ID: 376027 Reactome Database ID Release 43376027 Reactome, http://www.reactome.org ReactomeREACT_19439 has a Stoichiometric coefficient of 1 PathwayStep4598 CAP:Abl:Robo1:Slit2:Glypican-1 Reactome DB_ID: 428875 Reactome Database ID Release 43428875 Reactome, http://www.reactome.org ReactomeREACT_20355 has a Stoichiometric coefficient of 1 PathwayStep4597 Clasp:Abl:Robo1:Slit2:Glypican-1 Reactome DB_ID: 428876 Reactome Database ID Release 43428876 Reactome, http://www.reactome.org ReactomeREACT_19830 has a Stoichiometric coefficient of 1 3-ketopristanoyl-CoA + CoASH => 4,8,12-trimethyltridecanoyl-CoA + propionyl-CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 2.3.1.154 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal SCPx (Non-specific lipid transfer protein; SCP2) catalyzes the reaction of 3-ketopristanoyl-CoA and CoASH to form 4,8,12-trimethyltridecanoyl-CoA and propionyl-CoA. Both intact SCPx and an SCPx fragment corresponding to approximately the 430 aminoterminal residues of the protein are catalytically active in vitro; the latter form may predominate in vivo. Consistent with the role of SCPx in the beta-oxidation of branched-chain fatty acids in vitro, mutations in the protein are associated with elevated levels of pristanic acid in the blood in vivo and the development of neurological defects (Ferdinandusse et al. 2000, 2006). Pubmed10706581 Pubmed16685654 Reactome Database ID Release 43390224 Reactome, http://www.reactome.org ReactomeREACT_17019 Reviewed: Jassal, B, 2009-02-27 15:21:18 L1:NUMB:CRMP-2:alpha-adaptin Reactome DB_ID: 443657 Reactome Database ID Release 43443657 Reactome, http://www.reactome.org ReactomeREACT_22785 has a Stoichiometric coefficient of 1 3-hydroxypristanoyl-CoA + NAD+ => 3-ketoxypristanoyl-CoA + NADH + H+ Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 1.1.1.35 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal HSD17B4 dimer catalyzes the reaction of 3-hydroxypristanoyl-CoA and NAD+ to form 3-ketoxypristanoyl-CoA and NADH + H+. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's, the reaction annotated here, and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's (Jiang et al. 1996, 1997). Defects in the enzyme are associated with a severe disorder of peroxisomal fatty acid metabolism in humans (Ferdinandusse et al. 2006). Pubmed16385454 Pubmed8902629 Pubmed9089413 Reactome Database ID Release 43389995 Reactome, http://www.reactome.org ReactomeREACT_16976 Reviewed: Jassal, B, 2009-02-27 15:21:18 CRMP-2:NUMB:alpha adaptin Reactome DB_ID: 443669 Reactome Database ID Release 43443669 Reactome, http://www.reactome.org ReactomeREACT_22454 has a Stoichiometric coefficient of 1 PathwayStep4590 IFN-gamma upregulated CAMs Converted from EntitySet in Reactome Reactome DB_ID: 1031690 Reactome Database ID Release 431031690 Reactome, http://www.reactome.org ReactomeREACT_26072 Isomerization of (2R)-pristanoyl-CoA to (2S)-pristanoyl-CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 5.1.99.4 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal 2-methylacyl-CoA racemase (AMACR) catalyzes the isomerization of (2R)-pristanoyl-CoA to form (2S)-pristanoyl-CoA. The active form of the enzyme is a monomer (Schmitz et al. 1995; Amery et al. 2000; Ferdinandusse et al. 2000). Pubmed11060344 Pubmed11060359 Pubmed7649182 Reactome Database ID Release 43389897 Reactome, http://www.reactome.org ReactomeREACT_17018 Reviewed: Jassal, B, 2009-02-27 15:21:18 (2S)-pristanoyl-CoA + O2 => trans-2,3-dehydropristanoyl-CoA + H2O2 (ACOX2) Authored: D'Eustachio, P, 2009-03-16 18:50:14 Edited: D'Eustachio, P, 2009-03-18 13:33:40 In human liver and kidney tissue, monomeric peroxisomal ACOX2 catalyzes the reaction of (2S)-pristanoyl-CoA and O2 to form trans-2,3-dehydropristanoyl-CoA and H2O2 (Vanhove et al. 1993; Baumgart et al. 1996). Pubmed8387517 Pubmed8943006 Reactome Database ID Release 43389889 Reactome, http://www.reactome.org ReactomeREACT_17014 Reviewed: Jassal, B, 2009-02-27 15:21:18 (2S)-pristanoyl-CoA + O2 => trans-2,3-dehydropristanoyl-CoA + H2O2 (ACOX3) Authored: D'Eustachio, P, 2009-03-16 18:50:14 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal ACOX3 catalyzes the reaction of (2S)-pristanoyl-CoA and O2 to form trans-2,3-dehydropristanoyl-CoA and H2O2. ACOX3 protein and enzyme activity have been observed in prostate tumors, but are undetectable in normal prostate tissue as well as in liver and kidney (where ACOX2 catalyzes the oxidation of pristanoyl-CoA) (Zha et al. 2005; Vanhooren et al. 1997). The physiological consequences of this differential gene expression are unknown. Pubmed15599942 Pubmed9271077 Reactome Database ID Release 43389891 Reactome, http://www.reactome.org ReactomeREACT_16962 Reviewed: Jassal, B, 2009-02-27 15:21:18 PTPs-SHP1/2/PTP1B Converted from EntitySet in Reactome Reactome DB_ID: 997298 Reactome Database ID Release 43997298 Reactome, http://www.reactome.org ReactomeREACT_26675 trans-2,3-dehydropristanoyl-CoA + H2O => 3-hydroxypristanoyl-CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 4.2.1.74 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal HSD17B4 dimer catalyzes the reaction of trans-2,3-dehydropristanoyl-CoA and H2O to form 3-hydroxypristanoyl-CoA. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's, the reaction annotated here (Jiang et al. 1996, 1997). Defects in the enzyme are associated with a severe disorder of peroxisomal fatty acid metabolism in humans (Ferdinandusse et al. 2006). Pubmed16385454 Pubmed8902629 Pubmed9089413 Reactome Database ID Release 43389986 Reactome, http://www.reactome.org ReactomeREACT_16944 Reviewed: Jassal, B, 2009-02-27 15:21:18 2-hydroxyphytanoyl-CoA => pristanal + formyl-CoA Authored: D'Eustachio, P, 2009-01-10 20:36:15 EC Number: 4.1 Edited: D'Eustachio, P, 2009-01-10 20:36:15 Peroxisomal HACL1 catalyzes the reaction of 2-hydroxyphytanoyl-CoA to form pristanal and formyl-CoA. The active form of the enzyme is a homotetramer, with one Mg++ and one molecule of thiamin pyrophosphate bound to each monomer (Croes et al. 1997; Foulon et al. 1999). Pubmed10468558 Pubmed9166898 Reactome Database ID Release 43389611 Reactome, http://www.reactome.org ReactomeREACT_17035 Reviewed: Jassal, B, 2009-02-27 15:21:18 formyl-CoA + H2O => formate + CoASH Authored: D'Eustachio, P, 2009-01-10 20:36:15 Edited: D'Eustachio, P, 2009-01-10 20:36:15 Formyl-CoA formed during the alpha-oxidation of phytanoyl-CoA is spontaneously hydrolyzed to formate and CoASH (Croes et al. 1997). Pubmed9166898 Reactome Database ID Release 43389580 Reactome, http://www.reactome.org ReactomeREACT_16990 Reviewed: Jassal, B, 2009-02-27 15:21:18 pristanal + NAD+ => pristanate + NADH + H+ Authored: D'Eustachio, P, 2009-01-10 20:36:15 EC Number: 1.2.1.3 Edited: D'Eustachio, P, 2009-01-10 20:36:15 Peroxisomes contain a pristanal dehydrogenase activity that catalyzes the reaction of pristanal and NAD+ to form pristanate and NADH + H+. The enzyme responsible for this activity has not yet been purified (Jansen et al. 2001). Pubmed11341778 Reactome Database ID Release 43389609 Reactome, http://www.reactome.org ReactomeREACT_16919 Reviewed: Jassal, B, 2009-02-27 15:21:18 pristanate + CoA-SH + ATP => pristanoyl-CoA + AMP + pyrophosphate Authored: D'Eustachio, P, 2009-01-10 20:36:15 EC Number: 6.2.1.24 Edited: D'Eustachio, P, 2009-01-10 20:36:15 Pubmed10198260 Reactome Database ID Release 43389632 Reactome, http://www.reactome.org ReactomeREACT_17058 Reviewed: Jassal, B, 2009-02-27 15:21:18 VLCS (very long chain acyl-CoA synthetase), associated with the inner surface of the peroxisomal membrane, catalyzes the reaction of pristanate, CoA-SH and ATP to form pristanoyl-CoA, AMP and pyrophosphate (Steinberg et al. 1999). ISG15 E3 ligases Converted from EntitySet in Reactome Reactome DB_ID: 1169381 Reactome Database ID Release 431169381 Reactome, http://www.reactome.org ReactomeREACT_117149 PathwayStep4588 PathwayStep4589 AP2 clathrin:L1:KIF4:microtubule Reactome DB_ID: 445022 Reactome Database ID Release 43445022 Reactome, http://www.reactome.org ReactomeREACT_23331 has a Stoichiometric coefficient of 1 KIF4 dimer Reactome DB_ID: 445013 Reactome Database ID Release 43445013 Reactome, http://www.reactome.org ReactomeREACT_23088 has a Stoichiometric coefficient of 2 pL1 (S1204, 1248):ERK2:clathrin-dynamin complex Reactome DB_ID: 445005 Reactome Database ID Release 43445005 Reactome, http://www.reactome.org ReactomeREACT_23286 has a Stoichiometric coefficient of 1 pL1 (S1152):p90rsk:clathrin-dynamin complex Reactome DB_ID: 374597 Reactome Database ID Release 43374597 Reactome, http://www.reactome.org ReactomeREACT_23209 has a Stoichiometric coefficient of 1 L1 dimer:Ankyrin:Spectrin:F-actin Reactome DB_ID: 443654 Reactome Database ID Release 43443654 Reactome, http://www.reactome.org ReactomeREACT_22451 has a Stoichiometric coefficient of 1 spectrin based actin Reactome DB_ID: 392744 Reactome Database ID Release 43392744 Reactome, http://www.reactome.org ReactomeREACT_22921 has a Stoichiometric coefficient of 1 L1 trans-homodimer:Ankyrin Reactome DB_ID: 374569 Reactome Database ID Release 43374569 Reactome, http://www.reactome.org ReactomeREACT_22843 has a Stoichiometric coefficient of 1 L1 homodimer Reactome DB_ID: 446623 Reactome Database ID Release 43446623 Reactome, http://www.reactome.org ReactomeREACT_22876 has a Stoichiometric coefficient of 2 3-ketohexacosanoyl-CoA + CoASH => tetracosanoyl-CoA + acetyl-CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 2.3.1.16 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal ACAA1 catalyzes the reaction of 3-ketohexacosanoyl-CoA and CoASH to form tetracosanoyl-CoA + acetyl-CoA (Bout et al. 1991). Pubmed1679347 Reactome Database ID Release 43390250 Reactome, http://www.reactome.org ReactomeREACT_16946 Reviewed: Jassal, B, 2009-02-27 15:21:18 Sodium channel subunits Reactome DB_ID: 443632 Reactome Database ID Release 43443632 Reactome, http://www.reactome.org ReactomeREACT_22692 has a Stoichiometric coefficient of 1 acetyl-CoA + H2O => acetate + CoASH Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 3.1.2.1 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal ACOT8 catalyzes the hydrolysis of acetyl-CoA to form acetate and CoASH (Jones et al. 1999; Wanders and Waterham 2006). Pubmed10092594 Pubmed16756494 Reactome Database ID Release 43390304 Reactome, http://www.reactome.org ReactomeREACT_16974 Reviewed: Jassal, B, 2009-02-27 15:21:18 propionyl-CoA + carnitine => propionylcarnitine + CoASH Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 2.3.1.7 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal carnitineacetyltransferase (CRAT) catalyzes the reaction of propionyl-CoA and carnitine to form propionylcarnitine and CoASH. The active form of the enzyme is a monomer (Bloisi et al. 1990; Wu et al. 2003). Pubmed12562770 Pubmed2351134 Reactome Database ID Release 43390284 Reactome, http://www.reactome.org ReactomeREACT_16949 Reviewed: Jassal, B, 2009-02-27 15:21:18 4,8-dimethylnonanoyl-CoA + carnitine => 4,8-dimethylnonanoylcarnitine + CoASH Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 2.3.1.137 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal CROT catalyzes the reaction of 4,8-dimethylnonanoyl-CoA and carnitine to form 4,8-dimethylnonanoylcarnitine and CoASH (Ferdinandusse et al. 1999). Pubmed10486279 Reactome Database ID Release 43390281 Reactome, http://www.reactome.org ReactomeREACT_16985 Reviewed: Jassal, B, 2009-02-27 15:21:18 acetyl-CoA + carnitine => acetylcarnitine + CoASH Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 2.3.1.7 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal carnitineacetyltransferase (CRAT) catalyzes the reaction of acetyl-CoA and carnitine to form acetylcarnitine and CoASH. The active form of the enzyme is a monomer (Bloisi et al. 1990; Wu et al. 2003). Pubmed12562770 Pubmed2351134 Reactome Database ID Release 43390291 Reactome, http://www.reactome.org ReactomeREACT_16977 Reviewed: Jassal, B, 2009-02-27 15:21:18 trans-2,3-dehydrohexacosanoyl-CoA + H2O => 3-hydroxyhexacosanoyl-CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 4.2.1.74 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal HSD17B4 dimer catalyzes the reaction of trans-2,3-dehydrohexacosanoyl-CoA and H2O to form 3-hydroxyhexacosanoyl-CoA. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's, the reaction annotated here (Jiang et al. 1996, 1997). Defects in the enzyme are associated with a severe disorder of peroxisomal fatty acid metabolism in humans (Ferdinandusse et al. 2006). Pubmed16385454 Pubmed8902629 Pubmed9089413 Reactome Database ID Release 43390252 Reactome, http://www.reactome.org ReactomeREACT_16908 Reviewed: Jassal, B, 2009-02-27 15:21:18 3-hydroxyhexacosanoyl-CoA + NAD+ => 3-ketohexacosanoyl-CoA + NADH + H+ Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 1.1.1.35 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal HSD17B4 dimer catalyzes the reaction of 3-hydroxyhexacosanoyl-CoA and NAD+ to form 3-ketohexacosanoyl-CoA and NADH + H+. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's, the reaction annotated here, and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's (Jiang et al. 1996, 1997). Defects in the enzyme are associated with a severe disorder of peroxisomal fatty acid metabolism in humans (Ferdinandusse et al. 2006). Pubmed16385454 Pubmed8902629 Pubmed9089413 Reactome Database ID Release 43390251 Reactome, http://www.reactome.org ReactomeREACT_16971 Reviewed: Jassal, B, 2009-02-27 15:21:18 Peroxisomal uptake of very long-chain fatty acyl CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 3.6.3.47 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Homodimeric ABCD1 associated with the peroxisomal membrane mediates the uptake of cytosolic very long chain fatty acyl CoAs such as hexacosanoyl-CoA into the peroxisomal matrix. While the requirement for this uptake step in the catabolism of very long chain fatty acids is well-established, direct evidence for the function of ABCD1 as a transporter comes only from studies of its ability to restore peroxisomal long chain fatty acid catabolism in yeast strains whose endogenous transporters have been disrupted by mutation. ABCD1 is inferred to function as a dimer like other members of the ABCD transporter family. The energy requirements of peroxisomal fatty acid uptake (other ABCD transporter-mediated reactions are coupled to ATP hydrolysis) have not been established (van Roermund et al. 2008). Pubmed18757502 Reactome Database ID Release 43390393 Reactome, http://www.reactome.org ReactomeREACT_16917 Reviewed: Jassal, B, 2009-02-27 15:21:18 hexacosanoyl-CoA + O2 => trans-2,3-dehydrohexacosanoyl-CoA + H2O2 Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 1.3.3.6 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal ACOX1 catalyzes the reaction of hexacosanoyl-CoA and O2 to form trans-2,3-dehydrohexacosanoyl-CoA and H2O2. The active form of the enzyme is a homodimer with FAD as a cofactor (Chu et al. 1995). Mutations in the ACOX1 gene are asociated with accumulation of very long chain fatty acids. Two isoforms of ACOX1, generated by alternative splicing are known; a mutation affecting specifically the second isoform blocks the oxidation of very long chain fatty acids (Ferdinandusse et al. 2007). Pubmed17458872 Pubmed7876265 Reactome Database ID Release 43390256 Reactome, http://www.reactome.org ReactomeREACT_17054 Reviewed: Jassal, B, 2009-02-27 15:21:18 IRF 1-9 Converted from EntitySet in Reactome Reactome DB_ID: 1015695 Reactome Database ID Release 431015695 Reactome, http://www.reactome.org ReactomeREACT_26465 4,8,12-trimethyltridecanoyl-CoA + 2 O2 + 2 H2O + 2 NAD+ + 2 CoASH => 4,8-dimethylnonanoyl-CoA + 2 H2O2 + 2 NADH + 2 H+ + acetyl-CoA + propionyl-CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 In two cycles of beta-oxidation mediated by the same enzyme activities responsible for the conversion of pristanoyl-CoA to 4,8,12-trimethyltridecanoyl-CoA, the latter molecule is converted to 4,8-dimethylnonanoyl-CoA. Two molecules each of O2, H2O, NAD+, and CoASH are consumed in the process and two molecules of H2O2 and NADH + H+ are generated, together with single molecules of acetyl-CoA and propionyl-CoA (Verhoeven et al. 1998). Pubmed9469587 Reactome Database ID Release 43390276 Reactome, http://www.reactome.org ReactomeREACT_16894 Reviewed: Jassal, B, 2009-02-27 15:21:18 has a Stoichiometric coefficient of 2 L1:AP-2 Clathrin complex Reactome DB_ID: 392746 Reactome Database ID Release 43392746 Reactome, http://www.reactome.org ReactomeREACT_22916 has a Stoichiometric coefficient of 1 pL1 (Y1229):L1CAM Reactome DB_ID: 445008 Reactome Database ID Release 43445008 Reactome, http://www.reactome.org ReactomeREACT_22871 has a Stoichiometric coefficient of 1 Neurofascin:NrCAM:Ankyrin:spectrin based actin:Na+/K+ channel Reactome DB_ID: 373687 Reactome Database ID Release 43373687 Reactome, http://www.reactome.org ReactomeREACT_22749 has a Stoichiometric coefficient of 1 L1:FGFR1 Reactome DB_ID: 443643 Reactome Database ID Release 43443643 Reactome, http://www.reactome.org ReactomeREACT_22912 has a Stoichiometric coefficient of 1 L1:NCAM1 complex Reactome DB_ID: 374576 Reactome Database ID Release 43374576 Reactome, http://www.reactome.org ReactomeREACT_23047 has a Stoichiometric coefficient of 1 L1:NP-1 Reactome DB_ID: 374580 Reactome Database ID Release 43374580 Reactome, http://www.reactome.org ReactomeREACT_23153 has a Stoichiometric coefficient of 1 L1-EGFR trans-heterodimer Reactome DB_ID: 445016 Reactome Database ID Release 43445016 Reactome, http://www.reactome.org ReactomeREACT_22956 has a Stoichiometric coefficient of 1 L1:Integrin complex Reactome DB_ID: 374579 Reactome Database ID Release 43374579 Reactome, http://www.reactome.org ReactomeREACT_22722 has a Stoichiometric coefficient of 1 Integrins Converted from EntitySet in Reactome Reactome DB_ID: 374573 Reactome Database ID Release 43374573 Reactome, http://www.reactome.org ReactomeREACT_23070 palmitoyl-CoA + 2 NADPH + 2 H+ => hexadecanol + 2 NADP+ [FAR2] Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 1 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal fatty acyl-CoA reductase 2 (FAR2) catalyzes the reaction of palmitoyl-CoA and 2 NADPH + 2 H+ to form hexadecanol, CoASH, and 2 NADP+. As judged from mRNA levels, FAR2 is not widely expressed in the body but is abundant in brain (Cheng and Russell 2004). Pubmed15220348 Reactome Database ID Release 43390438 Reactome, http://www.reactome.org ReactomeREACT_17042 Reviewed: Jassal, B, 2009-02-27 15:21:18 has a Stoichiometric coefficient of 2 palmitoyl-CoA + DHAP => 1-palmitoylglycerone phosphate + CoASH Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 2.3.1.42 Peroxisomal glyceronephosphate O-acyltransferase (GNPAT) catalyzes the reaction of palmitoyl-CoA and DHAP to form 1-palmitoyl glycerone phosphate (1-palmitoyl dihydroxyacetone phosphate) and CoASH. The active form of the enzyme is one subunit of a heterotrimer with two molecules of the alkylglycerone phosphate synthase (AGPS) enzyme (Biermann et al. 1999). It was first purified and characterized biochemically by Ofman and Wanders (1994). Mutations in the GNPAT gene are associated with rhizomelic chondrodysplasia type 2 (Ofman et al. 1998, 2001). Pubmed10215861 Pubmed11237722 Pubmed8186247 Pubmed9536089 Reactome Database ID Release 4375879 Reactome, http://www.reactome.org ReactomeREACT_15 Reviewed: Jassal, B, 2009-02-27 15:21:18 1-palmitoylglycerone phosphate + hexadecanol => O-hexadecylglycerone phosphate + palmitate Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 2.5.1.26 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal alkylglycerone phosphate synthase (AGPS) catalyzes the reaction of 1-palmitoylglycerone phosphate and hexadecanol to form O-hexadecylglycerone phosphate and palmitate. The active form of the enzyme is post-translationally cleaved to remove its 58 aminoterminal residues, has a molecule of FAD as a cofactor, and occurs in the peroxisome as a complex with glyceronephosphate O-acyltransferase (GNPAT) (Biermann et al. 1999; Bierman and van den Bosch 1999; de Vet et al. 2000). Pubmed10215861 Pubmed10415121 Pubmed10692424 Reactome Database ID Release 43390427 Reactome, http://www.reactome.org ReactomeREACT_16930 Reviewed: Jassal, B, 2009-02-27 15:21:18 Movement of O-hexadecylglycerone phosphate from the peroxisomal matrix to the cytosol Authored: D'Eustachio, P, 2009-03-16 18:50:14 Edited: D'Eustachio, P, 2009-03-18 13:33:40 O-hexadecylglycerone phosphate is synthesized in the peroxisomal matrix but its further metabolism takes place in the cytosol and endoplasmic reticulum. The mechanism by which it leaves the peroxisome is unknown (Nagan and Zoeller 2001). Pubmed11275267 Reactome Database ID Release 43390402 Reactome, http://www.reactome.org ReactomeREACT_16999 Reviewed: Jassal, B, 2009-02-27 15:21:18 Conversion of acylated DHAP to lysophosphatidic acid acid AADHAPR catalyzes the reaction of O-hexadecyldihydroxyacetone phosphate and NADPH + H+ to form 1-hexadecyl glycerol-3-phosphate and NADP+. The enzyme is associated with the outer face of the peroxisomal membrane; its substrates and products are thought to be cytosolic. The enzyme appears to be well-conserved among animal species. The properties of the human enzyme are inferred from those of an activity partially purified from guinea pig liver (Datta et al. 1990). Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 1.1.1.101 O-hexadecylglycerone phosphate + NADPH + H+ => 1-hexadecyl glycerol-3-phosphate + NADP+ Pubmed2335525 Reactome Database ID Release 4375883 Reactome, http://www.reactome.org ReactomeREACT_759 Reviewed: Jassal, B, 2009-02-27 15:21:18 isocitrate + NADP+ => 2-oxoglutarate + CO2 + NADPH + H+ Authored: D'Eustachio, P, 2009-01-07 23:39:54 EC Number: 1.1.1.42 Edited: D'Eustachio, P, 2009-01-07 23:39:54 Peroxisomal IDH1 (isocitrate dehydrogenase 1) homodimer catalyzes the reaction of isocitrate and NADP+ to form 2-oxoglutarate, CO2, and NADPH + H+. The same enzyme can also localize to the cytosol in at least some cell types (Geisbrecht and Gould 1999; Xu et al. 2004). Pubmed10521434 Pubmed15173171 Reactome Database ID Release 43389550 Reactome, http://www.reactome.org ReactomeREACT_16932 Reviewed: Jassal, B, 2009-02-27 15:21:18 isocitrate + NADP+ => 2-oxoglutarate + CO2 + NADPH + H+ Authored: D'Eustachio, P, 2009-01-07 23:39:54 Cytosolic IDH1 (isocitrate dehydrogenase 1) homodimer catalyzes the reaction of isocitrate and NADP+ to form 2-oxoglutarate, CO2, and NADPH + H+. The same enzyme can also localize to peroxisomes (Geisbrecht and Gould 1999; Xu et al. 2004). EC Number: 1.1.1.42 Edited: D'Eustachio, P, 2009-01-07 23:39:54 Pubmed10521434 Pubmed15173171 Reactome Database ID Release 43389540 Reactome, http://www.reactome.org ReactomeREACT_17007 Reviewed: Jassal, B, 2009-02-27 15:21:18 Exchange of isocitrate and 2-oxoglutarate across the peroxisomal membrane A specific transport process that exchanges 2-oxoglutarate for isocitrate across a lipid membrane has been reconstituted in vitro with proteins purified from bovine peroxisomal membranes. The specific protein or proteins that mediate this transport process have not yet been identified in any mammalian system, however (Visser et al. 2006). Authored: D'Eustachio, P, 2009-01-07 23:39:54 Edited: D'Eustachio, P, 2009-01-07 23:39:54 Pubmed16919238 Reactome Database ID Release 43390347 Reactome, http://www.reactome.org ReactomeREACT_16889 Reviewed: Jassal, B, 2009-02-27 15:21:18 tetracosenoyl-CoA + 8 O2 + 8 H2O + 8 NAD+ + 8 CoASH => octanoyl-CoA + 8 H2O2 + 8 NADH + 8 H+ + 8 acetyl-CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 In eight cycles of beta-oxidation mediated by the same enzyme activities responsible for the conversion of hexacosanoyl-CoA to tetracosenoyl-CoA, the latter molecule is converted to octanoyl-CoA. Eight molecules each of O2, H2O, NAD+, and CoASH are consumed in the process and eight molecules of H2O2 and NADH + H+ are generated, together with eight molecules of acetyl-CoA (Wanders and Waterham 2006). Pubmed16756494 Reactome Database ID Release 43390302 Reactome, http://www.reactome.org ReactomeREACT_17013 Reviewed: Jassal, B, 2009-02-27 15:21:18 has a Stoichiometric coefficient of 8 Neurofascin:NrCAM:Ankyrin:spectrin based actin Reactome DB_ID: 443650 Reactome Database ID Release 43443650 Reactome, http://www.reactome.org ReactomeREACT_23030 has a Stoichiometric coefficient of 1 palmitoyl-CoA + 2 NADPH + 2 H+ => hexadecanol + 2 NADP+ [FAR1] Authored: D'Eustachio, P, 2009-03-16 18:50:14 EC Number: 1 Edited: D'Eustachio, P, 2009-03-18 13:33:40 Peroxisomal fatty acyl-CoA reductase 1 (FAR1) catalyzes the reaction of palmitoyl-CoA and 2 NADPH + 2 H+ to form hexadecanol, CoASH, and 2 NADP+. As judged from mRNA levels, FAR1 is widely expressed in the body (Cheng and Russell 2004). Pubmed15220348 Reactome Database ID Release 43390425 Reactome, http://www.reactome.org ReactomeREACT_17006 Reviewed: Jassal, B, 2009-02-27 15:21:18 has a Stoichiometric coefficient of 2 Neurofascin:NrCAM complex Reactome DB_ID: 373686 Reactome Database ID Release 43373686 Reactome, http://www.reactome.org ReactomeREACT_22606 has a Stoichiometric coefficient of 1 PathwayStep4560 PathwayStep4561 PathwayStep4564 PathwayStep4565 PathwayStep4562 PathwayStep4563 PathwayStep4558 Mevalonate is phosphorylated to mevalonate-5-phosphate Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 2.7.1.36 Mevalonate kinase (MK) catalyzes the phosphorylation of mevalonate to mevalonate-5-phosphate. Pubmed11111075 Pubmed1377680 Pubmed14730012 Reactome Database ID Release 43191380 Reactome, http://www.reactome.org ReactomeREACT_9448 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 PathwayStep4557 Reduction of HMG-CoA produces mevalonate 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the four-electron reduction of HMG-CoA to mevalonate. Mevalonate concentrations in the cell are tightly controlled through the activity of HMGR, which is one of the most highly regulated enzymes known (Goldstein and Brown 1990). Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 1.1.1.34 Pubmed10698924 Pubmed1967820 Reactome Database ID Release 43191352 Reactome, http://www.reactome.org ReactomeREACT_9482 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 has a Stoichiometric coefficient of 2 PathwayStep4556 Condensation of acetyl CoA with acetoacetyl CoA to form HMG-CoA 3-hydroxy-3-methylglutaryl Coenzyme A synthase (HMG-CoA synthase) catalyzes the condensation of acetyl CoA with acetoacetyl CoA to produce HMG-CoA. There are two forms of this enzyme, cytosolic and mitochondrial. The cytosolic form is ubiquitous in the body and is involved in cholesterol biosynthesis and synthesis of other isoprenoid products. The mitochondrial form, found solely in the liver and kidney, is involved in the ketogenic pathway. Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 2.3.3.10 Pubmed7913309 Reactome Database ID Release 43191323 Reactome, http://www.reactome.org ReactomeREACT_9443 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 PathwayStep4555 PathwayStep4559 Reduction of presqualene diphosphate to form squalene Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 2.5.1.21 In the second step, FDFT catalyzes the reduction of presqualene diphosphate to squalene (Pandit et al. 2000). Pubmed10896663 Reactome Database ID Release 43191402 Reactome, http://www.reactome.org ReactomeREACT_9504 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 Two FPP molecules dimerize to form presqualene diphosphate Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 2.5.1.21 Farnesyl diphosphate farnesyltransferase (FDFT; squalene synthase) catalyzes the reductive dimerization of two farnesyl diphosphate (FPP) molecules to form squalene. This happens in two distinct steps. The first step of dimerization forms presqualene diphosphate (Pandit et al. 2000). Pubmed10896663 Reactome Database ID Release 43191405 Reactome, http://www.reactome.org ReactomeREACT_9512 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 has a Stoichiometric coefficient of 2 Another isopentenyl pyrophosphate is added to geranyl pyrophosphate Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 2.5.1.10 Further condensation of an isopentenyl pyrophosphate with geranyl pyrophosphate to form farnesyl pyrophosphate is catalyzed by the prenyltransferases FPP synthase and GGPP synthase. (Kavanagh et al, 2006) Pubmed10026212 Pubmed16684881 Pubmed9741684 Reactome Database ID Release 43191303 Reactome, http://www.reactome.org ReactomeREACT_9451 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 Addition of isopentenyl pyrophosphate to DMAPP Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 2.5.1.1 Pubmed10026212 Pubmed16684881 Pubmed9741684 Reactome Database ID Release 43191322 Reactome, http://www.reactome.org ReactomeREACT_9467 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 The family of enzymes called prenyltransferases is involved in the biosynthesis of isoprenoids. Two members of this family are known to catalyse the sequential condensation of isopentenyl pyrophosphate to DMAPP: farnesyl pyrophosphate synthase (FPPS) and geranylgeranyl pyrophosphate synthetase (GGPPS) (Kavanaugh et al, 2006). Isopentenyl pyrophosphate rearranges to dimethylallyl pyrophosphate Authored: Jassal, B, 2007-01-24 15:15:12 Cytosolic isopentenyl diphosphate isomerase (IPP isomerase) catalyzes an essential activation step in the isoprenoid biosynthetic pathway. It rearranges isopentenyl pyrophosphate into its highly electrophilic isomer, dimethylallyl pyrophosphate (DMAPP). IPP isomerase may also be located in human peroxisomes but it's function there is not clear. EC Number: 5.3.3.2 Pubmed8806705 Reactome Database ID Release 43191382 Reactome, http://www.reactome.org ReactomeREACT_9517 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 Mevalonate-5-pyrophosphate is decarboxylated Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 4.1.1.33 Mevalonate pyrophosphate decarboxylase (MPD) decarboxylates mevalonate-5-pyrophosphate into isopentenyl pyrophosphate while hydrolysing ATP to ADP and orthophosphate. Pubmed8626466 Reactome Database ID Release 43191414 Reactome, http://www.reactome.org ReactomeREACT_9488 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 Mevalonate-5-phosphate is further phosphorylated. Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 2.7.4.2 Phosphomevalonate kinase (PMK) catalyzes the reversible, ATP-dependent phosphorylation of mevalonate-5-phosphate, producing mevalonate-5-pyrophosphate. Pubmed14729858 Pubmed16519518 Reactome Database ID Release 43191422 Reactome, http://www.reactome.org ReactomeREACT_9496 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 Netrin-1:DCC:pUNC5C Reactome DB_ID: 418827 Reactome Database ID Release 43418827 Reactome, http://www.reactome.org ReactomeREACT_22595 has a Stoichiometric coefficient of 1 pUNC5C:Netrin-1 Reactome DB_ID: 418821 Reactome Database ID Release 43418821 Reactome, http://www.reactome.org ReactomeREACT_22913 has a Stoichiometric coefficient of 1 UNC-5:Netrin-1 complex Reactome DB_ID: 373660 Reactome Database ID Release 43373660 Reactome, http://www.reactome.org ReactomeREACT_22538 has a Stoichiometric coefficient of 1 DCC bound to UNC-5:Netrin-1 Reactome DB_ID: 373654 Reactome Database ID Release 43373654 Reactome, http://www.reactome.org ReactomeREACT_22490 has a Stoichiometric coefficient of 1 Netrin-1:DCC:UNC5C Reactome DB_ID: 418818 Reactome Database ID Release 43418818 Reactome, http://www.reactome.org ReactomeREACT_22611 has a Stoichiometric coefficient of 1 UNC5C:Netrin-1 Reactome DB_ID: 418823 Reactome Database ID Release 43418823 Reactome, http://www.reactome.org ReactomeREACT_22617 has a Stoichiometric coefficient of 1 Active Cdc42 bound to Netrin:DCC complex Reactome DB_ID: 418820 Reactome Database ID Release 43418820 Reactome, http://www.reactome.org ReactomeREACT_22825 has a Stoichiometric coefficient of 1 Active Rac1 bound to Netrin-1-DCC complex Reactome DB_ID: 418826 Reactome Database ID Release 43418826 Reactome, http://www.reactome.org ReactomeREACT_22845 has a Stoichiometric coefficient of 1 Netrin:DCC:Nck:Cdc42-GTP:Active N-WASP:PIP2 Reactome DB_ID: 418834 Reactome Database ID Release 43418834 Reactome, http://www.reactome.org ReactomeREACT_22730 has a Stoichiometric coefficient of 1 PathwayStep4550 Netrin-1:DCC:pFyn:Nck:Rac1-GTP:Ablim Reactome DB_ID: 418814 Reactome Database ID Release 43418814 Reactome, http://www.reactome.org ReactomeREACT_23105 has a Stoichiometric coefficient of 1 PathwayStep4551 PathwayStep4552 PathwayStep4553 PathwayStep4554 PathwayStep4545 Squalene 2,3-epoxide cyclizes, forming lanosterol Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 5.4.99.7 Lanosterol synthase (LS) catalyzes the cyclization of squalene 2,3-epoxide to lanosterol, a reaction that forms the sterol nucleus.LS is located on the ER membrane and is active as the monomer (Ruf et al, 2004). Pubmed14766201 Pubmed5918048 Pubmed8593458 Reactome Database ID Release 43191366 Reactome, http://www.reactome.org ReactomeREACT_9391 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 PathwayStep4544 Squalene is oxidized to its epoxide Authored: Jassal, B, 2007-01-24 15:15:12 EC Number: 1.14.99.7 Pubmed10666321 Reactome Database ID Release 43191299 Reactome, http://www.reactome.org ReactomeREACT_9420 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 Squalene monooxygenase (squalene epoxidase, SE) is located on the endoplamic reticulum. It catalyzes the oxidation of squalene to squalene 2,3-epoxide. SE seems to be an important rate-limiting enzyme in cholesterol biosynthesis. PathwayStep4547 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol is reduced to 4,4-dimethylcholesta-8(9),24-dien-3beta-ol [LBR] 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + NADPH + H+ => 4,4-dimethylcholesta-8(9),24-dien-3beta-ol + NADP+ [LBR] 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol and NADPH + H+ react to form 4,4-dimethylcholesta-8(9),24-dien-3beta-ol and NADP+, catalyzed by LBR in the nuclear envelope. LBR protein spans the inner nuclear envelope, has an aminoterminal region with properties of a laminin receptor and a carboxyterminal domain with sequence similarity to sterol delta14-reductases (Holmer et al. 1998). Studies of material from an individual with HEM/Greenberg skeletal dysplasia indicate that LBR catalyzes the sterol delta14-reductase step of cholesterol biosynthesis in vivo. DNA sequencing revealed homozygosity for a mutant LBR allele encoding a truncated protein in the affected individual, and cells from the individual accumulated cholesta-8,14-dien-3beta-ol in culture. Transfection of wild-type LBR into the cultured cells reversed the accumulation of cholesta-8,14-dien-3beta-ol (Waterham et al. 2003). This observation is surprising because a second gene, TM7SF2, encodes an efficient sterol delta14-reductase that is localized to the endoplasmic reticulum whose expression is up-regulated in response to sterol depletion (Bennati et al. 2006). The physiological roles of LBR and TM7SF2 in vivo remain to be determined. Authored: D'Eustachio, P, 2007-04-21 18:31:40 EC Number: 1.3.1.70 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed12618959 Pubmed16784888 Pubmed9878250 Reactome Database ID Release 43194674 Reactome, http://www.reactome.org ReactomeREACT_9995 Reviewed: Jassal, B, 2007-04-21 18:33:24 PathwayStep4546 Lanosterol is oxidatively demethylated to 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.14.13.70 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Lanosterol, NADPH + H+, and O2 react to form 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol, NADP+, H2O and formate. This oxidative demethylation reaction, in the endoplasmic reticulum, is catalyzed by lanosterol 14alpha-demethylase (CYP51A1). Although the reaction is annotated here as a single concerted event, studies with purified rat enzyme indicate that the methyl group is converted successively to an alcohol and an aldehyde before being released as formate (Trzaskos et al. 1986; Fischer et al. 1991; Gaylor 2002). Pubmed11969204 Pubmed2007571 Pubmed3771545 Pubmed8619637 Reactome Database ID Release 43194678 Reactome, http://www.reactome.org ReactomeREACT_10006 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 4 lanosterol + 3 NADPH + 3 H+ + 3 O2 => 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + 3 NADP+ + 4 H2O + formate PathwayStep4549 PathwayStep4548 4-carboxycholesta-8(9),24-dien-3beta-ol + NAD+ => cholesta-8(9),24-dien-3-one (zymosterone) + CO2 + NADH + H+ 4-carboxycholesta-8(9),24-dien-3beta-ol and NAD+ react to form zymosterone (cholesta-8(9),24-dien-3-one), CO2, and NADH + H+. This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL (Caldas and Herman 2003). Defects in this enzyme are associated with CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) (Konig et al. 2000), but cholesterol biosynthesis in cells and tissues from affceted individuals has not been characterized. Instead, the mechanism and stoichiometry of the reaction are inferred from biochemical studies of partially purified rat enzyme (Rahimtula and Gaylor 1972). 4-carboxycholesta-8(9),24-dien-3beta-ol is decarboxylated and oxidized to form cholesta-8(9),24-dien-3-one (zymosterone) Authored: D'Eustachio, P, 2007-04-21 18:31:40 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed10710235 Pubmed14506130 Pubmed4401584 Reactome Database ID Release 43194718 Reactome, http://www.reactome.org ReactomeREACT_9949 Reviewed: Jassal, B, 2007-04-21 18:33:24 4-methylcholesta-8(9),24-dien-3beta-ol is oxidized to 4-carboxycholesta-8(9),24-dien-3beta-ol 4-methylcholesta-8(9),24-dien-3beta-ol + 3 NADPH + 3 H+ + 3 O2 => 4-carboxycholesta-8(9),24-dien-3beta-ol + 3 NADP+ + 4 H2O 4-methylcholesta-8(9),24-dien-3beta-ol, NADPH + H+, and O2 react to form 4-carboxycholesta-8(9),24-dien-3beta-ol, NADP+, and H2O. This reaction, in the endoplasmic reticulum, is catalyzed by SC4MOL (C-4 methylsterol oxidase). The human enzyme has been identified based on its sequence similarity to yeast methyl sterol oxidase (ERG25) and the ability of the cloned human gene to rescue ERG25-deficient yeast cells (Li and Kaplan 1996). The mechanism and stoichiometry of the reaction have been inferred from studies of partially purified rat enzyme (Gaylor et al. 1975; Fukushima et al. 1981). Authored: D'Eustachio, P, 2007-04-21 18:31:40 EC Number: 1.14.13.72 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed240818 Pubmed7228857 Pubmed8663358 Reactome Database ID Release 43194669 Reactome, http://www.reactome.org ReactomeREACT_10059 Reviewed: Jassal, B, 2007-04-21 18:33:24 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 4 4,4-dimethylcholesta-8(9),24-dien-3beta-ol is oxidized to 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol 4,4-dimethylcholesta-8(9),24-dien-3beta-ol + 3 NADPH + 3 H+ + 3 O2 => 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol + 3 NADP+ + 4 H2O 4,4-dimethylcholesta-8(9),24-dien-3beta-ol, NADPH + H+, and O2 react to form 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol, NADP+, and H2O. This reaction, in the endoplasmic reticulum, is catalyzed by SC4MOL (C-4 methylsterol oxidase). The human enzyme has been identified based on its sequence similarity to yeast methyl sterol oxidase (ERG25) and the ability of the cloned human gene to rescue ERG25-deficient yeast cells (Li and Kaplan 1996). The mechanism and stoichiometry of the reaction have been inferred from studies of partially purified rat enzyme (Gaylor et al. 1975; Fukushima et al. 1981). Authored: D'Eustachio, P, 2007-04-21 18:31:40 EC Number: 1.14.13.72 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed240818 Pubmed7228857 Pubmed8663358 Reactome Database ID Release 43194641 Reactome, http://www.reactome.org ReactomeREACT_10070 Reviewed: Jassal, B, 2007-04-21 18:33:24 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 4 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol is reduced to 4,4-dimethylcholesta-8(9),24-dien-3beta-ol [TM7SF2] 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol + NADPH + H+ => 4,4-dimethylcholesta-8(9),24-dien-3beta-ol + NADP+ [TM7SF2] 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol and NADPH + H+ react to form 4,4-dimethylcholesta-8(9),24-dien-3beta-ol and NADP+, catalyzed by TM7SF2 in the endoplasmic reticulum. TM7SF2 protein has sterol delta14-reductase activity in vitro, and expression of the gene is induced by sterol starvation in human cells, as expected for a gene involved in sterol biosynthesis (Bennati et al. 2006). However, molecular studies of material from an individual with HEM/Greenberg skeletal dysplasia indicate that LBR, a protein that spans the inner nuclear membrane and has both laminin receptor and sterol delta14-reductase activities, is required for normal sterol 14delta-reductase activity in human cells. It remains to be determined whether both LBR and TM7SF2 catalyze this reaction in vivo, and whether the role of TM7SF2 is essential (Waterham et al. 2003). Authored: D'Eustachio, P, 2007-04-21 18:31:40 EC Number: 1.3.1.70 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed12618959 Pubmed16784888 Reactome Database ID Release 43194698 Reactome, http://www.reactome.org ReactomeREACT_10081 Reviewed: Jassal, B, 2007-04-21 18:33:24 4-methylcholesta-8(9),24-dien-3-one is reduced to 4-methylcholesta-8(9),24-dien-3beta-ol 4-methylcholesta-8(9),24-dien-3-one + NADPH + H+ => 4-methylcholesta-8(9),24-dien-3beta-ol + NADP+ 4-methylcholesta-8(9),24-dien-3-one and NADPH + H+ react to form 4-methylcholesta-8(9),24-dien-3beta-ol and NADP+. This reaction takes place in the endoplasmic reticulum, catalyzed by HSD17B7. Two isoforms of the enzyme due to alternative splicing have been identified but only the first has been tested for enzymatic activity (Marijanovic et al. 2003). The human enzyme has not been studied extensively; molecular details of the reaction are inferred from those worked out in studies of material from rat liver (Gaylor 2002). Authored: D'Eustachio, P, 2007-04-21 18:31:40 EC Number: 1.1.1.270 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed11969204 Pubmed12829805 Reactome Database ID Release 43194689 Reactome, http://www.reactome.org ReactomeREACT_10036 Reviewed: Jassal, B, 2007-04-21 18:33:24 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol + NAD+ => 4-methylcholesta-8(9),24-dien-3-one + CO2 + NADH + H+ 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol and NAD+ react to form 4-methylcholesta-8(9),24-dien-3-one, CO2, and NADH + H+. This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL (Caldas and Herman 2003). Defects in this enzyme are associated with CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) (Konig et al. 2000), but cholesterol biosynthesis in cells and tissues from affected individuals has not been characterized. Instead, the mechanism and stoichiometry of the reaction are inferred from biochemical studies of partially purified rat enzyme (Rahimtula and Gaylor 1972). 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol is decarboxylated and oxidized to form 4-methylcholesta-8(9),24-dien-3-one Authored: D'Eustachio, P, 2007-04-21 18:31:40 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed10710235 Pubmed14506130 Pubmed4401584 Reactome Database ID Release 43194642 Reactome, http://www.reactome.org ReactomeREACT_10053 Reviewed: Jassal, B, 2007-04-21 18:33:24 DCC:Ezrin complex Reactome DB_ID: 374565 Reactome Database ID Release 43374565 Reactome, http://www.reactome.org ReactomeREACT_22661 has a Stoichiometric coefficient of 1 DCC&UNC5A:Netrin-4 Reactome DB_ID: 593689 Reactome Database ID Release 43593689 Reactome, http://www.reactome.org ReactomeREACT_23166 has a Stoichiometric coefficient of 1 Ezrin:PIP2 Reactome DB_ID: 374570 Reactome Database ID Release 43374570 Reactome, http://www.reactome.org ReactomeREACT_23169 has a Stoichiometric coefficient of 1 pEzrin:PIP2 Reactome DB_ID: 374558 Reactome Database ID Release 43374558 Reactome, http://www.reactome.org ReactomeREACT_22690 has a Stoichiometric coefficient of 1 Netrin-1:Neogenin Reactome DB_ID: 374592 Reactome Database ID Release 43374592 Reactome, http://www.reactome.org ReactomeREACT_23329 has a Stoichiometric coefficient of 1 PathwayStep4586 PathwayStep4587 Netrin1:pUnc5C:DCC:Shp2 Reactome DB_ID: 418825 Reactome Database ID Release 43418825 Reactome, http://www.reactome.org ReactomeREACT_23193 has a Stoichiometric coefficient of 1 PathwayStep4584 PathwayStep4585 PathwayStep4582 SIAH1 bound to DCC:Netrin-1 Reactome DB_ID: 374593 Reactome Database ID Release 43374593 Reactome, http://www.reactome.org ReactomeREACT_23235 has a Stoichiometric coefficient of 1 PathwayStep4583 SIAH2 bound to DCC:Netrin-1 Reactome DB_ID: 374590 Reactome Database ID Release 43374590 Reactome, http://www.reactome.org ReactomeREACT_22880 has a Stoichiometric coefficient of 1 PathwayStep4580 Robo:Slit Reactome DB_ID: 204367 Reactome Database ID Release 43204367 Reactome, http://www.reactome.org ReactomeREACT_22837 has a Stoichiometric coefficient of 1 PathwayStep4581 DCC:Robo:Slit Reactome DB_ID: 373666 Reactome Database ID Release 43373666 Reactome, http://www.reactome.org ReactomeREACT_23020 has a Stoichiometric coefficient of 1 Zymosterone (cholesta-8(9),24-dien-3-one) is reduced to zymosterol (cholesta-8(9),24-dien-3beta-ol) Authored: D'Eustachio, P, 2007-04-21 18:31:40 EC Number: 1.1.1.270 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed11969204 Pubmed12829805 Reactome Database ID Release 43194632 Reactome, http://www.reactome.org ReactomeREACT_10079 Reviewed: Jassal, B, 2007-04-21 18:33:24 Zymosterone (cholesta-8(9),24-dien-3-one) and NADPH + H+ react to form zymosterol (cholesta-8(9),24-dien-3beta-ol) and NADP+. This reaction takes place in the endoplasmic reticulum, catalyzed by HSD17B7. Two isoforms of the enzyme due to alternative splicing have been identified but only the first has been tested for enzymatic activity (Marijanovic et al. 2003). The human enzyme has not been studied extensively; molecular details of the reaction are inferred from those worked out in studies of material from rat liver (Gaylor 2002). zymosterone (cholesta-8(9),24-dien-3-one) + NADPH + H+ => zymosterol (cholesta-8(9),24-dien-3beta-ol) + NADP+ Reduction of desmosterol to cholesterol Authored: D'Eustachio, P, 2007-04-21 18:31:40 Desmosterol is reduced by NADPH + H+ to form cholesterol and NADP+, catalyzed by DHCR24 associated with the endoplasmic reticulum membrane. EC Number: 1.3.1.72 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed11519011 Reactome Database ID Release 43196417 Reactome, http://www.reactome.org ReactomeREACT_10122 Reviewed: Jassal, B, 2007-04-21 18:33:24 desmosterol + NADPH + H+ => cholesterol + NADP+ PathwayStep4579 Cholesta-5,7,24-trien-3beta-ol is reduced to desmosterol Authored: D'Eustachio, P, 2007-04-21 18:31:40 Cholesta-5,7,24-trien-3beta-ol and NADPH + H+ react to form desmosterol and NADP+. This reaction is catalyzed by DHCR7, associated with the endoplasmic reticulum membrane. The biochemical details of the reaction are inferred from those of the reaction catalyzed by the well-studied rat enzyme (Bae et al. 1999). EC Number: 1.3.1.21 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed10329655 Pubmed9465114 Reactome Database ID Release 43196402 Reactome, http://www.reactome.org ReactomeREACT_10029 Reviewed: Jassal, B, 2007-04-21 18:33:24 cholesta-5,7,24-trien-3beta-ol + NADPH + H+ => desmosterol + NADP+ PathwayStep4578 Cholesta-7,24-dien-3beta-ol is desaturated to form cholesta-5,7,24-trien-3beta-ol Authored: D'Eustachio, P, 2007-04-21 18:31:40 Cholesta-7,24-dien-3beta-ol, NADPH + H+, and O2 react to form cholesta-5,7,24-trien-3beta-ol, NADP+, and 2 H2O, catalyzed by SC5D. This reaction takes place in the endoplasmic reticulum. Its biochemical details are inferred from those of the reaction catalyzed by the purified rat protein (Kawata et al. 1985). The role of human SC5D in catalyzing this reaction in vivo is established from studies of patients in whom the enzyme is defective (Brunetti-Pierri et al. 2002; Krakowiak et al. 2003). Edited: D'Eustachio, P, 2007-04-21 18:31:40 Pubmed12189593 Pubmed12812989 Pubmed3997841 Reactome Database ID Release 43195664 Reactome, http://www.reactome.org ReactomeREACT_10092 Reviewed: Jassal, B, 2007-04-21 18:33:24 cholesta-7,24-dien-3beta-ol + NADPH + H+ + O2 => cholesta-5,7,24-trien-3beta-ol + NADP+ + 2 H2O has a Stoichiometric coefficient of 2 Importin alpha Converted from EntitySet in Reactome Reactome DB_ID: 1176065 Reactome Database ID Release 431176065 Reactome, http://www.reactome.org ReactomeREACT_116843 PathwayStep4577 Zymosterol => cholesta-7,24-dien-3beta-ol Authored: D'Eustachio, P, 2007-04-21 18:31:40 EC Number: 5.3.3.1 Edited: D'Eustachio, P, 2007-04-21 18:31:40 Isomerization of zymosterol to cholesta-7,24-dien-3beta-ol is catalyzed by EBP in the endoplasmic reticulum. The biochemical details of the reaction have been established through studies of purified rat EBP; the role of the human enzyme has been established through studies of patients deficient in it (Derry et al. 1999; Braverman et al. 1999). Pubmed10391218 Pubmed10391219 Pubmed2422166 Reactome Database ID Release 43195690 Reactome, http://www.reactome.org ReactomeREACT_9999 Reviewed: Jassal, B, 2007-04-21 18:33:24 Zymosterol is isomerized to cholesta-7,24-dien-3beta-ol SREBP1A/1C/2:SCAP Transits to the Golgi Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 In low concentrations of cholesterol SCAP interacts with Sec24 of the CopII coat complex causing SCAP:SREBP1A/1C/2 to be transported with the CopII complex from the endoplasmic reticulum to the Golgi. Reactome Database ID Release 431655834 Reactome, http://www.reactome.org ReactomeREACT_147789 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2:SCAP Transits to the Golgi SREBP1A/1C/2:SCAP Binds CopII Coat Complex Authored: May, B, 2011-09-28 Edited: May, B, 2011-09-28 Reactome Database ID Release 431655825 Reactome, http://www.reactome.org ReactomeREACT_147779 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2:SCAP Binds CopII Coat Complex SREBPs (SREBP1A, SREBP1C, SREBP2, also known as SREBFs) are transmembrane proteins that bind SCAP in the endoplasmic reticulum membrane. In the presence of cholesterol or oxysterols SCAP:SREBP1A/1C/2 binds INSIG and is retained in the endoplasmic reticulum. At cholesterol concentrations below 5 mol% SCAP changes conformation, SCAP:SREBP1A/1C/2 loses interaction with INSIG, binds the CopII coat complex, and is translocated to the Golgi. SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:INSIG:oxysterol Authored: May, B, 2012-06-10 Edited: May, B, 2012-06-10 INSIG binds oxysterols and the INSIG:oxysterol complex interacts with SCAP subunits of the SREBP1A/1C/2:SCAP (SREBF1A/1C/2:SCAP) complex. This interaction retains the SREBP1A/1C/2:SCAP:INSIG:oxysterol complex in the endoplasmic reticulum. The order of assembly of the SREBP1A/1C/2:SCAP:INSIG:oxysterol complex is unknown. Reactome Database ID Release 432317531 Reactome, http://www.reactome.org ReactomeREACT_147695 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 is retained in the endoplasmic reticulum by SCAP:INSIG:oxysterol has a Stoichiometric coefficient of 4 SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG Authored: May, B, 2012-06-10 Edited: May, B, 2012-06-10 Reactome Database ID Release 432317530 Reactome, http://www.reactome.org ReactomeREACT_147892 Reviewed: Liang, Guosheng, 2012-08-25 SREBF1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG SREBPs (SREBP1A/1C/2, SREBFs) bind SCAP in the endoplasmic reticulum membrane. Luminal loop 1 of SCAP binds cholesterol which prevents SCAP from interacting with Sec24 in the CopII coat complex and allows SCAP to interact with INSIG instead. These interactions retain SCAP:SREBP1A/1C/2 in the endoplasmic reticulum. The order of assembly of the SREBP1A/1C/2:SCAP:cholesterol:INSIG complex is unknown. has a Stoichiometric coefficient of 4 Importin alpha Converted from EntitySet in Reactome Reactome DB_ID: 1176071 Reactome Database ID Release 431176071 Reactome, http://www.reactome.org ReactomeREACT_117741 E2 congugating enzymes Converted from EntitySet in Reactome Reactome DB_ID: 1169378 Reactome Database ID Release 431169378 Reactome, http://www.reactome.org ReactomeREACT_117817 S1P Cleaves SREBP1A/1C/2 Authored: May, B, 2011-09-28 EC Number: 3.4.21 Edited: May, B, 2011-09-28 Pubmed10428864 Pubmed10644685 Pubmed17449569 Pubmed8156598 Pubmed8674110 Pubmed9488713 Reactome Database ID Release 431655842 Reactome, http://www.reactome.org ReactomeREACT_147792 Reviewed: Liang, Guosheng, 2012-08-25 S1P (MBTPS1, SKI-1), a membrane-bound protease in the Golgi, cleaves the intralumenal loop of SREBP1A/1C/2 (SREBF1A/1C/2), releasing the N-terminal domain of SREBP1A/1C/2, which remains bound to the membrane. S1P Cleaves SREBF1A/1C/2 SKI-1 Cleaves SREBP1A/1C/2 has a Stoichiometric coefficient of 4 TRPC1+4/5 Reactome DB_ID: 622385 Reactome Database ID Release 43622385 Reactome, http://www.reactome.org ReactomeREACT_22782 has a Stoichiometric coefficient of 1 Activated TRP channels Reactome DB_ID: 622374 Reactome Database ID Release 43622374 Reactome, http://www.reactome.org ReactomeREACT_22774 has a Stoichiometric coefficient of 1 Robo1/Robo2:Robo3A.1 Reactome DB_ID: 428496 Reactome Database ID Release 43428496 Reactome, http://www.reactome.org ReactomeREACT_19631 has a Stoichiometric coefficient of 1 Glypican-1:HSPG Reactome DB_ID: 428493 Reactome Database ID Release 43428493 Reactome, http://www.reactome.org ReactomeREACT_19843 has a Stoichiometric coefficient of 1 PathwayStep4573 PathwayStep4574 PathwayStep4575 Neogenin:RGD Reactome DB_ID: 374583 Reactome Database ID Release 43374583 Reactome, http://www.reactome.org ReactomeREACT_23351 has a Stoichiometric coefficient of 1 PathwayStep4576 Myosin-X:DCC/Neogenin Reactome DB_ID: 593674 Reactome Database ID Release 43593674 Reactome, http://www.reactome.org ReactomeREACT_23119 has a Stoichiometric coefficient of 1 PIKE-L:UNC5B Reactome DB_ID: 622358 Reactome Database ID Release 43622358 Reactome, http://www.reactome.org ReactomeREACT_22961 has a Stoichiometric coefficient of 1 PathwayStep4570 Netrin:DCC:PITP Reactome DB_ID: 418843 Reactome Database ID Release 43418843 Reactome, http://www.reactome.org ReactomeREACT_23076 has a Stoichiometric coefficient of 1 PathwayStep4571 pPLCgamma:PIP2 Reactome DB_ID: 622379 Reactome Database ID Release 43622379 Reactome, http://www.reactome.org ReactomeREACT_22512 has a Stoichiometric coefficient of 1 PathwayStep4572 TRPC channels Reactome DB_ID: 622392 Reactome Database ID Release 43622392 Reactome, http://www.reactome.org ReactomeREACT_22951 has a Stoichiometric coefficient of 1 PathwayStep4567 PathwayStep4566 PathwayStep4569 PathwayStep4568 EIF4E1/EIF4E3 Converted from EntitySet in Reactome Reactome DB_ID: 1678829 Reactome Database ID Release 431678829 Reactome, http://www.reactome.org ReactomeREACT_117695 EIF4G Converted from EntitySet in Reactome Reactome DB_ID: 1678828 Reactome Database ID Release 431678828 Reactome, http://www.reactome.org ReactomeREACT_116308 PathwayStep4766 PathwayStep4767 PathwayStep4764 PathwayStep4765 PathwayStep4768 PathwayStep4769 25-hydroxycholesterol is 7alpha-hydroxylated by CYP7B1 25-hydroxycholesterol is 7alpha-hydroxylated to cholest-5-ene-3beta,7alpha,25-triol by CYP7B1. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: D'Eustachio, P, 2007-04-30 14:43:26 Pubmed10588945 Reactome Database ID Release 43192065 Reactome, http://www.reactome.org ReactomeREACT_9950 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Co-transport (influx) of bile salts and acids and sodium ions by ASBT A molecule of extracellular bile salt or bile acid (cholate, chenodeoxycholate, or their glycine or taurine conjugates) and a sodium ion are transported into the cytosol, mediated by ASBT (apical sodium-dependent bile acid transporter; SLC10A2) in the plasma membrane. Within the cytosol, bile salts and acids are bound to a carrier protein, FABP6 (I-BABP) (Fujita et al. 1995). Studies in a rabbit model system suggest that translocation and FABP6 binding occur as a single concerted event (Kramer et al. 1995). In the body, ASBT is expressed on the apical surfaces of enterocytes, and this reaction is the first step in the process by which bile salts and acids are reaborbed from the intestinal lumen and returned to the liver (Kullak-Ublick et al. 2004; Trauner and Boyer 2002). Authored: D'Eustachio, P, 2007-03-09 21:29:31 Edited: D'Eustachio, P, 2007-03-09 21:29:31 Pubmed12663868 Pubmed14699511 Pubmed7588781 Pubmed7864816 Pubmed9109432 Pubmed9458785 Reactome Database ID Release 43194187 Reactome, http://www.reactome.org ReactomeREACT_10050 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5beta-cholestan-3alpha,7alpha,27-triol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-3alpha,7alpha,27-triol is transported from the cytosol to the mitochondrial matrix. The transporter that mediates its passage across the inner mitochondrial membrane is unknown: the StAR protein that performs this function for cholesterol at the start of steroid hormone biosynthesis is excluded as StAR is not expressed in liver. Other members of the START family of transporters are candidates, however (Russell 2003). Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed12543708 Reactome Database ID Release 43193808 Reactome, http://www.reactome.org ReactomeREACT_10080 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Cholesterol is hydroxylated to 25-hydroxycholesterol Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-04-30 14:43:26 Pubmed9852097 Reactome Database ID Release 43191983 Reactome, http://www.reactome.org ReactomeREACT_10030 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 The microsomal enzyme cholesterol 25-hydroxylase is a member of a lipid metabolizing enzyme family that utilizes oxygen and diiron-oxygen cofactor to hydroxylate, desaturate, epoxidate and acetylate substrates. Myod:phospho-E heterodimers Reactome DB_ID: 448886 Reactome Database ID Release 43448886 Reactome, http://www.reactome.org ReactomeREACT_22043 has a Stoichiometric coefficient of 1 Cytosolic cholate and chenodeoxycholate are conjugated with Coenzyme A (SLC27A5 BACS) Authored: Jassal, B, 2005-03-09 13:42:30 Cholate or chenodeoxycholate, coenzyme A, and ATP react to form their CoA conjugates, AMP, pyrophosphate and water. This reaction is catalyzed by SLC27A5 (BACS) associated with the endoplasmic reticulum membrane, but the substrates and products are cytosolic (Mihalik et al. 2002). EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-03-09 21:29:31 Pubmed11980911 Reactome Database ID Release 43159425 Reactome, http://www.reactome.org ReactomeREACT_10034 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 pp38 alpha/beta/gamma:ABL1:JLP:CDO complex Reactome DB_ID: 448881 Reactome Database ID Release 43448881 Reactome, http://www.reactome.org ReactomeREACT_21750 has a Stoichiometric coefficient of 1 Transport (influx) of glycocholate and taurocholate by OATP-8 A molecule of extracellular glycocholate or taurocholate is transported into the cytosol, mediated by OATP-8 (SLCO1B3) in the plasma membrane. Glycocholate and taurocholate exist in the blood as complexes with serum albumin, and their uptake by OATP-8 must involve disruption of these complexes, but the molecular mechanism coupling disruption and uptake is unknown. In the body, OATP-8 is expressed on the basolateral surfaces of hepatocytes and may play a role in the uptake of glycocholate and taurocholate by the liver under physiological conditions (Kullak-Ublick et al. 2004; Trauner and Boyer 2002). Authored: D'Eustachio, P, 2007-03-09 21:29:31 Edited: D'Eustachio, P, 2007-03-09 21:29:31 Pubmed11159893 Pubmed12663868 Pubmed14699511 Reactome Database ID Release 43194079 Reactome, http://www.reactome.org ReactomeREACT_10124 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 p38 alpha/beta/gamma:ABL1:JLP:CDO complex Reactome DB_ID: 448887 Reactome Database ID Release 43448887 Reactome, http://www.reactome.org ReactomeREACT_21610 has a Stoichiometric coefficient of 1 Transport (influx) of glycocholate and taurocholate by OATP-C A molecule of extracellular glycocholate or taurocholate is transported into the cytosol, mediated by OATP-C (SLCO1B1) in the plasma membrane. Glyco- and taurocholate exist in the blood as complexes with serum albumin, and its uptake by OATP-C must involve disruption of this complex, but the molecular mechanism coupling disruption and uptake is unknown. In the body, OATP-C is expressed on the basolateral surfaces of hepatocytes and may play a role in the uptake of glyco- and taurocholate by the liver under physiological conditions (Kullak-Ublick et al. 2004; Trauner and Boyer 2002). Authored: D'Eustachio, P, 2007-03-09 21:29:31 Edited: D'Eustachio, P, 2007-03-09 21:29:31 Pubmed10358072 Pubmed10644574 Pubmed11159893 Pubmed12663868 Pubmed14699511 Reactome Database ID Release 43194083 Reactome, http://www.reactome.org ReactomeREACT_10091 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 ABL1:JLP:CDO complex Reactome DB_ID: 449191 Reactome Database ID Release 43449191 Reactome, http://www.reactome.org ReactomeREACT_21587 has a Stoichiometric coefficient of 1 Transport (influx) of bile salts and acids by OATP-A A molecule of extracellular bile salt (glyco- or taurocholate or taurochenodeoxycholate) or bile acid (cholate or chenodeoxycholate) is transported into the cytosol, mediated by OATP-A (SLCO1A2) in the plasma membrane. Bile salts and acids exist in the blood as complexes with serum albumin, and their uptake by OATP-A must involve disruption of this complex, but the molecular mechanism coupling release of a bile salt or acid from albumin to its uptake by OATP-A is unknown. In the body, OATP-A is expressed only at low levels on the basolateral surfaces of hepatocytes and may play only a minor role in the uptake of bile salts and acids by the liver (Kullak-Ublick et al. 2004; Trauner and Boyer 2002). Authored: D'Eustachio, P, 2007-03-09 21:29:31 Edited: D'Eustachio, P, 2007-03-09 21:29:31 Pubmed12663868 Pubmed14699511 Pubmed7557095 Reactome Database ID Release 43194130 Reactome, http://www.reactome.org ReactomeREACT_10072 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Cadherin-catenin:JLP:CDO:BOC:Bnip2-Cdc42 Reactome DB_ID: 376011 Reactome Database ID Release 43376011 Reactome, http://www.reactome.org ReactomeREACT_21868 has a Stoichiometric coefficient of 1 Co-transport (influx) of bile salts and sodium ions by NTCP A molecule of extracellular bile salt (glyco- or taurocholate, or glyco- or taurochenodeoxycholate) and two sodium ions are transported into the cytosol, mediated by NTCP (Na+ / taurocholate cotransporter) in the plasma membrane. Bile salts exist in the blood as complexes with serum albumin, and their uptake by NTCP must involve disruption of this complex, but the molecular mechanism of the coupling of the release of a bile salt from albumin to its uptake by NTCP is unknown. In the body, NTCP is expressed on the basolateral surfaces of hepatocytes, and this reaction is the major route by which bile salts reaborbed from the intestinal lumen into the portal circulation are recovered by the liver (Kullak-Ublick et al. 2004; Trauner and Boyer 2002). Authored: D'Eustachio, P, 2007-03-09 21:29:31 Edited: D'Eustachio, P, 2007-03-09 21:29:31 Pubmed12663868 Pubmed14699511 Pubmed8132774 Reactome Database ID Release 43194121 Reactome, http://www.reactome.org ReactomeREACT_9958 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 has a Stoichiometric coefficient of 2 Cadherin-catenin:CDO:BOC:Bnip2:CDC42-GTP Reactome DB_ID: 448875 Reactome Database ID Release 43448875 Reactome, http://www.reactome.org ReactomeREACT_22063 has a Stoichiometric coefficient of 1 Transport (efflux) of bile salts by ABCC3 (MRP3) A molecule of glycocholate, taurocholate, or taurochenodeoxycholate is transported from the cytosol to the extracellular space, coupled to the hydrolysis of a molecule of cytosolic ATP to ADP and orthophosphate. This reaction is mediated by ABCB3 (MRP3). In the body, this reaction mediates the release of bile salts from enterocytes into the blood (Kullak-Ublick et al. 2004; Trauner and Boyer 2002). In the cytosol, bile salts and acids are bound to a carrier protein, FABP6 (I-BABP) (Fujita et al. 1995), and in the blood these molecules are complexed with albumin. The mechanisms by which transport across the plasma membrane is coupled to release FABP6 and binding to albumin are unknown, so the entire process is annotated as a single concerted event. Authored: D'Eustachio, P, 2007-03-09 21:29:31 Edited: D'Eustachio, P, 2007-03-09 21:29:31 Pubmed10987286 Pubmed12220224 Pubmed12663868 Pubmed12704183 Pubmed14699511 Pubmed7588781 Reactome Database ID Release 43194153 Reactome, http://www.reactome.org ReactomeREACT_10078 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Cadherin-catenin:CDO:BOC:Bnip2 Reactome DB_ID: 376008 Reactome Database ID Release 43376008 Reactome, http://www.reactome.org ReactomeREACT_21887 has a Stoichiometric coefficient of 1 PathwayStep4770 CDO:BOC:Trans-cadherin homodimer:catenin Reactome DB_ID: 375092 Reactome Database ID Release 43375092 Reactome, http://www.reactome.org ReactomeREACT_21975 has a Stoichiometric coefficient of 1 Cadherin:Catenin Reactome DB_ID: 448876 Reactome Database ID Release 43448876 Reactome, http://www.reactome.org ReactomeREACT_22028 has a Stoichiometric coefficient of 1 Trans-cadherin homodimers Reactome DB_ID: 448888 Reactome Database ID Release 43448888 Reactome, http://www.reactome.org ReactomeREACT_21790 has a Stoichiometric coefficient of 2 PathwayStep4774 PathwayStep4773 PathwayStep4772 PathwayStep4771 PathwayStep4775 Phosphorylation of SLP-76 by p-SYK Activation of DAP12-associated receptors leads to tyrosine phosphorylation of SLP-76, an adaptor protein with multiple binding domains (Gross et al. 1999). SLP-76 has three potential tyrosine phosphorylation sites within its amino terminus region: Y113, Y128, and Y145. Phosphorylation may be mediated by SYK, analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996). Authored: Garapati, P V, 2012-05-25 EC Number: 2.7.10 Edited: Garapati, P V, 2012-05-25 Pubmed10026222 Pubmed19592646 Pubmed8702662 Reactome Database ID Release 432396594 Reactome, http://www.reactome.org ReactomeREACT_147736 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 3 PathwayStep4776 Recruitment of VAV and BTK to p-SLP-76 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Pubmed10934226 Pubmed12640123 Pubmed15365099 Pubmed21659545 Reactome Database ID Release 432424481 Reactome, http://www.reactome.org ReactomeREACT_147785 Reviewed: Lanier, Lewis L, 2012-08-09 VAV2 and VAV3 are expressed in human NK cells and play a central role in NK cell-mediated cytotoxicity. They are required for DAP12-mediated signaling; their loss profoundly impairs DAP12-induced cytotoxicity (Billadeau et al. 2000, Cella et al. 2004). Phosphorylated SLP-76 tyrosines Y113 and Y128 provide binding sites for the SH2 domains of VAV. The binding of VAV to these phosphotyrosine residues may link SLP-76 to the Jun amino-terminal kinase (JNK) pathway and the actin cytoskeleton. Y145 has been implicated in the binding of SLP-76 to the Tec family kinase BTK (Kettner et al. 2003). BTK is required for secretion of pro-inflammatory cytokines, phosphorylation of ERK1/2 and PLCgamma and Ca2+ mobilization (Ormsby et al. 2010). PathwayStep4777 Phosphorylation of BTK by p-SYK Authored: Garapati, P V, 2012-05-25 EC Number: 2.7.10 Edited: Garapati, P V, 2012-05-25 In myeloid cells BTK is phosphorylated on Y551 upon DAP12 activation in a SYK kinase-dependent manner. Y551 is located in the activation loop of BTK, known to be required for activation and kinase activity. Y223 in the SH3 domain of BTK is autophosphorylated, which may also be involved in BTK activation (Ormsby et al. 2010, Rawlings et al. 1996). Pubmed21659545 Pubmed8629002 Reactome Database ID Release 432424484 Reactome, http://www.reactome.org ReactomeREACT_147834 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 2 PathwayStep4778 Phosphorylation of PLCgamma1 by p-BTK/p-SYK Authored: Garapati, P V, 2012-05-25 EC Number: 2.7.10 Edited: Garapati, P V, 2012-05-25 Pubmed11507089 Pubmed1708307 Pubmed21659545 Pubmed8657103 Reactome Database ID Release 432424487 Reactome, http://www.reactome.org ReactomeREACT_147801 Reviewed: Lanier, Lewis L, 2012-08-09 Three tyrosine residues at positions 771, 783 and 1254 in PLCgamma1 have been identified as the sites of receptor tyrosine kinase phosphorylation. Of these Y783 and Y1254 are required for PLC-gamma1 activation. <br>In myeloid cells phosphorylation of the tyrosine residues of PLC-gamma1 is mediated by SYK and BTK kinases (Ormsby et al. 2010, Kim et al. 1994, Law et al. 1996, Watanabe et al. 2001). has a Stoichiometric coefficient of 3 PathwayStep4779 Release of p-PLCG1 Activated PLC-gamma1 disassociates from LAT. Membrane binding is crucial for PLC-gamma 1 activity. The PH-domain of PLC-gamma 1 binds to phosphatidylinositol 3,4,5-trisphosphate [PdtIns(3,4,5)P3], and is targeted to the membrane (Todderud et al. 1990, Wang & Wang. 2003, Kim et al. 2000). Activated PLCG1 then hydrolyses PIP2 to Inositol 1,4,5-triphosphate (IP3) and DAG Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Pubmed11048639 Pubmed12911816 Pubmed2374928 Reactome Database ID Release 432424485 Reactome, http://www.reactome.org ReactomeREACT_147702 Reviewed: Lanier, Lewis L, 2012-08-09 Efflux of 27-hydroxycholesterol 27-hydroxycholesterol is transported from the mitochondrial matrix to the extracellular space. In humans, this event is the major source of 27-hydroxycholesterol in the blood and is the means by which the molecule, generated from cholesterol in a variety of cell types, notably macrophages, is transported to the liver for conversion to bile acids and bile salts (Babiker et al. 1999; Bjorkhem et al. 1994). While transport proteins are likely to play a role in this process, the relevant proteins have not been identified. Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed10428977 Pubmed8078928 Reactome Database ID Release 43193812 Reactome, http://www.reactome.org ReactomeREACT_9984 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Influx of 27-hydroxycholesterol 27-hydroxycholesterol is transported from the extracellular space to the endoplasmic reticulum. In humans, this event is the means by which the molecule, generated from cholesterol in the brain, is taken up by liver cells for conversion to bile acids and bile salts (Babiker et al. 1999; Bjorkhem et al. 1994). While transport proteins are likely to play a role in this process, these proteins have not been identified. Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed10428977 Pubmed8078928 Pubmed8790411 Pubmed9717719 Reactome Database ID Release 43193801 Reactome, http://www.reactome.org ReactomeREACT_10057 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 27-hydroxycholesterol is 7alpha-hydroxylated 27-hydroxycholesterol + NADPH + H+ + O2 => cholest-5-ene-3beta,7alpha,27-triol + H2O + NADP+ 27-hydroxycholesterol, NADPH + H+, and O2 react to form cholest-5-ene-3beta,7alpha,27-triol, H2O, and NADP+. This reaction is catalyzed by CYP7B1 in the endoplasmic reticulum membrane. Defects in CYB7B1 are associated with failure of 7alpha-hydroxylation in vivo, and with liver damage, confirming both the function of the enzyme and the central role of the liver in this metabolic process (Setchell et al. 1998). Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-04-30 14:43:26 Pubmed10588945 Pubmed9802883 Reactome Database ID Release 43191972 Reactome, http://www.reactome.org ReactomeREACT_9994 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Phosphorylation of LAT by p-SYK Authored: Garapati, P V, 2012-05-25 EC Number: 2.7.10 Edited: Garapati, P V, 2012-05-25 LAT is palmitoylated and hence membrane-associated. It rapidly becomes tyrosine-phosphorylated upon receptor engagement. LAT has nine conserved tyrosine residues of which five have been shown to undergo phosphorylation (Y127, Y132, Y171, Y191 and Y226). Src family kinases and SYK and ZAP-70 efficiently phosphorylate LAT on these tyrosine residues (Jiang & Cheng 2007, Paz et al. 2001). Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domain proteins PLC-gamma1, GRB2 and GADS, which indirectly bind SOS, VAV, SLP-76 and ITK (Wange 2000). Pubmed10072481 Pubmed11368773 Pubmed11752630 Pubmed16938345 Reactome Database ID Release 432395801 Reactome, http://www.reactome.org ReactomeREACT_147778 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 5 PLCgamma binds to p-5Y-LAT Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Pubmed10811803 Pubmed11390650 Pubmed20484116 Pubmed9830044 Reactome Database ID Release 432396606 Reactome, http://www.reactome.org ReactomeREACT_147817 Recruitment and activation of phospholipase C gamma (PLCgamma) is involved in DAP12 signal transduction. Phosphorylation of multiple substrates including PLCgamma1 has been observed in Ly49D/DAP12 triggered NK cells (McVicar et al. 1998). In myeloid cells, PLCgamma2 is recruited and then phosphorylated upon activation of TREM2 and DAP12 (Peng et al. 2010). PLCgamma is recruited to the plasma membrane by interactions with phosphorylated LAT mediated by the N-terminal SH2 domain of PLCgamma2, and by interactions with membrane phosphoinositides, mediated by the pleckstrin homology (PH) domain of PLCgamma2. Several studies have shown that LAT Y171 and Y191 also contribute to PLCgamma1 binding (Zhang et al. 2000). PLCgamma1 activity is dependent on the LAT-associated protein SLP-76 (Yablonski et al. 2001). Reviewed: Lanier, Lewis L, 2012-08-09 Recruitment of GADS:SLP-76 to p-5Y-LAT Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 GADS is member of the GRB2 adaptor family with a central SH2 domain and linker region flanked by amino- and carboxy-terminal SH3 domains. GADS constitutively interacts with SLP-76. This interaction is mediated by the C-terminal SH3 domain of GADS and a 20 amino acid proline rich region in SLP-76. Upon LAT phosphorylation, GADS interacts with LAT Y171 and Y191 via its SH2 domain. This interaction connects SLP-76 and LAT. The LAT-GADS-SLP-76 complex creates a platform for the recruitment of multiple signaling molecules, including PLCgamma1, GRB2, NCK, Rho GEFs, VAV and the Tec-family kinases ITK and BTK. PLCgamma1 binds the proline-rich domain of SLP-76 with its SH3 domain (Liu et al. 1999 & 2001, Asada et al. 1999, Yablonski et al. 2001). Pubmed10021361 Pubmed10224278 Pubmed11390650 Pubmed11607830 Pubmed16467851 Reactome Database ID Release 432396561 Reactome, http://www.reactome.org ReactomeREACT_147784 Reviewed: Lanier, Lewis L, 2012-08-09 Recruitment of GRB2:SOS to p-5Y-LAT Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 GRB2 is an adapter protein that contains a central SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). Following phosphorylation of LAT, the GRB2:SOS complex binds to the phosphorylated tyrosines and is thereby translocated to the inner face of the plasma membrane where inactive RAS:GDP resides. The three distal tyrosines, Y171, Y191 and Y226 of LAT are responsible for GRB2 association (Balagopalan et al. 2010, Zhang et al. 2000). Pubmed10811803 Pubmed20610546 Pubmed8493579 Reactome Database ID Release 432396599 Reactome, http://www.reactome.org ReactomeREACT_147717 Reviewed: Lanier, Lewis L, 2012-08-09 SOS mediated nucleotide exchange of RAS (SHC) Authored: Charalambous, M, 2005-01-07 11:17:43 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 GRB2-bound SOS promotes the formation of active GTP-bound RAS. This activates the mitogen-activated protein kinase (MAPK) cascade, leading to cell growth and differentiation. Pubmed9690470 Reactome Database ID Release 432424477 Reactome, http://www.reactome.org ReactomeREACT_147697 Reviewed: Lanier, Lewis L, 2012-08-09 5beta-cholestan-7alpha,27-diol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,27-triol 5Beta-cholesten-7alpha,27-diol-3-one and NADPH + H+ form 5beta-cholestan-3alpha,7alpha,27-triol and NAPDP+. The reaction is catalyzed by 3alpha-hydroxysteroid dehydrogenase (AKR1C4), a cytosolic enzyme belonging to the aldo-keto reductase family (Dufort et al. 2001). Biochemical studies with rat proteins raise the possibility that other related enzymes may also carry out this reaction in vivo (Russell 2003). 5beta-cholestan-7alpha,27-diol-3-one+ NADPH + H+ => 5beta-cholestan-3alpha,7alpha,27-triol + NADP+ Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed11158055 Pubmed12543708 Reactome Database ID Release 43193841 Reactome, http://www.reactome.org ReactomeREACT_10008 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5Beta-cholestan-7alpha,12alpha,27-triol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol 5Beta-cholestan-7alpha,12alpha,27-triol-3-one + NADPH + H+ => 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol + NAPDP+ 5Beta-cholesten-7alpha,12a,27-triol-3-one and NADPH + H+ form 5beta-cholestan-3alpha,7alpha,12a,27-tetrol and NAPDP+. The reaction is catalyzed by 3alpha-hydroxysteroid dehydrogenase (AKR1C4), a cytosolic enzyme belonging to the aldo-keto reductase family (Dufort et al. 2001). Biochemical studies with rat proteins raise the possibility that other related enzymes may also carry out this reaction in vivo (Russell 2003). Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed11158055 Pubmed12543708 Reactome Database ID Release 43193800 Reactome, http://www.reactome.org ReactomeREACT_10038 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol is translocated from the cytosol to the mitochondrial matrix. The transporter that mediates its passage across the inner mitochondrial membrane is unknown: the StAR protein that performs this function for cholesterol at the start of steroid hormone biosynthesis is excluded as StAR is not expressed in liver. Other members of the START family of transporters are candidates, however (Russell 2003). Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed12543708 Reactome Database ID Release 43193832 Reactome, http://www.reactome.org ReactomeREACT_9985 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 4-Cholesten-7alpha,27-diol-3-one is 12alpha-hydroxylated to 4-Cholesten-7alpha,12alpha,27-triol-3-one 4-Cholesten-7alpha,27-diol-3-one + NADPH + H+ + O2 => 4-Cholesten-7alpha,12alpha,27-triol-3-one + NADP+ + H2O 4-Cholesten-7alpha,27-diol-3-one, NADPH + H+, and O2 form 4-Cholesten-7alpha,12alpha,27-triol-3-one + NADP+ + H2O. This reaction is catalyzed by sterol 12alpha hydroxylase (CYP8B1), an enzyme associated with the endoplasmic reticulum membrane. While the human gene has been cloned (Gafvels et al. 1999), its protein product has not been characterized, and the enzymatic properties of human CYP8B1 protein are inferred from those of its well-characterized rabbit homolog (Ishida et al. 1992). Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.14.13.95 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed10051404 Pubmed1400444 Reactome Database ID Release 43193845 Reactome, http://www.reactome.org ReactomeREACT_10028 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Cholest-5-ene-3beta,7alpha,27-triol + NAD+ => 4-cholesten-7alpha,27-diol-3-one +NADH + H+ Authored: D'Eustachio, P, 2007-02-27 21:49:11 Cholest-5-ene-3beta,7alpha,27-triol and NAD+ react to form 4-cholesten-7alpha,27-diol-3-one and NADH + H+, in a reaction catalyzed by HSD3B7 (3 beta-hydroxysteroid dehydrogenase type 7) in the endoplasmic reticulum membrane. Its function in vivo has been confirmed in studies of patients with defects in bile acid synthesis (Schwarz et al. 2000). Cholest-5-ene-3beta,7alpha,27-triol is oxidized and isomerized to 4-cholesten-7alpha,27-diol-3-one EC Number: 1.1.1.145 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed11067870 Pubmed12679481 Reactome Database ID Release 43193816 Reactome, http://www.reactome.org ReactomeREACT_10115 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 4-cholesten-7alpha,27-diol-3-one is reduced to 5beta-cholestan-7alpha,27-diol-3-one 4-Cholesten-7alpha,27-diol-3-one, NADPH, and H+ react to form 5beta-cholestan-7alpha,27-diol-3-one and NADP+. This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). AKR1D1 is localized to the cytosol, and in the course of the reaction its steroid substrate moves from the endoplasmic reticulum membrane to the cytosol. It is unclear whether this translocation results simply from its increased hydrophilicity or is mediated by the enzyme or another transport protein (Russell 2003). 4-cholesten-7alpha,27-diol-3-one + NADPH + H+ => 5beta-cholestan-7alpha,27-diol-3-one + NADP+ Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed12543708 Pubmed7508385 Reactome Database ID Release 43193824 Reactome, http://www.reactome.org ReactomeREACT_10102 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 4-cholesten-7alpha,12alpha,27-triol-3-one is reduced to 5beta-cholestan-7alpha,12alpha,27-triol-3-one 4-Cholesten-7alpha,12alpha,27-triol-3-one and NADPH + H+ react to form 5beta-cholesten-7alpha,12alpha,27-triol-3-one + NADP+. This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). AKR1D1 is localized to the cytosol, and in the course of the reaction its steroid substrate moves from the endoplasmic reticulum membrane to the cytosol. It is unclear whether this translocation results simply from its increased hydrophilicity or is mediated by the enzyme or another transport protein (Russell 2003). 4-cholesten-7alpha,12alpha,27-triol-3-one + NADPH + H+ => 5beta-cholestan-7alpha,12alpha,27-triol-3-one + NADP+ Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 Pubmed12543708 Pubmed7508385 Reactome Database ID Release 43193821 Reactome, http://www.reactome.org ReactomeREACT_10018 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4781 PathwayStep4780 PathwayStep4783 PathwayStep4782 PathwayStep4785 PathwayStep4784 PathwayStep4748 PathwayStep4749 PathwayStep4746 p85 regulatory unit of PI3K binds p-6Y-SYK Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Phosphoinositide 3-kinases (PI3Ks) are one of the downstream effectors of activated SYK. The p85 alpha regulatory subunit of PI3K has been shown to interact with SYK phospho-tyrosine Y323. In DAP12 signaling SYK acts via the PI3K-dependent pathway to control NK cell-mediated cytotoxicity. SYK-coupled PI3K is rapidly activated and triggers a sequential activation of VAV2/VA3, RAC1, PAK1, MEK and ERK to mediate NK cell-mediated lysis (Jiang et al. 2002, Moon et al. 2005). Pubmed11907067 Pubmed15536084 Reactome Database ID Release 432424482 Reactome, http://www.reactome.org ReactomeREACT_147879 Reviewed: Lanier, Lewis L, 2012-08-09 PathwayStep4747 PI3K phosphorylates PIP2 to PIP3 Activated PI3K phosphorylates phosphatidylinositol (PI) 4-phosphate and PI 4,5-bisphosphate (PIP2) to generate PI 3,4-bisphosphate and PI 3,4,5-triphosphate (PIP3) and these second messengers recruit other signaling proteins containing plecstrin homology (PH) domain. Products of PI3K are involved in the regulation of PLC-gamma 1 and VAV activation. The PH domain of PLC-gamma 1 binds to PIP3 and is targeted to the membrane. PIP3 binds to the PH domain of VAV2/VAV3 and increases it activity and PI3K may also strongly stimulate VAV activity by converting an inhibitory regulator VAV to an activator (Toker & Cantley 1997, Fischer et al. 1998, Falasca et al. 1998). Authored: Garapati, P V, 2012-05-25 EC Number: 2.7.1.153 Edited: Garapati, P V, 2012-05-25 Pubmed12660731 Pubmed15536084 Pubmed9192891 Pubmed9430633 Pubmed9695188 Reactome Database ID Release 432424480 Reactome, http://www.reactome.org ReactomeREACT_147856 Reviewed: Lanier, Lewis L, 2012-08-09 PathwayStep4744 Recruitment of SYK to p-DAP12 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Phosphorylated ITAM on DAP12 serves as the docking site for the two SH2 domains of SYK or ZAP70. Binding leads to SYK activation (Lanier et al. 1998, McVicar et al. 1998). Pubmed18691974 Pubmed9396765 Pubmed9490415 Pubmed9830044 Reactome Database ID Release 43210289 Reactome, http://www.reactome.org ReactomeREACT_147772 Reviewed: Lanier, Lewis L, 2012-08-09 PathwayStep4745 Phosphorylation of SYK Authored: Garapati, P V, 2012-05-25 EC Number: 2.7.10 Edited: Garapati, P V, 2012-05-25 Pubmed20554527 Pubmed9396765 Pubmed9830044 Reactome Database ID Release 432395412 Reactome, http://www.reactome.org ReactomeREACT_147796 Reviewed: Lanier, Lewis L, 2012-08-09 The binding of SYK to DAP12 induces conformational changes that result in SYK activation. Around ten autophosporylated tyrosine residues have been identified in SYK, regulating activity and serving as docking sites for other proteins. Sites include Y131 of interdomain A, Y323, Y348, and Y352 of interdomain B, Y525 and Y526 within the activation loop of the kinase domain and Y630 in the C-terminus (Zhang et al. 2002, Lupher et al. 1998, Furlong et al. 1997). <br><br>SYK is phosphorylated by Src family kinases and this acts as an initiating trigger by generating a few molecules of activated SYK, which then initiate SYK autophosphorylation (Hillal et al. 1997, Castro et al. 2010) has a Stoichiometric coefficient of 6 PathwayStep4742 Interaction of DAP12 and CLM7 Authored: Garapati, P V, 2012-05-25 CLM7/TREM5 is a member of the CMRF-35/immune receptor expressed by myeloid cell (IREM) multigene family of immune receptors expressed on myeloid cells. It has a basic residue in its transmembrane domain and a functional tyrosine-based motif in its short cytoplasmic tail. This structural arrangement confers CLM7 the ability to signal through two independent pathways: one through associating with activating adaptor protein DAP12 and the other through the tyrosine motif in its cytoplasmic tail (Martinez-Barriocanal & Sayos 2006). Edited: Garapati, P V, 2012-05-25 Pubmed16920917 Reactome Database ID Release 432426566 Reactome, http://www.reactome.org ReactomeREACT_147706 Reviewed: Lanier, Lewis L, 2012-08-09 PathwayStep4743 Phosphorylation of DAP12 Authored: Garapati, P V, 2012-05-25 Crosslinking of receptors associated with DAP12 leads to phosphorylation of tyrosine residues in their cytoplasmic ITAM by SRC family kinases (Turnbull & Colonna 2007). This initiates downstream signaling. FYN and LCK have both been found physically and functionally associated with receptors using DAP12 signaling and have been demonstrated to be involved in DAP12 phosphorylation (Mason et al. 2006). EC Number: 2.7.10 Edited: Garapati, P V, 2012-05-25 Pubmed16709819 Pubmed17220916 Reactome Database ID Release 432395439 Reactome, http://www.reactome.org ReactomeREACT_147713 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 4 Interaction of SIGLEC14/15/16 and DAP12 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Pubmed17012248 Pubmed17483134 Pubmed18629938 Reactome Database ID Release 432172123 Reactome, http://www.reactome.org ReactomeREACT_147732 Reviewed: Lanier, Lewis L, 2012-08-09 SIGLECs are sialic acid-recognizing receptors of the immunoglobulin (Ig) superfamily expressed on immune cells. SEGLEC14 and SEGLEC15 preferentially recognise ligands containing the glycans N-acetylneuraminic acid (Neu5Ac). SEGLEC14, SEGLEC15 and SEGLEC16 are expressed by myeloid cells and associate with the activating adapter protein DAP12 via the arginine residue in their transmembrane domains (Angata et al. 2006, Angata et al. 2007, Cao et al. 2008). Interaction of DAP12 and IREM2 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Immune receptor expressed by myeloid cells 2 (IREM-2), is a member of the Ig-superfamily expressed on myeloid cells. The extracellular region contains a single Ig variable and a positively charged amino acid lysine in its transmembrane region followed by a short cytoplasmic tail. IREM-2 associates with activating adaptor DAP12, through the transmembrane basic amino acid residue. This association induces NFAT transcriptional activity (Aguilar et al. 2004). Pubmed15557162 Reactome Database ID Release 432426569 Reactome, http://www.reactome.org ReactomeREACT_147704 Reviewed: Lanier, Lewis L, 2012-08-09 Interaction of DAP12 and TREM1 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Pubmed10799849 Pubmed12776204 Pubmed15351648 Pubmed15884055 Pubmed17110943 Pubmed18192027 Pubmed18926286 Reactome Database ID Release 43210292 Reactome, http://www.reactome.org ReactomeREACT_147897 Reviewed: Lanier, Lewis L, 2012-08-09 TREM proteins (triggering receptors expressed on myeloid cells) are a family of cell surface receptors involved in innate immune responses. They are expressed in myeloid cells and have both positive and negative functions in regulating myeloid cell activation and differentiation. Humans have two members, TREM1 and TREM2. TREM1 is considered an amplifier of the immune response, while TREM2 is believed to be a negative regulator of inflammatory responses (Sharif & Knaap 2008). TREM proteins consist of a single extracellular V-type Ig-like domain, a transmembrane region and a short cytoplasmic tail lacking any signalling motifs (Kelker et al. 2004). Both receptors associate with DAP12 for signalling. <br>The ligand for TREM1 is unknown. TREM1 associates with DAP12 dimer. This interaction is mediated by aspartic acid and adjacent threonine residues in the DAP12 dimer that interface with lysine residues in the TREM1 transmembrane region. TREM1 engagement triggers the production of inflammatory chemokines and cytokines such as IL-8 and myeloperoxidase (MPO) in neutrophils and IL-8, MCP-1, and TNF in monocytes (Tessarz & Cerwenka 2008, Bouchon et al. 2000). Interaction of DAP12 and TREM2 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Pubmed11602640 Pubmed16887962 Pubmed16951310 Pubmed18926286 Reactome Database ID Release 43210300 Reactome, http://www.reactome.org ReactomeREACT_147773 Reviewed: Lanier, Lewis L, 2012-08-09 TREM2 is expressed on dendritic cells and macrophages. Like TREM1 the ligand for TREM2 is unknown. TREM2 signals through DAP12, leading to an increase in intracellular calcium and phosphorylation of ERK1/2 (Sharif & Knapp. 2008). TREM2 on immature dendritic cells triggers upregulation of molecules involved in T cell co-stimulation such as CD86, CD40 and MHC class II, as well as up-regulation of the chemokine receptor CCR7 (Bouchon et al. 2001). In macrophages TREM2 is a negative regulator of inflammatory responses (Hamerman et al. 2006, Turnbull et al. 2006). 3,7,24THCA [mitochondrial matrix] => 3,7,24THCA [cytosol] 3,7,24THCA (3alpha,7alpha,24(S)-trihydroxy-5beta-cholestanoate) is translocated from the mitochondrial matrix to the cytosol. The transporter that mediates its passage across the inner mitochondrial membrane has not been identified (Russell 2003). VLCS (SLC27A2), one of the enzymes that catalyzes CoA conjugation of 3,7,24THCA, may also be present in peroxisomes, and Mihalik et al. (2002) have hypothesized that 3,7,24THCA could be translocated unchanged from the mitochondrial matrix to the peroxisomal matrix and undergo conjugation there. 3,7,24THCA is translocated from the mitochondrial matrix to the cytosol Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed11980911 Pubmed12543708 Reactome Database ID Release 43193786 Reactome, http://www.reactome.org ReactomeREACT_9992 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 TetraHCA is conjugated with Coenzyme A (SLC27A5 BACS) Authored: D'Eustachio, P, 2007-02-23 20:35:09 EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed10479480 Pubmed10749848 Pubmed11980911 Reactome Database ID Release 43193766 Reactome, http://www.reactome.org ReactomeREACT_10000 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 TetraHCA (25(R) 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestanoate), coenzyme A, and ATP react to form the CoA conjugate of 25(R) TetraHCA, AMP, pyrophosphate and water. This cytosolic reaction is catalyzed by SLC27A5 (BACS). SLC27A2 (VLCS) also catalyzes this reaction; the relative contributions of the two enzymes to de novo bile acid synthesis in vivo are not certain (Mihalik et al. 2002). TetraHCA + ATP + CoASH => 25(R) TetraHCA-CoA + AMP + pyrophosphate + H2O (SCLS25A5 "BACS") 25(R) TetraHCA-CoA [ cytosol] => 25(R) TetraHCA-CoA [peroxisome] 25(R) TetraHCA-CoA is translocated from the cytosol to the peroxisome 25(R) TetraHCA-CoA is transported from the cytosol into the peroxisome. Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed12543708 Pubmed12966071 Reactome Database ID Release 43193761 Reactome, http://www.reactome.org ReactomeREACT_10121 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 3,7,24THCA is conjugated with Coenzyme A (SLC27A2 VLCS) 3,7,24THCA (25(R) 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestanoate), coenzyme A, and ATP react to form the CoA conjugate of 3,7,24THCA, AMP, pyrophosphate and water. This cytosolic reaction is catalyzed by SLC27A2 (VLCS). SLC27A5 (BACS) also catalyzes this reaction; the relative contributions of the two enzymes to de novo bile acid synthesis in vivo are not certain (Mihalik et al. 2002). 3,7,24THCA + ATP + CoASH => 3,7,24THCA-CoA + AMP + pyrophosphate + H2O (SLC27A2 "VLCS") Authored: D'Eustachio, P, 2007-02-23 20:35:09 EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed10479480 Pubmed10749848 Pubmed11980911 Reactome Database ID Release 43193743 Reactome, http://www.reactome.org ReactomeREACT_9970 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 TetraHCA is conjugated with Coenzyme A (SLC27A2 VLCS) Authored: D'Eustachio, P, 2007-02-23 20:35:09 EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed10479480 Pubmed10749848 Pubmed11980911 Reactome Database ID Release 43193727 Reactome, http://www.reactome.org ReactomeREACT_10106 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 TetraHCA (25(R) 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestanoate), coenzyme A, and ATP react to form the CoA conjugate of 25(R) TetraHCA, AMP, pyrophosphate and water. This cytosolic reaction is catalyzed by SLC27A2 (VLCS). SLC27A5 (BACS) also catalyzes this reaction; the relative contributions of the two enzymes to de novo bile acid synthesis in vivo are not certain (Mihalik et al. 2002). TetraHCA + ATP + CoASH => 25(R) THCA-CoA + AMP + pyrophosphate + H2O (SLC27A2 "VLCS") 3,7,24THCA is conjugated with Coenzyme A (SLC27A5 BACS) 3,7,24THCA (25(R) 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestanoate), coenzyme A, and ATP react to form the CoA conjugate of 3,7,24THCA, AMP, pyrophosphate and water. This cytosolic reaction is catalyzed by SLC27A5 (BACS). SLC27A2 (VLCS) also catalyzes this reaction; the relative contributions of the two enzymes to de novo bile acid synthesis in vivo are not certain (Mihalik et al. 2002). 3,7,24THCA + ATP + CoASH => 3,7,24THCA-CoA + AMP + pyrophosphate + H2O (SCLS25A5 "BACS") Authored: D'Eustachio, P, 2007-02-23 20:35:09 EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed10479480 Pubmed10749848 Pubmed11980911 Reactome Database ID Release 43193711 Reactome, http://www.reactome.org ReactomeREACT_10087 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Cholesterol is hydroxylated to 27-hydroxycholesterol by CYP27 Authored: Jassal, B, 2008-05-19 12:57:01 Cholesterol, NADPH + H+, and O2 react to form 27-hydroxycholesterol, H2O, and NADP+, in the mitochondrial matrix, catalyzed by CYP27A1. 27-Hydroxycholesterol is the most abundant oxysterol in the plasma in humans; its formation is thought to play a central role in the mobilization of cholesterol from non-hepatic tissues. Edited: D'Eustachio, P, 2007-04-30 14:43:26 Pubmed10428977 Pubmed1708392 Reactome Database ID Release 43192123 Reactome, http://www.reactome.org ReactomeREACT_9953 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 cholesterol + NADPH + H+ + O2 => 27-hydroxycholesterol + H2O + NADP+ 3,7,24THCA-CoA => (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA Authored: D'Eustachio, P, 2007-02-23 20:35:09 EC Number: 5.1.99.4 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Isomerization of 3,7,24THCA-CoA to (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA Pubmed10655068 Pubmed11060344 Pubmed7649182 Reactome Database ID Release 43193736 Reactome, http://www.reactome.org ReactomeREACT_9964 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 The isomerization of 3,7,24THCA-CoA to (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA, catalyzed by 2-methylacyl-CoA racemase, occurs in the peroxisomal matrix. 25(R) TetraHCA-CoA => (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA Authored: D'Eustachio, P, 2007-02-23 20:35:09 EC Number: 5.1.99.4 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Isomerization of 25(R) TetraHCA-CoA to (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA Pubmed10655068 Pubmed11060344 Pubmed7649182 Reactome Database ID Release 43193763 Reactome, http://www.reactome.org ReactomeREACT_10132 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 The isomerization of 25(R) TetraHCA-CoA to (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA, catalyzed by 2-methylacyl-CoA racemase, occurs in the peroxisomal matrix. 3,7,24THCA-CoA [ cytosol] => 3,7,24THCA-CoA [peroxisome] 3,7,24THCA-CoA is translocated from the cytosol to the peroxisome 3,7,24THCA-CoA is transported from the cytosol into the peroxisome. Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed12543708 Pubmed12966071 Reactome Database ID Release 43193753 Reactome, http://www.reactome.org ReactomeREACT_10118 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4752 PathwayStep4751 PathwayStep4750 FGFR2 mutants with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2033351 Reactome Database ID Release 432033351 Reactome, http://www.reactome.org ReactomeREACT_123373 PathwayStep4757 DAP12 interacts with NKG2C Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 NKG2C, a C-type lectin-like surface receptor, is a member of the NKG2 family and forms heterodimers with CD94 that is expressed on NK cells and a subset of T cells. The CD94/NKG2C killer lectin-like receptor (KLR) perform an important role in immunosurveillance by binding to HLA-E complexes that present peptides derived from the signal sequences of other HLA class I molecules (A, B, C, G), thereby monitoring MHC class I expression. It has been proposed that the activating receptor CD94/NKG2C may contribute with other NK stimulatory molecules (like NKp46, NKp44 and NKp30 and NKG2D) to trigger effector functions when the control exerted by inhibitory receptors is overcome (Guma et al. 2005). NKG2C/CD94 associates with the ITAM-containing adapter protein DAP12 and this leads to cell activation and cytotoxic function. The charged residues in the transmembrane domains of DAP12 and NKG2C are necessary for this interaction (Lanier et al. 1998). NK cells expressing the CD94/NKG2C receptor are preferentially expanded during cytomegalovirus infection in humans (Lopez-Verges et al. 2011) Pubmed15940674 Pubmed21825173 Pubmed9655483 Reactome Database ID Release 432172126 Reactome, http://www.reactome.org ReactomeREACT_147751 Reviewed: Lanier, Lewis L, 2012-08-09 PathwayStep4758 Interaction of DAP12 and NKG2D Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 NKG2D is a member of the NKG2 family of C-type lectin-like surface receptors. It is a homodimeric activating receptor expressed on natural killer (NK) cells, gamma/delta T-cells and CD8+ alpha/beta T-cells. NKG2D can mediate NK activation and cytotoxicity. NKG2D interacts with the stress-induced class I like molecules MICA, MICB and ULBPs expressed on target cells. Interaction of NKG2D and NKG2D ligands leads to NK cell activation (Cosman et al. 2001, Steinle et al. 2001, Long. 2002). In mice there are two alternatively spliced isoforms of NKG2D, designated NKG2D-S and NKG2D-L. DAP12 interacts with NKG2D-S, but not NKG2D-L, whereas the DAP10 adapter associates with both NKG2D-S and NKG2D-L (Gilfillan et al. 2002, Diefenbach et al. 2002). Humans only express an NKG2D-L isoform and exclusively associate with DAP10, and not DAP12 A Structural basis for the association of DAP12 with mouse, but not human, NKG2D (Rosen et al. 2004). Pubmed11239445 Pubmed11491531 Pubmed12447364 Reactome Database ID Release 43210295 Reactome, http://www.reactome.org ReactomeREACT_147745 Reviewed: Lanier, Lewis L, 2012-08-09 PathwayStep4759 Interaction of DAP12 and NKp44 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 NKp44 is a natural cytotoxicity receptor (NCR) family member selectively expressed by IL-2-activated NK cells. It is a transmembrane receptor involved in recognizing unidentified non-MHC ligands on tumor cells, mediating tumor cell lysis by activated NK cells. NKp44 is coupled to cytoplasmic signal transduction machinery via association with DAP12. Lysine-183 in the transmembrane region of NKp44 may be involved in the association with DAP12. The interaction with DAP12 influences NKp44 surface expression and hence NK cell activation (Campbell et al. 2004, Cantoni et al. 1999, Vitale et al. 1998). Pubmed10049942 Pubmed14707061 Pubmed9625766 Reactome Database ID Release 43210273 Reactome, http://www.reactome.org ReactomeREACT_147726 Reviewed: Lanier, Lewis L, 2012-08-09 PathwayStep4753 Interaction of DAP12 and KIR2DS4 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Killer cell immunoglobulin-like two-domain short-tail receptor 4 (KIR2DS4) is the most prevalent lineage III-activating KIR receptor. It interacts weakly but specifically with HLA-Cw3 and HLA-Cw4 and may also bind to an uncharacterised non-MHC molecule. It can associate with DAP12, activating NK cells. Pubmed15265913 Pubmed19858347 Reactome Database ID Release 432272753 Reactome, http://www.reactome.org ReactomeREACT_147866 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 2 PathwayStep4754 Interaction of DAP12 and KIR2DS5 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Killer cell immunoglobulin-like two-domain short-tail receptor 5 (KIR2DS5) is an activating KIR receptor expressed on natural killer (NK) cells and subpopulations of T lymphocytes (Nowak et al. 2010). KIR2DS5 has two Ig domains of the D1-D2 type, a short cytoplasmic tail and a positive charged transmembrane (TM) portion.<br>No physiological ligand has yet been identified for KIR2DS5 but it is able to associate with DAP12 and induce both cytotoxicity and cytokine release when KIR2DS5 is cross-linked with monoclonal antibody (Della Chiesa et al. 2008). Pubmed18624290 Pubmed20865034 Reactome Database ID Release 432272668 Reactome, http://www.reactome.org ReactomeREACT_147742 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 2 PathwayStep4755 Interaction of DAP12 and KIR3DS1 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Killer cell immunoglobulin-like three-domain short-tail receptor 1 (KIR3DS1) is a member of the KIR family expressed on peripheral natural killer (NK) cells and implicated in protection against HIV (Carr et al. 2007, Pascal et al. 2007). The physiological ligand for KIR3DS1 is not clearly determined but it has been suggested to bind HLA-B Bw4-80I on HIV-1-infected target cells (Qi et al. 2006). KIR3DS1 associates with DAP12 and this association enhances its cell surface expression. Crosslinking KIR3DS1 with a monoclonal antibody stimulates NK cell-mediated cytolysis and IFN-gamma production (Carr et al. 2007). Pubmed16933987 Pubmed17202323 Pubmed17641029 Reactome Database ID Release 43210298 Reactome, http://www.reactome.org ReactomeREACT_147782 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 2 PathwayStep4756 Interaction of DAP12 and MDL-1 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Myeloid DAP12-associating lectin (MDL)-1, also designated CLEC5A, is a type II transmembrane protein belonging to the C-type lectin superfamily and expressed exclusively in monocytes and macrophages. MDL-1 contains a charged residue in the transmembrane region and this enables it to pair with DAP12 dimers. MDL-1's natural mammalian ligand is unknown, but MDL-1 is a receptor for Dengue virus CLEC5A is critical for dengue-virus-induced lethal disease (Chen et al 2008). Engagement with DAP12 has been shown to regulate osteoclastogenesis and myeloid cell-associated inflammatory responses (Bakker et al. 1999, Aoki et al. 2009, Inui et al 2009, Joyce-Shaikh et al. 2010, Cheung et al. 2011). Pubmed10449773 Pubmed15884055 Pubmed18496526 Pubmed19074552 Pubmed19251634 Pubmed20212065 Pubmed22005300 Reactome Database ID Release 43210271 Reactome, http://www.reactome.org ReactomeREACT_147800 Reviewed: Lanier, Lewis L, 2012-08-09 Dimerization of DAP12 Authored: Garapati, P V, 2012-05-25 DAP12 is expressed as a disulfide-bonded homodimer on NK cells, myeloid cells and a subset of T cells. Cystine-7 in the extracellular domain is involved in the interchain disulphide bond (numbering according to Lanier et al. 1998). Edited: Garapati, P V, 2012-05-25 Pubmed16623599 Pubmed20890284 Pubmed9490415 Reactome Database ID Release 432130151 Reactome, http://www.reactome.org ReactomeREACT_147748 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 2 Interaction of DAP12 and KIR2DS1 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Killer cell immunoglobulin-like two-domain short-tail receptor 1 (KIR2DS1) is one of the activating KIR receptors expressed on the surface of NK cells. It recognizes and binds to ligand HLA-C2:peptide complexes. KIR2DS1 oligomerizes upon interaction with its HLA-Class I ligands. The interaction between the peptide-HLA and KIR2DS1 oligomers leads to activation of the DAP12 signaling cascade. The engagement of KIR2DS1 with HLA-C2 is not sufficient to drive NK cell cytotoxicity or IFN-gamma production (Stewart et al. 2005). Recognition of HLA-C2 by KIR2DS1 is involved in the anti-leukemic activity of alloreactive NK cells and associated with protection against Hodgkin's lymphoma (Cognet et al. 2010). The presence of the HLA-C2 allele HLA-Cw6 in combination with KIR2DS1 is a major risk factor for psoriasis (Ploski et al. 2006). Pubmed16141329 Pubmed16829306 Pubmed20093094 Reactome Database ID Release 432272795 Reactome, http://www.reactome.org ReactomeREACT_147830 Reviewed: Lanier, Lewis L, 2012-08-09 Interaction of DAP12 and KIR2DS2 Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Killer cell immunoglobulin-like two-domain short-tail receptor 2 (KIR2DS2) is an activating KIR receptor invariably expressed on the cell surface of NK cells and subsets of T cells. The ligand specificity of KIR2DS2 is unknown; it does not bind the HLA-Cw3 molecules recognised by the inhibitory receptor KIR2DL2, despite 99% extracellular amino acid identity (Saulquin et al. 2003). In the presence of DAP12, cross-linking of KIR2DS2 with monoclonal antibody leads to phosphorylation of JNK and ERK and activation of both cytotoxicity and IFN-production. Pubmed12668644 Reactome Database ID Release 43210309 Reactome, http://www.reactome.org ReactomeREACT_147777 Reviewed: Lanier, Lewis L, 2012-08-09 has a Stoichiometric coefficient of 2 FGFR3 cysteine mutants Converted from EntitySet in Reactome Reactome DB_ID: 2012043 Reactome Database ID Release 432012043 Reactome, http://www.reactome.org ReactomeREACT_124829 PathwayStep4761 PathwayStep4760 PathwayStep4763 PathwayStep4762 Overexpressed FGFR2 Converted from EntitySet in Reactome Reactome DB_ID: 2029960 Reactome Database ID Release 432029960 Reactome, http://www.reactome.org ReactomeREACT_125409 Calcidiol binds to DBP in the bloodstream and is delivered to the kidney Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-06-02 10:50:11 Pubmed11799400 Reactome Database ID Release 43209944 Reactome, http://www.reactome.org ReactomeREACT_13461 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Vitamin D binding protein (DBP), a plasma protein, carries the vitamin D metabolites in the circulation. Calcidiol translocates to the extracellular region where it binds with DBP and is transported to the kidney. 25-Hydroxylation of vitamin D3 in liver Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-28 09:06:10 Pubmed15465040 Reactome Database ID Release 43209845 Reactome, http://www.reactome.org ReactomeREACT_13458 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 To be functionally active, vitamin D is required to be dihydroxylated. The first hydroxylation at position 25 is carried out by vitamin D 25-hydroxylase (CYP2R1) in the liver, forming calcidiol. PathwayStep4729 Vitamin D3 translocates into the cytosol Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-06-02 10:50:11 Once vitamin D3 is released from DBP, it becomes available for hydroxylation. Pubmed9821970 Reactome Database ID Release 43350147 Reactome, http://www.reactome.org ReactomeREACT_13727 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep4728 Vitamin D3 translocates to the blood serum and is transported to the liver Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-06-02 10:50:11 Pubmed11799400 Reactome Database ID Release 43209738 Reactome, http://www.reactome.org ReactomeREACT_13585 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Vitamin D metabolites are lipophilic and must be transported in the circulation bound to plasma proteins. Vitamin D3 is transported to the liver bound to a plasma protein called vitamin D binding protein (DBP). Photolytic cleavage and thermal isomerization of 7-dehydrocholesterol Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-06-02 10:50:11 Reactome Database ID Release 43209754 Reactome, http://www.reactome.org ReactomeREACT_13666 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The skin's exposure to UV rays from sunlight induces the photolytic cleavage of 7-dehydrocholesterol to previtamin D3. This is followed by thermal isomerization to form vitamin D3 (Cholecalciferol). Estrone is hydrogenated to estradiol Authored: Stephan, R, 2010-05-26 EC Number: 1.1.1.62 Edited: Jassal, B, 2010-05-26 Expression of HSD17B1 which is the main enzyme that catalyzes the hydrogenation of estrone is strongly restricted to placenta, ovaries, endometrium and breast tissue (Moeller and Adamski, 2009). GENE ONTOLOGYGO:0006703 Pubmed19027824 Reactome Database ID Release 43804969 Reactome, http://www.reactome.org ReactomeREACT_25243 Reviewed: D'Eustachio, P, 2010-11-10 Androstenedione is converted to estrone by Aromatase (CYP19A1) Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed2171939 Pubmed8076586 Reactome Database ID Release 43193060 Reactome, http://www.reactome.org ReactomeREACT_9954 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 The conversion of androstenedione to estrone is catalyzed by aromatase (CYP19A1) associated with the endoplasmic reticulum membrane. Testosterone is converted to estradiol Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed2171939 Pubmed8076586 Reactome Database ID Release 43193143 Reactome, http://www.reactome.org ReactomeREACT_9963 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 The conversion of testosterone to estradiol is catalyzed by aromatase (CYP19A1) associated with the endoplasmic reticulum membrane. PathwayStep4723 PathwayStep4722 PathwayStep4721 PathwayStep4720 PathwayStep4727 PathwayStep4726 PathwayStep4725 PathwayStep4724 PathwayStep4730 DBP:Calcidiol is sequestered by cubilin on the cell surface Authored: Jassal, B, 2008-10-01 13:18:42 Cubilin is a membrane-associated protein colocalizing with megalin. Its function is to sequester steroid carrier complexes on the cell surface before megalin mediates their internalization. Edited: Jassal, B, 2008-06-02 10:50:11 Pubmed11717447 Reactome Database ID Release 43350186 Reactome, http://www.reactome.org ReactomeREACT_13631 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Megalin internalizes the cubilin-DBP:Calcidiol complex Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-06-02 10:50:11 Megalin (glycoprotein 330) is a member of the low density lipoprotein receptor family and is abundant in kidney proximal tubules. Megalin mediates the endocytic uptake of DBP:Calcidiol complexes to prevent loss of calcidiol in urine. Pubmed7768901 Pubmed8706697 Reactome Database ID Release 43350168 Reactome, http://www.reactome.org ReactomeREACT_13608 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Side chain cleavage of 17alpha-hydroxypregnenolone to yield DHA 17-alpha-hydroxypregnenolone, NADPH + H+, and O2 react to form DHA (dehydroepiandrostenedione), NADP+, H2O, and acetaldehyde. CYP17 (which also catalyzes 17-alpha-hydroxylation) catalyzes this lyase reaction. There are marked species differences in which substrate is used for this lyase activity. The human enzyme prefers 17alpha-pregnenolone (delta5 steroid) as substrate (Brock, BJ, Waterman, MR, 1999). Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). 17alpha-hydroxyprenenolone + NADPH + H+ + O2 => DHA (dehydroepiandrostenedione) + NADP+ + H2O + acetaldehyde Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.99.9 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed10406467 Pubmed9536209 Pubmed9931027 Reactome Database ID Release 43193070 Reactome, http://www.reactome.org ReactomeREACT_10026 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 PathwayStep4739 Conversion of 18-hydroxycorticosterone to aldosterone 18-Hydroxycorticosterone and NADPH + H+ react to form aldosterone, NADP+, and H2O. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. 18-hydroxycorticosterone + NADPH + H+ => aldosterone + NADP+ + 2H2O Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed2256920 Pubmed2592361 Reactome Database ID Release 43193965 Reactome, http://www.reactome.org ReactomeREACT_10094 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 has a Stoichiometric coefficient of 2 Hydroxylation of progesterone to form 17alpha-hydroxyprogesterone Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.99.9 Edited: Jassal, B, 2007-04-20 21:09:56 Progesterone, NADPH + H+, and O2 react to form 17alpha-hydroxyprogesterone, NADP+, and H2O, catalyzed by CYP17 (steroid 17alpha-monooxygenase), associated with the endoplasmic reticulum membrane. Pubmed10406467 Reactome Database ID Release 43193072 Reactome, http://www.reactome.org ReactomeREACT_10116 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 progesterone + NADPH + H+ + O2 => 17alpha-hydroxyprogesterone + NADP+ + H2O DHA isomerizes to 4-Androstene3,17-dione Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 5.3.3.1 Edited: Jassal, B, 2007-04-20 21:09:56 In this two-step reaction catalyzed by 3beta-HSD associated with the endoplasmic reticulum membrane, the 3-hydroxyl group of DHA is oxidized to a keto group and the double bond in the steroid nucleus is then isomerized from the five to the 4 position. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). Pubmed2243100 Pubmed9536209 Reactome Database ID Release 43193073 Reactome, http://www.reactome.org ReactomeREACT_10056 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 11-deoxycorticosterone translocates from the cytosol to the mitochondrial matrix 11-deoxycorticosterone is synthesized in a reaction at the endoplasmic reticulum membrane and is further metabolized, ultimately to yield aldosterone, in reactions catalyzed by mitochondrial enzymes. The means by which 11-deoxycorticosterone translocates into the mitochondrial matrix, however, is unknown. Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed15583024 Reactome Database ID Release 43193996 Reactome, http://www.reactome.org ReactomeREACT_9966 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Hydroxylation of corticosterone to form 18-hydroxycorticosterone Authored: Jassal, B, 2008-10-01 13:18:42 Corticosterone, NADPH + H+, and O2 react to form 18-hydroxycorticosterone, NADP+, and H2O. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed2256920 Pubmed2592361 Reactome Database ID Release 43193995 Reactome, http://www.reactome.org ReactomeREACT_10045 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 corticosterone + NADPH + H+ + O2 => 18-hydroxycorticosterone + NADP+ + H2O Hydroxylation of 11-deoxycorticosterone to form corticosterone 11-Deoxycorticosterone, NADPH + H+, and O2 react to form corticosterone, H2O, and NADP+. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. 11-deoxycorticosterone + NADPH + H+ + O2 => corticosterone + H2O + NADP+ Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.15.4 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed1741400 Pubmed2592361 Reactome Database ID Release 43194017 Reactome, http://www.reactome.org ReactomeREACT_10117 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 PathwayStep4732 PathwayStep4731 PathwayStep4734 PathwayStep4733 PathwayStep4736 PathwayStep4735 PathwayStep4738 PathwayStep4737 PathwayStep4740 PathwayStep4741 Side chain cleavage of 17alpha-hydroxyprogesterone to form 4-Androstene-3, 17-dione 17Alpha-hydroxyprogesterone, NADPH + H+, and O2 react to form 4-Androstene-3, 17-dione, NADP+, H2O, and acetaldehyde. CYP17 (which also catalyzes 17-alpha-hydroxylation) catalyzes this lyase reaction. There are marked species differences in which substrate is used for this lyase activity. 17alpha-hydroxyprogesterone + NADPH + H+ + O2 => 4-Androstene-3, 17-dione + NADP+ + H2O + acetaldehyde Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.99.9 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed10406467 Reactome Database ID Release 43193099 Reactome, http://www.reactome.org ReactomeREACT_10013 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Reduction of androstenedione to testosterone Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.1.1.63 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed2197970 Pubmed8075637 Pubmed8547185 Pubmed9536209 Reactome Database ID Release 43193064 Reactome, http://www.reactome.org ReactomeREACT_9948 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 The 17HSD family of enzymes catalyze the final step in the synthesis of estradiol and testosterone. They convert inactive 17-ketosteroids to their active 17beta-hydroxy forms. Androstenedione, a ketosteroid, is reduced to testosterone, a highly potent androgen, by the enzyme 17beta-hydroxysteroid dehydrogenase isoform III (17HSD3). The other human isoforms of 17HSDs to take part in the final steps of active steroid biosynthesis are types 1 and VII, which reduce estrone to estradiol.<br>Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).<br>In males, Lutropin (LH) stimulates testosterone production. Testosterone is converted to 5-alpha-dihydroxytestosterone Authored: Jassal, B, 2010-01-25 EC Number: 1.3.99.5 Edited: Jassal, B, 2010-01-25 Pubmed17986282 Pubmed1944596 Pubmed2339109 Pubmed9208814 Pubmed9536209 Reactome Database ID Release 43469659 Reactome, http://www.reactome.org ReactomeREACT_22210 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 The conversion of testosterone to the most potent androgen, 5-alpha-dihydrotestosterone (DHT), is catalyzed by the microsomal 5alpha-steroid reductase enzymes, of which there are three reported types in humans to date (SRD5A1-3) (Andersson S and Russell DW, 1990; Andersson S et al, 1991; Uemura M et al, 2008 respectively). These enzymes are expressed in the prostate and other androgen target sites. Defects in SRD5A2 are the cause of pseudovaginal perineoscrotal hypospadias, also known as male pseudohermaphroditism (Anwar R et al, 1997). Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). Pregn-5-ene-3,20-dione-17-ol isomerizes to 17-hydroxyprogesterone Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 5.3.3.1 Edited: Jassal, B, 2007-04-20 21:09:56 Pregn-5-ene-3,20-dione-17-ol isomerizes to 17-hydroxyprogesterone. This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads. Pubmed2243100 Reactome Database ID Release 43193961 Reactome, http://www.reactome.org ReactomeREACT_9981 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 17-hydroxypregnenolone + NAD+ => pregn-5-ene-3,20-dione-17-ol + NADH + H+ 17-Hydroxypregnenolone and NAD+ react to form pregn-5-ene-3,20-dione-17-ol and NADH + H+. This reaction is catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads. 17-Hydroxypregnenolone is dehydrogenated to form pregn-5-ene-3,20-dione-17-ol Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.1.1.145 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed12832414 Pubmed1944309 Pubmed2243100 Pubmed2770297 Reactome Database ID Release 43196372 Reactome, http://www.reactome.org ReactomeREACT_10031 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 PathwayStep4709 Cortisol translocates from the mitochondrial matrix to the cytosol Authored: Jassal, B, 2008-10-01 13:18:42 Cortisol is translocated from the mitochondrial matrix into the cytosol by an unknown mechanism. Edited: Jassal, B, 2007-04-20 21:09:56 Reactome Database ID Release 43194036 Reactome, http://www.reactome.org ReactomeREACT_10023 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 PathwayStep4708 11-deoxycortisol is oxidised to cortisol by CYP11B1 11-Deoxycortisol, NADPH + H+, and O2 react to form cortisol, NADP+, and H2O. This reaction is catalyzed by CYP11B1 associated with the inner mitochondrial membrane. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). 11-deoxycortisol + NADPH + H+ + O2 => cortisol + NADP+ + H2O Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.15.4 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed1741400 Pubmed2592361 Pubmed9536209 Reactome Database ID Release 43193997 Reactome, http://www.reactome.org ReactomeREACT_10037 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep4707 11-deoxycortisol translocates to the mitochondrion 11-deoxycortisol is synthesized in a reaction at the endoplasmic reticulum membrane and is further metabolized to cortisol in a reaction catalyzed by mitochondrial enzymes. The means by which 11-deoxycortisol translocates into the mitochondrial matrix, however, is unknown. Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed15583024 Reactome Database ID Release 43194025 Reactome, http://www.reactome.org ReactomeREACT_10093 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 PathwayStep4706 Hydroxylation of 17-hydroxyprogesterone to form 11-deoxycortisol 17-Hydroxyprogesterone, NADPH + H+, and O2 react to form 11-deoxycortisol, NADP+, and H2O. This reaction is catalyzed by CYP21A2 (steroid 21-hydroxylase) associated with the endoplasmic reticulum membrane. 17-hydroxyprogesterone + NADPH + H+ + O2 => 11-deoxycortisol + NADP+ + H2O Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.99.10 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed3038528 Pubmed3487786 Reactome Database ID Release 43193981 Reactome, http://www.reactome.org ReactomeREACT_9996 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 PathwayStep4705 PathwayStep4704 PathwayStep4703 PathwayStep4702 PathwayStep4701 PathwayStep4700 Pregn-5-ene-3,20-dione isomerizes to progesterone Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 5.3.3.1 Edited: Jassal, B, 2007-04-20 21:09:56 Pregn-5-ene-3,20-dione isomerizes to progesterone. This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads.<br>The hormone lutropin (LH) triggers ovulation and development of the corpus luteum, that in turn increases production of progesterone. Pubmed12832414 Pubmed1944309 Pubmed2243100 Pubmed2770297 Reactome Database ID Release 43193052 Reactome, http://www.reactome.org ReactomeREACT_10021 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 21-hydroxylation of progesterone to form 11-deoxycorticosterone Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.99.10 Edited: Jassal, B, 2007-04-20 21:09:56 Progesterone, NAPDH + H+, and O2 react to form 11-deoxycorticosterone, NADP+ and H2O. This reaction is catalyzed by CYP21A2 associated with the endoplasmic reticulum membrane. Pubmed3038528 Pubmed3487786 Reactome Database ID Release 43193964 Reactome, http://www.reactome.org ReactomeREACT_10032 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 progesterone + NAPDH + H+ + O2 => 11-deoxycorticosterone + NADP+ + H2O Oxidation of cortisol to yield cortisone Authored: Jassal, B, 2008-10-01 13:18:42 Cortisol and NADP+ react to form cortisone, NADPH, and H+. This reaction is catalyzed by 11beta-hydroxysteroid dehydrogenase (11beta-HSD), associated with the endoplasmic reticulum membrane. The conversion of cortisol, an active hormone, into inactive cortisone occurs in many tissues in the body, notably in the liver, and appears to play a role in regulating cortison activity. Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed1885595 Reactome Database ID Release 43194023 Reactome, http://www.reactome.org ReactomeREACT_10043 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 cortisol + NADP+ => cortisone + NADPH + H+ Pregnenolone + NAD+ => pregn-5-ene-3,20-dione + NADH + H+ Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.1.1.145 Edited: Jassal, B, 2007-04-20 21:09:56 Pregnenolone and NAD+ react to form pregn-5-ene-3,20-dione and NADH + H+. This reaction is catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads. Pregnenolone is dehydrogenated to form pregn-5-ene-3,20-dione Pubmed12832414 Pubmed1944309 Pubmed2243100 Pubmed2770297 Reactome Database ID Release 43196350 Reactome, http://www.reactome.org ReactomeREACT_9989 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Cytosolic chenodeoxycholoyl-CoA or choloyl-CoA are conjugated with glycine or taurine Authored: Jassal, B, 2005-03-09 13:42:30 Cytosolic bile acid-CoA conjugates (choloyl-CoA; chenodeoxycholoyl-CoA) react with the amino acids glycine and taurine, generating the corresponding bile salts and coenzyme A, catalyzed by BAAT (bile acid-CoA:amino acid N-acetyltransferase). In the body, this reaction occurs in hepatocytes and is the means by which bile acids recovered from the intestine are converted to bile salts before being released again into the bile (Kullak-Ublick et al. 2004; Trauner and Boyer 2002). EC Number: 2.3 Edited: D'Eustachio, P, 2007-03-09 21:29:31 GENE ONTOLOGYGO:0008206 Pubmed10884298 Pubmed12663868 Pubmed14699511 Pubmed2037576 Pubmed8034703 Reactome Database ID Release 43159431 Reactome, http://www.reactome.org ReactomeREACT_9991 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4718 Cholesterol is released into the inner mitochondrial membrane Authored: Jassal, B, 2008-10-01 13:18:42 Cholesterol is released from its complex with STAR in the mitochondrial intermembrane space. The mechanism of this process in vivo remains incompletely understood. Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed16973755 Reactome Database ID Release 43196086 Reactome, http://www.reactome.org ReactomeREACT_10076 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 PathwayStep4717 Cholesterol translocates to the inner mitochondrial membrane Authored: Jassal, B, 2008-10-01 13:18:42 Cholesterol traverses the cytosol and the mitochondrial intermembrane space complexed with carrier proteins. This process is essential for the synthesis of steroid hormones in humans. Nevertheless, molecular details of the transport process remain incompletely understood. A plausible model, supported by studies in vitro and in cells overexpressing cloned human proteins, is that cytosolic STAR-related proteins STARD4, 5, and 6 bind cholesterol liberated from lysosomes or cytosolic lipid droplets and carry it to the outer mitochondrial membrane (Rodriguez-Aguado et al. 2005; Soccio et al. 2002), where it is transferred to STAR protein and carried across the mitochondrial intermembrane space (Miller 2007).<p>Mutations in the gene encoding STAR block synthesis of all steroid hormones in humans, indicating the critical importance of this transport step in the biosynthetic process (Bose et al. 1996). The transport step is also a key site for normal regulation of steroid hormone synthesis, as STAR protein is unstable and its synthesis is up-regulated in response to signals such as the binding of ACTH to its receptors on adrenal cells (Stocco 2001). Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed11181954 Pubmed12011452 Pubmed15897605 Pubmed16973755 Pubmed8948562 Reactome Database ID Release 43196126 Reactome, http://www.reactome.org ReactomeREACT_9973 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Oxidation of 22beta-hydroxycholesterol to 20alpha,22beta-hydroxycholesterol 22beta-hydroxycholesterol + NADPH + H+ + O2 => 20alpha,22beta-hydroxycholesterol + NADP+ + H2O 22beta-hydroxycholesterol, NADPH + H+, and O2 react to form 20alpha,22beta-hydroxycholesterol, NADP+ and H2O, catalyzed by CYP11A (P450scc) associated with the inner mitochondrial membrane. Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.15.6 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed3024157 Pubmed9578606 Reactome Database ID Release 43193065 Reactome, http://www.reactome.org ReactomeREACT_10084 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 PathwayStep4719 Oxidation of cholesterol Authored: Jassal, B, 2008-10-01 13:18:42 Cholesterol and NADPH + H+ react to form 22beta-hydroxycholesterol, NADP+, and H2O, catalyzed by CYP11A (P450scc) associated with the inner mitochondrial membrane. EC Number: 1.14.15.6 Edited: Jassal, B, 2007-04-20 21:09:56 Oxidation of cholesterol to 22beta-hydroxycholesterol Pubmed3024157 Pubmed9578606 Reactome Database ID Release 43193054 Reactome, http://www.reactome.org ReactomeREACT_9956 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 cholesterol + NADPH + H+ => 22beta-hydroxycholesterol + NADP+ + H2O PathwayStep4714 PathwayStep4713 PathwayStep4716 PathwayStep4715 PathwayStep4710 PathwayStep4712 PathwayStep4711 20alpha,22beta-hydroxycholesterol is cleaved by CYP11A1 to yield pregnenolone and isocaproaldehyde 20alpha,22beta-hydroxycholesterol + NADPH + H+ + O2 => pregnenolone + isocaproaldehyde + NADP+ + H2O 20alpha,22beta-hydroxycholesterol, NADPH + H+, and O2 react to form pregnenolone, isocaproaldehyde, NADP+ and H2O. This cleavage reaction is catalyzed by CYP11A (P450scc) associated with the inner mitochondrial membrane. Pregnenolone is substantially more hydrophilic than cholesterol and hydroxycholesterol and is released into the mitochondrial matrix. Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.15.6 Edited: Jassal, B, 2007-04-20 21:09:56 Pubmed3024157 Pubmed9578606 Reactome Database ID Release 43193101 Reactome, http://www.reactome.org ReactomeREACT_10035 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 has a Stoichiometric coefficient of 2 Translocation of isocaproaldehyde from the mitochondrial matrix to the cytosol Isocaproaldehyde (4-methylpentanal) is translocated from the mitochondrial matrix to the cytosol. The transporter that mediates this reaction is unknown. The reaction is inferred to exist because isocaproaldehyde is generated within the mitochondrion while the enzyme that reduces it to the corresponding alcohol is located in the cytosol (Matsuura et al. 1996). Pubmed8645003 Reactome Database ID Release 43196125 Reactome, http://www.reactome.org ReactomeREACT_9961 Reduction of isocaproaldehyde to 4-methylpentan-1-ol EC Number: 1.1.1.21 Isocaproaldehyde is reduced by NADPH + H+ to yield 4-methylpentan-1-ol and NADP+. This cytosolic reaction is catalyzed by AKR1B1 (aldose reductase). The purified human enzyme has been shown to catalyze this reaction efficiently in vitro; its abundance in adrenal tissue in humans and other mammals and its concordant expression with other enzymes of steroid hormone synthesis are consistent with it performing this role in vivo as well (Matsuura et al. 1996; Lefrancois-Martinez et al. 2004). The metabolic fate of 4-methylpentan-1-ol is unknown. Pubmed15181092 Pubmed8645003 Reactome Database ID Release 43196060 Reactome, http://www.reactome.org ReactomeREACT_9986 isocaproaldehyde + NADPH + H+ => 4-methylpentan-1-ol + NADP+ Pregnenolone translocates from the mitochondrial matrix to the cytosol Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 Pregenolone is translocated from the mitochondrial matrix to the cytosol. Neither transport proteins to mediate its movement across the inner mitochondrial membrane nor carrier proteins to facilitate its movement in the cytosol have been identified, and the mechanism of this translocation is unknown. Reactome Database ID Release 43193097 Reactome, http://www.reactome.org ReactomeREACT_10063 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Hydroxylation of pregnenolone to form 17alpha-hydroxypregnenolone Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.99.9 Edited: Jassal, B, 2007-04-20 21:09:56 Pregnenolone and NADPH + H+ react to form 17alpha-hydroxypregnenolone, NADP+, and H2O. CYP17A1 (steroid 17alpha-monooxygenase) associated with the endoplasmic reticulum membrane catalyzes this reaction. Pubmed10406467 Reactome Database ID Release 43193068 Reactome, http://www.reactome.org ReactomeREACT_9993 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 pregnenolone + NADPH + H+ => 17alpha-hydroxypregnenolone + NADP+ + H2O incision complex for GG-NER Reactome DB_ID: 109946 Reactome Database ID Release 43109946 Reactome, http://www.reactome.org ReactomeREACT_5159 has a Stoichiometric coefficient of 1 ERCC1:XPF complex Reactome DB_ID: 109943 Reactome Database ID Release 43109943 Reactome, http://www.reactome.org ReactomeREACT_3454 has a Stoichiometric coefficient of 1 Incision complex with 3'-incised damaged DNA Reactome DB_ID: 109947 Reactome Database ID Release 43109947 Reactome, http://www.reactome.org ReactomeREACT_5099 has a Stoichiometric coefficient of 1 PIN1 mediated IRF3 degradation Authored: Garapati, P V, 2010-08-02 EC Number: 6.3.2.19 Edited: Garapati, P V, 2010-08-22 PIN1 acts as a negative regulator of IFN induction. Its association with IRF3 leads to ubiquitin-mediated proteosomal degradation of IRF3. PIN1 on its own does not have ubiquitin activation, transfer or ligase activities. Exactly how this IRF3 degradation is achieved is unclear at present. Immunoprecipitation of ubiquitin followed by immunoblot analysis for IRF3 demonstrated that polyubiquitination of IRF3 was induced by RNA stimulation and that polyubiquitination was augmented by PIN1 expression and abrogated by expression of PIN1-specific shRNA. Pubmed16699525 Pubmed16715065 Pubmed19125153 Reactome Database ID Release 43936462 Reactome, http://www.reactome.org ReactomeREACT_24932 Reviewed: Kawai, T, Akira, S, 2010-10-30 XPC:HR23B:damaged DNA complex Reactome DB_ID: 109940 Reactome Database ID Release 43109940 Reactome, http://www.reactome.org ReactomeREACT_3245 has a Stoichiometric coefficient of 1 Interaction of PIN1 with p-IRF3 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed16699525 Pubmed16715065 Pubmed19125153 Reactome Database ID Release 43936380 Reactome, http://www.reactome.org ReactomeREACT_25077 Reviewed: Kawai, T, Akira, S, 2010-10-30 Two cluster of serine residues in the C-terminus of IRF3 are essential for its activation. Cluster 1, comprising Ser385 and Ser386, is essential for the formation of IRF3 dimers. The second cluster include a series of serine and threonine residues between Ser396 and Ser405. Phosphorylation of residues in both clusters has been noted in response to virus infection and dsRNA treatment, and the IKKi/TBK1 kinase complex has been shown to phosphorylate both clusters. <br>Yamaoka et al has shown that IRF3 is also phosphorylated on Ser339 after dsRNA stimulation, however this phosphorylation is associated with destabilization rather than activation of IRF3. This Ser339 precedes a proline residue 340 (Pro340) and this serine-proline motif acts as a binding site for the protein PIN1, a peptidyl-prolyl-isomerase. PIN1 consist of two distinct domains, a short N-terminal WW domain and a C-terminal catalytic domain. The WW domain of PIN1 is involved in binding the ser339-pro340 region. Yamaoka et al showed that exogenous expression of PIN1 suppresses IRF3 activation and type I interferon production and, conversely, that siRNA silencing of PIN1 leads to enhancement of IRF3 activation and IFNB production. XPC:HR23B complex Reactome DB_ID: 109938 Reactome Database ID Release 43109938 Reactome, http://www.reactome.org ReactomeREACT_4017 has a Stoichiometric coefficient of 1 CYLD mediated deubiquitination of RIG-I Authored: Garapati, P V, 2010-08-02 CYLD is an ovarian tumor (OTU) domain-containing deubiquitinating enzyme (DUB) and has been identified as a negative regulator of RIG-I mediated antiviral signaling. CYLD associates with the CARD domain of RIG-I and removes K63-linked ubiquitin from the RIG-I CARDs that are conjugated by the E3 ubiquitin ligase, TRIM25 and RNF135. Edited: Garapati, P V, 2010-08-22 Pubmed18467330 Pubmed18636086 Reactome Database ID Release 43936390 Reactome, http://www.reactome.org ReactomeREACT_25235 Reviewed: Kawai, T, Akira, S, 2010-10-30 pre-incision complex with open DNA bubble Reactome DB_ID: 109945 Reactome Database ID Release 43109945 Reactome, http://www.reactome.org ReactomeREACT_5689 has a Stoichiometric coefficient of 1 Inhibition of RIG-I/MDA5 signaling by ATG5-ATG12 conjugate Authored: Garapati, P V, 2010-08-02 Autophagy protein 5 (ATG5) and autophagy-related protein 12 (ATG12) conjugate negatively regulates the type I IFN production pathway by directly associating with RIG-I/MDA5 and IPS-1 through the caspase recruitment domains (CARDs). The ATG5-ATG12 conjugate intercalates between the CARDs of RIG-I/MDA5 and IPS-1 and inhibits signal transmission, resulting in suppression of type I IFN production and innate antiviral immune responses. Edited: Garapati, P V, 2010-08-02 Pubmed17709747 Reactome Database ID Release 43936378 Reactome, http://www.reactome.org ReactomeREACT_24982 Reviewed: Kawai, T, Akira, S, 2010-10-30 pre-incision complex in GG-NER Reactome DB_ID: 109941 Reactome Database ID Release 43109941 Reactome, http://www.reactome.org ReactomeREACT_5795 has a Stoichiometric coefficient of 1 DNA-PK:DNA synaptic complex with ligatable ends Reactome DB_ID: 76324 Reactome Database ID Release 4376324 Reactome, http://www.reactome.org ReactomeREACT_2405 has a Stoichiometric coefficient of 2 DNA-PK:XRCC4:DNA ligase IV:DNA complex associated with ligatable DNA ends Reactome DB_ID: 75915 Reactome Database ID Release 4375915 Reactome, http://www.reactome.org ReactomeREACT_2526 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PIK3CA helical domain mutants Converted from EntitySet in Reactome Reactome DB_ID: 2399587 Reactome Database ID Release 432399587 Reactome, http://www.reactome.org ReactomeREACT_147938 XRCC4:DNA ligase IV complex Reactome DB_ID: 75912 Reactome Database ID Release 4375912 Reactome, http://www.reactome.org ReactomeREACT_3745 has a Stoichiometric coefficient of 1 p-IRF7 dimer interacts with coactivator CBP/p300 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed12604599 Reactome Database ID Release 43933536 Reactome, http://www.reactome.org ReactomeREACT_25099 Reviewed: Kawai, T, Akira, S, 2010-10-30 p-IRF7 dimers after translocation into nucleus interact with the coactivators p300 and CBP (CREB-binding protein) to form a stable complex. This interaction further increases the transcriptional activity of IRF7. Formation of VAF (virus-activated factor) complex Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 IRF3 and IRF7 associate with each other and they further interact with the coactivators CBP and p300 to form a more potent transcription factor complex called VAF (virus-activated factor). Pubmed9660935 Reactome Database ID Release 431028820 Reactome, http://www.reactome.org ReactomeREACT_25196 Reviewed: Kawai, T, Akira, S, 2010-10-30 VAF/pIRF7:CBP/p300 binds the promoters of type-I IFN genes Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 IRF7 and VAF transcription factors binds to IFN-alpha and IFN-beta promoter regions and induce the IFN-alpha and beta mRNA. Pubmed9822609 Reactome Database ID Release 431028819 Reactome, http://www.reactome.org ReactomeREACT_24975 Reviewed: Kawai, T, Akira, S, 2010-10-30 Interaction of MEKK1 with TRAF6 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed18984593 Reactome Database ID Release 43933528 Reactome, http://www.reactome.org ReactomeREACT_25003 Reviewed: Kawai, T, Akira, S, 2010-10-30 TRAF6 requires MEKK1 to activate NF-kB and MEKK1 may interact with TRAF6, which in turn contribute to the activation of IKK and MAPKK, leading to the activation of NF-kB and AP-1. (Yoshida et al) Activation of IKK by MEKK1 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 In Human, IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex and NFkB mediated antiviral responce are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO.[Solt et al 2009]; [Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it's remained unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.<br><br>This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.<br><br>IKK beta is the major IKK catalytic subunit for NF-kB activation. MEKK1 can activate both IKK-alpha (IKKA) and IKK-beta (IKKB) in vivo. MEKK1 phosphorylates Ser-176 and Ser-180 in IKKA and Ser-177 and Ser-181 in IKKB activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation. Pubmed12221085 Pubmed19666475 Pubmed9008162 Pubmed9689078 Reactome Database ID Release 43933530 Reactome, http://www.reactome.org ReactomeREACT_24935 Reviewed: Kawai, T, Akira, S, 2010-10-30 has a Stoichiometric coefficient of 4 RNF125 mediated ubiquitination of RIG-I, MDA5 and IPS-1 Authored: Garapati, P V, 2010-08-02 EC Number: 6.3.2.19 Edited: Garapati, P V, 2010-08-22 Pubmed17460044 Pubmed18703349 RNF125 acts as an E3-ubiquitin ligase that conjugates with RIG-I, MDA5 and IPS-1 and mediate their proteosomal degradation. UbcH1, UbcH5a, UbcH5b, and UbcH5c function as an E2 enzyme and conjugate ubiquitin to RNF125 and RIG-1 via K48. Among these enzymes UbcH5c is the major E2 enzyme showing enhanced ubiquitin conjugation to RIG-I. RNF125 mediated ubiquitination of RIG-I/MDA5 and IPS1 inhibits RIG-I signaling by shunting these proteins toward proteasomal degradation. Reactome Database ID Release 43936412 Reactome, http://www.reactome.org ReactomeREACT_25252 Reviewed: Kawai, T, Akira, S, 2010-10-30 BRCA1:BRCA2:PALB2 Reactome DB_ID: 517917 Reactome Database ID Release 43517917 Reactome, http://www.reactome.org ReactomeREACT_21702 has a Stoichiometric coefficient of 1 ub-FANCD- and ub-FANCI-bound chromatin Reactome DB_ID: 420761 Reactome Database ID Release 43420761 Reactome, http://www.reactome.org ReactomeREACT_18703 has a Stoichiometric coefficient of 1 Recruitment of IRF7 to TRAF6 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed15361868 Pubmed19479062 Reactome Database ID Release 43933538 Reactome, http://www.reactome.org ReactomeREACT_25308 Reviewed: Kawai, T, Akira, S, 2010-10-30 TRAF6 associates with and activates IRF7 but not IRF3. mono-ubiquitinated FANCI Reactome DB_ID: 420753 Reactome Database ID Release 43420753 Reactome, http://www.reactome.org ReactomeREACT_18503 has a Stoichiometric coefficient of 1 Recruitment of TBK1/IKK epsilon complex to TANK:TRAF6 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed10581243 Pubmed12133833 Pubmed19479062 Reactome Database ID Release 43933527 Reactome, http://www.reactome.org ReactomeREACT_25079 Reviewed: Kawai, T, Akira, S, 2010-10-30 TANK acts as an adapter protein and regulates the assembly of TBK1/IKK epsilon complex with upstream signaling molecules. SIKE (for Suppressor of IKKepsilon) interacts with IKKepsilon and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection. Overexpression of SIKE disrupted the interactions of IKKepsilon or TBK1 with RIG-1. mono-ubiquitinated FANCD2 Reactome DB_ID: 420752 Reactome Database ID Release 43420752 Reactome, http://www.reactome.org ReactomeREACT_18762 has a Stoichiometric coefficient of 1 Recruitment of TANK to TRAF6 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed17327220 Pubmed19479062 Pubmed19668221 Reactome Database ID Release 43933537 Reactome, http://www.reactome.org ReactomeREACT_24986 Reviewed: Kawai, T, Akira, S, 2010-10-30 TRAF family member-associated NF-kB activator (TANK also known as I-TRAF) plays an important role in IFN induction through both RIG-I and Toll-like receptor-dependent pathways. TANK has been identified as a TRAF6 binding protein. Transient transfection experiments in 293T cells revealed that TRAF6 associates with IPS-1, TBK1, IKKi, and TANK (Konno H et al). FA core complex Reactome DB_ID: 419526 Reactome Database ID Release 43419526 Reactome, http://www.reactome.org ReactomeREACT_18602 has a Stoichiometric coefficient of 1 Recruitment of TRAF6/TRAF2 to IPS-1 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 IPS-1 interacts with TRAF2 and TRAF6 through its consensus TRAF-interaction motif (TIM) (TRAF2 143-PVGET-147 and TRAF6 153-PGENSE-158 & 455-PEENEY-460). Although IPS-1 can bind to both TRAF6 and TRAF2, TRAF2 binding is not required for IPS-1 activation of NF-kB. Pubmed16153868 Pubmed17029998 Pubmed19479062 Reactome Database ID Release 43918230 Reactome, http://www.reactome.org ReactomeREACT_25262 Reviewed: Kawai, T, Akira, S, 2010-10-30 Active Pol II complex with repaired DNA template:mRNA hybrid Reactome DB_ID: 110296 Reactome Database ID Release 43110296 Reactome, http://www.reactome.org ReactomeREACT_2462 has a Stoichiometric coefficient of 1 Stalled Pol II in TC-NER Reactome DB_ID: 110294 Reactome Database ID Release 43110294 Reactome, http://www.reactome.org ReactomeREACT_4443 has a Stoichiometric coefficient of 1 Transcription-coupled (TC) repair complex Reactome DB_ID: 110276 Reactome Database ID Release 43110276 Reactome, http://www.reactome.org ReactomeREACT_3969 has a Stoichiometric coefficient of 1 Stalled Pol II complex with damaged DNA hybrid Reactome DB_ID: 110293 Reactome Database ID Release 43110293 Reactome, http://www.reactome.org ReactomeREACT_3072 has a Stoichiometric coefficient of 1 Phosphorylation and release of IRF7 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 IRF7 is activated through phosphorylation of residues Ser477 and Ser479 by TBK1/IKKi kinase complex. Pubmed16914100 Reactome Database ID Release 43933525 Reactome, http://www.reactome.org ReactomeREACT_25327 Reviewed: Kawai, T, Akira, S, 2010-10-30 has a Stoichiometric coefficient of 2 Active Pol II transcription complex with damaged DNA hybrid Reactome DB_ID: 110292 Reactome Database ID Release 43110292 Reactome, http://www.reactome.org ReactomeREACT_3609 has a Stoichiometric coefficient of 1 IPS-1 interacts with RIP-1 and FADD Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed16127453 Reactome Database ID Release 43168934 Reactome, http://www.reactome.org ReactomeREACT_25147 Receptor-interacting protein 1 (RIP1) and Fas-Associated Death Domain (FADD) are death domain (DD)-containing proteins. These proteins interact with IPS-1 and activate NF-kB through interaction and activation of caspase-8 and caspase-10. Reviewed: Kawai, T, Akira, S, 2010-10-30 PIK3CA ABD domain mutants Converted from EntitySet in Reactome Reactome DB_ID: 2399588 Reactome Database ID Release 432399588 Reactome, http://www.reactome.org ReactomeREACT_147943 Processing of caspases Authored: Garapati, P V, 2010-08-02 EC Number: 3.4.22 Edited: Garapati, P V, 2010-08-02 Processing of caspases is required for activation of downstream signaling and dsRNA stimulation inducese the processing of these caspases. The nonapoptotic caspase function of both caspase-8 and -10 does not require the protease activity and the DED-containing prodomains are sufficient for NF-kB activation. Pubmed11717445 Pubmed12884866 Pubmed16585540 Pubmed16618810 Pubmed18761323 Reactome Database ID Release 43933532 Reactome, http://www.reactome.org ReactomeREACT_24999 Reviewed: Kawai, T, Akira, S, 2010-10-30 has a Stoichiometric coefficient of 2 Recruitment of IKK complex Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed11002417 Pubmed12884866 Reactome Database ID Release 43933539 Reactome, http://www.reactome.org ReactomeREACT_25134 Reviewed: Kawai, T, Akira, S, 2010-10-30 The molecular mechanisms by which caspase-8/10 attribute to NF-kB signaling is unclear. Caspase-8 might act as a scaffolding protein by bringing the IKK-complex in close proximity to its activator TAK1. The prodomain of Caspase-8 could interact with IKK2 in the IKK complex whereas the protease homology domain failed to do so. These results indicate that the interaction of the DEDs-containing prodomain of caspase-8 with the IKKs may be crucial for the NF-kB induction by caspase-8. Recruitment of caspase-8 and -10 to FADD complex Authored: Garapati, P V, 2010-08-02 Caspase-8 (casp-8) and caspase-10 (casp-10) are involved in RIG-I/MDA5-dependent antiviral immune responses. Caspase-8/10 activation contributes to NF-kB activation in response to viral dsRNA.<br>Caspase-8/10 are synthesized as zymogens (procaspases), containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domain separated by a smaller linker region. FADD plays a crucial role in the recruitment and activation of procaspase-8/10. The two DED domains of procaspase-8/10 interacts with DED domain of FADD. Edited: Garapati, P V, 2010-08-02 Pubmed11717445 Pubmed12107169 Pubmed12884866 Pubmed16585540 Pubmed16618810 Pubmed18761323 Reactome Database ID Release 43933526 Reactome, http://www.reactome.org ReactomeREACT_25167 Reviewed: Kawai, T, Akira, S, 2010-10-30 Dimerzation of procaspase-8/10 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Procaspase-8/10 undergo dimerization and the subsequent conformational changes at the receptor complex results in the formation of catalytic active caspase dimers. Pubmed11717445 Pubmed12884866 Pubmed16585540 Pubmed16618810 Pubmed18761323 Reactome Database ID Release 43933523 Reactome, http://www.reactome.org ReactomeREACT_24946 Reviewed: Kawai, T, Akira, S, 2010-10-30 BRCA1:53BP1 complex at site of DNA double-strand break Reactome DB_ID: 110402 Reactome Database ID Release 43110402 Reactome, http://www.reactome.org ReactomeREACT_5695 has a Stoichiometric coefficient of 1 DNA double-strand break ends: MRN complex Reactome DB_ID: 75166 Reactome Database ID Release 4375166 Reactome, http://www.reactome.org ReactomeREACT_3443 has a Stoichiometric coefficient of 1 RAD51:BRCA2 complex Reactome DB_ID: 83621 Reactome Database ID Release 4383621 Reactome, http://www.reactome.org ReactomeREACT_4224 has a Stoichiometric coefficient of 1 RPA-coated 3'-ends of DNA double strand break Reactome DB_ID: 75993 Reactome Database ID Release 4375993 Reactome, http://www.reactome.org ReactomeREACT_3704 has a Stoichiometric coefficient of 1 heptameric RAD52 complex associated with ssDNA Reactome DB_ID: 83900 Reactome Database ID Release 4383900 Reactome, http://www.reactome.org ReactomeREACT_3435 has a Stoichiometric coefficient of 1 IRF3:CBP/p300 complex binds the promoters of IFN-beta Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 IRF3:CBP/p300 complex binds specifically to IFN-beta promoter region and induces IFN-beta mRNA expression. Pubmed9541017 Reactome Database ID Release 431028815 Reactome, http://www.reactome.org ReactomeREACT_25153 Reviewed: Kawai, T, Akira, S, 2010-10-30 PIK3CA kinase domain mutants Converted from EntitySet in Reactome Reactome DB_ID: 2399596 Reactome Database ID Release 432399596 Reactome, http://www.reactome.org ReactomeREACT_148407 Interaction of CBP/p300 with p-IRF3 dimer Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Phosphorylated IRF3 dimer translocated to the nucleus interacts with the coactivator CBP/p300. This interaction prevents the export of activated IRF3 dimer from nucleus and it may also alter the conformation of the DNA binding domain of IRF3, and induce specific DNA binding of IRF3. Pubmed10082512 Pubmed9463386 Pubmed9541017 Reactome Database ID Release 431028817 Reactome, http://www.reactome.org ReactomeREACT_25275 Reviewed: Kawai, T, Akira, S, 2010-10-30 ATM associated with DNA double-strand break ends Reactome DB_ID: 110403 Reactome Database ID Release 43110403 Reactome, http://www.reactome.org ReactomeREACT_3544 has a Stoichiometric coefficient of 1 Phosphorylation and release of IRF3/IRF7 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Human IRF3 is activated through a two-step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi, requiring Ser386 and/or Ser385- site 1; and a cluster of serine/threonine residues between Ser396 and Ser405- site 2 [Panne et al 2007]. Phosphorylated residues at site 2 (Ser396—Ser405) alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1 (Ser385 or Ser386). Phosphorylation at site 1 is required for IRF3 dimerization.<br>IRF3 and IRF7 transcription factors possess distinct structural characteristics; IRF7 is phosphorylated on Ser477 and Ser479 residues [Lin R et al 2000]. <br>Since the number of serine residues involved into IRF activation remains unclear this reaction represents a minimum stoichiometry to achieve the phosphorylation of at least 3 Ser residues per each IRF transcription factor. [Lin et al 2000, Ning et al 2008] Pubmed10893229 Pubmed12692549 Pubmed14703513 Pubmed16914100 Pubmed17526488 Pubmed9463386 Reactome Database ID Release 43918229 Reactome, http://www.reactome.org ReactomeREACT_25368 Reviewed: Kawai, T, Akira, S, 2010-10-30 has a Stoichiometric coefficient of 6 gamma-H2AX:NBS1 complex at the site of double-strand break Reactome DB_ID: 75171 Reactome Database ID Release 4375171 Reactome, http://www.reactome.org ReactomeREACT_3255 has a Stoichiometric coefficient of 1 Recruitment of IRF3/7  Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 IRF3 and IRF7 (IRF3/IRF7) are the two major members of the interferon regulatory factor (IRF) family, involved in modulating the IFN gene expression. However, their roles are different in these processes. In the early phase of viral infection, preexisting IRF-3 is activated and induces expression of IFN beta and IFN alpha4. These early produced IFNs transcriptionally induce IRF-7, and upon viral infection, the induced high-level IRF-7 is activated and transactivates multiple IFN genes, leading to robust production of IFNs in response to viral infection. IPS-1 interacts with both IRF3 and IRF7 and recruits them to RIG-1. TBK1/IKKi kinases phosphorylate and activate IRF3/IRF7. Pubmed12692549 Pubmed16153868 Pubmed16846591 Reactome Database ID Release 43918232 Reactome, http://www.reactome.org ReactomeREACT_25170 Reviewed: Kawai, T, Akira, S, 2010-10-30 53BP1:H2AX complex at site of double-strand break Reactome DB_ID: 110401 Reactome Database ID Release 43110401 Reactome, http://www.reactome.org ReactomeREACT_3104 has a Stoichiometric coefficient of 1 Translocation of phosphorylated IRF3/7 dimers into nucleus Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Phosphorylated IRF dimers after dimerization translocates into the nucleus and associate with general coactivators like CBP/p300 and bind to type-I IFN promoter region. Pubmed12604599 Reactome Database ID Release 431028816 Reactome, http://www.reactome.org ReactomeREACT_25352 Reviewed: Kawai, T, Akira, S, 2010-10-30 MRN MRE11:RAD50:NBS1 complex Reactome DB_ID: 75164 Reactome Database ID Release 4375164 Reactome, http://www.reactome.org ReactomeREACT_4350 has a Stoichiometric coefficient of 1 Dimerization of Phospho IRF3 or phospho IRF7 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Phosphorylation of these transcription factors IRF3 and IRF7 results in a conformational change that allows their dimerization to form homo- or hetero dimers. Each of the three different combinations of dimers (IRF3:IRF3, IRF7:IRF7 and IRF3:IRF7) may selectively effect the transcription of IFN-alpha gene subfamilies and IFN-beta genes. Pubmed12604599 Reactome Database ID Release 431028821 Reactome, http://www.reactome.org ReactomeREACT_24983 Reviewed: Kawai, T, Akira, S, 2010-10-30 has a Stoichiometric coefficient of 3 RAD50:MRE11 complex Reactome DB_ID: 75161 Reactome Database ID Release 4375161 Reactome, http://www.reactome.org ReactomeREACT_5426 has a Stoichiometric coefficient of 1 dsRNA binds to MDA5 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 MDA5 is the closest relative of RIG-I and contains two CARD-like regions, a DExD/H helicase domain, and a C-terminal region similar to the RD of RIG-I. MDA5 with its C-terminal domain (CTD) preferentially binds dsRNA with blunt ends, but does not associate with dsRNA with either 5' or 3' overhangs. Upon binding dsRNA, MDA5 is presumed to undergo structural alteration and, thereby unmask the CARDs enabling them to recruit downstream signal transducer proteins. Dihydroxyacetone kinase (DAK) binds to the CARD domains of MDA5 and acts as a negative regulator of MAD5. It is released upon the conformational change induced by viral RNA binding, allowing the MDA5 CARD domains to bind to IPS-1 CARD. Pubmed17600090 Pubmed18591409 Pubmed19531363 Reactome Database ID Release 43913725 Reactome, http://www.reactome.org ReactomeREACT_25160 Reviewed: Kawai, T, Akira, S, 2010-10-30 RIG-I/MDA5 interacts with IPS-1 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed16125763 Pubmed16127453 Pubmed16153868 Pubmed18307765 Reactome Database ID Release 43168909 Reactome, http://www.reactome.org ReactomeREACT_24957 Reviewed: Kawai, T, Akira, S, 2010-10-30 Upon binding the dsRNA, RIG-I and MDA5 recruit downstream signal transducer, a mitochondria-bound protein: IPS-1/VISA/MAVS/CARDIF. This mitochondria-bound adaptor has been given four different names according to the various groups who identified it: MAVS, mitochondrial antiviral signaling; IPS-1, interferonbeta promoter stimulator 1; VISA, virus-induced signaling adaptor; CARDIF, CARD adaptor inducing IFNbeta. IPS-1 is an adaptor protein with an N-terminal CARD-like domain (CLD) and with this it associates with the CARD regions of RIG-I and MDA5 and mediate the induction of interferons. Recruitment of TRAF3 to IPS-1 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed16306936 Pubmed16858409 Pubmed17190786 Reactome Database ID Release 43918227 Reactome, http://www.reactome.org ReactomeREACT_25364 Reviewed: Kawai, T, Akira, S, 2010-10-30 TRAF3 a E3 ligase for K63-linked polyubiquitination, is one of the critical molecules required for mediating IPS-1 dependent type I IFN production. TRAF3 interacts directly with IPS-1 through the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) with in IPS-1. TBK1/IKK epsilon complex interacts with IPS-1 bound TRAF3 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed16281057 Pubmed16306936 Reactome Database ID Release 43918225 Reactome, http://www.reactome.org ReactomeREACT_25051 Reviewed: Kawai, T, Akira, S, 2010-10-30 TRAF3 binds with both IPS-1 and downstream interferon regulatory factor 3/7 (IRF3/7) kinases TBK1 and IKK-epsilon (IKKi) and thus serves as a critical link between RIG-I/MDA5 adaptors and downstream regulatory kinases important for interferon regulatory factor (IRF) activation (Oganesyan et al). <br>SIKE (for Suppressor of IKKepsilon) interacts with IKKepsilon and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection. Overexpression of SIKE disrupted the interactions of IKKepsilon or TBK1 with RIG-I. DNA-PK synaptic complex DNA-PK:DNA:DNA-PK:DNA complex Reactome DB_ID: 75908 Reactome Database ID Release 4375908 Reactome, http://www.reactome.org ReactomeREACT_5513 has a Stoichiometric coefficient of 2 DNA-PK holoenzyme DNA-PK:DNA complex Reactome DB_ID: 75907 Reactome Database ID Release 4375907 Reactome, http://www.reactome.org ReactomeREACT_2311 has a Stoichiometric coefficient of 1 Ku:DNA double-strand break ends Reactome DB_ID: 75906 Reactome Database ID Release 4375906 Reactome, http://www.reactome.org ReactomeREACT_5272 has a Stoichiometric coefficient of 1 Ku70:Ku80 heterodimer Reactome DB_ID: 75905 Reactome Database ID Release 4375905 Reactome, http://www.reactome.org ReactomeREACT_3482 has a Stoichiometric coefficient of 1 RAD52:RPA complex Reactome DB_ID: 83620 Reactome Database ID Release 4383620 Reactome, http://www.reactome.org ReactomeREACT_2546 has a Stoichiometric coefficient of 1 heptameric RAD52 complex Reactome DB_ID: 83899 Reactome Database ID Release 4383899 Reactome, http://www.reactome.org ReactomeREACT_5674 has a Stoichiometric coefficient of 7 RAD51:resected ends of DNA double-strand break Reactome DB_ID: 109777 Reactome Database ID Release 43109777 Reactome, http://www.reactome.org ReactomeREACT_2547 has a Stoichiometric coefficient of 1 RAD51:RPA complex Reactome DB_ID: 83618 Reactome Database ID Release 4383618 Reactome, http://www.reactome.org ReactomeREACT_3100 has a Stoichiometric coefficient of 1 RAD51:RAD52:DNA double strand break end complex Reactome DB_ID: 83619 Reactome Database ID Release 4383619 Reactome, http://www.reactome.org ReactomeREACT_5752 has a Stoichiometric coefficient of 1 RAD52:DNA double-strand break Reactome DB_ID: 109778 Reactome Database ID Release 43109778 Reactome, http://www.reactome.org ReactomeREACT_3721 has a Stoichiometric coefficient of 1 LIG3:XRRC1-bound DNA strand containing the ligated residue Reactome DB_ID: 110343 Reactome Database ID Release 43110343 Reactome, http://www.reactome.org ReactomeREACT_3877 has a Stoichiometric coefficient of 1 Translocation of BIM to mitochondria GENE ONTOLOGYGO:0001844 In this reaction, 1 molecule of 'BIM' is translocated from cytosol to mitochondrial outer membrane.<br><br>This reaction takes place in the 'cytosol'.<br> Reactome Database ID Release 43139919 Reactome, http://www.reactome.org ReactomeREACT_750 POL Beta: APE1-bound 5' incised DNA strand break containing first resynthesized base Reactome DB_ID: 111252 Reactome Database ID Release 43111252 Reactome, http://www.reactome.org ReactomeREACT_2384 has a Stoichiometric coefficient of 1 POL Delta:APE1-bound 5' incised DNA strand break containing first resynthesized nucleotide Reactome DB_ID: 110344 Reactome Database ID Release 43110344 Reactome, http://www.reactome.org ReactomeREACT_3786 has a Stoichiometric coefficient of 1 Translocation of PUMA protein to mitochondria Authored: Gopinathrao, G, 2004-08-18 11:49:08 GENE ONTOLOGYGO:0001844 It is thought that due to its p53 dependence for expression, PUMA could function as a mediator of p53-induced apoptosis. Newly synthesized PUMA protein translocates to mitochondria and binds to BCL-2 and Bcl-X(L) through a BH3 domain. Pubmed11463391 Reactome Database ID Release 43139914 Reactome, http://www.reactome.org ReactomeREACT_104 Reviewed: Vaux, D, 0000-00-00 00:00:00 Phosphorylation of DLC1 by MAPK 8 At the beginning of this reaction, 1 molecule of 'BIM sequestered to dynein (DLC1)' is present. At the end of this reaction, 1 molecule of 'BIM', and 1 molecule of 'phospho-dynein(DLC1) on microtubules' are present.<br><br> This reaction takes place on the 'plasma membrane' and is mediated by the 'kinase activity' of 'Mitogen-activated protein kinase 8 '.<br> Pubmed12591950 Reactome Database ID Release 43139918 Reactome, http://www.reactome.org ReactomeREACT_1888 BAD displaces tBID from BCL-2 sequestration Authored: Gopinathrao, G, 2004-08-18 11:49:08 Pubmed12242151 Reactome Database ID Release 43139897 Reactome, http://www.reactome.org ReactomeREACT_1062 Reviewed: Vaux, D, 0000-00-00 00:00:00 Short peptides representing BAD and BIX were found to bind BCL-2 displacing BID-like BH3 domains that initiate mitochondrial dysfunction. Translocation of NOXA to mitochondria Authored: Gopinathrao, G, 2004-08-18 11:49:08 GENE ONTOLOGYGO:0001844 It was observed that cytosolic Noxa underwent BH3 motif-dependent localization to mitochondria and interacted with anti-apoptotic Bcl-2 family members, resulting in the activation of caspase-9. Pubmed10807576 Reactome Database ID Release 43140216 Reactome, http://www.reactome.org ReactomeREACT_1585 DNA containing unligated replacement-synthesized patch Reactome DB_ID: 110347 Reactome Database ID Release 43110347 Reactome, http://www.reactome.org ReactomeREACT_3364 has a Stoichiometric coefficient of 1 Ligated patch-repaired DNA Reactome DB_ID: 111434 Reactome Database ID Release 43111434 Reactome, http://www.reactome.org ReactomeREACT_5348 has a Stoichiometric coefficient of 1 HREV1:damaged DNA template complex Reactome DB_ID: 110283 Reactome Database ID Release 43110283 Reactome, http://www.reactome.org ReactomeREACT_3664 has a Stoichiometric coefficient of 1 FGFR3 point mutants with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2018770 Reactome Database ID Release 432018770 Reactome, http://www.reactome.org ReactomeREACT_123189 single-stranded DNA flap structure at the site of damaged residue Reactome DB_ID: 110346 Reactome Database ID Release 43110346 Reactome, http://www.reactome.org ReactomeREACT_2352 has a Stoichiometric coefficient of 1 APE1:DNA ligase I complex Reactome DB_ID: 110348 Reactome Database ID Release 43110348 Reactome, http://www.reactome.org ReactomeREACT_2969 has a Stoichiometric coefficient of 1 APE1:FEN1 complex Reactome DB_ID: 110408 Reactome Database ID Release 43110408 Reactome, http://www.reactome.org ReactomeREACT_4220 has a Stoichiometric coefficient of 1 FEN1:PCNA complex Reactome DB_ID: 110407 Reactome Database ID Release 43110407 Reactome, http://www.reactome.org ReactomeREACT_4419 has a Stoichiometric coefficient of 1 p-T,4S-IRF3 is dimerized Authored: Shamovsky, V, 2012-07-09 IRF3 phosphorylation promotes IRF3 dimerization and nuclear translocation, which results in the production of type I interferons (IFNs). Pubmed11035028 Pubmed17483521 Pubmed17526488 Reactome Database ID Release 432395992 Reactome, http://www.reactome.org ReactomeREACT_147821 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 has a Stoichiometric coefficient of 2 Phosphorylation and release of IRF3 Authored: Shamovsky, V, 2011-09-21 Edited: Shamovsky, V, 2012-02-23 IRF3 is activated through a two-step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi, requiring Ser386 and/or Ser385- site 1; and a cluster of serine/threonine residues between Ser396 and Ser405- site 2 [Panne et al 2007]. Phosphorylated residues at site 2 (Ser396 - Ser405) alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1 (Ser385 or Ser386). Phosphorylation at site 1 is required for IRF3 dimerization. Pubmed12692549 Pubmed17526488 Pubmed9463386 Reactome Database ID Release 431606327 Reactome, http://www.reactome.org ReactomeREACT_118685 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- has a Stoichiometric coefficient of 10 has a Stoichiometric coefficient of 2 Translocation of activated BAD protein to mitochondria GENE ONTOLOGYGO:0001844 In this reaction, 1 molecule of 'BAD protein' is translocated from cytosol to mitochondrial outer membrane.<br><br>This reaction takes place in the 'cytosol'.<br> Reactome Database ID Release 43139905 Reactome, http://www.reactome.org ReactomeREACT_2046 DAI recruits RIP1 and RIP3 Authored: Shamovsky, V, 2011-09-21 Edited: Shamovsky, V, 2012-02-23 Pubmed18941233 Pubmed19590578 Reactome Database ID Release 431810457 Reactome, http://www.reactome.org ReactomeREACT_118851 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- Two RIP homotypic interaction motifs (RHIM) were identified in the DAI protein sequence. These two domains were shown to be essential for DAI-induced NFkB activation in human embryonic kidney 293T (HEK293T) cells. DAI forms a complex with two RHIM-containing kinases - RIP1 and RIP3 (Kaiser WJ et al 2008, Rebsamen M et al 2009). Recruitment of RIP3 to DAI was reported to induce RIP3 autophosphorylation. Furthermore, knockdown of RIP1 or RIP3 affected DAI-induced NFkB signals in murine L929 fibroblast and human HEK293T cells (Kaiser WJ et al 2008, Rebsamen M et al 2009). Activation of BAD by calcineurin At the beginning of this reaction, 1 molecule of '143B:phospo-BAD complex' is present. At the end of this reaction, 1 molecule of 'BAD protein', and 1 molecule of '143B protein' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'calcium-dependent protein serine/threonine phosphatase regulator activity' of 'Calcineurin B complex'.<br> Pubmed10195903 Reactome Database ID Release 43139906 Reactome, http://www.reactome.org ReactomeREACT_1663 Dimerized phospho-IRF3 migrates to the nucleus Authored: Shamovsky, V, 2011-09-21 Edited: Shamovsky, V, 2012-02-23 IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm. Pubmed12692549 Reactome Database ID Release 432032396 Reactome, http://www.reactome.org ReactomeREACT_118567 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Jin, Lei, 2012-08-18 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- Sequestration of BAD protein by 14-3-3 At the beginning of this reaction, 1 molecule of '143B protein', and 1 molecule of 'Phospho-BAD' are present. At the end of this reaction, 1 molecule of '143B:phospo-BAD complex' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Pubmed12657644 Reactome Database ID Release 43139899 Reactome, http://www.reactome.org ReactomeREACT_1139 IFI16 binds cytosolic dsDNA Authored: Shamovsky, V, 2012-07-09 Interferon (IFN)-inducible IFI16 protein was shown to be critical for type I IFN and pro inflammatory responses in viral DNA-stimulated human and mouse cells [Unterholzner L et al 2010; Kerur N et al 2011; Li T et al 2012]. Despite being predominantly nuclear, IFI16 can sense pathogenic DNA in both the cytoplasm and the nucleus. Cytosolic IFI16 can directly bind viral dsDNA motifs via its HIN200 domains in human monocytic leukemia THP-1 cell extracts. IFI16-mediated response to cytosolic DNA was reported to induce type I IFN production in a STING-TBK1- and IRF3 dependent manner [Unterholzner L et al 2010]. <p>Nuclear IFI16 can detect kaposi sarcoma-associated herpesvirus (KSHV) DNA which results in IL-1beta maturation and caspase-1 inflammasome activation in human cells [Kerur N et al 2011]. Importantly, acetylation of the nuclear localization signal (NLS) of IFI16 in lymphocytes and macrophages leads to cytosolic accumulation of IFI16 and is important for its type I IFN stimulation ability in cytoplasm [Li T et al 2012]. Pubmed20890285 Pubmed21575908 Pubmed22691496 Reactome Database ID Release 431834951 Reactome, http://www.reactome.org ReactomeREACT_147878 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 Akt1 phosphorylates BAD protein At the beginning of this reaction, 1 molecule of 'BAD protein' is present. At the end of this reaction, 1 molecule of 'Phospho-BAD' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'kinase activity' of 'AKT1'.<br> Pubmed15183529 Reactome Database ID Release 43139903 Reactome, http://www.reactome.org ReactomeREACT_188 RIP1 facilitates IKK complex phosphorylation Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2011-08-12 In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.<p>This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.<p>IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation. Pubmed11479302 Pubmed12221085 Pubmed15145317 Pubmed15258597 Pubmed16115877 Pubmed16547522 Pubmed16603398 Pubmed19666475 RIP1 polyubiquitination was induced upon TNF- or poly(I-C) treatment of the macrophage cell line RAW264.7 and the U373 astrocytoma line (Cusson-Hermance et al 2005). These workers have suggested that RIP1 may use similar mechanisms to induce NF-kB in the TNFR1- and Trif-dependent TLR pathways.<p>RIP1 modification with Lys-63 polyubiquitin chains was shown to be essential for TNF-induced activation of NF-kB (Ea et al. 2006). It is thought that TRAF family members mediate this Lys63-linked ubiquitination of RIP1 (Wertz et al. 2004, Tada et al 2001, Vallabhapurapu and Karin 2009), which may facilitate recruitment of the TAK1 complex and thus activation of NF-kB. Binding of NEMO to Lys63-linked polyubiquitinated RIP1 is also required in the signaling cascade from the activated receptor to the IKK-mediated NF-kB activation (Wu et al. 2006). Reactome Database ID Release 43168910 Reactome, http://www.reactome.org ReactomeREACT_6973 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- Translocation of tBID to mitochondria In this reaction, 1 molecule of 'tBID' is translocated from cytosol to mitochondrial outer membrane.<br><br>This reaction takes place in the 'cytosol'.<br> Reactome Database ID Release 43139920 Reactome, http://www.reactome.org ReactomeREACT_1370 STING recruits TBK1 and IRF3 Authored: Shamovsky, V, 2012-07-09 Pubmed12133833 Pubmed15210742 Pubmed16281057 Pubmed16306936 Pubmed18818105 Pubmed19433799 Pubmed19776740 Pubmed19926846 Pubmed22394562 Pubmed22579474 Reactome Database ID Release 431834939 Reactome, http://www.reactome.org ReactomeREACT_147703 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are central regulators of type-I interferon induction during bacterial or viral infection. TBK1 was found to form complexes with distinct scaffolding proteins that appeared to target TBK1 to different subcellular compartments [Hemmi H et al 2004; Oganesyan G et al 2006; Chariot A et al 2002; Huang J et al 2004]. In dsDNA-stimulated human and mouse cells TBK1 has been shown to move to cytoplasmic punctate structures, where it associates with STING to induce IRF3 activation [Ishikawa H et al 2009; Saitoh T et al 2009; Sun W et al 2009; Tanaka Y and Chen ZJ 2012]. Co-immunoprecipitation assays in HEK 293T cells expressing HA-tagged STING and Flag-tagged TBK1 showed that TBK1 directly interacts with STING. Moreover, glutathione S-transferase (GST) pull-down assays showed that recruitment of TBK1 by STING was enhanced upon c-di-GMP binding [Ouyang S et al 2012].<p>STING was reported to mediate TBK1-dependent activation of transcription factor IRF3 [Zhong B et al 2008; Tanaka Y, and Chen ZJ 2012]. Both TBK1 and IRF3 can directly interact with STING through its C-terminal region [Tanaka Y, and Chen ZJ 2012]. A construct of human STING containing only 39 amino acid residues of its C-terminus (341 to 379) was sufficient to activate IRF3 in cytosolic extracts of HeLa cells. Further mutagenesis studies showed, that two residues, Ser366 and Leu374, within the C-terminal tail of STING were required for IRF3 binding and phosphorylation, but were dispensable for TBK1 binding and activation [Tanaka Y, and Chen ZJ 2012]. Thus, STING is thought to function as a scaffold to recruit cytosolic TBK1 and IRF3, which results in TBK1-dependent phosphorylation of IRF3. has a Stoichiometric coefficient of 2 STING binds c-di-GMP Authored: Shamovsky, V, 2012-07-09 Cyclic di-GMP (c-di-GMP) and cyclic-di-AMP (c-di-AMP) are ubiquitous secondary messengers secreted by bacteria, but not by eukarya. UV cross-linking experiment with radiolabeled c-di-GMP in lysates of human embryonic kidney 293T (HEK293T) cells expressing mouse Sting showed that STING recognizes and directly binds to c-di-GMP [Burdette DL et al 2011]. STING was reported to contain multiple trans-membrane regions at its N-terminus while its C-terminal domain (CTD) is cytosolic. Mutational analysis showed that the CTD is responsible for the binding to c-di-GMP and this binding enhances the recruitment of TBK1 by STING [Ouyang S et al 2012]. Furthermore, a C-terminal tail (CTT) within the CTD interacts with and activates TBK1 and IRF3 [Tanaka Y and Chen ZJ 2012]. Impotantly, Sting is required for both c-di-GMP and c-di-AMP induced type I IFN production in mouse cultured macrophages infected with intracellular pathogens in vitro [Jin L et al 2011; Sauer JD et al 2011]. Low levels of STING protein expressed in human embryonic kidney (HEK293T) cells were sufficient to reconstitute the responsiveness of the cells to both c-di-GMP and c-di-AMP [Burdette DL et al 2011]. However, structural studies of STING revealed, that STING prefers c-di-GMP over c-di-AMP [Ouyang S et al 2012]. <p>Several studies have demonstrated that human STING functions as a dimer and STING dimerization was essential for the induction of IFN response [Sun W et al 2009; Burdette DL et al 2011; Jin L et al 2011; Ouyang S et al 2012]. Mouse Sting/Myps has been also reported to exist as a dimer constitutively [Jin L et al 2008]. Moreover, STING can function as a ROS sensor, which forms a disulfide-linked homodimer under conditions of oxidative stress in HEK293T cells [Jin L et al 2010]. Structure analysis of the C-terminal domain in complex with c-di-GMP revealed that two STING molecules associate with one molecule of c-di-GMP [Ouyang S et al 2012; Yin Q et al 2012; Scu C et al 2012]. The STING dimer is thought to have a V-shaped structure, and the c-di-GMP binding site is located at the bottom of the V of the dimer interface [Scu C et al 2012]. Isothermal titration calorimetry (ITC) experiments confirmed the stoichiometry of STING to c-di-GMP as 2:1 with a binding dissociation constant (Kd) of ~2.4 microM [Yin Q et al 2012; Scu C et al 2012]. The data are consistent with a previous measurement of mouse STING CTD binding affinity to c-di-GMP using equilibrium dialysis [Burdette DL et al 2011]. Although STING is considered as a direct sensor of bacterial c-di-GMP, it is noteworthy, that the binding affinity of c-di-GMP to mammalian STING is much weaker than to bacterial sensors. For example, E.coli protein YcgR binds to c-di-GMP with a Kd of ~0.84 microM [Ryjenkov DA et al 2006]. Also taking into account that, the normal concentration of c-di-GMP in bacteria varies from 0.1~10 microM, it remains to be determined whether STING binds to c-di-GMP under physiological conditions. Pubmed16920715 Pubmed18559423 Pubmed19433799 Pubmed21098106 Pubmed21170271 Pubmed21813776 Pubmed21947006 Pubmed22394562 Pubmed22579474 Pubmed22705373 Pubmed22728658 Reactome Database ID Release 432396009 Reactome, http://www.reactome.org ReactomeREACT_147763 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 IRF3 is phosphorylated by TBK1 Authored: Shamovsky, V, 2012-07-09 EC Number: 2.7.11 IRF3 is activated through a two-step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi, requiring Ser386 and/or Ser385- site 1; and a cluster of serine/threonine residues between Ser396 and Ser405- site 2 [Panne et al 2007]. Phosphorylated residues at site 2 (Ser396 - Ser405) alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1 (Ser385 or Ser386). Phosphorylation at site 1 is required for IRF3 dimerization. Pubmed12692549 Pubmed17526488 Pubmed22394562 Reactome Database ID Release 432396007 Reactome, http://www.reactome.org ReactomeREACT_147769 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 has a Stoichiometric coefficient of 10 has a Stoichiometric coefficient of 2 TBK1 is phosphorylated whithin STING:TBK1:IRF3 complex Authored: Shamovsky, V, 2012-07-09 Pubmed11839743 Pubmed19307177 Pubmed22394562 Pubmed22619329 Reactome Database ID Release 432396002 Reactome, http://www.reactome.org ReactomeREACT_147901 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 TBK1 activity is regulated by phosphorylation of Ser-172 within the kinase activation loop [Kishore N et al 2002]. TBK1 phosphorylation is thought to be an autoactivation event. Biochemical analysis demonstrated that the kinase domain alone was sufficient to fully autoactivate TBK1 and was capable of phosphorylating both macromolecular and peptide substrates [Ma X et al 2012]. Furthermore, TBK1 can autophosphorylate at Ser-172 and autoactivate when overexpressed in HEK293 cells. Additionally, in co-transfection experiments wild type TBK1 associated with and phosphorylated the catalytically inactive mutant TBK1-(K38A) at Ser-172 [Clark K et al 2009]. Studies of the crystal structure of TBK1 in complex with a potent small-molecule inhibitor BX795 revealed that Ser-172 from one protomer is located in close proximity to the active site of the neighboring protomer, providing a snapshot of a potential transautoactivation reaction intermediate [Ma X et al 2012]. However, involvement of a distinct upstream activating kinase in the TBK1 phosphorylation should not be ruled out [Clark K et al 2009]. has a Stoichiometric coefficient of 2 Granzyme-B activates BID by cleavage At the beginning of this reaction, 1 molecule of 'BID' is present. At the end of this reaction, 1 molecule of 'tBID-p15' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'granzyme B activity' of 'Granzyme B'.<br> EC Number: 3.4.21 Pubmed11114298 Reactome Database ID Release 43139893 Reactome, http://www.reactome.org ReactomeREACT_1610 Pol eta:lesioned DNA template inserted with correct base complement Reactome DB_ID: 110290 Reactome Database ID Release 43110290 Reactome, http://www.reactome.org ReactomeREACT_3971 has a Stoichiometric coefficient of 1 Myristoylation of tBID by NMT1 After proteolytic activation, tBID is myristoylated by NMT-1 at an exposed glycine. N-myristoylation may enable the activated tBID to associate with the lipid components of the mitochondrial membrane. Authored: Gopinathrao, G, 2004-11-08 17:38:54 Pubmed11099414 Reactome Database ID Release 43141367 Reactome, http://www.reactome.org ReactomeREACT_1158 Pol zeta complex Reactome DB_ID: 110279 Reactome Database ID Release 43110279 Reactome, http://www.reactome.org ReactomeREACT_5310 has a Stoichiometric coefficient of 1 Recruitment of IRF3 to activated DAI:TBK1 Authored: Shamovsky, V, 2011-09-21 DAI dimer formation enables recruitment of TBK1 and IRF3 to the C-terminal region of DAI in response to cytosolic DNA in murine L929 cells. This interaction is DNA-dependent as DAI mutants that lack DNA binding domains neither recruited TBK1 nor activated IRF3 (Takaoka A et al 2007). Activation of IRF-3 and possibly IRF-7 promotes IFN gene expression. Edited: Shamovsky, V, 2012-02-23 Pubmed17618271 Reactome Database ID Release 431606345 Reactome, http://www.reactome.org ReactomeREACT_118613 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- has a Stoichiometric coefficient of 2 HREV1:lesioned DNA template with misinserted bases Reactome DB_ID: 110285 Reactome Database ID Release 43110285 Reactome, http://www.reactome.org ReactomeREACT_5530 has a Stoichiometric coefficient of 1 Pol eta:damaged DNA template complex Reactome DB_ID: 110288 Reactome Database ID Release 43110288 Reactome, http://www.reactome.org ReactomeREACT_2831 has a Stoichiometric coefficient of 1 TRAIL Mediated Activation of Pro-caspase 8 At the beginning of this reaction, 1 molecule of 'TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-8 precursor complex' is present. At the end of this reaction, 1 molecule of 'p10 subunit of Caspase 8', 1 molecule of 'TRAIL:TRAIL receptor-2:FADD complex', and 1 molecule of 'p18 subunit of Caspase 8' are present.<br><br> This reaction takes place in the 'cell'.<br> Reactome Database ID Release 43141156 Reactome, http://www.reactome.org ReactomeREACT_961 TNF Mediated Activation of Pro-caspase 8 At the beginning of this reaction, 1 molecule of 'TRADD:TRAF2:RIP1:FADD:Capase-8 Complex' is present. At the end of this reaction, 1 molecule of 'TRAF2:TRADD:RIP1:FADD', 1 molecule of 'p10 subunit of Caspase 8', and 1 molecule of 'p18 subunit of Caspase 8' are present.<br><br> This reaction takes place in the 'cell'.<br> Reactome Database ID Release 43141159 Reactome, http://www.reactome.org ReactomeREACT_663 Formation of Caspase-8 dimer At the beginning of this reaction, 1 molecule of 'p10 subunit of Caspase 8', and 1 molecule of 'p18 subunit of Caspase 8' are present. At the end of this reaction, 1 molecule of 'Caspase-8 dimer' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Reactome Database ID Release 43139952 Reactome, http://www.reactome.org ReactomeREACT_1159 Caspase-8 activates BID by cleavage Authored: Gopinathrao, G, 2005-04-27 18:07:06 EC Number: 3.4.22 Pubmed12804595 Pubmed9873064 Reactome Database ID Release 43139898 Reactome, http://www.reactome.org ReactomeREACT_1320 The caspase 8 -mediated cleavage of cytosolic, inactive p22 BID at internal Asp sites yields a major p15 and minor p13 and p11 fragments. After myristoylation, tBID translocates to mitochondria as an integral membrane protein. gamma H2AX:MDC1/NFBD1 complex at site of DNA double-strand break Reactome DB_ID: 110400 Reactome Database ID Release 43110400 Reactome, http://www.reactome.org ReactomeREACT_4269 has a Stoichiometric coefficient of 1 MDC1/NFBD1:gamma-H2AX complex Reactome DB_ID: 83566 Reactome Database ID Release 4383566 Reactome, http://www.reactome.org ReactomeREACT_5218 has a Stoichiometric coefficient of 1 dimeric phospho-ATM complex Reactome DB_ID: 83894 Reactome Database ID Release 4383894 Reactome, http://www.reactome.org ReactomeREACT_5755 has a Stoichiometric coefficient of 2 gamma H2AX-coated DNA double-strand break ends Reactome DB_ID: 110399 Reactome Database ID Release 43110399 Reactome, http://www.reactome.org ReactomeREACT_4416 has a Stoichiometric coefficient of 1 Pol zeta:damaged DNA template complex Reactome DB_ID: 110280 Reactome Database ID Release 43110280 Reactome, http://www.reactome.org ReactomeREACT_5394 has a Stoichiometric coefficient of 1 dimeric ATM kinase Reactome DB_ID: 83538 Reactome Database ID Release 4383538 Reactome, http://www.reactome.org ReactomeREACT_2479 has a Stoichiometric coefficient of 2 ADP-Ribosylation of HNP-1 Authored: Jupe, S, 2011-11-04 Edited: Jupe, S, 2011-11-04 HNP-1 is recognized as a substrate by arginine-specific ADP-ribosyltransferase-1 which ribosylates Arg-14 of the peptide. The modified defensin has reduced antimicrobial and cytotoxic activities but its chemotactic properties remain unchanged whilst its ability to induced the chemokine IL-8 is enhanced. Pubmed12060767 Pubmed21904558 Reactome Database ID Release 431972385 Reactome, http://www.reactome.org ReactomeREACT_115620 Reviewed: McDermott, AM, 2011-11-03 TRAIL:TRAIL-Receptor2 Trimer:FADD complex binds Caspase-8 FADD recruits caspase-8 precursor to trimeric complex of TRAIL and TRAIL receptor 2 (Sprick et al. 2000). Pubmed10894160 Reactome Database ID Release 4375146 Reactome, http://www.reactome.org ReactomeREACT_1543 Beta-defensins 4A and 103 bind CCR2 Authored: Jupe, S, 2011-11-04 Edited: Jupe, S, 2011-11-07 Pubmed20483750 Reactome Database ID Release 431973968 Reactome, http://www.reactome.org ReactomeREACT_115754 Reviewed: McDermott, AM, 2011-11-03 human beta-defensin (hBD)4A and 103 interact with CCR2, a chemokine receptor expressed on monocytes, macrophages, and neutrophils. TRAIL:TRAIL receptor-2 Trimer Binds FADD Pubmed10894160 Reactome Database ID Release 4375187 Reactome, http://www.reactome.org ReactomeREACT_1721 The trimeric complex of TRAIL and TRAIL receptor-2 (TRAIL:TRAIL receptor-2) binds FADD (Sprick et al. 2000). Beta-defensins 1, 4A and 103 bind CCR6 Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pubmed10521347 Pubmed10914484 Pubmed11934878 Reactome Database ID Release 431471338 Reactome, http://www.reactome.org ReactomeREACT_115591 Reviewed: McDermott, AM, 2011-11-03 The chemotactic activity of beta-defensins 1, 4A and 103 (hBD1-3) for immune and inflammatory cells such as memory T cells and immature dendritic cells is mediated through binding to the chemokine receptor CCR6. FAS Mediated Activation of Pro-caspase 8 At the beginning of this reaction, 1 molecule of 'FASL:FAS Receptor Trimer:FADD:pro-Caspase-8 DISC' is present. At the end of this reaction, 1 molecule of 'p10 subunit of Caspase 8', 1 molecule of 'p18 subunit of Caspase 8', and 1 molecule of 'FASL:FAS Receptor Trimer:FADD complex' are present.<br><br> This reaction takes place in the 'cell'.<br> Pubmed9721089 Reactome Database ID Release 4373945 Reactome, http://www.reactome.org ReactomeREACT_279 Beta-defensins bind microbial membranes causing disruption Authored: Jupe, S, 2011-04-28 Binding and disruption of microbial membranes is widely believed to be the primary mechanism of action for beta-defensins. There is no direct evidence of this, but a growing number of studies support this model (Pazgier et al. 2006). Beta-defensins have antimicrobial properties that correlate with membrane permeabilization effects (Antcheva et al. 2004, Sahl et al. 2005, Yenugu et al. 2004). The sensitivity of microbes to beta-defensins correlates with the lipid composition of the membrane; more negatively-charged lipids correlate with larger beta-defensin 103-induced changes in membrane capacitance (Bohling et al. 2006). Beta-defensin-103 was observed to give rise to ionic currents in Xenopus membranes (Garcia et al. 2001) and cell wall perforation was observed in S. aureus when treated with HBD-3 (Harder et al. 2001). Two models explain how membrane disruption takes place. The 'pore model' postulates that beta-defenisns form transmembrane pores in a similar manner to alpha-defensins, while the 'carpet model' suggests that beta-defensins act as detergents, causing a less organised disruption. Beta-defensins have a structure that is topologically distinct from that of alpha-defensins, suggesting a different mode of dimerization and an electrostatic charge-based mechanism of membrane permeabilization rather than a mechanism based on formation of bilayer-spanning pores (Hoover et al. 2000). Edited: Jupe, S, 2011-07-27 Pubmed10906336 Pubmed11085990 Pubmed11702237 Pubmed14742239 Pubmed15033915 Pubmed15582982 Pubmed16634647 Pubmed16710608 Reactome Database ID Release 431467269 Reactome, http://www.reactome.org ReactomeREACT_115564 Reviewed: McDermott, AM, 2011-11-03 TRAIL:TRAIL-Receptor2 Trimer:FADD complex binds Caspase-10 Caspase-10 precursor is recruited to the TRAIL:TRAIL receptor-2:FADD complex (Sprick et al. 2002) through interaction of death effector domains of caspase-10 and FADD (Wang et al. 2001). Pubmed11717445 Pubmed12198154 Reactome Database ID Release 43141316 Reactome, http://www.reactome.org ReactomeREACT_1143 Beta-defensins are secreted Authored: Jupe, S, 2011-04-28 Beta defensin precursors are more simple in structure than those of alpha defensins, having a signal sequence, a short or absent propiece and the mature defensin sequence at the C-terminus. The signal sequence is cleaved off by a signal peptidase in the endoplasmic reticulum (Ganz 2003). Mature beta defensins 1, 2, 3, and 4 are secreted primarily by epithelial cells but are also produced by some immune cells such as monocytes, macrophages and dendritic cells (Duits et al. 2000, Ryan et al. 2003). Edited: Jupe, S, 2011-07-27 Pubmed12153515 Pubmed15019211 Pubmed21122132 Pubmed2997278 Pubmed9541493 Reactome Database ID Release 431471322 Reactome, http://www.reactome.org ReactomeREACT_116066 Reviewed: McDermott, AM, 2011-11-03 Recruitment TBK1 to dsDNA:DAI followed by its activation Authored: Shamovsky, V, 2011-09-21 DAI dimer formation enables recruitment of TBK1 and IRF3 to the C-terminal region of DAI in response to cytosolic DNA in murine L929 cells. This interaction is DNA-dependent as DAI mutants that lack DNA binding domains neither recruited TBK1 nor activated IRF3 (Takaoka A et al 2007). Activation of IRF-3 and possibly IRF-7 promotes IFN gene expression. Edited: Shamovsky, V, 2012-02-23 Pubmed17618271 Reactome Database ID Release 431606324 Reactome, http://www.reactome.org ReactomeREACT_118783 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- has a Stoichiometric coefficient of 2 DAI binds cytosolic DNA Authored: Shamovsky, V, 2011-09-21 DAI binds to double-stranded DNA in vitro and in vivo (Wang ZC et al 2008; Takaoka A et al 2007). N-teminus of DAI contains two Z-DNA (Zalpha and Zbeta) and one B-DNA binding domains (D3 region). D3 region mediates initial binding of DAI to DNA with subsequent stabilization provided by the Zalpha and Zbeta domains. All tree DNA-binding domains are required for DAI full activation (Wang ZC et al 2008). <p>DAI was reported to form multimer upon DNA binding that might facilitate innate immune responces (Wang ZC et al 2008; Ha SC et al 2008). Edited: Shamovsky, V, 2012-02-23 Pubmed17618271 Pubmed18375758 Pubmed19095800 Pubmed21471454 Reactome Database ID Release 431591234 Reactome, http://www.reactome.org ReactomeREACT_118621 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- has a Stoichiometric coefficient of 2 Binding of defensins to lipid II Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 In S. aureus, rather than cause gross membrane changes, HNP-1 (de Leeuw et al. 2010) and hBD3 (Sass et al. 2011) appear to interfere with cell wall biosynthetic pathways by binding to Lipid II (undecaprenylpyrophosphate-MurNAc[pentapeptide]-GlcNAc), an essential precursor of bacterial cell walls and the target of several antibiotics (Breukink & de Krujiff 2007). The transformation of monomeric lipid II into a polymeric peptidoglycan by the bifunctional S. aureus enzyme Penicillin-binding protein 2 (PBP2) is inhibited by hBD3 (Sass et al. 2011) resulting in local lesions of the cell wall layer through which membranes and cytoplasmic contents ultimately protrude. Pubmed16531990 Pubmed20214904 Pubmed20385753 Reactome Database ID Release 431467209 Reactome, http://www.reactome.org ReactomeREACT_115839 Reviewed: McDermott, AM, 2011-11-03 Beta defensin 103 activates TLR1:TLR2 Authored: Jupe, S, 2011-11-07 Beta defensin 103 (hBD-3) can induce expression of the costimulatory molecules CD80, CD86 and CD40 on monocytes and myeloid dendritic cells in a Toll-like receptor (TLR)-dependent manner. Activation by hBD-3 is mediated by an interaction that requires TLRs 1 and 2 (Funderburg et al. 2007, 2011). Edited: Jupe, S, 2011-11-07 Pubmed18006661 Pubmed21896010 Reactome Database ID Release 431974676 Reactome, http://www.reactome.org ReactomeREACT_115718 Reviewed: McDermott, AM, 2011-11-03 TRADD:TRAF2:RIP1 complex dissociates from the TNF-alpha:TNF-R1 complex. Edited: Gillespie, ME, 0000-00-00 00:00:00 Once formed the TRADD:TRAF2:RIP1 complex may dissociate from the TNF:TNF-R1 platform and become cytosolic. If this complex recruits FADD then the cell will be pushed along the apoptotic pathway. Pubmed12887920 Reactome Database ID Release 4383582 Reactome, http://www.reactome.org ReactomeREACT_1856 Reviewed: Vaux, D, 0000-00-00 00:00:00 TRADD:TRAF2:RIP1 complex binds FADD Edited: Gillespie, ME, 0000-00-00 00:00:00 Once formed the TRADD:TRAF2:RIP1 complex may dissociate from the TNF:TNF-R1 platform and become cytosolic. If this complex recruits FADD then the cell will be pushed along the apoptotic pathway. Pubmed12887920 Reactome Database ID Release 43140978 Reactome, http://www.reactome.org ReactomeREACT_1766 Reviewed: Vaux, D, 0000-00-00 00:00:00 TNF Binds TNF-R1 Pubmed2848815 Reactome Database ID Release 4383660 Reactome, http://www.reactome.org ReactomeREACT_2096 TNF-alpha (tumor necrosis factor-alpha, TNF) binds TNF-RI (tumor necrosis factor receptor superfamily member 1A, TNFRSF1A) (Stauber et al. 1988). TNF:TNF-R1 binds TRADD, TRAF2 and RIP Complex Authored: Williams, MG, 2007-07-11 16:49:12 Edited: Gillespie, ME, 0000-00-00 00:00:00 Once the TNF-aplha:TNF-R1:TRADD complex is formed the two TNF-alpha mediated pathways are possible. The variable is the recruitment of FADD to the larger complex formed by the TNF-aplha:TNF-R1 platform via the interaction of the Death Domains. The steps leading to the Jun, NF kappaB, or apoptotic pathways are rife with modulation. Pubmed7758105 Reactome Database ID Release 4383656 Reactome, http://www.reactome.org ReactomeREACT_2175 Reviewed: Silverman, N, Lemaitre, B, 2008-06-20 10:21:55 Trimerization of TRAIL: TRAIL receptor-2 complex Pubmed10894160 Reactome Database ID Release 43141139 Reactome, http://www.reactome.org ReactomeREACT_1360 The complex of TRAIL and TRAIL receptor-2 trimerizes (Sprick et al. 2000). has a Stoichiometric coefficient of 3 HNP1-3 bind gp120 Alpha-defensins, theta-defensins and their synthetic analogues the retrocyclins have been shown in numerous studies to have anti-HIV-1 activity (Chang & Klotman 2004). This appears to be mediated via multiple mechanisms including direct viral inactivation and down regulation of host-cell target co-receptors important for viral entry (Furci et al. 2007, Seidel et al. 2010). HNP1-3 act as lectins, binding with relatively high affinity to gp120 (KD range, 15.8-52.8 nM) on the HIV-1 envelope and CD4 (KD range, 8.0-34.9 nM) on host target cells, both important molecules for viral entry (Wang et al. 2004). Retrocyclins, artificial theta defensins predicted from human defensin pseudogenes, bind with even higher affinity whereas HNP-4 binding is much weaker (Wu et al. 2005). Alpha defensins have been demonstrated to inhibit the binding of gp120 to CD4 thus blocking HIV-1 fusion with its target cells (Furci et al. 2007). Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pubmed15210812 Pubmed15595433 Pubmed15620707 Pubmed17132727 Pubmed20305815 Reactome Database ID Release 431471354 Reactome, http://www.reactome.org ReactomeREACT_115685 Reviewed: McDermott, AM, 2011-11-03 HNP1-3 bind CD4 Alpha-defensins, theta-defensins and their synthetic analogues the retrocyclins have been shown in numerous studies to have anti-HIV-1 activity (Chang & Klotman 2004). This appears to be mediated via multiple mechanisms including direct viral inactivation and down regulation of host-cell target co-receptors important for viral entry (Furci et al. 2007, Seidel et al. 2010). Further, HNPs 1 3, act as lectins and bind with relatively high affinity to gp120 (KD range, 15.8-52.8 nM) on the HIV-1 envelope and CD4 (KD range, 8.0-34.9 nM) on host target cells, both important molecules for viral entry (Wang et al. 2004). Artificial theta defensins, the retrocyclins, predicted from the human pseudogenes bind with even higher affinity whereas HNP-4 binding is much weaker (Wu et al. 2005). Alpha defensins have been demonstrated to inhibit the binding of gp120 to CD4 thus blocking HIV-1 fusion with its target cells (Furci et al. 2007). Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pubmed15210812 Pubmed15595433 Pubmed17132727 Pubmed19024344 Pubmed20305815 Reactome Database ID Release 431471314 Reactome, http://www.reactome.org ReactomeREACT_116084 Reviewed: McDermott, AM, 2011-11-03 TRADD:TRAF2:RIP1:FADD complex binds Pro-Caspase 8 Caspase-8-precursor (pro-caspase-8) binds TRAF2:TRADD:RIP1:FADD complex (Micheau and Tschopp, 2003). Pubmed12887920 Reactome Database ID Release 4375240 Reactome, http://www.reactome.org ReactomeREACT_737 TRAIL Binds TRAIL-Receptor2 Pubmed8777713 Reactome Database ID Release 4375238 Reactome, http://www.reactome.org ReactomeREACT_2170 TRAIL (TNF-related apoptosis-inducing ligand) binds TRAIL receptor-2 (TNFRSF10B) (Wiley et al. 1995). TDG glycosylase:uracil complex Reactome DB_ID: 110155 Reactome Database ID Release 43110155 Reactome, http://www.reactome.org ReactomeREACT_2792 has a Stoichiometric coefficient of 1 hSMUG1glycosylase:uracil complex Reactome DB_ID: 110163 Reactome Database ID Release 43110163 Reactome, http://www.reactome.org ReactomeREACT_3702 has a Stoichiometric coefficient of 1 FGFR3 (4;14) translocation mutants Converted from EntitySet in Reactome Reactome DB_ID: 2038374 Reactome Database ID Release 432038374 Reactome, http://www.reactome.org ReactomeREACT_122096 MBD4 glycosylase:thymine complex Reactome DB_ID: 110170 Reactome Database ID Release 43110170 Reactome, http://www.reactome.org ReactomeREACT_2977 has a Stoichiometric coefficient of 1 MBD4 glycosylase:uracil complex Reactome DB_ID: 110168 Reactome Database ID Release 43110168 Reactome, http://www.reactome.org ReactomeREACT_2450 has a Stoichiometric coefficient of 1 hNTH1 glycosylase:cytosine glycol complex Reactome DB_ID: 110179 Reactome Database ID Release 43110179 Reactome, http://www.reactome.org ReactomeREACT_3660 has a Stoichiometric coefficient of 1 hNTH1 glycosylase:dihydrouracil complex Reactome DB_ID: 110181 Reactome Database ID Release 43110181 Reactome, http://www.reactome.org ReactomeREACT_4252 has a Stoichiometric coefficient of 1 hNTH1 glycosylase: foramidopyrimidine complex Reactome DB_ID: 110183 Reactome Database ID Release 43110183 Reactome, http://www.reactome.org ReactomeREACT_2922 has a Stoichiometric coefficient of 1 hNTH1 glycosylase:thymine glycol complex Reactome DB_ID: 110177 Reactome Database ID Release 43110177 Reactome, http://www.reactome.org ReactomeREACT_3985 has a Stoichiometric coefficient of 1 DNA containing UNG2-bound apurinic/apyrimidinic site Reactome DB_ID: 110188 Reactome Database ID Release 43110188 Reactome, http://www.reactome.org ReactomeREACT_4455 has a Stoichiometric coefficient of 1 Alpha-defensins form biologically active dimers Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pubmed1445872 Pubmed17088326 Pubmed17254301 Pubmed2006422 Pubmed20097206 Pubmed20961099 Reactome Database ID Release 431462014 Reactome, http://www.reactome.org ReactomeREACT_115822 Reviewed: McDermott, AM, 2011-11-03 The crystal structure of human alpha-defensin HNP-3 revealed that it forms a dimer containing a six-stranded beta-sheet region (Hill et al. 1991). NMR studies indicate that HNP-1 can also form dimers or higher-order aggregates in solution and artificial lipid bilayers (Zhang et al. 1992, 2010a, 2010b). Models of alpha and beta defensins suggest that dimerization and/or higher order structures are characteristic, though not univeral or required for the biological effects of some beta-defensins (Suresh & Verma 2006, Pazgier et al. 2006). has a Stoichiometric coefficient of 2 pro-HD5 is cleaved by trypsin Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pro HD5 is stored and secreted from granules of Paneth cells in the small intestine (Porter et al. 1997, Cunliffe et al. 2001). The serine protease tryspin colocalizes to these granules as the inactive zymogen trypsinogen. Removal of the defensin propiece occurs extracellularly after release in to the crypt lumen, and is mediated by trypsin 2 (anionic trypsin) and/or trypsin-3 (mesotrypsin) which are converted to their active forms by enteroprotease like enzymes or by autoactivation (Ghosh et al. 2002, Ouelette 2011). Pubmed11156637 Pubmed12021776 Pubmed21560070 Pubmed9169779 Reactome Database ID Release 431461993 Reactome, http://www.reactome.org ReactomeREACT_116162 Reviewed: McDermott, AM, 2011-11-03 Alpha-defensin dimers multimerize to form a pore complex Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Once adsorbed/inserted into the membrane, alpha defensins are believed to aggregate into pore forming structures. Based on vesicle leakage and dextran permeability experiments, Wimley et al. (1994) proposed a multimeric pore model consisting of 6-8 defensin dimers which come together to form a large pore with inner diameter of 2-2.5nm. More recently using solid-state NMR and artificial lipid bilayers, Zhang et al. (2010) provide evidence of a dimer pore model in which the polar top of the dimer lines an aqueous pore while the hydrophobic bottom faces the lipid chains. Regardless of the exact conformation, the resulting pores then allow the efflux of essential microbial cell components. Pubmed20961099 Pubmed7833799 Reactome Database ID Release 431461982 Reactome, http://www.reactome.org ReactomeREACT_115546 Reviewed: McDermott, AM, 2011-11-03 has a Stoichiometric coefficient of 6 Alpha-defensin dimers adsorb onto microbial membrane anionic phospholipids Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pubmed18973303 Pubmed2668334 Pubmed7833799 Pubmed8401215 Pubmed9063901 Reactome Database ID Release 431461971 Reactome, http://www.reactome.org ReactomeREACT_115553 Reviewed: McDermott, AM, 2011-11-03 The alpha-defensin dimers adsorb onto microbial membrane anionic phospholipids, represented here as a complex of alpha-defensin dimers and a representative set of phospholipid molecules 'membrane anionic phospholipids'. The polar topology of defensins, with their spatially separated charged and hydrophobic regions, allows them to insert into microbial cell membranes, which contains more negatively charged phospholipids than mammalian cell membranes (Lohner et al. 1997). Defensins permeabilize membrane vesicles (Lehrer et al. 1989) with a greater effect on vesicles rich in negatively charged phospholipids (Fuji et al. 1993, Wimley et al. 1994). FASL:FAS Receptor Trimer:FADD complex binds pro-Caspase-10 FADD recruits caspase-10 precursor (pro-caspase-10) to FASL:FAS receptor trimer (Wang et al. 2001, Sprick et al. 2002). Pubmed11717445 Pubmed12198154 Reactome Database ID Release 43141310 Reactome, http://www.reactome.org ReactomeREACT_1418 HNP1-4 are released into phagocytic vacuoles Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Human neutrophils contain thousands of cytoplasmic granules. These membrane-bound organelles act as storage compartments destined for secretion or in the case of azurophil granules, destined for fusion with phagosomes. A small amount of defensin, but perhaps not enough for antimicrobial activity, may be released extracellularly by neutrophils (Ganz 1987). Pubmed10618521 Pubmed1302183 Pubmed3643886 Pubmed8329717 Reactome Database ID Release 431462041 Reactome, http://www.reactome.org ReactomeREACT_115688 Reviewed: McDermott, AM, 2011-11-03 FASL:FAS Receptor Trimer:FADD complex binds pro-Caspase-8 Caspase-8 precursor (Pro-Caspase-8, also known as MACH) binds the complex of FADD and FASL:FAS receptor trimer (Boldin et al. 1996). Pubmed8681376 Reactome Database ID Release 4383586 Reactome, http://www.reactome.org ReactomeREACT_1038 HNP1-4 are stored in primary neutrophil granules Alpha defensins HNP1-4, the neutrophil defensins, are stored in biologically active form in neutrophil primary (azurophil) granules, where they make up 5-10% of total cellular protein in these cells (Lehrere et al. 1993). The relative amounts of peptide for HNP-1 to -3 are 2:2:1 with HNP-4 being only a minor component. Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pubmed2500436 Pubmed2997278 Pubmed8476558 Reactome Database ID Release 431462003 Reactome, http://www.reactome.org ReactomeREACT_115583 Reviewed: McDermott, AM, 2011-11-03 FasL:Fas binds FADD Authored: Williams, MG, 2007-07-11 16:49:12 FADD (FAS-associating death domain-containing) protein binds FASL:FAS receptor trimer through interaction of death domains of FADD and FAS (Boldin et al. 1995). Pubmed7536190 Reactome Database ID Release 4383650 Reactome, http://www.reactome.org ReactomeREACT_2191 Reviewed: Silverman, N, Lemaitre, B, 2008-06-20 10:21:55 pro-defensin alpha 5 is secreted Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pro defensin alpha 5 is secreted from the storage granules of Paneth cells in the small intestine (Porter et al. 1997). Pubmed9169779 Reactome Database ID Release 431462005 Reactome, http://www.reactome.org ReactomeREACT_115910 Reviewed: McDermott, AM, 2011-11-03 pro-defensin alpha 5 is stored in Paneth cell granules Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pro-defensin alpha 5 is stored in the granules of Paneth cells in the small intestine (Porter et al. 1997). This pro-peptide has some antimicrobial activity but is not as effective as the mature peptide (Ghosh et al. 2002). Pubmed12021776 Pubmed9169779 Reactome Database ID Release 431461995 Reactome, http://www.reactome.org ReactomeREACT_115904 Reviewed: McDermott, AM, 2011-11-03 Pro-HNP1-4 are cleaved to biologically active defensin Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pubmed10614782 Pubmed1339298 Pubmed1547345 Pubmed17355880 Reactome Database ID Release 431462039 Reactome, http://www.reactome.org ReactomeREACT_115691 Reviewed: McDermott, AM, 2011-11-03 Synthesis of alpha defensins takes place in neutrophil precursor cells, the promyelocytes, in the bone marrow. Pro HNP1-4 are cleaved in the Golgi body, with HNP-2 being derived from cleavage of the N-terminal amino acid from HNP-1 or HNP-3. The defensin propiece is not only important for correct sub-cellular trafficking and sorting but also inhibits HNP activity (Valore et al. 1996, Wu et al. 2007). The resulting mature peptides are sorted to primary neutrophil (azurophil) granules for storage (Valore & Ganz 1992, Harwig et al. 1992, Cowland & Borregaard). DNA containing an hSMUG1-bound apurinic/apyrimidinic site Reactome DB_ID: 110192 Reactome Database ID Release 43110192 Reactome, http://www.reactome.org ReactomeREACT_5768 has a Stoichiometric coefficient of 1 DNA containing a hNTH1-bound apurinic/apyrimidinic site Reactome DB_ID: 110193 Reactome Database ID Release 43110193 Reactome, http://www.reactome.org ReactomeREACT_4919 has a Stoichiometric coefficient of 1 Recruitment of AIP4 and K-48 ubiquitination of MAVS/IPS-1 Authored: Garapati, P V, 2010-08-02 EC Number: 6.3.2.19 Edited: Garapati, P V, 2010-08-02 On viral infection PCB2 binds MAVS/IPS-1 and recruits the HECT domain-containing E3 ligase AIP4/ITCHY. AIP4 catalyses K48-polyubiquitination and degradation of MAVS. PCBP2 overexpression enhanced the interaction between MAVS and AIP4 and led to more degradation of MAVS. MAVS/IPS-1 regulation is very important in preventing excessive harmful immune responses. Pubmed19881509 Reactome Database ID Release 43990526 Reactome, http://www.reactome.org ReactomeREACT_25398 Reviewed: Kawai, T, Akira, S, 2010-10-30 FGFR4 enhanced kinase mutants Converted from EntitySet in Reactome Reactome DB_ID: 2038948 Reactome Database ID Release 432038948 Reactome, http://www.reactome.org ReactomeREACT_122417 Pre-pro-defensins are cleaved to remove the signal peptide Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pre-pro-defensins are cleaved in the golgi by undefined proteases which remove the signal peptide (Yang et al. 2004, Pazgier et al. 2006). Subsequently, alpha-defensins are cleaved again to produce the biologically active mature peptide. Beta defensins have much shorter propieces and may be active once the signal peptide is removed. Further N-terminal processing of the mature defensin may yield multiple forms of the same peptide (Pazgier et al. 2006). Pubmed12949495 Pubmed15032578 Pubmed16710608 Reactome Database ID Release 431462023 Reactome, http://www.reactome.org ReactomeREACT_115619 Reviewed: McDermott, AM, 2011-11-03 APE1-bound DNA strand break containing an incision 5' to an AP site Reactome DB_ID: 110334 Reactome Database ID Release 43110334 Reactome, http://www.reactome.org ReactomeREACT_5549 has a Stoichiometric coefficient of 1 POL Beta: APE1-bound DNA strand break containing incision 5' to AP site Reactome DB_ID: 110335 Reactome Database ID Release 43110335 Reactome, http://www.reactome.org ReactomeREACT_3091 has a Stoichiometric coefficient of 1 DNA containing an MBD4-bound apurinic/apyrimidinic site Reactome DB_ID: 110194 Reactome Database ID Release 43110194 Reactome, http://www.reactome.org ReactomeREACT_5011 has a Stoichiometric coefficient of 1 DNA containing an APE1-bound AP site Reactome DB_ID: 110332 Reactome Database ID Release 43110332 Reactome, http://www.reactome.org ReactomeREACT_5506 has a Stoichiometric coefficient of 1 LIG3:XRCC1:POL Beta complex at site of base repair Reactome DB_ID: 110339 Reactome Database ID Release 43110339 Reactome, http://www.reactome.org ReactomeREACT_4886 has a Stoichiometric coefficient of 1 LIG3:XRCC1:POL Beta:DNA strand break containing replaced unligated residue Reactome DB_ID: 110341 Reactome Database ID Release 43110341 Reactome, http://www.reactome.org ReactomeREACT_5009 has a Stoichiometric coefficient of 1 POL Beta-bound DNA strand break containing gap left by excised residue Reactome DB_ID: 110337 Reactome Database ID Release 43110337 Reactome, http://www.reactome.org ReactomeREACT_4249 has a Stoichiometric coefficient of 1 LIG3:XRRC1 complex Reactome DB_ID: 110338 Reactome Database ID Release 43110338 Reactome, http://www.reactome.org ReactomeREACT_5117 has a Stoichiometric coefficient of 1 DNA containing a TDG-bound apurinic/apyrimidinic site Reactome DB_ID: 110191 Reactome Database ID Release 43110191 Reactome, http://www.reactome.org ReactomeREACT_4825 has a Stoichiometric coefficient of 1 Interaction of PCBP2 with MAVS/IPS-1 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Poly(rC) binding protein 2 (PCB2), is one of the negative regulators of RIG-I/MDA5 signaling. It interacts with MAVS/IPS-1 and mediates its ubiquitin/proteasomal degradation by recruiting E3 ligase AIP4/ITCHY. Pubmed19881509 Reactome Database ID Release 43990528 Reactome, http://www.reactome.org ReactomeREACT_24967 Reviewed: Kawai, T, Akira, S, 2010-10-30 NLRC5 interacts with RIG-I/MDA5 and inhibit IPS-1 binding Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 NLRC5 competes with IPS-1 for binding to the CARD domain of RIG-I/MDA5. NLRC5 specifically recognize the CARD domains of RIG-I/MDA5 when the CARD domains become accessible after viral infection, leading to dampened activation of IRF3. Pubmed20434986 Reactome Database ID Release 43937343 Reactome, http://www.reactome.org ReactomeREACT_25113 Reviewed: Kawai, T, Akira, S, 2010-10-30 TAX1BP1:A20 inhibit TBK1/IKKi K63-polyubiquitination Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed20304918 Reactome Database ID Release 43937337 Reactome, http://www.reactome.org ReactomeREACT_25179 Reviewed: Kawai, T, Akira, S, 2010-10-30 TAX1BP1 functions as an adaptor molecule for A20 to terminate antiviral signaling. TAX1BP1 and A20 blocked antiviral signaling by disrupting K63-linked polyubiquitination of TBK1-IKKi. ISGylation of RIG-I Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 ISG15 is a ubiquitin (Ub)-like protein which is conjugated to intracellular proteins via an isopeptide bond. Similar to ubiquitination, the conjugation of ISG15 (ISGylation) requires a three-step process, involving an E1 activating enzyme (UBE1L), an E2 conjugating enzyme (UbcM8/H8), and HERC5/Ceb1 an IFN-inducible ISG15-specific E3 ligase. ISG15 conjugation may play an important regulatory role in IFN-mediated antiviral responses. IFN induces ISG15 conjugation to RIG-I protein and lowers cellular levels of unconjugated RIG-I protein and, thus, negatively regulates RIG-I-mediated antiviral signaling. ISGylated RIG-I protein becomes subject to an irreversible biochemical process, such as proteolysis or proteasomeal degradation. Pubmed18057259 Reactome Database ID Release 43936563 Reactome, http://www.reactome.org ReactomeREACT_25191 Reviewed: Kawai, T, Akira, S, 2010-10-30 NLRX1 inhibits IPS-1-RIG-I interaction. Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 NLRX1 is a member of nucleotide-binding domain and leucine-rich repeat containing (NLR) protein family. NLRX1 competes with RIG-I for IPS-1 interaction and has been identified as a negative regulator of RLR signaling. NLRX1 resides at the outer mitochondrial membrane where IPS-1 is located and this interaction is mediated by the CARD region of IPS-1 and a putative nucleotide-binding domain (NBD) of NLRX1. This interaction between NLRX1 and IPS-1 prevents the association between RIG-1/MDA5 and IPS-1. Pubmed18200010 Reactome Database ID Release 43936564 Reactome, http://www.reactome.org ReactomeREACT_25223 Reviewed: Kawai, T, Akira, S, 2010-10-30 Negative regulation of RIG-I/MDA5 signaling by TRIAD3A Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-22 Pubmed19893624 Reactome Database ID Release 43936475 Reactome, http://www.reactome.org ReactomeREACT_24974 Reviewed: Kawai, T, Akira, S, 2010-10-30 TRAF3 is dual regulated by DUBA and TRIAD3A. TRAF3 K63-polyubiquitin is removed by DUBA to disrupt TRAF3-TBK1/IKKi interactions. TRAF3 then undergoes a late phase K48-linked polyubiquitination by TRIAD3A, leading to TRAF3 proteasomal degradation. Thus TRIAD3A acts as a E3- ubiquitin ligase that negatively regulates RLR pathway. Negative regulation of RIG-I/MDA5 signaling by DUBA Authored: Garapati, P V, 2010-08-02 Deubiquitinating enzyme A (DUBA), an ovarian tumor (OTU) domain-containing deubiquitinating enzyme, is a negative regulator of type I IFN production. TRAF3 is one of the DUBA interacting protein and expression of DUBA increases the cleavage of K63-linked ubiquitin chains of TRAF3. TRAF3 ubiquitination facilitates the recruitment of downstream signaling components and DUBA mediated removal of ubiquitin chains reduce the TRAF3-TBK1 interaction and subsequent blockade of IRF3 and IRF7 phosphorylation. Edited: Garapati, P V, 2010-08-22 Pubmed17991829 Reactome Database ID Release 43936381 Reactome, http://www.reactome.org ReactomeREACT_25055 Reviewed: Kawai, T, Akira, S, 2010-10-30 Dimerization of FGFR2 point mutants with enhanced kinase activity Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11055896 Pubmed11781872 Pubmed17525745 Pubmed17552943 Pubmed17803937 Pubmed18552176 Pubmed18757403 Pubmed9857065 Reactome Database ID Release 432033479 Reactome, http://www.reactome.org ReactomeREACT_120878 Reviewed: Ezzat, S, 2012-05-15 Several missense mutations in the tyrosine kinase domain of FGFR2 have been identified in Crouzon syndrome and similar craniosynostosis disorders (Kan, 2002; Cunningham, 2007). The N549H and K660N mutations are paralogous to FGFR3 N540K and K650N/E mutations identified in hypochondroplasia and thanatophoric dysplasia II (Bellus, 2000). In FGFR3, these mutations have been demonstrated to have weak ligand-independent autophosphorylation and enhanced kinase activity mediated by disruption of a hydrogen-bonding network that holds the receptor in an inactive conformation (Chen, 2007; Bellus, 2000, Raffioni, 1998). Due to the highly conserved nature of these residues across all four FGF receptors, it is generally believed that these germline mutations in FGFR2 are also activating, though this remains to be demonstrated experimentally.<br><br><br>As further support of this notion, activating point mutations in the kinase domain of FGFR2 have also been identified in endometrial, uterine and cervical cancers (Pollock, 2007; Dutt, 2008), and in some cases have been shown to have enhanced kinase activity and to support anchorage-independent growth in NIH 3T3 cells (Dutt, 2008). Knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival (Dutt, 2008; Byron, 2008). Kinase-domain mutants show elevated levels of activity relative to the wild-type even in the absence of receptor phosphorylation, and although their kinase activity is further enhanced upon trans-autophosphorylation, the extent of this is less than that seen in the wild-type, suggesting that the mutant alleles are capable of of supporting ligand-independent activation (Chen, 2007)<br> has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR2 point mutants with enhanced kinase activity Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed11055896 Pubmed11781872 Pubmed17525745 Pubmed17552943 Pubmed17803937 Pubmed18552176 Pubmed18757403 Pubmed9857065 Reactome Database ID Release 432033490 Reactome, http://www.reactome.org ReactomeREACT_120851 Reviewed: Ezzat, S, 2012-05-15 Several missense mutations in the tyrosine kinase domain of FGFR2 have been identified in Crouzon syndrome and similar craniosynostosis disorders (Kan, 2002; Cunningham, 2007). The N549H and K660N mutations identified in FGFR2 in craniosynostosis disorders are paralogous to FGFR3 N540K and K650N/E mutations identified in hypochondroplasia and thanatophoric dysplasia II (Bellus, 2000). In FGFR3, these mutations have been demonstrated to have weak ligand-independent autophosphorylation and enhanced kinase activity mediated by disruption of a hydrogen-bonding network that holds the receptor in an inactive conformation (Chen, 2007; Bellus, 2000, Raffioni, 1998).<br><br> Characterization of FGFR2 proteins containing somatic mutations at these residues support the notion that they have elevated levels of kinase activity. FRS2 is constitutively phosphorylated in the FGFR2 N549K kinase mutant identified in endometrial tumors and knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival. FGFR2 knockdown also results in a significant decrease in the levels of phosphorylated Erk1/2 (Dutt, 2008; Byron, 2008; Pollock, 2007). Crystal structures of FGFR2 kinase mutants N549H and K650N show that the mutations disengage an 'auto-inhibitory brake' on the kinase domain of the receptor. Biochemically, the FGFR2 N549K and K660E mutants show elevated kinase activity relative to the unphosphorylated wild-type protein and have increased activity towards peptide substrates; this activity is stimulated upon receptor phosphorylation, but to a lesser extent than seen with the wild-type receptor (Chen, 2007). has a Stoichiometric coefficient of 16 Autocatalytic phosphorylation of FGFR2c mutants with enhanced ligand binding After aberrantly dimerizing in response to mesenchymally expressed ligands, FGFR2c S252W and P253R mutants are assumed to undergo transautophosphorylation analagous to the wild-type receptor, although this has not been explicitly demonstrated. Knock-down or chemical inhibition of other FGFR2-activating mutations identified in endometrial cancer cells has been shown to cause cell death (Byron, 2008). Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed18757403 Reactome Database ID Release 432033486 Reactome, http://www.reactome.org ReactomeREACT_121004 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 16 Autocatalytic phosphorylation of overexpressed FGFR2 variants Amplification of full length FGFR2 is only weakly transforming in NIH 3T3 cells, reflecting the presence of a putative transformation-inhibitory region in the c-terminus of the protein (Itoh, 1994, Cha, 2009). C-terminally truncated variants of FGFR2 that are preferrentially expressed in cancer show more potent transformation potential (Cha, 2008; Cha, 2009). These variants lack a number of carboxy-terminal tyrosine residues, including Y770 and Y773. Loss of Y770 contributes to transformation by enhancing FRS2 binding to the C-terminally truncated variant. This suggests that in the context of the full-length protein the presence of Y770 restricts access of FRS2 to the receptor. Loss or mutation of Y773 impairs internalization and degradation of the receptor and promotes sustained signaling (Cha, 2009). Gastric cancer cell lines with FGFR2 amplifications appear to undergo ligand-independent signaling and are sensitive to inhibition with ATP-competitive inhibitors (Takeda, 2007). <br><br><br>FGFR2 amplifications identified in 4% of triple negative breast cancers have also been shown to be constitutively active and to have elevated levels of phosphorylated FRS2 in the absence of ligand. Consistent with this, shRNA knockdown or chemical inhibition restricts proliferation and induces apoptosis in these cells (Kunii, 2008;Turner, 2010)<br><br> Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed17505008 Pubmed18337450 Pubmed18381441 Pubmed19103595 Pubmed20101236 Pubmed8205545 Reactome Database ID Release 432029989 Reactome, http://www.reactome.org ReactomeREACT_121157 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 6 Tyrosine kinase inhibitors bind to overexpressed FGFR2 variants Amplified FGFR2 has been shown to be a potential target for a number of ATP-competitive inhibitors, some of which are currently in clinical trials for therapeutic use (Takeda, 2007; Turner, 2010; http://clinicaltrials.gov). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed17505008 Pubmed20101236 Reactome Database ID Release 432029992 Reactome, http://www.reactome.org ReactomeREACT_121373 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Point mutants of FGFR2 bind and are inactivated by tyrosine kinase inhibitors Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR2 is inhibited by a range of in vitro tyrosine kinase inhibitors, including PD170734 and SU5402 (reviewed in Greulich and Pollock, 2010; Wesche, 2011). In addition, there are a number of FGFR2 inhibitors currently in clinical trials that for treatment of solid malignancies (http://ClinicalTrials.gov). Pubmed21367659 Pubmed21711248 Reactome Database ID Release 432077424 Reactome, http://www.reactome.org ReactomeREACT_121289 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Dimerization of overexpressed FGFR2 Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Overexpressed FGFR2 in gastric and breast cancer cells has been shown to undergo ligand-independent dimerization (Takeda, 2007; Kunii, 2008; Moffa, 2004; Turner, 2010). Full-length FGFR2 is weakly transforming in NIH 3T3 cells, and is thought to possess a transformation-inhibiting domain in the C-terminus (Itoh, 1994). Interestingly, many cancers with amplifications of FGFR2 show preferrential expression of C-terminally truncated FGFR2 variants, designated C2 and C3, with 788 or 769 residues instead of the wild-type 822 (Hattori, 1990; Itoh, 1994; Ueda, 1999). These variants, which lack a number of carboxy-terminal tyrosine residues, show increased transforming potency compared to the full-length receptor (Cha, 2008; Cha, 2009), and have been shown to be constitutively active and to dimerize spontaneously (Takeda, 2007). Pubmed10626794 Pubmed15561780 Pubmed17505008 Pubmed18337450 Pubmed18381441 Pubmed19103595 Pubmed20101236 Pubmed2377625 Pubmed8205545 Reactome Database ID Release 432029988 Reactome, http://www.reactome.org ReactomeREACT_121115 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR3 cysteine mutants Although each of FGFR3 R248C, S249C, G370C, S371C and Y373C have been shown to undergo ligand-independent dimerization and receptor autophosphorylation, there is conflicting evidence about which mutants also show increased phosphorylation upon ligand stimulation. Mutants showed elevated levels of ligand-independent MAPK pathway activation and supported expression of an in vivo reporter gene (d'Avis, 1998; Adar, 2009). Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed12009017 Pubmed9438390 Reactome Database ID Release 432012082 Reactome, http://www.reactome.org ReactomeREACT_120832 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 12 Constitutive dimerization of FGFR3 cysteine mutants Activating mutations in FGFR3 that introduce a mutant cysteine residue to the Ig2-Ig3 linker domain or the extracellular juxtamembrane region have been identified in the lethal neonatal disorder thanatophoric dysplasia (Tavormina, 1995a, b; Rousseau, 1996; reviewed in Webster and Donoghue, 1997; Burke, 1998). The presence of the mutant cysteine residue causes ligand-independent dimerization of the receptor through Cys-mediated intramolecular disulphide bonds and leads to increased biological signaling without changing the intrinsic kinase activity of the receptor (d'Avis, 1998; Adar, 2002). More recently, the same mutations, arising somatically, have been identified in a range of cancers including bladder, prostrate and cervical cancer, as well as in multiple myeloma and head and neck squamous cell carcinoma (reviewed in Wesche, 2011). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed12009017 Pubmed21711248 Pubmed7773297 Pubmed8589699 Pubmed8845844 Pubmed9154000 Pubmed9438390 Pubmed9538690 Reactome Database ID Release 432012084 Reactome, http://www.reactome.org ReactomeREACT_121391 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 GP369 inhibits activation of amplified FGFR2 signaling Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed20709759 Reactome Database ID Release 432067713 Reactome, http://www.reactome.org ReactomeREACT_120964 Reviewed: Ezzat, S, 2012-05-15 Treatment of FGFR2-amplified gastric and breast cancer cell lines with the antibody GP369 inhibits FGFR2 phosphorylation and downstream signaling and suppresses cell proliferation. Treatment of mice with GP369 inhibits the growth of human cancer xenografts carrying activating FGFR2 mutations. The GP369-binding epitope is contained in the ligand-binding region of the receptor, suggesting that the antibody works by disrupting the ligand-dependent activation of amplified FGFR2 (Bai, 2010). Dimerization of FGFR3 point mutants with enhanced kinase activity Activating point mutations G380R, N540K and K650E/M/N/Q in FGFR3 have been identified in achondroplasia, hypochondroplasia and thanatophoric dysplasia I and II (reviewed in Webster and Donoghue, 1997, Burke, 1998). These mutants, which occur in the transmembrane and the kinase domain, have been shown to undergo ligand-independent dimerization and autophosphorylation when transfected into NIH 3T3 cells, although the extent of constitutive activation varies depending on the precise mutation (Webster and Donoghue, 1996; Webster, 1996; Naski, 1996; Bellus, 2000). In addition, some of the mutants retain the ability to respond to exogenous ligand, while others appear to be completely ligand-independent (Naski, 1996; Goriely, 2009). Interestingly, the extent of kinase activation correlates with the severity of the resulting condition, with the K650M and E mutations associated with thanatophoric dysplasia showing the higher levels of kinase activity than the G380R mutation associated with achondroplasia (Naski, 1996; Bellus, 2000; Goriely, 2009). More recently, these same mutations, along with G382D, N540S, K650T, and G97C, have also been identified in a range of cancers, most notably in bladder cancer and multiple myeloma (Zhang, 2005; Ronchetti, 2001; van Rhijn, 2002; Lindgren, 2006; reveiewed in Wesche, 2011; Greulich and Pollock, 2011). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11055896 Pubmed11429702 Pubmed12461689 Pubmed15880580 Pubmed16532037 Pubmed19855393 Pubmed21367659 Pubmed21711248 Pubmed8599935 Pubmed8640234 Pubmed8754806 Pubmed9154000 Pubmed9538690 Reactome Database ID Release 432033476 Reactome, http://www.reactome.org ReactomeREACT_120782 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR3 point mutants with enhanced kinase activity Activated point mutants in the transmembrane and kinase domains of FGFR3 have been shown to undergo constitutive autophosphorylation in a ligand-independent manner (Naski, 1996; Webster, 1996 and Donoghue, 1996; Webster, 1996; Bellus, 2000; Goriely, 2009). Some of the point mutants, including K650E and G380R, may also be able to further respond after exposure to ligand (Naski, 1996). Dimerization and activation of the FGFR3 transmembrane mutants is thought to occur via the formation of non-native hydrogen bonds that promote intermolecular interactions (Webster and Donoghue 1996), while the kinase domain mutants activate phosphorylation by mimicking conformational changes in the activation loop (Webster, 1996). Mutants with enhanced kinase activity appear to be activated to differing extents that, for the most part, correlate with the severity of the disease phenotype (Webster, 1996; Bellus, 2000; Goriely, 2009), although the results of in vitro kinase assays with immunoprecipitated proteins do not fully recapitulate the pathological consequences of the mutation (Goriely, 2009). K650E has also been shown to transform NIH 3T3 cells (Chesi, 2001).<br><br> Authored: Rothfels, K, 2012-02-09 Autocatalytic phosphorylation of FGFR3 somatic point mutants with enhanced kinase activity EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed11055896 Pubmed11157491 Pubmed19855393 Pubmed8599935 Pubmed8640234 Pubmed8754806 Reactome Database ID Release 432033485 Reactome, http://www.reactome.org ReactomeREACT_121347 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 12 FGFR3c P250R mutant binds to ligand with enhanced affinity Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR3 P350R is associated with the development of Muenke syndrome, a milder craniosynostotic condition than Apert Syndrome (Bellus, 1996; Reardon, 1997). This mutation, which falls in the highly conserved Ser-Pro dipeptide in the IgII-IgIII linker, has been shown to increase the affinity of the receptor for its natural ligands, particularly for FGF9 (Ibrahimi, 2004a), without expanding the ligand-binding range of the receptor. This difference, compared to the paralogous FGFR2 S252W and P253R mutations, which bind an expanded range of ligands, is thought to account for the milder phenotype of Muenke Syndrome (Yu, 2000; Ibrahimi, 2004a, b). Pubmed11121055 Pubmed14613973 Pubmed15282208 Pubmed8841188 Pubmed9279753 Reactome Database ID Release 432012074 Reactome, http://www.reactome.org ReactomeREACT_121378 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR3c P250R mutant After high-affinity ligand binding, FGFR3 P250R is believed to undergo trans-autophosphorylation in a manner analogous to the wild-type receptor, although this remains to be experimentally validated (Ibrahimi, 2004a). Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed14613973 Reactome Database ID Release 432012073 Reactome, http://www.reactome.org ReactomeREACT_121032 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 12 AGE adducts Converted from EntitySet in Reactome Reactome DB_ID: 879487 Reactome Database ID Release 43879487 Reactome, http://www.reactome.org ReactomeREACT_24863 Dimerization of FGFR3 t(4;14) translocation mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10568829 Pubmed11157491 Pubmed11290605 Pubmed11429702 Pubmed19381019 Pubmed9207791 Pubmed9865713 Reactome Database ID Release 432038386 Reactome, http://www.reactome.org ReactomeREACT_120754 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 ~15% of multiple myelomas contain translocations that put the FGFR3 gene under the control of the strong IGH locus (Chesi, 1997; Avet-Loiseau, 1998). This translocation results in the overexpresssion of FGFR3 (Chesi, 1997), which leads to aberrant signaling in either a ligand-dependent (Otsuki, 1999; Qing, 2009) or independent fashion (Chesi, 2001). Overexpression of WT FGFR3 results in a low level of FGF-independent MAPK activation, suggesting that overexpression can lead to ligand-independent dimerization; however this response is more pronounced after ligand-stimulation (Chesi, 2001; Qing, 2009). ~5% of multiple myelomas with FGFR3 translocations also contain coding sequence activating mutations (Chesi, 1997; Avet-Loiseau, 1998). These mutations (R248C, Y373C, K650E and K650M) mimic activating mutations seen in bone development disoders, are believed to arise later in tumor progression than the translocation event and contribute to ligand-independent signaling (Chesi, 1997; Chesi, 2001; Li, 2001; Ronchetti, 2001). Autocatalytic phosphorylation of FGFR3 t(4;14) translocation mutants Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Overexpression of WT FGFR3 is weakly transforming when expressed in a mouse haematopoietic model, while expression of translocated FGFR3 carrying activating point mutations in the coding sequence is strongly transforming in both NIH 3T3 cells and the haematopoietic mouse model (Chesi, 2001; Ronchetti, 2001; Li, 2001). Activating mutations in FGFR3 are mutually exclusive with activating Ras mutations, and focus formation in NIH 3T3 cells is inhibited by cotransfection with dominant negative forms of ras or raf, suggesting that activation of the MAPK pathway is the primary oncogenic event in translocated myeloma lines (Chesi, 2001). Inhibition of FGFR3 in multiple myeloma lines and tumors has been shown to inhibit proliferation (Grand, 2004; Qing, 2009; Trudel, 2009; Krejci, 2010) Pubmed11157491 Pubmed11290605 Pubmed11429702 Pubmed15029211 Pubmed16467200 Pubmed19381019 Pubmed20439987 Reactome Database ID Release 432038387 Reactome, http://www.reactome.org ReactomeREACT_121327 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 12 FGFR3 mutants bind and are inactivated by tyrosine kinase inhibitors Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR3 has been shown to be a target of a range of different tyrosine kinase inhibitors, including those restricted to in vitro use as well as a number that are currently in clinical trials for therapeutic use (see for instance, Paterson, 2004; Trudel, 2004; Trudel, 2005; Grand, 2004, Chen, 2005; Bernard-Pierrot, 2006; http::/clinicaltrials.gov). There are also two anti-FGFR3 antibodies that have shown preliminary promise in cancer cell lines or mouse models (Qing, 2009; Trudel, 2006). Pubmed14715624 Pubmed14871245 Pubmed15029211 Pubmed15598814 Pubmed16091734 Pubmed16467200 Pubmed18757432 Pubmed19381019 Reactome Database ID Release 432077420 Reactome, http://www.reactome.org ReactomeREACT_121067 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Constitutive dimerization of FGFR4 Y367C mutant Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed18056464 Pubmed19946327 Pubmed8696350 Pubmed8845844 Pubmed9438390 Reactome Database ID Release 432012086 Reactome, http://www.reactome.org ReactomeREACT_120721 Reviewed: Ezzat, S, 2012-05-15 The Y367C mutation in FGFR4 was identified in a breast cancer cell line in a cDNA screen of kinase mutants (Ruhe, 2007). This residue is paralogous to the FGFR2 Y375C and FGFR3 Y373C mutations that have been shown to result in increased receptor activation (Prezylepa, 1996; Rousseau, 1996; d'Avis, 1998). Biochemical characterization of the FGFR4 Y367C mutation revealed that it undergoes spontaneous dimerization independent of ligand stimulation, presumably mediated by the aberrant cysteine residues in the extracellular region of the receptor (Roidl, 2009), thus affecting FGFR4 activity without directly altering its kinase activity. has a Stoichiometric coefficient of 2 Dimerization of FGFR4 mutants with enhanced kinase activity Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR4 is highly expressed in rhabdomyosarcoma (RMS) tissue, and high levels of expression are correlated with lower survival. Sequencing of exons from 94 RMS tumors identified 14 missense variants, 6 of which were localized in the tyrosine kinase domain, and four of which were in two amino acids (N535K/D and V550E/L). Mutations at amino acid 535 are predicted to eliminate an inhibitory H-bond that restricts receptor autophosphorylation, and mutations at amino acid 550 are believed to alter the ATP-binding site. Functional studies on N535K and V550 show that they undergo autophosphorylation when transfected into a murine RMS lines and transformed NIH 3T3 cells, leading to a metastatic phenotype (Taylor, 2009). Pubmed19809159 Reactome Database ID Release 432038946 Reactome, http://www.reactome.org ReactomeREACT_121020 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR4 Y367C mutant Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Expression of the FGFR4 Y367C mutant in MDA-MB453 breast cancer cell line results in constitutive tyrosine phosphorylation of the receptor and serum-independent activation of downstream signaling as monitored by Erk phosphorylation. Ectopic expression of FGFR4 Y367C in HEK cells also leads to Erk activation and enhanced cellular proliferation. Akt and phospho-AKT levels were not affected by overexpression of the FGFR4 Y367C mutant, however (Roidl, 2010) Pubmed19946327 Reactome Database ID Release 432012087 Reactome, http://www.reactome.org ReactomeREACT_121299 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 10 p-BCR-pFGFR1 recruits GRB2:GAB2 Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Proliferation of BCR-FGFR1 fusion proteins is blocked by treatment with the PI3K inhibitor LY294002, suggesting the activation of this pathway downstream of BCR-FGFR1 phosphorylation. Y177 has been shown to be a binding site for GRB2 and to be required for the both the phosphorylation of GAB2 and the development of CML-like disease (Roumiantsev, 2004, Demiroglu, 2001). By analogy with studies in BCR-ABL, where mutation of Y177 abrogates recruitment of PI3K activity to the fusion protein (Sattler, 2002), this suggests that Y177 may serve as a docking site for a complex of GRB2:GAB1:PI3K in the context of BCR-FGFR1 as well. Pubmed11739186 Pubmed12124177 Pubmed15050920 Reactome Database ID Release 431839095 Reactome, http://www.reactome.org ReactomeREACT_121232 Reviewed: Ezzat, S, 2012-05-15 GAB2 is phosphorylated by p-BCR-p-FGFR1 Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11739186 Pubmed12124177 Pubmed15050920 Reactome Database ID Release 431839110 Reactome, http://www.reactome.org ReactomeREACT_120831 Recruitment of GAB2 to the BCR-FGFR1 fusion protein results in GAB2 phosphorylation (Roumiatnetsev, 2004). As in the case of BCR-ABL (Sattler, 2002), recruitment and phosphorylation of GAB2 is dependent on BCR residue Y177. Deletion of Y177 abolishes GRB2 recruitment and converts the more aggressive MPD disorder induced by BCR-FGFR1 to the EMS characteristic of other FGFR1 fusions (Demiroglu, 2001; Roumianetsev, 2004) Reviewed: Ezzat, S, 2012-05-15 FGFR1 fusion protein-associated PI3K phosphorylates PIP2 to PIP3 Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Once recruited to the activated receptor, PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling. PI3K signaling has been demonstrated in ZMYM2-, FOP- and BCR-FGFR1 fusions (Chen, 2004; Demiroglu, 2001; Guasch, 2001), as well as downstream of a number of other FGFR mutants (see for instance, Byron, 2008; Kunii, 2008; Agazie, 2003; Takeda, 2007). Pubmed11689702 Pubmed11739186 Pubmed15448205 Reactome Database ID Release 431839091 Reactome, http://www.reactome.org ReactomeREACT_121382 Reviewed: Ezzat, S, 2012-05-15 Phosphorylation of BCR moiety of BCR-FGFR1 Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed15050920 Pubmed20226962 Reactome Database ID Release 431839067 Reactome, http://www.reactome.org ReactomeREACT_121389 Reviewed: Ezzat, S, 2012-05-15 Unique among FGFR1 fusion proteins, which generally give rise to an atypical myeloproliferative syndrome (EMS) (reviewed in Jackson, 2010), the BCR-FGFR1 fusion results in a more typical chronic myeloid leukemia (CML). Although both EMS and CML activate PLCgamma signaling, and mutation of the FGFR1 Y766 PLCgamma binding site attenuates both diseases, CML-specific signaling also appears to be mediated through the BCR portion of the fusion protein. BCR Y177 binds GRB2-GAB1 and induces CML-like leukemia in mice, while expression of a Y177F BCR-FGFR1 fusion induces EMS-like disease (Roumiantsev, 2004). has a Stoichiometric coefficient of 2 Recruitment of the catalytic subunit of PI3K to activated FGFR1 fusions Activation of the PI3K pathway has been demonstrated in the case of ZMYM2-FGFR1 (Chen, 2004), BCR-FGFR1 (Demiroglu, 2001) and FOP-FGFR1 (Guasch, 2001), and is presumed to occur to a greater or lesser extent in other FGFR1 fusions as well (reviewed in Jackson, 2010). Activation of the PI3K pathway suggests that the PIK3CA catalytic subunit must be recruited to the fusion protein. Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11689702 Pubmed11739186 Pubmed15448205 Pubmed20226962 Reactome Database ID Release 431839080 Reactome, http://www.reactome.org ReactomeREACT_121216 Reviewed: Ezzat, S, 2012-05-15 FGFR1OP-FGFR1 phosphorylates STAT1 and STAT3 Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Expression of FGFR1OP-FGFR1 in both Ba/F3 and Cos-1 cells leads to phosphorylation of STAT1 and STAT3 but not STAT5, and to activation of a STAT1/3-responsive reporter when expressed in NIH3T3 cells (Guasch, 2001). Activation of STAT proteins has also been shown to be oncogenic in the context of derivatives of FGFR1, 3 and 4 that lack the extracellular domain and are are targetted to the plasma membrane by a myristylation signal (Hart et al, 2000). Pubmed10918587 Pubmed11689702 Reactome Database ID Release 431888198 Reactome, http://www.reactome.org ReactomeREACT_121233 Reviewed: Ezzat, S, 2012-05-15 Phosphorylation of STAT5 by FGFR1 fusions Activation of a subset of FGFR1-fusions (ZMYM2, BCR, FGFR1OP2 and CUX) has been shown to result in downstream phosphorylation of STAT5 proteins at Y694. This phosphorylation is dependent on the FGFR1 fusion, as the STAT5 phosphorylation is abrogated in the presence of an FGFR1-kinase dead fusion (Heath and Cross, 2004; Smedley, 1999; Chase, 2007; Wasage, 2011). Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed10935490 Pubmed14660670 Pubmed17698633 Pubmed21330321 Reactome Database ID Release 431839112 Reactome, http://www.reactome.org ReactomeREACT_121048 Reviewed: Ezzat, S, 2012-05-15 BCR-FGFR1-associated PI3K phosphorylates PIP2 to PIP3. Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Once recruited to the activated BCR-FGFR1 fusion PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling (Roumiantsev, 2004; Demiroglu, 2001). Pubmed11739186 Pubmed15050920 Reactome Database ID Release 431839107 Reactome, http://www.reactome.org ReactomeREACT_121331 Reviewed: Ezzat, S, 2012-05-15 The catalytic subunit of PI3K is recruited to the BCR-FGFR1 fusion. Activation of the PI3K pathway has been demonstrated in the case of ZMYM2-FGFR1 (Chen, 2004), BCR-FGFR1 (Demiroglu, 2001) and FOP-FGFR1 (Guasch, 2001), and is presumed to occur to a greater or lesser extent in other FGFR1 fusions as well (reviewed in Jackson, 2010). Activation of the PI3K pathway suggests that the PIK3CA catalytic subunit must be recruited to the fusion protein. Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11689702 Pubmed11739186 Pubmed15448205 Pubmed20226962 Reactome Database ID Release 431839102 Reactome, http://www.reactome.org ReactomeREACT_121049 Reviewed: Ezzat, S, 2012-05-15 Recruitment of the p85 regulatory subunit of PI3K to the BCR-FGFR1 complex. Authored: Rothfels, K, 2012-02-09 Based on analogy with studies of the BCR-ABL fusion, phosphorylated GAB2 recruits the regulatory subunit of PI3K to the BCR-FGFR1 fusion (Sattler, 2002; Demiroglu, 2001; Roumiantsev, 2004). Edited: Rothfels, K, 2012-05-16 Pubmed11739186 Pubmed12124177 Pubmed15050920 Reactome Database ID Release 431839114 Reactome, http://www.reactome.org ReactomeREACT_121343 Reviewed: Ezzat, S, 2012-05-15 Dimerization of FGFR1 point mutants with enhanced kinase activity Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Large scale genomic characterization of glioblastoma tumors has identified three point mutants in the kinase domain of FGFR1: N546K, R576W and K656E (Rand, 2005, TCGA, 2008), representing the first kinase domain point mutants identified in this gene in any cancer. These mutants are believed or have been shown to have enhanced kinase activity and to be able to function in a ligand-independent manner (Petiot, 2002; Lew, 2009; Raffioni, 1998, Rand, 2005; Hart, 2000) Pubmed10918587 Pubmed12112473 Pubmed16186508 Pubmed18772890 Pubmed19224897 Pubmed9857065 Reactome Database ID Release 432023456 Reactome, http://www.reactome.org ReactomeREACT_120981 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR1 mutants with enhanced kinase activity Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed10053006 Pubmed10918587 Pubmed11781872 Pubmed12112473 Pubmed16186508 Pubmed17525745 Pubmed18552176 Pubmed18772890 Pubmed19224897 Pubmed9857065 Reactome Database ID Release 432023460 Reactome, http://www.reactome.org ReactomeREACT_120859 Reviewed: Ezzat, S, 2012-05-15 The three kinase domain mutants of FGFR1 that have been identified in glioblastoma are predicted or have been shown to result in enhanced kinase activity. The N546K (Rand, 2005) residue lies in a stretch of 9 amino acids that are conserved between all four FGFRs. Mutation of the paralogous residue in FGFR3 (N540K) has been shown to result in weak ligand-independent contstitutive activation in the autosomal disorder hypochodroplasia (Raffioni, 1998). In FGFR2 mutation of the paralogous residue to lysine has been identified in endometrial cancer and been shown to result in enhanced kinase activity (Dutt, 2008; Pollock, 2008); germline mutations at this site in FGFR2 are also associated with the development of Crouzon and Pfeiffer syndromes (Kan, 2002). The FGFR1 N546K mutations has accelerated rates of autophosphorylation and supports transformation when transfected into Rat-1 cells (Lew, 2009).<br><br><br>The FGFR1 K656E (TCGA, 2008) mutation is paralogous to activating mutations in FGFR3 kinase domain associated with the development of thanatophoric dysplasias (Tavormina, 1999; Bellus, 2000; Hart, 2000), and has itself been shown to activating when expressed in neural crest cells (Petiot, 2002).<br><br><br>The FGFR1 R576W (Rand, 2005) mutation increases the hydrophobicity of the receptor, and is postulated to enhance protein-protein interactions and thereby increase the likelihood of autophosphorylation of adjacent tyrosine residues, although this has not been explicitly demonstrated.<br><br><br> has a Stoichiometric coefficient of 16 Dimerization of FGFR2 ligand-independent mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Point mutations in FGFR2 that are thought to promote ligand-independent dimerization in the context of autosomal bone development disorders have also been identified in endometrial, ovarian, gastric and lung cancer (Greenman, 2007; Dutt, 2008; Davies, 2005; Byron, 2008; Byron, 2010, Pollock, 2007). Although functional studies on these mutations in FGFR2 in cancer cell lines is limited - only the S267P mutation identified in gastric cancer has been demonstrated biochemically to undergo ligand-independent dimerization (Anderson, 1998) - characterization of paralogous mutations in FGFR3 as well as in other mutations that create unpaired cysteine residues in FGFR2 support the notion that these mutant receptors undergo aberrant intermolecular disulphide bond formation that results in constitutive activation (Galvin, 1996; Neilson and Friesel,1995; Robertson, 1998; d'Avis, 1998) Pubmed16140923 Pubmed17344846 Pubmed17525745 Pubmed18552176 Pubmed18757403 Pubmed20106510 Pubmed8755573 Pubmed8798788 Pubmed9438390 Pubmed9539778 Pubmed9700203 Reactome Database ID Release 432029983 Reactome, http://www.reactome.org ReactomeREACT_121101 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR2 ligand-independent mutants Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 FGFR2 S267P undergoes ligand-independent dimerization, and appears unable to stably bind FGF2 ligand under the conditions examined (Anderson, 1998). FGFR2b S373C and Y376C are paralogous to the FGFR3 S371C and Y373C mutations that are seen in thanatophoric dysplasia I (Rousseau, 1996; Tavormina, 1995a) and which have been shown to undergo spontaneous dimerization in the absence of ligand (d'Avis, 1998; Adar, 2002). Moreover, other FGFR2 mutations that introduce unpaired cysteine residues have been shown to support formation of intermolecular disulphide bonds (Galvin, 1996; Neilson and Friesel, 1995), supporting the notion that the FGFR2b S373C and Y376C mutants may promote spontaneous receptor dimerization and activation. Pubmed12009017 Pubmed7647778 Pubmed7773297 Pubmed8755573 Pubmed8798788 Pubmed9438390 Pubmed9700203 Reactome Database ID Release 432029984 Reactome, http://www.reactome.org ReactomeREACT_120900 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 16 FGFR1 P252X mutants bind ligand with enhanced affinity Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11121055 Pubmed14613973 Pubmed15282208 Pubmed16140923 Pubmed18056464 Pubmed7874169 Reactome Database ID Release 432023451 Reactome, http://www.reactome.org ReactomeREACT_121358 Reviewed: Ezzat, S, 2012-05-15 The missense mutation C775G in exon 5 of FGFR1 encodes a Pro252R gain-of-function mutation that causes Pfeiffer syndrome, an autosomal dominant disorder characterized by premature fusion of bones in the skull and syndactyly of the hands and feet (Muenke, 1994). FGFR1 P252R binds to FGF1, FGF2, FGF4, and FGF6 with 2-5 fold-enhanced affinity, and with 30-fold affinity to FGF9. The enhanced ligand-affinity of the mutant receptor is the result of an additional set of ligand-receptor hydrogen bonds; in particular for FGF9, the additional receptor contacts are thought to compete with FGF9 autoinhibitory dimerization (Ibrahimi, 2004a). The increase in ligand-binding affinity in the absence of an expansion of ligand binding range is thought to account for the milder limb phenotype of Pfeiffer syndrome relative to FGFR2-mediated Apert syndrome (Yu, 2000; Ibrahimi, 2004b).<br><br>Somatic mutations in FGFR1 at P252 have also been identified in melanoma (P252S; Ruhe, 2007) and in lung cancer (P252T; Davies, 2005). Based on analogy to the FGFR1 P252R mutation that is found in Pfeiffer syndrome, these mutations are also predicted to increase the ligand-binding affinity of the receptor and to result in increased signaling, although this remains to be directly demonstrated for the S/T alleles (Ibrahimi, 2004a).<br> has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR1 P252X mutant dimers Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 FGFR1 gain-of-function mutations at P252 that result in increased binding affinity to ligand are presumed to be phosphorylated on the same sites as the wild-type receptor, although this has not been demonstrated (Ibrahimi, 2004a).<br><br> Pubmed14613973 Reactome Database ID Release 432023455 Reactome, http://www.reactome.org ReactomeREACT_121223 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 16 Autocatalytic phosphorylation of FGFR2b mutants with enhanced ligand binding After aberrantly dimerizing in response to epithelially expressed ligands, FGFR2b S252W and P253R mutants are assumed to undergo transautophosphorylation analagous to both the wild-type receptor, although this has not been explicitly demonstrated. Transformation of NIH 3T3 cells with the FGFR2b S252W mutant confers anchorage independent growth and results in increased phosphorylation of FRS2 in a manner that depends on a functional kinase domain (Dutt, 2008). Knock-down or chemical inhibition of other FGFR2-activating mutations identified in endometrial cancer cells has been shown to cause cell death (Byron, 2008).<br><br> Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed18552176 Pubmed18757403 Reactome Database ID Release 432033488 Reactome, http://www.reactome.org ReactomeREACT_121230 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 16 FGFR2b mutants bind an expanded range of ligands Apert sydrome is the most severe of the craniosynostosis syndromes and results almost entirely from two missense mutations in the conserved Ser252 and Pro253 residues in the IgII-IgIII linker of FGFR2 (Wilkie, 1995). These mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). More recently, the same mutations arising somatically have been identified in endometrial and ovarian cancer (Dutt, 2008; Byron, 2008; Pollock, 2007).<br><br><br>The IgII and IgIII domains and the intervening linker of the FGF receptor constitute a binding site for FGFs (Chellaiah, 1999; Stauber, 2000; Plotnikov, 1999). The epithelial isoform FGFR2b binds only to mesenchymally expressed ligands including FGF7 and FGF10 and does not respond to epithelial ligands FGF2, 4, 6, 8 and 9 (Ornitz, 1996). Introduction of the P252W and P252R mutations into FGFR2b allows the aberrant binding and activation by the epithelially expressed ligands FGF 2, 6 and 9, establishing an autocrine signaling loop in epithelial cells. These mutations also increase the binding affinity for the receptor's normal mesenchymal ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).<br> Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR2b somatic mutants bind an expanded range of ligands Pubmed10490103 Pubmed10574949 Pubmed10618369 Pubmed11121055 Pubmed15282208 Pubmed17525745 Pubmed18552176 Pubmed18757403 Pubmed20106510 Pubmed7719344 Pubmed8663044 Pubmed9502772 Reactome Database ID Release 432033474 Reactome, http://www.reactome.org ReactomeREACT_120790 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 FGFR2c mutants bind an expanded range of ligands Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Mutations in the highly conserved Pro-Ser dipeptide repeat of FGFR2 have been identified both in Apert syndrome and in endometrial and ovarian cancers (Wilkie, 1995; Dutt, 2008; Pollock, 2007; Byron, 2010). Missense S252W or P253R mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). In the context of endometrial cancer, these mutations are mutually exclusive with KRAS mutations, but are associated at high frequency with PTEN mutations (Byron, 2008). The S252W and P253R mutations allow the receptor to bind to an expanded range of ligands, such that the mesenchymal splice form (FGFR2c) is anomalously activated by the mesenchymal ligands FGF7 and FGF10, establishing an autocrine signaling loop. These mutations also increase the binding affinity for the receptor's normal epithelial ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).<br><br> Pubmed10618369 Pubmed11121055 Pubmed15282208 Pubmed17525745 Pubmed18552176 Pubmed18757403 Pubmed20106510 Pubmed7719344 Pubmed9502772 Reactome Database ID Release 432033472 Reactome, http://www.reactome.org ReactomeREACT_120984 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 FP-1039 acts as a ligand-trap for FGFR2b-binding ligands in endometrial cancer Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FP-1039 is a soluble fusion protein consisting of the extracellular region of FGFR1c bound to the Fc region of human IgG1. It is capable of binding to a wide range of FGF ligands and thereby prevents activation of multiple FGF receptors. FP-1039 is in Phase I clinical trials in solid malignancies and in Phase II trials for patients with endometrial cancers harbouring the activating mutations S252W and P253R (reviewed in Wesche, 2011). Pubmed21711248 Reactome Database ID Release 432077421 Reactome, http://www.reactome.org ReactomeREACT_121035 Reviewed: Ezzat, S, 2012-05-15 AKT1 E17K mutant phosphorylates p21Cip1 and p27Kip1 AKT1 E17K gain-of-function mutant preserves the ability to phosphorylate CDKN1B i.e. p27Kip1 (Malanga et al. 2008) and is expected to phosphorylate CDKN1A i.e. p21Cip1, like the wild-type AKT (Viglietto et al. 2002), although this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed12244303 Pubmed18256540 Reactome Database ID Release 432399969 Reactome, http://www.reactome.org ReactomeREACT_147868 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant phosphorylates GSK3 AKT1 E17K gain-of-function mutant preserves the ability to phosphorylate GSK3 (Malanga et al. 2008). AKT-mediated phosphorylation inactivates GSK3 and enables WNT-independent stabilization of beta-catenin (CTNNB1) (Haq et al. 2003). AKT-mediated inactivation of GSK3 also triggers changes in glucose metabolism (Ueki et al. 1997). Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed12668767 Pubmed18256540 Pubmed9478990 Reactome Database ID Release 432399966 Reactome, http://www.reactome.org ReactomeREACT_147823 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 PDPK1 phosphorylates AKT1 E17K mutant Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 PIP2-bound AKT1 E17K mutant is constitutively phosphorylated on threonine residue T308 (Carpten et al. 2007, Landgraf et al. 2008), presumably by PIP2-bound PDPK1 (Currie et al. 1999). Pubmed17611497 Pubmed18954143 Pubmed9895304 Reactome Database ID Release 432243942 Reactome, http://www.reactome.org ReactomeREACT_147862 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant phosphorylates TSC2, inhibiting it AKT1 E17K gain-of-function mutant is expected to phosphorylate TSC2 and inhibit it, like the wild-type AKT (Inoki et al. 2002, Manning et al. 2002), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed12150915 Pubmed12172553 Reactome Database ID Release 432399982 Reactome, http://www.reactome.org ReactomeREACT_147764 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 has a Stoichiometric coefficient of 2 AKT1 E17K mutant phosphorylates MDM2 AKT1 E17K gain-of-function mutant is expected to phosphorylate MDM2, like the wild-type AKT (Zhou et al. 2001, Feng et al. 2004, Milne et al. 2004), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed11715018 Pubmed15169778 Pubmed15527798 Reactome Database ID Release 432399981 Reactome, http://www.reactome.org ReactomeREACT_147833 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 has a Stoichiometric coefficient of 2 AKT1 E17K mutant phosphorylates AKT1S1 (PRAS40) AKT1 E17K gain-of-function mutant is expected to phosphorylate AKT1S1 (PRAS40), like the wild-type AKT (Kovacina et al. 2003), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed12524439 Reactome Database ID Release 432399977 Reactome, http://www.reactome.org ReactomeREACT_147737 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 has a Stoichiometric coefficient of 2 AKT1 E17K mutant phosphorylates BAD AKT1 E17K gain-of-function mutant phosphorylates BAD (Guo et al. 2010). AKT-mediated BAD phosphorylation inactivates BAD, thereby preventing BAD-mediated apoptosis (Del Peso et al. 1997). Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed20440266 Pubmed9381178 Reactome Database ID Release 432399941 Reactome, http://www.reactome.org ReactomeREACT_147775 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant translocates to the nucleus AKT1 E17K gain-of-function mutant is expected to translocate to the nucleus, like the wild-type AKT (Borgatti et al. 2003), but this has not been directly experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 Pubmed12767043 Reactome Database ID Release 432399997 Reactome, http://www.reactome.org ReactomeREACT_147831 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant phosphorylates caspase-9 AKT1 E17K gain-of-function mutant is expected to phosphorylate caspase-9 (CASP9), like the wild-type AKT (Cardone et al. 1998), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed9812896 Reactome Database ID Release 432399985 Reactome, http://www.reactome.org ReactomeREACT_147774 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant phosphorylates CHUK (IKKalpha) AKT1 E17K gain-of-function mutant is expected to phosphorylate CHUK (IKKalpha), like the wild-type AKT (Ozes et al. 1999), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed10485710 Reactome Database ID Release 432400001 Reactome, http://www.reactome.org ReactomeREACT_147740 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant phosphorylates CREB1 AKT1 E17K gain-of-function mutant is expected to phosphorylate CREB1, like the wild-type AKT (Du et al. 1998), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed9829964 Reactome Database ID Release 432399996 Reactome, http://www.reactome.org ReactomeREACT_147870 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant phosphorylates forkhead box transcription factors AKT1 E17K gain-of-function mutant phosphorylates FOXO3 (Carpten et al. 2007), and is expected to phosphorylate other forkhead box transcription factor family members, FOXO1 and FOXO4, like the wild-type AKT (Brunet et al. 1999, Rena et al. 1999, Matsuzaki et al. 2005), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed10102273 Pubmed10358075 Pubmed16272144 Pubmed17611497 Reactome Database ID Release 432399992 Reactome, http://www.reactome.org ReactomeREACT_147827 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 has a Stoichiometric coefficient of 3 AKT1 E17K mutant phosphorylates NR4A1 (NUR77) AKT1 E17K gain-of-function mutant is expected to phosphorylate NR4A1, like the wild-type AKT (Pekarsky et al. 2001), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed11274386 Reactome Database ID Release 432399988 Reactome, http://www.reactome.org ReactomeREACT_147721 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant phosphorylates RSK AKT1 E17K gain-of-function mutant is expected to phosphorylate ribosomal protein S6 kinase beta-2, like the wild-type AKT (Koh et al. 1999), but this has not been experimentally tested. Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed10490848 Reactome Database ID Release 432399999 Reactome, http://www.reactome.org ReactomeREACT_147791 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 has a Stoichiometric coefficient of 2 AKT inhibitors block AKT membrane recruitment AKT inhibitors bind AKT and prevent its association with the membrane, thereby blocking AKT activation (Kondapaka et al. 2003, Yap et al. 2011, Berndt et al. 2010). AKT inhibitors annotated here target all AKT isoforms (AKT1, AKT2 and AKT3). None of the annotated inhibitors are AKT E17K mutant specific and none of them have been approved for clinical use. For a recent review, please refer to Liu et al. 2009. Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 Pubmed14617782 Pubmed19644473 Pubmed20489726 Pubmed22025163 Reactome Database ID Release 432400010 Reactome, http://www.reactome.org ReactomeREACT_147895 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 IFN alpha/beta binds to IFNAR2 Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Pubmed10395669 Pubmed11786546 Pubmed12842042 Pubmed15312780 Pubmed15778442 Pubmed17969444 Pubmed8156998 Pubmed9121453 Pubmed9334213 Reactome Database ID Release 43909720 Reactome, http://www.reactome.org ReactomeREACT_25100 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The ligand IFNalpha/beta (IFNA/B), interacts independently with the two interferon receptor subunits. Based on detailed binding studies with the extracellular domains of the receptor subunits tethered onto solid-supported membranes, a two-step binding mechanism was experimentally confirmed, where the ligand binds first to one of the receptor subunits and then recruits the second subunit (Gavutis et al. 2005). The efficiency of recruitment of the IFNA receptor subunits by the IFN ligand depends on the absolute and relative concentration of the receptor subunits. <br>IFNAR2 chain constitutively associates with JAK1 kinase in its cytoplasmic domain. In addition IFNAR2 also binds STAT2 in a constitutive manner and this interaction is biochemically different from the interaction of STAT2 with phosphorylated IFNAR1. Although this interaction facilitates the recruitment of STAT2 to the receptors, the biological significance of this constitutive STAT2 interaction to IFNAR2 remains unclear (Nguyen et al, 2002). IFNAR2 not only associates with STAT2, but also with STAT1 and this binding of STAT1 to IFNAR2 depends on the presence of STAT2 but not vice versa.<br>IFNA/B may first bind to the high-affinity subunit IFNAR2 and subsequently recruit IFNAR1 in a transient fashion (Lamken et al. 2004). Different type I IFNs interact differently with the two IFNA receptor (IFNAR) subunits, IFNB generates a more stable signaling complex than IFNA subtypes. The interaction between IFNalpha2 (IFNA2) and IFNAR2 has an affinity in the nM range, whereas the affinity of the interaction with INFB is about tenfold tighter. PI3K inhibitors block PI3K catalytic activity A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. For a recent review, please refer to Liu et al. 2009. Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 Pubmed15834429 Pubmed16647110 Pubmed18606717 Pubmed18754654 Pubmed18829560 Pubmed19411071 Pubmed19644473 Pubmed20522708 Pubmed20713702 Pubmed21317208 Pubmed21368164 Pubmed21668414 Pubmed21976531 Pubmed22188813 Pubmed22588880 Pubmed22802530 Pubmed8657148 Reactome Database ID Release 432400009 Reactome, http://www.reactome.org ReactomeREACT_147854 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Activation of RAC1 by VAV2/3 Activated VAV2/3 act as guanine nucleotide exchange factors (GEFs) for RAC-1, catalysing the exchange of bound GDP for GTP. Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 Pubmed10744696 Pubmed11094073 Reactome Database ID Release 432424476 Reactome, http://www.reactome.org ReactomeREACT_147838 Reviewed: Lanier, Lewis L, 2012-08-09 Defective IDS does not hydrolyse sulfates from Lido Authored: Jassal, B, 2012-05-20 Defective IDS does not hydrolyse sulfates from L-iduronate units of DS or HS Edited: Jassal, B, 2012-05-20 Mucopolysaccharidosis II (MPS II, Hunter syndrome, MIM:309900) is an X-linked genetic disorder caused by defects in the gene encoding the enzyme iduronate 2-sulfatase (IDS, MIM:300823). This causes an accumulation of the GAGs dermatan sulfate and heparan sulfate and their excessive excretion in urine. MPS II has a broad range of severity with variable mental retardation and life expectancy. This disease has a prevelence of approximately 1 in 170,000 male births (Muenzer et al. 2009). The R468 codon may be a mutational hot-spot, as it has been noted in patients with diverse ethnic origins: R468W (Crotty et al. 1992), R468L and R468Q (Isogai et al. 1998). R443X is also a frequent mutation (Froissart et al. 1998). Pubmed1284597 Pubmed19901005 Pubmed9501270 Pubmed9660053 Reactome Database ID Release 432262743 Reactome, http://www.reactome.org ReactomeREACT_147818 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Phosphorylation and activation of VAV2/VAV3 by SYK Authored: Garapati, P V, 2012-05-25 EC Number: 2.7.10 Edited: Garapati, P V, 2012-05-25 Pubmed11007481 Pubmed8986718 Reactome Database ID Release 432424486 Reactome, http://www.reactome.org ReactomeREACT_147708 Reviewed: Lanier, Lewis L, 2012-08-09 VAV exists in an auto-inhibitory state, folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the calponin homology (CH) domain to the C1 region. Activation of VAV may involve three events which relieve this auto-inhibition: phosphorylation of tyrosines in the acidic domain causes them to be displaced from the DH domain; binding of a ligand to the CH domain may cause it to release the C1 domain; binding of the PI3K product PIP3 to the PH domain may alter its conformation (Aghazadeh et al. 2000). VAV2/3 are phosphorylated on Y172/Y173 respectively in the acidic domain. This is mediated by SYK and Src-family tyrosine kinases (Deckert et al. 1996, Schuebel et al. 1998). Once activated, VAV2/VAV3 are involved in the activation of RAC1, PAK1, MEK and ERK. has a Stoichiometric coefficient of 2 Defective IDUA does not hydrolyse Lido Absence of alpha-L-iduronidase (IDUA, MIM:252800), the enzyme responsible for the removal of non-reducing terminal alpha-L-iduronide (Lido) residues during the lysosomal degradation of heparan sulphate (HS) and dermatan sulfate (DS) is the cause of MPS I disorders (MIM:607014). The nonsense mutations, W402X and Q70X and the rarer P553R account for approximately 50% of all MPS I alleles in patients with predominantly European origins (Scott et al. 1992, Bunge et al. 1994, Scott et al. 1992b). There are, however, considerable differences in the frequency of these mutations in patients from Norway and Finland when compared with other Eurpoean countries. In Scandinavia, W402X and Q70X account for 17% and 62% of the MPSI alleles, respectively, while in the other European countries W402X is about 2.5 times more frequent (48%) than Q70X (19%). Authored: Jassal, B, 2012-04-26 Defective IDUA does not hydrolyse the alpha-L-iduronisidic linkage in HS or DS Edited: Jassal, B, 2012-04-26 Pubmed1301196 Pubmed1301941 Pubmed7951228 Reactome Database ID Release 432206299 Reactome, http://www.reactome.org ReactomeREACT_147696 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Defective NAGLU does not hydrolyse GlcNAc Authored: Jassal, B, 2012-05-21 Defective NAGLU does not hydrolyse N-acetylglucosamine from HS or heparan Edited: Jassal, B, 2012-05-21 MPS IIIB (Sanfilippo syndrome B, Mucopolysaccharidosis IIIB, MIM:252920) is an autosomal recessive genetic disorder due to loss of function of alpha-N-acetylglucosaminidase (NAGLU; MIM:609701), normally involved in the hydrolysis of terminal non-reducing N-acetyl-D-glucosamine residues in heparan sulfate (HS). Mutations that cause severe forms of MPSIIIB are R674C or H (Zhao et al. 1998), R297X (Yogalingam & Hopwood 2001, Zhao et al. 1998) and R626X (Beesley et al 2004). Pubmed11668611 Pubmed14984474 Pubmed9443875 Reactome Database ID Release 432263496 Reactome, http://www.reactome.org ReactomeREACT_147874 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Defective SGSH does not hydrolyse sulfates from SGlcN Authored: Jassal, B, 2012-05-21 Defective SGSH does not hydrolyse sulfates from N-sulphoglucosamine in HS Edited: Jassal, B, 2012-05-21 MPS IIIA (Sanfilippo syndrome A, mucopolysaccharidosis IIIA, MIM:252900) is a rare, autosomal recessive lysosomal storage disease. A deficiency of the enzyme N-sulphoglucosamine sulphohydrolase (SGSH, MIM:605270), which normally hydrolyses the sulfate group from the terminal N-sulphoglucosamine residue of heparan sulfate (HS) leads to the build up of HS in cells and tissues, characterised by severe CNS degeneration in early childhood leading to death between 10 and 20 years of age.<br>Four mutations (R74C, R245H, S66W, and 1091delC) are known to be prevalent in Polish (Bunge et al. 1997), Dutch (Weber et al. 1997), Italian (Di Natale et al. 1998), and Spanish (Montfort et al. 1998) populations, respectively. These mutations abolish the activity of SGSH being associated with the classic severe phenotype. Pubmed9285796 Pubmed9401012 Pubmed9554748 Pubmed9744479 Reactome Database ID Release 432263444 Reactome, http://www.reactome.org ReactomeREACT_147832 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 has a Stoichiometric coefficient of 2 Release of p-STAT2:p-STAT1 dimer Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Pubmed17351669 Pubmed8621447 Reactome Database ID Release 43909722 Reactome, http://www.reactome.org ReactomeREACT_25021 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The phosphorylated STAT2:STAT1 heterodimers thus formed disassociate from the IFNAR1 subunit and translocates to the nucleus. Phosphorylation of STAT2 Authored: Garapati, P V, 2010-07-07 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 Pubmed10542297 Pubmed16987978 Pubmed8197134 Reactome Database ID Release 43909732 Reactome, http://www.reactome.org ReactomeREACT_25291 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 STAT2 recruited to the IFNAR1 subunit then becomes tyrosine phosphorylated on residue 690 by TYK2 kinase. This phosphotyrosine provides a docking site for recruitment of STAT1 to IFNAR1, which is then tyrosine phosphorylated and activated. Phosphorylation of STAT1 Authored: Garapati, P V, 2010-07-07 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 Phosphotyrosine on STAT2 acts as docking site for STAT1 molecules. STAT1 binds to phosphorylated STAT2 and this is followed by STAT1 phosphorylation on tyrosine residue 701 (Y701) and is followed by p-STAT2:p-STAT1 heterodimer formation and nuclear translocation. Pubmed10982844 Pubmed8232552 Reactome Database ID Release 43909726 Reactome, http://www.reactome.org ReactomeREACT_25017 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Phosphorylation of INFAR1 by TYK2 Authored: Garapati, P V, 2010-07-07 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 Pubmed7526154 Pubmed8605876 Reactome Database ID Release 43909730 Reactome, http://www.reactome.org ReactomeREACT_25383 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 TYK2 functions as part of a receptor complex to trigger intracellular signaling in response to IFNA/B. TYK2 bound to IFNAR1 subunit is activated in response to IFNA/B treatment and this in turn phosphorylates two tyrosine residues Y466 and Y481 in the juxta-membrane region of IFNAR1. has a Stoichiometric coefficient of 2 Recruitment of STAT2 to p-IFNAR1 Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Phosphorylated tyrosine residue 466 on IFNAR1 acts as a docking site for STAT2. Latent STAT2 is recruited to this phosphotyrosine residue via its SH2 domain. Pubmed8605876 Reactome Database ID Release 43909719 Reactome, http://www.reactome.org ReactomeREACT_25238 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Recruitment of IFNAR1 Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 Pubmed15312780 Pubmed15449939 Pubmed16171819 Pubmed17969444 Reactome Database ID Release 43909724 Reactome, http://www.reactome.org ReactomeREACT_25206 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The extracellular domain of IFNAR1 is atypical, consisting of a tandem array of four FNIII domains and the first three N-terminal FNIII domains are involved in ligand recognition. IFNAR1 is recruited to the binary complex (IFNA/B:IFNAR2) on the membrane to form the ternary complex (IFNAR2:IFNA/B:IFNAR1). TYK2 kinase is pre-associated with IFNAR1 and JAK1 with IFNAR2. The binding of IFNA/B to IFNA receptors brings these JAK kinase together, allowing cross-phosphorylation and kinase activation. Activation of JAK kinases Authored: Garapati, P V, 2010-07-07 EC Number: 2.7.10 Edited: Garapati, P V, 2010-07-07 Pubmed11100472 Pubmed8702790 Pubmed9334213 Reactome Database ID Release 43909729 Reactome, http://www.reactome.org ReactomeREACT_25401 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 The two chains IFNAR1 and IFNAR2 are pre-associated with the JAK kinases TYK2 and JAK1, respectively. Receptor heterodimerization brings these JAK kinases into close proximity and they are activated by reciprocal trans-phosphorylation. Tyr-1054 and Tyr-1055 within the activation loop of TYK2 sub-domain VII are critical for TYK2 activation. For JAK1 two tyrosine residues with in the KEYY motif (Tyr 1034 and Tyr 1035) of the kinase domain are thought to be transphosphorylated. has a Stoichiometric coefficient of 3 Autocatalytic phosphorylation of FGFR4 mutants with enhanced kinase activity Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 FGFR4 N535K and FGFR4 V550E have been shown to undergo autophosphorylation when transfected into a murine rhabdomysarcoma (RMS) cell line and to promote transformation in NIH 3T3 cells. Receptor activation leads to increased signaling through STAT3, but decreased levels of phospho-AKT and phospho-Erk1/2 compared to vector control. Cells transfected with the N535K and V550E mutants also showed upregulation of cell cycle and DNA replication gene pathways and significantly higher growth rates (Taylor, 2009). Pubmed19809159 Reactome Database ID Release 432038944 Reactome, http://www.reactome.org ReactomeREACT_121260 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 10 Conversion of PIP2 to PIP3 by PI3K associated with FGFR mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Once recruited to the activated receptor, PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling. PI3K signaling has been demonstrated in ZMYM2-, FOP- and BCR-FGFR1 fusions (Chen, 2004; Demiroglu, 2001; Guasch, 2001), as well as downstream of a number of other FGFR mutants (see for instance, Byron, 2008; Kunii, 2008; Agazie, 2003; Takeda, 2007). Pubmed11689702 Pubmed11739186 Pubmed14534538 Pubmed15448205 Pubmed17505008 Pubmed18381441 Pubmed18757403 Reactome Database ID Release 431986647 Reactome, http://www.reactome.org ReactomeREACT_121187 Reviewed: Ezzat, S, 2012-05-15 c-src associated cx43 hemi-channel Reactome DB_ID: 191649 Reactome Database ID Release 43191649 Reactome, http://www.reactome.org ReactomeREACT_10665 has a Stoichiometric coefficient of 6 Recruitment of the catalytic subunit of PI3K by activated FGFR1 mutants Activation of the PI3K pathway has been demonstrated downstream of a number of FGFR mutants (reviewed in Wesche, 2001; see for instance, Agazie, 2003; Kunii, 2008; Takeda, 2007; Chen, 2004; Demiroglu, 2001; Guasch, 2001; Byron, 2008), and is presumed to occur in a manner analogous to the wild-type receptor. Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11689702 Pubmed11739186 Pubmed14534538 Pubmed15448205 Pubmed17505008 Pubmed18757403 Pubmed21711248 Reactome Database ID Release 431986645 Reactome, http://www.reactome.org ReactomeREACT_120860 Reviewed: Ezzat, S, 2012-05-15 c-src-associated Cx43 junctional channel Reactome DB_ID: 191635 Reactome Database ID Release 43191635 Reactome, http://www.reactome.org ReactomeREACT_10199 has a Stoichiometric coefficient of 2 GRB2:GAB1:PI3Kreg binds to p-FRS2:activated FGFR mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR1-amplified cells derived from lung cancer patients show phosphorylation of AKT and S6, demonstrating the activation of the PI3K signaling pathway in these lines. Inhibition of FGFR1 phosphorylation by treatment with the in vitro reagent PD173074 did not abrogate the phosphorylation of these substrates, however, indicating that the PI3K pathway is not the major signaling pathway activated by amplified FGFR1 (Weiss, 2010; Dutt, 2011). Activation of the PI3K pathway has also been demonstrated downstream of other FGFR mutants (see for instance, Agazie, 2003; Kunii, 2008, Takeda, 2007; Byron, 2008; Demiroglu, 2001; Guasch, 2001; Chen, 2004); however not all mutants activate the PI3K pathway to the same extent and in the case of the rhabdomyosarcoma FGFR4 mutants K535 and E550, phosphorylation of AKT is actually reduced compared to wild-type signaling (Taylor, 2009). Pubmed11689702 Pubmed11739186 Pubmed14534538 Pubmed15448205 Pubmed17505008 Pubmed18381441 Pubmed18757403 Pubmed19809159 Pubmed21160078 Pubmed21666749 Reactome Database ID Release 431986643 Reactome, http://www.reactome.org ReactomeREACT_121102 Reviewed: Ezzat, S, 2012-05-15 CCT/TriC (ADP) associated actin Reactome DB_ID: 390476 Reactome Database ID Release 43390476 Reactome, http://www.reactome.org ReactomeREACT_17090 has a Stoichiometric coefficient of 1 ESCRT-0/Cargo Complex Reactome DB_ID: 917704 Reactome Database ID Release 43917704 Reactome, http://www.reactome.org ReactomeREACT_27808 has a Stoichiometric coefficient of 1 Ras nucleotide exchange mediated by GRB2-SOS1 bound to FGFR mutants Activation of Erk1/2 downstream of FGFR mutants suggests that, as is the case for WT FGFR, FGFR mutant-associated SOS1 activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state (see for instance, Weiss, 2010; Dutt, 2011; Raffioni, 1998; Cha, 2009; Hart, 2000; Turner, 2010; Kunii, 2008; Byron, 2008; Roidl, 2010; Chesi, 2001; Ronchetti, 2001; reviewed in Wesche, 2011). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11157491 Pubmed11429702 Pubmed18381441 Pubmed18757403 Pubmed19103595 Pubmed19946327 Pubmed20179196 Pubmed21160078 Pubmed21666749 Pubmed21711248 Pubmed9857065 Reactome Database ID Release 431982085 Reactome, http://www.reactome.org ReactomeREACT_120761 Reviewed: Ezzat, S, 2012-05-15 tubulin-GTP folding intermediate Reactome DB_ID: 390457 Reactome Database ID Release 43390457 Reactome, http://www.reactome.org ReactomeREACT_17885 has a Stoichiometric coefficient of 1 closed Cx43 junctional channel Reactome DB_ID: 191637 Reactome Database ID Release 43191637 Reactome, http://www.reactome.org ReactomeREACT_10597 has a Stoichiometric coefficient of 2 GRB2-SOS1 is recruited by activated FGFR mutants Activation of FGFR mutants has in some cases been shown to result in phosphorylation of both FRS2alpha and ERK1/2, suggesting activation of the MAPK pathway through wild-type like recruitment of the GRB2-SOS1 complex (reviewed in Wesche, 2011; see for instance, Weiss, 2010; Dutt, 2011; Raffioni, 1998; Hart, 2000). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10918587 Pubmed21160078 Pubmed21666749 Pubmed21711248 Pubmed9857065 Reactome Database ID Release 431982082 Reactome, http://www.reactome.org ReactomeREACT_120735 Reviewed: Ezzat, S, 2012-05-15 FGFR mutants phosphorylate FRS2alpha After recruitment to activated FGFR mutants, FRS2alpha is believed to be phosphorylated, potentially on all 6 of the tyrosines phosphorylated by wild-type FGFRs. Phosphorylation of FRS2alpha by FGFR has been demonstrated in some cases (see for instance Qing, 2009; Bai, 2010; Ahmed, 2008; Raffioni, 1998) and is inferred to occur in others based on activation of downstream signaling modules (reviewed in Wesche, 2011; Turner and Grose, 2010). Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed17505008 Pubmed18373495 Pubmed19381019 Pubmed20094046 Pubmed20709759 Pubmed21666749 Pubmed21711248 Pubmed9857065 Reactome Database ID Release 431982077 Reactome, http://www.reactome.org ReactomeREACT_120797 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 6 Activated FGFR mutants bind FRS2alpha After activation, FGFR mutants are presumed to recruit FRS2alpha. This has been demonstrated in some cases (see for instance Ahmed, 2008; Weiss, 2010; Dutt, 2008; Dutt, 2011; Cha, 2009; Qing, 2009; Bai, 2010 ) and is inferred to occur in others by analogy with the wild-type receptor. Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed18373495 Pubmed18552176 Pubmed19103595 Pubmed19381019 Pubmed20709759 Pubmed21160078 Pubmed21666749 Reactome Database ID Release 431982073 Reactome, http://www.reactome.org ReactomeREACT_120949 Reviewed: Ezzat, S, 2012-05-15 FGFR4 kinase mutants are inhibited by PD170734 Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed19809159 Reactome Database ID Release 432046363 Reactome, http://www.reactome.org ReactomeREACT_120902 Reviewed: Ezzat, S, 2012-05-15 Treatment of cells expressing FGFR4 N535K or V550E with the in vitro FGFR inhibitor PD170734 reduces the levels of receptor autophosphorylation and increases the activation of caspase-3 and the number of cells undergoing apoptosis (Taylor, 2009). has a Stoichiometric coefficient of 2 GTP:beta-tubulin folding intermediate Reactome DB_ID: 391246 Reactome Database ID Release 43391246 Reactome, http://www.reactome.org ReactomeREACT_18072 has a Stoichiometric coefficient of 1 ESCRT-II/Cargo Complex Reactome DB_ID: 917698 Reactome Database ID Release 43917698 Reactome, http://www.reactome.org ReactomeREACT_27742 has a Stoichiometric coefficient of 1 cofactor A:GTP:beta-tubulin folding intermediate Reactome DB_ID: 391239 Reactome Database ID Release 43391239 Reactome, http://www.reactome.org ReactomeREACT_17443 has a Stoichiometric coefficient of 1 ESCRT-III Reactome DB_ID: 917723 Reactome Database ID Release 43917723 Reactome, http://www.reactome.org ReactomeREACT_27898 has a Stoichiometric coefficient of 1 Cofactor D:GTP:beta tubulin Reactome DB_ID: 391245 Reactome Database ID Release 43391245 Reactome, http://www.reactome.org ReactomeREACT_17888 has a Stoichiometric coefficient of 1 GTP-alpha-tubulin folding intermediate Reactome DB_ID: 391235 Reactome Database ID Release 43391235 Reactome, http://www.reactome.org ReactomeREACT_17776 has a Stoichiometric coefficient of 1 CCT/TriC(ATP)-associated actin Reactome DB_ID: 390499 Reactome Database ID Release 43390499 Reactome, http://www.reactome.org ReactomeREACT_17160 has a Stoichiometric coefficient of 1 Ubiquinated and PIP3 Endosmal Membrane Bound Cargo Reactome DB_ID: 917713 Reactome Database ID Release 43917713 Reactome, http://www.reactome.org ReactomeREACT_27685 has a Stoichiometric coefficient of 1 CCT/TriC(ATP) Reactome DB_ID: 390474 Reactome Database ID Release 43390474 Reactome, http://www.reactome.org ReactomeREACT_17683 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 8 ESCRT-0 Reactome DB_ID: 917726 Reactome Database ID Release 43917726 Reactome, http://www.reactome.org ReactomeREACT_27831 has a Stoichiometric coefficient of 1 Activated FGFR mutants bind PLC-gamma Although it has not been rigourously established, there is some evidence that PLC-gamma signaling may be activated after autophosphorylation of some FGFR mutants, analagous to the wild type receptor (see for instance, Hart, 2000; Chen, 2005; Cha, 2008; di Martino, 2009; Gartside, 2009; Cross, 2000; Hatch, 2006). The extent to which each of the mutants activates this pathway and to which proliferation and tumorigenesis relies on PLC-gamma dependent signaling, remains to be more firmly established. Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10652257 Pubmed10918587 Pubmed16091734 Pubmed16844695 Pubmed18337450 Pubmed19147536 Pubmed19749790 Reactome Database ID Release 432077380 Reactome, http://www.reactome.org ReactomeREACT_121127 Reviewed: Ezzat, S, 2012-05-15 CCT/TriC(ADP):Sphingosine kinase 1 Reactome DB_ID: 391256 Reactome Database ID Release 43391256 Reactome, http://www.reactome.org ReactomeREACT_18085 has a Stoichiometric coefficient of 1 ESCRT-I/Cargo Complex Reactome DB_ID: 917702 Reactome Database ID Release 43917702 Reactome, http://www.reactome.org ReactomeREACT_27922 has a Stoichiometric coefficient of 1 CCT/TriC:substrate complex Reactome DB_ID: 390481 Reactome Database ID Release 43390481 Reactome, http://www.reactome.org ReactomeREACT_17268 has a Stoichiometric coefficient of 1 ESCRT-II Reactome DB_ID: 917707 Reactome Database ID Release 43917707 Reactome, http://www.reactome.org ReactomeREACT_27749 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated PLC-gamma release by activated FGFR mutants Authored: Rothfels, K, 2012-02-09 Dissociation from the activated receptor quickly follows phosphorylation of PLC-gamma. Phosphorylated PLC-gamma catalyzes the hydrolysis of phosphatidylinositol(4, 5)bisphosphate to generate two second messengers, diacylglycerol and inositol (1,4,5) triphosphate. Edited: Rothfels, K, 2012-05-16 Pubmed10579907 Reactome Database ID Release 432077385 Reactome, http://www.reactome.org ReactomeREACT_121068 Reviewed: Ezzat, S, 2012-05-15 PLC-gamma phosphorylation by FGFR mutants Authored: Rothfels, K, 2012-02-09 By analogy with the wild-type pathway, PLC-gamma is presumed to be phosphorylated by activated FGFR mutants, resulting in PLC-gamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3. EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed10579907 Reactome Database ID Release 432077384 Reactome, http://www.reactome.org ReactomeREACT_121367 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 4 Defensins alpha 1-4 Converted from EntitySet in Reactome Reactome DB_ID: 1470042 Reactome Database ID Release 431470042 Reactome, http://www.reactome.org ReactomeREACT_117291 AKT1 E17K mutant binds PIP2 Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 Pubmed17611497 Pubmed18954143 Reactome Database ID Release 432219536 Reactome, http://www.reactome.org ReactomeREACT_147896 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Substitution of glutamic acid with lysine at position 17 of AKT1 results in constitutive plasma membrane localization of AKT1, independent of PI3K activity and PIP3 generation (Carpten et al. 2007). This constitutive plasma membrane targeting of AKT1 E17K mutant is due to an increased affinity for PIP2 (Landgraf et al. 2008). FANCD and ub-FANCI-bound chromatin Reactome DB_ID: 420771 Reactome Database ID Release 43420771 Reactome, http://www.reactome.org ReactomeREACT_18588 has a Stoichiometric coefficient of 1 Pro-defensins alpha 1-4 Converted from EntitySet in Reactome Reactome DB_ID: 1470043 Reactome Database ID Release 431470043 Reactome, http://www.reactome.org ReactomeREACT_116887 PTEN loss of function Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 3.1.3.67 Edited: Matthews, L, 2012-08-03 One of the functions of PTEN is to act as a phosphoinositide phosphatase that catalyzes dephosphorylation of PIP3 into PIP2. PTEN thus reduces the amount of available PIP3, counteracting PI3K activity and downregulating AKT signaling. PTEN is frequently targeted by loss of function mutations in cancer and in familial cancer syndromes known as PTHS (PTEN hamartoma tumor syndromes, a collection of diseases including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease). Some PTEN loss-of-function variants are also found in autism spectrum disorder patients. For a recent review of PTEN involvement in cancer, please refer to Hollander et al. 2011. <br> <br>The majority of missense mutations that impair phosphoinositide phosphatase activity of PTEN cluster in exon 5 of PTEN gene and result in substitution of amino acid residues in the catalytic cleft of the phosphatase domain. Arginine at position 130 is the most frequently substituted PTEN residue in cancer. R130 of human PTEN is the last arginine residue in the conserved H-C-K/R-A-G-K-G-R sequence (corresponding to HCXXGXXR motif of protein tyrosine phosphatases) in the catalytic cleft of the PTEN phosphatase domain and is essential for catalysis (Barford et al. 1994, Lee et al. 1999). PTEN R130 substitution mutants show markedly decreased phosphoinositide phosphatase activity (Han et al. 2000, Koul et al. 2002) and are frequently found in endometrial carcinoma (Kong et al. 1997, Konopka et al. 2007). The cysteine residue at position 124 (C124) of human PTEN, in the conserved H-C-K/R-A-G-K-G-R sequence, 'attacks' the phosphate group of a substrate and forms a thio-phosphate intermediate during the dephosphorylation reaction (Guan and Dixon 1991, Barford et al. 1994, Lee et al. 1999). Therefore, substitution of this critical C124 abolishes PTEN phosphatase activity (Han et al. 2000, Koul et al. 2002). Substitution of histidine H123 in the conserved H-C-K/R-A-G-K-G-R sequence also impairs PTEN phosphatase activity (Lee et al. 1999).<br><br>Missense mutations also target amino acid residues in the N-terminal phosphatase domain that are outside the catalytic cleft. Substitution of histidine at position 93 affects the conserved WPD loop of the phosphatase domain of PTEN, and PTEN H93 mutants show low phosphoinositide phosphatase activity (Lee et al. 1999). Serine residue S170 and histidine residue H173 participate in the formation of hydrogen bonds between the N-terminal phosphatase domain of PTEN and the C-terminal membrane-binding C2 domain (Lee et al. 1999). H173, and to a lesser extent S170, are targeted by missense mutations in cancer, and substitution mutants have impaired phosphoinositide phosphatase activity (Han et al. 2000). <br><br>Missense mutations also occur in the C2 domain of PTEN. The C2 domain is implicated in membrane binding and localization of PTEN, but also in PTEN roles unrelated to its phosphoinositide phosphatase function (Raftopoulou et al. 2004). Since the roles of these C2 domain PTEN mutants in cancer have not been clarified, these variants will be annotated when more information becomes available. <br><br>Besides missense mutations, nonsense mutations that result in PTEN protein truncation are also frequently found in cancer samples. The three residues most frequently targeted by nonsense mutations are R130, R233 and R335. While R130* mutation directly affects the phosphatase domain of PTEN, R233* and R335* affect the C2 domain. It is has not yet been elucidated whether R233* and R335* affect PTEN membrane localization or impair PTEN function in some other way. <br><br>In cancer, PTEN is also frequently inactivated by genomic deletions and loss of heterozygosity (LOH) affecting chromosome band 10q23 or by epigenetic silencing (reviewed by Hollander et al. 2011). Pubmed10555148 Pubmed10866302 Pubmed11948419 Pubmed14976311 Pubmed1654322 Pubmed17219201 Pubmed21430697 Pubmed8128219 Pubmed9326929 Reactome Database ID Release 432317387 Reactome, http://www.reactome.org ReactomeREACT_147756 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 PIP2-bound p-S473-AKT1 mutant binds PIP2-bound PDPK1 A portion of PDPK1 (PDK1) is anchored to the plasma membrane in the absence of PI3K activity through PIP2 binding (Currie et al. 1999). This PIP2-bound PDPK1 is able to bind and phosphorylate PIP2-bound AKT E17K mutants (Carpten et al. 2007, Landgraf et al. 2008) phosphorylated on serine residue S473. Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 Pubmed17611497 Pubmed18954143 Pubmed9895304 Reactome Database ID Release 432243937 Reactome, http://www.reactome.org ReactomeREACT_147790 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT1 E17K mutant is phosphorylated by TORC2 complex Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 PIP2-binding AKT1 E17K mutants are anchored to the plasma membrane in the absence of PI3K activity and are constitutively phosphorylated on serine S473, presumably by the TORC2 complex (Carpten et al. 2007, Landgraf et al. 2008). Pubmed17611497 Pubmed18954143 Reactome Database ID Release 432243938 Reactome, http://www.reactome.org ReactomeREACT_147858 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 phenylalanine + oxaloacetate => phenylpyruvate + aspartate [CCBL1] Authored: D'Eustachio, P, 2012-03-04 CCBL1 (KAT1) catalyzes the reaction of phenylalanine and oxaloacetate to form keto-phenylpyruvate and aspartate. The active form of CCBL1 is a homodimer with one molecule of pyridoxal phosphate bound to each monomer (Rossi et al. 2004). CCBL1 (KAT1) acts on phenylalanine and kynurenine with comparable efficiencies (Han et al. 2004), consistent with the idea that when phenylalanine levels are elevated CCBL1 (KAT1) activity could be a major source of phenylpyruvate. Oxaloacetate is one of several 2-oxoacids that function efficiently in CCBL1-mediated transamination (Han et al. 2004). Notably, neither tyrosine aminotransferase (Sivaraman and Kirsch 2006) nor glutamate-oxaloacetate aminotransferase (Cammarata and Cohen 1951) acts on phenylalanine. Edited: D'Eustachio, P, 2012-03-16 Pubmed14907689 Pubmed15364907 Pubmed15606768 Pubmed16640556 Reactome Database ID Release 432160461 Reactome, http://www.reactome.org ReactomeREACT_121130 Reviewed: Jassal, B, 2012-03-16 phenylalanine + H2O + O2 => phenylpyruvate + NH3 + H2O2 Authored: D'Eustachio, P, 2012-03-04 EC Number: 1.4.3.2 Edited: D'Eustachio, P, 2012-03-16 Extracellular IL4I1 catalyzes the reaction of phenylalanine, water, and molecular oxygen to form keto-phenylpyruvate, ammonia, and hydrogen peroxide. IL4I1, inferred to form a complex with FAD, has L-amino acid oxidase activity and with a strong preference for phenylalanine. The enzyme, found both in lysosomes and secreted into the extracellular space, is produced in the body by myeloid and dedritic cells (Boulland et al. 2007). Pubmed17356132 Reactome Database ID Release 432160492 Reactome, http://www.reactome.org ReactomeREACT_120997 Reviewed: Jassal, B, 2012-03-16 PI3K gain of function mutants phosphorylate PIP2 to PIP3 Authored: Orlic-Milacic, M, 2012-07-18 Constitutively active PI3K complex produces PIP3 in the absence of growth stimuli, resulting in aberrant activation of downstream AKT signaling that positively regulates cell growth and survival. The PIK3CA gene, encoding the catalytic subunit of PI3K (p110alpha), is one of the most frequently mutated oncogenes in cancer. Hotspot mutations are found in the helical domain and kinase domain of PIK3CA, with the most frequent mutations being E545K substitution in the helical domain and H1047R substitution in the kinase domain.<br> The oncogenic PIK3CA mutants annotated here preserve their ability to bind PIK3R1 (p85alpha) regulatory subunit, but are constitutively active either because the inhibitory interactions with PIK3R1 are relieved, or because the conformation of the catalytic domain is changed. Missense mutations that result in substitution of amino acids at positions 542, 545 or 546 of PI3K disrupt an inhibitory interaction between the helical domain of PIK3CA and the nSH2 domain of PIK3R1. The effect of substitution of glutamic acid residue at position 545 has been studied in detail in PIK3CA E545K mutant, where glutamic acid is replaced with lysine (Miled et al. 2007, Huang et al. 2007, Zhao et al. 2005). The gain-of-function has been experimentally confirmed for PIK3CA E545A mutant (Horn et al. 2008), while PIK3CA E545G, PIK3CA E545Q and PIK3CA E545V mutants are assumed to behave similarly. The structural and functional consequences of glutamic acid to lysine substitution at position 542, in PIK3CA E542K mutant, have been established (Miled et al. 2007, Horn et al. 2008) and are extrapolated to PIK3CA E542Q and PIK3CA E542V mutants. A less frequent substitution of glutamine residue at position 546 follows the same mechanism, as shown for PIK3CA Q546K mutant (Miled et al. 2007) and extrapolated to PIK3CA Q546E, PIK3CA Q546H, PIK3CA Q546L, PIK3CA Q546P and PIK3CA Q546R mutants.<br> In the kinase domain of PIK3CA, substitution of histidine residue at position 1047 or methionine residue at position 1043, detected in PIK3CA H1047R, PIK3CA H1047L, PIK3CA H1047Y, PIK3CA M1043I, PIK3CA M1043T and PIK3CA M1043V mutants, is predicted to change the conformation of the activation loop (Huang et al. 2007) and was shown to confer constitutive activity, in the absence of growth factors, to PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants (Zhao et al. 2005, Horn et al. 2008). The catalytic activity of PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants may be further increased by binding of PIK3R1 regulatory subunit to phosphopeptides generated by activated receptor tyrosine kinases (Hon et al. 2011). PIK3CA H1047Y, PIK3CA M1043T and PIK3CA M1043V mutants are expected to behave similarly.<br> The arginine residue at position 38 of PIK3CA (R38) is located at a contact site between the ABD and kinase domains of PIK3CA. Substitution of this arginine residue with histidine in PIK3CA R38H mutant is likely to disrupt the interaction between the ABD domain and the kinase domain, causing a conformational change of the kinase domain that leads to increased enzymatic activity (Huang et al. 2007). PIK3CA R38H mutant shows reduced PIK3R1 binding and modestly increased catalytic activity (measured indirectly, via AKT1 phosphorylation) under serum starved conditions (Zhao et al. 2005). PIK3CA R38C, PIK3CA R38G and PIK3CA R38S mutants are expected to behave similarly.<br> Mutations in other conserved domains of PIK3CA, such as membrane-binding C2 domain (Mandelker et al. 2009), have not been annotated as their mechanism of action needs to be further elucidated.<br> Although less common than mutations in PIK3CA, mutations in PIK3R1, encoding the regulatory subunit of PI3K (p85alpha) have been recently described. Mutations mapping to iSH2 and nSH2 domains, the two domains of PIK3R1 involved in the inhibition of PIK3CA, which were shown to result in constitutive activity of PIK3R1 complex, are annotated here. An experimentally studied nSH2 domain mutant is PIK3R1 G376R (Sun et al. 2010). PIK3R1 iSH2 domain mutants, affected by amino acid substitutions and small inframe deletions, PIK3R1 D560Y (Jaiswal et al. 2009), PIK3R1 N564D (Jaiswal et al. 2009), PIK3R1 N564K (Sun et al. 2010), PIK3R1 H450_E451del (Urick et al. 2011), PIK3R1 K459del (Urick et al. 2011), PIK3R1 R574_T576del (Urick et al. 2011) and PIK3R1 Y463_L466del (Urick et al. 2011), were all shown to bind PIK3CA and confer constitutive activity to PI3K complex. PIK3R1 D560H, PIK3R1 R574I and PIK3R1 R574T mutants are expected to behave similarly to functionally characterized D560 and R574 substitution mutants.<br> Co-occurrence of PIK3CA and PIK3R1 mutations has been documented in some tumors, but since it is rare and the exact clinical combinations of PIK3CA and PIK3R1 mutants have not been studied, complexes of PIK3CA mutants with PIK3R1 mutants are not shown (Urick et al. 2011).<br> Although rare, perturbations in genes encoding other isoforms of PI3K subunits have also been reported in cancers. Mutations in PIK3R2, encoding PI3K regulatory subunit isoform p85beta, are found infrequently in endometrial cancers, but have not been functionally studied (Cheung et al. 2011). They are not shown in this context. PIK3CB, encoding PI3K catalytic subunit isoform p110beta, can be overexpressed in cancer, mainly due to genomic gain. Several studies have shown that PTEN deficient cancer cell lines depend on PIK3CB (p110beta) for AKT activation and sustained growth (Wee et al. 2008, Jiang et al. 2010, Chen et al. 2011). PIK3CB activation synergizes with PTEN loss in mouse prostate cancer model (Jia et al. 2008). Mutations in PIK3CB are very rare, have not been functionally studied, and are therefore not shown. Structural studies indicate that, in comparison with PIK3CA (p110alpha), PIK3CB (p110beta) and PIK3CD (p110delta) form additional inhibitory contacts with the regulatory subunit p85alpha, and are therefore probably less prone to mutational activation (Burke et al. 2011). <br> For more information, please refer to recent reviews by Liu et al. 2009 and Vogt et al. 2009. EC Number: 2.7.1.153 Edited: Matthews, L, 2012-08-03 Pubmed16339315 Pubmed17626883 Pubmed18079394 Pubmed18317450 Pubmed18594509 Pubmed18755892 Pubmed19185485 Pubmed19644473 Pubmed19805105 Pubmed19962665 Pubmed20231295 Pubmed20713702 Pubmed21188471 Pubmed21478295 Pubmed21827948 Pubmed21984976 Pubmed22120714 Reactome Database ID Release 432394007 Reactome, http://www.reactome.org ReactomeREACT_147846 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 phenylpyruvate + NADH + H+ => phenyllactate + NAD+ Authored: D'Eustachio, P, 2012-03-04 Edited: D'Eustachio, P, 2012-03-16 Pubmed15421980 Reactome Database ID Release 432160489 Reactome, http://www.reactome.org ReactomeREACT_121215 Reviewed: Jassal, B, 2012-03-16 The ability of human lactate dehydrogenase to catalyze the reaction of phenylalanine with NADH + H+ to form phenyllactate and NAD+ is inferred from the properties of bovine heart lactate dehydrogenase (Meister 1951). As these studies were carried out only on the one bovine isoform, the reaction is inferred only for the corresponding human isoform. The reaction rate measured for bovine LDHB acting on phenylpyruvate is approximately 2% of its rate on pyruvate, but could yield appreciable amounts of phenyllactate under conditions of high phenylpyruvate concentration. actin/tubulin-bound CCT/TriC(ADP) Reactome DB_ID: 390495 Reactome Database ID Release 43390495 Reactome, http://www.reactome.org ReactomeREACT_17195 has a Stoichiometric coefficient of 1 CCT/TriC(ADP)-associated non-native tubulin Reactome DB_ID: 390501 Reactome Database ID Release 43390501 Reactome, http://www.reactome.org ReactomeREACT_17102 has a Stoichiometric coefficient of 1 Prefoldin-associated actin/tubulin Reactome DB_ID: 390460 Reactome Database ID Release 43390460 Reactome, http://www.reactome.org ReactomeREACT_18141 has a Stoichiometric coefficient of 1 CCT/TriC(ADP) Reactome DB_ID: 390455 Reactome Database ID Release 43390455 Reactome, http://www.reactome.org ReactomeREACT_17874 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 8 Frizzled receptors:Wnts Reactome DB_ID: 517518 Reactome Database ID Release 43517518 Reactome, http://www.reactome.org ReactomeREACT_21648 has a Stoichiometric coefficient of 1 Prefoldin Reactome DB_ID: 390452 Reactome Database ID Release 43390452 Reactome, http://www.reactome.org ReactomeREACT_17255 has a Stoichiometric coefficient of 1 USP1:UAF1 Reactome DB_ID: 419551 Reactome Database ID Release 43419551 Reactome, http://www.reactome.org ReactomeREACT_18986 has a Stoichiometric coefficient of 1 Smad7:SMURF1 Reactome DB_ID: 2169008 Reactome Database ID Release 432169008 Reactome, http://www.reactome.org ReactomeREACT_122356 has a Stoichiometric coefficient of 1 CCT/TriC(ATP):unfolded tubulin complex Reactome DB_ID: 390446 Reactome Database ID Release 43390446 Reactome, http://www.reactome.org ReactomeREACT_17889 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 8 Invaginating gap junction plaques Reactome DB_ID: 196145 Reactome Database ID Release 43196145 Reactome, http://www.reactome.org ReactomeREACT_10333 has a Stoichiometric coefficient of 1 Planar gap junction plaques associated with Dab2 and Dynamin Reactome DB_ID: 196018 Reactome Database ID Release 43196018 Reactome, http://www.reactome.org ReactomeREACT_10413 has a Stoichiometric coefficient of 1 planar gap junction plaques associated with Dab2 Reactome DB_ID: 196033 Reactome Database ID Release 43196033 Reactome, http://www.reactome.org ReactomeREACT_10755 has a Stoichiometric coefficient of 1 Clathrin Reactome DB_ID: 196043 Reactome Database ID Release 43196043 Reactome, http://www.reactome.org ReactomeREACT_11021 has a Stoichiometric coefficient of 1 Junctional channel Reactome DB_ID: 196171 Reactome Database ID Release 43196171 Reactome, http://www.reactome.org ReactomeREACT_10711 has a Stoichiometric coefficient of 2 gap junction plaque Reactome DB_ID: 196152 Reactome Database ID Release 43196152 Reactome, http://www.reactome.org ReactomeREACT_10872 has a Stoichiometric coefficient of 10 junctional plaque prior to invagination Reactome DB_ID: 196167 Reactome Database ID Release 43196167 Reactome, http://www.reactome.org ReactomeREACT_10909 has a Stoichiometric coefficient of 1 planar gap junction plaques containing Dab2 Reactome DB_ID: 196148 Reactome Database ID Release 43196148 Reactome, http://www.reactome.org ReactomeREACT_10520 has a Stoichiometric coefficient of 1 Defensins alpha 1-4 Converted from EntitySet in Reactome Reactome DB_ID: 1471313 Reactome Database ID Release 431471313 Reactome, http://www.reactome.org ReactomeREACT_116483 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA + H2O => (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA is hydrated to (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA is hydrated to form (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA. This reaction, catalyzed by the peroxisomal D-bifunctional enzyme (Huyghe et al. 2006), occurs in the peroxisomal matrix. Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 4.2.1.107 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed16766224 Pubmed8902629 Reactome Database ID Release 43193535 Reactome, http://www.reactome.org ReactomeREACT_9952 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 gap junction plaque Reactome DB_ID: 191660 Reactome Database ID Release 43191660 Reactome, http://www.reactome.org ReactomeREACT_10558 has a Stoichiometric coefficient of 10 (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA is oxidized to 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-one-CoA (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA + NAD+ => 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-one-CoA + NADH + H+ (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA and NAD+ react to form 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-one-CoA, NADH, and H+. This oxidation reaction, catalyzed by the peroxisomal D-bifunctional enzyme (Huyghe et al. 2006), occurs in the peroxisomal matrix. Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 1.1.1.35 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed16766224 Pubmed8902629 Reactome Database ID Release 43193455 Reactome, http://www.reactome.org ReactomeREACT_10065 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 planar gap junction plaques Reactome DB_ID: 196020 Reactome Database ID Release 43196020 Reactome, http://www.reactome.org ReactomeREACT_10866 has a Stoichiometric coefficient of 1 Defensins alpha 1-4 Converted from EntitySet in Reactome Reactome DB_ID: 1470049 Reactome Database ID Release 431470049 Reactome, http://www.reactome.org ReactomeREACT_117327 3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA + CoASH => chenodeoxycholoyl-CoA (3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA) + propionyl CoA 3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA and CoASH react to form chenodeoxycholoyl-CoA (3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA) and propionyl CoA. This reaction, in the peroxisomal matrix, is catalyzed by peroxisomal thiolase 2 (sterol carrier protein 2). Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 2.3.1.154 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10706581 Pubmed12543708 Pubmed1703300 Reactome Database ID Release 43193533 Reactome, http://www.reactome.org ReactomeREACT_10103 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Thiolysis of 3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA yields chenodeoxycholoyl-CoA (3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA) and propionyl CoA Hydrolysis of choloyl-CoA to cholate and CoASH Authored: D'Eustachio, P, 2007-02-17 19:40:28 Choloyl-CoA and water react to form cholate and CoASH. This reaction, catalyzed by acyl-coenzyme A thioesterase 8, occurs in the peroxisomal matrix (Jones et al. 1999; Hunt et al. 2002). While bile salts are the major product of the de novo biosynthetic pathway in the normal human liver, bile acids are major feedback regulators of this pathway and this hydrolysis reaction is thought to play a role in generating them (Russell 2003). Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10092594 Pubmed11673457 Pubmed12543708 Reactome Database ID Release 43193385 Reactome, http://www.reactome.org ReactomeREACT_10061 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA is oxidized to 3alpha,7alpha-dihydroxy-5beta-cholest-24-one-CoA (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA + NAD+ => 3alpha,7alpha-dihydroxy-5beta-cholest-24-one-CoA + NADH + H+ (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA and NAD+ react to form 3alpha,7alpha-dihydroxy-5beta-cholest-24-one-CoA, NADH, and H+. This oxidation reaction, catalyzed by the peroxisomal D-bifunctional enzyme (Huyghe et al. 2006), occurs in the peroxisomal matrix. Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 1.1.1.35 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed16766224 Pubmed8902629 Reactome Database ID Release 43193508 Reactome, http://www.reactome.org ReactomeREACT_9967 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA + CoASH => choloyl-CoA (3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA) + propionyl CoA 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA and CoASH react to form choloyl-CoA (3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA) and propionyl CoA. This reaction, in the peroxisomal matrix, is catalyzed by peroxisomal thiolase 2 (sterol carrier protein 2). Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 2.3.1.154 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10706581 Pubmed12543708 Pubmed1703300 Reactome Database ID Release 43192341 Reactome, http://www.reactome.org ReactomeREACT_10113 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Thiolysis of 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA yields choloyl-CoA (3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA) and propionyl CoA Chenodeoxycholoyl CoA reacts with glycine or taurine to form glycochenodeoxycholate or taurochenodeoxycholate Authored: Jassal, B, 2007-01-31 12:07:06 Chenodeoxycholoyl CoA reacts with glycine or taurine to form glycochenodeoxycholate or taurochenodeoxycholate, releasing CoASH. This reaction, which completes the de novo synthesis of bile salts from cholesterol in vivo, is catalyzed by BAAT (Bile acid CoA:amino acid N-acyltransferase - Falany et al. 1994) and occurs in the peroxisomal matrix (Solaas et al. 2000; Mihalik et al. 2002). In vivo, the relative amounts of glycochenodeoxycholate and taurochenodeoxycholate synthesized appear to be determined solely by the intracellular abundances of glycine and taurine (Russell 2003). EC Number: 2.3 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10884298 Pubmed11980911 Pubmed12543708 Pubmed8034703 Reactome Database ID Release 43193491 Reactome, http://www.reactome.org ReactomeREACT_9968 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 bile salts [peroxisomal matrix] => cholate bile salts [cytosol] Authored: Jassal, B, 2007-01-19 10:34:59 Bile salts are translocated from the peroxisomal matrix to the cytosol Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12543708 Reactome Database ID Release 43192315 Reactome, http://www.reactome.org ReactomeREACT_9965 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 The bile salts glycocholate, glycochenodeoxycholate, taurocholate, and taurochenodeoxycholate are translocated from the peroxisomal matrix to the cytosol. The transporter that mediates this process is unknown (Russell 2003). cholate [peroxisomal matrix] => cholate [cytosol] Authored: D'Eustachio, P, 2007-02-17 19:40:28 Cholate is translocated from the peroxisomal matrix to the cytosol Cholate is translocated from the peroxisomal matrix to the cytosol. The transporter that mediates this event is unknown. Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed11673457 Pubmed12543708 Reactome Database ID Release 43193399 Reactome, http://www.reactome.org ReactomeREACT_10130 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Choloyl CoA reacts with glycine or taurine to form glycocholate or taurocholate Authored: Jassal, B, 2007-01-31 12:07:06 Choloyl CoA reacts with glycine or taurine to form glycocholate or taurocholate, releasing CoASH. This reaction, which completes the de novo synthesis of bile salts from cholesterol in vivo, is catalyzed by BAAT (Bile acid CoA:amino acid N-acyltransferase - Falany et al. 1994) and occurs in the peroxisomal matrix (Solaas et al. 2000; Mihalik et al. 2002). In vivo, the relative amounts of glycocholate and taurocholate synthesized appear to be determined solely by the intracellular abundances of glycine and taurine (Russell 2003). EC Number: 2.3 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10884298 Pubmed11980911 Pubmed12543708 Pubmed8034703 Reactome Database ID Release 43192312 Reactome, http://www.reactome.org ReactomeREACT_9974 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Cx43 :ZO-1 gap junction Reactome DB_ID: 191652 Reactome Database ID Release 43191652 Reactome, http://www.reactome.org ReactomeREACT_10329 has a Stoichiometric coefficient of 2 Cx43:ZO-1 Reactome DB_ID: 191615 Reactome Database ID Release 43191615 Reactome, http://www.reactome.org ReactomeREACT_10187 has a Stoichiometric coefficient of 1 Cx43:ZO-1:c-src gap junction Reactome DB_ID: 191653 Reactome Database ID Release 43191653 Reactome, http://www.reactome.org ReactomeREACT_10511 has a Stoichiometric coefficient of 2 Cx43:ZO-1 hemi-channel Reactome DB_ID: 191641 Reactome Database ID Release 43191641 Reactome, http://www.reactome.org ReactomeREACT_10534 has a Stoichiometric coefficient of 6 phospho-Y265 Cx43:ZO-1 gap junction Reactome DB_ID: 191645 Reactome Database ID Release 43191645 Reactome, http://www.reactome.org ReactomeREACT_10386 has a Stoichiometric coefficient of 12 has a Stoichiometric coefficient of 2 Cx43:ZO-1:c-src hemi-channel Reactome DB_ID: 191644 Reactome Database ID Release 43191644 Reactome, http://www.reactome.org ReactomeREACT_10179 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 phospho-Y265 Cx43:ZO-1:c-src hemi-channel Reactome DB_ID: 191634 Reactome Database ID Release 43191634 Reactome, http://www.reactome.org ReactomeREACT_10822 has a Stoichiometric coefficient of 6 Alpha-defensins Converted from EntitySet in Reactome Reactome DB_ID: 1471333 Reactome Database ID Release 431471333 Reactome, http://www.reactome.org ReactomeREACT_117503 Transport (efflux) of bile salts by ABCB11 (bile salt export pump) A molecule of glycocholate, glycochenodeoxycholate, taurocholate, or taurochenodeoxycholate is transported from the cytosol to the extracellular space, coupled to the hydrolysis of a molecule of cytosolic ATP to ADP and orthophosphate. This reaction is mediated by ABCB11 (bile salt export pump). In the body, this reaction mediates the release of bile salts from the liver cells into the bile (Kullak-Ublick et al. 2004); the role of ABCB11 in the reaction is confirmed by the observed failure of bile salt export in patients in whom the transporter is defective (Noe et al. 2005). Authored: D'Eustachio, P, 2007-02-17 19:40:28 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12404239 Pubmed12404240 Pubmed14699511 Pubmed16039748 Reactome Database ID Release 43193362 Reactome, http://www.reactome.org ReactomeREACT_10101 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Hemi-channels Converted from EntitySet in Reactome Reactome DB_ID: 196163 Reactome Database ID Release 43196163 Reactome, http://www.reactome.org ReactomeREACT_10174 Trypsin 2, 3 Converted from EntitySet in Reactome Reactome DB_ID: 1460242 Reactome Database ID Release 431460242 Reactome, http://www.reactome.org ReactomeREACT_117709 Cholesterol is hydroxylated to 24-hydroxycholesterol by CYP46A1 Authored: Jassal, B, 2008-05-19 12:57:01 Cholesterol, NADPH + H+, and O2 react to form 24-hydroxycholesterol , NADP+, and H2O. This reaction is catalyzed by CYP46A1 in the endoplasmic reticulum membrane. In the body, this enzyme is expressed predominantly in the brain and is thought to play a major role in cholesterol turnover there (Javitt 2002). EC Number: 1.14.13.98 Edited: D'Eustachio, P, 2007-04-30 14:43:26 Pubmed10377398 Pubmed11969205 Pubmed14640697 Reactome Database ID Release 43192061 Reactome, http://www.reactome.org ReactomeREACT_10129 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 cholesterol + NADPH + H+ + O2 => 24-hydroxycholesterol + NADP+ + H2O Connexin 43 hemi-channel Reactome DB_ID: 196166 Reactome Database ID Release 43196166 Reactome, http://www.reactome.org ReactomeREACT_10477 has a Stoichiometric coefficient of 6 Efflux of 24-hydroxycholesterol 24-hydroxycholesterol is transported from the endoplasmic reticulum to the extracellular space. In humans, this event is the major source of 24-hydroxycholesterol in the blood and is the means by which the molecule, generated from cholesterol in the brain, is transported to the liver for conversion to bile acids and bile salts. While transport proteins are likely to play a role in this process, and the 24-hydroxycholesterol is likely to occur as part of a lipoprotein complex in the blood, the relevant proteins have not been identified (Lutjohann et al. 1996; Bjorkhem et al. 1998). Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed8790411 Pubmed9717719 Reactome Database ID Release 43193776 Reactome, http://www.reactome.org ReactomeREACT_10099 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Clathrin Reactome DB_ID: 196154 Reactome Database ID Release 43196154 Reactome, http://www.reactome.org ReactomeREACT_10280 has a Stoichiometric coefficient of 1 Influx of 24-hydroxycholesterol 24-hydroxycholesterol is transported from the extracellular space to the endoplasmic reticulum. In humans, this event is the means by which the molecule, generated from cholesterol in the brain, is taken up by liver cells for conversion to bile acids and bile salts. While transport proteins are likely to play a role in this process, these proteins have not been identified (Lutjohann et al. 1996; Bjorkhem et al. 1998). Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed8790411 Pubmed9717719 Reactome Database ID Release 43193767 Reactome, http://www.reactome.org ReactomeREACT_9979 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 24-hydroxycholesterol is 7alpha-hydroxylated to yield cholest-5-ene-3beta,7alpha,24-triol 24-hydroxycholesterol + NADPH + H+ + O2 => cholest-5-ene-3beta,7alpha,24-triol + NADP+ + H2O 24-hydroxycholesterol, NADPH + H+, and O2 react to form cholest-5-ene-3beta,7alpha,24-triol, NADP+, and H2O. This hydroxylation reaction is catalyzed by CYP39A1 in the membrane of the endoplasmic reticulum. In the body, expression of CYP39A1 is restricted to the liver. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: D'Eustachio, P, 2007-04-30 14:43:26 Pubmed10748047 Reactome Database ID Release 43192178 Reactome, http://www.reactome.org ReactomeREACT_10066 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Cholest-5-ene-3beta,7alpha,24(S)-triol + NAD+ => 4-cholesten-7alpha,24(S)-diol-3-one + NADH + H+ Authored: D'Eustachio, P, 2007-02-23 20:35:09 Cholest-5-ene-3beta,7alpha,24(S)-triol and NAD+ react to form 4-cholesten-7alpha,24(S)-diol-3-one and NADH + H+, catalyzed by HSD3B7 (3 beta-hydroxysteroid dehydrogenase type 7) in the endoplasmic reticulum membrane. Its function in vivo has been confirmed in studies of patients with defects in bile acid synthesis (Schwarz et al. 2000). Cholest-5-ene-3beta,7alpha,24(S)-triol is oxidized and isomerized to 4-cholesten-7alpha,24(S)-diol-3-one EC Number: 1.1.1.145 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed11067870 Pubmed12679481 Reactome Database ID Release 43193789 Reactome, http://www.reactome.org ReactomeREACT_10090 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 4-Cholesten-7alpha,24(S)-diol-3-one is 12alpha-hydroxylated to 4-cholesten-7-alpha,12-alpha,24(S)-triol-3-one 4-Cholesten-7alpha,24(S)-diol-3-one + NADPH + H+ + O2 => 4-cholesten-7-alpha,12-alpha,24(S)-triol-3-one + NADP+ + H2O 4-Cholesten-7alpha,24(S)-diol-3-one, NADPH + H+, and O2 form 4-cholesten-7-alpha,12-alpha,24(S)-triol-3-one + NADP+ + H2O. This reaction is catalyzed by sterol 12alpha hydroxylase (CYP8B1), an enzyme associated with the endoplasmic reticulum membrane. While the human gene has been cloned (Gafvels et al. 1999), its protein product has not been characterized, and the enzymatic properties of human CYP8B1 protein are inferred from those of its well-characterized rabbit homolog (Ishida et al. 1992). Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.14.13.95 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed10051404 Pubmed1400444 Reactome Database ID Release 43193709 Reactome, http://www.reactome.org ReactomeREACT_10016 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 4-cholesten-7alpha,12alpha,24(S)-triol-3-one is reduced to 5beta-cholestan-7alpha,12alpha,24(S)-triol-3-one 4-cholesten-7alpha,12alpha,24(S)-triol-3-one + NADPH + H+ => 5beta-cholestan-7alpha,12alpha,24(S)-triol-3-one + NADP+ 4-cholesten-7alpha,12alpha,24(S)-triol-3-one and NADPH + H+ react to form 5beta-cholesten-7alpha,12alpha,24(S)-triol-3-one and NADP+. This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). AKR1D1 is localized to the cytosol, and in the course of the reaction its steroid substrate moves from the endoplasmic reticulum membrane to the cytosol. It is unclear whether this translocation results simply from its increased hydrophilicity or is mediated by the enzyme or another transport protein (Russell 2003). Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed12543708 Pubmed7508385 Reactome Database ID Release 43193755 Reactome, http://www.reactome.org ReactomeREACT_10131 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 4-cholesten-7alpha,24(S)-diol-3-one is reduced to 5beta-cholestan-7alpha,24(S)-diol-3-one 4-Cholesten-7alpha,24(S)-diol-3-one, NADPH, and H+ react to form 5beta-cholestan-7alpha,24(S)-diol-3-one and NADP+. This reaction is catalyzed by AKR1D1 (3-oxo-5-beta-steroid 4-dehydrogenase). AKR1D1 is localized to the cytosol, and in the course of the reaction its steroid substrate moves from the endoplasmic reticulum membrane to the cytosol. It is unclear whether this translocation results simply from its increased hydrophilicity or is mediated by the enzyme or another transport protein (Russell 2003). 4-cholesten-7alpha,24(S)-diol-3-one + NADPH + H+ => 5beta-cholestan-7alpha,24(S)-diol-3-one + NADP+ Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed12543708 Pubmed7508385 Reactome Database ID Release 43193746 Reactome, http://www.reactome.org ReactomeREACT_10086 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5Beta-cholestan-7alpha,12alpha,24(S)-triol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol 5Beta-cholestan-7alpha,12alpha,24(S)-triol-3-one + NADPH + H+ => 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol + NAPDP+ 5Beta-cholesten-7alpha,12alpha,24(S)-triol-3-one and NADPH + H+ form 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol and NAPDP+. The reaction is catalyzed by 3alpha-hydroxysteroid dehydrogenase (AKR1C4), a cytosolic enzyme belonging to the aldo-keto reductase family (Dufort et al. 2001). Biochemical studies with rat proteins raise the possibility that other related enzymes may also carry out this reaction in vivo (Russell 2003). Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed11158055 Pubmed12543708 Reactome Database ID Release 43193781 Reactome, http://www.reactome.org ReactomeREACT_10044 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 THCA is conjugated with Coenzyme A (SLC27A2 VLCS) Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10479480 Pubmed10749848 Pubmed11980911 Reactome Database ID Release 43193401 Reactome, http://www.reactome.org ReactomeREACT_10049 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 THCA (25(R) 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate), coenzyme A, and ATP react to form the CoA conjugate of 25(R) THCA, AMP, and pyrophosphate. This cytosolic reaction is catalyzed by SLC27A2 (VLCS). SLC27A5 (BACS) also catalyzes this reaction; the relative contributions of the two enzymes to de novo bile acid synthesis in vivo are not certain (Mihalik et al. 2002). THCA + ATP + CoASH => 25(R) THCA-CoA + AMP + pyrophosphate (SLC27A2 "VLCS") Connexin 32 connexon Reactome DB_ID: 190647 Reactome Database ID Release 43190647 Reactome, http://www.reactome.org ReactomeREACT_9765 has a Stoichiometric coefficient of 6 DHCA [mitochondrial matrix] => DHCA [cytosol] Authored: Jassal, B, 2007-01-19 10:34:59 DHCA (3alpha, 7alpha-dihydroxy-5beta-cholestanoate) is translocated from the mitochondrial matrix to the cytosol. The transporter that mediates its passage across the inner mitochondrial membrane has not been identified. In particular, despite the structural and functional similarities between DHCA and long chain fatty acids, searches for carnitine - DHCA have failed (Russell 2003). VLCS (SLC27A2), one of the enzymes that catalyzes CoA conjugation of DHCA, may also be present in peroxisomes, and Mihalik et al. (2002) have hypothesized that DHCA could be translocated unchanged from the mitochondrial matrix to the peroxisomal matrix and undergo conjugation there. DHCA is translocated from the mitochondrial matrix to the cytosol Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed11980911 Pubmed12543708 Reactome Database ID Release 43193519 Reactome, http://www.reactome.org ReactomeREACT_10107 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Vamp8:SNAP23:Syn4 Secretory granule docking and fusion complex Reactome DB_ID: 376367 Reactome Database ID Release 43376367 Reactome, http://www.reactome.org ReactomeREACT_15240 has a Stoichiometric coefficient of 1 Vamp7:SNAP23:Syn4 Plasma membrane vesicle docking and fusion complex Reactome DB_ID: 376340 Reactome Database ID Release 43376340 Reactome, http://www.reactome.org ReactomeREACT_14917 has a Stoichiometric coefficient of 1 Vamp2:SNAP23:Syn4 Secretory granule docking and fusion complex Reactome DB_ID: 376372 Reactome Database ID Release 43376372 Reactome, http://www.reactome.org ReactomeREACT_15108 has a Stoichiometric coefficient of 1 AP-1 Complex Reactome DB_ID: 432702 Reactome Database ID Release 43432702 Reactome, http://www.reactome.org ReactomeREACT_20476 has a Stoichiometric coefficient of 1 Lysosome Cargo:AP-1:Beta-arrestin:Clathrin Triskelion:Vamp Complex Reactome DB_ID: 432691 Reactome Database ID Release 43432691 Reactome, http://www.reactome.org ReactomeREACT_19609 has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 52 Lysosome Destined Cargo:AP-1:beta-Arrestin-1:Vamp Complex Reactome DB_ID: 432687 Reactome Database ID Release 43432687 Reactome, http://www.reactome.org ReactomeREACT_19991 has a Stoichiometric coefficient of 1 Lysosome Destined Cargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin Complex Reactome DB_ID: 432704 Reactome Database ID Release 43432704 Reactome, http://www.reactome.org ReactomeREACT_20224 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 52 Lysosome Destined Cargo:AP-1:Arf1-GTP:beta-Arrestin-1:Vamp Complex Reactome DB_ID: 432700 Reactome Database ID Release 43432700 Reactome, http://www.reactome.org ReactomeREACT_19668 has a Stoichiometric coefficient of 1 AP-1 Complex Reactome DB_ID: 351186 Reactome Database ID Release 43351186 Reactome, http://www.reactome.org ReactomeREACT_14951 has a Stoichiometric coefficient of 1 Trimerization of the FASL:FAS receptor complex Pubmed8521815 Reactome Database ID Release 4371050 Reactome, http://www.reactome.org ReactomeREACT_606 The complex of FASL (FAS antigen ligand) and FAS receptor (CD95) trimerizes (Kischkel et al. 1995). has a Stoichiometric coefficient of 3 Defective GUSB does not hydrolyse glucuronate Authored: Jassal, B, 2012-06-13 Defects in beta-glucuronidase (GUSB; MIM:611499) cause mucopolysaccharidosis type VII (MPS VII, Sly syndrome, beta-glucuronidase deficiency; MIM:253220), an autosomal recessive lysosomal storage disease. Mutations causing severe forms of the disease are R356* (Shipley et al. 1993), A354V and R611W (Wu & Sly 1993), S52F (Vervoot et al. 1997) and R216W (Vervoort et al. 1996). Edited: Jassal, B, 2012-06-13 Pubmed7680524 Pubmed8111413 Pubmed8644704 Pubmed9099834 Reactome Database ID Release 432318373 Reactome, http://www.reactome.org ReactomeREACT_147741 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Defective HYAL1 does not hydrolyse 1-4-linkages between GlcNAc and GlcA Authored: Jassal, B, 2012-06-14 Defects in hyaluronidase 1 (HYAL1; MIM:607071) cause mucopolysaccharidosis type IX (MPS IX, Natowicz syndrome, Hyaluronidase deficiency, MIM:601492), a rare lysosomal storage disease. Triggs-Raine et al. identified a patient with two mutations in HYAL1 alleles, a nonconservative amino acid substitution (Glu268Lys) and a complex intragenic rearrangement (1361del37ins14) that results in a premature termination codon (Triggs-Raine et al. 1999). Edited: Jassal, B, 2012-06-14 Pubmed10339581 Reactome Database ID Release 432318585 Reactome, http://www.reactome.org ReactomeREACT_147837 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Smad7:SMURF1 complex translocates to the cytosol Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed12519765 Reactome Database ID Release 432169016 Reactome, http://www.reactome.org ReactomeREACT_121294 Reviewed: Huang, Tao, 2012-05-14 XPO1 (CRM1) bound to Smad7:SMURF1 complex enables translocation of Smad1:SMURF1 to the cytosol. In this study, recombinant human SMURF1, recombinant mouse Smad7 and recombinant XPO1 (species not specified, assumed to be human) were exogenously expressed in COS7 cells (Tajima et al. 2003). FASL binds FAS Receptor FASL (FAS antigen ligand) binds FAS receptor (CD95) (Brunner et al. 1995). GENE ONTOLOGYGO:0008624 Pubmed7530336 Reactome Database ID Release 4375244 Reactome, http://www.reactome.org ReactomeREACT_1426 Defective GNS does not hydrolyse 6-sulfate from GlcNAc6S Authored: Jassal, B, 2012-05-21 Defective GNS does not hydrolyse 6-sulfate from N-acetylglucosamine 6-sulfate of KS Due to the rarity of this disease, only approximately 20 mutations had been described. Recently a study by Valstar et al. revealed 15 of those mutations (Valstar et al. 2010). The group also conducted a literature survey of MPS IIID (MIM:252940). Mutations include R355X (Mok et al. 2003), Q390X (Jansen et al. 2007), Q272X (Beesley et al. 2007) and S94I (Valstar et al. 2010). Other mutations are not detailed here but can be referenced in the Valstar et al. review (Valstar et al. 2010). Edited: Jassal, B, 2012-05-21 Pubmed12573255 Pubmed16990043 Pubmed17998446 Pubmed20232353 Reactome Database ID Release 432263495 Reactome, http://www.reactome.org ReactomeREACT_147865 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 3alpha, 7alpha-dihydroxy-5beta-cholestan-26-al is oxidized to 3alpha, 7alpha-dihydroxy-5beta-cholestanoate (DHCA) 3alpha, 7alpha-dihydroxy-5beta-cholestan-26-al + NADPH + H+ + O2 => 3alpha, 7alpha-dihydroxy-5beta-cholestanoate (DHCA) + NADP+ + H2O 3alpha, 7alpha-dihydroxy-5beta-cholestan-26-al, NADPH + H+, and O2 react to form 3alpha, 7alpha-dihydroxy-5beta-cholestanoate (DHCA), NADP+ and H2O. This oxidation reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed1708392 Pubmed9660774 Reactome Database ID Release 43193460 Reactome, http://www.reactome.org ReactomeREACT_10005 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Defensins alpha 1-3 Converted from EntitySet in Reactome Reactome DB_ID: 1471337 Reactome Database ID Release 431471337 Reactome, http://www.reactome.org ReactomeREACT_117767 Defective GALNS does not hydrolyse sulfate from Gal6S Authored: Jassal, B, 2012-05-21 Defective GALNS does not hydrolyse sulfate from galactose 6-sulfate in KS Edited: Jassal, B, 2012-05-21 From a recent review of mutations for MPSIVA (MIM:253000) (Tomatsu et al. 2005), almost 80% of mutations in N-acetylgalactosamine 6-sulfatase (GALNS; MIM:612222) were missense mutations and of these, the most common ones are R386C, G301C and I113F. Pubmed16287098 Reactome Database ID Release 432263490 Reactome, http://www.reactome.org ReactomeREACT_147848 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 THCA [mitochondrial matrix] => THCA [cytosol] Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed11980911 Pubmed12543708 Reactome Database ID Release 43191971 Reactome, http://www.reactome.org ReactomeREACT_10089 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 THCA (3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate) is translocated from the mitochondrial matrix to the cytosol. The transporter that mediates its passage across the inner mitochondrial membrane has not been identified. In particular, despite the structural and functional similarities between THCA and long chain fatty acids, searches for carnitine - THCA have failed (Russell 2003). VLCS (SLC27A2), one of the enzymes that catalyzes CoA conjugation of THCA may also be present in peroxisomes, and Mihalik et al. (2002) have hypothesized that THCA could be translocated unchanged from the mitochondrial matrix to the peroxisomal matrix and undergo conjugation there. THCA is translocated from the mitochondrial matrix to the cytosol Defective GLB1 does not hydrolyse Gal Authored: Jassal, B, 2012-05-21 Defective GLB1 does not hydrolyse galactose from KS or GAG linker chain Defects in beta-galactosidase (GLB1, MIM:611458) result in galactose moieties not being hydrolysed from keratan sulfate (KS) or the GAG linker chain, a tetrasccharide sequence required for some GAG biosyntheses to take place. Mucopolysaccharidosis IV B (MPSIVB, Morquio's syndrome B; MIM:253010) is the result of GLB1 deficiency.<br>GLB1 mutations causing severe phenotypes are R482C (Ishii et al. 1995), W509C (Oshima et al. 1991), Y83C (Santamaria et al. 2006) and W273L Paschke et al. 2001. Mild phenotypes where a partial loss of enzyme activity occurs can involve the mutants G438E, N484K, T500A (Bagshaw et al. 2002) and Y83H (Ishii et al. 1995). These mild phenotype mutants are not detailed here. Edited: Jassal, B, 2012-05-21 Pubmed11511921 Pubmed12393180 Pubmed16941474 Pubmed1928092 Pubmed7586649 Reactome Database ID Release 432265534 Reactome, http://www.reactome.org ReactomeREACT_147709 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 5beta-cholestan-3alpha, 7alpha, 26-triol is oxidized to 3alpha, 7alpha-dihydroxy-5beta-cholestan-26-al 5beta-cholestan-3alpha, 7alpha, 26-triol + NADP+ => 3alpha,7alpha-dihydroxy-5beta-cholestan-26-al + NADPH + H+ 5beta-cholestan-3alpha, 7alpha, 26-triol and NADP+ react to form 3alpha, 7alpha-dihydroxy-5beta-cholestan-26-al and NADPH + H+. This oxidation reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed1708392 Pubmed9660774 Reactome Database ID Release 43193497 Reactome, http://www.reactome.org ReactomeREACT_9960 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Defective ARSB does not hydrolyse sulfate from GalNAc4S Authored: Jassal, B, 2012-05-28 Defective ARSB does not hydrolyse sulfate from N-acetylgalactosamine 4-sulfate units of DS/CS Defects in arylsulfatase B (ARSB, N-acetylgalactosamine 4-sulfatase; MIM:611542) cause mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, polydystrophic dwarfism; MIM:253200), an autosomal recessive lysosomal storage disorder. Severe forms of the disease are caused by the ARSB mutations Y86del (Karageorgos et al. 2004), P116H (Villani et al. 1999), C117R (Jin et al. 1992), G144R (Isbrandt et al. 1994) and R95Q/H393P (Litjens et al. 1996). Edited: Jassal, B, 2012-05-28 Pubmed10036316 Pubmed14974081 Pubmed1550123 Pubmed8116615 Pubmed8651289 Reactome Database ID Release 432282889 Reactome, http://www.reactome.org ReactomeREACT_147883 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-27-al is oxidized to 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate (THCA) 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-27-al + NADPH + H+ + O2 => 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate (THCA) + NADP+ + H2O 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-27-al, NADPH + H+, and O2 react to form 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate (THCA), NADP+, and H2O. This oxidation reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed1708392 Pubmed9660774 Reactome Database ID Release 43192054 Reactome, http://www.reactome.org ReactomeREACT_10001 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Beta-defensins Converted from EntitySet in Reactome Reactome DB_ID: 1471310 Reactome Database ID Release 431471310 Reactome, http://www.reactome.org ReactomeREACT_116840 5beta-cholestan-3alpha, 7alpha-diol is hydroxylated to 5beta-cholestan-3alpha, 7alpha, 26-triol 5beta-cholestan-3alpha, 7alpha-diol + NADPH + H+ + O2 => 5beta-cholestan-3alpha, 7alpha, 26-triol + NADP+ + H2O 5beta-cholestan-3alpha, 7alpha-diol, NADPH + H+, and O2 react to form 5beta-cholestan-3alpha, 7alpha, 26-triol + NADP+ + H2O. This reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed1708392 Pubmed2019602 Pubmed9660774 Reactome Database ID Release 43193393 Reactome, http://www.reactome.org ReactomeREACT_10075 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Beta-defensins Converted from EntitySet in Reactome Reactome DB_ID: 975681 Reactome Database ID Release 43975681 Reactome, http://www.reactome.org ReactomeREACT_116972 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol is oxidized to 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-27-al 5beta-cholestan-3alpha, 7alpha, 12alpha, 27-tetrol and NADP+ react to form 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-27-al and NADPH + H+. This oxidation reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol + NADP+ => 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-27-al + NADPH + H+ Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed1708392 Pubmed9660774 Reactome Database ID Release 43192042 Reactome, http://www.reactome.org ReactomeREACT_10025 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5beta-cholestan-3alpha, 7alpha-diol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-3alpha, 7alpha-diol is transported from the cytosol to the mitochondrial matrix. The transporter that mediates its passage across the inner mitochondrial membrane is unknown: the StAR protein that performs this function for cholesterol at the start of steroid hormone biosynthesis is excluded as StAR is not expressed in liver. Other members of the START family of transporters are candidates, however (Russell 2003). Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12543708 Reactome Database ID Release 43193537 Reactome, http://www.reactome.org ReactomeREACT_10085 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Defective HGSNAT does not acetylate GlcN Authored: Jassal, B, 2012-05-21 Defective HGSNAT does not acetylate glucosamine from HS or heparan Edited: Jassal, B, 2012-05-21 Enzyme misfolding due to missense mutations results in incorrect glycosylation therefore HGSNAT is not targeted to the lysosome and stays in the ER (Feldhammer et al. 2009). This, together with mutations giving rise to nonsense-mediated mRNA decay (Fedele & Hopwood 2010), appear to be the major molecular mechanisms underlying MPSIIIC. More than 50 mutations are known in the HGSNAT gene. Some of them drastically reduce enzyme activity; W403C/A615T double mutant (Fedele & Hopwood 2010), R344C, S518F and R384X (Fedele et al. 2007, Ruijter et al.2008). Pubmed17397050 Pubmed18024218 Pubmed19823584 Pubmed20583299 Reactome Database ID Release 432263492 Reactome, http://www.reactome.org ReactomeREACT_147794 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 5beta-cholestan-3alpha, 7alpha, 12alpha-triol is hydroxylated to 5beta-cholestan-3alpha, 7alpha, 12alpha, 27-tetrol 5beta-cholestan-3alpha, 7alpha, 12alpha-triol + NADPH + H+ + O2 => 5beta-cholestan-3alpha, 7alpha, 12alpha, 27-tetrol + NADP+ + H2O 5beta-cholestan-3alpha, 7alpha, 12alpha-triol, NADPH + H+, and O2 react to form 5beta-cholestan-3alpha, 7alpha, 12alpha, 27-tetrol + NADP+ + H2O. This reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed1708392 Pubmed2019602 Pubmed9660774 Reactome Database ID Release 43191999 Reactome, http://www.reactome.org ReactomeREACT_10009 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA + H2O => (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA (THCA-CoA) is hydrated to (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA (THCA-CoA) is hydrated to form (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA. This reaction, catalyzed by the peroxisomal D-bifunctional enzyme (Huyghe et al. 2006), occurs in the peroxisomal matrix. Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 4.2.1.107 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed16766224 Pubmed8902629 Reactome Database ID Release 43192331 Reactome, http://www.reactome.org ReactomeREACT_10019 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Junctional channel Reactome DB_ID: 191068 Reactome Database ID Release 43191068 Reactome, http://www.reactome.org ReactomeREACT_10244 has a Stoichiometric coefficient of 2 Docked Cx43-containing transport vesicles Reactome DB_ID: 194780 Reactome Database ID Release 43194780 Reactome, http://www.reactome.org ReactomeREACT_10422 has a Stoichiometric coefficient of 1 connexons in Golgi transport vesicle docked to microtubules Reactome DB_ID: 190556 Reactome Database ID Release 43190556 Reactome, http://www.reactome.org ReactomeREACT_10450 has a Stoichiometric coefficient of 1 Hemi-channels Converted from EntitySet in Reactome Reactome DB_ID: 191070 Reactome Database ID Release 43191070 Reactome, http://www.reactome.org ReactomeREACT_10652 Connexin 43 hemi-channel Reactome DB_ID: 158053 Reactome Database ID Release 43158053 Reactome, http://www.reactome.org ReactomeREACT_10289 has a Stoichiometric coefficient of 6 Connexin 26 Connexon Reactome DB_ID: 190641 Reactome Database ID Release 43190641 Reactome, http://www.reactome.org ReactomeREACT_21620 has a Stoichiometric coefficient of 6 Connexin 43 connexon Reactome DB_ID: 190652 Reactome Database ID Release 43190652 Reactome, http://www.reactome.org ReactomeREACT_9901 has a Stoichiometric coefficient of 6 Connexin 43 connexon in Golgi transport vesicle Reactome DB_ID: 190583 Reactome Database ID Release 43190583 Reactome, http://www.reactome.org ReactomeREACT_10502 has a Stoichiometric coefficient of 6 Connexon 26 Reactome DB_ID: 112301 Reactome Database ID Release 43112301 Reactome, http://www.reactome.org ReactomeREACT_10376 has a Stoichiometric coefficient of 6 DHCA is conjugated with Coenzyme A (SLC27A2 VLCS) Authored: Jassal, B, 2007-01-19 10:34:59 DHCA (25(R) 3alpha,7alpha-dihydroxy-5beta-cholestanoate), coenzyme A, and ATP react to form the CoA conjugate of 25(R) DHCA, AMP, and pyrophosphate. This cytosolic reaction is catalyzed by SLC27A2 (VLCS). SLC27A5 (BACS) also catalyzes this reaction; the relative contributions of the two enzymes to de novo bile acid synthesis in vivo are not certain (Mihalik et al. 2002). DHCA + ATP + CoASH => 25(R) DHCA-CoA + AMP + pyrophosphate (SLC27A2 "VLCS") EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10479480 Pubmed10749848 Pubmed11980911 Reactome Database ID Release 43193424 Reactome, http://www.reactome.org ReactomeREACT_10119 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 Connexin 26:Connexin 32 connexon Reactome DB_ID: 190632 Reactome Database ID Release 43190632 Reactome, http://www.reactome.org ReactomeREACT_9762 has a Stoichiometric coefficient of 3 25(R) THCA-CoA => 25(S) THCA-CoA Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 5.1.99.4 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Isomerization of 25(R) THCA-CoA to 25(S) THCA-CoA Pubmed10655068 Pubmed11060344 Pubmed7649182 Reactome Database ID Release 43192056 Reactome, http://www.reactome.org ReactomeREACT_9998 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 The isomerization of 25(R) THCA-CoA to 25(S) THCA-CoA, catalyzed by 2-methylacyl-CoA racemase, occurs in the peroxisomal matrix. 25(R) DHCA-CoA => 25(S) DHCA-CoA Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 5.1.99.4 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Isomerization of 25(R) DHCA-CoA to 25(S) DHCA-CoA Pubmed10655068 Pubmed11060344 Pubmed7649182 Reactome Database ID Release 43193452 Reactome, http://www.reactome.org ReactomeREACT_10047 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 The isomerization of 25(R) DHCA-CoA to 25(S) DHCA-CoA, catalyzed by 2-methylacyl-CoA racemase, occurs in the peroxisomal matrix. 25(S) THCA-CoA + O2 => THCA-CoA + H2O2 25(S) THCA-CoA and O2 react to form 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA (THCA-CoA) and H2O2. This dehydrogenation reaction occurs in the peroxisomal matrix. It is catalyzed by the FAD-containing peroxisomal enzyme branched chain acyl-CoA oxidase (ACOX2). The enzyme transfers electrons to molecular oxygen and hydrogen peroxide is produced as a byproduct. 25(S) THCA-CoA is dehydrogenated to 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA (THCA-CoA) Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 1.3.3.6 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed8387517 Pubmed8943006 Reactome Database ID Release 43192335 Reactome, http://www.reactome.org ReactomeREACT_10074 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 25(S) DHCA-CoA + O2 => 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA + H2O2 25(S) DHCA-CoA and O2 react to form 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA and H2O2. This dehydrogenation reaction occurs in the peroxisomal matrix. It is catalyzed by the FAD-containing peroxisomal enzyme branched chain acyl-CoA oxidase (ACOX2). The enzyme transfers electrons to molecular oxygen and hydrogen peroxide is produced as a byproduct. 25(S) DHCA-CoA is dehydrogenated to 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 1.3.3.6 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed8387517 Pubmed8943006 Reactome Database ID Release 43193369 Reactome, http://www.reactome.org ReactomeREACT_10003 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 THCA is conjugated with Coenzyme A (SLC27A5 BACS) Authored: Jassal, B, 2007-01-19 10:34:59 EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10479480 Pubmed10749848 Pubmed11980911 Reactome Database ID Release 43192137 Reactome, http://www.reactome.org ReactomeREACT_10020 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 THCA (25(R) 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate) , coenzyme A, and ATP react to form the CoA conjugate of 25(R) THCA, AMP, and pyrophosphate. This cytosolic reaction is catalyzed by SLC27A5 (BACS). SLC27A2 (VLCS) also catalyzes this reaction; the relative contributions of the two enzymes to de novo bile acid synthesis in vivo are not certain (Mihalik et al. 2002). THCA + ATP + CoASH => 25(R) THCA-CoA + AMP + pyrophosphate (SCLS25A5 "BACS") DHCA is conjugated with Coenzyme A (SLC27A5 BACS) Authored: Jassal, B, 2007-01-19 10:34:59 DHCA (25(R) 3alpha,7alpha-dihydroxy-5beta-cholestanoate) , coenzyme A, and ATP react to form the CoA conjugate of 25(R) DHCA, AMP, and pyrophosphate. This cytosolic reaction is catalyzed by SLC27A5 (BACS). SLC27A2 (VLCS) also catalyzes this reaction; the relative contributions of the two enzymes to de novo bile acid synthesis in vivo are not certain (Mihalik et al. 2002). DHCA + ATP + CoASH => 25(R) DHCA-CoA + AMP + pyrophosphate (SCLS25A5 "BACS") EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed10479480 Pubmed10749848 Pubmed11980911 Reactome Database ID Release 43193407 Reactome, http://www.reactome.org ReactomeREACT_10064 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 25(R) THCA-CoA [ cytosol] => 25(R) THCA-CoA [peroxisome] 25(R) THCA-CoA is translocated from the cytosol to the peroxisome 25(R) THCA-CoA is transported from the cytosol into the peroxisome. Indirect evidence suggests that a member of the ABC class of transporters mediates this reaction. Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12543708 Pubmed12966071 Reactome Database ID Release 43192325 Reactome, http://www.reactome.org ReactomeREACT_10105 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 25(R) DHCA-CoA [ cytosol] => 25(R) DHCA-CoA [peroxisome] 25(R) DHCA-CoA is translocated from the cytosol to the peroxisome 25(R) DHCA-CoA is transported from the cytosol into the peroxisome. Indirect evidence suggests that a member of the ABC class of transporters mediates this reaction. Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 Pubmed12543708 Pubmed12966071 Reactome Database ID Release 43193482 Reactome, http://www.reactome.org ReactomeREACT_10012 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 CERBERUS:NODAL Reactome DB_ID: 1181341 Reactome Database ID Release 431181341 Reactome, http://www.reactome.org ReactomeREACT_111457 has a Stoichiometric coefficient of 1 LEFTY:NODAL Reactome DB_ID: 1181340 Reactome Database ID Release 431181340 Reactome, http://www.reactome.org ReactomeREACT_111269 has a Stoichiometric coefficient of 1 PPARG:RXRA:Corepressor Complex Reactome DB_ID: 381226 Reactome Database ID Release 43381226 Reactome, http://www.reactome.org ReactomeREACT_27552 has a Stoichiometric coefficient of 1 FABP4:Ligands of PPARG Reactome DB_ID: 2026090 Reactome Database ID Release 432026090 Reactome, http://www.reactome.org ReactomeREACT_119193 has a Stoichiometric coefficient of 1 LEFTY:EGF-CFC:NODAL Receptor LEFTY:EGF-CFC Coreceptor Complex in the NODAL Receptor Reactome DB_ID: 1181346 Reactome Database ID Release 431181346 Reactome, http://www.reactome.org ReactomeREACT_111462 has a Stoichiometric coefficient of 1 ARF6 Complex PPARG:RXRA Heterodimer Peroxisome proliferator-activated receptor:retinoic acid receptor heterodimer Reactome DB_ID: 381281 Reactome Database ID Release 43381281 Reactome, http://www.reactome.org ReactomeREACT_27328 has a Stoichiometric coefficient of 1 Coatomer Reactome DB_ID: 199996 Reactome Database ID Release 43199996 Reactome, http://www.reactome.org ReactomeREACT_11329 has a Stoichiometric coefficient of 1 Coatomer:Arf1-GTP Complex Reactome DB_ID: 200463 Reactome Database ID Release 43200463 Reactome, http://www.reactome.org ReactomeREACT_11791 has a Stoichiometric coefficient of 1 Arf1-GDP Reactome DB_ID: 199988 Reactome Database ID Release 43199988 Reactome, http://www.reactome.org ReactomeREACT_11263 has a Stoichiometric coefficient of 1 Arf1-GTP Reactome DB_ID: 199981 Reactome Database ID Release 43199981 Reactome, http://www.reactome.org ReactomeREACT_11673 has a Stoichiometric coefficient of 1 PathwayStep4699 PathwayStep4698 PathwayStep4694 PathwayStep4695 Coatomer:Arf1-GTP:GAP Complex Reactome DB_ID: 200466 Reactome Database ID Release 43200466 Reactome, http://www.reactome.org ReactomeREACT_11350 has a Stoichiometric coefficient of 1 PathwayStep4696 Arf1-GDP Reactome DB_ID: 201340 Reactome Database ID Release 43201340 Reactome, http://www.reactome.org ReactomeREACT_11922 has a Stoichiometric coefficient of 1 PathwayStep4697 BLOC-1 Complex Reactome DB_ID: 429825 Reactome Database ID Release 43429825 Reactome, http://www.reactome.org ReactomeREACT_19646 has a Stoichiometric coefficient of 1 PathwayStep4690 Cargo:AP-1:Arf1-GTP:beta-Arrestin-1:Vamp Complex Reactome DB_ID: 432669 Reactome Database ID Release 43432669 Reactome, http://www.reactome.org ReactomeREACT_20036 has a Stoichiometric coefficient of 1 PathwayStep4691 AP-1 Complex Reactome DB_ID: 350811 Reactome Database ID Release 43350811 Reactome, http://www.reactome.org ReactomeREACT_14976 has a Stoichiometric coefficient of 1 PathwayStep4692 Clathrin Triskelion Reactome DB_ID: 350827 Reactome Database ID Release 43350827 Reactome, http://www.reactome.org ReactomeREACT_15049 has a Stoichiometric coefficient of 3 PathwayStep4693 Cargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin Complex Reactome DB_ID: 350825 Reactome Database ID Release 43350825 Reactome, http://www.reactome.org ReactomeREACT_14893 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 52 Cargo:AP-1:beta-Arrestin-1:Vamp Complex Reactome DB_ID: 432677 Reactome Database ID Release 43432677 Reactome, http://www.reactome.org ReactomeREACT_19464 has a Stoichiometric coefficient of 1 HSC70:Auxillin Complex Reactome DB_ID: 351175 Reactome Database ID Release 43351175 Reactome, http://www.reactome.org ReactomeREACT_15197 has a Stoichiometric coefficient of 1 Cargo:AP-1:Beta-arrestin:Clathrin Triskelion:Vamp Complex Reactome DB_ID: 351198 Reactome Database ID Release 43351198 Reactome, http://www.reactome.org ReactomeREACT_15080 has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 52 Beta defensins 1,4A,103 Converted from EntitySet in Reactome Reactome DB_ID: 1973976 Reactome Database ID Release 431973976 Reactome, http://www.reactome.org ReactomeREACT_117380 acyl-GPI (ethanolamineP) mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI Converted from EntitySet in Reactome Reactome DB_ID: 162704 Reactome Database ID Release 43162704 Reactome, http://www.reactome.org ReactomeREACT_5055 PathwayStep4688 (ethanolamineP) mannose (a1-2) (ethanolamineP) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI Reactome DB_ID: 162799 Reactome Database ID Release 43162799 Reactome, http://www.reactome.org ReactomeREACT_4577 Beta defensins 4A,103 Converted from EntitySet in Reactome Reactome DB_ID: 1973973 Reactome Database ID Release 431973973 Reactome, http://www.reactome.org ReactomeREACT_117302 PathwayStep4687 PathwayStep4689 PathwayStep4681 Netrin-3:Neogenin Reactome DB_ID: 448880 Reactome Database ID Release 43448880 Reactome, http://www.reactome.org ReactomeREACT_21427 has a Stoichiometric coefficient of 1 PathwayStep4682 CDO:BOC:Neogenin:Netrin-3 Reactome DB_ID: 375091 Reactome Database ID Release 43375091 Reactome, http://www.reactome.org ReactomeREACT_22053 has a Stoichiometric coefficient of 1 phospho p38:phospho MEF2 Reactome DB_ID: 448874 Reactome Database ID Release 43448874 Reactome, http://www.reactome.org ReactomeREACT_21504 has a Stoichiometric coefficient of 1 PathwayStep4680 MyoD:phospho-E:phospho MEF2 Reactome DB_ID: 448877 Reactome Database ID Release 43448877 Reactome, http://www.reactome.org ReactomeREACT_21758 has a Stoichiometric coefficient of 1 PathwayStep4685 PathwayStep4686 PathwayStep4683 PathwayStep4684 ALK4:ActRII:EGF-CFC ACVR1B:ACVR2:EGF-CFC Reactome DB_ID: 1181132 Reactome Database ID Release 431181132 Reactome, http://www.reactome.org ReactomeREACT_111648 has a Stoichiometric coefficient of 2 ALK7:ActRIIB:EGF-CFC ACVR1C:ACVR2B:EGF-CFC Reactome DB_ID: 1181141 Reactome Database ID Release 431181141 Reactome, http://www.reactome.org ReactomeREACT_111835 has a Stoichiometric coefficient of 2 Defensins that bind Lipid II Converted from EntitySet in Reactome Reactome DB_ID: 1973970 Reactome Database ID Release 431973970 Reactome, http://www.reactome.org ReactomeREACT_117409 NODAL:GDF1 Reactome DB_ID: 1226022 Reactome Database ID Release 431226022 Reactome, http://www.reactome.org ReactomeREACT_111795 has a Stoichiometric coefficient of 1 NODAL Receptor Converted from EntitySet in Reactome Reactome DB_ID: 1181125 Reactome Database ID Release 431181125 Reactome, http://www.reactome.org ReactomeREACT_111355 NODAL Ligands (Agonists) Converted from EntitySet in Reactome Reactome DB_ID: 1226027 Reactome Database ID Release 431226027 Reactome, http://www.reactome.org ReactomeREACT_111841 NODAL Dimer Reactome DB_ID: 1181130 Reactome Database ID Release 431181130 Reactome, http://www.reactome.org ReactomeREACT_111583 has a Stoichiometric coefficient of 2 TetraHCA [mitochondrial matrix] => TetraHCA [cytosol] Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed11980911 Pubmed12543708 Reactome Database ID Release 43193722 Reactome, http://www.reactome.org ReactomeREACT_10073 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 TetraHCA (3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestanoate) is translocated from the mitochondrial matrix to the cytosol. The transporter that mediates its passage across the inner mitochondrial membrane has not been identified (Russell 2003). VLCS (SLC27A2), one of the enzymes that catalyzes CoA conjugation of TetraHCA, may also be present in peroxisomes, and Mihalik et al. (2002) have hypothesized that TetraHCA could be translocated unchanged from the mitochondrial matrix to the peroxisomal matrix and undergo conjugation there. TetraHCA is translocated from the mitochondrial matrix to the cytosol 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestan-27-al is oxidized to 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestanoate (3,7,24THCA) 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestan-27-al + NADPH + H+ + O2 => 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestanoate (3,7,24THCA) + NADP+ + H2O 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestan-27-al, NADPH + H+, and O2 react to form 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestanoate (3,7,24THCA), NADP+, and H2O. This oxidation reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed1708392 Pubmed9660774 Reactome Database ID Release 43193737 Reactome, http://www.reactome.org ReactomeREACT_9988 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestan-27-al is oxidized to 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestanoate (TetraHCA) 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestan-27-al + NADPH + H+ + O2 => 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestanoate (TetraHCA) + NADP+ + H2O 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestan-27-al, NADPH + H+, and O2 react to form 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestanoate (TetraHCA), NADP+, and H2O. This oxidation reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed1708392 Pubmed9660774 Reactome Database ID Release 43193713 Reactome, http://www.reactome.org ReactomeREACT_10100 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5beta-cholestan-3alpha,7alpha,24(S),27-tetrol is oxidized to 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestan-27-al 5beta-cholestan-3alpha,7alpha,24(S),27-tetrol + NADPH + H+ + O2 => 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestan-27-al + NADP+ + H2O 5beta-cholestan-3alpha,7alpha,24(S),27-tetrol, NADPH + H+, and O2 react to form 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestan-27-al, NADP+, and H2O. This oxidation reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed1708392 Pubmed9660774 Reactome Database ID Release 43193719 Reactome, http://www.reactome.org ReactomeREACT_9976 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5beta-cholestan-3alpha,7alpha,12alpha,24(S),27-pentol is oxidized to 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestan-27-al 5beta-cholestan-3alpha,7alpha,12alpha,24(S),27-pentol + NADPH + H+ + O2 => 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestan-27-al + NADP+ + H2O 5beta-cholestan-3alpha,7alpha,12alpha,24(S),27-pentol, NADPH + H+, and O2 react to form 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestan-27-al, NADP+, and H2O. This oxidation reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed1708392 Pubmed9660774 Reactome Database ID Release 43193780 Reactome, http://www.reactome.org ReactomeREACT_10042 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 5beta-cholestan-3alpha,7alpha,24(S)-triol is hydroxylated to 5beta-cholestan-3alpha,7alpha,24(S), 27-tetrol 5beta-cholestan-3alpha,7alpha,24(S)-triol + NADPH + H+ + O2 => 5beta-cholestan-3alpha,7alpha,24(S),27-tetrol + NADP+ + H2O 5beta-cholestan-3alpha,7alpha,24(S)-triol, NADPH + H+, and O2 react to form 5beta-cholestan-3alpha,7alpha,24(S),27-tetrol, NADP+, and H2O. This reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed1708392 Pubmed2019602 Pubmed9660774 Reactome Database ID Release 43193792 Reactome, http://www.reactome.org ReactomeREACT_10096 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4679 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol is hydroxylated to 5beta-cholestan-3alpha,7alpha,12alpha,24(S), 27-pentol 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol + NADPH + H+ + O2 => 5beta-cholestan-3alpha,7alpha,12alpha,24(S),27-pentol + NADP+ + H2O 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol, NADPH + H+, and O2 react to form 5beta-cholestan-3alpha,7alpha,12alpha,24(S),27-pentol, NADP+, and H2O. This reaction occurs in the mitochondrial matrix, catalyzed by CYP27A1. Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed1708392 Pubmed2019602 Pubmed9660774 Reactome Database ID Release 43193787 Reactome, http://www.reactome.org ReactomeREACT_10104 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4678 5beta-cholestan-3alpha,7alpha,24(S)-triol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-3alpha,7alpha,24(S)-triol is transported from the cytosol to the mitochondrial matrix. The transporter that mediates its passage across the inner mitochondrial membrane is unknown: the StAR protein that performs this function for cholesterol at the start of steroid hormone biosynthesis is excluded as StAR is not expressed in liver. Other members of the START family of transporters are candidates, however (Russell 2003). Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed12543708 Reactome Database ID Release 43193715 Reactome, http://www.reactome.org ReactomeREACT_10112 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4677 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol is translocated from the cytosol to the mitochondrial matrix. The transporter that mediates its passage across the inner mitochondrial membrane is unknown: the StAR protein that performs this function for cholesterol at the start of steroid hormone biosynthesis is excluded as StAR is not expressed in liver. Other members of the START family of transporters are candidates, however (Russell 2003). Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed12543708 Reactome Database ID Release 43193774 Reactome, http://www.reactome.org ReactomeREACT_10015 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 PathwayStep4676 5beta-cholestan-7alpha,24(S)-diol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,24(S)-triol 5Beta-cholesten-7alpha,24(S)-diol-3-one and NADPH + H+ form 5beta-cholestan-3alpha,7alpha,24(S)-triol and NAPDP+. The reaction is catalyzed by 3alpha-hydroxysteroid dehydrogenase (AKR1C4), a cytosolic enzyme belonging to the aldo-keto reductase family (Dufort et al. 2001). Biochemical studies with rat proteins raise the possibility that other related enzymes may also carry out this reaction in vivo (Russell 2003). 5beta-cholestan-7alpha,24(S)-diol-3-one+ NADPH + H+ => 5beta-cholestan-3alpha,7alpha,24(S)-triol + NADP+ Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 Pubmed11158055 Pubmed12543708 Reactome Database ID Release 43193758 Reactome, http://www.reactome.org ReactomeREACT_10054 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 NODAL:ACVR1B:ACVR2:EGF-CFC Reactome DB_ID: 1225875 Reactome Database ID Release 431225875 Reactome, http://www.reactome.org ReactomeREACT_111526 has a Stoichiometric coefficient of 1 NODAL:p-ACVR1B:ACVR2:EGF-CFC Reactome DB_ID: 1225883 Reactome Database ID Release 431225883 Reactome, http://www.reactome.org ReactomeREACT_111458 has a Stoichiometric coefficient of 1 PathwayStep4670 p-ACVR1B:ACVR2:EGF-CFC PhosphoALK4:ActRII:EGF-CFC Complex Reactome DB_ID: 1181140 Reactome Database ID Release 431181140 Reactome, http://www.reactome.org ReactomeREACT_111667 has a Stoichiometric coefficient of 2 PathwayStep4671 NODAL:ACVR1C:ACVR2B:EGF-CFC Reactome DB_ID: 1225912 Reactome Database ID Release 431225912 Reactome, http://www.reactome.org ReactomeREACT_111650 has a Stoichiometric coefficient of 1 PathwayStep4672 PathwayStep4673 PathwayStep4674 PathwayStep4675 NODAL Ligand:NODAL Receptor NODAL Ligand Bound to NODAL Receptor Reactome DB_ID: 1181133 Reactome Database ID Release 431181133 Reactome, http://www.reactome.org ReactomeREACT_111368 has a Stoichiometric coefficient of 1 SMAD2/3:SMAD4:FOXO3:FoxO3a-binding Element Reactome DB_ID: 1535906 Reactome Database ID Release 431535906 Reactome, http://www.reactome.org ReactomeREACT_111746 has a Stoichiometric coefficient of 1 NODAL:p-ACVR1C:ACVR2B:EGF-CFC Reactome DB_ID: 1225915 Reactome Database ID Release 431225915 Reactome, http://www.reactome.org ReactomeREACT_111276 has a Stoichiometric coefficient of 1 p-ACVR1C:ACVR2B:EGF-CFC PhosphoALK7:ActRIIB:EGF-CFC Complex Reactome DB_ID: 1181126 Reactome Database ID Release 431181126 Reactome, http://www.reactome.org ReactomeREACT_111592 has a Stoichiometric coefficient of 2 NODAL:p-NODAL Receptor NODAL Bound to Phosphorylated NODAL Receptor Reactome DB_ID: 1181134 Reactome Database ID Release 431181134 Reactome, http://www.reactome.org ReactomeREACT_111362 has a Stoichiometric coefficient of 1 p-Nodal Receptor Converted from EntitySet in Reactome Phosphorylated NODAL Receptor Reactome DB_ID: 1181129 Reactome Database ID Release 431181129 Reactome, http://www.reactome.org ReactomeREACT_111384 SIGLEC14/15/16 Converted from EntitySet in Reactome Reactome DB_ID: 2326839 Reactome Database ID Release 432326839 Reactome, http://www.reactome.org ReactomeREACT_148032 FYN,LCK Converted from EntitySet in Reactome Reactome DB_ID: 2395419 Reactome Database ID Release 432395419 Reactome, http://www.reactome.org ReactomeREACT_148414 PathwayStep4666 PathwayStep4665 PathwayStep4668 PathwayStep4667 PathwayStep4669 Histone H1 Converted from EntitySet in Reactome Reactome DB_ID: 211243 Reactome Database ID Release 43211243 Reactome, http://www.reactome.org ReactomeREACT_14168 HMGB1/HMGB2 Converted from EntitySet in Reactome Reactome DB_ID: 266214 Reactome Database ID Release 43266214 Reactome, http://www.reactome.org ReactomeREACT_14288 AGER-1,2,3 bind AGEs Authored: Jupe, S, 2010-06-01 Edited: Jupe, S, 2010-11-09 In addition to AGER/RAGE, several other proteins have been identified as AGE-binding proteins. AGE binding proteins p60 and p90 (Yang et al. 1991) were subsequently identified as the Oligosaccharyl transferase 48 kDa subunit (Ost-48) and Glucosidease-2 subunit beta (Li et al. 1996). A third member was identified as Galectin-3 (Vlassara et al. 1995). These 3 proteins have been shown to be present on the plasma membrane of many cell types including vascular endothelium (Stitt et al. 1999). They have been designated AGE-R1, -R2 and -R3. Their suggested function is the removal and degradation of AGEs, but AGER-1 was found to negatively regulate AGER/RAGE (Lu et al. 2004), with kinetics that suggested a more complex interaction than simple competition for the same ligand. Pubmed10080935 Pubmed15289604 Pubmed1651976 Pubmed8529130 Pubmed8855306 Reactome Database ID Release 43879358 Reactome, http://www.reactome.org ReactomeREACT_25269 Reviewed: Yan, SD, 2010-11-09 AGER binds ERK1/2 Authored: Jupe, S, 2010-06-01 Binding of ligand to AGER results in the activation of multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade (Lander et al. 1997), cdc42/Rac (Huttunen et al. 1999), and activation of NF-?B (Tanaka et al. 2000). A membrane-proximal cytoplasmic region of the advanced glycation end-products receptor (AGER) is responsible for binding to extracellular signal-regulated protein kinase-1 and -2 (ERK1/2 or MAPK3/1). This region is similar to the D-domain, an ERK docking site which is conserved in some ERK substrates (Ishihara et al. 2003). Edited: Jupe, S, 2010-11-16 Pubmed10391939 Pubmed10829018 Pubmed12935895 Pubmed9211935 Reactome Database ID Release 43879362 Reactome, http://www.reactome.org ReactomeREACT_25020 Reviewed: Yan, SD, 2010-11-09 K-63-linked polyubiquitination of RIG-I Authored: Garapati, P V, 2010-08-02 EC Number: 6.3.2.19 Edited: Garapati, P V, 2010-08-02 On viral infection RIG-I undergoes robust ubiquitination at its N-terminal CARD region. TRIM25 a member of tripartite motif (TRIM) protein family and Riplet/RNF135/REUL are the ubiquitin E3 ligases involved in K-63-linked polyubiquitination of RIG-I. TRIM25 contains a cluster of domains including a RING-finger domain, a B box/coiled-coil domain and a SPRY domain. The interaction is mediated by the SPRY domain of TRIM25 and the N-terminal CARDs of RIG-I. The polyubiquitin chains added by TRIM25 are unanchored Lys-172 (K-172) residue of RIG-I is critical for efficient TRIM25-mediated ubiquitination and for IPS-1 binding, as well as the ability of RIG-I to induce antiviral signal transduction. RING-finger protein, RNF135 specifically associate with RIG-I through its PRY and SPRY domains. The Lys 154, 164, and 172 residues of the RIG-I CARD domain were determined to be critical for efficient RNF135-mediated ubiquitination and for the ability of RIG-I to induce antiviral signal transduction. (Michaela et al, Goa et al) Pubmed17392790 Pubmed19017631 Pubmed19484123 Pubmed20403326 Reactome Database ID Release 43918224 Reactome, http://www.reactome.org ReactomeREACT_25220 Reviewed: Kawai, T, Akira, S, 2010-10-30 has a Stoichiometric coefficient of 2 dsRNA binds to RIG-I Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed15208624 Pubmed18591409 RIG-I has two copies of caspase recruitment domain (CARD) in its N-terminus, DExD/H helicase domain with an ATP binding motif in the middle and a repressor domain (RD) in the C-terminus. In the absence of appropriate stimulation, RIG-I is in a 'closed' conformation in which the repressor domain phyically interacts with the helicase domain masking CARD. Upon viral infection the free triphosphate structure at the 5' end of the viral RNAs activate RIG-I by binding to its RNA helicase domain. This provokes change in RIG-I conformation exposing the CARD leading to RIG-I dimerization and allowing it to interact with the mitochondria-bound interferon beta promoter stimulator-1 (IPS-1). Reactome Database ID Release 43168935 Reactome, http://www.reactome.org ReactomeREACT_25357 Reviewed: Kawai, T, Akira, S, 2010-10-30 has a Stoichiometric coefficient of 2 dsDNA:AIM2:ASC cluster binds procaspase-1 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Reactome Database ID Release 43844618 Reactome, http://www.reactome.org ReactomeREACT_75890 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The ASC CARD domain recruits procaspase-1 leading to autoactivation, generating caspase-1. dsDNA:AIM2 clusters bind ASC Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Reactome Database ID Release 43844620 Reactome, http://www.reactome.org ReactomeREACT_75804 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 dsDNA:AIM2 clusters bind ASC via a PYD-PYD interaction. Advanced glycosylation end product-specific receptor (AGER/RAGE) is a multiligand receptor Advanced glycosylation end product specific receptor (AGER) also known as Receptor for advanced glycation end products (RAGE) is a multi-ligand membrane receptor belonging to the immunoglobulin superfamily. It recognizes a large variety of modified proteins known as advanced glycation/glycosylation endproducts (AGEs) a heterogenous group of structures (Ikeda et al. 1996) that accumulate in patients with diabetes, atherosclerosis, renal failure or ageing (Schmidt et al. 1999). The most prevalent class of AGE in vivo are N(6)-carboxymethyllysine (NECML) adducts (Kislinger et al. 1991). AGER is a receptor for amyloid-beta peptide (Ab)(Yan et al. 1996), mediating Ab neurotoxicity and promoting Ab influx into the brain (Zhang et al. 2009). AGER also responds to the proinflammatory S100/calgranulins (Hofmann et al. 1999) and High mobility group protein B1 (HMGB1/Amphoterin/DEF) (Hori et al. 1995). The major pathway is NFkappaB activation, but AGER can also activate rho-GTPases and thereby MAPK and JNK cascades. (Bierhaus et al. 2005). Authored: Jupe, S, 2010-06-01 Edited: Jupe, S, 2010-09-01 Pubmed10399917 Pubmed10531386 Pubmed16133426 Pubmed19672558 Pubmed7592757 Pubmed8672512 Pubmed8751438 Reactome Database ID Release 43879411 Reactome, http://www.reactome.org ReactomeREACT_25382 Reviewed: Yan, SD, 2010-11-09 The TRTK-12 fragment of F-actin capping protein alpha binds the AGER ligand S100B Authored: Jupe, S, 2010-06-01 Edited: Jupe, S, 2010-09-01 Pubmed10399917 Pubmed12470955 Pubmed7540176 Reactome Database ID Release 43879377 Reactome, http://www.reactome.org ReactomeREACT_25219 Reviewed: Yan, SD, 2010-11-09 The TRTK-12 fragment of the F-actin capping protein alpha subunit binds S100B in a calcium dependent manner. S100B undergoes a conformational change that is required for subsequent binding to effector proteins (Inman et al. 2002). S100B is a ligand for AGER (Hofmann et al. 1999). In addition this interaction between S100B andF-actin capping protein alpha could be important for regulating actin filament extension (Ivenkov et al. 1995). AIM2 oligomerizes AIM2 oligomerizes, forming AIM2 clusters that are able to interact with ASC (Fernandes-Alnemri et al. 2009, Hornung et al. 2009). The extent of oligomerization required is unknown. Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed19158675 Pubmed19158676 Reactome Database ID Release 43874079 Reactome, http://www.reactome.org ReactomeREACT_75859 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 AIM2 binds dsDNA AIM2 binds to cytosolic dsDNA via its C-terminal HIN domain. The source of the dsDNA can be can be viral, bacterial or derived from the host (Hornung et al. 2009, Muruve et al. 2008). Multiple AIM2 molecules may bind the same dsDNA (Fernandes-Alnemri et al. 2008). Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed18288107 Pubmed19158675 Pubmed19158676 Pubmed19158679 Reactome Database ID Release 43844619 Reactome, http://www.reactome.org ReactomeREACT_75821 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Exocytosis of nascent chylomicrons Authored: D'Eustachio, P, 2007-04-30 14:19:38 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0042158 Pubmed12692552 Reactome Database ID Release 43174587 Reactome, http://www.reactome.org ReactomeREACT_6813 While the export pathway for nascent chylomicrons has not been directly characterized in human cells, the requirement for SAR1B protein for normal chylomicron export in vivo (Jones et al. 2003) indicates that nascent chylomicrons are exported from the endoplasmic reticulum via the Golgi apparatus in COPII vesicles. nascent chylomicron [endoplasmic reticulum lumen] => nascent chylomicron [extracellular] ApoB-48 + 40 triacylglycerol + 60 phospholipid => ApoB-48:TG:PL complex Authored: D'Eustachio, P, 2007-04-30 14:19:38 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0042158 Phospholipid (PL) and triacylglycerol (TG) associate with the apo B-48 polypeptide as it is translated. This process is mediated by MTP (microsomal triacylglycerol transfer protein) in the form of a MTP:PDI (protein disulfide isomerase) heterodimer. MTP in vitro binds small amounts of PL and TG (annotated here as as one molecule of each) and efficiently transfers the bound lipid between membranes (Atzel and Wetterau 1994). In vivo, MTP:PDI directly interacts with apoB-48 polypeptide (Wu et al. 1996), and is thought to transfer lipid from the endoplasmic reticulum membrane to nascent apoB-48. While some of the molecular details of MTP function remain unclear, this function is clearly essential in vivo, as patients who lack MTP cannot produce chylomicrons (e.g., Wetterau et al. 1992; Narcisi et al. 1995). Pubmed1439810 Pubmed14732096 Pubmed7803401 Pubmed8533758 Pubmed8626595 Reactome Database ID Release 43174786 Reactome, http://www.reactome.org ReactomeREACT_6908 has a Stoichiometric coefficient of 40 has a Stoichiometric coefficient of 60 ApoB-48:TG:PL complex + 100 triacylglycerols + ApoA-I + ApoA-IV => nascent chylomicron Authored: D'Eustachio, P, 2007-04-30 14:19:38 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0042158 ISBN0079130356 Pubmed12518019 Pubmed14732096 Pubmed7288288 Reactome Database ID Release 43174741 Reactome, http://www.reactome.org ReactomeREACT_6915 The second phase of chylomicron assembly takes place in the lumen of the endoplasmic reticulum. ApoB-48 continues to bind triacylglycerol, as well as cholesterol, cholesterol esters, and molecules of apolipoproteins A-I, A-II, and A-IV. The reaction is annotated here to involve small numbers of these molecules, but the true numbers in vivo are much greater - a nascent chylomicron entering the lymphatic circulation contains >200,000 molecules of triacylglycerol (TG), ~35,000 of phospholipid, ~11,000 of cholesterol ester, ~8,000 of free cholesterol, ~60 copies of apolipoprotein A-I, ~15 copies of apolipoprotein A-IV, and copies of apolipoprotein A-II (Bhattacharya and Redgrave 1981; Havel and Kane 2001).<p>The presence of MTP:PDI (microsomal triacylglycerol transfer protein:protein disulfide isomerase) is required for lipid addition both in vitro and in vivo, but its molecular role at this stage of chylomicron formation is unclear and may be indirect (Gordon et al. 1995; Hussain et al. 2003). has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 NPC1L1 inactivation by ezetimibe Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Human NPC1L1, associated with the plasma membrane, binds ezetimibe and becomes incapable of mediating cholesterol uptake. The molecular mechanisms of cholesterol transport and ezetimibe inhibition, however, remain unclear (Garcia-Calvo et al. 2005; Weinglass et al. 2008). NPC1L1 + ezetimibe => NPC1L1:ezetimibe complex Pubmed15928087 Pubmed18187582 Reactome Database ID Release 43265456 Reactome, http://www.reactome.org ReactomeREACT_13435 Reviewed: Jassal, B, 2008-06-13 14:05:49 ABCG5:ABCG8-mediated export of cholesterol and phytosterols ABCG5/8 in the plasma membrane mediates the ATP-dependent export of cytosolic sterols (cholesterol and phytosterols). Mutations affecting the ABCG5/8 proteins are associated with the accumulation of high levels of cholesterol and phytosterols in the body, demonstrating the specificity and physiological importance of this process (Berge et al. 2000). Human ABCG5/8 has not been studied in detail, but the homologous mouse protein complex mediate ATP-dependent sterol export (Wang et al. 2006). The mouse proteins localize to the apical plasma membranes of enterocytes and hepatocytes, consistent with the hypothesis that in vivo ABCG5/8 mediates sterol export into the gut lumen and from hepatocytes into the bile (Graf et al. 2003). Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed11099417 Pubmed14504269 Pubmed16867993 Reactome Database ID Release 43265783 Reactome, http://www.reactome.org ReactomeREACT_13440 Reviewed: Jassal, B, 2008-06-13 14:05:49 sterols[cytosol] + ATP => sterols[extracellular] + ADP + Pi NPC1L1-mediated phytosterol uptake Authored: D'Eustachio, P, 2008-05-12 17:46:52 Dietary phytosterols (sterols derived from plants) are taken up into enterocytes from the gut lumen. The reaction is thought to be mediated by plasma membrane-associated NPC1L1 protein. Detailed studies in Maden-Darby canine kidney cells, both mediated by endogenous (canine) NPC1L1 and by overexpressed human protein, indicate a major role for NPC1L1 in the uptake of extracellular sterol. These studies have also shown that ezetimibe binds both human and canine proteins and renders them incapable of mediating sterol uptake. The molecular mechanisms of cholesterol transport and ezetimibe inhibition, however, remain unclear (Weinglass et al. 2008). Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed18187582 Reactome Database ID Release 43265545 Reactome, http://www.reactome.org ReactomeREACT_13559 Reviewed: Jassal, B, 2008-06-13 14:05:49 NPC1L1-mediated cholesterol uptake Authored: D'Eustachio, P, 2008-05-12 17:46:52 Dietary cholesterol is taken up into enterocytes from the gut lumen in a reaction mediated by plasma membrane-associated NPC1L1 protein. This role for NPC1L1 was first observed in studies of a mouse model system (Altman et al. 2004). Subsequent studies of human cultured cells confirmed the participation of NPC1L1 in cholesterol transport across membranes but suggested that this transport process might not be a major factor in dietary cholesterol uptake (Davies et al. 2005). Detailed studies in Maden-Darby canine kidney cells, both mediated by endogenous (canine) NPC1L1 and by overexpressed human protein, indicate a major role for NPC1L1 in the uptake of extracellular cholesterol. These studies have also shown that ezetimibe binds both human and canine proteins and renders them incapable of mediating cholesterol uptake. The molecular mechanisms of cholesterol transport and ezetimibe inhibition, however, remain unclear (Weinglass et al. 2008). Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed14976318 Pubmed15671032 Pubmed18187582 Reactome Database ID Release 43265443 Reactome, http://www.reactome.org ReactomeREACT_13411 Reviewed: Jassal, B, 2008-06-13 14:05:49 PNLIP:CLPS hydrolyses RPALM to atROL and PALM Authored: Stephan, R, 2010-09-19 Digestion of retinyl palmitate by extracellular PTL:colipase EC Number: 3.1.1.21 Edited: Jassal, B, 2010-10-01 Part of nutritional vitamin A is in the form of retinyl esters (REs). The main fatty acids which can form esters with retinol are palmitate, oleate, stearate and linoleate. REs are digested together with other lipids, and by the same enzymes. Pancreatic lipase catalyses the hydrolysis of RE to all-trans-retinol (atROL) and fatty acid which are then both taken up by enterocytic cell membranes (Bennekum et al. 2000). Pubmed10769148 Reactome Database ID Release 43975593 Reactome, http://www.reactome.org ReactomeREACT_25240 Reviewed: D'Eustachio, P, 2010-11-09 Digestion of triacylglycerols by extracellular pancreatic lipase-related protein 2 Authored: D'Eustachio, P, 2007-02-02 21:43:49 EC Number: 3.1.1.23 Pancreatic lipase-related protein 2 catalyzes the hydrolysis of extracellular triacylglycerols to yield diacylglycerols and free long-chain fatty acids. This enzyme, unlike the closely related pancreatic lipase protein, does not require colipase protein for activity. The protein is synthesized in the pancreas, but its role in the digestion of dietary fat has not been established (Giller et al. 1992). Pubmed1379598 Reactome Database ID Release 43192475 Reactome, http://www.reactome.org ReactomeREACT_9389 Digestion of triacylglycerols by extracellular PTL:colipase Authored: D'Eustachio, P, 2007-02-02 21:43:49 EC Number: 3.1.1.23 Pancreatic lipase catalyzes the hydrolysis of extracellular triacylglycerols to yield diacylglycerols and long-chain fatty acids. The enzyme is active only when complexed with colipase protein and plays a major role in the digestion of dietary triacylglycerols in the small intestine (Carriere et al. 2000; Giller et al. 1992). Pubmed11040182 Pubmed1379598 Reactome Database ID Release 43192422 Reactome, http://www.reactome.org ReactomeREACT_9501 Ubiquinated and PIP3 Endosmal Membrane Bound Cargo Reactome DB_ID: 917712 Reactome Database ID Release 43917712 Reactome, http://www.reactome.org ReactomeREACT_27362 has a Stoichiometric coefficient of 1 ESCRT-III/Cargo Complex Reactome DB_ID: 917699 Reactome Database ID Release 43917699 Reactome, http://www.reactome.org ReactomeREACT_27876 has a Stoichiometric coefficient of 1 RAB4A:GTP:KIF3:microtubule Reactome DB_ID: 1458522 Reactome Database ID Release 431458522 Reactome, http://www.reactome.org ReactomeREACT_148401 has a Stoichiometric coefficient of 1 RAB4A:GTP Reactome DB_ID: 1458538 Reactome Database ID Release 431458538 Reactome, http://www.reactome.org ReactomeREACT_148449 has a Stoichiometric coefficient of 1 KIF3 Reactome DB_ID: 2316334 Reactome Database ID Release 432316334 Reactome, http://www.reactome.org ReactomeREACT_148146 has a Stoichiometric coefficient of 1 p21/p27 Converted from EntitySet in Reactome Reactome DB_ID: 182558 Reactome Database ID Release 43182558 Reactome, http://www.reactome.org ReactomeREACT_8306 Vps/Vta1 Reactome DB_ID: 917724 Reactome Database ID Release 43917724 Reactome, http://www.reactome.org ReactomeREACT_27371 has a Stoichiometric coefficient of 1 14-3-3 eta dimer Reactome DB_ID: 2262715 Reactome Database ID Release 432262715 Reactome, http://www.reactome.org ReactomeREACT_148230 has a Stoichiometric coefficient of 2 14-3-3 dimer Converted from EntitySet in Reactome Reactome DB_ID: 1445138 Reactome Database ID Release 431445138 Reactome, http://www.reactome.org ReactomeREACT_147925 Phospho AS160:IRAP Phosphorylated TBC1D4:LNPEP Reactome DB_ID: 1445133 Reactome Database ID Release 431445133 Reactome, http://www.reactome.org ReactomeREACT_147981 has a Stoichiometric coefficient of 1 AS160:IRAP Reactome DB_ID: 1445125 Reactome Database ID Release 431445125 Reactome, http://www.reactome.org ReactomeREACT_148263 TBC1D4:LNPEP has a Stoichiometric coefficient of 1 K63 polyubiquitinated RIP2 associates with the TAK1 complex Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 K63-polyubiquitinated RIP2 is able to recruit the components of the TAK1 complex, which consists of TAK1, TAB1 and TAB2. Pubmed18079694 Reactome Database ID Release 43688985 Reactome, http://www.reactome.org ReactomeREACT_75887 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 TAK1 is activated Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed10702308 Pubmed14633987 Pubmed15327770 Reactome Database ID Release 43706479 Reactome, http://www.reactome.org ReactomeREACT_75766 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). A20 deubiquitinates RIP2 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed1381359 Pubmed16418393 Pubmed18079694 Pubmed18342009 Reactome Database ID Release 43688136 Reactome, http://www.reactome.org ReactomeREACT_75888 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The deubiquitinase A20 is a negative feedback regulator of inflammatory responses, induced by NFkappaB activation (Krikos et al. 1992) and NOD stimulation (Masumoto et al. 2006). A20 can deubiquitinate RIP2 and restricts NOD2 induced signals (Hitosumatsu et al. 2008). has a Stoichiometric coefficient of 6 P2X7 mediates loss of intracellular K+ Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Low level or transient activation of P2X7 leads to reversible opening of a membrane channel permeable to small cations such as Na+, Ca2+ and K+ (Adinolfi et al. 2005). Pubmed11157473 Pubmed18404507 Pubmed9023774 Reactome Database ID Release 43877187 Reactome, http://www.reactome.org ReactomeREACT_75889 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 ATP binds to P2X7 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 P2X7 is a receptor for extracellular ATP that acts as a ligand gated non-selective cation channel. It is also responsible for the ATP-dependent lysis of macrophages, which it brings about by mediating the formation of membrane pores permeable to large molecules (Adinolfi et al. 2005). Pubmed18404507 Reactome Database ID Release 43877178 Reactome, http://www.reactome.org ReactomeREACT_75791 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 P2X7 forms oligomeric non-selective cation channels At low to intermediate concentrations of extracellular ATP, P2X7 functions as a probably trimeric (Markwardt 2007) reversible ATP-gated, nondesensitizing cation channel. Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed18404439 Reactome Database ID Release 43877158 Reactome, http://www.reactome.org ReactomeREACT_75915 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 has a Stoichiometric coefficient of 3 Cyclin E Converted from EntitySet in Reactome Reactome DB_ID: 187493 Reactome Database ID Release 43187493 Reactome, http://www.reactome.org ReactomeREACT_9128 CARD9 binds RIP2 (and NOD2) Authored: Jupe, S, 2010-04-22 CARD9 binds RIP2 and NOD2. In addition overexpression of CARD9 strongly activates the kinases p38 and Jnk while CARD9-deficient mouse macrophages have defects in activation of p38 and Jnk but not NF-kappaB signaling, suggesting that CARD9 is involved in an NF-kappaB-independent signaling pathway (Hsu et al. 2007), but the mechanism is unclear. CARD9 is the key transducer of signals from dectin-1, the major mammalian pattern recognition receptor for the fungal component zymosan (Gross et al. 2006). Edited: Jupe, S, 2011-04-28 Pubmed16862125 Pubmed17187069 Reactome Database ID Release 43741395 Reactome, http://www.reactome.org ReactomeREACT_75873 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Activation of p38 MAPK Authored: Jupe, S, 2011-04-08 Edited: Jupe, S, 2011-04-28 Pubmed10066767 Pubmed15686620 Pubmed7693711 Pubmed8633070 Pubmed8663524 Pubmed9430721 Reactome Database ID Release 431247960 Reactome, http://www.reactome.org ReactomeREACT_75807 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 has a Stoichiometric coefficient of 8 p38 MAPK has 4 representative isoforms in humans, p38 alpha (Han et al. 1993), p38-beta (Jiang et al. 1996), p38-gamma (Lechner et al. 1996) and p38-delta (Hu et al. 1999). All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms (Zarubin & Han, 2005). p38 alpha and gamma are also activated by MKK3. TAK1 phosphorylates MKK6 Authored: Ray, KP, 2010-05-17 EC Number: 2.7.11.25 Edited: Jupe, S, 2010-05-17 Pubmed11460167 Pubmed18079694 Reactome Database ID Release 43727819 Reactome, http://www.reactome.org ReactomeREACT_22190 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Within the TAK1 complex (TAK1 plus TAB1 and TAB2/3) activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways. TAB2 within the TAK1 complex can be linked to polyubiquitinated TRAF6; current models of IL-1 signaling suggest that the TAK1 complex is linked to TRAF6, itself complexed with polyubiquitinated IRAK1 which is linked via NEMO to the IKK complex. The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex (Hasegawa et al. 2008). has a Stoichiometric coefficient of 2 NOD1 induced apoptosis is mediated by RIP2 and CARD8 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 NOD1 was found to coimmunoprecipitate with several procaspases containing long prodomains with CARDs or DEDs, including caspase-1, caspase-2, caspase-4, caspase-8, and caspase-9, but not those with short prodomains like caspase-3 or caspase-7. Deletions of caspase-9 determined that the CARD domain was required for this interaction (Inohara et al. 1999). More recently, NOD1 activation of apoptosis was shown to require the RIP2-dependent activation of caspase-8, this effect being inhibited by CASP8 and FADD-like apoptosis regulator, also called FLICE-inhibitory protein, FLIP or CLARP (da Silva Correia et al. 2007), which is a specific inhibitor of caspase-8 (Irmler et al. 1997). Pubmed10329646 Pubmed17186025 Pubmed9217161 Reactome Database ID Release 43622420 Reactome, http://www.reactome.org ReactomeREACT_75921 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4400 C4b binding protein binds Protein S Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 Pubmed15096498 Pubmed6454142 Reactome Database ID Release 43981665 Reactome, http://www.reactome.org ReactomeREACT_118836 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 The beta subunit of C4b binding protein binds and inactivates Protein S, a vitamin K dependent anticoagulation factor. This may represent part of a mechanism for fine-tuning the process of phagocytosis (Kask et al. 2004). iE-DAP elicits a NOD1 response Authored: Jupe, S, 2010-04-22 Early studies suggested that NOD1 and NOD2 responded to lipopolysaccharides (LPS), but this was later shown to be due to contamination of LPS with bacterial peptidoglycans (PGNs), the true elicitor for NODs. It is generally believed that PGNs bind NOD1 though this remains to be formally demonstrated. NOD1 senses PGN moieties with a minimal dipeptide structure of D-gamma-glutamyl-meso-diaminopimelic acid (iE-DAP), which is unique to PGN structures from all Gram-negative bacteria and certain Gram-positive bacteria, including the genus Listeria and Bacillus. Attachment of acyl residues enhances NOD1 stimulation several hundred fold, possibly by facilitating PGN entry into the cell (Hasegawa et al. 2007). Edited: Jupe, S, 2011-04-28 Pubmed12791997 Pubmed12796777 Pubmed17322292 Reactome Database ID Release 43168400 Reactome, http://www.reactome.org ReactomeREACT_75907 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 RIP2 binds NEMO An intermediate region located between the CARD and kinase domains mediates the interaction of RIP2 with the IKK complex regulatory subunit NEMO. This interaction is presumed to link NOD1:RIP2 to the IKK complex, ultimately leading to the phosphorylation of IkappaB-alpha and the activation of NF-kappaB (Inohara et al. 2000). Although every NOD molecule in the oligomeric complex is represented as binding RIP2, binding to every member of the complex may not be required for subsequent signaling events. Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed18079694 Reactome Database ID Release 43622415 Reactome, http://www.reactome.org ReactomeREACT_75893 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 RIP2 induces K63-linked ubiquitination of NEMO Authored: Jupe, S, 2010-04-22 EC Number: 6.3.2.19 Edited: Jupe, S, 2011-04-28 Pubmed17562858 RIP2 induces the K63-linked ubiquitination of NEMO at K285 and K399, positively modulating subsequent NF-kappaB activation (Abbot et al. 2007). TRAF6 E3 ligase is capable of performing this ubiquitination step when overexpressed in HEK239 cells, and this effect is blocked if RIP2 siRNA is co-transfected, but small interfering RNA (siRNA) experiments indicate that there are additional E3 ligases that can substitute for TRAF6 in NEMO ubiquitination. In addition to TRAF6, the K63-specific E2 ligase Ubc13 is required for NEMO ubiquitination suggesting a common mechanism for NEMO ubiquitination in NOD and TLR signaling. Reactome Database ID Release 43741386 Reactome, http://www.reactome.org ReactomeREACT_75924 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 CYLD deubiquitinates NEMO Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed12917691 Pubmed15620648 RIP2-induced ubiquitination of NEMO and consequent NFkappaB activation can be reversed in a dose-responsive manner by the deubiquitinase CYLD, suggesting that CYLD negatively regulates RIP2-induced NEMO ubiquitinylation. Reactome Database ID Release 43741411 Reactome, http://www.reactome.org ReactomeREACT_75903 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 RIP2 is K63 polyubiquitinated Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed17562858 Pubmed17947236 Pubmed18079694 Pubmed19464198 Pubmed19592251 Reactome Database ID Release 43688137 Reactome, http://www.reactome.org ReactomeREACT_75843 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The close physical proximity of RIP2 proteins that results from NOD oligomerization triggers the conjugation of lysine (K)-63 linked polyubiquitin chains onto RIP2. Ubiquitination at K209 within the kinase domain was required for subsequent NFkappaB signaling (Hasegawa et al. 2008). The identity of the ubiquitin ligase responsible is an open question, with several candidates capable of RIP2 ubiquitination. TRAF6 has been reported as the ubiquitin ligase responsible (Yang et al. 2007) but subsequent reports suggest it is not responsible (see Tao et al. 2009 and Bertrand et al. 2009). Other candidates include the HECT-domain containing E3 ubiquitin ligase ITCH, which is able to K63 ubiquitinate RIP2 (at an undetermined site that is not K209) and is required for optimal NOD2:RIP2-induced p38 and JNK activation, while inhibiting NOD2:RIP2-induced NFkappaB activation (Tao et al. 2009). The Baculoviral IAP repeat-containing proteins (Birc/cIAP) 2 and 3 have also been shown capable of RIP2 ubiquitination and required for NOD2 signaling (Bertrand et al. 2009). It has been suggested that ITCH and a K209 E3 ligase compete for ubiquitination of RIP2, so that a subset of RIP2 becomes ubiquitinated on K209 to stimulate NEMO ubiquitination and subsequent NFkappaB activation while a second subset of RIP2 is polyubiquitinated by ITCH to activate JNK and p38 signaling (Tao et al. 2009). has a Stoichiometric coefficient of 6 MDP elicits a NOD2 response Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Muramyl dipeptide (MDP) is an essential structural component of bacterial peptidoglycan (PGN) and the minimal elicitor recognized by NOD2. As MDP is present in nearly all bacteria NOD2 is a general sensor of bacteria. NOD2 has additionally been reported to respond to ssRNA (Sabbah et al. 2009) and play a role in T cell activation (Shaw et al. 2011). Pubmed12514169 Pubmed12527755 Pubmed19701189 Pubmed21251876 Reactome Database ID Release 43168412 Reactome, http://www.reactome.org ReactomeREACT_75796 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Activated NOD1 oligomerizes Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 NOD1 is activated by iE-DAP in a LRR domain dependent manner. The LRR domain has a negative influence on NOD1 self-association (Inohara et al. 2000); binding of iE-DAP likely causes conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on this observation, NOD1 and NOD2 are believed to form oligomers of this size (Martinon & Tschopp, 2005). Pubmed10329646 Pubmed10880512 Pubmed15967716 Reactome Database ID Release 43622310 Reactome, http://www.reactome.org ReactomeREACT_75809 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 has a Stoichiometric coefficient of 6 Activated NOD2 oligomerizes Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 NOD2 is activated by MDP in a LRR domain dependent manner. Based on studies of NOD1 activation and structural data from the NLR-related scaffold Apaf-1, the LRR domain is believed to have a negative influence on NOD2 self-association (Inohara et al. 2000, Riedl & Salvesen 2007); binding of MDP is believed to cause conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on these observations, NOD2 is generally believed to form hexamers or heptamers (Martinon & Tschopp, 2005). NOD2 oliogomerization has been observed in NOD2-transfected HEK293T cells (Zhao et al. 2007). Pubmed10880512 Pubmed15967716 Pubmed17303577 Pubmed17377525 Reactome Database ID Release 43708349 Reactome, http://www.reactome.org ReactomeREACT_75789 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 has a Stoichiometric coefficient of 6 Activated NOD oligomer recruites RIP2 (RICK) Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 NOD1 and NOD2 (NOD) interact with the inflammatory kinase RIP2 (RICK) via a homophilic association between CARD domains (Inohara et al. 1999, Ogura et al. 2001). This has the effect of bringing several RIP2 molecules into close proximity, enhancing RIP2-RIP2 interactions (Inohara et al. 2000), a key step in what is termed the 'Induced Proximity Model' for NOD activation of NFkappaB. Note that though the interaction of every NOD with RIP2 is implied here this may not be required for RIP2 activation. RIP2 recruitment leads to subsequent activation of NFkappaB. The kinase activity of RIP2 was initially described as not required (Inohara et al. 2000) but subsequently suggested to be involved in determining signal strength (Windheim et al. 2007) and recently found to be essential for maintaining RIP2 stability and it's role in mediating NOD signaling (Nembrini et al. 2009). Pubmed10224040 Pubmed10329646 Pubmed10880512 Pubmed11087742 Pubmed17348859 Pubmed19473975 Reactome Database ID Release 43168405 Reactome, http://www.reactome.org ReactomeREACT_75833 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 has a Stoichiometric coefficient of 6 AMPK-alpha2:AMPK-beta:AMPK-gamma:AMP Reactome DB_ID: 1454683 Reactome Database ID Release 431454683 Reactome, http://www.reactome.org ReactomeREACT_148254 has a Stoichiometric coefficient of 1 YWHAE dimer 14-3-3E homodimer Reactome DB_ID: 2457841 Reactome Database ID Release 432457841 Reactome, http://www.reactome.org ReactomeREACT_148579 has a Stoichiometric coefficient of 2 YWHAB dimer Reactome DB_ID: 2457850 Reactome Database ID Release 432457850 Reactome, http://www.reactome.org ReactomeREACT_148360 has a Stoichiometric coefficient of 2 14-3-3zeta dimer Reactome DB_ID: 2457851 Reactome Database ID Release 432457851 Reactome, http://www.reactome.org ReactomeREACT_147958 has a Stoichiometric coefficient of 2 PathwayStep4411 PathwayStep4410 pro-factor X, uncarboxylated Reactome DB_ID: 159754 Reactome Database ID Release 43159754 Reactome, http://www.reactome.org ReactomeREACT_4182 has a Stoichiometric coefficient of 1 native beta-tubulin:GTP Reactome DB_ID: 391237 Reactome Database ID Release 43391237 Reactome, http://www.reactome.org ReactomeREACT_17791 has a Stoichiometric coefficient of 1 native alpha tubulin-GTP Reactome DB_ID: 391249 Reactome Database ID Release 43391249 Reactome, http://www.reactome.org ReactomeREACT_17521 has a Stoichiometric coefficient of 1 RGC1:phospho-RGC2 RALGAPB:pSer486,696,pThr715-RALGAPA2 RGC1:p-486,696-T715-RGC2 Reactome DB_ID: 1458472 Reactome Database ID Release 431458472 Reactome, http://www.reactome.org ReactomeREACT_148586 has a Stoichiometric coefficient of 1 alpha-beta heterodimer Reactome DB_ID: 391248 Reactome Database ID Release 43391248 Reactome, http://www.reactome.org ReactomeREACT_18200 has a Stoichiometric coefficient of 1 RGC1:RGC2 RALGAPB:RALGAPA2 Reactome DB_ID: 1458509 Reactome Database ID Release 431458509 Reactome, http://www.reactome.org ReactomeREACT_148495 has a Stoichiometric coefficient of 1 beta-tubulin:GTP:Cofactor D:alpha-tubulin:GTP:Cofactor E : Cofactor C Reactome DB_ID: 391240 Reactome Database ID Release 43391240 Reactome, http://www.reactome.org ReactomeREACT_17144 has a Stoichiometric coefficient of 1 RAB8A/10/13/14:GTP RAB8A,10,13,14:GTP Reactome DB_ID: 1445137 Reactome Database ID Release 431445137 Reactome, http://www.reactome.org ReactomeREACT_148450 has a Stoichiometric coefficient of 1 beta tubulin:GTP: Cofactor D:alpha tubulin:GTP:Cofactor E Reactome DB_ID: 391236 Reactome Database ID Release 43391236 Reactome, http://www.reactome.org ReactomeREACT_17650 has a Stoichiometric coefficient of 1 RAB8A/10/13/14:GDP RAB8A,10,13,14:GDP Reactome DB_ID: 1445130 Reactome Database ID Release 431445130 Reactome, http://www.reactome.org ReactomeREACT_148262 has a Stoichiometric coefficient of 1 Cofactor E:GTP-alpha tubulin folding Reactome DB_ID: 391242 Reactome Database ID Release 43391242 Reactome, http://www.reactome.org ReactomeREACT_17474 has a Stoichiometric coefficient of 1 p-S237-TBC1D1:14-3-3 Reactome DB_ID: 1454696 Reactome Database ID Release 431454696 Reactome, http://www.reactome.org ReactomeREACT_148394 TBC1D1 (pSer237):14-3-3 has a Stoichiometric coefficient of 1 Cofactor B:GTP-alpha tubulin Reactome DB_ID: 391241 Reactome Database ID Release 43391241 Reactome, http://www.reactome.org ReactomeREACT_17838 has a Stoichiometric coefficient of 1 AMPK gamma:AMP Reactome DB_ID: 2316451 Reactome Database ID Release 432316451 Reactome, http://www.reactome.org ReactomeREACT_148575 has a Stoichiometric coefficient of 1 ASC is recruited via a PYD-PYD interaction Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 NLRP3 interacts with ASC (Manji et al. 2003) via their PYD domains (Dowds et al. 2004). NLRP3 oligomerization leads to PYD domain clustering which is believed to facilitate the interaction of NLRP3 with the PYD domain of ASC (Schroder & Tschopp, 2010). Pubmed11786556 Pubmed12615073 Pubmed20303873 Reactome Database ID Release 43844610 Reactome, http://www.reactome.org ReactomeREACT_75848 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4409 Pyrin binds ASC Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed11498534 Pubmed12615073 Pubmed12667444 Pubmed17964261 Reactome Database ID Release 43877361 Reactome, http://www.reactome.org ReactomeREACT_75855 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Trimeric pyrin interacts with ASC through its Pyrin domains, leading to oligomerization of ASC. This interaction interferes with the ability of NLRP3 (Cyropyrin) to associate with ASC and thus inhibits inflammasome activation (Chae et al. 2003). has a Stoichiometric coefficient of 3 Bcl-2 and Bcl-XL bind NLRP1 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed17418785 Reactome Database ID Release 43879201 Reactome, http://www.reactome.org ReactomeREACT_75844 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The anti-apoptotic proteins Bcl-2 and Bcl-XL (but not Mcl-1, Bcl-W, Bfl-1 or Bcl-B) bind to NLRP1, preventing MDP-induced activation. The CARD domain of ASC recruits Procaspase-1 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Procaspase-1 is recruited via a CARD-CARD interaction with ASC. This creates procaspase-1 clustering which is believed to stimulate procaspase-1 autocleavage, generating the p10/p20 fragments that assemble into the active capsase-1 tetramer (Schroder & Tschopp, 2010). Pubmed11967258 Pubmed12191486 Pubmed20303873 Reactome Database ID Release 43844612 Reactome, http://www.reactome.org ReactomeREACT_75834 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PSTPIP1 binds Pyrin Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) is a pyrin-binding protein, involved in regulation of the actin cytoskeleton (Li et al. 1998) and suggested as a regulator of inflammasome activation (Khare et al. 2010). A naturally occurring mutation of PSTPIP1 where Y344 is replaced by F blocks tyrosine phosphorylation and reduces pyrin binding. Mutations of PSTPIP1 that increase pyrin binding are associated with the inflammatory syndrome pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA). Expression of PSTPIP1 with these mutations in THP-11 cells resulted in substantially increased caspase-1 activation and IL-1beta secretion. PSTPIP1 binding to pyrin is believed to promote the unmasking of its PYD domain and enhance interactions with ASC, facilitating ASC oligomerization and caspase-1 recruitment (Yu et al. 2007). Pubmed14595024 Pubmed17964261 Pubmed21083527 Pubmed9857189 Reactome Database ID Release 43879221 Reactome, http://www.reactome.org ReactomeREACT_75934 Reviewed: Kufer, TA, 2011-04-28 PathwayStep4403 NLRP1 oligomerizes Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 NLRP1 in the presence of Mg2+ was seen to have altered electrophoretic mobility when MDP was added. This was interpreted as evidence of NLRP1 oligomerization. The extent of oligomerization is unknown. Pubmed17349957 Reactome Database ID Release 43844438 Reactome, http://www.reactome.org ReactomeREACT_75818 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4404 IPAF is activated Although a direct interaction between IPAF and an activating ligand has not been demonstrated, IPAF can be activated by cytosolic flagellin either applied experimentally or resulting from the activity of the virulence-associated type III or V secretion systems (Franchi et al. 2006, Miao et al 2007, 2008). Activation can also be flagellin-independent (Suzuki et al. 2007, Sutterwala et al. 2007), suggesting alternative mechanisms that are likely to involve recognition of components of the bacterial type III secretion system (Miao et al. 2010). The LRR domain of IPAF appears to repress activity in the absence of a ligand as removal of this domain leads to constitutive activation (Poyet et al. 2001). Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed11390368 Pubmed16648852 Pubmed17696608 Pubmed18070936 Pubmed18256184 Pubmed20133635 Reactome Database ID Release 43874084 Reactome, http://www.reactome.org ReactomeREACT_75906 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4401 NLRP1 senses MDP Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 In vitro studies using purified NLRP1 and caspase-1 suggest that MDP induces a conformational change in NLRP1 that allows it to bind nucleotides and oligomerize, creating a binding platform for caspase-1 (Faustin et al. 2008). There is no direct evidence that NLRP1 binds MDP so the mechanism that stimulates NLRP1 is unclear. Pubmed17349957 Reactome Database ID Release 43844447 Reactome, http://www.reactome.org ReactomeREACT_75756 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4402 MDP:NLRP1 binds ATP Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 MDP may induce a conformational change in NLRP1 which enables ATP binding, required for NLRP1 oligomerization (Faustin et al. 2007). Pubmed17349957 Reactome Database ID Release 43879222 Reactome, http://www.reactome.org ReactomeREACT_75872 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4407 PathwayStep4408 PathwayStep4405 IPAF binds procaspase-1 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 IPAF contains an N-terminal CARD domain, a central nucleotide-binding domain, and a C-terminal regulatory leucine-rich repeat domain. IPAF associates with the CARD domain of procaspase-1 through a CARD-CARD interaction. Pubmed11390368 Reactome Database ID Release 43844617 Reactome, http://www.reactome.org ReactomeREACT_75785 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4406 14-3-3 gamma dimer Reactome DB_ID: 2262713 Reactome Database ID Release 432262713 Reactome, http://www.reactome.org ReactomeREACT_148473 has a Stoichiometric coefficient of 2 DAPKs Converted from EntitySet in Reactome Reactome DB_ID: 418812 Reactome Database ID Release 43418812 Reactome, http://www.reactome.org ReactomeREACT_22954 pro-protein C Reactome DB_ID: 159772 Reactome Database ID Release 43159772 Reactome, http://www.reactome.org ReactomeREACT_5288 has a Stoichiometric coefficient of 1 14-3-3 theta dimer Reactome DB_ID: 2262714 Reactome Database ID Release 432262714 Reactome, http://www.reactome.org ReactomeREACT_148252 has a Stoichiometric coefficient of 2 14-3-3 sigma dimer Reactome DB_ID: 2262716 Reactome Database ID Release 432262716 Reactome, http://www.reactome.org ReactomeREACT_148077 has a Stoichiometric coefficient of 1 PathwayStep4420 PathwayStep4422 PathwayStep4421 DOHH:Fe++ Reactome DB_ID: 204627 Reactome Database ID Release 43204627 Reactome, http://www.reactome.org ReactomeREACT_12867 deoxyhypusine hydroxylase holoenzyme has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 14-3-3 sigma dimer Reactome DB_ID: 2457845 Reactome Database ID Release 432457845 Reactome, http://www.reactome.org ReactomeREACT_148474 has a Stoichiometric coefficient of 1 deoxyhypusine synthase tetramer Reactome DB_ID: 204644 Reactome Database ID Release 43204644 Reactome, http://www.reactome.org ReactomeREACT_13167 has a Stoichiometric coefficient of 4 14-3-3 gamma dimer Reactome DB_ID: 2457867 Reactome Database ID Release 432457867 Reactome, http://www.reactome.org ReactomeREACT_148531 has a Stoichiometric coefficient of 2 dolichyl-phosphate mannosyltransferase Reactome DB_ID: 162692 Reactome Database ID Release 43162692 Reactome, http://www.reactome.org ReactomeREACT_3881 has a Stoichiometric coefficient of 1 SUMF1:SUMF2 Reactome DB_ID: 1614330 Reactome Database ID Release 431614330 Reactome, http://www.reactome.org ReactomeREACT_123836 has a Stoichiometric coefficient of 1 14-3-3 theta dimer Reactome DB_ID: 2457862 Reactome Database ID Release 432457862 Reactome, http://www.reactome.org ReactomeREACT_147917 has a Stoichiometric coefficient of 2 pro-protein C Reactome DB_ID: 159731 Reactome Database ID Release 43159731 Reactome, http://www.reactome.org ReactomeREACT_5866 has a Stoichiometric coefficient of 1 Phospho AS160:14-3-3 Phosphorylated TBC1D4:14-3-3 Reactome DB_ID: 1445126 Reactome Database ID Release 431445126 Reactome, http://www.reactome.org ReactomeREACT_148102 has a Stoichiometric coefficient of 1 pro-factor X Reactome DB_ID: 159744 Reactome Database ID Release 43159744 Reactome, http://www.reactome.org ReactomeREACT_5343 has a Stoichiometric coefficient of 1 Phospho AS160:14-3-3:IRAP Phosphorylated TBC1D4:14-3-3:LNPEP Reactome DB_ID: 1445124 Reactome Database ID Release 431445124 Reactome, http://www.reactome.org ReactomeREACT_148392 has a Stoichiometric coefficient of 1 p-5S-T642-TBC1D4:14-3-3:LNPEP protein C Reactome DB_ID: 159830 Reactome Database ID Release 43159830 Reactome, http://www.reactome.org ReactomeREACT_5618 has a Stoichiometric coefficient of 1 14-3-3 eta dimer Reactome DB_ID: 2457859 Reactome Database ID Release 432457859 Reactome, http://www.reactome.org ReactomeREACT_148598 has a Stoichiometric coefficient of 2 factor X Reactome DB_ID: 159785 Reactome Database ID Release 43159785 Reactome, http://www.reactome.org ReactomeREACT_3453 has a Stoichiometric coefficient of 1 14-3-3 dimer Converted from EntitySet in Reactome Reactome DB_ID: 2457842 Reactome Database ID Release 432457842 Reactome, http://www.reactome.org ReactomeREACT_148152 P2X7 mediates membrane pores that include pannexin-1 At higher concentrations of extracellular ATP, the P2X7 channel acts as an inducer of nonselective macropores permeable to large (up to 800 Da) inorganic and organic molecules. These 'death complex' pores rapidly leads to complete collapse of ionic gradients, changing the cytosolic environment from high K/ low Na/ low Cl to low K/ high Na/ high Cl (Steinberg et al. 1987, Steinberg & Silverstein 1987, Kahlenberg & Dubyak 2004). The long carboxyl-terminal cytoplasmic domain of P2X7 (352-595) appears to be crucial for P2X7 pore formation (Cheewatrakoolpong et al. 2005, Adinolfi et al. 2005). P2X7 membrane pores were recently shown to include pannexin-1 (Locovei et al. 2007). Pannexins have low homology with the invertebrate innexin gap junction proteins, reported to form gap junction channels and also to function as hemi-gap junction channels that are sensitive to gap junction channel blockers (Bruzzone et al. 2003, 2005). The P2X7 receptor is generally accepted to be part of a multimeric complex, not fully characterized (Kim et al. 2001). Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed11707406 Pubmed14597722 Pubmed15075209 Pubmed15715654 Pubmed15896293 Pubmed17036048 Pubmed17240370 Pubmed18404507 Pubmed2182768 Pubmed3597398 Pubmed450099 Reactome Database ID Release 43877198 Reactome, http://www.reactome.org ReactomeREACT_75933 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 pro-factor X Reactome DB_ID: 159734 Reactome Database ID Release 43159734 Reactome, http://www.reactome.org ReactomeREACT_5090 has a Stoichiometric coefficient of 1 SGT1 binds HSP90 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed14761955 Reactome Database ID Release 43874087 Reactome, http://www.reactome.org ReactomeREACT_75814 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The ubiquitin ligase–associated protein SGT1 (SUGT1) has two putative HSP90 binding domains, a tetratricopeptide repeat and a p23-like CHORD and Sgt1 (CS) domain. The CS domain of human SGT1 physically interacts with HSP90. SGT1 and related proteins are believed to recruit heat shock proteins to multiprotein assemblies (Lee et al. 2004). pro-protein C, uncarboxylated Reactome DB_ID: 159852 Reactome Database ID Release 43159852 Reactome, http://www.reactome.org ReactomeREACT_3534 has a Stoichiometric coefficient of 1 SGT1:HSP90 binds inactive NLRP3 Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed17435760 Reactome Database ID Release 43873951 Reactome, http://www.reactome.org ReactomeREACT_75769 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 SGT1 and HSP90 bind the NLRP3 (NALP3) LRR domain. Genetic studies in plants suggest a role for SGT1-HSP90 as co-chaperones of plant resistance (R) proteins, serving to maintain them in an inactive but signaling-competent state. R-protein activation is beleived to lead to dissociation of the SGT1-HSP90 complex. SGT1 and HSP90 are highly conserved, while R proteins are structurally related to mammalian NLRs. Human SGT1 and HSP90 were found to bind NLRP3. Knockdown of human SGT1 by small interfering RNA or chemical inhibition of HSP90 abrogated NLRP3 inflammasome activity, indicating that they are involved in regulation of NLRP3 inflammasome signaling (Mayor et al. 2007). TXNIP binds reduced thioredoxin Authored: Jupe, S, 2011-04-15 Edited: Jupe, S, 2011-04-28 Pubmed10419473 Pubmed17603038 Reactome Database ID Release 431250264 Reactome, http://www.reactome.org ReactomeREACT_75760 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 TXNIP interacts with the redox-active domain of thioredoxin (TRX) and is believed to act as an oxidative stress mediator by inhibiting TRX activity or by limiting its bioavailability (Nishiyama et al. 1999, Liyanage et al. 2007). PathwayStep4412 ROS oxidize thioredoxin Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-04-28 Pubmed17132626 Pubmed18403674 Pubmed20023662 Reactome Database ID Release 431250280 Reactome, http://www.reactome.org ReactomeREACT_75816 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The presence of reactive oxygen species (ROS) leads to the oxidation of thioredoxin and consequent release of TXNIP (Zhou et al. 2010). The source of the ROS is unclear but they are known to be essential for caspase-1 activation (Cruz et al. 2007) and are produced in response to all known NLRP3 activators (Dostert et al. 2008, Zhou et al. 2010). The freed TXNIP binds NLRP3 and is proposed to activate the NLRP3 inflammasome, explaining how ROS can bring about NLRP3 activation. PathwayStep4413 TXNIP is released from oxidized thioredoxin Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-04-28 Pubmed20023662 ROS induce the dissociation of TXNIP from thioredoxin, freeing TXNIP to subsequently bind NLRP3 and bring about activation of the NLRP3 inflammasome (Zhou et al. 2010). Reactome Database ID Release 431250253 Reactome, http://www.reactome.org ReactomeREACT_75912 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4414 TXNIP binds NLRP3 Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-04-28 Pubmed20023662 Reactome Database ID Release 431250272 Reactome, http://www.reactome.org ReactomeREACT_75932 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Thioredoxin-interacting protein (TXNIP) binds NLRP3. Reactive oxygen species (ROS) such as H2O2 increase this interaction, while the ROS inhibitor APDC blocks it (Zhou et al. 2010). This interaction is proposed to activate the NLRP3 inflammasome. PathwayStep4415 NLRP3 activation by small molecules Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed11607846 Pubmed12766759 Pubmed15075209 Pubmed17036048 Pubmed17121814 Pubmed17132626 Pubmed18280002 Pubmed18604209 Pubmed18604214 Pubmed19501527 Pubmed19826485 Pubmed20303873 Reactome Database ID Release 431306876 Reactome, http://www.reactome.org ReactomeREACT_75765 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The NLRP3 inflammasome is activated by a range of stimuli of microbial, endogenous and exogenous origins including several viruses, bacterial pore forming toxins (e.g. Craven et al. 2009), and various irritants that form crystalline or particulate structures (see Cassel et al. 2009). Multiple studies have shown that phagocytosis of particulate elicitors is necessary for activation (e.g. Hornung et al. 2008) but not for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006), which is also involved in the response to nigericin and maitotoxin (Pellegrin & Suprenenant 2007). Direct binding of elicitors to NLRP3 has not been demonstrated and the exact process of activation is unclear, though speculated to involve changes in conformation that make available the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003).<br><br>Three overlapping mechanisms are believed to be involved in NLRP3 activation. ATP stimulates the P2X7 ATP-gated ion channel leading to K+ efflux which appears necessary for NLRP3 inflammasome activation (Kahlenberg & Dubyak 2004, Dostert et al. 2008), and is believed to induce formation of pannexin-1 membrane pores. These pores give direct access of NLPR3 agonists to the cytosol. A second mechanism is the endocytosis of crystalline or particulate structures, leading to damaged lysosomes which release their contents (Hornung et al. 2008, Halle et al. 2008). The third element is the generation of reactive oxygen species (ROS) which activate NLRP3, shown to be a critical step for the activation of caspase-1 following ATP stimulation (Cruz et al. 2007). The source of the ROS is unclear. PathwayStep4416 NLRP3 activation by elicitor proteins Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed11607846 Pubmed12766759 Pubmed15075209 Pubmed17036048 Pubmed17121814 Pubmed17132626 Pubmed18280002 Pubmed18604209 Pubmed18604214 Pubmed19501527 Pubmed19826485 Pubmed20303873 Reactome Database ID Release 43844440 Reactome, http://www.reactome.org ReactomeREACT_75877 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The NLRP3 inflammasome is activated by a range of stimuli of microbial, endogenous and exogenous origins including several viruses, bacterial pore forming toxins (e.g. Craven et al. 2009), and various irritants that form crystalline or particulate structures (see Cassel et al. 2009). Multiple studies have shown that phagocytosis of particulate elicitors is necessary for activation (e.g. Hornung et al. 2008) but not for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006), which is also involved in the response to nigericin and maitotoxin (Pellegrin & Suprenenant 2007). Direct binding of elicitors to NLRP3 has not been demonstrated and the exact process of activation is unclear, though speculated to involve changes in conformation that make available the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003).<br><br>Three overlapping mechanisms are believed to be involved in NLRP3 activation. ATP stimulates the P2X7 ATP-gated ion channel leading to K+ efflux which appears necessary for NLRP3 inflammasome activation (Kahlenberg & Dubyak 2004, Dostert et al. 2008), and is believed to induce formation of pannexin-1 membrane pores. These pores give direct access of NLPR3 agonists to the cytosol. A second mechanism is the endocytosis of crystalline or particulate structures, leading to damaged lysosomes which release their contents (Hornung et al. 2008, Halle et al. 2008). The third element is the generation of reactive oxygen species (ROS) which activate NLRP3, shown to be a critical step for the activation of caspase-1 following ATP stimulation (Cruz et al. 2007). The source of the ROS is unclear. PathwayStep4417 NLRP3 oligomerizes via NACHT domains Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2010-04-22 NLRP3 contains a NACHT/NOD domain that in related proteins is responsible for oligomerization (Inohara & Nunez 2001, 2003). NLRP1 forms oligomers upon stimulation with MDP (Faustin et al. 2007) and the enforced oligomerization of NLRP3 PYD domains enhances ASC-dependent effects on apoptosis (Dowds et al. 2002). NOD-mediated oligomerization is widely considered to be part of the activation process for the NLRP3 inflammasome (Schroder et al. 2010, Schroder & Tschopp, 2010). The extent of oligomerization is not known, but models based on the the apoptotic initiator protein Apaf-1 suggest a posible heptameric platform (Proell et al. 2008). Pubmed11607846 Pubmed12615073 Pubmed12766759 Pubmed17349957 Pubmed17703304 Pubmed18446235 Pubmed20075245 Reactome Database ID Release 431296421 Reactome, http://www.reactome.org ReactomeREACT_75761 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 PathwayStep4418 PathwayStep4419 Cleavage of C3 by C3 convertases Authored: de Bono, B, 2004-08-04 09:17:50 C4b and C2a bind to form the classical pathway C3-convertase (C4b2a complex), C3b and the Bb fragment of Factor B form the alternative pathway C3 convertase. The C3(H2O):Bb C3 convertase is sometimes called the initiating convertase, and the C5 convertases also have C3 convertase activity (Rawal & Pangburn 2001). EC Number: 3.4.21 Edited: Jupe, S, 2010-11-17 Pubmed11367526 Pubmed15199963 Reactome Database ID Release 43166817 Reactome, http://www.reactome.org ReactomeREACT_7990 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Creation of the Membrane Attack Complex (MAC) Authored: de Bono, B, 2004-08-04 09:17:50 Pubmed6177822 Reactome Database ID Release 43173725 Reactome, http://www.reactome.org ReactomeREACT_7988 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 The membrane attack complex is composed of one C5:C6:C7:C8 complex and between 12-15 C9 molecules (Podack et al. 1982 - 12 represented in this reaction). has a Stoichiometric coefficient of 12 Activation of C5 Authored: de Bono, B, 2004-08-04 09:17:50 EC Number: 3.4.21 ISBN0781735149 Reactome Database ID Release 43173680 Reactome, http://www.reactome.org ReactomeREACT_7989 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 The same complexes as for C3 activation are employed for the cleavage of C5. C3 convertases with an additional C3b molecule covalently deposited in the immediate vicinity form the C5 convertases C3b,Bb,C3b and C4b,2a,3b, respectively. The second C3b acts like an anvil for C5: it interacts with C5 and presents C5 in the correct conformation for cleavage by the C2a or Bb enzyme. Formation of classic C5 convertase Authored: de Bono, B, 2004-08-04 09:17:50 C5 convertases are serine proteases that cleave C5 with high efficiency; the C3 convertases can cleave C5 but have a poor affinity for C5, with a Km of 6-9 microM. The high affinity C5 convertases are generated when the low affinity C3/C5 convertases such as C4b:C2a deposit C3b by cleaving native C3. These C3b-containing C3/C5 convertases have Km values of 0.005 microM, well below the normal concentration of C5 in blood (0.37 microM). They have very low Vmax rates, just one C5 cleaved per 1–4 min per enzyme (Rawal & Pangburn 1998). Edited: Jupe, S, 2010-11-17 Pubmed12878586 Pubmed9642242 Reactome Database ID Release 43173636 Reactome, http://www.reactome.org ReactomeREACT_8022 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Formation of C5b:C6:C7 complex Authored: de Bono, B, 2004-08-04 09:17:50 Pubmed3052276 Reactome Database ID Release 43173709 Reactome, http://www.reactome.org ReactomeREACT_7950 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Formation of C5b:C6:C7:C8 complex Authored: de Bono, B, 2004-08-04 09:17:50 Pubmed3052276 Reactome Database ID Release 43173723 Reactome, http://www.reactome.org ReactomeREACT_7946 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 C7 allows complex to insert into membrane under attack Authored: de Bono, B, 2004-08-04 09:17:50 Pubmed3052276 Reactome Database ID Release 43173720 Reactome, http://www.reactome.org ReactomeREACT_7982 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 GPI-GnT GPI-N-acetylglucosaminyltransferase Reactome DB_ID: 162850 Reactome Database ID Release 43162850 Reactome, http://www.reactome.org ReactomeREACT_5237 has a Stoichiometric coefficient of 1 PIG-F:GPI7 complex Reactome DB_ID: 162728 Reactome Database ID Release 43162728 Reactome, http://www.reactome.org ReactomeREACT_5313 has a Stoichiometric coefficient of 1 GPI transamidase Reactome DB_ID: 162690 Reactome Database ID Release 43162690 Reactome, http://www.reactome.org ReactomeREACT_4592 has a Stoichiometric coefficient of 1 GNPNAT1 homodimer Reactome DB_ID: 771697 Reactome Database ID Release 43771697 Reactome, http://www.reactome.org ReactomeREACT_22659 has a Stoichiometric coefficient of 2 UAP1 homodimer Reactome DB_ID: 771695 Reactome Database ID Release 43771695 Reactome, http://www.reactome.org ReactomeREACT_22471 has a Stoichiometric coefficient of 2 unfolded protein:(Glc)3 (GlcNAc)2 (Man)9 (Asn)1 Reactome DB_ID: 532534 Reactome Database ID Release 43532534 Reactome, http://www.reactome.org ReactomeREACT_22818 has a Stoichiometric coefficient of 1 OST complex Reactome DB_ID: 532516 Reactome Database ID Release 43532516 Reactome, http://www.reactome.org ReactomeREACT_23228 has a Stoichiometric coefficient of 1 unfolded protein:(Glc)2 (GlcNAc)2 (Man)9 (Asn)1 Reactome DB_ID: 532669 Reactome Database ID Release 43532669 Reactome, http://www.reactome.org ReactomeREACT_24146 has a Stoichiometric coefficient of 1 unfolded protein:(Glc)2 (GlcNAc)2 (Man)9 (Asn)1:malectin Reactome DB_ID: 901051 Reactome Database ID Release 43901051 Reactome, http://www.reactome.org ReactomeREACT_24801 has a Stoichiometric coefficient of 1 C3 convertases spontaneously dissociate Authored: Jupe, S, 2010-10-26 C3b:Bb is naturally labile with a half-life of ~90 s. unless bound to properdin on the cell surface (Medicus et al. 1976). C4bC2a is also unstable, lasting at best a few minutes (Kerr et al. 1980). Decay is associated with the release of the Bb or C2a fragments respectively into the fluid phase. The liberated C3b/C4b is able to re-bind Bb/C2a if Factor B/C2 are present. Edited: Jupe, S, 2010-11-01 Pubmed6906228 Pubmed978134 Reactome Database ID Release 43981621 Reactome, http://www.reactome.org ReactomeREACT_118641 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 has a Stoichiometric coefficient of 3 Factor H binds to C3b Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 Factor H (FH) regulates the alternative pathway C3 convertase C3bBb and its C3b component both in plasma and at host cell surfaces. FH binds to plasma C3b, making it unavailable, and acts as a cofactor for the factor I-mediated proteolytic inactivation of C3b to iC3b. Pubmed1067618 Pubmed301546 Reactome Database ID Release 43976768 Reactome, http://www.reactome.org ReactomeREACT_118712 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Factor H binds host cell surface markers Authored: Jupe, S, 2010-11-09 Edited: Jupe, S, 2010-11-09 Factor H preferentially binds to host cells and surfaces that have negatively charged cell surface polyanions such as heparin and sialic acid commonly found on host cells (Kazatchkine et al. 1979, Meri & Pangburn 1990). This mediates protection of plasma-exposed host structures. Pubmed16192651 Pubmed762425 Reactome Database ID Release 431006169 Reactome, http://www.reactome.org ReactomeREACT_118604 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 GPI mannosyltransferase I Reactome DB_ID: 162829 Reactome Database ID Release 43162829 Reactome, http://www.reactome.org ReactomeREACT_2364 has a Stoichiometric coefficient of 1 PIG-F:PIG-O complex Reactome DB_ID: 162885 Reactome Database ID Release 43162885 Reactome, http://www.reactome.org ReactomeREACT_5770 has a Stoichiometric coefficient of 1 Factor B binds to surface-associated C3b Authored: de Bono, B, 2006-07-21 13:57:35 C3b on a surface binds Factor B from solution to form a complex (Schreiber et al. 1978; Muller-Eberhard 1988). Edited: Jupe, S, 2010-11-17 Pubmed279011 Pubmed3052276 Reactome Database ID Release 43183126 Reactome, http://www.reactome.org ReactomeREACT_7966 Reviewed: D'Eustachio, P, 2006-08-28 21:16:15 C3b binds to cell surface Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 Metastable C3b can bind a wide variety of proteins and carbohydrates expressed on biological surfaces (Coico & Sunshine, 2009; Kimball 2010). This is an essentially random event (Dodds & Law, 1998); binding may be to host or microorganism. However, certain surface sugars have greater C3b binding rates, perhaps explaining variations in microorganism suceptibility (Pangburn, M. in The Complement System, Ed. Rother et al. 1998). Pubmed268620 Pubmed9914899 Reactome Database ID Release 43981539 Reactome, http://www.reactome.org ReactomeREACT_25075 Reviewed: D'Eustachio, P, 2010-11-30 C3(H2O):Factor Bb cleaves C3 to C3b and C3a Authored: de Bono, B, 2006-02-16 13:19:05 C3(H2O):Factor Bb is a C3 convertase, sometimes referred to as the initial C3 convertase (iC3). The Factor Bb component catalyzes the hydrolysis of C3 to produce C3b and C3a. This reaction is not known to be directly coupled to the association of C3b complexes with a cell surface. It is believed that a small proportion of C3b spontaneously associates with the cell surface, otherwise it is rapidly inactivated (Muller-Eberhard 1988). EC Number: 3.4.21 Edited: Jupe, S, 2010-11-17 Pubmed3052276 Reactome Database ID Release 43183130 Reactome, http://www.reactome.org ReactomeREACT_7948 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Factor D cleaves C3(H2O)-bound Factor B Authored: de Bono, B, 2004-08-04 09:17:50 EC Number: 3.4.21 Edited: Jupe, S, 2010-11-17 Factor D, a constitutively active serine protease found in trace amounts in the blood, cleaves a specific Arg-Lys bond in the Factor B component of the soluble C3(H2O):Factor B complex, yielding C3(H2O):Factor Bb and an inactive polypeptide, Factor Ba (Fearon and Austin 1975; Lesavre and Muller-Eberhard 1978; Lesavre et al. 1979; Schreiber et al. 1978). Pubmed279011 Pubmed458145 Pubmed809512 Pubmed82604 Reactome Database ID Release 43173745 Reactome, http://www.reactome.org ReactomeREACT_7981 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Factor B binds to C3(H2O) Authored: de Bono, B, 2004-08-04 09:17:50 Edited: Jupe, S, 2010-11-17 Pubmed279011 Reactome Database ID Release 43173740 Reactome, http://www.reactome.org ReactomeREACT_8013 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Thioester bond hydrolysis causes conformational rearrangements that give C3(H2O) the ability to bind Factor B (Schreiber et al. 1978). The spontaneous hydrolysis rate of C3 under physiological conditions and temperature is about l% per hour, thus the C3b-like properties of C3(H2O) provide a continuous low level initiation of the alternative pathway of complement activation (Pangburn & Muller-Eberhard 1983). Spontaneous hydrolysis of C3 thioester Authored: de Bono, B, 2004-08-04 09:17:50 Edited: Jupe, S, 2010-11-17 Pubmed6586103 Pubmed6903192 Pubmed6912277 Pubmed6934510 Reactome Database ID Release 43173739 Reactome, http://www.reactome.org ReactomeREACT_8007 The thioester linkage between cysteine residue 1010 and glutamine residue 1013 in the alpha chain of Complement factor 3 (C3) can spontaneously hydrolyze, yielding so-called C3(H2O) (Tack et al. 1980; Pangburn & Muller-Eberhard 1980; Pangburn et al. 1981). Thioester bond hydrolysis causes conformational rearrangements that give C3(H2O) the ability to bind Factor B. The spontaneous hydrolysis rate of C3 under physiological conditions and temperature is about l% per hour, thus the C3b-like properties of C3(H2O) provide a continuous low level initiation of the alternative pathway of complement activation (Pangburn & Muller-Eberhard 1983). If not bound by Factor B, C3(H2O) binds Factor H and is inactivated by Factor I unfolded protein:glycan:chaperone:ERp57 Reactome DB_ID: 901040 Reactome Database ID Release 43901040 Reactome, http://www.reactome.org ReactomeREACT_24597 has a Stoichiometric coefficient of 1 unfolded protein:glycan Reactome DB_ID: 901017 Reactome Database ID Release 43901017 Reactome, http://www.reactome.org ReactomeREACT_24107 has a Stoichiometric coefficient of 1 calnexin/calreticulin Reactome DB_ID: 548862 Reactome Database ID Release 43548862 Reactome, http://www.reactome.org ReactomeREACT_24766 has a Stoichiometric coefficient of 1 unfolded protein:(Glc)1 (GlcNAc)2 (Man)9 (Asn)1:chaperone:ERp57 Reactome DB_ID: 909545 Reactome Database ID Release 43909545 Reactome, http://www.reactome.org ReactomeREACT_24059 has a Stoichiometric coefficient of 1 (un)folded protein:(GlcNAc)2 (Man)9 Reactome DB_ID: 912283 Reactome Database ID Release 43912283 Reactome, http://www.reactome.org ReactomeREACT_24760 has a Stoichiometric coefficient of 1 unfolded protein:glycan (no glucose) Reactome DB_ID: 901021 Reactome Database ID Release 43901021 Reactome, http://www.reactome.org ReactomeREACT_24309 has a Stoichiometric coefficient of 1 (un)folded protein:(GlcNAc)2 (Man)9 Reactome DB_ID: 909547 Reactome Database ID Release 43909547 Reactome, http://www.reactome.org ReactomeREACT_24075 has a Stoichiometric coefficient of 1 Formation of alternate C5 convertase Authored: de Bono, B, 2004-08-04 09:17:50 EC Number: 3.4.21 Pubmed16301317 Pubmed950465 Pubmed978134 Reactome Database ID Release 43174551 Reactome, http://www.reactome.org ReactomeREACT_7986 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 The complex of C3b:Factor Bb, stabilized on the cell surface by properdin, catalyzes the cleavage of C3 to yield C3b and C3a. The C3b is recruited to the C3b:Factor B complex through its interaction with properdin (Daha et al. 1976; Medicus et al. 1976; Hourcade 2006), yielding the alternate C5 convertase. glucosidase II Reactome DB_ID: 532671 Reactome Database ID Release 43532671 Reactome, http://www.reactome.org ReactomeREACT_24609 has a Stoichiometric coefficient of 1 Formation of C5b:C6 complex Authored: de Bono, B, 2004-08-04 09:17:50 Pubmed3052276 Reactome Database ID Release 43173705 Reactome, http://www.reactome.org ReactomeREACT_7976 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 unfolded protein:(Glc)1 (GlcNAc)2 (Man)9 (Asn)1:chaperone Reactome DB_ID: 909542 Reactome Database ID Release 43909542 Reactome, http://www.reactome.org ReactomeREACT_24814 has a Stoichiometric coefficient of 1 Factor D cleaves C3b-bound Factor B Authored: de Bono, B, 2006-07-21 15:55:23 EC Number: 3.4.21 Edited: Jupe, S, 2010-11-17 Factor D, a constitutively active serine protease found in trace amounts in the blood, cleaves a specific Arg-Lys bond in the Factor B component of the cell surface-associated C3b:Factor B complex, yielding the alternate C3 convertase C3bBb on the surface and releasing an inactive polypeptide, Factor Ba (Lesavre and Muller-Eberhard 1978; Lesavre et al. 1979; Schreiber et al. 1978). Pubmed279011 Pubmed3052276 Pubmed458145 Reactome Database ID Release 43183122 Reactome, http://www.reactome.org ReactomeREACT_8026 Reviewed: D'Eustachio, P, 2006-08-28 21:16:15 Properdin stabilizes C3b:Bb bound to cell surfaces Authored: de Bono, B, 2004-08-04 09:17:50 C3b:Bb is naturally labile with a half-life of ~90 s; association of the complex with properdin extends the half-life to ~30 min. (Medicus et al. 1976). Properdin is found in the blood as a mixture of multivalent oligomers: 30% dimers, 45% trimers, 10% tetramers, and 15% higher oligomers. Monomers associate with one another in a head-to-tail arrangement, producing closed circular structures (Smith et al. 1984). These features suggest that the properdin oligomer associated with a C3b:Bb complex on a surface such as a cell membrane can facilitate recruitment of additional C3b:Bb complexes to the site (Farries et al. 1988; Hourcade 2006). Pubmed16301317 Pubmed3421908 Pubmed6707020 Pubmed978134 Reactome Database ID Release 43173754 Reactome, http://www.reactome.org ReactomeREACT_8018 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 unfolded protein:(Glc)1 (GlcNAc)2 (Man)9 (Asn)1 Reactome DB_ID: 532672 Reactome Database ID Release 43532672 Reactome, http://www.reactome.org ReactomeREACT_24493 has a Stoichiometric coefficient of 1 Dimerization of FGFR1 fusion proteins 8p11 myeloproliferative syndrome (EMS) is a myeloproliferative disorder that rapidly progresses to acute myeloid leukemia if not treated (reviewed in Jackson, 2010, Knights and Cook, 2010). A characteristic feature of EMS is the presence of fusion proteins that contain the kinase domain of FGFR1 and the oligomerization domain of an unrelated protein. This is believed to promote the ligand independent dimerization and activation of the kinase domain. To date, there are 11 identified partners that form fusion proteins with FGFR1 in EMS: ZMYM2 (Xiao, 1998; Popovici, 1998; Reiter, 1998; Ollendorff, 1999; Xiao, 2000), FGFR1OP1 (Popovici, 1999), CNTRL (Guasch, 2000), BCR (Demiroglu, 2001), FGFR1OP2 (Grand, 2004), TRIM24 (Belloni, 2005), CUX1 (Wasag, 2011), MYO18A (Walz, 2005), CPSF6 (Hidalgo-Curtis, 2008), HERV-K (Guasch, 2003) and LRRFIP1 (Soler, 2009). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10480903 Pubmed10688839 Pubmed10887137 Pubmed11739186 Pubmed12393597 Pubmed15034873 Pubmed15609342 Pubmed15800673 Pubmed18205209 Pubmed19369959 Pubmed19874848 Pubmed20226962 Pubmed21330321 Pubmed9425908 Pubmed9576949 Pubmed9716603 Pubmed9949182 Reactome Database ID Release 431839031 Reactome, http://www.reactome.org ReactomeREACT_120809 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 Factor I inactivates MCP/CR1-bound C4b/C3b Authored: Jupe, S, 2010-10-26 EC Number: 3.4.21 Edited: Jupe, S, 2010-11-01 Factor I cleaves the truncated alpha (a') chain of C4b between Arg-1336 and Asn-1337 and then again between Arg-956 and Thr-957, producing a 16 kDa fragment known as alpha4, derived from the C terminus of the a' chain, followed by a 27 kDa alpha3 fragment. The remaining alpha 2 (C4d) fragment stays covalently bound to the cell membrane while the complex of disulfide-linked alpha3, alpha4, beta chain and gamma chain are released (C4c) into the fluid phase (Fujita et al. 1978). Pubmed1386357 Pubmed3295051 Pubmed6214588 Pubmed702059 Pubmed7391570 Reactome Database ID Release 43977615 Reactome, http://www.reactome.org ReactomeREACT_118673 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 has a Stoichiometric coefficient of 2 Tyrosine kinase inhibitors bind and inhibit overexpressed FGFR1 dimers Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed17121884 Pubmed20094046 Pubmed20179196 Pubmed21160078 Pubmed21666749 Pubmed21711248 Reactome Database ID Release 432023462 Reactome, http://www.reactome.org ReactomeREACT_121386 Reviewed: Ezzat, S, 2012-05-15 Treatment of FGFR1-amplified lung and breast cancer cell lines with the in vitro reagents PD173704, SU5402 and FIIN-1 inhibits proliferation, while cells expressing wild-type levels of FGFR1 are insensitive to inhibitors, suggesting that amplified FGFR1 may be a suitable therapeutic target in some cancer lines (Weiss, 2010; Reis-Filho, 2006; Dutt, 2011; Turner, 2010). In fact, a number of other small molecule inhibitors, including Dovitinib and AZD4547, are currently in clinical trials for treatment of FGFR1-amplified cancers (reviewed in Turner and Grose, 2010; Wesche, 2011; http://ClinicalTrials.gov) has a Stoichiometric coefficient of 2 Complement factor I binds to MCP, CR1:C4b, C3b Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 Membrane cofactor protein (MCP) and Complement Receptor 1 (CR1) act as cofactors for the protease activity of complement factor I which binds MCP or CR1 complexes with C3b or C4b, inactivating C3b/C4b. Pubmed1386357 Pubmed6214588 Reactome Database ID Release 43977602 Reactome, http://www.reactome.org ReactomeREACT_118631 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Ligand-independent phosphorylation of overexpressed FGFR1 Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 FGFR1-amplified lung cancer and breast cancer cells show strong phosphorylation of FGFR1 and do not show elevated levels of FGF ligand, suggesting that these receptors can undergo ligand-independent activation. Phosphorylation is enhanced in the presence of exogenous ligand, supporting the notion that overexpressed FGFR1 can be activated by both ligand- and ligand-independent pathways (Koziczak, 2004; Dutt, 2008; Weiss, 2010). The biochemical consequences of overexpression of FGFR1 in other cancer types remain to be determined (reviewed in Turner and Gross, 2010; Wesche, 2011. Pubmed15116089 Pubmed20094046 Pubmed21160078 Pubmed21666749 Pubmed21711248 Reactome Database ID Release 431982066 Reactome, http://www.reactome.org ReactomeREACT_120931 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 16 DAF accelerates C3bBb/C4bC2a dissociation Authored: Jupe, S, 2010-10-26 Decay accelerating factor (DAF, CD55) is a widely distributed membrane protein. It accelerates the dissociation of C3bBb and C4C2a, thereby inhibiting the amplification of complement. DAF can bind C3b and Bb but must bind both for efficient decay acceleration. The regulatory function of DAF is believed to be inhibition of activated C3 convertase enzymes rather than binding of inactive proenzymes (Harris et al. 2007). Edited: Jupe, S, 2010-11-01 Pubmed17182573 Pubmed6238120 Pubmed8786315 Reactome Database ID Release 43977619 Reactome, http://www.reactome.org ReactomeREACT_118584 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Ligand-independent dimerization of overexpressed FGFR1 Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR1-amplified lung cancer and breast cancer cells show strong phosphorylation of FGFR1 and do not show elevated levels of FGF ligand, suggesting that these receptors can undergo ligand-independent activation. Phosphorylation is enhanced in the presence of exogenous ligand, supporting the notion that overexpressed FGFR1 can be activated by both ligand- and ligand-independent pathways (Koziczak, 2004; Dutt, 2008; Weiss, 2010). The biochemical consequences of overexpression of FGFR1 in other cancer types remain to be determined (reviewed in Turner and Gross, 2010; Wesche, 2011. Pubmed15116089 Pubmed20094046 Pubmed21160078 Pubmed21666749 Pubmed21711248 Reactome Database ID Release 431982065 Reactome, http://www.reactome.org ReactomeREACT_121098 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 DAF binds C3bBb, C4bC2a Authored: Jupe, S, 2010-10-26 Decay-accelerating-factor (DAF, CD55) is a membrane- bound complement regulatory protein that inhibits autologous complement cascade activation. It is expressed on all cells that are in close contact with serum complement proteins, but also on cells outside the vascular space and on tumour cells. DAF binds to C3bBb and C4bC2a on cell surfaces, accelerating their dissociation and thereby inhibiting the amplification of complement. DAF can bind C3b and Bb, and must bind both for efficient decay acceleration. Although it can bind the inactive proenzymes C3b and C4b, the regulatory function of DAF is believed to be inhibition of activated C3 convertase enzymes (Harris et al. 2007). Edited: Jupe, S, 2010-11-01 Pubmed11694537 Pubmed17182573 Pubmed2420889 Reactome Database ID Release 43981535 Reactome, http://www.reactome.org ReactomeREACT_118782 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 has a Stoichiometric coefficient of 2 3' overhanging DNA at resected DSB ends Reactome DB_ID: 75156 Reactome Database ID Release 4375156 Reactome, http://www.reactome.org ReactomeREACT_5086 Complement factor I binds C4BP Authored: Jupe, S, 2010-10-26 C4b-binding protein is a cofactor for Complement Factor I, allowing it to bind and thereby mediating C4b proteolysis. Edited: Jupe, S, 2010-11-01 Pubmed293746 Pubmed702059 Reactome Database ID Release 43981658 Reactome, http://www.reactome.org ReactomeREACT_118647 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 3' ends of DNA double strand break Reactome DB_ID: 75155 Reactome Database ID Release 4375155 Reactome, http://www.reactome.org ReactomeREACT_5575 C4b-binding protein binds C4b Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 Pubmed2532155 Pubmed6222381 Pubmed6334079 Pubmed670886 Reactome Database ID Release 43977626 Reactome, http://www.reactome.org ReactomeREACT_118763 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 The most abundant form of C4b-binding protein (C4BP) consists of seven alpha-chains (70kDa) and one beta-chain (45kDa) all linked by disulphide bonds to form a native protein with a molecular weight of 570kDa (Hilarp et al. 1989). Each alpha chain can bind C4b; it is not known whether full occupancy is necessary for subsequent events. The beta chain binds and inactivates Protein S, a component of the coagulation system. C4BP down-regulates complement activity in several ways: It binds to C4b thus inhibiting the formation of the classical pathway C3 convertase C4bC2a; it acts as a decay accelerating factor for existing convertases, probably by promoting dissociation of C2a; it is a cofactor in Factor I mediated C4b proteolysis. has a Stoichiometric coefficient of 7 Heteroduplex DNA containing D-loop structure Reactome DB_ID: 83891 Reactome Database ID Release 4383891 Reactome, http://www.reactome.org ReactomeREACT_5108 C4b binding protein binds C4bC2a Authored: Jupe, S, 2010-10-26 C4 binding protein accelerates the decay of C4bC2a in a dose-dependent fashion, without causing degradation of C4b, and is presumed to bind to the convertase to mediate this effect. Edited: Jupe, S, 2010-11-01 Pubmed293746 Reactome Database ID Release 43981648 Reactome, http://www.reactome.org ReactomeREACT_118752 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 has a Stoichiometric coefficient of 7 Complement factor I inactivates C4BP-bound C4b Authored: Jupe, S, 2010-10-26 C4b-binding protein is a cofactor in Factor I mediated C4b proteolysis. C4b is cleaved, releasing C4c, leaving C4d bound to the cell surface. Edited: Jupe, S, 2010-11-01 Pubmed1386357 Reactome Database ID Release 43981637 Reactome, http://www.reactome.org ReactomeREACT_118719 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 has a Stoichiometric coefficient of 7 Repaired DNA after oxidative dealkylation Reactome DB_ID: 113677 Reactome Database ID Release 43113677 Reactome, http://www.reactome.org ReactomeREACT_2610 Alkylated DNA with 3-methylcytosine Reactome DB_ID: 113679 Reactome Database ID Release 43113679 Reactome, http://www.reactome.org ReactomeREACT_4006 Alkylated DNA with 1-ethyladenine Reactome DB_ID: 113680 Reactome Database ID Release 43113680 Reactome, http://www.reactome.org ReactomeREACT_5603 DNA double-strand break ends Reactome DB_ID: 75165 Reactome Database ID Release 4375165 Reactome, http://www.reactome.org ReactomeREACT_5340 6-O-methyguanine containing damaged DNA Reactome DB_ID: 109735 Reactome Database ID Release 43109735 Reactome, http://www.reactome.org ReactomeREACT_4587 DNA with no 6-O-methylated guanine Reactome DB_ID: 109736 Reactome Database ID Release 43109736 Reactome, http://www.reactome.org ReactomeREACT_4869 MCP binds C3b, C4b Authored: Jupe, S, 2010-11-09 Edited: Jupe, S, 2010-11-09 Membrane cofactor protein (MCP; CD46) is a widely distributed C3b/C4b-binding cell surface glycoprotein which is a cofactor for Complement factor I. Pubmed12055245 Pubmed1910685 Pubmed2481448 Reactome Database ID Release 431006143 Reactome, http://www.reactome.org ReactomeREACT_118575 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 has a Stoichiometric coefficient of 2 Alkylated DNA with 1-methyladenine Reactome DB_ID: 113675 Reactome Database ID Release 43113675 Reactome, http://www.reactome.org ReactomeREACT_3986 Glycoproteins with Man8 N-glycans Converted from EntitySet in Reactome Reactome DB_ID: 948002 Reactome Database ID Release 43948002 Reactome, http://www.reactome.org ReactomeREACT_26233 Glycoproteins with Man8 N-glycans Converted from EntitySet in Reactome Reactome DB_ID: 948022 Reactome Database ID Release 43948022 Reactome, http://www.reactome.org ReactomeREACT_25793 unfolded protein:(Glc)1 (GlcNAc)2 (Man)9 Reactome DB_ID: 912297 Reactome Database ID Release 43912297 Reactome, http://www.reactome.org ReactomeREACT_26238 has a Stoichiometric coefficient of 1 HMGCR gene Reactome DB_ID: 2393990 Reactome Database ID Release 432393990 Reactome, http://www.reactome.org ReactomeREACT_148338 unfolded protein:(GlcNAc)2 (Man)8a Reactome DB_ID: 1022115 Reactome Database ID Release 431022115 Reactome, http://www.reactome.org ReactomeREACT_25760 has a Stoichiometric coefficient of 1 ALAS1 gene Reactome DB_ID: 2466373 Reactome Database ID Release 432466373 Reactome, http://www.reactome.org ReactomeREACT_152034 unfolded protein:(GlcNAc)2 (Man)7aa Reactome DB_ID: 1022117 Reactome Database ID Release 431022117 Reactome, http://www.reactome.org ReactomeREACT_27046 has a Stoichiometric coefficient of 1 FDFT1 gene Reactome DB_ID: 2393991 Reactome Database ID Release 432393991 Reactome, http://www.reactome.org ReactomeREACT_147959 (un)folded protein:(GlcNAc)2 (Man)9 Reactome DB_ID: 915150 Reactome Database ID Release 43915150 Reactome, http://www.reactome.org ReactomeREACT_24185 has a Stoichiometric coefficient of 1 HMGCS1 gene Reactome DB_ID: 2393972 Reactome Database ID Release 432393972 Reactome, http://www.reactome.org ReactomeREACT_148380 C4b binding protein displaces C2a Authored: Jupe, S, 2010-10-26 C4 binding protein accelerates the decay of C4bC2a in a dose-dependent fashion. The mechanism of this is poorly understood, but is distinct from Factor I mediated degradation of C4b and believed to represent the displacement of C2a from specific binding sites on C4b (Gigli et al. 1979). Edited: Jupe, S, 2010-11-01 Pubmed293746 Reactome Database ID Release 43981680 Reactome, http://www.reactome.org ReactomeREACT_118738 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 has a Stoichiometric coefficient of 7 unfolded protein:(GlcNAc)2 (Man)8b Reactome DB_ID: 912284 Reactome Database ID Release 43912284 Reactome, http://www.reactome.org ReactomeREACT_25730 has a Stoichiometric coefficient of 1 SERPINE1 gene Reactome DB_ID: 2106592 Reactome Database ID Release 432106592 Reactome, http://www.reactome.org ReactomeREACT_123648 unfolded protein:(GlcNAc)2 (Man)8c Reactome DB_ID: 912295 Reactome Database ID Release 43912295 Reactome, http://www.reactome.org ReactomeREACT_26221 has a Stoichiometric coefficient of 1 MYC gene MYC gene on chromosome 8 Reactome DB_ID: 2127254 Reactome Database ID Release 432127254 Reactome, http://www.reactome.org ReactomeREACT_122467 has a fragment starting at 128747680 and ending at 128753674 RAD17 Converted from EntitySet in Reactome Reactome DB_ID: 176316 Reactome Database ID Release 43176316 Reactome, http://www.reactome.org ReactomeREACT_7880 p-PLCgamma dissociates from FGFR1 fusions Authored: Rothfels, K, 2012-02-09 Dissociation from the activated receptor quickly follows phosphorylation of PLC-gamma. Phosphorylated PLC-gamma catalyzes the hydrolysis of phosphatidylinositol(4, 5)bisphosphate to generate two second messengers, diacylglycerol and inositol (1,4,5) triphosphate. Edited: Rothfels, K, 2012-05-16 Pubmed10579907 Reactome Database ID Release 431839100 Reactome, http://www.reactome.org ReactomeREACT_121073 Reviewed: Ezzat, S, 2012-05-15 unfolded protein:(GlcNAc)2 (Man)8a Reactome DB_ID: 912285 Reactome Database ID Release 43912285 Reactome, http://www.reactome.org ReactomeREACT_26747 has a Stoichiometric coefficient of 1 CDKN2B gene Reactome DB_ID: 2187305 Reactome Database ID Release 432187305 Reactome, http://www.reactome.org ReactomeREACT_124341 FGFR1 fusion proteins recruit PIK3R1 Activation of the PI3K signaling pathway has been demonstrated for a number of FGFR1 fusion proteins and inhibitors of this pathway impair the proliferative and survival function of the fusions (Guasch, 2001; Demiroglu, 2001; Chen, 2004; Lelievre, 2008). FGFR1 fusions lack the FRS2-binding site of the full length protein, so the mechanism of PI3K recruitment is unclear. Unlike BCR-FGFR1, which has been shown to recruit GRB2 through the BCR Y177 site, GRB2 did not co-precipitate with the ZMYM2-FGFR1 fusion (Roumianetsev, 2004). In the case of FOP-FGFR1, Y730 has been shown to be required for the recruitment of the p85 subunit of PI3K; however, CEP110-FGFR1, which contains Y730 in the context of the same pYXXM motif, was not shown to recruit p85 at the centrosome (Guasch, 2001). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11689702 Pubmed11739186 Pubmed15050920 Pubmed15448205 Pubmed18412956 Reactome Database ID Release 431839078 Reactome, http://www.reactome.org ReactomeREACT_120762 Reviewed: Ezzat, S, 2012-05-15 unfolded protein:(GlcNAc)2 (Man)7aa Reactome DB_ID: 912280 Reactome Database ID Release 43912280 Reactome, http://www.reactome.org ReactomeREACT_26126 has a Stoichiometric coefficient of 1 JUNB gene Reactome DB_ID: 2187294 Reactome Database ID Release 432187294 Reactome, http://www.reactome.org ReactomeREACT_122531 FGFR1 fusions bind PLCgamma Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR1 fusions with ZMYM2, BCR, FGFR1OP and TRIM24 all result in recruitment and phosphorylation of PLCgamma, and where mutational studies have been performed, mutation of the PLCgamma binding site Y766 has been shown to abrogate this signaling (Guasch, 2001; Roumiantsev, 2004, Lelievre, 2008, Chase, 2007). In the case of BCR-FGFR1 and ZMYM2-FGFR1, mutation of the PLCgamma binding site significantly decreased the transformative phenotype of the FGFR1 fusion (Roumiantsev, 2004). Pubmed11689702 Pubmed15050920 Pubmed17698633 Pubmed18412956 Reactome Database ID Release 431839094 Reactome, http://www.reactome.org ReactomeREACT_121275 Reviewed: Ezzat, S, 2012-05-15 PLCgamma is phosphorylated by FGFR1-fusions Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 PLCgamma is phosphorylated by activated FGFR, resulting in PLCgamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3. Pubmed11689702 Pubmed15050920 Reactome Database ID Release 431839098 Reactome, http://www.reactome.org ReactomeREACT_120872 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 4 Phosphorylation of FGFR1 fusion dimers After ligand-independent dimerization, FGFR1 fusions are trans-autophosphorylated on tyrosine residues (see for instance Popovici, 1998; Ollendorff, 1999; Guasch, 2000). Although the sites of tyrosine phosphorylation have not been mapped in the context of the fusion proteins, at least some of the same residues appear to be phosphorylated as in full length FGFR1. For instance, phospho-specific antibodies have demonstrated that TRIM24 is phosphorylated on Y653 and Y654, the activation loop tyrosines of FGFR1 (Belloni, 2005). Likewise, FGFR1 fusions with ZMYM2, BCR, FGFR1OP and TRIM24 all result in recruitment and phosphorylation of PLCgamma, and where mutational studies have been performed, mutation of the PLCgamma binding site Y766 has been shown to abrogate this signaling (Roumiantsev, 2004, Lelievre, 2008, Chase, 2007). In the case of BCR-FGFR1, the BCR moiety of the fusion protein has also been shown to be phosphorylated on at least one tyrosine residue, Y177, which results in the recruitment of GRB2 (Roumiantsev, 2004). Authored: Rothfels, K, 2012-02-09 EC Number: 2.7.10 Edited: Rothfels, K, 2012-05-16 Pubmed10480903 Pubmed10688839 Pubmed15050920 Pubmed15609342 Pubmed17698633 Pubmed18412956 Pubmed9576949 Reactome Database ID Release 431839065 Reactome, http://www.reactome.org ReactomeREACT_121348 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 4 Tyrosine kinase inhibitors bind and inhibit FGFR1 fusion dimer phosphorylation Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 In a murine mouse model of ZNF198-FGFR1-induced EMS, treatment with the FGFR-inhibitor Midostaurin (PKC412) resulted in prolonged survival (Chen, 2004). Similarly, growth of ZNF-198-FGFR1-, FGFR1OP2-FGFR1-, and BCR-FGFR1-expressing lines is blocked by treatment with FGFR-inhibitors (Demiroglu, 2001; Gu, 2006; Chase, 2007; Zhen, 2007; Wasag, 2011). Pubmed11739186 Pubmed15448205 Pubmed16946300 Pubmed17533378 Pubmed17698633 Pubmed21330321 Reactome Database ID Release 431839039 Reactome, http://www.reactome.org ReactomeREACT_120841 Reviewed: Ezzat, S, 2012-05-15 has a Stoichiometric coefficient of 2 SMAD7 gene Reactome DB_ID: 2106587 Reactome Database ID Release 432106587 Reactome, http://www.reactome.org ReactomeREACT_124339 Complement factor I complex formation Authored: Jupe, S, 2010-10-26 Complement factor I (CFI) is a complex of one heavy and one light chain, both cleaved from the same precursor peptide. It inactivates complement subcomponents C3b, iC3b and C4b by proteolytic cleavage of the alpha chains of C4b and C3b in the presence of cofactors such as Factor H, C4b binding protein, Complement receptor 1 (CR1) or MCP (CD46). Edited: Jupe, S, 2010-11-01 Pubmed2956252 Pubmed301546 Reactome Database ID Release 43976801 Reactome, http://www.reactome.org ReactomeREACT_118674 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Factor H displaces Bb Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 Factor H greatly accelerates the displacement (decay) of Complement factor Bb from C3b. Pubmed1067618 Reactome Database ID Release 43977605 Reactome, http://www.reactome.org ReactomeREACT_118727 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Factor H binds to C3bBb Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 Factor H (FH) binds to C3bBb, leading to displacement of Bb. Complement factor H-related protein 3 (FHR-3) has also been reported to bind C3Bb leading to inhibition of C3Bb C3 convertase activity (Fritsche et al. 2010). FH also acts as a cofactor for the factor I-mediated proteolytic inactivation of C3b to iC3b. Pubmed1067618 Pubmed20843825 Pubmed301546 Reactome Database ID Release 43977363 Reactome, http://www.reactome.org ReactomeREACT_118710 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Factor H binds to membrane-associated C3b Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 Factor H (FH) regulates the alternative pathway C3 convertase C3bBb and its C3b component both in plasma and at host cell surfaces. FH binds to membrane-associated C3b, competing with Factor B and thereby preventing formation of the active C3 convertase C3bBb. In addition, it acts as a cofactor for the Factor I-mediated proteolytic inactivation of C3b to iC3b. Pubmed1067618 Reactome Database ID Release 43981728 Reactome, http://www.reactome.org ReactomeREACT_118815 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Elongated DNA template with bypassed lesion Reactome DB_ID: 110310 Reactome Database ID Release 43110310 Reactome, http://www.reactome.org ReactomeREACT_3182 Factor I inactivates Factor H-boundC3b Authored: Jupe, S, 2010-10-26 EC Number: 3.4.21 Edited: Jupe, S, 2010-11-01 Following the displacement of Bb from C3bBb, Factor I cleaves Factor H-bound C3b producing iC3b, which remains bound to the membrane. The majority of the C3b alpha chain is retained as two fragments which are tethered to the beta chain by disulphide bonds. iC3b is proteolytically inactive and cannot contribute to the complement cascade process, though it still contributes to opsonization. Pubmed3848661 Pubmed6219696 Reactome Database ID Release 43977371 Reactome, http://www.reactome.org ReactomeREACT_118841 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 damaged DNA substrate inserted with correct base complement Reactome DB_ID: 110289 Reactome Database ID Release 43110289 Reactome, http://www.reactome.org ReactomeREACT_5776 Complement factor I binds to membrane-associated Factor H:C3b Authored: Jupe, S, 2010-10-26 Complement factor I binds to the Factor H:C3b complex. Edited: Jupe, S, 2010-11-01 Pubmed3848661 Reactome Database ID Release 43977359 Reactome, http://www.reactome.org ReactomeREACT_118844 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 damaged DNA substrate Reactome DB_ID: 109939 Reactome Database ID Release 43109939 Reactome, http://www.reactome.org ReactomeREACT_2765 Factor I inactivates plasma Factor H-bound C3b Authored: Jupe, S, 2010-10-26 Complement factor I cleaves the alpha chain of C3b at two positions, generating inactivated C3b (iC3b) and a small fragment C3f which is released. The majority of the alpha chain is retained as two fragments which are tethered by disulphide bonds. iC3b is proteolytically inactive. EC Number: 3.4.21 Edited: Jupe, S, 2010-11-01 Pubmed6219696 Reactome Database ID Release 43976743 Reactome, http://www.reactome.org ReactomeREACT_118650 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 damaged DNA substrate with misinserted bases Reactome DB_ID: 110284 Reactome Database ID Release 43110284 Reactome, http://www.reactome.org ReactomeREACT_3020 Complement factor I binds to extracellular Factor H:C3b Authored: Jupe, S, 2010-10-26 Complement factor I binds the factor H:C3b complex. Edited: Jupe, S, 2010-11-01 Pubmed6219696 Reactome Database ID Release 43976810 Reactome, http://www.reactome.org ReactomeREACT_118583 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Pol Delta synthesized oligonucleotide Reactome DB_ID: 110345 Reactome Database ID Release 43110345 Reactome, http://www.reactome.org ReactomeREACT_3170 DNA containing ligated patch of replacement residues Reactome DB_ID: 110369 Reactome Database ID Release 43110369 Reactome, http://www.reactome.org ReactomeREACT_5110 dNTP Reactome DB_ID: 110300 Reactome Database ID Release 43110300 Reactome, http://www.reactome.org ReactomeREACT_2960 Replacement synthesized nucleotide Reactome DB_ID: 111251 Reactome Database ID Release 43111251 Reactome, http://www.reactome.org ReactomeREACT_3432 DNA strand break containing replaced unligated residue Reactome DB_ID: 110340 Reactome Database ID Release 43110340 Reactome, http://www.reactome.org ReactomeREACT_3294 DNA strand containing replaced ligated residue Reactome DB_ID: 110342 Reactome Database ID Release 43110342 Reactome, http://www.reactome.org ReactomeREACT_4950 Sec13p:Sec31p Complex Reactome DB_ID: 204015 Reactome Database ID Release 43204015 Reactome, http://www.reactome.org ReactomeREACT_12786 has a Stoichiometric coefficient of 1 Sec13p:Sec31p Complex Reactome DB_ID: 203993 Reactome Database ID Release 43203993 Reactome, http://www.reactome.org ReactomeREACT_13123 has a Stoichiometric coefficient of 1 Sar1b:Sec23p:Sec24p:Sec13p:Sec31p Complex Reactome DB_ID: 204019 Reactome Database ID Release 43204019 Reactome, http://www.reactome.org ReactomeREACT_12742 has a Stoichiometric coefficient of 1 Sec23p:Sec24p Complex Reactome DB_ID: 203975 Reactome Database ID Release 43203975 Reactome, http://www.reactome.org ReactomeREACT_13290 has a Stoichiometric coefficient of 1 Sar1b:GTP:Sec23p:Sec24p:Sec13p:Sec31p Complex Reactome DB_ID: 203999 Reactome Database ID Release 43203999 Reactome, http://www.reactome.org ReactomeREACT_13165 has a Stoichiometric coefficient of 1 LMAN1:MCFD2 Reactome DB_ID: 1017219 Reactome Database ID Release 431017219 Reactome, http://www.reactome.org ReactomeREACT_26123 has a Stoichiometric coefficient of 1 Sar1b:GDP Complex Reactome DB_ID: 203989 Reactome Database ID Release 43203989 Reactome, http://www.reactome.org ReactomeREACT_12715 has a Stoichiometric coefficient of 1 CR1 binds C3bBb/C4bC2a Authored: Jupe, S, 2010-10-26 Complement Receptor 1 (CR1) is a widely distributed cell surface protein that is a decay accelerating factor for the conventional (C4bC2a) and alternative (C3bBb) C3 convertases (Coico & Sunshine 2009). Edited: Jupe, S, 2010-11-01 Pubmed293688 Reactome Database ID Release 43977375 Reactome, http://www.reactome.org ReactomeREACT_118580 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 has a Stoichiometric coefficient of 2 unfolded protein:(GlcNAc)2 (Man)8a Reactome DB_ID: 947998 Reactome Database ID Release 43947998 Reactome, http://www.reactome.org ReactomeREACT_26107 has a Stoichiometric coefficient of 1 Displacement of C2a/Bb by CR1 Authored: Jupe, S, 2010-10-26 Complement Receptor 1 (CR1) displaces the activated enzyme components Bb and C2a from the conventional and alternative C3 convertases C4bC2a and C3bBb, respectivley. Edited: Jupe, S, 2010-11-01 Pubmed10531307 Pubmed11694537 Pubmed293688 Reactome Database ID Release 43977629 Reactome, http://www.reactome.org ReactomeREACT_118692 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 unfolded protein:(GlcNAc)2 (Man)8c Reactome DB_ID: 948006 Reactome Database ID Release 43948006 Reactome, http://www.reactome.org ReactomeREACT_25676 has a Stoichiometric coefficient of 1 unfolded protein:(GlcNAc)2 (Man)8b Reactome DB_ID: 948004 Reactome Database ID Release 43948004 Reactome, http://www.reactome.org ReactomeREACT_27066 has a Stoichiometric coefficient of 1 excised DNA fragment with lesion Reactome DB_ID: 109960 Reactome Database ID Release 43109960 Reactome, http://www.reactome.org ReactomeREACT_2556 damaged DNA with 3' incision Reactome DB_ID: 109942 Reactome Database ID Release 43109942 Reactome, http://www.reactome.org ReactomeREACT_3924 newly synthesized DNA fragment Reactome DB_ID: 109964 Reactome Database ID Release 43109964 Reactome, http://www.reactome.org ReactomeREACT_3448 incised DNA without lesion Reactome DB_ID: 109961 Reactome Database ID Release 43109961 Reactome, http://www.reactome.org ReactomeREACT_3852 damaged DNA substrate:nascent mRNA hybrid with 3' incision Reactome DB_ID: 110298 Reactome Database ID Release 43110298 Reactome, http://www.reactome.org ReactomeREACT_2845 Repaired double-stranded DNA Reactome DB_ID: 109966 Reactome Database ID Release 43109966 Reactome, http://www.reactome.org ReactomeREACT_4318 repaired DNA template:nascent mRNA hybrid Reactome DB_ID: 110295 Reactome Database ID Release 43110295 Reactome, http://www.reactome.org ReactomeREACT_5433 damaged DNA substrate:nascent mRNA hybrid with dual incisions Reactome DB_ID: 110303 Reactome Database ID Release 43110303 Reactome, http://www.reactome.org ReactomeREACT_5428 ATM/ATR kinase Converted from EntitySet in Reactome Reactome DB_ID: 421853 Reactome Database ID Release 43421853 Reactome, http://www.reactome.org ReactomeREACT_18974 MAN2:Zn2+ Converted from EntitySet in Reactome Reactome DB_ID: 975821 Reactome Database ID Release 43975821 Reactome, http://www.reactome.org ReactomeREACT_26817 Sec23p:Sec24p Complex Reactome DB_ID: 204023 Reactome Database ID Release 43204023 Reactome, http://www.reactome.org ReactomeREACT_12975 has a Stoichiometric coefficient of 1 MAN2A2:Zn2+ Reactome DB_ID: 975818 Reactome Database ID Release 43975818 Reactome, http://www.reactome.org ReactomeREACT_25411 has a Stoichiometric coefficient of 1 MAN2A1:Zn2+ Reactome DB_ID: 975820 Reactome Database ID Release 43975820 Reactome, http://www.reactome.org ReactomeREACT_26337 has a Stoichiometric coefficient of 1 C1GALT1:COSMC Reactome DB_ID: 1964504 Reactome Database ID Release 431964504 Reactome, http://www.reactome.org ReactomeREACT_116566 has a Stoichiometric coefficient of 1 GALNT:COSMC Reactome DB_ID: 914019 Reactome Database ID Release 43914019 Reactome, http://www.reactome.org ReactomeREACT_117496 has a Stoichiometric coefficient of 1 MIA40:ERV1 CHCHD4:GFER Reactome DB_ID: 1307797 Reactome Database ID Release 431307797 Reactome, http://www.reactome.org ReactomeREACT_119823 has a Stoichiometric coefficient of 1 TOMM70:TOMM40 Reactome DB_ID: 1252240 Reactome Database ID Release 431252240 Reactome, http://www.reactome.org ReactomeREACT_120217 TOM40 Complex TOM70 Complex TOM71 Complex TOMM40 Complex TOMM40:TOMM70:TOMM20:TOMM22:TOMM5:TOMM6:TOMM7 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TIMM8A:TIMM13 Reactome DB_ID: 1252231 Reactome Database ID Release 431252231 Reactome, http://www.reactome.org ReactomeREACT_119880 has a Stoichiometric coefficient of 3 TIMM8:TIMM13 Converted from EntitySet in Reactome Reactome DB_ID: 1299461 Reactome Database ID Release 431299461 Reactome, http://www.reactome.org ReactomeREACT_119612 alpha/beta tubulin folding intermediate Converted from EntitySet in Reactome Reactome DB_ID: 391243 Reactome Database ID Release 43391243 Reactome, http://www.reactome.org ReactomeREACT_17449 CCT/TriC substrate proteins with unknown chaperones Converted from EntitySet in Reactome Reactome DB_ID: 390473 Reactome Database ID Release 43390473 Reactome, http://www.reactome.org ReactomeREACT_17376 cleaved Holliday structure Reactome DB_ID: 83636 Reactome Database ID Release 4383636 Reactome, http://www.reactome.org ReactomeREACT_2367 Holliday structure Reactome DB_ID: 75220 Reactome Database ID Release 4375220 Reactome, http://www.reactome.org ReactomeREACT_5857 Heteroduplex DNA with D-loop structure with extended pairing between invading strand and complementary heteroduplex strand and containing newly synthesized ends Reactome DB_ID: 83898 Reactome Database ID Release 4383898 Reactome, http://www.reactome.org ReactomeREACT_2357 Heteroduplex DNA with D-loop structure with extended pairing between invading strand and complementary heteroduplex strand Reactome DB_ID: 83893 Reactome Database ID Release 4383893 Reactome, http://www.reactome.org ReactomeREACT_4075 processed (ligatable) DNA double strand break end Reactome DB_ID: 75914 Reactome Database ID Release 4375914 Reactome, http://www.reactome.org ReactomeREACT_3084 repaired DNA duplex Reactome DB_ID: 84010 Reactome Database ID Release 4384010 Reactome, http://www.reactome.org ReactomeREACT_4943 homologous duplex DNA Reactome DB_ID: 84008 Reactome Database ID Release 4384008 Reactome, http://www.reactome.org ReactomeREACT_5063 duplex containing reannealed extended strands from damaged DNA molecule Reactome DB_ID: 84009 Reactome Database ID Release 4384009 Reactome, http://www.reactome.org ReactomeREACT_2929 ligated DNA double-strand break ends Reactome DB_ID: 75927 Reactome Database ID Release 4375927 Reactome, http://www.reactome.org ReactomeREACT_3350 unknown endonuclease Reactome DB_ID: 177947 Reactome Database ID Release 43177947 Reactome, http://www.reactome.org ReactomeREACT_6978 TIMM9:TIMM10 Reactome DB_ID: 1955372 Reactome Database ID Release 431955372 Reactome, http://www.reactome.org ReactomeREACT_118963 has a Stoichiometric coefficient of 1 TIMM8:TIMM13:Protein Reactome DB_ID: 1299471 Reactome Database ID Release 431299471 Reactome, http://www.reactome.org ReactomeREACT_119483 has a Stoichiometric coefficient of 1 TIMM8B:TIMM13 Reactome DB_ID: 1252244 Reactome Database ID Release 431252244 Reactome, http://www.reactome.org ReactomeREACT_119891 has a Stoichiometric coefficient of 3 TOB Complex Reactome DB_ID: 1252247 Reactome Database ID Release 431252247 Reactome, http://www.reactome.org ReactomeREACT_120017 SAM50 Complex SAMM50 Complex has a Stoichiometric coefficient of 1 TIMM9:TIMM10:FXC1 Reactome DB_ID: 1252245 Reactome Database ID Release 431252245 Reactome, http://www.reactome.org ReactomeREACT_119795 has a Stoichiometric coefficient of 1 TIMM9:TIMM10:FXC1:TIM22:Protein Reactome DB_ID: 1299470 Reactome Database ID Release 431299470 Reactome, http://www.reactome.org ReactomeREACT_119578 has a Stoichiometric coefficient of 1 TIMM9:TIMM10:Protein Reactome DB_ID: 1955377 Reactome Database ID Release 431955377 Reactome, http://www.reactome.org ReactomeREACT_119702 has a Stoichiometric coefficient of 1 TIMM23 SORT:Precursor Cargo Reactome DB_ID: 1299473 Reactome Database ID Release 431299473 Reactome, http://www.reactome.org ReactomeREACT_120218 has a Stoichiometric coefficient of 1 PAM Complex Reactome DB_ID: 1252246 Reactome Database ID Release 431252246 Reactome, http://www.reactome.org ReactomeREACT_120135 has a Stoichiometric coefficient of 1 TIMM23 Complex Reactome DB_ID: 1252242 Reactome Database ID Release 431252242 Reactome, http://www.reactome.org ReactomeREACT_119853 has a Stoichiometric coefficient of 1 damaged DNA with open bubble structure Reactome DB_ID: 109944 Reactome Database ID Release 43109944 Reactome, http://www.reactome.org ReactomeREACT_5682 Glycoprotein with sialic acid Reactome DB_ID: 981615 Reactome Database ID Release 43981615 Reactome, http://www.reactome.org ReactomeREACT_26541 Glycoprotein with galactose Reactome DB_ID: 981618 Reactome Database ID Release 43981618 Reactome, http://www.reactome.org ReactomeREACT_26909 Cleaved collagen type I fibril Reactome DB_ID: 2537491 Reactome Database ID Release 432537491 Reactome, http://www.reactome.org ReactomeREACT_151702 Glycoprotein with fucosyl alpha-1,6-GlcNAc Reactome DB_ID: 1028779 Reactome Database ID Release 431028779 Reactome, http://www.reactome.org ReactomeREACT_26726 Glycoprotein with bifurcating GlcNAc in position 3 Reactome DB_ID: 981613 Reactome Database ID Release 43981613 Reactome, http://www.reactome.org ReactomeREACT_25989 Glycoprotein with GlcNAc in position 5 Reactome DB_ID: 981617 Reactome Database ID Release 43981617 Reactome, http://www.reactome.org ReactomeREACT_26240 Glycoprotein with GlcNAc in position 4 Reactome DB_ID: 981616 Reactome Database ID Release 43981616 Reactome, http://www.reactome.org ReactomeREACT_26694 TLR6/2 ligand associates with CD14 and CD36 within lipid rafts Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-16 Pubmed16880211 Reactome Database ID Release 432559464 Reactome, http://www.reactome.org ReactomeREACT_150409 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 Scavenger receptor CD36 has been reported to function as an essential co-receptor involved in recognition of LTA and certain diacylated lipoproteins and presenting them to the TLR2:TLR6 heterodimer at the cell surface. CD14, a GPI-anchored molecule found on the cell surface of human phagocytes, has been also implicated in TLR2:TLR6 signaling [Stuart L et al 2005; Hoebe KP et al 2005; Triantafilou M et al 2006; Nilsen NJ et al 2008] TLR6:TLR2 is recruited to ligand:CD14:CD36 Authored: D'Eustachio, P, Gay, NJ, Gale M, Jr, Zwaginga, JJ, 2006-04-19 04:09:58 Edited: Shamovsky, V, 2012-11-19 Pubmed10364168 Pubmed10426996 Pubmed10490993 Pubmed10549626 Pubmed11123271 Pubmed14977973 Reactome Database ID Release 43168950 Reactome, http://www.reactome.org ReactomeREACT_7984 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Reviewed: Gillespie, ME, 2010-11-30 TLR2 - in combination with TLR6 - plays a major role in recognizing lipoteichoic acid (LTA) and peptidoglycan wall products from Gram-positive bacteria, as well as Mycobacterial diacylated lipopeptides. MBL binds to repetitive carbohydrate structures on the surfaces of viruses, bacteria, fungi, and protozoa Authored: de Bono, B, 2004-08-04 09:17:50 Extracellular MBL oligomer complexed with MASP2 binds to a repetitive carbohydrate motif on a target surface to form a MASP2:MBL oligomer:carbohydrate complex on the surface. Such motifs occur on the surfaces of viruses, bacteria, fungi and protozoa. The affinity of any one MBL binding site for a carbohydrate ligand is low, but interaction between multiple binding sites on an MBL oligomer and a repetitive carbohydrate motif on a target surface allow high-avidity binding. The specificity of the MBL binding site (it does not bind glucose or sialic acid) and the requirement for a repeated target motif may account for the failure of MBL to bind human glycoproteins under normal conditions (Petersen et al. 2001). This reaction in particular represents the interaction of MBL with bacterial mannose repeats. Pubmed10639434 Pubmed11532276 Reactome Database ID Release 43166721 Reactome, http://www.reactome.org ReactomeREACT_7983 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 has a Stoichiometric coefficient of 4 Activation of MBL Authored: de Bono, B, 2004-08-04 09:17:50 In this reaction, the MASP2 serine protease moiety of an MBL oligomer:MASP2 complex bound to a target surface becomes catalytically active. Pubmed10925294 Reactome Database ID Release 43166726 Reactome, http://www.reactome.org ReactomeREACT_7965 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Activation of C1R Authored: de Bono, B, 2004-08-04 09:17:50 C1 activation requires interaction with two separate Fc domains, so pentavalent IgM antibody is far more efficient at complement activation than IgG antibody (Muller-Eberhard and Kunkel 1961). Antibody binding results in a conformational change in the C1r component of the C1 complex and a proteolytic cleavage of C1r, activating it (Ziccardi and Cooper 1976). This reaction is irreversible under physiological conditions. EC Number: 3.4.21 Pubmed1249422 Pubmed13726743 Reactome Database ID Release 43173626 Reactome, http://www.reactome.org ReactomeREACT_7978 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Conversion of C4 into C4a and C4b Authored: de Bono, B, 2004-08-04 09:17:50 EC Number: 3.4.21 Edited: Jupe, S, 2010-11-11 Pubmed12396008 Pubmed14280442 Pubmed15199963 Pubmed7391570 Pubmed9041627 Reactome Database ID Release 43166753 Reactome, http://www.reactome.org ReactomeREACT_8002 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 The alpha chain of C4 is cleaved, releasing an N-terminal portion of this chain as C4a. The beta and gamma chains are not cleaved and remain linked to the alpha chain by disulfide bonds (Nagasawa et al. 1976, 1980). The resulting C4b heterotrimer undergoes a gross conformational change; the internal thioester in C4b becomes exposed and able to form covalent bonds with surrounding molecules (Law and Dodds 1997). A large proportion of the bonds formed are with water, but some will attach C4b to biological surfaces (Rother et al. 1998). This irreversible reaction can be catalyzed by activated MBL, generated through the lectin pathway of complement activation (Fujita et al. 2004; Hajela et al. 2002), and by activated C1, generated through the classical pathway (Muller-Eberhard and Lepow 1965).<br><br>N.B. Humans have two highly polymorphic loci for Complement factor 4, C4A and C4B. C4A alleles carry the Rodgers (Rg) blood group antigens while the C4B alleles carry the Chido (Ch) blood group antigens. The two loci encode non identical C4 peptides; C4 derived from C4A reacts more rapidly with the amino groups of peptide antigens while C4B allotypes react more rapidly with the hydroxyl group of carbohydrate antigens. The names of the two loci are always represented in uppercase. C4a and C4b refer to the peptide products of Complement Factor 4 cleavage. has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 4 Prorenin-Prorenin Receptor Reactome DB_ID: 2065393 Reactome Database ID Release 432065393 Reactome, http://www.reactome.org ReactomeREACT_148518 has a Stoichiometric coefficient of 1 Activation of C1S Authored: de Bono, B, 2004-08-04 09:17:50 EC Number: 3.4.21 In this irreversible reaction, the activated C1r subunit of the C1:antibody:antigen complex cleaves the C1s subunit of the complex, activating it in turn (Ziccardi and Cooper 1976). The resulting complex is a C4 activator. Pubmed814163 Reactome Database ID Release 43173631 Reactome, http://www.reactome.org ReactomeREACT_7977 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Renin:Prorenin Receptor Reactome DB_ID: 2022360 Reactome Database ID Release 432022360 Reactome, http://www.reactome.org ReactomeREACT_148206 has a Stoichiometric coefficient of 1 Conversion of C2 into C2a and C2b Authored: de Bono, B, 2004-08-04 09:17:50 C2 is cleaved into the large C2a and the small C2b fragment. This irreversible, extracellular reaction can be catalyzed by activated MBL, generated through the lectin pathway of complement activation (Vorup-Jensen et al. 2000), and by activated C1, generated through the classical pathway (Nasagawa and Stroud 1977). N.B. Early literature refers to the larger fragment of C2 as C2a. However, complement scientists decided that the smaller of all C fragments should be designated with an 'a', the larger with a 'b', changing the nomenclature for C2. For this reason recent literature may refer to the larger C2 fragment as C2b, and the classical C3 convertase as C4bC2b. Throughout this pathway, Reactome uses the current (Feb 2012) Uniprot names which adhere to the original naming practice. EC Number: 3.4.21 Pubmed10925294 Pubmed12396008 Pubmed6019133 Pubmed70787 Reactome Database ID Release 43166792 Reactome, http://www.reactome.org ReactomeREACT_7959 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 ANPEP Dimer Reactome DB_ID: 2022361 Reactome Database ID Release 432022361 Reactome, http://www.reactome.org ReactomeREACT_148325 has a Stoichiometric coefficient of 2 C4b binds to cell surface Authored: Jupe, S, 2010-11-01 Edited: Jupe, S, 2010-11-01 Pubmed12791093 Pubmed6332733 Pubmed7391573 Pubmed8495193 Pubmed9914899 Reactome Database ID Release 43981713 Reactome, http://www.reactome.org ReactomeREACT_25166 Reviewed: D'Eustachio, P, 2010-11-30 The cleavage of C4 into C4a and C4b releases an acyl group from the intrachain thioester bond, allowing C4b to bond covalently to any adjacent biological substrates (Dodds & Law 1998). C4 is encoded at two loci, C4A and C4B. The C4b proteins derived from these genes are not identical and have different binding preferences (Law et al 1984, Sepp et al. 1993); C4A-derived C4b binds more efficiently than C4B-derived C4b to amino groups, while C4B-derived C4b is more effective than C4A in binding to hydroxyl groups. The site of C4b deposition is not clearly established (Møller-Kristensen et al. 2003) but generally accepted to be the activating cell membrane surface, though it may be the activating complex itself. ENPEP Dimer Reactome DB_ID: 2022357 Reactome Database ID Release 432022357 Reactome, http://www.reactome.org ReactomeREACT_148271 has a Stoichiometric coefficient of 2 Mitochondrial processing peptidase Reactome DB_ID: 1299458 Reactome Database ID Release 431299458 Reactome, http://www.reactome.org ReactomeREACT_119809 has a Stoichiometric coefficient of 1 Formation of Classical C3 convertase (C4b:C2a complex) Authored: de Bono, B, 2004-08-04 09:17:50 C4b and C2a form a complex termed the classical pathway C3 convertase (Muller-Eberhard et al. 1967). C2a that fails to bind C4b is rapidly inactivated. Edited: Jupe, S, 2010-11-17 Pubmed6019133 Reactome Database ID Release 43166795 Reactome, http://www.reactome.org ReactomeREACT_8014 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 TIMM23 SORT:Cargo Reactome DB_ID: 1299469 Reactome Database ID Release 431299469 Reactome, http://www.reactome.org ReactomeREACT_119235 has a Stoichiometric coefficient of 1 TIMM23 PAM:Cargo Reactome DB_ID: 1299474 Reactome Database ID Release 431299474 Reactome, http://www.reactome.org ReactomeREACT_120146 has a Stoichiometric coefficient of 1 TIMM23 PAM:Precursor Cargo Reactome DB_ID: 1299462 Reactome Database ID Release 431299462 Reactome, http://www.reactome.org ReactomeREACT_118867 has a Stoichiometric coefficient of 1 Sodium dependent Serotonin transporter Reactome DB_ID: 380618 Reactome Database ID Release 43380618 Reactome, http://www.reactome.org ReactomeREACT_15766 GABA(A) receptor alpha subunits Converted from EntitySet in Reactome GABA(A) receptor alpha (1,2,3) subunits Reactome DB_ID: 975253 Reactome Database ID Release 43975253 Reactome, http://www.reactome.org ReactomeREACT_26449 Voltage gated potassium channel subunits Kv1-12 Converted from EntitySet in Reactome Reactome DB_ID: 1296098 Reactome Database ID Release 431296098 Reactome, http://www.reactome.org ReactomeREACT_76085 VAMP/Synaptobrevin Converted from EntitySet in Reactome Reactome DB_ID: 181512 Reactome Database ID Release 43181512 Reactome, http://www.reactome.org ReactomeREACT_11688 ERBB4jmAcyt1s80 dimer Reactome DB_ID: 1252008 Reactome Database ID Release 431252008 Reactome, http://www.reactome.org ReactomeREACT_116961 has a Stoichiometric coefficient of 2 E4ICD Converted from EntitySet in Reactome ERBB4s80 Reactome DB_ID: 1251980 Reactome Database ID Release 431251980 Reactome, http://www.reactome.org ReactomeREACT_116936 (GlcNAc)2 (Man)7bc Reactome DB_ID: 901089 Reactome Database ID Release 43901089 Reactome, http://www.reactome.org ReactomeREACT_24316 Glycans (no glucose) bound to unfolded protein Converted from EntitySet in Reactome Reactome DB_ID: 901054 Reactome Database ID Release 43901054 Reactome, http://www.reactome.org ReactomeREACT_24224 (Glc)1 (GlcNAc)2 (Man)8c Reactome DB_ID: 901027 Reactome Database ID Release 43901027 Reactome, http://www.reactome.org ReactomeREACT_24169 (Glc)1 (GlcNAc)2 (Man)7bc Reactome DB_ID: 901056 Reactome Database ID Release 43901056 Reactome, http://www.reactome.org ReactomeREACT_24569 Glycans bound to unfolded protein Converted from EntitySet in Reactome Reactome DB_ID: 901080 Reactome Database ID Release 43901080 Reactome, http://www.reactome.org ReactomeREACT_24855 unfolded protein Reactome DB_ID: 381130 Reactome Database ID Release 43381130 Reactome, http://www.reactome.org ReactomeREACT_18756 mannose (a1) mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI Reactome DB_ID: 162719 Reactome Database ID Release 43162719 Reactome, http://www.reactome.org ReactomeREACT_2710 (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI Reactome DB_ID: 162843 Reactome Database ID Release 43162843 Reactome, http://www.reactome.org ReactomeREACT_2468 ERBB4jmAcyt2s80 dimer Reactome DB_ID: 1252007 Reactome Database ID Release 431252007 Reactome, http://www.reactome.org ReactomeREACT_116214 has a Stoichiometric coefficient of 2 Hemi-Connexin 62 Complex Reactome DB_ID: 375334 Reactome Database ID Release 43375334 Reactome, http://www.reactome.org ReactomeREACT_18050 has a Stoichiometric coefficient of 6 Connexin 62 Gap Junction Complex Reactome DB_ID: 375341 Reactome Database ID Release 43375341 Reactome, http://www.reactome.org ReactomeREACT_17390 has a Stoichiometric coefficient of 2 Hemi-Connexin 45 Complex Reactome DB_ID: 375347 Reactome Database ID Release 43375347 Reactome, http://www.reactome.org ReactomeREACT_17822 has a Stoichiometric coefficient of 6 Connexin 36/Connexin 45 Gap Junction Complex Reactome DB_ID: 375333 Reactome Database ID Release 43375333 Reactome, http://www.reactome.org ReactomeREACT_17318 has a Stoichiometric coefficient of 1 Connexon36 Reactome DB_ID: 158044 Reactome Database ID Release 43158044 Reactome, http://www.reactome.org ReactomeREACT_17519 has a Stoichiometric coefficient of 6 Connexin 36 Gap Junction Complex Reactome DB_ID: 375351 Reactome Database ID Release 43375351 Reactome, http://www.reactome.org ReactomeREACT_17249 has a Stoichiometric coefficient of 2 ERBB4s80:Tab2:Ncor1 Reactome DB_ID: 1253315 Reactome Database ID Release 431253315 Reactome, http://www.reactome.org ReactomeREACT_117876 has a Stoichiometric coefficient of 1 Tab2:Ncor1 Reactome DB_ID: 1253329 Reactome Database ID Release 431253329 Reactome, http://www.reactome.org ReactomeREACT_117227 has a Stoichiometric coefficient of 1 unfolded protein Reactome DB_ID: 1022114 Reactome Database ID Release 431022114 Reactome, http://www.reactome.org ReactomeREACT_26201 unfolded protein Reactome DB_ID: 915147 Reactome Database ID Release 43915147 Reactome, http://www.reactome.org ReactomeREACT_24830 unfolded protein Reactome DB_ID: 912296 Reactome Database ID Release 43912296 Reactome, http://www.reactome.org ReactomeREACT_24755 Pannexin 1/Pannexin 2 Gap Junction Complex Reactome DB_ID: 375332 Reactome Database ID Release 43375332 Reactome, http://www.reactome.org ReactomeREACT_17586 has a Stoichiometric coefficient of 1 Fatty acids Reactome DB_ID: 163730 Reactome Database ID Release 43163730 Reactome, http://www.reactome.org ReactomeREACT_3744 Guanine nucleotide-binding protein beta subunit Reactome DB_ID: 114545 Reactome Database ID Release 43114545 Reactome, http://www.reactome.org ReactomeREACT_3904 Iron Sulfur Cluster Iron Sulphur Cluster Reactome DB_ID: 113591 Reactome Database ID Release 43113591 Reactome, http://www.reactome.org ReactomeREACT_4380 ACC Converted from EntitySet in Reactome Reactome DB_ID: 200563 Reactome Database ID Release 43200563 Reactome, http://www.reactome.org ReactomeREACT_11654 Cleavage of the Signal Peptide of Preproghrelin Authored: May, B, 2009-06-10 EC Number: 3.4.21 Edited: May, B, 2009-06-10 Pubmed18396350 Pubmed19280057 Reactome Database ID Release 43422051 Reactome, http://www.reactome.org ReactomeREACT_19296 Reviewed: Zhang, Weizhen, 2009-08-29 The N-terminal 23 amino acid residues are cleaved from preproghrelin by the signal peptidase complex. The products are proghrelin (94 amino acid residues) or des-acyl-Gln14 proghrelin (93 amino acid residues), depending on the variant of the mRNA that was translated. Octanoylation of Proghrelin by Ghrelin O-acyltransferase Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Proghrelin is octanoylated by ghrelin O-acyltransferase (GOAT/MBOAT4), an enzyme present in the endoplasmic reticulum membrane which both transports the octanoic acid substrate and condenses it on the hydroxyl group of serine-3 of the mature protein. The most common acylated form of ghrelin is octanoyl ghrelin but decanoyl ghrelin is also detected. Ghrelin is the only protein known to undergo such a modification. Pubmed12414809 Pubmed18396350 Pubmed18443287 Pubmed19280057 Pubmed19628676 Reactome Database ID Release 43422104 Reactome, http://www.reactome.org ReactomeREACT_19318 Reviewed: Zhang, Weizhen, 2009-08-29 IGF2BP3 Binds Specific RNA Molecules Authored: May, B, 2009-07-04 Edited: May, B, 2009-07-04 Insulin-like Growth Factor mRNA Binding Factor-3 (IGF2BP3, also known as IMP3 and VICKZ3) binds several specific RNAs containing the sequence motif CAUH (where H is A, C, or U). Binding causes stabilization and subcellular localization of the RNA.<br>Isoforms of IGF2 mRNA containing leader-3 are bound by IGF2BP3 at the 5' UTR, repressing translation (other isoforms of IGF2 are constitutive). Pubmed11713986 Pubmed15601260 Pubmed16541107 Pubmed20371350 Pubmed9891060 Reactome Database ID Release 43428287 Reactome, http://www.reactome.org ReactomeREACT_22429 Reviewed: Chao, JA, 2010-05-30 Reviewed: Singer, RH, 2010-05-30 IGF2BP2 Binds Specific RNA Molecules Authored: May, B, 2009-07-04 Edited: May, B, 2009-07-04 Insulin-like Growth Factor mRNA Binding Factor-2 (IGF2BP2, also known as IMP2 and VICKZ2) binds several specific RNAs containing the sequence motif CAUH (where H is A, C, or U). Binding causes stabilization and subcellular localization of the RNA.<br>Isoforms of IGF2 mRNA containing leader-3 are bound by IGF2BP2 at the 5' UTR, repressing translation (Other isoforms of IGF2 are constitutive).<br>IGF2BP2 may be a causal factor in type 2 diabetes. Pubmed11713986 Pubmed15601260 Pubmed18618095 Pubmed19429674 Pubmed20371350 Pubmed9891060 Reactome Database ID Release 43428293 Reactome, http://www.reactome.org ReactomeREACT_22195 Reviewed: Chao, JA, 2010-05-30 Reviewed: Singer, RH, 2010-05-30 IGF2BP1 Binds Specific RNA Molecules Authored: May, B, 2009-07-04 Edited: May, B, 2009-07-04 Insulin-like Growth Factor mRNA Binding Factor-1 (IGF2BP1, also known as ZBP1, CRD-BP, IMP1, and VICKZ1) binds several specific RNAs containing the sequence motif CAUH (where H is A, C, or U). Binding causes stabilization and subcellular localization of the RNA.<br>Isoforms of IGF2 mRNA containing leader-3 are bound by IGF2BP1 at the 5' UTR, repressing translation (other isoforms of IGF2 are constitutive).<br>ZBP1 (IGF2BP1) uses its third and fourth KH domains to recognize the first 28 nts of the 3? UTR of Beta?actin mRNA. The KH domains are arranged as an anti-parallel pseudo-dimer that specifically recognize a bipartite element located in this RNA sequence.<br>MYC (c-MYC) and Beta-TRCP1 mRNAs are bound at sites termed Coding Region Determinants (CDRs) in the open reading frame of the message. Binding of the MYC mRNA shields it from degradation and increases its half-life<br> The CD44 mRNA is bound at the 3' UTR.<br>IGF2BP1 also binds the non-coding, imprinted H19 RNA. Pubmed10875929 Pubmed11713986 Pubmed12024010 Pubmed12894594 Pubmed15601260 Pubmed16541107 Pubmed16778892 Pubmed17652133 Pubmed19029303 Pubmed20080952 Pubmed20371350 Pubmed9891060 Reactome Database ID Release 43428296 Reactome, http://www.reactome.org ReactomeREACT_22241 Reviewed: Chao, JA, 2010-05-30 Reviewed: Singer, RH, 2010-05-30 Proteolysis of the IGF:IGFBP-5:ALS Complex by PAPP-A2 Both Pregnancy Associated Plasma Protein A (PAPP-A) and A2 (PAPP-A2) cleave IGFBP-5 in the IGF:IGFBP-5:ALS Complex between amino acids 163 and 164, releasing IGF. PPAP-A has also been shown to cleave IGFBP-5 that is not complexed with IGF. EC Number: 3.4.24 Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Pubmed11264294 Pubmed11522292 Pubmed11606061 Pubmed11788658 Pubmed12379487 Pubmed12466191 Pubmed17047378 Reactome Database ID Release 43381537 Reactome, http://www.reactome.org ReactomeREACT_15304 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Proteolysis of the IGF:IGFBP-4 Complex by PAPP-A EC Number: 3.4.24 Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Pregnancy associated Plasma Protein A (PPAP-A) cleaves IGFBP-4 in the IGF:IGFBP-4 Complex between amino acids 156 and 157, releasing IGF. Pubmed10077652 Pubmed10898936 Pubmed11158056 Pubmed12241545 Pubmed12379487 Pubmed12466191 Pubmed12904166 Pubmed17047378 Pubmed17249697 Pubmed17312271 Reactome Database ID Release 43381518 Reactome, http://www.reactome.org ReactomeREACT_15447 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Proteolysis of the IGF:IGFBP-3:ALS Complex by Thrombin EC Number: 3.4.21 Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Pubmed11739083 Pubmed12379487 Pubmed12466191 Pubmed17047378 Pubmed8817670 Reactome Database ID Release 43381446 Reactome, http://www.reactome.org ReactomeREACT_15373 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Thrombin cleaves IGFBP-3 in the IGF:IGFBP-3:ALS Complex between amino acids 124 and 125 and between amino acids 233 and 234, releasing IGF. Proteolysis of the IGF:IGFBP-3:ALS Complex by Prostate-specific Antigen EC Number: 3.4.21 Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Prostate specific Antigen (PSA) cleaves IGFBP-3 in the IGF:IGFBP-3:ALS Complex between amino acids 186 and 187. Other cleavage sites were observed but not reproducibly. These may have been caused by impurities in the PSA preparation. Pubmed10218588 Pubmed11751371 Pubmed12379487 Pubmed12466191 Pubmed1383255 Pubmed17047378 Pubmed7525634 Pubmed7525824 Pubmed7538844 Pubmed8817670 Reactome Database ID Release 43381466 Reactome, http://www.reactome.org ReactomeREACT_15465 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Proteolysis of the IGF:IGFBP-3:ALS Complex by Plasmin EC Number: 3.4.21 Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Plasmin cleaves IGFBP-3 in the IGF:IGFBP-3:ALS Complex between amino acids 124 and 125 and between amino acids 187 and 188, releasing IGF. Pubmed10990447 Pubmed11739083 Pubmed12379487 Pubmed12466191 Pubmed17047378 Pubmed7527330 Pubmed7588299 Pubmed8817670 Pubmed8894645 Pubmed8964575 Reactome Database ID Release 43381461 Reactome, http://www.reactome.org ReactomeREACT_15393 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Potassium Channel, closed (pancreatic beta cell) Reactome DB_ID: 446513 Reactome Database ID Release 43446513 Reactome, http://www.reactome.org ReactomeREACT_21231 Potassium Channel, open (pancreatic beta cell) Reactome DB_ID: 446505 Reactome Database ID Release 43446505 Reactome, http://www.reactome.org ReactomeREACT_20980 Guanine nucleotide-binding protein gamma subunit Reactome DB_ID: 114546 Reactome Database ID Release 43114546 Reactome, http://www.reactome.org ReactomeREACT_3712 HXEH Reactome DB_ID: 2161957 Reactome Database ID Release 432161957 Reactome, http://www.reactome.org ReactomeREACT_150886 hepoxilin specific epoxide hydrolase NEU1,4 Converted from EntitySet in Reactome Reactome DB_ID: 1605688 Reactome Database ID Release 431605688 Reactome, http://www.reactome.org ReactomeREACT_117337 ARS Converted from EntitySet in Reactome Reactome DB_ID: 1614312 Reactome Database ID Release 431614312 Reactome, http://www.reactome.org ReactomeREACT_124132 active ARS Converted from EntitySet in Reactome Reactome DB_ID: 1614309 Reactome Database ID Release 431614309 Reactome, http://www.reactome.org ReactomeREACT_122851 enoyl-CoA hydratase Reactome DB_ID: 70827 Reactome Database ID Release 4370827 Reactome, http://www.reactome.org ReactomeREACT_2716 Nicotinamide deaminase Reactome DB_ID: 197261 Reactome Database ID Release 43197261 Reactome, http://www.reactome.org ReactomeREACT_11492 ThDP kinase Reactome DB_ID: 997387 Reactome Database ID Release 43997387 Reactome, http://www.reactome.org ReactomeREACT_26649 uridine phosphorylase Converted from EntitySet in Reactome Reactome DB_ID: 977408 Reactome Database ID Release 43977408 Reactome, http://www.reactome.org ReactomeREACT_26026 Iron Sulfur Cluster Iron Sulphur Cluster Reactome DB_ID: 70986 Reactome Database ID Release 4370986 Reactome, http://www.reactome.org ReactomeREACT_5528 PathwayStep4391 PathwayStep4392 PathwayStep4390 PathwayStep4395 PathwayStep4396 PathwayStep4393 PathwayStep4394 PathwayStep4399 Autocatalytic phosphorylation of FGFR2b Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Pubmed11294897 Pubmed1379698 Pubmed1656221 Pubmed1697263 Pubmed8622701 Reactome Database ID Release 43190408 Reactome, http://www.reactome.org ReactomeREACT_9476 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The intrinsic protein tyrosine kinase activity of the activated FGFR2b receptor leads to multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Two isoforms of FGFR2b generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets. Based on sequence alignment, FGFR2 contains all 8 of the cytoplasmic tyrosine residues identified in FGFR1. has a Stoichiometric coefficient of 16 PathwayStep4397 PathwayStep4398 FGFR1c binds to FGF Authored: de Bono, B, 2007-01-10 10:27:18 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Pubmed15863029 Pubmed16597617 Reactome Database ID Release 43190256 Reactome, http://www.reactome.org ReactomeREACT_9460 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR1b Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Pubmed1379698 Pubmed16507368 Pubmed1656221 Pubmed8622701 Reactome Database ID Release 43190427 Reactome, http://www.reactome.org ReactomeREACT_9493 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. has a Stoichiometric coefficient of 14 FGFR2b binds to FGF Authored: de Bono, B, 2007-01-10 10:27:18 In this reaction, FGF receptor 2b in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Two isoforms of FGFR2b generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets. Pubmed15863029 Pubmed16597617 Pubmed1697263 Reactome Database ID Release 43190260 Reactome, http://www.reactome.org ReactomeREACT_9462 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR1c Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Pubmed11294897 Pubmed1379698 Pubmed16507368 Pubmed8622701 Pubmed9139660 Reactome Database ID Release 43190429 Reactome, http://www.reactome.org ReactomeREACT_9498 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. has a Stoichiometric coefficient of 16 Secretion of Acyl Ghrelin and C-Ghrelin Acyl ghrelin and C-ghrelin are secreted from secretory granules into the bloodstream. Five forms of acyl ghrelin have been detected: octanoyl ghrelin-28, decanoyl ghrelin-28, octanoyl ghrelin-27, decanoyl ghrelin-27, and decenoyl ghrelin-28. Unacylated ghrelin (des-acyl ghrelin) occurs at higher levels than acyl ghrelin however its function and mechanism of generation are controversial. The function, if any, of C-ghrelin is also unknown.<br>Secretion of ghrelin is stimulated by insulin-like growth factor-1 and muscarinic agonists; Secretion is inhibited by insulin, somatotropin, leptin, glucose, glucagon, and fatty acids. Carbohydrates have more inhibitory effect than fat does. The mechanisms by which the regulation is effected are unknown. Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Pubmed11089560 Pubmed11600536 Pubmed11756331 Pubmed12354137 Pubmed12553549 Pubmed14599721 Pubmed15126574 Pubmed17595255 Pubmed18396350 Pubmed19280057 Reactome Database ID Release 43422048 Reactome, http://www.reactome.org ReactomeREACT_19136 Reviewed: Zhang, Weizhen, 2009-08-29 Cleavage of Acyl Proghrelin by Prohormone Convertase 1/3 Acyl proghrelin is cleaved by prohormone convertase 1/3 (PC1/3) to yield acyl ghrelin (the N-terminal fragment) and C-ghrelin (the C-terminal fragment). Transfection experiments show that PC1/3 is sufficient to generate acyl ghrelin of 28 amino acid residues (acyl ghrelin-28). Acyl ghrelin of 27 amino acid residues (acyl ghrelin-27) can also be detected in plasma. How acyl ghrelin-27 is generated remains undetermined but it is speculated to derive from the cleavage of arginine-28 from the C-terminus of ghrelin by a carboxypeptidase B-like enzyme. Authored: May, B, 2009-06-10 EC Number: 3.4.21 Edited: May, B, 2009-06-10 Pubmed18396350 Pubmed19280057 Pubmed19628676 Reactome Database ID Release 43422021 Reactome, http://www.reactome.org ReactomeREACT_19170 Reviewed: Zhang, Weizhen, 2009-08-29 FGFR1b binds to FGF Authored: de Bono, B, 2007-01-10 10:27:18 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. NCAM and other members of the CAM protein family directly or indirectly modulate this interaction in a variety of neural tissues. The details of this interaction in vivo have not been definitively established at the molecular level, but are thought to play a central role in the regulation of the development of these tissues. Pubmed12791257 Pubmed15863029 Pubmed16045455 Pubmed16597617 Pubmed16709412 Pubmed7917292 Reactome Database ID Release 43190245 Reactome, http://www.reactome.org ReactomeREACT_9523 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 2 Deacylation of Acyl Ghrelin Authored: May, B, 2009-06-10 EC Number: 3.1 Edited: May, B, 2009-06-10 Pubmed15256494 Pubmed17289852 Pubmed18396350 Pubmed19280057 Reactome Database ID Release 43422058 Reactome, http://www.reactome.org ReactomeREACT_19294 Reviewed: Zhang, Weizhen, 2009-08-29 The majority of circulating ghrelin is not acylated (des-acyl ghrelin). Acyl ghrelin can be deacylated in the bloodstream by butyrylcholinesterase and platelet-activating factor acetylhydrolase, which are associated with circulating lipids. Other enzymes may also have this capability. It is unknown if a portion of des-acyl ghrelin in the bloodstream is generated by direct synthesis and secretion. BL Heme 1 cytochrome c1 cofactor Reactome DB_ID: 164585 Reactome Database ID Release 43164585 Reactome, http://www.reactome.org ReactomeREACT_6365 b562 Decanoylation of Proghrelin by Ghrelin O-acyltransferase Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Proghrelin is decanoylated by ghrelin O-acyltransferase (GOAT/MBOAT4), an enzyme present in the endoplasmic reticulum membrane which both transports the decanoic acid substrate and condenses it on the hydroxyl group of serine-3 of the mature protein. The most common acylated form of ghrelin is octanoyl ghrelin but decanoyl ghrelin is also detected in plasma. GOAT is able to use substrates up to tetradecanoic acid. Ghrelin is the only protein known to undergo such a modification. Pubmed12414809 Pubmed18396350 Pubmed18443287 Pubmed19280057 Pubmed19628676 Reactome Database ID Release 43422017 Reactome, http://www.reactome.org ReactomeREACT_19329 Reviewed: Zhang, Weizhen, 2009-08-29 UCP Converted from EntitySet in Reactome Reactome DB_ID: 166224 Reactome Database ID Release 43166224 Reactome, http://www.reactome.org ReactomeREACT_6451 b562 Heme bH Heme bL Reactome DB_ID: 164657 Reactome Database ID Release 43164657 Reactome, http://www.reactome.org ReactomeREACT_6569 b566 BH Heme 2 cytochrome c1 cofactor Reactome DB_ID: 164586 Reactome Database ID Release 43164586 Reactome, http://www.reactome.org ReactomeREACT_6535 b566 4Fe-4S Cluster 4Iron-4Sulfur Cluster Reactome DB_ID: 164292 Reactome Database ID Release 43164292 Reactome, http://www.reactome.org ReactomeREACT_6556 2Fe-2S Cluster 2Iron-2Sulfur Cluster Reactome DB_ID: 164296 Reactome Database ID Release 43164296 Reactome, http://www.reactome.org ReactomeREACT_6497 Biliverdin reductase Converted from EntitySet in Reactome Reactome DB_ID: 189387 Reactome Database ID Release 43189387 Reactome, http://www.reactome.org ReactomeREACT_22833 2Fe-2S Cluster 2Iron-2Sulfur Cluster Reactome DB_ID: 189408 Reactome Database ID Release 43189408 Reactome, http://www.reactome.org ReactomeREACT_9814 TMT Reactome DB_ID: 175986 Reactome Database ID Release 43175986 Reactome, http://www.reactome.org ReactomeREACT_7807 Thiol S-methyltransferase Trichloromethyl radical Reactome DB_ID: 76433 Reactome Database ID Release 4376433 Reactome, http://www.reactome.org ReactomeREACT_4348 UDPGT Reactome DB_ID: 2162090 Reactome Database ID Release 432162090 Reactome, http://www.reactome.org ReactomeREACT_122792 UDP-glucuronosyltransferase glutamine-N-acyltransferase Reactome DB_ID: 177742 Reactome Database ID Release 43177742 Reactome, http://www.reactome.org ReactomeREACT_7408 Autocatalytic phosphorylation of FGFR3c Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Pubmed11294897 Pubmed1379698 Pubmed1656221 Pubmed8622701 Reactome Database ID Release 43190388 Reactome, http://www.reactome.org ReactomeREACT_9419 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The intrinsic protein tyrosine kinase activity of activated FGF receptor 3 catalyzes multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Based on sequence alignment, FGFR3 contains 6 of the 8 cytoplasmic tyrosine residues identified in FGFR1. Mutagenesis studies highlight the importance of tyrosine residue 724 in signaling mediated by FGFR3, including transformation, SHP2 phosphorylation, and activation of MAPK, PI3K and STAT pathways. These studies also identified a role for the PLCgamma-binding tyrosine residue, Y760, in STAT activation, and a potential role for tyrosine 770 as a negative regulator of FGFR3 signaling. has a Stoichiometric coefficient of 12 FGFR3c binds to FGF Authored: de Bono, B, 2007-01-10 10:27:18 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Pubmed15863029 Pubmed16597617 Reactome Database ID Release 43190261 Reactome, http://www.reactome.org ReactomeREACT_9459 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR3b Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Pubmed11294897 Pubmed1379698 Pubmed1656221 Pubmed8622701 Reactome Database ID Release 43190385 Reactome, http://www.reactome.org ReactomeREACT_9519 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The intrinsic protein tyrosine kinase activity of activated FGF receptor 3 catalyzes multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Based on sequence alignment, FGFR3 contains 6 of the 8 cytoplasmic tyrosine residues identified in FGFR1. Mutagenesis studies highlight the importance of tyrosine residue 724 in signaling mediated by FGFR3, including transformation, SHP2 phosphorylation, and activation of MAPK, PI3K and STAT pathways. These studies also identified a role for the PLCgamma-binding tyrosine residue, Y760, in STAT activation, and a potential role for tyrosine 770 as a negative regulator of FGFR3 signaling. has a Stoichiometric coefficient of 12 FGFR3b binds to FGF Authored: de Bono, B, 2007-01-10 10:27:18 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Pubmed15863029 Pubmed16597617 Reactome Database ID Release 43190263 Reactome, http://www.reactome.org ReactomeREACT_9489 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of BetaKlotho-bound FGFR4 After being bound by BetaKlotho and FGF19, FGFR4 undergoes autophosphorylation on tyrosine residues in the intracellular portion of the receptor. The phosphorylation sites on FGFR4 have not been accurately determined in vitro or in vivo but are predicted based on sequence comparison with the other FGF receptors. Authored: Rothfels, K, 2011-08-15 Autocatalytic phosphorylation of betaKlotho-bound FGFR4 EC Number: 2.7.10 Pubmed1379698 Pubmed1656221 Pubmed17339340 Pubmed17623664 Pubmed19063940 Pubmed20080590 Pubmed8622701 Reactome Database ID Release 431307963 Reactome, http://www.reactome.org ReactomeREACT_111246 Reviewed: Gotoh, N, 2011-08-26 has a Stoichiometric coefficient of 10 FGFR4 binds BetaKlotho-bound FGF19 Authored: Rothfels, K, 2011-08-15 BetaKlotho is required for FGF19-dependent signaling through FGFR4. Pubmed17339340 Pubmed17623664 Pubmed19063940 Pubmed20080590 Reactome Database ID Release 431307955 Reactome, http://www.reactome.org ReactomeREACT_111078 Reviewed: Gotoh, N, 2011-08-26 has a Stoichiometric coefficient of 2 Autocatalytic phosphorylation of FGFR4 Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 Pubmed11294897 Pubmed1379698 Pubmed1656221 Pubmed8622701 Reactome Database ID Release 43190326 Reactome, http://www.reactome.org ReactomeREACT_9474 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The intrinsic protein tyrosine kinase activity of activated FGF receptor 4 catalyzes multiple phosphorylation events, creating a number of binding sites for membrane bound docking proteins to gather intracellular signaling mediators. Based on sequence alignment, FGFR4 contains 5 of the 8 cytoplasmic tyrosine residues identified in FGFR1. has a Stoichiometric coefficient of 10 FGFR4 binds to FGF Authored: de Bono, B, 2007-01-10 10:27:18 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Pubmed15863029 Pubmed16597617 Reactome Database ID Release 43190265 Reactome, http://www.reactome.org ReactomeREACT_9447 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 2 aminomuconate-semialdehyde dehydrogenase Reactome DB_ID: 71237 Reactome Database ID Release 4371237 Reactome, http://www.reactome.org ReactomeREACT_3638 Amino Acid Reactome DB_ID: 69599 Reactome Database ID Release 4369599 Reactome, http://www.reactome.org ReactomeREACT_2474 2-Oxoacid Reactome DB_ID: 1237175 Reactome Database ID Release 431237175 Reactome, http://www.reactome.org ReactomeREACT_76654 ACTIV ACTIVIN Converted from EntitySet in Reactome Reactome DB_ID: 1449689 Reactome Database ID Release 431449689 Reactome, http://www.reactome.org ReactomeREACT_111623 Hypotaurine dehydrogenase Reactome DB_ID: 1655455 Reactome Database ID Release 431655455 Reactome, http://www.reactome.org ReactomeREACT_117787 Autocatalytic phosphorylation of FGFR2c Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Pubmed11294897 Pubmed1379698 Pubmed1656221 Pubmed1697263 Pubmed8622701 Reactome Database ID Release 43190413 Reactome, http://www.reactome.org ReactomeREACT_9432 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The intrinsic protein tyrosine kinase activity of the activated FGFR2c receptor leads to multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Two isoforms of FGFR2c generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in autophosphorylation, but differ in their abilities to interact with downstream targets. Based on sequence alignment, FGFR2 contains all 8 of the cytoplasmic tyrosine residues identified in FGFR1. <br> has a Stoichiometric coefficient of 16 FGFR2c binds to FGF Authored: de Bono, B, 2007-01-10 10:27:18 In this reaction, FGF receptor 2c in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Two isoforms of FGFR2c generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets. Pubmed15863029 Pubmed16597617 Reactome Database ID Release 43190258 Reactome, http://www.reactome.org ReactomeREACT_9477 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 2 Double-strand DNA containing an adenine opposite to an 8-oxo guanine Reactome DB_ID: 110198 Reactome Database ID Release 43110198 Reactome, http://www.reactome.org ReactomeREACT_4167 Double-strand DNA containing a hypoxanthine Reactome DB_ID: 110205 Reactome Database ID Release 43110205 Reactome, http://www.reactome.org ReactomeREACT_3305 Double-strand DNA containing an ethenoadenine Reactome DB_ID: 110203 Reactome Database ID Release 43110203 Reactome, http://www.reactome.org ReactomeREACT_3149 Double-strand DNA containing 5-hydroxyuracil opposite to a guanine Reactome DB_ID: 110153 Reactome Database ID Release 43110153 Reactome, http://www.reactome.org ReactomeREACT_2459 DNA containing an apurinic/apyrimidinic (AP) site Reactome DB_ID: 110187 Reactome Database ID Release 43110187 Reactome, http://www.reactome.org ReactomeREACT_2655 Double-strand DNA containing a formamidopyrimidine Reactome DB_ID: 110182 Reactome Database ID Release 43110182 Reactome, http://www.reactome.org ReactomeREACT_2338 Double-strand DNA containing an 8-oxo guanine opposite to a cytosine Reactome DB_ID: 110184 Reactome Database ID Release 43110184 Reactome, http://www.reactome.org ReactomeREACT_2574 Phosphorylation of FRS2-alpha by activated FGFR Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Edited: Jupe, S, 2010-02-03 FRS2alpha is activated through tyrosine phosphorylation catalyzed by the protein kinase domain of the activated FGFR. FRS2-alpha contains four binding sites for the adaptor protein GRB2 at residues Y196, Y306, Y349 and Y392, and two binding sites for the protein tyrosine phosphatase SHP2 at residues Y436 and Y471. Different FGFR isoforms may generate different phosphorylation patterns on FRS2alpha leading to alternate downstream signaling. Pubmed12026167 Pubmed8780727 Pubmed9182757 Pubmed9632781 Reactome Database ID Release 43190353 Reactome, http://www.reactome.org ReactomeREACT_21307 Reviewed: Gotoh, N, 2011-08-26 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 6 Activated FGFR binds FRS2beta Authored: Rothfels, K, 2011-08-15 FRS2beta is predominantly expressed in the developing and adult neuroepithelium. As is the case for FRS2alpha, binding of FRS2beta to FGFR may be constitutive and/or independent of receptor activation. Elements of the downstream signaling mediated by the two FRS2 family members appear to be at least partially conserved, as FRS2beta is phosphorylated upon FGF stimulation, binds SHP2 and GRB2 and results in ERK activation. Moreover, expression of FRS2beta in FRS2alpha-/- MEFs restores ERK activation. Pubmed10629055 Pubmed15094036 Pubmed19187780 Pubmed9660748 Reactome Database ID Release 431268221 Reactome, http://www.reactome.org ReactomeREACT_111238 Reviewed: Gotoh, N, 2011-08-26 Activated FGFR and FRS2 bind to SHP2 Activated FGFR-alpha:p-FRS2 bind to SHP2 Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Pubmed14534538 Pubmed9632781 Reactome Database ID Release 43190358 Reactome, http://www.reactome.org ReactomeREACT_21248 Reviewed: Gotoh, N, 2011-08-26 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 p-FRS2alpha has two SHP2-binding sites at pY436 and pY471. Phosphorylation of FRS2-beta by activated FGFR Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Edited: Jupe, S, 2010-02-03 FRS2beta is activated through tyrosine phosphorylation catalyzed by the protein kinase domain of the activated FGFR. By sequence comparison, FRS2beta has the 2 SHP2-binding sites and has three of the four GRB2-binding sites. Pubmed12419216 Pubmed9182757 Reactome Database ID Release 43191471 Reactome, http://www.reactome.org ReactomeREACT_111201 Reviewed: Gotoh, N, 2011-08-26 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 5 GRB2:SOS1 binds to p-FRS2:activated FGFR Authored: Rothfels, K, 2011-08-15 Pubmed11353842 Pubmed11447289 Pubmed7559490 Pubmed8780727 Pubmed9182757 Reactome Database ID Release 431268255 Reactome, http://www.reactome.org ReactomeREACT_111204 Reviewed: Gotoh, N, 2011-08-26 Tyrosine phosphorylated FRS2 recruits GRB2:SOS1 complex by means of the SH3 domain of GRB2, leading to RAS-MAP kinase activation. The FRS2:GRB2-mediated pathway plays a minor role in the activation of RAS-MAP kinase pathway compared to that mediated by FRS2:SHP2. SHP2 is phosphorylated by activated FGFR Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Edited: Jupe, S, 2010-02-03 Pubmed14534538 Pubmed18373495 Pubmed9299490 Reactome Database ID Release 43190362 Reactome, http://www.reactome.org ReactomeREACT_21372 Reviewed: Gotoh, N, 2011-08-26 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Tyrosine phosphorylation of SHP2 by FGFR kinase is required for activation of the phosphatase activity of SHP2 and for downstream signaling. Tyrosine phosphorylated SHP2 plays a major role in the activation of RAS-MAP kinase pathway, although the precise role is not yet clear. has a Stoichiometric coefficient of 2 Ras nucleotide exchange by GRB2:SOS1 bound to p-FRS2:activated FGFR Authored: Rothfels, K, 2011-08-15 Pubmed8493579 Reactome Database ID Release 431268272 Reactome, http://www.reactome.org ReactomeREACT_111126 Reviewed: Gotoh, N, 2011-08-26 SOS, recruited by GRB2:p-FRS2 to activated FGFR, activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state. AGER ligands Converted from EntitySet in Reactome Reactome DB_ID: 879455 Reactome Database ID Release 43879455 Reactome, http://www.reactome.org ReactomeREACT_24759 Double-strand DNA containing a 3-methyladenine Reactome DB_ID: 110201 Reactome Database ID Release 43110201 Reactome, http://www.reactome.org ReactomeREACT_4400 adenosine phosphotransferase Reactome DB_ID: 2161183 Reactome Database ID Release 432161183 Reactome, http://www.reactome.org ReactomeREACT_124880 alpha Actin Chain Reactome DB_ID: 390576 Reactome Database ID Release 43390576 Reactome, http://www.reactome.org ReactomeREACT_17088 FGFR1c binds to Klotho-bound FGF23 Authored: de Bono, B, 2007-01-10 10:27:18 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Pubmed16597617 Pubmed17086194 Reactome Database ID Release 43190268 Reactome, http://www.reactome.org ReactomeREACT_9486 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 2 Activated FGFR binds FRS2alpha Authored: Rothfels, K, 2011-08-15 FRS2alpha is broadly expressed in adult and fetal tissues. Membrane-bound FRS2alpha interacts with FGFR as a first step in the phosphorylation of this docking protein. The juxtamembrane binding site for FRS2alpha does not contain tyrosine, so binding may be independent of receptor activation and/or constitutive. Activation of the FGFR receptor is required for FRS2alpha phosphorylation and subsequent recruitment of downstream effectors. Pubmed10629055 Pubmed18373495 Pubmed9660748 Reactome Database ID Release 431268220 Reactome, http://www.reactome.org ReactomeREACT_111055 Reviewed: Gotoh, N, 2011-08-26 Autocatalytic phosphorylation of Klotho-bound FGFR1c Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Pubmed11294897 Pubmed1379698 Pubmed16507368 Pubmed17086194 Pubmed8622701 Reactome Database ID Release 43191062 Reactome, http://www.reactome.org ReactomeREACT_9433 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. has a Stoichiometric coefficient of 16 Cyclin A Converted from EntitySet in Reactome Reactome DB_ID: 174074 Reactome Database ID Release 43174074 Reactome, http://www.reactome.org ReactomeREACT_7365 Double-strand DNA containing a dihydrouracil Reactome DB_ID: 110180 Reactome Database ID Release 43110180 Reactome, http://www.reactome.org ReactomeREACT_5125 Double-strand DNA containing a thymine glycol Reactome DB_ID: 110176 Reactome Database ID Release 43110176 Reactome, http://www.reactome.org ReactomeREACT_3196 Thymine glycol Reactome DB_ID: 110223 Reactome Database ID Release 43110223 Reactome, http://www.reactome.org ReactomeREACT_3342 cytosine glycol Reactome DB_ID: 110225 Reactome Database ID Release 43110225 Reactome, http://www.reactome.org ReactomeREACT_4879 single-stranded DNA containing an uracil Reactome DB_ID: 110162 Reactome Database ID Release 43110162 Reactome, http://www.reactome.org ReactomeREACT_5141 Double-strand DNA containing a thymine opposite to a guanine at CpG sequences Reactome DB_ID: 110169 Reactome Database ID Release 43110169 Reactome, http://www.reactome.org ReactomeREACT_4129 Double-strand DNA containing an uracil opposite to a guanine at CpG sequences Reactome DB_ID: 110167 Reactome Database ID Release 43110167 Reactome, http://www.reactome.org ReactomeREACT_4834 Double-strand DNA containing a cytosine glycol Reactome DB_ID: 110178 Reactome Database ID Release 43110178 Reactome, http://www.reactome.org ReactomeREACT_2927 Double-strand DNA containing an ethenocytosine Reactome DB_ID: 110189 Reactome Database ID Release 43110189 Reactome, http://www.reactome.org ReactomeREACT_3757 Double-strand DNA containing an uracil opposite to a guanine Reactome DB_ID: 110151 Reactome Database ID Release 43110151 Reactome, http://www.reactome.org ReactomeREACT_2780 dsDNA with T:G mismatch Double-strand DNA containing a thymine opposite to a guanine Reactome DB_ID: 110149 Reactome Database ID Release 43110149 Reactome, http://www.reactome.org ReactomeREACT_2790 Translocation of ATF6-alpha to the Golgi Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Pubmed11821395 Pubmed12110171 Pubmed15657421 Reactome Database ID Release 43381186 Reactome, http://www.reactome.org ReactomeREACT_18431 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The association between ATF6-alpha and BiP causes ATF6-alpha to be retained in the endoplasmic reticulum (ER). Once dissociated from BiP, the 2 Golgi Localization Sequences on ATF6-alpha are exposed and ATF6-alpha transits from the ER to the Golgi Apparatus. Traversal of the cortical actin network and docking at plasma membrane Authored: May, B, 2008-05-13 13:18:27 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Insulin-containing secretory granules are bound to Myosin Va via Rab27a in a complex of uncertain composition. Myosin Va moves along the cortical actin network (actin at the periphery of the cytoplasm), carrying the granules to the inner surface of the plasma membrane. A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the inner surface of the plasma membrane and a subset of about 100 docked granules form the "readily releasable" pool (granules which are released within about 5 minutes of glucose stimulation). Docking occurs by interaction between EXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located at the plasma membrane. Additional components (EXOC1, EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex.<br> Pubmed11815463 Pubmed15878854 Pubmed16714477 Pubmed9914469 Reactome Database ID Release 43265178 Reactome, http://www.reactome.org ReactomeREACT_15541 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Translocation of Insulin Secretory Granules to Cell Cortex Authored: May, B, 2008-05-13 13:18:27 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Insulin-containing secretory vesicles are translocated along microtubules (polymerized tubulin) from the trans-golgi to the cellular cortex. Motor activity is provided by Dynamin-1 but the complex that connects the secretory granule to the Kinesin-1 is not yet fully known. The process is stimulated by intracellular calcium ions (Ca2+). Pubmed16714477 Reactome Database ID Release 43265160 Reactome, http://www.reactome.org ReactomeREACT_15477 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Dissociation of ATF6-alpha:BiP Complex ATF6-alpha is a transmembrane protein located in the endoplasmic reticulum (ER) membrane with N-terminal cytoplasmic and C-terminal luminal domains. BiP binds the luminal domain of ATF6-alpha via the substrate binding domain of BiP. Binding of BiP blocks 2 Golgi localization sequences on ATF6-alpha, maintaining ATF6-alpha in the ER. <br> BiP is also a general chaperone capable of binding unfolded proteins in the ER lumen. When chaperone activity in the ER is overwhelmed, BiP dissociates from ATF6-alpha and binds the excess unfolded proteins. It is unclear whether the dissociation is due to competition of unfolded proteins for BiP or to a more specific interaction between BiP and ATF6-alpha. The dissociation exposes the Golgi localization sequences of ATF6-alpha and allows ATF6-alpha to transit to the Golgi. Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Pubmed11821395 Pubmed12110171 Pubmed15657421 Reactome Database ID Release 43381158 Reactome, http://www.reactome.org ReactomeREACT_18323 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Exocyst complex formation A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the inner surface of the plasma membrane and a subset of about 100 docked granules form the "readily releasable" pool (granules which are released within about 5 minutes of glucose stimulation). As inferred from rat MIN6 cells, docking occurs by interaction between EXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located at the plasma membrane (Tsuboi et al. 2005). Additional components (EXOC1, EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex. EXOC7 binds the plasma membrane (Matern et al. 2001). Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed11493706 Pubmed15878854 Pubmed16714477 Reactome Database ID Release 43265177 Reactome, http://www.reactome.org ReactomeREACT_15394 DNA strand break containing single nucleotide gap Reactome DB_ID: 110336 Reactome Database ID Release 43110336 Reactome, http://www.reactome.org ReactomeREACT_5226 DNA strand break containing an incision 5' to an AP site Reactome DB_ID: 110333 Reactome Database ID Release 43110333 Reactome, http://www.reactome.org ReactomeREACT_5772 Translocation of Cystine-bonded Proinsulin from the Endoplasmic Reticulum to the Golgi Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Proinsulin in the endoplasmic reticulum moves to the Golgi apparatus via vesicles that bud from the endoplasmic reticulum. Pubmed3896518 Pubmed9631292 Reactome Database ID Release 43265010 Reactome, http://www.reactome.org ReactomeREACT_15512 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Formation of Proinsulin-Zinc-Calcium Complex Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 In the presence of high concentrations of zinc and calcium, proinsulin spontaneously forms soluble complexes containing 6 molecules of proinsulin, 2 zinc ions, and 1 calcium ion. Zinc Transporters ZnT5, ZnT6, and ZnT7 are found in the membrane of the Golgi in pancreatic cells (and also in many other cell types). They play a role in maintaining the high zinc concentration in the Golgi lumen and thus catalyze the formation of the proinsulin-zinc-calcium complex. Other transporters, such as the newly identified ZnT9 and ZnT10, may also be involved but this is presently unknown. Pubmed10521251 Pubmed14704853 Pubmed16158220 Pubmed2669954 Pubmed9631292 Reactome Database ID Release 43264976 Reactome, http://www.reactome.org ReactomeREACT_15499 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Transport of Proinsulin-Zinc-Calcium Complex to Immature Secretory Granule Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Immature, clathrin-coated vesicles containing proinsulin-zinc-calcium complexes bud from the trans-golgi network. Pubmed3896518 Pubmed9631292 Reactome Database ID Release 43265153 Reactome, http://www.reactome.org ReactomeREACT_15362 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Processing of Proinsulin to Insulin Authored: May, B, 2008-05-13 13:18:27 EC Number: 3.4.17 EC Number: 3.4.21 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases Convertase 1/3 and Convertase 2. The exopeptidase Carboxypeptidase E then removes 2 amino acids from the carboxyl termini. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex is not soluble and forms crystals inside the secretory granules. Pubmed10521251 Pubmed11462236 Pubmed12136131 Pubmed12595704 Pubmed14617756 Pubmed1528899 Pubmed16158220 Pubmed16984975 Pubmed18180315 Pubmed3896518 Pubmed7626024 Pubmed7822759 Pubmed8916141 Pubmed8947461 Pubmed9166668 Pubmed9207799 Pubmed9631292 Pubmed9667917 Reactome Database ID Release 43265179 Reactome, http://www.reactome.org ReactomeREACT_15374 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Oxidation of Cysteine to Cystine in Proinsulin Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Cystine bonds are formed in Proinsulin-1 between cysteine residues 31 and 96, cysteine residues 43 and 109, and cysteine residues 95 and 100. Ero1-like alpha does not directly catalyze the oxidation of cysteines to cystine. Instead it maintains a suitably oxidizing environment for the reactions to occur . Though Ero1-like alpha can act via specific isomerases such as P4HB/PDI, there is currently no evidence that formation of cystine bonds in insulin requires a specific isomerase. Interestingly, even in beta cells of wild type animals, trace amounts of incorrectly bonded proinsulin can be detected. Thus, the formation of correct cystine bonds may involve a period of bond shuffling. Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed12590147 Pubmed12624089 Pubmed14744022 Pubmed15096212 Pubmed15705595 Pubmed9631292 Reactome Database ID Release 43264997 Reactome, http://www.reactome.org ReactomeREACT_15454 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Dissociation of PERK:BiP Heterodimer Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 PERK is a single-pass transmembrane protein located in the Endoplasmic Reticulum (ER) membrane. PERK has an N-terminal luminal domain and a C-terminal cytosolic domain. It is maintained in an inactive state by association of its luminal domain with BiP, a chaperone in the ER. Because BiP also binds unfolded proteins, BiP dissociates from PERK when unfolded proteins exceed chaperone activity in the ER. Pubmed11907036 Pubmed17956313 Reactome Database ID Release 43381086 Reactome, http://www.reactome.org ReactomeREACT_18413 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Translation and translocation of XBP1(S) to the Nucleus Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Phosphorylated IRE1-alpha homodimers with bound ADP have endoribonuclease activity in their C-terminal (cytosolic) regions. In particular, the homodimers cleave an internal 26 nucleotide segment out of the Xbp-1 mRNA. In yeast the resulting RNAs are ligated by a tRNA ligase but the corresponding human enzyme has not been identified. The cleavage and ligation leads to a frameshift which results in a longer ORF that encodes Xbp-1 (S), the active form of the Xbp-1 transcription factor.<br>The ribonuclease activity of IRE1-alpha also degrades subsets of mRNAs in the vicinity of the ER membrane, thereby reducing the amount of protein entering the ER.<br>Xbp-1 mRNA that has been cleaved by IRE1-alpha encodes a 40 kd protein designated Xbp-1 (S). Xbp-1 (S) is a potent bZIP transcription factor that transits from the cytosol to the nucleus and binds the sequence CCACG in the ER Stress Responsive Element (ERSE). Pubmed11779464 Pubmed16461360 Pubmed8657566 Reactome Database ID Release 43381203 Reactome, http://www.reactome.org ReactomeREACT_18336 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Cleavage of Xbp1 mRNA by IRE1alpha and Splicing of Cleaved Xbp1 mRNA Authored: May, B, 2009-06-03 Edited: May, B, 2009-06-03 Phosphorylated IRE1-alpha homodimers with bound ADP have endoribonuclease activity in their C-terminal (cytosolic) regions. The IRE1-alpha homodimers cleave an internal 26 nucleotide segment out of the Xbp-1 mRNA. In yeast the resulting RNAs are ligated by a tRNA ligase but the corresponding human ligase has not been identified. The cleavage and ligation leads to a frameshift in the Xbp-1 mRNA which results in a longer ORF that encodes Xbp-1 (S), the active form of the Xbp-1 transcription factor Pubmed11779464 Pubmed17026957 Pubmed18242182 Pubmed19622636 Reactome Database ID Release 43425923 Reactome, http://www.reactome.org ReactomeREACT_22313 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 ADP Binding by Phosphorylated IRE1 Homodimer Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Phosphorylation of the C-terminal region causes a loop in the C-terminus to change position, enabling access to an ADP-binding pocket. Phosphorylated IRE1-alpha dimers bind ADP in preference to ATP. Reactome Database ID Release 43381116 Reactome, http://www.reactome.org ReactomeREACT_18357 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 has a Stoichiometric coefficient of 2 Cleavage of ATF6-alpha by S1P Authored: May, B, 2009-06-02 00:51:49 EC Number: 3.4.21 Edited: May, B, 2009-06-02 00:51:49 Once in the Golgi, ATF6-alpha undergoes two sequential proteolytic cleavages. S1P catalyzes the first of these, probably cleaving the ATF6-alpha polypeptide between residues 418 and 419 based on homology with known S1P cleavage sites in other proteins. Pubmed10564271 Pubmed11163209 Pubmed15299016 Reactome Database ID Release 43381135 Reactome, http://www.reactome.org ReactomeREACT_18401 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Cleavage of ATF6-alpha by S2P Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Once in the Golgi, ATF6-alpha undergoes two sequential proteolytic cleavages. S2P catalyzes the second of these, cleaving the ATF6-alpha S1P cleavage product within its transmembrane domain. This cleavage liberates a 50 kD N-terminal fragment with bZIP transcription factor activity into the cytosol. Pubmed10564271 Pubmed11163209 Pubmed15299016 Reactome Database ID Release 43420818 Reactome, http://www.reactome.org ReactomeREACT_18387 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Dimerization of IRE1 Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Pubmed10835430 Pubmed11069889 Pubmed11897784 Pubmed16365312 Pubmed16973740 Pubmed18191223 Reactome Database ID Release 43381109 Reactome, http://www.reactome.org ReactomeREACT_18376 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The dissociation of the IRE1-alpha:BiP heterodimer liberates IRE1-alpha, which forms homodimers. Dimer formation is initiated by interaction between the N-terminal, luminal domains. has a Stoichiometric coefficient of 2 Autophosphorylation of IRE1 dimer Authored: May, B, 2009-06-02 00:51:49 Dimerization of the N-terminal luminal regions of IRE1-alpha brings the cytosolic C-terminal regions in proximity. The C-terminal region possesses kinase activity and the homodimer trans-autophosphorylates. From homology with Saccharomyces IRE1-alpha the phosphorylation of human IRE1-alpha is believed to be at Ser724. EC Number: 2.7.11 Edited: May, B, 2009-06-02 00:51:49 Pubmed11069889 Pubmed16973740 Pubmed9637683 Reactome Database ID Release 43381091 Reactome, http://www.reactome.org ReactomeREACT_18399 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 has a Stoichiometric coefficient of 2 Translocation of ATF6-alpha to the Nucleus Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Pubmed10564271 Pubmed10856300 Reactome Database ID Release 43381026 Reactome, http://www.reactome.org ReactomeREACT_18286 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The cytosolic N-terminal cleavage product of ATF6-alpha transits to the nucleus. PHD1/3 Converted from EntitySet in Reactome EGLN2 or EGLN3 PHD1 or PHD3 Reactome DB_ID: 1234124 Reactome Database ID Release 431234124 Reactome, http://www.reactome.org ReactomeREACT_125306 Dissociation of IRE1:BiP heterodimer Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 IRE1-alpha is a single-pass transmembrane protein with a luminal N-terminus and a cytoplasmic C-terminus. IRE1-alpha is maintained in an inactive state in the Endoplasmic Reticulum (ER) membrane by interaction between the luminal domain of IRE1-alpha and the ATPase domain of BiP within the ER. <br>BiP is a general chaperone that also binds unfolded proteins within the ER. Thus BiP dissociates from IRE1-alpha when chaperone activity is overwhelmed by unfolded proteins in the ER. Pubmed11897784 Pubmed16973740 Pubmed19538957 Reactome Database ID Release 43381217 Reactome, http://www.reactome.org ReactomeREACT_18294 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Proteolysis of the IGF:IGFBP-3:ALS Complex by Cathepsin G Authored: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Cathepsin G cleaves IGFBP-3 between amino acids 168 and 169 and between amino acids 226 and 227, releasing IGF from the IGF:IGFBP-3:ALS Complex. EC Number: 3.4.21 Edited: May, B, 2011-11-19 Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Pubmed10512690 Reactome Database ID Release 43381500 Reactome, http://www.reactome.org ReactomeREACT_15308 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Formation of the IGF:IGFBP-6 Complex Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 IGFBP-6 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP-6. IGFBP-6 binds IGF II with greater affinity than IGF I. Pubmed10951195 Pubmed12379487 Pubmed12466191 Pubmed15308688 Pubmed15525596 Pubmed17047378 Pubmed7525263 Pubmed7683646 Pubmed7689487 Pubmed8781553 Reactome Database ID Release 43381503 Reactome, http://www.reactome.org ReactomeREACT_15506 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Proteolysis of the IGF:IGFBP-3:ALS Complex by Matrix Metalloproteinase EC Number: 3.4.24 Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Matrix Metalloprotease-1 and -2 cleave IGFBP-3 in the IGF:IGFBP-3:ALS Complex between amino acids 126 and 127, releasing IGF. The reaction has been demonstrated in vivo. Pubmed12379487 Pubmed12466191 Pubmed17047378 Pubmed7523391 Pubmed8817670 Pubmed9922210 Reactome Database ID Release 43381435 Reactome, http://www.reactome.org ReactomeREACT_15475 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 hydroxyPro-HIF-alpha Converted from EntitySet in Reactome HIF-alpha with Hydroxylated Proline Reactome DB_ID: 1234132 Reactome Database ID Release 431234132 Reactome, http://www.reactome.org ReactomeREACT_124785 hydroxyPro-HIF-alpha Converted from EntitySet in Reactome HIF-alpha with Hydroxylated Proline HIF1A, HIF2A, HIF3A with Hydroxyproline Reactome DB_ID: 1234106 Reactome Database ID Release 431234106 Reactome, http://www.reactome.org ReactomeREACT_124968 HIF-alpha Converted from EntitySet in Reactome Hypoxia-inducible Factor Alpha Subunit Reactome DB_ID: 1234153 Reactome Database ID Release 431234153 Reactome, http://www.reactome.org ReactomeREACT_124671 Dimerization of PERK Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Once dissociated from BiP, PERK monomers form homodimers, the active form of the protein. Pubmed11907036 Pubmed17956313 Reactome Database ID Release 43381087 Reactome, http://www.reactome.org ReactomeREACT_18329 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 has a Stoichiometric coefficient of 2 Phosphorylation of eIF2-alpha by PERK Authored: May, B, 2009-06-02 00:51:49 EC Number: 2.7.11 Edited: May, B, 2009-06-02 00:51:49 Pubmed10026192 Pubmed11907036 Pubmed12370288 Pubmed16288713 Pubmed17956313 Pubmed18664456 Reactome Database ID Release 43381111 Reactome, http://www.reactome.org ReactomeREACT_18275 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The C-terminal domain of PERK has kinase activity when PERK homodimerizes. PERK kinase specifically phosphorylates Ser52 of eIF2-alpha, causing an arrest in translation. The result is that translation of ER-targeted proteins is halted on ribosomes in the vicinity of activated PERK. The general arrest of translation results in the loss of short-lived proteins such as Cyclin D1, causing an arrest of the cell cycle in G1. HIF-alpha Converted from EntitySet in Reactome HIF1A, EPAS1 (HIF2A), HIF3A Hypoxia-inducible Factor Alpha Subunit Reactome DB_ID: 1234147 Reactome Database ID Release 431234147 Reactome, http://www.reactome.org ReactomeREACT_125189 Formation of the IGF:IGFBP-1 Complex Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 IGFBP 1 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 1. IGFBP 1 is enriched in amniotic fluid and is produced in the liver under control of insulin (insulin suppresses production). IGFBP 1 acts to stimulate IGF function. It is unknown which if any protease degrades IGFBP 1. Pubmed12379487 Pubmed12466191 Pubmed17047378 Pubmed7519608 Pubmed7543116 Pubmed7683646 Pubmed7689487 Pubmed8781553 Pubmed9733769 Reactome Database ID Release 43381487 Reactome, http://www.reactome.org ReactomeREACT_15321 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 UBE2D1/2/3 Converted from EntitySet in Reactome Reactome DB_ID: 1234118 Reactome Database ID Release 431234118 Reactome, http://www.reactome.org ReactomeREACT_122290 UbcH5a/b/c Formation of the IGF:IGFBP-2 Complex Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 IGFBP 2 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 2. IGFBP 2 is enriched in cerebrospinal fluid and inhibits IGF function. IGFBP 2 is not significantly degraded in circulation. Pubmed10912521 Pubmed11751371 Pubmed12379487 Pubmed12466191 Pubmed17047378 Pubmed17985932 Pubmed2479552 Pubmed7519608 Pubmed7543116 Pubmed7683646 Pubmed7689487 Reactome Database ID Release 43381412 Reactome, http://www.reactome.org ReactomeREACT_15419 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Formation of the IGF:IGFBP-3:ALS Complex Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 IGFBP 3 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 3. IGFBP 3 also binds ALS via the C terminal portion of IGFBP 3. The interaction is dependent on the glycosylation of ALS.<br>IGFBP 3, which binds most IGF in the body, is enriched in follicular fluid and found in many other tissues. IGFBP 3 may be cleaved by plasmin, thrombin, Prostate specific Antigen (PSA), Matrix Metalloprotease 1, and Matrix Metalloprotease 2. IGFBP 3 also binds extracellular matrix and binding lowers its affinity for IGFs. IGFBP 3 stimulates the effects of IGFs.<br> Pubmed10026136 Pubmed10681634 Pubmed10810289 Pubmed11250653 Pubmed11316783 Pubmed11788658 Pubmed12379487 Pubmed12466191 Pubmed12810533 Pubmed1370451 Pubmed15126567 Pubmed15469690 Pubmed15485880 Pubmed17047378 Pubmed2476804 Pubmed7519608 Pubmed7543116 Pubmed7683646 Pubmed7689487 Pubmed8781553 Pubmed9497324 Pubmed9709957 Reactome Database ID Release 43381496 Reactome, http://www.reactome.org ReactomeREACT_15417 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Formation of the IGF:IGFBP-4 Complex Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 IGFBP 4 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 4. Pubmed12379487 Pubmed12466191 Pubmed12904166 Pubmed15642270 Pubmed17047378 Pubmed7519608 Pubmed7683646 Pubmed7689487 Pubmed8781553 Reactome Database ID Release 43381543 Reactome, http://www.reactome.org ReactomeREACT_15325 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Formation of the IGF:IGFBP-5:ALS Complex Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 IGFBP 5 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 5. IGFBP 5 also binds ALS via the central portion of IGFBP 5. About 55% of IGF:IGFBP 5 complexes contain ALS. IGFBP 5 is enriched in bone matrix and acts to stimulate IGF function. IGFBP 5 is cleaved by Pregnancy associated Plasma Protein A2 (PAPP A2), ADAM 9, complement C1s from smooth muscle, and thrombin. Only the cleavage site for PAPP A2 is known. About 55% of IGF:IGFBP 5 complexes contain ALS; 45% contain only IGF and IGFBP 5. Pubmed10614670 Pubmed10810289 Pubmed11316783 Pubmed11788658 Pubmed12379487 Pubmed12466191 Pubmed15126567 Pubmed17047378 Pubmed7519608 Pubmed7683646 Pubmed7689487 Pubmed8781553 Pubmed9497324 Pubmed9786878 Reactome Database ID Release 43381545 Reactome, http://www.reactome.org ReactomeREACT_15355 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 PathwayStep4316 PathwayStep4315 PathwayStep4314 PathwayStep4313 PathwayStep4319 PathwayStep4318 PathwayStep4317 GLUT4:TUG Reactome DB_ID: 1449566 Reactome Database ID Release 431449566 Reactome, http://www.reactome.org ReactomeREACT_148426 has a Stoichiometric coefficient of 1 RAC1:GTP Reactome DB_ID: 2316448 Reactome Database ID Release 432316448 Reactome, http://www.reactome.org ReactomeREACT_148456 has a Stoichiometric coefficient of 1 STX4:STXBP3 (MUNC18C) Reactome DB_ID: 2263479 Reactome Database ID Release 432263479 Reactome, http://www.reactome.org ReactomeREACT_147908 has a Stoichiometric coefficient of 1 RALA:GTP:MYO1C:Exocyst Reactome DB_ID: 2316343 Reactome Database ID Release 432316343 Reactome, http://www.reactome.org ReactomeREACT_148060 has a Stoichiometric coefficient of 1 TC10:GTP RHOQ:GTP Reactome DB_ID: 2316453 Reactome Database ID Release 432316453 Reactome, http://www.reactome.org ReactomeREACT_148007 has a Stoichiometric coefficient of 1 RALA:GTP:MYO1C:Calmodulin:F-actin Reactome DB_ID: 2316344 Reactome Database ID Release 432316344 Reactome, http://www.reactome.org ReactomeREACT_148239 has a Stoichiometric coefficient of 1 p-S1652-MYO5A:F-actin Reactome DB_ID: 2316339 Reactome Database ID Release 432316339 Reactome, http://www.reactome.org ReactomeREACT_148237 has a Stoichiometric coefficient of 1 RALA:GTP Reactome DB_ID: 1458506 Reactome Database ID Release 431458506 Reactome, http://www.reactome.org ReactomeREACT_148153 has a Stoichiometric coefficient of 1 MYO1C:CALM1 Reactome DB_ID: 2316345 Reactome Database ID Release 432316345 Reactome, http://www.reactome.org ReactomeREACT_148117 has a Stoichiometric coefficient of 1 PathwayStep4322 PathwayStep4323 RALA:GDP Reactome DB_ID: 1458466 Reactome Database ID Release 431458466 Reactome, http://www.reactome.org ReactomeREACT_147970 has a Stoichiometric coefficient of 1 PathwayStep4320 PathwayStep4321 PathwayStep4303 PathwayStep4302 PathwayStep4305 PathwayStep4304 PathwayStep4307 PathwayStep4306 PathwayStep4309 PathwayStep4308 CD3 epsilon gamma Reactome DB_ID: 198902 Reactome Database ID Release 43198902 Reactome, http://www.reactome.org ReactomeREACT_11874 has a Stoichiometric coefficient of 1 MHC Class II bearing antigen peptide Reactome DB_ID: 203463 Reactome Database ID Release 43203463 Reactome, http://www.reactome.org ReactomeREACT_13112 has a Stoichiometric coefficient of 1 MHC class II alpha/beta dimer Reactome DB_ID: 2213189 Reactome Database ID Release 432213189 Reactome, http://www.reactome.org ReactomeREACT_121884 has a Stoichiometric coefficient of 1 Antigen-bearing MHC Class II : TCR complex:CD4:p-Lck(Y505) Reactome DB_ID: 202154 Reactome Database ID Release 43202154 Reactome, http://www.reactome.org ReactomeREACT_12773 has a Stoichiometric coefficient of 1 Antigen-bearing MHC Class II : TCR complex:CD4:Lck Reactome DB_ID: 202157 Reactome Database ID Release 43202157 Reactome, http://www.reactome.org ReactomeREACT_13095 has a Stoichiometric coefficient of 1 T-cell receptor complex Reactome DB_ID: 198901 Reactome Database ID Release 43198901 Reactome, http://www.reactome.org ReactomeREACT_11910 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CD3 epsilon delta Reactome DB_ID: 198900 Reactome Database ID Release 43198900 Reactome, http://www.reactome.org ReactomeREACT_11418 has a Stoichiometric coefficient of 1 T-cell receptor Reactome DB_ID: 198183 Reactome Database ID Release 43198183 Reactome, http://www.reactome.org ReactomeREACT_11347 has a Stoichiometric coefficient of 1 PathwayStep4310 PathwayStep4311 VAMP2:STX4:SNAP23 Reactome DB_ID: 1449628 Reactome Database ID Release 431449628 Reactome, http://www.reactome.org ReactomeREACT_147982 has a Stoichiometric coefficient of 1 PathwayStep4312 Csk:p-PAG Reactome DB_ID: 202297 Reactome Database ID Release 43202297 Reactome, http://www.reactome.org ReactomeREACT_13273 has a Stoichiometric coefficient of 1 PathwayStep4339 PathwayStep4338 PathwayStep4337 PathwayStep4336 PathwayStep4335 GADS:p-5Y-LAT Reactome DB_ID: 202177 Reactome Database ID Release 43202177 Reactome, http://www.reactome.org ReactomeREACT_13309 has a Stoichiometric coefficient of 1 phospho tyrosine ZAP-70 Reactome DB_ID: 202345 Reactome Database ID Release 43202345 Reactome, http://www.reactome.org ReactomeREACT_13031 has a Stoichiometric coefficient of 1 Activated ZAP-70 Reactome DB_ID: 202181 Reactome Database ID Release 43202181 Reactome, http://www.reactome.org ReactomeREACT_13133 has a Stoichiometric coefficient of 1 PathwayStep4344 Antigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4 Reactome DB_ID: 203494 Reactome Database ID Release 43203494 Reactome, http://www.reactome.org ReactomeREACT_12725 has a Stoichiometric coefficient of 1 PathwayStep4345 T-cell receptor complex with phosphorylated ITAMs Reactome DB_ID: 203493 Reactome Database ID Release 43203493 Reactome, http://www.reactome.org ReactomeREACT_12993 has a Stoichiometric coefficient of 1 PathwayStep4342 PathwayStep4343 Antigen-bearing MHC Class II :TCR complex:CD4: Lck phosphorylated at Tyr394 Reactome DB_ID: 202266 Reactome Database ID Release 43202266 Reactome, http://www.reactome.org ReactomeREACT_12817 has a Stoichiometric coefficient of 1 PathwayStep4340 CD3 epsilon: CD3 gamma with phosphorylated ITAM Reactome DB_ID: 202167 Reactome Database ID Release 43202167 Reactome, http://www.reactome.org ReactomeREACT_13214 has a Stoichiometric coefficient of 1 PathwayStep4341 ZAP-70 bound to phosphorylated ITAM motifs Reactome DB_ID: 202330 Reactome Database ID Release 43202330 Reactome, http://www.reactome.org ReactomeREACT_13388 has a Stoichiometric coefficient of 1 CD3 epsilon: CD3 delta with phosphorylated ITAMs Reactome DB_ID: 202336 Reactome Database ID Release 43202336 Reactome, http://www.reactome.org ReactomeREACT_13126 has a Stoichiometric coefficient of 1 CD3 zeta dimer with phosphorylated ITAMs Reactome DB_ID: 202303 Reactome Database ID Release 43202303 Reactome, http://www.reactome.org ReactomeREACT_12849 has a Stoichiometric coefficient of 2 PathwayStep4329 PathwayStep4328 PathwayStep4325 PathwayStep4324 PathwayStep4327 PathwayStep4326 phopshorylated PLC-gamma1 bound to SLP-76 Reactome DB_ID: 202302 Reactome Database ID Release 43202302 Reactome, http://www.reactome.org ReactomeREACT_13258 has a Stoichiometric coefficient of 1 ZAP-70 and ITK tyrosine kinases Converted from EntitySet in Reactome Reactome DB_ID: 202282 Reactome Database ID Release 43202282 Reactome, http://www.reactome.org ReactomeREACT_12862 PathwayStep4331 SLP-76 bound to Gads:LAT Reactome DB_ID: 202151 Reactome Database ID Release 43202151 Reactome, http://www.reactome.org ReactomeREACT_13131 has a Stoichiometric coefficient of 1 PathwayStep4332 p-Y113,Y128,Y145-SLP-76:Gads: LAT Reactome DB_ID: 202162 Reactome Database ID Release 43202162 Reactome, http://www.reactome.org ReactomeREACT_13181 has a Stoichiometric coefficient of 1 PathwayStep4333 ITK bound to SLP-76:Gads:LAT Reactome DB_ID: 202359 Reactome Database ID Release 43202359 Reactome, http://www.reactome.org ReactomeREACT_13016 has a Stoichiometric coefficient of 1 PathwayStep4334 PLCG1:p-3Y-SLP-76:Gads:LAT Reactome DB_ID: 202279 Reactome Database ID Release 43202279 Reactome, http://www.reactome.org ReactomeREACT_13137 has a Stoichiometric coefficient of 1 PLCG1:p-5Y-LAT Reactome DB_ID: 202240 Reactome Database ID Release 43202240 Reactome, http://www.reactome.org ReactomeREACT_13281 has a Stoichiometric coefficient of 1 PLC-gamma1 bound to LAT or SLP-76 Converted from EntitySet in Reactome Reactome DB_ID: 202318 Reactome Database ID Release 43202318 Reactome, http://www.reactome.org ReactomeREACT_13341 Phosphorylated PLC-gamma1 bound to LAT or SLP-76 Converted from EntitySet in Reactome Reactome DB_ID: 202193 Reactome Database ID Release 43202193 Reactome, http://www.reactome.org ReactomeREACT_13004 PathwayStep4330 phosphorylated PLC-gamma1 bound to LAT Reactome DB_ID: 202310 Reactome Database ID Release 43202310 Reactome, http://www.reactome.org ReactomeREACT_13372 has a Stoichiometric coefficient of 1 Activated FGFR binds PLC-gamma Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Pubmed10652257 Pubmed1656221 Pubmed16844695 Pubmed9430633 Reactome Database ID Release 43190896 Reactome, http://www.reactome.org ReactomeREACT_21398 Recruitment of PLC-gamma by FGF receptors has been best studied in FGFR1c signaling, where it has been shown that autophosphorylation of Tyr766 in the C-terminal tail of FGFR1c creates a specific binding site for the SH2 domain of PLC-gamma. A mutant FGFR1c in which Y766 is replaced by phenylalanine is unable to activate PI hydrolysis and Ca2+ release in response to FGF stimulation. Membrane recruitment of PLC-gamma is also aided by binding of the Pleckstrin homology (PH) domain of this enzyme to PtIns(3,4,5) P3 molecules that are generated in response to PI-3 kinase stimulation. By sequence comparison, Y766 is conserved in all FGFR isoforms, and PLC-gamma signaling is observed, to a greater or lesser extent, downstream of all FGFR receptors upon stimulation with FGFs. Reviewed: Mohammadi, M, 2007-02-06 21:44:35 PLC-gamma phosphorylation by FGFR Authored: de Bono, B, 2007-01-10 10:27:18 EC Number: 2.7.10 Edited: Jupe, S, 2010-02-03 PLC gamma is phosphorylated by activated FGFR, resulting in PLC gamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3. Tyrosine phosphorylation of PLCgamma by FGFR4 is weaker than that seen by other isoforms of FGFR. Pubmed10579907 Reactome Database ID Release 43190898 Reactome, http://www.reactome.org ReactomeREACT_21329 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 has a Stoichiometric coefficient of 4 Activated PLC gamma release by activated FGFR Authored: de Bono, B, 2007-01-10 10:27:18 Dissociation from the activated receptor quickly follows phosphorylation of PLC-gamma. Phosphorylated PLC-gamma catalyzes the hydrolysis of phosphatidylinositol(4, 5)bisphosphate to generate two second messengers, diacylglycerol and inositol (1,4,5) triphosphate. Edited: Jupe, S, 2010-02-03 Pubmed10579907 Reactome Database ID Release 43190905 Reactome, http://www.reactome.org ReactomeREACT_21365 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Activated FGFR recruits SHC1 Although a role for SHC1 in FGF signalling has been implicated in many studies, it is not clear that SHC1 interacts directly with the receptor. Authored: Rothfels, K, 2011-08-15 Pubmed18840094 Pubmed7559490 Pubmed9045692 Pubmed9480847 Reactome Database ID Release 431268226 Reactome, http://www.reactome.org ReactomeREACT_111074 Reviewed: Gotoh, N, 2011-08-26 PathwayStep4359 GRB2:GAB1:PI3Kreg binds to p-SHP2 on p-FRS2:activated FGFR Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Pubmed11353842 Pubmed9045692 Pubmed9299490 Pubmed9632781 Reactome Database ID Release 43190401 Reactome, http://www.reactome.org ReactomeREACT_21411 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 p-SHP2 recruits GRB2-GAB1to the activated receptor. PI3K catalytic subunit is recruited by FGFR-associated PI3KR1 Authored: Rothfels, K, 2011-08-15 Pubmed11353842 Pubmed15863030 Reactome Database ID Release 431268262 Reactome, http://www.reactome.org ReactomeREACT_111043 Reviewed: Gotoh, N, 2011-08-26 The 110 kDa catalytic subunit (PIK3CA) binds to the 85 kDa regulatory subunit (PIK3R1) to create the active PIK3. Activated PLC gamma1 bound to PIP2 Reactome DB_ID: 202269 Reactome Database ID Release 43202269 Reactome, http://www.reactome.org ReactomeREACT_13147 has a Stoichiometric coefficient of 1 PathwayStep4357 PathwayStep4358 SHC1 is phosphorylated Authored: Rothfels, K, 2011-08-15 EC Number: 2.7.10 Pubmed18840094 Pubmed7559490 Pubmed8264585 Pubmed9045692 Reactome Database ID Release 431268281 Reactome, http://www.reactome.org ReactomeREACT_111110 Reviewed: Gotoh, N, 2011-08-26 The p46 and p53 isoforms of SHC1 have been shown to be phosphorylated upon FGF stimulation. Three consensus RTK phosphoryation sites are present in SHC1, although phosphorylation of these specific tyrosine residues has not been explicitly demonstrated in response to FGF stimulation. In contrast, the p66 isoform of SHC1 does not appear to undergo FGF-dependent phosphorylation. has a Stoichiometric coefficient of 3 GRB2:SOS1 is recruited to activated FGFR through p-SHC1 Authored: Rothfels, K, 2011-08-15 Phosphorylated SHC1 links FGFR to Grb2 (Klint et al. 1995) leading to the formation of a signaling complex including Shc, Grb2 and Sos. Transformation of NIH 3T3 cells with v-Src produced a strong constitutive association of FGFR1 with Shc, Grb2 and Sos (Curto et al. 1998) suggesting Src involvement. Recruitment of Grb2-Sos links FGFR to the Ras pathway. Pubmed7559490 Pubmed9045692 Pubmed9480847 Reactome Database ID Release 431268258 Reactome, http://www.reactome.org ReactomeREACT_111149 Reviewed: Gotoh, N, 2011-08-26 Ras nucleotide exchange by GRB2:SOS1 through p-SHC Authored: Rothfels, K, 2011-08-15 Pubmed8493579 Reactome Database ID Release 431268277 Reactome, http://www.reactome.org ReactomeREACT_111095 Reviewed: Gotoh, N, 2011-08-26 SOS, recruited by GRB2:p-FRS2 to activated FGFR, activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state. GRB2:GAB1:PI3Kreg binds directly to p-FRS2:activated FGFR Authored: Rothfels, K, 2011-08-15 Pubmed11353842 Pubmed14534538 Pubmed9182757 Pubmed9632781 Reactome Database ID Release 431268245 Reactome, http://www.reactome.org ReactomeREACT_111163 Reviewed: Gotoh, N, 2011-08-26 The direct GRB2-binding sites of FRS2alpha have a major role in activation of the PI3K pathway. PathwayStep4363 PKC theta (opened conformation) bound to DAG Reactome DB_ID: 202300 Reactome Database ID Release 43202300 Reactome, http://www.reactome.org ReactomeREACT_12758 has a Stoichiometric coefficient of 1 PathwayStep4362 Inactive PKC theta bound to DAG Reactome DB_ID: 202187 Reactome Database ID Release 43202187 Reactome, http://www.reactome.org ReactomeREACT_13197 has a Stoichiometric coefficient of 1 PathwayStep4361 PDK1 bound to either PIP3 or PI(3,4)P2 Reactome DB_ID: 202311 Reactome Database ID Release 43202311 Reactome, http://www.reactome.org ReactomeREACT_12991 has a Stoichiometric coefficient of 1 PathwayStep4360 p-SLP-76:NCK1:WASP Reactome DB_ID: 430186 Reactome Database ID Release 43430186 Reactome, http://www.reactome.org ReactomeREACT_21025 has a Stoichiometric coefficient of 1 PathwayStep4367 p-SLP-76:NCK:PAK Reactome DB_ID: 430189 Reactome Database ID Release 43430189 Reactome, http://www.reactome.org ReactomeREACT_21232 has a Stoichiometric coefficient of 1 PathwayStep4366 p-SLP-76:NCK1 Reactome DB_ID: 430188 Reactome Database ID Release 43430188 Reactome, http://www.reactome.org ReactomeREACT_20974 has a Stoichiometric coefficient of 1 PathwayStep4365 p-SLP-76:ADAP:Ena/VASP Reactome DB_ID: 430206 Reactome Database ID Release 43430206 Reactome, http://www.reactome.org ReactomeREACT_20995 has a Stoichiometric coefficient of 1 PathwayStep4364 p-SLP-76:ADAP Reactome DB_ID: 430124 Reactome Database ID Release 43430124 Reactome, http://www.reactome.org ReactomeREACT_20709 has a Stoichiometric coefficient of 1 Active PKC theta bound to DAG Reactome DB_ID: 202442 Reactome Database ID Release 43202442 Reactome, http://www.reactome.org ReactomeREACT_12934 has a Stoichiometric coefficient of 1 Activated ERK1/2 threonine-phosphorylate FRS2alpha. Authored: Rothfels, K, 2011-08-15 EC Number: 2.7.11.24 FRS2alpha has 8 canonical MAPK phosphorylation sites which are phosphorylated by activated ERK1/2 after FGF stimulation. Phosphorylation of these 8 threonine residues counteracts the activating effect of tyrosine phosphorylation of FRS2alpha, although the exact mechanism for this negative regulation is not known. Expression of a version of FRS2alpha in which the 8 threonine residues are mutated to valine results in enhanced tyrosine phosphorylation of FRS2alpha, enhanced GRB2-SOS1 recruitment and a more sustained MAPK response. The 8 threonine residues are not conserved in FRS2beta; as a result, signaling through FRS2beta complexes do not appear to be subject to this downregulation. Pubmed12419216 Pubmed12974390 Pubmed18452557 Pubmed19652666 Reactome Database ID Release 431270466 Reactome, http://www.reactome.org ReactomeREACT_111161 Reviewed: Gotoh, N, 2011-08-26 has a Stoichiometric coefficient of 8 p-CBL:GRB2 binds p-FRS2alpha:activated FGFR Authored: Rothfels, K, 2011-08-15 Pubmed11997436 Reactome Database ID Release 431270439 Reactome, http://www.reactome.org ReactomeREACT_111145 Reviewed: Gotoh, N, 2011-08-26 The ubiquitin ligase CBL exists in a complex with GRB2 and is recruited to tyrosine-phosphorylated FRS2 after FGF stimulation. In addition to promoting the ubiquitination, endocytosis, and degradation of the activated receptor complex, recruitment of the p-CBL:GRB2 complex seems to attenuate FGFR signaling by competing with GRB2:SOS1 for binding to the direct GRB2-binding sites on p-FRS2. FGFR-associated PI3K phosphorylates PIP2 to PIP3 Authored: Rothfels, K, 2011-08-15 Once recruited to the membrane, PI3K catalyzes the phosphorylation of PI(4,5)P2 to PI(3,4,5)P3. Pubmed11353842 Reactome Database ID Release 431268240 Reactome, http://www.reactome.org ReactomeREACT_111171 Reviewed: Gotoh, N, 2011-08-26 FGFR associated PI3K phosphorylates PIP2 to PIP3 Authored: Rothfels, K, 2011-08-15 Once recruited to the activated receptor, PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling. PI3K signaling has been demonstrated in ZMYM2-, FOP- and BCR-FGFR1 fusions (Chen, 2004; Demiroglu, 2001; Guasch, 2001), as well as downstream of a number of other FGFR mutants (see for instance, Byron, 2008; Kunii, 2008; Agazie, 2003; Takeda, 2007). Pubmed11353842 Pubmed15863030 Reactome Database ID Release 431272493 Reactome, http://www.reactome.org ReactomeREACT_111124 Reviewed: Gotoh, N, 2011-08-26 PI3K catalytic subunit binds to GRB2:GAB1:PI3Kreg (indirect) Authored: Rothfels, K, 2011-08-15 Pubmed11353842 Pubmed15863030 Reactome Database ID Release 431268265 Reactome, http://www.reactome.org ReactomeREACT_111233 Reviewed: Gotoh, N, 2011-08-26 The 110 kDa catalytic subunit (PIK3CA) binds to the 85 kDa regulatory subunit (PIK3R1) to create the active PIK3. PathwayStep4346 PathwayStep4347 PathwayStep4348 SPRY2 binds GRB2 Authored: Rothfels, K, 2011-08-15 Pubmed15637081 Pubmed16893902 Reactome Database ID Release 431295613 Reactome, http://www.reactome.org ReactomeREACT_111229 Reviewed: Gotoh, N, 2011-08-26 Some evidence suggests that SPRY2 may exert its negative effect by binding to GRB2 and competing with the GRB2:SOS1 interaction that is required for MAPK activation. SPRY2 phosphorylation at Y55 is stimulated in response to both FGF and EGF, and is required for SPRY2 to act as a negative regulator of FGF signaling. Y55 is not thought to be a GRB2 binding site, however. Instead, phosphorylation at Y55 is thought to cause a conformational change in SPRY2 that reveals a cryptic PXXPXPR GRB2-docking site in the C-terminal of SPRY2.<br>SPRY2 has also been shown to be phosphorylated at multiple tyrosine residues in its C-terminal in response to FGF, but not EGF, stimulation. This phosphorylation, in particular at residue 227, is thought to augment the ability of SPRY2 to inhibit FGF signaling through the MAPK cascade, although the mechanism remains to be elucidated. CARMA1 bound to PDK1 Reactome DB_ID: 202349 Reactome Database ID Release 43202349 Reactome, http://www.reactome.org ReactomeREACT_13330 has a Stoichiometric coefficient of 1 PathwayStep4349 Activated CARMA1 Reactome DB_ID: 202440 Reactome Database ID Release 43202440 Reactome, http://www.reactome.org ReactomeREACT_13227 has a Stoichiometric coefficient of 1 SPRY2 translocates to the plasma membrane Authored: Rothfels, K, 2011-08-15 Pubmed10887178 Pubmed11238463 Pubmed11279012 Pubmed12391162 Reactome Database ID Release 431295599 Reactome, http://www.reactome.org ReactomeREACT_111232 Reviewed: Gotoh, N, 2011-08-26 SPRY2 translocates to the plasma membrane upon activation of cells with FGF, and translocation is required for the inhibition of growth factor-stimulated cell migration, proliferation and differentiation. Translocation may be mediated by interactions with PIP2 in the membrane, palmitoylation of the C-terminal region of SPRY2 and/or interactions with caveolin-1. SRC phosphorylates SPRY2 on Y55 and Y227 Authored: Rothfels, K, 2011-08-15 EC Number: 2.7.10 Pubmed15004239 Pubmed15564375 Pubmed15637081 Reactome Database ID Release 431295609 Reactome, http://www.reactome.org ReactomeREACT_111096 Reviewed: Gotoh, N, 2011-08-26 Sprouty 2 protein is phosphorylated on tyrosine residue 55. The ability of SRC kinase to catalyze this reaction has been demonstrated with purified proteins in vitro (Li et al. 2004) and in cultured cells with studies of the effects of SRC-family pharmacological inhibitors and of dominant-negative mutant SRC proteins (Mason et al. 2004). SRC kinase also phosphorylates numerous tyrosine residues in the C terminal region of SPRY2 including Y227, in response to FGF but not EGF stimulation. has a Stoichiometric coefficient of 2 CBL ubiquitinates FRS2 and FGFR Authored: Rothfels, K, 2011-08-15 EC Number: 6.3.2.19 Grb2 bound to tyrosine phosphorylated FRS2 forms a ternary complex with Cbl through the binding of the SH3 domains of Grb2 to a proline rich region in Cbl. Grb2-mediated recruitment of Cbl results in ubiquitination of FGFR and FRS2. Cbl is a multidomain protein that posses an intrinsic ubiquitin ligase activity and also functions as a platform for recruitment of a variety of signaling proteins. Multiple mechanisms appear to be required for downregulation of FGFR, as internalization of the receptor is reduced but not abolished if recruitment of CBL to FRS2 is compromised by mutation of GRB2-binding sites. Pubmed11997436 Pubmed12815057 Reactome Database ID Release 431270444 Reactome, http://www.reactome.org ReactomeREACT_111231 Reviewed: Gotoh, N, 2011-08-26 PPA2A dephosphorylates SPRY2 Authored: Rothfels, K, 2011-08-15 In unstimulated cells, SPRY2 has been shown to be phosphorylated on multiple serine and threonine residues. In these cells, SPRY2 exists in a complex with the regulatory and catalytic subunits (A and C, respectively) of the serine/threonine phosphatase PP2A. After stimulation with FGF, the catalytic activity of PP2A increases and the phosphatase dephophorylates SPRY at serine 112 and serine 115. This is thought to promote changes in tertiary structure that promote GRB2 binding and phosphorylation of Y55 and Y227. Pubmed17255109 Reactome Database ID Release 431295632 Reactome, http://www.reactome.org ReactomeREACT_111094 Reviewed: Gotoh, N, 2011-08-26 has a Stoichiometric coefficient of 2 PathwayStep4350 rHes1 binds TLE A GST-tagged recombinant rat Hes1 protein exogenously expressed in HeLa cells co-immunoprecipitates endogenous TLE proteins. The WRPW motif of Hes1 is critical for this interaction. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed8649374 Pubmed8687460 Reactome Database ID Release 432065510 Reactome, http://www.reactome.org ReactomeREACT_118605 Reviewed: Haw, R, 2012-02-06 MALT1 trimer bound to Bcl10 and CARMA1 trimer Reactome DB_ID: 202468 Reactome Database ID Release 43202468 Reactome, http://www.reactome.org ReactomeREACT_13172 has a Stoichiometric coefficient of 1 MALT1 trimer Reactome DB_ID: 202487 Reactome Database ID Release 43202487 Reactome, http://www.reactome.org ReactomeREACT_12682 has a Stoichiometric coefficient of 3 PathwayStep4352 TRIKA1 Reactome DB_ID: 202463 Reactome Database ID Release 43202463 Reactome, http://www.reactome.org ReactomeREACT_12995 TRAF6-regulated IKK activator 1 Ubc13/Uev1A complex has a Stoichiometric coefficient of 1 PathwayStep4351 TRAF6 trimer bound to CBM complex Reactome DB_ID: 202471 Reactome Database ID Release 43202471 Reactome, http://www.reactome.org ReactomeREACT_12970 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep4354 Bcl10 bound to CARMA1 Reactome DB_ID: 202454 Reactome Database ID Release 43202454 Reactome, http://www.reactome.org ReactomeREACT_13143 has a Stoichiometric coefficient of 1 PathwayStep4353 CARMA1 trimer Reactome DB_ID: 202445 Reactome Database ID Release 43202445 Reactome, http://www.reactome.org ReactomeREACT_13044 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep4356 Bcl10 trimer bound to CARMA1 trimer Reactome DB_ID: 202475 Reactome Database ID Release 43202475 Reactome, http://www.reactome.org ReactomeREACT_12824 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep4355 Phosphorylated Bcl10 bound to CARMA1 and RIP2 Reactome DB_ID: 202480 Reactome Database ID Release 43202480 Reactome, http://www.reactome.org ReactomeREACT_12759 has a Stoichiometric coefficient of 1 Formation of cap binding complex (CBC) At the beginning of this reaction, 1 molecule of 'CBP80', and 1 molecule of 'CBP20' are present. At the end of this reaction, 1 molecule of 'Cap Binding Complex (CBC)' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4377094 Reactome, http://www.reactome.org ReactomeREACT_2093 Recognition and binding of the mRNA cap by the cap-binding complex Authored: Buratowski, S, 2003-10-15 15:18:41 Edited: Gopinathrao, G, 0000-00-00 00:00:00 Reactome Database ID Release 4377095 Reactome, http://www.reactome.org ReactomeREACT_687 The cap binding complex binds to the methylated GMP cap on the nascent mRNA transcript. Methylation of GMP-cap by RNA Methyltransferase Authored: Buratowski, S, 2003-10-15 15:18:41 EC Number: 2.1.1.56 In the final step of the capping reaction, the methyltransferase takes a methyl group from S-adenosyl-methionine to the N7 position of the cap guanine. N7G-methyltransferase (MT) mediated reaction can be represented as:<BR>GpppN(pN)n + S-adenosylmethionine (Adomet) ->m7GpppN(pN)n + S-adenosylhomocysteine (Adohcy).<P> Pubmed9790902 Reactome Database ID Release 4377090 Reactome, http://www.reactome.org ReactomeREACT_404 Dissociation of transcript with 5'-GMP from GT Authored: Buratowski, S, 2003-10-15 15:18:41 GMP capped mRNA transcript dissociates from GT for further modification. Reactome Database ID Release 4377085 Reactome, http://www.reactome.org ReactomeREACT_703 Transfer of GMP from the capping enzyme GT site to 5'-end of mRNA Authored: Buratowski, S, 2003-10-15 15:18:41 EC Number: 2.7.7.50 Pubmed9512541 Reactome Database ID Release 4377083 Reactome, http://www.reactome.org ReactomeREACT_1968 The diphosphate 5'-end of the mRNA is joined to the GMP, releasing it from the enzyme. At this time, it is unclear how the RNA diphosphate end is transferred from the active site of the triphosphatase to the guanylyltransferase site. The covalent enzyme-GMP complex can form in the absence of RNA.<BR>Guanylyltransferase (GT) catalyzed second reaction can be represented as:ppN(pN)n + GTP -> GpppN(pN)n + PPi<P> Formation of the CE:GMP intermediate complex A highly conserved lysine within the guanylyltransferase (GT) site of the mRNA capping enzyme attacks the alpha-phosphate of GTP. An enzyme-GMP covalent intermediate is formed.<BR> Authored: Buratowski, S, 2003-10-15 15:18:41 EC Number: 2.7.7.50 Pubmed9512541 Reactome Database ID Release 4377081 Reactome, http://www.reactome.org ReactomeREACT_1580 Hydrolysis of the 5'-end of the nascent transcript by the capping enzyme After the capping complex is formed, the RNA triphosphatase activity of the capping enzyme hydrolyzes the 5'-end phosphate group of the nascent mRNA transcript to a diphosphate.<BR>The RNA triphosphatase (RTP) domain of mammalian capping enzyme is a member of a superfamily of phosphatases that include the protein tyrosine phosphatases, some lipid phosphatases, and several nucleic acid phosphatases. This family uses a conserved nucleophilic cysteine residue to attack the target phosphate. A transient phospho-cysteinyl enzyme intermediate is then hydrolyzed to regenerate the enzyme active site. It should be noted that while higher eukaryotic capping enzymes use PTP-like triphosphatase domains, the yeast triphosphatases are a completely different class of enzymes. The yeast RTPs are metal-dependent phosphatases. RNA 5'-triphosphatase (RTP) catalyzed first reaction can be represented as:pppN(pN)n + GTP -> ppN(pN)n + Pi; (n=20-25)<P> Authored: Buratowski, S, 2003-10-15 15:18:41 EC Number: 3.1.3.33 Pubmed9512541 Reactome Database ID Release 4377078 Reactome, http://www.reactome.org ReactomeREACT_1368 Capping complex formation Authored: Buratowski, S, 2003-10-15 15:18:41 Edited: Gopinathrao, G, 0000-00-00 00:00:00 Reactome Database ID Release 4377077 Reactome, http://www.reactome.org ReactomeREACT_2186 The capping enzyme binds the 5'-end of the nascent transcript soon after it is synthesized on the DNA template, and results in the formation of the capping complex along with the C-terminal domain of RNA polymerase II, and Spt5. SPRY2 binds CBL Authored: Rothfels, K, 2011-08-15 Pubmed11053437 Pubmed12593796 Pubmed12815057 Reactome Database ID Release 431295622 Reactome, http://www.reactome.org ReactomeREACT_111241 Reviewed: Gotoh, N, 2011-08-26 The N terminal TKB domain of CBL binds to the phospho-tyrosine 55 of SPRY2, targeting SPRY2 for degradation by the 26S proteasome. Y55 is also a binding site for PP2A, which dephosphorylates numerous serine and threonine residues on SPRY2, allowing a conformational change that may promote a SPRY2:GRB2 interaction and limit the extent of MAPK activation following FGF stimulation. Phosphorylated SPRY2 is ubiquitinated by CBL Authored: Williams, MG, 2010-08-17 EC Number: 6.3.2.19 In humans, the phosphorylated adaptor protein Sprouty2 is ubiquitinated by the E3 ubiquitin ligase CBL, marking it for degradation by the 26S proteasome. Pubmed12593795 Pubmed12593796 Pubmed15004239 Reactome Database ID Release 43934604 Reactome, http://www.reactome.org ReactomeREACT_111141 Reviewed: Gotoh, N, 2011-08-26 CBL dissociates from ubiquitinated p-SPRY2 After ubiquitination, CBL dissociates from SPRY2 Authored: Rothfels, K, 2011-08-15 Pubmed12593795 Pubmed12593796 Reactome Database ID Release 431295621 Reactome, http://www.reactome.org ReactomeREACT_111107 Reviewed: Gotoh, N, 2011-08-26 SPRY2 is phosphorylated by phosphorylated MNK1 Authored: Williams, MG, 2010-08-17 EC Number: 2.7.11 In humans, the phosphorylated MNK1 kinase phosphorylates the adaptor protein Sprouty2 on Ser112 and Ser121, and also at some other serine and threonine residues. MNK1 appears not to form a complex with Sprouty2. Some of these (including the two main sites mentioned above) conform to the serine-containing consensus sites for phosphorylation by MNK1 kinase (K/R-X-X-S, R-X-S). It appears that serine phosphorylation is required to protect Sprouty2 from degradation.<br><br>In the absence of serine phosphorylation, phosphorylation of Tyr55 and subsequent binding to E3 ubiquitin ligase, CBL, is enhanced. Serine phosphorylation of Sprouty2 appears to stabilise the protein by interfering with its potential phosphorylation of Tyr55 (Sprouty2 appears to be a poor substrate for c-Src kinase) in response to growth factor stimulation. Pubmed16479008 Pubmed19690147 Reactome Database ID Release 43934559 Reactome, http://www.reactome.org ReactomeREACT_111063 Reviewed: Gotoh, N, 2011-08-26 has a Stoichiometric coefficient of 2 SPRY2 is serine phosphorylated in response to MAPK activation Authored: Rothfels, K, 2011-08-15 Pubmed11698404 Pubmed19690147 Reactome Database ID Release 431295634 Reactome, http://www.reactome.org ReactomeREACT_111121 Reviewed: Gotoh, N, 2011-08-26 Some evidence suggests that SPRY2 can exert its negative role on FGF signaling at the level of RAF activation. Hypophosphorylated SPRY2 binds to inactive B-RAF, preventing it from activating ERK signaling. MAPK activation results in phosphorylation of SPRY2 on six serine residues (S7, S42, S111, S120, S140 and S167), and inhibits B-RAF binding. Phosphorylation at S111 and S120 directly affects B-RAF binding while the remaining four sites appear to contribute indirectly. Oncogenic forms of B-RAF such as B-RAF V600E, which adopt active kinase conformations, do not associate with SPRY2, regardless of its phosphorylation status. This suggests that two mechanisms affect the SPRY2:B-RAF interaction: SPRY2 phosphorylation and B-RAF conformation. B-RAF dissociates from S111/S120 p-SPRY2 Authored: Rothfels, K, 2011-08-15 MAPK-dependent serine phosphorylation of SPRY2 disrupts complex formation with B-RAF. Pubmed19690147 Reactome Database ID Release 431295604 Reactome, http://www.reactome.org ReactomeREACT_111105 Reviewed: Gotoh, N, 2011-08-26 SHP2 dephosphorylates SPRY2 Authored: Rothfels, K, 2011-08-15 EC Number: 3.1.3.48 Pubmed15031289 Pubmed17993263 Reactome Database ID Release 431549564 Reactome, http://www.reactome.org ReactomeREACT_111157 Reviewed: Gotoh, N, 2011-08-26 SHP2 may exert its positive effects on MAPK activation in response to FGF stimulation by catalyzing the dephosphorylation of tyrosine resides on SPRY2. This dephosphorylation promotes dissociation of the GRB2/SPRY2 complex and as a consequence stimulates GRB2 association with the activated receptor, leading to sustained MAPK signaling. p-MEK phosphorylates ERK Authored: Rothfels, K, 2011-08-15 EC Number: 2.7.11 MEK1/2 phosphorylate critical tyrosine and threonine residues on ERK1/2, activating the kinase activity of the MAPKs. In FGFR signaling, this reaction appears to be negatively regulated by IL17RD through an unknown mechanism, limiting the extent of MAPK signaling after FGF stimulation. Pubmed12807873 Pubmed12958313 Pubmed14742870 Pubmed17035228 Pubmed8388392 Reactome Database ID Release 431268210 Reactome, http://www.reactome.org ReactomeREACT_111117 Reviewed: Gotoh, N, 2011-08-26 has a Stoichiometric coefficient of 2 Dissociation of p-ERK from p-MEK Authored: Rothfels, K, 2011-08-15 Pubmed15239952 Pubmed8388392 Reactome Database ID Release 431268206 Reactome, http://www.reactome.org ReactomeREACT_111113 Reviewed: Gotoh, N, 2011-08-26 p-ERK1/2 dissociates from p-MEK1/2, allowing dimerization of the activated MAPKs and translocation to the nucleus. In FGFR signaling, there is evidence that this dissociation event is negatively regulated by the golgi membrane form of IL17RD, preventing the nuclear localization of activated ERK1/2. p-ERK dimerizes After being phosphorylated, p-ERK1/2 dissociate from MEK1/2 and dimerize. Authored: Rothfels, K, 2011-08-15 Reactome Database ID Release 431295628 Reactome, http://www.reactome.org ReactomeREACT_111239 Reviewed: Gotoh, N, 2011-08-26 has a Stoichiometric coefficient of 2 TAB2/TAK1 complex Reactome DB_ID: 202504 Reactome Database ID Release 43202504 Reactome, http://www.reactome.org ReactomeREACT_13271 has a Stoichiometric coefficient of 1 TAK1/TAB2 complex bound to TRAF6/CBM complex Reactome DB_ID: 202507 Reactome Database ID Release 43202507 Reactome, http://www.reactome.org ReactomeREACT_12884 has a Stoichiometric coefficient of 1 PathwayStep4379 Ub-TRAF6 trimer bound to CBM complex Reactome DB_ID: 202456 Reactome Database ID Release 43202456 Reactome, http://www.reactome.org ReactomeREACT_12752 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep4389 Ub-NEMO Reactome DB_ID: 202530 Reactome Database ID Release 43202530 Reactome, http://www.reactome.org ReactomeREACT_12761 has a Stoichiometric coefficient of 1 PathwayStep4388 IKK complex with Ub-NEMO Reactome DB_ID: 202562 Reactome Database ID Release 43202562 Reactome, http://www.reactome.org ReactomeREACT_12853 has a Stoichiometric coefficient of 1 PathwayStep4387 IKK complex with phosphorylated IKK beta Reactome DB_ID: 202513 Reactome Database ID Release 43202513 Reactome, http://www.reactome.org ReactomeREACT_13373 has a Stoichiometric coefficient of 1 PathwayStep4386 phosphorylated TAK1 bound to TAB2 Reactome DB_ID: 202516 Reactome Database ID Release 43202516 Reactome, http://www.reactome.org ReactomeREACT_12782 has a Stoichiometric coefficient of 1 PathwayStep4385 PathwayStep4384 CD28:B7-2 Reactome DB_ID: 388768 Reactome Database ID Release 43388768 Reactome, http://www.reactome.org ReactomeREACT_20140 has a Stoichiometric coefficient of 1 PathwayStep4383 CD28:B7-1 Reactome DB_ID: 388767 Reactome Database ID Release 43388767 Reactome, http://www.reactome.org ReactomeREACT_19811 has a Stoichiometric coefficient of 1 PathwayStep4382 CD28 homodimer Reactome DB_ID: 179780 Reactome Database ID Release 43179780 Reactome, http://www.reactome.org ReactomeREACT_19916 has a Stoichiometric coefficient of 2 PathwayStep4381 PathwayStep4380 RAD9 Converted from EntitySet in Reactome Reactome DB_ID: 176222 Reactome Database ID Release 43176222 Reactome, http://www.reactome.org ReactomeREACT_7824 PathwayStep4368 PathwayStep4369 PathwayStep4376 PathwayStep4375 PathwayStep4378 PathwayStep4377 PathwayStep4372 PathwayStep4371 PathwayStep4374 PathwayStep4373 PathwayStep4370 CD28 bound to B7 ligands Reactome DB_ID: 388765 Reactome Database ID Release 43388765 Reactome, http://www.reactome.org ReactomeREACT_19594 has a Stoichiometric coefficient of 1 CTLA-4 homodimer Reactome DB_ID: 179766 Reactome Database ID Release 43179766 Reactome, http://www.reactome.org ReactomeREACT_19654 has a Stoichiometric coefficient of 2 CTLA-4:PP2A Reactome DB_ID: 389533 Reactome Database ID Release 43389533 Reactome, http://www.reactome.org ReactomeREACT_19731 has a Stoichiometric coefficient of 1 Active RAC1/CDC42 Converted from EntitySet in Reactome Reactome DB_ID: 389778 Reactome Database ID Release 43389778 Reactome, http://www.reactome.org ReactomeREACT_20094 PAK bound to Rac1 and Cdc42 Reactome DB_ID: 389782 Reactome Database ID Release 43389782 Reactome, http://www.reactome.org ReactomeREACT_19943 has a Stoichiometric coefficient of 1 acetoacetyl-CoA + CoA <=> 2 acetyl-CoA Acetyl-CoA acetyltransferase tetramer (ACAT1) in the mitochondrial matrix catalyzes the reversible reaction of acetoacetyl-CoA and CoA to form two molecules of acetyl-CoA (Middleton et al. 1986). EC Number: 2.3.1.9 Pubmed3709573 Reactome Database ID Release 4374181 Reactome, http://www.reactome.org ReactomeREACT_884 has a Stoichiometric coefficient of 2 Vav1 bound to PIP3 and Grb2:CD28 Reactome DB_ID: 389334 Reactome Database ID Release 43389334 Reactome, http://www.reactome.org ReactomeREACT_19524 has a Stoichiometric coefficient of 1 Gly-3-P+FAD->DHAP+FADH2 (catalyzed by mitochondrial Gly-Phos dehydrogenase) Authored: Gopinathrao, G, 2006-10-13 16:08:33 EC Number: 1.1.5.3 EC Number: 1.1.99.5 Edited: Gopinathrao, G, 2009-03-18 00:18:18 FAD-linked mitochondrial glycerol 3-phosphate dehydrogenase (GPD2, alias: mGPDH) and its NAD-linked cytosolic isoform (GPD1, alias:cGPDH) constitute glycerol phosphate shuttle. GPD2 catalyzes the unidirectional conversion of glycerol-3-phosphate (G-3-P) to dihydroxyacetone phosphate (DHAP) with concomitant reduction of the enzyme-bound FAD. Impaired activity of GPD2 has been suggested to be one of the primary causes of insulin secretory defects in beta-cells and thus it is a candidate gene for type 2 diabetes. ISBN0716720094 Pubmed7821823 Pubmed8163052 Pubmed8687421 Reactome Database ID Release 43188467 Reactome, http://www.reactome.org ReactomeREACT_16938 Reviewed: Jassal, B, 2009-02-27 15:21:18 pVav1:PIP3:Grb2:CD28 Reactome DB_ID: 389332 Reactome Database ID Release 43389332 Reactome, http://www.reactome.org ReactomeREACT_20129 has a Stoichiometric coefficient of 1 D-beta hydroxybutyrate+NAD+ <=> acetoacetate+NADH+H+ D-beta-hydroxybutyrate dehydrogenase tetramer (BDH1) in the mitochondrial matrix catalyzes the reversible reaction of D-beta hydroxybutyrate and NAD+ to form acetoacetate and NADH + H+ (Marks et al. 1992). EC Number: 1.1.1.30 Pubmed1639787 Reactome Database ID Release 4373920 Reactome, http://www.reactome.org ReactomeREACT_1493 CD28:Gads Reactome DB_ID: 389384 Reactome Database ID Release 43389384 Reactome, http://www.reactome.org ReactomeREACT_20416 has a Stoichiometric coefficient of 1 acetoacetate + succinyl-CoA <=> acetoacetyl-CoA + succinate 3-Oxoacid CoA-transferase dimer (OXCT1) in the mitochondrial matrix catalyzes the reversible reaction of acetoacetate and succinyl-CoA to form acetoacetyl-CoA and succinate (Kassovska-Bratinova et al. 1996). EC Number: 2.8.3.5 Pubmed8751852 Reactome Database ID Release 4374177 Reactome, http://www.reactome.org ReactomeREACT_1796 CD28:Grb2 Reactome DB_ID: 388786 Reactome Database ID Release 43388786 Reactome, http://www.reactome.org ReactomeREACT_20227 has a Stoichiometric coefficient of 1 Reduction of Acetoacetate to beta-Hydroxybutyrate D-beta-hydroxybutyrate dehydrogenase tetramer (BDH1) in the mitochondrial matris catalyzes the reversible reaction of acetoacetate with NADH + H+ to form D-beta hydroxybutyrate and NAD+ (Marks et al. 1992). EC Number: 1.1.1.30 Pubmed1639787 Reactome Database ID Release 4373912 Reactome, http://www.reactome.org ReactomeREACT_631 acetoacetic acid + NADH + H+ <=> beta-hydroxybutyrate + NAD+ HMG CoA => acetoacetic acid + acetyl CoA EC Number: 4.1.3.4 Hydroxymethylglutaryl-CoA lyase dimer (HMGCL) in the mitochondrial matrix catalyzes the reaction of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG CoA) to form acetyl-CoA and acetoacetate (Mitchell et al. 1993). Pubmed8440722 Reactome Database ID Release 4374180 Reactome, http://www.reactome.org ReactomeREACT_2103 acetoacetyl-CoA+acetyl-CoA => HMG-CoA + CoASH EC Number: 2.3.3.10 Hydroxymethylglutaryl-CoA synthase tetramer (HMGCS2) in the mitochondrial matrix catalyzes the reaction of acetoacetyl-CoA and acetyl-CoA to form beta-hydroxy-beta-methylglutaryl coenzyme A (HMG CoA) and CoA (Aledo et al. 2001). Pubmed11479731 Reactome Database ID Release 4373918 Reactome, http://www.reactome.org ReactomeREACT_1099 2 acetyl-CoA <=> acetoacetyl-CoA + CoA Acetyl-CoA acetyltransferase tetramer (ACAT1) in the mitochondrial matrix catalyzes the reversible reaction of two molecules of acetyl-CoA to form acetoacetyl-CoA and CoA (Middleton et al. 1986). EC Number: 2.3.1.9 Pubmed3709573 Reactome Database ID Release 4373916 Reactome, http://www.reactome.org ReactomeREACT_47 has a Stoichiometric coefficient of 2 L-methylmalonyl-CoA <=> succinyl-CoA At the beginning of this reaction, 1 molecule of 'L-methylmalonyl-CoA' is present. At the end of this reaction, 1 molecule of 'Succinyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'methylmalonyl-CoA mutase activity' of 'methylmalonyl-CoA mutase, homodimer'.<br> EC Number: 5.4.99.2 ISBN0079130356 Reactome Database ID Release 4371010 Reactome, http://www.reactome.org ReactomeREACT_19 D-methylmalonyl-CoA <=> L-methylmalonyl-CoA At the beginning of this reaction, 1 molecule of 'D-methylmalonyl-CoA' is present. At the end of this reaction, 1 molecule of 'L-methylmalonyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'methylmalonyl-CoA epimerase activity' of 'methylmalonyl-CoA epimerase'.<br> EC Number: 5.1.99.1 ISBN0079130356 Pubmed11481338 Pubmed13934211 Reactome Database ID Release 4371020 Reactome, http://www.reactome.org ReactomeREACT_1909 propionyl-CoA + CO2 + ATP <=> D-methylmalonyl-CoA + ADP + orthophosphate EC Number: 6.4.1.3 EC Number: ase ISBN0079130356 Propionyl CoA carboxylase in the mitochondrial matrix catalyzes the reaction of propionyl-CoA, CO2, and ATP to form D-methylmalonyl-CoA, ADP, and orthophosphate. The active form of the enzyme is a heteromultimer, probably consisting of six alpha subunits each bound to a biotin molecule and six beta subunits (Kaziro et al. 1961; Kalousek et al. 1980; Fenton et al. 2001). Both alpha and beta subunits are posttranslationally modified to remove amino-terminal mitochondrial import sequences (Stadler et al. 2005). Pubmed13752080 Pubmed16023992 Pubmed6765947 Reactome Database ID Release 4371031 Reactome, http://www.reactome.org ReactomeREACT_580 Removal of 2 Carbon atoms from trans,cis-Lauro-2,6-dienoyl-CoA to form 4-cis-decenoyl-CoA Authored: Gillespie, ME, 2004-01-19 00:00:00 EC Number: 1.1.1.35 EC Number: 1.3.99.3 EC Number: 2.3.1.155 EC Number: 4.2.1.17 GENE ONTOLOGYGO:0006635 ISBN0079130356 Reactome Database ID Release 43109342 Reactome, http://www.reactome.org ReactomeREACT_440 trans,cis-Lauro-2,6-dienoyl-CoA transits through the saturated beta-oxidation spiral a single time to yield 4-cis-decenoyl-CoA. dehydrogenation of 4-cis-decenoyl-CoA to form 2-trans-4-cis-decadienoyl-CoA 4-cis-decenoyl-CoA transits through the first step of the saturated beta-oxidation spiral to yield 2-trans-4-cis-decadienoyl-CoA. Authored: Gillespie, ME, 2004-01-19 00:00:00 EC Number: 1.3.99.3 GENE ONTOLOGYGO:0006635 ISBN0079130356 Reactome Database ID Release 43109341 Reactome, http://www.reactome.org ReactomeREACT_1111 Reduction of 2-trans-4-cis-decadienoyl-CoA to form 3-trans-decenoyl-CoA Authored: Gillespie, ME, 2004-01-19 00:00:00 EC Number: 1.6 GENE ONTOLOGYGO:0006635 ISBN0079130356 Reactome Database ID Release 43109343 Reactome, http://www.reactome.org ReactomeREACT_164 The second of the two accessory enzymes, 2,4-dienoyl-CoA reductase catalyses an oxidation-reduction (redox) reaction to yield 3-trans-decenoyl-CoA. Isomerization of 3-trans-decenoyl-CoA to form trans-dec-2-enoyl-CoA Authored: Gillespie, ME, 2004-01-19 00:00:00 EC Number: 5.3 GENE ONTOLOGYGO:0006635 ISBN0079130356 Once the second of the two double bonds has been reached 3,2-trans-enoyl-CoA isomerase, changes the spatial conformation of the second double bond from cis to trans. This step yields trans-dec-2-enoyl-CoA, which then enters the saturated beta-oxidation pathway. Reactome Database ID Release 43109998 Reactome, http://www.reactome.org ReactomeREACT_1445 (S)-Hydroxybutanoyl-CoA+NAD<=>Acetoacetyl-CoA+NADH+H At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-3-Hydroxybutanoyl-CoA' are present. At the end of this reaction, 1 molecule of 'acetoacetyl-CoA', 1 molecule of 'H+', and 1 molecule of 'NADH' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.<br> EC Number: 1.1.1.35 Pubmed10231530 Pubmed8687463 Reactome Database ID Release 4377312 Reactome, http://www.reactome.org ReactomeREACT_447 Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomer:Mal:activated TLR complex Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 IRAK4 deficient macrophages fail to induce IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1.<p>Phosphorylation sites of IRAK2 remain to be characterized. Pubmed18438411 Reactome Database ID Release 43937059 Reactome, http://www.reactome.org ReactomeREACT_25213 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 4 Crotonoyl-CoA+H2O<=>(S)-3-Hydroxybutanoyl-CoA At the beginning of this reaction, 1 molecule of 'Crotonoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-3-Hydroxybutanoyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.<br> EC Number: 4.2.1.17 Pubmed13295248 Reactome Database ID Release 4377314 Reactome, http://www.reactome.org ReactomeREACT_386 Isomerization of cis,cis-3,6-Dodecadienoyl-CoA to form trans,cis-Lauro-2,6-dienoyl-CoA At the beginning of this reaction, 1 molecule of 'cis,cis-3,6-Dodecadienoyl-CoA' is present. At the end of this reaction, 1 molecule of 'trans,cis-Lauro-2,6-dienoyl-CoA ' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'dodecenoyl-CoA delta-isomerase activity' of '3,2-trans-enoyl-CoA isomerase Homodimer'.<br> EC Number: 5.3.3.8 ISBN0079130356 Reactome Database ID Release 43109338 Reactome, http://www.reactome.org ReactomeREACT_588 Second phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal Authored: de Bono, B, 2005-08-16 10:54:15 EC Number: 2.7.11 Edited: Shamovsky, V, 2012-11-06 Pubmed14625308 Reactome Database ID Release 43166284 Reactome, http://www.reactome.org ReactomeREACT_6794 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity. has a Stoichiometric coefficient of 4 Removal of six carbons from Linoleoyl-CoA to form cis,cis-3,6- Dodecadienoyl-CoA Authored: Gillespie, ME, 2004-01-19 00:00:00 EC Number: 1.1.1.35 EC Number: 1.3.99.3 EC Number: 2.3.1.155 EC Number: 4.2.1.17 GENE ONTOLOGYGO:0006635 ISBN0079130356 Linoleoyl-CoA transits through the saturated beta-oxidation spiral three times. With each turn of the spiral two carbon atoms are removed until the double bond is reached. Reactome Database ID Release 43109339 Reactome, http://www.reactome.org ReactomeREACT_2238 has a Stoichiometric coefficient of 3 First phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal Authored: de Bono, B, 2005-08-16 10:54:15 EC Number: 2.7.11 Edited: Shamovsky, V, 2012-11-06 First, IRAK1 is phosphorylated at Thr209 by IRAK4. This results in a conformational change of the kinase domain, permitting further phosphorylations to take place. Substitution of Thr209 by alanine results in a kinase-inactive IRAK1. Pubmed11960013 Pubmed14625308 Reactome Database ID Release 43166119 Reactome, http://www.reactome.org ReactomeREACT_6833 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 4 TRAF6 binds to hp- IRAK1 Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 Hyperphosphorylated IRAK1, still within the receptor complex, binds TRAF6 through multiple regions including the death domain, the undefined domain and the C-terminal C1 domain (Li et al. 2001). The C-terminal region of IRAK-1 contains three potential TRAF6-binding sites; mutation of the amino acids (Glu544, Glu587, Glu706) in these sites to alanine greatly reduces activation of NFkappaB (Ye et al. 2002). Pubmed11287640 Pubmed12138165 Pubmed12140561 Pubmed18070982 Pubmed8837778 Reactome Database ID Release 43166363 Reactome, http://www.reactome.org ReactomeREACT_6856 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 4 Multiple IRAK1 autophosphorylation steps Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 Phosphorylation of IRAK-1 is due to three sequential phosphorylation steps, which leads to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the activated receptor complex. The kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), It has been suggested that IRAK1 primarily acts as an adaptor for TRAF6 (Conze et al. 2008). Pubmed10217414 Pubmed11923871 Pubmed14625308 Pubmed17337443 Pubmed18347055 Reactome Database ID Release 43166286 Reactome, http://www.reactome.org ReactomeREACT_6862 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 16 Butanoyl-CoA+FAD<=>Crotonoyl-CoA+FADH2 At the beginning of this reaction, 1 molecule of 'FAD', and 1 molecule of 'Butanoyl-CoA' are present. At the end of this reaction, 1 molecule of 'Crotonoyl-CoA', and 1 molecule of 'FADH2' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'SCAD acyl-CoA dehydrogenase homotetramer'.<br> EC Number: 1.3.99.3 Pubmed13295225 Pubmed3597357 Reactome Database ID Release 4377319 Reactome, http://www.reactome.org ReactomeREACT_1592 Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 Hyperphosphorylated IRAK1 and TRAF6 are thought to dissociate from the activated receptor. (Gottipati et al. 2007) but the IRAK1:TRAF6 complex may remain associated with the membrane (Dong et al. 2006).<p> Phosphorylated IRAK2, like its paralog IRAK1, possibly dissociates from the activated receptor as shown here, although mechanism of IRAK2 activation by IRAK4 followed by TRAF6 binding remains to be deciphered. Pubmed14625308 Pubmed16831874 Pubmed17890055 Reactome Database ID Release 43166362 Reactome, http://www.reactome.org ReactomeREACT_6736 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 4 TRAF6 binds to p-IRAK2 Authored: Shamovsky, V, 2012-04-19 Edited: Shamovsky, V, 2012-11-06 IRAK-2 has two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). IRAK2 point mutants with mutated TRAF6-binding motifs abrogate NFkB activation and are incapable to stimulate TRAF6 ubiquitination (Keating SE et al 2007). Pubmed12138165 Pubmed12140561 Pubmed17878161 Pubmed18070982 Pubmed8837778 Reactome Database ID Release 432262777 Reactome, http://www.reactome.org ReactomeREACT_120733 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 4 TLR1/2 ligand binds to CD14 Authored: Shamovsky, V, 2012-05-15 CD14, a GPI-anchored molecule found on the cell surface of human phagocytes, has been identified as a co-receptor that interacts with LPS. CD14 has been also implicated in TLR-2 signalling [Hajishengallis G et al 2006; Zivkovic A et al 2011]. Studies have demonstrated that CD14 can bind to triacylated lipoproteins and mediate the activation of the innate immune system trough TLR2:TLR1 complex [Nakata T et al 2006; Manukyan M et al 2005; Triantafilou M et al 2006] Edited: Shamovsky, V, 2012-11-19 Pubmed15714590 Pubmed16880211 Reactome Database ID Release 432559468 Reactome, http://www.reactome.org ReactomeREACT_150261 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 Dissociation of p-IRAK2:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 Hyperphosphorylated IRAK1 and TRAF6 are thought to dissociate from the activated receptor. (Gottipati et al. 2007) but the IRAK1:TRAF6 complex may remain associated with the membrane (Dong et al. 2006).<p> Phosphorylated IRAK2, like its paralog IRAK1, possibly dissociates from the activated receptor as shown here, although mechanism of IRAK2 activation by IRAK4 followed by TRAF6 binding remains to be deciphered. Pubmed14625308 Pubmed16831874 Pubmed17890055 Reactome Database ID Release 432262775 Reactome, http://www.reactome.org ReactomeREACT_121298 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 4 TLR1:TLR2 is recruited to ligand:CD14 Authored: D'Eustachio, P, Gay, NJ, Gale M, Jr, Zwaginga, JJ, 2006-04-19 04:09:58 Edited: Shamovsky, V, 2012-11-19 Pubmed10426996 Pubmed12975352 Pubmed15241424 Pubmed16455995 Reactome Database ID Release 43168951 Reactome, http://www.reactome.org ReactomeREACT_7951 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Reviewed: Gillespie, ME, 2010-11-30 The TLR2:TLR1 complex recognizes Neisserial PorB and Mycobacterial triacylated lipoproteins and peptides, amongst others. Hexanoyl-CoA+FAD<=>trans-Hex-2-enoyl-CoA+FADH2 At the beginning of this reaction, 1 molecule of 'Hexanoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'trans-Hex-2-enoyl-CoA', and 1 molecule of 'FADH2' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'SCAD acyl-CoA dehydrogenase homotetramer'.<br> EC Number: 1.3.99.3 Pubmed13295225 Pubmed3597357 Reactome Database ID Release 4377327 Reactome, http://www.reactome.org ReactomeREACT_1742 trans-Hex-2-enoyl-CoA+H2O<=>(S)-Hydroxyhexanoyl-CoA At the beginning of this reaction, 1 molecule of 'trans-Hex-2-enoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-Hydroxyhexanoyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.<br> EC Number: 4.2.1.17 Pubmed13295248 Reactome Database ID Release 4377325 Reactome, http://www.reactome.org ReactomeREACT_87 (S)-Hydroxyoctanoyl-CoA+NAD<=>3-Oxooctanoyl-CoA+NADH+H At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-Hydroxyoctanoyl-CoA' are present. At the end of this reaction, 1 molecule of '3-Oxooctanoyl-CoA', 1 molecule of 'H+', and 1 molecule of 'NADH' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.<br> EC Number: 1.1.1.35 Pubmed8687463 Reactome Database ID Release 4377331 Reactome, http://www.reactome.org ReactomeREACT_1908 3-Oxooctanoyl-CoA+CoA-SH<=>Hexanoyl-CoA At the beginning of this reaction, 1 molecule of '3-Oxooctanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Hexanoyl-CoA', and 1 molecule of 'Acetyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.<br> EC Number: 2.3.1.155 Pubmed1550553 Reactome Database ID Release 4377329 Reactome, http://www.reactome.org ReactomeREACT_481 (S)-Hydroxyhexanoyl-CoA+NAD<=>3-Oxohexanoyl-CoA+NADH+H At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-Hydroxyhexanoyl-CoA' are present. At the end of this reaction, 1 molecule of '3-Oxohexanoyl-CoA', 1 molecule of 'H+', and 1 molecule of 'NADH' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.<br> EC Number: 1.1.1.35 Pubmed8687463 Reactome Database ID Release 4377323 Reactome, http://www.reactome.org ReactomeREACT_2195 3-Oxohexanoyl-CoA+CoA-SH<=>Butanoyl-CoA At the beginning of this reaction, 1 molecule of '3-Oxohexanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Acetyl-CoA', and 1 molecule of 'Butanoyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.<br> EC Number: 2.3.1.155 Pubmed1550553 Reactome Database ID Release 4377321 Reactome, http://www.reactome.org ReactomeREACT_2140 MyD88 forms a complex with MAL:activated TLR2/4 Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 MyD88 binds to IRAK (IL-1 receptor-associated kinase) and the receptor heterocomplex (the signaling complex) and thereby mediates the association of IRAK with the receptor. MyD88 therefore couples a serine/threonine protein kinase to the receptor complex. Pubmed12447441 Pubmed12447442 Pubmed9430229 Reactome Database ID Release 43166072 Reactome, http://www.reactome.org ReactomeREACT_6797 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 2 MAL is phosphorylated by BTK Authored: Shamovsky, V, 2012-04-19 EC Number: 2.7.10 Edited: Shamovsky, V, 2012-11-06 MAL(TIRAP) undergoes tyrosine phosphorylation mediated by Bruton's tyrosine kinase (BTK). BTK-specific inhibitor, LFM-A13, blocked the phosphorylation of MAL in human HEK293 stimulated with LPS or macrophage-activating lipopeptide-2. LFM-A13 also inhibited activation of NF-kB in LPS-treated human monocytic cell line THP-1 [Gray P et al 2006; Jefferies CA et al 2003]. Tyr-86, Tyr-106 and Tyr-187 were identified as possible phosphorylation sites [Gray P et al 2006]. An additional study has shown that Tyr-86, Tyr-106, and Tyr-159 are important residues, as mutagenesis of these residues impaired MAL phosphorylation, affected its interaction with BTK and also impaired downstream signaling [Piao W et al 2008]. Pubmed12724322 Pubmed16439361 Pubmed18070880 Reactome Database ID Release 432201322 Reactome, http://www.reactome.org ReactomeREACT_120882 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Napetschnig, Johanna, 2012-11-16 Activated TLR2/4:MAL interacts with BTK Authored: Shamovsky, V, 2012-04-19 Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase, which plays an essential role in B cell receptor (BCR) signaling [Brunner C et al 2005]. BTK has been also implicated in TLR signaling [Lee KG et al 2012, Jefferies CA et al 2003]. Interaction studies revealed that BTK can associate with intracellular TIR-domains of TLRs 4, 6, 8 and 9. Furthermore, BTK was found to interact with other proteins involved in TLR2/4 signaling - MyD88, MAL and IRAK-1 [Jefferies CA et al 2003]. Edited: Shamovsky, V, 2012-11-06 Pubmed12724322 Pubmed15944945 Pubmed22454496 Reactome Database ID Release 432559414 Reactome, http://www.reactome.org ReactomeREACT_150418 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 2 Activated TLR2/4 interacts with MAL(TIRAP) Authored: Shamovsky, V, 2012-04-19 Edited: Shamovsky, V, 2012-11-06 Pubmed12447441 Pubmed12447442 Pubmed17726518 Pubmed19592497 Reactome Database ID Release 432201316 Reactome, http://www.reactome.org ReactomeREACT_121383 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Napetschnig, Johanna, 2012-11-16 TIRAP/Mal-deficient mice showed normal responses to the TLR3, TLR5, TLR7, and TLR9 ligands, but were defective in TLR4 and TLR2 ligand-induced proinflammatory cytokine production (Horng et al. 2002,Yamamoto et al. 2002). In contrast, TLR4 ligand-induced activation of IRF-3 and expression of IFN-inducible genes were not impaired in TIRAP/Mal knockout macrophages or in mice lacking both MyD88 and TIRAP/Mal (Horng et al. 2002,Yamamoto et al. 2002). Thus, TIRAP/Mal is an essential adapter that is involved in the MyD88-dependent pathway via TLR4 and TLR2, but not in the MyD88-independent pathway. Mal contains a phosphatidylinositol 4,5-bisphosphate-binding domain required for retention in the plasma membrane. The intracellular TIR domains of TLR2 or 4 associate with Mal at the cytoplasmic side of the plasma membrane, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel et al 2007]. has a Stoichiometric coefficient of 2 trans-Oct-2-enoyl-CoA+H2O<=>(S)-Hydroxyoctanoyl-CoA At the beginning of this reaction, 1 molecule of 'H2O', and 1 molecule of 'trans-Oct-2-enoyl-CoA' are present. At the end of this reaction, 1 molecule of '(S)-Hydroxyoctanoyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.<br> EC Number: 4.2.1.17 Pubmed13295248 Reactome Database ID Release 4377333 Reactome, http://www.reactome.org ReactomeREACT_109 TLR4:MD2:LPS:CD14 recruits TRAM Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2011-08-12 Pubmed12471095 Pubmed14556004 Pubmed15596121 Reactome Database ID Release 43166168 Reactome, http://www.reactome.org ReactomeREACT_6808 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 TRIF-related adapter molecule (TRAM, also called TIRP or TICAM-2) is 235 amino acids in length, and its TIR domain is most closely related to TRIF (and hence its name). Notably, both human and mouse TRAM contain a cysteine (C117 in humans) at the position where other adapters and TLRs have a conserved proline, although an adjacent proline (P116) is present. TRAM associates with TLR4 and TRIF, as well as the non-canonical NFkB kinases, IKK epsilon, and TBK1, which phosphorylate IRF3. TRAM provides specificity for the MyD88-independent component of TLR4 signaling. has a Stoichiometric coefficient of 2 Octanoyl-CoA+FAD<=>trans-Oct-2-enoyl-CoA+FADH2 At the beginning of this reaction, 1 molecule of 'Octanoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'FADH2', and 1 molecule of 'trans-Oct-2-enoyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'MCAD acyl-CoA dehydrogenase homotetramer'.<br> EC Number: 1.3.99.3 Pubmed13295225 Pubmed3597357 Reactome Database ID Release 4377338 Reactome, http://www.reactome.org ReactomeREACT_442 Endocytosis of TRAM Authored: Shamovsky, V, 2012-04-19 Edited: Shamovsky, V, 2012-05-25 Pubmed16757566 Pubmed18222170 Pubmed18297073 Reactome Database ID Release 432201341 Reactome, http://www.reactome.org ReactomeREACT_121217 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 TRIF-related adapter molecule (TRAM) is a sorting adapter which recruits TRIF to activated TLR4. Like TLR4, TRAM was detected both at the plasma membrane and in the endosomal compartment. TRAM was reported to recruit TRIF to the plasma membrane [Tanimuro N et al 2008]. However, TRAM did not induce TRIF-mediated signaling from the cell surface, instead, TRAM endocytosis was required for activation of IRF3 and induction of IFN-beta [Tanimuro N et al 2008; Kagan JC et al 2008]. Although, endocytosis of both TLR4 and TRAM and their association are required to trigger TRIF-mediated signaling, TRAM can target endosomes independently on its interaction with TLR4. TRAM cellular localization is controlled by myristoylation and phosphorylation of its N-terminal bipartite sorting signal motif [Kagan JC et al 2008]. <p>TRAM has been shown to undergo phosphorylation on Ser-16 by protein kinase C epsilon in LPS-treated human THP1 and murine embryonic fibroblasts (MEF) cells [McGettrick AF et al 2006]. 3-Oxodecanoyl-CoA+CoA-SH<=>Octanoyl-CoA At the beginning of this reaction, 1 molecule of '3-Oxodecanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Acetyl-CoA', and 1 molecule of 'Octanoyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.<br> EC Number: 2.3.1.155 Pubmed1550553 Reactome Database ID Release 4377340 Reactome, http://www.reactome.org ReactomeREACT_250 (S)-Hydroxydecanoyl-CoA+NAD<=>3-Oxodecanoyl-CoA+NADH+H At the beginning of this reaction, 1 molecule of '(S)-Hydroxydecanoyl-CoA', and 1 molecule of 'NAD+' are present. At the end of this reaction, 1 molecule of 'H+', 1 molecule of '3-Oxodecanoyl-CoA', and 1 molecule of 'NADH' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.<br> EC Number: 1.1.1.35 Pubmed8687463 Reactome Database ID Release 4377342 Reactome, http://www.reactome.org ReactomeREACT_2187 IRAK1 or IRAK2 binds to the activated IRAK4 :activated TLR:MyD88:Mal complex Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 IRAK1 is recruited to the TLR complex through binding with IRAK4[Lin SC et al 2010].<p> IRAK2 has been implicated in IL1R and TLR signaling by the observation that IRAK2 can associate with MyD88 and Mal (Muzio et al. 1997). Like IRAK1, IRAK2 is activated downstream of IRAK4 (Kawagoe et al. 2008). It has been suggested that IRAK1 activates IRAK2 (Wesche et al. 1999) but IRAK2 phosphorylation is observed in IRAK1–/– mouse macrophages while IRAK4 deficiency abrogates IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1. IL6 production in response to IL1beta is impaired in embryonic fibroblasts from IRAK1 or IRAK2 knockout mice and abrogated in IRAK1/2 dual knockouts (Kawagoe et al. 2007) suggesting that IRAK1 and IRAK2 are both involved in IL1R signaling downstream of IRAK4. Pubmed12150927 Pubmed16024789 Pubmed17878161 Pubmed17890055 Pubmed18438411 Pubmed19224918 Pubmed20485341 Pubmed21606490 Pubmed9374458 Reactome Database ID Release 43166091 Reactome, http://www.reactome.org ReactomeREACT_6929 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 4 IRAK4 autophosphorylation in the complex with activated TLR:MyD88:Mal Authored: Shamovsky, V, 2010-06-01 EC Number: 2.7.11 Edited: Shamovsky, V, 2012-11-06 IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346. Pubmed17141195 Pubmed17485511 Reactome Database ID Release 43937022 Reactome, http://www.reactome.org ReactomeREACT_25097 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 12 IRAK4 binds to the activated TLR receptor:Mal:MyD88 complex Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 IRAK4 is the mammalian homolog of Drosophila melanogaster Tube [Towb P et al 2009; Moncrieffe MC et al 2008]. Like Tube, IRAK4 possesses a conserved N-terminal death domain (DD), which mediates interactions with MyD88 at one binding site and a downstream IRAK kinase at the other, thereby bridging MyD88 and IRAK1/2 association [Towb P et al 2009; Lin SC e al 2010]. IRAK-4 plays a critical role in Toll receptor signaling - any interference with IRAK-4's kinase activity virtually abolishes downstream events. This is not the case with other members of the IRAK family [Suzuki N et al 2002; Li S et al 2002]. Pubmed11960013 Pubmed12297423 Pubmed18829464 Pubmed19498957 Pubmed19592493 Pubmed20485341 Reactome Database ID Release 43166082 Reactome, http://www.reactome.org ReactomeREACT_6975 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 4 MyD88 oligomerization within the complex of activated TLR:Mal:MyD88 Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 Pubmed19592493 Pubmed20485341 Pubmed20966070 Reactome Database ID Release 43937079 Reactome, http://www.reactome.org ReactomeREACT_25221 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 Structural analysis of MyD88:IRAK4 and MyD88:IRAK4:IRAK2 suggested that upon MyD88 recruitment to an activated dimerized TLR the MyD88 death domains clustering induces the formation of Mydosome, a large oligomeric signaling platform (Motshwene PG et al 2009, Lin SC et al 2010). Assembly of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. The oligomer complex stoichiometry was reported as 7:4 and 8:4 for MyD88:IRAK4 (Motshwene PG et al 2009), and 6:4:4 in the complex of MyD88:IRAK4:IRAK2(Lin SC et al 2010). has a Stoichiometric coefficient of 4 Rab5-mediated recruitment of class III PI3K to TLR9 Pubmed14751759 Pubmed17878374 Reactome Database ID Release 43188002 Reactome, http://www.reactome.org ReactomeREACT_9041 TLR9 signaling has the uncommon property of triggering PI3K-mediated cascades via Rab5. Engulfed CpG DNA binds to endosomal C-ter TLR9 Edited: Shamovsky, V, 2011-08-12 Pubmed15207506 Pubmed21604257 Reactome Database ID Release 43187895 Reactome, http://www.reactome.org ReactomeREACT_8991 Synthetic oligodeoxynucleotides (ODN) expressing non-methylated CpG motifs patterned after those present in bacterial DNA have characteristic immunomodulatory effects. CpG DNA is recognized as a pathogen-associated molecular pattern by TLR9, and triggers a rapid innate immune response. GPI-bound CD14 binds LPS At the beginning of this reaction, 1 molecule of 'GPI-anchored form of CD14', and 1 molecule of 'LBP complexed with bacterial LPS' are present. At the end of this reaction, 1 molecule of 'LPS complexed with GPI-anchored CD14', and 1 molecule of 'LBP' are present.<br><br> <br> Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2010-11-15 Pubmed9665271 Reactome Database ID Release 43166038 Reactome, http://www.reactome.org ReactomeREACT_6902 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 Association of LBP with LPS Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2010-11-16 Lipopolysaccharide-binding protein (LBP) is a ~60-kDa serum glycoprotein which transfers LPS to both membrane-bound and soluble CD14. The LPS binding site of LBP consists of basic residues that bind the phosphorylated head of the bacterial lipid A. <p>LBP is an acute-phase opsonin that binds gram-negative bacteria and bacterial fragments and promote the interaction of coated bacteria with phagocytes. Pubmed1698311 Pubmed19269309 Pubmed2477488 Reactome Database ID Release 43166015 Reactome, http://www.reactome.org ReactomeREACT_6834 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 Engulfed CpG DNA binds to endosomal N-ter TLR9 dimer Authored: Shamovsky, V, 2011-09-21 Edited: Shamovsky, V, 2012-02-19 Pubmed15207506 Pubmed21604257 Reactome Database ID Release 431679098 Reactome, http://www.reactome.org ReactomeREACT_118564 Reviewed: Gillespie, ME, 2012-02-09 TLR9 traffics to an endosomal vesicle where it is processed by cathepsin S at neural pH to generate an N-terminal product (TLR9 N-ter, aa 1-723). The N-terminal fragment of TLR9 also binds ligand, but in contrast to the C-terminal fragment it inhibits TLR9 signaling. Thus, a proper balance between the two proteolytic events probably regulates TLR9-mediated host responses. (Chockalingam A et al 2011). Endocytosis of TLR4:MD2:LPS:CD14 Authored: Shamovsky, V, 2012-04-19 Edited: Shamovsky, V, 2012-05-25 Pubmed16467847 Pubmed18233961 Pubmed18297073 Pubmed22078883 Pubmed22158869 Reactome Database ID Release 432201293 Reactome, http://www.reactome.org ReactomeREACT_121112 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta [Tanimuro N et al 2008; Kagan JC et al 2008]. While TLR4 translocation to endosomes is governed by known regulators of general endocytic processes such as dynamins and clathrin, other proteins that specifically regulate LPS-stimulated TLR4 endocytosis have been also identified [Husebye et al 2006; Kagan JC et al 2008; Zanoni I et al 2011]. Thus, CD14 has been implicated both in transporting LPS to TLR4 and in delivering TLR4 to an endosomal compartment. TLR4 translocation activated by CD14 appears to be Syk-mediated, and requires its downstream effector phospholipase C gamma 2 (PLCgamma2), which in turn induces a drop in the concentration of PIP2 required for endosomal sealing [Zanoni I et al 2011]. It has also been shown that PLCgamma2 induces inositol 1,4,5-trisphosphate (IP(3)) production and subsequent calcium (Ca2+) release. Released intracellular Ca2+ was reported to mediate TLR4 trafficking and subsequent activation of IRF3. [Aki D et al 2008; Chiang CY et al 2012]. Transfer of LPS onto TLR4 Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2011-08-12 Pubmed15276183 Pubmed17803912 Pubmed19252480 Pubmed9665271 Reactome Database ID Release 43166041 Reactome, http://www.reactome.org ReactomeREACT_6795 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 The Toll-like receptor 4 (TLR4) is a membrane-spanning protein distantly related to the IL1 receptor. Both CD14 and members of the Toll family contain multiple leucine-rich repeats. In addition, the latter possess a Toll-homology domain in the cytoplasmic tail, which is important in the generation of a transmembrane signal linked to LPS-induced cell activation. Of all Toll family members, TLR4 is probably the exclusive receptor for LPS from most Gram negative organisms.<p> Toll-like receptor 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that specifically recognizes structurally diverse LPS molecules. A structural study of TLR4:MD-2 complex revealed that MD-2 interaction with TLR4 relies on hydrogen and electrostatic bonds (Kim HM et al, 2007). LPS binds to the hydrophobic pocket of MD-2 and directly mediates the dimerization of the two TLR4:MD-2 complexes in a symmetrical manner. Both hydrophobic and hydrophilic interactions contribute to the main dimerization interaction between MD-2, LPS and TLR4 multimer components. The phosphate groups of LPS also contribute to the receptor multimerization by forming ionic interactions with positively charged residues of TLR4 and MD-2. (Park BS et al, 2009). </p><p>The activated TLR4 receptor is composed of two copies of the TLR4-MD2-LPS complex and initiates signal transduction by recruiting intracellular adaptor molecules. has a Stoichiometric coefficient of 2 Secreted CD14 binds LPS At the beginning of this reaction, 1 molecule of 'Secreted form of CD14', and 1 molecule of 'LBP complexed with bacterial LPS' are present. At the end of this reaction, 1 molecule of 'LBP', and 1 molecule of 'LPS complexed with secreted CD14' are present.<br><br> <br> Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2010-11-15 Pubmed9665271 Reactome Database ID Release 43169719 Reactome, http://www.reactome.org ReactomeREACT_6843 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 MAL(TIRAP) binds PIP2-rich regions in the plasma membrane Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-19 Pubmed11544529 Pubmed15585605 Pubmed16751103 Pubmed19509286 Reactome Database ID Release 432559456 Reactome, http://www.reactome.org ReactomeREACT_150399 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain [Kagan JC and Medzithov R 2007]. TLR2 or 4 associates with Mal(TIRAP) on the cell surface, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel R et al 2007, Nagpal K et al 2009]. CD14:LPS binds CR3 Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-19 Pubmed10201950 Pubmed16751103 Pubmed2462607 Pubmed3537192 Reactome Database ID Release 432559439 Reactome, http://www.reactome.org ReactomeREACT_150423 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 Upon LPS stimulation, CD14, in addition to promote endotoxin transfer to TLR4, also triggers complement receptor 3 (CR3) activation [Troelstra A et al 1999; Kagan JC and Medzithov R 2007]. LPS-mediated CR3 upregulation results in induction of PIP5K-dependent de novo synthesis of PIP2 in the lipid rafts through the phosphorylation of PI(4)P. Mal(TIRAP) is then recruited at the site of the newly generated PIP2 where it binds TLR4 via the TIR domain. Finally, MyD88 is recruited to the activated TLR4-CD14 complex via the TIRAP molecule and initiates a signaling cascade leading to a first wave of NF-kB activation from the plasma membrane [Kagan JC and Medzithov R 2007].<p> CR3 (CD11b/CD18) is a member of CD18 receptor family of cell surface glycoproteins, which are expressed in human phagocytes. Each of the three receptors (CR3, lymphocyte function-associated antigen LFA-1, and p150-95) is a heterodimer composed of a beta-chain (CD18) that is identical in all three receptors and a noncovalently associated alpha chain (CD11) that is unique to each molecule [ . CR3 is known as a receptor for the surface-bound complement protein C3bi, but it has been also reported to recognize several other ligands, including bacterial patterns such as LPS and lipid A. Two distinct binding sites on CR3 have been described: 1) a protein-binding-site that binds C3bi, fibrinogen, and Leishmania glycoprotein 63, and 2) a lipid- binding-site involved in the binding of LPS, lipid A [Wright SD et al 1989; Van Strijp J.A.G et al 1993].<p>CR3, LFA-1 and p150-95 have been reported to mediate not only LPS interaction but also promote the binding of Escherichia coli to human macrophages [Wright SD and Jong MTC 1986]. has a Stoichiometric coefficient of 2 GAD2 Activity Complex Converted from EntitySet in Reactome Reactome DB_ID: 947479 Reactome Database ID Release 43947479 Reactome, http://www.reactome.org ReactomeREACT_24233 Docked GABA loaded synaptic veiscle Reactome DB_ID: 917774 Reactome Database ID Release 43917774 Reactome, http://www.reactome.org ReactomeREACT_24328 has a Stoichiometric coefficient of 1 GABA Loaded synaptic vesicle Reactome DB_ID: 917748 Reactome Database ID Release 43917748 Reactome, http://www.reactome.org ReactomeREACT_24412 has a Stoichiometric coefficient of 1 Empty GABA synaptic vesicle Reactome DB_ID: 888597 Reactome Database ID Release 43888597 Reactome, http://www.reactome.org ReactomeREACT_24125 has a Stoichiometric coefficient of 1 STIM1:Calcium Reactome DB_ID: 1168371 Reactome Database ID Release 431168371 Reactome, http://www.reactome.org ReactomeREACT_119430 has a Stoichiometric coefficient of 1 Heterodimer of GAD1 and GAD2 Reactome DB_ID: 888583 Reactome Database ID Release 43888583 Reactome, http://www.reactome.org ReactomeREACT_24876 has a Stoichiometric coefficient of 1 p-BAM32:PIP3 Phosphorylated BAM32:Phosphatidylinositol-3,4,5-trisphosphate Complex Reactome DB_ID: 1168366 Reactome Database ID Release 431168366 Reactome, http://www.reactome.org ReactomeREACT_119758 has a Stoichiometric coefficient of 1 Homodimer of GAD2 Reactome DB_ID: 888574 Reactome Database ID Release 43888574 Reactome, http://www.reactome.org ReactomeREACT_24694 has a Stoichiometric coefficient of 2 p-PLC gamma1,2:PIP3 Phosphorylated Phospholipase C gamma2:Phosphatidylinositol-3,4,5-trisphosphate Complex Reactome DB_ID: 1168365 Reactome Database ID Release 431168365 Reactome, http://www.reactome.org ReactomeREACT_119293 has a Stoichiometric coefficient of 1 GAD2 Activity Complex Converted from EntitySet in Reactome Reactome DB_ID: 888569 Reactome Database ID Release 43888569 Reactome, http://www.reactome.org ReactomeREACT_24821 p-BTK:PIP3 Phosphorylated BTK:Phosphoinositol-3,4,5-trisphosphate Complex Reactome DB_ID: 1168364 Reactome Database ID Release 431168364 Reactome, http://www.reactome.org ReactomeREACT_119582 has a Stoichiometric coefficient of 1 Homodimer of GAD1 Reactome DB_ID: 888570 Reactome Database ID Release 43888570 Reactome, http://www.reactome.org ReactomeREACT_24565 has a Stoichiometric coefficient of 2 BLNK (SLP-65) Signalosome Reactome DB_ID: 984818 Reactome Database ID Release 43984818 Reactome, http://www.reactome.org ReactomeREACT_120226 has a Stoichiometric coefficient of 1 GAD1 activity Converted from EntitySet in Reactome Reactome DB_ID: 888566 Reactome Database ID Release 43888566 Reactome, http://www.reactome.org ReactomeREACT_24495 BCAP Signalosome Reactome DB_ID: 2045909 Reactome Database ID Release 432045909 Reactome, http://www.reactome.org ReactomeREACT_119322 has a Stoichiometric coefficient of 1 CD19:VAV1 Reactome DB_ID: 2076225 Reactome Database ID Release 432076225 Reactome, http://www.reactome.org ReactomeREACT_119973 has a Stoichiometric coefficient of 1 p-BLNK:GRB2:SOS1:CIN85:CBL Reactome DB_ID: 983686 Reactome Database ID Release 43983686 Reactome, http://www.reactome.org ReactomeREACT_119271 has a Stoichiometric coefficient of 1 Antigen:p-BCR:p-SYK:p-BLNK Activated B Cell Receptor: Phosphorylated SYK:Phosphorylated BLNK Complex Reactome DB_ID: 983687 Reactome Database ID Release 43983687 Reactome, http://www.reactome.org ReactomeREACT_120231 has a Stoichiometric coefficient of 1 PathwayStep4532 BLNK:GRB2:SOS1:CIN85:CBL Reactome DB_ID: 983692 Reactome Database ID Release 43983692 Reactome, http://www.reactome.org ReactomeREACT_120158 has a Stoichiometric coefficient of 1 PathwayStep4531 PathwayStep4530 PathwayStep4524 Phosphorylation and release of IRF7 upon TLR7/8 or 9 activation Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2010-11-15 IRF7 is phosphorylated on Ser477 and Ser479 residues [Lin R et al 2000] . IRAK1[Uematsu et al 2005] and IKK alpha[Hoshino et al 2006] are thought to mediate the phosphorylation upon TLR7/8/9 activation. Pubmed10893229 Pubmed11073981 Pubmed15767370 Pubmed16612387 Pubmed18710948 Pubmed20200270 Reactome Database ID Release 43975106 Reactome, http://www.reactome.org ReactomeREACT_25001 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 PathwayStep4525 Dimerization of p-IRF7 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Phosphorylation stimulates the C-terminal autoinhibitory domain of IRF7 to attain a highly extended conformation triggering dimerization through extensive contacts to a second IRF7 subunit. Pubmed11073981 Pubmed20043992 Reactome Database ID Release 43933533 Reactome, http://www.reactome.org ReactomeREACT_25292 Reviewed: Kawai, T, Akira, S, 2010-10-30 has a Stoichiometric coefficient of 2 PathwayStep4522 TRAF6 interacts with IRF7 upon TLR7/8 or 9 activation Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2010-11-15 Pubmed15361868 Pubmed15492225 Pubmed15767370 Reactome Database ID Release 43975188 Reactome, http://www.reactome.org ReactomeREACT_25312 Reviewed: Gillespie, ME, 2010-10-29 Upon TLR7/8 or 9 stimulation IRF7, but not IRF3, forms a signaling complex with MyD88, TRAF6[Honda K et al 2004, Kawai T et al 2004], IRAK1 [Uematsu S et al 2005], Also IRAK4 was shown to mediate IRF7 activation[Honda K et al 2004]. has a Stoichiometric coefficient of 4 PathwayStep4523 TRAF6 ubiquitinqtes IRF7 in a K63-dependent manner following TLR7/8 or 9 stimulation Authored: Shamovsky, V, 2010-08-25 EC Number: 6.3.2.19 Edited: Shamovsky, V, 2010-11-15 Pubmed15361868 Pubmed18710948 Reactome Database ID Release 43975118 Reactome, http://www.reactome.org ReactomeREACT_25090 Reviewed: Gillespie, ME, 2010-10-29 TRAF6 E3 ubiquitin ligase activity was shown to be essential for IRF7 activation, although the role of TRAF6-dependent ubiquitination remains unclear [Kawai T et al 2004]. It has been demonstrated that IRF7 is ubiquitinated by TRAF6 at multiple sites both in vitro and in vivo[Ning et al 2008].It has been also shown that K63-linked ubiquitination of IRF7 is independent of its C-terminal functional phosphorylation sites. has a Stoichiometric coefficient of 4 PathwayStep4528 PathwayStep4529 PathwayStep4526 Translocation of p-IRF7:p-IRF7 to nucleus Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed11073981 Pubmed20043992 Reactome Database ID Release 43933531 Reactome, http://www.reactome.org ReactomeREACT_24920 Reviewed: Kawai, T, Akira, S, 2010-10-30 p-IRF7 dimers are then transported into the nucleus and assemble with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes. PathwayStep4527 Engulfed CpG DNA binds to endosomal full-length TLR9 Authored: Shamovsky, V, 2011-09-21 Both the full-length receptor and cleaved fragment corresponding to the C-terminal part of TLR9 were capable to bind ligand, however only processed form (TLR9 C-ter, aa 471-1032) was shown to bind MyD88 and induce signaling in different mouse cells (Ewald SE et al 2008,). Edited: Shamovsky, V, 2012-02-19 Pubmed15207506 Pubmed18820679 Pubmed21604257 Reactome Database ID Release 431679589 Reactome, http://www.reactome.org ReactomeREACT_118633 Reviewed: Gillespie, ME, 2012-02-09 has a Stoichiometric coefficient of 2 Activated TRAF6:p-IRAK2 interacts with TAK1 complex upon TLR7/8 or 9 stimulation Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 Pubmed10882101 Pubmed15327770 Pubmed19675569 Reactome Database ID Release 43975097 Reactome, http://www.reactome.org ReactomeREACT_25322 Reviewed: Gillespie, ME, 2010-10-29 TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism. has a Stoichiometric coefficient of 3 Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 upon TLR7/8 or 9 activation Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 Pubmed10702308 Pubmed14633987 Pubmed15327770 Pubmed16186825 Pubmed16260493 Reactome Database ID Release 43975103 Reactome, http://www.reactome.org ReactomeREACT_25111 Reviewed: Gillespie, ME, 2010-10-29 The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). has a Stoichiometric coefficient of 6 IRAK2 induces TRAF6 oligomerization initiated from endosomal compartments Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 Pubmed17878161 Reactome Database ID Release 43975185 Reactome, http://www.reactome.org ReactomeREACT_24960 Reviewed: Gillespie, ME, 2010-10-29 The mechanism by which IRAK-2 induces TRAF6 E3 ligase activity remains to be deciphered, but one possibility is that IRAK-2 may direct TRAF6 oligomerization. has a Stoichiometric coefficient of 2 Acetylcholine Loaded Synaptic Vesicle Reactome DB_ID: 264786 Reactome Database ID Release 43264786 Reactome, http://www.reactome.org ReactomeREACT_17766 has a Stoichiometric coefficient of 1 Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 at endosome membrane Authored: Shamovsky, V, 2010-06-01 EC Number: 6.3.2.19 Edited: Shamovsky, V, 2010-11-15 Pubmed17135271 Reactome Database ID Release 43975147 Reactome, http://www.reactome.org ReactomeREACT_24996 Reviewed: Gillespie, ME, 2010-10-29 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. has a Stoichiometric coefficient of 9 Docked acetylcholine loaded Synaptic Vesicle Reactome DB_ID: 372534 Reactome Database ID Release 43372534 Reactome, http://www.reactome.org ReactomeREACT_17285 has a Stoichiometric coefficient of 1 Acetylcholine receptor alpha6 beta3 beta4 Reactome DB_ID: 549002 Reactome Database ID Release 43549002 Reactome, http://www.reactome.org ReactomeREACT_22979 has a Stoichiometric coefficient of 1 Antigen:p-BCR:p-SYK Activated B Cell Receptor:Phosphorylated SYK Complex Reactome DB_ID: 983690 Reactome Database ID Release 43983690 Reactome, http://www.reactome.org ReactomeREACT_120006 has a Stoichiometric coefficient of 1 Acetylcholine receptor alpha3-beta4-apha5 Reactome DB_ID: 629582 Reactome Database ID Release 43629582 Reactome, http://www.reactome.org ReactomeREACT_22857 has a Stoichiometric coefficient of 1 Antigen:p-BCR:SYK Activated B Cell Receptor:SYK Complex Reactome DB_ID: 983693 Reactome Database ID Release 43983693 Reactome, http://www.reactome.org ReactomeREACT_120132 has a Stoichiometric coefficient of 1 acetylcholine receptor alpha6 aplha4 beta3 Reactome DB_ID: 633773 Reactome Database ID Release 43633773 Reactome, http://www.reactome.org ReactomeREACT_22741 has a Stoichiometric coefficient of 1 Acetylcholine receptors alpha2(3) beta3(2) Reactome DB_ID: 633846 Reactome Database ID Release 43633846 Reactome, http://www.reactome.org ReactomeREACT_22667 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 Acetylcholine Receptors alpha4(3)-beta2(2) Reactome DB_ID: 532625 Reactome Database ID Release 43532625 Reactome, http://www.reactome.org ReactomeREACT_22470 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 Antigen:BCR B Cell Receptor:Antigen Complex Reactome DB_ID: 983689 Reactome Database ID Release 43983689 Reactome, http://www.reactome.org ReactomeREACT_119368 has a Stoichiometric coefficient of 1 beta-catenin Converted from EntitySet in Reactome Reactome DB_ID: 191727 Reactome Database ID Release 43191727 Reactome, http://www.reactome.org ReactomeREACT_10304 Highly calcium permeable nicotinic acetylcholine receptors Converted from EntitySet in Reactome Reactome DB_ID: 629586 Reactome Database ID Release 43629586 Reactome, http://www.reactome.org ReactomeREACT_22488 IgD Heavy Chain IgH Delta Heavy Chain Immunoglobulin Delta Heavy Chain Reactome DB_ID: 983675 Reactome Database ID Release 43983675 Reactome, http://www.reactome.org ReactomeREACT_118866 has a Stoichiometric coefficient of 1 Acetylcholine receptor alpha3-beta2-aplha5 Reactome DB_ID: 629584 Reactome Database ID Release 43629584 Reactome, http://www.reactome.org ReactomeREACT_22942 has a Stoichiometric coefficient of 1 p-BCR B Cell Receptor with Phosphorylated CD79A (Ig-alpha) and CD79B (Ig-beta) BCR with phosphorylated CD79A (Ig-alpha) and CD79B (Ig-beta) Reactome DB_ID: 983684 Reactome Database ID Release 43983684 Reactome, http://www.reactome.org ReactomeREACT_120259 has a Stoichiometric coefficient of 1 Acetylcholine Receptor (homomeric) Reactome DB_ID: 532595 Reactome Database ID Release 43532595 Reactome, http://www.reactome.org ReactomeREACT_22820 has a Stoichiometric coefficient of 5 Antigen:p-BCR Phosphorylated B Cell Receptor:Antigen Complex Reactome DB_ID: 983691 Reactome Database ID Release 43983691 Reactome, http://www.reactome.org ReactomeREACT_119697 has a Stoichiometric coefficient of 1 Ig Lambda Immunoglobulin Lambda Light Chain Reactome DB_ID: 2038790 Reactome Database ID Release 432038790 Reactome, http://www.reactome.org ReactomeREACT_120060 has a Stoichiometric coefficient of 1 Ig Kappa Immunoglobulin Kappa Light Chain Reactome DB_ID: 2038750 Reactome Database ID Release 432038750 Reactome, http://www.reactome.org ReactomeREACT_120299 has a Stoichiometric coefficient of 1 Homodimer of 4 aminobutyrate aminotransferase Reactome DB_ID: 916847 Reactome Database ID Release 43916847 Reactome, http://www.reactome.org ReactomeREACT_24451 has a Stoichiometric coefficient of 2 IgD Immunoglobulin Delta Reactome DB_ID: 983674 Reactome Database ID Release 43983674 Reactome, http://www.reactome.org ReactomeREACT_119074 has a Stoichiometric coefficient of 2 Heterodimer of GAD1 and GAD2 Reactome DB_ID: 947478 Reactome Database ID Release 43947478 Reactome, http://www.reactome.org ReactomeREACT_24368 has a Stoichiometric coefficient of 1 IgM Heavy Chain IgH Mu Heavy Chain Immunoglobulin Mu Heavy Chain Reactome DB_ID: 983669 Reactome Database ID Release 43983669 Reactome, http://www.reactome.org ReactomeREACT_120021 has a Stoichiometric coefficient of 1 PathwayStep4541 PathwayStep4540 PathwayStep4543 PathwayStep4542 PathwayStep4533 Multiple IRAK1 autophosphorylation steps within the complex pIRAK4:MyD88:activated TLR7/8 or 9 A series of sequential phosphorylation events lead to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the upstream adapters MyD88 and Tollip. The significance of these phosphorylation events is not clear; the kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), so IRAK1 is believed to act primarily as an adaptor for TRAF6 (Conze et al. 2008). Authored: Shamovsky, V, 2010-08-25 EC Number: 2.7.11 Edited: Shamovsky, V, 2010-11-15 Pubmed10217414 Pubmed11923871 Pubmed14625308 Pubmed17337443 Pubmed18347055 Reactome Database ID Release 43975125 Reactome, http://www.reactome.org ReactomeREACT_25184 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 16 PathwayStep4534 TRAF6 binds to hp- IRAK1/or p-IRAK2:p-IRAK4:MyD88:activated TLR7/8 or 9 Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2010-11-15 Hyperphosphorylated IRAK1, still within the receptor complex, binds TRAF6 through multiple regions including the death domain, the undefined domain and the C-terminal C1 domain (Li et al. 2001). The C-terminal region of IRAK-1 contains three potential TRAF6-binding sites; mutation of the amino acids (Glu544, Glu587, Glu706) in these sites to alanine greatly reduces activation of NFkappaB (Ye et al. 2002). IRAK-2 has two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). IRAK2 point mutants with mutated TRAF6-binding motifs abrogate NFkB activation and are incapable to stimulate TRAF6 ubiquitination (Keating SE et al 2007). Pubmed11287640 Pubmed12138165 Pubmed12140561 Pubmed17878161 Pubmed18070982 Pubmed8837778 Reactome Database ID Release 43975111 Reactome, http://www.reactome.org ReactomeREACT_25150 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 4 PathwayStep4535 Dissociation of hp-IRAK1/or IRAK2:TRAF6-oligomer from the p-IRAK4 :oligo-Myd88:activated TLR7/8 or 9 complex Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2010-11-15 Hyperphosphorylated IRAK1 and TRAF6 are thought to dissociate from the activated receptor. (Gottipati et al. 2007) but the IRAK1:TRAF6 complex may remain associated with the membrane (Dong et al. 2006).<p> Phosphorylated IRAK2, like its paralog IRAK1, possibly dissociates from the activated receptor as shown here, although mechanism of IRAK2 activation by IRAK4 followed by TRAF6 binding remains to be deciphered. Pubmed14625308 Pubmed16831874 Pubmed17890055 Reactome Database ID Release 43975100 Reactome, http://www.reactome.org ReactomeREACT_25251 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 4 PathwayStep4536 Pellino binds hp-IRAK1:TRAF6 upon TLR7/8 or 9 activation Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 Pellino isoforms -1, 2 and 3 have been shown to interact with IRAK1 and IRAK4 (Jiang et al. 2003, Strellow et al. 2003, Butler et al. 2005, 2007). It has been also reported that Pellino-1 forms a complex with TRAF6, but not TAK1 or IL1R (Jiang et al. 2003), suggesting that Pellino-1 function as intermediate complex with IRAK1 in the propagation of signal from the activated receptor to activation of TAK1. <p>All Pellino isoforms function as E3 ubiquitin ligases in conjunction with several different E2-conjugating enzymes - Ubc13-Uev1a, UbcH4, or UbcH5a/5b.(Schauvliege R et al. 2006, Butler MP et al. 2007, Ordureau A et al. 2008). Their C-terminus contains a RING-like domain which is responsible for IL1-induced Lys63-linked polyubiquitination of IRAK1 in vitro. Pubmed12496252 Pubmed12860405 Pubmed15917247 Pubmed16884718 Pubmed17675297 Pubmed17997719 Pubmed18326498 Pubmed19022706 Reactome Database ID Release 43975142 Reactome, http://www.reactome.org ReactomeREACT_25023 Reviewed: Gillespie, ME, 2010-10-29 PathwayStep4537 IRAK1 phosphorylates Pellino upon TLR7/8 or 9 activation Authored: Shamovsky, V, 2010-06-01 Both IRAK1 and IRAK4 were shown to phosphorylate Pellino isoforms in vitro. The phosphorylation of Pellino proteins is a necessary step in enhancing of their E3 ubiquitin ligase activity. It remains unclear whether IRAK1(as shown here), IRAK4, or both protein kinases mediate the activation of Pellino isoforms in vivo. Edited: Shamovsky, V, 2010-11-15 Pubmed17675297 Pubmed17997719 Pubmed19264966 Reactome Database ID Release 43975139 Reactome, http://www.reactome.org ReactomeREACT_25241 Reviewed: Gillespie, ME, 2010-10-29 PathwayStep4538 Pellino ubiquitinates hp-IRAK1 upon TLR7/8 or 9 activation<br> Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 IL1 induces the poly-ubiquitination and degradation of IRAK1. This was believed to be K48-linked polyubiquitination, targeting IRAK1 for proteolysis by the proteasome, but recently IL-1R signaling has been shown to lead to K63-linked polyubiquitination of IRAK1 (Windheim et al. 2008; Conze et al. 2008), and demonstrated to have a role in the activation of NF-kappaB. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al. 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al. 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. <br>Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13–Uev1a to catalyze K63-linked ubiquitylation (Ordureau et al. 2008). Pubmed16884718 Pubmed17675297 Pubmed17997719 Pubmed18180283 Pubmed18326498 Pubmed18347055 Pubmed19022706 Reactome Database ID Release 43975122 Reactome, http://www.reactome.org ReactomeREACT_24976 Reviewed: Gillespie, ME, 2010-10-29 PathwayStep4539 NEMO subunit of IKK complex binds to activated IRAK1 upon stimulation of TLR7/8 or 9. Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008). Pubmed16547522 Pubmed16603398 Pubmed18180283 Pubmed18347055 Pubmed19022706 Reactome Database ID Release 43975119 Reactome, http://www.reactome.org ReactomeREACT_25072 Reviewed: Gillespie, ME, 2010-10-29 Homodimer of GAD2 Reactome DB_ID: 947480 Reactome Database ID Release 43947480 Reactome, http://www.reactome.org ReactomeREACT_24231 has a Stoichiometric coefficient of 2 Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomer:activated TLR 7/8 or 9 Authored: Shamovsky, V, 2010-06-01 EC Number: 2.7.11 Edited: Shamovsky, V, 2010-11-15 IRAK4 deficient macrophages fail to induce IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1.<p>Phosphorylation sites of IRAK2 remain to be characterized. Pubmed18438411 Reactome Database ID Release 43975160 Reactome, http://www.reactome.org ReactomeREACT_25002 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 4 First phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR 7/8 or 9 Authored: Shamovsky, V, 2010-08-25 EC Number: 2.7.11 Edited: Shamovsky, V, 2010-11-15 First, IRAK1 is phosphorylated at Thr209 by IRAK4. This results in a conformational change of the kinase domain, permitting further phosphorylations to take place. Substitution of Thr209 by alanine results in a kinase-inactive IRAK1. Pubmed11960013 Pubmed14625308 Reactome Database ID Release 43975180 Reactome, http://www.reactome.org ReactomeREACT_25086 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 4 Second phosphorylation of IRAK1 by IRAK4 bound to MyD88: activated TLR 7/8 or 9 Authored: Shamovsky, V, 2010-08-25 EC Number: 2.7.11 Edited: Shamovsky, V, 2010-11-15 Pubmed14625308 Reactome Database ID Release 43975134 Reactome, http://www.reactome.org ReactomeREACT_24948 Reviewed: Gillespie, ME, 2010-10-29 Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity. has a Stoichiometric coefficient of 4 Voltage Gated Ca2+ Channel Converted from EntitySet in Reactome Reactome DB_ID: 210378 Reactome Database ID Release 43210378 Reactome, http://www.reactome.org ReactomeREACT_12910 BCR B Cell Receptor Reactome DB_ID: 983677 Reactome Database ID Release 43983677 Reactome, http://www.reactome.org ReactomeREACT_119956 has a Stoichiometric coefficient of 1 Hemi-Pannexin 2 Complex Reactome DB_ID: 375325 Reactome Database ID Release 43375325 Reactome, http://www.reactome.org ReactomeREACT_17282 has a Stoichiometric coefficient of 6 Grb2:pBTLA:HVEM Reactome DB_ID: 389921 Reactome Database ID Release 43389921 Reactome, http://www.reactome.org ReactomeREACT_20022 has a Stoichiometric coefficient of 1 Hemi-Pannexin 1 Complex Reactome DB_ID: 375349 Reactome Database ID Release 43375349 Reactome, http://www.reactome.org ReactomeREACT_17368 has a Stoichiometric coefficient of 6 SHP-1/SHP-2:pBTLA:HVEM Reactome DB_ID: 389935 Reactome Database ID Release 43389935 Reactome, http://www.reactome.org ReactomeREACT_19540 has a Stoichiometric coefficient of 1 pBTLA-HVEM complex Reactome DB_ID: 389920 Reactome Database ID Release 43389920 Reactome, http://www.reactome.org ReactomeREACT_19709 has a Stoichiometric coefficient of 1 Noradrenalin loaded synaptic vesicle Reactome DB_ID: 374911 Reactome Database ID Release 43374911 Reactome, http://www.reactome.org ReactomeREACT_17964 has a Stoichiometric coefficient of 1 calcium channel multimer of R type VGCC Reactome DB_ID: 210394 Reactome Database ID Release 43210394 Reactome, http://www.reactome.org ReactomeREACT_12964 has a Stoichiometric coefficient of 1 Ig Antibody Light Chain Converted from EntitySet in Reactome Reactome DB_ID: 2038853 Reactome Database ID Release 432038853 Reactome, http://www.reactome.org ReactomeREACT_119752 calcium channel multimer of P/Q type VGCC Reactome DB_ID: 210492 Reactome Database ID Release 43210492 Reactome, http://www.reactome.org ReactomeREACT_12815 has a Stoichiometric coefficient of 1 IgM Immunoglobulin Mu Reactome DB_ID: 983673 Reactome Database ID Release 43983673 Reactome, http://www.reactome.org ReactomeREACT_119908 has a Stoichiometric coefficient of 2 calcium channel multimer of N type VGCC Reactome DB_ID: 210504 Reactome Database ID Release 43210504 Reactome, http://www.reactome.org ReactomeREACT_12912 has a Stoichiometric coefficient of 1 IgM or IgD Converted from EntitySet in Reactome Immunoglobulin Mu or Delta Reactome DB_ID: 983676 Reactome Database ID Release 43983676 Reactome, http://www.reactome.org ReactomeREACT_119408 PathwayStep4510 BTLA-HVEM complex Reactome DB_ID: 389525 Reactome Database ID Release 43389525 Reactome, http://www.reactome.org ReactomeREACT_20471 has a Stoichiometric coefficient of 1 T-cell receptor complex with dephosphorylated CD3 zeta chain Reactome DB_ID: 390341 Reactome Database ID Release 43390341 Reactome, http://www.reactome.org ReactomeREACT_20438 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Antigen-bearing MHC Class II: TCR with dephosphorylated CD3 zeta chain:CD4 Reactome DB_ID: 390339 Reactome Database ID Release 43390339 Reactome, http://www.reactome.org ReactomeREACT_19788 has a Stoichiometric coefficient of 1 PathwayStep4506 IRAK4 autophosphorylation in the complex with MyD88:activated TLR 7/8 or 9 Authored: Shamovsky, V, 2010-06-01 EC Number: 2.7.11 Edited: Shamovsky, V, 2010-11-15 IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346. Pubmed17141195 Pubmed17485511 Reactome Database ID Release 43975170 Reactome, http://www.reactome.org ReactomeREACT_25011 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 12 PathwayStep4507 IRAK1/or IRAK2 binds to the activated IRAK4 :MyD88:activated TLR 7/8 or 9. Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2010-11-15 IRAK2 has been implicated in IL1R and TLR signaling by the observation that IRAK2 can associate with MyD88 and Mal (Muzio et al. 1997). Like IRAK1, IRAK2 is activated downstream of IRAK4 (Kawagoe et al. 2008). It has been suggested that IRAK1 activates IRAK2 (Wesche et al. 1999) but IRAK2 phosphorylation is observed in IRAK1–/– mouse macrophages while IRAK4 deficiency abrogates IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1. IL6 production in response to IL1beta is impaired in embryonic fibroblasts from IRAK1 or IRAK2 knockout mice and abrogated in IRAK1/2 dual knockouts (Kawagoe et al. 2007) suggesting that IRAK1 and IRAK2 are both involved in IL1R signaling downstream of IRAK4. MYD88 recruits unphosphorylated, inactive IRAK1 to the IL1 receptor complex. Pubmed12150927 Pubmed15767370 Pubmed16024789 Pubmed17878161 Pubmed17890055 Pubmed18438411 Pubmed19224918 Pubmed9374458 Reactome Database ID Release 43975115 Reactome, http://www.reactome.org ReactomeREACT_24966 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 4 PathwayStep4504 MyD88 oligomerization within the complex of activated TLR 7/8 or 9 : MyD88 Authored: Shamovsky, V, 2010-09-22 Edited: Shamovsky, V, 2010-11-15 Pubmed19592493 Pubmed20485341 Pubmed20966070 Reactome Database ID Release 43975098 Reactome, http://www.reactome.org ReactomeREACT_25392 Reviewed: Gillespie, ME, 2010-10-29 Structural analysis of MyD88:IRAK4 and MyD88:IRAK4:IRAK2 suggested that upon MyD88 recruitment to an activated dimerized TLR the MyD88 death domains clustering induces the formation of Mydosome, a large oligomeric signaling platform (Motshwene PG et al 2009, Lin SC et al 2010). Assembly of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. The oligomer complex stoichiometry was reported as 7:4 and 8:4 for MyD88:IRAK4 (Motshwene PG et al 2009), and 6:4:4 in the complex of MyD88:IRAK4:IRAK2(Lin SC et al 2010). has a Stoichiometric coefficient of 4 PathwayStep4505 IRAK4 binds to the activated TLR7/8 or 9 receptor:MyD88 complex Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2010-11-15 IRAK4 is the mammalian homolog of Drosophila melanogaster Tube [Towb P et al 2009; Moncrieffe MC et al 2008]. Like Tube, IRAK4 possesses a conserved N-terminal death domain (DD), which mediates interactions with MyD88 at one binding site and a downstream IRAK kinase at the other, thereby bridging MyD88 and IRAK1/2 association [Towb P et al 2009; Lin SC e al 2010]. IRAK-4 plays a critical role in Toll receptor signaling - any interference with IRAK-4's kinase activity virtually abolishes downstream events. This is not the case with other members of the IRAK family [Suzuki N et al 2002; Li S et al 2002]. Pubmed11960013 Pubmed12297423 Pubmed16286015 Pubmed18794297 Reactome Database ID Release 43975156 Reactome, http://www.reactome.org ReactomeREACT_24953 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 4 PathwayStep4502 Ligand binds to TLR7 or TLR8 Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2011-08-12 Endosomal recognition of influenza genomic RNA and imidazoquinoline compounds occurs by means of TLR7 and TLR8. Pubmed11812998 Pubmed12032557 Pubmed14976261 Pubmed14976262 Reactome Database ID Release 43167983 Reactome, http://www.reactome.org ReactomeREACT_9012 Reviewed: Gay, NJ, 2006-04-24 16:48:17 PathwayStep4503 MyD88 interacts with the activated TLR receptor 7, 8 or 9 Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2010-11-15 MyD88 binds to IRAK (IL-1 receptor-associated kinase) and the receptor heterocomplex (the signaling complex) and thereby mediates the association of IRAK with the receptor. MyD88 therefore couples a serine/threonine protein kinase to the receptor complex. Pubmed12447442 Pubmed15361868 Pubmed15492225 Pubmed9430229 Reactome Database ID Release 43975175 Reactome, http://www.reactome.org ReactomeREACT_24964 Reviewed: Gillespie, ME, 2010-10-29 has a Stoichiometric coefficient of 2 PathwayStep4500 Phosphorylated TAK1 leaves activated TLR receptor complex Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2011-08-12 Phosphorylated TAK1 complexed with TRAF6-TAB1-TAB2/TAB3 leaves the activated TLR4 complex and translocates to the cytosol Pubmed12242293 Pubmed12609980 Reactome Database ID Release 43937075 Reactome, http://www.reactome.org ReactomeREACT_25183 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 PathwayStep4501 Flagellin binds to TLR5 Edited: Shamovsky, V, 2011-08-12 Fragments of extracelllar flagellin bind the TLR5 homodimer. Pubmed11323673 Pubmed12807870 Pubmed15241424 Pubmed16439799 Reactome Database ID Release 43188025 Reactome, http://www.reactome.org ReactomeREACT_9059 Reviewed: Gale M, Jr, 2006-10-31 16:45:01 Reviewed: Gillespie, ME, 2011-02-10 has a Stoichiometric coefficient of 2 Activated TLR:TRIF:K63-pUb-TRAF6 recruits TAK1complex Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-16 Pubmed10882101 Pubmed15327770 Pubmed19675569 Reactome Database ID Release 43936947 Reactome, http://www.reactome.org ReactomeREACT_25261 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism. has a Stoichiometric coefficient of 2 Activation of TAK1 complex bound to activated TLR Authored: Shamovsky, V, 2010-06-01 EC Number: 2.7.11 Edited: Shamovsky, V, 2011-08-12 Pubmed10702308 Pubmed14633987 Pubmed15327770 Pubmed16186825 Pubmed16260493 Pubmed17496917 Reactome Database ID Release 43936951 Reactome, http://www.reactome.org ReactomeREACT_25288 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). has a Stoichiometric coefficient of 4 PathwayStep4508 PathwayStep4509 Docked serotonin loaded synaptic vesicle Reactome DB_ID: 380900 Reactome Database ID Release 43380900 Reactome, http://www.reactome.org ReactomeREACT_17565 has a Stoichiometric coefficient of 1 pCTLA-4:Src kinases:SHP2 Reactome DB_ID: 388793 Reactome Database ID Release 43388793 Reactome, http://www.reactome.org ReactomeREACT_19498 has a Stoichiometric coefficient of 1 Serotonin loaded synaptic vesicle Reactome DB_ID: 380903 Reactome Database ID Release 43380903 Reactome, http://www.reactome.org ReactomeREACT_16110 has a Stoichiometric coefficient of 1 Phospho CTLA-4 dimer Reactome DB_ID: 388794 Reactome Database ID Release 43388794 Reactome, http://www.reactome.org ReactomeREACT_20361 has a Stoichiometric coefficient of 2 Glutamate loaded synaptic vesicle Reactome DB_ID: 210380 Reactome Database ID Release 43210380 Reactome, http://www.reactome.org ReactomeREACT_12769 has a Stoichiometric coefficient of 1 ICOS:ICOSL Reactome DB_ID: 388788 Reactome Database ID Release 43388788 Reactome, http://www.reactome.org ReactomeREACT_20114 has a Stoichiometric coefficient of 1 Empty Glutamate Synaptic Vesicle Reactome DB_ID: 264795 Reactome Database ID Release 43264795 Reactome, http://www.reactome.org ReactomeREACT_14482 has a Stoichiometric coefficient of 1 PIP3:PDK1:active AKT Reactome DB_ID: 198338 Reactome Database ID Release 43198338 Reactome, http://www.reactome.org ReactomeREACT_13230 has a Stoichiometric coefficient of 1 Dopamine loaded synaptic vesicle Reactome DB_ID: 380575 Reactome Database ID Release 43380575 Reactome, http://www.reactome.org ReactomeREACT_15992 has a Stoichiometric coefficient of 1 PD-1:PD-1 ligands Reactome DB_ID: 388800 Reactome Database ID Release 43388800 Reactome, http://www.reactome.org ReactomeREACT_20041 has a Stoichiometric coefficient of 1 Docked Glutamate Loaded Synaptic Vesicle Reactome DB_ID: 210458 Reactome Database ID Release 43210458 Reactome, http://www.reactome.org ReactomeREACT_12825 has a Stoichiometric coefficient of 1 ICOS:PI3K Reactome DB_ID: 388785 Reactome Database ID Release 43388785 Reactome, http://www.reactome.org ReactomeREACT_19686 has a Stoichiometric coefficient of 1 synaptic vesicle Empty Acetylcholine Synaptic Vesicle Reactome DB_ID: 210372 Reactome Database ID Release 43210372 Reactome, http://www.reactome.org ReactomeREACT_12740 has a Stoichiometric coefficient of 1 SHP-1/SHP-2 bound to phospho PD-1 Reactome DB_ID: 389749 Reactome Database ID Release 43389749 Reactome, http://www.reactome.org ReactomeREACT_19972 has a Stoichiometric coefficient of 1 Docked dopamine loaded synaptic vesicle Reactome DB_ID: 380573 Reactome Database ID Release 43380573 Reactome, http://www.reactome.org ReactomeREACT_15684 has a Stoichiometric coefficient of 1 Phosphorylated PD-1 bound to B7DC/B7H1 Reactome DB_ID: 389746 Reactome Database ID Release 43389746 Reactome, http://www.reactome.org ReactomeREACT_19810 has a Stoichiometric coefficient of 1 PathwayStep4521 PathwayStep4520 Auto ubiquitination of TRAF6 bound to the activated TLR complex Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-16 Pubmed17135271 Reactome Database ID Release 43936952 Reactome, http://www.reactome.org ReactomeREACT_25318 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. has a Stoichiometric coefficient of 3 phospho CTLA4:B7-1/B7-2 Reactome DB_ID: 388796 Reactome Database ID Release 43388796 Reactome, http://www.reactome.org ReactomeREACT_19718 has a Stoichiometric coefficient of 1 Phosphorylated CTLA-4 bound to kinases Reactome DB_ID: 388795 Reactome Database ID Release 43388795 Reactome, http://www.reactome.org ReactomeREACT_19872 has a Stoichiometric coefficient of 1 PathwayStep4515 TLR3/4-induced ripoptosome assembly Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-19 Pubmed12181749 Pubmed12752666 Pubmed14739303 Pubmed15814722 Pubmed21737329 Pubmed21737330 Pubmed22421964 Reactome Database ID Release 432562541 Reactome, http://www.reactome.org ReactomeREACT_150447 Reviewed: Fitzgerald, Katherine A, 2012-11-13 TRIF was repored to efficiently induce apoptosis when overexpressed in human HEK293T cells. TRIF-induced apoptosis occurred through activation of the FADD-caspase-8 axis [Kaiser WJ and Offermann MK 2005; Kalai M et al 2002; Estornes Y et al 2012]. C-terminus of TRIF was shown to form complexes with both RIP1 and RIP3, and disruption of these interactions by mutating the RHIM eliminated the ability of TRIF to induce apoptosis [Kaiser WJ and Offermann MK 2005].<p> Prevention of RIP1 ubiquitination leads to a strong association of RIP1 and caspase-8 [Feoktistova M et al 2011, Tenev et al 2011]. has a Stoichiometric coefficient of 2 PathwayStep4516 Caspase-8 processing Authored: Shamovsky, V, 2012-05-15 EC Number: 3.4.22 Edited: Shamovsky, V, 2012-11-19 GENE ONTOLOGYGO:0008624 Pubmed12181749 Pubmed12620240 Pubmed15814722 Pubmed19278658 Pubmed20308068 Pubmed21737330 Pubmed22421964 Reactome Database ID Release 432562564 Reactome, http://www.reactome.org ReactomeREACT_150381 Reviewed: Fitzgerald, Katherine A, 2012-11-13 TLR3/4 signaling component were shown to mediate apoptosis in various human cell lines in the FADD:caspasse-8-dependent manner [Kalai M et al 2002; Kaiser WJ and Offermann MK 2005; Estornes Y et al 2012]. Caspase-8 zymogens (procaspase-8) are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region [Donepudi M et al 2003; Keller N et al 2009]. Dimerization is required for caspase-8 activation [Donepudi M et al 2003]. The dimerization event occurs at the receptor signaling complex. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is compsed of a large p18 and a small p10 subunit [Keller N et al 2009; Oberst A et al 2010]. PathwayStep4517 RIP3 binds TRIF to mediate necroptosis Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-19 GENE ONTOLOGYGO:0060555 Pubmed12181749 Pubmed15814722 Pubmed21737330 Pubmed22123964 Reactome Database ID Release 432569057 Reactome, http://www.reactome.org ReactomeREACT_150365 Reviewed: Fitzgerald, Katherine A, 2012-11-13 TLR3 and TLR4 -directed programmed necrosis (necroptosis) is mediated by the TRIF-RIP3 pathway in mouse macrophages [He S e al 2011]. RIP3 was shown to be essential mediator in TLR3-induced necroptotic cell death in human epithelial cell lines. Knockdown of RIP3 in human keratinocyte HaCaT cells blocked TLR3-mediated necroptosis without affecting the apoptotic response. Moreover, overexpression of RIP3 in human epithelial carcinoma cell line HeLa led to increased caspase-independent TLR3-induced cell death in the absence of IAPs [Feoktistova M et al 2011]. In addition, in caspase-8- or FADD-deficient human Jurkat cells dsRNA induced programmed necrosis, instead of apoptosis [Kalai M et al 2002]. Thus, when caspase-dependent apoptosis is inhibited or absent, the alternative RIP3-mediated programmed cell death is induced. has a Stoichiometric coefficient of 4 PathwayStep4518 Activated TLR3/4:TRIF recruits TRAF6 Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2011-08-12 Pubmed11057907 Pubmed15814722 Pubmed16306937 Pubmed20047764 Pubmed9744859 Reactome Database ID Release 43936985 Reactome, http://www.reactome.org ReactomeREACT_24952 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 TRAF6 is recruited to the N-terminal domain of TICAM1 and this event is followed by auto polyubiquitination and oligomerization of TRAF6. PathwayStep4511 Dimerized phospho-IRF3/IRF7 is transported to the nucleus Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2011-08-12 IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm. Pubmed12692549 Reactome Database ID Release 43177671 Reactome, http://www.reactome.org ReactomeREACT_6864 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 PathwayStep4512 TRIF:activated TLR3/TLR4 complex recruits RIP1 Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2011-08-12 Pubmed15064760 Pubmed15814722 Pubmed16115877 Pubmed16246838 Pubmed21931591 RIP1 is recruited to the activated TLR receptor by binding to TICAM1(TRIF) via its RHIM motif, followed by its polyubiquitination. Polyubiquitination is possibly mediated by TRAF6 that is also recruited to the TICAM1 [Cusson-Hermance N et al 2005]. Other E3-ubiquitin ligases - cIAP1 and cIAP2 - have been reported to promote polyubiquitination of RIP proteins [Bertrand MJM et al 2011].<p> RIP3 was shown to inhibit TRIF-induced NF-kB activation in dose-dependent manner when overexpressed in HEK293T cells by competing with TRIF to bind RIP1 [Meylan E et al 2004]. Reactome Database ID Release 43168921 Reactome, http://www.reactome.org ReactomeREACT_6713 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 has a Stoichiometric coefficient of 2 PathwayStep4513 K63-linked ubiquitination of RIP1 bound to the activated TLR complex Authored: de Bono, B, 2005-08-16 10:54:15 EC Number: 6.3.2.19 Edited: Shamovsky, V, 2011-08-12 Pubmed11479302 Pubmed15064760 Pubmed15258597 Pubmed16115877 Pubmed16547522 Pubmed16603398 Pubmed21931591 RIP1 polyubiquitination was induced upon TNF- or poly(I-C) treatment of the macrophage cell line RAW264.7 and the U373 astrocytoma line (Cusson-Hermance et al 2005). These workers have suggested that RIP1 may use similar mechanisms to induce NF-kB in the TNFR1- and Trif-dependent TLR pathways.<p>RIP1 modification with Lys-63 polyubiquitin chains was shown to be essential for TNF-induced activation of NF-kB (Ea et al. 2006). It is thought that TRAF family members mediate this Lys63-linked ubiquitination of RIP1 (Wertz et al. 2004, Tada et al 2001, Vallabhapurapu and Karin 2009), which may facilitate recruitment of the TAK1 complex and thus activation of NF-kB. Binding of NEMO to Lys63-linked polyubiquitinated RIP1 is also required in the signaling cascade from the activated receptor to the IKK-mediated NF-kB activation (Wu et al. 2006). Reactome Database ID Release 43168915 Reactome, http://www.reactome.org ReactomeREACT_6884 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 has a Stoichiometric coefficient of 2 PathwayStep4514 Nemo subunit of IKK complex binds polyubiquinated RIP1 Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2011-08-12 Pubmed16547522 Pubmed16603398 Pubmed19185524 Pubmed19303852 Reactome Database ID Release 43937029 Reactome, http://www.reactome.org ReactomeREACT_25373 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 Structural studies showed that NEMO binds both Lys-63- and linear polyubiquitin chains,both critical for NF-kB activation. Docked Noradrenalin loaded synaptic vesicle Reactome DB_ID: 374939 Reactome Database ID Release 43374939 Reactome, http://www.reactome.org ReactomeREACT_15843 has a Stoichiometric coefficient of 1 PP2A:CTLA4:B7-1/B7-2 Reactome DB_ID: 388784 Reactome Database ID Release 43388784 Reactome, http://www.reactome.org ReactomeREACT_19452 has a Stoichiometric coefficient of 1 SNARE complex Reactome DB_ID: 210441 Reactome Database ID Release 43210441 Reactome, http://www.reactome.org ReactomeREACT_12700 has a Stoichiometric coefficient of 1 Rab3-RIM complex Reactome DB_ID: 210374 Reactome Database ID Release 43210374 Reactome, http://www.reactome.org ReactomeREACT_13268 has a Stoichiometric coefficient of 1 Dimerization of phosphorylated IRF3/IRF7 Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2011-08-12 Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300. Pubmed12692549 Pubmed14555995 Reactome Database ID Release 43168933 Reactome, http://www.reactome.org ReactomeREACT_6793 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 has a Stoichiometric coefficient of 2 PathwayStep4519 Viral dsRNA binds the Toll-Like Receptor 3 (TLR3) Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2012-02-19 Pubmed11607032 Pubmed18420935 Reactome Database ID Release 43168092 Reactome, http://www.reactome.org ReactomeREACT_6753 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Viral dsRNA triggers an antiviral pathway mediated by toll like receptor 3. TLR3 dimerization occurs upon ligand binding to positivly charged residues on the ectodomain termini of TLR3 wich are responsible for the interaction with sugar-phosphate groups of dsRNA. has a Stoichiometric coefficient of 2 TRAF6 binds MEKK1 Authored: de Bono, B, 2005-08-16 10:54:15 Edited: de Bono, B, 2005-08-16 10:54:15 Pubmed10465784 Pubmed9008162 Pubmed9689078 Pubmed9836645 Reactome Database ID Release 43166869 Reactome, http://www.reactome.org ReactomeREACT_6962 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 TRAF6 binding to MAPK kinase kinase 1 (MEKK1) is mediated by the adapter protein evolutionarily conserved signaling intermediate in Toll pathway or in short ECSIT (Kopp E et al 1999). Induced MEKK1 can activate both IKK alpha and IKK beta thus leading to induction of NF-kappa-B activation. MEKK1 was also shown to induce ERK1/2 and JNK activation [Yujiri T et al 1998].<p>Although TRAF6 interacts with several upstream mediators (IRAK1, IRAK2, TRIF), there is no data showing MEKK1 participating in the interaction with the TRAF6 activators. Therefore this reaction is simplified to include only TRAF6 and MEKK1. Viral dsRNA:TLR3 recruits TRIF Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2009-12-16 Pubmed12539043 Pubmed12855817 Pubmed14517278 Reactome Database ID Release 43168929 Reactome, http://www.reactome.org ReactomeREACT_6919 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 TIR-domain-containing adaptor inducing interferon-beta (TRIF or TICAM1) was shown to play an essential role in TLR3 signaling. All poly(I:C)-induced pathways leading to NFkB and IRF3 activation were abolished in TRIF-/- mice [Yamamoto et al. 2003]. has a Stoichiometric coefficient of 2 APC fragment (1-777) Converted from EntitySet in Reactome Reactome DB_ID: 202956 Reactome Database ID Release 43202956 Reactome, http://www.reactome.org ReactomeREACT_12313 TRAM:TLR4:MD2:LPS:CD14 recruits TRIF Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2011-08-12 Pubmed12855817 Pubmed14517278 Pubmed14556004 Reactome Database ID Release 43166175 Reactome, http://www.reactome.org ReactomeREACT_6799 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 TRIF mediates the MyD88-independent pathway from TLR4. has a Stoichiometric coefficient of 2 TRAF3 binds to TRIF:activated TLR3/4 complex Authored: Shamovsky, V, 2012-04-26 Edited: Shamovsky, V, 2012-05-25 Pubmed16306936 Pubmed16306937 Pubmed19898473 Reactome Database ID Release 432201338 Reactome, http://www.reactome.org ReactomeREACT_121070 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Fitzgerald, Katherine A, 2012-11-13 TRAF3 is a ubiquitin ligase recruited to both MYD88- and TRIF-assembled signalling complexes [Hacker H et al 2006]. However, TRAF3 controls the production of interferon and proinflammatory cytokines in different ways [Tseng PH et al 2010]. Positive or negative type of regulation is dictated by TRAF3 subcellular distribution and its mode of ubiquitination. Thus, TRIF-mediated signaling initiated on endosomes triggers TRAF3 self-ubiquitination through noncanonical (K63-linked) polyubiquitination, which is essential for activation of IRF3/7 and the interferon response. In contrast, during MyD88-dependent signaling initiated from plasma membrane TRAF3 functions as a negative regulator of inflammatory cytokines and mitogen-activated protein kinases (MAPKs), unless it undergoes degradative (K48-linked) polyubiquitination mediated by TRAF6 and a pair of the ubiquitin ligases cIAP1 and cIAP2. The degradation of TRAF3 is essential for MAPK activation via TAK1 and MEKK1 [Tseng PH et al 2010]. has a Stoichiometric coefficient of 2 Negative regulator SARM binds to TRIF Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-19 Pubmed16964262 Pubmed19656901 Reactome Database ID Release 432559568 Reactome, http://www.reactome.org ReactomeREACT_150310 Reviewed: Fitzgerald, Katherine A, 2012-11-13 SARM (sterile alpha-and armadillo-motif-containing protein) is a TIR-domain-containing adaptor, which functions as a negative regulator of TRIF-dependent Toll-like receptor signaling in humans. LPS treatment led to a rapid increase of the SARM expression in peripheral blood mononuclear cells (PBMCs) and as a result an increased association between SARM and TRIF. SARM expression was also shown to inhibit poly(I:C)-induced TRIF-dependent NF-kB activaion, RANTES production and IRF activation in human embryonic kidney HEK293 cells [Carty M et al 2006]. Moreover, suppression of endogenous SARM expression by siRNA led to enhanced TLR3- and TLR4-dependent gene induction in both transformed HEK293 and primary PBMC cells, while endotoxin-tolerant human monocytes showed increased expression of SARM and decreased activation of TRIF-dependent cytokines [Carty M et al 2006; Piao W et al 2009]. Thus, SARM inhibits TLR4 and TLR3 signaling by targeting TRIF. The complex of TRIF:SARM is thought to inhibit downstream TRIF signaling by preventing the recruitment of TRIF effector proteins [Carty M et al 2006]. Recruitment of TBK1/IKK epsilon to K63-poly-Ub-TRAF3:TRIF:activated TLR3/TLR4 followed by their phosphorylation Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2011-08-12 Pubmed12692549 Pubmed15210742 Pubmed17047224 Pubmed17599067 Reactome Database ID Release 43936941 Reactome, http://www.reactome.org ReactomeREACT_25081 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 The mechanism of TBK1 or IKKi{epsilon} activation by TICAM1 is unclear. It was suggested that these protein kinases undergo autophosphorylation. The most recent studies showed that phosphorylation and the activation of TBK1/ IKKi are catalyzed by a distinct protein kinase (Clark et al. 2009). Other studies demonstrated an essential role of TRAF3 in the activation of TBK1 (Hacker et al 2006).<p>It was also shown that the ubiquitin like domain (ULD) of TBK1 and IKK-i, a regulatory component, is involved in the control of kinase activation, substrate presentation and downstream signaling. has a Stoichiometric coefficient of 2 Auto-ubiquitination of TRAF3 Authored: Shamovsky, V, 2012-04-26 EC Number: 6.3.2.19 Edited: Shamovsky, V, 2012-05-25 Pubmed19898473 Reactome Database ID Release 432213017 Reactome, http://www.reactome.org ReactomeREACT_120820 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Fitzgerald, Katherine A, 2012-11-13 TRIF signaling activates TRAF3 self-mediated polyubiquitination trough Lys-63 of ubiquitin. The ubiquitinated TRAF3 in turn activates the interferon response [Tseng PH et al 2010]. IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2011-08-12 Pubmed11070172 Pubmed14517278 Pubmed14703513 Pubmed15210742 Pubmed17157040 Pubmed9566918 Reactome Database ID Release 43166271 Reactome, http://www.reactome.org ReactomeREACT_6917 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 SH2-containing protein tyrosine phosphatase 2 (SHP-2) has been shown to inhibit the TRIF-dependent production of proin?ammatory cytokines and type I interferon in LPS or poly(I-C)-stimulated mouse peritoneal macrophages. SHP-2 overexpression also inhibited TRIF-induced IFN-? luciferase reporter gene expression in human embryonic kidney HEK293 cells. Experiments with truncated SHP-2 or truncated TBK1 mutants revealed that C-terminal domain of SHP-2 associates with N-terminal domain of TBK1 when coexpressed in HEK293 cells. Furthermore, SHP-2 is thought to prevent TBK1-mediated downstream substrate phosphorylation in tyrosine phosphatase activity independent manner by binding to kinase domain of TBK1 [An H et al 2006]. Two members of the interferon regulatory factor (IRF) family IRF-3 and IRF-7 are the major modulators of IFN gene expression. Activation of IRF-3 and IRF-7, which is mediated by TBK1/IKK protein kinases, promotes IFN gene expression and the production of IFN developing an effective antiviral immune response.<p>Irf-3 deficient mice were found to be more vulnerable to virus infection. Mouse cells defective in IRF-3 and IRF-7 expression totally fail to induce IFN genes in response to viral infection. It was shown on mice and mouse cells that both IRF-3 and IRF-7 have non redundant and distinct roles. IRF-3 is expressed at a basal level in normally growing cells and is a major factor in the early induction phase of IFN-alpha/beta production, while the IRF-7 gene expression is induced upon IFNs stimulation and IRF-7 is involved in the late induction phase.<br> has a Stoichiometric coefficient of 2 AMPA receptors containing GluR1 and GluR2 Reactome DB_ID: 416309 Reactome Database ID Release 43416309 Reactome, http://www.reactome.org ReactomeREACT_18810 has a Stoichiometric coefficient of 2 Phosphorylation of IRF-3/IRF7 and their release from the activated TLR complex Authored: de Bono, B, 2005-08-16 10:54:15 EC Number: 2.7.11 Edited: Shamovsky, V, 2011-08-12 Human IRF-3 is activated through a two step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKK-i. It requires Ser386 and/or Ser385 (site 1) and a cluster of serine/threonine residues between Ser396 and Ser405 (site 2) [Panne et al 2007]. Phosphorylated residues at site 2 alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1. Phosphorylation at site 1 is required for IRF-3 dimerization.<p>IRF-3 and IRF-7 transcription factors possess distinct structural characteristics; IRF-7 is phosphorylated on Ser477 and Ser479 residues [Lin R et al 2000]. TRAF6 mediated ubiquitination of IRF7 is also required and essential for IRF7 phosphorylation and activation. The K-63 linked ubiquitination occurs on the last three C-terminal lysine sites (positions 444, 446, and 452) of human IRF7 independently of its C-terminal functional phosphorylation sites.[Ning et al 2008]. Pubmed10893229 Pubmed12692549 Pubmed14703513 Pubmed17526488 Pubmed18710948 Reactome Database ID Release 43166245 Reactome, http://www.reactome.org ReactomeREACT_6728 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 6 AP2 complex Reactome DB_ID: 416629 Reactome Database ID Release 43416629 Reactome, http://www.reactome.org ReactomeREACT_18535 has a Stoichiometric coefficient of 1 APC Converted from EntitySet in Reactome Reactome DB_ID: 195265 Reactome Database ID Release 43195265 Reactome, http://www.reactome.org ReactomeREACT_10434 Ca impermeable AMPA receptors Converted from EntitySet in Reactome Reactome DB_ID: 399713 Reactome Database ID Release 43399713 Reactome, http://www.reactome.org ReactomeREACT_18797 AMPA receptors containing GluR2 (heteromers) Reactome DB_ID: 399704 Reactome Database ID Release 43399704 Reactome, http://www.reactome.org ReactomeREACT_18781 has a Stoichiometric coefficient of 2 AMPA receptors containing GluR2 (homomers) Reactome DB_ID: 416314 Reactome Database ID Release 43416314 Reactome, http://www.reactome.org ReactomeREACT_18759 has a Stoichiometric coefficient of 4 AMPA receptors with phopho GluR2 (homomers) Reactome DB_ID: 421010 Reactome Database ID Release 43421010 Reactome, http://www.reactome.org ReactomeREACT_18552 has a Stoichiometric coefficient of 4 AMPA receptors containing GluR1 and GluR2 Reactome DB_ID: 399701 Reactome Database ID Release 43399701 Reactome, http://www.reactome.org ReactomeREACT_18566 has a Stoichiometric coefficient of 2 AMPA receptors containing GluR2 (homomers) Reactome DB_ID: 416289 Reactome Database ID Release 43416289 Reactome, http://www.reactome.org ReactomeREACT_19042 has a Stoichiometric coefficient of 4 Ca impermeable AMPA receptors (with phospho GluR2 S880) Converted from EntitySet in Reactome Reactome DB_ID: 421001 Reactome Database ID Release 43421001 Reactome, http://www.reactome.org ReactomeREACT_19016 AMPA receptors (heteromers) with phopho GluR2 Reactome DB_ID: 421004 Reactome Database ID Release 43421004 Reactome, http://www.reactome.org ReactomeREACT_19081 has a Stoichiometric coefficient of 2 IRAK1 phosphorylates Pellino Authored: Shamovsky, V, 2010-06-01 Both IRAK1 and IRAK4 were shown to phosphorylate Pellino isoforms in vitro. The phosphorylation of Pellino proteins is a necessary step in enhancing of their E3 ubiquitin ligase activity. It remains unclear whether IRAK1(as shown here), IRAK4, or both protein kinases mediate the activation of Pellino isoforms in vivo. Edited: Shamovsky, V, 2012-11-06 Pubmed17675297 Pubmed17997719 Pubmed19264966 Reactome Database ID Release 43937034 Reactome, http://www.reactome.org ReactomeREACT_25200 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 Pellino binds hp-IRAK1:TRAF6 Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 Pellino isoforms -1, 2 and 3 have been shown to interact with IRAK1 and IRAK4 (Jiang et al. 2003, Strellow et al. 2003, Butler et al. 2005, 2007). It has been also reported that Pellino-1 forms a complex with TRAF6, but not TAK1 or IL1R (Jiang et al. 2003), suggesting that Pellino-1 function as intermediate complex with IRAK1 in the propagation of signal from the activated receptor to activation of TAK1. <p>All Pellino isoforms function as E3 ubiquitin ligases in conjunction with several different E2-conjugating enzymes - Ubc13-Uev1a, UbcH4, or UbcH5a/5b.(Schauvliege R et al. 2006, Butler MP et al. 2007, Ordureau A et al. 2008). Their C-terminus contains a RING-like domain which is responsible for IL1-induced Lys63-linked polyubiquitination of IRAK1 in vitro. Pubmed12496252 Pubmed12860405 Pubmed15917247 Pubmed16884718 Pubmed17675297 Pubmed17997719 Pubmed18326498 Pubmed19022706 Reactome Database ID Release 43937044 Reactome, http://www.reactome.org ReactomeREACT_25142 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 Dissociation of hp-IRAK1:TRAF6 or IRAK2:TRAF6-oligomer from the activated TLR5 or 10:oligo-Myd88:p-IRAK4 complex Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 Hyperphosphorylated IRAK1 and TRAF6 are thought to dissociate from the activated receptor. (Gottipati et al. 2007) but the IRAK1:TRAF6 complex may remain associated with the membrane (Dong et al. 2006).<p> Phosphorylated IRAK2, like its paralog IRAK1, possibly dissociates from the activated receptor as shown here, although mechanism of IRAK2 activation by IRAK4 followed by TRAF6 binding remains to be deciphered. Pubmed14625308 Pubmed16831874 Pubmed17890055 Reactome Database ID Release 43975879 Reactome, http://www.reactome.org ReactomeREACT_27177 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 4 Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 Authored: Shamovsky, V, 2010-06-01 EC Number: 6.3.2.19 Edited: Shamovsky, V, 2012-11-06 Pubmed17135271 Reactome Database ID Release 43936942 Reactome, http://www.reactome.org ReactomeREACT_25022 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. has a Stoichiometric coefficient of 9 IRAK2 induces TRAF6 oligomerization Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 Pubmed17878161 Reactome Database ID Release 43936963 Reactome, http://www.reactome.org ReactomeREACT_25119 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 The mechanism by which IRAK-2 induces TRAF6 E3 ligase activity remains to be deciphered, but one possibility is that IRAK-2 may direct TRAF6 oligomerization. has a Stoichiometric coefficient of 2 NEMO subunit of IKK complex binds to activated IRAK1 Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008). Pubmed16547522 Pubmed16603398 Pubmed18180283 Pubmed18347055 Pubmed19022706 Reactome Database ID Release 43937032 Reactome, http://www.reactome.org ReactomeREACT_25305 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 Pellino ubiquitinates hp-IRAK1 Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 IL1R/TLR induces the Lys48- polyubiquitination and proteosomal degradation of IRAK1. IRAK1 has been shown to undergo Lys63-linked polyubiquitination which induced activation of NFkB (Windheim et al 2008; Conze et al 2008). These two forms of ubiquitination are not mutually exclusive for a protein (Newton K et al 2008). Upon stimulation Lys63-linked ubiquitination may occur first to activate NFkB, but at later time Lys48-linked ubiquitination occurs to target the proteins for proteosomal degradation.<p>IRAK1 is ubiquitinated on Lys134 and Lys180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is a stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. <br>Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al 2008; Butler et al 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and Lys48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13/Uev1a to catalyze Lys63-linked ubiquitylation (Ordureau et al 2008). Pubmed16884718 Pubmed17675297 Pubmed17997719 Pubmed18180283 Pubmed18326498 Pubmed18347055 Pubmed18724939 Pubmed19022706 Reactome Database ID Release 43937050 Reactome, http://www.reactome.org ReactomeREACT_24943 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 has a Stoichiometric coefficient of 2 Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 Authored: Shamovsky, V, 2010-06-01 EC Number: 2.7.11 Edited: Shamovsky, V, 2012-11-06 Pubmed10702308 Pubmed10838074 Pubmed11323434 Pubmed14633987 Pubmed15327770 Pubmed16186825 Pubmed16260493 Pubmed16289117 Pubmed8638164 Reactome Database ID Release 43936991 Reactome, http://www.reactome.org ReactomeREACT_25375 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). has a Stoichiometric coefficient of 6 NMDA receptor complex Reactome DB_ID: 419566 Reactome Database ID Release 43419566 Reactome, http://www.reactome.org ReactomeREACT_20772 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 NR1 interacting proteins Reactome DB_ID: 432787 Reactome Database ID Release 43432787 Reactome, http://www.reactome.org ReactomeREACT_21059 has a Stoichiometric coefficient of 1 Activated TRAF6 synthesizes unanchored polyubiquitin chains Authored: Shamovsky, V, 2010-06-01 EC Number: 6.3.2.19 Edited: Shamovsky, V, 2012-11-06 Polyubiquitinated TRAF6 (as E3 ubiquitin ligase) generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase. Pubmed19675569 Reactome Database ID Release 43936986 Reactome, http://www.reactome.org ReactomeREACT_25362 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 Ca impermeable AMPA receptor ligand complex Reactome DB_ID: 420974 Reactome Database ID Release 43420974 Reactome, http://www.reactome.org ReactomeREACT_18924 has a Stoichiometric coefficient of 1 Activated TRAF6:p-IRAK2 interacts with TAK1 complex Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 Pubmed10882101 Pubmed15327770 Pubmed19675569 Pubmed19935683 Reactome Database ID Release 43936960 Reactome, http://www.reactome.org ReactomeREACT_24985 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism. has a Stoichiometric coefficient of 3 NMDA receptor-Mg complex Reactome DB_ID: 438039 Reactome Database ID Release 43438039 Reactome, http://www.reactome.org ReactomeREACT_20969 has a Stoichiometric coefficient of 1 SPHK Converted from EntitySet in Reactome Reactome DB_ID: 428276 Reactome Database ID Release 43428276 Reactome, http://www.reactome.org ReactomeREACT_20002 sphingosine kinases AMPA receptors containing GluR1 and Phospho GluR2 Reactome DB_ID: 421002 Reactome Database ID Release 43421002 Reactome, http://www.reactome.org ReactomeREACT_18806 has a Stoichiometric coefficient of 2 APC fragment (778-2843) Converted from EntitySet in Reactome Reactome DB_ID: 202952 Reactome Database ID Release 43202952 Reactome, http://www.reactome.org ReactomeREACT_12296 Ca permeable AMPA receptor ligand complex Reactome DB_ID: 420976 Reactome Database ID Release 43420976 Reactome, http://www.reactome.org ReactomeREACT_18904 has a Stoichiometric coefficient of 1 NMDA receptor ligand complex Reactome DB_ID: 432783 Reactome Database ID Release 43432783 Reactome, http://www.reactome.org ReactomeREACT_21126 has a Stoichiometric coefficient of 1 RasGRF Reactome DB_ID: 442734 Reactome Database ID Release 43442734 Reactome, http://www.reactome.org ReactomeREACT_20701 has a Stoichiometric coefficient of 2 NR2 interacting proteins Reactome DB_ID: 432793 Reactome Database ID Release 43432793 Reactome, http://www.reactome.org ReactomeREACT_20724 has a Stoichiometric coefficient of 1 CaMKII Reactome DB_ID: 432792 Reactome Database ID Release 43432792 Reactome, http://www.reactome.org ReactomeREACT_21174 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 IRAK4 autophosphorylation within the complex activated TLR:MyD88 Authored: Shamovsky, V, 2010-10-06 EC Number: 2.7.11 Edited: Shamovsky, V, 2011-08-12 IRAK4 is activated by autophosphorylation at 3 positions within the kinase activation loop, Thr-342, Thr-345 and Ser-346. Pubmed17141195 Pubmed17485511 Reactome Database ID Release 43975865 Reactome, http://www.reactome.org ReactomeREACT_27180 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 12 IRAK4 binds to MyD88 bound to the activated TLR5 or 10 receptor Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 IRAK4 is the mammalian homolog of Drosophila melanogaster Tube [Towb P et al 2009; Moncrieffe MC et al 2008]. Like Tube, IRAK4 possesses a conserved N-terminal death domain (DD), which mediates interactions with MyD88 at one binding site and a downstream IRAK kinase at the other, thereby bridging MyD88 and IRAK1/2 association [Towb P et al 2009; Lin SC e al 2010]. IRAK-4 plays a critical role in Toll receptor signaling - any interference with IRAK-4's kinase activity virtually abolishes downstream events. This is not the case with other members of the IRAK family [Suzuki N et al 2002; Li S et al 2002]. Pubmed11960013 Pubmed12297423 Reactome Database ID Release 43975873 Reactome, http://www.reactome.org ReactomeREACT_27293 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 4 Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomerl:activated TLR5 or 10 complex Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 IRAK4 deficient macrophages fail to induce IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1.<p>Phosphorylation sites of IRAK2 remain to be characterized. Pubmed18438411 Reactome Database ID Release 43975861 Reactome, http://www.reactome.org ReactomeREACT_27165 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 4 IRAK1/or IRAK2 binds to the activated IRAK4 :oligo MyD88:activated TLR5 or 10 complex Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 IRAK2 has been implicated in IL1R and TLR signaling by the observation that IRAK2 can associate with MyD88 and Mal (Muzio et al. 1997). Like IRAK1, IRAK2 is activated downstream of IRAK4 (Kawagoe et al. 2008). It has been suggested that IRAK1 activates IRAK2 (Wesche et al. 1999) but IRAK2 phosphorylation is observed in IRAK1–/– mouse macrophages while IRAK4 deficiency abrogates IRAK2 phosphorylation (Kawagoe et al. 2008), suggesting that activated IRAK4 phosphorylates IRAK2 as it does IRAK1. IL6 production in response to IL1beta is impaired in embryonic fibroblasts from IRAK1 or IRAK2 knockout mice and abrogated in IRAK1/2 dual knockouts (Kawagoe et al. 2007) suggesting that IRAK1 and IRAK2 are both involved in IL1R signaling downstream of IRAK4. MYD88 recruits unphosphorylated, inactive IRAK1 to the IL1 receptor complex. Pubmed12150927 Pubmed16024789 Pubmed17878161 Pubmed17890055 Pubmed18438411 Pubmed19224918 Pubmed9374458 Reactome Database ID Release 43975852 Reactome, http://www.reactome.org ReactomeREACT_27140 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 4 MyD88 oligomerization within the complex of activated TLR:MyD88 Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 Pubmed19592493 Pubmed20485341 Reactome Database ID Release 43975880 Reactome, http://www.reactome.org ReactomeREACT_27210 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 Structural analysis of MyD88:IRAK4 and MyD88:IRAK4:IRAK2 suggested that upon MyD88 recruitment to an activated dimerized TLR the MyD88 death domains clustering induces the formation of Mydosome, a large oligomeric signaling platform (Motshwene PG et al 2009, Lin SC et al 2010). Assembly of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. The oligomer complex stoichiometry was reported as 7:4 and 8:4 for MyD88:IRAK4 (Motshwene PG et al 2009), and 6:4:4 in the complex of MyD88:IRAK4:IRAK2(Lin SC et al 2010). has a Stoichiometric coefficient of 4 MyD88 forms a complex with the activated TLR receptor Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 MyD88 is the downstream adaptor which is utilized by all TLRs, except TLR3. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR. Upon ligand binding to the IL-1R or a TLR, MyD88 is rapidly recruited to the activated receptor via homotypic interactions of TIR domain, whereas the DD module recruits serine/threonine kinases such as interleukin-1-receptor-associated kinases (IRAKs). Pubmed12447442 Pubmed9430229 Reactome Database ID Release 43975866 Reactome, http://www.reactome.org ReactomeREACT_27256 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 2 SGPP Converted from EntitySet in Reactome Reactome DB_ID: 428667 Reactome Database ID Release 43428667 Reactome, http://www.reactome.org ReactomeREACT_20306 sphingosine-1-phosphate phosphatase First phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 First, IRAK1 is phosphorylated at Thr209 by IRAK4. This results in a conformational change of the kinase domain, permitting further phosphorylations to take place. Substitution of Thr209 by alanine results in a kinase-inactive IRAK1. Pubmed11960013 Pubmed14625308 Reactome Database ID Release 43975878 Reactome, http://www.reactome.org ReactomeREACT_27228 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 4 Second phosphorylation of IRAK1 by IRAK4 bound to MyD88:activated TLR complex Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 Pubmed14625308 Reactome Database ID Release 43975874 Reactome, http://www.reactome.org ReactomeREACT_27163 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 Second, Thr387 in the activation loop is phosphorylated, leading to full enzymatic activity. has a Stoichiometric coefficient of 4 0-acteylcholine bound to calcium permeable nictonic acteylcholine receptor complex Reactome DB_ID: 629600 Reactome Database ID Release 43629600 Reactome, http://www.reactome.org ReactomeREACT_23302 has a Stoichiometric coefficient of 1 Multiple IRAK1 autophosphorylation within the complex p-IRAK4:oligo MyD88:activated TLR A series of sequential phosphorylation events lead to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the upstream adapters MyD88 and Tollip. The significance of these phosphorylation events is not clear; the kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), so IRAK1 is believed to act primarily as an adaptor for TRAF6 (Conze et al. 2008). Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 Pubmed10217414 Pubmed11923871 Pubmed14625308 Pubmed17337443 Pubmed18347055 Reactome Database ID Release 43975853 Reactome, http://www.reactome.org ReactomeREACT_27151 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 16 Highly sodium permeable nicotinic acetylcholine receptors Converted from EntitySet in Reactome Reactome DB_ID: 629576 Reactome Database ID Release 43629576 Reactome, http://www.reactome.org ReactomeREACT_23370 TRAF6 binds to hp- IRAK1 or p-IRAK2 Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2011-08-12 Hyperphosphorylated IRAK1, still within the receptor complex, binds TRAF6 through multiple regions including the death domain, the undefined domain and the C-terminal C1 domain (Li et al. 2001). The C-terminal region of IRAK-1 contains three potential TRAF6-binding sites; mutation of the amino acids (Glu544, Glu587, Glu706) in these sites to alanine greatly reduces activation of NFkappaB (Ye et al. 2002). IRAK-2 has two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). IRAK2 point mutants with mutated TRAF6-binding motifs abrogate NFkB activation and are incapable to stimulate TRAF6 ubiquitination (Keating SE et al 2007). Pubmed11287640 Pubmed12138165 Pubmed12140561 Pubmed17878161 Pubmed18070982 Pubmed8837778 Reactome Database ID Release 43975857 Reactome, http://www.reactome.org ReactomeREACT_27141 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 has a Stoichiometric coefficient of 8 Acetylcholine Receptor alpha4(2)-beta2(3) subunits Reactome DB_ID: 532622 Reactome Database ID Release 43532622 Reactome, http://www.reactome.org ReactomeREACT_22854 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 Acetylcholine receptor alpha3(2)-beta4(3) Reactome DB_ID: 629575 Reactome Database ID Release 43629575 Reactome, http://www.reactome.org ReactomeREACT_23044 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 Acetylcholine receptor alpha3-beta4 Reactome DB_ID: 532621 Reactome Database ID Release 43532621 Reactome, http://www.reactome.org ReactomeREACT_22834 has a Stoichiometric coefficient of 1 LASS proteins Converted from EntitySet in Reactome LAG1 homologs, ceramide synthases Reactome DB_ID: 428153 Reactome Database ID Release 43428153 Reactome, http://www.reactome.org ReactomeREACT_20175 O-Acetylcholine bound to Acetylcholine receptor Reactome DB_ID: 629590 Reactome Database ID Release 43629590 Reactome, http://www.reactome.org ReactomeREACT_23014 has a Stoichiometric coefficient of 1 Highly calcium permeable postsynaptic nicotinic acetylcholine receptors Converted from EntitySet in Reactome Reactome DB_ID: 629581 Reactome Database ID Release 43629581 Reactome, http://www.reactome.org ReactomeREACT_22452 Acetylcholine receptor containing alpha7 subunit Reactome DB_ID: 629577 Reactome Database ID Release 43629577 Reactome, http://www.reactome.org ReactomeREACT_22557 has a Stoichiometric coefficient of 1 O-acteylcholine bound to calcium permeable postsynaptic nicotinic acetylcholine receptors Reactome DB_ID: 629592 Reactome Database ID Release 43629592 Reactome, http://www.reactome.org ReactomeREACT_23170 has a Stoichiometric coefficient of 1 Ca permeable AMPA receptors Converted from EntitySet in Reactome Reactome DB_ID: 416325 Reactome Database ID Release 43416325 Reactome, http://www.reactome.org ReactomeREACT_18563 TARP-PSD95-Mdm2 Reactome DB_ID: 416851 Reactome Database ID Release 43416851 Reactome, http://www.reactome.org ReactomeREACT_18885 has a Stoichiometric coefficient of 1 Ca permeable AMPA receptors Converted from EntitySet in Reactome Reactome DB_ID: 399714 Reactome Database ID Release 43399714 Reactome, http://www.reactome.org ReactomeREACT_18763 AMPA receptors containing GluR1 (heteromers) Reactome DB_ID: 416295 Reactome Database ID Release 43416295 Reactome, http://www.reactome.org ReactomeREACT_18908 has a Stoichiometric coefficient of 2 AMPA receptors containing GluR1 (homomers) Reactome DB_ID: 416304 Reactome Database ID Release 43416304 Reactome, http://www.reactome.org ReactomeREACT_18919 has a Stoichiometric coefficient of 4 PPAP2 Converted from EntitySet in Reactome Reactome DB_ID: 428110 Reactome Database ID Release 43428110 Reactome, http://www.reactome.org ReactomeREACT_19766 phosphatidate phosphatase 2 TARP-PSD95-Mdm2 Reactome DB_ID: 416329 Reactome Database ID Release 43416329 Reactome, http://www.reactome.org ReactomeREACT_19058 has a Stoichiometric coefficient of 1 CaMKII Reactome DB_ID: 417004 Reactome Database ID Release 43417004 Reactome, http://www.reactome.org ReactomeREACT_18980 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 AMPA receptors containing GluR1 (heteromers) Reactome DB_ID: 399696 Reactome Database ID Release 43399696 Reactome, http://www.reactome.org ReactomeREACT_18648 has a Stoichiometric coefficient of 2 GluR1 receptors AMPA receptors containing GluR1 (homomers) Reactome DB_ID: 399700 Reactome Database ID Release 43399700 Reactome, http://www.reactome.org ReactomeREACT_19030 has a Stoichiometric coefficient of 4 Ca impermeable AMPA receptors Converted from EntitySet in Reactome Reactome DB_ID: 416323 Reactome Database ID Release 43416323 Reactome, http://www.reactome.org ReactomeREACT_19064 AMPA receptors containing GluR2 (heteromers) Reactome DB_ID: 416312 Reactome Database ID Release 43416312 Reactome, http://www.reactome.org ReactomeREACT_18660 has a Stoichiometric coefficient of 2 GGT Reactome DB_ID: 2161915 Reactome Database ID Release 432161915 Reactome, http://www.reactome.org ReactomeREACT_152031 gamma-glutamyltransferase ALDH Aldehyde dehydrogenase Reactome DB_ID: 2161598 Reactome Database ID Release 432161598 Reactome, http://www.reactome.org ReactomeREACT_150894 GPX1/2/4 Converted from EntitySet in Reactome Reactome DB_ID: 2161954 Reactome Database ID Release 432161954 Reactome, http://www.reactome.org ReactomeREACT_151628 DPEP Dipeptidase Reactome DB_ID: 2161751 Reactome Database ID Release 432161751 Reactome, http://www.reactome.org ReactomeREACT_150941 PIK3(2) Converted from EntitySet in Reactome Reactome DB_ID: 1806189 Reactome Database ID Release 431806189 Reactome, http://www.reactome.org ReactomeREACT_121821 SYNJ/INPP5(1) Converted from EntitySet in Reactome Reactome DB_ID: 1806214 Reactome Database ID Release 431806214 Reactome, http://www.reactome.org ReactomeREACT_123158 TXDH 11-Hydroxythromboxane B2 reductase 11-dehydroxythromboxane B2 dehydrogenase Reactome DB_ID: 2161595 Reactome Database ID Release 432161595 Reactome, http://www.reactome.org ReactomeREACT_151406 PIP4K2/5K1 Converted from EntitySet in Reactome Reactome DB_ID: 1806163 Reactome Database ID Release 431806163 Reactome, http://www.reactome.org ReactomeREACT_124837 5-HEDH 5-hydroxy-eicosatetraenoic acid dehydrogenase Reactome DB_ID: 2161764 Reactome Database ID Release 432161764 Reactome, http://www.reactome.org ReactomeREACT_151995 GPX1/2/4 Converted from EntitySet in Reactome Reactome DB_ID: 2161766 Reactome Database ID Release 432161766 Reactome, http://www.reactome.org ReactomeREACT_151285 15-HEDH 15-hydroxy-eicosatetraenoic acid dehydrogenase Reactome DB_ID: 2161674 Reactome Database ID Release 432161674 Reactome, http://www.reactome.org ReactomeREACT_152213 PLA2(11) Converted from EntitySet in Reactome Reactome DB_ID: 1524151 Reactome Database ID Release 431524151 Reactome, http://www.reactome.org ReactomeREACT_123899 PLA2(10) Converted from EntitySet in Reactome Reactome DB_ID: 1524155 Reactome Database ID Release 431524155 Reactome, http://www.reactome.org ReactomeREACT_124872 PLA2(9) Converted from EntitySet in Reactome Reactome DB_ID: 1524157 Reactome Database ID Release 431524157 Reactome, http://www.reactome.org ReactomeREACT_122991 PLA2(8) Converted from EntitySet in Reactome Reactome DB_ID: 1524040 Reactome Database ID Release 431524040 Reactome, http://www.reactome.org ReactomeREACT_123135 PLA2(7) Converted from EntitySet in Reactome Reactome DB_ID: 1524112 Reactome Database ID Release 431524112 Reactome, http://www.reactome.org ReactomeREACT_124354 PLA2(6) Converted from EntitySet in Reactome Reactome DB_ID: 1524107 Reactome Database ID Release 431524107 Reactome, http://www.reactome.org ReactomeREACT_123786 PLA2(5) Converted from EntitySet in Reactome Reactome DB_ID: 1524120 Reactome Database ID Release 431524120 Reactome, http://www.reactome.org ReactomeREACT_121566 ACHE oligomer Converted from EntitySet in Reactome Reactome DB_ID: 1524056 Reactome Database ID Release 431524056 Reactome, http://www.reactome.org ReactomeREACT_117773 PLA2(4) Converted from EntitySet in Reactome Reactome DB_ID: 1524135 Reactome Database ID Release 431524135 Reactome, http://www.reactome.org ReactomeREACT_125685 PLA2(12) Converted from EntitySet in Reactome Reactome DB_ID: 1524141 Reactome Database ID Release 431524141 Reactome, http://www.reactome.org ReactomeREACT_121663 PIK3C2A/G Converted from EntitySet in Reactome Reactome DB_ID: 1806247 Reactome Database ID Release 431806247 Reactome, http://www.reactome.org ReactomeREACT_124283 PLA2(2) Converted from EntitySet in Reactome Reactome DB_ID: 1524137 Reactome Database ID Release 431524137 Reactome, http://www.reactome.org ReactomeREACT_122246 CHK/ETNK Converted from EntitySet in Reactome Reactome DB_ID: 1500619 Reactome Database ID Release 431500619 Reactome, http://www.reactome.org ReactomeREACT_124966 RORE (DNA) DNA Containing an ROR Element Reactome DB_ID: 1368102 Reactome Database ID Release 431368102 Reactome, http://www.reactome.org ReactomeREACT_111419 3-hydroxyacyl-CoA dehydratase Reactome DB_ID: 548833 Reactome Database ID Release 43548833 Reactome, http://www.reactome.org ReactomeREACT_22738 Pristanal dehydrogenase Reactome DB_ID: 389603 Reactome Database ID Release 43389603 Reactome, http://www.reactome.org ReactomeREACT_17759 E-box (DNA) DNA Containing an E-box Element Reactome DB_ID: 549373 Reactome Database ID Release 43549373 Reactome, http://www.reactome.org ReactomeREACT_25457 isocitrate-oxoglutarate transporter Reactome DB_ID: 390344 Reactome Database ID Release 43390344 Reactome, http://www.reactome.org ReactomeREACT_18178 AADHAPR Reactome DB_ID: 76161 Reactome Database ID Release 4376161 Reactome, http://www.reactome.org ReactomeREACT_4622 acyl/alkyl dihydroxyacetone phosphate reductase DGAT1/2 Converted from EntitySet in Reactome Reactome DB_ID: 1500588 Reactome Database ID Release 431500588 Reactome, http://www.reactome.org ReactomeREACT_125599 PLA2(1) Converted from EntitySet in Reactome Reactome DB_ID: 1500634 Reactome Database ID Release 431500634 Reactome, http://www.reactome.org ReactomeREACT_124501 CaMKII Reactome DB_ID: 444796 Reactome Database ID Release 43444796 Reactome, http://www.reactome.org ReactomeREACT_20828 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 CaMKII-Ca2+/Calmodulin Reactome DB_ID: 444601 Reactome Database ID Release 43444601 Reactome, http://www.reactome.org ReactomeREACT_20912 has a Stoichiometric coefficient of 1 CaMKII Reactome DB_ID: 445374 Reactome Database ID Release 43445374 Reactome, http://www.reactome.org ReactomeREACT_21044 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 PLA2(3) Converted from EntitySet in Reactome Reactome DB_ID: 1524128 Reactome Database ID Release 431524128 Reactome, http://www.reactome.org ReactomeREACT_122279 RasGRF:Ca/calmodulin Reactome DB_ID: 442735 Reactome Database ID Release 43442735 Reactome, http://www.reactome.org ReactomeREACT_21180 has a Stoichiometric coefficient of 1 Ras:GDP Reactome DB_ID: 206896 Reactome Database ID Release 43206896 Reactome, http://www.reactome.org ReactomeREACT_21149 has a Stoichiometric coefficient of 1 active Calmodulin Reactome DB_ID: 194447 Reactome Database ID Release 43194447 Reactome, http://www.reactome.org ReactomeREACT_10340 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 RasGTP-B raf compex Reactome DB_ID: 1063687 Reactome Database ID Release 431063687 Reactome, http://www.reactome.org ReactomeREACT_26693 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Ras:GTP Reactome DB_ID: 206946 Reactome Database ID Release 43206946 Reactome, http://www.reactome.org ReactomeREACT_21235 has a Stoichiometric coefficient of 1 Activated B-raf complex Reactome DB_ID: 1063697 Reactome Database ID Release 431063697 Reactome, http://www.reactome.org ReactomeREACT_25467 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 R-Ras-GTP Reactome DB_ID: 399865 Reactome Database ID Release 43399865 Reactome, http://www.reactome.org ReactomeREACT_20411 has a Stoichiometric coefficient of 1 INPP5(3)/ITPK1 Converted from EntitySet in Reactome Reactome DB_ID: 2023888 Reactome Database ID Release 432023888 Reactome, http://www.reactome.org ReactomeREACT_152089 beta-xylosidase Reactome DB_ID: 2247521 Reactome Database ID Release 432247521 Reactome, http://www.reactome.org ReactomeREACT_124529 DSPGs Converted from EntitySet in Reactome Dermatan sulfate proteoglycans Reactome DB_ID: 2065214 Reactome Database ID Release 432065214 Reactome, http://www.reactome.org ReactomeREACT_121927 CSPGs Chondroitin sulfate proteoglycans Converted from EntitySet in Reactome Reactome DB_ID: 2024088 Reactome Database ID Release 432024088 Reactome, http://www.reactome.org ReactomeREACT_124804 HGSNAT oligomer Reactome DB_ID: 1678773 Reactome Database ID Release 431678773 Reactome, http://www.reactome.org ReactomeREACT_124887 HSPGs Converted from EntitySet in Reactome Heparan sulfate/heparin proteoglycans Reactome DB_ID: 2076618 Reactome Database ID Release 432076618 Reactome, http://www.reactome.org ReactomeREACT_122831 CSPGs Chondroitin sulfate proteoglycans Converted from EntitySet in Reactome Reactome DB_ID: 2065110 Reactome Database ID Release 432065110 Reactome, http://www.reactome.org ReactomeREACT_124864 DSPGs Converted from EntitySet in Reactome Dermatan sulfate proteoglycans Reactome DB_ID: 2065240 Reactome Database ID Release 432065240 Reactome, http://www.reactome.org ReactomeREACT_122485 DSPGs Converted from EntitySet in Reactome Dermatan sulfate proteoglycans Reactome DB_ID: 2065267 Reactome Database ID Release 432065267 Reactome, http://www.reactome.org ReactomeREACT_122660 CSPGs Chondroitin sulfate proteoglycans Converted from EntitySet in Reactome Reactome DB_ID: 2064124 Reactome Database ID Release 432064124 Reactome, http://www.reactome.org ReactomeREACT_123227 Edited Kainate Receptor-glutamate complex Reactome DB_ID: 451304 Reactome Database ID Release 43451304 Reactome, http://www.reactome.org ReactomeREACT_21503 has a Stoichiometric coefficient of 1 Edited GRIK1 homomer Reactome DB_ID: 451321 Reactome Database ID Release 43451321 Reactome, http://www.reactome.org ReactomeREACT_21471 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 SMPD2,3 Converted from EntitySet in Reactome Reactome DB_ID: 1606272 Reactome Database ID Release 431606272 Reactome, http://www.reactome.org ReactomeREACT_116536 phospho-CaMK IV:Calmodulin Reactome DB_ID: 111904 Reactome Database ID Release 43111904 Reactome, http://www.reactome.org ReactomeREACT_15743 has a Stoichiometric coefficient of 1 Ca(4)CaM Active Calmodulin Reactome DB_ID: 629658 Reactome Database ID Release 43629658 Reactome, http://www.reactome.org ReactomeREACT_23175 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Calmodulin:CaMK IV Reactome DB_ID: 112281 Reactome Database ID Release 43112281 Reactome, http://www.reactome.org ReactomeREACT_15747 has a Stoichiometric coefficient of 1 Calmodulin:CaMK IV Reactome DB_ID: 111900 Reactome Database ID Release 43111900 Reactome, http://www.reactome.org ReactomeREACT_15739 has a Stoichiometric coefficient of 1 Edited GRIK2 homomer Reactome DB_ID: 451319 Reactome Database ID Release 43451319 Reactome, http://www.reactome.org ReactomeREACT_21804 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Edited GRIK1 and GRIK2 heteroteramer Reactome DB_ID: 451324 Reactome Database ID Release 43451324 Reactome, http://www.reactome.org ReactomeREACT_21971 has a Stoichiometric coefficient of 2 Edited Kainate receptors Reactome DB_ID: 451279 Reactome Database ID Release 43451279 Reactome, http://www.reactome.org ReactomeREACT_21924 has a Stoichiometric coefficient of 1 active Calmodulin Reactome DB_ID: 194846 Reactome Database ID Release 43194846 Reactome, http://www.reactome.org ReactomeREACT_15760 has a Stoichiometric coefficient of 1 PTEN mRNA translation negatively regulated by microRNAs Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 PTEN protein synthesis is negatively regulated by microRNAs miR-26A1 and miR-26A2, which recruit the RISC complex to PTEN mRNA. Overexpression of miR-26A2, caused by genomic amplification of MIR26A2 locus on chromosome 12, is frequently observed in human brain glioma tumors possessing one wild-type PTEN allele, and is thought to contribute to tumor progression by repressing the remaining PTEN protein expression (Huse et al. 2009). Pubmed19487573 Reactome Database ID Release 432321904 Reactome, http://www.reactome.org ReactomeREACT_147819 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 viral plus strand DNA with sticky 3' end Reactome DB_ID: 175429 Reactome Database ID Release 43175429 Reactome, http://www.reactome.org ReactomeREACT_7330 Host genomic DNA Reactome DB_ID: 175158 Reactome Database ID Release 43175158 Reactome, http://www.reactome.org ReactomeREACT_7748 viral minus strand DNA with sticky 3' end Reactome DB_ID: 175079 Reactome Database ID Release 43175079 Reactome, http://www.reactome.org ReactomeREACT_7325 Collagen type VIII fibril Reactome DB_ID: 2482216 Reactome Database ID Release 432482216 Reactome, http://www.reactome.org ReactomeREACT_151708 NRG1/2 Converted from EntitySet in Reactome Neuregulins NRG1 and NRG2 Reactome DB_ID: 1227956 Reactome Database ID Release 431227956 Reactome, http://www.reactome.org ReactomeREACT_117513 Okazaki fragment Reactome DB_ID: 68452 Reactome Database ID Release 4368452 Reactome, http://www.reactome.org ReactomeREACT_4386 Flap Reactome DB_ID: 68454 Reactome Database ID Release 4368454 Reactome, http://www.reactome.org ReactomeREACT_3907 Remaining Flap Reactome DB_ID: 68467 Reactome Database ID Release 4368467 Reactome, http://www.reactome.org ReactomeREACT_4584 Okazaki fragment minus Flap Reactome DB_ID: 68469 Reactome Database ID Release 4368469 Reactome, http://www.reactome.org ReactomeREACT_2427 ligated okazaki fragment Reactome DB_ID: 69172 Reactome Database ID Release 4369172 Reactome, http://www.reactome.org ReactomeREACT_4394 AKT phosphorylates CREB1 AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed9829964 Reactome Database ID Release 43199298 Reactome, http://www.reactome.org ReactomeREACT_12597 Reviewed: Greene, LA, 2007-11-08 15:39:37 genomic DNA with staggered 5' ends Reactome DB_ID: 175520 Reactome Database ID Release 43175520 Reactome, http://www.reactome.org ReactomeREACT_9149 PTEN dephosphorylates PIP3 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 3.1.3.67 Pubmed9593664 Reactome Database ID Release 43199456 Reactome, http://www.reactome.org ReactomeREACT_12542 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Maehema et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase. The role of other phosphoinositide phosphatases (INPP5D, INPPL1, INPP5K, PTPRQ, INPP4B) in the negative regulation of PI3K/AKT signaling will be described in future editions of Reactome. AKT can phosphorylate NR4A1 (NUR77) AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362). Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed11274386 Reactome Database ID Release 43199863 Reactome, http://www.reactome.org ReactomeREACT_12614 Reviewed: Greene, LA, 2007-11-08 15:39:37 AKT can phosphorylate RSK Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed10490848 Reactome Database ID Release 43199839 Reactome, http://www.reactome.org ReactomeREACT_12485 Reviewed: Greene, LA, 2007-11-08 15:39:37 Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT. has a Stoichiometric coefficient of 2 AKT can phosphorylate forkhead box transcription factors Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Cell survival and growth are also promoted by AKT phosphorylation of Forkhead box (FOX) transcription factors, most notably FoxO1, FoxO3a and FoxO4. Once phosphorylated by AKT, these factors are removed from the nucleus, associate with 14-3-3 proteins, and are retained in the cytoplasm, thus producing a change in their transcriptional activity. For instance, unphosphorylated FoxO3a in the nucleus triggers apoptosis, most likely by inducing the expression of critical genes, such as the Fas ligand gene. In another example, AKT phosphorylation of FOXO4 prevents FOXO4-mediated upregulation of p27Kip1. EC Number: 2.7.11 Pubmed10102273 Pubmed10358075 Pubmed16272144 Reactome Database ID Release 43199299 Reactome, http://www.reactome.org ReactomeREACT_12572 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 3 MIR26A microRNAs bind PTEN mRNA Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 MIR26A microRNAs, miR-26A1 and miR-26A2, transcribed from genes on chromosome 3 and 12, respectively, bind PTEN mRNA (Huse et al. 2009).<br><br> The MIR26A2 locus is frequently amplified in glioma tumors that retained one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to downregulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and prevent loss of heterozigosity at the PTEN locus in a mouse PTEN +/- glioma model, based on a monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010). Pubmed19487573 Pubmed20080666 Reactome Database ID Release 432318752 Reactome, http://www.reactome.org ReactomeREACT_147761 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Interleukin-1 Converted from EntitySet in Reactome Reactome DB_ID: 445744 Reactome Database ID Release 43445744 Reactome, http://www.reactome.org ReactomeREACT_22576 PDPK1 binds PIP2 Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999). Pubmed9895304 Reactome Database ID Release 432219524 Reactome, http://www.reactome.org ReactomeREACT_147701 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Interleukin 1 receptors Converted from EntitySet in Reactome Reactome DB_ID: 445750 Reactome Database ID Release 43445750 Reactome, http://www.reactome.org ReactomeREACT_23342 PHLPP dephosphorylates S473 in AKT Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Matthews, L, 2012-08-03 Pubmed15808505 Pubmed17386267 Reactome Database ID Release 43199425 Reactome, http://www.reactome.org ReactomeREACT_12403 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 The PH domain leucine-rich repeat-containing protein phosphatases, PHLPP1 (Gao et al. 2005) and PHLPP2 (Brognard et al. 2007) can specifically dephosphorylate the serine residue and inactivate AKT. THEM4 (CTMP) and/or TRIB3 inhibit AKT phosphorylation Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Matthews, L, 2012-08-03 Pubmed11598301 Pubmed12791994 Reactome Database ID Release 43199443 Reactome, http://www.reactome.org ReactomeREACT_12567 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003). PP2A regulatory subunit B56 Converted from EntitySet in Reactome Reactome DB_ID: 196216 Reactome Database ID Release 43196216 Reactome, http://www.reactome.org ReactomeREACT_10194 Phosphodiesterases, cyclic GMP-selective Converted from EntitySet in Reactome Reactome DB_ID: 418542 Reactome Database ID Release 43418542 Reactome, http://www.reactome.org ReactomeREACT_24458 Platelet alpha granule membrane components that are released on degranulation Converted from EntitySet in Reactome Reactome DB_ID: 964722 Reactome Database ID Release 43964722 Reactome, http://www.reactome.org ReactomeREACT_26523 Platelet alpha granule contents Converted from EntitySet in Reactome Reactome DB_ID: 481033 Reactome Database ID Release 43481033 Reactome, http://www.reactome.org ReactomeREACT_22076 Platelet alpha granule contents Converted from EntitySet in Reactome Reactome DB_ID: 481003 Reactome Database ID Release 43481003 Reactome, http://www.reactome.org ReactomeREACT_21970 Integrin alphaIIb beta3 ECM ligands Converted from EntitySet in Reactome Reactome DB_ID: 377603 Reactome Database ID Release 43377603 Reactome, http://www.reactome.org ReactomeREACT_17269 Cleaved collagen type III fibril Reactome DB_ID: 2485102 Reactome Database ID Release 432485102 Reactome, http://www.reactome.org ReactomeREACT_152357 Pellino 1,2,3 Converted from EntitySet in Reactome Reactome DB_ID: 450814 Reactome Database ID Release 43450814 Reactome, http://www.reactome.org ReactomeREACT_22780 NRGs/EGF-like ligands Converted from EntitySet in Reactome Neuregulins/EGF-like ligands Reactome DB_ID: 1233236 Reactome Database ID Release 431233236 Reactome, http://www.reactome.org ReactomeREACT_116669 Cleaved collagen type VIII fibril Reactome DB_ID: 2482192 Reactome Database ID Release 432482192 Reactome, http://www.reactome.org ReactomeREACT_152082 Collagen type III fibril Reactome DB_ID: 2466125 Reactome Database ID Release 432466125 Reactome, http://www.reactome.org ReactomeREACT_151761 cGMP phosphodiesterases Converted from EntitySet in Reactome Reactome DB_ID: 418560 Reactome Database ID Release 43418560 Reactome, http://www.reactome.org ReactomeREACT_24101 Gab1:Grb2 binds to EGF:Phospho-EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 GAB1 binds to EGF receptors via tyrosine autophosphorylation sites on the receptor. Pubmed10913131 Reactome Database ID Release 43177940 Reactome, http://www.reactome.org ReactomeREACT_12423 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Gab1 binds phosphatidylinositol-3,4,5-trisphosphate Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed10648629 Reactome Database ID Release 43179467 Reactome, http://www.reactome.org ReactomeREACT_12534 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The pleckstrin homology (PH) domain of GAB1 binds to PIP3 and can target GAB1 to the plasma membrane in response to EGF stimulation. This mechanism provides a positive feedback loop with respect to PI3K activation, to enhance EGFR signalling. Activation of SHP2 through the binding to phospho-Gab1 Authored: Castagnoli, L, 2006-10-10 13:09:34 Pubmed11323411 Pubmed14701753 Reactome Database ID Release 43177944 Reactome, http://www.reactome.org ReactomeREACT_12466 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The SH2 domains repress phosphatase activity of SHP2. Binding of these domains to phosphotyrosine-containing proteins relieves this autoinhibition, possibly by inducing a conformational change in the enzyme. Gab1 phosphorylation by EGFR kinase Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 2.7.10 EGFR kinase phosphorylates the phosphorylation sites tyrosine 627 and 659 on GAB1 Pubmed15231819 Pubmed9890893 Reactome Database ID Release 43177930 Reactome, http://www.reactome.org ReactomeREACT_12490 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 5 SHP2 dephosphorylates Tyr 992 on EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 Pubmed14560030 Reactome Database ID Release 43177935 Reactome, http://www.reactome.org ReactomeREACT_12629 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The tyrosine-protein phosphatase SHP2 is a positive effector of EGFR signalling. SHP2 inhibits the tyrosine-dependent translocation of RasGAP (catalyses Ras inactivation) to the plasma membrane, thereby keeping it away from Ras-GTP (its substrate). This inhibition is achieved by the dephosphorylation of a RasGAP binding site on the EGF receptor. Dephosphorylation of Gab1 by SHP2 Authored: Castagnoli, L, 2006-10-10 13:09:34 Phosphorylated GAB1 can bind PI3 kinase by its regulatory alpha subunit. SHP2 dephosphorylation of the tyrosine residues 447, 472 and 589 on GAB1 means PI3 kinase can no longer bind to the complex in the plasma membrane and cannot be activated. Pubmed10734310 Reactome Database ID Release 43177924 Reactome, http://www.reactome.org ReactomeREACT_12605 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 3 Sustained activation of SRC kinase by SHP2 Authored: Castagnoli, L, 2006-10-10 13:09:34 Pubmed15574420 Reactome Database ID Release 43177923 Reactome, http://www.reactome.org ReactomeREACT_12601 Reviewed: Heldin, CH, 2008-02-12 09:44:02 SHP2 can dephosphorylate paxillin, which leads to Csk dissociation from the paxillin-Src complex and Src activation. Src is an SHP2 effector in EGF-stimulated Erk activation and cell migration. hp-IRAK1, IRAK4 Converted from EntitySet in Reactome Reactome DB_ID: 450810 Reactome Database ID Release 43450810 Reactome, http://www.reactome.org ReactomeREACT_23241 Dephosphorylation of PAG by SHP2 Authored: Castagnoli, L, 2006-10-10 13:09:34 Dephosphorylation of CBP/PAG negatively regulates the recruitment of the Src inhibiting kinase, Csk. Src is not negatively regulated by phosphorylation by Csk. Pubmed14665621 Reactome Database ID Release 43177926 Reactome, http://www.reactome.org ReactomeREACT_12390 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Phosphorylation of CBL (EGFR:CBL) Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 2.7.10 EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity. Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed15117950 Pubmed7657591 Reactome Database ID Release 43182969 Reactome, http://www.reactome.org ReactomeREACT_12424 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 2 Binding of CBL to EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Phosphorylation at tyrosine Y1045 of EGFR creates a major docking site for E3 ubiquitin-protein ligase, CBL (Casitas B-lineage lymphoma proto- oncogene) and is required to sort the EGFR to lysosomes for degradation. The E3 ligase CBL plays a crucial role in these events as it dually participates in early events of internalization via a CIN85-endophilin dependent mechanism and endocytic sorting by mediating multiple monoubiquitylation of the receptor. Pubmed15475003 Reactome Database ID Release 43183055 Reactome, http://www.reactome.org ReactomeREACT_12632 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 2 AKT binds PDPK1 Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005) Pubmed12167717 Pubmed15718470 Reactome Database ID Release 432317314 Reactome, http://www.reactome.org ReactomeREACT_147711 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 PIP3 recruits PDPK1 to the membrane Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Matthews, L, 2012-08-03 PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999). Pubmed9895304 Reactome Database ID Release 432316429 Reactome, http://www.reactome.org ReactomeREACT_147873 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 TORC2 (mTOR) phosphorylates AKT at S473 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Pubmed12167717 Pubmed15268862 Pubmed15314020 Pubmed15467718 Pubmed15718470 Pubmed19303758 Reactome Database ID Release 43198640 Reactome, http://www.reactome.org ReactomeREACT_12391 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.<br> Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005). nascent polypeptide with signal sequence Reactome DB_ID: 1799333 Reactome Database ID Release 431799333 Reactome, http://www.reactome.org ReactomeREACT_116459 cleaved nascent polypeptide Reactome DB_ID: 1799321 Reactome Database ID Release 431799321 Reactome, http://www.reactome.org ReactomeREACT_116731 nascent polypeptide with signal sequence Reactome DB_ID: 1799338 Reactome Database ID Release 431799338 Reactome, http://www.reactome.org ReactomeREACT_117841 Met-tRNAi Met-tRNAf Reactome DB_ID: 72393 Reactome Database ID Release 4372393 Reactome, http://www.reactome.org ReactomeREACT_4829 fMet-tRNA methionyl initiator tRNA RNA-binding protein in RNP (ribonucleoprotein) complexes Reactome DB_ID: 72595 Reactome Database ID Release 4372595 Reactome, http://www.reactome.org ReactomeREACT_3670 eIF1 Reactome DB_ID: 72617 Reactome Database ID Release 4372617 Reactome, http://www.reactome.org ReactomeREACT_3030 eIF-1 translation initiation factor 1 L13a kinase Reactome DB_ID: 170641 Reactome Database ID Release 43170641 Reactome, http://www.reactome.org ReactomeREACT_6440 Phospho-MEK1, phospho-SEK1 Converted from EntitySet in Reactome Reactome DB_ID: 451654 Reactome Database ID Release 43451654 Reactome, http://www.reactome.org ReactomeREACT_22945 mRNA Transcripts Stabilized by HuR with Unknown Phosphorylation Converted from EntitySet in Reactome Reactome DB_ID: 450480 Reactome Database ID Release 43450480 Reactome, http://www.reactome.org ReactomeREACT_26762 MEK1, SEK1 Converted from EntitySet in Reactome Reactome DB_ID: 451647 Reactome Database ID Release 43451647 Reactome, http://www.reactome.org ReactomeREACT_22657 CD83 mRNA 001 CD83 Antigen Precursor ENST00000379153 Reactome DB_ID: 450486 Reactome Database ID Release 43450486 Reactome, http://www.reactome.org ReactomeREACT_25728 mRNA Transcript Targeted by HuR Phosphorylated on Ser158 and Ser318 Reactome DB_ID: 450425 Reactome Database ID Release 43450425 Reactome, http://www.reactome.org ReactomeREACT_25423 mRNA Transcript Targeted by HuR Phosphorylated on Ser221 and Ser318 Reactome DB_ID: 517560 Reactome Database ID Release 43517560 Reactome, http://www.reactome.org ReactomeREACT_25598 PIP3 recruits AKT to the membrane Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Matthews, L, 2012-08-03 PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied. Pubmed12167717 Pubmed17914025 Reactome Database ID Release 432317332 Reactome, http://www.reactome.org ReactomeREACT_147886 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 PI3K phosphorylates PIP2 to PIP3 A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity.<br><br>In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011). Authored: Orlic-Milacic, M, 2012-07-18 EC Number: 2.7.1.153 Edited: Matthews, L, 2012-08-03 Pubmed10648629 Pubmed10722704 Pubmed11353842 Pubmed11520784 Pubmed12660731 Pubmed12670391 Pubmed1374684 Pubmed1381348 Pubmed15059917 Pubmed15526160 Pubmed15863030 Pubmed16483568 Pubmed16612002 Pubmed19411071 Pubmed19805105 Pubmed21827948 Pubmed2466336 Pubmed7543144 Pubmed8621607 Pubmed9687533 Pubmed9739761 Reactome Database ID Release 432316434 Reactome, http://www.reactome.org ReactomeREACT_147781 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 PIK3 converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3) Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 2.7.1.153 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed10648629 Reactome Database ID Release 43177939 Reactome, http://www.reactome.org ReactomeREACT_12636 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The kinase activity of PIK3 mediates the phosphorylation of PIP2 to form PIP3 PIK3 catalytic subunit binds to EGF:EGFR:GRB2:GAB1:PIK3R1 Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed10648629 Reactome Database ID Release 43177927 Reactome, http://www.reactome.org ReactomeREACT_12501 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The 110 kDa catalytic subunit (PIK3CA) binds to the 85 kDa regulatory subunit (PIK3R1) to create the active PIK3. GRB2:GAB1:PIK3R1 binds to phosphorylated EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed9356464 Reactome Database ID Release 43177941 Reactome, http://www.reactome.org ReactomeREACT_12425 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The regulatory subunit of PIK3 mediates the association of GAB1 and receptor protein-tyrosine kinases such as the EGF receptor, which can phosphorylate GAB1. It appears that the PIK3 regulatory subunit acts as an adaptor protein allowing GAB1 to serve as a substrate for several tyrosine kinases. SHC kinases in IL2 signaling Converted from EntitySet in Reactome Reactome DB_ID: 453105 Reactome Database ID Release 43453105 Reactome, http://www.reactome.org ReactomeREACT_27386 Binding of PIK3 regulatory alpha subunit to GRB2:GAB1 Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed11606067 Reactome Database ID Release 43177931 Reactome, http://www.reactome.org ReactomeREACT_12616 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1. Binding of GRB2 to GAB1 Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 GRB2 (Growth factor receptor-bound protein 2) binds to GAB1 (GRB2-associated binding protein 1). Pubmed10913131 Pubmed12766170 Reactome Database ID Release 43177920 Reactome, http://www.reactome.org ReactomeREACT_12535 Reviewed: Heldin, CH, 2008-02-12 09:44:02 AKT phosphorylates AKT1S1 (PRAS40) Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 PRAS40 (proline-rich Akt/PKB substrate 40 kDa) is a substrate of AKT, the phosphorylation of which leads to the binding of this protein to 14-3-3. PRAS40 binds to mTOR complexes, mediating AKT signals to mTOR. Interaction of PRAS40 with the mTOR kinase domain is induced under conditions that inhibit mTOR signalling, such as growth factor deprivation. Binding of PRAS40 inhibits mTOR. PRAS40 phosphorylation by AKT and association with the cytosolic anchor protein 14-3-3, lead to mTOR stimulation (Vander Haar E, et al, 2007). Although it was originally identified in the context of insulin signalling, it was later shown that PRAS40 may also play a role in nerve growth factor-mediated neuroprotection (Saito A, et al, 2004). Pubmed12524439 Pubmed14973226 Pubmed17277771 Reactome Database ID Release 43200143 Reactome, http://www.reactome.org ReactomeREACT_12383 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 2 AKT translocates to the nucleus AKT, phosphorylated at threonine (AKT1 308; AKT2 309; AKT3 305) and serine (AKT1 473; AKT2 474; AKT3 472) translocates to the nucleus, reaching a maximum after 15 min and returning to a basal level after 45 min of NGF stimulation. Control of the amount of nuclear AKT is achieved through the action of the phosphatase PP2A. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Reactome Database ID Release 43198298 Reactome, http://www.reactome.org ReactomeREACT_12558 Reviewed: Greene, LA, 2007-11-08 15:39:37 PSF3p Reactome DB_ID: 176944 Reactome Database ID Release 43176944 Reactome, http://www.reactome.org ReactomeREACT_7682 Unwound fork Reactome DB_ID: 169509 Reactome Database ID Release 43169509 Reactome, http://www.reactome.org ReactomeREACT_7610 Replication Fork Reactome DB_ID: 169515 Reactome Database ID Release 43169515 Reactome, http://www.reactome.org ReactomeREACT_7812 anaphase-promoting complex (APC) Reactome DB_ID: 69007 Reactome Database ID Release 4369007 Reactome, http://www.reactome.org ReactomeREACT_3388 DNA primer Reactome DB_ID: 68424 Reactome Database ID Release 4368424 Reactome, http://www.reactome.org ReactomeREACT_2531 cyclin Reactome DB_ID: 68379 Reactome Database ID Release 4368379 Reactome, http://www.reactome.org ReactomeREACT_2838 RNA primer Reactome DB_ID: 68422 Reactome Database ID Release 4368422 Reactome, http://www.reactome.org ReactomeREACT_3288 polypeptide Reactome DB_ID: 141681 Reactome Database ID Release 43141681 Reactome, http://www.reactome.org ReactomeREACT_3573 ARS Reactome DB_ID: 68419 Reactome Database ID Release 4368419 Reactome, http://www.reactome.org ReactomeREACT_3087 autonomously replicating sequence origin origin of replication signal peptide Reactome DB_ID: 1799320 Reactome Database ID Release 431799320 Reactome, http://www.reactome.org ReactomeREACT_117600 peptidyl-tRNA with elongated peptide Reactome DB_ID: 141678 Reactome Database ID Release 43141678 Reactome, http://www.reactome.org ReactomeREACT_2291 AKT phosphorylates IKKalpha AKT mediates IKKalpha (Inhibitor of nuclear factor kappa B kinase subunit alpha) phosphorylation at threonine 23, which is required for NF-kB activation. NF-kB promoted gene transcription enhances neuronal survival. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed10485710 Reactome Database ID Release 43198611 Reactome, http://www.reactome.org ReactomeREACT_12461 Reviewed: Greene, LA, 2007-11-08 15:39:37 SHIP1,2 Converted from EntitySet in Reactome Reactome DB_ID: 913467 Reactome Database ID Release 43913467 Reactome, http://www.reactome.org ReactomeREACT_24095 AKT phosphorylates MDM2 AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of ubiquitin-protein ligase E3 MDM2 promotes nuclear localization and inhibits interaction between MDM2 and p19ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001). Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed11715018 Pubmed15169778 Pubmed15527798 Reactome Database ID Release 43198599 Reactome, http://www.reactome.org ReactomeREACT_12537 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 2 AKT phosphorylates TSC2, inhibiting it AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a TSC1-TSC2 protein complex that is a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.<br>The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed12150915 Pubmed12172553 Reactome Database ID Release 43198609 Reactome, http://www.reactome.org ReactomeREACT_12532 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 2 AKT phosphorylates p21Cip1 and p27Kip1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes. Pubmed12244303 Reactome Database ID Release 43198613 Reactome, http://www.reactome.org ReactomeREACT_12420 Reviewed: Greene, LA, 2007-11-08 15:39:37 AKT phosphorylates BAD AKT phosphorylates the BCL-2 family member BAD at serine 136, blocking the BAD-induced death (of neurons). Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed9381178 Reactome Database ID Release 43198347 Reactome, http://www.reactome.org ReactomeREACT_12565 Reviewed: Greene, LA, 2007-11-08 15:39:37 PDPK1 phosphorylates AKT at T308 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Edited: Matthews, L, 2012-08-03 Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005). Pubmed7637810 Pubmed9736715 Reactome Database ID Release 43198270 Reactome, http://www.reactome.org ReactomeREACT_12584 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 AKT phosphorylates caspase-9 AKT can phosphorylate the apoptotic protease caspase-9, inhibiting it. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed9812896 Reactome Database ID Release 43198621 Reactome, http://www.reactome.org ReactomeREACT_12395 Reviewed: Greene, LA, 2007-11-08 15:39:37 FYN-like kinases Converted from EntitySet in Reactome Reactome DB_ID: 912625 Reactome Database ID Release 43912625 Reactome, http://www.reactome.org ReactomeREACT_24391 AKT phosphorylates GSK3 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 GSK3 (glycogen synthase kinase-3) participates in the Wnt signaling pathway. It is implicated in the hormonal control of several regulatory proteins including glycogen synthase, and the transcription factors MYB and JUN. GSK3 phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. GSK3 is inhibited when phosphorylated by AKT1. Reactome Database ID Release 43198371 Reactome, http://www.reactome.org ReactomeREACT_12549 Reviewed: Greene, LA, 2007-11-08 15:39:37 HA polymer Hyaluronan Hyaluronic acid Reactome DB_ID: 2142896 Reactome Database ID Release 432142896 Reactome, http://www.reactome.org ReactomeREACT_122338 HA polymer Hyaluronan Hyaluronic acid Reactome DB_ID: 2160848 Reactome Database ID Release 432160848 Reactome, http://www.reactome.org ReactomeREACT_124014 (HA)50 Hyaluronan Hyaluronic acid Reactome DB_ID: 2160894 Reactome Database ID Release 432160894 Reactome, http://www.reactome.org ReactomeREACT_122218 (HA)50 Hyaluronan Hyaluronic acid Reactome DB_ID: 2160864 Reactome Database ID Release 432160864 Reactome, http://www.reactome.org ReactomeREACT_121659 (HA)2 Hyaluronan Hyaluronic acid Reactome DB_ID: 2160866 Reactome Database ID Release 432160866 Reactome, http://www.reactome.org ReactomeREACT_123492 GlcNAc-GlcA-GlcNAc Reactome DB_ID: 2162223 Reactome Database ID Release 432162223 Reactome, http://www.reactome.org ReactomeREACT_125048 keratan sulfate 1,4-beta-D-galactosidase Reactome DB_ID: 1793214 Reactome Database ID Release 431793214 Reactome, http://www.reactome.org ReactomeREACT_124590 GALNS oligomer Reactome DB_ID: 1630327 Reactome Database ID Release 431630327 Reactome, http://www.reactome.org ReactomeREACT_121429 triokinase Reactome DB_ID: 70345 Reactome Database ID Release 4370345 Reactome, http://www.reactome.org ReactomeREACT_5816 starch (amylopectin) Reactome DB_ID: 189071 Reactome Database ID Release 43189071 Reactome, http://www.reactome.org ReactomeREACT_9826 starch (amylose) Reactome DB_ID: 189075 Reactome Database ID Release 43189075 Reactome, http://www.reactome.org ReactomeREACT_9907 SHC1 phosphorylation by phosphorylated EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 2.7.10.1 Edited: Orlic-Milacic, Marija, 2011-08-25 Once bound to EGFR, SHC1 is phosphorylated on two tyrosines (Y349, Y350). Pubmed7535773 Pubmed8036006 Reactome Database ID Release 43177933 Reactome, http://www.reactome.org ReactomeREACT_12592 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 2 SHC1 binds to the phosphorylated EGF receptor:ligand complex Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed9544989 Reactome Database ID Release 43177925 Reactome, http://www.reactome.org ReactomeREACT_12580 Reviewed: Heldin, CH, 2008-02-12 09:44:02 SHC1 (Src homology 2 domain-containing) transforming protein can bind to either tyrosine 1148 and/or tyrosine 1173 sites on the EGF receptor. SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:SHC1:GRB2:SOS1) Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed8493579 Reactome Database ID Release 43177945 Reactome, http://www.reactome.org ReactomeREACT_12402 Reviewed: Heldin, CH, 2008-02-12 09:44:02 SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP). GRB2:SOS1 binds to phosphorylated SHC1 in complex with EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed8493579 Reactome Database ID Release 43177936 Reactome, http://www.reactome.org ReactomeREACT_12514 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The tyrosine sites on SHC1 become possible binding sites for the GRB2:SOS1 complex. Stabilisation of RAS:RAF by 14-3-3 14-3-3 has been displaced from Ser259. 14-3-3 may now bind its higher affinity Ser621 (S2) site. This stabilises an 'open' Raf-1 conformation that is catalytically active, and bound to p21ras via both p21ras-binding domains, CRD and RBD. Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Pubmed9069260 Reactome Database ID Release 43109802 Reactome, http://www.reactome.org ReactomeREACT_996 Stabilisation of RAF by further phosphorylation An unidentified protein tyrosine kinase located in the plasma membrane phosphorylates tyrosine residues at 340 and 341 (Y1, Y2 in diagram) of Raf-1. This serves to further stabilise the active 'open' Raf-1 conformation. While the kinase has not been definitively identified, Src is a plausible candidate: coexpression of Raf-1 and Src in Sf9 cells resulted in phosphorylation of Y340/Y341 and enzymatic activationof Raf-1; Raf-1 interacts with Src and co-immunoprecipitates with Src/Fyn in NIH-3T3 cells. Authored: Charalambous, M, 2005-01-07 11:17:43 EC Number: 2.7.10 Edited: Schmidt, EE, 0000-00-00 00:00:00 Pubmed7517401 Pubmed7692235 Pubmed9069260 Reactome Database ID Release 43109829 Reactome, http://www.reactome.org ReactomeREACT_525 has a Stoichiometric coefficient of 2 Phosphorylated human RAF1 binds to RAS:GTP complex A key event for Ras transformation involves the direct physical association between Ras and the Raf-1 kinase. This interaction promotes both Raf translocation to the plasma membrane and activation of Raf kinase activity. Authored: Williams, MG, 2007-10-30 11:44:05 Edited: Jupe, S, 2010-08-06 Pubmed7730360 Pubmed7811320 Reactome Database ID Release 43209207 Reactome, http://www.reactome.org ReactomeREACT_23877 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Activated RAF1 complex binds MEK Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 MEK-1/2 have a proline rich domain (P) and critical Serine residues (MEK-1 S218/222, MEK-2 unknown, S) upon which the molecules may be phosphorylated. MEK1/2 are found in the cytoplasm of unstimulated cells.<br>MEK-1/2 bind to active Raf-1 via the proline-rich domain. Active Raf-1 is able to phosphorylate target Serine and Threonine residues in the presence of ATP. Reactome Database ID Release 43109830 Reactome, http://www.reactome.org ReactomeREACT_143 RAF1 phosphorylates MEK1 Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Reactome Database ID Release 43109841 Reactome, http://www.reactome.org ReactomeREACT_545 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 has a Stoichiometric coefficient of 2 RAF1 phosphorylates MEK2 Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Reactome Database ID Release 43109852 Reactome, http://www.reactome.org ReactomeREACT_1727 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 has a Stoichiometric coefficient of 2 HSPGs Converted from EntitySet in Reactome Heparan sulfate/heparin proteoglycans Reactome DB_ID: 2076619 Reactome Database ID Release 432076619 Reactome, http://www.reactome.org ReactomeREACT_124539 Promotor region of interferon alpha Reactome DB_ID: 994028 Reactome Database ID Release 43994028 Reactome, http://www.reactome.org ReactomeREACT_26381 Promotor region of interferon beta Reactome DB_ID: 1008217 Reactome Database ID Release 431008217 Reactome, http://www.reactome.org ReactomeREACT_25836 IFNA/B Converted from EntitySet in Reactome IFN alpha/beta (IFNA/B) Reactome DB_ID: 909690 Reactome Database ID Release 43909690 Reactome, http://www.reactome.org ReactomeREACT_26595 Promoter region of type-I IFN genes Converted from EntitySet in Reactome Reactome DB_ID: 1027363 Reactome Database ID Release 431027363 Reactome, http://www.reactome.org ReactomeREACT_25653 fibrin digestion products (plasmin) Reactome DB_ID: 158774 Reactome Database ID Release 43158774 Reactome, http://www.reactome.org ReactomeREACT_5325 Ligand to TREM-1 on the platelet membrane Reactome DB_ID: 203159 Reactome Database ID Release 43203159 Reactome, http://www.reactome.org ReactomeREACT_12176 Mannose-carrying cell recognition molecules Converted from EntitySet in Reactome Reactome DB_ID: 375083 Reactome Database ID Release 43375083 Reactome, http://www.reactome.org ReactomeREACT_18192 (S)-3-Hydroxytetradecanoyl-CoA+NAD<=>3-Oxotetradecanoyl-CoA+NADH+H At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-3-Hydroxytetradecanoyl-CoA' are present. At the end of this reaction, 1 molecule of 'H+', 1 molecule of '3-Oxotetradecanoyl-CoA', and 1 molecule of 'NADH' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'Trifunctional Protein'.<br> EC Number: 1.1.1.35 Pubmed1550553 Reactome Database ID Release 4377283 Reactome, http://www.reactome.org ReactomeREACT_343 3-Oxotetradecanoyl-CoA+CoA-SH<=>Lauroyl-CoA At the beginning of this reaction, 1 molecule of '3-Oxotetradecanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Lauroyl-CoA', and 1 molecule of 'Acetyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.<br> EC Number: 2.3.1.155 Pubmed1550553 Reactome Database ID Release 4377271 Reactome, http://www.reactome.org ReactomeREACT_1519 lauroyl-CoA+FAD<=>2-trans-Dodecenoyl-CoA+FADH2 At the beginning of this reaction, 1 molecule of 'Lauroyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'FADH2', and 1 molecule of '2-trans-Dodecenoyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'LCAD acyl-CoA dehydrogenase homotetramer'.<br> EC Number: 1.3.99.3 Pubmed13295225 Pubmed1540149 Reactome Database ID Release 4377263 Reactome, http://www.reactome.org ReactomeREACT_1177 2-trans-Dodecenoyl-CoA+H2O<=>(S)-3-Hydroxydodecanoyl-CoA At the beginning of this reaction, 1 molecule of '2-trans-Dodecenoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-3-Hydroxydodecanoyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.<br> EC Number: 4.2.1.17 Pubmed13295248 Reactome Database ID Release 4377256 Reactome, http://www.reactome.org ReactomeREACT_64 Interleukin-1 family propeptides Converted from EntitySet in Reactome Reactome DB_ID: 449039 Reactome Database ID Release 43449039 Reactome, http://www.reactome.org ReactomeREACT_24212 myristoyl-CoA+FAD<=>trans-Tetradec-2-enoyl-CoA+FADH2 At the beginning of this reaction, 1 molecule of 'myristoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'FADH2', and 1 molecule of 'trans-Tetradec-2-enoyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'LCAD acyl-CoA dehydrogenase homotetramer'.<br> EC Number: 1.3.99.3 Pubmed13295225 Pubmed1540149 Reactome Database ID Release 4377274 Reactome, http://www.reactome.org ReactomeREACT_1912 trans-Tetradec-2-enoyl-CoA+H2O<=>(S)-3-Hydroxytetradecanoyl-CoA At the beginning of this reaction, 1 molecule of 'trans-Tetradec-2-enoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-3-Hydroxytetradecanoyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'Trifunctional Protein'.<br> EC Number: 4.2.1.17 Pubmed1550553 Reactome Database ID Release 4377277 Reactome, http://www.reactome.org ReactomeREACT_1081 fibrin multimer, crosslinked Reactome DB_ID: 157771 Reactome Database ID Release 43157771 Reactome, http://www.reactome.org ReactomeREACT_2721 (S)-3-Hydroxydodecanoyl-CoA+NAD<=>3-Oxododecanoyl-CoA+NADH+H At the beginning of this reaction, 1 molecule of '(S)-3-Hydroxydodecanoyl-CoA', and 1 molecule of 'NAD+' are present. At the end of this reaction, 1 molecule of 'H+', 1 molecule of '3-Oxododecanoyl-CoA', and 1 molecule of 'NADH' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'short chain 3-hydroxyacyl-CoA dehydrogenase homodimer'.<br> EC Number: 1.1.1.35 Pubmed8687463 Reactome Database ID Release 4377254 Reactome, http://www.reactome.org ReactomeREACT_242 Platelet alpha granule membrane components that are released on degranulation Converted from EntitySet in Reactome Reactome DB_ID: 964721 Reactome Database ID Release 43964721 Reactome, http://www.reactome.org ReactomeREACT_25913 3-Oxododecanoyl-CoA+CoA-SH<=>Decanoyl-CoA At the beginning of this reaction, 1 molecule of '3-Oxododecanoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Decanoyl-CoA', and 1 molecule of 'Acetyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.<br> EC Number: 2.3.1.155 Pubmed1550553 Reactome Database ID Release 4377309 Reactome, http://www.reactome.org ReactomeREACT_1749 factor Vi heavy chain Reactome DB_ID: 141054 Reactome Database ID Release 43141054 Reactome, http://www.reactome.org ReactomeREACT_5569 Decanoyl-CoA+FAD<=>trans-Dec-2-enoyl-CoA+FADH2 At the beginning of this reaction, 1 molecule of 'Decanoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'trans-Dec-2-enoyl-CoA', and 1 molecule of 'FADH2' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'MCAD acyl-CoA dehydrogenase homotetramer'.<br> EC Number: 1.3.99.3 Pubmed13295225 Pubmed3597357 Reactome Database ID Release 4377345 Reactome, http://www.reactome.org ReactomeREACT_1862 Heparin Reactome DB_ID: 140798 Reactome Database ID Release 43140798 Reactome, http://www.reactome.org ReactomeREACT_4737 trans-Dec-2-enoyl-CoA+H2O<=>(S)-Hydroxydecanoyl-CoA At the beginning of this reaction, 1 molecule of 'trans-Dec-2-enoyl-CoA', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of '(S)-Hydroxydecanoyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'enoyl-CoA hydratase hexamer'.<br> EC Number: 4.2.1.17 Pubmed13295248 Reactome Database ID Release 4377344 Reactome, http://www.reactome.org ReactomeREACT_583 Histidine/di-peptides Converted from EntitySet in Reactome Reactome DB_ID: 427984 Reactome Database ID Release 43427984 Reactome, http://www.reactome.org ReactomeREACT_20346 Histidine/di-peptides Converted from EntitySet in Reactome Reactome DB_ID: 428003 Reactome Database ID Release 43428003 Reactome, http://www.reactome.org ReactomeREACT_20464 Kinesins Converted from EntitySet in Reactome Reactome DB_ID: 984770 Reactome Database ID Release 43984770 Reactome, http://www.reactome.org ReactomeREACT_26925 microtubule Reactome DB_ID: 190599 Reactome Database ID Release 43190599 Reactome, http://www.reactome.org ReactomeREACT_10446 Chromokinesin monomers Converted from EntitySet in Reactome Reactome DB_ID: 984725 Reactome Database ID Release 43984725 Reactome, http://www.reactome.org ReactomeREACT_25504 Chromokinesin dimers Converted from EntitySet in Reactome Reactome DB_ID: 984722 Reactome Database ID Release 43984722 Reactome, http://www.reactome.org ReactomeREACT_26861 Histone H3 mono- or unmethylated at K9 Converted from EntitySet in Reactome Reactome DB_ID: 997233 Reactome Database ID Release 43997233 Reactome, http://www.reactome.org ReactomeREACT_27021 Promotor region of beta-globin Reactome DB_ID: 1008228 Reactome Database ID Release 431008228 Reactome, http://www.reactome.org ReactomeREACT_25634 Interleukin-1 family Converted from EntitySet in Reactome Reactome DB_ID: 449063 Reactome Database ID Release 43449063 Reactome, http://www.reactome.org ReactomeREACT_24453 Interleukin-1 family N-terminal propeptides Converted from EntitySet in Reactome Reactome DB_ID: 449026 Reactome Database ID Release 43449026 Reactome, http://www.reactome.org ReactomeREACT_24044 Interleukin-1 family Converted from EntitySet in Reactome Reactome DB_ID: 449027 Reactome Database ID Release 43449027 Reactome, http://www.reactome.org ReactomeREACT_24480 Histone H3 mono or di-methylated at K9 Converted from EntitySet in Reactome Reactome DB_ID: 997256 Reactome Database ID Release 43997256 Reactome, http://www.reactome.org ReactomeREACT_27055 REST DNA binding sites Reactome DB_ID: 996771 Reactome Database ID Release 43996771 Reactome, http://www.reactome.org ReactomeREACT_26991 f-actin Reactome DB_ID: 994160 Reactome Database ID Release 43994160 Reactome, http://www.reactome.org ReactomeREACT_25435 trans-octadec-2-enoyl-CoA + NADPH + H+ => stearoyl-CoA + NADP+ Authored: D'Eustachio, P, 2010-03-14 Pubmed12482854 Reactome Database ID Release 43548831 Reactome, http://www.reactome.org ReactomeREACT_22330 Trans-2,3-enoyl-CoA reductase (TECR) catalyzes the reaction of trans-octadec-2-enoyl-CoA and NADPH + H+ to form stearoyl-CoA and NADP+. This activity of TECR protein and its localization to the endoplasmic reticulum membrane was established in studies of transfected cells expressing the protein (Moon and Horton 2003). 3-hydroxyoctadecanoyl-CoA => trans-octadec-2-enoyl-CoA + H2O Authored: D'Eustachio, P, 2010-03-14 EC Number: 4.2.1.74 Edited: D'Eustachio, P, 2010-03-14 Pubmed16564093 Pubmed4379659 Reactome Database ID Release 43548810 Reactome, http://www.reactome.org ReactomeREACT_22293 Studies of the overall process of very long chain fatty acid biosynthesis have established that the reaction of 3-hydroxyoctadecanoyl-CoA to form trans-octadec-2-enoyl-CoA and H2O is part of the process but the human dehydratase that catalyzes the reaction has not been identified (Jakobsson et al. 2006; Nugteren 1965). 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) + NADPH + H+ => 3-hydroxyoctadecanoyl-CoA + NADP+ Authored: D'Eustachio, P, 2010-03-14 EC Number: 1.1.1.211 Edited: D'Eustachio, P, 2010-03-14 Hydroxysteroid (17-beta) dehydrogenase 12 (HSD17B12) catalyzes the reaction of 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) and NADPH + H+ to form 3-hydroxyoctadecanoyl-CoA and NADP+. This activity of HSD17B12 protein and its localization to the endoplasmic reticulum membrane was established in studies of transfected cells expressing the protein (Moon and Horton 2003). Pubmed12482854 Reactome Database ID Release 43548818 Reactome, http://www.reactome.org ReactomeREACT_22155 arachidoyl-CoA + malonyl-CoA => 3-oxobehenoyl-CoA + CO2 + CoASH [ELOVL7] Authored: D'Eustachio, P, 2010-03-14 Edited: D'Eustachio, P, 2010-03-14 Elongation of very long chain fatty acids protein 7 (ELOVL7) catalyzes the reaction of arachidoyl-CoA (C20:0) and malonyl-CoA to form 3-oxobehenoyl-CoA, CO2, and CoASH. ELOVL7 is localized to the endoplasmic reticulum in transfected cells expressing the cloned cDNA (Tamura et al. 2009). Pubmed19826053 Reactome Database ID Release 43548815 Reactome, http://www.reactome.org ReactomeREACT_22192 Conversion of Glycerol to Glycerol-3-phosphate Authored: Gopinathrao, G, 2003-10-02 00:00:00 EC Number: 2.7.1.30 Glycerol can be a source for glycerol-3-phosphate, in which case, a phosphate form ATP is transferred to glycerol by glycerol kinase forming glycerol-3-phosphate and ADP.<BR> Pubmed15845384 Reactome Database ID Release 4375887 Reactome, http://www.reactome.org ReactomeREACT_724 DHAP is converted to G3P by GPD1/GPD1L Authored: Gopinathrao, G, 2003-10-02 00:00:00 Conversion of Dihydroxyacetone Phosphate to Glycerol -3- phosphate Dihydroxyacetone phosphate (DHAP) is converted to glycerol-3-phosphate (G3P) by glycerol-3-phosphate dehydrogenase (GPD1) or by glycerol-3-phosphate dehydrogenase-like (GPD1L) enzymes (Ou et al. 2006, Valdivia et al. 2009). The active forms of both enzymes are homodimers. This reaction may be found in white adipose tissues where glycerol-3-kinase activity is not observed in sufficient levels. GPD1/GPD1L reduces dihydroxyacetone phosphate with NADH donating electrons to this reduction. EC Number: 1.1.1.8 Edited: Williams, MG, 2011-08-12 Pubmed16460752 Pubmed19666841 Reactome Database ID Release 4375889 Reactome, http://www.reactome.org ReactomeREACT_1146 PathwayStep4459 palmitoyl-CoA + malonyl-CoA => 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) + CO2 + CoASH [ELOVL6] Authored: D'Eustachio, P, 2010-03-14 Edited: D'Eustachio, P, 2010-05-08 Elongation of very long chain fatty acids protein 6 (ELOVL6) catalyzes the reaction of palmitoyl-CoA and malonyl-CoA to form 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA), CO2, and CoASH (Shimamura et al. 2009). The localization of ELOVL6 to the endoplasmic reticulum membrane is inferred from that experimentally determined for the homologous mouse protein (Moon et al. 2001; Matsuzaka et al. 2002). Pubmed11567032 Pubmed12032166 Pubmed19505953 Reactome Database ID Release 43548842 Reactome, http://www.reactome.org ReactomeREACT_22219 PathwayStep4458 arachidonoyl-CoA + malonyl-CoA => 3-oxo-(7,10,13,16)-docosatetraenoyl-CoA + CO2 + CoASH [ELOVL5] Authored: D'Eustachio, P, 2010-03-14 Edited: D'Eustachio, P, 2010-05-08 Elongation of very long chain fatty acids protein 5 (ELOVL5) catalyzes the reaction of arachidonyl-CoA and malonyl-CoA to form 3-oxo-(7,10,13,16)-docosatetraenoyl-CoA, CO2, and CoASH. Localization of ELOVL5 to the endoplasmic reticulum membrane is inferred from that of other human ELOVL proteins; its catalytic activity has been studied in ELO- yeast cells expressing human ELOVL5 protein (Leonard et al. 2000). Pubmed10970790 Reactome Database ID Release 43548800 Reactome, http://www.reactome.org ReactomeREACT_22350 PathwayStep4457 lignoceroyl-CoA + malonyl-CoA => 3-oxocerotoyl-CoA + CO2 + CoASH [ELOVL4] Authored: D'Eustachio, P, 2010-03-14 Edited: D'Eustachio, P, 2010-05-08 Elongation of very long chain fatty acids protein 4 (ELOVL4) catalyzes the reaction of lignoceroyl-CoA and malonyl-CoA to form 3-oxocerotoyl-CoA, CO2, and CoASH. ELOVL4 is abundant in retinal cells, where it is localized to the endoplasmic reticulum membrane (Grayson and Molday 2005). The catalytic activity of ELOVL4 has not been examined directly but is inferred from that of the homologous mouse protein, which is also active on polyunsaturated fatty acids (PUFAs) (Agbada et al. 2008). Pubmed16036915 Pubmed18728184 Reactome Database ID Release 43548830 Reactome, http://www.reactome.org ReactomeREACT_22242 PathwayStep4456 palmitoyl-CoA + malonyl-CoA => 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) + CO2 + CoASH [ELOVL3] Authored: D'Eustachio, P, 2010-03-14 Edited: D'Eustachio, P, 2010-05-08 Elongation of very long chain fatty acids protein 3 (ELOVL3) catalyzes the reaction of palmitoyl-CoA and malonyl-CoA to form 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA), CO2, and CoASH. Indirect data from studies of transfected cells expressing ELOVL3 are consistent with its localization to the endoplasmic reticulum and activity on palmitoyl-CoA (Kobayashi et al. 2007). Pubmed17583696 Reactome Database ID Release 43548825 Reactome, http://www.reactome.org ReactomeREACT_22133 PathwayStep4465 SCF-beta-TrCP2 complex Reactome DB_ID: 1168592 Reactome Database ID Release 431168592 Reactome, http://www.reactome.org ReactomeREACT_119643 has a Stoichiometric coefficient of 1 PathwayStep4466 NF-kappaB:p-IkB:SCF-betaTrCP Reactome DB_ID: 1168617 Reactome Database ID Release 431168617 Reactome, http://www.reactome.org ReactomeREACT_119791 has a Stoichiometric coefficient of 1 PathwayStep4463 NF-kappaB p65:p65:p-IKB Reactome DB_ID: 1168594 Reactome Database ID Release 431168594 Reactome, http://www.reactome.org ReactomeREACT_119897 has a Stoichiometric coefficient of 1 PathwayStep4464 SCF-beta-TrCp1/2 Converted from EntitySet in Reactome Reactome DB_ID: 1168601 Reactome Database ID Release 431168601 Reactome, http://www.reactome.org ReactomeREACT_119753 SCF-beta-TrCp1 or SCF-beta-TrCP2 PathwayStep4461 NF-kappaB p50:c-Rel:ub-p-IKB Reactome DB_ID: 1168587 Reactome Database ID Release 431168587 Reactome, http://www.reactome.org ReactomeREACT_119666 has a Stoichiometric coefficient of 1 PathwayStep4462 NF-kappaB p50:p65:ub-p-IKB Reactome DB_ID: 1168590 Reactome Database ID Release 431168590 Reactome, http://www.reactome.org ReactomeREACT_119022 has a Stoichiometric coefficient of 1 NF-kappaB p50/p65/c-Rel:ub-p-IKB Converted from EntitySet in Reactome NF-kappa-B (p50, p65, c-Rel):Ubiquitinated p-IKB Reactome DB_ID: 1168613 Reactome Database ID Release 431168613 Reactome, http://www.reactome.org ReactomeREACT_120175 PathwayStep4460 NF-KappaB p50:p50:ub-p-IKBA Reactome DB_ID: 1168606 Reactome Database ID Release 431168606 Reactome, http://www.reactome.org ReactomeREACT_119047 has a Stoichiometric coefficient of 1 NF-kappaB p65:p65:ub-p-IkB Reactome DB_ID: 1168596 Reactome Database ID Release 431168596 Reactome, http://www.reactome.org ReactomeREACT_119078 has a Stoichiometric coefficient of 1 NF-kappaB p50/p65/c-Rel Dimer Converted from EntitySet in Reactome Reactome DB_ID: 1168598 Reactome Database ID Release 431168598 Reactome, http://www.reactome.org ReactomeREACT_118873 palmitoyl-CoA+FAD<=>trans-Hexadec-2-enoyl-CoA+FADH2 At the beginning of this reaction, 1 molecule of 'palmitoyl-CoA', and 1 molecule of 'FAD' are present. At the end of this reaction, 1 molecule of 'FADH2', and 1 molecule of 'trans-Hexadec-2-enoyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'acyl-CoA dehydrogenase activity' of 'VLCAD acyl-CoA dehydrogenase homodimer'.<br> EC Number: 1.3.99.3 Pubmed13295225 Pubmed1540149 Reactome Database ID Release 4377299 Reactome, http://www.reactome.org ReactomeREACT_398 Conversion of Diacylglycerol to Triacylglycerol [DGAT2] 1,2-diacyl-glycerol + acyl-CoA => triacylglycerol + CoASH [DGAT2] Diacylglycerol O-acyltransferase 1 (DGAT2) associated with the endoplasmic reticulum membrane catalyzes the reaction of 1,2-diacyl-glycerol and acyl-CoA to form triacylglycerol + CoASH (Cases et al. 2001, Wakimoto et al. 2003). EC Number: 2.3.1.20 Pubmed11481335 Pubmed14521909 Reactome Database ID Release 43549192 Reactome, http://www.reactome.org ReactomeREACT_22179 (S)-3-Hydroxyhexadecanoyl-CoA+NAD<=>3-Oxopalmitoyl-CoA+NADH+H At the beginning of this reaction, 1 molecule of 'NAD+', and 1 molecule of '(S)-3-Hydroxyhexadecanoyl-CoA' are present. At the end of this reaction, 1 molecule of '3-Oxopalmitoyl-CoA', 1 molecule of 'H+', and 1 molecule of 'NADH' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the '3-hydroxyacyl-CoA dehydrogenase activity' of 'Trifunctional Protein'.<br> EC Number: 1.1.1.35 Pubmed1550553 Reactome Database ID Release 4377303 Reactome, http://www.reactome.org ReactomeREACT_488 trans-Hexadec-2-enoyl-CoA+H2O<=>(S)-3-Hydroxyhexadecanoyl-CoA At the beginning of this reaction, 1 molecule of 'H2O', and 1 molecule of 'trans-Hexadec-2-enoyl-CoA' are present. At the end of this reaction, 1 molecule of '(S)-3-Hydroxyhexadecanoyl-CoA' is present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'enoyl-CoA hydratase activity' of 'Trifunctional Protein'.<br> EC Number: 4.2.1.17 Pubmed1550553 Reactome Database ID Release 4377301 Reactome, http://www.reactome.org ReactomeREACT_1513 3-Oxopalmitoyl-CoA+CoA-SH<=>myristoyl-CoA At the beginning of this reaction, 1 molecule of '3-Oxopalmitoyl-CoA', and 1 molecule of 'CoA' are present. At the end of this reaction, 1 molecule of 'Acetyl-CoA', and 1 molecule of 'myristoyl-CoA' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'transferase activity' of 'Trifunctional Protein'.<br> EC Number: 2.3.1.155 Pubmed1550553 Reactome Database ID Release 4377304 Reactome, http://www.reactome.org ReactomeREACT_582 PathwayStep4449 G3P is acylated to 1-acyl LPA by AGPAT6 Authored: Gopinathrao, G, 2003-10-02 00:00:00 Conversion of glycerol-3-phosphate to lysophosphatidic acid EC Number: 2.3.1.15 Edited: Williams, MG, 2011-08-12 Glycerol-3-phosphate (G3P) is acylated to 1-acyl lysophosphatidic acid (LPA) by the enzymes glycerol-3-phosphate acyltransferase 4 (AGPAT6) at the endoplasmic reticulum (ER) membrane (Cao et al., 2006; Chen et al., 2008). Pubmed17170135 Pubmed18238778 Pubmed18718904 Reactome Database ID Release 43549112 Reactome, http://www.reactome.org ReactomeREACT_22419 glycerol 3-phosphate + acyl-CoA => 1-acylglycerol 3-phosphate + CoASH [ER membrane-associated] PathwayStep4446 1-acyl LPA is acylated to PA by AGPAT (LPAAT) 1-acyl-glycerol 3-phosphate + acyl-CoA => 1,2-diacyl-glycerol 3-phosphate + CoASH At the endoplasmic reticulum (ER) membrane, 1-acyl-lysophosphatidic acid (LPA) is acylated to phosphatidic acid (PA) by the enzymes 1-acyl-sn-glycerol-3-phosphate acyltransferases (AGPAT1 through 11), and lysophosphatidylcholine acyltransferase (LPCAT1) (Aguado and Campbell 1998).<br><br>See recent review by Agarwal (2012, in press).<br><br>AGPAT1, 2, 3 and LPCAT1 have been characterized biochemically (AGPAT1, 2: Yamashita et al. 2007, West et al. 1997, Aguado and Campbell 1998, Gale et al. 2006; AGPAT3: Agarwal et al. 2006; LPCAT1: Nakanishi et al. 2006, Chen et al. 2006). Two additional proteins, AGPAT4 and AGPAT5, are inferred to have such activity based on studies of homologous mouse enzymes (Lu et al. 2005). These enzymes differ in their tissue specific patterns of expression in the body and in their preferences for specific acyl CoA molecules (Shindou and Shimizu 2009; Takeuchi and Reue 2009).<br> EC Number: 2.3.1.51 Pubmed15367102 Pubmed16495223 Pubmed16620771 Pubmed16704971 Pubmed16864775 Pubmed17707131 Pubmed18718904 Pubmed19336658 Pubmed9212163 Pubmed9461603 Reactome Database ID Release 4375885 Reactome, http://www.reactome.org ReactomeREACT_2042 lysophosphatidic acid + fatty acyl CoA => phosphatidic acid + CoA (1) PathwayStep4445 Conversion of glycerol-3-phosphate to lysophosphatidic acid Authored: Gopinathrao, G, 2003-10-02 00:00:00 EC Number: 2.3.1.15 Either of GPAM or GPAT2 (glycerol-3-phosphate acyltransferase, mitochondrial; glycerol-3-phosphate acyltransferase 2, mitochondrial) associated with the outer mitochondrial membrane catalyzes the reaction of cytosolic glycerol 3-phosphate and acyl-CoA to form 1-acylglycerol 3-phosphate and CoASH. The biochemical properties and location of human GPAM have been established through studies of the recombinant protein (Chen et al. 2008); those features of GPAT2 have been inferred from the properties of its rat homologue and those of GPAM. GPAM and GPAT2 differ in their their preferences for acyl-CoA substrates (Shindou & Shimizu 2009) and in their expression patterns in the body (Takeuchi & Reue 2009). Pubmed18238778 Pubmed18718904 Pubmed19336658 Reactome Database ID Release 4375886 Reactome, http://www.reactome.org ReactomeREACT_839 glycerol 3-phosphate + acyl-CoA => 1-acylglycerol 3-phosphate + CoASH [mitochondrial membrane-associated] PathwayStep4448 Conversion of Diacylglycerol to Triacylglycerol [DGAT1] 1,2-diacyl-glycerol + acyl-CoA => triacylglycerol + CoASH [DGAT1] EC Number: 2.3.1.20 Pubmed11672446 Reactome Database ID Release 4375900 Reactome, http://www.reactome.org ReactomeREACT_659 Tetrameric diacylglycerol O-acyltransferase 1 (DGAT1) associated with the endoplasmic reticulum membrane catalyzes the reaction of 1,2-diacyl-glycerol and acyl-CoA to form triacylglycerol + CoASH (Cheng et al. 2001). NF-kappaB p50/p65/c-Rel Dimer Converted from EntitySet in Reactome Reactome DB_ID: 1168608 Reactome Database ID Release 431168608 Reactome, http://www.reactome.org ReactomeREACT_119326 PathwayStep4447 Conversion of Phosphatidic Acid to Diacylglycerol 1,2-diacyl-glycerol 3-phosphate + H2O => 1,2-diacyl-glycerol + orthophosphate Authored: Gopinathrao, G, 2003-10-02 00:00:00 EC Number: 3.1.3.4 Lipin proteins LPIN1, 2, and 3, associated with the endoplasmic reticulum membrane, can each catalyze the hydrolysis of phosphatidate to yield 1,2-diacyl-glycerol and orthophosphate. The activities of LPIN1 and LPIN2 have been established experimentally (Grimsey et al. 2008); that of LPIN3 is inferred from its structural similarities both to its human paralogues and to its mouse ortholog (Donkor et al. 2007). Only LPIN1 has been shown to be stably associated with the endoplasmic reticulum, but all three enzymes appear to be catalytically active at that location (Grimsey et al. 2008; Donkor et al. 2007). Pubmed17158099 Pubmed18694939 Reactome Database ID Release 4375899 Reactome, http://www.reactome.org ReactomeREACT_395 PathwayStep4452 NF-kappaB p50:c-Rel Reactome DB_ID: 1168614 Reactome Database ID Release 431168614 Reactome, http://www.reactome.org ReactomeREACT_119839 has a Stoichiometric coefficient of 1 PathwayStep4453 NF-kappaB p65:p65 Reactome DB_ID: 1168591 Reactome Database ID Release 431168591 Reactome, http://www.reactome.org ReactomeREACT_120184 has a Stoichiometric coefficient of 2 PathwayStep4454 NF-kappaB p50:p50 Reactome DB_ID: 1168597 Reactome Database ID Release 431168597 Reactome, http://www.reactome.org ReactomeREACT_120137 has a Stoichiometric coefficient of 2 PathwayStep4455 p-RasGRP1,3:DAG Phosphorylated RasGRP1/3:Diacylglycerol Phosphorylated RasGRP3:Diacylglycerol and phosphorylated RasGRP1:Diacylglycerol Reactome DB_ID: 1168369 Reactome Database ID Release 431168369 Reactome, http://www.reactome.org ReactomeREACT_118884 has a Stoichiometric coefficient of 1 E1 bound ubiquitin Reactome DB_ID: 976164 Reactome Database ID Release 43976164 Reactome, http://www.reactome.org ReactomeREACT_76108 has a Stoichiometric coefficient of 1 Ub:E2s Reactome DB_ID: 976165 Reactome Database ID Release 43976165 Reactome, http://www.reactome.org ReactomeREACT_76303 Ubiquitin:E2 conjugating enzymes has a Stoichiometric coefficient of 1 PathwayStep4450 SCF RBX1-CUL1-SKP1-CDC4 Reactome DB_ID: 976110 Reactome Database ID Release 43976110 Reactome, http://www.reactome.org ReactomeREACT_76392 SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex has a Stoichiometric coefficient of 1 PathwayStep4451 RBX1-CUL2-EloB/C-VHL ECV E3 ligase complex Reactome DB_ID: 976093 Reactome Database ID Release 43976093 Reactome, http://www.reactome.org ReactomeREACT_76823 has a Stoichiometric coefficient of 1 VBC complex Reactome DB_ID: 390483 Reactome Database ID Release 43390483 Reactome, http://www.reactome.org ReactomeREACT_76227 has a Stoichiometric coefficient of 1 Inactivation of over-expressed wild type EGFR by Cetuximab recombinant antibody Authored: Orlic-Milacic, M, 2011-11-04 Cetuximab binds to the extracellular domain of EGFR and blocks ligand binding, leading to receptor inactivation, internalization and degradation. Cetuximab is approved for combination therapy and monotherapy of metastatic colorectal cancer and advanced squamous cell carcinoma of head and neck in patients whose tumors over-express wild-type EGFR protein, usually due to amplification of EGFR gene. Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15269313 Pubmed15837620 Pubmed16314626 Reactome Database ID Release 431248677 Reactome, http://www.reactome.org ReactomeREACT_115741 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Transport of Citrate from Mitochondrial Matrix to cytosol Reactome Database ID Release 4375849 Reactome, http://www.reactome.org ReactomeREACT_1605 SLC25A1, in the inner mitochondrial membrane, mediates the exchange of mitochondrial citrate for cytosolic malate. Covalent tyrosine kinase inhibitors bind and inhibit wild-type EGF:EGFR dimers Authored: Orlic-Milacic, M, 2011-11-04 Covalent (irreversible) TKIs, pelitinib, WZ4002, HKI-272, canertinib and afatinib, inhibit the wild-type EGFR through formation of the covalent bond with the cysteine residue C397. Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed20033049 Reactome Database ID Release 431225978 Reactome, http://www.reactome.org ReactomeREACT_116096 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 phosphorylated perilipin + H2O -> perilipin + orthophosphate Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed9755872 Rat perilipin is dephosphorylated by protein phosphatase 1 (Clifford et al. 1998). All three protein phosphatase 1 isoforms appear competent to carry out this reaction and there are no data to indicate which one preferentially acts on perilipin in vivo. Dephosphorylation of human perilipin has not been studied in detail, so the human reaction is inferred from the well-studied rat one. Reactome Database ID Release 43163568 Reactome, http://www.reactome.org ReactomeREACT_403 Amyloid precursor proteins form ordered fibrils Amyloid fibril formation is associated with a wide range of diseases (Chiti & Dobson 2006), thoughthe accumulation and deposition of fibrillar material does not correlate well with disease pathogenesis and it is now widely believed that oligomeric amyloid forms are largely responsible for the cytotoxic effects of amyloid (Glabe 2009). Fibrils have been described as more like crystalline polymer structures than the protein monomers they are derived from (Wetzel et al. 2007). Fibril formation is usually preceded by the association of monomers into oligomeric structures (Kodali & Wetzel 2007). For Beta-amyloid, these are spherical structures with around 12 units (Bernstein et al. 2005). Larger structures called protofibrils are also observed, non-spherical filamentous structures lacking a periodic substructure (Goldsbury 2005). Authored: Jupe, S, 2010-10-15 Edited: Jupe, S, 2011-04-08 Pubmed10391242 Pubmed10411933 Pubmed11401442 Pubmed11467836 Pubmed1270801 Pubmed15713083 Pubmed15962837 Pubmed16095615 Pubmed16756495 Pubmed17198370 Pubmed17251001 Pubmed1837051 Pubmed18449172 Pubmed18484335 Pubmed1849145 Pubmed2118650 Pubmed2195544 Pubmed279930 Pubmed2900981 Pubmed3035556 Pubmed3053705 Pubmed3080684 Pubmed3094007 Pubmed3142462 Pubmed8097946 Pubmed8159701 Pubmed8464497 Pubmed8490014 Pubmed8870004 Pubmed9006323 Pubmed9054935 Pubmed9862427 Reactome Database ID Release 43977136 Reactome, http://www.reactome.org ReactomeREACT_75876 Reviewed: Perry, G, 2011-04-08 phosphorylated HSL + H2O -> HSL + orthophosphate Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10940339 Pubmed2822414 Pubmed8240253 Rat HSL is inactivated by dephosphorylation. The catalyst of this reaction is unknown. Protein phosphatases 1 and 2A are both abundant in rat adipocytes and both are active on HSL (Olsson and Belfrage 1987; Wood et al. 1993). Whether these enzymes act on phosphate groups attached to serine residues 659 and 660 of HSL is unknown, however (Holm et al. 2000). Although the reaction is annotated as though the phosphatase acts on phosphorylated HSL monomers, this also is unknown: does the HSL:FABP complex dissociate before HSL dephosphorylation (as implied here), or does dephosphorylation of HSL drive dissociation of the complex?<p>Dephosphorylation of human HSL has not been studied in detail, so the human reaction is inferred from the well-studied rat one. Reactome Database ID Release 43163489 Reactome, http://www.reactome.org ReactomeREACT_233 Serum amyloid P-component forms homopentamers Authored: Jupe, S, 2010-10-15 Edited: Jupe, S, 2011-04-08 Pubmed8114934 Reactome Database ID Release 43976723 Reactome, http://www.reactome.org ReactomeREACT_75902 Reviewed: Perry, G, 2011-04-08 Serum amyloid P component (SAP) is a member of the pentraxin family, characterized by the formation of pentameric ring structures. Each member of the ring has two associated calcium ions. SAP is an acute phase reactant, highly induced by IL-6. It has 50% homology with the related C-reactive peptide. has a Stoichiometric coefficient of 10 has a Stoichiometric coefficient of 5 2-acylglycerol + H2O -> glycerol + fatty acid Authored: D'Eustachio, P, 2005-05-02 18:38:43 EC Number: 3.1.1.23 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed1249056 Pubmed3955067 Rat monoacylglycerol lipase (MGLL) catalyzes the hydrolysis of 2-acylglycerol to yield glycerol + fatty acid (Tornqvist and Belfrage 1976; Fredrikson et al. 1986). Localization of the enzyme to lipid particles is plausible, given its low solubility and its involvement in acylglycerol metabolism, but this localization has not been directly experimentally verified. The human reaction is inferred from the well-studied rat one. Reactome Database ID Release 43163595 Reactome, http://www.reactome.org ReactomeREACT_594 HSP90 is inactivated by binding to benzaquinoid ansamycins Authored: Orlic-Milacic, M, 2011-11-04 Benzoquinoid ansamycins (geldanamycin, herbimycin, and geldanamycin derivatives 17-AAG, 17-DMAG and IPI-504) are antitumor antibiotics that inactivate HSP90 by binding to its substrate-binding pocket. Edited: D'Eustachio, P, 2011-11-07 Edited: Jassal, B, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed9108479 Reactome Database ID Release 431218824 Reactome, http://www.reactome.org ReactomeREACT_115865 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 diacylglycerol + H2O -> 2-acylglycerol + fatty acid Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed6643478 Rat HSL catalyzes the hydrolysis of diacylglycerol to yield 2-acylglycerol + fatty acid (Fredrikson and Belfrage 1983). The human event has not been studied in detail and is inferred from the rat one. Reactome Database ID Release 43163402 Reactome, http://www.reactome.org ReactomeREACT_731 triacylglycerol + H2O -> diacylglycerol + fatty acid Activated rat HSL at the lipid particle hydrolyzes triacylglycerol to yield diacylglycerol + fatty acid. In vitro, activated partially purified HSL catalyzes this reaction at only about two times the rate measured with non-activated enzyme (Fredrikson et al. 1981). The much greater rate increase caused by HSL phosphorylation in vivo appears to be due to its phosphorylation-dependent translocation to the surface of the lipid particle (Birnbaum 2003).<p>HSL-mediated triacylglycerol hydrolysis in humans has not been studied in detail, so the human reaction is inferred from the well-studied rat one. Authored: D'Eustachio, P, 2005-05-02 18:38:43 EC Number: 3.1.1.3 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed12810703 Pubmed7240206 Reactome Database ID Release 43163551 Reactome, http://www.reactome.org ReactomeREACT_538 Covalent tyrosine kinase inhibitors bind and inactivate EGFR kinase domain mutant dimers resistant to non-covalent tyrosine kinase inhibitors Authored: Orlic-Milacic, M, 2011-11-04 Covalent (irreversible) tyrosine kinase inhibitors (TKIs), pelitinib, WZ4002, HKI-272, canertinib and afatinib, form a covalent bond with the EGFR cysteine residue C397 and inhibit trans-autophosphorylation of mutants resistant to non-covalent TKIs. However, effective concentrations of covalent TKIs also inhibit wild type EGFR, resulting in severe side effects. Hence, covalent TKIs have not shown much promise as therapeutics. Edited: D'Eustachio, P, 2011-11-07 Edited: Jassal, B, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed20033049 Pubmed20966921 Reactome Database ID Release 431220611 Reactome, http://www.reactome.org ReactomeREACT_115744 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 cholesterol ester + H2O -> cholesterol + fatty acid Activated rat HSL hydrolyzes cholesterol ester to yield cholesterol + fatty acid (Fredrikson et al. 1981). The human reaction has not been studied in detail, and is inferred from the well-characterized rat one. Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed7240206 Reactome Database ID Release 43163432 Reactome, http://www.reactome.org ReactomeREACT_764 Non-covalent tyrosine kinase inhibitors bind and inactivate sensitive ligand-responsive EGFR cancer mutants Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Jassal, B, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Non-covalent (reversible) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, lapatinib and vandetanib, selectively inhibit EGFR-stimulated tumor cell growth by blocking EGFR mutant autophosphorylation through competitive inhibition of ATP binding to the kinase domain. A number of EGFR kinase domain mutants and extracellular domain point mutants show increased senistivity to non-covalent TKIs compared with the wild-type EGFR. EGFR kinase domain mutants may be resistant to non-covalent TKIs due to primary or secondary mutations in the kinase domain that increase the affinity of the kinase domain for ATP, such as small insertions within exon 20, and substituion of threonine 790 with methionine (T790M). Pubmed17177598 Pubmed17349580 Reactome Database ID Release 431220610 Reactome, http://www.reactome.org ReactomeREACT_115609 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 phosphorylated HSL dimer + FABP4 -> phosphorylated HSL dimer:FABP4 complex Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10318917 Pubmed11682468 Pubmed15456755 Rat FABPA associates with HSL and increases the rate of triacylglycerol hydrolysis, possibly by sequestering the released fatty acids (Shen et al. 1999; Shen et al. 2001). A similar association of HSL and FABP4 at the lipid droplet surface has been demonstrated in human adipocytes (Smith et al. 2004). The stoichiometry of the fatty acid:FABP complex is unknown. This model implies that HSL-associated FABP loaded with fatty acid should exchange with unloaded, unassociated FABP, allowing HSL to continue to work efficiently while moving newly generated fatty acids away from the lipid particle. To date, there is no evidence for or against such a shuttling process. Reactome Database ID Release 43163549 Reactome, http://www.reactome.org ReactomeREACT_1140 PathwayStep4437 Phosphorylated HSL dimer translocates from the cytosol to the lipid particle Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In primary adipocytes from young rats and in adipocytes derived from 3T3-L1 cells in vitro, phosphorylated hormone-sensitive lipase translocates from the cytosol to the surfaces of lipid particles following the phosphorylation of perilipin (Clifford et al. 2000; Su et al. 2003; Sztalryd et al. 2003)<p>The human reaction is inferred from the well-studied rat one. Pubmed10671541 Pubmed12810697 Pubmed12832420 Reactome Database ID Release 43163554 Reactome, http://www.reactome.org ReactomeREACT_644 PathwayStep4436 perilipin + 2 ATP -> phosphorylated perilipin + 2 ADP Authored: D'Eustachio, P, 2005-05-02 18:38:43 EC Number: 2.7.11 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed12477720 Pubmed15111495 Pubmed2040638 Pubmed2905457 Pubmed7665999 Pubmed9733764 Rat perilipin, the major protein at the surfaces of cytosolic lipid particles in adipocytes and steroidogenic cells (Blanchette-Mackie et al. 1995), is phosphorylated by protein kinase A catalytic subunit (Greenberg et al. 1991) on serine residues 81, 223, and 277 (Tansey et al. 2003). All three serine residues and the adjoining sequences that mediate phosphorylation (Cohen 1988) are conserved in mouse perilipin, while only the first and third are conserved in human perilipin. By inference, PKA targets these three mouse and two human serines as well. Phosphorylated perilipin is redistributed on the droplet surfaces (Souza et al. 1998). While two isoforms of rat perilipin protein are found on lipid particles in adipocytes, only the larger isoform appears to regulate lipolysis (Tansey et al 2003). The single human and mouse isoforms of perilipin correspond to the large rat isoform. In mouse 3T3-L1 cells, perilipin phosphorylation requires the presence of caveolin-1 at the surface of the lipid particle (Cohen et al. 2004). This positive regulatory effect of caveolin-1 is inferred for rat and human. Reactome Database ID Release 43163418 Reactome, http://www.reactome.org ReactomeREACT_1734 has a Stoichiometric coefficient of 2 PathwayStep4435 PathwayStep4434 Formation of serum amyloid P decamer At physiological pH serum amyloid P component is a decamer of two pentameric rings lying face to face. This non-covalent interaction is readily dissociated by reducing the pH. Authored: Jupe, S, 2010-10-15 Edited: Jupe, S, 2011-04-08 Pubmed8114934 Reactome Database ID Release 43976817 Reactome, http://www.reactome.org ReactomeREACT_75878 Reviewed: Perry, G, 2011-04-08 has a Stoichiometric coefficient of 2 Amyloid fibrils have additional components Authored: Jupe, S, 2010-10-15 Edited: Jupe, S, 2011-04-08 In addition to the main fibril peptide, mature amyloid fibrils have additional components. Serum amyloid P component (SAP) binds to all types of amyloid fibrils and is a universal constituent of amyloid deposits. SAP binding protects amyloid fibrils from proteolytic degradation (Tennent et al. 1995, Westermark 2005). SAP may function as a chaperone for amyloid formation (Coker et al. 2000). Glycosaminoglycans (GAGs) and proteoglycans are found associated with all types of amyloid deposits (Alexandrescu 2005). Of the different types of GAG heparan sulfate and dermatan sulfate are the most prominent in amyloid deposits (Hirschfield & Hawkins, 2003). GAGs have been implicated in the nucleation of fibrils, they can also stabilize mature fibrils against dissociation (Yamaguchi et al. 2003) and proteolytic degradation (Gupta-Bansal et al. 1995). Perlecan coimmunolocalizes with all types of amyloids (Snow & Wright 1989), accelerating fibril formation (Castillo et al. 1998), stabilizing them once formed (Castillo et al. 1997), and protecting them from proteolytic degradation (Gupta-Bansal et al. 1995). ApoE tightly binds to soluble ABeta peptide forming complexes that resist dissociation; it also binds to ABeta in its fibril form (Bales et al. 2002). Pubmed10583407 Pubmed10812074 Pubmed118839 Pubmed12911560 Pubmed12962700 Pubmed14993413 Pubmed15576561 Pubmed16302959 Pubmed20807650 Pubmed2409350 Pubmed2682326 Pubmed7629198 Pubmed7753801 Pubmed9375678 Pubmed9568695 Reactome Database ID Release 43976734 Reactome, http://www.reactome.org ReactomeREACT_75905 Reviewed: Perry, G, 2011-04-08 PathwayStep4439 PathwayStep4438 Serum amyloid P binds DNA and chromatin Authored: Jupe, S, 2010-10-15 Edited: Jupe, S, 2011-04-08 Pubmed10371509 Pubmed2358775 Pubmed3675579 Pubmed8033412 Reactome Database ID Release 43977224 Reactome, http://www.reactome.org ReactomeREACT_75858 Reviewed: Perry, G, 2011-04-08 Serum amyloid P component (SAP) binds DNA and chromatin in a calcium dependent manner in physiological conditions (Pepys et al. 1987). This binding displaces H1-type histones (Butler et al. 1990), solubilizing chromatin which is otherwise insoluble in extracellular fluids. SAP may therefore participate in the in vivo handling of chromatin exposed by cell death. SAP knockout mice spontaneously develop antinuclear autoimmunity and severe glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune disease, suggesting that SAP binding may play a role in reducing the immunogenicity of chromatin and preventing autoimmunity (Bickerstaff et al. 1999). CARMA1:BCL10:MALT1:TAK1:IKK Reactome DB_ID: 1168620 Reactome Database ID Release 431168620 Reactome, http://www.reactome.org ReactomeREACT_118993 has a Stoichiometric coefficient of 1 PathwayStep4440 IKK Complex IKKA:IKKB:NEMO Reactome DB_ID: 1168621 Reactome Database ID Release 431168621 Reactome, http://www.reactome.org ReactomeREACT_118960 has a Stoichiometric coefficient of 1 p-CARMA1 Oligomer Reactome DB_ID: 1168616 Reactome Database ID Release 431168616 Reactome, http://www.reactome.org ReactomeREACT_119302 has a Stoichiometric coefficient of 2 CARMA1:MALT1:BCL10 Reactome DB_ID: 1168622 Reactome Database ID Release 431168622 Reactome, http://www.reactome.org ReactomeREACT_119308 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep4443 STIM1:TRPC1 Reactome DB_ID: 2089954 Reactome Database ID Release 432089954 Reactome, http://www.reactome.org ReactomeREACT_119530 has a Stoichiometric coefficient of 1 PathwayStep4444 CARMA1 oligomer Reactome DB_ID: 1169088 Reactome Database ID Release 431169088 Reactome, http://www.reactome.org ReactomeREACT_119167 has a Stoichiometric coefficient of 2 PathwayStep4441 PathwayStep4442 NF-kappa-B p50,/p65,/c-Rel:IKB Converted from EntitySet in Reactome Reactome DB_ID: 1168593 Reactome Database ID Release 431168593 Reactome, http://www.reactome.org ReactomeREACT_119154 NF-KappaB p50:p50:IKBA Reactome DB_ID: 1168605 Reactome Database ID Release 431168605 Reactome, http://www.reactome.org ReactomeREACT_119654 has a Stoichiometric coefficient of 1 CARMA1:BCL10:MALT1:TAK1 Reactome DB_ID: 1168619 Reactome Database ID Release 431168619 Reactome, http://www.reactome.org ReactomeREACT_119896 has a Stoichiometric coefficient of 1 Active IKK complex Inhibitor of KappaB kinase (IKK) Complex Reactome DB_ID: 727820 Reactome Database ID Release 43727820 Reactome, http://www.reactome.org ReactomeREACT_119869 has a Stoichiometric coefficient of 1 palmitoyl-CoA + malonyl-CoA => 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) + CO2 + CoASH [ELOVL1] Authored: D'Eustachio, P, 2010-03-14 Edited: D'Eustachio, P, 2010-05-08 Elongation of very long chain fatty acids protein 1 (ELOVL1) catalyzes the reaction of palmitoyl-CoA and malonyl-CoA to form 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA), CO2, and CoASH. Limited data are available for human ELOVL1 protein. Its localization to the endoplasmic reticulum membrane and catalytic activity are inferred from the properties of better-studied human ELOVL proteins (Jakobsson et al. 2006; Shimamura et al. 2009). Pubmed16564093 Pubmed19505953 Reactome Database ID Release 43548814 Reactome, http://www.reactome.org ReactomeREACT_22270 palmitate + CoASH + ATP => palmitoyl-CoA + AMP + pyrophosphate + H2O [ACSL6] Acyl-CoA synthetase long-chain family member 6 (ACSL6) associated with the plasma membrane catalyzes the reaction of palmitate, CoASH, and ATP to form palmitoyl-CoA, AMP, pyrophosphate, and water. In the body, ACSL6 is found in red blood cells. It is active on oleic acid as well as palmitic acid (Malhotra et al. 1999). Authored: D'Eustachio, P, 2010-03-14 EC Number: 6.2.1.3 Edited: Jupe, S, 2010-05-18 Pubmed10548543 Reactome Database ID Release 43548792 Reactome, http://www.reactome.org ReactomeREACT_22247 palmitoyl-CoA + malonyl-CoA => 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) + CO2 + CoASH [ELOVL2] Authored: D'Eustachio, P, 2010-03-14 Edited: D'Eustachio, P, 2010-05-08 Elongation of very long chain fatty acids protein 2 (ELOVL2) catalyzes the reaction of palmitoyl-CoA and malonyl-CoA to form 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA), CO2, and CoASH. Indirect data from studies of transfected cells expressing ELOVL2 are consistent with its localization to the endoplasmic reticulum and activity on palmitoyl-CoA. It may also catalyze the condensation of arachidonyl-CoA with malonyl-CoA (Kobayashi et al. 2007). Pubmed17583696 Reactome Database ID Release 43548805 Reactome, http://www.reactome.org ReactomeREACT_22097 palmitate + CoASH + ATP => palmitoyl-CoA + AMP + pyrophosphate + H2O [ACSL3] EC Number: 6.2.1.3 Membrane-associated acyl-CoA synthetase long-chain family member 3 (ACSL3) catalyzes the reaction of palmitate, CoASH, and ATP to form palmitoyl-CoA, AMP, pyrophosphate, and water. The enzyme is probably associated specifically with the endoplasmic reticulum membrane, and can also associate with lipid droplets. It is active on oleic acid as well as on palmitic acid (Fujimoto ea 2007). Pubmed17379924 Reactome Database ID Release 4375880 Reactome, http://www.reactome.org ReactomeREACT_930 Conversion of malonyl-CoA and acetyl-CoA to palmitate Authored: Joshi-Tope, G, 2003-10-23 17:11:00 Cytosolic fatty acid synthase (FAS) complex catalyzes the reaction of acetyl-CoA with 7 malonyl-CoA and 14 NADHP + 14 H+ to form a molecule of palmitate and 7 CO2, 14 NADP+, 8 CoASH, and 6 H2O. The process proceeds via the successive condensations of malonyl groups onto the growing acyl chain,each followed by loss of CO2 and three steps of reduction (Smith et al. 2003). EC Number: 2.3.1.85 Pubmed12689621 Reactome Database ID Release 4375872 Reactome, http://www.reactome.org ReactomeREACT_1497 acetyl-CoA + 7 malonyl-CoA + 14 NADHP + 14 H+ => palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6 H2O has a Stoichiometric coefficient of 14 has a Stoichiometric coefficient of 6 has a Stoichiometric coefficient of 7 has a Stoichiometric coefficient of 8 palmitate + CoASH + ATP => palmitoyl-CoA + AMP + pyrophosphate + H2O [ACSL5] Acyl-CoA synthetase long-chain family member 5 (ACSL5) associated with the endoplasmic reticulum membrane catalyzes the reaction of palmitate, CoASH, and ATP to form palmitoyl-CoA, AMP, pyrophosphate, and water (Gassler et al. 2007). Authored: D'Eustachio, P, 2005-07-26 19:04:36 EC Number: 6.2.1.3 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed17681178 Reactome Database ID Release 43164987 Reactome, http://www.reactome.org ReactomeREACT_22410 arachidonate + CoASH + ATP => arachidonoyl-CoA + AMP + pyrophosphate + H2O [ACSL4] Acyl-CoA synthetase long-chain family member 4 (ACSL4) associated with the endoplasmic reticulum membrane catalyzes the reaction of arachidonate, CoASH, and ATP to form arachidonyl-CoA, AMP, pyrophosphate, and water (Longo et al. 2003; Meloni et al. 2003). Authored: D'Eustachio, P, 2010-03-14 EC Number: 6.2.1.3 Edited: D'Eustachio, P, 2010-03-14 Pubmed11889465 Pubmed12525535 Reactome Database ID Release 43548843 Reactome, http://www.reactome.org ReactomeREACT_22376 PathwayStep4424 Generation of Cytoplasmic Acetyl CoA from Citrate Authored: Gopinathrao, G, 2003-10-03 00:00:00 EC Number: 2.3.3.8 Pubmed1371749 Reactome Database ID Release 4375848 Reactome, http://www.reactome.org ReactomeREACT_1141 While fatty acid synthesis from acetyl CoA proceeds in the cytosol, most acetyl CoA in the cell is generated within the mitochondria, by oxidative decarboxylation of the pyruvate derived from glycolysis, as well as from a number of reactions of amino acid catabolism.<BR>Mitochondrial Acetyl-CoA is transported to cytoplasm as citrate to participate in fatty acid biosynthesis. Mitochondrial citrate synthase, a tricarboxylic acid transporter in the inner mitochondrial membrane, and cytosolic citrate lyase are involved in this transport. PathwayStep4423 PathwayStep4426 Formation of fatty acid synthase (FAS) dimer Association of cytosolic FAS into multimers is linked to increased catalytic activity (Locke et al. 2008). Pubmed18455495 Reactome Database ID Release 43163756 Reactome, http://www.reactome.org ReactomeREACT_1903 has a Stoichiometric coefficient of 2 PathwayStep4425 Formation of Malonyl-CoA from Acetyl-CoA (liver) Authored: Gopinathrao, G, 2003-10-03 00:00:00 Cytosolic acetyl-CoA carboxylase 1 (ACACA) catalyzes the reaction of bicarbonate, ATP, and acetyl-CoA to form malonyl-CoA, ADP, and orthophosphate. The reaction is positively regulated by citrate. The human ACACA cDNA has been cloned (Abu-Elheiga et al. 1995) and the biochemical properties of the human enzyme have recently been described (Cheng et al. 2007; Locke et al. 2008). Four ACACA isoforms generated by alternative splicing have been identified as mRNAs - the protein product of the first has been characterized experimentally. EC Number: 6.4.1.2 Pubmed16854592 Pubmed18455495 Pubmed7732023 Reactome Database ID Release 43200555 Reactome, http://www.reactome.org ReactomeREACT_11201 acetyl-CoA + bicarbonate + ATP => malonyl-CoA + H2O + ADP + orthophosphate PathwayStep4428 PathwayStep4427 PathwayStep4429 NF-kappaB p50:p65:IKB Reactome DB_ID: 1168603 Reactome Database ID Release 431168603 Reactome, http://www.reactome.org ReactomeREACT_119528 has a Stoichiometric coefficient of 1 NF-kappaB p65:p65:IKB Reactome DB_ID: 1168609 Reactome Database ID Release 431168609 Reactome, http://www.reactome.org ReactomeREACT_120117 has a Stoichiometric coefficient of 1 NF-kappaB p65:p65 Reactome DB_ID: 1168602 Reactome Database ID Release 431168602 Reactome, http://www.reactome.org ReactomeREACT_120277 has a Stoichiometric coefficient of 2 NF-kappa-B p50/ p65/c-Rel:p-IKB Converted from EntitySet in Reactome Reactome DB_ID: 1168588 Reactome Database ID Release 431168588 Reactome, http://www.reactome.org ReactomeREACT_119527 PathwayStep4430 PathwayStep4431 NF-kappaB p50:p50 Reactome DB_ID: 1168595 Reactome Database ID Release 431168595 Reactome, http://www.reactome.org ReactomeREACT_118896 has a Stoichiometric coefficient of 2 PathwayStep4432 NF-kappaB p50:c-Rel:IkB Reactome DB_ID: 1168589 Reactome Database ID Release 431168589 Reactome, http://www.reactome.org ReactomeREACT_119187 has a Stoichiometric coefficient of 1 PathwayStep4433 NF-kappaB p50:c-Rel Reactome DB_ID: 1168586 Reactome Database ID Release 431168586 Reactome, http://www.reactome.org ReactomeREACT_119640 has a Stoichiometric coefficient of 1 NF-KappaB p50:p50:p-IKBA Reactome DB_ID: 1168600 Reactome Database ID Release 431168600 Reactome, http://www.reactome.org ReactomeREACT_119342 has a Stoichiometric coefficient of 1 NF-kappaB p50:c-Rel:p-IKB Reactome DB_ID: 1168612 Reactome Database ID Release 431168612 Reactome, http://www.reactome.org ReactomeREACT_119676 has a Stoichiometric coefficient of 1 NF-kappaB p50:p65:p-IKB Reactome DB_ID: 1168611 Reactome Database ID Release 431168611 Reactome, http://www.reactome.org ReactomeREACT_119566 has a Stoichiometric coefficient of 1 Binding of GRB2:SOS1 to p-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 Binding of GRB2:SOS1 complex to phosphorylated EGFR mutants Direct binding of GRB2:SOS1 complex to phosphorylated homodimers of EGFR cancer mutants has not been tested. GRB2 binds to phosphorylated tyrosine residues Y1068 and Y1086 (corresponding to Y1092 and Y1110, respectively, when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus). Phosphorylation of Y1068 (i.e. Y1092) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Lynch et al. 2004, Greulich et al. 2005, Yang et al. 2006, Choi et al. 2007); EGFR G719S mutant (Greulich et al. 2005, Choi et al. 2007); EGFR L747_P753insS mutant (Sordella et al. 2004, Lynch et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP (Greulich et al. 2005); EGFR L747_S752del mutant (Pao et al. 2004); EGFR L861Q mutant (Lee et al. 2006, Yang et al. 2006); EGFRvIII mutant (Huang et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR T263P mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15118073 Pubmed15284455 Pubmed15329413 Pubmed16187797 Pubmed16849543 Pubmed16953218 Pubmed17177598 Pubmed17646646 Pubmed17712310 Reactome Database ID Release 431225950 Reactome, http://www.reactome.org ReactomeREACT_116141 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with p-EGFR mutants) Authored: Orlic-Milacic, M, 2011-11-04 Based on the wild-type EGFR signaling, it is assumed that the guanine nucleotide exchange factor SOS1 interacts with phosphorylated EGFR mutants through the adaptor protein, GRB2. Upon formation of this complex, SOS1 activates RAS by promoting GDP release and GTP binding. Although this reaction has not been directly confirmed for EGFR cancer mutants, activation of RAF/MAP kinase cascade has been demonstrated, through detection of phosphorylated ERK1/2, in cells expressing EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Shimamura et al. 2005), EGFR E746_A750del mutant (Sordella et al. 2004, Shimamura et al. 2005), EGFR L747_P753delinsS mutant (Sordella et al. 2004) and EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005). Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15118125 Pubmed15284455 Pubmed16024644 Reactome Database ID Release 431225951 Reactome, http://www.reactome.org ReactomeREACT_116154 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Binding of SHC1 to p-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15284455 Pubmed16187797 Pubmed16969069 Pubmed17372273 Pubmed17646646 Pubmed17712310 Reactome Database ID Release 431225947 Reactome, http://www.reactome.org ReactomeREACT_116063 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 SHC1 (Src homology 2 domain-containing transforming protein) is known to bind two phosphorylated tyrosine docking sites of EGFR: Y1148 and Y1173 (corresponding to Y1172 and Y1197 when counting from the first amino acid of EGFR precursor, before the cleavage of the 24-amino acid signal peptide at the N-terminus takes place). Phosphorylation of Y1173 tyrosine residue was directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Greulich et al. 2005); EGFR G719S mutant (Greulich et al. 2005); EGFR L747_P753delinsS mutant (Sordella et al. 2004); EGFR L747_A750delinsP (Greulich et al. 2005); EGFRvIII mutant (Han et al. 2006, Grandal et al. 2007); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). Phosphorylation of Y1148 was shown in EGFRvIII mutant (Huang et al. 2007). <br> Besides EGFR L858R mutant, which was directly shown to bind SHC1 (Greulich et al. 2005), binding of SHC1 was not tested in other EGFR cancer mutants. Nonetheless, it is assumed that SHC1 binds EGFR cancer mutants in the same way it binds wild-type EGFR. Phosphorylation of SHC1 by p-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 Constitutive phosphorylation of SHC1 was directly demonstrated in cells expressing EGFR L858R mutant (Greulich et al. 2005). Other EGFR cancer mutants were not directly tested for their ability to phosphorylate SHC1, but are assumed to interact with SHC1 in the same way as the wild-type EGFR protein. EC Number: 2.7.10 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed16187797 Reactome Database ID Release 431225952 Reactome, http://www.reactome.org ReactomeREACT_115841 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 Tyrosine phosphorylated (activated) STAT1/STAT3 Converted from EntitySet in Reactome Reactome DB_ID: 1112571 Reactome Database ID Release 431112571 Reactome, http://www.reactome.org ReactomeREACT_27534 Phosphorylated SHC1 in complex with p-EGFR mutants recruits GRB2:SOS1 complex Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15284455 Pubmed8493579 Reactome Database ID Release 431225961 Reactome, http://www.reactome.org ReactomeREACT_115562 Recruitment of GRB2:SOS1 complex by SHC1 bound to phosphorylated dimers of EGFR cancer mutants has not been directly tested, but is assumed to happen in the same way it happens with the SHC1 bound to the phosphorylated homodimer of wild-type EGFR. Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Tyrosine/serine phosphorylated STAT1, STAT3 Converted from EntitySet in Reactome Reactome DB_ID: 1112740 Reactome Database ID Release 431112740 Reactome, http://www.reactome.org ReactomeREACT_27783 STAT1, STAT3 Converted from EntitySet in Reactome Reactome DB_ID: 1112559 Reactome Database ID Release 431112559 Reactome, http://www.reactome.org ReactomeREACT_27778 LCAT + spherical HDL <=> LCAT:spherical HDL complex Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 LCAT (lecithin-cholesterol acyltransferase) associates strongly but reversibly with spherical HDL particles (Jonas 2000). Pubmed11111093 Pubmed9829992 Reactome Database ID Release 43266315 Reactome, http://www.reactome.org ReactomeREACT_13735 Reviewed: Jassal, B, 2008-06-13 14:05:49 JAK1, JAK2, TYK2 Converted from EntitySet in Reactome Reactome DB_ID: 1067656 Reactome Database ID Release 431067656 Reactome, http://www.reactome.org ReactomeREACT_27873 LCAT:spherical HDL complex <=> LCAT + spherical HDL Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed9829992 Reactome Database ID Release 43266310 Reactome, http://www.reactome.org ReactomeREACT_13706 Reviewed: Jassal, B, 2008-06-13 14:05:49 The LCAT:spherical HDL complex dissociates reversibly to yield LCAT and a spherical HDL particle. cholesterol + phosphatidylcholine (lecithin) => cholesterol ester + 2-lysophosphatidylcholine (lysolecithin) Authored: D'Eustachio, P, 2008-05-12 17:46:52 EC Number: 2.3.1.43 Edited: D'Eustachio, P, 2008-06-13 14:03:50 LCAT activated by apoA-I catalyzes the reaction of cholesterol and phosphatidylcholine to yield cholesterol esterified with a long-chain fatty acid and 2-lysophosphatidylcholine. While this reaction was first studied in vitro using purified proteins in solution, it occurs in vivo on the surfaces of HDL particles where transiently-bound LCAT is activated by HDL-associated apoA-I protein and consumes HDL-associated cholesterol and phosphatidylcholine. The cholesterol ester reaction product is strongly associated with the HDL particle because of its increased hydrophobicity, while the 2-lysophosphatidylcholine product is released from the particle (Fielding et al. 1972 [2 references]; Adimoolam et al. 1998). Pubmed4335615 Pubmed4340992 Pubmed9829992 Reactome Database ID Release 43264695 Reactome, http://www.reactome.org ReactomeREACT_13506 Reviewed: Jassal, B, 2008-06-13 14:05:49 Spontaneous dimerization of ligand-responsive EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 EGFR ligand-responsive mutants dimerize spontaneously, without ligand binding, although ligand binding ability is preserved. This was experimentally demonstrated for EFGR L858R mutant and is presumed to happen in other constitutively active EGFR kinase domain mutants and EGFR extracellular domain point mutants. Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed16187797 Pubmed16777603 Pubmed17349580 Pubmed19560417 Reactome Database ID Release 431220614 Reactome, http://www.reactome.org ReactomeREACT_115980 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 Serum albumin binds 2-lysophosphatidylcholine 2 2-lysophosphatidylcholine + serum albumin => albumin:2-lysophosphatidylcholine complex Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed4360812 Pubmed5865378 Reactome Database ID Release 43264679 Reactome, http://www.reactome.org ReactomeREACT_13766 Reviewed: Jassal, B, 2008-06-13 14:05:49 Serum albumin binds 2-lysophosphatidylcholine (lysolecithin) to form a complex. Two molecules of lipid bind strongly to a molecule of albumin; an additional five molecules bind more weakly (Nakagawa and Nishida 1973). The fate of the complex in vivo is unclear. In vitro 2-lysophosphatidylcholine can be esterified with fatty acid to generate phosphatidylcholine. Such a process could replenish the phosphatidylcholine consumed by cholesterol esterification in HDL particles, but the extent to which it occurs in vivo is unclear (Nakagawa and Nishida 1973; Switzer and Eder 1965). has a Stoichiometric coefficient of 2 Trans-autophosphorylation of activated ligand-responsive EGFR mutant dimers Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15284455 Pubmed16777603 Pubmed17177598 Pubmed17349580 Reactome Database ID Release 431169421 Reactome, http://www.reactome.org ReactomeREACT_115772 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Activation of ligand-responsive EGFR mutants through spontaneous or EGF-induced dimerization results in trans-autophosphorylation of 5 tyrosine residues (Y992, Y1068, Y1086, Y1148 and Y1173), which enables constitutive receptor signaling as it provides specific binding sites for cytosolic target proteins involved in signal transduction (Zhang et al. 2006, Yun et al. 2007, Sordella et al. 2004, Lee et al. 2006). Tyrosine residue Y1045, involved in EGFR down-regulation, is usually phosphorylated in ligand-responsive EGFR mutants (Sordella et al. 2004, Lee et al. 2006). The exact phosphorylation pattern has not been examined for each mutant, but is assumed to closely follow, based on existing experimental evidence, the trans-autophosphorylation pattern of the wild-type EGFR. has a Stoichiometric coefficient of 12 spherical HDL and SR-BI receptor form a complex at the cell surface An extracellular spherical HDL particle binds to the plasma membrance-associated SR-BI receptor with high affinity (Murao et al. 1997). In the body SR-BI receptors are abundant on the surfaces of steroidogenic cells in the adrenal glands and gonads, and on hepatocytes. SR-BI thus appears to play a central role in cholesterol uptake for steroid hormone synthesis and for bile acid synthesis and cholesterol excretion (Rigotti et al. 2003; Silver and Tall 2001). Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed11561168 Pubmed12788804 Pubmed9211901 Reactome Database ID Release 43349637 Reactome, http://www.reactome.org ReactomeREACT_13459 Reviewed: Jassal, B, 2008-06-13 14:05:49 CRK Converted from EntitySet in Reactome Reactome DB_ID: 912777 Reactome Database ID Release 43912777 Reactome, http://www.reactome.org ReactomeREACT_24469 EGFRvIII mutant binds chaperone proteins HSP90 and CDC37. Association of EGFRvIII mutant with HSP90 chaperone protein and its co-chaperone CDC37 is necessary for the proper functioning of mutant EGFR. Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed12471035 Reactome Database ID Release 431247999 Reactome, http://www.reactome.org ReactomeREACT_115549 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Disassembly of SR-BI-bound spherical HDL Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed11561168 Pubmed12788804 Reactome Database ID Release 43349638 Reactome, http://www.reactome.org ReactomeREACT_13762 Reviewed: Jassal, B, 2008-06-13 14:05:49 Spherical HDL particles bound to the cell-surface SR-BI receptor are disassembled, with the release of pre-beta HDL (essentially apoA-I lipoprotein with a few molecules of bound lipid) and the cellular uptake of the bulk of the HDL-associated cholesterol, cholesterol esters, phospholipids, and triacylglycerols. The specificity and efficiency of this process has been demonstrated through a variety of studies in tissue culture model systems (Rigotti et al. 2003; Silver and Tall 2001). The process is annotated here as a concerted event occuring at the cell surface but its molecular details remain incompletely defined and it is possible that the HDL particle is internalized while undergoing disassembly. has a Stoichiometric coefficient of 134 has a Stoichiometric coefficient of 156 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 20 has a Stoichiometric coefficient of 38 Ligand-independent dimerization of EGFRvIII mutant Authored: Orlic-Milacic, M, 2011-11-04 EGFRvIII mutant lacks the ligand binding domain and is therefore unable to bind EGFR ligands, but is able to dimerize spontaneously. Self-dimerization may be dependent on N-linked glycosylation. Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed11087732 Reactome Database ID Release 431248002 Reactome, http://www.reactome.org ReactomeREACT_115887 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 CETP-mediated lipid exchange: spherical HDL gains triacylglycerol Authored: D'Eustachio, P, 2008-05-12 17:46:52 CETP (cholesterol ester transfer protein) complexed with triacylglycerol interacts with a spherical HDL (high density lipoprotein) particle, acquiring cholesterol ester molecules and donating triacylglycerol to the HDL (Swenson et al. 1988; Morton and Zilversmit 1983). This process is reversible but in the body proceeds in the direction annotated here. A model for the lipid exchange process has been proposed based on recent studies of the structure of CETP:lipid complexes (Qiu et al. 2007). CETP:triacylglycerol complex + spherical HDL <=> CETP:cholesterol ester complex + spherical HDL:triacylglycerol Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed17237796 Pubmed2833496 Pubmed6619141 Reactome Database ID Release 43266328 Reactome, http://www.reactome.org ReactomeREACT_13408 Reviewed: Jassal, B, 2008-06-13 14:05:49 Trans-autophosphorylation of EGFRvIII mutant dimers Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed16969069 Pubmed17646646 Reactome Database ID Release 431248655 Reactome, http://www.reactome.org ReactomeREACT_115610 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Upon dimerization, EGFRvIII mutants trans-autophosphorylate on tyrosine residues Y992, Y1068, Y0186, Y1143 and Y1173 while the tyrosine residue Y1045, a docking site for CBL, remains either unphosphorylated or hypophosphorylated, allowing EGFRvIII to activate downstream signaling cascades while escaping downregulation. has a Stoichiometric coefficient of 10 CETP + spherical HDL + torcetrapib => CETP:spherical HDL:torcetrapib complex Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed16326978 Reactome Database ID Release 43349404 Reactome, http://www.reactome.org ReactomeREACT_13803 Reviewed: Jassal, B, 2008-06-13 14:05:49 Torcetrapib associates with a molecule of CETP and a spherical HDL particle to form a stable complex, thus trapping CETP and inhibiting CETP-mediated lipid transfer between HDL and LDL (Clark et al. 2006). CETP-mediated lipid exchange: LDL gains cholesterol ester Authored: D'Eustachio, P, 2008-06-13 14:03:50 CETP (cholesterol ester transfer protein) complexed with cholesterol esters interacts with an LDL (low density lipoprotein) particle, acquiring triacylglycerol molecules and donating cholesterol ester to the LDL (Swenson et al. 1988; Morton and Zilversmit 1983). This process is reversible but in the body proceeds in the direction annotated here. A model for the lipid exchange process has been proposed based on recent studies of the structure of CETP:lipid complexes (Qiu et al. 2007). CETP:cholesterol ester complex + LDL <=> LDL:cholesterol ester complex + CETP:triacylglycerol complex Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed17237796 Pubmed2833496 Pubmed6619141 Reactome Database ID Release 43266350 Reactome, http://www.reactome.org ReactomeREACT_13690 Reviewed: Jassal, B, 2008-06-13 14:05:49 apoA-I binds to CUBN:AMN Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Extracellular apoA-I protein binds to the CUBN (cubilin) subunit of the CUBN:AMN complex associated with the plasma membrane. In the body, this complex is found on the apical surfaces of kidney glomerular cells, where it mediates binding and endocytosis of proteins in the glomerular filtrate, and on the apical surfaces of enterocytes, where it mediates uptake of several vitamins complexed with carrier proteins (notably vitamin B12 (cobalamin):intrinsic factor) (Kozyraki et al. 1999; Fyfe et al. 2004). Pubmed10371504 Pubmed17652309 Reactome Database ID Release 43264848 Reactome, http://www.reactome.org ReactomeREACT_13688 Reviewed: Jassal, B, 2008-06-13 14:05:49 Phosphorylation of CBL by ligand-responsive p-6Y-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 EGFR L858R mutant was shown to directly phosphorylate CBL on tyrosine residue Y371. Other EGFR cancer mutants with phosphorylation of tyrosine Y1045 (Y1069) are assumed to bind and phosphorylate CBL in a manner similar to the wild-type EGFR. Edited: D'Eustachio, P, 2011-11-07 Edited: Gillespie, ME, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed16849543 Reactome Database ID Release 431225960 Reactome, http://www.reactome.org ReactomeREACT_115796 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 Inefficient ubiquitination of ligand-responsive EGFR mutants by phosphorylated CBL Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 6.3.2.19 Edited: D'Eustachio, P, 2011-11-07 Edited: Gillespie, ME, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Phosphorylated CBL does not ubiquitinate EGFR kinase domain mutants efficiently, which enables mutant proteins to escape degradation. There are indications that phosphorylated CBL shows decreased affinity for EGFR kinase domain mutants compared to wild-type EGFR proteins, and quickly dissociates, before ubiquitination is completed. This decreased affinity may be due to altered structure of EGFR kinase domain mutants or to the presence of the chaperone protein HSP90 in complex with the mutant protein. Weaker afinity for phosphorylated CBL was directly demonstrated for EGFR L858R mutant (Yang et al. 2006), and poor ubiquitination inspite of CBL binding was shown for EGFR L858R and EGFR E746_A750del mutants (Yang et al. 2006, Padron et al. 2007). Pubmed16849543 Pubmed17699773 Reactome Database ID Release 431225956 Reactome, http://www.reactome.org ReactomeREACT_115732 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 Dissociation of phosphorylated PLC-gamma 1 from p-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Once phosphorylated, PLC-gamma 1 is expected to dissociate from phosphorylated EGFR cancer mutants and induce downstream signaling in the same way it does when activated by the wild-type EGFR. However, except for the phosphorylation of PLCG1 binding site in EGFR cancer mutants, other events involved in activation of PLCG1 signaling have not been studied in cells expressing EGFR cancer mutants. Pubmed15284455 Reactome Database ID Release 431247842 Reactome, http://www.reactome.org ReactomeREACT_115903 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Binding of CBL to phosphorylated ligand-responsive EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 CBL binds to phosphorylated tyrosine Y1045 residue of EGFR cancer mutants. Phosphorylation of Y1045 (corresponding to Y1069 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Greulich et al. 2005, Choi et al. 2007); EGFR G719S mutant (Sordella et al. 2004, Greulich et al. 1005, Choi et al. 2007); EGFR L747_P753delinsS mutant (Sordella et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP mutant (Greulich et al. 2005); EGFR L861Q mutant (Choi et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005; Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). Very little if any phosphorylation of Y1045 was shown in EGFR T263P mutant (Lee et al. 2006) and EGFR D770_N771insNPH mutant (Xu et al. 2007). Direct binding of CBL was demonstrated for the EGFR L858R mutant (Yang et al. 2006, Padron et al. 2007) and EGFR E746_A750del mutant (Padron et al. 2007). In EGFRvIII mutant, Y1045 (Y1069) is not phosphorylated (Han et al. 2006, Grandal et al. 2007). Han et al. detected no CBL binding to EGFRvIII mutant (Han et al. 2006), while Grandal et al. detected very little binding, which they explained by indirect recruitment of CBL to EGFRvIII through GRB2 (Grandal et al. 2007). Edited: D'Eustachio, P, 2011-11-07 Edited: Gillespie, ME, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15284455 Pubmed16187797 Pubmed16849543 Pubmed16953218 Pubmed16969069 Pubmed17177598 Pubmed17372273 Pubmed17699773 Pubmed17712310 Reactome Database ID Release 431225949 Reactome, http://www.reactome.org ReactomeREACT_115614 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 PathwayStep4489 apolipoprotein(a) + LDL => Lp(a) As an alternative to LDLR-mediated uptake and degradation, a LDL particle can bind a single molecule of LPA (apolipoprotein A), forming a Lp(a) lipoprotein particle. Although LPA is synthesized in liver cells, LPA - LDL binding appears to occur primarily extracellularly in vivo, on the hepatocyte surface or in the blood (Lobentanz et al. 1998). Lp(a) particles are relatively long-lived, with a half-life in human plasma of three to four days (Krempler et al. 1980), and the molecular mechanism of their clearance from the blood in vivo remains obscure. Lp(a) particles are of clinical interest because elevated levels of them are correlated with elevated risk of coronary heart disease (reviewed by Marcovina et al. 2003). Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0042157 Pubmed14578310 Pubmed7410552 Pubmed9548923 Reactome Database ID Release 43176879 Reactome, http://www.reactome.org ReactomeREACT_6958 SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with phosphorylated SHC1 and p-EGFR mutants) Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15118125 Pubmed15284455 Pubmed16024644 Reactome Database ID Release 431225957 Reactome, http://www.reactome.org ReactomeREACT_115809 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1, recruited by GRB2 bound to p-SHC1:p-EGFR mutants, is assumed to activate RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP). Although this reaction has not been shown to occur directly for EGFR cancer mutants, activation of RAF/MAP kinase cascade, through detection of phosphorylated ERK1/2, has been demonstrated in cells expressing EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Shimamura et al. 2005), EGFR E746_A750 mutant (Sordella et al. 2004, Shimamura et al. 2005), EGFR L747_P753delinS mutant (Sordella et al. 2004), and EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005). LDL + LDLR => LDL:LDLR complex Authored: D'Eustachio, P, 2007-04-30 14:17:00 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 Low density lipoprotein (LDL) particles associate with LDL receptors (LDLR) at the cell surface (Goldstein et al. 1979). This binding is mediated by the apoprotein B-100 component of the LDL particle, which binds LDLR with 1:1 stoichiometry (van Driel et al. 1989). Pubmed221835 Pubmed2722848 Reactome Database ID Release 43171122 Reactome, http://www.reactome.org ReactomeREACT_6940 STAT5 Converted from EntitySet in Reactome Reactome DB_ID: 1295523 Reactome Database ID Release 431295523 Reactome, http://www.reactome.org ReactomeREACT_117383 Binding of GRB2:GAB1:PIK3R1 complex to p-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 Direct binding of GRB2:GAB1:PIK3R1 complex to phosphorylated homodimers of EGFR cancer mutants has not been tested. This complex is recruted to EGFR via GRB2 binding to phosphorylated tyrosine residues Y1068 and Y1086 (corresponding to Y1092 and Y1110, respectively, when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus). Phosphorylation of Y1068 (i.e. Y1092) has been directly demonstrated in the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Lynch et al. 2004, Greulich et al. 2005, Yang et al. 2006, Choi et al. 2007); EGFR G719S mutant (Greulich et al. 2005, Choi et al. 2007); EGFR L747_P753insS mutant (Sordella et al. 2004, Lynch et al. 2004, Choi et al. 2007); EGFR L747_A750delinsP (Greulich et al. 2005); EGFR L747_S752del mutant (Pao et al. 2004); EGFR L861Q mutant (Lee et al. 2006, Yang et al. 2006); EGFRvIII mutant (Huang et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR G598V mutant (Lee et al. 2006); EGFR R108K mutant (Lee et al. 2006); EGFR T263P mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15118073 Pubmed15284455 Pubmed15329413 Pubmed16187797 Pubmed16849543 Pubmed16953218 Pubmed17177598 Pubmed17646646 Pubmed17712310 Reactome Database ID Release 431226016 Reactome, http://www.reactome.org ReactomeREACT_115604 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Internalization of LDL:LDLR complex (LDLRAP1-dependent) Authored: D'Eustachio, P, 2007-04-30 14:17:00 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 LDL:LDLR complex [plasma membrane] => LDL:LDLR complex [clathrin-coated vesicle] (LDLRAP1-dependent) Low density lipoprotein (LDL) particles bound to their receptors (LDLR) in coated pits on the cell surface are taken up into clathrin-coated vesicles (Goldstein et al. 1979). In hepatocytes and lymphocytes, but not in fibroblasts, this process requires the presence of an additional protein, LDLRAP1 (ARH1). In human patients, LDLRAP1 deficiency is associated with hypercholesterolemia, emphasizing the central role of the liver in clearance of circulating LDL in vivo (Eden et al. 2002; Garuti et al. 2005; He et al. 2002; Michaely et al. 2004). In vitro, LDLRAP1 protein binds both to LDLR and to components of the clathrin coat, suggesting that it might play an essential bridging function during the movement of LDL:LDLR complexes into clathrin-coated vesicles. This role has not yet been demonstrated in vivo, however, nor is it clear what might substitute for such a bridging function in fibroblasts. Pubmed12221107 Pubmed12464675 Pubmed15166224 Pubmed16179341 Pubmed221835 Reactome Database ID Release 43171118 Reactome, http://www.reactome.org ReactomeREACT_6924 p-STAT5 Converted from EntitySet in Reactome Reactome DB_ID: 1295524 Reactome Database ID Release 431295524 Reactome, http://www.reactome.org ReactomeREACT_116820 Internalization of LDL:LDLR complex (LDLRAP1-independent) Authored: D'Eustachio, P, 2007-04-30 14:17:00 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 LDL:LDLR complex [plasma membrane] => LDL:LDLR complex [clathrin-coated vesicle] (LDLRAP1-independent) Low density lipoprotein (LDL) particles bound to their receptors (LDLR) in coated pits on the cell surface are taken up into clathrin-coated vesicles (Goldstein et al. 1979). In hepatocytes and lymphocytes, but not in fibroblasts, this process requires the presence of an additional protein, LDLRAP1 (ARH1). In human patients, LDLRAP1 deficiency is associated with hypercholesterolemia, emphasizing the central role of the liver in clearance of circulating LDL in vivo (Eden et al. 2002; Garuti et al. 2005; He et al. 2002; Michaely et al. 2004). In vitro, LDLRAP1 protein binds both to LDLR and to components of the clathrin coat, suggesting that it might play an essential bridging function during the movement of LDL:LDLR complexes into clathrin-coated vesicles. This role has not yet been demonstrated in vivo, however, nor is it clear what might substitute for such a bridging function in fibroblasts. Pubmed12221107 Pubmed12464675 Pubmed15166224 Pubmed16179341 Pubmed221835 Reactome Database ID Release 43171141 Reactome, http://www.reactome.org ReactomeREACT_6860 PI3K-regulatory subunits Converted from EntitySet in Reactome Reactome DB_ID: 1295511 Reactome Database ID Release 431295511 Reactome, http://www.reactome.org ReactomeREACT_117127 Movement of LDL:LDLR complex to early endosome Authored: D'Eustachio, P, 2007-04-30 14:17:00 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 LDL:LDLR complexes move rapidly from clathrin-coated vesicles to endosomes (Goldstein et al. 1979). LDLR:LDL complex [coated vesicle membrane] => LDLR:LDL complex [endosome membrane] Pubmed221835 Reactome Database ID Release 43171059 Reactome, http://www.reactome.org ReactomeREACT_6901 PLC-gamma 1 binds to p-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15284455 Pubmed16187797 Pubmed16953218 Pubmed17177598 Pubmed17712310 Reactome Database ID Release 431247841 Reactome, http://www.reactome.org ReactomeREACT_115745 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Tyrosine residue Y992, a docking site for PLC-gamma 1 (PLCG1), is phosphorylated in EGFR cancer mutants and expected to recruit PLC-gamma 1 in the same way as the wild-type EGFR receptor. Phosphorylation of Y992 (corresponding to Y1016 when counting from the first amino acid of the EGFR precursor, prior to cleavage of the 24-amino acid signal peptide at the N-terminus) has been directly demonstrated for the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Choi et al. 2007); EGFR G719S mutant (Choi et al. 2007); EGFR L747_P753delinsS mutant (Sordella et al. 2004, Choi et ak, 2007); EGFR L861Q mutant (Choi et al. 2007); EGFRvIII mutant (Grandal et al. 2007); EGFR A289V mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007). LDLR:LDL complex => LDLR + LDL Authored: D'Eustachio, P, 2007-04-30 14:17:00 Dissociation of the LDL:LDLR complex in the early endosome Dissociation of the LDL:LDLR complex in the early endosome frees the LDL particle to be transferred to lysosomes for degradation while the LDL receptor is returned to the plasma membrane (Goldstein et al. 1979). Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 Pubmed221835 Reactome Database ID Release 43171106 Reactome, http://www.reactome.org ReactomeREACT_6775 Phosphorylation of PLC-gamma 1 by p-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Once recruited, PLC-gamma 1 is assumed to be phosphorylated by EGFR cancer mutants in the same way it is phosphorylated by the wild-type EGFR. Pubmed1689311 Pubmed2472219 Reactome Database ID Release 431247844 Reactome, http://www.reactome.org ReactomeREACT_115627 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 4 Recycling of LDLR to plasma membrane Authored: D'Eustachio, P, 2007-04-30 14:17:00 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 LDL receptors in the endosome membrane are quickly returned to the cell surface (Goldstein et al. 1979). LDLR [endosome membrane] => LDLR [plasma membrane] Pubmed221835 Reactome Database ID Release 43171087 Reactome, http://www.reactome.org ReactomeREACT_6810 Binding of PI3K p110 subunit alpha (PIK3CA) to complex of GRB2:GAB1:PIK3R1 and p-EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15284455 Reactome Database ID Release 431226012 Reactome, http://www.reactome.org ReactomeREACT_116004 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 The 110 kDa catalytic subunit of PI3K (PIK3CA) binds to the 85 kDa regulatory subunit of PI3K (PIK3R1) to create the active PI3K. EGFR cancer mutants are assumed to mediate the assembly of active PI3K in a manner similar to wild-type EGFR. hormone-sensitive lipase (HSL) + 2 ATP -> phosphorylated HSL + 2 ADP Authored: D'Eustachio, P, 2005-05-02 18:38:43 Cytosolic rat HSL is phosphorylated on serine residues 659 and 660 by protein kinase A catalytic subunit (Anthonsen et al. 1998; Su et al. 2003). Three isoforms of protein kinase A are known, but with no known differences in substrate specificity or tissue specific expression patterns, so a generic PKA (with all three forms as instances) is annotated as the catalyst of this reaction. Other serine residues in HSL can be phosphorylated both in vitro and in vivo, and while these other phosphorylations appear not to affect triacylglycerol hydrolysis by HSL directly, they may affect the efficiency with which serines 659 and 660 themselves are phosphorylated, or affect the efficiency with which HSL is translocated to cytosolic lipid particles (Holm et al. 2000).<p>Phosphorylation of human HSL has not been studied in detail, so the human reaction is inferred from the well-studied rat one. By BLAST alignment, human HSL residues 649 and 650 correspond to rat serines 659 and 660. EC Number: 2.7.11 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10940339 Pubmed12832420 Pubmed9417067 Reactome Database ID Release 43163416 Reactome, http://www.reactome.org ReactomeREACT_1078 has a Stoichiometric coefficient of 2 Conversion of PIP2 to PIP3 by PI3K bound to phosphorylated EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.1.153 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed15118125 Pubmed15284455 Pubmed16024644 Pubmed16187797 Pubmed17177598 Pubmed17712310 Reactome Database ID Release 431226014 Reactome, http://www.reactome.org ReactomeREACT_115884 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 The kinase activity of PI3K mediates the phosphorylation of PIP2 to form PIP3. It is assumed that EGFR cancer mutants induce PI3K/AKT signaling in a manner similar to wild-type EGFR. Phosphorylation of AKT on serine residue S473, and therby activation of PI3K/AKT signaling cascade, has been directly demonstrated in cells expressing the following EGFR cancer mutants: EGFR L858R mutant (Sordella et al. 2004, Paez et al. 2004, Greulich et al. 2005, Shimamura et al. 2005); EGFR G719S mutant (Greulich et al. 2005); EGFR E746_A750del mutant (Sordella et al. 2004, Shimamura et al. 2005); EGFR L747_P753insS mutant (Sordella et al. 2004); EGFR L747_A750delinsP mutant (Greulich et al. 2005); EGFR L861Q mutant (Lee et al. 2006); EGFR D770_N771insNPG mutant (Greulich et al. 2005, Xu et al. 2007); EGFR D770_N771insNPH mutant (Xu et al. 2007); EGFR V738_K739insKIPVAI mutant (Xu et al. 2007); EGFR M766_A767insASV mutant (Xu et al. 2007); EGFR E746_A750del;T790M double mutant (Shimamura et al. 2005). 2 phosphorylated HSL monomers -> phosphorylated HSL dimer Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10694408 Reactome Database ID Release 43163602 Reactome, http://www.reactome.org ReactomeREACT_1191 While both monomeric and homodimeric forms of rat HSL protein have been detected, the predominant species, and the one with substantially greater catalytic activity when activated by phosphorylation, is the homodimer so HSL-mediated lipolysis is annotated in Reactome with dimeric phosphorylated enzyme as the catalyst. Phosphorylation appears to be required for dimerization to proceed (Shen et al. 2000).<p>Dimerization of human HSL has not been studied in detail, so the human reaction is inferred from the well-studied rat one. has a Stoichiometric coefficient of 2 perilipin:CGI-58 complex -> perilipin + CGI-58 Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In unstimulated mouse 3T3-L1 adipocytes, perilipin is localized to the surfaces of cytosolic lipid particles as a complex with CGI-58. Catecholamine stimulation (and by inference glucagon stimulation) is associated with rapid dissociation of the complex and relocalization of the CGI-58 protein away from the lipid particle. The stoichiometry of the complex is unknown. Dissociation of the perilipin:CGI-58 complex appears to precede perilipin phosphorylation, although the molecular link between these two steps is unknown (Subramanian et al. 2004).<p>The interaction of human CGI-58 and perilipin on the lipid particle surface has not been studied in detail, so the human reaction is inferred from the well-studied mouse one. The observation that humans homozygous for CGI-58 mutations suffer from Chanarin-Dorfman Syndrome, characterized by the abnormal accumulation of triacylglycerol droplets in most tissues (Lefevre et al. 2001), provides indirect evidence that human and mouse CGI-58 proteins have similar functions. Pubmed11590543 Pubmed15292255 Reactome Database ID Release 43163539 Reactome, http://www.reactome.org ReactomeREACT_37 PathwayStep4491 PathwayStep4490 PathwayStep4497 PathwayStep4496 PathwayStep4499 PathwayStep4498 PathwayStep4493 PathwayStep4492 PathwayStep4495 PathwayStep4494 Sprouty lures membrane-bound CBL away from EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed12234920 Pubmed12593795 Reactome Database ID Release 43183035 Reactome, http://www.reactome.org ReactomeREACT_12441 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The NEYTEG motif is very similar to the CBL binding motif around Tyr-1045 in EGFR. Tyrosine-phosphorylated Sprouty (hSpry) binds to CBL, which then cannot ubiquitinate EGFR. Sprouty acts as a decoy to lure CBL away from EGFR and targets it for degradation. RBX1-CUL3-BTB Reactome DB_ID: 976101 Reactome Database ID Release 43976101 Reactome, http://www.reactome.org ReactomeREACT_76798 has a Stoichiometric coefficient of 1 CDC42 lures CBL away from the receptor Activated CDC42 binds to Beta-Pix (p85Cool-1), a protein that directly associates with CBL. This inhibits the binding of CBL to the EGF receptor and thus prevents CBL from catalyzing receptor ubiquitination. Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed14505571 Reactome Database ID Release 43183094 Reactome, http://www.reactome.org ReactomeREACT_12465 Reviewed: Heldin, CH, 2008-02-12 09:44:02 RBX1-CUL5-EloB/C-ASB Reactome DB_ID: 976079 Reactome Database ID Release 43976079 Reactome, http://www.reactome.org ReactomeREACT_75949 has a Stoichiometric coefficient of 1 PathwayStep4478 Beta-Pix pushes CIN85 away from CBL Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 High concentrations of active CDC42 and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 from the CBL complex. This competitive mechanism could block the CIN85-imposed clustering phenomenon on CBL that is required for tighter binding. Pubmed16407834 Reactome Database ID Release 43183002 Reactome, http://www.reactome.org ReactomeREACT_12412 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 2 hydroxyAsn-HIF1A/HIF2A Converted from EntitySet in Reactome HIF1A/HIF2A (hydroxyasparagine) HIF1A/HIF2A with Hydroxylated Asparagine Reactome DB_ID: 1234148 Reactome Database ID Release 431234148 Reactome, http://www.reactome.org ReactomeREACT_124608 PathwayStep4479 Localization of CBL:GRB2 to the membrane Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed11823423 Reactome Database ID Release 43183067 Reactome, http://www.reactome.org ReactomeREACT_12626 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Upon EGF stimulation and consequent EGFR phosphorylation, GRB2 binds phosphorylated tyrosines has a Stoichiometric coefficient of 2 Phosphorylation of CBL (EGFR:GRB2:CBL) Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 2.7.10 EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity. Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed15117950 Pubmed7657591 Reactome Database ID Release 43183058 Reactome, http://www.reactome.org ReactomeREACT_12491 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 2 Ubiquitination of stimulated EGFR (CBL:GRB2) Authored: Castagnoli, L, 2006-10-10 13:09:34 CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain. EC Number: 6.3.2.19 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed10514377 Pubmed15021893 Reactome Database ID Release 43183036 Reactome, http://www.reactome.org ReactomeREACT_12562 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 2 Sprouty lures cytosolic CBL away from EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed12234920 Pubmed12593795 Reactome Database ID Release 43182988 Reactome, http://www.reactome.org ReactomeREACT_12500 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The NEYTEG motif is very similar to the CBL binding motif around Tyr-1045 in EGFR. Tyrosine-phosphorylated Sprouty (hSpry) binds to CBL, which then cannot ubiquitinate EGFR. Sprouty acts as a decoy to lure CBL away from EGFR and targets it for degradation. SOCS Converted from EntitySet in Reactome Reactome DB_ID: 1169199 Reactome Database ID Release 431169199 Reactome, http://www.reactome.org ReactomeREACT_111744 chylomicron remnant:apoE complex + LDLR => chylomicron remnant:apoE:LDLR complex Authored: D'Eustachio, P, 2007-04-30 14:19:38 Chylomicron micron remnants containing apolipoprotein E associate with the surfaces of cells in a process that probably involves several steps and that requires the presence (but not the catalytic activity) of heparan sulfate proteoglycan (HSPG)-associated hepatic lipase (HL). This process ultimately results in binding of the remnant to cell-surface LDL receptors (LDLR) (Ji et al. 1994). The molecular details of LDLR binding, and of the following steps of remnant endocytosis, are inferred from those of the coorresponding step of LDLR-mediated low-density lipoprotein (LDL) endocytosis. In the body, this process occurs in the liver. Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 Pubmed8300609 Reactome Database ID Release 43174657 Reactome, http://www.reactome.org ReactomeREACT_6849 CBL binds and ubiquitinates phosphorylated Sprouty Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 6.3.2.19 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed12593796 Reactome Database ID Release 43183089 Reactome, http://www.reactome.org ReactomeREACT_12432 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL.The CBL-mediated ubiquitination of Sprouty targets the protein for degradation by the 26S proteosome. chylomicron remnant:apoE:LDLR complex [plasma membrane] => chylomicron remnant:apoE:LDLR complex [clathrin-coated vesicle] (LDLRAP1-dependent) Authored: D'Eustachio, P, 2007-04-30 14:19:38 Edited: D'Eustachio, P, 2006-02-20 18:35:05 Reactome Database ID Release 43174706 Reactome, http://www.reactome.org ReactomeREACT_6803 The molecular details of this event are inferred from those of LDLR-mediated low-density lipoprotein (LDL) endocytosis into coated vesicles. p(Y701)-STAT1, p(Y705)-STAT3 Converted from EntitySet in Reactome Reactome DB_ID: 1169218 Reactome Database ID Release 431169218 Reactome, http://www.reactome.org ReactomeREACT_111312 Ubiquitination of stimulated EGFR (CBL) Authored: Castagnoli, L, 2006-10-10 13:09:34 CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain. EC Number: 6.3.2.19 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed10514377 Pubmed15021893 Reactome Database ID Release 43182993 Reactome, http://www.reactome.org ReactomeREACT_12515 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 2 TG-depleted chylomicron + spherical HDL => chylomicron remnant + spherical HDL:apoA-I:apoA-II:apoA-IV:apoC-II:apoC-III Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2006-02-20 18:35:05 ISBN0079130356 Reactome Database ID Release 43174690 Reactome, http://www.reactome.org ReactomeREACT_6852 Reviewed: Jassal, B, 2008-06-13 14:05:49 Triacylglycerol (TG)-depleted chylomicrons transfer A and C apoproteins to spherical (mature) HDL, generating chylomicron remnants (Havel and Kane 2001). This transfer is arbitrarily annotated here as involving one molecule of each apolipoprotein. The molecular difference that enables nascent chylomicrons to accept apolipoproteins from sperical HDL and TG-depleted chylomicrons to donate them is unclear. CBL binds to GRB2 Authored: Castagnoli, L, 2006-10-10 13:09:34 CBL binds multiple signalling proteins including GRB2. The CBL:GRB2 complex translocates to the plasma membrane where it can bind to GRB2-specific docking sites on the EGF receptor. Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed8621719 Reactome Database ID Release 43183052 Reactome, http://www.reactome.org ReactomeREACT_12635 Reviewed: Heldin, CH, 2008-02-12 09:44:02 chylomicron remnant + apoE => chylomicron remnant:apoE complex Authored: D'Eustachio, P, 2007-04-30 14:19:38 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0042159 In the body, this binding involved apoE synthesized by hepatocytes and concentrated in the space of Disse, an extracellular compartment adjacent to the hepatocytes to which blood-borne lipoprotein particles have free access (Ji et al. 1994). Pubmed8300609 Reactome Database ID Release 43174739 Reactome, http://www.reactome.org ReactomeREACT_6865 HIF1A/HIF2A Converted from EntitySet in Reactome Reactome DB_ID: 1234109 Reactome Database ID Release 431234109 Reactome, http://www.reactome.org ReactomeREACT_125211 nascent chylomicron + spherical HDL:apoC-II:apoC-III:apoE =>spherical HDL + chylomicron Authored: D'Eustachio, P, 2008-05-12 17:46:52 Circulating nascent chylomicrons acquire copies of apolipoproteins C-II, C-III, and E from circulating spherical (mature) high-density lipoprotein particles, becoming mature chylomicrons (Havel et al. 1973; Bisgaier and Glickman 1983). Here, this interaction is annotated to involve the transfer of a single copy of each lipoprotein, but a mature chylomicron in fact contains approximately 25 copies of apolipoprotein E and 180 copies of C apolipoproteins (Bhattacharya and Redgrave 1981). Edited: D'Eustachio, P, 2006-02-20 18:35:05 Pubmed4345202 Pubmed6405679 Pubmed7288288 Reactome Database ID Release 43174660 Reactome, http://www.reactome.org ReactomeREACT_6727 Reviewed: Jassal, B, 2008-06-13 14:05:49 chylomicron => TG-depleted chylomicron + 50 long-chain fatty acids + 50 diacylglycerols Authored: D'Eustachio, P, 2007-04-30 14:19:38 EC Number: 3.1.1.34 Edited: D'Eustachio, P, 2006-02-20 18:35:05 Lipoprotein lipase dimers (LPL:LPL) are tethered to heparan sulfate proteoglycans (HSPG) at endothelial cell surfaces (Fernandez-Borja et al. 1996; Peterson et al. 1992). Both syndecan 1 (Rosenberg et al. 1997) and perlecan (Goldberg 1996) HSPG molecules are capable of tethering LPL. The LPL enzyme catalyzes the hydrolysis and release of triacylglycerols (TG) associated with circulating chylomicrons to leave a CM remnant (CR). This reaction is annotated here as causing the hydrolysis and release of 50 molecules of TG. In vivo, the number is much larger, and TG depletion probably occurs in the course of multiple encounters between a chylomicron and endothelial LPL. This reaction is strongly activated by chylomicron-associated apo C-II protein both in vivo and in vitro (Jackson et al. 1986). Chylomicron-associated apoC-II protein inhibits LPL activity in vitro (Brown and Baginsky 1972), and recent studies have indicated a positive regulatory role for apoA-5 protein, though its molecular mechanism of action remains unclear (Marcais et al. 2005; Merkel and Heeren 2005). CRs can then be taken up by liver parenchymal cells in two ways; 1) directly by the LDL receptor or 2) apoE/HSPG-directed uptake by LDL receptor-related proteins. Pubmed1279089 Pubmed16200205 Pubmed16200213 Pubmed3942763 Pubmed5057882 Pubmed8728311 Pubmed8732771 Pubmed9151776 Reactome Database ID Release 43174757 Reactome, http://www.reactome.org ReactomeREACT_6734 has a Stoichiometric coefficient of 50 PathwayStep4480 ABCA1 tetramer binds apoA-I ABCA1 associated with the plasma membrane binds extracellular apoA-I protein, forming a membrane-associated complex. The predominant form of ABCA1 is a heterotetramer (Denis et al. 2004), although studies in model systems in vitro are consistent with the hypothesis that the protein may also occur as a dimer (Trompier et al. 2006). Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed15280376 Pubmed16709568 Reactome Database ID Release 43216727 Reactome, http://www.reactome.org ReactomeREACT_13575 Reviewed: Jassal, B, 2008-06-13 14:05:49 Conversion of pro-apoA-I to apoA-I Authored: D'Eustachio, P, 2008-05-12 17:46:52 EC Number: 3.4.24 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed16548525 Pubmed17071617 Pubmed17580958 Reactome Database ID Release 43264758 Reactome, http://www.reactome.org ReactomeREACT_13407 Reviewed: Jassal, B, 2008-06-13 14:05:49 The six aminoterminal residues of pro-apolipoprotein A-1 are removed to generate the mature, lipid-binding form of the protein. Studies of tissue culture systems suggest that BMP1 catalyzes this reaction (Chau et al. 2006, 2007). While BMP1 is annotated here as a monomer, its subunit structure is not known, and its 1:1 association with Zn++ is inferred from its sequence similarity to known metallopeptidases. Alpha2-macroglobulin at concentrations found in plasma in inflammatory responses inhibits this reaction in vitro, suggesting a possible link between inflammation and perturbation of HDL function (Zhang et al. 2006; Chau et al. 2007). chylomicron remnant:apoE:LDLR complex => chylomicron remnant:apoE + LDLR Authored: D'Eustachio, P, 2007-04-30 14:19:38 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 Reactome Database ID Release 43174624 Reactome, http://www.reactome.org ReactomeREACT_6951 The molecular details of this event are inferred from the dissociation of the LDL:LDLR complex in the endosome. chylomicron remnant:apoE:LDLR complex [coated vesicle membrane] => chylomicron remnant:apoE:LDLR complex [endosome membrane] Authored: D'Eustachio, P, 2007-04-30 14:19:38 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 Reactome Database ID Release 43174808 Reactome, http://www.reactome.org ReactomeREACT_6720 The molecular details of this event are inferred from those of LDLR-mediated low-density lipoprotein (LDL) transport from coated vesicles to endosomes. PathwayStep4484 E3:K48-polyubiquitinated substrate Reactome DB_ID: 983134 Reactome Database ID Release 43983134 Reactome, http://www.reactome.org ReactomeREACT_75972 has a Stoichiometric coefficient of 1 PathwayStep4483 Ub:substrate Reactome DB_ID: 983130 Reactome Database ID Release 43983130 Reactome, http://www.reactome.org ReactomeREACT_75992 has a Stoichiometric coefficient of 1 PathwayStep4482 E3:Ub:substrate Reactome DB_ID: 983131 Reactome Database ID Release 43983131 Reactome, http://www.reactome.org ReactomeREACT_76185 has a Stoichiometric coefficient of 1 PathwayStep4481 Ag-substrate:E3:E2:Ub Reactome DB_ID: 983126 Reactome Database ID Release 43983126 Reactome, http://www.reactome.org ReactomeREACT_76727 has a Stoichiometric coefficient of 1 PathwayStep4488 APC/C E3 ligase complex Anaphase promoting complex (APC/C) Reactome DB_ID: 976123 Reactome Database ID Release 43976123 Reactome, http://www.reactome.org ReactomeREACT_76391 has a Stoichiometric coefficient of 1 PathwayStep4487 RBX1-CUL7-SKP1-FBXW8 Reactome DB_ID: 976074 Reactome Database ID Release 43976074 Reactome, http://www.reactome.org ReactomeREACT_76145 has a Stoichiometric coefficient of 1 PathwayStep4486 RBX1-CUL5-EloB/C-SOCS ECS (Elongin-Cullin-SOCS) E3 ligase Reactome DB_ID: 976147 Reactome Database ID Release 43976147 Reactome, http://www.reactome.org ReactomeREACT_75981 has a Stoichiometric coefficient of 1 PathwayStep4485 RBX1-CUL5-EloB/C-ASB Reactome DB_ID: 976109 Reactome Database ID Release 43976109 Reactome, http://www.reactome.org ReactomeREACT_76665 has a Stoichiometric coefficient of 1 PathwayStep4467 PathwayStep4468 PathwayStep4469 Binding of EGF to ligand-responsive EGFR mutants Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Ligand-responsive EGFR mutants are able to bind EGF and exhibit increased activity in the presence of EGF. Pubmed16187797 Pubmed17177598 Reactome Database ID Release 431220612 Reactome, http://www.reactome.org ReactomeREACT_115811 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 EGF-induced dimerization of ligand-responsive EGFR mutants Although ligand-responsive EGFR mutants dimerize spontaneously, dimerization is increased in the presence of EGF. Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed16187797 Pubmed16777603 Pubmed17349580 Pubmed19560417 Reactome Database ID Release 431220613 Reactome, http://www.reactome.org ReactomeREACT_115623 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 Sprouty sequesters CBL away from active EGFR Authored: Castagnoli, L, 2006-10-10 13:09:34 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed15962011 Reactome Database ID Release 43182990 Reactome, http://www.reactome.org ReactomeREACT_12387 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Sprouty can constitutively interact with two SH3 domains of CIN85 whereas the third SH3 domain of CIN85 can still associate with CBL on cell activation with EGF. This allows Sprouty to block CIN85-mediated clustering of CBL molecules, stablization of CBL-EGFR interactions and efficient ubiquitination and down-regulation of EGFR. Binding of ligand-responsive EGFR mutants to chaperoning proteins HSP90 and CDC37 Authored: Orlic-Milacic, M, 2011-11-04 EGFR kinase domain mutants need continuous association with HSP90 chaperone protein for proper functioning. CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 binds a protein kinase through its N-terminal domain and HSP90 through its C-terminal domain, arresting ATP-ase activity of HSP90 and enabling the loading of a client kinase. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (reviewed by Gray Jr. et al. 2008). Association of EGFR extracellular domain point mutants with HSP90 chaperone has not been tested. Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed14718169 Pubmed16024644 Pubmed16849543 Reactome Database ID Release 431218833 Reactome, http://www.reactome.org ReactomeREACT_115768 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 CBL ubiquitinates Sprouty Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 6.3.2.19 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed12593796 Reactome Database ID Release 43183051 Reactome, http://www.reactome.org ReactomeREACT_12381 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL. The CBL-mediated ubiquitination of Sprouty targets the protein for degradation by the 26S proteasome. CBL-mediated ubiquitination of CIN85 Authored: Castagnoli, L, 2006-10-10 13:09:34 EC Number: 6.3.2.19 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed12218189 Reactome Database ID Release 43182986 Reactome, http://www.reactome.org ReactomeREACT_12520 Reviewed: Heldin, CH, 2008-02-12 09:44:02 The adaptor protein CIN85 is monoubiquitinated by CBL after EGF stimulation. Monoubiquitination is thought to regulate receptor internalization and endosomal sorting. Assembly in clathrin-coated vesicles (CCVs) Authored: Castagnoli, L, 2006-10-10 13:09:34 Epsin directly modifies membrane curvature on binding to PIP2 in conjunction with clathrin polymerization. Pubmed10567358 Reactome Database ID Release 43183077 Reactome, http://www.reactome.org ReactomeREACT_12495 Reviewed: Heldin, CH, 2008-02-12 09:44:02 pre-beta HDL binds membrane-associated cholesterol and phospholipid to form a discoidal HDL particle Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pre-beta HDL (lipid-poor apoA-I) interacts with phospholipid- and cholesterol-rich membrane patches formed through the action of ABCA1, binding these two lipids to form a discoidal (small nascent) HDL particle (HDL 3c - Kontush and Chapman 2006). Pubmed16968945 Pubmed17478755 Reactome Database ID Release 43349657 Reactome, http://www.reactome.org ReactomeREACT_13717 Reviewed: Jassal, B, 2008-06-13 14:05:49 has a Stoichiometric coefficient of 22 has a Stoichiometric coefficient of 9 EGFR non-clathrin mediated endocytosis At higher concentrations of ligand, a substantial fraction of the receptor (>50%) is endocytosed through a clathrin independent, lipid-raft-dependent route as the receptor becomes Y1045 phosphorylated and ubiquitnated. Eps15 and Epsin are found in caveolae. Eps15 and Epsin are immunoprecipated with the EGF receptor. Non-clathrin internalization of ubiquitinated EGFR depends on its interaction with proteins harbouring the UIM Ub-interacting motif, as shown through the ablation of three Ub-interacting motif-containing proteins, Eps15, Eps15R and Epsin. Authored: Castagnoli, L, 2006-10-10 13:09:34 Pubmed12072436 Pubmed15701692 Reactome Database ID Release 43183072 Reactome, http://www.reactome.org ReactomeREACT_12527 Reviewed: Heldin, CH, 2008-02-12 09:44:02 ABCG1-mediated transport of intracellular cholesterol to the cell surface Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 In an ATP-dependent reaction, ABCG1 mediates the movement of intracellular cholesterol to the extracellular face of the plasma membrane. In a tissue culture model system, the active form of ABCG1 is predominantly a tetramer (Vuaghan and Oram 2005). The number of lipid molecules transported per ATP consumed is not known. Pubmed15994327 Reactome Database ID Release 43266082 Reactome, http://www.reactome.org ReactomeREACT_13681 Reviewed: Jassal, B, 2008-06-13 14:05:49 CBL escapes CDC42-mediated inhibition by down-regulating the adaptor molecule Beta-Pix Authored: Castagnoli, L, 2006-10-10 13:09:34 Beta-Pix (Cool-1) associates with CBL, which appears to be a critical step in CDC42-mediated inhibition of EGFR ubiquitylation and downregulation. The SH3 domain of Beta-Pix specifically interacts with a proline-arginine motif (PxxxPR) present within CBL, which mediates ubiquitylation and subsequent degradation of Beta-Pix. EC Number: 6.3.2.19 Edited: Orlic-Milacic, Marija, 2011-08-25 Pubmed16407834 Reactome Database ID Release 43183084 Reactome, http://www.reactome.org ReactomeREACT_12451 Reviewed: Heldin, CH, 2008-02-12 09:44:02 has a Stoichiometric coefficient of 2 Discoidal HDL binds membrane-associated free cholesterol Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Extracellular discoidal HDL particles interact with cholesterol-rich membrane patches formed through the action of ABCG1 (Vaughan and Oram 2005). In the body this reaction is a key step in the process of reverse cholesterol transport, by which excess cholesterol is recovered from cells such a macrophages and transported ultimately to the liver. At a molecular level, it is one of the steps in the transformation of discoidal (small nascent) HDL particles into spherical ones, distinct from the similar reaction in which cholesterol is transferred to lipid-free apoA-I protein (Oram and Vaughan 2006; Kontush and Chapman 2006). Pubmed15994327 Pubmed16968945 Pubmed17095732 Reactome Database ID Release 43266089 Reactome, http://www.reactome.org ReactomeREACT_13678 Reviewed: Jassal, B, 2008-06-13 14:05:49 PHD2/3 Converted from EntitySet in Reactome EGLN1 or EGLN3 PHD2 or PHD3 Reactome DB_ID: 1234122 Reactome Database ID Release 431234122 Reactome, http://www.reactome.org ReactomeREACT_125291 Assembly of EGFR complex in clathrin-coated vesicles Authored: Castagnoli, L, 2006-10-10 13:09:34 CBl-CIN85-Endophilin complex mediates ligand-induced down-regulation of the EGF receptor. The BAR domain of endophilin induces membrane curvature. The three SH3 domains of CIN85 bind to atypical proline-arginine motifs (PxxxPR) present in the carboxyl termini of CBL and CBL-b. In this way, CIN85 clusters CBL molecules, which is crucial for efficient EGFR endocytosis and degradation. Pubmed11894095 Reactome Database ID Release 43182994 Reactome, http://www.reactome.org ReactomeREACT_12521 Reviewed: Heldin, CH, 2008-02-12 09:44:02 LCAT + discoidal HDL <=> LCAT:discoidal HDL complex Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 LCAT (lecithin-cholesterol acyltransferase) associates strongly but reversibly with discoidal HDL particles (Jonas 2000). Pubmed11111093 Pubmed9829992 Reactome Database ID Release 43264678 Reactome, http://www.reactome.org ReactomeREACT_13548 Reviewed: Jassal, B, 2008-06-13 14:05:49 ABCA1-mediated transport of intracellular cholesterol to the cell surface Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 In an ATP-dependent reaction, ATPA1 mediates the movement of intracellular cholesterol to the extracellular face of the plasma membrane. Cholesterol associated with cytosolic vesicles is a substrate for this reaction. Under physiologocal conditions, the active form of ABCA1 is predominantly a tetramer associated with apoA-I lipoprotein (Denis et al. 2004; Vedhachalam et al., 2007). The number of lipid molecules transported per ATP consumed is not known. Pubmed15280376 Pubmed17604270 Reactome Database ID Release 43216723 Reactome, http://www.reactome.org ReactomeREACT_13622 Reviewed: Jassal, B, 2008-06-13 14:05:49 ABCA1-mediated transport of intracellular phospholipid to the cell surface Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 In an ATP-dependent reaction, ATPA1 mediates the movement of intracellular phospholipid to the extracellular face of the plasma membrane. Cholesterol associated with cytosolic vesicles is a substrate for this reaction. Under physiologocal conditions, the active form of ABCA1 is predominantly a tetramer associated with apoA-I lipoprotein (Denis et al. 2004; Vedhachalam et al., 2007). The number of lipid molecules transported per ATP consumed is not known. Pubmed15280376 Pubmed17604270 Reactome Database ID Release 43216757 Reactome, http://www.reactome.org ReactomeREACT_13627 Reviewed: Jassal, B, 2008-06-13 14:05:49 Apolipoprotein A-I binds membrane-associated cholesterol and phospholipid to form a discoidal HDL particle Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Extracellular apolipoprotein A-I interacts with phospholipid- and cholesterol-rich membrane patches formed through the action of ABCA1, binding these two lipids to form a discoidal (small nascent) HDL particle (HDL 3c - Kontush and Chapman 2006). The apoA-I molecules that accept lipids in this reaction appear to be different from the ones that activate ABCA1 at the plasma membrane (Hassan et al. 2007; Vedhachalam et al. 2007). Pubmed16968945 Pubmed17478755 Pubmed17656736 Reactome Database ID Release 43216756 Reactome, http://www.reactome.org ReactomeREACT_13610 Reviewed: Jassal, B, 2008-06-13 14:05:49 has a Stoichiometric coefficient of 10 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 25 Spherical HDL binds C and E apolipoproteins Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed16968945 Reactome Database ID Release 43266303 Reactome, http://www.reactome.org ReactomeREACT_13783 Reviewed: Jassal, B, 2008-06-13 14:05:49 Spherical HDL particles can bind apoC-II, apoC-III and and apoE proteins. The sources of these proteins and their role or roles in HDL function under physiological conditions are not well understood, however (Kontush and Chapman 2006). LCAT:discoidal HDL complex <=> LCAT + discoidal HDL Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed9829992 Reactome Database ID Release 43264689 Reactome, http://www.reactome.org ReactomeREACT_13604 Reviewed: Jassal, B, 2008-06-13 14:05:49 The LCAT:discoidal HDL complex dissociates reversibly to yield LCAT and a discoidal HDL particle. Spherical HDL binds membrane-associated free cholesterol and phospholipids Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 Pubmed14559902 Reactome Database ID Release 43266299 Reactome, http://www.reactome.org ReactomeREACT_13674 Reviewed: Jassal, B, 2008-06-13 14:05:49 Spherical (mature) HDL particles can acquire additional molecules of free cholesterol and phospholipid from cell membranes. In the body, this is an important step in the so-called reverse cholesterol transport process in which excess cholesterol, notably in foam cells in atherosclerotic plaques, is transferred to HDL particles and transported ultimately to the liver. While studies in vitro and in mutant mice indicate that PLTP (phospholipid transfer protein) plays a major role in this process, its molecular details remain unclear (Oram et al. 2003). PathwayStep4471 PathwayStep4470 PathwayStep4473 PathwayStep4472 PathwayStep4475 PathwayStep4474 PathwayStep4477 PathwayStep4476 CDK11p58 Converted from EntitySet in Reactome Reactome DB_ID: 380452 Reactome Database ID Release 43380452 Reactome, http://www.reactome.org ReactomeREACT_16059 Phospho-Ribosomal protein S6 kinase Converted from EntitySet in Reactome Reactome DB_ID: 199849 Reactome Database ID Release 43199849 Reactome, http://www.reactome.org ReactomeREACT_12696 Ribosomal protein S6 kinase Converted from EntitySet in Reactome Reactome DB_ID: 199858 Reactome Database ID Release 43199858 Reactome, http://www.reactome.org ReactomeREACT_13229 Phospho-ELK1 Converted from EntitySet in Reactome Reactome DB_ID: 198666 Reactome Database ID Release 43198666 Reactome, http://www.reactome.org ReactomeREACT_13225 Phospho-MEF2 Converted from EntitySet in Reactome Reactome DB_ID: 199933 Reactome Database ID Release 43199933 Reactome, http://www.reactome.org ReactomeREACT_12996 MEF2 Converted from EntitySet in Reactome Reactome DB_ID: 199911 Reactome Database ID Release 43199911 Reactome, http://www.reactome.org ReactomeREACT_13049 p-ERK1/2/5 Converted from EntitySet in Reactome Reactome DB_ID: 199878 Reactome Database ID Release 43199878 Reactome, http://www.reactome.org ReactomeREACT_13301 PathwayStep2891 ERK1/2/5 Converted from EntitySet in Reactome Reactome DB_ID: 199955 Reactome Database ID Release 43199955 Reactome, http://www.reactome.org ReactomeREACT_13316 PathwayStep2890 PathwayStep2893 PathwayStep2892 ERK-specific DUSP Converted from EntitySet in Reactome Reactome DB_ID: 203792 Reactome Database ID Release 43203792 Reactome, http://www.reactome.org ReactomeREACT_12976 PathwayStep2887 PathwayStep2888 PathwayStep2889 PathwayStep2883 PathwayStep2884 PathwayStep2885 PathwayStep2886 PathwayStep2898 PathwayStep2899 PathwayStep2896 PathwayStep2897 PathwayStep2894 PathwayStep2895 PathwayStep2869 PathwayStep2864 PathwayStep2863 PathwayStep2862 PathwayStep2861 PathwayStep2868 PathwayStep2867 PathwayStep2866 PathwayStep2865 PathwayStep2870 PathwayStep2871 PathwayStep2873 PathwayStep2872 PathwayStep2875 PathwayStep2874 PathwayStep2877 PathwayStep2876 PathwayStep2879 PathwayStep2878 PathwayStep2880 PathwayStep2881 PathwayStep2882 PathwayStep2849 PathwayStep2848 PathwayStep2847 PathwayStep2846 PathwayStep2845 PathwayStep2844 PathwayStep2843 PathwayStep2842 PathwayStep2841 PathwayStep2840 PathwayStep2859 PathwayStep2858 PathwayStep2855 PathwayStep2854 PathwayStep2857 PathwayStep2856 PathwayStep2851 PathwayStep2850 PathwayStep2853 PathwayStep2852 PathwayStep2860 PathwayStep2820 PathwayStep2823 PathwayStep2824 PathwayStep2821 PathwayStep2822 PathwayStep2827 PathwayStep2828 PathwayStep2825 PathwayStep2826 PathwayStep2829 PathwayStep2830 PathwayStep2831 PathwayStep2832 PathwayStep2833 PathwayStep2834 PathwayStep2835 PathwayStep2836 PathwayStep2837 PathwayStep2838 PathwayStep2839 PathwayStep2801 PathwayStep2802 PathwayStep2800 PathwayStep2809 PathwayStep2807 PathwayStep2808 PathwayStep2805 PathwayStep2806 PathwayStep2803 PathwayStep2804 PathwayStep2810 PathwayStep2811 PathwayStep2812 PathwayStep2813 PathwayStep2818 PathwayStep2819 PathwayStep2814 PathwayStep2815 PathwayStep2816 PathwayStep2817 The 5-HT3 receptor complex is permeable to Na+,K+, and Ca2+ when it binds serotonin (5-HT) Authored: Jassal, B, 2010-09-23 Edited: Jassal, B, 2010-09-23 Pubmed17392525 Pubmed7565620 Pubmed9950429 Reactome Database ID Release 43975311 Reactome, http://www.reactome.org ReactomeREACT_25246 Reviewed: He, L, 2010-11-15 The 5-hydroxytryptamine receptor (5-HT3) family are members of the superfamily of LGICs. Five receptors (5-HT3A-E) form a heteropentamer. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor complex opens the channel, which, in turn, leads to an excitatory response in neurons and is permeable to sodium, potassium, and calcium ions (Miyake et al, 1995; Davies et al, 1999; Niesler et al, 2007). P-type ATPase type IV subfamily transporters may mediate phospholipid transfer Authored: Jassal, B, 2010-09-01 EC Number: 3.6.3.1 Edited: Jassal, B, 2010-09-01 Pubmed15919184 Reactome Database ID Release 43939763 Reactome, http://www.reactome.org ReactomeREACT_24989 Reviewed: He, L, 2010-11-15 The plasma membrane contains a broad range of lipids making up the bilayer. Aminophospholipids such as phosphatidylserine (PS) and phosphatidylethanolamine (PE) are distributed in this bilayer and their arrangement is mediated by the P-type ATPases type IV family (Paulusma and Oude Elferink, 2005). Aminophospholipids are transported from in the internal to the external side of the plasma membrane Authored: Jassal, B, 2010-09-08 EC Number: 3.6.3.1 Edited: Jassal, B, 2010-09-08 Pubmed15919184 Reactome Database ID Release 43947591 Reactome, http://www.reactome.org ReactomeREACT_115892 Reviewed: He, L, 2010-11-15 The plasma membrane contains a broad range of lipids making up the bilayer. Aminophospholipids such as phosphatidylserine (PS) and phosphatidylethanolamine (PE) are distributed in this bilayer and their arrangement is mediated by the P-type ATPases type IV family (Paulusma and Oude Elferink, 2005). The Na+/K+-transporting ATPase trimer exchanges sodium for potassium Authored: Jassal, B, 2010-08-24 EC Number: 3.6.3.9 Edited: Jassal, B, 2010-08-24 Pubmed11062458 Pubmed12119109 Pubmed12953268 Pubmed15174025 Pubmed15260953 Pubmed2430951 Pubmed2477373 Pubmed2559024 Pubmed2838329 Pubmed8798450 Pubmed8918259 Pubmed9048881 Reactome Database ID Release 43936897 Reactome, http://www.reactome.org ReactomeREACT_25287 Reviewed: He, L, 2010-11-15 The sodium/potassium-transporting ATPase is composed of three subunits - alpha (catalytic part), beta and gamma. The trimer catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane, creating the electrochemical gradient which provides energy for the active transport of various nutrients.<br>Four human genes encode the catalytic alpha subunits, ATP1A1-4 (Kawakami et al, 1986; Shull et al, 1989; Ovchinnikov et al, 1988; Keryanov and Gardner, 2002). Defects in ATP1A2 cause alternating hemiplegia of childhood (AHC) (Swoboda et al, 2004). Another defect in ATP1A2 causes familial hemiplegic migraine type 2 (FHM2) (Vanmolkot et al, 2003). Defects in ATP1A3 are the cause of dystonia type 12 (DYT12) (de Carvalho Aguiar et al, 2004).<br><br>Three human genes encode the non-catalytic beta subunits, ATP1B1-3. The beta subunits are thought to mediate the number of sodium pumps transported to the plasma membrane (Lane et al, 1989; Ruiz et al, 1996; Malik et al, 1996). The human gene FXYD2 encodes the non-catalytic gamma subunit of Na+/K+ ATPase (Kim et al, 1997). Defects in FXYD2 are the cause of hypomagnesemia type 2 (HOMG2) (Meij et al, 2000). The K+-transporting ATPase mediates the exchange of potassium and hydrogen ions Authored: Jassal, B, 2010-08-26 EC Number: 3.6.3.10 Edited: Jassal, B, 2010-08-26 Pubmed1656976 Pubmed2160952 Pubmed8045293 Reactome Database ID Release 43937311 Reactome, http://www.reactome.org ReactomeREACT_25173 Reviewed: He, L, 2010-11-15 The potassium-transporting ATPase heterodimer catalyzes the hydrolysis of ATP coupled with the exchange of H+ and K+ ions across the plasma membrane. It is composed of alpha and beta chains. Two human genes encode the catalytic alpha subunit, ATP4A and ATP12A (Maeda et al, 1990; Grishin et al, 1994). ATP4A is responsible for acid production in the stomach. <br>ATP12A is responsible for potassium absorption in various tissues. One human gene encodes the beta subunit, ATP4B (Ma et al, 1991). Calcium is sequestered to the golgi by secretory pathway calcium-ATPases (SPCAs) Accumulation of calcium into the Golgi apparatus is mediated by sarco(endo)plasmic reticulum calcium-ATPases (SERCAs) and by secretory pathway calcium-ATPases (SPCAs). There are two human genes which encode SPCAs; ATP2C1 and ATP2C2 which encode magnesium-dependent calcium-transporting ATPase type 2C members 1 and 2 (ATP2C1 and 2) respectively (Sudbrak et al, 2000; Vanoevelen et al, 2005). Defects in ATP2C1 are the cause of Hailey-Hailey disease (HHD), an autosomal dominant disease characterized by persistent blisters and erosions of the skin (Hu et al, 2000). Authored: Jassal, B, 2010-08-24 EC Number: 3.6.3.8 Edited: Jassal, B, 2010-08-24 Pubmed10615129 Pubmed10767338 Pubmed15831496 Reactome Database ID Release 43936883 Reactome, http://www.reactome.org ReactomeREACT_25301 Reviewed: He, L, 2010-11-15 Sequestration of Ca2+ to intracellular stores Authored: Akkerman, JW, 2009-06-03 EC Number: 3.6.3.8 Edited: Jupe, S, 2010-11-25 Intracellular pools of calcium serve as the source for inositol 1,4,5-trisphosphate (IP3) -induced alterations in cytoplasmic free calcium. In most human cells calcium is stored in the lumen of the sarco/endoplastic reticulum by ATPases known as SERCAs. In platelets, SERCAs transport calcium into the platelet dense tubular network. SERCAs are P-type ATPases, similar to the plasma membrane Na and Ca-ATPases. Humans have three genes for SERCA pumps; SERCA1, SERCA2 and SERCA3. Studies on SERCA1 suggest that it binds two Ca ions from the cytoplasm and is subsequently phosphorylated at Asp351 before translocating the Ca into the SR lumen. There is a counter transport of two or possibly three protons ensuring partial charge balancing. Pubmed12167852 Pubmed2844796 Pubmed2953725 Pubmed7702581 Reactome Database ID Release 43427910 Reactome, http://www.reactome.org ReactomeREACT_25316 Reviewed: He, L, 2010-11-15 has a Stoichiometric coefficient of 2 Copper sequestration by copper-transporting ATPase 2 Authored: Jassal, B, 2010-08-24 Edited: Jassal, B, 2010-08-24 Pubmed7626145 Pubmed8298639 Pubmed9307043 Reactome Database ID Release 43936895 Reactome, http://www.reactome.org ReactomeREACT_24963 Reviewed: He, L, 2010-11-15 The human gene ATP7B encodes the copper-transporting ATPase 2 (ATPase2, Wilson's protein) which is expressed mainly in the liver, brain and kidneys (Bull et al, 1993). ATPase2 resides on the trans-Golgi membrane where it it thought to sequester copper from the cytosol into the golgi (Yang et al, 1997). Defects in ATP7B are the cause of Wilson disease (WD), an autosomal recessive disorder of copper metabolism characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain (Thomas et al, 1995). Copper export from cells by copper-transporting ATPase1 Authored: Jassal, B, 2010-08-24 EC Number: 3.6.3.4 Edited: Jassal, B, 2010-08-24 Pubmed10401004 Pubmed10484781 Pubmed8490646 Pubmed8490659 Pubmed9147644 Reactome Database ID Release 43936802 Reactome, http://www.reactome.org ReactomeREACT_25071 Reviewed: He, L, 2010-11-15 The human gene ATP7A (MNK) encode the copper-transporting ATPase 1 (ATPase1, Menkes protein) which is expressed in most tissues except the liver (Vulpe et al, 1993; Chelly et al, 1993). Normally, ATPase1 resides on the trans-Golgi membrane (Dierick et al, 1997). When cells are exposed to excessive copper levels, it is rapidly relocalized to the plasma membrane where it functions in copper efflux (Petris and Mercer, 1999). Defects in ATP7A are the cause of Menkes disease (MNKD), an X-linked recessive disorder of copper metabolism characterized by generalized copper deficiency (Ambrosini and Mercer, 1999). Ferritin stores iron Authored: Stephan, R, 2011-01-10 EC Number: 1.16.3.1 Edited: Jassal, B, 2011-09-05 Ferritin oxidises Fe(II) ions to Fe(III), migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Harrison & Arrosio 1996). Pubmed8695634 Reactome Database ID Release 431562626 Reactome, http://www.reactome.org ReactomeREACT_115629 Reviewed: D'Eustachio, P, 2011-10-26 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 L1 dimer binds Ankyrin Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 recruits membrane skeletal component ankyrin to cell to cell contact sites in response to cis interaction with homophilic axonin 1/TAG 1 or trans L1 L1 homophilic interaction although in mammalian cells trans binding interactions are not required. L1 interacts with ankyrin proteins through two highly conserved amino acid sequence motifs, LADY and FIGQY.<br>Ankyrin binding immobilizes L1 molecules in the neuronal plasma membrane. This interaction is required for axon maintenance. L1 also elevates cyclic AMP levels in neurons via ankyrin B and mediates Ca+2 dependent attraction.The L1/ankyrin interaction is a vital determinant of synaptic targeting of retinal axons to the superior colliculus and cooperates with EphrinB/EphB signaling to induce axon branch attraction. Pubmed11222639 Pubmed12925712 Pubmed18171935 Pubmed19110015 Pubmed9837910 Reactome Database ID Release 43443049 Reactome, http://www.reactome.org ReactomeREACT_22204 Reviewed: Maness, PF, 2010-02-16 PRDM9 Binds Recombination Hotspot Motifs in DNA Authored: May, B, 2010-07-19 Edited: May, B, 2010-07-19 PR-domain containing 9 (PRDM9) protein is a meiosis specific histone H3 lysine 4 (H3K4) methyltransferase, with a zinc finger domain at the C-terminus. Meiotic recombination hotspots in humans and mice are known to be sites for histone modification. PRDM9 has been shown to affect recombination profiles and meiotic recombination hotspot activity, by binding specific sequence motifs within or close to recombination hotspots (Baudat et al. 2010, Myers et al. 2010), and reorganizing chromatin structure. Variation within this protein has been proven to negatively affect human male fertility, with certain patients harboring variants at the PRDM9 locus exhibiting azoospermia. PRDM9 recognizes a specific sequence motif, but also acts at human hotspots lacking the motif, suggesting it is capable of acting in cis to regulate hotspot activity.<br>These specific sequence motifs also appear to be species specific, as the degenerate 13-bp motif associated with 40% of human hotspots does not function in chimpanzees, probably as a result of the rapidly evolving zinc finger domain (Myers et al. 2010). Subtle changes in the zinc finger array in humans can have global effects on recombination throughout the human genome, enhancing or decreasing the activity of a hotspot, or even creating entirely new hotspots (Berg et al. 2010). In addition to its role in regulating recombination hotspot activity, PRDM9 also appears to have a role in maintaining stability within the human genome, as variation in the PRDM9 gene can lead to large-scale genomic rearrangements and minisatellite instability in humans. Pubmed20044539 Pubmed20044541 Pubmed20818382 Reactome Database ID Release 43912363 Reactome, http://www.reactome.org ReactomeREACT_27253 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Trimethylation of Histone H3 by PRDM9 As inferred from experiments in vitro with mouse Prdm9, human PRDM9 methylates histone H3 dimethylated at lysine-4 to yield histone H3 trimethylated at lysine-4. Authored: May, B, 2011-02-07 Edited: May, B, 2011-02-07 Pubmed16292313 Reactome Database ID Release 431214188 Reactome, http://www.reactome.org ReactomeREACT_27242 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 has a Stoichiometric coefficient of 2 Formation of Double-strand Break in DNA by SPO11 Authored: May, B, 2010-07-19 EC Number: 3.1.21 Edited: May, B, 2010-07-19 Reactome Database ID Release 43912368 Reactome, http://www.reactome.org ReactomeREACT_27239 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 The gene encoding SPO11 shares sequence similarity to TopoVI, a type II topoisomerase. SPO11 dimers cleave both strands of DNA. Each subunit of the dimer remains covalently attached to the 5' end of one strand of DNA via a phosphodiester linkage to a conserved tyrosine residue of SPO11. In addition to SPO11, work from budding yeast has shown a total of 7 proteins essential for double strand break formation. The mammalian ortholog of Mei4 (S. cerevisiae) as well as a mammalian-specific gene called Mei1 are essential to formation of meiotic double strand breaks. Heterdimerization of CEACAMs Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed17167768 Reactome Database ID Release 43202717 Reactome, http://www.reactome.org ReactomeREACT_12073 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 The presence of CEACAM dimers was shown to lead to an increase in the binding of the integrin alph5 beta1 receptor to its ligand fibronectin, without changing its cell surface levels, resulting in increased adhesion of these cells to fibronectin. has a Stoichiometric coefficient of 2 TGFBR2 is recruited to tight junctions-associated, Pard6a-bound, TGFBR1 after TGF-beta stimulation Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 In human embryonic kidney cell line, HEK293, TGFBR2 binds TGFBR1 anchored to tight junctions through association with exogenously expressed FLAG-tagged mouse Pard6a (Ozdamar et al. 2005). Pubmed15761148 Reactome Database ID Release 432161160 Reactome, http://www.reactome.org ReactomeREACT_120950 Reviewed: Huang, Tao, 2012-05-14 Recruitment of GRB2:Sos1 to P-Shc1:P-Erbb2mut complex Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Exogenously expressed human GRB2 in complex with mouse Sos1 is recruited to phosphorylated mouse Shc1 bound to rat Neu oncoprotein (mutant Erbb2 with valine 661 replaced with glutamic acid, isolated from rat neuroblastoma) stably expressed in transformed mouse fibroblasts. Pubmed8530511 Reactome Database ID Release 431250500 Reactome, http://www.reactome.org ReactomeREACT_115920 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Calcineurin Dephosphorylates NFATC1/2/3 As inferred from mouse (Okamura et al. 2000), calcineurin dephosphorylates NFATC2 at 13 serine residues (Batiuk et al. 1997, Kim et al. 2000). B lymphocytes also contain NFATC2 and NFATC3 which are inferred to undergo dephosphorylation at homologous serines. Dephosphorylation of NFATs exposes a nuclear localization signal which cause NFATs to be imported into the nucleus (Kim et al. 2000). In mouse, Calcineurin is observed to also transit into the nucleus in a complex with NFATs and may remain associated (Shibasaki et al. 1996). Authored: May, B, 2011-12-11 Edited: May, B, 2011-12-11 Pubmed11030334 Pubmed11231878 Pubmed7657645 Pubmed8684469 Pubmed9106655 Pubmed9312192 Reactome Database ID Release 432025882 Reactome, http://www.reactome.org ReactomeREACT_118664 Reviewed: Wienands, J, 2012-02-11 Uchl5 deubiquitinates TGFBR1 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 3.1.2.15 Edited: Jassal, B, 2012-04-10 Pubmed16027725 Reactome Database ID Release 432179313 Reactome, http://www.reactome.org ReactomeREACT_120821 Recombinant mouse Uchl5 (Uch37) exogenously expressed in HEK293 cells deubiquitinates recombinant human TGFBR1. This stabilizes TGFBR1 and prolongs signaling by TGF-beta receptor complex. Deubiqutination of Smad7 has not been examined in this context (Wicks et al. 2005). Reviewed: Huang, Tao, 2012-05-14 The glycine receptor complex is permeable to Cl- when glycine binds to it Authored: Jassal, B, 2010-09-24 Edited: Jassal, B, 2010-09-24 Pubmed2155780 Pubmed8717357 Pubmed9677400 Reactome Database ID Release 43975389 Reactome, http://www.reactome.org ReactomeREACT_25304 Reviewed: He, L, 2010-11-15 The glycine receptor is a ligand-gated ion channel. It is functional as a heteropentamer, consisting of alpha and beta subunits. With no ligand bound, the receptor complex is closed to chloride ions. Binding of the inhibitory neurotransmitter glycine to this receptor complex increases chloride conductance into neurons and thus produces hyperpolarization (inhibition of neuronal firing) (Grenningloh et al 1990; Nikolic et al, 1998; Handford et al, 1996). Reduction of extracellular Fe3+ Authored: Stephan, R, 2010-07-05 Cytochrome b reductase 1 not only reduces ferrous iron in the brush-border membrane but also in the airways. It is upregulated on iron starvation. However, its electron donor molecule is still unknown (Oakhill et al, 2007; Turi et al, 2006). EC Number: 1.16 Edited: Jassal, B, 2010-07-30 Pubmed16510471 Pubmed18194661 Reactome Database ID Release 43917805 Reactome, http://www.reactome.org ReactomeREACT_25114 Reviewed: D'Eustachio, P, 2010-11-05 Oxidation of Fe2+ by ceruloplasmin Authored: Stephan, R, 2010-07-04 EC Number: 1.16.3.1 Edited: Jassal, B, 2010-07-30 In tissues other than the duodenum, ceruloplasmin oxidizes ferrous iron after it is exported from the cell (Sato et al, 1990). Pubmed2154449 Reactome Database ID Release 43917891 Reactome, http://www.reactome.org ReactomeREACT_25098 Reviewed: D'Eustachio, P, 2010-11-05 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Passive Transport of Glycerol out of Cell by Aquaporin-7 Aquaporin-7 (AQP7) passively transports glycerol and water across the plasma membrane according to the osmotic gradient. AQP7 is expressed in adipocytes under the direct control of the PPARG and RXRA nuclear receptors. Expression of AQP7 correlates with release of glycerol from adipocytes. AQP7 is seen to translocate from the nuclear periphery to the plasma membrane during adrenaline-stimulated lipolysis. In rat AQP7 also transports urea. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed11952783 Pubmed16325777 Pubmed17961083 Pubmed18555844 Pubmed9405233 Reactome Database ID Release 43432074 Reactome, http://www.reactome.org ReactomeREACT_23873 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport of Glycerol into Cell by Aquaporin-9 Aquaporin-9 (AQP9) passively transports water, glycerol, urea, and some other small neutral solutes across the plasma membrane according to the osmotic gradient. AQP9 is expressed in the sinusoidal plasma membrane in the liver facing the portal vein where it is believed to be responsible for glycerol uptake as part of gluconeogenesis. AQP9 is also expressed in glia, neurons, and peripheral leukocytes. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed10564231 Pubmed11027599 Pubmed17961083 Pubmed18762715 Pubmed19590626 Reactome Database ID Release 43432049 Reactome, http://www.reactome.org ReactomeREACT_23966 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Extracellular ferriheme uptake through the apical membrane of enterocytes Authored: Stephan, R, 2010-07-01 Edited: Jassal, B, 2010-07-30 Pubmed16143108 Reactome Database ID Release 43917870 Reactome, http://www.reactome.org ReactomeREACT_25025 Reviewed: D'Eustachio, P, 2010-11-05 Uptake of iron from meat happens in the form of ferriheme, and via the same transporter that is used for folate. The process is more effective than taking up iron ions (Shayeghi M et al, 2005). Oxidation of Fe2+ by hephaestin Authored: Stephan, R, 2010-07-04 EC Number: 1.16.3.1 Edited: Jassal, B, 2010-07-30 Hephaestin oxidizes ferrous iron after export from duodenal cells to enable its transport via transferrin (Griffiths et al, 2005). Pubmed16274220 Reactome Database ID Release 43917933 Reactome, http://www.reactome.org ReactomeREACT_25198 Reviewed: D'Eustachio, P, 2010-11-05 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 apo-Transferrin is loaded with two iron ions Authored: Stephan, R, 2010-07-07 Edited: Jassal, B, 2010-07-30 Pubmed16793765 Reactome Database ID Release 43917888 Reactome, http://www.reactome.org ReactomeREACT_25385 Reviewed: D'Eustachio, P, 2010-11-05 Transferrin is the main transporter of iron in the blood. It can take up two ferric iron ions (Wally et al, 2006). has a Stoichiometric coefficient of 2 Passive Transport of Water out of Cell by Aquaporin-4 Aquaporin-4 (AQP4) passively transports water across the plasma membrane according to the osmotic gradient. AQP4 is expressed in the collecting duct of the kidney and in astroglial cells at the blood-brain barrier and ependymal cells lining the ventricles of the brain. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed14514735 Pubmed17178220 Pubmed18511455 Pubmed19170255 Pubmed19383790 Pubmed8855281 Reactome Database ID Release 43432067 Reactome, http://www.reactome.org ReactomeREACT_24005 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport of Water out of Cell by Aquaporin-3 Aquaporin-3 (AQP3) passively transports water and glycerol across the plasma membrane according to the osmotic gradient. AQP3 is expressed in airway epithelia, secretory glands, skin, the collecting ducts of the kidney, and the basolateral surface of intestinal epithelium.. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed15703994 Pubmed18678926 Pubmed7503232 Pubmed7526388 Pubmed7538665 Pubmed8063828 Pubmed9369468 Pubmed9374639 Pubmed9374640 Reactome Database ID Release 43445714 Reactome, http://www.reactome.org ReactomeREACT_23789 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport of Water out of Cell by Aquaporin-1 Aquaporin-1 (AQP1) passively transports water across the plasma membrane according to the osmotic gradient. In the kidney AQP1 is expressed in endothelial cells of the vasa recta, the proximal tubule, and thin descending limb of Henle, where it functions to recover water from filtrate during urine formation. AQP1 is expressed in many other tissues, such as red blood cells, pancreas, and choroid plexus. AQP1 plays a role in forming cerebrospinal fluid. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed11034202 Pubmed12801959 Pubmed1373524 Pubmed14514735 Pubmed14592814 Pubmed14701836 Pubmed1510932 Pubmed18202181 Pubmed3049610 Pubmed7678419 Pubmed9829975 Reactome Database ID Release 43432054 Reactome, http://www.reactome.org ReactomeREACT_23786 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Acidification of Tf:TfR1 containing endosome Authored: Stephan, R, 2010-07-13 Edited: Jassal, B, 2010-07-30 Pubmed17662945 Reactome Database ID Release 43917841 Reactome, http://www.reactome.org ReactomeREACT_25268 Reviewed: D'Eustachio, P, 2010-11-05 The function of V-type proton pumping ATPases is basically the same as that of F-type ATPases, except that V-ATPases cannot synthesize ATP from the proton motive force, the reverse reaction of pumping. When pumping, ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons into the phagosome (Adachi et al. 2007). has a Stoichiometric coefficient of 3 Iron separates from the Tf:TfR1 complex Authored: Stephan, R, 2010-07-14 Edited: Jassal, B, 2010-07-30 Pubmed16564538 Reactome Database ID Release 43917835 Reactome, http://www.reactome.org ReactomeREACT_25277 Reviewed: D'Eustachio, P, 2010-11-05 When endosomal pH reaches 6,0, protons replace the iron ions in the transferrin/receptor complex (Hemadi et al, 2006). has a Stoichiometric coefficient of 4 Reduction of Fe3+ in the endosome Authored: Stephan, R, 2010-07-14 EC Number: 1.16.1 Edited: Jassal, B, 2010-07-30 Pubmed16227996 Pubmed16609065 Reactome Database ID Release 43917811 Reactome, http://www.reactome.org ReactomeREACT_24919 Reviewed: D'Eustachio, P, 2010-11-05 The iron ions that are no longer bound to transferrin are reduced by the metalloreductase STEAP3, an endosomal membrane protein. The electron donor partner of the enzyme is unknown (Ohgami et al, 2005; Ohgami et al, 2006). Iron diffuses out of the endosome Authored: Stephan, R, 2010-07-20 Edited: Jassal, B, 2010-07-30 Mucolipin-1 is an iron ion channel specifically expressed in endosome and lysosome membranes. It catalyzes the diffusion of Fe2+ ions into the cytosol (Dong et al, 2008). Pubmed18794901 Reactome Database ID Release 43917936 Reactome, http://www.reactome.org ReactomeREACT_25069 Reviewed: D'Eustachio, P, 2010-11-05 Recycling of Tf endosome to plasma membrane Acidification of the endosome does not continue further, and the endosome fuses again with the plasma membrane (Willingham et al, 1984; Harding et al, 1983). Authored: Stephan, R, 2010-07-20 Edited: Jassal, B, 2010-07-30 Pubmed6141558 Pubmed6309857 Reactome Database ID Release 43917814 Reactome, http://www.reactome.org ReactomeREACT_25389 Reviewed: D'Eustachio, P, 2010-11-05 apo-Transferrin dissociates from the receptor complex After about 15 minutes on the cell surface, the equilibrium favors dissociation of transferrin, and the transferrin receptor 1 dimer is available again for binding (Hemadi et al., 2006). Authored: Stephan, R, 2010-07-28 Edited: Jassal, B, 2010-07-30 Pubmed16564538 Reactome Database ID Release 43917839 Reactome, http://www.reactome.org ReactomeREACT_24927 Reviewed: D'Eustachio, P, 2010-11-05 has a Stoichiometric coefficient of 2 Export of heme to the blood by ABCG2 Authored: Stephan, R, 2010-07-07 Edited: Jassal, B, 2010-07-30 Pubmed12958161 Pubmed14576842 Pubmed15044468 Reactome Database ID Release 43917979 Reactome, http://www.reactome.org ReactomeREACT_25155 Reviewed: D'Eustachio, P, 2010-11-05 The efflux pump ABCG2 can relieve cells from toxic heme concentrations even against a concentration gradient. It is expressed in placenta, liver, and small intestine (Krishnamurthy et al, 2004; Doyle & Ross, 2003; Zhang et al, 2003). Export of heme to the blood by FLVCR Authored: Stephan, R, 2010-07-06 Edited: Jassal, B, 2010-07-30 Pubmed15369674 Pubmed18815190 Reactome Database ID Release 43917892 Reactome, http://www.reactome.org ReactomeREACT_25203 Reviewed: D'Eustachio, P, 2010-11-05 The heme transporter FLVCR is expressed in intestine and liver tissue, but also in developing erythroid cells where it is required to protect them from heme toxicity (Quigley et al, 2004; Rey et al, 2008). Separation of endosome from the plasma membrane Authored: Stephan, R, 2010-07-12 Edited: Jassal, B, 2010-07-30 Pubmed6141558 Pubmed6309857 Reactome Database ID Release 43917807 Reactome, http://www.reactome.org ReactomeREACT_24977 Reviewed: D'Eustachio, P, 2010-11-05 The transferrin/receptor complex is internalized as a clathrin-coated vesicle (Willingham et al, 1984; Harding et al, 1983). Loaded transferrin binds to TfR1 Authored: Stephan, R, 2010-07-11 Edited: Jassal, B, 2010-07-30 Pubmed11800564 Reactome Database ID Release 43917987 Reactome, http://www.reactome.org ReactomeREACT_24945 Reviewed: D'Eustachio, P, 2010-11-05 Transferrin receptor 1 molecules can be found on the outside of any cell. Transferrin transports two iron ions through the blood and two transferrins bind to a TfR1 dimer (West et al, 2001). has a Stoichiometric coefficient of 2 Dissociation of SHC-P from insulin receptor At the beginning of this reaction, 1 molecule of 'phospho-SHC: activated insulin receptor' is present. At the end of this reaction, 1 molecule of 'phospho-SHC', and 1 molecule of 'activated insulin receptor' are present.<br><br> This reaction takes place on the 'internal side of plasma membrane'.<br> Reactome Database ID Release 4374743 Reactome, http://www.reactome.org ReactomeREACT_596 Phosphorylation of SHC At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'SHC:activated insulin receptor' are present. At the end of this reaction, 1 molecule of 'phospho-SHC: activated insulin receptor', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'transmembrane receptor protein tyrosine kinase activity' of 'SHC:activated insulin receptor'.<br> EC Number: 2.7.10.1 Reactome Database ID Release 4374742 Reactome, http://www.reactome.org ReactomeREACT_2015 Binding of SHC to insulin receptor At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'SHC transforming protein' are present. At the end of this reaction, 1 molecule of 'SHC:activated insulin receptor' is present.<br><br> This reaction takes place on the 'internal side of plasma membrane'.<br> Reactome Database ID Release 4374740 Reactome, http://www.reactome.org ReactomeREACT_106 Formation of Early Recombination Nodule Authored: May, B, 2010-07-19 Edited: May, B, 2010-07-19 Formation of Meiotic Single-stranded DNA Invasion Complex Pubmed10562567 Pubmed15164066 Pubmed16123081 Pubmed17541404 Pubmed17981954 Pubmed18535008 Pubmed20062530 Pubmed9008167 Pubmed9311981 Pubmed9826763 Reactome Database ID Release 43912503 Reactome, http://www.reactome.org ReactomeREACT_27160 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Two RecA homologs, RAD51 and the meiosis-specific DMC1, coat single-stranded 3' ends of DNA produced by resection of double-strand breaks (Barlow et al. 1997, Masson et al. 1999, Sehorn et al. 2004, Sheridan et al. 2008, Okorokov et al. 2010). RAD51 and DMC1 interact and colocalize to the same early recombination nodules (Masson et al. 1999). Knockouts of DMC1 abolish recombination and synapsis therefore RAD51 is not sufficient for recombination.<br>Immunocytology shows the RPA heterotrimer arrives at recombination nodules with or after RAD51 and DMC1 (Golub et al. 1999, Oliver-Bonet et al. 2005, Oliver-Bonet et al. 2007)). (In mitotic recombination RPA precedes RAD51.)<br>BRCA1 and BRCA2 are found extensively distributed on synaptonemal complexes. Results from human cells and knockout mice indicate that BRCA2, RAD51C, and TEX15 participate in loading RAD51 and DMC1 onto single-stranded DNA (Thorslund et al. 2007). BRCA1 participates in loading RAD51 but not DMC1 (Scully et al. 1997).<br>The kinase ATM is also localized to double-strand breaks where it phosphorylates histone H2AX.<br>In human spermatocytes about 350 early recombination nodules form but only about 10% will continue on to make crossovers. The remaining 90% are believed to be resolved by synthesis-dependent strand annealing, which transfers short segments of DNA (about 0.2-2.0 kilobases) between homologs. Meiotic Strand Invasion Authored: May, B, 2010-07-19 Edited: May, B, 2010-07-19 Following double strand break (DSB) formation and strand resection, RAD51 and DMC1 coat single-stranded 3' ends of DNA and catalyze the search for homology and strand invasion into the DNA duplex of the chromosomal homolog (Baumann et al. 1996, Barlow et al. 1997, Benson et al. 1998, Baumann and West 1999, Masson et al. 1999, Sehorn et al. 2004, Murayama et al. 2008). The invading strand displaces the original strand of the chromosomal homolog creating a D-loop structure. Other proteins present in the complex are inferred from cytology (Barlow et al. 1997, Oliver-Bonet et al. 2005, Oliver-Bonet et al. 2007). Formation of Meiotic Heteroduplex Pubmed10438626 Pubmed10562567 Pubmed15164066 Pubmed16123081 Pubmed17981954 Pubmed18256600 Pubmed8929543 Pubmed9311981 Pubmed9450758 Reactome Database ID Release 43912458 Reactome, http://www.reactome.org ReactomeREACT_27300 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Removal of SPO11 and Resection of 5' Ends of DNA Authored: May, B, 2010-07-19 Edited: May, B, 2010-07-19 Pubmed17965729 Reactome Database ID Release 43912397 Reactome, http://www.reactome.org ReactomeREACT_27209 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 SPO11 forms a dimer and each subunit cleaves a single strand of DNA, thus creating a double-strand break. After cleaving DNA, a SPO11 subunit remains covalently attached to each 5' end via a tyrosine residue. SPO11 is removed from the DNA by cleavage of single strands 3' to the attached SPO11. The products are a resected 5' end (protruding 3' overhang) and a covalent complex of SPO11 with an oligonucleotide. Two size classes of oligonucleotide are observed: 12 to 26 nucleotides and 28 to 34 nucleotides. The enzyme responsible for excision of SPO11:oligonucleotide in mammals is inferred to be MRE11 in the MRE11:RAD50:NBS1:CtIP complex based on conservation of the reaction mechanism across yeast, plants, and animals (Sartori et al. 2007).<br>In fission and budding yeast the Mre11:Rad50:Xrs2/Nbs1 (MRN/MRX) complex is required for removal of SPO11. In human somatic cells the MRN complex together with CtIP resects double-strand breaks in somatic cells but the role of the MRN complex in mammalian meiosis, though essential, is unclear (Sartori et al. 2007).<br>After excision of SPO11:oligonucleotide the recessed 5' end is further resected by unknown exonucleases. Insulin binding Authored: Williams, MG, 2008-09-08 16:49:12 Pubmed11737239 Pubmed7781591 Pubmed8276779 Reactome Database ID Release 4374716 Reactome, http://www.reactome.org ReactomeREACT_1459 Under normal physiological conditions blood glucose levels are kept under tight control by a series of regulated steps that ensure glucose homeostasis. Upon feeding glucose levels rise and in response to this the body secretes insulin from pancreatic beta-cells into the blood. At physiological concentrations insulin is present in the blood in its monomeric form. Binding of insulin to its receptor occurs on the receptor alpha-subunits. There are two binding domains involved on the receptor (L1 and L2) and it is thought that the amino-terminus of insulin binds with L1 on one of the alpha-subunits and the carboxyterminus with L2 on the other alpha-subunit.<p>The binding of insulin to its receptor causes a conformational change in the alpha-subunits. This in turn produces a conformational change in the beta-subunits leading to the activation of the intrinsic insulin receptor tyrosine kinase. Autophosphorylation of insulin receptor Authored: Bevan, AP, 2003-07-31 08:01:55 EC Number: 2.7.10.1 For the receptor to autophosphorylate requires a lysine at position 1030 to stabilize the gamma phosphate of ATP whilst the adenosine of ATP itself interacts with three glycines at residues 1003 - 1008. The first tyrosine residues to be autophosphorylated are 1158, 1162 and 1163 in the tyrosine kinase domain. This is shortly followed by tyrosine 972 in the juxtamembrane domain and tyrosines 1328 and 1330. These tyrosines fall into the three distinct tyrosine phosphorylation domains of the beta-subunit. In total there are 13 potential tyrosines that may be phosphorylated. The receptor phosphorylates itself in a trans rather than cis manner. That is one beta-subunit of the receptor phosphorylates the other rather than itself. Pubmed8039601 Pubmed8276779 Reactome Database ID Release 4374715 Reactome, http://www.reactome.org ReactomeREACT_2211 has a Stoichiometric coefficient of 12 Formation of Meiotic Holliday Junction Authored: May, B, 2010-07-02 Edited: May, B, 2010-07-02 Formation of Meiotic Recombination Intermediate Pubmed10029069 Pubmed10728666 Pubmed10734115 Pubmed15304223 Pubmed16123081 Pubmed17977839 Reactome Database ID Release 43912496 Reactome, http://www.reactome.org ReactomeREACT_27234 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 The 3' end of the invading strand is extended by an unknown DNA polymerase and the extended strand is then ligated back to the original homolog, generating a double Holliday junction. MSH4 and MSH5 form heterodimers which bind Holliday junctions and, in the presence of ATP, slide along the parental duplexes (Bocker et al. 1999, Snowden et al. 2004, Snowden et al. 2008). MSH4 is present at hundreds of meiotic nodules during late zygotene but only about 10% of these nodules become crossovers (Oliver-Bonet et al. 2005). Bloom Syndrome protein (BLM) and Topoisomerase IIIa (TOP3A) are also present and may promote homologous recombination repair without crossing over (Johnson et al. 2000, Wu et al. 2000). Resolution of Meiotic Holliday Junction Authored: May, B, 2010-07-02 Edited: May, B, 2010-07-02 Meiotic Holliday junctions are cleaved to yield either crossovers or non?crossovers (gene conversions). The resolvase or resolvases responsible for cleavage are unknown but a resolvase complex may include SLX4 and/or GEN1.<br>Two classes of crossovers have been defined: class I crossovers are dependent on the MutL homologs, MLH1 and MLH3, while class II crossovers are dependent on the MUS81-EME1 endonuclease. Class I crossovers constitute 90-95% of all crossovers, and correspond to meiotic nodules that contain MLH1and MLH3. These arise as a subset of the many hundreds of MSH4/MSH5-positive meiotic nodules that arise at the time of double Holliday junction formation. What happens to all the other meiotic nodules is not clear, but they most likely follow a second pathway that results in non-crossovers (or gene conversions). MLH1 and MLH3 form heterodimers that repair mismatches in duplex DNA. In mouse, MLH1 is required for crossovers but not for non?crossover resolution of Holliday junctions. About 10% of early meiotic nodules are somehow selected to become Class I crossover events, possibly by first losing BLM (and probably associated TOP3A), and acquiring MLH1 and MLH3.<br>The selection of sites for class II crossovers follows an, as yet, unknown pathway, but almost certainly stems from the same initiating D-loop intermediate.<br>In the process known as crossover interference, the presence of a crossover nodule inhibits formation of nearby crossover nodules so that crossovers are not clustered and each chromosome bivalent has at least one crossover. In mouse, crossover interference is seen among nodules at two stages: RPA?containing nodules during late zygonema and MLH1?containing nodules during pachynema. Class II crossovers are not subject to interference constraints. Pubmed10928988 Pubmed11292842 Pubmed16123081 Pubmed16322221 Pubmed9781043 Reactome Database ID Release 43912429 Reactome, http://www.reactome.org ReactomeREACT_27206 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 TSG101 Converted from EntitySet in Reactome Reactome DB_ID: 184307 Reactome Database ID Release 43184307 Reactome, http://www.reactome.org ReactomeREACT_27851 ubiquitin Converted from EntitySet in Reactome Reactome DB_ID: 184258 Reactome Database ID Release 43184258 Reactome, http://www.reactome.org ReactomeREACT_27496 Cdc25 Converted from EntitySet in Reactome Reactome DB_ID: 186979 Reactome Database ID Release 43186979 Reactome, http://www.reactome.org ReactomeREACT_9309 OAT1-3 transport organic anions with antiport of dicarboxylic acids Authored: Jassal, B, 2010-03-25 Edited: Jassal, B, 2010-03-25 Pubmed10049739 Pubmed11327718 Pubmed14586168 Pubmed15901346 Pubmed9762842 Pubmed9887087 Pubmed9950961 Reactome Database ID Release 43561041 Reactome, http://www.reactome.org ReactomeREACT_22250 Reviewed: He, L, 2010-05-10 The human gene SLC22A6 encodes organic anion transporter1 (OAT1). It was originally characterized in mouse as Novel Kidney Transcript (NKT). OAT1 is located on the basolateral membrane of the proximal tubule in human kidney as well as in the brain (Reid G et al, 1998; Lu R et al, 1999; Hosoyamada M et al, 1999). The human gene SLC22A7 encodes organic anion transporter 2 (OAT2) and is highly expressed in the liver and kidney (Sun W et al, 2001; Kobayashi Y et al, 2005). The human gene SLC22A8 encodes organic anion transporter 3 (OAT3) which is expressed mainly in the brain and kidney (Race JE et al, 1999; Bakhiya A et al, 2003). <br>OAT1-3 transport organic anions such as p-aminohippurate and drugs such as cimetidine and acyclovir. This transport is is coupled with an efflux of one molecule of endogenous dicarboxylic acid such as alpha-ketoglutarate (2-oxoglutarate). OAT2 is classified as both a transporter of organic anions and sulphate conjugates. OAT2 and OAT4 mediate transport of sulphate conjugates Authored: Jassal, B, 2010-03-25 Edited: Jassal, B, 2010-03-25 Pubmed10660625 Pubmed11327718 Pubmed15037815 Pubmed15901346 Reactome Database ID Release 43561059 Reactome, http://www.reactome.org ReactomeREACT_22294 Reviewed: He, L, 2010-05-10 The human gene SLC22A7 encodes organic anion transporter 2 (OAT2) and is highly expressed in the liver and kidney (Sun W et al, 2001; Kobayashi Y et al, 2005). The human gene SLC22A11 encodes organic anion transporter 4 (OAT4) which is highly expressed in the placenta and kidney (Cha SH et al, 2000; Ekaratanawong S et al, 2004). Both of these transporters mediate the influx of sulfate conjugates with antiport of dicarboxylic acid. OAT2 is classified as both a transporter of organic anions and sulphate conjugates. Carnitine transporters mediates sodium-dependent uptake of carnitine Authored: Jassal, B, 2010-03-19 Edited: Jassal, B, 2010-03-19 Pubmed10072434 Pubmed12089149 Pubmed12372408 Pubmed12384147 Pubmed15107849 Pubmed9685390 Reactome Database ID Release 43549297 Reactome, http://www.reactome.org ReactomeREACT_22187 Reviewed: He, L, 2010-05-10 The human gene SLC22A5 encodes the organic cation/carnitine transporter 2 (OCTN2). OCTN2 is strongly expressed in the kidney, skeletal muscle, heart and placenta (Tamai I et al, 1998). Defects in SLC22A5 are the cause of systemic primary carnitine deficiency (CDSP) (Tang NL et al, 1999) and susceptibility to Crohn disease (CD) (Peltekova VD et al, 2004). The human gene SLC22A15 encodes the fly-like putative transporter1 (FLIPT1). FLIPT1 is a novel transporter highly expressed in kidney and brain is shown to be homologous to other carnitine transporters (Eraly SA and Nigan SK, 2002). The human gene SLC22A16 encodes the organic cation/carnitine transporter 6 (also called the fly-like putative transporter 2, FLIPT2) (Enomoto A et al, 2002). FLIPT2 is strongly expressed in the testis and epididymas as well as generally in other tissues and in leukaemia cells ( Enomoto A et al, 2002; Gong S et al, 2002). All of these transporters are sodium-dependent, high affinity carnitine cotransporters. ORCTL2 mediates the transport of chloroquine and quinidine with efflux of protons Authored: Jassal, B, 2010-04-14 Edited: Jassal, B, 2010-04-14 Pubmed9520460 Pubmed9744804 Reactome Database ID Release 43597628 Reactome, http://www.reactome.org ReactomeREACT_22432 Reviewed: He, L, 2010-05-10 The human gene SLC22A18 encodes organic cation transporter-like protein 2 (ORCTL2). It is expressed to high levels in kidney, liver and colon. ORCTL2 can transport chloroquine and quinidine with the antiport of protons (Reece M et al, 1998). Defects in SLC22A18 may play a role in tumorigenesis (Schwienbacher C et al, 1998). OCT3 mediates renal uptake of organic cations Authored: Jassal, B, 2010-03-25 Edited: Jassal, B, 2010-03-25 Pubmed10196521 Pubmed10966924 Reactome Database ID Release 43561072 Reactome, http://www.reactome.org ReactomeREACT_22167 Reviewed: He, L, 2010-05-10 The human gene SLC22A3 encodes organic cation transporter OCT3. It is mainly expressed in skeletal muscle, liver, placenta, kidney and heart, and to a lesser extent in brain. OCT3 is involved in the biliary excretion of cationic drugs. In CNS, ganglia and heart, OCT3 regulates the interstitial concentrations of monoamine neurotransmitters and cationic drugs. In placenta, OCT3 is responsible for the release of acetylcholine during nonneuronal cholinergic regulation (Grundemann D et al,1998; Wu X et al, 2000). OCT4 mediates transport of ergothioneine Authored: Jassal, B, 2010-03-19 Edited: Jassal, B, 2010-03-19 Pubmed15107849 Pubmed15795384 Reactome Database ID Release 43549241 Reactome, http://www.reactome.org ReactomeREACT_22304 Reviewed: He, L, 2010-05-10 The human gene SLC22A4 encodes the ergothioneine transporter (ETT). It was originally discovered as a organic cation/carnitine transporter (OCTN1) (Tamai I et al, 1997) but its main substrate is not carnitine. It is widely expressed and transports ergothioneine more than 100 times more efficiently than tetraethylammonium and carnitine (Grundemann D et al, 2005), leading to the name change from OCTN1 to ETT. Defects in SLC22A4 may be a cause of susceptibility to Crohn disease (CD) (Peltekova VD et al, 2004). Cdc25 Converted from EntitySet in Reactome Reactome DB_ID: 170108 Reactome Database ID Release 43170108 Reactome, http://www.reactome.org ReactomeREACT_6588 Concentrative transport (import) of a nucleoside and a sodium ions by solute carrier family 28 (sodium-coupled nucleoside transporter), member 1 Authored: D'Eustachio, P, 2004-01-13 13:00:00 Edited: D'Eustachio, P, 2004-01-13 13:00:00 Pubmed9124315 Reactome Database ID Release 43109530 Reactome, http://www.reactome.org ReactomeREACT_714 Reviewed: He, L, 2010-05-10 The plasma membrane-associated protein SLC28A1 mediates the transport of one molecule of 2'-deoxyadenosine, adenosine, cytidine, thymidine, or uridine, and one sodium ion, from the extracellular space to the cytosol. Concentrative transport (import) of a nucleoside and two sodium ions by solute carrier family 28 (sodium-coupled nucleoside transporter), member 3 Authored: D'Eustachio, P, 2004-01-13 13:00:00 Edited: D'Eustachio, P, 2004-01-13 13:00:00 Pubmed11032837 Reactome Database ID Release 43109538 Reactome, http://www.reactome.org ReactomeREACT_1504 Reviewed: He, L, 2010-05-10 The plasma membrane-associated protein SLC28A3 mediates the transport of one molecule of adenosine, cytidine, guanosine, inosine, thymidine, or uridine, and two sodium ions, from the extracellular space to the cytosol. has a Stoichiometric coefficient of 2 URAT1 regulates urate levels in blood with exchange for organic anions Authored: Jassal, B, 2010-03-31 Edited: Jassal, B, 2010-03-31 Pubmed12024214 Pubmed15634722 Reactome Database ID Release 43561253 Reactome, http://www.reactome.org ReactomeREACT_22238 Reviewed: He, L, 2010-05-10 Urate is a naturally occurring product of purine metabolism and is a scavenger of biological oxidants. Due to this ability, changes in urate levels are implicated in numerous disease processes. The human gene SLC22A12 encodes urate transporter 1 (URAT1), predominantly expressed in the kidney and is involved in the regulation of blood urate levels. This transport can be trans-stimulated by organic anions such as L-lactate (Enomoto A et al, 2002). Defects in SLC22A12 result in idiopathic renal hypouricaemia (lack of blood urate) (Wakida N et al, 2005). Na+-dependent multivitamin transporter Authored: Jassal, B, 2009-07-17 Biotin (vitamin H or B7) is a water-soluble B-complex vitamin. Biotin is a cofactor in the metabolism of fatty acids and leucine, and it plays a role in gluconeogenesis. D-Pantothoate (vitamin B5), is a water-soluble vitamin needed to form coenzyme-A (CoA), and is critical in the metabolism and synthesis of carbohydrates, proteins, and fats. Lipoic acid is an organosulfur compound, the R-enantiomer of which is an essential cofactor for many enzyme complexes.<br><br>The human SLC5A6 encodes the Na+-dependent multivitamin transporter SMVT (Prasad PD et al, 1999; Wang H et al, 1999). SMVT co-transports these vitamins/cofactors into cells with Na+ ions electrogenically. Edited: Jassal, B, 2009-07-17 Pubmed10329687 Pubmed10334869 Reactome Database ID Release 43429581 Reactome, http://www.reactome.org ReactomeREACT_22320 Reviewed: He, L, 2009-08-24 has a Stoichiometric coefficient of 2 SLCO1B1, SLCO4A1 and SLCO1C1 mediate the transport of thyroid hormones Authored: Jassal, B, 2010-06-18 Edited: Jassal, B, 2010-06-18 Pubmed10358072 Pubmed10601278 Pubmed10873595 Pubmed11316767 Pubmed12351693 Reactome Database ID Release 43879575 Reactome, http://www.reactome.org ReactomeREACT_23913 Reviewed: He, L, 2010-07-07 Three organic anion transporting polypeptides (OATPs; now called solute carrier organic anion transporters, SLCOs) are able to mediate the transport of thryoid hormones, predominantly thyroxine (T4) and triiodothyronine (T3) (Fujiwara K et al, 2001). SLCO1B1 (formerly OATP-C), which can also transport bile salts, is mainly expressed in the liver (Abe T et al, 1999; Hsiang B et al, 1999). SLCO4A1 (formerly OATP-E) is mainly expressed in peripheral tissue and has a broad substrate specificty (Tamai I et al, 2000). SLCO1C1 (formerly OATP-F) is highly expressed in brain and is also a high affinity thyroid hormone transporter (Pizzagalli F et al, 2002). Passive Transport of Glycerol into Cells by Aquaporins Aquaporin-3 (AQP3), AQP7, AQP9, and AQP10 are 6-pass transmembrane proteins that passively transport glycerol across the plasma membrane through a pore in each subunit of a homotetramer. Authored: May, B, 2010-02-09 Edited: May, B, 2010-02-09 Pubmed10510269 Pubmed10564231 Pubmed11027599 Pubmed11573934 Pubmed11952783 Pubmed12084581 Pubmed16325777 Pubmed16596446 Pubmed18555844 Pubmed18678926 Pubmed18762715 Pubmed19590626 Pubmed9369468 Pubmed9405233 Reactome Database ID Release 43507869 Reactome, http://www.reactome.org ReactomeREACT_23921 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport of Water out of Cells by Aquaporins Aquaporin-0 (AQP0, also known as MIP), AQP1, AQP2, AQP3, AQP4, AQP5, AQP7, AQP8, AQP9, and AQP10 are 6-pass transmembrane proteins that passively transport water across the plasma membrane according to the concentration gradient. Each molecule contains a water channel and subunits assemble into homotetramers. In principle water can move in either direction through an aquaporin, however in vivo flow may occur in only one direction. Conductance of water by AQP0 is very low relative to other aquaporins. Authored: May, B, 2010-02-09 Edited: May, B, 2010-02-09 Pubmed10510269 Pubmed10564231 Pubmed11001937 Pubmed11027599 Pubmed11034202 Pubmed11076974 Pubmed11231887 Pubmed11532455 Pubmed11573934 Pubmed11952783 Pubmed12084581 Pubmed12801959 Pubmed1373524 Pubmed14514735 Pubmed14592814 Pubmed14701836 Pubmed1510932 Pubmed15703994 Pubmed15948717 Pubmed16325777 Pubmed16596446 Pubmed17178220 Pubmed17374283 Pubmed17920625 Pubmed18202181 Pubmed18501347 Pubmed18511455 Pubmed18555844 Pubmed18678926 Pubmed18762715 Pubmed18768791 Pubmed18948439 Pubmed19144687 Pubmed19170255 Pubmed19383790 Pubmed19590626 Pubmed19857466 Pubmed20147624 Pubmed3049610 Pubmed7510718 Pubmed7530250 Pubmed7535000 Pubmed7678419 Pubmed8140421 Pubmed8621489 Pubmed8855281 Pubmed9369468 Pubmed9405233 Pubmed9806845 Pubmed9829975 Reactome Database ID Release 43507870 Reactome, http://www.reactome.org ReactomeREACT_23851 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport of Water into Cells by Aquaporins Aquaporin-0 (AQP0, also known as MIP), AQP1, AQP2, AQP3, AQP4, AQP5, AQP7, AQP8, AQP9, and AQP10 are 6-pass transmembrane proteins that passively transport water across the plasma membrane according to the concentration gradient. Each molecule contains a water channel and subunits assemble into homotetramers. In principle water can move in either direction through an aquaporin, however in vivo flow may occur in only one direction. Conductance of water by AQP0 is very low relative to other aquaporins. Authored: May, B, 2010-02-09 Edited: May, B, 2010-02-09 Pubmed10510269 Pubmed10564231 Pubmed11001937 Pubmed11027599 Pubmed11034202 Pubmed11076974 Pubmed11231887 Pubmed11532455 Pubmed11573934 Pubmed11952783 Pubmed12084581 Pubmed12801959 Pubmed1373524 Pubmed14514735 Pubmed14592814 Pubmed14701836 Pubmed1510932 Pubmed15703994 Pubmed15948717 Pubmed16325777 Pubmed16407156 Pubmed16596446 Pubmed17178220 Pubmed17374283 Pubmed17920625 Pubmed18202181 Pubmed18501347 Pubmed18511455 Pubmed18555844 Pubmed18678926 Pubmed18762715 Pubmed18768791 Pubmed18948439 Pubmed19144687 Pubmed19170255 Pubmed19383790 Pubmed19574955 Pubmed19590626 Pubmed19857466 Pubmed20147624 Pubmed3049610 Pubmed7510718 Pubmed7530250 Pubmed7535000 Pubmed7678419 Pubmed8140421 Pubmed8621489 Pubmed8855281 Pubmed9369468 Pubmed9405233 Pubmed9806845 Pubmed9829975 Reactome Database ID Release 43507868 Reactome, http://www.reactome.org ReactomeREACT_23858 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport of Anions out of Vesicles by Aquaporin-6 Aquaporin-6 (AQP6) passively transports anions across membranes. Rat AQP6 has been shown to transport anions, with the highest permeability for nitrate, the lowest permeability for fluoride, and low permeability for water. In rat AQP6 is expressed in the acid-secreting type-A intercalated cells of renal ducts where it co-localizes with the proton-ATPase in the membranes of intracellular vesicles. AQP6 is gated by low pH. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed8812490 Reactome Database ID Release 43432036 Reactome, http://www.reactome.org ReactomeREACT_23883 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 PDS5 Converted from EntitySet in Reactome PDS5A/B PDS5A/PDS5B Reactome DB_ID: 2468151 Reactome Database ID Release 432468151 Reactome, http://www.reactome.org ReactomeREACT_151059 Passive Transport of Anions into Vesicles by Aquaporin-6 Aquaporin-6 (AQP6) passively transports anions across membranes. Rat AQP6 has been shown to transport anions, with the highest permeability for nitrate, the lowest permeability for fluoride, and low permeability for water. In rat AQP6 is expressed in the acid-secreting type-A intercalated cells of renal ducts where it co-localizes with the proton-ATPase in the membranes of intracellular vesicles. AQP6 is gated by low pH. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed8812490 Reactome Database ID Release 43432034 Reactome, http://www.reactome.org ReactomeREACT_23819 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 SLCO2B1 has a narrow substrate specificity Authored: Jassal, B, 2010-06-18 Edited: Jassal, B, 2010-06-18 Pubmed11159893 Reactome Database ID Release 43879562 Reactome, http://www.reactome.org ReactomeREACT_23829 Reviewed: He, L, 2010-07-07 SLCO2B1 (formerly OATP-B) is abundantly expressed in human liver, where it is localized at the basolateral membrane of hepatocytes. It has a narrow substrate range, able to transport bromosulphophthalein (BSP), estrone-3-sulphate and dehydroepiandrosterone-sulphate (DHEAS) (Kullak-Ublick GA et al, 2001). PGT transports prostaglandins Authored: Jassal, B, 2010-06-18 Edited: Jassal, B, 2010-06-18 Pubmed8787677 Reactome Database ID Release 43879528 Reactome, http://www.reactome.org ReactomeREACT_23779 Reviewed: He, L, 2010-07-07 The human gene SLCO2A1 encodes prostaglandin transporter PGT. It is ubiquitously expressed and can transport PGD2, PGE1, PGE2 and PGF2A (Lu R et al, 1996). SLCO4C1 mediates the transport of digoxin Authored: Jassal, B, 2010-06-18 Digoxin is a commonly prescribed drug for the treatment of heart failure. It is mainly eliminated from the body by the kidneys. Human SLCO4C1 (formerly OATP-H) is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. It is found on the baolateral membrane of the nephron and is thought to be the first step of the transport of digoxin into urine (Mikkaichi T et al, 2004). Edited: Jassal, B, 2010-06-18 Pubmed14993604 Reactome Database ID Release 43879594 Reactome, http://www.reactome.org ReactomeREACT_23909 Reviewed: He, L, 2010-07-07 SLCO3A1 isoform 1 has abroad substrate specificity Authored: Jassal, B, 2010-06-18 Edited: Jassal, B, 2010-06-18 Pubmed16971491 Reactome Database ID Release 43879584 Reactome, http://www.reactome.org ReactomeREACT_23822 Reviewed: He, L, 2010-07-07 The human gene SLCO3A1 encodes the organic anion transporting polypeptide D. Several variants are expressed but isoform 1 is ubiquitous and can transport a range of substrates including the prostaglandins E1 and E2, thyroxine and vasopressin (AVP) (Huber RD et al, 2007). Passive Transport of Glycerol out of Cells by Aquaporins Aquaporin-3 (AQP3), AQP7, AQP9, and AQP10 are 6-pass transmembrane proteins that passively transport glycerol across the plasma membrane through a pore in each subunit of a homotetramer. Authored: May, B, 2010-02-09 Edited: May, B, 2010-02-09 Pubmed10510269 Pubmed10564231 Pubmed11027599 Pubmed11573934 Pubmed11952783 Pubmed12084581 Pubmed16325777 Pubmed16596446 Pubmed18555844 Pubmed18678926 Pubmed18762715 Pubmed19590626 Pubmed9369468 Pubmed9405233 Reactome Database ID Release 43507871 Reactome, http://www.reactome.org ReactomeREACT_23780 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport of Urea into Cells by Aquaporins Aquaporin-9 (AQP9) and AQP10 are 6-pass transmembrane proteins that passively transport urea across the plasma membrane through a pore in each subunit of a homotetramer. Authored: May, B, 2010-02-09 Edited: May, B, 2010-02-09 Pubmed10564231 Pubmed11027599 Pubmed11573934 Pubmed12084581 Pubmed18678926 Pubmed18762715 Pubmed19590626 Reactome Database ID Release 43507875 Reactome, http://www.reactome.org ReactomeREACT_23825 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 GAG polyprotein Converted from EntitySet in Reactome Reactome DB_ID: 184275 Reactome Database ID Release 43184275 Reactome, http://www.reactome.org ReactomeREACT_9720 ESCO Converted from EntitySet in Reactome ESCO1/2 ESCO1/ESCO2 Reactome DB_ID: 2468046 Reactome Database ID Release 432468046 Reactome, http://www.reactome.org ReactomeREACT_151079 Passive Transport of Water into Cell by Aquaporin-2 Phosphorylated on Serine256 Aquaporin-2 (AQP2) passively transports water across membranes according to the osmotic gradient. AQP2 is mainly expressed in principal cells of the collecting duct and connecting tubule in the kidney. AQP2 function is acutely regulated by the antidiuretc hormone vasopressin. In the presence of vasopressin AQP is phosphorylated at Ser256, As inferred from rat and mouse Ser261, Ser264, and Thr269 may also be phosphorylated. These phosphorylations are thought to influence AQP2 trafficking and compartmentalization. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed11076974 Pubmed15703994 Pubmed19144687 Pubmed7510718 Pubmed7535000 Pubmed8140421 Pubmed9829975 Reactome Database ID Release 43432065 Reactome, http://www.reactome.org ReactomeREACT_23788 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport of Water into Cell by Aquaporin-1 Aquaporin-1 (AQP1) passively transports water across the plasma membrane according to the osmotic gradient. In the kidney AQP1 is expressed in endothelial cells of the vasa recta, the proximal tubule, and thin descending limb of Henle, where it functions to recover water from filtrate during urine formation. AQP1 is expressed in many other tissues, such as red blood cells, pancreas, and choroid plexus. AQP1 plays a role in forming cerebrospinal fluid. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 Pubmed11034202 Pubmed12801959 Pubmed1373524 Pubmed14514735 Pubmed14592814 Pubmed14701836 Pubmed1510932 Pubmed16407156 Pubmed18202181 Pubmed19574955 Pubmed3049610 Pubmed7678419 Pubmed9829975 Reactome Database ID Release 43432010 Reactome, http://www.reactome.org ReactomeREACT_23841 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Translocation of Aquaporin-2 from Intracellular Vesicles to the Apical Plasma Membrane Authored: May, B, 2009-08-11 Edited: May, B, 2009-08-11 Intracellular vesicles bearing phosphorylated Aquaporin-2 tetramers are transported to the plasma membrane by a mechanism that may involve motor activity of myosin VB (inferred from rat, Nedvetsky et al. 2007) and dynein (inferred from toad bladder, Marples et al. 1996). Pubmed11076974 Pubmed12194985 Pubmed16120822 Pubmed17156409 Pubmed8683474 Pubmed9227644 Reactome Database ID Release 43432237 Reactome, http://www.reactome.org ReactomeREACT_23863 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Phosphorylation of Aquaporin-2 by Protein Kinase A (PKA) Activated Protein Kinase A phosphorylates Aquaporin-2 at Serine 256. The phosphorylated form of AQP2 then traffics from intracellular vesicles to the apical plasma membrane. Authored: May, B, 2009-08-11 EC Number: 2.7.11.11 Edited: May, B, 2009-08-11 Pubmed12194985 Pubmed9227644 Reactome Database ID Release 43432232 Reactome, http://www.reactome.org ReactomeREACT_23840 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Exchange of GDP for GTP by AVP:AVPR2:Heterotrimeric G(s) Complex Authored: May, B, 2009-08-11 Edited: May, B, 2009-08-11 Pubmed10649434 Pubmed11968001 Reactome Database ID Release 43432195 Reactome, http://www.reactome.org ReactomeREACT_23926 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 The AVP:AVPR2 complex activates G-protein alpha s by causing a conformational change in G-protein alpha s that causes it to release GDP and bind GTP. Binding of Inactive Heterotrimeric G(s) Complex by AVP:AVPR2 Complex Authored: May, B, 2009-08-11 Edited: May, B, 2009-08-11 Pubmed8621513 Pubmed9756892 Reactome Database ID Release 43432188 Reactome, http://www.reactome.org ReactomeREACT_23894 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 The vasopressin receptor type 2 (AVPR2) interacts with G-protein alpha s via the third intracellular loop of AVPR2. Vasopressin receptor type 2 bind vasopressin Authored: Jassal, B, 2009-03-02 13:07:02 Edited: Jassal, B, 2009-03-02 13:07:02 Pubmed1534149 Pubmed2991279 Pubmed4065330 Reactome Database ID Release 43392263 Reactome, http://www.reactome.org ReactomeREACT_16964 Reviewed: Beitz, E, 2010-06-24 The arginine vasopressin (AVP) receptor AVPR2 (Birnbaumer M et al, 1992) is expressed in the kidneys and can bind vasopressin (AVP) (Mohr E et al, 1985; Sausville E et al, 1985). This receptor uses the G protein alpha s subunit as its second messenger system. Passive Transport of Urea out of Cells by Aquaporins Aquaporin-9 (AQP9) and AQP10 are 6-pass transmembrane proteins that passively transport urea across the plasma membrane through a pore in each subunit of a homotetramer. Authored: May, B, 2010-02-09 Edited: May, B, 2010-02-09 Pubmed10564231 Pubmed11027599 Pubmed11573934 Pubmed12084581 Pubmed18762715 Pubmed19590626 Reactome Database ID Release 43507873 Reactome, http://www.reactome.org ReactomeREACT_23949 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Equilibrative transport (import) of adenosine and biogenic amines by solute carrier family 29 (nucleoside transporters), member 4 Authored: Jassal, B, 2010-05-12 Edited: Jassal, B, 2010-05-12 Pubmed15448143 Pubmed16873718 Reactome Database ID Release 43727740 Reactome, http://www.reactome.org ReactomeREACT_22315 Reviewed: He, L, 2010-05-10 The human gene SLC29A4 encodes the equilibrative nucleoside transporter 4 (ENT4). It is ubiquitously expressed and mediates the reversible transport of the nucleoside adenosine at acidic pH (this transport is absent at pH 7.4) (Barnes K et al, 2006). ENT4 has also been shown to mediate the transport of biogenic amines such as serotonin, dopamine, norepinephrine and epinephrine. For this reason, ENT4 is also known as the plasma membrane monoamine transporter (PMAT) (Engel K et al, 2004). Equilibrative transport (export) of adenosine and biogenic amines by solute carrier family 29 (nucleoside transporters), member 4 Authored: Jassal, B, 2010-05-12 Edited: Jassal, B, 2010-05-12 Pubmed15448143 Pubmed16873718 Reactome Database ID Release 43727768 Reactome, http://www.reactome.org ReactomeREACT_22188 Reviewed: He, L, 2010-05-10 The human gene SLC29A4 encodes the equilibrative nucleoside transporter 4 (ENT4). It is ubiquitously expressed and mediates the reversible transport of the nucleoside adenosine at acidic pH (this transport is absent at pH 7.4) (Barnes K et al, 2006). ENT4 has also been shown to mediate the transport of biogenic amines such as serotonin, dopamine, norepinephrine and epinephrine. For this reason, ENT4 is also known as the plasma membrane monoamine transporter (PMAT) (Engel K et al, 2004). Cdc25 Converted from EntitySet in Reactome Reactome DB_ID: 69261 Reactome Database ID Release 4369261 Reactome, http://www.reactome.org ReactomeREACT_3533 AT1 transports acetyl-CoA into the Golgi lumen Authored: Jassal, B, 2010-05-12 Edited: Jassal, B, 2010-05-12 Pubmed19061983 Pubmed9096318 Reactome Database ID Release 43727759 Reactome, http://www.reactome.org ReactomeREACT_22226 Reviewed: He, L, 2010-05-10 The human gene SLC33A1 encodes acetyl-CoA transporter AT1 (Kanamori A et al, 1997).Acetyl-CoA is transported to the lumen of the Golgi apparatus, where it serves as the substrate of acetyltransferases that modify the sialyl residues of gangliosides and glycoproteins. Defects in SLC33A1 are the cause of spastic paraplegia autosomal dominant type 42 (SPG42) which is a neurodegenerative disorder (Lin P et al, 2008). phospho-E2F1/E2F3 Converted from EntitySet in Reactome Reactome DB_ID: 187930 Reactome Database ID Release 43187930 Reactome, http://www.reactome.org ReactomeREACT_9247 Concentrative transport (import) of nucleosides plus sodium ions by solute carrier family 28 (sodium-coupled nucleoside transporter), member 2 Authored: D'Eustachio, P, 2004-01-13 13:00:00 Edited: D'Eustachio, P, 2004-01-13 13:00:00 Pubmed10455109 Pubmed9435697 Reactome Database ID Release 43109539 Reactome, http://www.reactome.org ReactomeREACT_2011 Reviewed: He, L, 2010-05-10 The plasma membrane-associated protein SLC28A2 mediates the transport of one molecule of adenosine, guanosine, inosine, or uridine, and one sodium ion, from the extracellular space to the cytosol. Equilibrative transport (export) of nucleosides and free bases by solute carrier family 29 (nucleoside transporters), member 2 Authored: D'Eustachio, P, 2004-01-13 13:00:00 Edited: D'Eustachio, P, 2004-01-13 13:00:00 Pubmed9478986 Reactome Database ID Release 43109529 Reactome, http://www.reactome.org ReactomeREACT_1268 Reviewed: He, L, 2010-05-10 The plasma membrane-associated protein SLC29A2 mediates the reversible transport of one molecule of adenine, adenosine, cytidine, cytosine, guanine, guanosine, hypoxanthine, inosine, thymidine, thymine, uracil, or uridine from the cytosol to the extracellular space. E2F1/E2F3 Converted from EntitySet in Reactome Reactome DB_ID: 187942 Reactome Database ID Release 43187942 Reactome, http://www.reactome.org ReactomeREACT_9082 Equilibrative transport (export) of nucleosides and free bases by solute carrier family 29 (nucleoside transporters), member 1 Authored: D'Eustachio, P, 2004-01-13 13:00:00 Edited: D'Eustachio, P, 2004-01-13 13:00:00 Pubmed8986748 Reactome Database ID Release 43109534 Reactome, http://www.reactome.org ReactomeREACT_1054 Reviewed: He, L, 2010-05-10 The plasma membrane-associated protein SLC29A1 mediates the reversible transport of one molecule of adenosine, cytosine, guanosine, inosine, thymidine, or uridine from the extracellular space to the cytosol. Equilibrative transport (import) of nucleosides and free bases by solute carrier family 29 (nucleoside transporters), member 2 Authored: D'Eustachio, P, 2004-01-13 13:00:00 Edited: D'Eustachio, P, 2004-01-13 13:00:00 Pubmed9478986 Reactome Database ID Release 43109527 Reactome, http://www.reactome.org ReactomeREACT_958 Reviewed: He, L, 2010-05-10 The plasma membrane-associated protein SLC29A2 mediates the reversible transport of one molecule of adenine, adenosine, cytidine, cytosine, guanine, guanosine, hypoxanthine, inosine, thymidine, thymine, uracil, or uridine from the extracellular space to the cytosol. Equilibrative transport (import) of nucleosides and free bases by solute carrier family 29 (nucleoside transporters), member 1 Authored: D'Eustachio, P, 2004-01-13 13:00:00 Edited: D'Eustachio, P, 2004-01-13 13:00:00 Pubmed8986748 Reactome Database ID Release 43109536 Reactome, http://www.reactome.org ReactomeREACT_806 Reviewed: He, L, 2010-05-10 The plasma membrane-associated protein SLC29A1 mediates the reversible transport of one molecule of adenosine, guanosine, inosine, or uridine from the cytosol to the extracellular space. Equilibrative transport (import) of nucleosides and adenine by solute carrier family 29 (nucleoside transporters), member 3 Authored: Jassal, B, 2010-05-12 Edited: Jassal, B, 2010-05-12 Pubmed15701636 Reactome Database ID Release 43727767 Reactome, http://www.reactome.org ReactomeREACT_22395 Reviewed: He, L, 2010-05-10 The human gene SLC29A3 encodes the equilibrative nucleoside transporter 3 (ENT3). It is abundant in many tissues, especially the placenta and is localized intracellularly on the lysosomal membrane. ENT3 mediates the reversible transport of nucleosides and the nucleobase adenine (Baldwin SA et al, 2005). Defects in SLC29A3 are the cause of H syndrome, an autosomal recessive disorder(Molho-Pessach V et al, 2008). Equilibrative transport (export) of nucleosides and adenine by solute carrier family 29 (nucleoside transporters), member 3 Authored: Jassal, B, 2010-05-12 Edited: Jassal, B, 2010-05-12 Pubmed15701636 Pubmed18940313 Reactome Database ID Release 43727749 Reactome, http://www.reactome.org ReactomeREACT_22212 Reviewed: He, L, 2010-05-10 The human gene SLC29A3 encodes the equilibrative nucleoside transporter 3 (ENT3). It is abundant in many tissues, especially the placenta and is localized intracellularly on the lysosomal membrane. ENT3 mediates the reversible transport of nucleosides and the nucleobase adenine (Baldwin SA et al, 2005). Defects in SLC29A3 are the cause of H syndrome, an autosomal recessive disorder(Molho-Pessach V et al, 2008). PDS5 Converted from EntitySet in Reactome PDS5A/B PDS5A/PDS5B Reactome DB_ID: 2468261 Reactome Database ID Release 432468261 Reactome, http://www.reactome.org ReactomeREACT_151997 N-myristoyl GAG polyprotein Converted from EntitySet in Reactome Reactome DB_ID: 184394 Reactome Database ID Release 43184394 Reactome, http://www.reactome.org ReactomeREACT_117021 FATP1, 4 and 6 can mediate the influx of long chain fatty acids into cells Authored: Jassal, B, 2010-06-18 Edited: Jassal, B, 2010-06-18 Of the six fatty acid transporter proteins (FATP) characterized, only three have been shown to mediate the influx into cells of long chain fatty acids (LCFAs); FATP1, 4 and 6. They have been shown to transport the prototypical LCFA oleic acid but are believed to be able to transport LCFAs with chain lengths longer than 10 carbons. FATP1 is highly expressed in adipose tissue and muscle (Hatch GM et al, 2002). FATP4 is the major intestinal LCFA transporter (Fitscher BA et al, 1998; Stahl A et al, 1999). FATP6 is localized to cardiac myocytes (Gimeno RE et al, 2003). Pubmed10518211 Pubmed12235169 Pubmed12556534 Pubmed9878842 Reactome Database ID Release 43879585 Reactome, http://www.reactome.org ReactomeREACT_23817 Reviewed: He, L, 2010-07-07 SLC35D2 mediates the antiport of GDP-mannose in exchange for GMP Authored: Jassal, B, 2010-05-17 Edited: Jassal, B, 2010-05-17 Pubmed15082721 Pubmed15607426 Reactome Database ID Release 43744230 Reactome, http://www.reactome.org ReactomeREACT_22122 Reviewed: He, L, 2010-05-10 The human gene SLC35D2 encodes the UDP-N-acetylglucosamine/UDP-glucose/GDP-mannose transporter (UGTREL8; homolog of Fringe connection protein 1, HFRC1). It resides on the Golgi membrane where it mediates the antiport of GDP-mannose into the Golgi lumen in exchange for GMP (Suda T et al, 2004; Ishida N et al, 2005). SLC35B2 and SLC35B3 mediate the antiport of PAPS into the Golgi lumen in exchange for PAP Authored: Jassal, B, 2010-05-14 Edited: Jassal, B, 2010-05-14 Pubmed12716889 Pubmed16492677 Pubmed8619988 Pubmed8619989 Reactome Database ID Release 43741449 Reactome, http://www.reactome.org ReactomeREACT_22255 Reviewed: He, L, 2010-05-10 The human gene SLC35B2 encodes the adenosine 3'-phospho 5'-phosphosulfate transporter 1 (PAPST1) (Ozeran JD et al, 1996 (page 3695); Kamiyama S et al, 2003). In human tissues, PAPST1 is highly expressed in the placenta and pancreas and present at lower levels in the colon and heart. The human gene SLC35B3 encodes a human PAPS transporter gene that is closely related to human PAPST1. This gene is called PAPST2 and is predominantly expressed in the colon (Kamiyama S et al, 2006). Both these transporters mediate the antiport of PAPS into the Golgi lumen in exchange for PAP (Ozeran JD et al, 1996). SLC35A3 mediates the antiport of UDP-GlcNAc in exchange for UMP Authored: Jassal, B, 2010-05-14 Edited: Jassal, B, 2010-05-14 Pubmed10393322 Reactome Database ID Release 43741450 Reactome, http://www.reactome.org ReactomeREACT_22160 Reviewed: He, L, 2010-05-10 The human gene SLC35A3 encodes the UDP-GlcNAc transporter (Ishida N et al, 1999). It is ubiquitously expressed and resides on the Golgi membrane where it transports UDP- N-acetylglucosamine (GlcNAc) into the Golgi lumen in exchange for UMP. SLC35A2 mediates the antiport of UDP-Gal and UDP-GalNAc in exchange for UMP Authored: Jassal, B, 2010-05-13 Edited: Jassal, B, 2010-05-13 Pubmed11784306 Pubmed8889805 Reactome Database ID Release 43735702 Reactome, http://www.reactome.org ReactomeREACT_22299 Reviewed: He, L, 2010-05-10 The human gene SLC35A2 encodes the UDP-galactose transporter (Miura N et al, 1996). It is located on the Golgi membrane and mediates the antiport of UDP-Gal into the Golgi lumen in exchange for UMP. This transporter is also known to transport UDP-N-acetylgalactosamine (UDP-GalNAc) in the same way as UDP-Gal (Segawa H et al, 2002). SLC35A1 mediates the antiport of CMP-sialic acid in exchange for CMP Authored: Jassal, B, 2010-05-12 Edited: Jassal, B, 2010-05-12 Pubmed15576474 Pubmed9010752 Reactome Database ID Release 43727807 Reactome, http://www.reactome.org ReactomeREACT_22111 Reviewed: He, L, 2010-05-10 The human gene SLC35A1 encodes the CMP-sialic acid transporter which mediates the antiport of CMP-sialic acid into the Golgi lumen in exchange for CMP (Ishida N et al, 1996). Defects in SLC35A1 are the cause of congenital disorder of glycosylation type 2F (CDG2F). CDGs are a family of severe inherited diseases caused by a defect in protein N-glycosylation (Martinez-Duncker I et al, 2005). SLC35D2 mediates the antiport of UDP-sugars in exchange for UMP Authored: Jassal, B, 2010-05-17 Edited: Jassal, B, 2010-05-17 Pubmed15082721 Pubmed15607426 Reactome Database ID Release 43744231 Reactome, http://www.reactome.org ReactomeREACT_22287 Reviewed: He, L, 2010-05-10 The human gene SLC35D2 encodes the UDP-N-acetylglucosamine/UDP-glucose/GDP-mannose transporter (UGTREL8; homolog of Fringe connection protein 1, HFRC1). It resides on the Golgi membrane where it mediates the antiport of nucleotide sugars such as UDP-GlcNAc and UDP-glucose into the Golgi lumen in exchange for UMP (Suda T et al, 2004; Ishida N et al, 2005). SLC35C1 mediates the transport of UDP-fucose into the Golgi lumen Authored: Jassal, B, 2010-05-17 Edited: Jassal, B, 2010-05-17 Pubmed11326280 Reactome Database ID Release 43742345 Reactome, http://www.reactome.org ReactomeREACT_22259 Reviewed: He, L, 2010-05-10 The human gene SLC35C1 encodes the GDP-fucose transporter FUCT1. It resides on the Golgi membrane and mediates the transport of UDP-fucose into the Golgi lumen. Defects in SLC35C1 causes the congenital disorder of glycosylation type 2C, also known as leukocyte adhesion deficiency type II (LAD2) (Lubke T et al, 2001). SLC35B4 mediates the transport of UDP-N-acetylglucosamine into the Golgi lumen Authored: Jassal, B, 2010-05-17 Edited: Jassal, B, 2010-05-17 Pubmed15911612 Reactome Database ID Release 43742354 Reactome, http://www.reactome.org ReactomeREACT_22323 Reviewed: He, L, 2010-05-10 The human gene SLC35B4 encodes the bifunctional UDP-xylose and UDP-N-acetylglucosamine transporter YEA4. YEA4 resides on the Golgi membrane and mediates the influx of UDP-N-acetylglucosamine into the lumen (Ashikov A et al, 2005). SLC35B4 mediates the transport of UDP-xylose into the Golgi lumen Authored: Jassal, B, 2010-05-17 Edited: Jassal, B, 2010-05-17 Pubmed15911612 Reactome Database ID Release 43742373 Reactome, http://www.reactome.org ReactomeREACT_22300 Reviewed: He, L, 2010-05-10 The human gene SLC35B4 encodes the bifunctional UDP-xylose and UDP-N-acetylglucosamine transporter YEA4. YEA4 resides on the Golgi membrane and mediates the influx of UDP-xylose into the lumen (Ashikov A et al, 2005). PathwayStep139 Cyclin A Converted from EntitySet in Reactome Reactome DB_ID: 170089 Reactome Database ID Release 43170089 Reactome, http://www.reactome.org ReactomeREACT_6541 PathwayStep137 Cyclin B Converted from EntitySet in Reactome Reactome DB_ID: 75031 Reactome Database ID Release 4375031 Reactome, http://www.reactome.org ReactomeREACT_3010 PathwayStep138 PathwayStep131 E2F1 targets Converted from EntitySet in Reactome Reactome DB_ID: 539110 Reactome Database ID Release 43539110 Reactome, http://www.reactome.org ReactomeREACT_22550 PathwayStep132 PathwayStep130 PathwayStep135 PathwayStep136 PathwayStep133 PathwayStep134 PathwayStep126 PDS5 Converted from EntitySet in Reactome PDS5A/B PDS5A/PDS5B Reactome DB_ID: 2468044 Reactome Database ID Release 432468044 Reactome, http://www.reactome.org ReactomeREACT_151762 PathwayStep127 PathwayStep128 PathwayStep129 phosphorylated Cyclin A:Cdk2 substrate proteins Converted from EntitySet in Reactome Reactome DB_ID: 187920 Reactome Database ID Release 43187920 Reactome, http://www.reactome.org ReactomeREACT_9246 PathwayStep120 Cdc25 A/B Converted from EntitySet in Reactome Reactome DB_ID: 187904 Reactome Database ID Release 43187904 Reactome, http://www.reactome.org ReactomeREACT_9277 PathwayStep121 PathwayStep122 PathwayStep123 PathwayStep124 PathwayStep125 PathwayStep119 PathwayStep117 PathwayStep118 PathwayStep115 PathwayStep116 PathwayStep113 PathwayStep114 NF-kappaB inhibitor Converted from EntitySet in Reactome Reactome DB_ID: 168143 Reactome Database ID Release 43168143 Reactome, http://www.reactome.org ReactomeREACT_7017 PathwayStep111 PathwayStep112 PathwayStep110 TAB2/3 Converted from EntitySet in Reactome Reactome DB_ID: 975105 Reactome Database ID Release 43975105 Reactome, http://www.reactome.org ReactomeREACT_25580 Cyclin E Converted from EntitySet in Reactome Reactome DB_ID: 68373 Reactome Database ID Release 4368373 Reactome, http://www.reactome.org ReactomeREACT_5154 PathwayStep108 PathwayStep109 PathwayStep104 Max Converted from EntitySet in Reactome Reactome DB_ID: 188359 Reactome Database ID Release 43188359 Reactome, http://www.reactome.org ReactomeREACT_9295 PathwayStep105 PathwayStep106 PathwayStep107 PathwayStep100 PathwayStep101 PathwayStep102 PathwayStep103 TAB2/3 Converted from EntitySet in Reactome Reactome DB_ID: 446874 Reactome Database ID Release 43446874 Reactome, http://www.reactome.org ReactomeREACT_23192 Syntaxin 10 Converted from EntitySet in Reactome Reactome DB_ID: 181497 Reactome Database ID Release 43181497 Reactome, http://www.reactome.org ReactomeREACT_11316 BONT/E cleaved SNAP25 fragment Converted from EntitySet in Reactome Reactome DB_ID: 168774 Reactome Database ID Release 43168774 Reactome, http://www.reactome.org ReactomeREACT_11570 Syntaxin 16 Converted from EntitySet in Reactome Reactome DB_ID: 181558 Reactome Database ID Release 43181558 Reactome, http://www.reactome.org ReactomeREACT_11506 Syntaxin 3 Converted from EntitySet in Reactome Reactome DB_ID: 181500 Reactome Database ID Release 43181500 Reactome, http://www.reactome.org ReactomeREACT_11448 Syntaxin 2 Converted from EntitySet in Reactome Reactome DB_ID: 181523 Reactome Database ID Release 43181523 Reactome, http://www.reactome.org ReactomeREACT_11865 PathwayStep2967 PathwayStep2966 PathwayStep2965 PathwayStep2964 PathwayStep2963 PathwayStep2962 PathwayStep2961 PathwayStep2960 PathwayStep2969 PathwayStep2968 PathwayStep2970 PathwayStep2976 CD151 interacts with BP180 and the integrin alpha 6 subunit Authored: Matthews, L, 2009-11-04 CD151 interacts with the extracellular domain of the integrin alpha 6 subunit. CD151 is thought to play a role in the formation and stability of hemidesmosomes by providing a framework for the spatial organization of the hemidesmosomal components (Sterk et al., 2000). Edited: Matthews, L, 2009-11-13 Pubmed10811835 Reactome Database ID Release 43446083 Reactome, http://www.reactome.org ReactomeREACT_20665 Reviewed: Sonnenberg, A, 2009-11-15 PathwayStep2975 BP230 interacts with keretin K5/K14 Authored: Matthews, L, 2009-11-04 BP230 interacts with cytokeratins K5/K14 (Fontao et al., 2003). Edited: Matthews, L, 2009-11-13 Pubmed12802069 Reactome Database ID Release 43446077 Reactome, http://www.reactome.org ReactomeREACT_20615 Reviewed: Sonnenberg, A, 2009-11-15 PathwayStep2978 Phosphorylation of ITIM in SIRP alpha Authored: Garapati, P V, 2009-02-12 18:17:40 EC Number: 2.7.10 Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed16691243 Pubmed17584740 Reactome Database ID Release 43391156 Reactome, http://www.reactome.org ReactomeREACT_23920 Reviewed: Barclay, AN, 2010-05-20 Various growth factors and events such as integrin-mediated cell adhesion to extracellular matrix (ECM) proteins induce the tyrosine phosphorylation of SIRP alpha. The cytoplasmic tail of SIRP alpha has two ITIMs with four tyrosine residues that are potential sites for phosphorylation. Phosphorylation is not dependent on CD47 engagement but the presence of CD47 may enhance the effect. Src family kinases may be involved in the phosphorylation. has a Stoichiometric coefficient of 4 PathwayStep2977 SIRP alpha binds CD47 Authored: Garapati, P V, 2009-02-12 18:17:40 CD47 is an extracellular ligand for SIRP alpha. SIRP alpha directly binds to the loops of the Ig variable like domain of CD47 in an end-to-end fashion. The SIRP alpha/CD47 interaction is unusual in that it can lead to bidirectional signaling through SIRP alpha and CD47. The major function of this interaction is prevention of phagocytosis of RBC and platelets by macrophages. Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed10572074 Pubmed17070842 Pubmed17369261 Pubmed18657508 Pubmed19628875 Reactome Database ID Release 43391158 Reactome, http://www.reactome.org ReactomeREACT_23830 Reviewed: Barclay, AN, 2010-05-20 PathwayStep2972 BP180 interacts intracellularly with plectin and integrin beta4 Authored: Matthews, L, 2009-11-04 BP180 interacts with Plectin following the association of Plectin with Integrin b4 (b4) (Koster et al., 2003). It is not clear whether the binding of BP180 to Plectin and b4 occurs sequentially or at the same time as the interaction between BP180 and Laminin?332. Edited: Matthews, L, 2009-11-13 Pubmed12482924 Reactome Database ID Release 43432952 Reactome, http://www.reactome.org ReactomeREACT_20589 Reviewed: Sonnenberg, A, 2009-11-15 PathwayStep2971 Interaction of Plectin with Integrin beta 4 Authored: Matthews, L, 2009-11-04 Edited: Matthews, L, 2009-10-21 Pubmed10525545 Pubmed14668477 Pubmed19242489 Pubmed9264458 Reactome Database ID Release 43432909 Reactome, http://www.reactome.org ReactomeREACT_20528 Reviewed: Sonnenberg, A, 2009-11-15 The actin-binding domain of plectin interacts with the first pair of FNIII repeats and the N-terminal 35 amino acids of the connecting segment of integrin b4 ( Geerts et al., 1999; Niessen et al., 1997; Koster et al., 2004). This interaction is thought to be the initial step in hemidesmosome (HD) assembly and is critical for the mechanical stability of the HD. This interaction is destabilized when HD disassembly is required, for example, to allow cell migration during wound healing. The Integrin a6b4 also associates extracellularly with laminin-332 (See Koster et al., 2003). PathwayStep2974 BP230 is recruited to the hemidesmosome Authored: Matthews, L, 2009-11-04 Edited: Matthews, L, 2009-11-04 Following the association of BP180 with the forming hemidesmosome, BP230 is recruited through associations with BP180 and a region on beta 4 integrin that includes the C-terminal 21 amino acids of the connecting segment and the second pair of FNIII repeats (Hopkinson et al.,2000). Pubmed10637308 Reactome Database ID Release 43432956 Reactome, http://www.reactome.org ReactomeREACT_20561 Reviewed: Sonnenberg, A, 2009-11-15 PathwayStep2973 BP180 interacts extracellularly with Laminin 332 Authored: Matthews, L, 2009-11-04 BP180 interacts with Plectin following the association of Plectin with Integrin b4 (b4) (Koster et al., 2003). It is not clear whether the binding of BP180 to Plectin and b4 occurs sequentially or at the same time as the interaction between BP180 and Laminin?332. Edited: Matthews, L, 2009-11-13 Pubmed12482924 Reactome Database ID Release 43446089 Reactome, http://www.reactome.org ReactomeREACT_20660 Reviewed: Sonnenberg, A, 2009-11-15 Migfilin interacts with VASP Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-12 Migfilin interacts with VASP and regulates VASP localization to cell-matrix adhesions (Zhang et al., 2006). Interaction between migfilin and VASP is critical for migfilin-mediated regulation of cell migration (Zhang et al., 2006). Pubmed16531412 Reactome Database ID Release 43446364 Reactome, http://www.reactome.org ReactomeREACT_20572 Reviewed: Wu, C, 2009-11-12 PathwayStep2979 PathwayStep2980 PathwayStep2981 Recruitment of SHP-2 and SHP-1 to pSIRP alpha Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed17584740 Pubmed19144521 Reactome Database ID Release 43391150 Reactome, http://www.reactome.org ReactomeREACT_23882 Reviewed: Barclay, AN, 2010-05-20 SIRP alpha functions as a docking protein. The tyrosine-phosphorylated residues of SIRP alpha trigger the binding and activation of tyrosine phosphatases SHP-1 and SHP-2. All four phosphotyrosines of SIRP alpha may serve as substrates for SHP-1 and SHP-2. SIRP alpha binds mostly to SHP-1 in hematopoietic cells and with SHP-2 in non-hematopoietic cells. These phosphatases mediate the specific functions of SIRP alpha. PathwayStep2985 PathwayStep2984 PathwayStep2983 PathwayStep2982 PathwayStep2989 PathwayStep2988 PathwayStep2987 PathwayStep2986 PathwayStep2991 PathwayStep2992 PathwayStep2990 PathwayStep2994 PathwayStep2993 PathwayStep2996 PathwayStep2995 PathwayStep2998 PathwayStep2997 PathwayStep2999 PathwayStep2928 PathwayStep2929 PathwayStep2926 PathwayStep2927 PathwayStep2924 PathwayStep2925 PathwayStep2922 PathwayStep2923 PathwayStep2920 PathwayStep2921 PathwayStep2939 PathwayStep2935 PathwayStep2936 PathwayStep2937 PathwayStep2938 PathwayStep2931 PathwayStep2932 PathwayStep2933 PathwayStep2934 PathwayStep2930 PathwayStep2948 PathwayStep2949 PathwayStep2946 PathwayStep2947 PathwayStep2940 PathwayStep2941 PathwayStep2944 PathwayStep2945 PathwayStep2942 PathwayStep2943 PathwayStep2957 PathwayStep2958 PathwayStep2959 PathwayStep2950 PathwayStep2951 PathwayStep2952 PathwayStep2953 PathwayStep2954 PathwayStep2955 PathwayStep2956 ABC7, mABC1 and mABC2 mediate heme transport Authored: Gopinathrao, G, 2008-11-23 14:00:06 Edited: Gopinathrao, G, 2008-11-23 14:00:06 Mitochondrial ABC transporters are thought to play a key role in iron metabolism and heme biosynthesis. All mitochondrial ABC transporters described to date are of the half-transporter type and would probably function as dimers (Ramjeesingh et al. 2003) but their dimerization partners have not yet been identified. ABC7 is the functional human orthologue of yeast Atm1p (Csere et al. 1998), is predicted to dimerize in the same way as Atm1p (Chloupková et al. 2004) and is probably involved in iron homeostasis. Defects in ABCB7 are the cause of X-linked sideroblastic anemia with ataxia (ASAT) [MIM:301310] (Allikmets et al. 1999). Human genes ABCB8 and ABCB10 encode mABC1 and mABC2 respectively (Hogue et al. 1999, Zhang et al 2000 respectively). They would be expected to dimerize, as demonstrated for mABC2 (Graf et al. 2004). Both are believed to have similar functionality to ABC7 although this has not been demonstrated yet. Pubmed10196363 Pubmed10922475 Pubmed12892562 Pubmed15215243 Pubmed15225610 Pubmed9878413 Pubmed9883897 Reactome Database ID Release 43382560 Reactome, http://www.reactome.org ReactomeREACT_22342 Reviewed: D'Eustachio, P, 2011-08-23 Reviewed: Matthews, L, 2008-12-02 15:41:53 MTABC3 transports porphyrin into mitochondria Authored: Jassal, B, 2011-07-04 Edited: Jassal, B, 2011-07-04 Pubmed10837493 Pubmed17006453 Reactome Database ID Release 431369065 Reactome, http://www.reactome.org ReactomeREACT_111156 Reviewed: D'Eustachio, P, 2011-08-23 The human gene ABCB6 encodes a mitochondrial half-type ATP-binding cassette (ABC) protein MTABC3 which is uniquely located on the outer mitochondrial membrane and is functional as a homodimer (Krishnamurthy et al. 2006). It plays a crucial role in heme synthesis by mediating porphyrin uptake into mitochondria (Mitsuhashi et al. 2000, Krishnamurthy et al. 2006). ABCD1/D2/D3 mediate long chain fatty acid transport in to peroxisomes Authored: Gopinathrao, G, 2008-11-23 14:00:06 Edited: Gopinathrao, G, 2008-11-23 16:44:55 Pubmed10777694 Pubmed11248239 Pubmed12176987 Pubmed15209530 Pubmed8411712 Pubmed8507690 Reactome Database ID Release 43382575 Reactome, http://www.reactome.org ReactomeREACT_15322 Reviewed: D'Eustachio, P, 2011-08-23 Reviewed: Matthews, L, 2008-12-02 15:41:53 The 70-kDa peroxisomal membrane protein (PMP70) and the adrenoleukodystrophy protein (ALDP) are half ATP binding cassette (ABC) transporters in the peroxisome membrane. Mutations in the ALD gene encoding ALDP result in the X-linked neurodegenerative disorder adrenoleukodystrophy (Roerig et al. 2001). They are involved in metabolic transport of long and very long chain fatty acids into peroxisomes. ATP binding/hydrolysis by and phosphorylation of PMP70 and ALDP are involved in the regulation of fatty acid transport into peroxisomes (Tanaka et al. 2002). ABCG4 may mediate cholesterol efflux Authored: Jassal, B, 2011-07-19 Edited: Jassal, B, 2011-07-19 Human ABCG4 shows sequence homology to the Drosophila white gene, the product of which must dimerise to become functionally active. ABCG4 is closely related to ABCG1 with 74% identity and is thus thought to play a role in the efflux of excess cholesterol (Engel et al. 2001). Northern Blot analysis shows that ABCG4 is expressed specifically in brain and the eye (Oldfield et al. 2002). Pubmed11606068 Pubmed12183068 Reactome Database ID Release 431454928 Reactome, http://www.reactome.org ReactomeREACT_111034 Reviewed: D'Eustachio, P, 2011-08-23 ABCA4 mediates atRAL transport Authored: Jassal, B, 2011-08-01 Edited: Jassal, B, 2011-08-01 Pubmed10075733 Pubmed11123914 Pubmed9490294 Reactome Database ID Release 431467466 Reactome, http://www.reactome.org ReactomeREACT_111189 Reviewed: D'Eustachio, P, 2011-08-23 Rhodopsin (RHO) is localised to both the disc membrane and the plasma membrane of rod outer segments (ROS). All-trans-retinal (atRAL) released from rhodopsin during the bleaching process, needs to translocate to the cytosol for reduction to all-trans-retinol (atROL) via all-trans-retinol dehydrogenases. Although atRAL can diffuse through membranes unaided, there exists an ABC transporter on disc membranes which may facilitate the transport of excess atRAL. Retinal-specific ATP-binding cassette transporter (ABCA4, ABCR) is the only ABC transporter which mediates the transport of retinoids (Biswas & Biswas 2000). Studies using bovine ABCA4 demonstrates atRAL transport (Sun et al. 1999). Human ABCR was found to be identical to the ABC transporter linked to Stargardt's disease type 1 (STGD1, MIM:248200), a cause of macular degeneration in childhood (Nasonkin et al. 1998). atRAL(membrane) is transported to atRAL(cytosol) by ABCA4 Cl-/HCO3- exchanger transport Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 Pubmed2594752 Pubmed3015590 Pubmed7506871 Pubmed7530501 Pubmed7923606 Pubmed8206915 Pubmed9312167 Reactome Database ID Release 43425482 Reactome, http://www.reactome.org ReactomeREACT_19263 Reviewed: He, L, 2009-08-24 The proteins responsible for the exchange of Cl- with HCO3- are members of the SLC4 (1-3) and SLC26 (3, 4, 6, 7 and 9) transporter families. The SLC26 members are discussed under the section "Multifunctional anion exchangers".<br><br>SLC4A1 (Band 3, AE1, anion exchanger 1) was the first bicarbonate transporter gene to be cloned and sequenced (Lux SE et al, 1989). It is ubiquitous throughout vertebrates and in humans, is present on erythrocytes and the basolateral surfaces of kidney cells. The erythrocyte and kidney forms are different isoforms of the same protein (Kollert-Jons A et al, 1993). Mutations of erythroid AE1 determine the Diego blood group system (Bruce LJ et al, 1994). A more serious consequence of mutated erythroid AE1 is Hereditary spherocytosis (a disorder leading to haemolytic anaemia) (Jarolim P et al, 1995). Defects in the kidney form of AE1 cause distal (type1) renal tubular acidosis (an inability to acidify urine) (Bruce LJ et al, 1997).<br><br>SLC4A2 (Non-erythroid band 3-like protein, AE2, anion exchanger 2) is widely expressed and is considered to be the 'housekeeping' isoform of the bicarbonate transporters (Demuth DR et al, 1986). SLC4A3 (Cardiac/brain band 3-like protein, AE3) is expressed in heart and brain (Yannoukakos D et al, 1994).<br><br> The ABCC family mediates organic anion transport Authored: Jassal, B, 2011-07-19 Edited: Jassal, B, 2011-07-19 Pubmed16816140 Reactome Database ID Release 431454916 Reactome, http://www.reactome.org ReactomeREACT_111162 Reviewed: D'Eustachio, P, 2011-08-23 The multidrug resistance associated protein (MRPs) subfamily of the ABC transporter family can transport a wide and diverse range of organic anions that can be endogenous compounds and xenobiotics and their metabolites. All human MRPs (except MRP9) can mediate these transport reactions (Deeley et al. 2006).<p>Separately, specific reactions have also been annotated to describe the roles of ABCC4 in platelet dense granule assembly, of ABCC1 in LTC4 export (an aspect of leukotriene synthesis), and of ABCC3 in bile salt efflux. ABCA8, B1 and B5 mediate xenobiotic efflux Authored: Jassal, B, 2011-08-01 EC Number: 3.6.3.44 Edited: Jassal, B, 2011-08-01 Pubmed12379217 Pubmed15899824 Pubmed19135557 Pubmed2900833 Pubmed3457471 Reactome Database ID Release 431467457 Reactome, http://www.reactome.org ReactomeREACT_111164 Reviewed: D'Eustachio, P, 2011-08-23 Some members of the ABC transporter superfamily are able to mediate the efflux of a broad range of cytotoxic drugs from cells, leading to the name multidrug resistance (MDR) proteins (Seeger and van Veen 2009). The ABCB1 (P-glycoprotein 1[PGP], multidrug resistance protein 1 [MRP1]) is the most characterised MDR (Shen et al. 1986, Gottesman & Pastan 1988). ABCB5 (Frank et al. 2005) and ABCA8 (Tsuruoka et al. 2002) are newer members of MDRs. PEX-19 docks ABCD1/D2/D3 to peroximal membrane Authored: Gopinathrao, G, 2008-11-23 14:00:06 Edited: Gopinathrao, G, 2008-11-23 16:45:13 PEX19 is a chaperone protein that binds a broad spectrum of peroxisomal membrane proteins (PMPs), and interacts with regions of PMPs required for their targeting to peroxisomes. PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. The ABC transporters D1, D2 and D3 must first form dimers to become fully functional (Liu et al.1999) which then can bind with PEX19. Pubmed10551832 Pubmed10704444 Pubmed10777694 Pubmed15007061 Pubmed9345306 Reactome Database ID Release 43382613 Reactome, http://www.reactome.org ReactomeREACT_15396 Reviewed: Matthews, L, 2008-12-02 15:41:53 ABCA7:Apo1A-mediated phospholipid efflux ABCA7 has the ability to bind apolipoproteins and promote efflux of cellular phospholipids and may have a possible role in cellular phospholipid metabolism in peripheral tissues. Like many other ABC-transporters, the exact role of ABCA7 is waiting to be elucidated. Authored: Gopinathrao, G, 2008-11-23 14:00:06 Edited: Gopinathrao, G, 2008-11-23 14:00:06 Pubmed10873640 Pubmed11095984 Pubmed12509503 Pubmed12917409 Pubmed14570867 Pubmed14592415 Reactome Database ID Release 43382553 Reactome, http://www.reactome.org ReactomeREACT_15367 Reviewed: Matthews, L, 2008-12-02 15:41:53 K+-independent Li+/Ca2+ exchanger transport Authored: Jassal, B, 2009-06-08 Edited: Jassal, B, 2009-06-08 Pubmed14625281 Pubmed15060069 Reactome Database ID Release 43425822 Reactome, http://www.reactome.org ReactomeREACT_19367 Reviewed: He, L, 2009-08-24 SLC24A6 (NCKX6, NCLX) (Palty R et al, 2004) encodes a protein which can transport Li+ or Na+ in exchange for Ca2+ in an K+-independent manner (Cai X and Lytton J, 2004). Lithium exchange with calcium is shown here. has a Stoichiometric coefficient of 4 Na+/H+ exchanger transport (at cell membrane) Authored: Jassal, B, 2009-06-11 Edited: Jassal, B, 2009-06-11 NHE1 (SLC9A1) is present in most cells and is the most extensively characterized member of this family (Sardet C et al, 1989). NHE2-4 (SLC9A2-4) (Malakooti J et al, 1999; Brant SR et al, 1995) are expressed mainly in the kidney and GI tract. NHE5 (SLC9A5) (Baird NR et al, 1999) is highly expressed in neuronal-enriched areas of the CNS. Pubmed10444453 Pubmed2536298 Pubmed7631746 Pubmed9933641 Reactome Database ID Release 43425994 Reactome, http://www.reactome.org ReactomeREACT_19224 Reviewed: He, L, 2009-08-24 Na+/H+ exchanger transport (at early endosome membrane) Authored: Jassal, B, 2009-06-11 Edited: Jassal, B, 2009-06-11 NHE6 (SLC9A6) (Brett CL et al, 2002; Nakamura N et al, 2005) is expressed ubiquitously and thought to play a housekeeping role in pH homeostasis in early endosomes. Pubmed11940519 Pubmed15522866 Reactome Database ID Release 43425983 Reactome, http://www.reactome.org ReactomeREACT_19253 Reviewed: He, L, 2009-08-24 Na+/H+ exchanger transport (at trans-golgi membrane) Authored: Jassal, B, 2009-06-11 Edited: Jassal, B, 2009-06-11 NHE7 and 8 (SLC9A7,8) (Nakamura N et al, 2005) are expressed ubiquitously and thought to play a housekeeping role in pH homeostasis in the trans-golgi network. Pubmed11279194 Pubmed15522866 Reactome Database ID Release 43426015 Reactome, http://www.reactome.org ReactomeREACT_19218 Reviewed: He, L, 2009-08-24 Na+/H+ exchanger transport (at late endosome membrane) Authored: Jassal, B, 2009-06-11 Edited: Jassal, B, 2009-06-11 NHE9 (SLC9A9) (Nakamura N et al, 2005) is expressed ubiquitously and thought to play a housekeeping role in pH homeostasis in the late endosome membrane. Pubmed15522866 Reactome Database ID Release 43425965 Reactome, http://www.reactome.org ReactomeREACT_19303 Reviewed: He, L, 2009-08-24 Na+/Cl- cotransport Authored: Jassal, B, 2009-06-12 Edited: Jassal, B, 2009-06-12 Pubmed8528245 Pubmed8812482 Reactome Database ID Release 43426130 Reactome, http://www.reactome.org ReactomeREACT_19417 Reviewed: He, L, 2009-08-24 The SLC12A3 gene encodes for the Thiazide-sensitive sodium-chloride cotransporter (TSC). TSC mediates sodium and chloride removal from the distal convoluted tubule of the kidney (Mastroianni N et al, 1996). Defects in SLC12A3 are the cause of Gitelman syndrome (GS). GS is an autosomal recessive disorder that allows the kidneys to pass sodium, magnesium, chloride, and potassium into the urine, rather than being reabsorbed into the bloodstream (Simon DB et al, 1996). This cotransporter is the major target for thiazide-type diuretics, used in the treatment of hypertension, extracellular fluid overload and renal stone disease. Na+, K+/2Cl- cotransport Authored: Jassal, B, 2009-06-12 Edited: Jassal, B, 2009-06-12 Pubmed7629105 Pubmed8640224 Reactome Database ID Release 43426086 Reactome, http://www.reactome.org ReactomeREACT_19223 Reviewed: He, L, 2009-08-24 Two genes (SLC12A1 and SLC12A2) encode Na+,K+/2Cl- cotransporters (NKCC2 and NKCC1 respectively). SLC12A1 (Simon DB et al, 1996) is kidney-specific whilst SLC12A2 (Payne JA et al, 1995) is ubiquitously expressed. Two Cl- ions are electroneutrally transported into cells with a Na+ ion and a K+ ion. has a Stoichiometric coefficient of 2 Na+-coupled HCO3- cotransport Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 Pubmed10347222 Pubmed10362779 Pubmed10545938 Pubmed10978526 Pubmed11305939 Pubmed11788353 Pubmed9235899 Pubmed9651366 Reactome Database ID Release 43425483 Reactome, http://www.reactome.org ReactomeREACT_19247 Reviewed: He, L, 2009-08-24 Some members of the SLC4A family couple the transport of bicarbonate (HCO3-) to the movement of sodium ions (Na+), they being members 4, 5, 7 and 9. SLC4A4 (NBCe1) is an electrogenic sodium/bicarbonate cotransporter with a Na+:HCO3- stoichiometry of 1:3, although it can also be 1:2 (Burnham CE et al, 1997). SLC4A4 encodes a protein which is expressed in the kidney and pancreas, with lesser expression in many other tissues (Abuladze N et al, 1998). Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis (pRTA) (results in accumulation of acid in the body due to a failure of the kidneys to effectively acidify urine) with ocular abnormalities (Igarashi T et al, 1999).<br><br>SLC4A5 encodes a protein which is expressed in liver, spleen and testes, with lower levels expressed in parts of the brain and kidney (Sassani P et al, 2002). It may have a housekeeping function in regulating the pH of these tissues (Pushkin A et al, 2000). SLC4A7 (NBC3, NBCn1) encodes a protein which performs electroneutral cotransport of Na+ and HCO3- with a 1:1 stoichiometry. It is highly expressed in testes and spleen and, to a lesser extent, in many other tissues including heart, muscle, kidney and GI tract (Pushkin A et al, 1999).<br><br>SLC4A9 (AE4) was originally thought to exchange Cl- with HCO3- (hence the name AE4) but this has not been reported. Consensus has emerged that it is indeed a Na+/HCO3- co-transporter (Lipovich L et al, 2001). It is predominantly expressed in the kidney, salivary glands, testes, thyroid glands and trachea (Parker MD et al, 2001). has a Stoichiometric coefficient of 3 K+-dependent Na+/Ca2+ exchanger transport Authored: Jassal, B, 2009-06-05 Edited: Jassal, B, 2009-06-05 Pubmed10662833 Pubmed11294880 Pubmed12379639 Pubmed16357253 Pubmed9856482 Reactome Database ID Release 43425678 Reactome, http://www.reactome.org ReactomeREACT_19339 Reviewed: He, L, 2009-08-24 The five members of the NCKX (SLC24) family are all able to exchange one Ca2+ and one K+ for four Na+. They play a major role in the phototransduction cascade by controlling the Ca2+ concentration of the outer segments of retinal rod and cone cells during light and dark conditions. NCKX1 (SLC24A1) encodes an exchanger protein which is the most extensively studied member (Tucker JE et al, 1998). It is highly expressed in the eye. Other members are expressed in the brain and skin as well as the eye (Prinsen CF et al, 2000; Kraev A et al, 2001; Li XF et al, 2002; Lamason RL et al, 2005). has a Stoichiometric coefficient of 4 Na+-driven Cl-/HCO3- exchanger transport Authored: Jassal, B, 2009-06-05 Edited: Jassal, B, 2009-06-05 Pubmed10362779 Pubmed18319254 Reactome Database ID Release 43425577 Reactome, http://www.reactome.org ReactomeREACT_19291 Reviewed: He, L, 2009-08-24 Two genes encode Na+-dependent Cl-/HCO3- exchangers; SLC4A8 (NDCBE1) and 10 (NCBE). SLC4A8 (NDCBE1) encodes a exchanger protein which mediates Na+:HCO3- transport with a stoichiometry of 1:2:1 (Na+/HCO3-/Cl-). This protein is highly expressed in brain and spine and moderately expressed in trachea, thyroid, and kidney (Amlal H et al, 1999). SLC4A10 (NCBE, NBCn2) encodes a Na+-driven Cl-/HCO3- exchanger protein (Parker MD et al, 2008). It transports extracellular Na+ and HCO3- into cells in exchange for intracellular Cl- and H+, thus raising the intracellular pH. GLUT7 and GLUT11 transport glucose and fructose Authored: Jassal, B, 2009-07-10 Edited: Jassal, B, 2009-07-10 Pubmed11583593 Pubmed11741323 Pubmed15033637 Pubmed16154905 Reactome Database ID Release 43428779 Reactome, http://www.reactome.org ReactomeREACT_19138 Reviewed: He, L, 2009-08-24 SLC2A7 encodes GLUT7, a class II facilitative glucose transporter which was cloned from a human intestinal cDNA library (Li Q et al, 2004). It has a high affinity for glucose and fructose uptake. GLUT7 is found predominantly in the small intestine, colon, testis and prostate.<br><br>SLC2A11 encodes GLUT11 (Doege H et al, 2001), another member of the class II facilitative glucose transporters. It has the highest similarity with GLUT5 and in humans, three isoforms are expressed (GLUT11A-C) (Sasaki T et al, 2001). Human GLUT11 has been shown to transport glucose and fructose but not galactose when expressed in Xenopus oocytes ( Scheepers A et al, 2005). GLUT9 transports glucose, fructose and urate Authored: Jassal, B, 2009-07-14 Edited: Jassal, B, 2009-07-14 Pubmed10860667 Pubmed14739288 Pubmed18327257 Reactome Database ID Release 43429036 Reactome, http://www.reactome.org ReactomeREACT_19288 Reviewed: He, L, 2009-08-24 The human SLC2A9 gene encodes two isoforms of class II facilitative glucose transporter 9; GLUT9 (Phay JE et al, 2000) and GLUT9DeltaN (Augustin R et al, 2004). GLUT9 is expressed mainly in kidney (proximal tubules of epithelial cells) and liver while GLUT9DeltaN is expressed mainly in kidney and placenta. As well as mediating the uptake of fructose and glucose (at a low rate), GLUT9 can also mediate the tranpsort of urate (uric acid), the end product of purine metabolism in humans and great apes (Vitart V et al, 2008). Mutations in SLC2A9 influence serum urate concentrations with excess serum accumulation of urate leading to the development of gout (Vitart V et al, 2008). Type III Na+/Pi cotransport Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Pubmed10516278 Pubmed2078500 Pubmed8302848 Reactome Database ID Release 43427605 Reactome, http://www.reactome.org ReactomeREACT_19410 Reviewed: He, L, 2009-08-24 There are two transporters of this type; The genes SLC20A1 and SLC20A2 encode for PiT1 (phosphate transporter 1) and PiT2 respectively. They both have a broad tissue distribution and may play a general housekeeping role in phosphate transport such as absorbing phosphate from interstitial fluid and in extracellular matrix and cartilage calcification as well as in vascular calcification. These proteins were originally described as retroviral receptors for the gibbin ape leukemia virus receptor 1 (GLVR1, now called PiT1) (O'Hara B et al, 1990) and GLVR2 (now called PiT2) (van Zeijl M et al, 1994). However, they were found to possess Na+-coupled phosphate cotransporter function (Fernandes I et al, 1999). The transport is electrogenic with a stoichiometry of 2:1 (Na+:Pi). has a Stoichiometric coefficient of 2 Glucose transport by class I GLUTs Authored: Jassal, B, 2009-07-10 Edited: Jassal, B, 2009-07-10 Pubmed10227690 Pubmed10987651 Pubmed1756912 Pubmed1918382 Pubmed2656669 Pubmed3170580 Pubmed3399500 Pubmed3839598 Reactome Database ID Release 43428825 Reactome, http://www.reactome.org ReactomeREACT_19335 Reviewed: He, L, 2009-08-24 The class I facilitative glucose transporters contain GLUT1-4. As well as glucose, these proteins can transport other hexoses such as fructose, galactose and glucosamine. GLUT1 was cloned from a HepG2 cell line (Mueckler M et al, 1985). GLUT1 is expressed by SLC2A1 mainly in brain and erythrocytes but is also expressed at lower levels in many other tissues containing endothelial and epithelial barriers. Defects in SLC2A1 are the cause of autosomal dominant GLUT1 deficiency syndrome which results in impaired glucose transport across the brain tissue barrier and is characterized by infantile seizures, delayed development and acquired microcephaly (Klepper J et al, 1999).<br><br>GLUT2 is expressed by SLC2A2 and is a low affinity glucose transporter (Fukumoto H et al, 1988). It is expressed mainly in the kidney, liver and pancreatic beta-cells. In beta-cells, it functions as a glucose-sensor for insulin secretion and in the liver, it allows for bi-directional glucose transport. In this reaction, it is shown to mediate the influx of glucose. In the next reaction, it is shown to be mediating efflux of glucose. Defects in SLC2A2 are the cause of Fanconi-Bickel syndrome (FBS). It is characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose (Burwinkel B et al, 1999).<br><br>SLC2A3 encodes GLUT3 which is mainly expressed in the brain but also in a wide range of tissues. If has a high affinity for glucose and can also transport other sugars (Kayano T et al, 1988). GLUT4, encoded by SLC2A4, is an insulin-responsive glucose transporter found in heart, skeletal muscle, brain and adipose tissue. Due to its sensitivity to insulin, it may play a role in diabetes. In a non-insulin condition, GLUT4 is localized in intracellular GLUT4-containing vesicles. On insulin stimulation, GLUT4 translocates to the plasma membrane where it can increase glucose transport 10-20-fold (Fukumoto H et al, 1989). Defects in SLC2A4 may be a cause of non-insulin-dependent diabetes mellitus (NIDDM) (Kusari J et al, 1991; Choi WH et al, 1991). Electrogenic Na+/Pi cotransport Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Pubmed10329428 Pubmed12324554 Pubmed16960801 Pubmed8327470 Reactome Database ID Release 43427656 Reactome, http://www.reactome.org ReactomeREACT_19133 Reviewed: He, L, 2009-08-24 SLC34A1 encodes Na+/Pi cotransporter (NaPi-IIa) which is expressed in the kidney in the renal proximal tubule (Magagnin S et al, 1993). SLC34A2 encodes NaPi-IIb which is abundantly expressed in lung and to a lesser degree in tissues of epithelial origin including small intestine, pancreas, prostate, and kidney (Field JA et al, 1999). Both NaPi-IIa and NaPi-IIb cotransport divalent Pi (HPO4[2-]) with three Na+ ions (electrogenic transport).<br><br>Defects in SLC34A1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1) (Prie D et al, 2002). Defects in SLC34A2 are a cause of pulmonary alveolar microlithiasis (Corut A et al, 2006). has a Stoichiometric coefficient of 3 Electroneutral Na+/Pi cotransport Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Pubmed11880379 Pubmed16358214 Reactome Database ID Release 43427645 Reactome, http://www.reactome.org ReactomeREACT_19211 Reviewed: He, L, 2009-08-24 SLC34A3 is almost exclusively expressed in the kidney and encodes the Na+/Pi cotransporter NaPi-IIc (Segawa H et al, 2002). The protein is located at apical membranes of proximal tubules. It cotransports two Na+ ions with every Pi (electroneutral transport). Defects in SLC34A3 are the cause of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) (Bergwitz C et al, 2006) has a Stoichiometric coefficient of 2 PathwayStep2912 Group 3 - Selective Cl- transport Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Group 3 members (SLC26A7 and 9) function as ion channels. SLC26A7 encodes an ion channel which is abundantly expressed in medullary collecting duct cells of the kidney, high endothelial venule enothelial cells (HEVEC) and gastric parietal cells (Vincourt JB et al, 2002; Lohi H et al, 2002). SLC26A9 encodes an ion channel which is predominantly expressed on the lumenal side of the bronchiolar and alveolar epithelium of lung (Lohi H et al, 2002). Both these ion channels appear to transport Cl- without cotransport of HCO3- (Kim KH et al, 2005; Dorwart MR et al, 2007). Pubmed11829495 Pubmed11834742 Pubmed15591059 Pubmed17673510 Reactome Database ID Release 43427570 Reactome, http://www.reactome.org ReactomeREACT_19248 Reviewed: He, L, 2009-08-24 PathwayStep2911 Group 2 - Cl-/HCO3- exchanger transport Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Pubmed11247665 Pubmed11834742 Pubmed7683425 Pubmed8896562 Pubmed9398842 Reactome Database ID Release 43427666 Reactome, http://www.reactome.org ReactomeREACT_19235 Reviewed: He, L, 2009-08-24 The proteins responsible for the exchange of Cl- with HCO3- are members of the SLC4 (1-3) and SLC26 (3, 4 and 6) transporter families. SLC4 members are discussed in the section "Bicarbonate transporters".<br><br>SLC26A3 (Chloride anion exchanger, Down-regulated in adenoma, DRA) is expressed in the mucosa of the colon and helps mediate electrolyte and fluid absorption (Schweinfest CW et al, 1993). Defects in SLC26A3 cause congenital chloride diarrhea (CLD), a disease characterized by watery stools containing an excess of chloride (Hoeglund P et al, 1996).<br><br>SLC26A4 (Pendrin) is highly expressed in the adult thyroid and its activity is necessary for production of thyroid hormone. (Everett et al, 1997). Mutations in this gene are associated with Pendred syndrome, an autosomal-recessive disease. It is the most common form of syndromic deafness (Everett et al, 1997). Pendred syndrome is also characterized by hypothyroidism.<br><br>SLC26A6 encodes a protein involved in transporting chloride, oxalate, sulfate and bicarbonate (Waldegger S et al, 2001). It is ubiquitously expressed, the highest levels present in kidney and pancreas. PathwayStep2910 Group 1 - Sulphate transport Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Pubmed12713736 Pubmed7923357 Reactome Database ID Release 43427555 Reactome, http://www.reactome.org ReactomeREACT_19330 Reviewed: He, L, 2009-08-24 The SLC26A1 and 2 genes encode proteins that facilitate sulfate uptake into cells. The mechanism by which these transporters work is unclear but may be enhanced by extracellular halides or acidic pH environments, cotransporting protons electroneutrally. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) (Regeer RR et al, 2003) which can transport sulfate and oxalate across the basolateral membrane of epithelial cells. It is most abundantly expressed in the liver and kidney, with lower levels expressed in many other parts of the body.<br.><br>SLC26A2 is ubiquitously expressed and encodes a sulfate transporter (Diastrophic dysplasia protein, DTD, DTDST) (Hastbacka J et al, 1994). This transporter provides sulfate for proteoglycan sulfation which is needed for cartilage development. Defects in SLC26A2 are implicated in the pathogenesis of several human chondrodysplasias. has a Stoichiometric coefficient of 2 K+/Cl- cotransport Authored: Jassal, B, 2009-06-12 Edited: Jassal, B, 2009-06-12 K+/Cl- cotransport is implicated not only in regulatory volume decrease, but also in transepithelial salt absorption, renal K+ secretion, myocardial K+ loss during ischemia and regulation of neuronal Cl- concentration. Four genes (SLC12A4-7) encode the K+/Cl- cotransporters KCC1-4 respectively. Cotransport of K+ and Cl- is electroneutral with a 1:1 stoichiometry. These cotransporters function as homomultimers or heteromultimers with other K+/Cl- cotransporters.<br>SLC12A4 encodes KCC1 (Gillen CM et al, 1996). KCC1 is ubiquitously expressed, suggesting a housekeeping role in the regulation of cell volume. SLC12A5 encodes KCC2 (Song L et al, 2002). KCC2's expression is restricted to neurons in the CNS and retina. It is thought KCC2 is important for Cl- homeostasis in neurons. SLC12A6 encodes KCC3 (Race JE et al, 1999; Mount DB et al, 1999). KCC3 is highly expressed in heart, brain, spinal cord, kidney, muscle, pancreas and placenta. Defects in SLC12A6 are a cause of agenesis of the corpus callosum with peripheral neuropathy (ACCPN) (Howard HC et al, 2002). SLC12A7 encodes KCC4 (Mount DB et al, 1999) which is widely expressed, especially in the kidney. It is thought to play a role in transepithelial transport of Cl- by the proximal tubule. Pubmed10347194 Pubmed10600773 Pubmed12106695 Pubmed12368912 Pubmed8663127 Reactome Database ID Release 43426155 Reactome, http://www.reactome.org ReactomeREACT_19385 Reviewed: He, L, 2009-08-24 PathwayStep2919 PathwayStep2918 PathwayStep2917 PathwayStep2916 PathwayStep2915 PathwayStep2914 PathwayStep2913 ZnT1 mediates the efflux of zinc from the cell Authored: Jassal, B, 2009-09-09 Edited: Jassal, B, 2009-08-21 Pubmed15276077 Reactome Database ID Release 43435366 Reactome, http://www.reactome.org ReactomeREACT_20614 Reviewed: He, L, 2009-11-12 The human gene SLC30A1 encodes the zinc transporter ZnT1. It is widely expressed throughout the body and it's expression is regulated by zinc. ZnT1 is the only member of the SLC30 gene family that is located on the plasma membrane and mediates the transport of zinc out of the cell (Devergnas S et al, 2004). HMIT co-transports myo-inositol with a proton Authored: Jassal, B, 2009-07-14 Edited: Jassal, B, 2009-07-14 Pubmed11500374 Reactome Database ID Release 43429101 Reactome, http://www.reactome.org ReactomeREACT_19215 Reviewed: He, L, 2009-08-24 SLC2A13 encodes a H+/myo-inositol co-transporter, HMIT (Uldry M et al, 2001) which is abundantly expressed in the brain. A proton is co-transported with myo-inositol uptake into cells. No glucose transport function has been detected to date. DCT1 (NRAMP2) mediates divalent iron uptake across the apical membrane of enterocytes Authored: Jassal, B, 2009-09-09 Edited: Jassal, B, 2009-08-21 Pubmed10625641 Reactome Database ID Release 43435349 Reactome, http://www.reactome.org ReactomeREACT_20526 Reviewed: He, L, 2009-11-12 The primary site for absorption of dietary iron is the duodenum. Ferrous iron (Fe2+) is taken up from the gut lumen across the apical membranes of enterocytes and released into the portal vein circulation across basolateral membranes.<br>The human gene SLC11A2 encodes the divalent cation transporter DCT1 (NRAMP2, Natural resistance-associated macrophage protein 2). NRAMP2 resides on the apical membrane of enterocytes and mediates the uptake of ferrous iron into these cells (Tandy S et al, 2000). DCT1 can also accept a broad range of transition metal ions. Ferroportin mediates iron influx across the basolateral membrane of enterocytes Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-08-21 Pubmed15692071 Pubmed17486601 Pubmed19452451 Reactome Database ID Release 43442368 Reactome, http://www.reactome.org ReactomeREACT_20531 Reviewed: He, L, 2009-11-12 The primary site for absorption of dietary iron is the duodenum. Ferrous iron (Fe2+) is taken up from the gut lumen across the apical membranes of enterocytes and released into the portal vein circulation across basolateral membranes.<br>The human gene SLC40A1 encodes a metal transporter protein MTP1 (also called ferroportin or IREG1). This protein resides on the basolateral membrane of enterocytes and mediates ferrous iron efflux into the portal vein (Schimanski LM et al, 2005). MTP1 colocalizes with hephaestin (HEPH) which stablizes MTP1 and is necessary for the efflux reaction to occur (Han O and Kim EY, 2007; Chen H et al, 2009). As well as the dudenum, MTP1 is also highly expressed on macrophages (where it mediates iron efflux from the breakdown of haem) and the placenta (where it may mediate the transport of iron from maternal to foetal circulation). It is also expressed in muscle and spleen. Ferroportin mediates iron efflux on macrophages Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-08-21 MTP1 is also highly expressed on macrophages where it mediates iron efflux from the breakdown of haem.<br>The human gene SLC40A1 encodes a metal transporter protein MTP1 (also called ferroportin or IREG1) (Schimanski LM et al, 2005). MTP1 colocalizes with ceruloplasmin (CP) which stablizes MTP1 and is necessary for the efflux reaction to occur (Texel SJ et al, 2008). Ceruloplasmin also catalyzes the conversion of iron from ferrous (Fe2+) to ferric form (Fe3+), therefore assisting in its transport in the plasma in association with transferrin, which can only carry iron in the ferric state. As well as on macrophages, MTP1 is also highly expressed in the duodenum, placenta (where it may mediate the transport of iron from maternal to foetal circulation), in muscle and the spleen. Pubmed15692071 Pubmed19021540 Reactome Database ID Release 43904830 Reactome, http://www.reactome.org ReactomeREACT_23996 Reviewed: He, L, 2009-11-12 Co-transport (influx) of glucose/mannose and Na+ ions by SGLT4 Authored: Jassal, B, 2009-07-17 Edited: Jassal, B, 2009-07-17 Pubmed15607332 Reactome Database ID Release 43429567 Reactome, http://www.reactome.org ReactomeREACT_19292 Reviewed: He, L, 2009-08-24 The human gene SLC5A9 encodes a low affinity transporter for glucose and mannose (SGLT4). Of the tissues tested, SGLT4 appears to be highly expressed in the kidney and intestine, with lower levels detected in the liver. Human SGLT4 expressed in african green monkey cells exhibited glucose and mannose co-transport with Na+ ions (Tazawa S et al, 2005). Co-transport (influx) of glucose and Na+ ions by SGLT2 Authored: Jassal, B, 2009-07-17 Edited: Jassal, B, 2009-07-17 Pubmed1415574 Pubmed14614622 Reactome Database ID Release 43429613 Reactome, http://www.reactome.org ReactomeREACT_19399 Reviewed: He, L, 2009-08-24 The human gene SLC5A2 encodes a sodium-dependent glucose transporter, SGLT2 (Wells RG et al, 1992). SGLT2 is expressed in many tissues but primarily in the kidney, specifically the renal proximal tubules (S1 and S2 segments).It is a low affinity, high capacity transporter of glucose across the apical membrane, with co-transport of Na+ ions in a 1:1 ratio. Unlike SGLT1, it doesn't transport galactose. SGLT2 is the main transporter of glucose in the kidney, responsible for approximately 98% of glucose reabsorption (reaminder by SGLT1). Defects in SLC5A2 are the cause of renal glucosuria (GLYS1), an autosomal recessive renal tubular disorder (Calado J et al, 2004). PathwayStep2901 Co-transport (influx) of myo-inositol/D-chiro-inositol and two Na+ ions by SGLT6 Authored: Jassal, B, 2009-07-17 Edited: Jassal, B, 2009-07-17 Pubmed12039040 Pubmed19032932 Pubmed8626564 Reactome Database ID Release 43429571 Reactome, http://www.reactome.org ReactomeREACT_19299 Reviewed: He, L, 2009-08-24 The human SLC5A11 gene encodes a high affinity myo-inositol transporter (SMIT2, SGLT6) (Ostlund RE et al, 1996; Roll P et al, 2002). It can transport myo-inositol and D-chiro-inositol, together with two Na+ ions. It was thought SGLT6 could transport glucose but there is no evidence for this so far (Lin X et al, 2009). has a Stoichiometric coefficient of 2 PathwayStep2900 Co-transport (influx) of myo-inositol and two Na+ ions by SMIT Authored: Jassal, B, 2009-07-17 Edited: Jassal, B, 2009-07-17 Pubmed7789985 Reactome Database ID Release 43429663 Reactome, http://www.reactome.org ReactomeREACT_19415 Reviewed: He, L, 2009-08-24 The human SLC5A3 gene encodes a Na+/myo-inositol transporter, SMIT (Berry GT et al, 1995). SMIT functions in cellular osmoregulation and is expressed in many human tissues including skeletal muscle, brain, kidney, and placenta. It transports myo-inositol together with two Na+ ions. SMIT is also thought to act as a glucose sensor that generates an intracellular glucose signal. has a Stoichiometric coefficient of 2 Glucose transport by class III GLUTs Authored: Jassal, B, 2009-07-14 Class III facilitative transporters consist of five members; GLUT6, 8, 10, 12 and HMIT (a H+/myo-inositol transporter). They possess a characteristic glycosylation site on loop 9 (found in loop 1 of classes I and II transporters).<br><br>Four class III facilitative transporters can transport glucose. SLC2A6 encodes GLUT6, expressed mainly in brain, spleen and leucocytes (Doege H et al, 2000a). In literature, this protein is incorrectly described as GLUT9. SLC2A8 encodes GLUT8 and is expressed in brain, testis and adipose tissue (Doege H et al, 2000b). SLC2A10 (located in the Type 2 diabetes-linked region of human chromosome 20q12-13.1) encodes GLUT10, a transporter with high affinity for glucose (McVie-Wylie AJ et al, 2001) . GLUT10 is highly expressed in liver and pancreas but is present in most tissues in lower levels. Defects in SLC2A10 are the cause of arterial tortuosity syndrome (ATS), an autosomal recessive disorder characterized by tortuosity and elongation of major arteries, often resulting in death at a young age (Coucke PJ et al, 2006). SLC2A12 encodes GLUT12, which is highly expressed in skeletal muscle, heart and prostate, with lower levels in brain, placenta and kidney. It was originally cloned from the human breast cancer cell line MCF-7 (Rogers S et al, 2002). Edited: Jassal, B, 2009-07-14 Pubmed10821868 Pubmed10970791 Pubmed11247674 Pubmed11832379 Pubmed16550171 Reactome Database ID Release 43429094 Reactome, http://www.reactome.org ReactomeREACT_19350 Reviewed: He, L, 2009-08-24 PathwayStep2907 PathwayStep2906 PathwayStep2909 PathwayStep2908 PathwayStep2903 PathwayStep2902 PathwayStep2905 PathwayStep2904 ZIP7 mediates zinc efflux from the endoplasmic reticulum Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-08-21 Pubmed14525538 Reactome Database ID Release 43442393 Reactome, http://www.reactome.org ReactomeREACT_20575 Reviewed: He, L, 2009-11-12 The human gene SLC39A7 encodes the zinc transporter ZIP7 (HKE4, Histidine-rich membrane protein Ke4). It is expressed in many tissues but especially in liver, kidney and the hormonal tissues apart from brain. Unlike the other members of the LZT subfamily, ZIP7 is localized to intracellular membranes of the ER rather than the plasma membrane and mediates zinc efflux into the cytoplasm (Taylor KM et al, 2004). ZIP6 and ZIP14 mediate zinc influx into cells Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-08-21 Pubmed12839489 Pubmed15642354 Reactome Database ID Release 43442317 Reactome, http://www.reactome.org ReactomeREACT_20648 Reviewed: He, L, 2009-11-12 The human gene SLC39A6 encodes the zinc transporter ZIP6 (LIV-1). The gene is oestrogen-regulated and has been implicated in metastatic breast cancer. ZIP6 mediates the transport of zinc into cells, is localized to the plasma membrane and is expressed mainly in hormonal tissues such as breast, prostate and brain (Taylor KM et al, 2003).<br><br>The human gene SLC39A14 encodes the zinc transporter ZIP14. This protein is ubiquitously expressed with higher expression seen in heart, liver and pancreas. ZIP14 is localized to the plasma membrane and mediates zinc influx into cells (Taylor KM et al, 2005). hZIP5 mediates zinc uptake by cells Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-08-21 Pubmed15322118 Reactome Database ID Release 43442405 Reactome, http://www.reactome.org ReactomeREACT_20641 Reviewed: He, L, 2009-11-12 The human gene SLC39A5 encodes the zinc transporter hZIP5 (Wang F et al, 2004). Highest expressions are seen in liver, kidney, pancreas and throughout the small intestine and colon with little expression detected in other tissues. hZIP5 is localized to the basolateral membrane of cells in these tissues. The functionality of ZIP5 as a zinc transporter was determined using mouse protein (mZIP5) (Wang F et al, 2004). hZIP1-4 mediate zinc uptake by cells Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-08-21 Pubmed10364181 Pubmed10610721 Pubmed10681536 Pubmed11301334 Pubmed12032886 Pubmed12068297 Pubmed17550612 Pubmed18003899 Pubmed19755388 Reactome Database ID Release 43442422 Reactome, http://www.reactome.org ReactomeREACT_20673 Reviewed: He, L, 2009-11-12 The human gene SLC39A1 encodes the zinc transporter hZIP1. It is ubiquitously expressed (Lioumi M et al, 1999) and mediates the influx of zinc into cells (Gaither LA and Eide DJ, 2001).<br>The human gene SLC39A2 encodes the zinc transporter hZIP2. It is expressed exclusively in prostate and uterine epithelial cells and mediates zinc transport into cells (Gaither LA and Eide DJ, 2000).<br><br>Normal prostate cells have the ability to accumulate high levels of zinc. In prostate cancer, hZIP1-3 transporters are down-regulated and the cells lose the ability to accumulate zinc. Zinc plays a role as a tumour-suppressing agent thus prostate cells can become cancerous. Silencing of the genes that express hZIP1-3 transporters is a required event for malignancy (Costello LC et al, 1999; Desouki MM et al, 2007).<br><br>The human gene SLC39A4 encodes the zinc transporter hZIP4 (Kury S et al, 2002). The role of zinc in tumour progression is complicated and, subsequently, so are the role of ZIP transporters. For example, ZIP4 can actually enhance cancer progression (Li M et al, 2007; Li M et al, 2009). Defects in SLC39A4 result in the inherited condition acrodermatitis enteropathica (AE) results from defective absorption of dietary zinc from the duodenum and jejunum. Clinical features include growth retardation, immune system dysfunction, severe dermatitis and mental disorders (Wang K et al, 2002). ZnT2 facilitates zinc vesicular sequestration Authored: Jassal, B, 2009-09-09 Edited: Jassal, B, 2009-08-21 Pubmed8617223 Reactome Database ID Release 43435375 Reactome, http://www.reactome.org ReactomeREACT_20674 Reviewed: He, L, 2009-11-12 The human gene SLC30A2 encodes zinc transporter ZnT2. Its function is inferred from experiments using rat Znt2 (Palmiter RD et al, 1996). ZnT3 transports zinc into synaptic vesicles Authored: Jassal, B, 2009-09-11 Edited: Jassal, B, 2009-08-21 Pubmed8962159 Reactome Database ID Release 43437084 Reactome, http://www.reactome.org ReactomeREACT_20502 Reviewed: He, L, 2009-11-12 The human gene SLC30A3 encodes zinc transporter ZnT3. Through experiments on the mouse homologue Znt3, it is thought this transporter is expressed mainly in brain and testis and mediated the accumulation of zinc into synaptic vesicles (Palmiter et al, 1996). ZnT7 transports zinc into the golgi apparatus Authored: Jassal, B, 2009-09-11 Edited: Jassal, B, 2009-08-21 Pubmed12446736 Reactome Database ID Release 43437129 Reactome, http://www.reactome.org ReactomeREACT_20512 Reviewed: He, L, 2009-11-12 The human gene SLC30A7 encodes the zinc transporter ZnT7. It is thought to be present in the small intestine and lung in humans (Kirschke CP and Huang L, 2003). Functional properties assigned to ZnT7 are based on studies conducted with mouse experiments. ZnT8 transports zinc into the secretory vesicles of pancreatic beta cells specifically Authored: Jassal, B, 2009-09-11 Edited: Jassal, B, 2009-08-21 Pubmed16984975 Reactome Database ID Release 43437136 Reactome, http://www.reactome.org ReactomeREACT_20678 Reviewed: He, L, 2009-11-12 The human SLC30A8 gene encodes the zinc transporter ZnT8 which is specifically expressed in pancreatic beta cells. Zinc is required for zinc-insulin crystallization within secretory vesicles of these cells. After glucose stimulation, large amounts of zinc are secreted locally in the extracellular matrix together with insulin. It has been suggested that this co-secreted zinc plays a role in islet cell paracrine and/or autocrine communication<br>(Chimienti F et al, 2006). ZnT5 transports zinc into secretory granules in pancreatic beta cells Authored: Jassal, B, 2009-09-11 Edited: Jassal, B, 2009-08-21 Pubmed11904301 Reactome Database ID Release 43437085 Reactome, http://www.reactome.org ReactomeREACT_20545 Reviewed: He, L, 2009-11-12 The human gene SLC30A5 encodes the zinc transporter ZnT5. This protein is widely expressed but is most abundant in pancreatic beta cells (Kambe T et al, 2002). In these cells, ZnT5 mediates the transport of zinc into secretory granules that contain insulin. ZnT6 transports zinc into the golgi apparatus Authored: Jassal, B, 2009-09-11 Edited: Jassal, B, 2009-08-21 Pubmed11997387 Reactome Database ID Release 43437139 Reactome, http://www.reactome.org ReactomeREACT_20607 Reviewed: He, L, 2009-11-12 Two human genes mediate the transport of zinc into the TGN and they are both localized to the TGN. The human gene SLC30A6 encodes the zinc transporter ZnT6. By Western blot studies, ZnT6 is only found in the brain and lung in human (Huang L et al, 2002). Sodium- and chloride-dependent choline transport by CHT Authored: Jassal, B, 2009-07-17 Edited: Jassal, B, 2009-07-17 Pubmed11027560 Pubmed11068039 Reactome Database ID Release 43429594 Reactome, http://www.reactome.org ReactomeREACT_20595 Reviewed: He, L, 2009-08-24 The human SLC5A7 gene encodes a sodium- and chloride-dependent, high affinity choline transporter, CHT (Apparsundaram S et al, 2000). CHT transports choline from the extracellular space into neuronal cells and is dependent on Na+ and Cl- ions for transport (Okuda T and Haga T, 2000). Choline uptake is the rate-limiting step in acetylcholine synthesis. VMAT1/2 can mediate the transport of biogenic amines Authored: Jassal, B, 2009-10-22 Edited: Jassal, B, 2009-08-21 Pubmed8245983 Pubmed8643547 Reactome Database ID Release 43444160 Reactome, http://www.reactome.org ReactomeREACT_20519 Reviewed: He, L, 2009-11-12 The human gene SLC18A1 encodes the vesicular monoamine transporter 1 (VMAT1) (Erickson JD et al, 1996). VMAT1 is mainly expressed in neuroendocrine cells. The human gene SLC18A2 encodes VMAT2 (Erickson JD and Eiden LE, 1993). Both transporters can mediate the transport of biogenic amines into secretory vesicles, which can then discharge their contents into the extracellular space by exocytosis. Predominant biogenic amines these proteins can transport are serotonin, dopamine, adrenaline, noradrenaline and histamine. HUT2 and HUT11 mediate urea transport in kidney and erythrocytes respectively Authored: Jassal, B, 2009-10-22 Carrier-mediated urea transport allows rapid urea movement across the cell membrane, which is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues. Two carriers exist in humans, HUT2 which is renal-specific (Olives B et al, 1996) and HUT11, which is erythrocyte-specific (Olives B et al, 1994). Edited: Jassal, B, 2009-08-21 Pubmed7989337 Pubmed8647271 Reactome Database ID Release 43444126 Reactome, http://www.reactome.org ReactomeREACT_20655 Reviewed: He, L, 2009-11-12 ZIP8 mediates zinc influx into cells Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-08-21 Pubmed18390834 Pubmed19265717 Reactome Database ID Release 43442387 Reactome, http://www.reactome.org ReactomeREACT_20516 Reviewed: He, L, 2009-11-12 The human gene SLC39A8 encodes the zinc transporter ZIP8 (BIGM103, BCG-induced integral membrane protein in monocyte clone 103 protein). It is highly expressed in the pancreas and localized to the plasma membrane where it mediates the influx of zinc into the cell (Besecker B et al, 2008). The highly homologous mouse ZIP8 have been shown to play important roles in regulating zinc homeostasis and determining sensitivity to cadmium toxicity in mouse testicular endothelium and kidney tissue. It is expected the human transporter plays a similar role (He L et al, 2009). ZIP8 belongs to the LZT subfamily of ZIP transporters. hZIP10 mediates zinc influx into cells Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-08-21 Pubmed16804107 Pubmed17359283 Reactome Database ID Release 43442345 Reactome, http://www.reactome.org ReactomeREACT_20536 Reviewed: He, L, 2009-11-12 The human gene SLC39A10 encodes the zinc transporter hZIP10. It is thought to be involved in the invasive behaviour of breast cancer cells where depletion of hZIP10 and intracellular zinc levels inhibit the migratory effects these cells (Kagara N et al, 2007). Functional characterization of this transporter was elucidated in the rat orthologue rZip10. Cellular copper transport is mediated by human copper transporter 1 hCTR1 Authored: Jassal, B, 2009-09-14 Copper (Cu2+) is essential for many important biological processes such as mitochondrial oxidative phosphorylation, detoxification of free radicals, iron metabolism and neurotransmiter synthesis. Too much influx results in cell poisoning. In humans, there are two member of the SLC31 gene family that are implicated in copper transport. The human gene SLC31A1 encodes human copper transporter 1, hCTR1 and is ubiquitiously expressed, with highest levels seen in the liver.. It was first identified by functional complementation in ctr1-deficient yeast (Zhou B and Gitschier J, 1997). hCTR1 exists as a homotrimer at the plasma membrane of cells (De Feo CJ et al, 2007) and is responsible for high-affinity copper uptake (Lee J et al, 2002). The second gene product, hCTR2, has not be characterized yet. Edited: Jassal, B, 2009-08-21 Pubmed11734551 Pubmed17211682 Pubmed9207117 Reactome Database ID Release 43437300 Reactome, http://www.reactome.org ReactomeREACT_20667 Reviewed: He, L, 2009-11-12 MagT transporters mediate magnesium uptake into cells Authored: Jassal, B, 2009-09-29 Edited: Jassal, B, 2009-08-21 Magnesium (Mg2+) is an abundant cation that is important for many intracellular biochemical functions, especially as a cofactor for ATP. Intracellular Mg2+ concentrations must be finely regulated and recently, transporters for this cation have been elucidated. The human genes SLC41A1 and SLC41A2 encode magnesium transport proteins 1 and 2 respectively (MagT1 and MagT2). They both mediate the uptake of Mg2+ into cells (Goytain A and Quamme GA, 2005; Sahni J et al, 2007). A third human gene, SLC41A3, is also thought to encode a MagT protein but has not been characterized yet. Pubmed15804357 Pubmed16984228 Reactome Database ID Release 43442661 Reactome, http://www.reactome.org ReactomeREACT_20680 Reviewed: He, L, 2009-11-12 NAT1 mediates norepinephrine uptake Authored: Jassal, B, 2009-10-20 Edited: Jassal, B, 2009-08-21 Noradrenaline (norepinephrine) is a neurotransmitter whose action is mediated by the noradrenaline transporter NAT1. NAT1 is a monoamine transporter that transports noradrenaline from the synapse back to its vesicles for storage until later use. NAT1 is encoded by the human gene SLC6A2 and is expressed in the CNS and adrenal gland (Pacholczyk T et al, 1991). Defects in SLC6A2 results in orthostatic intolerance (OI), which is a syndrome characterized by lightheadedness, fatigue and development of symptoms during upright standing, relieved by sitting back down again (Shannon JR et al, 2000). Pubmed10684912 Pubmed2008212 Reactome Database ID Release 43443997 Reactome, http://www.reactome.org ReactomeREACT_20592 Reviewed: He, L, 2009-11-12 GLYT1/2 mediate glycine uptake Authored: Jassal, B, 2009-10-22 Edited: Jassal, B, 2009-08-21 Pubmed16751771 Pubmed8183239 Pubmed9845349 Reactome Database ID Release 43444120 Reactome, http://www.reactome.org ReactomeREACT_20620 Reviewed: He, L, 2009-11-12 The amino acid glycine plays an important role in neurotransmission. Its action is terminated by rapid re-uptake into the pre-synaptic terminal or surrounding glial cells. This re-uptake is mediated by the sodium- and chloride-dependent glycine transporters 1 and 2 (GLYT1 and GLYT2 respectively). GLYT1 is encoded by the human gene SLC5A9 and is expressed in the brain, liver, kidney, pancreas, lung and placenta (Kim KM et al, 1994). GLYT2 is encoded by the human gene SLC6A5 and is predominantly expressed in the medulla (Morrow JA et al, 1998). Defects in SLC6A5 cause startle disease (STHE or hyperekplexia). STHE is is a human neurological disorder characterized by an excessive startle response (Rees MI et al, 2006). PROT mediates L-proline uptake Authored: Jassal, B, 2009-10-22 Edited: Jassal, B, 2009-08-21 Pubmed7651355 Reactome Database ID Release 43444100 Reactome, http://www.reactome.org ReactomeREACT_20557 Reviewed: He, L, 2009-11-12 The amino acid L-proline can act as a neurotransmitter. Its actions are terminated by its re-uptake from the synaptic cleft into the pre-synaptic terminal in the brain. This re-uptake is mediated by a sodium-dependent proline transporter, PROT (Shafqat S et al, 1995). OCT3 mediates renal clearance of organic cations Authored: Jassal, B, 2010-03-19 Edited: Jassal, B, 2010-03-19 Pubmed10196521 Pubmed10966924 Reactome Database ID Release 43549304 Reactome, http://www.reactome.org ReactomeREACT_22373 Reviewed: He, L, 2010-05-10 The human gene SLC22A3 encodes organic cation transporter OCT3. It is mainly expressed in skeletal muscle, liver, placenta, kidney and heart, and to a lesser extent in brain. OCT3 is involved in the biliary excretion of cationic drugs. In CNS, ganglia and heart, OCT3 regulates the interstitial concentrations of monoamine neurotransmitters and cationic drugs. In placenta, OCT3 is responsible for the release of acetylcholine during nonneuronal cholinergic regulation (Grundemann D et al,1998; Wu X et al, 2000). OCT2 mediates tubular secretion of organic cations in the kidney Authored: Jassal, B, 2010-03-25 Edited: Jassal, B, 2010-03-25 Pubmed9260930 Reactome Database ID Release 43561054 Reactome, http://www.reactome.org ReactomeREACT_22327 Reviewed: He, L, 2010-05-10 The human gene SLC22A2 encodes the organic cation transporter OCT2. It is expressed in a variety of tissues, especially the kidney and placenta. OCT2 can mediate the reversible transport of a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (Gorboulev V et al, 1997). Pharmaceuticals that up-regulate OCT2 in the kidney can increase the renal excretion of cationic drugs. OCT1 transports organic cations out of hepatic cells Authored: Jassal, B, 2010-03-19 Edited: Jassal, B, 2010-03-19 Pubmed9260930 Pubmed9655880 Reactome Database ID Release 43549322 Reactome, http://www.reactome.org ReactomeREACT_22348 Reviewed: He, L, 2010-05-10 The human gene SLC22A1 expresses the organic cation transporter 1 (OCT1) mainly in the liver. It can mediate the reversible transport of a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (Zhang L et al, 1998; Gorboulev V et al, 1997). OCT2 mediates tubular uptake of organic cations in the kidney Authored: Jassal, B, 2010-03-19 Edited: Jassal, B, 2010-03-19 Pubmed9260930 Reactome Database ID Release 43549279 Reactome, http://www.reactome.org ReactomeREACT_22283 Reviewed: He, L, 2010-05-10 The human gene SLC22A2 encodes the organic cation transporter OCT2. It is expressed in a variety of tissues, especially the kidney and placenta. OCT2 can mediate the reversible transport of a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (Gorboulev V et al, 1997). Pharmaceuticals that up-regulate OCT2 in the kidney can increase the renal excretion of cationic drugs. RhCG mediates ammonium efflux out of kidney collecting duct cells Authored: Jassal, B, 2009-11-12 Edited: Jassal, B, 2009-11-12 Pubmed10852913 Pubmed11062476 Reactome Database ID Release 43446277 Reactome, http://www.reactome.org ReactomeREACT_20505 Reviewed: He, L, 2009-11-12 The human gene RhCG encodes the Rhesus blood group family type C glycoprotein which is mainly expressed in kidney collecting duct but also found in testis. RhCG is located on the apical membrane and mediates the bi-directional transport of ammonium into and out of renal collecting duct cells in an electroneutral manner, with H+ transported the other way (Liu Z et al, 2000; Marini AM et al, 2000). OCT1 transports organic cations into hepatic cells Authored: Jassal, B, 2010-03-17 Edited: Jassal, B, 2010-03-17 Pubmed9260930 Pubmed9655880 Reactome Database ID Release 43549129 Reactome, http://www.reactome.org ReactomeREACT_22221 Reviewed: He, L, 2010-05-10 The human gene SLC22A1 expresses the organic cation transporter 1 (OCT1) mainly in the liver. It can mediate the reversible transport of a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (Zhang L et al, 1998; Gorboulev V et al, 1997). RhBG mediates ammonium influx into kidney collecting duct cells Authored: Jassal, B, 2009-11-12 Edited: Jassal, B, 2009-11-12 Pubmed11024028 Pubmed15284342 Reactome Database ID Release 43446278 Reactome, http://www.reactome.org ReactomeREACT_20571 Reviewed: He, L, 2009-11-12 The human gene RhBG encodes a Rhesus blood group family type B glycoprotein which is expressed mainly in the kidney but is also found in the liver. The liver and kidney are important tissues for ammonium metabolism and excretion. RhBG is located on the basolateral membrane and mediates the reversible transport of ammonium in and out of renal collecting duct cells in an electroneutral manner, with H+ transported the other way (Ludewig U, 2004; Liu Z et al, 2001). RhCG mediates ammonium influx into kidney collecting duct cells Authored: Jassal, B, 2009-10-23 Edited: Jassal, B, 2009-08-21 Pubmed10852913 Pubmed11062476 Reactome Database ID Release 43444393 Reactome, http://www.reactome.org ReactomeREACT_20677 Reviewed: He, L, 2009-11-12 The human gene RhCG encodes the Rhesus blood group family type C glycoprotein which is mainly expressed in kidney collecting duct but also found in testis. RhCG is located on the apical membrane and mediates the bi-directional transport of ammonium into and out of renal collecting duct cells in an electroneutral manner, with H+ transported the other way (Liu Z et al, 2000; Marini AM et al, 2000). RhAG mediates ammounium export from red blood cells Authored: Jassal, B, 2009-10-23 Edited: Jassal, B, 2009-08-21 Pubmed11062476 Pubmed11861637 Pubmed9454778 Reactome Database ID Release 43444416 Reactome, http://www.reactome.org ReactomeREACT_20532 Reviewed: He, L, 2009-11-12 The human gene RhAG encodes a Rhesus blood group family type A glycoprotein which is expressed specifically in erythroid cells. It is thought to mediate ammonium export from these cells (Marini AM et al, 2000; Westhoff CM et al, 2002). Defects in RHAG are the cause of regulator type Rh-null hemolytic anemia (RHN) (Rh-deficiency syndrome). RHN is a form of chronic hemolytic anemia (Hyland CA et al, 1998). RhBG mediates ammonium effflux out of kidney collecting duct cells Authored: Jassal, B, 2009-10-23 Edited: Jassal, B, 2009-08-21 Pubmed11024028 Pubmed15284342 Reactome Database ID Release 43444419 Reactome, http://www.reactome.org ReactomeREACT_20654 Reviewed: He, L, 2009-11-12 The human gene RhBG encodes a Rhesus blood group family type B glycoprotein which is expressed mainly in the kidney but is also found in the liver. The liver and kidney are important tissues for ammonium metabolism and excretion. RhBG is located on the basolateral membrane and mediates the reversible transport of ammonium in and out of renal collecting duct cells in an electroneutral manner, with H+ transported the other way (Ludewig U, 2004; Liu Z et al, 2001). ACTIVATION GENE ONTOLOGYGO:0004726 Reactome Database ID Release 43180501 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004726 Reactome Database ID Release 43180501 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43180302 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004726 Reactome Database ID Release 43180501 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016314 Reactome Database ID Release 43199445 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43199438 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199274 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199274 Reactome, http://www.reactome.org ELK1 Converted from EntitySet in Reactome Reactome DB_ID: 198710 Reactome Database ID Release 43198710 Reactome, http://www.reactome.org ReactomeREACT_13391 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199274 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199274 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431482936 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43183057 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431181060 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43183074 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43182979 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43183039 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43182995 Reactome, http://www.reactome.org Activated JAK1, JAK2, TYK2 Converted from EntitySet in Reactome Reactome DB_ID: 1112596 Reactome Database ID Release 431112596 Reactome, http://www.reactome.org ReactomeREACT_27853 p-MEK1 Converted from EntitySet in Reactome Reactome DB_ID: 112340 Reactome Database ID Release 43112340 Reactome, http://www.reactome.org ReactomeREACT_3339 ACTIVATION GENE ONTOLOGYGO:0004726 Reactome Database ID Release 43180501 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43183074 Reactome, http://www.reactome.org MEK1 Converted from EntitySet in Reactome Reactome DB_ID: 112336 Reactome Database ID Release 43112336 Reactome, http://www.reactome.org ReactomeREACT_2607 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43183047 Reactome, http://www.reactome.org Active MAPKAP kinase Converted from EntitySet in Reactome Reactome DB_ID: 450261 Reactome Database ID Release 43450261 Reactome, http://www.reactome.org ReactomeREACT_22086 Active MAPKAP kinase Converted from EntitySet in Reactome Reactome DB_ID: 187726 Reactome Database ID Release 43187726 Reactome, http://www.reactome.org ReactomeREACT_12330 Phospho-MAP kinase p38 alpha/beta Converted from EntitySet in Reactome Reactome DB_ID: 198703 Reactome Database ID Release 43198703 Reactome, http://www.reactome.org ReactomeREACT_12925 phospho-p27/p21 Converted from EntitySet in Reactome Reactome DB_ID: 187849 Reactome Database ID Release 43187849 Reactome, http://www.reactome.org ReactomeREACT_9142 MAPKAP kinase Converted from EntitySet in Reactome Reactome DB_ID: 450217 Reactome Database ID Release 43450217 Reactome, http://www.reactome.org ReactomeREACT_21556 MAP kinase p38 alpha/beta Converted from EntitySet in Reactome Reactome DB_ID: 203795 Reactome Database ID Release 43203795 Reactome, http://www.reactome.org ReactomeREACT_21706 Cyclin E Converted from EntitySet in Reactome Reactome DB_ID: 157462 Reactome Database ID Release 43157462 Reactome, http://www.reactome.org ReactomeREACT_5284 phospho-CDK4/6 Converted from EntitySet in Reactome Reactome DB_ID: 69211 Reactome Database ID Release 4369211 Reactome, http://www.reactome.org ReactomeREACT_4864 Phosphorylated JNKs: MAPK8, MAPK9, MAPK10 Converted from EntitySet in Reactome Reactome DB_ID: 450253 Reactome Database ID Release 43450253 Reactome, http://www.reactome.org ReactomeREACT_22035 PPP2R3B Converted from EntitySet in Reactome PP2A B" beta Reactome DB_ID: 1362431 Reactome Database ID Release 431362431 Reactome, http://www.reactome.org ReactomeREACT_111729 phosphorylated JNKs: MAPK8_MAPK9_MAPK10 Converted from EntitySet in Reactome Reactome DB_ID: 450226 Reactome Database ID Release 43450226 Reactome, http://www.reactome.org ReactomeREACT_21549 JNKs: MAPK8_MAPK9_MAPK10 Converted from EntitySet in Reactome Reactome DB_ID: 450289 Reactome Database ID Release 43450289 Reactome, http://www.reactome.org ReactomeREACT_21895 Recruitment of PYK2 to pSIRP alpha Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Protein tyrosine kinase 2 beta (PYK2), a cytosolic tyrosine kinase related to FAK, has been shown to complex with SIRP alpha. The evidence for this interaction is from immunoprecipitation experiments performed in COS-7 lysates. Pubmed10469599 Pubmed12023008 Reactome Database ID Release 43391152 Reactome, http://www.reactome.org ReactomeREACT_24015 Reviewed: Barclay, AN, 2010-05-20 Recruitment of FYB to pSIRP alpha Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed10469599 Pubmed12023008 Reactome Database ID Release 43391151 Reactome, http://www.reactome.org ReactomeREACT_23963 Reviewed: Barclay, AN, 2010-05-20 The Fyn binding protein (FYB/SLAP130/ADAP) has been found to associate with SIRP alpha. Recruitment of FYB to SIRP alpha requires SCAP in the SIRP alpha complex. The evidence for this interaction is from immunoprecipitation experiments performed in COS-7 lysates. Recruitment of SCAP2 to pSIRP alpha Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed10469599 Reactome Database ID Release 43391157 Reactome, http://www.reactome.org ReactomeREACT_23995 Reviewed: Barclay, AN, 2010-05-20 SRC-family-associated phosphoprotein 2 (SCAP2) has been shown to bind to SIRP alpha. Evidence from immunoprecipitation experiments performed in COS-7 lysates suggests that the SH3 domain of SCAP2 is involved in the interaction. Cdk4/6 Converted from EntitySet in Reactome Reactome DB_ID: 69209 Reactome Database ID Release 4369209 Reactome, http://www.reactome.org ReactomeREACT_4552 INK4A Converted from EntitySet in Reactome Reactome DB_ID: 182588 Reactome Database ID Release 43182588 Reactome, http://www.reactome.org ReactomeREACT_8915 SIRP gamma binds CD47 Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed10572074 Pubmed15294972 Pubmed15383453 Pubmed16691243 Reactome Database ID Release 43391168 Reactome, http://www.reactome.org ReactomeREACT_23927 Reviewed: Barclay, AN, 2010-05-20 SIRP gamma is expressed by T cells and has been shown to engage with CD47, albeit with lower affinity than SIRP alpha. The engagement of SIRP gamma on the surface of T cells with cell-surface-expressed CD47 increased cell-cell adhesion. Interaction of DAP12 and SIRP beta Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed10604985 Pubmed10940905 Pubmed16691243 Reactome Database ID Release 43210274 Reactome, http://www.reactome.org ReactomeREACT_23798 Reviewed: Barclay, AN, 2010-05-20 SIRP beta , also named CD172b, is expressed mainly on myeloid cells and has a very short cytoplasmic region of only six amino acids, lacking the signaling motifs for association with phosphatases that are found in the highly related SIRP alpha receptor. Instead, SIRP associates with a dimeric protein DAP12 to transmit activating signals via an ITAM in the cytoplasmic domain of DAP12. A positively charged amino acid in the transmembrane domain of DAP12 associate with a basic amino acid in SIRP beta's transmembrane region. SP-A/SP-D binds SIRP alpha Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed14531999 Pubmed16213021 Pulmonary surfactant proteins A and D (SP-A and SP-D) are soluble multivalent ligands shown to bind SIRP alpha on resident alveolar cells and macrophages via their lectin domain (globular head). SP-A and SP-D bind to the same regions of SIRP alpha as CD47, as shown by their ability to block subsequent binding of CD47. Reactome Database ID Release 43391155 Reactome, http://www.reactome.org ReactomeREACT_23944 Reviewed: Barclay, AN, 2010-05-20 Recruitment of Grb2 to pSIRP alpha Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Grb2 binds to phosphorylated tyrosine residues in SIRP alpha in vitro; this interaction has negative regulatory effects on cellular responses induced by growth factors, oncogenes or insulin. Pubmed9062191 Reactome Database ID Release 43391153 Reactome, http://www.reactome.org ReactomeREACT_23943 Reviewed: Barclay, AN, 2010-05-20 Cyclin D Converted from EntitySet in Reactome Reactome DB_ID: 182582 Reactome Database ID Release 43182582 Reactome, http://www.reactome.org ReactomeREACT_8530 DSCAM binds Netrin-1 Authored: Garapati, P V, 2010-01-05 DSCAM binds netrin-1 and directs the turning of axons towards netrin-1 source independent of DCC or cooperatively depending on the cellular and developmental context. Signaling mechanisms activated by netrin-1 downstream of DSCAM involve phosphorylation of Fyn and PAK1. Edited: Garapati, P V, 2010-01-05 Pubmed18585357 Reactome Database ID Release 43376126 Reactome, http://www.reactome.org ReactomeREACT_25010 Reviewed: Clemens, JC, 2010-08-10 DSCAM binds DCC Authored: Garapati, P V, 2010-01-05 DSCAM and DCC (Deleted in Colorectal Carcinoma) form a receptor complex in commissural axons in the absence of netrin1. They associate through a transmembrane interaction. The functional implication of this interaction is not known, but may allow DCC and DSCAM to contribute to other guidance pathways in a netrin1 independent fashion. It may serve as a way to hold DSCAM and DCC in a resting state, until netrin1 reaches a critical concentration at which both receptors are activated. Edited: Garapati, P V, 2010-01-05 Pubmed18585357 Reactome Database ID Release 43451345 Reactome, http://www.reactome.org ReactomeREACT_25013 Reviewed: Clemens, JC, 2010-08-10 phospho MKK4/ phospho MKK7 Converted from EntitySet in Reactome Reactome DB_ID: 450299 Reactome Database ID Release 43450299 Reactome, http://www.reactome.org ReactomeREACT_21783 DSCAM/DSCAML1 homodimerization Authored: Garapati, P V, 2010-01-05 DSCAM and DSCAML1 proteins are involved in homophilic intercellular interactions and these recognition events may play a role in neural connectivity. Recent studies in mouse demonstrate that DSCAM is selectively expressed in subclasses of cells and suggest that it uses homophilic repulsion to simultaneously promote both self avoidance (an essential developmental mechanism that allows axonal and dendrite processes to uniformly cover their synaptic fields) and tiling (ensures that the receptive fields of neurons from the same class do not overlap with one another) (Fuerst et al. 2008). Edited: Garapati, P V, 2010-01-05 Pubmed10925149 Pubmed11453658 Pubmed18216854 Pubmed18216855 Reactome Database ID Release 43376122 Reactome, http://www.reactome.org ReactomeREACT_25036 Reviewed: Clemens, JC, 2010-08-10 has a Stoichiometric coefficient of 2 Cdk4/6 Converted from EntitySet in Reactome Reactome DB_ID: 182702 Reactome Database ID Release 43182702 Reactome, http://www.reactome.org ReactomeREACT_8412 MKK4/MKK7 Converted from EntitySet in Reactome Reactome DB_ID: 450305 Reactome Database ID Release 43450305 Reactome, http://www.reactome.org ReactomeREACT_21423 Nuclear factor NF-kappa-B Converted from EntitySet in Reactome Reactome DB_ID: 177662 Reactome Database ID Release 43177662 Reactome, http://www.reactome.org ReactomeREACT_7847 Heterodimerization of nephrin and NEPH2/NEPH3 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 NEPH2 and NEPH3 specifically interact with the extracellular domains of nephrin in the slit diaphragm of podocytes and potentially other tissues as well (eg. brain). The functional significance of these interactions is unknown. Pubmed15843475 Pubmed20233749 Reactome Database ID Release 43451757 Reactome, http://www.reactome.org ReactomeREACT_23777 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- Cis-Heterodimerization of nephrin and NEPH1 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 Nephrin forms heterodimers with NEPH1 molecules in a cis-configuration within the SD. This heterologous protein protein interaction seems to be an important factor in maintaining the normal permeability characteristics of the slit diaphragm by relaying signals from the extracellular side into the podocyte. Interestingly, the Nephrin-NEPH heterodimer formation is highly conserved from C.elegans to human and serves different functions in different species and different tissues. Pubmed12660326 Pubmed12865409 Pubmed17923684 Pubmed20233749 Reactome Database ID Release 43373714 Reactome, http://www.reactome.org ReactomeREACT_24011 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- Nephrin binds NCK Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 Nephrin tyrosine phophorylation regulates podocyte cell morphology via NCK adaptor proteins. NCK via its SH2 domain interacts with the three phosphotyrosines (1176, 1193 and 1217) on nephrin, and through its SH3 domain can recruit several other proteins involved in the regulation of the actin cytoskeleton such as N WASP, WIP, ARP2/3 and PAK to the slit diaphragm. The importance of this mechanism is the maintenance of the filtration barrier. When rapid actin polymerization and cytoskeletal reorganization is needed, for example during development or injury and repair, the level of nephrin phosphorylation increases and leads to recruitment of NCK and its downstream effectors to the cytoplasmic side of the slit diaphragm. Pubmed16525419 Pubmed16630808 Pubmed19443634 Reactome Database ID Release 43373724 Reactome, http://www.reactome.org ReactomeREACT_23852 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- Cdk4/6 Converted from EntitySet in Reactome Reactome DB_ID: 182699 Reactome Database ID Release 43182699 Reactome, http://www.reactome.org ReactomeREACT_8720 Phosphorylation of nephrin by the Src family kinase Fyn Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 EC Number: 2.7.10 Edited: Garapati, P V, 2010-03-01 Nephrin has eight putative phosphorylation sites, which nicely match with substrate sites for the Src kinase family. Nephrin, is tyrosine phosphorylated by the Src family tyrosine kinase, Fyn in developing and injured podocytes. Phosphorylation of three of these tyrosines (1176, 1193 and 1217) results in the formation of a preferred binding motif (YDXV) for the SH2 domain of the adaptor protein NCK, which is one of the bricks linking Nephrin to the cytoskeleton. Phosphorylation of tyrosine 1158 results in a binding motif for the p85 regulatory subunit of PI3K. Pubmed12668668 Pubmed12846735 Pubmed15579503 Pubmed16543952 Pubmed18033240 Reactome Database ID Release 43373747 Reactome, http://www.reactome.org ReactomeREACT_23929 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- has a Stoichiometric coefficient of 4 Activation of JNK by DSCAM Authored: Garapati, P V, 2010-01-05 DSCAM can stimulate the activation of JNK, one of the downstream events induced by activated PAK1. From the experiment using various dominant negative mutants it was suggested that PAK1 and MKK4 play a role in JNK activation. EC Number: 2.7.11 Edited: Garapati, P V, 2010-01-05 Pubmed15169762 Reactome Database ID Release 43451347 Reactome, http://www.reactome.org ReactomeREACT_25384 Reviewed: Clemens, JC, 2010-08-10 has a Stoichiometric coefficient of 2 DSCAM associates with Rac1-GTP:pPAK1 Authored: Garapati, P V, 2010-01-05 DSCAM directly binds to serine/threonine-protein kinase PAK1 and this interaction is enhanced by the presence of Rac1 protein. Rac1 interacts with the CRIB motif in the N-terminal domain of PAK1 and DSCAM interacts with the kinase domain of PAK1. Rac1-bound PAK1, which is already active, has higher affinity for DSCAM, which may further regulate PAK1 activation. Edited: Garapati, P V, 2010-01-05 Pubmed15169762 Reactome Database ID Release 43376123 Reactome, http://www.reactome.org ReactomeREACT_24940 Reviewed: Clemens, JC, 2010-08-10 Nephrin trans-homophilic interaction Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 Foot processes are long slender, actin rich protrusions of the cytoplasm that are anchored to the glomerular basement membrane. Adjacent foot processes are laterally interconnected by a highly specialized cell cell junction, the so called slit diaphragm (SD). Nephrin is the critical structural component within the slit diaphragm. Nephrin molecules of adjacent foot processes from neighboring podocytes interact with each other in the middle of the slit diaphragm forming a filter with a zipper like structure and with pores just the size of albumin on both sides of the midline density. Pubmed10393930 Pubmed10541305 Pubmed12660326 Pubmed14633607 Pubmed15545998 Pubmed17893108 Reactome Database ID Release 43373732 Reactome, http://www.reactome.org ReactomeREACT_23987 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- has a Stoichiometric coefficient of 2 Activation of p38MAPK by DSCAM Authored: Garapati, P V, 2010-01-05 EC Number: 2.7.11.24 Edited: Garapati, P V, 2010-01-05 Its also observed that DSCAM can activate p38 MAP kinase along with JNK. Human DSCAM likely activates PAK1, JNK and p38 MAP kinase and these intracellular signaling events are similar to those activated by Drosophila Dscam. This suggests that the human DSCAM molecule may have physiological functions similar to Drosophila Dscam in axon guidance. Pubmed15169762 Reactome Database ID Release 43451366 Reactome, http://www.reactome.org ReactomeREACT_25129 Reviewed: Clemens, JC, 2010-08-10 has a Stoichiometric coefficient of 2 Nuclear factor NF-kappa-B Converted from EntitySet in Reactome Reactome DB_ID: 177656 Reactome Database ID Release 43177656 Reactome, http://www.reactome.org ReactomeREACT_7351 Cyclin D Converted from EntitySet in Reactome Reactome DB_ID: 182700 Reactome Database ID Release 43182700 Reactome, http://www.reactome.org ReactomeREACT_8063 Nephrin interacts with Podocin Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 NPHS2 encodes podocin, a protein exclusively expressed in podocytes in developing and mature glomeruli. Podocin is a member of the stomatin protein family with a short N terminal domain, a membrane-anchoring region, and a cytosolic C-terminal domain. Podocin accumulates in an oligomeric form in lipid rafts of the slit diaphragm. The C-terminal domain of Podocin binds to the cytoplasmic domain of nephrin thus it may function as a scaffolding protein connecting nephrin with the actin cytoskeleton. Beside nephrin it was shown that podocin also interacts with several other SD proteins, hence forming functional microdomains Pubmed11562357 Pubmed11733557 Pubmed14570703 Reactome Database ID Release 43373734 Reactome, http://www.reactome.org ReactomeREACT_23984 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- Nephrin mediated activation of N-WASP Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 Pubmed11340081 Pubmed16525419 Reactome Database ID Release 43532603 Reactome, http://www.reactome.org ReactomeREACT_23820 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- The NCK adaptor protein binds to a proline rich region on WASP and N-WASP through its SH3 domains and has been implicated in the recruitment of WASP/N-WASP to sites of tyrosine phosphorylation. NCK stimulates actin nucleation by N WASP:Arp2/3 complexes. Recruitment of NCK to phosphorylated YDxV sites on nephrin could therefore directly control the cytoskeletal actin architecture of podocytes. p21/p27 Converted from EntitySet in Reactome Reactome DB_ID: 182504 Reactome Database ID Release 43182504 Reactome, http://www.reactome.org ReactomeREACT_8233 Phospho-NF-kappaB Inhibitor Converted from EntitySet in Reactome Reactome DB_ID: 177678 Reactome Database ID Release 43177678 Reactome, http://www.reactome.org ReactomeREACT_7645 Nephrin binds CD2AP Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 CD2-associated protein (CD2AP) is an adapter molecule of the immunoglobulin superfamily that was first identified as an SH3-containing protein that binds to the cytoplasmic domain of CD2. In the glomerulus, CD2AP is located in the cytoplasm beneath the slit-diaphragm, where it binds to the cytoplasmic domain of nephrin. CD2AP acts as a linker protein and may be involved in connecting nephrin to the actin cytoskeleton in podocytes, although direct evidence of this is still lacking. Interaction with CD2AP might be important in the steady-state situation. In addition CD2AP can facilitate nephrin-induced PI3K-AKT signaling, a pathway that has been shown to be important for nephrin-mediated actin reorganization in podocytes and protection of podocytes from apoptosis. Edited: Garapati, P V, 2010-03-01 Pubmed10997929 Reactome Database ID Release 43373727 Reactome, http://www.reactome.org ReactomeREACT_23844 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- ABCAs mediate lipid efflux ABCA3 plays an important role in the formation of pulmonary surfactant, probably by transporting lipids such as cholesterol (Klugbauer and Hofmann 1996, Yamano et al. 2001). Defects in ABCA3 are the cause of pulmonary surfactant metabolism dysfunction type 3 (SMDP3) [MIM:610921] (Shulenin et al. 2004).<br>The exact roles of ABCA2 (Vulevic et al. 2001, Kaminski et al. 2001), ABCA6 (Kaminski & Wenzel et al. 2001), ABCA9 (Piehler et al. 2002), ABCA10 (Wenzel et al. 2003) and ABCA12 (Annilo et al. 2002), candidates for ABC lipid transporter-related activities, need to be elucidated. Even thought cholesterol-responsiveness has been noted in experimental systems, contribution of these proteins in regulation or in active transport is not yet clear. Authored: Jassal, B, 2011-07-04 Edited: Jassal, B, 2011-07-04 Pubmed11178988 Pubmed11309290 Pubmed11435397 Pubmed11478798 Pubmed11718719 Pubmed12150964 Pubmed12697999 Pubmed12821155 Pubmed12915478 Pubmed15044640 Reactome Database ID Release 431369028 Reactome, http://www.reactome.org ReactomeREACT_111067 Reviewed: D'Eustachio, P, 2011-08-23 Reviewed: Matthews, L, 2008-12-02 15:41:53 HCO3- transport through ion channel Authored: Gopinathrao, G, 2008-11-23 14:00:06 Edited: Gopinathrao, G, 2008-11-24 14:15:13 Pubmed11562789 Pubmed12403779 Pubmed1377674 Reactome Database ID Release 43383190 Reactome, http://www.reactome.org ReactomeREACT_15300 Regulation of epithelial chloride flux, which is defective in patients with cystic fibrosis, may be mediated by phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) by cyclic AMP-dependent protein kinase (PKA) or protein kinase C (PKC). CFTR regulates both HCO(3)(-) secretion and HCO(3)(-) salvage in secretory epithelia. Reviewed: Matthews, L, 2008-12-02 15:41:53 Smad7 recruits GADD34:PP1CC to phosphorylated TGF-beta receptor complex Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2012-04-10 Full length mouse Smad7 was used to screen a human chondrocyte cDNA library in a yeast two-hybrid system and PPP1R15A (GADD34) was identified as a binding partner of Smad7. The interaction was confirmed by cotransfection of mouse Smad7 and human PPP1R15A (GADD34) into COS1 cells. The association was positively affected by TGF-beta treatment. Exogenously expressed human TGFB1 receptors and catalytic subunit of PP1, PP1CC, could also be identified in the complex of Smad7 and GADD34. Formation of a complex of TGF-beta receptors, Smad7 and PP1 was dependent on the function of SARA, as shown by expression of dominant negative SARA mutants in COS1 cells. SARA interacts with the catalytic subunit of PP1, likely serving as a membrane anchor for PP1CC (Shi et al. 2004). Pubmed14718519 Reactome Database ID Release 432167890 Reactome, http://www.reactome.org ReactomeREACT_121180 Reviewed: Huang, Tao, 2012-05-14 Strap binds unphosphorylated TGF-beta receptor complex Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 In COS-1 cells, recombinant mouse Strap was shown to bind TGF-beta-induced unphosphorylated complex of recombinant human kinase dead TGFBR2 and recombinant human TGFBR1 (Datta et al. 1998). Pubmed9856985 Reactome Database ID Release 432128990 Reactome, http://www.reactome.org ReactomeREACT_120724 Reviewed: Huang, Tao, 2012-05-14 Interaction of nephrin with adherens junction-associated proteins Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 Pubmed15994232 Reactome Database ID Release 43451403 Reactome, http://www.reactome.org ReactomeREACT_23807 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- The nephrin-slit diaphragm protein complex contains a group of scaffolding proteins that function to connect junctional membrane proteins to the actin cytoskeleton and signaling cascades. By mass spectrometry four of the proteins identified, alphaII spectrin, betaII spectrin, alpha-actinin, and IQGAP1, represent adherens junction-associated proteins, and two, MAGI-2/S-SCAM and CASK, represent MAGUK family scaffolding proteins that associate with Ig superfamily proteins. The presence of these proteins in slit diaphragms and their association with nephrin suggests that they may form a scaffolding protein complex in the podocyte slit diaphragm and thus contribute to the regulation of ultrafiltration by binding slit membrane proteins and establishing their cytosolic connections. Interaction of IQGAP1 with nephrin Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 IQGAP1, an effector protein of the small GTPases Rac1 and Cdc42 and a putative regulator of cell-cell adherens junctions, is expressed in podocytes at significant levels, and located in the immediate vicinity of the slit diaphragm. IQGAP1 is identified as one of the interacting partners of nephrin. This interaction takes place strictly and specifically between the C-terminal half of the nephrin intracellular domain and IQGAP1. IQGAP1 knock-out mouse does not have any obvious nephrotic phenotype, hence IQGAP1 function can either be substituted by other proteins or its role in vivo is much less important than that attributed to it from cell culture experiments. Pubmed10611248 Pubmed15331416 Pubmed15634346 Pubmed15994232 Reactome Database ID Release 43451377 Reactome, http://www.reactome.org ReactomeREACT_24018 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- Nephrin binds CASK Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 CASK is a scaffolding protein that participates in maintenance of polarized epithelial cell architecture by linking membrane proteins and signaling molecules to the actin cytoskeleton. CASK is identified as one of the binding partners of nephrin and this interaction likely plays an important role in establishing the structural integrity and functional properties of the glomerular slit diaphragm. Edited: Garapati, P V, 2010-03-01 Pubmed15331416 Reactome Database ID Release 43373722 Reactome, http://www.reactome.org ReactomeREACT_23922 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- p85 associates with both p-Nephrin and CD2AP Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 Reactome Database ID Release 43451758 Reactome, http://www.reactome.org ReactomeREACT_24013 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- The regulatory p85 subunit of PI3K recognizes and binds to both phosphorylated nephrin and its binding partner, CD2AP. By mutation analysis, nephrin Y1158 was shown to be necessary for the interaction. This interaction allows the catalytic subunit p110 to act on phospholipids of the inner leaflet of the cell membrane. This leads to downstream phosphorylation and inactivation of the apoptotic factor Bad via the serine-threonine kinase AKT. ABCAs mediate lipid influx ABCA3 plays an important role in the formation of pulmonary surfactant, probably by transporting lipids such as cholesterol (Klugbauer and Hofmann 1996, Yamano et al. 2001). Defects in ABCA3 are the cause of pulmonary surfactant metabolism dysfunction type 3 (SMDP3) [MIM:610921] (Shulenin et al. 2004).<br>The exact roles of ABCA2 (Vulevic et al. 2001, Kaminski et al. 2001), ABCA6 (Kaminski & Wenzel et al. 2001), ABCA9 (Piehler et al. 2002), ABCA10 (Wenzel et al. 2003) and ABCA12 (Annilo et al. 2002), candidates for ABC lipid transporter-related activities, need to be elucidated. Even thought cholesterol-responsiveness has been noted in experimental systems, contribution of these proteins in regulation or in active transport is not yet clear. Authored: Gopinathrao, G, 2008-11-23 14:00:06 Edited: Jassal, B, 2011-07-04 Pubmed11178988 Pubmed11309290 Pubmed11435397 Pubmed11478798 Pubmed11718719 Pubmed12150964 Pubmed12697999 Pubmed12821155 Pubmed12915478 Pubmed15044640 Reactome Database ID Release 431369052 Reactome, http://www.reactome.org ReactomeREACT_111169 Reviewed: D'Eustachio, P, 2011-08-23 Reviewed: Matthews, L, 2008-12-02 15:41:53 PathwayStep2663 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198368 Reactome, http://www.reactome.org PathwayStep2664 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198368 Reactome, http://www.reactome.org PathwayStep2665 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198368 Reactome, http://www.reactome.org PathwayStep2666 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198368 Reactome, http://www.reactome.org PathwayStep2667 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198368 Reactome, 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43179804 Reactome, http://www.reactome.org PathwayStep4789 PathwayStep2646 ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43179871 Reactome, http://www.reactome.org PathwayStep4786 PathwayStep2647 ACTIVATION GENE ONTOLOGYGO:0004322 Reactome Database ID Release 431562606 Reactome, http://www.reactome.org PathwayStep4787 PathwayStep2648 PathwayStep2641 ACTIVATION GENE ONTOLOGYGO:0004697 Reactome Database ID Release 43198312 Reactome, http://www.reactome.org PathwayStep2642 ACTIVATION GENE ONTOLOGYGO:0004435 Reactome Database ID Release 43167676 Reactome, http://www.reactome.org PathwayStep2643 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43212705 Reactome, http://www.reactome.org PathwayStep2644 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43179862 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004683 Reactome Database ID Release 43111908 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43111918 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008294 Reactome Database ID Release 43111927 Reactome, http://www.reactome.org PathwayStep2649 PathwayStep217 PathwayStep216 PathwayStep215 PathwayStep214 PathwayStep219 PathwayStep218 PathwayStep4792 PathwayStep4791 PathwayStep4790 PathwayStep2651 PathwayStep2650 PathwayStep4796 PathwayStep213 PathwayStep4795 PathwayStep212 PathwayStep4794 PathwayStep211 PathwayStep4793 PathwayStep210 PathwayStep4797 PathwayStep2658 PathwayStep4798 PathwayStep2659 PathwayStep4799 PathwayStep2656 ACTIVATION GENE ONTOLOGYGO:0015036 Reactome Database ID Release 431222698 Reactome, http://www.reactome.org PathwayStep2657 ACTIVATION GENE ONTOLOGYGO:0015036 Reactome Database ID Release 431222602 Reactome, http://www.reactome.org PathwayStep2654 ACTIVATION GENE ONTOLOGYGO:0015036 Reactome Database ID Release 431222743 Reactome, http://www.reactome.org PathwayStep2655 ACTIVATION GENE ONTOLOGYGO:0004148 Reactome Database ID Release 431222335 Reactome, http://www.reactome.org PathwayStep2652 ACTIVATION GENE ONTOLOGYGO:0015036 Reactome Database ID Release 431243097 Reactome, http://www.reactome.org PathwayStep2653 ACTIVATION GENE ONTOLOGYGO:0004791 Reactome Database ID Release 431222356 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015343 Reactome Database ID Release 431222570 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016614 Reactome Database ID Release 431500763 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004322 Reactome Database ID Release 431562602 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052873 Reactome Database ID Release 431222683 Reactome, http://www.reactome.org PathwayStep204 PathwayStep203 PathwayStep206 PathwayStep205 PathwayStep208 PathwayStep207 PathwayStep209 PathwayStep2662 PathwayStep2661 PathwayStep2660 PathwayStep200 PathwayStep202 PathwayStep201 ACTIVATION GENE ONTOLOGYGO:0008785 Reactome Database ID Release 431222643 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004601 Reactome Database ID Release 431222554 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004096 Reactome Database ID Release 431222563 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004784 Reactome Database ID Release 431222303 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004784 Reactome Database ID Release 431222715 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003840 Reactome Database ID Release 431222289 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015450 Reactome Database ID Release 431222636 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016620 Reactome Database ID Release 431222575 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008113 Reactome Database ID Release 431222305 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051920 Reactome Database ID Release 431222606 Reactome, http://www.reactome.org PathwayStep234 PathwayStep235 PathwayStep232 PathwayStep233 PathwayStep230 PathwayStep231 PathwayStep238 PathwayStep239 PathwayStep236 PathwayStep237 ACTIVATION GENE ONTOLOGYGO:0051920 Reactome Database ID Release 431222367 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051920 Reactome Database ID Release 431500775 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015078 Reactome Database ID Release 431222297 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015197 Reactome Database ID Release 431500800 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051139 Reactome Database ID Release 43445828 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008941 Reactome Database ID Release 431222307 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003746 Reactome Database ID Release 43192829 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004308 Reactome Database ID Release 43195916 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016504 Reactome Database ID Release 43169166 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016175 Reactome Database ID Release 431222383 Reactome, http://www.reactome.org PathwayStep221 PathwayStep222 PathwayStep223 PathwayStep224 Ras Converted from EntitySet in Reactome Reactome DB_ID: 1250471 Reactome Database ID Release 431250471 Reactome, http://www.reactome.org ReactomeREACT_116395 PathwayStep220 PathwayStep229 PathwayStep225 PathwayStep226 PathwayStep227 PathwayStep228 ACTIVATION GENE ONTOLOGYGO:0003968 Reactome Database ID Release 43192665 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003968 Reactome Database ID Release 43192665 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003968 Reactome Database ID Release 43192665 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003968 Reactome Database ID Release 43192665 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003746 Reactome Database ID Release 43192666 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003968 Reactome Database ID Release 43192665 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003968 Reactome Database ID Release 43192665 Reactome, http://www.reactome.org PathwayStep2689 PathwayStep2686 PathwayStep260 ACTIVATION GENE ONTOLOGYGO:0005215 Reactome Database ID Release 43189145 Reactome, http://www.reactome.org PathwayStep2685 ACTIVATION GENE ONTOLOGYGO:0003968 Reactome Database ID Release 43192665 Reactome, http://www.reactome.org PathwayStep2688 PathwayStep2687 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org Classic Cadherin Converted from EntitySet in Reactome Reactome DB_ID: 418977 Reactome Database ID Release 43418977 Reactome, http://www.reactome.org ReactomeREACT_20296 PathwayStep2692 PathwayStep252 PathwayStep2693 PathwayStep253 PathwayStep2694 PathwayStep250 PathwayStep2695 PathwayStep251 PathwayStep256 PathwayStep257 PathwayStep2690 PathwayStep254 PathwayStep2691 PathwayStep255 PathwayStep258 PathwayStep259 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43113431 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005087 Reactome Database ID Release 43180697 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43165544 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019107 Reactome Database ID Release 43167549 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008829 Reactome Database ID Release 43180615 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43180584 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43180548 Reactome, http://www.reactome.org PathwayStep2699 PathwayStep2698 PathwayStep2697 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43170708 Reactome, http://www.reactome.org PathwayStep2696 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43170699 Reactome, http://www.reactome.org PathwayStep240 PathwayStep241 PathwayStep242 PathwayStep243 PathwayStep244 PathwayStep245 PathwayStep246 PathwayStep247 PathwayStep248 PathwayStep249 PathwayStep2629 PathwayStep2628 PathwayStep2627 PathwayStep2622 PathwayStep2621 PathwayStep2620 PathwayStep2626 PathwayStep2625 PathwayStep2624 PathwayStep2623 PathwayStep2640 PathwayStep2639 PathwayStep2638 Association of Cyclin A:Cdk2 with Cdh1 Authored: Lorca, T, Castro, A, 2006-10-10 10:03:43 Cyclin A-Cdk2 prevents unscheduled APC reactivation during S phase by binding and subsequently phosphorylating Cdh1. Phosphorylation-dependent dissociation of the Cdh1-activating subunit inhibits the APC/C. Edited: Matthews, L, 2006-10-10 08:05:07 Pubmed11340163 Reactome Database ID Release 43188371 Reactome, http://www.reactome.org ReactomeREACT_9051 Reviewed: Peters, JM, 2006-10-10 10:07:26 Cohesin binding to decondensed chromatin is facilitated by NIPBL:MAU2 Authored: Orlic-Milacic, M, 2012-10-02 Cohesin, in complex with WAPAL and PDS5 (PDS5A or PDS5B) binds decondensed chromatin in telophase (Kueng et al. 2006). This binding is facilitated by the NIPBL:MAU2 complex, also known as the 'cohesin loading complex'. NIPBL:MAU2 complex is associated with chromatin from telophase until prophase (Watrin et al. 2006) but seems to form a transient rather than stable complex with cohesin. Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed16682347 Pubmed17113138 Reactome Database ID Release 432470935 Reactome, http://www.reactome.org ReactomeREACT_150390 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 2 PathwayStep2631 Dissociation of phospho-Cdh1 from the APC/C complex Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Following its phosphorylation, Cdh1 dissociates from the APC/C, rendering the APC/C inactive. This allows the stabilization of proteins required for subsequent cell cycle progression. GENE ONTOLOGYGO:0051436 Pubmed10548110 Reactome Database ID Release 43174139 Reactome, http://www.reactome.org ReactomeREACT_6845 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep2630 Phosphorylation of Cdh1 by Cyclin A:Cdk2 At the G1/S transition, the Cdh1 subunit of the APC:Cdh1 complex is phosphorylated by Cyclin A:Cdk2 and dissociates from APC/C. This inactivates APC/C and permits the accumulation of cell cycle proteins required for DNA synthesis and entry into mitosis. Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 2.7.11.22 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0051436 Pubmed10548110 Reactome Database ID Release 43174079 Reactome, http://www.reactome.org ReactomeREACT_6721 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep2633 Association of Emi1 with Cdc20 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0051436 In addition to its association with Cdh1 in G1 phase, Emi1 further contributes the inactivation of the APC/C between G2 and prophase by associating with another APC/C activator, Cdc20. Pubmed11988738 Pubmed14743218 Reactome Database ID Release 43174235 Reactome, http://www.reactome.org ReactomeREACT_6745 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep2632 Association of Emi1 with Cdh1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Emi1 promotes the accumulation of Cyclin A and entry into S phase by associating with and inhibiting the APC/C:Cdh1 complex at G1/S. GENE ONTOLOGYGO:0051436 Pubmed11988738 Reactome Database ID Release 43174097 Reactome, http://www.reactome.org ReactomeREACT_6773 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep2635 Phosphorylation of the Emi1 DSGxxS degron by Plk1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 2.7.11 Edited: Matthews, L, 2006-02-17 05:22:55 Pubmed15469984 Reactome Database ID Release 43174174 Reactome, http://www.reactome.org ReactomeREACT_6861 Reviewed: Peters, JM, 2006-03-27 22:55:09 The phosphorylation of Emi1 by Plk1 is believed to be involved in the degradation of Emi1 during mitosis. Plk1 phosphorylates serine residues in the DSGxxS degron sequence of Emi1 recruiting the SCF(betaTrCP) ubiquitin ligase. has a Stoichiometric coefficient of 2 PathwayStep2634 Phosphorylation of the Emi1 DSGxxS degron by Cyclin B:Cdc2 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 2.7.11.22 Edited: Matthews, L, 2006-02-17 05:21:42 Emi1 is also believed to be phosphorylated by Cyclin B:Cdc2 on a CDK consensus site at Ser 182. While Plk1 mediated phosphorylation of Emi1 at the DSGxxS (βTrCP recognition) motif is essential for Emi1 destruction in mitosis, Cdk phosphorylation has been shown to play an important regulatory role. Pubmed12791267 Reactome Database ID Release 43174122 Reactome, http://www.reactome.org ReactomeREACT_6891 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep2637 Ubiquitination of Emi1 by SCF-beta-TrCP Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 6.3.2.19 Edited: Matthews, L, 2006-01-30 00:00:00 Following its association with SCF-βTrCP, phospho-Emi1 is poly-ubiquitinated. Pubmed15469984 Reactome Database ID Release 43174159 Reactome, http://www.reactome.org ReactomeREACT_6827 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 3 PathwayStep2636 Phosphorylated Emi1 binds the beta-TrCP in the SCF complex Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Cdk mediated phosphorylation of Emi1 is believed to promotes its phospho- Ser145-Ser149 dependent association with beta-TrCP. Edited: Matthews, L, 2006-02-17 05:46:22 Pubmed10023660 Pubmed12791267 Pubmed15469984 Reactome Database ID Release 43174209 Reactome, http://www.reactome.org ReactomeREACT_6863 Reviewed: Peters, JM, 2006-03-27 22:55:09 Cohesin binds PDS5 and WAPAL Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed17112726 Pubmed17113138 Pubmed19696148 Reactome Database ID Release 432468040 Reactome, http://www.reactome.org ReactomeREACT_150350 Reviewed: Zhang, Nenggang, 2012-10-22 WAPAL (WAPL) and PDS5 proteins (PDS5A and/or PDS5B) are associated with cohesin throughout most of the cell cycle (Kueng et al. 2006, Gandhi et al. 2006). FGF motifs present in the N-terminal region of WAPAL participate in WAPAL binding to PDS5 and cohesin subunits RAD21, STAG1 (SA1) and STAG2 (SA2) (Shintomi and Hirano 2009). Cdh1 Converted from EntitySet in Reactome Reactome DB_ID: 176429 Reactome Database ID Release 43176429 Reactome, http://www.reactome.org ReactomeREACT_7798 Degradation of multiubiquitinated Securin Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Following ubiquitination, securin is degraded by the 26S proteasome. Pubmed12070128 Reactome Database ID Release 43174202 Reactome, http://www.reactome.org ReactomeREACT_6777 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 4 PathwayStep2609 Cdc20/Cdh1 Converted from EntitySet in Reactome Reactome DB_ID: 186977 Reactome Database ID Release 43186977 Reactome, http://www.reactome.org ReactomeREACT_9215 PathwayStep2608 PathwayStep2607 PathwayStep2606 Cdc20/Cdh1 Converted from EntitySet in Reactome Reactome DB_ID: 177320 Reactome Database ID Release 43177320 Reactome, http://www.reactome.org ReactomeREACT_7808 PathwayStep2605 PathwayStep2604 Regulation of NUDC by phosphorylation EC Number: 2.7.11 Pubmed12679384 Pubmed12852857 Reactome Database ID Release 43156682 Reactome, http://www.reactome.org ReactomeREACT_1326 The polo-like kinase PLK1 phosphorylates NUDC on serine residues S274 and S326. PathwayStep2603 Regulation of KIF20A (MKL2) by phosphorylation EC Number: 2.7.11 Pubmed12939256 Reactome Database ID Release 43156723 Reactome, http://www.reactome.org ReactomeREACT_1120 The polo-like kinase PLK1 phosphorylates KIF20A (also known as MKLP2 i.e. mitotic kinesin-like protein 2) on serine residue S528. PathwayStep2602 Regulation of KIF23 (MKLP1) by phosphorylation EC Number: 2.7.11 Pubmed15199097 Reactome Database ID Release 43156673 Reactome, http://www.reactome.org ReactomeREACT_1930 The polo-like kinase PLK1 phosphorylates KIF23 (also known as MKLP1 i.e. mitotic kinesin-like protein 1) on serine residues S904 and S905. PathwayStep2601 Deacetylation of cleaved cohesin Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Histone deacetylase HDAC8 deacetylates SMC3 cohesin subunit. SMC3 deacetylation promotes dissociation of cleaved RAD21 fragments from other cohesin proteins and their replacement with intact RAD21, thereby allowing restoration of the cohesin complex (Deardorff et al. 2012). HDAC8 mutations, as well as mutations in NIPBL, SMC1A and SMC3, can cause Cornelia de Lang syndrome (Deardorff et al. 2012). Pubmed22885700 Reactome Database ID Release 432545203 Reactome, http://www.reactome.org ReactomeREACT_150294 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 2 PathwayStep2600 Separation of sister chromatids Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed11081627 Pubmed11509732 Pubmed12194817 Reactome Database ID Release 432467811 Reactome, http://www.reactome.org ReactomeREACT_150148 Reviewed: Zhang, Nenggang, 2012-10-22 The cleavage of RAD21 subunit of centromeric cohesin by ESPL1 (separin i.e. separase) promotes dissociation of cohesin complexes from centromeric chromatin at the onset of anaphase, allowing for sister chromatid separation and segregation of replicated chromosomes to daughter cells (Waizenegger et al. 2000, Hauf et al. 2001, Waizenegger et al. 2002). has a Stoichiometric coefficient of 2 EPSL1 (Separin) cleaves centromeric cohesin Authored: Orlic-Milacic, M, 2012-10-02 ESPL1 (separin i.e. separase) cleaves RAD21 (SCC1) subunit of centromeric cohesin at two sites that conform to the consensus separase recognition site E-X-X-R: after arginine residue R172 and after arginine residue R450 (Hauf et al. 2001). Phosphorylation of RAD21 at the serine residue S454 by PLK1 in prometaphase facilitates ESPL1-mediated cleavage of RAD21 at the C-terminal cleavage site R450 (Hauf et al. 2005). The N-terminal and C-terminal RAD21 cleavage fragments remain bound to the rest of the cohesin complex (Deardorff et al. 2012). It is not clear whether RAD21 middle fragment also continues to be associated with cohesin. Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed11509732 Pubmed15737063 Pubmed22885700 Reactome Database ID Release 432467809 Reactome, http://www.reactome.org ReactomeREACT_150369 Reviewed: Zhang, Nenggang, 2012-10-22 Autocleavage of Separase After APC/C-mediated degradation of PTTG1 (securin), ESPL1 (separin i.e. separase) is rapidly autocatalytically cleaved after arginine residues at positions 1506 and 1535. The N-terminal and C-terminal fragments remain bound to each other after cleavage. It has not been examined what happens with the short middle fragment of ESPL1, so it is annotated as a part of the autocleaved ESPL1 complex. The autocatalytic cleavage of ESPL1 is not a prerequisite for the subsequent cleavage of the cohesin subunit RAD21 (Waizenegger et al. 2002). Authored: Orlic-Milacic, M, 2012-10-02 Autocleavage of ESPL1 (Separin) Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed12194817 Reactome Database ID Release 432467775 Reactome, http://www.reactome.org ReactomeREACT_150308 Reviewed: Zhang, Nenggang, 2012-10-22 Securin sequesters Separase Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 PTTG1 (Securin) sequesters ESPL1 (Separase) Pubmed10411507 Pubmed11081627 Pubmed11371342 Pubmed12194817 Pubmed9892021 Reactome Database ID Release 432467798 Reactome, http://www.reactome.org ReactomeREACT_150297 Reviewed: Zhang, Nenggang, 2012-10-22 Up to anaphase onset, ESPL1 (separase i.e. separin) forms a complex with PTTG1 (pituitary tumor-transforming gene 1) i.e. securin. PTTG1 sequesters ESPL1 and block its catalytic site, preventing it from cleaving centromeric cohesin and causing premature separation of sister chromatids (Zou et al. 1999, Waizenegger et al. 2001, Waizenegger et al. 2002). PTTG1 is overexpressed in cancer and acts as an oncogene (Zhang et al. 1999). Regulation of PTTG1 cellular level is important for chromosomal stability in human cells (Jallepalli et al. 2001). Association of Securin with Cdc20:APC/C complex Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Pubmed12070128 Reactome Database ID Release 43174121 Reactome, http://www.reactome.org ReactomeREACT_6893 Reviewed: Peters, JM, 2006-03-27 22:55:09 Securin is thought to be recognized by the APC/C:Cdc20 complex through its conserved D-box sequence. Ubiquitination of Securin by phospho-APC/C:Cdc20 complex Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 6.3.2.19 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0042787 Pubmed12070128 Reactome Database ID Release 43174144 Reactome, http://www.reactome.org ReactomeREACT_6723 Reviewed: Peters, JM, 2006-03-27 22:55:09 Securin is ubiquitinated by APC/C:Cdc20 (Hagting et al., 2002). has a Stoichiometric coefficient of 4 phospho-Cdh1 phosphatase Converted from EntitySet in Reactome Reactome DB_ID: 174146 Reactome Database ID Release 43174146 Reactome, http://www.reactome.org ReactomeREACT_7586 PathwayStep2617 PathwayStep2616 (APC/C:Cdh1)-targeted cell cycle proteins Converted from EntitySet in Reactome Reactome DB_ID: 174056 Reactome Database ID Release 43174056 Reactome, http://www.reactome.org ReactomeREACT_7387 PathwayStep2619 PathwayStep2618 PathwayStep2613 CDK1 phosphorylates condensin I Authored: Orlic-Milacic, M, 2012-10-12 CDK1 (CDC2) in complex with CCNB (cyclin B) phosphorylates condensin I subunits NCAPD2, NCAPG and NCAPH in mitosis (Kimura et al. 2001, Takemoto et al. 2006), but other mitotic kinases may also be involved. CDK1 phosphorylation sites in NCAPH have not been established. NCAPD2 threonine residues T1339, T1384 and T1389 are inferred to be phosphorylated by CDK1 based on homologues sites in Xenopus laevis Ncapd2 (Kimura et al. 1998). NCAPG threonine residues T308 and T332 are phosphorylated by CDK1 in vitro and functionally important. The functional importance of threonine T931, also phosphorylated by CDK1 in vitro, has not been demonstrated (Murphy et al. 2008). Phosphorylation by CDK1 is required for mitotic activation of condensin I and promotes chromosomal binding, introduction of positive supercoils into DNA, and chromatin condensation (Kimura et al. 1998, Kimura et al. 2001, Takemoto et al. 2006). EC Number: 2.7.11.22 Edited: D'Eustachio, P, 2012-10-19 Edited: Matthews, L, 2012-10-18 Pubmed11136719 Pubmed17066080 Pubmed18977199 Pubmed9774278 Reactome Database ID Release 432514854 Reactome, http://www.reactome.org ReactomeREACT_150232 Reviewed: Kalitsis, Paul, 2012-11-12 has a Stoichiometric coefficient of 6 PathwayStep2612 Dephosphorylation of CK2-modified condensin I Authored: Orlic-Milacic, M, 2012-10-12 EC Number: 3.1.3.16 Edited: D'Eustachio, P, 2012-10-19 Edited: Matthews, L, 2012-10-18 Inhibitory phosphate groups that were added to condensin I subunits by CK2 during interphase have to be removed for full mitotic activation of condensin I (Takemoto et al. 2006). The responsible phosphatase has not been identified. Pubmed17066080 Reactome Database ID Release 432529015 Reactome, http://www.reactome.org ReactomeREACT_150403 Reviewed: Kalitsis, Paul, 2012-11-12 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 6 PathwayStep2615 Down Regulation of Emi1 through Phosphorylation of Emi1 Authored: Lee, KS, 2004-12-08 21:18:23 During the early stages of mitosis, Cdc2 and PLK1 cooperate to phosphorylate Emi1 and this modification induces Emi1 degradation through a Skp1-Cullin1 F-box protein (SCF) ubiquitin ligase-mediated proteolysis. Degradation of Emi1 permits activation of anaphase promoting complex and thereby the onset of anaphase. EC Number: 2.7.11 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0007092 Pubmed15148369 Pubmed15469984 Reactome Database ID Release 43163010 Reactome, http://www.reactome.org ReactomeREACT_496 PathwayStep2614 Phosphorylated condensin I promotes condensation of prometaphase chromosomes Authored: Orlic-Milacic, M, 2012-10-12 Edited: D'Eustachio, P, 2012-10-19 Edited: Matthews, L, 2012-10-18 Pubmed11136719 Pubmed15146063 Pubmed15572404 Pubmed17066080 Pubmed17356064 Pubmed18977199 Pubmed19481522 Pubmed21498573 Pubmed9774278 Reactome Database ID Release 432520883 Reactome, http://www.reactome.org ReactomeREACT_150278 Reviewed: Kalitsis, Paul, 2012-11-12 While condensin II complex (consisting of subunits SMC2, SMC4, NCAPD3, NCAPG2 and NCAPH2), responsible for condensation of chromosomes in prophase (Hirota et al. 2004, Abe et al. 2011), is nuclear, condensin I is cytosolic and gains access to chromosomes only after the nuclear envelope breakdown at the start of prometaphase (Ono et al. 2004). Condensin I, activated by CDK1 phosphorylation (Kimura et al. 1998, Kimura et al. 2001, Takemoto et al. 2006, Murphy et al. 2008), promotes further condensation of chromosomes in prometaphase and metaphase, visible as longitudinal chromosome shortening (Hirota et al. 2004). Besides CDK1-mediated phosphorylation, association of condensin I with chromosomes may be regulated by AURKB (Lipp et al. 2007). In budding yeast, condensin phosphorylation by Cdc2 (CDK1 ortholog) is followed by Cdc5-mediated phosphorylation (Cdc5 is PLK1 ortholog), which is important for the sustained mitotic activity of condensin complex (St-Pierre et al. 2009). Phosphorylation by PLK1 is also important for the activation of human condensin II complex (Abe et al. 2011). Phosphorylation of cohesin by PLK1 at centromeres Authored: Lee, KS, 2004-12-08 21:18:23 EC Number: 2.7.11 Edited: Gillespie, ME, 2005-04-12 04:40:16 GENE ONTOLOGYGO:0007062 Prior to anaphase onset, sister-chromatids are held together by cohesin complexes distributed along chromosomal arms and at centromeres. In prometaphase, PLK1, likely recruited to cohesin complexes by binding to CDK1-phosphorylated CDCA5 (Sororin) (Zhang et al. 2011), phosphorylates cohesin subunits STAG2 (SA2) and RAD21 (Hauf et al. 2005). PLK1-mediated phosphorylation of cohesin subunits at centromeres is counteracted by the phosphatase activity of PP2A complex (containing the regulatory subunit B56 i.e. PPP2R5), which is recruited to the kinetochore by shugoshin proteins, SGOL1 and SGOL2 (Kitajima et al. 2006). Therefore, while cohesin complexes dissociate from chromosomal arms in prometaphase (Hauf et al. 2001), they remain bound to centromeres until anaphase onset (Hauf et al. 2001, Hauf et al. 2005, Kitajima et al. 2006). When separase is activated after its inhibitor securin is degraded by APC/C at the onset of anaphase, RAD21 is cleaved by separase. Phosphorylation of RAD21 by PLK1 facilitates subsequent cleavage of RAD21 by separase (Hauf et al. 2005). There are several potential PLK1 phosphorylation sites in STAG2 and RAD21, but the exact positions of in vivo phosphorylation of STAG2 and RAD21 by PLK1 have not been explicitly established (Hauf et al. 2005). Pubmed11509732 Pubmed15737063 Pubmed16541025 Reactome Database ID Release 431638803 Reactome, http://www.reactome.org ReactomeREACT_150152 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 2 CDK1 phosphorylates CDCA5 (Sororin) at centromeres Authored: Orlic-Milacic, M, 2012-10-02 EC Number: 2.7.11.22 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Phosphorylation of CDCA5 (Sororin) coincides with dissociation of CDCA5 from chromosomal arms in prometaphase, but phosphorylated CDCA5 persists on centromeres throughout prophase and metaphase. Several serine and threonine residues in CDCA5 are phosphorylated by CDK1 in prometaphase, but only the three sites that perfectly match the CDK1 consensus phosphorylation sequence are shown here - serines S21 and S75 and threonine T159 (Drier et al. 2011, Zhang et al. 2011). Pubmed21878504 Pubmed21987589 Reactome Database ID Release 432468287 Reactome, http://www.reactome.org ReactomeREACT_150414 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 3 PathwayStep2611 CK2 phosphorylates condensin I subunits Authored: Orlic-Milacic, M, 2012-10-12 Edited: D'Eustachio, P, 2012-10-19 Edited: Matthews, L, 2012-10-18 Protein levels of condensin subunits are constant during the cell cycle. Four subunits, SMC4, NCAPD2, NCAPG and NCAPH, are phosphorylated in interphase cells (Takemoto et al. 2004) by CK2 i.e. casein kinase II (Takemoto et al. 2006). Except for the phosphorylation of NCAPH subunit on serine residue S570, CK2 phosphorylation sites in condensin I subunits have not been identified. Phosphorylation by CK2 inhibits condensin I-mediated introduction of positive supercoils into DNA and chromatin condensation. Mitotic activation of condensin I involves removal of phosphate groups added by CK2 (Takemoto et al. 2006), but the responsible phosphatase has not been identified. Pubmed14607834 Pubmed17066080 Reactome Database ID Release 432529020 Reactome, http://www.reactome.org ReactomeREACT_150239 Reviewed: Kalitsis, Paul, 2012-11-12 has a Stoichiometric coefficient of 4 PathwayStep2610 PP2A-B56 dephosphorylates centromeric cohesin Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 PLK1-mediated phosphorylation of the STAG2 subunit of centromeric cohesin (Hauf et al. 2005) is counteracted by the kinetochore PP2A phosphatase, containing the 56 kDa regulatory B subunit (PP2A-B56 i.e. PP2A-PPP2R5). PP2A-B56 is recruited to the centromeric cohesin complex by shugoshin proteins (SGOL1 and SGOL2) (Kitajima et al. 2006), which are also kinetochore constituents (Cheeseman and Desai 2008). SGOL1 localization to centromeres depends on another kinetochore protein, BUB1 (Kitajima et al. 2004, Kitajima et al. 2005). Shugoshin- and PP2A-B56-regulated dephosphorylation of centromeric STAG2 ensures that the cohesin complex remains bound to centromeres throughout prometaphase and metaphase, thereby preventing premature separation of sister chromatids (Salic et al. 2004, Kitajima et al. 2004, Kitajima et al. 2005, Kitajima et al. 2006). Pubmed14730319 Pubmed15339662 Pubmed15723797 Pubmed15737063 Pubmed16541025 Pubmed18097444 Reactome Database ID Release 431638821 Reactome, http://www.reactome.org ReactomeREACT_150250 Reviewed: Zhang, Nenggang, 2012-10-22 Necl-1:Necl-2 trans heterodimer interaction Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-25 Necl-1 displays Ca2+-independent heterophilic cell-cell adhesion activity with Necl-2 (Kakunaga et al., 2005). Pubmed15741237 Reactome Database ID Release 43420586 Reactome, http://www.reactome.org ReactomeREACT_19130 Reviewed: Ebnet, K, 2009-08-26 Necl-2:Nectin 3 trans heterodimer interaction Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-26 Necl-2 and Nectin 3 form a trans heterodimer. Pubmed12759359 Reactome Database ID Release 43420595 Reactome, http://www.reactome.org ReactomeREACT_19220 Reviewed: Ebnet, K, 2009-08-26 Necl-1:Nectin-1 trans heterodimer interaction Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-25 Necl-1 displays Ca2+-independent heterophilic cell-cell adhesion activity with Nectin-1 (Kakunaga et al., 2005). Pubmed11544254 Pubmed15741237 Reactome Database ID Release 43420582 Reactome, http://www.reactome.org ReactomeREACT_19202 Reviewed: Ebnet, K, 2009-08-26 Necl-1:Nectin 3 trans heterodimer interaction Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-26 Necl-1 displays Ca2+-independent heterophilic cell-cell adhesion activity with Nectin-3 (Kakunaga et al., 2005). Pubmed11544254 Pubmed15741237 Reactome Database ID Release 43420584 Reactome, http://www.reactome.org ReactomeREACT_19267 Reviewed: Ebnet, K, 2009-08-26 Nectin-1:Nectin-4 trans heterodimer formation Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-26 Nectin-1 and Nectin-4 interact forming a trans heterodimer. Pubmed11544254 Reactome Database ID Release 43420598 Reactome, http://www.reactome.org ReactomeREACT_19201 Reviewed: Ebnet, K, 2009-08-26 Nectin-2:Nectin 3 trans heterodimer interaction Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-27 Nectin-2 and Nectin-3 interact forming a trans heterodimer. Pubmed11544254 Reactome Database ID Release 43420591 Reactome, http://www.reactome.org ReactomeREACT_19176 Reviewed: Ebnet, K, 2009-08-26 Nectin-1:Nectin 3 trans heterodimer formation Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-31 Nectin-1 and Nectin 3 interact forming a trans heterodimer. Pubmed11544254 Reactome Database ID Release 43420580 Reactome, http://www.reactome.org ReactomeREACT_19302 Reviewed: Ebnet, K, 2009-08-26 Recruitment of PAR-3:PAR-6:aPKC complex to tight junctions Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-05-18 16:34:30 Edited: Matthews, L, 2009-08-19 PAR-3 exists in a ternary complex with aPKC and PAR-6 to form the PAR-aPKC complex (Macara, 2004; Suzuki and Ohno, 2006). This complex is critically involved in the development of Tight Junctions (TJs) from primordial spot-like Adherens Junctions (AJs) (Suzuki et al., 2002). PAR-3 directly interacts with Junctional Adhesion Molecules (JAM)-A, -B, and -C (Ebnet et al., 2001; Ebnet et al., 2004).The interaction with JAM-A might anchor the PAR-aPKC complex to TJs but might also be necessary to recruit the PAR-aPKC complex to primordial spot-like AJs where it becomes activated in response to cell-cell adhesion (reviewed in (Ebnet et al., 2008). The PAR-aPKC complex might also be physically linked to the second polarity protein complex at TJs, the CRB3-Pals1-PATJ complex through a direct interaction between PAR-6 and Pals1 (Hurd et al., 2003). Pubmed11447115 Pubmed12186943 Pubmed12545177 Pubmed12953056 Pubmed14657270 Pubmed14991002 Pubmed16525119 Pubmed18508678 Reactome Database ID Release 43419981 Reactome, http://www.reactome.org ReactomeREACT_19353 Reviewed: Ebnet, K, 2009-08-26 Claudins create paired strands through homophilic and heterophilic cis and trans interactions Authored: Matthews, L, 2009-05-15 19:26:33 Claudins are the major cell adhesion molecules in tight junctions and are involved in regulating the paracellular flux of water-soluble molecules between adjacent cells (reviewed in (Furuse and Tsukita, 2006). Claudins create paired strands through homophilic and heterophilic cis and trans interactions. A strand of one cell associates laterally with a strand in the apposing membrane of an adjacent cell creating a paired TJ strand (Tsukita et al., 2001). The TJ strands contain aqueous pores with size and charge selectivity that are permeable to water-soluble molecules. Differences in the barrier properties in epithelia of different tissues have been explained by the expression of a unique set of claudins in a given tissue (Van Itallie and Anderson, 2006). 24 claudins were identified in humans, which allows a large number of possible combinations and specific barrier properties. Edited: Matthews, L, 2009-05-18 16:34:30 Pubmed11283726 Pubmed16460278 Pubmed16537104 Reactome Database ID Release 43420019 Reactome, http://www.reactome.org ReactomeREACT_19338 Reviewed: Ebnet, K, 2009-08-26 has a Stoichiometric coefficient of 2 Necl-5:Nectin 3 trans heterodimer interaction Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-26 Necl-5 and Nectin 3 interact forming a trans heterodimer. Pubmed12759359 Reactome Database ID Release 43420593 Reactome, http://www.reactome.org ReactomeREACT_19151 Reviewed: Ebnet, K, 2009-08-26 PARVB/Affixin interacts with alpha PIX Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-12 Pubmed12499396 Pubmed15005707 Pubmed16314921 Reactome Database ID Release 43432946 Reactome, http://www.reactome.org ReactomeREACT_20672 Reviewed: Wu, C, 2009-11-12 The Rho GTPases, Cdc42 and Rac1, play critical roles in cell migration by integrating cell-substrate adhesion and actin polymerization. PARVB/affixin appears to participate in the activation of Rac and Cdc42 by associating with alpha PIX through its CH1 domain (Mishima et al., 2004; Rosenberger et al., 2005). This activity of PARVB/affixin could promote the polymerization of actin through the activation of downstream effectors of Rac1/Cdc42, including WASP-Arp2/3 and Mena/VASP. Alpha-PIX, ILK and PARVB can be found at the leading edge of spreading cells (Rosenberger et al., 2005 ), and it is likely that activation of Rac1 and Cdc42 at the lamellipodia in some cells is stimulated by interactions of aPIX with PARVB and regulated by interaction of ILK and PARVB (see Sepulveda and Wu, 2005 ). Rsu-1 interacts with Pinch1 Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-12 Pubmed15596544 Pubmed18436335 Reactome Database ID Release 43430311 Reactome, http://www.reactome.org ReactomeREACT_20616 Reviewed: Wu, C, 2009-11-12 The Ras suppressor, Rsu-1, interacts with the LIM 5 domain of PINCH1 (but not PINCH2) and may inhibit cell migration by stabilizing the Pinch-ILK-parvin adhesion complex (Dougherty et al., 2008; Kadrmas et al., 2004). Association of PARVA with TESK1 Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-12 Pubmed11555644 Pubmed12027893 Pubmed15584898 Pubmed15817463 Reactome Database ID Release 43446372 Reactome, http://www.reactome.org ReactomeREACT_20609 Reviewed: Wu, C, 2009-11-12 The association of PARVA with TESK1 appears to suppress cell spreading (Lalonde et al. 2005). TESK1 can phosphorylate cofilin and promote F-actin polymerization and cell spreading (Tsumura et al., 2005 ; Toshima et al., 2001; Leeksma et al., 2002). PARVA associates with testicular protein kinase 1 (TESK1) and inhibits its activity (Lalonde et al. 2005). PARVB interacts with Alpha-actinin Authored: Matthews, L, 2009-10-12 Edited: Wu, C, 2009-11-12 PARVB interacts with the actin cross-linking protein Alpha-actinin (Yamaji et al. 2004). The ILK-PARVB complex may serve as an integrin-anchoring site for alpha-actinin and thereby mediate integrin signaling to alpha-actinin, which has been shown to play an important role in actin polymerization at focal adhesions (Yamaji et al., 2004). Pubmed15159419 Reactome Database ID Release 43430308 Reactome, http://www.reactome.org ReactomeREACT_20671 Reviewed: Wu, C, 2009-11-12 Crumbs forms a ternary complex with Pals1 and PATJ at tight junctions Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-05-18 16:34:30 Pubmed11964389 Pubmed12771187 Pubmed15738264 Pubmed16129888 Pubmed16771626 Reactome Database ID Release 43420661 Reactome, http://www.reactome.org ReactomeREACT_19144 Reviewed: Ebnet, K, 2009-08-26 The CRB3–Pals1–PATJ complex is the second major cell polarity protein complex at Tight Junctions (TJs) (Shin et al., 2006). The integral membrane protein CRB3 localizes to the apical domain of epithelial cells and is concentrated at TJs. CRB3 directly associates with Pals1 which interacts with PATJ, a proteins consisting of 10 PDZ domains. The interaction with CRB3 might recruit the Pals1-PATJ complex to TJs (Lemmers et al., 2002; Roh et al., 2003). Although its precise functions of the individual components have not been established, the complex is required for TJ formation, in part through the stabilization of apical and lateral components of tight junctions (Michel et al., 2005; Shin et al., 2005). Formation of the PINCH-ILK-parvin complex Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-12 Pubmed10574708 Pubmed11078733 Pubmed11331308 Pubmed12432066 Pubmed12651156 Pubmed14551191 Reactome Database ID Release 43446391 Reactome, http://www.reactome.org ReactomeREACT_20645 Reviewed: Wu, C, 2009-11-12 The PINCH-ILK-parvin complex (Tu et al., 2001; Zhang et al., 2002; Li et al., 1999) localizes to focal adhesions and plays a critical role in the regulation of cell adhesion, cell shape modulation, motility and ECM deposition (Velyvis et al., 2001; Braun et al, 2003). ILK binds PINCH through its N-terminal domain and binds PARVA or PARVB through its C-terminal domain, resulting in formation of the ternary PINCH-ILK-parvin complex (Tu et al., 2001). These complexes form before they are localized to integrin-rich adhesion sites (Zhang et al., 2002). Formation of the ILK-PINCH-parvin complexes stabilizes these proteins by protecting them from degradation by the proteasome (Fukuda et al., 2003). ILK interacts with beta-1 integrin Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-12 ILK interacts with the cytoplasmic domain of beta1-integrin (Hannigan et al., 1996). Pubmed8538749 Reactome Database ID Release 43432897 Reactome, http://www.reactome.org ReactomeREACT_20656 Reviewed: Wu, C, 2009-11-12 PARVA associates with Paxillin Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-10 Pubmed18508764 Pubmed18940607 Reactome Database ID Release 43446322 Reactome, http://www.reactome.org ReactomeREACT_20542 Reviewed: Wu, C, 2009-11-12 The focal adhesion protein alpha-parvin, interacts with paxillin, through the C-terminal CH-containing fragment of the alpha-parvin and paxillin LD motif (Wang et al., 2008; Lorenz et al., 2008). This interaction likely contributes to the localization of the PINCH-ILK-parvin complexes to focal adhesions. MigFilin associates with Filamin and F-actin Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-12 Migfilin associates with actin filaments as a result of its interaction with filamin (Tu et al., 2003). Migfilin associates with actin filaments and loss of migfilin decreases the level of F-actin suggesting that, in addition to providing an anchoring site for actin filaments at cell-ECM adhesions, migfilin also functions in the regulation of filamin-mediated cross-linking and stabilization of actin filaments (Tu et al., 2003). Pubmed12679033 Reactome Database ID Release 43430347 Reactome, http://www.reactome.org ReactomeREACT_20513 Reviewed: Wu, C, 2009-11-12 Mig-2 recruits Migfilin to the cell-ECM adhesions Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-10-12 Migfilin functions in cell shape modulation regulating filamin-mediated cross-linking and stabilization of actin filaments. Migfilin is recruited to cell–Extra Cellular Matrix adhesion sites in a variety of fibroblasts, epithelial, and endothelial cells by interaction with Mig-2 (Tu et al., 2003). Pubmed12679033 Reactome Database ID Release 43430341 Reactome, http://www.reactome.org ReactomeREACT_20555 Reviewed: Wu, C, 2009-11-12 Direct recruitment of GRB2:Sos1 to P-Erbb2mut dimer Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Exogenously expressed human GRB2 in complex with mouse Sos1 is directly recruited to phosphorylated rat Neu onocoprotein (Erbb2 mutant isolated from rat neuroblastoma, with valine at position 661 replaced with glutamic acid) stably expressed in transformed mouse fibroblasts. Pubmed8530511 Reactome Database ID Release 431250475 Reactome, http://www.reactome.org ReactomeREACT_150435 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Smad7:SMURF2 complex translocates to the cytosol Authored: Orlic-Milacic, M, 2012-04-04 Coexpression of tagged recombinant human SMURF2 and mouse Smad7 in Mv1Lu cells (a mink lung epithelial cell line) leads to translocation of SMURF2 from the nucleus into the cytosol (Kavsak et al. 2000). Edited: Jassal, B, 2012-04-10 Pubmed11163210 Reactome Database ID Release 432167888 Reactome, http://www.reactome.org ReactomeREACT_121132 Reviewed: Huang, Tao, 2012-05-14 TGFBR1 is recruited to tight junction by binding Pard6a Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 FLAG-tagged mouse Pard6a exogenously expressed in human embryonic kidney cell line, HEK293, binds HA-tagged human TGFBR1. According to studies in confluent normal murine mammary monolayers, NMuMG, exogenous human Myc-tagged TGFBR1 and exogenously expressed mouse FLAG-tagged Pard6a co-localize with endogenous ZO1 protein, a marker of tight junctions (Ozdamar et al. 2005). Pubmed15761148 Reactome Database ID Release 432161147 Reactome, http://www.reactome.org ReactomeREACT_120717 Reviewed: Huang, Tao, 2012-05-14 Ras guanyl-nucleotide exchange mediated by Sos1 in complex with GRB2 and P-Erbb2mut Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed8530511 Reactome Database ID Release 431250468 Reactome, http://www.reactome.org ReactomeREACT_115638 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Sos1 bound to exogenously expressed human GRB2 in complex with phosphorylated rat oncoprotein Erbb2mut catalyzes endogenous Ras guanyl--nucleotide exchange in mouse fibroblasts. Mouse JAK2 binds human common beta chain Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 JAK2 associates with IL3 reecptor beta chain (IL3RB) better known as the cytokine recetpor common beta chain (Bc). This association was not found to be dependent upon, or influenced by, the presence of GM-CSF or the GM-CSF receptor alpha chain, suggesting that JAK2 and Bc may be constitutively associated (Quelle et al. 1994). Pubmed7775438 Pubmed8007942 Reactome Database ID Release 43879922 Reactome, http://www.reactome.org ReactomeREACT_23802 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 CDK8 phosphorylates xNICD1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 2.7.11.22 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15546612 Reactome Database ID Release 432065178 Reactome, http://www.reactome.org ReactomeREACT_118651 Reviewed: Haw, R, 2012-02-06 TAD and PEST domains of NOTCH intracellular domain contain multiple conserved cyclin-dependent kinase phosphorylation sites. In vitro, recombinant human CDK8 in complex with recombinant human cyclin C (CDK8:CCNC) readily phosphorylates recombinant Xenopus NICD1 (xNICD1). This phosphorylation also occurs when these recombinant proteins are expressed in HeLa cells, and was directly shown to involve conserved serine residues in the PEST domain. Phosphorylation by CDK8 targets xNICD1 for ubiquitination and subsequent degradation, thereby coordinating NICD1 transcriptional activity with NICD1 turnover. p53 and Sin3a bind c-Myb Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-16 Pubmed10378697 Pubmed14761981 Pubmed15509555 Pubmed16597594 Pubmed1709592 Pubmed19252138 Pubmed20599537 Pubmed2413449 Pubmed8710361 Reactome Database ID Release 43992753 Reactome, http://www.reactome.org ReactomeREACT_25186 Reviewed: Ouwehand, WH, 2010-11-12 The DNA-binding domain of c-Myb binds the co-repressor protein SIN3A (Nomura et al. 2004). The tumor repressor p53 also binds MYB directly (Tanikawa et al. 2004), promoting formation of a trimeric SIN3A:c-Myb:p53 complex. This does not affect the ability of c-Myb to bind to DNA, but may represent the mechanism that allows p53 to to regulate specific Myb target genes. <br>c-Myb (gene symbol MYB) is highly conserved in all vertebrates and some invertebrate species (Lipsick 1996). It plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells (Duprey & Boettiger 1985); Down-regulation of c-Myb is believed to be critical for the commitment of cells to terminal differentiation (Oh & Reddy, 1999). c-Myb interacts with many other transcription factors including CBP, several CCAAT binding protein (c/EBP) family members, and Ets family proteins such as Ets-2 (Oh & Reddy, 1999). <br>Loss of c-Myb function results in embryonic lethality due to failure of fetal hepatic hematopoiesis (Mucenski et al. 1991). Uchl5 is recruited to TGF-beta receptor complex through Smad7 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Endogenous UCHL5 and SMAD7 were shown to form a complex in human fibroblast cell line U4A. By expressing recombinant tagged mouse Uchl5 and Smad7, along with recombinant human TGF-beta receptors, in HEK293 cells, it was shown that Uchl5 binds Smad7 in complex with TGFBR1 (Wicks et al. 2005). Pubmed16027725 Reactome Database ID Release 432179307 Reactome, http://www.reactome.org ReactomeREACT_120965 Reviewed: Huang, Tao, 2012-05-14 Myristoylation of Nef GENE ONTOLOGYGO:0006499 Nef amino terminal myristoylation has been shown to be critical for many of Nef's functions. As expected myristoylated Nef can be identified as co-fractionating with cell membranes and cytoskeletal components. Pubmed15613341 Pubmed7797518 Pubmed8124721 Pubmed8151761 Reactome Database ID Release 43162914 Reactome, http://www.reactome.org ReactomeREACT_116143 Mouse emilin-1 binds human elastin and mouse fibulin-5 Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Elastin microfibril interface located protein (EMILIN)-1 is localized to the microfibril-elastin interface (Bressan et al. 1993). It can bind elastin and fibulin-5 (Zanetti et al. 2004). Emilin1 knockout mice have ultrastructural alterations of the elastic fibers in aorta and skin, abnormal cell morphology and anchorage of endothelial and smooth muscle cells to elastic lamellae, and abnormal elastic fibers in cultured embryonic fibroblasts. Pubmed14701737 Pubmed8458869 Reactome Database ID Release 432426460 Reactome, http://www.reactome.org ReactomeREACT_150181 Reviewed: Muiznieks, Lisa, 2012-11-02 Association of Nek2A with MCC:APC/C Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-07-10 14:28:40 Nek2A does not appear to be recruited to the APC/C by Cdc20 but rather binds directly to the APC/C in an interaction involving the NEK2A C-terminal methionine–arginine (MR) dipeptide tail (Hayes et al., 2006). Pubmed11742988 Pubmed16648845 Reactome Database ID Release 43179410 Reactome, http://www.reactome.org ReactomeREACT_7992 Reviewed: Peters, JM, 2006-03-27 22:55:09 Multiubiquitination of Nek2A Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 6.3.2.19 Edited: Matthews, L, 2006-07-10 14:28:40 Nek2A is ubiquitinated by the APC/C-Cdc20 ubiquitin ligase. Pubmed11742988 Reactome Database ID Release 43179417 Reactome, http://www.reactome.org ReactomeREACT_7995 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 3 Degradation of multiubiquitinated Nek2A Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-07-10 14:28:40 Nek2A is degraded by the 26S proteasome following ubiquitylation by the E3 ubiquitin ligase APC/C: Cdc20. Pubmed11742988 Pubmed16648845 Reactome Database ID Release 43179421 Reactome, http://www.reactome.org ReactomeREACT_8025 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 3 Connection of adjacent cells through calcium-dependent trans-dimerization of cadherin Authored: Matthews, L, 2009-05-15 19:26:33 Cadherins are the major cell adhesion molecules at adherens junctions (AJs). Classical cadherins are Ca2+-dependent, homophilic adhesion molecules that link adjacent cells (Gumbiner, 2005; Halbleib and Nelson, 2006; Pokutta and Weis, 2007). The extracellular domain of classical cadherins consists of five cadherin-type repeats (called "extracellular cadherin" (EC) -domains). In the presence of Ca2+, the monomers form parallel cis-dimers resulting in a rod-like structure (Gumbiner, 2005). The cis-dimers undergo trans homophilic interactions to mediate homotypic cell-cell interactions. The cytoplasmic tails of classical cadherins interact with different proteins (primarily catenins) to regulate cell surface expression levels, linkage to the actin cytoskeleton, and cell signaling. Non-classical cadherins (Atypical cadherins, Proto-cadherins, cadherin-related proteins) have a variable number of cadherin-type repeats, do not associate with catenins, and are not associated with AJs (Halbleib and Nelson, 2006). Edited: Matthews, L, 2009-08-25 Pubmed16025097 Pubmed17158740 Pubmed17539752 Pubmed9219219 Reactome Database ID Release 43419001 Reactome, http://www.reactome.org ReactomeREACT_19416 Reviewed: Ebnet, K, 2009-08-26 has a Stoichiometric coefficient of 2 Interaction of cadherin with Beta/gamma catenin, alpha catenin and p120 catenin Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-26 Pubmed16025097 Pubmed16325583 Pubmed17005550 Pubmed17158740 Pubmed18093941 Pubmed7806582 Reactome Database ID Release 43419002 Reactome, http://www.reactome.org ReactomeREACT_19131 Reviewed: Ebnet, K, 2009-08-26 The cytoplasmic tails of classical cadherins form a multiprotein complex with alpha-catenin, beta/gamma-catenins and p120 catenin (p120ctn) (Gumbiner, 2005). Beta-catenin and p120ctn directly interact with the cadherin molecule through highly conserved regions in the membrane-distal and membrane-proximal domains, respectively, of the cadherin. The interactions with beta-catenin and p120ctn regulate cadherin localization at cell-cell contacts as well as its adhesive activity (Halbleib and Nelson, 2006). The association of beta-catenin and alpha-catenin probably serves to link the cadherin-catenin complex to the F-actin cytoskeleton through the protein ELPIN (Abe and Takeichi, 2008). Independently of its association with the cadherin-catenin complex, alpha-catenin also regulates the bundling and growth of actin filaments at sites of cell-cell contact formation (Drees et al., 2005; Weis and Nelson, 2006). Interaction of Afadin with F-actin Afadin serves as a linker of the actin cytoskeleton to the plasma membrane at cell-to-cell Adherens Junctions (Mandai et al., 1997). Authored: Matthews, L, 2009-08-19 Edited: Matthews, L, 2009-08-19 Pubmed9334353 Reactome Database ID Release 43433725 Reactome, http://www.reactome.org ReactomeREACT_19163 Reviewed: Ebnet, K, 2009-08-26 Cis-homodimerization of nectins Authored: Matthews, L, 2009-08-19 Edited: Matthews, L, 2009-08-19 Pubmed17942295 Pubmed9845526 Reactome Database ID Release 43433711 Reactome, http://www.reactome.org ReactomeREACT_19169 Reviewed: Ebnet, K, 2009-08-26 The Nectin family of Ca2+-independent cell adhesion molecules (CAMs) is comprised of four members, nectin-1, nectin-2, nectin-3, and nectin-4 (reviewed in Sakisaka et al., 2007). Each nectin first forms homophilic cis-dimers and then forms homophilic or heterophilic trans-dimers involved in cell–cell adhesion. Heterophilic trans-interactions are stronger than homophilic trans-interactions. has a Stoichiometric coefficient of 2 Interaction of Nectins with Afadin Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-26 Nectins are immunoglobulin-like cell adhesion molecules comprising a family of four members, nectin 1 - 4 (Takai and Nakanishi, 2003). In contrast to classical cadherins which interact only homophilically, nectins undergo trans-homophilic and trans-heterophilic interactions with nectins and nectin-like molecules (Takai et al., 2008b). Nectins cooperate with cadherins in regulating the formation of adherens junctions (AJs) and the strength of cell-cell adhesion. Nectins are linked to the underlying actin cytoskeleton through their interaction with the actin-binding protein Afadin (Takai et al., 2008a). Nectin-based cell–cell adhesions contribute to formation of many types of cell-cell junctions including AJs, tight junctions, and synaptic junctions. Pubmed10225955 Pubmed12456712 Pubmed18648374 Reactome Database ID Release 43419003 Reactome, http://www.reactome.org ReactomeREACT_19214 Reviewed: Ebnet, K, 2009-08-26 Transhomodimerization of Nectin-like (Necl) proteins Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-25 Pubmed12050160 Pubmed15363801 Pubmed16467305 Pubmed17942295 Pubmed17967169 Pubmed18648374 Reactome Database ID Release 43420592 Reactome, http://www.reactome.org ReactomeREACT_19179 Reviewed: Ebnet, K, 2009-08-26 The nectin-like (Necl) family comprises five members, called Necl-1 to -5. Necl have an overall organization like that of nectins with three Ig-like domains, a transmembrane region and a cytoplasmic domain. Necls have a greater variety of functions than nectins and are ubiquitously expressed. In contrast to nectins, Necls do not interact with afadin. Transhomodimerization has been described for Necl-1, -2 and -3 but not for Necl-4 and -5. (Sakisaka et al., 2007; Sakisaka and Takai, 2004; Takai et al., 2008). has a Stoichiometric coefficient of 2 Transhomodimerization of Nectins Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-25 Nectins are Ca(2+)-independent cell adhesion molecules which interact homophilically and heterophilically in trans to form cell-cell adhesions (reviewed in (Sakisaka et al., 2007; Takai et al., 2008). Each nectin first forms homo-cis-dimers and then homo- or hetero-trans-dimers through the extracellular region, causing cell–cell adhesion. The Nectin protein family is made up of four members, nectin-1, -2, -3, and -4, all of which have an extracellular region with three Ig-like loops, a single transmembrane region, and a cytoplasmic tail region. Pubmed10225955 Pubmed17942295 Pubmed18593353 Pubmed9845526 Reactome Database ID Release 43419011 Reactome, http://www.reactome.org ReactomeREACT_19364 Reviewed: Ebnet, K, 2009-08-26 has a Stoichiometric coefficient of 2 PathwayStep4817 PathwayStep4816 PathwayStep4819 PathwayStep4818 RFC dissociates after sliding clamp formation on the C-strand of the telomere Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed9822671 Reactome Database ID Release 43174447 Reactome, http://www.reactome.org ReactomeREACT_7967 Replication factor C is proposed to dissociate from PCNA following sliding clamp formation, and the DNA toroid alone tethers pol delta to the DNA. Reviewed: Price, C, 2006-07-13 18:33:38 Loading of PCNA - Sliding Clamp Formation on the C-strand of the telomere Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed2165567 Pubmed9660172 Reactome Database ID Release 43174439 Reactome, http://www.reactome.org ReactomeREACT_8000 Reviewed: Price, C, 2006-07-13 18:33:38 The binding of the primer recognition complex involves the loading of proliferating cell nuclear antigen (PCNA). Replication Factor C transiently opens the PCNA toroid in an ATP-dependent reaction, and then allows PCNA to re-close around the double helix adjacent to the primer terminus. This leads to the formation of the "sliding clamp". PathwayStep4811 RFC binding displaces Pol Alpha on the C-strand of the telomere Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Once the RNA-DNA primer is synthesized, replication factor C (RFC) initiates a reaction called "polymerase switching"; pol delta, the processive enzyme replaces pol alpha, the priming enzyme. RFC binds to the 3'-end of the RNA-DNA primer on the Primosome, to displace the pol alpha primase complex. The binding of RFC triggers the binding of the primer recognition complex. Pubmed10656791 Pubmed10656792 Pubmed1671046 Reactome Database ID Release 43174452 Reactome, http://www.reactome.org ReactomeREACT_8008 Reviewed: Price, C, 2006-07-13 18:33:38 PathwayStep4810 PathwayStep4813 PathwayStep4812 PathwayStep4815 PathwayStep4814 Removal of remaining Flap from the C-strand Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed10409700 Pubmed10806216 Pubmed11825897 Pubmed7876218 Pubmed8131753 Pubmed8824221 Pubmed9080773 Reactome Database ID Release 43174446 Reactome, http://www.reactome.org ReactomeREACT_7975 Reviewed: Price, C, 2006-07-13 18:33:38 The remaining flap, which is too short to support RPA binding, is then processed by FEN-1. There is evidence that binding of RPA to the displaced end of the RNA-containing Okazaki fragment prevents FEN-1 from accessing the substrate. FEN-1 is a structure-specific endonuclease that cleaves near the base of the flap at a position one nucleotide into the annealed region. Biochemical studies have shown that the preferred substrate for FEN-1 consists of a one-nucleotide 3'-tail on the upstream primer in addition to the 5'-flap of the downstream primer. Recruitment of Dna2 endonuclease to the C strand After RPA binds the long flap, it recruits the Dna2 endonuclease. Dna2 endonuclease removes most of the flap, but the job of complete removal of the flap is then completed by FEN-1. Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed11473323 Reactome Database ID Release 43174451 Reactome, http://www.reactome.org ReactomeREACT_8015 Reviewed: Price, C, 2006-07-13 18:33:38 Removal of RNA primer and dissociation of RPA and Dna2 from the C-strand Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed10748138 Pubmed11473323 Reactome Database ID Release 43174441 Reactome, http://www.reactome.org ReactomeREACT_7955 Reviewed: Price, C, 2006-07-13 18:33:38 The Dna2 endonuclease removes the initiator RNA along with several downstream deoxyribonucleotides. The cleavage of the single-stranded RNA substrate results in the disassembly of RPA and Dna2. The current data for the role of the Dna2 endonuclease has been derived from studies with yeast and Xenopus Dna2. Formation of the Flap Intermediate on the C-strand Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed11473323 Pubmed11724925 Pubmed7711022 Reactome Database ID Release 43174438 Reactome, http://www.reactome.org ReactomeREACT_7973 Reviewed: Price, C, 2006-07-13 18:33:38 When the polymerase delta:PCNA complex reaches a downstream Okazaki fragment, strand displacement synthesis occurs. The primer containing 5'-terminus of the downstream Okazaki fragment is folded into a single-stranded flap. RPA binds to the Flap on the C-strand Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed11473323 Reactome Database ID Release 43174445 Reactome, http://www.reactome.org ReactomeREACT_7949 Reviewed: Price, C, 2006-07-13 18:33:38 The first step in the removal of the flap intermediate is the binding of Replication Protein A (RPA) to the long flap structure. RPA is a eukaryotic single-stranded DNA binding protein. Formation of Processive Complex on the C-strand of the telomere Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed1682322 Pubmed1974050 Pubmed7713898 Pubmed8104944 Reactome Database ID Release 43174448 Reactome, http://www.reactome.org ReactomeREACT_7979 Reviewed: Price, C, 2006-07-13 18:33:38 The loading of proliferating cell nuclear antigen (PCNA) leads to recruitment of pol delta. Human PCNA is a homotrimer of 36 kDa subunits that form a toroidal structure. The loading of PCNA by RFC is a key event in the transition from the priming mode to the extension mode of DNA synthesis. The processive complex is composed of the pol delta holoenzyme and PCNA. Formation of C-strand Okazaki fragments After RFC initiates the assembly of the primer recognition complex, the complex of pol delta and PCNA is responsible for incorporating the additional nucleotides prior to the position of the next downstream initiator RNA primer. On the lagging strand, short discontinuous segments of DNA, called Okazaki fragments, are synthesized on RNA primers. The average length of the Okazaki fragments is 100 nucleotides. Polymerase switching is a key event that allows the processive synthesis of DNA by the pol delta and PCNA complex. Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 EC Number: 2.7.7.7 GENE ONTOLOGYGO:0000722 Pubmed1328683 Pubmed1671046 Pubmed1974050 Pubmed8104944 Pubmed8144677 Pubmed9081985 Reactome Database ID Release 43174444 Reactome, http://www.reactome.org ReactomeREACT_8029 Reviewed: Price, C, 2006-07-13 18:33:38 PathwayStep4808 PathwayStep4807 PathwayStep4806 PathwayStep4805 PathwayStep4809 PathwayStep4800 Disassociation of Processive Complex and Completed Telomere End At some point in the extension process a sufficient number of regulatory factors that repress telomere extension become bound to the extending telomere. These factors include the TRF1 complexes, TRF2 complexes, telomerase, other factors, and the telomere itself. As repeats are added to the G-rich strand, and once lagging strand synthesis completes the duplex, new binding sites become available for these repressive factors. Once a balance is reached between telomere extension and the telomere repression factors, extension ceases. In this state extension machinery disassociates, leaving the telomere to be folded into a stable conformation.<P>This module details a single transit through the telomere extension process, detailing the addition of two repeats, and the corresponding synthesis of a section of lagging strand. An actual round of <i>in vivo</i> telomere extension would require thousands of telomere repeat additions, and it is the repressive effect of the factors bound to these repeats that turns off telomere extension. Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000723 Reactome Database ID Release 43176702 Reactome, http://www.reactome.org ReactomeREACT_7954 Reviewed: Price, C, 2006-07-13 18:33:38 Joining of adjacent Okazaki fragments of the C-strand Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed10959839 Pubmed8392066 Pubmed9081985 Pubmed9759502 Reactome Database ID Release 43174456 Reactome, http://www.reactome.org ReactomeREACT_7994 Removal of the flap by FEN-1 leads to the generation of a nick between the 3'-end of the upstream Okazaki fragment and the 5'-end of the downstream Okazaki fragment. DNA ligase I then seals the nicks between adjacent processed Okazaki fragments to generate intact double-stranded DNA at the telomere. Reviewed: Price, C, 2006-07-13 18:33:38 Incorporation Of Extended And Processed Telomere End Into Higher Order T-Loop And Associated Protein Structure Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0016233 In addition to telomerase-mediated elongation and C-strand synthesis, other DNA processing steps are likely involved in telomere maintenance. In humans, nucleolytic activity is proposed to be involved in generating the G-rich 3' single strand overhang. In addition, differences in the structure of the overhang at telomeres that have undergone leading vs. lagging strand replication suggest that DNA processing may be different at these telomeres (Chai et al. 2006). <br> Electron microscopy studies of purified human telomeric DNA have provided evidence for telomeric loops, or t-loops (Griffith et al. 1999). t-loops are proposed to result from invasion of the 3' G-rich single strand overhang into the double stranded portion of the telomeric TTAGGG repeat tract. The strand displaced by invasion forms a structure called a D loop. The function of the t-loop is presumed to be the protection of the 3' telomeric end. In vitro, the double strand telomeric DNA binding protein TRF2 can increase the frequency of t-loop formation. The prevalence of the t-loops in vivo is not known. <br> Many proteins associate with telomeric DNA. One complex that binds telomeres is called shelterin. Shelterin is a six-protein complex composed of TRF1 and TRF2, which can bind double-stranded telomeric DNA, POT1, which can bind single-stranded telomeric DNA, and three other factors, RAP1, TIN2, and TPP1 (reviewed in de Lange 2006 "Telomeres"). Human telomeric DNA is also bound by nucleosomes (Makarov et al. 1993; Nikitina and Woodcock 2004). A number of other proteins, including some that play roles in the DNA damage response, can be found at telomeres (Zhu et al. 2000; Verdun et al. 2005). <br> Studies in yeast and humans indicate that the association of many proteins with telomeres is regulated through the cell cycle (Smith et al. 1993; Zhu et al. 2000; Taggart et al. 2002; Fisher et al. 2004; Takata et al. 2004; Takata et al. 2005; Verdun et al. 2005). For instance, TRF1, MRE11, POT1, ATM, and NBS1 display cell cycle regulated chromatin immunoprecipitation of telomeric DNA (Zhu et al. 2000; Verdun et al. 2005), and cytologically observable hTERT and hTERC localize to a subset of telomeres only in S-phase (Jady et al. 2006; Tomlinson et al. 2006). These data indicate that telomeres are dynamically remodeled through the cell cycle. Pubmed10888888 Pubmed12169735 Pubmed15149600 Pubmed15249582 Pubmed15531893 Pubmed15721260 Pubmed16307919 Pubmed16319170 Pubmed16339074 Pubmed16455497 Pubmed8702494 Reactome Database ID Release 43176700 Reactome, http://www.reactome.org ReactomeREACT_8031 Reviewed: Price, C, 2006-07-13 18:33:38 Incorporation Of Extended And Processed Telomere End Into Associated Protein Structure Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0016233 In addition to telomerase-mediated elongation and C-strand synthesis, other DNA processing steps are likely involved in telomere maintenance. In humans, nucleolytic activity is proposed to be involved in generating the G-rich 3' single strand overhang. In addition, differences in the structure of the overhang at telomeres that have undergone leading vs. lagging strand replication suggest that DNA processing may be different at these telomeres (Chai et al. 2006). <P> Many proteins associate with telomeric DNA. One complex that binds telomeres is called shelterin. Shelterin is a six-protein complex composed of TRF1 and TRF2, which can bind double-stranded telomeric DNA, POT1, which can bind single-stranded telomeric DNA, and three other factors, RAP1, TIN2, and TPP1 (reviewed in de Lange 2006 "Telomeres"). Human telomeric DNA is also bound by nucleosomes (Makarov et al. 1993; Nikitina and Woodcock 2004). A number of other proteins, including some that play roles in the DNA damage response, can be found at telomeres (Zhu et al. 2000; Verdun et al. 2005). <P> Studies in yeast and humans indicate that the association of many proteins with telomeres is regulated through the cell cycle (Zhu et al. 2000; Taggart et al. 2002; Fisher et al. 2004; Takata et al. 2004; Takata et al. 2005; Verdun et al. 2005). For instance, TRF1, MRE11, POT1, ATM, and NBS1 display cell cycle regulated chromatin immunoprecipitation of telomeric DNA (Zhu et al. 2000; Verdun et al. 2005), and cytologically observable hTERT and hTERC localize to a subset of telomeres only in S-phase (Jady et al. 2006; Tomlinson et al. 2006). These data indicate that telomeres are dynamically remodeled through the cell cycle. Pubmed10888888 Pubmed12169735 Pubmed15149600 Pubmed15249582 Pubmed15531893 Pubmed15721260 Pubmed16166375 Pubmed16307919 Pubmed16319170 Pubmed16339074 Pubmed16455497 Pubmed8702494 Reactome Database ID Release 43181450 Reactome, http://www.reactome.org ReactomeREACT_7971 Reviewed: Price, C, 2006-07-13 18:33:38 PathwayStep4804 PathwayStep4803 PathwayStep4802 PathwayStep4801 Recruitment of ATR Kinase to Unsynapsed Regions Authored: May, B, 2010-07-19 Edited: May, B, 2010-07-19 Pubmed19146767 Reactome Database ID Release 43912450 Reactome, http://www.reactome.org ReactomeREACT_75923 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Unsynapsed regions of chromosomes accumulate BRCA1, the kinase ATR, and the phosphorylated histone gammaH2AX. In mouse the recruitment of ATR depends on BRCA1. ATR Phosphorylates Histone H2A.X at Unsynapsed Regions Authored: May, B, 2010-07-19 EC Number: 2.7.11 Edited: May, B, 2010-07-19 Pubmed11673449 Pubmed19146767 Reactome Database ID Release 43912470 Reactome, http://www.reactome.org ReactomeREACT_75904 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 The ATR kinase phosphorylates histone H2A.X at serine 139 (Ward and Chen 2001, Garcia-Cruz et al. 2009). Formation of Axial/Lateral Elements of Synaptonemal Complex Authored: May, B, 2010-07-19 Axial elements begin assembling as short linear segments along the long axis of the chromosome in leptotene phase. Eventually the short segments will fuse to form the complete axial element along the entire length of the chromosome. After synapsis the axial elements are also known as lateral elements of the synaptonemal complex. Within axial elements the sister chromatids are bound together by meiotic cohesin (Prieto et al. 2004, Garcia-Cruz et al. 2010). The bound chromatids are anchored to a complex containing SYCP2 and SYCP3 via a direct or indirect interaction with cohesin (Garcia-Cruz et al. 2010). Edited: May, B, 2010-07-19 Pubmed15125634 Pubmed20634189 Reactome Database ID Release 43912389 Reactome, http://www.reactome.org ReactomeREACT_75874 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Formation of the telomere bouquet As sections of the axial elements form, the telomeres migrate to one site on the inner nuclear membrane to form the telomere bouquet (Scherthan et al. 1996). A current model shows the synaptonemal complex interacting with SUN1 and SUN2, which span the inner membrane and bind Nesprin-1 and Nesprin-2, which span the outer membrane and bind cytoplasmic actin. Lamin-B1 and Lamin-C2 are located adjacent to the attachment plate on the inner membrane. Authored: May, B, 2010-07-19 Edited: May, B, 2010-07-19 Pubmed8794855 Reactome Database ID Release 43912408 Reactome, http://www.reactome.org ReactomeREACT_75817 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Telomere clustering at the nuclear membrane Synapsis Authored: May, B, 2010-07-02 Edited: May, B, 2010-07-02 Formation of Central Elements of the Synaptonemal Complex Initiation of recombination precedes and is required for synapsis (Roig et al. 2004). The synaptonemal complex forms when transverse filaments of SYCP1 link axial/lateral elements of sister chromatids to a central element comprising SYCE1, SYCE2, and other proteins (Tarsounas et al. 1997). The order of assembly is unknown. Pubmed15235794 Pubmed9285814 Reactome Database ID Release 43912505 Reactome, http://www.reactome.org ReactomeREACT_75849 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Recruitment of BRCA1 to Unsynapsed Regions Authored: May, B, 2010-07-19 Edited: May, B, 2010-07-19 Pubmed19146767 Pubmed9008167 Reactome Database ID Release 43912467 Reactome, http://www.reactome.org ReactomeREACT_75884 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Unsynapsed regions of chromosomes are silenced during pachytene phase by a process called Meiotic Silencing of Unsynapsed Chromatin (MSUC) and, in the case of the X and Y chromosomes, Meiotic Sex Chromosome Inactivation (MSCI). Unsynapsed meiotic chromatin recruits BRCA1 (Scully et al. 1997, Garcia-Cruz et al. 2009). In mouse, the recruitment requires SYCP3 of axial elements of the synaptonemal complex, which may remain exposed in unsynapsed regions. PR Converted from EntitySet in Reactome Protease Reactome DB_ID: 173126 Reactome Database ID Release 43173126 Reactome, http://www.reactome.org ReactomeREACT_8869 Association of Cdh1 with the APC/C Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Following its dephosphorylation in late mitosis, Cdh1 replaces Cdc20 as the APC/C activator. Pubmed10793135 Reactome Database ID Release 43174070 Reactome, http://www.reactome.org ReactomeREACT_6741 Reviewed: Peters, JM, 2006-03-27 22:55:09 Degradation of multiubiquitinated cell cycle proteins Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Cell cycle proteins mulitubiquitinated by the APC/C are targeted for degradation by the 26S proteasome. Edited: Matthews, L, 2006-01-30 00:00:00 Reactome Database ID Release 43174105 Reactome, http://www.reactome.org ReactomeREACT_6826 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 4 APC/C:Cdh1-mediated degradation of Skp2 Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-10-01 21:26:42 Pubmed15014502 Pubmed15014503 Reactome Database ID Release 43188191 Reactome, http://www.reactome.org ReactomeREACT_9035 Reviewed: Peters, JM, 2006-03-27 22:55:09 Skp2 is degraded by the anaphase promoting complex/Cyclosome and its activator Cdh1 [APC/C(Cdh1)] (Bashir et al, 2004; Wei et al, 2004). The tight regulation of APC/C(Cdh1) activity ensures the timely elimination Skp2 and, thus, plays a critical role in controlling the G1/S transition. has a Stoichiometric coefficient of 4 Association of cell cycle proteins with the APC/C:Cdh1 complex Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-02-17 00:25:47 Pubmed10733526 Pubmed12446569 Reactome Database ID Release 43174088 Reactome, http://www.reactome.org ReactomeREACT_6974 Reviewed: Peters, JM, 2006-03-27 22:55:09 The APC/C:Cdh1 complex recognizes substrates containing a D box, a KEN box (Pfleger and Kirschner, 2000) or a D box activated (DAD) domain (Castro et al., 2002). Ubiquitination of cell cycle proteins targeted by the APC/C:Cdh1complex At the beginning of this reaction, 3 molecules of 'ubiquitin', and 1 molecule of 'cell cycle proteins:phospho-APC/C:Cdh1 complex' are present. At the end of this reaction, 1 molecule of 'multiubiquitinated cell cycle protein:APC/C:Cdh1 complex' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'cell cycle proteins:phospho-APC/C:Cdh1 complex'.<br> Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 6.3.2.19 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0042787 Reactome Database ID Release 43174195 Reactome, http://www.reactome.org ReactomeREACT_6914 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 4 Mis18 Complex Binds the Centromere. Authored: May, B, 2010-04-15 Edited: May, B, 2010-04-15 Pubmed15369671 Pubmed16622420 Pubmed17199038 Pubmed17339379 Reactome Database ID Release 43606349 Reactome, http://www.reactome.org ReactomeREACT_22169 Reviewed: Almouzni-Pettinotti, G, Dunleavy, EM, 2010-05-30 Reviewed: Foltz, DR, 2010-06-14 The Mis18 complex (containing Mis18-alpha, Mis18-beta, Mis18BP1, RBap46, and RbAp48) transiently binds the centromere in late anaphase-telophase to early G1. The mechanism by which the Mis18 complex binds the centromere is unknown. The Mis18 complex is required for deposition of new CENPA-containing nucleosomes at the centromere. The CENPH-I complex is constitutively associated with centromeres and is required for deposition of new CENPA-containing nucleosomes. HJURP:CENPA Complex Localizes to the Centromere. Authored: May, B, 2010-04-15 Edited: May, B, 2010-04-15 Pubmed17199038 Pubmed19410544 Pubmed19410545 Pubmed20080577 Reactome Database ID Release 43606326 Reactome, http://www.reactome.org ReactomeREACT_22146 Reviewed: Almouzni-Pettinotti, G, Dunleavy, EM, 2010-05-30 Reviewed: Foltz, DR, 2010-06-14 The HJURP complex binds free, newly synthesized CENPA-H4 tetramers. A direct interaction occurs between HJURP and CENPA. The CATD domain of CENPA is sufficient for the interaction. The complex then localizes to the centromere in early G1 phase. HJURP is required for deposition of new CENPA-containing nucleosomes. Multiubiquitination of APC/C-associated Cdh1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Cdh1 is multiubiquitinated by the APC/C:Cdh1 complex prior to degradation by the 26S proteasome. EC Number: 6.3.2.19 Edited: Matthews, L, 2006-02-17 05:21:42 GENE ONTOLOGYGO:0042787 Pubmed15029244 Reactome Database ID Release 43174057 Reactome, http://www.reactome.org ReactomeREACT_6791 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 3 Degradation of multiubiquitinated Cdh1 At the beginning of this reaction, 1 molecule of 'multiubiquitinated Cdh1 associated with APC/C' is present. At the end of this reaction, 1 molecule of 'phosphorylated anaphase promoting complex (APC/C)', and 3 molecules of 'ubiquitin' are present.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'endopeptidase activity' of '26S proteasome'.<br> Authored: Matthews, L, 2006-01-30 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Pubmed15029244 Reactome Database ID Release 43174058 Reactome, http://www.reactome.org ReactomeREACT_6715 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 3 Deposition of New CENPA-containing Nucleosomes at the Centromere. A new centromeric nucleosome containing histone H2A, histone H2B, histone H4, and CENPA is deposited at the centromere in late telophase/early G1 phase. The exact mechanism by which the new CENPA-containing nucleosome is transferred to DNA is unknown. HJURP directly binds newly synthesized CENPA before deposition. The Mis18 and HJURP complexes are required for deposition of newly synthesized CENPA-containing nucleosomes. The exact stoichiometries and interactions of the complexes are unknown. Authored: May, B, 2010-04-15 Edited: May, B, 2010-04-15 Pubmed16622420 Pubmed17199038 Pubmed19398759 Pubmed19410544 Pubmed19410545 Pubmed20080577 Reactome Database ID Release 43606289 Reactome, http://www.reactome.org ReactomeREACT_22185 Reviewed: Almouzni-Pettinotti, G, Dunleavy, EM, 2010-05-30 Reviewed: Foltz, DR, 2010-06-14 has a Stoichiometric coefficient of 2 Biogenesis And Assembly Of The Telomerase RNP Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0007004 Pubmed10197982 Pubmed10591218 Pubmed10835362 Pubmed10983983 Pubmed11074001 Pubmed11274138 Pubmed11432839 Pubmed11509658 Pubmed11751869 Pubmed11956201 Pubmed12083802 Pubmed12198499 Pubmed12221125 Pubmed12676087 Pubmed12699629 Pubmed14528011 Pubmed14981093 Pubmed15371412 Pubmed16319170 Pubmed16339074 Pubmed16714764 Pubmed17395830 Pubmed18358808 Pubmed18523010 Pubmed19179534 Pubmed2769858 Pubmed8602368 Pubmed9858580 Reactome Database ID Release 43164616 Reactome, http://www.reactome.org ReactomeREACT_7997 Reviewed: Price, C, 2006-07-13 18:33:38 TERC RNA + 2 TERT + 2 DKC1 (dyskerin) => telomerase RNP hTERC is transcribed as a precursor and is processed at its 3' end to yield a 451 nucleotide RNA (Zaug et al. 1996). The accumulation of hTERC that has undergone this processing event requires a conserved region of sequence termed the box H/ACA motif (Mitchell et al. 1999a). This motif is bound by a complex containing dyskerin, and mutations in dyskerin affect the processing and accumulation of hTERC (Mitchell et al. 1999b; Mitchell and Collins 2000; Fu and Collins 2003). Recent studies of purified, catalytically active telomerase indicate that the minimal structure that has telomerase activity in vitro is a complex of one molecule of hTERC RNA and two each of hTERT and DKC1 (dyskerin) proteins (Cohen et al. 2007). Several additional proteins may associate with this minimal complex and modulate its activity. RUVBL1 (pontin), RUVBL2 (reptin), and TCAB1 (telomere Cajal body protein 1) are found associated with human telomerase RNPs purified from HeLa cells, and activities of these proteins are required for telomerase RNP assembly in vivo (Venteicher et al. 2008, 2009). NHP2 (NOLA2) is likewise associated with telomerase ribonucleoprotein complexes (Pogacic et al. 2000) and homozygosity for NHP2 mutations is associated with telomerase failure (dyskeratosis congenita) in humans (Vuillamy et al. 2008). The exact roles of the additional proteins in the assembly and function of telomerase RNP in vivo remain unclear, however, so they are annotated simply as positively regulating telomerase RNP formation.<br><br><br>The core components hTERC and hTERT undergo trafficking in the cell that may be important for telomerase function. hTERC has been found localized in multiple nuclear structures, including Cajal bodies, nucleoli, and at telomeres (Mitchell et al. 1999a; Jady et al. 2004; Zhu et al. 2004; Jady et al. 2006; Tomlinson et al. 2006). hTERT is also reported localize in Cajal bodies, nucleoli, and to associate with telomeres (Etheridge et al. 2002; Wong et al. 2002; Yang et al. 2002; Zhu et al. 2004; Tomlinson et al. 2006). Some of the factors that regulate trafficking of these two core components of telomerase have been identified, such as nucleolin (Khurts et al. 2004), SMN (Bachand et al. 2002), and 14-3-3 (Seimiya et al. 2000). Cytological studies of HeLa cells suggest that the localization of the telomerase core components can change through the cell-cycle (Jady et al. 2006; Tomlinson et al. 2006). Despite these studies, it is not clear in which compartment hTERT and hTERC assemble to form functional telomerase RNP.<br><br><br>The assembly of telomerase involves the chaperone proteins p23 and Hsp90, which stably associate with telomerase in vitro (Holt et al. 1999; Forsythe et al. 2001; Keppler et al. 2006). A number of other proteins interact with the telomerase RNP, but it is not clear if they play a role in telomerase assembly. Interestingly, assembled human telomerase RNP can multimerize, though the function of multimerization remains unclear (Beattie et al. 2001; Wenz et al. 2001; Arai et al. 2002). has a Stoichiometric coefficient of 2 RSF Complex Binds the Centromere. Authored: May, B, 2010-04-15 Edited: May, B, 2010-04-15 Pubmed19398759 Reactome Database ID Release 43606287 Reactome, http://www.reactome.org ReactomeREACT_22217 Reviewed: Almouzni-Pettinotti, G, Dunleavy, EM, 2010-05-30 Reviewed: Foltz, DR, 2010-06-14 The RSF complex binds the centromere in mid-G1 phase after deposition of new CENPA-containing nucleosomes has occurred. The RSF complex is required for stable incorporation of the previously deposited CENPA-containing nucleosomes. Recruitment of Telomerase RNP to the Telomeric Chromosome End Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0007004 Pubmed11017190 Pubmed11239396 Pubmed11572773 Pubmed12169735 Pubmed12589054 Pubmed15060173 Pubmed15189140 Pubmed15469829 Pubmed1585795 Pubmed16120835 Pubmed16319170 Pubmed16339074 Pubmed8413255 Reactome Database ID Release 43163096 Reactome, http://www.reactome.org ReactomeREACT_7960 Reviewed: Price, C, 2006-07-13 18:33:38 Studies in yeast and humans indicate that recruitment of telomerase to a telomere may be influenced by multiple variables, including regulatory protein factors, hTERT domains, telomere length, and the cell cycle. First, in yeast, the telomerase associated factor Est1 and the single-strand DNA binding protein Cdc13 play roles in telomerase recruitment (Pennock et al. 2001; Bianchi et al. 2004). Analogous proteins exist in human cells (Est1A, Est1B, Est1C, and POT1, respectively); however, how or whether these proteins are directly involved in telomerase recruitment remains to be elucidated. Second, N-terminal residues of hTERT within the DAT (dissociate the activities of telomerase) domain may have a role in binding single stranded telomeric DNA as the "anchor site" (Lee et al. 1993; Moriarty et al. 2005). Third, a cis-acting mechanism in yeast and humans that regulates telomere length maintenance may modulate telomerase access to the telomere (reviewed in Blackburn 2001; Smogorzewska and de Lange, 2004). Long telomeres, which have more associated protein factors, are in a state that is acted on by telomerase less frequently than that of short telomeres, which have fewer associated factors. Whether short telomeres actively recruit telomerase remains to be determined. Last, the recruitment of telomerase to telomeres shows cell-cycle regulation (Taggart et al. 2002; Smith et al. 2003; Fisher et al. 2004; Jady et al. 2006; Tomlinson et al. 2006). Further studies will be needed to determine the details of how human telomerase is recruited to a telomere. <br> Alignment Of The RNA Template On The Telomeric Chromosome End Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0007004 In vitro studies of telomerase complexes derived from multiple organisms indicate that at least two types of interactions are important for telomerase RNP catalytic site alignment at the 3' G-rich single-strand telomere end. In one interaction, an alignment region in hTERC base-pairs with the 3' G-rich single-strand telomeric DNA end to form an RNA-DNA hybrid, which positions the template adjacent to the 3' end of the telomere. In a second interaction, a portion of hTERT is proposed to interact with the DNA 5' of the telomerase RNA/DNA primer hybrid (Harrington and Greider 1991; Morin 1991; Moriarty et al. 2005), which is important for the catalytic rate (Lee and Blackburn, 1993) and presumably allows telomerase to maintain contact with the chromosome during the translocation step. How the anchor site binding and template hybridization are coordinated is not known.<br> Pubmed15189140 Pubmed16120835 Pubmed1896088 Pubmed1896089 Pubmed8413255 Reactome Database ID Release 43163099 Reactome, http://www.reactome.org ReactomeREACT_7968 Reviewed: Price, C, 2006-07-13 18:33:38 Elongation Of The Telomeric Chromosome End Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0007004 Pubmed10825187 Pubmed14630939 Pubmed15189140 Pubmed15776019 Pubmed8330740 Pubmed9049315 Pubmed9548747 Reactome Database ID Release 43163090 Reactome, http://www.reactome.org ReactomeREACT_8019 Reviewed: Price, C, 2006-07-13 18:33:38 The template of hTERC directs the sequential addition of nucleotides to the 3' telomeric DNA end. Following addition of a nucleotide, the template and catalytic site must move relative to one another within the telomerase RNP to place the appropriate template residue in the active site. As base-pairing and nucleotide addition occur at one end of the template, base pair melting occurs at the other (Collins and Greider 1993; Wang and Blackburn, 1997; Hammond and Cech 1998; Benjamin et al. 2000; Forstemann and Lingner 2005). This un-pairing is thought to reduce the energy used for mediating the subsequent translocation step. Nucleotide addition can occur up until the template boundary which in hTERC is defined by a helix called P1b (Chen and Greider 2003).<br> Translocation Of Telomerase RNP And Alignment Of RNA Template (TERC) To Extended Single Stranded Telomeric Chromosome-End Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0007004 Pubmed15189140 Reactome Database ID Release 43164620 Reactome, http://www.reactome.org ReactomeREACT_7957 Reviewed: Price, C, 2006-07-13 18:33:38 The human telomerase RNP can catalyze multiple rounds of repeat addition on the same telomeric substrate in vitro. Before initiating synthesis of another repeat, telomerase undergoes a translocation step to reposition itself on the telomere. Base pairs in the DNA/RNA hybrid are unannealed, the RNA template is repositioned relative to the active site, and the template base-pairs at the 3' end of the newly synthesized DNA. The anchor site interaction with DNA 5' of the RNA-DNA duplex is thought to maintain the interaction of telomerase with DNA during the translocation step. <br> Elongation of Extended Telomeric Chromosome End Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0007004 Pubmed10825187 Pubmed14630939 Pubmed15189140 Pubmed15776019 Pubmed8330740 Pubmed9049315 Pubmed9548747 Reactome Database ID Release 43164617 Reactome, http://www.reactome.org ReactomeREACT_7985 Reviewed: Price, C, 2006-07-13 18:33:38 The elongation reaction proceeds as follows: The template of hTERC directs the sequential addition of nucleotides to the 3' telomeric DNA end. Following addition of a nucleotide, the template and catalytic site must move relative to one another within the telomerase RNP to place the appropriate template residue in the active site. As base-pairing and nucleotide addition occur at one end of the template, base pair melting occurs at the other (Collins and Greider 1993; Wang and Blackburn, 1997; Hammond and Cech 1998; Benjamin et al. 2000; Forstemann and Lingner 2005). This un-pairing is thought to reduce the energy used for mediating the subsequent translocation step. Nucleotide addition can occur up until the template boundary which in hTERC is defined by a helix called P1b (Chen and Greider 2003).<br> Disassociation of Telomerase RNP and the Chromosome End Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0007004 In vitro, telomerase can disassociate from the primer following addition of each nucleotide or during the translocation step. The regulation of telomerase disassociation from the telomere in vivo is not well-characterized. One factor that may be involved is a helicase termed hPIF1, which can unanneal the telomerase RNA/telomeric DNA hybrid (Boule et al., 2005; Zhang et al., 2006).<br> Pubmed11850778 Pubmed14690602 Pubmed15189140 Pubmed15316005 Pubmed16121131 Pubmed16522649 Reactome Database ID Release 43163120 Reactome, http://www.reactome.org ReactomeREACT_7996 Reviewed: Price, C, 2006-07-13 18:33:38 The primase component of DNA polymerase:primase synthesizes a 6-10 nucleotide RNA primer on the G strand of the telomere Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 EC Number: 2.7.7.6 GENE ONTOLOGYGO:0000722 Pubmed6693436 Reactome Database ID Release 43174425 Reactome, http://www.reactome.org ReactomeREACT_7998 Reviewed: Price, C, 2006-07-13 18:33:38 The complementary strand is synthesized by the polymerase primase complex using conventional RNA priming. The polymerase component of DNA polymerase alpha:primase synthesizes a 20-nucleotide primer on the G strand of the telomere Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 EC Number: 2.7.7.7 GENE ONTOLOGYGO:0000722 Reactome Database ID Release 43174427 Reactome, http://www.reactome.org ReactomeREACT_8004 Reviewed: Price, C, 2006-07-13 18:33:38 The complementary strand is synthesized by the polymerase primase complex using conventional RNA priming. Env gp120 Converted from EntitySet in Reactome Reactome DB_ID: 171197 Reactome Database ID Release 43171197 Reactome, http://www.reactome.org ReactomeREACT_8094 'PLTP [extracellular region]' positively regulates 'Spherical HDL binds membrane-associated free cholesterol and phospholipids' ACTIVATION Reactome Database ID Release 43266320 Reactome, http://www.reactome.org ReactomeREACT_14769 PathwayStep149 'LDLRAP1 [plasma membrane]' is required for 'LDL:LDLR complex [plasma membrane] => LDL:LDLR complex [clathrin-coated vesicle] (LDLRAP1-dependent)' ACTIVATION Reactome Database ID Release 43171103 Reactome, http://www.reactome.org ReactomeREACT_7941 PathwayStep148 'apoA-I [extracellular region]' positively regulates 'cholesterol + phosphatidylcholine (lecithin) => cholesterol ester + 2-lysophosphatidylcholine (lysolecithin)' ACTIVATION Reactome Database ID Release 43264701 Reactome, http://www.reactome.org ReactomeREACT_14727 Env gp41 Converted from EntitySet in Reactome Reactome DB_ID: 171252 Reactome Database ID Release 43171252 Reactome, http://www.reactome.org ReactomeREACT_8250 PathwayStep143 PathwayStep142 PathwayStep141 PathwayStep140 PathwayStep4862 PathwayStep147 PathwayStep4861 PathwayStep146 PathwayStep4860 PathwayStep145 PathwayStep144 PathwayStep4854 PathwayStep4855 PathwayStep4852 PathwayStep4853 PathwayStep4858 PathwayStep4859 PathwayStep150 PathwayStep4856 PathwayStep4857 'apoC-III [extracellular region]' negatively regulates 'chylomicron => TG-depleted chylomicron + 50 long-chain fatty acids + 50 diacylglycerols' INHIBITION Reactome Database ID Release 43174677 Reactome, http://www.reactome.org ReactomeREACT_7939 'hepatic lipase [extracellular region]' is required for 'chylomicron remnant:apoE complex + LDLR => chylomicron remnant:apoE:LDLR complex' ACTIVATION Reactome Database ID Release 43174591 Reactome, http://www.reactome.org ReactomeREACT_7924 'LDLRAP1 [plasma membrane]' is required for 'chylomicron remnant:apoE:LDLR complex [plasma membrane] => chylomicron remnant:apoE:LDLR complex [clathrin-coated vesicle] (LDLRAP1-dependent)' ACTIVATION Reactome Database ID Release 43174774 Reactome, http://www.reactome.org ReactomeREACT_7919 'alpha2-macroglobulin [extracellular region]' negatively regulates 'Conversion of pro-apoA-I to apoA-I' INHIBITION Reactome Database ID Release 43264772 Reactome, http://www.reactome.org ReactomeREACT_14751 'MTP:PDI:lipid complex [endoplasmic reticulum lumen]' is required for 'ApoB-48:TG:PL complex + 100 triacylglycerols + ApoA-I + ApoA-IV => nascent chylomicron' ACTIVATION Reactome Database ID Release 43174632 Reactome, http://www.reactome.org ReactomeREACT_7932 'SAR1B GTP-binding protein [cytosol]' is required for 'nascent chylomicron [endoplasmic reticulum lumen] => nascent chylomicron [extracellular]' ACTIVATION Reactome Database ID Release 43174789 Reactome, http://www.reactome.org ReactomeREACT_7927 'apoA-V [extracellular region]' positively regulates 'chylomicron => TG-depleted chylomicron + 50 long-chain fatty acids + 50 diacylglycerols' ACTIVATION Reactome Database ID Release 43174695 Reactome, http://www.reactome.org ReactomeREACT_7930 'apoC-II [extracellular region]' positively regulates 'chylomicron => TG-depleted chylomicron + 50 long-chain fatty acids + 50 diacylglycerols' ACTIVATION Reactome Database ID Release 43174621 Reactome, http://www.reactome.org ReactomeREACT_7931 PathwayStep159 Dissociation of Cdc20 from APC/C complex Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 In late mitosis, Cdc20 dissociates from the APC/C and is replaced by the activator Cdh1. Reactome Database ID Release 43174224 Reactome, http://www.reactome.org ReactomeREACT_6748 Reviewed: Peters, JM, 2006-03-27 22:55:09 Dephosphorylation of phospho-Cdh1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 3.1.3.16 Edited: Matthews, L, 2006-02-17 05:23:25 Phosphorylation by mitotic kinases is believed to alter the conformation of Cdh1 preventing it from associating with the APC/C. Cdc14 is thought to contribute to the dephosphorylation of Cdh1 in late mitosis. Dephosphorylated Cdh1 then associates with and activates the APC/C. Pubmed11598127 Reactome Database ID Release 43174124 Reactome, http://www.reactome.org ReactomeREACT_6910 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep152 Degradation of multiubiquitinated Cyclin B Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Mulitubiquitinated Cyclin B is targeted for degradation by the 26S proteasome. Pubmed11285280 Reactome Database ID Release 43174157 Reactome, http://www.reactome.org ReactomeREACT_6749 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 4 PathwayStep151 Ubiquitination of Cyclin B by phospho-APC/C:Cdc20 complex At the beginning of this reaction, 1 molecule of 'Cdc20:phospho-APC/C:Cyclin B:Cdc2 complex', and 3 molecules of 'ubiquitin' are present. At the end of this reaction, 1 molecule of 'multiubiquitinated Cyclin B:Cdc2:Cdc20:phospho-APC/C complex' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'Cdc20:Phospho-APC/C'.<br> Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 6.3.2.19 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0042787 Pubmed11285280 Reactome Database ID Release 43174227 Reactome, http://www.reactome.org ReactomeREACT_6735 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 4 PathwayStep154 Association of Cyclin B:Cdc2 with Cdc20:APC/C complex Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Cyclin B is believed to be recognized by the APC/C:Cdc20 complex through its D-box sequence. Edited: Matthews, L, 2006-01-30 00:00:00 Reactome Database ID Release 43174120 Reactome, http://www.reactome.org ReactomeREACT_6766 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep153 Activation of APC/C:Cdc20 by dissociation of Cdc20:phospho-APC/C from Cdc20:phospho-APC/C:Mad2:Bub3:BubR1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2004-11-18 13:25:08 Edited: Matthews, L, 2006-02-17 00:25:47 GENE ONTOLOGYGO:0051437 One model ( the direct inhibition model) describing the inhibition of the APC/C during the mitotic spindle checkpoint suggests that the association of the hBUBR1:hBUB3:MAD2*:CDC20 mitotic checkpoint complex (MCC) with APC/C results in the inactivation of APC/C. The affinity between MCC and APC/C is not high, thus inhibition is readily reversible when the mitotic spindle checkpoint has been satisfied. Pubmed11535616 Reactome Database ID Release 43174238 Reactome, http://www.reactome.org ReactomeREACT_6733 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep156 Free APC/C phosphorylated by Cyclin B:Cdc2 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 2.7.11.22 Edited: Matthews, L, 2006-01-30 00:00:00 Phosphorylation of the APC/C is believed to be required for its activation. While the identity of the essential phosphorylation sites and the kinase(s) responsible are not known with certainty, in vitro studies have shown that the Apc1 and the tetratricopeptide repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7 are phosphorylated and that the Cdk1 and Plk1 kinases may play a role. Pubmed11859075 Pubmed14657031 Reactome Database ID Release 43174132 Reactome, http://www.reactome.org ReactomeREACT_6942 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep155 Free APC/C phosphorylated by Plk1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 2.7.11 Edited: Matthews, L, 2006-01-30 00:00:00 Phosphorylation of the APC/C is believed to be required for its activation. While the identity of the essential phosphorylation sites and the kinase(s) responsible are not known with certainty, in vitro studies have shown that the Apc1 and the tetratricopeptide repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7 are phosphorylated and that the Cdk1 and Plk1 kinases may play a role. Pubmed11859075 Pubmed14657031 Reactome Database ID Release 43174119 Reactome, http://www.reactome.org ReactomeREACT_6859 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep4851 PathwayStep158 Phosphorylation of Cdh1 by Cyclin B1:Cdc2 At the onset of mitosis, Cdh1 is phosphorylated by Cyclin B-Cdc2 resulting in a conformational change that prevents Cdh1 from activating the APC/C. Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 EC Number: 2.7.11.22 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0051436 Pubmed11598127 Reactome Database ID Release 43174251 Reactome, http://www.reactome.org ReactomeREACT_6811 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep4850 PathwayStep157 SCF-mediated degradation of Emi1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Multiubiquitinated Emi1 is degraded by the 26S proteasome. Pubmed15469984 Reactome Database ID Release 43174203 Reactome, http://www.reactome.org ReactomeREACT_6878 Reviewed: Peters, JM, 2006-03-27 22:55:09 has a Stoichiometric coefficient of 4 PathwayStep4841 PathwayStep4842 PathwayStep4843 PathwayStep4844 PathwayStep4845 PathwayStep4846 PathwayStep4847 PathwayStep160 PathwayStep4848 PathwayStep161 PathwayStep4849 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ALAS1' ACTIVATION Pubmed19710929 Reactome Database ID Release 431989808 Reactome, http://www.reactome.org ReactomeREACT_118007 'Steroid hormone receptor ERR1 [nucleoplasm]' positively regulates 'Expression of ALAS1' ACTIVATION ERR1 (ERRalpha) probably interacts with coactivator PG-1beta to activate ALAS1 (Shao et al. Shao et al. 2010). Pubmed20561910 Reactome Database ID Release 431605570 Reactome, http://www.reactome.org ReactomeREACT_118044 'ALAS1 gene:NRF1:PPARGC1B [nucleoplasm]' positively regulates 'Expression of ALAS1' ACTIVATION Pubmed20561910 Reactome Database ID Release 431592257 Reactome, http://www.reactome.org ReactomeREACT_118057 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase (HMGCR)' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989785 Reactome, http://www.reactome.org ReactomeREACT_117932 'SREBP1A/2:NF-Y:HMGCR gene [nucleoplasm]' positively regulates 'Expression of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase (HMGCR)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Pubmed8647822 Pubmed8833906 Pubmed9062341 Pubmed9616204 Pubmed9748295 Reactome Database ID Release 431655873 Reactome, http://www.reactome.org ReactomeREACT_118005 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Hydroxymethylglutaryl CoA Reductase gene (HMGCR) and enhance transcription (Shimano et al. 1996,Vallett et al. 1996, Shiman et al. 1997, Horton et al. 1998, Pai et al. 1998, Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002). 'caveolin-1 [lipid particle]' positively regulates 'perilipin + 2 ATP -> phosphorylated perilipin + 2 ADP' ACTIVATION Reactome Database ID Release 43163651 Reactome, http://www.reactome.org ReactomeREACT_5997 'Citrate [cytosol]' positively regulates 'acetyl-CoA + bicarbonate + ATP => malonyl-CoA + H2O + ADP + orthophosphate' ACTIVATION Pubmed18455495 Reactome Database ID Release 43539127 Reactome, http://www.reactome.org ReactomeREACT_23402 'Acetyl-CoA [cytosol]' negatively regulates 'phosphoenolpyruvate + ADP => pyruvate + ATP' INHIBITION-ALLOSTERIC Reactome Database ID Release 4371663 Reactome, http://www.reactome.org ReactomeREACT_5985 PathwayStep4840 PathwayStep169 PathwayStep168 PathwayStep167 PathwayStep166 PathwayStep165 PathwayStep164 PathwayStep163 PathwayStep162 PathwayStep4836 PathwayStep171 'D-Fructose 1,6-bisphosphate [cytosol]' positively regulates 'phosphoenolpyruvate + ADP => pyruvate + ATP' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371662 Reactome, http://www.reactome.org ReactomeREACT_6087 PathwayStep4837 PathwayStep172 '3',5'-Cyclic AMP [cytosol]' negatively regulates 'phosphoenolpyruvate + ADP => pyruvate + ATP' INHIBITION Reactome Database ID Release 4371664 Reactome, http://www.reactome.org ReactomeREACT_6035 PathwayStep4834 PathwayStep4835 PathwayStep170 PathwayStep4832 PathwayStep4833 PathwayStep4830 PathwayStep4831 'D-sorbitol 6-phosphate [cytosol]' negatively regulates 'cytosolic GCK1:GKRP complex <=> glucokinase (GCK1) + glucokinase regulatory protein (GKRP)' INHIBITION Pubmed14627435 Reactome Database ID Release 43170800 Reactome, http://www.reactome.org ReactomeREACT_7926 'alpha-D-glucose [nucleoplasm]' positively regulates 'nucleoplasmic GCK1:GKRP complex => glucokinase (GCK1) + glucokinase regulatory protein (GKRP)' ACTIVATION Reactome Database ID Release 43170807 Reactome, http://www.reactome.org ReactomeREACT_7925 'D-Fructose 2,6-bisphosphate [cytosol]' positively regulates 'D-fructose 6-phosphate + ATP => D-fructose 2,6-bisphosphate + ADP' ACTIVATION Reactome Database ID Release 43163759 Reactome, http://www.reactome.org ReactomeREACT_6052 'Citrate [cytosol]' negatively regulates 'D-fructose 6-phosphate + ATP => D-fructose 1,6-bisphosphate + ADP' INHIBITION Reactome Database ID Release 4371508 Reactome, http://www.reactome.org ReactomeREACT_6029 'AMP [cytosol]' positively regulates 'D-fructose 6-phosphate + ATP => D-fructose 1,6-bisphosphate + ADP' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371504 Reactome, http://www.reactome.org ReactomeREACT_6020 'ATP [cytosol]' negatively regulates 'D-fructose 6-phosphate + ATP => D-fructose 1,6-bisphosphate + ADP' INHIBITION-ALLOSTERIC Reactome Database ID Release 4371507 Reactome, http://www.reactome.org ReactomeREACT_5962 PathwayStep4838 'D-Fructose 2,6-bisphosphate [cytosol]' positively regulates 'D-fructose 6-phosphate + ATP => D-fructose 1,6-bisphosphate + ADP' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371506 Reactome, http://www.reactome.org ReactomeREACT_6066 PathwayStep4839 'ADP [cytosol]' positively regulates 'D-fructose 6-phosphate + ATP => D-fructose 1,6-bisphosphate + ADP' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371505 Reactome, http://www.reactome.org ReactomeREACT_5988 'L-Aspartate [lysosomal lumen]' negatively regulates 'Beta-glucuronidase (GUSB) hydrolyses glucuronate from the linker chain' INHIBITION Reactome Database ID Release 432090086 Reactome, http://www.reactome.org ReactomeREACT_125705 'ADP' negatively regulates 'ATP + beta-D-fructose => ADP + D-fructose 1-phosphate' INHIBITION-COMPETITIVE Reactome Database ID Release 4370334 Reactome, http://www.reactome.org ReactomeREACT_6133 PathwayStep178 PathwayStep177 PathwayStep179 PathwayStep174 PathwayStep173 PathwayStep176 PathwayStep175 PathwayStep4823 PathwayStep180 PathwayStep4824 PathwayStep181 PathwayStep4825 PathwayStep182 'alpha-D-Glucose 6-phosphate [cytosol]' negatively regulates 'PGYM dimer, b form + 2 AMP <=> PGYM b dimer:AMP complex' INHIBITION Reactome Database ID Release 43453374 Reactome, http://www.reactome.org ReactomeREACT_22092 PathwayStep4826 PathwayStep183 PathwayStep4820 PathwayStep4821 PathwayStep4822 'adenosine 5'-monophosphate [cytosol]' negatively regulates 'D-fructose 1,6-bisphosphate + H2O => D-fructose 6-phosphate + orthophosphate' INHIBITION-ALLOSTERIC Reactome Database ID Release 4371497 Reactome, http://www.reactome.org ReactomeREACT_6080 'cAMP-dependent protein kinase activity of PKA catalytic subunit [cytosol]' negatively regulates 'Phosphorylation of PF2K-Pase by PKA catalytic subunit' INHIBITION Reactome Database ID Release 43163766 Reactome, http://www.reactome.org ReactomeREACT_5959 'ATP [nucleoplasm]' negatively regulates 'phosphoenolpyruvate + ADP => pyruvate + ATP' INHIBITION-ALLOSTERIC Reactome Database ID Release 4371661 Reactome, http://www.reactome.org ReactomeREACT_6112 'Acetyl-CoA [mitochondrial matrix]' positively regulates 'Pyruvate + CO2 + ATP => ADP + Orthophosphate + Oxaloacetate' ACTIVATION Reactome Database ID Release 4371425 Reactome, http://www.reactome.org ReactomeREACT_5955 PathwayStep4827 'Calcium [cytosol]' positively regulates 'glycogen phosphorylase (PYGL) dimer b + 2 ATP => glycogen phosphorylase (PYGL) dimer a + 2 ADP' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371589 Reactome, http://www.reactome.org ReactomeREACT_5995 PathwayStep4828 'ATP [cytosol]' negatively regulates 'PGYM dimer, b form + 2 AMP <=> PGYM b dimer:AMP complex' INHIBITION Reactome Database ID Release 43453366 Reactome, http://www.reactome.org ReactomeREACT_22093 PathwayStep4829 'alpha-D-Glucose 6-phosphate [cytosol]' positively regulates '8 UDP-glucose + ((1,4)-alpha-D-glucosyl)4 glycogenin => 8 UDP + ((1,4)-alpha-D-glucosyl)8 glycogenin [GYS D form]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371575 Reactome, http://www.reactome.org ReactomeREACT_5987 'Calcium [cytosol]' positively regulates 'glycogen phosphorylase (PYGM) dimer b + 2 ATP => glycogen phosphorylase (PYGM) dimer a + 2 ADP' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4371542 Reactome, http://www.reactome.org ReactomeREACT_6026 PathwayStep186 PathwayStep187 PathwayStep184 PathwayStep185 ACTIVATION GENE ONTOLOGYGO:0003964 Reactome Database ID Release 43173777 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004523 Reactome Database ID Release 43182837 Reactome, http://www.reactome.org PathwayStep188 ACTIVATION GENE ONTOLOGYGO:0004523 Reactome Database ID Release 43173785 Reactome, http://www.reactome.org PathwayStep189 'Zn++ [extracellular]' is required for 'kininogen + C1q binding protein tetramer -> kininogen:C1q binding protein tetramer' ACTIVATION Reactome Database ID Release 43158223 Reactome, http://www.reactome.org ReactomeREACT_5933 DAG binding by PKC stimulates PKC activation ACTIVATION Protein Kinase C (PKC) is positively regulated by events that increase the plasma membrane concentration of diacylglycerol (DAG). Activation of PKC requires the coordinated binding of two membrane-targeting domains. The C1 domain binds diacylglycerol, the C2 domain binds phosphatidylserine. Each can bind the membrane independently, but with insufficient affinity for membrane recruitment and activation. Pubmed19033211 Reactome Database ID Release 43425851 Reactome, http://www.reactome.org ReactomeREACT_19116 'Calcium [extracellular]' positively regulates 'factor IX -> factor IXa + factor IX activation peptide (factor XIa catalyst)' ACTIVATION Reactome Database ID Release 43158643 Reactome, http://www.reactome.org ReactomeREACT_6015 'kininogen [plasma membrane]' positively regulates 'factor XII -> factor XIIa' ACTIVATION Reactome Database ID Release 43158654 Reactome, http://www.reactome.org ReactomeREACT_6014 'Gab2 binds the p85 subunit of Class 1A PI3 kinases' positively regulates 'PIP3 recruits PDK1 and AKT to the membrane' ACTIVATION Reactome Database ID Release 43912556 Reactome, http://www.reactome.org ReactomeREACT_24898 'Nitric oxide [cytosol]' positively regulates 'Soluble guanylate cyclase converts GTP to cGMP' ACTIVATION Reactome Database ID Release 43478867 Reactome, http://www.reactome.org ReactomeREACT_24904 PathwayStep4899 PathwayStep190 ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43173811 Reactome, http://www.reactome.org PathwayStep4898 ACTIVATION GENE ONTOLOGYGO:0004523 Reactome Database ID Release 43182891 Reactome, http://www.reactome.org PathwayStep4897 ACTIVATION GENE ONTOLOGYGO:0004523 Reactome Database ID Release 43173770 Reactome, http://www.reactome.org PathwayStep4896 ACTIVATION GENE ONTOLOGYGO:0004523 Reactome Database ID Release 43182888 Reactome, http://www.reactome.org PathwayStep194 ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43109879 Reactome, http://www.reactome.org 'fibrin multimer [extracellular]' positively regulates 'factor XIII -> factor XIII cleaved tetramer + 2 factor XIII A activation peptides' ACTIVATION Reactome Database ID Release 43140615 Reactome, http://www.reactome.org ReactomeREACT_5974 PathwayStep193 'Calcium [extracellular]' positively regulates 'factor VIIIa + factor IXa -> factor VIIIa:factor IXa' ACTIVATION Reactome Database ID Release 43158645 Reactome, http://www.reactome.org ReactomeREACT_5919 PathwayStep192 ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43173775 Reactome, http://www.reactome.org 'protein S [plasma membrane]' positively regulates 'factor Va -> factor Vi' ACTIVATION Reactome Database ID Release 43141049 Reactome, http://www.reactome.org ReactomeREACT_6129 PathwayStep191 ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 43175581 Reactome, http://www.reactome.org 'Platelet Factor 4 [extracellular region]' positively regulates 'protein C -> activated protein C + protein C heavy chain activation peptide' ACTIVATION Pubmed15118540 Reactome Database ID Release 43203103 Reactome, http://www.reactome.org ReactomeREACT_12378 PathwayStep195 PathwayStep196 PathwayStep4890 PathwayStep197 PathwayStep4891 PathwayStep198 PathwayStep4892 PathwayStep199 ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43109879 Reactome, http://www.reactome.org PathwayStep4893 ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org PathwayStep4894 ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43109879 Reactome, http://www.reactome.org PathwayStep4895 ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org 'D-sorbitol 6-phosphate [cytosol]' positively regulates 'glucokinase (GCK1) + glucokinase regulatory protein (GKRP) <=> GCK1:GKRP complex' ACTIVATION Pubmed14627435 Reactome Database ID Release 43170808 Reactome, http://www.reactome.org ReactomeREACT_7922 'D-Fructose 1-phosphate [cytosol]' negatively regulates 'glucokinase (GCK1) + glucokinase regulatory protein (GKRP) <=> GCK1:GKRP complex' INHIBITION Pubmed14627435 Reactome Database ID Release 43170816 Reactome, http://www.reactome.org ReactomeREACT_7942 'NF-E2:Promoter region of beta-globin [nucleoplasm]' positively regulates 'Expression of globin genes under control of the beta globin control region' ACTIVATION Reactome Database ID Release 431015871 Reactome, http://www.reactome.org ReactomeREACT_27114 'Heparan Sulphate [extracellular region]' positively regulates 'Basigin binds CyPA' ACTIVATION Pubmed11943775 Reactome Database ID Release 43204490 Reactome, http://www.reactome.org ReactomeREACT_13392 'Heterdimerization of CEACAMs' positively regulates 'Integrin alpha V beta 1 binds fibronectin' ACTIVATION Pubmed17167768 Reactome Database ID Release 43202743 Reactome, http://www.reactome.org ReactomeREACT_12377 'JAM-B binds JAM-C' positively regulates 'VLA-4 binds JAM-B' ACTIVATION Reactome Database ID Release 43203321 Reactome, http://www.reactome.org ReactomeREACT_12375 'Zn++ [extracellular]' is required for 'plasminogen + histidine-rich glycoprotein -> plasminogen:histidine-rich glycoprotein' ACTIVATION Reactome Database ID Release 43159017 Reactome, http://www.reactome.org ReactomeREACT_6120 PathwayStep4886 ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org PathwayStep4885 ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org PathwayStep4888 ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 43109910 Reactome, http://www.reactome.org PathwayStep4887 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43113433 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 43113432 Reactome, http://www.reactome.org PathwayStep4889 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43167189 Reactome, http://www.reactome.org 'D-Fructose 6-phosphate [cytosol]' negatively regulates 'cytosolic GCK1:GKRP complex <=> glucokinase (GCK1) + glucokinase regulatory protein (GKRP)' INHIBITION Pubmed14627435 Reactome Database ID Release 43170795 Reactome, http://www.reactome.org ReactomeREACT_7943 'D-Fructose 1-phosphate [cytosol]' positively regulates 'cytosolic GCK1:GKRP complex <=> glucokinase (GCK1) + glucokinase regulatory protein (GKRP)' ACTIVATION Pubmed14627435 Reactome Database ID Release 43170806 Reactome, http://www.reactome.org ReactomeREACT_7918 'D-Fructose 6-phosphate [cytosol]' positively regulates 'glucokinase (GCK1) + glucokinase regulatory protein (GKRP) <=> GCK1:GKRP complex' ACTIVATION Pubmed14627435 Reactome Database ID Release 43170801 Reactome, http://www.reactome.org ReactomeREACT_7920 PathwayStep4883 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43109859 Reactome, http://www.reactome.org PathwayStep4884 PathwayStep4881 PathwayStep4882 PathwayStep4880 'p-2S-SMAD2/3:SMAD4 [nucleoplasm]' positively regulates 'SMAD2/3:SMAD4 complex positively regulates JUNB transcription' ACTIVATION Pubmed10022869 Reactome Database ID Release 432187299 Reactome, http://www.reactome.org ReactomeREACT_125691 'p-2S-SMAD2/3:SMAD4:SP1 [nucleoplasm]' positively regulates 'SMAD2/3:SMAD4:SP1 complex stimulates transcription of CDKN2B' ACTIVATION Reactome Database ID Release 432187304 Reactome, http://www.reactome.org ReactomeREACT_125709 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199934 Reactome, http://www.reactome.org 'Methylcytosine: MBD2 Complex [nucleoplasm]' negatively regulates 'UBF-1 Binds rDNA Promoter' INHIBITION Methylcytosine in the promoter of a rRNA gene binds MBD2 (and possibly other Methyl Domain Binding Proteins) and prevents the transcription factor UBF-1 from binding. In mouse, methylation of the cytosine 133 nucleotides upstream of the start of transcription is sufficient. In the human rRNA promoter methylation of cytosines 9, 102, and 347 nucleotides upstream inhibit transcription. Pubmed11583633 Pubmed14610093 Reactome Database ID Release 43427398 Reactome, http://www.reactome.org ReactomeREACT_20487 'nucleosome (deacetylated) [nucleoplasm]' negatively regulates 'UBF-1 Binds rDNA Promoter' INHIBITION Reactome Database ID Release 43427347 Reactome, http://www.reactome.org ReactomeREACT_20497 ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43199956 Reactome, http://www.reactome.org 'Histone H3 dimethylated at lysine-9: HP1gamma Complex [nucleoplasm]' positively regulates 'Elongation of pre-rRNA transcript' ACTIVATION Reactome Database ID Release 43427361 Reactome, http://www.reactome.org ReactomeREACT_20498 ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43203785 Reactome, http://www.reactome.org 'TTF-I: rRNA Promoter: CSB: G9a Complex [nucleoplasm]' positively regulates 'Recruitment of Acetylated SL1 to phosUBF-1:rDNA Promoter' ACTIVATION Knockdown of CSB reduces recruitment of SL1 and RNA Polymerase I to active rRNA genes. Reactome Database ID Release 43427325 Reactome, http://www.reactome.org ReactomeREACT_20494 PathwayStep4879 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199864 Reactome, http://www.reactome.org Positive Regulation of Termination by NF1 A ACTIVATION Pubmed11118217 Reactome Database ID Release 43113459 Reactome, http://www.reactome.org ReactomeREACT_6002 The biochemically purified NF1 family proteins exert strong effects on transcriptional termination and increase the number of rounds of transcription in vitro. Detailed analysis of this effect has been confined to the VAI gene, which harbors consensus NF1 binding sites that overlap its two terminators and are essential for the transcription termination activity of NF1. However, terminator-overlapping NF1 sites are not a general feature of hspol III-transcribed genes. Involvement of NF1 proteins in transcription of genes lacking NF1-binding sites, conceivably through interaction with TFIIIC2, has been referred to (Wang et al., 2000) but not presented in concrete detail. [Nor has the implicit conflict with the proposed essential character of NF1-binding sites at the VAI gene terminator been resolved.] Biochemically purified NF1 has been reported to exert no effect on transcription in a highly purified system consisting only of recombinant TFIIIB, immunopurified TFIIIC and pol III (Wang et al., 2000). PathwayStep4878 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199939 Reactome, http://www.reactome.org Positive Regulation of Termination by NF1 C ACTIVATION Pubmed11118217 Reactome Database ID Release 43113461 Reactome, http://www.reactome.org ReactomeREACT_5971 The biochemically purified NF1 family proteins exert strong effects on transcriptional termination and increase the number of rounds of transcription in vitro. Detailed analysis of this effect has been confined to the VAI gene, which harbors consensus NF1 binding sites that overlap its two terminators and are essential for the transcription termination activity of NF1. However, terminator-overlapping NF1 sites are not a general feature of hspol III-transcribed genes. Involvement of NF1 proteins in transcription of genes lacking NF1-binding sites, conceivably through interaction with TFIIIC2, has been referred to (Wang et al., 2000) but not presented in concrete detail. [Nor has the implicit conflict with the proposed essential character of NF1-binding sites at the VAI gene terminator been resolved.] Biochemically purified NF1 has been reported to exert no effect on transcription in a highly purified system consisting only of recombinant TFIIIB, immunopurified TFIIIC and pol III (Wang et al., 2000). PathwayStep4877 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198671 Reactome, http://www.reactome.org Positive Regulation of Termination by NF1 B ACTIVATION Pubmed11118217 Reactome Database ID Release 43113460 Reactome, http://www.reactome.org ReactomeREACT_5918 The biochemically purified NF1 family proteins exert strong effects on transcriptional termination and increase the number of rounds of transcription in vitro. Detailed analysis of this effect has been confined to the VAI gene, which harbors consensus NF1 binding sites that overlap its two terminators and are essential for the transcription termination activity of NF1. However, terminator-overlapping NF1 sites are not a general feature of hspol III-transcribed genes. Involvement of NF1 proteins in transcription of genes lacking NF1-binding sites, conceivably through interaction with TFIIIC2, has been referred to (Wang et al., 2000) but not presented in concrete detail. [Nor has the implicit conflict with the proposed essential character of NF1-binding sites at the VAI gene terminator been resolved.] Biochemically purified NF1 has been reported to exert no effect on transcription in a highly purified system consisting only of recombinant TFIIIB, immunopurified TFIIIC and pol III (Wang et al., 2000). PathwayStep4876 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198647 Reactome, http://www.reactome.org Positive Regulation of Termination by La ACTIVATION Pubmed11134326 Reactome Database ID Release 43113458 Reactome, http://www.reactome.org ReactomeREACT_6132 PathwayStep4875 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43109861 Reactome, http://www.reactome.org PathwayStep4874 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198713 Reactome, http://www.reactome.org PathwayStep4870 PathwayStep4871 PathwayStep4872 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199892 Reactome, http://www.reactome.org PathwayStep4873 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199934 Reactome, http://www.reactome.org Positive Regulation of Termination by NF1 X ACTIVATION Pubmed11118217 Reactome Database ID Release 43113456 Reactome, http://www.reactome.org ReactomeREACT_6070 The biochemically purified NF1 family proteins exert strong effects on transcriptional termination and increase the number of rounds of transcription in vitro. Detailed analysis of this effect has been confined to the VAI gene, which harbors consensus NF1 binding sites that overlap its two terminators and are essential for the transcription termination activity of NF1. However, terminator-overlapping NF1 sites are not a general feature of hspol III-transcribed genes. Involvement of NF1 proteins in transcription of genes lacking NF1-binding sites, conceivably through interaction with TFIIIC2, has been referred to (Wang et al., 2000) but not presented in concrete detail. [Nor has the implicit conflict with the proposed essential character of NF1-binding sites at the VAI gene terminator been resolved.] Biochemically purified NF1 has been reported to exert no effect on transcription in a highly purified system consisting only of recombinant TFIIIB, immunopurified TFIIIC and pol III (Wang et al., 2000). 'ATP [cytosol]' is required for 'Ribosomal scanning ' ACTIVATION Reactome Database ID Release 4372781 Reactome, http://www.reactome.org ReactomeREACT_6040 'GTP' is required for 'Met-tRNAi binds to eIF2:GTP to form the ternary complex' ACTIVATION Reactome Database ID Release 4372779 Reactome, http://www.reactome.org ReactomeREACT_6078 'Mg++ [mitochondrial matrix]' is required for 'pyrophosphate + H2O => 2 orthophosphate [mitochondrial]' ACTIVATION Reactome Database ID Release 43449942 Reactome, http://www.reactome.org ReactomeREACT_22088 'Magnesium [cytosol]' is required for 'pyrophosphate + H2O => 2 orthophosphate [cytosolic]' ACTIVATION Pubmed6022858 Pubmed656444 Reactome Database ID Release 43449940 Reactome, http://www.reactome.org ReactomeREACT_22091 PathwayStep4868 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431251937 Reactome, http://www.reactome.org 'RPA:Cdc45:CDK:DDK:Mcm10:pre-replicative complex' positively regulates 'DNA polymerase alpha:primase binds at the origin' ACTIVATION Reactome Database ID Release 4369385 Reactome, http://www.reactome.org ReactomeREACT_6082 PathwayStep4867 ACTIVATION GENE ONTOLOGYGO:0004190 Reactome Database ID Release 43157355 Reactome, http://www.reactome.org 'Nuclear Pore Complex (NPC) [nuclear envelope]' is required for 'snRNP nuclear import and release' ACTIVATION Reactome Database ID Release 43191812 Reactome, http://www.reactome.org ReactomeREACT_11030 ACTIVATION GENE ONTOLOGYGO:0004379 Reactome Database ID Release 43184469 Reactome, http://www.reactome.org 'Nuclear Pore Complex (NPC) [nuclear envelope]' is required for 'Nuclear export of snRNA transcripts' ACTIVATION Reactome Database ID Release 43191896 Reactome, http://www.reactome.org ReactomeREACT_11033 PathwayStep4869 ACTIVATION GENE ONTOLOGYGO:0003964 Reactome Database ID Release 43173806 Reactome, http://www.reactome.org 'eIF5' is required for 'eIF2:GTP is hydrolyzed, eIFs are released ' ACTIVATION Reactome Database ID Release 4372782 Reactome, http://www.reactome.org ReactomeREACT_6123 PathwayStep4864 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43199915 Reactome, http://www.reactome.org PathwayStep4863 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43167971 Reactome, http://www.reactome.org PathwayStep4866 ACTIVATION GENE ONTOLOGYGO:0004705 Reactome Database ID Release 43450228 Reactome, http://www.reactome.org PathwayStep4865 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43198713 Reactome, http://www.reactome.org 'RPA:Cdc45:CDK:DDK:Mcm10:pre-replicative complex' positively regulates 'DNA polymerase epsilon binds at the origin' ACTIVATION Reactome Database ID Release 4368961 Reactome, http://www.reactome.org ReactomeREACT_6018 ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431299262 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431299251 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005249 Reactome Database ID Release 431297364 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005242 Reactome Database ID Release 431299202 Reactome, http://www.reactome.org PathwayStep2766 ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431297363 Reactome, http://www.reactome.org PathwayStep2767 ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431297372 Reactome, http://www.reactome.org PathwayStep2768 PathwayStep2769 PathwayStep2762 ACTIVATION GENE ONTOLOGYGO:0005242 Reactome Database ID Release 431368988 Reactome, http://www.reactome.org PathwayStep2763 ACTIVATION GENE ONTOLOGYGO:0005242 Reactome Database ID Release 431297377 Reactome, http://www.reactome.org PathwayStep2764 ACTIVATION GENE ONTOLOGYGO:0005242 Reactome Database ID Release 431299208 Reactome, http://www.reactome.org PathwayStep2765 ACTIVATION GENE ONTOLOGYGO:0005261 Reactome Database ID Release 431297433 Reactome, http://www.reactome.org PathwayStep330 PathwayStep2770 PathwayStep2772 PathwayStep2771 PathwayStep334 PathwayStep333 PathwayStep332 PathwayStep331 PathwayStep338 PathwayStep337 PathwayStep336 PathwayStep335 PathwayStep339 ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43170675 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43170664 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005254 Reactome Database ID Release 43975455 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015467 Reactome Database ID Release 431013015 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431297373 Reactome, http://www.reactome.org PathwayStep2779 PathwayStep2777 ACTIVATION GENE ONTOLOGYGO:0004683 Reactome Database ID Release 43111914 Reactome, http://www.reactome.org PathwayStep2778 PathwayStep2775 ACTIVATION GENE ONTOLOGYGO:0015276 Reactome Database ID Release 43451274 Reactome, http://www.reactome.org PathwayStep2776 ACTIVATION GENE ONTOLOGYGO:0015276 Reactome Database ID Release 43451278 Reactome, http://www.reactome.org PathwayStep2773 ACTIVATION GENE ONTOLOGYGO:0005254 Reactome Database ID Release 43975314 Reactome, http://www.reactome.org PathwayStep2774 ACTIVATION GENE ONTOLOGYGO:0001664 Reactome Database ID Release 43500710 Reactome, http://www.reactome.org PathwayStep2783 PathwayStep2782 PathwayStep2781 PathwayStep2780 PathwayStep321 PathwayStep320 PathwayStep323 PathwayStep322 PathwayStep325 PDS5 Converted from EntitySet in Reactome PDS5A/B PDS5A/PDS5B Reactome DB_ID: 2484796 Reactome Database ID Release 432484796 Reactome, http://www.reactome.org ReactomeREACT_151114 PathwayStep324 PathwayStep327 PathwayStep326 PathwayStep329 PathwayStep328 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Docking of TAP, Aly/Ref, and the mature intronless transcript derived mRNA at the NPC' ACTIVATION Reactome Database ID Release 43159062 Reactome, http://www.reactome.org ReactomeREACT_6085 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43112341 Reactome, http://www.reactome.org 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Transport of TAP, Aly/Ref, and the mature intronless transcript derived mRNA through the NPC' ACTIVATION Reactome Database ID Release 43159055 Reactome, http://www.reactome.org ReactomeREACT_6008 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43450303 Reactome, http://www.reactome.org 'Nuclear Pore Complex (NPC) [nuclear membrane]' is required for 'Release of TAP. Aly/Ref and the mature intronless derived mRNA from the NPC' ACTIVATION Reactome Database ID Release 43159063 Reactome, http://www.reactome.org ReactomeREACT_5956 PathwayStep2784 ACTIVATION GENE ONTOLOGYGO:0004712 Reactome Database ID Release 43450239 Reactome, http://www.reactome.org 'AMP [cytosol]' positively regulates 'Activation of cytosolic AMPK by phosphorylation' ACTIVATION Reactome Database ID Release 43201329 Reactome, http://www.reactome.org ReactomeREACT_11993 PathwayStep2785 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43177696 Reactome, http://www.reactome.org 'ATP [cytosol]' negatively regulates 'Activation of cytosolic AMPK by phosphorylation' INHIBITION Reactome Database ID Release 43201328 Reactome, http://www.reactome.org ReactomeREACT_11991 PathwayStep2786 ACTIVATION GENE ONTOLOGYGO:0008545 Reactome Database ID Release 43450334 Reactome, http://www.reactome.org 'Malonyl-CoA [cytosol]' negatively regulates 'palmitoyl-CoA + carnitine => palmitoylcarnitine + CoASH' INHIBITION-ALLOSTERIC Pubmed11790793 Pubmed14711372 Reactome Database ID Release 43200418 Reactome, http://www.reactome.org ReactomeREACT_11992 PathwayStep2787 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43177696 Reactome, http://www.reactome.org 'WWTR1:p-2S-SMAD2/3:SMAD4 [nucleoplasm]' positively regulates 'WWTR1:SMAD stimulates transcription of SMAD7' ACTIVATION Pubmed18568018 Reactome Database ID Release 432106584 Reactome, http://www.reactome.org ReactomeREACT_125695 PathwayStep2788 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43450351 Reactome, http://www.reactome.org 'p-2S-SMAD2/3:SMAD4:TGIF:HDAC1 [nucleoplasm]' negatively regulates 'WWTR1:SMAD stimulates transcription of SERPINE1 while TGIF:SMAD inhibits it' INHIBITION Pubmed10199400 Pubmed11427533 Reactome Database ID Release 432186613 Reactome, http://www.reactome.org ReactomeREACT_125707 PathwayStep2789 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43177696 Reactome, http://www.reactome.org 'WWTR1:p-2S-SMAD2/3:SMAD4 [nucleoplasm]' positively regulates 'WWTR1:SMAD stimulates transcription of SERPINE1 while TGIF:SMAD inhibits it' ACTIVATION Pubmed18568018 Reactome Database ID Release 432106588 Reactome, http://www.reactome.org ReactomeREACT_125694 ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43450295 Reactome, http://www.reactome.org Negative regulation of MYC transcription by RBL1:SMAD complex INHIBITION Pubmed12150994 Reactome Database ID Release 431484103 Reactome, http://www.reactome.org ReactomeREACT_125701 ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43168781 Reactome, http://www.reactome.org PathwayStep312 PathwayStep311 PathwayStep310 PathwayStep2790 PathwayStep2792 PathwayStep2791 PathwayStep2794 PathwayStep2793 PathwayStep319 PathwayStep318 PathwayStep317 PathwayStep316 PathwayStep315 PathwayStep314 PathwayStep313 ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43168781 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43194783 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43194814 Reactome, http://www.reactome.org PathwayStep2797 ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43181676 Reactome, http://www.reactome.org PathwayStep2798 ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431299263 Reactome, http://www.reactome.org PathwayStep2795 ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43194817 Reactome, http://www.reactome.org PathwayStep2796 ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43181683 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431299269 Reactome, http://www.reactome.org PathwayStep2799 ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431299258 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005267 Reactome Database ID Release 431299274 Reactome, http://www.reactome.org PathwayStep301 PathwayStep300 PathwayStep307 PathwayStep306 PathwayStep309 PathwayStep308 PathwayStep303 PathwayStep302 PathwayStep305 PathwayStep304 PathwayStep381 PathwayStep380 PathwayStep379 PathwayStep373 PathwayStep374 PathwayStep371 PathwayStep372 PathwayStep377 PathwayStep378 PathwayStep375 PathwayStep376 PathwayStep370 PathwayStep368 PathwayStep369 PathwayStep360 PathwayStep361 PathwayStep362 PathwayStep363 PathwayStep364 PathwayStep365 PathwayStep366 PathwayStep367 ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43442985 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004016 Reactome Database ID Release 43443463 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43111895 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43444294 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004683 Reactome Database ID Release 43443531 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004683 Reactome Database ID Release 43111914 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005231 Reactome Database ID Release 43432784 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004683 Reactome Database ID Release 43444599 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43443469 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004683 Reactome Database ID Release 43444599 Reactome, http://www.reactome.org PathwayStep359 PathwayStep357 HDAC8 Converted from EntitySet in Reactome Reactome DB_ID: 2545205 Reactome Database ID Release 432545205 Reactome, http://www.reactome.org ReactomeREACT_151192 PathwayStep358 PathwayStep355 PathwayStep356 PathwayStep353 PathwayStep354 PathwayStep351 PathwayStep352 PathwayStep350 ACTIVATION GENE ONTOLOGYGO:0005231 Reactome Database ID Release 43399707 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005231 Reactome Database ID Release 43399707 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005231 Reactome Database ID Release 43399708 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 43442736 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 431063686 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43444233 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005231 Reactome Database ID Release 43399708 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005231 Reactome Database ID Release 43399708 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005231 Reactome Database ID Release 43432784 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005231 Reactome Database ID Release 43432784 Reactome, http://www.reactome.org PathwayStep346 PathwayStep347 PathwayStep348 PathwayStep349 PathwayStep342 PathwayStep343 PathwayStep344 PathwayStep345 PathwayStep340 PathwayStep341 PathwayStep6970 PathwayStep6974 PathwayStep6973 PathwayStep6972 PathwayStep6971 PathwayStep6966 PathwayStep6967 PathwayStep6964 PathwayStep6965 PathwayStep6968 PathwayStep6969 PathwayStep6981 PathwayStep6980 PathwayStep6983 PathwayStep6982 PathwayStep6985 PathwayStep6984 PathwayStep6975 PathwayStep6976 Phosphorylation of Cyclin E1:Cdk2 complexes by Myt1 At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'Cyclin E1:Cdk2 complex' are present. At the end of this reaction, 1 molecule of 'Cyclin E1:phospho-Cdk2 complex', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'kinase activity' of 'Myt1 kinase'.<br> Reactome Database ID Release 4369690 Reactome, http://www.reactome.org ReactomeREACT_1657 PathwayStep6977 Phosphorylation of Cyclin E2:Cdk2 complexes by Myt1 At the beginning of this reaction, 1 molecule of 'Cyclin E2:Cdk2 complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'Cyclin E2:phospho-Cdk2 complex', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'kinase activity' of 'Myt1 kinase'.<br> Reactome Database ID Release 4369691 Reactome, http://www.reactome.org ReactomeREACT_384 PathwayStep6978 Dephosphorylation of Cyclin E:Cdk2 complexes by Cdc25A Authored: Joshi-Tope, G, 2003-06-12 05:55:26 Cdc25A dephosphorylates Cdk2 and activates cyclin E-Cdk2 and cyclin A-Cdk2 kinases (Blomberg and Hoffmann, 1999). EC Number: 3.1.3.16 Edited: Matthews, L, 2003-09-10 06:00:00 Pubmed10454565 Reactome Database ID Release 4369199 Reactome, http://www.reactome.org ReactomeREACT_592 Reviewed: Manfredi, J, 0000-00-00 00:00:00 PathwayStep6979 PP2A mediated localization of RB1 protein in chromatin At the beginning of this reaction, 1 molecule of 'phospho-Retinoblastoma protein', and 1 molecule of 'RNA primer-DNA primer:origin duplex with DNA damage' are present. At the end of this reaction, 1 molecule of 'Rb1:RNA primer-DNA primer:origin duplex with DNA damage' is present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'phosphoprotein phosphatase activity' of 'PP2A'.<br> EC Number: 3.1.3.16 Pubmed14527418 Pubmed17991896 Reactome Database ID Release 43113503 Reactome, http://www.reactome.org ReactomeREACT_421 Replication initiation regulation by Rb1/E2F1 Authored: Gopinathrao, G, 2004-05-26 17:05:00 Reactome Database ID Release 43113643 Reactome, http://www.reactome.org ReactomeREACT_1277 This set of events is inferred from annotated events in Drosophila.<BR><BR>Rb1 is normally hyperphosphorylated by CycD/CDK4/CDK6 and Cyclin E/CDK2 for transition into S-phase. PP2A can then reverse this reaction, in this case, in response to DNA damage induced checkpoint. Activation of Cyclin B/Cdk1 by Cdc25a (string) protein At the end of this reaction, 1 molecule of 'Cyclin B:Cdk1 complex', and 1 molecule of 'Cdc25A' are present. <br><br> This reaction takes place in the 'nucleus'.<br> Pubmed12411508 Reactome Database ID Release 43113505 Reactome, http://www.reactome.org ReactomeREACT_1205 CAK-mediated phosphorylation of Cyclin E:Cdk2 Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-28 04:25:14 Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK kinase activity. The association of p21/p27 with the Cyclin A/E:Cdk2 complex prevents CAK mediated phosphorylation of Cdk2 (Aprelikova et al., 1995). Pubmed7629134 Reactome Database ID Release 43188350 Reactome, http://www.reactome.org ReactomeREACT_9067 Reviewed: Coqueret, O, 2006-10-06 08:59:06 Association of Rb with Cyclin E:Cdk2 complexes Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-10-10 08:05:07 Pubmed9482921 Pubmed9891042 Reactome Database ID Release 43188386 Reactome, http://www.reactome.org ReactomeREACT_9050 Reviewed: Coqueret, O, 2006-10-06 08:59:06 pRB contains, in its C terminus, a cyclin-cdk interaction motif like that found in E2F1 and p21 that enables it to be recognized and phosphorylated by cyclin-cdk complexes. Cyclin E:Cdk2-mediated phosphorylation of Rb Authored: Pagano, M, 2006-09-19 08:23:10 Cyclin E forms a complex with cdk2 and collaborates with the cyclin D-dependent kinases in phosphorylating Rb. EC Number: 2.7.11.22 Edited: Matthews, L, 2006-10-10 08:05:07 Reactome Database ID Release 43188390 Reactome, http://www.reactome.org ReactomeREACT_8993 Reviewed: Coqueret, O, 2006-10-06 08:59:06 Detection of damage during initiation of DNA synthesis in S-phase At the beginning of this reaction, 1 molecule of 'RNA primer-DNA primer:origin duplex' is present. At the end of this reaction, 1 molecule of 'DNA polymerase alpha:primase', and 1 molecule of 'RNA primer-DNA primer:origin duplex with DNA damage' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43113504 Reactome, http://www.reactome.org ReactomeREACT_1408 PathwayStep6996 PathwayStep6995 PathwayStep6994 PathwayStep6993 PathwayStep6992 PathwayStep6991 PathwayStep6990 PathwayStep2706 PathwayStep2707 PathwayStep2704 PathwayStep2705 PathwayStep6988 PathwayStep6989 PathwayStep6986 PathwayStep2708 PathwayStep6987 PathwayStep2709 PathwayStep2702 PathwayStep2703 PathwayStep2700 PathwayStep2701 PathwayStep2715 PathwayStep2716 PathwayStep2717 PathwayStep2718 PathwayStep6997 PathwayStep2719 PathwayStep6998 PathwayStep6999 PathwayStep2710 PathwayStep2711 PathwayStep2712 PathwayStep2713 PathwayStep2714 p130 (RBL2) in complex with E2F4/5:DP1/2 binds to cyclin E/A:CDK2 Authored: Orlic-Milacic, Marija, 2011-06-14 Pubmed9199292 Reactome Database ID Release 431363303 Reactome, http://www.reactome.org ReactomeREACT_111109 Reviewed: MacPherson, D, 2011-08-25 p130 (RBL2) in complex with E2F4/5 and DP1/2 binds to cyclin A or cyclin E in complex with CDK2 through its conserved LFG pocket domain motif and amino terminus, leading to inhibition of CDK2 kinase activity and suppression of cellular growth. Formation of Cyclin D:Cdk4/6 complexes Edited: Matthews, L, 2006-07-03 08:41:56 Pubmed9106657 Reactome Database ID Release 4369213 Reactome, http://www.reactome.org ReactomeREACT_2081 The formation of CyclinD:CDK4/6 complexes is promoted by two proteins, p21Cip1/Waf1 and p27kip1. Activity of the cyclin-dependent kinases 4 and 6 can be inhibited by the binding of several small CDK-inhibitory proteins (CKIs). PathwayStep2725 p130 (RBL2) binds Cyclin E/A:CDK2 Authored: Orlic-Milacic, Marija, 2011-06-14 Pubmed9199292 Reactome Database ID Release 431363306 Reactome, http://www.reactome.org ReactomeREACT_111079 Reviewed: MacPherson, D, 2011-08-25 p130 (RBL2) is able to bind complexes of CDK2 with either cyclin A or cyclin E through the cyclin-binding LFG motif within the pocket domain, which is conserved in p107 (RBL1) and p21/WAF1/Cip1 family of cyclin-dependent kinases. In addition to LFG motif, amino terminal region of p130 (RBL2), conserved in p107 (RBL1), is necessary for inhibition of CDK2 kinase activity. Presence of E2F is not required for this interaction. PathwayStep2724 p107 (RBL1) in complex with E2F4:DP1/2 binds to cyclin E/A:CDK2 Authored: Orlic-Milacic, Marija, 2011-06-14 Pubmed9199292 Reactome Database ID Release 431363311 Reactome, http://www.reactome.org ReactomeREACT_111039 Reviewed: MacPherson, D, 2011-08-25 p107 (RBL1) in complex with E2F4 and DP1/2 binds to cyclin A or cyclin E in complex with CDK2 through its conserved LFG pocket domain motif and amino terminus, leading to inhibition of CDK2 kinase activity and suppression of cellular growth. PathwayStep2723 p107 (RBL1) binds CyclinE/A:CDK2 Authored: Orlic-Milacic, Marija, 2011-06-14 Pubmed9199292 Reactome Database ID Release 431363314 Reactome, http://www.reactome.org ReactomeREACT_111202 Reviewed: MacPherson, D, 2011-08-25 p107 (RBL1) is able to bind complexes of CDK2 with either cyclin A or cyclin E, through cyclin-binding LFG motif in the pocket domain, which is conserved in p130 (RBL2) and p21/WAF1/Cip1 family of cyclin-dependent kinase inhibitors. In addition to the LFG motif, the amino terminal sequence conserved in the p107 (RBL1) and p130 (RBL2) is needed for inhibition of CDK2 kinase activity. Presence of E2F is not required for this interaction. PathwayStep2722 Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 Authored: Orlic-Milacic, Marija, 2011-06-14 In G0 and early G1, expression of E2F target genes such as Cyclin A, E2F1, CDC2 and MYBL2 is inhibited by complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1. Pubmed11959842 Reactome Database ID Release 431362300 Reactome, http://www.reactome.org ReactomeREACT_111173 Reviewed: MacPherson, D, 2011-08-25 PathwayStep2721 Recruitment of HDAC1 by p130 (RBL2) Authored: Orlic-Milacic, Marija, 2011-06-14 HDAC1 + p130(RBL2):E2F4/5:DP1 => HDAC1-p130(RBL2):E2F4/5:DP1 Pubmed9724731 Reactome Database ID Release 431227670 Reactome, http://www.reactome.org ReactomeREACT_111037 Reviewed: MacPherson, D, 2011-08-25 p130 (RBL2) in complex with E2F4 or E2F5 and DP1 or DP2 recruits histone deacetylase HDAC1, probably in complex with other chromatin modification factors, and represses transcription of E2F target promoters during G0 in quiescent cells. PathwayStep2720 Recruitment of HDAC1 by p107 (RBL1) Authored: Orlic-Milacic, Marija, 2011-06-14 HDAC1 + p107(RBL1):E2F4:DP1 => HDAC1-p107(RBL2):E2F4:DP1 Pubmed9724731 Reactome Database ID Release 431227671 Reactome, http://www.reactome.org ReactomeREACT_111090 Reviewed: MacPherson, D, 2011-08-25 p107 (RBL1) in complex with E2F4 and DP1 or DP2 recruits histone deacetylase HDAC1 (possibly in complex with other chromatin modification proteins) through LXCXE-like motif, shared by pocket proteins, to repress transcription of E2F target genes in early G1. Transcription of E2F targets under negative control by DREAM complex Authored: Orlic-Milacic, Marija, 2011-06-14 DREAM complex is evolutionarily conserved and is reponsible for transcriptional repressession of cell cycle-regulated genes in G0 and early G1. Pubmed17531812 Reactome Database ID Release 431362277 Reactome, http://www.reactome.org ReactomeREACT_111167 Reviewed: MacPherson, D, 2011-08-25 p130 (RBL2) associates with MuvB to form DREAM complex Authored: Orlic-Milacic, Marija, 2011-06-14 In G0 and early G1, p130 (RBL2) bound to E2F4 or E2F5 and DP1 or DP2 associates with the MuvB complex, consisting of LIN9, LIN37, LIN52, LIN54 and RBBP4 to form evolutionarily conserved DREAM complex. Phosphorylation of LIN52 on serine residue S28 is critical for association of MuvB complex with p130 (RBL2). Pubmed17531812 Pubmed21498570 Reactome Database ID Release 431362261 Reactome, http://www.reactome.org ReactomeREACT_111236 Reviewed: MacPherson, D, 2011-08-25 PathwayStep2729 PathwayStep2728 PathwayStep2727 PathwayStep2726 Formation of the MCC complex Authored: Yen, T, 2004-05-05 00:00:00 Pubmed11535616 Reactome Database ID Release 43141437 Reactome, http://www.reactome.org ReactomeREACT_36 Reviewed: Peters, JM, 2006-03-27 22:55:09 Upon release from the kinetochore, Mad2 associates with Cdc20, hBUBR1, and hBUB3 to form the Mitotic Checkpoint Complex (MCC). Assembly of this complex does not depend on kinetochores but this complex can only inhibit APC/C that has undergone mitotic modifications. Binding of the MCC complex to the APC/C complex Authored: Yen, T, 2004-05-05 00:00:00 Edited: Matthews, L, 2006-03-07 23:46:51 In the direct inhibition model, association of the MCC with APCC results in the inactivation of APC/C. However, the affinity between MCC and APC/C is not high, so that the inhibition is readily reversible. The role of unattached kinetochores is to sensitize the APC/C to prolonged inhibition by the MCC. Pubmed11535616 Reactome Database ID Release 43141423 Reactome, http://www.reactome.org ReactomeREACT_1951 Reviewed: Peters, JM, 2006-03-27 22:55:09 Phosphorylation of LIN52 component of MuvB by DYRK1A Authored: Orlic-Milacic, Marija, 2011-06-14 LIN52 subunit of MuvB complex is phosphorylated by the protein kinase DYRK1A on the serine residue S28, promoting association of MuvB with p130 (RBL2). From model organism studies, DYRK proteins are known to function in cell cycle regulation, differentiation and stress response. Pubmed21498570 Reactome Database ID Release 431362270 Reactome, http://www.reactome.org ReactomeREACT_111075 Reviewed: MacPherson, D, 2011-08-25 PathwayStep2734 MAD2 converted to an inhibitory state via interaction with Mad1 Authored: Yen, T, 2004-05-05 00:00:00 In vitro structural studies have shown that Mad2 undergoes a major conformational change upon binding to Mad1. This conformational change is postulated to activate Mad2 into a high affinity state which can bind and sequester Cdc20 from the APC. Pubmed11804586 Reactome Database ID Release 43141422 Reactome, http://www.reactome.org ReactomeREACT_2215 PathwayStep2733 MAD2 associates with the Mad1 kinetochore complex Authored: Yen, T, 2004-05-05 00:00:00 Mad2 is recruited to the kinetochore through an interaction with Mad1. Pubmed11181178 Reactome Database ID Release 43141431 Reactome, http://www.reactome.org ReactomeREACT_1922 PathwayStep2736 Inactivation of APC/C via CDC20 sequestration Authored: Yen, T, 2004-05-05 00:00:00 Edited: Matthews, L, 2006-02-17 05:19:32 In the sequestration model, the Mad2 molecules that dissociate from unattached kinetochores are perceived to bind to Cdc20, a protein that recruits specific substrates to the APC/C. Consequently, Mad2 indirectly inhibits the APC/C by sequestering its activator, Cdc20. This requires interaction between Mad1 and Mad2. Cdc20 and Mad1 bind to the same site on Mad2. Reactome Database ID Release 43141429 Reactome, http://www.reactome.org ReactomeREACT_433 Reviewed: Peters, JM, 2006-03-27 22:55:09 PathwayStep2735 Release of activated MAD2 from kinetochores Authored: Yen, T, 2004-05-05 00:00:00 Pubmed12006501 Reactome Database ID Release 43141439 Reactome, http://www.reactome.org ReactomeREACT_88 The mechanism by which the conformationally altered inhibitory form of Mad2 is released from its association with Mad1 at the kinetochore is not known. Mad1 and Cdc20 have a common 10 residue Mad2 binding motif. Therefore, one possibility is that Mad2 is transferred competitively from Mad1 to Cdc20 (Luo et al., 2002; Sironi et al., 2002). PathwayStep2730 Activation of claspin Authored: Borowiec, JA, 2006-02-25 17:40:15 Claspin is a replication fork-associated protein important for Chk1 activation. Claspin loads onto the fork during replication origin firing and travels with the fork during DNA synthesis. Upon fork uncoupling and ATR-ATRIP binding to persistent ssDNA, the activated ATR kinase phosphorylates claspin at two primary sites. Modification increases the affinity of claspin for Chk1. Studies of human or Xenopus claspin indicate that phosphorylation of both sites is essential for significant claspin-Chk1 association. Following claspin modification by ATR, Chk1 can be transiently recruited to the stalled replication fork for subsequent phosphorylation and activation by ATR. Activation of Chk1 allows modification of additional downstream targets, thus amplifying the checkpoint signal. While much of the mechanistic information concerning claspin action has been obtained using Xenopus laevis egg extracts and Xenopus claspin, factors with similar activity have been found in various eukaryotic species including S. cerevisiae (MRC1), S. pombe (mrc1), and humans.<p>Activated ATR phosphorylates human claspin on two sites, threonine 916 and serine 945. EC Number: 2.7.11 Edited: D'Eustachio, P, 2006-02-25 17:41:28 GENE ONTOLOGYGO:0006260 Pubmed11090622 Pubmed12545175 Pubmed12620222 Pubmed15279790 Pubmed15707391 Reactome Database ID Release 43176298 Reactome, http://www.reactome.org ReactomeREACT_6750 has a Stoichiometric coefficient of 2 PathwayStep2732 Mad1 binds kinetochore Authored: Yen, T, 2004-05-05 00:00:00 Pubmed11181178 Reactome Database ID Release 43141409 Reactome, http://www.reactome.org ReactomeREACT_914 The association of Mad1 with the kinetochore is the first step in the process of Mad2 mediated amplification of the signal from defective kinetochores. PathwayStep2731 Phosphorylation of Cdc25C at Ser 216 by Chk1 Authored: Matthews, L, 2003-08-05 01:10:00 EC Number: 2.7.11 Edited: Matthews, L, 2006-07-10 19:19:59 Phosphorylation of Cdc25C at Ser 216 results in both the inhibition of Cdc25C phosphatase activity and the creation of a 14-3-3 docking site (Peng et al. 1997). Pubmed9278512 Reactome Database ID Release 4375010 Reactome, http://www.reactome.org ReactomeREACT_1170 PathwayStep2738 PathwayStep2737 PathwayStep2739 PathwayStep2750 PathwayStep2743 Association of Cks1 with SCF(Skp2) complex Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-19 08:32:00 Pubmed11231585 Pubmed11463388 Reactome Database ID Release 43187545 Reactome, http://www.reactome.org ReactomeREACT_9017 Reviewed: Coqueret, O, 2006-10-06 08:59:06 The accessory protein, Cks1 promotes efficient interaction between phosphorylated p27 and the SCF (Skp2) complex (Ganoth et al., 2001; Spruck et al., 2001). Cks1 binds to Skp2 in the leucine-rich repeat (LRR) domain and C-terminal tail (Hao et al., 2005). The phosphorylated Thr187 side chain of p27 associates with a phosphate binding site on Cks1, and the side chain containing Glu185 is positioned in the interface between Skp2 and Cks1 where it interacts with both (Hao et al., 2005). PathwayStep2742 Cyclin E/A:Cdk2-mediated phosphorylation of p27/p21 Authored: Pagano, M, 2006-09-19 08:23:10 EC Number: 2.7.11.22 Edited: Matthews, L, 2006-09-19 08:32:00 Pubmed10323868 Pubmed10375532 Pubmed10559916 Pubmed15130491 Reactome Database ID Release 43187520 Reactome, http://www.reactome.org ReactomeREACT_8998 Reviewed: Coqueret, O, 2006-10-06 08:59:06 The interaction between the Skp2 subunit of the SCF(Skp2) complex and p27 is dependent upon Cdk2:Cyclin A/E mediated phosphorylation of p27 at Thr 187 (Carrano et al, 1999; Tsvetkov et al, 1999). There is evidence that Cyclin A/B:Cdk1 can also bind and phosphorylate p27 on Thr 187 (Nakayama et al., 2004). This phosphorylation is also essential for the subsequent ubiquitination of p27. PathwayStep2741 Translocation of p27 to the nucleoplasm Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-19 08:32:00 Pubmed9632134 Reactome Database ID Release 43187506 Reactome, http://www.reactome.org ReactomeREACT_9043 p27 translocates to the nucleoplasm where it associates with CyclinE:Cdk2 complexes. Localization of p27 to the nucleus is necessary to inhibit Cdk activation by Cdk-activating kinase. PathwayStep2740 Translocation of p21 to the nucleus Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-21 11:52:25 Pubmed9632134 Reactome Database ID Release 43187828 Reactome, http://www.reactome.org ReactomeREACT_9068 p21 associates with and inhibits Cyclin:Cdk complexes in the nucleus. PathwayStep2747 Phosphorylation of Cyclin E:Cdk2 complexes by Wee-1 Pubmed11585773 Pubmed7743995 Reactome Database ID Release 4369195 Reactome, http://www.reactome.org ReactomeREACT_773 Wee1 phosphorylates Cdk2, inhibiting entry into S-phase (Watanabe et al., 1995; Wu et al., 2001). PathwayStep2746 Degradation of ubiquitinated p27/p21 by the 26S proteasome Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-19 08:32:00 Following ubiquitination by the SCF(Skp2):Cks1 complex, phospho-p27/p21 is degraded by the 26S proteasome. Pubmed10375532 Pubmed10559916 Reactome Database ID Release 43187574 Reactome, http://www.reactome.org ReactomeREACT_9034 Reviewed: Coqueret, O, 2006-10-06 08:59:06 has a Stoichiometric coefficient of 3 PathwayStep2745 Ubiquitination of phospho-p27/p21 Authored: Pagano, M, 2006-09-19 08:23:10 EC Number: 6.3.2.19 Edited: Matthews, L, 2006-09-19 08:32:00 Once in tight contact with the SCF (Skp2):Cks1 complex, phosphorylated p27/p21 is ubiquitinated. Pubmed11231585 Reactome Database ID Release 43187575 Reactome, http://www.reactome.org ReactomeREACT_9026 Reviewed: Coqueret, O, 2006-10-06 08:59:06 has a Stoichiometric coefficient of 3 PathwayStep2744 Binding of phospho-p27/p21:Cdk2:Cyclin E/A to the SCF(Skp2):Cks1 complex Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-19 08:32:00 Pubmed10375532 Pubmed11231585 Pubmed15199159 Pubmed16209941 Reactome Database ID Release 43187552 Reactome, http://www.reactome.org ReactomeREACT_9060 Reviewed: Coqueret, O, 2006-10-06 08:59:06 The association of Cks1 with both Skp2 and phosphorylated p27 promotes a tight interaction between p27 and the SCF complex (Hao et al., 2005). PathwayStep2749 PathwayStep2748 Translocation of Cyclin E:Cdk2 complex to the nucleus Follow their formation, the Cyclin E:Cdk2 complexes are translocated to the nucleus. Pubmed11907280 Reactome Database ID Release 43157906 Reactome, http://www.reactome.org ReactomeREACT_425 Formation of Cyclin E:Cdk2 complexes Pubmed7799941 Reactome Database ID Release 4369191 Reactome, http://www.reactome.org ReactomeREACT_1683 The E-type cyclins and Cyclin Dependent Kinase 2 control the transition from G1 to S phase. Cdk2 is competent to carry out the necessary reactions only when complexed with Cyclin E. Ubiquitination of p130 (RBL2) by SCF (Skp2) As quiescent G0 cells reenter the cell cycle, p130 (RBL2) is phosphorylated by CDK4/6. This phosphorylated p130 (RBL2) binds ubiquitin ligase SCF (Skp2) in complex with Cks1, and is subsequently ubiquitinated and degraded similarly to p27, which is another target of SCF (Skp2). Authored: Orlic-Milacic, Marija, 2011-06-14 EC Number: 6.3.2.19 Pubmed12435635 Reactome Database ID Release 431363331 Reactome, http://www.reactome.org ReactomeREACT_111089 Reviewed: MacPherson, D, 2011-08-25 PathwayStep2760 PathwayStep2761 PathwayStep2752 Cyclin D:Cdk4/6 mediated phosphorylation of Rb and dissociation of phospho-Rb from the E2F1/2/3:DP-1 complexes Cyclin D:Cdk4 mediated phosphorylation of RB1 releases RB1 from the transcriptional regulator E2F and activates E2F function. EC Number: 2.7.11.22 Pubmed9190208 Reactome Database ID Release 4369227 Reactome, http://www.reactome.org ReactomeREACT_1882 PathwayStep2751 Phosphorylation of Cyclin D:Cdk4/6 complexes Authored: O'Connell, M, Walworth, N, 2003-06-05 08:03:09 Edited: Matthews, L, 2005-10-07 06:13:50 Phosphorylation of CDK4 on Thr172 depends on prior D-type cyclin binding (Bockstaele et al., 2006). Pubmed16782892 Reactome Database ID Release 4369223 Reactome, http://www.reactome.org ReactomeREACT_96 Reviewed: Manfredi, J, 0000-00-00 00:00:00 PathwayStep2754 Cyclin D:CDK4/6 mediated phosphorylation of p107 (RBL1) and dissociation of phosphorylated p107 (p-RBL1) from DP1:E2F4 complex Authored: Orlic-Milacic, Marija, 2011-06-14 EC Number: 2.7.11.22 In late G1, cyclin D dependent kinases CDK4 and CDK6 phosphorylate RBL1 (p107) on four serine and threonine residues (S964, S975, T369 and S640), leading to dissociation of phosphorylated RBL1 (p107) from E2F4 in complex with either DP-1 or DP-2. E2F4, which lacks nuclear localization signal, is then thought to translocate to the cytosol, allowing E2F promoter sites to become occupied by activating E2Fs (E2F1, E2F2, and E2F3), resulting in transcription of E2F targets needed for cell cycle progression. Pubmed11884610 Pubmed7797074 Pubmed9144196 Reactome Database ID Release 431226095 Reactome, http://www.reactome.org ReactomeREACT_111248 Reviewed: MacPherson, D, 2011-08-25 has a Stoichiometric coefficient of 4 PathwayStep2753 Association of INK4A with Cdk4/6 Edited: Matthews, L, 2005-10-07 06:13:50 Prior to mitogen activation, the inhibitory proteins, INK4 (p15, p16, p18, and p19) associate with the catalytic domain of free CDK4/6, preventing its association with cyclin, and thus its activation. Pubmed8001816 Pubmed8078588 Pubmed8259215 Pubmed8741839 Reactome Database ID Release 43182594 Reactome, http://www.reactome.org ReactomeREACT_7947 PathwayStep2756 Cyclin D:Cdk4/6 mediated phosphorylation of p130 (RBL2) and dissociation of phosphorylated p130 (RBL2) from DP1:E2F4/5 complex At G1 entry from G0, p130 (RBL2) is phosphorylated on three threonine and serine residues by cyclin D1 dependent kinases CDK4 and/or CDK6, leading to dissociation of p130 (RBL2) from complexes it formed with E2F4 or E2F5 and DP1 or DP2. This is thought to promote translocation of E2F4 and E2F5, which lack nuclear localization signals, to the cytosol, allowing activating E2Fs (E2F1, E2F2 and E2F3) to bind E2F promoters and activate transcription of genes needed for G1 progression. Authored: Orlic-Milacic, Marija, 2011-06-14 EC Number: 2.7.11.22 Pubmed11157749 Pubmed9144196 Reactome Database ID Release 431226094 Reactome, http://www.reactome.org ReactomeREACT_111206 Reviewed: MacPherson, D, 2011-08-25 has a Stoichiometric coefficient of 3 PathwayStep2755 Dephosphorylation of p107 by PP2A Authored: Orlic-Milacic, Marija, 2011-06-14 Dephosphorylation of p107 (RBL1) by PP2A Dephosphorylation of p107 (RBL1) by PP2A complex containing either PPP2R3B (B" beta) or PPP2R2A (B alpha) regulatory subunit plays a role in maintaining the equilibrium of hyperphosphorylated and hypophosphorylated p107 (RBL1), through counteracting action of cyclin dependent kinases (CDKs) throughout the cell cycle. It is assumed that PP2A dephosphorylates p107 (RBL1) on all four phosphorylation sites, but further experiments are needed to confirm this. EC Number: 3.1.3.16 Pubmed20663872 Reactome Database ID Release 431363274 Reactome, http://www.reactome.org ReactomeREACT_111148 Reviewed: Grana, X, 2011-06-15 has a Stoichiometric coefficient of 4 PathwayStep2758 Phosphorylated p130 (RBL2) binds SCF(Skp2):Cks1 complex Authored: Orlic-Milacic, Marija, 2011-06-14 Phosphorylated p130 (RBL2) binds SCF (Skp2) ubiquitin ligase in complex with Cks1. Phosphorylation of p130 (RBL2) serine residue S672 by CDK4/6 is critical for this interaction. Pubmed12435635 Reactome Database ID Release 431363328 Reactome, http://www.reactome.org ReactomeREACT_111194 Reviewed: MacPherson, D, 2011-08-25 PathwayStep2757 Dephosphorylation of p107 by PP2A Authored: Orlic-Milacic, Marija, 2011-06-14 Dephosphorylation of p130 (RBL2) by PP2A Dephosphorylation of p130 (RBL2) by PP2A complex containing either PPP2R3B (B" beta) or PPP2R2A (B alpha) regulatory subunit plays a role in maintaining the equilibrium of hyperphosphorylated and hypophosphorylated p130 (RBL2), through counteracting action of cyclin dependent kinases (CDKs). It is assumed that PP2A dephosphorylates p130 (RBL2) on all three phosphorylation sites, but further experiments are needed to confirm this. EC Number: 3.1.3.16 Pubmed20663872 Reactome Database ID Release 431363276 Reactome, http://www.reactome.org ReactomeREACT_111170 Reviewed: Grana, X, 2011-06-15 has a Stoichiometric coefficient of 3 PathwayStep2759 Translocation of Cyclin D:Cdk4/6 complexes from the cytoplasm to the nucleus Cyclin D:CDK4/6 complexes translocate to the nucleus from the cytoplasm, and this nuclear accumulation is directed by p21/p27 (LaBaer et al. 1997). Edited: Matthews, L, 2006-07-10 19:20:13 Pubmed9106657 Reactome Database ID Release 43141299 Reactome, http://www.reactome.org ReactomeREACT_713 Translocation of Cyclin B1:phospho-Cdc2 to the cytoplasm During interphase, cyclin B1 shuttles continuously in and out of the nucleus. The cyclin B cytoplasmic retention sequence (CRS), which is responsible for its interphase cytoplasmic localization, functions as a nuclear export sequence (Yang et al., 1998). Pubmed9670027 Pubmed9679058 Reactome Database ID Release 43170072 Reactome, http://www.reactome.org ReactomeREACT_6183 Translocation of Cdc25B to the cytoplasm Cdc25B shuttles between the nucleus and the cytoplasm. Translocation out of the nucleus involves a nuclear export sequence in the N-terminus of Cdc25B (Lindqvist et al., 2004). Pubmed15456846 Reactome Database ID Release 43170120 Reactome, http://www.reactome.org ReactomeREACT_6163 Translocation of Cyclin B1:phospho-Cdc2 complexes to the nucleus During interphase, cyclin B1:Cdc2 shuttles continuously in and out of the nucleus. Cyclin B1:Cdc2 is transported into the nucleus by an unusual mechanism that requires importin b but not importin a or Ran. Dissociation of the cyclin-B1:Cdc2:importin complex in the nucleus requires ATP and involves other yet unidentified nuclear factors (Takizawa et al.,1991). Pubmed10393926 Pubmed9670027 Pubmed9679058 Reactome Database ID Release 43170044 Reactome, http://www.reactome.org ReactomeREACT_6345 CAK-mediated phosphorylation of Cyclin B1:Cdc2 complexes Full activity of most CDKs is dependent on CAK mediated phosphorylation at a conserved residue (Thr 161 in Cdc2). This modification is thought to improve substrate binding. Cyclin B:Cdc2 complexes have considerably low activity in the absence of CAK mediated phosphorylation (Desai et al 1995). Pubmed7799941 Reactome Database ID Release 43170076 Reactome, http://www.reactome.org ReactomeREACT_6314 Translocation of Cdc25 to the nucleus Pubmed11063929 Pubmed11313932 Pubmed15456846 Pubmed15572030 Reactome Database ID Release 43170159 Reactome, http://www.reactome.org ReactomeREACT_6156 The localization of the Cdc25A, B and C proteins is dynamic involving the shuttling of these proteins between the nucleus and the cytoplasm. Sequences in these proteins mediate both nuclear export and import (Kallstrom et al., 2005; Lindqvist et al., 2004; Graves et al, 2001; Takizawa and Morgan, 2000). Translocation of CRS phosphorylated Cyclin B1:Cdc2 complexes Pubmed10395539 Reactome Database ID Release 43170131 Reactome, http://www.reactome.org ReactomeREACT_6343 The rapid translocation of cyclin B1:Cdc2 from the cytoplasm to the nucleus at the onset of mitosis is a result of an increase in the rate of import and, likely, a decreased rate of export. The increased rate of nuclear import is dependent upon phosphorylation of the CRS which creates a nuclear import signal in the amino terminus of cyclin B1 (Hagting et al, 1999). Phosphorylation of Cyclin B1 in the CRS domain At the onset of mitosis, cyclin B is phosphorylated in the CRS sequence which creates a nuclear import signal in the amino terminus. The kinase(s) responsible for this phosphorylation are not yet known (Hagting et al., 1999). Pubmed10395539 Reactome Database ID Release 43170126 Reactome, http://www.reactome.org ReactomeREACT_6353 has a Stoichiometric coefficient of 4 Dephosphorylation of cytoplasmic Cyclin B1:phospho-Cdc2 (Thr 14, Tyr 15) complexes by Cdc25 phosphatases Activation of the mitotic cyclin:Cdc2 complexes at mitosis requires the removal of the inhibitory phosphate groups on Cdc2. This dephosphorylation is achieved by the activity of the Cdc25 family of phosphatases. The Cdc25 members, Cdc25A, Cdc25B, and Cdc25C are kept inactive during interphase and are activated at the G2/M transition. Cyclin B1:Cdc2 itself appears to participate in the full activation of Cdc25 in a process that involves an amplication loop (see Wolfe and Gould, 2004). The initial activation of the cyclin B1-Cdc2 complex occurs in the cytoplasm in prophase (Jackman et al., 2003). Cdc25B, which is present at highest concentrations in the cytoplasm at this time, is thought to trigger the activation of cyclin B1-Cdc2 (Lindqvist et al. 2004; Honda et al., 1993). Active cyclin B:Cdc2 then phosphorylates and activates Cdc25C and stabilizes Cdc25A (Strausfeld et al., 1994; Hoffman et al.,1993; Mailand et al, 2002). This creates positive feedback loops that allows Cdc25A and Cdc25C to dephosphorylate and further activate Cdc2. EC Number: 3.1.3.16 Pubmed10827953 Pubmed12411508 Pubmed12524548 Pubmed15107615 Pubmed15456846 Pubmed8119945 Pubmed8428594 Pubmed8440392 Reactome Database ID Release 43170161 Reactome, http://www.reactome.org ReactomeREACT_6257 has a Stoichiometric coefficient of 2 Phosphorylation of M phase proteins by active Cyclin B1:Cdc2 complexes A description of the mitotic proteins targeted by the mitotic cyclin:CDK complexes will be covered in a later release. EC Number: 2.7.11.22 Reactome Database ID Release 43170157 Reactome, http://www.reactome.org ReactomeREACT_6338 Dephosphorylation of nuclear Cyclin B1:phospho-Cdc2 (Thr 14, Tyr15) complexes by Cdc25 phosphatases EC Number: 3.1.3.16 Following its translocation to the nucleus, Cdc25 dephosphorylates and activates nuclear cyclin B1:Cdc2 complexes (Strausfeld et al., 1991). Pubmed1828290 Reactome Database ID Release 43170153 Reactome, http://www.reactome.org ReactomeREACT_6255 has a Stoichiometric coefficient of 2 Dephosphorylation of cyclin B2:phospho-Cdc2 (Thr 14) by Cdc25 At the beginning of this reaction, 1 molecule of 'Cyclin B2:phospho-Cdc2(Thr 14, Thr 161)', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of 'Cyclin B2:phospho-Cdc2(Thr 161)', and 1 molecule of 'Orthophosphate' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'phosphoprotein phosphatase activity' of 'Cdc25'.<br> EC Number: 3.1.3.16 Reactome Database ID Release 43170162 Reactome, http://www.reactome.org ReactomeREACT_6175 Phosphorylation of proteins involved in G2/M transition by active Cyclin B2:Cdc2 complexes EC Number: 2.7.11.22 Pubmed10395539 Pubmed10559878 Pubmed11238451 Pubmed1717476 Pubmed7737117 Pubmed9539739 Pubmed9582266 Pubmed9670027 Pubmed9679058 Reactome Database ID Release 4369759 Reactome, http://www.reactome.org ReactomeREACT_852 Substrate specificity of cyclin B:Cdk1 complexes is primarily conferred by their subcellular localization (Draviam et al., 2001).<br>Cyclin B1 is primarily cytoplasmic but shuttles continuously between the nucleus and the cytoplasm during interphase (Hagting et al. 1998 Down; Toyoshima et al. 1998 Down; Yang et al. 1998 Down). At the end of prophase, it abruptly translocates into the nucleus (Furuno et al. 1999 Down; Hagting et al. 1999 Down) and then associates with mitotic apparatus (Pines and Hunter 1991 Down; Hagting et al. 1998 Down; Clute and Pines 1999 Down). Cyclin B2 is primarily associated with the Golgi apparatus during interphase and mitosis (Jackman et al. 1995 Down; Brandeis et al. 1998 Down). Cyclin B1–CDK1 promotes chromosome condensation, reorganization microtubule reorgnization, and disassembly of the nuclear lamina and the Golgi apparatus. Cyclin B2–CDK1 functions in disassembly of the Golgi apparatus (Draviam et al., 2001).<br><br> Inactivation of Wee1 kinase *Plk1 is shown to phosphorylate Wee1A, an event that is likely critical for recognition and ubiquitination of Wee1A by SCF and therefore for the subsequent degradation of Wee1A . **Plk1 phosphorylates Wee1A at S53, creating the second phosphodegron, PD53. ** Evidence also exists in budding yeast that the budding yeast polo homolog Cdc5 directly phosphorylates and down-regulate the budding yeast Wee1 ortholog Swe1. Thus, polo kinase-dependent phosphorylation and degradation of Wee1A (or Swe1) is likely conserved throughout evolution and is critical for normal mitotic entry. Authored: Watanabe, N, Hunter, T, 2008-05-07 23:35:33 EC Number: 2.7.11 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0051726 Pubmed15037762 Pubmed15070733 Pubmed7681363 Pubmed8515817 Reactome Database ID Release 43156699 Reactome, http://www.reactome.org ReactomeREACT_1944 Activation of Cdc25C Authored: Lee, KS, 2004-12-08 21:18:23 EC Number: 2.7.11 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0051726 It has been shown that Xenopus polo homolog,Plx1, directly phosphorylates and activates Cdc25C, which in turn dephosphoryates and activates Cdc2. This step is critical for the onset of mitosis. Since Plx1-dependent Cdc25C phosphorylation occurs in the absence of Cdc2 activity, it is likely that Plx1 is a triggering kinase, which leads to the activation of Cdc2 and therefore the normal onset of mitosis. Pubmed11408585 Pubmed11897663 Pubmed8703070 Reactome Database ID Release 43156678 Reactome, http://www.reactome.org ReactomeREACT_2119 Inactivation of Myt1 kinase At mitotic entry Plk1 phosphorylates and inhibits Myt1 activity. Cyclin B1-bound Cdc2, which is the target of Myt1, functions in a feedback loop and phosphorylates and further inhibits Myt1. Authored: Lee, KS, 2004-12-08 21:18:23 EC Number: 2.7.11 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0051726 Pubmed12738781 Pubmed15692562 Reactome Database ID Release 43162657 Reactome, http://www.reactome.org ReactomeREACT_414 Recruitment of Plk1 to centrosomes Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-09 05:12:41 Plk1 is associated with the centrosomes early in mitosis (Golsteyn et al. 1995). Plk1 activity is necessary for the maturation of centrosomes at the G2/M transition and the establishment of a bipolar spindle (Lane and Nigg 1996). Specific inhibitors against Plk1 or silencing of Plk1 produce a monopolar mitotic apparatus (Sumara et al, 2004, van Vugt et al, 2004, McInnes et al, 2006, Peters et al, 2006, Lénárt et al, 2007). Pubmed15210710 Pubmed15458642 Pubmed17028580 Pubmed17028581 Pubmed17291761 Pubmed7790358 Pubmed8991084 Reactome Database ID Release 43380311 Reactome, http://www.reactome.org ReactomeREACT_15470 Reviewed: Merdes, A, 2008-11-17 13:55:29 Recruitment of CDK11p58 to the centrosomes Authored: Matthews, L, 2008-11-11 14:53:40 CDK11p58 is a kinase that is active during mitosis when it associates with centrosomes, and has a crucial role in centrosome maturation and bipolar spindle formation (Petretti et al., 2006). CDK11p58 facilitates microtubule nucleation and is required for the recruitment of Aurora and Plk1 to the centrosome (Petretti et al., 2006). Edited: Matthews, L, 2008-11-11 14:53:40 Pubmed16462731 Reactome Database ID Release 43380455 Reactome, http://www.reactome.org ReactomeREACT_15401 Reviewed: Merdes, A, 2008-11-17 13:55:29 Translocation of NuMA to the centrosomes Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-12 17:55:26 Pubmed8838651 Reactome Database ID Release 43380508 Reactome, http://www.reactome.org ReactomeREACT_15444 Reviewed: Merdes, A, 2008-11-17 13:55:29 The mechanism by which human NuMA is translocated to the centrosomes has not yet been determined. Cyclin B/Cdk1 mediate phosphorylation of NuMA After the initiation of DNA condensation during mitosis, NuMA is phosphorylated by Cdc2 kinase and transported rapidly to the centrosomal region (Hsu and Yeh, 1996). Another phosphorylation event occurs when NuMA associates with the mitotic spindle (Gaglio et al., 1995; Hsu and Yeh, 1996). While p34cdc2/cyclin B-dependent phosphorylation appears to plays an essential role in the targeting of NuMA to the spindle apparatus (Compton and Luo, 1995)(Hsu and Yeh, 1996), there may be additional protein kinases that promote the release of NuMA from the nuclear compartment at nuclear envelope breakdown (Saredi et al., 1997). Authored: Matthews, L, 2008-11-11 14:53:40 EC Number: 2.7.11.22 Edited: Matthews, L, 2008-11-09 05:12:41 Pubmed7593190 Pubmed7769006 Pubmed8838651 Pubmed9202389 Reactome Database ID Release 43380278 Reactome, http://www.reactome.org ReactomeREACT_15543 Reviewed: Merdes, A, 2008-11-17 13:55:29 Association of NuMA with microtubules Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-09 05:12:41 Edited: Matthews, L, 2008-11-24 13:58:10 NuMA can interact with microtubules by direct binding to tubulin. Binding occurs through amino acids 1868-1967 of human NuMA (tail IIA) and appears to play a role in the organization of the spindle poles by stably crosslinking microtubule fibers (Haren and Merdes 2002). While the exact mechanism of microtubule bundling is not known, NuMA has been shown to form large fibrous networks (Saredi et al., 1996; Gueth-Hallonet et al., 1998; Harborth et al., 1999) apparently as a result of dimerization of the NuMA rod domains followed by association of multiple NuMA dimers through their tail domains. Pubmed10075938 Pubmed11956313 Pubmed8907707 Pubmed9743603 Reactome Database ID Release 43380316 Reactome, http://www.reactome.org ReactomeREACT_15294 Reviewed: Merdes, A, 2008-11-17 13:55:29 Phosphorylation of GORASP1, GOLGA2 and RAB1A by CDK1:CCNB Authored: Orlic-Milacic, M, 2012-07-20 EC Number: 2.7.11.22 Edited: Gillespie, ME, 2012-08-07 GORASP1 (GRASP65) and GOLGA2 (GM130) form a complex on cis-Golgi membranes. RAB1A or RAB1B, small RAS GTP-ases, can also associate with this complex through interaction with GOLGA2 (Moyer et al. 2001, Weide et al. 2001). GOLGA2 provides a docking site for the USO1 (p115) homodimer (Nakamura et al. 1995, Seeman et al. 2000). RAB1 also participates in this interaction and facilitates it when in the GTP-bound state (Moyer et al. 2001). Binding of USO1 to GORASP1:GOLGA2:RAB1:GTP complex enables fusion of vesicles originating in the endoplasmic reticulum (ER) with cisternae of cis-Golgi. <br> In mitotic prophase, CDK1 (CDC2) in complex with either CCNB1 (cyclin B1) or CCNB2 (cyclin B2), as both CCNB1 and CCNB2 can localize to Golgi (Jackman et al. 1995, Draviam et al. 2001), phosphorylates GORASP1, GOLGA2 and RAB1 (Bailly et al. 1991, Lowe et al. 1998, Preisinger et al. 2005). Phosphorylation of GOLGA2 and RAB1 impairs their association with USO1, which inhibits thethering and subsequent fusion of ER-originating vesicles with cis-Golgi cisternae, resulting in cessation of ER to Golgi protein trafficking at the start of mitosis and increase in the number of Golgi trafficking vesicles at the expense of Golgi cisternae (Lowe et al. 1998, Seeman et al. 2000, Moyer et al. 2001, Diao et al. 2008). Pubmed10679020 Pubmed11238451 Pubmed11285137 Pubmed11306556 Pubmed15678101 Pubmed18167358 Pubmed1902553 Pubmed7737117 Pubmed9150144 Pubmed9753325 Reactome Database ID Release 432172183 Reactome, http://www.reactome.org ReactomeREACT_147845 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Malhotra, Vivek, 2012-08-15 Reviewed: Wang, Yanzhuang, 2012-08-19 has a Stoichiometric coefficient of 5 GOLGA2 phosphorylated by CDK1 is unable to promote fusion of ER to Golgi transport vesicles with cis-Golgi Authored: Orlic-Milacic, M, 2012-07-20 Edited: Gillespie, ME, 2012-08-07 Pubmed10679020 Pubmed18167358 Pubmed9753325 Reactome Database ID Release 432314569 Reactome, http://www.reactome.org ReactomeREACT_147730 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Malhotra, Vivek, 2012-08-15 Reviewed: Wang, Yanzhuang, 2012-08-19 USO1 (p115) protein, localizing to membranes of ER to Golgi transport vesicles, binds GOLGA2 (GM130), localizing to membranes of cis-Golgi cisternae. Binding of USO1 to GOLGA2 enables tethering of ER to Golgi transport vesicles to cis-Golgi cisternae, and is facilitated by a Ras-related GTPase RAB1. Fusion of ER to Golgi transport vesicles with cis-Golgi succeeds tethering and depends on STX5 (syntaxin-5). In mitosis, phosphorylation of GOLGA2 by cyclin B-activated CDK1 prevents USO1 docking. This results in cessation of ER to Golgi transport. Halting ER to Golgi transport increases the number of transport vesicles at the expense of Golgi cisternae, since transport vesicles keep budding from the ER but are unable to fuse with Golgi cisternae and deliver their content (Lowe et al. 1998, Seeman et al. 2000, Diao et al. 2008). Plk1-mediated phosphorylation of Nlp Authored: Matthews, L, 2008-11-11 14:53:40 EC Number: 2.7.11 Edited: Matthews, L, 2008-11-09 05:12:41 Phosphorylation of NlP by Plk1 regulates the interaction of Nlp with both centrosomes and ?-TuRCs (Casenghi et al., 2003). Pubmed12852856 Reactome Database ID Release 43380272 Reactome, http://www.reactome.org ReactomeREACT_15386 Reviewed: Merdes, A, 2008-11-17 13:55:29 Dissociation of Phospho-Nlp from the centrosome Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-09 05:12:41 Mitotic activation of Plk1 is required for efficient displacement of Nlp from the centrosome (Casenghi et al., 2003). Pubmed12852856 Reactome Database ID Release 43380303 Reactome, http://www.reactome.org ReactomeREACT_15440 Reviewed: Merdes, A, 2008-11-17 13:55:29 Recruitment of additional gamma tubulin/ gamma TuRC to the centrosome Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-09 05:12:41 Microtubule nucleation at the centrosome is mediated by the gamma tubulin ring complex (gamma TuRC) (reviewed in Raynaud-Messina and Merdes, 2006; Wiese and Zheng, 2006). In humans, this large complex contains the tubulin superfamily member gamma-tubulin, five gamma complex proteins (GCP2-GPC6) and NEDD1/GCP-WD. A current model of the arrangement of subunits within the gamma-TuRC proposes that 6-7 TuSC subcomplexes are held together by the other Grip proteins (at an unknown stoichiometry), which together form the cap subunits. In many animal cells, the recruitment of gamma-tubulin complexes to the centrosome rapidly increases (3–5 fold ) before mitosis  to support the formation of new spindle microtubules (Khodjakov and Rieder 1999).  NEDD1/GCP-WD  plays  an essential role in recruitment of these complexes to the centrosomes (Haren et al., 2006;  Luders et al., 2006) and to the mitotic spindle (Luders et al., 2006). GCP-WD/NEDD1  associates directly with the  gamma-TuRC.  The carboxy-terminal half  binds to the gamma-TuRC whereas the amino-terminal half, corresponding to the WD-repeat domain,  is responsible for its attachment to the centrosome (Haren et al., 2006). Additional centrosomal proteins have also been implicated in the docking of gamma-TuRC to the centrosomes. CG-NAP/AKAP450  and kendrin  are  necessary for the initiation of microtubule nucleation and interact  with GCP2/GCP3 and GCP2, respectively (Takahashi et al., 2002).  Pericentrin  plays an important role in  microtubule organization in mitotic cells and anchors gamma- TuRC through domains that bind GCP2 and GCP3  (Zimmerman  et al. 2004). Ninein localizes to the centriole via its C-terminus and interacts with gamma-tubulin-containing complexes via its N-terminus. Pubmed10444067 Pubmed12221128 Pubmed15146056 Pubmed16378099 Pubmed16461362 Pubmed17038541 Pubmed17178454 Reactome Database ID Release 43380283 Reactome, http://www.reactome.org ReactomeREACT_15467 Reviewed: Merdes, A, 2008-11-17 13:55:29 Loss of C-Nap-1 from centrosomes Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-25 15:37:17 Pubmed11076968 Pubmed12140259 Pubmed9647649 Reactome Database ID Release 43380294 Reactome, http://www.reactome.org ReactomeREACT_15313 Reviewed: Merdes, A, 2008-11-17 13:55:29 The centrosomal protein C-Nap1 is thought to play an important role in centrosome cohesion during interphase (Fry et al.,1998). At the onset of mitosis, when centrosomes separate to form the bipolar spindle, C-Nap1 dissociates (Mayor et al., 2000). Dissociation of C-Nap1 from mitotic centrosomes appears to be regulated by phosphorylation (Mayor et al. 2002). GORASP1 phosphorylated by PLK1 and GORASP2 phosphorylated by MAPK3-3/MAPK1 are unable to promote Golgi cisternae stacking Adjacent cisternae of the Golgi apparatus are stacked and linked by tubules to from a Golgi ribbon (Nakamura et al. 2012). GORASP1 (GRASP65), a protein localizing to membranes of cis-Golgi cisternae, enables stacking by in trans dimerization/oligomerization through its PDZ domains (Tang et al. 2010). In mitosis, GORASP1 is phosphorylated by CDK1 and PLK1 (Preisinger et al. 2005). PLK1-mediated phosphorylation of GORASP1 prevents stacking of Golgi cisternae and contributes to unlinking and fragmentation of the Golgi apparatus, probably by interfering with GORASP1 oligomerization (Wang et al. 2003, Sengupta and Linstedt 2010). Similarly, GORASP2 (GRASP55), localized to median Golgi cisternae, promotes stacking by trans-oligomerization. Trans-oligomerization of GORASP2 is prevented by mitotic phosphorylation of GORASP2 downstream of MEK/ERK cascade, and contributes to the Golgi fragmentation in prophase (Xiang and Wang 2010). Authored: Orlic-Milacic, M, 2012-07-20 Edited: Gillespie, ME, 2012-08-07 Pubmed12839990 Pubmed15678101 Pubmed20083603 Pubmed20214750 Pubmed20937827 Pubmed22726585 Reactome Database ID Release 432314566 Reactome, http://www.reactome.org ReactomeREACT_147809 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Malhotra, Vivek, 2012-08-15 Reviewed: Wang, Yanzhuang, 2012-08-19 MAPK3-3 or MAPK1 phosphorylate GORASP2 Authored: Orlic-Milacic, M, 2012-07-20 EC Number: 2.7.11 Edited: Gillespie, ME, 2012-08-07 GORASP2 (GRASP55) localizes to the median region of Golgi, where it forms a complex with BLZF1 (Golgin 45) and RAB2A GTPase (Short et al. 2001). Similar to GORASP1, GORASP2 is involved in the maintenance of Golgi structure and positively regulates stacking of Golgi cisternae (Xiang and Wang 2010). In addition, GORASP2, probably through its association with RAB2A GTPase, regulates trafficking through the Golgi (Short et al. 2001). In G2 and mitotic prophase, GORASP2 is phosphorylated by MEK1/2 activated MAP kinases. Monophosphorylated MAPK3 (ERK1) isoform, MAPK3 3 i.e. ERK1b (known as ERK1c in rat), likely activated by a MEK1 isoform MEK1b (Shaul et al. 2009), as well as MAPK1 (ERK2) are implicated in GORASP2 phosphorylation during mitosis (Jesch et al. 2001, Colanzi et al. 2003, Shaul and Seger 2006, Feinstein and Linstedt 2007, Duran et al. 2008, Feinstein and Linstedt 2008). Threonine residues T222 and T225 were implicated as targets of MAPK mediated GORASP2 phosphorylation in studies that used directional mutagenesis (Jesch et al. 2001, Feinstein and Linstedt 2008). However both T222 and T225 were simultaneously mutated in these studies and their roles have not been individually investigated. Using mass spectroscopy, T225 but not T222 was identified as a GORASP2 residue phosphorylated by mitotic cytosol (Duran et al. 2008). T249 residue of GORASP2 was also phosphorylated by mitotic cytosol, but the involvement of ERKs in T249 phosphorylation has not been examined (Duran et al. 2008). Pubmed11408587 Pubmed11739401 Pubmed12695496 Pubmed16533948 Pubmed17182854 Pubmed18385516 Pubmed18434598 Pubmed19651986 Pubmed20083603 Reactome Database ID Release 432422927 Reactome, http://www.reactome.org ReactomeREACT_147850 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Malhotra, Vivek, 2012-08-15 Reviewed: Wang, Yanzhuang, 2012-08-19 has a Stoichiometric coefficient of 2 PLK1 phosphorylates GORASP1 Activation of the Anaphase Promoting Complex (APC) by PLK1 Authored: Lee, KS, 2004-12-08 21:18:23 CDK1-mediated phosphorylation of GORASP1 (GRASP65) enables GORASP1 to recruit PLK1 (Preisinger et al. 2005). PLK1 phosphorylates GORASP1 on serine residue S189 (Sengupta and Linstedt 2010). This serine residue is near the GORASP1 region involved in GORASP1 dimerization and oligomerization, a process underlying the stacking of cis-Golgi cisternae (Wang et al. 2003). The phosphorylation of S189 by PLK1 impairs Golgi cisternae stacking (tethering), contributing to Golgi unlinking and fragmentation in mitosis, probably by preventing formation of GORASP1 dimers and oligomers (Sutterlin et al. 2001, Sengupta and Linstedt, 2010). Two other potential phosphorylation sites that match PLK1 substrate consensus sequence exist in GORASP1, but their functional significance has not yet been examined (Sengupta and Linstedt, 2010). Edited: Gillespie, ME, 2005-04-04 01:40:57 GENE ONTOLOGYGO:0007092 Pubmed11447294 Pubmed12839990 Pubmed15678101 Pubmed20937827 Reactome Database ID Release 432214351 Reactome, http://www.reactome.org ReactomeREACT_147881 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Malhotra, Vivek, 2012-08-15 Reviewed: Wang, Yanzhuang, 2012-08-19 Recruitment of PLK1 to phosphorylated GORASP1 (GRASP65) Authored: Orlic-Milacic, M, 2012-07-20 Edited: Gillespie, ME, 2012-08-07 Phosphorylation of GORASP1 (GRASP65) by cyclin B-associated CDK1 creates a docking site for PLK1. PLK1 is also able to bind to CDK1-phosphorylated RAB1, but not to CDK1-phosphorylated GOLGA2 (Preisinger et al. 2005). Pubmed15678101 Reactome Database ID Release 432172194 Reactome, http://www.reactome.org ReactomeREACT_147849 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Malhotra, Vivek, 2012-08-15 Reviewed: Wang, Yanzhuang, 2012-08-19 p-S62-ARPP19/p-S67-ENSA binds PP2A-PPP2R2D ARPP19 and ENSA, activated by MASTL (GWL) mediated phosphorylation, bind and inhibit PP2A complexed with the regulatory subunit PPP2R2D (B55-delta). Inhibition of PP2A-PPP2R2D phosphatase activity allows mitotis entry and mainetance by preventing dephosphorylation of CDK1 mitotic targets (Mochida et al. 2010, Gharbi-Ayachi et al. 2010). Authored: Orlic-Milacic, M, 2012-09-04 Edited: Gillespie, ME, 2012-09-14 Pubmed21164013 Pubmed21164014 Reactome Database ID Release 432430552 Reactome, http://www.reactome.org ReactomeREACT_150301 Reviewed: Burgess, A, 2012-09-28 Reviewed: Mochida, Satoru, 2012-09-26 Kinetochore capture of astral microtubules Authored: Matthews, L, 2008-08-24 03:27:07 Edited: Matthews, L, 2008-08-24 03:27:07 Pubmed11553716 Pubmed16622419 Pubmed16622420 Pubmed17030981 Pubmed17129783 Pubmed18097444 Reactome Database ID Release 43375302 Reactome, http://www.reactome.org ReactomeREACT_14798 Reviewed: Cheeseman, IM, 2008-09-02 04:22:10 The human kinetochore, is a complex proteinaceous structure that assembles on centromeric DNA and mediates the association of mitotic chromosomes with spindle microtubules in prometaphase. The molecular composition of the human kinetochore is reviewed in detail in Cheeseman et al., 2008. This complex structure is composed of numerous protein complexes and networks including: the constitutive centromere-associated network (CCAN) containing several sub-networks such as (CENP-H, I, K), (CENP-50/U, O, P, Q, R), the KMN network (containing KNL1, the Mis12 complex, and the Ndc80 complex), the chromosomal passenger complex, the mitotic checkpoint complex, the nucleoporin 107-160 complex and the RZZ complex. <br>At prometaphase, following breakdown of the nuclear envelope, the kinetochores of condensed chromosomes begin to interact with spindle microtubules. In humans, 15-20 microtubules are bound to each kinetochore (McEwen et al., 2001), and the attachment of 15 microtubules to the kinetochore is shown in this reaction. Recently, it was found that the core kinetochore-microtubule attachment site is within the KMN network and is likely to be formed by two closely apposed low-affinity microtubule-binding sites, one in the Ndc80 complex and a second in KNL1 (Cheeseman et al., 2006). has a Stoichiometric coefficient of 15 CDK1 phosphorylates CDCA5 (Sororin) at chromosomal arms Authored: Orlic-Milacic, M, 2012-10-02 EC Number: 2.7.11.22 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Phosphorylation of CDCA5 (Sororin) coincides with dissociation of CDCA5 from chromosomal arms in prometaphase. Several serine and threonine residues in CDCA5 are phosphorylated by CDK1 in prometaphase, but only the three sites that perfectly match the CDK1 consensus phosphorylation sequence are shown here - serines S21 and S75 and threonine T159 (Drier et al. 2011, Zhang et al. 2011). Pubmed21878504 Pubmed21987589 Reactome Database ID Release 432468293 Reactome, http://www.reactome.org ReactomeREACT_150454 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 3 Phosphorylation of cohesin by PLK1 at chromosomal arms Authored: Lee, KS, 2004-12-08 21:18:23 EC Number: 2.7.11 Edited: Gillespie, ME, 2005-04-12 04:40:16 GENE ONTOLOGYGO:0007062 Prior to anaphase onset, sister-chromatids are held together by cohesin complexes. PLK1-dependent phosphorylation of the cohesin subunit STAG2 (SA2) (Hauf et al. 2005) promotes dissociation of cohesins from chromosomal arms in prometaphase (Hauf et al. 2001). Besides phosphorylating STAG2, PLK1 also phosphorylates RAD21 cohesin subunit, but the phosphorylation of RAD21 is not required for the dissociation of cohesin from chromosomal arms in early mitosis (Hauf et al. 2005). There are several potential PLK1 phosphorylation sites in STAG2 and RAD21, but the exact positions of in vivo phosphorylation of STAG2 and RAD21 by PLK1 have not been explicitly established (Hauf et al. 2005). It is likely that the phosphorylation of cohesin-bound CDCA5 (Sororin) by CDK1 creates a docking site for PLK1 at threonine T159 of CDCA5, thus enabling PLK1 to phosphorylate cohesin subunits (Zhang et al. 2011). Pubmed11509732 Pubmed11931760 Pubmed15241476 Pubmed15737063 Pubmed21987589 Reactome Database ID Release 432466068 Reactome, http://www.reactome.org ReactomeREACT_150246 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 2 CDK1 phosphorylates MASTL At the beginning of mitosis, MASTL (GWL, Greatwall kinase) is activated by phosphorylation at several key sites. Many of these sites, including functionally important threonine residues T194, T207 and T741 (corresponding to Xenopus residues T193, T206 and T748), are proline directed, matching CDK1 consensus sequence, and thus probably phosphorylated by CDK1, as shown by in vitro studies (Yu et al. 2006. Blake-Hodek et al. 2012). Phosphorylation of the serine residue S875 (S883 in Xenopus) is implicated as critical for the mitotic function of MASTL (Vigneron et al. 2011) and likely occurs through autophosphorylation (Blake-Hodek et al. 2012). Other kinases, such as PLK1 (Vigneron et al. 2011) and other MASTL phosphorylation sites may also be involved in mitotic activation of MASTL (Yu et al. 2006, Vigneron et al. 2011, Blake-Hodek et al. 2012). Phosphorylation of the serine residue S102 (S101 in Xenopus) is functionally important but the responsible kinase has not been identified (Blake-Hodek et al. 2012). Authored: Orlic-Milacic, M, 2012-09-04 EC Number: 2.7.11.22 Edited: Gillespie, ME, 2012-09-14 Pubmed16600872 Pubmed21444715 Pubmed22354989 Reactome Database ID Release 432430533 Reactome, http://www.reactome.org ReactomeREACT_150461 Reviewed: Burgess, A, 2012-09-28 Reviewed: Mochida, Satoru, 2012-09-26 has a Stoichiometric coefficient of 3 MASTL (GWL) phosphorylates ARPP19 Authored: Orlic-Milacic, M, 2012-09-04 EC Number: 2.7.11 Edited: Gillespie, ME, 2012-09-14 MASTL (GWL i.e. Greatwall kinase) phosphorylates ARPP19 on serine residue S62 (Gharbi-Ayachi et al. 2010). S62 of human ARPP19 corresponds to serine residue S67 of Xenopus Arpp19, which is phosphorylated by Xenopus Mastl (Mochida et al. 2010). Pubmed21164013 Pubmed21164014 Reactome Database ID Release 432168079 Reactome, http://www.reactome.org ReactomeREACT_150326 Reviewed: Burgess, A, 2012-09-28 Reviewed: Mochida, Satoru, 2012-09-26 MASTL phosphorylates ENSA Authored: Orlic-Milacic, M, 2012-09-04 EC Number: 2.7.11 Edited: Gillespie, ME, 2012-09-14 MASTL (GWL) activates ENSA by phosphorylating it on serine residue S67 (Mochida et al. 2010, Gharbi-Ayachi et al. 2010). Pubmed21164013 Pubmed21164014 Reactome Database ID Release 432430535 Reactome, http://www.reactome.org ReactomeREACT_150207 Reviewed: Burgess, A, 2012-09-28 Reviewed: Mochida, Satoru, 2012-09-26 Deacetylation of cohesin Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 HDAC8 deacetylates cohesin in prometaphase, after cohesin dissociates from chromosomal arms (Deardorff et al. 2012). Pubmed22885700 Reactome Database ID Release 432545253 Reactome, http://www.reactome.org ReactomeREACT_150215 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 2 Resolution of sister chromatids Authored: Orlic-Milacic, M, 2012-10-02 Cohesin complexes dissociate from chromosomal arms in prometaphase, leading to sister chromatid resolution. Sister chromatid resolution involves separation of sister chromosomal arms while cohesion at sister centromeres persists (Losada et al. 1998, Hauf et al. 2001, Hauf et al. 2005). Cohesin and CDCA5 (Sororin) simultaneously dissociate from chromosomal arms in prometaphase (Nishiyama et al. 2010, Zhang et al. 2011). This process, triggered by CDK1-mediated phosphorylation of CDCA5 (Dreier et al. 2011, Zhang et al. 2011) and PLK1-mediated phosphorylation of the STAG2 cohesin subunit (Hauf et al. 2005), is controlled by WAPAL (Gandhi et al. 2006, Kueng et al. 2006, Shintomi and Hirano 2009). WAPAL controls cohesion of sister chromatids likely through competing with CDCA5 for binding to cohesin-associated PDS5 (PDS5A and PDS5B) (Nishiyama et al. 2010). While the interaction of WAPAL with PDS5 depends on CDCA5 (Nishiyama et al. 2010), WAPAL maintains its association with cohesin through interaction with cohesin subunits (Kueng et al. 2006, Shintomi and Hirano 2009). Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed11509732 Pubmed15737063 Pubmed16682347 Pubmed17112726 Pubmed17113138 Pubmed19696148 Pubmed21111234 Pubmed21878504 Pubmed21987589 Pubmed9649503 Reactome Database ID Release 432467794 Reactome, http://www.reactome.org ReactomeREACT_150267 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 2 Kinetochore assembly Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed18097444 Reactome Database ID Release 432484822 Reactome, http://www.reactome.org ReactomeREACT_150388 Reviewed: Zhang, Nenggang, 2012-10-22 The kinetochore assembly on centromeres of replicated chromosomes is completed by mitotic prometaphase. Some kinetochore components are associated with centromeres throughout the cell cycle while others associate with centromeres during mitosis. The sequential kinetochore assembly and kinetochore dynamics is not shown here. For a review of this process, please refer to Cheeseman and Desai 2008. has a Stoichiometric coefficient of 2 PathwayStep4912 PathwayStep4911 PathwayStep4914 PathwayStep4913 PathwayStep4910 PathwayStep4919 PathwayStep4916 PathwayStep4915 PathwayStep4918 PathwayStep4917 PathwayStep4903 PathwayStep4902 PathwayStep4901 PathwayStep4900 Association of Cyclin B/Cdk1 with replicative origin inhibits pre-RC formation Authored: Gopinathrao, G, 2004-06-16 18:53:38 Reactome Database ID Release 43113638 Reactome, http://www.reactome.org ReactomeREACT_555 This event is inferred from the fission yeast. Cyclin B activity is thought to inhibit pre-RC formation by first associating with ORC during DNA replication. PathwayStep4909 PathwayStep4908 PathwayStep4907 PathwayStep4906 PathwayStep4905 PathwayStep4904 Phosphorylation of Cyclin D1 at T286 by glycogen synthase kinase-3 beta At the beginning of this reaction, 1 molecule of 'Cyclin D1:Cdk4', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'phospho(T286)-Cyclin D1:Cdk4', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'glycogen synthase kinase-3 beta'.<br> Pubmed16732330 Reactome Database ID Release 4375820 Reactome, http://www.reactome.org ReactomeREACT_132 IN Converted from EntitySet in Reactome Integrase Reactome DB_ID: 175319 Reactome Database ID Release 43175319 Reactome, http://www.reactome.org ReactomeREACT_8284 Formation of Cyclin A:Cdk2 complexes Authored: Pagano, M, 2006-09-19 08:23:10 During G1 phase of the cell cycle, cyclin A is synthesized and associates with Cdk2. Edited: Matthews, L, 2006-09-28 11:06:10 Pubmed1312467 Reactome Database ID Release 43174054 Reactome, http://www.reactome.org ReactomeREACT_8996 Reviewed: Coqueret, O, 2006-10-06 08:59:06 Translocation of Cyclin A:Cdk2 complexes to the nucleus After forming in the cytoplasm, the Cyclin A:Cdk2 complexes are translocated to the nucleus. Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-28 04:25:14 Pubmed11907280 Reactome Database ID Release 43174273 Reactome, http://www.reactome.org ReactomeREACT_9065 Reviewed: Coqueret, O, 2006-10-06 08:59:06 Phosphorylation of Cyclin A:Cdk2 at Tyr 15 Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-28 04:25:14 Pubmed1396589 Reactome Database ID Release 43174164 Reactome, http://www.reactome.org ReactomeREACT_9057 Reviewed: Coqueret, O, 2006-10-06 08:59:06 The CDK activity of the Cyclin A:Cdk2 complex is inhibited by phosphorylation at Tyr 15, presumably by the Wee1 kinase. Cdc25A mediated dephosphorylation of Cyclin A:phospho-Cdk2 Authored: Pagano, M, 2006-09-19 08:23:10 Cdc25A, and probably Cdc25B, regulate the entry into S phase cell cycle by removing inhibitory phosphates from the Cdk2 subunit of Cyclin A:Cdk2. EC Number: 3.1.3.16 Edited: Matthews, L, 2006-09-28 04:25:14 Pubmed10454565 Reactome Database ID Release 43174110 Reactome, http://www.reactome.org ReactomeREACT_9062 Reviewed: Coqueret, O, 2006-10-06 08:59:06 CAK-mediated phosphorylation of Cyclin A:Cdk2 Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-28 04:25:14 Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK kinase activity. The association of p21/p27 with the Cyclin A/E:Cdk2 complex prevents CAK mediated phosphorylation of Cdk2 (Aprelikova et al., 1995). Pubmed7629134 Reactome Database ID Release 43187949 Reactome, http://www.reactome.org ReactomeREACT_9070 Reviewed: Coqueret, O, 2006-10-06 08:59:06 Cyclin A:Cdk2 mediated phosphorylation of p27/p21 Authored: Pagano, M, 2006-09-19 08:23:10 EC Number: 2.7.11.22 Edited: Matthews, L, 2006-09-28 04:25:14 Pubmed10323868 Pubmed11231585 Reactome Database ID Release 43187916 Reactome, http://www.reactome.org ReactomeREACT_8995 Recognition of p27 by SCF(Skp2) and the subsequent ubiquitination of p27 is dependent upon Cyclin E/A:Cdk2-mediated phosphorylation of p27 at Thr 187 (Montagnoli et al., 1999). p21 is also phosphorylated at a specific site (Ser130) by Cyclin E/A:Cdk2, stimulating its ubiquitination. Unlike p27, however, p21 ubiquitination can take place in the absence of phosphorylation, although with less efficiency (Bornstein et al.,2003). Reviewed: Coqueret, O, 2006-10-06 08:59:06 Inactivation of Cyclin A:Cdk2 complexes by p27/p21 Authored: Pagano, M, 2006-09-19 08:23:10 During G1, the activity of cyclin-dependent kinases (CDKs) is kept in check by the CDK inhibitors (CKIs) p27 and p21, thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). Edited: Matthews, L, 2006-09-28 04:25:14 Pubmed10323868 Pubmed7624798 Reactome Database ID Release 43187934 Reactome, http://www.reactome.org ReactomeREACT_9005 Reviewed: Coqueret, O, 2006-10-06 08:59:06 Phosphorylation of proteins involved in the G1/S transition by Cyclin A:Cdk2 Active Cyclin A:Cdk2 complexes phosphorylate and inactivate proteins required for maintaining the G1/S phase including: Cdh1, RB1, p21 and p27. All this creates auto-amplification loops that render Cdk2 increasingly more active. In G2, Cdk2, in association with cyclin A, phosphorylates E2F1 and E2F3 resulting in the inactivation and possibly degradation of these two transcription factors (Dynlacht et al., 1994; Krek et al., 1994). Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-28 04:25:14 Pubmed10323868 Pubmed10375532 Pubmed12730199 Pubmed16582612 Reactome Database ID Release 43187948 Reactome, http://www.reactome.org ReactomeREACT_9007 Reviewed: Coqueret, O, 2006-10-06 08:59:06 PathwayStep4930 Relocalization of nuclearly localized Cyclin D1 to the cytoplasm In this reaction, 1 molecule of 'phospho(T286)-Cyclin D1' is translocated from nucleoplasm to cytosol.<br><br>This reaction takes place in the 'nuclear envelope'.<br> Reactome Database ID Release 4375823 Reactome, http://www.reactome.org ReactomeREACT_1180 Relocalization of nuclearly localized phospho-(T286):cyclin D1:Cdk4 to cytoplasm In this reaction, 1 molecule of 'phospho(T286)-Cyclin D1:Cdk4' is translocated from nucleoplasm to cytosol.<br><br>This reaction takes place in the 'nuclear envelope'.<br> Reactome Database ID Release 4375822 Reactome, http://www.reactome.org ReactomeREACT_752 PathwayStep4932 PathwayStep4931 PathwayStep4934 PathwayStep4933 PathwayStep4936 PathwayStep4935 PathwayStep4938 PathwayStep4937 Jak1, Jak2, Tyk2 Converted from EntitySet in Reactome Reactome DB_ID: 1067678 Reactome Database ID Release 431067678 Reactome, http://www.reactome.org ReactomeREACT_27599 PathwayStep4939 Association of Cyclin A:phospho-Cdk2(Thr 160) with E2F1/E2F3 Authored: Pagano, M, 2006-09-19 08:23:10 Edited: Matthews, L, 2006-09-28 04:25:14 In G2, the cyclin A:Cdk2 complex associates with E2F1 and E2F3. Pubmed7958856 Pubmed8033208 Reactome Database ID Release 43187937 Reactome, http://www.reactome.org ReactomeREACT_9021 Phosphorylation of E2F1/E2F3 by Cyclin A:phosph-Cdk2(Thr 160) Authored: Pagano, M, 2006-09-19 08:23:10 EC Number: 2.7.11.22 Edited: Matthews, L, 2006-09-28 04:25:14 In G2 Cdk2, in association with cyclin A, phosphorylates E2F1 and E2F3 resulting in the inactivation and possibly degradation of these two transcription factors (Dynlacht et al., 1994; Krek et al., 1994). Pubmed7958856 Pubmed8033208 Reactome Database ID Release 43187959 Reactome, http://www.reactome.org ReactomeREACT_9023 Reviewed: Coqueret, O, 2006-10-06 08:59:06 CDCA5 (Sororin) enables cohesion of sister chromosomal arms Authored: Orlic-Milacic, M, 2012-10-02 CDCA5 (Sororin) is essential for the establishment of sister chromatid cohesion in mammalian cells (Rankin et al. 2005) in the S-phase of the cell cycle (Nishiyama et al. 2010). Several factors contribute to the recruitment of CDCA5 to chromatin-associated cohesin: DNA replication (i.e. presence of two sister chromatids), association of cohesin complex with PDS5, and acetylation of the SMC3 cohesin subunit by ESCO1/ESCO2 acetyltransferases. Experiments in which a recombinant tagged mouse CDCA5 was expressed in human HeLa cell line showed that CDCA5 starts to accumulate on chromatin in S-phase and dissociates from chromosomal arms in prophase (Nishiyama et al. 2010). <br><br> CDCA5 is essential for the establishment of chromosomal cohesion only in the presence of WAPAL, suggesting that the key role of CDCA5 (Sororin) is to antagonize WAPAL. Both CDCA5 and WAPAL contain an FGF (phenylalanine-glycine-phenylalanine) motif that is essential for PDS5 binding and is also essential for CDCA5 function in cohesion establishment. Indeed, CDCA5 is able to displace WAPAL from PDS5:WAPAL heterodimers in vitro. In vivo experiments in Xenopus egg extracts suggest that CDCA5 rearranges the topology of cohesin associated proteins so that WAPAL is no longer able to inhibit sister chromatid cohesion but remains associated with cohesin (Nishiyama et al. 2010). Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed15837422 Pubmed21111234 Reactome Database ID Release 432468041 Reactome, http://www.reactome.org ReactomeREACT_150264 Reviewed: Zhang, Nenggang, 2012-10-22 CDCA5 (Sororin) enables cohesion of sister centromeres Authored: Orlic-Milacic, M, 2012-10-02 CDCA5 (Sororin) is essential for the establishment of sister chromatid cohesion at centromeres. Experiments in which a recombinant tagged mouse CDCA5 was expressed in human HeLa cell line showed that CDCA5 starts to accumulate on chromatin in S-phase and dissociates from centromeres in anaphase (Nishiyama et al. 2010). Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed21111234 Reactome Database ID Release 432473151 Reactome, http://www.reactome.org ReactomeREACT_150445 Reviewed: Zhang, Nenggang, 2012-10-22 Acetylation of SMC3 subunit of chromosomal arm associated cohesin by ESCO1 or ESCO2 Acetyltransferases ESCO1 and ESCO2 are homologs of the S. cerevisiae acetyltransferase Eco1, essential for viability in yeast. ESCO1 and ESCO2 share sequence homology in the C-terminal region, consisting of a H2C2 zinc finger motif and an acetyltransferase domain (Hou and Zou 2005). Both ESCO1 and ESCO2 acetylate the cohesin subunit SMC3 on two lysine residues, K105 and K106 (Zhang et al. 2008), an important step in the establishment of sister-chromatid cohesion during the S-phase of the cell cycle. ESCO1 and ESCO2 differ in their N-termini, which are necessary for chromatin binding, and may perform distinct functions in sister chromatid cohesion (Hou and Zou 2005), as suggested by the study of Esco2 knockout mice (Whelan et al. 2012). Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed15958495 Pubmed18614053 Pubmed21111234 Pubmed22101327 Reactome Database ID Release 432468039 Reactome, http://www.reactome.org ReactomeREACT_150456 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 2 Acetylation of SMC3 subunit of centromeric chromatin associated cohesin by ESCO1 or ESCO2 Acetyltransferases ESCO1 and ESCO2 are homologs of the S. cerevisiae acetyltransferase Eco1, essential for viability in yeast. ESCO1 and ESCO2 share sequence homology in the C-terminal region, consisting of a H2C2 zinc finger motif and an acetyltransferase domain (Hou and Zou 2005). Both ESCO1 and ESCO2 acetylate the cohesin subunit SMC3 on two lysine residues, K105 and K106 (Zhang et al. 2008), an important step in the establishment of sister-chromatid cohesion during the S-phase of the cell cycle. Divergent N-termini of ESCO1 and ESCO2, necessary for chromatin binding, suggest that ESCO1 and ESCO2 may perform distinct functions in sister chromatid cohesion (Hou and Zou 2005). Several studies suggest that ESCO2 may be predominantly involved in acetylation of the SMC3 subunit of centromeric cohesin. A conditional targeting of Esco2 locus in mice leads to pre-implantational loss of homozygous Esco2 -/- embryos at the eight-cell stage. Prometaphase chromosomes isolated from two-cell stage Esco2 knockout embryos show marked cohesion defect at centromeres (Whelan et al. 2012). ESCO2 protein appears in the S-phase (Hou and Zou 2005, Whelan et al. 2012) and in mouse embryonic fibroblasts Esco2 predominantly localizes to pericentric heterochromatin (Whelan et al. 2012). Mutations in the ESCO2 gene (Vega et al. 2005) that impair ESCO2 acetyltransferase activity (Gordillo et al. 2008) are the cause of the Roberts syndrome, an autosomal recessive disorder characterized by craniofacial and limb abnormalities, and intellectual disability. Metaphase chromosomes of Roberts syndrome patients exhibit loss of cohesion at heterochromatic regions of centromeres and the Y chromosome, with a characteristic 'railroad track appearance' (Van den Berg and Francke 1993, Vega et al. 2005). Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed15821733 Pubmed15958495 Pubmed18411254 Pubmed18614053 Pubmed21111234 Pubmed22101327 Pubmed8291532 Reactome Database ID Release 432473152 Reactome, http://www.reactome.org ReactomeREACT_150144 Reviewed: Zhang, Nenggang, 2012-10-22 has a Stoichiometric coefficient of 2 Ubiquitination of Cyclin D1 Authored: Matthews, L, 2006-04-14 06:50:45 Cyclin D is targeted for degradation by multi-ubiquitination. EC Number: 6.3.2.19 Edited: Matthews, L, 2006-04-14 06:51:12 Reactome Database ID Release 4375824 Reactome, http://www.reactome.org ReactomeREACT_715 has a Stoichiometric coefficient of 3 Proteasome mediated degradation of Cyclin D1 Edited: Matthews, L, 2006-04-14 06:51:12 Phosphorylated Cyclin D1 is degraded during S phase by the 26S proteasome allowing for efficient DNA synthesis. Pubmed15735756 Reactome Database ID Release 4375825 Reactome, http://www.reactome.org ReactomeREACT_2142 has a Stoichiometric coefficient of 3 PathwayStep4921 Formation of Cyclin A:Cdc2 complexes Cyclin A is synthesized and associates with Cdc2 in G1. Cyclin dependent kinases are themselves catalytically inactive due to the fact that their active sites are blocked by a portion of the CDK molecule itself. Binding to their corresponding cyclin partner results in a conformational change that partially exposes the active site. Pubmed1717476 Pubmed9001210 Reactome Database ID Release 43170084 Reactome, http://www.reactome.org ReactomeREACT_6308 PathwayStep4920 Translocation of Cyclin A:phospho-Cdc2 (Thr 14) to the nucleus Cyclin A:Cdc2 complexes translocate to the nucleus in G1 and may associate with condensing chromosomes in prophase (Pines and Hunter 1991). Pubmed1717476 Reactome Database ID Release 43170088 Reactome, http://www.reactome.org ReactomeREACT_6276 Myt-1 mediated phosphorylation of Cyclin A:Cdc2 Myt1, which localizes preferentially to the endoplasmic reticulum and Golgi complex, phosphorylates Cdc2 on threonine 14 ( Liu et al., 1997). Pubmed9001210 Pubmed9268380 Reactome Database ID Release 43170116 Reactome, http://www.reactome.org ReactomeREACT_6342 PathwayStep4925 PathwayStep4924 PathwayStep4923 PathwayStep4922 PathwayStep4929 PathwayStep4928 PathwayStep4927 PathwayStep4926 Phosphorylation of proteins involved in G2/M transition by active Cyclin A1:Cdc2 complexes At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'G2/M transition protein' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'phospho-G2/M transition protein' are present.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'cyclin-dependent protein kinase activity' of 'Cyclin A1:Cdc2'.<br> EC Number: 2.7.11.22 Reactome Database ID Release 4369754 Reactome, http://www.reactome.org ReactomeREACT_406 Phosphorylation of proteins involved in G2/M transition by active Cyclin A2:Cdc2 complexes At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'G2/M transition protein' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'phospho-G2/M transition protein' are present.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'cyclin-dependent protein kinase activity' of 'Cyclin A2:Cdc2'.<br> EC Number: 2.7.11.22 Pubmed7969176 Reactome Database ID Release 4369756 Reactome, http://www.reactome.org ReactomeREACT_1627 Formation of Cyclin B:Cdc2 complexes Cyclin dependent kinases are themselves catalytically inactive due to the fact that their active site is blocked by a portion of the Cdk molecule itself. Binding to their corresponding cyclin partner results in conformational change that partially exposes the active site. Pubmed1717476 Reactome Database ID Release 43170057 Reactome, http://www.reactome.org ReactomeREACT_6216 CAK-mediated phosphorylation of Cyclin A:Cdc2 complexes Full activity of most CDKs is dependent on CAK mediated phosphorylation at a conserved residue (Thr 161 in Cdc2). This modification is thought to improve substrate binding. High affinity binding of Cyclin A within the Cyclin A:Cdc2 complex requires this phosphorylation (Desai et al 1995). Pubmed7799941 Reactome Database ID Release 43170087 Reactome, http://www.reactome.org ReactomeREACT_6139 Wee1-mediated phosphorylation of Cyclin A:phospho-Cdc2 complexes Pubmed7743995 Reactome Database ID Release 43170156 Reactome, http://www.reactome.org ReactomeREACT_6327 The human Wee1 kinase phosphorylates Cdc2 on tyrosine 15 inactivating the cyclin:CDK complex (Watanabe et al., 1995). Translocation of active Cdc25C to the nucleus During interphase, phopshorylated Cdc25C is associated with 14-3-3 proteins preventing nuclear import. At the onset of mitosis, dephosphorylation of Cdc25C and dissociation of 14-3-3 increases the rate of import (see Takizawa and Morgan, 2000) Pubmed11063929 Reactome Database ID Release 43170149 Reactome, http://www.reactome.org ReactomeREACT_6279 Dephosphorylation of nuclear Cyclin A:phospho-Cdc2 complexes Activation of the mitotic cyclin:Cdc2 complexes at mitosis requires the removal of the inhibitory phosphate groups on Cdc2. This dephosphorylation is achieved by the activity of the Cdc25 family of phosphatases. The Cdc25 members, Cdc25A, Cdc25B, and Cdc25C are kept inactive during interphase and are activated at the G2/M transition (see Wolfe and Gould 2004) EC Number: 3.1.3.16 Pubmed15107615 Reactome Database ID Release 43170158 Reactome, http://www.reactome.org ReactomeREACT_6294 has a Stoichiometric coefficient of 2 PathwayStep4961 ACTIVATION GENE ONTOLOGYGO:0004777 Reactome Database ID Release 43916830 Reactome, http://www.reactome.org PathwayStep4960 PathwayStep289 ACTIVATION GENE ONTOLOGYGO:0005326 Reactome Database ID Release 43374898 Reactome, http://www.reactome.org PathwayStep288 ACTIVATION GENE ONTOLOGYGO:0005332 Reactome Database ID Release 43444014 Reactome, http://www.reactome.org PathwayStep287 ACTIVATION GENE ONTOLOGYGO:0003867 Reactome Database ID Release 43916852 Reactome, http://www.reactome.org PathwayStep286 PathwayStep285 PathwayStep284 PathwayStep283 PathwayStep4959 PathwayStep4957 PathwayStep292 PathwayStep4958 PathwayStep293 PathwayStep4955 PathwayStep290 ACTIVATION GENE ONTOLOGYGO:0008504 Reactome Database ID Release 43380614 Reactome, http://www.reactome.org PathwayStep4956 PathwayStep291 ACTIVATION GENE ONTOLOGYGO:0008168 Reactome Database ID Release 43379385 Reactome, http://www.reactome.org PathwayStep4953 ACTIVATION GENE ONTOLOGYGO:0008131 Reactome Database ID Release 43141714 Reactome, http://www.reactome.org PathwayStep4954 ACTIVATION GENE ONTOLOGYGO:0008131 Reactome Database ID Release 43141714 Reactome, http://www.reactome.org PathwayStep4951 ACTIVATION GENE ONTOLOGYGO:0008168 Reactome Database ID Release 43379385 Reactome, http://www.reactome.org PathwayStep4952 ACTIVATION GENE ONTOLOGYGO:0008504 Reactome Database ID Release 43379484 Reactome, http://www.reactome.org PathwayStep299 ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43210482 Reactome, http://www.reactome.org PathwayStep298 ACTIVATION GENE ONTOLOGYGO:0015179 Reactome Database ID Release 43212649 Reactome, http://www.reactome.org PathwayStep4950 ACTIVATION GENE ONTOLOGYGO:0015276 Reactome Database ID Release 43629585 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015276 Reactome Database ID Release 43629574 Reactome, http://www.reactome.org PathwayStep295 PathwayStep294 PathwayStep297 PathwayStep296 ACTIVATION GENE ONTOLOGYGO:0004029 Reactome Database ID Release 4371722 Reactome, http://www.reactome.org Rev Converted from EntitySet in Reactome Reactome DB_ID: 174992 Reactome Database ID Release 43174992 Reactome, http://www.reactome.org ReactomeREACT_8241 PathwayStep4948 PathwayStep4949 PathwayStep4944 PathwayStep4945 ACTIVATION GENE ONTOLOGYGO:0004698 Reactome Database ID Release 43139850 Reactome, http://www.reactome.org PathwayStep4946 PathwayStep4947 PathwayStep4940 ACTIVATION GENE ONTOLOGYGO:0004683 Reactome Database ID Release 43417000 Reactome, http://www.reactome.org PathwayStep4941 ACTIVATION GENE ONTOLOGYGO:0015276 Reactome Database ID Release 43629578 Reactome, http://www.reactome.org PathwayStep4942 ACTIVATION GENE ONTOLOGYGO:0016887 Reactome Database ID Release 43416995 Reactome, http://www.reactome.org PathwayStep4943 ACTIVATION GENE ONTOLOGYGO:0004698 Reactome Database ID Release 43139850 Reactome, http://www.reactome.org p-S62-ARPP19/p-S67-ENSA Converted from EntitySet in Reactome Reactome DB_ID: 2430548 Reactome Database ID Release 432430548 Reactome, http://www.reactome.org ReactomeREACT_150512 PathwayStep264 PathwayStep263 PathwayStep262 PathwayStep261 PathwayStep4983 PathwayStep268 PathwayStep4982 PathwayStep267 PathwayStep4981 PathwayStep266 PathwayStep4980 PathwayStep265 PathwayStep269 PathwayStep4975 PathwayStep4976 PathwayStep4973 PathwayStep4974 PathwayStep4979 PathwayStep270 PathwayStep271 PathwayStep4977 PathwayStep4978 PathwayStep273 PathwayStep272 PathwayStep275 PathwayStep274 PathwayStep4970 PathwayStep277 PathwayStep276 PathwayStep4972 PathwayStep279 PathwayStep4971 PathwayStep278 p6 protein Converted from EntitySet in Reactome Reactome DB_ID: 175031 Reactome Database ID Release 43175031 Reactome, http://www.reactome.org ReactomeREACT_8499 PathwayStep4962 PathwayStep4963 PathwayStep4964 PathwayStep4965 PathwayStep4966 PathwayStep4967 PathwayStep280 PathwayStep4968 PathwayStep281 PathwayStep4969 PathwayStep282 ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 432022380 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 432022401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 432022390 Reactome, http://www.reactome.org PathwayStep4999 ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 432022390 Reactome, http://www.reactome.org PathwayStep4998 ACTIVATION GENE ONTOLOGYGO:0004181 Reactome Database ID Release 432022376 Reactome, http://www.reactome.org PathwayStep4997 ACTIVATION GENE ONTOLOGYGO:0070573 Reactome Database ID Release 432022372 Reactome, http://www.reactome.org PathwayStep4996 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43381447 Reactome, http://www.reactome.org PathwayStep4995 ACTIVATION GENE ONTOLOGYGO:0008234 Reactome Database ID Release 432022373 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004181 Reactome Database ID Release 432022376 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004181 Reactome Database ID Release 432028287 Reactome, http://www.reactome.org PathwayStep4991 PathwayStep4992 PathwayStep4993 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432537497 Reactome, http://www.reactome.org PathwayStep4994 PathwayStep4990 PathwayStep4989 ACTIVATION GENE ONTOLOGYGO:0005262 Reactome Database ID Release 43210481 Reactome, http://www.reactome.org PathwayStep4988 ACTIVATION GENE ONTOLOGYGO:0008504 Reactome Database ID Release 43372532 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43374903 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43374917 Reactome, http://www.reactome.org PathwayStep4985 ACTIVATION GENE ONTOLOGYGO:0005243 Reactome Database ID Release 43375327 Reactome, http://www.reactome.org PathwayStep4984 ACTIVATION GENE ONTOLOGYGO:0005243 Reactome Database ID Release 43375336 Reactome, http://www.reactome.org PathwayStep4987 ACTIVATION GENE ONTOLOGYGO:0005243 Reactome Database ID Release 43375331 Reactome, http://www.reactome.org PathwayStep4986 ACTIVATION GENE ONTOLOGYGO:0005243 Reactome Database ID Release 43375346 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008131 Reactome Database ID Release 43141714 Reactome, http://www.reactome.org NC Converted from EntitySet in Reactome Nucleocapsid Reactome DB_ID: 173121 Reactome Database ID Release 43173121 Reactome, http://www.reactome.org ReactomeREACT_8906 ACTIVATION GENE ONTOLOGYGO:0008504 Reactome Database ID Release 43372532 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005326 Reactome Database ID Release 43374898 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43212646 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005313 Reactome Database ID Release 43210513 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43380907 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43380904 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43210384 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43380571 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43210491 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43210531 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43380625 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005277 Reactome Database ID Release 43264621 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015220 Reactome Database ID Release 43264626 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43373336 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43373333 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004351 Reactome Database ID Release 43888586 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004351 Reactome Database ID Release 43888587 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43916832 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43917771 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43918002 Reactome, http://www.reactome.org TFIIF Reactome DB_ID: 109631 Reactome Database ID Release 43109631 Reactome, http://www.reactome.org ReactomeREACT_4708 has a Stoichiometric coefficient of 1 Capping complex (initial) Reactome DB_ID: 77063 Reactome Database ID Release 4377063 Reactome, http://www.reactome.org ReactomeREACT_4555 has a Stoichiometric coefficient of 1 Capping complex (hydrolyzed) Reactome DB_ID: 77064 Reactome Database ID Release 4377064 Reactome, http://www.reactome.org ReactomeREACT_4969 has a Stoichiometric coefficient of 1 CE:Pol II CTD:Spt5 complex Reactome DB_ID: 77061 Reactome Database ID Release 4377061 Reactome, http://www.reactome.org ReactomeREACT_2332 has a Stoichiometric coefficient of 1 rHes1:TLE Reactome DB_ID: 2065508 Reactome Database ID Release 432065508 Reactome, http://www.reactome.org ReactomeREACT_119628 has a Stoichiometric coefficient of 1 CAK Reactome DB_ID: 69221 Reactome Database ID Release 4369221 Reactome, http://www.reactome.org ReactomeREACT_5717 has a Stoichiometric coefficient of 1 TFIIH Reactome DB_ID: 109634 Reactome Database ID Release 43109634 Reactome, http://www.reactome.org ReactomeREACT_3832 has a Stoichiometric coefficient of 1 RNA Polymerase II holoenzyme complex (phosphorylated) Reactome DB_ID: 113716 Reactome Database ID Release 43113716 Reactome, http://www.reactome.org ReactomeREACT_5819 has a Stoichiometric coefficient of 1 RNA polymerase II (phosphorylated):TFIIF complex Reactome DB_ID: 113404 Reactome Database ID Release 43113404 Reactome, http://www.reactome.org ReactomeREACT_4593 has a Stoichiometric coefficient of 1 PathwayStep6898 AKT1/PDK1 Converted from EntitySet in Reactome Reactome DB_ID: 432180 Reactome Database ID Release 43432180 Reactome, http://www.reactome.org ReactomeREACT_24667 PathwayStep6899 PathwayStep409 PathwayStep400 PathwayStep404 PathwayStep403 PathwayStep402 PathwayStep401 PathwayStep408 PathwayStep407 PathwayStep406 PathwayStep405 PathwayStep6889 PathwayStep6887 PathwayStep6888 PathwayStep411 PathwayStep410 PathwayStep6893 PathwayStep413 PathwayStep6892 PathwayStep412 PathwayStep6891 PathwayStep415 PathwayStep6890 PathwayStep414 PathwayStep6897 PathwayStep417 PathwayStep6896 PathwayStep416 PathwayStep6895 PathwayStep419 PathwayStep6894 PathwayStep418 PathwayStep6877 PathwayStep6876 PathwayStep6879 PathwayStep6878 PathwayStep6883 PathwayStep6884 PathwayStep6885 PathwayStep6886 PathwayStep6880 PathwayStep6881 PathwayStep6882 PathwayStep6869 PathwayStep6868 PathwayStep6867 PathwayStep6866 PathwayStep6865 PathwayStep6874 PathwayStep6875 PathwayStep6872 PathwayStep6873 PathwayStep6870 PathwayStep6871 PathwayStep6855 PathwayStep6854 PathwayStep6857 PathwayStep6856 PathwayStep6859 PathwayStep6858 PathwayStep6860 PathwayStep6861 PathwayStep6862 PathwayStep6863 PathwayStep6864 PathwayStep6846 PathwayStep6845 PathwayStep6844 PathwayStep6843 PathwayStep6849 PathwayStep6848 PathwayStep6847 PathwayStep6852 PathwayStep6853 PathwayStep6850 PathwayStep6851 PathwayStep464 PathwayStep2482 PathwayStep463 PathwayStep2481 PathwayStep466 PathwayStep2480 PathwayStep465 PathwayStep460 PathwayStep2486 PathwayStep2485 PathwayStep462 PathwayStep2484 PathwayStep461 PathwayStep2483 phospho CD28:B7-1/B7-2 Reactome DB_ID: 388777 Reactome Database ID Release 43388777 Reactome, http://www.reactome.org ReactomeREACT_19582 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CD28:PI3K Reactome DB_ID: 388783 Reactome Database ID Release 43388783 Reactome, http://www.reactome.org ReactomeREACT_19529 has a Stoichiometric coefficient of 1 CD80 (B7-1) homodimer Reactome DB_ID: 179787 Reactome Database ID Release 43179787 Reactome, http://www.reactome.org ReactomeREACT_19742 has a Stoichiometric coefficient of 2 Phospho CD28 homodimer Reactome DB_ID: 388778 Reactome Database ID Release 43388778 Reactome, http://www.reactome.org ReactomeREACT_20268 has a Stoichiometric coefficient of 2 PathwayStep468 Active PDGF dimers (AA, AB, BB) Converted from EntitySet in Reactome Reactome DB_ID: 380760 Reactome Database ID Release 43380760 Reactome, http://www.reactome.org ReactomeREACT_17845 PathwayStep467 PDGF:Phospho-PDGF receptor dimer:PI3K Reactome DB_ID: 186789 Reactome Database ID Release 43186789 Reactome, http://www.reactome.org ReactomeREACT_17825 has a Stoichiometric coefficient of 1 PDGF A/B heterodimer Reactome DB_ID: 380759 Reactome Database ID Release 43380759 Reactome, http://www.reactome.org ReactomeREACT_18197 has a Stoichiometric coefficient of 1 PathwayStep469 PDGF A homodimer Reactome DB_ID: 380761 Reactome Database ID Release 43380761 Reactome, http://www.reactome.org ReactomeREACT_17491 has a Stoichiometric coefficient of 2 PI3K:p-KIT:sSCF dimer:p-KIT Reactome DB_ID: 205177 Reactome Database ID Release 43205177 Reactome, http://www.reactome.org ReactomeREACT_111423 has a Stoichiometric coefficient of 1 p-KIT complex Reactome DB_ID: 205310 Reactome Database ID Release 43205310 Reactome, http://www.reactome.org ReactomeREACT_111273 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-7Y-KIT:sSCF dimer:p-7Y-KIT sSCF dimer Reactome DB_ID: 1433307 Reactome Database ID Release 431433307 Reactome, http://www.reactome.org ReactomeREACT_111693 has a Stoichiometric coefficient of 2 PathwayStep2478 PathwayStep2479 PathwayStep2476 PathwayStep2477 PathwayStep477 PathwayStep476 PathwayStep475 PathwayStep2471 PathwayStep474 PathwayStep2470 PathwayStep473 PathwayStep2473 PathwayStep472 PathwayStep2472 PathwayStep471 PathwayStep2475 PathwayStep470 PathwayStep2474 Activated FGFR4 homodimer Reactome DB_ID: 190328 Reactome Database ID Release 43190328 Reactome, http://www.reactome.org ReactomeREACT_9792 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR3c homodimer Reactome DB_ID: 190389 Reactome Database ID Release 43190389 Reactome, http://www.reactome.org ReactomeREACT_9623 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR3b homodimer Reactome DB_ID: 190380 Reactome Database ID Release 43190380 Reactome, http://www.reactome.org ReactomeREACT_9635 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR:p-FRS2-alpha:p-SHP2 Reactome DB_ID: 190361 Reactome Database ID Release 43190361 Reactome, http://www.reactome.org ReactomeREACT_21961 has a Stoichiometric coefficient of 1 Activated FGFR:p-FRS2alpha:p-SHP2:GRB2:GAB1:PI3KR1 Reactome DB_ID: 1315468 Reactome Database ID Release 431315468 Reactome, http://www.reactome.org ReactomeREACT_76289 has a Stoichiometric coefficient of 1 PathwayStep479 Activated FGFR:p-FRS2alpha:p-SHP2:GRB2:GAB1:PI3K Reactome DB_ID: 1268236 Reactome Database ID Release 431268236 Reactome, http://www.reactome.org ReactomeREACT_111518 has a Stoichiometric coefficient of 1 PathwayStep478 Activated FGFR4 bound to FGF19:BetaKlotho Reactome DB_ID: 1307958 Reactome Database ID Release 431307958 Reactome, http://www.reactome.org ReactomeREACT_76324 has a Stoichiometric coefficient of 2 Activated FGFR2c long homodimer Reactome DB_ID: 190418 Reactome Database ID Release 43190418 Reactome, http://www.reactome.org ReactomeREACT_9563 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR2c short homodimer bound to FGF Reactome DB_ID: 192592 Reactome Database ID Release 43192592 Reactome, http://www.reactome.org ReactomeREACT_9850 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR2b short homodimer bound to FGF Reactome DB_ID: 192597 Reactome Database ID Release 43192597 Reactome, http://www.reactome.org ReactomeREACT_9845 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR2c homodimer bound to FGF Converted from EntitySet in Reactome Reactome DB_ID: 192616 Reactome Database ID Release 43192616 Reactome, http://www.reactome.org ReactomeREACT_9576 PathwayStep2465 PathwayStep480 PathwayStep2466 PathwayStep2467 PathwayStep2468 PathwayStep2469 PathwayStep482 PathwayStep2464 PathwayStep481 PathwayStep2463 PathwayStep484 PathwayStep2462 PathwayStep483 PathwayStep2461 PathwayStep486 PathwayStep2460 PathwayStep485 PathwayStep488 PathwayStep487 Secreted Klotho homodimer Reactome DB_ID: 190203 Reactome Database ID Release 43190203 Reactome, http://www.reactome.org ReactomeREACT_9864 has a Stoichiometric coefficient of 2 PathwayStep489 Membrane-bound Klotho homodimer Reactome DB_ID: 190204 Reactome Database ID Release 43190204 Reactome, http://www.reactome.org ReactomeREACT_9626 has a Stoichiometric coefficient of 2 Activated FGFR2b long homodimer Reactome DB_ID: 190411 Reactome Database ID Release 43190411 Reactome, http://www.reactome.org ReactomeREACT_9713 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR2b homodimer bound to FGF Converted from EntitySet in Reactome Reactome DB_ID: 192606 Reactome Database ID Release 43192606 Reactome, http://www.reactome.org ReactomeREACT_9543 Klotho Converted from EntitySet in Reactome Reactome DB_ID: 190207 Reactome Database ID Release 43190207 Reactome, http://www.reactome.org ReactomeREACT_9821 Klotho homodimer Reactome DB_ID: 190309 Reactome Database ID Release 43190309 Reactome, http://www.reactome.org ReactomeREACT_9693 has a Stoichiometric coefficient of 2 Klotho bound to FGF23 Reactome DB_ID: 190208 Reactome Database ID Release 43190208 Reactome, http://www.reactome.org ReactomeREACT_9620 has a Stoichiometric coefficient of 1 Activated FGFR:p-FRS2alpha Reactome DB_ID: 190350 Reactome Database ID Release 43190350 Reactome, http://www.reactome.org ReactomeREACT_21467 has a Stoichiometric coefficient of 1 Activated FGFR1b homodimer Reactome DB_ID: 190430 Reactome Database ID Release 43190430 Reactome, http://www.reactome.org ReactomeREACT_9538 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR1c homodimer Reactome DB_ID: 190425 Reactome Database ID Release 43190425 Reactome, http://www.reactome.org ReactomeREACT_9810 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR1c bound to FGF23:Klotho Reactome DB_ID: 500333 Reactome Database ID Release 43500333 Reactome, http://www.reactome.org ReactomeREACT_21886 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep2458 PathwayStep2459 PathwayStep2456 PathwayStep2457 PathwayStep490 PathwayStep2454 PathwayStep491 PathwayStep2455 PathwayStep495 PathwayStep2451 PathwayStep494 PathwayStep2450 PathwayStep493 PathwayStep2453 PathwayStep492 PathwayStep2452 PathwayStep499 PathwayStep498 PathwayStep497 PathwayStep496 Activated FGFR:p-FRS2alpha:GRB2:GAB1:PI3KR1 Reactome DB_ID: 1268238 Reactome Database ID Release 431268238 Reactome, http://www.reactome.org ReactomeREACT_111473 has a Stoichiometric coefficient of 1 Activated FGFR:p-FRS2alpha:GRB2:GAB1:PI3K Reactome DB_ID: 1268234 Reactome Database ID Release 431268234 Reactome, http://www.reactome.org ReactomeREACT_111264 has a Stoichiometric coefficient of 1 Activator:PI3K Converted from EntitySet in Reactome Reactome DB_ID: 2316432 Reactome Database ID Release 432316432 Reactome, http://www.reactome.org ReactomeREACT_148170 EGF:p-6Y-EGFR:GRB2:GAB1:PIK3 EGF:Phospho-EGFR-GRB2:GAB1:PI3Kreg:PI3Kcat Reactome DB_ID: 179791 Reactome Database ID Release 43179791 Reactome, http://www.reactome.org ReactomeREACT_12738 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:GRB2:GAB1:PIK3R1 EGF:Phospho-EGFR-GRB2:GAB1:PI3Kreg Reactome DB_ID: 179867 Reactome Database ID Release 43179867 Reactome, http://www.reactome.org ReactomeREACT_13343 has a Stoichiometric coefficient of 1 GRB2:GAB1 Reactome DB_ID: 179849 Reactome Database ID Release 43179849 Reactome, http://www.reactome.org ReactomeREACT_12705 has a Stoichiometric coefficient of 1 GRB2:GAB1:PIK3R1 Reactome DB_ID: 179864 Reactome Database ID Release 43179864 Reactome, http://www.reactome.org ReactomeREACT_12870 has a Stoichiometric coefficient of 1 EGF:Phospho-EGFR:Phospho-SHC EGF:p-6Y-EGFR:p-Y349,350-SHC1 Reactome DB_ID: 180337 Reactome Database ID Release 43180337 Reactome, http://www.reactome.org ReactomeREACT_12720 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1 GRB2:SOS-Phospho-SHC:EGF:Phospho-EGFR dimer Reactome DB_ID: 180331 Reactome Database ID Release 43180331 Reactome, http://www.reactome.org ReactomeREACT_13054 has a Stoichiometric coefficient of 1 Activated RAF1 complex:MEK2 Reactome DB_ID: 109795 Reactome Database ID Release 43109795 Reactome, http://www.reactome.org ReactomeREACT_4223 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:SHC1 EGF:Phospho-EGFR-SHC Reactome DB_ID: 180301 Reactome Database ID Release 43180301 Reactome, http://www.reactome.org ReactomeREACT_12643 has a Stoichiometric coefficient of 1 PathwayStep2447 PathwayStep2448 PathwayStep2449 PathwayStep2443 PathwayStep2444 PathwayStep2445 PathwayStep2446 PathwayStep427 PathwayStep428 PathwayStep429 PathwayStep423 HRAS:GTP Reactome DB_ID: 167204 Reactome Database ID Release 43167204 Reactome, http://www.reactome.org ReactomeREACT_24217 has a Stoichiometric coefficient of 1 PathwayStep424 Ras:GTP:p-Raf1(S259,S621) Reactome DB_ID: 206716 Reactome Database ID Release 43206716 Reactome, http://www.reactome.org ReactomeREACT_24177 has a Stoichiometric coefficient of 1 PathwayStep425 Activated RAF1 complex:MEK Reactome DB_ID: 112406 Reactome Database ID Release 43112406 Reactome, http://www.reactome.org ReactomeREACT_3953 has a Stoichiometric coefficient of 1 PathwayStep426 Activated RAF1 complex:MEK1 Reactome DB_ID: 109794 Reactome Database ID Release 43109794 Reactome, http://www.reactome.org ReactomeREACT_4256 has a Stoichiometric coefficient of 1 PathwayStep420 PathwayStep421 PathwayStep422 PathwayStep2441 PathwayStep2442 PathwayStep2440 PathwayStep2435 PathwayStep2434 PathwayStep2433 PathwayStep2432 PathwayStep2439 PathwayStep2438 PathwayStep2437 PathwayStep2436 GRB2:SOS1 Reactome DB_ID: 109797 Reactome Database ID Release 43109797 Reactome, http://www.reactome.org ReactomeREACT_4435 has a Stoichiometric coefficient of 1 active PKC (alpha, gamma, delta) Reactome DB_ID: 112002 Reactome Database ID Release 43112002 Reactome, http://www.reactome.org ReactomeREACT_16103 has a Stoichiometric coefficient of 1 p-Raf1(S259,S621):14-3-3 protein beta/alpha Reactome DB_ID: 109787 Reactome Database ID Release 43109787 Reactome, http://www.reactome.org ReactomeREACT_4612 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:GRB2:SOS1 GRB2:SOS-EGF-Phospho-EGFR dimer Reactome DB_ID: 179820 Reactome Database ID Release 43179820 Reactome, http://www.reactome.org ReactomeREACT_12657 has a Stoichiometric coefficient of 1 RAS:RAF:14-3-3 Reactome DB_ID: 109789 Reactome Database ID Release 43109789 Reactome, http://www.reactome.org ReactomeREACT_3642 has a Stoichiometric coefficient of 1 RAS:RAF Reactome DB_ID: 109788 Reactome Database ID Release 43109788 Reactome, http://www.reactome.org ReactomeREACT_3036 has a Stoichiometric coefficient of 1 Activated RAF1 complex Reactome DB_ID: 109793 Reactome Database ID Release 43109793 Reactome, http://www.reactome.org ReactomeREACT_4906 has a Stoichiometric coefficient of 1 PathwayStep438 PathwayStep439 PathwayStep436 active Cam-PDE 1 Reactome DB_ID: 111953 Reactome Database ID Release 43111953 Reactome, http://www.reactome.org ReactomeREACT_3728 has a Stoichiometric coefficient of 1 PathwayStep437 GRK2:calmodulin Reactome DB_ID: 111965 Reactome Database ID Release 43111965 Reactome, http://www.reactome.org ReactomeREACT_17570 has a Stoichiometric coefficient of 1 PathwayStep434 PathwayStep435 Cam-PDE 1C homodimer Reactome DB_ID: 111976 Reactome Database ID Release 43111976 Reactome, http://www.reactome.org ReactomeREACT_2760 has a Stoichiometric coefficient of 2 PathwayStep432 PathwayStep433 PathwayStep430 PathwayStep431 PathwayStep2430 PathwayStep2431 PathwayStep2422 PathwayStep2421 PathwayStep2424 PathwayStep2423 PathwayStep2426 PathwayStep2425 PathwayStep2428 PathwayStep2427 Activated EGFR:Phospho-PLC-gamma1 EGF:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1 Reactome DB_ID: 212703 Reactome Database ID Release 43212703 Reactome, http://www.reactome.org ReactomeREACT_13347 has a Stoichiometric coefficient of 1 PathwayStep2429 EGF:p-6Y-EGFR:PLCG1 Activated EGFR:PLC-gamma1 Reactome DB_ID: 212717 Reactome Database ID Release 43212717 Reactome, http://www.reactome.org ReactomeREACT_13280 has a Stoichiometric coefficient of 1 EGF:Phospho-EGFR Reactome DB_ID: 179860 Reactome Database ID Release 43179860 Reactome, http://www.reactome.org ReactomeREACT_9712 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR EGF:Phospho-EGFR (Y992, Y1068, Y1086, Y1148, Y1173) dimer Reactome DB_ID: 179882 Reactome Database ID Release 43179882 Reactome, http://www.reactome.org ReactomeREACT_9673 has a Stoichiometric coefficient of 2 Cam-PDE 1B homodimer Reactome DB_ID: 111975 Reactome Database ID Release 43111975 Reactome, http://www.reactome.org ReactomeREACT_2651 has a Stoichiometric coefficient of 2 Cam-PDE 1A homodimer Reactome DB_ID: 111974 Reactome Database ID Release 43111974 Reactome, http://www.reactome.org ReactomeREACT_2988 has a Stoichiometric coefficient of 2 Cam-PDE 1 homodimer Converted from EntitySet in Reactome Reactome DB_ID: 111952 Reactome Database ID Release 43111952 Reactome, http://www.reactome.org ReactomeREACT_5507 phospho-CREB dimer Reactome DB_ID: 111911 Reactome Database ID Release 43111911 Reactome, http://www.reactome.org ReactomeREACT_17630 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep445 PathwayStep446 PathwayStep447 EGF:EGFR Reactome DB_ID: 179847 Reactome Database ID Release 43179847 Reactome, http://www.reactome.org ReactomeREACT_9893 has a Stoichiometric coefficient of 1 PathwayStep448 EGF:EGFR dimer Reactome DB_ID: 179845 Reactome Database ID Release 43179845 Reactome, http://www.reactome.org ReactomeREACT_9820 has a Stoichiometric coefficient of 2 PathwayStep449 PathwayStep2420 PathwayStep440 PathwayStep441 PathwayStep442 PathwayStep443 PathwayStep444 PathwayStep2417 PathwayStep2416 PathwayStep2415 PathwayStep2414 PathwayStep2413 PathwayStep2412 ADAM:Zn2+ ADAM metalloprotease:Zinc cofactor Reactome DB_ID: 179842 Reactome Database ID Release 43179842 Reactome, http://www.reactome.org ReactomeREACT_9655 has a Stoichiometric coefficient of 1 PathwayStep2411 PathwayStep2410 BfrA dimer Reactome DB_ID: 1562633 Reactome Database ID Release 431562633 Reactome, http://www.reactome.org ReactomeREACT_123779 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 BfrA complex Reactome DB_ID: 1562615 Reactome Database ID Release 431562615 Reactome, http://www.reactome.org ReactomeREACT_125193 has a Stoichiometric coefficient of 24 BfrB dimer Reactome DB_ID: 1562623 Reactome Database ID Release 431562623 Reactome, http://www.reactome.org ReactomeREACT_124033 has a Stoichiometric coefficient of 2 BfrB complex Reactome DB_ID: 1562601 Reactome Database ID Release 431562601 Reactome, http://www.reactome.org ReactomeREACT_125633 has a Stoichiometric coefficient of 24 Lpd dimer Reactome DB_ID: 1222635 Reactome Database ID Release 431222635 Reactome, http://www.reactome.org ReactomeREACT_123663 has a Stoichiometric coefficient of 2 AhpD trimer Reactome DB_ID: 1222514 Reactome Database ID Release 431222514 Reactome, http://www.reactome.org ReactomeREACT_122585 has a Stoichiometric coefficient of 3 PathwayStep2419 IrtAB:Rv2895c Reactome DB_ID: 1222486 Reactome Database ID Release 431222486 Reactome, http://www.reactome.org ReactomeREACT_125392 has a Stoichiometric coefficient of 1 PathwayStep2418 TrxB dimer Reactome DB_ID: 1222425 Reactome Database ID Release 431222425 Reactome, http://www.reactome.org ReactomeREACT_124367 has a Stoichiometric coefficient of 2 PathwayStep458 PathwayStep459 KatG dimer Reactome DB_ID: 1222385 Reactome Database ID Release 431222385 Reactome, http://www.reactome.org ReactomeREACT_123044 has a Stoichiometric coefficient of 2 PathwayStep456 PathwayStep457 PathwayStep450 PathwayStep451 PathwayStep454 PathwayStep455 PathwayStep452 PathwayStep453 PathwayStep2404 PathwayStep2403 PathwayStep2406 PathwayStep2405 PathwayStep2400 PathwayStep2402 PathwayStep2401 PathwayStep2408 PathwayStep2407 PathwayStep2409 UBF-1:rDNA Promoter Reactome DB_ID: 73684 Reactome Database ID Release 4373684 Reactome, http://www.reactome.org ReactomeREACT_4561 has a Stoichiometric coefficient of 1 Nucleosome (Deacetylated) Reactome DB_ID: 427402 Reactome Database ID Release 43427402 Reactome, http://www.reactome.org ReactomeREACT_20128 has a Stoichiometric coefficient of 2 PAR-SMAD2/3:PAR-SMAD4 Reactome DB_ID: 2187328 Reactome Database ID Release 432187328 Reactome, http://www.reactome.org ReactomeREACT_123857 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-2S-SMAD2/3:SMAD4:PPM1A Reactome DB_ID: 2187392 Reactome Database ID Release 432187392 Reactome, http://www.reactome.org ReactomeREACT_124331 has a Stoichiometric coefficient of 1 Acetylated SL1 Reactome DB_ID: 73693 Reactome Database ID Release 4373693 Reactome, http://www.reactome.org ReactomeREACT_4702 has a Stoichiometric coefficient of 1 Acetylayed SL1:PhosUBF-1:rDNA promoter Reactome DB_ID: 73694 Reactome Database ID Release 4373694 Reactome, http://www.reactome.org ReactomeREACT_5418 has a Stoichiometric coefficient of 1 phospho-ERK-1 dimer Reactome DB_ID: 109845 Reactome Database ID Release 43109845 Reactome, http://www.reactome.org ReactomeREACT_3152 has a Stoichiometric coefficient of 2 SL1 Reactome DB_ID: 73692 Reactome Database ID Release 4373692 Reactome, http://www.reactome.org ReactomeREACT_3015 has a Stoichiometric coefficient of 1 Methylcytosine: MBD2 Complex Reactome DB_ID: 427343 Reactome Database ID Release 43427343 Reactome, http://www.reactome.org ReactomeREACT_19920 has a Stoichiometric coefficient of 1 Phosphorylated UBF-1:rDNA promoter Reactome DB_ID: 73685 Reactome Database ID Release 4373685 Reactome, http://www.reactome.org ReactomeREACT_3329 has a Stoichiometric coefficient of 1 Ub-SKI/Ub-SKIL Reactome DB_ID: 2186733 Reactome Database ID Release 432186733 Reactome, http://www.reactome.org ReactomeREACT_123776 has a Stoichiometric coefficient of 1 p-SMAD2/3:SMAD4:TRIM33 Reactome DB_ID: 870446 Reactome Database ID Release 43870446 Reactome, http://www.reactome.org ReactomeREACT_122570 has a Stoichiometric coefficient of 1 Ub-SMAD4 Reactome DB_ID: 870463 Reactome Database ID Release 43870463 Reactome, http://www.reactome.org ReactomeREACT_122324 has a Stoichiometric coefficient of 1 p-T-2S-SMAD2/3:SMAD4:SMURF2 Reactome DB_ID: 2179277 Reactome Database ID Release 432179277 Reactome, http://www.reactome.org ReactomeREACT_121618 has a Stoichiometric coefficient of 1 Ub-p-T-2S-SMAD2/3 Reactome DB_ID: 2179273 Reactome Database ID Release 432179273 Reactome, http://www.reactome.org ReactomeREACT_125159 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-2S-SMAD2/3:SMAD4:PARP1 Reactome DB_ID: 2187322 Reactome Database ID Release 432187322 Reactome, http://www.reactome.org ReactomeREACT_124426 has a Stoichiometric coefficient of 1 Ub-SMAD4 Reactome DB_ID: 870482 Reactome Database ID Release 43870482 Reactome, http://www.reactome.org ReactomeREACT_122129 has a Stoichiometric coefficient of 1 Ub-SMAD4:USP9X Reactome DB_ID: 870520 Reactome Database ID Release 43870520 Reactome, http://www.reactome.org ReactomeREACT_124723 has a Stoichiometric coefficient of 1 p-T-2S-SMAD2/3:SMAD4:NEDDL4 Reactome DB_ID: 2176495 Reactome Database ID Release 432176495 Reactome, http://www.reactome.org ReactomeREACT_122635 has a Stoichiometric coefficient of 1 Ub-p-T-2S-SMAD2/3:SMAD4 Reactome DB_ID: 2176504 Reactome Database ID Release 432176504 Reactome, http://www.reactome.org ReactomeREACT_123049 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 WWTR1:p-2S-SMAD2/3:SMAD4 Reactome DB_ID: 2106580 Reactome Database ID Release 432106580 Reactome, http://www.reactome.org ReactomeREACT_123695 has a Stoichiometric coefficient of 1 p-2S-SMAD2/3:SMAD4:TGIF:HDAC1 Reactome DB_ID: 2186606 Reactome Database ID Release 432186606 Reactome, http://www.reactome.org ReactomeREACT_124044 has a Stoichiometric coefficient of 1 RBL1:E2F4/5:DP1/2 Reactome DB_ID: 2127252 Reactome Database ID Release 432127252 Reactome, http://www.reactome.org ReactomeREACT_123979 has a Stoichiometric coefficient of 1 p107:E2F4/5:DP1/2 p-SMAD2/3:SMAD4:RBL1:E2F4/5:DP1/2 Reactome DB_ID: 2127250 Reactome Database ID Release 432127250 Reactome, http://www.reactome.org ReactomeREACT_122929 has a Stoichiometric coefficient of 1 SMAD7:RNF111 Reactome DB_ID: 2186769 Reactome Database ID Release 432186769 Reactome, http://www.reactome.org ReactomeREACT_124335 has a Stoichiometric coefficient of 1 Ub-SMAD7 Reactome DB_ID: 2186778 Reactome Database ID Release 432186778 Reactome, http://www.reactome.org ReactomeREACT_124908 has a Stoichiometric coefficient of 1 p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCOR Phospho-R-SMAD:CO-SMAD:SKI complex Reactome DB_ID: 177110 Reactome Database ID Release 43177110 Reactome, http://www.reactome.org ReactomeREACT_7221 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-2S-SMAD2/3:SMAD4:SKI/SKIL:NCOR:RNF111/SMURF2 Reactome DB_ID: 2186744 Reactome Database ID Release 432186744 Reactome, http://www.reactome.org ReactomeREACT_124107 has a Stoichiometric coefficient of 1 p-2S-SMAD2/3:SMAD4:SP1 Reactome DB_ID: 2187302 Reactome Database ID Release 432187302 Reactome, http://www.reactome.org ReactomeREACT_124646 has a Stoichiometric coefficient of 1 p-2S-SMAD2/3:SMAD4:MEN1 Reactome DB_ID: 2186642 Reactome Database ID Release 432186642 Reactome, http://www.reactome.org ReactomeREACT_124410 has a Stoichiometric coefficient of 1 WWTR1:p-2S-SMAD2/3:SMAD4 Reactome DB_ID: 2031357 Reactome Database ID Release 432031357 Reactome, http://www.reactome.org ReactomeREACT_121541 has a Stoichiometric coefficient of 1 PPARA:RXRA Coactivator Complex Reactome DB_ID: 400154 Reactome Database ID Release 43400154 Reactome, http://www.reactome.org ReactomeREACT_20439 has a Stoichiometric coefficient of 1 Activated PPARA:RXRA Heterodimer Reactome DB_ID: 422412 Reactome Database ID Release 43422412 Reactome, http://www.reactome.org ReactomeREACT_19669 has a Stoichiometric coefficient of 1 Phospho(S363,S380,T573)-ribosomal S6 kinase Converted from EntitySet in Reactome Reactome DB_ID: 445403 Reactome Database ID Release 43445403 Reactome, http://www.reactome.org ReactomeREACT_20941 PPARA: Fatty Acid Complex (Activated PPARA) Reactome DB_ID: 422413 Reactome Database ID Release 43422413 Reactome, http://www.reactome.org ReactomeREACT_20029 has a Stoichiometric coefficient of 1 p-2S-SMAD2/3:SMAD4 Phospho-R-SMAD:CO-SMAD complex Reactome DB_ID: 171175 Reactome Database ID Release 43171175 Reactome, http://www.reactome.org ReactomeREACT_7344 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-2S-SMAD2/3:SMAD4 Phospho-R-SMAD:CO-SMAD complex Reactome DB_ID: 173511 Reactome Database ID Release 43173511 Reactome, http://www.reactome.org ReactomeREACT_7382 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Ribosomal S6 kinase Converted from EntitySet in Reactome Reactome DB_ID: 444247 Reactome Database ID Release 43444247 Reactome, http://www.reactome.org ReactomeREACT_20775 p-T,2S-SMAD2/3:SMAD4 Reactome DB_ID: 2176487 Reactome Database ID Release 432176487 Reactome, http://www.reactome.org ReactomeREACT_122238 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CDK8:CCNC/ CDK9:CCNT Converted from EntitySet in Reactome Reactome DB_ID: 2176485 Reactome Database ID Release 432176485 Reactome, http://www.reactome.org ReactomeREACT_125482 CDK8:CCNC Reactome DB_ID: 1604465 Reactome Database ID Release 431604465 Reactome, http://www.reactome.org ReactomeREACT_118957 has a Stoichiometric coefficient of 1 P-TEFb complex Reactome DB_ID: 112431 Reactome Database ID Release 43112431 Reactome, http://www.reactome.org ReactomeREACT_3433 has a Stoichiometric coefficient of 1 Rap1 Converted from EntitySet in Reactome Reactome DB_ID: 377600 Reactome Database ID Release 43377600 Reactome, http://www.reactome.org ReactomeREACT_16117 PathwayStep2389 PathwayStep2388 ATP6V0 Reactome DB_ID: 1222405 Reactome Database ID Release 431222405 Reactome, http://www.reactome.org ReactomeREACT_125335 has a Stoichiometric coefficient of 1 TBX5:WWTR1:PCAF Reactome DB_ID: 2032799 Reactome Database ID Release 432032799 Reactome, http://www.reactome.org ReactomeREACT_119245 has a Stoichiometric coefficient of 1 RUNX2:WWTR1(TAZ) Reactome DB_ID: 2064919 Reactome Database ID Release 432064919 Reactome, http://www.reactome.org ReactomeREACT_119164 has a Stoichiometric coefficient of 1 TEAD:YAP1 Reactome DB_ID: 2032772 Reactome Database ID Release 432032772 Reactome, http://www.reactome.org ReactomeREACT_119773 has a Stoichiometric coefficient of 1 ATP6V1G dimer Reactome DB_ID: 912608 Reactome Database ID Release 43912608 Reactome, http://www.reactome.org ReactomeREACT_24166 has a Stoichiometric coefficient of 2 PathwayStep2390 TEAD:WWTR1(TAZ) Reactome DB_ID: 2032762 Reactome Database ID Release 432032762 Reactome, http://www.reactome.org ReactomeREACT_120065 has a Stoichiometric coefficient of 1 ATP6V1B trimer Reactome DB_ID: 912611 Reactome Database ID Release 43912611 Reactome, http://www.reactome.org ReactomeREACT_24654 has a Stoichiometric coefficient of 3 KRAB-ZNF / KAP Complex Reactome DB_ID: 975037 Reactome Database ID Release 43975037 Reactome, http://www.reactome.org ReactomeREACT_27587 has a Stoichiometric coefficient of 1 Oligopeptide importer Reactome DB_ID: 1500757 Reactome Database ID Release 431500757 Reactome, http://www.reactome.org ReactomeREACT_123352 has a Stoichiometric coefficient of 1 NR-MED1 Coactivator Complex Reactome DB_ID: 376420 Reactome Database ID Release 43376420 Reactome, http://www.reactome.org ReactomeREACT_19894 has a Stoichiometric coefficient of 1 Lactoferrin (loaded) Reactome DB_ID: 1222432 Reactome Database ID Release 431222432 Reactome, http://www.reactome.org ReactomeREACT_122842 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CSL NICD coactivator complex Reactome DB_ID: 212451 Reactome Database ID Release 43212451 Reactome, http://www.reactome.org ReactomeREACT_14859 has a Stoichiometric coefficient of 1 ATP6V0A Reactome DB_ID: 1222519 Reactome Database ID Release 431222519 Reactome, http://www.reactome.org ReactomeREACT_122928 has a Stoichiometric coefficient of 1 TRAP coactivator complex Reactome DB_ID: 212379 Reactome Database ID Release 43212379 Reactome, http://www.reactome.org ReactomeREACT_13344 has a Stoichiometric coefficient of 1 ATP6V0C hexamer Reactome DB_ID: 1222484 Reactome Database ID Release 431222484 Reactome, http://www.reactome.org ReactomeREACT_125576 has a Stoichiometric coefficient of 6 DRIP coactivator complex Reactome DB_ID: 212340 Reactome Database ID Release 43212340 Reactome, http://www.reactome.org ReactomeREACT_13011 has a Stoichiometric coefficient of 1 ATP6V1 Reactome DB_ID: 912583 Reactome Database ID Release 43912583 Reactome, http://www.reactome.org ReactomeREACT_24241 has a Stoichiometric coefficient of 1 ARC coactivator complex Reactome DB_ID: 212374 Reactome Database ID Release 43212374 Reactome, http://www.reactome.org ReactomeREACT_12961 has a Stoichiometric coefficient of 1 ATP6V1A trimer Reactome DB_ID: 912610 Reactome Database ID Release 43912610 Reactome, http://www.reactome.org ReactomeREACT_24226 has a Stoichiometric coefficient of 3 PathwayStep393 PathwayStep2397 PathwayStep394 PathwayStep2398 AKT Converted from EntitySet in Reactome Reactome DB_ID: 202052 Reactome Database ID Release 43202052 Reactome, http://www.reactome.org ReactomeREACT_13267 PathwayStep395 PathwayStep2395 ATP6V0E Reactome DB_ID: 1222508 Reactome Database ID Release 431222508 Reactome, http://www.reactome.org ReactomeREACT_123021 has a Stoichiometric coefficient of 1 PathwayStep396 PathwayStep2396 ATP6V0D Reactome DB_ID: 1222374 Reactome Database ID Release 431222374 Reactome, http://www.reactome.org ReactomeREACT_123213 has a Stoichiometric coefficient of 1 PathwayStep397 PathwayStep2393 PathwayStep398 PathwayStep2394 PathwayStep399 PathwayStep2391 PathwayStep2392 Rap1 cAMP-GEFs Converted from EntitySet in Reactome Reactome DB_ID: 392485 Reactome Database ID Release 43392485 Reactome, http://www.reactome.org ReactomeREACT_17998 PathwayStep392 PathwayStep391 PathwayStep2399 PathwayStep390 G-protein alpha (q):GDP Reactome DB_ID: 428711 Reactome Database ID Release 43428711 Reactome, http://www.reactome.org ReactomeREACT_20732 has a Stoichiometric coefficient of 1 ADP:P2Y purinoceptor 1 Reactome DB_ID: 418583 Reactome Database ID Release 43418583 Reactome, http://www.reactome.org ReactomeREACT_21127 has a Stoichiometric coefficient of 1 ADP:P2Y purinoceptor 1:G-protein Gq (inactive) Reactome DB_ID: 428714 Reactome Database ID Release 43428714 Reactome, http://www.reactome.org ReactomeREACT_21023 has a Stoichiometric coefficient of 1 LKB1:STRAD:MO25 Reactome DB_ID: 380967 Reactome Database ID Release 43380967 Reactome, http://www.reactome.org ReactomeREACT_17994 has a Stoichiometric coefficient of 1 SodC dimer Reactome DB_ID: 1222313 Reactome Database ID Release 431222313 Reactome, http://www.reactome.org ReactomeREACT_122453 has a Stoichiometric coefficient of 2 p-AMPK heterotrimer Reactome DB_ID: 380934 Reactome Database ID Release 43380934 Reactome, http://www.reactome.org ReactomeREACT_17720 has a Stoichiometric coefficient of 1 Heterotrimeric G-protein G alphaq:beta1:gamma2 (inactive) Reactome DB_ID: 428710 Reactome Database ID Release 43428710 Reactome, http://www.reactome.org ReactomeREACT_21012 has a Stoichiometric coefficient of 1 Sec complex Reactome DB_ID: 1222323 Reactome Database ID Release 431222323 Reactome, http://www.reactome.org ReactomeREACT_122152 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 AMPK heterotrimer (active) Reactome DB_ID: 200408 Reactome Database ID Release 43200408 Reactome, http://www.reactome.org ReactomeREACT_11854 has a Stoichiometric coefficient of 1 SodB tetramer Reactome DB_ID: 1222672 Reactome Database ID Release 431222672 Reactome, http://www.reactome.org ReactomeREACT_125005 has a Stoichiometric coefficient of 4 NOTCH1 NTM-NEC 1 heterodimer Reactome DB_ID: 157027 Reactome Database ID Release 43157027 Reactome, http://www.reactome.org ReactomeREACT_4661 has a Stoichiometric coefficient of 1 Tpx dimer Reactome DB_ID: 1222584 Reactome Database ID Release 431222584 Reactome, http://www.reactome.org ReactomeREACT_123816 has a Stoichiometric coefficient of 2 MscR:Zn2+ Reactome DB_ID: 1222283 Reactome Database ID Release 431222283 Reactome, http://www.reactome.org ReactomeREACT_27528 has a Stoichiometric coefficient of 1 AMPK heterotrimer Reactome DB_ID: 380961 Reactome Database ID Release 43380961 Reactome, http://www.reactome.org ReactomeREACT_18135 has a Stoichiometric coefficient of 1 AhpE dimer (red.) Reactome DB_ID: 1500773 Reactome Database ID Release 431500773 Reactome, http://www.reactome.org ReactomeREACT_123888 has a Stoichiometric coefficient of 2 rDll1:NOTCH1 Reactome DB_ID: 2076709 Reactome Database ID Release 432076709 Reactome, http://www.reactome.org ReactomeREACT_120182 has a Stoichiometric coefficient of 1 AhpE dimer (ox.) Reactome DB_ID: 1500809 Reactome Database ID Release 431500809 Reactome, http://www.reactome.org ReactomeREACT_125669 has a Stoichiometric coefficient of 2 PathwayStep384 GlbN:Ferriheme dimer Reactome DB_ID: 1222369 Reactome Database ID Release 431222369 Reactome, http://www.reactome.org ReactomeREACT_125635 has a Stoichiometric coefficient of 2 CalDAG-GEFs Converted from EntitySet in Reactome Reactome DB_ID: 392488 Reactome Database ID Release 43392488 Reactome, http://www.reactome.org ReactomeREACT_18194 PathwayStep385 AhpC hexamer Reactome DB_ID: 1222632 Reactome Database ID Release 431222632 Reactome, http://www.reactome.org ReactomeREACT_122224 has a Stoichiometric coefficient of 6 PathwayStep382 PathwayStep383 GlbN:Heme dimer Reactome DB_ID: 1222294 Reactome Database ID Release 431222294 Reactome, http://www.reactome.org ReactomeREACT_124216 has a Stoichiometric coefficient of 2 PathwayStep388 PathwayStep389 PathwayStep386 PathwayStep387 PathwayStep2369 PathwayStep2368 PathwayStep2367 PathwayStep2366 intronless pre-mRNA cleavage complex Reactome DB_ID: 112162 Reactome Database ID Release 43112162 Reactome, http://www.reactome.org ReactomeREACT_3895 has a Stoichiometric coefficient of 1 Segment 6 RNP Reactome DB_ID: 195943 Reactome Database ID Release 43195943 Reactome, http://www.reactome.org ReactomeREACT_10870 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 upstream mRNA fragment:CPSF:PAP:PABPN1 complex Reactome DB_ID: 112164 Reactome Database ID Release 43112164 Reactome, http://www.reactome.org ReactomeREACT_3436 has a Stoichiometric coefficient of 1 Segment 7 RNP Reactome DB_ID: 195939 Reactome Database ID Release 43195939 Reactome, http://www.reactome.org ReactomeREACT_10503 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 CPSF:capped intronless pre-mRNA:CBC complex Reactome DB_ID: 112160 Reactome Database ID Release 43112160 Reactome, http://www.reactome.org ReactomeREACT_3837 has a Stoichiometric coefficient of 1 CstF:CPSF:capped intronless pre-mRNA:CBC complex Reactome DB_ID: 112161 Reactome Database ID Release 43112161 Reactome, http://www.reactome.org ReactomeREACT_3025 has a Stoichiometric coefficient of 1 Segment 2 RNP Reactome DB_ID: 195950 Reactome Database ID Release 43195950 Reactome, http://www.reactome.org ReactomeREACT_10270 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 U7 snRNP:ZFP100 Complex Reactome DB_ID: 110765 Reactome Database ID Release 43110765 Reactome, http://www.reactome.org ReactomeREACT_5001 has a Stoichiometric coefficient of 1 Segment 3 RNP Reactome DB_ID: 195952 Reactome Database ID Release 43195952 Reactome, http://www.reactome.org ReactomeREACT_10968 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Capped Intronless Histone pre-mRNA:CBP80:CBP20:SLBP Reactome DB_ID: 110759 Reactome Database ID Release 43110759 Reactome, http://www.reactome.org ReactomeREACT_3458 has a Stoichiometric coefficient of 1 Segment 8 RNP Reactome DB_ID: 195949 Reactome Database ID Release 43195949 Reactome, http://www.reactome.org ReactomeREACT_10273 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Segment 1 RNP Reactome DB_ID: 195947 Reactome Database ID Release 43195947 Reactome, http://www.reactome.org ReactomeREACT_10624 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 RNP pre-assembly complex Reactome DB_ID: 196496 Reactome Database ID Release 43196496 Reactome, http://www.reactome.org ReactomeREACT_11005 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 24 has a Stoichiometric coefficient of 8 capped intronless pre-mRNA:CBC complex Reactome DB_ID: 112159 Reactome Database ID Release 43112159 Reactome, http://www.reactome.org ReactomeREACT_3948 has a Stoichiometric coefficient of 1 Intracellular assembly complex Matrix associated RNP pre-assembly complex Reactome DB_ID: 195925 Reactome Database ID Release 43195925 Reactome, http://www.reactome.org ReactomeREACT_10426 Ribonucleoprotein (RNP) Complex has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 1000 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 has a Stoichiometric coefficient of 45 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 matrix associated complete RNP complex Capped Intronless Histone pre-mRNA:CBC:ZFP100 Complex Reactome DB_ID: 112045 Reactome Database ID Release 43112045 Reactome, http://www.reactome.org ReactomeREACT_5338 has a Stoichiometric coefficient of 1 Sialic Acid Bound Influenza A Viral Particle Reactome DB_ID: 195945 Reactome Database ID Release 43195945 Reactome, http://www.reactome.org ReactomeREACT_10492 has a Stoichiometric coefficient of 1 Capped Intronless Histone pre-mRNA:CBP80:CBP20:SLBP:ZFP100 Complex Reactome DB_ID: 110766 Reactome Database ID Release 43110766 Reactome, http://www.reactome.org ReactomeREACT_3667 has a Stoichiometric coefficient of 1 Ribonucleoprotein (RNP) Complex Membrane enveloped Influenza Virion RNP complex Reactome DB_ID: 196497 Reactome Database ID Release 43196497 Reactome, http://www.reactome.org ReactomeREACT_10297 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 1000 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 has a Stoichiometric coefficient of 45 has a Stoichiometric coefficient of 500 has a Stoichiometric coefficient of 60 U7 snRNP-specific Sm core complex Reactome DB_ID: 110762 Reactome Database ID Release 43110762 Reactome, http://www.reactome.org ReactomeREACT_3858 has a Stoichiometric coefficient of 1 Trimeric palmitylated HA Reactome DB_ID: 196488 Reactome Database ID Release 43196488 Reactome, http://www.reactome.org ReactomeREACT_10402 has a Stoichiometric coefficient of 3 PathwayStep2371 PathwayStep2372 PathwayStep2370 PathwayStep2375 PathwayStep2376 PathwayStep2373 PathwayStep2374 PathwayStep2378 PathwayStep2377 PathwayStep2379 NS1 Homodimer Reactome DB_ID: 169145 Reactome Database ID Release 43169145 Reactome, http://www.reactome.org ReactomeREACT_6381 has a Stoichiometric coefficient of 2 Influenza A Viral Particle Reactome DB_ID: 195941 Reactome Database ID Release 43195941 Reactome, http://www.reactome.org ReactomeREACT_10742 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 NS1:Viral dsRNA Complex Reactome DB_ID: 169075 Reactome Database ID Release 43169075 Reactome, http://www.reactome.org ReactomeREACT_6623 has a Stoichiometric coefficient of 1 NS1 Homodimer:PKR Complex Reactome DB_ID: 169142 Reactome Database ID Release 43169142 Reactome, http://www.reactome.org ReactomeREACT_6636 has a Stoichiometric coefficient of 1 NS1:PAB II Complex Reactome DB_ID: 169102 Reactome Database ID Release 43169102 Reactome, http://www.reactome.org ReactomeREACT_6465 has a Stoichiometric coefficient of 1 NS1 Homodimer Reactome DB_ID: 169143 Reactome Database ID Release 43169143 Reactome, http://www.reactome.org ReactomeREACT_6545 has a Stoichiometric coefficient of 2 Cytochrome b-245 Reactome DB_ID: 1222510 Reactome Database ID Release 431222510 Reactome, http://www.reactome.org ReactomeREACT_124680 has a Stoichiometric coefficient of 1 V-ATPase Reactome DB_ID: 1222549 Reactome Database ID Release 431222549 Reactome, http://www.reactome.org ReactomeREACT_122063 has a Stoichiometric coefficient of 1 PB1-F2: ANT 3 Complex Reactome DB_ID: 169235 Reactome Database ID Release 43169235 Reactome, http://www.reactome.org ReactomeREACT_6551 has a Stoichiometric coefficient of 1 NOX2 complex Reactome DB_ID: 1222368 Reactome Database ID Release 431222368 Reactome, http://www.reactome.org ReactomeREACT_123618 has a Stoichiometric coefficient of 1 PathwayStep2380 PathwayStep2381 PathwayStep2382 PathwayStep2383 PathwayStep2384 PathwayStep2385 CPSF:NS1 Complex Reactome DB_ID: 169074 Reactome Database ID Release 43169074 Reactome, http://www.reactome.org ReactomeREACT_6585 has a Stoichiometric coefficient of 1 PathwayStep2386 PathwayStep2387 VAV family Converted from EntitySet in Reactome Reactome DB_ID: 442295 Reactome Database ID Release 43442295 Reactome, http://www.reactome.org ReactomeREACT_21194 PathwayStep6950 PathwayStep6952 PathwayStep6951 PathwayStep6942 PathwayStep6943 PathwayStep6944 PathwayStep6945 PathwayStep6946 PathwayStep6947 PathwayStep6948 PathwayStep6949 VAV1 effectors Converted from EntitySet in Reactome Reactome DB_ID: 442294 Reactome Database ID Release 43442294 Reactome, http://www.reactome.org ReactomeREACT_21176 p-Vav Converted from EntitySet in Reactome Reactome DB_ID: 442272 Reactome Database ID Release 43442272 Reactome, http://www.reactome.org ReactomeREACT_24324 PathwayStep6963 PathwayStep6962 PathwayStep6961 PathwayStep6960 PathwayStep6955 PathwayStep6956 PathwayStep6953 PathwayStep6954 PathwayStep6959 PathwayStep6957 PathwayStep6958 SYK/LCK Converted from EntitySet in Reactome Reactome DB_ID: 434838 Reactome Database ID Release 43434838 Reactome, http://www.reactome.org ReactomeREACT_24482 VAV3 effectors Converted from EntitySet in Reactome Reactome DB_ID: 442311 Reactome Database ID Release 43442311 Reactome, http://www.reactome.org ReactomeREACT_24783 VAV2 effectors Converted from EntitySet in Reactome Reactome DB_ID: 442284 Reactome Database ID Release 43442284 Reactome, http://www.reactome.org ReactomeREACT_24141 PathwayStep6930 PathwayStep6924 PathwayStep6925 PathwayStep6926 PathwayStep6927 PathwayStep6920 PathwayStep6921 PathwayStep6922 PathwayStep6923 PI3K-regulatory subunits Converted from EntitySet in Reactome Reactome DB_ID: 391342 Reactome Database ID Release 43391342 Reactome, http://www.reactome.org ReactomeREACT_24857 VAV Converted from EntitySet in Reactome Reactome DB_ID: 430172 Reactome Database ID Release 43430172 Reactome, http://www.reactome.org ReactomeREACT_21165 PathwayStep6928 PathwayStep6929 PI3-kinase gamma, regulatory subunit Converted from EntitySet in Reactome Reactome DB_ID: 425644 Reactome Database ID Release 43425644 Reactome, http://www.reactome.org ReactomeREACT_20171 PathwayStep6941 PathwayStep6940 PathwayStep6937 PathwayStep6938 PathwayStep6935 PathwayStep6936 PathwayStep6933 PathwayStep6934 PathwayStep6931 PathwayStep6932 AKT Converted from EntitySet in Reactome Reactome DB_ID: 202088 Reactome Database ID Release 43202088 Reactome, http://www.reactome.org ReactomeREACT_12946 PathwayStep6939 PathwayStep6907 G-protein alpha (i) Converted from EntitySet in Reactome Reactome DB_ID: 112270 Reactome Database ID Release 43112270 Reactome, http://www.reactome.org ReactomeREACT_20243 PathwayStep6906 PathwayStep6909 PathwayStep6908 PathwayStep6901 PathwayStep6900 PathwayStep6903 G-protein alpha (q/11) Converted from EntitySet in Reactome Reactome DB_ID: 374848 Reactome Database ID Release 43374848 Reactome, http://www.reactome.org ReactomeREACT_18229 PathwayStep6902 PathwayStep6905 PathwayStep6904 PathwayStep6919 PathwayStep6918 PAR1, 3, 4 Converted from EntitySet in Reactome Reactome DB_ID: 453302 Reactome Database ID Release 43453302 Reactome, http://www.reactome.org ReactomeREACT_21743 PathwayStep6917 PathwayStep6912 PathwayStep6911 PathwayStep6910 PathwayStep6916 PathwayStep6915 PathwayStep6914 PAR N-teminal fragments Converted from EntitySet in Reactome Reactome DB_ID: 453303 Reactome Database ID Release 43453303 Reactome, http://www.reactome.org ReactomeREACT_21736 PathwayStep6913 Thrombin-activated PAR Converted from EntitySet in Reactome Reactome DB_ID: 114530 Reactome Database ID Release 43114530 Reactome, http://www.reactome.org ReactomeREACT_5629 ERK Converted from EntitySet in Reactome Reactome DB_ID: 169291 Reactome Database ID Release 43169291 Reactome, http://www.reactome.org ReactomeREACT_24485 Phospho-ERK Converted from EntitySet in Reactome Reactome DB_ID: 169289 Reactome Database ID Release 43169289 Reactome, http://www.reactome.org ReactomeREACT_24269 PathwayStep6777 PathwayStep6778 PathwayStep6779 Claudin Converted from EntitySet in Reactome Reactome DB_ID: 421245 Reactome Database ID Release 43421245 Reactome, http://www.reactome.org ReactomeREACT_19480 PathwayStep6781 PathwayStep525 PathwayStep6780 PathwayStep524 PathwayStep6783 PathwayStep523 PathwayStep6782 PathwayStep522 PathwayStep6785 PathwayStep529 PathwayStep6784 PathwayStep528 PathwayStep6787 PathwayStep527 PathwayStep6786 PathwayStep526 PathwayStep521 PathwayStep520 PathwayStep6768 PathwayStep6769 PathwayStep6766 PathwayStep6767 PathwayStep6772 PathwayStep534 PathwayStep6771 PathwayStep533 PathwayStep6770 PathwayStep536 PathwayStep535 PathwayStep6776 PathwayStep538 PathwayStep6775 PathwayStep537 PathwayStep6774 PathwayStep6773 PathwayStep539 PathwayStep530 PathwayStep532 PathwayStep531 PathwayStep2510 PathwayStep2511 PHLPP (Mn2+ cofactor) Reactome DB_ID: 199450 Reactome Database ID Release 43199450 Reactome, http://www.reactome.org ReactomeREACT_13329 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep2512 PDPK1:PIP2 Reactome DB_ID: 2219520 Reactome Database ID Release 432219520 Reactome, http://www.reactome.org ReactomeREACT_148508 has a Stoichiometric coefficient of 1 PathwayStep2513 PathwayStep2514 PathwayStep2515 PathwayStep2516 PathwayStep2517 AKT:PIP3 Reactome DB_ID: 2317329 Reactome Database ID Release 432317329 Reactome, http://www.reactome.org ReactomeREACT_147984 has a Stoichiometric coefficient of 1 PathwayStep2518 PDK1:PIP3 PDPK1:PIP3 Reactome DB_ID: 377179 Reactome Database ID Release 43377179 Reactome, http://www.reactome.org ReactomeREACT_148385 has a Stoichiometric coefficient of 1 PathwayStep2519 CD19 Signalosome Reactome DB_ID: 2076233 Reactome Database ID Release 432076233 Reactome, http://www.reactome.org ReactomeREACT_119603 has a Stoichiometric coefficient of 1 Claudin Converted from EntitySet in Reactome Reactome DB_ID: 419998 Reactome Database ID Release 43419998 Reactome, http://www.reactome.org ReactomeREACT_20372 PIK3CD:PIK3R1 PI3-kinase p85:PI3-kinase p110 PI3K p85:p110 Phosphoinositide 3-kinase p85:p110 Reactome DB_ID: 1045152 Reactome Database ID Release 431045152 Reactome, http://www.reactome.org ReactomeREACT_119117 has a Stoichiometric coefficient of 1 PathwayStep6799 AKT:PIP3:THEM4/TRIB3 Reactome DB_ID: 199453 Reactome Database ID Release 43199453 Reactome, http://www.reactome.org ReactomeREACT_12823 has a Stoichiometric coefficient of 1 p-S-AKT:PDPK1:PIP3 Reactome DB_ID: 2317313 Reactome Database ID Release 432317313 Reactome, http://www.reactome.org ReactomeREACT_148335 has a Stoichiometric coefficient of 1 PathwayStep508 p-S-AKT:PIP3 Reactome DB_ID: 2317310 Reactome Database ID Release 432317310 Reactome, http://www.reactome.org ReactomeREACT_148552 has a Stoichiometric coefficient of 1 PathwayStep509 TORC2 complex Reactome DB_ID: 198626 Reactome Database ID Release 43198626 Reactome, http://www.reactome.org ReactomeREACT_13222 has a Stoichiometric coefficient of 1 PathwayStep507 PathwayStep506 PathwayStep505 PathwayStep504 PathwayStep503 miR-26A RISC Converted from EntitySet in Reactome Reactome DB_ID: 2318737 Reactome Database ID Release 432318737 Reactome, http://www.reactome.org ReactomeREACT_148347 miR-26A-induced Silencing Complex PathwayStep502 PathwayStep501 PathwayStep500 PathwayStep2500 PathwayStep2501 PathwayStep2504 PathwayStep2505 PathwayStep2502 PathwayStep2503 PathwayStep2508 PathwayStep2509 PathwayStep2506 Nectin Converted from EntitySet in Reactome Reactome DB_ID: 419017 Reactome Database ID Release 43419017 Reactome, http://www.reactome.org ReactomeREACT_20136 PathwayStep2507 PathwayStep519 PathwayStep6788 PathwayStep6789 PathwayStep6798 PathwayStep516 PathwayStep6797 PathwayStep515 PathwayStep6796 PathwayStep518 PathwayStep6795 PathwayStep517 PathwayStep6794 PathwayStep512 PathwayStep6793 PathwayStep511 beta-catenin Converted from EntitySet in Reactome Reactome DB_ID: 191731 Reactome Database ID Release 43191731 Reactome, http://www.reactome.org ReactomeREACT_19962 PathwayStep6792 PathwayStep514 PathwayStep6791 PathwayStep513 PathwayStep6790 PathwayStep510 PathwayStep6734 PathwayStep6733 PathwayStep6736 PathwayStep6735 PathwayStep6738 PathwayStep6737 PathwayStep6739 PathwayStep6740 PathwayStep6741 PathwayStep6742 PathwayStep6743 PathwayStep6725 PathwayStep6724 PathwayStep6723 PathwayStep6722 PathwayStep6729 PathwayStep6728 PathwayStep6727 PathwayStep6726 PathwayStep6731 PathwayStep6732 PathwayStep6730 PathwayStep6759 PathwayStep6756 PathwayStep6755 PathwayStep6758 PathwayStep6757 PathwayStep6762 PathwayStep6763 PathwayStep6764 PathwayStep6765 PathwayStep6760 PathwayStep6761 PathwayStep6749 PathwayStep6748 PathwayStep6747 PathwayStep6746 PathwayStep6745 PathwayStep6744 PathwayStep6753 PathwayStep6754 PathwayStep6751 PathwayStep6752 PathwayStep6750 EGF:Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIs:HSP90:CDC37 Reactome DB_ID: 1809167 Reactome Database ID Release 431809167 Reactome, http://www.reactome.org ReactomeREACT_117164 has a Stoichiometric coefficient of 1 EGF:Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIs:HSP90:CDC37 Reactome DB_ID: 1809164 Reactome Database ID Release 431809164 Reactome, http://www.reactome.org ReactomeREACT_117097 has a Stoichiometric coefficient of 1 Ligand-responsive p-6Y-EGFR mutants:HSP90:CDC37 Converted from EntitySet in Reactome Reactome DB_ID: 1220650 Reactome Database ID Release 431220650 Reactome, http://www.reactome.org ReactomeREACT_117656 Dimers of ligand-responsive p-6Y-EGFR mutants Reactome DB_ID: 1220654 Reactome Database ID Release 431220654 Reactome, http://www.reactome.org ReactomeREACT_117779 has a Stoichiometric coefficient of 2 Ligand-responsive p-6Y-EGFR mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 1181062 Reactome Database ID Release 431181062 Reactome, http://www.reactome.org ReactomeREACT_117728 EGF:Ligand-responsive p-6Y-EGFR mutants:HSP90:CDC37 Converted from EntitySet in Reactome Reactome DB_ID: 1220648 Reactome Database ID Release 431220648 Reactome, http://www.reactome.org ReactomeREACT_116389 Dimers of EGF:Ligand-responsive p-6Y-EGFR mutants Reactome DB_ID: 1220652 Reactome Database ID Release 431220652 Reactome, http://www.reactome.org ReactomeREACT_116345 has a Stoichiometric coefficient of 2 PathwayStep2585 PathwayStep2584 PathwayStep2583 PathwayStep2582 PathwayStep2581 PathwayStep2580 PathwayStep2579 PathwayStep2577 PathwayStep2578 PathwayStep2575 PathwayStep2576 EGF:Ligand-responsive EGFR mutants sensitive to non-covalent TKIs:HSP90:CDC37 Reactome DB_ID: 1220580 Reactome Database ID Release 431220580 Reactome, http://www.reactome.org ReactomeREACT_116412 has a Stoichiometric coefficient of 1 EGF:Ligand-responsive EGFR mutants dimer Reactome DB_ID: 1500847 Reactome Database ID Release 431500847 Reactome, http://www.reactome.org ReactomeREACT_116688 has a Stoichiometric coefficient of 2 Ligand-responsive EGFR mutants dimer Reactome DB_ID: 1500849 Reactome Database ID Release 431500849 Reactome, http://www.reactome.org ReactomeREACT_117130 has a Stoichiometric coefficient of 2 Active dimers of ligand-responsive EGFR mutants Converted from EntitySet in Reactome Reactome DB_ID: 1220582 Reactome Database ID Release 431220582 Reactome, http://www.reactome.org ReactomeREACT_116938 EGF:Ligand-responsive EGFR mutants resistant to non-covalent TKIs:HSP90:CDC37 Reactome DB_ID: 1220573 Reactome Database ID Release 431220573 Reactome, http://www.reactome.org ReactomeREACT_116381 has a Stoichiometric coefficient of 1 EGF:Ligand-responsive EGFR mutants:HSP90:CDC37 Converted from EntitySet in Reactome Reactome DB_ID: 1220578 Reactome Database ID Release 431220578 Reactome, http://www.reactome.org ReactomeREACT_116916 Ligand-responsive EGFR mutants sensitive to non-covalent TKIs:HSP90:CDC37 Reactome DB_ID: 1220583 Reactome Database ID Release 431220583 Reactome, http://www.reactome.org ReactomeREACT_117232 has a Stoichiometric coefficient of 1 Ligand-responsive EGFR mutants resistant to non-covalent TKIs:HSP90:CDC37 Reactome DB_ID: 1220581 Reactome Database ID Release 431220581 Reactome, http://www.reactome.org ReactomeREACT_116923 has a Stoichiometric coefficient of 1 Ligand-responsive EGFR mutants:HSP90:CDC37 Converted from EntitySet in Reactome Reactome DB_ID: 1218825 Reactome Database ID Release 431218825 Reactome, http://www.reactome.org ReactomeREACT_116857 CDC37 CDC37 homodimer Reactome DB_ID: 1225828 Reactome Database ID Release 431225828 Reactome, http://www.reactome.org ReactomeREACT_117086 has a Stoichiometric coefficient of 2 PathwayStep2572 PathwayStep2571 PathwayStep2574 PathwayStep2573 PathwayStep2570 PathwayStep2568 PathwayStep2569 PathwayStep2564 PathwayStep2565 PathwayStep2566 PathwayStep2567 HSP90 HSP90 homodimer Reactome DB_ID: 1221657 Reactome Database ID Release 431221657 Reactome, http://www.reactome.org ReactomeREACT_117107 has a Stoichiometric coefficient of 2 CIN85 ubiquitinated Reactome DB_ID: 182926 Reactome Database ID Release 43182926 Reactome, http://www.reactome.org ReactomeREACT_13254 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:SPRY1/2:Endophilin:Epsin:Eps15R:Eps15 EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85-Sprouty:Endophilin:Epsin:Eps15R:Eps15 complex Reactome DB_ID: 182931 Reactome Database ID Release 43182931 Reactome, http://www.reactome.org ReactomeREACT_12661 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 EGF:p-6Y-EGFR:p-Y371-CBL:Ub-CIN85:Endophilin:Epsin:Eps15R:Eps15 EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85 ubiquitinated:Endophilin:Epsin:Eps15R:Eps15 complex Reactome DB_ID: 182936 Reactome Database ID Release 43182936 Reactome, http://www.reactome.org ReactomeREACT_13370 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CIN85 ubiquitinated:Endophilin Reactome DB_ID: 187073 Reactome Database ID Release 43187073 Reactome, http://www.reactome.org ReactomeREACT_12922 has a Stoichiometric coefficient of 1 Ligand-responsive p-6Y-EGFR mutants:p-Y371-CBL Reactome DB_ID: 1225857 Reactome Database ID Release 431225857 Reactome, http://www.reactome.org ReactomeREACT_117735 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Ligand-responsive p-6Y-EGFR mutants:CBL Reactome DB_ID: 1225855 Reactome Database ID Release 431225855 Reactome, http://www.reactome.org ReactomeREACT_116570 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 HSP90:Benzoquinoid ansamycins Complex of heat shock protein 90 and one of the benzoquinoid ansamycins Reactome DB_ID: 1218829 Reactome Database ID Release 431218829 Reactome, http://www.reactome.org ReactomeREACT_116873 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Ligand-responsive Ub-p-6Y-EGFR mutants:p-Y371-CBL Reactome DB_ID: 1225852 Reactome Database ID Release 431225852 Reactome, http://www.reactome.org ReactomeREACT_116599 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep589 Dimers of EGF:Ligand-responsive EGFR mutants resistant to non-covalent TKIs Reactome DB_ID: 1220574 Reactome Database ID Release 431220574 Reactome, http://www.reactome.org ReactomeREACT_116994 has a Stoichiometric coefficient of 2 PathwayStep588 Resistant ligand-responsive EGFR mutants Converted from EntitySet in Reactome Reactome DB_ID: 1220585 Reactome Database ID Release 431220585 Reactome, http://www.reactome.org ReactomeREACT_117827 Sensitive ligand-responsive EGFR mutants:Non-covalent EGFR TKIs Reactome DB_ID: 1220587 Reactome Database ID Release 431220587 Reactome, http://www.reactome.org ReactomeREACT_117305 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Dimers of ligand-responsive EGFR mutants resistant to non-covalent TKIs Reactome DB_ID: 1220575 Reactome Database ID Release 431220575 Reactome, http://www.reactome.org ReactomeREACT_117705 has a Stoichiometric coefficient of 2 PathwayStep585 PathwayStep584 PathwayStep587 PathwayStep586 PathwayStep581 PathwayStep580 PathwayStep583 p-EGFR mutants:p-Y472,771,783,1254-PLCG1 Reactome DB_ID: 1247846 Reactome Database ID Release 431247846 Reactome, http://www.reactome.org ReactomeREACT_116620 has a Stoichiometric coefficient of 1 PathwayStep582 PathwayStep2599 PathwayStep2597 PathwayStep590 PathwayStep2598 p-EGFR mutants:GRB2:GAB1:PI3K GRB2:GAB1:PI3Kreg:PI3Kcat-Active dimers of phospho-EGFR KD mutants:HSP90:CDC37 Reactome DB_ID: 1226013 Reactome Database ID Release 431226013 Reactome, http://www.reactome.org ReactomeREACT_116903 has a Stoichiometric coefficient of 1 p-EGFR mutants:PLCG1 Phospho-EGFRmutKD:PLCgamma1 Reactome DB_ID: 1247845 Reactome Database ID Release 431247845 Reactome, http://www.reactome.org ReactomeREACT_117319 has a Stoichiometric coefficient of 1 p-EGFR mutants:GRB2:SOS1 GRB2:SOS1-Active dimers of phospho-EGFR KD mutants:HSP90:CDC37 GRB2:SOS1:Phospho-EGFRmutKD:HSP90:CDC37 Reactome DB_ID: 1225859 Reactome Database ID Release 431225859 Reactome, http://www.reactome.org ReactomeREACT_116562 has a Stoichiometric coefficient of 1 Phospho-EGFRvIIImut:HSP90:CDC37 Reactome DB_ID: 1248651 Reactome Database ID Release 431248651 Reactome, http://www.reactome.org ReactomeREACT_117366 has a Stoichiometric coefficient of 1 p-5Y-EGFRvIII mutant dimer Activated phospho-EGFRvIIImut:HSP90:CDC37 Reactome DB_ID: 1248654 Reactome Database ID Release 431248654 Reactome, http://www.reactome.org ReactomeREACT_116729 has a Stoichiometric coefficient of 2 EGFRvIII mutant dimer Activated EGFRvIIImut:HSP90:CDC37 Reactome DB_ID: 1248010 Reactome Database ID Release 431248010 Reactome, http://www.reactome.org ReactomeREACT_117412 has a Stoichiometric coefficient of 2 p-EGFR mutants:GRB2:GAB1:PIK3R1 GRB2:GAB1:PI3Kreg-Active dimers of phospho-EGFR KD mutants:HSP90:CDC37 Reactome DB_ID: 1226015 Reactome Database ID Release 431226015 Reactome, http://www.reactome.org ReactomeREACT_117295 has a Stoichiometric coefficient of 1 p-EGFR mutants:p-Y349,350-SHC1:GRB2:SOS1 GRB2:SOS1-Phospho-SHC1:Active dimers of phospho-EGFR KD mutants:HSP90:CDC37 GRB2:SOS1:Phospho-SHC1:Phospho-EGFRmutKD:HSP90:CDC37 Reactome DB_ID: 1225856 Reactome Database ID Release 431225856 Reactome, http://www.reactome.org ReactomeREACT_116797 has a Stoichiometric coefficient of 1 Filamin Converted from EntitySet in Reactome Reactome DB_ID: 446328 Reactome Database ID Release 43446328 Reactome, http://www.reactome.org ReactomeREACT_20988 p-EGFR mutants:p-Y349,350-SHC1 Reactome DB_ID: 1225854 Reactome Database ID Release 431225854 Reactome, http://www.reactome.org ReactomeREACT_117226 has a Stoichiometric coefficient of 1 PathwayStep599 p-EGFR mutants:SHC1 Active dimers of phospho-EGFR KD mutants:HSP90:CDC37:SHC1 Reactome DB_ID: 1225858 Reactome Database ID Release 431225858 Reactome, http://www.reactome.org ReactomeREACT_116600 has a Stoichiometric coefficient of 1 PathwayStep598 PathwayStep2590 PathwayStep597 PathwayStep596 PathwayStep2592 PathwayStep595 PathwayStep2591 PathwayStep594 PathwayStep2594 PathwayStep593 PathwayStep2593 PathwayStep592 PathwayStep2596 PINCH Converted from EntitySet in Reactome Reactome DB_ID: 446301 Reactome Database ID Release 43446301 Reactome, http://www.reactome.org ReactomeREACT_21063 PathwayStep591 PathwayStep2595 PathwayStep2586 PathwayStep2587 PathwayStep2588 PathwayStep2589 EGFRvIIImut:HSP90:CDC37 EGFRvIII mutant:HSP90:CDC37 Reactome DB_ID: 1248004 Reactome Database ID Release 431248004 Reactome, http://www.reactome.org ReactomeREACT_117752 has a Stoichiometric coefficient of 1 Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIs:HSP90:CDC37 Reactome DB_ID: 1809168 Reactome Database ID Release 431809168 Reactome, http://www.reactome.org ReactomeREACT_116252 has a Stoichiometric coefficient of 1 Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIs:HSP90:CDC37 Reactome DB_ID: 1809170 Reactome Database ID Release 431809170 Reactome, http://www.reactome.org ReactomeREACT_117650 has a Stoichiometric coefficient of 1 PathwayStep2540 RNA Polymerase I Transcription Initiation complex Reactome DB_ID: 73716 Reactome Database ID Release 4373716 Reactome, http://www.reactome.org ReactomeREACT_4081 has a Stoichiometric coefficient of 1 PathwayStep2541 Active RNA Polymerase I Reactome DB_ID: 73715 Reactome Database ID Release 4373715 Reactome, http://www.reactome.org ReactomeREACT_2755 has a Stoichiometric coefficient of 1 PathwayStep560 RNA Polymerase I Holoenzyme Reactome DB_ID: 73859 Reactome Database ID Release 4373859 Reactome, http://www.reactome.org ReactomeREACT_4039 has a Stoichiometric coefficient of 1 PathwayStep561 TTF-I:Sal Box Reactome DB_ID: 74977 Reactome Database ID Release 4374977 Reactome, http://www.reactome.org ReactomeREACT_5864 has a Stoichiometric coefficient of 1 PathwayStep562 TTF-I: rRNA Promoter: CSB: G9a Complex Reactome DB_ID: 427352 Reactome Database ID Release 43427352 Reactome, http://www.reactome.org ReactomeREACT_20432 has a Stoichiometric coefficient of 1 PathwayStep563 PathwayStep564 PathwayStep565 PathwayStep566 alpha/beta parvin Converted from EntitySet in Reactome Reactome DB_ID: 446032 Reactome Database ID Release 43446032 Reactome, http://www.reactome.org ReactomeREACT_20989 PathwayStep567 EGF:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2 EGF:Phospho-EGFR (Y1045) dimer:CBL:Phospho-Sprouty ubiquitinated Reactome DB_ID: 182939 Reactome Database ID Release 43182939 Reactome, http://www.reactome.org ReactomeREACT_12687 has a Stoichiometric coefficient of 1 PathwayStep568 Ub-p-Y53/55-SPRY1/2 Phospho-SPROUTY ubiquitinated Reactome DB_ID: 182967 Reactome Database ID Release 43182967 Reactome, http://www.reactome.org ReactomeREACT_13220 has a Stoichiometric coefficient of 1 PathwayStep569 PTRF:Polymerase I/Nascent Pre rRNA Complex:TTF-I:Sal Box Reactome DB_ID: 74982 Reactome Database ID Release 4374982 Reactome, http://www.reactome.org ReactomeREACT_4203 has a Stoichiometric coefficient of 1 EGF:Ub-p-6Y-EGFR:p-Y371-CBL EGF:Phospho-EGFR (Y1045) dimer Ubiquitinated:Phospho-CBL Reactome DB_ID: 182930 Reactome Database ID Release 43182930 Reactome, http://www.reactome.org ReactomeREACT_12986 has a Stoichiometric coefficient of 2 PINCH Converted from EntitySet in Reactome Reactome DB_ID: 446104 Reactome Database ID Release 43446104 Reactome, http://www.reactome.org ReactomeREACT_20717 RNA Polymerase I:rRNATranscript:TTF-1:Sal Box Complex Reactome DB_ID: 74979 Reactome Database ID Release 4374979 Reactome, http://www.reactome.org ReactomeREACT_2713 has a Stoichiometric coefficient of 1 Nucleosome with Deacetylated H4 and H3 Dimethylated at Lysine-9 Reactome DB_ID: 427331 Reactome Database ID Release 43427331 Reactome, http://www.reactome.org ReactomeREACT_23375 has a Stoichiometric coefficient of 2 Nucleosome with H3 dimethylated at lysine-9: HP1gamma Complex Reactome DB_ID: 427344 Reactome Database ID Release 43427344 Reactome, http://www.reactome.org ReactomeREACT_19440 has a Stoichiometric coefficient of 1 RNA Polymerase I promoter escape complex Reactome DB_ID: 73717 Reactome Database ID Release 4373717 Reactome, http://www.reactome.org ReactomeREACT_5158 has a Stoichiometric coefficient of 1 PXN:SRC Paxillin:Src complex Reactome DB_ID: 180523 Reactome Database ID Release 43180523 Reactome, http://www.reactome.org ReactomeREACT_13128 has a Stoichiometric coefficient of 1 PXN:CSK:SRC Paxillin:CSK:Src complex Reactome DB_ID: 180522 Reactome Database ID Release 43180522 Reactome, http://www.reactome.org ReactomeREACT_12813 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:p-Y371-CBL EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL Reactome DB_ID: 182953 Reactome Database ID Release 43182953 Reactome, http://www.reactome.org ReactomeREACT_13081 has a Stoichiometric coefficient of 2 EGF:p-6Y-EGFR:CBL EGF:Phospho-EGFR (Y1045) dimer:CBL Reactome DB_ID: 182960 Reactome Database ID Release 43182960 Reactome, http://www.reactome.org ReactomeREACT_12959 has a Stoichiometric coefficient of 2 EGF:p-5Y-EGFR:GRB2:p-5Y-GAB1:SHP2 Reactome DB_ID: 180326 Reactome Database ID Release 43180326 Reactome, http://www.reactome.org ReactomeREACT_13205 SHP2:GRB2:Phospho GAB1-EGF-Phospho-EGFR (-Y992) dimer has a Stoichiometric coefficient of 1 GRB2:Phospho-GAB1(partially dephosphorylated) Reactome DB_ID: 180511 Reactome Database ID Release 43180511 Reactome, http://www.reactome.org ReactomeREACT_12923 has a Stoichiometric coefficient of 1 EGF:Phospho-EGFR (- Y992) Reactome DB_ID: 180277 Reactome Database ID Release 43180277 Reactome, http://www.reactome.org ReactomeREACT_12667 has a Stoichiometric coefficient of 1 PathwayStep2539 EGF:Phospho-EGFR (-Y992) dimer Reactome DB_ID: 180343 Reactome Database ID Release 43180343 Reactome, http://www.reactome.org ReactomeREACT_12756 has a Stoichiometric coefficient of 2 PathwayStep2538 PathwayStep2537 PathwayStep2536 PathwayStep2535 PathwayStep2534 PathwayStep2533 PathwayStep2532 PathwayStep2531 PathwayStep571 HsRPC6:HsRPC3:HsRPC7 Reactome DB_ID: 1964442 Reactome Database ID Release 431964442 Reactome, http://www.reactome.org ReactomeREACT_116333 has a Stoichiometric coefficient of 1 PathwayStep572 RNA Polymerase III Holoenzyme Reactome DB_ID: 83716 Reactome Database ID Release 4383716 Reactome, http://www.reactome.org ReactomeREACT_4447 has a Stoichiometric coefficient of 1 HsRPC4:HsRPC5 Reactome DB_ID: 1964428 Reactome Database ID Release 431964428 Reactome, http://www.reactome.org ReactomeREACT_116277 has a Stoichiometric coefficient of 1 PathwayStep570 PathwayStep2530 HsRPC8:HsRPC9 Reactome DB_ID: 1964452 Reactome Database ID Release 431964452 Reactome, http://www.reactome.org ReactomeREACT_117485 has a Stoichiometric coefficient of 1 PathwayStep575 PathwayStep576 PathwayStep573 TFIIIB-Type 1 and 2 Promoter Selective Complex Reactome DB_ID: 83719 Reactome Database ID Release 4383719 Reactome, http://www.reactome.org ReactomeREACT_5002 has a Stoichiometric coefficient of 1 PathwayStep574 RNA polymerase III:TFIIIB:TFIIIC:TFIIIA:Type 1 Open Promoter Complex Reactome DB_ID: 112147 Reactome Database ID Release 43112147 Reactome, http://www.reactome.org ReactomeREACT_2429 has a Stoichiometric coefficient of 1 PathwayStep579 EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2 Reactome DB_ID: 180269 Reactome Database ID Release 43180269 Reactome, http://www.reactome.org ReactomeREACT_12771 SHP2-GRB2:Phospho GAB1-EGF-Phospho-EGFR dimer has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:GRB2:p-Y627,659-GAB1:SHP2 Reactome DB_ID: 180503 Reactome Database ID Release 43180503 Reactome, http://www.reactome.org ReactomeREACT_12652 SHP2-GRB2:Phospho GAB1(dephos)-EGF-Phospho-EGFR dimer has a Stoichiometric coefficient of 1 PAR-6 Converted from EntitySet in Reactome Reactome DB_ID: 419970 Reactome Database ID Release 43419970 Reactome, http://www.reactome.org ReactomeREACT_19459 PathwayStep577 PathwayStep578 RNA Polymerase III:TFIIIB:TFIIIC:Type 2 Open Promoter Complex Reactome DB_ID: 112148 Reactome Database ID Release 43112148 Reactome, http://www.reactome.org ReactomeREACT_3405 has a Stoichiometric coefficient of 1 TFIIIC Reactome DB_ID: 83698 Reactome Database ID Release 4383698 Reactome, http://www.reactome.org ReactomeREACT_5844 has a Stoichiometric coefficient of 1 TFIIIB-Type 3 Promoter Selective Complex Reactome DB_ID: 83722 Reactome Database ID Release 4383722 Reactome, http://www.reactome.org ReactomeREACT_4449 has a Stoichiometric coefficient of 1 RNA Polymerase III:TFIIIB:SNAPc:Type 3 Open Promoter Complex Reactome DB_ID: 112151 Reactome Database ID Release 43112151 Reactome, http://www.reactome.org ReactomeREACT_4790 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:GRB2:p-5Y-GAB1 GRB2:Phospho GAB1-EGF-Phospho-EGFR dimer Reactome DB_ID: 180286 Reactome Database ID Release 43180286 Reactome, http://www.reactome.org ReactomeREACT_12983 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:GRB2:GAB1 GAB1:GRB2-EGF-Phospho-EGFR dimer Reactome DB_ID: 180348 Reactome Database ID Release 43180348 Reactome, http://www.reactome.org ReactomeREACT_13196 has a Stoichiometric coefficient of 1 GRB2:GAB1:PIP3 PIP3:GAB1:GRB2 Reactome DB_ID: 180282 Reactome Database ID Release 43180282 Reactome, http://www.reactome.org ReactomeREACT_13218 has a Stoichiometric coefficient of 1 PTEN mRNA:miR-26A RISC Reactome DB_ID: 2318750 Reactome Database ID Release 432318750 Reactome, http://www.reactome.org ReactomeREACT_147972 has a Stoichiometric coefficient of 1 PathwayStep2529 Argonaute1/3/4: miR-26A Reactome DB_ID: 2318739 Reactome Database ID Release 432318739 Reactome, http://www.reactome.org ReactomeREACT_148452 has a Stoichiometric coefficient of 1 miR-26A Nonendonucleolytic Minimal RISC PathwayStep2528 miR-26A Nonendonucleolytic RISC Reactome DB_ID: 2318738 Reactome Database ID Release 432318738 Reactome, http://www.reactome.org ReactomeREACT_148026 has a Stoichiometric coefficient of 1 miR-26A Endonucleolytic Minimal RISC Argonaute2: miR-26A (single-stranded) Reactome DB_ID: 2318741 Reactome Database ID Release 432318741 Reactome, http://www.reactome.org ReactomeREACT_148442 has a Stoichiometric coefficient of 1 miR-26A Endonucleolytic RISC Reactome DB_ID: 2318744 Reactome Database ID Release 432318744 Reactome, http://www.reactome.org ReactomeREACT_148037 has a Stoichiometric coefficient of 1 PathwayStep2525 PathwayStep2524 PathwayStep2527 PathwayStep2526 PathwayStep2521 PathwayStep2520 PathwayStep2523 PathwayStep2522 GRB2:Phospho-GAB1 Reactome DB_ID: 180304 Reactome Database ID Release 43180304 Reactome, http://www.reactome.org ReactomeREACT_13053 has a Stoichiometric coefficient of 1 PathwayStep540 RNA polymerase III:TFIIIB:TFIIIC:TFIIIA:Type 1 Promoter Complex Reactome DB_ID: 83717 Reactome Database ID Release 4383717 Reactome, http://www.reactome.org ReactomeREACT_2997 has a Stoichiometric coefficient of 1 PathwayStep541 Elongating RNA Polymerase III Transcription Complex Reactome DB_ID: 112479 Reactome Database ID Release 43112479 Reactome, http://www.reactome.org ReactomeREACT_4544 has a Stoichiometric coefficient of 1 PathwayStep542 SNAPc Reactome DB_ID: 83730 Reactome Database ID Release 4383730 Reactome, http://www.reactome.org ReactomeREACT_3727 has a Stoichiometric coefficient of 1 PathwayStep543 PathwayStep2562 TFIIIB:TFIIIC:Type 2 Promoter Complex Reactome DB_ID: 83749 Reactome Database ID Release 4383749 Reactome, http://www.reactome.org ReactomeREACT_3826 has a Stoichiometric coefficient of 1 PathwayStep2563 RNA Polymerase III:TFIIIB:TFIIIC:Type 2 Promoter Complex Reactome DB_ID: 83750 Reactome Database ID Release 4383750 Reactome, http://www.reactome.org ReactomeREACT_5655 has a Stoichiometric coefficient of 1 PathwayStep2560 TFIIIC:TFIIIA:Type I Promoter Complex Reactome DB_ID: 76053 Reactome Database ID Release 4376053 Reactome, http://www.reactome.org ReactomeREACT_4465 has a Stoichiometric coefficient of 1 PathwayStep2561 TFIIIB:TFIIIC:TFIIIA:Type 1 Promoter Complex Reactome DB_ID: 76055 Reactome Database ID Release 4376055 Reactome, http://www.reactome.org ReactomeREACT_3594 has a Stoichiometric coefficient of 1 PathwayStep548 PathwayStep549 TFIIIB:SNAPc:Oct-1:Staf:Type 3 Promoter Complex Reactome DB_ID: 83754 Reactome Database ID Release 4383754 Reactome, http://www.reactome.org ReactomeREACT_4686 has a Stoichiometric coefficient of 1 RNA Polymerase III:TFIIIB:SNAPc:Type 3 Promoter Complex Reactome DB_ID: 83755 Reactome Database ID Release 4383755 Reactome, http://www.reactome.org ReactomeREACT_3694 has a Stoichiometric coefficient of 1 TFIIIC:Type 2 Promoter Complex Reactome DB_ID: 83748 Reactome Database ID Release 4383748 Reactome, http://www.reactome.org ReactomeREACT_3586 has a Stoichiometric coefficient of 1 Eps15:HGS:STAM Reactome DB_ID: 182947 Reactome Database ID Release 43182947 Reactome, http://www.reactome.org ReactomeREACT_12763 has a Stoichiometric coefficient of 1 PathwayStep544 EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:Epsin:Eps15R:Eps15:Clathrin EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:GRB2:CIN85:Endophilin:Epsin:Eps15R:Eps15 complex:Clathrin Reactome DB_ID: 182941 Reactome Database ID Release 43182941 Reactome, http://www.reactome.org ReactomeREACT_13237 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep545 Clathrin-coated vesicle Reactome DB_ID: 177505 Reactome Database ID Release 43177505 Reactome, http://www.reactome.org ReactomeREACT_13103 has a Stoichiometric coefficient of 1 PathwayStep546 EGF:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15 EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:CIN85:Endophilin:Epsin:Eps15R:Eps15 complex Reactome DB_ID: 182961 Reactome Database ID Release 43182961 Reactome, http://www.reactome.org ReactomeREACT_13366 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep547 EGF:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2 EGF:Phospho-EGFR dimer:CBL:Phospho-Sprouty Reactome DB_ID: 182935 Reactome Database ID Release 43182935 Reactome, http://www.reactome.org ReactomeREACT_13028 has a Stoichiometric coefficient of 1 PAR-6 Converted from EntitySet in Reactome Reactome DB_ID: 419985 Reactome Database ID Release 43419985 Reactome, http://www.reactome.org ReactomeREACT_20412 EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP EGF:Phospho-EGFR (Y1045) dimer:CBL:Cool/Pix:CDC42-GTP Reactome DB_ID: 182932 Reactome Database ID Release 43182932 Reactome, http://www.reactome.org ReactomeREACT_12733 has a Stoichiometric coefficient of 2 EGF:p-6Y-EGFR:CBL:CIN85 EGF:Phospho-EGFR (Y1045) dimer:CBL:CIN85 Reactome DB_ID: 182943 Reactome Database ID Release 43182943 Reactome, http://www.reactome.org ReactomeREACT_13382 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CIN85:Endophilin Reactome DB_ID: 182934 Reactome Database ID Release 43182934 Reactome, http://www.reactome.org ReactomeREACT_12741 has a Stoichiometric coefficient of 1 Ub-Beta-Pix:CDC42:GTP Cool/Pix Ubiquitinated:CDC42-GTP Reactome DB_ID: 182915 Reactome Database ID Release 43182915 Reactome, http://www.reactome.org ReactomeREACT_13061 has a Stoichiometric coefficient of 1 AP-2 complex Adaptor protein 2 complex Reactome DB_ID: 177480 Reactome Database ID Release 43177480 Reactome, http://www.reactome.org ReactomeREACT_13288 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:GRB2:CIN85:Endophilin Reactome DB_ID: 182946 Reactome Database ID Release 43182946 Reactome, http://www.reactome.org ReactomeREACT_12726 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep2556 PathwayStep2555 PathwayStep2554 PathwayStep2553 PathwayStep2559 PathwayStep2558 PathwayStep2557 PathwayStep553 PathwayStep554 PathwayStep551 PathwayStep552 PathwayStep550 PathwayStep2550 PathwayStep2551 PathwayStep2552 PathwayStep559 PathwayStep557 CBL:Beta-Pix:CDC42:GTP CBL:Cool/Pix:CDC42:GTP Reactome DB_ID: 182956 Reactome Database ID Release 43182956 Reactome, http://www.reactome.org ReactomeREACT_13219 has a Stoichiometric coefficient of 1 PathwayStep558 Beta-Pix:CDC42:GTP Cool/Pix:CDC42-GTP Reactome DB_ID: 182917 Reactome Database ID Release 43182917 Reactome, http://www.reactome.org ReactomeREACT_12882 has a Stoichiometric coefficient of 1 PathwayStep555 CBL:Beta-Pix CBL:Cool-Pix Reactome DB_ID: 182942 Reactome Database ID Release 43182942 Reactome, http://www.reactome.org ReactomeREACT_13162 has a Stoichiometric coefficient of 1 PathwayStep556 CDC42:GTP CDC42-GTP Reactome DB_ID: 182921 Reactome Database ID Release 43182921 Reactome, http://www.reactome.org ReactomeREACT_12889 has a Stoichiometric coefficient of 1 EGF:Ub-p-6Y-EGFR:p-Y371-CBL:GRB2 EGF:Phospho-EGFR (Y1045) dimer Ubiquitinated:Phospho-CBL:GRB2 Reactome DB_ID: 182945 Reactome Database ID Release 43182945 Reactome, http://www.reactome.org ReactomeREACT_12838 has a Stoichiometric coefficient of 2 EGF:p-6Y-EGFR:p-Y371-CBL:GRB2 EGF:Phospho-EGFR (Y1045) dimer:Phospho-CBL:GRB2 Reactome DB_ID: 182948 Reactome Database ID Release 43182948 Reactome, http://www.reactome.org ReactomeREACT_13256 has a Stoichiometric coefficient of 2 EGF:p-6Y-EGFR:CBL:GRB2 EGF:Phospho-EGFR (Y1045) dimer:CBL:GRB2 Reactome DB_ID: 182928 Reactome Database ID Release 43182928 Reactome, http://www.reactome.org ReactomeREACT_13163 has a Stoichiometric coefficient of 2 CBL:GRB2 Reactome DB_ID: 182910 Reactome Database ID Release 43182910 Reactome, http://www.reactome.org ReactomeREACT_13333 has a Stoichiometric coefficient of 1 CBL:SPRY1/2 CBL:Sprouty Reactome DB_ID: 182938 Reactome Database ID Release 43182938 Reactome, http://www.reactome.org ReactomeREACT_13051 has a Stoichiometric coefficient of 1 CBL:SPRY1/2 CBL:Sprouty Reactome DB_ID: 182914 Reactome Database ID Release 43182914 Reactome, http://www.reactome.org ReactomeREACT_12947 has a Stoichiometric coefficient of 1 Phospho-CBL:GRB2 Reactome DB_ID: 182964 Reactome Database ID Release 43182964 Reactome, http://www.reactome.org ReactomeREACT_13063 has a Stoichiometric coefficient of 1 PathwayStep2543 PathwayStep2542 PathwayStep2545 PathwayStep2544 PathwayStep2547 PathwayStep2546 PathwayStep2549 PathwayStep2548 Expression of DDX11 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791116 Reactome, http://www.reactome.org ReactomeREACT_116074 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The DDX11 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Translatable mRNA Complex Reactome DB_ID: 429977 Reactome Database ID Release 43429977 Reactome, http://www.reactome.org ReactomeREACT_21129 has a Stoichiometric coefficient of 1 Expression of DCTN1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791092 Reactome, http://www.reactome.org ReactomeREACT_115756 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The DCTN1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Partially Deadenylated mRNA Complex Reactome DB_ID: 429989 Reactome Database ID Release 43429989 Reactome, http://www.reactome.org ReactomeREACT_20682 has a Stoichiometric coefficient of 1 Expression of DNAJB9 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791124 Reactome, http://www.reactome.org ReactomeREACT_115866 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The DNAJB9 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. YARS2 dimer Reactome DB_ID: 379656 Reactome Database ID Release 43379656 Reactome, http://www.reactome.org ReactomeREACT_18046 has a Stoichiometric coefficient of 2 Expression of DNAJB11 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed10827079 Reactome Database ID Release 431791075 Reactome, http://www.reactome.org ReactomeREACT_116120 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The DNAJB11 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PPA2 dimer Reactome DB_ID: 449923 Reactome Database ID Release 43449923 Reactome, http://www.reactome.org ReactomeREACT_21920 has a Stoichiometric coefficient of 2 Expression of EXTL3 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791144 Reactome, http://www.reactome.org ReactomeREACT_115825 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The EXTL3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. CCR4-NOT Complex Reactome DB_ID: 429896 Reactome Database ID Release 43429896 Reactome, http://www.reactome.org ReactomeREACT_21110 has a Stoichiometric coefficient of 1 Expression of EDEM Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16461360 Reactome Database ID Release 431791155 Reactome, http://www.reactome.org ReactomeREACT_116092 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The EDEM gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of ARFGAP1 (GAP) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791064 Reactome, http://www.reactome.org ReactomeREACT_115613 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The GAP gene is transcribed to yield mRNA and the mRNA is translated to yield protein. hPAN Complex PAN2-PAN3 Complex Reactome DB_ID: 429882 Reactome Database ID Release 43429882 Reactome, http://www.reactome.org ReactomeREACT_20697 has a Stoichiometric coefficient of 1 Expression of FKBP14 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791114 Reactome, http://www.reactome.org ReactomeREACT_115587 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The FKBP14 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PARN homodimer Reactome DB_ID: 429886 Reactome Database ID Release 43429886 Reactome, http://www.reactome.org ReactomeREACT_21052 has a Stoichiometric coefficient of 2 KARS dimer Reactome DB_ID: 379687 Reactome Database ID Release 43379687 Reactome, http://www.reactome.org ReactomeREACT_15848 has a Stoichiometric coefficient of 2 SARS2 dimer Reactome DB_ID: 379672 Reactome Database ID Release 43379672 Reactome, http://www.reactome.org ReactomeREACT_15712 has a Stoichiometric coefficient of 2 Expression of Cullin-7 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791058 Reactome, http://www.reactome.org ReactomeREACT_115788 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The Cullin-7 (CUL7) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of CXXC1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791158 Reactome, http://www.reactome.org ReactomeREACT_115869 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The CXXC1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. GARS dimer Reactome DB_ID: 379593 Reactome Database ID Release 43379593 Reactome, http://www.reactome.org ReactomeREACT_17609 has a Stoichiometric coefficient of 2 Expression of CTDSP2 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791130 Reactome, http://www.reactome.org ReactomeREACT_115909 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The CTDSP2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Xbp1(S) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed10958673 Reactome Database ID Release 431791121 Reactome, http://www.reactome.org ReactomeREACT_115803 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The XBP1 gene is transcribed to yield mRNA, the mRNA is spliced to yield Xbp(s) mRNA, and the mRNA is translated to yield protein. GARS dimer Reactome DB_ID: 379600 Reactome Database ID Release 43379600 Reactome, http://www.reactome.org ReactomeREACT_15693 has a Stoichiometric coefficient of 2 Expression of HSP90B1 (Endoplasmin) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed2377606 Reactome Database ID Release 431791163 Reactome, http://www.reactome.org ReactomeREACT_115872 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The Endoplasmin (HSP90B1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. FARS A2B2 tetramer Reactome DB_ID: 379637 Reactome Database ID Release 43379637 Reactome, http://www.reactome.org ReactomeREACT_16104 has a Stoichiometric coefficient of 2 Expression of Calreticulin Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed9837962 Reactome Database ID Release 431791082 Reactome, http://www.reactome.org ReactomeREACT_116001 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The Calreticulin gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SARS dimer Reactome DB_ID: 379557 Reactome Database ID Release 43379557 Reactome, http://www.reactome.org ReactomeREACT_18078 has a Stoichiometric coefficient of 2 Expression of CHOP (DDIT3, GADD153) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed10958673 Pubmed14630918 Reactome Database ID Release 431791107 Reactome, http://www.reactome.org ReactomeREACT_115551 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The CHOP (DDIT3) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. TARS dimer Reactome DB_ID: 379624 Reactome Database ID Release 43379624 Reactome, http://www.reactome.org ReactomeREACT_16019 has a Stoichiometric coefficient of 2 Expression of C19orf10 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791102 Reactome, http://www.reactome.org ReactomeREACT_115959 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The C19orf10 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. WARS dimer Reactome DB_ID: 379684 Reactome Database ID Release 43379684 Reactome, http://www.reactome.org ReactomeREACT_15987 has a Stoichiometric coefficient of 2 Expression of ATP6VOD1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791184 Reactome, http://www.reactome.org ReactomeREACT_115786 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The ATP6VOD1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. YARS dimer Reactome DB_ID: 379566 Reactome Database ID Release 43379566 Reactome, http://www.reactome.org ReactomeREACT_16005 has a Stoichiometric coefficient of 2 Expression of ADD1 (Adducin alpha) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791076 Reactome, http://www.reactome.org ReactomeREACT_115808 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The ADD1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PPA1 dimer Reactome DB_ID: 71726 Reactome Database ID Release 4371726 Reactome, http://www.reactome.org ReactomeREACT_3635 has a Stoichiometric coefficient of 2 inorganic pyrophosphatase dimer Expression of ACADVL Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791069 Reactome, http://www.reactome.org ReactomeREACT_115600 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The ACADVL gene is transcribed to yield mRNA and the mRNA is translated to yield protein. DARS2 dimer Reactome DB_ID: 379573 Reactome Database ID Release 43379573 Reactome, http://www.reactome.org ReactomeREACT_15709 has a Stoichiometric coefficient of 2 Expression of BIP (78 kDa Glucose-regulated protein, GRP78, HSPA5) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed14973138 Reactome Database ID Release 431791150 Reactome, http://www.reactome.org ReactomeREACT_115545 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The BIP (HSPA5) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. DARS homodimer Reactome DB_ID: 379685 Reactome Database ID Release 43379685 Reactome, http://www.reactome.org ReactomeREACT_15891 has a Stoichiometric coefficient of 2 CARS dimer Reactome DB_ID: 379858 Reactome Database ID Release 43379858 Reactome, http://www.reactome.org ReactomeREACT_17681 has a Stoichiometric coefficient of 2 Expression of Sec12 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791083 Reactome, http://www.reactome.org ReactomeREACT_116123 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The Sec12 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of SYVN1 (HRD1) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed18664523 Reactome Database ID Release 431791084 Reactome, http://www.reactome.org ReactomeREACT_115682 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The SYVN1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. mRNA Cleaved by SMG6 Reactome DB_ID: 927845 Reactome Database ID Release 43927845 Reactome, http://www.reactome.org ReactomeREACT_76273 has a Stoichiometric coefficient of 1 Expression of SRPRB (SRP Receptor subunit beta) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791060 Reactome, http://www.reactome.org ReactomeREACT_115588 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The SRPRB gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PP2A (Aalpha:B55alpha:Calpha) Reactome DB_ID: 377182 Reactome Database ID Release 43377182 Reactome, http://www.reactome.org ReactomeREACT_76435 has a Stoichiometric coefficient of 1 Expression of SRPR (SRP Receptor subunit alpha) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791139 Reactome, http://www.reactome.org ReactomeREACT_116080 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The SRPR gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Phosphorylated UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNP Reactome DB_ID: 927854 Reactome Database ID Release 43927854 Reactome, http://www.reactome.org ReactomeREACT_76275 has a Stoichiometric coefficient of 1 Expression of SULT1A3 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791108 Reactome, http://www.reactome.org ReactomeREACT_115832 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The SULT1A3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SMG1:UPF1:EJC:Translated mRNP Reactome DB_ID: 927767 Reactome Database ID Release 43927767 Reactome, http://www.reactome.org ReactomeREACT_76647 SMG1:UPF1:eRF1:eRF3 Complex:Exon Junction Complex on Translated mRNA has a Stoichiometric coefficient of 1 Expression of SSR1 (Trap alpha) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791164 Reactome, http://www.reactome.org ReactomeREACT_115957 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The SSR1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SMG1:Phosphorylated UPF1:EJC:Translated mRNP Reactome DB_ID: 927890 Reactome Database ID Release 43927890 Reactome, http://www.reactome.org ReactomeREACT_76156 has a Stoichiometric coefficient of 1 Expression of PPP2R5B Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791096 Reactome, http://www.reactome.org ReactomeREACT_115580 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The PPP2R5B gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Core Exon Junction Complex (Core EJC) Reactome DB_ID: 927869 Reactome Database ID Release 43927869 Reactome, http://www.reactome.org ReactomeREACT_76521 has a Stoichiometric coefficient of 1 Expression of PLA2G4B Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791071 Reactome, http://www.reactome.org ReactomeREACT_115814 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The PLA2GB4B gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SMG1 Complex Reactome DB_ID: 927853 Reactome Database ID Release 43927853 Reactome, http://www.reactome.org ReactomeREACT_76062 SMG1:SMG8:SMG9 Complex has a Stoichiometric coefficient of 1 Expression of SHC1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791134 Reactome, http://www.reactome.org ReactomeREACT_115794 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The SHC1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. 60S ribosomal complex Reactome DB_ID: 72499 Reactome Database ID Release 4372499 Reactome, http://www.reactome.org ReactomeREACT_2629 has a Stoichiometric coefficient of 1 Expression of SERP1 (RAMP4) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed10601334 Pubmed21282569 Reactome Database ID Release 431791167 Reactome, http://www.reactome.org ReactomeREACT_115764 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The RAMP4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Exon Junction:UPF2:UPF3 Complex Reactome DB_ID: 927798 Reactome Database ID Release 43927798 Reactome, http://www.reactome.org ReactomeREACT_76254 has a Stoichiometric coefficient of 1 40S ribosomal complex Reactome DB_ID: 72392 Reactome Database ID Release 4372392 Reactome, http://www.reactome.org ReactomeREACT_5094 has a Stoichiometric coefficient of 1 GDP bound eRF3 Reactome DB_ID: 143378 Reactome Database ID Release 43143378 Reactome, http://www.reactome.org ReactomeREACT_5718 has a Stoichiometric coefficient of 1 Expression of PDIA6 (Protein disulfide-isomerase A6) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed12204115 Pubmed15466936 Pubmed7590364 Reactome Database ID Release 431791131 Reactome, http://www.reactome.org ReactomeREACT_116071 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The PDIA6 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. 80S ribosome 80S monosome Reactome DB_ID: 72500 Reactome Database ID Release 4372500 Reactome, http://www.reactome.org ReactomeREACT_4330 has a Stoichiometric coefficient of 1 Expression of PDIA5 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791122 Reactome, http://www.reactome.org ReactomeREACT_115818 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The PDIA5 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of LMNA Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791128 Reactome, http://www.reactome.org ReactomeREACT_116134 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The LMNA gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of KLHDC3 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791177 Reactome, http://www.reactome.org ReactomeREACT_115919 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The KLHDC3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Decapped mRNA:LSM1-7 Complex Reactome DB_ID: 429996 Reactome Database ID Release 43429996 Reactome, http://www.reactome.org ReactomeREACT_21085 has a Stoichiometric coefficient of 1 Expression of KDELR3 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791123 Reactome, http://www.reactome.org ReactomeREACT_115630 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The KDELR3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. DCP1-DCP2 Decapping Complex Reactome DB_ID: 429991 Reactome Database ID Release 43429991 Reactome, http://www.reactome.org ReactomeREACT_20836 has a Stoichiometric coefficient of 1 Expression of HYOU1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791066 Reactome, http://www.reactome.org ReactomeREACT_115877 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The HYOU1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Translated mRNA Complex with Premature Termination Codon Preceding Exon Junction Reactome DB_ID: 927773 Reactome Database ID Release 43927773 Reactome, http://www.reactome.org ReactomeREACT_76510 has a Stoichiometric coefficient of 1 Expression of HDGF Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791112 Reactome, http://www.reactome.org ReactomeREACT_115773 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The HDGF gene is transcribed to yield mRNA and the mRNA is translated to yield protein. mRNA Complex with a Premature Termination Codon Preceding an Exon Junction Reactome DB_ID: 927743 Reactome Database ID Release 43927743 Reactome, http://www.reactome.org ReactomeREACT_76207 has a Stoichiometric coefficient of 1 Expression of GSK3A Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791054 Reactome, http://www.reactome.org ReactomeREACT_115594 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The GSK3A gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Exosome Complex Reactome DB_ID: 429971 Reactome Database ID Release 43429971 Reactome, http://www.reactome.org ReactomeREACT_20841 has a Stoichiometric coefficient of 1 Expression of GOSR2 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791154 Reactome, http://www.reactome.org ReactomeREACT_116129 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The GOSR2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Exosome Ring Hexamer Reactome DB_ID: 430046 Reactome Database ID Release 43430046 Reactome, http://www.reactome.org ReactomeREACT_21115 has a Stoichiometric coefficient of 1 Expression of GFPT1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791088 Reactome, http://www.reactome.org ReactomeREACT_115595 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The GFPT1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Lsm1-7 Complex Reactome DB_ID: 430001 Reactome Database ID Release 43430001 Reactome, http://www.reactome.org ReactomeREACT_21014 has a Stoichiometric coefficient of 1 Deadenylated mRNA:Lsm1-7 Complex Reactome DB_ID: 429908 Reactome Database ID Release 43429908 Reactome, http://www.reactome.org ReactomeREACT_20909 has a Stoichiometric coefficient of 1 Expression of G0S2 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed20110263 Reactome Database ID Release 431989759 Reactome, http://www.reactome.org ReactomeREACT_115967 Reviewed: Kersten, S, 2009-06-08 The G0S2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. pol II open pre-initiation complex Reactome DB_ID: 109876 Reactome Database ID Release 43109876 Reactome, http://www.reactome.org ReactomeREACT_4930 has a Stoichiometric coefficient of 1 Phospho-alpha receptor homodimer Reactome DB_ID: 186816 Reactome Database ID Release 43186816 Reactome, http://www.reactome.org ReactomeREACT_18119 has a Stoichiometric coefficient of 2 Expression of FHL2 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989747 Reactome, http://www.reactome.org ReactomeREACT_116040 Reviewed: Kersten, S, 2009-06-08 The FHL2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Phospho- PDGF receptor dimer Converted from EntitySet in Reactome Reactome DB_ID: 186821 Reactome Database ID Release 43186821 Reactome, http://www.reactome.org ReactomeREACT_17245 Expression of GRHL1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989748 Reactome, http://www.reactome.org ReactomeREACT_115770 Reviewed: Kersten, S, 2009-06-08 The GRHL1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Aborted early elongation complex Reactome DB_ID: 113410 Reactome Database ID Release 43113410 Reactome, http://www.reactome.org ReactomeREACT_3362 has a Stoichiometric coefficient of 1 Expression of GLIPR1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed20110263 Reactome Database ID Release 431989772 Reactome, http://www.reactome.org ReactomeREACT_115533 Reviewed: Kersten, S, 2009-06-08 The GLIPR1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Aborted elongation complex after arrest Reactome DB_ID: 113722 Reactome Database ID Release 43113722 Reactome, http://www.reactome.org ReactomeREACT_6654 has a Stoichiometric coefficient of 1 C4c, C3f Converted from EntitySet in Reactome Reactome DB_ID: 977621 Reactome Database ID Release 43977621 Reactome, http://www.reactome.org ReactomeREACT_119917 RIP2 ubiquitin ligases Converted from EntitySet in Reactome Reactome DB_ID: 1248659 Reactome Database ID Release 431248659 Reactome, http://www.reactome.org ReactomeREACT_76470 NLRP3 elicitors:NLRP3 oligomer Reactome DB_ID: 1296409 Reactome Database ID Release 431296409 Reactome, http://www.reactome.org ReactomeREACT_75982 MDP:NLRP1:ATP oligomer Reactome DB_ID: 1296412 Reactome Database ID Release 431296412 Reactome, http://www.reactome.org ReactomeREACT_76874 PathwayStep2489 IPAF elicitors Converted from EntitySet in Reactome Reactome DB_ID: 1252386 Reactome Database ID Release 431252386 Reactome, http://www.reactome.org ReactomeREACT_76533 PathwayStep2488 dsDNA:AIM2 oligomer Reactome DB_ID: 1296424 Reactome Database ID Release 431296424 Reactome, http://www.reactome.org ReactomeREACT_76301 PathwayStep2487 KIR2DS1 oligomer Reactome DB_ID: 2272704 Reactome Database ID Release 432272704 Reactome, http://www.reactome.org ReactomeREACT_148477 DAP12 receptors Converted from EntitySet in Reactome Reactome DB_ID: 2424471 Reactome Database ID Release 432424471 Reactome, http://www.reactome.org ReactomeREACT_148484 ISRE promoter elements in type I IFN-regulated genes Reactome DB_ID: 1015692 Reactome Database ID Release 431015692 Reactome, http://www.reactome.org ReactomeREACT_26432 CaMKII and PKC-delta Converted from EntitySet in Reactome Reactome DB_ID: 909568 Reactome Database ID Release 43909568 Reactome, http://www.reactome.org ReactomeREACT_26704 PathwayStep2492 PathwayStep2493 PathwayStep2490 PathwayStep2491 PathwayStep2496 PathwayStep2497 PathwayStep2494 PathwayStep2495 Phospho-alpha-Phospho-beta receptor heterodimer Reactome DB_ID: 186769 Reactome Database ID Release 43186769 Reactome, http://www.reactome.org ReactomeREACT_17200 has a Stoichiometric coefficient of 1 Arrested processive elongation complex Reactome DB_ID: 113721 Reactome Database ID Release 43113721 Reactome, http://www.reactome.org ReactomeREACT_4675 has a Stoichiometric coefficient of 1 Phospho-beta receptor homodimer Reactome DB_ID: 186805 Reactome Database ID Release 43186805 Reactome, http://www.reactome.org ReactomeREACT_18171 has a Stoichiometric coefficient of 2 Processive elongation complex Reactome DB_ID: 113719 Reactome Database ID Release 43113719 Reactome, http://www.reactome.org ReactomeREACT_3018 has a Stoichiometric coefficient of 1 PI3K bound to TRAT Reactome DB_ID: 202283 Reactome Database ID Release 43202283 Reactome, http://www.reactome.org ReactomeREACT_13152 has a Stoichiometric coefficient of 1 Expression of CYP1A1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989764 Reactome, http://www.reactome.org ReactomeREACT_116079 Reviewed: Kersten, S, 2009-06-08 The CYP1A1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. RNA Polymerase II holoenzyme complex (hyperphosphorylated) Reactome DB_ID: 109909 Reactome Database ID Release 43109909 Reactome, http://www.reactome.org ReactomeREACT_4889 has a Stoichiometric coefficient of 1 Phospho-IRS1/2:PI3K(p85:p110) Reactome DB_ID: 198344 Reactome Database ID Release 43198344 Reactome, http://www.reactome.org ReactomeREACT_12858 has a Stoichiometric coefficient of 1 Expression of CYP4A11 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed12505311 Pubmed19710929 Reactome Database ID Release 431989755 Reactome, http://www.reactome.org ReactomeREACT_115547 Reviewed: Kersten, S, 2009-06-08 The CYP4A11 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PI3K:GRB2:GAB1:P-ERBB2:P-EGFR EGF:p-EGFR:p-ERBB2:GRB2:GAB1:PI3K Reactome DB_ID: 1306961 Reactome Database ID Release 431306961 Reactome, http://www.reactome.org ReactomeREACT_116434 has a Stoichiometric coefficient of 1 Expression of CYP7A1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed10777541 Reactome Database ID Release 431989746 Reactome, http://www.reactome.org ReactomeREACT_115550 Reviewed: Kersten, S, 2009-06-08 The CYP7A1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. RNA Polymerase II holoenzyme complex (hypophosphorylated):TFIIF complex Reactome DB_ID: 113427 Reactome Database ID Release 43113427 Reactome, http://www.reactome.org ReactomeREACT_5870 has a Stoichiometric coefficient of 1 PI3Kp85:GRB2:GAB1:P-ERBB2:P-EGFR EGF:p-EGFR:p-ERBB2:GRB2:GAB1:PIK3R1 Reactome DB_ID: 1306962 Reactome Database ID Release 431306962 Reactome, http://www.reactome.org ReactomeREACT_116584 has a Stoichiometric coefficient of 1 Expression of FABP1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed15130092 Pubmed19710929 Reactome Database ID Release 431989751 Reactome, http://www.reactome.org ReactomeREACT_115721 Reviewed: Kersten, S, 2009-06-08 The FABP1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. RNA Pol II (hypophosphorylated):capped pre-mRNA complex Reactome DB_ID: 113715 Reactome Database ID Release 43113715 Reactome, http://www.reactome.org ReactomeREACT_5658 has a Stoichiometric coefficient of 1 EGF:p-EGFR:p-ERBB2:GRB2:GAB1 Reactome DB_ID: 1306958 Reactome Database ID Release 431306958 Reactome, http://www.reactome.org ReactomeREACT_117153 has a Stoichiometric coefficient of 1 Expression of FADS1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989757 Reactome, http://www.reactome.org ReactomeREACT_115953 Reviewed: Kersten, S, 2009-06-08 The FADS1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. RNA Pol II (hypophosphorylated) complex bound to DSIF protein Reactome DB_ID: 113406 Reactome Database ID Release 43113406 Reactome, http://www.reactome.org ReactomeREACT_4417 has a Stoichiometric coefficient of 1 NRG1/2:p-ERBB3:p-ERBB2:PI3K Reactome DB_ID: 1250508 Reactome Database ID Release 431250508 Reactome, http://www.reactome.org ReactomeREACT_116598 has a Stoichiometric coefficient of 1 Expression of FATP1 (SLC27A1) Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed12118000 Reactome Database ID Release 431989750 Reactome, http://www.reactome.org ReactomeREACT_115979 Reviewed: Kersten, S, 2009-06-08 The FATP1 (SLC27A1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. DSIF:NELF:early elongation complex Reactome DB_ID: 113408 Reactome Database ID Release 43113408 Reactome, http://www.reactome.org ReactomeREACT_4575 has a Stoichiometric coefficient of 1 NRG1/2:p-ERBB3:p-ERBB2:PIK3R1 Reactome DB_ID: 1250191 Reactome Database ID Release 431250191 Reactome, http://www.reactome.org ReactomeREACT_117674 has a Stoichiometric coefficient of 1 Expression of CPT1A Authored: May, B, 2011-10-23 Edited: May, B, 2011-10-23 Pubmed12505311 Pubmed19710929 Pubmed7892212 Reactome Database ID Release 431801587 Reactome, http://www.reactome.org ReactomeREACT_115644 Reviewed: Delaunay, F, 2012-01-28 Reviewed: Kersten, S, 2009-06-08 The CPT1A gene is transcribed to yield mRNA and the mRNA is translated to yield protein. NELF complex Reactome DB_ID: 112432 Reactome Database ID Release 43112432 Reactome, http://www.reactome.org ReactomeREACT_2737 has a Stoichiometric coefficient of 1 Expression of CD36 (platelet glycoprotein IV, FAT) Authored: May, B, 2010-03-23 Edited: May, B, 2010-03-23 Induction of Platelet glycoprotein IV (PAS IV, CD36, GPIV) Expression During Adipogenesis Pubmed16380219 Reactome Database ID Release 43560517 Reactome, http://www.reactome.org ReactomeREACT_27168 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Kersten, S, 2009-06-08 Reviewed: Sethi, JK, 2011-02-09 The Platelet glycoprotein IV gene (CD36, PAS IV, GPIV) is transcribed to yield mRNA and the mRNA is translated to yield proteind. Elongin Complex Reactome DB_ID: 112425 Reactome Database ID Release 43112425 Reactome, http://www.reactome.org ReactomeREACT_5616 has a Stoichiometric coefficient of 1 Expression of APOA5 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989761 Reactome, http://www.reactome.org ReactomeREACT_115631 Reviewed: Kersten, S, 2009-06-08 The APOA5 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Paused processive elongation complex Reactome DB_ID: 113720 Reactome Database ID Release 43113720 Reactome, http://www.reactome.org ReactomeREACT_3066 has a Stoichiometric coefficient of 1 Expression of APOA2 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989776 Reactome, http://www.reactome.org ReactomeREACT_116133 Reviewed: Kersten, S, 2009-06-08 The APOA2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. RNA Polymerase II holoenzyme complex (hyperphosphorylated):TFIIF complex Reactome DB_ID: 113425 Reactome Database ID Release 43113425 Reactome, http://www.reactome.org ReactomeREACT_3841 has a Stoichiometric coefficient of 1 NRGs/EGFLs:p-ERBB4cyt1:p-ERBB2:PI3K Reactome DB_ID: 1306974 Reactome Database ID Release 431306974 Reactome, http://www.reactome.org ReactomeREACT_117020 has a Stoichiometric coefficient of 1 Ligands recognized by TLR7 and TLR8 Converted from EntitySet in Reactome Reactome DB_ID: 1216505 Reactome Database ID Release 431216505 Reactome, http://www.reactome.org ReactomeREACT_27596 Expression of CPT2 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989773 Reactome, http://www.reactome.org ReactomeREACT_115927 Reviewed: Kersten, S, 2009-06-08 The CPT2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. ssRNA Reactome DB_ID: 167963 Reactome Database ID Release 43167963 Reactome, http://www.reactome.org ReactomeREACT_9240 PathwayStep2499 K63 Ligated polyubiquitin Chain Reactome DB_ID: 450271 Reactome Database ID Release 43450271 Reactome, http://www.reactome.org ReactomeREACT_22034 PathwayStep2498 ssRNA Reactome DB_ID: 170292 Reactome Database ID Release 43170292 Reactome, http://www.reactome.org ReactomeREACT_27829 Ligands recognized by TLR7 and TLR8 Converted from EntitySet in Reactome Reactome DB_ID: 188130 Reactome Database ID Release 43188130 Reactome, http://www.reactome.org ReactomeREACT_9278 Cell surface Reactome DB_ID: 983438 Reactome Database ID Release 43983438 Reactome, http://www.reactome.org ReactomeREACT_26575 Properdin oligomer Reactome DB_ID: 182548 Reactome Database ID Release 43182548 Reactome, http://www.reactome.org ReactomeREACT_8730 TLR1:TLR2 recognized ligand Converted from EntitySet in Reactome Reactome DB_ID: 168944 Reactome Database ID Release 43168944 Reactome, http://www.reactome.org ReactomeREACT_8189 Bacterial mannose-based carbohydrate surface pattern Reactome DB_ID: 166718 Reactome Database ID Release 43166718 Reactome, http://www.reactome.org ReactomeREACT_8923 C4d, iC3b Converted from EntitySet in Reactome Reactome DB_ID: 977624 Reactome Database ID Release 43977624 Reactome, http://www.reactome.org ReactomeREACT_119732 NRGs/EGFLs:p-ERBB4cyt1:p-ERBB2:PIK3R1 Reactome DB_ID: 1306942 Reactome Database ID Release 431306942 Reactome, http://www.reactome.org ReactomeREACT_116930 has a Stoichiometric coefficient of 1 Phosphorylated ERBB2:ERBB4cyt1 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963568 Reactome Database ID Release 431963568 Reactome, http://www.reactome.org ReactomeREACT_117511 NRGs/EGFLs:p-ERBB4cyt1:p-7Y-ERBB2 Reactome DB_ID: 1963579 Reactome Database ID Release 431963579 Reactome, http://www.reactome.org ReactomeREACT_117564 has a Stoichiometric coefficient of 1 Expression of ACSL1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989778 Reactome, http://www.reactome.org ReactomeREACT_115978 Reviewed: Kersten, S, 2009-06-08 The ACSL1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PI3K:p-ERBB4cyt1 Reactome DB_ID: 1250373 Reactome Database ID Release 431250373 Reactome, http://www.reactome.org ReactomeREACT_117442 has a Stoichiometric coefficient of 1 pol II transcription complex containing 4-9 nucleotide long transcript Reactome DB_ID: 75890 Reactome Database ID Release 4375890 Reactome, http://www.reactome.org ReactomeREACT_3928 has a Stoichiometric coefficient of 1 NRGs/EGFLs:p-ERBB4cyt1:p-6Y-ERBB2 Reactome DB_ID: 1250316 Reactome Database ID Release 431250316 Reactome, http://www.reactome.org ReactomeREACT_117100 has a Stoichiometric coefficient of 1 TFIIA Reactome DB_ID: 109629 Reactome Database ID Release 43109629 Reactome, http://www.reactome.org ReactomeREACT_5743 has a Stoichiometric coefficient of 1 NRGs/EGF-like ligands:P-ERBB4cyt1 Reactome DB_ID: 1250305 Reactome Database ID Release 431250305 Reactome, http://www.reactome.org ReactomeREACT_117493 has a Stoichiometric coefficient of 1 Expression of ANKRD1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed20110263 Reactome Database ID Release 431989779 Reactome, http://www.reactome.org ReactomeREACT_115878 Reviewed: Kersten, S, 2009-06-08 The ANKRD1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. DSIF complex Reactome DB_ID: 112420 Reactome Database ID Release 43112420 Reactome, http://www.reactome.org ReactomeREACT_2797 has a Stoichiometric coefficient of 1 p-ERBB4jmBcyt1 Phosphorylated ERBB4jmBcyt1 homodimer Reactome DB_ID: 1251954 Reactome Database ID Release 431251954 Reactome, http://www.reactome.org ReactomeREACT_117022 has a Stoichiometric coefficient of 2 Expression of APOA1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed9748239 Reactome Database ID Release 431989754 Reactome, http://www.reactome.org ReactomeREACT_116159 Reviewed: Kersten, S, 2009-06-08 The APOA1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Pol II Promoter Escape Complex Reactome DB_ID: 75859 Reactome Database ID Release 4375859 Reactome, http://www.reactome.org ReactomeREACT_3851 has a Stoichiometric coefficient of 1 NRGs/EGF-like ligands:P-ERBB4jmBcyt1 Reactome DB_ID: 1251958 Reactome Database ID Release 431251958 Reactome, http://www.reactome.org ReactomeREACT_117267 has a Stoichiometric coefficient of 1 Expression of AGT Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed15067378 Reactome Database ID Release 431989774 Reactome, http://www.reactome.org ReactomeREACT_115879 Reviewed: Kersten, S, 2009-06-08 The AGT gene is transcribed to yield mRNA and the mRNA is translated to yield protein. FACT complex Reactome DB_ID: 112417 Reactome Database ID Release 43112417 Reactome, http://www.reactome.org ReactomeREACT_4314 has a Stoichiometric coefficient of 1 PIK3R1:p-ERBB4cyt1 Reactome DB_ID: 1250356 Reactome Database ID Release 431250356 Reactome, http://www.reactome.org ReactomeREACT_117201 has a Stoichiometric coefficient of 1 Expression of ANGPTL4 Authored: May, B, 2010-03-23 Edited: May, B, 2010-03-23 Induction of Angiopoietin-related protein 4 (ANGPTL4) Expression Pubmed19710929 Pubmed19934321 Reactome Database ID Release 43560473 Reactome, http://www.reactome.org ReactomeREACT_27173 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Kersten, S, 2009-06-08 Reviewed: Sethi, JK, 2011-02-09 The ANGPTL4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Elongin B:C complex Reactome DB_ID: 112424 Reactome Database ID Release 43112424 Reactome, http://www.reactome.org ReactomeREACT_2434 has a Stoichiometric coefficient of 1 p-ERBB4cyt1 homodimers Converted from EntitySet in Reactome Phosphorylated ERBB4cyt1 homodimers Reactome DB_ID: 1250351 Reactome Database ID Release 431250351 Reactome, http://www.reactome.org ReactomeREACT_116404 Transcriptional activation of GP-acyl transferase gene by ChREBP:MLX At the end of this reaction, 1 molecule of '1-acyl-sn-glycerol-3-phosphate acyltransferase alpha ' is present. <br><br>This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43163748 Reactome, http://www.reactome.org ReactomeREACT_787 Transcriptional activation of Acetyl-CoA carboxylase by ChREBP:MLX At the end of this reaction, 1 molecule of 'Acetyl-CoA carboxylase 2 ' is present. <br><br>This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43163743 Reactome, http://www.reactome.org ReactomeREACT_355 KARS homodimer Reactome DB_ID: 379612 Reactome Database ID Release 43379612 Reactome, http://www.reactome.org ReactomeREACT_16061 has a Stoichiometric coefficient of 2 pol II transcription complex containing 9 nucleotide long transcript Reactome DB_ID: 75882 Reactome Database ID Release 4375882 Reactome, http://www.reactome.org ReactomeREACT_5212 has a Stoichiometric coefficient of 1 Synthesis of prepro-Glucose-dependent Insulinotropic Polypeptide (preproGIP) in Intestinal K Cells Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-09-09 Pubmed16219666 Pubmed18593849 Pubmed8428636 Reactome Database ID Release 43400500 Reactome, http://www.reactome.org ReactomeREACT_23838 Reviewed: Bloom, SR, 2010-06-24 The transcription factors PDX-1 and PAX6 binds the promoter of the human GIP gene between 145 and 184 nucleotides upstream of the start of transcription and enhance transcription of GIP. In mouse Pdx-1 also increases the number of GIP-producing K cells. Consensus binding sites for other transcription factors such as AP-1, AP-2, and Sp1 have been identified in the promoter of the GIP gene but their role is unknown. The human GIP promoter is responsive to cAMP by an unknown mechanism. aminoacyl-tRNA synthetase multienzyme complex Reactome DB_ID: 379688 Reactome Database ID Release 43379688 Reactome, http://www.reactome.org ReactomeREACT_15869 has a Stoichiometric coefficient of 1 Transcriptional activation of pyruvate kinase gene by ChREBP:MLX At the end of this reaction, 1 molecule of 'pyruvate kinase, liver and RBC' is present. <br><br>This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43163669 Reactome, http://www.reactome.org ReactomeREACT_1891 Elongation complex with separated and uncleaved transcript Reactome DB_ID: 113726 Reactome Database ID Release 43113726 Reactome, http://www.reactome.org ReactomeREACT_5512 has a Stoichiometric coefficient of 1 Transcriptional activation of Citrate lyase monomer gene by ChREBP:MLX At the end of this reaction, 1 molecule of 'citrate lyase monomer' is present. <br><br>This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43163770 Reactome, http://www.reactome.org ReactomeREACT_1577 Elongation complex prior to separation Reactome DB_ID: 113724 Reactome Database ID Release 43113724 Reactome, http://www.reactome.org ReactomeREACT_5853 has a Stoichiometric coefficient of 1 Transcriptional activation of FAS monomer gene by ChREBP:MLX At the end of this reaction, 1 molecule of 'Fatty acid synthase ' is present. <br><br>This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43163733 Reactome, http://www.reactome.org ReactomeREACT_229 Elongation complex Reactome DB_ID: 112433 Reactome Database ID Release 43112433 Reactome, http://www.reactome.org ReactomeREACT_3511 has a Stoichiometric coefficient of 1 Expression of TRIB3 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed20110263 Reactome Database ID Release 431989767 Reactome, http://www.reactome.org ReactomeREACT_115815 Reviewed: Kersten, S, 2009-06-08 The TRIB3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Early elongation complex with hyperphosphorylated Pol II CTD Reactome DB_ID: 113426 Reactome Database ID Release 43113426 Reactome, http://www.reactome.org ReactomeREACT_2481 has a Stoichiometric coefficient of 1 Expression of TXNRD1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989752 Reactome, http://www.reactome.org ReactomeREACT_115677 Reviewed: Kersten, S, 2009-06-08 The TXNRD1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Pol II transcription complex containing extruded transcript to +30 Reactome DB_ID: 157171 Reactome Database ID Release 43157171 Reactome, http://www.reactome.org ReactomeREACT_4335 has a Stoichiometric coefficient of 1 Expression of UGT1A9 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed12582161 Reactome Database ID Release 431989758 Reactome, http://www.reactome.org ReactomeREACT_115777 Reviewed: Kersten, S, 2009-06-08 The UGT1A9 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Pol II transcription complex containing transcript to +30 Reactome DB_ID: 111261 Reactome Database ID Release 43111261 Reactome, http://www.reactome.org ReactomeREACT_4399 has a Stoichiometric coefficient of 1 Synthesis of Preproglucagon in Intestinal L Cells Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-09-09 Pubmed11564718 Pubmed12540594 Pubmed12810581 Pubmed1499644 Pubmed16219666 Pubmed16728727 Pubmed3841689 Reactome Database ID Release 43381799 Reactome, http://www.reactome.org ReactomeREACT_24009 Reviewed: Bloom, SR, 2010-06-24 TCF-4 and Beta-Catenin form a heterodimer that bind the G2 element of the promoter of the Proglucagon (GCG) gene in L2 cells of the intestine. CDX-2 binds an AT-rich sequence in the G1 enhancer element of the GCG promoter. Transcription of the GCG gene is enhanced by cAMP, calcium, and insulin and the Beta-Catenin:TCF-4 binding region of the promoter is necessary for this regulation. It is therefore postulated that the Wnt signaling pathway (Beta-Catenin) crosstalks with the cAMP-PKA pathway and/or the cAMP-EPAC pathway. pol II transcription complex containing 11 nucleotide long transcript Reactome DB_ID: 75902 Reactome Database ID Release 4375902 Reactome, http://www.reactome.org ReactomeREACT_3183 has a Stoichiometric coefficient of 1 ISG15 targets Converted from EntitySet in Reactome Reactome DB_ID: 1169379 Reactome Database ID Release 431169379 Reactome, http://www.reactome.org ReactomeREACT_117251 Importin Converted from EntitySet in Reactome Reactome DB_ID: 1176060 Reactome Database ID Release 431176060 Reactome, http://www.reactome.org ReactomeREACT_117371 GAS promoter region in IFNG-regulated genes Reactome DB_ID: 1031708 Reactome Database ID Release 431031708 Reactome, http://www.reactome.org ReactomeREACT_26763 pol II transcription complex containing 3 Nucleotide long transcript Reactome DB_ID: 75878 Reactome Database ID Release 4375878 Reactome, http://www.reactome.org ReactomeREACT_3251 has a Stoichiometric coefficient of 1 Expression of TNFRSF21 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989771 Reactome, http://www.reactome.org ReactomeREACT_115875 Reviewed: Kersten, S, 2009-06-08 The TNFRSF21 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. pol II transcription complex containing 4 nucleotide long transcript Reactome DB_ID: 75881 Reactome Database ID Release 4375881 Reactome, http://www.reactome.org ReactomeREACT_4148 has a Stoichiometric coefficient of 1 Expression of TIAM2 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed20110263 Reactome Database ID Release 431989768 Reactome, http://www.reactome.org ReactomeREACT_115593 Reviewed: Kersten, S, 2009-06-08 The TIAM2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of SULT2A1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed15635043 Pubmed20110263 Reactome Database ID Release 431989775 Reactome, http://www.reactome.org ReactomeREACT_115729 Reviewed: Kersten, S, 2009-06-08 The SULT2A1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Interleukin receptor complexes with activated Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks Converted from EntitySet in Reactome Reactome DB_ID: 912535 Reactome Database ID Release 43912535 Reactome, http://www.reactome.org ReactomeREACT_24797 Growth hormone oligomer Reactome DB_ID: 982799 Reactome Database ID Release 43982799 Reactome, http://www.reactome.org ReactomeREACT_111776 Interleukin receptor compexes with activated Shc:GRB2:GAB2 Converted from EntitySet in Reactome Reactome DB_ID: 912537 Reactome Database ID Release 43912537 Reactome, http://www.reactome.org ReactomeREACT_24494 Interleukin receptor complexes with activated Shc:GRB2:p-GAB2 Converted from EntitySet in Reactome Reactome DB_ID: 912533 Reactome Database ID Release 43912533 Reactome, http://www.reactome.org ReactomeREACT_24779 Importin Converted from EntitySet in Reactome Reactome DB_ID: 1176073 Reactome Database ID Release 431176073 Reactome, http://www.reactome.org ReactomeREACT_117856 Interleukin receptor complexes with activated SHC1 Converted from EntitySet in Reactome Reactome DB_ID: 912534 Reactome Database ID Release 43912534 Reactome, http://www.reactome.org ReactomeREACT_24730 Expression of PPARA Authored: May, B, 2010-06-18 Edited: May, B, 2010-06-18 Pubmed19710929 Pubmed7981125 Reactome Database ID Release 43879724 Reactome, http://www.reactome.org ReactomeREACT_25084 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Reviewed: Kersten, S, 2009-06-08 The PPARA gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind the scond intron of the PPARA gene and activate transcription of PPARA. Pol II initiation complex Reactome DB_ID: 83551 Reactome Database ID Release 4383551 Reactome, http://www.reactome.org ReactomeREACT_5487 has a Stoichiometric coefficient of 1 Expression of RGL1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed20110263 Reactome Database ID Release 431989777 Reactome, http://www.reactome.org ReactomeREACT_115625 Reviewed: Kersten, S, 2009-06-08 The RGL1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. pol II promoter:TFIID:TFIIA:TFIIB:Pol II:TFIIF:TFIIE complex Reactome DB_ID: 75871 Reactome Database ID Release 4375871 Reactome, http://www.reactome.org ReactomeREACT_4404 has a Stoichiometric coefficient of 1 Expression of PEX11A Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989753 Reactome, http://www.reactome.org ReactomeREACT_115962 Reviewed: Kersten, S, 2009-06-08 The PEX11A gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Pol II Initiation complex with phosphodiester-PPi intermediate Reactome DB_ID: 83601 Reactome Database ID Release 4383601 Reactome, http://www.reactome.org ReactomeREACT_2410 has a Stoichiometric coefficient of 1 Expression of PLIN2 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989770 Reactome, http://www.reactome.org ReactomeREACT_115542 Reviewed: Kersten, S, 2009-06-08 The Adipophilin (PLIN2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. RNA Polymearse II:NTP:TFIIF complex Reactome DB_ID: 83591 Reactome Database ID Release 4383591 Reactome, http://www.reactome.org ReactomeREACT_4655 has a Stoichiometric coefficient of 1 Expression of ME1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989756 Reactome, http://www.reactome.org ReactomeREACT_115847 Reviewed: Kersten, S, 2009-06-08 The ME1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. pol II promoter:TFIID:TFIIA:TFIIB:Pol II:TFIIF complex Reactome DB_ID: 109632 Reactome Database ID Release 43109632 Reactome, http://www.reactome.org ReactomeREACT_2469 has a Stoichiometric coefficient of 1 Expression of NPAS2 Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Pubmed9012850 Reactome Database ID Release 431368065 Reactome, http://www.reactome.org ReactomeREACT_116112 Reviewed: Delaunay, F, 2012-01-28 Reviewed: Kersten, S, 2009-06-08 The NPAS2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of NPAS2 is enhanced by the RORA:Coactivator complex and repressed by the REV-ERBA:Corepressor complex. pol II closed pre-initiation complex Reactome DB_ID: 109635 Reactome Database ID Release 43109635 Reactome, http://www.reactome.org ReactomeREACT_5734 has a Stoichiometric coefficient of 1 pol II promoter:TFIID complex Reactome DB_ID: 109628 Reactome Database ID Release 43109628 Reactome, http://www.reactome.org ReactomeREACT_5906 has a Stoichiometric coefficient of 1 Expression of HMGCS2 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989760 Reactome, http://www.reactome.org ReactomeREACT_116136 Reviewed: Kersten, S, 2009-06-08 The HMGCS2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. pol II promoter:TFIID:TFIIA:TFIIB complex Reactome DB_ID: 109630 Reactome Database ID Release 43109630 Reactome, http://www.reactome.org ReactomeREACT_2339 has a Stoichiometric coefficient of 1 TGF beta Converted from EntitySet in Reactome Reactome DB_ID: 114507 Reactome Database ID Release 43114507 Reactome, http://www.reactome.org ReactomeREACT_5021 PathwayStep6807 PathwayStep6808 PathwayStep6809 PathwayStep6803 PathwayStep6804 PathwayStep6805 PathwayStep6806 PathwayStep6800 PathwayStep6801 PathwayStep6802 PathwayStep6820 PathwayStep6818 PathwayStep6819 PathwayStep6816 PathwayStep6817 PathwayStep6814 PathwayStep6815 PathwayStep6812 PathwayStep6813 PathwayStep6810 PathwayStep6811 Paused RNA Polymerase III Transcription Complex Reactome DB_ID: 113453 Reactome Database ID Release 43113453 Reactome, http://www.reactome.org ReactomeREACT_5042 has a Stoichiometric coefficient of 1 TFIIIA:Type 1 Promoter complex Reactome DB_ID: 76051 Reactome Database ID Release 4376051 Reactome, http://www.reactome.org ReactomeREACT_2832 has a Stoichiometric coefficient of 1 TFAM:mitochondrial promoter complex Reactome DB_ID: 163298 Reactome Database ID Release 43163298 Reactome, http://www.reactome.org ReactomeREACT_2565 has a Stoichiometric coefficient of 1 POLRMT:TFB2M complex Reactome DB_ID: 163306 Reactome Database ID Release 43163306 Reactome, http://www.reactome.org ReactomeREACT_3761 has a Stoichiometric coefficient of 1 PathwayStep6831 PathwayStep6830 SNAPc:Oct-1:Staf:Type 3 Promoter Complex Reactome DB_ID: 83753 Reactome Database ID Release 4383753 Reactome, http://www.reactome.org ReactomeREACT_3792 has a Stoichiometric coefficient of 1 Platelet dense granule membrane components Converted from EntitySet in Reactome Reactome DB_ID: 481006 Reactome Database ID Release 43481006 Reactome, http://www.reactome.org ReactomeREACT_22010 PathwayStep6829 Platelet dense granule membrane components Converted from EntitySet in Reactome Reactome DB_ID: 481004 Reactome Database ID Release 43481004 Reactome, http://www.reactome.org ReactomeREACT_21483 PathwayStep6821 PathwayStep6822 TFIIE Reactome DB_ID: 109633 Reactome Database ID Release 43109633 Reactome, http://www.reactome.org ReactomeREACT_2368 has a Stoichiometric coefficient of 1 PathwayStep6823 PathwayStep6824 PathwayStep6825 mTERF:mitochondrial transcription termination sequence Reactome DB_ID: 163321 Reactome Database ID Release 43163321 Reactome, http://www.reactome.org ReactomeREACT_2598 has a Stoichiometric coefficient of 1 PathwayStep6826 POLRMT:TFB2M:TFAM:mitochondrial promoter complex Reactome DB_ID: 163307 Reactome Database ID Release 43163307 Reactome, http://www.reactome.org ReactomeREACT_4311 has a Stoichiometric coefficient of 1 PathwayStep6827 TFIID Reactome DB_ID: 109626 Reactome Database ID Release 43109626 Reactome, http://www.reactome.org ReactomeREACT_5886 has a Stoichiometric coefficient of 1 PathwayStep6828 pol II transcription complex Reactome DB_ID: 109878 Reactome Database ID Release 43109878 Reactome, http://www.reactome.org ReactomeREACT_2954 has a Stoichiometric coefficient of 1 PathwayStep6842 PathwayStep6841 PathwayStep6840 PathwayStep6834 PathwayStep6835 PathwayStep6832 PathwayStep6833 PathwayStep6838 PathwayStep6839 PathwayStep6836 PathwayStep6837 Expression of Sec31A Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791133 Reactome, http://www.reactome.org ReactomeREACT_115578 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The Sec31A gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of TATDN2 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791156 Reactome, http://www.reactome.org ReactomeREACT_115723 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The TATDN2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Protein Kinase C, conventional Converted from EntitySet in Reactome Reactome DB_ID: 114528 Reactome Database ID Release 43114528 Reactome, http://www.reactome.org ReactomeREACT_4876 Expression of TPP1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791138 Reactome, http://www.reactome.org ReactomeREACT_115883 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The TPP1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of TSPYL2 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791057 Reactome, http://www.reactome.org ReactomeREACT_116034 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The TSPYL2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Talin-1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791137 Reactome, http://www.reactome.org ReactomeREACT_115665 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The Talin-1 (TLN1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of WFS1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791169 Reactome, http://www.reactome.org ReactomeREACT_115977 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The WFS1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of WIPI1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791172 Reactome, http://www.reactome.org ReactomeREACT_116014 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The WIPI1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of YIF1A Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791143 Reactome, http://www.reactome.org ReactomeREACT_115805 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The YIF1A gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of ZBTB17 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16539657 Reactome Database ID Release 431791186 Reactome, http://www.reactome.org ReactomeREACT_116103 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The ZBTB17 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of DNAJC3 (p58IPK) Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed8666242 Reactome Database ID Release 431791157 Reactome, http://www.reactome.org ReactomeREACT_115787 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The p58IPK (DNAJC3) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Alpha-2 adrenoceptor Converted from EntitySet in Reactome Reactome DB_ID: 390664 Reactome Database ID Release 43390664 Reactome, http://www.reactome.org ReactomeREACT_18048 Diacylglycerol kinase Converted from EntitySet in Reactome Reactome DB_ID: 426070 Reactome Database ID Release 43426070 Reactome, http://www.reactome.org ReactomeREACT_20449 Diacylglycerol lipase Converted from EntitySet in Reactome Reactome DB_ID: 426024 Reactome Database ID Release 43426024 Reactome, http://www.reactome.org ReactomeREACT_19676 Protein kinase C, novel isoforms Converted from EntitySet in Reactome Protein Kinase C, unconventional isoforms Reactome DB_ID: 425850 Reactome Database ID Release 43425850 Reactome, http://www.reactome.org ReactomeREACT_22540 PathwayStep6641 PathwayStep6642 PathwayStep6643 PathwayStep6644 PathwayStep6640 PathwayStep6639 PathwayStep6638 PathwayStep6635 PathwayStep6634 PathwayStep6637 PathwayStep6636 PathwayStep6632 PathwayStep6633 PathwayStep6630 PathwayStep6631 PathwayStep6629 PathwayStep6628 PathwayStep6627 PathwayStep6626 PathwayStep6625 PathwayStep6624 PathwayStep6623 PathwayStep601 PathwayStep602 PathwayStep600 PathwayStep605 PathwayStep6620 PathwayStep606 PathwayStep6621 PathwayStep603 PathwayStep6622 PathwayStep604 PathwayStep6613 PathwayStep6612 PathwayStep609 PathwayStep6615 PathwayStep608 PathwayStep6614 PathwayStep607 PathwayStep6617 PathwayStep6616 PathwayStep6619 PathwayStep6618 PathwayStep610 PathwayStep611 PathwayStep612 PathwayStep613 PathwayStep6610 PathwayStep614 PathwayStep6611 PathwayStep615 PathwayStep616 PathwayStep617 PathwayStep6609 PathwayStep6604 PathwayStep619 PathwayStep6603 PathwayStep618 PathwayStep6602 PathwayStep6601 PathwayStep6608 PathwayStep6607 PathwayStep6606 PathwayStep6605 PathwayStep620 PathwayStep6680 PathwayStep6686 PathwayStep628 PathwayStep6685 PathwayStep627 PathwayStep6688 PathwayStep626 PathwayStep6687 PathwayStep625 PathwayStep6682 PathwayStep624 PathwayStep6681 PathwayStep623 PathwayStep6684 PathwayStep622 PathwayStep6683 PathwayStep621 PathwayStep6678 PathwayStep6679 PathwayStep629 PathwayStep631 PathwayStep630 PathwayStep6677 PathwayStep637 PathwayStep6676 PathwayStep636 PathwayStep6675 PathwayStep639 PathwayStep6674 PathwayStep638 PathwayStep6673 PathwayStep633 PathwayStep6672 PathwayStep632 PathwayStep6671 PathwayStep635 PathwayStep6670 PathwayStep634 PathwayStep6669 PathwayStep6667 PathwayStep6668 PathwayStep642 PathwayStep641 PathwayStep640 PathwayStep6660 PathwayStep646 PathwayStep645 PathwayStep6662 PathwayStep644 PathwayStep6661 PathwayStep643 PathwayStep6664 PathwayStep6663 PathwayStep649 PathwayStep6666 PathwayStep648 PathwayStep6665 PathwayStep647 PathwayStep6656 PathwayStep6657 PathwayStep6658 PathwayStep6659 PathwayStep651 PathwayStep650 PathwayStep653 PathwayStep652 PathwayStep6651 PathwayStep655 PathwayStep6650 PathwayStep654 PathwayStep657 PathwayStep656 PathwayStep6655 PathwayStep659 PathwayStep6654 PathwayStep658 PathwayStep6653 PathwayStep6652 PathwayStep6647 PathwayStep6648 PathwayStep6645 PathwayStep6646 PathwayStep6649 PathwayStep669 Kv8 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296108 Reactome Database ID Release 431296108 Reactome, http://www.reactome.org ReactomeREACT_75987 PathwayStep665 PathwayStep666 PathwayStep667 PathwayStep668 PathwayStep661 Kv7 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296100 Reactome Database ID Release 431296100 Reactome, http://www.reactome.org ReactomeREACT_76730 PathwayStep662 PathwayStep663 PathwayStep664 PathwayStep2200 PathwayStep660 Kv6 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296106 Reactome Database ID Release 431296106 Reactome, http://www.reactome.org ReactomeREACT_76052 PathwayStep678 PathwayStep679 Kv5 subunit of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296104 Reactome Database ID Release 431296104 Reactome, http://www.reactome.org ReactomeREACT_76904 PathwayStep676 PathwayStep677 PathwayStep674 PathwayStep675 Kv4 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296101 Reactome Database ID Release 431296101 Reactome, http://www.reactome.org ReactomeREACT_76216 PathwayStep672 PathwayStep673 PathwayStep670 PathwayStep671 PathwayStep687 PathwayStep688 PathwayStep689 Dicer:TRBP:duplex miRNA Reactome DB_ID: 629638 Reactome Database ID Release 43629638 Reactome, http://www.reactome.org ReactomeREACT_23068 has a Stoichiometric coefficient of 1 Ran:GTP Reactome DB_ID: 180686 Reactome Database ID Release 43180686 Reactome, http://www.reactome.org ReactomeREACT_8632 has a Stoichiometric coefficient of 1 Ran:GTP:Exportin-5 Reactome DB_ID: 209672 Reactome Database ID Release 43209672 Reactome, http://www.reactome.org ReactomeREACT_13157 has a Stoichiometric coefficient of 1 pre-miRNA:Ran:GTP:Exportin-5 Reactome DB_ID: 209660 Reactome Database ID Release 43209660 Reactome, http://www.reactome.org ReactomeREACT_13389 has a Stoichiometric coefficient of 1 TREK members Converted from EntitySet in Reactome Reactome DB_ID: 1299261 Reactome Database ID Release 431299261 Reactome, http://www.reactome.org ReactomeREACT_76609 Ran-GTP Reactome DB_ID: 180738 Reactome Database ID Release 43180738 Reactome, http://www.reactome.org ReactomeREACT_8980 has a Stoichiometric coefficient of 1 PathwayStep680 Ran:GTP:Exportin-5 Reactome DB_ID: 203870 Reactome Database ID Release 43203870 Reactome, http://www.reactome.org ReactomeREACT_12753 has a Stoichiometric coefficient of 1 PathwayStep681 DGCR8:Drosha MicroProcessor Complex Reactome DB_ID: 203817 Reactome Database ID Release 43203817 Reactome, http://www.reactome.org ReactomeREACT_13360 has a Stoichiometric coefficient of 1 PathwayStep682 UPF1:eRF3 Complex on Translated mRNA Reactome DB_ID: 927762 Reactome Database ID Release 43927762 Reactome, http://www.reactome.org ReactomeREACT_76212 has a Stoichiometric coefficient of 1 PathwayStep683 mRNA Complex with a Premature Termination Codon Not Preceding an Exon Junction Reactome DB_ID: 927823 Reactome Database ID Release 43927823 Reactome, http://www.reactome.org ReactomeREACT_76342 has a Stoichiometric coefficient of 1 PathwayStep684 Translated mRNA Complex with Premature Termination Codon Not Preceding Exon Junction Reactome DB_ID: 927787 Reactome Database ID Release 43927787 Reactome, http://www.reactome.org ReactomeREACT_76767 has a Stoichiometric coefficient of 1 PathwayStep685 PathwayStep686 PathwayStep6689 PathwayStep6692 PathwayStep6693 PathwayStep698 PathwayStep6694 PathwayStep699 PathwayStep6695 PathwayStep6696 PathwayStep6697 PathwayStep6698 PathwayStep6699 PathwayStep692 PathwayStep693 PathwayStep690 PathwayStep691 PathwayStep696 Kv9 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296105 Reactome Database ID Release 431296105 Reactome, http://www.reactome.org ReactomeREACT_76088 PathwayStep697 Voltage-gated K+ channel beta subunits Converted from EntitySet in Reactome Reactome DB_ID: 1297369 Reactome Database ID Release 431297369 Reactome, http://www.reactome.org ReactomeREACT_76232 PathwayStep694 PathwayStep6690 PathwayStep695 PathwayStep6691 PathwayStep2236 PathwayStep2237 PathwayStep2234 PathwayStep2235 PathwayStep2238 PathwayStep2239 Synaptotagmins Converted from EntitySet in Reactome Reactome DB_ID: 181553 Reactome Database ID Release 43181553 Reactome, http://www.reactome.org ReactomeREACT_11540 PathwayStep2240 PathwayStep2244 PathwayStep2243 PathwayStep2242 PathwayStep2241 PathwayStep2223 PathwayStep2224 PathwayStep2225 PathwayStep2226 PathwayStep2227 PathwayStep2228 PathwayStep2229 PathwayStep2231 PathwayStep2230 BoNT Heavy Chain Converted from EntitySet in Reactome Reactome DB_ID: 168790 Reactome Database ID Release 43168790 Reactome, http://www.reactome.org ReactomeREACT_11812 PathwayStep2233 PathwayStep2232 PathwayStep2218 PathwayStep2219 PathwayStep2216 PathwayStep2217 PathwayStep2214 PathwayStep2215 PathwayStep2212 PathwayStep2213 PathwayStep2222 PathwayStep2221 PathwayStep2220 PathwayStep2209 PathwayStep2205 PathwayStep2206 PathwayStep2207 PathwayStep2208 PathwayStep2201 PathwayStep2202 PathwayStep2203 PathwayStep2204 PathwayStep2211 PathwayStep2210 BoNT Heavy Chain Converted from EntitySet in Reactome Reactome DB_ID: 181563 Reactome Database ID Release 43181563 Reactome, http://www.reactome.org ReactomeREACT_11919 eIF4A subunits complex Reactome DB_ID: 72576 Reactome Database ID Release 4372576 Reactome, http://www.reactome.org ReactomeREACT_5786 has a Stoichiometric coefficient of 1 eIF4E:4E-BP Reactome DB_ID: 72581 Reactome Database ID Release 4372581 Reactome, http://www.reactome.org ReactomeREACT_3978 has a Stoichiometric coefficient of 1 43S complex Reactome DB_ID: 72571 Reactome Database ID Release 4372571 Reactome, http://www.reactome.org ReactomeREACT_3677 eIF3:eIGF1A:40S:Met-tRNAi:eIF2:GTP has a Stoichiometric coefficient of 1 ternary complex Met-tRNAi:eIF2:GTP Reactome DB_ID: 72532 Reactome Database ID Release 4372532 Reactome, http://www.reactome.org ReactomeREACT_4168 has a Stoichiometric coefficient of 1 eIF2:GTP Reactome DB_ID: 72531 Reactome Database ID Release 4372531 Reactome, http://www.reactome.org ReactomeREACT_3909 has a Stoichiometric coefficient of 1 MP Reactome DB_ID: 72515 Reactome Database ID Release 4372515 Reactome, http://www.reactome.org ReactomeREACT_5135 eIF2 subunit complex has a Stoichiometric coefficient of 1 40S:eIF3:eIF1A Reactome DB_ID: 72570 Reactome Database ID Release 4372570 Reactome, http://www.reactome.org ReactomeREACT_2456 has a Stoichiometric coefficient of 1 eIF3 subunits complex Reactome DB_ID: 72555 Reactome Database ID Release 4372555 Reactome, http://www.reactome.org ReactomeREACT_4891 has a Stoichiometric coefficient of 1 PathwayStep2155 HuR with phosphoserine221 and phosphoserine318:mRNA Complex Reactome DB_ID: 517553 Reactome Database ID Release 43517553 Reactome, http://www.reactome.org ReactomeREACT_26462 has a Stoichiometric coefficient of 1 PathwayStep2156 HuR with phosphoserine221 and phosphoserine158:mRNA Complex Reactome DB_ID: 517624 Reactome Database ID Release 43517624 Reactome, http://www.reactome.org ReactomeREACT_25722 has a Stoichiometric coefficient of 1 PathwayStep2153 PathwayStep2154 PathwayStep2151 PathwayStep2152 PathwayStep2150 PathwayStep2149 PathwayStep2148 PathwayStep2147 PathwayStep2146 HuR:mRNA Complexes Converted from EntitySet in Reactome Reactome DB_ID: 517615 Reactome Database ID Release 43517615 Reactome, http://www.reactome.org ReactomeREACT_26913 HuR with Unknown Phosphorylation: mRNA Complex Reactome DB_ID: 450395 Reactome Database ID Release 43450395 Reactome, http://www.reactome.org ReactomeREACT_26059 has a Stoichiometric coefficient of 1 HuR:mRNA Complex Converted from EntitySet in Reactome Reactome DB_ID: 517713 Reactome Database ID Release 43517713 Reactome, http://www.reactome.org ReactomeREACT_25608 HuR:APRIL:pp32:SET/SETalpha:Nup214/SETbeta:CRM1 Complex Reactome DB_ID: 450537 Reactome Database ID Release 43450537 Reactome, http://www.reactome.org ReactomeREACT_25847 has a Stoichiometric coefficient of 1 Phospho-MAP kinase p38 (Mg2+ cofactor) Reactome DB_ID: 170993 Reactome Database ID Release 43170993 Reactome, http://www.reactome.org ReactomeREACT_12273 has a Stoichiometric coefficient of 1 Phosphorylated KSRP (Ser193):14-3-3zeta Complex Reactome DB_ID: 450446 Reactome Database ID Release 43450446 Reactome, http://www.reactome.org ReactomeREACT_26013 has a Stoichiometric coefficient of 1 HuR with phosphoserine221 and phosphoserine318:mRNA Complex Reactome DB_ID: 517751 Reactome Database ID Release 43517751 Reactome, http://www.reactome.org ReactomeREACT_25770 has a Stoichiometric coefficient of 1 HuR with phosphoserine221 and phosphoserine158:mRNA Complex Reactome DB_ID: 517672 Reactome Database ID Release 43517672 Reactome, http://www.reactome.org ReactomeREACT_27037 has a Stoichiometric coefficient of 1 PathwayStep2164 PathwayStep2165 PathwayStep2166 KSRP:mRNA Degradation Complex Reactome DB_ID: 450479 Reactome Database ID Release 43450479 Reactome, http://www.reactome.org ReactomeREACT_26058 has a Stoichiometric coefficient of 1 PathwayStep2167 PathwayStep2160 PathwayStep2161 PathwayStep2162 PathwayStep2163 PathwayStep2158 PathwayStep2157 PathwayStep2159 HuR with Unknown Phosphorylation: mRNA Complex Reactome DB_ID: 450512 Reactome Database ID Release 43450512 Reactome, http://www.reactome.org ReactomeREACT_27034 has a Stoichiometric coefficient of 1 Phosphorylated BRF1 (Ser92, Ser203):mRNA:14-3-3 Complex Reactome DB_ID: 450585 Reactome Database ID Release 43450585 Reactome, http://www.reactome.org ReactomeREACT_26426 has a Stoichiometric coefficient of 1 Phosphorylated BRF1 (Ser54, Ser92, Ser203):mRNA Complex Reactome DB_ID: 450502 Reactome Database ID Release 43450502 Reactome, http://www.reactome.org ReactomeREACT_25904 has a Stoichiometric coefficient of 1 Phosphorylated BRF1 (Ser92, Ser203):mRNA Complex Reactome DB_ID: 450378 Reactome Database ID Release 43450378 Reactome, http://www.reactome.org ReactomeREACT_25600 has a Stoichiometric coefficient of 1 BRF1:mRNA Degradation Complex Reactome DB_ID: 450430 Reactome Database ID Release 43450430 Reactome, http://www.reactome.org ReactomeREACT_25561 has a Stoichiometric coefficient of 1 Phosphorylated TTP:mRNA Complex Reactome DB_ID: 450541 Reactome Database ID Release 43450541 Reactome, http://www.reactome.org ReactomeREACT_25681 has a Stoichiometric coefficient of 1 TTP:mRNA Degradation Complex Reactome DB_ID: 450436 Reactome Database ID Release 43450436 Reactome, http://www.reactome.org ReactomeREACT_25473 has a Stoichiometric coefficient of 1 TTP:mRNA Complex Reactome DB_ID: 450365 Reactome Database ID Release 43450365 Reactome, http://www.reactome.org ReactomeREACT_26727 has a Stoichiometric coefficient of 1 Phosphorylated BRF1 (Ser54, Ser92, Ser203):mRNA:14-3-3 Complex Reactome DB_ID: 482787 Reactome Database ID Release 43482787 Reactome, http://www.reactome.org ReactomeREACT_25856 has a Stoichiometric coefficient of 1 PathwayStep2130 PathwayStep2133 PathwayStep2134 PathwayStep2131 PathwayStep2132 PathwayStep2127 PathwayStep2126 PathwayStep2125 PathwayStep2124 PathwayStep2129 PathwayStep2128 Active dimers of ligand-responsive EGFR mutants sensitive to non-covalent TKIs Converted from EntitySet in Reactome Reactome DB_ID: 1220572 Reactome Database ID Release 431220572 Reactome, http://www.reactome.org ReactomeREACT_117019 Phosphorylated TTP:mRNA:14-3-3 Complex Reactome DB_ID: 450420 Reactome Database ID Release 43450420 Reactome, http://www.reactome.org ReactomeREACT_25699 has a Stoichiometric coefficient of 1 KSRP:mRNA Complex Reactome DB_ID: 450608 Reactome Database ID Release 43450608 Reactome, http://www.reactome.org ReactomeREACT_26697 has a Stoichiometric coefficient of 1 Phosphorylated AUF1 p40 Dimer Reactome DB_ID: 450375 Reactome Database ID Release 43450375 Reactome, http://www.reactome.org ReactomeREACT_25745 has a Stoichiometric coefficient of 2 BoNT Heavy Chain Converted from EntitySet in Reactome Reactome DB_ID: 168793 Reactome Database ID Release 43168793 Reactome, http://www.reactome.org ReactomeREACT_11415 AUF1 Tetramer (isoform p37 or p40) Converted from EntitySet in Reactome Reactome DB_ID: 450451 Reactome Database ID Release 43450451 Reactome, http://www.reactome.org ReactomeREACT_26472 AUF1 Tetramer: Destabilized mRNA Complex Reactome DB_ID: 450598 Reactome Database ID Release 43450598 Reactome, http://www.reactome.org ReactomeREACT_26524 has a Stoichiometric coefficient of 1 Phosphorylated AUF1 p40 Tetramer Reactome DB_ID: 450525 Reactome Database ID Release 43450525 Reactome, http://www.reactome.org ReactomeREACT_26519 has a Stoichiometric coefficient of 4 AUF1 p37 Tetramer Reactome DB_ID: 450414 Reactome Database ID Release 43450414 Reactome, http://www.reactome.org ReactomeREACT_25446 has a Stoichiometric coefficient of 4 Ubiquitinated AUF1 Tetramer: Destabilized mRNA Complex Reactome DB_ID: 450458 Reactome Database ID Release 43450458 Reactome, http://www.reactome.org ReactomeREACT_26356 has a Stoichiometric coefficient of 1 AUF1 Complexed with Translation and Heat Shock Proteins AUF1- and signal transduction-regulated complex (ASTRC) Reactome DB_ID: 450623 Reactome Database ID Release 43450623 Reactome, http://www.reactome.org ReactomeREACT_25605 has a Stoichiometric coefficient of 1 PathwayStep2140 PathwayStep2141 PathwayStep2142 PathwayStep2143 PathwayStep2144 PathwayStep2145 PathwayStep2136 PathwayStep2135 PathwayStep2138 PathwayStep2137 PathwayStep2139 Ubiquitinated AUF1 Tetramer Reactome DB_ID: 450417 Reactome Database ID Release 43450417 Reactome, http://www.reactome.org ReactomeREACT_26274 has a Stoichiometric coefficient of 4 26S proteasome Reactome DB_ID: 68819 Reactome Database ID Release 4368819 Reactome, http://www.reactome.org ReactomeREACT_2353 has a Stoichiometric coefficient of 1 BRF1:mRNA Complex Reactome DB_ID: 450589 Reactome Database ID Release 43450589 Reactome, http://www.reactome.org ReactomeREACT_26687 has a Stoichiometric coefficient of 1 PathwayStep2199 PathwayStep2198 PathwayStep2197 PathwayStep2196 PathwayStep2195 PathwayStep2194 PathwayStep2193 PathwayStep2192 PathwayStep2191 PathwayStep2190 Synaptotagmins Converted from EntitySet in Reactome Reactome DB_ID: 194784 Reactome Database ID Release 43194784 Reactome, http://www.reactome.org ReactomeREACT_11744 SRP receptor Reactome DB_ID: 265092 Reactome Database ID Release 43265092 Reactome, http://www.reactome.org ReactomeREACT_15899 has a Stoichiometric coefficient of 1 SRP receptor:SRP:ribosome:polypeptide+signal Reactome DB_ID: 1799323 Reactome Database ID Release 431799323 Reactome, http://www.reactome.org ReactomeREACT_117314 has a Stoichiometric coefficient of 1 Translocon:TRAP Reactome DB_ID: 264969 Reactome Database ID Release 43264969 Reactome, http://www.reactome.org ReactomeREACT_15589 has a Stoichiometric coefficient of 1 TRAP Complex Reactome DB_ID: 444589 Reactome Database ID Release 43444589 Reactome, http://www.reactome.org ReactomeREACT_20681 Translocon-associated Complex has a Stoichiometric coefficient of 1 SRP:polypeptide+signal:ribosome Reactome DB_ID: 1799337 Reactome Database ID Release 431799337 Reactome, http://www.reactome.org ReactomeREACT_116458 has a Stoichiometric coefficient of 1 BoNT Heavy Chain with inserted N-terminal Converted from EntitySet in Reactome Reactome DB_ID: 181577 Reactome Database ID Release 43181577 Reactome, http://www.reactome.org ReactomeREACT_11669 membrane-bound ribosome:mRNA:cleaved polypeptide Reactome DB_ID: 1799325 Reactome Database ID Release 431799325 Reactome, http://www.reactome.org ReactomeREACT_117242 has a Stoichiometric coefficient of 1 Translocon Reactome DB_ID: 444587 Reactome Database ID Release 43444587 Reactome, http://www.reactome.org ReactomeREACT_20898 has a Stoichiometric coefficient of 1 polypeptide+signal:Translocon Reactome DB_ID: 1799322 Reactome Database ID Release 431799322 Reactome, http://www.reactome.org ReactomeREACT_116321 has a Stoichiometric coefficient of 1 membrane-bound ribosome:mRNA:polypeptide+signal Reactome DB_ID: 1799336 Reactome Database ID Release 431799336 Reactome, http://www.reactome.org ReactomeREACT_117673 has a Stoichiometric coefficient of 1 cleaved polypeptide:Translocon Reactome DB_ID: 1799324 Reactome Database ID Release 431799324 Reactome, http://www.reactome.org ReactomeREACT_116785 has a Stoichiometric coefficient of 1 PathwayStep2174 VAMP 1 Converted from EntitySet in Reactome Reactome DB_ID: 181454 Reactome Database ID Release 43181454 Reactome, http://www.reactome.org ReactomeREACT_11525 PathwayStep2173 PathwayStep2172 PathwayStep2171 PathwayStep2178 80S:Met-tRNAi:mRNA Reactome DB_ID: 72505 Reactome Database ID Release 4372505 Reactome, http://www.reactome.org ReactomeREACT_4537 has a Stoichiometric coefficient of 1 PathwayStep2177 eIF5B:GDP Reactome DB_ID: 72502 Reactome Database ID Release 4372502 Reactome, http://www.reactome.org ReactomeREACT_4697 has a Stoichiometric coefficient of 1 PathwayStep2176 80S:Met-tRNAi:mRNA:eIF5B:GTP Reactome DB_ID: 72504 Reactome Database ID Release 4372504 Reactome, http://www.reactome.org ReactomeREACT_2486 has a Stoichiometric coefficient of 1 PathwayStep2175 eIF5B:GTP Reactome DB_ID: 72503 Reactome Database ID Release 4372503 Reactome, http://www.reactome.org ReactomeREACT_3457 has a Stoichiometric coefficient of 1 BoNT F cleaved VAMP 1 Converted from EntitySet in Reactome Reactome DB_ID: 194788 Reactome Database ID Release 43194788 Reactome, http://www.reactome.org ReactomeREACT_11394 60s ribosomal complex lacking L13a subunit Reactome DB_ID: 156817 Reactome Database ID Release 43156817 Reactome, http://www.reactome.org ReactomeREACT_4690 has a Stoichiometric coefficient of 1 phospho-L13a associated wth the 3' UTR GAIT element of ceruloplasmin mRNA within the translation initiation complex Reactome DB_ID: 156824 Reactome Database ID Release 43156824 Reactome, http://www.reactome.org ReactomeREACT_5151 has a Stoichiometric coefficient of 1 eIF2B subunits complex Reactome DB_ID: 72526 Reactome Database ID Release 4372526 Reactome, http://www.reactome.org ReactomeREACT_3897 has a Stoichiometric coefficient of 1 eIF2:GDP: eIF2B Reactome DB_ID: 72529 Reactome Database ID Release 4372529 Reactome, http://www.reactome.org ReactomeREACT_3553 has a Stoichiometric coefficient of 1 BoNT D cleaved VAMP 1 Converted from EntitySet in Reactome Reactome DB_ID: 194787 Reactome Database ID Release 43194787 Reactome, http://www.reactome.org ReactomeREACT_11756 PathwayStep2170 ribosome:mRNA:polypeptide+signal Reactome DB_ID: 1799327 Reactome Database ID Release 431799327 Reactome, http://www.reactome.org ReactomeREACT_117711 has a Stoichiometric coefficient of 1 Signal Recognition Particle Reactome DB_ID: 264932 Reactome Database ID Release 43264932 Reactome, http://www.reactome.org ReactomeREACT_15665 has a Stoichiometric coefficient of 1 signal recognition particle, endoplasmic reticulum targeting PathwayStep2168 PathwayStep2169 PathwayStep2183 PathwayStep2182 PathwayStep2185 SNAP-25 (active) Converted from EntitySet in Reactome Reactome DB_ID: 181542 Reactome Database ID Release 43181542 Reactome, http://www.reactome.org ReactomeREACT_11728 PathwayStep2184 PathwayStep2187 PathwayStep2186 eIF4F Reactome DB_ID: 72587 Reactome Database ID Release 4372587 Reactome, http://www.reactome.org ReactomeREACT_4441 cap-binding complex has a Stoichiometric coefficient of 1 PathwayStep2189 mRNP Reactome DB_ID: 72596 Reactome Database ID Release 4372596 Reactome, http://www.reactome.org ReactomeREACT_3493 has a Stoichiometric coefficient of 1 PathwayStep2188 eIF4F:mRNP Reactome DB_ID: 72597 Reactome Database ID Release 4372597 Reactome, http://www.reactome.org ReactomeREACT_4731 has a Stoichiometric coefficient of 1 mRNA:eIF4F:eIF4B:eIF4H Reactome DB_ID: 72593 Reactome Database ID Release 4372593 Reactome, http://www.reactome.org ReactomeREACT_2596 has a Stoichiometric coefficient of 1 43S:mRNA:eIF4F:eIF4B:eIF4H Reactome DB_ID: 72592 Reactome Database ID Release 4372592 Reactome, http://www.reactome.org ReactomeREACT_4439 has a Stoichiometric coefficient of 1 Ceruloplasmin mRNA:eIF4F:eIF4B:eIF4H Reactome DB_ID: 156809 Reactome Database ID Release 43156809 Reactome, http://www.reactome.org ReactomeREACT_2288 has a Stoichiometric coefficient of 1 43S: Ceruloplasmin mRNA:eIF4F:eIF4B:eIF4H:PABP Reactome DB_ID: 156804 Reactome Database ID Release 43156804 Reactome, http://www.reactome.org ReactomeREACT_3267 has a Stoichiometric coefficient of 1 BONT/A cleaved SNAP25 fragment Converted from EntitySet in Reactome Reactome DB_ID: 194810 Reactome Database ID Release 43194810 Reactome, http://www.reactome.org ReactomeREACT_11708 48S complex Reactome DB_ID: 72594 Reactome Database ID Release 4372594 Reactome, http://www.reactome.org ReactomeREACT_5152 has a Stoichiometric coefficient of 1 40S:Met-tRNAi:mRNA Reactome DB_ID: 72508 Reactome Database ID Release 4372508 Reactome, http://www.reactome.org ReactomeREACT_3073 has a Stoichiometric coefficient of 1 PathwayStep2181 eIF2:GDP Reactome DB_ID: 72530 Reactome Database ID Release 4372530 Reactome, http://www.reactome.org ReactomeREACT_2996 has a Stoichiometric coefficient of 1 BONT/C cleaved SNAP25 fragment Converted from EntitySet in Reactome Reactome DB_ID: 194791 Reactome Database ID Release 43194791 Reactome, http://www.reactome.org ReactomeREACT_11882 PathwayStep2180 PathwayStep2179 PathwayStep6700 PathwayStep6701 PathwayStep6702 PathwayStep6703 PathwayStep6704 Nonendonucleolytic RISC Reactome DB_ID: 427774 Reactome Database ID Release 43427774 Reactome, http://www.reactome.org ReactomeREACT_119049 has a Stoichiometric coefficient of 1 PathwayStep6705 Nonendonucleolytic RISC:Target RNA (exact match) Nonendonucleolytic RISC: Target RNA Complex with Exact Match between Target RNA and Guide RNA Reactome DB_ID: 426510 Reactome Database ID Release 43426510 Reactome, http://www.reactome.org ReactomeREACT_118948 has a Stoichiometric coefficient of 1 PathwayStep6706 AUF1 p37 Dimer Reactome DB_ID: 450539 Reactome Database ID Release 43450539 Reactome, http://www.reactome.org ReactomeREACT_26166 has a Stoichiometric coefficient of 2 PathwayStep6707 AUF1 Dimer (isoform p37 or p40) Converted from EntitySet in Reactome Reactome DB_ID: 450391 Reactome Database ID Release 43450391 Reactome, http://www.reactome.org ReactomeREACT_25445 PathwayStep6708 PathwayStep6709 Minimal RISC Converted from EntitySet in Reactome RNA-induced Silencing Complex Reactome DB_ID: 427783 Reactome Database ID Release 43427783 Reactome, http://www.reactome.org ReactomeREACT_119277 RISC:Target RNA (inexact match) RISC: Target RNA Complex with Inexact Match Between Target RNA and Guide RNA Reactome DB_ID: 426501 Reactome Database ID Release 43426501 Reactome, http://www.reactome.org ReactomeREACT_119703 has a Stoichiometric coefficient of 1 RISC Reactome DB_ID: 2106609 Reactome Database ID Release 432106609 Reactome, http://www.reactome.org ReactomeREACT_119190 has a Stoichiometric coefficient of 1 Argonaute1/3/4: Guide RNA Converted from EntitySet in Reactome Nonendonucleolytic Minimal RISC Reactome DB_ID: 210807 Reactome Database ID Release 43210807 Reactome, http://www.reactome.org ReactomeREACT_120000 PathwayStep6710 AGO4:siRNA Reactome DB_ID: 2106627 Reactome Database ID Release 432106627 Reactome, http://www.reactome.org ReactomeREACT_119673 has a Stoichiometric coefficient of 1 Argonaute2: Guide RNA Converted from EntitySet in Reactome Endonucleolytic Minimal RISC Reactome DB_ID: 203852 Reactome Database ID Release 43203852 Reactome, http://www.reactome.org ReactomeREACT_120257 PathwayStep6713 PathwayStep6714 PathwayStep6711 PathwayStep6712 AGO3:siRNA Reactome DB_ID: 2106622 Reactome Database ID Release 432106622 Reactome, http://www.reactome.org ReactomeREACT_118872 has a Stoichiometric coefficient of 1 PathwayStep6717 AGO1:siRNA Reactome DB_ID: 2106624 Reactome Database ID Release 432106624 Reactome, http://www.reactome.org ReactomeREACT_120097 has a Stoichiometric coefficient of 1 PathwayStep6718 Minimal RISC (siRNA) Converted from EntitySet in Reactome Reactome DB_ID: 2106611 Reactome Database ID Release 432106611 Reactome, http://www.reactome.org ReactomeREACT_120188 PathwayStep6715 AGO2:siRNA Reactome DB_ID: 2106601 Reactome Database ID Release 432106601 Reactome, http://www.reactome.org ReactomeREACT_119631 has a Stoichiometric coefficient of 1 PathwayStep6716 AGO4:duplex siRNA Reactome DB_ID: 2106600 Reactome Database ID Release 432106600 Reactome, http://www.reactome.org ReactomeREACT_119258 has a Stoichiometric coefficient of 1 PathwayStep6719 AGO2:duplex siRNA Reactome DB_ID: 2106605 Reactome Database ID Release 432106605 Reactome, http://www.reactome.org ReactomeREACT_119659 has a Stoichiometric coefficient of 1 AGO3:duplex siRNA Reactome DB_ID: 2106618 Reactome Database ID Release 432106618 Reactome, http://www.reactome.org ReactomeREACT_119898 has a Stoichiometric coefficient of 1 pre-RISC (siRNA) Converted from EntitySet in Reactome Reactome DB_ID: 2106630 Reactome Database ID Release 432106630 Reactome, http://www.reactome.org ReactomeREACT_120078 AGO1:duplex siRNA Reactome DB_ID: 2106607 Reactome Database ID Release 432106607 Reactome, http://www.reactome.org ReactomeREACT_119509 has a Stoichiometric coefficient of 1 PathwayStep6721 PathwayStep6720 DICER:TRBP:duplex siRNA Reactome DB_ID: 629637 Reactome Database ID Release 43629637 Reactome, http://www.reactome.org ReactomeREACT_119892 has a Stoichiometric coefficient of 1 Minimal RISC (miRNA) Converted from EntitySet in Reactome Reactome DB_ID: 2106628 Reactome Database ID Release 432106628 Reactome, http://www.reactome.org ReactomeREACT_119094 AGO4:duplex miRNA Reactome DB_ID: 2106602 Reactome Database ID Release 432106602 Reactome, http://www.reactome.org ReactomeREACT_120262 has a Stoichiometric coefficient of 1 AGO2:miRNA Reactome DB_ID: 2106621 Reactome Database ID Release 432106621 Reactome, http://www.reactome.org ReactomeREACT_120200 has a Stoichiometric coefficient of 1 AGO1:miRNA Reactome DB_ID: 2106629 Reactome Database ID Release 432106629 Reactome, http://www.reactome.org ReactomeREACT_119104 has a Stoichiometric coefficient of 1 AGO4:miRNA Reactome DB_ID: 2106626 Reactome Database ID Release 432106626 Reactome, http://www.reactome.org ReactomeREACT_118984 has a Stoichiometric coefficient of 1 AGO3:miRNA Reactome DB_ID: 2106613 Reactome Database ID Release 432106613 Reactome, http://www.reactome.org ReactomeREACT_120122 has a Stoichiometric coefficient of 1 pre-RISC (miRNA) Converted from EntitySet in Reactome Reactome DB_ID: 2106632 Reactome Database ID Release 432106632 Reactome, http://www.reactome.org ReactomeREACT_118897 AGO1:duplex miRNA Reactome DB_ID: 2106620 Reactome Database ID Release 432106620 Reactome, http://www.reactome.org ReactomeREACT_119888 has a Stoichiometric coefficient of 1 AGO2:duplex miRNA Reactome DB_ID: 2106619 Reactome Database ID Release 432106619 Reactome, http://www.reactome.org ReactomeREACT_119512 has a Stoichiometric coefficient of 1 AGO3:duplex miRNA Reactome DB_ID: 2106606 Reactome Database ID Release 432106606 Reactome, http://www.reactome.org ReactomeREACT_119459 has a Stoichiometric coefficient of 1 PathwayStep722 PathwayStep723 PathwayStep720 PathwayStep721 PathwayStep726 PathwayStep727 PathwayStep724 PathwayStep6500 PathwayStep725 PathwayStep6501 PathwayStep729 PathwayStep728 PathwayStep730 PathwayStep731 PathwayStep732 PathwayStep733 PathwayStep734 PathwayStep735 PathwayStep736 PathwayStep737 PathwayStep738 PathwayStep739 PathwayStep704 PathwayStep6520 PathwayStep705 PathwayStep6521 PathwayStep702 PathwayStep6522 PathwayStep703 PathwayStep6523 PathwayStep700 PathwayStep701 PathwayStep6518 PathwayStep6517 PathwayStep6519 PathwayStep709 PathwayStep6514 PathwayStep708 PathwayStep6513 PathwayStep707 PathwayStep6516 PathwayStep706 PathwayStep6515 PathwayStep713 PathwayStep6511 PathwayStep714 PathwayStep6512 PathwayStep715 PathwayStep716 PathwayStep6510 PathwayStep710 PathwayStep711 PathwayStep712 PathwayStep6509 PathwayStep6508 PathwayStep6507 PathwayStep6506 PathwayStep718 PathwayStep6505 PathwayStep717 PathwayStep6504 PathwayStep6503 PathwayStep719 PathwayStep6502 PathwayStep767 PathwayStep766 PathwayStep765 PathwayStep6541 PathwayStep764 PathwayStep6540 PathwayStep6543 PathwayStep6542 PathwayStep769 PathwayStep6545 PathwayStep768 PathwayStep6544 PathwayStep763 PathwayStep762 PathwayStep761 PathwayStep760 PathwayStep6535 PathwayStep6536 PathwayStep6537 PathwayStep6538 PathwayStep6539 PathwayStep776 PathwayStep6530 PathwayStep775 PathwayStep778 PathwayStep777 PathwayStep6534 PathwayStep779 PathwayStep6533 PathwayStep6532 PathwayStep6531 PathwayStep770 PathwayStep772 PathwayStep771 PathwayStep774 PathwayStep773 PathwayStep6526 PathwayStep6527 PathwayStep6524 PathwayStep6525 PathwayStep6528 PathwayStep6529 PathwayStep749 PathwayStep6565 PathwayStep748 PathwayStep6564 PathwayStep747 PathwayStep6567 PathwayStep746 PathwayStep6566 PathwayStep745 PathwayStep6561 PathwayStep744 PathwayStep6560 PathwayStep743 PathwayStep6563 PathwayStep742 PathwayStep6562 PathwayStep741 PathwayStep740 PathwayStep6557 PathwayStep6558 PathwayStep6559 PathwayStep758 PathwayStep6556 PathwayStep757 PathwayStep6555 PathwayStep6554 PathwayStep759 PathwayStep6553 PathwayStep754 PathwayStep6552 PathwayStep753 PathwayStep6551 PathwayStep756 PathwayStep6550 PathwayStep755 PathwayStep750 PathwayStep752 PathwayStep751 PathwayStep6548 PathwayStep6549 PathwayStep6546 PathwayStep6547 PathwayStep6579 PathwayStep6580 PathwayStep6581 PathwayStep6584 PathwayStep6585 PathwayStep6582 PathwayStep6583 PathwayStep6588 PathwayStep6589 PathwayStep6586 PathwayStep6587 PathwayStep6569 PathwayStep6568 CaMKII gamma/delta subunits Converted from EntitySet in Reactome Reactome DB_ID: 444779 Reactome Database ID Release 43444779 Reactome, http://www.reactome.org ReactomeREACT_20943 CaMKII alpha/beta Converted from EntitySet in Reactome Reactome DB_ID: 445366 Reactome Database ID Release 43445366 Reactome, http://www.reactome.org ReactomeREACT_21241 PathwayStep6570 CaMKII delta/gamma Converted from EntitySet in Reactome Reactome DB_ID: 445372 Reactome Database ID Release 43445372 Reactome, http://www.reactome.org ReactomeREACT_21043 PathwayStep6571 PathwayStep6572 PathwayStep6573 PathwayStep6574 PathwayStep6575 PathwayStep6576 PathwayStep6577 PathwayStep6578 PathwayStep2319 PathwayStep2314 PathwayStep2313 PathwayStep2312 PathwayStep2311 PathwayStep2318 PathwayStep2317 PathwayStep2316 PathwayStep2315 PathwayStep782 PathwayStep783 PathwayStep784 PathwayStep785 PathwayStep2320 PathwayStep2321 PathwayStep780 PathwayStep781 CaMKII alpha/beta subunits Converted from EntitySet in Reactome Reactome DB_ID: 444794 Reactome Database ID Release 43444794 Reactome, http://www.reactome.org ReactomeREACT_20684 PathwayStep786 PathwayStep787 Ca/calmodulin activated Adenylate Cyclase Converted from EntitySet in Reactome Reactome DB_ID: 443461 Reactome Database ID Release 43443461 Reactome, http://www.reactome.org ReactomeREACT_20929 PathwayStep788 PathwayStep789 PathwayStep2309 PathwayStep2308 PathwayStep2301 PathwayStep2300 PathwayStep2303 PathwayStep2302 PathwayStep2305 PathwayStep2304 PathwayStep2307 PathwayStep2306 PathwayStep795 PathwayStep796 PathwayStep6590 Phospho(S363,S380,T573)- ribosomal S6 kinase Converted from EntitySet in Reactome Reactome DB_ID: 444261 Reactome Database ID Release 43444261 Reactome, http://www.reactome.org ReactomeREACT_20714 PathwayStep793 PathwayStep6591 PathwayStep794 PathwayStep6592 PathwayStep791 PathwayStep792 PathwayStep790 PathwayStep2310 PathwayStep6597 Phospho(S221,S363,S380,T573)- ribosomal S6 kinase Converted from EntitySet in Reactome Reactome DB_ID: 444291 Reactome Database ID Release 43444291 Reactome, http://www.reactome.org ReactomeREACT_20750 PathwayStep6598 PathwayStep6599 PathwayStep799 PathwayStep6593 PathwayStep6594 PathwayStep797 PathwayStep6595 PathwayStep798 PathwayStep6596 PathwayStep2339 PathwayStep2337 PathwayStep2338 Small conductance Ca2+ activated potassium channel subunits Converted from EntitySet in Reactome Reactome DB_ID: 1297361 Reactome Database ID Release 431297361 Reactome, http://www.reactome.org ReactomeREACT_76208 PathwayStep2335 PathwayStep2336 PathwayStep2333 PathwayStep2334 PathwayStep2343 G-protein beta subunits (1-3) Converted from EntitySet in Reactome Reactome DB_ID: 1013018 Reactome Database ID Release 431013018 Reactome, http://www.reactome.org ReactomeREACT_26405 PathwayStep2342 PathwayStep2341 PathwayStep2340 G-protein Gamma subunits Converted from EntitySet in Reactome Reactome DB_ID: 1013010 Reactome Database ID Release 431013010 Reactome, http://www.reactome.org ReactomeREACT_26360 GABA(A)-rho receptor subunits Converted from EntitySet in Reactome Reactome DB_ID: 975443 Reactome Database ID Release 43975443 Reactome, http://www.reactome.org ReactomeREACT_26787 PathwayStep2326 PathwayStep2327 PathwayStep2328 PathwayStep2329 PathwayStep2322 PathwayStep2323 PathwayStep2324 PathwayStep2325 Kir3.x channels Converted from EntitySet in Reactome Reactome DB_ID: 975318 Reactome Database ID Release 43975318 Reactome, http://www.reactome.org ReactomeREACT_25623 PathwayStep2330 PathwayStep2332 Kirx.x that interacts with Kir2.1 Converted from EntitySet in Reactome Reactome DB_ID: 975240 Reactome Database ID Release 43975240 Reactome, http://www.reactome.org ReactomeREACT_25513 PathwayStep2331 PathwayStep2357 PathwayStep2358 PathwayStep2355 PathwayStep2356 PathwayStep2359 PathwayStep2361 GABA(A) receptor gamma subunits Converted from EntitySet in Reactome Reactome DB_ID: 975308 Reactome Database ID Release 43975308 Reactome, http://www.reactome.org ReactomeREACT_26270 PathwayStep2360 PathwayStep2365 PathwayStep2364 PathwayStep2363 PathwayStep2362 PathwayStep2344 PathwayStep2345 PathwayStep2346 PathwayStep2347 PathwayStep2348 PathwayStep2349 PLC-beta 1/2/3 Converted from EntitySet in Reactome Reactome DB_ID: 425749 Reactome Database ID Release 43425749 Reactome, http://www.reactome.org ReactomeREACT_20354 PathwayStep2350 GABA(A) receptor beta subunits Converted from EntitySet in Reactome Reactome DB_ID: 975288 Reactome Database ID Release 43975288 Reactome, http://www.reactome.org ReactomeREACT_26731 PathwayStep2352 PathwayStep2351 PathwayStep2354 GRIK1, GRIK2, GRIK3 Converted from EntitySet in Reactome Reactome DB_ID: 450203 Reactome Database ID Release 43450203 Reactome, http://www.reactome.org ReactomeREACT_22017 PathwayStep2353 PathwayStep2250 PathwayStep2251 PathwayStep2254 Cyclin A:Cdk2:substrate complex Reactome DB_ID: 187947 Reactome Database ID Release 43187947 Reactome, http://www.reactome.org ReactomeREACT_9192 has a Stoichiometric coefficient of 1 PathwayStep2255 PathwayStep2252 PathwayStep2253 ubiquitinated Cdc6 Reactome DB_ID: 68570 Reactome Database ID Release 4368570 Reactome, http://www.reactome.org ReactomeREACT_5308 has a Stoichiometric coefficient of 1 ubiquitinated Orc1 Reactome DB_ID: 68586 Reactome Database ID Release 4368586 Reactome, http://www.reactome.org ReactomeREACT_5173 has a Stoichiometric coefficient of 1 ubiquitinated Orc1 Reactome DB_ID: 113570 Reactome Database ID Release 43113570 Reactome, http://www.reactome.org ReactomeREACT_5402 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdk2(Thr160) complex Reactome DB_ID: 187952 Reactome Database ID Release 43187952 Reactome, http://www.reactome.org ReactomeREACT_9292 has a Stoichiometric coefficient of 1 RFC Heteropentamer Reactome DB_ID: 68436 Reactome Database ID Release 4368436 Reactome, http://www.reactome.org ReactomeREACT_4881 has a Stoichiometric coefficient of 1 Unwinding complex at replication fork Reactome DB_ID: 176949 Reactome Database ID Release 43176949 Reactome, http://www.reactome.org ReactomeREACT_7007 has a Stoichiometric coefficient of 1 GINS complex Reactome DB_ID: 176952 Reactome Database ID Release 43176952 Reactome, http://www.reactome.org ReactomeREACT_7704 has a Stoichiometric coefficient of 1 Mcm4:Mcm6:Mcm7 Mcm4,6,7 complex Reactome DB_ID: 69018 Reactome Database ID Release 4369018 Reactome, http://www.reactome.org ReactomeREACT_3276 has a Stoichiometric coefficient of 1 replicative helicase RFC Heteropentamer:RNA primer-DNA primer:origin duplex Reactome DB_ID: 68437 Reactome Database ID Release 4368437 Reactome, http://www.reactome.org ReactomeREACT_5241 has a Stoichiometric coefficient of 1 PathwayStep2248 PathwayStep2247 PathwayStep2246 PathwayStep2245 PathwayStep2249 PathwayStep2260 PathwayStep2261 PathwayStep2262 PathwayStep2263 PathwayStep2264 PathwayStep2265 PathwayStep2266 RFA DNA Replication Factor A RPA Reactome DB_ID: 68567 Reactome Database ID Release 4368567 Reactome, http://www.reactome.org ReactomeREACT_5149 has a Stoichiometric coefficient of 1 Cdc45:CDK:DDK:Mcm10:pre-replicative complex Reactome DB_ID: 68564 Reactome Database ID Release 4368564 Reactome, http://www.reactome.org ReactomeREACT_4546 has a Stoichiometric coefficient of 1 DNA polymerase epsilon:origin complex Reactome DB_ID: 68485 Reactome Database ID Release 4368485 Reactome, http://www.reactome.org ReactomeREACT_3283 has a Stoichiometric coefficient of 1 RPA:Cdc45:CDK:DDK:Mcm10:pre-replicative complex Reactome DB_ID: 68568 Reactome Database ID Release 4368568 Reactome, http://www.reactome.org ReactomeREACT_2568 has a Stoichiometric coefficient of 1 primosome DNA Pol alpha:primase DNA polymerase alpha:primase Reactome DB_ID: 68507 Reactome Database ID Release 4368507 Reactome, http://www.reactome.org ReactomeREACT_3725 has a Stoichiometric coefficient of 1 DNA polymerase epsilon Reactome DB_ID: 68483 Reactome Database ID Release 4368483 Reactome, http://www.reactome.org ReactomeREACT_4621 has a Stoichiometric coefficient of 1 RNA primer:origin duplex:DNA polymerase alpha:primase complex Reactome DB_ID: 68423 Reactome Database ID Release 4368423 Reactome, http://www.reactome.org ReactomeREACT_5709 has a Stoichiometric coefficient of 1 DNA polymerase alpha:primase:DNA polymerase alpha:origin complex Reactome DB_ID: 68510 Reactome Database ID Release 4368510 Reactome, http://www.reactome.org ReactomeREACT_3167 has a Stoichiometric coefficient of 1 RNA primer-DNA primer:origin duplex Reactome DB_ID: 68425 Reactome Database ID Release 4368425 Reactome, http://www.reactome.org ReactomeREACT_5497 has a Stoichiometric coefficient of 1 pre-replicative complex (Orc1-minus) Reactome DB_ID: 157563 Reactome Database ID Release 43157563 Reactome, http://www.reactome.org ReactomeREACT_3695 has a Stoichiometric coefficient of 1 PathwayStep2257 PathwayStep2256 PathwayStep2259 PathwayStep2258 PathwayStep2276 Cdt1:geminin Reactome DB_ID: 156502 Reactome Database ID Release 43156502 Reactome, http://www.reactome.org ReactomeREACT_5344 has a Stoichiometric coefficient of 1 PathwayStep2277 Processive complex:nicked DNA from adjacent Okazaki fragments Reactome DB_ID: 68470 Reactome Database ID Release 4368470 Reactome, http://www.reactome.org ReactomeREACT_4371 has a Stoichiometric coefficient of 1 PathwayStep2274 Processive complex:Okazaki fragments:Remaining Flap Reactome DB_ID: 68468 Reactome Database ID Release 4368468 Reactome, http://www.reactome.org ReactomeREACT_4338 has a Stoichiometric coefficient of 1 PathwayStep2275 PathwayStep2272 PathwayStep2273 PathwayStep2270 PathwayStep2271 IN bound to sticky 3' ends of viral DNA Reactome DB_ID: 175332 Reactome Database ID Release 43175332 Reactome, http://www.reactome.org ReactomeREACT_7266 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 IN:viral DNA bound to host genomic DNA with staggered ends Reactome DB_ID: 175224 Reactome Database ID Release 43175224 Reactome, http://www.reactome.org ReactomeREACT_9176 has a Stoichiometric coefficient of 1 TGFB1:TGFBR2:p-TGFBR1:Strap Reactome DB_ID: 2128981 Reactome Database ID Release 432128981 Reactome, http://www.reactome.org ReactomeREACT_125536 has a Stoichiometric coefficient of 1 TGFBR2 homodimer Reactome DB_ID: 170866 Reactome Database ID Release 43170866 Reactome, http://www.reactome.org ReactomeREACT_7415 Type II receptor complex has a Stoichiometric coefficient of 2 Dimeric TGFB1 Dimeric TGF-beta 1 Reactome DB_ID: 170852 Reactome Database ID Release 43170852 Reactome, http://www.reactome.org ReactomeREACT_6996 has a Stoichiometric coefficient of 2 p-TGFBR1 Phospho-TGF-beta I receptor complex Reactome DB_ID: 170863 Reactome Database ID Release 43170863 Reactome, http://www.reactome.org ReactomeREACT_7673 has a Stoichiometric coefficient of 2 TGFB1:TGFBR2:p-TGFBR1 Reactome DB_ID: 170841 Reactome Database ID Release 43170841 Reactome, http://www.reactome.org ReactomeREACT_7428 TGF-beta 1:type II receptor:Phospho-type I receptor complex has a Stoichiometric coefficient of 1 PathwayStep2269 PathwayStep2268 PathwayStep2267 PathwayStep2285 PathwayStep2286 PathwayStep2287 RFC Heteropentamer:RNA primer-DNA primer:origin duplex:PCNA homotrimer Reactome DB_ID: 68471 Reactome Database ID Release 4368471 Reactome, http://www.reactome.org ReactomeREACT_5474 has a Stoichiometric coefficient of 1 PathwayStep2288 PCNA homotrimer Reactome DB_ID: 68440 Reactome Database ID Release 4368440 Reactome, http://www.reactome.org ReactomeREACT_2542 has a Stoichiometric coefficient of 3 PathwayStep2281 PathwayStep2282 PathwayStep2283 PathwayStep2284 RPA heterotrimer Reactome DB_ID: 68462 Reactome Database ID Release 4368462 Reactome, http://www.reactome.org ReactomeREACT_3427 has a Stoichiometric coefficient of 1 Processive complex:Okazaki fragment:Flap Reactome DB_ID: 68455 Reactome Database ID Release 4368455 Reactome, http://www.reactome.org ReactomeREACT_4984 has a Stoichiometric coefficient of 1 Processive complex:Okazaki fragment:Flap:RPA heterotrimer:dna2 Reactome DB_ID: 68466 Reactome Database ID Release 4368466 Reactome, http://www.reactome.org ReactomeREACT_3597 has a Stoichiometric coefficient of 1 PathwayStep2280 Processive complex:Okazaki fragment:Flap:RPA heterotrimer Reactome DB_ID: 68463 Reactome Database ID Release 4368463 Reactome, http://www.reactome.org ReactomeREACT_4699 has a Stoichiometric coefficient of 1 DNA Polymerase delta tetramer Reactome DB_ID: 68450 Reactome Database ID Release 4368450 Reactome, http://www.reactome.org ReactomeREACT_5801 has a Stoichiometric coefficient of 1 RNA primer-DNA primer:origin duplex:PCNA Reactome DB_ID: 68441 Reactome Database ID Release 4368441 Reactome, http://www.reactome.org ReactomeREACT_4810 has a Stoichiometric coefficient of 1 Processive complex:Okazaki fragment complex Reactome DB_ID: 68453 Reactome Database ID Release 4368453 Reactome, http://www.reactome.org ReactomeREACT_5537 has a Stoichiometric coefficient of 1 Processive complex Reactome DB_ID: 68451 Reactome Database ID Release 4368451 Reactome, http://www.reactome.org ReactomeREACT_3120 has a Stoichiometric coefficient of 1 PathwayStep2279 PathwayStep2278 Kv11 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296103 Reactome Database ID Release 431296103 Reactome, http://www.reactome.org ReactomeREACT_76620 PathwayStep2291 Kv10 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296110 Reactome Database ID Release 431296110 Reactome, http://www.reactome.org ReactomeREACT_76045 PathwayStep2290 PathwayStep2295 PathwayStep2294 PathwayStep2293 PathwayStep2292 PathwayStep2299 PathwayStep2298 PathwayStep2297 PathwayStep2296 PathwayStep2289 p-T161-CDK1:CCNB1 Cyclin B1:phospho-Cdc2(Thr 161) Reactome DB_ID: 170160 Reactome Database ID Release 43170160 Reactome, http://www.reactome.org ReactomeREACT_6540 has a Stoichiometric coefficient of 1 Kv3 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296107 Reactome Database ID Release 431296107 Reactome, http://www.reactome.org ReactomeREACT_76611 Collagen type XVII Reactome DB_ID: 2172315 Reactome Database ID Release 432172315 Reactome, http://www.reactome.org ReactomeREACT_152062 has a Stoichiometric coefficient of 3 Cleaved collagen type XVII Reactome DB_ID: 2471876 Reactome Database ID Release 432471876 Reactome, http://www.reactome.org ReactomeREACT_152161 has a Stoichiometric coefficient of 3 Phosphorylated ERBB2:ERBB3 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963572 Reactome Database ID Release 431963572 Reactome, http://www.reactome.org ReactomeREACT_116858 NRG1/2:p-10Y-ERBB3:p-Y-ERBB2 Reactome DB_ID: 1963583 Reactome Database ID Release 431963583 Reactome, http://www.reactome.org ReactomeREACT_117310 has a Stoichiometric coefficient of 1 NRG1/2:P-ERBB3 Reactome DB_ID: 1248743 Reactome Database ID Release 431248743 Reactome, http://www.reactome.org ReactomeREACT_116652 has a Stoichiometric coefficient of 1 Kv2 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296096 Reactome Database ID Release 431296096 Reactome, http://www.reactome.org ReactomeREACT_76333 Kv12 subunit of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296097 Reactome Database ID Release 431296097 Reactome, http://www.reactome.org ReactomeREACT_76451 viral DNA with 3' sticky ends Reactome DB_ID: 175146 Reactome Database ID Release 43175146 Reactome, http://www.reactome.org ReactomeREACT_7525 has a Stoichiometric coefficient of 1 viral PIC proteins Reactome DB_ID: 177527 Reactome Database ID Release 43177527 Reactome, http://www.reactome.org ReactomeREACT_9170 has a Stoichiometric coefficient of 1 Integration intermediate Reactome DB_ID: 175148 Reactome Database ID Release 43175148 Reactome, http://www.reactome.org ReactomeREACT_9115 has a Stoichiometric coefficient of 1 IN:viral DNA bound to host genomic DNA Reactome DB_ID: 175339 Reactome Database ID Release 43175339 Reactome, http://www.reactome.org ReactomeREACT_9250 has a Stoichiometric coefficient of 1 ATP sensitive Potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296027 Reactome Database ID Release 431296027 Reactome, http://www.reactome.org ReactomeREACT_76106 Kir channels 2x Converted from EntitySet in Reactome Reactome DB_ID: 1296069 Reactome Database ID Release 431296069 Reactome, http://www.reactome.org ReactomeREACT_76007 Kv1 subunits of voltage gated potassium channels Converted from EntitySet in Reactome Reactome DB_ID: 1296109 Reactome Database ID Release 431296109 Reactome, http://www.reactome.org ReactomeREACT_76856 eEF2:GTP Reactome DB_ID: 156916 Reactome Database ID Release 43156916 Reactome, http://www.reactome.org ReactomeREACT_2807 has a Stoichiometric coefficient of 1 elongating polypeptide chain 80S Ribosome:mRNA:peptidyl-tRNA with elongating peptide Reactome DB_ID: 141952 Reactome Database ID Release 43141952 Reactome, http://www.reactome.org ReactomeREACT_4835 has a Stoichiometric coefficient of 1 eEF2:GDP Reactome DB_ID: 156922 Reactome Database ID Release 43156922 Reactome, http://www.reactome.org ReactomeREACT_5865 has a Stoichiometric coefficient of 1 80S:aminoacyl tRNA:mRNA:eEF1A:GTP Reactome DB_ID: 156903 Reactome Database ID Release 43156903 Reactome, http://www.reactome.org ReactomeREACT_5558 has a Stoichiometric coefficient of 1 80S:Met-tRNAi:mRNA:aminoacyl-tRNA Reactome DB_ID: 72506 Reactome Database ID Release 4372506 Reactome, http://www.reactome.org ReactomeREACT_3365 has a Stoichiometric coefficient of 1 eEF1A:GDP Reactome DB_ID: 156929 Reactome Database ID Release 43156929 Reactome, http://www.reactome.org ReactomeREACT_5872 has a Stoichiometric coefficient of 1 Elongation complex with growing peptide chain Reactome DB_ID: 156927 Reactome Database ID Release 43156927 Reactome, http://www.reactome.org ReactomeREACT_5024 has a Stoichiometric coefficient of 1 Signal Peptidase Reactome DB_ID: 264960 Reactome Database ID Release 43264960 Reactome, http://www.reactome.org ReactomeREACT_15945 has a Stoichiometric coefficient of 1 eEF1A:GTP:aminoacyl-tRNA complex Reactome DB_ID: 156911 Reactome Database ID Release 43156911 Reactome, http://www.reactome.org ReactomeREACT_3062 has a Stoichiometric coefficient of 1 eEF1A:GTP Reactome DB_ID: 156921 Reactome Database ID Release 43156921 Reactome, http://www.reactome.org ReactomeREACT_3513 has a Stoichiometric coefficient of 1 SMN complex Reactome DB_ID: 191762 Reactome Database ID Release 43191762 Reactome, http://www.reactome.org ReactomeREACT_10714 has a Stoichiometric coefficient of 2 Spliceosomal m3G capped snRNA:SMN:SM:Snurportin complex Reactome DB_ID: 191778 Reactome Database ID Release 43191778 Reactome, http://www.reactome.org ReactomeREACT_10792 has a Stoichiometric coefficient of 1 m3G capped Spliceosomal snRNA Reactome DB_ID: 191780 Reactome Database ID Release 43191780 Reactome, http://www.reactome.org ReactomeREACT_10157 has a Stoichiometric coefficient of 1 Spliceosomal m3G capped snRNA loaded with the SM complex Reactome DB_ID: 191870 Reactome Database ID Release 43191870 Reactome, http://www.reactome.org ReactomeREACT_10264 has a Stoichiometric coefficient of 1 Orc2:origin Reactome DB_ID: 68511 Reactome Database ID Release 4368511 Reactome, http://www.reactome.org ReactomeREACT_4170 has a Stoichiometric coefficient of 1 snRNP Sm core complex Reactome DB_ID: 191846 Reactome Database ID Release 43191846 Reactome, http://www.reactome.org ReactomeREACT_10955 has a Stoichiometric coefficient of 1 Methylosome Reactome DB_ID: 191849 Reactome Database ID Release 43191849 Reactome, http://www.reactome.org ReactomeREACT_10865 has a Stoichiometric coefficient of 1 Spliceosomal m7G capped snRNAs with SMN:SM protein complex bound Reactome DB_ID: 191813 Reactome Database ID Release 43191813 Reactome, http://www.reactome.org ReactomeREACT_10860 has a Stoichiometric coefficient of 1 Spliceosomal m3G capped snRNAs with SMN:SM protein complex bound Reactome DB_ID: 191891 Reactome Database ID Release 43191891 Reactome, http://www.reactome.org ReactomeREACT_10845 has a Stoichiometric coefficient of 1 m3G capped Spliceosomal snRNA Reactome DB_ID: 191834 Reactome Database ID Release 43191834 Reactome, http://www.reactome.org ReactomeREACT_10776 has a Stoichiometric coefficient of 1 m7G capped Spliceosomal snRNA Reactome DB_ID: 191853 Reactome Database ID Release 43191853 Reactome, http://www.reactome.org ReactomeREACT_10232 has a Stoichiometric coefficient of 1 m7G capped snRNA:CBC:PHAX complex Reactome DB_ID: 191887 Reactome Database ID Release 43191887 Reactome, http://www.reactome.org ReactomeREACT_10849 has a Stoichiometric coefficient of 1 eRF3-GDP:eRF1:80S Ribosome:mRNA:tRNA Complex Reactome DB_ID: 143396 Reactome Database ID Release 43143396 Reactome, http://www.reactome.org ReactomeREACT_4303 has a Stoichiometric coefficient of 1 eRF3-GDP:eRF1:80S Ribosome:mRNA:peptidyl-tRNA Complex Reactome DB_ID: 143381 Reactome Database ID Release 43143381 Reactome, http://www.reactome.org ReactomeREACT_5057 has a Stoichiometric coefficient of 1 SMN:SM protein complex Reactome DB_ID: 191791 Reactome Database ID Release 43191791 Reactome, http://www.reactome.org ReactomeREACT_10415 has a Stoichiometric coefficient of 1 SMN complex Reactome DB_ID: 191881 Reactome Database ID Release 43191881 Reactome, http://www.reactome.org ReactomeREACT_10606 has a Stoichiometric coefficient of 2 GTP bound eRF3 Reactome DB_ID: 143383 Reactome Database ID Release 43143383 Reactome, http://www.reactome.org ReactomeREACT_5462 has a Stoichiometric coefficient of 1 eRF3-GTP:eRF1:80S Ribosome:mRNA:peptidyl-tRNA Complex Reactome DB_ID: 143397 Reactome Database ID Release 43143397 Reactome, http://www.reactome.org ReactomeREACT_4059 has a Stoichiometric coefficient of 1 eEF1B complex Reactome DB_ID: 156920 Reactome Database ID Release 43156920 Reactome, http://www.reactome.org ReactomeREACT_3047 has a Stoichiometric coefficient of 1 eEF1B:GDP exchange complex Reactome DB_ID: 156917 Reactome Database ID Release 43156917 Reactome, http://www.reactome.org ReactomeREACT_3385 has a Stoichiometric coefficient of 1 CDK:DDK:Mcm10:pre-replicative complex Reactome DB_ID: 68561 Reactome Database ID Release 4368561 Reactome, http://www.reactome.org ReactomeREACT_2458 has a Stoichiometric coefficient of 1 DDK Reactome DB_ID: 68388 Reactome Database ID Release 4368388 Reactome, http://www.reactome.org ReactomeREACT_4813 has a Stoichiometric coefficient of 1 phosphorylated Mcm2-7 complex Reactome DB_ID: 68569 Reactome Database ID Release 4368569 Reactome, http://www.reactome.org ReactomeREACT_4259 has a Stoichiometric coefficient of 1 Mcm10:pre-replicative complex Reactome DB_ID: 68560 Reactome Database ID Release 4368560 Reactome, http://www.reactome.org ReactomeREACT_5685 has a Stoichiometric coefficient of 1 Mcm10:active pre-replicative complex Reactome DB_ID: 156564 Reactome Database ID Release 43156564 Reactome, http://www.reactome.org ReactomeREACT_2683 has a Stoichiometric coefficient of 1 active pre-replicative complex Reactome DB_ID: 156562 Reactome Database ID Release 43156562 Reactome, http://www.reactome.org ReactomeREACT_5627 has a Stoichiometric coefficient of 1 CDK Reactome DB_ID: 68380 Reactome Database ID Release 4368380 Reactome, http://www.reactome.org ReactomeREACT_5476 has a Stoichiometric coefficient of 1 CDT1:CDC6:ORC:origin complex Reactome DB_ID: 68544 Reactome Database ID Release 4368544 Reactome, http://www.reactome.org ReactomeREACT_5333 has a Stoichiometric coefficient of 1 Mcm2-7 complex Reactome DB_ID: 68558 Reactome Database ID Release 4368558 Reactome, http://www.reactome.org ReactomeREACT_4763 has a Stoichiometric coefficient of 1 preRC Reactome DB_ID: 68559 Reactome Database ID Release 4368559 Reactome, http://www.reactome.org ReactomeREACT_4388 has a Stoichiometric coefficient of 1 pre-replicative complex geminin:ubiquitin complex Reactome DB_ID: 68585 Reactome Database ID Release 4368585 Reactome, http://www.reactome.org ReactomeREACT_2422 has a Stoichiometric coefficient of 1 Cdt1:geminin Reactome DB_ID: 68537 Reactome Database ID Release 4368537 Reactome, http://www.reactome.org ReactomeREACT_5120 has a Stoichiometric coefficient of 1 CDC6:ORC:origin complex Reactome DB_ID: 68543 Reactome Database ID Release 4368543 Reactome, http://www.reactome.org ReactomeREACT_4079 has a Stoichiometric coefficient of 1 Orc2 associated with MCM8 Reactome DB_ID: 176970 Reactome Database ID Release 43176970 Reactome, http://www.reactome.org ReactomeREACT_7878 has a Stoichiometric coefficient of 1 ORC complex bound to origin Reactome DB_ID: 176958 Reactome Database ID Release 43176958 Reactome, http://www.reactome.org ReactomeREACT_7859 has a Stoichiometric coefficient of 1 ORC:origin Reactome DB_ID: 68540 Reactome Database ID Release 4368540 Reactome, http://www.reactome.org ReactomeREACT_3844 has a Stoichiometric coefficient of 1 Orc4:Orc5:Orc3:Orc2:origin Reactome DB_ID: 68520 Reactome Database ID Release 4368520 Reactome, http://www.reactome.org ReactomeREACT_4462 has a Stoichiometric coefficient of 1 Orc1:Orc4:Orc5:Orc3:Orc2:origin Reactome DB_ID: 68592 Reactome Database ID Release 4368592 Reactome, http://www.reactome.org ReactomeREACT_2696 has a Stoichiometric coefficient of 1 PathwayStep6600 Orc3:Orc2:origin Reactome DB_ID: 68514 Reactome Database ID Release 4368514 Reactome, http://www.reactome.org ReactomeREACT_5183 has a Stoichiometric coefficient of 1 Orc5:Orc3:Orc2:origin Reactome DB_ID: 68517 Reactome Database ID Release 4368517 Reactome, http://www.reactome.org ReactomeREACT_2818 has a Stoichiometric coefficient of 1 Ligands of PPARA Converted from EntitySet in Reactome Reactome DB_ID: 400149 Reactome Database ID Release 43400149 Reactome, http://www.reactome.org ReactomeREACT_20348 Acyl chain remodelling of PS Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0036150 In the acyl chain remodelling pathway (Lands cycle), phosphatidylserine (PS) is hydrolysed by phopholipases and subsequently reacylated by acyltransferases. These cycles modify the fatty acid composition of glycerophospholipids to generate diverse molecules asymmetrically distributed in the cell membrane (Ghomashchi et al. 2010, Singer et al. 2002, Cao et al. 2008; Hishikawa et al. 2008). Pubmed12359733 Pubmed18287005 Pubmed18458083 Pubmed20705608 Reactome Database ID Release 431482801 Reactome, http://www.reactome.org ReactomeREACT_121384 Synthesis of PS Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006659 Phosphatidylserine (PS) is synthesized by facilitating the exchange of L-Serine (L-Ser) with the choline (Cho) head group in phosphatidylcholine (PC) and with the ethanolamine (ETA) head group in phosphatidylethanolamine (PE) (Saito et al. 1998, Tomohiro et al. 2009). Pubmed19014349 Pubmed9642289 Reactome Database ID Release 431483101 Reactome, http://www.reactome.org ReactomeREACT_120823 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PI Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006661 Phosphatidylinositol (PI) is synthesized when phosphatidic acid (PA) and cytidine triphosphate (CTP) are converted into cytidine diphosphate-diacylglycerol (CDP-DAG) followed by conversion into PI and cytidine monophosphate (CMP) (Stuhne-Sekalec et al 1986, Lykidis et al. 1997). Pubmed3718705 Pubmed9407135 Reactome Database ID Release 431483226 Reactome, http://www.reactome.org ReactomeREACT_121000 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PE <i>De novo</i> (Kennedy pathway) synthesis of phosphatidylethanolamine (PE) involves phosphorylation of ethanolamine (ETA) to phosphoethanolamine (PETA) followed by condensing with cytidine triphosphate (CTP) to form CDP-ethanolamine (CDP-ETA). Diacylglycerol (DAG) and CDP-ETA together then form PE. Alternatively, PE is formed when phosphatidylserine (PS) is decarboxylated by phosphatidylserine decarboxylase proenzyme (PISD) (Henneberry et al. 2002, Vance 1991, Vance 1990). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006646 Pubmed12221122 Pubmed1898727 Pubmed2332429 Reactome Database ID Release 431483213 Reactome, http://www.reactome.org ReactomeREACT_120919 Reviewed: Wakelam, Michael, 2012-05-14 crosslinked fibrin multimer:tissue plasminogen activator (one-chain):plasminogen -> crosslinked fibrin multimer:tissue plasminogen activator (one-chain) + plasmin Authored: D'Eustachio, P, 2005-02-08 21:36:34 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasminogen bound to fibrin is cleaved and activated by tissue plasminogen activator also bound to the fibrin. The association of both plasminogen and tissue plasminogen activator with a fibrin clot juxtaposes the two molecules, facilitating their interaction (Hoylaerts et al. 1982). Early studies suggested that tissue plasminogen activator itself might require activation (conversion to its two-chain form) before it could catalyze this reaction (e.g., Higgins and Vehar 1987). More recent work (Boose et al. 1989) indicates that the single-chain form of the molecule is catalytically active, although cleavage increases its activity and may thus serve to accelerate the later stages of fibrinolysis. Pubmed2496749 Pubmed2962641 Pubmed7199524 Reactome Database ID Release 43158750 Reactome, http://www.reactome.org ReactomeREACT_1456 Acyl chain remodelling of PE Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0036152 In the acyl chain remodelling pathway (Lands cycle), phosphatidylethanolamine (PE) is hydrolyzed by phopholipases and subsequently reacylated by acyltransferases. These cycles modify the fatty acid composition of glycerophospholipids to generate diverse molecules asymmetrically distributed in the cell membrane (Ghomashchi et al. 2010, Singer et al. 2002, Cao et al. 2008, Zhao et al. 2008, Hishikawa et al. 2008). Pubmed12359733 Pubmed18195019 Pubmed18287005 Pubmed18458083 Pubmed20705608 Reactome Database ID Release 431482839 Reactome, http://www.reactome.org ReactomeREACT_121369 Reviewed: Wakelam, Michael, 2012-05-14 Hydrolysis of LPE Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006644 Lysophosphatidylethanolamine (LPE) is hydrolyzed by phospholipases to produce glycerophosphoethanolamine (GPETA) which is in turn hydrolyzed by glycerophosphocholine phosphodiesterase to produce ethanolamine (ETA) and glycerol-3-phosphate (G3P) (Yamashita et al. 2009, Yamashita et al. 2005). Pubmed15944408 Pubmed19501189 Reactome Database ID Release 431483152 Reactome, http://www.reactome.org ReactomeREACT_120785 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PC <i>De novo</i> (Kennedy pathway) synthesis of phosphatidylcholine (PC) involves phosphorylation of choline (Cho) to phosphocholine (PCho) followed by condensing with cytidine triphosphate (CTP) to form CDP-choline (CDP-Cho). Diacylglycerol (DAG) and CDP-ETA together then form PC. Alternatively, PC is formed when phosphatidylethanolamine (PE) is methylated by phosphatidylethanolamine N-methyltransferase (PEMT) (Henneberry et al. 2002; Wright & McMaster 2002). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006656 Pubmed12216837 Pubmed12221122 Reactome Database ID Release 431483191 Reactome, http://www.reactome.org ReactomeREACT_121238 Reviewed: Wakelam, Michael, 2012-05-14 histidine-rich glycoprotein:plasminogen <-> histidine-rich glycoprotein + plasminogen Authored: D'Eustachio, P, 2005-02-05 20:25:20 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasminogen reversibly binds histidine-rich glycoprotein (HRG). The resulting complex interacts poorly with fibrin, suggesting that HRG might have an anti-fibrinolytic (clot-stabilizing) effect in vivo (Lijnen et al. 1980). Consistent with this suggestion, individuals with chronically reduced plasma HRG concentrations are susceptible to thrombosis (Shigekiyo et al. 1998). Pubmed3011081 Pubmed6448849 Pubmed9414276 Reactome Database ID Release 43158721 Reactome, http://www.reactome.org ReactomeREACT_2193 PI and PC transport between ER and Golgi membranes Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0015914 Pubmed16854452 Pubmed18636990 Pubmed20332109 Pubmed21915936 Reactome Database ID Release 431483196 Reactome, http://www.reactome.org ReactomeREACT_121079 Reviewed: Wakelam, Michael, 2012-05-14 The phosphatidylinositol transfer protein beta isoform (PITPNB) bound to phosphatidylinositol (PI) complex transports from the endoplasmic reticulum (ER) membrane to the Golgi membrane, where phosphatidylcholine (PC) is exchanged for PI. PITPNB now in complex with PC transports back to the ER membrane where PI is now exchanged for PC, and the cycle repeats. This process has been characterized in detail in bovine and rodent model systems (e.g., Wirtz et al. 2006; Ghosh and Bankaitis 2011), which provide a framework for organizing the more limited data available for the very well conserved human proteins and processes( Carvou et al. 2010, Shadan et al. 2008). histidine-rich glycoprotein + plasminogen <-> histidine-rich glycoprotein:plasminogen Authored: D'Eustachio, P, 2005-02-05 20:25:20 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasminogen reversibly binds histidine-rich glycoprotein (HRG). The resulting complex interacts poorly with fibrin, suggesting that HRG might have an anti-fibrinolytic (clot-stabilizing) effect in vivo (Lijnen et al. 1980). Consistent with this suggestion, individuals with chronically reduced plasma HRG concentrations are susceptible to thrombosis (Shigekiyo et al. 1998). Pubmed3011081 Pubmed6448849 Pubmed9414276 Reactome Database ID Release 43158722 Reactome, http://www.reactome.org ReactomeREACT_746 Acyl chain remodelling of PC Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0036151 In the acyl chain remodelling pathway (Lands cycle), phosphatidylcholine (PC) is hydrolysed by phopholipases and subsequently reacylated by acyltransferases. These cycles modify the fatty acid composition of glycerophospholipids to generate diverse molecules asymmetrically distributed in the cell membrane (Ghomashchi et al. 2010, Singer et al. 2002, Cao et al. 2008, Zhao et al. 2008). Pubmed12359733 Pubmed18195019 Pubmed18458083 Pubmed20705608 Reactome Database ID Release 431482788 Reactome, http://www.reactome.org ReactomeREACT_120829 Reviewed: Wakelam, Michael, 2012-05-14 crosslinked fibrin multimer:tissue plasminogen activator (one-chain) + plasminogen -> crosslinked fibrin multimer:tissue plasminogen activator (one-chain):plasminogen Authored: D'Eustachio, P, 2005-02-08 21:36:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasminogen associates with tissue plasminogen activator bound to fibrin. Pubmed2318848 Pubmed7199524 Reactome Database ID Release 43158784 Reactome, http://www.reactome.org ReactomeREACT_565 Hydrolysis of LPC Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006644 Lysophosphatidylcholine (LPC) is hydrolyzed by phospholipases to produce glycerophosphocholine (GPCho) which is in turn hydrolyzed by glycerophosphocholine phosphodiesterase to produce choline (Cho) and glycerol-3-phosphate (G3P) (Yamashita et al. 2009, Yamashita et al. 2005, Ghomashchi et al. 2010). Pubmed15944408 Pubmed19501189 Pubmed20705608 Reactome Database ID Release 431483115 Reactome, http://www.reactome.org ReactomeREACT_120977 Reviewed: Wakelam, Michael, 2012-05-14 crosslinked fibrin multimer + tissue plasminogen activator (one-chain) -> crosslinked fibrin multimer:tissue plasminogen activator (one-chain) Authored: D'Eustachio, P, 2005-02-08 21:36:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed2962641 Pubmed6433976 Pubmed7199524 Reactome Database ID Release 43158781 Reactome, http://www.reactome.org ReactomeREACT_1328 The first step in the dissolution of a fibrin clot is the association of the one-chain form of tissue plasminogen activator with fibrin. activated thrombin (factor IIa) + thrombomodulin -> activated thrombin:thrombomodulin Activated thrombin (factor IIa) binds to thrombomodulin at the external face of the plasma membrane, forming a thrombin:thrombomodulin complex. In this complexed form, the activity of thrombin towards protein C is greatly increased, and as thrombomodulin is particularly abundant on the surfaces of endothelial cells, this association plays a major role in restricting clot formation. Authored: D'Eustachio, P, 2004-08-26 13:13:00 Pubmed2538457 Reactome Database ID Release 43141046 Reactome, http://www.reactome.org ReactomeREACT_1834 thrombin:cleaved antithrombin III:heparin -> thrombin:cleaved antithrombin III + heparin Authored: D'Eustachio, P, 2004-08-24 14:00:00 Pubmed12907439 Reactome Database ID Release 43140872 Reactome, http://www.reactome.org ReactomeREACT_1283 The same conformational change that traps thrombin in its complex with cleaved antithrombin III also decreases the affinity of the latter for heparin, and the complex of cleaved antithrombin III and thrombin dissociates from the cell-bound heparin molecule. factor Va -> factor Vi Activated protein C cleaves peptide bonds in activated factor V (factor Va), converting it to an inactive form (factor Vi). The exact site(s) of cleavage are unknown. Protein S, on the endothelial cell surface, positively regulates this reaction. Although the mechanism of this regulation is unclear, the regulation is physiologically important, as people with reduced amounts of protein S, like people with reduced amounts of protein C, are susceptible to thromboembolism. Authored: D'Eustachio, P, 2004-08-26 13:13:00 EC Number: 3.4.21 Pubmed2538457 Reactome Database ID Release 43141026 Reactome, http://www.reactome.org ReactomeREACT_1071 protein C -> activated protein C + protein C heavy chain activation peptide Authored: Ouwehand, W.H., 2007-11-12 16:45:54 EC Number: 3.4.21 Pubmed2538457 Pubmed468991 Reactome Database ID Release 43141040 Reactome, http://www.reactome.org ReactomeREACT_374 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function. thrombin:antithrombin III:heparin -> thrombin:cleaved antithrombin III:heparin Antithrombin III in the complex is cleaved by thrombin, thereupon undergoing a conformational change that stabilizes the thrombin:antithrombin III complex, trapping and inactivating the thrombin moiety. Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Pubmed12907439 Reactome Database ID Release 43140870 Reactome, http://www.reactome.org ReactomeREACT_1500 Acyl chain remodeling of DAG and TAG Acyl chain remodeling of triacylglycerol (TAG) and diacylglycerol (DAG) progresses through their hydrolysis by patatin-like phospholipase domain-containing proteins 2/3 (PNPLA2/3). DAG is reacylated back to TAG by acylglycerol O-acyltransferase 1/2 (DGAT1/2), while DAG and its hydrolysis product 2-monoacylglycerol (2-MAG) are transacylated back to TAG by PNPLA2/3. In addition, the DAG hydrolysis product 2-MAG is subsequently hydrolyzed to fatty acid and glycerol by monoglyceride lipase (MGLL) (Jenkins et al. 2004). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0036155 Pubmed15364929 Reactome Database ID Release 431482883 Reactome, http://www.reactome.org ReactomeREACT_121122 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PA Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006654 In the <i>de novo</i> synthesis of phosphatidic acid (PA), lysophosphatidic acid (LPA) is initially formed by the esterification of <i>sn-1</i> by glycerol 3-phosphate acyltransferase (GPAT) from glycerol 3-phosphate (G3P). Next, LPA is converted to PA by a LPA acyltransferase (AGPAT, also known as LPAAT). In addition to this, PA is also formed when phosphatidylcholine (PC) is hydrolyzed by phospholipase D1/2 (PLD1/2). PA is involved in acyl chain remodeling via cleavage by phospholipases followed by reacylation by acyltransferases (Ghomashchi et al. 2010, Singer et al. 2002, Prasad et al. 2011, Shindou & Shimizu 2009, Cao et al. 2006). Pubmed12359733 Pubmed17170135 Pubmed18718904 Pubmed20705608 Pubmed21173190 Reactome Database ID Release 431483166 Reactome, http://www.reactome.org ReactomeREACT_120906 Reviewed: Wakelam, Michael, 2012-05-14 Glycerophospholipid biosynthesis Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0046474 Glycerophospholipids are important structural and functional components of biological membranes and constituents of serum lipoproteins and the pulmonary surfactant. In addition, glycerophospholipids act as precursors of lipid mediators such as platelet-activating factor and eicosanoids. Cellular membranes contains a distinct composition of various glycerophospholipids such as phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), cardiolipin (CL), lysophosphatidic acid (LPA) and lysobisphosphatidic acid (also known as bis(monoacylglycerol) hydrogen phosphate - BMP).<br><br>Glycerophospholipids are first formed by the <i>de novo</i> (Kennedy) pathway using fatty acids activated as acyl-CoA donors. However, the acyl groups of glycerophospholipids are highly diverse and distributed in an asymmetric manner. Saturated and monounsaturated fatty acids are usually esterified at the <i>sn-1</i> position, whereas polyunsaturated acyl groups are esterified at the <i>sn-2</i> position. Subsequent acyl chain remodeling (Lands cycle) generates the diverse glycerophospholipid composition and asymmetry characteristic of cell membranes.<br><br>In the <i>de novo</i> pathway of glycerophospholipid biosynthesis, lysophosphatidic acid (LPA) is initially formed from glycerol 3-phosphate (G3P). Next, LPA is converted to PA by a LPA acyltransferase (AGPAT, also known as LPAAT), then PA is metabolized into two types of glycerol derivatives. The first is diacylglycerol (DAG) which is converted to triacylglycerol (TAG), PC, and PE. Subsequently, PS is synthesized from PC or PE. The second is cytidine diphosphate-diacylglycerol (CDP-DAG), which is processed into PI, PG, CL, and BMP. Each glycerophospholipid is involved in acyl chain remodeling via cleavage by phospholipases followed by reacylation by an acyltransferase.<br><br>Most of the glycerophospholipids are synthesized at the endoplasmic reticulum (ER), however, some, most notably cardiolipin, and BMP are synthesized in the mitochondrial and endosomal membranes respectively. Since the most of the glycerophospholipids are found in all membrane compartments, there must be extensive network of transport of glycerophospholipids from one membrane compartment to another via various mechanisms including diffusion through the cytosol, formation of transportation complexes, and diffusion via membrane contact sites (MCS) (Osman et al. 2011, Lebiedzinska et al. 2009, Lev 2010, Scherer & Schmitz 2011, Orso et al. 2011, Hermansson et al. 2011, Vance & Vance 2008). ISBN978-0-444-53219-0 Pubmed19703651 Pubmed20823909 Pubmed21220505 Pubmed21382416 Pubmed21683693 Pubmed21704024 Reactome Database ID Release 431483206 Reactome, http://www.reactome.org ReactomeREACT_121401 Phospholipid metabolism Authored: Williams, MG, 2011-08-12 Edited: Williams, MG, 2011-09-09 GENE ONTOLOGYGO:0006644 Phospholipids contain a polar head group and two long-chain fatty acyl moieties, one of which is generally unsaturated. The head group is a glycerol or serine phosphate attached to a polar group such as choline. These molecules are a major constituent of cellular membranes, where their diverse structures and asymmetric distributions play major roles in determining membrane properties (Dowhan 1997). The four major classes of phospholipids in human plasma membranes are phosphatidylethanolamine, phosphatidylserine, phosphatidylcholine, and sphingomyelin. The first three are derivatives of glycerol while sphingomyelin is a derivative of serine.<p>Here, pathways for the metabolism of glycerophospholipids, phosphphatidylinositol (PI), and sphingolipids are annotated. Pubmed9242906 Reactome Database ID Release 431483257 Reactome, http://www.reactome.org ReactomeREACT_120870 Reviewed: D'Eustachio, P, 2012-05-19 Glucocorticoid biosynthesis Authored: Jassal, B, 2008-10-01 13:18:42 Cortisol, the major human glucocorticoid, is synthesized in the zona fasciculata of the adrenal cortex from pregnenolone. Pregnenolone is converted to 17alpha-hydoxyprogesterone in two reactions, both catalyzed by 3-beta-hydroxysteroid dehydrogenase/isomerase. 17Alpha-hydroxyprogesterone is hydroxylated by CYP21A2 to form 11-deoxycortisol, which in turn is converted to cortisol by CYP11B1. The conversion of the active steroid hormone, cortisol, to inactive cortisone occurs in many tissues, notably the liver (Payne and Hales 2004). Edited: Jassal, B, 2007-04-20 21:09:56 GENE ONTOLOGYGO:0006704 Pubmed15583024 Reactome Database ID Release 43194002 Reactome, http://www.reactome.org ReactomeREACT_11036 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Mineralocorticoid biosynthesis Aldosterone, the major human mineralocorticoid, is synthesized in the zona glomerulosa of the adrenal cortex from pregnenolone. Pregnenolone is converted to progesterone in two reactions, both catalyzed by 3-beta-hydroxysteroid dehydrogenase/isomerase. Progesterone is hydroxylated by CYP21A2 to form deoxycorticosterone, which in turn is converted to aldosterone in a three-reaction sequence catalyzed by CYP11B2 (Payne and Hales 2004). Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 GENE ONTOLOGYGO:0006705 Pubmed15583024 Reactome Database ID Release 43193993 Reactome, http://www.reactome.org ReactomeREACT_11047 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Vitamin D (calciferol) metabolism Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-06-02 10:50:11 GENE ONTOLOGYGO:0042359 Pubmed15951480 Reactome Database ID Release 43196791 Reactome, http://www.reactome.org ReactomeREACT_13523 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Vitamin D3 (cholecalciferol) is a steroid hormone that plays a role in regulating calcium and bone metabolism. It is obtained from the diet and produced in the skin by photolysis of 7-dehydrocholesterol and released into the bloodstream. Only a few food sources have significant amounts of vitamins D2 and D3 but many foodstuffs nowadays are fortified with vitamin D. The metabolites of vitamin D3 are carried in the circulation bound to a plasma protein called vitamin D binding protein (VDBP). Vitamin D3 undergoes two subsequent hydroxylations to form the active form of the vitamin, 1,25(OH)2 vitamin D3 (calcitriol). The first hydroxylation takes place in the liver and subsequent transport to the kidney allows the second hydroxylation. Calciferol acts by binding to nuclear vitamin D receptors. plasminogen:histidine-rich glycoprotein -> plasmin + histidine-rich glycoprotein (uPA [one-chain] catalyst) Authored: D'Eustachio, P, 2005-02-14 18:06:15 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasminogen, tethered to the cell surface by its association with histidine-rich glycoprotein, is cleaved and activated to plasmin by the action of urokinase plasminogen activator bound to uPAR, its cell-surface receptor. The association of both substrate and enzyme with the cell surface is necessary for the reaction to proceed efficiently (Ellis et al. 1991). While the one-chain form of urokinase plasminogen activator is lower than that of the two-chain form, it is still sufficient to initiate the process of plasmin activation (Ellis et al. 1989; Lijnen et al. 1986). Pubmed1829461 Pubmed2521625 Pubmed2935528 Reactome Database ID Release 43158982 Reactome, http://www.reactome.org ReactomeREACT_739 Retinoid metabolism and transport Authored: Jassal, B, 2010-10-01 Authored: Stephan, R, 2010-09-19 Edited: Jassal, B, 2010-10-01 GENE ONTOLOGYGO:0001523 Pubmed11340090 Pubmed16011460 Reactome Database ID Release 43975634 Reactome, http://www.reactome.org ReactomeREACT_24968 Reviewed: D'Eustachio, P, 2010-11-09 Vitamin A (all-trans-retinol) must be taken up, either as carotenes from plants, or as retinyl esters from animal food. The most prominent carotenes are alpha-carotene, lycopene, lutein, beta-cryptoxanthine, and especially beta-carotene. After uptake they are mostly broken down to retinal. Retinyl esters are hydrolysed like other fats. In enterocytes, retinoids bind to retinol-binding protein (RBP). Transport from enterocytes to the liver happens via chylomicrons (Harrison & Hussain 2001, Harrison 2005). plasminogen + histidine-rich glycoprotein -> plasminogen:histidine-rich glycoprotein Authored: D'Eustachio, P, 2005-02-14 18:06:15 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Extracellular plasminogen binds with high affinity to histidine-rich glycoprotein on the plasma membrane. Binding requires Zn++ in concentrations higher than those found in normal plasma, but that can be generated, e.g., by platelet activation (Jones et al. 2004). Pubmed15220341 Reactome Database ID Release 43158941 Reactome, http://www.reactome.org ReactomeREACT_2235 Androgen biosynthesis Androgens are the determining factors for male development and behaviour in vertebrates (Miller 2002). Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 GENE ONTOLOGYGO:0006702 Pubmed12428201 Reactome Database ID Release 43193048 Reactome, http://www.reactome.org ReactomeREACT_11059 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 urokinase plasminogen activator + urokinase plasminogen activator receptor (uPAR) -> urokinase plasminogen activator:uPAR Authored: D'Eustachio, P, 2005-02-14 18:06:15 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed1846368 Pubmed2156852 Pubmed3023326 Reactome Database ID Release 43158959 Reactome, http://www.reactome.org ReactomeREACT_1386 The uncleaved (one-chain) form of urokinase plasminogen activator associates with urokinase plasminogen activator receptor (uPAR), forming a complex at the cell surface (Cubellis et al. 1986). The complex is anchored to the outer face of the plasma membrane by a glycophosphatidylinositol moiety at the carboxy terminus of uPAR (Behrendt et al. 1990; Ploug et al. 1991). Estrogen biosynthesis Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 GENE ONTOLOGYGO:0006703 In female vertebrates, estrogens control reproductive system development and reproductive functions (Payne AH and Hales DB, 2004). Pubmed15583024 Reactome Database ID Release 43193144 Reactome, http://www.reactome.org ReactomeREACT_11037 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 alpha-2-antiplasmin + plasmin -> alpha-2-antiplasmin:plasmin Authored: D'Eustachio, P, 2005-02-10 21:51:29 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasmin binds the serpin alpha-2-antiplasmin, forming a stable and catalytically inactive complex. While several serpin proteins bind and inactivate plasmin in vitro, alpha-2-antiplasmin appears to be the only one with substantial plasmin-neutralizing activity in vivo (Moroi and Aoki 1976; Lijnen et al. 1987). Pubmed134998 Pubmed2440681 Reactome Database ID Release 43158893 Reactome, http://www.reactome.org ReactomeREACT_221 fibrin multimer, crosslinked:tissue plasminogen activator (one-chain) + plasminogen activator inhibitor 1 -> fibrin multimer, crosslinked:tissue plasminogen activator (one-chain):plasminogen activator inhibitor 1 Authored: D'Eustachio, P, 2005-02-08 22:51:14 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasminogen activator inhibitor 1, a serpin, binds to fibrin-associated tissue plasminogen activator. The resulting stable complex remains associated with fibrin but cannot activate plasminogen (Wagner et al. 1989). The importance of this step in the regulation of clot dissolution in vivo is indicated by the occurence of thrombosis in individuals with abnormally little tissue plasminogen activator or abnormally much plasminogen activator inhibitor (Juhan-Vague et al. 1987). Pubmed2503541 Pubmed3109059 Reactome Database ID Release 43158795 Reactome, http://www.reactome.org ReactomeREACT_427 fibrin multimer, crosslinked:tissue plasminogen activator (two-chain) + plasminogen activator inhibitor 1 -> fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen activator inhibitor 1 Authored: D'Eustachio, P, 2005-02-08 22:51:14 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasminogen activator inhibitor 1, a serpin, binds to fibrin-associated tissue plasminogen activator. The resulting stable complex remains associated with fibrin but cannot activate plasminogen (Wagner et al. 1989). The importance of this step in the regulation of clot dissolution in vivo is indicated by the occurence of thrombosis in individuals with abnormally little tissue plasminogen activator or abnormally much plasminogen activator inhibitor (Juhan-Vague et al. 1987). Pubmed2503541 Pubmed3109059 Reactome Database ID Release 43158800 Reactome, http://www.reactome.org ReactomeREACT_747 crosslinked fibrin multimer:tissue plasminogen activator (two-chain):plasminogen -> crosslinked fibrin multimer:tissue plasminogen activator (two-chain) + plasmin At the beginning of this reaction, 1 molecule of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen' is present. At the end of this reaction, 1 molecule of 'plasmin', and 1 molecule of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain)' are present.<br><br> This reaction takes place in the 'extracellular region' and is mediated by the 'plasminogen activator activity' of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen'.<br> EC Number: 3.4.21 Pubmed2318848 Pubmed2962641 Reactome Database ID Release 43158744 Reactome, http://www.reactome.org ReactomeREACT_2226 crosslinked fibrin multimer:tissue plasminogen activator (two-chain) + plasminogen -> crosslinked fibrin multimer:tissue plasminogen activator (two-chain):plasminogen At the beginning of this reaction, 1 molecule of 'plasminogen', and 1 molecule of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain)' are present. At the end of this reaction, 1 molecule of 'fibrin multimer, crosslinked:tissue plasminogen activator (two-chain):plasminogen' is present.<br><br> This reaction takes place in the 'extracellular region'.<br> Pubmed2962641 Reactome Database ID Release 43158756 Reactome, http://www.reactome.org ReactomeREACT_791 crosslinked fibrin multimer:tissue plasminogen activator (one-chain) -> crosslinked fibrin multimer:tissue plasminogen activator (two-chain) Authored: D'Eustachio, P, 2005-02-08 21:36:34 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Once plasmin has been activated, in the initial stage of the fibrinolysis process, it can catalyze the conversion of fibrin-bound tissue plasminogen activator (one-chain) to its more active two-chain form, increasing the rate at which additional plasminogen molecules can be activated. Pubmed2496749 Pubmed2962641 Reactome Database ID Release 43158747 Reactome, http://www.reactome.org ReactomeREACT_2028 fibrin multimer, crosslinked -> fibrin digestion products (plasmin) Authored: D'Eustachio, P, 2005-02-08 21:36:34 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasmin, generated at the surfaces of the fibrin clot by tissue plasminogen activator or at the surfaces of cells by urokinase plasminogen activator, catalyzes the hydrolysis of fibrin to soluble fragments (Chapman 1997). Pubmed2318848 Pubmed9330876 Reactome Database ID Release 43158766 Reactome, http://www.reactome.org ReactomeREACT_729 PIPs transport between Golgi and plasma membranes A secretory vesicle containing primarily containing the phospholipid phosphatidylinositol 4-phosphate (PI4P) is exported from the Golgi membrane to the plasma membrane (Szentpetery et al. 2010, Godi et al. 2004, Hammond et al. 2009). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0045332 Pubmed15107860 Pubmed19508231 Pubmed20404150 Reactome Database ID Release 431660510 Reactome, http://www.reactome.org ReactomeREACT_120914 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PIPs at the Golgi membrane At the Golgi membrane, phosphatidylinositol 4-phosphate (PI4P) is primarily generated from phosphorylation of phosphatidylinositol (PI). Other phosphoinositides are also generated by the action of various kinases and phosphatases such as: phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (Godi et al. 1999, Minogue et al. 2001, Rohde et al. 2003, Sbrissa et al. 2007, Sbrissa et al. 2008, Domin et al. 2000, Arcaro et al. 2000). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006661 Pubmed10559940 Pubmed10766823 Pubmed10805725 Pubmed11279162 Pubmed14527956 Pubmed17556371 Pubmed18950639 Reactome Database ID Release 431660514 Reactome, http://www.reactome.org ReactomeREACT_120836 Reviewed: Wakelam, Michael, 2012-05-14 PI Metabolism Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006644 Phosphatidylinositol (PI), a membrane phospholipid, can be reversibly phosphorylated at the 3, 4, and 5 positions of the inositol ring to generate seven phosphoinositides: phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4-phosphate (PI4P), phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate PI(3,4)P2, phosphatidylinositol 4,5-bisphosphate PI(4,5)P2, phosphatidylinositol 3,5-bisphosphate PI(3,5)P2, and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). These seven phosphoinositides, which are heterogeneously distributed within cells, can serve as signature components of different intracellular compartment membranes and so help to mediate specificity of membrane interactions. Phosphoinositide levels are tightly regulated spatially and temporally by the action of various kinases and phosphatases whilst PI(4,5)P2 is also a substrate for phospholipase C. The differential localisation of each of these enzymes on specific compartment membranes ensures maintenance of the heterogeneous distribution of phosphoinositides despite the continuous membrane flow from one compartment to another.<br><br>PI is primarily synthesised in the endoplasmic reticulum from where the phospholipid is exported to other compartments via membrane traffic or via cytosolic phospholipid transfer proteins. Phosphorylation of PI to PI4P primarily occurs in the Golgi, where PI4P plays an important role in the biogenesis of transport vesicles such as the secretory vesicle involved in its transport to the plasma membrane. At this place, PI4P has a major function acting as a precursor of PI(4,5)P2, which is located predominantly at this membrane. PI(4,5)P2 binds and regulates a wide range of proteins that function on the cell surface and serves as a precursor for second messengers. Additionally, it helps define this membrane as a target for secretory vesicles, functions as a coreceptor in endocytic processes, and functions as a cofactor for actin nucleation.<br><br>At the plasma membrane, PI(4,5)P2 is further phosphorylated to PI(3,4,5)P3, another phosphoinositide with important signalling functions including stimulating cell survival and proliferation. The inositol 3-phosphatase, phosphatase and tensin homolog (PTEN) regenerates PI (4,5)P2, while the 5-phosphatases convert PI(3,4,5)P3 into the phosphoinositide, PI(3,4)P2, propagating the signal initiated by PI(3,4,5)P3. PI(3,4)P2 is further dephosphorylated in the endocytic pathway by inositol 4-phosphatases to PI3P, the signature phosphoinositide of the early endosomal compartment and a ligand for numerous endosomal proteins. However, the bulk of PI3P is generated directly in the endosomes by phosphorylation of PI. The subsequent endosomal phosphorylation of PI3P to PI(3,5)P2 is believed to generate docking sites for recruitment of cytosolic factors responsible for the control of outgoing traffic from the endosomes. The main localisation and function of the low abundance phosphoinositide PI5P, that can be generated by several pathways, remains to be determined (Krauss & Haucke 2007, Leventis & Grinstein 2010, Roth 2004, Gees et al. 2010, De Matteis & Godi 2004, van Meer et al. 2008, Vicinanza et al. 2008, Lemmon 2008, Kutaleladze 2010, Robinson & Dixon 2006, Blero et al. 2007, Liu & Bankaitis 2010, McCrea & De Camilli 2009, Vicinanza et al. 2008, Di Paolo & De Camilli, 2006). Pubmed15170460 Pubmed15269334 Pubmed16828287 Pubmed17035995 Pubmed17330069 Pubmed17605038 Pubmed18216767 Pubmed18216768 Pubmed18726176 Pubmed18784754 Pubmed19196647 Pubmed20043944 Pubmed20192774 Pubmed20559318 Pubmed20861159 Reactome Database ID Release 431483255 Reactome, http://www.reactome.org ReactomeREACT_121175 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PIPs at the ER membrane At the endoplasmic reticulum (ER) membrane, phosphatidylinositol (PI) and phosphatidylinositol 4-phosphate (PI4P) are interconverted (Wong et al. 1997, Gehrmann et al. 1999, Wei et al. 2002, Rohde et al. 2003). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006661 Pubmed10101268 Pubmed12324459 Pubmed14527956 Pubmed9148941 Reactome Database ID Release 431483248 Reactome, http://www.reactome.org ReactomeREACT_121168 Reviewed: Wakelam, Michael, 2012-05-14 Acyl chain remodeling of CL Acyl chain remodeling of cardiolipin (CL) occurs in the inner mitochondria membranes (IM) via hydrolysis by phopholipases and subsequent reacylation by acyltransferases. At the endoplasmic reticulum (ER) membrane the situation is more complicated with monolysocardiolipin (MLCL) involved in hydrolysis and subsequent reacylation back to CL (Zachman et al. 2010, Malhotra et al. 2009, Xu et al. 2003, Taylor & Hatch 2009, Cao et al. 2004, Zhao et al. 2009, Buckland et al. 1998). Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0035965 Pubmed14551214 Pubmed15152008 Pubmed19075029 Pubmed19416660 Pubmed19737925 Pubmed19741254 Pubmed9487141 Reactome Database ID Release 431482798 Reactome, http://www.reactome.org ReactomeREACT_121006 Synthesis of BMP Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:2001312 Lysobisphosphatidic acid, also known as bis(monoacylglycerol) hydrogen phosphate (BMP), is enriched in late endosomes and not found in the endoplasmic reticulum (ER) or mitochondria where phosphatidylglycerol (PG) is synthesized. Late endosomes form membrane contact sites with the ER, providing a means for PG to enter the late endosome and be converted to BMP via hydrolysis by a phospholipase A2, followed by acylation, and a reorientation of the phosphoryl ester (Poorthuis & Hostetler 1978, Heravi & Waite 1999, Hullin-Matsuda et al. 2007, Gallala & Sandhoff 2010). Pubmed10101262 Pubmed17558022 Pubmed21136156 Pubmed650089 Reactome Database ID Release 431483171 Reactome, http://www.reactome.org ReactomeREACT_121039 Acyl chain remodelling of PG Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0036148 In the acyl chain remodelling pathway (Lands cycle), phosphatidylglycerol (PG) is hydrolyzed by phopholipases and subsequently reacylated by acyltransferases. These cycles modify the fatty acid composition of glycerophospholipids to generate diverse molecules asymmetrically distributed in the cell membrane. The events occur additionally in the inner mitochondria membranes (IM) as well as in the endoplasmic reticulum (ER) membrane (Ghomashchi et al. 2010, Singer et al. 2002, Cao et al. 2008, Yang et al. 2004, Nie et al. 2010). Pubmed12359733 Pubmed15485873 Pubmed18458083 Pubmed20025994 Pubmed20705608 Reactome Database ID Release 431482925 Reactome, http://www.reactome.org ReactomeREACT_121324 Synthesis of CL Authored: Williams, MG, 2011-09-14 Cardiolipin(CL) is synthesized in the inner mitochondrial membrane (IM), when phosphatidylglycerol (PG) and cytidine diphosphate-diacylglycerol (CDP-DAG) are converted into CL (Lu et al. 2006, Houtkooper et al. 2006). Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0032049 Pubmed16547353 Pubmed16678169 Reactome Database ID Release 431483076 Reactome, http://www.reactome.org ReactomeREACT_120920 Acyl chain remodelling of PI Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0036149 In the acyl chain remodelling pathway (Lands cycle), phosphatidylinositol (PI) is hydrolyzed by phospholipases and subsequently reacylated by acyltransferases. These cycles modify the fatty acid composition of glycerophospholipids to generate diverse molecules asymmetrically distributed in the cell membrane (Ghomashchi et al. 2010, Singer et al. 2002, Gijon et al. 2008, Lee et al. 2008). Pubmed12359733 Pubmed18094042 Pubmed18772128 Pubmed20705608 Reactome Database ID Release 431482922 Reactome, http://www.reactome.org ReactomeREACT_120722 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PG Authored: Williams, MG, 2011-09-14 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006655 Phosphatidylglycerol (PG) is synthesised at the inner mitochondrial (IM) membrane, phosphatidic acid (PA) and cytidine triphosphate (CTP) are converted into cytidine diphosphate-diacylglycerol (CDP-DAG), which in turn is converted with glycerol-3-phosphate (G3P) into phosphatidylglycerophosphate (PGP) and cytidine monophosphate (CMP). Finally, PGP is dephosphorylated to PG. In addition, PG can be synthesised at the endoplamic reticulum (ER) membrane when phospholipase D transphosphatidylates phosphatidylcholine (PC) with glycerol to displace choline (Cho) and form PG (Piazza & Marmer 2007, Stuhne-Sekalec et al. 1986, Lykidis et al. 1997, Cao & Hatch 1994). Pubmed3718705 Pubmed7968268 Pubmed9407135 Reactome Database ID Release 431483148 Reactome, http://www.reactome.org ReactomeREACT_121280 Beta oxidation of octanoyl-CoA to hexanoyl-CoA Authored: Gillespie, ME, 2003-09-19 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 ISBN0079130356 Reactome Database ID Release 4377348 Reactome, http://www.reactome.org ReactomeREACT_1697 The fifth pass through the beta-oxidation spiral picks up where the last left off with the saturated fatty acid octanoyl-CoA and produces hexanoyl-CoA. Four enzymatic steps are required starting with MCAD CoA dehydrogenase (Medium Chain) activity, followed by the enoyl-CoA hydratase activity of crotonase, the 3-hydroxyacyl-CoA dehydrogenase activity of the short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and completed by the ketoacyl-CoA thiolase activity, present in the mitochondrial membrane associated trifunctional protein. ACTIVATION GENE ONTOLOGYGO:0003985 Reactome Database ID Release 4370842 Reactome, http://www.reactome.org Beta oxidation of hexanoyl-CoA to butanoyl-CoA Authored: Gillespie, ME, 2003-09-19 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 ISBN0079130356 Reactome Database ID Release 4377350 Reactome, http://www.reactome.org ReactomeREACT_1887 The sixth pass through the beta-oxidation spiral picks up where the last left off with the saturated fatty acid hexanoyl-CoA and produces butanoyl-CoA. Four enzymatic steps are required starting with SCAD CoA dehydrogenase (Short Chain) activity, followed by the enoyl-CoA hydratase activity of crotonase, the 3-hydroxyacyl-CoA dehydrogenase activity of the short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and completed by the ketoacyl-CoA thiolase activity, present in the mitochondrial membrane associated trifunctional protein. ACTIVATION GENE ONTOLOGYGO:0004368 Reactome Database ID Release 43188456 Reactome, http://www.reactome.org Beta oxidation of butanoyl-CoA to acetyl-CoA Authored: Gillespie, ME, 2003-09-19 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 ISBN0079130356 Reactome Database ID Release 4377352 Reactome, http://www.reactome.org ReactomeREACT_419 The seventh and final pass through the beta-oxidation spiral picks up where the last left off with the saturated fatty acid butanoyl-CoA and at the third step produces acetoacetyl-CoA, which can be used to generate 2 acetyl-CoA molecules or can be turned toward the synthesis of ketone bodies pathway. Four enzymatic steps are required starting with SCAD CoA dehydrogenase (Short Chain) activity, followed by the enoyl-CoA hydratase activity of crotonase, the 3-hydroxyacyl-CoA dehydrogenase activity of the short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD). The final enzymatic step, creating two acetyl-CoA molecules requires a specific ketoacyl-CoA thiolase, Acetoacetyl-CoA thiolase. mitochondrial fatty acid beta-oxidation of unsaturated fatty acids Authored: Gillespie, ME, 2003-10-25 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006635 ISBN0079130356 Pubmed12397064 Reactome Database ID Release 4377288 Reactome, http://www.reactome.org ReactomeREACT_160 The complete beta-oxidation spiral produces and consumes intermediates with a trans configuration. Mitochondrial beta-oxidation of unsaturated fatty acids leads to intermediates not compatible with the four enzymatic steps responsible for the beta-oxidation of saturated fatty acids. Unsaturated fatty acids that have bonds in the cis configuration require three separate enzymatic steps to prepare these molecules for the beta-oxidation pathway. The further processing of these intermediates requires additional enzymes, depending on the position of the double bonds in the original fatty acids. Described here is the beta-oxidation of linoleoyl-CoA. Propionyl-CoA catabolism Authored: 2003-04-11 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0019626 ISBN0079130356 Propionyl-CoA is a product of the catabolism of the amino acids, leucine, methionine, and threonine, and of the beta-oxidation of fatty acids with odd numbers of carbon atoms. The three reactions of this pathway convert propionyl-CoA to succinyl-CoA, an intermediate of the citric acid cycle. Through these reactions, carbon atoms from these sources can be fully oxidized to produce energy, or can be directed to gluconeogenesis. The three reactions of propionyl-CoA catabolism take place in the mitochondrial matrix. Reactome Database ID Release 4371032 Reactome, http://www.reactome.org ReactomeREACT_993 Release of platelet cytosolic components Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Platelet releasate contains a range of proteins that do not originate in specialized storage granules. In some cases platelet lysis may contribute to the presence of these proteins in the platelet relesate. Pubmed14630798 Reactome Database ID Release 43482772 Reactome, http://www.reactome.org ReactomeREACT_21347 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 ACTIVATION GENE ONTOLOGYGO:0048244 Reactome Database ID Release 43389595 Reactome, http://www.reactome.org Ketone body metabolism Acetoacetate, beta-hydroxybutyrate, and acetone collectively are called ketone bodies. The first two are synthesized from acetyl-CoA, in the mitochondria of liver cells; acetone is formed by spontaneous decarboxylation of acetoacetate. Ketone body synthesis in liver is effectively irreversible because the enzyme that catalyzes the conversion of acetoacetate to acetoacetyl-CoA is not present in liver cells.<P>Ketone bodies, unlike fatty acids and triglycerides, are water-soluble. They are exported from the liver, and are taken up by other tissues, notably brain and skeletal and cardiac muscle. There, they are broken down to acetyl-CoA which is oxidized via the TCA cycle to yield energy. In a normal person, this pathway of ketone body synthesis and utilization is most active during extended periods of fasting. Under these conditions, mobilization and breakdown of stored fatty acids generates abundant acetyl-CoA acetyl-CoA in liver cells for synthesis of ketone bodies, and their utilization in other tissues minimizes the demand of these tissues for glucose (Sass 2011). Authored: Gopinathrao, G, 2003-07-23 10:32:00 GENE ONTOLOGYGO:0046950 Pubmed21479626 Reactome Database ID Release 4374182 Reactome, http://www.reactome.org ReactomeREACT_1861 Surface deployment of platelet alpha granule membrane components Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Constituents of the platelet alpha granule membrane are incorporated into the platelet membrane following exocytosis of granule content. Pubmed8467233 Reactome Database ID Release 43481044 Reactome, http://www.reactome.org ReactomeREACT_21394 ACTIVATION GENE ONTOLOGYGO:0016830 Reactome Database ID Release 43389618 Reactome, http://www.reactome.org Synthesis of Ketone Bodies Authored: Joshi-Tope, G, 2003-10-19 14:58:00 GENE ONTOLOGYGO:0046951 In a healthy, well-nourished individual, the production of ketone bodies occurs at a relatively low rate. During periods of normal physiological responses to carbohydrate shortages, the liver increases the production of ketone bodies from acetyl-CoA generated from fatty acid oxidation. This allows heart and skeletal muscle to use ketone bodies as the primary source of energy, thereby preserving the limited glucose supply for use in brain tissue.<p>In untreated <i>diabetes mellitus</i>, a huge buildup of ketone bodies occurs due to an increase in fatty acid oxidation. The production of ketone bodies exceeds the ability of peripheral tissues to oxidize them, and results in lowering the pH of blood. Blood acidification is dangerous, chiefly as it impairs the ability of hemoglobin to bind oxygen.<p>Ketone body synthesis proceeds via the synthesis of ccetoacetic acid in three steps from acetyl CoA, followed by the reduction of acetoacetic acid to beta-hydroxybutyrate. In the body, these reactions occur in the mitochondria of liver cells (Sass 2011). Pubmed21479626 Reactome Database ID Release 4377111 Reactome, http://www.reactome.org ReactomeREACT_1464 ACTIVATION GENE ONTOLOGYGO:0000295 Reactome Database ID Release 43389649 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050197 Reactome Database ID Release 43389629 Reactome, http://www.reactome.org Release of (inferred) platelet cytosolic components Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Platelet releasate contains a range of proteins that do not originate in specialized storage granules. In some cases platelet lysis may contribute to the presence of these proteins in the platelet relesate. Pubmed14630798 Reactome Database ID Release 43482775 Reactome, http://www.reactome.org ReactomeREACT_21290 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 sequestered tissue factor -> tissue factor Authored: D'Eustachio, P, 2004-08-24 14:00:00 Pubmed2704749 Reactome Database ID Release 43140761 Reactome, http://www.reactome.org ReactomeREACT_1596 Tissue factor sequestered in the wall of a blood vessel is exposed to circulating blood when the endothelial lining of the vessel is injured. formation of TF:F7 complex Authored: D'Eustachio, P, 2004-08-24 14:00:00 Pubmed3527261 Reactome Database ID Release 43140783 Reactome, http://www.reactome.org ReactomeREACT_1669 Tissue factor exposed at the endothelial cell surface forms a complex with factor VII from plasma. tissue factor (TF) + factor VII (F7) -> TF:F7 complex activation of factor X by TF:F7 Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Factor VII, bound to tissue factor at the endothelial cell surface, catalyzes the activation of factor X from plasma with moderate efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.) Pubmed3275472 Pubmed3527261 Pubmed6980899 Reactome Database ID Release 43140777 Reactome, http://www.reactome.org ReactomeREACT_493 factor X -> factor Xa + factor X activation peptide (TF:F7 catalyst) activation of factor VII Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Factor Xa catalyzes the activation of factor VII from plasma. Pubmed8639673 Reactome Database ID Release 43140769 Reactome, http://www.reactome.org ReactomeREACT_9 factor VII -> factor VIIa Beta oxidation of myristoyl-CoA to lauroyl-CoA Authored: Gillespie, ME, 2003-09-19 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 ISBN0079130356 Reactome Database ID Release 4377285 Reactome, http://www.reactome.org ReactomeREACT_2108 The second pass through the beta-oxidation spiral starts with the saturated fatty acid myristoyl-CoA (from the first swing through the beta oxidation spiral) and produces lauroyl-CoA. Four enzymatic steps are required starting with LCAD CoA dehydrogenase (Long Chain) activity, followed by three enzymatic steps, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and ketoacyl-CoA thiolase activities, all present in the mitochondrial membrane associated trifunctional protein. Release of platelet secretory granule components Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Platelet releasate contains a range of proteins that do not originate in specialized storage granules. In some cases platelet lysis may contribute to the presence of these proteins in the platelet relesate. Pubmed14630798 Reactome Database ID Release 43482770 Reactome, http://www.reactome.org ReactomeREACT_21324 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Release of Calumenin After Platelet activation 'Calumenin' from the endoplasmic reticulum lumen is released in to the extracellular platelet releasate. Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Edited: Garapati, P V, 2008-05-13 11:04:33 Pubmed14630798 Pubmed6457647 Reactome Database ID Release 43350745 Reactome, http://www.reactome.org ReactomeREACT_13580 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA Authored: Gillespie, ME, 2003-09-19 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 ISBN0079130356 Reactome Database ID Release 4377346 Reactome, http://www.reactome.org ReactomeREACT_1708 The fourth pass through the beta-oxidation spiral picks up where the last left off with the saturated fatty acid decanoyl-CoA and produces octanoyl-CoA. Four enzymatic steps are required starting with MCAD CoA dehydrogenase (Medium Chain) activity, followed by the enoyl-CoA hydratase activity of crotonase, the 3-hydroxyacyl-CoA dehydrogenase activity of the short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and completed by the ketoacyl-CoA thiolase activity, present in the mitochondrial membrane associated trifunctional protein. Note that the 3-hydroxyacyl-CoA dehydrogenase activity of SCHAD is not actually limited to short chain fatty acids, in fact SCHAD has a broad substrate specificity. Release of 78 kDa glucose-regulated protein After Platelet activation '78 kDa glucose-regulated protein' from the endoplasmic reticulum lumen is released in to the extracellular platelet releasate. Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Edited: Garapati, P V, 2008-05-13 11:04:33 Pubmed14630798 Pubmed6457647 Reactome Database ID Release 43351323 Reactome, http://www.reactome.org ReactomeREACT_13546 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA Authored: Gillespie, ME, 2003-09-19 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 ISBN0079130356 Reactome Database ID Release 4377310 Reactome, http://www.reactome.org ReactomeREACT_735 The third pass through the beta-oxidation spiral picks up where the last left off with the saturated fatty acid lauroyl-CoA and produces decanoyl-CoA. Four enzymatic steps are required starting with LCAD CoA dehydrogenase (Long Chain) activity, followed by the enoyl-CoA hydratase activity of crotonase, the 3-hydroxyacyl-CoA dehydrogenase activity of the short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and completed by the ketoacyl-CoA thiolase activity, present in the mitochondrial membrane associated trifunctional protein. Note that the 3-hydroxyacyl-CoA dehydrogenase activity of SCHAD is not actually limited to short chain fatty acids, in fact SCHAD has a broad substrate specificity. Exocytosis of Proactivator polypeptide After Platelet activation 'Proactivator polypeptide' from the lysosomal lumen is released in to the extracellular platelet releasate. Edited: Garapati, P V, 2008-05-13 11:04:33 Pubmed14630798 Reactome Database ID Release 43351341 Reactome, http://www.reactome.org ReactomeREACT_13534 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Triglyceride Biosynthesis GENE ONTOLOGYGO:0019432 Pubmed8944226 Reactome Database ID Release 4375109 Reactome, http://www.reactome.org ReactomeREACT_1190 The overall process of triglyceride (triacylglycerol) biosynthesis consists of four biochemical pathways: fatty acyl-CoA biosynthesis, conversion of fatty acyl-CoA to phosphatidic acid, conversion of phosphatidic acid to diacylglycerol, and conversion fo diacylglycerol to triacylglycerol. Triacylglycerol biosynthesis Gal-glycan-protein Converted from EntitySet in Reactome Reactome DB_ID: 2046271 Reactome Database ID Release 432046271 Reactome, http://www.reactome.org ReactomeREACT_122582 Fatty Acyl-CoA Biosynthesis Authored: Gopinathrao, G, 2003-10-03 00:00:00 Fatty acyl-CoA biosynthesis involves following steps:<BR> -Palmitate synthesis catalyzed by Acetyl-CoA carboxylase and Fatty acid synthase<BR>-Conversion of palmitic acid to long chain fatty acids and<BR>-Conversion of long chain fatty acids to fatty acyl-CoA by acyl-CoA synthases.<BR> GENE ONTOLOGYGO:0035338 Reactome Database ID Release 4375105 Reactome, http://www.reactome.org ReactomeREACT_1319 Hormone-sensitive lipase (HSL)-mediated triacylglycerol hydrolysis Authored: D'Eustachio, P, 2005-05-02 18:38:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0019433 Pubmed10940339 Pubmed12364542 Pubmed15337753 Reactome Database ID Release 43163560 Reactome, http://www.reactome.org ReactomeREACT_494 Triacylglycerol is a major energy store in the body and its hydrolysis to yield fatty acids and glycerol is a tightly regulated part of energy metabolism. A central part in this regulation is played by hormone-sensitive lipase (HSL), a neutral lipase abundant in adipocytes and skeletal and cardiac muscle, but also abundant in ovarian and adrenal tissue, where it mediates cholesterol ester hydrolysis, yielding cholesterol for steroid biosynthesis. The hormones to which it is sensitive include catecholamines (e.g., epinephrine), ACTH, and glucagon, all of which trigger signaling cascades that lead to its phosphorylation and activation, and insulin, which sets off events leading to its dephosphorylation and inactivation (Holm et al. 2000; Kraemer and Shen 2002).<p>The processes of triacylglycerol and cholesterol ester hydrolysis are also regulated by subcellular compartmentalization: these lipids are packaged in cytosolic particles and the enzymes responsible for their hydrolysis, and perhaps for additional steps in their metabolism, are organized at the surfaces of these particles (e.g., Brasaemle et al. 2004). This organization is dynamic: the inactive form of HSL is not associated with the particles, but is translocated there after being phosphorylated. Conversely, perilipin, a major constituent of the particle surface, appears to block access of enzymes to the lipids within the particle; its phosphorylation allows greater access. <p>Here, HSL-mediated triacylglycerol hydrolysis is described as a pathway containing twelve reactions. The first six of these involve activation: phosphorylation of HSL, dimerization of HSL, disruption of CGI-58:perilipin complexes at the surfaces of cytosolic lipid particles, phosphorylation of perilipin, association of phosphorylated HSL with FABP, and translocation of HSL from the cytosol to the surfaces of lipid particles. The next four reactions are the hydrolysis reactions themselves: the hydrolysis of cholesterol esters, and the successive removal of three fatty acids from triacylglycerol. The last two reactions, dephosphorylation of perilipin and HSL, negatively regulate the pathway. These events are outlined in the figure below. Inputs (substrates) and outputs (products) of individual reactions are connected by black arrows; blue lines connect output activated enzymes to the other reactions that they catalyze. <p>Despite the undoubted importance of these reactions in normal human energy metabolism and in the pathology of diseases such as type II diabetes, they have been studied only to a limited extent in human cells and tissues. Most experimental data are derived instead from two rodent model systems: primary adipocytes from rats, and mouse 3T3-L1 cells induced to differentiate into adipocytes. Fatty acid, triacylglycerol, and ketone body metabolism Authored: Jassal, B, Gillespie, ME, Gopinathrao, G, D'Eustachio, P, 2007-02-02 21:56:36 GENE ONTOLOGYGO:0044255 Reactome Database ID Release 43535734 Reactome, http://www.reactome.org ReactomeREACT_22279 The reactions involved in the metabolism of fatty acids and of the triacylglycerols and ketone bodies derived from them form a closely interrelated, coordinately regulated module that plays a central role in human energy metabolism. mitochondrial fatty acid beta-oxidation of saturated fatty acids Authored: Gillespie, ME, 2003-09-19 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 ISBN0079130356 Once fatty acids have been imported into the mitochondrial matrix by the carnitine acyltransferases, the beta-oxidation spiral begins. Each turn of this spiral concludes with the repetitive removal of two carbon units from the fatty acyl chain. beta-oxidation of saturated fatty acids (fatty acids with even numbered carbon chains and no double bonds) involves four different enzymatic steps: oxidation, hydration, a second oxidation, and a concluding thiolysis step, resulting in the two-carbon acetyl-CoA and a newly CoA primed acyl-CoA for the next turn of the spiral. Reactome Database ID Release 4377286 Reactome, http://www.reactome.org ReactomeREACT_1541 Beta oxidation of palmitoyl-CoA to myristoyl-CoA Authored: Gillespie, ME, 2003-09-19 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 ISBN0079130356 Reactome Database ID Release 4377305 Reactome, http://www.reactome.org ReactomeREACT_2025 This first pass through the beta-oxidation spiral starts with the saturated fatty acid palmitoyl-CoA and produces myristoyl-CoA. Four enzymatic steps are required, starting with VLCAD CoA dehydrogenase (Very Long Chain) activity, followed by three enzymatic steps, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and ketoacyl-CoA thiolase activities, all present in the mitochondrial membrane associated trifunctional protein. Synthesis of very long-chain fatty acyl-CoAs Authored: Gopinathrao, G, 2003-03-10 00:00:00 Conversion of palmitic acid to very long chain fatty acyl-CoAs GENE ONTOLOGYGO:0035338 Pubmed16564093 Pubmed4379659 Reactome Database ID Release 4375876 Reactome, http://www.reactome.org ReactomeREACT_380 Very long-chain fatty acyl-CoA molecules are synthesized from palmitic acid (C16) or other fatty acids that are synthesized de novo or obtained from the diet. Before they can be elongated, these fatty acids are activated by conversion to fatty acyl-CoAs in reactions catalyzed by the five members of the ACSL (acyl-CoA synthetase long-chain) enzyme family. Elongation proceeds by a four-step reaction sequence parallel to that responsible for the synthesis of palmitate (C16) from acetyl-CoA and malonyl-CoA: a molecule of malonyl-CoA condenses with the long chain fatty acyl-CoA forming a 3-oxoacyl-CoA containing two more carbon atoms than the starting long chain fatty acyl-CoA and CO2. This reaction is catalyzed by one of the seven members of the ELOVL (Elongation of very long chain fatty acids protein) enzyme family. The 3-oxoacyl-CoA is reduced to a 3-hydroxyacyl-CoA by HSD17B12 (hydroxysteroid (17-beta) dehydrogenase 12), 3-hydroxyacyl-CoA is dehydrated to a trans-2,3-enoyl-CoA, and the trans-2,3-enoyl-CoA is reduced to a fatty acid two carbon atoms longer than the input one by TECR (trans-2,3-enoyl-CoA reductase) enzyme. All of these enzyme activities are associated with separate polypeptides associated with the endoplasmic reticulum membrane, unlike the multifunctional and cytosolic FAS complex responsible for synthesis of palmitic acid (Jakobsson ea 2006; Nugteren 1965).<p>The specific reactions annotated here mediate the synthesis of stearoyl-CoA (3-hydroxyoctadecanoyl-CoA) from palmitate, as well as the activation and condensation with malonyl-CoA of arachidonic acid, a 20-carbon unsaturated fatty acid that plays a central role in the synthesis of prostaglandins and related hormones. Human cells contain a wide range of very long chain fatty acids, and the enzymes involved in these reactions are believed to have broader substrate specificities than are shown in these annotations, but few direct experimental data are available to support more extensive annotations. Mitochondrial Fatty Acid Beta-Oxidation Authored: Gillespie, ME, 2003-09-19 00:00:00 Beta-oxidation begins once fatty acids have been imported into the mitochondrial matrix by carnitine acyltransferases. The beta-oxidation spiral of fatty acids metabolism involves the repetitive removal of two carbon units from the fatty acyl chain. There are four steps to this process: oxidation, hydration, a second oxidation, and finally thiolysis. The last step releases the two-carbon acetyl-CoA and a ready primed acyl-CoA that takes another turn down the spiral. In total each turn of the beta-oxidation spiral produces one NADH, one FADH2, and one acetyl-CoA.<p>Further oxidation of acetyl-CoA via the tricarboxylic acid cycle generates additional FADH2 and NADH. All reduced cofactors are used by the mitochondrial electron transport chain to form ATP. The complete oxidation of a fatty acid molecule produces numerous ATP molecules. Palmitate, used as the model here, produces 129 ATPs.<p>Beta-oxidation pathways differ for saturated and unsaturated fatty acids. The beta-oxidation of saturated fatty acids requires four different enzymatic steps. Beta-oxidation produces and consumes intermediates with a trans configuration; unsaturated fatty acids that have bonds in the cis configuration require three separate enzymatic steps to prepare these molecules for the beta-oxidation pathway. Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006635 ISBN0079130356 Pubmed10527676 Pubmed11826276 Pubmed1431593 Pubmed7951672 Reactome Database ID Release 4377289 Reactome, http://www.reactome.org ReactomeREACT_1473 formation of TF:F7a complex Authored: D'Eustachio, P, 2004-08-24 14:00:00 Pubmed8598903 Reactome Database ID Release 43140748 Reactome, http://www.reactome.org ReactomeREACT_137 Tissue factor exposed at the endothelial cell surface forms a complex with F7a (activated factor VII) from the plasma tissue factor (TF) + activated factor VII (F7a) -> TF:F7a complex activation of factor X by TF:F7a Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Factor VIIa, bound to tissue factor at the endothelial cell surface (the "extrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.) Pubmed2248955 Pubmed6980899 Pubmed8578528 Reactome Database ID Release 43140736 Reactome, http://www.reactome.org ReactomeREACT_245 factor X -> factor Xa + factor X activation peptide (TF:F7a catalyst) has a Stoichiometric coefficient of 20 activation of factor IX (TF:F7a catalyst) Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Factor VIIa, bound to tissue factor at the endothelial cell surface, catalyzes the formation of activated factor IX with high efficiency. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.) Pubmed2040636 Pubmed2248955 Reactome Database ID Release 43140823 Reactome, http://www.reactome.org ReactomeREACT_158 factor IX -> factor IXa + factor IX activation peptide (TF:F7a catalyst) factor XI + platelet glycoprotein (GP) Ib:IX:V complex -> factor XI:platelet glycoprotein (GP) Ib:IX:V complex Authored: D'Eustachio, P, 2005-01-20 14:44:36 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasma factor XI binds to the platelet glycoprotein Ib:IX:V complex (Baglia et al. 2002; Greengard et al. 1986). In the body, this reaction occurs specifically on the surfaces of activated platelets, but not on endothelial cells (Baird and Walsh 2002). The stoichiometry of the platelet glycoprotein Ib:IX:V complex has not been established directly, but is inferred from the relative abundances of its components in platelet membranes (Modderman et al. 1992; Shrimpton et al. 2002). Pubmed11696542 Pubmed12167623 Pubmed12391017 Pubmed1730602 Pubmed3017409 Reactome Database ID Release 43158145 Reactome, http://www.reactome.org ReactomeREACT_177 factor XI:platelet glycoprotein (GP) Ib:IX:V complex -> factor XIa:platelet glycoprotein (GP) Ib:IX:V complex (XIIa catalyst) Authored: D'Eustachio, P, 2005-01-20 14:44:36 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). Chemically, this reaction involves the cleavage of a single peptide bond in each subunit of the factor XI homodimer; intra- and inter-chain disulfide bonds hold the resulting four polypeptides together (Bouma and Griffin 1977; Kurachi and Davie 1977; McMullen et al. 1991). In the body, this reaction occurs on the surfaces of activated platelets (Greengard et al. 1986; Baglia et al. 2002; Baird and Walsh 2002); when this reaction occurs as a step in the intrinsic ("contact") pathway of blood coagulation, it is catalyzed by activated factor XIIa (Kurachi and Davie 1977, Baglia and Walsh 2000) which in turn is generated through the interactions of factor XII, kallikrein, and kininogen on endothelial cell surfaces (Schmaier 2004). Pubmed10781579 Pubmed11696542 Pubmed12167623 Pubmed14691562 Pubmed1998667 Pubmed3017409 Pubmed588558 Pubmed893417 Reactome Database ID Release 43158300 Reactome, http://www.reactome.org ReactomeREACT_905 kallikrein:kininogen:C1q binding protein tetramer -> kallikrein + activated kininogen:C1q binding protein tetramer + bradykinin Authored: D'Eustachio, P, 2005-01-20 14:44:36 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed3484703 Pubmed4054110 Pubmed500690 Pubmed9427705 Reactome Database ID Release 43158311 Reactome, http://www.reactome.org ReactomeREACT_2004 The cleavage of kininogen (HK, high molecular weight kininogen) yields activated kininogen and the vasoactive peptide bradykinin (Kerbirou and Griffin 1979; Lottspeich et al. 1985; Kellerman et al. 1986). In vivo, this reaction is catalyzed by activated kallikrein, takes places within the kallikrein:kininogen:C1q binding protein tetramer complex on the endothelial cell surface, and results in the release of kallikrein and bradykinin (Motta et al. 1998). The hormonal functions of bradykinin will be annotated in a future version of Reactome. factor XII -> factor XIIa Authored: D'Eustachio, P, 2005-01-20 14:44:36 Cleavage of a single peptide bond converts factor XII to activated factor XII (factor XIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). Identification of the catalytic activity or activities responsible for this cleavage has not been straightforward. Studies in vitro have demonstrated the autoactivation of factor XII as well as activation by kallikrein. Both reactions require the presence of negatively charged surfaces and are accelerated in the presence of kininogen (high molecular weight kininogen, HK) (Griffin and Cochrane 1976; Meier et al. 1977; Silverberg et al. 1980). Recent work suggests that factor XII activation in vivo may occur primarily on endothelial cell surfaces and that, as in vitro, association with kininogen may accelerate the reaction (Mahdi et al. 2002; Schmaier 2004), although alternative pathways and alternative mechanisms for associating factor XII with the cell surface have not been excluded (Joseph et al. 2001). EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed1066663 Pubmed11204562 Pubmed11986212 Pubmed14691562 Pubmed3886654 Pubmed6604055 Pubmed7391081 Pubmed874082 Reactome Database ID Release 43158313 Reactome, http://www.reactome.org ReactomeREACT_1455 LDL endocytosis Authored: D'Eustachio, P, 2007-04-30 14:17:00 Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0006898 LDL (low density lipoproteins) are complexes of a single molecule of apoprotein B-100 (apoB-100) non-covalently associated with triacylglycerol, free cholesterol, cholesterol esters, and phospholipids. LDL complexes contain single molecules of apoB-100, but their content of lipids is variable (Chapman et al. 1988; Mateu et al. 1972; Tardieu et al. 1976). High levels of LDL in the blood are strongly correlated with increased risk of atherosclerosis, and recent studies have raised the possibility that this risk is further increased in individuals whose blood LDL population is enriched in high-density (low lipid content) LDL complexes (Rizzo and Berneis 2006). The LDL complex annotated here is given a lipid composition that is the average of those measured in the studies by Chapman, Mateu, Tardieu and their colleagues.<p>Annotation of LDL biology in Reactome to date is largely centered on the process of LDL endocytosis. As outlined in the figure below, extracellular low density lipoprotein (LDL) complexes bind to LDL receptors associated with coated pits at the cell surface (a), forming complexes that are internalized and passed via clathrin-coated vesicles (b) to endosomes (c), where they dissociate. The LDL particles move into lysosomes (d) and are degraded while the LDL receptors are returned to the cell surface (e). This process occurs in most cell types but is especially prominent in hepatocytes. It plays a major role in returning cholesterol from peripheral tissues to the liver.<p>Familial hypercholesterolemia due to mutations affecting the LDL receptor (or, rarely, the apolipoprotein B-100 (apoB-100) component of LDL or the LDLRAP1 accessory protein involved in receptor uptake into clathrin-coated vesicles) is one of the commonest human genetic diseases, affecting approximately one person in 500 in many populations worldwide (Hobbs et al. 1990; Jeon and Blacklow 2005). LDL-mediated lipid transport Pubmed15952897 Pubmed16371404 Pubmed184289 Pubmed2088165 Pubmed3392462 Pubmed4342194 Reactome Database ID Release 43171052 Reactome, http://www.reactome.org ReactomeREACT_6934 prekallikrein + kininogen:C1q binding protein tetramer -> prekallikrein:kininogen:C1q binding protein tetramer Authored: D'Eustachio, P, 2005-01-20 14:44:36 Prekallikrein (PK) associates specifically with kininogen (HK) on cell surfaces. In vivo, this reaction may occur primarily on the surfaces of endothelial cells in response to platelet activation (Lin et al. 1997; Motta et al. 1998; Mahdi et al. 2003). Pubmed12944405 Pubmed3521732 Pubmed9226169 Pubmed9427705 Reactome Database ID Release 43158218 Reactome, http://www.reactome.org ReactomeREACT_1335 HDL-mediated lipid transport Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 GENE ONTOLOGYGO:0042157 HDL particles play a central role in the reverse transport of cholesterol, the process by which cholesterol in tissues other than the liver is returned to the liver for conversion to bile salts and excretion from the body and provided to tissues such as the adrenals and gonads for steroid hormone synthesis (Tall et al. 2008).<p>HDL particles are heterogeneous and can be fractionated into sub-populations based on their electrophoretic mobility, their density, or their content of various apolipoproteins. Sub-populations yielded by any one fractionation strategy, however, remain heterogeneous with respect to the other two parameters (Kontush and Chapman 2006). All HDL particles share two key features: they are assembled on a protein scaffold provided by apolipoprotein A-I (apoA-I), and they are recycled to allow a net flow of lipids from peripheral tissues to the liver and steroidogenic tissues while allowing apoA-I molecules to be re-used.<p>The HDL life cycle annotated here does not capture the full complexity of HDL structure and function but rather is an attempt to outline the key steps by which HDL particles assemble and transfer their lipid content. These steps include the assembly of nascent (discoidal) HDL particles on newly synthesized apoA-I, a process that in the body occurs primarily in the liver, the loading of discoidal HDL with additional lipid through interaction with cells carrying excess cholesterol (transformation to spherical HDL), the conversion of HDL-associated cholesterol to cholesterol esters (remodeling of spherical HDL), the transfer of HDL lipids to target cells with the regeneration of pre-beta HDL (lipid-poor apoA-I), and the conversion of pre-beta HDL to discoidal HDL to complete the cycle. Additional reactions provide houekeeping functions needed for the efficient operation of the cycle: binding and release of CETP, dispersal of byproducts of the CETP reaction, and export and degradation of excess apoA-I protein. Finally, the function of torcetrapib as an inhibitor of CETP function is annotated. Pubmed10488948 Pubmed14592845 Pubmed15738977 Pubmed16968945 Pubmed18460328 Reactome Database ID Release 43194223 Reactome, http://www.reactome.org ReactomeREACT_13621 Reviewed: Jassal, B, 2008-06-13 14:05:49 prekallikrein:kininogen:C1q binding protein tetramer -> kallikrein:kininogen:C1q binding protein tetramer Authored: D'Eustachio, P, 2005-01-20 14:44:36 EC Number: 3.4.16 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Prekallikrein in a complex with kininogen and C1q binding protein on the plasma membrane is cleaved to generate active kallikrein, which remains bound to the complex. In the body, this reaction appears to occur on the surfaces of endothelial cells and may require the presence of activated platelets. Recent work indicates that the protease that cleaves prekallikrein under these conditions is prolylcarboxypeptidase. Although this enzyme was originally isolated from lysosomes (Odya et al. 1978; Tan et al. 1993), it is associated with plasma membranes of cultured human endothelial cells in vitro (Moreira et al. 2002; Shariat-Madar et al. 2002), and the purified recombinant enzyme efficiently cleaves prekallikrein (Shariat-Madar et al. 2004). In contrast factor XII, despite its activity on prekallikrein in vitro, appears not to be responsible for prekallikrein activation on the cell surface (Rojkjaer et al. 1998). Pubmed11830581 Pubmed12123826 Pubmed14996700 Pubmed28321 Pubmed8344943 Pubmed9684789 Reactome Database ID Release 43158251 Reactome, http://www.reactome.org ReactomeREACT_6 Inactivation of factor VIIa by TFPI Authored: D'Eustachio, P, 2004-08-24 14:00:00 Pubmed2271516 Reactome Database ID Release 43140825 Reactome, http://www.reactome.org ReactomeREACT_654 TFPI + TF:F7a + factor Xa -> TFPI:TF:F7a:factor Xa TFPI binds to the factor VIIa:TF complex and to factor Xa at the endothelial surface, forming a stable heterotetrameric complex in which factor VIIa is catalytically inactive. kininogen + C1q binding protein tetramer -> kininogen:C1q binding protein tetramer Authored: D'Eustachio, P, 2005-01-20 14:44:36 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Kininogen (high molecular weight kininogen; HK) associates with C1q binding protein on the cell surface in a reaction dependent on Zn++ (Joseph et al. 1996). In the body, the Zn++ needed to drive this reaction may be provided locally by Zn++ release from activated platelets (Mahdi et al. 2002). The C1q binding protein is inferred to form tetramers based on the properties of purified recombinant protein in vitro (Ghebrehiwet et al. 1994); the stoichiometry of the cell surface complex has not been determined directly. Pubmed11986212 Pubmed500690 Pubmed8195709 Pubmed8710908 Reactome Database ID Release 43158354 Reactome, http://www.reactome.org ReactomeREACT_2239 Pregnenolone biosynthesis Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2007-04-20 21:09:56 GENE ONTOLOGYGO:0006700 Pubmed11181954 Pubmed15583024 Reactome Database ID Release 43196108 Reactome, http://www.reactome.org ReactomeREACT_11038 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 The first process in the synthesis of all steroid hormones is the synthesis of pregnenolone from cholesterol. In this process, cholesterol mobilized from cytosolic lipid droplets or from lysosomes is transported to mitochondria and becomes localized to the inner mitochondrial membrane. Cholesterol transport appears to be rate-limiting for steroid hormone synthesis and its regulation, at the step of StAR-mediated traversal of the mitochondrial membrane, plays a central role in determining the amounts and identities of steroid hormones made in the body. In the inner mitochondrial membrane, cholesterol is converted to pregnenolone in a sequence of three reactions, all catalyzed by CYP11A (side chain cleavage enzyme). Finally, pregnenolone re-enters the cytosol (Payne and Hales 2004; Stocco 2001). ACTIVATION GENE ONTOLOGYGO:0008609 Reactome Database ID Release 43390423 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000140 Reactome Database ID Release 4376162 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016491 Reactome Database ID Release 43390408 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016287 Reactome Database ID Release 4376167 Reactome, http://www.reactome.org Synthesis of bile acids and bile salts via 24-hydroxycholesterol Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 GENE ONTOLOGYGO:0006699 In the body, 24-hydroxycholesterol is synthesized in the brain, exported to the liver, and converted there to bile acids and bile salts. This pathway is only a minor source of bile acids and bile salts, but appears to be critical for the disposal of excess cholesterol from the brain (Bjorkhem et al. 1998; Javitt 2002).<p>In the liver, conversion of 24-hydroxycholesterol to bile acids and bile salts is initiated with hydroxylation and oxidoreductase reactions to form 4-cholesten-7alpha,24(S)-diol-3-one. The pathway then branches: hydroxylation of 4-cholesten-7alpha,24(S)-diol-3-one to 4-cholesten-7alpha,12alpha,24(S)-triol-3-one leads ultimately to the formation of cholate, while its reduction to 5beta-cholestan-7alpha,24(S)-diol-3-one leads to chenodeoxycholate formation. In both branches, reactions in the cytosol, the mitochondrial matrix, and the peroxisomal matrix result in modifications to the ring structure, shortening and oxidation of the side chain, conversion to a Coenzyme A derivative, and conjugation with the amino acids glycine or taurine (Russell 2003). These reactions are outlined in the figure below. The final three reactions are identical to ones of bile salt synthesis initiated by 7alpha-hydroxylation and are shown as arrows with no substrates. Pubmed11969205 Pubmed12543708 Pubmed9717719 Reactome Database ID Release 43193775 Reactome, http://www.reactome.org ReactomeREACT_11053 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 ACTIVATION GENE ONTOLOGYGO:0003988 Reactome Database ID Release 43390234 Reactome, http://www.reactome.org Synthesis of bile acids and bile salts via 27-hydroxycholesterol Authored: D'Eustachio, P, 2007-02-27 21:49:11 Edited: D'Eustachio, P, 2007-02-27 21:49:11 GENE ONTOLOGYGO:0006699 In the body, 27-hydroxycholesterol is synthesized in multiple tissues, exported to the liver, and converted there to bile acids and bile salts. This pathway is only a minor source of bile acids and bile salts, but may play a significant role particularly in the mobilization of cholesterol from lung phagocytes (Bjorkhem et al. 1994; Babiker et al. 1999; Javitt 2002).<p>In the liver, conversion of 27-hydroxycholesterol to bile acids and bile salts is initiated with hydroxylation and oxidoreductase reactions to form 4-cholesten-7alpha,27-diol-3-one. The pathway then branches: hydroxylation of 4-cholesten-7alpha,27-diol-3-one to 4-cholesten-7alpha,12alpha,27-triol-3-one leads ultimately to the formation of cholate, while its reduction to 5beta-cholestan-7alpha,27-diol-3-one leads to chenodeoxycholate formation. In both branches, reactions in the cytosol, the mitochondrial matrix, and the peroxisomal matrix result in modifications to the ring structure, shortening and oxidation of the side chain, conversion to a Coenzyme A derivative, and conjugation with the amino acids glycine or taurine (Russell 2003). These reactions are outlined in the figure below. The final nine reactions are identical to ones of bile salt synthesis initiated by 7alpha-hydroxylation and are shown as arrows with no substrates. Pubmed10428977 Pubmed11969205 Pubmed12543708 Pubmed8078928 Reactome Database ID Release 43193807 Reactome, http://www.reactome.org ReactomeREACT_11048 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 ACTIVATION GENE ONTOLOGYGO:0016491 Reactome Database ID Release 43390410 Reactome, http://www.reactome.org Recycling of bile acids and salts Authored: Jassal, B, 2005-03-09 13:42:30 Edited: D'Eustachio, P, 2007-03-09 21:29:31 GENE ONTOLOGYGO:0015721 Of the 20-40 grams of bile salts released daily by the liver, all but approximately 0.5 grams are reabsorbed from the intestine, returned to the liver, and re-used. This recycling involves a series of transport processes: uptake by enterocytes mediated by ASBT (SLC10A2), traversal of the enterocyte cytosol mediated by ileal bile acid binding protein (I-BABP - FABP6), efflux from enterocytes mediated by MRP3 (ABCC3), travel through the portal blood as a complex with albumin, and uptake by hepatocytes mediated by Na+-taurocholate transporting protein (NTPC - SLC10A1) and, to a lesser extent by organic anion transporting proteins A, C, and 8 (OATPA - SLCO1A2, OATPC - SLCO1B1, and OATP-8 - SLCO1B3). Once returned to the hepatocyte cytosol, bile acids (generated in the intestine by the action of bacteria on secreted bile salts) are activated by conjugation with coenzyme A, then coupled to glycine or taurine, regenerating bile salts for re-export into the bile, mediated by the bile salt export pump, ABCB11 (Kullak-Ublick et al. 2004; Mihalik et al. 2002; Trauner and Boyer 2003). Unmodified bile salts returned to the hepatocyte cytosol can be re-exported by ABCB11 without further modification.<br> Pubmed11980911 Pubmed12663868 Pubmed14699511 Pubmed621437 Pubmed8034703 Reactome Database ID Release 43159418 Reactome, http://www.reactome.org ReactomeREACT_11042 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 ACTIVATION GENE ONTOLOGYGO:0016508 Reactome Database ID Release 43389989 Reactome, http://www.reactome.org Metabolism of steroid hormones and vitamins A and D Authored: Jassal, B, 2007-04-20 21:09:56 Edited: Jassal, B, 2007-04-20 21:09:56 GENE ONTOLOGYGO:0008202 Pubmed15583024 Reactome Database ID Release 43196071 Reactome, http://www.reactome.org ReactomeREACT_11057 Reviewed: D'Eustachio, P, 2007-04-20 21:11:21 Steroid hormones are synthesized primarily in the adrenal gland and gonads. They regulate energy metabolism and stress responses (glucocorticoids), salt balance (mineralocorticoids), and sexual development and function (androgens and estrogens). All steroids are synthesized from cholesterol. Steroid hormone synthesis is largely regulated at the initial steps of cholesterol mobilization and transport into the mitochondrial matrix for conversion to pregnenolone. In the body, the fate of pregnenolone is tissue-specific: in the zona fasciculata of the adrenal cortex it is converted to cortisol, in the zona glomerulosa to aldosterone, and in the gonads to testosterone and then to estrone and estradiol. These pathways are outlined in the figure below, which also diagrams the sites on the cholesterol molecule that undergo modification in the course of these reactions.<p>Vitamin D3 (cholecalciferol) is a steroid hormone that plays a role in regulating calcium and bone metabolism. The processes by which it is synthesized, modified, and transported in the body are annotated here. ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 43193365 Reactome, http://www.reactome.org factor XI:platelet glycoprotein (GP) Ib:IX:V complex -> factor XIa:platelet glycoprotein (GP) Ib:IX:V complex (thrombin catalyst) Authored: D'Eustachio, P, 2005-01-20 14:44:36 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Factor XI, bound to the cell surface, is converted to activated factor XI (factor XIa). In the body, this reaction occurs on the surfaces of activated platelets (Baglia et al. 2002). Small quantities of factor XI can be activated in a reaction catalyzed by factor XIIa, to initiate formation of a fibrin clot. However, the efficient activation of larger quantities of factor XI, needed to propagate the blood clotting process, appears to be mediated by thrombin (Baglia and Walsh 2000; Gailani and Broze 1993; Naito and Fujikawa 1991; Oliver et al. 1999; Monroe et al. 2002). Pubmed10781579 Pubmed11696542 Pubmed12231555 Pubmed2019570 Pubmed8338946 Pubmed9888880 Reactome Database ID Release 43158419 Reactome, http://www.reactome.org ReactomeREACT_1581 activation of factor IX (factor XIa catalyst) Authored: D'Eustachio, P, 2005-01-20 14:44:36 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Factor XIa, bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface, catalyzes the formation of activated factor IX with high efficiency in a reaction that requires Ca++. The amino terminal part of the heavy chain of factor IX, the factor IX activation peptide, is released. (This peptide has no known function.) Pubmed11342438 Pubmed681330 Reactome Database ID Release 43158333 Reactome, http://www.reactome.org ReactomeREACT_2073 factor IX -> factor IXa + factor IX activation peptide (factor XIa catalyst) factor VIII + von Willebrand factor multimer -> factor VIII:von Willibrand factor multimer Authored: D'Eustachio, P, 2005-01-20 14:44:36 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Factor VIII binds to von Willebrand factor to form a complex. This complex stabilizes factor VIII, which otherwise has a very short half-life in the blood.<P>Factor VIII (Vehar et al. 1984) is a heterodimer containing a heavy and a light polypeptide chain, generated by the proteolytic cleavage of a single large precursor polypeptide. Several forms of the heavy chain are found in vivo, all functionally the same but differing in the amount of the B domain removed by proteolysis. The single form annotated here is the shortest one (Eaton et al. 1986; Hill-Eubanks et al. 1989).<P>In vitro, von Willebrand factor (Titani et al. 1986) can form complexes with factor VIII with a 1:1 stoichiometry. The complexes that form in vivo, however, involve large multimers of von Willebrand factor and varied, but always low, proportions of factor VIII (Vlot et al. 1995). A stoichiometry of one molecule of factor VIII associated with 50 of von Willebrand factor is typical in vivo, and is used here to annotate the factor VIII:von Willebrand factor complex. Pubmed2505252 Pubmed3082357 Pubmed3134349 Pubmed3524673 Pubmed6438527 Pubmed7756647 Reactome Database ID Release 43158118 Reactome, http://www.reactome.org ReactomeREACT_531 Bile acid and bile salt metabolism Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-04-30 14:43:26 GENE ONTOLOGYGO:0008206 In a healthy adult human, about 500 mg of cholesterol is converted to bile salts daily. Newly synthesized bile salts are secreted into the bile and released into the small intestine where they emulsify dietary fats (Russell 2003). About 95% of the bile salts in the intestine are recovered and returned to the liver (Kullak-Ublick et al. 2004; Trauner and Boyer 2002). The major pathway for bile salt synthesis in the liver begins with the conversion of cholesterol to 7alpha-hydroxycholesterol. Bile salt synthesis can also begin with the synthesis of an oxysterol - 24-hydroxycholesterol or 27-hydroxycholesterol. In the body, the initial steps of these two pathways occur in extrahepatic tissues, generating intermediates that are transported to the liver and converted to bile salts via the 7alpha-hydroxycholesterol pathway. These extrahepatic pathways contribute little to the total synthesis of bile salts, but are thought to play important roles in extrahepatic cholesterol homeostasis (Javitt 2002). Pubmed11969205 Pubmed12543708 Pubmed12663868 Pubmed14699511 Reactome Database ID Release 43194068 Reactome, http://www.reactome.org ReactomeREACT_11040 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 factor VIII:von Willibrand factor multimer -> factor VIIIa + factor VIIIa B A3 acidic polypeptide + von Willibrand factor multimer Authored: D'Eustachio, P, 2005-01-20 14:44:36 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Factor VIII complexed to von Willibrand factor in the blood is cleaved into several smaller polypeptides that remain associated. The acidic polypeptide on the aminoterminal side of the A3 domain of the light chain is released, however, and as this polypeptide mediates the association of factor VIII with von Willibrand factor, the activated factor VIII is released. While several proteases are capable of catalyzing these cleavages in vitro, only thrombin is active on factor VIII:von Willibrand factor complexes under physiological conditions (Eaton et al. 1986; Hill-Eubanks et al. 1989; Lollar et al. 1988; Pieters et al. 1989) Pubmed2502206 Pubmed2505252 Pubmed3082357 Pubmed3134349 Reactome Database ID Release 43158137 Reactome, http://www.reactome.org ReactomeREACT_217 Activation of Gene Expression by SREBP (SREBF) After transiting to the nucleus SREBPs (SREBP1A/1C/2, SREBFs) bind short sequences, sterol regulatory elements (SREs), in the promoters of target genes (reviewed in Eberle et al. 2004, Weber et al. 2004). SREBPs alone are relatively weak activators of transcription, with SREBP1C being significantly weaker than SREBP1A or SREBP2. In combination with other transcription factors such as SP1 and NF-Y the SREBPs are much stronger activators. SREBP1C seems to more specifically target genes involved in fatty acid synthesis while SREBP2 seems to target genes involved in cholesterol synthesis (Pai et al. 1998). Authored: May, B, 2012-07-26 Edited: May, B, 2012-07-26 Pubmed15457548 Pubmed15589694 Pubmed9748295 Reactome Database ID Release 432426168 Reactome, http://www.reactome.org ReactomeREACT_147904 Reviewed: Liang, Guosheng, 2012-08-25 factor VIIIa + factor IXa -> factor VIIIa:factor IXa Authored: D'Eustachio, P, 2005-01-20 14:44:36 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed8626656 Reactome Database ID Release 43158278 Reactome, http://www.reactome.org ReactomeREACT_112 The activated forms of factors VIII and IX associate on a cell surface to form a complex that very efficiently catalyzes the activation of factor X, the so-called "intrinsic tenase complex". In vitro, negatively charged phospholipids can provide an appropriate surface. In the body, the surface is provided by the plasma membranes of activated platelets (Gilbert and Arena 1996). Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-12 16:13:17 GENE ONTOLOGYGO:0006699 In the liver, synthesis of bile acids and bile salts is initiated with the conversion of cholesterol to 7alpha-hydroxycholesterol and of 7alpha-hydroxycholesterol to 4-cholesten-7alpha-ol-3-one. The pathway then branches: hydroxylation of 4-cholesten-7alpha-ol-3-one to 4-cholesten-7alpha, 12alpha-diol-3-one leads ultimately to the formation of cholate, while its reduction to 5beta-cholestan-7alpha-ol-3-one leads to chenodeoxycholate formation. The amounts of substrate following each branch appear to be determined by abundance of the hydroxylase enzyme: in human liver, cholate synthesis predominates.<p>In both branches, reactions in the cytosol, the mitochondrial matrix, and the peroxisomal matrix result in modifications to the ring structure, shortening and oxidation of the side chain, conversion to a Coenzyme A derivative, and conjugation with the amino acids glycine or taurine. In the body, glycocholate, taurocholate, glycochenodeoxycholate, and taurochenodeoxycholate are released from hepatocytes into the bile and ultimately into the lumen of the small intestine, where they function as detergents to solubilize dietary fats. The liver synthetic pathway also yields small amounts of bile acids, cholate and deoxycholate, which may play a feedback role in regulating the bile acid synthetic pathway (Russell 2003). These reactions are outlined in the figure below. Pubmed12543708 Reactome Database ID Release 43193368 Reactome, http://www.reactome.org ReactomeREACT_11041 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 activation of factor X by VIIIa:IXa Authored: D'Eustachio, P, 2005-01-20 14:44:36 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Factor IXa, in a complex with factor VIIIa on the surfaces of activated platelets (the "intrinsic tenase complex"), catalyzes the formation of activated factor X with high efficiency. The amino terminal part of the heavy chain of factor X, the factor X activation peptide, is released. (This peptide has no known function.) Pubmed2110473 Reactome Database ID Release 43158164 Reactome, http://www.reactome.org ReactomeREACT_1668 factor X -> factor Xa + factor X activation peptide (VIIIa:IXa catalyst) has a Stoichiometric coefficient of 20 Synthesis of bile acids and bile salts Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-17 19:40:28 GENE ONTOLOGYGO:0006699 In a healthy adult human, about 500 mg of cholesterol is converted to bile salts daily (Russell 2003). The major pathway for bile salt synthesis in the liver begins with the conversion of cholesterol to 7alpha-hydroxycholesterol. Bile salt synthesis can also begin with the synthesis of an oxysterol - 24-hydroxycholesterol or 27-hydroxycholesterol. In the body, the initial steps of these two pathways occur in extrahepatic tissues, generating intermediates that are transported to the liver and converted to bile salts via the 7alpha-hydroxycholesterol pathway. These extrahepatic pathways contribute little to the total synthesis of bile salts, but are thought to play important roles in cholesterol homeostasis (Javitt 2002). Pubmed11969205 Pubmed12543708 Reactome Database ID Release 43192105 Reactome, http://www.reactome.org ReactomeREACT_11054 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26 kallikrein + C1Inh -> kallikrein:C1Inh Activated kallikrein binds to C1Inh (plasma protease C1 inhibitor) (Bock et al. 1986), forming a stable and enzymatically inactive complex. This reaction appears to be the major means by which kallikrein is inactivated (kallikrein can also be inactivated by binding to alpha2-macroglobulin) (Harpel et al. 1985; Ratnoff et al. 1969). Authored: D'Eustachio, P, 2005-01-20 14:44:36 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed2579948 Pubmed3756141 Pubmed4178758 Reactome Database ID Release 43158399 Reactome, http://www.reactome.org ReactomeREACT_1486 kallikrein + alpha2-macroglobulin -> kallikrein:alpha2-macrogloulin Activated kallikrein binds to alpha2-macroglobulin (Sottrup-Jensen et al. 1984), forming a stable and enzymatically inactive complex. Under normal conditions in vivo, this reaction appears to be responsible for the inactivation of about 1/6 of activated kallikrein (with C1Inh responsible for the inactivation of about 5/6) (Harpel et al. 1985). Authored: D'Eustachio, P, 2005-01-20 14:44:36 Pubmed2579948 Pubmed6203908 Reactome Database ID Release 43158340 Reactome, http://www.reactome.org ReactomeREACT_25 factor XIIa + C1Inh -> factor XIIa:C1Inh Activated factor XII (factor XIIa) binds to C1Inh (C1 inhibitor - Bock et al. 1986) to form a stable, inactive complex (Schneider et al. 1973). While several protease inhibitors can form stable complexes with XIIa in vitro, only C1Inh does so to a significant extent under normal conditions in vivo (Pixley et al. 1985). Authored: D'Eustachio, P, 2005-01-20 14:44:36 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed2578463 Pubmed3756141 Pubmed4703226 Reactome Database ID Release 43158357 Reactome, http://www.reactome.org ReactomeREACT_825 ACTIVATION GENE ONTOLOGYGO:0003997 Reactome Database ID Release 43390231 Reactome, http://www.reactome.org Regulation of Cholesterol Biosynthesis by SREBP (SREBF) Authored: May, B, 2011-09-28 Edited: May, B, 2011-10-13 Pubmed15457548 Pubmed18974038 Pubmed19933148 Reactome Database ID Release 431655829 Reactome, http://www.reactome.org ReactomeREACT_147797 Reviewed: Liang, Guosheng, 2012-08-25 Sterol regulatory element binding proteins (SREBPs, SREBFs) respond to low cholesterol concentrations by transiting to the nucleus and activating genes involved in cholesterol and lipid biosynthesis (reviewed in Brown and Goldstein 2009, Osborne and Espenshade 2009, Weber et al. 2004).<br> Newly synthesized SREBPs are transmembrane proteins that bind SCAP in the endoplasmic reticulum (ER) membrane. SCAP binds cholesterol which causes a conformational change that allows SCAP to interact with INSIG, retaining the SCAP:SREBP complex in the ER. INSIG binds oxysterols, which cause INSIG to bind SCAP and retain SCAP:SREBP in the endoplasmic reticulum.<br>In low cholesterol (below about 5 mol%) SCAP no longer interacts with cholesterol or INSIG and binds Sec24 of the CopII coat complex instead. Thus SCAP:SREBP transits with the CopII complex from the ER to the Golgi. In the Golgi SREBP is cleaved by S1P and then by S2P, releasing the N-terminal fragment of SREBP into the cytosol. The N-terminal fragment is imported to the nucleus by importin-beta and then acts with other factors, such as SP1 and NF-Y, to activate transcription of target genes. Targets of SREBP include the genes encoding all enzymes of cholesterol biosynthesis and several genes involved in lipogenesis. SREBP2 most strongly activates cholesterol biosynthesis while SREBP1C most strongly activates lipogenesis. prothrombin -> activated thrombin (factor IIa) + thrombin activation peptide (Xa catalyst) Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Membrane-bound factor Xa catalyzes the activation of small amounts of thrombin. The amino terminal portion of prothrombin is released as an activation peptide, which can be cleaved further by activated thrombin. Neither the full-length activation peptide nor its cleavage products have known functions. Pubmed14982929 Reactome Database ID Release 43140700 Reactome, http://www.reactome.org ReactomeREACT_1097 ACTIVATION GENE ONTOLOGYGO:0005325 Reactome Database ID Release 43390390 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004092 Reactome Database ID Release 43390278 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050632 Reactome Database ID Release 43192310 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008458 Reactome Database ID Release 43390282 Reactome, http://www.reactome.org NADPH regeneration Authored: D'Eustachio, P, 2009-01-07 23:39:54 Edited: D'Eustachio, P, 2009-01-07 23:39:54 GENE ONTOLOGYGO:0006740 Pubmed10521434 Reactome Database ID Release 43389542 Reactome, http://www.reactome.org ReactomeREACT_16904 Reviewed: Jassal, B, 2009-02-27 15:21:18 The conversion of isocitrate to 2-oxoglutarate (alpha-ketoglutarate) with the concomitant synthesis of NADPH from NADP+ is thought to play a significant role in supplying NADPH for other reactions in both the cytosol and the peroxisome (Geisbrecht and Gould 1999). ACTIVATION GENE ONTOLOGYGO:0004092 Reactome Database ID Release 43390278 Reactome, http://www.reactome.org Cholesterol biosynthesis Authored: Jassal, B, 2007-01-24 15:15:12 Cholesterol is synthesized de novo from from acetyl CoA. The overall synthetic process is outlined in the figure below. Enzymes whose regulation plays a major role in determining the rate of cholesterol synthesis in the body are highlighted in red, and connections to other metabolic processes are indicated. The transformation of lanosterol into cholesterol requires multiple steps, including the removal of three methyl groups, the reduction of one double bond and the migration of another. These reactions may not occur in a single fixed order in the body, so the linear pathway laid out here following the work of Gaylor and colleagues (Gaylor 2002) is an oversimplification of the process that occurs in vivo. Defects in several of the enzymes involved in this process are associated with human disease and have provided useful insights into the regulatory roles of cholesterol and its synthetic intermediates in human development (Herman 2003; Song et al. 2005). GENE ONTOLOGYGO:0006695 Pubmed11969204 Pubmed12668600 Pubmed1390320 Pubmed16054061 Pubmed3524618 Reactome Database ID Release 43191273 Reactome, http://www.reactome.org ReactomeREACT_9405 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07 ACTIVATION GENE ONTOLOGYGO:0003986 Reactome Database ID Release 43390301 Reactome, http://www.reactome.org Beta-oxidation of very long chain fatty acids Authored: D'Eustachio, P, 2009-03-16 18:50:14 Edited: D'Eustachio, P, 2009-03-18 13:33:40 GENE ONTOLOGYGO:0033540 Linear fatty acids containing more than 18 carbons are broken down by beta-oxidation in peroxisomes to yield acetyl-CoA and medium chain-length fatty acyl CoA's such as octanoyl-CoA (Wanders and Waterham 2006). Pubmed16756494 Reactome Database ID Release 43390247 Reactome, http://www.reactome.org ReactomeREACT_17062 Reviewed: Jassal, B, 2009-02-27 15:21:18 Plasmalogen biosynthesis 1-Acylglycerol-3-phosphate is synthesized from dihydroxyacetone phosphate, an acyl CoA molecule and NADPH + H+ in four reactions catalyzed by peroxisomal enzymes, either in the matrix of the organelle or associated with its membrane. These reactions are annotated here for palmityl (C16:0) CoA. In a series of less well-characterized reactions in the cytosol and endoplasmic reticulum, these molecules are converted to ether lipids (plasmalogens). The functions of plasmalogens are not well understood. They are an abundant subclass of phospholipids, however, and defects in their metabolism are associated with serious human disease (de Vet et al. 1999; Nagan and Zoeller 2001). Authored: D'Eustachio, P, 2009-02-11 15:12:47 Edited: D'Eustachio, P, 2009-03-18 13:33:40 GENE ONTOLOGYGO:0008611 Pubmed10553003 Pubmed11275267 Reactome Database ID Release 4375896 Reactome, http://www.reactome.org ReactomeREACT_1407 Reviewed: Jassal, B, 2009-02-27 15:21:18 Synthesis of lysophosphatidic acid from dihydroxyacetone phosphate ACTIVATION GENE ONTOLOGYGO:0016402 Reactome Database ID Release 43389903 Reactome, http://www.reactome.org Alpha-oxidation of phytanate Authored: D'Eustachio, P, 2009-01-10 20:36:15 Edited: D'Eustachio, P, 2009-01-10 20:36:15 GENE ONTOLOGYGO:0001561 Phytanic acid arises through ruminant metabolism of chlorophyll and enters the human diet as a constituent of dairy products (Baxter 1968). It can act as an agonist for PPAR and other nuclear hormone receptors, but its normal role in human physiology, if any, is unclear. It is catabolized via a five-step alpha-oxidation reaction sequence that yields pristanoyl-CoA, which is turn is a substrate for beta-oxidation. These reactions take place in the peroxisomal matrix and their failure is associated with Refsum disease (Wanders et al. 2003). Pubmed12633678 Pubmed4177872 Reactome Database ID Release 43389599 Reactome, http://www.reactome.org ReactomeREACT_17003 Reviewed: Jassal, B, 2009-02-27 15:21:18 ACTIVATION GENE ONTOLOGYGO:0016508 Reactome Database ID Release 43389989 Reactome, http://www.reactome.org Beta-oxidation of pristanoyl-CoA Authored: D'Eustachio, P, 2009-03-16 18:50:14 Edited: D'Eustachio, P, 2009-03-18 13:33:40 GENE ONTOLOGYGO:0033540 Pristanoyl-CoA, generated in the peroxisome by alpha-oxidation of dietary phytanic acid, is further catabolized by three cycles of peroxisomal beta-oxidation to yield 4,8-dimethylnonanoyl-CoA, acetyl-CoA and two molecules of propionyl-CoA. These molecules in turn are converted to carnitine conjugates, which can be transported to mitochondria (Wanders and Waterham 2006, Verhoeven et al. 1998, Ferdinandusse et al. 1999). Pubmed10486279 Pubmed16756494 Pubmed9469587 Reactome Database ID Release 43389887 Reactome, http://www.reactome.org ReactomeREACT_17017 Reviewed: Jassal, B, 2009-02-27 15:21:18 ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 43193365 Reactome, http://www.reactome.org NTP Converted from EntitySet in Reactome Reactome DB_ID: 30595 Reactome Database ID Release 4330595 Reactome, http://www.reactome.org ReactomeREACT_4491 prothrombin -> activated thrombin (factor IIa) + thrombin activation peptide (prothrombinase catalyst) Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Pubmed14982929 Pubmed3052293 Reactome Database ID Release 43140664 Reactome, http://www.reactome.org ReactomeREACT_1446 The membrane-bound Va:Xa (prothrombinase) complex rapidly activates large amounts of thrombin. fibrinogen -> fibrin monomer + 2 fibrinopeptide A + 2 fibrinopeptide B Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Pubmed2742826 Reactome Database ID Release 43140840 Reactome, http://www.reactome.org ReactomeREACT_214 The alpha and beta chains of fibrinogen hexamer are cleaved by thrombin to generate fibrin monomer. The amino terminal regions of the cleaved alpha and beta chains are released (fibrinopeptides A and B respectively). has a Stoichiometric coefficient of 2 factor V -> factor Va + factor V activation peptide Activated thrombin (factor IIa) catalyzes the conversion of factor V to factor Va (activated factor V). The activation peptide released in this reaction has no known function. Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Pubmed14982929 Reactome Database ID Release 43140696 Reactome, http://www.reactome.org ReactomeREACT_708 factor Va + factor Xa -> Va:Xa complex (prothrombinase) Authored: D'Eustachio, P, 2004-08-24 14:00:00 Factors Va and Xa associate on a membrane surface to form a complex in which the activity of factor Xa on prothrombin is greatly increased (Mann et al. 1988). The presence of negatively charged phospholipid in the membrane greatly facilitates this process, a feature that may contribute to its localization, as such phospholipids are normally on the cytosolic face of the plasma membrane (Devaux 1992), but could be exposed to the extracellular space following platelet activation or mechanical injury to endothelial cells. Pubmed1525472 Pubmed3052293 Reactome Database ID Release 43140686 Reactome, http://www.reactome.org ReactomeREACT_675 Peroxisomal lipid metabolism Authored: D'Eustachio, P, 2009-02-11 15:12:47 Edited: D'Eustachio, P, 2009-02-11 15:12:47 GENE ONTOLOGYGO:0044255 In humans, the catabolism of phytanate, pristanate, and very long chain fatty acids as well as the first four steps of the biosynthesis of plasmalogens are catalyzed by peroxisomal enzymes. Defects in any of these enzymes or in the assembly of peroxisomes are associated with severe developmental disorders (Wanders and Watherham 2006). Pubmed16756494 Reactome Database ID Release 43390918 Reactome, http://www.reactome.org ReactomeREACT_16957 Reviewed: Jassal, B, 2009-02-27 15:21:18 factor XIII cleaved tetramer + 2 Ca++ -> factor XIIIa + 2 factor XIII B chain Authored: D'Eustachio, P, 2004-08-24 14:00:00 Once the A chains of the Factor XIII tetramer have been cleaved by thrombin, the complex dissociates and the resulting A chain dimer binds Ca++ (one per peptide monomer) to form activated factor XIII (factor XIIIa). Pubmed2866798 Reactome Database ID Release 43140847 Reactome, http://www.reactome.org ReactomeREACT_1314 has a Stoichiometric coefficient of 2 PPARA Activates Gene Expression Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed10529898 Pubmed11330046 Pubmed14999402 Pubmed18288277 Pubmed20936127 Reactome Database ID Release 431989781 Reactome, http://www.reactome.org ReactomeREACT_116145 Reviewed: Kersten, S, 2009-06-08 The set of genes regulated by PPAR-alpha is not fully known in humans, however many examples have been found in mice. Genes directly activated by PPAR-alpha contain peroxisome proliferator receptor elements (PPREs) in their promoters and include: <br>1) genes involved in fatty acid oxidation and ketogenesis (Acox1, Cyp4a, Acadm, Hmgcs2);<br>2) genes involved in fatty acid transport (Cd36, , Slc27a1, Fabp1, Cpt1a, Cpt2);<br>3) genes involved in producing fatty acids and very low density lipoproteins (Me1, Scd1);<br>4) genes encoding apolipoproteins (Apoa1, Apoa2, Apoa5);<br>5) genes involved in triglyceride clearance ( Angptl4);<br>6) genes involved in glycerol metabolism (Gpd1 in mouse);<br>7) genes involved in glucose metabolism (Pdk4);<br>8) genes involved in peroxisome proliferation (Pex11a);<br>9) genes involved in lipid storage (Plin, Adfp).<br>Many other genes are known to be regulated by PPAR-alpha but whether their regulation is direct or indirect remains to be found. These genes include: ACACA, FAS, SREBP1, FADS1, DGAT1, ABCA1, PLTP, ABCB4, UGT2B4, SULT2A1, Pnpla2, Acsl1, Slc27a4, many Acot genes, and others (reviewed in Rakhshandehroo et al. 2010). fibrin multimer -> fibrin multimer, crosslinked + NH4+ Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 2.3.2.13 Fibrin multimers are stabilized by the formation of multiple covalent crosslinks between the side chains of specific lysine and glutamine residues in fibrinogen alpha and gamma chains, catalyzed by factor XIIIa. Reactome Database ID Release 43140851 Reactome, http://www.reactome.org ReactomeREACT_1852 Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha) Authored: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-06-08 Edited: May, B, 2011-11-08 Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is the major regulator of fatty acid oxidation in the liver. PPARalpha is also the target of fibrate drugs used to treat abnormal plasma lipid levels. <br>PPAR-alpha is a type II nuclear receptor (its subcellular location does not depend on ligand binding). PPAR-alpha forms heterodimers with Retinoid X receptor alpha (RXR-alpha), another type II nuclear receptor. PPAR-alpha is activated by binding fatty acid ligands, especially polyunsaturated fatty acids having 18-22 carbon groups and 2-6 double bonds. <br>The PPAR-alpha:RXR-alpha heterodimer binds peroxisome proliferator receptor elements (PPREs) in and around target genes. Binding of fatty acids and synthetic ligands causes a conformational change in PPAR-alpha such that it releases the corepressors and binds coactivators (CBP-SRC-HAT complex, ASC complex, and TRAP-Mediator complex) which initiate transcription of the target genes.<br>Target genes of PPAR-alpha participate in fatty acid transport, fatty acid oxidation, triglyceride clearance, lipoprotein production, and cholesterol homeostasis. Pubmed10529898 Pubmed16476485 Pubmed16503871 Pubmed18288277 Reactome Database ID Release 43400206 Reactome, http://www.reactome.org ReactomeREACT_19241 Reviewed: Kersten, S, 2009-06-08 n fibrin monomers -> fibrin multimer Authored: D'Eustachio, P, 2004-08-24 14:00:00 Fibrin monomers rapidly and spontaneously associate into large multimers, binding to one another via sites created by fibrinopeptide release (Laudano and Doolittelle 1980). The process of multimerization, and the range of multimer structures that can form in vivo and in vitro, have been studied in detail (Doolittle 1984). Here, multimer size has arbitrarily been set to three fibrin monomers. Pubmed6383194 Pubmed7356959 Reactome Database ID Release 43140842 Reactome, http://www.reactome.org ReactomeREACT_1329 has a Stoichiometric coefficient of 3 Ketone body catabolism Authored: Joshi-Tope, G, 2003-10-19 14:58:00 GENE ONTOLOGYGO:0046952 Pubmed21479626 Reactome Database ID Release 4377108 Reactome, http://www.reactome.org ReactomeREACT_59 The levels of acetone in ketone bodies are much lower than those of acetoacetic acid and beta-hydroxybutyric acid. Acetone cannot be converted back to acetyl-CoA, and is excreted in urine, or breathed out through the lungs. Extrahepatic tissues utilize ketone bodies by converting the beta-hydroxybutyrate successively to acetoacetate, acetoacetatyl-CoA, finally to acetyl-CoA (Sass 2011). Utilization of Ketone Bodies factor XIII -> factor XIII cleaved tetramer + 2 factor XIII A activation peptides Activated thrombin cleaves the A chains of factor XIII tetramers in a reaction stimulated by the presence of fibrin multimers. The amino terminal portions of the A chains are released as activation peptides, which have no known function. The resulting factor XIII tetramer remains catalytically inactive. Authored: D'Eustachio, P, 2004-08-24 14:00:00 EC Number: 3.4.21 Pubmed2866798 Reactome Database ID Release 43140599 Reactome, http://www.reactome.org ReactomeREACT_1536 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0070251 Reactome Database ID Release 43389637 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004029 Reactome Database ID Release 43389625 Reactome, http://www.reactome.org antithrombin III + heparin -> antithrombin III:heparin Antithrombin III binds to membrane-associated heparin, e.g., on the surface of a normal endothelial cell. This binding event increases the affinity of antithrombin III for thrombin approximately 1000-fold. Authored: D'Eustachio, P, 2004-08-24 14:00:00 Pubmed12907439 Reactome Database ID Release 43140806 Reactome, http://www.reactome.org ReactomeREACT_102 ACTIVATION GENE ONTOLOGYGO:0016402 Reactome Database ID Release 43389900 Reactome, http://www.reactome.org activated thrombin (factor IIa) + antithrombin III:heparin -> thrombin:antithrombin III:heparin Activated thrombin binds to the antithrombin III:heparin complex on the cell surface. Authored: D'Eustachio, P, 2004-08-24 14:00:00 Pubmed12907439 Reactome Database ID Release 43140791 Reactome, http://www.reactome.org ReactomeREACT_1822 ACTIVATION GENE ONTOLOGYGO:0008111 Reactome Database ID Release 43191973 Reactome, http://www.reactome.org PR Converted from EntitySet in Reactome Protease Reactome DB_ID: 175011 Reactome Database ID Release 43175011 Reactome, http://www.reactome.org ReactomeREACT_8508 Release of CSK from SRC Authored: Garapati, P V, 2008-06-16 17:13:06 CSK bound to integrin alphaIIb beta3 negatively regulates SRC by phosphorylating the Tyr-530. Platelet adhesion to fibrinogen causes the disassociation of CSK from alphaIIb beta3 complex. Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed11940607 Pubmed16005629 Pubmed1722201 Reactome Database ID Release 43377644 Reactome, http://www.reactome.org ReactomeREACT_15349 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004310 Reactome Database ID Release 43191305 Reactome, http://www.reactome.org Clustering of Integrin alphaIIb beta3 complexes Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed10508650 Pubmed15157149 Pubmed16005629 Reactome Database ID Release 43377641 Reactome, http://www.reactome.org ReactomeREACT_15403 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 The fibrinogen-bound integrin alphaIIb beta3 clusters platelets together to form a platelet plug and generates intracellular signals (outside-in) causing further platelet activation and platelet plug retraction.<br>Intracellular integrin alphaIIb beta3 clustering brings SRCs bound to integrin beta3 chains into proximity. SRC associates constitutively with integrin alphaIIb beta3. In unstimulated cells this SRC is inactive, auto-inhibited by an internal interaction between phosphorylated Y530 and the SH2 domain. CSK is selective for the Y530 residue and prevents access to SRC of PTP1B, a protein tyrosine phosphatase that is capable of de-phosphorylating Y530. Interaction of integrin alphaIIb beta3 with Fibrinogen Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed10446041 Pubmed10508650 Pubmed11468358 Pubmed14754902 Pubmed16040750 Reactome Database ID Release 43354149 Reactome, http://www.reactome.org ReactomeREACT_15500 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 The overall shape of integrins is that of a globular 'head' supported by two rod like legs. The ligand-binding pocket is formed by the combination of A-domain or beta-I domain on the beta3 subunit and the putative beta-propeller fold on the alphaIIb subunit in the head regions. The binding of ligand to integrin is also dependent on divalent cations (usually Mn++ or Mg++or Ca++). A conserved motif, the metal ion-dependant adhesion site (MIDAS) is located in the alpha and the beta chains that coordinate the divalent cation at the top of the domain. <br>Active integrin alphaIIb beta3 interacts with a variety of plasma proteins such as fibrinogen, vWF, thrombin, thrombospondin, and fibronectin. The ability of alphaIIbbeta3 to bind fibrinogen plays a crucial role in platelet aggregation and hemostasis. Most of these matrix proteins have integrin binding sites of 3-6 amino acids length, of which the best known are the 'RGD' and 'KGD' motifs. The alpha and beta integrin subunits are both required for ligand binding. Integrin alphaIIb beta3 activation Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed10446041 Pubmed11940607 Pubmed14754902 Pubmed16102045 Pubmed17218263 Pubmed17624957 Pubmed18434644 Reactome Database ID Release 43354077 Reactome, http://www.reactome.org ReactomeREACT_15490 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 The interaction between talin and integrin alphaIIb beta3 breaks the putative salt bridge between the alphaIIb (R995) and beta3 (D723) integrin chains and induces conformational changes in their external domains increasing their affinity for fibrinogen and other ECM ligands. Breaking of this salt bridge is necessary but not sufficient for full activation.<br>The Talin F3 subdomain of the FERM domain has a phosphotyrosine binding (PTB) domain fold. This domain interacts with the membrane-proximal (MP) region within the integrin beta3 chain. The primary function of this interaction is to provide an initial strong linkage between talin and integrin and this interaction holds the key to the molecular recognition required for activation. In platelets SRC kinase and its negative regulator CSK associates constitutively with integrin alphaIIbbeta3. SRC is involved in alphaIIbbeta3 dependent activation of SYK, and both SRC and SYK are required to initiate cytoskeletal events responsible for platelet spreading on fibrinogen. Activation of Talin Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed12585966 Pubmed16102045 Pubmed17624957 Pubmed18434644 Reactome Database ID Release 43354097 Reactome, http://www.reactome.org ReactomeREACT_15350 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 Talin is one of the major cytoskeletal proteins involved in integrin activation and linking the resulting focal adhesion (FA) with cytoskeleton. Talin comprises an N-ter head region and a flexible rod domain. The head region has the FERM domain (subdivided into F1, F2 and F3 subdomains), which has the binding sites for beta integrin cytoplasmic regions and actin binding sites close to the C-terminal rod domain. <br>Talin exists in closed inactive conformation, where the head region interacts with the rod domain masking the integrin binding sites. At the plasma membrane the RIAM bound to active Rap1 recruits talin to form the integrin activation complex. This interaction exposes the integrin-binding site in talin F3 domain leading to integrin activation. <br> Dermatan sulfate biosynthesis Authored: Jassal, B, 2011-12-01 Dermatan sulfate (DS) consists of N-acetylgalactosamine (GalNAc) residues alternating in glycosidic linkages with glucuronic acid (GlcA) or iduronic acid (IdoA) residues. As with CS, GalNAc residues can be sulfated in CS chains but also the uronic acid <br>residues may be substituted with sulfate at the 2- and 4- positions. The steps below outline the synthesis of a simple DS chain (Silbert & Sugumaran 2002). Edited: Jassal, B, 2011-12-01 GENE ONTOLOGYGO:0030208 Pubmed12512856 Reactome Database ID Release 432022923 Reactome, http://www.reactome.org ReactomeREACT_120800 Reviewed: D'Eustachio, P, 2012-03-28 Chondroitin sulfate biosynthesis Authored: Jassal, B, 2011-12-01 Chondroitin sulfate (CS) glycosaminoglycan <br>consists of N-acetylgalactosamine (GalNAc) residues <br>alternating in glycosidic linkages with glucuronic acid (GlcA). GalNAc residues are sulfated to varying degrees on 4- and/or 6- positions. The steps below describe the biosynthesis of a simple CS molecule (Pavao et al. 2006, Silbert & Sugumaran 2002). Edited: Jassal, B, 2011-12-01 GENE ONTOLOGYGO:0030206 Pubmed12512856 Pubmed17239764 Reactome Database ID Release 432022870 Reactome, http://www.reactome.org ReactomeREACT_120989 Reviewed: D'Eustachio, P, 2012-03-28 Chondroitin sulfate/dermatan sulfate metabolism Authored: Jassal, B, 2011-10-21 Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG). CS chains are unbranched polysaccharides of varying length containing two alternating monosaccharides: D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc). The chains are usually attached to proteins forming a proteoglycan. CS is an important structural component of cartilage due to it's ability to withstand compression. It is also a widely used dietary supplement for osteoarthritis. When some of the GlcA residues are epimerized into L-iduronic acid (IdoA) the resulting disaccharide is then referred to as dermatan sulfate (DS) (Silbert & Sugumaran 2002). DS is the most predominant GAG in skin but is also found in blood vessels, heart valves, tendons, and the lungs. It may play roles in cardiovascular disease, tumorigenesis, infection, wound repair and fibrosis (Trowbridge & Gallo 2002). Edited: Jassal, B, 2011-10-21 GENE ONTOLOGYGO:0030204 Pubmed12213784 Pubmed12512856 Pubmed17239764 Reactome Database ID Release 431793185 Reactome, http://www.reactome.org ReactomeREACT_121206 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0004506 Reactome Database ID Release 43191350 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004310 Reactome Database ID Release 43191305 Reactome, http://www.reactome.org Keratan sulfate degradation Authored: Jassal, B, 2011-12-01 Edited: Jassal, B, 2011-12-01 GENE ONTOLOGYGO:0042340 Keratan sulfate proteoglycans (KSPGs) are degraded in lysosomes as part of normal homeostasis of glycoproteins. Glycoproteins must be completely degraded to avoid undigested fragments building up and causing a variety of lysosomal storage diseases. KSPGs are Asn-linked glycoproteins and are acted upon by exo-glycosidases to release sugar monomers. The main steps of degradation are shown representing the types of cleavage reactions that occur so the full degradation of KS is not shown to avoid repetition. The proteolysis of the core protein of the glycoprotein is not shown here (Winchester 2005, Aronson & Kuranda 1989). Pubmed15647514 Pubmed2531691 Reactome Database ID Release 432022857 Reactome, http://www.reactome.org ReactomeREACT_121313 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0008398 Reactome Database ID Release 43194693 Reactome, http://www.reactome.org Keratan sulfate biosynthesis Authored: Jassal, B, 2011-12-01 Edited: Jassal, B, 2011-12-01 GENE ONTOLOGYGO:0018146 Keratan sulfate (KSI) is the best characterised keratan sulfate. It is 10 times more abundant in cornea than cartilage. KSI is attached to an asparagine (Asn) residue on the core protein via an N-linked branched oligosaccharide (an N-glycan core structure used as a precursor in N-glycan biosynthesis). KSI is elongated by the alternate additions of galactose (Gal) and N-acetylglucosamine (GlcNAc), mediated by glycosyltransferases. Elongation is terminated by the addition of a single N acetylneuraminic acid (sialyl) residue. KSI is also sulfated on Gal and GlcNAc residues by at least two sulfotransferases (Funderburgh 2000, Funderburgh 2002, Quantock et al. 2010). KSI can be attached to asparagine residues on core proteins, creating so called proteoglycans (PGs). Seven common core proteins found in corneal and skeletal tissues are used as examples here. Pubmed11030741 Pubmed12512857 Pubmed20213925 Reactome Database ID Release 432022854 Reactome, http://www.reactome.org ReactomeREACT_121120 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0000250 Reactome Database ID Release 43191416 Reactome, http://www.reactome.org Keratan sulfate/keratin metabolism Authored: Jassal, B, 2011-10-05 Edited: Jassal, B, 2011-10-05 GENE ONTOLOGYGO:0042339 Keratan sulfate (KS) (a glycosaminoglycan, GAG) is a linear polysaccharide that consists of the repeating disaccharide unit GlcNAc-Gal (N-acetylglucosamine-galactose). KS can perform a structural function and is found in bone, cartilage and the cornea. In joints, it also acts as a shock absorber due to its highly hydrated nature. There are several classes of KS, KSI, II and III. KSI is N-linked to asparagine (Asn) residues in the core protein and is predominantly found in the cornea. KSII is O-linked to serine (Ser) or Thr (threonine) residues in the core protein and is found predominantly in cartilage linked to the protein aggrecan, forming the most abundant proteoglycan in cartilage. A third class of KS, KSIII, are proteoglycans in the brain. KSIII chains are linked to Ser/Thr residues in the core protein via mannose (Funderburgh 2000, Funderburgh 2002).<br><br>Normally, the body degrades GAGs as a natural turnover. Defects in the degradative enzymes cause the autosomal recessive mucopolysaccharide storage disease Morquio's syndrome (also called mucopolysaccharidosis IV). This involves the build up of KS in lysosomes, manifesting clinically as skeletal, dental and corneal abnormalities (Tomatsu et al. 2005). Pubmed11030741 Pubmed12512857 Pubmed16287098 Reactome Database ID Release 431638074 Reactome, http://www.reactome.org ReactomeREACT_121288 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0050613 Reactome Database ID Release 43194714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050613 Reactome Database ID Release 43194706 Reactome, http://www.reactome.org HS-GAG degradation Authored: Jassal, B, 2011-12-14 Edited: Jassal, B, 2011-12-14 GENE ONTOLOGYGO:0006027 Lysosomal degradation of glycoproteins is part of the cellular homeostasis of glycosylation (Winchester 2005). The steps outlined below describe the degradation of heparan sulfate/heparin. Complete degradation of glycoproteins is required to avoid build up of glycosaminoglycan fragments which can cause lysosomal storage diseases. The proteolysis of the core protein of the glycoprotein is not shown here. Pubmed15647514 Reactome Database ID Release 432024096 Reactome, http://www.reactome.org ReactomeREACT_120752 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0000252 Reactome Database ID Release 43194724 Reactome, http://www.reactome.org HS-GAG biosynthesis Authored: Jassal, B, 2011-12-01 Edited: Jassal, B, 2011-12-01 GENE ONTOLOGYGO:0006024 Heparan sulfate (HS) and heparin (sometimes collectively called HS-GAG) consist of the disaccharide unit GlcNAc-GlcA (N-acetylglucosamine-glucuronic acid) connected by a beta1,4 linkage. Heparin is exclusively made in mast cells whereas HS is made by virtually every type of cell in the body. As the chain length increases, the polysaccharides can undergo modifcations such as epimerisation of glucuronic acid to iduronic acid and deacetylation and sulfation of GlcNAc to form sulfated glucosamine (Stringer & Gallagher 1997, Sasisekharan & Venkataraman 2000). Pubmed11102866 Pubmed9251237 Reactome Database ID Release 432022928 Reactome, http://www.reactome.org ReactomeREACT_121248 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0000254 Reactome Database ID Release 43194699 Reactome, http://www.reactome.org A tetrasaccharide linker sequence is required for GAG synthesis Authored: Jassal, B, 2011-11-04 Edited: Jassal, B, 2011-11-04 GENE ONTOLOGYGO:0030203 Pubmed17239764 Pubmed4139221 Reactome Database ID Release 431971475 Reactome, http://www.reactome.org ReactomeREACT_121408 Reviewed: D'Eustachio, P, 2012-03-28 The biosynthesis of dermatan sulfate/chondroitin sulfate and heparin/heparan sulfate glycosaminoglycans (GAGs) starts with the formation of a tetrasaccharide linker sequence to the core protein. The first step is the addition of xylose to the hydroxy group of specific serine residues on the core protein. Subsequent additions of two galactoses and a glucuronide moiety completes the linker sequence. From here, the next hexosamine addition is critical as it determines which GAG is formed (Lamberg & Stoolmiller 1974, Pavao et al. 2006). ACTIVATION GENE ONTOLOGYGO:0000254 Reactome Database ID Release 43194699 Reactome, http://www.reactome.org Heparan sulfate/heparin (HS-GAG) metabolism Authored: Jassal, B, 2011-10-07 Edited: Jassal, B, 2011-10-07 GENE ONTOLOGYGO:0030203 Pubmed10716625 Pubmed11102866 Pubmed19111581 Pubmed9251237 Reactome Database ID Release 431638091 Reactome, http://www.reactome.org ReactomeREACT_121314 Reviewed: D'Eustachio, P, 2012-03-28 The acronym HS-GAG is used to describe both heparin and heparan sulfate. HS-GAG is a member of the glycosaminoglycan family and consists of a variably sulfated repeating disaccharide unit, the most common one (50% of the total) being glucuronic acid (GlcA) linked to N-acetylglucosamine (GlcNAc). GlcA can be epimerized to iduronic acid. Higher degrees of sulfation and iduronic acid content in the polysaccharide chain confers the name heparin rather than heparan sulfate to the chain. HS-GAG, like the majority of GAGs in the body, are linked to core proteins, forming proteoglycans (mucopolysaccharides). Two or three HS-GAG chains attach to a core protein on the cell surface or in the extracellular matrix (Sasisekharan & Venkataraman 2000). HS-GAG bound to a core protein can regulate many biological processes such as angiogenesis, blood coagulation and tumour metastasis (Stringer & Gallagher 1997, Tumova et al. 2000). Degradation of HS-GAG is required to maintain a natural turnover of GAGs. Defects in the degradative enzymes result in lysosomal storage diseases, where GAGs build up rather than being broken down and having pathological effects (Ballabio & Gieselmann 2009). ACTIVATION GENE ONTOLOGYGO:0000253 Reactome Database ID Release 43194731 Reactome, http://www.reactome.org Phosphorylation of p130Cas by SRC-FADK1 complex Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed12585966 Pubmed12640026 Pubmed16581250 Reactome Database ID Release 43372693 Reactome, http://www.reactome.org ReactomeREACT_15375 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 SH3-mediated binding of p130Cas to FAK is linked to enhanced tyrosine phosphorylation of p130Cas at multiple sites. The Cas substrate domain contains 15 separate YxxP motifs after phosphorylation recruits the SH2 mediated binding of Crk adaptor protein that affect the downstream MAPK signalling pathway, resulting in cell survival and increased motility. Recruitment of p130Cas to FADK1 Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed16581250 Pubmed16919435 Reactome Database ID Release 43372705 Reactome, http://www.reactome.org ReactomeREACT_15348 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 p130Cas (Crk-associated substrate) is an adaptor protein that promotes protein-protein interactions, leading to the multiprotein complexes. The interaction of p130Cas with other proteins modulates cell motility, survial and proliferation. P130Cas is one of the main phosphorylation targets of the FAK/Src complex. The p130Cas SH3 domain binds to PR1 and PR2 (‘PxxP’) domains in the FAK C-terminal domain. Integrin alpha IIb beta3 T779 phosphorylation blocks SHC binding Authored: Akkerman, JW, 2009-09-04 EC Number: 2.7.11 Edited: Jupe, S, 2010-09-01 Pubmed10896934 Reactome Database ID Release 43432110 Reactome, http://www.reactome.org ReactomeREACT_24004 Reviewed: Heemskerk, JW, 2010-09-01 The binding of SHC to integrin alpha IIb beta 3 is blocked by phosphorylation of beta 3 at Thr-779, or by substitution of this residue for Asp. PDK1 and Akt1/PKB-alpha both specifically target Thr-779 in in vitro assays. ACTIVATION GENE ONTOLOGYGO:0004450 Reactome Database ID Release 43389544 Reactome, http://www.reactome.org Crk binding to p130cas Authored: Garapati, P V, 2008-06-16 17:13:06 Crk is an adaptor protein with one SH2 and two SH3 domains. It is involved in integrin mediated signalling and is recruited to the focal adhesion complexes by interacting with p130Cas or paxillin through its SH2 domain. Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed10777559 Pubmed12640026 Pubmed16581250 Reactome Database ID Release 43372697 Reactome, http://www.reactome.org ReactomeREACT_15397 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 ACTIVATION GENE ONTOLOGYGO:0004450 Reactome Database ID Release 43389538 Reactome, http://www.reactome.org Interaction of SOS with GRB2 bound to FADK1 Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed7997267 Reactome Database ID Release 43354165 Reactome, http://www.reactome.org ReactomeREACT_15405 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 Son of sevenless protein homolog 1(SOS) is an activating nucleotide exchange factor for H-Ras (p21Ras). SOS is brought close to the H-Ras by interacting with the FADK1 bound GRB2. Recruitment of GRB2 to p-FADK1 Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Phosphorylated tyrosine 925 in the FAT domain of FADK1 creates a docking site for the SH2 domain of GRB2 and recruits the GRB2/SOS complex. FADK1 may use this mechanism to activate Ras and the MAP kinase pathway. Pubmed12005431 Pubmed2809592 Pubmed7997267 Pubmed9566877 Reactome Database ID Release 43354087 Reactome, http://www.reactome.org ReactomeREACT_15323 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 UDP-glucuronosyltransferase (O-glucuronide forming isozymes) Converted from EntitySet in Reactome Reactome DB_ID: 174920 Reactome Database ID Release 43174920 Reactome, http://www.reactome.org ReactomeREACT_7236 ACTIVATION GENE ONTOLOGYGO:0046943 Reactome Database ID Release 43390348 Reactome, http://www.reactome.org Phosphorylation of pFADK1 by SRC Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed11476890 Pubmed16919435 Reactome Database ID Release 43354124 Reactome, http://www.reactome.org ReactomeREACT_15368 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 The recruitment of FADK1 to active SRC leads to the efficient tyrosine phosphorylation of multiple additional sites on FADK1. SRC trans-phosphorylates FADK1 within the kinase doman activation loop (Y576 and Y577) and within the FADK1 C-terminal domain (Y861 and Y925). has a Stoichiometric coefficient of 5 ACTIVATION GENE ONTOLOGYGO:0004631 Reactome Database ID Release 43191287 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004496 Reactome Database ID Release 43191389 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004420 Reactome Database ID Release 43191301 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004421 Reactome Database ID Release 43191334 Reactome, http://www.reactome.org Dephosphorylation of inactive SRC by PTPB1 Authored: Garapati, P V, 2008-06-16 17:13:06 EC Number: 3.1.3.48 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed16005629 Pubmed16115959 Pubmed7532003 Reactome Database ID Release 43377643 Reactome, http://www.reactome.org ReactomeREACT_15464 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 The integrin alphaIIb beta3:Inactive SRC complex recruits PTP1B protein tyrosine phosphatase resulting in the dephosphorylation of SRC tyrosine 530. The phosphorylated tail of SRC tail interacts with the SH2 domain thereby repressing kinase activity; removal of phosphorylation activates SRC kinase activity. has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004337 Reactome Database ID Release 43981559 Reactome, http://www.reactome.org Autophosphorylation of SRC Authored: Garapati, P V, 2008-06-16 17:13:06 Clustering of Integrin alphaIIb beta3 complexes results in the trans auto-phosphorylation of SRC tyrosine residue 419 (often referred to as 418 in the literature, as the initiating methionine is cleaved in the mature peptide) in SRC's kinase activation loop. EC Number: 2.7.10 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed16005629 Reactome Database ID Release 43377640 Reactome, http://www.reactome.org ReactomeREACT_15545 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004161 Reactome Database ID Release 43981571 Reactome, http://www.reactome.org Translocation of FADK1 to Focal complexes As integrins do not have an intrinsic catalytic activity, the signals initiated by the ECM-integrin interactions are transduced into cells through the integrin bound protein-tyrosine kinases. Focal adhesion kinase 1 (FADK1, FAK) is one of the protein tyrosine kinases that plays a prominent role in integrin signaling. FAK has been implicated in controlling cell motility and transmitting a cell survival signal from ECM. <br><br>FAK is recruited to sites of integrin clustering by directly binding to integrin associated c-Src.<br> Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed11476890 Pubmed16005629 Pubmed16919435 Reactome Database ID Release 43354066 Reactome, http://www.reactome.org ReactomeREACT_15371 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 ACTIVATION GENE ONTOLOGYGO:0004452 Reactome Database ID Release 43191346 Reactome, http://www.reactome.org Autophosphorylation of FADK1 at Y397 Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed11476890 Pubmed16919435 Reactome Database ID Release 43354073 Reactome, http://www.reactome.org ReactomeREACT_15535 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 The co-localization of FAK with integrins in focal adhesions and the actin cytoskeleton is essential for the activation and phosphorylation of FAK. <br>FAK has six tyrosine phosphorylation sites and tyrosine 397 is the main auto-phosphorylation site present upstream of the kinase domain. ACTIVATION GENE ONTOLOGYGO:0004163 Reactome Database ID Release 43191297 Reactome, http://www.reactome.org Thrombin binding to GP1b:IX:V Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-09-01 Pubmed11084032 Pubmed12855811 Reactome Database ID Release 43429529 Reactome, http://www.reactome.org ReactomeREACT_23955 Reviewed: Heemskerk, JW, 2010-09-01 Thrombin binds to the GP1b-IX-V receptor during platelet aggregation. This leads to increased PAR activation, possibly due to favourable orientation of thrombin towards the PAR extracellular domain. IPs transport between ER lumen and cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0033271 Inositol phosphates IP3 and IP5 are imported into the cytosol from the endoplasmic reticulum (ER) lumen (Caffrey et al. 1999, Chi et al. 1999, Nalaskowski et al. 2002, Ho et al. 2002, Brehm et al. 2007). The molecular details of these transport processes remain uncertain. Pubmed10087200 Pubmed11909533 Pubmed12027805 Pubmed17705785 Pubmed9923613 Reactome Database ID Release 431855215 Reactome, http://www.reactome.org ReactomeREACT_150405 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Alpha-2 adrenoceptors bind catecholamines Alpha-2 adrenoceptors couple with G protein alpha-i subtype which decreases adenylyl cyclase activity, thus reducing cAMP intracellular levels resulting in smooth muscle contraction. There are three alpha-2 subtypes in humans; 2A (Kobilka BK et al, 1987), 2B (Weinshank RL et al, 1990) and 2C (Hirasawa A et al, 1993). Authored: Jassal, B, 2009-02-10 10:07:58 Edited: Jassal, B, 2009-02-10 10:07:58 Pubmed2172775 Pubmed2823383 Pubmed8396931 Reactome Database ID Release 43390663 Reactome, http://www.reactome.org ReactomeREACT_17002 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 SYK activation by SRC Authored: Akkerman, JW, 2009-06-03 EC Number: 2.7.10 Edited: Jupe, S, 2010-09-01 Pubmed7513017 Pubmed7961845 Pubmed9351824 Reactome Database ID Release 43429441 Reactome, http://www.reactome.org ReactomeREACT_23775 Reviewed: Heemskerk, JW, 2010-09-01 SYK activation in integrin signalling is associated with increased tyrosine phosphorylation. SYK activation and phosphorylation of SYK targets can be blocked by SRC inhibitors or expression of dominant negative SRC mutants. has a Stoichiometric coefficient of 2 Activation of Protein Kinase C novel isoforms Activation of the novel Protein Kinase C (nPKC) isoforms (delta, epsilon, eta and theta) requires binding to the membrane lipid diacylglycerol (DAG). nPKC activation is sensitive to DAG concentration. Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed19033211 Pubmed9601053 Reactome Database ID Release 43425861 Reactome, http://www.reactome.org ReactomeREACT_23917 Reviewed: Kunapuli, SP, 2010-06-07 Calcium and Diacylglycerol activate CalDAG-GEFs (RasGRPs) Authored: Akkerman, JW, 2009-06-03 Calcium and DAG regulated guanine nucleotide exchange factors (CalDAG-GEFs, also called RasGRPs) contain a regulatory C1 diacylglycerol (DAG) -binding domain analogous to the C1 domain found in Protein Kinase C, and a pair of calcium-binding EF-hand domains. All forms show enhanced activity in response to DAG and bind calcium, but the effect of Ca2+ seems to differ between isoforms. CalDAG-GEFI exhibited additive enhancement of Rap1 activation in response to Ca2+ ionophore and phorbol ester (Kawasaki et al. 1998). RasGRP2, an isofom of CalDAG-GEFI with an alternatively spliced N-terminal extension, reported to target it to the plasma membrane, was stimulated by diacylglycerol but inhibited by calcium (Clyde-Smith et al. 2000). CalDAG-GEF II/RasGRP1 was additively stimulated by Ca2+ ionophore and phorbol ester.<br><br>CalDAG-GEFI was found to primarily target Rap1A and inhibit Ras-dependent activation of the Erk/MAP kinase cascade (Kawasaki et al. 1998). RasGRP2 selectively activated N- and Ki-Ras, but not Ha-Ras. It also had Rap1A stimulating activity, but less than CalDAG-GEFI. The difference in substrate specificity seen for these isoforms may be due to their different cellular locations, as prolonged exposure to phorbol esters, or growth in serum, resulted in localization of CalDAG-GEFI to the cell membrane and restoration of Ras exchange activity (Clyde-Smith et al. 2000). CalDAG-GEF II/RasGRP1 targeted Ras proteins rather than Rap (Kawasaki et al. 1998, Ebinu et al. 1998).<br> <br>Mouse platelets that lack CalDAG-GEFI are severely compromised in integrin-dependent aggregation as a consequence of their inability to signal through CalDAG-GEFI to its target, the small GTPase Rap1 (Crittenden et al. 2004) Edited: Jupe, S, 2010-06-07 Pubmed10918068 Pubmed15221855 Pubmed15334074 Pubmed9582122 Reactome Database ID Release 43392831 Reactome, http://www.reactome.org ReactomeREACT_23930 Reviewed: Kunapuli, SP, 2010-06-07 Binding of IP3 to IP3 receptor Edited: Jupe, S, 2009-09-09 Pubmed11413485 Pubmed17429043 Reactome Database ID Release 43139941 Reactome, http://www.reactome.org ReactomeREACT_1144 The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. <br>Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms. IN Converted from EntitySet in Reactome Integrase Reactome DB_ID: 173113 Reactome Database ID Release 43173113 Reactome, http://www.reactome.org ReactomeREACT_8226 Thrombopoietin binds the thrombopoietin receptor Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed15518238 Pubmed16673285 Pubmed7492761 Pubmed8073287 Reactome Database ID Release 43443926 Reactome, http://www.reactome.org ReactomeREACT_23812 Reviewed: Kunapuli, SP, 2010-06-07 Thrombopoietin (TPO) is a primary regulator of megakaryocytopoiesis. Binding of TPO to its receptor TPOR (c-Mpl) mediates pleiotropic effects on megakaryocyte development leading to significant increase in circulating platelet numbers. TPOR knockout mice show a marked reduction in bone marrow megakaryocytes and blood platelets. Although thrombopoietin (TPO) by itself has little or no effect on platelet aggregation, pretreatment of platelets with TPO augments the aggregation induced by various agonists such as ADP, thrombin, collagen, and adrenaline. ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192006 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033778 Reactome Database ID Release 43192125 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192098 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192006 Reactome, http://www.reactome.org Chylomicron-mediated lipid transport Authored: D'Eustachio, P, 2007-04-30 14:19:38 Chylomicrons transport triacylglycerol, phospholipid, and cholesterol derived from dietary lipid from the small intestine to other tissues of the body. Each chylomicron assembles around a single molecule of apolipoprotein B-48 (Phillips et al. 1997) which at the time the particle leaves the intestine and enters the lymphatic circulation is complexed with >200,000 molecules of triacylglycerol (TG), ~35,000 of phospholipid, ~11,000 of cholesterol ester, ~8,000 of free cholesterol, ~60 copies of apolipoprotein A-I, ~15 copies of apolipoprotein A-IV, and copies of apolipoprotein A-II (Bhattacharya and Redgrave 1981; Havel and Kane 2001). As chylomicrons circulate in the body, they acquire molecules of apolipoproteins C and E, and through interaction with endothelial lipases can lose a large fraction of their triacylglycerol. These changes convert them to chylomicron remnants which bind to LDL receptors, primarily on the surfaces of liver cells, clearing them from the circulation. This whole sequence of events is rapid: the normal lifespan of a chylomicron is 30 - 60 minutes (Havel and Kane 2001). Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0042157 ISBN0079130356 Pubmed7288288 Pubmed9215545 Reactome Database ID Release 43174800 Reactome, http://www.reactome.org ReactomeREACT_6841 Lipoprotein metabolism Because of their hydrophobicity, lipids are found in the extracellular spaces of the human body primarily in the form of lipoprotein complexes. <b>Chylomicrons</b> form in the small intestine and transport dietary lipids to other tissues in the body. <b>Very low density lipoproteins (VLDL)</b> form in the liver and transport triacylglycerol synthesized there to other tissues of the body. As they circulate, VLDL are acted on by lipoprotein lipases on the endothelial surfaces of blood vessels, liberating fatty acids and glycerol to be taken up by tissues and converting the VLDL first to <b>intermediate density lipoproteins (IDL)</b> and then to <b>low density lipoproteins (LDL)</b>. IDL and LDL are cleared from the circulation via a specific cell surface receptor, found in the body primarily on the surfaces of liver cells. <b>High density lipoprotein (HDL)</b> particles, initially formed primarily by the liver, shuttle several kinds of lipids between tissues and other lipoproteins. Notably, they are responsible for the so-called reverse transport of cholesterol from peripheral tissues to LDL for return to the liver.<p>Three aspects of lipoprotein function are currently annotated in Reactome: <b>chylomicron-mediated lipid transport</b>, <b>LDL endocytosis and degradation</b>, and <b>HDL-mediated lipid transport</b>. Edited: D'Eustachio, P, 2006-02-20 18:35:05 GENE ONTOLOGYGO:0042157 Reactome Database ID Release 43174824 Reactome, http://www.reactome.org ReactomeREACT_6823 SHC1 dissociates from integrin alphaIIb beta3 Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-09-01 In a mechanism that is presumed to be analagous to signaling of SHC downstream of the insulin and TrkA receptors, SHC becomes phosphorylated and dissociates from the integrin alphaIIb beta3 complex. Pubmed10964917 Pubmed8755247 Reactome Database ID Release 43443910 Reactome, http://www.reactome.org ReactomeREACT_22439 Reviewed: Heemskerk, JW, 2010-09-01 ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org Trafficking of dietary sterols Authored: D'Eustachio, P, 2008-05-12 17:46:52 Edited: D'Eustachio, P, 2008-06-13 14:03:50 GENE ONTOLOGYGO:0015918 NPC1L1 protein mediates the uptake of dietary sterols from the gut lumen. These include cholesterol and plant sterols (phytosterols). Half to two-thirds of the 250-500 milligrams of cholesterol consumed daily from a typical western diet is taken up by this route and exported from enterocytes into the lymph in chylomicrons. Of the 200-400 milligrams of dietary phytosterol, only about 5% is absorbed.The drug ezetimibe interferes with NPC1L1-mediated sterol uptake (Oram and Vaughan 2006).<p>Both cholesterol and phytosterols are secreted from the liver into the bile (Salen et al. 1970). Mutations affecting the ABCG5/8 transporter complex inhibit this process (e.g., Berge et al. 2000), while the molecular details of sterol export in human cells have not been worked out, they can be inferred from the properties of the homologous mouse proteins (Graf et al. 2003; Wang et al. 2006). Pubmed11099417 Pubmed14504269 Pubmed16867993 Pubmed17095732 Pubmed5441548 Reactome Database ID Release 43265473 Reactome, http://www.reactome.org ReactomeREACT_13781 Reviewed: Jassal, B, 2008-06-13 14:05:49 SYK binds to integrin alphaIIb beta3 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-09-01 Integrin alphaIIb beta3 'outside-in' signalling involves multiple proteins including SRC, SYK, SLP-76 and PLCgamma2. SRC is constitutively associated with the C-terminal tail of integrin beta 3. SYK is recruited to the beta3 tail and subsequently activated by SRC. Pubmed11940607 Pubmed12171941 Pubmed15205259 Pubmed17055557 Pubmed9351824 Reactome Database ID Release 43429415 Reactome, http://www.reactome.org ReactomeREACT_23931 Reviewed: Heemskerk, JW, 2010-09-01 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org Digestion of dietary lipid Authored: D'Eustachio, P, 2007-02-02 21:43:49 Dietary lipids such as long-chain triacylglycerols and cholesterol esters are digested in the stomach and small intestine to yield long-chain fatty acids, monoacylglycerols, glycerol and cholesterol through the action of a variety of lipases, and are then absorbed into enterocytes. GENE ONTOLOGYGO:0044241 Pubmed11514232 Pubmed12454260 Reactome Database ID Release 43192456 Reactome, http://www.reactome.org ReactomeREACT_9518 Activated integrin alphaIIb beta3 binds SHC1 Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-09-01 Pubmed10548108 Pubmed10964917 Pubmed8631894 Reactome Database ID Release 43432096 Reactome, http://www.reactome.org ReactomeREACT_23801 Reviewed: Heemskerk, JW, 2010-09-01 The beta 3 integrin cytoplasmic tail binds SH2-containing protein (SHC), an adapter in Ras signaling. Phosphorylation of Y785 may be necessary for binding; phosphorylation of T779 inhibits SHC binding. Mice expressing a mutated beta 3 where Y773 and Y785 have been mutated to F exhibit rebleeding from tail wounds and subtle defects in clot retraction and platelet aggregation. Lipid and lipoprotein metabolism Authored: Jassal, B, Gillespie, ME, Gopinathrao, G, D'Eustachio, P, 2007-02-02 21:56:36 Edited: D'Eustachio, P, Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006629 Lipid digestion, mobilization, and transport Processes annotated here include the digestion of dietary lipids, sterol uptake, the formation and turnover of lipoproteins (chylomicrons, VLDL, LDL, and HDL), and the mobilization of fatty acids through the action of hormone-sensitive lipase. Reactome Database ID Release 4373923 Reactome, http://www.reactome.org ReactomeREACT_602 SHC1 bound to integrin alphaIIb beta3 is phosphorylated somehow Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-09-01 In a mechanism that is presumed to be analagous to signaling of SHC downstream of the insulin and TrkA receptors, SHC becomes phosphorylated and dissociates from the integrin alphaIIb beta3 complex. Pubmed10964917 Pubmed8755247 Reactome Database ID Release 43443905 Reactome, http://www.reactome.org ReactomeREACT_23821 Reviewed: Heemskerk, JW, 2010-09-01 Metabolism of lipids and lipoproteins Authored: Jassal, B, Gillespie, ME, Gopinathrao, G, D'Eustachio, P, 2007-02-02 21:56:36 Edited: D'Eustachio, P, Joshi-Tope, G, 0000-00-00 00:00:00 Lipids are hydrophobic but otherwise chemically diverse molecules that play a wide variety of roles in human biology. They include ketone bodies, fatty acids, triacylglycerols, phospholipids and sphingolipids, eicosanoids, cholesterol, bile salts, steroid hormones, and fat-soluble vitamins. They function as a major source of energy (fatty acids, triacylglycerols, and ketone bodies), are major constituents of cell membranes (cholesterol and phospholipids), play a major role in their own digestion and uptake (bile salts), and participate in numerous signaling and regulatory processes (steroid hormones, eicosanoids, phosphatidylinositols, and sphingolipids). Because of their poor solubility in water, most lipids in extracellular spaces in the human body are found as complexes with specific carrier proteins. Regulation of the formation and movement of these lipoprotein complexes is a critical aspect of human lipid metabolism, and lipoprotein abnormalities are associated with major human disease processes including atherosclerosis and diabetes.<p>The central steroid in human biology is cholesterol, obtained from animal fats consumed in the diet or synthesized de novo from acetyl-coenzyme A. (Vegetable fats contain various sterols but no cholesterol.) Cholesterol is an essential constituent of lipid bilayer membranes and is the starting point for the biosyntheses of bile acids and salts, steroid hormones, and vitamin D. Bile acids and salts are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (glucocorticoids), salt balance (mineralocorticoids), and sexual development and function (androgens and estrogens). At the same time, chronically elevated cholesterol levels in the body are associated with the formation of atherosclerotic lesions and hence increased risk of heart attacks and strokes. The human body lacks a mechanism for degrading excess cholesterol, although an appreciable amount is lost daily in the form of bile salts and acids that escape recycling.<p>Aspects of lipid metabolism currently annotated in Reactome include lipid digestion, mobilization, and transport; fatty acid, triacylglycerol, and ketone body metabolism; peroxisomal lipid metabolism; phospholipid and sphingolipid metabolism; cholesterol biosynthesis; bile acid and bile salt metabolism; and steroid hormone biosynthesis. Reactome Database ID Release 43556833 Reactome, http://www.reactome.org ReactomeREACT_22258 ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org Synthesis of IP2, IP, and Ins in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0043647 Inositol phosphates IP2, IP and the six-carbon cyclic alcohol inositol (Ins) are produced by various phosphatases and the inositol-3-phosphate synthase 1 (ISYNA1) (Ju et al. 2004, Ohnishi et al. 2007, Irvine & Schell 2001, Bunney & Katan 2010). Pubmed11331907 Pubmed15024000 Pubmed17068342 Pubmed20414202 Reactome Database ID Release 431855183 Reactome, http://www.reactome.org ReactomeREACT_150352 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192098 Reactome, http://www.reactome.org IPs transport between nucleus and ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0033271 Inositol phosphate IP6 is imported to the endoplasmic reticulum (ER) lumen from the nucleus (Caffrey et al. 1999). The molecular details of these transport processes remain uncertain. Pubmed9923613 Reactome Database ID Release 431855192 Reactome, http://www.reactome.org ReactomeREACT_150265 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org IPs transport between ER lumen and nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0033271 Inositol phosphates IP4 and IP5 are exported from the endoplasmic reticulum (ER) lumen to the nucleus (Caffrey et al. 1999, Chi et al. 1999, Nalaskowski et al. 2002, Verbsky et al. 2002, Brehm et al. 2007, Choi et al. 2007). The molecular details of these transport processes remain uncertain. Pubmed10087200 Pubmed12027805 Pubmed12084730 Pubmed17702752 Pubmed17705785 Pubmed9923613 Reactome Database ID Release 431855156 Reactome, http://www.reactome.org ReactomeREACT_150164 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org Activation of conventional Protein Kinase C Pubmed19033211 Pubmed9601053 Pubmed9814702 Reactome Database ID Release 43114553 Reactome, http://www.reactome.org ReactomeREACT_286 The conventional Protein Kinase C (cPKC) isoforms have two membrane-targetting domains, a C1 domain which binds to the membrane lipid diacylglycerol (DAG) and a C2 domain which binds membrane phospholipids such as phosphatidylserine, in a calcium-dependent manner. Association of both domains with the plasma membrane produces a conformational change that releases an autoinhibitory pseudosubstrate segment from the substrate-binding cavity, allowing substrate binding and downstream signaling. DAG kinase produces phosphatidic acid from DAG Authored: Jupe, S, 2009-06-11 Diacylglycerol kinases (DGKs) are intracellular lipid kinases that use ATP to phosphorylate diacylglycerol (DAG)., generating phosphatidic acid (PA). This lowers membrane DAG levels, regulating signalling proteins that require DAG for membrane association such as Protein Kinase C. PA is a signalling molecule that regulates Raf-1 and PKC zeta, and a substrate for the resynthesis of phosphatidylinositol. EC Number: 2.7.1.107 Edited: Jupe, S, 2009-09-09 Pubmed11080611 Pubmed18062770 Pubmed2175712 Pubmed8626548 Reactome Database ID Release 43426240 Reactome, http://www.reactome.org ReactomeREACT_19402 Reviewed: Akkerman, JW, 2009-09-04 Phosphorylation of Syntaxin-4 At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'Syntaxin 4' are present. At the end of this reaction, 1 molecule of 'Phosphorylated syntaxin 4', and 1 molecule of 'ADP' are present.<br><br> This reaction is mediated by the 'calcium-dependent protein kinase C activity' of 'Activated Ca++ and DAG dependent PKC'.<br> Pubmed10856305 Reactome Database ID Release 43114684 Reactome, http://www.reactome.org ReactomeREACT_1045 Phosphorylation of Platelet Sec-1 At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'Platelet SEC1 protein' are present. At the end of this reaction, 1 molecule of 'Phosphorylated platelet SEC1 protein', and 1 molecule of 'ADP' are present.<br><br> This reaction is mediated by the 'calcium-dependent protein kinase C activity' of 'Activated Ca++ and DAG dependent PKC'.<br> Pubmed10194441 Reactome Database ID Release 43114683 Reactome, http://www.reactome.org ReactomeREACT_133 Exocytosis of platelet dense granule content ADP is the most important constituent of dense granules, essential for recruiting platelets to the site of vascular injury. Other components include ATP, Ca++, GDP, GTP, Mg++, orthophospate, pyrophosphate, and serotonin. Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Pubmed1435334 Pubmed19073150 Pubmed4132863 Pubmed4426930 Pubmed4809565 Reactome Database ID Release 43481009 Reactome, http://www.reactome.org ReactomeREACT_21354 ABCC4 accumulation of dense granule contents ABCC4 (Multidrug resistance protein 4 /MOAT-B) is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, capable of pumping a wide variety of endogenous and xenobiotic anionic compounds out of the cell. ABCC4 also transports molecules involved in cellular signalling, including cyclic nucleotides, eicosanoids, urate and conjugated steroids. ABCC4 has a dual localisation in polarised cells that suggests a key function in cellular protection and extracellular signalling pathways. It is also highly expressed on platelet dense granule membranes where it is believed to contribute to the accumulation of dense granule content. Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed15297306 Pubmed18353444 Reactome Database ID Release 43429157 Reactome, http://www.reactome.org ReactomeREACT_23865 Reviewed: Kunapuli, SP, 2010-06-07 Exocytosis of platelet alpha granule contents Alpha granules contain mainly polypeptides such as fibrinogen, von Willebrand factor, growth factors and protease inhibitors that supplement thrombin generation at the site of injury. In addtion to their role in hemostasis, platelets also contain angiogenesis stimulators and inhibitors (Italiano et al. 2008). Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Pubmed14630798 Pubmed15790929 Pubmed1737102 Pubmed17962514 Pubmed2110384 Pubmed2531289 Pubmed2752154 Pubmed287022 Pubmed3457014 Pubmed3965505 Pubmed444675 Pubmed47244 Pubmed501196 Pubmed5084810 Pubmed5789664 Pubmed59727 Pubmed6338048 Pubmed6414553 Pubmed6457647 Pubmed6459901 Pubmed6603475 Pubmed6946465 Pubmed7306699 Pubmed8467233 Pubmed8514871 Pubmed9684805 Reactome Database ID Release 43481007 Reactome, http://www.reactome.org ReactomeREACT_21351 Surface deployment of platelet dense granule membrane components Authored: de Bono, B, Pace, N.P., Farndale, R, 2004-09-25 17:06:19 Constituents of the platelet dense granule membrane are incorporated into the platelet membrane following exocytosis of granule content. Pubmed1377048 Pubmed1435334 Pubmed8743190 Reactome Database ID Release 43481010 Reactome, http://www.reactome.org ReactomeREACT_21266 ACTIVATION GENE ONTOLOGYGO:0004769 Reactome Database ID Release 43195674 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000253 Reactome Database ID Release 43194731 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000252 Reactome Database ID Release 43194724 Reactome, http://www.reactome.org Synthesis of IPs in the ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0043647 In the endoplasmic reticulum (ER) lumen, inositol phosphates IP4, IP5, and IP6 are dephosphorylated by multiple inositol polyphosphate phosphatase 1 (MINPP1) (Caffrey et al. 1999, Chi et al. 1999, Deleu et al. 2006, Nogimori et al. 1991). Pubmed10087200 Pubmed15979280 Pubmed1653239 Pubmed9923613 Reactome Database ID Release 431855231 Reactome, http://www.reactome.org ReactomeREACT_150253 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 IPs transport between cytosol and ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0033271 Inositol phosphates IP4, IP5, and IP6 are exported from the cytosol to the endoplasmic reticulum (ER) lumen (Caffrey et al. 1999, Chi et al. 1999). The molecular details of these transport processes remain uncertain. Pubmed10087200 Pubmed9923613 Reactome Database ID Release 431855184 Reactome, http://www.reactome.org ReactomeREACT_150204 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 IPs transport between nucleus and cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0033271 Inositol phosphates (IPs) synthesised in the nucleus are imported into the cytosol from the nucleus. The molecular details of these transport processes remain uncertain (Nalaskowski et al. 2002; Ho et al. 2002, Brehm et al. 2007, Saiardi et al. 2001, Saiardi et al. 2000, Fridy et al. 2007, Leslie et al. 2002). Pubmed10827188 Pubmed11502751 Pubmed11909533 Pubmed12027805 Pubmed12121577 Pubmed17690096 Pubmed17705785 Reactome Database ID Release 431855170 Reactome, http://www.reactome.org ReactomeREACT_150458 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 DAG activation of TRPC channels Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed10488066 Pubmed11805119 Pubmed12032305 Pubmed12765690 Pubmed8986787 Pubmed9930701 Reactome Database ID Release 43426209 Reactome, http://www.reactome.org ReactomeREACT_24007 Reviewed: Kunapuli, SP, 2010-06-07 TRPC3, 6 and 7 are non-selective cation channels that are activated by diacylglycerol (DAG) independently of protein kinase C activation by DAG. By analogy with the structures of voltage-regulated calcium channels, TRPC channels are probably tetramers of TRPC protein; heterotetramers within the 3/6/7 group have been observed. Synthesis of IPs in the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0043647 Pubmed10827188 Pubmed11331907 Pubmed11502751 Pubmed12027805 Pubmed12223481 Pubmed16293229 Pubmed16781889 Pubmed17412958 Pubmed17943301 Pubmed18355727 Pubmed20359876 Reactome Database ID Release 431855191 Reactome, http://www.reactome.org ReactomeREACT_150275 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Within the nucleus, inositol polyphosphate multikinase (IPMK), inositol-pentakisphosphate 2-kinase (IPPK), inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) produce IP5, IP6, IP7, and IP8 inositol phosphate molecules (Irvine & Schell 2001, Alcazar-Romain & Wente 2008, York 2006, Monserrate and York 2010, Nalaskowski et al. 2002, Chang et al. 2002, Chang & Majerus 2006, Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008, Mulugu et al. 2007). DAG is metabolized by DAGL to 2-AG Authored: Jupe, S, 2009-06-11 Diacylglycerol lipase (DAGL) hydrolyzes diacylglycerol (DAG) at the sn-1 position, producing 2-monoacylglycerols, including 2-arachidonlyglycerol (2-AG) and free fatty acid. This reaction was first characterised for the release of arachidonate from membrane phospholipids in platelets, but is also involved in the spatial and temporal regulation of endocannabinoid signaling in the brain. DAGL exhibits strong selectivity for diacylglycerols over phospholipids, monoacylglycerols, triacylglycerols and fatty acid amides, and prefers the acyl group at sn-1 position to that at sn-2. EC Number: 3.1.1.23 Edited: Jupe, S, 2009-09-09 Pubmed10348910 Pubmed19126434 Reactome Database ID Release 43426032 Reactome, http://www.reactome.org ReactomeREACT_19135 Reviewed: Akkerman, JW, 2009-06-03 ACTIVATION GENE ONTOLOGYGO:0003854 Reactome Database ID Release 43192106 Reactome, http://www.reactome.org IP6 and IP7 transport between cytosol and nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0033271 Pubmed11502751 Pubmed17412958 Reactome Database ID Release 431855229 Reactome, http://www.reactome.org ReactomeREACT_150169 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 The inositol phosphates IP6 and IP7 are exported from the cytosol to the nucleus (Saiardi et al. 2001, Mulugu et al. 2007). The molecular details of these transport processes remain uncertain. 2-AG hydrolysis to arachidonate by MAGL Authored: Jupe, S, 2009-06-11 EC Number: 3.1.1.23 Edited: Jupe, S, 2009-09-09 Monoacylglycerol lipase (MAGL) is a key enzyme in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol to arachidonate and glycerol. In adipocytes MAGL and hormone-sensitive lipase (LIPE) hydrolyze intracellular triglyceride stores. MAGL may also complement lipoprotein lipase (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides. Pubmed11470505 Pubmed16116451 Pubmed18096503 Pubmed7295321 Reactome Database ID Release 43426043 Reactome, http://www.reactome.org ReactomeREACT_19155 Reviewed: Akkerman, JW, 2009-09-04 ACTIVATION GENE ONTOLOGYGO:0008123 Reactome Database ID Release 43192120 Reactome, http://www.reactome.org Synthesis of pyrophosphates in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0043647 Inositol phosphates such as IP4, IP5 and IP6 are converted to an even wider variety of IPs including the di- and triphospho inositol phosphates, also known as pyrophosphates (Irvine & Schell 2001, Alcazar-Romain & Wente 2008, York 2006, Monserrate and York 2010, Ho et al. 2002, Saiardi et al. 2001, Draskovic et al. 2008, Choi et al. 2007, Caffrey et al. 2000, Leslie et al. 2002). Pubmed10777568 Pubmed11331907 Pubmed11502751 Pubmed11909533 Pubmed12121577 Pubmed16781889 Pubmed17702752 Pubmed17943301 Pubmed18355727 Pubmed20359876 Reactome Database ID Release 431855167 Reactome, http://www.reactome.org ReactomeREACT_150188 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 43381068 Reactome, http://www.reactome.org Inositol phosphate metabolism Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0043647 Inositol phosphates (IPs) are molecules involves in signalling processes in eukaryotes. myo-Inositol consists of a six-carbon cyclic alcohol with an axial 2-hydroxy and five equatorial hydroxyls. Mono-, di-, and triphosphorylation of the inositol ring generates a wide variety of stereochemically distinct signalling entities. Inositol 1,4,5-trisphosphate (I(1,4,5)P3), is formed when the phosphoinositide phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is hydrolysed by a phospholipase C isozyme. An array of inositol trisphosphate (IP3) and tetrakisphosphate (IP4) molecules are synthesised by the action of various kinases and phosphatases in the cytosol. These species then transport between the cytosol and the nucleus where they are acted on by inositol polyphosphate multikinase (IPMK), inositol-pentakisphosphate 2-kinase (IPPK), inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2), to produce IP5, IP6, IP7, and IP8 molecules. Some of these nuclear produced IPs transport back to the cytosol where they are converted to an even wider variety of IPs, by kinases and phosphatases, including the di- and triphospho inositol phosphates aka pyrophosphates (Irvine & Schell 2001, Bunney & Katan 2010, Alcazar-Romain & Wente 2008, York 2006, Monserrate and York 2010). Pubmed11331907 Pubmed16781889 Pubmed17943301 Pubmed20359876 Pubmed20414202 Reactome Database ID Release 431483249 Reactome, http://www.reactome.org ReactomeREACT_150154 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43380995 Reactome, http://www.reactome.org CS/DS degradation Authored: Jassal, B, 2011-12-14 Edited: Jassal, B, 2011-12-14 GENE ONTOLOGYGO:0030207 Lysosomal degradation of glycoproteins is part of the cellular homeostasis of glycosylation (Winchester 2005). The steps outlined below describe the degradation of chondroitin sulfate and dermatan sulfate. Complete degradation of glycoproteins is required to avoid build up of glycosaminoglycan fragments which can cause lysosomal storage diseases. Complete degradation steps are not shown as they are repetitions of the main ones described here. The proteolysis of the core protein of the glycoprotein is not shown here. Pubmed15647514 Reactome Database ID Release 432024101 Reactome, http://www.reactome.org ReactomeREACT_120888 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0050614 Reactome Database ID Release 43196404 Reactome, http://www.reactome.org IP3 and IP4 transport between cytosol and nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0033271 Inositol trisphosphate (IP3) and tetrakisphosphate (IP4) molecules are exported from the cytosol to the nucleus (Dewaste et al. 2003, Nalaskowski et al. 2002). It is unknown whether this occurs by diffusion or is mediated by a transporter. Pubmed12027805 Pubmed12747803 Reactome Database ID Release 431855196 Reactome, http://www.reactome.org ReactomeREACT_150354 Reviewed: Challiss, John, 2012-11-09 ACTIVATION GENE ONTOLOGYGO:0047598 Reactome Database ID Release 43196403 Reactome, http://www.reactome.org Synthesis of IP3 and IP4 in the cytosol An array of inositol trisphosphate (IP3) and tetrakisphosphate (IP4) molecules are synthesised by the action of various kinases and phosphatases in the cytosol (Irvine & Schell 2001, Bunney & Katan 2010). Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 GENE ONTOLOGYGO:0043647 Pubmed11331907 Pubmed20414202 Reactome Database ID Release 431855204 Reactome, http://www.reactome.org ReactomeREACT_150312 Reviewed: Challiss, John, 2012-11-09 ACTIVATION GENE ONTOLOGYGO:0000248 Reactome Database ID Release 43195666 Reactome, http://www.reactome.org Elongating transcript prior to separation Reactome DB_ID: 113714 Reactome Database ID Release 43113714 Reactome, http://www.reactome.org ReactomeREACT_5639 Elongating transcript prior to cleavage Reactome DB_ID: 113725 Reactome Database ID Release 43113725 Reactome, http://www.reactome.org ReactomeREACT_4890 mature mRNA (eukaryotic, capped and polyadenylated) Reactome DB_ID: 430014 Reactome Database ID Release 43430014 Reactome, http://www.reactome.org ReactomeREACT_21060 mature mRNA (eukaryotic, capped and partially deadenylated) Reactome DB_ID: 429909 Reactome Database ID Release 43429909 Reactome, http://www.reactome.org ReactomeREACT_20760 template DNA:11 nucleotide transcript hybrid Reactome DB_ID: 75901 Reactome Database ID Release 4375901 Reactome, http://www.reactome.org ReactomeREACT_5290 template:capped transcript hybrid Reactome DB_ID: 113424 Reactome Database ID Release 43113424 Reactome, http://www.reactome.org ReactomeREACT_2594 CYP3A43 Converted from EntitySet in Reactome Reactome DB_ID: 216602 Reactome Database ID Release 43216602 Reactome, http://www.reactome.org ReactomeREACT_14617 CYP2S1 Converted from EntitySet in Reactome Reactome DB_ID: 216584 Reactome Database ID Release 43216584 Reactome, http://www.reactome.org ReactomeREACT_13891 ACTIVATION GENE ONTOLOGYGO:0016746 Reactome Database ID Release 43193371 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016746 Reactome Database ID Release 43193371 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015432 Reactome Database ID Release 43193367 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033781 Reactome Database ID Release 43192143 Reactome, http://www.reactome.org template DNA:9 nucleotide transcript hybrid Reactome DB_ID: 75888 Reactome Database ID Release 4375888 Reactome, http://www.reactome.org ReactomeREACT_5461 ACTIVATION GENE ONTOLOGYGO:0033989 Reactome Database ID Release 43192350 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 43193365 Reactome, http://www.reactome.org Template DNA hybrid with phosphodiester-PPi intermediate Reactome DB_ID: 83602 Reactome Database ID Release 4383602 Reactome, http://www.reactome.org ReactomeREACT_4127 ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 43193365 Reactome, http://www.reactome.org template DNA opened from -10 to +2, with first nucleotide base-paired at 5'-end Reactome DB_ID: 71063 Reactome Database ID Release 4371063 Reactome, http://www.reactome.org ReactomeREACT_5586 ACTIVATION GENE ONTOLOGYGO:0050632 Reactome Database ID Release 43192310 Reactome, http://www.reactome.org template DNA:4 nucleotide transcript hybrid Reactome DB_ID: 75884 Reactome Database ID Release 4375884 Reactome, http://www.reactome.org ReactomeREACT_5593 ACTIVATION GENE ONTOLOGYGO:0050632 Reactome Database ID Release 43192310 Reactome, http://www.reactome.org template DNA:3 nucleotide transcript hybrid Reactome DB_ID: 75858 Reactome Database ID Release 4375858 Reactome, http://www.reactome.org ReactomeREACT_5797 ACTIVATION GENE ONTOLOGYGO:0016289 Reactome Database ID Release 43193529 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003997 Reactome Database ID Release 43192336 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003997 Reactome Database ID Release 43192336 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008111 Reactome Database ID Release 43191973 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008111 Reactome Database ID Release 43191973 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033989 Reactome Database ID Release 43192350 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org decapped mRNA with 5' monophosphate Reactome DB_ID: 429875 Reactome Database ID Release 43429875 Reactome, http://www.reactome.org ReactomeREACT_20726 ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43192026 Reactome, http://www.reactome.org oligoribonucleotide with a 5'-diphosphate Reactome DB_ID: 429925 Reactome Database ID Release 43429925 Reactome, http://www.reactome.org ReactomeREACT_20778 ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43192026 Reactome, http://www.reactome.org capped oligoribonucleotide Reactome DB_ID: 429926 Reactome Database ID Release 43429926 Reactome, http://www.reactome.org ReactomeREACT_20913 ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43193506 Reactome, http://www.reactome.org mature mRNA (eukaryotic, capped and deadenylated) Reactome DB_ID: 429974 Reactome Database ID Release 43429974 Reactome, http://www.reactome.org ReactomeREACT_20743 ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43193506 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192098 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192098 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192006 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192006 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003854 Reactome Database ID Release 43192106 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033778 Reactome Database ID Release 43192125 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008396 Reactome Database ID Release 43192129 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004421 Reactome Database ID Release 4374170 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003985 Reactome Database ID Release 4370842 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003858 Reactome Database ID Release 4374155 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004419 Reactome Database ID Release 4374179 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004658 Reactome Database ID Release 4371030 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016860 Reactome Database ID Release 43109997 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004494 Reactome Database ID Release 4371008 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004493 Reactome Database ID Release 4371018 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008260 Reactome Database ID Release 4374278 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003858 Reactome Database ID Release 4374155 Reactome, http://www.reactome.org p66 subunit of RT Converted from EntitySet in Reactome Reactome DB_ID: 173117 Reactome Database ID Release 43173117 Reactome, http://www.reactome.org ReactomeREACT_8615 Porphobilinogen deaminase Converted from EntitySet in Reactome Reactome DB_ID: 189437 Reactome Database ID Release 43189437 Reactome, http://www.reactome.org ReactomeREACT_9656 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of Hydroxymethylglutaryl coenzyme A synthase (HMGCS1)' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989814 Reactome, http://www.reactome.org ReactomeREACT_117924 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of Farnesyldiphosphate Farnesyltransferase (FDFT1, Squalene Synthase)' ACTIVATION Pubmed10731415 Pubmed20110263 Reactome Database ID Release 431989809 Reactome, http://www.reactome.org ReactomeREACT_117993 'SREBP1A/1C/2:NF-Y:SP1:FDFT1 gene [nucleoplasm]' positively regulates 'Expression of Farnesyldiphosphate Farnesyltransferase (FDFT1, Squalene Synthase)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Pubmed8833906 Pubmed9062341 Pubmed9575211 Pubmed9604010 Pubmed9616204 Pubmed9748295 Reactome Database ID Release 431655863 Reactome, http://www.reactome.org ReactomeREACT_117940 SREBF1A/1C/2 (SREBP1A/1C/2) and NF-Y bind the promoter of the Farnesyldiphosphate Farnesyltransferase (FDFT1, Squalene Synthase) gene and enhance transcription (Shimano et al. 1996, Shimano et al. 1997, Guan et al. 1998, Horton et al. 1998, Inoue et al. 1998, Pai et al. 1998, Sakakura et al. 2001, Reed et al. 2008, reviewed in Reed et al. 2002). 'SREBP1A/1C/2:NF-Y:HMGCS1 gene [nucleoplasm]' positively regulates 'Expression of Hydroxymethylglutaryl coenzyme A synthase (HMGCS1)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed12177166 Pubmed18654640 Pubmed8833906 Pubmed9062341 Pubmed9604010 Pubmed9616204 Pubmed9748295 Reactome Database ID Release 431655870 Reactome, http://www.reactome.org ReactomeREACT_118042 SREBF1A/1C/2 (SREBP1A/1C/2) and NF-Y bind the promoter of the Hydroxymethylglutaryl coenzyme A synthase (HMGCS1) gene and enhance transcription (Shimano et al. 1996, Shimano et al. 1997, Horton et al. 1998, Inoue et al. 1998, Pai et al. 1998, Sakakura et al. 2001, Amemiya-Kudo et al. 2002, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/2:NF-Y:SP1:DHCR7 gene [nucleoplasm]' positively regulates 'Expression of 7-Dehydrocholesterol Reductase (DHCR7)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Reactome Database ID Release 431655860 Reactome, http://www.reactome.org ReactomeREACT_148666 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the 7-Dehydrocholesterol Reductase (DHCR) gene and enhance transcription (Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/1C:ACACA gene [nucleoplasm]' positively regulates 'Expression of Acetyl CoA Carboxylase 1 (ACACA, ACC1)' ACTIVATION Pubmed10585467 Pubmed11994399 Pubmed18559965 Pubmed8833906 Pubmed9062341 Pubmed9300785 Reactome Database ID Release 431655875 Reactome, http://www.reactome.org ReactomeREACT_148656 SREBF1A (SREBP1A) and SREBF1C (SREBP1C) bind the promoter of the Acetyl-CoA carboxylase 1 (ACACA, ACC1) gene and enhance transcription (Shimano et al. 1996, Magana et al. 1997, Shimano et al. 1997, Shimano et al. 1999, Rome et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/1C:ACACB gene [nucleoplasm]' positively regulates 'Expression of Acetyl CoA Carboxylase 2 (ACACB, ACC2)' ACTIVATION As inferred from rat, SREBF1 binds promoter II of the Acetyl-CoA carboxylase 2 gene (ACACB, ACC2) and enhances transcription (Oh et al. 2003). Pubmed11994399 Pubmed12764144 Reactome Database ID Release 431655854 Reactome, http://www.reactome.org ReactomeREACT_148679 'SREBP1A/2:MVD gene [nucleoplasm]' positively regulates 'Expression of Diphosphomevalonate Decarboxylase (MVD)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Reactome Database ID Release 431655874 Reactome, http://www.reactome.org ReactomeREACT_148652 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Diphosphomevalonate Decarboxylase (DMVD) gene and enhance transcription (Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/1C/2:ELOVL6 gene [nucleoplasm]' positively regulates 'Expression of ELOVL6' ACTIVATION As inferred from mouse, SREBF1A/1C/2 (SREBP1A/1C/2) bind the promoter of the ELOVL6 gene and enhances transcription (Moon et al. 2001, Matsuzaka et al. 2002, Kumadaki et al. 2008). Pubmed11567032 Pubmed12032166 Pubmed18226595 Reactome Database ID Release 431655862 Reactome, http://www.reactome.org ReactomeREACT_148683 'SREBP1A/1C/2:NF-Y:FDPS gene [nucleoplasm]' positively regulates 'Expression of Farnesyl Diphosphate Synthase (FDPS)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed12177166 Pubmed18654640 Pubmed20450493 Pubmed8570665 Pubmed8798690 Pubmed8864955 Pubmed9616204 Pubmed9748295 Reactome Database ID Release 431655856 Reactome, http://www.reactome.org ReactomeREACT_148668 SREBF1A/1C/2 (SREBP1A/1C/2) and NF-Y bind the promoter of the Farnesyl Diphosphate Synthase (FDPS) gene and activate transcription (Ericsson et al. 1996, Jackson et al. 1996, Horton et al. 1998, Pai et al. 1998, Sakakura 2001, Amemiya-Kudo et al. 2002, Reed et al. 2008, Ishimoto et al. 2010, reviewed in Horton et al. 2002). Heme oxygenase Converted from EntitySet in Reactome Reactome DB_ID: 189382 Reactome Database ID Release 43189382 Reactome, http://www.reactome.org ReactomeREACT_22577 mitochondrial aspartate glutamate carrier Converted from EntitySet in Reactome Reactome DB_ID: 372469 Reactome Database ID Release 43372469 Reactome, http://www.reactome.org ReactomeREACT_15225 'SREBP1A/2:NF-Y:SP1:GGPS1 gene [nucleoplasm]' positively regulates 'Expression of Geranylgeranyl Pyrophosphate Synthase (GGPS1)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Reactome Database ID Release 431655876 Reactome, http://www.reactome.org ReactomeREACT_148658 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Geranylgeranyl pyrophosphate synthase gene (GGPS1) and enhance transcription (Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002) Pyruvate kinase, R/L type Converted from EntitySet in Reactome Reactome DB_ID: 211386 Reactome Database ID Release 43211386 Reactome, http://www.reactome.org ReactomeREACT_13102 'SREBP1A/1C:NF-Y:SP1:FASN gene [nucleoplasm]' positively regulates 'Expression of Fatty Acid Synthase (FASN)' ACTIVATION Pubmed10207099 Pubmed10535992 Pubmed10585467 Pubmed10759542 Pubmed11994399 Pubmed12177166 Pubmed17197698 Pubmed18559965 Pubmed18682402 Pubmed7592729 Pubmed8833906 Pubmed8955100 Pubmed9786926 Reactome Database ID Release 431655857 Reactome, http://www.reactome.org ReactomeREACT_118058 SREBF1A (SREBP1A) and SREBF1C (SREBP1C) bind the promoter of the fatty acid synthase gene (FASN) and enhance transcription (Bennett et al. 1995, Magana and Osborne 1996, Shimano et al. 1996, Boizard et al. 1998, Foretz et al. 1999, Shimano et al. 1999, Amemiya-Kudo et al. 2002, Griffin et al. 2007, Choi et al. 2008, Rome et al. 2008, reviewed in Horton et al. 2002). The enhancer activity of SREBF1 requires simultaneous binding of NF-Y and SP1 to the promoter (Xiong et al. 2000). 'SREBP1A/2:NF-Y:SP1:IDI1 gene [nucleoplasm]' positively regulates 'Expression of Isopentenyl-diphosphate Delta-isomerase 1 (IDI1)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Reactome Database ID Release 431655869 Reactome, http://www.reactome.org ReactomeREACT_148671 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Isopentenyl-diphosphate Delta-isomerase 1 (IDI1) gene and enhance transcription (Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/1C:NF-Y:GPAM gene [nucleoplasm]' positively regulates 'Expression of Glycerol-3-phosphate Acyltransferase (GPAM, GPAT)' ACTIVATION As inferred from mouse, SREBF1A (SREBP1A) and SREBF1C (SREBP1C) bind the promoter of the Glycerol-3-phosphate acyltransferase gene (GPAM, GPAT) and enhance transcription (Ericsson et al. 1997, Shimano et al. 1999, Griffin et al. 2007, Yoshida et al. 2009, reviewed in Horton et al. 2002). Pubmed10585467 Pubmed11994399 Pubmed17197698 Pubmed18983939 Pubmed9054427 Reactome Database ID Release 431655868 Reactome, http://www.reactome.org ReactomeREACT_148690 'SREBP1A/2:SQLE gene [nucleoplasm]' positively regulates 'Expression of Squalene Monooxygenase (SQLE)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed12083769 Pubmed17027328 Pubmed18654640 Reactome Database ID Release 431655871 Reactome, http://www.reactome.org ReactomeREACT_148651 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Squalene Monooxygenase (SQLE) gene and enhance transcription (Sakakura et al. 2001, Nagai et al. 2002, Murphy et al. 2006, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/2:NF-Y:SP1:PMVK gene [nucleoplasm]' positively regulates 'Expression of Phosphomevalonate Kinase (PMVK)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Reactome Database ID Release 431655853 Reactome, http://www.reactome.org ReactomeREACT_148649 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Phosphomevalonate kinase (PMVK) gene and enhance transcription (Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/2:NF-Y:SP1:MVK gene [nucleoplasm]' positively regulates 'Expression of Mevalonate Kinase (MVK)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Reactome Database ID Release 431655867 Reactome, http://www.reactome.org ReactomeREACT_148674 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Mevalonate kinase (MVK) gene and enhance transcription (Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/2:NF-Y:SC5DL gene [nucleoplasm]' positively regulates 'Expression of Lathosterol Oxidase (SC5D, SC5DL)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Reactome Database ID Release 431655855 Reactome, http://www.reactome.org ReactomeREACT_148675 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Lathosterol oxidase gene (SC5D) and enhance transcription (Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/2:LSS gene [nucleoplasm]' positively regulates 'Expression of Lanosterol Synthase (LSS)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed18654640 Pubmed9748295 Reactome Database ID Release 431655866 Reactome, http://www.reactome.org ReactomeREACT_148659 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Lanosterol Synthase (LSS) gene and enhance transcription (Pai et al. 1998, Sakakura et al. 2001, Reed et al. 2008, reviewed in Horton et al. 2002). 'SREBP1A/2:NF-Y:SP1:CYP51A1 gene [nucleoplasm]' positively regulates 'Expression of Lanosterol Demethylase (CYP51A1)' ACTIVATION Pubmed11485325 Pubmed11994399 Pubmed12145339 Pubmed18654640 Pubmed9748295 Reactome Database ID Release 431655865 Reactome, http://www.reactome.org ReactomeREACT_148643 SREBF1A (SREBP1A) and SREBF2 (SREBP2) bind the promoter of the Lanosterol Demethylase (CYP51A1) gene and enhance transcription (Pai et al. 1998, Sakakura et al. 2001, Halder et al. 2002, Reed et al. 2008, reviewed in Horton et al. 2002). 'Corticotropin [cytosol]' positively regulates 'Side chain cleavage of 17alpha-hydroxypregnenolone to yield DHA' ACTIVATION Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). Reactome Database ID Release 431449712 Reactome, http://www.reactome.org ReactomeREACT_111902 'Corticotropin [cytosol]' positively regulates 'DHA isomerizes to 4-Androstene3,17-dione' ACTIVATION Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). Pubmed9536209 Reactome Database ID Release 431449719 Reactome, http://www.reactome.org ReactomeREACT_111908 'Corticotropin [cytosol]' positively regulates '11-deoxycortisol is oxidised to cortisol by CYP11B1' ACTIVATION Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of cortisol from the adrenal cortex (Bornstein and Chrousos, 1999). Pubmed10323408 Reactome Database ID Release 431449717 Reactome, http://www.reactome.org ReactomeREACT_111898 'Lutropin [extracellular region]' positively regulates 'Pregn-5-ene-3,20-dione isomerizes to progesterone' ACTIVATION Lutropin (LH) triggers ovulation and development of the corpus luteum, that in turn increases production of progesterone. Reactome Database ID Release 431449722 Reactome, http://www.reactome.org ReactomeREACT_111915 'SREBP1A/1C/2:NF-Y:TM7SF2 gene [nucleoplasm]' positively regulates 'Expression of TM7SF2' ACTIVATION Pubmed16784888 Pubmed20138239 Reactome Database ID Release 431655859 Reactome, http://www.reactome.org ReactomeREACT_148687 SREBF2 (SREBP2) binds the promoter of the TM7SF2 gene and enhances transcription (Bennati et al. 2006, Schiavone et al. 2010). 'SUMF2 [endoplasmic reticulum lumen]' negatively regulates 'SUMF1 mediates the oxidation of cysteine to formylglycine, producing active arylsulfatases' INHIBITION Reactome Database ID Release 431623971 Reactome, http://www.reactome.org ReactomeREACT_125706 'Lutropin [extracellular region]' positively regulates 'Reduction of androstenedione to testosterone' ACTIVATION In females, lutropin (LH) can trigger ovulation whereas in males it stimulates testosterone production, as shown here. Reactome Database ID Release 431433630 Reactome, http://www.reactome.org ReactomeREACT_111921 'Corticotropin [cytosol]' positively regulates 'Reduction of androstenedione to testosterone' ACTIVATION Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). Reactome Database ID Release 431449723 Reactome, http://www.reactome.org ReactomeREACT_111926 'OSBP [cytosol]' positively regulates 'CERT:ceramide [ER] => ceramide [Golgi] + CERT [ER]' ACTIVATION Reactome Database ID Release 43429728 Reactome, http://www.reactome.org ReactomeREACT_20492 'Corticotropin [cytosol]' positively regulates 'Testosterone is converted to 5-alpha-dihydroxytestosterone' ACTIVATION Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997). Reactome Database ID Release 431449720 Reactome, http://www.reactome.org ReactomeREACT_111929 G-protein beta-gamma complex positively regulates inhibition (closing) of Calcium Channels ACTIVATION Reactome Database ID Release 43400060 Reactome, http://www.reactome.org ReactomeREACT_19099 'G-protein alpha i/o:GTP Complex [plasma membrane]' positively regulates 'Opening of ATP-sensitive Potassium Channels by Gi/o alpha:GTP' ACTIVATION Reactome Database ID Release 43400078 Reactome, http://www.reactome.org ReactomeREACT_19096 'PKA catalytic subunit [cytosol]' positively regulates 'Closing of Potassium voltage-gated channels by PKA' ACTIVATION Protein kinase A acts to antagonize voltage-gated potassium channels (Kv channels) by increasing the polarizing voltage required to open them. Maintenance of the Kv channels in the closed state prolongs depolarization and insulin secretion. The exact mechanism of the interaction between PKA and the Kv channels is unknown. Pubmed12198249 Pubmed12475787 Pubmed17306374 Reactome Database ID Release 43422333 Reactome, http://www.reactome.org ReactomeREACT_19103 'PKA catalytic subunit [cytosol]' positively regulates 'Opening of ER calcium channels by activated PKA' ACTIVATION Activated Protein Kinase A promotes the release of calcium from the endoplasmic reticulum into the cytosol. This may be due to phosphorylation of ER calcium channels by PKA, however this has not been demonstrated. Pubmed12475787 Pubmed15569269 Pubmed17306374 Pubmed8830891 Reactome Database ID Release 43422336 Reactome, http://www.reactome.org ReactomeREACT_19105 'active STS dimer [endoplasmic reticulum membrane]' positively regulates 'Steryl sulfatase hydrolyses sulfate from steroid sulfates' ACTIVATION Reactome Database ID Release 431663719 Reactome, http://www.reactome.org ReactomeREACT_117938 'Adrenaline/Noradrenaline:Alpha-2A/2C Adrenergic Receptor Complex [plasma membrane]' positively regulates 'Activation of Gi/o Heterotrimeric G Proteins by Alpha Adrenergic Receptors Alpha-2A/2C' ACTIVATION Reactome Database ID Release 43660807 Reactome, http://www.reactome.org ReactomeREACT_23403 Vpr protein Converted from EntitySet in Reactome Reactome DB_ID: 173104 Reactome Database ID Release 43173104 Reactome, http://www.reactome.org ReactomeREACT_8643 Leptin Stimulates Secretion of GLP-1 ACTIVATION Pubmed12540594 Reactome Database ID Release 43400475 Reactome, http://www.reactome.org ReactomeREACT_24896 Fatty Acids Stimulate GLP-1 Secretion via GPR119 ACTIVATION Pubmed18202141 Reactome Database ID Release 43400505 Reactome, http://www.reactome.org ReactomeREACT_24891 'Epac2:cAMP Complex [plasma membrane]' positively regulates 'Exchange of GTP for GDP by Rap1A' ACTIVATION Epac1 and Epac2 are activated by binding cAMP and positively regulate the exchange of GDP for GTP by the small GTPase Rap1A. The downstream effects of Rap1A:GTP in beta cells are uncertain but may involve increasing the number of "restless newcomer" secretory granules near the plasma membrane and thereby increasing secretion of insulin.<br> Other effects of Rap1A :GTP may include regulating beta cell proliferation through activation of the Raf/MEK/ERK mitogenic cascade and activation of the PI3 Kinase/PDK/PKC cell growth pathway. Pubmed15569269 Pubmed16973695 Pubmed17306374 Reactome Database ID Release 43422330 Reactome, http://www.reactome.org ReactomeREACT_19100 'Epac1:cAMP Complex [plasma membrane]' positively regulates 'Exchange of GTP for GDP by Rap1A' ACTIVATION Epac1 and Epac2 are activated by binding cAMP and positively regulate the exchange of GDP for GTP by the small GTPase Rap1A. The downstream effects of Rap1A:GTP in beta cells are uncertain but may involve increasing the number of "restless newcomer" secretory granules near the plasma membrane and thereby increasing secretion of insulin.<br> Other effects of Rap1A :GTP may include regulating beta cell proliferation through activation of the Raf/MEK/ERK mitogenic cascade and activation of the PI3 Kinase/PDK/PKC cell growth pathway. Pubmed15569269 Pubmed16973695 Pubmed17306374 Reactome Database ID Release 43422328 Reactome, http://www.reactome.org ReactomeREACT_19102 Fatty Acids Stimulate GLP-1 Secretion via GPR120 ACTIVATION Pubmed15619630 Reactome Database ID Release 43400515 Reactome, http://www.reactome.org ReactomeREACT_24900 GPR40:Fatty Acid Complex Stimulates Secretion of GLP-1 ACTIVATION Pubmed17498508 Reactome Database ID Release 43416524 Reactome, http://www.reactome.org ReactomeREACT_24912 Acetylcholine Stimulates Secretion of GLP-1 ACTIVATION Pubmed17498508 Reactome Database ID Release 43400545 Reactome, http://www.reactome.org ReactomeREACT_24892 Gastric Releasing Peptide Stimulates Secretion of GLP-1 ACTIVATION Reactome Database ID Release 43400469 Reactome, http://www.reactome.org ReactomeREACT_24910 Fatty Acids Stimulate Secretion of GIP via GPR119 ACTIVATION Pubmed18202141 Reactome Database ID Release 43400531 Reactome, http://www.reactome.org ReactomeREACT_24907 Glucose Stimulates Secretion of GLP-1 ACTIVATION Pubmed17498508 Reactome Database ID Release 43400558 Reactome, http://www.reactome.org ReactomeREACT_24902 Gustducin Stimulates Secretion of GLP-1 from Intestinal L Cells ACTIVATION Pubmed18202141 Reactome Database ID Release 43400559 Reactome, http://www.reactome.org ReactomeREACT_24895 The G-protein coupled receptor Alpha-Gustducin is present in human intestinal L cells. The sweet taste receptors TIR2 and TIR3 are also detectable. Experiments in mice lacking Alpha-Gustducin show that it is required for stimulation of GLP-1 secretion by glucose. p51 subunit of RT Converted from EntitySet in Reactome Reactome DB_ID: 173778 Reactome Database ID Release 43173778 Reactome, http://www.reactome.org ReactomeREACT_8651 'PKA catalytic subunit [cytosol]' positively regulates 'Closing of Inward Rectifying, ATP-sensitive Potassium Channels (KATP channels)' ACTIVATION Activated PKA promotes the closing of inward rectifying potassium channels thus leading to depolarization of the plasma membrane of the beta cell and, via opening of voltage-gated calcium channels, causing exocytosis of insulin granules. PKA presumably acts by phosphorylating the potassium channel, but this is not certain. Pubmed12198249 Pubmed12475787 Pubmed17306374 Reactome Database ID Release 43422332 Reactome, http://www.reactome.org ReactomeREACT_19107 GPR40:Fatty Acid Complex Stimulates Secretion of GIP ACTIVATION Pubmed17498508 Reactome Database ID Release 43416525 Reactome, http://www.reactome.org ReactomeREACT_24909 'Epac2:cAMP Complex [plasma membrane]' positively regulates 'Closing of Inward Rectifying, ATP-sensitive Potassium Channels (KATP channels)' ACTIVATION Epac2 is activated by binding cAMP, forms a complex with inward rectifying ATP-sensitive potassium channels, ands acts to inhibit (close) the channels. Pubmed16613879 Pubmed18202100 Reactome Database ID Release 43446922 Reactome, http://www.reactome.org ReactomeREACT_21244 'Epac1:cAMP Complex [plasma membrane]' positively regulates 'Closing of Inward Rectifying, ATP-sensitive Potassium Channels (KATP channels)' ACTIVATION Epac1 is activated by binding cAMP, forms a complex with inward rectifying ATP-sensitive potassium channels, and acts to inhibit (close) the channels. Pubmed16613879 Pubmed18202100 Reactome Database ID Release 43446924 Reactome, http://www.reactome.org ReactomeREACT_21246 '1D-myo-Inositol 1,4,5-trisphosphate [cytosol]' positively regulates 'Release of calcium from intracellular stores by IP3 receptor activation' ACTIVATION Reactome Database ID Release 43111886 Reactome, http://www.reactome.org ReactomeREACT_23413 'Potassium Channel, open (pancreatic beta cell) [plasma membrane]' negatively regulates 'Exocytosis of Insulin' INHIBITION Pubmed12684222 Pubmed14514350 Pubmed17900700 Pubmed18162464 Pubmed7641683 Pubmed8997178 Reactome Database ID Release 43741372 Reactome, http://www.reactome.org ReactomeREACT_23414 The major effect of adrenaline and noradrenaline on insulin secretion is the inhibition of exocytosis of pre-existing insulin secretory granules. The inhibition occurs at a "distal site", that is, the effect is most pronounced on granules already near the cytosolic face of the plasma membrane. The effect is caused by the Gi/o alpha:GTP complex but the exact mechanism by which Gi/o alpha:GTP inhibits exocytosis is unknown. 'G-protein alpha i/o:GTP Complex [plasma membrane]' negatively regulates 'Exocytosis of Insulin' INHIBITION Pubmed12684222 Pubmed14514350 Pubmed17900700 Pubmed18162464 Pubmed7641683 Pubmed8997178 Reactome Database ID Release 43422251 Reactome, http://www.reactome.org ReactomeREACT_19097 The major effect of adrenaline and noradrenaline on insulin secretion is the inhibition of exocytosis of pre-existing insulin secretory granules. The inhibition occurs at a "distal site", that is, the effect is most pronounced on granules already near the cytosolic face of the plasma membrane. The effect is caused by the Gi/o alpha:GTP complex but the exact mechanism by which Gi/o alpha:GTP inhibits exocytosis is unknown. 'Voltage-gated Calcium Channels Type Cav1 (closed) [plasma membrane]' negatively regulates 'Exocytosis of Insulin' INHIBITION Pubmed12684222 Pubmed14514350 Pubmed17900700 Pubmed18162464 Pubmed7641683 Pubmed8997178 Reactome Database ID Release 43741369 Reactome, http://www.reactome.org ReactomeREACT_23409 The major effect of adrenaline and noradrenaline on insulin secretion is the inhibition of exocytosis of pre-existing insulin secretory granules. The inhibition occurs at a "distal site", that is, the effect is most pronounced on granules already near the cytosolic face of the plasma membrane. The effect is caused by the Gi/o alpha:GTP complex but the exact mechanism by which Gi/o alpha:GTP inhibits exocytosis is unknown. Calcium Released from Intracellular Stores Stimulates Secretion of Insulin ACTIVATION Intracellular calcium ions activate exocytosis of insulin-containing secretory granules by promoting fusion of the granule with the plasma membrane. Pubmed15914509 Pubmed17101212 Pubmed17130640 Reactome Database ID Release 43434319 Reactome, http://www.reactome.org ReactomeREACT_20495 'cAMP hydrolysis by PDE 4' negatively regulates 'cAMP induces dissociation of inactive PKA tetramers' INHIBITION Reactome Database ID Release 43111963 Reactome, http://www.reactome.org ReactomeREACT_5977 'cAMP hydrolysis by Cam-PDE 1' negatively regulates 'cAMP induces dissociation of inactive PKA tetramers' INHIBITION Reactome Database ID Release 43111958 Reactome, http://www.reactome.org ReactomeREACT_6083 INHBs Converted from EntitySet in Reactome Inhibin beta-subunits Reactome DB_ID: 1449655 Reactome Database ID Release 431449655 Reactome, http://www.reactome.org ReactomeREACT_111432 HAS1,2,3 Converted from EntitySet in Reactome Hyaluronan synthases 1,2,3 Reactome DB_ID: 2142875 Reactome Database ID Release 432142875 Reactome, http://www.reactome.org ReactomeREACT_121848 HA receptors Converted from EntitySet in Reactome Reactome DB_ID: 2160926 Reactome Database ID Release 432160926 Reactome, http://www.reactome.org ReactomeREACT_124198 N-glycan-protein Converted from EntitySet in Reactome Reactome DB_ID: 2046280 Reactome Database ID Release 432046280 Reactome, http://www.reactome.org ReactomeREACT_122505 ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43192026 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43192026 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org Syk phosphorylates Vav Authored: Akkerman, JW, 2009-09-04 EC Number: 2.7.10.2 Edited: Jupe, S, 2010-06-07 Pubmed11007481 Pubmed11262396 Pubmed17054426 Pubmed8986718 Reactome Database ID Release 43437936 Reactome, http://www.reactome.org ReactomeREACT_23793 Reviewed: Kunapuli, SP, 2010-06-07 Tyrosine phosphorylateion is believed to be a general activation mechansim for the Vav family. VAV1 Tyr-174 binds to the Dbl homology region, inhibiting GEF activity. Phosphorylation of this residue by Syk relieves inhibition, activating Vav1. In Jurkat cells T-cell receptor activation leads to increased Vav2 tyrosine phosphorylation; the expression of Lck, Fyn, Zap70, or Syk stimulated this phosphorylation. Vav is regulated downstream of the thrombin and thrombopoietin receptors (Miyakawa et al. 1997) and integrins, including the major platelet integrin alphaIIbbeta3. Vav family proteins are involved in filopodia and lamellipodia formation; mouse platelets deficient in Vav1 and Vav3 exhibit reduced filopodia and lamellipodia formation during spreading on fibrinogen. This is accompanied by reduced alphaIIbbeta3-mediated PLCgamma2 tyrosine phosphorylation and reduced Ca(2+) mobilization (Pearce et al. 2007). Syk binds Vav Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Reactome Database ID Release 43437932 Reactome, http://www.reactome.org ReactomeREACT_23954 Reviewed: Kunapuli, SP, 2010-06-07 The SH2 region of Vav1 binds to Syk at a site including phosphorylated tyrosine Y348. Mutation of this residue to F abolishes binding and subsequent Vav1 phosphorylation. Vav2 has also been shown to bind Syk. VAV2 is a GEF for Rho/Rac family kinases Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2009-09-09 Members of the Vav family are guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav2 is a GEF for RhoA, RhoB and RhoG, and possibly Rac1 and Cdc42 Pubmed15886116 Pubmed18589439 Pubmed8990121 Pubmed9032261 Reactome Database ID Release 43442291 Reactome, http://www.reactome.org ReactomeREACT_23806 Reviewed: Kunapuli, SP, 2010-06-07 VAV1 is a GEF for Rho/Rac family kinases Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2009-09-09 Pubmed15886116 Pubmed17054426 Pubmed18589439 Pubmed8990121 Pubmed9032261 Reactome Database ID Release 43442273 Reactome, http://www.reactome.org ReactomeREACT_24016 Reviewed: Kunapuli, SP, 2010-06-07 Vav family members are guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav1 is a GEF for Rac1, Rac2 and RhoG, and possibly RhoA and Cdc42 Syk/Lck phosphorylate LAT Activated Syk (or possibly the related kinase Lck) phosphorylates two key tyrosine residues of LAT. Authored: Akkerman, JW, 2009-09-04 EC Number: 2.7.10 Edited: Jupe, S, 2010-06-07 Pubmed11901197 Pubmed16102042 Pubmed16938345 Reactome Database ID Release 43434836 Reactome, http://www.reactome.org ReactomeREACT_23803 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 has a Stoichiometric coefficient of 2 VAV3 is a GEF for Rho/Rac family kinases Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed15886116 Pubmed18589439 Pubmed8990121 Pubmed9032261 Reactome Database ID Release 43442314 Reactome, http://www.reactome.org ReactomeREACT_23936 Reviewed: Kunapuli, SP, 2010-06-07 Vav3 is a guanine nucleotide exchange factors (GEF) for RhoA, RhoB and to a lesser extent Rac1. SLP-76 stimulates PLC gamma 2 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed10469124 Pubmed11050236 Pubmed12813055 Pubmed12832405 Reactome Database ID Release 43429497 Reactome, http://www.reactome.org ReactomeREACT_20573 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 SLP-76 has a well-established role in recruitment of PLC gamma 1 in immunoreceptor signalling; its role in the recruitment of PLC gamma 2 in integrin signalling is less clear. Results from SLP-76 null mice imply a functional role in GPVI signalling. Platelets from SLP-76 null mice exhibit a marked reduction in spreading and a decrease in whole cell phosphotyrosine levels when adhered to a fibrinogen-coated surface. In vivo reconstitution of SLP-76 by retroviral gene transfer corrects bleeding diathesis and restores normal responses to both collagen and fibrinogen (Judd et al., 2000). Syk activation leads to SLP-76 activation Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed10026222 Pubmed11050236 Pubmed11901197 Pubmed12555096 Pubmed16493428 Pubmed8702662 Pubmed9884330 Reactome Database ID Release 43429449 Reactome, http://www.reactome.org ReactomeREACT_20638 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Stimulation of platelets with collagen-related peptide leads to tyrosine phosphorylation of SLP-76, an adaptor protein with multiple binding domains (Gross et al. 1999). This may be mediated by Syk , analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996). The phosphorylated tyrosine residues provide a binding site for the SH2 domains of downstream signalling proteins like Vav, Itk and ADAP (Jordan et al. 2003). Platelets from mice defective in SLP76 do not connect GPVI engagement with downstream signaling (Clements et al. 1999, Judd et al. 2000). GPVI signaling via SLP-76 does not appear to require LAT or GADS (Judd et al. 2002) suggesting that the mechanism is not identical to that of T-cells. LAT and SLP-76 are both required for P-selectin expression and degranulation but may function independently, or rely on proteins not required by T-cells (Jordan et al. 2003). has a Stoichiometric coefficient of 3 PLC gamma 2-mediated PIP2 hydrolysis At the beginning of this reaction, 1 molecule of '1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate' is present. At the end of this reaction, 1 molecule of '1D-myo-Inositol 1,4,5-trisphosphate', and 1 molecule of '1,2-Diacylglycerol' are present.<br><br> This reaction is mediated by the 'phospholipase C activity' of 'Phosphorylated phospholipase C gamma 2'.<br> Edited: Jupe, S, 2009-09-09 Pubmed2841328 Reactome Database ID Release 43114689 Reactome, http://www.reactome.org ReactomeREACT_265 p-SLP-76 binds VAV Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed11262396 Pubmed11607831 Pubmed15708849 Pubmed8673706 Reactome Database ID Release 43430158 Reactome, http://www.reactome.org ReactomeREACT_20538 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 SLP-76 is a hematopoietic cell-specific adapter protein. Studies indicate that three phosphotyrosines in SLP-76 (Y113, Y128, and Y145) are required for interactions with the SH2 domains of Vav1 (and Nck and Itk). This interaction is essential for membrane recruitment of Vav1. Similarly, association of Vav3 with SLP-76 was found to be essential for membrane recruitment. Vav2 has been shown to interact with SLP-76 in resting Jurkat cells. GPVI stimulates PI3K beta, gamma Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2009-11-03 GPVI downstream signaling involves PI3K. Mouse knockouts of PI3Kbeta/PI3Kgamma suggest that though both isoforms are required for a full platelet response, only beta is absolutely required for Akt phosphorylation, Rap1 activation, and platelet aggregation downstream. The pathway connecting GPVI to PI3K is unclear. Two possible routes are suggested by interactions of the PI3K p85 regulatory subunit with LAT and with peptides representing the ITAM motif of Fc Epsilon R1 gamma. Pubmed19515725 Pubmed19700402 Pubmed9852111 Reactome Database ID Release 43437118 Reactome, http://www.reactome.org ReactomeREACT_20675 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 PIP2 inhibits Vav Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2009-11-03 Pubmed9438848 Reactome Database ID Release 43434633 Reactome, http://www.reactome.org ReactomeREACT_20604 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Vav interacts directly with PIP2 and PIP3, with a fivefold selectivity for PIP3 over PIP2. PIP3 gives a twofold stimulation of Vav1 GEF activity while PIP2 leads to 90% inhibition. Binding probably occurs through the PH domain, known to bind phosphoinositides. PIP3 stimulates Vav Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2009-11-03 Pubmed9438848 Reactome Database ID Release 43434637 Reactome, http://www.reactome.org ReactomeREACT_20577 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Vav interacts directly with PIP2 and PIP3, with a fivefold selectivity for PIP3 over PIP2. PIP3 gives a twofold stimulation of Vav1 GEF activity while PIP2 leads to 90% inhibition. Binding probably occurs through the PH domain, known to bind phosphoinositides. PDK1 activates PKC zeta 3-phosphoinositide dependent protein kinase-1 (PDK1, also known as PKB kinase because of its activity at Protein kinase B) phosphorylates T410 of Protein kinase C zeta type (PKC zeta), leading to activation. The motif surrounding T410 is highly conserved in other PKC family members suggesting that PDK1 might activate other PKCs. Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2009-11-03 Pubmed9768361 Reactome Database ID Release 43437195 Reactome, http://www.reactome.org ReactomeREACT_20600 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 PDK1 binds PKC zeta 3-phosphoinositide dependent protein kinase-1 (PDK1) and Protein kinase C zeta type (PKC zeta) are associated in fibroblasts. PDK1, also known as Protein kinase B kinase (PKBK), is known to co-localise with Protein kinase B (PKB) in transfected fibroblasts and platelets, suggesting a complex of PDK1, PKB and PKC zeta. Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2009-11-03 Pubmed11825911 Pubmed9768361 Reactome Database ID Release 43437192 Reactome, http://www.reactome.org ReactomeREACT_20552 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 PIP3 recruits PDK1 and AKT to the membrane Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Phosphatidylinositides generated by PI3K recruit phosphatidylinositide-dependent protein kinase 1 (PDK1) and AKT (also known as protein kinase B) to the membrane, through their PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation. In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied. Pubmed12167717 Pubmed17914025 Reactome Database ID Release 43198284 Reactome, http://www.reactome.org ReactomeREACT_12388 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 2 PI3K alpha, beta, gamma convert PIP2 to PIP3 Authored: Akkerman, JW, 2009-09-04 Class I Phosphoinositide 3-kinases (PI3Ks) are heterodimeric proteins, each having a catalytic subunit of 110-120 kDa and an associated regulatory subunit. PI3Ks alpha, beta and delta share a common regulatory p85 subunit, PI3K gamma has a p101 regulatory subunit. All the class I PI3Ks are able to phosphorylate PtdIns, PtdIns-4-P, or PtdIns-4,5-P2 (PIP2) on the free 3-position, and have a strong preference for PIP2.They are activated by receptor tyrosine kinases and by Ras and Rho family GTPases. EC Number: 2.7.1.153 Edited: Jupe, S, 2009-11-03 Pubmed17371249 Pubmed7624799 Pubmed8246984 Pubmed9759495 Reactome Database ID Release 43437162 Reactome, http://www.reactome.org ReactomeREACT_20608 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Translocation of RIAM to plasma membrane Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed12585966 Pubmed15469846 Pubmed16757337 Pubmed17624957 Pubmed18434644 Reactome Database ID Release 43354060 Reactome, http://www.reactome.org ReactomeREACT_15305 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 Upon the production of activated Rap1A at the plasma membrane, RIAM interacts with Rap1A-GTP with its N-ter RA domain, and with its C-ter PH domain it interacts with PIP2. Activation of Rap1 by membrane-associated GEFs Authored: Jupe, S, 2010-09-01 Edited: Jupe, S, 2010-09-01 Pubmed12585966 Pubmed15334074 Pubmed15469846 Pubmed16076873 Pubmed16757337 Reactome Database ID Release 43939265 Reactome, http://www.reactome.org ReactomeREACT_23833 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 Signals from agonist receptors (such as GPVI) trigger the production of PIP3, DAG, cAMP and elevated Ca++ levels. This leads to the activation and translocation of active Rap1-GTP to the plasma membrane. Rap-GEFs stimulate the replacement of GDP for GTP, activating Rap1. Several Rap1 GEFs have been identified enabling Rap1 to respond to diverse stimuli. CalDAG-GEFs activate Rap1 in response to calcium and DAG, downstream of Phospholipase C. EPAC (exchange proteins directly activated by cAMP) GEFs are activated by binding cAMP. Activation of Rap1 by cytosolic GEFs Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed12585966 Pubmed15334074 Pubmed15469846 Pubmed16076873 Pubmed16757337 Reactome Database ID Release 43354173 Reactome, http://www.reactome.org ReactomeREACT_15507 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 Signals from agonist receptors (such as GPVI) trigger the production of PIP3, DAG, cAMP and elevated Ca++ levels. This leads to the activation and translocation of active Rap1-GTP to the plasma membrane. Rap-GEFs stimulate the replacement of GDP for GTP, activating Rap1. Several Rap1 GEFs have been identified enabling Rap1 to respond to diverse stimuli. CalDAG-GEFs activate Rap1 in response to calcium and DAG, downstream of Phospholipase C. EPAC (exchange proteins directly activated by cAMP) GEFs are activated by binding cAMP. Dissociation of the TP:G13 complex Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43428918 Reactome, http://www.reactome.org ReactomeREACT_20559 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). Dissociation of the TP:Gq complex Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43428752 Reactome, http://www.reactome.org ReactomeREACT_20658 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). Thrombin-activated PAR binds G-protein Gq Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed8982657 Pubmed9296496 Reactome Database ID Release 43396996 Reactome, http://www.reactome.org ReactomeREACT_23902 Reviewed: Kunapuli, SP, 2010-06-07 Thrombin signalling through PARs is mediated in part through the Gq family of G-proteins. Gq knockout mice have defective platelet responses to thrombin (as well as to ADP and thromboxane). Thrombin-mediated activation of Proteinase-activated receptors EC Number: 3.4.21 Pubmed1672265 Pubmed9087410 Pubmed9618465 Reactome Database ID Release 43114697 Reactome, http://www.reactome.org ReactomeREACT_72 Thrombin signaling is mediated at least in part by a small family of G protein-coupled Proteinase Activated Receptors (PARs). Human platelet activation by thrombin is mediated predominantly by PAR1; PAR4-induced platelet responses are less pronounced. PAR2 is not present in human platelets. PARs 1, 3 and 4 are activated when thrombin cleaves an N-terminal exodomain. This cleavage event unmasks a new N-terminus that serves as a tethered ligand that binds intramolecularly to the body of the receptor to effect transmembrane signaling. Intermolecular ligation of one PAR molecule by another can occur but, not surprisingly, appears to be less efficient than self-ligation. A synthetic peptide of sequence SFLLRN, the first six amino acids of the new N-terminus generated when thrombin cleaves PAR1, can activate PAR1 independent of protease and receptor cleavage. In addition to providing evidence for the tethered ligand mechanism, such tethered ligand-mimicking peptides have provided a convenient pharmacological tool for probing the effects of PAR activation in cells and tissues. Activated PAR1 binds Beta-arrestin-1 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Following receptor activation, PAR1 complexes with beta-arrestin. Beta-arrestins are adaptor proteins that play a central role in GPCR desensitization and internalization, and also act as scaffolds for the formation of signalling complexes that are independent of G-protein signalling. Pubmed16580177 Pubmed17305471 Reactome Database ID Release 43418091 Reactome, http://www.reactome.org ReactomeREACT_23835 Reviewed: Kunapuli, SP, 2010-06-07 Dissociation of the PAR:G12/13 complex Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43397891 Reactome, http://www.reactome.org ReactomeREACT_23796 Reviewed: Jupe, S, 2010-06-07 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). has a Stoichiometric coefficient of 2 Dissociation of the PAR:Gq complex Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43397835 Reactome, http://www.reactome.org ReactomeREACT_23818 Reviewed: Kunapuli, SP, 2010-06-07 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). Gq activation by PAR Activated PAR stimulates the G alpha (q) subunit to release GDP and bind GTP (which is present in much greater concentrations physiologically). This activation is required for Gq to participate in downstream signalling events. Pubmed16102047 Reactome Database ID Release 43114558 Reactome, http://www.reactome.org ReactomeREACT_1430 G12/13 activation by PAR PAR1, 3 and 4 have been shown to directly couple with G12/13 (Offermanns et al. 1994). G12 and G13 have overlapping but distinct signalling roles (Suzuki et al. 2009). Evidence from conditional knockout mice (KOs) suggests that G13 is the subtype responsible for platelet shape change and aggregation responses in response to low and intermediate concentrations of thrombin, thromboxane and collagen. Platelets from G12 KOs were indistinguishable from wild-type, while those from mice with disrupted G13 had impaired shape change and aggregation responses, failed to form stable thrombi ex vivo, and exhibited a large increase in tailbleeding times (Moers et al. 2003). Both subtypes of G12/13 are unnecessary for platelet shape change and aggregation at higher agonist concentrations. The alpha-subunits of G12 and 13 bind RhoGEFs (guanine nucleotide exchange factors, which activate small G proteins) providing a path to Rho-mediated cytoskeletal responses that are involved in shape change in platelets and permeability and migration in endothelial cells.<br> Pubmed14528298 Pubmed16102047 Pubmed19212140 Pubmed8290554 Reactome Database ID Release 43114552 Reactome, http://www.reactome.org ReactomeREACT_637 Thrombin-activated PAR binds G-protein G12/13 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed15878870 Pubmed8290554 Pubmed9296496 Reactome Database ID Release 43396941 Reactome, http://www.reactome.org ReactomeREACT_23839 Reviewed: Kunapuli, SP, 2010-06-07 Thrombin receptors activate G-proteins in the G12/13 family. Gq knockout mice exhibit defective platelet activation, but retain shape change responses to thrombin, mediated by G12/13. Amine-derived hormones Authored: Jassal, B, 2008-10-01 13:18:42 Catecholamines and thyroxine are synthesized from tyrosine, and serotonin and melatonin from tryptophan. Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed10691773 Pubmed16942634 Pubmed3297964 Reactome Database ID Release 43209776 Reactome, http://www.reactome.org ReactomeREACT_15513 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Regulation of ornithine decarboxylase (ODC) Authored: Gopinathrao, G, 2008-05-19 18:50:15 GENE ONTOLOGYGO:0006521 Polyamines increase the production of antizyme (AZ). The carboxy-terminal half of antizyme interacts with ODC, generating an inactive AZ:ODC heterodimer complex. A carboxy-terminal domain of ODC is exposed only within the heterodimer, and is the target for subsequent degradation. A domain within the amino-terminal portion of antizyme provides a function needed for efficient degradation of ODC by the proteasome. <br>The proteasome cycle starts with the processing of AZ:ODC, sequestering ODC and then degrading it to peptides but releasing AZ. AZ participates in additional rounds of binding and degradation. Antizyme-mediated inhibition and destruction of ODC reduces synthesis of polyamines. Additionally, antizyme also inhibits polyamine transport into the cell. Antizyme production is reduced, completing the regulatory circuit (Coffino, 2001).<br>The following illustration is adapted from a minireview by Pegg, 2006; J. Biol. Chem., Vol. 281, Issue 21, 14529-14532. Pubmed10623564 Pubmed11265248 Pubmed16205122 Pubmed16459331 Reactome Database ID Release 43350562 Reactome, http://www.reactome.org ReactomeREACT_13565 Reviewed: D'Eustachio, P, 2008-06-12 17:57:32 Methionine salvage pathway Authored: Stephan, R, 2010-10-24 Edited: Jassal, B, 2011-03-30 GENE ONTOLOGYGO:0019509 Methionine salvage is a sequential pathway of six reactions that create methionine from 5'-methylthioadenosine (MTA) which is a byproduct of polyamine biosynthesis in nearly all organisms. The process happens completely in the cytosol. It is important in humans for recycling of sulphur that has to be assimilated using energy. (Pirkov et al, 2008; Albers, 2009) Pubmed18625006 Pubmed19946895 Reactome Database ID Release 431237112 Reactome, http://www.reactome.org ReactomeREACT_75881 Reviewed: D'Eustachio, P, 2011-05-23 Src bound to beta-arrestin-2 is not activated Activated PAR1 can induce the formation of signalling complexes with a beta-arrestin scaffold. When beta-arrestin-1 is incorporated this leads to Src and subsequent ERK activation. In contrast, complexes containing beta-arrestin-2 do not lead to Src and ERK activation. Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed16580177 Reactome Database ID Release 43418200 Reactome, http://www.reactome.org ReactomeREACT_23899 Reviewed: Kunapuli, SP, 2010-06-07 Activation of beta-arrestin-1-bound Src kinase Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed16580177 Pubmed9924018 Reactome Database ID Release 43418158 Reactome, http://www.reactome.org ReactomeREACT_23958 Reviewed: Kunapuli, SP, 2010-06-07 The activity of Src-kinase is increased when bound to Beta-arrestin-1. The mechanism for this activation is not clear. Src bound to beta -arrestin 1 is substantially dephosphorylated at Tyr530 and this is often associated with Src activation. Binding results with Y530F mutants of Src suggest that binding of Src to arrestin causes a conformational activation of the kinase, rather than a change in phosphorylation. However, increased phosphorylation of Src Tyr419 in cells overexpressing beta-arrestin-1 has been reported to correlate with PAR1 activation, beta-arrestin signalling complex formation, and increased ERK activation. Beta-arrestin-2 acts as scaffold for a PAR1 signalling complex Authored: Akkerman, JW, 2009-06-03 Beta-arrestins can serve as scaffolding molecules that facilitate G-protein independent cell signaling Edited: Kunapuli, SP, 2010-06-07 Pubmed16580177 Pubmed17305471 Reactome Database ID Release 43418176 Reactome, http://www.reactome.org ReactomeREACT_23960 Reviewed: Kunapuli, SP, 2010-06-07 Beta-arrestin-1 acts as scaffold for a PAR1 signalling complex Authored: Akkerman, JW, 2009-06-03 Beta-arrestins can serve as scaffolding molecules that facilitate G-protein independent cell signaling Edited: Jupe, S, 2010-06-07 Pubmed16580177 Pubmed17305471 Pubmed9924018 Reactome Database ID Release 43418170 Reactome, http://www.reactome.org ReactomeREACT_23781 Reviewed: Kunapuli, SP, 2010-06-07 Activated PAR1 binds beta-arrestin-2 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Following receptor activation, PAR1 complexes with beta-arrestin. Beta-arrestins are adaptor proteins that play a central role in GPCR desensitization and internalization, and also act as scaffolds for the formation of signalling complexes that are independent of G-protein signalling. Pubmed16580177 Pubmed17305471 Reactome Database ID Release 43418172 Reactome, http://www.reactome.org ReactomeREACT_23805 Reviewed: Kunapuli, SP, 2010-06-07 Urea cycle Authored: D'Eustachio, P, 2003-06-24 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0000050 ISBN0079130356 Reactome Database ID Release 4370635 Reactome, http://www.reactome.org ReactomeREACT_847 The urea cycle yields urea, the major form in which excess nitrogen is excreted from the human body, and the amino acid arginine (Brusilow and Horwich 2001). It consists of four reactions: that of ornithine and carbamoyl phosphate to form citrulline, of citrulline and aspartate to form argininosuccinate, the cleavage of argininosuccinate to yield fumarate and arginine, and the cleavage of arginine to yield urea and re-form ornithine. The carbamoyl phosphate consumed in this cycle is synthesized in the mitochondria from bicarbonate and ammonia, and this synthesis in turn is dependent on the presence of N-acetylglutamate, which allosterically activates carbamoyl synthetase I enzyme. The synthesis of N-acetylglutamate is stimulated by high levels of arginine. Increased levels of free amino acids, indicated by elevated arginine levels, thus stimulate urea synthesis.<p>Two enzymes catalyze the hydrolysis of arginine to yield ornithine and urea. Cytosolic ARG1 is the canonical urea cycle enzyme. Mitochondrial ARG2 likewise catalyzes urea production from arginine and may have a substantial sparing effect in patients lacking ARG1 enzyme, so its reaction is annotated here although the role of ARG2 under normal physiological conditions remains unclear. Urea synthesis Carnitine synthesis Authored: 2003-04-29 00:00:00 Carnitine is synthesized in four steps from trimethyllysine (generated in turn by the S-adenosyl-methionine-mediated methylation of lysine residues in proteins, followed by protein hydrolysis). The enzymes that catalyze the first three steps of carnitine synthesis, converting trimethyllysine to gamma-butyrobetaine, are widely distributed in human tissues. The enzyme that catalyzes the last reaction, converting gamma-butyrobetaine to carnitine, is found only in liver and kidney cells, and at very low levels in brain tissues. Other tissues that require carnitine, such as muscle, are dependent on transport systems that mediate its export from the liver and uptake by other tissues (Kerner and Hoppel 1998). Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0045329 Pubmed9706223 Reactome Database ID Release 4371262 Reactome, http://www.reactome.org ReactomeREACT_2125 Tryptophan catabolism Authored: D'Eustachio, P, 2005-07-20 13:46:37 Edited: D'Eustachio, P, 2005-07-20 13:46:37 GENE ONTOLOGYGO:0006569 Pubmed1772073 Reactome Database ID Release 4371240 Reactome, http://www.reactome.org ReactomeREACT_916 Tryptophan is catabolized in seven steps to yield aminomuconate. Intermedistes in this process are used as well for the synthesis of serotonin and kynurenine (Peters 1991). Syk is released Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed18689684 Pubmed8617742 Pubmed9099676 Reactome Database ID Release 43453183 Reactome, http://www.reactome.org ReactomeREACT_23764 Reviewed: Kunapuli, SP, 2010-06-07 Structural and biophysical studies indicate that the adaptability of the Syk tandem SH2 domains is made possible by relatively weak interactions between the two SH2 domains and the flexibility of interdomain A (Zhang et al. 2008). A large proportion of phosphorylated Syk is released into the cytosol. One factor that has been proposed for modulating the interactions of Syk with the receptor ITAM is the phosphorylation of Syk on Y130 (Keshvara et al. 1997). Agmatine biosynthesis Agmatine is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine. Agmatine binds to several target receptors in the brain and has been proposed as a novel neuromodulator (Reghunathan 2006). Agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in inflammation (Satriano, 2003). Authored: Gopinathrao, G, 2008-05-21 17:26:32 Edited: Gopinathrao, G, 2006-04-27 13:13:48 GENE ONTOLOGYGO:0097055 Pubmed15028567 Pubmed15028568 Pubmed15784477 Pubmed17025265 Reactome Database ID Release 43351143 Reactome, http://www.reactome.org ReactomeREACT_14800 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Syk autophosphorylates Authored: Akkerman, JW, 2009-09-04 Binding of Syk causes conformational changes that lead to Syk activation by autophosphorylation. Syk can be activated by a number of phosphorylation events, and it has been proposed that Syk may function as a switch whereby any of several possible stimuli trigger the acquisition of similar activated conformations. (Tsang et al. 2008). These phosphorylations both modulate Syk's catalytic activity (Keshvara et al. 1997) and generate docking sites for SH2 domain-containing proteins, such as c-Cbl, PLC, and Vav1. EC Number: 2.7.10.2 Edited: Jupe, S, 2010-06-07 Pubmed11481033 Pubmed1874735 Pubmed18818202 Pubmed19409513 Pubmed9099676 Reactome Database ID Release 43453200 Reactome, http://www.reactome.org ReactomeREACT_23800 Reviewed: Kunapuli, SP, 2010-06-07 Interconversion of polyamines Authored: Gopinathrao, G, 2008-05-21 17:26:32 Edited: Gopinathrao, G, 2006-04-27 13:13:48 GENE ONTOLOGYGO:0006596 Pubmed11564948 Pubmed12686127 Pubmed15221502 Pubmed15784477 Reactome Database ID Release 43351200 Reactome, http://www.reactome.org ReactomeREACT_14805 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 The reactions catalyzed by aminopropyl-transferases annotated above are generally irreversible. But spermine and spermidine can be recycled respectively into spermidine and putrescine. These events require the formation of N-acetylated intermediates, N1-acetylspermine and N1-acetylspermidine catalyzed by a cytosolic acetyl-CoA:spermidine/spermine N1-acetyl-tranferase (SSAT) enzyme.<br>Subsequently, polyamine-oxidase (PAO), a FAD enzyme present in the peroxysomes, yields a polyamine with release of an aldehyde (3-acetamindopropanal) and H2O2.<br>In addition, SMOX, a FAD-dependent, polyamine oxidase (PAOh1/SMO) that can efficiently use spermine as a substrate and is involved in interconversion reactions. Binding of Syk tyrosine kinase Pubmed10669724 Reactome Database ID Release 43139842 Reactome, http://www.reactome.org ReactomeREACT_2221 Syk binds to the phosphorylated ITAM motif of Fc epsilon R1 gamma chain, each SH2 domain binding a phosphorylated tyrosine. Unlike Zap70, Syk appears to autophosphorylate, so does not require Src family kinases for activation. Creatine metabolism Authored: 2003-04-23 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006600 In humans, creatine is synthesized primarily in the liver and kidney, from glycine, arginine, and S-adenosylmethionine, in a sequence of two reactions. From the liver, creatine is exported to tissues such as skeletal muscle and brain, where it undergoes phosphorylation and serves as a short-term energy store. The mechanism by which creatine leaves producer tissues is unclear, but its uptake by consumer tissues is mediated by the SLC6A8 transporter.<P>Once formed, phosphocreatine undergoes a slow spontaneous reaction to form creatinine, which is excreted from the body. Pubmed10893433 Pubmed9706223 Reactome Database ID Release 4371288 Reactome, http://www.reactome.org ReactomeREACT_813 Fyn/Lyn-mediated phosphorylation of FcR1 gamma At the beginning of this reaction, 1 molecule of 'GP VI:Fc Epsilon R1 gamma:Collagen IV complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'GP VI:phosphorylated Fc Epsilon R1 gamma:Collagen IV complex' are present.<br><br> This reaction is mediated by the 'protein-tyrosine kinase activity' of 'GP VI: Fc Epsilon R1 gamma: Collagen IV: SRC'.<br> EC Number: 2.7.10 Pubmed9028946 Reactome Database ID Release 43114600 Reactome, http://www.reactome.org ReactomeREACT_191 has a Stoichiometric coefficient of 2 Metabolism of polyamines Authored: Gopinathrao, G, 2008-05-21 17:26:32 GENE ONTOLOGYGO:0006595 Polyamines is a family of molecules (i.e. putrescine, spermine, spermidine) derived from ornithine according to a decarboxylation/condensative process. More recently, it has been demonstrated that arginine can be metabolised according to the same pathway leading to agmatine formation. Polyamines are essential for the growth, the maintenance and the function of normal cells. The complexity of their metabolism and the fact that polyamines homeostasis is tightly regulated support the idea that polyamines are essential to cell survival. Multiple abnormalities in the control of polyamines metabolism might be implicated in several pathological processes (Moinard et al., 2005). Legend for the following figure: Pubmed11564948 Pubmed12686127 Pubmed15784477 Reactome Database ID Release 43351202 Reactome, http://www.reactome.org ReactomeREACT_14820 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Activated Src activates ERK Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed16580177 Pubmed9228083 Reactome Database ID Release 43418163 Reactome, http://www.reactome.org ReactomeREACT_23900 Reviewed: Kunapuli, SP, 2010-06-07 Within the beta-arrestin-1:Src:ERK complex, activated Src phosphorylates and activates ERK. ERK activation requires dual Thr and Tyr phosphorylations, at Thr202/Tyr204 for human ERK1 and Thr185/Tyr187 for human ERK2. Significant ERK activation requires phosphorylation at both sites, with Tyr phosphorylation preceding that of Thr. This reaction is given as a black-box event because the phosphorylation state of ERK on binding to beta-arrestin-1 is unknown. ACTIVATION GENE ONTOLOGYGO:0004507 Reactome Database ID Release 43193999 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050327 Reactome Database ID Release 43193120 Reactome, http://www.reactome.org GPIb-IX-V binding to 14-3-3 zeta is reduced by shear stress Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 High shear stress, or immobilization of VWF under high shear conditions induce VWF binding to GPIb-IX-V. This activation mechanism is believed to involve shear-stress induced conformational changes in vWF. Pubmed10627461 Pubmed2010539 Pubmed8631758 Reactome Database ID Release 43430073 Reactome, http://www.reactome.org ReactomeREACT_23970 Reviewed: Kunapuli, SP, 2010-06-07 ACTIVATION GENE ONTOLOGYGO:0003865 Reactome Database ID Release 43469661 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004508 Reactome Database ID Release 43193113 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004508 Reactome Database ID Release 43193113 Reactome, http://www.reactome.org Histidine catabolism Authored: D'Eustachio, P, 2003-06-24 00:00:00 Edited: D'Eustachio, P, 2003-06-24 00:00:00 GENE ONTOLOGYGO:0006548 Pubmed5057083 Reactome Database ID Release 4370921 Reactome, http://www.reactome.org ReactomeREACT_1249 The major pathway of histidine catabolism, annotated here, proceeds in four steps to yield glutamate and, in the process, convert one molecule of tetrahydrofolate to 5-formiminotetrahydrofolate (Morris et al. 1972). Histidine can also be decarboxylated to form histamine. ACTIVATION GENE ONTOLOGYGO:0004508 Reactome Database ID Release 43193113 Reactome, http://www.reactome.org Lysine catabolism Authored: D'Eustachio, P, 2003-06-24 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006554 ISBN0079130356 In humans, most catabolism of L-lysine normally proceeds via a sequence of seven reactions which feeds into the pathway for fatty acid catabolism. In the first two reactions, catalyzed by a single enzyme complex, lysine is combined with alpha-ketoglutarate to form saccharopine, which in turn is cleaved and oxidized to yield glutamate and alpha-ketoadipic semialdehyde. The latter molecule is further oxidized to alpha-ketoadipate. Alpha-ketoadipate is oxidatively decarboxylated by the alpha-ketoglutarate dehydrogenase complex (the same enzyme complex responsible for the conversion of alpha-ketoglutarate to succinyl-CoA in the citric acid cycle), yielding glutaryl-CoA. Glutaryl-CoA is converted to crotonyl-CoA, crotonyl-CoA is converted to beta-hydroxybutyryl-CoA, and beta-hydroxybutyryl-CoA is converted to acetoacetyl-CoA. The products of lysine catabolism are thus exclusively ketogenic; i.e., under starvation conditions they can be used for the synthesis of ketone bodies, beta-hydroxybutyrate and acetoacetate, but not for the net synthesis of glucose (Cox 2001; Goodman and Freeman 2001). Pubmed12126930 Pubmed6434529 Reactome Database ID Release 4371064 Reactome, http://www.reactome.org ReactomeREACT_1298 ACTIVATION GENE ONTOLOGYGO:0004769 Reactome Database ID Release 43193169 Reactome, http://www.reactome.org Phenylalanine and tyrosine catabolism Authored: D'Eustachio, P, 2003-06-24 00:00:00 Edited: D'Eustachio, P, 2003-06-24 00:00:00 GENE ONTOLOGYGO:0006559 ISBN0079130356 Reactome Database ID Release 4371182 Reactome, http://www.reactome.org ReactomeREACT_1786 The first reaction in this pathway converts phenylalanine to tyrosine, coupled to the conversion of tetrahydrobiopterin to 4a-hydroxytetrahydrobiopterin, catalyzed by phenylalanine hydroxylase. (Deficiencies in this enzyme are responsible for the commonest form of phenylketonuria (PKU) in humans.) This reaction functions both as the first step in the pathway by which the body disposes of excess phenylalanine, and as a source of the amino acid tyrosine. The next two reactions are responsible for the regeneration of tetrahydrobiopterin from 4a-hydroxytetrahydrobiopterin. The following five reactions convert tyrosine to fumarate, an intermediate in the citric acid cycle, and acetoacetate, a ketone body. ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43193967 Reactome, http://www.reactome.org Proline catabolism Authored: D'Eustachio, P, 2003-06-24 00:00:00 Edited: D'Eustachio, P, 2003-06-24 00:00:00 GENE ONTOLOGYGO:0006562 ISBN0079130356 Proline is catabolized in two steps to yield L-glutamate gamma-semialdehyde, which can react further with glutamate to yield ornithine and alpha-ketoglutarate (annotated as a reaction of amino acid synthesis and interconversion) or with NAD+ to yield glutamate and NADH + H+ (Phang et al. 2001). Reactome Database ID Release 4370688 Reactome, http://www.reactome.org ReactomeREACT_1002 ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43193967 Reactome, http://www.reactome.org Amino acid synthesis and interconversion (transamination) Authored: 2003-04-29 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008652 Reactome Database ID Release 4370614 Reactome, http://www.reactome.org ReactomeREACT_238 These reactions mediate the synthesis of aspartate, asparagine, glutamate, and glutamine from ammonia and intermediates of glycolysis, and allow the utilization of the carbon atoms from these four amino acids for glucose synthesis under fasting conditions.<P>These reactions also provide a means to collect nitrogen, both as ammonia and as amino groups, and direct it towards urea synthesis. Transamination, the conversion of an amino acid to the corresponding alpha-keto acid coupled to the conversion of a molecule of alpha-ketoglutarate to glutamate, is the first step in the catabolism of most amino acids. Transamination reactions are freely reversible so they also provide a means to balance concentrations of various amino acids and alpha-keto (2-oxo) acids in the cytosol. GP1b signaling involves c-Src Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed10224142 Pubmed11389024 Pubmed12324454 Pubmed12393736 Pubmed14656219 Pubmed14726383 Pubmed16102041 Pubmed7523416 Reactome Database ID Release 43443418 Reactome, http://www.reactome.org ReactomeREACT_24010 Reviewed: Kunapuli, SP, 2010-06-07 Src and its downstream signaling molecule PLC gamma 2 are implicated in GPIb-IX-V (GPIbR) signalling. GPIbR-mediated platelet activation correlates with cytoskeletal association of Src, activation of PI3K and the appearance of multiple tyrosine-phosphorylated proteins (Jackson et al. 1994). von Willebrand Factor (vWF) and the vWF modulator botrocetin induce tyrosine phosphorylation of FceRIgamma, Syk, LAT and PLCgamma2. Src kinase inhibition markedly suppresses these events (Wu et al. 2001). Src and Lyn form a complex with FceRIgamma and Syk upon GPIbR/vWF interaction (Wu et al. 2003). FcgammaRIIa was tyrosine phosphorylated upon vWF and ristocetin-induced-platelet activation, followed by Syk and PLCgamma2 activation. A selective Src kinase inhibitor inhibited these events (Torti et al. 1994).<br> Though a considerable body of evidence suggests Src as a signaling molecule downstream of GPIbR the mechanism that connects Src to GPIbR is not clear. There are obvious similarities with the GPIV signal transduction pathway but also important differences: Src appears to be recruited to GPIbR upon platelet activation, while Lyn and Fyn constitutively associate with GPVI; GPVI activation induces a robust level of inositol phosphate production and PLCgamma2 activity, while GPIbRactivation PLCgamma2 activation is modest and the tyrosine phosphorylation sites of PLCgamma2 are distinct from those of GPVI stimulation (Suzuki-Inoue et al. 2004). GPVI signalling requires the FCeRIgamma chain while mouse knockouts suggest it is not required for GPIbR signalling (Kaiser-Friede et al. 2004).<br> Studies on GPIbalpha transgenic mice suggested that GPIbR activates AlphaIIbBeta3 Integrin through Src and PLC gamma2 activation (Kaiser-Friede et al. 2004). An alternative suggested mechansim is indirect association via 14-3-3-zeta and the p85 subunit of PI3K; the p85 subunit of PI3K constitutively associates with GPIbR so upon vWF/GPIb-IX-V interaction can bind Src via its SH3 domain (Wu et al. 2003).<br> Although many studies support a role for Src signaling in vWF/GPIb induced platelet activation, Src-independent platelet activation has been reported for platelets spreading on surfaces coated with echicetin, a GPIb-cross-linking component of snake venom (Navdaev & Clemetson, 2002). Amino acid and derivative metabolism Authored: D'Eustachio, P, 2003-11-03 05:38:33 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0034641 Metabolism of amino acids and derivatives Reactome Database ID Release 4371291 Reactome, http://www.reactome.org ReactomeREACT_13 This group of reactions is responsible for: 1) the breakdown of amino acids; 2) the synthesis of urea from ammonia and amino groups generated by amino acid breakdown; 3) the synthesis of the ten amino acids that are not essential components of the human diet; and 4) the synthesis of related nitrogen-containing molecules including carnitine and creatine.<p>Transport of these molecuels across lipid bilayer membranes is annotated separately as part of the module on "transmembrane transport of small molecules". c-Src binds Raf1 Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed18494562 Pubmed7517401 Pubmed7692235 Pubmed9171352 Reactome Database ID Release 43443439 Reactome, http://www.reactome.org ReactomeREACT_23808 Reviewed: Kunapuli, SP, 2010-06-07 c-Src binds to Raf1, the interaction involves the SH2 and SH3 domains of c-Src and requires serine phosphorylation of Raf1. Coexpression of Raf1 and c-Src in Sf9 cells results in c-Src/Raf-1 complexes, tyrosine phosphorylation of Raf-1, and stimulation of Raf-1 kinase activity. Tyr-340 and Tyr-341 were found to be the major tyrosine phosphorylation sites of Raf1 when coexpressed with activated tyrosine kinases. However, the significance of tyrosine phosphorylation under physiological conditions remains unclear, as tyrosine phosphorylation of endogenous Raf-1 following activation has been disputed and may be limited to cells of hematopoietic origin. Branched-chain amino acid catabolism Authored: D'Eustachio, P, 2003-06-24 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0009083 ISBN0079130356 Reactome Database ID Release 4370895 Reactome, http://www.reactome.org ReactomeREACT_197 The branched-chain amino acids, leucine, isoleucine, and valine, are all essential amino acids (i.e., ones required in the diet). They are major constituents of muscle protein. The breakdown of these amino acids starts with two common steps catalyzed by enzymes that act on all three amino acids: reversible transamination by branched-chain amino acid aminotransferase, and irreversible oxidative decarboxylation by the branched-chain ketoacid dehydrogenase complex. Isovaleryl-CoA is produced from leucine by these two reactions, alpha-methylbutyryl-CoA from isoleucine, and isobutyryl-CoA from valine. These acyl-CoA's undergo dehydrogenation, catalyzed by three different but related enzymes, and the breakdown pathways then diverge. Leucine is ultimately converted to acetyl-CoA and acetoacetate; isoleucine to acetyl-CoA and succinyl-CoA; and valine to succinyl-CoA. Under fasting conditions, substantial amounts of all three amino acids are generated by protein breakdown. In muscle, the final products of leucine, isoleucine, and valine catabolism can be fully oxidized via the citric acid cycle; in liver they can be directed toward the synthesis of ketone bodies (acetoacetate and acetyl-CoA) and glucose (succinyl-CoA) (Chuang & Shih 2001, Sweetman & Williams 2001). 14-3-3-zeta binds Raf1 14-3-3 family proteins can bind Raf1 and have been suggested to activate Raf1, but this has been refuted. Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed7760835 Pubmed7935795 Reactome Database ID Release 43443831 Reactome, http://www.reactome.org ReactomeREACT_23766 Reviewed: Kunapuli, SP, 2010-06-07 Serine biosynthesis Authored: Stephan, R, 2010-10-16 Edited: Jassal, B, 2010-10-18 GENE ONTOLOGYGO:0006564 L-Serine is needed in human brain in large amounts as precursor to important biomolecules such as nucleotides, phospholipids and the neurotransmitters glycine and D-serine. The pathway for its synthesis starts with 3-phosphoglycerate and it later needs glutamate as an amination agent. Deficiencies in the participating enzymes lead to severe neurological symptoms that are treatable with serine if treatment starts early (de Koning & Klomp 2004). Pubmed15021249 Reactome Database ID Release 43977347 Reactome, http://www.reactome.org ReactomeREACT_115789 Reviewed: D'Eustachio, P, 2011-10-26 ADP binds to P2Y purinoceptor 12 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 P2RY12 is one of two ADP receptors expressed in platelets. P2Y12 activation leads to irreversible platelet aggregation. Defects in this receptor are associated with bleeding disorders. Pubmed11196645 Reactome Database ID Release 43392180 Reactome, http://www.reactome.org ReactomeREACT_20574 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Activated P2Y purinoceptor 12 binds G-protein Gi Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed11196645 Reactome Database ID Release 43392187 Reactome, http://www.reactome.org ReactomeREACT_20523 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The activated receptor binds the inactive, GDP-bound form of the heterotrimeric G-protein Gi. Gi activation by P2Y purinoceptor 12 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed11196645 Pubmed8554519 Reactome Database ID Release 43392195 Reactome, http://www.reactome.org ReactomeREACT_20507 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The G-protein alpha subunit exchanges GDP for GTP Molybdenum cofactor biosynthesis Authored: Stephan, R, 2010-09-05 Edited: Jassal, B, 2010-09-08 GENE ONTOLOGYGO:0032324 Molybdenum cofactor (MoCo) is needed by three enzymes in humans: sulfite oxidase, xanthine oxidase and aldehyde oxidase. The pathway of its synthesis is so conserved that plants and bacteria can readily use human enzymes. Bacteria, however, diverge after the first three steps from this path and their final MoCo differs from that of the eukaryotes. Plants and animals have also developed a refinement of their MoCo which is needed for the function of their xanthine and aldehyde oxidases. This means, in humans we find sulfurated instead of desulfurated molybdenum cofactor on these two enzymes (Schwarz 2005; Schwarz, Mendel, Ribbe 2009). Pubmed16261263 Pubmed19675644 Reactome Database ID Release 43947581 Reactome, http://www.reactome.org ReactomeREACT_25073 Reviewed: D'Eustachio, P, 2010-11-05 Dissociation of the P2Y purinoceptor 12:Gi complex Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43392202 Reactome, http://www.reactome.org ReactomeREACT_20630 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). ACTIVATION GENE ONTOLOGYGO:0004509 Reactome Database ID Release 43194007 Reactome, http://www.reactome.org Metabolism of folate and pterines Folates are essential cofactors that provide one-carbon moieties in various states of reduction for biosynthetic reactions. Processes annotated here include transport reactions by which folates are taken up by cells and moved intracellularly, folate conjugation with glutamate (required for folate retention within a cell), and some of the key reactions in the generation of reduced folates and one-carbon derivatives of folate. GENE ONTOLOGYGO:0046655 Pubmed10466189 Pubmed11001804 Reactome Database ID Release 43196757 Reactome, http://www.reactome.org ReactomeREACT_11167 ADP binds to P2Y purinoceptor 1 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed9038354 Pubmed9442040 Reactome Database ID Release 43418580 Reactome, http://www.reactome.org ReactomeREACT_20590 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Two platelet ADP receptors, P2Y1 and P2Y12, initiate platelet activation when stimulated in concert. Both are heterotrimeric G-protein-coupled receptors; P2Y1 signals through Gq while P2Y12 signals through Gi. Stimulation of P2Y1 leads to intracellular calcium mobilization and platelet shape change. ACTIVATION GENE ONTOLOGYGO:0004769 Reactome Database ID Release 43193169 Reactome, http://www.reactome.org GP1b-IX-V binds filamin Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 GP1b-IX-V interacts with filamin-1; within the cytoplasmic domain of GP1b alpha amino acids 557-568 and 569-579 are critical for this association. GPIb-filamin-1 association links the receptor complex to the membrane skeleton and has been proposed to regulate the ability of GPIb-IX-V to adhere to vWf under conditions of high shear. Pubmed10037692 Pubmed11700320 Pubmed3155520 Reactome Database ID Release 43430096 Reactome, http://www.reactome.org ReactomeREACT_23834 Reviewed: Kunapuli, SP, 2010-06-07 GP1b-IX-V:13-3-3-zeta complexes with p85 PI3K Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed10887121 Pubmed16102041 Reactome Database ID Release 43443402 Reactome, http://www.reactome.org ReactomeREACT_23952 Resting platelets contain a heterotrimeric complex of GPIb-IX-V, 14-3-3-zeta and the p85 subunit of PI-3K. While GPIb-IX-V has no apparent binding sites for PI3K so the interaction with p85 is likely to be mediated by 14-3-3-zeta. Reviewed: Kunapuli, SP, 2010-06-07 ACTIVATION GENE ONTOLOGYGO:0004509 Reactome Database ID Release 43194007 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004507 Reactome Database ID Release 43193999 Reactome, http://www.reactome.org Nicotinamide salvaging GENE ONTOLOGYGO:0006769 Nicotinamide levels are modulated by the action of three enzymes involved in nicotinamide salvaging. They are nicotinamide deaminase, nicotinamide phosphoribosyltransferase and nicotinate phosphoribosyltransferase. These enzymes are poorly characterized in humans, depsite their importance in nicotinamide utilization. Pubmed14704851 Reactome Database ID Release 43197264 Reactome, http://www.reactome.org ReactomeREACT_11213 ACTIVATION GENE ONTOLOGYGO:0003845 Reactome Database ID Release 43193976 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003854 Reactome Database ID Release 43196330 Reactome, http://www.reactome.org Biotin metabolism Authored: Jassal, B, 2007-04-24 08:38:46 Biotin is an essential cofactor in a variety of carboxylation reactions. It is abundant in the human diet, and can be taken up from the intestinal lumen by the SLC5A6 transporter (Zempleni et al. 2009). Its covalent attachment to carboxylase enzymes is catalyzed by the HLCS enzyme in a reaction to be annotated in a future release of Reactome. GENE ONTOLOGYGO:0006768 Pubmed19319844 Reactome Database ID Release 43196780 Reactome, http://www.reactome.org ReactomeREACT_11153 ACTIVATION GENE ONTOLOGYGO:0004032 Reactome Database ID Release 43196106 Reactome, http://www.reactome.org Nicotinate metabolism GENE ONTOLOGYGO:0019674 Nicotinate (niacin) and nicotinamide are precursors of the coenzymes nicotinamide-adenine dinucleotide (NAD+) and nicotinamide-adenine dinucleotide phosphate (NADP+). When NAD+ and NADP+ are interchanged in a reaction with their reduced forms, NADH and NADPH respectively, they are important cofactors in several hundred redox reactions. Nicotinate is synthesized from 2-amino-3-carboxymuconate semialdehyde, an intermediate in the catabolism of the essential amino acid tryptophan. Pubmed14704851 Reactome Database ID Release 43196807 Reactome, http://www.reactome.org ReactomeREACT_11088 ACTIVATION GENE ONTOLOGYGO:0004508 Reactome Database ID Release 43193113 Reactome, http://www.reactome.org Coenzyme A biosynthesis Authored: Jassal, B, 2007-04-24 08:38:46 Coenzyme A (CoA) is a ubiquitous cofactor that functions as an acyl group carrier in diverse processes including fatty acid metabolism and the TCA cycle (Lipmann 1953). It is synthesized from the vitamin pantothenate in a sequence of five reactions (Daugherty et al. 2002; Leonardi et al. 2005; Robishaw and Neely 1985). These reactions all occur in the cytosol or the mitochondrial intermembrane space (Leonardi et al. 2005). A recently described transport protein appears to mediate the uptake of Coenzyme A into the mitochondrial matrix (Prohl et al. 2001). GENE ONTOLOGYGO:0009108 Pubmed11158296 Pubmed11923312 Pubmed13032008 Pubmed15893380 Pubmed2981478 Reactome Database ID Release 43196783 Reactome, http://www.reactome.org ReactomeREACT_11218 ACTIVATION GENE ONTOLOGYGO:0003854 Reactome Database ID Release 43196330 Reactome, http://www.reactome.org Vitamins B6 activation to pyridoxal phosphate Animals cannot synthesize pyridoxal 5'-phosphate (PLP) which is a ligand in aminotransferases and other enzymes. PLP's accessible derivatives pyridoxine, pyridoxal, and pyridoxamine are traditionally called vitamins B6. They are taken up nutritionally from bacteria and plants, but also created from PLP in the body. The pathways used to recycle PLP from these three compounds can therefore be called vitamin B6 activation as well as PLP salvage. Because of the close similarity of the molecules, only two enzymes are needed for the task (McCormick & Chen, 1999). Authored: Stephan, R, 2010-09-16 Edited: Jassal, B, 2010-09-20 GENE ONTOLOGYGO:0042816 Pubmed10024608 Reactome Database ID Release 43964975 Reactome, http://www.reactome.org ReactomeREACT_25012 Reviewed: D'Eustachio, P, 2010-11-08 ACTIVATION GENE ONTOLOGYGO:0004769 Reactome Database ID Release 43193169 Reactome, http://www.reactome.org Vitamin B5 (pantothenate) metabolism Authored: D'Eustachio, P, 2007-07-09 22:03:12 GENE ONTOLOGYGO:0015939 Panthothenate (vitamin B5) is the precursor of coenzyme A (Robishaw and Neely 1985) and is the prosthetic group of acyl carrier protein (ACP) (Joshi et al. 2003). Its name is derived from the Greek pantothen meaning "from everywhere" and small quantities of pantothenic acid are found in nearly every foodstuff. Pubmed12815048 Pubmed2981478 Reactome Database ID Release 43199220 Reactome, http://www.reactome.org ReactomeREACT_11172 TP receptor can bind thromboxane Authored: Jassal, B, 2009-04-02 10:56:26 Edited: Jassal, B, 2009-04-02 10:56:26 Pubmed1825698 Pubmed19073150 Pubmed9152406 Reactome Database ID Release 43391939 Reactome, http://www.reactome.org ReactomeREACT_18364 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Thromboxane (TBXA2) is a potent stimulator for platelet aggregation and clot formation and also plays a role in vascular tone. The thromboxane receptor TP (Hirata et al. 1991) is found on the surface of vascular endothelium, platelets and in the placenta. Once bound to its ligand, TP's effects are mediated via coupling to G q/11 activation of a phosphatidylinositol-calcium second messenger system (Kinsella BT et al, 1997). TP signaling also involves G12/13 signaling; selective activation of G12/13 results in dense granule release in a mechanism that is independent of Gq/phospholipase C. The downstream mechanism for this is thought to be RhoA mediated activation of PKCdelta, as PAR-mediated dense granule release is inhibited if RhoA is blocked, and RhoA regulates PKCdelta T505 phosphorylation (Jin et al. 2009). Vitamin B2 (riboflavin) metabolism GENE ONTOLOGYGO:0006771 Pubmed4915004 Reactome Database ID Release 43196843 Reactome, http://www.reactome.org ReactomeREACT_11070 Riboflavin (vitamin B2, E101) is an essential component for the cofactors FAD (flavin-adenine dinucleotide) and FMN (flavin mononucleotide). Together with NAD+ and NADP+, FAD and FMN are important hydrogen carriers and take part in more than 100 redox reactions involved in energy metabolism. Riboflavin is present in many vegetables and meat and during digestion, various flavoproteins from food are degraded and riboflavin is resorbed. The major degradation and excretion product in humans is riboflavin (Rivlin 1970). Activated TP receptor binds G-proten Gq Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed1851174 Pubmed9152406 Reactome Database ID Release 43428749 Reactome, http://www.reactome.org ReactomeREACT_20520 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The TP receptor can activate Gq leading to stimulation of Phospholipase C and consequent increase in intracellular calcium. Vitamin B1 (thiamin) metabolism Authored: Jassal, B, 2007-04-24 08:38:46 GENE ONTOLOGYGO:0042723 Pubmed3060175 Reactome Database ID Release 43196819 Reactome, http://www.reactome.org ReactomeREACT_11117 Vitamin B1 (thiamin) is found naturally in certain foodstuffs such as green peas, spinach, liver, bananas, whole grains and legumes. Human diseases associated with thiamin deficiency include beriberi, due to a thiamin-deficient diet, TMRA, due to defects in the SLC19A2 transport protein, and Wernicke-Korsakoff Syndrome, associated with thiamin deficiency in alcoholism (Haas 1988). Thiamin is water-soluble so is not stored in the body. When pyrophosphorylated, thiamin is converted into the coenzyme thiamin pyrophosphate (ThPP, codecarboxylase) which plays an essential role in oxidative decarboxylation and group transfer reactions. Src activation following P2Y purinoceptor activation Activation of Src lies selectively downstream of P2Y1, but not P2Y12. The precise mechanism is not known, but Src regulation of the PI3K component of the intracellular calcium response downstream of P2Y12 represents a point of reciprocal cross-talk between P2Y1 and P2Y12 receptors. Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed15187029 Reactome Database ID Release 43418662 Reactome, http://www.reactome.org ReactomeREACT_20585 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Vitamin C (ascorbate) metabolism Authored: Jassal, B, 2007-04-24 08:38:46 GENE ONTOLOGYGO:0019852 Pubmed17222174 Reactome Database ID Release 43196836 Reactome, http://www.reactome.org ReactomeREACT_11202 Vitamin C (ascorbate) is an antioxidant and a cofactor in reactions catalyzed by Cu+-dependent monooxygenases and Fe++-dependent dioxygenases. Many mammals can synthesize ascorbate de novo; humans and other primates cannot due to an evolutionarily recent mutation in the gene catalyzing the last step of the biosynthetic pathway. Reactions annotated here mediate the uptake of ascorbate and its fully oxidized form, dehydroascorbate (DHA) by cells, and the reduction of DHA and monodehydroascorbate to regenerate ascorbate (Linster and Van Schaftingen 2007). P2Y purinoceptor 1 activates MAP kinase p38 alpha ADP activates human platelets and induces endothelial cell migration. These effects are partly mediated by the P2Y1 purinocetor, inducing p38 MAP kinase activation via an uncharacterised factor. Possible mechanisms include flotillin-mediated stimulation of SRC family kinases in lipid rafts (Sugawara et al. 2007). Authored: Akkerman, JW, 2009-06-03 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jupe, S, 2009-11-03 Pubmed10759852 Pubmed17307333 Pubmed18174464 Reactome Database ID Release 43428941 Reactome, http://www.reactome.org ReactomeREACT_20632 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 has a Stoichiometric coefficient of 2 Metabolism of water-soluble vitamins and cofactors Authored: Jassal, B, 2007-04-24 08:38:46 GENE ONTOLOGYGO:0006767 Reactome Database ID Release 43196849 Reactome, http://www.reactome.org ReactomeREACT_11238 Vitamins are a diverse group of organic compounds, required in small amounts in the diet. They have distinct biochemical roles, often as coenzymes, and are either not synthesized or synthesized only in limited amounts by human cells. Vitamins are classified according to their solubility, either fat-soluble or water-soluble. The physiological processes dependent on vitamin-requiring reactions include many aspects of intermediary metabolism, vision, bone formation, and blood coagulation, and vitamin deficiencies are associated with a correspondingly diverse and severe group of diseases.<p>Water-soluble vitamins include ascorbate (vitamin C) and the members of the B group: thiamin (vitamin B1), riboflavin (B2), niacin (B3), pantothenate (B5), pyridoxine (B6), biotin (B7), folate (B9), and cobalamin (B12). Metabolic processes annotated here include the synthesis of thiamin pyrophosphate (TPP) from thiamin (B1), the synthesis of FMN and FAD from riboflavin (B2), the synthesis of nicotinic acid (niacin - B3) from tryptophan, the synthesis of Coenzyme A from pantothenate (B5), and features of the metabolism of folate (B9). G13 activation by TP receptor Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed16418336 Reactome Database ID Release 43428917 Reactome, http://www.reactome.org ReactomeREACT_20567 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The G-protein alpha subunit exchanges GDP for GTP ACTIVATION GENE ONTOLOGYGO:0008386 Reactome Database ID Release 43193154 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008386 Reactome Database ID Release 43193154 Reactome, http://www.reactome.org Activated TP receptor binds G-protein G13 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed16212421 Pubmed16418336 Reactome Database ID Release 43428909 Reactome, http://www.reactome.org ReactomeREACT_20501 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The thromboxane receptor (TP) can activate G12 and G13. Gq activation by TP receptor Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed9152406 Reactome Database ID Release 43428750 Reactome, http://www.reactome.org ReactomeREACT_20511 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The G-protein alpha subunit exchanges GDP for GTP ACTIVATION GENE ONTOLOGYGO:0008386 Reactome Database ID Release 43193154 Reactome, http://www.reactome.org Gq activation by P2Y purinoceptor 1 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed14742685 Reactome Database ID Release 43418579 Reactome, http://www.reactome.org ReactomeREACT_20636 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The G-protein alpha subunit exchanges GDP for GTP Dissociation of the P2Y purinoceptor 1:Gq complex Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43418576 Reactome, http://www.reactome.org ReactomeREACT_20551 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). Activated P2Y purinoceptor 1 binds G-protein Gq Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 P2Y1 is coupled to the Gq family of G protein alpha subunits, causing increases in intracellular calcium concentration through stimulation of PLC. Pubmed8733591 Reactome Database ID Release 43418581 Reactome, http://www.reactome.org ReactomeREACT_20525 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Pyrimidine biosynthesis Authored: D'Eustachio, P, 2010-02-05 Edited: D'Eustachio, P, 2010-02-18 GENE ONTOLOGYGO:0046134 ISBN0079130356 Pubmed6105839 Reactome Database ID Release 43500753 Reactome, http://www.reactome.org ReactomeREACT_21376 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 The pyrimidine orotate (orotic acid) is synthesized in a sequence of four reactions, deriving its atoms from glutamine, bicarbonate, and aspartate. A single multifunctional cytosolic enzyme catalyzes the first three of these reactions, while the last one is catalyzed by an enzyme associated with the inner mitochondrial membrane. In two further reactions, catalyzed by a bifunctional cytosolic enzyme, orotate reacts with 1-phosphoribosyl 5-pyrophosphate (PRPP) to yield orotidine 5'-monophosphate, which is decarboxylated to yield uridine 5'-monophosphate (UMP). While several individual reactions in this pathway are reversible, other irreversible reactions drive the pathway in the direction of UMP biosynthesis in the normal cell. All reactions are thus annotated here only in the forward direction.<P>This pathway has been most extensively analyzed at the genetic and biochemical level in hamster cell lines. All three enzymes have also been purified from human sources, however, and the key features of these reactions have been confirmed from studies of this human material (Jones 1980; Webster et al. 2001).<p>All other pyrimidines are synthesized from UMP. The reactions annotaed here, catalyzed by dCMP deaminase and dUTP diphosphatase yield dUMP, which in turn is converted to TMP by thymidylate synthase. ACTIVATION GENE ONTOLOGYGO:0008508 Reactome Database ID Release 43194135 Reactome, http://www.reactome.org Pyrimidine salvage reactions Authored: Jassal, B, 2003-06-17 09:00:25 GENE ONTOLOGYGO:0043097 ISBN0079130356 In pyrimidine salvage reactions, nucleosides and free bases generated by DNA and RNA breakdown are converted back to nucleotide monophosphates, allowing them to re-enter the pathways of pyrimidine biosynthesis (interconversion). Reactome Database ID Release 4373614 Reactome, http://www.reactome.org ReactomeREACT_655 ACTIVATION GENE ONTOLOGYGO:0015125 Reactome Database ID Release 43194128 Reactome, http://www.reactome.org Pyrimidine catabolism Authored: Jassal, B, 2003-06-17 09:00:26 GENE ONTOLOGYGO:0046135 ISBN0079130356 In parallel sequences of three reactions each, thymine is converted to beta-aminoisobutyrate and uracil is converted to beta-alanine. Both of these molecules are excreted in human urine and appear to be normal end products of pyrimidine catabolism (Griffith 1986; Webster et al. 2001). Mitochondrial AGXT2, however, can also catalyze the transamination of both molecules with pyruvate, yielding 2-oxoacids that can be metabolized further by reactions of branched-chain amino acid and short-chain fatty acid catabolism (Tamaki et al. 2000). The importance of these reactions in normal human pyrimidine catabolism has not been well worked out. Pubmed10989446 Pubmed3090932 Reactome Database ID Release 4373621 Reactome, http://www.reactome.org ReactomeREACT_1023 Synthesis and interconversion of nucleotide di- and triphosphates An array of kinases catalyze the reversible phosphorylation of nucleotide monophosphates to form nucleotide diphosphates and triphosphates.<p>Nucleoside monophosphate kinases catalyze the reversible phosphorylation of nucleoside and deoxynucleoside 5'-monophosphates to form the corresponding nucleoside 5'-diphosphates. Most appear to have restricted specificities for nucleoside monophosphates, and to use ATP preferentially (Van Rompay et al. 2000; Anderson 1973; Noda 1973). The total number of human enzymes that catalyze these reactions in vivo is not clear. In six cases, a well-defined biochemical activity has been associated with a purified protein, and these are annotated here. However, additional nucleoside monophosphate kinase-like human proteins have been identified in molecular cloning studies whose enzymatic activities are unknown, and several distinctive nucleoside monophosphate kinase activities detected in cell extracts, e.g., a GTP-requiring adenylate kinase activity (Wilson et al. 1976) and one or more guanylate kinase activities (Jamil et al. 1975) have not been unambiguously associated with specific human proteins.<P>The nucleoside monophosphates against which each of the six well-characterized enzymes is active is shown in the table (Van Rompay et al. 2000). All six efficiently use ATP as a phosphate donor, but have some activity with other nucleoside triphosphates as well in vitro. The high concentrations of ATP relative to other nucleoside triphosphates in vivo makes it the likely major phosphate donor in these reactions under most conditions.<P>All of these phosphorylation reactions are freely reversible in vitro when carried out with purified enzymes and substrates, having equilibrium constants near 1. In vivo, high ratios of ATP to ADP are likely to favor the forward direction of these reactions, i.e., the conversion of (d)NMP and ATP to (d)NDP and ADP. At the same time, the reversibility of the reactions and the overlapping substrate specificities of the enzymes raises the possibility that this group of reactions can buffer the intracellular nucleotide pool and regulate the relative concentrations of individual nucleotides in the pool: if any one molecule builds up to unusually high levels, multiple routes appear to be open not only to dispose of it but to use it to increase the supply of less abundant nucleotides.<p>Ribonucleotide reductase catalyzes the synthesis of deoxyribonucleotide diphosphates from ribonucleotide diphosphates. Authored: D'Eustachio, P, 2010-02-05 Edited: D'Eustachio, P, 2010-02-05 GENE ONTOLOGYGO:0015949 ISBN0121227022 Pubmed11008000 Pubmed177353 Pubmed5940 Reactome Database ID Release 43499943 Reactome, http://www.reactome.org ReactomeREACT_21330 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 ACTIVATION GENE ONTOLOGYGO:0015432 Reactome Database ID Release 43194154 Reactome, http://www.reactome.org Phosphate bond hydrolysis by NUDT proteins Authored: D'Eustachio, P, 2012-07-06 Edited: D'Eustachio, P, 2012-07-06 Enzymes that belong to the NUDT (Nudix) superfamily catalyze the hydrolysis of phosphodiester bonds in molecules including nucleoside triphosphates and diphosphates and nucleotide sugars. Family members are defined by the presence of an amino acid sequence motif shared with the E. coli MutT gene product, and are involved in diverse physiological processes (Mildvan et al. 2005; McLennan 2006). The hydrolysis of nucleoside di and triphosphates whose purine bases have been oxidized or deaminated may protect the cell from the mutational damage that would occur if modified deoxyribonucleotides were incorporated into DNA and from the aberrant protein synthesis that would occur if modified ribonucleotides were incorporated into mRNA (Iyama et al. 2010; Takagi et al. 2012). The hydrolysis of ADP ribose may prevent the aberrant spontaneous ADP ribosylation of cellular proteins that could occur were this molecule to accumulate to high levels in the cell (Perraud et al. 2003; Shen et al. 2003). GENE ONTOLOGYGO:0034656 Pubmed12427752 Pubmed12948489 Pubmed15581572 Pubmed16378245 Pubmed20385596 Pubmed22556419 Reactome Database ID Release 432393930 Reactome, http://www.reactome.org ReactomeREACT_150237 Reviewed: Ito, Riyoko, 2012-10-05 Cation influx mediated by TRPC3/6/7 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed11805119 Pubmed17579562 Pubmed8646775 Pubmed9930701 Reactome Database ID Release 43426223 Reactome, http://www.reactome.org ReactomeREACT_23771 Reviewed: Kunapuli, SP, 2010-06-07 TRP channels are non-selectively permeable to cations, allowing enty into the cell via concentration gradients. All mammalian TRPCs require PLC for activation. ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43192026 Reactome, http://www.reactome.org Metabolism of vitamins and cofactors Authored: Jassal, B, 2007-04-24 08:38:46 GENE ONTOLOGYGO:0006766 Reactome Database ID Release 43196854 Reactome, http://www.reactome.org ReactomeREACT_11193 Vitamins are a diverse group of organic compounds, required in small amounts in the diet. They have distinct biochemical roles, often as coenzymes, and are either not synthesized or synthesized only in limited amounts by human cells. Vitamins are classified according to their solubility, either fat-soluble or water-soluble. The physiological processes dependent on vitamin-requiring reactions include many aspects of intermediary metabolism, vision, bone formation, and blood coagulation, and vitamin deficiencies are associated with a correspondingly diverse and severe group of diseases. The metabolism of water-soluble vitamins and of vitamin D are annotated in Reactome. P2X1-mediated entry of Ca++ from plasma Pubmed11816716 Pubmed12521992 Pubmed12913094 Pubmed15087444 Pubmed16368572 Pubmed19118095 Pubmed2457808 Pubmed9565569 Reactome Database ID Release 43139855 Reactome, http://www.reactome.org ReactomeREACT_500 The P2X1 receptor is a rapidly-desensitized ATP-gated cation channel with relatively high calcium permeability. It has highest expression in smooth muscle and platelets. P2X1 receptor activation cannot induce platelet aggregation but does contribute to aggregation seen in response to collagen (Oury et al. 2001; Hechler et al. 2003). The role of P2X1 is more significant under flow conditions characterized by high shear stress (Hechler et al. 2003; Oury et al. 2004). P2X1 knockout mice havereduced incidence of thrombosis of mesenteric arterioles triggered by laser-induced vessel wall injury and are resistant to the acute systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline (Hechler et al. 2003). Conversely, increased systemic thrombosis has been reported in mice overexpressing the human P2X1 receptor (Oury et al. 2003). P2X1 binding to ATP mediates synaptic transmission between neurons and from neurons to smooth muscle, controlling sympathetic vasoconstriction in small arteries, arterioles and vas deferens. ACTIVATION GENE ONTOLOGYGO:0016746 Reactome Database ID Release 43159410 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015125 Reactome Database ID Release 43194120 Reactome, http://www.reactome.org STIM1 activation of CRAC Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed16921385 Pubmed17703229 Pubmed17965774 Pubmed18187424 Pubmed18596693 Pubmed18769136 Pubmed18952890 Pubmed19249086 Reactome Database ID Release 43434700 Reactome, http://www.reactome.org ReactomeREACT_23904 Reviewed: Kunapuli, SP, 2010-06-07 Sustained calcium signalling in lymphocytes and platelets requires the uptake of extracellular calcium when intracellular stores are depleted. The process whereby intracellular calcium depletion stimulates calcium uptake is often referred to as Store-operated calcium entry (SOCE). Store depletion is sensed by stromal interaction molecule 1 (STIM1), which then translocates to the plasma membrane and associates with 2 dimers of Orai1 to form a calcium-release activated calcium (CRAC) channel. has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0015125 Reactome Database ID Release 43194088 Reactome, http://www.reactome.org LDL binds to LRP8 Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 LPR8 (apoER2) is the platelet low density lipoprotein (LDL) receptor. Mice lacking ApoE develop hypercholesterolemia and later atherosclerosis (Zhang et al. 1992). Similiar results are seen in familial hypercholesterolemia, where defective apoB/E receptors fail to remove LDL from the circulation. Pubmed1411543 Pubmed15459198 Reactome Database ID Release 43432121 Reactome, http://www.reactome.org ReactomeREACT_23972 Reviewed: Kunapuli, SP, 2010-06-07 ACTIVATION GENE ONTOLOGYGO:0008508 Reactome Database ID Release 43194178 Reactome, http://www.reactome.org FGR binds and phosphorylates LRP8 Authored: Akkerman, JW, 2009-09-04 EC Number: 2.7.10 Edited: Jupe, S, 2010-06-07 Pubmed15459198 Reactome Database ID Release 43432129 Reactome, http://www.reactome.org ReactomeREACT_23918 Reviewed: Kunapuli, SP, 2010-06-07 Tyrosine phosphorylation of LDL:LRP8 is mediated by the Src-family kinase FGR, based on a correlation of increased LRP8 phosphorylation on LDL stimulation of platelets, and a transient increased co-precipitation of FGR with LRP8 upon LDL stimulation. ACTIVATION GENE ONTOLOGYGO:0008396 Reactome Database ID Release 43192095 Reactome, http://www.reactome.org Fgr may phosphorylate p38 MAPK Authored: Akkerman, JW, 2009-09-04 EC Number: 2.7.10.2 Edited: Jupe, S, 2010-06-07 LDL stimulation of platelets leads to increased p38 MAPK activation by phosphorylation. An Src family kinase is responsible for this; Fgr is a strong candidate as it is known to bind the LDL receptor in platelets responding to LDL and in chemoattractant-induced degranulation of neutrophils activation of p38 MAPK is blocked by a triple Hck/Fgr/Lyn knockout. However fMLP-stimulated phosphorylation of MAPKs in a double hck/fgr PMNs was observed to be normal, suggesting that Lyn, rather than Fyn, is involved. Pubmed10754332 Pubmed17339487 Reactome Database ID Release 43432148 Reactome, http://www.reactome.org ReactomeREACT_23951 Reviewed: Kunapuli, SP, 2010-06-07 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192119 Reactome, http://www.reactome.org Phosphorylation of cPLA2 by MAPK p38 alpha Authored: Akkerman, JW, 2009-06-03 EC Number: 2.7.11 Edited: Jupe, S, 2009-11-03 MAPK p38 alpha activates cPLA2 by phosphorylation of two serine residues.<br>cPLA2 can be phosphorylated and activated by ERK2 (Lin et al. 1993), and were believed to be responsible for the phosphorylation of cPLA2. However, phosphorylation of cPLA2 occurred in the absence of ERK activation in human platelets stimulated with the thrombin receptor agonist peptide SFLLRN (Kramer et al. 1995), and cPLA2 phosphorylation induced by thrombin or collagen was unaffected by PKC inhibitors that prevent ERK activation (Börsch-Haubold et al. 1995). In addition, a specific inhibitor of ERKs did not block thrombin-induced cPLA2 phosphorylation (Börsch-Haubold et al. 1996). Pubmed7592775 Pubmed7782348 Pubmed8381049 Pubmed8761473 Pubmed8910365 Pubmed9468497 Reactome Database ID Release 43428961 Reactome, http://www.reactome.org ReactomeREACT_20541 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192098 Reactome, http://www.reactome.org Purine salvage Authored: Jassal, B, 2003-07-17 08:31:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0043101 Nucleosides and free bases generated by DNA and RNA breakdown are converted back to nucleotide monophosphates, allowing them to re-enter the pathway of purine biosynthesis. Nucleosides and free bases generated by DNA breakdown are converted back to nucleotide monophosphates, allowing them to re-enter the pathway of purine biosynthesis. Nucleosides and free bases generated by RNA breakdown are converted back to nucleotide monophosphates, allowing them to re-enter the pathways of purine biosynthesis. Under normal conditions, DNA turnover is limited and deoxyribonucleotide salvage operates at a correspondingly low level (Watts 1974). Pubmed4620886 Reactome Database ID Release 4374217 Reactome, http://www.reactome.org ReactomeREACT_1923 Calcium influx via CRAC Activation of Calcium-release-activated (CRAC) channels allows influx of calcium. The Orai component of CRAC is responsible for the selectivity of the channel, while the Stim component is responsible for activation. Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed18769136 Reactome Database ID Release 43434798 Reactome, http://www.reactome.org ReactomeREACT_23967 Reviewed: Kunapuli, SP, 2010-06-07 Purine ribonucleoside monophosphate biosynthesis Authored: Jassal, B, 2003-06-26 04:06:16 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0009168 Pubmed1574589 Reactome Database ID Release 4373817 Reactome, http://www.reactome.org ReactomeREACT_1776 The purine ribonucleotide inosine 5'-monophosphate (IMP) is assembled on 5-phospho-alpha-D-ribose 1-diphosphate (PRPP), with atoms derived from aspartate, glutamine, glycine, N10-formyl-tetrahydrofolate, and carbon dioxide. Although several of the individual reactions in this sequence are reversible, as indicated by the double-headed arrows in the diagram, other irreversible steps drive the pathway in the direction of IMP synthesis in the normal cell. All of these reactions are thus annotated here only in the direction of IMP synthesis. Guanosine 5'-monophosphate (GMP) and adenosine 5'-monophosphate (AMP) are synthesized from IMP. Sequestration of Ca2+ to dense tubular network lumen Authored: Akkerman, JW, 2009-06-03 EC Number: 3.6.3.8 Edited: Jupe, S, 2010-06-07 Intracellular pools of calcium serve as the source for inositol 1,4,5-trisphosphate (IP3) -induced alterations in cytoplasmic free calcium. In most human cells calcium is stored in the lumen of the sarco/endoplastic reticulum by ATPases known as SERCAs. In platelets, SERCAs transport calcium into the platelet dense tubular network. SERCAs are P-type ATPases, similar to the plasma membrane Na and Ca-ATPases. Humans have three genes for SERCA pumps; SERCA1, SERCA2 and SERCA3. Studies on SERCA1 suggest that it binds two Ca ions from the cytoplasm and is subsequently phosphorylated at Asp351 before translocating the Ca into the SR lumen. There is a counter transport of two or possibly three protons ensuring partial charge balancing. Pubmed12167852 Pubmed2844796 Pubmed2953725 Pubmed7702581 Reactome Database ID Release 43418365 Reactome, http://www.reactome.org ReactomeREACT_23784 Reviewed: Kunapuli, SP, 2010-06-07 has a Stoichiometric coefficient of 2 Pyrimidine metabolism Authored: D'Eustachio, P, 2003-10-25 14:57:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006206 Pubmed16098809 Reactome Database ID Release 4373848 Reactome, http://www.reactome.org ReactomeREACT_957 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 The events of human pyrimidine metabolism are conveniently, if somewhat arbitrarily, grouped into four pathways: de novo synthesis of the pyrimidine ring and its conversion to uridine 5'-monophosphate (UMP), the biosynthesis of other pyrimidine ribo- and deoxyribonucleotides, pyrimidine salvage reactions, and pyrimidine catabolism (Loffler et al. 2005).<P><B>De novo synthesis of the pyrimidine ring and its conversion to UMP.</B> The pyrimidine base orotate is synthesized from glutamine, bicarbonate, and aspartate. Orotate reacts with 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and is then decarboxylated to form the pyrimidine nucleotide UMP.<P><B>Pyrimidine biosynthesis [interconversion].</B> Pyrimidine ribo- and deoxyribonucleotide di- and triphosphates are synthesized, both from UMP and from pyrimidine ribonucleotide monophosphates generated in salvage reactions. <P><B>Pyrimidine salvage reactions.</B> Pyrimidine nucleosides and free bases generated by DNA and RNA breakdown are converted to nucleotide monophosphates.<P><B>Pyrimidine catabolism.</B> The pyrimidine bases thymine and uracil are degraded to beta-aminoisobutyrate and beta-alanine, respectively, which are excreted from the body. PMCA extrusion of Ca2+ Authored: Akkerman, JW, 2009-06-03 EC Number: 3.6.3.8 Edited: Jupe, S, 2010-06-07 Pubmed15709690 Pubmed2844759 Pubmed5961668 Pubmed6218823 Reactome Database ID Release 43418309 Reactome, http://www.reactome.org ReactomeREACT_23956 Reviewed: Kunapuli, SP, 2010-06-07 The plasma membrane Ca-ATPase (PMCA) is a P-type Ca-ATPase regulated by calmodulin. The PMCA also counter-transports a proton. PMCA is important for Ca homeostasis and function. Purine catabolism Authored: Jassal, B, 2003-07-17 08:31:43 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006195 Pubmed4620886 Reactome Database ID Release 4374259 Reactome, http://www.reactome.org ReactomeREACT_2086 The purine bases guanine and hypoxanthine (derived from adenine by events in the purine salvage pathways) are converted to xanthine and then to uric acid, which is excreted from the body (Watts 1974). The end-point of this pathway in humans and hominoid primates is unusual. Most other mammals metabolize uric acid further to yield more soluble end products, and much speculation has centered on possible roles for high uric acid levels in normal human physiology. Na+/Ca2+ exchanger transport Authored: Jassal, B, 2009-06-05 Edited: Jassal, B, 2009-06-05 Pubmed12406570 Pubmed1374913 Pubmed8021246 Reactome Database ID Release 43425661 Reactome, http://www.reactome.org ReactomeREACT_19164 Reviewed: He, L, 2009-08-24 The NCX (SCL8, Na+/Ca2+ exchanger) family is one of three families that control Ca2+ flux across the plasma membrane or intracellular compartments. They extrude Ca2+ from the cell, using the electrochemical gradient of Na+ as it flows into the cell. One Ca2+ is exchanged for three Na+. During this electrogenic exchange, the membrane potential is altered. NCX1 (SLC8A1) has a ubiquitous expression profile (highest expression in heart, brain and kidney) and was originally cloned and characterized from human cardiac muscle (Komuro I et al, 1992). Both NCX2 (SLC8A2) (Li Z et al, 1994) and NCX3 (SLC8A3) (Gabellini N et al, 2002) are expressed in the brain. has a Stoichiometric coefficient of 3 G6Pase Converted from EntitySet in Reactome Reactome DB_ID: 981604 Reactome Database ID Release 43981604 Reactome, http://www.reactome.org ReactomeREACT_26119 SLC37A4 Converted from EntitySet in Reactome Reactome DB_ID: 198493 Reactome Database ID Release 43198493 Reactome, http://www.reactome.org ReactomeREACT_11907 Mitochondrial Uncoupling Proteins Authored: Brand, MD, Esteves, TC, Jassal, B, 2005-11-09 10:46:33 GENE ONTOLOGYGO:0015992 Pubmed14603310 Pubmed14715917 Pubmed15111103 Pubmed15738989 Pubmed15886331 Pubmed16005426 Pubmed16098826 Reactome Database ID Release 43166187 Reactome, http://www.reactome.org ReactomeREACT_6341 Uncoupling proteins (UCPs) are members of the mitochondrial transport carrier family, and have been implicated in a wide range of physiological and pathological conditions. Physiological conditions include thermogenesis, fatty acid metabolism and protection against free radicals and ageing; pathological conditions include involvement in obesity, diabetes and degenerative, neurological and immunological diseases.<br><br>The UCPs share general structural features with the other mitochondrial transport carriers. They have a tripartite structure, consisting of three homologous sequence repeats of approximately 100 residues. The carriers also have a signature motif, which is repeated in all members of the family and in all three repeats. The transmembrane arrangement of UCPs is 6 alpha-helix regions (2 regions per repeat) spanning the lipid bilayer with the amino and carboxyl termini facing the cytosolic side. The crystal structure of one member of the family, the adenine nucleotide translocase, is known, and UCPs can be successfully folded into this structure to indicate their probable 3D arrangement (<i>Pebay-Peyroula et al., 2003; Kunji, 2004; Esteves and Brand, 2005</i>).<br><br>The paradigm of this family, UCP1, catalyzes adaptive thermogenesis (i.e. heat generation) in mammalian brown adipose tissue. It does so by promoting a leak of protons through the mitochondrial inner membrane, which uncouples ATP production from substrate oxidation, leading to fast oxygen consumption and ultimately to heat production. The thermogenic activity of UCP1 in brown adipose tissue plays an important role when the organism needs extra heat, e.g. during cold weather conditions (for small rodents), the cold stress of birth and arousal from hibernation. UCP1 homologs have also been found in lower vertebrates such as fish, where their role is still unclear (<i>Cannon and Nedergaard, 2004; Jastroch et al., 2005</i>).<br><br>The proton conductance of UCP1 in brown adipose tissue is tightly controlled. It is strongly inhibited by purine nucleotides at physiological concentrations, and this inhibition is overcome by fatty acids, which are released from intracellular triacylglycerol stores following adrenergic activation in response to cold or overfeeding.<br><br>In the late 1990’s, UCP2 and UCP3 were identified. These new UCPs have high amino acid sequence homology to UCP1 (59 and 57% amino-acid identity to UCP1, respectively). UCP2 has been identified in lung, spleen, pancreatic beta-cells and kidney, whereas UCP3 is found in brown adipose tissue and skeletal muscle. Homologs of UCP2 and UCP3 are found in marsupials, birds, fish and plants.<br><br>UCP2 and UCP3 only catalyze proton leak when activated. These proteins will transport protons and increase the net proton conductance of mitochondria in the presence of specific activators, in a way that is inhibited by purine nucleotides. Activators include superoxide, retinoic acid, the retinoid 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphtalenyl)-1-propenyl]benzoic acid (TTNPB) and reactive alkenals, such as hydroxynonenal. Activation might require fatty acids. UCP1 is also activated by these compounds.<br><br>There is strong evidence that the regulated uncoupling caused by these proteins attenuates mitochondrial reactive oxygen species production, protects against cellular damage, and (in beta-cells) diminishes insulin secretion. There are also untested suggestions that their transport of fatty acids may be physiologically important (<i>Brand and Esteves, 2005; Esteves and Brand, 2005; Krauss et al., 2005</i>).<br><br>A number of models have been proposed for the molecular mechanism by which fatty acids lead to increased proton conductance by UCP1 in brown adipose tissue mitochondria, and presumably by the other UCPs as well. These are the "fatty acid cycling" model and the "proton buffering" model. The fatty acid cycling model Pubmed10653472 Pubmed8576230 Pubmed9821950 Reactome Database ID Release 43167826 Reactome, http://www.reactome.org ReactomeREACT_6258 The "fatty acid cycling" hypothesis proposes that protonated fatty acids flip-flop in the membrane and deliver a proton to the matrix side. UCP1 catalyses the return of the fatty acid anion to the cytosolic side of the membrane, resulting in net proton transport catalysed by the protein. Respiratory electron transport Authored: Jassal, B, 2005-04-21 10:42:20 GENE ONTOLOGYGO:0022904 Mitochondria are often described as the "powerhouse" of a cell as it is here that energy is largely released from the oxidation of food. Reducing equivalents generated from beta-oxidation of fatty acids and from the Krebs cycle enter the <b><i>electron transport chain</b></i> (also called the <b><i>respiratory chain</b></i>). During a series of redox reactions, electrons travel down the chain releasing their energy in controlled steps. These reactions drive the active transport of H<sup>+</sup> ions from the mitochondrial matrix , through the inner membrane to the intermembrane space. The respiratory chain consists of five main types of carrier; flavins, iron-sulfur centres, quinones, cytochromes (heme proteins) and copper. The two main reducing equivalents entering the respiratory chain are NADH and FADH<sub>2</sub>. NADH is linked through the NADH-specific dehydrogenase whereas FADH<sub>2</sub> is reoxidised within succinate dehydrogenase and a ubiquinone reductase of the fatty acid oxidation pathway. Oxygen is the final acceptor of electrons and with H<sup>+</sup> ions, is converted to form water, the end product of aerobic cellular respiration.<br><br>A <b><i>proton electrochemical gradient</b></i> (often called <b><i>protonmotive force</b></i>) is established across the inner membrane, with positive charge in the intermembrane space relative to the matrix. Protons driven by the proton-motive force, can enter ATP synthase thus returning to the mitochondrial matrix. ATP synthases use this exergonic flow to form ATP in the matrix, a process called <b><i>chemiosmotic coupling</b></i>. A by-product of this process is heat generation.<br><br>An antiport, ATP-ADP translocase, preferentially exports ATP from the matrix thereby maintaining a high ADP:ATP ratio in the matrix. The tight coupling of electron flow to ATP synthesis means oxygen consumption is dependent on ADP availability (termed <b><i>respiratory control</b></i>). High ADP (low ATP) increases electron flow thereby increasing oxygen consumption and low ADP (high ATP) decreases electron flow and thereby decreases oxygen consumption. There are many inhibitors of mitochondrial ATP synthesis. Most act by either blocking the flow of electrons (eg cyanide, carbon monoxide, rotenone) or uncoupling electron flow from ATP synthesis (eg dinitrophenol). Thermogenin is a natural protein found in brown fat. Newborn babies have a large amount of brown fat and the heat generated by thermogenin is an alternative to ATP synthesis (and thus electron flow only produces heat) and allows the maintenance of body temperature in newborns.<br><br>The electron transport chain is located in the inner mitochondrial membrane and comprises some 80 proteins organized in four enzymatic complexes (<b><font color="orange">I-IV</font></b>). Complex V generates ATP but has no electron transfer activity. In addition to these 5 complexes, there are also two electron shuttle molecules; Coenzyme Q (also known as ubiquinone, <b><font color="brown">CoQ</font></b>) and Cytochrome c (<b><font color="brown">Cytc</font></b>). These two molecules shuttle electrons between the large complexes in the chain.<br><br>How many ATPs are generated by this process? Theoretically, for each glucose molecule, 32 ATPs can be produced. As electrons drop from NADH to oxygen in the chain, the number of protons pumped out and returning through ATP synthase can produce 2.5 ATPs per electron pair. For each pair donated by FADH<sub>2</sub>, only 1.5 ATPs can be formed. Twelve pairs of electrons are removed from each glucose molecule;<br><br>10 by NAD<sup>+</sup> = 25 ATPs<br>2 by FADH<sub>2</sub> = 3 ATPs.<br><br>Making a total of 28 ATPs. However, 2 ATPs are formed during the Krebs' cycle and 2 ATPs formed during glycolysis for each glucose molecule therefore making a total ATP yield of <b>32 ATPs</b>. In reality, the energy from the respiratory chain is used for other processes (such as active transport of important ions and molecules) so under conditions of normal respiration, the <i>actual</i> ATP yield probably does not reach 32 ATPs.<br><br>The reducing equivalents that fuel the electron transport chain, namely NADH and FADH2, are produced by the Krebs cycle (TCA cycle) and the beta-oxidation of fatty acids. At three steps in the Krebs cycle (isocitrate conversion to oxoglutarate; oxoglutarate conversion to succinyl-CoA; Malate conversion to oxaloacetate), a pair of electrons (2e-) are removed and transferred to NAD+, forming NADH and H+. At a single step, a pair of electrons are removed from succinate, reducing FAD to FADH2. From the beta-oxidation of fatty acids, one step in the process forms NADH and H+ and another step forms FADH2.<br><br>Cytoplasmic NADH, generated from glycolysis, has to be oxidized to reform NAD+, essential for glycolysis, otherwise glycolysis would cease to function. There is no carrier that transports NADH directly into the mitochondrial matrix and the inner mitochondrial membrane is impermeable to NADH so the cell uses two shuttle systems to move reducing equivalents into the mitochondrion and regenerate cytosolic NAD+. <br>The first is the glycerol phosphate shuttle, which uses electrons from cytosolic NADH to produce FADH2 within the inner membrane. These electrons then flow to Coenzyme Q. Complex I is bypassed so only 1.5 ATPs can be formed per NADH via this route. The overall balanced equation, summing all the reactions in this system, is<br><br><b>NADH</b><sub>cytosol</sub> + <b>H<sup>+</sup></b><sub>cytosol</sub> + <b>NAD<sup>+</sup></b><sub>mito</sub> -> <b>NAD<sup>+</sup></b><sub>cytosol</sub> + <b>NADH</b><sub>mito</sub> + <b>H<sup>+</sup></b><sub>mito</sub><br><br>The malate-aspartate shuttle uses the oxidation of malate to generate NADH in the mitochondrial matrix. This NADH can then be fed directly to complex I and thus can form 3 ATPs via the respiratory chain. The overall balanced equation is<br><br><b>NADH</b><sub>cytosol</sub> + <b>H<sup>+</sup></b><sub>cytosol</sub> + <b>FAD</b><sub>inner memb</sub> -> <b>NAD<sup>+</sup></b><sub>cytosol</sub> + <b>FADH<sub>2</sub></b><sub> inner memb</sub><br><br>Both of these shuttle systems regenerate cytosolic NAD<sup>+</sup>.<br><br>The entry point for NADH is complex I (NADH dehydrogenase) and the entry point for FADH<sub>2</sub> is Coenzyme Q. The input of electrons from fatty acid oxidation via ubiquinone is complicated and not shown in the diagram. Pubmed10647174 Pubmed2862839 Reactome Database ID Release 43611105 Reactome, http://www.reactome.org ReactomeREACT_22393 Reviewed: Ferguson, SJ, 2005-05-12 01:00:00 ACTIVATION GENE ONTOLOGYGO:0008396 Reactome Database ID Release 43192095 Reactome, http://www.reactome.org Formation of ATP by chemiosmotic coupling Authored: Jassal, B, 2005-06-29 14:35:05 GENE ONTOLOGYGO:0042776 Pubmed4517936 Reactome Database ID Release 43163210 Reactome, http://www.reactome.org ReactomeREACT_6759 The re-entry of protons into the mitochondrial matrix through Complex V causes conformational changes which result in ATP synthesis. Complex V (ATP synthase) is composed of 3 parts; an F1 catalytic core (approx 5 subunits), an F0 membrane proton channel (approx 9 subunits) and two stalks linking F1 to F0. F1 contains three alpha subunits, three beta subunits, and one each of gamma, delta, and epsilon subunits. Each beta subunit contains an active site for ATP synthesis. F0 has at least 9 subunits (a-g, A6L and F6), with one copy each of subunits b, d and F6.<br>The mechanism of ATP synthesis by Complex V was predicted by Boyer et al in 1973: ADP and Pi bind to the enzyme resulting in a conformational change. ATP is then synthesized, still bound to the enzyme. Another change in the active site results in the release of free ATP into the matrix. The overall reaction is:<br><b>ADP</b> + <b>Pi</b> + <b>H<sup>+</sup></b> + <b><i>n</i>H<sup>+</sup></b><sub>memb. space</sub> -> <b>ATP</b> + <b>H<sub>2</sub>O</b> + <b><i>n</i>H<sup>+</sup></b><sub>matrix</sub><br> ACTIVATION GENE ONTOLOGYGO:0003854 Reactome Database ID Release 43192106 Reactome, http://www.reactome.org Purine metabolism Authored: Jassal, B, 2003-06-26 04:06:16 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006144 Pubmed4620886 Reactome Database ID Release 4373847 Reactome, http://www.reactome.org ReactomeREACT_522 Reviewed: Rush, MG, 2008-01-11 00:00:00 The events of human purine metabolism are conveniently, if somewhat arbitrarily, grouped into four pathways: de novo synthesis of inosine 5'-monophosphate (IMP), the biosynthesis of other purine ribo- and deoxyribonucleotides, purine salvage reactions, and purine catabolism (Watts 1974).<P><B>De novo synthesis of inosine 5'-monophosphate (IMP).</B> The purine ribonucleotide IMP is assembled on 5-phospho-alpha-D-ribose 1-diphosphate (PRPP).<P><B>Purine biosynthesis [interconversion].</B> Purine ribo- and deoxyribonucleotide di- and triphosphates are synthesized, both from IMP and from guanosine and adenosine ribo- and deoxyribonucleotide monophosphates generated in salvage reactions. <P><B>Purine salvage reactions.</B> Purine nucleosides and free bases generated by DNA and RNA breakdown are converted to nucleotide monophosphates.<P><B>Purine catabolism.</B> The purine bases guanine and hypoxanthine are degraded to uric acid, which is excreted from the body. ACTIVATION GENE ONTOLOGYGO:0033778 Reactome Database ID Release 43192125 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192006 Reactome, http://www.reactome.org The proton buffering model GENE ONTOLOGYGO:0015992 Pubmed11239490 Pubmed14871489 Pubmed8300577 Reactome Database ID Release 43167827 Reactome, http://www.reactome.org ReactomeREACT_6196 The "proton buffering" model proposes that UCP1 is intrinsically a proton carrier, and that fatty acid acts as a prosthetic group during proton transport. Fatty acid penetrates from the lipid phase, with its carboxyl group oriented to the proton translocation path. Here, it works as a donor-acceptor of protons between the residual carboxyl groups of UCP1. Ultimately, protons are extruded to the matrix side of the membrane.<br>Rial et al (2004) suggest fatty acids are inducers of proton transport by UCP by allowing themselves to become substrates for UCP and activation of the proton buffering mechanism itself. Binding of nucleotides to UCP inhibits it's proton transport capability. UCP accepts purine ribose tri- and di- nucleotides; GTP, ATP, GDP and ADP. The monophosphates GMP and AMP are poor ligands for UCP binding. PECAM-1 binds PP2A Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 PECAM-1 co-immunoprecipitates with PP2A Pubmed12775720 Reactome Database ID Release 43432143 Reactome, http://www.reactome.org ReactomeREACT_23942 Reviewed: Kunapuli, SP, 2010-06-07 ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192006 Reactome, http://www.reactome.org Nucleotide metabolism Authored: Jassal, B, 2003-06-26 04:06:16 Edited: D'Eustachio, P, Gillespie, ME, Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0055086 Metabolism of nucleotides Nucleotides and their derivatives are used for short-term energy storage (ATP, GTP), for intra- and extra-cellular signaling (cAMP; adenosine), as enzyme cofactors (NAD, FAD), and for the synthesis of DNA and RNA. Most dietary nucleotides are consumed by gut flora; the human body's own supply of these molecules is synthesized de novo. Additional metabolic pathways allow the interconversion of nucleotides, the salvage and reutilization of nucleotides released by degradation of DNA and RNA, and the catabolism of excess nucleotides (Rudolph 1994). These pathways are regulated to control the total size of the intracellular nucleotide pool, to balance the relative amounts of individual nucleotides, and to couple the synthesis of deoxyribonucleotides to the onset of DNA replication (S phase of the cell cycle).<P>These pathways are also of major clinical interest as they are the means by which nucleotide analogues used as anti-viral and anti-tumor drugs are taken up by cells, activated, and catabolized (Weilin and Nordlund 2010). As well, differences in nuclotide metabolic pathways between humans and aplicomplexan parasites like Plasmodium have been exploited to design drugs to attack the latter (Hyde 2007).<p>The movement of nucleotides and purine and pyrimidine bases across lipid bilayer membranes, mediated by SLC transporters, is annotated as part of the module "transmembrane transport of small molecules". Pubmed17266529 Pubmed20494131 Pubmed8283301 Reactome Database ID Release 4315869 Reactome, http://www.reactome.org ReactomeREACT_1698 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 LDL leads to activation of PECAM1 Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 LDL causes a transient increase in p38 MAPK activity in platelets. After an initial phase in which LDL leads to the activation of p38MAPK, LDL leads to activation of PECAM-1, stimulating the Ser/Thr phosphatases PP1/PP2Aand reducing the activity of p38MAPK by dephosphorylation. Pubmed12775720 Reactome Database ID Release 43435244 Reactome, http://www.reactome.org ReactomeREACT_23906 Reviewed: Kunapuli, SP, 2010-06-07 ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43192098 Reactome, http://www.reactome.org GPIb-IX-V binds to vWF:Collagen complex Pubmed15507277 Pubmed17624957 Pubmed1939645 Reactome Database ID Release 43114670 Reactome, http://www.reactome.org ReactomeREACT_436 The initial tethering of platelets at sites of vascular injury is mediated by a receptor complex of glycoproteins 1b, IX and V (GP1b-IX-V - frequently referred to as the GPIb receptor). The GP1b component binds to von Willebrand factor (vWF) complexed with collagen exposed in vascular epithelium following injury. In conditions of high shear stress, when a blood vessel is partially blocked, vWF can bind to GP1b:V:IX in tha absence of collagen, a major factor in heart attack and stroke. GPIb-IX-V interaction with vWF:collagen potentiates the ability of alphaIIb betaIII integrin to bind vWF and fibrinogen, triggering stable platelet adhesion and generation of further signals that lead to aggregation. ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43193506 Reactome, http://www.reactome.org GP1b-IX-V binds 14-3-3-zeta Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed10627461 Pubmed15507277 Pubmed17897012 Pubmed8034572 Pubmed8631758 Pubmed9425086 Reactome Database ID Release 43430076 Reactome, http://www.reactome.org ReactomeREACT_23993 Reviewed: Kunapuli, SP, 2010-06-07 The Gp1b-IX-V complex binds to 14-3-3-zeta, a scaffolding protein. The highly conserved cytoplasmic domain of GpIb alpha binds directly to dimeric 14-3-3 zeta adapter protein. Binding also involves regions of GpV, and is enhanced by phosphorylation of GP1b at Ser-609 or Ser-166 of Gp1b alpha and beta respectively. For Gp1b beta this phosphorylation is PKA-dependent. ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43193506 Reactome, http://www.reactome.org Binding of GPVI:Fc Epsilon R1 gamma receptor complex with collagen Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Edited: Jupe, S, 2009-11-02 GPVI receptor has little affinity for soluble forms of collagen but binds collagen fibrils. Recent structural models indicate that each GPVI receptor complex could bind up to 3 collagen fibrils (Jung & Moroi 2008). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FceRIgamma complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FceRIgamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. Pubmed19065783 Pubmed9295288 Reactome Database ID Release 43114577 Reactome, http://www.reactome.org ReactomeREACT_1088 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 ACTIVATION GENE ONTOLOGYGO:0008111 Reactome Database ID Release 43191973 Reactome, http://www.reactome.org vWF binds to collagen At the beginning of this reaction, 1 molecule of 'Collagen I', and 1 molecule of 'Von Willebrand factor precursor' are present. At the end of this reaction, 1 molecule of 'Collagen IV : vWF complex' is present.<br><br> <br> Pubmed3872140 Reactome Database ID Release 43114671 Reactome, http://www.reactome.org ReactomeREACT_1523 ACTIVATION GENE ONTOLOGYGO:0008111 Reactome Database ID Release 43191973 Reactome, http://www.reactome.org Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. Authored: Jassal, B, 2005-04-21 10:42:20 GENE ONTOLOGYGO:0022904 Oxidation of fatty acids and pyruvate in the mitochondrial matrix yield large amounts of NADH. The respiratory electron transport chain couples the re-oxidation of this NADH to NAD+ to the export of protons from the mitochonrial matrix, generating a chemiosmotic gradient across the inner mitochondrial membrane. This gradient is used to drive the synthesis of ATP; it can also be bypassed by uncoupling proteins to generate heat, a reaction in brown fat that may be important in regulation of body temperature in newborn children. Reactome Database ID Release 43163200 Reactome, http://www.reactome.org ReactomeREACT_6305 Reviewed: Ferguson, SJ, 2005-05-12 01:00:00 Interaction of GPVI and FceRI gamma Authored: de Bono, B, 2008-02-06 09:45:07 Edited: Jupe, S, 2009-11-02 Glycoprotein VI (GPVI) was identified as a collagen receptor from studies of patients with a GPVI deficiency. GPVI-deficient platelets lack collagen-induced aggregation and the ability to form thrombi on a collagen surface under flow conditions. GPVI complexes with the Fc epsilon R1 receptor gamma chain, with a possible stochiometry of two GPVI molecules and one FceRI gamma-chain dimer (Jung & Moroi 2008). GPVI binding to FcR gamma is necessary for high affinity GPVI binding to collagen. Pubmed15381385 Pubmed16102042 Pubmed19065783 Pubmed9280292 Reactome Database ID Release 43210282 Reactome, http://www.reactome.org ReactomeREACT_20664 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Interconversion of 2-oxoglutarate and 2-hydroxyglutarate Authored: D'Eustachio, P, 2010-06-25 Edited: D'Eustachio, P, 2010-06-25 GENE ONTOLOGYGO:0006103 Pubmed16601864 Pubmed18772396 Pubmed19935646 Reactome Database ID Release 43880009 Reactome, http://www.reactome.org ReactomeREACT_25367 Reviewed: Jassal, B, 2010-11-09 Reviewed: Rush, MG, 2011-01-31 The two stereoisomers of 2-hydroxyglutarate are normally converted to 2-oxoglutarate in the mitochondrial matrix, and can then be metabolized by the citric acid cycle. The physiological sources of 2-hydroxyglutarate have not been established although plausible hypotheses are that it is generated by lysine breakdown or as a byproduct of delta-aminolevulinate metabolism. The stereoisomers are oxidized to 2-oxoglutarate in FAD-dependent reactions catalyzed by the enzymes D2HGDH (specific for R(-)-2-hydroxyglutarate) and L2HGDH (specific for S(-)-2-hydroxyglutarate). An inherited deficiency in either enzyme is associated with accumulation of 2-hydroxyglutarate and variable neurological symptoms. R(-)-2-hydroxyglutarate also reacts reversibly with succinate semialdehyde to form 4-hydroxybutyrate and 2-oxoglutarate, catalyzed by ADHFE1. No deficiencies of this enzyme have been found in patients with elevated 2-hydroxyglutarate levels (Struys 2006).<p>Somatic mutations affecting arginine residue 132 of IDH1 (isocitrate dehydrogenase 1, a cytosolic enzyme that normally catalyzes the NADP+-dependent conversion of isocitrate to 2-oxoglutarate), are very commonly found in human glioblastomas (Parsons et al. 2008). These mutant proteins efficiently catalyze the NADPH-dependent reduction of 2-oxoglutarate to form 2-hydroxyglutarate. Cells expressing the mutant protein accumulate elevated levels of 2-hydroxyglutarate, probably in the cytosol as IDH1 is a cytosolic enzyme. The fate of the 2-hydroxyglutarate is unclear, but the high frequency with which the mutation is found in surveys of primary tumors is consistent with the possibility that it is advantageous to the tumor cells (Dang et al 2009). GPVI binds Fyn and Lyn Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-02 Fyn and Lyn constitutively associate with GPVI-Fc epsilon R1 gamma in platelets. The proline-rich region of GPVI is required for this interaction. Pubmed11943772 Reactome Database ID Release 43432295 Reactome, http://www.reactome.org ReactomeREACT_20629 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43192037 Reactome, http://www.reactome.org Citric acid cycle (TCA cycle) Authored: Birney, E, 2003-01-28 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006099 In the citric acid or tricarboxylic acid (TCA) cycle, the acetyl group of acetyl CoA (derived primarily from oxidative decarboxylation of pyruvate, beta-oxidation of long-chain fatty acids, and catabolism of ketone bodies and several amino acids) can be completely oxidized to CO2 in reactions that also yield one high-energy phosphate bond (as GTP or ATP) and four reducing equivalents (three NADH + H+, and one FADH2). The NADH and FADH2 are then oxidized by the electron transport chain to yield nine more high-energy phosphate bonds (as ATP). All reactions of the citric acid cycle take place in the mitochondrion.<p>Eight canonical reactions mediate the synthesis of citrate from acetyl-CoA and oxaloacetate and the metabolism of citrate to re-form oxaloacetate. Six additional reactions are included here. Three reversible reactions, the interconversions of citrate and isocitrate, of fumarate and malate, and of malate and oxaloacetate are annotated in both their canonical (forward) and reverse directions. The synthesis of succinate from succinyl-CoA can be coupled to the phosphorylation of either GDP (the canonical reaction) or ADP; both reactions are annotated. Two mitochondrial isocitrate dehydrogenase isozymes catalyze the oxidative decarboxylation of isocitrate to form alpha-ketoglutarate (2-oxoglutarate): IDH3 catalyzes the canonical reaction coupled to the reduction of NAD+, while IDH2 catalyzes the same reaction coupled to reduction of NADP+, a reaction whose normal physiological function is unclear. Both reactions are annotated. Finally, a reaction is annotated in which reducing equivalents are transferred from NADPH to NAD+ coupled to proton import across the inner mitochondrial membrane.<p>The cyclical nature of the reactions responsible for the oxidation of acetate was first suggested by Hans Krebs, from biochemical studies of pigeon breast muscle (Krebs et al. 1938; Krebs and Eggleston 1940). Many of the molecular details of individual reactions were worked out by Ochoa and colleagues, largely through studies of enzymes purified from pig heart (Ochoa 1980). While the human homologues of these enzymes have all been identified, their biochemical characterization has in general been limited and many molecular details of the human reactions are inferred from those worked out in studies of the model systems. Pubmed16746585 Pubmed16747180 Pubmed6773467 Reactome Database ID Release 4371403 Reactome, http://www.reactome.org ReactomeREACT_1785 Interaction of PECAM-1 and SHP-2 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 PECAM-1 becomes tyrosine-phosphorylated during the platelet aggregation process; the phosphorylation of two tandem tyrosine residues (Y663 and Y686) within the cytoplasmic domain is required for downstream signalling events. Phosphorylation creates docking sites for the protein-tyrosine phosphatase SHP-2. The interaction between SHP-2 and PECAM-1 is dependent upon integrin-mediated platelet/platelet interactions and occurs via the Src homology 2 (SH2) domains of the phosphatase and highly conserved phosphatase-binding motifs encompassing phosphotyrosines 663 and 686 within the cytoplasmic domain of PECAM-1. Pubmed9054388 Reactome Database ID Release 43210294 Reactome, http://www.reactome.org ReactomeREACT_12509 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Integrin alpha2beta1 collagen adhesion Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Integrin Alpha2 Beta1, known on leukocytes as VLA-2, is the major platelet collagen receptor (Kunicki et al. 1988). It requires Mg2+ to interact with collagen and may require initiation mediated by the activation of AlphaIIbBeta3 (van de Walle 2007). Binding occurs via the alpha2 subunit I domain to a collagen motif with the sequence Gly-Phe-Hyp-Gly-Glu-Arg (Emsley 2000). Binding of collagen to Alpha2 Beta1 generates the intracellular signals that contribute to platelet activation. Pubmed10778855 Pubmed16985184 Pubmed2832397 Reactome Database ID Release 43114563 Reactome, http://www.reactome.org ReactomeREACT_1990 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Interaction of PECAM-1 and SHP-1 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Pubmed10350061 Pubmed9774457 Reactome Database ID Release 43210277 Reactome, http://www.reactome.org ReactomeREACT_12552 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The phosphorylation of two tandem tyrosine residues (Y663 and Y686) within the cytoplasmic domain of PECAM-1 is required for the downstream signalling events observed following PECAM-1 ligation. Both SH2 domains of SHP-1 are required in tandem to bind PECAM-1. Metabolism of nitric oxide Authored: Hemish, J, 2007-10-19 18:00:42 GENE ONTOLOGYGO:0046209 Nitric oxide (NO), a multifunctional second messenger, is implicated in physiological functions in mammals that range from immune response and potentiation of synaptic transmission to dilation of blood vessels and muscle relaxation. NO is a highly active molecule that diffuses across cell membranes and cannot be stored inside the producing cell. Its signaling capacity must be controlled at the levels of biosynthesis and local availability. Indeed, NO production by NO synthases is under complex and tight control, being regulated at transcriptional and translational levels, through co- and posttranslational modifications, and by subcellular localization. NO is synthesized from L-arginine by a family of nitric oxide synthases (NOS). Three NOS isoforms have been characterized: neuronal NOS (nNOS, NOS1) primarily found in neuronal tissue and skeletal muscle; inducible NOS (iNOS, NOS2) originally isolated from macrophages and later discovered in many other cells types; and endothelial NOS (eNOS, NOS3) present in vascular endothelial cells, cardiac myocytes, and in blood platelets. The enzymatic activity of all three isoforms is dependent on calmodulin, which binds to nNOS and eNOS at elevated intracellular calcium levels, while it is tightly associated with iNOS even at basal calcium levels. As a result, the enzymatic activity of nNOS and eNOS is modulated by changes in intracellular calcium levels, leading to transient NO production, while iNOS continuously releases NO independent of fluctuations in intracellular calcium levels and is mainly regulated at the gene expression level (Pacher et al. 2007).<p>The NOS enzymes share a common basic structural organization and requirement for substrate cofactors for enzymatic activity. A central calmodulin-binding motif separates an oxygenase (NH2-terminal) domain from a reductase (COOH-terminal) domain. Binding sites for cofactors NADPH, FAD, and FMN are located within the reductase domain, while binding sites for tetrahydrobiopterin (BH4) and heme are located within the oxygenase domain. Once calmodulin binds, it facilitates electron transfer from the cofactors in the reductase domain to heme enabling nitric oxide production. Both nNOS and eNOS contain an additional insert (40-50 amino acids) in the middle of the FMN-binding subdomain that serves as autoinhibitory loop, destabilizing calmodulin binding at low calcium levels and inhibiting electron transfer from FMN to the heme in the absence of calmodulin. iNOS does not contain this insert.<p>Because NOS enzymatic activity is modulated by the presence of its substrates and cofactors within the cell, under certain conditions, NOS may generate superoxide instead of NO, a process referred to as uncoupling (uncoupling of NADPH oxidation and NO synthesis).<p>The molecular details of eNOS function are annotated here. Pubmed17237348 Reactome Database ID Release 43202131 Reactome, http://www.reactome.org ReactomeREACT_12508 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 SMURF1 ubiquitinates Smad7 and phosphorylated TGFBR1 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed11278251 Reactome Database ID Release 432176396 Reactome, http://www.reactome.org ReactomeREACT_121376 Reviewed: Huang, Tao, 2012-05-14 When recombinant mouse Smad7 and recombinant human SMURF1, TGFBR1 and TGFBR2 are exogenously expressed in COS1 cells, SMURF1 (recruited to the activated TGF-beta receptor complex through interaction with Smad7) ubiquitinates both Smad7 and TGFBR1 (Ebisawa et al. 2001). has a Stoichiometric coefficient of 2 eNOS activation and regulation GENE ONTOLOGYGO:0050999 Originally identified as endothelium-derived relaxing factor, eNOS derived NO is a critical signaling molecule in vascular homeostasis. It regulates blood pressure and vascular tone, and is involved in vascular smooth muscle cell proliferation, platelet aggregation, and leukocyte adhesion. Loss of the bioavailability of endothelium derived NO is a key feature of endothelial dysfunction and is implicated in the pathogenesis of cardiovascular disease such as hypertension and atherosclerosis. The endothelial isoform eNOS is unique among the nitric oxide synthase (NOS) family in that it is co-translationally modified at its amino terminus by myristoylation and is further acylated by palmitoylation (two residues next to the myristoylation site). These modifications target eNOS to the plasma membrane caveolae and lipid rafts. <br><br>eNOS activation and subsequent nitric oxide (NO) production is stimulated by a variety of stimuli, such as fluid shear stress generated by blood flow, vascular endothelial growth factor (VEGF), bradykinin, estrogen, insulin, and angiopoietin. The activity of eNOS is further regulated by numerous post-translational modifications, including protein-protein interactions, phosphorylation, and subcellular localization.<br><br>Following activation, eNOS shuttles between caveolae and other subcellular compartments such as the noncaveolar plasma membrane portions, Golgi apparatus, and perinuclear structures. This subcellular distribution is variable depending upon cell type and mode of activation. Subcellular localization of eNOS has a profound effect on its ability to produce NO as the availability of its substrates and cofactors will vary with location. eNOS is primarily particulate, and depending on the cell type, eNOS can be found in several membrane compartments: plasma membrane caveolae, lipid rafts, and intracellular membranes such as the Golgi complex. In addition, it has been reported that eNOS can also be detected in the nucleus, however, the conditions associated with nuclear localization of eNOS and its precise role in this cell compartment remains to be determined. <br><br>Several stimuli can trigger a transient displacement of eNOS from the plasma membrane to other subcellular locations. This process can be mediated through various protein-protein interactions and/or changes in post-translational modifications. Knowledge of the precise molecular mechanisms governing the intracellular redistribution process is still rather limited. Pubmed12842859 Pubmed16722822 Reactome Database ID Release 43203765 Reactome, http://www.reactome.org ReactomeREACT_12389 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 Hydrolysis of cAMP to 5' AMP by Phosphorylated PDE3B At the beginning of this reaction, 1 molecule of '3',5'-Cyclic AMP' is present. At the end of this reaction, 1 molecule of 'AMP' is present.<br><br> This reaction is mediated by the 'hydrolase activity' of 'Phosphorylated PDE3B'.<br> EC Number: 3.1.4.17 Pubmed8562305 Pubmed9102399 Reactome Database ID Release 43162425 Reactome, http://www.reactome.org ReactomeREACT_325 Activated prostacyclin receptor binds G-protein Gs Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed16460020 Reactome Database ID Release 43392852 Reactome, http://www.reactome.org ReactomeREACT_23938 Reviewed: Kunapuli, SP, 2010-06-07 The human prostacyclin receptor (IP) and G-protein alpha (s) physically interact through contacts between the IP iLP1 domain and the C-terminal residues of the G alpha (s) protein. Prostacyclin binds the Prostacyclin receptor PTGIR Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Prostacyclin binds the G-protein coupled prostacyclin receptor, often referred to as the IP receptor. Pubmed12446735 Pubmed2474350 Pubmed7514139 Reactome Database ID Release 43392849 Reactome, http://www.reactome.org ReactomeREACT_23795 Reviewed: Kunapuli, SP, 2010-06-07 Phosphorylation of Gorasp1, Golga2 and RAB1A by CDK1:CCNB Authored: Orlic-Milacic, M, 2012-07-20 EC Number: 2.7.11.22 Edited: Gillespie, ME, 2012-08-07 Pubmed10679020 Pubmed11238451 Pubmed11285137 Pubmed11306556 Pubmed15678101 Pubmed1902553 Pubmed7737117 Pubmed9753325 Reactome Database ID Release 432422970 Reactome, http://www.reactome.org ReactomeREACT_147793 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Wang, Yanzhuang, 2012-08-19 The existence of Gorasp1:Golga2:Uso1:Rab1:GTP complex was established by co-immunoprecipitation of exogenously expressed human RAB1A (identical sequence to rat Rab1A) from normal rat kidney cells, NRKs (Moyer et al. 2001). It was also shown that human RAB1B binds human GM130 (Weide et al. 2001). In mitotic prophase, human CDK1 (CDC2) in complex with either CCNB1 (cyclin B1) or CCNB2 (cyclin B2), as both CCNB1 and CCNB2 can localize to Golgi (Jackman et al. 1995, Draviam et al. 2001), was shown to phosphorylate recombinant rat Gorasp1 and Golga2, as well as RAB1A (Bailly et al. 1991, Lowe et al. 1998, Preisinger et al. 2005) . Phosphorylation of Golga2 and RAB1A impairs their association with Uso1 (Lowe et al. 1998, Seeman et al. 2000, Moyer et al. 2001). has a Stoichiometric coefficient of 5 Cleavage of P-ERBB4jmA isoforms by Adam17 Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 3.4.24 Edited: Matthews, L, 2011-11-07 Phosphorylated ligand-bound homodimers of ERBB4 JM-A isoforms, exogenously expressed in mouse fibroblasts, are cleaved by Adam17 metalloproteinase to yield ligand-bound ERBB4 extracellular domain and membrane bound ERBB4 fragment of 80 kDa (ERBB4m80). Pubmed10744726 Pubmed12869563 Reactome Database ID Release 431251988 Reactome, http://www.reactome.org ReactomeREACT_115992 Reviewed: Harris, RC, 2011-11-11 Reviewed: Zeng, F, 2011-11-11 Regulation of pyruvate dehydrogenase (PDH) complex Authored: Gopinathrao, G, 2007-11-26 20:29:38 GENE ONTOLOGYGO:0010510 Pubmed12676647 Reactome Database ID Release 43204174 Reactome, http://www.reactome.org ReactomeREACT_12528 Reviewed: D'Eustachio, P, 2008-01-11 20:49:08 The mitochondrial pyruvate dehydrogenase (PDH) complex catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis. PDH inactivation is crucial for glucose conservation when glucose is scarce, while adequate PDH activity is required to allow both ATP and fatty acid production from glucose. The mechanisms that control human PDH activity include its phosphorylation (inactivation) by pyruvate dehydrogenase kinases (PDK 1-4) and its dephosphorylation (activation, reactivation) by pyruvate dehydrogenase phosphate phosphatases (PDP 1 and 2). Isoform-specific differences in kinetic parameters, regulation, and phosphorylation site specificity of the PDKs introduce variations in the regulation of PDC activity in differing endocrine and metabolic states (Sugden and Holness 2003). Pyruvate metabolism Cori Cycle (interconversion of glucose and lactate) GENE ONTOLOGYGO:0006090 Pubmed2188967 Pubmed7273846 Pyruvate sits at an intersection of key pathways of energy metabolism. It is the end product of glycolysis and the starting point for gluconeogenesis, and can be generated by transamination of alanine. It can be converted by the pyruvate dehydrogenase complex to acetyl CoA (Reed and Hackert 1990) which can enter the TCA cycle or serve as the starting point for the syntheses of long chain fatty acids, steroids, and ketone bodies depending on the tissue and metabolic state in which it is formed. It also plays a central role in balancing the energy needs of various tissues in the body. Under conditions in which oxygen supply is limiting, e.g., in exercising muscle, or in the absence of mitochondria, e.g., in red blood cells, re-oxidation of NADH produced by glycolysis cannot be coupled to generation of ATP. Instead, re-oxidation is coupled to the reduction of pyruvate to lactate. This lactate is released into the blood, and is taken up primarily by the liver, where it is oxidized to pyruvate and can be used for gluconeogenesis (Cori 1981). Reactome Database ID Release 4370268 Reactome, http://www.reactome.org ReactomeREACT_2071 ACTIVATION GENE ONTOLOGYGO:0004622 Reactome Database ID Release 431524030 Reactome, http://www.reactome.org Pyruvate metabolism and Citric Acid (TCA) cycle Authored: Birney, E, D'Eustachio, P, Schmidt, EE, 2003-11-03 05:38:33 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pyruvate metabolism and the citric acid (TCA) cycle together link the processes of energy metabolism in a human cell with one another and with key biosynthetic reactions. Pyruvate, derived from the reversible oxidation of lactate or transamination of alanine, can be converted to acetyl CoA. Other sources of acetyl CoA include breakdown of free fatty acids and ketone bodies in the fasting state. Acetyl CoA can enter the citric acid cycle, a major source of reducing equivalents used to synthesize ATP, or enter biosynthetic pathways.<p>In addition to its role in energy generation, the citric acid cycle is a source of carbon skeletons for amino acid metabolism and other biosynthetic processes. One such process included here is the interconversion of 2-hydroxyglutarate, probably derived from porphyrin and amino acid metabolism, and 2-oxoglutarate (alpha-ketoglutarate), a citric acid cycle intermediate. Reactome Database ID Release 4371406 Reactome, http://www.reactome.org ReactomeREACT_1046 The citric acid (TCA) cycle and respiratory electron transport Authored: Birney, E, D'Eustachio, P, Schmidt, EE, 2003-11-03 05:38:33 Edited: Jassal, B, 2011-07-07 Reactome Database ID Release 431428517 Reactome, http://www.reactome.org ReactomeREACT_111083 The metabolism of pyruvate provides one source of acetyl-CoA which enters the citric acid (TCA, tricarboxylic acid) cycle to generate energy and the reducing equivalent NADH. These reducing equivalents are re-oxidized back to NAD+ in the electron transport chain (ETC), coupling this process with the export of protons across the inner mitochondrial membrane. The chemiosmotic gradient created is used to drive ATP synthesis. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 Pubmed10727395 Pubmed17555404 Pubmed18321209 Pubmed21550412 Reactome Database ID Release 431474151 Reactome, http://www.reactome.org ReactomeREACT_111176 Reviewed: D'Eustachio, P, 2011-08-23 Tetrahydrobiopterin (BH4) is an essential co-factor for the aromatic amino acid hydroxylases and glycerol ether monooxygenase and it regulates nitric oxide synthase (NOS) activity. Inherited BH4 deficiency leads to hyperphenylalaninemia, and dopamine and neurotransmitter deficiency in the brain. BH4 maintains enzymatic coupling to L-arginine oxidation to produce NO. Oxidation of BH4 to BH2 results in NOS uncoupling, resulting in superoxide (O2.-) formation rather than NO. Superoxide rapidly reacts with NO to produce peroxynitrite which can further uncouple NOS.<br>These reactive oxygen species (superoxide and peroxynitrite) can contribute to increased oxidative stress in the endothelium leading to atherosclerosis and hypertension (Thöny et al. 2000, Crabtree & Channon 2011, Schulz et al. 2008, Schmidt & Alp 2007). The synthesis, recycling and effects of BH4 are shown here. Three enzymes are required for the de novo biosynthesis of BH4 and two enzymes for the recycling of BH4. ACTIVATION GENE ONTOLOGYGO:0047144 Reactome Database ID Release 431524045 Reactome, http://www.reactome.org NOSTRIN mediated eNOS trafficking GENE ONTOLOGYGO:0050999 Pubmed12446846 Pubmed12842859 Pubmed16234328 Pubmed16722822 Reactome Database ID Release 43203641 Reactome, http://www.reactome.org ReactomeREACT_12541 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 eNOS traffic inducer (NOSTRIN) is a novel 506-amino acid eNOS-interacting protein. Along with a decrease in eNOS activity, NOSTRIN causes translocation of eNOS from the plasma membrane to intracellular vesicular structures. NOSTRIN functions as an adaptor protein through homotrimerization and recruitment of eNOS, dynamin-2, and N-WASP to its SH3 domain. Studies indicated that NOSTRIN may facilitate vesicle fission and endocytosis of eNOS by coordinating the function of dynamin and N-WASP, which in turn, recruits the Arp2/3 complex, initiating actin filament polymerization. Overall, this process is thought to occur via caveolar endocytosis. <br><br><br><br> ACTIVATION GENE ONTOLOGYGO:0008970 Reactome Database ID Release 431524121 Reactome, http://www.reactome.org NOSIP mediated eNOS trafficking GENE ONTOLOGYGO:0050999 Pubmed11149895 Pubmed12842859 Pubmed16135813 Pubmed16234328 Pubmed16722822 Reactome Database ID Release 43203754 Reactome, http://www.reactome.org ReactomeREACT_12510 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 eNOS-interacting protein (NOSIP) is a 34-kDa nucleocytoplasmic shuttling protein that binds to the COOH-terminal region (amino acids 366-486) of the eNOS oxygenase domain. This protein association promotes translocation of eNOS from the plasma membrane caveolae to the cytoskeleton and inhibits eNOS activity. Studies have found that NOSIP accumulates in the cytoplasm specifically during the G2 phase of the cell cycle. ACTIVATION GENE ONTOLOGYGO:0004622 Reactome Database ID Release 431524030 Reactome, http://www.reactome.org eNOS activation GENE ONTOLOGYGO:0050999 Pubmed10551886 Pubmed11208594 Pubmed12482742 Pubmed16722822 Reactome Database ID Release 43203615 Reactome, http://www.reactome.org ReactomeREACT_12477 Reviewed: Enikolopov, G, 2008-02-28 17:52:44 eNOS activity is regulated by numerous post-translational modifications including phosphorylation and acylation, which also modulate its interactions with other proteins and its subcellular localization.<p>In general, following myristoylation and palmitoylation, eNOS localizes to caveolae in the plasma membrane, where in resting cells, it is bound to caveolin and remains inactive. Several agonists that raise intracellular calcium concentrations promote calmodulin binding to eNOS and the dissociation of caveolin from the enzyme, leading to an activated eNOS-calmodulin complex.<p>Phosphorylation plays a significant role in regulating eNOS activity, especially the phosphorylation of Ser1177, located within the reductase domain, which increases enzyme activity by enhancing reductase activity and calcium sensitivity. In unstimulated, cultured endothelial cells, Ser1177 is rapidly phosphorylated following a variety of stimuli: fluid shear stress, insulin, estrogen, VEGF, or bradykinin. The kinases involved in this process depend upon the stimuli applied. For instance, shear stress phosphorylates Ser1177 by activating Akt and PKA; insulin activates both Akt and the AMP-activated protein kinase (AMPK); estrogen and VEGF mainly phosphorylate eNOS via Akt; whereas the bradykinin-induced phosphorylation of Ser1177 is mediated by CaMKII. When Ser1177 is phosphorylated, NO production is increased several-fold above basal levels.<p>The phosphorylation of a threonine residue (Thr 495), located in the CaM binding domain, is associated with a decrease in eNOS activity. When this residue is dephosphorylated, substantially more CaM binds to eNOS and elevates enzyme activity. Stimuli associated with dephosphorylation of Thr495 (e.g., bradykinin, histamine, and Ca2+ ionophores) also increase Ca2+ levels resulting in the phosphorylation of Ser1177.<p>Additional phosphorylation sites, such as Ser114 and Ser633, and tyrosine phosphorylation have all been detected, but their functional relevance remains unclear. It is speculated that the tyrosine phosphorylation of eNOS is unlikely to affect enzyme activity directly, but more likely to impact the protein-protein interactions with associated scaffolding and regulatory proteins. ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431602353 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524133 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524129 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008970 Reactome Database ID Release 431524134 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431524039 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004609 Reactome Database ID Release 431524158 Reactome, http://www.reactome.org Soluble guanylate cyclase converts GTP to cGMP Authored: Akkerman, JW, 2009-06-03 EC Number: 4.6.1.2 Edited: Jupe, S, 2010-06-07 Pubmed19089323 Reactome Database ID Release 43392152 Reactome, http://www.reactome.org ReactomeREACT_23790 Reviewed: Kunapuli, SP, 2010-06-07 Soluble guanylate cyclase (sGC) is a heterodimeric hemoprotein that selectively binds Nitric Oxide (NO). NO binding stimulates the synthesis of cGMP, which then binds to phosphodiesterases (PDE), ion-gated channels, and cGMP-dependent protein kinases (cGK) to regulate several physiological functions including vasodilation, platelet aggregation and neurotransmission. cGMP is degraded by PDEs Authored: Akkerman, JW, 2009-06-03 Cyclic GMP phosphodiesterase are hydrolases selective for cAMP (PDE4, 7 and 8), cGMP (PDE5, 6 and 9) or able to hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10 and 11).  The dual-specificity PDEs allow for cross-regulation of the cAMP and cGMP pathways, e.g. PDE2 can hydrolyse both, but binding of cGMP to the regulatory GAF-B domain increases cAMP affinity and hydrolysis.<br>PDE2, 3 and 5 are expressed in platelets. EC Number: 3.1.4.35 Edited: Jupe, S, 2010-06-07 Pubmed17307970 Pubmed8557689 Reactome Database ID Release 43418456 Reactome, http://www.reactome.org ReactomeREACT_23959 Reviewed: Kunapuli, SP, 2010-06-07 Incretin Synthesis, Secretion, and Inactivation Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-05-18 21:31:59 GENE ONTOLOGYGO:0050796 Incretins are peptide hormones produced by the gut that enhance the ability of glucose to stimulate insulin secretion from beta cells in the pancreas. Two incretins have been identified: Glucagon-like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP, initially named Gastric Inhibitory Peptide). Both are released by cells of the small intestine, GLP-1 from L cells and GIP from K cells.<br>The control of incretin secretion is complex. Fatty acids, phospholipids, glucose, acetylcholine, leptin, and Gastrin-releasing Peptide all stimulate secretion of GLP-1. Fatty acids and phospholipids are the primary stimulants of secretion of GIP in humans (carbohydrates have more effect in rodents).<br>Incretins secreted into the bloodstream are subject to rapid inactivation by Dipeptidyl Peptidase IV (DPP IV), which confers half-lives of only a few minutes onto GLP-1 and GIP. Inhibitors of DPP IV, for example sitagliptin, are now being used in the treatment of Type 2 diabetes. Pubmed17263764 Pubmed17498508 Pubmed19074620 Reactome Database ID Release 43400508 Reactome, http://www.reactome.org ReactomeREACT_23974 Reviewed: Bloom, SR, 2010-06-24 cGMP stimulates Protein Kinase G Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Protein Kinase G (PKG) is a homodimer held together by a leucine zipper present in the N terminus. Each member of the dimer has two cyclic GMP (cGMP) binding sites, one low affinity and one high affinity. PKG was first described in various arthropods. Mammals have two PKG genes, prkg1 and prkg2, that encode PKG1 (cGKI) and PKG2 (cGKII). The N terminus (the first 90-100 residues) of PKG1 is encoded by two alternatively spliced exons that produce the isoforms PKG1alpha and PKG1beta. Both are cytosolic. PKG1 is present in high concentrations (>0.1 µM) in all smooth muscles, platelets, cerebellum, hippocampus, dorsal root ganglia, neuromuscular endplate, and kidney. PKG1beta is the predominant PKG isoform in platelets. PKG1 is required for the inhibition of platelet activation by NO/cGMP. PKG2 is anchored at the plasma membrane by myristoylation of the N-terminal Gly-2 residue. PKG2 phosphorylates cystic fibrosis transmembrane conductance regulator. Pubmed10209042 Pubmed15545263 Reactome Database ID Release 43418451 Reactome, http://www.reactome.org ReactomeREACT_23934 Reviewed: Kunapuli, SP, 2010-06-07 has a Stoichiometric coefficient of 2 PKG1 phosphorylates BK channels Authored: Akkerman, JW, 2009-06-03 EC Number: 2.7.11.12 Edited: Jupe, S, 2010-06-07 NO-induced activation of cGMP-dependent protein kinase (PKG) increases the open probability of large conductance Ca2+-activated K+ channels (BK channels) by direct phosphorylation. Pubmed10196172 Reactome Database ID Release 43418549 Reactome, http://www.reactome.org ReactomeREACT_23991 Reviewed: Kunapuli, SP, 2010-06-07 PKG1 phosphorylates IRAG:IP3R1 inhibiting IP3-stimulated Ca2+ release Authored: Akkerman, JW, 2009-06-03 EC Number: 2.7.11.12 Edited: Jupe, S, 2010-06-07 IRAG, PKG1(cGKI), and IP3 receptor type 1 can be isolated as a complex in human platelets. Phosphorylation of IRAG by PKG1 inhibits IP3 receptor-mediated Ca2+ release, representing the primary mechanism by which NO suppresses platelet activation. Pubmed16990611 Reactome Database ID Release 43418442 Reactome, http://www.reactome.org ReactomeREACT_24000 Reviewed: Kunapuli, SP, 2010-06-07 Transport of Ca++ from platelet dense tubular system to cytoplasm Edited: Jupe, S, 2009-09-09 Pubmed11413485 Pubmed1693919 Pubmed17429043 Reactome Database ID Release 43139854 Reactome, http://www.reactome.org ReactomeREACT_118637 The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. <br>Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms. Binding of ATP to P2X1 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to the binding of extracellular adenosine triphosphate (ATP). All members of the family are thought to be functionally trimeric. The ionotropic P2X1 receptor has relatively high calcium permeability. It is predominantly expressed in smooth muscle and platelets, but also has a role in synaptic transmission between neurons and from neurons to smooth muscle. Mouse studies suggest that this receptor is essential for normal male reproductive function. ADP has been suggested as a ligand for this receptor but this is no longer widely accepted. Pubmed12907444 Pubmed9606184 Reactome Database ID Release 43419490 Reactome, http://www.reactome.org ReactomeREACT_23915 Reviewed: Kunapuli, SP, 2010-06-07 Insulin effects increased synthesis of Xylulose-5-Phosphate Authored: Gopinathrao, G, 2005-05-13 15:44:47 GENE ONTOLOGYGO:0005999 ISBN0781721458 One of the downstream effects of insulin, mediated via protein phosphatase 2A (PP2A), is increased synthesis of Fructose-2,6-bisphosphate, an allosteric activator of phosphofructokinase 1 (PFK1). PFK1 in turn catalyzes the committed step of glycolysis so the net effect of this whole sequence of events set off by insulin is to increase cytosolic concentrations of the small molecules formed in the course of glycolysis. This in turn drives the increased synthesis of Xylulose-5-phosphate, itself a positive regulator of PP2A. Pubmed12110366 Pubmed3539386 Reactome Database ID Release 43163754 Reactome, http://www.reactome.org ReactomeREACT_939 Gs activation by prostacyclin receptor Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed15980156 Reactome Database ID Release 43392870 Reactome, http://www.reactome.org ReactomeREACT_23823 Reviewed: Kunapuli, SP, 2010-06-07 The G-protein alpha subunit exchanges GDP for GTP PKA-mediated phosphorylation of key metabolic factors Authored: Gopinathrao, G, 2005-05-12 21:32:40 GENE ONTOLOGYGO:0007243 Pubmed12626323 Pubmed12721358 Reactome Database ID Release 43163358 Reactome, http://www.reactome.org ReactomeREACT_1525 Upon dissociation of protein kinase A (PKA) tetramers in the presence of cAMP, the released PKA catalytic monomers phosphorylate specific serine and threonine residues of several metabolic enzymes. These target enzymes include glycogen phosphorylase kinase, glycogen synthase and PF2K-Pase. PKA also phosphorylates ChREBP (Carbohydrate Response Element Binding Protein), preventing its movement into the nucleus and thus its function as a positive transcription factor for genes involved in glycolytic and lipogenic reactions. Dissociation of the Prostacyclin receptor:Gs complex Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed18577758 Pubmed3141418 Pubmed8736705 Reactome Database ID Release 43392874 Reactome, http://www.reactome.org ReactomeREACT_23792 Reviewed: Kunapuli, SP, 2010-06-07 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). PP2A-mediated dephosphorylation of key metabolic factors A member of the PP2A family of phosphatases dephosphorylates both cytosolic and nuclear forms of ChREBP (Carbohydrate Response Elemant Binding Protein). In the nucleus, dephosphorylated ChREBP complexes with MLX protein and binds to ChRE sequence elements in chromosomal DNA, activating transcription of genes involved in glycolysis and lipogenesis. The phosphatase is activated by Xylulose-5-phosphate, an intermediate of the pentose phosphate pathway (Kabashima et al. 2003). The rat enzyme has been purified to homogeneity and shown by partial amino acid sequence analysis to differ from previously described PP2A phosphatases (Nishimura and Uyeda 1995) - the human enzyme has not been characterized. Authored: Gopinathrao, G, 2005-05-12 21:32:40 Pubmed12684532 Pubmed12721358 Pubmed7592845 Reactome Database ID Release 43163767 Reactome, http://www.reactome.org ReactomeREACT_705 Nitric Oxide Synthase (NOS) produces Nitric Oxide (NO) Authored: Akkerman, JW, 2009-06-03 EC Number: 1.14.13.39 Edited: Jupe, S, 2010-06-07 Nitric oxide synthase (NOS) produces NO from L-arginine. There are three isoforms of NOS, endothelial, neuronal and inducible (eNOS, nNOS, and iNOS). eNOS and nNOS are constitutively expressed while iNOS is induced by immunostimulatory signals. The constitutive isoforms are regulated in vivo by the binding of calcium and calmodulin. NO produced by NOS acts as a signalling molecule by diffusing across cell membranes to activate soluble guanylate cyclase (sGC). Pubmed19089323 Reactome Database ID Release 43418436 Reactome, http://www.reactome.org ReactomeREACT_23872 Reviewed: Kunapuli, SP, 2010-06-07 ACTIVATION GENE ONTOLOGYGO:0004307 Reactome Database ID Release 431500586 Reactome, http://www.reactome.org AMPK inhibits chREBP transcriptional activation activity AMP-activated protein kinase (AMPK) is a sensor of cellular energy levels. A high cellular ratio of AMP:ATP triggers the phosphorylation and activation of AMPK. Activated AMPK in turn phosphorylates a wide array of target proteins, as shown in the figure below (reproduced from (Hardie et al. 2003), with the permission of D.G. Hardie). These targets include ChREBP (Carbohydrate Response Element Binding Protein), whose inactivation by phosphorylation reduces transcription of key enzymes of the glycolytic and lipogenic pathways. Authored: Gopinathrao, G, 2005-05-12 21:32:40 GENE ONTOLOGYGO:0042304 Pubmed10698692 Pubmed11724780 Pubmed12829246 Pubmed15509864 Reactome Database ID Release 43163680 Reactome, http://www.reactome.org ReactomeREACT_1988 NO binds to Guanylate Cyclase Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed19089323 Reactome Database ID Release 43392143 Reactome, http://www.reactome.org ReactomeREACT_23945 Reviewed: Kunapuli, SP, 2010-06-07 Soluble guanylate cyclase (sGC) is a heterodimeric hemoprotein that selectively binds Nitric Oxide (NO). NO binding stimulates the synthesis of cGMP, which then binds to phosphodiesterases (PDE), ion-gated channels, and cGMP-dependent protein kinases (cGK) to regulate several physiological functions including vasodilation, platelet aggregation and neurotransmission. ACTIVATION GENE ONTOLOGYGO:0008195 Reactome Database ID Release 431500627 Reactome, http://www.reactome.org Synthesis, Secretion, and Inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-09-09 In K cells of the intestine the transcription factors PAX6 and PDX-1 activate transcription of the gene encoding Glucose-dependent Insulinotropic Polypeptide (GIP, first called Gastric Inhibitory Peptide). ProGIP is cleaved in secretory granules by Prohormone Convertase 1 (PC1) at 2 sites to yield mature GIP. In response to fat the GIP is secreted into the bloodstream. The half-life of GIP in the bloodstream is determined by Dipeptidyl Peptidase IV, which cleaves 2 amino acids at the amino terminus of GIP, rendering it biologically inactive. Pubmed17263764 Pubmed17498508 Pubmed19074620 Reactome Database ID Release 43400511 Reactome, http://www.reactome.org ReactomeREACT_23824 Reviewed: Bloom, SR, 2010-06-24 ACTIVATION GENE ONTOLOGYGO:0004306 Reactome Database ID Release 431500628 Reactome, http://www.reactome.org Synthesis, Secretion, and Inactivation of Glucagon-like Peptide-1 (GLP-1) Authored: May, B, 2009-05-18 21:31:59 Edited: May, B, 2009-09-09 In L cells of the intestine the transcription factors TCF-4 (TCF7L2) and Beta-catenin form a heterodimer and bind the G2 enhancer of the Proglucagon gene GCG,activating its transcription to yield Proglucagon mRNA and, following translation, Proglucagon protein. The prohormone convertase PC1 present in the secretory granules of L cells cleaves Proglucagon at two sites to yield mostly Glucagon-like Peptide-1 (7-36) with a small amount of Glucagon-like Peptide-1 (7-37). Glucagon-like Peptide-1 (7-36 and 7-37) (GLP-1) is secreted into the bloodstream in response to glucose, fatty acids, insulin, leptin, gastrin-releasing peptide, cholinergic transmitters, beta-adrenergic transmitters, and peptidergic transmitters. The half-life of GLP-1 in the bloodstream is determined by Dipeptidyl Peptidase IV, which cleaves 2 amino acids at the amino terminus of GLP-1, rendering it biologically inactive. Pubmed11564718 Pubmed1499644 Pubmed17263764 Pubmed17498508 Pubmed17928588 Pubmed19074620 Reactome Database ID Release 43381771 Reactome, http://www.reactome.org ReactomeREACT_24019 Reviewed: Bloom, SR, 2010-06-24 ACTIVATION GENE ONTOLOGYGO:0052732 Reactome Database ID Release 432267363 Reactome, http://www.reactome.org PKA activation in glucagon signalling Adenylate cyclase catalyses the synthesis of cyclic AMP (cAMP) from ATP. In the absence of cAMP, protein kinase A (PKA) exists as inactive tetramers of two catalytic subunits and two regulatory subunits. cAMP binding to PKA tetramers causes them to dissociate and release their catalytic subunits as active monomers. Four isoforms of the regulatory subunit are known, that differ in their tissue specificity and functional characteristics, but the specific isoform activated in response to glucagon signaling has not yet been identified. Authored: Gopinathrao, G, D'Eustachio, P, 2005-05-19 14:01:31 Reactome Database ID Release 43164378 Reactome, http://www.reactome.org ReactomeREACT_1946 ACTIVATION GENE ONTOLOGYGO:0004305 Reactome Database ID Release 431500609 Reactome, http://www.reactome.org Glucagon signaling in metabolic regulation Authored: Gopinathrao, G, 2005-04-27 21:11:16 GENE ONTOLOGYGO:0071377 Glucagon and insulin are peptide hormones released from the pancreas into the blood, that normally act in complementary fashion to stabilize blood glucose concentration. When blood glucose levels rise, insulin release stimulates glucose uptake from the blood, glucose breakdown (glycolysis), and glucose storage as glycogen. When blood glucose levels fall, glucagon release stimulates glycogen breakdown and de novo glucose synthesis (gluconeogenesis), while inhibiting glycolysis and glycogen synthesis.<br>At a molecular level, the binding of glucagon to the extracellular face of its receptor causes conformational changes in the receptor that allow the dissociation and activation of subunits Gs and Gq. The activation of Gq leads to the activation of phospholipase C, production of inositol 1,4,5-triphosphate, and subsequent release of intracellular calcium. The activation of Gs leads to activation of adenylate cyclase, an increase in intracellular cAMP levels, and activation of protein kinase A (PKA). Active PKA phosphorylates key enzymes of glycogenolysis, glycogenesis, gluconeogenesis, and glycolysis, modifying their activities. These signal transduction events, and some of their downstream consequences, are illustrated below (adapted from Jiang and Zhang, 2003). Pubmed12626323 Reactome Database ID Release 43163359 Reactome, http://www.reactome.org ReactomeREACT_1665 ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 431500582 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016411 Reactome Database ID Release 431500577 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016411 Reactome Database ID Release 431500577 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004465 Reactome Database ID Release 431500597 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004144 Reactome Database ID Release 431500598 Reactome, http://www.reactome.org ChREBP activates metabolic gene expression Authored: Gopinathrao, G, 2005-05-12 21:32:40 ChREBP (Carbohydrate Response Element Binding Protein) is a large multidomain protein containing a nuclear localization signal near its amino terminus, polyproline domains, a basic helix-loop-helix-leucine zipper domain, and a leucine-zipper-like domain (Uyeda et al., 2002). Its dephosphorylation in response to molecular signals associated with the well-fed state allows it to enter the nucleus, interact with MLX protein, and bind to ChRE DNA sequence motifs near Acetyl-CoA carboxylase, Fatty acid synthase, and Pyruvate kinase (L isoform) genes (Ishi et al.2004). This sequence of events is outlined schematically in the picture below (adapted from Kawaguchi et al. (2001) - copyright (2001) National Academy of Sciences, U.S.A.). GENE ONTOLOGYGO:0031325 Pubmed11698644 Pubmed12110366 Pubmed15118080 Pubmed15496471 Pubmed15664996 Reactome Database ID Release 43163765 Reactome, http://www.reactome.org ReactomeREACT_2122 Integration of energy metabolism Authored: Gopinathrao, G, D'Eustachio, P, 2005-05-11 18:49:22 GENE ONTOLOGYGO:0006112 Many hormones that affect individual physiological processes including the regulation of appetite, absorption, transport, and oxidation of foodstuffs influence energy metabolism pathways. While <b>insulin</b> mediates the storage of excess nutrients, <b>glucagon</b> is involved in the mobilization of energy resources in response to low blood glucose levels, principally by stimulating hepatic glucose output. Small doses of glucagon are sufficient to induce significant glucose elevations. These hormone-driven regulatory pathways enable the body to sense and respond to changed amounts of nutrients in the blood and demands for energy.<br>Glucagon and Insulin act through various metabolites and enzymes that target specific steps in metabolic pathways for sugar and fatty acids. The processes responsible for the long-term control of fat synthesis and short term control of glycolysis by key metabolic products and enzymes are annotated in this module as six specific pathways:<br><b>Pathway 1. Glucagon signalling in metabolic pathways:</b> In response to low blood glucose, pancreatic alpha-cells release glucagon. The binding of glucagon to its receptor results in increased cAMP synthesis, and Protein Kinase A (PKA) activation.<br><b>Pathway 2. PKA mediated phosphorylation:</b>PKA phosphorylates key enzymes, e.g., 6-Phosphofructo-2-kinase /Fructose-2,6-bisphosphatase (PF2K-Pase) at serine 36, and regulatory proteins, e.g., Carbohydrate Response Element Binding Protein (ChREBP) at serine 196 and threonine 666.<br>Insulin mediated responses to high blood glucose will be annotated in future versions of Reactome. In brief, the binding of insulin to its receptor leads to increased protein phosphatase activity and to hydrolysis of cAMP by cAMP phosphodiesterase. These events counteract the regulatory effects of glucagon.<br><b>Pathway 3: Insulin stimulates increased synthesis of Xylulose-5-phosphate (Xy-5-P)</b>. Activation of the insulin receptor results indirectly in increased Xy-5-P synthesis from Glyceraldehyde-3-phosphate and Fructose-6-phosphate. Xy-5-P, a metabolite of the pentose phosphate pathway, stimulates protein phosphatase PP2A.<br><b>Pathway 4: AMP Kinase (AMPK) mediated response to high AMP:ATP ratio:</b> In response to diet with high fat content or low energy levels, the cytosolic AMP:ATP ratio is increased. AMP triggers a complicated cascade of events. In this module we have annotated only the phosphorylation of ChREBP by AMPK at serine 568, which inactivates this transcription factor.<br><b>Pathway 5: Dephosphorylation of key metabolic factors by PP2A: </b>Xy-5-P activated PP2A efficiently dephosphorylates phosphorylated PF2K-Pase resulting in the higher output of F-2,6-P2 that enhances PFK activity in the glycolytic pathway. PP2A also dephosphorylates (and thus activates) cytosolic and nuclear ChREBP.<br><b>Pathway 6: Transcriptional activation of metabolic genes by ChREBP:</b> Dephosphorylated ChREBP activates the transcription of genes involved in glucose metabolism such as pyruvate kinase, and lipogenic genes such as acetyl-CoA carboxylase, fatty acid synthetase, acyl CoA synthase and glycerol phosphate acyl transferase.<br> The illustration below summarizes this network of events. Black lines are metabolic reactions, red lines are negative regulatory events, and green lines are positive regulatory events (figure reused with permission from Veech (2003) - Copyright (2003) National Academy of Sciences, U.S.A.). Pubmed12626323 Pubmed12684532 Pubmed12721358 Pubmed15509864 Reactome Database ID Release 43163685 Reactome, http://www.reactome.org ReactomeREACT_1505 Reviewed: Rush, MG, 2005-09-10 14:11:36 ACTIVATION GENE ONTOLOGYGO:0004366 Reactome Database ID Release 431500616 Reactome, http://www.reactome.org Glycosphingolipid metabolism Authored: Jassal, B, 2011-10-14 Edited: Jassal, B, 2011-10-14 GENE ONTOLOGYGO:0006687 Pubmed20919643 Reactome Database ID Release 431660662 Reactome, http://www.reactome.org ReactomeREACT_116105 Reviewed: Stephan, R, 2011-10-31 The steps involved in the synthesis of glycosphingolipids (sphingolipids with one or more sugars attached) are annotated here (Gault et al. 2010). ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431500631 Reactome, http://www.reactome.org Sphingolipid de novo biosynthesis Authored: D'Eustachio, P, 2009-08-20 Edited: Jassal, B, 2011-10-14 GENE ONTOLOGYGO:0030148 Pubmed12011104 Pubmed20919643 Reactome Database ID Release 431660661 Reactome, http://www.reactome.org ReactomeREACT_115810 The main steps involved in de novo sphingolipid synthesis are annotated here (Merrill 2002, Gault et al. 2010). ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431500640 Reactome, http://www.reactome.org Sphingolipid metabolism Authored: D'Eustachio, P, 2009-08-20 Edited: D'Eustachio, P, 2009-08-20 GENE ONTOLOGYGO:0006665 Pubmed12011104 Pubmed18165232 Pubmed18216770 Reactome Database ID Release 43428157 Reactome, http://www.reactome.org ReactomeREACT_19323 Reviewed: Hannun, YA, Luberto, C, 2009-11-18 Reviewed: Jassal, B, 2009-08-20 Sphingolipids are derivatives of long chain sphingoid bases such as sphingosine (trans-1,3-dihydroxy 2-amino-4-octadecene), an 18-carbon unsaturated amino alcohol which is the most abundant sphingoid base in mammals. Amide linkage of a fatty acid to sphingosine yields ceramides. Esterification of phosphocholine to ceramides yields sphingomyelin, and ceramide glycosylation yields glycosylceramides. Introduction of sialic acid residues yields gangliosides. These molecules appear to be essential components of cell membranes, and intermediates in the pathways of sphingolipid synthesis and breakdown modulate processes including apoptosis and T cell trafficking.<p>While sphingolipids are abundant in a wide variety of foodstuffs, these dietary molecules are mostly degraded by the intestinal flora and intestinal enzymes. The body primarily depends on de novo synthesis for its sphingolipid supply (Hannun and Obeid 2008; Merrill 2002). De novo synthesis proceeds in four steps: the condensation of palmitoyl-CoA and serine to form 3-ketosphinganine, the reduction of 3-ketosphinganine to sphinganine, the acylation of sphinganine with a long-chain fatty acyl CoA to form dihydroceramide, and the desaturation of dihydroceramide to form ceramide.<p>Other sphingolipids involved in signaling are derived from ceramide and its biosynthetic intermediates. These include sphinganine (dihydrosphingosine) 1-phosphate, phytoceramide, sphingosine, and sphingosine 1-phosphate.<p>Sphingomyelin is synthesized in a single step in the membrane of the Golgi apparatus from ceramides generated in the endoplasmic reticulum (ER) membrane and transferred to the Golgi by CERT (ceramide transfer protein), an isoform of COL4A3BP that is associated with the ER membrane as a complex with PPM1L (protein phosphatase 1-like) and VAPA or VAPB (VAMP-associated proteins A or B). Sphingomyelin synthesis appears to be regulated primarily at the level of this transport process through the reversible phosphorylation of CERT (Saito et al. 2008).<br> ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431500599 Reactome, http://www.reactome.org Regulation of Insulin Secretion by Free Fatty Acids Authored: May, B, 2009-06-08 Edited: May, B, 2009-06-08 Free fatty acids augment the glucose-triggered secretion of insulin. The augmentation is believed to be due to the additive effects of the activation of the free fatty acid receptor 1 (FFAR1 or GPR40) and the metabolism of free fatty acids within the pancreatic beta cell. This module describes each pathway. Pubmed15047616 Pubmed17130640 Pubmed17395749 Pubmed18606873 Pubmed18827341 Reactome Database ID Release 43400451 Reactome, http://www.reactome.org ReactomeREACT_19375 Reviewed: Kebede, M, 2009-09-09 Reviewed: Madiraju, MS, 2009-10-02 Reviewed: Poitout, V, 2009-09-09 ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431602403 Reactome, http://www.reactome.org Regulation of Insulin Secretion by Acetylcholine Acetylcholine released by parasympathetic nerve endings in the pancreas causes a potentiation of insulin release when glucose is present at concentrations greater than about 7 mM. Acetylcholine binds the Muscarinic Acetylcholine Receptor M3 on pancreatic beta cells. The binding has two effects: an increase in permeability of the cell to Na+ ions through an unknown mechanism, and the activation of Phospholipase C beta-1 through a heterotrimeric G protein, G(q).<br>After acetylcholine binds the Muscarinic Acetycholine Receptor M3, the receptor activates the G protein Gq by causing the alpha subunit of Gq to exchange GDP for GTP. Activation of Gq in turn activates Phospholipase C beta-1. Phospholipase C beta-1 hydrolyzes the phosphodiester bond at the third position of phosphoinositol 4,5-bisphosphate, producing diacylglycerols (DAG) and inositol 1,4,5-trisphosphate.<br>DAG remains in the cell membrane and causes Protein Kinase C alpha (PKC alpha) to translocate from the cytosol to the membrane. This results in the activation of PKC alpha which then phosphorylates target proteins on serine and threonine residues. One known target of PKC alpha is Myristoylated Alanine-rich C Kinase Substrate (MARCKS), which is believed to affect vesicle transport and may be responsible for the increased traffic of insulin granules seen in response to acetylcholine.<br>Inositol trisphophate binds a receptor, the IP3 receptor, on calcium stores in the cell (probably the endoplasmic reticulum). The release of calcium into the cytosol stimulates the exocytosis of insulin granules. Authored: May, B, 2009-05-28 03:44:04 Edited: May, B, 2009-05-28 03:44:04 Pubmed11588141 Pubmed12161432 Reactome Database ID Release 43399997 Reactome, http://www.reactome.org ReactomeREACT_18405 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 ACTIVATION GENE ONTOLOGYGO:0004630 Reactome Database ID Release 431500629 Reactome, http://www.reactome.org Inhibition of Insulin Secretion by Adrenaline/Noradrenaline Authored: May, B, 2009-05-27 03:41:50 Edited: May, B, 2009-05-27 03:41:50 Pubmed10449730 Pubmed12684222 Pubmed14514350 Pubmed17900700 Pubmed18162464 Pubmed7641683 Pubmed8997178 Reactome Database ID Release 43400042 Reactome, http://www.reactome.org ReactomeREACT_18339 Reviewed: D'Eustachio, P, 2009-06-02 00:48:17 The catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) inhibit insulin secretion from pancreatic beta cells. Four effects are seen in the cells:<br>1. Inhibition of exocytosis of secretory granules, the major effect.<br>2. Opening of ATP-sensitive potassium channels (KATP channels) and repolarization of the cell.<br>3. Closing of L-type voltage-dependent calcium channels and inhibition of calcium influx.<br>4. Inhibition of adenylyl cyclase activity.<br>The first event in adrenaline/noradrenaline signaling in beta cells is the binding of adrenaline or noradrenaline to alpha-2 adrenergic receptors, which are G-protein coupled receptors. Binding activates the alpha subunits in heterotrimeric Gi and Go complexes to exchange GDP for GTP, forming the active G alpha:GTP complex. Experiments using specific antibodies against the alpha subunits in mice show that Gi alpha-1, Gi alpha-2, and Go alpha-2 are responsible for adrenergic effects. The exact beta and gamma subunits of the heterotrimeric G-proteins are unknown.<br>After activation by GTP, the heterotrimeric complex dissociates into the G alpha:GTP complex and the beta:gamma complex. The G alpha:GTP complex causes the inhibition of exocytosis by an unknown mechanism that involves protein acylation. This is responsible for most of the observed inhibition of insulin secretion. Additionally, the G alpha:GTP complex activates (opens) KATP channels, allowing the cell to repolarize. The beta:gamma complex inhibits (closes) voltage-dependent calcium channels, reducing the intracellular calcium concentration, and inhibits adenylyl cyclase, reducing the intracellular cAMP concentration. Regulation of Insulin Secretion Authored: May, B, 2009-05-28 15:33:45 Edited: May, B, 2009-05-28 15:33:45 GENE ONTOLOGYGO:0050796 Pancreatic beta cells integrate signals from several metabolites and hormones to control the secretion of insulin. In general, glucose triggers insulin secretion while other factors can amplify or inhibit the amount of insulin secreted in response to glucose. Factors which increase insulin secretion include the incretin hormones Glucose-dependent insulinotropic polypeptide (GIP and glucagon-like peptide-1 (GLP-1), acetylcholine, and fatty acids. Factors which inhibit insulin secretion include adrenaline and noradrenaline.<p>Increased blood glucose levels from dietary carbohydrate play a dominant role in insulin release from the beta cells of the pancreas. Glucose catabolism in the beta cell is the transducer that links increased glucose levels to insulin release. Glucose uptake and glycolysis generate cytosolic pyruvate; pyruvate is transported to mitochondria and converted both to oxaloacetate which increases levels of TCA cycle intermediates, and to acetyl-CoA which is oxidized to CO2 via the TCA cycle. The rates of ATP synthesis and transport to the cytosol increase, plasma membrane ATP-sensitive inward rectifying potassium channels (KATP channels) close, the membrane depolarizes, and voltage-gated calcium channels in the membrane open (Muoio and Newgard 2008; Wiederkehr and Wollheim 2006).<p>Elevated calcium concentrations near the plasma membrane cause insulin secretion in two phases: an initial high rate within minutes of glucose stimulation and a slow, sustained release lasting longer than 30 minutes. In the initial phase, 50-100 insulin granules already docked at the membrane are exocytosed. Exocytosis is rendered calcium-dependent by Synaptotagmin V/IX, a calcium-binding membrane protein located in the membrane of the docked granule, although the exact action of Synapototagmin in response to calcium is unknown. Calcium also causes a translocation of reserve granules within the cell towards the plasma membrane for release in the second, sustained phase of secretion. Human cells contain L-type (continually reopening), P/Q-type (long burst), R-type (long burst), and T-type (short burst) calcium channels and these partly account for differences between the two phases of secretion. Other factors that distinguish the two phases are not yet fully known (Bratanova-Tochkova et al. 2002; Henquin 2000; MacDonald et al. 2005). Pubmed11078440 Pubmed11815463 Pubmed16321791 Pubmed16556766 Pubmed18200017 Reactome Database ID Release 43422356 Reactome, http://www.reactome.org ReactomeREACT_18325 Reviewed: D'Eustachio, P, 2009-09-07 ACTIVATION GENE ONTOLOGYGO:0004806 Reactome Database ID Release 431500645 Reactome, http://www.reactome.org Regulation of Insulin Secretion by Glucagon-like Peptide-1 Authored: May, B, 2009-05-28 03:42:50 Edited: May, B, 2009-05-28 03:42:50 Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in the intestine in response to glucose and fatty acids. GLP-1 circulates to the beta cells of the pancreas where it binds a G-protein coupled receptor, GLP-1R, on the plasma membrane. The binding activates the heterotrimeric G-protein G(s), causing the alpha subunit of G(s) to exchange GDP for GTP and dissociate from the beta and gamma subunits.<br>The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors.<br>Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene.<br>cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A.. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane. Pubmed11078440 Pubmed11815463 Pubmed12475787 Pubmed15569269 Pubmed17306374 Pubmed17900700 Pubmed8830891 Pubmed9914469 Reactome Database ID Release 43381676 Reactome, http://www.reactome.org ReactomeREACT_18274 Reviewed: Gillespie, ME, 2009-06-02 00:59:01 Regulation of Insulin Secretion by Fatty Acids Bound to GPR40 (FFAR1) Authored: May, B, 2009-08-28 Edited: May, B, 2009-08-28 Fatty acids augment the glucose triggered secretion of insulin through two mechanisms: intracellular metabolism and activation of FFAR1 (GPR40), a G-protein coupled receptor. Based on studies with inhibitors of G proteins such as pertussis toxin FFAR1 is believed to signal through Gq/11. Binding of free fatty acids by FFAR1 activates the heterotrimeric Gq complex which then activates Phospholipase C, producing inositol 1,4,5-trisphosphate and eventually causing the release of intracellular calcium into the cytosol. From experiments in knockout mice it is estimated that signaling through FFAR1 is responsible for about 50% of the augmentation of insulin secretion produced by free fatty acids. Reactome Database ID Release 43434316 Reactome, http://www.reactome.org ReactomeREACT_19193 Reviewed: Kebede, M, 2009-09-09 Reviewed: Madiraju, MS, 2009-10-02 Reviewed: Poitout, V, 2009-09-09 ACTIVATION GENE ONTOLOGYGO:0047173 Reactome Database ID Release 43975652 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431500640 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016287 Reactome Database ID Release 431500614 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43193170 Reactome, http://www.reactome.org Arachidonic acid metabolism Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 Eicosanoids, oxygenated, 20-carbon fatty acids, are autocrine and paracrine signaling molecules that modulate physiological processes including pain, fever, inflammation, blood clot formation, smooth muscle contraction and relaxation, and the release of gastric acid. Eicosanoids are synthesized in humans primarily from arachidonic acid (all-cis 5,8,11,14-eicosatetraenoic acid) that is released from membrane phospholipids. Once released, arachidonic acid is acted on by prostaglandin G/H synthases (PTGS, also known as cyclooxygenases (COX)) to form prostaglandins and thromboxanes, by arachidonate lipoxygenases (ALOX) to form leukotrienes, epoxygenases (cytochrome P450s and epoxide hydrolase) to form epoxides such as 15-eicosatetraenoic acids, and omega-hydrolases (cytochrome P450s) to form hydroxyeicosatetraenoic acids (Buczynski et al. 2009, Vance & Vance 2008).<br>Levels of free arachidonic acid in the cell are normally very low so the rate of synthesis of eicosanoids is determined primarily by the activity of phospholipase A2, which mediates phospholipid cleavage to generate free arachidonic acid. The enzymes involved in arachidonic acid metabolism are typically constitutively expressed so the subset of these enzymes expressed by a cell determines the range of eicosanoids it can synthesize.<br>Eicosanoids are unstable, undergoing conversion to inactive forms with half-times under physiological conditions of seconds or minutes. Many of these reactions appear to be spontaneous. GENE ONTOLOGYGO:0019369 ISBN978-0-444-53219-0 Pubmed19244215 Reactome Database ID Release 432142753 Reactome, http://www.reactome.org ReactomeREACT_147851 Reviewed: Rush, MG, 2012-11-10 ACTIVATION GENE ONTOLOGYGO:0004498 Reactome Database ID Release 43209953 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004197 Reactome Database ID Release 43350178 Reactome, http://www.reactome.org Synthesis of Leukotrienes (LT) and Eoxins (EX) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:0006691 ISBN978-0-444-53219-0 Leukotrienes (LTs) are biologically active molecules formed in response to inflammatory stimuli. They cause contraction of bronchial smooth muscles, stimulation of vascular permeability, and attraction and activation of leukocytes. LTs were discovered in 1938 and were termed the "slow release substance" (SRS) until their structures were determined in 1979 and they were then renamed to leukotrienes. LTs are derived from arachidonic acid through action by arachidonate 5-lipoxygenase (ALOX5). Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are generated as products derived from leukotriene A4 (LTA4). Eoxins are generated from leukotrienes (LTs) and resemble cysteinyl leukotrienes but have a different three-dimensional structure (Murphy & Gijon 2007, Hammarstrom 1983, MA.Claesson 2009, Vance & Vance 2008, Buczynski et al. 2009). Pubmed17623009 Pubmed19130894 Pubmed19244215 Pubmed6311078 Reactome Database ID Release 432142691 Reactome, http://www.reactome.org ReactomeREACT_150420 Reviewed: Rush, MG, 2012-11-10 ACTIVATION GENE ONTOLOGYGO:0042954 Reactome Database ID Release 43350169 Reactome, http://www.reactome.org Synthesis of Prostaglandins (PG) and Thromboxanes (TX) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:0019371 ISBN978-0-444-53219-0 Pubmed19244215 Pubmed20655950 Reactome Database ID Release 432162123 Reactome, http://www.reactome.org ReactomeREACT_150149 Reviewed: Rush, MG, 2012-11-10 The bioactive prostaglandin (PG) signalling molecules, including PGA2, PGE2, PGF2a, and PGI2 (prostacyclin) are synthesised from arachidonic acid and its products by various prostaglandin synthase type enzymes. Prostaglandin H2 (PGH2) is the starting point for the synthesis of Thromboxanes (TXs) (Buczynski et al. 2009, Vance & Vance 2008). PGs and TXs are collectively known as the prostanoids.<br>Two enzymes, PTGS1 and 2 (COX1 and 2) both catalyze the two-step conversion of arachidonic acid to PGH2. PTGS1 is constitutively expressed in many cell types while PTGS2 is induced in response to stress and mediates the syntheses of prostaglandins associated with pain, fever, and inflammation. Aspirin irreversibly inactivates both enzymes (though it acts more efficiently on PTGS1), explaining both its antiinflammatory effects and side effects like perturbed gastic acid secretion. Drugs like celecoxib, by specifically inhibiting PTGS2, have a strong anti-inflammatory effect with fewer side effects. These PTGS2-specific drugs, however, probably because of their effects on the balance of prostaglandin synthesis in platelets and endothelial cells, can also promote blood clot formation (Buczynski et al. 2009; Stables & Gilroy 2011). ACTIVATION GENE ONTOLOGYGO:0030343 Reactome Database ID Release 43209900 Reactome, http://www.reactome.org Synthesis of 15-eicosatetraenoic acid derivatives Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:0019372 ISBN978-0-444-53219-0 Pubmed19244215 Reactome Database ID Release 432142770 Reactome, http://www.reactome.org ReactomeREACT_150422 Reviewed: Rush, MG, 2012-11-10 The 15-eicosatetraenoic acids: 15-hydroperoxy-eicosatetraenoic acid (15-HpETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-oxo-eicosatetraenoic acid (15-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 15-lipoxygenases (ALOX15 and ALOX15B) (Buczynski et al. 2009, Vance & Vance 2008). ACTIVATION GENE ONTOLOGYGO:0016616 Reactome Database ID Release 43975647 Reactome, http://www.reactome.org Synthesis of 5-eicosatetraenoic acids 5-hydroperoxy-eicosatetraenoic acid (5-HpETE), 5-hydroxyeicosatetraenoic acid (5S-HETE) and 5-oxo-eicosatetraenoic acid (5-oxoETE) are formed after the initial step of arachidonic acid oxidation by arachidonate 5-lipoxygenase (ALOX5) (Buczynski et al. 2009, Vance & Vance 2008). Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:0019372 ISBN978-0-444-53219-0 Pubmed19244215 Reactome Database ID Release 432142688 Reactome, http://www.reactome.org ReactomeREACT_150209 Reviewed: Rush, MG, 2012-11-10 ACTIVATION GENE ONTOLOGYGO:0003834 Reactome Database ID Release 43975601 Reactome, http://www.reactome.org Synthesis of Lipoxins (LX) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:2001300 ISBN978-0-444-53219-0 Lipoxins A4 (LXA4) and B4 (LXB4), structurally characterized from human neutrophils incubated with 15-hydroperoxy-eicosatetraenoic acid (15-HpETE), each contain three hydroxyl moieties and a conjugated tetraene. The third hydroxyl of LXA4 is positioned at C-6, and of LXB4 at C-14. The action of arachidonate 5-lipoxygenase (ALOX5), in concert with an arachidonate 12-lipoxygenase (ALOX12) or arachidonate 15-lipoxygenase (ALOX15) activity, has been shown to produce lipoxins by three distinct pathways. Neutrophil ALOX5 can produce and secrete leukotriene A4 (LTA4) that is taken up by platelets, where it is acted upon by ALOX12 to form lipoxins. Likewise, ALOX15s can generate either 15-hydroperoxy-eicosatetraenoic acid (15-HpETE) or 15-hydro-eicosatetraenoic acid (15-HETE) that can be taken up by monocytes and neutrophils, where highly expressed ALOX5 uses it to generate lipoxins. Finally, aspirin acetylated prostaglandin G/H synthase 2 (PTGS2), rendered unable to synthesize prostaglandins, can act as a 15-lipoxygenase. This leads to the formation of 15R-HETE and culminates in creation of epi-lipoxins, which have altered stereochemistry at the C-15 hydroxyl but similar biological potency (Chiang et al. 2006, Buczynski et al. 2009, Vance & Vance 2008). Pubmed16968948 Pubmed19244215 Reactome Database ID Release 432142700 Reactome, http://www.reactome.org ReactomeREACT_150320 Reviewed: Rush, MG, 2012-11-10 ACTIVATION GENE ONTOLOGYGO:0050253 Reactome Database ID Release 43975631 Reactome, http://www.reactome.org Synthesis of 12-eicosatetraenoic acid derivatives Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:0019372 ISBN978-0-444-53219-0 Pubmed19244215 Reactome Database ID Release 432142712 Reactome, http://www.reactome.org ReactomeREACT_150201 Reviewed: Rush, MG, 2012-11-10 The 12-eicosatetraenoic acids: 12-hydroperoxy-eicosatetraenoic acid (12-HpETE), 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-oxo-eicosatetraenoic acid (12-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 12 and 15 lipoxygenases (ALOX12, ALOX12B and ALOX15 respectively). This part of the pathway is bifurcated at the level of 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE), which can either be reduced to 12S-hydro-eicosatetraenoic acid (12S-HETE) or converted to hepoxilins (Buczynski et al. 2009, Vance & Vance 2008). ACTIVATION GENE ONTOLOGYGO:0030342 Reactome Database ID Release 43215644 Reactome, http://www.reactome.org Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:0097267 ISBN978-0-444-53219-0 Pubmed10681399 Pubmed19244215 Reactome Database ID Release 432142816 Reactome, http://www.reactome.org ReactomeREACT_150134 Reviewed: Rush, MG, 2012-11-10 Similar to the lipoxygenases, cytochrome P450 (CYP) enzymes catalyse the hydroxylation and epoxygenation of arachidonic acid. However, whereas lipoxygenases use an active non-heme iron to abstract hydrogen directly from arachidonic acid, CYPs contain a heme-iron active site that oxidizes its substrate by a different mechanism. They hydroxylate arachidonic acid between C-5 and C-15 to produce lipoxygenase-like hydroxyeicosatetraenoic acids (HETEs) and add a hydroxyl moiety to the sp3-hybridized omega-carbons to form a unique class of HETEs. The transfer of oxygen to the unstable arachidonic acid intermediate terminates the reaction by forming HETE or epoxy-eicosatrienoic acid (EETs), respectively (Capdevila et al. 2000, Buczynski et al. 2009, Vance & Vance 2008). Synthesis of Hepoxilins (HX) and Trioxilins (TrX) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:0051121 Hepoxilins are biologically relevant signalling molecules produced by certain arachidonate 12-lipoxygenase (ALOX12s). Hepoxilin A3 (HXA3) and B3 (HXB3) have been identified, both of which incorporate an epoxide across the C-11 and C-12 double bond, as well as an additional hydroxyl moiety. HXA3 has a C-8 hydroxyl, whereas the HXB3 hydroxyl occurs at C-10. The epoxy moiety is labile and can be hydrolyzed either by a hepoxilin specific epoxide hydrolase (HXEH) or in acidic aqueous solution to form the corresponding diol metabolites trioxilin A3 (TrXA3) and B3 (TrXB3) (Buczynski et al. 2009, Vance & Vance 2008). ISBN978-0-444-53219-0 Pubmed19244215 Reactome Database ID Release 432142696 Reactome, http://www.reactome.org ReactomeREACT_150292 Reviewed: Rush, MG, 2012-11-10 Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) Authored: Williams, MG, 2012-02-24 Edited: Williams, MG, 2012-02-24 GENE ONTOLOGYGO:0019373 ISBN978-0-444-53219-0 Pubmed10681399 Pubmed19244215 Reactome Database ID Release 432142670 Reactome, http://www.reactome.org ReactomeREACT_150417 Reviewed: Rush, MG, 2012-11-10 The epoxidation of arachidonic acid by cytochrome P450s (CYPs) results in the formation of unique bioactive lipid mediators termed epoxyeicosatrienoic acids (EETs). Each double bond has been shown to be susceptible to oxidation, resulting in 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. The majority of the EET biological activities are diminished by the hydrolysis to the corresponding dihydroxyeicosatrienoic acids (DHET) (Capdevila et al. 2000, Buczynski et al. 2009, Vance & Vance 2008). ACTIVATION GENE ONTOLOGYGO:0004303 Reactome Database ID Release 43804965 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008395 Reactome Database ID Release 43193170 Reactome, http://www.reactome.org alpha-linolenic acid (ALA) metabolism Alpha-linolenic acid (ALA, 18:3(n-3)) is an omega-3 fatty acid, supplied through diet as it cannot be synthesized by humans. ALA has an important role in human health. It is converted to long chain more unsaturated n-3 fatty acids by a series of alternating desaturation and elongation reactions. Omega-3 products of ALA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce inflammation and may help lower risk of chronic diseases, such as heart disease and arthritis. All the desaturation and elongation steps occur in the endoplasmic reticulum (ER) except for the final step which requires translocation to peroxisomes for partial beta-oxidation.<br><br>The alpha-linolenic acid pathway involves the following steps: 18:3(n-3)--> 18:4(n-3)-->20:4(n-3)-->20:5(n-3)-->22:5(n-3)-->24:5(n-3)-->24:6(n-3)-->22:6(n-3). Two desaturation enzymes are involved in this process: delta-6 desaturase that converts 18:3(n-3) to 18:4(n-3) and 24:5(n-3) to 24:6(n-3) respectively, delta-5 desaturase 20:4(n-3) to 20:5(n-3). (Sprecher 2002). Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 GENE ONTOLOGYGO:0036109 Pubmed16828546 Pubmed8443237 Reactome Database ID Release 432046106 Reactome, http://www.reactome.org ReactomeREACT_121147 Linoleic acid (LA) metabolism Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 GENE ONTOLOGYGO:0043651 Linoleic acid (LA, 18:2(n-6)) is an omega-6 fatty acid obtained through diet, mainly from vegetable oils. Omega-6 fatty acids helps stimulate skin and hair growth, maintain bone health, regulate metabolism, and maintain the reproductive system. All the desaturation and elongation steps occur in the endoplasmic reticulum (ER) except for the final step which requires translocation to peroxisomes for partial beta-oxidation. The linoleic acid pathway involves the following steps: 18:2(n-6)-->18:3(n-6)--> 20:3(n-6)-->20:4(n-6)-->22:4(n-6)-->24:4(n-6)-->24:5(n-6)-->22:5(n-6). Two desaturation enzymes are involved in this process: delta-6 desaturase which converts 18:2(n-6) to 18:3 (n-6) and 24:4(n-6) to 24:5(n-6) respectively, and delta-5 desaturase which converts 20:3(n-6) to 20:4(n-6). (Sprecher 2002). Pubmed10903473 Pubmed12324224 Pubmed14636670 Pubmed17168669 Pubmed8609415 Reactome Database ID Release 432046105 Reactome, http://www.reactome.org ReactomeREACT_121100 PIPs transport between late endosome and Golgi membranes Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0045332 Pubmed16954148 Reactome Database ID Release 431660508 Reactome, http://www.reactome.org ReactomeREACT_120874 Reviewed: Wakelam, Michael, 2012-05-14 The phosphoinositide phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is exported from the late endosome membrane to the Golgi membrane (Rutherford et al. 2006). alpha-linolenic (omega3) and linoleic (omega6) acid metabolism Authored: Garapati, P V, 2012-01-11 Edited: Garapati, P V, 2012-01-11 GENE ONTOLOGYGO:0033559 Pubmed10903473 Pubmed12324224 Pubmed16828546 Reactome Database ID Release 432046104 Reactome, http://www.reactome.org ReactomeREACT_121284 There are two major classes of polyunsaturated fatty acids (PUFAs): the omega-3 (n-3) and the omega-6 (n-6) fatty acids, where the number corresponds to the position of the first double bond proximate to the methyl end of the fatty acid. Omega-3 and omega-6 fatty acids are considered essential fatty acids. Humans cannot synthesize them, instead they are supplied through diet. Linoleic acid (LA, 18:2(n-6)), a major component of omega-6 fatty acids and alpha-linolenic acid (ALA, 18:2(n-3)) a major component of omega-3 fatty acids are the two main dietary essential fatty acids (EFAs) in humans. ALA and LA obtained from diet are converted in the body into their longer chain and more unsaturated omega-3 and omega-6 products by a series of desaturation and elongation steps. Metabolism of ALA and LA to their corresponding products is mediated via common enzyme systems. In humans ALA is finally converted to docosahexaenoic acid (DHA, C22:6(n-3)), and LA is converted to docosapentaenoic acid (DPA, C22:5(n-6)). The intermediary omega-3 and omega-6 series fatty acids play a significant role in health and disease by generating potent modulatory molecules for inflammatory responses, including eicosanoids (prostaglandins, and leukotrienes), and cytokines (interleukins) and affecting the gene expression of various bioactive molecules (Kapoor & Huang 2006, Sprecher 2002, Burdge 2006). PIPs transport between early and late endosome membranes Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0045332 Pubmed11285266 Pubmed16448788 Pubmed16510848 Reactome Database ID Release 431660502 Reactome, http://www.reactome.org ReactomeREACT_121209 Reviewed: Wakelam, Michael, 2012-05-14 The maturation of the early endosome compartment into a late endosome is triggered by the presence of phosphoinositide phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (Cabezas et al. 2006, Ikonomov et al. 2006, Ikonomov et al. 2001). Synthesis of PIPs at the late endosome membrane At the late endosome membrane, the primary event is the dephosphorylation of the phosphoinositide phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) to phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 5-phosphate (PI5P) (Sbrissa et al. 2007, Sbrissa et al. 2008, Cao et al. 2007, Cao et al. 2008, Arcaro et al. 2000, Kim et al. 2002). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006661 Pubmed10805725 Pubmed11733541 Pubmed17556371 Pubmed17651088 Pubmed18524850 Pubmed18950639 Reactome Database ID Release 431660517 Reactome, http://www.reactome.org ReactomeREACT_120918 Reviewed: Wakelam, Michael, 2012-05-14 Synthesis of PIPs at the early endosome membrane At the early endosome membrane, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is generated in two steps from phosphatidylinositol 3,4-bisphosphate PI(3,4)P2 by the action of various kinases and phosphatases (Sbrissa et al. 2007, Sbrissa et al. 2008, Cao et al. 2007, Cao et al. 2008, Arcaro et al. 2000, Kim et al. 2002). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006661 Pubmed10805725 Pubmed11733541 Pubmed17556371 Pubmed17651088 Pubmed18524850 Pubmed18950639 Reactome Database ID Release 431660516 Reactome, http://www.reactome.org ReactomeREACT_120756 Reviewed: Wakelam, Michael, 2012-05-14 PIPs transport between early endosome and Golgi membranes Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0045332 Pubmed16954148 Reactome Database ID Release 431660537 Reactome, http://www.reactome.org ReactomeREACT_121208 Reviewed: Wakelam, Michael, 2012-05-14 The phosphoinositide phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is exported from the early endosome membrane to the Golgi membrane (Rutherford et al. 2006). Synthesis of PIPs at the plasma membrane At the plasma membrane, subsequent phosphorylation of phosphatidylinositol 4-phosphate (PI4P) produces phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) while the actions of various other kinases and phosphatases produces phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (Zhang et al. 1997, Gurung et al. 2003, Guo et al. 1999, Vanhaesebroeck et al. 1997, Tolias et al. 1998, Schaletzky et al. 2003, Kim et al. 2002, Clarke et al. 2010). Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0006661 Pubmed10224048 Pubmed11733541 Pubmed12536145 Pubmed12646134 Pubmed19896968 Pubmed9113989 Pubmed9211928 Pubmed9660759 Reactome Database ID Release 431660499 Reactome, http://www.reactome.org ReactomeREACT_121025 Reviewed: Wakelam, Michael, 2012-05-14 PIPs transport between plasma and early endosome membranes Authored: Williams, MG, 2011-10-18 Edited: Williams, MG, 2011-08-12 GENE ONTOLOGYGO:0045332 Pubmed14604433 Pubmed15716355 Reactome Database ID Release 431660524 Reactome, http://www.reactome.org ReactomeREACT_121164 Reviewed: Wakelam, Michael, 2012-05-14 The phosphoinositide phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) translocates from the plasma membrane to the early endosome membrane (Watt et al. 2004, Ivetac et al. 2005). Myosin heavy chain Converted from EntitySet in Reactome Reactome DB_ID: 390566 Reactome Database ID Release 43390566 Reactome, http://www.reactome.org ReactomeREACT_17823 Synthesis of Preproghrelin Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Pubmed10604470 Pubmed12050285 Pubmed15142980 Pubmed15604212 Pubmed18396350 Pubmed19280057 Pubmed19327128 Reactome Database ID Release 43422088 Reactome, http://www.reactome.org ReactomeREACT_19166 Reviewed: Zhang, Weizhen, 2009-08-29 The ghrelin gene is transcribed and spliced to yield two variants: isoform 1 encodes full-length preproghrelin and isoform 2 encodes des-acyl-Gln14 preproghrelin, which is missing glutamine at position 14 of the mature peptide. Des-acyl-Gln14 ghrelin is found in rodents but is present in negligible quantities in humans. Somatostatin and leptin inhibit ghrelin mRNA levels. Estrogen increases ghrelin mRNA levels. The KLF4 transcription factor binds the ghrelin promoter and activates transcription. Putative binding sites for other transcription factors have been identified but their functions have not been demonstrated. Transactivation of NOXA by p53 At the end of this reaction, 1 molecule of 'NOXA protein' is present. <br><br><br> Pubmed15126337 Reactome Database ID Release 43140214 Reactome, http://www.reactome.org ReactomeREACT_2201 Expression of IGFBP1 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16687408 Reactome Database ID Release 431791180 Reactome, http://www.reactome.org ReactomeREACT_115690 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The IGFBP1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of IL-8 Authored: May, B, 2010-02-17 Edited: May, B, 2010-02-17 Pubmed16912112 Pubmed16931790 Pubmed2663993 Pubmed2664463 Pubmed3260265 Reactome Database ID Release 43517731 Reactome, http://www.reactome.org ReactomeREACT_115727 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The IL-8 gene is transcribed to yield mRNA which is translated to yield protein. Expression of CCL2 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed16931790 Reactome Database ID Release 431791056 Reactome, http://www.reactome.org ReactomeREACT_116114 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The CCL2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of HERPUD Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed14742429 Reactome Database ID Release 431791095 Reactome, http://www.reactome.org ReactomeREACT_116082 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The HERPUD gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of ATF3 Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed20022965 Reactome Database ID Release 431791173 Reactome, http://www.reactome.org ReactomeREACT_115743 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The ATF3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Asparagine Synthetase Authored: May, B, 2011-10-13 Edited: May, B, 2011-10-13 Pubmed18840095 Reactome Database ID Release 431791118 Reactome, http://www.reactome.org ReactomeREACT_115759 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The Aspariagine Synthetase (ASNS) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Translation and translocation of ATF4 Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Phosphorylation of eIF2-alpha causes increased translation of ATF4 mRNA. In mouse the mRNA of ATF4 contains 2 upstream ORFs (uORFs) (Vattem and Wek 2004). The second uORF overlaps the ORF encoding ATF4 and thus prevents translation of ATF4. When eIF2-alpha is phosphorylated, translation of the uORFs is suppressed and translation of the ORF encoding ATF4 is increased. Pubmed15314157 Pubmed18426796 Reactome Database ID Release 43381128 Reactome, http://www.reactome.org ReactomeREACT_18270 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 OCT1,2,3 Converted from EntitySet in Reactome Reactome DB_ID: 2161529 Reactome Database ID Release 432161529 Reactome, http://www.reactome.org ReactomeREACT_121588 SLC22A1,2,3 ACTIVATION GENE ONTOLOGYGO:0008889 Reactome Database ID Release 431524092 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004608 Reactome Database ID Release 431524127 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004103 Reactome Database ID Release 431524073 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052731 Reactome Database ID Release 431500635 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003990 Reactome Database ID Release 431524052 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015220 Reactome Database ID Release 43444463 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004142 Reactome Database ID Release 431524063 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004142 Reactome Database ID Release 431524061 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004102 Reactome Database ID Release 43264613 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004105 Reactome Database ID Release 431524105 Reactome, http://www.reactome.org Transactivation of PUMA by E2F1 At the end of this reaction, 1 molecule of 'PUMA protein' is present. <br><br><br> Pubmed14684737 Reactome Database ID Release 43140221 Reactome, http://www.reactome.org ReactomeREACT_284 Transactivation of PUMA by p53 At the end of this reaction, 1 molecule of 'PUMA protein' is present. <br><br><br> Pubmed11463392 Reactome Database ID Release 43139913 Reactome, http://www.reactome.org ReactomeREACT_1555 NOTCH1 stimulates HES5 transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NICD1 binds to the HES5 promoter and stimulates HES5 transcription. Pubmed20972443 Reactome Database ID Release 431980078 Reactome, http://www.reactome.org ReactomeREACT_118794 Reviewed: Haw, R, 2012-02-06 template DNA with first transcript dinucleotide, opened to +8 position Reactome DB_ID: 109877 Reactome Database ID Release 43109877 Reactome, http://www.reactome.org ReactomeREACT_3318 NOTCH1 stimulates MYC transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NICD1 binds to the MYC promoter and stimulates MYC transcription. Pubmed17114293 Reactome Database ID Release 431980067 Reactome, http://www.reactome.org ReactomeREACT_118596 Reviewed: Haw, R, 2012-02-06 template DNA:4-9 nucleotide transcript hybrid Reactome DB_ID: 75897 Reactome Database ID Release 4375897 Reactome, http://www.reactome.org ReactomeREACT_3607 NOTCH1 stimulates HES1 transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH1 coactivator complex binds the promoter of HES1 gene and directly stimulates HES1 transcription. HES1 belongs to the bHLH family of transcription factors. Pubmed7566092 Reactome Database ID Release 431980047 Reactome, http://www.reactome.org ReactomeREACT_118680 Reviewed: Haw, R, 2012-02-06 Transcription of beta-casein (CSN2) Authored: Orlic-Milacic, M, 2011-11-04 ERBB4s80:STAT5A complex binds to and stimulates transcription from the beta-casein (CSN2) promoter, and it probably regulates transcription of other lactation-related genes in mammary cells. By over-expressing either human ERBB4cyt1s80 or ERBB4cyt2s80 in mouse mammary cell line HC11 or transgenic mice, Muraoka-Cook et al. showed differential effects of CYT1 and CYT2 isoforms on mammary epithelium. CYT1s80 over-expression decreases cell proliferation, promotes STAT5A-mediated transcription of beta-casein (CSN2) and lactogenic differentiation. In contrast, CYT2s80 over-expression causes epithelial hyperplasia, increased levels of Wnt and beta-catenin, as well as elevated expression of c-myc and cyclin D1 (Muraoka-Cook et al. 2009). Edited: Matthews, L, 2011-11-07 Pubmed15534001 Pubmed18653779 Pubmed19596786 Reactome Database ID Release 431254290 Reactome, http://www.reactome.org ReactomeREACT_116088 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 mNICD1 stimulates Hes1 transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed7566092 Reactome Database ID Release 432065278 Reactome, http://www.reactome.org ReactomeREACT_118814 Recombinant mouse NICD1 (mNICD1) expressed in HeLa cells (human cervical carcinoma cell line) associates with human RBPJ and, after binding to a recombinant mouse Hes1 promoter, activates transcription of a reporter gene. Reviewed: Haw, R, 2012-02-06 Polymerase III gene DNA with a termination site Reactome DB_ID: 113448 Reactome Database ID Release 43113448 Reactome, http://www.reactome.org ReactomeREACT_4018 Activation of E2F target genes at G1/S Authored: Gopinathrao, G, 2004-06-16 19:22:00 E2F1 binds to E2F binding sites on the genome activating the synthesis of the target proteins. For annotation purposes, the reactions regulated by E2F1 are grouped under this pathway and information about the target genes alone are displayed for annotation purposes. <br>Cellular targets for activation by E2F1 include thymidylate synthetase, Rir2, Dihydrofolate reductase, Cdc2, Cyclin A1, Cdc6 (DeGregori et al., 1995), Cdt1 (Yoshida and Inoue, 2004), CDC45 (Arata et al., 2000), CDC6 (Yan et al., 1998; Ohtani et al., 1998), Cyclin E (Ohtani et al., 1996), Emi1 (Hsu et al., 2002), and Orc1 (Ohtani et al., 1997). The activation of TK2 (Dnk1) and Cdc25A by E2F1 have been inferred from similar events in Drosophila (Duronio and O'Farrell, 1994;Reis and Edgar, 2004). <br>Rir2 protein is involved in dNTP level regulation and activation of this enzyme results in higher levels of dNTPs in anticipation of S-phase. E2F activation of Rir2 has been shown also in Drosophila by Duronio and O'Farrell (1994). E2F1 activation of CDC45 is shown in mouse cells by using human E2F1 construct (Arata et al., 2000). Cyclin E is also transcriptionally regulated by E2F1. Cyclin E protein plays important role in the transition of G1 in S-phase by associating with Cdk2 (Ohtani et al., 1996). E2F activation of PCNA has been demonstrated in Drosophila (DeGregori et al., 1995) and in some human cells by using recombinant adenovirus constructs. E2F activation of Polymerase A (Pol A) has been demonstrated in some human cells. It has also been demonstrated in Drosophila by Ohtani and Nevins (1994). It has been observed in Drosophila that E2F1 regulated expression of Orc1 stimulates ORC1-6 complex formation and binding to the origin of replication (Asano and Wharton, 1999). Orc1-6 recruit Cdc6 and Cdt1 that are required to recruit the MCM2-7 replication helicases. E2F1 regulation incorporates a feedback mechanism where in Geminin can inhibit MCM2-7 recruitment of ORC1-6 complex by interacting with Cdc6/Cdt1. The activation of Cdc25A and TK2 (Dnk1) by E2F1 has been inferred from similar events in Drosophila (Duronio RJ, O'Farrell 1994; Reis and Edgar, 2004). E2F1 activates string (Cdc25) that in turn activates Cyclin B/Cdk1. A similar phenomenon has been observed in mouse NIH 3T3 cells and in Rat1 cells. Pubmed10228158 Pubmed10692433 Pubmed11988738 Pubmed14990995 Pubmed15084262 Pubmed7623816 Pubmed8050359 Pubmed8114698 Pubmed8618861 Pubmed8943353 Pubmed9520412 Pubmed9778043 Reactome Database ID Release 43539107 Reactome, http://www.reactome.org ReactomeREACT_22145 Reviewed: Bosco, G, 2004-06-16 19:24:21 released pre-mRNA Pol III transcript Reactome DB_ID: 112478 Reactome Database ID Release 43112478 Reactome, http://www.reactome.org ReactomeREACT_3678 Activation of Cdc25A by c-myc Authored: Matthews, L, 2006-09-29 13:59:34 Edited: Matthews, L, 2006-10-10 08:05:07 Pubmed8700224 Reactome Database ID Release 43188345 Reactome, http://www.reactome.org ReactomeREACT_9013 Reviewed: Coqueret, O, 2006-10-06 08:59:06 The Myc/Max heterodimer binds to elements in the cdc25A gene and activates transcription in mid to late G1. mitochondrial DNA promoter Reactome DB_ID: 163305 Reactome Database ID Release 43163305 Reactome, http://www.reactome.org ReactomeREACT_2810 Transcriptional activation of p21 by p53 after DNA damage Authored: Matthews, L, 2006-09-29 13:54:26 Edited: Matthews, L, 2006-10-10 08:05:07 Pubmed8242752 Reactome Database ID Release 43188383 Reactome, http://www.reactome.org ReactomeREACT_9064 Reviewed: Coqueret, O, 2006-10-06 08:59:06 p21 is transcriptionally activated by p53 after DNA damage. mitochondrial transcription termination sequence Reactome DB_ID: 164569 Reactome Database ID Release 43164569 Reactome, http://www.reactome.org ReactomeREACT_3490 damaged DNA substrate:nascent mRNA hybrid Reactome DB_ID: 110291 Reactome Database ID Release 43110291 Reactome, http://www.reactome.org ReactomeREACT_3022 Elongating transcript in processive Pol II mediated elongation Reactome DB_ID: 113717 Reactome Database ID Release 43113717 Reactome, http://www.reactome.org ReactomeREACT_4250 DNA containing RNA Polymerase II promoter Reactome DB_ID: 109627 Reactome Database ID Release 43109627 Reactome, http://www.reactome.org ReactomeREACT_2835 Open DNA -10 to +2 containing RNA Polymerase II promoter Reactome DB_ID: 109875 Reactome Database ID Release 43109875 Reactome, http://www.reactome.org ReactomeREACT_5384 Transactivation of NOXA by E2F1 At the end of this reaction, 1 molecule of 'NOXA protein' is present. <br><br><br> Pubmed14684737 Reactome Database ID Release 43140217 Reactome, http://www.reactome.org ReactomeREACT_1872 DNA containing Pol II promoter with transcript with 2 or 3 nucleotides Reactome DB_ID: 110068 Reactome Database ID Release 43110068 Reactome, http://www.reactome.org ReactomeREACT_3936 xenobiotic/medium-chain fatty acid:CoA ligases Converted from EntitySet in Reactome Reactome DB_ID: 177125 Reactome Database ID Release 43177125 Reactome, http://www.reactome.org ReactomeREACT_7086 NOTCH1 stimulates HEY transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed10964718 Pubmed11044625 Pubmed15107403 Pubmed20972443 RBPJ binding sites in the promoters of HEY1, HEY2 and HEYL genes are conserved between humans and mice (Maier and Gessler 2000), and expression of human NICD1 was directly shown to activate transcription from human HEY2 and HEYL promoters (Arnett et al. 2010). Based on the evolutionary conservation of RBPJ sites and the existing findings from human and mouse studies, NOTCH1 is expected to directly stimulate transcription of HEY1, HEY2 and HEYL (Fischer et al. 2004, Leimeister et al. 2000). Reactome Database ID Release 431980065 Reactome, http://www.reactome.org ReactomeREACT_118817 Reviewed: Haw, R, 2012-02-06 Expression of BMAL1 (ARNTL). Authored: May, B, 2009-05-17 22:04:50 Edited: May, B, 2009-06-02 00:51:49 Pubmed9079689 Pubmed9144434 Reactome Database ID Release 43400342 Reactome, http://www.reactome.org ReactomeREACT_25233 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The BMAL1 (ARNTL) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The ROR-alpha transcription factor binds the RORE element of the BMAL1 (ARNTL) promoter and activates transcription of the BMAL1 gene. The REV-ERBA transcription factor binds the same RORE element and represses transcription of the BMAL1 gene. Activated PKC-alpha can activate MMP3 Authored: Jassal, B, Tripathi, S, 2012-04-04 Edited: Jassal, B, Tripathi, S, 2012-04-04 Gastrin activated PKC pathway leads to the induction of matrix metalloproteinase 3 (MMP3) synthesis (Reuben et al. 2002). The cleavage and autocatalysis steps to obtain the fully activated form of MMP3 have been omitted here. Pubmed11836255 Reactome Database ID Release 432179413 Reactome, http://www.reactome.org ReactomeREACT_120731 Reviewed: D'Eustachio, P, 2012-04-23 Mitoferrin1/2 Converted from EntitySet in Reactome Reactome DB_ID: 1362399 Reactome Database ID Release 431362399 Reactome, http://www.reactome.org ReactomeREACT_152226 Expression of FACTOR VII (F7) Authored: May, B, 2010-03-19 Edited: May, B, 2010-03-19 Pubmed8618898 Reactome Database ID Release 43549428 Reactome, http://www.reactome.org ReactomeREACT_25092 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The FACTOR VII (F7) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mouse the F7 gene shows circadian expression due to activation by the Bmal1:Clock heterodimer. elongating pre-mRNA Pol III transcript plus 1 nucleotide Reactome DB_ID: 113704 Reactome Database ID Release 43113704 Reactome, http://www.reactome.org ReactomeREACT_4233 Expression of DEC2 (BHLHE41, BHLHB3) Authored: May, B, 2010-06-18 Edited: May, B, 2010-06-18 Pubmed11162494 Reactome Database ID Release 43879770 Reactome, http://www.reactome.org ReactomeREACT_25212 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The DEC2 (BHLHE41, BHLHB3) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the BMAL1:CLOCK heterodimer binds E-box elements in the DEC2 promoter and activates transcription of DEC2. Polymerase III gene DNA with transcription bubble (single-stranded region) Reactome DB_ID: 113443 Reactome Database ID Release 43113443 Reactome, http://www.reactome.org ReactomeREACT_3117 Expression of NOCTURNIN Authored: May, B, 2010-03-19 Edited: May, B, 2010-03-19 Pubmed18587630 Reactome Database ID Release 43549424 Reactome, http://www.reactome.org ReactomeREACT_25395 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The NOCTURNIN gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The NOCTURNIN gene shows circadian expression because the BMAL1:CLOCK heterodimer binds an E-box element in the NOCTURNIN promoter and activates transcription. elongating pre-mRNA Pol III transcript Reactome DB_ID: 111987 Reactome Database ID Release 43111987 Reactome, http://www.reactome.org ReactomeREACT_3498 Expression of AVP Authored: May, B, 2010-06-18 Edited: May, B, 2010-06-18 Pubmed2991279 Reactome Database ID Release 43879782 Reactome, http://www.reactome.org ReactomeREACT_24929 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The AVP gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind an E-box enhancer in the promoter of the AVP gene and activate transcription of AVP. DNA with RNA Polymerase III Type 2 Open Promoter Reactome DB_ID: 112134 Reactome Database ID Release 43112134 Reactome, http://www.reactome.org ReactomeREACT_5104 Expression of CLOCK Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Pubmed10198158 Reactome Database ID Release 431368119 Reactome, http://www.reactome.org ReactomeREACT_118740 Reviewed: Delaunay, F, 2012-01-28 The CLOCK gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of CLOCK is repressed by REV-ERBA. DNA with RNA Polymerase III Type 3 Open Promoter Reactome DB_ID: 112135 Reactome Database ID Release 43112135 Reactome, http://www.reactome.org ReactomeREACT_3408 Expression of DEC1 (BHLHE40, BHLHB2) Authored: May, B, 2010-06-18 Edited: May, B, 2010-06-18 Pubmed14672706 Reactome Database ID Release 43879798 Reactome, http://www.reactome.org ReactomeREACT_25132 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The DEC1 (BHLHE40, BHLHB2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The DEC1 gene contains E-box elements in its promoter which bind the BMAL:CLOCK heterodimer and confer circadian rhythm on its expression. elongating pre-mRNA Pol III oligonucleotide Reactome DB_ID: 111980 Reactome Database ID Release 43111980 Reactome, http://www.reactome.org ReactomeREACT_4709 Expression of DBP Authored: May, B, 2010-06-18 Edited: May, B, 2010-06-18 Pubmed7835883 Reactome Database ID Release 43879762 Reactome, http://www.reactome.org ReactomeREACT_25278 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The DBP gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind E-boxes in the DBP promoter and activate transcription of DBP. released pre-mRNA Pol III oligonucleotide Reactome DB_ID: 111984 Reactome Database ID Release 43111984 Reactome, http://www.reactome.org ReactomeREACT_2689 paused pre-mRNA Pol III transcript Reactome DB_ID: 112475 Reactome Database ID Release 43112475 Reactome, http://www.reactome.org ReactomeREACT_2667 DNA with RNA Polymerase III Type 3 Closed Promoter Reactome DB_ID: 83752 Reactome Database ID Release 4383752 Reactome, http://www.reactome.org ReactomeREACT_4406 DNA with RNA Polymerase III Type 2 Closed Promoter Reactome DB_ID: 83747 Reactome Database ID Release 4383747 Reactome, http://www.reactome.org ReactomeREACT_2515 DNA with RNA Polymerase III Type 1 Closed Promoter Reactome DB_ID: 76050 Reactome Database ID Release 4376050 Reactome, http://www.reactome.org ReactomeREACT_4215 Expression of CRYPTOCHROME-2 Authored: May, B, 2010-03-11 Edited: May, B, 2010-03-11 Pubmed14507900 Pubmed9801304 Reactome Database ID Release 43549470 Reactome, http://www.reactome.org ReactomeREACT_24956 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The CRYPTOCHROME-2 (CRY2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the CRY2 protein shows circadian rhythm in the suprachiasmatic nucleus (SCN) and in peripheral tissues. The mRNA shows circadian rhythm in muscle but not in the SCN. Expression is dependent on CLOCK. Expression of CRYPTOCHROME-1 Authored: May, B, 2010-03-11 Edited: May, B, 2010-03-11 Pubmed14507900 Pubmed8921389 Reactome Database ID Release 43549467 Reactome, http://www.reactome.org ReactomeREACT_25365 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The CRYPTOCHROME-1 (CRY1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. CRY1 mRNA and protein show circadian expression. The promoter of the CRY1 gene contains an E-box which is bound by the BMAL1:CLOCK heterodimer (and probably also the BMAL1:NPAS2 heterodimer), which activates transcription of CRY1. Expression of NAMPT (NamPRT, PBEF, Visfatin) Authored: May, B, 2011-06-29 Edited: May, B, 2011-06-29 Pubmed11241162 Reactome Database ID Release 431368889 Reactome, http://www.reactome.org ReactomeREACT_115946 Reviewed: Albrecht, U, 2010-06-23 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The NAMPT (NamPRT) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the BMAL1:CLOCK heterodimer enhances transcription of NAMPT. Expression of PAI-1 Authored: May, B, 2010-03-19 Edited: May, B, 2010-03-19 Pubmed11018023 Pubmed12406875 Pubmed12738229 Pubmed16857194 Reactome Database ID Release 43549364 Reactome, http://www.reactome.org ReactomeREACT_25123 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The PAI-1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The PAI-1 gene shows circadian expression due to direct transcriptional activation by the BMAL1:CLOCK heterodimer and the BMAL2(CLIF, ARNTL2):CLOCK heterodimer. Expression of ELOVL3 Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Reactome Database ID Release 431368116 Reactome, http://www.reactome.org ReactomeREACT_118691 Reviewed: Delaunay, F, 2012-01-28 The ELOVL3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Peroxisome Proliferator Receptor Element (PPRE) Reactome DB_ID: 422139 Reactome Database ID Release 43422139 Reactome, http://www.reactome.org ReactomeREACT_20340 Expression of NR1D1 (REV-ERBA) Authored: May, B, 2010-03-19 Edited: May, B, 2010-03-19 Pubmed2539258 Pubmed8622974 Reactome Database ID Release 43549475 Reactome, http://www.reactome.org ReactomeREACT_25225 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The NR1D1 (REV-ERBA) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mouse the Rev-erba gene shows circadian expression due to transactivation by the BMAL1:CLOCK heterodimer. REV-ERBA binds the promoter of its own gene and represses its own expression (Adelmont et al. 1996). p-T,2S-SMAD2/3 Converted from EntitySet in Reactome Reactome DB_ID: 2176482 Reactome Database ID Release 432176482 Reactome, http://www.reactome.org ReactomeREACT_121647 Expression of PERIOD-2 Authored: May, B, 2010-03-11 Edited: May, B, 2010-03-11 Pubmed18317514 Pubmed9427249 Reactome Database ID Release 43549493 Reactome, http://www.reactome.org ReactomeREACT_25321 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The PERIOD-2 (PER2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The promoter of the PER2 gene contains an E-box which binds the BMAL1:CLOCK heterodimer (and probably also the BMAL1:NPAS2 heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER2. NCOR Converted from EntitySet in Reactome NCOR corepressor protein Reactome DB_ID: 349716 Reactome Database ID Release 43349716 Reactome, http://www.reactome.org ReactomeREACT_119825 Expression of PERIOD-1 Authored: May, B, 2010-03-11 Edited: May, B, 2010-03-11 Pubmed14750904 Pubmed17994337 Pubmed9333243 Pubmed9427249 Reactome Database ID Release 43549533 Reactome, http://www.reactome.org ReactomeREACT_25237 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The PERIOD-1 (PER1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The promoter of the PER1 gene contains E-boxes which are bound by the BMAL1:CLOCK heterodimer (and probably also the BMAL1:NPAS2 heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER1. SMAD2/3 Converted from EntitySet in Reactome R-SMAD2/3 Reactome DB_ID: 2187387 Reactome Database ID Release 432187387 Reactome, http://www.reactome.org ReactomeREACT_122471 SMAD2/3 Converted from EntitySet in Reactome R-SMAD2/3 Reactome DB_ID: 171172 Reactome Database ID Release 43171172 Reactome, http://www.reactome.org ReactomeREACT_7451 rDNA Promoter Reactome DB_ID: 73682 Reactome Database ID Release 4373682 Reactome, http://www.reactome.org ReactomeREACT_3973 Expression of RORA (ROR-alpha) Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Pubmed7926749 Reactome Database ID Release 431368133 Reactome, http://www.reactome.org ReactomeREACT_118635 Reviewed: Delaunay, F, 2012-01-28 The RORA gene is transcribed to yield mRNA and the mRNA is transcribed to yield protein. dsDNA with 5-mC Double-Stranded DNA containing 5-methylcytosine Reactome DB_ID: 212172 Reactome Database ID Release 43212172 Reactome, http://www.reactome.org ReactomeREACT_20463 Expression of PPARGC1A (PGC-1alpha) Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Pubmed10643692 Pubmed10713165 Pubmed12563009 Reactome Database ID Release 431368140 Reactome, http://www.reactome.org ReactomeREACT_118642 Reviewed: Delaunay, F, 2012-01-28 The PPARGC1A (PGC-1alpha) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Sal Box Reactome DB_ID: 74975 Reactome Database ID Release 4374975 Reactome, http://www.reactome.org ReactomeREACT_3776 elongating pre-rRNA transcript Reactome DB_ID: 74985 Reactome Database ID Release 4374985 Reactome, http://www.reactome.org ReactomeREACT_4088 DNA with RNA Polymerase III Type 1 Open Promoter Reactome DB_ID: 112051 Reactome Database ID Release 43112051 Reactome, http://www.reactome.org ReactomeREACT_4674 nascent pre-rRNA transcript Reactome DB_ID: 74978 Reactome Database ID Release 4374978 Reactome, http://www.reactome.org ReactomeREACT_3141 Expression of SREBF1 (SREBP1) Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Pubmed8060328 Pubmed8156598 Pubmed8402897 Pubmed9062340 Reactome Database ID Release 431368081 Reactome, http://www.reactome.org ReactomeREACT_118734 Reviewed: Delaunay, F, 2012-01-28 The SREBF1 (SREBP1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Capped intronless pre-mRNA Reactome DB_ID: 112158 Reactome Database ID Release 43112158 Reactome, http://www.reactome.org ReactomeREACT_5389 HNF1B- and FGF10-dependent synthesis of PTF1A protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43210788 Reactome, http://www.reactome.org ReactomeREACT_13701 Reviewed: Jensen, J, 2008-05-12 21:46:53 The PTF1A gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. PTF1A transcription requires the activity of the HNF1B transcription factor and FGF10. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. HNF1B-dependent synthesis of HNF6 protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43210784 Reactome, http://www.reactome.org ReactomeREACT_13463 Reviewed: Jensen, J, 2008-05-12 21:46:53 The HNF6 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. HNF6 transcription requires the activity of the HNF1B transcription factor. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. HNF6- and FGF10-dependent synthesis of PDX1 protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43210769 Reactome, http://www.reactome.org ReactomeREACT_13807 Reviewed: Jensen, J, 2008-05-12 21:46:53 The PDX1 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. PDX1 transcription requires the activities of the HNF6 transcription factor and FGF10. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. HNF6-dependent synthesis of ONECUT3 protein during early pancreas specification Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43210767 Reactome, http://www.reactome.org ReactomeREACT_13692 Reviewed: Jensen, J, 2008-05-12 21:46:53 The ONECUT3 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. ONECUT3 transcription requires the activity of the HNF6 transcription factor. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. PDX1-dependent synthesis of NKX6-1 protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43210780 Reactome, http://www.reactome.org ReactomeREACT_13758 Reviewed: Jensen, J, 2008-05-12 21:46:53 The NKX6-1 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. NKX6-1 transcription requires the activity of the PDX1 transcription factor. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. Mature Intronless transcript derived Histone mRNA Reactome DB_ID: 111676 Reactome Database ID Release 43111676 Reactome, http://www.reactome.org ReactomeREACT_2823 PDX1-dependent synthesis of NR5A2 protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed12972592 Reactome Database ID Release 43210773 Reactome, http://www.reactome.org ReactomeREACT_13755 Reviewed: Jensen, J, 2008-05-12 21:46:53 The NR5A2 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. NR5A2 transcription requires the activity of the PDX1 transcription factor. These events and interactions have not been studied in vivo in humans, but are inferred from corresponding ones worked out in the mouse and from in vitro studies of PDX1 protein binding to the Nr5A2 gene (Annicotte et al. 2003). Mature intronless transcript derived Histone mRNA Reactome DB_ID: 113820 Reactome Database ID Release 43113820 Reactome, http://www.reactome.org ReactomeREACT_2638 HNF6-dependent synthesis of ONECUT3 protein during morphogenesis Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43210837 Reactome, http://www.reactome.org ReactomeREACT_13722 Reviewed: Jensen, J, 2008-05-12 21:46:53 The ONECUT3 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus during morphogenesis of the pancreas. ONECUT3 transcription requires the activity of the HNF6 transcription factor. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. 3'-polyadenylated, capped pre-mRNA Reactome DB_ID: 72184 Reactome Database ID Release 4372184 Reactome, http://www.reactome.org ReactomeREACT_5683 HNF6-dependent synthesis of HNF1B protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43210824 Reactome, http://www.reactome.org ReactomeREACT_13556 Reviewed: Jensen, J, 2008-05-12 21:46:53 The HNF1B gene is transcribed, its mRNA is translated, and the protein products are transported to the nucleus. HNF1B transcription requires the activity of the HNF6 transcription factor. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. mature mRNA Reactome DB_ID: 159254 Reactome Database ID Release 43159254 Reactome, http://www.reactome.org ReactomeREACT_4074 Intronless Histone pre-mRNA Reactome DB_ID: 110756 Reactome Database ID Release 43110756 Reactome, http://www.reactome.org ReactomeREACT_2672 HNF6-dependent synthesis of NEUROG3 protein during morphogenesis Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43210836 Reactome, http://www.reactome.org ReactomeREACT_13662 Reviewed: Jensen, J, 2008-05-12 21:46:53 The NEUROG3 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus during morphogenesis of the pancreas. NEUROG3 transcription requires the activity of the HNF6 transcription factor. HES1 represses NEUROG3 transcription. In vivo, the interplay between HNF6 and HES6 deteremines the timing and level of NEUROG3 expression, which is critical for normal development of the pancreas. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. U7 snRNA Reactome DB_ID: 110761 Reactome Database ID Release 43110761 Reactome, http://www.reactome.org ReactomeREACT_3032 Mature intronless transcript derived mRNA Reactome DB_ID: 158444 Reactome Database ID Release 43158444 Reactome, http://www.reactome.org ReactomeREACT_4033 Mature intronless derived mRNA Reactome DB_ID: 158443 Reactome Database ID Release 43158443 Reactome, http://www.reactome.org ReactomeREACT_5526 upstream intronless mRNA fragment Reactome DB_ID: 112163 Reactome Database ID Release 43112163 Reactome, http://www.reactome.org ReactomeREACT_3673 downstream intronless mRNA fragment Reactome DB_ID: 112165 Reactome Database ID Release 43112165 Reactome, http://www.reactome.org ReactomeREACT_3064 Cytosolic GST Converted from EntitySet in Reactome Reactome DB_ID: 176039 Reactome Database ID Release 43176039 Reactome, http://www.reactome.org ReactomeREACT_7167 excised intron Reactome DB_ID: 72158 Reactome Database ID Release 4372158 Reactome, http://www.reactome.org ReactomeREACT_5309 lariat containing 5'-end cleaved mRNA Reactome DB_ID: 156756 Reactome Database ID Release 43156756 Reactome, http://www.reactome.org ReactomeREACT_3829 U12 snRNA Reactome DB_ID: 77471 Reactome Database ID Release 4377471 Reactome, http://www.reactome.org ReactomeREACT_5715 U11 snRNA Reactome DB_ID: 77461 Reactome Database ID Release 4377461 Reactome, http://www.reactome.org ReactomeREACT_2916 PDX1-dependent synthesis of NKX6-1 protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 In mature beta-cells of the pancreas, the NKX6-1 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. NKX6-1 transcription is positively regulated by the activity of the PDX1 transcription factor. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. Reactome Database ID Release 43211350 Reactome, http://www.reactome.org ReactomeREACT_13801 Reviewed: Jensen, J, 2008-05-12 21:46:53 hPrp18 Reactome DB_ID: 72070 Reactome Database ID Release 4372070 Reactome, http://www.reactome.org ReactomeREACT_3085 NEUROD1- and PDX1-dependent synthesis of glucokinase (GCK) protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43211346 Reactome, http://www.reactome.org ReactomeREACT_13517 Reviewed: Jensen, J, 2008-05-12 21:46:53 The glucokinase (GCK) gene is transcribed and its mRNA is translated. GCK transcription is positively regulated by the activity of the NEUROD1 and PDX1 transcription factors. These events and interactions are inferred from corresponding ones studied in molecular detail in the mouse. hSLU7 Reactome DB_ID: 72073 Reactome Database ID Release 4372073 Reactome, http://www.reactome.org ReactomeREACT_5157 MAFA-, NKX2-2-, PAX6-, and PDX1-dependent synthesis of insulin precursor protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43211289 Reactome, http://www.reactome.org ReactomeREACT_13617 Reviewed: Jensen, J, 2008-05-12 21:46:53 The INS1 gene, encoding insulin precursor protein, is transcribed and its mRNA is translated on membrane-associated ribosomes. INS1 transcription is positively regulated by the activities of the MAFA, NKX2-2, PAX6, and PDX1 transcription factors. These events and interactions are inferred from corresponding ones studied in molecular detail in the mouse. hPrp43 Reactome DB_ID: 72072 Reactome Database ID Release 4372072 Reactome, http://www.reactome.org ReactomeREACT_5171 PDX1-dependent synthesis of IAPP protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43211301 Reactome, http://www.reactome.org ReactomeREACT_13725 Reviewed: Jensen, J, 2008-05-12 21:46:53 The IAPP gene, encoding islet amyloid precursor protein, is transcribed and its mRNA is translated. IAPP transcription is positively regulated by PDX1 transcription factor. These events and interactions are inferred from corresponding ones studied in molecular detail in the mouse. hPrp22 Reactome DB_ID: 72071 Reactome Database ID Release 4372071 Reactome, http://www.reactome.org ReactomeREACT_3038 NEUROG3-dependent synthesis of INSM1 Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed16511571 Reactome Database ID Release 43210913 Reactome, http://www.reactome.org ReactomeREACT_13811 Reviewed: Jensen, J, 2008-05-12 21:46:53 The INSM1 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. INSM1 transcription requires the activity of the NEUROG3 transcription factor (Mellitzer et al. 2006). FOXOA2-, MAFA-, and PAX6-dependent synthesis of PDX1 protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome Database ID Release 43211272 Reactome, http://www.reactome.org ReactomeREACT_13782 Reviewed: Jensen, J, 2008-05-12 21:46:53 The PDX1 (IPF1) gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. PDX1 transcription is positively regulated by the activities of the FOXA2, MAFA, and PAX6 transcription factors. It is negatively regulated by FOXO1A, so events that deplete the nucleoplasmic pool of FOXO1A increase expression of PDX1. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. NEUROG3-dependent synthesis of NEUROD1 Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed12403815 Pubmed16511571 Reactome Database ID Release 43210920 Reactome, http://www.reactome.org ReactomeREACT_13647 Reviewed: Jensen, J, 2008-05-12 21:46:53 The NEUROD1 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. NEUROD1 transcription requires the activity of the NEUROG3 transcription factor (Heremans et al. 2002; Mellitzer et al. 2006). NEUROG3-dependent synthesis of NKX2-2 Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed12403815 Pubmed16511571 Reactome Database ID Release 43210921 Reactome, http://www.reactome.org ReactomeREACT_13545 Reviewed: Jensen, J, 2008-05-12 21:46:53 The NKX2-2 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. NKX2-2 transcription requires the activity of the NEUROG3 transcription factor (Heremans et al. 2002; Mellitzer et al. 2006). Bifunctional APS synthetase Converted from EntitySet in Reactome Reactome DB_ID: 174400 Reactome Database ID Release 43174400 Reactome, http://www.reactome.org ReactomeREACT_7300 RBPJ- and NOTCH1-dependent synthesis of HES1 protein during morphogenesis Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed9111040 Reactome Database ID Release 43210834 Reactome, http://www.reactome.org ReactomeREACT_13473 Reviewed: Jensen, J, 2008-05-12 21:46:53 The HES1 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus during morphogenesis of the pancreas. HES1 transcription requires the activity of the RBPJ transcription factor and the NOTCH1 intracellular domain, probably as a complex (Aster et al. 1997). These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. U6 ATAC snRNA Reactome DB_ID: 77466 Reactome Database ID Release 4377466 Reactome, http://www.reactome.org ReactomeREACT_4280 NEUROG3-dependent synthesis of PAX4 protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed12403815 Pubmed16511571 Reactome Database ID Release 43210886 Reactome, http://www.reactome.org ReactomeREACT_13802 Reviewed: Jensen, J, 2008-05-12 21:46:53 The PAX4 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. PAX4 transcription requires the activity of the NEUROG3 transcription factor (Heremans et al. 2002; Mellitzer et al. 2006). U4 ATAC snRNA Reactome DB_ID: 77464 Reactome Database ID Release 4377464 Reactome, http://www.reactome.org ReactomeREACT_4663 SULT1C1 monomer Converted from EntitySet in Reactome Reactome DB_ID: 176634 Reactome Database ID Release 43176634 Reactome, http://www.reactome.org ReactomeREACT_7099 3'-end cleaved mRNA with spliced exons Reactome DB_ID: 71998 Reactome Database ID Release 4371998 Reactome, http://www.reactome.org ReactomeREACT_3713 hPrp5 Reactome DB_ID: 72123 Reactome Database ID Release 4372123 Reactome, http://www.reactome.org ReactomeREACT_3263 hTra2 Reactome DB_ID: 72063 Reactome Database ID Release 4372063 Reactome, http://www.reactome.org ReactomeREACT_4242 CC1.3 protein /3 RRM, RS Reactome DB_ID: 72051 Reactome Database ID Release 4372051 Reactome, http://www.reactome.org ReactomeREACT_4848 UBA, Tudor - FLJ21007 Reactome DB_ID: 72052 Reactome Database ID Release 4372052 Reactome, http://www.reactome.org ReactomeREACT_3970 Expression of KLF5 Authored: May, B, 2009-05-15 01:16:49 Edited: May, B, 2009-05-15 01:16:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Increased expression of KLF5 occurs after activation of the transcription factors CEBPB and CEBPD during differentiation and activation of KLF5 depends on CEBPB and CEBPD. Both CEBPB and CEBPD bind the promoter of the KLF5 gene upstream of the site of transcription initiation and activate transcription of KLF5. Pubmed17011499 Reactome Database ID Release 43381377 Reactome, http://www.reactome.org ReactomeREACT_27305 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 SMC2 (P-loop, DA-box) Reactome DB_ID: 72056 Reactome Database ID Release 4372056 Reactome, http://www.reactome.org ReactomeREACT_2529 Expression of EBF1 Authored: May, B, 2010-10-18 Edited: May, B, 2010-10-18 Reactome Database ID Release 43977271 Reactome, http://www.reactome.org ReactomeREACT_27252 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The gene encoding transcription factor EBF1 is transcribed to yield mRNA and the mRNA is translated to yield protein in pre-adipocytes and adipocytes. Transcription of EBF1 is enhanced by CEBPB and CEBPD, which bind the EBF1 promoter. ASR2B Reactome DB_ID: 72050 Reactome Database ID Release 4372050 Reactome, http://www.reactome.org ReactomeREACT_5122 Expression of PPARG Authored: May, B, 2009-05-15 01:16:49 Edited: May, B, 2009-05-15 01:16:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed11872672 Pubmed17011499 Pubmed9065481 Reactome Database ID Release 43381283 Reactome, http://www.reactome.org ReactomeREACT_27156 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The transcription factors CEBPB, CEBPD, and KLF5 simultaneously bind the PPARG promoter and synergistically activate transcription of the PPARG gene. These three factors activate transcription after initial stimulation of adipocyte differentiation but then are replaced by CEBPA within 10 days. CEBPA and other factors may be responsible for long term maintenance of PPARG expression and the differentiated state.<br>Pre-adipose tissue contains both the widely expressed PPARG isoform 1 mRNA and the more tissue-specific PPARG isoform 2. The PPARG isoform 2 mRNA is translated to yield PPARG isoform 2 protein, which has 505 amino acid residues (57 KDa) and is the longest of the 4 observed variants. Isoform 2 is specific to preadipose and adipose tissue (Mukherjee et al. 1997). Confusingly, the longest variant is called isoform 1 in some publications. DnaJ hom. NP_055602 Reactome DB_ID: 72055 Reactome Database ID Release 4372055 Reactome, http://www.reactome.org ReactomeREACT_4415 HNF1A-dependent synthesis of HNF4G protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed11717395 Reactome Database ID Release 43211467 Reactome, http://www.reactome.org ReactomeREACT_13715 Reviewed: Jensen, J, 2008-05-12 21:46:53 The HNF4G gene is transcribed, its mRNA is translated, and the protein product is localized to the nucleoplasm. HNF4G expression is positively regulated by HNF1A. The molecular details of HNF4G expression in intact pancreatic beta cells have not been studied in humans, but are inferred from corresponding ones worked out in the mouse (Boj et al. 2001). HNF1A-dependent synthesis of FOXA3 Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed11717395 Reactome Database ID Release 43211482 Reactome, http://www.reactome.org ReactomeREACT_13553 Reviewed: Jensen, J, 2008-05-12 21:46:53 The FOXA3 gene is transcribed, its mRNA is translated, and the protein product is localized to the nucleoplasm. FOXA3 expression is positively regulated by HNF1A. The molecular details of FOXA3 expression in intact pancreatic beta cells have not been studied in humans, but are inferred from corresponding ones worked out in the mouse (Boj et al. 2001). Expression of CEBPB Authored: May, B, 2009-05-15 01:16:49 Edited: May, B, 2009-05-15 01:16:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Expression of the CEBPB and CEBPD transcription factors is induced by at least three factors:<br>1) Mitogens such as those present in fetal serum act via the Krox20 transcription factor to activate expression of CEBPB.<br>2) Glucocorticoids activate expression of CEBPD.<br>3) Hormones or drugs that increase intracellular cAMP act via pCREB to activate expression of CEBPB.<br> The detailed mechanisms of activation are not yet known. Pubmed17011499 Reactome Database ID Release 43381337 Reactome, http://www.reactome.org ReactomeREACT_27153 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 Expression of CEBPD Authored: May, B, 2009-05-15 01:16:49 Edited: May, B, 2009-05-15 01:16:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Expression of the CEBPB and CEBPD transcription factors is induced by at least three factors:<br>1) Mitogens such as those present in fetal serum act via the Krox20 transcription factor to activate expression of CEBPB.<br>2) Glucocorticoids activate expression of CEBPD.<br>3) Hormones or drugs that increase intracellular cAMP act via pCREB to activate expression of CEBPB.<br> The detailed mechanisms of activation are not yet known. Pubmed17011499 Reactome Database ID Release 43977392 Reactome, http://www.reactome.org ReactomeREACT_27195 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 HNF1A-dependent synthesis of GLUT2 protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed11575290 Pubmed11978637 Reactome Database ID Release 43211476 Reactome, http://www.reactome.org ReactomeREACT_13728 Reviewed: Jensen, J, 2008-05-12 21:46:53 The GLUT2 gene is transcribed, its mRNA is translated, and the protein product is localized to the plasma membrane. GLUT2 expression is positively regulated by HNF1A. In vivo, pancreatic GLUT2 expression is positively regulated by HNF1A. Mutations in HNF1A are associated with a form of MODY (maturity onset diabetes of the young) (Fanjans et al. 2001) and interactions between the HNF1A protein product and the GLUT2 promoter have been demomstrated in vitro (Ban et al. 2002). However, the molecular details of GLUT2 expression in intact pancreatic beta cells have not been studied in humans, but are inferred from corresponding ones worked out in the mouse. CF I - 72 kDa subunit Cleavage Factor I 72 kDa subunit Reactome DB_ID: 72014 Reactome Database ID Release 4372014 Reactome, http://www.reactome.org ReactomeREACT_5170 HNF1A-dependent synthesis of the L isoform of PKLR protein Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed11575290 Reactome Database ID Release 43211461 Reactome, http://www.reactome.org ReactomeREACT_13675 Reviewed: Jensen, J, 2008-05-12 21:46:53 The PKLR gene is transcribed, its mRNA is translated, spliced, and translated to yield the L isoform of PKLR protein. PKLR expression is positively regulated by HNF1A. Mutations in HNF1A are associated with a form of MODY (maturity onset diabetes of the young) (Fanjans et al. 2001) but the molecular details of PKLR expression in intact pancreatic beta cells have not been studied in humans, and are inferred from corresponding ones worked out in the mouse. CF I - 68 kDa subunit Cleavage Factor I 68 kDa subunit Reactome DB_ID: 72013 Reactome Database ID Release 4372013 Reactome, http://www.reactome.org ReactomeREACT_2952 HNF1A-dependent synthesis of HNF4A Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed11717395 Pubmed12235114 Reactome Database ID Release 43211466 Reactome, http://www.reactome.org ReactomeREACT_13577 Reviewed: Jensen, J, 2008-05-12 21:46:53 The HNF4A gene is transcribed from either of two promoters, P1 and P2, the resulting mRNA is translated, and the protein products localize in the nucleoplasm. Transcription is positively regulated by HNF1A. Many of the molecular details of these events have not been studied experimentally in humans, but are inferred from mouse model systems (Boj et al. 2001). Transcription in mouse and human pancreatic beta cells is P2-dependent and in humans yields three isoforms of mature HNF4A protein. A point mutation in the human P2 genomic DNA sequence is associated with MODY (maturity onset diabetes of the young), consistent with the hypothesis that P2-mediated transcription is essential for HNF4A expression and normal beta cell function (Hansen et al. 2002). CPSF4 - 30 kDa subunit Reactome DB_ID: 71994 Reactome Database ID Release 4371994 Reactome, http://www.reactome.org ReactomeREACT_3227 Expression of GLUT4 Authored: May, B, 2011-02-08 Edited: May, B, 2011-02-08 Pubmed8325954 Reactome Database ID Release 431183032 Reactome, http://www.reactome.org ReactomeREACT_27264 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The GLUT4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. dsRNA duplex Reactome DB_ID: 75086 Reactome Database ID Release 4375086 Reactome, http://www.reactome.org ReactomeREACT_4119 Connexin synthesis (generic) Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Connexins (Cxs) are encoded by a large gene family predicted to include at least 20 isoforms in humans. Most mammalian Cx genes consist of two exons. The first consists of untranslated sequence, and the second contains the entire coding sequence. Exceptionally, Cx36 and Cx45 contain 3 exons and 2 introns and the third exon contains the coding sequence (Belluardo et al. 1999 ; Jacob and Beyer 2001). Connexins have been divided in two major subgroups, alpha and beta, according to their amino acid sequence similarity (see Bruzzone et al., 2001; Willecke et al., 2002). Alternative names and additional subgroups have been suggested as well. Cx are synthesized by ribosomes in the endoplasmic reticulum (ER) membrane. All Cx proteins contain four trans-membrane domains (TM1 to TM4), two extracellular loops (E1 and E2) and one cytoplasmic loop. The amino- and carboxyl termini are located in the cytosol (reviewed in Segretain and Falk, 2004). After targeting to the ER, connexins are checked by a quality control system to prevent misfolded forms from progressing through the secretory pathway. Aberrant proteins are removed by endoplasmic-reticulum-associated degradation (ERAD). Edited: Matthews, L, 2007-01-07 14:51:44 Pubmed10191254 Pubmed10462698 Pubmed11242539 Pubmed11737941 Pubmed12108537 Pubmed15033576 Pubmed7929580 Reactome Database ID Release 43190682 Reactome, http://www.reactome.org ReactomeREACT_9410 C to U edited ApoB RNA Reactome DB_ID: 75085 Reactome Database ID Release 4375085 Reactome, http://www.reactome.org ReactomeREACT_5760 capped, methylated pre-mRNA Reactome DB_ID: 77507 Reactome Database ID Release 4377507 Reactome, http://www.reactome.org ReactomeREACT_3578 A to I edited RNA Reactome DB_ID: 75088 Reactome Database ID Release 4375088 Reactome, http://www.reactome.org ReactomeREACT_3805 p68 DEAH protein Reactome DB_ID: 72038 Reactome Database ID Release 4372038 Reactome, http://www.reactome.org ReactomeREACT_4900 MT-B Reactome DB_ID: 72092 Reactome Database ID Release 4372092 Reactome, http://www.reactome.org ReactomeREACT_3004 Expression of Phosphoenolpyruvate carboxykinase 1 (PEPCK-C) Authored: May, B, 2010-03-23 Edited: May, B, 2010-03-23 Pubmed16380219 Reactome Database ID Release 43560472 Reactome, http://www.reactome.org ReactomeREACT_27194 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The PEPCK-C gene is transcribed to yield mRNA and the mRNA is translated to yield protein. U1snRNP C protein Reactome DB_ID: 71916 Reactome Database ID Release 4371916 Reactome, http://www.reactome.org ReactomeREACT_3989 Expression of Lipoprotein lipase (LPL) Authored: May, B, 2010-03-23 Edited: May, B, 2010-03-23 Pubmed16380219 Reactome Database ID Release 43560498 Reactome, http://www.reactome.org ReactomeREACT_27312 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The LPL gene is transcribed to yield mRNA and the mRNA is translated to yield protein. hPrp19 Reactome DB_ID: 72044 Reactome Database ID Release 4372044 Reactome, http://www.reactome.org ReactomeREACT_3274 Expression of FABP4 (aP2) Authored: May, B, 2010-03-23 Edited: May, B, 2010-03-23 Pubmed10425206 Pubmed15273253 Pubmed19115207 Pubmed20101261 Reactome Database ID Release 43560510 Reactome, http://www.reactome.org ReactomeREACT_27226 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The FABP4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of FABP4 is activated during adipogenesis. HuR /3 RRM protein Reactome DB_ID: 72046 Reactome Database ID Release 4372046 Reactome, http://www.reactome.org ReactomeREACT_5767 Expression of Perilipin (PLIN) Authored: May, B, 2010-03-23 Edited: May, B, 2010-03-23 Pubmed16380219 Reactome Database ID Release 43560493 Reactome, http://www.reactome.org ReactomeREACT_27159 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The Perilipin (PLIN) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Perilipin is upregulated during adipogenesis. NFAR-2 protein Reactome DB_ID: 72039 Reactome Database ID Release 4372039 Reactome, http://www.reactome.org ReactomeREACT_4072 Expression of Leptin Authored: May, B, 2011-02-08 Edited: May, B, 2011-02-08 Pubmed12213831 Pubmed8643605 Pubmed8770873 Reactome Database ID Release 431183003 Reactome, http://www.reactome.org ReactomeREACT_27275 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The Ob gene encoding leptin is transcribed to yield mRNA and translated to yield protein. Expression of leptin is positively regulated by C/EBPalpha (CEBPA, Miller et al. 1996, Melzner et al. 2002) and negatively regulated by PPARG in adipocytes (De Vos et al. 1996). Expression of Adiponectin Authored: May, B, 2011-02-08 Edited: May, B, 2011-02-08 Pubmed12829629 Pubmed15850785 Pubmed15919796 Pubmed18931025 Reactome Database ID Release 431183058 Reactome, http://www.reactome.org ReactomeREACT_27292 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The Adiponectin gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of Adiponectin is upregulated during adipogenesis by C/EBPalpha (CEBPA), PPARG, and CEBPB (Segawa et al. 2009, Qiao et al. 2005, Iwaki et al. 2003, Kita et al. 2005). Expression of CEBPA Authored: May, B, 2010-03-23 Edited: May, B, 2010-03-23 Pubmed16380219 Reactome Database ID Release 43560491 Reactome, http://www.reactome.org ReactomeREACT_27244 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The CEBPA gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Maintenance of PPARG Expression in Differentiated Adipocytes Authored: May, B, 2009-05-15 01:16:49 Edited: May, B, 2009-05-15 01:16:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 In mouse, by 10 days after induction of adipocyte differentiation Cebpa, but neither Cebpb nor Cebpd, is detectable at the Pparg promoter. While adipocyte differentiation can proceed without Cebpa, adipocytes differentiated from Cebpa-knockout cells are insulin insensitive due to a defect in GLUT4 vesicle trafficking. Pubmed17011499 Reactome Database ID Release 43381268 Reactome, http://www.reactome.org ReactomeREACT_27217 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 Synthesis of Cx32 Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Cx proteins are cotranslationally inserted into ER membranes in an SRP (signal recognition particle)-dependent process (Falk et al., 1994). Edited: Matthews, L, 2007-01-07 14:51:44 Pubmed7929580 Reactome Database ID Release 43190693 Reactome, http://www.reactome.org ReactomeREACT_9442 Synthesis of Cx43 Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Cx proteins are cotranslationally inserted into ER membranes in an SRP (signal recognition particle)-dependent process (Falk et al., 1994). It has been observed, however, that the oligomerization of Cx43 into connexons does not occur before the Trans-Golgi network (Musil and Goodenough, 1993; Koval, 2006). Pubmed15536180 Pubmed16490353 Pubmed7691412 Pubmed7929580 Reactome Database ID Release 43191072 Reactome, http://www.reactome.org ReactomeREACT_9473 Expression of IFN-beta Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed11244049 Pubmed20627800 Reactome Database ID Release 431028812 Reactome, http://www.reactome.org ReactomeREACT_25400 Reviewed: Kawai, T, Akira, S, 2010-10-30 The IFN-beta genes are transcribed and translated yielding IFNB proteins which are secreted. This process is positively regulated by IRF3:CBP/p300 transcription factor complex. Expression of Carbonic Anhydrase IX (CA9) Authored: May, B, 2011-03-20 Edited: May, B, 2011-03-20 Pubmed11156414 Pubmed15184875 Reactome Database ID Release 431235035 Reactome, http://www.reactome.org ReactomeREACT_121133 Reviewed: Rantanen, Krista, 2012-05-19 The gene encoding carbonic anhydrase IX (CA9) is transcribed to yield mRNA and the mRNA is translated to yield protein. Hypoxia-inducible factor binds the promoter of CA9 and enhances expression of CA9. Expression of VEGF (isoform 1) Authored: May, B, 2011-03-20 Edited: May, B, 2011-03-20 Pubmed17804822 Pubmed8756616 Pubmed8917528 Reactome Database ID Release 431235037 Reactome, http://www.reactome.org ReactomeREACT_121365 Reviewed: Rantanen, Krista, 2012-05-19 The VEGFA (VEGF) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Hypoxia-inducible factor binds the VEGF promoter, recruits p300 and CBP, and enhances transcription. Expression of Erythropoietin (EPO) Authored: May, B, 2011-03-20 Edited: May, B, 2011-03-21 Pubmed7836384 Pubmed8387214 Pubmed8663540 Pubmed8917528 Pubmed9027736 Reactome Database ID Release 431235070 Reactome, http://www.reactome.org ReactomeREACT_121407 Reviewed: Rantanen, Krista, 2012-05-19 The EPO gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of EPO is enhanced by Hypoxia-inducible factor, which binds to the EPO promoter. Synthesis of Cx26 Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Cx proteins are cotranslationally inserted into ER membranes in an SRP (signal recognition particle)-dependent process (Falk et al., 1994). Cx26 has also been reported to insert post-translationally into the ER membrane (Zhang et al., 1996; Ahmad et al., 1999 ; Ahmad and Evans, 2002). Pubmed10191254 Pubmed11985493 Pubmed7929580 Pubmed8868474 Reactome Database ID Release 431629787 Reactome, http://www.reactome.org ReactomeREACT_115750 UDP-glucuronosyltransferase (N-glucuronide forming isozymes) Converted from EntitySet in Reactome Reactome DB_ID: 174917 Reactome Database ID Release 43174917 Reactome, http://www.reactome.org ReactomeREACT_7154 p-2S-SMAD2/3 Converted from EntitySet in Reactome Phospho-R-SMAD Reactome DB_ID: 171182 Reactome Database ID Release 43171182 Reactome, http://www.reactome.org ReactomeREACT_7364 p-S465/423,467/425-SMAD2/3 GCK, HK1, HK2, HK3 Converted from EntitySet in Reactome Reactome DB_ID: 450097 Reactome Database ID Release 43450097 Reactome, http://www.reactome.org ReactomeREACT_21846 glucokinase and hexokinases Coactivators of PPARalpha Converted from EntitySet in Reactome Reactome DB_ID: 400216 Reactome Database ID Release 43400216 Reactome, http://www.reactome.org ReactomeREACT_20313 alpha-amylase Converted from EntitySet in Reactome Reactome DB_ID: 189046 Reactome Database ID Release 43189046 Reactome, http://www.reactome.org ReactomeREACT_9564 TEAD Converted from EntitySet in Reactome Reactome DB_ID: 2032773 Reactome Database ID Release 432032773 Reactome, http://www.reactome.org ReactomeREACT_119570 CIS, SOCS1-3 Converted from EntitySet in Reactome Reactome DB_ID: 1169189 Reactome Database ID Release 431169189 Reactome, http://www.reactome.org ReactomeREACT_111344 MATE1/2 Converted from EntitySet in Reactome Reactome DB_ID: 446605 Reactome Database ID Release 43446605 Reactome, http://www.reactome.org ReactomeREACT_20810 Monocarboxylate transporters Converted from EntitySet in Reactome Reactome DB_ID: 434162 Reactome Database ID Release 43434162 Reactome, http://www.reactome.org ReactomeREACT_21092 FBXW7alpha/gamma Converted from EntitySet in Reactome Reactome DB_ID: 1602299 Reactome Database ID Release 431602299 Reactome, http://www.reactome.org ReactomeREACT_120194 PHT cotransporters Converted from EntitySet in Reactome Reactome DB_ID: 428024 Reactome Database ID Release 43428024 Reactome, http://www.reactome.org ReactomeREACT_19869 Cap-bound mRNA is activated by helicases Pubmed6853548 Reactome Database ID Release 4372647 Reactome, http://www.reactome.org ReactomeREACT_1521 The DEAD-box RNA helicase eIF4A, together with the RNA-binding proteins eIF4B or eIF4H, is thought to unwind RNA secondary structures near the 5'-end of the mRNA and in the presence of ATP. Formation of translation initiation complexes containing mRNA that does not circularize Pubmed592399 Pubmed641056 Pubmed6853548 Pubmed9732867 Reactome Database ID Release 43157849 Reactome, http://www.reactome.org ReactomeREACT_1904 The translation initiation complex forms when the 43S complex binds the mRNA that is associated with eIF4F, eIF4B and eIF4H. eIF4G in the eIF4F complex can directly contact eIF3 in the 43S complex. eIF1A is necessary for the formation of this complex. Formation of translation initiation complexes yielding circularized Ceruloplasmin mRNA in a 'closed-loop' conformation Authored: Matthews, L, 2004-12-13 00:33:09 Edited: Matthews, L, 0000-00-00 00:00:00 Pubmed11058101 Pubmed9857202 Reactome Database ID Release 43156808 Reactome, http://www.reactome.org ReactomeREACT_1515 The precise order of events leading to the circularization of poly (A) mRNA during translation initiation is unknown. Here the association of PABP with the poly (A) mRNA and the association of PABP with eIF4F are represented as occuring simultaneously after formation of the initiation complex. However, it is also possible that these interactions occur during the formation of the translation initiation complex. The binding of eIF4F to the cap and binding of PABP to the poly (A) tail, for example, may occur at the same time. In fact, the eIF4G-PABP interaction helps eIF4F to bind tighter to the cap (Borman et al. 2000.) In addition, eIF4B and eIF4H bind more transiently to the mRNA and may not be part of an initial complex in which PABP has not yet touched eIF4G. Ribosomal scanning Pubmed10364207 Pubmed592399 Pubmed641056 Pubmed7000367 Pubmed8943342 Pubmed9045610 Reactome Database ID Release 4372621 Reactome, http://www.reactome.org ReactomeREACT_1516 The mRNA-bound ribosomal complex moves along the 5'-untranslated region (5'-UTR) of the mRNA from its initial site to the initiation codon to form a 48S complex, in which the initiation codon (AUG) is base paired to the anticodon of the Met-tRNAi. It is not known whether eIF4A (or another ATPase, such as DED1) facilitates scanning by melting mRNA secondary structures or by actively propelling the ribosome. Release of eIF4E from the inactive eIF4E:4E-BP complex Pubmed7935836 Reactome Database ID Release 4372622 Reactome, http://www.reactome.org ReactomeREACT_237 eIF4E gets released from the inactive eIF4E:4EBP complex. Formation of the cap-binding eIF4F complex Pubmed8449919 Reactome Database ID Release 4372631 Reactome, http://www.reactome.org ReactomeREACT_441 eIF4A interacts with eIF4G, and eIF4E interacts with the amino-terminal domain of eIF4G to form the cap-binding complex eIF4F. eIF4F binds to mRNP Pubmed291969 Pubmed6853548 Reactome Database ID Release 4372635 Reactome, http://www.reactome.org ReactomeREACT_918 The factor eIF4E within the eIF4F (cap-binding) complex directly binds the 5'-cap on eukaryotic mRNAs. Note that the mRNA is in complex with cytoplasmic proteins constituting an mRNP complex. PEPT cotransporters Converted from EntitySet in Reactome Reactome DB_ID: 427958 Reactome Database ID Release 43427958 Reactome, http://www.reactome.org ReactomeREACT_19865 Excitatory amino acid transporters Converted from EntitySet in Reactome Reactome DB_ID: 427969 Reactome Database ID Release 43427969 Reactome, http://www.reactome.org ReactomeREACT_19879 Synthesis of nascent polypeptide containing signal sequence Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: D'Eustachio, P, 2011-10-23 Pubmed20444697 Reactome Database ID Release 431799335 Reactome, http://www.reactome.org ReactomeREACT_115572 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 The synthesis of a protein destined for the endoplasmic reticulum starts with the canonical events of cytosolic translation initiation and proceeds to the point where a nascent polypeptide chain containing a signal sequence protrudes from the mRNA:ribosome complex. Merrick (2010) provides an overview of these events. Association of a nascent polypeptide:mRNA:ribosome complex with a signal recognition particle (SRP) Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed12853463 Pubmed16469117 Pubmed18455985 Reactome Database ID Release 431799332 Reactome, http://www.reactome.org ReactomeREACT_115921 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 The Ribosome Nascent Complex containing the ribosome and protruding signal peptide of preprolactin is bound by the Signal Recognition Particle Complex. Translation is paused during this step. INF-gamma induced phosphorylation of L13a Authored: Matthews, L, 2004-12-13 00:49:48 Pubmed14567916 Reactome Database ID Release 43156832 Reactome, http://www.reactome.org ReactomeREACT_1825 The L13a subunit of the 60s ribosome is phosphorylated about 16 hours after INF gamma induction by an unknown kinase. At this time, L13a is also released from the 60s subunit (Mazumder et al.,2003). It is unclear, however, whether phosphorylation occurs before or after the release of L13a. Here, phosphorylation is shown as occurring after release. Association of phospho-L13a with GAIT element of Ceruloplasmin mRNA Although the mechanism through which L13a prevents translation initiation has not been determined, Mazumder et al. (2003) have described four alternatives. L13a could (1) inhibit the function of eIF4F, (2) block the recruitment of the 43S preinitiation complex, (3) prevent scanning of the 43S complex to the initiation codon, or 4) interfere with joining of the 60S ribosomal subunit. Authored: Matthews, L, 2004-12-13 00:49:48 Edited: Matthews, L, 0000-00-00 00:00:00 Pubmed12588972 Pubmed14567916 Reactome Database ID Release 43156823 Reactome, http://www.reactome.org ReactomeREACT_1595 eIF2 activation Pubmed2491852 Pubmed3356695 Reactome Database ID Release 4372722 Reactome, http://www.reactome.org ReactomeREACT_1401 eIF2B is a guanine nucleotide releasing factor that is required to cause GDP release so that a new GTP molecule can bind and activate eIF2, so that it can be reused. Dissociation of L13a from the 60s ribosomal subunit Authored: Matthews, L, 2004-12-13 00:49:48 Pubmed14567916 Reactome Database ID Release 43156826 Reactome, http://www.reactome.org ReactomeREACT_940 The L13a subunit of the 60s ribosome is phosphorylated about 16 hours after INF gamma induction by an unknown kinase. At this time, L13a is also released from the 60s subunit (Mazumder et al.,2003). It is unclear, however, whether phosphorylation occurs before or after the release of L13a. Here, phosphorylation is shown as occurring after release. The 60S subunit joins the translation initiation complex Joining of the 60S subunit to form the 80S ribosome is catalyzed by the presence of GTP-bound eIF5B. Pubmed10659855 Pubmed1095581 Pubmed592398 Reactome Database ID Release 4372672 Reactome, http://www.reactome.org ReactomeREACT_198 Formation of eIF2:GDP:eIF2B intermediate Inactive eIF2:GDP binds eIF2B to form an eIF2:GDP:eIF2B intermediate. Pubmed2491852 Pubmed3356695 Reactome Database ID Release 4372670 Reactome, http://www.reactome.org ReactomeREACT_175 eIF5B:GTP is hydrolyzed and released Once the 60S subunit joins the translation initiation complex, eIF5B hydrolyzes its GTP and is released from the now 80S monosome. The fully assembled 80s ribosome is now ready to start elongation of the polypeptide chain. Pubmed10659855 Pubmed1095581 Reactome Database ID Release 4372671 Reactome, http://www.reactome.org ReactomeREACT_3 eIF2:GTP is hydrolyzed, eIFs are released Once the Met-tRNAi has recognized the AUG, eIF2-bound GTP is hydrolyzed. The reaction is catalyzed by eIF5 (or eIF5B) and is thought to cause dissociation of all other initiation factors and allow joining of the large 60S ribosomal subunit. Release of the initiation factors from 40S leaves the Met-tRNAi in the ribosomal P-site base-paired to the start codon on the mRNA. Pubmed10659855 Pubmed1095581 Pubmed11018020 Pubmed1856230 Pubmed429297 Pubmed592398 Pubmed592399 Pubmed641056 Reactome Database ID Release 4372619 Reactome, http://www.reactome.org ReactomeREACT_1060 Start codon recognition Pubmed9732867 Reactome Database ID Release 4372697 Reactome, http://www.reactome.org ReactomeREACT_656 The AUG initiation codon in the mRNA is recognized by base pairing with the anticodon of the Met-tRNAi. This reaction requires eIF1, eIF1A, eIF2 and eIF5. Kinesin-13 monomers Converted from EntitySet in Reactome Reactome DB_ID: 990510 Reactome Database ID Release 43990510 Reactome, http://www.reactome.org ReactomeREACT_26496 Signal peptide cleavage from ribosome-associated nascent protein As the signal peptide of the nascent protein enters the lumen of the endoplasmic reticulum (ER), the signal peptide is recognized and cleaved by the ER membrane-associated Signal Peptidase. Translation of the protein then proceeds to completion. Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 EC Number: 3.4.21 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Reactome Database ID Release 431799329 Reactome, http://www.reactome.org ReactomeREACT_115742 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 eEF1A complexes with GTP Authored: Gopinathrao, G, 2005-03-11 20:46:56 Reactome Database ID Release 43156909 Reactome, http://www.reactome.org ReactomeREACT_90 The cycle of elongation starts with an empty ribosomal A-site and the peptidyl-tRNA in the P-site. eEF1A is activated by GTP binding and allows for the subsequent binding of aminoacyl-tRNA (aa-tRNA).This process is illustrated below with a GTP molecule in white and eEF1A protein in yellow. eEF1A:GTP:aminoacyl tRNA ternary complex formation. Authored: Gopinathrao, G, 2005-03-11 20:46:56 Pubmed2207148 Reactome Database ID Release 43156908 Reactome, http://www.reactome.org ReactomeREACT_1242 The binding of eEF1A:GTP to aminoacyl tRNA (aa-tRNA) results in the formation of a ternary complex (eEF1A:GTP:aa-tRNA). Human eEF1A and rabbit eEF1A are 100% identical, and prokaryotic homologue of eEF1A (EF-Tu) shows 59% identity in the GTP-binding domain.This process is illustrated below with: a GTP molecule in white and eEF1A protein in yellow. Aminoacyl-tRNA binds to the ribosome at the A-site Authored: Gopinathrao, G, 2005-03-11 20:46:56 Once the correct codon-anticodon match occurs between the mRNA and aa-tRNA, the decoding event triggers GTP hydrolysis on eEF1A. The resulting conformational change releases the aa-tRNA to the A-site, and GDP bound form eEF1A is released from the ribosome.<br>Insight into the mechanics of this system has been obtained from earlier works with rabbit reticulocytes and the E.coli system.<br>This process is illustrated below with: an amino acyl-tRNA with an amino acid, a peptidyl-tRNA with a growing peptide and a ribosome with A,P and E sites to accommodate these two forms of tRNA. Pubmed8722040 Reactome Database ID Release 43156907 Reactome, http://www.reactome.org ReactomeREACT_2075 Hydrolysis of eEF1A:GTP Authored: Gopinathrao, G, 2005-03-17 13:24:01 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Once the correct codon-anticodon match occurs between the mRNA and aa-tRNA, the decoding event triggers GTP hydrolysis on eEF1A. The resulting conformational change releases the aa-tRNA to the A-site, and GDP bound form of eEF1A is released from the ribosome.<br>This process is illustrated below with: an amino acyl-tRNA with an amino acid,a peptidyl-tRNA with a growing peptide and a ribosome with A,P and E sites to accommodate these two forms of tRNA. Pubmed6568109 Reactome Database ID Release 43156923 Reactome, http://www.reactome.org ReactomeREACT_552 Peptide transfer from P-site tRNA to the A-site tRNA EC Number: 2.3.2.12 Pubmed12297040 Pubmed1620067 Reactome Database ID Release 43156912 Reactome, http://www.reactome.org ReactomeREACT_1227 The A- and P-sites of the ribosome positions the aa-tRNA and peptidyl-tRNA such that a nucleophilic attack can occur between the amine group of the A-site aa-tRNA and the carbonyl group of the growing peptide chain on the P-site tRNA, resulting in the formation of a peptide bond. The carboxyl end of the peptide chain is uncoupled from the tRNA molecule in the P-site and forms a new peptide bond with the amino acid that is in the A-site.<br>This process is illustrated below with: a peptidyl-tRNA with a growing peptide,a deacylated tRNA with an -OH and a ribosome with A,P and E sites to accommodate these three forms of tRNA. Translocation of ribosome by 3 bases in the 3' direction Authored: Gopinathrao, G, 2005-02-08 19:10:56 Following peptide bond formation, GTP-bound eEF2 catalyzes the translocation of the deacylated tRNA in the P-site and the peptidyl-tRNA in the A-site (the pre-translocation state) into the E- and P- sites (the post-translocation state), respectively. Thus, the mRNA advances by three bases to expose the next codon in the A-site. After translocation, GDP-bound eEF2 leaves the ribosome to allow another round of elongation. eEF2 is reactivated by the release of GDP and binds GTP for subsequent rounds. <br>This process is illustrated below with a peptidyl-tRNA with a growing peptide, a deacylated tRNA with an -OH and a ribosome with A,P and E sites to accommodate these three forms of tRNA is also shown. Pubmed1620067 Pubmed1703007 Reactome Database ID Release 43156915 Reactome, http://www.reactome.org ReactomeREACT_1937 has a Stoichiometric coefficient of 2 GTP-binding activates eEF2 At the beginning of this reaction, 1 molecule of 'eEF2', and 1 molecule of 'GTP' are present. At the end of this reaction, 1 molecule of 'eEF2:GTP' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Reactome Database ID Release 43156930 Reactome, http://www.reactome.org ReactomeREACT_2173 Regeneration of eEF1A:GTP by eEF1B activity Authored: Gopinathrao, G, 2005-03-11 20:46:56 Pubmed10368288 Pubmed2207149 Pubmed3276514 Reactome Database ID Release 43156913 Reactome, http://www.reactome.org ReactomeREACT_67 The eEF1B complex binds to eEF1A and regulates its activity by catalyzing the release of GDP. Subsequently, GTP is able to bind eEF1A allowing the formation of the ternary complex (eEF1A-GTP-aa-tRNA).In metazoans eEF1 protein family is composed of four subunits: eEF1A and eEF1B alpha, beta, and gamma (formerly EF-1alpha, EF-1beta, EF-1delta, and EF-1gamma, respectively). Both eEF1B alpha and eEF1B beta function as nucleotide exchange proteins. eEF1B gamma associates with eEF1B alpha and stimulates its exchange activity.<br>This process is illustrated below with a GTP molecule in white and eEF1A protein in yellow.The three subunits of eEF1B are also shown. Translocation of signal-containing nascent peptide to Endoplasmic Reticulum Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed11964406 Pubmed18166647 Pubmed9631292 Reactome Database ID Release 431799326 Reactome, http://www.reactome.org ReactomeREACT_115582 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 The Signal Recognition Particle (SRP) receptor mediates transfer of the ribosome:mRNA:nascent protein complex to the Translocon Complex. A coupled reaction (not annotated here) in which GTP molecules are hydrolyzed by the alpha subunit of the SRP Receptor and the SRP54 subunit of the SRP is thought to ensure release of the SRP only after the ribosome is properly reoriented. At the end of this process, the ribosome is attached to the endoplasmic reticulum (ER) membrane with its associated nascent polypeptide protruding through the Translocon Complex into the ER lumen. The SRP receptor binds the SRP:nascent peptide:ribosome complex Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed12853463 Pubmed9631292 Reactome Database ID Release 431799330 Reactome, http://www.reactome.org ReactomeREACT_116124 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 The SRP receptor in the the endoplasmic reticulum (ER) membrane binds via its alpha subunit to the the SRP54 subunit of the Signal Recognition Particle (SRP), which itself is bound to a ribosome:mRNA:polypeptide complex. This interaction tethers the ribosome to the ER membrane, oriented so that the nacent polypeptide will traverse the ER membrane and enter the ER lumen. This process has been characterized in detail in cultured canine cells; this human event is inferred by homology from its canine counterpart. GTP bound eRF3:eRF1 complex binds the peptidyl tRNA:mRNA:80S Ribosome complex Authored: Gillespie, ME, 2005-01-26 20:24:54 GENE ONTOLOGYGO:0006415 Please note that this reaction was inferred from experiments performed using Saccharomyces cerevisiae. Pubmed7990965 Pubmed9712840 Reactome Database ID Release 43141691 Reactome, http://www.reactome.org ReactomeREACT_227 GTP Hydrolysis by eRF3 bound to the eRF1:mRNA:polypeptide:80S Ribosome complex Authored: Gillespie, ME, 2005-01-26 20:24:54 GENE ONTOLOGYGO:0006415 Please note that this reaction was inferred from experiments performed using Saccharomyces cerevisiae. Pubmed10358005 Reactome Database ID Release 43141673 Reactome, http://www.reactome.org ReactomeREACT_1654 Loading and methylation of Sm proteins onto SMN Complexes Authored: Gillespie, ME, 2007-01-29 20:29:54 GENE ONTOLOGYGO:0000387 Pubmed10601333 Pubmed10725331 Pubmed10747894 Pubmed10851237 Pubmed11714716 Pubmed11715014 Pubmed11720283 Pubmed11748230 Pubmed12065586 Pubmed9323129 Pubmed9323130 Reactome Database ID Release 43191790 Reactome, http://www.reactome.org ReactomeREACT_10041 Reviewed: Luhrmann, R, 2007-04-30 18:31:22 The survival of motor neurons (SMN) complex binds to Sm proteins and small nuclear RNAs (snRNAs) in the cytoplasm. Sm is part the SMN multiprotein complex that contains Gemins 2 – 7, including the DEAD-box RNA helicase Gemin3. The binding of the SMN complex to the snRNAs depends on the presence of specific, high-affinity (nanomolar) binding domains in the snRNAs. The SMN complex binds the Sm proteins through the Sm domains interaction with the Gemins, the TUDOR domain, and through unique arginine- and glycine-rich (RG) domains found in three of these, SmB, SmD1 and SmD3. The association with RG domains is strongly enhanced by the post-translational symmetric dimethylation of specific arginines in these domains, a process that is carried out by the methylosome (JBP1 or PRMT5) complex. snRNP complex assembly Authored: Gillespie, ME, 2007-01-29 20:29:54 GENE ONTOLOGYGO:0000387 Pubmed10556282 Pubmed12441251 Pubmed9845364 Reactome Database ID Release 43191786 Reactome, http://www.reactome.org ReactomeREACT_9957 Reviewed: Luhrmann, R, 2007-04-30 18:31:22 To facilitate snRNP assembly, the SMN complex must bring together the Sm proteins and an Sm-site-containing snRNA. The SMN:Sm protein complex binds to the m7G capped snRNAs in the cytoplasm. Polypeptide release from the eRF3-GDP:eRF1:mRNA:80S Ribosome complex Authored: Gillespie, ME, 2005-01-26 20:24:54 GENE ONTOLOGYGO:0006415 Please note that this reaction was inferred from experiments performed using Saccharomyces cerevisiae. Pubmed10358005 Reactome Database ID Release 43141671 Reactome, http://www.reactome.org ReactomeREACT_389 Nuclear export of snRNA transcripts Authored: Gillespie, ME, 2007-01-29 20:29:54 GENE ONTOLOGYGO:0051168 Pubmed11333016 Reactome Database ID Release 43191825 Reactome, http://www.reactome.org ReactomeREACT_10069 Reviewed: Luhrmann, R, 2007-04-30 18:31:22 The snRNAs, except U6 snRNA, are transcribed by RNA polymerase II, co-transcriptionally capped and exported rapidly to the cytoplasm in association with a cap-binding complex and the export factor PHAX. snRNP nuclear import and release A properly assembled Sm core and the m3G cap structure are prerequisites for small nuclear ribonucleoprotein (snRNP) import into the nucleus. Once imported into the nucleus, the snRNPs are initially concentrated in Cajal bodies (CBs), where there is further processing of the snRNAs plus binding of additional proteins, from CRBs they transit to "speckles", from where they are engaged for pre-mRNA splicing. The SMN complexes in the nucleus are found throughout the nucleoplasm but are particularly concentrated in Gems, the "twins" of the snRNP-rich CBs. Authored: Gillespie, ME, 2007-01-29 20:29:54 GENE ONTOLOGYGO:0051170 Pubmed10531003 Reactome Database ID Release 43191830 Reactome, http://www.reactome.org ReactomeREACT_10010 Reviewed: Luhrmann, R, 2007-04-30 18:31:22 Orc3 associates with Orc2 constitutively bound at origins of replication At the beginning of this reaction, 1 molecule of 'Orc2:origin', and 1 molecule of 'Orc3' are present. At the end of this reaction, 1 molecule of 'Orc3:Orc2:origin' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11046155 Pubmed11323433 Pubmed11395502 Pubmed9733749 Reactome Database ID Release 4368595 Reactome, http://www.reactome.org ReactomeREACT_533 snRNA Cap hypermethylation Authored: Gillespie, ME, 2007-01-29 20:29:54 GENE ONTOLOGYGO:0000387 Pubmed11983179 Pubmed12776181 Pubmed2944599 Pubmed8196654 Reactome Database ID Release 43191784 Reactome, http://www.reactome.org ReactomeREACT_10002 Reviewed: Luhrmann, R, 2007-04-30 18:31:22 The snRNA:SMN:SM protein complex is engaged by a hypermethylase that hypermethylates the snRNA cap from m7G (7-methylguanosine) to m3G (2,2,7-trimethylguanosine). snRNP:Snurportin complex formation Authored: Gillespie, ME, 2007-01-29 20:29:54 GENE ONTOLOGYGO:0000387 Pubmed12095920 Pubmed12776181 Pubmed9670026 Reactome Database ID Release 43191763 Reactome, http://www.reactome.org ReactomeREACT_9946 Reviewed: Luhrmann, R, 2007-04-30 18:31:22 The nuclear import signal has two parts; Cap hypermethylation triggers nuclear import via snurportin1 binding and by receptor recognition of the Sm proteins. Snurportin1 (SPN) is an adaptor that links the assembled snRNP to the nuclear transport machinery, recruiting importin beta for nuclear import. The import receptor that recognizes the Sm proteins is not yet known. Formation of eEF1B complex At the beginning of this reaction, 1 molecule of 'eEF1B alpha', 1 molecule of 'eEF1B gamma', and 1 molecule of 'eEF1B beta' are present. At the end of this reaction, 1 molecule of 'eEF1B complex' is present.<br><br> This reaction takes place in the 'cytosol'.<br> Reactome Database ID Release 43156910 Reactome, http://www.reactome.org ReactomeREACT_1395 VGLUTs Converted from EntitySet in Reactome Reactome DB_ID: 428606 Reactome Database ID Release 43428606 Reactome, http://www.reactome.org ReactomeREACT_19634 Free CDT1 associates with CDC6:ORC:origin complexes At the beginning of this reaction, 1 molecule of 'CDT1', and 1 molecule of 'CDC6:ORC:origin complex' are present. At the end of this reaction, 1 molecule of 'CDT1:CDC6:ORC:origin complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11125146 Reactome Database ID Release 4368826 Reactome, http://www.reactome.org ReactomeREACT_1975 Ubiquitinated geminin is degraded by the proteasome At the beginning of this reaction, 1 molecule of 'geminin:ubiquitin complex' is present. At the end of this reaction, 1 molecule of 'ubiquitin' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of '26S proteasome'.<br> Pubmed11125146 Pubmed9635433 Reactome Database ID Release 4368825 Reactome, http://www.reactome.org ReactomeREACT_1471 Mcm2-7 associates with the Cdt1:CDC6:ORC:origin complex, forming the pre-replicative complex (preRC) Genetic studies in S. cerevisiae indicate that wild-type Cdc6 function is required for correctly timed loading of Mcm2-7 onto ORC. Biochemical studies indicate that the human and Xenopus Cdc6 proteins likewise are required for Mcm2-7 loading, and that they are ATPase switches. Specifically, Cdc6 may function as a clamp loader, assembling Mcm2-7 onto DNA in an ATP-dependent reaction. All known Cdc6 proteins have the Walker A and Walker B sequence motifs characteristic of the AAA+ superfamily of ATPases. As expected for an AAA+ protein, human Cdc6 binds and slowly hydrolyzes ATP in vitro. ATP hydrolysis was disrupted by mutations of the Walker B motif, while both binding and hydrolysis were disrupted by Walker A mutations. Microinjection of either mutant protein into HeLa cells blocked their progression through S phase. Both wild-type and mutant proteins can dimerize in vitro, and studies with Xenopus egg extracts suggest that Cdc6 functions in vivo as a dimer or larger multimer. In Xenopus extracts depleted of Cdc6 and reconstituted with either mutant protein, recruitment of Mcm2-7 to chromatin failed. Pubmed10436018 Pubmed10801458 Pubmed11006548 Pubmed11950940 Pubmed9407030 Reactome Database ID Release 4368849 Reactome, http://www.reactome.org ReactomeREACT_1770 Association of MCM8 with ORC:origin complex Authored: Tye, BK, 2006-03-17 14:46:24 Edited: Gopinathrao, G, 2006-03-17 14:47:28 Pubmed15684404 Reactome Database ID Release 43176973 Reactome, http://www.reactome.org ReactomeREACT_6731 The MCM2-7 complex, an essential component of the pre-replication complex, recruits CDC6 and CDT1 proteins to the origin. MCM8, another member of the MCM family has been found to bind to chromatin during early G1 phase. MCM8 interacts specifically with the ORC2 protein. Orc6 associates with Orc1:Orc4:Orc5:Orc3:Orc2:origin complexes, forming ORC:origin complexes At the beginning of this reaction, 1 molecule of 'Orc1:Orc4:Orc5:Orc3:Orc2:origin', and 1 molecule of 'Orc6' are present. At the end of this reaction, 1 molecule of 'ORC complex bound to origin' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11323433 Pubmed11395502 Reactome Database ID Release 4368615 Reactome, http://www.reactome.org ReactomeREACT_984 PCAF Converted from EntitySet in Reactome Reactome DB_ID: 350078 Reactome Database ID Release 43350078 Reactome, http://www.reactome.org ReactomeREACT_15287 The geminin component of geminin:Cdt1 complexes is ubiquitinated, releasing Cdt1 At the beginning of this reaction, 1 molecule of 'ubiquitin', and 1 molecule of 'Cdt1:geminin' are present. At the end of this reaction, 1 molecule of 'geminin:ubiquitin complex', and 1 molecule of 'Cdt1' are present.<br><br> This reaction takes place in the 'cytosol'.<br> Pubmed11125146 Pubmed9635433 Reactome Database ID Release 4368712 Reactome, http://www.reactome.org ReactomeREACT_1787 CDC6 association with ORC:origin complexes mediated by MCM8 At the beginning of this reaction, 1 molecule of 'ORC:origin', and 1 molecule of 'CDC6' are present. At the end of this reaction, 1 molecule of 'CDC6:ORC:origin complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Davey, MJ, O'Donnell, M, Tye, BK, 2006-03-17 16:01:39 Pubmed11046155 Pubmed15684404 Reactome Database ID Release 4368688 Reactome, http://www.reactome.org ReactomeREACT_282 Orc5 associates with Orc3:Orc2:origin complexes At the beginning of this reaction, 1 molecule of 'Orc3:Orc2:origin', and 1 molecule of 'Orc5' are present. At the end of this reaction, 1 molecule of 'Orc5:Orc3:Orc2:origin' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11323433 Pubmed11395502 Pubmed9765232 Reactome Database ID Release 4368603 Reactome, http://www.reactome.org ReactomeREACT_146 Orc1 associates with Orc4:Orc5:Orc3:Orc2:origin complexes At the beginning of this reaction, 1 molecule of 'Orc4:Orc5:Orc3:Orc2:origin', and 1 molecule of 'Orc1' are present. At the end of this reaction, 1 molecule of 'Orc1:Orc4:Orc5:Orc3:Orc2:origin' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11046155 Pubmed11323433 Pubmed11395502 Pubmed11739726 Reactome Database ID Release 4368611 Reactome, http://www.reactome.org ReactomeREACT_664 NICD Converted from EntitySet in Reactome Reactome DB_ID: 212420 Reactome Database ID Release 43212420 Reactome, http://www.reactome.org ReactomeREACT_15269 Orc4 associates with Orc5:Orc3:Orc2:origin complexes At the beginning of this reaction, 1 molecule of 'Orc4', and 1 molecule of 'Orc5:Orc3:Orc2:origin' are present. At the end of this reaction, 1 molecule of 'Orc4:Orc5:Orc3:Orc2:origin' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11323433 Pubmed11395502 Reactome Database ID Release 4368610 Reactome, http://www.reactome.org ReactomeREACT_1295 The polymerase component of DNA polymerase alpha:primase synthesizes a 20-nucleotide primer at the origin At the beginning of this reaction, 1 molecule of 'dTTP', 1 molecule of 'dGTP', 1 molecule of 'dATP', 1 molecule of 'RNA primer:origin duplex:DNA polymerase alpha:primase complex', and 1 molecule of 'dCTP' are present. At the end of this reaction, 1 molecule of 'RNA primer-DNA primer:origin duplex' is present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed DNA polymerase activity' of 'DNA polymerase alpha:primase'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 4368950 Reactome, http://www.reactome.org ReactomeREACT_91 The primase component of DNA polymerase:primase synthesizes a 6-10 nucleotide RNA primer at the origin At the beginning of this reaction, 1 molecule of 'DNA polymerase alpha:primase:DNA polymerase alpha:origin complex', and 1 molecule of 'NTP' are present. At the end of this reaction, 1 molecule of 'DNA polymerase epsilon', and 1 molecule of 'RNA primer:origin duplex:DNA polymerase alpha:primase complex' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed RNA polymerase activity' of 'DNA polymerase alpha:primase'.<br> EC Number: 2.7.7.6 Pubmed6693436 Reactome Database ID Release 4368913 Reactome, http://www.reactome.org ReactomeREACT_1611 DNA polymerase epsilon binds at the origin At the beginning of this reaction, 1 molecule of 'origin of replication', and 1 molecule of 'DNA polymerase epsilon' are present. At the end of this reaction, 1 molecule of 'DNA polymerase epsilon:origin complex' is present.<br><br> <br> Pubmed12045100 Reactome Database ID Release 4368960 Reactome, http://www.reactome.org ReactomeREACT_1344 DNA polymerase alpha:primase binds at the origin DNA polymerase alpha:primase is comprised of four subunits, p180, p70, p58, and p49. The two primase subunits, p58 and p49, form a tight complex. The p49 subunit contains the DNA primase activity and one role of p58 appears to be tethering p49 to p180, the DNA polymerase catalytic subunit. The fourth subunit, p70, binds p180 and may tether the DNA polymerase alpha:primase complex to Cdc45. Pubmed10757793 Pubmed10882098 Pubmed11395402 Pubmed12045100 Pubmed8253737 Reactome Database ID Release 4368914 Reactome, http://www.reactome.org ReactomeREACT_929 DNA Replication Factor A (RPA) associates with the pre-replicative complex at the origin After pre-RC assembly and Cdc45 association with the origin of replication, Replication Protein A (RPA) also associates with chromatin. RPA is a heterotrimeric complex containing p70, p34, and p11 subunits, and also is required for DNA recombination and DNA repair. The p70 subunit of RPA binds to the primase subunits of Pol alpha:primase. The p70 and p34 subunits of RPA are phosphorylated in a cell cycle-dependent manner. RPA is a single-strand DNA (ssDNA) binding protein and its association with chromatin at this stage suggests that DNA is partially unwound. This suggestion has been confirmed by detection of ssDNA in budding yeast origins of replication using chemical methods. Pubmed10473346 Pubmed10757793 Pubmed10882098 Pubmed1311258 Pubmed2200738 Pubmed9242902 Reactome Database ID Release 4368916 Reactome, http://www.reactome.org ReactomeREACT_789 Cdc45 associates with the pre-replicative complex at the origin Once the Mcm2-7 complex has been assembled onto the origin of replication, the next step is the assembly of Cdc45, an essential replication protein, in late G1. The assembly of Cdc45 onto origins of replication forms a complex distinct from the pre-replicative complex, sometimes called the pre-initiation complex. The assembly of Cdc45 onto origins correlates with the time of initiation. Like the Mcm2-7 proteins, Cdc45 binds specifically to origins in the G1 phase of the cell cycle and then to non-origin DNA during S phase and is therefore thought to travel with the replication fork. Indeed, S. cerevisiae Cdc45 is required for DNA replication elongation as well as replication initiation. Cdc45 is required for the association of alpha DNA polymerase:primase with chromatin. Based on this observation and the observation that in S. cerevisiae, cCdc45 has been found in large complexes with some components of Mcm2-7 complex, it has been suggested that Cdc45 plays a scaffolding role at the replication fork, coupling Pol-alpha:primase to the replication fork through the helicase. Association of Cdc45 with origin DNA is regulated in the cell cycle and its association is dependent on the activity of cyclin-dependent kinases but not the Cdc7/Dbf4 kinase. In Xenopus egg extracts, association of Cdc45 with chromatin is dependent on Xmus101. TopBP1, the human homolog of Xmus1, is essential for DNA replication and interacts with DNA polymerase epsilon, one of the polymerases involved in replicating the genome. TopBP1 homologs have been found in S. cerevisiae and S. pombe. Sld3, an additional protein required for Cdc45 association with chromatin in S. cerevisiae and S. pombe, has no known human homolog. Pubmed10430907 Pubmed10518787 Pubmed10757793 Pubmed10790374 Pubmed11296242 Pubmed11756551 Pubmed12438414 Pubmed7708676 Pubmed9335335 Pubmed9554851 Pubmed9660782 Reactome Database ID Release 4368917 Reactome, http://www.reactome.org ReactomeREACT_135 Mcm2-7 is phosphorylated by DDK At the beginning of this reaction, 1 molecule of 'Mcm2-7 complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'phosphorylated Mcm2-7 complex', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.<br> Pubmed10846177 Reactome Database ID Release 4368954 Reactome, http://www.reactome.org ReactomeREACT_907 CDK and DDK associate with the Mcm10:pre-replicative complex At the beginning of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', 1 molecule of 'DDK', and 1 molecule of 'CDK' are present. At the end of this reaction, 1 molecule of 'CDK:DDK:Mcm10:pre-replicative complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed10373557 Pubmed10523313 Reactome Database ID Release 4368918 Reactome, http://www.reactome.org ReactomeREACT_2227 Cdt1 is displaced from the pre-replicative complex. At the beginning of this reaction, 1 molecule of 'Mcm10:pre-replicative complex' is present. At the end of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', and 1 molecule of 'CDT1' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed12045100 Reactome Database ID Release 4368940 Reactome, http://www.reactome.org ReactomeREACT_951 Mcm10 associates with the pre-replicative complex, stabilizing Mcm2-7 MCM10 is required for human DNA replication. In S. cerevisiae, Mcm10, like Mcm2-7, is required for minichromosome maintenance, but Mcm10 has no sequence homology with these other proteins (Merchant et al., 1997). Genetic studies have demonstrated that Mcm10 is required for DNA replication in S. pombe (Aves et al., 1998) and S. cerevisiae cells (Homesley et al., 2000) and immunodepletion of XlMcm10 interferes with DNA replication in Xenopus egg extracts (Wohlschlegel et al., 2002). Human Mcm10 interacts with chromatin in G1 phase and then dissociates during G2 phase. In S. cerevisiae, Mcm10 has been shown to localize to origins during G1 (Ricke and Bielinsky, 2004), and it may stabilize the association of Mcm2-7 with the pre-replicative complex (Sawyer et al., 2004). This timing of association is consistent with studies that demonstrate that, in Xenopus egg extracts, Mcm10 is required for association of Cdc45, but not Mcm2-7 with chromatin. Biochemical evidence that Mcm10 plays a direct role in the activation of the pre-replicative complex includes the requirement for SpMcm10 in the phosphorylation of the Mcm2-7 complex by DDK (Lee et al., 2004) and the fact that SpMcm10 binds and stimulates DNA polymerase alpha activity (Fien et al., 2004). Pubmed10783164 Pubmed11095689 Pubmed11282021 Pubmed11864598 Pubmed12604790 Pubmed14766746 Pubmed15201046 Pubmed15494305 Pubmed9154825 Pubmed9745018 Reactome Database ID Release 4368919 Reactome, http://www.reactome.org ReactomeREACT_541 NR Converted from EntitySet in Reactome Reactome DB_ID: 376224 Reactome Database ID Release 43376224 Reactome, http://www.reactome.org ReactomeREACT_15626 Cytoplasmic phosphorylated Cdc6 is ubiquitinated by the anaphase-promoting complex At the beginning of this reaction, 1 molecule of 'phosphorylated Cdc6', 1 molecule of 'ubiquitin', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'ubiquitinated Cdc6' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of 'anaphase-promoting complex (APC)'.<br> Pubmed10995389 Reactome Database ID Release 4369015 Reactome, http://www.reactome.org ReactomeREACT_1673 Phosphorylated Cdc6 is exported from the nucleus In this reaction, 1 molecule of 'phosphorylated Cdc6' is translocated from nucleoplasm to cytosol.<br><br>This movement of the molecule occurs through the 'nuclear pore'.<br> Pubmed10339564 Reactome Database ID Release 4369006 Reactome, http://www.reactome.org ReactomeREACT_448 Rearrangement and mobilization of Mcm2-7 At the start of the elongation phase of DNA replication, the Mcm2-7 complex may re-arrange to function as the replicative helicase associated with the replication fork. In general, a replicative helicase is associated with the replication fork and unwinds DNA ahead of the polymerase. In yeast, the Mcm proteins associate with origin DNA in G1 phase and then exit the origin upon replication initiation, consistent with moving out of the origin with the replication fork. The Mcm2-7 complex is a ring-shaped hexamer. Complexes of Mcm4, Mcm6 and Mcm7 proteins from humans or S. pombe display a modest ATP-dependent helicase activity in vitro. Consistent with the hypothesis that eukaryotic Mcm complexes function as helicases, an archaeal Mcm homolog is a ring-shaped double hexamer that has a processive DNA unwinding activity. Mcm proteins may have additional functions during elongation, as uninterrupted function of all six is required for replication fork progression in budding yeast. Mcm4,6,7 helicase activity may be negatively regulated in two ways. Mcm2, Mcm4, Mcm6, and Mcm7 also form a stable complex which, however, has no helicase activity, suggesting that Mcm2 inhibits DNA unwinding by Mcm4,6,7. In addition, phosphorylation of human Mcm4,6,7 complex by CDK inhibits its helicase activity. Mcm4,6,7 trimer forms and associates with the replication fork Pubmed10567526 Pubmed10611290 Pubmed10677495 Pubmed10748114 Pubmed10834843 Pubmed10872463 Pubmed10884341 Pubmed11282021 Pubmed11454864 Pubmed12364596 Pubmed9305914 Pubmed9335335 Reactome Database ID Release 4369019 Reactome, http://www.reactome.org ReactomeREACT_1303 Ubiquitinated Cdc6 is degraded by the proteasome At the beginning of this reaction, 1 molecule of 'ubiquitinated Cdc6' is present. At the end of this reaction, 1 molecule of 'ubiquitin' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of '26S proteasome'.<br> Pubmed11046155 Reactome Database ID Release 4369016 Reactome, http://www.reactome.org ReactomeREACT_1210 MCM2-7 mediated fork unwinding Authored: Tye, BK, 2005-11-29 10:17:56 Edited: Gopinathrao, G, 2005-11-29 21:05:54 In budding yeast, all MCM proteins have been proved to be essential for elongation. The active form of this protein complex may be a heterohexamer. A subcomplex of MCM proteins consisting fo MCM4,6, and -7 has a weak helicase activity that may contribute to DNA unwinding. Pubmed10834843 Reactome Database ID Release 43169468 Reactome, http://www.reactome.org ReactomeREACT_6922 Orc1 is phosphorylated by cyclin A/CDK2 At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'pre-replicative complex' are present. At the end of this reaction, 1 molecule of 'phosphorylated Orc1', 1 molecule of 'pre-replicative complex (Orc1-minus)', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'Cyclin A:Cdk2 complex'.<br> Pubmed11931757 Reactome Database ID Release 4368944 Reactome, http://www.reactome.org ReactomeREACT_2111 Ubiquitinated Orc1 enters the cytosol In this reaction, 1 molecule of 'ubiquitinated Orc1' is translocated from nucleoplasm to cytosol.<br><br>This movement of the molecule occurs through the 'nuclear pore'.<br> Pubmed11931757 Reactome Database ID Release 4368947 Reactome, http://www.reactome.org ReactomeREACT_210 Phosphorylated Orc1 is ubiquitinated while still associated with chromatin At the beginning of this reaction, 1 molecule of 'ubiquitin', and 1 molecule of 'phosphorylated Orc1' are present. At the end of this reaction, 1 molecule of 'ubiquitinated Orc1' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11931757 Reactome Database ID Release 4368946 Reactome, http://www.reactome.org ReactomeREACT_1626 Cdc6 protein is phosphorylated by CDK At the beginning of this reaction, 1 molecule of 'CDC6', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'phosphorylated Cdc6' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'CDK'.<br> Pubmed10339564 Reactome Database ID Release 4369005 Reactome, http://www.reactome.org ReactomeREACT_1279 Ubiquitinated Orc1 is degraded by the proteasome At the beginning of this reaction, 1 molecule of 'ubiquitinated Orc1' is present. At the end of this reaction, 1 molecule of 'ubiquitin' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of '26S proteasome'.<br> Pubmed11931757 Reactome Database ID Release 4368948 Reactome, http://www.reactome.org ReactomeREACT_480 Formation of the Flap Intermediate Pubmed11473323 Pubmed11724925 Pubmed7711022 Reactome Database ID Release 4369127 Reactome, http://www.reactome.org ReactomeREACT_1572 When the polymerase delta:PCNA complex reaches a downstream Okazaki fragment, strand displacement synthesis occurs. The primer containing 5'-terminus of the downstream Okazaki fragment is folded into a single-stranded flap. Formation of Okazaki fragments After RFC initiates the assembly of the primer recognition complex, the complex of pol delta and PCNA is responsible for incorporating the additional nucleotides prior to the position of the next downstream initiator RNA primer. On the lagging strand, short discontinuous segments of DNA, called Okazaki fragments, are synthesized on RNA primers. The average length of the Okazaki fragments is 100 nucleotides. Polymerase switching is a key event that allows the processive synthesis of DNA by the pol delta and PCNA complex. EC Number: 2.7.7.7 Pubmed1328683 Pubmed1671046 Pubmed1974050 Pubmed8104944 Pubmed8144677 Pubmed9081985 Reactome Database ID Release 4369116 Reactome, http://www.reactome.org ReactomeREACT_1024 Processive synthesis on the leading strand Polymerase switching is a key event that allows the processive synthesis of DNA by the pol delta and PCNA complex. Polymerase delta possesses polymerization and proofreading activities, which increases the overall fidelity of DNA replication. The pol delta holoenzyme is a heterotetrameric complex that contains p125, p66, p50, and p12 subunits, in human cells. Pubmed10751307 Pubmed1671046 Pubmed7378348 Pubmed9191022 Reactome Database ID Release 4369098 Reactome, http://www.reactome.org ReactomeREACT_149 Formation of Processive Complex Pubmed1682322 Pubmed1974050 Pubmed7713898 Pubmed8104944 Reactome Database ID Release 4369074 Reactome, http://www.reactome.org ReactomeREACT_1009 The loading of proliferating cell nuclear antigen (PCNA) leads to recruitment of pol delta. Human PCNA is a homotrimer of 36 kDa subunits that form a toroidal structure. The loading of PCNA by RFC is a key event in the transition from the priming mode to the extension mode of DNA synthesis. The processive complex is composed of the pol delta holoenzyme and PCNA. Formation of GINS complex At the beginning of this reaction, 1 molecule of 'PSF3p', 1 molecule of 'SLD5P', 1 molecule of 'PSF2p', and 1 molecule of 'PSF1p' are present. At the end of this reaction, 1 molecule of 'GINS complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43176956 Reactome, http://www.reactome.org ReactomeREACT_6747 MCM8 mediated fork unwinding Authored: Tye, BK, 2005-11-29 10:17:56 Edited: Gopinathrao, G, 2005-11-29 21:05:54 Pubmed15707891 Reactome Database ID Release 43169461 Reactome, http://www.reactome.org ReactomeREACT_6768 The MCM2-7 related protein, MCM8, is required to replicate chromosomal DNA in Xenopus egg extracts. MCM8 binds chromatin upon initiation of DNA synthesis. It may function as an helicase in the elongation step. RFC dissociates after sliding clamp formation Pubmed9822671 Reactome Database ID Release 4369068 Reactome, http://www.reactome.org ReactomeREACT_351 Replication factor C is proposed to dissociate from PCNA following sliding clamp formation, and the DNA toroid alone tethers pol delta to the DNA. Loading of PCNA - Sliding Clamp Formation Pubmed2165567 Pubmed9660172 Reactome Database ID Release 4369063 Reactome, http://www.reactome.org ReactomeREACT_1994 The binding of the primer recognition complex involves the loading of proliferating cell nuclear antigen (PCNA). Replication Factor C transiently opens the PCNA toroid in an ATP-dependent reaction, and then allows PCNA to re-close around the double helix adjacent to the primer terminus. This leads to the formation of the "sliding clamp". RFC binding displaces Pol Alpha Once the RNA-DNA primer is synthesized, replication factor C (RFC) initiates a reaction called "polymerase switching"; pol delta, the processive enzyme replaces pol alpha, the priming enzyme. RFC binds to the 3'-end of the RNA-DNA primer on the Primosome, to displace the pol alpha primase complex. The binding of RFC triggers the binding of the primer recognition complex. Pubmed10656791 Pubmed10656792 Pubmed1671046 Reactome Database ID Release 4369053 Reactome, http://www.reactome.org ReactomeREACT_1871 Multiple proteins are localized at replication fork Authored: Tye, BK, 2006-03-17 14:46:24 By applying the chromatin immunoprecipitation technique to paused forks, certain proteins like DNA pol alpha, DNA pol delta, DNA pol epsilon, MCM2-7, CDC45, GINS and MCM10 were identified. By uncoupling a helicase at the site using a polymerase inhibitor, MCM2-7, GINS complex and CDC45 alone were found to be enriched at the paused fork suggesting these proteins may form a part of an "unwindosome" at the replicating fork. Edited: Gopinathrao, G, 2006-03-17 14:47:28 Pubmed16483939 Reactome Database ID Release 43176942 Reactome, http://www.reactome.org ReactomeREACT_6963 ACTIVATION GENE ONTOLOGYGO:0016798 Reactome Database ID Release 432065101 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016798 Reactome Database ID Release 432065101 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003943 Reactome Database ID Release 431606816 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004423 Reactome Database ID Release 431678645 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004563 Reactome Database ID Release 431605773 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003940 Reactome Database ID Release 431678683 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008459 Reactome Database ID Release 432018681 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047757 Reactome Database ID Release 432022049 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008146 Reactome Database ID Release 432022062 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0001537 Reactome Database ID Release 432022068 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047238 Reactome Database ID Release 431971478 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050510 Reactome Database ID Release 431971466 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004566 Reactome Database ID Release 431678848 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004565 Reactome Database ID Release 431605789 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050659 Reactome Database ID Release 432018675 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047328 Reactome Database ID Release 431971459 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047756 Reactome Database ID Release 431971529 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015019 Reactome Database ID Release 431678732 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004561 Reactome Database ID Release 431678739 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016250 Reactome Database ID Release 431678719 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047326 Reactome Database ID Release 432023903 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000824 Reactome Database ID Release 432023945 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035299 Reactome Database ID Release 432023933 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000827 Reactome Database ID Release 432023953 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052831 Reactome Database ID Release 432023909 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052835 Reactome Database ID Release 432023895 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008440 Reactome Database ID Release 432023913 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000825 Reactome Database ID Release 432023893 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052725 Reactome Database ID Release 432023853 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052830 Reactome Database ID Release 432023900 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052726 Reactome Database ID Release 432023874 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052659 Reactome Database ID Release 432023846 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052659 Reactome Database ID Release 432023857 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008440 Reactome Database ID Release 432023862 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051717 Reactome Database ID Release 432023851 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004435 Reactome Database ID Release 432023860 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004435 Reactome Database ID Release 432023871 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004415 Reactome Database ID Release 431793220 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004435 Reactome Database ID Release 432023847 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003943 Reactome Database ID Release 431606816 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004565 Reactome Database ID Release 431793215 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0045130 Reactome Database ID Release 432046178 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004565 Reactome Database ID Release 431605789 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0043890 Reactome Database ID Release 431630318 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004563 Reactome Database ID Release 431605773 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008449 Reactome Database ID Release 431638056 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046525 Reactome Database ID Release 431889994 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030158 Reactome Database ID Release 431877999 Reactome, http://www.reactome.org FGF binding is significantly affected by presence of heparin ACTIVATION Reactome Database ID Release 43190313 Reactome, http://www.reactome.org ReactomeREACT_9921 FGF binding is significantly affected by presence of heparin ACTIVATION Reactome Database ID Release 43190312 Reactome, http://www.reactome.org ReactomeREACT_9919 FGF binding is significantly affected by presence of heparin ACTIVATION Reactome Database ID Release 43190311 Reactome, http://www.reactome.org ReactomeREACT_9943 'Heparan Sulphate [extracellular region]' is required for 'FGFR4 binds BetaKlotho-bound FGF19' ACTIVATION Reactome Database ID Release 431307970 Reactome, http://www.reactome.org ReactomeREACT_111896 FGF binding is significantly affected by presence of heparin ACTIVATION Reactome Database ID Release 43190318 Reactome, http://www.reactome.org ReactomeREACT_9925 FGF binding is significantly affected by presence of heparin ACTIVATION Reactome Database ID Release 43190316 Reactome, http://www.reactome.org ReactomeREACT_9940 FGF binding is significantly affected by presence of heparin ACTIVATION Reactome Database ID Release 43190314 Reactome, http://www.reactome.org ReactomeREACT_9922 p-SHP2 activates RAS-MAP kinase cascade ACTIVATION Reactome Database ID Release 431549552 Reactome, http://www.reactome.org ReactomeREACT_111909 p-SHP2, recruited to the FGF receptor through p-FRS2, is the major activator of the RAS-MAP kinase cascade in response to FGF stimulation. pThr-FRS2alpha negatively regulates tyrosine phosphorylation of FRS2alpha:activated FGFR INHIBITION Pubmed12419216 Pubmed19652666 Reactome Database ID Release 431270464 Reactome, http://www.reactome.org ReactomeREACT_76921 FGF binding is significantly affected by presence of heparin ACTIVATION Reactome Database ID Release 43190319 Reactome, http://www.reactome.org ReactomeREACT_9916 'AKT:PIP3:THEM4/TRIB3 [plasma membrane]' negatively regulates 'TORC2 (mTOR) phosphorylates AKT at S473' INHIBITION Reactome Database ID Release 43199457 Reactome, http://www.reactome.org ReactomeREACT_13397 Impaired ubiquitination of active dimers of phospho-EGFR KD mutants in complex with HSP90 and CDC37. Association of HSP90 with active dimers of phospho-EGFR KD mutants negatively affects phospho-CBL-mediated ubiquitination of EGFR. Binding of HSP90 may decrease the affinity of active dimers of phospho-EGFR KD mutants for phospho-CBL, so that CBL dissociates from the complex upon phosphorylation and cannot perform ubiquitination. INHIBITION Pubmed16849543 Pubmed17699773 Reactome Database ID Release 431225948 Reactome, http://www.reactome.org ReactomeREACT_117945 'PTEN mRNA:miR-26A RISC [cytosol]' negatively regulates 'PTEN mRNA translation negatively regulated by microRNAs' INHIBITION Pubmed19487573 Reactome Database ID Release 432321906 Reactome, http://www.reactome.org ReactomeREACT_148662 'insulin [extracellular region]' negatively regulates 'Secretion of Acyl Ghrelin and C-Ghrelin' INHIBITION Insulin inhibits secretion of ghrelin by an unknown mechanism. Pubmed12161550 Pubmed12531744 Reactome Database ID Release 43422034 Reactome, http://www.reactome.org ReactomeREACT_20493 'Leptin [extracellular region]' negatively regulates 'Secretion of Acyl Ghrelin and C-Ghrelin' INHIBITION Leptin inhibits secretion of ghrelin by an unknown mechanism. Pubmed17923797 Pubmed17992641 Reactome Database ID Release 43422083 Reactome, http://www.reactome.org ReactomeREACT_20486 'Fatty Acids [extracellular region]' negatively regulates 'Secretion of Acyl Ghrelin and C-Ghrelin' Fatty acids inhibit the secretion of ghrelin by an unknown mechanism. Fatty acids have less effect than carbohydrates do. INHIBITION Pubmed16645013 Reactome Database ID Release 43422071 Reactome, http://www.reactome.org ReactomeREACT_20489 'alpha-D-glucose [extracellular region]' negatively regulates 'Secretion of Acyl Ghrelin and C-Ghrelin' Glucose inhibits ghrelin secretion by an unknown mechanism. Carbohydrates have a greater effect than fatty acids do. INHIBITION Pubmed16487433 Reactome Database ID Release 43422075 Reactome, http://www.reactome.org ReactomeREACT_20496 'Glucagon [extracellular region]' negatively regulates 'Secretion of Acyl Ghrelin and C-Ghrelin' Glucagon inhibits the secretion of ghrelin in humans by an unknown mechanism. INHIBITION Pubmed16131602 Reactome Database ID Release 43422101 Reactome, http://www.reactome.org ReactomeREACT_20488 'Somatotropin [extracellular region]' negatively regulates 'Secretion of Acyl Ghrelin and C-Ghrelin' INHIBITION Pubmed15941929 Reactome Database ID Release 43422084 Reactome, http://www.reactome.org ReactomeREACT_20483 Somatotropin (growth hormone) inhibits secretion of ghrelin by an unknown mechanism. FGF binding is significantly affected by presence of heparin ACTIVATION Reactome Database ID Release 43190317 Reactome, http://www.reactome.org ReactomeREACT_9927 'IGF1 [extracellular region]' positively regulates 'Secretion of Acyl Ghrelin and C-Ghrelin' ACTIVATION Insulin-like growth factor-1 stimulates secretion of ghrelin by an unknown mechanism Pubmed15292338 Pubmed17054474 Reactome Database ID Release 43422065 Reactome, http://www.reactome.org ReactomeREACT_20485 ACTIVATION GENE ONTOLOGYGO:0017095 Reactome Database ID Release 432076304 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050379 Reactome Database ID Release 432024110 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004561 Reactome Database ID Release 431678739 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015019 Reactome Database ID Release 431678732 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003940 Reactome Database ID Release 431678683 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004423 Reactome Database ID Release 431678645 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030305 Reactome Database ID Release 431678634 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030305 Reactome Database ID Release 431666996 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016250 Reactome Database ID Release 431678719 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003940 Reactome Database ID Release 431678683 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008467 Reactome Database ID Release 432076328 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050508 Reactome Database ID Release 432022845 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008467 Reactome Database ID Release 432076583 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004394 Reactome Database ID Release 432076430 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050379 Reactome Database ID Release 432024110 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015016 Reactome Database ID Release 432022920 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050119 Reactome Database ID Release 432022873 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050509 Reactome Database ID Release 432022849 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050508 Reactome Database ID Release 432022845 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050509 Reactome Database ID Release 432022849 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047220 Reactome Database ID Release 431889957 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015018 Reactome Database ID Release 431889977 Reactome, http://www.reactome.org 'FRAT1/FRAT2:GSK3beta Complex [cytosol]' negatively regulates 'Phosphorylation of phospho-(Ser45 ) at Thr 41 by GSK-3' INHIBITION Pubmed11237732 Pubmed12095675 Reactome Database ID Release 431226064 Reactome, http://www.reactome.org ReactomeREACT_76916 'FRAT1/FRAT2:GSK3beta Complex [cytosol]' negatively regulates 'Phosphoryation of phospho- (Ser45, Thr41) beta-catenin at Ser37 by GSK-3' INHIBITION Pubmed11237732 Pubmed12095675 Reactome Database ID Release 431226062 Reactome, http://www.reactome.org ReactomeREACT_76919 ACTIVATION GENE ONTOLOGYGO:0004566 Reactome Database ID Release 431678848 Reactome, http://www.reactome.org RGS proteins that are GAPs for G alpha (q) ACTIVATION Pubmed12223533 Pubmed20374713 Reactome Database ID Release 43921130 Reactome, http://www.reactome.org ReactomeREACT_24905 Regulators of G protein signaling (RGS) proteins all contain a 120 amino acid RGS domain that defines the family and enable the protein to bind to active G alpha:GTP. RGS binding greatly increases the intrinsic GTPase activity of G alpha subunits; RGS proteins are GTPase-activating proteins (GAPs) for G alpha. In vitro there is often little or no selectivity for GPCR or G alpha subtype, but in vitro there are marked preferences. Some RGS proteins contain many additional domains and have diverse functions, not limited to modulating GPCR signaling (McCoy & Hepler 2009). ACTIVATION GENE ONTOLOGYGO:0004415 Reactome Database ID Release 431793220 Reactome, http://www.reactome.org 'DARPP-32 phosphorylated on Thr75 [cytosol]' negatively regulates 'PKA phosphorylates PDE4B' INHIBITION Reactome Database ID Release 43180077 Reactome, http://www.reactome.org ReactomeREACT_18253 RGS proteins that are GAPs for G alpha (i) ACTIVATION Pubmed12223533 Pubmed20374713 Reactome Database ID Release 43921125 Reactome, http://www.reactome.org ReactomeREACT_24890 Regulators of G protein signaling (RGS) proteins all contain a 120 amino acid RGS domain that defines the family and enable the protein to bind to active G alpha:GTP. RGS binding greatly increases the intrinsic GTPase activity of G alpha subunits; RGS proteins are GTPase-activating proteins (GAPs) for G alpha. In vitro there is often little or no selectivity for GPCR or G alpha subtype, but in vitro there are marked preferences. Some RGS proteins contain many additional domains and have diverse functions, not limited to modulating GPCR signaling (McCoy & Hepler 2009). RGS proteins that are GAPs for G alpha (z) ACTIVATION Pubmed12223533 Pubmed20374713 Reactome Database ID Release 43921141 Reactome, http://www.reactome.org ReactomeREACT_24903 Regulators of G protein signaling (RGS) proteins all contain a 120 amino acid RGS domain that defines the family and enable the protein to bind to active G alpha:GTP. RGS binding greatly increases the intrinsic GTPase activity of G alpha subunits; RGS proteins are GTPase-activating proteins (GAPs) for G alpha. In vitro there is often little or no selectivity for GPCR or G alpha subtype, but in vitro there are marked preferences. Some RGS proteins contain many additional domains and have diverse functions, not limited to modulating GPCR signaling (McCoy & Hepler 2009). Gz alpha inhibits adenylate cyclase INHIBITION Reactome Database ID Release 43392138 Reactome, http://www.reactome.org ReactomeREACT_20482 ACTIVATION GENE ONTOLOGYGO:0003831 Reactome Database ID Release 43975894 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003831 Reactome Database ID Release 43975894 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003836 Reactome Database ID Release 432046209 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0001517 Reactome Database ID Release 432046153 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004563 Reactome Database ID Release 431605773 Reactome, http://www.reactome.org Gs alpha stimulates adenylate cyclase ACTIVATION Reactome Database ID Release 43668802 Reactome, http://www.reactome.org ReactomeREACT_23408 ACTIVATION GENE ONTOLOGYGO:0004566 Reactome Database ID Release 431678848 Reactome, http://www.reactome.org Gi alpha inhibits adenylate cyclase INHIBITION Reactome Database ID Release 43500806 Reactome, http://www.reactome.org ReactomeREACT_22090 ACTIVATION GENE ONTOLOGYGO:0003831 Reactome Database ID Release 43975894 Reactome, http://www.reactome.org Hedgehog releases Smoothened from Patched repression INHIBITION Reactome Database ID Release 43517522 Reactome, http://www.reactome.org ReactomeREACT_22087 ACTIVATION GENE ONTOLOGYGO:0008532 Reactome Database ID Release 432046204 Reactome, http://www.reactome.org Gamma-secretase complex cleaves DNER:NOTCH1 ACTIVATION Pubmed15965470 Reactome Database ID Release 431980114 Reactome, http://www.reactome.org ReactomeREACT_120354 'PCOLCEs [extracellular region]' positively regulates 'Removal of fibrillar collagen C-propeptides' ACTIVATION Pubmed12393877 Reactome Database ID Release 432267335 Reactome, http://www.reactome.org ReactomeREACT_125711 'Endostatin [extracellular region]' negatively regulates 'Autocatalytic activation of proMMP2' INHIBITION Pubmed12690120 Reactome Database ID Release 432225580 Reactome, http://www.reactome.org ReactomeREACT_125713 'Highly sulphated glycosaminoglycans [extracellular region]' positively regulates 'Autocatalytic activation of MMP7' ACTIVATION Reactome Database ID Release 431604786 Reactome, http://www.reactome.org ReactomeREACT_120348 'Endostatin [extracellular region]' negatively regulates 'Activation of proMMP9 by proteases' INHIBITION Pubmed12690120 Reactome Database ID Release 432225579 Reactome, http://www.reactome.org ReactomeREACT_125699 'AMOT proteins [cytosol]' positively regulates 'Phosphorylation of YAP by LATS2' ACTIVATION Pubmed21205866 Pubmed21832154 Reactome Database ID Release 432028608 Reactome, http://www.reactome.org ReactomeREACT_120332 'Phosphorylation of WWTR1 (TAZ) by LATS2' negatively regulates 'Translocation of WWTR1 (TAZ) to the nucleus' INHIBITION Reactome Database ID Release 432032789 Reactome, http://www.reactome.org ReactomeREACT_120359 'AMOT proteins [cytosol]' positively regulates 'Phosphorylation of WWTR1 (TAZ) by LATS2' ACTIVATION Pubmed21205866 Reactome Database ID Release 432028666 Reactome, http://www.reactome.org ReactomeREACT_120327 'FOXH1:DRAP1 [nucleoplasm]' negatively regulates 'Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXH1 Binds Activin Response Element' As inferred from mouse, DRAP1 binds FOXH1 and inhibits activation of gene expression in response to NODAL signaling. INHIBITION Pubmed12471260 Reactome Database ID Release 431226032 Reactome, http://www.reactome.org ReactomeREACT_111895 p51 subunit of RT Converted from EntitySet in Reactome Reactome DB_ID: 175064 Reactome Database ID Release 43175064 Reactome, http://www.reactome.org ReactomeREACT_8314 'Phosphorylation of YAP by LATS1' negatively regulates 'Translocation of YAP1 to the nucleus' INHIBITION Reactome Database ID Release 432032787 Reactome, http://www.reactome.org ReactomeREACT_120318 'FRAT1/FRAT2:GSK3beta Complex [cytosol]' negatively regulates 'Phosphorylation of phospho-(Ser45,Thr41,Ser37) at Ser33 by GSK-3' INHIBITION Pubmed11237732 Pubmed12095675 Reactome Database ID Release 431226061 Reactome, http://www.reactome.org ReactomeREACT_76923 'Phosphorylation of YAP by LATS2' negatively regulates 'Translocation of YAP1 to the nucleus' INHIBITION Reactome Database ID Release 432032784 Reactome, http://www.reactome.org ReactomeREACT_120343 'AS160 [cytoplasmic vesicle membrane]' positively regulates 'RAB8A/10/13/14 Hydrolyze GTP' ACTIVATION Pubmed15971998 Pubmed21041651 Reactome Database ID Release 431449643 Reactome, http://www.reactome.org ReactomeREACT_148681 The GAP domain of TBC1D4 (AS160) activates the GTPase activity of RAB proteins (Sano et al. 2007). The effect of TBC1D4 on RAB13 is inferred from rat muscle cells (Sun et al. 2010). 'TBC1D1 [cytoplasmic vesicle membrane]' positively regulates 'RAB8A/10/13/14 Hydrolyze GTP' ACTIVATION As inferred from mouse, TBC1D1 activates GTPase activity of RAB2A, 8A, 8B, 10, and 14 (Roach et al. 2007). Pubmed17274760 Reactome Database ID Release 431454728 Reactome, http://www.reactome.org ReactomeREACT_148684 'LEFTY Binds the EGF-CFC Coreceptor in the NODAL Receptor' negatively regulates 'The NODAL Receptor Binds NODAL Ligands' INHIBITION LEFTY1 and LEFTY2 bind the EGF-CFC coreceptor (CRIPTO or CRYPTIC) and prevent it from interacting with Activin type I and type II receptors, thereby interfering with the assembly of the NODAL receptor. Pubmed15062104 Reactome Database ID Release 431433621 Reactome, http://www.reactome.org ReactomeREACT_111919 'LEFTY Binds NODAL' negatively regulates 'The NODAL Receptor Binds NODAL Ligands' INHIBITION LEFTY1 and LEFTY2 form heterodimers with NODAL, preventing NODAL from activating the NODAL receptor. Pubmed15062104 Reactome Database ID Release 431433626 Reactome, http://www.reactome.org ReactomeREACT_111897 'RAB8A/10/13/14:GTP [cytoplasmic vesicle membrane]' positively regulates 'Translocation of GLUT4 Vesicle and Docking at the Plasma Membrane' ACTIVATION As inferred from mouse (Sano et al. 2007) and rat (Ishikura et al. 2007, Ishikura and Klip 2008, Sun et al. 2010), RAB:GTP activates translocation of GLUT4 to the plasma membrane, possibly by interacting with myosins. RAB8A, RAB10, and RAB14 predominate in 3T3-L1 adipocytes; RAB13 predominates in L6 muscle cells. Pubmed17208202 Pubmed17403373 Pubmed18701652 Pubmed21041651 Reactome Database ID Release 431458572 Reactome, http://www.reactome.org ReactomeREACT_148665 'RAC1:GTP [plasma membrane]' positively regulates 'Translocation of GLUT4 Vesicle and Docking at the Plasma Membrane' ACTIVATION As inferred from mouse (Ueda et al. 2008, Ueda et al. 2010) and rat (Chiu et al. 2010), RAC1:GTP enhances translocation of GLUT4 to the plasma membrane by causing actin remodeling that requires ARP2/3. The exact mechanism of RAC1 action is unknown. Pubmed18482007 Pubmed20203090 Pubmed20739464 Reactome Database ID Release 431458541 Reactome, http://www.reactome.org ReactomeREACT_148682 'RGC1:RGC2 [cytosol]' positively regulates 'RALA Hydrolyzes GTP' ACTIVATION As inferred from mouse, RGC1:RGC2 (RALGAPB:RALGAPA2) activate the GTPase activity of RALA (Chen et al. 2011). Pubmed21148297 Reactome Database ID Release 431458520 Reactome, http://www.reactome.org ReactomeREACT_148685 'TC10:GTP [plasma membrane]' positively regulates 'Translocation of GLUT4 Vesicle and Docking at the Plasma Membrane' ACTIVATION As inferred from mouse, TC10 participates in the translocation and docking of GLUT4 vesicles at the plasma membrane (Chang et al. 2007). Pubmed17008399 Reactome Database ID Release 432316462 Reactome, http://www.reactome.org ReactomeREACT_148646 'CERBERUS Binds NODAL' negatively regulates 'The NODAL Receptor Binds NODAL Ligands' CERBERUS forms heterodimers with NODAL, preventing NODAL from activating the NODAL receptor. INHIBITION Pubmed10067895 Reactome Database ID Release 431433623 Reactome, http://www.reactome.org ReactomeREACT_111918 'NCAM-1:ATP [plasma membrane]' negatively regulates 'NCAM1 binds FGFR-1' INHIBITION-COMPETITIVE Reactome Database ID Release 43500284 Reactome, http://www.reactome.org ReactomeREACT_22096 'Endostatin [extracellular region]' negatively regulates 'Autocatalytic activation of proMMP13' INHIBITION Pubmed12690120 Reactome Database ID Release 432225577 Reactome, http://www.reactome.org ReactomeREACT_125693 'ECSIT [cytosol]' is required for 'TRAF6 binds MEKK1' ACTIVATION Pubmed14665666 Reactome Database ID Release 43181968 Reactome, http://www.reactome.org ReactomeREACT_8989 'SARM:TRIF:activated TLR3/TLR4 [endosome membrane]' negatively regulates 'TRAF3 binds to TRIF:activated TLR3/4 complex' INHIBITION Reactome Database ID Release 432559577 Reactome, http://www.reactome.org ReactomeREACT_152541 'SHP2 [cytosol]' negatively regulates 'IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR' INHIBITION Reactome Database ID Release 432569047 Reactome, http://www.reactome.org ReactomeREACT_152534 'RIP3 [cytosol]' negatively regulates 'TRIF:activated TLR3/TLR4 complex recruits RIP1' INHIBITION Reactome Database ID Release 432562512 Reactome, http://www.reactome.org ReactomeREACT_152535 'SARM:TRIF:activated TLR3/TLR4 [endosome membrane]' negatively regulates 'TRIF:activated TLR3/TLR4 complex recruits RIP1' INHIBITION Reactome Database ID Release 432559569 Reactome, http://www.reactome.org ReactomeREACT_152537 'K63-linked ubiquitination of RIP1 bound to the activated TLR complex' negatively regulates 'TLR3/4-induced ripoptosome assembly' INHIBITION Reactome Database ID Release 432569044 Reactome, http://www.reactome.org ReactomeREACT_152538 'SARM:TRIF:activated TLR3/TLR4 [endosome membrane]' negatively regulates 'Activated TLR3/4:TRIF recruits TRAF6' INHIBITION Reactome Database ID Release 432559573 Reactome, http://www.reactome.org ReactomeREACT_152544 'EEA1:EEA1 [endosome membrane]' positively regulates 'Engulfed CpG DNA binds to endosomal N-ter TLR9 dimer' ACTIVATION Reactome Database ID Release 431679582 Reactome, http://www.reactome.org ReactomeREACT_120336 'PKA/PKG phosphorylate Rap1GAP2' negatively regulates '14-3-3 proteins beta and zeta bind and inhibit Rap1Gap2' INHIBITION Reactome Database ID Release 43939811 Reactome, http://www.reactome.org ReactomeREACT_24893 'H+ [endosome lumen]' positively regulates 'TLR processing at low pH' ACTIVATION Reactome Database ID Release 432134525 Reactome, http://www.reactome.org ReactomeREACT_120357 p66 subunit of RT Converted from EntitySet in Reactome Reactome DB_ID: 175252 Reactome Database ID Release 43175252 Reactome, http://www.reactome.org ReactomeREACT_8368 'RAB11A:GTP [cytoplasmic vesicle membrane]' positively regulates 'Translocation of GLUT4 Vesicle and Docking at the Plasma Membrane' ACTIVATION As inferred from mouse (Zeigerer et al. 2002) and rat (Uhlig et al. 2005), RAB11A enhances translocation of GLUT4 to the plasma membrane by mobilizing GLUT4 from endosomes to insulin responsive vesicles. Pubmed12134080 Pubmed15866422 Reactome Database ID Release 431458528 Reactome, http://www.reactome.org ReactomeREACT_148655 'Cyclophilin A:Cyclosporin A [cytosol]' negatively regulates 'Calcineurin Dephosphorylates NFATC1/2/3' INHIBITION Pubmed12218175 Pubmed7523407 Reactome Database ID Release 432026015 Reactome, http://www.reactome.org ReactomeREACT_120320 'FKBP1A:Tacrolimus [cytosol]' negatively regulates 'Calcineurin Dephosphorylates NFATC1/2/3' INHIBITION Pubmed7523407 Pubmed8524402 Reactome Database ID Release 432026021 Reactome, http://www.reactome.org ReactomeREACT_120329 'RUVBL1 [nucleoplasm]' positively regulates 'Biogenesis And Assembly Of The Telomerase RNP' ACTIVATION Pubmed18358808 Reactome Database ID Release 43418320 Reactome, http://www.reactome.org ReactomeREACT_19114 ACTIVATION GENE ONTOLOGYGO:0004373 Reactome Database ID Release 4371601 Reactome, http://www.reactome.org 'RUVBL2 [nucleoplasm]' positively regulates 'Biogenesis And Assembly Of The Telomerase RNP' ACTIVATION Pubmed18358808 Reactome Database ID Release 43418324 Reactome, http://www.reactome.org ReactomeREACT_19110 ACTIVATION GENE ONTOLOGYGO:0008466 Reactome Database ID Release 4370215 Reactome, http://www.reactome.org 'NHP2 [nucleoplasm]' positively regulates 'Biogenesis And Assembly Of The Telomerase RNP' ACTIVATION Pubmed11074001 Pubmed18523010 Reactome Database ID Release 43418322 Reactome, http://www.reactome.org ReactomeREACT_19108 ACTIVATION GENE ONTOLOGYGO:0003844 Reactome Database ID Release 4371577 Reactome, http://www.reactome.org 'CDK1 Phosphorylated Condensin I [cytosol]' positively regulates 'Phosphorylated condensin I promotes condensation of prometaphase chromosomes' ACTIVATION Reactome Database ID Release 432520881 Reactome, http://www.reactome.org ReactomeREACT_152540 ACTIVATION GENE ONTOLOGYGO:0004373 Reactome Database ID Release 4371572 Reactome, http://www.reactome.org 'TCAB1 [nucleoplasm]' positively regulates 'Biogenesis And Assembly Of The Telomerase RNP' ACTIVATION Pubmed19179534 Reactome Database ID Release 43418387 Reactome, http://www.reactome.org ReactomeREACT_19111 'p-T216,S189,S274,S373-GORASP1:p-S37-GOLGA2:p-RAB1:GTP:PLK1 [Golgi membrane]' negatively regulates 'GORASP1 phosphorylated by PLK1 and GORASP2 phosphorylated by MAPK3-3/MAPK1 are unable to promote Golgi cisternae stacking' INHIBITION Pubmed20937827 Reactome Database ID Release 432314562 Reactome, http://www.reactome.org ReactomeREACT_148653 'p-T222,225-GORASP2:BLZF1:RAB2A:GTP [Golgi membrane]' negatively regulates 'GORASP1 phosphorylated by PLK1 and GORASP2 phosphorylated by MAPK3-3/MAPK1 are unable to promote Golgi cisternae stacking' INHIBITION Pubmed20937827 Reactome Database ID Release 432422960 Reactome, http://www.reactome.org ReactomeREACT_148654 ACTIVATION GENE ONTOLOGYGO:0003983 Reactome Database ID Release 4370285 Reactome, http://www.reactome.org 'CDK11p58 [cytosol]' positively regulates 'Recruitment of Plk1 to centrosomes' ACTIVATION Reactome Database ID Release 43380722 Reactome, http://www.reactome.org ReactomeREACT_18255 ACTIVATION GENE ONTOLOGYGO:0004614 Reactome Database ID Release 4370219 Reactome, http://www.reactome.org 'p-T216,S274,S373-GORASP1:p-S37-GOLGA2:p-RAB1:GTP [Golgi membrane]' negatively regulates 'GOLGA2 phosphorylated by CDK1 is unable to promote fusion of ER to Golgi transport vesicles with cis-Golgi' INHIBITION Reactome Database ID Release 432314565 Reactome, http://www.reactome.org ReactomeREACT_148650 ACTIVATION GENE ONTOLOGYGO:0004689 Reactome Database ID Release 4371521 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004689 Reactome Database ID Release 4371521 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008184 Reactome Database ID Release 4371514 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004689 Reactome Database ID Release 4371535 Reactome, http://www.reactome.org 'p-KIT (S741,746):PKC alpha [plasma membrane]' negatively regulates 'Autophosphorylation of KIT' INHIBITION Pubmed10582339 Pubmed16483568 Pubmed7539802 Reactome Database ID Release 431433574 Reactome, http://www.reactome.org ReactomeREACT_111927 'RAC:GTP [plasma membrane]' is required for 'GTP-bound RAC contributes to JNK activation' ACTIVATION Reactome Database ID Release 431050113 Reactome, http://www.reactome.org ReactomeREACT_27107 ERBB4s80:ESR1 complex regulates transcription of NR3C3 and CXCL12 ACTIVATION Reactome Database ID Release 431254402 Reactome, http://www.reactome.org ReactomeREACT_118010 ERBB4s80:TAB2:NCOR1 complex negatively regulates transcription of GFAP and S100B INHIBITION Pubmed17018285 Reactome Database ID Release 431253313 Reactome, http://www.reactome.org ReactomeREACT_118037 ACTIVATION GENE ONTOLOGYGO:0004454 Reactome Database ID Release 4370330 Reactome, http://www.reactome.org GRB10 disrupts association of IRS with INSR INHIBITION-COMPETITIVE Pubmed12493740 Reactome Database ID Release 43110016 Reactome, http://www.reactome.org ReactomeREACT_6005 ACTIVATION GENE ONTOLOGYGO:0004614 Reactome Database ID Release 4370219 Reactome, http://www.reactome.org 'Inhibition of TSC complex formation by PKB' positively regulates 'GTP loading by Rheb' ACTIVATION Pubmed15951850 Reactome Database ID Release 43165197 Reactome, http://www.reactome.org ReactomeREACT_7934 ACTIVATION GENE ONTOLOGYGO:0008184 Reactome Database ID Release 4371587 Reactome, http://www.reactome.org 'Phosphorylated Raptor [cytosol]' negatively regulates 'Activation of S6K1' INHIBITION Reactome Database ID Release 43447081 Reactome, http://www.reactome.org ReactomeREACT_21242 ACTIVATION GENE ONTOLOGYGO:0008184 Reactome Database ID Release 4371514 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004135 Reactome Database ID Release 4371551 Reactome, http://www.reactome.org 'DNA repair protein RAD51 homolog 3 [nucleoplasm]' positively regulates 'Formation of Meiotic Single-stranded DNA Invasion Complex' ACTIVATION As inferred from mouse, RAD51C participates in loading RAD51 and DMC1 onto single-stranded DNA at resected double-strand breaks. Pubmed17312021 Reactome Database ID Release 43914162 Reactome, http://www.reactome.org ReactomeREACT_28009 ACTIVATION GENE ONTOLOGYGO:0004134 Reactome Database ID Release 4371550 Reactome, http://www.reactome.org 'Testis-expressed sequence 15 protein [nucleoplasm]' positively regulates 'Formation of Meiotic Single-stranded DNA Invasion Complex' ACTIVATION As inferred from mouse, TEX15 participates in loading RAD51 and DMC1 onto single-stranded DNA at resected double-strand breaks. Pubmed18283110 Reactome Database ID Release 43914161 Reactome, http://www.reactome.org ReactomeREACT_27982 ACTIVATION GENE ONTOLOGYGO:0008184 Reactome Database ID Release 4371587 Reactome, http://www.reactome.org 'HOP2(TBPIP):MND1 Complex [nucleoplasm]' positively regulates 'Formation of Meiotic Heteroduplex' ACTIVATION Pubmed16407260 Reactome Database ID Release 43913507 Reactome, http://www.reactome.org ReactomeREACT_28014 The HOP2(TBPIP):MND1 complex stimulates RAD51 and DMC1 mediated strand exchange by an unknown mechanism. GRB10 prohibits SHC phosphorylation by INSR INHIBITION-COMPETITIVE Pubmed14615605 Reactome Database ID Release 43110031 Reactome, http://www.reactome.org ReactomeREACT_6103 Vif Converted from EntitySet in Reactome Reactome DB_ID: 175526 Reactome Database ID Release 43175526 Reactome, http://www.reactome.org ReactomeREACT_8103 Viral Infectivity Factor ACTIVATION GENE ONTOLOGYGO:0004335 Reactome Database ID Release 4370354 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050354 Reactome Database ID Release 4370346 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004332 Reactome Database ID Release 43469725 Reactome, http://www.reactome.org 'c-Jun [nucleoplasm]' positively regulates 'NOTCH4 gene transcription' ACTIVATION Pubmed15684396 Reactome Database ID Release 432250429 Reactome, http://www.reactome.org ReactomeREACT_125697 miR-34 negatively regulates NOTCH1 mRNA translation INHIBITION Reactome Database ID Release 431980089 Reactome, http://www.reactome.org ReactomeREACT_120345 miR-449 negatively regulates NOTCH1 mRNA translation INHIBITION Reactome Database ID Release 431980095 Reactome, http://www.reactome.org ReactomeREACT_120311 miR-200B/C negatively regulates NOTCH1 mRNA translation INHIBITION Reactome Database ID Release 431980087 Reactome, http://www.reactome.org ReactomeREACT_120321 p53 positively regulates transcription of miR-34 microRNAs ACTIVATION Pubmed17554337 Pubmed17823410 Reactome Database ID Release 432152394 Reactome, http://www.reactome.org ReactomeREACT_120317 ACTIVATION GENE ONTOLOGYGO:0003978 Reactome Database ID Release 4370368 Reactome, http://www.reactome.org 'CCND1:CREBBP [nucleoplasm]' positively regulates 'NOTCH1 gene transcription' ACTIVATION Pubmed20090754 Reactome Database ID Release 432247947 Reactome, http://www.reactome.org ReactomeREACT_125698 ACTIVATION GENE ONTOLOGYGO:0008108 Reactome Database ID Release 4370360 Reactome, http://www.reactome.org 'E2F1/3:DP1/2 [nucleoplasm]' positively regulates 'NOTCH1 gene transcription' ACTIVATION Pubmed21875955 Reactome Database ID Release 432248827 Reactome, http://www.reactome.org ReactomeREACT_125716 ACTIVATION GENE ONTOLOGYGO:0017057 Reactome Database ID Release 4371295 Reactome, http://www.reactome.org 'PRLR ligands:p(S349)- PRLR:JAK2 dimer:SCF beta-TrCP complex [plasma membrane]' negatively regulates 'Prolactin receptor ligands bind the prolactin receptor' INHIBITION Reactome Database ID Release 431370510 Reactome, http://www.reactome.org ReactomeREACT_117939 ACTIVATION GENE ONTOLOGYGO:0004345 Reactome Database ID Release 4370374 Reactome, http://www.reactome.org 'PRLR ligands:Activated PRLR:JAK2 dimer:SH2B1 beta [plasma membrane]' positively regulates 'JAK2 phosphorylation' ACTIVATION Reactome Database ID Release 431675485 Reactome, http://www.reactome.org ReactomeREACT_117930 ACTIVATION GENE ONTOLOGYGO:0004750 Reactome Database ID Release 4371302 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004616 Reactome Database ID Release 4371298 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004802 Reactome Database ID Release 4371323 Reactome, http://www.reactome.org 'NOTCH1 Coactivator Complex [nucleoplasm]' positively regulates 'NOTCH1 gene transcription' ACTIVATION Pubmed17685488 Reactome Database ID Release 432247933 Reactome, http://www.reactome.org ReactomeREACT_125710 ACTIVATION GENE ONTOLOGYGO:0004750 Reactome Database ID Release 4371302 Reactome, http://www.reactome.org 'NOTCH3 Coactivator Complex [nucleoplasm]' positively regulates 'NOTCH3 gene transcription' ACTIVATION Pubmed19150886 Reactome Database ID Release 432248835 Reactome, http://www.reactome.org ReactomeREACT_125702 ACTIVATION GENE ONTOLOGYGO:0004801 Reactome Database ID Release 4371333 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004802 Reactome Database ID Release 4371323 Reactome, http://www.reactome.org RAB6A positively regulates transport of NOTCH precursor through the Golgi and trans-Golgi network for S1 cleavage and cell surface expression. ACTIVATION Pubmed10459009 Reactome Database ID Release 431980098 Reactome, http://www.reactome.org ReactomeREACT_120338 Calcium ATP-ases positively regulate proper NOTCH trafficking and processing ACTIVATION Endoplasmic reticulum calcium ATPases are required for maintenance of high levels of calcium and positively regulate NOTCH trafficking, perhaps by ensuring proper NOTCH folding. Pubmed10545110 Reactome Database ID Release 431980104 Reactome, http://www.reactome.org ReactomeREACT_120331 'TMED2 [Golgi membrane]' negatively regulates 'Mature NOTCH heterodimer traffics to the plasma membrane' INHIBITION Pubmed10366590 Reactome Database ID Release 432043096 Reactome, http://www.reactome.org ReactomeREACT_120361 ACTIVATION GENE ONTOLOGYGO:0004801 Reactome Database ID Release 4371333 Reactome, http://www.reactome.org SEL1L sequesters misfolded NOTCH precursors in the endoplasmic reticulum INHIBITION Pubmed8722778 Reactome Database ID Release 431980101 Reactome, http://www.reactome.org ReactomeREACT_120352 Gamma-secretase complex cleaves CNTN1:NOTCH1 ACTIVATION Pubmed14567914 Reactome Database ID Release 431980110 Reactome, http://www.reactome.org ReactomeREACT_120323 'TMED2 [Golgi membrane]' negatively regulates 'Transport of fringe-modified NOTCH to plasma membrane' INHIBITION Pubmed10366590 Reactome Database ID Release 432043098 Reactome, http://www.reactome.org ReactomeREACT_120347 ACTIVATION GENE ONTOLOGYGO:0004751 Reactome Database ID Release 4371305 Reactome, http://www.reactome.org miR-34 negatively regulates NOTCH2 mRNA translation INHIBITION Reactome Database ID Release 431980097 Reactome, http://www.reactome.org ReactomeREACT_120316 ACTIVATION GENE ONTOLOGYGO:0004751 Reactome Database ID Release 4371305 Reactome, http://www.reactome.org miR-150 negatively regulates NOTCH3 mRNA translation INHIBITION Reactome Database ID Release 431980091 Reactome, http://www.reactome.org ReactomeREACT_120363 ACTIVATION GENE ONTOLOGYGO:0004802 Reactome Database ID Release 4371323 Reactome, http://www.reactome.org miR-206 negatively regulates NOTCH3 mRNA translation INHIBITION Reactome Database ID Release 431980096 Reactome, http://www.reactome.org ReactomeREACT_120358 ACTIVATION GENE ONTOLOGYGO:0004802 Reactome Database ID Release 4371323 Reactome, http://www.reactome.org miR-181C negatively regulates NOTCH4 mRNA translation INHIBITION Reactome Database ID Release 431980092 Reactome, http://www.reactome.org ReactomeREACT_120313 ACTIVATION GENE ONTOLOGYGO:0008514 Reactome Database ID Release 432142862 Reactome, http://www.reactome.org miR-302A negatively regulates NOTCH4 mRNA translation INHIBITION Reactome Database ID Release 431980094 Reactome, http://www.reactome.org ReactomeREACT_120344 ACTIVATION GENE ONTOLOGYGO:0050501 Reactome Database ID Release 432142876 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004749 Reactome Database ID Release 43111174 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004749 Reactome Database ID Release 4373486 Reactome, http://www.reactome.org PANK1;3;4 Converted from EntitySet in Reactome Pantothenate kinase 1;3;4 Reactome DB_ID: 199195 Reactome Database ID Release 43199195 Reactome, http://www.reactome.org ReactomeREACT_11650 ACTIVATION GENE ONTOLOGYGO:0004415 Reactome Database ID Release 432160850 Reactome, http://www.reactome.org Vpu protein Converted from EntitySet in Reactome Reactome DB_ID: 175290 Reactome Database ID Release 43175290 Reactome, http://www.reactome.org ReactomeREACT_8301 Shc1 binds phosphorylated ERBB2:ERBB3 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed8665853 Reactome Database ID Release 431248753 Reactome, http://www.reactome.org ReactomeREACT_115633 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Shc1 binds phosphorylated ERBB2:ERBB3 heterodimer in engineered mouse 32D cells. Cleavage of collagen type VIII by ELANE Authored: Jupe, S, 2012-09-25 Collagen type VIII is a short chain, network-forming collagen,thought to play a role in tissue remodeling and repair (Shuttleworth 1997, Weitkamp et al. 1999). There are two alpha chain subtypes, found in a ratio of two alpha-1 to one alpha-2 chains (Mann et al. 1990) in the typical collagen heterotrimer. Studies suggest that type VIII collagen is a major component of the hexagonal lattice seen in Descemet's membrane (Mann et al. 1990). Mutations in both alpha chains have been associated with Fuchs endothelial corneal dystrophy (FECD), a degenerative disease of the corneal endothelium (Jun et al. 2012). Collagen type VIII can be degraded by neutrophil elastase (ELANE, ELA2; Kittelberger et al. 1992). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed10428768 Pubmed1515454 Pubmed22002996 Pubmed2226849 Pubmed9438378 Reactome Database ID Release 432482182 Reactome, http://www.reactome.org ReactomeREACT_150438 Reviewed: Sorsa, Timo, 2012-10-08 PP1CC dephosphorylates TGFBR1 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 EC Number: 3.1.3.16 Edited: Jassal, B, 2012-04-10 Phosphorylated TGFBR1 is significantly dephosphorylated when incubated with Smad7, PPP1R15A (GADD34) and PP1CC, immunoprecipitated from previously transfected COS1 cells. Dephosphorylation is inhibited by addition of PP1 inhibitor I-1 (Shi et al. 2004). Pubmed14718519 Reactome Database ID Release 432167872 Reactome, http://www.reactome.org ReactomeREACT_120899 Reviewed: Huang, Tao, 2012-05-14 has a Stoichiometric coefficient of 6 Collagen type III degradation by MMP10 Authored: Jupe, S, 2012-09-28 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 MMP10 (Stromelysin-2) degrades collagen type III (Nicholson et al. 1989). Pubmed2548603 Reactome Database ID Release 432485115 Reactome, http://www.reactome.org ReactomeREACT_150318 Reviewed: Sorsa, Timo, 2012-10-08 Calcineurin Binds NFATC1/2/3 Authored: May, B, 2011-12-11 Calcium activates calcineurin in two ways: binding the regulatory subunit of calcineurin directly and binding calmodulin which then interacts with the catalytic subunit of calcineurin. As inferred from mouse, B lymphocytes contain the R1 regulatory subunit (PPP3R1) and the beta catalytic subunit (PPP3CB).<br>In the presence of calcium and calcium:calmodulin calcineurin binds phosphorylated and unphosphorylated NFATs at 2 regions in the N-terminus (Luo et al. 1996, Garcia-Cozar et al. 1998, Park et al. 2000, evidence from mouse in Loh et al. 1996 and Wesselborg et al. 1996). Calcineurin also weakly interacts with NFATs in the absence of calcium (Garcia-Cozar et al. 1998). Edited: May, B, 2011-12-11 Pubmed10860980 Pubmed8576111 Pubmed8631904 Pubmed8799126 Pubmed9727000 Reactome Database ID Release 432025890 Reactome, http://www.reactome.org ReactomeREACT_118703 Reviewed: Wienands, J, 2012-02-11 has a Stoichiometric coefficient of 4 Complex of NOTCH1 with its ligand is cleaved to produce NEXT1 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Ligand binding induces a conformational change in the NOTCH1, probably through mechanical stretching of NOTCH1 triggered by endocytosis of the ligand attached to the receptor. This conformational change exposes the S2 site in the extracellular region of NOTCH1 and results in cleavage of NOTCH1 by ADAM10 metalloprotease, the mammalian homolog of Kuzbanian (Pan and Rubin, 1997), generating the membrane-anchored NOTCH1 fragment NEXT1.This model is supported by the crystal structure of human NOTCH2 negative regulatory region, showing that NOTCH adopts an autoinhibited conformation where extensive interdomain interactions within the negative regulatory region bury S2. A substantial conformational movement, triggered by ligand binding in trans, is needed to expose S2 (Gordon et al. 2007). After S2 cleavage, the extracellular NOTCH1 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. ADAM17 is able to perform cleavage at the S2 site in vitro (Brou et al. 2000), but ADAM10 was shown to be necessary in studies done on mouse cell lines deficient in different ADAM enzymes (van Tetering et al. 2009). Adam10 knockout mice die at embryonal day 9.5 with multiple defects in the developing central nervous system, somites and cardiovascular system, and exhibit decreased expression of the Notch target Hes5 in the neural tube (Hartmann et al. 2002). Pubmed10882063 Pubmed12354787 Pubmed17401372 Pubmed19726682 Pubmed9244301 Reactome Database ID Release 43157632 Reactome, http://www.reactome.org ReactomeREACT_410 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 Notch 2-ligand complex is cleaved to produce NEXT2 Ligand binding induces a conformational change in the NOTCH2, probably through mechanical pulling of NOTCH2 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH2 and results in cleavage of NOTCH2 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH2 fragment NEXT2. The extracellular NOTCH2 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. Pubmed10958687 Pubmed20156974 Reactome Database ID Release 43157629 Reactome, http://www.reactome.org ReactomeREACT_267 Notch 3-ligand complex is cleaved to produce NEXT3 Ligand binding induces a conformational change in the NOTCH3, probably through mechanical pulling of NOTCH3 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH3 and results in cleavage of NOTCH3 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH3 fragment NEXT3. The extracellular NOTCH3 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. Pubmed10882063 Pubmed10958687 Pubmed12794186 Reactome Database ID Release 43157626 Reactome, http://www.reactome.org ReactomeREACT_1552 Notch 4-ligand complex is cleaved to produce NEXT4 Ligand binding induces a conformational change in the NOTCH4, probably through mechanical pulling of NOTCH4 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH4 and results in cleavage of NOTCH4 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH4 fragment NEXT4. The extracellular NOTCH4 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. Pubmed10882063 Pubmed10958687 Pubmed12794186 Reactome Database ID Release 43157649 Reactome, http://www.reactome.org ReactomeREACT_1011 KRAB-ZNF Converted from EntitySet in Reactome Reactome DB_ID: 974995 Reactome Database ID Release 43974995 Reactome, http://www.reactome.org ReactomeREACT_27820 Phosphorylation of PDE3B At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'PDE3B' are present. At the end of this reaction, 1 molecule of 'Phosphorylated PDE3B', and 2 molecules of 'ADP' are present.<br><br> This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.<br> Reactome Database ID Release 43162363 Reactome, http://www.reactome.org ReactomeREACT_1878 has a Stoichiometric coefficient of 2 KAP (KRAB-Domain Associated Protein) Converted from EntitySet in Reactome Reactome DB_ID: 975006 Reactome Database ID Release 43975006 Reactome, http://www.reactome.org ReactomeREACT_27366 Recruitment of Dna2 endonuclease After RPA binds the long flap, it recruits the Dna2 endonuclease. Dna2 endonuclease removes most of the flap, but the job of complete removal of the flap is then completed by FEN-1. Pubmed11473323 Reactome Database ID Release 4369142 Reactome, http://www.reactome.org ReactomeREACT_1278 Removal of RNA primer and dissociation of RPA and Dna2 Pubmed10748138 Pubmed11473323 Reactome Database ID Release 4369144 Reactome, http://www.reactome.org ReactomeREACT_315 The Dna2 endonuclease removes the initiator RNA along with several downstream deoxyribonucleotides. The cleavage of the single-stranded RNA substrate results in the disassembly of RPA and Dna2. The current data for the role of the Dna2 endonuclease has been derived from studies with yeast and Xenopus Dna2. RPA binds to the Flap Pubmed11473323 Reactome Database ID Release 4369140 Reactome, http://www.reactome.org ReactomeREACT_2026 The first step in the removal of the flap intermediate is the binding of Replication Protein A (RPA) to the long flap structure. RPA is a eukaryotic single-stranded DNA binding protein. Cdt1 associates with geminin At the beginning of this reaction, 1 molecule of 'geminin', and 1 molecule of 'CDT1' are present. At the end of this reaction, 1 molecule of 'Cdt1:geminin' is present.<br><br> This reaction takes place in the 'nucleoplasm'.<br> Pubmed11125146 Reactome Database ID Release 4369299 Reactome, http://www.reactome.org ReactomeREACT_757 Strap binds phosphorylated TGF-beta receptor complex Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 In COS-1 cells, recombinant mouse Strap binds the complex of recombinant human TFGBR2 and recombinant human TGFBR1 phosphorylated as a result of TGF-beta treatment (Datta et al. 1998). Pubmed9856985 Reactome Database ID Release 432128982 Reactome, http://www.reactome.org ReactomeREACT_120975 Reviewed: Huang, Tao, 2012-05-14 Removal of remaining Flap Pubmed10409700 Pubmed10806216 Pubmed11825897 Pubmed7876218 Pubmed8131753 Pubmed8824221 Pubmed9080773 Reactome Database ID Release 4369152 Reactome, http://www.reactome.org ReactomeREACT_2024 The remaining flap, which is too short to support RPA binding, is then processed by FEN-1. There is evidence that binding of RPA to the displaced end of the RNA-containing Okazaki fragment prevents FEN-1 from accessing the substrate. FEN-1 is a structure-specific endonuclease that cleaves near the base of the flap at a position one nucleotide into the annealed region. Biochemical studies have shown that the preferred substrate for FEN-1 consists of a one-nucleotide 3'-tail on the upstream primer in addition to the 5'-flap of the downstream primer. Joining of adjacent Okazaki fragments Pubmed10959839 Pubmed8392066 Pubmed9081985 Pubmed9759502 Reactome Database ID Release 4369173 Reactome, http://www.reactome.org ReactomeREACT_1889 Removal of the flap by FEN-1 leads to the generation of a nick between the 3'-end of the upstream Okazaki fragment and the 5'-end of the downstream Okazaki fragment. DNA ligase I then seals the nicks between adjacent processed Okazaki fragments to generate intact double-stranded DNA. Collagen type XVII ectodomain shedding Authored: Jupe, S, 2012-09-27 Collagen type XVII (BP180) forms a family with collagen type XIII. It is an important structural component of hemidesmosomes, complexes found in the dermal-epidermal basement membrane zone that mediate adhesion of keratinocytes to the underlying membrane (Franzke et al. 2005). The intracellular ligands of collagen XVII include Beta 4-integrins, plectin and BP230 in the hemidesmosomal plaque (Koster et al. 2003). Extracellular ligands include alpha 6-integrin and laminin-5 in anchoring filaments (Hopkinson et al. 1995, Tasanen et al. 2004). Mutations in the human collagen XVII gene COL17A1 lead to diminished epidermal adhesion and skin blistering in response to minimal shearing forces, a disorder called junctional epidermolysis bullosa (JEB).<br><br>A soluble ectodomain form of collagen type XVII referred to as LAD-1 is generated by proteolytic processing of the full length form (Hirako et al. 1988, Schäcke et al. 1998). Collagen XVII has a furin consensus sequence but is cleaved by proteinases of the ADAM family rather than furin convertases. ADAM-17 (TACE) appears to be the major physiologically-relevant sheddase for collagen XVII, though ADAM-9 and -10 may substitute (Franzke et al. 2002). These proteinases are activated by furin (Franzke et al. 2005). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed12356719 Pubmed12482924 Pubmed15161638 Pubmed15561712 Pubmed7790367 Pubmed9545306 Pubmed9748270 Reactome Database ID Release 432484957 Reactome, http://www.reactome.org ReactomeREACT_150205 Reviewed: Sorsa, Timo, 2012-10-08 has a Stoichiometric coefficient of 3 Transesterification to connect viral DNA 3' ends to host DNA 5' ends Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed12407101 Pubmed1310932 Pubmed1317268 Pubmed1329090 Pubmed15308744 Pubmed15677323 Pubmed16260736 Pubmed7956067 Pubmed8883604 Pubmed9557688 Reactome Database ID Release 43164523 Reactome, http://www.reactome.org ReactomeREACT_9048 Reviewed: Bushman, FD, 2006-10-30 22:19:13 The first chemical step of integration involves a single step transesterification, in which the recessed 3' hydroxyl of the viral DNA becomes covalently joined to a protruding 5' end in the target DNA. This step at the same time cleaves the target DNA. CDK1 phosphorylates Mastl Authored: Orlic-Milacic, M, 2012-09-04 EC Number: 2.7.11.22 Edited: Gillespie, ME, 2012-09-14 Phosphorylation of MASTL (GWL) by CDK1 (Cdc2) was established using Mastl (Gwl) purified from Xenopus egg extracts and recombinant human CDK1. Phosphopeptide mapping identified several CDK1 phosphorylation sites in Mastl of which threonine residues T193 (Blake-Hodek et al. 2012), T206 (Blake-Hodek et al. 2012) and T748 (Yu et al. 2006) were found to be functionally important. These threonine residues are conserved and they correspond to T194, T207 and T741 of human MASTL. In addition, phosphorylation of Xenopus Mastl on serines S101 and S883 is important for the mitotic function of Mastl, but these sites, although conserved in Xenopus, human and mouse, do not conform to the CDK1 consensus, and the responsible kinase has not been identified. S883 may represent an autophosphorylation site (Blake-Hodek et al. 2012). Pubmed16600872 Pubmed22354989 Reactome Database ID Release 432434198 Reactome, http://www.reactome.org ReactomeREACT_150132 Reviewed: Burgess, A, 2012-09-28 Reviewed: Mochida, Satoru, 2012-09-26 has a Stoichiometric coefficient of 3 Vpr protein Converted from EntitySet in Reactome Reactome DB_ID: 175366 Reactome Database ID Release 43175366 Reactome, http://www.reactome.org ReactomeREACT_8257 MNK1-dependent serine phosphorylation of SPRY2 antagonizes tyrosine phosphorylation INHIBITION MNK1-dependent serine phosphorylation stabilizes SPRY2 by antagonizing tyrosine phosphorylation and CBL binding, thus limiting ubiquitin-mediated degradation. Pubmed16479008 Reactome Database ID Release 431295631 Reactome, http://www.reactome.org ReactomeREACT_111917 'Cdk4/6:INK4A complex [cytosol]' negatively regulates 'Formation of Cyclin D:Cdk4/6 complexes ' INHIBITION Reactome Database ID Release 43182599 Reactome, http://www.reactome.org ReactomeREACT_8988 'CASP8 and FADD-like apoptosis regulator precursor' negatively regulates 'TRAIL:TRAIL receptor-2 Trimer Binds FADD' INHIBITION Reactome Database ID Release 43141117 Reactome, http://www.reactome.org ReactomeREACT_5998 'IL17RD [Golgi membrane]' negatively regulates 'Dissociation of p-ERK from p-MEK' INHIBITION One report has suggested that the plasma membrane form of IL17RD (SEF) acts as a spatial regulator of ERK signaling by preventing the dissociation of activated ERK1/2 from the MEK1/2 complex. As a result, ERK1/2 can not translocate into the nucleus and activation of nuclear, but not cytoplasmic targets, is abrogated. Pubmed15239952 Reactome Database ID Release 431268203 Reactome, http://www.reactome.org ReactomeREACT_111920 'IL17RD [cytosol]' negatively regulates 'p-MEK phosphorylates ERK' IL17RD, or SEF, is a negative regulator of FGF signaling. There are at least two isoforms in humans, a transmembrane version and a cytosolic splice variant. SEF appears to function at multiple points in the FGFR pathway, perhaps dependent on cell type. SEF appears to attenuate signaling through the MAPK pathway, although the precise point of action remains to be clarified. Some reports have indicated that SEF acts upstream of Ras, and indeed the plasma membrane form has been shown to coimmunoprecipitate with FGRFR1 and 2. Other reports show that MEK1/2 phosphorylation is unaffected by SEF, but that the regulator acts by inhibiting the phosphorylation of ERK1/2. INHIBITION Pubmed12807873 Pubmed12958313 Pubmed14742870 Pubmed17035228 Reactome Database ID Release 431268214 Reactome, http://www.reactome.org ReactomeREACT_111924 'p-ERK dimer [cytosol]' is required for 'SPRY2 is serine phosphorylated in response to MAPK activation' ACTIVATION Phosphorylation of serine residues 111 and 120 on SPRY2 requires MAPK activation, however the identity of the phosphorylating kinase has not been established. Pubmed11698404 Pubmed19690147 Reactome Database ID Release 431295627 Reactome, http://www.reactome.org ReactomeREACT_111903 'HDAC1:RBL1:E2F4:DP1/2 [nucleoplasm]' negatively regulates 'Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1' INHIBITION Reactome Database ID Release 431362438 Reactome, http://www.reactome.org ReactomeREACT_111916 'HDAC1:RBL2:E2F4/5:DP1/2 [nucleoplasm]' negatively regulates 'Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1' INHIBITION Reactome Database ID Release 431362441 Reactome, http://www.reactome.org ReactomeREACT_111912 DREAM complex represses transcription of cell cycle genes in G0/early G1 INHIBITION Pubmed17531812 Reactome Database ID Release 431362278 Reactome, http://www.reactome.org ReactomeREACT_111910 'Association of HMGB1/HMGB2 with chromatin' positively regulates 'Cleavage of DNA by DFF40' ACTIVATION Reactome Database ID Release 43266218 Reactome, http://www.reactome.org ReactomeREACT_14759 'APC/C:Cdh1-mediated degradation of Skp2' negatively regulates 'Association of Cks1 with SCF(Skp2) complex' INHIBITION Reactome Database ID Release 43188196 Reactome, http://www.reactome.org ReactomeREACT_9381 DOCK-GEFs Converted from EntitySet in Reactome Reactome DB_ID: 1012978 Reactome Database ID Release 431012978 Reactome, http://www.reactome.org ReactomeREACT_26129 'Crm1 [nucleoplasm]' positively regulates 'Translocation of Cyclin B1:phospho-Cdc2 to the cytoplasm' ACTIVATION Pubmed9670027 Reactome Database ID Release 43170059 Reactome, http://www.reactome.org ReactomeREACT_6707 RAC1, CDC42 Converted from EntitySet in Reactome Reactome DB_ID: 1012988 Reactome Database ID Release 431012988 Reactome, http://www.reactome.org ReactomeREACT_25943 CABLES Converted from EntitySet in Reactome Reactome DB_ID: 1013880 Reactome Database ID Release 431013880 Reactome, http://www.reactome.org ReactomeREACT_26006 Kinesin-1 light chains Converted from EntitySet in Reactome Reactome DB_ID: 983226 Reactome Database ID Release 43983226 Reactome, http://www.reactome.org ReactomeREACT_26537 Kinesin-1 heavy chain Converted from EntitySet in Reactome Reactome DB_ID: 983211 Reactome Database ID Release 43983211 Reactome, http://www.reactome.org ReactomeREACT_26554 KIF3A partners Converted from EntitySet in Reactome Reactome DB_ID: 984629 Reactome Database ID Release 43984629 Reactome, http://www.reactome.org ReactomeREACT_25838 Kinesin-3 monomers Converted from EntitySet in Reactome Reactome DB_ID: 984739 Reactome Database ID Release 43984739 Reactome, http://www.reactome.org ReactomeREACT_26661 KIF4 Chromosome-associated kinesin KIF4 Converted from EntitySet in Reactome KIF4A KIF4B Reactome DB_ID: 445000 Reactome Database ID Release 43445000 Reactome, http://www.reactome.org ReactomeREACT_22917 Kinesin-6 Converted from EntitySet in Reactome Reactome DB_ID: 984628 Reactome Database ID Release 43984628 Reactome, http://www.reactome.org ReactomeREACT_26851 Platelet Adhesion to exposed collagen Authored: de Bono, B, 2004-08-13 07:29:26 Initiation of platelet adhesion is the first step in the formation of the platelet plug. Circulating platelets are arrested and subsequently activated by exposed collagen and vWF. Several collagen binding proteins are expressed on platelets, including integrin alpha2 beta1, GPVI, and GPIV. Integrin alpha2 beta1, known on leukocytes as VLA-2, is the major platelet collagen receptor (Kunicki et al. 1988). It requires Mg2+ to interact with collagen and may require initiation mediated by the activation of integrin alphaIIb beta3 (van de Walle 2007). Binding occurs via the alpha2 subunit I domain to a collagen motif with the sequence Gly-Phe-Hyp-Gly-Glu-Arg (Emsley 2000). Binding of collagen to alpha2 beta1 generates intracellular signals that contribute to platelet activation. These facilitate the engagement of the lower-affinity collagen receptor, GPVI (Keely 1996), the key receptor involved in collagen-induced platelet activation. The GPVI receptor is a complex of the GPVI protein with a dimer of Fc epsilon R1 gamma (FceRI gamma). The Src family kinases Fyn and Lyn constitutively associate with the GPVI:FceRIgamma complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in FceRI gamma, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. vWF protein is a polymeric structure of variable size. It is secreted in two directions, by the endothelium basolaterally and into the bloodstream. Shear-induced aggregation is achieved when vWF binds via its A1 domain to GPIb (part of GPIb-IX-V), and via its A3 domain mediating collagen binding to the subendothelium. The interaction between vWF and GPIb is regulated by shear force; an increase in the shear stress results in a corresponding increase in the affinity of vWF for GPIb. Pubmed12356768 Pubmed16985184 Pubmed2832397 Pubmed9295288 Reactome Database ID Release 4375892 Reactome, http://www.reactome.org ReactomeREACT_1230 alanine + tRNA(Ala) + ATP => Ala-tRNA(Ala) + AMP + pyrophosphate AARS (cytosolic alanyl tRNA synthetase) catalyzes the reaction of alanine, tRNA(ala), and ATP to form Ala tRNA(Ala), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a monomer (Shiba et al. 1995). A mutation in the editing domain of the mouse <I>Aars</I> gene results in misincorporation of non-cognate amino acids into cellular proteins. This is associated with protein misfolding in Purkinje cells and a phenotype consistent with human ataxia (Lee et al. 2006). Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.7 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed16906134 Pubmed7654687 Reactome Database ID Release 43379864 Reactome, http://www.reactome.org ReactomeREACT_15409 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Platelet sensitization by LDL Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Physiological concentrations (1g/L) of Low density lipoprotein (LDL) enhance platelet aggregation responses initiated by thrombin, collagen, and ADP. This enhancement involves the rapid phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) at Thr180 and Tyr182. The receptor for LDL is ApoER2, a splice variant of the classical ApoE receptor. ApoER2 stimulation leads to association of the Src family kinase Fgr which is probably responsible for subsequent phosphorylation of p38MAPK. This stimulation is transient because LDL also increases the activity of PECAM-1, which stimulates phosphatases that dephosphorylate p38MAPK. Pubmed12038793 Pubmed12775720 Pubmed15459198 Reactome Database ID Release 43432142 Reactome, http://www.reactome.org ReactomeREACT_23879 Reviewed: Kunapuli, SP, 2010-06-07 arginine + tRNA(Arg) + ATP => Arg-tRNA(Arg) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.19 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed16055448 RARS (cytosolic arginyl tRNA synthetase) catalyzes the reaction of arginine, tRNA(Arg), and ATP to form Arg-tRNA(Arg), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is a monomer found in the cell as a component of the mutienzyme aminoacyl-tRNA synthetase complex (Ling et al. 2005). Reactome Database ID Release 43379993 Reactome, http://www.reactome.org ReactomeREACT_15489 Reviewed: Antonellis, A, 2008-12-02 16:58:45 GP1b-IX-V activation signalling Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed11001899 Pubmed15507277 Pubmed17585075 Pubmed17597991 Pubmed2424116 Reactome Database ID Release 43430116 Reactome, http://www.reactome.org ReactomeREACT_23847 Reviewed: Kunapuli, SP, 2010-06-07 The platelet GPIb complex (GP1b-IX-V) together with GPVI are primarily responsible for regulating the initial adhesion of platelets to the damaged blood vessel and platelet activation. The importance of GPIb is demonstrated by the bleeding problems in patients with Bernard-Soulier syndrome where this receptor is either absent or defective. GP1b-IX-V binds von Willebrand Factor (vWF) to resting platelets, particularly under conditions of high shear stress. This transient interaction is the first stage of the vascular repair process. Activation of GP1b-IX-V on exposure of the fibrous matrix following atherosclerotic plaque rupture, or in occluded arteries, is a major contributory factor leading to thrombus formation leading to heart attack or stroke. GpIb also binds thrombin (Yamamoto et al. 1986), at a site distinct from the site of vWF binding, acting as a docking site for thrombin which then activates Proteinase Activated Receptors leading to enhanced platelet activation (Dormann et al. 2000). asparagine + tRNA(Asn) + ATP => Asn-tRNA(Asn) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.22 Edited: D'Eustachio, P, 2008-11-29 15:41:00 NARS (cytosolic asparaginyl tRNA synthetase) catalyzes the reaction of asparagine, tRNA(Asn), and ATP to form Asn-tRNA(Asn), AMP, and pyrophosphate. The enzyme is a class I tRNA synthetase (Beaulande et al. 1998). Pubmed9421509 Reactome Database ID Release 43379996 Reactome, http://www.reactome.org ReactomeREACT_15414 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Platelet activation, signaling and aggregation Authored: de Bono, B, 2004-08-13 07:29:26 GENE ONTOLOGYGO:0030168 Platelet activation begins with the initial binding of adhesive ligands and of the excitatory platelet agonists (released or generated at the sites of vascular trauma) to cognate receptors on the platelet membrane (Ruggeri 2002). Intracellular signaling reactions then enhance the adhesive and procoagulant properties of tethered platelets or of platelets circulating in the proximity. Once platelets have adhered they degranulate, releasing stored secondary agents such as ADP, ATP, and synthesize thromboxane A2. These amplify the response, activating and recruiting further platelets to the area and promoting platelet aggregation. These amplify the response, activating and recruiting further platelets to the area and promoting platelet aggregation. Adenosine nucleotides signal through P2 purinergic receptors on the platelet membrane. ADP activates P2Y1 and P2Y12, which signal via both the alpha and gamma:beta components of the heterotrimeric G-protein (Hirsch et al. 2001, 2006), while ATP activates the ionotropic P2X1 receptor (Kunapuli et al. 2003). Activation of these receptors initiates a complex signaling cascade that ultimately results in platelet activation, aggregation and thrombus formation (Kahner et al. 2006). Integrin AlphaIIbBeta3 is the most abundant platelet receptor, with 40 000 to 80 000 copies per resting platelet, acting as a major receptor for fibrinogen and other adhesive molecules (Wagner et al. 1996). Activation of AlphaIIbBeta3 enhances adhesion and leads to platelet-platelet interactions, and thus aggregation (Philips et al. 1991). GP VI is the most potent collagen receptor initiating signal generation, an ability derived from its interaction with the FcRI gamma chain. This results in the phosphorylation of the gamma-chain by non-receptor tyrosine kinases of the Src family (1). The phosphotyrosine motif is recognized by the SH2 domains of Syk, a tyrosine kinase. This association activates the Syk enzyme, leading to activation (by tyrosine phosphorylation) of PLC gamma2 (2). Thrombin is an important platelet agonist generated on the membrane of stimulated platelets. Thrombin acts via cell surface Protease Activated Receptors (PARs). PARs are G-protein coupled receptors activated by a proteolytic cleavage in an extracellular loop (Vu, 1991) (3). Activated PARs signal via G alpha q (4) and via the beta:gamma component of the G-protein (5). Both stimulate PLC giving rise to PIP2 hydrolysis and consequent activation of PI3K (6). PLCgamma2 activation also gives rise to IP3 (7) which stimulates the IP3 receptor (8) leading to increased intracellular calcium. Platelet activation further results in the scramblase-mediated transport of negatively-charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase complex (formed by the activated forms of the blood coagulation factors factor VIII and factor I). Pubmed11511514 Pubmed12411949 Pubmed12681240 Pubmed16543958 Pubmed1672265 Pubmed17059469 Pubmed2018971 Pubmed8704248 Reactome Database ID Release 4376002 Reactome, http://www.reactome.org ReactomeREACT_798 Reviewed: Kunapuli, SP, 2010-06-07 aspartate + tRNA(Asp) + ATP => Asp-tRNA(Asp) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 DARS (cytosolic aspartyl tRNA synthetase) catalyzes the reaction of aspartate, tRNA(Asp), and ATP to form Asp-tRNA(Asp), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a homodimer found in the cell as a component of the mutienzyme aminoacyl-tRNA synthetase complex (Escalante and Yang 1993). EC Number: 6.1.1.12 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed8449960 Reactome Database ID Release 43379867 Reactome, http://www.reactome.org ReactomeREACT_15346 Reviewed: Antonellis, A, 2008-12-02 16:58:45 cysteine + tRNA(Cys) + ATP => Cys-tRNA(Cys) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 CARS (cytosolic cysteinyl tRNA synthetase) catalyzes the reaction of cysteine, tRNA(cys), and ATP to form Cys-tRNA(Cys), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is a homomultimer, probably a dimer (Davidson et al. 2001). EC Number: 6.1.1.16 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed11347887 Reactome Database ID Release 43379887 Reactome, http://www.reactome.org ReactomeREACT_15527 Reviewed: Antonellis, A, 2008-12-02 16:58:45 glutamate + tRNA(Glu) + ATP => Glu-tRNA(Glu) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.17 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Multifunctional EPRS (cytosolic glutamyl prolyl tRNA synthetase) catalyzes the reaction of glutamate, tRNA(Glu), and ATP to form Glu tRNA(Glu), AMP, and pyrophosphate. The same enzyme also catalyzes the charging of tRNA(Pro) with proline. The enzyme is found in the cell as a component of the mutienzyme aminoacyl tRNA synthetase complex (Kaiser et al. 1994). Pubmed8188258 Reactome Database ID Release 43379861 Reactome, http://www.reactome.org ReactomeREACT_15345 Reviewed: Antonellis, A, 2008-12-02 16:58:45 glutamine + tRNA(Gln) + ATP => Gln-tRNA(Gln) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.18 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed8078941 QARS (cytosolic glutaminyl tRNA synthetase) catalyzes the reaction of glutamine, tRNA(Gln), and ATP to form Gln-tRNA(Gln), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is found in the cell as a component of the mutienzyme aminoacyl-tRNA synthetase complex. The same gene encodes both the cytosolic and mitochondrial QARS enzymes (Lamour et al. 1994). Reactome Database ID Release 43379982 Reactome, http://www.reactome.org ReactomeREACT_15361 Reviewed: Antonellis, A, 2008-12-02 16:58:45 glycine + tRNA(Gly) + ATP => Gly-tRNA(Gly) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.14 Edited: D'Eustachio, P, 2008-11-29 15:41:00 GARS (cytosolic glycyl tRNA synthetase) catalyzes the reaction of glycine, tRNA(Gly), and ATP to form Gly tRNA(Gly), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a dimer. Cytosolic and mitochondrial glycyl tRNA synthetase enzymes are both encoded by the same gene; the cytosolic protein lacks an aminoterminal 54 residue sequence found in the mitochondrial protein. Mutations in <I>GARS</I> are associated with Charcot Marie Tooth disease and distal spinal muscular atrophy, two diseases characterized by axonal dysfunction (Antonellis et al. 2006) Pubmed12690580 Reactome Database ID Release 43380048 Reactome, http://www.reactome.org ReactomeREACT_15522 Reviewed: Antonellis, A, 2008-12-02 16:58:45 GATA proteins Converted from EntitySet in Reactome Reactome DB_ID: 996770 Reactome Database ID Release 43996770 Reactome, http://www.reactome.org ReactomeREACT_26707 CAPZA Converted from EntitySet in Reactome F-actin capping protein alpha subunit Reactome DB_ID: 879442 Reactome Database ID Release 43879442 Reactome, http://www.reactome.org ReactomeREACT_25420 Thrombin signalling through proteinase activated receptors (PARs) Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-07 Pubmed11001069 Pubmed16102047 Pubmed8982657 Reactome Database ID Release 43456926 Reactome, http://www.reactome.org ReactomeREACT_21384 Reviewed: Kunapuli, SP, 2010-06-07 Thrombin activates proteinase activated receptors (PARs) that signal through heterotrimeric G proteins of the G12/13 and Gq families, thereby connecting to a host of intracellular signaling pathways. Thrombin activates PARs by cleaving an N-terminal peptide that then binds to the body of the receptor to effect transmembrane signaling. Intermolecular ligation of one PAR molecule by another can occur but is less efficient than self-ligation. A synthetic peptide of sequence SFLLRN, the first six amino acids of the new N-terminus generated when thrombin cleaves PAR1, can activate PAR1 independent of protease and receptor cleavage. PARs are key to platelet activation. Four PARs have been identified, of which PARs 1 ,3 and 4 are substrates for thrombin. In humans PAR 1 is the predominant thrombin receptor followed by PAR4 which is less responsive to thrombin. PAR 3 is not considered important for human platelet responses as it is minimally expressed, though this is not the case for mouse. PAR2 is not expressed in platelets. In mouse platelets, Gq is necessary for platelet secretion and aggregation in response to thrombin but is not necessary for thrombin-triggered shape change. G13 appears to contribute to platelet aggregation as well as shape change in response to low concentrations of thrombin but to be unnecessary at higher agonist concentrations; G12 appears to be dispensable for thrombin signaling in platelets. G alpha (q) activates phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinase cassettes and other proteins that mediate cellular responses ranging from granule secretion, integrin activation, and aggregation in platelets. Gbeta:gamma subunits can activate phosphoinositide-3 kinase and other lipid modifying enzymes, protein kinases, and channels. PAR1 activation indirectly leads to activation of cell surface 'sheddases' that liberate ligands for receptor tyrosine kinases, providing a link between thrombin and receptor tyrosine kinases involved in cell growth and differentiation. The pleiotrophic effects of PAR activation are consistent with many of thrombin's diverse actions on cells. ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 43192462 Reactome, http://www.reactome.org GPVI-mediated activation cascade Edited: Jupe, S, 2009-11-03 Pubmed11943772 Pubmed12649139 Pubmed16102042 Pubmed17127307 Reactome Database ID Release 43114604 Reactome, http://www.reactome.org ReactomeREACT_1695 The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. <br><br>The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76. ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 43192478 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 43192462 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 43192478 Reactome, http://www.reactome.org Signal amplification Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 In the initial response to injury, platelets adhere to damaged blood vessels, responding to the exposure of collagen from the vascular epithelium. Once adhered they degranulate, releasing stored secondary agents such as ADP and ATP, and synthesized thromboxane A2. These amplify the response, activating and recruiting further platelets to the area and promoting platelet aggregation. Adenosine nucleotides secreted following platelet activation signal through P2 purinergic receptors on the platelet membrane. ADP activates P2Y1 and P2Y12 while ATP activates the ionotropic P2X1 receptor (Kunapuli et al. 2003). Activation of these receptors initiates a complex signaling cascade that ultimately results in platelet activation and thrombus formation (Kahner et al. 2006). ADP stimulation of P2Y1 and P2Y12 involves signaling via both the alpha and gamma:beta components of the heterotrimeric G-protein (Hirsch et al. 2001, 2006). Pubmed11511514 Pubmed12681240 Pubmed16543958 Pubmed17059469 Pubmed18077812 Reactome Database ID Release 43392518 Reactome, http://www.reactome.org ReactomeREACT_20524 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 ACTIVATION GENE ONTOLOGYGO:0052832 Reactome Database ID Release 432024053 Reactome, http://www.reactome.org ADP signalling through P2Y purinoceptor 12 Authored: Jassal, B, 2009-02-27 14:41:36 Co-activation of P2Y1 and P2Y12 is necessary for complete platelet activation. P2Y1 is coupled to Gq and helps trigger the release of calcium from internal stores, leading to weak and reversible platelet aggregation. P2Y12 is Gi coupled, inhibiting adenylate cyclase, leading to decreased cAMP, a consequent decrease in cAMP-dependent protein kinase activity which increases cytoplasmic [Ca2+], necessary for activation (Woulfe et al. 2001).<br> In activated platelets, P2Y12 signaling is required for the amplification of aggregation induced by all platelet agonists including collagen, thrombin, thromboxane, adrenaline and serotonin. P2Y12 activation causes potentiation of thromboxane generation, secretion leading to irreversible platelet aggregation and thrombus stabilization. Edited: Jupe, S, 2009-09-10 Pubmed11196645 Pubmed11413156 Pubmed16466948 Reactome Database ID Release 43392170 Reactome, http://www.reactome.org ReactomeREACT_20653 Reviewed: Akkerman, JW, 2009-09-04 ACTIVATION GENE ONTOLOGYGO:0004771 Reactome Database ID Release 43192461 Reactome, http://www.reactome.org ADP signalling through P2Y purinoceptor 1 Authored: Jupe, S, 2009-04-24 10:43:00 Co-activation of P2Y1 and P2Y12 is necessary for complete platelet activation. P2Y1 is coupled to Gq and helps trigger the release of calcium from internal stores, leading to weak and reversible platelet aggregation. P2Y12 is Gi coupled, inhibiting adenylate cyclase, leading to decreased cAMP, a consequent decrease in cAMP-dependent protein kinase activity which increases cytoplasmic [Ca2+], necessary for activation (Woulfe et al. 2001).<br> In activated platelets, P2Y12 signaling is required for the amplification of aggregation induced by all platelet agonists including collagen, thrombin, thromboxane, adrenaline and serotonin. P2Y12 activation causes potentiation of thromboxane generation, secretion leading to irreversible platelet aggregation and thrombus stabilization. Edited: Jupe, S, 2009-09-10 Pubmed11413156 Pubmed16466948 Pubmed9442040 Reactome Database ID Release 43418592 Reactome, http://www.reactome.org ReactomeREACT_19140 Reviewed: Akkerman, JW, 2009-09-04 Thromboxane signalling through TP receptor Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed14751539 Pubmed18374420 Reactome Database ID Release 43428930 Reactome, http://www.reactome.org ReactomeREACT_20647 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Thromboxane (TXA2) binds to the thromboxane receptor (TP). There are 2 splice variant forms of TP, differing in their cytoplasmic carboxyl terminal tails. TP beta was first identified in endothelial cells. TP alpha was identified in platelets and placenta. The major signalling route for TP is Gq-mediated stimulation of PLC and consequent increase in cellular calcium. TP also couples to G13, leading to stimulation of Rho and Rac. ACTIVATION GENE ONTOLOGYGO:0004512 Reactome Database ID Release 432024047 Reactome, http://www.reactome.org Hemostasis Authored: D'Eustachio, P, Pace, N.P., Farndale, R, de Bono, B, 2004-01-21 22:18:59 Blood coagulation Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0007596 Hemostasis is a physiological response that culminates in the arrest of bleeding from an injured vessel. Under normal conditions the vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma, vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and by the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction (Becker et al. 2000). The chief trigger for the change in endothelial function that leads to the formation of a haemostatic thrombus is the loss of the endothelial cell barrier between blood and extracellular matrix components (Ruggeri 2002). Circulating platelets identify and discriminate areas of endothelial lesions; here, they adhere to the exposed sub endothelium. Their interaction with the various thrombogenic substrates and locally generated or released agonists results in platelet activation. This process is described as possessing two stages, firstly, adhesion - the initial tethering to a surface, and secondly aggregation - the platelet-platelet cohesion (Savage & Cattaneo et al. 2001). Three mechansism contribute to the loss of blood following vessel injury. The vessel constricts, reducing the loss of blood. Platelets adhere to the site of injury, become activated and aggregate with fibrinogen into a soft plug that limits blood loss, a process termed primary hemostasis. Proteins and small molecules are released from granules by activated platelets, stimulating the plug formation process. Fibrinogen from plasma forms bridges between activated platelets. These events initiate the clotting cascade (secondary hemostasis). Negatively-charged phospholipids exposed at the site of injury and on activated platelets interact with tissue factor, leading to a cascade of reactions that culminates with the formation of an insoluble fibrin clot. Pubmed10798271 Pubmed11604561 Pubmed12411949 Reactome Database ID Release 43109582 Reactome, http://www.reactome.org ReactomeREACT_604 Reviewed: Brummel, K, Rush, MG, Stafford, DW, 0000-00-00 00:00:00 phenylalanine + tRNA(Phe) + ATP => Phe-tRNA(Phe) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.20 Edited: D'Eustachio, P, 2008-11-29 15:41:00 FARS (cytosolic phenylalanyl tRNA synthetase) catalyzes the reaction of phenylalanine, tRNA(Phe), and ATP to form Phe-tRNA(Phe), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a heterotetramer of two alpha and two beta subunits (Moor et al. 2002). Pubmed11858721 Reactome Database ID Release 43379848 Reactome, http://www.reactome.org ReactomeREACT_15328 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Inhibition of HSL Reactome Database ID Release 43164928 Reactome, http://www.reactome.org ReactomeREACT_1123 proline + tRNA(Pro) + ATP => Pro-tRNA(Pro) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.15 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Multifunctional EPRS (cytosolic glutamyl-prolyl tRNA synthetase) catalyzes the reaction of proline, tRNA(Pro), and ATP to form Pro-tRNA(Pro), AMP, and pyrophosphate. The same enzyme also catalyzes the charging of tRNA(Glu) with glutamate. The enzyme is found in the cell as a component of the mutienzyme aminoacyl-tRNA synthetase complex (Kaiser et al. 1994). Pubmed8188258 Reactome Database ID Release 43379865 Reactome, http://www.reactome.org ReactomeREACT_15436 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor Authored: Jassal, B, 2004-12-17 11:53:55 GENE ONTOLOGYGO:0007220 Pubmed10693756 Pubmed10882062 Pubmed10882063 Reactome Database ID Release 43156988 Reactome, http://www.reactome.org ReactomeREACT_2001 Some transmembrane proteins such as the Notch receptor can be cleaved to release a cytosolic domain that translocates to the nucleus to control gene transcription. This is an example of a process called regulated intramembrane proteolysis (Rip). Rip is a control mechanism that is conserved from bacteria to humans and influences processes from cellular differentiation to lipid metabolism.<br>Once the ligand binds with the receptor, a proposed conformational change in the Notch receptor occurs which relieves an inhibition on the S2 protease cleavage site proximal to the plasma membrane. The S2 cleavage is catalyzed by an ADAM metalloprotease called TACE (TNF alpha converting enzyme). This enzyme is a homolog of the Drosophila Kuzbanian gene product which performs the same task. Cleavage at the S2 site generates a transient intermediate peptide termed NEXT (Notch EXtracellular Truncation). The remainder of the Notch receptor is still bound with the ligand at this point. lysine + tRNA(Lys) + ATP => Lys-tRNA(Lys) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.6 Edited: D'Eustachio, P, 2008-11-29 15:41:00 KARS (cytosolic lysyl tRNA synthetase) catalyzes the reaction of lysine, tRNA(Lys), and ATP to form Lys-tRNA(Lys), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a homodimer found in the cell as a component of the mutienzyme aminoacyl-tRNA synthetase complex. The same gene encodes both cytosolic and mitochondrial KARS enzymes (Shiba et al. 1997). Pubmed9278442 Reactome Database ID Release 43380008 Reactome, http://www.reactome.org ReactomeREACT_15342 Reviewed: Antonellis, A, 2008-12-02 16:58:45 methionine + tRNA(Met) + ATP => Met-tRNA(Met) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.10 Edited: D'Eustachio, P, 2008-11-29 15:41:00 MARS (cytosolic methionyl tRNA synthetase) catalyzes the reaction of methionine, tRNA(Met), and ATP to form Met-tRNA(Met), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is a monomer found in the cell as a component of the mutienzyme aminoacyl-tRNA synthetase complex (Kaminska et al. 2001). Pubmed11714285 Reactome Database ID Release 43379994 Reactome, http://www.reactome.org ReactomeREACT_15420 Reviewed: Antonellis, A, 2008-12-02 16:58:45 tryptophan + tRNA(Trp) + ATP => Trp-tRNA(Trp) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.2 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed1373391 Pubmed14660560 Pubmed1761529 Reactome Database ID Release 43379977 Reactome, http://www.reactome.org ReactomeREACT_15412 Reviewed: Antonellis, A, 2008-12-02 16:58:45 WARS (cytosolic tryptophanyl tRNA synthetase) catalyzes the reaction of tryptophan, tRNA(Trp), and ATP to form Trp-tRNA(Trp), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is a homodimer (Bange et al. 1992; Rubin et al. 1991; Yu et al. 2004). tyrosine + tRNA(Tyr) + ATP =>Tyr-tRNA(Tyr) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.1 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed14671330 Pubmed16429158 Reactome Database ID Release 43379980 Reactome, http://www.reactome.org ReactomeREACT_15492 Reviewed: Antonellis, A, 2008-12-02 16:58:45 YARS (cytosolic tyrosyl tRNA synthetase) catalyzes the reaction of tyrosine, tRNA(Tyr), and ATP to form Tyr tRNA(Tyr), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is a homodimer (Yang et al. 2003). Mutations in the <I>YARS</I> gene are associated with dominant-intermediate Charcot-Marie-Tooth disease – a form of peripheral neuropathy characterized by axon and Schwann cell dysfunction (Jordanova et al. 2006). serine + tRNA(Ser) + ATP => Ser-tRNA(Ser) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.11 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed7540217 Pubmed9431993 Reactome Database ID Release 43379992 Reactome, http://www.reactome.org ReactomeREACT_15400 Reviewed: Antonellis, A, 2008-12-02 16:58:45 SARS (cytosolic seryl tRNA synthetase) catalyzes the reaction of serine, tRNA(Ser), and ATP to form Ser-tRNA(Ser), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a homodimer (Hartlein and Cusack 1995; Vincent et al. 1997). threonine + tRNA(Thr) + ATP => Thr-tRNA(Thr) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.3 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed7118399 Reactome Database ID Release 43380002 Reactome, http://www.reactome.org ReactomeREACT_15487 Reviewed: Antonellis, A, 2008-12-02 16:58:45 TARS (cytosolic threonyl tRNA synthetase) catalyzes the reaction of threonine, tRNA(Thr), and ATP to form Thr-tRNA(Thr), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a homodimer (Pan et al. 1982). leucine + tRNA(Leu) + ATP => Leu-tRNA(Leu) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.4 Edited: D'Eustachio, P, 2008-11-29 15:41:00 LARS (cytosolic leucyl tRNA synthetase) catalyzes the reaction of leucine, tRNA(Leu), and ATP to form Leu-tRNA(Leu), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is found in the cell as a component of the mutienzyme aminoacyl-tRNA synthetase complex (Ling et al. 2005). Pubmed16055448 Reactome Database ID Release 43379974 Reactome, http://www.reactome.org ReactomeREACT_15504 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Histone H3 methylated at lysine-9 Converted from EntitySet in Reactome Reactome DB_ID: 427391 Reactome Database ID Release 43427391 Reactome, http://www.reactome.org ReactomeREACT_25651 Reduction of cytosolic Ca++ levels Authored: Akkerman, JW, 2009-06-03 During steady state conditions, cytoplasmic [Ca2+] is reduced by the accumulation of Ca2+ in intracellular stores and Ca2+ extrusion. Edited: Jupe, S, 2010-06-07 Pubmed18308196 Reactome Database ID Release 43418359 Reactome, http://www.reactome.org ReactomeREACT_23765 Reviewed: Kunapuli, SP, 2010-06-07 Platelet calcium homeostasis Authored: Akkerman, JW, 2009-06-03 Ca2+ homeostasis is controlled by processes that elevate or counter the elevation of cytosolic Ca2+. During steady state conditions, cytoplasmic Ca2+ is reduced by the accumulation of Ca2+ in intracellular stores and by Ca2+ extrusion. The primary intracellular calcium store in platelets is the dense tubular system, the equivalent of the ER system in other cell types. Ca2+ is extruded by Ca2+-ATPases including plasma membrane Ca2+ ATPases (PMCAs) and sarco/endoplasmic reticulum Ca2+ -ATPase isoforms (SERCAs). <br><br>Activation of non- excitable cells involves the agonist-induced elevation of cytosolic Ca2+, an essential process for platelet activation. It occurs through Ca2+ release from intracellular stores and Ca2+ entry through the plasma membrane. Ca2+ store release involves phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP3), which in turn stimulates IP3 receptor channels to release Ca2+ from intracellular stores. This is followed by Ca2+ entry into the cell through plasma membrane calcium channels, a process referred to as store-operated calcium entry (SOCE). Stromal interaction molecule 1 (STIM1), a Ca2+ sensor molecule in intracellular stores, and the four transmembrane channel protein Orai1 are the key players in platelet SOCE. Other major Ca2+ entry mechanisms are mediated by the direct receptor-operated calcium (ROC) channel, P2X1 and transient receptor potential channels (TRPCs). Edited: Jupe, S, 2010-06-07 Pubmed18308196 Pubmed19422456 Reactome Database ID Release 43418360 Reactome, http://www.reactome.org ReactomeREACT_23905 Reviewed: Kunapuli, SP, 2010-06-07 isoleucine + tRNA(Ile) + ATP => Ile-tRNA(Ile) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.5 Edited: D'Eustachio, P, 2008-11-29 15:41:00 IARS (cytosolic aspartyl tRNA synthetase) catalyzes the reaction of isoleucine, tRNA(Ile), and ATP to form Ile-tRNA(Ile), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is found in the cell as a component of the mutienzyme aminoacyl-tRNA synthetase complex (Shiba et al. 1994). Pubmed8052601 Reactome Database ID Release 43379893 Reactome, http://www.reactome.org ReactomeREACT_15516 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Elevation of cytosolic Ca2+ levels Activation of non- excitable cells involves the agonist-induced elevation of cytosolic Ca2+, an essential process for platelet activation. It occurs through Ca2+ release from intracellular stores and Ca2+ entry through the plasma membrane. Ca2+ store release involves phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP3), which in turn stimulates IP3 receptor channels to release Ca2+ from intracellular stores. This is followed by Ca2+ entry into the cell through plasma membrane calcium channels, a process referred to as store-operated calcium entry (SOCE). Stromal interaction molecule 1 (STIM1), a Ca2+ sensor molecule in intracellular stores, and the four transmembrane channel protein Orai1 are the key players in platelet SOCE. Other major Ca2+ entry mechanisms are mediated by the direct receptor-operated calcium (ROC) channel, P2X1 and transient receptor potential channels (TRPCs). Pubmed17703229 Pubmed18308196 Pubmed19422456 Reactome Database ID Release 43139853 Reactome, http://www.reactome.org ReactomeREACT_162 histidine + tRNA(His) + ATP => His-tRNA(His) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.21 Edited: D'Eustachio, P, 2008-11-29 15:41:00 HARS (cytosolic histidyl tRNA synthetase) catalyzes the reaction of histidine, tRNA(His), and ATP to form His-tRNA(His), AMP, and pyrophosphate (Lee et al. 2002). Pubmed11829477 Reactome Database ID Release 43379844 Reactome, http://www.reactome.org ReactomeREACT_15315 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Nitric oxide stimulates guanylate cyclase Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Nitric Oxide (NO) inhibits smooth muscle cell proliferation and migration, oxidation of low-density lipoproteins, and platelet aggregation and adhesion. It can stimulate vasodilatation of the endothelium, disaggregation of  preformed platelet aggregates and inhibits activated platelet recruitment to the aggregate. NO is synthesized from L-arginine by a family of isoformic enzymes known as nitric oxide synthase (NOS). Three isoforms, namely endothelial, neuronal, and inducible NOS (eNOS, nNOS, and iNOS, respectively), have been identified. The eNOS isoform is found in the endothelium and platelets. NO regulation of cyclic guanosine-3,5-monophosphate (cGMP), via activation of soluble guanylate cyclase, is the principal mechanism of negative control over platelet activity. Defects in this control mechanism have been associated with platelet hyperaggregability and associated thrombosis. Pubmed12881475 Pubmed16319917 Pubmed18327704 Reactome Database ID Release 43392154 Reactome, http://www.reactome.org ReactomeREACT_23862 Reviewed: Kunapuli, SP, 2010-06-07 cGMP effects Authored: Akkerman, JW, 2009-06-03 Cyclic guanosine monophosphate (cGMP) is an important secondary messenger synthesized by guanylate cyclases. cGMP has effects on phosphodiesterases (PDE), ion-gated channels, and the cGMP-dependent protein kinases (cGK, Protein Kinase G or PKG). It is involved in regulation of several physiological functions including vasodilation, platelet aggregation and neurotransmission. Elevation of intracellular cGMP activates PKG (Haslam et al. 1999) which regulates several intracellular molecules and pathways including the vasodilator-stimulated phosphoprotein (VASP) (Halbrugge et al. 1990) and the ERK pathway (Hood and Granger 1998, Li et al. 2001). cGMP mediates nitric oxide (NO)-induced vascular smooth muscle relaxation (Furchgott and Vanhoutte 1989). Phosphodiesterase 5 (PDE5) hydrolyzes cGMP; the PDE5 inhibitor sildenafil (Viagra) increases intracellular cGMP and thereby can be used as a treatment for erectile dysfunction (Corbin and Francis 1999). The role of the cGMP and PKG in platelet activation was controversial as increases in platelet cGMP levels were observed in response to both platelet agonists (thrombin, ADP or collagen) and inhibitors (NO donors such as sodium nitroprusside), but it is currently accepted that PKG inhibits platelet activation (Haslam et al. 1999). Consistent with this, nitric oxide (NO) donors that inhibit platelet activation enhance intracellular cGMP (Haslam et al. 1999). cGMP also plays an important stimulatory role in GPIb-IX-mediated platelet activation. Platelet responses to cGMP have been proposed to be biphasic, consisting of an early stimulatory response that promotes platelet activation followed by a delayed platelet inhibition that serves to limit the size of platelet aggregates (Li et al 2003). Edited: Jupe, S, 2010-06-07 Pubmed10318772 Pubmed10605732 Pubmed11522789 Pubmed12526795 Pubmed14597579 Pubmed2154470 Pubmed2545495 Pubmed7913615 Pubmed9722588 Reactome Database ID Release 43418457 Reactome, http://www.reactome.org ReactomeREACT_23767 Reviewed: Kunapuli, SP, 2010-06-07 Platelet homeostasis Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Pubmed10798271 Pubmed16297879 Reactome Database ID Release 43418346 Reactome, http://www.reactome.org ReactomeREACT_23876 Reviewed: Kunapuli, SP, 2010-06-07 Under normal conditions the vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma, vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and by the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction (Becker et al. 2000). Cyclooxygenase-2 (COX-2) and endothelial nitric oxide synthase (eNOS) are primarily expressed in endothelial cells. Both are important regulators of vascular function. Under normal conditions, laminar flow induces vascular endothelial COX-2 expression and synthesis of Prostacyclin (PGI2) which in turn stimulates endothelial Nitric Oxide Synthase (eNOS) activity. PGI2 and NO both oppose platelet activation and aggregation, as does the CD39 ecto-ADPase, which decreases platelet activation and recruitment by metabolizing platelet-released ADP. Prostacyclin signalling through prostacyclin receptor Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-06-07 Prostacyclin (PGI2) is continuously produced by healthy vascular endothelial cells. It inhibits platelet activation through interaction with the Gs-coupled receptor PTGIR, leading to increased cAMP, a consequent increase in cAMP-dependent protein kinase activity which prevents increases of cytoplasmic [Ca2+] necessary for activation (Woulfe et al. 2001). PGI2 is also an effective vasodilator. These effects oppose the effects of thromboxane (TXA2), another eicosanoid, creating a balance of blood circulation and platelet activation. Pubmed11413156 Pubmed17164137 Reactome Database ID Release 43392851 Reactome, http://www.reactome.org ReactomeREACT_23946 Reviewed: Kunapuli, SP, 2010-06-07 Lagging Strand Synthesis Due to the antiparallel nature of DNA, DNA polymerization is unidirectional, and one strand is synthesized discontinuously. This strand is called the lagging strand. Although the polymerase switching on the lagging strand is very similar to that on the leading strand, the processive synthesis on the two strands proceeds quite differently. Short DNA fragments, about 100 bases long, called Okazaki fragments are synthesized on the RNA-DNA primers first. Strand-displacement synthesis occurs, whereby the primer-containing 5'-terminus of the adjacent Okazaki fragment is folded into a single-stranded flap structure. This flap structure is removed by endonucleases, and the adjacent Okazaki fragments are joined by DNA ligase. Pubmed9081985 Reactome Database ID Release 4369186 Reactome, http://www.reactome.org ReactomeREACT_312 Polymerase switching After the primers are synthesized, Replication Factor C binds to the 3'-end of the initiator DNA to trigger polymerase switching. The non-processive nature of pol alpha catalytic activity and the tight binding of Replication Factor C to the primer-template junction presumably lead to the turnover of the pol alpha:primase complex. After the Pol alpha-primase primase complex is displaced from the primer, the proliferating cell nuclear antigen (PCNA) binds to form a "sliding clamp" structure. Replication Factor C then dissociates, and DNA polymerase delta binds and catalyzes the processive synthesis of DNA. Pubmed1670772 Pubmed1671046 Pubmed1967833 Reactome Database ID Release 4369091 Reactome, http://www.reactome.org ReactomeREACT_1792 CBP/p300 Converted from EntitySet in Reactome Reactome DB_ID: 1027362 Reactome Database ID Release 431027362 Reactome, http://www.reactome.org ReactomeREACT_25880 Processive synthesis on the lagging strand Pubmed1671046 Reactome Database ID Release 4369183 Reactome, http://www.reactome.org ReactomeREACT_1385 The key event that allows the processive synthesis on the lagging strand, is polymerase switching from pol alpha to pol delta, as on the leading strand. However, the processive synthesis on the lagging strand proceeds very differently. DNA synthesis is discontinuous, and involves the formation of short fragments called the Okazaki fragments. During the synthesis of Okazaki fragments, the RNA primer is folded into a single-stranded flap, which is removed by endonucleases. This is followed by the ligation of adjacent Okazaki fragments. Removal of the Flap Intermediate Pubmed7644470 Pubmed7926735 Pubmed8131753 Reactome Database ID Release 4369166 Reactome, http://www.reactome.org ReactomeREACT_70 Two endonucleases, Dna2 and flap endonuclease 1 (FEN-1), are responsible for resolving the nascent flap structure (Tsurimoto and Stillman 1991). The Dna2 endonuclease/helicase in yeast is a monomer of approximately 172 kDa. Human FEN-1 is a single polypeptide of approximately 42 kDa. Replication Protein A regulates the switching of endonucleases during the removal of the displaced flap. Regulation of DNA replication DNA replication is regulated at various levels via ORC proteins. This pathway includes annotation of individual events that lead to the regulation of replication. Reactome Database ID Release 4369304 Reactome, http://www.reactome.org ReactomeREACT_829 Reviewed: Manfredi, J, 0000-00-00 00:00:00 Association of licensing factors with the pre-replicative complex Reactome Database ID Release 4369298 Reactome, http://www.reactome.org ReactomeREACT_1181 The eukaryotic six-subunit origin recognition complex (ORC) governs the initiation site of DNA replication and formation of the prereplication complex. Removal of licensing factors from origins Licensing factors are removed from the origin by various means like biochemical modification (phosphorylation) or by physical association with other proteins. This pathway includes the annotations of events in which the fates of different proteins at the origin are outlined. Reactome Database ID Release 4369300 Reactome, http://www.reactome.org ReactomeREACT_207 Post-Elongation Processing of the Transcript Authored: Kornblihtt, AR, Proudfoot, NJ, 2003-09-11 12:45:33 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Post-transcriptional splicing of introns is affected neither by the elongating properties of RNA polymerase II, nor by the binding of splicing regulatory factors to the enzyme. It is only affected by the relative abundance of constitutive and/or regulatory splicing factors at the sites where splicing takes place. Nevertheless it is important to point out that cytological evidence indicates that unspliced or partially spliced pre-mRNAs do not diffuse in the nucleoplasm far from the transcription sites. Therefore, recruitment of splicing factors to transcription sites would still favor the post-transcriptional splicing of introns. Reactome Database ID Release 4376044 Reactome, http://www.reactome.org ReactomeREACT_78 Post-Elongation Processing of Intron-Containing pre-mRNA Reactome Database ID Release 43112296 Reactome, http://www.reactome.org ReactomeREACT_397 Post-Elongation Processing of Intronless pre-mRNA Reactome Database ID Release 43112297 Reactome, http://www.reactome.org ReactomeREACT_717 CDT1 association with the CDC6:ORC:origin complex Initiation protein Cdt1 was first identified in X. laevis, where it has been shown to be the second component of licensing factor (RLF-B) and in S. pombe. Cdt1 homologs have been identified in D. melanogaster, humans, and S. cerevisiae. Genetic studies in S. pombe have shown that binding of Cdc6 to chromatin requires the prior binding of Cdc18, the S. pombe homolog of Cdc6. In humans, the function of CDT1 is regulated during the cell cycle by its tight association with an inhibitory factor, geminin. Pubmed10766247 Pubmed10766248 Pubmed10898791 Pubmed11125146 Pubmed11175741 Pubmed11836525 Pubmed9442876 Pubmed9635433 Reactome Database ID Release 4368827 Reactome, http://www.reactome.org ReactomeREACT_1949 CDC6 protein is synthesized under the control of E2F transcription factors At the end of this reaction, 1 molecule of 'Cdc6' is present. <br><br><br> Pubmed9520412 Pubmed9778043 Reactome Database ID Release 4368637 Reactome, http://www.reactome.org ReactomeREACT_1601 IFNA Converted from EntitySet in Reactome Reactome DB_ID: 909688 Reactome Database ID Release 43909688 Reactome, http://www.reactome.org ReactomeREACT_25958 interferon alpha interferon alpha subtypes Expression of Interferon-alpha and beta Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Pubmed20627800 Pubmed2475256 Reactome Database ID Release 43994034 Reactome, http://www.reactome.org ReactomeREACT_25209 Reviewed: Ouwehand, WH, 2010-11-12 The Interferon alpha and beta genes are transcribed and translated yielding IFNA and IFNB which are secreted. This process is positively regulated by Interferon Regulatory Factor 1 and negatively regulated by Interferon Regulatory Factor 2, which compete for binding to the same regulatory element (Harada et al. 1989). Expression of NPPA (ANF) Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 Pubmed16332960 Reactome Database ID Release 432032800 Reactome, http://www.reactome.org ReactomeREACT_118863 Reviewed: Sudol, M, 2012-02-03 Transcription of the NPPA (ANF) gene is stimulated by the action of a transcription factor complex that includes WWTR1 (TAZ), TBX5, and the PCAF (KAT2B) histone acetyltransferase (Murakami et al. 2005). Leading Strand Synthesis Pubmed2175912 Pubmed7378348 Pubmed9191022 Reactome Database ID Release 4369109 Reactome, http://www.reactome.org ReactomeREACT_1838 The processive complex is responsible for synthesizing at least 5-10 kb of DNA in a continuous manner during leading strand synthesis. The incorporation of nucleotides by pol delta is quite accurate. However, incorporation of an incorrect nucleotide does occur occasionally. Misincorporated nucleotides are removed by the 3' to 5' exonucleolytic proofreading capability of pol delta. Pol II mediated transcription of microRNA genes Authored: Gopinathrao, G, May, B, 2007-11-18 23:55:40 Edited: Gopinathrao, G, May, B, 2007-11-18 23:55:40 Pubmed15364901 Pubmed15372072 Pubmed15525708 Pubmed17057362 Pubmed17099701 Reactome Database ID Release 43203901 Reactome, http://www.reactome.org ReactomeREACT_12505 Reviewed: Karginov, F, Hannon, GJ, 2008-02-08 15:41:16 Transcription of miRNA genes. Most miRNAs are transcribed by RNA polymerase II. The miRNAs may be autonomous transcription units or they may be located in other transcripts, including locations within introns and other untranslated regions. Of the polymerase II transcribed miRNAs, about 60% are located in introns of protein coding genes, 12 % are in introns of non-coding RNAs, 18% are in exons of non-coding RNAs, and 10% uncertain. <br>A second class of miRNA genes are associated with Alu and other repetitive elements and are cotranscribed with these elements by RNA polymerase III. There are currently only a few proven examples of polymerase III transcribed miRNAs. Expression of ACADM Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989745 Reactome, http://www.reactome.org ReactomeREACT_116020 Reviewed: Kersten, S, 2009-06-08 The ACADM gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of ACOX1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Pubmed20110263 Reactome Database ID Release 431989749 Reactome, http://www.reactome.org ReactomeREACT_115624 Reviewed: Kersten, S, 2009-06-08 The ACOX1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of ABCA1 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989765 Reactome, http://www.reactome.org ReactomeREACT_115994 Reviewed: Kersten, S, 2009-06-08 The ABCA1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Expression of ABCB4 Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19710929 Reactome Database ID Release 431989762 Reactome, http://www.reactome.org ReactomeREACT_115807 Reviewed: Kersten, S, 2009-06-08 The ABCB4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. DNA replication initiation DNA polymerases are not capable of de novo DNA synthesis and require synthesis of a primer, usually by a DNA-dependent RNA polymerase (primase) to begin DNA synthesis. In eukaryotic cells, the primer is synthesized by DNA polymerase alpha:primase. First, the DNA primase portion of this complex synthesizes approximately 6-10 nucleotides of RNA primer and then the DNA polymerase portion synthesizes an additional 20 nucleotides of DNA (Frick & Richardson 2002; Wang et al 1984). GENE ONTOLOGYGO:0006270 Pubmed11395402 Pubmed6693436 Reactome Database ID Release 4368952 Reactome, http://www.reactome.org ReactomeREACT_2244 Switching of origins to a post-replicative state Reactome Database ID Release 4369052 Reactome, http://www.reactome.org ReactomeREACT_2148 Activation of the pre-replicative complex In S. cerevisiae, two ORC subunits, Orc1 and Orc5, both bind ATP, and Orc1 in addition has ATPase activity. Both ATP binding and ATP hydrolysis appear to be essential functions in vivo. ATP binding by Orc1 is unaffected by the association of ORC with origin DNA (ARS) sequences, but ATP hydrolysis is ARS-dependent, being suppressed by associated double-stranded DNA and stimulated by associated single-stranded DNA. These data are consistent with the hypothesis that ORC functions as an ATPase switch, hydrolyzing bound ATP and changing state as DNA unwinds at the origin immediately before replication. It is attractive to speculate that ORC likewise functions as a switch as human pre-replicative complexes are activated, but human Orc proteins are not well enough characterized to allow the model to be critically tested. mRNAs encoding human orthologs of all six Orc proteins have been cloned, and ATP-binding amino acid sequence motifs have been identified in Orc1, Orc4, and Orc5. Interactions among proteins expressed from the cloned genes have been characterized, but the ATP-binding and hydrolyzing properties of these proteins and complexes of them have not been determined. Pubmed10402192 Pubmed10801458 Pubmed10970868 Pubmed11323433 Pubmed11395502 Pubmed11459976 Pubmed11779870 Pubmed12169736 Pubmed7502077 Pubmed9038340 Pubmed9353276 Pubmed9765232 Pubmed9829972 Reactome Database ID Release 4368962 Reactome, http://www.reactome.org ReactomeREACT_1095 Synthesis of DNA Reactome Database ID Release 4369239 Reactome, http://www.reactome.org ReactomeREACT_2014 The actual synthesis of DNA occurs in the S phase of the cell cycle. This includes the initiation of DNA replication, when the first nucleotide of the new strand is laid down during the synthesis of the primer. The DNA replication preinitiation events begin in late M or early G1 phase. DNA strand elongation Accurate and efficient genome duplication requires coordinated processes to replicate two template strands at eucaryotic replication forks. Knowledge of the fundamental reactions involved in replication fork progression is derived largely from biochemical studies of the replication of simian virus and from yeast genetic studies. Since duplex DNA forms an anti-parallel structure, and DNA polymerases are unidirectional, one of the new strands is synthesized continuously in the direction of fork movement. This strand is designated as the leading strand. The other strand grows in the direction away from fork movement, and is called the lagging strand. Several specific interactions among the various proteins involved in DNA replication underlie the mechanism of DNA synthesis, on both the leading and lagging strands, at a DNA replication fork. These interactions allow the replication enzymes to cooperate in the replication process (Hurwitz et al 1990; Brush et al 1996; Ayyagari et al 1995; Budd & Campbell 1997; Bambara et al 1997). Authored: Tom, S, Bambara, RA, 2003-06-05 08:03:21 GENE ONTOLOGYGO:0006271 Pubmed1536007 Pubmed1976634 Pubmed7623835 Pubmed8594377 Pubmed9081985 Reactome Database ID Release 4369190 Reactome, http://www.reactome.org ReactomeREACT_932 Expression of CTGF Authored: May, B, 2011-11-08 Edited: May, B, 2011-11-08 Pubmed19324876 Pubmed19324877 Pubmed20110263 Reactome Database ID Release 431989766 Reactome, http://www.reactome.org ReactomeREACT_116163 Reviewed: Kersten, S, 2009-06-08 The CTGF gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of the CTGF gene is increased by both YAP1:TEAD and WWTR1(TAZ):TEAD transcriptional coactivator:transcription factor complexes, so that CTFG is one of the many genes whose expression is downregulated by the action of the hippo cascade (Zhang et al. 2009; Zhao et al. 2008). Unwinding of DNA Authored: Tye, BK, 2006-03-17 14:46:24 DNA Replication is regulated accurately and precisely by various protein complexes. Many members of the MCM protein family are assembled into the pre-Replication Complexes (pre-RC) at the end of M phase of the cell cycle. DNA helicase activity of some of the MCM family proteins are important for the unwinding of DNA and initiation of replication processes. This section contains four events which have been proved in different eukaryotic experimental systems to involve various proteins for this essential step during DNA Replication. Edited: Gopinathrao, G, 2006-03-17 14:47:28 Pubmed10834843 Pubmed15707891 Reactome Database ID Release 43176974 Reactome, http://www.reactome.org ReactomeREACT_6776 Orc1 removal from chromatin Pubmed1110244 Pubmed11739726 Pubmed11809796 Pubmed11931757 Reactome Database ID Release 4368949 Reactome, http://www.reactome.org ReactomeREACT_1156 CDK-mediated phosphorylation and removal of Cdc6 As cells enter S phase, HsCdc6p is phosphorylated by CDK promoting its export from the nucleus (see Bell and Dutta 2002). Pubmed11046155 Pubmed12045100 Reactome Database ID Release 4369017 Reactome, http://www.reactome.org ReactomeREACT_1221 pyrophosphate + H2O => 2 orthophosphate [mitochondrial] Authored: D'Eustachio, P, 2009-12-09 EC Number: 3.6.1.1 Edited: D'Eustachio, P, 2010-02-18 Mitochondrial PPA2 (pyrophosphatase (inorganic) 2) catalyzes the hydrolysis of pyrophosphate to yield two molecules of orthophosphate. The enzyme requires Mg++ for activity (Curbo et al. 2006). The enzyme is inferred to be a homodimer by analogy to its cytosolic isoform. Pubmed16300924 Reactome Database ID Release 43449937 Reactome, http://www.reactome.org ReactomeREACT_21277 Reviewed: Jassal, B, 2010-02-26 has a Stoichiometric coefficient of 2 valine + tRNA(Val) + ATP => Val-tRNA(Val) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.9 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed15779907 Reactome Database ID Release 43380199 Reactome, http://www.reactome.org ReactomeREACT_15429 Reviewed: Antonellis, A, 2008-12-02 16:58:45 VARS2 (mitochondrial valyl tRNA synthetase) catalyzes the reaction of valine, mitochondrial tRNA(val), and ATP to form Val-tRNA(Val), AMP, and pyrophosphate. The VARS2 gene has been identified by computational analysis of the human genome sequence; its function has been inferred from those of the biochemically characterized mitochondrial aspartyl and tyrosyl tRNA synthetases (Bonnefond et al. 2005). Deadenylation of mRNA by PARN Authored: May, B, 2009-07-22 EC Number: 3.1.13.4 Edited: May, B, 2009-07-22 Pubmed10882133 Pubmed11283721 Pubmed1355481 Pubmed14749774 Pubmed15475613 Pubmed16141059 Pubmed17052452 Pubmed17245413 Pubmed19239894 Pubmed9099687 Reactome Database ID Release 43429992 Reactome, http://www.reactome.org ReactomeREACT_20662 Reviewed: Wilusz, J, 2009-09-17 The PARN exoribonuclease hydrolyzes adenosine residues at the 3' ends of polyadenylated mRNA, shortening the poly(A) tail from about 80 adenosine residues to about 10-15 residues and yielding adenosine 5'-monophosphate. PARN interacts simultaneously with the poly(A) tail and with the 7-methylguanosine cap of the mRNA, therefore it is believed that PARN displaces the eIF4F cap-binding complex. The trigger for deadenylation by PARN is unknown. PARN is also part of a complex that regulates poly(A) tail length and hence translation in developing oocytes. Partial Deadenylation of mRNA by the PAN2-PAN3 Complex Authored: May, B, 2009-07-22 EC Number: 3.1.13.4 Edited: May, B, 2009-07-22 Pubmed11283721 Pubmed14583602 Pubmed14749774 Pubmed15475613 Pubmed16141059 Pubmed16284618 Pubmed17245413 Pubmed17595167 Pubmed18625844 Pubmed19239894 Reactome Database ID Release 43430021 Reactome, http://www.reactome.org ReactomeREACT_20606 Reviewed: Wilusz, J, 2009-09-17 The PAN2-PAN3 exoribonuclease complex hydrolyzes the poly(A) tail of a mRNA, shortening the tail from about 200 adenosine residues to about 80 adenosine residues and yielding adenosine 5'-monophosphate. PAN2 is the exoribonuclease component of the complex; PAN3 is required for cellular localization. The poly(A)-binding protein (PABP) interacts with PAN3 and recruits the PAN2-PAN3 complex to mRNA. Hexose uptake Authored: D'Eustachio, P, 2006-11-03 14:36:07 GENE ONTOLOGYGO:0008645 Hexose transport Hexoses, notably fructose, glucose, and galactose, generated in the lumen of the small intestine by breakdown of dietary carbohydrate are taken up by enterocytes lining the microvilli of the small intestine and released from them into the blood. Uptake into enterocytes is mediated by two transporters localized on the lumenal surfaces of the cells, SGLT1 (glucose and galactose, together with sodium ions) and GLUT5 (fructose). GLUT2, localized on the basolateral surfaces of enterocytes, mediates the release of these hexoses into the blood (Wright et al. 2004). GLUT2 may also play a role in hexose uptake from the gut lumen into enterocytes when the lumenal content of monosaccharides is very high (e.g., Kellet and Brot-Laroche, 2005) and GLUT5 mediates fructose uptake from the blood into cells of the body, notably hepatocytes.<p>Cells take up glucose by facilitated diffusion, via glucose transporters (GLUTs) associated with the plasma membrane, a reversible reaction. Four tissue-specific GLUT isoforms are known. Glucose in the cytosol is phosphorylated by tissue-specific kinases to yield glucose 6-phosphate, which cannot cross the plasma membrane because of its negative charge. In the liver, this reaction is catalyzed by glucokinase which has a low affinity for glucose (Km about 10 mM) but is not inhibited by glucose 6-phosphate. In other tissues, this reaction is catalyzed by isoforms of hexokinase. Hexokinases are feedback-inhibited by glucose 6-phosphate and have a high affinity for glucose (Km about 0.1 mM). Liver cells can thus accumulate large amounts of glucose 6-phosphate but only when blood glucose concentrations are high, while most other tissues can take up glucose even when blood glucose concentrations are low but cannot accumulate much intracellular glucose 6-phosphate. These differences are consistent with the view that that the liver functions to buffer blood glucose concentrations, while most other tissues take up glucose to meet immediate metabolic needs.<p>Glucose 6-phosphatase, expressed in liver and kidney, allows glucose 6-phosphate generated by gluconeogenesis (both tissues) and glycogen breakdown (liver) to leave the cell. The absence of glucose 6-phosphatase from other tissues makes glucose uptake by these tissues essentially irreversible, consistent with the view that cells in these tissues take up glucose for local metabolic use. Pubmed15546855 Pubmed16186415 Reactome Database ID Release 43189200 Reactome, http://www.reactome.org ReactomeREACT_9441 Reviewed: Wright, EM, 2007-01-15 21:00:45 3' to 5' Exoribonuclease Digestion of mRNA by the Exosome Complex Authored: May, B, 2009-07-22 Edited: May, B, 2009-07-22 Pubmed11283721 Pubmed14749774 Pubmed15231747 Pubmed15475613 Pubmed16141059 Pubmed17174896 Pubmed17245413 Pubmed17545563 Pubmed19060886 Pubmed19225159 Pubmed19239894 Reactome Database ID Release 43430028 Reactome, http://www.reactome.org ReactomeREACT_20588 Reviewed: Wilusz, J, 2009-09-17 The exosome complex hydrolyzes capped, deadenylated mRNA from 3' to 5' and yields ribonucleotides having 5'-monophosphates. In yeast the Ski2-Ski3-Ski8 complex assists degradation by the exosome complex, however little is known about the function of the homologous Ski complex in mammals. Although many exosomal components contain exonuclease signatures, only two components have been shown to degrade RNA. Rrp6/PMSCL-100 has been shown to be involved in the 3’-5’ decay of nuclear mRNAs in yeast. Rrp6 may also function in the absence of the core exosomal components. The Rrp44/dDis3 component of the core exosome has been shown to possess both 3’-5’ exonuclease activity along with endonuclease activity via its PIN domain. Glucose transport Authored: 2003-02-15 00:00:00 Cells take up glucose by facilitated diffusion, via glucose transporters (GLUTs) associated with the plasma membrane, a reversible reaction (Joost and Thorens 2001). Four tissue-specific GLUT isoforms are known. Glucose in the cytosol is phosphorylated by tissue-specific kinases to yield glucose 6-phosphate, which cannot cross the plasma membrane because of its negative charge. In the liver, this reaction is catalyzed by glucokinase which has a low affinity for glucose (Km about 10 mM) but is not inhibited by glucose 6-phosphate. In other tissues, this reaction is catalyzed by isoforms of hexokinase. Hexokinases are feedback-inhibited by glucose 6-phosphate and have a high affinity for glucose (Km about 0.1 mM). Liver cells can thus accumulate large amounts of glucose 6-phosphate but only when blood glucose concentrations are high, while most other tissues can take up glucose even when blood glucose concentrations are low but cannot accumulate much intracellular glucose 6-phosphate. These differences are consistent with the view that that the liver functions to buffer blood glucose concentrations, while most other tissues take up glucose to meet immediate metabolic needs.<p>Glucose 6-phosphatase, expressed in liver and kidney, allows glucose 6-phosphate generated by gluconeogenesis (both tissues) and glycogen breakdown (liver) to leave the cell. The absence of glucose 6-phosphatase from other tissues makes glucose uptake by these tissues essentially irreversible, consistent with the view that cells in these tissues take up glucose for local metabolic use. GENE ONTOLOGYGO:0015758 Pubmed11780753 Reactome Database ID Release 4370153 Reactome, http://www.reactome.org ReactomeREACT_212 Deadenylation of mRNA by the CCR4-NOT Complex Authored: May, B, 2009-07-22 EC Number: 3.1.13.4 Edited: May, B, 2009-07-22 Pubmed10637334 Pubmed11283721 Pubmed11889047 Pubmed14749774 Pubmed15475613 Pubmed16141059 Pubmed16284618 Pubmed17245413 Pubmed18625844 Pubmed19239894 Pubmed19558367 Reactome Database ID Release 43429955 Reactome, http://www.reactome.org ReactomeREACT_20651 Reviewed: Wilusz, J, 2009-09-17 The CCR4-NOT complex hydrolyzes adenosine residues at the 3' end of polyadenylated mRNA, shortening the number of adenosine residues to about 10-15 residues and yielding adenosine 5'-monophosphate. CNOT6 and CNOT6L are the exoribonucleases responsible for hydrolysis. Activity of the CCR4-NOT complex is inhibited by PABP bound to the poly(A) tail of the mRNA. The trigger for activation of deadenylation by the CCR4-NOT complex is unknown. Complexes containing CNOT7 rather than CNOT8 appear to be responsible for cytoplasmic mRNA decay. Regulation of Glucokinase by Glucokinase Regulatory Protein Edited: D'Eustachio, P, 2006-02-20 18:39:56 GENE ONTOLOGYGO:0010827 Glucokinase (GCK1) is negatively regulated by glucokinase regulatory protein (GKRP), which reversibly binds the enzyme to form an inactive complex. Binding is stimulated by fructose 6-phosphate and sorbitol 6-phosphate (hence high concentrations of these molecules tend to reduce GCK1 activity) and inhibited by fructose 1-phosphate (hence a high concentration of this molecule tends to increase GCK1 activity). Once formed, the complex is translocated to the nucleus. In the presence of high glucose concentrations, the nuclear GCK1:GKRP complex dissociates, freeing GCK1 to return to the cytosol. The free GKRP is thought also to return to the cytosol under these conditions, but this return has not been confirmed experimentally. Possible physiological roles for this sequestration process are to decrease futile cycling between glucose and glucose 6 phosphate in hepatocytes under low-glucose conditions, and to decrease the lag between a rise in intracellular glucose levels and the onset of glucose phosphorylation in both hepatocytes and pancreatic beta cells (Brocklehurst et al. 2004; Shiota et al. 1999). Pubmed10601273 Pubmed14627435 Reactome Database ID Release 43170822 Reactome, http://www.reactome.org ReactomeREACT_6804 Binding of Lsm1-7 Complex to Deadenylated mRNA Authored: May, B, 2009-07-22 Edited: May, B, 2009-07-22 Pubmed11283721 Pubmed14749774 Pubmed15231747 Pubmed15475613 Pubmed15711010 Pubmed16051491 Pubmed16141059 Pubmed17245413 Pubmed19239894 Pubmed19279404 Reactome Database ID Release 43429978 Reactome, http://www.reactome.org ReactomeREACT_20540 Reviewed: Wilusz, J, 2009-09-17 The Lsm1-7 complex forms a heptameric ring that binds the 3' oligoadenylated ends of mRNAs that have been deadenylated. The bound Lsm1-7 may prevent access of the exosome (a 3' to 5' exonuclease) to the 3' end and thereby direct the mRNA to the 5' to 3' exonuclease pathway. The yeast Lsm1-7 complex has a preference for oligoadenylated RNA compared to polyadenylated RNA, however other determinants of binding by Lsm1-7 are unknown. Glucose metabolism Authored: Schmidt, EE, 2003-02-05 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006006 Glucose is the major form in which dietary sugars are made available to cells of the human body. Its breakdown is a major source of energy for all cells, and is essential for the brain and red blood cells. Glucose utilization begins with its uptake by cells and conversion to glucose 6-phosphate, which cannot traverse the cell membrane. Fates open to cytosolic glucose 6-phosphate include glycolysis to yield pyruvate, glycogen synthesis, and the pentose phosphate pathway. In some tissues, notably the liver and kidney, glucose 6-phosphate can be synthesized from pyruvate by the pathway of gluconeogenesis. Reactome Database ID Release 4370326 Reactome, http://www.reactome.org ReactomeREACT_723 Scavenging of the 7-methylguanosine Cap by DCPS Authored: May, B, 2009-07-22 Edited: May, B, 2009-07-22 Pubmed11283721 Pubmed14749774 Pubmed15068804 Pubmed15273322 Pubmed15475613 Pubmed15769464 Pubmed16141059 Pubmed17245413 Pubmed18441014 Pubmed19239894 Reactome Database ID Release 43429961 Reactome, http://www.reactome.org ReactomeREACT_20556 Reviewed: Wilusz, J, 2009-09-17 The scavenging nuclease DCPS hydrolyzes the triphosphate bond between the 7-methylguanosine cap and the remaining oligoribonucleotide body of the mRNA. The products are 7-methylguanosine 5'-monophosphate and an oligoribonucleotide with a 5'-diphosphate. Elongation arrest and recovery Reactome Database ID Release 43112387 Reactome, http://www.reactome.org ReactomeREACT_1892 5' to 3' Exoribonuclease Digestion of Decapped mRNA Authored: May, B, 2009-07-22 Edited: May, B, 2009-07-22 Pubmed11283721 Pubmed12515382 Pubmed14749774 Pubmed15475613 Pubmed16141059 Pubmed16299471 Pubmed17245413 Pubmed19239894 Reactome Database ID Release 43429845 Reactome, http://www.reactome.org ReactomeREACT_20533 Reviewed: Wilusz, J, 2009-09-17 The XRN1 exoribonuclease hydrolyzes decapped mRNA from 5' to 3' and yields ribonucleotides having 5'-monophosphates. In yeast Xrn1 associates with the Lsm1-7 complex. Metabolism GENE ONTOLOGYGO:0044281 Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. The processes of energy metabolism can be classified into two groups according to whether they involve carbohydrate-derived or lipid-derived molecules, and within each group it is useful to distinguish processes that mediate the breakdown and oxidation of these molecules to yield energy from ones that mediate their synthesis and storage as internal energy reserves. Synthetic reactions are conveniently grouped by the chemical nature of the end products, such as nucleotides, amino acids and related molecules, and porphyrins. Detoxification reactions (biological oxidations) are likewise conveniently classified by the chemical nature of the toxin.<p>At the same time, all of these processes are tightly integrated. Intermediates in reactions of energy generation are starting materials for biosyntheses of amino acids and other compounds, broad-specificity oxidoreductase enzymes can be involved in both detoxification reactions and biosyntheses, and hormone-mediated signaling processes function to coordinate the operation of energy-generating and energy-storing reactions and to couple these to other biosynthetic processes. Reactome Database ID Release 431430728 Reactome, http://www.reactome.org ReactomeREACT_111217 Decapping of mRNA by the DCP1-DCP2 Complex Authored: May, B, 2009-07-22 EC Number: 3.1.13 Edited: May, B, 2009-07-22 Pubmed11283721 Pubmed12218187 Pubmed12417715 Pubmed12486012 Pubmed12923261 Pubmed14749774 Pubmed15085179 Pubmed15475613 Pubmed16141059 Pubmed16246173 Pubmed17245413 Pubmed18039849 Pubmed19061636 Pubmed19239894 Reactome Database ID Release 43429860 Reactome, http://www.reactome.org ReactomeREACT_20560 Reviewed: Wilusz, J, 2009-09-17 The DCP1-DCP2 decapping complex binds the 7-methylguanosine cap of mRNA and hydrolyzes the triphosphate bond to yield 7-methylguanosine 5'-diphosphate and RNA with 5'-monophosphate. The DCP2 subunit of the complex catalyzes the hydrolysis. DCP2 has higher affinity for some subsets of mRNA. Carbohydrate metabolism Authored: D'Eustachio, P, Schmidt, EE, 2003-11-03 05:38:33 Edited: D'Eustachio, P, Schmidt, EE, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0005975 Metabolism of carbohydrates Reactome Database ID Release 4371387 Reactome, http://www.reactome.org ReactomeREACT_474 These pathways together are responsible for: 1) the extraction of energy and carbon skeletons for biosyntheses from dietary sugars and related molecules; 2) the short-term storage of glucose in the body (as glycogen) and its mobilization during a short fast; and 3) the synthesis of glucose from pyruvate during extended fasts. Digestion of dietary carbohydrate Authored: D'Eustachio, P, 2006-11-03 14:36:07 Carbohydrate is a major component of the human diet, and includes starch (amylose and amylopectin) and disaccharides such as sucrose, lactose, maltose and, in small amounts, trehalose. The digestion of starch begins with the action of amylase enzymes secreted in the saliva and small intestine, which convert it to maltotriose, maltose, limit dextrins, and some glucose. Digestion of the limit dextrins and disaccharides, both dietary and starch-derived, to monosaccharides - glucose, galactose, and fructose - is accomplished by enzymes located on the luminal surfaces of enterocytes lining the microvilli of the small intestine (Semenza et al. 2001). GENE ONTOLOGYGO:0044245 ISBN0079130356 Reactome Database ID Release 43189085 Reactome, http://www.reactome.org ReactomeREACT_9472 Reviewed: Nichols, BL, 2007-01-15 21:51:24 Gluconeogenesis Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006094 Pubmed8379904 Reactome Database ID Release 4370263 Reactome, http://www.reactome.org ReactomeREACT_1520 Reviewed: Harris, RA, 2008-09-10 18:47:12 The reactions of gluconeogenesis convert mitochondrial pyruvate to cytosolic glucose 6-phosphate which in turn can be hydrolyzed to glucose and exported from the cell. Gluconeogenesis is confined to cells of the liver and kidney and enables glucose synthesis from molecules such as lactate and alanine and other amino acids when exogenous glucose is not available (reviewed, e.g., by Gerich 1993). The process of gluconeogenesis as diagrammed below occurs in two parts: a network of reactions converts mitochondrial pyruvate to cytosolic phosphoenolpyruvate; then phosphoenolpyruvate is converted to glucose 6-phosphate in a single sequence of cytosolic reactions.<p>Three variants of the first part of the process are physiologically important. 1) A series of transport and transamination reactions convert mitochondrial oxaloacetate to cytosolic oxaloacetate which is converted to phosphoenolpyruvate by a hormonally regulated, cytosolic isoform of phosphoenolpyruvate carboxykinase. This variant allows regulated glucose synthesis from lactate. 2) Mitochondrial oxaloacetate is reduced to malate, which is exported to the cytosol and re-oxidized to oxaloacetate. This variant provides reducing equivalents to the cytosol, needed for glucose synthesis from amino acids such as alanine and glutamine. 3) Constitutively expressed mitochondrial phosphoenolpyruvate carboxykinase catalyzes the conversion of mitochondrial oxaloacetate to phosphoenolpyruvate which is then transported to the cytosol. The exact path followed by any one molecule of pyruvate through this reaction network is determined by the tissue in which the reactions are occurring, the source of the pyruvate, and the physiological stress that triggered gluconeogenesis.<p>In all cases, the synthesis of glucose from two molecules of pyruvate requires the generation and consumption of two reducing equivalents as cytosolic NADH + H+. For pyruvate derived from lactate (variants 1 and 3), NADH + H+ is generated with the oxidation of lactate to pyruvate in the cytosol (a reaction of pyruvate metabolism not shown in the diagram). For pyruvate derived from amino acids (variant 2), mitochondrial NADH + H+ generated by glutamate dehydrogenase (a reaction of amino acid metabolism, not shown) is used to reduce oxaloacetate to malate, which is transported to the cytosol and re-oxidized, generating cytosolic NADH + H+. The synthesis of glucose from pyruvate also requires the consumption of six high-energy phosphates, four from ATP and two from GTP.<p>In the second part of gluconeogenesis, cytosolic phosphoenolpyruvate, however derived, is converted to fructose 1,6-bisphosphate by reactions that are the reverse of steps of glycolysis. Hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate is catalyzed by fructose 1,6-bisphosphatase, and fructose 6-phosphate is reversibly isomerized to glucose 6-phosphate. Glycolysis Authored: Schmidt, EE, 2003-01-28 00:00:00 GENE ONTOLOGYGO:0006096 Pubmed16051738 Reactome Database ID Release 4370171 Reactome, http://www.reactome.org ReactomeREACT_1383 The reactions of glycolysis (e.g., van Wijk and van Solinge 2005) convert glucose 6-phosphate to pyruvate. The entire process is cytosolic. Glucose 6-phosphate is reversibly isomerized to form fructose 6-phosphate. Phosphofructokinase 1 catalyzes the physiologically irreversible phosphorylation of fructose 6-phosphate to form fructose 1,6-bisphosphate. In six reversible reactions, fructose 1,6-bisphosphate is converted to two molecules of phosphoenolpyruvate and two molecules of NAD+ are reduced to NADH + H+. Each molecule of phosphoenolpyruvate reacts with ADP to form ATP and pyruvate in a physiologically irreversible reaction. Under aerobic conditions the NADH +H+ can be reoxidized to NAD+ via electron transport to yield additional ATP, while under anaerobic conditions or in cells lacking mitochondria NAD+ can be regenerated via the reduction of pyruvate to lactate. UPF1 Binds an mRNP with a Termination Codon Preceding an Exon Junction Complex Authored: May, B, 2010-08-06 Edited: May, B, 2010-08-06 Pubmed11532962 Pubmed11546874 Pubmed11551508 Pubmed12718880 Pubmed14973490 Pubmed15034551 Pubmed16186820 Pubmed16209946 Pubmed16452507 Pubmed16601204 Pubmed17352659 Pubmed17363904 Pubmed17803942 Pubmed18066079 Pubmed18256688 Pubmed18423202 Pubmed18524595 Pubmed18657639 Pubmed19359157 Pubmed19417104 Pubmed19478851 Pubmed19503078 Pubmed19556969 Pubmed19859661 Pubmed19909264 Pubmed20479275 Pubmed20691628 Pubmed21419344 Reactome Database ID Release 43927832 Reactome, http://www.reactome.org ReactomeREACT_75753 Reviewed: Neu-Yilik, G, 2011-05-19 The presence of an exon junction complex (EJC) downstream of a termination codon enhances nonsense-mediated decay (NMD) but is not absolutely required for NMD. The EJC is deposited during splicing and remains bound to the mRNA until a ribosome dislodges it during the pioneer round of translation, distinguished by the presence of the cap-binding complex at the 5' end. If translation terminates at least 50-55 nucleotides 5' to an EJC during the pioneer round then termination factors (eRF1 and eRF3) and the EJC recruit UPF1 and other NMD machinery (Lykke-Andersen et al. 2001, Ishigaki et al. 2001, Le Hir et al. 2001, Gehring et al. 2003, Hosoda et al. 2005, Kashima et al. 2006, Singh et al. 2007, Chamieh et al. 2008, Ivanov et al. 2008, Buchwald et al. 2010).<br>A current model for NMD enhanced by the EJC posits recruitment of UPF1, SMG1, SMG8, and SMG9 to eRF3 at the ribosome to form the SURF complex (Kashima et al. 2006, Chang et al. 2007, Isken et al. 2008, Muhlemann et al. 2008, Stalder and Muhlemann 2008, Chamieh et al. 2009, Maquat and Gong 2009, Rebbapragada and Lykke-Andersen 2009, Hwang et al. 2010, Nicholson et al. 2010). UPF1 and SMG1 then interact with components of the EJC, activating phosphorylation of UPF1 by SMG1.<br>The model of the NMD mechanism is inferred from known protein interactions:<br>eRF1 and eRF3 interact with UPF1, the key regulator of NMD which also binds SMG1, UPF2, and UPF3 (UPF3a or UPF3b) to form the SURF complex (Kashima et al.2006, Ivanov et al. 2008, Clerici et al. 2009, Chakrabarti et al. 2011). UPF1 also interacts with CBP80 at the cap of the mRNA (Hwang et al. 2010).<br>SMG8 and SMG9 associate with SMG1 and the SURF complex and modulate the phosphorylation activity of SMG1 (Yamashita et al. 2009).<br>UPF2 and UPF3 are peripheral components of the EJC and thus may link the EJC to the SURF complex (Chamieh et al. 2008). UPF3b binds UPF1 and a composite surface formed by the Y14, MAGOH, and eIF4A3 subunits of the core EJC (Gehring et al. 2003, Kunz et al. 2006, Buchwald et al. 2010). SMG1 also interacts with the EJC (Kashima et al. 2006, Yamashita et al. 2009). UPF3a more weakly activates NMD than does UPF3b (Kunz et al. 2006) and UPF3a levels increase in response to loss of UPF3b (Chan et al. 2009).<br>The binding of UPF1 to translated RNAs may occur in two steps: Binding of the SURF complex to the terminating ribosome followed by transfer of UPF1 and SMG1 to the EJC (Kashima et al. 2006, Hwang et al. 2010).<br>The core EJC (Y14, MAGOH, eIF4A3, and BTZ) can activate NMD without UPF2, however RNPS1, another EJC subunit, requires UPF2 to activate NMD (Gehring et al. 2005). RNAs show differential dependence on RNPS1-activated NMD (Gehring et al. 2005). Also, NMD of some transcripts requires EJC component eIF4A3 but not UPF3b (Chan et al. 2007) therefore there may be more than one route to activating NMD via the EJC. Decay of mRNA in SMG6:SMG5:SMG7:mRNA Complex Authored: May, B, 2010-08-06 Edited: May, B, 2010-08-06 Pubmed12417715 Pubmed12554878 Pubmed12832468 Pubmed14527413 Pubmed14636577 Pubmed14742663 Pubmed15546618 Pubmed16284618 Pubmed18974281 Pubmed19060897 Pubmed19859661 Pubmed20023408 Pubmed20930030 Pubmed21145460 Reactome Database ID Release 43927830 Reactome, http://www.reactome.org ReactomeREACT_75794 Reviewed: Neu-Yilik, G, 2011-05-19 SMG6 endonucleolytically cleaves an mRNA it is believed that the resulting fragments are degraded by exonucleases, possibly XRN1, a 5'-to-3' nuclease, and the exosome complex, a 3'-to-5' nuclease (Huntzinger et al. 2008, Eberle et al. 2009). Inhibition of XRN1 is observed to cause accumulation of SMG6-cleaved intermediates therefore XRN1 is postulated to act downstream of SMG6 (Huntzinger et al. 2008).<br>In general, during Nonsense-Mediated Decay mRNAs are observed to be deadenlyated (implicating the PAN2 complex, PARN complex, and CCR4 complex), decapped (implicating the DCP1:DCP2 complex), and exoribonucleolytically digested (implicating the XRN1 5'-to-3' exonuclease and exosome 3'-to-5' exonuclease) (Lykke-Andersen 2002, Chen et al. 2003, Lejeune et al. 2003, Couttet and Grange 2004, Unterholzner and Izaurralde 2004, Yamashita et al. 2005). UPF1 is observed to associate with the decapping enzymes DCP1a and DCP2, however the specific decay reactions that occur after SMG6, SMG5 and SMG7 have associated with an mRNA are unknown (Lykke-Andersen et al. 2002). Likewise, SMG6 may be present in complexes separate from SMG5 and SMG7 and these complexes may have different routes of decay (reviewed in Nicholson et al. 2010, Muhlemann and Lykke-Andersen 2010).<br>ATPase activity of UPF1 is necessary for NMD and may reflect ATP-dependent helicase activity that disassembles the mRNA-protein complex (Franks et al. 2010). UPF1 must be dephosphorylated by PP2A for NMD to continue (Ohnishi et al. 2003, Chiu et al. 2003). Presumably the dephosphoryation recycles UPF1 for interaction with other mRNA complexes. SMG6 Cleaves mRNA with Premature Termination Codon Authored: May, B, 2010-08-06 Edited: May, B, 2010-08-06 Pubmed17053788 Pubmed18974281 Pubmed19060897 Reactome Database ID Release 43927836 Reactome, http://www.reactome.org ReactomeREACT_75787 Reviewed: Neu-Yilik, G, 2011-05-19 SMG6 is an endoribonuclease which cleaves the mRNA bound by UPF1 near the premature termination codon (Glavan et al. 2006, Eberle et al. 2009). Phosphorylated UPF1 Recruits SMG5, SMG7, SMG6, and PP2A Authored: May, B, 2010-08-06 Edited: May, B, 2010-08-06 Pubmed12554878 Pubmed14636577 Pubmed15546618 Pubmed15721257 Pubmed17053788 Pubmed17893241 Pubmed18423202 Pubmed19060897 Pubmed20023408 Pubmed20930030 Reactome Database ID Release 43927813 Reactome, http://www.reactome.org ReactomeREACT_75891 Reviewed: Neu-Yilik, G, 2011-05-19 SMG6, SMG5 and SMG7 contain 14-3-3 domains which are believed to bind phosphorylated SQ motifs in UPF1 (Chiu et al. 2003, Ohnishi et al. 2003, Unterholzner and Izaurralde 2004, Fukuhara et al. 2005, Durand et al. 2007). SMG7 has been shown to bind UPF1 directly, target UPF1 for dephosphorylation by PP2A, and recruit enzymes that degrade RNA (Ohnishi et al. 2003, Unterholzner and Izaurralde 2004, Fukuhara et al. 2005). UPF3AS (the small isoform of UPF3A) also associates with the complex (Ohnishi et al. 2003). SMG6 is an endoribonuclease that cleaves the mRNA bound by UPF1 and also recruits phosphatase PP2A to dephosphorylate UPF1 (Chiu et al. 2003, Glavan et al. 2006, Eberle et al. 2009) .<br>Though immunofluorescence in vivo indicates that SMG5 and SMG7 exist in separate complexes from SMG6 (Unterholzner and Izaurralde 2004) immunoprecipitation shows that SMG6 is present in complexes that also contain SMG5, SMG7, UPF1, UPF2, Y14, Magoh, and PABP (Kashima et al. 2010). SMG5, SMG6, and SMG7 are therefore represented here together in the same RNP complex. It is possible that some complexes contain only SMG6 or SMG5:SMG7 (reviewed in Nicholson et al. 2010, Muhlemann and Lykke-Andersen 2010). Note that "Smg5/7a" in Chiu et al. 2003 actually refers to SMG6.<br>Phosphorylated UPF1 also inhibits translation initiation by inhibiting conversion of 40S:tRNAmet:mRNA to 80S:tRNAmet:mRNA complexes (Isken et al. 2008) SMG1 Phosphorylates UPF1 (Enhanced by Exon Junction Complex) Authored: May, B, 2010-08-06 EC Number: 2.7.11 Edited: May, B, 2010-08-06 Pubmed11331269 Pubmed11544179 Pubmed14636577 Pubmed16452507 Pubmed19359157 Pubmed19417104 Pubmed20817927 Reactome Database ID Release 43927889 Reactome, http://www.reactome.org ReactomeREACT_75910 Reviewed: Neu-Yilik, G, 2011-05-19 SMG1 phosphorylates UPF1 in vitro and in vivo (Denning et al. 2001, Yamashita et al. 2001, Kashima et al. 2006). Serines 1073, 1078, 1096, and 1116 in isoform 2 (Serines 1084, 1089, 1107, 1127 in isoform 1) are phosphorylated in vitro and phosphorylation at serines 1078 and 1096 has been confirmed in vivo (Yamashita et al. 2001, Ohnishi et al. 2003, Kashima et al. 2006). UPF1 also contains additional serine and threonine residues that could be phosphorylated. SMG8 and SMG9 associate with SMG1 and regulate the kinase activity of SMG1 (Yamashita et al. 2009). The phosphorylation reaction is rate-limiting in nonsense-mediated decay and is therefore regarded as a licensing step (reviewed in Rebbapragada and Lykke-Andersen 2009). Phosphorylation is enhanced by the exon junction complex, which can interact with UPF1 via UPF2 and/or UPF3 (Kashima et al. 2006, Ivanov et al. 2008) or via Y14:Magoh (Ivanov et al. 2008). SMG8 and SMG9 bind SMG1 and regulate its kinase activity (Yamashita et al. 2009, Fernandez et al. 2011). has a Stoichiometric coefficient of 4 Proton-coupled neutral amino acid transporters Authored: Jassal, B, 2009-07-06 Edited: Jassal, B, 2009-07-06 Pubmed12748860 Reactome Database ID Release 43428559 Reactome, http://www.reactome.org ReactomeREACT_19348 Reviewed: He, L, 2009-08-24 The human SLC36A gene family encodes four proton-coupled neutral amino acid transporters, PAT1-4. PAT1 and 2 mediate electroneutral symport of protons and small neutral amino acids like glycine, alanine and proline. PAT3 and 4 are orphans with unknown function (Boll M et al, 2004). Exportin complex translocates pre-miRNA to cytosol Authored: Gopinathrao, G, May, B, 2007-11-18 23:55:40 Edited: May, B, 2009-06-16 Nuclear Export by Exportin-5. The pre-microRNA is bound by the Exportin-5:RanGTP complex in the nucleus and the complex is translocated through the nuclear pore into the cytoplasm. In the process GTP is hydrolyzed to GDP. Pubmed14631048 Pubmed14681208 Pubmed14730017 Reactome Database ID Release 43203906 Reactome, http://www.reactome.org ReactomeREACT_12608 Reviewed: Karginov, F, Hannon, GJ, 2008-02-08 15:41:16 Amino acid transport across the plasma membrane Amino acid transport across plasma membranes is critical to the uptake of these molecules from the gut, to their reabsortion in the kidney proximal tubulues, and to their distribution to cells in which they are required for the synthesis of proteins and of amino acid derived small molecules such as neurotransmitters. Physiological studies have defined 18 "systems" that mediate amino acid transport, each characterized by its amino acid substrates, as well as its pH sensitivity and its association (or not) with ion transport. More recently, molecular cloning studies have allowed the identification of the plasma membrane transport proteins that mediate these reactions. Amino acid uptake mediated by 17 of these transporters is annotated here (Broer 2008). Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 GENE ONTOLOGYGO:0006865 Pubmed18195088 Reactome Database ID Release 43352230 Reactome, http://www.reactome.org ReactomeREACT_13796 Reviewed: Jassal, B, 2008-06-03 13:06:01 Exportin-5 recognizes 3' overhang of pre-miRNA Authored: Gopinathrao, G, May, B, 2007-11-18 23:55:40 Edited: May, B, 2009-06-10 Exportin-5 binds pre-microRNAs having 2-nucleotide overhangs at the 3' end. Binding is independent of sequence and depends on GTP. Pubmed14631048 Pubmed14681208 Pubmed14730017 Reactome Database ID Release 43203922 Reactome, http://www.reactome.org ReactomeREACT_12458 Reviewed: Karginov, F, Hannon, GJ, 2008-02-08 15:41:16 Proton/oligonucleotide cotransporters Authored: Jassal, B, 2009-06-30 Edited: Jassal, B, 2009-06-30 Pubmed12905028 Reactome Database ID Release 43427975 Reactome, http://www.reactome.org ReactomeREACT_19328 Reviewed: He, L, 2009-08-24 The human SLC15 gene family encode four proton-coupled oligopeptide transporters; PEPT1 (SLC15A1), PEPT2 (SLC15A2), PHT2 (SLC15A3) and PHT1 (SLC15A4). These cotransporters are part of the Proton-coupled Oligopeptide Transporter (POT) superfamily (also called Peptide Transporter (PTR) family) (Daniel H and Kottra G, 2004). Microprocessor complex cleaves pri-miRNA to pre-miRNA Authored: Gopinathrao, G, May, B, 2007-11-18 23:55:40 EC Number: 3.1.26.3 Edited: May, B, 2009-06-16 Nuclear processing by Drosha Microprocessor complex. The primary-microRNA (pri-miRNA) is recognized by the Microprocessor complex (Drosha:DGCR8) and both strands of the pri-miRNA are cleaved by Drosha near the free 5' and 3' ends of the pri-miRNA, that is, at the ends distal from the internal loop. The product is a double-stranded RNA having 2 nucleotides protruding at the 3' end and having an internal loop. Pubmed14508493 Pubmed15531877 Pubmed15531879 Pubmed15574589 Reactome Database ID Release 43203893 Reactome, http://www.reactome.org ReactomeREACT_12414 Reviewed: Karginov, F, Hannon, GJ, 2008-02-08 15:41:16 Organic anion transporters Authored: Jassal, B, 2009-07-06 Edited: Jassal, B, 2009-07-06 Pubmed12811560 Pubmed18446519 Reactome Database ID Release 43428643 Reactome, http://www.reactome.org ReactomeREACT_19372 Reviewed: He, L, 2009-08-24 The SLC17 gene family encode proteins which are organic anion transporters. There are three distinct subfamilies within SLC17; vesicular glutamate transporters (VGLUT1-3 encoded by SLC17A7,6 and 8), type I Na+-coupled phosphate co-transporters (encoded by SLC17A1-4) and a proton-coupled sialic acid co-transporter (encoded by SLC17A5) (Reimer RJ and Edwards RH, 2004).<br><br>Two members of the SLC5 gene family encode carboxylate transporters, SMCT1 and SMCT2 (Ganapathy V et al, 2008). Formation of UPF1:eRF3 Complex on mRNA with a Premature Termination Codon and No Exon Junction Complex Authored: May, B, 2010-08-06 Edited: May, B, 2010-08-06 Nonsense-mediated decay of an mRNA can be triggered even if the termination codon does not precede an exon junction (Buhler et al. 2006, Eberle et al. 2008, Silva et al. 2008, Singh et al. 2008, Ivanov et al. 2008). UPF1 and PABP seem to modulate the efficiency of translation termination and PABP in the proximity of a termination codon prevents NMD likely by outcompeting UPF1 for interaction with eRF3 (Singh et al. 2008, Ivanov et al. 2008, Silva et al. 2008). Factors in the competition may be the length and secondary structure of the 3' UTR (Buhler et al. 2006, Eberle et al. 2008). UPF1 preferentially binds some but not all longer UTRs (Hogg and Goff 2010).<br>Interaction of eRF3 with PABP stimulates ribosome dissociation and initiation of a new round of translation on the mRNA. Interaction of eRF3 with UPF1 appears to promote nonsense-mediated decay. It is possible but not yet demonstrated that all components of the SURF complex (SMG1, UPF1, eRF1, eRF3) are assembled on an mRNA without an exon junction complex and that UPF1 is phosphorylated by SMG1. Pubmed16622410 Pubmed18230761 Pubmed18256688 Pubmed18447580 Pubmed18447585 Pubmed21029861 Reactome Database ID Release 43927789 Reactome, http://www.reactome.org ReactomeREACT_75917 Reviewed: Neu-Yilik, G, 2011-05-19 Pyrophosphate hydrolysis Authored: D'Eustachio, P, 2003--0-4- Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0071344 Many biosynthetic reactions are coupled to the cleavage of ATP to yield AMP and pyrophosphate. These reactions are typically freely reversible when carried out with purified substrates and enzymes in vitro. In vivo, however, the pyrophosphate is rapdily and essentially irreversibly hydrolyzed by a ubiquitous inorganic pyrophosphatase. This hydrolysis has the effect of pulling the first reaction strongly in the direction of biosynthesis, at the expense of two high-energy phosphate bonds. Studies of human cells have identified two forms of the enzyme, one localized to the cytosol and the other to the mitochondrial matrix (Raja et al. 1981). Pubmed6120771 Reactome Database ID Release 4371737 Reactome, http://www.reactome.org ReactomeREACT_21259 Amino acid and oligopeptide SLC transporters Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 Eight SLC gene families are involved in the transport of amino acids and oligopeptides. Pubmed19164095 Reactome Database ID Release 43425374 Reactome, http://www.reactome.org ReactomeREACT_19419 Reviewed: He, L, 2009-08-24 Kinesins Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 GENE ONTOLOGYGO:0007018 Kinesins are a superfamily of microtubule-based motor proteins that have diverse functions in transport of vesicles, organelles and chromosomes, and regulate microtubule dynamics. There are 14 families of kinesins, all reprsented in humans. A standardized nomenclature was published in 2004 (Lawrence et al.). Pubmed15479732 Pubmed18626067 Pubmed19851335 Pubmed20930137 Reactome Database ID Release 43983189 Reactome, http://www.reactome.org ReactomeREACT_25201 Reviewed: Ouwehand, WH, 2010-11-12 Dicer cleaves pre-miRNA to yield duplex miRNA Authored: Gopinathrao, G, May, B, 2007-11-18 23:55:40 EC Number: 3.1.26.3 Edited: May, B, 2009-06-10 Pubmed11201747 Pubmed11452083 Pubmed11641272 Pubmed12411504 Pubmed12411505 Pubmed14528307 Pubmed15973356 Pubmed16142218 Pubmed16357216 Pubmed16424907 Pubmed17452327 Pubmed18178619 Pubmed22163034 Reactome Database ID Release 43203862 Reactome, http://www.reactome.org ReactomeREACT_12438 Reviewed: Karginov, F, Hannon, GJ, 2008-02-08 15:41:16 Reviewed: Tomari, Y, 2012-02-10 The pre-miRNA substrate has an internal loop and a protruding 3' end created by cleavage by Drosha:DGCR8. The Dicer:TRBP complex recognizes this structure and the Dicer component cleaves the pre-miRNA near the loop. The product is a double-stranded RNA of 21-25 nucleotides having 2-nucleotide protrusions at each 3' end. The products have 5' phosphates and 3' hydroxyl groups. Proton-coupled monocarboxylate transport Authored: Jassal, B, 2009-08-25 Edited: Jassal, B, 2009-08-25 Pubmed18523892 Pubmed19085840 Reactome Database ID Release 43433692 Reactome, http://www.reactome.org ReactomeREACT_20515 Reviewed: He, L, 2009-11-12 The SLC16A gene family encode proton-linked monocarboxylate transporters (MCT) which mediate the transport of monocarboxylates such as lactate and pyruvate. Monocarboxylates are a major energy source for all cells in the body so their transport in and out of cells is crucial for cellular function. To date, 14 SLC16A members have been identified through sequence homology. Of these 14 members, only seven isoforms have been functionally characterized and not all of these function as proton-coupled transporters. A number can transport diuretics, thyroid hormones and aromatic amino acids. The seven remaining SLC16A members are classed as orphan MCTs (Morris ME and Felmlee MA, 2008; Merezhinskaya N and Fishbein WN, 2009). Sodium-coupled sulphate, di- and tri-carboxylate transporters Authored: Jassal, B, 2009-08-21 Edited: Jassal, B, 2009-08-21 Five human SLC13 genes encode sodium-coupled sulphate, di- and tri-carboxylate transporters located on the plasma membrane. Two transporters (NaS1 and NaS2) co-transport sulphate with sodium. The other members (NaDC1, NaDC3, and NaCT) co-transport sodium with di- and tri-carboxylates such as succinate, citrate and alpha-ketoglutarate (Pajor AM, 2006). Pubmed16211368 Reactome Database ID Release 43433137 Reactome, http://www.reactome.org ReactomeREACT_20646 Reviewed: He, L, 2009-11-12 Bile salt and organic anion SLC transporters Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 Four SLC gene families encode proteins that mediate the transport of bile salts and organic anions; SLC10, SLC13, SLC16 and SLC47 (He L et al, 2009). Pubmed19164095 Reactome Database ID Release 43425471 Reactome, http://www.reactome.org ReactomeREACT_20633 Reviewed: He, L, 2009-11-12 C-terminal EH domain containing proteins Converted from EntitySet in Reactome Reactome DB_ID: 1011595 Reactome Database ID Release 431011595 Reactome, http://www.reactome.org ReactomeREACT_26767 alanine + tRNA(Ala) + ATP => Ala-tRNA(Ala) + AMP + pyrophosphate AARS2 (mitochondrial alanyl tRNA synthetase) catalyzes the reaction of alanine, mitochondrial tRNA(Ala), and ATP to form Ala-tRNA(Ala), AMP, and pyrophosphate. The AARS2 gene has been identified by computational analysis of the human genome sequence; its function has been inferred from those of the biochemically characterized mitochondrial aspartyl and tyrosyl tRNA synthetases (Bonnefond et al. 2005). Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.7 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed15779907 Reactome Database ID Release 43380177 Reactome, http://www.reactome.org ReactomeREACT_15463 Reviewed: Antonellis, A, 2008-12-02 16:58:45 pyrophosphate + H2O => 2 orthophosphate [cytosolic] Cytosolic PPA1 (pyrophosphatase (inorganic) 1) catalyzes the hydrolysis of pyrophosphate to yield two molecules of orthophosphate. The enzyme, a homodimer, requires Mg++ for activity (Fisher et al. 1974; Pynes and Younathan 1967; Thuiller et al. 1978). EC Number: 3.6.1.1 Pubmed4130389 Pubmed6022858 Pubmed656444 Reactome Database ID Release 4371732 Reactome, http://www.reactome.org ReactomeREACT_206 has a Stoichiometric coefficient of 2 glutamine + tRNA(Glu) + ATP => Glu-tRNA(Glu) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.18 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed8078941 QARS (mitochondrial glutaminyl tRNA synthetase) catalyzes the reaction of glutamine, tRNA(Gln), and ATP to form Gln-tRNA(Gln), AMP, and pyrophosphate. The enzyme is a class I tRNA synthetase. The same gene encodes both the cytosolic and mitochondrial QARS enzymes (Lamour et al. 1994). Reactome Database ID Release 43380241 Reactome, http://www.reactome.org ReactomeREACT_15363 Reviewed: Antonellis, A, 2008-12-02 16:58:45 glutamate + tRNA(Glu) + ATP => Glu-tRNA(Glu) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EARS2 (mitochondrial glutamyl tRNA synthetase) catalyzes the reaction of glutamate, mitochondrial tRNA(Glu), and ATP to form Glu-tRNA(Glu), AMP, and pyrophosphate. The EARS2 gene has been identified by computational analysis of the human genome sequence; its function has been inferred from those of the biochemically characterized mitochondrial aspartyl and tyrosyl tRNA synthetases (Bonnefond et al. 2005). EC Number: 6.1.1.17 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed15779907 Reactome Database ID Release 43380216 Reactome, http://www.reactome.org ReactomeREACT_15505 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Formation of Fibrin Clot (Clotting Cascade) Authored: D'Eustachio, P, 2004-08-24 14:00:00 GENE ONTOLOGYGO:0007596 Pubmed12524220 Pubmed1931959 Reactome Database ID Release 43140877 Reactome, http://www.reactome.org ReactomeREACT_2051 The formation of a fibrin clot at the site of an injury to the wall of a normal blood vessel is an essential part of the process to stop blood loss after vascular injury. The reactions that lead to fibrin clot formation are commonly described as a cascade, in which the product of each step is an enzyme or cofactor needed for following reactions to proceed efficiently. The entire clotting cascade can be divided into three portions, the extrinsic pathway, the intrinsic pathway, and the common pathway. The extrinsic pathway begins with the release of tissue factor at the site of vascular injury and leads to the activation of factor X. The intrinsic pathway provides an alternative mechanism for activation of factor X, starting from the activation of factor XII. The common pathway consists of the steps linking the activation of factor X to the formation of a multimeric, cross-linked fibrin clot. Each of these pathways includes not only a cascade of events that generate the catalytic activities needed for clot formation, but also numerous positive and negative regulatory events. histidine + tRNA(His) + ATP => His-tRNA(His) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.21 Edited: D'Eustachio, P, 2008-11-29 15:41:00 HARS2 (mitochondrial histidyl tRNA synthetase) catalyzes the reaction of histidine, mitochondrial tRNA(His), and ATP to form His-tRNA(His), AMP, and pyrophosphate. The enzyme is a class II tRNA synthetase (O'Hanlon et al. 1995). Pubmed7755634 Reactome Database ID Release 43380234 Reactome, http://www.reactome.org ReactomeREACT_15376 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Extrinsic Pathway Authored: D'Eustachio, P, 2004-08-24 14:00:00 Factor VII, the protease that initiates the normal blood clotting cascade, circulates in the blood in both its proenzyme (factor VII) and its activated (factor VIIa) forms. No clotting occurs, however, because neither form of the protein has any catalytic activity when free in solution. Blood clotting is normally initiated when tissue factor (TF), an intrinsic plasma membrane protein, is exposed to the blood by injury to the wall of a blood vessel. TF is then able to bind factor VIIa from plasma, and possibly also factor VII, to form complexes capable of catalyzing the conversion of factor X, from plasma, into its activated form, factor Xa. Factor Xa catalyzes the conversion of additional factor VII molecules to their activated form, increasing the amount of tissue factor:factor VIIa complex available at the site of injury, accelerating the generation of factor Xa, and allowing the activation of factor IXa as well. This process is self-limiting because as levels of factor Xa increase, tissue factor:factor VIIa complexes become trapped in the form of catalytically inactive heterotetramers with factor Xa and the protein TFPI (tissue pathway factor inhibitor). At this point the intinsic pathway, as an independent source of activated factor X, is thought to become critical for the continuation of clot formation (Broze 1995; Mann et al. 2003).<br>The nature of the initial tissue factor:factor VII complexes formed is controversial. One model, building on the observation that the complex of factor VII and TF has low but measurable proteolytic activity on factor X, suggests that this complex begins the activation of factor X, and that as factor VIIa accumulates, tissue factor:factor VIIa complexes also form, accelerating the process (Nemerson 1988). A second model, building on the observation that normal plasma contains low levels of activated factor VII constitutively, suggests that complexes with factor VIIa form immediately at the onset of clotting (Rapaport and Rao 1995). The two models are not mutually exclusive, and in any event, the central roles of tissue factor and factor VIIa in generating an initial supply of factors IXa and Xa, and the self-limiting nature of the process due to the action of TFPI, are all well-established.<br>These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions, and blue lines connect output activated enzymes to the other reactions that they catalyze. GENE ONTOLOGYGO:0007598 Generation of extrinsic Factor X activating complex Pubmed12524220 Pubmed3275472 Pubmed7598447 Pubmed8578528 Reactome Database ID Release 43140834 Reactome, http://www.reactome.org ReactomeREACT_1573 glycine + tRNA(Gly) + ATP => Gly-tRNA(Gly) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.14 Edited: D'Eustachio, P, 2008-11-29 15:41:00 GARS (mitochondrial glycyl tRNA synthetase) catalyzes the reaction of glycine, tRNA(Gly), and ATP to form Gly-tRNA(Gly), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a dimer. Cytosolic and mitochondrial glycyl tRNA synthetase enzymes are both encoded by the same gene; the cytosolic protein lacks an aminoterminal 54-residue sequence found in the mitochondrial protein. Mutations in GARS are associated with Charcot-Marie-Tooth disease (Antonellis et al. 2007). Pubmed12690580 Reactome Database ID Release 43380240 Reactome, http://www.reactome.org ReactomeREACT_15471 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Intrinsic Pathway Authored: D'Eustachio, P, 2004-08-24 14:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0007597 Generation of intrinsic Factor X activating complex Pubmed12231555 Pubmed14691562 Pubmed1931959 Pubmed7598447 Reactome Database ID Release 43140837 Reactome, http://www.reactome.org ReactomeREACT_326 Reviewed: Rush, MG, 2008-01-11 00:00:00 The intrinsic pathway of blood clotting connects interactions among kininogen (high molecular weight kininogen, HK), prekallikrein (PK), and factor XII to the activation of clotting factor X by a series of reactions that is independent of the extrinsic pathway and that is not subject to inhibition by TFPI. It is thus essential for the prolongation of the clotting cascade: while the reactions of the extrinsic pathway appear to be sufficient to initiate clot formation, those of the intrinsic pathway are required to maintain it (Broze 1995; Davie et al. 1991; Monroe et al. 2002). The intrinsic pathway can be divided into three parts: 1) reactions involving interactions of kininogen, prekallikrein, and factor XII, leading to the activation of factor XII, 2) reactions involving factor XI, factor IX, factor VIII, and von Willebrand factor (vWF) leading to the activation of factors VIII and IX, and 3) reactions that inactivate factor XIIa and kallikrein.<p>Kininogen, prekallikrein, and factor XII were first identified as proteins needed for the rapid formation of clots when whole blood is exposed to negatively charged surfaces in vitro. Studies in vitro have identified several possible sets of interactions, in which small quantities of one or more of these proteins 'autoactivate' and then catalyze the formation of larger quantities of activated factors. Recent work, however, suggests that these factors form complexes on endothelial cell surfaces mediated by C1q binding protein (C1q bp), that the first activation event is the cleavage of prekallikrein by prolylcarboxypeptidase, and that the resulting kallikrein catalyzes the activation of factor XII (Schmaier 2004).<p>The second group of events, occurs in vivo on the surfaces of activated platelets (although most biochemical characterization of the reactions was originally done with purified proteins in solution). Factor XI binds to the platelet glycoprotein (GP) Ib:IX:V complex, where it can be activated by cleavage either by thrombin (generated by reactions of the common pathway) or by activated factor XII (generated in the first part of the intrinsic pathway). Activated factor XI in turn catalyzes the activation of factor IX. Simultaneously, factor VIII, complexed with vWF, is cleaved by thrombin, activating it and causing its release from vWF. Activated factors VIII and IX form a complex on the platelet surface that very efficiently converts factor X to activated factor X. (Activated factors X and V then form a complex that efficiently activates thrombin.)<p>While these two groups of events can be viewed as forming a single functional pathway (e.g., Davie et al. 1991), human clinical genetic data cast doubt on this view. Individuals deficient in kininogen, prekallikrein, or factor XII proteins exhibit normal blood clot formation in vivo. In contrast, deficiencies of factor XI can be associated with failure of blood clotting under some conditions, and deficiencies of vWF, factor VIII, or factor IX cause severe abnormalities - von Willebrand disease, hemophilia A, and hemophilia B, respectively. These data suggest that while the second group of events is essential for normal clot formation in vivo, the first group has a different function (e.g., Schmaier 2004).<p>Finally, reactions neutralize proteins activated in the first part of the intrinsic pathway. Kallikrein forms stable complexes with either C1 inhibitor (C1Inh) or with alpha2-macroglobulin, and factor XIIa forms stable complexes with C1Inh. The relevance of these neutralization events to the regulation of blood clotting is unclear, however. The physiological abnormalities observed in individuals who lack C1Inh appear to be due entirely to abnormalities of complement activation; blood clotting appears to proceed normally. This observation is consistent with the hypothesis, above, that factor XIIa plays a limited role in normal blood clotting under physiological conditions.<p>These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions; blue lines connect activated enzymes to the reactions they catalyze. asparagine + tRNA(Asn) + ATP => Asn-tRNA(Asn) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.22 Edited: D'Eustachio, P, 2008-11-29 15:41:00 NARS2 (mitochondrial asparaginyl tRNA synthetase) catalyzes the reaction of asparagine, mitochondrial tRNA(Asn), and ATP to form Asn-tRNA(Asn), AMP, and pyrophosphate. The NARS2 gene has been identified by computational analysis of the human genome sequence; its function has been inferred from those of the biochemically characterized mitochondrial aspartyl and tyrosyl tRNA synthetases (Bonnefond et al. 2005). Pubmed15779907 Reactome Database ID Release 43380227 Reactome, http://www.reactome.org ReactomeREACT_15340 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Common Pathway Authored: D'Eustachio, P, 2004-08-24 14:00:00 GENE ONTOLOGYGO:0007596 Pubmed1931959 Reactome Database ID Release 43140875 Reactome, http://www.reactome.org ReactomeREACT_1439 The common pathway consists of the cascade of activation events leading from the formation of activated factor X to the formation of active thrombin, the cleavage of fibrinogen by thrombin, and the formation of cleaved fibrin into a stable multimeric, cross-linked complex. Thrombin also efficiently catalyzes the activation of several factors required earlier in the clotting cascade, thus acting in effect as a positive regulator of clotting. At the same time, thrombin activates protein C, which in turn catalyzes the inactivation of several of these upstream factors, thereby limiting the clotting process. Thrombin can also be trapped in a stable, inactive complex with antithrombin-3, a circulating blood protein. The quantitative interplay among these positive and negative modulators is critical to the normal regulation of clotting, facilitating the rapid formation of a protective clot at the site of injury, while limiting and physically confining the process.<br>These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions, and blue lines connect output activated enzymes to the other reactions that they catalyze. arginine + tRNA(Arg) + ATP => Arg-tRNA(Arg) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.19 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed17847012 RARS2 (mitochondrial arginyl tRNA synthetase) catalyzes the reaction of arginine, mitochondrial tRNA(Arg), and ATP to form Arg tRNA(Arg), AMP, and pyrophosphate. The enzyme is a class I tRNA synthetase. Homozygosity for <I>RARS2</I> mutations has been associated with pontocerebellar hypoplasia – a disease characterized by a severe reduction in cerebellum and brainstem size (Edvardson et al. 2007). Reactome Database ID Release 43380224 Reactome, http://www.reactome.org ReactomeREACT_15544 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Dissolution of Fibrin Clot Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0042730 Pubmed10853003 Pubmed11460480 Pubmed9330876 Reactome Database ID Release 4375205 Reactome, http://www.reactome.org ReactomeREACT_641 Reviewed: Rush, MG, 2008-01-11 00:00:00 The crosslinked fibrin multimers in a clot are broken down to soluble polypeptides by plasmin, a serine protease. Plasmin can be generated from its inactive precursor plasminogen and recruited to the site of a fibrin clot in two ways, by interaction with tissue plasminogen activator at the surface of a fibrin clot, and by interaction with urokinase plasminogen activator at a cell surface. The first mechanism appears to be the major one responsible for the dissolution of clots within blood vessels. The second, although capable of mediating clot dissolution, may normally play a major role in tissue remodeling, cell migration, and inflammation (Chapman 1997; Lijnen 2001). These other functions of urokinase plasminogen activator will be annotated in future versions of Reactome.<br>Clot dissolution is regulated in two ways. First, efficient plasmin activation and fibrinolysis occur only in complexes formed at the clot surface or on a cell membrane - proteins free in the blood are inefficient catalysts and are rapidly inactivated. Second, both plasminogen activators and plasmin itself are inactivated by specific serpins, proteins that bind to serine proteases to form stable, enzymatically inactive complexes (Kohler and Grant 2000).<br>These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions, and blue lines connect output activated enzymes to the other reactions that they catalyze. cysteine + tRNA(Cys) + ATP => Cys-tRNA(Cys) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 CARS2 (mitochondrial cysteinyl tRNA synthetase) catalyzes the reaction of cysteine, mitochondrial tRNA(Cys), and ATP to form Cys-tRNA(Cys), AMP, and pyrophosphate. The CARS2 gene has been identified by computational analysis of the human genome sequence; its function has been inferred from those of the biochemically characterized mitochondrial aspartyl and tyrosyl tRNA synthetases (Bonnefond et al. 2005). EC Number: 6.1.1.16 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed15779907 Reactome Database ID Release 43380158 Reactome, http://www.reactome.org ReactomeREACT_15359 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Cell surface interactions at the vascular wall Authored: Ouwehand, W.H., 2007-11-12 16:45:54 GENE ONTOLOGYGO:0050900 Leukocyte extravasation is a rigorously controlled process that guides white cell movement from the vascular lumen to sites of tissue inflammation. The powerful adhesive interactions that are required for leukocytes to withstand local flow at the vessel wall is a multistep process mediated by different adhesion molecules. Platelets adhered to injured vessel walls form strong adhesive substrates for leukocytes. For instance, the initial tethering and rolling of leukocytes over the site of injury are mediated by reversible binding of selectins to their cognate cell-surface glycoconjugates.<p> Endothelial cells are tightly connected through various proteins, which regulate the organization of the junctional complex and bind to cytoskeletal proteins or cytoplasmic interaction partners that allow the transfer of intracellular signals. An important role for these junctional proteins in governing the transendothelial migration of leukocytes under normal or inflammatory conditions has been established.<p> This pathway describes some of the key interactions that assist in the process of platelet and leukocyte interaction with the endothelium, in response to injury. Pubmed10798271 Pubmed11282294 Pubmed14615387 Pubmed16115029 Pubmed17525755 Pubmed8578462 Reactome Database ID Release 43202733 Reactome, http://www.reactome.org ReactomeREACT_12051 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 aspartate + tRNA(Asp) + ATP => Asp-tRNA(Asp) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 DARS2 (mitochondrial aspartyl tRNA synthetase) catalyzes the reaction of aspartate, mitochondrial tRNA(Asp), and ATP to form Asp tRNA(Asp), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a homodimer (Bonnefond et al. 2005). Homozygosity for <I>DARS2</I> mutations is associated with leukoencephalopathy with brainstem and spinal cord involvement plus lactate elevation (Scheper et al 2007). EC Number: 6.1.1.12 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed15779907 Pubmed17384640 Reactome Database ID Release 43380229 Reactome, http://www.reactome.org ReactomeREACT_15437 Reviewed: Antonellis, A, 2008-12-02 16:58:45 PECAM1 interactions Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 PECAM-1/CD31 is a member of the immunoglobulin superfamily (IgSF) and has been implicated to mediate the adhesion and trans-endothelial migration of T-lymphocytes into the vascular wall, T cell activation and angiogenesis. It has six Ig homology domains within its extracellularly and an ITIM motif within its cytoplasmic region. PECAM-1 mediates cellular interactions by both homophilic and heterophilic interactions. The cytoplasmic domain of PECAM-1 contains tyrosine residues which serves as docking sites for recruitment of cytosolic signaling molecules. Under conditions of platelet activation, PECAM-1 is phosphorylated by Src kinase members. The tyrosine residues 663 and 686 are required for recruitment of the SH2 domain containing PTPs. Pubmed12681475 Pubmed14619965 Reactome Database ID Release 43210990 Reactome, http://www.reactome.org ReactomeREACT_12519 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Tie2 Signaling Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Pubmed11191051 Pubmed11566266 Pubmed11969368 Pubmed9764820 Reactome Database ID Release 43210993 Reactome, http://www.reactome.org ReactomeREACT_12621 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The Tie2/Tek receptor tyrosine kinase plays a pivotal role in vascular and hematopoietic development and is expressed exclusively on endothelial lineage. Tie2 interacts with a group of ligands belonging to angiopoietin family and undergoes activation.<br>These ligands show opposing actions, angiopoietin 1 and angiopoietin 4 stimulate the Tie2 phosphorylation and angiopoietin 2 inhibits it. Upon tyrosine phosphorylation Tie2 acts as a scaffold for various signaling proteins involved in different signal transduction cascades that can effect survival of endothelium and angiogenic sprout formation. Factors involved in megakaryocyte development and platelet production Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Megakaryocytes (MKs) give rise to circulating platelets (thrombocytes) through terminal differentiation of MKs which release cytoplasmic fragments as circulating platelets. As MKs mature they undergo endoreduplication (polyploidisation) and expansion of cytoplasmic mass to cell sizes larger than 50-100 microns, and ploidy ranges up to 128 N. As MK's mature, the polyploid nucleus becomes horseshoe-shaped, the cytoplasm expands, and platelet organelles and the demarcation membrane system are amplified. Proplatelet projections form which give rise to de novo circulating platelets (Deutsch & Tomer 2006). <br>The processes of megakaryocytopoiesis and platelet production occur within a complex microenvironment where chemokines, cytokines and adhesive interactions play major roles (Avecilla et al. 2004). Megakaryocytopoiesis is regulated at several levels including proliferation, differentiation and platelet release (Kaushansky 2003). Thrombopoietin (TPO/c-Mpl ligand) is the most potent cytokine stimulating proliferation and maturation of MK progenitors (Kaushansky 2005) but many other growth factors are involved. MK development is controlled by the action of multiple Transcriptin Factors, many MK-specific genes are co-regulated by GATA and friend of GATA (FOG), RUNX1 and ETS proteins. Nuclear factor erythroid 2 (NF-E2) which has an MK-erythroid specific 45-kDa subunit controls terminal MK maturation, proplatelet formation and platelet release (Schulze & Shivdasani 2004). NF-E2 deficient mice have profound thrombocytopenia (Shiraga et al. 1999). c-myb functions with p300 as a negative regulator of thrombopoiesis (Metcalf et al. 2005). During MK maturation, internal membrane systems, granules and organelles are assembled. Cytoplasmic fragmentation requires changes in the MK cytoskeleton and formation of organelles and channels. Individual organelles migrate from the cell body to the proplatelet ends, with approximately 30 percent of organelles/granules in motion at any given time (Richardson et al. 2005). Pubmed10613901 Pubmed12871295 Pubmed14702636 Pubmed15354260 Pubmed15665109 Pubmed16118320 Pubmed16322778 Pubmed16856888 Pubmed17635743 Pubmed17934486 Reactome Database ID Release 43983231 Reactome, http://www.reactome.org ReactomeREACT_24970 Reviewed: Ouwehand, WH, 2010-11-12 SH2B family Converted from EntitySet in Reactome Reactome DB_ID: 997265 Reactome Database ID Release 43997265 Reactome, http://www.reactome.org ReactomeREACT_26906 Basigin interactions Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Basigin is a widely expressed transmembrane glycoprotein that belongs to the Ig superfamily and is highly enriched on the surface of epithelial cells. Basigin is involved in intercellular interactions involved in various immunologic phenomena, differentiation, and development, but a major function of basigin is stimulation of synthesis of several matrix metalloproteinases. Basigin also induces angiogenesis via stimulation of VEGF production.<br>Basigin has an extracellular region with two Ig-like domains of which the N-term Ig-like domain is involved in interactions. It undergoes interactions between basigin molecules on opposing cells or on neighbouring cells. It also interacts with a variety of other proteins like caveolin-1, cyclophilins, integrins and annexin II that play important roles in cell proliferation, energy metabolism, migration, adhesion and motion, especially in cancer metastasis. Edited: Garapati, P V, 2009-03-16 17:55:42 Pubmed17700972 Reactome Database ID Release 43210991 Reactome, http://www.reactome.org ReactomeREACT_12560 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 valine + tRNA(Val) + ATP => Val-tRNA(Val) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.9 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed8428657 Reactome Database ID Release 43380042 Reactome, http://www.reactome.org ReactomeREACT_15329 Reviewed: Antonellis, A, 2008-12-02 16:58:45 VARS (cytosolic valyl tRNA synthetase) catalyzes the reaction of valine, tRNA(Val), and ATP to form Val-tRNA(Val), AMP, and pyrophosphate. The enzyme is a class I tRNA synthetase (Vilalta et al. 1993). Small Maf family members Converted from EntitySet in Reactome Reactome DB_ID: 1008234 Reactome Database ID Release 431008234 Reactome, http://www.reactome.org ReactomeREACT_25969 lysine + tRNA(Lys) + ATP => Lys-tRNA(Lys) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.6 Edited: D'Eustachio, P, 2008-11-29 15:41:00 KARS (mitochondrial lysyl tRNA synthetase) catalyzes the reaction of lysine, tRNA(Lys), and ATP to form Lys-tRNA(Lys), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a homodimer. The same gene encodes both cytosolic and mitochondrial KARS enzymes (Shiba et al. 1997). Pubmed9278442 Reactome Database ID Release 43380233 Reactome, http://www.reactome.org ReactomeREACT_15537 Reviewed: Antonellis, A, 2008-12-02 16:58:45 leucine + tRNA(Leu) + ATP => Leu-tRNA(Leu) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.4 Edited: D'Eustachio, P, 2008-11-29 15:41:00 LARS2 (mitochondrial leucyl tRNA synthetase) catalyzes the reaction of leucine, mitochondrial tRNA(Leu), and ATP to form Leu-tRNA(Leu), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is a monomer (Bullard et al. 2000). Pubmed10684970 Reactome Database ID Release 43380200 Reactome, http://www.reactome.org ReactomeREACT_15357 Reviewed: Antonellis, A, 2008-12-02 16:58:45 isoleucine + tRNA(Ile) + ATP => Ile-tRNA(Ile) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.5 Edited: D'Eustachio, P, 2008-11-29 15:41:00 IARS2 (mitochondrial isoleucyl tRNA synthetase) catalyzes the reaction of isoleucine, mitochondrial tRNA(Ile), and ATP to form Ile-tRNA(Ile), AMP, and pyrophosphate. The enzyme is a class I tRNA synthetase (Degoul et al. 1995). Pubmed9466989 Reactome Database ID Release 43380176 Reactome, http://www.reactome.org ReactomeREACT_15423 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Platelet Aggregation (Plug Formation) Authored: de Bono, B, 2004-08-13 07:29:26 Pubmed17585075 Pubmed18174460 Reactome Database ID Release 4376009 Reactome, http://www.reactome.org ReactomeREACT_278 The tethering of platelets to the site of vascular injury is the first step in the formation of a platelet thrombus. Firm adhesion of these tethered platelets, as well as the additional recruitment of others onto their surface leads to the formation of large platelet aggregates. The formation of a thrombus is strictly dependent on the formation of interplatelet bonds. tyrosine + tRNA(Tyr) + ATP => Tyr-tRNA(Tyr) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.1 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed15779907 Reactome Database ID Release 43380170 Reactome, http://www.reactome.org ReactomeREACT_15351 Reviewed: Antonellis, A, 2008-12-02 16:58:45 YARS2 (mitochondrial tyrosyl tRNA synthetase) catalyzes the reaction of tyrosine, mitochondrial tRNA(Tyr), and ATP to form Tyr-tRNA(Tyr), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is a homodimer (Bonnefond et al. 2005). tryptophan + tRNA(Trp) + ATP => Trp-tRNA(Trp) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.2 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed10828066 Reactome Database ID Release 43380222 Reactome, http://www.reactome.org ReactomeREACT_15343 Reviewed: Antonellis, A, 2008-12-02 16:58:45 WARS2 (mitochondrial tryptophanyl tRNA synthetase) catalyzes the reaction of tryptophan, mitochondrial tRNA(Trp), and ATP to form Trp-tRNA(Trp), AMP, and pyrophosphate. The enzyme is a class I tRNA synthetase (Jorgensen et al. 2000). threonine + tRNA(Thr) + ATP => Thr-tRNA(Thr) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.3 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed15779907 Reactome Database ID Release 43380201 Reactome, http://www.reactome.org ReactomeREACT_15330 Reviewed: Antonellis, A, 2008-12-02 16:58:45 TARS2 (mitochondrial threonyl tRNA synthetase) catalyzes the reaction of threonine, mitochondrial tRNA(Thr), and ATP to form Thr-tRNA(Thr), AMP, and pyrophosphate. The TARS2 gene has been identified by computational analysis of the human genome sequence; its function has been inferred from those of the biochemically characterized mitochondrial aspartyl and tyrosyl tRNA synthetases (Bonnefond et al. 2005). p130Cas linkage to MAPK signaling for integrins Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Integrin signaling is linked to the MAP kinase pathway by recruiting p130cas and Crk to the FAK/Src activation complex. Reactome Database ID Release 43372708 Reactome, http://www.reactome.org ReactomeREACT_15381 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 serine + tRNA(Ser) + ATP => Ser-tRNA(Ser) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.11 Edited: D'Eustachio, P, 2008-11-29 15:41:00 Pubmed10764807 Reactome Database ID Release 43380239 Reactome, http://www.reactome.org ReactomeREACT_15501 Reviewed: Antonellis, A, 2008-12-02 16:58:45 SARS2 (mitochondrial seryl tRNA synthetase) catalyzes the reaction of serine, mitochondrial tRNA(Ser), and ATP to form Ser-tRNA(Ser), AMP, and pyrophosphate. SARS2 is a class II tRNA synthetase inferred from the biochemical properties of its bovine homologue to function as a dimer (Yokogawa et al. 2000). Adrenaline signalling through Alpha-2 adrenergic receptor Adrenaline (epinephrine) signalling via the alpha-2 adrenergic receptor has many effects including inhibition of insulin release in pancreas, iinduction of glucagon release from pancreas, contraction of sphincters of the gastrointestinal tract, negative feedback processes in neuronal synapses and stimulation of platelet aggregation. This receptor preferentially couples to members of the Gi class of heterotrimeric G-proteins, leading to inhibition af adenylate cyclase and thereby decreased cAMP levels. Authored: Jupe, S, 2009-02-26 15:48:59 Edited: Jupe, S, 2009-09-10 Pubmed10636873 Pubmed2823383 Pubmed8099279 Reactome Database ID Release 43392023 Reactome, http://www.reactome.org ReactomeREACT_19180 Reviewed: Akkerman, JW, 2009-09-04 proline + tRNA(Pro) + ATP => Pro-tRNA(Pro) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.15 Edited: D'Eustachio, P, 2008-11-29 15:41:00 PARS2 (mitochondrial prolyl tRNA synthetase) catalyzes the reaction of proline, mitochondrial tRNA(Pro), and ATP to form Pro-tRNA(Pro), AMP, and pyrophosphate. The PARS2 gene has been identified by computational analysis of the human genome sequence; its function has been inferred from those of the biochemically characterized mitochondrial aspartyl and tyrosyl tRNA synthetases (Bonnefond et al. 2005). Pubmed15779907 Reactome Database ID Release 43380198 Reactome, http://www.reactome.org ReactomeREACT_15310 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Integrin alphaIIb beta3 signaling At the sites of vascular injury bioactive molecules such as thrombin, ADP, collagen, fibrinogen and thrombospondin are generated, secreted or exposed. These stimuli activate platelets, converting the major platelet integrin alphaIIbbeta3 from a resting state to an active conformation, in a process termed integrin priming or ‘inside-out signalling’. Integrin activation refers to the change required to enhance ligand-binding activity. The activated alphaIIbbeta3 interacts with the fibrinogen and links platelets together in an aggregate to form a platelet plug. AlphaIIbbeta3 bound to fibrin generates more intracellular signals (outside-in signalling), causing further platelet activation and platelet-plug retraction. <br>In the resting state the alpha and beta tails are close together. This interaction keeps the membrane proximal regions in a bent conformation that maintains alphaIIbbeta3 in a low affinity state. <br>Integrin alphaIIbbeta3 is released from its inactive state by interaction with the protein talin. Talin interacts with the beta3 cytoplasmic domain and disrupts the salt bridge between the alpha and beta chains. This separation in the cytoplasmic regions triggers the conformational change in the extracellular domain that increases its affinity to fibrinogen. <br>Much of talin exists in an inactive cytosolic pool, and the Rap1 interacting adaptor molecule (RIAM) is implicated in talin activation and translocation to beta3 integrin cytoplasmic domain.<br> Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:13:06 Pubmed10508650 Pubmed10605720 Pubmed14754902 Pubmed15205259 Pubmed16102042 Pubmed17624957 Reactome Database ID Release 43354192 Reactome, http://www.reactome.org ReactomeREACT_15523 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 phenylalanine + tRNA(Phe) + ATP => Phe-tRNA(Phe) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.20 Edited: D'Eustachio, P, 2008-11-29 15:41:00 FARS2 (mitochondrial phenylalanyl tRNA synthetase) catalyzes the reaction of phenylalanine, mitochondrial tRNA(Phe), and ATP to form Phe-tRNA(Phe), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a monomer (Bullard et al. 1999). Pubmed10329163 Reactome Database ID Release 43380203 Reactome, http://www.reactome.org ReactomeREACT_15462 Reviewed: Antonellis, A, 2008-12-02 16:58:45 GRB2:SOS provides linkage to MAPK signaling for Intergrins Authored: Garapati, P V, 2008-06-16 17:13:06 Edited: Garapati, P V, 2008-06-16 17:32:15 Integrin signaling is linked to the MAP kinase pathway by recruiting Grb2 to the FADK1/SRC activation complex. Pubmed12005431 Pubmed7997267 Pubmed9566877 Reactome Database ID Release 43354194 Reactome, http://www.reactome.org ReactomeREACT_15443 Reviewed: Shattil, SJ, 2008-09-16 06:21:39 methionine + tRNA(Met) + ATP => Met-tRNA(Met) + AMP + pyrophosphate Authored: D'Eustachio, P, 2008-11-29 15:41:00 EC Number: 6.1.1.10 Edited: D'Eustachio, P, 2008-11-29 15:41:00 MARS2 (mitochondrial methionyl tRNA synthetase) catalyzes the reaction of methionine, mitochondrial tRNA(Met), and ATP to form Met-tRNA(Met), AMP, and pyrophosphate. The enzyme, a class I tRNA synthetase, is a monomer (Spencer et al. 2004). Pubmed15274629 Reactome Database ID Release 43380157 Reactome, http://www.reactome.org ReactomeREACT_15446 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Disinhibition of SNARE formation Reactome Database ID Release 43114516 Reactome, http://www.reactome.org ReactomeREACT_1178 Response to elevated platelet cytosolic Ca2+ Activation of phospholipase C enzymes results in the generation of second messengers of the phosphatidylinositol pathway. The events resulting from this pathway are a rise in intracellular calcium and activation of Protein Kinase C (PKC). Phospholipase C cleaves the phosphodiester bond in PIP2 to form 1,2 Diacylglycerol (DAG) and 1,4,5-inositol trisphosphate (IP3). IP3 opens Ca2+ channels in the platelet dense tubular system, raising intracellular Ca2+ levels. DAG is a second messenger that regulates a family of Ser/Thr kinases consisting of PKC isozymes (Nishizuka 1995). DAG achieves activation of PKC isozymes by increasing their affinity for phospholipid. Most PKC enzymes are also calcium-dependent, so their activation is in synergy with the rise in intracellular Ca2+. Platelets contain several PKC isoforms that can be activated by DAG and/or Ca2+ (Chang 1997). Authored: de Bono, B, 2004-08-13 07:29:26 Pubmed8424766 Reactome Database ID Release 4376005 Reactome, http://www.reactome.org ReactomeREACT_1280 Arachidonate production from DAG Authored: Jupe, S, 2009-06-11 Diacylglycerol (DAG) is an important source of arachidonic acid, a signalling molecule and the precursor of the prostaglandins. In human platelet almost all the DAG produced from phosphatidylinositol degradation contains arachidonate (Takamura et al. 1987). DAG is hydrolysed by DAG lipase to 2-arachidonylglycerol (2-AG) which is further hydrolysed by monoacylglycerol lipase. 2-AG is an agonist of cannabinoid receptor 1. Edited: Jupe, S, 2009-09-09 Pubmed11588122 Pubmed3102469 Pubmed6788766 Pubmed7295321 Reactome Database ID Release 43426048 Reactome, http://www.reactome.org ReactomeREACT_19308 Reviewed: Akkerman, JW, 2009-09-04 Effects of PIP2 hydrolysis Edited: Jupe, S, 2009-09-09 Hydrolysis of phosphatidyl inositol-bisphosphate (PIP2) by phospholipase C (PLC) produces diacylglycerol (DAG) and inositol triphosphate (IP3). Both are potent second messengers. IP3 diffuses into the cytosol, but as DAG is a hydrophobic lipid it remains within the plasma membrane. IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, while DAG activates the conventional and unconventional protein kinase C (PKC) isoforms, facilitating the translocation of PKC from the cytosol to the plasma membrane. The effects of DAG are mimicked by tumor-promoting phorbol esters. DAG is also a precursor for the biosynthesis of prostaglandins, the endocannabinoid 2-arachidonoylglycerol and an activator of a subfamily of TRP-C (Transient Receptor Potential Canonical) cation channels 3, 6, and 7. Pubmed17157506 Pubmed9601053 Reactome Database ID Release 43114508 Reactome, http://www.reactome.org ReactomeREACT_2202 Platelet degranulation GENE ONTOLOGYGO:0002576 Platelets function as exocytotic cells, secreting a plethora of effector molecules at sites of vascular injury. Platelets contain a number of distinguishable storage granules including alpha granules, dense granules and lysosomes. On activation platelets release a variety of proteins, largely from storage granules but also as the result of apparent cell lysis. These act in an autocrine or paracrine fashion to modulate cell signaling. <br><br><br> Alpha granules contain mainly polypeptides such as fibrinogen, von Willebrand factor, growth factors and protease inhibitors that that supplement thrombin generation at the site of injury. Dense granules contain small molecules, particularly adenosine diphosphate (ADP), adenosine triphosphate (ATP), serotonin and calcium, all recruit platelets to the site of injury. Pubmed14630798 Reactome Database ID Release 43114608 Reactome, http://www.reactome.org ReactomeREACT_318 ZFPM1, ZFPM2 Converted from EntitySet in Reactome Reactome DB_ID: 996742 Reactome Database ID Release 43996742 Reactome, http://www.reactome.org ReactomeREACT_25560 ACTIVATION GENE ONTOLOGYGO:0004165 Reactome Database ID Release 43109984 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4377275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4377282 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4377275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050633 Reactome Database ID Release 4377268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4377282 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050633 Reactome Database ID Release 4377268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377336 Reactome, http://www.reactome.org Iodotyrosine dehalogenase Converted from EntitySet in Reactome Reactome DB_ID: 209947 Reactome Database ID Release 43209947 Reactome, http://www.reactome.org ReactomeREACT_15644 ACTIVATION GENE ONTOLOGYGO:0016651 Reactome Database ID Release 43109993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4371061 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050633 Reactome Database ID Release 4377268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377317 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4371049 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4371061 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050633 Reactome Database ID Release 4377268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4371061 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377317 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4371049 Reactome, http://www.reactome.org TPO Converted from EntitySet in Reactome Reactome DB_ID: 209836 Reactome Database ID Release 43209836 Reactome, http://www.reactome.org ReactomeREACT_15659 Thyroid peroxidase ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4371049 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4371061 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050633 Reactome Database ID Release 4377268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377336 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4371049 Reactome, http://www.reactome.org OAZ Converted from EntitySet in Reactome Ornithine Decarboxylase antizymes Reactome DB_ID: 350592 Reactome Database ID Release 43350592 Reactome, http://www.reactome.org ReactomeREACT_14433 ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4371061 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050633 Reactome Database ID Release 4377268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377336 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4371049 Reactome, http://www.reactome.org Tyrosine 3-hydroxylase Converted from EntitySet in Reactome Reactome DB_ID: 209893 Reactome Database ID Release 43209893 Reactome, http://www.reactome.org ReactomeREACT_15823 Tyrosine 3-monooxygenase ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377280 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4377275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004144 Reactome Database ID Release 4376102 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004144 Reactome Database ID Release 43549191 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4377259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4377275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4377282 Reactome, http://www.reactome.org Spermidine Oxidase (SMOX) Converted from EntitySet in Reactome Reactome DB_ID: 353585 Reactome Database ID Release 43353585 Reactome, http://www.reactome.org ReactomeREACT_14616 ACTIVATION GENE ONTOLOGYGO:0050633 Reactome Database ID Release 4377268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4377282 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050633 Reactome Database ID Release 4377268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431500600 Reactome, http://www.reactome.org Assembly of the pre-replicative complex Authored: Davey, MJ, O'Donnell, M, Tye, BK, 2006-03-17 16:01:39 DNA replication pre-initiation in eukaryotic cells begins with the formation of the pre-replicative complex (pre-RC) during the late M phase and continues in the G1 phase of the mitotic cell cycle, a process also called DNA replication origin licensing. The association of initiation proteins (ORC, Cdc6, Cdt1, Mcm2-7) with the origin of replication in both <i>S. cerevisiae</i> and humans has been demonstrated by chromatin immunoprecipitation experiments. In <i>S. cerevisiae</i>, pre-replicative complexes are assembled from late M to G1. In mammalian cells as well, pre-replicative complexes are assembled from late M to G1, as shown by biochemical fractionation and immunostaining. There are significant sequence similarities among some of the proteins in the pre-replicative complex. The ORC subunits Orc1, Orc4 and Orc5 are homologous to one another and to Cdc6. The six subunits of the Mcm2-7 complex are homologous to one another. In addition, Orc1, Orc4, Orc5, Cdc6, and the Mcm2-7 subunits, are members of the AAA+ superfamily of ATPases. Since the initial identification of these pre-RC components other factors that participate in this complex have been found, including Cdt1 in human, <i>Xenopus</i>, <i>S. pombe</i>, and <i>S. cerevisiae</i> cells. Pubmed11046155 Pubmed11801723 Pubmed9288745 Pubmed9335335 Pubmed9407030 Pubmed9829972 Pubmed9927482 Reactome Database ID Release 4368867 Reactome, http://www.reactome.org ReactomeREACT_2243 ACTIVATION GENE ONTOLOGYGO:0004366 Reactome Database ID Release 4376113 Reactome, http://www.reactome.org DNA Replication Pre-Initiation Although, DNA replication occurs in the S phase of the cell cycle, the formation of the DNA replication pre-initiation complex begins during G1 phase. Authored: Davey, MJ, O'Donnell, M, Tye, BK, 2006-03-17 16:01:39 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Reactome Database ID Release 4369002 Reactome, http://www.reactome.org ReactomeREACT_734 M/G1 Transition Finally, progression out of mitosis and division of the cell into two daughters (cytokinesis) requires the inactivation of Cyclin B - Cdc2 by ubiquitin-dependent proteolysis of Cyclin A and B, which is regulated by a large E3 ubiquitin ligase complex known as the Anaphase Promoting Complex (APC).<p>The detailed annotation of the M/G1 transition will be completed in a later version of GK. GENE ONTOLOGYGO:0000216 Reactome Database ID Release 4368874 Reactome, http://www.reactome.org ReactomeREACT_1725 Reviewed: Manfredi, J, 0000-00-00 00:00:00 ACTIVATION GENE ONTOLOGYGO:0008195 Reactome Database ID Release 43549156 Reactome, http://www.reactome.org DNA Replication Authored: Bambara, RA, Catlett, M, Davey, MJ, Forsburg, S, O'Donnell, M, Tom, S, Tye, BK, 2003-01-06 00:00:00 Edited: D'Eustachio, P, Joshi-Tope, G, Nickerson, E, 0000-00-00 00:00:00 Pubmed10966477 Pubmed11257218 Pubmed12045100 Pubmed1536007 Pubmed1579437 Pubmed8223461 Reactome Database ID Release 4369306 Reactome, http://www.reactome.org ReactomeREACT_383 Reviewed: Mendez, J, Aladjem, M, 0000-00-00 00:00:00 Studies in the past decade have suggested that the basic mechanism of DNA replication initiation is conserved in all kingdoms of life. Initiation in unicellular eukaryotes, in particular Saccharomyces cerevisiae (budding yeast), is well understood, and has served as a model for studies of DNA replication initiation in multicellular eukaryotes, including humans. In general terms, the first step of initiation is the binding of the replication initiator to the origin of replication. The replicative helicase is then assembled onto the origin, usually by a helicase assembly factor. Either shortly before or shortly after helicase assembly, some local unwinding of the origin of replication occurs in a region rich in adenine and thymine bases (often termed a DNA unwinding element, DUE). The unwound region provides the substrate for primer synthesis and initiation of DNA replication. The best-defined eukaryotic origins are those of S. cerevisiae, which have well-conserved sequence elements for initiator binding, DNA unwinding and binding of accessory proteins. In multicellular eukaryotes, unlike S. cerevisiae, these loci appear not to be defined by the presence of a DNA sequence motif. Indeed, choice of replication origins in a multicellular eukaryote may vary with developmental stage and tissue type. In cell-free models of metazoan DNA replication, such as the one provided by Xenopus egg extracts, there are only limited DNA sequence specificity requirements for replication initiation (Kelly & Brown 2000; Bell & Dutta 2002; Marahrens & Stillman 1992; Cimbora & Groudine 2001; Mahbubani et al 1992, Hyrien & Mechali 1993). ACTIVATION GENE ONTOLOGYGO:0004367 Reactome Database ID Release 431500607 Reactome, http://www.reactome.org snRNP Assembly Authored: Gillespie, ME, 2007-01-29 20:29:54 GENE ONTOLOGYGO:0000387 Pubmed15130578 Reactome Database ID Release 43191859 Reactome, http://www.reactome.org ReactomeREACT_11066 Reviewed: Luhrmann, R, 2007-04-30 18:31:22 Small nuclear ribonucleoproteins (snRNPs) are crucial for pre-mRNA processing to mRNAs. Each snRNP contains a small nuclear RNA (snRNA) and an extremely stable core of seven Sm proteins. The U6 snRNA differs from the other snRNAs; it binds seven Sm-like proteins and its assembly does not involve a cytoplasmic phase. The snRNP biogenesis pathway for all of the other snRNAs is complex, involving nuclear export of snRNA, Sm-core assembly in the cytoplasm and re-import of the mature snRNP. The assembly of the snRNA:Sm-core is carried out by the survival of motor neurons (SMN) complex. The SMN complex stringently scrutinizes RNAs for specific features that define them as snRNAs and binds the RNA-binding Sm proteins. ACTIVATION GENE ONTOLOGYGO:0017099 Reactome Database ID Release 43548793 Reactome, http://www.reactome.org Non-coding RNA Metabolism GENE ONTOLOGYGO:0034660 Metabolism of non-coding RNA Reactome Database ID Release 43194441 Reactome, http://www.reactome.org ReactomeREACT_11052 The term non-coding is commonly employed for RNA that does not encode a protein, but this does not mean that such RNAs do not contain information nor have function. There is considerable evidence that the majority of mammalian and other complex organism's genomes is transcribed into non-coding RNAs, many of which are alternatively spliced and/or processed into smaller products. Around 98% of all transcriptional output in humans is non-coding RNA. RNA-mediated gene regulation is widespread in higher eukaryotes and complex genetic phenomena like RNA interference are mediated by such RNAs. These non-coding RNAs are a growing list and include rRNAs, tRNAs, snRNAs, snoRNAs siRNAs, 7SL RNA, 7SK RNA, the RNA component of RNase P RNA, the RNA component of RNase MRP, and the RNA component of telomerase. ACTIVATION GENE ONTOLOGYGO:0004366 Reactome Database ID Release 431500613 Reactome, http://www.reactome.org Eukaryotic Translation Termination Authored: Bedwell, DM, 2004-11-09 15:40:58 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006415 Pubmed15314182 Pubmed2684966 Reactome Database ID Release 4372764 Reactome, http://www.reactome.org ReactomeREACT_1986 The arrival of any of the three stop codons (UAA, UAG and UGA) into the ribosomal A-site triggers the binding of a release factor (RF) to the ribosome and subsequent polypeptide chain release. In eukaryotes, the RF is composed of two proteins, eRF1 and eRF3. eRF1 is responsible for the hydrolysis of the peptidyl-tRNA, while eRF3 provides a GTP-dependent function. The ribosome releases the mRNA and dissociates into its two complex subunits, which can reassemble on another molecule to begin a new round of protein synthesis. It should be noted that at present, there is no factor identified in eukaryotes that would be the functional equivalent of the bacterial ribosome release (or recycling) factor, RRF, that catalyzes dissociation of the ribosome from the mRNA following release of the polypeptide ACTIVATION GENE ONTOLOGYGO:0004370 Reactome Database ID Release 4376115 Reactome, http://www.reactome.org Peptide chain elongation Authored: Gopinathrao, G, 2005-03-13 01:37:39 Pubmed12297040 Reactome Database ID Release 43156902 Reactome, http://www.reactome.org ReactomeREACT_1404 The mechanism of a peptide bond requires the movement of three protons. First the deprotonation of the ammonium ion generates a reactive amine, allowing a nucleophilic attack on the carbonyl group. This is followed by the loss of a proton from the reaction intermediate, only to be taken up by the oxygen on the leaving group (from the end of the amino acid chain bound to the tRNA in the P-site). The peptide bond formation results in the net loss of one water molecule, leaving a deacylated-tRNA in the P-site, and a nascent polypeptide chain one amino acid larger in the A-site.<br>For the purpose of illustration, the figures used in the section show one amino acid being added to a peptidyl-tRNA with a growing peptide chain.<br> ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548807 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016508 Reactome Database ID Release 43548839 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016509 Reactome Database ID Release 43548828 Reactome, http://www.reactome.org CDC6 association with the ORC:origin complex Authored: Davey, MJ, O'Donnell, M, Tye, BK, 2006-03-17 16:01:39 Cdc6 is a regulator of DNA replication initiation in both yeasts and human cells, but its mechanism of action differs between the two systems. Genetic studies in budding yeast (S. cerevisiae) and fission yeast (S. pombe) indicate that the normal function of Cdc6 protein is required to restrict DNA replication to once per cell cycle. Specifically, Cdc6 may function as an ATPase switch linked to Mcm2-7 association with the Cdt1:Cdc6:ORC:origin complex. In S. cerevisiae, Cdc6 protein is expressed late in the M phase of the cell cycle and, in cells with a prolonged G1 phase, late in G1. This protein has a short half-life, and is destroyed by ubiquitin-mediated proteolysis, mediated by the SCF complex. Human Cdc6 protein levels are reduced early in G1 but otherwise are constant throughout the cell cycle. Some reports have suggested that after cells enter S phase, Cdc6 is phosphorylated, excluded from the nucleus and subject to ubiquitination and degradation. Replenishing Cdc6 protein levels during G1 appears to be regulated by E2F transcription factors. Pubmed10339564 Pubmed10712901 Pubmed10801458 Pubmed10995389 Pubmed11046155 Pubmed11532947 Pubmed7641697 Pubmed9312054 Pubmed9520412 Pubmed9566895 Pubmed9889196 Reactome Database ID Release 4368689 Reactome, http://www.reactome.org ReactomeREACT_1707 Assembly of the ORC complex at the origin of replication Authored: Davey, MJ, O'Donnell, M, 2003-06-05 08:03:13 In Saccharomyces cerevisiae, the entire ORC complex is constitutively bound to the origin of replication. However, in mammalian cells, Orc1, and possibly other Orc subunits, dissociate from origins of replication, while Orc2 remains stably associated with chromatin across the cell cycle. The first step in formation of the pre-RC is assembly of the hexameric Origin Recognition Complex (ORC) at the origin of replication. Recent work on human (Hs) ORC has suggested that the heterohexamer assembles in an ordered manner. HsOrc2 appears to be constitutively bound to origins of replication. HsOrc2 and HsOrc3 form a complex that interacts with HsOrc4 and HsOrc5. Recruitment of HsOrc5 into the complex is important for the association of HsOrc1. HsOrc6 is also capable of interacting with the core HsOrc2:3:4:5 complex, but not smaller complexes. Interestingly, HsOrc1 and a subunit of the Mcm2-7 complex (HsMcm2) interact with a histone acetyltransferase, HsHBO1 (Bell & Stillman 1992; Diffley et al. 1994; Lee & Bell 1997; Wenger et al. 1975; Li & DePamphili;s 2001; Dhar et al. 2001; Vashee et al, 2001; Iizuka & Stillman 1999 Burke et al. 2001). Pubmed10438470 Pubmed1110244 Pubmed11278932 Pubmed11323433 Pubmed11395502 Pubmed11739726 Pubmed1579162 Pubmed8044842 Pubmed9372948 Reactome Database ID Release 4368616 Reactome, http://www.reactome.org ReactomeREACT_567 'Mg2+ [nucleoplasm]' is required for 'NUDT16 hydrolyses IDP to IMP' ACTIVATION Pubmed20385596 Reactome Database ID Release 432509822 Reactome, http://www.reactome.org ReactomeREACT_152539 'Mg2+ [nucleoplasm]' is required for 'NUDT16 hydrolyses dIDP to dIMP' ACTIVATION Pubmed20385596 Reactome Database ID Release 432509821 Reactome, http://www.reactome.org ReactomeREACT_152543 'Mg2+ [cytosol]' is required for 'ITPA hydrolyses XTP to XMP' ACTIVATION Pubmed11278832 Reactome Database ID Release 432509854 Reactome, http://www.reactome.org ReactomeREACT_152533 'Mg2+ [cytosol]' is required for 'ITPA hydrolyses dITP to dIMP' ACTIVATION Pubmed11278832 Reactome Database ID Release 432509853 Reactome, http://www.reactome.org ReactomeREACT_152542 'Mg2+ [cytosol]' is required for 'ITPA hydrolyses ITP to IMP' ACTIVATION Pubmed11278832 Reactome Database ID Release 432509855 Reactome, http://www.reactome.org ReactomeREACT_152536 'ATP [cytosol]' positively regulates 'NDP + reduced thioredoxin => dNDP + oxidized thioredoxin + H2O' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43111757 Reactome, http://www.reactome.org ReactomeREACT_5967 'dATP [cytosol]' negatively regulates 'NDP + reduced thioredoxin => dNDP + oxidized thioredoxin + H2O' INHIBITION-ALLOSTERIC Reactome Database ID Release 43111770 Reactome, http://www.reactome.org ReactomeREACT_6065 'dATP [cytosol]' negatively regulates 'NDP + reduced glutaredoxin => dNDP + oxidized glutaredoxin + H2O' INHIBITION-ALLOSTERIC Reactome Database ID Release 43111772 Reactome, http://www.reactome.org ReactomeREACT_6023 'ATP [cytosol]' positively regulates 'NDP + reduced glutaredoxin => dNDP + oxidized glutaredoxin + H2O' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43111767 Reactome, http://www.reactome.org ReactomeREACT_6119 'ADP [cytosol]' positively regulates '(d)CMP, TMP, or (d)UMP + H2O => (deoxy)cytidine, thymidine, or (deoxy)uridine + orthophosphate [NT5C1A]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43109381 Reactome, http://www.reactome.org ReactomeREACT_5948 ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548820 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548806 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548832 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548822 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548801 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43548817 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43165003 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43548838 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 43548811 Reactome, http://www.reactome.org ASMT Converted from EntitySet in Reactome Hydroxyindole O-methyltransferase Reactome DB_ID: 209877 Reactome Database ID Release 43209877 Reactome, http://www.reactome.org ReactomeREACT_15985 'ADP [cytosol]' positively regulates '2'-deoxyadenosine 5'-monophosphate (dAMP) + H2O => 2'-deoxyadenosine + orthophosphate' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43109388 Reactome, http://www.reactome.org ReactomeREACT_6021 'ADP [cytosol]' positively regulates 'AMP + H2O => adenosine + orthophosphate [NT5C1B]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43109416 Reactome, http://www.reactome.org ReactomeREACT_6126 'ADP [cytosol]' positively regulates '(d)AMP, (d)GMP, or (d)IMP + H2O => (d)A, (d)G, or (d)I + orthophosphate [NT5C1A]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43109377 Reactome, http://www.reactome.org ReactomeREACT_5946 'adenylosuccinate [cytosol]' negatively regulates 'inosine 5'-monophosphate + L-aspartate + GTP => adenylosuccinate + guanosine 5'-diphosphate + orthophosphate' INHIBITION-COMPETITIVE Reactome Database ID Release 43111530 Reactome, http://www.reactome.org ReactomeREACT_5980 'D-Fructose 1,6-bisphosphate [cytosol]' negatively regulates 'inosine 5'-monophosphate + L-aspartate + GTP => adenylosuccinate + guanosine 5'-diphosphate + orthophosphate' INHIBITION-NONCOMPETITIVE Reactome Database ID Release 43111533 Reactome, http://www.reactome.org ReactomeREACT_6131 'GMP [cytosol]' negatively regulates 'inosine 5'-monophosphate + L-aspartate + GTP => adenylosuccinate + guanosine 5'-diphosphate + orthophosphate' INHIBITION-COMPETITIVE Reactome Database ID Release 43111531 Reactome, http://www.reactome.org ReactomeREACT_5994 'GDP [cytosol]' negatively regulates 'inosine 5'-monophosphate + L-aspartate + GTP => adenylosuccinate + guanosine 5'-diphosphate + orthophosphate' INHIBITION-COMPETITIVE Reactome Database ID Release 43111532 Reactome, http://www.reactome.org ReactomeREACT_5984 'Formation of phosphoribosyl pyrophosphate amidotransferase tetramer' negatively regulates '5-phospho-alpha-D-ribose 1-diphosphate (PRPP) + H2O + L-glutamine => 5-phosphoribosylamine + L-glutamate +pyrophosphate' INHIBITION Reactome Database ID Release 43111296 Reactome, http://www.reactome.org ReactomeREACT_5989 'XMP [cytosol]' negatively regulates 'IMP + H2O + NAD+ => XMP + NADH + H+ [IMPDH1,2]' INHIBITION-COMPETITIVE Reactome Database ID Release 43111589 Reactome, http://www.reactome.org ReactomeREACT_6115 'Dissociation of phosphoribosyl pyrophosphate amidotransferase tetramer' positively regulates '5-phospho-alpha-D-ribose 1-diphosphate (PRPP) + H2O + L-glutamine => 5-phosphoribosylamine + L-glutamate +pyrophosphate' ACTIVATION Reactome Database ID Release 43111295 Reactome, http://www.reactome.org ReactomeREACT_6046 ACTIVATION GENE ONTOLOGYGO:0004312 Reactome Database ID Release 43539119 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004806 Reactome Database ID Release 43163447 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016298 Reactome Database ID Release 43163604 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 43163500 Reactome, http://www.reactome.org TPH Converted from EntitySet in Reactome Reactome DB_ID: 209933 Reactome Database ID Release 43209933 Reactome, http://www.reactome.org ReactomeREACT_17665 Tryptophan 5-hydroxylase ACTIVATION GENE ONTOLOGYGO:0016298 Reactome Database ID Release 43163604 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015142 Reactome Database ID Release 43372450 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43163421 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003989 Reactome Database ID Release 43200565 Reactome, http://www.reactome.org DIO2 Converted from EntitySet in Reactome Reactome DB_ID: 350910 Reactome Database ID Release 43350910 Reactome, http://www.reactome.org ReactomeREACT_18158 ACTIVATION GENE ONTOLOGYGO:0003878 Reactome Database ID Release 4376189 Reactome, http://www.reactome.org 'Mg++ [mitochondrial matrix]' is required for 'PDP-catalyzed dephosphorylation (activation) of phospho E1 alpha subunit' ACTIVATION Reactome Database ID Release 43210326 Reactome, http://www.reactome.org ReactomeREACT_13394 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43163605 Reactome, http://www.reactome.org 'Purine nucleotide [cytosol]' negatively regulates 'Protons are translocated from the intermembrane space to the matrix' INHIBITION Reactome Database ID Release 43170035 Reactome, http://www.reactome.org ReactomeREACT_6711 'Long-chain fatty acid [cytosol]' positively regulates 'Protons are translocated from the intermembrane space to the matrix' ACTIVATION Reactome Database ID Release 43170038 Reactome, http://www.reactome.org ReactomeREACT_6710 'Mn2+ [mitochondrial matrix]' positively regulates '(R)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2' ACTIVATION Pubmed15070399 Reactome Database ID Release 43880068 Reactome, http://www.reactome.org ReactomeREACT_27128 'Zn2+ [mitochondrial matrix]' positively regulates '(R)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2' ACTIVATION Pubmed15070399 Reactome Database ID Release 43880065 Reactome, http://www.reactome.org ReactomeREACT_27092 '5-phospho-alpha-D-ribose 1-diphosphate [cytosol]' positively regulates 'Dissociation of phosphoribosyl pyrophosphate amidotransferase tetramer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43111290 Reactome, http://www.reactome.org ReactomeREACT_5914 'GMP [cytosol]' positively regulates 'Formation of phosphoribosyl pyrophosphate amidotransferase tetramer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43111287 Reactome, http://www.reactome.org ReactomeREACT_6079 'IMP [cytosol]' positively regulates 'Formation of phosphoribosyl pyrophosphate amidotransferase tetramer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43111288 Reactome, http://www.reactome.org ReactomeREACT_6081 'adenosine 5'-monophosphate [cytosol]' positively regulates 'Formation of phosphoribosyl pyrophosphate amidotransferase tetramer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 43111286 Reactome, http://www.reactome.org ReactomeREACT_5920 ACTIVATION GENE ONTOLOGYGO:0004607 Reactome Database ID Release 43264680 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43163605 Reactome, http://www.reactome.org 'Co2+ [mitochondrial matrix]' positively regulates '(R)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2' ACTIVATION Pubmed15070399 Reactome Database ID Release 43880066 Reactome, http://www.reactome.org ReactomeREACT_27089 'ADP [mitochondrial matrix]' positively regulates 'isocitrate + NAD+ => alpha-ketoglutarate + CO2 + NADH + H+ [IDH3]' ACTIVATION Reactome Database ID Release 43451016 Reactome, http://www.reactome.org ReactomeREACT_22094 ACTIVATION GENE ONTOLOGYGO:0004465 Reactome Database ID Release 43174759 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005319 Reactome Database ID Release 43174782 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015248 Reactome Database ID Release 43265785 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017127 Reactome Database ID Release 43352534 Reactome, http://www.reactome.org DIO1 Converted from EntitySet in Reactome Reactome DB_ID: 350899 Reactome Database ID Release 43350899 Reactome, http://www.reactome.org ReactomeREACT_18144 ACTIVATION GENE ONTOLOGYGO:0017127 Reactome Database ID Release 43266084 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005548 Reactome Database ID Release 43216736 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017127 Reactome Database ID Release 43216766 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43264761 Reactome, http://www.reactome.org 'cAMP-dependent protein kinase activity of PKA catalytic subunit [nucleoplasm]' negatively regulates 'Phosphorylation of ChREBP at Thr(666) by PKA' INHIBITION Reactome Database ID Release 43163746 Reactome, http://www.reactome.org ReactomeREACT_6049 'cAMP-dependent protein kinase activity of PKA catalytic subunit [cytosol]' negatively regulates 'Phosphorylation of p-ChREBP (Thr 666) at Ser(196) by PKA' INHIBITION Reactome Database ID Release 43163758 Reactome, http://www.reactome.org ReactomeREACT_5960 'Fatty acids [cytosol]' positively regulates 'Phosphorylation of ChREBP at Thr(666) by AMP kinase' ACTIVATION Reactome Database ID Release 43163742 Reactome, http://www.reactome.org ReactomeREACT_6062 'AMP [cytosol]' negatively regulates 'Phosphorylation of ChREBP at Thr(666) by AMP kinase' INHIBITION Reactome Database ID Release 43163735 Reactome, http://www.reactome.org ReactomeREACT_6038 '2GCHFR:GCH1 [cytosol]' negatively regulates 'GCH1 reduces GTP to dihydroneopterin triphosphate' INHIBITION Pubmed12607127 Reactome Database ID Release 431474118 Reactome, http://www.reactome.org ReactomeREACT_111899 'L-Phe [cytosol]' positively regulates 'GCH1 reduces GTP to dihydroneopterin triphosphate' ACTIVATION Reactome Database ID Release 431474173 Reactome, http://www.reactome.org ReactomeREACT_111928 'Acetyl-CoA [mitochondrial matrix]' positively regulates 'PDK-catalyzed phosphorylation (inactivation) of PDC E1 alpha subunit' ACTIVATION Reactome Database ID Release 43210332 Reactome, http://www.reactome.org ReactomeREACT_13393 'BH4 [cytosol]' negatively regulates 'GCH1 reduces GTP to dihydroneopterin triphosphate' INHIBITION Pubmed12607127 Reactome Database ID Release 431474156 Reactome, http://www.reactome.org ReactomeREACT_111914 'NADH [mitochondrial matrix]' positively regulates 'PDK-catalyzed phosphorylation (inactivation) of PDC E1 alpha subunit' ACTIVATION Reactome Database ID Release 43210348 Reactome, http://www.reactome.org ReactomeREACT_13395 'PYR [mitochondrial matrix]' negatively regulates 'PDK-catalyzed phosphorylation (inactivation) of PDC E1 alpha subunit' INHIBITION Reactome Database ID Release 43210344 Reactome, http://www.reactome.org ReactomeREACT_13399 ACTIVATION GENE ONTOLOGYGO:0017127 Reactome Database ID Release 43352534 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 43192485 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050253 Reactome Database ID Release 43975585 Reactome, http://www.reactome.org 'D-Xylulose 5-phosphate [cytosol]' positively regulates 'Activation of PP2A by Xylulose-5-phosphate' ACTIVATION Reactome Database ID Release 43166240 Reactome, http://www.reactome.org ReactomeREACT_5983 'Importin beta-3 [nucleoplasm]' positively regulates 'Viral Polymerase Assembly' ACTIVATION Reactome Database ID Release 43192952 Reactome, http://www.reactome.org ReactomeREACT_9924 'NP [nucleoplasm]' positively regulates 'Assembly of an Active Transcription Complex' ACTIVATION Reactome Database ID Release 43192819 Reactome, http://www.reactome.org ReactomeREACT_9935 'Nuclear Pore Complex (NPC) [nuclear envelope]' is required for 'Docking and transport of the RNP:Karyopherin complex through the nuclear pore' ACTIVATION Reactome Database ID Release 43188869 Reactome, http://www.reactome.org ReactomeREACT_9377 'HSP90 [nucleoplasm]' positively regulates 'Viral Polymerase Assembly' ACTIVATION Reactome Database ID Release 43192953 Reactome, http://www.reactome.org ReactomeREACT_9915 'NP [nucleoplasm]' positively regulates 'Initiation of cRNA Synthesis' ACTIVATION Reactome Database ID Release 43192800 Reactome, http://www.reactome.org ReactomeREACT_9934 'P58(IPK) [cytosol]' positively regulates 'Viral Protein Synthesis' ACTIVATION Reactome Database ID Release 43192799 Reactome, http://www.reactome.org ReactomeREACT_9913 'RNA Polymerase II (phosphorylated):TFIIF:capped pre-mRNA [nucleoplasm]' positively regulates 'The 5’ end of vRNA binds to PB1' ACTIVATION Reactome Database ID Release 43192796 Reactome, http://www.reactome.org ReactomeREACT_9923 Regulation Of Viral mRNA Splicing By The Host Splicing Pathway ACTIVATION Reactome Database ID Release 43449175 Reactome, http://www.reactome.org ReactomeREACT_21243 'Clathrin [plasma membrane]' is required for 'Clathrin-Mediated Pit Formation And Endocytosis Of The Influenza Virion' ACTIVATION Reactome Database ID Release 43189132 Reactome, http://www.reactome.org ReactomeREACT_9382 'Association of Vif with APOBEC3G' negatively regulates 'Association of APOBEC3G with Gag' INHIBITION Pubmed14527406 Reactome Database ID Release 43180638 Reactome, http://www.reactome.org ReactomeREACT_9944 'RanGap1 [nuclear membrane]' positively regulates 'Hydrolysis of Ran:GTP to Ran:GDP' ACTIVATION Reactome Database ID Release 43167671 Reactome, http://www.reactome.org ReactomeREACT_6709 'NP [nucleoplasm]' positively regulates 'Newly synthesized vRNP for export' ACTIVATION Reactome Database ID Release 43192870 Reactome, http://www.reactome.org ReactomeREACT_9932 'HSP70' negatively regulates 'Binding of M1 to vRNP' INHIBITION Reactome Database ID Release 43192889 Reactome, http://www.reactome.org ReactomeREACT_9918 'Nuclear Pore Complex (NPC) [nuclear envelope]' is required for 'vRNP Export through the nuclear pore' ACTIVATION Reactome Database ID Release 43192711 Reactome, http://www.reactome.org ReactomeREACT_9929 'calnexin [endoplasmic reticulum lumen]' positively regulates 'Glycosylation and Folding of HA' ACTIVATION Reactome Database ID Release 43195911 Reactome, http://www.reactome.org ReactomeREACT_11032 'calreticulin [endoplasmic reticulum lumen]' positively regulates 'Glycosylation and Folding of HA' ACTIVATION Reactome Database ID Release 43195910 Reactome, http://www.reactome.org ReactomeREACT_11031 LRIG1inhibits EGF binding to EGFR INHIBITION Pubmed16847455 Reactome Database ID Release 43204695 Reactome, http://www.reactome.org ReactomeREACT_12376 'diacylglycerols [plasma membrane]' positively regulates 'DAG stimulates protein kinase C-delta' ACTIVATION Reactome Database ID Release 431489502 Reactome, http://www.reactome.org ReactomeREACT_111913 'Active Calmodulin [cytosol]' positively regulates 'Calmodulin activates Cam-PDE 1' ACTIVATION Reactome Database ID Release 431489501 Reactome, http://www.reactome.org ReactomeREACT_111900 'PKC phosphorylates GRK2' negatively regulates 'Inhibition of GRK2 by calmodulin' INHIBITION Reactome Database ID Release 43111972 Reactome, http://www.reactome.org ReactomeREACT_18256 'NS1 [cytosol]' positively regulates 'Viral Protein Synthesis' ACTIVATION Reactome Database ID Release 43192828 Reactome, http://www.reactome.org ReactomeREACT_9920 'GRSF-1' positively regulates 'Viral Protein Synthesis' ACTIVATION Reactome Database ID Release 43192921 Reactome, http://www.reactome.org ReactomeREACT_9933 Rev Converted from EntitySet in Reactome Reactome DB_ID: 173122 Reactome Database ID Release 43173122 Reactome, http://www.reactome.org ReactomeREACT_7473 CXCR4 protein Converted from EntitySet in Reactome Reactome DB_ID: 175126 Reactome Database ID Release 43175126 Reactome, http://www.reactome.org ReactomeREACT_8185 Env gp120 with exposed coreceptor binding site Converted from EntitySet in Reactome Reactome DB_ID: 171282 Reactome Database ID Release 43171282 Reactome, http://www.reactome.org ReactomeREACT_8635 'Munc 13 [cytosol]' positively regulates 'Synaptic vesicle docking and priming' ACTIVATION Reactome Database ID Release 43349516 Reactome, http://www.reactome.org ReactomeREACT_14726 'Ca2+ influx through voltage gated Ca2+ channels' is required for 'release of L-Glutamate at the synapse' ACTIVATION Reactome Database ID Release 43210503 Reactome, http://www.reactome.org ReactomeREACT_13396 'captopril [extracellular region]' negatively regulates 'Secreted ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' INHIBITION Pubmed10536878 Pubmed15236580 Pubmed1848554 Pubmed1851160 Pubmed2558510 Pubmed3017438 Pubmed6269175 Pubmed6270633 Reactome Database ID Release 432065429 Reactome, http://www.reactome.org ReactomeREACT_148676 'Activation of GIRK/Kir3 Channels' negatively regulates 'Ca2+ influx through voltage gated Ca2+ channels' INHIBITION Reactome Database ID Release 431015860 Reactome, http://www.reactome.org ReactomeREACT_27117 'Cl- [extracellular region]' positively regulates 'Secreted ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' ACTIVATION Reactome Database ID Release 432065425 Reactome, http://www.reactome.org ReactomeREACT_148647 'enalaprilat [extracellular region]' negatively regulates 'Secreted ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' INHIBITION Pubmed10536878 Pubmed15236580 Pubmed1848554 Pubmed1851160 Reactome Database ID Release 432065426 Reactome, http://www.reactome.org ReactomeREACT_148688 'ramiprilat [extracellular region]' negatively regulates 'Secreted ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' INHIBITION Pubmed10536878 Reactome Database ID Release 432065433 Reactome, http://www.reactome.org ReactomeREACT_148657 'lisinopril [extracellular region]' negatively regulates 'Secreted ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' INHIBITION Pubmed12540854 Pubmed18853057 Reactome Database ID Release 432065432 Reactome, http://www.reactome.org ReactomeREACT_148686 'enalaprilat [extracellular region]' negatively regulates 'ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' INHIBITION Pubmed10536878 Pubmed15236580 Pubmed1848554 Pubmed1851160 Reactome Database ID Release 432022409 Reactome, http://www.reactome.org ReactomeREACT_148660 'Cl- [extracellular region]' positively regulates 'ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' ACTIVATION Reactome Database ID Release 432022391 Reactome, http://www.reactome.org ReactomeREACT_148691 'lisinopril [extracellular region]' negatively regulates 'ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' INHIBITION Pubmed12540854 Pubmed1668266 Reactome Database ID Release 432022375 Reactome, http://www.reactome.org ReactomeREACT_148648 'Flap endonuclease-1 [nucleoplasm]' is required for 'Removal of plus-strand flap and gap closure complete synthesis of linear duplex viral DNA' ACTIVATION Reactome Database ID Release 43182825 Reactome, http://www.reactome.org ReactomeREACT_9384 'Interaction of Vpr with importin alpha' positively regulates 'Import of PIC to the Host Nucleus' ACTIVATION Reactome Database ID Release 43180642 Reactome, http://www.reactome.org ReactomeREACT_9375 'Vpr binds nucleoporins' positively regulates 'Import of PIC to the Host Nucleus' ACTIVATION Reactome Database ID Release 43180640 Reactome, http://www.reactome.org ReactomeREACT_9378 'RanBP1 [nuclear membrane]' positively regulates 'Hydrolysis of Ran:GTP to Ran:GDP' ACTIVATION Reactome Database ID Release 43167670 Reactome, http://www.reactome.org ReactomeREACT_6708 'IL6:Tyrosine phosphorylated hexameric IL-6 receptor:Activated JAKs:p-SHP2 [plasma membrane]' positively regulates 'ERK1 activation' ACTIVATION IL-6-type receptor activation leads to induction of the MAPK cascade. Experiments using gp130 identified that the gp130 SHP2 (SH2-domain-containing tyrosine phosphatase)-binding site Tyr-759 (Stahl et al. 1995) is required for this activation. Mutation of gp130 Tyr-759 impairs IL-6 induced activation of the MAPK cascade (Kim et al. 1998). While there is a consensus that SHP2 is involved in IL-6-induced activation of the MAPK pathway, the molecular details are uncertain. One proposed mechanism suggests SHP2 acts as an adaptor for Grb2-Sos recruitment (Fukada et al. 1996, Kim & Baumann 1999). IL-6 induced SHP2 recruitment to p-Tyr-759 of gp130 was demonstrated but relatively little of the SHP2 remained associated with gp130, suggesting that SHP2 dissociates from the receptor when phosphorylated. This seems inconsistent with a Grb2-Sos recruitment role for SHP2, though it is possible that only low levels or transient recruitment are required. IL-6 induced ERK activation was not inhibited in cells transfected with a phosphatase inactive mutant of SHP2, whereas an SHP2 mutant missing the Grb2 interaction region significantly suppressed ERK activation. This suggests phosphatase activity is not required for ERK activation while SHP-2 interaction with Grb2 is important. However, overexpression studies can generate artefactual interactions and this interpretation has been questioned (Dance et al. 2008). An alternative proposal suggests that SHP2 and the adaptor protein Gab1 couple gp130 signalling to Erk activation. In this proposal phosphorylated SHP2 dissociates from gp130 and becomes associated with membrane associated Gab1 in a complex with PI3-kinase (Takahashi-Tezuka et al. 1998, Eulenfeld & Schaper 2009). SHP2 interaction is suggested to induce a conformational change in Gab1 that permits Gab1-PI3-kinase activation and enhancement of IL-6-induced Erk pathway activation. However this is speculative, the role of SHP2 phosphatase activity is unclear. Other possible mechanisms are outlined by Dance et al. (2008), extrapolated from growth factor receptor mechanisms but with unknown relevance to IL-6/gp130. Pubmed10409724 Pubmed17993263 Pubmed19050043 Pubmed7871433 Pubmed8934572 Pubmed9488469 Pubmed9632795 Reactome Database ID Release 431112768 Reactome, http://www.reactome.org ReactomeREACT_28015 'IL6:Tyrosine phosphorylated hexameric IL-6 receptor:Activated JAKs:p-SHP2 [plasma membrane]' positively regulates 'ERK2 activation' ACTIVATION IL-6-type receptor activation leads to induction of the MAPK cascade. Experiments using gp130 identified that the gp130 SHP2 (SH2-domain-containing tyrosine phosphatase)-binding site Tyr-759 (Stahl et al. 1995) is required for this activation. Mutation of gp130 Tyr-759 impairs IL-6 induced activation of the MAPK cascade (Kim et al. 1998). While there is a consensus that SHP2 is involved in IL-6-induced activation of the MAPK pathway, the molecular details are uncertain. One proposed mechanism suggests SHP2 acts as an adaptor for Grb2-Sos recruitment (Fukada et al. 1996, Kim & Baumann 1999). IL-6 induced SHP2 recruitment to p-Tyr-759 of gp130 was demonstrated but relatively little of the SHP2 remained associated with gp130, suggesting that SHP2 dissociates from the receptor when phosphorylated. This seems inconsistent with a Grb2-Sos recruitment role for SHP2, though it is possible that only low levels or transient recruitment are required. IL-6 induced ERK activation was not inhibited in cells transfected with a phosphatase inactive mutant of SHP2, whereas an SHP2 mutant missing the Grb2 interaction region significantly suppressed ERK activation. This suggests phosphatase activity is not required for ERK activation while SHP-2 interaction with Grb2 is important. However, overexpression studies can generate artefactual interactions and this interpretation has been questioned (Dance et al. 2008). An alternative proposal suggests that SHP2 and the adaptor protein Gab1 couple gp130 signalling to Erk activation. In this proposal phosphorylated SHP2 dissociates from gp130 and becomes associated with membrane associated Gab1 in a complex with PI3-kinase (Takahashi-Tezuka et al. 1998, Eulenfeld & Schaper 2009). SHP2 interaction is suggested to induce a conformational change in Gab1 that permits Gab1-PI3-kinase activation and enhancement of IL-6-induced Erk pathway activation. However this is speculative, the role of SHP2 phosphatase activity is unclear. Other possible mechanisms are outlined by Dance et al. (2008), extrapolated from growth factor receptor mechanisms but with unknown relevance to IL-6/gp130. Pubmed10409724 Pubmed17993263 Pubmed19050043 Pubmed7871433 Pubmed8934572 Pubmed9488469 Pubmed9632795 Reactome Database ID Release 431112769 Reactome, http://www.reactome.org ReactomeREACT_28018 'DNA ligase I [nucleoplasm]' is required for 'Removal of plus-strand flap and gap closure complete synthesis of linear duplex viral DNA' ACTIVATION Reactome Database ID Release 43182796 Reactome, http://www.reactome.org ReactomeREACT_9376 'ATP [cytosol]' regulates 'Activation of ATP sensitive Potassium channels' Reactome Database ID Release 431306812 Reactome, http://www.reactome.org ReactomeREACT_76918 membrane depolarization upon activation of Ca impermeable AMPA receptor ACTIVATION Pubmed9648857 Reactome Database ID Release 43438047 Reactome, http://www.reactome.org ReactomeREACT_21245 'p-MEK1 [cytosol]' negatively regulates 'MEK1 phosphorylates ERK-1' INHIBITION Reactome Database ID Release 43112343 Reactome, http://www.reactome.org ReactomeREACT_6097 'AGER ligands:AGER [plasma membrane]' positively regulates 'Released NFkB complex is transported to nucleus' ACTIVATION Pubmed11723063 Reactome Database ID Release 43879381 Reactome, http://www.reactome.org ReactomeREACT_24911 Though the signaling cascade is unclear, several pieces of experimental data suggest that activation of AGER leads to sustained activation and upregulation of NFkappaB, measured as NFkappaB translocation to the nucleus, and increased levels of de novo synthesized NFkappaB. Env gp120 protein after second conformation change Converted from EntitySet in Reactome Reactome DB_ID: 171292 Reactome Database ID Release 43171292 Reactome, http://www.reactome.org ReactomeREACT_8430 Env gp41 fusion peptide inserted into host membrane Converted from EntitySet in Reactome Reactome DB_ID: 171296 Reactome Database ID Release 43171296 Reactome, http://www.reactome.org ReactomeREACT_8929 Env gp41 with heptad repeats (HR) 1 and 2 in hairpin fold Converted from EntitySet in Reactome Reactome DB_ID: 171277 Reactome Database ID Release 43171277 Reactome, http://www.reactome.org ReactomeREACT_8228 NC Converted from EntitySet in Reactome Nucleocapsid Reactome DB_ID: 175167 Reactome Database ID Release 43175167 Reactome, http://www.reactome.org ReactomeREACT_8930 'Histone H2A.x (H2a/x)' positively regulates 'MDC1/NFBD1 relocalizes to nuclear foci ' ACTIVATION Pubmed12607005 Reactome Database ID Release 4383561 Reactome, http://www.reactome.org ReactomeREACT_6024 'Breast cancer type 1 susceptibility protein' positively regulates 'Phosphorylation of NBS1 by ATM' ACTIVATION Pubmed12773400 Reactome Database ID Release 4383557 Reactome, http://www.reactome.org ReactomeREACT_5949 'MDC1/NFBD1' positively regulates 'Phosphorylation of BRCA1 at multiple sites by ATM' ACTIVATION Pubmed12611903 Reactome Database ID Release 4383578 Reactome, http://www.reactome.org ReactomeREACT_6116 ACTIVATION GENE ONTOLOGYGO:0030351 Reactome Database ID Release 432024013 Reactome, http://www.reactome.org Interaction of APE1 with DNA ligase I positively regulates Ligation of DNA at sites of patch replacement ACTIVATION Reactome Database ID Release 43110372 Reactome, http://www.reactome.org ReactomeREACT_6094 ADC Arginine Decarboxylase Converted from EntitySet in Reactome Reactome DB_ID: 350582 Reactome Database ID Release 43350582 Reactome, http://www.reactome.org ReactomeREACT_15190 ACTIVATION GENE ONTOLOGYGO:0052828 Reactome Database ID Release 432024028 Reactome, http://www.reactome.org Vpu protein Converted from EntitySet in Reactome Reactome DB_ID: 173119 Reactome Database ID Release 43173119 Reactome, http://www.reactome.org ReactomeREACT_8183 ACTIVATION GENE ONTOLOGYGO:0052658 Reactome Database ID Release 432024033 Reactome, http://www.reactome.org 'heme [mitochondrial matrix]' negatively regulates 'Succinyl CoA and glycine condense to form 5-aminolevulinate (ALA)' INHIBITION Reactome Database ID Release 43189417 Reactome, http://www.reactome.org ReactomeREACT_9937 ACTIVATION GENE ONTOLOGYGO:0052826 Reactome Database ID Release 432024020 Reactome, http://www.reactome.org 'Pb++ [mitochondrial matrix]' negatively regulates 'Ferrous iron is inserted into protoporphyrin IX to form heme' INHIBITION Reactome Database ID Release 43190303 Reactome, http://www.reactome.org ReactomeREACT_9928 ACTIVATION GENE ONTOLOGYGO:0004441 Reactome Database ID Release 432024034 Reactome, http://www.reactome.org 'Homocysteine [cytosol]' positively regulates 'Excess homocysteine yields homolanthionine and H2S' ACTIVATION Reactome Database ID Release 431655890 Reactome, http://www.reactome.org ReactomeREACT_117992 ACTIVATION GENE ONTOLOGYGO:0052658 Reactome Database ID Release 432024039 Reactome, http://www.reactome.org 'L-Cys [cytosol]' positively regulates 'Excess cysteine yields lanthionine and H2S' ACTIVATION Reactome Database ID Release 431655888 Reactome, http://www.reactome.org ReactomeREACT_117966 ACTIVATION GENE ONTOLOGYGO:0008934 Reactome Database ID Release 432024043 Reactome, http://www.reactome.org 'Interaction between FEN1 and PCNA' positively regulates 'Cleavage of flap structures' ACTIVATION Reactome Database ID Release 43110365 Reactome, http://www.reactome.org ReactomeREACT_6043 ACTIVATION GENE ONTOLOGYGO:0052833 Reactome Database ID Release 432024030 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052829 Reactome Database ID Release 432024032 Reactome, http://www.reactome.org 'Glutathione [cytosol]' negatively regulates 'gamma-glutamylcysteine combines with glycine to form glutathione' GSH acts as a feedback inhibitor of the cycle because it can competitively inhibit gGCS (Ristoff and Larsson, 1998). INHIBITION Pubmed9679548 Reactome Database ID Release 431260991 Reactome, http://www.reactome.org ReactomeREACT_76917 ACTIVATION GENE ONTOLOGYGO:0017161 Reactome Database ID Release 432024025 Reactome, http://www.reactome.org Interaction of APE1 with FEN1 positively regulates Cleavage of Flap structures ACTIVATION Reactome Database ID Release 43110411 Reactome, http://www.reactome.org ReactomeREACT_6037 'Renin:Prorenin Receptor [plasma membrane]' positively regulates 'Renin:Prorenin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10)' ACTIVATION Pubmed12045255 Reactome Database ID Release 432022417 Reactome, http://www.reactome.org ReactomeREACT_148672 'aliskiren [extracellular region]' negatively regulates 'Prorenin:Prorenin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10)' INHIBITION Pubmed12927775 Pubmed22193701 Reactome Database ID Release 432065428 Reactome, http://www.reactome.org ReactomeREACT_148661 'aliskiren [extracellular region]' negatively regulates 'Renin:Prorenin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10)' INHIBITION Pubmed12927775 Pubmed22193701 Reactome Database ID Release 432022374 Reactome, http://www.reactome.org ReactomeREACT_148673 'captopril [extracellular region]' negatively regulates 'ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' INHIBITION Pubmed10536878 Pubmed15236580 Pubmed1848554 Pubmed1851160 Pubmed2558510 Pubmed3017438 Pubmed6269175 Pubmed6270633 Reactome Database ID Release 432065430 Reactome, http://www.reactome.org ReactomeREACT_148680 'ramiprilat [extracellular region]' negatively regulates 'ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8)' INHIBITION Pubmed10536878 Reactome Database ID Release 432022414 Reactome, http://www.reactome.org ReactomeREACT_148677 'MDC1/NFBD1' positively regulates 'MNR complex relocalizes to nuclear foci' ACTIVATION Pubmed12611903 Reactome Database ID Release 4383573 Reactome, http://www.reactome.org ReactomeREACT_6009 'MDC1/NFBD1' positively regulates 'BRCA1 relocalizes to nuclear foci' ACTIVATION Pubmed12611903 Reactome Database ID Release 4383571 Reactome, http://www.reactome.org ReactomeREACT_5930 'FANCJ/BRIP1 [nucleoplasm]' negatively regulates 'Strand exchange/Branch migration' INHIBITION Reactome Database ID Release 43622319 Reactome, http://www.reactome.org ReactomeREACT_23415 'FANCI [nucleoplasm]' is required for 'Monoubiquitination of FANCD2 by the FA ubiquitin ligase complex' ACTIVATION Reactome Database ID Release 43422565 Reactome, http://www.reactome.org ReactomeREACT_19106 'FANCD2 [nucleoplasm]' is required for 'Monoubiquitination of FANCI by the FA ubiquitin ligase complex' ACTIVATION Reactome Database ID Release 43422563 Reactome, http://www.reactome.org ReactomeREACT_19101 'aliskiren [extracellular region]' negatively regulates 'Renin Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10)' INHIBITION Pubmed12927775 Pubmed22193701 Reactome Database ID Release 432022384 Reactome, http://www.reactome.org ReactomeREACT_148644 'GTP [mitochondrial matrix]' negatively regulates 'alpha-ketoglutarate + NH4+ + NAD(P)H + H+ <=> glutamate + NAD(P)+ [GLUD1]' INHIBITION-ALLOSTERIC Pubmed11903050 Pubmed12054821 Reactome Database ID Release 4370591 Reactome, http://www.reactome.org ReactomeREACT_5978 'Magnesium [cytosol]' is required for 'A phosphoribosyl group is added to nicotinate to form nicotinate mononucleotide (NaMN)' ACTIVATION Reactome Database ID Release 43389378 Reactome, http://www.reactome.org ReactomeREACT_18254 ACTIVATION GENE ONTOLOGYGO:0052840 Reactome Database ID Release 432023970 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000827 Reactome Database ID Release 432023967 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052839 Reactome Database ID Release 432023982 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052825 Reactome Database ID Release 432023962 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000829 Reactome Database ID Release 432023919 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035299 Reactome Database ID Release 432023961 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047325 Reactome Database ID Release 432023985 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052839 Reactome Database ID Release 432023930 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052836 Reactome Database ID Release 432023947 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000828 Reactome Database ID Release 432023923 Reactome, http://www.reactome.org 'Thyrotropin [extracellular region]' positively regulates 'Two DITs combine to form thyroxine' ACTIVATION Reactome Database ID Release 431449728 Reactome, http://www.reactome.org ReactomeREACT_111925 'ACTIV [extracellular region]' positively regulates 'Follitropin is a heterodimer' ACTIVATION Pubmed16885530 Reactome Database ID Release 431449726 Reactome, http://www.reactome.org ReactomeREACT_111905 'INHIB [extracellular region]' negatively regulates 'Follitropin is a heterodimer' INHIBITION Pubmed16885530 Reactome Database ID Release 431449713 Reactome, http://www.reactome.org ReactomeREACT_111907 Mitochondrial ornithine transporters Converted from EntitySet in Reactome Reactome DB_ID: 374018 Reactome Database ID Release 43374018 Reactome, http://www.reactome.org ReactomeREACT_15253 ACTIVATION GENE ONTOLOGYGO:0051717 Reactome Database ID Release 432024007 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052841 Reactome Database ID Release 432023955 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000829 Reactome Database ID Release 432024000 Reactome, http://www.reactome.org 'L-Phe [cytosol]' negatively regulates 'kynurenine + pyruvate => 4-(2-aminophenyl)-2,4-dioxobutanoic acid + alanine [CCBL1]' INHIBITION Phenylalanine is an effective competitive inhibitor of kinurenine aminotransferase 1 (Han et al. 2004). Pubmed15606768 Reactome Database ID Release 432160520 Reactome, http://www.reactome.org ReactomeREACT_125692 ACTIVATION GENE ONTOLOGYGO:0052841 Reactome Database ID Release 432023955 Reactome, http://www.reactome.org 'L-Arginine [mitochondrial matrix]' positively regulates 'glutamate + acetyl CoA => N-acetyl glutamate + CoA' ACTIVATION Reactome Database ID Release 4370543 Reactome, http://www.reactome.org ReactomeREACT_6006 ACTIVATION GENE ONTOLOGYGO:0000829 Reactome Database ID Release 432023999 Reactome, http://www.reactome.org 'N-acetyl glutamate' positively regulates '2 ATP + NH4+ + HCO3- => 2 ADP + 2 orthophosphate + carbamoyl phosphate [mitochondrial]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370556 Reactome, http://www.reactome.org ReactomeREACT_6036 ACTIVATION GENE ONTOLOGYGO:0052836 Reactome Database ID Release 432023988 Reactome, http://www.reactome.org 'Thyrotropin [extracellular region]' positively regulates 'DIT and MIT combine to form triiodothyronine' ACTIVATION Reactome Database ID Release 431449716 Reactome, http://www.reactome.org ReactomeREACT_111911 ACTIVATION GENE ONTOLOGYGO:0052842 Reactome Database ID Release 432023976 Reactome, http://www.reactome.org 'ADP [mitochondrial matrix]' positively regulates 'alpha-ketoglutarate + NH4+ + NAD(P)H + H+ <=> glutamate + NAD(P)+ [GLUD1]' ACTIVATION-ALLOSTERIC Pubmed11903050 Pubmed12054821 Reactome Database ID Release 4370590 Reactome, http://www.reactome.org ReactomeREACT_6076 ACTIVATION GENE ONTOLOGYGO:0000828 Reactome Database ID Release 432023991 Reactome, http://www.reactome.org 'GTP [mitochondrial matrix]' negatively regulates 'glutamate + NAD(P)+ => alpha-ketoglutarate + NH4+ + NAD(P)H + H+ [GLUD1]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370602 Reactome, http://www.reactome.org ReactomeREACT_6045 ACTIVATION GENE ONTOLOGYGO:0052842 Reactome Database ID Release 432023976 Reactome, http://www.reactome.org 'ADP [mitochondrial matrix]' positively regulates 'glutamate + NAD(P)+ => alpha-ketoglutarate + NH4+ + NAD(P)H + H+ [GLUD1]' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370601 Reactome, http://www.reactome.org ReactomeREACT_5963 ACTIVATION GENE ONTOLOGYGO:0000828 Reactome Database ID Release 432023958 Reactome, http://www.reactome.org 'S40L-PAH [cytosol]' negatively regulates 'phenylalanine + tetrahydrobiopterin + O2 => tyrosine + 4a-hydroxytetrahydrobiopterin + H2O' INHIBITION Inactivating mutations in the PAH protein (e.g., Guldberg eta l. 1996) block the conversion of phenylalanine to tyrosine. Pubmed8889590 Reactome Database ID Release 432160452 Reactome, http://www.reactome.org ReactomeREACT_125712 Phosphorylated HuR (Ser221, Ser158) Binds mRNA Authored: May, B, 2010-02-17 Edited: May, B, 2010-02-17 HuR (ELAV1) phosphorylated on serine221 and serine158 binds COX-2 mRNA in the nucleus. The phosphorylation of serine 158 appears to affect RNA-binding while phosphorylation on serine 221 affects nucleocytoplasmic shuffling. Pubmed17392515 Reactome Database ID Release 43517674 Reactome, http://www.reactome.org ReactomeREACT_24962 Reviewed: Wilusz, J, 2010-06-29 Formation of the 43S pre-initiation complex Pubmed429297 Pubmed592399 Pubmed641056 Reactome Database ID Release 4372691 Reactome, http://www.reactome.org ReactomeREACT_1354 The ternary complex (Met-tRNAi:eIF2:GTP) binds to the complex formed by the 40S subunit, eIF3 and eIF1A, to form the 43S complex. eIF1A promotes binding of the ternary complex to the 40S subunit within 43S. The initiator methionyl-tRNA from the ternary complex is positioned at the ribosomal P site. Release of 40S and 60S subunits from the 80S ribosome 80S monosomes dissociate into 40S and 60S ribosomal subunits. eIF1A promotes this dissociation. Reactome Database ID Release 4372673 Reactome, http://www.reactome.org ReactomeREACT_928 eIF3 and eIF1A bind to the 40S subunit Pubmed12493757 Pubmed429297 Pubmed592399 Pubmed641056 Pubmed6901506 Reactome Database ID Release 4372676 Reactome, http://www.reactome.org ReactomeREACT_608 eIF3 and eIF1A bind to the 40S ribosomal subunit. De novo formation of eIF2:GTP Activation of eIF2 through direct binding of GTP. Pubmed1104615 Reactome Database ID Release 4372663 Reactome, http://www.reactome.org ReactomeREACT_77 Met-tRNAi binds to eIF2:GTP to form the ternary complex Pubmed1104615 Reactome Database ID Release 4372669 Reactome, http://www.reactome.org ReactomeREACT_1664 The ternary complex forms upon binding of the initiator methionyl-tRNA to the active eIF2:GTP complex. Phosphorylated HuR (Ser221, Ser318) Binds mRNA Authored: May, B, 2010-02-17 Edited: May, B, 2010-02-17 HuR phosphorylated on ser221 and ser318 binds AU-rich regions of mRNAs. Phosphorylation on ser318 appears to affect RNA binding and phosphorylation of ser221 affects nucleocytoplasmic shuttling. Pubmed18285462 Pubmed20086103 Reactome Database ID Release 43517705 Reactome, http://www.reactome.org ReactomeREACT_24973 Reviewed: Wilusz, J, 2010-06-29 HuR Binds mRNAs in the Nucleus Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 HuR binds AU-rich elements of mRNAs. Bound HuR can form oligomers on longer AU-rich elements. Phosphorylated HuR binds mRNA more tightly than unphosphorylated HuR does. Pubmed11018049 Pubmed11834731 Pubmed14981256 Pubmed16484227 Pubmed17517897 Reactome Database ID Release 43450494 Reactome, http://www.reactome.org ReactomeREACT_25067 Reviewed: Wilusz, J, 2010-06-29 Association of HuR with the CRM1 Nuclear Export Machinery Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 HuR interacts with SETalpha (Template activating factor 1), SETbeta (CAN/Nup214), APRIL, pp32, and the nuclear export factor CRM1. Pubmed11018049 Pubmed17178712 Pubmed19130553 Reactome Database ID Release 43450387 Reactome, http://www.reactome.org ReactomeREACT_25286 Reviewed: Wilusz, J, 2010-06-29 Export of HuR:mRNA Complex from the Nucleus to the Cytoplasm Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed15257295 Pubmed17178712 Pubmed19130553 Reactome Database ID Release 43450595 Reactome, http://www.reactome.org ReactomeREACT_24924 Reviewed: Wilusz, J, 2010-06-29 mRNA bound to HuR is exported from the nucleus by a mechanism that requires the shuttle protein APRIL but not pp32. Phosphorylation of APRIL determines its subcellular localization: APRIL phosphorylated at threonine244 is found in both the nucleus and cytoplasm while APRIL that is not phosphorylated at threonine244 is cytoplasmic.<br>HuR bound to mRNAs in the cytoplasm acts to stabilize the mRNAs by an unknown mechanism. Phosphorylation of HuR by PKCalpha Authored: May, B, 2009-12-29 EC Number: 2.7.11 Edited: May, B, 2009-12-29 Protein kinase C alpha (PKCalpha) phosphorylates HuR (ELAVL1) on serine221 and serine 158. Pubmed17392515 Reactome Database ID Release 43450550 Reactome, http://www.reactome.org ReactomeREACT_25016 Reviewed: Wilusz, J, 2010-06-29 has a Stoichiometric coefficient of 2 Phosphorylation of HuR by PKCdelta Authored: May, B, 2009-12-29 EC Number: 2.7.11 Edited: May, B, 2009-12-29 Protein kinase C delta (PKCdelta) phosphorylates HuR (ELAVL1) at serine 221 and serine 318. Pubmed18285462 Reactome Database ID Release 43450533 Reactome, http://www.reactome.org ReactomeREACT_25202 Reviewed: Wilusz, J, 2010-06-29 has a Stoichiometric coefficient of 2 Phosphorylated KSRP (Ser193) Binds 14-3-3zeta in the Nucleus Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 KSRP phosphorylated at serine193 binds 14-3-3zeta which impairs the ability of KSRP to destabilize RNA. Thus the RNAs become stabilized. KSRP is able to shuttle between the nucleus and the cytoplasm. 14-3-3zeta is nucleoplasmic. Binding of KSRP to 14-3-3zeta causes KSRP to be retained in the nucleus. Pubmed19198587 Reactome Database ID Release 43450620 Reactome, http://www.reactome.org ReactomeREACT_25152 Reviewed: Wilusz, J, 2010-06-29 Phosphorylation of KSRP by MAP kinase p38 Activated MAPK p38 alpha and beta phosphorylate KSRP at threonine692. The phosphorylation interferes with the ability of KSRP to bind and destabilize RNA. Thus RNAs become stabilized. Authored: May, B, 2009-12-29 EC Number: 2.7.11 Edited: May, B, 2009-12-16 Edited: May, B, 2009-12-29 Pubmed16364914 Reactome Database ID Release 43451152 Reactome, http://www.reactome.org ReactomeREACT_24965 Reviewed: Wilusz, J, 2010-06-29 KSRP Recruits RNA Degradation Activities Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 KSRP (KHSRP) forms a complex with the PARN deadenylase, exosome components (3' to 5' mRNA decay), and the decapping enzyme DCP2. Tethering KSRP to a mRNA is sufficient to target the mRNA for degradation. Pubmed11719186 Pubmed15175153 Pubmed16648466 Reactome Database ID Release 43450422 Reactome, http://www.reactome.org ReactomeREACT_25257 Reviewed: Wilusz, J, 2010-06-29 Phosphorylation of KSRP by Protein Kinase B/Akt Authored: May, B, 2009-12-29 EC Number: 2.7.11 Edited: May, B, 2009-12-29 KSRP is phosphorylated by activated protein kinase B/AKT at serine 193. Phosphorylation does not prevent KSRP from binding RNA. Pubmed17177604 Pubmed19198587 Reactome Database ID Release 43450499 Reactome, http://www.reactome.org ReactomeREACT_25187 Reviewed: Wilusz, J, 2010-06-29 Phosphorylated Tristetraproline (TTP) binds 14-3-3beta Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Phosphorylated tristetraproline (TTP) binds 14-3-3, which inhibits the ability of TTP to destabilize RNA. Thus RNAs bound by TTP become stabilized. The binding of 14-3-3 causes TTP to be excluded from stress granules. Pubmed14688255 Pubmed15014438 Pubmed15944294 Pubmed18481987 Reactome Database ID Release 43450394 Reactome, http://www.reactome.org ReactomeREACT_24978 Reviewed: Wilusz, J, 2010-06-29 KSRP Binds AU-rich Element in 3' UTR of mRNA Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 KSRP (KHSRP) binds AU-rich regions of target RNAs via its four K-homology (KH) domains. Pubmed15514971 Pubmed17177604 Pubmed18684992 Pubmed19141871 Pubmed19854161 Reactome Database ID Release 43450592 Reactome, http://www.reactome.org ReactomeREACT_25230 Reviewed: Wilusz, J, 2010-06-29 TTP Recruits RNA Degradation Activities Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed11719186 Pubmed12748283 Pubmed15687258 Pubmed17133347 Reactome Database ID Release 43450431 Reactome, http://www.reactome.org ReactomeREACT_25297 Reviewed: Wilusz, J, 2010-06-29 TTP interacts directly with exonucleases (XRN1 and the exosome) and decapping enzymes (DCP1a and DCP2) which hydrolyze the mRNA bound by TTP. TTP also recruits PARN deadenylase, however a direct interaction between TTP and PARN has not been demonstrated. Phosphorylation of Tristetraproline (TTP) by MK2 Authored: May, B, 2009-12-29 EC Number: 2.7.11 Edited: May, B, 2009-12-29 Pubmed14688255 Pubmed15014438 Pubmed15944294 Pubmed16262601 Pubmed18481987 Reactome Database ID Release 43450463 Reactome, http://www.reactome.org ReactomeREACT_25171 Reviewed: Wilusz, J, 2010-06-29 TTP is phosphorylated by MK2 at serines 60 and 186. has a Stoichiometric coefficient of 2 Hyaluronan uptake and degradation Authored: Jassal, B, 2012-03-05 Edited: Jassal, B, 2012-03-05 GENE ONTOLOGYGO:0030214 Hyaluronan (HA) turnover can occur locally at the tissue of origin, where it is taken up by cells to be degraded, or released into the lymphatic and vascular systems, where it can be eliminated by the liver and kidneys. Uptake of HA into cells for degradation involves receptor-mediated processes. Once HA enters lysosomes, the acidic conditions favour hyaluronidases to cleave it into small oligosaccharides, the most common size being a tetrasaccharide. Beta-glucuronidases participate in degrading the small oligosaccharides in the lysosome. Ultimately, HA is degraded into its constituent sugars (glucuronic acid and N-acetylglucosamine) which can be used to reform many glycosaminoglycans (GAGs) when released from the lysosome.<br>A third of the total HA content in humans is turned over daily and it has a short half life of minutes in circulation up to days in many tissues. The reasons why the body eliminates HA so rapidly are unknown but one possible explanation could be HA's role as a reactive oxygen species (ROS) scavenger. Removing these toxic compounds could explain the rapid elimination of HA (Lepperdinger et al. 2004, Menzel & Farr 1998, Erickson & Stern 2012, Stern 2003). ISBN9780080443829 Pubmed14514708 Pubmed22216413 Pubmed9839614 Reactome Database ID Release 432160916 Reactome, http://www.reactome.org ReactomeREACT_120996 Reviewed: D'Eustachio, P, 2012-03-28 Glycosaminoglycan metabolism Authored: Jassal, B, 2011-10-05 Edited: Jassal, B, 2011-10-05 GENE ONTOLOGYGO:0030203 Glycosaminoglycans (GAGs) are long, unbranched polysaccharides containing a repeating disaccharide unit composed of a hexosamine (either N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc)) and a uronic acid (glucuronate or iduronate). They can be heavily sulfated. GAGs are located primarily in the extracellular matrix (ECM) and on cell membranes, acting as a lubricating fluid for joints and as part of signalling processes. They have structural roles in connective tissue, cartilage, bone and blood vessels (Esko et al. 2009). GAGs are degraded in the lysosome as part of their natural turnover. Defects in the lysosomal enzymes responsible for the metabolism of membrane-associated GAGs lead to lysosomal storage diseases called mucopolysaccharidoses (MPS). MPSs are characterised by the accumulation of GAGs in lysosomes resulting in chronic, progressively debilitating disorders that in many instances lead to severe psychomotor retardation and premature death (Cantz & Gehler 1976, Clarke 2008). The biosynthesis and breakdown of the main GAGs (hyaluronate, keratan sulfate, chondroitin sulfate, dermatan sulfate and heparan sulfate) is described here. Pubmed18201392 Pubmed20301236 Pubmed820626 Reactome Database ID Release 431630316 Reactome, http://www.reactome.org ReactomeREACT_121315 Reviewed: D'Eustachio, P, 2012-03-28 Phosphorylated BRF1 (Ser92, Ser203) Binds 14-3-3 Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Phosphorylated BRF1 interacts with 14-3-3, becomes localized to the cytoskeleton, and no longer promotes RNA degradation. Phosphorylated BRF1 is, however, still able to bind RNA. Pubmed15538381 Pubmed17030608 Reactome Database ID Release 43450406 Reactome, http://www.reactome.org ReactomeREACT_24951 Reviewed: Wilusz, J, 2010-06-29 PRPP biosynthesis 5-Phospho-alpha-D-ribose 1-diphosphate (PRPP) is a key intermediate in both the de novo and salvage pathways of purine and pyrimidine synthesis. PRPP and the enzymatic activity responsible for its synthesis were first described by Kornberg et al. (1955). The enzyme, phosphoribosyl pyrophosphate synthetase 1, has been purified from human erythrocytes and characterized biochemically. The purified enzyme readily forms multimers; its smallest active form appears to be a dimer and for simplicity it is annotated as a dimer here. It specifically catalyzes the transfer of pyrophosphate from ATP or dATP to D-ribose 5-phosphate, and has an absolute requirement for Mg++ and orthophosphate (Fox and Kelley 1971; Roth et al. 1974). The significance of the reaction with dATP in vivo is unclear, as the concentration of cytosolic dATP is normally much lower than that of ATP. The importance of this enzyme for purine synthesis in vivo has been established by demonstrating excess phosphoribosyl pyrophosphate synthetase activity, correlated with elevated enzyme levels or altered enzyme properties, in individuals whose rates of uric acid production are constitutively abnormally high (Becker and Kim 1987; Roessler et al. 1993).<P>Molecular cloning studies have revealed the existence of two additional genes that encode phosphoribosyl pyrophosphate synthetase-like proteins, one widely expressed (phosphoribosyl pyrophosphate synthetase 2) and one whose expression appears to be confined to the testis (phosphoribosyl pyrophosphate synthetase 1-like 1) (Taira et al. 1989; 1991). Neither of these proteins has been purified and characterized enzymatically, nor have variations in the abundance or sequence of either protein been associated with alterations in human nucleotide metabolism (Roessler et al. 1993; Becker et al. 1996), so their dimerization and ability to catalyze the synthesis of PRPP from D-ribose 5-phosphate are inferred here on the basis of their predicted amino acid sequence similarity to phosphoribosyl pyrophosphate synthetase 1. 5-Phosphoribose 1-diphosphate biosynthesis Authored: D'Eustachio, P, 2004-02-09 03:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006015 Pubmed14392173 Pubmed2168892 Pubmed2444588 Pubmed2537655 Pubmed4328836 Pubmed4358634 Pubmed8253776 Pubmed8702702 Reactome Database ID Release 4373843 Reactome, http://www.reactome.org ReactomeREACT_850 Synthesis of cytosolic 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) from D-ribose 5-phosphate Phosphorylated BRF1 (Ser54, Ser92, Ser203) Binds 14-3-3 Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Phosphorylated BRF1 interacts with 14-3-3, becomes localized to the cytoskeleton, and no longer promotes RNA degradation. Phosphorylated BRF1 is, however, still able to bind RNA. Pubmed18326031 Reactome Database ID Release 43482788 Reactome, http://www.reactome.org ReactomeREACT_25272 Reviewed: Wilusz, J, 2010-06-29 Hyaluronan biosynthesis and export Authored: Jassal, B, 2012-02-24 Edited: Jassal, B, 2012-02-24 GENE ONTOLOGYGO:0030213 Hyaluronan (hyaluronic acid, HA) is composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine [-4GlcAb1-3GlcNAcb1-]. It is synthesized in the cell membrane by adding monosaccharides to the reducing end of the chain using the precursors UDP-glucuronic acid and UDP-N-acetylglucosamine in the presence of Mg2+. The integral membrane dual-action glycosyltransferase proteins hyaluronan synthases, of which vertebrates have three types (HAS1-3), catalyze these monosaccharide additions. Unlike other GAGs, HA is synthesized as a free glycan, not attached to a protein (Laurent 1987, Weigel & DeAngelis, 2007). As HA is synthesised it is extruded from the cell by an ABC-type transporter into the extracellular medium. Pubmed17981795 Pubmed3124495 Reactome Database ID Release 432142850 Reactome, http://www.reactome.org ReactomeREACT_121301 Reviewed: D'Eustachio, P, 2012-03-28 Tristetraproline (TTP) Binds AU-rich Elements in 3' UTR of Target mRNAs Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed10330172 Pubmed12324455 Pubmed12639954 Pubmed12646273 Pubmed12705825 Pubmed15117938 Pubmed17133347 Pubmed17369404 Pubmed18367721 Pubmed19729507 Reactome Database ID Release 43450400 Reactome, http://www.reactome.org ReactomeREACT_25366 Reviewed: Wilusz, J, 2010-06-29 Tristetraprolin (TTP) binds UUAUUUAUU motifs in the AU-rich elements of mRNAs. TTP binds Transportin-1 (Importin beta-2) which plays a role in shuttling TTP between P-bodies and stress granules. Hyaluronan metabolism Authored: Jassal, B, 2012-02-24 Edited: Jassal, B, 2012-02-24 GENE ONTOLOGYGO:0030212 Hyaluronan (hyaluronic acid, hyaluronate or HA) is an anionic glycosaminoglycan (GAG) distributed widely throughout connective, epithelial, and neural tissues and most abundant in the extracellular matrix and skin. HA is unique among the GAGs in that it is not sulfated and is not found covalently attached to proteins as a proteoglycan. HA polymers are very large (they can reach molecular weights of 10 million Da) and can displace a large volume of water making them excellent lubricators and shock absorbers. Another unique feature of HA is that it is synthesized at the plasma membrane unlike other GAGs which are formed in the Golgi. HA is a polymer of the disaccharide unit D-glucuronic acid and D-N-acetylglucosamine, linked via alternating beta-1,4 and beta-1,3 glycosidic bonds (Toole 2000, 2004, Volpi et al. 2009). Pubmed10930435 Pubmed15229478 Pubmed19442142 Reactome Database ID Release 432142845 Reactome, http://www.reactome.org ReactomeREACT_121083 Reviewed: D'Eustachio, P, 2012-03-28 Fructose catabolism Authored: 2003-03-01 00:00:00 Fructose occurs naturally in foods as a free monosaccharide and as a component of the disaccharide sucrose. It is also widely used as a sweetener. In the body, fructose is converted to dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate, two intermediates in the glycolytic pathway, in a sequence of three reactions: fructose is phosphorylated, then cleaved by aldolase to yield dihydroxyacetone phosphate and D-glyceraldehyde, and the latter compound is phosphorylated to yield D-glyceraldehyde 3-phosphate. Other pathways exist for the conversion of D-glyceraldehyde to intermediates of glycolysis, but these appear to play only a minor role in normal fructose metabolism.<P>The cleavage of fructose 1-phosphate is catalyzed by the same enzyme that catalyzes the reversible cleavage of fructose 1,6-bisphosphate in glycolysis. The isoform of this enzyme found in liver, kidney, and intestine (B) is approximately equally active with fructose 1-phosphate and fructose 1,6-bisphosphate as substrates, while the muscle and brain isoforms (A and C, respectively), have little activity with fructose 1-phosphate. Fructose metabolism thus occurs mainly in tissues expressing the B isoform, and mutations that affect the catalytic activity of this isoform are associated with hereditary fructose intolerance (Steinmann et al. 2001). GENE ONTOLOGYGO:0006001 Reactome Database ID Release 4370350 Reactome, http://www.reactome.org ReactomeREACT_1571 Glycogen breakdown (glycogenolysis) Authored: 2003-02-15 00:00:00 GENE ONTOLOGYGO:0005980 Glycogen breakdown occurs via the same chemical steps in all tissues but is separately regulated via tissue specific isozymes and signaling pathways that enable distinct physiological fates for liver glycogen and that in other tissues. Glycogen phosphorylase, which can be activated by phosphorylase kinase, catalyzes the removal of glucose residues as glucose 1-phosphate from the ends of glycogen branches. The final four residues of each branch are removed in two steps catalyzed by debranching enzyme, and further glycogen phosphorylase activity completes the process of glycogen breakdown. The figure shows the actions of phosphorylase and debranching enzyme. The first glucose residue in each branch is released as free glucose; all other residues are released as glucose 1-phosphate. The latter molecule can be converted to glucose 6-phosphate in a step shared with other pathways (Villar-Palasi and Larner 1970; Hers 1976). Pubmed183599 Pubmed4320262 Reactome Database ID Release 4370221 Reactome, http://www.reactome.org ReactomeREACT_1008 Pentose phosphate pathway (hexose monophosphate shunt) Authored: 2003-02-15 00:00:00 GENE ONTOLOGYGO:0006098 Pubmed18987987 Pubmed3790084 Pubmed5666113 Reactome Database ID Release 4371336 Reactome, http://www.reactome.org ReactomeREACT_1859 The pentose phosphate pathway is responsible for the generation of a substantial fraction of the cytoplasmic NADPH required for biosynthetic reactions, and for the generation of ribose 5-phosphate for nucleotide synthesis. Although the pentose phosphate pathway and glycolysis are distinct, they involve three common intermediates, glucose 6-phosphate, glyceraldehyde 3-phosphate, and fructose 6-phosphate, so the two pathways are interconnected. The pentose phosphate pathway consists of eight reactions:1. Conversion glucose 6-phosphate to D-glucono-1,5-lactone 6-phosphate, with the formation of NADPH; 2. Conversion of D-glucono-1,5-lactone 6-phosphate to 6-phospho-D-gluconate; 3. Conversion of 6-phospho-D-gluconate to ribulose 5-phosphate, with the formation of NADPH; 4. Conversion of ribulose 5-phosphate to xylulose 5-phosphate; 5. Conversion of ribulose 5-phosphate to ribose 5-phosphate; 6. Rearrangement of ribose 5-phosphate and xylulose 5-phosphate to form sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate; 7. Rearrangement of sedoheptulose 7-phosphate and glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate; and 8. Rearrangement of xylulose 5-phosphate and erythrose 4-phosphate to form glyceraldehyde 3-phosphate and fructose-6-phosphate.<P>The oxidative branch of the pentose phosphate pathway, reactions 1-3, generates NADPH and pentose 5-phosphate. The non-oxidative branch of the pathway, reactions 4-8, converts pentose 5-phosphate to other sugars.<P>The overall pathway can operate to generate only NADPH (glucose 6-phosphate is converted to pentose 5-phosphates, which are directed to the synthesis of fructose 6-phosphate and glyceraldehyde 3-phosphate, which in turn are converted back to glucose 6-phosphate). The reactions of the non-oxidative branch can operate to generate net amounts of ribose 5-phosphate with no production of NADPH. Net flux through this network of reactions appears to depend on the metabolic state of the cell and the nature of the biosynthetic reactions underway (Casazza and Veech 1987).<p>G6PD, the enzyme that catalyzes the first reaction of the pathway, is more extensively mutated in human populations than any other enzyme, pehaps because these mutant alleles confer malaria resistance (Luzzatto and Afolayan 1968). Mutations affecting other parts of the pathway are rare, though several have been described and studies of their effects have contributed to our understanding of the normal flux of metabolites through this network of reactions (Wamelink et al. 2008). Galactose catabolism Authored: 2003-02-25 00:00:00 GENE ONTOLOGYGO:0019388 Pubmed11261429 Reactome Database ID Release 4370370 Reactome, http://www.reactome.org ReactomeREACT_532 The main sources of galactose in the human diet are milk and milk products. The disaccharide lactose from these sources is hydrolyzed in the intestine to its constituent monosaccharides, glucose and galactose. Galactose is metabolized primarily in the liver in a sequence of three reactions that yield one molecule of glucose 1-phosphate per molecule of galactose. First, it is phosphorylated to yield galactose 1-phosphate. Then, galactose 1-phosphate and UDP-glucose react to form UDP-galactose and glucose 1-phosphate, and UDP-galactose undergoes epimerization to form UDP-glucose. In a reaction shared with other pathways, glucose 1-phosphate can be converted into glucose 6-phosphate (Holton et al. 2001; Elsas and Lai 2001). Association of AUF1 with Translation and Heat Shock Proteins Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed10205060 Pubmed12819195 Pubmed16556936 Pubmed18573886 Reactome Database ID Release 43450551 Reactome, http://www.reactome.org ReactomeREACT_25267 Reviewed: Wilusz, J, 2010-06-29 Tetrameric AUF1 bound to RNA forms a complex with other proteins, including elongation factor eIF4G, polyA-binding protein PABP, Hsp, Hsc70, and Hsp27. AUF1 also directly interacts with polyadenylate. Glycogen synthesis Authored: 2003-02-15 00:00:00 GENE ONTOLOGYGO:0005978 Glycogen, a highly branched glucose polymer, is formed and broken down in most human tissues, but is most abundant in liver and muscle, where it serves as a major stored fuel. Glycogen metabolism has been studied in most detail in muscle, although considerable experimental data are available concerning these reactions in liver as well. Glycogen metabolism in other tissues has not been studied as extensively, and is thought to resemble the muscle process (Hers 1976; Lomako et al. 2004; Villar-Palasi and Larner 1970).<p>Glycogen synthesis involves five reactions. The first two, conversion of glucose 6-phosphate to glucose 1-phosphate and synthesis of UDP-glucose from glucose 1-phosphate and UTP, are shared with several other pathways. The next three reactions, the auto-catalyzed synthesis of a glucose oligomer on glycogenin, the linear extension of the glucose oligomer catalyzed by glycogen synthase, and the formation of branches catalyzed by glycogen branching enzyme, are unique to glycogen synthesis. These reactions are shown in the figure. Repetition of the last two reactions generates large, extensively branched glycogen polymers. The catalysis of several of these reactions by distinct isozymes in liver and muscle allows them to be regulated independently in the two tissues. Pubmed15238248 Pubmed183599 Pubmed4320262 Reactome Database ID Release 4370302 Reactome, http://www.reactome.org ReactomeREACT_1736 Ubiquitination of AUF1 (hnRNP D0) AUF1 is ubiquitinated at unknown sites. The number of ubiquitin molecules conjugated to AUF1 and their linkage is unknown. Ubiquitination is required for subsequent degradation of both AUF1 and the mRNA bound by AUF1. It is uncertain if AUF1 is in a larger complex when it is ubiquitinated. Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed10205060 Pubmed10559216 Pubmed11842200 Pubmed12136087 Reactome Database ID Release 43450580 Reactome, http://www.reactome.org ReactomeREACT_25315 Reviewed: Wilusz, J, 2010-06-29 has a Stoichiometric coefficient of 4 Destruction of AUF1 and mRNA Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed10205060 Pubmed11842200 Pubmed12136087 Pubmed15257295 Reactome Database ID Release 43450466 Reactome, http://www.reactome.org ReactomeREACT_25343 Reviewed: Wilusz, J, 2010-06-29 Ubiquitin-dependent proteolysis of AUF1 and nuclease-dependent destruction of AUF1-bound mRNA are coupled in an unknown way. It is possible that ubiquitinated AUF1 targets other members of the AUF1 and signal transduction regulated complex (ASTRC), such as polyA-binding protein, for degradation and this renders the mRNA susceptible to nucleases. Butyrate Response Factor1 (BRF1) Binds AU-rich Element in 3' UTR of mRNA Authored: May, B, 2009-12-29 Butyrate response factor 1 (BRF1) binds AU-rich elements in the 3' untranslated region of mRNAs. Edited: May, B, 2009-12-29 Pubmed12198173 Pubmed15538381 Pubmed17030608 Pubmed18326031 Reactome Database ID Release 43450517 Reactome, http://www.reactome.org ReactomeREACT_25293 Reviewed: Wilusz, J, 2010-06-29 BRF1 Complex Recruits RNA Degradation Activities Authored: May, B, 2009-12-29 BRF1 recruits RNA degradation activities to hydrolyze the RNA bound to BRF1. Coimmunoprecipitation has shown BRF1 interacts with the exosome (3' to 5' nuclease), XRN1 (5' to 3' nuclease), and DCP1a and DCP2 (decapping). BRF1 localizes RNAs to processing bodies, sites of translation repression and possible sites of RNA degradation. Edited: May, B, 2009-12-29 Pubmed11719186 Pubmed14976220 Pubmed15687258 Pubmed17369404 Reactome Database ID Release 43450488 Reactome, http://www.reactome.org ReactomeREACT_25265 Reviewed: Wilusz, J, 2010-06-29 Phosphorylation of BRF1 by Protein Kinase B/Akt Authored: May, B, 2009-12-29 BRF1 is phosphorylated at Serine92 and Serine203 by Protein kinase B/AKT. Protein kinase B is activated by phosphatidylinositol 3-kinase. Phosphorylation of BRF1 does not interfere with the ability of BRF1 to bind RNA or interact with enzymes that catalyze RNA degradation therefore larger complexes may contain phosphorylated BRF1. EC Number: 2.7.11 Edited: May, B, 2009-12-29 Pubmed12198173 Pubmed15538381 Pubmed17030608 Reactome Database ID Release 43450490 Reactome, http://www.reactome.org ReactomeREACT_25335 Reviewed: Wilusz, J, 2010-06-29 has a Stoichiometric coefficient of 2 Phosphorylation of BRF1 by MK2 Authored: May, B, 2009-12-29 EC Number: 2.7.11 Edited: May, B, 2009-12-29 MAPK-activated protein kinase 2 (MK2) phosphorylates BRF1 at serine 54, serine 92, serine 203, and an unknown site in the C terminus. Phosphorylation inhibits the ability of BRF1 to cause degradation of RNA. It is unknown if tetraphosphorylated BRF1 binds 14-3-3 in the same way as diphosphorylated BRF1 does. Pubmed18326031 Reactome Database ID Release 43450474 Reactome, http://www.reactome.org ReactomeREACT_25285 Reviewed: Wilusz, J, 2010-06-29 has a Stoichiometric coefficient of 3 Binding of Exactly Matching Target RNAs by Nonendonucleolytic RISC Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Pubmed16284623 Pubmed16289642 Pubmed17128271 Pubmed17632058 RISCs containing Argonautes1, 3, and 4 (AGO1/3/4) bind to target RNAs by base-pairing between the target RNA and the guide RNA of the RISC. AGO1/3/4 do not possess ribonuclease activity therefore exact matches between the guide and the target do not result in cleavage of the target. Rather, the effect of binding is inhibition of translation followed by decay of the target RNA. Argonaute proteins have been shown to interact with ribosomal proteins and with components of processing bodies (P-bodies) where RNA degradation occurs. Direct interaction between AGO and a TNRC6 protein is required for inhibition of translation and targeting to P-bodies in vivo. Reactome Database ID Release 43426522 Reactome, http://www.reactome.org ReactomeREACT_118624 Reviewed: Tomari, Y, 2012-02-10 AUF1(hnRNP D0) Dimers Bind AU-rich Element in 3' UTR of Transcripts AUF1 monomers form dimers which bind the U-rich sequences in AU-rich elements of mRNAs. Binding of the mRNA causes the dimers of AUF1 to form tetramers. Nonphosphorylated AUF1 isoform p40 causes the mRNA to form a rigid structure whereas p40 that is phosphorylated at serines 83 and 87 does not. This difference may cause nonphosphorylated p40 to fail to destabilize the bound mRNA. Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed10559216 Pubmed11124962 Pubmed12819194 Pubmed12819195 Pubmed12944492 Pubmed14976220 Pubmed15257295 Pubmed17486099 Pubmed18240226 Pubmed18573886 Pubmed19074427 Pubmed8246982 Pubmed9346902 Reactome Database ID Release 43450434 Reactome, http://www.reactome.org ReactomeREACT_24997 Reviewed: Wilusz, J, 2010-06-29 has a Stoichiometric coefficient of 2 Cleavage of Target RNAs by Endonucleolytic RISC Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Human Argonaute2 (AGO2) possesses ribonucleolytic activity in its PIWI domain and cleaves target RNAs that are exactly complementary to the guide RNA at a location around 10 nucleotides from the 5' end of the match with the guide RNA. The products of cleavage have a 5' phosphate and a 3' hydroxyl group. Both complexes containing siRNAs and miRNAs are capable of cleavage. Although Argonaute proteins interact with many other proteins, the complex of AGO2 and the guide RNA are sufficient to direct cleavage of target RNAs in vitro. In vivo, cleavage requires interaction of AGO2 with a TNRC6 protein and MOV10. Pubmed12154197 Pubmed15260970 Pubmed15284456 Pubmed15800637 Pubmed16289642 Pubmed17632058 Pubmed18978028 Pubmed19470757 Reactome Database ID Release 43426520 Reactome, http://www.reactome.org ReactomeREACT_118741 Reviewed: Tomari, Y, 2012-02-10 has a Stoichiometric coefficient of 2 Binding of Inexactly Matching Target RNAs by RISC. Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Pubmed15014042 Pubmed16284623 Pubmed16289642 Pubmed17128271 Pubmed17632058 Pubmed18461144 Pubmed18978028 Pubmed19383768 Pubmed19398495 Pubmed19470757 RISCs can bind target RNAs that do not exactly match the guide RNA carried by Argonaute. Binding is especially dependent on base-pairing between the target RNA and the eight 5' nucleotides of the guide RNA (miRNA or siRNA). After binding, Argonautes1,3, and 4 are incapable of cleavage in all cases. Argonaute2 is capable of cleaving the target RNA but not if mismatches exist in the middle of the guide (centered about 10 nucloetides from the 5' end of the guide RNA). In the absence of cleavage the target RNA remains bound by the RISC, which inhibits translation of the target RNA and causes the RNA to enter the decay pathway. In vivo, inhibition of translation requires interaction of AGO with a TNRC6 protein and MOV10. Reactome Database ID Release 43426489 Reactome, http://www.reactome.org ReactomeREACT_118839 Reviewed: Tomari, Y, 2012-02-10 Duplex miRNA is loaded into Argonaute Authored: May, B, 2012-02-05 Edited: May, B, 2012-02-05 Pubmed15973356 Pubmed16142218 Pubmed16357216 Pubmed18178619 Pubmed19966796 Pubmed22106413 Reactome Database ID Release 432106614 Reactome, http://www.reactome.org ReactomeREACT_118663 Reviewed: Tomari, Y, 2012-02-10 The duplex miRNA (miRNA-miRNA*) is transferred from Dicer to an Argonaute protein. A complex appears to transiently form that contains Dicer, the duplex miRNA, TRBP, and an Argonaute. After transfer of the duplex miRNA the Argonaute:duplex miRNA complex dissociates. Duplex and single-stranded small RNAs can be transferred to Argonaute in the absence of Dicer so formation of the Dicer:miRNA:TRBP:Argonaute complex may not be obligatory. Removal of miRNA passenger strand A short double-stranded RNA is passed from Dicer to an Argonaute and rendered single-stranded by removal and loss of the passenger strand. All Argonautes (AGO1, AGO2, AGO3, AGO4) can remove the passenger strand without cleaving it and most miRNAs are processed in this way. AGO2 can cleave the passenger strand of a subset of miRNAs that have no mismatches in the central region (Shin 2008). <br>RNA helicase A is associated with the RISC loading complex can facilitate removal of the passenger strand.<br>The mechanism that selects which strand is retained as the guide RNA is not well understood in humans. Overhanging nucleotides and strength of base-pairing at each end of the input duplex are observed to influence strand selection.<br>Argonaute proteins directly or indirectly bind many other proteins and appear to be present in more than one distinct complex. Authored: Gopinathrao, G, May, B, 2007-11-18 23:55:40 Edited: May, B, 2009-06-10 Pubmed15284456 Pubmed16271386 Pubmed16357216 Pubmed17531811 Pubmed17932509 Pubmed18178619 Pubmed18728384 Pubmed18782830 Pubmed18842624 Pubmed19401777 Pubmed19966796 Reactome Database ID Release 43210805 Reactome, http://www.reactome.org ReactomeREACT_118810 Reviewed: Tomari, Y, 2012-02-10 Cleavage-based removal of the siRNA passenger strand by AGO2 Authored: Gopinathrao, G, May, B, 2007-11-18 23:55:40 Edited: May, B, 2009-06-10 In the case of AGO2, cleavage of one strand (the "passenger" strand) of the 21-25 nucleotide double-stranded RNA facilitates the loss of the passenger strand and the retention of the guide strand (Matranga et al. 2005). RNA helicase A has also been shown to enhance this reaction. AGO2 of humans may contain either miRNAs or siRNAs.<br>The mechanism that selects which strand is retained as the guide RNA is not well understood in humans. Overhanging nucleotides and strength of base-pairing at each end of the input duplex are observed to influence strand selection.<br>Argonaute proteins directly or indirectly bind many other proteins and appear to be present in more than one distinct complex. Pubmed15284456 Pubmed16271386 Pubmed17531811 Pubmed17932509 Pubmed18782830 Pubmed18842624 Pubmed19401777 Pubmed19966796 Pubmed22106413 Reactome Database ID Release 43203934 Reactome, http://www.reactome.org ReactomeREACT_118602 Reviewed: Tomari, Y, 2012-02-10 Removal of siRNA passenger strand A short double-stranded RNA is passed from Dicer to an Argonaute and rendered single-stranded by removal and loss of the passenger strand. All Argonautes (AGO1, AGO2, AGO3, AGO4) can remove the passenger strand without cleaving it. AGO2 possesses endonucleolytic activity and cleaves the passenger strand of siRNAs, which facilitates but is not required for removal of the passenger strand (Matranga et al. 2005). <br>RNA helicase A is associated with the RISC loading complex can facilitate removal of the passenger strand.<br>The mechanism that selects which strand is retained as the guide RNA is not well understood in humans. Overhanging nucleotides and strength of base-pairing at each end of the input duplex are observed to influence strand selection.<br>Argonaute proteins directly or indirectly bind many other proteins and appear to be present in more than one distinct complex. Authored: May, B, 2012-02-05 Edited: May, B, 2012-02-05 Pubmed16271386 Pubmed17531811 Pubmed17932509 Pubmed18782830 Pubmed19401777 Pubmed19966796 Pubmed22106413 Reactome Database ID Release 432106615 Reactome, http://www.reactome.org ReactomeREACT_118852 Reviewed: Tomari, Y, 2012-02-10 Dicer cleaves double-stranded RNA to yield double-stranded siRNA Authored: May, B, 2009-06-10 Dicer is an RNase III enzyme which cleaves double-stranded RNAs to yield short double-stranded RNAs of 21-25 nucleotides. Small interfering RNAs (siRNAs) are produced by Dicer and are similar to miRNAs in their final structure but differ from miRNAs in their source: siRNAs are produced from long double stranded RNAs that originate from viruses, transposable elements, centromeric repeats and other repetitive structures. EC Number: 3.1.26.3 Edited: May, B, 2009-06-10 Pubmed11201747 Pubmed12411504 Pubmed12411505 Pubmed15973356 Pubmed16142218 Pubmed16357216 Pubmed16424907 Pubmed17452327 Pubmed18178619 Pubmed20184375 Pubmed22163034 Reactome Database ID Release 43426464 Reactome, http://www.reactome.org ReactomeREACT_118784 Reviewed: Tomari, Y, 2012-02-10 Duplex siRNA is loaded into Argonaute Authored: May, B, 2012-02-05 Edited: May, B, 2012-02-05 Pubmed15973356 Pubmed16142218 Pubmed16357216 Pubmed18178619 Pubmed18842624 Pubmed19966796 Pubmed22106413 Reactome Database ID Release 432106625 Reactome, http://www.reactome.org ReactomeREACT_118706 Reviewed: Tomari, Y, 2012-02-10 The duplex siRNA is transferred from Dicer to an Argonaute protein. A complex appears to transiently form that contains Dicer, the duplex miRNA, TRBP, and an Argonaute. After transfer of the duplex siRNA the Argonaute:duplex siRNA complex dissociates. Duplex and single-stranded small RNAs can be transferred to Argonaute in the absence of Dicer so formation of the Dicer:miRNA:TRBP:Argonaute complex may not be obligatory. PKA regulatory subunit Converted from EntitySet in Reactome Reactome DB_ID: 111921 Reactome Database ID Release 43111921 Reactome, http://www.reactome.org ReactomeREACT_5395 PKA catalytic subunit Converted from EntitySet in Reactome Reactome DB_ID: 111920 Reactome Database ID Release 43111920 Reactome, http://www.reactome.org ReactomeREACT_3031 Dual-specific AKAPs Converted from EntitySet in Reactome Reactome DB_ID: 992722 Reactome Database ID Release 43992722 Reactome, http://www.reactome.org ReactomeREACT_25713 Mitofusins Converted from EntitySet in Reactome Reactome DB_ID: 992720 Reactome Database ID Release 43992720 Reactome, http://www.reactome.org ReactomeREACT_26095 Monocarboxylate Transporter Set (MCT) Converted from EntitySet in Reactome Reactome DB_ID: 374008 Reactome Database ID Release 43374008 Reactome, http://www.reactome.org ReactomeREACT_17955 Late Phase of HIV Life Cycle GENE ONTOLOGYGO:0022415 Pubmed10550206 Pubmed10562489 Pubmed15183343 Pubmed15719065 Pubmed2784194 Pubmed2825027 Pubmed3031512 Pubmed9891806 Reactome Database ID Release 43162599 Reactome, http://www.reactome.org ReactomeREACT_6361 Reviewed: Peterlin, BM, 2005-01-05 00:00:00 The late phase of the HIV-1 life cycle includes the regulated expression of the HIV gene products and the assembly of viral particles. The assembly of viral particles will be covered in a later release of Reactome. HIV-1 gene expression is regulated by both cellular and viral proteins. Although the initial activation of the HIV-1 transcription is facilitated by cellular transcription factors including NF-kappa B (Nabel and Baltimore, 1987), this activation results in the production of primarily short transcripts (Kao et al., 1987). Expression of high levels of the full length HIV-1 transcript requires the function of the HIV-1 Tat protein which promotes elongation of the HIV-1 transcript (reviewed in Karn, 1999; Taube et al. 1999; Liou et al., 2004; Barboric and Peterlin 2005). The HIV-1 Rev protein is required post-transcriptionally for the expression of the late genes. Rev functions by promoting the nuclear export of unspliced and partially spliced transcripts that encode the major structural proteins Gag, Pol and Env, and the majority of the accessory proteins (Malim et al., 1989; reviewed in Pollard and Malim 1998 . Autointegration results in viral DNA circles Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 In this pathway, the viral integration machinery uses a site within the viral DNA as an integration target. This results in a covalent rearrangment of the viral DNA. The resulting DNA forms are not substrates for integration.<br>It has been suggested that the cellular BAF protein binds to viral DNA and diminishes autointegration by coating and condensing the viral DNA, thereby making it a less efficient integration target.<br> Pubmed7937898 Pubmed9465049 Reactome Database ID Release 43177539 Reactome, http://www.reactome.org ReactomeREACT_6866 Reviewed: Bushman, FD, 2006-10-30 22:19:13 Transcription of the HIV genome Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Expression of the integrated HIV-1 provirus is dependent on the host cell Pol II transcription machinery, but is regulated in critical ways by HIV-1 Tat and Rev proteins. The long terminal repeats (LTR) located at either end of the proviral DNA contain regulatory sequences that recruit cellular transcription factors. The U3 region of the 5' LTR contains numerous cis-acting elements that regulate Pol II-mediated transcription initiation. The full-length transcript, which encodes nine genes, functions as an mRNA and is packaged as genomic RNA. Smaller (subgenomic) viral mRNAs are generated by alternative splicing. The activities of Tat and Rev create two phases of gene expression (see Karn 1999; Cullen 1991). The Tat protein is an RNA specific trans-activator of LTR-mediated transcription. Association of Tat with TAR, a RNA stem-loop within the RNA leader sequence, is required for efficient elongation of the HIV-1 transcript. In the early phase of viral transcription, a multiply-spliced set of mRNAs is generated, producing the transcripts of the regulatory proteins, Tat, Rev, and Nef. In the late phase, Rev regulates nuclear export of HIV-1 mRNAs, repressing expression of the early regulatory mRNAs and promoting expression of viral structural proteins. Nuclear export of the unspliced and partially spliced late HIV-1 transcripts that encode the structural proteins requires the association of Rev with a cis-acting RNA sequence in the transcripts (Rev Response Element, RRE). GENE ONTOLOGYGO:0019083 Pubmed10550206 Pubmed1995941 Pubmed9791012 Reactome Database ID Release 43167172 Reactome, http://www.reactome.org ReactomeREACT_6233 Reviewed: Peterlin, BM, 2005-01-05 00:00:00 HIV-1 Transcription Initiation Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Formation of the open complex exposes the template strand to the catalytic center of the RNA polymerase II enzyme. This facilitates formation of the first phosphodiester bond, which marks transcription initiation. As a result of this, the TFIIB basal transcription factor dissociates from the initiation complex.<p>The open transcription initiation complex is unstable and can revert to the closed state. Initiation at this stage requires continued (d)ATP-hydrolysis by TFIIH. Dinucleotide transcripts are not stably associated with the transcription complex. Upon dissociation they form abortive products. The transcription complex is also sensitive to inhibition by small oligo-nucleotides. <p>Dinucleotides complementary to position -1 and +1 in the template can also direct first phosphodiester bond formation. This reaction is independent on the basal transcription factors TFIIE and TFIIH and does not involve “full” open complex formation. This reaction is sensitive to inhibition by single-stranded oligonucleotides. GENE ONTOLOGYGO:0006367 Reactome Database ID Release 43167161 Reactome, http://www.reactome.org ReactomeREACT_6332 RNA Polymerase II HIV-1 Promoter Escape Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 RNA Polymerase II promoter escape occurs after the first phosphodiester bond has been created. Reactome Database ID Release 43167162 Reactome, http://www.reactome.org ReactomeREACT_6253 RNA Pol II CTD phosphorylation and interaction with CE Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167160 Reactome, http://www.reactome.org ReactomeREACT_6237 To facilitate co-transcriptional capping, and thereby restrict the cap structure to RNAs made by RNA polymerase II, the capping enzymes bind directly to the RNA polymerase II. The C-terminal domain of the largest Pol II subunit contains several phosphorylation sites on its heptapeptide repeats. The capping enzyme guanylyltransferase and the methyltransferase bind specifically to CTD phosphorylated at Serine 5 within the CTD. Kinase subunit of TFIIH, Cdk7, catalyzes this phosphorylation event that occurs near the promoter. In addition, it has been shown that binding of capping enzyme to the Serine-5 phosphorylated CTD stimulates guanylyltransferase activity in vitro. HIV-1 Transcription Elongation Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 GENE ONTOLOGYGO:0006368 In the absence of the HIV-1 protein Tat, transcription of the proviral DNA is inefficient and results in the production of truncated transcripts (Kao et al., 1987). While initiation of transcription from the HIV-1 LTR and formation of the early elongation complex occurs normally, transcription elongation is incomplete with non-processive polymerases disengaging from the proviral DNA template prematurely (reviewed in Karn 1999). The mechanism of Tat-mediated elongation is described below. Pubmed10550206 Pubmed15049426 Pubmed2825027 Reactome Database ID Release 43167169 Reactome, http://www.reactome.org ReactomeREACT_6274 Formation of the HIV-1 Early Elongation Complex Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed11940650 Pubmed12370301 Pubmed12653964 Reactome Database ID Release 43167158 Reactome, http://www.reactome.org ReactomeREACT_6319 This HIV-1 event was inferred from the corresponding human RNA Poll II transcription event. The details relevant to HIV-1 are described below. Formation of the early elongation complex involves hypophosphorylation of RNA Pol II CTD by FCP1P protein, association of the DSIF complex with RNA Pol II, and formation of DSIF:NELF:HIV-1 early elongation complex as described below (Mandal et al 2002; Kim et al 2003; Yamaguchi et al 2002). Tat-mediated elongation of the HIV-1 transcript GENE ONTOLOGYGO:0050434 Pubmed10199401 Pubmed10550206 Pubmed10562489 Pubmed10757782 Pubmed10866664 Pubmed11940650 Pubmed14701750 Pubmed15183343 Pubmed15719065 Pubmed2476805 Pubmed2825027 Pubmed7853496 Pubmed9450929 Pubmed9491887 Reactome Database ID Release 43167246 Reactome, http://www.reactome.org ReactomeREACT_6162 The Tat protein is a viral transactivator protein that regulates HIV-1 gene expression by controlling RNA Pol II-mediated elongation (reviewed in Karn 1999; Taube et al. 1999; Liou et al. 2004; Barboric and Peterlin 2005). Tat appears to be required in order to overcome the arrest of RNA Pol II by the negative transcriptional elongation factors DSIF and NELF (Wada et al. 1998; Yamaguchi et al. 1999; Yamaguchi et al 2002; Fujinaga et al. 2004). While Pol II can associate with the proviral LTR and initiate transcription in the absence of Tat, these polymerase complexes are non-processive and dissociate from the template prematurely producing very short transcripts (Kao et al. 1987). Tat associates with the RNA element, TAR, which forms a stem loop structure in the leader RNA sequence (Dingwall et al. 1989). Tat also associates with the cellular kinase complex P-TEFb(Cyclin T1:Cdk9) and recruits it to the TAR stem loop structure (Herrmann, 1995) (Wei et al. 1998). This association between Tat, TAR and P-TEFb(Cyclin T1:Cdk9) is believed to bring the catalytic subunit of this kinase complex (Cdk9) in close proximity to Pol II where it hyperphosphorylates the CTD of RNA Pol II (Zhou et al. 2000). The RD subunits of NELF and the SPT5 subunit of DSIF, which associate through RD with the bottom stem of TAR, are also phosphorylated by P-TEFb(Cyclin T1:Cdk9) (Yamaguchi et al. 2002; Fujinaga et al. 2004; Ivanov et al. 2000). Phosphorylation of RD results in its dissociation from TAR. Thus, Tat appears to facilitate transcriptional elongation of the HIV-1 transcript by hyperphosphorylating the RNA Poll II CTD and by removing the negative transcription elongation factors from TAR. In addition, there is evidence that the association of Tat with P-TEFb(Cyclin T1:Cdk9) alters the substrate specificity of P-TEFb enhancing phosphorylation of ser5 residues in the CTD of RNA Pol II (Zhou et al. 2000). Formation of HIV-1 elongation complex containing HIV-1 Tat Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed10757782 Pubmed14701750 Pubmed15564463 Pubmed7853496 Pubmed9491887 Reactome Database ID Release 43167200 Reactome, http://www.reactome.org ReactomeREACT_6346 This HIV-1 event was inferred from the corresponding human RNA Poll II transcription event in Reactome. The details relevant to HIV-1 are described below. For a more detailed description of the general mechanism, see the link to the corresponding RNA Pol II transcription event below. The formation of the HIV-1 elongation complex involves Tat mediated recruitment of P-TEFb(Cyclin T1:Cdk9) to the TAR sequence (Wei et al, 1998) and P-TEFb(Cyclin T1:Cdk9) mediated phosphorylation of the RNA Pol II CTD as well as the negative transcriptional elongation factors DSIF and NELF (Herrmann, 1995; Ivanov et al. 2000; Fujinaga et al. 2004; Zhou et al., 2004). Formation of HIV-1 elongation complex in the absence of HIV-1 Tat Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167152 Reactome, http://www.reactome.org ReactomeREACT_22201 HIV-1 elongation arrest and recovery RNA Pol II arrest is believed to be a result of irreversible backsliding of the enzyme by ~7-14 nucleotides. TFIIS reactivates arrested RNA Pol II by promoting the excision of nascent transcript ~7-14 nucleotides upstream of the 3' end. Reactome Database ID Release 43167287 Reactome, http://www.reactome.org ReactomeREACT_6259 Abortive elongation of HIV-1 transcript in the absence of Tat Pubmed10199401 Pubmed2825027 Pubmed9450929 Reactome Database ID Release 43167242 Reactome, http://www.reactome.org ReactomeREACT_6261 This event was inferred from the corresponding Reactome human Poll II transcription elongation event. The details specific to HIV-1 transcription elongation are described below. In the absence of the HIV-1 Tat protein, the RNA Pol II complexes associated with the HIV-1 template are non-processive. RNA Pol II is arrested after promoter clearance by the negative transcriptional elongation factors DSIF and NELF as occurs during early elongation of endogenous templates (Wada et al, 1998; Yamaguchi et al. 1999). This arrest cannot be overcome by P-TEFb mediated phosphorylation in the absence of Tat however, and elongation aborts resulting in the accumulation of short transcripts (Kao et al., 1987). Glc,GlcNAc-Fuc-Pre-NOTCH Converted from EntitySet in Reactome FRINGE glycosylated NOTCH receptor precursors Reactome DB_ID: 1911434 Reactome Database ID Release 431911434 Reactome, http://www.reactome.org ReactomeREACT_119767 Pausing and recovery of Tat-mediated HIV-1 elongation After Pol II pauses by back tracking 2 -4 nuleotides on the HIV-1 template, elongation of the HIV-1 transcript resumes. Reactome Database ID Release 43167238 Reactome, http://www.reactome.org ReactomeREACT_6143 HIV-1 Transcription Termination Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 GENE ONTOLOGYGO:0006369 Reactome Database ID Release 43167168 Reactome, http://www.reactome.org ReactomeREACT_6241 Termination of HIV-1 transcription is believed to be mechanistically the same as termination of endogenous human messages. Pausing and recovery of HIV-1 elongation After Pol II pauses by back tracking 2 -4 nuleotides on the HIV-1 template, elongation of the HIV-1 transcript resumes. Reactome Database ID Release 43167290 Reactome, http://www.reactome.org ReactomeREACT_6244 Tat-mediated HIV-1 elongation arrest and recovery RNA Pol II arrest is believed to be a result of irreversible backsliding of the enzyme by ~7-14 nucleotides. TFIIS reactivates arrested RNA Pol II by promoting the excision of nascent transcript ~7-14 nucleotides upstream of the 3' end. Reactome Database ID Release 43167243 Reactome, http://www.reactome.org ReactomeREACT_6344 Synthesis And Processing Of GAG, GAGPOL Polyproteins Evidence suggests that the RNA molecules used for the synthesis of Gag and Gag-Pro-Pol are not the same molecules that are packaged into virions. Gag proteins do not appear to aggregate around and capture the RNA contained in the polyribosome from which they emerged, but rather bind to and ultimately encapsidate free transcripts elsewhere. During the replication of retroviruses, large numbers of Gag molecules must be generated to serve as precursors to the structural proteins of the virions. Retroviruses have developed a mechanism that permits expression of the Gag protein at high levels relative to the protein sequences encoded in the pro and pol genes, while retaining coregulated expression. This linkage results from the use of the same initiation codon in the same mRNA to express the gag, pro, and pol genes. Translation of this RNA leads occasionally to synthesis of a fusion protein that is usually called the Gag-Pol precursor but is now more appropriately called the Gag-Pro-Pol precursor GENE ONTOLOGYGO:0019082 ISBN0-87969-571-4 Reactome Database ID Release 43174495 Reactome, http://www.reactome.org ReactomeREACT_115860 Synthesis and organization of GAG, GAGPOL polyproteins Rev-mediated nuclear export of HIV-1 RNA Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2006-06-07 20:09:58 Pubmed12932730 Pubmed14701878 Pubmed15749819 Pubmed2406030 Pubmed2784194 Pubmed7512159 Pubmed8076606 Pubmed8805303 Pubmed9791012 Reactome Database ID Release 43165054 Reactome, http://www.reactome.org ReactomeREACT_6190 Reviewed: Kumar, A, 2007-01-31 22:47:49 The HIV-1 genome contains 9 genes encoded by a single transcript. In order for the virus to replicate, unspliced, singly-spliced and fully spliced viral mRNA must be exported from the nucleus. The HIV-1 mRNA splice sites are inefficient resulting it the accumulation of a pool of incompletely spliced RNAs (Staffa and Cochrane, 1994). In the early stages of the viral life cycle, or in the absence of the viral Rev protein, completely spliced viral mRNA which encode the regulatory proteins Tat, Nef and Rev are exported from the nucleus while the incompletely spliced structural protein encoding transcripts are held within the nucleus by cellular proteins that normally function in preventing the nuclear export of cellular pre-mRNA. Export of both unspliced and partially spliced mRNA is mediated by the viral protein Rev which is recruited, along with cellular cofactors, to the Rev Response Element (RRE) within the HIV-1 mRNA sequence (Malim et al., 1990; Fischer et al., 1994). The cellular hRIP protein is essential for correct Rev-mediated export of viral RNAs to the cytoplasm (Sanchez-Velar et al., 2004; Yu et al., 2005). Assembly of HIV virion GENE ONTOLOGYGO:0019068 Reactome Database ID Release 43175474 Reactome, http://www.reactome.org ReactomeREACT_6818 This pathway module includes annotations of events leading to synthesis and organization of GAG, GAGPOL and ENV proteins. This section will annotated in future. Budding and maturation of HIV-1 virion GENE ONTOLOGYGO:0019067 Reactome Database ID Release 43162588 Reactome, http://www.reactome.org ReactomeREACT_6359 This part of the <b>Late Phase</b> will be annotated in a future release of Reactome.<br> Synthesis and processing of accessory proteins GENE ONTOLOGYGO:0019082 Reactome Database ID Release 43174489 Reactome, http://www.reactome.org ReactomeREACT_115706 Interactions of Vpr with host cellular proteins Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-05-15 07:16:46 Pubmed10620603 Pubmed10684278 Pubmed10958988 Pubmed11531413 Pubmed11815283 Pubmed15817944 Pubmed16354571 Pubmed7474080 Pubmed7474100 Pubmed8041786 Pubmed8709199 Pubmed9188632 Pubmed9436978 Pubmed9582382 Reactome Database ID Release 43176033 Reactome, http://www.reactome.org ReactomeREACT_6757 Reviewed: Zhao, RY, 2006-07-11 22:08:52 Vpr has been implicated in multiple processes during HIV-1 replication, including nuclear import of the pre-integration complex (PIC)(Heinzinger et al., 1994), apoptosis (Stewart et al., 1997) and induction of cell cycle G2/M arrest (He et al., 1995; Re et al., 1995; Zhao et al., 1996).<br><br> Interactions between Vpr and host nucleoporins (importin α) appear to facilitate the nuclear import of the PIC (Popov et al., 1998; Vodicka et al., 1998) while interactions between Vpr the adenine nucleotide transporter (ANT) protein at the inner mitochondrial membrane may contribute to release of apoptosis factors by promoting permeabilization of the mitochondrial outer membrane (Jacotot et al., 2000). <br> <br>Vpr induces cell cycle G2/M arrest by promoting hyperphosphorylation of Cdk1/Cdc2 (Re et al., 1995; Zhao et al., 1996). However, it is unclear which protein(s) Vpr interacts with to cause this effect. For recent reviews, see, (Li et al., 2005; Zhao, Bukrinsky, and Elder, 2005). Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdk1/Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. The activity of Cdk1/Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyr15) on Cdk1/Cdc2, which is phosphorylated by Wee1 kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdk1/Cdc2 regulators are the downstream targets of two well-characterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. It is clear that Vpr induces cell cycle G2/M arrest by promoting Tyr15 phosphorylation of Cdk1/Cdc2 both in human and fission yeast cells (Elder et al., 2000; Re et al., 1995; Zhao et al., 1996), which modulates host cell cycle machinery to benefit viral survival or replication. Although some aspects of Vpr-induced G2/M arrest resembles induction of host cellular checkpoints, increasing evidence suggests that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest (Elder, Benko, and Zhao, 2002; Elder et al., 2001; Masuda et al., 2000). Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions. Host Interactions of HIV factors Like all viruses, HIV-1 must co-opt the host cell macromolecular transport and processing machinery. HIV-1 Vpr and Rev proteins play key roles in this co-optation. Efficient HIV-1 replication likewise requires evasion of APOBEC3G-mediated mutagenesis of reverse transcripts, a process mediated by the viral Vif protein. Reactome Database ID Release 43162909 Reactome, http://www.reactome.org ReactomeREACT_6288 Reviewed: Benarous, R, Zhao, RY, Peterlin, BM, 2006-10-30 22:12:28 APOBEC3G mediated resistance to HIV-1 infection Authored: Matthews, L, 2006-06-07 20:09:24 Edited: Matthews, L, 2007-01-30 11:27:41 Pubmed12167863 Pubmed15098018 Pubmed15152192 Pubmed16414984 Reactome Database ID Release 43180689 Reactome, http://www.reactome.org ReactomeREACT_9406 Representatives of the apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) family provide innate resistance to exogeneous and endogenous retroviruses (see Cullen 2006 for a recent review). Humans and other primates encode a cluster of seven different cytidine deaminases with APOBEC3G, APOBEC3F and APOBEC3B having some anti HIV-1 activity. Our understanding is most complete for APOBEC3G which has been described first and the reactions described herein will focus on this representative enzyme.<br><br>APOBEC3G is a cytoplasmic protein which strongly restricts replication of Vif deficient HIV-1 (Sheehy 2002). It is expressed in cell populations that are susceptible to HIV infection (e.g., T-lymphocytes and macrophages). In the producer cell, APOBEC3G is incorporated into budding HIV-1 particles through an interaction with HIV-1 gag nucleocapsid (NC) protein in a RNA-dependent fashion. <br><br>Within the newly infected cell (= target cell), virus-associated APOBEC3G regulates the infectivity of HIV-1 by deaminating cytidine to uracil in the minus-strand viral DNA intermediate during reverse transcription. Deamination results in the induction of G-to-A hypermutations in the plus-strand viral DNA which subsequently can either be integrated as a non-functional provirus or degraded before integration. Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 Vif-mediated degradation of APOBEC3G Authored: Matthews, L, 2006-05-15 23:53:25 Edited: Matthews, L, 2007-01-30 11:27:41 Pubmed12167863 Pubmed14527406 Pubmed14528300 Pubmed14564014 Pubmed15781449 Pubmed16354571 Reactome Database ID Release 43180585 Reactome, http://www.reactome.org ReactomeREACT_9453 Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 The HIV-1 accessory protein Vif (Viral infectivity factor) is required for the efficient infection of primary cell populations (e.g., lymphocytes and macrophages) and “non-permissive” cell lines. Vif neutralises the host DNA editing enzyme, APOBEC3G, in the producer cell. Indeed, in the absence of a functional Vif, APOBEC3G is selectively incorporated into the budding virions and in the next cycle of infection leads to the deamination of deoxycytidines (dC) within the minus-strand cDNA during reverse transcription (Sheehy et al 2003; Li et al., 2005 ; Stopak et al. 2003).<br>Deamination changes cytidine to uracil and thus results in G to A transitions and stop codons in the provirus. The aberrant cDNAs produced in the infected cell can either be integrated in form of non-functional proviruses or degraded. Vif counteracts the antiviral activity of APOBEC3G by associating directly with it and promoting its polyubiquitination and degradation by the 26S proteasome. <br>Vif binds APOBEC3G and recruits it into an E3 ubiquitin-enzyme complex composed by the cytoplasmic proteins Cullin5, Rbx, ElonginC and ElonginB (Yu et al., 2003) . Thus, in the presence of Vif, APOBEC3G incorporation into the virion is minimal.<br> Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-06-02 10:55:44 In one model of Vpr mediated induction of apoptosis, Vpr acts directly on the mitochondrial permeability transition pore complex through its interaction with adenine nucleotide translocator (ANT). This interaction promotes the permeabiliztion of the mitochondrial membranes resulting in the release of cytochrome c and apoptosis-inducing factors. Pubmed10620603 Reactome Database ID Release 43180897 Reactome, http://www.reactome.org ReactomeREACT_8016 Reviewed: Zhao, RY, 2006-07-11 22:08:52 Vpr-mediated nuclear import of PICs Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-06-07 20:08:05 Reactome Database ID Release 43180910 Reactome, http://www.reactome.org ReactomeREACT_7991 Reviewed: Zhao, RY, 2006-07-11 22:08:52 Vpr appears to function in anchoring the PIC to the nuclear envelope. This anchoring likely involves interactions between Vpr and host nucleoporins. Interactions of Rev with host cellular proteins Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2006-03-24 13:43:41 In order to facilitate the transport of incompletely spliced HIV-1 transcripts, Rev shuttles between the cytoplasm and nucleus using host cell transport mechanisms (reviewed in Li et al. 2005). Nuclear import appears to be achieved by the association of Rev with importin–beta and B23 and docking at the nuclear pore through interactions between importin-beta and nucleoporins. The dissociation of Rev with the import machinery and the subsequent export of Rev-associated HIV-1 mRNA complex requires Ran-GTP. Ran GTP associates with importin-beta, displacing its cargo. Crm1 associates with the Rev:RNA complex and Ran:GTP and is believed to interact with nucleoporins facilitating docking of the RRE-Rev-CRM1-RanGTP complex to the nuclear pore and the translocation of the complex across the nuclear pore complex. In the cytoplasm, RanBP1 associates with Ran-GTP causing the Crm1-Rev-Ran-GTP complex to disassemble. The Ran GAP protein promotes the hydrolysis of RanGTP to Ran GDP. The activities of Ran GAP in the cytoplasm and Ran-GEF, which converts RAN-GDP to Ran-GTP in the nucleus, produce a gradient of Ran-GTP/GDP required for this shuttling of Rev and other cellular transport proteins. Pubmed9837918 Reactome Database ID Release 43177243 Reactome, http://www.reactome.org ReactomeREACT_6916 Reviewed: Kumar, A, 2007-01-31 22:47:49 Nuclear import of Rev protein Authored: Matthews, L, 2006-06-08 06:14:23 Edited: Matthews, L, 2007-01-31 22:42:03 Nuclear import of Rev involves the cellular proteins including importin-beta and B23 and is mediated by an arginine-rich nuclear localization signal (NLS) within the RNA binding domain of the Rev protein. The NLS of Rev associates with importin- beta as well as B23 which has been shown to function in the nuclear import of ribosomal proteins. The Rev-importin β-B23 complex associates with the nuclear pore through interactions between importin β and nucleoporin. Upon entry into the nucleus, Ran-GTP associates with importin β resulting in in the disassembly of the importin β-Rev-B23 complex and the release of Rev cargo. Reactome Database ID Release 43180746 Reactome, http://www.reactome.org ReactomeREACT_9395 Reviewed: Kumar, A, 2007-01-31 22:47:49 Endopeptidases for SCF processing Converted from EntitySet in Reactome Reactome DB_ID: 1433401 Reactome Database ID Release 431433401 Reactome, http://www.reactome.org ReactomeREACT_111360 NRP-2 Converted from EntitySet in Reactome Reactome DB_ID: 195379 Reactome Database ID Release 43195379 Reactome, http://www.reactome.org ReactomeREACT_13365 Voltage gated Potassium channels Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Pubmed18446619 Pubmed20393197 Reactome Database ID Release 431296072 Reactome, http://www.reactome.org ReactomeREACT_75770 Reviewed: Jassal, B, 2010-09-23 Voltage-gated K+ channels (Kv) determine the excitability of heart, brain and skeletal muscle cells. Kv form octameric channel with alpha subunits that forms the pore of the channel and associated beta subunits. The alpha subunits associate with beta subunits with a stoichiometry of alpha4beta4.The alpha subunits have been classified into 12 families, 1-12 with several representatives from each family. Members of Kv 1-4 form both homotetramers and heterotetramers, however, members of Kv 5-12 form functional heterotetramers. Kv's are expressed in the axon, at axon nodes, somatodendritic sites and axon termini. Classical Kir channels Authored: Mahajan, SS, 2011-05-18 Classical Kir channels are inwardly rectifying K+ channels with strong inwardly rectifying currents that contribute to highly negative resting membrane potential, prolonged action potential plateau and rapid repolarization in the final stage of action potential. Classical Kir channels are found in various cells such as cardiac myocytes, purkinje fibers, atrial and ventricular tissues. Rectification is caused by intracellular Mg2+ ions and polyamines. Edited: Mahajan, SS, 2011-05-23 Pubmed10599834 Reactome Database ID Release 431296053 Reactome, http://www.reactome.org ReactomeREACT_75870 Reviewed: Jassal, B, 2010-09-23 Tandem of pore domain in a weak inwardly rectifying K+ channels (TWIK) Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed19959478 Reactome Database ID Release 431299308 Reactome, http://www.reactome.org ReactomeREACT_75779 Reviewed: Jassal, B, 2010-09-23 TWIK channels exhibit very low current and comprise of TWIK1, TWIK2 and KCNK7 members. TWIK current may be low due to rapid recycling of the channels from the plasma membrane. Tandem pore domain potassium channels Authored: Mahajan, SS, 2011-05-19 Edited: Mahajan, SS, 2011-05-23 Pubmed20393194 Pubmed20529081 Reactome Database ID Release 431296346 Reactome, http://www.reactome.org ReactomeREACT_75897 Reviewed: Jassal, B, 2010-09-23 Tandem pore domain K+ channels (K2p) produce leak K+ current which stabilizes negative membrane potential and counter balances depolarization. These channels are regulated by voltage independent mechanisms such as membrane stretch, pH, temperature. Tandem pore domain K+ channels have been classified into six subfamilies; tandem pore domains in weak rectifying K+ channel (TWIK), TWIK-related K+ channel (TREK), TWIK-related acid-sensitive K+ channel (TASK), TWIK-related alkaline pH-activated K+ channel (TALK), tandem pore domain halothane-inhibted K+ channel (THIK), TWIK-releated spinal cord K+ channel). TWIK-releated acid-sensitive K+ channel (TASK) Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed18824070 Reactome Database ID Release 431299316 Reactome, http://www.reactome.org ReactomeREACT_75899 Reviewed: Jassal, B, 2010-09-23 TASK 1 and 3 are closely related both structurally and functionally. TASK1 and TASK3 are activated by extracellular acidification and inhibited by decrease in pH. TASK 1 and Task 3 form functional homodimers and heterodimers, however the biophysical properties of TAS1 and TASK3 heteromers are different form parent subunit properties. TWIK related potassium channel (TREK) Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Pubmed19840997 Reactome Database ID Release 431299503 Reactome, http://www.reactome.org ReactomeREACT_75819 Reviewed: Jassal, B, 2010-09-23 TREK1 and TREK 2 are activated by physiochemical changes like stretch, convex deformation of the plasma membrane, depolarization, heat and intracellular acidosis. Polyunsaturated fatty acids (PUFA) including arachidonic acid open TREK channels. TWIK-related spinal cord K+ channel (TRESK) Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed20215114 Reactome Database ID Release 431299344 Reactome, http://www.reactome.org ReactomeREACT_75801 Reviewed: Jassal, B, 2010-09-23 TRESK subfamily of tandem domain K+ channels has one only member. TRESK is regulated by Ca/calmodulin dependent protein phosphatase, calcineurin. TWIK-related alkaline pH activated K+ channel (TALK) Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed20393194 Reactome Database ID Release 431299361 Reactome, http://www.reactome.org ReactomeREACT_75850 Reviewed: Jassal, B, 2010-09-23 TWIK related alkaline pH activated K+ channels are activated by increase in the extracellular pH. TALK1 and TALK 2 are members of the TALK subfamily and are both are activated by rise in extracellular pH. TALK 2 is expressed in proximal tubule cells and collecting duct cells. TASK 2 is involved in the resorption of bicarbonate. Botulinum neurotoxicity Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Botulism, caused by botulinum neurotoxin (BoNT), is characterized by descending flaccid paralysis as a result of inhibition of neurotransmitter release at the neuromuscular junction - NMJ (Turton et al., 2002). According to their antigenic properties, BoNTs are classified into seven different toxin types (A, B, C1, D, E, F and G) although more than 50 sequences encoding 18 subtypes are known (Smith et al., 2005). The toxin is released as a 900 kDa complex containing some accessory proteins of unknown functions (Chen et al., 1998). The toxin types A, B and E are mainly involved in human botulism whereas C and D predominantly cause animal botulism (Poulain et al, 2006). The toxin is absorbed from the gut or other epithelium and reaches neuromuscular junctions by transcytosis (Park and Simpson, 2003). The binding sites for the toxins are distributed across the apical surface of the epithelium (Ahsan et al., 2005). It has been observed that the neurotoxin alone is capable of transcytosis across epithelial cells (Maksymowych and Simpson, 2004). Once internalized, the neurotoxin is dissociated from the non-toxic components of the progenitor toxin in endosome (Uotsu et al., 2006). <br> The neurological inhibition is caused by the specific cleavage of a group of proteins integral to NMJ exocytosis, SNARE proteins (soluble NSF-attachment protein receptors). One or more SNARE proteins are cleaved by BoNT, blocking the release of synaptic vesicular contents like acetylcholine as in the case of motor neurons. <br>BoNTs are synthesized as polypeptides of 150 kDa that are cleaved into heavy and light chains linked by a single disulfide bond. Cleavage takes place within a surface-exposed loop at the N-terminal of the Heavy chain subunit. Both bacterial and host endopeptidases can catalyze BoNT cleavage into heavy and light chains, but bacterial enzymes are thought to carry out this function in vivo.The Heavy Chain (HC) has two 50 kDa functional domains: the N-terminal translocation domain is capable of forming channels in lipid bilayers; the C-terminal ganglioside-binding domain is important for membrane binding and subsequent internalization of toxins by host neurons. The 50 kDa Light chain (LC) is a zinc-dependent endopeptidase specific for core components of neurotransmitter release complexes.<br>BoNT action proceeds in the following steps: binding of cleaved toxin to the target cell membrane; transcytosis from epithelial membrane to target neuromuscular junction cells; release of BoNT Light chain into the target cell cytosol; and proteolytic cleavage of target cell proteins catalyzed by the BoNT Light chain.<br> Edited: Gopinathrao, G, 2006-06-15 22:12:29 GENE ONTOLOGYGO:0007269 Neurotoxicity of Botulinum toxins Pubmed12417130 Pubmed12595426 Pubmed15140915 Pubmed16113261 Pubmed16144978 Pubmed16413070 Pubmed7527117 Pubmed9596697 Reactome Database ID Release 43168799 Reactome, http://www.reactome.org ReactomeREACT_11184 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 Tandem pore domain halothane-inhibited K+ channel (THIK) Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed16683720 Reactome Database ID Release 431299287 Reactome, http://www.reactome.org ReactomeREACT_75880 Reviewed: Jassal, B, 2010-09-23 THIK channels are K+ leak channels that are not regulated by pH or temperature changes. Adapter proteins Converted from EntitySet in Reactome Reactome DB_ID: 1433422 Reactome Database ID Release 431433422 Reactome, http://www.reactome.org ReactomeREACT_111747 Tyrosine kinases Converted from EntitySet in Reactome Reactome DB_ID: 1433353 Reactome Database ID Release 431433353 Reactome, http://www.reactome.org ReactomeREACT_111786 BoNT Light Chain Types B, D, and F cleave VAMP/Synaptobrevin Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed16008342 Pubmed16519520 Pubmed7803399 Pubmed8175689 Reactome Database ID Release 43168769 Reactome, http://www.reactome.org ReactomeREACT_11076 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 VAMP1 is located on the synaptic vesicle membranes and interacts with other VAMP family members. This protein can be cleaved by BoNTs of types B, D and G. Proteolytic cleavage of SNARE complex proteins Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed10865130 Pubmed11520923 Pubmed12417130 Pubmed16101679 Pubmed7527117 Pubmed9334741 Reactome Database ID Release 43168782 Reactome, http://www.reactome.org ReactomeREACT_11242 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 VAMP/synaptobrevin, SNAP-25 and syntaxin are important for synaptic vesicle fusion at the nerve terminal. These proteins constitute the synaptic members of SNARE family (soluble N-ethylmaleimide-sensitive fusion protein) attachment protein receptor, which is central to all membrane fusion events (Umland et al. 1997). These proteins are involved in docking and/or fusion of synaptic vesicles with the presynaptic membrane. BoNTs achieve total blockage of neurotransmitter release by selectively inactivating the synaptic SNAREs by proteolysis.<br>The L chains of BoNTs of different serotypes specifically cleave distinct members of the SNARE family: serotypes B, D, F and G act on VAMP/synaptobrevin localized on synaptic vesicles; BoNT-A and E cleave SNAP-25; and BoNT-C cleaves both syntaxin 1 and SNAP-25, two proteins of the pre-synaptic plasma membrane.<br>Sudhof et al. (2001) and Liu et al. (2005) had observed that alpha-laterotoxins from black widow spider target identical neurmuscular junctions by opposite mechanism resulting in massive vesicle exocytosis. The exact molecular details of the action of these toxins may reveal the underlying processes of synaptic vesicle exocytosis/inbition and their regulation. Translocation of BoNT Light chain Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed12417130 Pubmed12459720 Pubmed13678859 Pubmed7527117 Pubmed8206166 Reactome Database ID Release 43181363 Reactome, http://www.reactome.org ReactomeREACT_11085 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 Translocation of the BoNT Light chain (LC) from an endocytic vesicle into the cytosol is essential for neurotoxicity. It has been proposed that acidic pH within the endosome triggers a conformational change in the Heavy chain (HC) N-terminal domain enabling its insertion into the endosomal lipid bilayer membrane to form a channel large enough to accommodate the unfolded L chain. The L chain moiety of the BoNT protein then traverses this channel towards the cytosol, the disulfide bond holding the H and L chains together is broken, and the L chain refolds and is released into the cytosol. Koriazova and Montal (2003) proposed that the "LC refolds at the interface and dissociates from the HC in the reducing cytosolic milieu where it cleaves its substrate SNAP-25".The molecular details of this process are not yet well understood.<br> MAP kinase activation in TLR cascade Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2010-02-27 GENE ONTOLOGYGO:0051403 Pubmed11242034 Pubmed11861597 Pubmed17637696 Pubmed19196711 Reactome Database ID Release 43450294 Reactome, http://www.reactome.org ReactomeREACT_21308 Reviewed: Gillespie, ME, 2010-02-27 The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002). <p>There are three major groups of MAP kinases<ul><li>the extracellular signal-regulated protein kinases ERK1/2, <li>the p38 MAP kinase<li> and the c-Jun NH-terminal kinases JNK.</ul><p>ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).<p>MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.<p>The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.<p>The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear. TAK1 activates NFkB by phosphorylation and activation of IKKs complex Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2011-08-12 GENE ONTOLOGYGO:0051092 NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression. Pubmed11460167 Pubmed15145317 Pubmed15837794 Reactome Database ID Release 43445989 Reactome, http://www.reactome.org ReactomeREACT_21281 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-02-27 Reviewed: Napetschnig, Johanna, 2012-11-16 TRAF6 Mediated Induction of proinflammatory cytokines Authored: Shamovsky, V, 2009-09-29 Edited: Shamovsky, V, 2009-12-16 GENE ONTOLOGYGO:0002756 In human, together with ubiquitin-conjugating E2-type enzymes UBC13 and UEV1A (also known as UBE2V1), TRAF6 catalyses Lys63-linked ubiquitination. It is believed that auto polyubiquitination and oligomerization of TRAF6 is followed by binding the ubiquitin receptors of TAB2 or TAB3 (TAK1 binding protein 2 and 3), which stimulates phosphorylation and activation of TGF beta-activated kinase 1(TAK1).<p>TAK1 phosphorylates IKK alpha and IKK beta, which in turn phosphorylate NF-kB inhibitors - IkB and eventually results in IkB degradation and NF-kB translocation to the nucleus. Also TAK1 mediates JNK and p38 MAP kinases activation by phosphorylating MKK4/7 and MKK3/6 respectivly resulting in the activation of many transcription factors. <p>The role of TRAF6 is somewhat controversial and probably cell type specific. TRAF6 autoubiquitination was found to be dispensable for TRAF6 function to activate TAK1 pathway. These findings are consistent with the new mechanism of TRAF6-mediated NF-kB activation that was suggested by Xia et al. (2009). TRAF6 generates unanchored Lys63-linked polyubiquitin chains that bind to the regulatory subunits of TAK1 (TAB2 or TAB3) and IKK(NEMO), leading to the activation of the kinases.<p> Xia et al. (2009) demonstrated in vitro that unlike polyubiquitin chains covalently attached to TRAF6 or IRAK, TAB2 and NEMO-associated ubiquitin chains were found to be unanchored and susceptible to N-terminal ubiquitin cleavage. Only K63-linked polyubiquitin chains, but not monomeric ubiquitin, activated TAK1 in a dose-dependent manner. Optimal activation of the IKK complex was achieved using ubiquitin polymers containing both K48 and K63 linkages.<p>Furthermore, the authors proposed that the TAK1 complexes might be brougt in close proximity by binding several TAB2/3 to a single polyubiquitin chain to facilitate TAK1 kinase trans-phosphorylation. Alternativly, the possibility that polyUb binding promotes allosteric activation of TAK1 complex should be considered (Walsh et al 2008). Pubmed12609980 Pubmed19112497 Pubmed19675569 Reactome Database ID Release 43168180 Reactome, http://www.reactome.org ReactomeREACT_6782 Reviewed: Gay, NJ, 2006-04-24 16:48:17 BoNT Light Chain Types A, C1, E cleave SNAP-25 Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 BoNTs of serotypes A, C1 and E cleave SNAP-25 (synaptosomal-associated protein, 25kDa), a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. BoNT A removes nine amino-acid residues from the carboxyl terminus, whereas BoNT E removes 26 C-terminal amino-acid residues (Bajohrs et al.,2004). Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed15486565 Pubmed8243676 Pubmed8294407 Pubmed8611567 Pubmed9886085 Reactome Database ID Release 43181546 Reactome, http://www.reactome.org ReactomeREACT_11240 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 ERK activation Activated MEK phosphorylates and activates ERK. GENE ONTOLOGYGO:0000187 Reactome Database ID Release 43112409 Reactome, http://www.reactome.org ReactomeREACT_1482 Reviewed: Greene, LA, 2007-11-08 15:39:37 activated TAK1 mediates p38 MAPK activation Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2010-02-27 GENE ONTOLOGYGO:0000187 Pubmed10878576 Pubmed15837794 Pubmed8533096 Pubmed8622669 Reactome Database ID Release 43450302 Reactome, http://www.reactome.org ReactomeREACT_21399 Reviewed: Gillespie, ME, 2010-02-27 p38 mitogen-activated protein kinase (MAPK) belongs to a highly conserved family of serine/threonine protein kinases. <p>The p38 MAPK-dependent signaling cascade is activated by pro-inflammatory or stressful stimuli such as ultraviolet radiation, oxidative injury, heat shock, cytokines, and other pro-inflammatory stimuli. p38 MAPK exists as four isoforms (alpha, beta, gamma, and delta). Of these, p38alpha and p38beta are ubiquitously expressed while p38gamma and p38delta are differentially expressed depending on tissue type. Each isoform is activated by upstream kinases including MAP kinase kinases (MKK) 3, 4, and 6, which in turn are phosphorylated by activated TAK1 at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.<p>Once p38 MAPK is phosphorylated it activates numerous downstream substrates, including MAPK-activated protein kinase-2 and 3 (MAPKAPK-2 or 3) and mitogen and stress-activated kinase-1/2 (MSK1/2). MAPKAPK-2/3 and MSK1/2 function to phosphorylate heat shock protein 27 (HSP27) and cAMP-response element binding protein transcriptional factor, respectively. Other transcription factors, including activating transcription factor 2, Elk, CHOP/GADD153, and myocyte enhancer factor 2, are known to be regulated by these kinases. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 Authored: Shamovsky, V, 2009-12-16 C-Jun NH2 terminal kinases (JNKs) are an evolutionarily conserved family of serine/threonine protein kinases, that belong to mitogen activated protein kinase family (MAPKs - also known as stress-activated protein kinases, SAPKs). The JNK pathway is activated by heat shock, or inflammatory cytokines, or UV radiation. <p>The JNKs are encoded by at least three genes: JNK1/SAPK-gamma, JNK2/SAPK-alpha and JNK3/ SAPK-beta. The first two are ubiquitously expressed, whereas the JNK3 protein is found mainly in brain and to a lesser extent in heart and testes. As a result of alternative gene splicing all cells express distinct active forms of JNK from 46 to 55 kDa in size. Sequence alignment of these different products shows homologies of >80%. In spite of this similarity, the multiple JNK isoforms differ in their ability to bind and phosphorylate different target proteins, thus leading to the distinctive cellular processes: induction of apoptosis, or enhancment of cell survival, or proliferation.<p>Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7). Edited: Shamovsky, V, 2010-02-27 GENE ONTOLOGYGO:0007254 Pubmed11460167 Pubmed13130464 Pubmed15837794 Pubmed16937364 Pubmed8177321 Pubmed9851932 Reactome Database ID Release 43450321 Reactome, http://www.reactome.org ReactomeREACT_21368 Reviewed: Gillespie, ME, 2010-02-27 p-STATs Converted from EntitySet in Reactome Reactome DB_ID: 1469979 Reactome Database ID Release 431469979 Reactome, http://www.reactome.org ReactomeREACT_111653 p-STATs Converted from EntitySet in Reactome Reactome DB_ID: 1433413 Reactome Database ID Release 431433413 Reactome, http://www.reactome.org ReactomeREACT_111405 STATs Converted from EntitySet in Reactome Reactome DB_ID: 1433551 Reactome Database ID Release 431433551 Reactome, http://www.reactome.org ReactomeREACT_111833 STAT1, STAT5A, STAT5B CREB phosphorylation Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Nerve growth factor (NGF) activates multiple signalling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133. CREB phosphorylation at serine 133 is a crucial event in neurotrophin signalling, being mediated by ERK/RSK, ERK/MSK1 and p38/MAPKAPK2 pathways. Several kinases, such as MSK1, RSK1/2/3 (MAPKAPK1A/B/C), and MAPKAPK2, are able to directly phosphorylate CREB at S133. MSK1 is also able to activate ATF (Cyclic-AMP-dependent transcription factor). However, the NGF-induced CREB phosphorylation appears to correlate better with activation of MSK1 rather than RSK1/2/3, or MAPKAPK2. In retrograde signalling, activation of CREB occurs within 20 minutes after neurotrophin stimulation of distal axons. Reactome Database ID Release 43199920 Reactome, http://www.reactome.org ReactomeREACT_12524 Reviewed: Greene, LA, 2007-11-08 15:39:37 ERKs are inactivated MAP Kinases are inactivated by a family of protein named MAP Kinase Phosphatases (MKPs). They act through dephosphorylation of threonine and/or tyrosine residues within the signature sequence -pTXpY- located in the activation loop of MAP kinases (pT=phosphothreonine and pY=phosphotyrosine). MKPs are divided into three major categories depending on their preference for dephosphorylating; tyrosine, serine/threonine and both the tyrosine and threonine (dual specificity phoshatases or DUSPs). The tyrosine-specific MKPs include PTP-SL, STEP and HePTP, serine/threonine-specific MKPs are PP2A and PP2C, and many DUSPs acting on MAPKs are known. Activated MAP kinases trigger activation of transcription of MKP genes. Therefore, MKPs provide a negative feedback regulatory mechanism on MAPK signaling, by inactivating MAPKs via dephosphorylation, in the cytoplasm and the nucleus. Some MKPs are more specific for ERKs, others for JNK or p38MAPK. Pubmed15115656 Pubmed17322878 Reactome Database ID Release 43202670 Reactome, http://www.reactome.org ReactomeREACT_12436 Reviewed: Greene, LA, 2007-11-08 15:39:37 Membrane binding and targetting of GAG proteins GENE ONTOLOGYGO:0046788 ISBN0-87969-571-4 One of the mysteries of Gag protein involvement in HIV virion assembly is how the proteins are targeted to the proper membrane for budding. Infectious retroviruses do not bud from all of the available membrane surfaces within an infected cell, but primarily from the plasma membrane, which constitutes a small proportion of the total membrane surface in most cells. In polarized cells, the sites of budding are further restricted to the basolateral membrane. Pubmed15473846 Pubmed16683918 Reactome Database ID Release 43174490 Reactome, http://www.reactome.org ReactomeREACT_115893 Activation of the AP-1 family of transcription factors Activator protein-1 (AP-1) is a collective term referring to a group of transcription factors that bind to promoters of target genes in a sequence-specific manner. AP-1 family consists of hetero- and homodimers of bZIP (basic region leucine zipper) proteins, mainly of Jun-Jun, Jun-Fos or Jun-ATF. <p>AP-1 members are involved in the regulation of a number of cellular processes including cell growth, proliferation, survival, apoptosis, differentiation, cell migration. The ability of a single transcription factor to determine a cell fate critically depends on the relative abundance of AP-1 subunits, the composition of AP-1 dimers, the quality of stimulus, the cell type, the co-factor assembly. </p><p>AP-1 activity is regulated on multiple levels; transcriptional, translational and post-translational control mechanisms contribute to the balanced production of AP-1 proteins and their functions. Briefly, regulation occurs through:<ol><li>effects on jun, fos, atf gene transcription and mRNA turnover.<li> AP-1 protein members turnover. <li>post-translational modifications of AP-1 proteins that modulate their transactivation potential (effect of protein kinases or phosphatases).<li>interactions with other transcription factors that can either induce or interfere with AP-1 activity.</ol> Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2010-02-27 GENE ONTOLOGYGO:0051090 Pubmed15564374 Pubmed19167516 Pubmed7622446 Pubmed9069263 Reactome Database ID Release 43450341 Reactome, http://www.reactome.org ReactomeREACT_21326 Reviewed: Gillespie, ME, 2010-02-27 ERK2 activation Activated MEK2 phosphorylates and activates ERK2. Authored: Charalambous, M, 2005-02-04 06:50:22 Edited: Schmidt, EE, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0070371 Reactome Database ID Release 43112411 Reactome, http://www.reactome.org ReactomeREACT_1183 Reviewed: Greene, LA, 2007-11-08 15:39:37 ERK1 activation Activated MEK1 phosphorylates and activates ERK1. Authored: Charalambous, M, 2005-02-04 06:50:22 Edited: Schmidt, EE, 0000-00-00 00:00:00 Reactome Database ID Release 43110056 Reactome, http://www.reactome.org ReactomeREACT_1391 Reviewed: Greene, LA, 2007-11-08 15:39:37 ERK/MAPK targets Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 ERK/MAPK kinases have a number of targets within the nucleus, usually transcription factors or other kinases. The best known targets, ELK1, ETS1, ATF2, MITF, MAPKAPK2, MSK1, RSK1/2/3 and MEF2 are annotated here. Reactome Database ID Release 43198753 Reactome, http://www.reactome.org ReactomeREACT_12599 Reviewed: Greene, LA, 2007-11-08 15:39:37 MAPK targets/ Nuclear events mediated by MAP kinases Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2010-02-27 MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity. <p>The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.</p><p>Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).</p><p>JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK. Pubmed12471242 Pubmed16393692 Pubmed17158707 Pubmed17637696 Pubmed19767751 Reactome Database ID Release 43450282 Reactome, http://www.reactome.org ReactomeREACT_21328 Reviewed: Gillespie, ME, 2010-02-27 HIV Infection Authored: Bukrinsky, M, D'Eustachio, P, Gillespie, ME, Gopinathrao, G, Iordanskiy, S, Morrow, MP, Matthews, L, Rice, AP, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0016032 Pubmed16354571 Pubmed9759480 Reactome Database ID Release 43162906 Reactome, http://www.reactome.org ReactomeREACT_6185 The global pandemic of Human Immunodeficiency Virus (HIV) infection has resulted in tens of millions of people infected by the virus and millions more affected. UNAIDS estimates around 40 million HIV/AIDS patients worldwide with 75% of them living in sub-Saharan Africa. The primary method of HIV infection is by sexual exposure while nonsexual HIV transmission also can occur through transfusion with contaminated blood products, injection drug use, occupational exposure,accidental needlesticks or mother-to-child transmission. HIV damages the immune system, leaving the infected person vulnerable to a variety of "opportunistic" infections arising from host immune impairment (Hare, 2004).<br>HIV-1 and the less common HIV-2 belong to the family of retroviruses. HIV-1 contains a single-stranded RNA genome that is 9 kilobases in length and contains 9 genes that encode 15 different proteins. These proteins are classified as: structural proteins (Gag, Pol, and Env), regulatory proteins (Tat and Rev), and accessory proteins (Vpu, Vpr, Vif, and Nef) (Frankel and Young,1998).<br><b>HIV infection </b>cycle can be divided into two phases:<br>1. An <b>Early phase</b> consisting of early events occuring after HIV infection of a susceptible target cell and a <br>2. <b>Late phase</b> comprising the later events in the HIV-infected cell resulting in the assembly of new infectious virions. The section titled <b>HIV lifecycle</b> consists of annotations of events in these two phases.<br>The virus has developed various molecular strategies to suppress the antiviral immune responses (innate, cellular and humoral) of the host. HIV-1 viral auxiliary proteins (Tat, Rev, Nef, Vif, Vpr and Vpu) play important roles in these host-pathogen interactions (Li et al.,2005). The section titled <b>Host interactions of HIV factors</b> will highlight these complex post-infection processes and the annotations will be released in near future.<br> Disease Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.<p>The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.<p>Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources. Reactome Database ID Release 431643685 Reactome, http://www.reactome.org ReactomeREACT_116125 HER4 CYT-1 isoforms Converted from EntitySet in Reactome ERBB4 CYT-1 isoforms Reactome DB_ID: 1233231 Reactome Database ID Release 431233231 Reactome, http://www.reactome.org ReactomeREACT_117355 HIV Life Cycle Authored: Bukrinsky, M, D'Eustachio, P, Gillespie, ME, Gopinathrao, G, Iordanskiy, S, Morrow, MP, Matthews, L, Rice, AP, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0016032 Pubmed9188609 Pubmed9759480 Reactome Database ID Release 43162587 Reactome, http://www.reactome.org ReactomeREACT_6256 The life cycle of HIV-1 is divided into early and late phases, shown schematically in the figure. In the <b>early</b> phase, an HIV-1 virion binds to receptors and co-receptors on the human host cell surface (a), viral and host cell membranes fuse and the viral particle is uncoated (b), the viral genome is reverse transcribed and the viral preintegration complex (PIC) forms (c), the PIC is transported through the nuclear pore into the nucleoplasm (d), and the viral reverse transcript is integrated into a host cell chromosome (e). In the <b>late</b> phase, viral RNAs are transcribed from the integrated viral genome and processed to generate viral mRNAs and full-length viral genomic RNAs (f), the viral RNAs are exported through the nuclear pore into the cytosol (g), viral mRNAs are translated and the resulting viral proteins are post-translationally processed (h), core particles containing viral genomic RNA and proteins assemble at the host cell membrane and immature viral particles are released by budding. The released particles mature to become infectious (j), completing the cycle (Frankel and Young 1998; Miller and Bushman 1997).<br>Most of the crucial concepts used to describe these processes were originally elucidated in studies of retroviruses associated with tumors in chickens, birds, and other animal model systems, and the rapid elucidation of the basic features of the HIV-1 life cycle was critically dependent on the intellectual framework provided by these earlier studies. This earlier work has been very well summarized (e.g., Weiss et al. 1984; Coffin et al. 1997); here for brevity and clarity we focus on experimental studies specific to the HIV-1 life cycle. Integration of viral DNA into host genomic DNA Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Following nuclear entry, the viral preintegration complex (PIC) must select a site for integration in a host cell chromosome, and then carry out the chemical steps of the reaction. <p>At the chromosomal level, HIV has been found to favor active transcription units for integration. Subsequent studies established that the cellular PSIP1/LEDGF/p75 protein is important in this reaction. PSIP1/LEDGF/p75 binds tightly to HIV integrase, and also to chromatin. Knocking down PSIP1/LEDGF/p75 in cells resulted in several perturbations of integration targeting in vivo, including reduced integration in transcription units. Thus PSIP1/LEDGF/p75 has been hypothesized to act as a tethering factor that dictates at least in part the placement of HIV integration sites. <p>The integration target DNA is also expected to be coated with nucleosomes. Tests of integration into mononucleosomes in vitro have shown that wrapping integration target DNA actually boosts integration activity. Kinked positions on the DNA gyre are particularly favored for integration. <p>Integration does not take place at a unique sequence in the integration target DNA (i.e. it is not like a restriction enzyme). However, favored and disfavored primary sequences can be detected when many integration sites are aligned. Synthesis and testing of favored HIV integration sites showed that they were favored for integration by PICs in vitro. <p>After a target DNA is bound, the integration reactions take place via a single-step transesterification.<p>Integration of both ends of the viral DNA, followed by melting of the target DNA segments between the points of joining, yields single stranded gaps at each host-virus DNA junction, and a two base overhang derived from the viral DNA. The manner by which this intermediate is subsequently repaired to yield the fully integrated provirus is unclear. For many parasitic DNA replication reactions, the parasite carries out reaction steps only up to a point that the host cannot easily reverse, forcing the host to complete the job (Bushman 2001; Craig et al. 2002). For retroviral integration, it is reasonable to infer that host DNA repair enzymes complete provirus formation. DNA gap repair enzymes are known to be involved in a variety of DNA repair pathways, so their recruitment to gaps at host-virus DNA junctions is readily envisioned. Consistent with this, known gap repair enzymes have been shown to act on model host-virus DNA junctions in vitro (Yoder and Bushman, 2000). GENE ONTOLOGYGO:0019047 Pubmed16175173 Pubmed16291214 Pubmed16482214 Pubmed8041787 Pubmed9188609 Reactome Database ID Release 43175567 Reactome, http://www.reactome.org ReactomeREACT_8990 Reviewed: Bushman, FD, 2006-10-30 22:19:13 Integration of provirus Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 For retroviral DNA to direct production of progeny virions it must become covalently integrated into the host cell chromosome (reviewed in Coffin et al. 1997; Hansen et al. 1998). Analyses of mutants have identified the viral integrase coding region (part of the retroviral pol gene) as essential for the integration process (Donehower 1988; Donehower and Varmus 1984; Panganiban and Temin 1984; Quinn and Grandgenett 1988; Schwartzberg et al. 1984). Also essential are regions at the ends of the viral long terminal repeats (LTRs) that serve as recognition sites for integrase protein (Colicelli and Goff 1985, 1988; Panganiban and Temin 1983).<p>The viral genomic RNA is reverse transcribed to form a linear double-stranded DNA molecule, the precursor to the integrated provirus (Brown et al. 1987, 1989; Fujiwara and Mizuuchi 1988). The provirus is colinear with unintegrated linear viral DNA (Dhar et al. 1980; Hughes et al. 1978) but differs from the reverse transcription product in that it is missing two bases from each end (Hughes et al. 1981). Flanking the integrated HIV provirus are direct repeats of the cellular DNA that are 5 base pairs in length (Vincent et al. 1990). This duplication of cellular sequences flanking the viral DNA is generated as a consequence of the integration mechanism (Coffin et al., 1997). <p>Linear viral DNA is found in a complex with proteins in the cytoplasm of infected cells. These complexes (termed "preintegration complexes", PICs) can be isolated and have been shown to mediate integration of viral DNA into target DNA in vitro (Bowerman et al. 1989; Brown et al. 1987; Ellison et al. 1990; Farnet and Haseltine 1990, 1991). <p>The development of in vitro assays with purified integrase has allowed its enzymatic functions to be elucidated. The provirus is formed by two reactions catalyzed by the viral integrase: terminal cleavage and strand transfer. Studies with purified integrase have shown that it is sufficient for both 3' end cleavage (Bushman and Craigie 1991; Craigie et al. 1990; Katzman et al. 1989; Sherman and Fyfe 1990) and joining of the viral DNA to the cellular chromosome or naked target DNA (Bushman et al. 1990; Craigie et al. 1990; Katz et al. 1990). HIV integrase catalyze the removal of two bases from the 3' end of each viral DNA strand, leaving recessed 3' hydroxyl groups (Brown et al. 1989; Fujiwara and Mizuuchi 1988; Roth et al. 1989; Sherman and Fyfe 1990). This terminal cleavage reaction is required for proper integration. It may allow the virus to create a standard end from viral DNA termini that can be heterogeneous due to the terminal transferase activity of reverse transcriptase (Miller et al. 1997; Patel and Preston 1994). In addition, the terminal cleavage step is coupled to the formation of a stable integrase-DNA complex (Ellison and Brown 1994; Vink et al. 1994). Following terminal cleavage, a recessed hydroxyl is exposed that immediately follows a CA dinucleotide. More internal LTR sites are also important for integration (Balakrishnan and Jonsson 1997; Bushman and Craigie 1990; Leavitt et al. 1992). After end processing, integrase catalyzes the covalent attachment of hydroxyl groups at the viral DNA termini to protruding 5' phosphoryl ends of the host cell DNA (Brown et al. 1987; Brown et al. 1989; Fujiwara and Mizuuchi 1988). The DNA cleavage and joining reactions involved in integration are shown in the figure below. Both the viral DNA 3' end cleavage and strand transfer reactions are mediated by single-step transesterification chemistry as shown by stereochemical analysis of reaction products (Engelman et al. 1991). Biochemical analysis of purified integrase revealed that it requires a divalent metal - either Mg2+ or Mn2+ - to carry out reactions with model substrates, that probably mediate the reaction chemistry (Bushman and Craigie 1991; Craigie et al. 1990; Katzman et al. 1989; Sherman and Fyfe 1990; Gao et al. 2004). GENE ONTOLOGYGO:0019047 Pubmed15194746 Pubmed1548767 Pubmed16291214 Pubmed1760846 Pubmed1847518 Pubmed2002549 Pubmed215325 Pubmed2164223 Pubmed2167180 Pubmed2170022 Pubmed2171144 Pubmed2214030 Pubmed2235486 Pubmed2335814 Pubmed2349226 Pubmed2539592 Pubmed2546673 Pubmed2555556 Pubmed2721960 Pubmed2836614 Pubmed2845117 Pubmed3032450 Pubmed3351923 Pubmed3401925 Pubmed4028161 Pubmed6083562 Pubmed6204767 Pubmed6208550 Pubmed6254003 Pubmed6270669 Pubmed6316141 Pubmed7507249 Pubmed7937134 Pubmed8041787 Pubmed8995622 Pubmed9188609 Pubmed9666555 Reactome Database ID Release 43162592 Reactome, http://www.reactome.org ReactomeREACT_6918 Reviewed: Bushman, FD, 2006-10-30 22:19:13 Plus-strand DNA synthesis Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 GENE ONTOLOGYGO:0006278 Pubmed10723025 Pubmed9371584 Reactome Database ID Release 43164525 Reactome, http://www.reactome.org ReactomeREACT_9037 Reviewed: Hughes, SH, 2006-10-30 22:00:51 Two specific polypurine tracts (PPT sequences) in the viral RNA, one within the pol gene (central or cPPT) and one immediately preceding the U3 sequence (3' PPT), are spared from degradation during minus strand DNA synthesis and prime plus-strand synthesis. At least two discrete steps of DNA replication, removal of the PPT RNAs and the tRNA primer that initiated minus-strand synthesis, and a strand transfer lead to the synthesis of a linear duplex DNA corresponding to the full length of the HIV genomic RNA with long terminal repeat (LTR) sequences at both ends. Both DNA synthesis and RNA degradation are catalyzed by domains of the HIV-1 reverse transcriptase (RT) heterodimer. During plus-strand synthesis, Preston and colleagues observed secondary sites of plus-strand initiation at low frequency both in the cell-free system and in cultured virus-infected cells (Klarman et al., 1997). Minus-strand DNA synthesis Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 GENE ONTOLOGYGO:0006278 In the first part of reverse transcription, minus-strand synthesis, a DNA strand complementary to the HIV genomic RNA is synthesized, using the viral RNA as a template and a host cell lysine tRNA molecule as primer. The synthesis proceeds in two discrete steps, separated by a strand transfer event. As minus strand DNA is synthesized, the viral genomic RNA is degraded, also in several discrete steps. Two specific polypurine tracts (PPT sequences) in the viral RNA, one within the pol gene (central or cPPT) and one immediately preceding the U3 sequence (3' PPT) are spared from degradation and serve to prime synthesis of DNA complementary to the minus strand (plus-strand synthesis). During plus-strand synthesis, Preston and colleagues observed secondary sites of plus-strand initiation at low frequency both in the cell-free system and in cultured virus (Klarman et al., 1997). Both DNA synthesis and RNA degradation activities are catalyzed by the HIV-1 reverse transcriptase (RT) heterodimer. Pubmed10723025 Pubmed1282352 Pubmed1382072 Pubmed7514143 Pubmed9371584 Reactome Database ID Release 43164516 Reactome, http://www.reactome.org ReactomeREACT_9055 Reviewed: Hughes, SH, 2006-10-30 22:00:51 minus-strand DNA synthesis Reverse Transcription of HIV RNA Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 GENE ONTOLOGYGO:0006278 Pubmed10723025 Pubmed1377403 Pubmed4316300 Pubmed4316301 Pubmed7518928 Pubmed7687065 Pubmed8627740 Reactome Database ID Release 43162589 Reactome, http://www.reactome.org ReactomeREACT_6880 Reviewed: Hughes, SH, 2006-10-30 22:00:51 The RNA genome of HIV-1, like that of other retroviruses, is reverse-transcribed (Baltimore 1970; Temin and Mizutani 1970) into double-stranded DNA, which is then integrated into a host cell chromosome and transcribed to yield both viral mRNAs and viral genomic RNAs. HIV-1 reverse transcription takes place in the cytosol of a newly infected host cell and involves multiple steps of RNA synthesis and degradation of the RNA strand of RNA:DNA duplexes mediated by the HIV-1 RT protein, as well as two template switches, to yield a DNA duplex colinear with the viral genomic RNA but with additional Long Terminal Repeat (LTR) sequence motifs at both ends (Telesnitsky and Goff 1997; Jonckheere et al. 2000).<p>HIV-1 RT has two catalytic activities essential for transcription of a DNA duplex copy of the viral genomic RNA: a reverse transcriptase activity and an RNase H activity. The reverse transcriptase is primer dependent and can transcribe both RNA and DNA templates in a 5'-3' direction. The RNaseH acts on the RNA strand of RNA:DNA duplexes and can catalyze both endo- and exonucleolytic cleavage of such an RNA strand. RT is a heterodimer of 66 and 51 kD polypeptides, both generated by cleavage of the HIV-1 Pol gene product: p66 contains Pol amino acid residues 599-1158; p51 contains residues 599-1038. Both active sites of the HIV-1 RT enzyme are contained in the p66 polypeptide, the polymerase activity in its aminoterminal region, and the RNase in its carboxyterminus. The p51 subunit lacks an RNaseH domain, and while its polymerase domain is intact, its conformation in the p66:p51 heterodimer occludes the active site (Hughes et al. 1996; Jacobo-Molina et al. 1993; Kohlstaedt et al. 1992; Wang et al. 1994).<p>The process of reverse transcription is outlined in the figure below: viral genomic RNA and primer tRNA are shown in black, "minus" strand DNA is shown in red, and "plus" strand DNA is shown in blue. Uncoating of the HIV Virion Authored: Iordanskiy, S, Bukrinsky, M, 2006-04-03 16:17:37 Edited: Gopinathrao, G, 2006-02-17 18:35:46 GENE ONTOLOGYGO:0019061 HIV-1 uncoating is a poorly understood process. It likely involves a progressive and partial dissembly of matrix and capsid layers. While viral proteins like MA and Nef are thought to be involved, the primary cause seems to be the cytosolic pH and a simple dilution effect. Successful uncoating generates the viral reverse transcription complex, which comprises the diploid viral RNA genome, tRNALys primer, RT, IN, MA, nucleocapsid (NC), viral protein R (Vpr) and various host proteins; the reverse-transcription complex is thus liberated from the plasma membrane. It is believed that the transiting viral nucleoprotein complex associates with the elements of cytoskeleton like actin microfilaments. Pubmed12091904 Pubmed12417576 Pubmed15502876 Pubmed15700618 Reactome Database ID Release 43162585 Reactome, http://www.reactome.org ReactomeREACT_6965 Reviewed: Aiken, C, 2006-10-30 22:04:39 Binding and entry of HIV virion Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 GENE ONTOLOGYGO:0030260 HIV enters cells by fusion at the cell surface, that results in a productive infection. The envelope (Env) protein of HIV mediates entry. Env is composed of a surface subunit, gp120, and a transmembrane subunit, gp41, which assemble as heterotrimers on the virion surface.The trimeric, surface gp120 protein (SU) on the virion engages CD4 on the host cell, inducing conformational changes that promote binding to select chemokine receptors CCR5 and CXCR4.<br>The sequential interplay between SU, CD4 and chemokine coreceptors prompts a conformational change in the transmembrane gp41. This coiled coil protein, assembled as a trimer on the virion membrane, springs open to project three peptide fusion domains that 'harpoon' the lipid bilayer of the target cell. A hairpin structure (also referred to as a "coiled coil bundle") is subsequently formed when the extracellular portion of gp41 collapses, and this hairpin formation promotes the fusion of virion and target cell membranes by bringing them into close proximity. Virion and target cell membrane fusion leads to the release of HIV viral cores into the cell interior.<br> Reactome Database ID Release 43173107 Reactome, http://www.reactome.org ReactomeREACT_6903 Reviewed: Reeves, J, 2006-06-12 15:22:40 Early Phase of HIV Life Cycle Authored: Iordanskiy, S, Morrow, MP, Gopinathrao, G, D'Eustachio, P, Bukrinsky, M, 2006-05-16 18:51:52 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 GENE ONTOLOGYGO:0022415 In the <b>early phase </b> of HIV lifecycle, an active virion binds and enters a target cell mainly by specific interactions of the viral envelope proteins with host cell surface receptors. The virion core is uncoated to expose a viral nucleoprotein complex containing RNA and viral proteins. HIV RNA genome is reverse transcribed by the viral Reverse Transcriptase to form a cDNA copy, that gets inserted into host cell DNA. The viral Integrase enzyme is vital to carry out the integration of the viral cDNA into the host genome. The host DNA repair enzymes probably repair the breaks in DNA at the sites of integration. Pubmed12091904 Reactome Database ID Release 43162594 Reactome, http://www.reactome.org ReactomeREACT_6266 Reviewed: Aiken, C, Bushman, FD, Hughes, SH, Reeves, J, 2006-10-30 22:07:21 2-LTR circle formation Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed14517098 Pubmed16175173 Pubmed16291214 Reactome Database ID Release 43164843 Reactome, http://www.reactome.org ReactomeREACT_9058 Reviewed: Bushman, FD, 2006-10-30 22:19:13 The formation of 2-LTR circles requires the action of the cellular non-homologous DNA end-joining pathway. Specifically the cellular Ku, XRCC4 and ligase IV proteins are needed. Evidence for this is provided by the observation that cells mutant in these functions do not support detectable formation of 2-LTR circles, though integration and formation of 1-LTR circles are mostly normal. The reaction takes place in the nucleus, and formation of 2-LTR circles has been used as a surrogate assay for nuclear transport. It has also been suggested that the NHEJ system affects the toxicity of retroviral infection. PathwayStep7085 PathwayStep7084 UCP3 Converted from EntitySet in Reactome Mitochondrial uncoupling protein 3 Reactome DB_ID: 166382 Reactome Database ID Release 43166382 Reactome, http://www.reactome.org ReactomeREACT_6696 PathwayStep7087 PathwayStep7086 PathwayStep7081 PathwayStep7080 PathwayStep7083 PathwayStep7082 PathwayStep7089 PathwayStep7088 SMURF2 binds SMAD3 phosphorylated in the linker region Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed22045334 Reactome Database ID Release 432179274 Reactome, http://www.reactome.org ReactomeREACT_121396 Reviewed: Huang, Tao, 2012-05-14 SMURF2 binds SMAD2/3:SMAD4 heterotrimer through ineraction with SMAD3. Phosphorylation of threonine T179 in the linker region of SMAD3 is critical for SMURF2 binding. SMURF2 also interacts with SMAD2 phosphorylated in the linker region. Phosphorylation of UBF-1:rDNA Promoter Authored: Comai, L, 2003-07-03 17:13:29 EC Number: 2.7.11.24 Edited: Gillespie, ME, 0000-00-00 00:00:00 Phosphorylation of UBF-1, bound to the promoter, activates UBF-1 and recruits SL1, and eventually polymerase. This phosphorylation of UBF-1 by Erk1, has been shown to both weaken the binding of UBF-1 to DNA and to activate transcription (the authors of the paper showing these data suggest that loosening the binding of UBF-1 with the promoter may somehow promote transcription initiation). Though not definitively worked out phosphorylation of UBF-1 by Erk1 plays a role in the activation of the UBF-1:rDNA complex. Pubmed11741541 Reactome Database ID Release 4373722 Reactome, http://www.reactome.org ReactomeREACT_180 Type II receptor Converted from EntitySet in Reactome Reactome DB_ID: 201804 Reactome Database ID Release 43201804 Reactome, http://www.reactome.org ReactomeREACT_12229 Formation of SL1 Human SL1 is a four subunit complex composed of the TATA-binding protein (TBP) and three TBP-associated factors (TAFs): TAF(1)110, TAF(1)63, and TAF(1)48. Note that none of these three TAFs for Pol I show any homology to the Pol II or Pol III TAFs. TAFs SL1 is a species specific factor. Pubmed1547496 Pubmed2805069 Pubmed7801123 Reactome Database ID Release 4373729 Reactome, http://www.reactome.org ReactomeREACT_934 Dephosphorylated SMAD2/3 translocates to the cytosol After dephosphorylation by PPM1A, SMAD2 and SMAD3 translocate to the cytosol. Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed16751101 Reactome Database ID Release 432187395 Reactome, http://www.reactome.org ReactomeREACT_120826 Reviewed: Huang, Tao, 2012-05-14 UBF-1 Binds rDNA Promoter Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed2330041 Reactome Database ID Release 4373718 Reactome, http://www.reactome.org ReactomeREACT_2084 UBF-1 binds directly to the CORE and UCE elements of the ribosomal DNA promoter. This binding is mediated by the HMG boxes (primarily HMG box1). Phosphorylation may play a role in the modulation of UBF's DNA binding activity, as well as in subsequent steps. UBF is thought to bind DNA in a conformation specific manner (as opposed to a sequence specific manner). The binding of UBF to the minor groove of DNA induces strong DNA bending. PPM1A protein phosphatase binds phosphorylated SMAD2/3 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 PPM1A protein phosphatase binds phosphorylated SMAD2 and SMAD3 in the nucleus. Pubmed16751101 Reactome Database ID Release 432187388 Reactome, http://www.reactome.org ReactomeREACT_121278 Reviewed: Huang, Tao, 2012-05-14 PPM1A dephosphorylates nuclear SMAD2/3 Authored: Williams, MG, 2007-03-22 16:49:12 Edited: Jassal, B, 2012-04-10 In the nucleus, protein type 2C phosphatase, PPM1A, dephosphorylates SMAD2 and SMAD3, resulting in dissociation of SMAD2/3:SMAD4 heterotrimeric complexes. Pubmed16751101 Reactome Database ID Release 43209055 Reactome, http://www.reactome.org ReactomeREACT_121342 Reviewed: Huang, Tao, 2012-05-14 has a Stoichiometric coefficient of 2 PARP1 binds SMAD2/3:SMAD4 heterotrimer Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 PARP1 (poly [ADP-ribose] polymerase 1) binds SMAD2/3:SMAD4 heterotrimers associated with DNA SMAD-binding elements (SBEs). Pubmed21095583 Reactome Database ID Release 432187330 Reactome, http://www.reactome.org ReactomeREACT_121212 Reviewed: Huang, Tao, 2012-05-14 PARP1 ADP-ribosylates SMAD3 and SMAD4 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 2.4.2.30 Edited: Jassal, B, 2012-04-10 PARP1 ADP-ribosylates SMAD3 and SMAD4 in SMAD2/3:SMAD4 heterotrimer. ADP-ribosyl group is attached to glutamic acid residues E50 and E52 of SMAD3 and unknown amino acid residues of SMAD4. ADP-ribose monomer attached to SMAD3 and SMAD4 is subsequently extended to poly (ADP-ribosyl) chains (i.e. PAR chains) by PARP1, which is not shown here. ADP-ribosylation (PARylation) of SMAD3 and SMAD4 by PARP1 inhibits binding of SMAD2/3:SMAD4 heterotrimers to SMAD binding elements (SBEs) in promoters of SMAD-target genes. Pubmed21095583 Reactome Database ID Release 432187325 Reactome, http://www.reactome.org ReactomeREACT_120778 Reviewed: Huang, Tao, 2012-05-14 SMURF2 monoubiquitinates SMAD3 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed22045334 Reactome Database ID Release 432179276 Reactome, http://www.reactome.org ReactomeREACT_120960 Reviewed: Huang, Tao, 2012-05-14 SMURF2 monoubiquitinates SMAD3 on lysine residues in the MH2 domain. Lysines K333 and K378 are likely the major sites for monoubiquitination. Lysine K409 is also monoubiquitinated, and possibly lysine K341. Since lysines K333 and K378 are predicted to stabilize the interaction of SMAD3 with SMAD4, monoubiquitination of these lysine residues is expected to disrupt SMAD2/3:SMAD4 heterotrimer. SMURF2-mediated disruption of endogenous Smad2/3:Smad4 heterotrimers was demonstrated in mouse embryonic fibroblasts. SMURF2 also ubiquitinates SMAD2 phosphorylated in the linker region, but loss of Smurf2 has less impact on Smad2 ubiquitination than on Smad3 in vivo. has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 TGIF recruits HDAC1 to SMAD2/3:SMAD4 heterotrimer Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed10199400 Pubmed11427533 Reactome Database ID Release 432186607 Reactome, http://www.reactome.org ReactomeREACT_121142 Reviewed: Huang, Tao, 2012-05-14 Transcriptional repressors TGIF1 and TGIF2 bind SMAD2/3:SMAD4 heterotrimer through interaction with SMAD2 and/or SMAD3. TGIF1 and TGIF2 recruit hystone deacetylase HDAC1 to SMAD2/3:SMAD4 heterotrimer. PathwayStep7098 PathwayStep7097 PathwayStep7096 PathwayStep7095 PathwayStep7094 PathwayStep7093 PathwayStep7092 PathwayStep7091 RhoBTB Converted from EntitySet in Reactome Reactome DB_ID: 194873 Reactome Database ID Release 43194873 Reactome, http://www.reactome.org ReactomeREACT_10533 PathwayStep7099 Rac1 Converted from EntitySet in Reactome Reactome DB_ID: 195347 Reactome Database ID Release 43195347 Reactome, http://www.reactome.org ReactomeREACT_10410 USP9X (FAM) binds to ubiquitinated SMAD4 Authored: Williams, MG, 2010-06-08 Edited: Jassal, B, 2012-04-10 In the cytosol, a ubiquitin hydrolase USP9X (FAM) binds to ubiquitinated SMAD4 (Dupont et al. 2009). Pubmed19135894 Reactome Database ID Release 43870479 Reactome, http://www.reactome.org ReactomeREACT_121227 Reviewed: Huang, Tao, 2012-05-14 USP9X (FAM) deubiquitinates SMAD4 Authored: Williams, MG, 2010-06-08 EC Number: 3.1.2.15 Edited: Jassal, B, 2012-04-10 Pubmed19135894 Reactome Database ID Release 43870437 Reactome, http://www.reactome.org ReactomeREACT_120856 Reviewed: Huang, Tao, 2012-05-14 USP9X (FAM) deubiquitinates SMAD4, thereby opposing the negative regulatory activity of TRIM33 (Ectodermin) (Dupont et al. 2009). NEDD4L binds phosphorylated linker region of SMAD2/3 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8 or CDK9 creates a docking site for E3-ubiquitin ligase NEDD4L. Pubmed19917253 Reactome Database ID Release 432176491 Reactome, http://www.reactome.org ReactomeREACT_120772 Reviewed: Huang, Tao, 2012-05-14 NEDD4L ubiquitinates SMAD2/3 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 NEDD4L ubiquitinates nuclear SMAD2 and SMAD3 phosphorylated at the linker region by CDK8 or CDK9, targeting SMAD2 and SMAD3 for degradation. Pubmed19917253 Reactome Database ID Release 432176502 Reactome, http://www.reactome.org ReactomeREACT_121162 Reviewed: Huang, Tao, 2012-05-14 has a Stoichiometric coefficient of 2 Cdc42 Converted from EntitySet in Reactome Reactome DB_ID: 194843 Reactome Database ID Release 43194843 Reactome, http://www.reactome.org ReactomeREACT_10181 Ubiquitination of SKI/SKIL by RNF111/SMURF2 Authored: Orlic-Milacic, M, 2012-04-04 E3 ubiqutin ligases RNF111 (Arkadia) (Levy et al. 2007, Nagano et al. 2007) and SMURF2 (Bonni et al. 2001) ubiquitinate SKI/SKIL transcriptional repressors bound to activated SMAD2/3. The role of RNF111 was inferred from experiments that used recombinant mouse RNF111 and endogenous human SMADs and SKI/SKIL. The role of SMURF2 was inferred from experiments involving human proteins only. EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed11389444 Pubmed17510063 Pubmed17591695 Reactome Database ID Release 432186747 Reactome, http://www.reactome.org ReactomeREACT_121300 Reviewed: Huang, Tao, 2012-05-14 TRIM33 (Ectodermin) binds SMAD heterotrimer in the nucleus Authored: Williams, MG, 2010-06-08 E3 ubiquitin protein ligase TRIM33 (also known as Ecto, Ectodermin or Tif1-gamma) binds to the SMAD heterotrimer, composed of SMAD4 and two phosphorylated R-SMADs (SMAD2 and/or SMAD3), in the nucleus (Dupont et al. 2009, Dupont et al. 2005, He et al. 2006). Edited: Jassal, B, 2012-04-10 Pubmed15820681 Pubmed16751102 Pubmed19135894 Reactome Database ID Release 43870538 Reactome, http://www.reactome.org ReactomeREACT_121012 Reviewed: Huang, Tao, 2012-05-14 TRIM33 monoubiquitinates SMAD4 Authored: Williams, MG, 2010-06-08 EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed15820681 Pubmed19135894 Reactome Database ID Release 43870449 Reactome, http://www.reactome.org ReactomeREACT_120873 Reviewed: Huang, Tao, 2012-05-14 TRIM33 (also known as Ecto, Ectodermin or Tif1-gamma) monoubiquitinates nuclear SMAD4 on lysine residue K519. This leads to disruption of heterotrimeric complexes composed of SMAD4 and two phosphorylated R-SMADs (SMAD2 and/or SMAD3). TRIM33 inhibits SMAD activity without affecting steady state levels of SMAD4 (Dupont et al. 2009, Dupont et al. 2005). has a Stoichiometric coefficient of 2 Ligand Trap Converted from EntitySet in Reactome Reactome DB_ID: 201828 Reactome Database ID Release 43201828 Reactome, http://www.reactome.org ReactomeREACT_12128 Ubiquitinated SMAD4 translocates from the nucleus to the cytosol Authored: Williams, MG, 2010-06-08 Edited: Jassal, B, 2012-04-10 Pubmed15820681 Pubmed19135894 Reactome Database ID Release 43870477 Reactome, http://www.reactome.org ReactomeREACT_121081 Reviewed: Huang, Tao, 2012-05-14 SMAD4 monoubiquitinated by TRIM33 translocates from the nucleus to the cytosol (Dupont et al. 2009, Dupont et al. 2005). PathwayStep7090 SMAD2/3 activation induces binding of RNF111/SMURF2 to SKI/SKIL After phosphorylated SMAD2/3 accumulate in the nucleus in response to TGF-beta stimulation, E3 ubiqutin ligases RNF111 (Arkadia) (Levy et al. 2007) and SMURF2 (Bonni et al. 2001) bind SKI/SKIL in complex with SMAD2/3:SMAD4 heterotrimer. The role of RNF111 was inferred from experiments that used recombinant mouse RNF111 and endogenous human SMADs and SKI/SKIL (Levy et al. 2007). The role of SMURF2 was inferred from experiments involving human proteins only (Bonni et al. 2001). Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11389444 Pubmed17591695 Reactome Database ID Release 432186741 Reactome, http://www.reactome.org ReactomeREACT_121054 Reviewed: Huang, Tao, 2012-05-14 PathwayStep7061 PathwayStep7060 PathwayStep7063 PathwayStep7062 PathwayStep7065 PathwayStep7064 PathwayStep7067 PathwayStep7066 PathwayStep7069 PathwayStep7068 RNA Polymerase III Promoter Opening at Type 2 Promoters Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pol III initiation complexes open the promoter spontaneously. Indeed, this is the general case for DNA-dependent RNA polymerases. Only pol II, with its requirement for TFIIH-directed and ATP-dependent promoter opening is exceptional. TFIIH introduces a layer of mechanism that is not in the repertoire of any other transcriptase. Thus, it is pol III-mediated transcription that is, from a mechanistic perspective, most directly comparable with archaeal and also bacterial transcription. <p>As promoter opening has been analyzed only in the S. cerevisiae this event is Inferred from the homologous pathway in yeast. Reactome Database ID Release 43112150 Reactome, http://www.reactome.org ReactomeREACT_793 RNA Polymerase III Promoter Opening at Type 3 Promoters Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pol III initiation complexes open the promoter spontaneously. Indeed, this is the general case for DNA-dependent RNA polymerases. Only pol II, with its requirement for TFIIH-directed and ATP-dependent promoter opening is exceptional. TFIIH introduces a layer of mechanism that is not in the repertoire of any other transcriptase. Thus, it is pol III-mediated transcription that is, from a mechanistic perspective, most directly comparable with archaeal and also bacterial transcription. <p>As promoter opening has been analyzed only in the S. cerevisiae this event is Inferred from the homologous pathway in yeast. Reactome Database ID Release 43112152 Reactome, http://www.reactome.org ReactomeREACT_1485 Phospho-R-SMAD1/5/9 Converted from EntitySet in Reactome Reactome DB_ID: 201444 Reactome Database ID Release 43201444 Reactome, http://www.reactome.org ReactomeREACT_12365 RNA Polymerase III Productive Transcription Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43113705 Reactome, http://www.reactome.org ReactomeREACT_2251 The principal cleavage products are dinucleotides, and they are produced in large stoichiometric excess over complete transcripts. Overall productive RNA chain elongation proceeds quite rapidly. This event is inferred from an event in Saccharomyces cerevisiae. RNA Polymerase III Promoter Opening at Type 1 Promoters Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Pol III initiation complexes open the promoter spontaneously. Indeed, this is the general case for DNA-dependent RNA polymerases. Only pol II, with its requirement for TFIIH-directed and ATP-dependent promoter opening is exceptional. TFIIH introduces a layer of mechanism that is not in the repertoire of any other transcriptase. Thus, it is pol III-mediated transcription that is, from a mechanistic perspective, most directly comparable with archaeal and also bacterial transcription. <p>As promoter opening has been analyzed only in the S. cerevisiae this event is Inferred from the homologous pathway in yeast. Reactome Database ID Release 4376060 Reactome, http://www.reactome.org ReactomeREACT_796 p-2S-SMAD1/5/8 Converted from EntitySet in Reactome Phospho-R-SMAD1/5/8 Reactome DB_ID: 201482 Reactome Database ID Release 43201482 Reactome, http://www.reactome.org ReactomeREACT_12324 RNA Polymerase III Retractive RNase Activity at U-tract Pause Sites Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Productive transcription is accompanied by retractive RNase activity at U-tract pause sites and at the terminator. The principal cleavage products are dinucleotides, and they are produced in large stoichiometric excess over complete transcripts, despite the rapid overall rate of productive RNA chain elongation. This event is inferred from an event in Saccharomyces cerevisiae. Reactome Database ID Release 43113442 Reactome, http://www.reactome.org ReactomeREACT_2248 RNA Polymerase III Simple Start Sequence Initiation At Type 1 Promoters Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43112153 Reactome, http://www.reactome.org ReactomeREACT_2210 Transcription by pol III initiates at characteristic, simple start sequences. The universal core of these start sites is a pyrimidine-purine step, transcription initiating most frequently with ATP or GTP. This event is inferred from an event in Saccharomyces cerevisiae. I-SMAD Converted from EntitySet in Reactome Reactome DB_ID: 173495 Reactome Database ID Release 43173495 Reactome, http://www.reactome.org ReactomeREACT_7835 RNA Polymerase III Abortive Initiation At Type 2 Open Promoters Abortive initiation, the repetitive formation of short oligonucleotides, is a ubiquitous feature of transcriptional initiation. This event is inferred from an event in Saccharomyces cerevisiae. Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43112149 Reactome, http://www.reactome.org ReactomeREACT_1061 RNA Polymerase III Abortive Initiation At Type 3 Open Promoters Abortive initiation, the repetitive formation of short oligonucleotides, is a ubiquitous feature of transcriptional initiation. This event is inferred from an event in Saccharomyces cerevisiae. Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43112054 Reactome, http://www.reactome.org ReactomeREACT_1616 Dissociation of PTRF:Polymerase I/Nascent Pre rRNA Complex:TTF-I:Sal Box Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 PTRF binds the quaternary complex and mediates the dissociation of paused complex. PTRF interacts with the RNA polymerase I largest subunit (p194), TTF-I and the U-rich 3' end of the nascent pre-rRNA. Pubmed9582279 Reactome Database ID Release 4374992 Reactome, http://www.reactome.org ReactomeREACT_513 RNA Polymerase III Abortive Initiation At Type 1 Open Promoters Abortive initiation, the repetitive formation of short oligonucleotides, is a ubiquitous feature of transcriptional initiation. This event is inferred from an event in Saccharomyces cerevisiae. Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43112055 Reactome, http://www.reactome.org ReactomeREACT_1241 PathwayStep7072 PathwayStep7071 PathwayStep7070 PathwayStep7076 PathwayStep7075 PathwayStep7074 PathwayStep7073 PathwayStep7079 PathwayStep7078 PathwayStep7077 Binding of Rrn3 to RNA Polymerase I After the assembly of the RNA Polymerase I Holoenzyme, Rrn3 binding occurs. Authored: Gillespie, ME, 2003-09-02 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 Reactome Database ID Release 4373757 Reactome, http://www.reactome.org ReactomeREACT_1173 Recruitment of Active RNA Polymerase I to SL1:phos.UBF-1:rDNA Promoter Authored: Comai, L, 2003-07-03 17:13:29 Composed of Acetylated SL1, phosphorylated UBF-1 bound the rDNA promoter as well as the active RNA polymerase holoenzyme, rrn3 and TFIIH the transcription initiation complex is complete. The assembly picture is incomplete, as the point at which TFIIH joins the complex is unknown, though by the time that this complex is formed TFIIH is present (it has been included at this step for completeness). This forms the transcriptionally active enzyme, that is capable of initiating transcription from the rDNA promoter. Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed12393749 Reactome Database ID Release 4373758 Reactome, http://www.reactome.org ReactomeREACT_139 Loss of Rrn3 from RNA Polymerase I promoter escape complex Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed12646563 Reactome Database ID Release 4373769 Reactome, http://www.reactome.org ReactomeREACT_373 Upon transcription initiation it is thought that RRN3 is inactivated and dissociates from the Loss of Rrn3 from the RNA Polymerase I promoter escape complex. SL1 and UBF are thought to remain bound to the promoter for multiple rounds of transcription initiation Elongation of pre-rRNA transcript At the beginning of this reaction, 1 molecule of 'elongating pre-rRNA transcript', and 1 molecule of 'NTP' are present. At the end of this reaction, 1 molecule of 'elongating pre-rRNA transcript' is present.<br><br> This reaction takes place in the 'nucleolus' and is mediated by the 'DNA-directed RNA polymerase activity' of 'RNA Polymerase I promoter escape complex'.<br> EC Number: 2.7.7.6 Reactome Database ID Release 4374986 Reactome, http://www.reactome.org ReactomeREACT_872 TTF-I binds to the Sal Box Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed3458534 Pubmed7597036 Reactome Database ID Release 4374987 Reactome, http://www.reactome.org ReactomeREACT_768 The Transcription termination factor (TTF-1) binds an 18 base pair sequence element found in multiple copies in the nontranscribed spacer downstream of the 18S rRNA coding region. This element is the termination signal for ribosomal gene transcription. It is bound by TTF-I, which mediates the pausing of the elongating transcription complex. Polymerase I Transcription Complex/Nascent Pre rRNA Complex pauses at the TTF-I:Sal Box Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Reactome Database ID Release 4374994 Reactome, http://www.reactome.org ReactomeREACT_2228 The Polymerase I promoter escape complex/with the now complete nascent pre rRNA transcript pauses at the TTF-I bound Sal Box. SMAD1/5/8 Converted from EntitySet in Reactome R-Smad1/5/8 Reactome DB_ID: 201424 Reactome Database ID Release 43201424 Reactome, http://www.reactome.org ReactomeREACT_12167 PTRF Binds the Polymerase I Transcription Complex/Nascent Pre rRNA Complex paused at the TTF-I:Sal Box Authored: Comai, L, 2003-07-03 17:13:29 Dissociation of paused ternary complexes requires the Polymerase I-transcript release factor (PTRF) a leucine zipper protein. PTRF is capable of dissociating ternary Pol I transcription complexes, interacting with both TTF-I and Pol I to mediate the release of both Pol I and nascent transcripts from the template. Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed9582279 Reactome Database ID Release 4374993 Reactome, http://www.reactome.org ReactomeREACT_211 Type I receptor Converted from EntitySet in Reactome Reactome DB_ID: 201805 Reactome Database ID Release 43201805 Reactome, http://www.reactome.org ReactomeREACT_12266 p-4S-BMPRI Converted from EntitySet in Reactome Phospho-Type I receptor Reactome DB_ID: 201826 Reactome Database ID Release 43201826 Reactome, http://www.reactome.org ReactomeREACT_12243 Acetylation of SL1 Acetylation of the TAFI63 subunit of SL1 by PCAF stimulates the association of TAFI63 with DNA and stimulates pol I transcription in vitro. Conversely, deacetylation by the NAD+-dependent deacetylase Sir2 represses pol I transcription. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed11250901 Reactome Database ID Release 4373736 Reactome, http://www.reactome.org ReactomeREACT_2113 Recruitment of Acetylated SL1 to phosUBF-1:rDNA Promoter Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Human SL1 does not bind to DNA itself, rather it is recruited to the rDNA promoter through a physical interaction with UBF-1. Phosphorylation of UBF-1 within the carboxy-terminal region is required for SL1 binding. SL1 consists of TATA-binding protein (TBP) and three associated factors (TAFIs). SL1 has no sequence-specific DNA binding activity its recruitment to the promoter being mediated by specific interactions with UBF. Once bound the SL1 complex makes direct contact with the DNA promoter and guides promoter-specific initiation. <p>Studies to identify the mechanistic relationship between SL1 and UBF-1 have indicated that the interaction between UBF-1 and SL1 is regulated by tumor suppressor proteins such as Rb and P53, although it has also been proposed that Rb prevents UBF-1 from binding to DNA itself. Pubmed10082553 Pubmed10913176 Pubmed11042686 Pubmed11486020 Pubmed7491500 Reactome Database ID Release 4373739 Reactome, http://www.reactome.org ReactomeREACT_105 Assembly of RNA Polymerase I Holoenzyme (human) At the beginning of this reaction, 1 molecule of 'DNA-directed RNA polymerases I, II, and III 17.1 kDa polypeptide ', 1 molecule of 'DNA-directed RNA polymerase I 135 kDa polypeptide ', 1 molecule of 'DNA-directed RNA polymerases I, II, and III 7.0 kDa polypeptide ', 1 molecule of 'DNA-directed RNA polymerase I 16 kDa polypeptide ', 1 molecule of 'DNA-directed RNA polymerase I 40 kDa polypeptide ', and 1 molecule of 'DNA-directed RNA polymerase I largest subunit ' are present. At the end of this reaction, 1 molecule of 'RNA Polymerase I Holoenzyme (Human)' is present.<br><br> This reaction takes place in the 'nucleolus'.<br> Reactome Database ID Release 4373865 Reactome, http://www.reactome.org ReactomeREACT_1773 PathwayStep7048 PathwayStep7049 PathwayStep7044 PathwayStep7045 PathwayStep7046 PathwayStep7047 PathwayStep7040 PathwayStep7041 PathwayStep7042 PathwayStep7043 Fuc-Pre-NOTCH Converted from EntitySet in Reactome Fucosylated NOTCH receptor precursor Reactome DB_ID: 1911414 Reactome Database ID Release 431911414 Reactome, http://www.reactome.org ReactomeREACT_120233 Pre-NOTCH Converted from EntitySet in Reactome NOTCH receptor precursor Reactome DB_ID: 1464801 Reactome Database ID Release 431464801 Reactome, http://www.reactome.org ReactomeREACT_118931 PathwayStep7059 PathwayStep7057 PathwayStep7058 PathwayStep7055 PathwayStep7056 PathwayStep7053 PathwayStep7054 PathwayStep7051 PathwayStep7052 PathwayStep7050 TGF-beta 1 precursor Converted from EntitySet in Reactome Reactome DB_ID: 170833 Reactome Database ID Release 43170833 Reactome, http://www.reactome.org ReactomeREACT_7858 UCHL5/USP15 Converted from EntitySet in Reactome Reactome DB_ID: 2179332 Reactome Database ID Release 432179332 Reactome, http://www.reactome.org ReactomeREACT_122261 PathwayStep7022 PathwayStep7023 PathwayStep7024 PathwayStep7025 PathwayStep7026 PathwayStep7027 PathwayStep7028 PathwayStep7029 PathwayStep7020 PathwayStep7021 Glc,Fuc-Pre-NOTCH Converted from EntitySet in Reactome Reactome DB_ID: 1911440 Reactome Database ID Release 431911440 Reactome, http://www.reactome.org ReactomeREACT_119436 PathwayStep7019 PathwayStep7035 PathwayStep7036 PathwayStep7033 PathwayStep7034 PathwayStep7039 PathwayStep7037 PathwayStep7038 PathwayStep7031 PathwayStep7032 PathwayStep7030 Glc,Fuc-Pre-NOTCH Converted from EntitySet in Reactome Glucosylated and fucosylated pre-NOTCH Reactome DB_ID: 1911442 Reactome Database ID Release 431911442 Reactome, http://www.reactome.org ReactomeREACT_119529 PathwayStep7008 PathwayStep7009 Addition of nucleotides between position +11 and +30 Authored: Timmers, H. T. M., 2003-09-11 07:42:30 EC Number: 2.7.7.6 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed11433015 Pubmed11486021 Pubmed7601352 Pubmed9353262 RNA polymerase II transcription complexes are susceptible to transcriptional stalling and arrest, when extending nascent transcripts to 30-nt. This susceptibility depends on presence on down-stream DNA, the particular DNA-sequence of the template and presence of transcription factors. Transcription factor TFIIH remains associated to the RNA pol II elongation complex until position +30. At this stage transcription elongation factor TFIIS can rescue stalled transcription elongation complexes. The transcription bubble varies between 13- and 22-nt in size. Reactome Database ID Release 43111264 Reactome, http://www.reactome.org ReactomeREACT_209 Nucleophillic Attack by 3'-hydroxyl Oxygen of nascent transcript on the Alpha Phosphate of NTP At the beginning of this reaction, 1 molecule of 'Pol II initiation complex' is present. At the end of this reaction, 1 molecule of 'Pol II Initiation complex with phosphodiester-PPi intermediate' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375866 Reactome, http://www.reactome.org ReactomeREACT_1467 Newly Formed Phosphodiester Bond Stabilized and PPi Released At the beginning of this reaction, 1 molecule of 'Pol II Initiation complex with phosphodiester-PPi intermediate' is present. At the end of this reaction, 1 molecule of 'pyrophosphate', and 1 molecule of 'pol II transcription complex' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375864 Reactome, http://www.reactome.org ReactomeREACT_1055 RNA Polymerase II Promoter Opening: First Transition After assembly of the complete RNA polymerase II-preinitiation complex, the next step is separation of the two DNA strands. This isomerization step is known as the closed-to-open complex transition and occurs prior to the initiation of mRNA synthesis. In the RNA polymerase II system this step requires the hydrolysis of ATP or dATP into Pi and ADP or dADP (in contrast to the other RNA polymerase systems) and is catalyzed by the XPB subunit of TFIIH. The region of the promoter, which becomes single-stranded , spans from –10 to +2 relative to the transcription start site.<p>Negative supercoiling in the promoter region probably induces transient opening events and can alleviate requirement of TFIIE, TFIIH and ATP-hydrolysis for open complex formation. ATP is also used in this step by the cdk7-subunit of TFIIH to phosphorylate the heptad repeats of the C-terminal domain of the largest subunit of RNA polymerase II (RPB1) on serine-2 Authored: Timmers, H. T. M., 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed10024882 Pubmed10723029 Pubmed1310361 Pubmed7151173 Pubmed8156590 Pubmed8490964 Pubmed8946909 Pubmed9405375 Reactome Database ID Release 4375949 Reactome, http://www.reactome.org ReactomeREACT_1844 NTP Binds Active Site of RNA Polymerase II At the beginning of this reaction, 1 molecule of 'pol II open pre-initiation complex', and 2 molecules of 'NTP' are present. At the end of this reaction, 1 molecule of 'Pol II initiation complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375861 Reactome, http://www.reactome.org ReactomeREACT_1160 has a Stoichiometric coefficient of 2 Addition of Nucleotides 5 through 9 on the growing Transcript Authored: Timmers, H. T. M., 2003-09-11 07:42:30 EC Number: 2.7.7.6 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Formation of the second phosphodiester bond creates a 3-nt product. This transcript is still loosely associated with the RNA polymerase II initiation complex and can dissociate to yield abortive products, which are not further extended. At this stage pausing by RNA polymerase II may result in repeated slippage and reextension of the nascent RNA. The transcription complex still requires continued ATP-hydrolysis by TFIIH for efficient promoter escape. Basal transcription factor TFIIE dissociates from the initiation complex before position +10. <p>Basal transcription factor TFIIF may reassociate and can stimulate transcription elongation at multiple stages. The open region (“transcription bubble”) expands concomitant with the site of RNA-extension, eventually reaching an open region from -9 to +9. Pubmed11739720 Pubmed7601352 Pubmed9256425 Pubmed9405375 Reactome Database ID Release 4375873 Reactome, http://www.reactome.org ReactomeREACT_581 has a Stoichiometric coefficient of 5 Addition of nucleotides 10 and 11 on the growing transcript: Third Transition Authored: Timmers, H. T. M., 2003-09-11 07:42:30 EC Number: 2.7.7.6 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Formation of phosphodiester bonds nine and ten creates RNA products, which do not dissociate from the RNA pol II initiation complex. The transcription complex has enter the productive elongation phase. TFIIH and ATP-hydrolysis are required for efficient promoter escape. The open region (“transcription bubble”) expands concomitant with the site of RNA-extension. The region upstream from the transcription start site (-9 to -3) collapses to the double-stranded state. TFIIH remains associated to the RNA pol II initiation complex. Pubmed7601352 Pubmed9405375 Reactome Database ID Release 4376576 Reactome, http://www.reactome.org ReactomeREACT_1082 has a Stoichiometric coefficient of 2 Addition of the third nucleotide on the nascent transcript Authored: Timmers, H. T. M., 2003-09-11 07:42:30 EC Number: 2.7.7.6 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Formation of the second phosphodiester bond creates a 3-nt product. This short transcript is still loosely associated with the RNA polymerase II initiation complex and can dissociate to yield abortive products, which are not further extended. The transcription complex still requires continued ATP-hydrolysis by TFIIH and remains sensitive to single-stranded oligo-nucleotide inhibition.<p>The open region (“transcription bubble”) expands concomitant with the site of RNA-extension. In this case this region spans positions -9 to +3. Pubmed11784853 Pubmed9405375 Reactome Database ID Release 4375850 Reactome, http://www.reactome.org ReactomeREACT_40 Addition of the fourth nucleotide on the Nascent Transcript: Second Transition Authored: Timmers, H. T. M., 2003-09-11 07:42:30 EC Number: 2.7.7.6 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Formation of the third phosphodiester bond creates a 4-nt product. This commits the initiation complex to promoter escape. The short 4-nt transcript is still loosely associated with the RNA polymerase II initiation complex and can dissociate to yield abortive products, which are not further extended. Inhibition of ATP-hydrolysis by TFIIH does not lead to collapse of the open region any longer. The transcription complex has lost the sensitivity to single-stranded oligo-nucleotide inhibition. However, ATP-hydrolysis and TFIIH are required for efficient promoter escape. The open region (“transcription bubble”) expands concomitant with the site of RNA-extension. In this case this region spans positions -9 to +4. Pubmed11784853 Pubmed9405375 Reactome Database ID Release 4375869 Reactome, http://www.reactome.org ReactomeREACT_1817 Formation of the closed pre-initiation complex Authored: Reinberg, D, 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed8946909 Reactome Database ID Release 43109639 Reactome, http://www.reactome.org ReactomeREACT_632 The binding of TFIIH completes the assembly of the preinitiation complex (PIC) for RNA Polymerase II transcription. Although RNA polymerase binds the TATA box on the promoter DNA, no initiation of transcription occurs until TFIIH is bound to the PIC. TFIIH is the only factor with known enzymatic activities. PathwayStep7010 PathwayStep7012 PathwayStep7011 PathwayStep7014 PathwayStep7013 PathwayStep7016 PathwayStep7015 PathwayStep7018 PathwayStep7017 Hypophosphorylation of RNA Pol II CTD by FCP1P protein Authored: Gopinathrao, G, 2004-04-28 10:54:00 EC Number: 3.1.3.16 FCP1 dephosphorylates RNAP II in ternary elongation complexes as well as in solution and, therefore, is thought to function in the recycling of RNAP II during the transcription cycle. Biochemical experiments suggest that human FCP1 targets CTDs that are phosphorylated at serine 2 (CTD-serine 2) and/or CTD-serine 5. It is also observed to stimulate elongation independent of its catalytic activity. Dephosphorylation of Ser2 - phosphorylated Pol II results in hypophosphorylated form that disengages capping enzymes (CE). Pubmed12370301 Reactome Database ID Release 43112383 Reactome, http://www.reactome.org ReactomeREACT_1251 DSIF complex binds to RNA Pol II (hypophosphorylated) Authored: Gopinathrao, G, 2004-05-03 18:16:42 DSIF is a heterodimer consisting of hSPT4 (human homolog of yeast Spt4- p14) and hSPT5 (human homolog of yeast Spt5-p160). DSIF association with Pol II may be enabled by Spt5 binding to Pol II creating a scaffold for NELF binding (Wada et al.,1998). Spt5 subunit of DSIF can be phosphorylated by P-TEFb. Pubmed12653964 Pubmed9450929 Reactome Database ID Release 43113407 Reactome, http://www.reactome.org ReactomeREACT_802 Formation of DSIF:NELF:early elongation complex Authored: Gopinathrao, G, 2004-06-22 14:12:50 NELF complex is a ~ 300 kDa multiprotein complex composed of 5 peptides (A - E): ~66,61,59,58 and 46 kDa. All these peptides are required for NELF-mediated inhibition of Pol II elongation. NELF complex has been reported to bind to the pre-formed DSIF:RNA Pol II complex that may act as a scaffold for its binding. NELF-A is suspected to be involved in Wolf-Hirschhorn syndrome. <BR>Binding of DSIF:NELF to RNA Pol II CTD results in abortive termination of early elongation steps by the growing transcripts. Pubmed11940650 Reactome Database ID Release 43113402 Reactome, http://www.reactome.org ReactomeREACT_981 Hyperphosphorylation (Ser2) of RNA Pol II CTD by P-TEFb complex Authored: Gopinathrao, G, 2004-05-06 22:00:00 Cdk-9 is the kinase subunit of P-TEFb that phosphorylates Serine 2 on the heptapeptide repeats of Pol II CTD alleviating the negative action of DSIF-NELF complex. This reaction is considered to be a rate limiting step for processive elongation. P-TEFb complex, that has a DRB-sensitive cyclin-dependent kinase activity, is composed of ~43 kDa, Cdk9 kinase (PITALRE), and either Cyclin T1, Cyclin T2a, Cyclin T2b, or Cyclin K. The exact mechanism by which P-TEFb removes the inhibition of elongation by DSIF-NELF is not yet known. P-TEFb is also capable of phosphorylating Spt5 subunit of DSIF complex. <BR> A P-TEFb complex (which contains only the Cyclin T1) is implicated in the efficient synthesis of human immunodeficiency virus-1 (HIV-1) transcripts. Cyclin T1 subunit of the P-TEFb(Cyclin T1:Cdk9) complex interacts with HIV-1 encoded Tat protein that binds to the transactivation response (TAR) element in the nascent HIV-1 transcript (reviewed in Price,2000). <BR>The mechanism by which DSIF, NELF and P-TEFb or TAK/P-TEFb act together in Pol II-regulated elongation is yet to be fully understood. Various biochemical evidences point to a model in which DSIF and NELF negatively regulate elongation through interactions with polymerase containing a hypophosphorylated CTD. Subsequent phosphorylation of the Pol II CTD by P-TEFb might promote elongation by inhibiting interactions of DSIF and NELF with the elongation complex.<BR> Pubmed10733565 Pubmed9857195 Reactome Database ID Release 43112381 Reactome, http://www.reactome.org ReactomeREACT_2066 Recruitment of elongation factors to form elongation complex At the beginning of this reaction, 1 molecule of 'FACT complex', 1 molecule of 'Elongin Complex', 1 molecule of 'Early elongation complex with hyperphosphorylated Pol II CTD', 1 molecule of 'TFIIH', 1 molecule of 'RNA polymerase II elongation factor ELL', and 1 molecule of 'TFIIS protein' are present. At the end of this reaction, 1 molecule of 'Elongation complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43112379 Reactome, http://www.reactome.org ReactomeREACT_949 Addition of nucleotides leads to transcript elongation Authored: Gopinathrao, G, 2004-06-22 14:12:50 High-resolution structures of free, catalytically active yeast Pol II and of an elongating form reveal that Pol II elongation complex includes features like: <BR> - RNA-DNA hybrid, an unwound template ahead of 3'-OH terminus of growing transcript and an exit groove at the base of the CTD, possibly for dynamic interaction of processing and transcriptional factors.<BR>- a cleft or channel created by Rpb1 and Rpb2 subunits to accommodate DNA template, extending to Mg2+ ion located deep in the enzyme core <BR> -a 50 kDa "clamp" with open confirmation in free polymerase, allowing entry of DNA strands but closed in the processive elongation phase. <BR> The clamp is composed of portions of Rpb1,Rpb2 and Rpb3 , five loops or "switches" that change from unfolded to well-folded structures stabilizing the elongation complex, and a long "bridging helix" that emanates from Rpb1 subunit, crossing near the Mg2+ ion. The bridging helix is thought to "bend" to push on the base pair at the 3'-end of RNA-DNA hybrid like a ratchet, translocating Pol II along the DNA (Cramer et al.,2001; Gnatt et al.,2001).In addition to its dynamic biochemical potential, Pol II possess a repertoire of functions to serve as a critical platform of recruiting and coordinating the actions of a host of additional enzyme and proteins involved in various pathways.<BR> Pubmed11313498 Pubmed11313499 Reactome Database ID Release 43112385 Reactome, http://www.reactome.org ReactomeREACT_751 Pol II elongation complex moves on the template as transcript elongates At the beginning of this reaction, 1 molecule of 'Processive elongation complex', and 1 molecule of 'NTP' are present. At the end of this reaction, 1 molecule of 'Elongation complex prior to separation', and 1 molecule of 'NTP' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43113412 Reactome, http://www.reactome.org ReactomeREACT_2053 Separation of elongating transcript from template At the beginning of this reaction, 1 molecule of 'Elongation complex prior to separation' is present. At the end of this reaction, 1 molecule of 'Elongation complex with separated and uncleaved transcript' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43112396 Reactome, http://www.reactome.org ReactomeREACT_2030 Phosphorylation (Ser5) of RNA pol II CTD Authored: Buratowski, S, 2003-10-15 15:18:41 Phosphorylation of serine 5 residue at the CTD of pol II largest subunit is an important step signaling the end of initiation and escape into processive elongation processes. Cdk7 protein subunit of TFIIH phosphorylates RNA Pol II CTD serine 5 residues on its heptad repeats. Reactome Database ID Release 4377071 Reactome, http://www.reactome.org ReactomeREACT_1185 Extrusion of 5'-end of 30 nt long transcript through the pore in Pol II complex At the beginning of this reaction, 1 molecule of 'Pol II transcription complex containing transcript to +30' is present. At the end of this reaction, 1 molecule of 'Pol II transcription complex containing extruded transcript to +30' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43113430 Reactome, http://www.reactome.org ReactomeREACT_1567 PathwayStep7003 PathwayStep7002 PathwayStep7001 PathwayStep7000 PathwayStep7007 PathwayStep7006 PathwayStep7005 PathwayStep7004 RNA Polymerase III Simple Start Sequence Initiation At Type 2 Promoters Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43112155 Reactome, http://www.reactome.org ReactomeREACT_2178 Transcription by pol III initiates at characteristic, simple start sequences. The universal core of these start sites is a pyrimidine-purine step, transcription initiating most frequently with ATP or GTP. This event is inferred from an event in Saccharomyces cerevisiae. Binding of TFIIIA To type 1 Promoter Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed1438283 Pubmed7001457 Pubmed7789179 Pubmed9242690 Reactome Database ID Release 4376052 Reactome, http://www.reactome.org ReactomeREACT_1545 TFIIIA contains nine C2H2 zinc fingers (Arakawa et al., 1995). It binds to both the ICR region of the 5S RNA genes and to 5S RNA to form the 7S storage ribonucleoprotein particle (Pelham and Brown, 1980). Upon TFIIIA binding to the 5S gene, the TFIIIA zinc fingers are aligned over the length of the ICR with the C-terminal zinc fingers in proximity to the 5 end, and the N-terminal zinc fingers in proximity to the 3 end, of the ICR. Zinc fingers 1-3 contact the C block within the ICR and have been reported to contribute most of the binding energy of the full-length protein (Clemens et al., 1992). However, TFIIIA fragments containing zinc fingers 4-9 bind to the A block and intermediate element within the ICR with affinities close to those of the full-length protein. This and other observations suggest that simultaneous binding by all nine TFIIIA zinc fingers requires energetically unfavorable distortions within the DNA, the protein, or both (Kehres et al., 1997). RNA Polymerase III Transcriptional Pause at Terminator Sequence Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed8308883 RNA Polymerase III terminates transcription at extremely simple sites, consistent with its role in producing small transcripts. These sites are essentially "Tn" (in the non-transcribed strand). Reactome Database ID Release 43113449 Reactome, http://www.reactome.org ReactomeREACT_2064 RNA Polymerase III Termination and release of transcribed mRNA Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 Efficient transcript production requires efficient release of RNA polymerase at the terminator; slow release at the terminator of a short transcription unit quickly becomes rate limiting for transcription at steady state. Although pol III autonomously recognizes sequence terminators, proteins that help to rapidly detach pol III from the terminator can affect the productivity of transcription if they eliminate termination as the rate-limiting step.<p>La, NF1 family proteins, PC4 and topoisomerase I have been proposed as accessory pol III transcription factors that facilitate multi-cycle transcription by hspol III, and are hence described as positive regulators of termination. GENE ONTOLOGYGO:0006386 Pubmed11118217 Pubmed8035818 Pubmed8308883 Pubmed9660958 Reactome Database ID Release 43113454 Reactome, http://www.reactome.org ReactomeREACT_1301 RNA Polymerase III Simple Start Sequence Initiation At Type 3 Promoters Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43112156 Reactome, http://www.reactome.org ReactomeREACT_251 Transcription by pol III initiates at characteristic, simple start sequences. The universal core of these start sites is a pyrimidine-purine step, transcription initiating most frequently with ATP or GTP. This event is inferred from an event in Saccharomyces cerevisiae. Binding of TFIIIC to Type 2 promoter Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Proteolytic and scanning electron microscopy studies indicate that S. cerevisiae TFIIIC consists of two globular domains separated by a flexible linker, one of which, designated tau B, binds strongly to the B box, and the other, designated tau A, binds weakly to the A box, of type 2 promoters (Marzouki et al., 1986). DNA footprinting and protein-protein interaction studies (Hsieh et al., 1999; Hsieh et al., 1999; Kovelman and Roeder, 1992; Shen et al., 1996; Yoshinaga et al., 1989) support the models shown in the figure. The components of Brf1-TFIIIB (see TFIIIB entries) are shown in grey, and TFIIIA is shown in blue. Sites of strong protein-DNA cross-linking are indicated by small ovals. Black and grey rectangles show protein-protein contacts observed in human and S. cerevisiae TFIIIC subunits, respectively. The general arrangement of the TFIIIC subunits on type 1 and 2 promoters is strikingly similar (Bartholomew et al., 1990; Braun et al., 1992a).<p>On a type 2 promoter, the S. cerevisiae Tfc3 subunit cross-links primarily just upstream of the B box and Tfc6 cross-links at the end of the gene (Bartholomew et al., 1990). Tfc1 and Tfc7 have strong cross-links within and near the 3 end of the A box, respectively (Bartholomew et al., 1990). Tfc8 does not cross-link to DNA, and after partial protease digestion of TFIIIC, is found in the tB domain. In addition, however, Tfc8 displays genetic interactions with Tfc1, TBP, and ScBdp1, and it associates with TBP in vitro, suggesting that it is also present in the tA domain. The Tfc4 subunit cross-links to sites around and upstream of the transcription start site (Bartholomew et al., 1990) and directly contacts both the ScBrf1 and ScBdp1 subunits of TFIIIB.<p>Numerous protein-protein contacts between various TFIIIC subunits have been described, which are symbolized by small rectangles in the figure. The black rectangles indicate contacts identified with human TFIIIC subunits, the grey rectangles with S. cerevisiae TFIIIC subunits. Thus, Tfc7 interacts directly with Tfc1. TTFIIIC90 interacts with TFIIIC220, TFIIIC110, and TFIIIC63 (Hsieh et al., 1999). TFIIIC102 interacts with TFIIIC63 (Hsieh et al., 1999). Various TFIIIC subunits also interact directly with Brf1-TFIIIB subunits, as shown in the figure. Pubmed10373544 Pubmed10523658 Pubmed1447193 Pubmed2303478 Pubmed2732244 Pubmed3528868 Pubmed8754815 Reactome Database ID Release 4383788 Reactome, http://www.reactome.org ReactomeREACT_1501 Recruitment of RNA polymerase III to TFIIIB:TFIIIC:TFIIIA:Type 1 Promoter Complex Authored: Hernandez, N, 2003-09-11 07:42:29 Cross-linking experiments performed in the yeast system have shown that within the transcription initiation complex, eight RNA polymerase III subunits can be cross-linked to DNA (Bartholomew et al., 1993). The C34 subunit, which is known to be required specifically for transcription initiation but not elongation (Wang and Roeder, 1997; Werner et al., 1993), maps the furthest upstream of the transcription start site, in close proximity to Brf1-TFIIIB (Bartholomew et al., 1993). Indeed, this subunit interacts with Brf1 (Khoo et al., 1994; Werner et al., 1993). The figure illustrates this and other protein-protein contacts involving RNA polymerase III subunits and either TFIIIC or Brf1-TFIIIB subunits. The contacts identified with S. cerevisiae proteins are indicated by stippled arrows, those identified with human protein by solid arrows. Both the S. cerevisiae RNA polymerase III subunits C53 and ABC10a interact with Tfc4 (Dumay et al., 1999; Flores et al., 1999), and both C17 and C34 interact with Brf1. The human subunit RPC62 interacts with TIIIC63, and RPC39 with the TFIIIC subunits TFIIIC90 and TFIIIC63 (Hsieh et al., 1999a) and the Brf1-TFIIIB subunits Brf1 and TBP (Wang and Roeder, 1997). The contacts between RNA polymerase III and TFIIIC subunits are not absolutely required for transcription in vitro with the S. cerevisiae system, in which TFIIIC can be stripped from the DNA after assembly of TFIIIB without compromising transcription (Kassavetis et al., 1990) or, indeed, where transcription can be performed in the absence of TFIIIC on TATA box-containing promoters (Kassavetis et al., 1995; Rth et al., 1996). Nevertheless, they may contribute to the recruitment of RNA polymerase III in vivo. Edited: Gillespie, ME, 0000-00-00 00:00:00 Reactome Database ID Release 4376056 Reactome, http://www.reactome.org ReactomeREACT_704 Binding of TFIIIB to TFIIIC:TFIIIA:Type I Promoter complex Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed10373544 Pubmed10523658 Pubmed11684692 Pubmed2303478 Pubmed8598299 Reactome Database ID Release 4383723 Reactome, http://www.reactome.org ReactomeREACT_901 The recruitment of Brf1-TFIIIB to type 1 and 2 promoters has been intensively studied in S. cerevisiae (Joazeiro et al., 1996). The Tfc4 subunit of TFIIIC, which protrudes upstream of the transcription start site (Bartholomew et al., 1990), can interact with the Brf1 subunit of Brf1-TFIIIB (Moir et al., 1997). The Tfc4 subunit, which contains 11 copies of the tetratricopeptide repeat (TPR), appears to undergo conformational changes during binding that promote association with ScBrf1 and accommodate variable placements of TFIIIB (Moir et al., 1997). As shown in the figure, a number of protein-protein associations involving both S. cerevisiae and human TFIIIC and TFIIIB subunits have been described, which may participate in the recruitment of TFIIIB to type 1 and 2 promoters. Thus, Tfc8 has been show to interact with Bdp1 and TBP, and the corresponding human protein TFIIIC90 with Brf1 (Hsieh et al., 1999); Tfc4 with Brf1 and Bdp1, and the corresponding human protein TFIIIC102 with Brf1 and TBP (Hsieh et al., 1999); and the human protein TFIIIC63 with Brf1 and TBP (Hsieh et al., 1999). Binding of TFIIIC to TFIIIA:Type I Promoter complex Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Proteolytic and scanning electron microscopy studies indicate that S. cerevisiae TFIIIC consists of two globular domains separated by a flexible linker, one of which, designated tau B, binds strongly to the B box, and the other, designated tau A, binds weakly to the A box, of type 2 promoters (Schultz et al., 1989). DNA footprinting and protein-protein interaction studies (Hsieh et al., 1999a; Hsieh et al., 1999b; Kovelman and Roeder, 1992; Shen et al., 1996; Yoshinaga et al., 1989) support the models shown in the figure. The components of Brf1-TFIIIB (see TFIIIB entries) are shown in grey, and TFIIIA is shown in blue. Sites of strong protein-DNA cross-linking are indicated by small ovals. Black and grey rectangles show protein-protein contacts observed in human and S. cerevisiae TFIIIC subunits, respectively. The general arrangement of the TFIIIC subunits on type 1 and 2 promoters is strikingly similar (Bartholomew et al., 1990; Braun et al., 1992a). <p>On type 1 promoters, S. cerevisiae TFIIIA cross-links strongly to the A box and more weakly over most of the gene, suggesting that it extends over most of the gene (Braun et al., 1992a). Tfc3 is shifted downstream as compared to its position in the tRNA gene, with a main cross-link at the 3 end of the C box and another one further downstream. The Tfc6 subunit cross-links at the end of the gene, like in type 2 genes. There is no indication that the Tfc7 subunit contacts DNA in type 1 genes, but the Tfc1 subunit cross-links strongly upstream of the A box. The Tfc4 subunit crosslinks to sites around and upstream of the start site of transcription (Braun et al., 1992a). <p>Numerous protein-protein contacts between various TFIIIC subunits have been described, which are symbolized by small rectangles in the figure. The black rectangles indicate contacts identified with human TFIIIC subunits, the grey rectangles with S. cerevisiae TFIIIC subunits. Thus, Tfc7 interacts directly with Tfc1 (Manaud et al., 1998). TTFIIIC90 interacts with TFIIIC220, TFIIIC110, and TFIIIC63 (Hsieh et al., 1999). TFIIIC102 interacts with TFIIIC63 (Hsieh et al., 1999). Various TFIIIC subunits also interact directly with Brf1-TFIIIB subunits, as shown in the figure. These protein-protein contacts are discussed below. Pubmed10373544 Pubmed10523658 Pubmed1447193 Pubmed2684647 Reactome Database ID Release 4376054 Reactome, http://www.reactome.org ReactomeREACT_28 Binding of TFIIIB to TFIIC: Type 2 Promoter Complex Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed10373544 Pubmed10523658 Pubmed11684692 Pubmed2303478 Pubmed8598299 Reactome Database ID Release 4383790 Reactome, http://www.reactome.org ReactomeREACT_1598 The recruitment of Brf1-TFIIIB to type 1 and 2 promoters has been intensively studied in S. cerevisiae (Joazeiro et al., 1996). The Tfc4 subunit of TFIIIC, which protrudes upstream of the transcription start site (Bartholomew et al., 1990), can interact with the Brf1 subunit of Brf1-TFIIIB (Moir et al., 1997). The Tfc4 subunit, which contains 11 copies of the tetratricopeptide repeat (TPR), appears to undergo conformational changes during binding that promote association with ScBrf1 and accommodate variable placements of TFIIIB (Moir et al., 1997). As shown in the figure, a number of protein-protein associations involving both S. cerevisiae and human TFIIIC and TFIIIB subunits have been described, which may participate in the recruitment of TFIIIB to type 1 and 2 promoters. Thus, Tfc8 has been show to interact with Bdp1 and TBP, and the corresponding human protein TFIIIC90 with Brf1 (Hsieh et al., 1999); Tfc4 with Brf1 and Bdp1, and the corresponding human protein TFIIIC102 with Brf1 and TBP (Hsieh et al., 1999); and the human protein TFIIIC63 with Brf1 and TBP (Hsieh et al., 1999). Cleaved collagen alpha-2(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2470438 Reactome Database ID Release 432470438 Reactome, http://www.reactome.org ReactomeREACT_150674 Binding of SNAPc, Oct-1, and Staf to Type 3 Promoter Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Reactome Database ID Release 4383791 Reactome, http://www.reactome.org ReactomeREACT_1607 SNAPc binds specifically to the PSE. This binding is mediated in part by an unusual Myb domain within SNAP190 (Mittal et al., 1999; Wong et al., 1998). However, even though a SNAP190 segment consisting of just the Myb domain binds DNA, within the complex the Myb domain is not sufficient for binding. The smallest characterized subassembly of SNAPc subunits that binds specifically to DNA consists of SNAP190 aa 84-505, SNAP43 aa 1-268, and SNAP50 (Ma and Hernandez, 2000). Consistent with the requirement for parts of SNAP190 and SNAP50 for DNA binding, UV cross-linking experiments suggest that both SNAP190 (Yoon et al., 1995) and SNAP50 (Henry et al., 1996) are in close contact with DNA.<p>The binding of SNAPc to the PSE is stabilized by a number of cooperative interactions with other members of the transcription initiation complex including Oct-1, TBP, and Brf2.<p>The binding of SNAPc to the core promoter is stabilized by a direct protein-protein contact with the Oct-1 POU domain.<p>SNAPc does not bind very efficiently to the PSE on its own. It contains a damper of DNA binding that resides within the C-terminal two thirds of SNAP190 and/or SNAP45, because a subcomplex of SNAPc (mini-SNAPc) lacking these sequences binds much more efficiently to DNA than complete SNAPc (Mittal et al., 1999). The damper within SNAPc is deactivated, probably through a conformational change, by a direct protein-protein contact with the Oct-1 POU domain. The transcription initiation complex is illustrated in Figure 6. The protein-protein contact between the Oct-1 POU domain and SNAPc involves a glutamic acid at position 7 within the Oct-1 POUS domain and a lysine at position 900 within SNAP190, which are symbolized in Figure 6 by small triangles (Ford et al., 1998; Hovde et al., 2002; Mittal et al., 1999). The octamer sequence within the DSE and the PSE are separated by more than 150 base pairs, but the direct protein-protein contact is rendered possible by the presence of a positioned nucleosome between the DSE and the PSE, which, as shown in the figure, probably brings into close proximity the Oct-1 POU domain and SNAPc (Stunkel et al., 1997; Zhao et al., 2001). Recruitment of RNA Polymerase III to the TFIIIB:TFIIIC: Type 2 Promoter Complex At the beginning of this reaction, 1 molecule of 'TFIIIB:TFIIIC:Type 2 Promoter Complex', and 1 molecule of 'RNA Polymerase III Holoenzyme' are present. At the end of this reaction, 1 molecule of 'RNA Polymerase III:TFIIIB:TFIIIC:Type 2 Promoter Complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4383805 Reactome, http://www.reactome.org ReactomeREACT_1779 Recruitment of RNA Polymerase III to TFIIIB:SNAPc:Type 3 Promoter Complex Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed11564744 Pubmed12016223 Pubmed12391172 Pubmed12621023 Pubmed9027316 Reactome Database ID Release 4383803 Reactome, http://www.reactome.org ReactomeREACT_254 The binding of SNAPc to the PSE is stabilized not only by cooperative interactions with the Oct-1 POU domain, but also by cooperative interactions with TBP and Brf2 (Hinkley et al., 2003 ; Ma and Hernandez, 2002; Mittal and Hernandez, 1997). Moreover, Brf2, which cannot bind to DNA on its own, recognizes and stabilizes TBP bound to the TATA box (Cabart and Murphy, 2001; Cabart and Murphy, 2002; Ma and Hernandez, 2002). Thus, the U6 transcription initiation complex is stabilized by a complex network of protein-protein and protein-DNA interactions. Nothing is known, however, about how the complex recruits RNA polymerase III. Binding of TFIIIB to SNAPc:Oct-1:Staf:Type 3 Promoter Complex Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed1535687 Pubmed1868835 Pubmed8339931 Reactome Database ID Release 4383793 Reactome, http://www.reactome.org ReactomeREACT_328 The snRNA activating protein complex (SNAPc) (Sadowski et al., 1993), the PSE binding protein (PBP) (Waldschmidt et al., 1991), or the PSE transcription factor (PTF) (Murphy et al., 1992). The complex contains five types of subunits and binds to the PSE. Type 3 promoters also recruit Brf2-TFIIIB through a combination of protein-protein contacts with SNAPc and a direct association of the TBP component of Brf2-TFIIIB with the TATA box. This then allows RNA polymerase III to join the complex. Resumption of RNA Polymerase III Productive Transcription Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43113451 Reactome, http://www.reactome.org ReactomeREACT_1374 The principal cleavage products are dinucleotides, and they are produced in large stoichiometric excess over complete transcripts. Overall productive RNA chain elongation proceeds quite rapidly. This event is inferred from an event in Saccharomyces cerevisiae. Initiation of RNA Polymerase III Productive Transcription Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Reactome Database ID Release 43113446 Reactome, http://www.reactome.org ReactomeREACT_1179 The transition from abortive to productive transcription may occur at bp +5. The primary transcripts of pol III-transcribed genes are short, ~90 to 120 nt for tRNA and 5s RNA genes (which constitute the great majority of products) and even the longest transcripts (e.g. the RNA of the signal recognition particles) are only ~500 nt. This event is inferred from an event in Saccharomyces cerevisiae. Association of TFAM:mt promoter complex with POLRMT:TFB2M At the beginning of this reaction, 1 molecule of 'POLRMT:TFB2M complex', and 1 molecule of 'TFAM:mitochondrial promoter complex' are present. At the end of this reaction, 1 molecule of 'POLRMT:TFB2M:TFAM:mitochondrial promoter complex' is present.<br><br> This reaction takes place in the 'mitochondrial matrix'.<br> Pubmed12068295 Pubmed15526033 Reactome Database ID Release 43163296 Reactome, http://www.reactome.org ReactomeREACT_268 TFAM binds to mitochondrial promoters Authored: Gustafsson, C, 2005-04-25 22:00:00 Edited: Matthews, L, 0000-00-00 00:00:00 Pubmed3594571 Pubmed6697390 Pubmed7599198 Reactome Database ID Release 43163310 Reactome, http://www.reactome.org ReactomeREACT_875 Reviewed: Cantatore, P, 0000-00-00 00:00:00 Studies of human LSP have revealed that a minimal DNA fragment corresponding to position -28 to +16 relative to the transcription initiation site is able to support transcription initiation in a mitochondrial extract (Chang and Clayton, 1984). TFAM interacts directly with nucleotides between positions -35 and -17 (Fisher et al., 1987), and the exact distance between the TFAM-binding site and the transcription start site is essential for promoter activity (Dairaghi et al., 1995). Abortive initiation after formation of the first phosphodiester bond At the beginning of this reaction, 1 molecule of 'pol II transcription complex' is present. At the end of this reaction, 1 molecule of 'TFIIA', 1 molecule of 'TFIIH', 1 molecule of 'TFIIE', 1 molecule of 'TFIID', 1 molecule of 'TFIIB', 1 molecule of 'RNA Polymerase II (unphosphorylated):TFIIF complex', and 1 molecule of 'template DNA with first transcript dinucleotide, opened to +8 position' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed1939271 Reactome Database ID Release 4373946 Reactome, http://www.reactome.org ReactomeREACT_653 Association of mTERF with the termination sequence Authored: Gustafsson, C, 2005-04-25 22:00:00 Edited: Matthews, L, 0000-00-00 00:00:00 Pubmed11713324 Pubmed2752429 Pubmed7525579 Pubmed7681833 Pubmed9118945 Reactome Database ID Release 43163320 Reactome, http://www.reactome.org ReactomeREACT_2027 Reviewed: Cantatore, P, 0000-00-00 00:00:00 The 39-kDa mitochondrial transcription termination factor (mTERF), binds to a 28-base pair region of mtDNA (3237-3249) located within the tRNALeu(UUR) gene, at a position immediately downstream of the rRNA 16S gene (Fernandez-Silva et al., 1997; Kruse et al., 1989; Daga et al., 1993). mTERF binding to the termination sequence block transcription bidirectionally in a partially purified human mitochondrial system (Shang and Clayton, 1994). A polar termination activity has been also observed for the sea urchin homologue of mTERF, referred to as mtDBP with respect of phage RNA polymerases (Fernandez Silva et al. 2001). Formation of P-TEFb complex At the beginning of this reaction, 1 molecule of 'Cdk 9 protein', 1 molecule of 'Cyclin T1', and 1 molecule of 'Cyclin T2' are present. At the end of this reaction, 1 molecule of 'P-TEFb complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43112430 Reactome, http://www.reactome.org ReactomeREACT_307 Formation of NELF complex At the beginning of this reaction, 1 molecule of 'NELF-A protein', 1 molecule of 'RD protein', 1 molecule of 'NELF-B protein', and 1 molecule of 'NELF-C/D protein' are present. At the end of this reaction, 1 molecule of 'NELF complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43112437 Reactome, http://www.reactome.org ReactomeREACT_168 Formation of FACT complex At the beginning of this reaction, 1 molecule of 'FACT 140 kDa subunit', and 1 molecule of 'FACT 80 kDa subunit' are present. At the end of this reaction, 1 molecule of 'FACT complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43112429 Reactome, http://www.reactome.org ReactomeREACT_294 Formation of Elongin BC complex At the beginning of this reaction, 1 molecule of 'Elongin B protein', and 1 molecule of 'Elongin C protein' are present. At the end of this reaction, 1 molecule of 'Elongin B:C complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43112435 Reactome, http://www.reactome.org ReactomeREACT_936 Formation of DSIF complex At the beginning of this reaction, 1 molecule of 'SUPT5H protein', and 1 molecule of 'SPT4H1 protein' are present. At the end of this reaction, 1 molecule of 'DSIF complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43112434 Reactome, http://www.reactome.org ReactomeREACT_1635 Abortive Initiation Before Second Transition At the beginning of this reaction, 1 molecule of 'Pol II Promoter Escape Complex' is present. At the end of this reaction, 1 molecule of 'TFIIA', 1 molecule of 'TFIIH', 1 molecule of 'TFIIE', 1 molecule of 'TFIID', 1 molecule of 'TFIIB', 1 molecule of 'RNA Polymerase II (unphosphorylated):TFIIF complex', and 1 molecule of 'DNA containing Pol II promoter with transcript with 2 or 3 nucleotides' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed1939271 Reactome Database ID Release 4375856 Reactome, http://www.reactome.org ReactomeREACT_543 Abortive Initiation After Second Transition At the beginning of this reaction, 1 molecule of 'pol II transcription complex containing 4-9 nucleotide long transcript' is present. At the end of this reaction, 1 molecule of 'template DNA:4-9 nucleotide transcript hybrid', 1 molecule of 'TFIIH', 1 molecule of 'TFIIE', and 1 molecule of 'RNA Polymerase II (unphosphorylated):TFIIF complex' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed1939271 Reactome Database ID Release 4375891 Reactome, http://www.reactome.org ReactomeREACT_1793 2-4 nt.backtracking of Pol II complex on the template leading to elongation pausing Authored: Gopinathrao, G, 2004-06-23 11:10:00 Pol II pausing is believed to result from reversible backtracking of the Pol II enzyme complex by ~2 to 4 nucleotides. This leads to misaligned 3'-OH terminus that is unable to be an acceptor for the incoming NTPs in synthesis of next phosphodiester bond (reviewed by Shilatifard et al., 2003). Pubmed12676794 Reactome Database ID Release 43113411 Reactome, http://www.reactome.org ReactomeREACT_234 Resumption of elongation after recovery from pausing Authored: Gopinathrao, G, 2004-06-23 11:10:00 Pubmed12676794 Reactome Database ID Release 43112392 Reactome, http://www.reactome.org ReactomeREACT_1638 Recovery from pausing occurs spontaneously after a variable length of time as the enzyme spontaneously slides forward again. This renders the transcript's 3'-OH terminus realigned with the catalytic Mg2+ site of the enzyme. TFIIS is capable of excising the nascent transcript at 2 or 3 nucleotides upstream of the transcript's 3'-end to reinitiate processive elongation (reviewed by Shilatifard et al., 2003). Formation of elongin complex At the beginning of this reaction, 1 molecule of 'Elongin A1 protein', and 1 molecule of 'Elongin B:C complex' are present. At the end of this reaction, 1 molecule of 'Elongin Complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43112436 Reactome, http://www.reactome.org ReactomeREACT_51 Cleaved collagen alpha-1(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2470444 Reactome Database ID Release 432470444 Reactome, http://www.reactome.org ReactomeREACT_151206 Fall Back to Closed Pre-initiation Complex At the beginning of this reaction, 1 molecule of 'pol II open pre-initiation complex' is present. At the end of this reaction, 1 molecule of 'pol II closed pre-initiation complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed2449431 Reactome Database ID Release 4375862 Reactome, http://www.reactome.org ReactomeREACT_1702 Elongating transcript encounters a lesion in the template At the beginning of this reaction, 1 molecule of 'Processive elongation complex' is present. At the end of this reaction, 1 molecule of 'DSIF complex', 1 molecule of 'FACT complex', 1 molecule of 'RNA Polymerase II holoenzyme complex (hyperphosphorylated)', 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid', 1 molecule of 'Elongin Complex', 1 molecule of 'FCP1P protein', 1 molecule of 'P-TEFb complex', 1 molecule of 'NELF complex', 1 molecule of 'RNA polymerase II elongation factor ELL', 1 molecule of 'NTP', 1 molecule of 'TFIIS protein', and 1 molecule of 'TFIIF' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43113429 Reactome, http://www.reactome.org ReactomeREACT_1138 Binding of TFIIA and TFIIB to the pol II promoter:TFIID complex Authored: Reinberg, D, 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed8946909 Reactome Database ID Release 43109637 Reactome, http://www.reactome.org ReactomeREACT_266 The general transcription factor TFIIB is a single polypeptide of approximately 35 kDa. There is a Zn-binding domain near the N terminus of TFIIB, and the C-terminal domain encompasses two imperfect repeats; between the N and C termini is a phylogenetically conserved region. The C terminus interacts with TBP and RNA Polymerase II, whereas the N terminus interacts with factor TFIIF and RNA polymerase II. TFIIB is a sequence-specific factor, and it interacts with the BRE element within the promoter.<p>TFIIB interacts with the Rpb1 subunit of RNA polymerase II to define transcription strat sites. Several activators directly bind TFIIB, and stimulate transcription. The N-terminus and the C-terminus can participate in intramolecular interactions, and this can be disrupted by specific activators by causing a conformational change in TFIIB.<p> TFIIA also binds the preinitiation complex along with TFIIB. However, TFIIA is not required for accurate initiation, but rather functions as a coactivator of transcription. Recognition and Binding of Core Promoter Elements by TFIID Although TBP (TATA box binding factor) is necessary and sufficient for initiation of basal transcription, the other subunits of the general transcription factor TFIID, the TBP-associated factors, are required for response to transcriptional activators. TBP binds to the TATA box (a core promoter element), and bends the DNA 80 degrees toward the major groove. This conformation of TBP-TATA box provides the proper topology for the binding of the general transcription factor TFIIB.<p>Transcriptional activators function by affecting the kinetics of binding of TBP to the promoter DNA. Authored: Reinberg, D, 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed8330735 Pubmed8946909 Reactome Database ID Release 43109636 Reactome, http://www.reactome.org ReactomeREACT_745 TFIIS-mediated recovery of elongation from arrest Authored: Gopinathrao, G, 2004-06-23 11:10:00 Pubmed12676794 Reactome Database ID Release 43113413 Reactome, http://www.reactome.org ReactomeREACT_1094 TFIIS reactivates arrested RNA Pol II directly interacting with the enzyme resulting in endonucleolytic excision of nascent transcript ~7-14 nucleotides upstream of the 3' end. This reaction is catalyzed by the catalytic site and results in the generation of a new 3'-OH terminus that could be used for re-extension from the correctly base paired site (reviewed by Shilatifard et al., 2003). 7-14 nt. Backtracking of Pol II complex on the template leading to elongation arrest Authored: Gopinathrao, G, 2004-06-23 11:10:00 Pubmed12676794 RNA Pol II arrest is believed to be a result of irreversible backsliding of the enzyme by ~7-14 nucleotides. It is suggested that, arrest leads to extrusion of displaced transcripts 3'-end through the small pore near the Mg2+ ion. Pol II arrest may lead to abortive termination of elongation due to irreversible trapping of the 3'-end of the displaced transcript in the pore (reviewed by Shilatifard et al., 2003). Reactome Database ID Release 43113414 Reactome, http://www.reactome.org ReactomeREACT_1645 Abortive termination of elongation after arrest At the beginning of this reaction, 1 molecule of 'Arrested processive elongation complex' is present. At the end of this reaction, 1 molecule of 'Aborted elongation complex after arrest' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed12676794 Reactome Database ID Release 43112395 Reactome, http://www.reactome.org ReactomeREACT_6355 Abortive termination of early transcription elongation by DSIF:NELF Authored: Gopinathrao, G, 2004-04-28 10:54:00 In the early elongation phase, shorter transcripts typically of ~30 nt in length are generated due to random termination of elongating nascent transcripts. This abortive cessation of elongation has been observed mainly in the presence of DSIF-NELF bound to Pol II complex. (Reviewed in Conaway et al.,2000; Shilatifard et al., 2003 ). Pubmed10916156 Pubmed12676794 Reactome Database ID Release 43113409 Reactome, http://www.reactome.org ReactomeREACT_989 Binding of TFIIE to the growing preinitiation complex Authored: Reinberg, D, 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Factor TFIIE enters the preinitiation complex after TFIIF recruits RNA Polymerase II. TFIIE is composed of two subunits of 56 kDA and 34 kDa. TFIIE facilitates the recruitment of factor TFIIH to the preinitiation complex, and it also stimulates the phosphorylation of the RNA Polymerase II CTD by TFIIH. Pubmed8946909 Reactome Database ID Release 4375095 Reactome, http://www.reactome.org ReactomeREACT_1821 Recruitment of RNA Polymerase II Holoenzyme by TFIIF to the pol II promoter:TFIID:TFIIA:TFIIB complex Authored: Reinberg, D, 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed8946909 Reactome Database ID Release 43109638 Reactome, http://www.reactome.org ReactomeREACT_1684 The general transcription factor TFIIF has a high affinity for the RNA Polymerase II holoenzyme. TFIIF stabilizes the preinitiation complex, and suppresses non-specific binding of RNA Pol II to DNA, and is thus critical for start site recognition. Packaging of Eight RNA Segments Authored: Marsh, G, 2007-04-30 20:49:40 For a budding influenza virus to be fully infectious is it essential that it contains a full complement of the eight vRNA segments. Two different models have been proposed for packaging of the vRNPs into newly assembling virus particles; the random incorporation model and the selective incorporation model.<br>The random incorporation model as its name suggests proposes that there is no selection at all on which vRNPs are packaged. It is assumed that each vRNP has equal probability of being packaged, and that if enough vRNPS are packaged a particular percentage of budding virions will receive at least one copy of each genome segment. This model is supported by evidence that infectious virions may possess more than eight vRNPs assuring the presence of a full complement of eight vRNPs in a significant percentage of virus particles. Mathematical analysis of packaging suggested that twelve RNA segments would need to be packaged in order to obtain approximately 10% of virus particles that are fully infectious (Enami, 1991), a number that is compatible with experimental data (Donald, 1954). Due to the low amount of RNA per virion (estimated at 1-2% w/w), enumeration of the precise number of RNAs packaged in a virion is difficult.<br>The selective incorporation model, suggests that each vRNA segment contains a unique "packaging signal" allowing it to act independently, with each vRNA segment being packaged selectively. There is increasing evidence to support the theory of a packaging signal within the coding regions at both the 5' and 3' end of the genomic RNA, with signals being reported for all segments except segment 7 (Ozawa 2007, Muramoto 2006, Fujii 2005, Fujii 2003, Watanabe 2003, Liang 2005). The exact method by which individual vRNP segments are packaged is not known but it has been hypothesized to occur via specific RNA-RNA or protein-RNA interactions. This model is also supported by thin section electron microscopy images of influenza particles that show eight distinct "dots", presumably vRNPs within virus particles (Noda 2006). GENE ONTOLOGYGO:0019072 Pubmed0 Pubmed12574509 Pubmed12970442 Pubmed13174769 Pubmed15731270 Pubmed16051827 Pubmed16437116 Pubmed16474138 Pubmed17050598 Pubmed1833874 Reactome Database ID Release 43168303 Reactome, http://www.reactome.org ReactomeREACT_6235 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Budding Authored: Marsh, G, 2007-04-30 20:49:40 GENE ONTOLOGYGO:0019068 Pubmed12359424 Pubmed12604801 Pubmed15567494 Pubmed16139601 Pubmed9448697 Pubmed9576955 Reactome Database ID Release 43168302 Reactome, http://www.reactome.org ReactomeREACT_6212 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The process by which influenza virus particles bud from an infected cell is not very well understood. Accumulation of M1 at the inner leaflet of the plasma membrane is thought to be the trigger for the initiation of bud formation. This bud formation continues until the inner core of the virus is completely enveloped. Completion of the budding process requires the membrane at the base of the bud to fuse. Although M1 is thought to be the driving force for bud formation, other viral and cellular proteins have been demonstrated to affect size and shape of the virus particle. Generally, influenza virus particles are either spherical or filamentous and this characteristic morphology is genetically linked to the M segment (Bourmakina, 2003; Roberts, 1998). Host factors such as polarization and the actin cytoskeleton play a critical role in determining the shape of filamentous particles (Roberts, 1998; Simpson-Holley, 2002). NEP/NS2 Interacts with the Cellular Export Machinery Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 GENE ONTOLOGYGO:0046796 Pubmed11118210 Pubmed12970177 Pubmed17081640 Pubmed1913813 Pubmed9427762 Reactome Database ID Release 43168333 Reactome, http://www.reactome.org ReactomeREACT_6179 Reviewed: Squires, B, 2007-02-12 19:39:22 The viral RNP complex is exported from the nucleus via the host cell CRM1 export pathway (Fukuda, 1997; Neumann, 2000; reviewed in Buolo, 2006). The vRNP complex does not interact directly with CRM1 to form an export complex. Rather, an additional viral protein, nuclear export protein (NEP/NS2), acts as an adaptor, binding the viral matrix M1 protein and CRM1, thus linking the viral RNP with CRM1 (Martin, 1991; O'Neill, 1998; Neumann, 2000; Akarsu, 2003). The CRM1/exportin-1 complex recruits additional host cell proteins, and traverses the nuclear pore into the cytosol. Virus Assembly and Release GENE ONTOLOGYGO:0019067 Influenza viruses assemble and bud from the apical plasma membrane of polarized cells e.g. lung epithelial cells of the infected host. This asymmetrical process (i.e. apical [Influenza virus] or basolateral [Marburg virus]) is thought to have an important role in viral pathogenesis and tissue tropism. In most cases the individual viral envelope proteins are seen to accumulate at the same polar surface from which virus budding occurs, suggesting that they determine the maturation site Pubmed0 Pubmed16139601 Pubmed283416 Reactome Database ID Release 43168268 Reactome, http://www.reactome.org ReactomeREACT_6270 Assembly of Viral Components at the Budding Site Authored: Steel, J, 2007-04-30 20:49:24 Following synthesis on membrane-bound ribosomes, the three viral integral membrane proteins, HA (hemagglutinin), NA (neuraminidase) and M2 (ion channel) enter the host endoplasmic reticulum (ER) where all three are folded and HA and NA are glycosylated. Subsequently HA is assembled into a trimer. HA, NA and M2 are transported to the Golgi apparatus where cysteine residues on HA and M2 are palmitoylated. Furin cleaves HA into HA1 and HA2 subunits and all three proteins are directed to the virus assembly site on the apical plasma membrane via apical sorting signals. The signals for HA and NA reside on the transmembrane domains (TMD) while the sorting signal for M2 is not yet characterized. The TMDs of HA and NA also contain the signals for lipid raft association. Lipid rafts are non-ionic detergent-resistant lipid microdomains within the plasma membrane that are rich in sphingolipids and cholesterol. Examination of purified virus particles indicates that influenza virus buds preferentially from these microdomains. GENE ONTOLOGYGO:0019068 Pubmed0 Reactome Database ID Release 43168316 Reactome, http://www.reactome.org ReactomeREACT_6277 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Transport of HA trimer, NA tetramer and M2 tetramer from the endoplasmic reticulum to the Golgi Apparatus Authored: Steel, J, 2007-04-30 20:49:24 GENE ONTOLOGYGO:0019060 Processed viral proteins are transported from the endoplasmic reticulum to the Golgi apparatus. Pubmed0 Reactome Database ID Release 43168874 Reactome, http://www.reactome.org ReactomeREACT_6215 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 vRNA Synthesis Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed15163719 Pubmed15308750 Pubmed16513387 Pubmed7561757 Reactome Database ID Release 43192814 Reactome, http://www.reactome.org ReactomeREACT_9497 Reviewed: Squires, B, 2007-02-12 19:39:22 The synthesis of full-length negative strand viral RNA from a cRNA template is believed to follow the same principles as the synthesis of cRNA from a vRNA template. The cRNA, complexed with viral nucleocapsid (NP) protein, is used as template by the trimeric viral polymerase (Pritlove, 1995; Vreede, 2004; Crow, 2004), and newly synthesized vRNA molecules are immediately packaged with NP molecules to form ribonucleoprotein complexes (Vreede, 2004). There is some evidence that the production of vRNA-containing vRNP occurs in the nuclear matrix as well as the nucleoplasm (Takizawa, 2006). Viral mRNA Translation Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed10359774 Pubmed11726970 Pubmed11773396 Pubmed12239318 Pubmed14645908 Pubmed1577765 Pubmed16630668 Pubmed17166899 Pubmed3023655 Pubmed7499349 Reactome Database ID Release 43192823 Reactome, http://www.reactome.org ReactomeREACT_9491 Reviewed: Squires, B, 2007-02-12 19:39:22 Spliced and unspliced viral mRNA in the cytoplasm are translated by host cell ribosomal translation machinery (reviewed in Kash, 2006). At least ten viral proteins are synthesized: HA, NA, PB1, PB2, PA, NP, NS1, NEP/NS2, M1, and M2. Viral mRNA translation is believed to be enhanced by conserved 5'UTR sequences that interact with the ribosomal machinery and at least one cellular RNA-binding protein, G-rich sequence factor 1 (GRSF-1), has been found to specifically interact with the viral 5' UTRs. (Park, 1995; Park, 1999). The viral NS1 protein and the cellular protein P58(IPK) enhance viral translation indirectly by preventing the activation of the translational inhibitor PKR (Salvatore, 2002; Goodman, 2006). The viral NS1 protein has also been proposed to specifically enhance translation through interaction with host poly(A)-binding protein 1 (PABP1) (Burgui, 2003). Simultaneously, host cell protein synthesis is downregulated in influenza virus infection through still uncharacterized mechanisms (Katze, 1986; Garfinkel, 1992; Kash, 2006). In most human influenza A strains (such as PR8), the PB1 mRNA segment is capable of producing a second protein, PB1-F2, from a short +1 open reading frame initiating downstream of the PB1 ORF initiation codon (Chen, 2001). Export of Viral Ribonucleoproteins from Nucleus Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 GENE ONTOLOGYGO:0046796 Influenza genomic RNA (vRNA), synthesized in the nucleus of the infected host cell, is packaged into ribonucleoprotein (RNP) complexes containing viral polymerase proteins and NP (nucleocapsid). NP trimers bind the sugar phosphate backbone of the vRNA. As influenza viral RNP complexes are too large for passive diffusion out of the nucleus, utilization of the cellular nuclear export machinery is achieved by viral adaptor proteins. Matrix protein (M1) is critical for export of the complex from the nucleus, mediating the interaction of the RNP complex with the viral NEP/NS2 protein, which in turn interacts with host cell CRM1/exportin-1 nuclear export protein (Martin, 1991; O'Neill, 1998; Neumann et al., 2000; Elton, 2001; Cros, 2003; Ye, 2006; reviewed in Boulo, 2006). Pubmed11118210 Pubmed11119609 Pubmed16806605 Pubmed17081640 Reactome Database ID Release 43168274 Reactome, http://www.reactome.org ReactomeREACT_6296 Reviewed: Squires, B, 2007-02-12 19:39:22 Viral RNP Complexes in the Host Cell Nucleus Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 GENE ONTOLOGYGO:0019070 Pubmed11531417 Pubmed15661164 Pubmed16513387 Pubmed17148142 Reactome Database ID Release 43168330 Reactome, http://www.reactome.org ReactomeREACT_6198 Reviewed: Squires, B, 2007-02-12 19:39:22 Viral RNP is assembled in the host cell nucleus through the interaction of full-length negative strand viral RNA (vRNA) and the viral nucleocapsid (NP) and matrix (M1) proteins. Studies of interactions of the purified components in vitro and of tissue culture model systems expressing various combinations of the components have established roles for both NP and M1 proteins in the assembly of a complex that has the physical properties of vRNP purified from virions and that can be exported from the host cell nucleus (Whittaker, 1996; Huang, 2001; Baudin, 2001). Viral RNP complexes have been found in the nucleoplasm, and also in the nuclear periphery, associated with the nuclear matrix or chromatin, particularly for vRNA-containing complexes and M1 protein (Elton, 2005; Garcia-Robles, 2005; Takizawa et al., 2006). Miro1 Converted from EntitySet in Reactome Reactome DB_ID: 194851 Reactome Database ID Release 43194851 Reactome, http://www.reactome.org ReactomeREACT_10454 MMP1,2,3,9 Converted from EntitySet in Reactome Reactome DB_ID: 2470630 Reactome Database ID Release 432470630 Reactome, http://www.reactome.org ReactomeREACT_152171 Cleaved collagen alpha-1(XII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2470720 Reactome Database ID Release 432470720 Reactome, http://www.reactome.org ReactomeREACT_150619 MMP3,13 Converted from EntitySet in Reactome Reactome DB_ID: 2470415 Reactome Database ID Release 432470415 Reactome, http://www.reactome.org ReactomeREACT_152152 MMP3,13 Converted from EntitySet in Reactome Reactome DB_ID: 2484887 Reactome Database ID Release 432484887 Reactome, http://www.reactome.org ReactomeREACT_152236 RhoBTB Converted from EntitySet in Reactome Reactome DB_ID: 194916 Reactome Database ID Release 43194916 Reactome, http://www.reactome.org ReactomeREACT_10802 cRNA Synthesis Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed10438824 Pubmed15163719 Pubmed15308750 Pubmed15557242 Pubmed16474140 Pubmed2453679 Reactome Database ID Release 43192869 Reactome, http://www.reactome.org ReactomeREACT_9527 Reviewed: Squires, B, 2007-02-12 19:39:22 Synthesis of full length complementary viral RNA (cRNA) requires that vRNA transcription initiates without the help of a host cell methyl RNA cap as a primer (Crow, 2004; Vreede, 2004; Deng, 2006), and that it proceeds to the 5' end of the vRNA template without stuttering on the sub-terminal poly-U sequence. Free viral NP protein appears to play a central role in enabling both of these features of cRNA synthesis, although the molecular details of its role remain unclear (Shapiro, 1988; Medcalf, 1999; Mullin, 2004). vRNP Assembly Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 For each of eight gene segments, a viral ribonucleoprotein (vRNP), containing a viral negative-sense RNA (vRNA) segment complexed with nucleoprotein (NP) and the trimeric influenza polymerase (PB1, PB2, and PA), is assembled in the nucleus (Braam, 1983; Jones, 1986; Cros, 2003; reviewed in Buolo, 2006). The vRNP functions in three modes (reviewed in Mikulasova, 2000; Neumann, 2004): (1) transcription, which synthesizes viral messenger RNA from the vRNA template using as primers 5' ends of cellular mRNAs containing the cap; (2) replication, which produces positive-sense complementary RNA (cRNA) and subsequently vRNA, both complexed with NP and the trimeric polymerase; or (3), the vRNP is exported from the nucleus into the cytoplasm and is incorporated into assembling virions at the plasma membrane. Pubmed11252672 Pubmed12921991 Pubmed15298169 Pubmed17081640 Pubmed3023071 Pubmed6616622 Reactome Database ID Release 43192905 Reactome, http://www.reactome.org ReactomeREACT_9434 Reviewed: Squires, B, 2007-02-12 19:39:22 Viral Messenger RNA Synthesis Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 GENE ONTOLOGYGO:0019083 Like the mRNAs of the host cell, influenza virus mRNAs are capped and polyadenylated (reviewed in Neumann, 2004). The methylated caps, however, are scavenged from host cell mRNAs and serve as primers for viral RNA synthesis, a process termed 'cap-snatching' (Krug, 1981; Hagen, 1994). The PB2 polymerase protein binds the cap, activating endonucleolytic cleavage of the host mRNA by PB1. The 3' poly-A tracts on viral messages are generated by polymerase stuttering on poly-U tracts near the 5' end of the template vRNA (Robertson, 1981; Zheng, 1999). The second process allows polyadenylation of viral mRNAs when the host cell polyadenylation process has been inhibited (Engelhardt, 2006; Amorim, 2006). Notably, early transcripts (including NP and NS1) accumulate in the cytoplasm before late transcripts (M1, HA, and NS2), and in varying abundances, suggesting additional control mechanisms regulating viral gene expression (Shapiro, 1987; Hatada, 1989; Amorim, 2006). Pubmed10233995 Pubmed15298169 Pubmed16806605 Pubmed16933365 Pubmed2760014 Pubmed3806797 Pubmed6269803 Pubmed7241649 Pubmed8107213 Reactome Database ID Release 43168325 Reactome, http://www.reactome.org ReactomeREACT_6354 Reviewed: Squires, B, 2007-02-12 19:39:22 Transport of Ribonucleoproteins into the Host Nucleus An unusual characteristic of the influenza virus life cycle is its dependence on the nucleus. Trafficking of the viral genome into and out of the nucleus is a tightly regulated process with all viral RNA synthesis occurring in the nucleus. The eight influenza virus genome segments never exist as naked RNA but are associated with four viral proteins to form viral ribonucleoprotein complexes (vRNPs). The major viral protein in the RNP complex is the nucleocapsid protein (NP), which coats the RNA. The remaining proteins PB1, PB2 and PA bind to the partially complementary ends of the viral RNA, creating the distinctive panhandle structure. These RNPs (10-20nm wide) are too large to passively diffuse into the nucleus and therefore, once released from an incoming particle must rely on the active import mechanism of the host cell nuclear pore complex. All proteins in the RNP complex can independently localize to the nucleus due to the presence of nuclear localization signals (NLSs) which mediate their interaction with the nuclear import machinery, including the RanGTPase (Fodor, 2004; Deng et al., 2006). However the signals on NP have been shown to be both sufficient and necessary for the import of viral RNA. Authored: Gillespie, ME, 2005-11-14 17:18:07 GENE ONTOLOGYGO:0046796 Pubmed0 Pubmed15308710 Pubmed15702989 Pubmed17005651 Pubmed2196448 Pubmed8113737 Reactome Database ID Release 43168271 Reactome, http://www.reactome.org ReactomeREACT_6248 Reviewed: Squires, B, 2006-10-29 16:42:09 Influenza Viral RNA Transcription and Replication Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 GENE ONTOLOGYGO:0019083 In the host cell nucleus, the viral negative-strand RNA (vRNA) serves as a template for the synthesis both of capped, polyadenylated viral messenger RNA and of full-length positive-strand RNA or complementary RNA (cRNA). The cRNA is associated with the same viral proteins as the vRNA. It serves as a template for the synthesis of new vRNA molecules, which in turn serve as a template for mRNA particularly early in infection, and cRNA. Viral RNA polymerase subunits (PB1, PB2, and PA) and nucleoprotein (NP) enter the host cell nucleus and catalyze all three of these reactions. During initial infection, these proteins enter the nucleus as part of the viral RNP complex. After the first round of viral mRNA synthesis (primary transcription) and translation, newly synthesized viral polymerase proteins and NP localize to the nucleus to catalyze further mRNA transcription and vRNA/cRNA replication. Late in the infection process, the synthesis of vRNA and nuclear export of newly synthesized vRNP (vRNA complexed with NP and viral polymerase) is increased relative to transcription (Krug, 1981; Braam, 1983; Kawakami, 1983; Huang, 1990; Cros, 2003; Fodor, 2004; Deng, 2005; Amorim, 2006; reviewed in Neumann, 2004; Engelhardt, 2006; Buolo, 2006). Pubmed12921991 Pubmed15298169 Pubmed15308710 Pubmed15956611 Pubmed16806605 Pubmed16933365 Pubmed17081640 Pubmed2214032 Pubmed6269803 Pubmed6616622 Pubmed6863242 Reactome Database ID Release 43168273 Reactome, http://www.reactome.org ReactomeREACT_6152 Reviewed: Squires, B, 2007-02-12 19:39:22 Fusion of the Influenza Virion to the Host Cell Endosome After the virus binds to the target cell surface and is endocytosed, the low pH of the endosome causes the viral HA (hemagglutinin) to undergo a structural change which frees the fusion peptide of its HA2 subunit allowing it to interact with the endosome membrane. The transmembrane domain of the HA2 (inserted into the viral membrane) and the fusion peptide (inserted into the endosomal membrane) are in juxtaposition in the acidic pH structure of HA. The concerted structural change of several hemagglutinin molecules then opens a pore through which the viral RNP will be able to pass into the host cell cytosol. GENE ONTOLOGYGO:0019064 Pubmed15609499 Pubmed2500008 Pubmed3663665 Reactome Database ID Release 43168288 Reactome, http://www.reactome.org ReactomeREACT_6351 Uncoating of the Influenza Virion GENE ONTOLOGYGO:0019061 Pubmed1985199 Pubmed7688826 Pubmed8841994 Reactome Database ID Release 43168336 Reactome, http://www.reactome.org ReactomeREACT_6321 The precise timing and location of uncoating (early vs. late endosomes) depends on the pH-mediated transition of the specific viral hemagglutinin (HA) molecule involved. The uncoating of influenza viruses in endosomes is blocked by changes in pH caused by weak bases (e.g. ammonium chloride and chloroquine) or ionophores (e.g. monensin). Effective uncoating is also dependent on the presence of the viral M2 ion channel protein. Early on it was recognized that amantadine and rimantadine inhibit replication immediately following virus infection. Later it was found that the virus-associated M2 protein allows the influx of H+ ions into the virion, which disrupts protein-protein interactions, resulting in the release of viral RNP free of the viral matrix (M1) protein. Amantadine and rimantadine have been shown to block the ion channel activity of the M2 protein and thus uncoating. The HA mediated fusion of the viral membrane with the endosomal membrane and the M2-mediated release of the RNP results in the appearance of free RNP complexes in the cytosol. This completes the uncoating process. The time frame for the uncoating process has been examined by inhibiting virus penetration with ammonium chloride. Typically, virus particles show a penetration half time of about 25 minutes after viral adsorption. Ten minutes later (half time of 34 minutes after adsorption) RNP complexes are found in the nucleus. Uptake of RNP molecules through nuclear pores is an active process, involving the nucleo-cytoplasmic trafficking machinery of the host cell. Entry of Influenza Virion into Host Cell via Endocytosis GENE ONTOLOGYGO:0019065 Pubmed0 Reactome Database ID Release 43168275 Reactome, http://www.reactome.org ReactomeREACT_6147 Virus particles bound to the cell surface can be internalized by four mechanisms. Most internalization appears to be mediated by clathrin-coated pits, but internalization via caveolae, macropinocytosis, and by non-clathrin, non-caveolae pathways has also been described for influenza viruses. Fusion and Uncoating of the Influenza Virion GENE ONTOLOGYGO:0046718 Pubmed0 Pubmed2500008 Pubmed3663665 Pubmed563896 Pubmed8841994 Reactome Database ID Release 43168270 Reactome, http://www.reactome.org ReactomeREACT_6282 Uncoating of viral particles takes place in the host cell endosome. Acidification of the endosome promotes fusion of the viral and endosomal membranes, causing a structural change in the viral hemagglutinin (HA) and freeing the fusion peptide of its HA2 subunit to interact with the endosome membrane. The concerted structural change of several HA molecules opens up a pore through which the viral RNP passes into the cytosol of the cell. The precise timing and the location of uncoating (early vs. late endosomes) depends on the pH-mediated transition of the specific HA molecule involved. The virus-associated M2 ion channel protein allows the influx of H+ ions into the virion, which disrupts protein-protein interactions, resulting in the release of RNP free of the viral M1 matrix protein. Thus the HA mediated fusion of the viral membrane with the endosomal membrane and the M2-mediated release of the RNP results in the release of the RNP complex into the cytosol. Amantadine and rimantadine have been shown to block the ion channel activity of the M2 protein and thus interfere with uncoating. Influenza Life Cycle GENE ONTOLOGYGO:0016032 Pubmed0 Reactome Database ID Release 43168255 Reactome, http://www.reactome.org ReactomeREACT_6145 Reviewed: Garcia-Sastre, A, 2004-05-12 19:00:00 Reviewed: Garcia-Sastre, A, Squires, B, 2006-10-30 21:55:36 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 The virus particle initially associates with a human host cell by binding to sialic acid-containing receptors on the host cell surface. The bound virus is endocytosed by one of four distinct mechanisms. The low endosomal pH sets in motion a number of steps that lead to viral membrane fusion mediated by the viral hemagglutinin (HA) protein, and the eventual release of the uncoated viral ribonucleoprotein complex into the cytosol of the host cell. The ribonucleoprotein complex is transported through the nuclear pore into the nucleus. Once in the nucleus, the incoming negative-sense viral RNA (vRNA) is transcribed into messenger RNA (mRNA) by a primer-dependent mechanism. Replication occurs via a two step process. A full-length complementary RNA (cRNA), a positive-sense copy of the vRNA, is first made and this in turn is used as a template to produce more vRNA. The viral proteins are expressed and processed and eventually assemble with vRNAs at budding sites within the host cell membrane. The viral protein complexes and ribonucleoproteins are assembled into viral particles and bud from the host cell, enveloped in the host cell's membrane.<p>This release contains a framework for the further annotation of the viral life-cycle. Miro2 Converted from EntitySet in Reactome Reactome DB_ID: 194861 Reactome Database ID Release 43194861 Reactome, http://www.reactome.org ReactomeREACT_10535 TCL Converted from EntitySet in Reactome Reactome DB_ID: 194874 Reactome Database ID Release 43194874 Reactome, http://www.reactome.org ReactomeREACT_10491 Signaling by EGFR Authored: Jassal, B, Castagnoli, L, 2008-02-28 00:00:00 Edited: Orlic-Milacic, Marija, 2011-08-25 Epidermal Growth Factor Receptor (EGFR) signaling GENE ONTOLOGYGO:0007173 Pubmed10404636 Pubmed10459005 Pubmed12297041 Pubmed15142631 Pubmed21252999 Reactome Database ID Release 43177929 Reactome, http://www.reactome.org ReactomeREACT_9417 Reviewed: Muthuswamy, S, Heldin, CH, 2008--0-2- The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1045 in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011. EGFR interacts with phospholipase C-gamma Activated epidermal growth factor receptors (EGFR) can stimulate phosphatidylinositol (PI) turnover. Activated EGFR can activate phospholipase C-gamma1 (PLC-gamma1, i.e. PLCG1) which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is instrumental in the release of calcium from intracellular stores and DAG is involved in protein kinase C activation. Authored: Jassal, B, 2008-02-13 11:13:12 GENE ONTOLOGYGO:0007165 Pubmed1501243 Reactome Database ID Release 43212718 Reactome, http://www.reactome.org ReactomeREACT_12478 Reviewed: Heldin, CH, 2008-02-12 09:44:02 DAG and IP3 signaling Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Pubmed16260143 Reactome Database ID Release 431489509 Reactome, http://www.reactome.org ReactomeREACT_111064 Reviewed: Greene, LA, 2007-11-08 15:39:37 This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events. CaM pathway Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Calmodulin (CaM) is a small acidic protein that contains four EF-hand motifs, each of which can bind a calcium ion, therefore it can bind up to four calcium ions. The protein has two approximately symmetrical domains, separated by a flexible hinge region. Calmodulin is the prototypical example of the E–F-hand family of Ca2+-sensing proteins. Changes in intracellular Ca2+ concentration regulate calmodulin in three distinct ways. First, by directing its subcellular distribution. Second, by promoting association with different target proteins. Third, by directing a variety of conformational states in calmodulin that result in target-specific activation. Calmodulin binds and activates several effector protein (e.g. the CaM-dependent adenylyl cyclases, phosphodiesterases, protein kinases and the protein phosphatase calcineurin). Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed10884684 Reactome Database ID Release 43111997 Reactome, http://www.reactome.org ReactomeREACT_9053 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Response of Mtb to phagocytosis <i>Mtb</i> encounters a vastly changed environment, soon after it gets internalized by macrophages. The compartment it resides in, the phagosome, is acidified and devoid of important metal ions. It is flooded with reactive oxygen and nitrogen species. And steps will be soon taken by the macrophage to "mature" the phagosome with all kinds of lysosomal digestive enzymes. However, unlike most other bacteria species <i>Mtb.</i> has evolved solutions to each of these threats and, after making sure these are installed, it soon will enter a dormant state (de Chastellier, 2009; Flannagan et al, 2009). A combination of the host defense and the response of the infecting bacillus (active and passive) ensure suppression of bacterial metabolic activity and replication, resulting in a non-replicating state (Russell 2011, Russell et al. 2010). <br><br> Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0052572 Pubmed19261352 Pubmed19369951 Pubmed20466922 Pubmed21349098 Reactome Database ID Release 431222499 Reactome, http://www.reactome.org ReactomeREACT_121042 Reviewed: Warner, D, 2012-04-30 Tolerance by Mtb to nitric oxide produced by macrophages Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0052060 Pubmed15378046 Reactive nitrogen species (RNS), like reactive oxygen species, have numerous target molecules in the bacterial cell, and <i>Mtb</i> has developed remedies to the most important ones of them. This is a key reason for its ability to stay alive in the hostile environment of the late phagosome within human macrophages.<br><i>Mtb</i> repairs single-base DNA damage caused by DNA alkylation; it scavenges nitric oxide with large amounts of mycothiol and methionine-rich proteins (the nitroso compounds later being reduced). Nitric oxide and peroxynitrite are also directly reduced by a battery of hemoglobins and peroxiredoxins, supported by a network of thioredoxins and respective NADPH-dependent reductases (Fang. 2004). Reactome Database ID Release 431222538 Reactome, http://www.reactome.org ReactomeREACT_120983 Reviewed: Warner, D, 2012-04-30 Tolerance of reactive oxygen produced by macrophages Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0052059 Pubmed11970850 Reactome Database ID Release 431222387 Reactome, http://www.reactome.org ReactomeREACT_121009 Reviewed: Warner, D, 2012-04-30 The expression of <i>AhpC</i> in Mycobacteria does not correlate with virulence; instead, the most important parts of the antioxidant system in <i>Mtb</i> appear to be the lipid cell wall, the enzymes SodB/SodC (superoxide dismutases), and the catalase/peroxidase KatG. Together with the enzyme system that acts on nitrosative stress and the sequestration of iron, these appear to be critical in defending against the macrophage's production of ROS/RNS, and enable the bacterium to exist in the phagosome for extended periods (Zahrt & Deretic 2002). Cell redox homeostasis Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0045454 Pubmed17012768 Pubmed21270886 Reactome Database ID Release 431222541 Reactome, http://www.reactome.org ReactomeREACT_121394 Reviewed: Warner, D, 2012-04-30 The most important response of <i>Mtb</i> to oxidative stress is provided by catalase and peroxiredoxins, both of which get their reducing equivalents through a network of disulfide proteins and, finally, from NAD(P)H. Multiple redundancies make choosing a good drug target difficult (Koul et al. 2011). Optimum efficacy can only be expected from inhibitors of the most upstream components of the redox cascades, i.e. the NAD(P)H-dependent reductases TrxB and Lpd (Jaeger & Flohe 2006). Mtb iron assimilation by chelation Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0033214 Pubmed17804665 Reactome Database ID Release 431222449 Reactome, http://www.reactome.org ReactomeREACT_121118 Reviewed: Warner, D, 2012-04-30 Uptake of iron in <i>Mtb</i>, especially when the bacterium is in the host, strongly depends on siderophores. Humans, through secretion of lactoferrin, maintain an iron concentration of 10^(-18) M within macrophages, and the bacterium has evolved the siderophores mycobactin T and exomycobactin T (formerly exochelin) to cope with this shortage. While nonpolar mycobactin T stays in the cell wall and only moves around in liquid droplets, polar exochelin is abundantly secreted. As it can bind iron with higher affinity than lactoferrin, it frequently scavenges iron ions from this molecule (Miethke & Marahiel 2007). Signaling by EGFR in Cancer Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Gillespie, ME, 2011-11-07 Edited: Haw, R, 2011-11-07 Edited: Jassal, B, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Reactome Database ID Release 431643713 Reactome, http://www.reactome.org ReactomeREACT_115871 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 The pathway "Signaling by EGFR in Cancer" shows "Signaling by constitutively active EGFR" in parallel with "Signaling by EGFR". This allows users to compare signaling by constitutively active EGFR cancer mutants with the wild-type EGFR protein. Red lines emphasize cancer related events and physical entities, while wild-type entities and events are shaded. Please refer to "Signaling by constitutively active EGFR" and "Signaling by EGFR" for detailed pathway summations. Arap2 Converted from EntitySet in Reactome Reactome DB_ID: 195150 Reactome Database ID Release 43195150 Reactome, http://www.reactome.org ReactomeREACT_10612 SrGAP1 Converted from EntitySet in Reactome Reactome DB_ID: 195175 Reactome Database ID Release 43195175 Reactome, http://www.reactome.org ReactomeREACT_10449 SrGAP3 Converted from EntitySet in Reactome Reactome DB_ID: 195173 Reactome Database ID Release 43195173 Reactome, http://www.reactome.org ReactomeREACT_10287 Influenza Virus Induced Apoptosis GENE ONTOLOGYGO:0046732 Influenza A virus induces apoptosis in a variety of ways including activation of host TGF-beta by expression of viral NA, M1 and M2 proteins, and by the binding of viral PB1-F2 to host mitochondrial adenine nucleotide translocator 3 (ANT3). Pubmed0 Pubmed11483732 Pubmed11799156 Pubmed12021867 Pubmed15143063 Pubmed7504071 Pubmed9934696 Reactome Database ID Release 43168277 Reactome, http://www.reactome.org ReactomeREACT_6213 Latent infection of Homo sapiens with Mycobacterium tuberculosis Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0051701 Infection by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) is soon countered by the host's immune system, the organism is however almost never eradicated; ten per cent of infections will develop into "open tuberculosis", while the other ninety per cent become "latent", a state that can persist for decades until loss of immune control. A third of the world's population is estimated to harbour latent tuberculosis. Latent infection involves the bacterium being internalized by macrophages where it stops and counters the innate immune answer (Russell 2011, Russell et al. 2010). When a status-quo is reached, <i>Mtb</i> enters a non-replicating persistent state (Barry et al. 2009, Boshoff & Barry 2005). Pubmed15608701 Pubmed19855401 Pubmed20466922 Pubmed21349098 Reactome Database ID Release 431222352 Reactome, http://www.reactome.org ReactomeREACT_121237 Reviewed: Warner, D, 2012-04-30 Inhibition of IFN-beta GENE ONTOLOGYGO:0030683 Pubmed14645582 Reactome Database ID Release 43168888 Reactome, http://www.reactome.org ReactomeREACT_6320 Since the presence of intracellular dsRNA serves as the signal for virus infection and triggers host interferon (IFN) synthesis the simplest model for viral NS1 protein function is that it sequesters dsRNA and thus prevents the downstream signaling required to activate IRF-3, NF-kB and AP-1. These findings are strongly supported by mutational analyses of NS1 that indicate that the IFN antagonist properties of NS1 depend on its ability to bind dsRNA. However, a compensatory mutation (S42G), which was acquired during the passaging of the mutant RNA-binding virus, results in partial restoration of wild-type phenotype but does not restore RNA binding. This indicates that the ability of NS1 to inhibit IFN synthesis is not solely dependent on dsRNA binding and that additional mechanisms may be involved. Inhibition of PKR GENE ONTOLOGYGO:0030683 Reactome Database ID Release 43169131 Reactome, http://www.reactome.org ReactomeREACT_6350 The key role played by PKR in the innate response to virus infection is emphasized by the large number of viruses that encode PKR inhibitors. Phagosomal maturation (early endosomal stage) Alveolar macrophages normally develop their phagosome along the endolysosomal pathway. However, after having internalized <i>Mtb</i>, this development is arrested at an early stage and only includes acidification, nitric oxide and superoxide production, as well as the use of a few other proteins that can be gained from other endosomes which still can interact with the phagosome (Flannagan et al. 2009). Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 GENE ONTOLOGYGO:0090382 Pubmed19369951 Reactome Database ID Release 431222556 Reactome, http://www.reactome.org ReactomeREACT_121256 Reviewed: Warner, D, 2012-04-30 Release Authored: Marsh, G, 2007-04-30 20:49:40 GENE ONTOLOGYGO:0019076 Once the viral envelope has separated from the cell membrane Influenza virus particles are actively released to complete the budding process. HA (hemagglutinin) anchors the virus to the cell by binding to sialic acid-containing receptors on the cell surface. The enzymatic activity of the neuraminidase (NA) protein removes the sialic acid and releases the virus from the host cell. NA activity is also required to remove sialic acid from the carbohydrates present on the viral glycoproteins to prevent the viral particles from aggregating. Pubmed15567494 Pubmed16139601 Reactome Database ID Release 43168298 Reactome, http://www.reactome.org ReactomeREACT_6326 Reviewed: Squires, B, Rush, MG, 2007-04-30 20:48:45 Inhibition of Host mRNA Processing and RNA Silencing GENE ONTOLOGYGO:0046778 Pubmed10205180 Pubmed7958859 Pubmed8313914 Reactome Database ID Release 43168315 Reactome, http://www.reactome.org ReactomeREACT_6173 The Influenza Virus NS1 protein inhibits the cleavage and polyadenylation specificity factor CPSF and the PABII components of the host cell 3' end processing machinery, preventing efficient 3' end processing of host pre-mRNAs. NS1 also inhibits the splicing of pre-mRNAs, resulting in their retention within the host cell nucleus. Inhibition of Interferon Synthesis GENE ONTOLOGYGO:0030683 Interferon Synthesis is inhibited. Reactome Database ID Release 43168305 Reactome, http://www.reactome.org ReactomeREACT_6301 Host Interactions with Influenza Factors GENE ONTOLOGYGO:0019048 Infection of a human host cell with influenza virus triggers an array of host processes that interfere with viral replication, notably the production of type I interferon. The viral NS1 protein plays a central role in these virus-host interactions. Pubmed0 Reactome Database ID Release 43168253 Reactome, http://www.reactome.org ReactomeREACT_6323 Reviewed: Gale M, Jr, 2004-05-12 19:00:00 NS1 Mediated Effects on Host Pathways GENE ONTOLOGYGO:0019054 Pubmed0 Pubmed7571411 Pubmed8548659 Reactome Database ID Release 43168276 Reactome, http://www.reactome.org ReactomeREACT_6222 Viral NS1 protein is a nuclear, dimeric protein that is highly expressed in infected cells and has dsRNA-binding activity. The RNA-binding domain lies within the N-terminal portion of the protein. The NS1 RNA-binding domain forms a symmetric homodimer with a six-helical fold. Mutational analysis has demonstrated that dimer formation is crucial for RNA-binding. The basic residues are believed to make contact with the phosphate backbone of the RNA which is consistent with an observed lack of sequence specificity. Neither NS1 nor its bound RNA undergo any significant structural changes upon binding. The NS1 dimer spans the minor groove of canonical A-form dsRNA. The non-RNA binding portion of NS1 has been termed the effector domain and includes binding sites for host cell poly (A)-binding protein II (PABII) and the 30kDa subunit of cleavage and polyadenylation specificity factor (CPSF). Cdc42 Converted from EntitySet in Reactome Reactome DB_ID: 195342 Reactome Database ID Release 43195342 Reactome, http://www.reactome.org ReactomeREACT_10718 Cleaved collagen alpha-1(XIV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2470796 Reactome Database ID Release 432470796 Reactome, http://www.reactome.org ReactomeREACT_150838 NR3C3 Converted from EntitySet in Reactome Reactome DB_ID: 376291 Reactome Database ID Release 43376291 Reactome, http://www.reactome.org ReactomeREACT_116791 SDF1 CXCL12 Converted from EntitySet in Reactome Reactome DB_ID: 1254393 Reactome Database ID Release 431254393 Reactome, http://www.reactome.org ReactomeREACT_117307 SDF-1 p-Y419/420/426-N-myristoyl-SRC/FYN/YES1 Converted from EntitySet in Reactome Reactome DB_ID: 1810413 Reactome Database ID Release 431810413 Reactome, http://www.reactome.org ReactomeREACT_116628 The role of Nef in HIV-1 replication and disease pathogenesis Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed12545074 Pubmed1470917 Pubmed16354571 Pubmed2531920 Pubmed3262235 Pubmed9365760 Pubmed9420207 Pubmed9790524 Reactome Database ID Release 43164952 Reactome, http://www.reactome.org ReactomeREACT_6835 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The HIV-1 Nef protein is a 27-kDa myristoylated protein that is abundantly produced during the early phase of viral replication cycle. It is highly conserved in all primate lentiviruses, suggesting that its function is essential for survival of these pathogens. The protein name "Nef" was derived from early reports of its negative effect on viral replication, thus 'negative factor' or Nef. Subsequently it has been demonstrated that Nef plays an important role in several steps of HIV replication. In addition, it appears to be a critical pathogenic factor, as Nef-deficient SIV and HIV are significantly less pathogenic than the wild-type viruses, whereas Nef-transgenic mice show many features characteristic to HIV disease.<br><br>The role of Nef in HIV-1 replication and disease pathogenesis is determined by at least four independent activities of this protein. Nef affects the cell surface expression of several cellular proteins, interferes with cellular signal transduction pathways, enhances virion infectivity and viral replication, and regulates cholesterol trafficking in HIV-infected cells. Interactions of Tat with host cellular proteins Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2006-03-24 13:43:41 Pubmed7853496 Pubmed9491887 Reactome Database ID Release 43176034 Reactome, http://www.reactome.org ReactomeREACT_6905 The elongation of HIV-1 mRNA depends upon the interaction of Tat with the host P-TEFb complex (Hermann and Rice, 1995; Wei et al., 1998). Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters Authored: Gillespie, ME, 2007-07-25 19:42:36 GENE ONTOLOGYGO:0050690 Pubmed11208076 Pubmed11285224 Pubmed11463741 Pubmed12486136 Pubmed12970439 Pubmed16103193 Pubmed2014052 Pubmed8612235 Pubmed9384576 Pubmed9564030 Pubmed9586638 Pubmed9736718 Pubmed9811606 Pubmed9811611 Reactome Database ID Release 43164938 Reactome, http://www.reactome.org ReactomeREACT_11149 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The maximal virulence of HIV-1 requires Nef, a virally encoded peripheral membrane protein. Nef binds to the adaptor protein (AP) complexes of coated vesicles, inducing an expansion of the endosomal compartment and altering the surface expression of cellular proteins including CD4 and class I major histocompatibility complex.<br> Nef affects the cell surface expression of several cellular proteins. It down-regulates CD4, CD8, CD28, and major histocompatibility complex class I and class II proteins, but upregulates the invariant chain of MHC II (CD74). To modulate cell surface receptor expression, Nef utilizes several strategies, linked to distinct regions within the Nef protein.<br>Since all these receptors are essential for proper functions of the immune system, modulation of their surface expression by Nef has profound effects on anti-HIV immune responses. Down-regulation of MHC I protects HIV-infected cells from host CTL response, whereas down-modulation of CD28 and CD4 probably limits the adhesion of a Nef-expressing T cell to the antigen-presenting cell, thus promoting the movement of HIV-infected cells into circulation and the spread of the virus. Nef and signal transduction Authored: Gillespie, ME, 2007-07-25 19:42:36 GENE ONTOLOGYGO:0050690 Nef interferes with cellular signal transduction pathways in a number of ways. Nef is associated with lipid rafts through its amino-terminal myristoylation and a proline-rich SH3-binding domain. These cholesterol-rich membrane microdomains appear to concentrate potent signaling mediators. Nef was found to complex with and activate serine/threonine protein kinase PAK-2, which may contribute to activation of infected cells. In vitro, HIV-infected T cells produce enhanced levels of interleukin-2 during activation. When expressed in macrophages, Nef intersects the CD40L signaling pathway inducing secretion of chemokines and other factors that attract resting T cells and promote their infection by HIV. Pubmed10618429 Pubmed12853962 Pubmed8570619 Reactome Database ID Release 43164944 Reactome, http://www.reactome.org ReactomeREACT_11068 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Nef mediated downregulation of MHC class I complex cell surface expression Authored: Gillespie, ME, 2007-07-25 19:42:36 Down-regulation of MHC class I involves Nef-mediated connection in the endosomes between MHC-I's cytoplasmic tail and the phosphofurin acidic cluster sorting protein-1 (PACS-1)-dependent protein-sorting pathway. Down-regulation of MHC I protects HIV-infected cells from host CTL response. GENE ONTOLOGYGO:0050690 Pubmed10707087 Pubmed11593029 Pubmed12414957 Pubmed12526811 Pubmed15569716 Pubmed8612235 Pubmed9586638 Reactome Database ID Release 43164940 Reactome, http://www.reactome.org ReactomeREACT_11103 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Nef mediated downregulation of CD28 cell surface expression Authored: Gillespie, ME, 2007-07-25 19:42:36 Down-regulation of CD28 receptors involves a dileucine-based motif in the second disordered loop of Nef, which connects Nef to adaptor protein (AP) complex, which is a part of cellular endocytosis machinery. Nef induces accelerated endocytosis of CD28 via clathrin-coated pits followed by lysosomal degradation. GENE ONTOLOGYGO:0050690 Pubmed11285224 Pubmed12486136 Reactome Database ID Release 43164939 Reactome, http://www.reactome.org ReactomeREACT_11139 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Nef Mediated CD8 Down-regulation Authored: Gillespie, ME, 2007-07-25 19:42:36 GENE ONTOLOGYGO:0050690 Human immunodeficiency virus (HIV) Nef is a membrane-associated protein decreasing surface expression of CD4, CD28, and major histocompatibility complex class I on infected cells. Nef also strongly down-modulates surface expression of the beta-chain of the CD8alphabeta receptor by accelerated endocytosis, while CD8 alpha-chain expression is less affected. Mutational analysis of the cytoplasmic tail of the CD8 beta-chain indicates that an FMK amino acid motif is critical for the Nef-induced endocytosis. Although independent of CD4, endocytosis of the CD8 beta-chain is abrogated by the same mutations in Nef that affect CD4 down-regulation, suggesting common molecular interactions. The ability to down-regulate the human CD8 beta-chain was conserved in HIV-1, HIV-2, and simian immunodeficiency virus SIVmac239 Nef and required an intact AP-2 complex. Pubmed12032142 Pubmed16103193 Reactome Database ID Release 43182218 Reactome, http://www.reactome.org ReactomeREACT_11200 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Nef Mediated CD4 Down-regulation Authored: Gillespie, ME, 2007-07-25 19:42:36 GENE ONTOLOGYGO:0050690 Pubmed11264384 Pubmed2014052 Pubmed7831289 Pubmed8124721 Pubmed8756680 Reactome Database ID Release 43167590 Reactome, http://www.reactome.org ReactomeREACT_11166 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The presence of Nef accelerates endocytosis and lysosomal degradation of the transmembrane glycoprotein CD4. CD4 has its own internalization motif, though this motif is normally concealed by CD4 interaction with Lck, a tyrosine kinase. Nef is known to disrupt this interaction and then facilitate a cascade of protein interactions that ultimately result in the degradation of internalized CD4 protein. The final set of protein interactions that direct Nef to the beta-subunit of the COPI coatomers are at this time unclear.<br><br>A benefit for the virus from CD4 down-modulation is abolition of interaction between the receptor and the Env protein of the budding virus, which likely increases HIV release from infected cell as well as infectivity of viral particles. Influenza Infection Authored: Luo, F, Squires, B, Scheuermann, RH, 2006-01-05 15:13:12 Edited: D'Eustachio, P, Gillespie, ME, 2006-01-07 21:50:17 For centuries influenza epidemics have plagued man, and influenza was probably the disease described by Hippocrates in 412 BC. Today it remains a major cause of morbidity and mortality worldwide with large segments of the human population affected every year. Many animal species can be infected by influenza viruses, often with catastrophic consequences. A continuing threat is the possibility of a pandemic similar to that experienced in 1918, estimated to have been responsible for 50 million deaths worldwide.<p>Influenza viruses belong to the family of Orthomyxoviridae; viruses with segmented RNA genomes that are negative sense and single-stranded (Baltimore 1971).<p>Influenza virus strains are named according to their type (A, B, or C), the species from which the virus was isolated (omitted if human), location of isolate, the number of the isolate, the year of isolation, and in the case of influenza A viruses, the hemagglutinin (H) and neuraminidase (N) subtype. For example, the virus of H5N1 subtype isolated from chickens in Hong Kong in 1997 is: influenza A/chicken/Hong Kong/220/97(H5N1) virus. Currently 16 different hemagglutinin (H1 to H16) subtypes and 9 different neuraminidase (N1 to N9) subtypes are known for influenza A viruses. Most human disease is due to Influenza viruses of the A type, so the events of Influenza infection have been annotated in Reactome with reference to this type. GENE ONTOLOGYGO:0019058 Pubmed0 Reactome Database ID Release 43168254 Reactome, http://www.reactome.org ReactomeREACT_6167 Reviewed: Garcia-Sastre, A, Squires, B, 2006-10-30 21:55:36 Vpu mediated degradation of CD4 Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-05-15 07:16:46 Pubmed15578980 Pubmed16354571 Reactome Database ID Release 43180534 Reactome, http://www.reactome.org ReactomeREACT_9031 Reviewed: Benarous, R, 2006-09-21 14:25:23 The HIV-1 Vpu protein promotes the degradation of the CD4 receptor by recruiting an SCF like ubiquitination complex that promotes CD4 degradation. Vpu links beta-TrCP to CD4 at the ER membrane through interactions with beta-TrCP and the cytoplasmic tail of CD4. The SKP1 component of the SCF complex is then recruited to the Vpu:beta-TrCP:CD4 promoting ubiquitination and subsequent proteasome-mediated degradation of CD4 (reviewed in Li et al., 2005). Vpu has also been shown to also increases progeny virus secretion from infected cells. Although the precise role of Vpu in this process is not yet known, it may affect ion conductive membrane pore formation and/or interference with TASK-1, an acid-sensitive K+ channel that inhibits virion release in some cells (see references in Li et al., 2005). WWP1/ITCH Converted from EntitySet in Reactome Reactome DB_ID: 1253275 Reactome Database ID Release 431253275 Reactome, http://www.reactome.org ReactomeREACT_117486 Growth Hormone Converted from EntitySet in Reactome Reactome DB_ID: 982814 Reactome Database ID Release 43982814 Reactome, http://www.reactome.org ReactomeREACT_111755 Transport of Mature mRNA Derived from an Intronless Transcript Reactome Database ID Release 43159231 Reactome, http://www.reactome.org ReactomeREACT_1835 Transport of mRNA from the nucleus to the cytoplasm, where it is translated into protein, is highly selective and closely coupled to correct RNA processing. Transport of the SLBP independent Mature mRNA Reactome Database ID Release 43159227 Reactome, http://www.reactome.org ReactomeREACT_424 Transport of the SLBP independent Mature mRNA through the nuclear pore. Transport of the SLBP Dependant Mature mRNA Reactome Database ID Release 43159230 Reactome, http://www.reactome.org ReactomeREACT_405 Transport of U7 snRNP and stem-loop binding protein (SLBP) processed mRNA. Transport of Mature mRNAs Derived from Intronless Transcripts Authored: Gillespie, ME, 2005-03-13 17:31:37 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006406 Reactome Database ID Release 43159234 Reactome, http://www.reactome.org ReactomeREACT_338 Transport of mature mRNAs derived from intronless transcripts require some of the same protein complexes as mRNAs derived from intron containing complexes, including TAP and Aly/Ref. However a number of the splicing related factors are lacking from the intronless derived mRNAs, as they required no splicing. pre-mRNA splicing GENE ONTOLOGYGO:0000398 Reactome Database ID Release 4372163 Reactome, http://www.reactome.org ReactomeREACT_467 The splicing of pre-mRNA occurs within a large, very dynamic complex, designated the 'spliceosome'. The 50-60S spliceosomes are estimated to be 40-60 nm in diameter, and have molecular weights in the range of 3-5 million kDa. Small nuclear RNAs (snRNAs) U1, U2, U4, U5, and U6, are some of the best characterized components of spliceosomes, and are known to play key roles not only in spliceosomal assembly, but also in the two catalytic steps of the splicing reaction. Over 150 proteins have been detected in spliceosomes, and only a subset of these has been characterized. The characterization, and the determination of the functions of the protein components of the spliceosome, is still work in progress.<p>During spliceosome assembly, the snRNAs and the spliceosomal proteins assemble on the pre-mRNA in a stepwise pathway. First the E complex forms, followed by complexes A and B; the C complex forms next and contains the products of the first step of the splicing reaction. Complexes called i and D form as a consequence of the second step of the splicing reaction, which contain the excised intron and the spliced exons, respectively. U2 Dependent Splicing mRNA Splicing - Major Pathway mRNA Splicing GENE ONTOLOGYGO:0008380 Pubmed12226669 Reactome Database ID Release 4372172 Reactome, http://www.reactome.org ReactomeREACT_1735 The process in which excision of introns from the primary transcript of messenger RNA (mRNA) is followed by ligation of the two exon termini exposed by removal of each intron, is called mRNA splicing. Most of the mRNA is spliced by the major pathway, involving the U1, U2, U4, U5 and U6 snRNPs. A minor fraction, about 1 %, of the mRNAs are spliced via the U12 dependent pathway. Transport of Mature mRNA derived from an Intron-Containing Transcript GENE ONTOLOGYGO:0006406 Reactome Database ID Release 43159236 Reactome, http://www.reactome.org ReactomeREACT_1597 Transport of mRNA from the nucleus to the cytoplasm, where it is translated into protein, is highly selective and closely coupled to correct RNA processing. This coupling is achieved by the nuclear pore complex, which recognizes and transports only completed mRNAs. Transport of Mature Transcript to Cytoplasm Authored: Joshi-Tope, G, 2003-09-02 11:48:00 GENE ONTOLOGYGO:0006406 Reactome Database ID Release 4372202 Reactome, http://www.reactome.org ReactomeREACT_1281 Transport of mRNA through the Nuclear Pore Complex (NPC) is a dynamic process involving distinct machinery and receptor subsets. The separation of the two compartments and the regulation of this transport provide spatial and temporal control over mRNA expression and ultimately control over translation. It should be noted that mRNA export does not rely on a specific motif in the mRNA molecule, but rather transport appears to be coupled to processing and regulation. The specific proteins that are bound to the mRNA determine when it will be transported to the cytoplasm. This limitation insures that transport overwhelmingly favors transport of fully processed mRNA molecules. mRNA 3'-end processing Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0031124 Pubmed10357856 Pubmed10371034 Pubmed11909521 Pubmed2408761 Reactome Database ID Release 4372187 Reactome, http://www.reactome.org ReactomeREACT_1849 The 3' ends of eukaryotic mRNAs are generated by posttranscriptional processing of an extended primary transcript. For almost all RNAs, 3'-end processing consists of two steps: (i) the mRNA is first cleaved at a particular phosphodiester bond downstream of the coding sequence, (ii) the upstream fragment then receives a poly(A) tail of approximately 250 adenylate residues, whereas the downstream fragment is degraded. The two partial reactions are coupled so that reaction intermediates are usually undetectable. While 3' processing can be studied as an isolated event <i>in vitro</i>, it appears to be connected to transcription, splicing, and transcription termination <i>in vivo</i>.<p>The only known exception to the rule of cleavage followed by polyadenylation are the major histone mRNAs, which are cleaved but not polyadenylated. U12 Dependent Splicing Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0000398 Pubmed10207048 Pubmed9149533 Reactome Database ID Release 4372165 Reactome, http://www.reactome.org ReactomeREACT_1753 The splicing of a subset of pre-mRNA introns occurs by a second pathway, designated the AT-AC or U12-dependent splicing pathway. AT-AC introns have highly conserved, non-canonical splice sites that are removed by the AT-AC spliceosome, which contains distinct snRNAs (U11, U12, U4atac, U6atac) that are structurally and functionally analogous to the major spliceosome. U5 snRNA as well as many of the protein factors appear to be conserved between the two spliceosomes. mRNA Splicing - Minor Pathway FGFR3 ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 FGFR3 is a receptor tyrosine kinase of the FGF receptor family, known to have a negative regulatory effect on long bone growth. Somatically, some of the same activating mutations are associated with hypochondroplasia, multiple myeloma, and cervical and vesical carcinoma. GENE ONTOLOGYGO:0008543 Pubmed15748888 Pubmed16597617 Pubmed9045692 Reactome Database ID Release 43190239 Reactome, http://www.reactome.org ReactomeREACT_9439 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 FGFR3c ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 GENE ONTOLOGYGO:0008543 Pubmed16597617 Reactome Database ID Release 43190372 Reactome, http://www.reactome.org ReactomeREACT_9510 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR3c. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. FGFR3b ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 GENE ONTOLOGYGO:0008543 Pubmed16597617 Reactome Database ID Release 43190371 Reactome, http://www.reactome.org ReactomeREACT_9508 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR3b. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. FGFR4 ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 FGFR4 is expressed mainly in mature skeletal muscle, and disruption of FGFR4 signaling interrupts limb muscle formation in vertebrates. GENE ONTOLOGYGO:0008543 Pubmed1385111 Pubmed15467729 Pubmed16597617 Pubmed7518429 Reactome Database ID Release 43190322 Reactome, http://www.reactome.org ReactomeREACT_9452 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Klotho-mediated ligand binding Authored: Rothfels, K, 2011-08-15 Pubmed17339340 Pubmed19063940 Reactome Database ID Release 431307973 Reactome, http://www.reactome.org ReactomeREACT_111247 Reviewed: Gotoh, N, 2011-08-26 The endocrine FGFs (19, 21 and 23) have lower affinity for heparin and HSPG compared to their paracrine or autocrine coutnerparts. Binding of these ligands to their receptors is generally aided by the FGF-binding Klotho proteins. betaKlotho-mediated ligand binding Authored: Rothfels, K, 2011-08-15 FGF21 and FGF19 require betaKlotho for efficient signaling through FGFR1c and FGFR3c. betaKlotho does not interact with 'b' receptor isoforms, and only weakly with FGFR2c. In addition, FGF19, but not FGF21, signals through FGFR4 in a betaKlotho-dependent fashion Pubmed17623664 Pubmed19063940 Reactome Database ID Release 431307965 Reactome, http://www.reactome.org ReactomeREACT_111046 Reviewed: Gotoh, N, 2011-08-26 FGFR1c and Klotho ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 FGF23 is a member of the endocrine subfamily of FGFs. It is produced in bone tissue and regulates kidney functions. Klotho is essential for endogenous FGF23 function as it converts FGFR1c into a specific FGF23 receptor. GENE ONTOLOGYGO:0008543 Pubmed16436388 Pubmed17086194 Reactome Database ID Release 43190374 Reactome, http://www.reactome.org ReactomeREACT_9484 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Downstream signaling of activated FGFR Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Pubmed10377388 Pubmed15863030 Pubmed15863038 Pubmed8752212 Reactome Database ID Release 43190333 Reactome, http://www.reactome.org ReactomeREACT_21272 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Signaling via FGFRs is mediated via direct recruitment of signaling proteins that bind to tyrosine auto-phosphorylation sites on the activated receptor and via closely linked docking proteins that become tyrosine phosphorylated in response to FGF-stimulation and form a complex with additional complement of signaling proteins. <br><br>The activation loop in the catalytic domain of FGFR maintains the PTK domain in an inactive or low activity state. The activation-loop of FGFR1, for instance, contains two tyrosine residues that must be autophosphorylated for maintaining the catalytic domain in an active state. In the autoinhibited configuration, a kinase invariant proline residue at the C-terminal end of the activation loop interferes with substrate binding while allowing access to ATP in the nucleotide binding site.<br>In addition to the catalytic PTK core, the cytoplasmic domain of FGFR contains several regulatory sequences. The juxtamembrane domain of FGFRs is considerably longer than that of other receptor tyrosine kinases. This region contains a highly conserved sequence that serves as a binding site for the phosphotyrosine binding (PTB) domain of FRS2. A variety of signaling proteins are phosphorylated in response to FGF stimulation, including Shc, phospholipase-C gamma and FRS2 leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. FRS2-mediated cascade Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Pubmed10377388 Pubmed11447289 Pubmed15863030 Pubmed16682955 Pubmed18452557 Pubmed9182757 Reactome Database ID Release 43190345 Reactome, http://www.reactome.org ReactomeREACT_21247 Reviewed: Gotoh, N, 2011-08-26 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The FRS family of scaffolding adaptor proteins has two members, FRS2alpha and FRS2beta (also known as FRS3 or SNT-2). Activation of FGFR tyrosine kinase allows FRS2 proteins to become phosphorylated on tyrosine residues and then bind to the adaptor GRB2 and the tyrosine phosphatase SHP2. Subsequently, SHP2 activates the RAS-MAP kinase pathway and GRB2 activates the RAS-MAP kinase , PI-3-kinase and ubiquitinations/degradation pathways by binding to SOS, GAB1 and CBL, respectively, via the SH3 domains of GRB2. FRS2alpha acts as a central mediator in FGF signaling mainly because it induces sustained levels of activation of ERK with ubiquitous expression.<br><br><br> Phospholipase C-mediated cascade Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Phospholipase C-gamma (PLC-gamma) is a substrate of the fibroblast growth factor receptor (FGFR) and other receptors with tyrosine kinase activity. It is known that the src homology region 2 (SH2 domain) of PLC-gamma and of other signaling molecules (such as GTPase-activating protein and phosphatidylinositol 3-kinase-associated p85) direct their binding toward autophosphorylated tyrosine residues of the FGFR. Recruitment of PLC-gamma results in its phosphorylation and activation by the receptor. Activated PLC-gamma hydrolyzes phosphatidyl inositol[4,5] P2 to form the second messengers diacylglycerol (DAG) and Ins [1,4,5]P3, which stimulate calcium release and activation of calcium/calmodulin dependent kinases.<br> Pubmed10579907 Pubmed15863030 Pubmed1656221 Reactome Database ID Release 43190347 Reactome, http://www.reactome.org ReactomeREACT_21310 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 Insulin Synthesis and Processing Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed11815450 Pubmed11815463 Pubmed16549443 Pubmed16714477 Pubmed9631292 Reactome Database ID Release 43264876 Reactome, http://www.reactome.org ReactomeREACT_15550 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 The generation of insulin-containing secretory granules from proinsulin in the lumen of the endoplasmic reticulum (ER) can be described in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin to yield insulin, translocation of the granules across the cytosol to the plasma membrane.<br>Transcription of the human insulin gene INS is activated by 4 important transcription factors: Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at the promoters of the insulin gene and act synergistically to promote transcription. Expression of the transcription factors is upregulated in response to glucose.<br>The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is cleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA is stabilized by glucose.<br>In the process annotated in detail here, within the ER, three intramolecular disulfide bonds form between cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result of the conformation of proinsulin and the oxidizing environment of the ER, which is maintained by Ero1-like alpha<br>The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. High concentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7 and the proinsulin forms complexes with zinc and calcium.<br>Proinsulin-zinc-calcium complexes bud in vesicles from the trans-Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules the endoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sites of the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the cystine-bonded A and B chains of mature insulin and the C peptide, which will also be secreted with the insulin. The insulin-zinc-calcium complexes form insoluble crystals within the granule<br>The insulin-containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin-1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.<br>A pancreatic beta cell contains about 10000 insulin granules of which about 1000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE-type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin-2/VAMP2 on the granule membrane. Exocytosis is a calcium-dependent process due to interaction of the calcium-binding membrane protein Synaptotagmin V/IX with the SNARE-type proteins. Binding of RNA by Insulin-like Growth Factor-2 mRNA Binding Proteins (IGF2BPs/IMPs/VICKZs) Authored: May, B, 2009-07-04 Edited: May, B, 2009-07-04 Insulin-like Growth Factor-2 mRNA Binding Proteins (IGF2BPs) bind specific sets of RNA and regulate their translation, stability, and subcellular localization. IGF2BP1, IGF2BP2, and IGF2BP3 bind about 8400 protein-coding transcripts. The target RNAs contain the sequence motif CAUH (where H is A, U, or, C) and binding of IGFBPs increases the stability of the target RNAs. Pubmed11713986 Pubmed15601260 Pubmed16541107 Pubmed17652133 Pubmed20371350 Pubmed9891060 Reactome Database ID Release 43428359 Reactome, http://www.reactome.org ReactomeREACT_22166 Reviewed: Chao, JA, 2010-05-30 Reviewed: Singer, RH, 2010-05-30 PERK regulated gene expression Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 GENE ONTOLOGYGO:0006987 PERK is a single-pass transmembrane protein located in the endoplasmic reticulum (ER) membrane such that the N-terminus of PERK is luminal and the C-terminus is cytosolic. PERK is maintained in an inactive form by interaction of its luminal domain with BiP, an ER chaperone. BiP also binds unfolded proteins and so BiP dissociates from PERK when unfolded proteins accumulate in the ER. Dissociated PERK monomers spontaneously form homodimers and the homodimeric form of PERK possesses kinase activity in its cytosolic C-terminal domain. The kinase specifically phosphorylates the translation factor eIF2alpha at Ser52, resulting in an arrest of translation. Thus translation of proteins targeted to the ER is downregulated. The translation arrest also causes depletion of Cyclin D1, a rapidly turned over protein. The depletion of Cyclin D1 in turn causes arrest of the cell cycle in G1 phase. Pubmed17956313 Pubmed18038217 Pubmed18048764 Pubmed18436705 Reactome Database ID Release 43381042 Reactome, http://www.reactome.org ReactomeREACT_18277 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Activation of Chaperone Genes by XBP1(S) Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Pubmed14559994 Pubmed16461360 Pubmed16539657 Pubmed17612490 Pubmed18664523 Reactome Database ID Release 43381038 Reactome, http://www.reactome.org ReactomeREACT_18273 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Xbp-1 (S) binds the sequence CCACG in ER Stress Responsive Elements (ERSE, consensus sequence CCAAT (N)9 CCACG) located upstream from many genes. The ubiquitous transcription factor NF-Y, a heterotrimer, binds the CCAAT portion of the ERSE and together the IRE1-alpha: NF-Y complex activates transcription of a set of chaperone genes including DNAJB9, EDEM, RAMP4, p58IPK, and others. This results in an increase in protein folding activity in the ER. Regulation of IGF Activity by IGFBP Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Pubmed11606061 Pubmed11751371 Pubmed12379487 Pubmed12466191 Pubmed12904166 Pubmed17047378 Reactome Database ID Release 43381426 Reactome, http://www.reactome.org ReactomeREACT_15428 Regulation of Insulin-like Growth Factor (IGF) Activity by Insulin-like Growth Factor Binding Proteins (IGFBPs) Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 The family of Insulin like Growth Factor Binding Proteins (IGFBPs) share 50% amino acid identity with conserved N terminal and C terminal regions responsible for binding Insulin like Growth Factors I and II (IGF I and IGF II). Most circulating IGFs are in complexes with IGFBPs, which are believed to increase the residence of IGFs in the body, modulate availability of IGFs to target receptors for IGFs, reduce insulin like effects of IGFs, and act as signaling molecules independently of IGFs. About 75% of circulating IGFs are in 1500 220 KDa complexes with IGFBP 3 and ALS. Such complexes are too large to pass the endothelial barrier. The remaining 20 25% of IGFs are bound to other IGFBPs in 40 50 KDa complexes. IGFs are released from IGF:IGFBP complexes by proteolysis of the IGFBP. IGFs become active after release, however IGFs may also have activity when still bound to some IGFBPs. IGFBP 1 is enriched in amniotic fluid and is produced in the liver under control of insulin (insulin suppresses production). IGFBP 1 binding stimulates IGF function. It is unknown which if any protease degrades IGFBP 1. IGFBP 2 is enriched in cerebrospinal fluid; its binding inhibits IGF function. IGFBP 2 is not significantly degraded in circulation. IGFBP 3, which binds most IGF in the body is enriched in follicular fluid and found in many other tissues. IGFBP 3 may be cleaved by plasmin, thrombin, Prostate specific Antigen (PSA), Matrix Metalloprotease 1, and Matrix Metalloprotease 2. IGFBP 3 also binds extracellular matrix and binding lowers its affinity for IGFs. IGFBP 3 binding stimulates the effects of IGFs. IGFBP 4 acts to inhibit IGF function and is cleaved by Pregnancy associated Plasma Protein A (PAPP A) to release IGF. IGFBP 5 is enriched in bone matrix; its binding stimulates IGF function. IGFBP 5 is cleaved by Pregnancy Associated Plasma Protein A2 (PAPP A2), ADAM 9, complement C1s from smooth muscle, and thrombin. Only the cleavage site for PAPP A2 is known. IGFBP 6 is enriched in cerebrospinal fluid. It is unknown which if any protease degrades IGFBP 6. Activation of Genes by ATF4 ATF4 is a transcription factor and activates expression of IL-8, MCP1, IGFBP-1, CHOP, HERP1 and ATF3. Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Pubmed14630918 Pubmed14742429 Pubmed16687408 Pubmed16912112 Pubmed16931790 Pubmed18426796 Pubmed18840095 Pubmed20022965 Reactome Database ID Release 43380994 Reactome, http://www.reactome.org ReactomeREACT_18355 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Activation of Chaperones by ATF6-alpha ATF6-alpha is a transmembrane protein that normally resides in the Endoplasmic Reticulum (ER) membrane. Here its luminal C-terminal domain is associated with BiP, shielding 2 Golgi-targeting regions and thus keeping ATF6-alpha in the ER. Upon interaction of BiP with unfolded proteins in the ER, ATF6-alpha dissociates and transits to the Golgi where it is cleaved by the S1P and S2P proteases that reside in the Golgi, releasing the N-terminal domain of ATF6-alpha into the cytosol. After transiting to the nucleus, the N-terminal domain acts as a transcription factor to activate genes encoding chaperones. Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 GENE ONTOLOGYGO:0006987 Pubmed18038217 Pubmed18048764 Pubmed18436705 Reactome Database ID Release 43381033 Reactome, http://www.reactome.org ReactomeREACT_18348 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Unfolded Protein Response Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 GENE ONTOLOGYGO:0030968 Pubmed15952902 Pubmed16365312 Pubmed18038217 Pubmed18048764 Pubmed18436705 Reactome Database ID Release 43381119 Reactome, http://www.reactome.org ReactomeREACT_18356 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The Unfolded Protein Response (UPR) is a regulatory system that protects the Endoplasmic Reticulum (ER) from overload. The UPR is provoked by the accumulation of improperly folded protein in the ER during times of unusually high secretion activity. Analysis of mutants with altered UPR, however, shows that the UPR is also required for normal development and function of secretory cells.<br>One level at which the URP operates is transcriptional and translational regulation: mobilization of ATF6 and IRE1 leads to increased transcription of genes encoding chaperones, and mobilization of PERK (pancreatic eIF2alpha kinase) leads to phosphorylation of the translation initiation factor eIF2alpha and global down-regulation of protein synthesis. These three regulatory pathways are annotated here. Activation of Chaperones by IRE1alpha Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 GENE ONTOLOGYGO:0006987 IRE1-alpha is a single-pass transmembrane protein that resides in the endoplasmic reticulum (ER) membrane. The C-terminus of IRE1-alpha is located in the cytosol; the N-terminus is located in the ER lumen. In unstressed cells IRE1-alpha exists in an inactive heterodimeric complex with BiP such that BiP in the ER lumen binds the N-terminal region of IRE1-alpha. Upon accumulation of unfolded proteins in the ER, BiP binds the unfolded protein and the IRE1-alpha:BiP complex dissociates. The dissociated IRE1-alpha then forms homodimers. Initially the luminal N-terminal regions pair. This is followed by trans-autophosphorylation of IRE1-alpha at Ser724 in the cytosolic C-terminal region. The phosphorylation causes a conformational change that allows the dimer to bind ADP, causing a further conformational change to yield back-to-back pairing of the cytosolic C-terminal regions of IRE1-alpha. The fully paired IRE1-alpha homodimer has endoribonuclease activity and cleaves the mRNA encoding Xbp-1. A 26 residue polyribonucleotide is released and the 5' and 3' fragments of the original Xbp-1 mRNA are rejoined. The spliced Xbp-1 message encodes Xbp-1 (S), a potent activator of transcription. Xbp-1 (S) together with the ubiquitous transcription factor NF-Y bind the ER Stress Responsive Element (ERSE) in a number of genes encoding chaperones. Recent data suggest that the IRE1-alpha homodimer can also cleave specific subsets of mRNAs, including the insulin (INS) mRNA in pancreatic beta cells. Pubmed18038217 Pubmed18048764 Pubmed18436705 Reactome Database ID Release 43381070 Reactome, http://www.reactome.org ReactomeREACT_18368 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 Activation of Chaperone Genes by ATF6-alpha Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, 2009-06-02 00:51:49 Pubmed10856300 Pubmed10866666 Pubmed10958673 Pubmed14973138 Reactome Database ID Release 43381183 Reactome, http://www.reactome.org ReactomeREACT_18423 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 The N-terminal fragment of ATF6-alpha contains a bZIP domain and binds the sequence CCACG in ER Stress Response Elements (ERSEs). ATF6-alpha binds ERSEs together with the heterotrimeric transcription factor NF-Y, which binds the sequence CCAAT in the ERSEs, and together the two factors activate transcription of ER stress-responsive genes. Evidence from overexpression and knockdowns indicates that ATF6-alpha is a potent activator but its homolog ATF6-beta is not and ATF6-beta may actually reduce expression of ER stress proteins. Synthesis, Secretion, and Deacylation of Ghrelin Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Ghrelin is a peptide hormone of 28 amino acid residues which is acylated at the serine-3 of the mature peptide. Ghrelin is synthesized in several tissues: X/A-like cells of the gastric mucosa (the major source of ghrelin), hypothalamus, pituitary, adrenal gland, thyroid, breast, ovary, placenta, fallopian tube, testis, prostate, liver, gall bladder, pancreas, fat tissue, human lymphocytes, spleen, kidney, lung, skeletal muscle, myocardium, vein and skin. Ghrelin binds the GHS-R1a receptor present in hypothalamus pituitary, and other tissues. Binding causes appetite stimulation and release of growth hormone. Levels of circulating ghrelin rise during fasting, peak before a meal, and fall according to the calories ingested.<br>Preproghrelin is cleaved to yield proghrelin which is then acylated by ghrelin O-acyltransferase to yield octanoyl ghrelin and decanoyl ghrelin. Only octanoyl ghrelin is able to bind and activate the GHS-R1a receptor. Unacylated ghrelin (des-acyl ghrelin) is also present in plasma but its function is controversial.<br>Acyl proghrelin is cleaved by prohormone convertase 1/3 to yield the mature acyl ghrelin and C-ghrelin. Secretion of ghrelin is inhibited by insulin, growth hormone (somatotropin), leptin, glucose, glucagon, and fatty acids. Secretion is stimulated by insulin-like growth factor-1 and muscarinic agonists.<br>In the bloodstream acyl ghrelin is deacylated by butyrylcholinesterase and platelet-activating factor acetylhydrolase. Other enzymes may also deacylate acyl ghrelin. Pubmed18396350 Pubmed19280057 Reactome Database ID Release 43422085 Reactome, http://www.reactome.org ReactomeREACT_19189 Reviewed: Zhang, Weizhen, 2009-08-29 Signaling by FGFR in disease Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-15 Pubmed15863030 Pubmed19247306 Pubmed21711248 Pubmed9154000 Pubmed9538690 Reactome Database ID Release 431226099 Reactome, http://www.reactome.org ReactomeREACT_120736 Reviewed: Ezzat, S, 2012-05-15 The pathway 'Signaling by FGFR in disease' shows 'Signaling by FGFR mutants' in parallel with the wild-type pathway 'Signaling by FGFR', allowing users to compare disease and normal events. FGFR mutants and events associated with germline diseases and cancer are highlighted in red. The wild-type pathway is shaded in the background. For detailed pathway summations, please see 'Signaling by FGFR mutants' and 'Signaling by FGFR'. FGFR2c ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 GENE ONTOLOGYGO:0008543 Pubmed16597617 Reactome Database ID Release 43190375 Reactome, http://www.reactome.org ReactomeREACT_9413 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR2c. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. FGFR2b ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 GENE ONTOLOGYGO:0008543 Pubmed16597617 Reactome Database ID Release 43190377 Reactome, http://www.reactome.org ReactomeREACT_9416 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR2b. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. FGFR2 ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 Dominant mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson- Weiss, Pfeiffer, and Apert syndromes. FGFR2 binds a number of different FGFs preferentially, as illustrated in this pathway.<br><br>FGFR is probably activated by NCAM very differently from the way by which it is activated by FGFs, reflecting the different conditions for NCAM–FGFR and FGF–FGFR interactions. The affinity of FGF for FGFR is approximately 10e6 times higher than that of NCAM for FGFR. Moreover, in the brain NCAM is constantly present on the cell surface at a much higher (micromolar) concentration than FGFs, which only appear transiently in the extracellular environment in the nanomolar range. Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 GENE ONTOLOGYGO:0008543 Pubmed16597617 Pubmed16844695 Pubmed17133345 Reactome Database ID Release 43190241 Reactome, http://www.reactome.org ReactomeREACT_9390 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 FGFR1c ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 GENE ONTOLOGYGO:0008543 Pubmed16597617 Reactome Database ID Release 43190373 Reactome, http://www.reactome.org ReactomeREACT_9515 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR1c. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. FGFR1b ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 GENE ONTOLOGYGO:0008543 Pubmed16597617 Reactome Database ID Release 43190370 Reactome, http://www.reactome.org ReactomeREACT_9400 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR1b. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. FGFR1 ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 GENE ONTOLOGYGO:0008543 Pubmed12141425 Pubmed12791257 Pubmed16045455 Pubmed16597617 Reactome Database ID Release 43190242 Reactome, http://www.reactome.org ReactomeREACT_9483 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The vertebrate fibroblast growth factor receptor 1 (FGFR1) is alternatively spliced generating multiple variants that are differentially expressed during embryo development and in the adult body. The restricted expression patterns of FGFR1 isoforms, together with differential expression and binding of specific ligands, leads to activation of common FGFR1 signal transduction pathways, but may result in distinctively different biological responses as a result of differences in cellular context. FGFR1 isoforms are also present in the nucleus in complex with various fibroblast growth factors where they function to regulate transcription of target genes.<br><br>FGFR is probably activated by NCAM very differently from the way by which it is activated by FGFs, reflecting the different conditions for NCAM–FGFR and FGF–FGFR interactions. The affinity of FGF for FGFR is approximately 10e6 times higher than that of NCAM for FGFR. Moreover, in the brain NCAM is constantly present on the cell surface at a much higher (micromolar) concentration than FGFs, which only appear transiently in the extracellular environment in the nanomolar range. FGFR ligand binding and activation Authored: de Bono, B, 2007-01-10 10:27:18 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 GENE ONTOLOGYGO:0008543 Pubmed16597617 Pubmed19247306 Pubmed20094046 Pubmed20940169 Pubmed7730326 Pubmed7730327 Pubmed8954625 Reactome Database ID Release 43190376 Reactome, http://www.reactome.org ReactomeREACT_9396 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The FGFs are a family of 22 secreted glycoproteins that are sequestered in the extracellular matrix (ECM) through their interaction with heparin and heparin sulphate proteoglycans (HSPGs). Release of FGFs from the ECM through the action of heparinases or proteases allows FGFs to act in a paracrine or autocrine manner on local FGF receptors. Binding to the receptor is stabilized by cell surface HSPG, forming a ternary complex. A subset of FGFs (FGF19, 21 and 23) have lower affinity for heparin and HSPG and act in an endocrine manner over greater distances to regulate energy, bile acid, glucose, lipid phosphate, and vitamin D homeostasis. Binding of these ligands to their receptors is generally aided by the FGF-binding Klotho proteins. The intracrine subfamily of FGFs (FGF11, 12, 13 and 14) are not secreted but act intracellularly in an FGF receptor-independent manner to regulate electrical impulses in neurons.<br><br>There are four FGFR genes (FGFR1-4) encoding receptors with 3 extracellular immunoglobulin domains (D1-D3), a single pass transmembrane domain and an intracellular tyrosine kinase domain. D2 and D3 are necessary and sufficient for ligand binding, while D1 and a serine-rich region between D1 and D2 known as the acid box are thought to play a role in receptor autoinhibition. Exon skipping generates isoforms of FGF receptors lacking D1 and the acid box, and these receptors show higher affinity for ligand than their counterparts with 3 Ig domains. FGFR1, 2 and 3, but not FGFR4, are also subject to alternative splicing in the second half of the D3 domain to yield 'b' and 'c' isoforms, which are expressed predominantly in epithelial or mesenchymal tissue, respectively. FGF ligands are produced in either epithelial or mesenchymal tissue and bind to receptors of the opposite tissue type. An exception to this is FGF1 which can bind to both 'b' and 'c' isoforms. In general, the epithelial 'b' receptor isoforms bind a narrower range of ligands than the mesenchymal 'c' versions. <br><br>FGFRs also contain a short amino acid motif within the second immunoglobulin domain that shares sequence homology with functional motifs present in neural adhesion molecules such as NCAM and N-cadherin. This so called CAM homology domain (CHD) forms a contiguous sequence with the acid box region and is crucial for this mode of activation. Interactions between the neural cell adhesion molecules are important for a number of developmental events and have also been implicated in tumor progression. Although the interaction can be seen over most of the cell surface, it is not seen at points of cell-cell contact where the adhesion molecules accumulate at stable junctions. The FGFR interaction with N-cadherin and NCAM (but not FGF) is absolutely dependent on the presence of the acid box motif. As this motif can be spliced out of all four FGFRs, this suggests a mechanism that can regulate the interaction of the receptor with different ligand classes. Signaling by FGFR Authored: de Bono, B, 2007-01-10 10:27:18 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 Fibroblast Growth Factor Receptor (FGFR) signaling GENE ONTOLOGYGO:0008543 Pubmed12080084 Pubmed15567848 Pubmed15863030 Pubmed15863038 Pubmed16597617 Pubmed19247306 Pubmed20602996 Pubmed7917292 Reactome Database ID Release 43190236 Reactome, http://www.reactome.org ReactomeREACT_9470 Reviewed: Gotoh, N, 2011-08-26 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.<br><br>Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.<br><br>This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.<br> Chimaerin alpha Converted from EntitySet in Reactome Reactome DB_ID: 195126 Reactome Database ID Release 43195126 Reactome, http://www.reactome.org ReactomeREACT_10153 Chimaerin beta Converted from EntitySet in Reactome Reactome DB_ID: 195148 Reactome Database ID Release 43195148 Reactome, http://www.reactome.org ReactomeREACT_10580 MEK activation Authored: Charalambous, M, 2004-04-29 09:21:24 GENE ONTOLOGYGO:0000186 MEK is phosphorylated and activated by RAF. Reactome Database ID Release 43110049 Reactome, http://www.reactome.org ReactomeREACT_962 Reviewed: Greene, LA, 2007-11-08 15:39:37 RAF activation Authored: Charalambous, M, 2004-04-29 09:21:24 Phosphorylated RAF is activated by Ras binding and stabilised in its active form by transient disassociation and reassociation of 14-3-3, as well as further phosphorylation. Pubmed9069260 Reactome Database ID Release 43110029 Reactome, http://www.reactome.org ReactomeREACT_2077 Reviewed: Greene, LA, 2007-11-08 15:39:37 RAF phosphorylates MEK Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active. Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Reactome Database ID Release 43112407 Reactome, http://www.reactome.org ReactomeREACT_614 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Calmodulin induced events Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 One important physiological role for Calmodulin is the regulation of adenylylcyclases. Four of the nine known adenylylcyclases are calcium sensitive, in particular type 8 (AC8). Pubmed15381755 Reactome Database ID Release 43111933 Reactome, http://www.reactome.org ReactomeREACT_9000 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PKA activation A number of inactive tetrameric PKA holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. When cAMP binds to two specific binding sites on the regulatory subunits, these undergo a conformational change that causes the dissociation of a dimer of regulatory subunits bound to four cAMP from two monomeric, catalytically active PKA subunits. Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 GENE ONTOLOGYGO:0034199 Pubmed2165385 Reactome Database ID Release 43163615 Reactome, http://www.reactome.org ReactomeREACT_15530 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PKA-mediated phosphorylation of CREB Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Cyclic adenosine 3',5'-monophosphate (cAMP) induces gene transcription through activation of cAMP-dependent protein kinase (PKA), and subsequent phosphorylation of the transcription factor cAMP response element-binding protein, CREB, at serine-133. Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed15337521 Pubmed16125054 Reactome Database ID Release 43111931 Reactome, http://www.reactome.org ReactomeREACT_15497 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Cam-PDE 1 activation Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Human Ca2+/calmodulin-dependent phosphodiesterase PDE1 is activated by the binding of calmodulin in the presence of Ca(2+). PDE1 has three subtypes PDE1A, PDE1B and PDE1C and their role is to hydrolyze both cGMP and cAMP. Their role is to antagonize the increased concentration of the intracellular second messengers determined by the synthetic activity of the adenylate cyclase enzymes thus governing intracellular cAMP dynamics in response to changes in the cytosolic Ca2+ concentration. PDE1 are mainly cytosolic but different isoforms are expressed in different tissues. Pubmed10442095 Pubmed16786160 Reactome Database ID Release 43111957 Reactome, http://www.reactome.org ReactomeREACT_15408 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 CaMK IV-mediated phosphorylation of CREB Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed10366852 Reactome Database ID Release 43111932 Reactome, http://www.reactome.org ReactomeREACT_15502 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The Ca2+-calmodulin-dependent protein kinase (CaM kinase) cascade includes three kinases: CaM-kinase kinase (CaMKK); and the CaM kinases CaMKI and CaMKIV, which are phosphorylated and activated by CaMKK. Members of this cascade respond to elevation of intracellular Ca2+ levels. CaMKK and CaMKIV localize both to the nucleus and to the cytoplasm, whereas CaMKI is only cytosolic. Nuclear CaMKIV regulates transcription through phosphorylation of several transcription factors, including CREB. In the cytoplasm, there is extensive cross-talk between CaMKK, CaMKIV and other signaling cascades, including those that involve the cAMP-dependent kinase (PKA), MAP kinases and protein kinase B (PKB/Akt). RAF/MAP kinase cascade Authored: Charalambous, M, 2004-04-29 09:21:24 GENE ONTOLOGYGO:0000165 Pubmed15520807 Pubmed17496910 Reactome Database ID Release 43109869 Reactome, http://www.reactome.org ReactomeREACT_634 Reviewed: Greene, LA, 2007-11-08 15:39:37 The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus. GRB2 events in EGFR signaling Authored: Castagnoli, L, 2006-10-10 13:09:34 Autophosphorylated EGFR tyrosine residues are docking sites for many downstream effectors in EGFR signaling. The adaptor protein GRB2 binds to phosphotyrosine residues in the C-tail of EGFR through its SH2 domain. GRB2 is constitutively associated with SOS, a guanine nucleotide exchange factor of RAS. GRB2 binding to phosphorylated EGFR results in the recruitment of SOS to the plasma membrane where it comes in proximity to RAS. This mechanism has been seen to be the model for RAS activation. Pubmed11498013 Pubmed11706405 Reactome Database ID Release 43179812 Reactome, http://www.reactome.org ReactomeREACT_12606 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Rich1 Converted from EntitySet in Reactome Reactome DB_ID: 195168 Reactome Database ID Release 43195168 Reactome, http://www.reactome.org ReactomeREACT_10592 Diabetes pathways Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Reactome Database ID Release 43381150 Reactome, http://www.reactome.org ReactomeREACT_15380 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 This module groups several normal processes that have key roles in the synthesis and function of insulin, insulin-like growth factors and ghrelin, and whose derangement is thus central to the pathogenesis of diabetes. Amyloids Amyloid is a term used to describe typically extracellular deposits of aggregated proteins, sometimes known as plaques. Abnormal accumulation of amyloid is amyloidosis, a term associated with diseased organs and tissues, particularly neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntingdon's. Amyloid deposits consist predominantly of amyloid fibrils, rigid, non-branching structures that form ordered assemblies, characteristically with a cross beta-sheet structure where the sheets run parallel to the direction of the fibril (Sawaya et al. 2007). Often the fibril has a left-handed twist (Nelson & Eisenberg 2006). At least 27 human proteins form amyloid fibrils (Sipe et al. 2010). Many of these proteins have non-pathological functions; the trigger that leads to abnormal aggregations differs between proteins and is not well understood but in many cases the peptides are abnormal fragments or mutant forms arising from polymorphisms, suggesting that the initial event may be aggregation of misfolded or unfolded peptides. Early studies of Amyloid-Beta assembly led to a widely accepted model that assembly was a nucleation-dependent polymerization reaction (Teplow 1998) but it is now understood to be more complex, with multiple 'off-pathway' events leading to a variety of oligomeric structures in addition to fibrils (Roychaudhuri et al. 2008). An increasing body of evidence suggests that these oligomeric forms are primarily responsible for the neurotoxic effects of Amyloid-beta (Roychaudhuri et al. 2008), alpha-synuclein (Winner et al. 2011) and tau (Dance & Strobel 2009, Meraz-Rios et al. 2010). Amyloid oligomers are believed to have a common structural motif that is independent of the protein involved and not present in fibrils (Kayed et al. 2003). Conformation dependent, aggregation specific antibodies suggest that there are 3 general classes of amyloid oligomer structures (Glabe 2009) including annular structures which may be responsible for the widely reported membrane permeabilization effect of amyloid oligomers. Toxicity of amyloid oligomers preceeds the appearance of plaques in mouse models (Ferretti et al. 2011). Fibrils are often associated with other molecules, notably heparan sulfate proteoglycans and Serum Amyloid P-component, which are universally associated and seem to stabilize fibrils, possibly by protecting them from degradation. Authored: Jupe, S, 2010-10-15 Edited: Jupe, S, 2011-04-08 Pubmed12702875 Pubmed16302959 Pubmed17190616 Pubmed17468747 Pubmed18845536 Pubmed19943854 Pubmed21039326 Pubmed21143159 Pubmed21325059 Pubmed9686307 Reactome Database ID Release 43977225 Reactome, http://www.reactome.org ReactomeREACT_75925 Reviewed: Perry, G, 2011-04-08 AKT phosphorylates targets in the cytosol Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2011-05-11 Following activation, AKT can phosphorylate an array of target proteins in the cytoplasm, many of which are involved in cell survival control. Phosphorylation of TSC2 feeds positively to the TOR kinase, which, in turn, contributes to AKT activation (positive feedback loop). Reactome Database ID Release 43198323 Reactome, http://www.reactome.org ReactomeREACT_12564 Reviewed: Greene, LA, 2007-11-08 15:39:37 PIP3 activates AKT signaling Pubmed17604717 Reactome Database ID Release 431257604 Reactome, http://www.reactome.org ReactomeREACT_75829 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. GAB1 signalosome Authored: Castagnoli, L, 2006-10-10 13:09:34 GAB1 is recruited to the activated EGFR indirectly, through GRB2. GAB1 acts as an adaptor protein that enables formation of an active PIK3, through recruitment of PIK3 regulatory subunit PIK3R1 (also known as PI3Kp85), which subsequently recruits PIK3 catalytic subunit PIK3CA (also known as PI3Kp110). PIK3, in complex with EGFR, GRB2 and GAB1, catalyzes phosphorylation of PIP2 and its conversion to PIP3, which leads to the activation of the AKT signaling. Pubmed15550174 Reactome Database ID Release 43180292 Reactome, http://www.reactome.org ReactomeREACT_12578 Reviewed: Heldin, CH, 2008-02-12 09:44:02 SHC1 events in EGFR signaling Authored: Castagnoli, L, 2006-10-10 13:09:34 GRB2 can bind EGFR directly or through another SH2-containing protein, SHC1. This association leads to RAS activation. Pubmed11498013 Pubmed8755247 Reactome Database ID Release 43180336 Reactome, http://www.reactome.org ReactomeREACT_12579 Reviewed: Heldin, CH, 2008-02-12 09:44:02 Signaling by constitutively active EGFR Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Gillespie, ME, 2011-11-07 Edited: Haw, R, 2011-11-07 Edited: Jassal, B, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed11087732 Pubmed12471035 Pubmed14718169 Pubmed15118073 Pubmed15269313 Pubmed15284455 Pubmed15837620 Pubmed16024644 Pubmed16187797 Pubmed16314626 Pubmed16777603 Pubmed16849543 Pubmed16969069 Pubmed17085664 Pubmed17177598 Pubmed17349580 Pubmed17646646 Pubmed17699773 Pubmed18511936 Pubmed19560417 Pubmed20033049 Reactome Database ID Release 431236382 Reactome, http://www.reactome.org ReactomeREACT_115852 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Signaling by EGFR is frequently activated in cancer through either genomic amplification of the EGFR locus, resulting in over-expression of the wild-type protein, or through activating mutations in the coding sequence of the EGFR gene, resulting in expression of a constitutively active mutant protein. <br><br>Epidermal growth factor receptor kinase domain mutants are present in ~16% of non-small-cell lung cancers (NSCLCs), but are also found in other cancer types, such as breast cancer, colorectal cancer, ovarian cancer and thyroid cancer. EGFR kinase domain mutants harbor activating mutations in exons 18-21 which code for the kinase domain (amino acids 712-979) . Small deletions, insertions or substitutions of amino acids within the kinase domain lock EGFR in its active conformation in which the enzyme can dimerize and undergo autophosphorylation spontaneously, without ligand binding (although ligand binding ability is preserved), and activate downstream signaling pathways that promote cell survival (Greulich et al. 2005, Zhang et al. 2006, Yun et al. 2007, Red Brewer et al. 2009). <br><br>In glioblastoma, the most prevalent EGFR mutation, present in ~25% of tumors, is the deletion of the ligand binding domain of EGFR, accompanied with amplification of the mutated allele, which results in over-expression of the mutant protein known as EGFRvIII. EGFRvIII mutant is not able to bind a ligand, but dimerizes and autophosphorylates spontaneously and is therefore constitutively active (Fernandes et al. 2001). Point mutations in the extracellular domain of EGFR are also frequently found in glioblastoma. Similar to kinase domain mutations, point mutations in the extracellular domain result in constitutively active EGFR proteins that signal in the absence of ligands, but ligand binding ability and responsiveness are preserved (Lee et al. 2006). <br><br>Both EGFR kinase domain mutants and EGFRvIII mutant need to maintain association with the chaperone heat shock protein 90 (HSP90) for proper functioning (Shimamura et al. 2005, Lavictoire et al. 2003). CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (Roe et al. 2004, reviewed by Gray Jr. et al. 2008). <br><br>Over-expression of the wild-type EGFR or EGFR cancer mutants results in aberrant activation of downstream signaling cascades, namely RAS/RAF/MAP kinase signaling and PI3K/AKT signaling, and possibly signaling by PLCG1, which leads to increased cell proliferation and survival, providing selective advantage to cancer cells that harbor activating mutations in the EGFR gene (Sordella et al. 2004, Huang et al. 2007). <br><br>While growth factor activated wild-type EGFR is promptly down-regulated by internalization and degradation, cancer mutants of EGFR demonstrate prolonged activation (Lynch et al. 2004). Association of HSP90 with EGFR kinase domain mutants negatively affects CBL-mediated ubiquitination, possibly through decreasing the affinity of EGFR kinase domain mutants for phosphorylated CBL, so that CBL dissociates from the complex upon phosphorylation and cannot perform ubiquitination (Yang et al. 2006, Padron et al. 2007). EGFRvIII mutant does not autophosorylate on the tyrosine residue Y1045, a docking site for CBL, and is therefore unable to recruit CBL ubiquitin ligase, which enables it to escape degradation (Han et al. 2006). <br><br>Various molecular therapeutics are being developed to target aberrantly activated EGFR in cancer. Non-covalent (reversible) small tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, selectively bind kinase domain of EGFR, competitively inhibiting ATP binding and subsequent autophosphorylation of EGFR dimers. EGFR kinase domain mutants sensitive to non-covalent TKIs exhibit greater affinity for TKIs than ATP compared with the wild-type EGFR protein, and are therefore preferential targets of non-covalent TKI therapeutics (Yun et al. 2007). EGFR proteins that harbor point mutations in the extracellular domain also show sensitivity to non-covalent tyrosine kinase inhibitors (Lee et al. 2006). EGFR kinase domain mutants harboring small insertions in exon 20 or a secondary T790M mutation are resistant to reversible TKIs (Balak et al. 2006) due to increased affinity for ATP (Yun et al. 2008), and are targets of covalent (irreversible) TKIs that form a covalent bond with EGFR cysteine residue C397. However, effective concentrations of covalent TKIs also inhibit wild-type EGFR, causing severe side effects (Zhou et al. 2009). Hence, covalent TKIs have not shown much promise in clinical trials (Reviewed by Pao and Chmielecki in 2010). Recombinant monoclonal antibody Cetuximab acts as an antagonist of EGFR ligand binding, and is approved for the treatment of tumors that over-express wild-type EGFR receptor (Cunningham et al. 2004, Li et al. 2005, Burtness et al. 2005). EGFR downregulation Authored: Castagnoli, L, 2006-10-10 13:09:34 GENE ONTOLOGYGO:0042059 Pubmed11283727 Pubmed14641021 Pubmed15021893 Reactome Database ID Release 43182971 Reactome, http://www.reactome.org ReactomeREACT_12484 Regulation of receptor tyrosine kinase (RTK) activity is implicated in the control of almost all cellular functions. One of the best understood RTKs is epidermal growth factor receptor (EGFR). Growth factors can bind to EGFR and activate it to initiate signalling cascades within the cell. EGFRs can also be recruited to clathrin-coated pits which can be internalised into endocytic vesicles. From here, EGFRs can either be recycled back to the plasma membrane or directed to lysosomes for destruction.This provides a mechanism by which EGFR signalling is negatively regulated and controls the strength and duration of EGFR-induced signals. It also prevents EGFR hyperactivation as commonly seen in tumorigenesis.<br><br>The proto-oncogene Cbl can negatively regulate EGFR signalling. The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation. All Cbl proteins have a unique domain that recognises phosphorylated tyrosine residues on activated EGFRs. They also direct the ubiquitination and degradation of activated EGFRs by recruiting ubiquitin-conjugation enzymes. Cbl proteins function by specifically targeting activated EGFRs and mediating their down-regulation, thus providing a means by which signaling processes can be negatively regulated.<br><br>Cbl also promotes receptor internalization via it's interaction with an adaptor protein, CIN85 (Cbl-interacting protein of 85kDa). CIN85 binds to Cbl via it's SH3 domain and is enhanced by the EGFR-induced tyrosine phosphorylation of Cbl. The proline-rich region of CIN85 interacts with endophilins which are regulatory components of clathrin-coated vesicles (CCVs). Endophilins bind to membranes and induce membrane curvature, in conjunction with other proteins involved in CCV formation. The rapid recruitment of endophilin to the activated receptor complex by CIN85 is the mechanism which controls receptor internalization. Reviewed: Heldin, CH, 2008-02-12 09:44:02 Negative regulation of the PI3K/AKT network Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Reactome Database ID Release 43199418 Reactome, http://www.reactome.org ReactomeREACT_12447 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 The PI3K/AKT network is negatively regulated by phosphatases that dephosphorylate PIP3, thus hampering AKT activation. AKT phosphorylates targets in the nucleus After translocation into the nucleus, AKT can phosphorylate a number of targets there such as CREB, forkhead transcription factors, SRK and NUR77. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Reactome Database ID Release 43198693 Reactome, http://www.reactome.org ReactomeREACT_12442 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep7188 PathwayStep7187 PathwayStep7189 PathwayStep7180 PathwayStep7182 PathwayStep7181 PathwayStep7184 PathwayStep7183 PathwayStep7186 PathwayStep7185 PathwayStep7199 PathwayStep7198 PathwayStep7193 PathwayStep7192 PathwayStep7191 PathwayStep7190 PathwayStep7197 PathwayStep7196 PathwayStep7195 PathwayStep7194 THTR1; THTR2 Converted from EntitySet in Reactome Reactome DB_ID: 199656 Reactome Database ID Release 43199656 Reactome, http://www.reactome.org ReactomeREACT_11312 SLC19A2; SLC19A3 Thiamine transporters 1 and 2 PathwayStep7140 PathwayStep7141 PathwayStep7142 PathwayStep7143 PathwayStep7144 PathwayStep7145 PathwayStep7146 PathwayStep7147 PathwayStep7148 PathwayStep7149 PathwayStep7152 PathwayStep7153 PathwayStep7150 PathwayStep7151 PathwayStep7156 PathwayStep7157 PathwayStep7154 PathwayStep7155 PathwayStep7158 PathwayStep7159 PathwayStep7161 PathwayStep7162 PathwayStep7163 PathwayStep7164 PathwayStep7160 PathwayStep7169 PathwayStep7165 PathwayStep7166 PathwayStep7167 PathwayStep7168 SVCT1; SVCT2 Converted from EntitySet in Reactome Reactome DB_ID: 198780 Reactome Database ID Release 43198780 Reactome, http://www.reactome.org ReactomeREACT_11407 AMPK beta Converted from EntitySet in Reactome Reactome DB_ID: 381854 Reactome Database ID Release 43381854 Reactome, http://www.reactome.org ReactomeREACT_17873 PathwayStep7174 GLUT1; GLUT3 Converted from EntitySet in Reactome Reactome DB_ID: 198841 Reactome Database ID Release 43198841 Reactome, http://www.reactome.org ReactomeREACT_11567 PathwayStep7175 PathwayStep7172 PathwayStep7173 PathwayStep7170 PathwayStep7171 PathwayStep7178 PathwayStep7179 PathwayStep7176 PathwayStep7177 AMPK gamma Converted from EntitySet in Reactome Reactome DB_ID: 381851 Reactome Database ID Release 43381851 Reactome, http://www.reactome.org ReactomeREACT_17787 AMPK alpha Converted from EntitySet in Reactome Reactome DB_ID: 381845 Reactome Database ID Release 43381845 Reactome, http://www.reactome.org ReactomeREACT_17384 ArhGAP9 Converted from EntitySet in Reactome Reactome DB_ID: 195127 Reactome Database ID Release 43195127 Reactome, http://www.reactome.org ReactomeREACT_10411 ArhGAP12 Converted from EntitySet in Reactome Reactome DB_ID: 195167 Reactome Database ID Release 43195167 Reactome, http://www.reactome.org ReactomeREACT_10207 PathwayStep7107 PathwayStep7108 PathwayStep7109 CPT1A or B Converted from EntitySet in Reactome Reactome DB_ID: 549205 Reactome Database ID Release 43549205 Reactome, http://www.reactome.org ReactomeREACT_22458 PathwayStep7115 PathwayStep7114 PathwayStep7117 PathwayStep7116 PathwayStep7111 PathwayStep7110 PathwayStep7113 PathwayStep7112 Myosin-IXb Converted from EntitySet in Reactome Reactome DB_ID: 195174 Reactome Database ID Release 43195174 Reactome, http://www.reactome.org ReactomeREACT_10399 Depdc7 Converted from EntitySet in Reactome Reactome DB_ID: 195206 Reactome Database ID Release 43195206 Reactome, http://www.reactome.org ReactomeREACT_10643 MED16 Converted from EntitySet in Reactome Reactome DB_ID: 212364 Reactome Database ID Release 43212364 Reactome, http://www.reactome.org ReactomeREACT_12888 PathwayStep7106 PathwayStep7105 PathwayStep7104 PathwayStep7103 PathwayStep7102 PathwayStep7101 PathwayStep7100 Graf Converted from EntitySet in Reactome Ophn1l Reactome DB_ID: 195191 Reactome Database ID Release 43195191 Reactome, http://www.reactome.org ReactomeREACT_10161 PathwayStep7129 PathwayStep7133 PathwayStep7132 PathwayStep7135 PathwayStep7134 PathwayStep7137 PathwayStep7136 PathwayStep7139 PathwayStep7138 PathwayStep7131 PathwayStep7130 STRAD Converted from EntitySet in Reactome Reactome DB_ID: 380963 Reactome Database ID Release 43380963 Reactome, http://www.reactome.org ReactomeREACT_17339 p-AMPK alpha Converted from EntitySet in Reactome Reactome DB_ID: 381844 Reactome Database ID Release 43381844 Reactome, http://www.reactome.org ReactomeREACT_17705 PathwayStep7118 PathwayStep7119 MO25 Converted from EntitySet in Reactome Reactome DB_ID: 380975 Reactome Database ID Release 43380975 Reactome, http://www.reactome.org ReactomeREACT_17734 PathwayStep7124 PathwayStep7123 PathwayStep7122 PathwayStep7121 PathwayStep7128 PathwayStep7127 PathwayStep7126 PathwayStep7125 PathwayStep7120 MED27 Converted from EntitySet in Reactome Reactome DB_ID: 213200 Reactome Database ID Release 43213200 Reactome, http://www.reactome.org ReactomeREACT_12651 CSL Converted from EntitySet in Reactome RBPJ Reactome DB_ID: 212415 Reactome Database ID Release 43212415 Reactome, http://www.reactome.org ReactomeREACT_14926 MAML Converted from EntitySet in Reactome Reactome DB_ID: 212357 Reactome Database ID Release 43212357 Reactome, http://www.reactome.org ReactomeREACT_15027 CBP Converted from EntitySet in Reactome Reactome DB_ID: 212328 Reactome Database ID Release 43212328 Reactome, http://www.reactome.org ReactomeREACT_15241 SNW Converted from EntitySet in Reactome Reactome DB_ID: 212438 Reactome Database ID Release 43212438 Reactome, http://www.reactome.org ReactomeREACT_15167 SKIP MED15 Converted from EntitySet in Reactome Reactome DB_ID: 212339 Reactome Database ID Release 43212339 Reactome, http://www.reactome.org ReactomeREACT_13286 HS(2)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076425 Reactome Database ID Release 432076425 Reactome, http://www.reactome.org ReactomeREACT_122101 MED23 Converted from EntitySet in Reactome Reactome DB_ID: 212389 Reactome Database ID Release 43212389 Reactome, http://www.reactome.org ReactomeREACT_13180 MED8 Converted from EntitySet in Reactome Reactome DB_ID: 212363 Reactome Database ID Release 43212363 Reactome, http://www.reactome.org ReactomeREACT_13179 HS(1)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076452 Reactome Database ID Release 432076452 Reactome, http://www.reactome.org ReactomeREACT_121587 MED26 Converted from EntitySet in Reactome Reactome DB_ID: 212431 Reactome Database ID Release 43212431 Reactome, http://www.reactome.org ReactomeREACT_13246 NDSTs Converted from EntitySet in Reactome Reactome DB_ID: 2022936 Reactome Database ID Release 432022936 Reactome, http://www.reactome.org ReactomeREACT_123253 SMAC-mediated dissociation of IAP:caspase complexes Pubmed12042762 Reactome Database ID Release 43111464 Reactome, http://www.reactome.org ReactomeREACT_1767 Smac/DIABLO regulates IAP function. Residues 56–59 of Smac/DIABLO are homologous to the amino-terminal motif that is used by caspase-9 to bind to the BIR3 domain of XIAP. Binding of Smac/DIABLO to XIAP thus displaces caspase-9 from the XIAP:Caspase complex (reviewed in Salvesen et al., 2002). Apoptotic execution phase Authored: Alnemri, E, 2004-02-17 00:23:30 Edited: Matthews, L, 2008-02-12 16:13:52 GENE ONTOLOGYGO:0006921 In the execution phase of apoptosis, effector caspases cleave vital cellular proteins leading to the morphological changes that characterize apoptosis. These changes include destruction of the nucleus and other organelles, DNA fragmentation, chromatin condensation, cell shrinkage and cell detachment and membrane blebbing (reviewed in Fischer et al., 2003). Pubmed12655297 Reactome Database ID Release 4375153 Reactome, http://www.reactome.org ReactomeREACT_995 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 Apoptotic cleavage of cellular proteins Apoptotic cell death is achieved by the caspase-mediated cleavage of various vital proteins. Among caspase targets are proteins such as E-cadherin, Beta-catenin, alpha fodrin, GAS2, FADK, alpha adducin, HIP-55, and desmoglein involved in cell adhesion and maintenance of the cytoskeletal architecture. Cleavage of proteins such as APC and CIAP1 can further stimulate apoptosis by produce proapoptotic proteins (reviewed in Fischer et al., 2003. See also Wee et al., 2006 and the CASVM Caspase Substrates Database: http://www.casbase.org/casvm/squery/index.html ). Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 Edited: Matthews, L, 2008-02-08 00:41:49 Pubmed12655297 Pubmed17254298 Pubmed17599937 Reactome Database ID Release 43111465 Reactome, http://www.reactome.org ReactomeREACT_107 Reviewed: Ranganathan, S, 2007-11-23 00:10:26 Caspase-mediated cleavage of cytoskeletal proteins Authored: Schulze-Osthoff, K, 2007-09-03 07:52:18 Caspase-mediated cleavage of a number of proteins in the cortical actin network ( ) microfilament system and others involved in maintenance of the cytoskeletal architecture (vimentin, or Gas2 and plectin) may directly contribute to apoptotic changes in cell shape. Edited: Matthews, L, 2008-04-13 23:06:00 Edited: Matthews, L, 2008-06-12 00:23:53 Pubmed12655297 Pubmed17254298 Pubmed17599937 Reactome Database ID Release 43264870 Reactome, http://www.reactome.org ReactomeREACT_13541 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Apoptotic cleavage of cell adhesion proteins Apoptotic cells show dramatic rearrangements of tight junctions, adherens junctions, and desmosomes (Abreu et al., 2000). Desmosome-specific members of the cadherin superfamily of cell adhesion molecules including desmoglein-3, plakophilin-1 and desmoplakin are cleaved by caspases after onset of apoptosis (Weiske et al., 2001). Cleavage results in the disruption of the desmosome structure and thus contributes to cell rounding and disintegration of the intermediate filament system (Weiske et al., 2001). Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Edited: Matthews, L, 2008-06-12 00:23:53 Pubmed11500511 Pubmed16286477 Pubmed17559062 Reactome Database ID Release 43351906 Reactome, http://www.reactome.org ReactomeREACT_13579 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Breakdown of the nuclear lamina Activated caspases cleave nuclear lamins causing the irreversible breakdown of the nuclear lamina. Authored: Schulze-Osthoff, K, 2008-05-18 10:00:05 Edited: Matthews, L, 2008-05-20 07:46:51 Pubmed12655297 Reactome Database ID Release 43352238 Reactome, http://www.reactome.org ReactomeREACT_13472 Reviewed: Ranganathan, S, 2008-06-11 19:13:33 Apoptosis induced DNA fragmentation Authored: Matthews, L, 2008-04-25 11:29:13 DNA fragmentation in response to apoptotic signals is achieved through the activity of two apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) and endonuclease G (Endo G) (reviewed in Widlak and Garrard, 2005). These endonucleases cleave chromatin producing 3'-hydroxyl groups and 5'-phosphate residues. 50-300 kb cleavage products are produced followed by internucleosomal DNA fragmentation. Although the activities of DFF and Endo G are similar, they reside in different locations within the cell and are regulated in different ways. Edited: Matthews, L, 2008-05-18 15:19:12 GENE ONTOLOGYGO:0006309 Pubmed15723341 Reactome Database ID Release 43140342 Reactome, http://www.reactome.org ReactomeREACT_1213 Reviewed: Widlak, P, 2008-04-25 14:11:44 Activation of DNA fragmentation factor Authored: Matthews, L, 2008-01-29 12:03:24 DNA fragmentation in response to apoptotic signals is achieved, in part, through the activity of apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) (reviewed in Widlak and Garrard, 2005). In non-apoptotic cells, DFF is a nuclear heterodimer consisting of a 45 kD chaperone and inhibitor subunit (DFF45)/inhibitor of CAD (ICAD-L)] and a 40 kD nuclease subunit (DFF40/CAD)( Liu et al. 1997, 1998; Enari et al. 1998). During apoptosis, activated caspase-3 or -7 cleave DFF45/ICAD releasing active DFF40/CAD nuclease. The activity of DFF is tightly controlled at multiple stages. During translation, DFF45/ICAD, Hsp70, and Hsp40 proteins play a role in insuring the appropriate folding of DFF40 during translation(Sakahira and Nagata, 2002). The nuclease activity of DFF40 is enhanced by the chromosomal proteins histone H1, Topoisomerase II and HMGB1/2(Widlak et al., 2000). In addition, the inhibitors (DFF45/35; ICAD-S/L) are produced in stoichiometric excess (Widlak et al., 2003). Edited: Matthews, L, 2008-05-02 11:33:14 Pubmed10318789 Pubmed10713148 Pubmed12748178 Pubmed15723341 Pubmed9422506 Reactome Database ID Release 43211227 Reactome, http://www.reactome.org ReactomeREACT_13462 Reviewed: Widlak, P, 2008-05-07 23:54:18 Stimulation of the cell death response by PAK-2p34 Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-03 20:50:13 Edited: Matthews, L, 2008-06-12 00:23:53 In response to stress signals, the p21-activated protein kinase PAK-2 stimulates a cell death response characterized by increased cell rounding and apoptotic chromatin condensation (see Jakobi et al., 2003). PAK-2 is proteolytically cleaved by caspase-3 producing a constitutively active fragment, PAK-2p34. Following cleavage, PAK-2p34 is autophosphorylated at Thr 402 and transported to the nucleus where it accumulates due to the loss of its nuclear export signal motif (Jakobi et al., 2003). The activity of PAK-2p34 appears to be regulated both by proteosomal degradation (Jakobi et al., 2003) and by association with the GTPase-activating protein PS-GAP/ RHG-10. This interaction inhibits the kinase activity of PAK-2p34 and changes the localization of PAK-2p34 from the nucleus to the perinuclear region (Koeppel et al., 2004). PAK-2p34 may function in the down-regulation of translation initiation in apoptosis through phosphorylation of Mnk1 (Orton et al.,2004). Pubmed12853446 Pubmed15234964 Pubmed15471851 Pubmed9786869 Reactome Database ID Release 43211736 Reactome, http://www.reactome.org ReactomeREACT_13532 Reviewed: Chang, E, 2008-05-21 00:05:41 Regulation of Apoptosis A regulated balance between cell survival and apoptosis is essential for normal development and homeostasis of multicellular organisms (see Matsuzawa, 2001). Defects in control of this balance may contribute to autoimmune disease, neurodegeneration and cancer. Protein ubiquitination and degradation is one of the major mechanisms that regulate apoptotic cell death (reviewed in Yang and Yu 2003). Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-12 16:13:24 Edited: Matthews, L, 2008-06-12 00:23:53 GENE ONTOLOGYGO:0042981 Pubmed11432772 Pubmed12724336 Reactome Database ID Release 43169911 Reactome, http://www.reactome.org ReactomeREACT_13648 Reviewed: Chang, E, 2008-05-21 00:05:41 Miro2 Converted from EntitySet in Reactome Reactome DB_ID: 194864 Reactome Database ID Release 43194864 Reactome, http://www.reactome.org ReactomeREACT_10688 TCL Converted from EntitySet in Reactome Reactome DB_ID: 194881 Reactome Database ID Release 43194881 Reactome, http://www.reactome.org ReactomeREACT_10781 Miro1 Converted from EntitySet in Reactome Reactome DB_ID: 194918 Reactome Database ID Release 43194918 Reactome, http://www.reactome.org ReactomeREACT_11009 Activation, translocation and oligomerization of BAX As a result of binding to Bid, Bax oligomerizes and integrates in the outer mitochondrial membrane that triggers cytochrome c release. Bax mitochondrial membrane insertion triggered by Bid may represent a key step in pathways leading to apoptosis (Eskes et al., 2000). GENE ONTOLOGYGO:1901030 Pubmed10629050 Pubmed11136736 Pubmed12193163 Reactome Database ID Release 43114294 Reactome, http://www.reactome.org ReactomeREACT_584 Activation and oligomerization of BAK protein GENE ONTOLOGYGO:1901030 Reactome Database ID Release 43111452 Reactome, http://www.reactome.org ReactomeREACT_707 tBID binds to its mitochondrial partner BAK to release cytochrome c. Activated tBID results in an allosteric activation of BAK. This may induce its intramembranous oligomerization into a pore for cytochrome c efflux. Apoptotic factor-mediated response In response to apoptotic signals, mitochondrial proteins are released into the cytosol and activate both caspase-dependent and -independent cell death pathways. Cytochrome c induces apoptosome formation, AIF and endonuclease G function in caspase independent apoptotic nuclear DNA damage. Smac/DIABLO and HtrA2/OMI both promote caspase activation and caspase-independent cytotoxicity (Saelens et al., 2004). Pubmed12042762 Pubmed15077149 Reactome Database ID Release 43111471 Reactome, http://www.reactome.org ReactomeREACT_963 Cytochrome c-mediated apoptotic response Authored: Matthews, L, 2004-08-06 15:00:00 Pubmed11711427 Pubmed15184073 Reactome Database ID Release 43111461 Reactome, http://www.reactome.org ReactomeREACT_831 Reviewed: Vaux, D, 0000-00-00 00:00:00 Upon its release from the mitochondrial intermembrane space, Cytochrome c binds to and causes a conformational change in the cytoplasmic protein Apaf1. This conformational change allows the Cytochrome c:Apaf1 complex to associate with ATP triggering oligomerization of the Apaf1:Cytochrome c:ATP complex. The apoptosome then associates with Procaspase-9 resulting in the formation of the active caspase-9 holoenzyme which functions in cleaving effector caspases. Permeabilization of mitochondria Activation and oligomerization of Bax and Bak result in the destabilization of the outer mitochondrial membrane. This results in the release of the apoptotic factors Cytochrome c and SMAC from the intermembrane space. Authored: Matthews, L, 2004-08-06 15:00:00 Pubmed11711427 Pubmed12941691 Reactome Database ID Release 43111455 Reactome, http://www.reactome.org ReactomeREACT_1365 Reviewed: Vaux, D, 0000-00-00 00:00:00 Release of apoptotic factors from the mitochondria Apoptotic factors released from the mitochondria promote apoptosis through several different mechanisms. Cytochrome C participates in Apoptosome driven effector caspase activation while SMAC relieves IAP mediated caspase inhibition. Authored: Matthews, L, 2004-08-06 15:00:00 Pubmed10913597 Pubmed12660240 Pubmed12941691 Pubmed15077149 Reactome Database ID Release 43111457 Reactome, http://www.reactome.org ReactomeREACT_1322 Reviewed: Vaux, D, 0000-00-00 00:00:00 SMAC-mediated apoptotic response Authored: Matthews, L, 2004-08-06 15:00:00 Once released from the mitochondria, SMAC binds to IAP family proteins displacing them from Caspase:IAP complexes liberating the active caspases. Pubmed12042762 Pubmed15077149 Reactome Database ID Release 43111469 Reactome, http://www.reactome.org ReactomeREACT_666 Reviewed: Vaux, D, 0000-00-00 00:00:00 SMAC binds to IAPs Pubmed12042762 Reactome Database ID Release 43111463 Reactome, http://www.reactome.org ReactomeREACT_2190 SMAC binds to the XIAP:caspase complexes. Formation of apoptosome Cytoplasmic cytochrome c binds to apoptotic protease activating factor-1 (Apaf-1) promoting the formation of an Apaf-1 oligomer (the apoptosome) which in turn binds and activates caspase-9. Pubmed10206961 Pubmed15184073 Reactome Database ID Release 43111458 Reactome, http://www.reactome.org ReactomeREACT_89 Activation of caspases through apoptosome-mediated cleavage Authored: Alnemri, E, 2004-02-17 00:23:30 GENE ONTOLOGYGO:0008635 Procaspase-3 and 7 are cleaved by the apoptosome. Pubmed9390557 Pubmed9922454 Reactome Database ID Release 43111459 Reactome, http://www.reactome.org ReactomeREACT_607 Heparan(4)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076346 Reactome Database ID Release 432076346 Reactome, http://www.reactome.org ReactomeREACT_125688 GDI proteins Converted from EntitySet in Reactome Reactome DB_ID: 194862 Reactome Database ID Release 43194862 Reactome, http://www.reactome.org ReactomeREACT_10263 SYDE1 Converted from EntitySet in Reactome Reactome DB_ID: 350780 Reactome Database ID Release 43350780 Reactome, http://www.reactome.org ReactomeREACT_14639 Intrinsic Pathway for Apoptosis Authored: Matthews, L, 2004-08-06 15:00:00 GENE ONTOLOGYGO:0008629 Pubmed11711427 Pubmed12042762 Pubmed14561771 Pubmed14634621 Pubmed15077149 Reactome Database ID Release 43109606 Reactome, http://www.reactome.org ReactomeREACT_964 The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows: <p> 1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption. <p> 2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane. Activation of BID and translocation to mitochondria Activation, myristolyation of BID and translocation to mitochondria Authored: Gopinathrao, G, 2004-08-19 20:25:42 BID may promote cell death by activating BAX and BAK while inactivating anti-apoptotic proteins. The engagement of cell surface receptors activates the caspase-8, a heterodimer, that cleaves BID in its amino terminal region. This particular event may act as a link between Extrinsic (caspase 8/10 dependent) and Intrinsic (Bcl-2 inhibitable) pathways although some evidences from mouse genetic experiments suggest the contrary. It has been suggested that the death signals from the extrinsic or death receptor pathway may get amplified by the mechanisms of intrinsic pathway and that this functional loop may be enabled by the molecules like tBID (truncated BID).<BR> Cleavage of BID to tBID can also be achieved by Granzyme B. The truncated protein is myristoylated and translocates to mitochondria. GENE ONTOLOGYGO:1900740 Pubmed14634621 Pubmed9727492 Reactome Database ID Release 4375108 Reactome, http://www.reactome.org ReactomeREACT_701 Reviewed: Vaux, D, 0000-00-00 00:00:00 Activation of BH3-only proteins Authored: Gopinathrao, G, 2004-08-19 20:25:42 GENE ONTOLOGYGO:1900740 Pubmed12209154 Pubmed14634621 Reactome Database ID Release 43114452 Reactome, http://www.reactome.org ReactomeREACT_697 Reviewed: Vaux, D, 0000-00-00 00:00:00 The BH3-only members act as sentinels that selectively trigger apoptosis in response to developmental cues or stress-signals like DNA damages. Widely expressed mammalian BH3-only proteins are thought to act by binding to and neutralizing their pro-survival counterparts. Activation of BH3-only proteins directly or indirectly results in the activation of proapoptotic BAX and BAK to trigger cell death. Anti-apoptotic BCL-2 or BCL-XL may bind and sequester BH3-only molecules to prevent BAX, BAK activation. The individual BH3-only members are held in check by various mechanisms with in the cells. They are recruited for death duties in response to death cues by diverse activation processes.The mechanisms involved in activation and release of BH3-only proteins for apoptosis will be discussed in this section. <p>The following figure has been reproduced here with the kind permission from the authors. Activation of BAD and translocation to mitochondria Authored: Gopinathrao, G, 2004-08-19 20:25:42 GENE ONTOLOGYGO:1900740 Pubmed12209154 Pubmed15231831 Reactome Database ID Release 43111447 Reactome, http://www.reactome.org ReactomeREACT_549 Reviewed: Vaux, D, 0000-00-00 00:00:00 The switching on/off of its phosphorylation by growth/survival factors regulates BAD activity. BAD remains sequestered by 14-3-3 scaffold proteins after phosphorylation by Akt1. Calcineurin activates BAD by dephosphorylation. Activation of Pro-Caspase 8 GENE ONTOLOGYGO:0006919 Pro-caspase-8 is known to be activated by various factors in response to a variety of external and internal stimuli. These include FAS, TRAIL, and TNF. Reactome Database ID Release 4369416 Reactome, http://www.reactome.org ReactomeREACT_832 BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members GENE ONTOLOGYGO:2001244 Reactome Database ID Release 43111453 Reactome, http://www.reactome.org ReactomeREACT_330 Activation of NOXA and translocation to mitochondria GENE ONTOLOGYGO:1900740 NOXA is transactivated in a p53-dependent manner and by E2F1. Activated NOXA is translocated to mitochondria. Pubmed14684737 Pubmed15126337 Reactome Database ID Release 43111448 Reactome, http://www.reactome.org ReactomeREACT_1194 Activation of PUMA and translocation to mitochondria GENE ONTOLOGYGO:1900740 Pubmed11463392 Pubmed14684737 Puma is transactivated in a p53-dependent manner and by E2F1. Activated Puma is translocated to mitochondria. Reactome Database ID Release 43139915 Reactome, http://www.reactome.org ReactomeREACT_121 Activation of BIM and translocation to mitochondria Authored: Gopinathrao, G, 2004-08-19 20:25:42 BIM acts as a sentinel to check the integrity of the cytoskeleton. It exists as two variant proteins: BIM-EL and BIM-L. In healthy cells, these two isoforms are sequestered to the dynein motor complex on microtubules via the dynein light chain DLC1. JNK or MAPK8 releases BIM in response to UV irradiation by phosphorylation. GENE ONTOLOGYGO:1900740 Pubmed14634621 Pubmed14764673 Reactome Database ID Release 43111446 Reactome, http://www.reactome.org ReactomeREACT_1650 Reviewed: Vaux, D, 0000-00-00 00:00:00 Activation of BMF and translocation to mitochondria Authored: Gopinathrao, G, 2004-08-19 20:25:42 GENE ONTOLOGYGO:1900740 In healthy cells, BMF is bound to the myosin V motor complex through its interaction with DLC2. UV irradiation or anoikis induces MAPK8 (JNK) to phosphorylate Dynein Light Chain 2 (DLC2) to release BMF. Pubmed14634621 Reactome Database ID Release 43139910 Reactome, http://www.reactome.org ReactomeREACT_2100 Reviewed: Vaux, D, 0000-00-00 00:00:00 ArhGAP28 Converted from EntitySet in Reactome Reactome DB_ID: 200795 Reactome Database ID Release 43200795 Reactome, http://www.reactome.org ReactomeREACT_11284 ArhGAP25 Converted from EntitySet in Reactome Reactome DB_ID: 200794 Reactome Database ID Release 43200794 Reactome, http://www.reactome.org ReactomeREACT_11494 Heparan(3)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076535 Reactome Database ID Release 432076535 Reactome, http://www.reactome.org ReactomeREACT_123848 Interferon (IFN)-gamma mediated induction of ceruloplasmin expression Authored: Matthews, L, 2004-12-20 12:28:36 Ceruloplasmin (Cp) is an acute phase protein synthesized and secreted by hepatocytes and cytokine stimulated macrophages and is believed to play a role in macrophage-mediated host defense. Interferon (IFN)-gamma induces Cp mRNA and protein expression in monocytic cells and peripheral blood monocytes (Mazumder et al., 1997). Edited: Matthews, L, 0000-00-00 00:00:00 Pubmed9257859 Reactome Database ID Release 43156830 Reactome, http://www.reactome.org ReactomeREACT_521 Apoptosis Apoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and membrane blebbing characterize apoptosis in general. Mitochondria remain morphologically unchanged. In 1972 Kerr et al introduced the concept of apoptosis as a distinct form of "cell-death", and the mechanisms of various apoptotic pathways are still being revealed today. <BR>The two principal pathways of apoptosis are (1) the Bcl-2 inhibitable or intrinsic pathway induced by various forms of stress like intracellular damage, developmental cues, and external stimuli and (2) the caspase 8/10 dependent or extrinsic pathway initiated by the engagement of death receptors<BR> The caspase 8/10 dependent or extrinsic pathway is a death receptor mediated mechanism that results in the activation of caspase-8 and caspase-10. Activation of death receptors like Fas/CD95, TNFR1, and the TRAIL receptor is promoted by the TNF family of ligands including FASL (APO1L OR CD95L), TNF, LT-alpha, LT-beta, CD40L, LIGHT, RANKL, BLYS/BAFF, and APO2L/TRAIL. These ligands are released in response to microbial infection, or as part of the cellular, humoral immunity responses during the formation of lymphoid organs, activation of dendritic cells, stimulation or survival of T, B, and natural killer (NK) cells, cytotoxic response to viral infection or oncogenic transformation. <BR> The Bcl-2 inhibitable or intrinsic pathway of apoptosis is a stress-inducible process, and acts through the activation of caspase-9 via Apaf-1 and cytochrome c. The rupture of the mitochondrial membrane, a rapid process involving some of the Bcl-2 family proteins, releases these molecules into the cytoplasm. Examples of cellular processes that may induce the intrinsic pathway in response to various damage signals include: auto reactivity in lymphocytes, cytokine deprivation, calcium flux or cellular damage by cytotoxic drugs like taxol, deprivation of nutrients like glucose and growth factors like EGF, anoikis, transactivation of target genes by tumor suppressors including p53.<BR> In many non-immune cells, death signals initiated by the extrinsic pathway are amplified by connections to the intrinsic pathway. The connecting link appears to be the truncated BID (tBID) protein a proteolytic cleavage product mediated by caspase-8 or other enzymes. Authored: Alnemri, E, Hengartner, M, Tschopp, J, Tsujimoto, Y, Hardwick, JM, 2004-01-16 16:01:51 Edited: Gopinathrao, G, Matthews, L, Gillespie, ME, Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006915 Pubmed12189384 Pubmed12209154 Pubmed12505355 Pubmed14561771 Pubmed14634621 Pubmed15218528 Pubmed4561027 Reactome Database ID Release 43109581 Reactome, http://www.reactome.org ReactomeREACT_578 Reviewed: Hengartner, M, Ranganathan, S, Vaux, D, 0000-00-00 00:00:00 MPS IX - Natowicz syndrome Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis type IX (MPS IX, Natowicz syndrome, Hyaluronidase deficiency, MIM:601492) is a rare lysosomal storage disease characterized by high hyaluronan (HA) concentration in the serum resulting from deficiency in hyaluronidase 1 (HYAL1, MIM:607071) which normally hydrolyses 1-4 linkages between N-acetylglucosamine (GlcNAc) and D-glucuronate (GlcA) residues. Symptoms of MPS IX are periodically painful soft tissue masses around the joints, acquired short stature and erosion of the hip joint, although joint movement and intelligence are normal (Natowicz et al. 1996, Triggs-Raine et al. 1999). Pubmed10339581 Pubmed8793927 Reactome Database ID Release 432206280 Reactome, http://www.reactome.org ReactomeREACT_147739 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Nuclear Translocation of APOBEC-1 and ACF ACF and APOBEC-1 are translocated from cytosol to nucleus to participate in the formation of editosome. Authored: Gopinathrao, G, 2003-11-30 18:34:56 Reactome Database ID Release 4375093 Reactome, http://www.reactome.org ReactomeREACT_620 TRAIL signaling Authored: Gillespie, ME, 2004-08-31 03:31:31 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed14634624 Reactome Database ID Release 4375158 Reactome, http://www.reactome.org ReactomeREACT_402 Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family. This group of apoptosis induction pathways all work through protein interactions mediated by the intracellular death domain (DD), encoded within the cytoplasmic domain of the receptor. TRAIL selectively induces apoptosis through its interaction with the Fas-associated death domain protein (FADD). Caspase-8 is formed from procaspase-8 Caspase-8 is formed from the precursor protein pro-Caspase-8 as a cleavage product. GENE ONTOLOGYGO:0006919 Pubmed14644197 Reactome Database ID Release 43140534 Reactome, http://www.reactome.org ReactomeREACT_1503 FasL/ CD95L signaling Authored: Gillespie, ME, 2004-08-18 21:05:31 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008624 Pubmed11048727 Pubmed1713127 Pubmed2469768 Pubmed7538907 Reactome Database ID Release 4375157 Reactome, http://www.reactome.org ReactomeREACT_900 Reviewed: Vaux, D, 0000-00-00 00:00:00 The Fas family of cell surface receptors initiate the apototic pathway through interaction with the external ligand, FasL. The cytoplasmic domain of Fas interacts with a number of molecules in the transduction of the external signal to the cytoplasmic side of the cell membrane. The most notable cytoplasmic domain is the Death Domain (DD) that is involved in recruiting the FAS-associating death domain-containing protein (FADD). This interaction drives downstream events. TNF signaling Authored: Gillespie, ME, 2004-08-24 21:32:45 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed12040173 Reactome Database ID Release 4375893 Reactome, http://www.reactome.org ReactomeREACT_1432 The Tumor Necrosis Factor alpha (TNF-alpha) mediated apoptosis pathway has been implicated in the pathogenesis of a number of diseases including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. The TNF signaling network provides extensive cross talk between the apoptotic pathway, and the other NF-B, and JNK pathways that also emanate from TNF-R. Extrinsic Pathway for Apoptosis Authored: Gillespie, ME, 2004-08-10 16:59:18 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008624 Known as the "death receptor pathway" the extrinsic or caspase 8/10 dependent pathway is activated by ligand binding. The "death receptors" are specialized cell-surface receptors including Fas/CD95, tumor necrosis factor-alpha (TNF-alpha) receptor 1, and two receptors, DR4 and DR5, that bind to the TNF-alpha related apoptosis-inducing ligand (TRAIL). The extrinsic and intrinsic pathways unite in the activation of Caspase-3, though the two pathways communicate through the pro-apoptotic Bcl-2 family member Bid before uniting at the shared activation of Caspase-3. Pubmed11048727 Reactome Database ID Release 43109607 Reactome, http://www.reactome.org ReactomeREACT_1059 Reviewed: Vaux, D, 0000-00-00 00:00:00 Death Receptor Signalling Authored: Gillespie, ME, 2004-08-10 16:59:18 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008624 Reactome Database ID Release 4373887 Reactome, http://www.reactome.org ReactomeREACT_1619 Reviewed: Vaux, D, 0000-00-00 00:00:00 The death receptors, all cell-surface receptors, begin the process of caspase activation. The common feature of these type 1 transmembrane proteins is the "death-domain" a conserved cytoplasmic motif found on all of the three receptors (FAS/CD95, TNF-receptor, and TRAIL-receptor) that binds the Fas-associated protein with death domain (FADD) Heparan(2)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076412 Reactome Database ID Release 432076412 Reactome, http://www.reactome.org ReactomeREACT_125452 ARHGAP20 Converted from EntitySet in Reactome Reactome DB_ID: 200778 Reactome Database ID Release 43200778 Reactome, http://www.reactome.org ReactomeREACT_11359 ArhGAP8 Converted from EntitySet in Reactome Reactome DB_ID: 200770 Reactome Database ID Release 43200770 Reactome, http://www.reactome.org ReactomeREACT_11618 MPS IIIC - Sanfilippo syndrome C Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis III (Sanfilippo syndrome) was described in 1963 by a pediatrician named Sylvester Sanfilippo (J. Pediat. 63: 837838, 1963, no reference). Mucopolysaccharidosis type IIIC (MPS IIIC, Sanfilippo syndrome C; MIM:252930) is an autosomal recessive genetic disorder due to the loss of heparan alpha-glucosaminide N-acetyltransferase (HGSNAT; MIM:610453) that normally acetylates the non-reducing terminal alpha-glucosamine residue of heparan sulfate. The molecular defects underlying MPS IIIC remained unknown for almost three decades due to the low tissue content and instability of HGSNAT. But, during the last decade, the gene was cloned in parallel by two different groups and shown to contain 18 exons and span approximately 62Kb (Fan et al. 2006, Hrebicek et al. 2006). Loss of HGSNAT results in build up of this glycosaminglycan (GAG) in cells and tissues and is characterized by severe central nervous system degeneration but only with mild somatic disease and death occurs typically during the second or third decade of life (Kresse et al. 1978, Klein et al. 1978, Feldhammer et al. 2009, de Ruijter et al. 2011). Pubmed153835 Pubmed16960811 Pubmed17033958 Pubmed19479962 Pubmed21235449 Pubmed33384 Reactome Database ID Release 432206291 Reactome, http://www.reactome.org ReactomeREACT_147860 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 MPS IIIB - Sanfilippo syndrome B Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis III (Sanfilippo syndrome) was described in 1963 by a pediatrician named Sylvester Sanfilippo (J. Pediat. 63: 837838, 1963, no reference). MPS IIIB (Mucopolysaccharidosis type IIIB, MPS IIIB, Sanfilippo syndrome type B; MIM:252920) is an autosomal recessive genetic disorder due to loss of function of alpha-N-acetylglucosaminidase (NAGLU; MIM:609701), involved in the hydrolysis of terminal non-reducing N-acetylglucosamine residues in heparan sulfate (HS) The gene encoding NAGLU was cloned in 1996 by Zhao and colleagues. It contains 6 exons and spans 8.3 kb on chromosome 17q21 (Zhao et al. 1996). MPSIIIB is characterized by severe CNS retardation but only mild somatic disease and death usually occurs in the second or third decade of life (Zhao et al. 1996, Yogalingam & Hopwood 2001, de Ruijter et al. 2011). MPS IIIB shows extensive molecular heterogeneity (Schmidtchen et al. 1998). Pubmed11668611 Pubmed21235449 Pubmed8650226 Pubmed9443878 Reactome Database ID Release 432206282 Reactome, http://www.reactome.org ReactomeREACT_147788 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 MPS IV - Morquio syndrome A Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis IV A (MPS IVA, MPS4A, Morquio's syndrome, Morquio's; MIM:253000) is a rare, autosomal recessive mucopolysaccharide storage disease, first described simultaneously in 1929 by L Morquio (Morquio L, Sur une forme de distrophie familiale, Bull Soc Pediat, Paris, 27, 1929, 145-152) and JF Brailsford (Brailsford, JF, Chondro-osteo-dystrophy: roentgenographic and clinical features of child with dislocation of vertebrae, Am j Surg, 7, 1929, 404-410). MPSIVA is caused by a deficiency in N-acetylgalactosamine 6-sulfatase (GALNS; MIM:612222) which normally hydrolyses 6-sulfate groups of N-acetylgalactosamine 6-sulfate units of chondroitin sulfate (CS) and of galactose 6-sulfate units of keratan sulfate (KS) (Matalon et al. 1974). The result is accumulation of KS/DS in cells and overexcretion in urine. Severe osteochondrodysplasia is a commonly seen phenotype for this disease. The severity of the disease is variable but severe cases limits lifespan to their 20's or 30's (Prat et al. 2008, Tomatsu et al. 2011). The gene coding for human GALNS was mapped to chromosome 16q24.3 (Masuno et al. 1993) and its structure described at the same time by two independent groups as comprising 14 exons and spanning approximately 40-50 kb (Nakashima et al.1994, Morris et al.1994). Pubmed18456538 Pubmed21506915 Pubmed4218100 Pubmed8001980 Pubmed8020961 Pubmed8325655 Reactome Database ID Release 432206290 Reactome, http://www.reactome.org ReactomeREACT_147825 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 MPS IIID - Sanfilippo syndrome D Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis III (Sanfilippo syndrome) was described in 1963 by a pediatrician named Sylvester Sanfilippo (J. Pediat. 63: 837-838, 1963, no reference). Mucopolysaccharidosis type IIID (MPS IIID, Sanfilippo syndrome D, MIM:252940) is an autosomal recessive genetic disorder due to the loss of N-acetyl-D-glucosamine 6-sulfatase (GNS; MIM:607664), that hydrolyses the 6-sulfate groups of the N-acetyl-D-glucosamine 6-sulfate units of the glycosaminoglycans (GAGs) heparan sulfate and keratan sulfate. GNS is localized to chromosome 12q14 and has 14 exons spanning 46 kb (Robertson et al. 1988, Mok et al. 2003). Loss of enzyme activity leads to lysosomal accumulation and urinary excretion of heparan sulfate and N-acetylglucosamine 6-sulfate residues (Mok et al. 2003). Keratan sulphate does not accumulate in MPS IIID, as beta-linked N-acetyl-D-glucosamine 6-sulphate can be cleaved by beta-hexosaminidase A (Kresse et al. 1980). This disorder is characterized by progressive mental deterioration but only moderate physical abnormalities and death duing the second or third decade of life, presenting a phenotype similar to MPSIIIA (Jones et al. 1997, de Ruijter et al. 2011). Pubmed12573255 Pubmed21235449 Pubmed3391615 Pubmed6450420 Pubmed9329460 Reactome Database ID Release 432206305 Reactome, http://www.reactome.org ReactomeREACT_147749 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 MPS VI - Maroteaux-Lamy syndrome Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 ISBN1416029990 Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, polydystrophic dwarfism; MIM:253200) is an autosomal recessive lysosomal storage disorder caused by a deficiency in arylsulfatase B (ARSB, N-acetyl-galactosamine 4-sulfatase; MIM:611542). It is named after two French physicians, Pierre Maroteaux and Maurice Emil Joseph Lamy. Maroteaux first described this disorder as a novel dysostosis associated with increased urinary excretion of chondroitin sulfate (CS; Maroteaux et al. 1963). The gene encoding ARSB is mapped to chromosome 5q11-q13 (Fidzianska et al. 1984) and contains 8 exons spanning about 206 kb (Karangeorgos et al. 2007). Defective ARSB results in build up of dermatan sulfate (DS) and chondroitin sulfate (CS) in soft tissues causing compression and blockages in blood vessels, nerves, trachea, corneal clouding and disrupting normal bone development. Symptoms are similar to MPS I but with normal intelligence generally (Rapini et al. 2007, Valayannopoulos et al. 2010). Pubmed14091597 Pubmed17458871 Pubmed20385007 Pubmed6467990 Reactome Database ID Release 432206285 Reactome, http://www.reactome.org ReactomeREACT_147719 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Ashworth, Jane, 2012-08-28 Reviewed: Coutinho, Maria, 2012-08-27 MPS IV - Morquio syndrome B Authored: Jassal, B, 2012-04-26 Defects in beta-galactosidase (GLB1; MIM:611458) can result in GM1 gangliosidosis (GM1; MIM:230500) (Nishimoto et al. 1991) (not described here), with several phenotypes indicating mental deterioration, as well as in mucopolysaccharidosis IVB, a characteristic mucopolysaccharidosis with no neurological symptoms (Callahan 1999).<br><br>Mucopolysaccharidosis IVB (MPS IVB, Morquio's syndrome B; MIM:253010) is a rare, autosomal recessive mucopolysaccharide storage disease characterized by intracellular accumulation of keratan sulfate (KS), skeletal dysplasia and corneal clouding. There is no central nervous system involvement, intelligence is normal and there is increased KS excretion in urine (Suzuki et al. "Beta-galactosidase deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease", p3775-3809 in Stryer et al. 2001). MPSIVB is caused by a defect in betagalactosidase (GLB1), which normally cleaves terminal galactosyl residues from glycosaminoglycans, gangliosides and glycoproteins. The GLB1 gene spans 62.5 kb and contains 16 exons (Oshima et al.1988, Santamaria et al. 2007) and maps to chromosome 3p21.33 (Takano & Yamanouchi 1993).<br> Edited: Jassal, B, 2012-04-26 ISBN0079130356 Pubmed10571006 Pubmed17309651 Pubmed1909089 Pubmed3143362 Pubmed7693577 Reactome Database ID Release 432206308 Reactome, http://www.reactome.org ReactomeREACT_147798 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 MPS VII - Sly syndrome Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis type VII (MPS VII, Sly syndrome, beta-glucuronidase deficiency; MIM:253220) is an autosomal recessive lysosomal storage disease characterized by a deficiency of the enzyme beta-glucuronidase (GUSB; MIM:611499) which would normally cleave glucuronide residues from dematan sulphate, keratan sulphate and chondroitin sulphate, resulting in build up of these GAGs in cells and tissues (Sly et al. 1973). The gene encoding GUSB is 21 kb long, contains 12 exons and gives rise to two different types of cDNAs, through an alternate splicing mechanism (Miller et al. 1990). It maps to 7q11.21-q11.22 (Speleman et al. 1996). The phenotype is highly variable, ranging from severe causing death, non-immune hydrops fetalis (Vervoort et al. 1996) to mild forms with survival into adulthood (Storch et al. 2003). Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (Shipley et al. 1993, Tomatsu et al. 2009). Pubmed12522561 Pubmed19224584 Pubmed2347593 Pubmed4265197 Pubmed7680524 Pubmed8565635 Pubmed8644704 Reactome Database ID Release 432206292 Reactome, http://www.reactome.org ReactomeREACT_147759 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Ashworth, Jane, 2012-08-28 Reviewed: Coutinho, Maria, 2012-08-27 MPS I - Hurler syndrome Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis type I (MPS I, Hurler syndrome, Hurler's disease, gargoylism, Scheie, Hirler-Scheie syndrome; MIM:607014, 607015 and 607016) is an autosomal recessive genetic disorder where there is a deficiency of alpha-L iduronidase (IDUA, MIM:252800), a glycosidase that removes non-reducing terminal alpha-L-iduronide residues during the lysosomal degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate (McKusick 1959). In 1992, Scott and colleagues were able to clone and purify the gene that encodes this enzyme, IDUA, demonstrating that it spans approximately 19 kb and contains 14 exons (Scott et al. 1992).<br>Hurler syndrome is named after a German paediatrician Gertrud Hurler (1919, no reference available). The result is build up of heparan sulfate and dermatan sulfate in the body and increased urinary excretion of these GAGs. Symptoms and signs include hepatosplenomegaly, dwarfism, unique facial features, corneal clouding, retinopathy, progressive mental retardation appears during childhood and early death can occur due to organ damage (Campos & Monaga 2012). MPS I is divided into three subtypes, ranging from severe to mild phenotypes; Mucopolysaccharidosis type IH (MPSIH, Hurler syndrome, MIM:607014), mucopolysaccharidosis type IH/S (MPSIH/S, HurlerScheie syndrome, MIM: 607015) and mucopolysaccharidosis type IS (MPSIS, Scheie syndrome, MIM: 607016) respectively (McKusick 1972). Pubmed13629198 Pubmed1505961 Pubmed22527994 Pubmed4112371 Reactome Database ID Release 432206302 Reactome, http://www.reactome.org ReactomeREACT_147857 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Ashworth, Jane, 2012-08-28 Reviewed: Coutinho, Maria, 2012-08-27 MPS IIIA - Sanfilippo syndrome A Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis III (MPS III, Sanfilippo syndrome) was described in 1963 by a pediatrician named Sylvester Sanfilippo (J. Pediat. 63: 837-838, 1963, no reference). Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome A, MIM:252900) is a rare, autosomal recessive lysosomal storage disease characterised by severe CNS degeneration in early childhood leading to death between 10 and 20 years of age. A deficiency of the enzyme N-sulphoglucosamine sulphohydrolase (SGSH, MIM:605270), which normally hydrolyses the sulfate group from the terminal N-sulphoglucosamine residue of heparan sulfate (HS), leads to the build-up of HS in cells and tissues and its presence in urine (van de Kamp et al. 1981, Yogalingam & Hopwood 2001, de Ruijter et al. 2011). The gene encoding N-sulfoglucosamine sulfohydrolase, SGSH, was cloned in 1995 (Scott et al.1995) and, later, shown to contain 8 exons spanning approximately 11 kb (Karageorgos et al. 1996). Pubmed11668611 Pubmed21235449 Pubmed6796310 Pubmed7493035 Pubmed8946167 Reactome Database ID Release 432206307 Reactome, http://www.reactome.org ReactomeREACT_147753 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 MPS II - Hunter syndrome Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 Mucopolysaccharidosis II (MPS II, Hunter syndrome, MIM:309900) is an X-linked, recessive genetic disorder which therefore primarily affects males. MPS II was first described in 1917, by Major Charles Hunter (Hunter 1917) and is caused by a deficiency (or absence) of iduronate-2-sulfatase (IDS, MIM:300823), which would normally hydrolyse the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin. Without IDS, these GAGs accumulate in the body and are excessively excreted in urine. Although the disease was known since the early 1970s, being the first MPS to be defined clinically in humans, it wasn’t until the 1990s that IDS was cloned. It is now known to be localized to Xq28 (Wilson et al. 1991) and contain 9 exons (Flomen et al. 1993) spanning approximately 24 kb (Wilson et al. 1993).<br>Build up can occur in the liver and spleen as well as in the walls and valves of the heart (reduced hepatic and cardiac function, liver/spleen hepatosplenomegaly), airways (leading to obstructive airway disease), all major joints and bones (joint stiffness and skeletal deformities) and in brain (severe mental retardation). The rate of progression and degree of severity of the disorder can be different for each person with MPS II. Severe forms of the disorder can result in death in childhood whereas those with a "milder" form can expect to live to their 20's or 30's. Some patients even survive into their fifth and sixth decades of life (Wraith et al. 2008, Beck 2011). Pubmed18038146 Pubmed1901826 Pubmed19979883 Pubmed21235446 Pubmed8244397 Pubmed8490623 Reactome Database ID Release 432206296 Reactome, http://www.reactome.org ReactomeREACT_147734 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 RhoGAP102A homolog Converted from EntitySet in Reactome Reactome DB_ID: 200632 Reactome Database ID Release 43200632 Reactome, http://www.reactome.org ReactomeREACT_11957 Signaling by FGFR4 mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR4 is perhaps the least well studied of the FGF receptors, and unlike the case for the other FGFR genes, mutations in FGFR4 are not known to be associated with any developmental disorders. Recently, however, somatically arising mutations in the FGFR4 coding sequence have begun to be identified in some cancers. 8% of rhabdomyosarcomas have activating mutations in the kinase domain of FGFR4. Two of these mutations - N535K (paralogous to the FGFR2 N550K allele found in endometrial cancers) and V550E - have been shown to support the oncogenic transformation of NIH 3T3 cells (Taylor, 2009). An FGFR4 Y367C mutation has also been identified in breast cancers (Ruhe, 2007; Roidl, 2010); mutations of paralogous residues in FGFR2 and FGFR3 are associated with both skeletal dysplasias and the development of diverse cancers (Pollock, 2007; Ruhe, 2007; Rousseau, 1996; Chesi, 1997, 2001).<br><br><br>Finally, a SNP at position 388 of FGFR4 is associated with aggressive disease development. Expression of the G388R allele in breast, colorectal and prostate cancers is correlated with rapid progression times and increased rates of recurrence and metastasis (Bange, 2002; Spinola, 2005; Wang, 2004). Pubmed11157491 Pubmed11830541 Pubmed15448004 Pubmed16012724 Pubmed17525745 Pubmed18056464 Pubmed19809159 Pubmed19946327 Pubmed8845844 Pubmed9207791 Reactome Database ID Release 431839128 Reactome, http://www.reactome.org ReactomeREACT_121286 Reviewed: Ezzat, S, 2012-05-15 t(4;14) translocations of FGFR3 Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10568829 Pubmed11157491 Pubmed11429702 Pubmed12835230 Pubmed16467200 Pubmed17942756 Pubmed19381019 Pubmed9207791 Pubmed9865713 Reactome Database ID Release 432033515 Reactome, http://www.reactome.org ReactomeREACT_121011 Reviewed: Ezzat, S, 2012-05-15 Translocations which put the FGFR3 gene under the control of the strong IGH promoter have been identified in 15% of multiple myelomas (Avet-Loiseau, 1998; Chesi, 1997; Chesi, 2001). This translocation, which occurs 70kb upstream of the FGFR3 gene, also involves the nearby multiple myeloma SET-domain containing (MMSET) gene (Lauring, 2008), and although the contribution of each of these genes to the development of cancer has not been fully elucidated, several studies have shown that t(4:14) myeloma cell lines are sensitive to FGFR3 inhibitors (Trudel, 2006; Qing, 2009). In ~5% of cases, the translocation is accompanied by activating mutations of FGFR3 (Onwuazor, 2003; Ronchetti, 2001). The t(4;14) translocation results in overexpression of FGFR3 and subsequent ligand independent or anomalous ligand-dependent signaling (Otsuki, 1999). Signaling by activated point mutants of FGFR3 Activating point mutations in FGFR3 are found in the extracellular ligand-binding domain, the transmembrane region and the tyrosine kinase domain and are believed to result in ligand-independent activation of the receptor (Webster and Donoghue, 1996; Wenbster, 1997). These mutations, although initially characterized in the context of autosomal skeletal disorders, are now being identified in a range of cancers including bladder, cervical, breast, prostate, head and neck, and multiple myeloma (reviewed in Wesche, 2011). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed21711248 Pubmed8599935 Pubmed8754806 Reactome Database ID Release 431839130 Reactome, http://www.reactome.org ReactomeREACT_121337 Reviewed: Ezzat, S, 2012-05-15 Signaling by FGFR3 mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10053006 Pubmed10377013 Pubmed10471491 Pubmed11055896 Pubmed11466624 Pubmed15282208 Pubmed19066716 Pubmed19749790 Pubmed21711248 Pubmed7647778 Pubmed7670477 Pubmed7773297 Pubmed7847369 Pubmed7913883 Pubmed8078586 Pubmed8589699 Pubmed8640234 Pubmed8841188 Pubmed8845844 Pubmed9154000 Pubmed9207791 Pubmed9279753 Pubmed9438390 Pubmed9538690 Pubmed9865713 Reactome Database ID Release 432033514 Reactome, http://www.reactome.org ReactomeREACT_121249 Reviewed: Ezzat, S, 2012-05-15 The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. <br><br>Activating mutations in FGFR3 are associated with the development of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke, 1998; Harada, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau, 1994; Shiang, 1994; Bellus, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau, 1995; Rousseau, 1996, D'Avis,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina, 1999; Bellus, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski, 1996; Bellus, 2000) <br><br>In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus, 1996; Reardon, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi, 2004b).<br><br><br>Of all the FGF receptors, FGFR3 has perhaps the best established link to the development in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen, 1999; Naski, 1996; di Martino, 2009, Sibley, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau, 1998; Chesi, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi, 1997). Mucopolysaccharidoses Authored: Jassal, B, 2012-04-26 Edited: Jassal, B, 2012-04-26 ISBN0079130356 Pubmed16414358 Pubmed19111581 Pubmed22013531 Pubmed22210669 Pubmed22210670 Reactome Database ID Release 432206281 Reactome, http://www.reactome.org ReactomeREACT_147853 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Ashworth, Jane, 2012-08-28 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders caused by deficiencies of enzymes catalyzing the stepwise degradation of glycosaminoglycans (GAGs, originally called mucopolysaccharides) (Neufeld & Muenzer in Scriver et al. 2001). Catabolism of the GAGs dermatan sulfate, heparan sulfate, heparin, keratan sulfate, chondroitin sulfate or hyaluronan may be blocked at one or more steps, resulting in lysosomal accumulation of GAG fragments of varying size. Over time these collect in the cells, blood and connective tissues ultimately resulting in progressive irreversible cellular damage which affects appearance, physical abilities, organ and system function, vision, and usually mental development (Lehman et al. 2011, Ashworth et al. 2006). Life expectancy is also reduced. There are 11 known enzyme deficiencies that give rise to 7 distinct MPS. These disorders are biochemically characterized by elevated levels of partially or undegraded GAGs in lysosomes, blood, urine and cerebro-spinal fluid (Muenzer 2011, Coutinho et al. 2012). The MPS are part of the lysosomal storage disease family, a group of about 50 genetic disorders caused by deficient lysosomal proteins (Ballabio & Gieselmann 2009). Constitutive PI3K/AKT Signaling in Cancer Authored: Orlic-Milacic, M, 2012-07-18 Class IA PI3K is a heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). In the absence of activating signals, the regulatory subunit stabilizes the catalytic subunit while inhibiting its activity. The complex becomes activated when extracellular signals stimulate the phosphorylation of the cytoplasmic domains of transmembrane receptors or receptor-associated proteins. The p85 regulatory subunit binds phosphorylated motifs of activator proteins, which induces a conformational change that relieves p85-mediated inhibition of the p110 catalytic subunit and enables PI3K to phosphorylate PIP2 to form PIP3. The phosphoinositide kinase activity of PI3K is opposed by the phosphoinositide phosphatase activity of PTEN. <br><br>PIP3 acts as a messenger that recruits PDPK1 (PDK1) and AKT (AKT1, AKT2 or AKT3) to the plasma membrane. PDPK1 also possesses a low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane. Binding of AKT to PIP3 induces a conformational change that enables TORC2 complex to phosphorylate AKT at a conserved serine residue (S473 in AKT1). Phosphorylation at the serine residue enables AKT to bind to PDPK1 and exposes a conserved threonine residue (T308) that is phosphorylated by PDPK1. AKT phosphorylated at both serine and threonine residues dissociates from the plasma membrane and acts as a serine/threonine kinase that phosphorylates a number of cytosolic and nuclear targets involved in regulation of cell metabolism, survival and gene expression. For a recent review, please refer to Manning and Cantley, 2007. <br> Signaling by PI3K/AKT is frequently constitutively activated in cancer. This activation can be via gain-of-function mutations in PI3KCA (encoding catalytic subunit p110alpha), PIK3R1 (encoding regulatory subunit p85alpha) and AKT1. The PI3K/AKT pathway can also be constitutively activated by loss-of-function mutations in tumor suppressor genes such as PTEN. <br> Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011). While AKT1 gene copy number, expression level and phosphorylation are often increased in cancer, only one low frequency point mutation has been repeatedly reported in cancer and functionally studied. This mutation represents a substitution of a glutamic acid residue with lysine at position 17 of AKT1, and acts by enabling AKT1 to bind PIP2. PIP2-bound AKT1 is phosphorylated by TORC2 complex and by PDPK1 that is always present at the plasma membrane, due to low affinity for PIP2. Therefore, E17K substitution abrogates the need for PI3K in AKT1 activation (Carpten et al. 2007, Landgraf et al. 2008). <br> Loss-of-function mutations affecting the phosphatase domain of PTEN are frequently found in sporadic cancers (Kong et al. 1997, Lee et al. 1999, Han et al. 2000), as well as in PTEN hamartoma tumor syndromes (PHTS) (Marsh et al. 1998). PTEN can also be inactivated by gene deletion or epigenetic silencing, or indirectly by overexpression of microRNAs that target PTEN mRNA (Huse et al. 2009). Cells with deficient PTEN function have increased levels of PIP3, and therefore increased AKT activity. For a recent review, please refer to Hollander et al. 2011.<br> Because of their clear involvement in human cancers, PI3K and AKT are targets of considerable interest in the development of small molecule inhibitors. Although none of the currently available inhibitors display preference for mutant variants of PIK3CA or AKT, several inhibitors targeting the wild-type kinases are undergoing clinical trials. These include dual PI3K/mTOR inhibitors, class I PI3K inhibitors, pan-PI3K inhibitors, and pan-AKT inhibitors. While none have yet been approved for clinical use, these agents show promise for future therapeutics. In addition, isoform-specific PI3K and AKT inhibitors are currently being developed, and may provide more specific treatments along with reduced side-effects. For a recent review, please refer to Liu et al. 2009. Pubmed10555148 Pubmed10866302 Pubmed16339315 Pubmed17604717 Pubmed17611497 Pubmed17626883 Pubmed18079394 Pubmed18317450 Pubmed18954143 Pubmed19487573 Pubmed19644473 Pubmed19962665 Pubmed20009532 Pubmed20713702 Pubmed21430697 Pubmed21478295 Pubmed9326929 Pubmed9467011 Reactome Database ID Release 432219530 Reactome, http://www.reactome.org ReactomeREACT_147727 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 PI3K/AKT Signaling in Cancer Authored: Orlic-Milacic, M, 2012-07-18 Edited: Matthews, L, 2012-08-03 Pubmed17604717 Pubmed19644473 Pubmed21430697 Reactome Database ID Release 432219528 Reactome, http://www.reactome.org ReactomeREACT_147723 Reviewed: Thorpe, Lauren, 2012-08-13 Reviewed: Yuzugullu, Haluk, 2012-08-13 Reviewed: Zhao, Jean J, 2012-08-13 This pathway describes how normal signaling by PI3K/AKT, presented in the contained module 'PIP3 Activates AKT Signaling' and recently reviewed by Manning and Cantley in 2007, is perturbed in cancer, as described in the contained module 'Constitutive Signaling by PI3K/AKT'. Please refer to Liu et al. 2009 and Hollander et al. 2011 for recent reviews. Abnormal metabolism in phenylketonuria Authored: D'Eustachio, P, 2012-03-04 Edited: D'Eustachio, P, 2012-03-16 Phenylalanine hydroxylase (PAH) catalyzes the conversion of phenylalanine to tyrosine. In the absence of functional PAH, phenylalanine accumulates to high levels in the blood (Mitchell and Scriver 2010) and is converted to phenylpyruvate and phenyllactate (Clemens et al. 1990; Langenbeck et al. 1992). The extent of these conversions is modulated by genetic factors distinct from PAH, as siblings with the identical PAH defect can produce different amounts of them (Treacy et al. 1996).<p>Both L-amino acid oxidase (Boulland et al. 2004) and Kynurenine--oxoglutarate transaminase 3 (Han et al. 2004) can catalyze the conversion of phenylalanine to phenylpyruvate and lactate dehydrogenase can catalyze the conversion of the latter molecule to phenyllactate (Meister 1951). Elevated levels of phenylalanine, phenylpyruvate, and phenyllactate are all thought to contribute to the symptoms of phenylketonuria. One possible target is the metabolism of kynurenine. Pubmed15606768 Pubmed1583868 Pubmed17356132 Pubmed20301677 Pubmed2116554 Pubmed8892014 Reactome Database ID Release 432160456 Reactome, http://www.reactome.org ReactomeREACT_121117 Reviewed: Jassal, B, 2012-03-16 Signaling by FGFR2 amplification mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 FGFR2 amplifications have been identified in 10% of gastric cancers, where they are associated with poor prognosis diffuse cancers (Hattori, 1996; Ueda, 1999; Shin, 2000; Kunii, 2008) , and in ~1% of breast cancers (Turner, 2010; Tannheimer, 2000). FGFR2 amplification often occur in conjunction with deletions of C-terminal exons, resulting in expression of a internalization- and degradation-resistant form of the receptor (Takeda, 1999; Cha, 2008, 2009). Amplification affects signaling without altering the intrinsic kinase activity of the receptor. Signaling through overexpressed FGFR2 also shows evidence of being ligand-independent and sensitive to FGFR inhibitors (Lorenzi, 1997; Takeda, 1999; Cha, 2009). Pubmed10626794 Pubmed11003564 Pubmed11056689 Pubmed17505008 Pubmed18337450 Pubmed18381441 Pubmed19103595 Pubmed20101236 Pubmed9266968 Pubmed9816310 Reactome Database ID Release 432023837 Reactome, http://www.reactome.org ReactomeREACT_121255 Reviewed: Ezzat, S, 2012-05-15 Activated point mutants of FGFR2 Authored: Rothfels, K, 2012-02-09 Autosomal dominant mutations in FGFR2 are associated with the development of a range of skeletal disorders including Beare-Stevensen cutis gyrata syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome, Crouzon syndrome and Apert Syndrome (reveiwed in Burke, 1998; Webster and Donoghue 1997; Cunningham, 2007). Mutations that give rise to Crouzon, Jackson-Weiss and Pfeiffer syndromes tend to cluster in the third Ig-like domain of the receptor, either in exon IIIa (shared by the IIIb and the IIIc isoforms) or in the FGFR2c-specific exon IIIc. These mutations frequently involve creation or removal of a cysteine residue, leading to the formation of an unpaired cysteine residue that is thought to promote intramolecular dimerization and thus constitutive, ligand-independent activation (reviewed in Burke, 1998; Webster and Donoghue, 1997; Cunningham, 2007). Mutations in FGFR2 that give rise to Apert Syndrome cluster to the highly conserved Pro-Ser dipeptide in the IgII-Ig III linker; mutations in the paralogous residues of FGFR1 and 3 give rise to Pfeiffer and Muenke syndromes, respectively (Muenke, 1994; Wilkie, 1995; Bellus, 1996). Development of Beare-Stevensen cutis gyrata is associated with mutations in the transmembrane-proximal region of the receptor (Przylepa, 1996), and similar mutations in FGFR3 are linked to the development of thanatophoric dysplasia I (Tavormina, 1995a). These mutations all affect FGFR2 signaling without altering the intrinsic kinase activity of the receptor.<br><br><br>Activating point mutations have also been identified in FGFR2 in ~15% of endometrial cancers, as well as to a lesser extent in ovarian and gastric cancers (Dutt, 2008; Pollock, 2007; Byron, 2010; Jang, 2001). These mutations are found largely in the extracellular region and in the kinase domain of the receptor, and parallel activating mutations seen in autosomal dominant disorders described above.<br><br><br>Activating mutations in FGFR2 are thought to contribute to receptor activation through diverse mechanisms, including constitutive ligand-independent dimerization (Robertson, 1998), expanded range and affinity for ligand (Ibrahimi, 2004b; Yu, 2000) and enhanced kinase activity (Byron, 2008; Chen, 2007). Edited: Rothfels, K, 2012-05-16 Pubmed11121055 Pubmed11325814 Pubmed15282208 Pubmed17525745 Pubmed17552943 Pubmed17803937 Pubmed18552176 Pubmed18757403 Pubmed20106510 Pubmed7719344 Pubmed7773297 Pubmed7874169 Pubmed8696350 Pubmed8841188 Pubmed9154000 Pubmed9538690 Pubmed9539778 Reactome Database ID Release 432033519 Reactome, http://www.reactome.org ReactomeREACT_120863 Reviewed: Ezzat, S, 2012-05-15 Heparan(1)-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076416 Reactome Database ID Release 432076416 Reactome, http://www.reactome.org ReactomeREACT_122863 Signaling by FGFR2 mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed17505008 Pubmed17552943 Pubmed18381441 Pubmed19147536 Pubmed21367659 Pubmed21711248 Pubmed9154000 Pubmed9538690 Reactome Database ID Release 431839126 Reactome, http://www.reactome.org ReactomeREACT_121155 Reviewed: Ezzat, S, 2012-05-15 The FGFR2 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. Activating FGFR2 mutations in the germline give rise to a range of craniosynostotic conditions including Pfeiffer, Apert, Jackson-Weiss, Crouzon and Beare-Stevensen Cutis Gyrata syndromes. These autosomal dominant skeletal disorders are characterized by premature fusion of several sutures in the skull, and in some cases also involve syndactyly (abnormal bone fusions in the hands and feet) (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007). <br><br>Activating FGFR2 mutations arising somatically have been linked to the development of gastric and endometrial cancers (reviewed in Greulich and Pollock, 2011; Wesche, 2011). Many of these mutations are similar or identical to those that contribute to the autosomal disorders described above. Notably, loss-of-function mutations in FGFR2 have also been recently described in melanoma (Gartside, 2009). FGFR2 may also contribute to tumorigenesis through overexpression, as FGFR2 has been identified as a target of gene amplification in gastric and breast cancers (Kunii, 2008; Takeda, 2007). dlc-2 Converted from EntitySet in Reactome Reactome DB_ID: 200597 Reactome Database ID Release 43200597 Reactome, http://www.reactome.org ReactomeREACT_11892 STARD13 Signaling by FGFR1 amplification mutants Amplification or activation of FGFR1 has been reported in lung cancer (Weiss, 2001; Marek, 2009; Dutt, 2011), breast cancer (Reis-Filho, 2006; Turner, 2010), oral squamous carcinoma (Freier, 2007), esophageal squamous cell carcinomas (Ishizuka, 2002), ovarian cancer (Gorringe, 2007), bladder cancer (Simon, 2001), prostate cancer (Edwards, 2003; Acevedo, 2007) and rhabodomyosarcoma (Missiaglia, 2009). Unlike the case for FGFR2 amplifications, FGFR1 amplifications are not associated with additional point mutations and affect signaling without altering the intrinsic kinase activity of the receptor. Overexpressed FGFR1 appears to signal at a basal level in a ligand-independent fashion, but is also able to be stimulated by exogenous ligand. Downstream activation may be the result of aberrant paracrine or autocrine stimulation (reviewed in Turner and Gross, 2010; Greulich and Pollock, 2011). FGFR1 amplification has not been conclusively demonstrated to be the causative oncogenic agent in all of the cancer types mentioned above, and other genes in the 8p11 region may also be candidates in some cases (Bass, 2009; Bernard-Pierrot, 2008; Ray, 2004). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed11389083 Pubmed12147242 Pubmed14614009 Pubmed14729606 Pubmed16807070 Pubmed17121884 Pubmed17699850 Pubmed18068632 Pubmed18757432 Pubmed18849352 Pubmed19235922 Pubmed19801978 Pubmed20094046 Pubmed20179196 Pubmed21160078 Pubmed21367659 Pubmed21666749 Reactome Database ID Release 431839120 Reactome, http://www.reactome.org ReactomeREACT_120827 Reviewed: Ezzat, S, 2012-05-15 Signaling by FGFR1 mutants Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed14613973 Pubmed16140923 Pubmed16186508 Pubmed17552943 Pubmed18056464 Pubmed18772890 Pubmed20094046 Pubmed20226962 Pubmed21367659 Pubmed21711248 Pubmed7874169 Pubmed9154000 Pubmed9538690 Reactome Database ID Release 431839124 Reactome, http://www.reactome.org ReactomeREACT_120999 Reviewed: Ezzat, S, 2012-05-15 The FGFR1 gene has been shown to be subject to activating mutations, chromosomal rearrangements and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007; Wesche, 2011; Greulich and Pollock, 2011). <br><br><br>Activating mutation P252R in FGFR1 is associated with the development of Pfeiffer syndrome, characterized by craniosynostosis (premature fusion of several sutures in the skull) and broadened thumbs and toes (Muenke, 1994; reviewed in Cunningham, 2007). This residue falls in a highly conserved Pro-Ser dipeptide between the second and third Ig domains of the extracellular region of the receptor. The mutation is thought to increase the number of hydrogen bonds formed with the ligand and to thereby increase ligand-binding affinity (Ibrahimi, 2004a). Unlike other FGF receptors, few activating point mutations in the FGFR1 coding sequence have been identified in cancer. Point mutations in the Ig II-III linker analagous to the P252R Pfeiffer syndrome mutation have been identified in lung cancer and melanoma (Ruhe, 2007; Davies, 2005), and two kinase-domain mutations in FGFR1 have been identified in glioblastoma (Rand, 2005, Network TCGA, 2008).<br><br>In contrast, FGFR1 is a target of chromosomal rearrangements in a number of cancers. FGFR1 has been shown to be recurrently translocated in the 8p11 myeloproliferative syndrome (EMS), a pre-leukemic condition also known as stem cell leukemia/lymphoma (SCLL) that rapidly progresses to leukemia. This translocation fuses the kinase domain of FGFR1 with the dimerization domain of one of 10 identified fusion partners, resulting in the constitutive dimerization and activation of the kinase (reviewed in Jackson, 2010). <br><br>Amplification of the FGFR1 gene has been implicated as a oncogenic factor in a range of cancers, including breast, ovarian, bladder, lung, oral squamous carcinomas, and rhabdomyosarcoma (reviewed in Turner and Grose, 2010; Wesche, 2011; Greulich and Pollock, 2011), although there are other candidate genes in the amplified region and the definitive role of FGFR1 has not been fully established.<br> Signaling by activated point mutants of FGFR1 Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10053006 Pubmed11055896 Pubmed16140923 Pubmed16186508 Pubmed17552943 Pubmed18056464 Pubmed18772890 Pubmed20094046 Pubmed21711248 Pubmed7670477 Pubmed7773297 Pubmed7874169 Pubmed9154000 Pubmed9538690 Reactome Database ID Release 431839122 Reactome, http://www.reactome.org ReactomeREACT_121153 Reviewed: Ezzat, S, 2012-05-15 Unlike other FGFR2 and 3, FGFR1 appears not to be a frequent target of activating point mutations (reviewed in Wesche, 2011; Turner and Grose, 2010). Germline point mutations at residue P252 have been identified in Pfeiffer syndrome (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007) while mutation of the same residue arising somatically has been identified in melanoma and lung cancer (Ruhe, 2007; Davies, 2005). Two kinase domain mutations have been characterized in glioblastoma (Rand, 2005; Network TCGA, 2008), both at positions that are also mutated in an autosomal disorder in one of the FGFR family members (Muenke, 1994; Bellus, 1995a; Bellus, 2000; Tavormina, 1995a; Tavormina, 1999). Signaling by FGFR1 fusion mutants 8p11 myeloproliferative syndrome (EMS) is an aggressive disorder that is associated with a translocation event at the FGFR1 gene on chromosome 8p11. Typical symptoms upon diagnosis include eosinophilia and associated T-cell lymphoblastic lymphoma; the disease rapidly advances to acute leukemia, usually of myeloid lineage. At present the only effective treatment is allogenic stem cell transplantation (reviewed in Jackson, 2010). <br><br>At the molecular level, EMS appears to be caused by translocation events on chromosome 8 that create gene fusions between the intracellular domain of FGFR1 and an N-terminal partner gene that encodes a dimerization domain. The resulting fusion protein dimerizes in a ligand-independent fashion based the N-terminal domain provided by the partner protein and stimulates constititutive downstream FGFR1 signaling without altering the intrisic kinase activity of the receptor. To date, 11 partner genes have been identified: ZMYM2, FGFR1OP, FGFR1OP2, HERVK, TRIM24, CUX1, BCR, CEP110, LRRFIP1, MYO18A and CPSF6, although not all have been functionally characterized (reviewed in Jackson, 2010, Turner and Grose, 2010; Wesche, 2011). <br>Where examined, cell lines carrying FGFR1 fusion genes have been shown to be transforming and to support IL3-independent proliferation through anti-apoptotic, prosurvival pathways(Lelièvre, 2008; Ollendorff, 1999; Chase, 2007; Guasch, 2001; Wasag 2011; Roumiantsev, 2004; Demiroglu, 2001; Smedley, 1999). Signaling appears to occur predominantly through PLCgamma, PI3K and STAT signaling, with a more minor contribution from MAPK activation. Because the fusion proteins lack the FRS2-binding site, the mechanism of MAPK activation is unclear. Recruitment of GRB2:SOS1 through recruitment of SHC is one possibility (Guasch, 2001). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10480903 Pubmed10935490 Pubmed11689702 Pubmed11739186 Pubmed15050920 Pubmed17698633 Pubmed18412956 Pubmed20094046 Pubmed20226962 Pubmed21330321 Pubmed21367659 Pubmed21711248 Reactome Database ID Release 431839117 Reactome, http://www.reactome.org ReactomeREACT_121141 Reviewed: Ezzat, S, 2012-05-15 Negative regulation of FGFR signaling Authored: Rothfels, K, 2011-08-15 Once activated, the FGFR signaling pathway is regulated by numerous negative feedback mechanisms. These include downregulation of receptors through CBL-mediated ubiquitination and endocytosis, ERK-mediated inhibition of FRS2-tyrosine phosphorylation and the attenuation of ERK signaling through the action of dual-specificity phosphatases, IL17RD/SEF, Sprouty and Spred proteins. A number of these inhibitors are themselves transcriptional targets of the activated FGFR pathway. Pubmed11997436 Pubmed12815057 Pubmed18452557 Pubmed20940169 Reactome Database ID Release 431270470 Reactome, http://www.reactome.org ReactomeREACT_111184 Reviewed: Gotoh, N, 2011-08-26 PI-3K cascade Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Pubmed10918587 Pubmed11057895 Pubmed12089343 Pubmed12558974 Pubmed15863030 Reactome Database ID Release 43190926 Reactome, http://www.reactome.org ReactomeREACT_21270 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals. Signaling by FGFR mutants A number of skeletal and developmental diseases have been shown to arise as a result of mutations in the FGFR1, 2 and 3 genes. These include dwarfism syndromes (achondroplasia, hypochondroplasia and the neonatal lethal disorders thanatophoric dysplasia I and II), as well as craniosynostosis disorders such as Pfeiffer, Apert, Crouzon, Jackson-Weiss and Muenke syndromes (reviewed in Webster and Donoghue 1997; Burke, 1998, Cunningham, 2009; Harada, 2009). These mutations fall into four general regions of the receptor: a) the immunoglobulin (Ig)-like domain II-III linker region, b) the alternatively spliced second half of the Ig III domain, c) the transmembrane domain and d) the tyrosine kinase domain (reviewed in Webster and Donoghue, 1997). With the exception of mutations in class b), which affect only the relevant splice variant, these mutations may be present in either the 'b' or 'c' isoforms. These activating mutations affect FGFR function by altering or expanding the ligand-binding range of the receptors (see for instance Ibrahimi, 2004a), by promoting ligand-independent dimerization (for instance, Galvin,1996; Neilson and Friesel, 1996; d'Avis,1998) or by increasing the activity of the kinase domain (for instance, Webster, 1996; Naski, 1996; Tavormina, 1999; Bellus, 2000). Thus, a number of the point mutations found in FGFR receptors alter their activity without altering their intrinsic kinase activity. Many of the mutations that promote constitutive dimerization do so by creating or removing cysteine residues; the presence of an unpaired cysteine in the receptor is believed to promote dimerization through the formation of intramolecular disulphide bonds (Galvin, 1996; Robertson, 1998). Paralogous mutations at equivalent positions have been identified in more than one FGF receptor, sometimes giving rise to different diseases. For instance, mutation of the highly conserved FGFR2 Ser252-Pro253 dipeptide in the region between the second and third Ig domain is responsible for virtually all cases of Apert Syndrome (Wilkie, 1995), while paralogous mutations in FGFR1 (S252R) and FGFR3 (P250R) are associated with Pfeiffer and Crouzon syndromes, respectively (Bellus, 1996). FGFR4 is unique in that mutations of this gene are not known to be associated with any developmental disorders.<br><br>Recently, many of the same activating mutations in the FGFR genes that have been characterized in skeletal and developmental disorders have begun to be identified in a range of cancers (reviewed in Turner and Gross, 2010; Greulich and Pollock, 2011; Wesche, 2011). The best established link between a somatic mutation of an FGFR and the development of cancer is in the case of FGFR3, where 50% of bladder cancers have mutations in the FGFR3 coding sequence. Of these mutations, which largely match the activating mutations seen in thanatophoric dysplasias, over half occur at a single residue (S249C) (Cappellen, 1999; van Rhijn, 2002). Activating mutations have also been identified in the coding sequences of FGFR1, 2 and 4 (for review, see Wesche, 2011)<br><br>In addition to activating point mutations, the FGFR1, 2 and 3 genes are subject to misregulation in cancer through gene amplification and translocation events, which are thought to lead to overexpression and ligand-independent dimerization (Weiss, 2010; Turner, 2010; Kunii, 2008; Takeda, 2007; Chesi, 1997; Avet-Loiseau, 1998; Ronchetti, 2001). It is important to note, however, that in each of these cases, the amplification or translocation involve large genomic regions encompassing additional genes, and the definitive roles of the FGFR genes in promoting oncogenesis has not been totally established. In the case of FGFR1, translocation events also give rise to FGFR1 fusion proteins that contain the intracellular kinase domain of the receptor fused to a dimerization domain from the partner gene. These fusions, which are expressed in a pre-leukemic myeloproliferative syndrome, dimerize constitutively based on the dimerization domain provided by the fusion partner and are constitutively active (reviewed in Jackson, 2010).<br><br> Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10053006 Pubmed10471491 Pubmed11055896 Pubmed11429702 Pubmed12461689 Pubmed14613973 Pubmed17505008 Pubmed17552943 Pubmed18381441 Pubmed19066716 Pubmed20094046 Pubmed20179196 Pubmed20226962 Pubmed21160078 Pubmed21367659 Pubmed21711248 Pubmed7719344 Pubmed8640234 Pubmed8754806 Pubmed8755573 Pubmed8798788 Pubmed8841188 Pubmed9154000 Pubmed9207791 Pubmed9438390 Pubmed9538690 Pubmed9539778 Pubmed9865713 Reactome Database ID Release 431839131 Reactome, http://www.reactome.org ReactomeREACT_121398 Reviewed: Ezzat, S, 2012-05-15 TAGAP Converted from EntitySet in Reactome Reactome DB_ID: 200587 Reactome Database ID Release 43200587 Reactome, http://www.reactome.org ReactomeREACT_11474 Spry regulation of FGF signaling Authored: Rothfels, K, 2011-08-15 Pubmed16893902 Pubmed19570949 Pubmed19690147 Pubmed9458049 Reactome Database ID Release 431295596 Reactome, http://www.reactome.org ReactomeREACT_111080 Reviewed: Gotoh, N, 2011-08-26 Sprouty was initially characterized as a negative regulator of FGFR signaling in Drosophila. Human cells contain four genes encoding Sprouty proteins, of which Spry2 is the best studied and most widely expressed. Spry proteins modulate the duration and extent of signaling through the MAPK cascade after FGF stimulation, although the mechanism appears to depend on the particular biological context. Some studies have suggested that Sprouty binds to GRB2 and interferes with the recruitment of GRB2-SOS1 to the receptor, while others have shown that Sprouty interferes with the MAPK cascade at the level of RAF activation. In addition to modulating the MAPK pathway in response to FGF stimulation, Sprouty itself appears to be subject to complex post-translational modification that regulates its activity and stability. SHC-mediated cascade Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Pubmed15863030 Pubmed18840094 Pubmed7559490 Pubmed8264585 Pubmed9045692 Pubmed9480847 Reactome Database ID Release 43190346 Reactome, http://www.reactome.org ReactomeREACT_21374 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 The exact role of SHC1 in FGFR signaling remains unclear. Numerous studies have shown that the p46 and p52 isoforms of SHC1 are phosphorylated in response to FGF stimulation, but direct interaction with the receptor has not been demonstrated. Co-precipitation of p46 and p52 with the FGFR2 IIIc receptor has been reported, but this interaction is thought to be indirect, possibly mediated by SRC. Consistent with this, co-precipitation of SHC1 and FGFR1 IIIc is seen in mammalian cells expressing v-SRC. The p66 isoform of SHC1 has also been co-precipitated with FGFR3, but this occurs independently of receptor stimulation, and the p66 isoform not been shown to undergo FGF-dependent phosphorylation. SHC1 has been shown to associate with GRB2 and SOS1 in response to FGF stimulation, suggesting that the recruitment of SHC1 may contribute to activation of the MAPK cascade downstream of FGFR. p190 Converted from EntitySet in Reactome Reactome DB_ID: 195116 Reactome Database ID Release 43195116 Reactome, http://www.reactome.org ReactomeREACT_10940 OCRL-1 Converted from EntitySet in Reactome Reactome DB_ID: 195216 Reactome Database ID Release 43195216 Reactome, http://www.reactome.org ReactomeREACT_10233 GlcA-Gal-Gal-Xyl-HS proteins Converted from EntitySet in Reactome Reactome DB_ID: 2076551 Reactome Database ID Release 432076551 Reactome, http://www.reactome.org ReactomeREACT_124611 Heparan-PGs Converted from EntitySet in Reactome Reactome DB_ID: 2076465 Reactome Database ID Release 432076465 Reactome, http://www.reactome.org ReactomeREACT_124579 ArhGAP6 Converted from EntitySet in Reactome Reactome DB_ID: 195211 Reactome Database ID Release 43195211 Reactome, http://www.reactome.org ReactomeREACT_10321 FilGAP/p73RhoGAP Converted from EntitySet in Reactome Reactome DB_ID: 195177 Reactome Database ID Release 43195177 Reactome, http://www.reactome.org ReactomeREACT_10227 Catecholamine biosynthesis Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-05-28 09:06:10 GENE ONTOLOGYGO:0042423 Pubmed10691773 Pubmed1684650 Pubmed363400 Reactome Database ID Release 43209905 Reactome, http://www.reactome.org ReactomeREACT_15551 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The catecholamine neurotransmitters dopamine, noradrenaline and adrenaline are found in nervous tissue of animals. They are synthesized in catecholaminergic neurons by four enzymes from tyrosine to adrenaline: tyrosine hydroxylase (TH); aromatic L-amino acid decarboxylase (AADC); dopamine beta-hydroxylase (DBH); and phenylethanolamine N-methyltransferase (PNMT). Peptide hormone biosynthesis Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-11-17 10:09:58 GENE ONTOLOGYGO:0016486 Peptide hormones are peptides that are secreted directly into the blood stream (endocrine hormones). They are synthesized as precursors that require proteolytic processing (not discussed here) to generate the biologically active peptides that mediate neurotransmission and hormonal action. Glycoprotein hormones (those which include carbohydrate side-chains) and the processing of corticotropin are annotated here. Pubmed4368999 Reactome Database ID Release 43209952 Reactome, http://www.reactome.org ReactomeREACT_15452 Reviewed: D'Eustachio, P, 2008-11-29 15:53:45 Serotonin and melatonin biosynthesis Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-05-28 09:06:10 GENE ONTOLOGYGO:0046219 Pubmed16942634 Pubmed18155917 Reactome Database ID Release 43209931 Reactome, http://www.reactome.org ReactomeREACT_15439 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Serotonin (5-HT) is a hormone and neurotransmitter used for regulatory purposes in animal CNS. In the human brain, serotonin is involved in many physiological functions such as sleep, pain, mood and is the precursor to melatonin, a hormone produced in the pineal gland. Regulation of thyroid hormone activity Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed17016550 Reactome Database ID Release 43350864 Reactome, http://www.reactome.org ReactomeREACT_15297 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The iodothyronine deiodinases (DIO) are dimeric, membrane-bound enzymes that regulate the activity of thyroid hormone by removal of specific iodines from the precursor T4. There are three types of DIOs in humans; types I, II and III (D1, D2 and D3 respectively) which are proteins of about 250 residues that contain a selenocysteine at their active site. Signaling by thyroid hormone can change in individual tissues by this activation or inactivation process, even when serum concentrations of the hormone remain normal. Generally, cell types express just one type of DIO at any one time. The exception is the pituitary gland which expresses all three. Thyroxine biosynthesis Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-05-28 09:06:10 GENE ONTOLOGYGO:0006590 Pubmed3297964 Reactome Database ID Release 43209968 Reactome, http://www.reactome.org ReactomeREACT_15292 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Thyroxine (3,5,3',5'-tetraiodothyronine, T4) promotes normal growth and development. It also regulates heat and energy production. T4 is released from the thyroid gland, the largest endocrine organ in the human body. The primary hormone released is T4 although T3 (3,5,3'-triiodothyronine) is also released in small quantities. Tyrosine residues in thyroglobulin (a glycoprotein scaffold containing many tyrosine residues) are iodinated to form mono- or diiodo-tyrosine which can then couple to form either T3 or T4. Cysteine formation from homocysteine Authored: Stephan, R, 2010-10-24 Edited: Jassal, B, 2011-09-29 GENE ONTOLOGYGO:0019346 Pubmed15497768 Pubmed20817827 Reactome Database ID Release 431614603 Reactome, http://www.reactome.org ReactomeREACT_115589 Reviewed: D'Eustachio, P, 2011-10-13 Transsulfuration is the interconversion of homocysteine and cysteine, and it fully takes place in bacteria and some plants and fungi. Animals however have only one direction of this bidirectional path, the synthesis of cysteine from homocysteine via cystathionine. Because excess cysteine is degraded to hydrogen sulfide, which is now known as a neuromodulator and smooth muscle relaxant, this pathway is also the main source of its production, which takes place in the cytosol, as well as in extracellular space (Dominy & Stipanuk 2004, Bearden et al. 2010). Sulfur amino acid metabolism Authored: Stephan, R, 2010-10-24 Edited: Jassal, B, 2011-09-29 GENE ONTOLOGYGO:0000096 Pubmed16702333 Reactome Database ID Release 431614635 Reactome, http://www.reactome.org ReactomeREACT_115639 Reviewed: D'Eustachio, P, 2011-10-13 The main sulfur amino acids are methionine, cysteine, homocysteine and taurine. Of these, the first two are proteinogenic.<br><br>This group of reactions contains all processes that 1) break down sulfur amino acids, 2) interconvert between them, and 3) synthesize them from solved sulfide which comes from sulfate assimilation and reduction. Only plants and microorganisms employ all processes. Humans cannot de novo synthesize any sulfur amino acid, nor convert cysteine to methionine (Brosnan & Brosnan, 2006). Glyoxylate metabolism Authored: D'Eustachio, P, 2009-01-11 19:48:01 Edited: D'Eustachio, P, 2009-03-03 14:28:53 GENE ONTOLOGYGO:0046487 Glyoxylate is generated in the course of glycine and hydroxyproline catabolism and can be converted to oxalate. In humans, this process takes place in the liver. Defects in two enzymes of glyoxylate metabolism, alanine:glyoxylate aminotransferase (AGXT) and glycerate dehydrogenase/glyoxylate reductase (GRHPR), are associated with pathogenic overproduction of oxalate (Danpure 2005). The reactions that interconvert glycine, glycolate, and glyoxylate and convert glyoxylate to oxalate have been characterized in molecular detail in humans. A reaction sequence for the conversion of hydroxyproline to glyoxylate has been inferred from studies of partially purified extracts of rat and bovine liver but the enzymes involved in the corresponding human reactions have not been identified. Pubmed15956068 Reactome Database ID Release 43389661 Reactome, http://www.reactome.org ReactomeREACT_16925 Reviewed: Jassal, B, 2009-03-03 14:29:24 Glycoprotein hormones Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-11-17 10:09:58 More complex protein hormones have carbohydrate side chains and are called glycoprotein hormones. Hormones in this class are Follicle-stimulating hormone (FSH; follitropin), Luteinizing hormone (LH), Thyroid-stimulating hormone (TSH; thyrotropin) and human chorionic gonadotropin (hCG). The alpha subunit of glycoprotein hormones is a 92 aa peptide and serves as the alpha subunit for FSH, LH, hCG and TSH (Fiddes JC and Goodman HM, 1981). The beta subunits for these hormones are unique and confer biological specificity to them. These two subunits combine via disulphide bonding to produce the mature glycoprotein hormone dimer. Pubmed6267989 Pubmed6286817 Reactome Database ID Release 43209822 Reactome, http://www.reactome.org ReactomeREACT_15398 Reviewed: D'Eustachio, P, 2008-11-29 15:53:45 Degradation of cysteine and homocysteine Authored: Stephan, R, 2010-10-24 Edited: Jassal, B, 2011-09-29 GENE ONTOLOGYGO:0000098 Pubmed20162368 Reactome Database ID Release 431614558 Reactome, http://www.reactome.org ReactomeREACT_115654 Reviewed: D'Eustachio, P, 2011-10-13 While in humans excess methionine is converted to homocysteine, homocysteine and its transsulfuration product cysteine can be degraded to several end products, two of which, taurine and hydrogen sulfide, have uses in other biological processes (Stipanuk & Ueki 2011). Heme degradation GENE ONTOLOGYGO:0042167 Most of the heme degraded in humans comes from hemoglobin. Approximately 6-8 grams of hemoglobin is degraded daily which is equivalent to approximately 300 milligrams of heme per day. Heme is not recycled so it must be degraded and excreted. The iron, however, is conserved. There are two steps to heme degradation;<br>1. cleavage of the heme ring by a microsomal heme oxygenase producing biliverdin<br>2. biliverdin is reduced to bilirubin.<br>Bilirubin can then be conjugated with glucuronic acid and excreted. Pubmed12909459 Reactome Database ID Release 43189483 Reactome, http://www.reactome.org ReactomeREACT_22297 Reviewed: Sassa, S, 2007-01-24 10:18:36 Heme biosynthesis Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Eight enzymes are involved in heme biosynthesis, four each in the mitochondria and the cytosol. The process starts in the mitochondria with the condensation of succinyl CoA (from the TCA cycle) and glycine to form 5-aminolevulinate (ALA). The next four steps take place in the cytosol. Two molecules of ALA are condensed to form the monopyrrole porphobilinogen (PBG). The next two steps convert four molecules of PBG into the cyclic tetrapyrrole uroporphyringen III, which is then decarboxylated into coproporphyrinogen III. The last three steps occur in the mitochondria and involve modifications to the tetrapyrrole side chains and finally, insertion of iron. In addition to these synthetic steps, a spontaneous cytosolic reaction allows the formation of uroporphyringen I which is then enzymatically decarboxylated to coproporphyrinogen I, which cannot be metabolized further in humans. Also, lead can inactivate ALAD, the enzyme that catalyzes PBG synthesis, and ferrochelatase, the enzyme that catalyzes heme synthesis.<br>The porphyrias are disorders that arise from defects in the enzymes of heme biosynthesis. Defective pathway enzymes after ALA synthase result in accumulated substrates which can cause either skin problems, neurological complications, or both due to their toxicity in higher concentrations. They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction of the substrate. Each defect is described together with the reaction it affects. GENE ONTOLOGYGO:0006783 Pubmed10522552 Pubmed16839620 Reactome Database ID Release 43189451 Reactome, http://www.reactome.org ReactomeREACT_9465 Reviewed: Sassa, S, 2007-01-24 10:18:36 Phase 1 - Functionalization of compounds Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006805 Phase 1 of metabolism is concerned with <i><b>functionalization</b></i>, that is the introduction or exposure of functional groups on the chemical structure of a compound. This provides a 'handle' for phase 2 conjugating species with which to react with. Many xenobiotics are lipophilic and almost chemically inert (e.g. PAHs) so would not necessarily undergo a phase 2 reaction. Making them more chemically reactive would facilitate their excretion but also increases their chance of reacting with cellular macromolecules (e.g. proteins, DNA). There is a fine balance between producing a more reactive metabolite and conjugation reactions.<br>There are two groups of enzymes in phase 1 - oxidoreductases and hydrolases. Oxidoreductases introduce an oxygen atom into or remove electrons from their substrates. The major oxidoreductase enzyme system is called the P450 monooxygenases. Other systems include flavin-containing monooxygenases (FMO), cyclooxygenases (COX) and monoamine oxidases (MAO). Hydrolases hydrolyse esters, amides, epoxides and glucuronides. Pubmed12369887 Pubmed16584116 Pubmed17125408 Reactome Database ID Release 43211945 Reactome, http://www.reactome.org ReactomeREACT_13705 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Biological oxidations All organisms are constantly exposed to foreign chemicals every day. These can be man-made (drugs, industrial chemicals) or natural (alkaloids, toxins from plants and animals). Uptake is usually via ingestion but inhalation and transdermal routes are also common.</p><p>The very nature of many chemicals that make them suitable for uptake by these routes, in other words their lipophilicty (favours fat solubility) is also the main reason organisms have developed mechanisms that convert them to hydrophilic (favours water solubility) compounds which are readily excreted via bile and urine. Otherwise, lipophilic chemicals would accumulate in the body and overwhelm defense mechanisms. This process is called <b><i>biotransformation</i></b> and is catalyzed by enzymes mainly in the liver of higher organisms but a number of other organs have considerable ability to process xenobiotica such as kidneys, gut and lungs. As well as xenobiotics, many endogenous compounds are commonly eliminated by this process.</br></br>This mechanism is of ancient origin and a major factor for its development in animals is plants. Most animals are plant eaters and thus are subject to a huge variety of chemical compounds which plants produce to stop themselves being eaten. This complex set of enzymes have several features which make them ideal for biotransformation;</p><p><i>(<b>1</b>) metabolites of the parent chemical are usually made more water soluble so it favours rapid excretion via bile and urine</p><p>(<b>2</b>) the enzymes possess broad and overlapping specificity to be able to deal with newly exposed chemicals</p><p>(<b>3</b>) metabolites of the parent generally don't have adverse biological effects.</i></p><p>In the real world however, all these criteria have exceptions. Many chemicals are transformed into reactive metabolites. In pharmacology, the metabolites of some parent drugs exert the desired pharmacological effect but in the case of polycyclic aromatic hydrocarbons (PAHs), which can undergo epoxidation, it results in the formation of an electrophile which can attack proteins and DNA.</p><p>Metabolism of xenobiotica occurs in several steps called <i><b>Phase 1 (functionalization)</b></i> and <i><b>Phase 2 (conjugation)</b></i>. To improve water solubility, a functional group is added to or exposed on the chemical in one or more steps (Phase 1) to which hydrophilic conjugating species can be added (Phase 2). Functional groups can either be electrophilic (epoxides, carbonyl groups) or nucleophilic (hydroxyls, amino and sulfhydryl groups, carboxylic groups) <i>(see picture)</i>.</p><p>Once chemicals undergo functionalization, the electrophilic or nucleophilic species can be detrimental to biological systems. Electrophiles can react with electron-rich macromolecules such as proteins, DNA and RNA by covalent interaction whilst nucleophiles have the potential to interact with biological receptors. That's why conjugation is so important as it mops up these potentially reactive species.</p><p>Many chemicals, when exposed to certain metabolizing enzymes can induce those enzymes, a process called <i><b>enzyme induction</b></i>. The effect of this is that these chemicals accelerate their own biotransformation and excretion. The reverse is also true where some chemicals cause enzyme inhibition. Some other factors that alter enzyme levels are sex, age and genetic predisposition. Between species, there can be considerable differences in biotransformation ability which is a problem faced by drug researchers interpreting toxicological results to humans.</p> Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006805 Reactome Database ID Release 43211859 Reactome, http://www.reactome.org ReactomeREACT_13433 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Porphyrin metabolism GENE ONTOLOGYGO:0006778 Metabolism of porphyrins Porphyrins are heterocyclic macrocycles, consisting of four pyrrole subunits (tetrapyrrole) linked by four methine (=CH-) bridges. The extensive conjugated porphyrin macrocycle is chromatic and the name itself, <b>porphyrin</b>, is derived from the Greek word for <i>purple</i>. The aromatic character of porphyrins can be seen by NMR spectroscopy.<br>Porphyrins readily combine with metals by coordinating them in the central cavity. Iron (heme) and magnesium (chlorophyll) are two well known examples although zinc, copper, nickel and cobalt form other known metal-containing phorphyrins. A porphyrin which has no metal in the cavity is called a <i>free base</i>.<br>Some iron-containing porphyrins are called hemes (heme-containing proteins or hemoproteins) and these are found extensively in nature ie. hemoglobin. Hemoglobin is quantitatively the most important hemoprotein. The hemoglobin iron is the transfer site of oxygen and carries it in the blood all round the body for cell respiration. Other examples are cytochromes present in mitochondria and endoplasmic reticulum which takes part in electron transfer events, catalase and peroxidase whic protect the body against the oxidant hydrogen peroxide and tryptophan oxygenase which is present in intermediary metabolism. Hemoproteins are synthesized in all mammalian cells and the major sites are erythropoietic tissue and the liver.<p>The processes by which heme is synthesized, transported, and metabolized are a critical part of human iron metabolism (Severance and Hamze 2009); here the core processes of heme biosynthesis and catabolism have been annotated. Reactome Database ID Release 43189445 Reactome, http://www.reactome.org ReactomeREACT_9431 Reviewed: Sassa, S, 2007-01-24 10:18:36 Sulfide oxidation to sulfate Authored: Stephan, R, 2010-10-24 Edited: Jassal, B, 2011-09-29 GENE ONTOLOGYGO:0070221 Pubmed20162368 Reactome Database ID Release 431614517 Reactome, http://www.reactome.org ReactomeREACT_116010 Reviewed: D'Eustachio, P, 2011-10-13 While the human body is very economical with sulfur amino acids (SAA), superfluous SAA are degraded via cysteine to toxic hydrogen sulfide which must be dealt with. The pathway to oxidize this gas is localized to mitochondria and is highly conserved, pointing back to a time when life was immersed in sulfide-rich waters.<br>The pathway for sulfide oxidation consists of five reactions, one of which, the sulfur transfer from thiosulfate to glutathione, is still to be characterized fully. A mutation in one enzyme has been identified that is associated with ethylmalonyl encephalopathy and where tissue sulfide is elevated (Stipanuk & Ueki 2011). Endogenous sterols A number of CYPs take part in cholesterol biosynthesis and elimination, thus playing an important role in maintaining cholesterol homeostasis. Under normal physiological conditions, cholesterol intake (diet or synthesized de novo from acetyl CoA) equals cholesterol elimination (degraded to bile salts, secreted in bile and used in steroid hormone synthesis). These processes are under tight regulatory control and any disruption leads to increased cholesterol levels resulting in cardiovacular disease. The CYPs involved in cholesterol homeostasis could serve as potential targets for cholesterol-lowering drugs. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed15102545 Pubmed16584116 Pubmed16872679 Reactome Database ID Release 43211976 Reactome, http://www.reactome.org ReactomeREACT_13812 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Cytochrome P450 - arranged by substrate type <p>The P450 isozyme system is the major phase 1 biotransforming system in man, accounting for more than 90% of drug biotransformations. This system has huge catalytic versatility and a broad substrate specificity, acting upon xenobiotica and endogenous compounds. It is also called the mixed-function oxidase system, the P450 monooxygenases and the heme-thiolate protein system. All P450 enzymes are a group of <i><b>heme-containing isozymes</b></i> which are located on the membrane of the smooth endoplasmic reticulum. They can be found in all tissues of the human body but are most concentrated in the liver. The name "cytochrome P450" (CYP) is derived from the spectral absorbance maximum at 450nm when carbon monoxide binds to CYP in its reduced (ferrous, Fe<sup>2+</sup>) state. The basic reaction catalyzed by CYP is <i><b>mono-oxygenation</b></i>, that is the transfer of one oxygen atom from molecular oxygen to a substrate. The other oxygen atom is reduced to water during the reaction with the equivalents coming from the cofactor NADPH. The basic reaction is;</p><b><p align=center> RH (substrate) + O<sub>2</sub> + NADPH + H<sup>+</sup> = ROH (product) + H<sub>2</sub>O + NADP<sup>+</sup></p></b><p>The end results of this reaction can be (N-)hydroxylation, epoxidation, heteroatom (N-, S-) oxygenation, heteroatom (N-, S-, O-) dealkylation, ester cleavage, isomerization, dehydrogenation, replacement by oxygen or even reduction under anaerobic conditions.</p><p>The metabolites produced from these reactions can either be mere intermediates which have relatively little reactivity towards cellular sysytems and are readily conjugated, or, they can be disruptive to cellular systems. Indeed, inert compounds need to be prepared for conjugation and thus the formation of potentially reactive metabolites is in most cases unavoidable.</p><p>There are 57 human CYPs (in 18 families and 42 subfamilies), mostly concentrated in the endoplasmic reticulum of liver cells although many tissues have them to some extent (Nelson DR et al, 2004). CYPs are grouped into 14 families according to their sequence similarity. Generally, enzymes in the same family share 40% sequence similarity and 55% within a subfamily. Nomenclature of P450s is as follows. CYP (to represent cytochrome P450 superfamily), followed by an arabic number for the family, a capital letter for the subfamily and finally a second arabic number to denote the isoenzyme. An example is CYP1A1 which is the first enzyme in subfamily A of cytochrome P450 family 1.</p><p>The majority of the enzymes are present in the CYP1-4 families. CYP1-3 are primarily concerned with xenobiotic biotransformation whereas the other CYPs deal primarily with endogenous compounds. The CYP section is structured by the typical substrate they act upon. Of the 57 human CYPs, 7 encode mitochondrial enzymes, all involved in sterol biosynthesis. Of the remaining 50 microsomal enzymes, 20 act upon endogenous compounds, 15 on xenobiotics and 15 are the so-called "orphan enzymes" with no substrate identified.</p><p>The P450 catalytic cycle <i>(picture)</i> shows the steps involved when a substrate binds to the enzyme.</p><p><font color=red>(1)</font> The normal state of a P450 with the iron in its ferric [Fe<sup>3+</sup>] state.</p><p><font color=red>(2)</font> The substrate binds to the enzyme.</p><p><font color=red>(3)</font> The enzyme is reduced to the ferrous [Fe<sup>2+</sup>] state by the addition of an electron from NADPH cytochrome P450 reductase. The bound substrate facilitates this process.</p><p><font color=red>(4,5)</font> Molecular oxygen binds and forms an Fe<sup>2+</sup>OOH complex with the addition of a proton and a second donation of an electron from either NADPH cytochrome P450 reductase or cytochrome b5. A second proton cleaves the Fe<sup>2+</sup>OOH complex to form water.</p><p><font color=red>(6)</font> An unstable [FeO]<sup>3+</sup> complex donates its oxygen to the substrate <font color=red>(7)</font>. The oxidised substrate is released and the enzyme returns to its initial state <font color=red>(1)</font>.</p> Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed12369887 Pubmed15102545 Pubmed15128046 Pubmed16584116 Reactome Database ID Release 43211897 Reactome, http://www.reactome.org ReactomeREACT_13567 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Xenobiotics Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Of the 50 microsomal CYPs, 15 act on xenobiotics. They all possess wide substrate specificity to cater for most foreign compounds that find their way into the body. Pubmed12369887 Pubmed15102545 Pubmed16584116 Reactome Database ID Release 43211981 Reactome, http://www.reactome.org ReactomeREACT_13543 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Sterols are 12-hydroxylated by CYP8B1 Authored: Jassal, B, 2008-05-19 12:57:01 Cytochrome P450 8B1 (CYP8B1, sterol 12-alpha- hydroxylase) has a broad substrate specificity including a number of 7-alpha- hydroxylated C27 steroids. It is also involved in bile acid synthesis and is responsible for the balance between the formation of cholic acid and chenodeoxycholic acid. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed10051404 Reactome Database ID Release 43211994 Reactome, http://www.reactome.org ReactomeREACT_13438 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 FMO oxidizes nucleophiles Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Flavin-containing monooxygenases (FMOs) are the second family of microsomal oxidative enzymes with broad and overlapping specificity. The major reactions FMOs catalyze are nucleophilic hetero-atom compounds such as nitrogen, sulfur or phosphorus as the hetero-atom to form N-oxides, S-oxides or P-oxides respectively. Despite the functional overlap with cytochrome P450s, the mechanism of action differs. FMOs bind and activate molecular oxygen before the substrate binds to the enzyme (picture). They also require flavin adenosine dinucleotide (FAD) as a cofactor. Unlike cytochrome P450 enzymes, FMOs are heat-labile, a useful way to distinguish which enzyme system is at work for researchers studying metabolism. Also, FMOs are not inducible by substrates, unlike the P450 enzymes.\n<font color=red>(1)</font> NADPH binds to the enzyme and reduces the prosthetic group FAD to FADH<sub>2</sub>. NADP<sup>+</sup> remains bound to the enzyme.\n<font color=red>(2)</font> Incorporation of molecular oxygen to form a hydroperoxide.\n<font color=red>(3)</font> A peroxide oxygen is transferred to the substrate.\n<font color=red>(4)</font> Water is released.\n<font color=red>(5)</font> NADP<sup>+</sup> dissociates returning the enzyme to its initial state.\n\nTo date, there are 6 isozymes of FMO (FMO1-6) in humans, the most prominent and active one being FMO3. The FMO6 gene does not encode for a functional enzyme although it has the greatest sequence similarity with FMO3 (71%), whilst the others range from 50-58% sequence similarity with FMO3. FMO1-3 are the ones that exhibit activity towards nucleophiles, the others are insignificant in this respect. Pubmed12951812 Pubmed15922018 Reactome Database ID Release 43217271 Reactome, http://www.reactome.org ReactomeREACT_13653 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Miscellaneous substrates Approximately a quarter of the 57 human CYPs still remain "orphans" in the sense that their function, expression sites, and regulation are largely not elucidated. While there is enough experimental evidence to know that all these proteins get made and can catalyze CYP-like reactions in vitro, evidence of in vivo function and substrate specificity is insufficient to allow them to be placed in any of the classes in the functional scheme. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed15102545 Pubmed16126164 Pubmed17786643 Reactome Database ID Release 43211958 Reactome, http://www.reactome.org ReactomeREACT_13425 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Vitamins A number of CYPs can act upon vitamins. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006766 Pubmed15102545 Pubmed16584116 Reactome Database ID Release 43211916 Reactome, http://www.reactome.org ReactomeREACT_13450 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Eicosanoids Arachidonic acid is metabolized via three major enzymatic pathways: cyclooxygenase, lipoxygenase, and cytochrome P450. The cytochrome P450 pathway metabolites are oxygenated metabolites of arachidonic acid. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006690 Pubmed15102545 Pubmed16584116 Pubmed7922394 Reactome Database ID Release 43211979 Reactome, http://www.reactome.org ReactomeREACT_13645 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Fatty acids Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed16824612 Pubmed17164129 Reactome Database ID Release 43211935 Reactome, http://www.reactome.org ReactomeREACT_13814 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The CYP4 family are the main CYPs involved in the metabolism of long-chain fatty acids. CYP2E1 reactions Authored: Jassal, B, 2008-05-19 12:57:01 CYP2E1 can metabolize and activate a large number of solvents and industrial monomers as well as drugs. This quality of CYP2E1 may make it an important determinant of human susceptibility to the toxic effects of industrial and environmental chemicals. Typical CYP2E1 substrates include acetaminophen, benzene, CCl4, halothane, ethanol and vinyl chloride. CYP2E1 contributes to oxidative stress by producing oxidising species called reactive oxygen species (ROS) which can lead to damage to mitochondria, DNA and initiate lipid peroxidation or even cell death. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed10397283 Pubmed14744237 Pubmed15603755 Reactome Database ID Release 43211999 Reactome, http://www.reactome.org ReactomeREACT_13797 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Aromatic amines can be N-hydroxylated or N-dealkylated by CYP1A2 Authored: Jassal, B, 2008-05-19 12:57:01 CYP1A2 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. It is most active in catalyzing N-hydroxylation or N-dealkylation reactions. Edited: Jassal, B, 2008-05-19 12:57:01 Reactome Database ID Release 43211957 Reactome, http://www.reactome.org ReactomeREACT_13721 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Monoamines are oxidized to aldehydes by MAOA and MAOB, producing NH3 and H2O2 Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Human monoamine oxidases (MAOs) are flavin-containing enzymes that are present on the outer mitochondrial membrane and act on primary, secondary and tertiary amines. In contrast to the P450s which have a large number of isozymes, MAOs number only two isozymes, MAO-A and MAO-B. These gene products share over 70% sequence identity, are approximately 59KDa in size and have overlapping substrates (for example dopamine, tryamine and tryptamine) but each form also has distinct substrate specificities. MAO-A (primary type in fibroblasts) preferentially oxidises serotonin (5-Hydroxytryptamine) whereas MAO-B (primary type in platelets) prefers phenylethylamine. MAOs are of particular clinical interest because of the use of MAO inhibitors (MAOI) as antidepressants or in the treatment of neurodegenerative diseases. Pubmed11468017 Pubmed9443166 Reactome Database ID Release 43141333 Reactome, http://www.reactome.org ReactomeREACT_416 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Amine Oxidase reactions Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Human amine oxidases (AO) catalyze the oxidative deamination of biogenic amines (neurotransmitters such as serotonin, noradrenaline, the hormone adrenaline and polyamines such as the spermines) and xenobiotic amines (exogenous dietary tyramine and phenylethylamine). The basic reaction is the oxidative cleavage of the alpha-H to form an imine product with the concomitant reduction of a FAD cofactor. The imine product then hydrolyses to an aldehyde and ammonia (or amine for secondary and tertiary amine substrates). Reduced FAD is reoxidized to form hydrogen peroxide to complete the catalytic cycle.<p>The reaction can be summarized as</p><p><b>RCH2NH2 + H2O + O2 = RCHO + NH3 + H2O2</b></p><p>The resultant hydrogen peroxide is the source of the most toxic free radical, the hydroxyl radical (.OH). This free radical is produced in the Fenton reaction with the use of ferrous (Fe2+) iron.</p> Pubmed11468017 Pubmed6206782 Pubmed9443166 Reactome Database ID Release 43140179 Reactome, http://www.reactome.org ReactomeREACT_1875 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 COX reactions Arachidonic acid (AA) is a 20 carbon unsaturated fatty acid which is present in the lipid bilayer of all mammalian cells. AA is released from the membrane by phospholipases, thus making it available for conversion to bioactive lipids. The cyclooxygenase pathway is one of three pathways (the others being lipoxygenase and P450 monooxygenase pathways) that perform this conversion.\n\nThe enzyme that acts in the cyclooxygenase pathway is called cyclooxygenase (COX) or prostaglandin H synthase (PGHS). PGHS exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase catalyzes the initial conversion of AA to an intermediate, prostaglandin G2 (PGG2) whilst the peroxidase converts PGG2 to prostaglandin H2 (PGH2) via a two-electron reduction. PGH2 is the intermediate for products that play critical roles in immune function regulation, kidney development and mucosal integrity of the GI tract.\n\nPGHS exists in two isoforms, 1 and 2 and both forms can perform the above reactions. Form 1 is constitutively expressed in most tissues and is involved in performing normal physiological functions. Form 2, in contrast, is inducible and is involved in critical steps of rheumatic disease, inflammation and tumorigenesis. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed10966456 Reactome Database ID Release 43140180 Reactome, http://www.reactome.org ReactomeREACT_1396 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Methylation Authored: Jassal, B, 2005-02-03 14:13:47 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0032259 Methylation is a common but minor pathway of Phase II conjugation compared to glucuronidation or sulfonation. The cofactor used in methylation conjugation is S-adenosylmethionine (SAM). SAM is the second most widely used enzyme substrate after ATP and is involved in a wide range of important biological processes. SAM is sythesized from methionine's reaction with ATP, catalyzed by methionine adenosyltransferase (MAT). There are two genes, MAT1A and MAT2A, which encode for two homologous MAT catalytic subunits, 1 and 2.<br>During conjugation with nucleophilic substrates, the methyl group attached to the sulfonium ion of SAM is transferred to the substrate forming the conjugate. SAM, having lost the methyl moiety, is converted to S-adenosylhomocysteine (SAH). SAH can be hydrolyzed to form adenosine and homocysteine. Homocysteine can either be converted to glutathione or methylated to form methionine, thus forming the starting point for SAM synthesis and completing the cycle.<br>Fuctional groups attacked are phenols, catechols, aliphatic and aromatic amines and sulfhydryl-containing groups. The enzymes that catalyze the transfer of the methyl group to these functional groups are the methyltransferases (MT). MTs are small, cytosolic, monomeric enzymes that utilize SAM as a methyl donor. There are many MTs but the best studied ones are named on the basis of their prototypical substrates: <i><b>COMT</b> (catechol O-methyltransferase)</i>, <i><b>TPMT</b> (thiopurine methyltransferase)</i>, <i><b>TMT</b> (thiol methyltransferase)</i>, <i><b>HNMT</b> (histamine N-methyltransferase)</i> and <i><b>NNMT</b> (nicotinamide N-methyltransferase)</i>. An example of each enzyme mentioned is given. In each case, a typical substrate for the enzyme is shown. Pubmed10331075 Pubmed10898761 Pubmed15130560 Reactome Database ID Release 43156581 Reactome, http://www.reactome.org ReactomeREACT_6946 Glutathione conjugation Authored: Jassal, B, 2004-11-30 11:49:48 Edited: Jassal, B, 2008-05-19 12:57:01 Glutathione S-Transferases (GSTs; EC 2.5.1.18) are another major set of phase II conjugation enzymes. They can be found in the cytosol as well as being microsomal membrane-bound. Cytosolic GSTs are encoded by at least 5 gene families (alpha, mu, pi, theta and zeta GST) whereas membrane-bound enzymes are encoded by single genes. Soluble GSTs are homo- or hetero-dimeric enzymes (approximately 25KDa subunits) which can act on a wide range of endogenous and exogenous electrophiles. GSTs mediate conjugation using glutathione (GSH), a tripeptide synthesized from its precursor amino acids gamma-glutamate, cysteine and glycine. A generalized reaction is<p><b>RX + GSH -> HX + GSR</b></p>Glutathione conjugates are excreted in bile and converted to cysteine and mercapturic acid conjugates in the intestine and kidneys. GSH is the major, low molecular weight, non-protein thiol synthesized <i>de novo</i> in mammalian cells. As well as taking part in conjugation reactions, GSH also has antioxidant ability and can metabolize endogenous and exogenous compounds. The nucleophilic GSH attacks the electrophilic substrate forming a thioether bond between the cysteine residue of GSH and the electrophile. The result is generally a less reactive and more water-soluble conjugate that can be easily excreted. In some cases, GSTs can activate compounds to reactive species such as certain haloalkanes and haloalkenes. Substrates for GSTs include epoxides, alkenes and compounds with electrophilic carbon, sulfur or nitrogen centres. There are two types of conjugation reaction with glutathione: <i>displacement reactions</i> where glutathione displaces an electron-withdrawing group and <i>addition reactions</i> where glutathione is added to activated double bond structures or strained ring systems. Reactome Database ID Release 43156590 Reactome, http://www.reactome.org ReactomeREACT_6926 Reviewed: D'Eustachio, P, 2011-05-23 ACTIVATION GENE ONTOLOGYGO:0051800 Reactome Database ID Release 431806248 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052811 Reactome Database ID Release 431806274 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035005 Reactome Database ID Release 431806197 Reactome, http://www.reactome.org Polyamines are oxidized to amines, aldehydes and H2O2 by PAOs Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Polyamine oxidases (PAOs), like MAOs, are also FAD-dependant and form aldehydes and hydrogen peroxide. PAOs are approximately 60KDa in size, are monomers and are located in peroxisomes. They act on endogenous polyamines as well as some xenobiotics. The polyamines of the spermine and spermidine families are important physiologically as they mediate cell function and growth and also play a role in programmed cell death. The balance between biosynthesis, degradation and uptake of these polyamines is strictly controlled in cells and the PAO system is one of a set of enzymes that maintains this regulation. Pubmed11468017 Pubmed6206782 Reactome Database ID Release 43141334 Reactome, http://www.reactome.org ReactomeREACT_505 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 ACTIVATION GENE ONTOLOGYGO:0052810 Reactome Database ID Release 431806279 Reactome, http://www.reactome.org Ethanol oxidation Alcohol catabolism Authored: Jassal, B, 2008-05-19 12:57:01 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Ethanol and related alcohols can be ingested as part of the diet and are formed by microorganisms in the intestinal tract. Ethanol oxidation to acetate occurs primarily in liver cells in a multistep process first described by Racker (1949). First, in the cytosol, ethanol is oxidized to acetaldehyde, with the formation of NADH. Second, in the mitochondrion, acetaldehyde is oxidized to acetate with the formation of NADH. Finally, acetate in the mitochondrion can be condensed with coenzyme A to form acetyl CoA. Polymorphisms in the enzymes catalyzing the first two steps are associated with variation in the efficiency of alcohol catabolism in human populations (Chen et al. 1999; Lange et al. 1976; Jornvall 1985). The molecular mechanism by which cytosolic acetaldehyde enters the mitochondrial matrix is not known (Lemasters 2007).<p>Cytosolic enzymes capable of oxidizing acetaldehyde to acetate have also been identified and characterized in vitro (Inoue et al. 1979) so a purely cytosolic pathway for ethanol oxidation to acetate and conversion to acetyl-CoA can be annotated. The role of this pathway in vivo is unclear, though limited attempts to correlate deficiencies in the cytosolic enzyme with alcohol intolerance have yielded suggestive data (Yoshida et al. 1989). Additional peroxisomal and microsomal pathways for the oxidation of ethanol to acetaldehyde have been described; their physiological significance is unclear and they are not annotated here. GENE ONTOLOGYGO:0006069 Pubmed10441588 Pubmed17567461 Pubmed18110463 Pubmed224930 Pubmed2729894 Pubmed3893466 Pubmed9982 Reactome Database ID Release 4371384 Reactome, http://www.reactome.org ReactomeREACT_34 ACTIVATION GENE ONTOLOGYGO:0000285 Reactome Database ID Release 431806190 Reactome, http://www.reactome.org Phase II conjugation Authored: Jassal, B, 2004-11-29 11:42:34 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006805 Phase II of biotransformation is concerned with <b><i>conjugation</i></b>, that is using groups from cofactors to react with functional groups present or introduced from phase I on the compound. The enzymes involved are a set of transferases which perform the transfer of the cofactor group to the substrate. The resultant conjugation results in greatly increasing the excretory potential of compounds. Although most conjugations result in pharmacological inactivation or detoxification, some can result in bioactivation. Most of the phase II enzymes are located in the cytosol except UDP-glucuronosyltransferases (UGT), which are microsomal. Phase II reactions are typically much faster than phase I reactions therefore the rate-limiting step for biotransformation of a compound is usually the phase I reaction.<br>Phase II metabolism can deal with all the products of phase I metabolism, be they reactive (Type I substrate) or unreactive/poorly active (Type II substrate) compounds. With the exception of glutathione, the conjugating species needs to be made chemically reactive after synthesis. The availability of the cofactor in the synthesis may be a rate-limiting factor in some phase II pathways as it may prevent the formation of enough conjugating species to deal with the substrate or it's metabolite. As many substrates and/or their metabolites are chemically reactive, their continued presence may lead to toxicity. Pubmed11805192 Reactome Database ID Release 43156580 Reactome, http://www.reactome.org ReactomeREACT_6959 ACTIVATION GENE ONTOLOGYGO:0016316 Reactome Database ID Release 431806174 Reactome, http://www.reactome.org Glucuronidation Authored: Jassal, B, 2004-11-29 11:42:34 Edited: Jassal, B, 2008-05-19 12:57:01 Glucuronidation conjugation utilizes UDP-glucuronosyltransferases (UGTs; EC 2.4.1.17) to catalyze a wide range of diverse endogenous and xenobiotic compounds. Glucuronidation is the major pathway in phase II metabolism and accounts for approximately 35% of drug conjugation. UGTs are microsomal membrane-bound and catalyze the transfer of a glucuronate group of uridine diphosphoglucuronate (UDPGA, a co-substrate) to the functional group of specific substrates. UDPGA is synthesized from glucose-1-phosphate (G1P). G1P is required for glycolysis and is present in high concentrations in the cell, making it is unlikely to be a limiting factor in UDPGA synthesis. UDP is added to G1P to form UDP-glucose which is then dehydrogenated to form UDPGA. The basic reaction is<p><b>UDP-Glucuronate + acceptor -> UDP + acceptor-beta-D-glucuronide</b></p>The effect of this conjugation is to confer polarity to the substrate which can then be easily excreted in urine or bile. Functional groups acted on include hydroxyl, carboxylate, amino and sulfate groups. There are 2 families of UGTs, UGT1 and UGT2 which are further sub-divided into 3 subfamilies, UGT1A, UGT2A and UGT2B. There are more than 26 different isozymes in humans, of which 18 are functional proteins. They are composed of 527-530 residues and have a molecular weight of 50-57KDa.<br>The UGT1 family comprises of 9 proteins (UGT1A1, 1A3-1A10) but only 5 have been isolated in humans. Example substrates which are glucuronidated are acetaminophen by UGT1A6 and bilirubin by UGT1A1. Members of the UGT2 subfamily are each encoded by their own genes, in contrast to UGT1As which are encoded at the UGT1 locus. Example substrates are morphine conjugation by UGT2B7 and androgenic steroid conjugation by UGT2B17.<br>Xenobiotics conjugated with glucuronic acid can be substrates for beta-glucuronidase, an enzyme common in gut microflora. This enzyme can release the parent or phase I metabolite which can be reabsorbed. It can then either re-exert it's original effects or be conjugated by glucuronic acid again. This cycle is called <i>enterohepatic circulation</i> and can delay the elimination of the xenobiotic. Pubmed10836148 Pubmed14977861 Reactome Database ID Release 43156588 Reactome, http://www.reactome.org ReactomeREACT_6784 ACTIVATION GENE ONTOLOGYGO:0004438 Reactome Database ID Release 431806277 Reactome, http://www.reactome.org Formation of the active cofactor, UDP-glucuronate Authored: Jassal, B, 2004-11-30 16:21:24 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006065 Glucose 1-phosphate and UTP are the precursors to UDP-glucuronate formation. After oxidation of the resultant complex, UDP-glucuronate is transported to the ER lumen. Pubmed17482904 Reactome Database ID Release 43173599 Reactome, http://www.reactome.org ReactomeREACT_6737 ACTIVATION GENE ONTOLOGYGO:0016309 Reactome Database ID Release 431806209 Reactome, http://www.reactome.org Cytosolic sulfonation of small molecules Authored: Jassal, B, 2004-11-29 11:42:34 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0050427 Pubmed10503886 Pubmed11154739 Pubmed12372849 Pubmed15167709 Pubmed16322073 Pubmed9034160 Reactome Database ID Release 43156584 Reactome, http://www.reactome.org ReactomeREACT_6913 Two groups of sulfotransferease (SULT) enzymes catalyze the transfer of a sulfate group from 3-phosphoadenosine 5-phosphosulfate (PAPS) to a hydroxyl group on an acceptor molecule, yielding a sulfonated acceptor and 3-phosphoadenosine 5-phosphate (PAP). One is localized to the Golgi apparatus and mediates the sulfonation of proteoglycans. The second, annotated here, is cytosolic and mediates the sulfonation of a diverse array of small molecules, increasing their solubilities in water and modifying their physiological functions. There are probably thirteen or more human cytosolic SULT enzymes; eleven of these have been purified and characterized enzymatically, and are annotated here (Blanchard et al. 2004; Gamage et al. 2005). These enzymes appear to be active as dimers. Their substrate specificities are typically broad, and not related in an obvious way to their structures; indeed, apparently orthologous human and rodent SULT enzymes can have different substrate specificities (Glatt 2000), and none has been exhaustively characterized. The substrates listed in the table and annotated here are a sample of the known ones, chosen to indicate the range of activity of these enzymes and to capture some of their known physiologically important targets. Absence of a small molecule - enzyme pair from the table, however, may only mean that it has not yet been studied. Formation of PAPS Activation of sulfate GENE ONTOLOGYGO:0050428 PAPS (3'-phosphoadenosine-5'-phosphosulfate), which functions as a sulfate donor in the cell, is synthesized from sulfate and two molecules of ATP in a two-step process (Robbins and Lipmann 1958) catalyzed in vertebrates (including humans - Venkatachalam et al. 1998) by a bifunctional enzyme. PAPS synthesis takes place in the cytosol, and it is either consumed there in the sulfonation of a variety of hormones and xenobiotics, or it is transported to the Golgi apparatus and consumed in the synthesis of proteoglycans like chondroitin sulfate. Two isoforms of the human bifunctional enzyme are known, mutations in one of which are associated with defects in proteoglycan biosynthesis (Girard et al. 1998; ul Haque et al. 1998). Pubmed13575436 Pubmed9576487 Pubmed9668121 Pubmed9771708 Reactome Database ID Release 43174362 Reactome, http://www.reactome.org ReactomeREACT_6840 ACTIVATION GENE ONTOLOGYGO:0043813 Reactome Database ID Release 431806194 Reactome, http://www.reactome.org Acetylation Authored: Jassal, B, 2004-11-30 16:21:24 Edited: Jassal, B, 2008-05-19 12:57:01 N-acetyltransferases (NATs; EC 2.3.1.5) utilize acetyl Co-A in acetylation conjugation reactions. This is the preferred route of conjugating aromatic amines (R-NH2, converted to aromatic amides R-NH-COCH3) and hydrazines (R-NH-NH2, converted to R-NH-NH-COCH3). Aliphatic amines are not substrates for NAT. The basic reaction is<br><p><b>Acetyl-CoA + an arylamine = CoA + an N- acetylarylamine</b></p><br>NATs are cytosolic and in humans, 2 isoforms are expressed, NAT1 and NAT2. A third isoform, NATP, is a pseudogene and is not expressed. The NAT2 gene contains mutations that decrease NAT2 activity. This mutations was first seen as <i>slow acetylation</i> compared to the normal, <i>fast acetylation</i> of the antituberculosis drug isoniazid. Incidence of the slow acetylator phenotype is high in Middle Eastern populations (70%), average (50%) in Europeans, Americans and Australians and low in Asians (<25% in Chinese, Japanese and Koreans). N-acetylation and methylation pathways differ from other conjugation pathways in that they mask an amine with a nonionizable group so that the conjugates are less water soluble than the parent compound. However, certain N-acetlylations facilitate urinary excretion.<br>N-acetylation occurs in two sequential steps via a <i>ping-pong Bi-Bi mechanism</i>. In the first step, the acetyl group from acetyl-CoA is transferred to a cysteine residue in NAT, with consequent release of coenzyme-A. In the second step, the acetyl group is released from the acetylated NAT to the substrate, subsequently regenerating the enzyme. Pubmed12052143 Pubmed1559981 Pubmed2340091 Reactome Database ID Release 43156582 Reactome, http://www.reactome.org ReactomeREACT_6732 ACTIVATION GENE ONTOLOGYGO:0052629 Reactome Database ID Release 431806177 Reactome, http://www.reactome.org Uptake of Carbon Dioxide and Release of Oxygen by Erythrocytes Authored: May, B, 2011-03-24 Carbon dioxide (CO2) in plasma is hydrated to yield protons (H+) and bicarbonate (HCO3-) by carbonic anhydrase IV (CA4) located on the apical plasma membranes of endothelial cells. Plasma CO2 is also taken up by erythrocytes via AQP1 and RhAG. Within erythrocytes CA1 and, predominantly, CA2 hydrate CO2 to HCO3- and protons (reviewed in Geers & Gros 2000, Jensen 2004, Boron 2010). The HCO3- is transferred out of the erythrocyte by the band 3 anion exchange protein (AE1, SLC4A1) which cotransports a chloride ion (Cl-) into the erythrocyte.<br>Also within the erythrocyte, CO2 combines with the N-terminal alpha amino groups of HbA to form carbamates while protons bind histidine residues in HbA. The net result is the Bohr effect, a conformational change in HbA that reduces its affinity for O2 and hence assists the delivery of O2 to tissues. Edited: May, B, 2011-03-24 GENE ONTOLOGYGO:0015701 Pubmed10747205 Pubmed15491402 Pubmed19879980 Reactome Database ID Release 431237044 Reactome, http://www.reactome.org ReactomeREACT_121329 Reviewed: Jassal, B, 2012-04-27 ACTIVATION GENE ONTOLOGYGO:0004430 Reactome Database ID Release 431806244 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0034596 Reactome Database ID Release 431806162 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016316 Reactome Database ID Release 431806174 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000285 Reactome Database ID Release 431806278 Reactome, http://www.reactome.org Conjugation of benzoate with glycine Authored: Jassal, B, 2004-11-30 16:21:24 Benzoic acid, widely used as a food preservative, is converted to hippuric acid by activation and conjugation with glycine. This was one of the first detoxification pathways discovered, and was formerly exploited clinically as an alternative means of nitrogen excretion in patients with urea cycle defects (Brusilow and Horwich 2001). Edited: D'Eustachio, P, 2006-03-23 15:51:01 GENE ONTOLOGYGO:0006805 ISBN0079130356 Reactome Database ID Release 43177135 Reactome, http://www.reactome.org ReactomeREACT_6933 ACTIVATION GENE ONTOLOGYGO:0043813 Reactome Database ID Release 431806268 Reactome, http://www.reactome.org Conjugation of phenylacetate with glutamine Authored: Jassal, B, 2004-11-30 16:21:24 Edited: D'Eustachio, P, 2006-03-23 15:51:01 GENE ONTOLOGYGO:0006805 ISBN0079130356 Phenylacetate metabolism is of clinical importance because its conjugation with glutamine to form phenylacetylglutamine, which can be excreted in the urine, provides an alternative pathway for nitrogen excretion in patients with urea cycle defects (James et al. 1972; Batshaw et al. 2001; Brusilow and Horwich 2001). This conjugation proceeds in two steps. First, phenylacetate and ATP react with coenzyme A to form phenylacetyl CoA, AMP, and pyrophosphate (Vessey et al. 1999). Two human CoA ligases have been characterized that catalyze this reaction efficiently in vitro: acyl-CoA synthetase medium-chain family member 1 (BUCS1) (Fujino et al. 2001) and xenobiotic/medium-chain fatty acid:CoA ligase (Vessey et al. 2003). Their relative contributions to phenylacetate metabolism in vivo are unknown. Second, phenylacetyl CoA and glutamine react to form phenyacetyl glutamine and Coenzyme A. The enzyme that catalyzes this reaction has been purified from human liver mitochondria and shown to be a distinct polypeptide species from glycine-N-acyltransferase (Webster et al. 1976). This human glutamine-N-acyltransferase activity has not been characterized by sequence analysis at the protein or DNA level, however, and thus cannot be associated with a known human protein in the annotation of phenylacetate conjugation. Pubmed10434065 Pubmed11148549 Pubmed11470804 Pubmed12616642 Pubmed4403084 Pubmed931988 Reactome Database ID Release 43177162 Reactome, http://www.reactome.org ReactomeREACT_6800 ACTIVATION GENE ONTOLOGYGO:0052629 Reactome Database ID Release 431806176 Reactome, http://www.reactome.org Amino Acid conjugation Authored: Jassal, B, 2005-03-10 15:37:26 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006805 Reactome Database ID Release 43156587 Reactome, http://www.reactome.org ReactomeREACT_6971 Xenobiotics that contain either a carboxylic group or an aromatic hydroxylamine group are possible substrates for amino acid conjugation. Xenobiotics with a <i>carboxylic group</i> conjugate with an <i>amino group</i> of amino acids such as glycine, taurine and glutamine. The <i>hydroxylamine group</i> conjugates with the <i>carboxylic group</i> of amino acids such as proline and serine. The amino acid is first activated by an aminoacyl-tRNA-synthetase which then reacts with the hydroxylamine group to form a reactive N-ester. N-esters can degrade to form electrophilic nitrenium (R-N<sup>+</sup>-R') and carbonium (R-C<sup>+</sup>H<sub>2</sub>) ions. The pyrolysis product of tryptophan, an N-hydroxy intermediate, can potentially form these reactive electrophilic ions. ACTIVATION GENE ONTOLOGYGO:0016303 Reactome Database ID Release 431806222 Reactome, http://www.reactome.org Conjugation of carboxylic acids Authored: Jassal, B, 2005-03-10 15:37:26 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006805 Reactome Database ID Release 43159424 Reactome, http://www.reactome.org ReactomeREACT_6889 Xenobiotics and endogenous compounds containing carboxylate groups can be activated with coenzyme A to produce acyl-CoA thioesters and then conjugated with the amino groups of glycine or glutamine to form amide-linked conjugates. Clinically important substrates include benzoic acid, phenylacetic acid, and salicylic acid. ACTIVATION GENE ONTOLOGYGO:0004438 Reactome Database ID Release 431806170 Reactome, http://www.reactome.org Electron Transport from NADPH to Ferredoxin Authored: Lill, R, 2012-09-24 Authored: May, B, 2011-06-04 Edited: May, B, 2012-06-29 NADPH, ferredoxin reductase (FDXR, Adrenodoxin reductase), and ferredoxins (FDX1, FDX1L) comprise a short electron transport chain that provides electrons for biosynthesis of iron-sulfur clusters and steroid hormones (Sheftel et al. 2010, Shi et al. 2012, reviewed in Grinberg et al. 2000, Lambeth et al. 1982). Pubmed10899784 Pubmed20547883 Pubmed22101253 Pubmed7050653 Reactome Database ID Release 432395516 Reactome, http://www.reactome.org ReactomeREACT_150128 Reviewed: Rouault, TA, 2012-10-11 Reviewed: Tong, Wing-Hang, 2012-10-11 ACTIVATION GENE ONTOLOGYGO:0004430 Reactome Database ID Release 431806244 Reactome, http://www.reactome.org O2/CO2 exchange in erythrocytes Authored: May, B, 2011-11-01 Edited: May, B, 2011-11-01 GENE ONTOLOGYGO:0015701 In capillaries of the lungs erythrocytes release carbon dioxide (CO2) and acquire oxygen (O2). In other tissues of the body the reverse reaction occurs (reviewed in Nikinmaa 1997, Jensen 2004).<br>In the lungs, CO2 bound as carbamate to the N-terminus of hemoglobin (HbA) and protons bound to histidine residues in HbA are released as HbA binds oxygen. Bicarbonate (HCO3-) present in plasma is taken up by erythrocytes via the band3 anion exchanger (AE1, SLC4A1) and combined with protons by carbonic anhydrases I and II (CA1, CA2) to yield water and CO2 (reviewed by Esbaugh & Tufts 2006, De Rosa et al. 2007). The CO2 is passively transported out of the erythrocyte by AQP1 and RhAG. HCO3- in plasma is also directly dehydrated by extracellular carbonic anhydrase IV (CA4) present on endothelial cells lining the capillaries in the lung.<br>In non-pulmonary tissues CO2 in plasma is hydrated to yield protons and HCO3- by CA4 located on the apical plasma membranes of endothelial cells. Plasma CO2 is also taken up by erythrocytes via AQP1 and RhAG. Within erythrocytes CA1 and, predominantly, CA2 hydrate CO2 to yield HCO3- and protons (reviewed in Geers & Gros 2000, Jensen 2004, Boron 2010). HCO3- is transferred out of the erythrocyte by the band 3 anion exchange protein (AE1, SLC4A1) which cotransports a chloride ion into the erythrocyte.<br>Also within the erythrocyte, CO2 combines with the N-terminal alpha amino groups of HbA to form carbamates while protons bind histidine residues in HbA. The net result is the Bohr effect, a conformational change in HbA that reduces its affinity for O2 and hence assists the delivery of O2 to tissues. Pubmed10747205 Pubmed15491402 Pubmed16679072 Pubmed17573207 Pubmed19879980 Pubmed9050246 Reactome Database ID Release 431480926 Reactome, http://www.reactome.org ReactomeREACT_120969 Reviewed: Jassal, B, 2012-04-27 ACTIVATION GENE ONTOLOGYGO:0035005 Reactome Database ID Release 431806261 Reactome, http://www.reactome.org Conjugation of salicylate with glycine Authored: Jassal, B, 2004-11-30 16:21:24 Edited: D'Eustachio, P, 2006-03-23 15:51:01 GENE ONTOLOGYGO:0006805 In the body, aspirin (acetylsalicylic acid) is hydrolyzed to salicylic acid. Salicylic acid (2-hydroxybenzoic acid) can then be hydroxylated to yield gentisic acid, conjugated with glucuronate, or conjugated with glycine to yield molecules that are excreted by the kidneys. The third of these conjugation processes is annotated here, and proceeds in two steps. First, salicylate and ATP react with coenzyme A to form salicylate CoA, AMP, and pyrophosphate in a reaction catalyzed by xenobiotic/medium-chain fatty acid:CoA ligase (Vessey et al. 2003). Second, salicylate CoA and glycine react to form salicyluric acid and Coenzyme A (Mawal and Qureshi 1994). Pubmed12616642 Pubmed7802672 Reactome Database ID Release 43177128 Reactome, http://www.reactome.org ReactomeREACT_6812 Mitochondrial Iron-Sulfur Cluster Biogenesis Authored: Lill, R, 2012-09-24 Authored: May, B, 2011-06-04 Edited: May, B, 2011-06-04 Iron-sulfur (Fe-S) proteins are localized in the cytosol, nucleus, and mitochondria of mammalian cells (reviewed in Stemmler et al. 2010, Rouault 2012, Bandyopadhyay et al. 2008, Lill 2009, Lill et al. 2012). Fe-S protein biogenesis in the mitochondrial matrix involves the iron-sulfur cluster (ISC) assembly machinery. Ferrous iron is transported across the inner mitochondrial membrane into the mitochondrial matrix by Mitoferrin-1 and Mitoferrin-2. (Mitoferrin-1 is enriched in erythroid cells while Mitoferrin-2 is ubiquitous.) Frataxin binds ferrous iron in the mitochondrial matrix. The cysteine desulfurase NFS1 in a subcomplex with ISD11 provides the sulfur by converting cyteine into alanine and forming a persulfide which is used for cluster formation on ISCU, the scaffold protein. Interaction between NFS1 and ISD11 is necessary for desulfurase activity. Frataxin binds to a complex containing NFS1, ISD11, and ISCU and is proposed to function as an iron donor to ISCU or as an allosteric switch that activates sulfur transfer and Fe-S cluster assembly (Tsai and Barondeau 2010). Cluster formation also involves the electron transfer chain ferredoxin reductase and ferredoxin. ISCU initially forms clusters containing 2 iron atoms and 2 sulfur atoms ([2Fe-2S] clusters). They are released by the function of HSP70-HSC20 chaperones and the monothiol glutaredoxin GLRX5 and used for assembly of [2Fe-2S] proteins. Assembly of larger clusters such as [4Fe-4S] clusters may involve the function of ISCA1, ISCA2, and IBA57. The clusters are transferred to apo-enzymes such as the respiratory complexes, aconitase, and lipoate synthase through dedicated targeting factors such as IND1, NFU1, and BOLA3. Pubmed19021507 Pubmed19675643 Pubmed20060739 Pubmed20522547 Pubmed20873749 Pubmed22382365 Pubmed22609301 Reactome Database ID Release 431362409 Reactome, http://www.reactome.org ReactomeREACT_150353 Reviewed: Rouault, TA, 2012-10-11 Reviewed: Tong, Wing-Hang, 2012-10-11 Glutathione synthesis and recycling Authored: Jassal, B, 2004-11-30 16:21:24 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006750 Pubmed3053703 Reactome Database ID Release 43174403 Reactome, http://www.reactome.org ReactomeREACT_6960 Reviewed: D'Eustachio, P, 2011-05-23 The combination of glutamate, cysteine and ATP is required to form glutathione. The steps involved in the synthesis and recycling of glutathione are outlined (Meister, 1988). MMP2,3,7,10,11 Converted from EntitySet in Reactome Reactome DB_ID: 1604372 Reactome Database ID Release 431604372 Reactome, http://www.reactome.org ReactomeREACT_119635 ACTIVATION GENE ONTOLOGYGO:0052810 Reactome Database ID Release 431806232 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016303 Reactome Database ID Release 431806222 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0043813 Reactome Database ID Release 431806249 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052629 Reactome Database ID Release 431806254 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000285 Reactome Database ID Release 431806250 Reactome, http://www.reactome.org Metabolism of mRNA Authored: May, B, 2009-11-19 Edited: Matthews, L, 2009-11-19 GENE ONTOLOGYGO:0016071 Once synthesized mRNA can be utilized until degraded. Degradation itself is the final mode of gene expression regulation. Reactome Database ID Release 43447010 Reactome, http://www.reactome.org ReactomeREACT_20605 Muscle contraction Authored: Gillespie, ME, 2009-02-10 03:05:16 Edited: Gillespie, ME, 2009-03-10 20:55:39 In this module, the processes by which calcium binding triggers actin - myosin interactions and force generation in smooth and striated muscle tissues are annotated. Reactome Database ID Release 43397014 Reactome, http://www.reactome.org ReactomeREACT_17044 Striated Muscle Contraction Authored: Gillespie, ME, 2009-02-10 03:05:16 Edited: Gillespie, ME, 2009-03-10 20:55:39 GENE ONTOLOGYGO:0030049 Pubmed13165697 Pubmed13175187 Pubmed15173217 Pubmed15173218 Reactome Database ID Release 43390522 Reactome, http://www.reactome.org ReactomeREACT_16969 Reviewed: Rush, MG, 2008-01-11 00:00:00 Striated muscle contraction is a process whereby force is generated within striated muscle tissue, resulting in a change in muscle geometry, or in short, increased force being exerted on the tendons. Force generation involves a chemo-mechanical energy conversion step that is carried out by the actin/myosin complex activity, which generates force through ATP hydrolysis. Striated muscle is a type of muscle composed of myofibrils, containing repeating units called sarcomeres, in which the contractile myofibrils are arranged in parallel to the axis of the cell, resulting in transverse or oblique striations observable at the level of the light microscope.<br>Here striated muscle contraction is represented on the basis of calcium binding to the troponin complex, which exposes the active sites of actin. Once the active sites of actin are exposed, the myosin complex bound to ADP can bind actin and the myosin head can pivot, pulling the thin actin and thick myosin filaments past one another. Once the myosin head pivots, ADP is ejected, a fresh ATP can be bound and the energy from the hydrolysis of ATP to ADP is channeled into kinetic energy by resetting the myosin head. With repeated rounds of this cycle the sarcomere containing the thin and thick filaments effectively shortens, forming the basis of muscle contraction. ACTIVATION GENE ONTOLOGYGO:0045485 Reactome Database ID Release 432046077 Reactome, http://www.reactome.org Smooth Muscle Contraction Authored: Gillespie, ME, 2009-03-09 02:39:27 Edited: Gillespie, ME, 2009-11-18 GENE ONTOLOGYGO:0006936 Layers of smooth muscle cells can be found in the walls of numerous organs and tissues within the body. Smooth muscle tissue lacks the striated banding pattern characteristic of skeletal and cardiac muscle. Smooth muscle is triggered to contract by the autonomic nervous system, hormones, autocrine/paracrine agents, local chemical signals, and changes in load or length.<br> Actin:myosin cross bridging is used to develop force with the influx of calcium ions (Ca2+) initiating contraction. Two separate protein pathways, both triggered by calcium influx contribute to contraction, a calmodulin driven kinase pathway, and a caldesmon driven pathway.<br> Recent evidence suggests that actin, myosin, and intermediate filaments may be far more volatile then previously suspected, and that changes in these cytoskeletal elements along with alterations of the focal adhesions that anchor these proteins may contribute to the contractile cycle.<br> Contraction in smooth muscle generally uses a variant of the same sliding filament model found in striated muscle, except in smooth muscle the actin and myosin filaments are anchored to focal adhesions, and dense bodies, spread over the surface of the smooth muscle cell. When actin and myosin move across one another focal adhesions are drawn towards dense bodies, effectively squeezing the cell into a smaller conformation. The sliding is triggered by calcium:caldesmon binding, caldesmon acting in an analogous fashion to troponin in striated muscle. Phosphorylation of myosin light chains also is involved in the initiation of an effective contraction.<br> Pubmed10679361 Pubmed14627618 Pubmed18596210 Reactome Database ID Release 43445355 Reactome, http://www.reactome.org ReactomeREACT_20558 Reviewed: Rush, MG, 2008-01-11 00:00:00 Abacavir transmembrane transport Authored: D'Eustachio, P, 2012-03-14 Cytosolic levels of abacavir are determined by the balance of its facilitated diffusion into the cell mediated by organic cation transporters SLC22A1, 2, and 3, and its ATP-dependent efflux from cells mediated by ABCG2 and ABCB1 (Klaasen and Aleksunes 2010; Pan et al. 2007; Shaik et al. 2007). Edited: D'Eustachio, P, 2012-03-16 GENE ONTOLOGYGO:0006855 Pubmed17437964 Pubmed17709369 Pubmed20103563 Reactome Database ID Release 432161517 Reactome, http://www.reactome.org ReactomeREACT_120801 Reviewed: Jassal, B, 2012-03-16 ACTIVATION GENE ONTOLOGYGO:0016213 Reactome Database ID Release 432046082 Reactome, http://www.reactome.org Abacavir metabolism Abacavir activation proceeds steps of phosphorylation, deamination to yield carbovir monophosphate, and phosphorylation of the latter compound to yield the triphosphate. In addition, abacavir can be conjugated with glucuronide or oxidized to its 5'-carboxylate derivative, the two major forms in which it is excreted from the body (Yuen et al. 2008). Authored: D'Eustachio, P, 2012-03-14 Edited: D'Eustachio, P, 2012-03-16 GENE ONTOLOGYGO:0017144 Pubmed18479171 Reactome Database ID Release 432161541 Reactome, http://www.reactome.org ReactomeREACT_121388 Reviewed: Jassal, B, 2012-03-16 ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548806 Reactome, http://www.reactome.org Reversible Hydration of Carbon Dioxide Authored: May, B, 2011-08-06 Carbonic anhydrases reversibly catalyze the hydration of carbon dioxide and directly produce bicarbonate and protons, bypassing the formation of carbonic acid (reviewed in Lindskog 1997, Breton 2001, Esbaugh and Tufts 2006, Boron 2010, Gilmour 2010). Carbonic anhydrase deprotonates water to yield a zinc-hydroxyl group and a proton which is transferred to external buffer molecules via histidine or glutamate residues in carbonic anhydrase. The hydroxyl group reacts with carbon dioxide in the active site to yield bicarbonate. A water molecule displaces the bicarbonate and the reaction cycle begins again. There are currently 12 known active carbonic anhydrases in humans. Edited: May, B, 2011-08-06 GENE ONTOLOGYGO:0015701 Pubmed11875253 Pubmed16679072 Pubmed19879980 Pubmed20541618 Pubmed9336012 Reactome Database ID Release 431475029 Reactome, http://www.reactome.org ReactomeREACT_121123 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 ACTIVATION GENE ONTOLOGYGO:0004438 Reactome Database ID Release 431806246 Reactome, http://www.reactome.org Metabolism of RNA Edited: Matthews, L, 2010-03-01 GENE ONTOLOGYGO:0016070 RNA metabolism consists of both mRNA degradative pathways and non-coding RNA metabolism. Non-coding RNA metabolism includes the processing and packaging of the small nuclear ribonucleoproteins (snRNPs). Reactome Database ID Release 43532600 Reactome, http://www.reactome.org ReactomeREACT_21257 ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 432046080 Reactome, http://www.reactome.org Abacavir transport and metabolism Abacavir is a nucleoside analogue reverse transcriptase inhibitor with antiretroviral activity, widely used in combination with other drugs to treat HIV-1 infection (Yuen et al. 2008). Its uptake across the plasma membrane is mediated by organic cation transporters SLC22A1, 2, and 3; the transport proteins ABCB1 and ABCG2 mediate its efflux. Abacavir itself is a prodrug. Activation requires phosphorylation by a cytosolic adenosine phosphotransferase and deamination by ADAL deaminase to yield carbovir monophosphate. Cytosolic nucleotide kinases convert carbovir monophosphate to carbovir triphosphate, the active HIV reverse transcriptase inhibitor. Abacavir can be glucuronidated or oxidized to a 5'-carboxylate; these are the major forms in which it is excreted from the body. Authored: D'Eustachio, P, 2012-03-14 Edited: D'Eustachio, P, 2012-03-16 Pubmed18479171 Reactome Database ID Release 432161522 Reactome, http://www.reactome.org ReactomeREACT_121189 Reviewed: Jassal, B, 2012-03-16 Uptake of Oxygen and Release of Carbon Dioxide by Erythrocytes Authored: May, B, 2011-04-04 Edited: May, B, 2011-04-04 Erythrocytes circulating through the capillaries of the lung must exchange carbon dioxide (CO2) for oxygen (O2) during their short (0.5-1 sec.) transit time in pulmonary tissue (Reviewed in Jensen 2004, Esbaugh and Tufts 2006, Boron 2010). CO2 bound as carbamate to the N-terminus of hemoglobin and protons (H+) bound to histidine residues in hemoglobin are released as hemoglobin (HbA) binds O2. Bicarbonate (HCO3-) present in plasma is taken up by erythrocytes via the band3 anion exchanger (AE1, SLC4A1) and combined with H+ by carbonic anhydrases I and II (CA1/CA2) to yield water and CO2 (Reviewed by Esbaugh and Tufts 2006). CO2 is passively transported out of the erythrocyte by AQP1 and RhAG. HCO3- in plasma is also directly dehydrated by extracellular carbonic anhydrase IV (CA4) present on endothelial cells lining the capillaries in the lung. GENE ONTOLOGYGO:0015701 Pubmed15491402 Pubmed16679072 Pubmed19879980 Reactome Database ID Release 431247673 Reactome, http://www.reactome.org ReactomeREACT_121380 Reviewed: Jassal, B, 2012-04-27 U2 snRNA Reactome DB_ID: 71956 Reactome Database ID Release 4371956 Reactome, http://www.reactome.org ReactomeREACT_3568 U5 snRNA Reactome DB_ID: 71874 Reactome Database ID Release 4371874 Reactome, http://www.reactome.org ReactomeREACT_4762 U1 snRNA Reactome DB_ID: 71911 Reactome Database ID Release 4371911 Reactome, http://www.reactome.org ReactomeREACT_4202 Ceruloplasmin mRNA Ceruloplasmin 3 ' UTR (GAIT element and poly-A tail) Reactome DB_ID: 156798 Reactome Database ID Release 43156798 Reactome, http://www.reactome.org ReactomeREACT_4369 Depyrimidination Authored: Matthews, L, 2004-02-09 03:00:00 Depyrimidination of a damaged nucleotide is mediated by a pyrimidine-specific DNA glycosylase. The glycosylase cleaves the N-C1' glycosidic bond between the damaged DNA base and the deoxyribose sugar generating a free base and an apyrimidinic (AP) site. GENE ONTOLOGYGO:0045008 Pubmed10583946 Reactome Database ID Release 4373928 Reactome, http://www.reactome.org ReactomeREACT_1405 18S rRNA Reactome DB_ID: 72391 Reactome Database ID Release 4372391 Reactome, http://www.reactome.org ReactomeREACT_2593 U6 snRNA Reactome DB_ID: 71892 Reactome Database ID Release 4371892 Reactome, http://www.reactome.org ReactomeREACT_3558 mature GLP-1 Converted from EntitySet in Reactome Reactome DB_ID: 381662 Reactome Database ID Release 43381662 Reactome, http://www.reactome.org ReactomeREACT_19088 mature Glucagon-like Peptide-1 Recognition and association of DNA glycosylase with site containing an affected purine Authored: Matthews, L, 2004-02-09 03:00:00 GENE ONTOLOGYGO:0045007 Pubmed9724657 Reactome Database ID Release 43110330 Reactome, http://www.reactome.org ReactomeREACT_2176 The recognition and cleavage of an altered base by a DNA glycosylase is thought to involve the diffusion of the enzyme along the minor grove of the DNA molecule. The enzyme presumably compresses the backbone of the affected DNA strand at the site of damage. This compression is thought to result in an outward rotation of the damaged residue into a "pocket" of the enzyme that recognizes and cleaves the altered base (Parikh et al., 1998). U4 snRNA Reactome DB_ID: 71888 Reactome Database ID Release 4371888 Reactome, http://www.reactome.org ReactomeREACT_3860 Cleavage of the damaged purine Damaged purines are first cleaved by purine-specific glycosylases (see Lindahl and Wood 1999). GENE ONTOLOGYGO:0045007 Pubmed10583946 Reactome Database ID Release 43110331 Reactome, http://www.reactome.org ReactomeREACT_1729 Base-Excision Repair, AP Site Formation Base excision repair is initiated by DNA glycosylases that hydrolytically cleave of the base-deoxyribose glycosyl bond of a damaged nucleotide residue releasing the damaged base (Lindahl and Wood, 1999). GENE ONTOLOGYGO:0006285 Pubmed10583946 Pubmed11937636 Reactome Database ID Release 4373929 Reactome, http://www.reactome.org ReactomeREACT_804 mature GLP-1 Converted from EntitySet in Reactome Reactome DB_ID: 400574 Reactome Database ID Release 43400574 Reactome, http://www.reactome.org ReactomeREACT_18896 mature Glucagon-like Peptide-1 Depurination Authored: Matthews, L, 2004-02-09 03:00:00 Depurination of a damaged nucleotide is mediated by a purine-specific DNA glycosylase. The glycosylase cleaves the N-C1' glycosidic bond between the damaged DNA base and the deoxyribose sugar generating a free base and an apurinic (AP) site. GENE ONTOLOGYGO:0045007 Reactome Database ID Release 4373927 Reactome, http://www.reactome.org ReactomeREACT_626 5S rRNA Reactome DB_ID: 72494 Reactome Database ID Release 4372494 Reactome, http://www.reactome.org ReactomeREACT_3902 DNA Repair Authored: Hoeijmakers, JH, Lees-Miller, S, Thompson, L, Gopinathrao, G, Matthews, L, Schultz, R, Pegg, A, 2003-07-10 00:12:38 DNA repair is a phenomenal multi-enzyme, multi-pathway system required to ensure the integrity of the cellular genome. These cellular mechanisms that must cope with the plethora of DNA base pair adducts that arise.<p>DNA damage can arise spontaneously in the cellular milieu through chemical alteration of base nucleotides or as a consequence of errors during DNA replication. For example, it is well known that normal cellular pH and temperature offer an environment, which is hostile to the integrity of DNA and its nucleotide components. Additionally, DNA damage may be induced in response to environmental exposures, including exposure to physical agents such as ionizing or ultraviolet (UV) radiation. Finally, specific chemical agents are known to alkylate or cross-link DNA bases, produce bulky adducts on DNA bases, or break DNA phosphate-sugar backbone.<p>The pioneering work from a number of laboratories have elucidated the basic mechanisms underlying distinct DNA repair pathways that include nucleotide excision repair (NER), base excision repair (BER), DNA strand break repair (DSBR), direct reversal of DNA damage, and the replication past DNA lesions by specialized DNA bypass polymerases (bypass replication). Defects in most of these repair pathways have been associated with one or more specific human diseases. Additionally, the repair of damaged DNA is intimately associated with a number of other distinct cellular processes such as DNA replication, DNA recombination, cell cycle checkpoint arrest, and other basic cellular mechanisms as outlined herein. Edited: Matthews, L, Gopinathrao, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006281 Reactome Database ID Release 4373894 Reactome, http://www.reactome.org ReactomeREACT_216 Reviewed: Khanna, KK, Lindahl, T, West, SC, Wood, RD, 0000-00-00 00:00:00 28S rRNA Reactome DB_ID: 72498 Reactome Database ID Release 4372498 Reactome, http://www.reactome.org ReactomeREACT_4585 Base Excision Repair Authored: Joshi-Tope, G, 2003-07-14 15:01:00 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006284 Of the three major pathways involved in the repair of nucleotide damage in DNA, base excision repair (BER) involves the greatest number of individual enzymatic activities. This is the consequence of the numerous individual glycosylases, each of which recognizes and removes a specific modified base(s) from DNA. BER is responsible for the repair of the most prevalent types of DNA lesions, alterations, which arise intracellularly as a consequence of normal mitochondrial metabolism or by oxidative free radicals resulting from ionizing radiation, lipid peroxidation or activated phagocytic cells. BER is a two-step process initiated by one of the DNA glycosylases that recognizes a specific modified base(s) and removes that base through the catalytic cleavage of the glycosylic bond, leaving an abasic site without disruption of the phosphate-sugar DNA backbone. Subsequently, abasic sites are resolved by a series of enzymes that cleave the backbone, synthesize the replacement residue(s), and ligate the DNA strand. BER may occur by either a single-nucleotide replacement pathway or a multiple-nucleotide patch replacement pathway, depending on the structure of the terminal sugar phosphate residue. The glycosylases found in human cells recognize "foreign adducts" and not standard functional modifications such as DNA methylation. Pubmed10583946 Pubmed11937636 Reactome Database ID Release 4373884 Reactome, http://www.reactome.org ReactomeREACT_1104 A third proteolytic cleavage releases NICD Authored: Jassal, B, 2005-01-07 13:14:17 GENE ONTOLOGYGO:0007220 Pubmed10206645 Pubmed12209127 Pubmed15194119 Pubmed15274632 Pubmed9620803 Reactome Database ID Release 43157212 Reactome, http://www.reactome.org ReactomeREACT_691 The third proteolytic cleavage releases the Notch IntraCellular Domain (NICD) from the NEXT fragment. The catalyst for this cleavage is a membrane protease complex called gamma-secretase (GS). GS cleaves type I membrane proteins such as the Notch receptor and amyloid beta-protein precursor (APP, implicated in Alzheimer's disease). GS is made up of 4 components: Presenilin, nicastrin, APH-1 and PEN-2. Presenilins are homodimeric, multipass transmembrane proteins and are believed to be the catalytic core of GS. All aspartyl proteases have two catalytic aspartates and presenilin contains these residues. The others are essential cofactors for the correct function of GS. Adenylyl cyclase (pancreatic beta cell) Converted from EntitySet in Reactome Reactome DB_ID: 446658 Reactome Database ID Release 43446658 Reactome, http://www.reactome.org ReactomeREACT_20747 NICD traffics to nucleus Authored: Jassal, B, 2005-01-10 12:51:46 NICD translocates to the nucleus and assembles into a ternary complex with the CSL (human RBPJ i.e. CBF1/ fly Suppressor of Hairless/ worm Lag1) DNA-binding protein and the Mastermind co-activator. This complex activates the transcription of downstream gene targets like HES (Hairy/Enhancer of Split) and HES-related (HRT, also named CHF, HEY, HESR, gridlock) genes. Reactome Database ID Release 43157052 Reactome, http://www.reactome.org ReactomeREACT_2155 3' -UTR-mediated translational regulation Authored: Matthews, L, 2004-12-20 12:26:45 Edited: Matthews, L, 0000-00-00 00:00:00 Pubmed11533233 Pubmed12575997 Pubmed15459663 Reactome Database ID Release 43157279 Reactome, http://www.reactome.org ReactomeREACT_1762 Translational control mechanisms often involve interactions between the 3' - or 5' -untranslated regions (UTRs) of mRNA and RNA-binding proteins. One such mechanism requires circularization of the mRNA molecule involving protein-protein interactions between the mRNA termini (Mazumder et al., 2001). While the circularization of mRNA during translation initiation is thought to contribute to an increase in the efficiency of translation, it also appears to provide a mechanism for translational silencing. This might be achieved by bringing inhibitory 3' UTR-binding proteins into a position in which they interfere either with the function of the translation initiation complex or with the assembly of the ribosome. ACTIVATION GENE ONTOLOGYGO:0008970 Reactome Database ID Release 431524140 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047144 Reactome Database ID Release 431524055 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431602403 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004630 Reactome Database ID Release 431524118 Reactome, http://www.reactome.org Resolution of Abasic Sites (AP sites) Reactome Database ID Release 4373933 Reactome, http://www.reactome.org ReactomeREACT_1893 Resolution of AP sites can occur through the single-nucleotide replacement pathway or through the multiple-nucleotide patch replacement pathway. Resolution of AP sites via the single-nucleotide replacement pathway Authored: Matthews, L, 2004-02-09 03:00:00 Pubmed10583946 Reactome Database ID Release 43110381 Reactome, http://www.reactome.org ReactomeREACT_933 The single-nucleotide replacement pathway of base excision repair appears to facilitate the repair of most damaged bases. Following DNA glycosylase mediated cleavage of the damaged base, the endonuclease, APE1 is recruited to the site of damage where it cleaves the 5' side of the base-free deoxyribose residue. DNA polymerase, POL Beta then displaces the DNA glycosylase and cleaves the 3' side of the sugar phosphate. APE1 is subsequently released, the XRCC1:LIG3 complex is recruited and POL Beta mediates the synthesis of the replacement residue. Following LIG3 ligase mediated ligation of the replaced residue, the XRCC1:LIG3 complex dissociates (see Lindahl and Wood, 1999). An alternative BER pathway is employed when the structure of the terminal sugar phosphate is such that it can not be cleaved through the AP lyase activity of POL Beta. Recognition and association of DNA glycosylase with site containing an affected pyrimidine Base excision repair is initiated by a DNA glycosylase which first recognizes and removes a damaged or incorrect (e.g. mismatched) base. GENE ONTOLOGYGO:0045008 Pubmed11937636 Reactome Database ID Release 43110328 Reactome, http://www.reactome.org ReactomeREACT_702 Cleavage of the damaged pyrimidine Damaged pyrimidines are first cleaved by pyrimide-specific glycosylases (see Lindahl and Wood 1999). GENE ONTOLOGYGO:0045008 Pubmed10583946 Reactome Database ID Release 43110329 Reactome, http://www.reactome.org ReactomeREACT_2156 Removal of DNA patch containing abasic residue During removal of DNA patch containing abasic residue, DNA glycosylase is displaced by APE1 which endonucleolytically cleaves the 5' side of the base-free deoxyribose residue. POL Beta is recruited to the AP site where it mediates incorporation of the first replacement nucleotide. Association of POL delta with the AP site displaces POL Beta. DNA strand displacement synthesis then follows and flap structures are cleaved. Reactome Database ID Release 43110362 Reactome, http://www.reactome.org ReactomeREACT_2192 ACTIVATION GENE ONTOLOGYGO:0004605 Reactome Database ID Release 431524097 Reactome, http://www.reactome.org Resolution of AP sites via the multiple-nucleotide patch replacement pathway Authored: Matthews, L, 2004-02-09 03:00:00 Pubmed10460157 Pubmed10559261 Pubmed10583946 Pubmed9214649 Reactome Database ID Release 43110373 Reactome, http://www.reactome.org ReactomeREACT_1128 While the single-nucleotide replacement pathway appears to facilitate the repair of most damaged bases, an alternative BER pathway is evoked when the structure of the terminal sugar phosphate is such that it can not be cleaved through the AP lyase activity of DNA polymerase, POL Beta. Under these circumstances, a short stretch of residues containing the abasic site is excised and replaced (Dianov et al., 1999). Following DNA glycosylase mediated cleavage of the damaged base, the endonuclease APE1 is recruited to the site of damage where it cleaves the 5' side of the base-free deoxyribose residue. POL Beta then displaces the DNA glycosylase and synthesizes the first replacement residue. DNA polymerase, POL Delta replaces POL Beta and mediates the synthesis of several additional residues resulting in the displacement of a DNA flap containing the abasic sugar phosphate and 3’ flanking residues. The flap structure is recognized and cleaved by the flap endonuclease, FEN1 and the replacement residues are then ligated by the DNA ligase, LIG1 (Klungland and Lindahl, 1997; Matsumoto et al., 1999). Displacement of DNA glycosylase by APE1 Following cleavage of the damaged base, DNA glycosylase is displaced by APE1. Pubmed9724657 Reactome Database ID Release 43110357 Reactome, http://www.reactome.org ReactomeREACT_1064 ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431500640 Reactome, http://www.reactome.org Potassium voltage-gated channels (beta cell, closed) Converted from EntitySet in Reactome Reactome DB_ID: 381655 Reactome Database ID Release 43381655 Reactome, http://www.reactome.org ReactomeREACT_18467 Base-free sugar-phosphate removal via the single-nucleotide replacement pathway Base-free sugar-phosphate removal via the single-nucleotide replacement pathway requires displacement of DNA glycosylase by APE1, APE1 mediated endonucleolytic cleavage at the 5' side of the base-free deoxyribose residue, recruitment of POL Beta to the AP site and Excision of the abasic sugar phosphate (dRP) residue at the strand break (Lindahl and Wood, 1999). Pubmed10583946 Reactome Database ID Release 4373930 Reactome, http://www.reactome.org ReactomeREACT_1357 ACTIVATION GENE ONTOLOGYGO:0008444 Reactome Database ID Release 431524058 Reactome, http://www.reactome.org Potassium voltage-gated channels (beta cell, open) Converted from EntitySet in Reactome Reactome DB_ID: 381640 Reactome Database ID Release 43381640 Reactome, http://www.reactome.org ReactomeREACT_18949 ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431524031 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431500631 Reactome, http://www.reactome.org Translesion synthesis by DNA polymerases bypassing lesion on DNA template Pubmed10583946 Pubmed10856253 Reactome Database ID Release 43110313 Reactome, http://www.reactome.org ReactomeREACT_2198 Ubiquitous environmental and endogenous genotoxic agents cause lesions that can interfere with normal DNA metabolism including DNA replication, eventually resulting in mutations that lead to carcinogenesis and/or cell death. While cells posses repair mechanisms like nucleotide excision and base excision repair pathways to maintain the integrity of the genome, not all lesions on the genome can be repaired efficiently by these processes in time for DNA replication, and some types of lesion are repaired very inefficiently. To prevent acute cell death through arrested DNA replication at unrepaired lesions, cells have a mechanism, referred to as translesion synthesis, which allows DNA synthesis to proceed past lesions (Masutani et al., 2000). ACTIVATION GENE ONTOLOGYGO:0047144 Reactome Database ID Release 431524046 Reactome, http://www.reactome.org DNA Damage Bypass Authored: Gopinathrao, G, 2004-02-02 17:30:34 In addition to various processes for removing damaging lesions from the DNA, cells have developed specific mechanisms for tolerating unexcised damages during the replication of the genome. Such processes are collectively called DNA damage bypass pathways. Several proteins including novel Y-family polymerases that have been recently identified in multitude of organisms are involved in this process.<BR> Translesion synthesis (TLS) or replicative bypass of damaged bases that are known to arrest high fidelity, highly processive polymerases involved in DNA replication is carried out by error-prone polymerases Pol zeta, Pol eta and Rev3 protein among others. TLS is implicated in UV and chemical induced mutagenesis of normal human cells where lesions in the replicating genome are carried over to the newly formed daughter cells.<BR> All these 3 enzymes are found to lack 3’->5’ exonuclease activity, while exhibiting low fidelity, weak processivity and sufficient polymerase activities. An outline of the bypass synthesis by these 3 enzymes is annotated here. Complete details of damage recognition and discrimination, initiation of specific polymerase activity and the finer mechanisms are yet to be elucidated. Pubmed10925197 Pubmed11595180 Pubmed12800216 Reactome Database ID Release 4373893 Reactome, http://www.reactome.org ReactomeREACT_2174 ACTIVATION GENE ONTOLOGYGO:0008970 Reactome Database ID Release 431524145 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008970 Reactome Database ID Release 431524148 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524136 Reactome, http://www.reactome.org Translesion synthesis by HREV1 Authored: Gopinathrao, G, 2004-02-02 17:30:34 HREV1 encodes a template dependent dCMP transferase activity that can insert a C residue opposite an abasic site.<BR> Pubmed10536157 Pubmed10760286 Reactome Database ID Release 43110312 Reactome, http://www.reactome.org ReactomeREACT_8 ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431524025 Reactome, http://www.reactome.org Translesion synthesis by Pol eta Authored: Gopinathrao, G, 2004-02-02 17:30:34 Pol eta consists of 713 amino acids and can bypass thymidine-thymidine dimers adding two A’s correctly opposite to the lesion. Mutations in Pol eta gene result in the loss of this bypass activity in accounting for the XP variant phenotype (XPV) among human xeroderma pigmentosum disorder patients. Pol eta can carry out TLS past various UV and chemical induced lesions via two steps: a. preferential incorporation of correct bases opposite to the lesion<BR>b. conditional elongation only at the sites where such correct bases are inserted.<BR> Pubmed10369688 Pubmed10856253 Reactome Database ID Release 43110320 Reactome, http://www.reactome.org ReactomeREACT_1287 Translesion synthesis by Pol zeta Authored: Gopinathrao, G, 2004-02-02 17:30:34 Pol zeta consists of two proteins: HREV3 with polymerase activity and HREV7, an accessory factor with unidentified activity. It has the ability to bypass pyrimidine dimers and other adducts in DNA.<BR> Pubmed10102035 Pubmed9618506 Reactome Database ID Release 43110325 Reactome, http://www.reactome.org ReactomeREACT_822 DNA Damage Reversal Authored: Pegg, A, 2004-02-04 15:50:05 DNA damage can be directly reversed by dealkylation. Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006281 Reactome Database ID Release 4373942 Reactome, http://www.reactome.org ReactomeREACT_127 Reversal of Alkylation Damage By DNA Dioxygenases Authored: Gopinathrao, G, 2004-06-16 19:20:00 DNA in cells is susceptible to different types of cytotoxic and mutagenic damages caused by alkylating agents. These genotoxic chemicals generate major lesions like 1-methyladenine and 3-methylcytosine in single-stranded DNA and 3-methyladenine and O6-methylguanine in double-stranded DNA . Cells have inbuilt repair mechanisms against such toxic molecules. For example, 3-methyladeninie-DNA glycosylases excise some methylated bases while MGMT/hAGT protein transfers alkyl groups from others lesions onto cysteine residues. E.coli AlkB protein has a unique function wherein 1-methyladenine and 3-methylcytosine are demethylated by a combination of oxidative decarboxylation and hydroxylation activities. AlkB and its human orthologs, ABH2 and ABH3 belong to alpha-ketoglutarate deoxygenase family of enzymes that oxidize chemically inert compounds in the presence of alpha-ketoglutarate, oxygen and ferrous ions. As a byproduct of these chemical reactions, formaldehyde is released in the case of methylated lesions and acetaldehyde in the case 1-ethyladenine in DNA. CO2 and succinate are also released in an intermediate step not shown in the following illustration.Unlike other mechanisms which involve some kind of nuclease activities, this type of repair mechanism leaves the repaired bases intact by just removing the reactive alkyl groups that get bound to the bases thereby effecting accurate restoration of damaged DNA sequences. GENE ONTOLOGYGO:0006307 Pubmed12226667 Pubmed12486230 Pubmed15040447 Reactome Database ID Release 4373943 Reactome, http://www.reactome.org ReactomeREACT_2020 Beta-catenin Converted from EntitySet in Reactome Reactome DB_ID: 201920 Reactome Database ID Release 43201920 Reactome, http://www.reactome.org ReactomeREACT_24457 ABH3 mediated Reversal of Alkylation Damage AlkB is an alpha-ketoglutarate- and Fe(II)-dependent dioxygenase that oxidizes the relevant methyl groups and releases them as formaldehyde. The human homologs of both these enzymes remove 1-methyladenine and 3-methylcytosine from methylated polynucleotides in an alpha-ketoglutarate-dependent reaction. They act by direct damage reversal with the regeneration of the unsubstituted bases. E.coli AlkB, and human ABH2, and ABH3 can also repair 1-ethyladenine residues in DNA with the release of acetaldehyde (Duncan et al., 2002). GENE ONTOLOGYGO:0006307 Pubmed12486230 Pubmed15040447 Pubmed16174769 Reactome Database ID Release 43112126 Reactome, http://www.reactome.org ReactomeREACT_1662 ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524077 Reactome, http://www.reactome.org ABH2 mediated Reversal of Alkylation Damage AlkB is an alpha-ketoglutarate- and Fe(II)-dependent dioxygenase that oxidizes the relevant methyl groups and releases them as formaldehyde. The human homologs of both these enzymes remove 1-methyladenine and 3-methylcytosine from methylated polynucleotides in an alpha-ketoglutarate-dependent reaction. They act by direct damage reversal with the regeneration of the unsubstituted bases. E.coli AlkB, and human ABH2, and ABH3 can also repair 1-ethyladenine residues in DNA with the release of acetaldehyde (Duncan et al., 2002). GENE ONTOLOGYGO:0006307 Pubmed12486230 Pubmed15040447 Pubmed16174769 Reactome Database ID Release 43112122 Reactome, http://www.reactome.org ReactomeREACT_526 ACTIVATION GENE ONTOLOGYGO:0043337 Reactome Database ID Release 431524138 Reactome, http://www.reactome.org hTCF-4 Converted from EntitySet in Reactome Reactome DB_ID: 201924 Reactome Database ID Release 43201924 Reactome, http://www.reactome.org ReactomeREACT_24422 Homologous Recombination Repair Authored: Thompson, L, 2003-07-14 15:03:24 Edited: Matthews, L, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0000724 Pubmed11242102 Pubmed11376695 Pubmed12427531 Pubmed12954758 Reactome Database ID Release 4373888 Reactome, http://www.reactome.org ReactomeREACT_1874 Reviewed: West, SC, 0000-00-00 00:00:00 The HRR pathway is an "error free" DNA repair mechanism that utilizes information encoded by homologous sequence to repair double-strand breaks (DSBs). HRR acts on DSBs occurring within replicated DNA (replication-independent DSBs) or on DSBs that are generated at broken replication forks (replication-dependent DSBs). Repair by homologous recombination involves processing of the ends of the DNA double-strand break, homologous DNA pairing and strand exchange, repair DNA synthesis, and resolution of the heteroduplex molecules. ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431602353 Reactome, http://www.reactome.org Double-Strand Break Repair Authored: Lees-Miller, S, Thompson, L, 2003-07-14 15:03:24 Edited: Matthews, L, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006302 Numerous types of DNA damage can occur within a cell due to the endogenous production of oxygen free radicals, normal alkylation reactions, or exposure to exogenous radiations and chemicals. Double-strand breaks (DSBs), one of the most dangerous type of DNA damage along with interstrand crosslinks, are caused by ionizing radiation or certain chemicals such as bleomycin, and occur normally during the processes of DNA replication, meiotic exchange, and V(D)J recombination. <p>Two distinct mechanisms for DSB repair are the error-free homologous recombination repair (HRR) pathway and the error-prone nonhomologous end-joining (NHEJ) pathway. The choice of pathway may be determined by whether the DNA region has already replicated and the precise nature of the break. NHEJ functions at all stages of the cell cycle, but plays the predominant role in both the G1 phase and in S-phase regions of DNA that have not yet replicated (Rothkamm et al. 2003). HRR functions primarily in repairing both one-sided DSBs that arise at DNA replication forks and two-sided DSBs arising in S or G2-phase chromatid regions that have replicated. Pubmed12897142 Reactome Database ID Release 4373890 Reactome, http://www.reactome.org ReactomeREACT_2054 ACTIVATION GENE ONTOLOGYGO:0047144 Reactome Database ID Release 431524051 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431524084 Reactome, http://www.reactome.org Homologous recombination repair of replication-independent double-strand breaks Homologous recombination repair of replication-independent double-strand breaks requires the activation of ATM followed by ATM mediated phosphorylation of DNA repair proteins. DNA repair and signaling proteins are then recruited to double-strand breaks. The ends of the DNA double strand breaks must be resectioned and RPA complexes associate with the resulting ssDNA. Homologous DNA pairing and strand exchange then occurs followed by DNA repair synthesis and resolution of D-loop structures. Reactome Database ID Release 4373951 Reactome, http://www.reactome.org ReactomeREACT_1587 ACTIVATION GENE ONTOLOGYGO:0008374 Reactome Database ID Release 431524093 Reactome, http://www.reactome.org Epac2 Converted from EntitySet in Reactome Reactome DB_ID: 381710 Reactome Database ID Release 43381710 Reactome, http://www.reactome.org ReactomeREACT_18767 ACTIVATION GENE ONTOLOGYGO:0047184 Reactome Database ID Release 431524068 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008374 Reactome Database ID Release 431524093 Reactome, http://www.reactome.org Epac1 Converted from EntitySet in Reactome Reactome DB_ID: 381717 Reactome Database ID Release 43381717 Reactome, http://www.reactome.org ReactomeREACT_19050 Assembly of the RAD50-MRE11-NBS1 complex at DNA double-strand breaks Assembly of the RAD50-MRE11-NBS1 complex at DNA double-strand breaks involves the formation of RAD50:MRE11 complex, association of RAD50:MRE11 complex with NBS1 through MRE11 and association of the MRN with sites of DSB. Reactome Database ID Release 4375177 Reactome, http://www.reactome.org ReactomeREACT_486 Processing of DNA double-strand break ends Reactome Database ID Release 4383626 Reactome, http://www.reactome.org ReactomeREACT_2055 The processing of DNA double strand breaks requires resectioning of the broken ends followed by the association of RPA complexes with ssDNA. Recruitment of repair and signaling proteins to double-strand breaks Authored: Matthews, L, 2003-11-18 00:00:00 Following exposure to ionizing radiation, a number of recombination/repair proteins and complexes relocalize to nuclear foci that are believed to correspond to the sites of double-strand breaks. These proteins include gamma-H2AX, ATM, RAD51, BRCA1, BRCA2, NBS1, RPA, and MDC1/NFBD1 and the MRE11-RAD50-NBS1. Gamma-H2AX, the phosphorylated form of H2AX, is one of the first proteins to appear within nuclear foci and plays an essential role in recruiting other repair proteins (Paull et al., 2000).<P>One model illustrating the organization of the recruited repair proteins (Van den Bosch et al., 2003) is shown here. (A) Undamaged section of a chromosome, showing two chromatin loops and an inactive ATM dimer. (B,C) Induction of a DNA double-stranded break (DSB), modification of chromatin, activation of ATM and recruitment of both ATM and MRE11/RAD50/NBS1(MRN). The possibility that MRN binds before ATM is shown, but the activation of ATM appears to require the MDC1 and the MRN complex (Uziel, et al 2003; Mochan et al. 2003). The thin black line indicates modified chromatin. (D,E) Following DNA damage, a wave of H2AX phosphorylation occurs and the mediator proteins (mediator of DNA damage checkpoint protein 1 (MDC1), p53-binding protein 1(53BP1), and breast-cancer-associated protein 1(BRCA1)) are recruited to the growing focus where they are phosphorylated in an ATM-dependent manner. The molecular architecture of the focus is unknown. (F) Disassembly of the focus, ATM inactivation and chromatin remodeling. The model suggests at least two distinct forms of soluble ATM: an inactive oligomer and an active monomer, and at least two distinct active, insoluble forms: one directly at the lesion and another integral to the growing focus. Note that the MRN complex is also a component of the growing focus, but for clarity, has been omitted here. Complex persistent lesions are thought to be more difficult to repair, and this is reflected in the size attained by the growing focus. Pubmed10959836 Pubmed12949583 Pubmed14532133 Pubmed14695167 Reactome Database ID Release 4375154 Reactome, http://www.reactome.org ReactomeREACT_97 MRN complex relocalizes to nuclear foci Authored: Matthews, L, 2003-11-23 12:20:00 MRN complexes localize to nuclear foci in response to double-strand breaks and have been implicated in DNA end-processing during homologous recombination repair (Trujillo et al., 1998). The MRN complex may function as a bridge between double-strand break ends through interactions between the coiled-coil domains of RAD50 (Hoptner et al., 2002). Pubmed12152085 Pubmed9554850 Pubmed9705271 Reactome Database ID Release 4383572 Reactome, http://www.reactome.org ReactomeREACT_1884 ATM mediated response to DNA double-strand break Authored: Matthews, L, 2003-11-18 00:00:00 Detection of DNA double-strand breaks involves sensor proteins that become activated setting off of signaling cascades. This signaling leads to the recruitment of repair proteins and subsequent repair of the damaged DNA. ATM is one of the primary candidate sensors in double-strand break repair. Pubmed12034743 Reactome Database ID Release 4383542 Reactome, http://www.reactome.org ReactomeREACT_204 ACTIVATION GENE ONTOLOGYGO:0008374 Reactome Database ID Release 431524104 Reactome, http://www.reactome.org ATM mediated phosphorylation of repair proteins Authored: Matthews, L, 2003-11-18 00:00:00 Following the detection of DSBs, ATM mediates the phosphorylation of proteins involved in DNA repair (Thompson and Schild, 2002). Pubmed12427531 Reactome Database ID Release 4375148 Reactome, http://www.reactome.org ReactomeREACT_1924 ACTIVATION GENE ONTOLOGYGO:0008374 Reactome Database ID Release 431524086 Reactome, http://www.reactome.org PathwayStep7264 ACTIVATION GENE ONTOLOGYGO:0034596 Reactome Database ID Release 431806172 Reactome, http://www.reactome.org PathwayStep7265 ACTIVATION GENE ONTOLOGYGO:0004430 Reactome Database ID Release 431806156 Reactome, http://www.reactome.org PathwayStep7266 ACTIVATION GENE ONTOLOGYGO:0004438 Reactome Database ID Release 431806284 Reactome, http://www.reactome.org GLP-1 Converted from EntitySet in Reactome Glucagon-like Peptide-1 Reactome DB_ID: 879886 Reactome Database ID Release 43879886 Reactome, http://www.reactome.org ReactomeREACT_24372 PathwayStep7267 ACTIVATION GENE ONTOLOGYGO:0016303 Reactome Database ID Release 431806222 Reactome, http://www.reactome.org PathwayStep7268 Resolution of D-loop structures Authored: Matthews, L, 2003-08-11 05:43:00 Once repair synthesis has occurred, the D-loop structure may be resolved either through Holliday junction intermediates of through synthesis-dependent strand-annealing. Pubmed12902160 Reactome Database ID Release 4375149 Reactome, http://www.reactome.org ReactomeREACT_2229 ACTIVATION GENE ONTOLOGYGO:0004430 Reactome Database ID Release 431806239 Reactome, http://www.reactome.org PathwayStep7269 Assembly of the RAD51-ssDNA nucleoprotein complex Authored: Matthews, L, 2003-09-10 06:00:00 GENE ONTOLOGYGO:0000730 Pubmed10921897 Pubmed11080452 Pubmed11459989 Pubmed11751636 Pubmed12606939 Reactome Database ID Release 4376000 Reactome, http://www.reactome.org ReactomeREACT_2141 The RAD51-ssDNA nucleoprotein filament is a right-hand helical nucleoprotein filament referred to as the presynaptic filament. This nucleoprotein complex contains a binding site for the double-stranded homologous DNA molecule with which it interacts during strand exchange. Loading of RAD51 onto ssDNA is thought to be facilitated by recombination mediator RAD52 (McIlwraith et al., 2000), RAD51 paralogs: RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 (Sigurdsson et al., 2001), by the association of RAD52 with ssDNA (Parsons et al., 2000) and by the association of RAD51 with BRCA2 (Tarsounas et al., 2003). ACTIVATION GENE ONTOLOGYGO:0008374 Reactome Database ID Release 431524086 Reactome, http://www.reactome.org Presynaptic phase of homologous DNA pairing and strand exchange Reactome Database ID Release 4376003 Reactome, http://www.reactome.org ReactomeREACT_408 The presynaptic phase of homologous DNA pairing and strand exchange begins with the displacement of RPA from ssDNA, followed by the association of RAD51 with BRCA2, formation of RAD52 heptameric ring structure complexes on ssDNA, association of RAD52 with the RPA complex, association of RAD52 with ssDNA at resected ends of double-strand break and assembly of the RAD51-ssDNA nucleoprotein complex. ACTIVATION GENE ONTOLOGYGO:0004430 Reactome Database ID Release 431806241 Reactome, http://www.reactome.org GLP-1 Converted from EntitySet in Reactome Glucagon-like Peptide-1 Reactome DB_ID: 400477 Reactome Database ID Release 43400477 Reactome, http://www.reactome.org ReactomeREACT_24529 Homologous DNA pairing and strand exchange Authored: Matthews, L, 2003-11-23 12:20:00 Pubmed12205100 Pubmed12912992 Pubmed9880493 Reactome Database ID Release 4376010 Reactome, http://www.reactome.org ReactomeREACT_1763 The presynaptic phase of homologous DNA pairing and strand exchange begins with the displacement of RPA from ssDNA, followed by the association of RAD51 with BRCA2, formation of RAD52 heptameric ring structure complexes on ssDNA, association of RAD52 with the RPA complex, association of RAD52 with ssDNA at resected ends of double-strand break and assembly of the RAD51-ssDNA nucleoprotein complex. Stable synaptic pairing between recombining DNA molecules involves the invasion of homologous duplex DNA by the processed single-stranded ends of the double-strand break, followed by displacement of the non-complimentary strand of the duplex. This results in the formation of a D-loop structure. Invasion of the heteroduplex DNA by RAD51 nucleoprotein filament involves the identification of a region of homology between these two molecules. The mechanism by which this occurs is not yet known. RAD51 catalyses the invasion of the nucleoprotein filament into homologous double-stranded DNA. Watson-Crick hydrogen bonding between the ssDNA within the nucleoprotein filament and the homologous strand of the invaded DNA duplex result in the displacement of the non-pairing strand (strand displacement) and formation of the D-loop structure (Sung et al., 2003). <p>The RAD51 nucleoprotein filament has independent binding sites for the ssDNA strand upon which it assembles and the recombining homologous duplex DNA. The repair proteins RPA, RAD52, and RAD54 appear to promote RAD51 mediated invasion and homologous DNA pairing reaction (McIlwraith et al, 2000 and Sigurdsson et al., 2002). The conformation of the RAD52-ssDNA complex is thought to place the ssDNA on an exposed surface of the protein, in a configuration that may promote the DNA-DNA annealing of complementary DNA strands. RAD54 may function in the transient separation of the duplex DNA strands via its ATP hydrolysis-mediated DNA supercoiling function (Sigurdsson et al., 2002). Branch migration or strand exchange occurs as the complimentary duplex DNA strand is progressively taken up into the nucleoprotein filament to base pair with the invading single-strand sequence (Sung et al., 2003). ACTIVATION GENE ONTOLOGYGO:0034596 Reactome Database ID Release 431806179 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524096 Reactome, http://www.reactome.org PathwayStep7260 PathwayStep7261 PathwayStep7262 PathwayStep7263 ACTIVATION GENE ONTOLOGYGO:0000285 Reactome Database ID Release 431806283 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0034485 Reactome Database ID Release 431806226 Reactome, http://www.reactome.org GLP-1 (Cleaved) Converted from EntitySet in Reactome Glucagon-like Peptide-1 (Cleaved at N-terminus) Reactome DB_ID: 400520 Reactome Database ID Release 43400520 Reactome, http://www.reactome.org ReactomeREACT_24381 ACTIVATION GENE ONTOLOGYGO:0052812 Reactome Database ID Release 431806282 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016314 Reactome Database ID Release 43199445 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 431806243 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004439 Reactome Database ID Release 431806203 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016308 Reactome Database ID Release 431806262 Reactome, http://www.reactome.org CD26 Converted from EntitySet in Reactome Dipeptidyl Peptidase 4 Dipeptidyl Peptidase IV Reactome DB_ID: 400536 Reactome Database ID Release 43400536 Reactome, http://www.reactome.org ReactomeREACT_24264 ACTIVATION GENE ONTOLOGYGO:0004439 Reactome Database ID Release 431806225 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051800 Reactome Database ID Release 431806220 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035005 Reactome Database ID Release 431806285 Reactome, http://www.reactome.org PathwayStep7270 ACTIVATION GENE ONTOLOGYGO:0043813 Reactome Database ID Release 431806273 Reactome, http://www.reactome.org PathwayStep7273 PathwayStep7274 PathwayStep7271 PathwayStep7272 ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431524024 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008970 Reactome Database ID Release 431524123 Reactome, http://www.reactome.org IP3 receptor Converted from EntitySet in Reactome Reactome DB_ID: 169685 Reactome Database ID Release 43169685 Reactome, http://www.reactome.org ReactomeREACT_12226 ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524124 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524115 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004622 Reactome Database ID Release 431524030 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004622 Reactome Database ID Release 431524022 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047144 Reactome Database ID Release 431524043 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008970 Reactome Database ID Release 431524121 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431602379 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431602353 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004622 Reactome Database ID Release 431524030 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008889 Reactome Database ID Release 431524092 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016740 Reactome Database ID Release 431524119 Reactome, http://www.reactome.org SNAP-25 Converted from EntitySet in Reactome Reactome DB_ID: 265186 Reactome Database ID Release 43265186 Reactome, http://www.reactome.org ReactomeREACT_18216 ACTIVATION GENE ONTOLOGYGO:0016740 Reactome Database ID Release 431524132 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004622 Reactome Database ID Release 431524022 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047144 Reactome Database ID Release 431524049 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524152 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431524041 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431500631 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524153 Reactome, http://www.reactome.org Unc18-1 Converted from EntitySet in Reactome Reactome DB_ID: 265206 Reactome Database ID Release 43265206 Reactome, http://www.reactome.org ReactomeREACT_16070 ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524144 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003841 Reactome Database ID Release 431524032 Reactome, http://www.reactome.org Syntaxin 1A Converted from EntitySet in Reactome Reactome DB_ID: 181524 Reactome Database ID Release 43181524 Reactome, http://www.reactome.org ReactomeREACT_11517 ACTIVATION GENE ONTOLOGYGO:0003881 Reactome Database ID Release 431524066 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431524149 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004623 Reactome Database ID Release 431602403 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004605 Reactome Database ID Release 431524098 Reactome, http://www.reactome.org PathwayStep7210 PathwayStep7211 PathwayStep7212 PathwayStep7213 PathwayStep7214 PathwayStep7215 PathwayStep7216 G alpha (i/o) (candidates) Converted from EntitySet in Reactome Reactome DB_ID: 400032 Reactome Database ID Release 43400032 Reactome, http://www.reactome.org ReactomeREACT_18441 G-protein gamma subunit (candidates) Converted from EntitySet in Reactome Reactome DB_ID: 400062 Reactome Database ID Release 43400062 Reactome, http://www.reactome.org ReactomeREACT_18500 Beta Subunit of Voltage-dependent Calcium Channel (pancreatic beta cell) Converted from EntitySet in Reactome Reactome DB_ID: 392458 Reactome Database ID Release 43392458 Reactome, http://www.reactome.org ReactomeREACT_17597 G-protein beta subunit (candidates) Converted from EntitySet in Reactome Reactome DB_ID: 400093 Reactome Database ID Release 43400093 Reactome, http://www.reactome.org ReactomeREACT_18899 PathwayStep7207 PathwayStep7206 PathwayStep7209 PathwayStep7208 PathwayStep7200 PathwayStep7201 Alpha-2A/2C Adrenergic Receptors Converted from EntitySet in Reactome Reactome DB_ID: 400086 Reactome Database ID Release 43400086 Reactome, http://www.reactome.org ReactomeREACT_18657 PathwayStep7204 PathwayStep7205 PathwayStep7202 PathwayStep7203 Gal-Gal-Xyl-proteins (Gal)2 (Xyl)1 (Ser)1 Converted from EntitySet in Reactome Reactome DB_ID: 2064214 Reactome Database ID Release 432064214 Reactome, http://www.reactome.org ReactomeREACT_125558 GlcA-Gal-Gal-Xyl-proteins Converted from EntitySet in Reactome Reactome DB_ID: 2064225 Reactome Database ID Release 432064225 Reactome, http://www.reactome.org ReactomeREACT_123660 PLC beta 1/2/3 Converted from EntitySet in Reactome Phospholipase C Beta (pancreatic beta cell) Reactome DB_ID: 400005 Reactome Database ID Release 43400005 Reactome, http://www.reactome.org ReactomeREACT_18548 G(q) alpha 11/14/15/Q Converted from EntitySet in Reactome G(q) alpha subunit (pancreatic beta cell) Reactome DB_ID: 400000 Reactome Database ID Release 43400000 Reactome, http://www.reactome.org ReactomeREACT_18880 Adenylate Cyclase V or VI Converted from EntitySet in Reactome Reactome DB_ID: 446432 Reactome Database ID Release 43446432 Reactome, http://www.reactome.org ReactomeREACT_20885 PathwayStep7250 PathwayStep7252 PathwayStep7251 PathwayStep7254 PathwayStep7253 PathwayStep7256 PathwayStep7255 PathwayStep7258 PathwayStep7257 PathwayStep7259 PathwayStep7241 PathwayStep7240 PathwayStep7245 PathwayStep7244 PathwayStep7243 PathwayStep7242 PathwayStep7249 PathwayStep7248 PathwayStep7247 PathwayStep7246 PathwayStep7239 PathwayStep7230 PathwayStep7236 PathwayStep7235 PathwayStep7238 PathwayStep7237 PathwayStep7232 PathwayStep7231 PathwayStep7234 PathwayStep7233 PathwayStep7228 PathwayStep7229 PathwayStep7227 PathwayStep7226 PathwayStep7225 PathwayStep7224 PathwayStep7223 PathwayStep7222 PathwayStep7221 PathwayStep7220 PathwayStep7219 PathwayStep7217 PathwayStep7218 Prolysyl oxidases Converted from EntitySet in Reactome Reactome DB_ID: 2022092 Reactome Database ID Release 432022092 Reactome, http://www.reactome.org ReactomeREACT_150550 RNA Polymerase I Transcription Initiation Authored: Comai, L, 2003-07-03 17:13:29 During initiation the double-stranded DNA must be melted and transcription begins. SL1 forms and interacts with UBF-1 and the rDNA promoter. It is this platform that will recruit active RNA polymerase I to the SL1:phosphorlated UBF-1:rDNA promoter complex.<p>Mammalian rRNA genes are preceded by a terminator element that is recognized by the SL1 complex. This SL1 modulated acetylation of the basal Pol I transcription machinery has functional consequences suggesting that the reversible acetylation may be one way to regulate rDNA transcription. Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006361 Reactome Database ID Release 4373762 Reactome, http://www.reactome.org ReactomeREACT_953 RNA Polymerase I Promoter Escape As the active RNA Polymerase I complex leaves the promoter Rrn3 dissociates from the complex. RNA polymerase I Promoter Clearance is complete and Chain Elongation begins. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006361 Reactome Database ID Release 4373772 Reactome, http://www.reactome.org ReactomeREACT_1913 Collagen type VII NC2 proteinases Converted from EntitySet in Reactome Reactome DB_ID: 2214322 Reactome Database ID Release 432214322 Reactome, http://www.reactome.org ReactomeREACT_151983 YAP1- and WWTR1 (TAZ)-stimulated gene expression Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 GENE ONTOLOGYGO:0006367 Pubmed16332960 Pubmed20452772 Reactome Database ID Release 432032785 Reactome, http://www.reactome.org ReactomeREACT_118713 Reviewed: Sudol, M, 2012-02-03 YAP1 and WWTR1 (TAZ) are transcriptional co-activators, both homologues of the Drosophila Yorkie protein. They both interact with members of the TEAD family of transcription factors, and WWTR1 interacts as well with TBX5 and RUNX2, to promote gene expression. Their transcriptional targets include genes critical to regulation of cell proliferation and apoptosis. Their subcellular location is regulated by the Hippo signaling cascade: phosphorylation mediated by this cascade leads to the cytosolic sequestration of both proteins (Murakami et al. 2005; Oh and Irvine 2010). Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0006351 In the nucleus, SMAD2/3:SMAD4 heterotrimer complex acts as a transcriptional regulator. The activity of SMAD2/3 complex is regulated both positively and negatively by association with other transcription factors (Chen et al. 2002, Varelas et al. 2008, Stroschein et al. 1999, Wotton et al. 1999) . In addition, the activity of SMAD2/3:SMAD4 complex can be inhibited by nuclear protein phosphatases and ubiquitin ligases (Lin et al. 2006, Dupont et al. 2009). Pubmed10199400 Pubmed10531062 Pubmed12150994 Pubmed16751101 Pubmed18568018 Pubmed19135894 Reactome Database ID Release 432173793 Reactome, http://www.reactome.org ReactomeREACT_121061 Reviewed: Huang, Tao, 2012-05-14 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription After phosphorylated SMAD2 and/or SMAD3 form a heterotrimer with SMAD4, SMAD2/3:SMAD4 complex translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003). In the nucleus, linker regions of SMAD2 and SMAD3 within SMAD2/3:SMAD4 complex can be phosphorylated by CDK8 associated with cyclin C (CDK8:CCNC) or CDK9 associated with cyclin T (CDK9:CCNT). CDK8/CDK9-mediated phosphorylation of SMAD2/3 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes it for ubiquitination and consequent degradation (Alarcon et al. 2009). <br><br>The transfer of SMAD2/3:SMAD4 complex to the nucleus can be assisted by other proteins, such as WWTR1. In human embryonic cells, WWTR1 (TAZ) binds SMAD2/3:SMAD4 heterotrimer and mediates TGF-beta-dependent nuclear accumulation of SMAD2/3:SMAD4. The complex of WWTR1 and SMAD2/3:SMAD4 binds promoters of SMAD7 and SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) genes and stimulates their transcription (Varelas et al. 2008). Stimulation of SMAD7 transcription by SMAD2/3:SMAD4 represents a negative feedback loop in TGF-beta receptor signaling. SMAD7 can be downregulated by RNF111 ubiquitin ligase (Arkadia), which binds and ubiquitinates SMAD7, targeting it for degradation (Koinuma et al. 2003). <br><br>SMAD2/3:SMAD4 heterotrimer also binds the complex of RBL1 (p107), E2F4/5 and TFDP1/2 (DP1/2). The resulting complex binds MYC promoter and inhibits MYC transcription. Inhibition of MYC transcription contributes to anti-proliferative effect of TGF-beta (Chen et al. 2002). SMAD2/3:SMAD4 heterotrimer also associates with transcription factor SP1. SMAD2/3:SMAD4:SP1 complex stimulates transcription of a CDK inhibitor CDKN2B (p15-INK4B), also contributing to the anti-proliferative effect of TGF-beta (Feng et al. 2000). <br><br>MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, forms a complex with SMAD2/3:SMAD4 heterotrimer, but transcriptional targets of SMAD2/3:SMAD4:MEN1 have not been elucidated (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012). <br><br>JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999). Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0045944 Pubmed10022869 Pubmed10934479 Pubmed11013220 Pubmed11274402 Pubmed11294908 Pubmed12150994 Pubmed12592392 Pubmed14657019 Pubmed15150273 Pubmed18568018 Pubmed19914168 Pubmed22275377 Reactome Database ID Release 432173796 Reactome, http://www.reactome.org ReactomeREACT_120734 Reviewed: Huang, Tao, 2012-05-14 Downregulation of SMAD2/3:SMAD4 transcriptional activity Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0000122 Pubmed10199400 Pubmed10485843 Pubmed10531062 Pubmed10535941 Pubmed10549282 Pubmed11389444 Pubmed11427533 Pubmed16751101 Pubmed17591695 Pubmed19135894 Pubmed19917253 Pubmed21095583 Pubmed22045334 Reactome Database ID Release 432173795 Reactome, http://www.reactome.org ReactomeREACT_121111 Reviewed: Huang, Tao, 2012-05-14 Transcriptional activity of SMAD2/3:SMAD4 heterotrimer can be inhibited by formation of a complex with SKI or SKIL (SNO), where SKI or SKIL recruit NCOR and possibly other transcriptional repressors to SMAD-binding promoter elements (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Higher levels of phosphorylated SMAD2 and SMAD3, however, may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001) through recruitment of SMURF2 (Bonni et al. 2001) or RNF111 i.e. Arkadia (Levy et al. 2007) ubiquitin ligases to SKI/SKIL by SMAD2/3. Therefore,the ratio of SMAD2/3 and SKI/SKIL determines the outcome: inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL. SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex. <br>SMAD4 can be monoubiquitinated by a nuclear ubiquitin ligase TRIM33 (Ecto, Ectodermin, Tif1-gamma). Monoubiquitination of SMAD4 disrupts SMAD2/3:SMAD4 heterotrimers and leads to SMAD4 translocation to the cytosol. In the cytosol, SMAD4 can be deubiquitinated by USP9X (FAM), reversing TRIM33-mediated negative regulation (Dupont et al. 2009).<br>Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8 or CDK9 primes SMAD2/3:SMAD4 complex for ubiquitination by NEDD4L and SMURF ubiquitin ligases. NEDD4L ubiquitinates SMAD2/3 and targets SMAD2/3:SMAD4 heterotrimer for degradation (Gao et al. 2009). SMURF2 monoubiquitinates SMAD2/3, leading to disruption of SMAD2/3:SMAD4 complexes (Tang et al. 2011). <br>Transcriptional repressors TGIF1 and TGIF2 bind SMAD2/3:SMAD4 complexes and inhibit SMAD-mediated transcription by recruitment of histone deacetylase HDAC1 to SMAD-binding promoter elements (Wotton et al. 1999, Melhuish et al. 2001).<br>PARP1 can attach poly ADP-ribosyl chains to SMAD3 and SMAD4 within SMAD2/3:SMAD4 heterotrimers. PARylated SMAD2/3:SMAD4 complexes are unable to bind SMAD-binding DNA elements (SBEs) (Lonn et al. 2010). <br>Phosphorylated SMAD2 and SMAD3 can be dephosphorylated by PPM1A protein phosphatase, leading to dissociation of SMAD2/3 complexes and translocation of unphosphorylated SMAD2/3 to the cytosol (Lin et al. 2006). RNA Polymerase I, RNA Polymerase III, and Mitochondrial Transcription Authored: Comai, L, Conaway, JW, Conaway, RC, Gustafsson, C, Hernandez, N, Hu, P, Larsson, N-G, Proudfoot, NJ, Reinberg, D, Timmers, HTM, 2003--0-9- Edited: Gillespie, ME, Gopinathrao, G, Joshi-Tope, G, 0000-00-00 00:00:00 Reactome Database ID Release 43504046 Reactome, http://www.reactome.org ReactomeREACT_21352 Reviewed: Paule, M, Zhao, X, Willis, I, 0000-00-00 00:00:00 Transcription by RNA Polymerase I, RNA Polymerase III and transcription from mitochondrial promoters. RNA Polymerase I Transcription Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006360 Reactome Database ID Release 4373864 Reactome, http://www.reactome.org ReactomeREACT_1309 Reviewed: Paule, M, Zhao, X, 0000-00-00 00:00:00 The rRNA genes are transcribed by RNA polymerase I, one of three eukaryotic nuclear RNA polymerases. The polymerase is a multisubunit complex, composed of two large subunits (the most conserved portions include the catalytic site that shares similarity with other eukaryotic and bacterial multisubunit RNA polymerases) and a number of smaller subunits. Under a number of experimental conditions the core is competent to mediate ribonucleic acid synthesis, in vivo however, it requires additional factors to select the appropriate template. In humans the RNA transcript (45S) is approximately 13,000 nucleotides long. Before leaving the nucleus as assembled ribosomal particles, the 45S rRNA is cleaved to give one copy each of the 28S rRNA, the 18S rRNA, and the 5.8S rRNA. Equal quantities of the three rRNAs are produced by initially transcribing them as one transcript. RNA Polymerase I Promoter Clearance Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006361 Promoter clearance is one of the rate-limiting steps in Polymerase I transcription. This step is composed of three phases, promoter opening, transcription initiation and promoter escape. Reactome Database ID Release 4373854 Reactome, http://www.reactome.org ReactomeREACT_1974 RNA Polymerase I Promoter Opening Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006361 Reactome Database ID Release 4373728 Reactome, http://www.reactome.org ReactomeREACT_2232 The activity of the upstream binding factor (UBF-1) plays an important role in the regulation of rRNA synthesis. Studies reveal that phosphorylation of UBF-1 is required for its interaction with the RNA polymerase I complex, suggesting that phosphorylation of UBF-1 bound to the rDNA promoter during promoter opening modulates the assembly of the transcription initiation complex. Nuclear Receptor transcription pathway A classic example of bifunctional transcription factors is the family of Nuclear Receptor (NR) proteins. These are DNA-binding transcription factors that bind certain hormones, vitamins, and other small, diffusible signaling molecules. The non-liganded NRs recruit specific corepressor complexes of the NCOR/SMRT type, to mediate transcriptional repression of the target genes to which they are bound. During signaling, ligand binding to a specific domain the NR proteins induces a conformational change that results in the exchange of the associated CoR complex, and its replacement by a specific coactivator complex of the TRAP / DRIP / Mediator type. These coactivator complexes typically nucleate around a MED1 coactivator protein that is directly bound to the NR transcription factor.<p>A general feature of the 49 human NR proteins is that in the unliganded state, they each bind directly to an NCOR corepressor protein, either NCOR1 or NCOR2 (NCOR2 was previously named "SMRT"). This NCOR protein nucleates the assembly of additional, specific corepressor proteins, depending on the cell and DNA context. The NR-NCOR interaction is mediated by a specific protein interaction domain (PID) present in the NRs that binds to specific cognate PID(s) present in the NCOR proteins. Thus, the human NRs each take part in an NR-NCOR binding reaction in the absence of binding by their ligand.<p>A second general feature of the NR proteins is that they each contain an additional, but different PID that mediates specific binding interactions with MED1 proteins. In the ligand-bound state, NRs each take part in an NR-MED1 binding reaction to form an NR-MED1 complex. The bound MED1 then functions to nucleate the assembly of additional specific coactivator proteins, depending on the cell and DNA context, such as what specific target gene promoter they are bound to, and in what cell type.<p>The formation of specific MED1-containing coactivator complexes on specific NR proteins has been well-characterized for a number of the human NR proteins (see Table 1 in (Bourbon, 2004)). For example, binding of thyroid hormone (TH) to the human TH Receptor (THRA or THRB) was found to result in the recruitment of a specific complex of Thyroid Receptor Associated Proteins - the TRAP coactivator complex - of which the TRAP220 subunit was later identified to be the Mediator 1 (MED1) homologue.<p>Similarly, binding of Vitamin D to the human Vitamin D3 Receptor was found to result in the recruitment of a specific complex of D Receptor Interacting Proteins - the DRIP coactivator complex, of which the DRIP205 subunit was later identified to be human MED1. Authored: Caudy, M, 2008-11-20 05:11:03 Edited: Caudy, M, 2009-05-26 21:05:28 GENE ONTOLOGYGO:0006367 Reactome Database ID Release 43383280 Reactome, http://www.reactome.org ReactomeREACT_15525 Reviewed: Freedman, LP, 2009-08-29 Generic Transcription Pathway <b>OVERVIEW OF TRANSCRIPTION REGULATION:</b> <br><br>Detailed studies of gene transcription regulation in a wide variety of eukaryotic systems has revealed the general principles and mechanisms by which cell- or tissue-specific regulation of differential gene transcription is mediated (reviewed in Naar, 2001. Kadonaga, 2004, Maston, 2006, Barolo, 2002; Roeder, 2005, Rosenfeld, 2006). Of the three major classes of DNA polymerase involved in eukaryotic gene transcription, Polymerase II generally regulates protein-encoding genes. Figure 1 shows a diagram of the various components involved in cell-specific regulation of Pol-II gene transcription. <br><br>Core Promoter: Pol II-regulated genes typically have a Core Promoter where Pol II and a variety of general factors bind to specific DNA motifs: <br> i: the TATA box (TATA DNA sequence), which is bound by the "TATA-binding protein" (TBP).<br> ii: the Initiator motif (INR), where Pol II and certain other core factors bind, is present in many Pol II-regulated genes.<br> iii: the Downstream Promoter Element (DPE), which is present in a subset of Pol II genes, and where additional core factors bind. <br>The core promoter binding factors are generally ubiquitously expressed, although there are exceptions to this.<br><br>Proximal Promoter: immediately upstream (5') of the core promoter, Pol II target genes often have a Proximal Promoter region that spans up to 500 base pairs (b.p.), or even to 1000 b.p.. This region contains a number of functional DNA binding sites for a specific set of transcription activator (TA) and transcription repressor (TR) proteins. These TA and TR factors are generally cell- or tissue-specific in expression, rather than ubiquitous, so that the presence of their cognate binding sites in the proximal promoter region programs cell- or tissue-specific expression of the target gene, perhaps in conjunction with TA and TR complexes bound in distal enhancer regions. <br><br>Distal Enhancer(s): many or most Pol II regulated genes in higher eukaryotes have one or more distal Enhancer regions which are essential for proper regulation of the gene, often in a cell or tissue-specific pattern. Like the proximal promoter region, each of the distal enhancer regions typically contain a cluster of binding sites for specific TA and/or TR DNA-binding factors, rather than just a single site. <br><br> Enhancers generally have three defining characteristics:<br> i: They can be located very long distances from the promoter of the target gene they regulate, sometimes as far as 100 Kb, or more.<br> ii: They can be either upstream (5') or downstream (3') of the target gene, including within introns of that gene.<br> iii: They can function in either orientation in the DNA.<br><br>Combinatorial mechanisms of transcription regulation: The specific combination of TA and TR binding sites within the proximal promoter and/or distal enhancer(s) provides a "combinatorial transcription code" that mediates cell- or tissue-specific expression of the associated target gene. Each promoter or enhancer region mediates expression in a specific subset of the overall expression pattern. In at least some cases, each enhancer region functions completely independently of the others, so that the overall expression pattern is a linear combination of the expression patterns of each of the enhancer modules.<br><br>Co-Activator and Co-Repressor Complexes: DNA-bound TA and TR proteins typically recruit the assembly of specific Co-Activator (Co-A) and Co-Repressor (Co-R) Complexes, respectively, which are essential for regulating target gene transcription. Both Co-A's and Co-R's are multi-protein complexes that contain several specific protein components.<br><br>Co-Activator complexes generally contain at lease one component protein that has Histone Acetyl Transferase (HAT) enzymatic activity. This functions to acetylate Histones and/or other chromatin-associated factors, which typically increases that transcription activation of the target gene. By contrast, Co-Repressor complexes generally contain at lease one component protein that has Histone De-Acetylase (HDAC) enzymatic activity. This functions to de-acetylate Histones and/or other chromatin-associated factors. This typically increases the transcription repression of the target gene.<br><br>Adaptor (Mediator) complexes: In addition to the co-activator complexes that assemble on particular cell-specific TA factors, - there are at least two additional transcriptional co-activator complexes common to most cells. One of these is the Mediator complex, which functions as an "adaptor" complex that bridges between the tissue-specific co-activator complexes assembled in the proximal promoter (or distal enhancers). The human Mediator complex has been shown to contain at least 19 protein distinct components. Different combinations of these co-activator proteins are also found to be components of specific transcription Co-Activator complexes, such as the DRIP, TRAP and ARC complexes described below. <br><br>TBP/TAF complex: Another large Co-A complex is the "TBP-associated factors" (TAFs) that assemble on TBP (TATA-Binding Protein), which is bound to the TATA box present in many promoters. There are at least 23 human TAF proteins that have been identified. Many of these are ubiquitously expressed, but TAFs can also be expressed in a cell or tissue-specific pattern. <br><br> <b> Specific Coactivator Complexes for DNA-binding Transcription Factors.</b> <br><br>A number of specific co-activator complexes for DNA-binding transcription factors have been identified, including DRIP, TRAP, and ARC (reviewed in Bourbon, 2004, Blazek, 2005, Conaway, 2005, and Malik, 2005). The DRIP co-activator complex was originally identified and named as a specific complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). Similarly, the TRAP co-activator complex was originally identified as a complex that associates with the thyroid receptor (Yuan, 1998). It was later determined that all of the components of the DRIP complex are also present in the TRAP complex, and the ARC complex (discussed further below). For example, the DRIP205 and TRAP220 proteins were show to be identical, as were specific pairs of the other components of these complexes (Rachez, 1999).<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator ("adaptor") complex proteins (reviewed in Bourbon, 2004). The Mediator proteins were originally identified in yeast by Kornberg and colleagues, as complexes associated with DNA polymerase (Kelleher, 1990). In higher organisms, Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (Figure 1). However, many of the Mediator homologues can also be found in complexes associated with specific transcription factors in higher organisms. A unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004). For example, the DRIP205 / TRAP220 proteins are now identified as Mediator 1 (Rachez, 1999), based on homology with yeast Mediator 1.<br><br> <b>Example Pathway: Specific Regulation of Target Genes During Notch Signaling:</b> <br><br>One well-studied example of cell-specific regulation of gene transcription is selective regulation of target genes during Notch signaling. Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL. <br><br>In Drosophila, Su(H) is known to be bifunctional, in that it represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.<br><br>Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).<br><br>In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila. <br><br>During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus (Figure 2). Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-R complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002). <br><br>Thus, CSL is a good example of a bifunctional DNA-binding transcription factor that mediates repression of specific targets genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling. GENE ONTOLOGYGO:0006367 Pubmed10235266 Pubmed11395415 Pubmed11861166 Pubmed12023297 Pubmed14744435 Pubmed14986688 Pubmed15175151 Pubmed15680972 Pubmed15680973 Pubmed15690163 Pubmed15896744 Pubmed16429119 Pubmed16719718 Pubmed16751179 Pubmed16921404 Reactome Database ID Release 43212436 Reactome, http://www.reactome.org ReactomeREACT_12627 Reviewed: Freedman, LP, 2008-02-25 20:35:15 Notch-HLH transcription pathway <b>THE NOTCH-HLH TRANSCRIPTION PATHWAY:</b> <br><br> Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL.<br><br>CSL is an example of a bifunctional DNA-binding transcription factor that mediates repression of specific target genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling.<br><br>In Drosophila, Su(H) represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.<br><br>Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).<br><br>In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila. <br><br>During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus. Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-A complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002).<br><br>Mammalian CSL Corepressor Complexes: In the absence of activated Notch signaling, DNA-bound CSL proteins recruit a corepressor complex to maintain target genes in the repressed state until Notch is specifically activated. The mammalian corepressor complexes include NCOR complexes, but may also include additional corepressor proteins, such as SHARP (reviewed in Mumm, 2000 and Kovall, 2007). The exact composition of the CSL NCOR complex is not known, but in other pathways the "core" NCOR corepressor complex includes at least one NCOR protein (NCOR1, NCOR2, CIR), one Histone Deacetylase protein (HDAC1, HDAC2, HDAC3, etc), and one TBL1 protein (TBL1X, TBL1XR1) (reviewed in Rosenfeld, 2006). In some contexts, the core NCOR corepressor complex may also recruit additional corepressor proteins or complexes, such as the SIN3 complex, which consists of SIN3 (SIN3A, SIN3B), and SAP30, or other SIN3-associated proteins. An additional CSL - NCOR binding corepressor, SHARP, may also contribute to the CSL corepressor complex in some contexts (Oswald, 2002). The CSL corepressor complex also includes a bifunctional cofactor, SKIP, that is present in both CSL corepressor complexes and CSL coactivator complexes, and may function in the binding of NICD and displacement of the corepressor complex during activated Notch signaling (Zhou, 2000).<br><br>Mammalian CSL Coactivator Complexes: Upon activation of Notch signaling, cleavage of the transmembrane Notch receptor releases the Notch Intracellular Domain (NICD), which translocates to the nucleus, where it binds to CSL and displaces the corepressor complex from CSL (reviewed in Mumm, 2000 and Kovall, 2007). The resulting CSL-NICD "binary complex" then recruits an additional coactivator, Mastermind (Mam), to form a ternary complex. The ternary complex then recruits additional, more general coactivators, such as CREB Binding Protein (CBP), or the related p300 coactivator, and a number of Histone Acetytransferase (HAT) proteins, including GCN5 and PCAF (Fryer, 2002). There is evidence that Mam also can subsequently recruit specific kinases that phosphorylate NICD, to downregulate its function and turn off Notch signaling (Fryer, 2004).<br><br>Combinatorial Complexity in Transcription Cofactor Complexes: HDAC9 has at least 7 splice isoforms, with some having distinct interaction and functional properties. Isoforms 6 and 7 interact with NCOR1. Isoforms 1 and 4 interact with MEF2 (Sparrow, 1999), which is a specific DNA-binding cofactor for a subset of HLH proteins. Isoform 3 interacts with both NCOR1 and MEF2. Although many HDACs only have one or two isoforms, this complexity for HDAC9 illustrates the level of transcript complexity and functional specificity that such "general" transcriptional cofactors can have. GENE ONTOLOGYGO:0006367 Pubmed10487760 Pubmed10713164 Pubmed11112321 Pubmed11535832 Pubmed11604511 Pubmed12050117 Pubmed12370315 Pubmed12374742 Pubmed12897056 Pubmed14986688 Pubmed15546612 Pubmed16024779 Pubmed16429119 Pubmed16530045 Pubmed16921404 Pubmed17157496 Reactome Database ID Release 43350054 Reactome, http://www.reactome.org ReactomeREACT_14835 Lysyl oxidases Converted from EntitySet in Reactome Reactome DB_ID: 2022119 Reactome Database ID Release 432022119 Reactome, http://www.reactome.org ReactomeREACT_150669 SLBP Dependent Processing of Replication-Dependent Histone Pre-mRNAs Authored: Marzluff, WF, 2003-08-22 00:29:39 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008334 Pubmed2017161 Pubmed8479907 Reactome Database ID Release 4377588 Reactome, http://www.reactome.org ReactomeREACT_1364 There are two well-documented trans-acting factors required for histone pre-mRNA processing. These are:<p>1 Stem-loop binding protein (SLBP), also termed hairpin binding protein (HBP). This 32 kDa protein is likely the first protein that binds to the histone pre-mRNA as it is being transcribed. <p>The U7 snRNP. This particle contains the U7 snRNA, the smallest of the snRNAs which varies from 57-70 nts long depending on the species. The 5’ end of U7 snRNA binds to a sequence 3’ of the stemloop, termed the histone downstream element (HDE). There are a number of proteins found in the U7 snRNP. There are 7 Sm proteins, as are present in the spliceosomal snRNP. Five of these proteins are the same as ones found in the spliceosomal snRNPs and there are 2, Lsm10 and Lsm11 that are unique to U7 snRNP.<p> A third protein joins the U7 snRNP, ZFP100, a large zinc finger protein. ZFP100 interacts with SLBP bound to the histone pre-mRNA and with Lsm11 and likely plays a critical role in recruiting U7 snRNP to the histone pre-mRNA.<p> It should be noted that there must be other trans-acting factors, including the factor that catalyzes the cleavage reaction. The cleavage occurs in the presence of EDTA as does the cleavage reaction in polyadenylation, it is likely that this reaction is catalyzed by a protein. There may well be additional proteins associated with U7 snRNP, and since under some conditions in vitro processing occurs in the absence of SLBP, it is possible that all of the other factors required for processing are associated with the active form of U7 snRNP. SLBP independent Processing of Histone Pre-mRNAs Authored: Marzluff, WF, 2003-08-22 00:29:39 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008334 Reactome Database ID Release 43111367 Reactome, http://www.reactome.org ReactomeREACT_185 This class of mRNAs is expressed from genes that lack introns yet the transcripts end in polyA tails. These tails are formed by a mechanism similar to that for pre-mRNAs containing introns. It is believed that there is a cis-element that replaces the 3’ splice site that normally serves to activate polyadenylation of intron containing pre-mRNAs. Processing of Capped Intronless Pre-mRNA Authored: Marzluff, WF, 2003-08-22 00:29:39 Co-transcriptional pre-mRNA splicing is not obligatory. Pre-mRNA splicing begins co-transcriptionally and often continues post-transcriptionally. Human genes contain an average of nine introns per gene, which cannot serve as splicing substrates until both 5' and 3' ends of each intron are synthesized. Thus the time that it takes for pol II to synthesize each intron defines a minimal time and distance along the gene in which splicing factors can be recruited. The time that it takes for pol II to reach the end of the gene defines the maximal time in which splicing could occur co-transcriptionally. Thus, the kinetics of transcription can affect the kinetics of splicing.<br> There are two classes of intronless pre-mRNAs (mRNAs expressed from genes that lack introns). The first class encodes the replication dependent histone mRNAs. These mRNAs have unique 3' ends that do not have a polyA tail. The replication dependent histone mRNAs in all metazoans, as well as Chlamydomonas and Volvox fall into this class. <p>The second class of mRNAs end in polyA tails, which are formed by a mechanism similar to that which poly-adenylate pre-mRNAs containing introns. In the intronless genes there is a different method of replacing the 3' splice site that activates polyadenylation. Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0031124 Pubmed10571029 Pubmed11031238 Pubmed12242288 Pubmed12408966 Pubmed7597053 Reactome Database ID Release 4375067 Reactome, http://www.reactome.org ReactomeREACT_1768 Import of palmitoyl-CoA into the mitochondrial matrix Authored: Gopinathrao, G, 2007-07-29 21:03:03 GENE ONTOLOGYGO:0006853 Pubmed10856709 Pubmed11257506 Reactome Database ID Release 43200425 Reactome, http://www.reactome.org ReactomeREACT_11082 Reviewed: D'Eustachio, P, 2007-07-31 18:50:15 The mitochondrial carnitine system catalyzes the transport of long-chain fatty acids into the mitochondrial matrix where they undergo beta oxidation. This transport system consists of the malonyl-CoA sensitive carnitine palmitoyltransferase I (CPT-I) localized in the mitochondrial outer membrane, the carnitine:acylcarnitine translocase, an integral inner membrane protein, and carnitine palmitoyltransferase II localized on the matrix side of the inner membrane. (Kerner and Hoppel, 2000). Gene Expression Authored: Kornblihtt, AR, Proudfoot, NJ, Caudy, M, D'Eustachio, P, 2008-12-03 01:43:15 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0010467 Gene Expression covers the pathways by which genomic DNA is transcribed to yield RNA, the regulation of these transcription processes, and the pathways by which newly-made RNA Transcripts are processed. Most annotation is centered on the generation of messenger RNAs (mRNAs) by regulated RNA polymerase II (PolII) transcription, although the activities of PolI and PolIII are also covered briefly, as are some aspects of microRNA generation and function.<p>Aspects of mRNA synthesis annotated here include the assembly of transcription factor complexes and their role in targeting specific genes for transcription, PolII-mediated transcription (RNA synthesis) itself, and the co- and post-translational processing of this RNA, via capping, splicing, and 3'-cleavage and polyadenylation to yield mature mRNA molecules that are exported from the nucleus. mRNA editing and nonsense-mediated decay are also annotated. Processes leading to mRNA breakdown are described: deadenylation-dependent mRNA decay, microRNA-mediated RNA cleavage, and regulation of mRNA stability by proteins that bind AU-rich elements.<p>Other pathways included here are tRNA aminoacylation and snRNP assembly. Reactome Database ID Release 4374160 Reactome, http://www.reactome.org ReactomeREACT_71 Processing of Intronless Pre-mRNAs Authored: Wahle, E, 2003-06-05 08:30:31 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed11909521 Reactome Database ID Release 4377595 Reactome, http://www.reactome.org ReactomeREACT_1096 The 3' ends of eukaryotic mRNAs are generated by posttranscriptional processing of an extended primary transcript. For almost all RNAs, 3' processing consists of two steps: The mRNA is first cleaved at a particular phosphodiester bond downstream of the coding sequence. The upstream fragment then receives a poly(A) tail of approximately 250 adenylate residues whereas the downstream fragment is degraded. The two partial reactions are coupled so that reaction intermediates are usually undetectable. While 3' processing can be studied as an isolated event in vitro, it appears to be connected to transcription, splicing and transcription termination in vivo. Activated AMPK stimulates fatty-acid oxidation in muscle AMPK plays a central role in regulating fatty acid oxidation in muscle. In order for fatty acids taken up and converted to fatty acyl CoA’s by muscle cells to undergo beta-oxidation, they must be transported into the mitochondrial matrix by carnitine palmitoyl transferase (CPT). This transport process is negatively regulated by malonyl CoA, synthesized by ACC2 enzyme on the outer mitochondrial membrane. Phosphorylation and activation of AMPK as a result of signaling via leptin, adiponectin, and alpha-adrenergic receptors, however, enables this enzyme to phosphorylate and <b><i>in</b></i>activate ACC2, reducing the levels of malonyl CoA and thus facilitating CPT-mediated fatty acid transport (Kahn et al.,2005). <br>The mitochondrial CPT transport system consists of the malonyl-CoA sensitive carnitine palmitoyltransferase I (CPT-I) localized in the mitochondrial outer membrane, the carnitine:acylcarnitine translocase, an integral inner membrane protein, and carnitine palmitoyltransferase II localized on the matrix side of the inner membrane (Kerner and Hoppel, 2000).<br>In this module, the effect of activated AMPK on fatty acid beta oxidation as mediated by malonyl CoA in muscle cells is annotated. The mechanisms by which leptin and adrenergic receptors modulate AMPK activity will be annotated in the future. Authored: Gopinathrao, G, 2007-07-29 21:03:03 GENE ONTOLOGYGO:0046320 Pubmed10856709 Pubmed11797013 Pubmed16054041 Reactome Database ID Release 43200409 Reactome, http://www.reactome.org ReactomeREACT_11163 Reviewed: D'Eustachio, P, 2007-07-31 18:50:15 RNA Polymerase II Transcription Pre-Initiation And Promoter Opening Authored: Reinberg, D, 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Formation of the pre-initiation complex GENE ONTOLOGYGO:0006367 Pubmed8946909 Reactome Database ID Release 4373779 Reactome, http://www.reactome.org ReactomeREACT_1655 RNA Polymerase II Transcription Initiation And Promoter Clearance Reactome Database ID Release 4376042 Reactome, http://www.reactome.org ReactomeREACT_834 RNA Polymerase II Transcription Initiation Authored: Timmers, H. T. M., 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Formation of the open complex exposes the template strand to the catalytic center of the RNA polymerase II enzyme. This facilitates formation of the first phosphodiester bond, which marks transcription initiation. As a result of this, the TFIIB basal transcription factor dissociates from the initiation complex.<p>The open transcription initiation complex is unstable and can revert to the closed state. Initiation at this stage requires continued (d)ATP-hydrolysis by TFIIH. Dinucleotide transcripts are not stably associated with the transcription complex. Upon dissociation they form abortive products. The transcription complex is also sensitive to inhibition by small oligo-nucleotides. <p>Dinucleotides complementary to position -1 and +1 in the template can also direct first phosphodiester bond formation. This reaction is independent on the basal transcription factors TFIIE and TFIIH and does not involve “full” open complex formation. This reaction is sensitive to inhibition by single-stranded oligonucleotides. GENE ONTOLOGYGO:0006367 Pubmed11784853 Pubmed3667620 Pubmed7601352 Pubmed8612591 Pubmed9405375 Reactome Database ID Release 4375953 Reactome, http://www.reactome.org ReactomeREACT_1851 RNA Polymerase II Promoter Escape Authored: Timmers, H. T. M., 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006368 Pubmed9405375 RNA Polymerase II promoter escape occurs after the first phosphodiester bond has been created. Reactome Database ID Release 4373776 Reactome, http://www.reactome.org ReactomeREACT_2089 POLRMT chain elongation Authored: Gustafsson, C, 2005-04-25 22:00:00 Edited: Matthews, L, 0000-00-00 00:00:00 Reactome Database ID Release 43163318 Reactome, http://www.reactome.org ReactomeREACT_1575 Reviewed: Cantatore, P, 0000-00-00 00:00:00 The details of the mechanism of POLRMT chain elongation have not yet been determined. Mitochondrial transcription termination Authored: Gustafsson, C, 2005-04-25 22:00:00 Edited: Matthews, L, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006393 Pubmed2276421 Pubmed2752429 Pubmed3018722 Pubmed6086013 Pubmed6185947 Pubmed6883508 Pubmed9118945 Reactome Database ID Release 43163316 Reactome, http://www.reactome.org ReactomeREACT_610 Reviewed: Cantatore, P, 0000-00-00 00:00:00 Transcription of the heavy (H)-strand of mitochondrial DNA (mtDNA) involves two overlapping transcription units (Montoyaet al.,1982; Montoya et al., 1983). The first unit starts right upstream of the tRNAPhe gene and spans the tRNAPhe, rRNA 12S, rRNA 16S and tRNAVal genes (initiation site IH1). The other starts about 100 bp further downstream (initiation site IH2), at the boundary between tRNAPhe and rRNA12S genes, and produces a single polycistronic RNA that encompasses almost the entire length of the H-strand. The ribosomal transcription unit is transcribed at a much higher rate compared to the other transcription unit and control of its expression is exerted both at the level of initiation and termination (Gelfand and Attardi, 1981; Attardi et al., 1990). A central role in the control of termination has been attributed to the mitochondrial transcription termination factor (mTERF), a 39-kDa protein that binds to a 28-base pair region of mtDNA located within the tRNALeu(UUR) gene, at a position immediately downstream of the rRNA 16S gene (Fernandez-Silva et al.,1997; Kruse et al., 1989). Lysyl oxidase propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2022080 Reactome Database ID Release 432022080 Reactome, http://www.reactome.org ReactomeREACT_151701 RNA Polymerase II Transcription GENE ONTOLOGYGO:0006366 Reactome Database ID Release 4373857 Reactome, http://www.reactome.org ReactomeREACT_1366 RNA Polymerase II Pre-transcription Events Reactome Database ID Release 43674695 Reactome, http://www.reactome.org ReactomeREACT_22107 Mitochondrial transcription initiation Authored: Gustafsson, C, 2005-04-25 22:00:00 Edited: Matthews, L, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006391 Human mtDNA is transcribed by a dedicated mitochondrial RNA polymerase (POLRMT), which displays significant sequence similarity to the monomeric RNA polymerases found in bacteriophages. In contrast to the phage T7 RNA polymerase, POLRMT cannot interact with promoter DNA and initiate transcription on its own, but requires the presence of the mitochondrial transcription factor A (TFAM), and either transcription factor B1 (TFB1M) or B2 (TFB2M). The 4 proteins of the basal mitochondrial transcription machinery have been purified in recombinant form and used to reconstitute transcription in vitro with a promoter containing DNA fragment (Falkenberg et al., 2002). Although both TFB1M and TFB2M can support in vitro transcription with POLRMT, TFB2M is at least two orders of magnitude more active than TFB1M and the physiological role of TFB1M in mitochondrial transcription has not yet been completely defined. The TFB1M and TFB2M display primary sequence similarity to a family of rRNA methyltransferases, which dimethylates two adjacent adenosine bases near the 3’ end of the small subunit rRNA during ribosome biogenesis (Falkenberg et al., 2002; McCulloch et al., 2002). Human TFB1M is, in fact, a dual function protein, which not only support mitochondrial transcription in vitro, but also acts as a rRNA methyltransferase (Seidel-Rogol et al., 2003). The methyltransferase activity is not required for transcription, since point mutations in conserved methyltransferase motifs of TFB1M revealed that it stimulates transcription in vitro independently of S-adenosylmethionine binding and rRNA methyltransferase activity. Pubmed11041509 Pubmed11809803 Pubmed12068295 Pubmed12496758 Pubmed12525854 Reactome Database ID Release 43163282 Reactome, http://www.reactome.org ReactomeREACT_367 Reviewed: Cantatore, P, 0000-00-00 00:00:00 Transcription from mitochondrial promoters Authored: Gustafsson, C, 2005-04-25 22:00:00 Edited: Matthews, L, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006390 Pubmed1809353 Pubmed3018722 Pubmed6185947 Pubmed6883508 Pubmed7219536 Pubmed9242913 Reactome Database ID Release 4375944 Reactome, http://www.reactome.org ReactomeREACT_1484 Reviewed: Cantatore, P, 0000-00-00 00:00:00 Thirteen of the ~80 different proteins present in the respiratory chain of human mitochondria are encoded by the mitochondrial genome (mtDNA). The circular mtDNA, which is present in 1000 to 10000 copies in the human cell, also encodes for 2 ribosomal RNAs, and 22 transfer RNAs. The double-stranded mitochondrial genome lacks introns and the longer non-coding region contains the control elements for transcription and replication of mtDNA (Shadel and Clayton, 1997). The two mtDNA strands are referred to as the heavy (H-strand) and the light (L-strand) due to their differing G+T content. In human cells, each strand contains one single promoter for transcriptional initiation, the light-strand promoter (LSP) or the heavy-strand promoter (HSP). Transcription from the mitochondrial promoters produce polycistronic precursor RNA encompassing all the genetic information encoded in each of the specific strands. The primary transcripts are processed to produce the individual tRNA and mRNA molecules (Clayton, 1991; Ojala et al., 1981). There is likely a second initiation site for heavy strand transcription, which produces RNAs spanning the rDNA region. The resulting transcript including the genes for the two mitochondrial rRNAs and ends at the boundary between the 16 S rRNA and the tRNALeu(UUR) genes (Montoya et al., 1982; Montoya et al.,1983; Christianson and Clayton 1986). The existence of such a separate transcription unit may explain why the steady-state levels of rRNAs are much higher than the steady state levels of mRNAs. RNA Polymerase III Transcription Termination Authored: Kassavetis, GA, Geiduschek, EP, 2004-02-27 13:21:23 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006386 Reactome Database ID Release 4373980 Reactome, http://www.reactome.org ReactomeREACT_63 RNA Polymerase III Transcription Initiation From Type 3 Promoter Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed1535687 Pubmed1868835 Pubmed2853685 Pubmed2905684 Pubmed8336708 Pubmed8339931 Pubmed8979085 Pubmed9705341 Pubmed9776743 Reactome Database ID Release 4376071 Reactome, http://www.reactome.org ReactomeREACT_571 The metazoan-specific type 3 promoters, which are exemplified by the human U6 promoter, recruit a complex variously called the snRNA activating protein complex (SNAPc) (Sadowski et al., 1993), the PSE binding protein (PBP) (Waldschmidt et al., 1991), or the PSE transcription factor (PTF) (Murphy et al., 1992). The complex contains five types of subunits and binds to the PSE. Type 3 promoters also recruit Brf2-TFIIIB through a combination of protein-protein contacts with SNAPc and a direct association of the TBP component of Brf2-TFIIIB with the TATA box. This then allows RNA polymerase III to join the complex.<p>The down stream element (DSE) of type 3 promoters, which enhances transcription from the core promoter, almost invariably contains an octamer sequence and an SPH element (also called NONOCT element)(Cheung et al., 1993; Danzeiser et al., 1993; Kunkel et al., 1996; Myslinski et al., 1992). The octamer sequence recruits the POU domain protein Oct-1 (Herr et al., 1988; Sturm et al., 1988), and the SPH element recruits a zinc finger protein known as Staf or SPH binding factor (SBF), which has been cloned from humans (Myslinski et al., 1998; Rincon et al., 1998). RNA Polymerase III Chain Elongation Authored: Kassavetis, GA, Geiduschek, EP, 2004-02-27 13:21:23 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006385 Pol III initiation complexes open the promoter spontaneously similar to the mechanism employed in archaeal and bacterial transcription. Reactome Database ID Release 4373780 Reactome, http://www.reactome.org ReactomeREACT_756 RNA Polymerase III Transcription Initiation From Type 1 Promoter Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed3967290 Pubmed3972795 Pubmed6153931 Pubmed6356356 Pubmed7226225 Reactome Database ID Release 4376061 Reactome, http://www.reactome.org ReactomeREACT_347 The type 1 promoters recruit TFIIIA, the founding member of the C2H2 zinc finger family of DNA-binding proteins (Engelke et al., 1980; Sakonju et al., 1981). The binding of TFIIIA then allows the binding of TFIIC (Lassar et al., 1983), a complex consisting of five subunits (which differs from the six subunits in S. cerevisiae) in human cells and S. pombe. Once the DNA/TFIIIA/TFIIIC complex is formed, Brf1-TFIIIB joins the complex and this in turn allows the recruitment of RNA polymerase III (Bieker et al., 1985; Setzer and Brown, 1985). RNA Polymerase III Transcription Initiation From Type 2 Promoter Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Reactome Database ID Release 4376066 Reactome, http://www.reactome.org ReactomeREACT_1036 The type 2 promoters can recruit TFIIIC without the help of TFIIIA because TFIIIC binds directly to the A and B boxes. As for the type 1 promoters, this then allows the binding of Brf1-TFIIIB and RNA polymerase III. Importantly, in the yeast system, once Brf1-TFIIIB has been recruited to type 1 or 2 promoters, TFIIIA and/or TFIIIC can be stripped from the DNA with high salt or heparin treatment. Brf1-TFIIIB remains bound to the DNA and is sufficient to direct multiple rounds of transcription . RNA Polymerase III Abortive And Retractive Initiation Abortive initiation, the repetitive formation of short oligonucleotides, is a ubiquitous feature of transcriptional initiation. This Pathway contains events inferred from events in Saccharomyces cerevisiae. Authored: Geiduschek, E, 2004-03-29 17:50:49 Edited: Gillespie, ME, 0000-00-00 00:00:00 Reactome Database ID Release 43749476 Reactome, http://www.reactome.org ReactomeREACT_22339 RNA Polymerase III Transcription Initiation Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed2308839 Pubmed2752422 Pubmed6947245 Pubmed7312050 Pubmed7357599 Pubmed7357604 Reactome Database ID Release 4376046 Reactome, http://www.reactome.org ReactomeREACT_281 There are three basic types of RNA polymerase III promoters. The three types of RNA polymerase III promoters are known as type 1, type 2, and type 3 promoters. Type 1 promoters are found in the 5S genes and consist of a gene-internal element called the internal control region (ICR), that is subdivided into A block, intermediate element, and C block (Bogenhagen, 1985; Sakonju et al., 1980). Type 2 promoters are found in tRNA genes, Adenovirus 2 VAI gene, and other genes (Galli et al., 1981; Sharp et al., 1981). These promoters consists of two gene-internal elements called the A and the B boxes. Type 3 promoters consist of a distal sequence element (DSE) that serves as an enhancer, a proximal sequence element (PSE), and a TATA box (Baer et al., 1989; Lobo and Hernandez, 1989). <p>Some promoters combine elements from type 2 and 3 promoters. For example, the <i>S. cerevisiae</i> U6 promoter, also shown in the figure, contains the TATA box typical of type 3 promoters and the A and B boxes typical of type 2 promoters. Moreover, in <i>S. pombe</i>, nearly all tRNA and 5S genes contain a TATA box in addition to gene-internal elements, and the TATA box is required for transcription.   RNA Polymerase I Transcription Termination Authored: Comai, L, 2003-07-03 17:28:24 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006363 Reactome Database ID Release 4373863 Reactome, http://www.reactome.org ReactomeREACT_1074 Termination of transcription by RNA polymerase I is a 4 step process. Initially TTF-1 binds the template rDNA. This complex pauses polymerase I allowing PTRF to interact with the quaternary complex releasing both pre-rRNA and Pol I from the template and TTF-1. RNA Polymerase III Transcription Authored: Hernandez, N, 2003-09-11 07:42:29 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006383 Pubmed11040218 Pubmed11121026 Pubmed9308965 RNA polymerase III is one of three types of nuclear RNA polymerases present in eucaryotic cells. About 10% of the total transcription in dividing cells can be attributed to its activity. It synthesizes an eclectic collection of catalytic or structural RNA molecules, some of which are involved in protein synthesis, pre-mRNA splicing, tRNA processing, and the control of RNA polymerase II elongation, whereas some others have still unknown functions. Like other RNA polymerases, RNA polymerase III cannot recognize its target promoters directly. Instead it is recruited to specific promoter sequences through the help of transcription factors. There are three basic types of RNA polymerase III promoters, called types 1, 2, and 3(Geiduschek and Kassavetis, 1992). Although in vivo, RNA polymerase III may be recruited to these promoters as part of a large complex (holo RNA polymerase III) containing the polymerase and its initiation factors (Wang et al., 1997), in vitro the reaction can be divided into several steps. First, the promoter elements are recognized by DNA binding factors, which then recruit a factor known as TFIIIB. TFIIIB itself then directly contacts RNA polymerase III. In human cells but not in <i>S. cerevisiae</i>, there are at least two versions of TFIIIB. One contains TBP, Bdp1, and Brf1 (Brf1-TFIIIB), and the other TBP, Bdp1, and Brf2 (Brf2-TFIIIB) (Schramm et al., 2000; Teichmann et al., 2000). Reactome Database ID Release 4374158 Reactome, http://www.reactome.org ReactomeREACT_1371 RNA Polymerase I Chain Elongation GENE ONTOLOGYGO:0006362 Reactome Database ID Release 4373777 Reactome, http://www.reactome.org ReactomeREACT_2204 Nonsense Mediated Decay Independent of the Exon Junction Complex Authored: May, B, 2010-10-08 Edited: May, B, 2010-10-08 Nonsense-mediated decay has been observed with mRNAs that do not have an exon junction complex (EJC) downstream of the termination codon (reviewed in Isken and Maquat 2007, Chang et al. 2007, Behm-Ansmant et al. 2007, Rebbapragada and Lykke-Andersen 2009, Nicholson et al. 2010). In these cases the trigger is unknown but a correlation with the length of the 3' UTR has sometimes been seen. The current model posits a competition between PABP and UPF1 for access to eRF3 at the terminating ribosome (Ivanov et al. 2008, Singh et al. 2008, reviewed in Bhuvanagiri et al. 2010). Abnormally long 3' UTRs may prevent PABP from efficiently interacting with eRF3 and allow UPF1 to bind eRF3 instead. Long UTRs with hairpin loops may bring PABP closer to eRF3 and help evade NMD (Eberle et al. 2008).<br>The pathway of degradation taken during EJC-independent NMD has not been elucidated. It is thought that phosphorylation of UPF1 by SMG1 and recruitment of SMG6 or SMG5 and SMG7 are involved, as with EJC-enhanced NMD, but this has not yet been shown. Pubmed17352659 Pubmed17531985 Pubmed17671086 Pubmed18256688 Pubmed18447580 Pubmed18447585 Pubmed19359157 Pubmed19859661 Pubmed20795950 Reactome Database ID Release 43975956 Reactome, http://www.reactome.org ReactomeREACT_75768 Reviewed: Neu-Yilik, G, 2011-05-19 Nonsense Mediated Decay Enhanced by the Exon Junction Complex Authored: May, B, 2010-10-08 During normal translation termination eRF3 associates with the ribosome and then interacts with PABP bound to the polyadenylate tail of the mRNA to release the ribosome and allow a new round of translation to commence. Nonsense-mediated decay (NMD) is triggered if eRF3 at the ribosome interacts with UPF1, which may compete with PABP (reviewed in Isken and Maquat 2007, Chang et al. 2007, Behm-Ansmant et al. 2007, Rebbapragada and Lykke-Andersen 2009, Bhuvanagiri et al. 2010, Nicholson et al. 2010, Durand and Lykke-Andersen 2011). An exon junction located 50-55 nt downstream of a termination codon is observed to enhance NMD.<br> Exon-junction complexes (EJCs) are deposited on the mRNA during splicing in the nucleus, remain on mRNAs after transport to the cytosol, and are dislodged by the ribosome as it progresses along the mRNA during the pioneer round of translation (Gehring et al. 2009). EJCs contain the core factors eIF4A-III, Magoh-Y14, and CASC3 as well as the peripheral factors RNPS1, UPF2, and UPF3. UPF2 and UPF3 recruit UPF1 to eRF3 at the terminating ribosome. Thus an EJC downstream of a termination codon will not have been dislodged during translation and will recruit UPF1, triggering NMD.<br>UPF1 is believed to form a complex containing SMG1, SMG8, and SMG9. In the key regulatory step of NMD SMG1 phosphorylates UPF1. The phosphorylated UPF1 then recruits either SMG6 or SMG5 and SMG7. SMG6 is itself an endoribonuclease that cleaves the mRNA. SMG5 and SMG7 do not have endoribonuclease activty, but are thought to recruit ribonucleases. Nonsense-mediated decay has been observed to involve deadenlyation, decapping, and both 5' to 3' and 3' to 5' exonuclease activities, but the exact degradative pathways taken by a given mRNA are not yet known.<br>UPF1 also plays roles in Staufen-mediated decay, histone mRNA decay, telomere maintenance, genome integrity, and may play a role in normal termination of translation. Edited: May, B, 2010-10-08 Pubmed17352659 Pubmed17531985 Pubmed17671086 Pubmed19359157 Pubmed19410547 Pubmed19859661 Pubmed20795950 Pubmed21496649 Reactome Database ID Release 43975957 Reactome, http://www.reactome.org ReactomeREACT_75822 Reviewed: Neu-Yilik, G, 2011-05-19 MicroRNA (miRNA) Biogenesis Authored: Gopinathrao, G, May, B, 2007-11-18 23:55:40 Biogenesis of microRNAs (miRNAs) can be summarized in five steps (reviewed in Ketting 2011, Nowotny and Yang 2009, Kim et al. 2009, Chua et al. 2009, Hannon and He 2004):<br>1. Transcription. miRNA transcripts may come from autonomously transcribed genes, they may be contained in cotranscripts with other genes, or they may be located in introns of host genes. Most miRNAs are transcribed by RNA polymerase II, however a few miRNAs originate as RNA polymerase III cotranscripts with neighboring repetitive elements. The initial transcript, termed a primary microRNA (pri-miRNA), contains an imperfectly double-stranded region within a hairpin loop. Longer sequences extend from the 5' and 3' ends of the hairpin and may also contain double-stranded regions. <br>2. Cleavage by Drosha. The 5' and 3' ends of the pri-miRNA are removed during endoribonucleolytic cleavage by the Drosha nuclease in a complex with the RNA-binding protein DGCR8 (the Microprocessor complex). The cleavage product is a short hairpin of about 60 to 70 nt called the pre-microRNA (pre-miRNA). <br>3. Nuclear export by Exportin-5. The resulting pre-miRNA is bound by Exportin-5 in a complex with Ran and GTP. The complex translocates the pre-miRNA through the nuclear pore into the cytoplasm. <br>4. Cleavage by Dicer. Once in the cytoplasm the pre-miRNA is bound and cleaved by the Dicer ribonuclease in complex with the RNA-binding protein TRBP (TAR binding protein). The product is an imperfectly double-stranded miRNA of about 21 to 23 nucleotides. At this stage the double-stranded miRNA has protruding single-stranded 3' ends of 2-3 nt. <br>5. Strand selection and incorporation into RNA-Induced Silencing Complex (RISC). At this stage the miRNA has two strands: the passenger strand, which will be removed and degraded, and the guide strand, which will be retained and guides the RISC to target mRNAs. An Argonaute protein is already bound to the Dicer:miRNA complex or subsequently binds the complex (the order is unknown). The human genome encodes 4 Argonaute proteins, however only Argonaute2 can cleave target mRNAs with perfect or nearly perfect complementarity to the guide miRNA. In mammalian cells, such endogenous interactions are very rare; most miRNAs only cause translational repression. For complexes that contain Argonaute2, cleavage of the passenger strand of the double-stranded miRNA accompanies removal of the passenger strand. Complexes containing other Argonautes may use a helicase to remove the passenger strand but this is not fully known. The resulting single-stranded miRNA (the guide strand) remains in a complex containing Argonaute, Dicer, TRBP, and other proteins termed the RNA-induced Silencing Complex (RISC). The full set of proteins composing RISC is not yet known. Edited: May, B, 2009-03-17 16:05:37 Pubmed14744438 Pubmed15145345 Pubmed15211354 Pubmed15364901 Pubmed15372072 Pubmed15525708 Pubmed15944707 Pubmed17057362 Pubmed17099701 Pubmed19165215 Pubmed19330724 Pubmed19477631 Pubmed21755468 Pubmed8252621 Reactome Database ID Release 43203927 Reactome, http://www.reactome.org ReactomeREACT_12417 Reviewed: Karginov, F, Hannon, GJ, 2008-02-08 15:41:16 Regulatory RNA pathways Authored: Gopinathrao, G, 2008-01-22 19:43:40 Edited: May, B, 2009-06-10 In this module, the biology of various types of regulatory non-coding RNAs are described. Currently, biogenesis and functions of small interfering RNAs (siRNAs) and microRNAs are annotated. Pubmed15741316 Pubmed16510870 Pubmed17560368 Pubmed19165215 Pubmed19239886 Pubmed19412884 Pubmed21755468 Reactome Database ID Release 43211000 Reactome, http://www.reactome.org ReactomeREACT_12472 Reviewed: Karginov, F, Hannon, GJ, 2008-02-08 15:41:16 Post-transcriptional Silencing By Small RNAs Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Pubmed12154197 Pubmed15260970 Pubmed15284456 Pubmed16510870 Pubmed17128271 Pubmed17197185 Pubmed17560368 Pubmed17632058 Pubmed18692607 Pubmed19174539 Pubmed19239886 Pubmed19330724 Pubmed19412884 Pubmed19477631 Reactome Database ID Release 43426496 Reactome, http://www.reactome.org ReactomeREACT_118699 Reviewed: Tomari, Y, 2012-02-10 Small RNAs act with components of the RNA-induced silencing complex (RISC) to repress expression of mRNAs (reviewed in Nowotny and Yang 2009, Chua et al. 2009). Two mechanisms exist: 1) cleavage of target RNAs by complexes containing Argonaute2 (AGO2) and a guide RNA that exactly matches the target mRNA and 2) inhibition of translation of target RNAs by complexes containing AGO2 and an inexactly matching guide RNA or by complexes containing a nonendonucleolytic Argonaute (AGO1, AGO3, or AGO4) and a guide RNA of exact or inexact match. Small interfering RNAs (siRNAs) and microRNAs (miRNAs) can serve as guide RNAs in both types of mechanism. <br>RNAi also appears to direct chromatin modifications that cause transcriptional gene silencing (reviewed in Verdel et al. 2009). Small Interfering RNA (siRNA) Biogenesis Authored: May, B, 2009-06-10 Edited: May, B, 2009-06-10 Pubmed15741316 Pubmed19165215 Pubmed19239886 Reactome Database ID Release 43426486 Reactome, http://www.reactome.org ReactomeREACT_118560 Reviewed: Tomari, Y, 2012-02-10 Small interfering RNAs (siRNAs) are 21-25 nucleotide single-stranded RNAs produced by cleavage of longer double-stranded RNAs by the enzyme Dicer. Typically the long double-stranded substrates originate from viruses or repetitive elements in the genome and the two strands of the substrate are exactly complementary.<br>After cleavage by Dicer the 21-25 nucleotide double-stranded product is loaded into an Argonuate protein (humans contain 4 Argonautes) and rendered single-stranded. Collagen alpha-1(XXIV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192928 Reactome Database ID Release 432192928 Reactome, http://www.reactome.org ReactomeREACT_123266 Deadenylation of mRNA Authored: May, B, 2009-07-22 Deadenylation of mRNA proceeds in two steps. According to current models, in the first step the poly(A) tail is shortened from about 200 adenosine residues to about 80 residues by the PAN2-PAN3 complex. In the second step the poly(A) tail is further shortened to 10-15 residues by either the CCR4-NOT complex or by the PARN exoribonuclease. How a particular mRNA is targeted to CCR4-NOT or PARN is unknown.<br>A number of other deadenylase enzymes can be identified in genomic searches. One particularly interesting one is nocturin, a protein that is related to the CCR-1 deadenylase and plays a role in circadian rhythms.<br>There is also evidence for networking between deadenylation and other aspects of gene expression. CCR4-NOT, for example, is known to be a transcription factor. PARN is part of a complex that regulates poly(A) tail length and hence translation in developing oocytes. Edited: May, B, 2009-07-22 GENE ONTOLOGYGO:0000289 Pubmed11283721 Pubmed14749774 Pubmed15475613 Pubmed16141059 Pubmed17052452 Pubmed17245413 Pubmed18608124 Pubmed19239894 Reactome Database ID Release 43429947 Reactome, http://www.reactome.org ReactomeREACT_20514 Reviewed: Wilusz, J, 2009-09-17 mRNA Decay by 3' to 5' Exoribonuclease Authored: May, B, 2009-07-22 Edited: May, B, 2009-07-22 GENE ONTOLOGYGO:0043928 Pubmed11283721 Pubmed14749774 Pubmed15475613 Pubmed16141059 Pubmed17245413 Pubmed19239894 Reactome Database ID Release 43429958 Reactome, http://www.reactome.org ReactomeREACT_20619 Reviewed: Wilusz, J, 2009-09-17 The degradation of mRNA from 3' to 5' occurs in two steps. First, the exosome exoribonuclease complex binds the 3' end of the oligoadenylated mRNA and hydrolyzes it from 3' to 5', yielding ribonucleotides having 5'-monophosphates, until a capped oligoribonucleotide remains. Second, the scavenging decapping enzyme DCPS hydrolyzes the 7-methylguanosine cap. mRNA Decay by 5' to 3' Exoribonuclease Authored: May, B, 2009-07-22 Degradation of mRNA from 5' to 3' occurs in three steps. First, the mRNA is bound at its 3' end by the Lsm1-7 complex. The bound Lsm1-7 may prevent nucleases from accessing the 3' end. Second, the 7-methylguanosine cap of the mRNA is hydrolyzed by the DCP1-DCP2 complex. Third, the 5' end of the decapped mRNA is attacked by the XRN1 exoribonuclease which digests the remainder of the mRNA from 5' to 3'. These processes may be physically connected by PATL1, the homolog of yeast Pat1, which stably binds the Lsm1-7 complex and interacts with the DCP1-DCP2 decapping complex and the Ccr4-NOT deadenylation complex (Ozgur et al. 2010). Edited: May, B, 2009-07-22 GENE ONTOLOGYGO:0043928 Pubmed11283721 Pubmed14749774 Pubmed15475613 Pubmed16141059 Pubmed17245413 Pubmed19239894 Pubmed20584987 Reactome Database ID Release 43430039 Reactome, http://www.reactome.org ReactomeREACT_20518 Reviewed: Wilusz, J, 2009-09-17 Nonsense-Mediated Decay Authored: May, B, 2010-08-06 Edited: May, B, 2010-08-06 GENE ONTOLOGYGO:0000184 Pubmed17352659 Pubmed17531985 Pubmed17671086 Pubmed18524595 Pubmed19010255 Pubmed19359157 Pubmed19859661 Pubmed20795950 Pubmed21496649 Reactome Database ID Release 43927802 Reactome, http://www.reactome.org ReactomeREACT_75886 Reviewed: Neu-Yilik, G, 2011-05-19 The Nonsense-Mediated Decay (NMD) pathway activates the destruction of mRNAs containing premature termination codons (PTCs) (reviewed in Isken and Maquat 2007, Chang et al. 2007, Behm-Ansmant et al. 2007, Neu-Yilik and Kulozik 2008, Rebbapragada and Lykke-Andersen 2009, Bhuvanagiri et al. 2010, Nicholson et al. 2010, Durand and Lykke-Andersen 2011). In mammalian cells a termination codon can be recognized as premature if it precedes an exon-exon junction by at least 50-55 nucleotides or if it is followed by an abnormal 3' untranslated region (UTR). While length of the UTR may play a part, the qualifications for being "abnormal" have not been fully elucidated. Also, some termination codons preceding exon junctions are not degraded by NMD so the criteria for triggering NMD are not yet fully known (reviewed in Rebbapragada and Lykke-Andersen 2009). While about 30% of disease-associated mutations in humans activate NMD, about 10% of normal human transcripts are also degraded by NMD (reviewed in Stalder and Muhlemann 2008, Neu-Yilik and Kulozik 2008, Bhuvanagiri et al. 2010, Nicholson et al. 2010). Thus NMD is a normal physiological process controlling mRNA stability in unmutated cells.<br>Exon junction complexes (EJCs) are deposited on an mRNA during splicing in the nucleus and are displaced by ribosomes during the first round of translation. When a ribosome terminates translation the A site encounters the termination codon and the eRF1 factor enters the empty A site and recruits eRF3. Normally, eRF1 cleaves the translated polypeptide from the tRNA in the P site and eRF3 interacts with Polyadenylate-binding protein (PABP) bound to the polyadenylated tail of the mRNA.<br>During activation of NMD eRF3 interacts with UPF1 which is contained in a complex with SMG1, SMG8, and SMG9. NMD can arbitrarily be divided into EJC-enhanced and EJC-independent pathways. In EJC-enhanced NMD, an exon junction is located downstream of the PTC and the EJC remains on the mRNA after termination of the pioneer round of translation. The core EJC is associated with UPF2 and UPF3, which interact with UPF1 and stimulate NMD. Once bound near the PTC, UPF1 is phosphorylated by SMG1. The phosphorylation is the rate-limiting step in NMD and causes UPF1 to recruit either SMG6, which is an endoribonuclease, or SMG5 and SMG7, which recruit ribonucleases. SMG6 and SMG5:SMG7 recruit phosphatase PP2A to dephosphorylate UPF1 and allow further rounds of degradation. How EJC-independent NMD is activated remains enigmatic but may involve competition between PABP and UPF1 for eRF3. tRNA Aminoacylation Authored: D'Eustachio, P, 2008-11-29 15:41:00 Edited: D'Eustachio, P, 2008-11-29 15:41:00 GENE ONTOLOGYGO:0006418 Pubmed16125937 Pubmed182209 Pubmed18682559 Pubmed18767960 Pubmed1894595 Pubmed5324172 Pubmed5324173 Pubmed764868 Reactome Database ID Release 43379724 Reactome, http://www.reactome.org ReactomeREACT_15482 Reviewed: Antonellis, A, 2008-12-02 16:58:45 tRNA synthetases catalyze the ligation of tRNAs to their cognate amino acids in an ATP-dependent manner. The reaction proceeds in two steps. First, amino acid and ATP form an aminoacyl adenylate molecule, releasing pyrophosphate. The aminoacyl adenylate remains associated with the synthetase enzyme where, in the second step it reacts with tRNA to form aminoacyl tRNA and AMP. The rapid hydrolysis of pyrophosphate makes these reactions essentially irreversible under physiological conditions (Fersht and Kaethner 1976a). Specificity of the tRNA charging reactions is achieved both by specific recognition of amino acid and tRNA substrates by the synthetase, and by an editing process in which incorrect aminoacyl adenylate molecules (e.g., valyl adenylate associated with isoleucyl tRNA synthetase) are hydrolyzed rather than conjugated to tRNAs in the second step of the reaction (Baldwin and Berg 1966a,b; Fersht and Kaethner 1976b). The tRNA synthetases can be divided into two structural classes based on conserved amino acid sequence features (Burnbaum and Schimmel 1991).<p>A single synthetase mediates the charging of all of the tRNA species specific for any one amino acid but, with three exceptions, glycine, lysine, and glutamine, the synthetase that catalyzes aminoacylation of mitochondrial tRNAs is encoded by a different gene than the one that acts on mitochondrial tRNAs. Both mitochondrial and cytosolic tRNA synthetase enzymes are encoded by genes in the nuclear genome.<p>A number of tRNA synthetases are known to have functions distinct from tRNA charging (reviewed by Park et al. 2005). Additionally, mutations in several of the tRNA synthetases, often affecting protein domains that are dispensable in vitro for aminoacyl tRNA synthesis, are associated with a diverse array of neurological and other diseases (Antonellis and Green 2008; Park et al. 2008). These findings raise interest into the role of these enzymes in human development and disease.<p> Cleavage of Growing Transcript in the Termination Region Authored: Proudfoot, NJ, 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006369 Reactome Database ID Release 43109688 Reactome, http://www.reactome.org ReactomeREACT_387 This section includes the cleavage of both polyadenylated and non-polyadenylated transcripts.<p> In the former case polyadenylation has to precede transcript cleavage, while in the latter case there is no polyadenylation. RNA Polymerase II Transcription Termination Authored: Proudfoot, NJ, 2003-09-11 07:42:30 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006369 Reactome Database ID Release 4373856 Reactome, http://www.reactome.org ReactomeREACT_894 The detailed annotation of this section will be completed in the next release. Formation of RNA Pol II elongation complex Authored: Gopinathrao, G, 2004-06-22 14:12:50 GENE ONTOLOGYGO:0006368 Pubmed12676794 Reactome Database ID Release 43112382 Reactome, http://www.reactome.org ReactomeREACT_1845 TFIIS is a transcription factor involved in different phases of transcription, occurring in a major ubiquitous form and other tissue specific forms. TFIIS stimulates RNA Pol II complex out of elongation arrest. <BR> Other transcription factors like ELL, Elongin family members and TFIIF interact directly with elongating Pol II and increase its elongation rate. These factors have been observed to act on naked DNA templates by suppressing transient pausing by the enzyme at all or most steps of nucleotide addition. In Drosophila, ELL is found at a large number of transcriptionally active sites on polytene chromosomes. In general, ELL is suspected to have more unidentified functions.<BR> Elongin is a heterotrimeric protein complex that stimulates the overall rate of elongation. In addition, Elongin may act as an E3 Ubiquitin ligase. Ubiquitylation of RNA Pol II occurs rapidly after genotoxic assault by UV light or chemicals, and results in degradation by proteasome. The FACT complex appears to promote elongation by facilitating passage of polymerase through chromatin.<BR> All these factors contribute to the formation of a processive elongation complex centered around the RNA Pol II complex positioned on the DNA:RNA hybrid. This enables the RNA Pol II elongation complex to function as a platform that coordinates mRNA processing and export (Reviewed by Shilatifard et al., 2003). Deadenylation-dependent mRNA decay After undergoing rounds of translation, mRNA is normally destroyed by the deadenylation-dependent pathway. Though the trigger is unclear, deadenylation likely proceeds in two steps: one catalyzed by the PAN2-PAN3 complex that shortens the poly(A) tail from about 200 adenosine residues to about 80 residues and one catalyzed by the CCR4-NOT complex or by the PARN enzyme that shortens the tail to about 10-15 residues.<br>After deadenylation the mRNA is then hydrolyzed by either the 5' to 3' pathway or the 3' to 5' pathway. It is unknown what determinants target a mRNA to one pathway or the other.<br>The 5' to 3' pathway is initiated by binding of the Lsm1-7 complex to the 3' oligoadenylate tail followed by decapping by the DCP1-DCP2 complex. The 5' to 3' exoribonuclease XRN1 then hydrolyzes the remaining RNA.<br>The 3' to 5' pathway is initiated by the exosome complex at the 3' end of the mRNA. The exosome processively hydrolyzes the mRNA from 3' to 5', leaving only a capped oligoribonucleotide. The cap is then removed by the scavenging decapping enzyme DCPS. Authored: May, B, 2009-07-22 Edited: May, B, 2009-07-22 GENE ONTOLOGYGO:0000288 Pubmed11283721 Pubmed14749774 Pubmed15475613 Pubmed16141059 Pubmed17245413 Pubmed19239894 Reactome Database ID Release 43429914 Reactome, http://www.reactome.org ReactomeREACT_20639 Reviewed: Wilusz, J, 2009-09-17 Mitochondrial tRNA aminoacylation Authored: D'Eustachio, P, 2008-11-29 15:41:00 Edited: D'Eustachio, P, 2008-11-29 15:41:00 GENE ONTOLOGYGO:0006418 Mitochondrial tRNA synthetases act in the mitochondrial matrix to catalyze the reactions of tRNAs encoded in the mitochondrial genome, their cognate amino acids, and ATP to form aminoacyl-tRNAs, AMP, and pyrophosphate (Schneider et al. 2000). The synthetase enzymes that catalyze these reactions are all encoded in the nuclear genome. In three cases, glycine, lysine, and glutamine, a single gene encodes two enzyme isoforms, one cytosolic and one mitochondrial. All other mitochondrial tRNA synthetases are encoded by genes different from the ones encoding the corresponding cytosolic enzymes. Pubmed11121736 Reactome Database ID Release 43379726 Reactome, http://www.reactome.org ReactomeREACT_15302 Reviewed: Antonellis, A, 2008-12-02 16:58:45 Cytosolic tRNA aminoacylation Authored: D'Eustachio, P, 2008-11-29 15:41:00 Cytosolic tRNA synthetases catalyze the reactions of tRNAs encoded in the nuclear genome, their cognate amino acids, and ATP to form aminoacyl-tRNAs, AMP, and pyrophosphate. Eight of the tRNA synthetases, those specific for arginine, aspartate, glutamate and proline, glutamine, isoleucine, leucine, lysine, and methionine, associate to form a complex with three accessory proteins. Each of the component synthetases is active in vitro as a purified protein; complex formation is thought to channel aminoacylated tRNAs more efficiently to the site of protein synthesis in mRNA:ribosome complexes (Quevillon et al. 1999; Wolfe et al. 2003, 2005). Edited: D'Eustachio, P, 2008-11-29 15:41:00 GENE ONTOLOGYGO:0006418 Pubmed14500886 Pubmed16169847 Pubmed9878398 Reactome Database ID Release 43379716 Reactome, http://www.reactome.org ReactomeREACT_15306 Reviewed: Antonellis, A, 2008-12-02 16:58:45 (Xyl)1 (Ser)1 Converted from EntitySet in Reactome Reactome DB_ID: 2064201 Reactome Database ID Release 432064201 Reactome, http://www.reactome.org ReactomeREACT_124300 xylosyl-core proteins Collagen alpha-1(XXVII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192961 Reactome Database ID Release 432192961 Reactome, http://www.reactome.org ReactomeREACT_124442 RNA Polymerase II Transcription Elongation Authored: Conaway, JW, Conaway, RC, 2003--0-9- Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006368 Pubmed11018013 Pubmed12676794 Pubmed14550628 Reactome Database ID Release 4375955 Reactome, http://www.reactome.org ReactomeREACT_833 The mechanisms governing the process of elongation during eukaryotic mRNA synthesis are being unraveled by recent studies. These studies have led to the expected discovery of a diverse collection of transcription factors that directly regulate the activities of RNA Polymerase II and unexpected discovery of roles for many elongation factors in other basic processes like DNA repair, recombination, etc. The transcription machinery and structural features of the major RNA polymerases are conserved across species. The genes active during elongation fall under different classes like, housekeeping, cell-cycle regulated, development and differentiation specific genes etc. The list of genes involved in elongation has been growing in recent times, and include: -TFIIS,DSIF, NELF, P-Tefb etc. that are involved in drug induced or sequence-dependent arrest - TFIIF, ELL, elongin, elongator etc. that are involved in increasing the catalytic rate of elongation by altering the Km and/or the Vmax of Pol II -FACT, Paf1 and other factors that are involved chromatin modification - DNA repair proteins, RNA processing and export factors, the 19S proteasome and a host of other factors like Spt5-Spt5, Paf1, and NELF complexes, FCP1P etc. (Arndt and Kane, 2003). Elongation also represents processive phase of transcription in which the activities of several mRNA processing factors are coupled to transcription through their binding to RNA polymerase (Pol II). One of the key events that enables this interaction is the differential phosphorylation of Pol II CTD. Phosphorylation pattern of CTD changes during transcription, most significantly at the beginning and during elongation process. TFIIH-dependent Ser5 phosphorylation is observed primarily at promoter regions while P-Tefb mediated Ser2 phosphorylation is seen mainly in the coding regions, during elongation. Experimental evidence suggests a dynamic association of RNA processing factors with differently modified forms of the polymerase during the transcription cycle. (Komarnitsky et al., 2000). [Komarnitsky et al 2000, Arndt & Kane 2003, Shilatifard et al 2003] Formation of the Early Elongation Complex Authored: Gopinathrao, G, 2004-05-06 22:00:00 GENE ONTOLOGYGO:0006368 Pubmed10916156 Pubmed11940650 Reactome Database ID Release 43113418 Reactome, http://www.reactome.org ReactomeREACT_846 Transcription elongation by RNA polymerase II (RNAPII) is controlled by a number of trans-acting transcription elongation factors as well as by cis-acting elements. Transcription elongation is a rate-limiting step for proper mRNA production in which the phosphorylation of Pol II CTD is a crucial biochemical event. The role of CTD phosphorylation in transcription by Pol II is greatly impaired by protein kinase inhibitors such as 5,6-dichloro-1- ribofuranosylbenzimidazole (DRB), which block CTD phosphorylation and induce arrest of elongating Pol II. DRB-sensitive activation Pol II CTD during elongation has enabled the isolation of two sets of factors -Negative Elongation Factors (NELF) and DRB sensitivity inducing factor (DSIF). P-Tefb is a DRB-sensitive, cyclin-dependent CTD kinase composed of Cdk9 that carries out Serine-2 phosphorylation of Pol II CTD during elongation.<BR>The mechanism by which DSIF, NELF and P-TEFb act together in Pol II-regulated elongation is yet to be fully understood. Various biochemical evidences point to a model in which DSIF and NELF negatively regulate elongation through interactions with polymerase containing a hypophosphorylated CTD. Subsequent phosphorylation of the Pol II CTD by P-Tefb might promote elongation by inhibiting interactions of DSIF and NELF with the elongation complex.<BR> RNA Pol II CTD phosphorylation and interaction with CE Authored: Gopinathrao, G, 2003-10-15 15:18:37 Reactome Database ID Release 4377075 Reactome, http://www.reactome.org ReactomeREACT_975 To facilitate co-transcriptional capping, and thereby restrict the cap structure to RNAs made by RNA polymerase II, the capping enzymes bind directly to the RNA polymerase II. The C-terminal domain of the largest Pol II subunit contains several phosphorylation sites on its heptapeptide repeats. The capping enzyme guanylyltransferase and the methyltransferase bind specifically to CTD phosphorylated at Serine 5 within the CTD. Kinase subunit of TFIIH, Cdk7, catalyzes this phosphorylation event that occurs near the promoter. In addition, it has been shown that binding of capping enzyme to the Serine-5 phosphorylated CTD stimulates guanylyltransferase activity in vitro. L13a-mediated translational silencing of Ceruloplasmin expression Authored: Matthews, L, 2004-12-13 00:49:48 Edited: Matthews, L, 0000-00-00 00:00:00 Pubmed11533233 Pubmed12588972 Pubmed14567916 Pubmed9257859 Reactome Database ID Release 43156827 Reactome, http://www.reactome.org ReactomeREACT_79 While circularization of mRNA during translation initiation is thought to contribute to an increase in the efficiency of translation, it also appears to provide a mechanism for translational silencing. This might be achieved by bringing inhibitory 3' UTR-binding proteins into a position in which they interfere either with the function of the translation initiation complex or with the assembly of the ribosome (Mazumder et al 2001). Translational silencing of Ceruloplasmin (Cp) occurs 16 hrs after its induction by INF-gamma (Mazumder et al., 1997). Although the mechanism by which silencing occurs has not yet been determined, this process is mediated by the L13a subunit of the 60s ribosome and thought to require circularization of the Cp mRNA (Sampath et al., 2003; Mazumder et al., 2001; Mazumder et al., 2003). Between 14 and 16 hrs after INF gamma induction, the L13a subunit of the 60s ribosome is phosphorylated and released from the 60s subunit. Phosphorylated L13a then associates with the GAIT element in the 3' UTR of the Cp mRNA inhibiting its translation. Cap-independent Translation Initiation Initiation on several viral and cellular mRNAs is cap-independent and is mediated by binding of the ribosome to internal ribosome entry site (IRES) elements. These elements are often found in characteristically long structured regions on the 5'-UTR of an mRNA that may or may not have regulatory upstream open reading frames (uORFs). Both of these features on the 5'-end of the mRNA hinder ribosomal scanning, and thus promote a cap-independent translation initiation mechanism. IRESs act as specific translational enhancers that allow translation initiation to occur in response to specific stimuli and under the control of different trans-acting factors, as for example when cap-dependent protein synthesis is shut off during viral infection. Such regulatory elements have been identified in the mRNAs of growth factors, protooncogenes, angiogenesis factors, and apoptosis regulators, which are translated under a variety of stress conditions, including hypoxia, serum deprivation, irradiation and apoptosis. Thus, cap-independent translational control might have evolved to regulate cellular responses in acute but transient stress conditions that would otherwise lead to cell death, while the same mechanism is of major importance for viral mRNAs to bypass the shutting-off of host protein synthesis after infection. Encephalomyocarditis virus (EMCV) and hepatitis C virus exemplify two distinct mechanisms of IRES-mediated initiation. In contrast to cap-dependent initiation, the eIF4A and eIF4G subunits of eIF4F bind immediately upstream of the EMCV initiation codon and promote binding of a 43S complex. Accordingly, EMCV initiation does not involve scanning and does not require eIF1, eIF1A, and the eIF4E subunit of eIF4F. Nonetheless, initiation on some EMCV-like IRESs requires additional non-canonical initiation factors, which alter IRES conformation and promote binding of eIF4A/eIF4G. Initiation on the hepatitis C virus IRES is simpler: a 43S complex containing only eIF2 and eIF3 binds directly to the initiation codon as a result of specific interaction of the IRES and the 40S subunit. Pubmed11050335 Reactome Database ID Release 4372771 Reactome, http://www.reactome.org ReactomeREACT_1264 Eukaryotic Translation Elongation Authored: Gopinathrao, G, 2005-03-12 20:38:06 GENE ONTOLOGYGO:0006414 Pubmed15189156 Pubmed9265629 Reactome Database ID Release 43156842 Reactome, http://www.reactome.org ReactomeREACT_1477 The translation elongation cycle adds one amino acid at a time to a growing polypeptide according to the sequence of codons found in the mRNA. The next available codon on the mRNA is exposed in the aminoacyl-tRNA (aa-tRNA) binding site (A site) on the 30S subunit.<br>A: Ternary complexes of aa -tRNA:eEF1A:GTP enter the ribosome and enable the anticodon of the tRNA to make a codon/anticodon interaction with the A-site codon of the mRNA. B: Upon cognate recognition, the eEF1A:GTP is brought into the GTPase activating center of the ribosome, GTP is hydrolyzed and eEF1A:GDP leaves the ribosome. C: The peptidyl transferase center of ribosome catalyses the formation of a peptide bond between the incoming amino acid and the peptide found in the peptidyl-tRNA binding site (P site). D: In the pre-translocation state of the ribosome, the eEF2:GTP enters the ribosome, physically translocating the peptidyl-tRNA out of the A site to P site and leaves the ribosome eEF2:GDP. This action of eEF2:GTP accounts for the precise movement of the mRNA by 3 nucleotides.Consequently, deacylated tRNA is shifted to the E site. A ribosome associated ATPase activity is proposed to stimulate the release of deacylated tRNA from the E site subsequent to translocation (Elskaya et al., 1991). In this post-translocation state, the ribosome is now ready to receive a new ternary complex.<br>This process is illustrated below with: an amino acyl-tRNA with an amino acid, a peptidyl-tRNA with a growing peptide, a deacylated tRNA with an -OH, and a ribosome with A,P and E sites to accommodate these three forms of tRNA. SRP-dependent cotranslational protein targeting to membrane Authored: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Edited: D'Eustachio, P, 2011-10-23 GENE ONTOLOGYGO:0006614 Reactome Database ID Release 431799339 Reactome, http://www.reactome.org ReactomeREACT_115902 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 The process for translation of a protein destined for the endoplasmic reticulum (ER) branches from the canonical cytoslic translation process at the point when a nascent polypeptide containing a hydrophobic signal sequence is exposed on the surface of the cytosolic ribosome:mRNA:peptide complex. The signal sequence mediates the interaction of this complex with a cytosolic signal recognition particle (SRP) to form a complex which in turn docks with an SRP receptor complex on the ER membrane. There the ribosome complex is transferred from the SRP complex to a translocon complex embedded in the ER membrane and reoriented so that the nascent polypeptide protrudes through a pore in the translocon into the ER lumen. Translation, which had been halted by SRP binding, now resumes, the signal peptide is cleaved from the polypeptide, and elongation proceeds, with the growing polypeptide oriented into the ER lumen. Processing of DNA ends prior to end rejoining Authored: Matthews, L, 2003-09-07 08:47:00 Ionizing radiation induced DNA double strand breaks often contain end groups that must be processed before the DNA can be rejoined. Possible candidate proteins for the processing steps include Artemis (a nuclease) (Ma and Lieber, 2002); WRN (a helicase with exonuclease activity) (Li and Comai, 2001; Yannone et al., 2002; Karmakar, et al., 2002a, 2002b); PNK (a 5'-OH kinase and 3'-phosphate phosphatase) (Chappell et al., 2002); the Mre11/Rad50/Nbs1 nuclease complex (D' Amours and Jackson, 2002); or hTdp1 (tyrosyl-DNA phosphodiesterase, which removes 3'-glycolates)(Inamdar et al., 2002; Valerie and Povirk, 2003). Precisely when processing of the DNA ends occurs during NHEJ is not known. Pubmed11152456 Pubmed11477099 Pubmed11889123 Pubmed11955432 Pubmed11988766 Pubmed12023295 Pubmed12032095 Pubmed12177300 Pubmed12947387 Reactome Database ID Release 4375924 Reactome, http://www.reactome.org ReactomeREACT_1201 Nucleotide Excision Repair Authored: Hoeijmakers, JH, 2003-07-24 11:08:38 Edited: Gopinathrao, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006289 NER was first described in the model organism E. coli in the early 1960s as a process whereby bulky base damage is enzymatically removed from DNA, facilitating the recovery of DNA synthesis and cell survival. Deficient NER processes have been identified from the cells of cancer-prone patients with different variants of xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne’s syndrome. These XP cells exhibited an ultraviolet radiation hypersensitivity leading to a hypermutability response to UV, offering a direct connection between deficient NER, increased mutations, and cancer. While the NER pathway in prokaryotes is unique, the pathway utilized in yeast and higher eukaryotes is highly conserved and includes a variety of proteins that interact to form complexes.<BR> NER is involved in the repair of bulky adducts in DNA, such as UV-induced photo lesions [of both 6-4 photoproducts (6-4 pps) and cyclobutane pyrimidine dimer (CPDs)], intrastrand cross-links, large chemical adducts formed from exposure to aflatoxin, benzopyrene and other genotoxic agents. Specific proteins have been identified that participate in base damage recognition, cleavage of the damaged strand on both sides of the lesion, excision of the oligonucleotide bearing the lesion, and accessory proteins necessary for efficient function. Polymerization and ligation restore the strand to its original state. NER consists of two related pathways called global genomic repair (GG-NER) and transcription-coupled NER (TC-NER). The pathways differ in the way in which DNA damage is initially recognized, but the majority of the participating molecules are shared between these two branches of NER". GG-NER is considered to be transcription-independent, removing lesions from non-transcribed regions of genome in addition to non-transcribed strands of transcribed regions. The preferential repair of UV-induced damage in transcribed strands of active genes is known as Transcription-coupled NER (TC-NER).<BR>Several of the proteins involved in NER are key components of the basal transcription complex TFIIH. NER proteins have also been shown to interact with the 19S regulatory subunit of the proteasome, suggesting a role in cellular regulation signal pathways. The establishment of mutant mouse models for NER genes and other DNA repair-related genes have been useful in demonstrating the associations between NER defects and cancer.<BR><BR> Pubmed10583946 Pubmed11900249 Pubmed14599765 Reactome Database ID Release 4373885 Reactome, http://www.reactome.org ReactomeREACT_1826 Global Genomic NER (GG-NER) Authored: Gopinathrao, G, 2004-02-02 17:30:34 GG-NER is considered to be transcription-independent, removing lesions from non-transcribed regions of genome in addition to non-transcribed strands of transcribed regions.<BR> The three events that characterize NER are well characterized in GG-NER: damage recognition, bimodal incision of DNA via repair protein complex, resulting excision of DNA fragment with the lesion. Post-excision polymerization and ligation restore back the native chemistry and configuration to the damaged DNA.<BR> Reactome Database ID Release 43109970 Reactome, http://www.reactome.org ReactomeREACT_2253 DNA Damage Recognition in GG-NER Authored: Joshi-Tope, G, 2003-07-14 15:01:00 GENE ONTOLOGYGO:0000715 Reactome Database ID Release 4373940 Reactome, http://www.reactome.org ReactomeREACT_476 Several subunits of the NER multiprotein repair machinery are required for the recognition of damage in DNA. Mainly, XPC, HR23B, XPA and RPA are implicated in this process. XPA and RPA are thought to be binding to the damage site after the binding of XPC-HR23B complex.<BR> Formation of incision complex in GG-NER Authored: Joshi-Tope, G, 2003-07-14 15:01:00 Binding of XPC complex to the damaged site on the DNA substrate is followed by XPA and RPA recruitment. XPA is a metalloprotein that binds to different types of DNA damage. Binding of RPA, or Replicative protein A, a heterotrimer, initiates the formation of incision complex. This includes a serial assembly of the rest of the NER machinery consisting of TFIIH, XPG etc. Action of helicases in TFIIH complex opens up a bubble structure in the DNA template, exposing a fragment of DNA with lesion for endonuclease activity.<BR> Reactome Database ID Release 4373935 Reactome, http://www.reactome.org ReactomeREACT_257 Dual incision reaction in GG-NER Authored: Joshi-Tope, G, 2003-07-14 15:01:00 Dual incision at defined positions flanking the DNA damage is carried out by XPG (3' -incision) and ERCC1-XPF (5'-incision) complex. The resulting excised fragment is ~27-30 bp long and contains the lesion.<BR> GENE ONTOLOGYGO:0000718 Pubmed10583946 Reactome Database ID Release 4373941 Reactome, http://www.reactome.org ReactomeREACT_311 Translation initiation complex formation Pubmed592399 Pubmed641056 Pubmed6853548 Pubmed9732867 Reactome Database ID Release 4372649 Reactome, http://www.reactome.org ReactomeREACT_1979 The translation initiation complex forms when the 43S complex binds the mRNA that is associated with eIF4F, eIF4B and eIF4H. eIF4G in the eIF4F complex can directly contact eIF3 in the 43S complex. eIF1A is necessary for the formation of this complex. Ribosomal scanning and start codon recognition Pubmed592399 Pubmed641056 Pubmed7000367 Pubmed9732867 Reactome Database ID Release 4372702 Reactome, http://www.reactome.org ReactomeREACT_931 The 80S ribosome bound to the mRNA moves along the mRNA molecule from its initial site to the initiation codon and forms a 48S complex, in which the initiation codon is base paired to the anticodon of the Met-tRNAi. Proper recognition of the AUG initiation codon depends on base pairing with the anticodon of the Met-tRNAi and requires eIF1, eIF1A, eIF2 and eIF5. GTP hydrolysis and joining of the 60S ribosomal subunit Hydrolysis of eIF2-GTP occurs after the Met-tRNAi has recognized the AUG. This reaction is catalyzed by eIF5 (or eIF5B) and is thought to cause dissociation of all other initiation factors and allow joining of the large 60S ribosomal subunit. The 60S subunit joins - a reaction catalyzed by eIF5 or eIF5B - resulting in a translation-competent 80S ribosome. Following 60S subunit joining, eIF5B hydrolyzes its GTP and is released from the 80S ribosome, which is now ready to start elongating the polypeptide chain. Pubmed10659855 Pubmed1095581 Pubmed11018020 Pubmed1856230 Pubmed429297 Pubmed592398 Pubmed592399 Pubmed641056 Reactome Database ID Release 4372706 Reactome, http://www.reactome.org ReactomeREACT_2085 Recycling of eIF2:GDP Pubmed7063012 Reactome Database ID Release 4372731 Reactome, http://www.reactome.org ReactomeREACT_1815 The active eIF2:GTP complex may be formed by direct binding of GTP to free eIF2 or by GDP-GTP exchange on the eIF2:GDP:eIF2B complex. The eIF2:GDP complex binds eIF2B forming an eIF2:GDP:eIF2B intermediate complex. eIF2B is a guanine nucleotide releasing factor required to cause GDP release so that a new GTP molecule can bind and activate eIF2. Phosphorylated eIF2:GDP sequesters all eIF2B as an inactive complex, and thus, reuse of eIF2 is inhibited as a consequence of the tight bond it forms with eIF2B, which prevents nucleotide exchange. Therefore, in the absence of free eIF2B, excess eIF2 remains in its inactive GDP-bound form and protein synthesis slows dramatically. Resolution of D-loop structures through Holliday junction intermediates Authored: Matthews, L, 2003-11-24 02:08:00 Following the synthesis of new DNA at resected 5' ends of the DSB, the heterologous DNA molecules may be ligated resulting in the formation of Holliday junctions. The Holliday structures are then cleaved resulting in reciprocal exchange of sequence between sister chromatids. Reactome Database ID Release 4375228 Reactome, http://www.reactome.org ReactomeREACT_977 Resolution of D-loop structures through synthesis-dependent strand-annealing Authored: Matthews, L, 2003-11-24 02:08:00 GENE ONTOLOGYGO:0045003 In the synthesis-dependant strand-annealing (SDSA) model of D-loop resolution, strand exchange intermediates revert (dissociate from the heteroduplex), synthesis of the resected regions is completed and the newly synthesized ends are reannealed to the resected 5' end. Reactome Database ID Release 4383667 Reactome, http://www.reactome.org ReactomeREACT_684 Formation of the ternary complex, and subsequently, the 43S complex Binding of the methionyl-tRNA initiator to the active eIF2:GTP complex results in the formation of the ternary complex. Subsequently, this Met-tRNAi:eIF2:GTP (ternary) complex binds to the complex formed by the 40S subunit, eIF3 and eIF1A, to form the 43S complex. Pubmed1104615 Pubmed429297 Pubmed592399 Pubmed641056 Reactome Database ID Release 4372695 Reactome, http://www.reactome.org ReactomeREACT_1079 Homologous recombination repair of replication-dependent double-strand breaks Authored: Matthews, L, 2003-11-18 00:00:00 Homologous recombination repair of replication-dependent DNA double-strand breaks will be described in a later version of GKB. Reactome Database ID Release 4373950 Reactome, http://www.reactome.org ReactomeREACT_1454 Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S Pubmed592399 Pubmed641056 Pubmed6853548 Pubmed9732867 Reactome Database ID Release 4372662 Reactome, http://www.reactome.org ReactomeREACT_1258 The cap-binding complex is constituted by the initiation factors eIF4A, eIF4G and eIF4E. First, eIF4E must be released from the inactive eIF4E:4E-BP complex. Then eIF4A interacts with eIF4G, and eIF4E binds to the amino-terminal domain of eIF4G, resulting in the formation of the cap-binding complex eIF4F. eIF4A together with eIF4B or eIF4H is thought to unwind RNA secondary structures near the 5'-end of the mRNA. The translation initiation complex is formed when the 43S complex binds the cap-bound mRNA. Nonhomologous End-joining (NHEJ) Authored: Lees-Miller, S, 2003-07-14 15:03:25 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006303 Pubmed10207111 Pubmed10908332 Pubmed11030616 Pubmed11376007 Pubmed12016139 Pubmed12379113 Pubmed14506474 Pubmed8621537 Pubmed9826654 Reactome Database ID Release 4373889 Reactome, http://www.reactome.org ReactomeREACT_1022 Reviewed: West, SC, 0000-00-00 00:00:00 The NHEJ pathway is initiated in response to the formation of a DNA double-strand break (DSB) induced by a DNA-damaging agent such as ionizing radiation. First, the Ku70/80 heterodimer binds to the ends of the DSB. The catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) is then recruited to DNA-bound Ku to form the DNA-PK holoenzyme. The ends of the break are brought together as two molecules of DNA-PK (one at each end of the break) are joined in a synaptic complex. Other factors, such as polynucleotide kinase (PNK), Artemis, the MRE complex, hTdp1 or the Werner Syndrome protein (WRN) may be required for processing of the DNA ends prior to end rejoining, but exactly when processing takes place is not known. Following the formation of the synaptic complex, the XRCC4/DNA ligase IV complex is recruited. Prior to end rejoining, protein factors must be removed from the DNA. This may involve DNA-PK autophosphorylation (Chan and Lees-Miller, 1996; Douglas et al., 2001; 2002; Merkle et al., 2002). After removal of the repair factors, the DNA ends are ligated and the DNA is repaired. Both Mg-ATP and the protein kinase activity of DNA-PKcs are required for NHEJ (Kurimasa et al.,1999; Kienker et al, 2000; Baumann and West, 1998), probably through phosphorylation of DNA-PKcs and/or other proteins. In addition, inositol hexaphosphate (IP6) stimulates end joining in vitro (Hanakahi et al., 2000) and binds to Ku, but its precise role in NHEJ is unknown. Formation of a pool of free 40S subunits Reactome Database ID Release 4372689 Reactome, http://www.reactome.org ReactomeREACT_1797 The 80S ribosome dissociates into free 40S (small) and 60S (large) ribosomal subunits. Each ribosomal subunit is constituted by several individual ribosomal proteins and rRNA. Cap-dependent Translation Initiation Reactome Database ID Release 4372737 Reactome, http://www.reactome.org ReactomeREACT_2099 Translation initiation is a complex process in which the Met-tRNAi initiator, 40S, and 60S ribosomal subunits are assembled by eukaryotic initiation factors (eIFs) into an 80S ribosome at the start codon of an mRNA. The basic mechanism for this process can be described as a series of five steps: 1) formation of a pool of free 40S subunits, 2) formation of the ternary complex (Met-tRNAi/eIF2/GTP), and subsequently, the 43S complex (comprising the 40S subunit, Met-tRNAi/eIF2/GTP, eIF3 and eIF1A), 3) activation of the mRNA upon binding of the cap-binding complex eIF4F, and factors eIF4A, eIF4B and eIF4H, with subsequent binding to the 43S complex, 4) ribosomal scanning and start codon recognition, and 5) GTP hydrolysis and joining of the 60S ribosomal subunit. Eukaryotic Translation Initiation GENE ONTOLOGYGO:0006413 Initiation of translation in the majority of eukaryotic cellular mRNAs depends on the 5'-cap (m7GpppN) and involves ribosomal scanning of the 5' untranslated region (5'-UTR) for an initiating AUG start codon. Therefore, this mechanism is often called cap-dependent translation initiation. Proximity to the cap, as well as the nucleotides surrounding an AUG codon, influence the efficiency of the start site recognition during the scanning process. However, if the recognition site is poor enough, scanning ribosomal subunits will ignore and skip potential starting AUGs, a phenomenon called leaky scanning. Leaky scanning allows a single mRNA to encode several proteins that differ in their amino-termini. Merrick (2010) provides an overview of this process and hghlights several features of it that remain incompletely understood.<p>Several eukaryotic cell and viral mRNAs initiate translation by an alternative mechanism that involves internal initiation rather than ribosomal scanning. These mRNAs contain complex nucleotide sequences, called internal ribosomal entry sites, where ribosomes bind in a cap-independent manner and start translation at the closest downstream AUG codon. Pubmed20444697 Reactome Database ID Release 4372613 Reactome, http://www.reactome.org ReactomeREACT_2159 Translation Authored: Merrick, WC, Bedwell, D, Gebauer, F, Anand, M, Balar, BA, Gross, S, Ortiz, PA, Ozturk, S, Pittman, YR, Ulloque, R, Hentze, MW, Kinzy, TG, 2005-03-29 13:13:22 Edited: Tello-Ruiz, MK, Gillespie, ME, Gopinathrao, G, Matthews, L, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006412 Protein synthesis is accomplished through the process of translation of an mRNA sequence into a polypeptide chain. This process can be divided into three distinct stages: initiation, elongation and termination. During the initiation phase, the two subunits of the ribosome are brought together to the translation start site on the mRNA where the polypeptide chain is to begin. Extension of the polypeptide chain occurs when a specific aminoacyl-tRNA, as determined by the template mRNA, binds an elongating ribosome. The protein chain is released from the ribosome when any one of three stop codons in the relevant reading frame on the mRNA is reached. Individual reactions at each one of these stages are catalyzed by a number of initiation, elongation and release factors, respectively. Reactome Database ID Release 4372766 Reactome, http://www.reactome.org ReactomeREACT_1014 Reviewed: Hershey, JW, Sonenberg, N, Hinnebusch, AG, 0000-00-00 00:00:00 Stabilization of mRNA by HuR Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 HuR (ELAVL1) is a ubiquitous protein that binds AU-rich elements in mRNAs and acts to stabilize the mRNAs. HuR activity is controlled by phosphorylation, with PKC alpha and PCK delta enhancing the ability of HuR to bind and stabilize mRNAs. Binding of mRNAs occurs in the nucleus and HuR then interacts with the CRM1 export pathway to transfer the mRNA to the cytoplasm. The mechanism by which HuR shields the mRNA from degradation is unknown.<br>HuR also regulates translation of some mRNAs, in some cases repressing translation and in some cases enhancing translation of bound mRNAs by recruiting them to polysomes.<br>HuR binds and regulates mRNAs encoding Cyclooxygenase-2 (COX2, PTGS2), Cyclin A (CCNA, CCNA2), Cyclin D1 (CCND1), Cyclin B1 (CCNB1), CD83 antigen (CD83), and proto-oncogene c-Fos (FOS).<br>HuR is a member of a family of proteins that also contains HuD (ELAVL4), HuB (ELAVL2), and HuC (ELAVL3). HuB, HuC, and HuD are specifically expressed in neural tissue.<br>HuR participates in apoptosis. During lethal stress HuR becomes mostly cytoplasmic and is a target of Caspase-3 and Caspase-7. The cleavage products of HuR in turn promote apoptosis. Pubmed12440953 Pubmed12704645 Pubmed14976220 Pubmed16391004 Pubmed17392515 Pubmed18285462 Reactome Database ID Release 43450520 Reactome, http://www.reactome.org ReactomeREACT_25218 Reviewed: Wilusz, J, 2010-06-29 Gal-Xyl-proteins (Gal)1 (Xyl)1 (Ser)1 Converted from EntitySet in Reactome Reactome DB_ID: 2064058 Reactome Database ID Release 432064058 Reactome, http://www.reactome.org ReactomeREACT_125578 Collagen alpha-1(VII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2214318 Reactome Database ID Release 432214318 Reactome, http://www.reactome.org ReactomeREACT_152021 GXYLTs Converted from EntitySet in Reactome Reactome DB_ID: 1877994 Reactome Database ID Release 431877994 Reactome, http://www.reactome.org ReactomeREACT_122530 PCOLCEs Converted from EntitySet in Reactome Reactome DB_ID: 2267331 Reactome Database ID Release 432267331 Reactome, http://www.reactome.org ReactomeREACT_123718 Destabilization of mRNA by Tristetraprolin (TTP) Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed12440953 Pubmed12704645 Pubmed16391004 Pubmed18481987 Reactome Database ID Release 43450513 Reactome, http://www.reactome.org ReactomeREACT_25064 Reviewed: Wilusz, J, 2010-06-29 Tristetraproline (TTP) binds RNAs that contain AU-rich elements and recruits enzymes that degrade RNA. TTP interacts with the exosome (3' to 5' exonuclease), XRN1 (5' to 3' exonuclease), and the decapping enzymes DCP1 and DCP2a.<br>The activity of TTP is regulated by phosphorylation. MK2 phosphorylates TTP, which then binds 14-3-3.The interaction with 14-3-3 prevents phosphorylated TTP from entering stress granules and stabilizes mRNA bound by phosphorylated TTP. Tristetraproline is known to bind AU-rich elements in the following mRNAs: Tumor necrosis factor alpha (TNFA), Granulocyte-macrophage colony stimulating factor (CSF2, GM-CSF), Interleukin-2 (IL-2), and Proto-oncogene C-FOS (FOS, c-fos). Mice deficient in TTP exhibit arthritis, weight loss, skin lesions, autoimmunity, and myeloid hyperplasia. Destabilization of mRNA by KSRP Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 KSRP binds to AU-rich sequences in the 3' untranslated regions of mRNAs. KSRP causes the bound mRNA to be targeted for hydrolysis by recruiting exonucleases and decapping enzymes. The activity of KSRP is regulated by phosphorylation. Protein kinase B/Akt phosphorylates KSRP at serine193. The phosphorylation inhibits the ability of KSRP to destabilize mRNA. KSRP phosphorylated at serine193 binds 14-3-3zeta which causes KSRP to be retained in the nucleus. Pubmed12440953 Pubmed12704645 Pubmed16391004 Reactome Database ID Release 43450604 Reactome, http://www.reactome.org ReactomeREACT_25042 Reviewed: Wilusz, J, 2010-06-29 Destabilization of mRNA by AUF1 (hnRNP D0) AUF1 (hnRNP D0) dimers bind U-rich regions of AU-rich elements (AREs) in the 3' untranslated regions of mRNAs. The binding causes AUF1 dimers to assemble into higher order tetrameric complexes. Diphosphorylated AUF1 bound to RNA recruits additional proteins, including eIF4G, polyA-binding protein, Hsp, Hsc70, Hsp27, NSEP-1, NSAP-1, and IMP-2 which target the mRNA and AUF1 for degradation. Unphosphorylated AUF1 is thought to be less able to recruit additional proteins. AUF1 also interacts directly or indirectly with HuR and the RNA-induced silencing complex (RISC).<br>AUF1 complexed with RNA and other proteins is ubiquitinated and targeted for destruction by the proteasome while the bound mRNA is degraded. Inhibition of ubiquitin addition to AUF1 blocks mRNA degradation. The mechanism by which ubiquitin-dependent proteolysis is coupled to mRNA degradation is unknown.<br>At least 4 isoforms of AUF1 exist: p45 (45 kDa) contains all exons, p42 lacks exon 2, p40 lacks exon 7, and p37 lacks exons 2 and 7. The presence of exon 7 in p42 and p45 seems to block ubiquitination while the absence of exon 7 (p37 and p40) targets AUF1 for ubiquitination and destabilizes bound RNAs. Lack of exon 2 (p37 and p42) is associated with higher affinity for RNA and 14-3-3sigma.<br>AUF1 binds and destabilizes mRNAs encoding Interleukin-1 beta (IL1B), Tumor Necrosis Factor alpha (TNFA), Cyclin-dependent kinase inhibitor 1 (CDNK1A, p21), Cyclin-D1 (CCND1), Granulocyte-macrophage colony stimulating factor (GM-CSF, CSF2), inducible Nitric oxide synthase (iNOS, NOS2), Proto-oncogene cFos (FOS), Myc proto-oncogene (MYC), Apoptosis regulator Bcl-2 (BCL2). Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed10205060 Pubmed12440953 Pubmed12704645 Pubmed12819195 Pubmed16391004 Pubmed18573886 Reactome Database ID Release 43450408 Reactome, http://www.reactome.org ReactomeREACT_25325 Reviewed: Wilusz, J, 2010-06-29 Destabilization of mRNA by Butyrate Response Factor 1 (BRF1) Authored: May, B, 2009-12-29 Butyrate Response Factor 1 (BRF1, ZFP36L1, not to be confused with transcription factor IIIB) binds AU-rich elements in the 3' region of mRNAs. After binding, BRF1 recruits exonucleases (XRN1 and the exosome) and decapping enzymes (DCP1a and DCP2) to hydrolyze the RNA. The ability of BRF1 to direct RNA degradation is controlled by phosphorylation of BRF1. Protein kinase B/AKT1 phosphorylates BRF1 at serines 92 and 203. Phosphorylated BRF1 can still bind RNA but is sequestered by binding 14-3-3 protein, preventing BRF1 from destabilizing RNA. BRF1 is also phosphorylated by MK2 at serines 54, 92, 203, and at an unknown site in the C-terminus. It is unknown if this particular phosphorylated form of BRF1 binds 14-3-3. Edited: May, B, 2009-12-29 Pubmed11719186 Pubmed12440953 Pubmed12704645 Pubmed15687258 Pubmed16391004 Reactome Database ID Release 43450385 Reactome, http://www.reactome.org ReactomeREACT_24915 Reviewed: Wilusz, J, 2010-06-29 Regulation of mRNA Stability by Proteins that Bind AU-rich Elements Authored: May, B, 2009-12-29 Edited: May, B, 2009-12-29 Pubmed12440953 Pubmed12704645 Pubmed15460540 Pubmed16391004 RNA elements rich in adenine and uracil residues (AU-rich elements) bind specific proteins which either target the RNA for degradation or, more rarely, stabilize the RNA. The activity of the AU-element binding proteins is regulated, usually by phosphorylation but also by subcellular localization. Reactome Database ID Release 43450531 Reactome, http://www.reactome.org ReactomeREACT_24994 Reviewed: Wilusz, J, 2010-06-29 Synthesis of dolichyl-phosphate mannose Authored: Dall'Olio, GM, 2009-11-10 Dolichyl-phosphate-mannose (DPM) is the donor of mannose groups in the synthesis of the dolichyl pyrophosphate-linked precursor oligosaccharide in asparagine-linked glycosylation, in the synthesis of the glycosyl phosphatidylinositol (GPI) anchor precursor, in protein O-mannosylation and in protein C-mannosylation. Its synthesis proceeds in two steps. First, cytosolic GDP-mannose reacts with dolichyl phosphate exposed on the cytosolic face of the endoplasmic reticulum membrane to form DPM with its mannose moiety oriented toward the cytosol. The DPM molecule then flips in the endoplasmic reticulum membrane, so that its mannose moiety is in the endoplasmic reticulum lumen, accessible to the enzymes that catalyze its transfer to growing glycolipids and glycoproteins (Kinoshita and Inoue, 2000; Maeda et al, 2000). Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0018279 Pubmed10835346 Pubmed11102867 Reactome Database ID Release 43162699 Reactome, http://www.reactome.org ReactomeREACT_2032 Reviewed: Gagneux, P, 2010-04-16 Post-translational modification: synthesis of GPI-anchored proteins GENE ONTOLOGYGO:0006501 Glycosylphosphatidyl inositol (GPI) acts as a membrane anchor for many cell surface proteins. GPI is synthesized in the endoplasmic reticulum. In humans, a single pathway consisting of eleven reactions appears to be responsible for the synthesis of the major GPI species involved in membrane protein anchoring.<p>As a nascent protein fated to become GPI-anchored moves into the lumen of the endoplasmic reticulum, it is attacked by a transamidase complex that cleaves it near its carboxy terminus and attaches an acylated GPI moiety. The GPI moiety is deacylated, yielding a protein-GPI conjugate that can be efficiently transported to the Golgi apparatus. Reactome Database ID Release 43163125 Reactome, http://www.reactome.org ReactomeREACT_1853 Synthesis of glycosylphosphatidylinositol (GPI) Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0016254 Glycosylphosphatidyl inositol (GPI) acts as a membrane anchor for many cell surface proteins. GPI is synthesized in the endoplasmic reticulum. In humans, a single pathway consisting of nine reactions appears to be responsible for the synthesis of the major GPI species involved in membrane protein anchoring. This pathway is shown in the figure. Two additional reactions, not shown, allow the synthesis of variant forms of GPI, one with an additional mannose residue and one with an additional ethanolamine (Tauron et al. 2004; Shishioh et al. 2005). These variant GPI molecules may be used for tissue-specific protein modifications, or may function independently.<p>The steps of GPI synthesis were first identified by isolating large numbers of mutant cell lines that had lost the ability to express GPI anchored proteins on their surfaces. Somatic cell hybrid analyses of these lines allowed the definition of complementation groups corresponding to distinct mutated genes, and cDNAs corresponding to normal forms of these genes were identified on the basis of their abilities to restore normal cell surface protein expression in mutant cells. Co-precipitation experiments with tagged cloned proteins have allowed the identification of additional proteins involved in GPI anchor biosynthesis. Pubmed11102867 Pubmed15208306 Pubmed15632136 Reactome Database ID Release 43162710 Reactome, http://www.reactome.org ReactomeREACT_952 Reviewed: Orlean, P, 0000-00-00 00:00:00 Removal of aminoterminal propeptides from gamma-carboxylated proteins Authored: D'Eustachio, P, 2005-03-17 16:24:57 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Furin is an endopeptidase localized to the Golgi membrane that cleaves many proteins on the carboxyterminal side of the sequence motif Arg-[any residue]-(Lys or Arg)-Arg (Jones et al. 1995; Leduc et al. 1992). In the case of gamma-carboxylated proteins, if this cleavage does not occur, the proteins are still secreted but do not function properly (Bristol et al. 1993; Lind et al. 1997). The aminoterminal fragments, "propeptides", generated in this reaction have no known function; the carboxylated, cleaved proteins are delivered to the cell membrane or secreted from the cell via pathways to be annotated in a future release of Reactome. GENE ONTOLOGYGO:0006508 Pubmed1629222 Pubmed8463288 Pubmed8846780 Pubmed9108399 Reactome Database ID Release 43159782 Reactome, http://www.reactome.org ReactomeREACT_733 Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus Authored: D'Eustachio, P, 2005-03-17 16:24:57 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Reactome Database ID Release 43159763 Reactome, http://www.reactome.org ReactomeREACT_1906 The details of the vesicle-mediated transport of proteins from the endoplasmic reticulum to the Golgi apparatus will be annotated in a future release of Reactome. The activation of arylsulfatases Authored: Jassal, B, 2011-10-14 Edited: Jassal, B, 2011-10-14 Pubmed16124866 Pubmed17558559 Reactome Database ID Release 431663150 Reactome, http://www.reactome.org ReactomeREACT_121036 Reviewed: D'Eustachio, P, 2012-05-14 Sulfatase activity requires a unique posttranslational modification (PTM) of a catalytic cysteine residue into a formylglycine. This modification is impaired in patients with multiple sulfatase deficiency (MSD) due to defects in the SUMF1 (sulfatase-modifying factor 1) gene responsible for this PTM. SUMF2 can inhibit the activity of SUMF1 thereby providing a mechanism for the regulation of sulfatase activation (Ghosh 2007, Diez-Roux & Ballabio 2005). Hypusinylation Authored: Johansson, HE, 2007-11-28 23:26:30 Cytosolic eIF5A undergoes a unique two-step post-translational modification at Lys 50 via deoxyhypusine (Dhp) to hypusine (Hyp). In the first step deoxyhypusine synthase transfers the aminobutyl group of spermidine to the epsilon-amino group of lysine 50, using NAD+ as a cofactor. Hydroxylation of the C2 of the newly added moiety in the second step is catalyzed by deoxyhypusine hydroxylase/monooxygenase with molecular oxygen as the source. The molecular function of eIF5A is unknown, but the protein is required for viability in eukaryotic cells and its normal function requires hypusinylation. eIF5A is the only protein known to undergo hypusinylation (Park 2006). Edited: D'Eustachio, P, 2007-11-28 23:33:46 GENE ONTOLOGYGO:0008612 Hypusine synthesis from eIF5A-lysine Pubmed16452303 Reactome Database ID Release 43204626 Reactome, http://www.reactome.org ReactomeREACT_12469 Reviewed: Jassal, B, 2008-01-28 15:51:00 PTM: gamma carboxylation, hypusine formation and arylsulfatase activation After translation, many newly formed proteins undergo further covalent modifications that alter their functional properties and that are essentially irreversible under physiological conditions in the body. These modifications include the vitamin K-dependent attachment of carboxyl groups to glutamate residues and the conversion of lysine residues to hypusine. Authored: D'Eustachio, P, 2005-05-07 21:32:05 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0043687 Reactome Database ID Release 43163841 Reactome, http://www.reactome.org ReactomeREACT_1069 Reviewed: Orlean, P, Stafford, DW, 0000-00-00 00:00:00 Gamma-carboxylation of protein precursors Authored: D'Eustachio, P, 2005-03-17 16:24:57 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0017187 Gamma-carboxylation of a cluster of glutamate residues near the amino termini of thrombin, factor VII, factor IX, factor X, protein C, protein S, protein Z, and Gas 6 is required for these proteins to bind Ca++ and function efficiently in blood clotting. A single enzyme, vitamin K-dependent gamma-carboxylase, catalyzes the gamma-carboxylation of all eight proteins involved in clotting (Morris et al. 1995; Brenner et al. 1998; Spronk et al. 2000). In the carboxylation reaction, the enzyme binds its substrate protein via a sequence motif on the amino terminal side of the glutamate residues to be carboxylated (Furie et al. 1999), then processively carboxylates all glutamates in the cluster before releasing the substrate (Morris et al. 1995; Berkner 2000; Stenina et al. 2001). The reaction occurs in the endoplasmic reticulum (Bristol et al. 1996). Pubmed10068650 Pubmed10917896 Pubmed11071668 Pubmed11513608 Pubmed8530480 Pubmed8839851 Pubmed9845520 Reactome Database ID Release 43159740 Reactome, http://www.reactome.org ReactomeREACT_1050 Gamma-carboxylation, transport, and amino-terminal cleavage of proteins A number of proteins, including eight required for normal blood clot formation and its regulation (Prothrombin (factor II), factor VII, factor IX, factor X, protein C, protein S, protein Z, and Gas6) share a sequence motif rich in glutamate residues near their amino termini. Carboxylation of the glutamate residues within this motif followed by removal of an aminoterminal propeptide is required for each of these proteins to function. These modifications occur as the proteins move through the endoplasmic reticulum and Golgi apparatus. Authored: D'Eustachio, P, 2005-03-17 16:24:57 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0017187 Reactome Database ID Release 43159854 Reactome, http://www.reactome.org ReactomeREACT_1132 Reviewed: Stafford, DW, 0000-00-00 00:00:00 Calnexin/calreticulin cycle Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-07-02 Pubmed18303019 Pubmed18337472 Reactome Database ID Release 43901042 Reactome, http://www.reactome.org ReactomeREACT_23810 Reviewed: Gagneux, P, 2010-08-17 The unfolded protein is recognized by a chaperon protein (calnexin or calreticulin) and the folding process starts. The binding of these protein requires a mono-glucosylated glycan (Caramelo JJ and Parodi AJ, 2008), but in certain cases can occur even in the absence of glycosylation (Ireland BS et al, 2008). N-glycan trimming in the ER and Calnexin/Calreticulin cycle After being synthesized in the ER membrane the 14-sugars lipid-linked oligosaccharide is co-translationally transferred to an unfolded protein, as described in the previous steps. After this point the N-glycan is progressively trimmed of the three glucoses and some of the mannoses before the protein is transported to the cis-Golgi. The role of these trimming reactions is that the N-glycan attached to an unfolded glycoprotein in the ER assume the role of 'tags' that direct the interactions of the glycoprotein with different elements that mediate its folding. The removal of the two outer glucoses leads to an N-glycan with only one glucose, which is a signal for the binding of either one of two chaperone proteins, calnexin (CNX) and calreticulin (CRT). These chaperones provide an environment where the protein can fold more easily. The interaction with these proteins is not transient and is terminated by the trimming of the last remaining glucose, after which the glycoprotein is released from CNX or CRT and directed to the ER Quality Control compartment (ERQC) if it still has folding defects, or transported to the Golgi if the folding is correct. The involvement of N-glycans in the folding quality control of proteins in the ER explains why this form of glycosylation is so important, and why defects in the enzymes involved in these reactions are frequently associated with congenital diseases. However, there are many unknown points in this process, as it is known that even proteins without N-glycosylation sites can be folded properly (Caramelo JJ and Parodi AJ, 2008). Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-03-02 GENE ONTOLOGYGO:0006457 Pubmed18303019 Reactome Database ID Release 43532668 Reactome, http://www.reactome.org ReactomeREACT_23878 Reviewed: Gagneux, P, 2010-08-17 Synthesis of dolichyl-phosphate-glucose Authored: Dall'Olio, GM, 2009-11-10 Dolichyl-phosphate-glucose functions as a donor of glucose groups in reactions including three steps of N-glycan precursor biosynthesis. Dolichyl-phosphate-glucose itself is synthesized from UDP-glucose and dolichol phosphate on the cytosolic face of the endoplasmic reticulum membrane, then flipped to the luminal surface of that membrane. Edited: Jassal, B, 2010-01-27 GENE ONTOLOGYGO:0018279 Reactome Database ID Release 43480985 Reactome, http://www.reactome.org ReactomeREACT_22346 Reviewed: Gagneux, P, 2010-04-16 Synthesis of GDP-mannose Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 GDP-mannose is the mannose donor for the first 5 mannose addition reactions in the N-glycan precursor synthesis, and also for the synthesis of Dolichyl-phosphate-mannose involved in other mannose transfer reactions. It is synthesized from fructose 6-phosphate and GTP in three steps. GENE ONTOLOGYGO:0009298 Reactome Database ID Release 43446205 Reactome, http://www.reactome.org ReactomeREACT_22423 Reviewed: Gagneux, P, 2010-04-16 Synthesis of UDP-N-acetyl-glucosamine Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 GENE ONTOLOGYGO:0006048 Reactome Database ID Release 43446210 Reactome, http://www.reactome.org ReactomeREACT_22394 Reviewed: Gagneux, P, 2010-04-16 UDP-acetylglucosamine acts as a donor for the first two steps of the N-glycan precursor biosynthesis pathway, and is later used as a substrate for further modifications after the precursor has been attached to the protein. It is synthesized from fructose 6-phosphate, glutamine, acetyl-CoA, and UTP in four steps. Synthesis of Dolichyl-phosphate Authored: Dall'Olio, GM, 2009-11-10 Dolichol is a polyisoprenol lipid comprised of five-carbon isoprene units linked linearly in a head-to-tail fashion. In the N-glycan biosynthesis pathway, dolichyl phosphate is used as an anchor for the N-glycan sugar to the ER membrane, and as an initiation point for the synthesis. Dolichyl phosphate can be obtained either from direct phosphorylation of dolichol or from de-phosphorylation of dolichyl diphosphate, released at the end of the N-glycan biosynthesis pathway. Edited: Jassal, B, 2009-11-10 GENE ONTOLOGYGO:0006489 Reactome Database ID Release 43446199 Reactome, http://www.reactome.org ReactomeREACT_22230 Reviewed: Gagneux, P, 2010-04-16 Synthesis of substrates in N-glycan biosythesis Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed18597486 Reactions for the synthesis of the small nucleotide-linked sugar substrates that are used in the synthesis of the N-glycan precursor and in the later steps of glycosylation are annotated here.<br>All these nucleotide-linked sugar donors are synthesized in the cytosol; however, to participate in the later reactions of N-glycan precursor biosynthesis (when the glycan is oriented toward the lumen of the endoplasmic reticulum (ER)), these substrates must be attached to a dolichyl-phosphate molecule and then flipped toward the luminal side of the ER, through a mechanism which is still not known but which involves a different protein than the one that mediates the flipping of the LLO itself (Sanyal S et al, 2008).<br>Two of the genes encoding enzymes involved in these reactions, MPI and PMM2, are known to be associated with Congenital Disorders of Glycosylation (CDG) diseases of type I. Of these, CDG-Ia, associated with defects in PMM2, is the most frequent CDG disease reported. Reactome Database ID Release 43446219 Reactome, http://www.reactome.org ReactomeREACT_22387 Reviewed: Gagneux, P, 2010-04-16 Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 GENE ONTOLOGYGO:0006488 N-linked glycosylation commences with the 14-step synthesis of a dolichol lipid-linked oligosaccharide (LLO) consisting of 14 sugars (2 core GlcNAcs, 9 mannoses and 3 terminal GlcNAcs). This pathway is highly conserved in eukaryotes, and a closely related pathway is found in many eubacteria and Archaea. Mutations in the genes associated with N-glycan precursor synthesis lead to a diverse group of disorders collectively known as Congenital Disorders of Glycosylation (type I and II) (Sparks et al, 1993). The phenotypes of these disorders reflect the important role that N-glycosylation has during development, controlling the folding and the properties of proteins in the secretory pathway, and proteins that mediate cell-to-cell interactions or timing of development. Pubmed20301507 Reactome Database ID Release 43446193 Reactome, http://www.reactome.org ReactomeREACT_22433 Reviewed: Gagneux, P, 2010-04-16 Asparagine N-linked glycosylation Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 GENE ONTOLOGYGO:0018279 N-linked glycosylation is the most important form of post-translational modification for proteins synthesized and folded in the Endoplasmic Reticulum (Stanley P et al, 2009). An early study in 1999 revealed that about 50% of the proteins in the Swiss-Prot database at the time were N-glycosylated (Apweiler R et al, 1999). It is now established that the majority of the proteins in the secretory pathway require glycosylation in order to achieve proper folding.<br>The addition of an N-glycan to a protein can have several roles (Shental-Bechor D and Levy Y, 2009). First, glycans enhance the solubility and stability of the proteins in the ER, the golgi and on the outside of the cell membrane, where the composition of the medium is strongly hydrophilic and where proteins, that are mostly hydrophobic, have difficulty folding properly. Second, N-glycans are used as signal molecules during the folding and transport process of the protein: they have the role of labels to determine when a protein must interact with a chaperon, be transported to the golgi, or targeted for degradation in case of major folding defects. Third, and most importantly, N-glycans on completely folded proteins are involved in a wide range of processes: they help determine the specificity of membrane receptors in innate immunity or in cell-to-cell interactions, they can change the properties of hormones and secreted proteins, or of the proteins in the vesicular system inside the cell.<br>All N-linked glycans are derived from a common 14-sugar oligosaccharide synthesized in the ER, which is attached co-translationally to a protein while this is being translated inside the reticulum. The process of the synthesis of this glycan, known as Synthesis of the N-glycan precursor or LLO, constitutes one of the most conserved pathways in eukaryotes, and has been also observed in some eubacteria. The attachment usually happens on an asparagine residue within the consensus sequence asparagine-X-threonine by an complex called oligosaccharyl transferase (OST).<br>After being attached to an unfolded protein, the glycan is used as a label molecule in the folding process (also known as Calnexin/Calreticulin cycle) (Lederkremer GZ, 2009). The majority of the glycoproteins in the ER require at least one glycosylated residue in order to achieve proper folding, even if it has been shown that a smaller portion of the proteins in the ER can be folded without this modification.<br>Once the glycoprotein has achieved proper folding, it is transported via the Cis-golgi through all the Golgi compartments, where the glycan is further modified according to the properties of the glycoprotein. This process involves relatively few enzymes but due to its combinatorial nature, can lead to several millions of different possible modifications. The exact topography of this network of reactions has not been established yet, representing one of the major challenges after the sequencing of the human genome (Hossler P et al, 2006).<br>Since N-glycosylation is involved in an great number of different processes, from cell-cell interaction to folding control, mutations in one of the genes involved in glycan assembly and/or modification can lead to severe development problems (often affecting the central nervous system). All the diseases in genes involved in glycosylation are collectively known as Congenital Disorders of Glycosylation (CDG) (Sparks SE et al, 2003), and classified as CDG type I for the genes in the LLO synthesis pathway, and CDG type II for the others. Pubmed10580125 Pubmed16807922 Pubmed19616933 Pubmed19647993 Pubmed20301244 Pubmed20301507 Reactome Database ID Release 43446203 Reactome, http://www.reactome.org ReactomeREACT_22426 Reviewed: Gagneux, P, 2010-04-16 Attachment of GPI anchor to uPAR Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0016255 Pubmed1846368 Reactome Database ID Release 43162791 Reactome, http://www.reactome.org ReactomeREACT_1830 The mature form of urokinase plasminogen activator receptor (uPAR) is attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor (Ploug et al. 1991). As nascent uPAR polypeptide moves into the lumen of the endoplasmic reticulum, it is attacked by a transamidase complex that cleaves the uPAR polypeptide after residue 305, releasing the carboxyterminal peptide of uPAR and replacing it with an acylated GPI moiety. In a second step, the GPI moiety is deacylated, yielding a uPAR-GPI conjugate that can be efficiently transported to the Golgi apparatus. This transport process and the other events needed to generate fully glycosylated uPAR-GPI associated with the plasma membrane will be annotated in a future release of Reactome. Repair synthesis for gap-filling by DNA polymerase in TC-NER Reactome Database ID Release 43109977 Reactome, http://www.reactome.org ReactomeREACT_1993 Gap-filling DNA repair synthesis and ligation in TC-NER Authored: Gopinathrao, G, 2004-02-11 18:33:11 Polymerization is carried out by DNA polymerases, delta and epsilon. Reactome Database ID Release 43109979 Reactome, http://www.reactome.org ReactomeREACT_74 Regulation of the Fanconi anemia pathway Authored: Matthews, L, 2009-05-02 17:26:55 Edited: Matthews, L, 2009-05-20 15:51:04 Pubmed16916645 Pubmed16943440 Pubmed18082604 Pubmed18931676 Reactome Database ID Release 43419552 Reactome, http://www.reactome.org ReactomeREACT_18265 Reviewed: Huang, TT, 2009-05-20 17:48:24 The Fanconi anemia DNA repair pathway is negatively regulated by the deubiquitination of FANCD2 an postively regulated by phosphorylation of the FANCD2 and FANCI. The USP1 deubiquitinating enzyme is responsible for FANCD2 deubiquitination and is activated by the WD40-repeat containing UAF1 protein through formation of a stable USP1/UAF1 protein complex (Cohn et al., 2007). ATR and ATM dependent phosphorylation of FANCD2 at T691 and S717 promotes the monoubiquitination of FANCD2 stimulating the FA pathway (Ho et al., 2006). Multiple phosphorylation sites within FANCI are functionally important for inducing monoubiquitination of FANCD2 and thus the activation of the FA pathway (Ishiai et al., 2008) . Fanconi Anemia pathway Authored: Matthews, L, 2009-05-02 17:26:55 Edited: Matthews, L, 2009-05-20 15:51:04 Fanconi anemia (FA) is a genetic disease of genome instability characterized by congenital skeletal defects, aplastic anemia, susceptibility to leukemias, and cellular sensitivity to DNA damaging agents. Patients with FA have been categorized into at least 13 complementation groups (FA-A, -B, -C, -D1, -D2, -E, -F, -G, -I, -J, -L, -M, and -N). These complementation groups correspond to the genes FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCJ/BRIP1, FANCL, FANCM, and FANCN/PALB2. Although the functions of most of these proteins are mostly unknown, eight of them, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM products together with AAP24 and FAAP100 form a nuclear complex termed the FA core complex. The core complex is essential for FANCD2 and FANCI monoubiquitination after DNA damage. FANCD2 and FANCI are mutually dependent on one another for their respective monoubiquitination. After DNA damage and during S phase, FANCD2 localizes to chromatin, forming foci that overlap those containing proteins involved in homologous recombination, such as BRCA1 and RAD51. The FA pathway is regulated by the deubiquitination of FANCD2 and the phosphorylation FANCD2 and FANCI. The USP1/UAF1 complex is responsible for deubiquitination of FANCD2 and negatively regulates the FA pathway (Cohn et al., 2007) ATR and ATM dependent phosphorylation of FANCD2 promotes the monoubiquitination of FANCD2 stimulating the FA pathway (Cohn and D'Andrea, 2008; Wang, 2007). Pubmed17768402 Pubmed18082604 Pubmed18995829 Reactome Database ID Release 43419524 Reactome, http://www.reactome.org ReactomeREACT_18410 Reviewed: Huang, TT, 2009-05-20 17:48:24 Transcription Authored: Comai, L, Conaway, JW, Conaway, RC, Gustafsson, C, Hernandez, N, Hu, P, Larsson, N-G, Proudfoot, NJ, Reinberg, D, Timmers, HTM, 2003--0-9- Edited: Gillespie, ME, Gopinathrao, G, Joshi-Tope, G, 0000-00-00 00:00:00 Reactome Database ID Release 4374159 Reactome, http://www.reactome.org ReactomeREACT_1788 Reviewed: Paule, M, Zhao, X, Willis, I, 0000-00-00 00:00:00 Transcription by RNA Polymerase I, RNA Polymerase III and transcription from mitochondrial promoters. Gap-filling DNA repair synthesis and ligation in GG-NER Authored: Gopinathrao, G, 2004-02-02 17:30:34 GENE ONTOLOGYGO:0006297 Pubmed9111189 Reactome Database ID Release 4374969 Reactome, http://www.reactome.org ReactomeREACT_1998 The resultant gap is filled by polymerase activities of Pol delta and Pol epsilon. Accessory replication protein complexes of RPA, PCNA and RFC play a role in this synthesis. DNA Ligase 1 seals the gap restoring the covalent integrity of the repaired strand.<BR> Transcription-coupled NER (TC-NER) Authored: Joshi-Tope, G, 2003-07-14 15:01:00 GENE ONTOLOGYGO:0006283 Pubmed11823795 Pubmed3466163 Reactome Database ID Release 4373937 Reactome, http://www.reactome.org ReactomeREACT_1628 The preferential repair of UV-induced damage in transcribed strands of active genes is known as Transcription-coupled NER (TC-NER). Impairment of the ability for TC-NER results in the onset of a severe hereditary disorder called Cockayne’s syndrome, an autosomal recessive disease characterized by hypersensitivity to UV light . Many types of helix distorting lesions can block the movement of elongating RNA Pol II leading to its stalling and subsequent triggering of repair mechanisms. The repair of DNA damage in active genes occurs much faster compared to the repair in non-transcribed genomic regions (via GG-NER). Also, the non-transcribed strand of the same gene is repaired at a similar rate as that of non-transcribed genomic regions.<BR>The transcriptional responses to DNA damage in terms of stalling of Pol II, its displacement from the lesion site etc. are not well elucidated. The following annotation in GK provides an overall picture of TC-NER and will be updated as and when new insights are obtained about these crucial steps.<BR> Repair synthesis of patch ~27-30 bases long by DNA polymerase Authored: Gopinathrao, G, 2004-02-02 17:30:34 Reactome Database ID Release 4374967 Reactome, http://www.reactome.org ReactomeREACT_378 Repair synthesis is carried out by the DNA dependent DNA polymerases, delta and epsilon.<BR> Dual incision reaction in TC-NER Authored: Gopinathrao, G, 2004-02-11 18:33:11 Dual incisions are carried out by XPG, and ERCC1-XPF complex as seen in GG-NER.<BR> Reactome Database ID Release 43110304 Reactome, http://www.reactome.org ReactomeREACT_2222 Formation of transcription-coupled NER (TC-NER) repair complex Authored: Gopinathrao, G, 2004-02-02 17:30:34 Reactome Database ID Release 43110302 Reactome, http://www.reactome.org ReactomeREACT_1941 The “road block” induced by the DNA damage to the transcription machinery triggers assembly of a transcription couple repair complex, whose composition and function are yet to fully understood. Damage recognition is achieved by the arrest of Pol II active complex. Subsequently various factors like CSA, CSB, TFIIH, XPG, XPF-ERCC1 complexes are recruited. The importance of active CSA and CSB are known from the mutation profile of the patients bearing the corresponding disease phenotypes. CSB can act as a ‘repair-transcription uncoupling factor’ that may use its DNA translocase activity to remove the Pol II activity from the lesion site. TFIIS may cleave up to 35 nucleotides from the 3’ end of the nascent RNA product leading to the enhanced access to damage site on the corresponding template DNA. Post-translational protein modification After translation, many newly formed proteins undergo further covalent modifications that alter their functional properties and that are essentially irreversible under physiological conditions in the body. These modifications include the internal peptide bond cleavages that activate proenzymes, the attachment of oligosaccharide moieties to membrane-bound and secreted proteins, the attachment of lipid or glycolipid moieties that serve to anchor proteins to cellular membranes, and the vitamin K-dependent attachment of carboxyl groups to glutamate residues. Authored: D'Eustachio, P, 2005-04-18 15:58:56 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0043687 Reactome Database ID Release 43597592 Reactome, http://www.reactome.org ReactomeREACT_22161 Reviewed: Orlean, P, Stafford, DW, 0000-00-00 00:00:00 Post-chaperonin tubulin folding pathway Alpha and beta tubulin folding intermediates are formed through ATP–dependent interaction with TriC/CCT. In order to form a functional heterodimer, these folding intermediates undergo a series of interactions with five proteins: (cofactors A-E) following release from TriC/CCT (reviewed in Cowan and Lewis et al., 2001). These interactions are described in the reactions below. Ultimately, alpha tubulin, when associated with cofactor E, interacts with cofactor D-bound beta-tubulin. The entry of cofactor C into this complex results in the discharge of native heterodimer triggered by GTP hydrolysis in beta tubulin (Tian et al., 1997). Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 04:38:35 GENE ONTOLOGYGO:0007023 Pubmed11868281 Pubmed17709011 Pubmed9265649 Reactome Database ID Release 43389977 Reactome, http://www.reactome.org ReactomeREACT_16967 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Association of TriC/CCT with target proteins during biosynthesis Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 04:38:35 Pubmed19011634 Reactome Database ID Release 43390471 Reactome, http://www.reactome.org ReactomeREACT_16907 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 TRiC has broad recognition specificities, but in the cell it interacts with only a defined set of substrates (Yam et al. 2008). Many of its substrates that are targeted during biosynthesis are conserved between mammals and yeast (Yam et al. 2008). Folding of actin by CCT/TriC Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 04:38:35 GENE ONTOLOGYGO:0051086 Nucleotide-independent transfer of beta-actin from prefoldin to CCT occurs when prefoldin binds to CCT (Vainberg et al., 1998). Following ATP- dependent folding within CCT (Gao et al., 1992), beta-actin is released as a soluble, monomeric protein. Pubmed1351421 Pubmed8104191 Pubmed9630229 Reactome Database ID Release 43390450 Reactome, http://www.reactome.org ReactomeREACT_17050 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Protein folding Authored: Matthews, L, 2008-12-01 04:46:41 Due to the crowded envirnoment within the cell, many proteins must interact with molecular chaperones to attain their native conformation (reviewed in Young et al., 2004). Chaperones recognize and associate with proteins in their non-native state and facilitate their folding by stabilizing the conformation of productive folding intermediates. Chaperones that take part broadly in de novo protein folding, such as the Hsp70s and the chaperonins, facilitate the folding process through cycles of substrate binding and release regulated by their ATPase activity (see Young et al., 2004; Spiess et al., 2004; Bigotti and Clarke, 2008). Edited: Matthews, L, 2009-02-21 04:38:35 GENE ONTOLOGYGO:0051084 Pubmed15459659 Pubmed15519848 Pubmed18395510 Reactome Database ID Release 43391251 Reactome, http://www.reactome.org ReactomeREACT_16952 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Metabolism of proteins Authored: Matthews, L, 2009-03-04 22:13:42 Edited: Matthews, L, 2009-03-04 17:45:55 GENE ONTOLOGYGO:0044267 Protein metabolism comprises the pathways of translation, post-translational modification and protein folding. Reactome Database ID Release 43392499 Reactome, http://www.reactome.org ReactomeREACT_17015 Formation of tubulin folding intermediates by CCT/TriC Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 04:38:35 GENE ONTOLOGYGO:0006457 Pubmed11868281 Pubmed1361170 Pubmed8096061 Pubmed9265649 Reactome Database ID Release 43389960 Reactome, http://www.reactome.org ReactomeREACT_16956 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 TriC/CCT forms a binary complex with unfolded alpha- or beta-tubulin (Frydman et al., 1992; Gao et al., 1993). The tubulin folding intermediates produced by TriC are unstable (Gao et al., 1993). Five additional protein cofactors (cofactor A-E) are required for the generation of properly folded alpha- and beta-tubulin and for the formation of alpha/beta-tubulin heterodimers (Gao et al., 1993) (Tian et al., 1997, Cowan and Lewis 2001). Prefoldin mediated transfer of substrate to CCT/TriC Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 04:38:35 Pubmed11580269 Reactome Database ID Release 43389957 Reactome, http://www.reactome.org ReactomeREACT_16936 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Unfolded actins and tubulins bound to prefoldin are transferred to CCT via a docking mechanism (McCormack and Willison, 2001). Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 04:38:35 In the case of actin and tubulin folding, and perhaps other substrates, the emerging polypeptide chain is transferred from the ribosome to TRiC via Prefoldin (Vainberg et al., 1998). Pubmed9630229 Reactome Database ID Release 43389958 Reactome, http://www.reactome.org ReactomeREACT_17029 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Chaperonin-mediated protein folding Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 04:38:35 GENE ONTOLOGYGO:0006457 Pubmed10753735 Pubmed11580265 Pubmed11868281 Pubmed12354605 Pubmed12697815 Pubmed15519848 Pubmed18708324 Pubmed9630229 Reactome Database ID Release 43390466 Reactome, http://www.reactome.org ReactomeREACT_17004 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 The eukaryotic chaperonin TCP-1 ring complex (TRiC/ CCT) plays an essential role in the folding of a subset of proteins prominent among which are the actins and tubulins (reviewed in Altschuler and Willison, 2008). CCT/TRiC is an example of a type II chaperonin, defined (in contrast to type I) as functioning in the absence of a cochaperonin. TriC/CCT is a multisubunit toroidal complex that forms a cylinder containing two back-to-back stacked rings enclosing a cavity where substrate folding occurs in an ATP dependent process (reviewed in Altschuler and Willison, 2008 ). CCT/TriC contains eight paralogous subunits that are conserved throughout eukaryotic organisms (Leroux and Hartl 2000; Archibald et al. 2001; Valpuesta et al. 2002). CCT-mediated folding of non-native substrate protein involves capture through hydrophobic contacts with multiple chaperonin subunits followed by transfer of the protein into the central ring cavity where it folds. Although folding is initiated within this central cavity, only 5%–20% of proteins that are released have partitioned to the native state. The remaining portion is then recaptured by other chaperonin molecules (Cowan and Lewis 2001). This cycling process may be repeated multiple times before a target protein partitions to the native state. In the cell, binding to CCT occurs via presentation of target protein bound to upstream chaperones. During translation, the emerging polypeptide chain may be transferred from the ribosome to CCT via the chaperone Prefoldin (Vainberg et al., 1998) or the Hsp70 chaperone machinery (Melville et al., 2003). While the majority of CCT substrates ultimately partition to the native state as soluble, monomeric proteins, alpha and beta tubulin are unusual in that they require additional cofactors that are required to assemble the tubulin heterodimer (Cowan and Lewis 2001). Reuptake of GABA Authored: Mahajan, SS, 2010-08-02 Edited: Mahajan, SS, 2010-06-29 Pubmed19924586 Reactome Database ID Release 43888593 Reactome, http://www.reactome.org ReactomeREACT_23910 Reuptake of GABA from the synapse terminates the action of GABA thus regulating GABA action. GABA taken up from the synapse into the neurons is reused for synaptic loading. GABA taken up by astrocytes is degraded into C02 and glutamine. Glutamine is transported into the neurons for glutamate and GABA synthesis. Reviewed: Restituito, S, 2008-11-27 12:38:49 Degradation of GABA Authored: Mahajan, SS, 2010-07-31 Edited: Mahajan, SS, 2010-06-29 GABA is metabolized to succinated by the serial action of two enzymes, 4-aminobutyrate aminotransferase and suucinate semialdehyde dehydrogenase. Pubmed19172412 Reactome Database ID Release 43916853 Reactome, http://www.reactome.org ReactomeREACT_23964 Reviewed: Restituito, S, 2008-11-27 12:38:49 Neurotransmitter Clearance In The Synaptic Cleft Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 GENE ONTOLOGYGO:0042136 Neurotransmitter released in the synaptic cleft binds to specific receptors on the post-synaptic cell and the excess of the neurotransmitter is cleared to prevent over activation of the post-synaptic cell. The neurotransmitter is cleared by either re-uptake by the pre-synaptic neuron, diffusion in the perisynaptic area, uptake by astrocytes surrounding the synaptic cleft or enzymatic degradation of the neurotransmitter.<BR>This topic will be annotated in a future release. Reactome Database ID Release 43112311 Reactome, http://www.reactome.org ReactomeREACT_13583 Reviewed: Restituito, S, 2008-11-27 12:38:49 Dopamine Neurotransmitter Release Cycle Authored: Mahajan, SS, 2008-01-14 16:01:52 Dopamine neurotransmitter cycle occurs in dopaminergic neurons. Dopamine is synthesized and loaded into the clathrin sculpted monoamine transport vesicles. The vesicles are docked, primed and fused with the plasmamembrane in the synapse to release dopamine into the synaptic cleft. Edited: Mahajan, SS, 2008-11-18 00:03:09 Pubmed16613554 Reactome Database ID Release 43212676 Reactome, http://www.reactome.org ReactomeREACT_15293 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Acetylcholine Neurotransmitter Release Cycle Acetylcholine neurotransmitter release cycle involves syntheis of choline, loading of clathrin scultpted synaptic vesicles, docking and priming of the acetyl choline loaded synaptic vesicles and then release of acetylcholine. This cycle occurs in neurons of central nervous system (CNS), peripheral, autonomic and somatic nervous system. In the CNS, the acetylcholine is released by the presynaptic neurons into the synaptic cleft where the released acetylcholine is accessible to acetylcholine receptors located on the postsynaptic neurons. Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-11-18 00:03:09 Pubmed18029057 Reactome Database ID Release 43264642 Reactome, http://www.reactome.org ReactomeREACT_15309 Reviewed: Kavalali, E, 2008-04-24 16:31:34 GABA synthesis, release, reuptake and degradation Authored: Mahajan, SS, 2010-06-29 Edited: Mahajan, SS, 2010-06-29 GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. GABA modulates neuronal excitability throughout the nervous system. Disruption of GABA neurotransmission leads to many neurological diseases including epilepsy and a general anxiety disorder. GABA is synthesized by two distinct enzymes GAD67 and GAD65 that differ in their cellular localization, functional properties and co-factor requirements. GABA synthesized by GAD65 is used for neurotransmission whereas GABA synthesized by GAD67 is used for processes other than neurotransmission such as synaptogenesis and protection against neuronal injury. GABA is loaded into synaptic vesicle with the help of vesicular inhibitory amino acid transporter or VGAT. GAD65 and VGAT are functionally linked at the synaptic vesicle membrane and GABA synthesized by GAD65 is preferentially loaded into the synaptic vesicle over GABA synthesized in cytoplasm by GAD67.The GABA loaded synaptic vesicles are docked at the plasma membrane with the help of the SNARE complexes and primed by interplay between various proteins including Munc18, complexin etc. Release of GABA loaded synaptic vesicle is initiated by the arrival of action potential at the presynaptic bouton and opening of N or P/Q voltage gated Ca2+ channels. Ca2+ influx results in Ca2+ binding by synaptobrevin, which is a part of the SNARE complex that also includes SNAP25 and syntaxin, leading to synaptic vesicle fusion. Release of GABA in the synaptic cleft leads to binding of GABA by the GABA receptors and post ligand binding events. Pubmed16787421 Pubmed19428801 Reactome Database ID Release 43888590 Reactome, http://www.reactome.org ReactomeREACT_23947 Reviewed: Restituito, S, 2008-11-27 12:38:49 GABA synthesis Authored: Mahajan, SS, 2010-06-29 Edited: Mahajan, SS, 2010-06-29 GABA synthesized uniquely by two forms of glutamate decarboxylases, GAD65 and GAD67, that are functionally distinct and have different co-factor requirements. GAD65 is functionally linked to VGAT, the GABA transporter and selectively GABA synthesized by GAD65 is preferably loaded into the synaptic vesicles. GABA synthesized by GAD67 may be used for functions other than nuerotransmission. Pubmed12467378 Pubmed9777630 Pubmed9871412 Reactome Database ID Release 43888568 Reactome, http://www.reactome.org ReactomeREACT_24020 Reviewed: Restituito, S, 2008-11-27 12:38:49 Norepinephrine Neurotransmitter Release Cycle Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-11-18 00:03:09 Noradrenalin release cycle consists of reacidification of the empty clathrin sculpted monoamine transport vesicle, loading of dopamine into reacidified clathrin coated monamine transport vesicle, conversion of dopamine into Noradrenalin, docking and priming of the noradrenalin synaptic veiscle and then release of noradrenalin synaptic vesicle. In the peripheral nervous system in the peripheral nervous system noradrenalin is stored in large and small dense vesicles and is realesed from large vesicles. Pubmed12519779 Pubmed17478680 Pubmed17891149 Reactome Database ID Release 43181430 Reactome, http://www.reactome.org ReactomeREACT_15418 Reviewed: Restituito, S, 2008-11-27 12:38:49 Glutamate Neurotransmitter Release Cycle Authored: Mahajan, SS, 2008-01-14 16:01:52 Communication at the synapse involves the release of glutamate from the presynaptic neuron and its binding to glutamate receptors on the postsynaptic cell to generate a series of events that lead to propagation of the synaptic transmission. This process begins with the formation of synaptic vesicles in the presynaptic neuron, proceeds to the loading of glutamate into the vesicles, and concludes with the release of glutamate into the synaptic cleft.<br><br>The glutamate life cycle in the neuron begins with the loading of the nascent synaptic vesicles with cytosolic glutamate with the help the transporter protein, VGLUT1, located in the synaptic vesicular membrane. Glutamate loaded vesicles are formed in the cytoplasm and then transported to a site close to the plasma membrane where the vesicle is docked with the help of several proteins. One of the key players in the docking process in Munc 18, which interacts with syntaxin (in the plasma membrane), MINT (Munc18 interacting molecule), and DOC2. These interactions along with the secondary interactions are needed for docking the synaptic vesicle to the plasma membrane.<br><br><br>The docked synaptic vesicle is not ready for release until it undergoes molecular changes to prime it for fusion with the plasma membrane. Munc13 is one of the main players in the priming process. Munc 13 interacts with RIM (Rab3A interacting molecule) located in the synaptic vesicle. Munc 13 also interacts with DOC2. The precise molecular mechanisms of the interactions that result in docking versus priming are not clear and the docking and priming process have been combined in this annotation of this pathway. Once primed the synaptic vesicle is ready for release.<br><br><br>Synaptic transmission involves an action potential that is generated in the presynaptic cell which induces the opening of voltage gated Ca2+ channels (VGCC) located in the plasma membrane of the presynaptic neuron. Typically N, P/Q and R type of VGCCs are involved in the neurotransmitter release. Ca2+ influx through these channels results in the rise of intracellular Ca2+ concentration. In the microdomain of glutamatergic synapses, the Ca2+ concentration could rise between 10-25 micro molar. Synaptotagmin, a Ca2+-binding protein located in the synaptic vesicular membrane, responds to the rise in the Ca2+ levels in the microdomain and induces a synaptic vesicle membrane curvature that favors vesicle fusion. Fusion of the synaptic vesicle with the plasma membrane is characterized by the formation of a trimeric trans-SNARE complex that involves VAMP2 from the synaptic vesicle membrane, and syntaxin and SNAP-25 from plasma membrane. Vesicle fusion incorporates the synaptic vesicle membrane into the plasma membrane, releasing the vesicle contents (glutamate) into the synaptic cleft. Postfusion the synaptic vesicle membrane proteins (VAMP2, Rab3A, VGLUT1, and synaptotagmin) are also found in the plasma membrane. Edited: Mahajan, SS, 2008-01-14 16:06:22 GENE ONTOLOGYGO:0014047 Pubmed10440375 Pubmed11001057 Pubmed16704978 Pubmed16990140 Pubmed17478680 Pubmed8825650 Pubmed9701566 Reactome Database ID Release 43210500 Reactome, http://www.reactome.org ReactomeREACT_12591 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Serotonin Neurotransmitter Release Cycle Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-11-18 00:03:09 Reactome Database ID Release 43181429 Reactome, http://www.reactome.org ReactomeREACT_15425 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Serotonin is synthesized in the serotonergic neurons in the central nervous system and the enterochrommaffin cells of the gastroinetstinal system. Serotonin is loaded into the clathrin sculpted monoamine transport vesicles. The vesicles are docked, primed and release after the change in the membrane potential that activates voltage gated calcium channels and the reponse by several proetins to the changes in intracellular Ca2+ increase leads to fusion of the vesicle and release of serotonin into the synapse. PP2A-regulatory subunit B delta isoform Converted from EntitySet in Reactome Reactome DB_ID: 165962 Reactome Database ID Release 43165962 Reactome, http://www.reactome.org ReactomeREACT_3606 Acetylcholine Binding And Downstream Events Authored: Mahajan, SS, 2008-01-14 16:01:52 Reactome Database ID Release 43181431 Reactome, http://www.reactome.org ReactomeREACT_15461 Reviewed: Restituito, S, 2008-11-27 12:38:49 Activation of Nicotinic Acetylcholine Receptors Authored: Mahajan, SS, 2010-04-22 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholine receptors (nAchR) are a subtype of acetylcholine receptors that are activated by nicotine and allow the influx of monovalent (sodium) and divalent cations(calcium), however, the permeability of sodium and/or calcium maybe high or low depending on the subunit composition of the receptor. Nicotinic acetylcholine receptors are expressed widely in the central and peripheral nervous system in the presynaptic terminal, terminal bouton and post-synaptic neuron. Functionally nicotinic acetylcholine receptors in the pre-synaptic and postsynaptic terminals behave similarly. Nicotinic AChR are a family of acetylcholine gated pentameric receptors that are formed by the association of various combinations of mostly alpha, beta subunits and sometimes gamma delta, episilon subunits. In addition, receptors may be more diverse due the fact that some receptor have same subunits but the stoichiometry of the subunits is different. Pubmed11532443 Pubmed18691557 Pubmed19126755 Pubmed19481063 Reactome Database ID Release 43629602 Reactome, http://www.reactome.org ReactomeREACT_22126 Reviewed: Cooper, E, 2010-05-24 PP2A-catalytic subunit C Converted from EntitySet in Reactome Reactome DB_ID: 165974 Reactome Database ID Release 43165974 Reactome, http://www.reactome.org ReactomeREACT_3140 Astrocytic Glutamate-Glutamine Uptake And Metabolism Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 In astrocytic glutamate-glutamine cycle, the excess glutamate released by the pre-synaptic neuron in the synaptic cleft is transported into the astrocyte by a family glutamate transporters called the excitatory amino acid transporters 1 and 2, EAAT1 and EAAT2. Astrocytes carrying these transporters exist in close apposition to the synapse to clear excess glutamate to prevent excessive activation of neurons and hence neuronal death. Glutamate in astrocytes is converted to glutamine by glutamine synthetase. Glutamine is then transported into the extracellular space by system N transporters. The glutamate in the extracellular space is available for neuronal uptake. Reactome Database ID Release 43210455 Reactome, http://www.reactome.org ReactomeREACT_13639 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell Authored: Mahajan, SS, 2008-01-14 16:01:52 Reactome Database ID Release 43112314 Reactome, http://www.reactome.org ReactomeREACT_15370 Reviewed: Restituito, S, Kavalali, E, 2008-12-02 04:33:19 The neurotransmitter in the synaptic cleft released by the pre-synaptic neuron binds specific receptors located on the post-synaptic terminal. These receptors are either ion channels or G protein coupled receptors that function to transmit the signals from the post-synaptic membrane to the cell body. Metabolism of serotonin Authored: Mahajan, SS, 2008-10-16 20:20:56 Edited: Gillespie, ME, 2009-11-19 Metabolism of seratonin Reactome Database ID Release 43380612 Reactome, http://www.reactome.org ReactomeREACT_15532 Reviewed: Restituito, S, 2008-11-27 12:38:49 Serotonin is first metabolized to 5-hydroxyindole acetaldehyde by monoamine oxidase. 5-hydroxyindole acetaldehyde is then catalyzed by aldehyde dehydrogenase to form 5-hydroxyindole acetic acid. PP2A-subunit A Converted from EntitySet in Reactome Reactome DB_ID: 165997 Reactome Database ID Release 43165997 Reactome, http://www.reactome.org ReactomeREACT_3019 Neurotransmitter uptake and Metabolism In Glial Cells Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 GENE ONTOLOGYGO:0001504 Neuotransmitter uptake by astrocytes is mediated by specific transporter located on the astrocytic membrane. The imported neurotransmitter in the astrocytes is metabolized and transported back to the neuron via specialized transporters. Reactome Database ID Release 43112313 Reactome, http://www.reactome.org ReactomeREACT_13594 Reviewed: Restituito, S, Kavalali, E, 2008-12-02 04:33:19 Clearance of seratonin Authored: Mahajan, SS, 2008-01-14 16:01:52 Clearance of serotonin Edited: Mahajan, SS, 2008-11-18 00:03:09 Reactome Database ID Release 43380615 Reactome, http://www.reactome.org ReactomeREACT_15391 Reviewed: Restituito, S, 2008-11-27 12:38:49 Serotonergic neurotransmission affects a wide range of behaviors, from food intake and reproductive activity, to sensory processing and motor activity, to cognition and emotion. One such key regulator is the serotonin transporter (5-HTT), which is observed to remove serotonin released into the synaptic cleft. Serotonin clearance from the synaptic cleft Enzymatic degradation of Dopamine by monoamine oxidase Alternately dopamine is metabolized to homovanillic acid in a two-step reaction in which dopamine is first oxidized to 3,4-dihydroxypheylacetic acid (DOPAC) and then converted to homovanillic acid by catecholamine o-methyltransferase. Reactome Database ID Release 43379398 Reactome, http://www.reactome.org ReactomeREACT_15511 Reviewed: Restituito, S, 2008-11-27 12:38:49 Enzymatic degradation of dopamine by COMT Authored: Mahajan, SS, 2008-08-05 20:29:44 Dopamine once taken up by the dopamine transporter from the extracellular space into the cytosol is metabolized in a two step reaction to homovanillic acid.The first reaction is catalyzed by catecholamine o-methyl transferase and the subsequent reaction is catalyzed by monoamine oxidase A. Edited: Gillespie, ME, 2009-11-19 Pubmed17185601 Reactome Database ID Release 43379397 Reactome, http://www.reactome.org ReactomeREACT_15548 Reviewed: Restituito, S, 2008-11-27 12:38:49 Clearance of dopamine Authored: Mahajan, SS, 2008-01-14 16:01:52 Dopamine clearance from the synaptic cleft Edited: Mahajan, SS, 2008-11-18 00:03:09 Reactome Database ID Release 43379401 Reactome, http://www.reactome.org ReactomeREACT_15514 Reviewed: Restituito, S, 2008-11-27 12:38:49 The human gene SLC6A3 encodes the sodium-dependent dopamine transporter, DAT which mediates the re-uptake of dopamine from the synaptic cleft (Vandenbergh DJ et al, 2000). Dopamine can then be degraded by either COMT or monoamine oxidase. Transport to the Golgi and subsequent modification At least two mechanisms of transport of proteins from the ER to the Golgi have been described. One is a general flow requiring no export signals (Wieland et al, 1987; Martínez-Menárguez et al, 1999). The other is mediated by LMAN1/MCFD2, mannose-binding lectins that recognize a glycan signal (Zhang B et al, 2003). Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-09-15 Pubmed10412983 Pubmed12717434 Pubmed3594573 Reactome Database ID Release 43948021 Reactome, http://www.reactome.org ReactomeREACT_25046 Reviewed: Gagneux, P, 2010-11-18 ACTIVATION GENE ONTOLOGYGO:0042392 Reactome Database ID Release 43428700 Reactome, http://www.reactome.org ER to Golgi Transport Authored: Gillespie, ME, 2007-07-13 20:42:29 Edited: Gillespie, ME, 2007-07-19 14:52:10 GENE ONTOLOGYGO:0006888 Pubmed11252894 Reactome Database ID Release 43199977 Reactome, http://www.reactome.org ReactomeREACT_11203 Reviewed: Gagneux, P, 2010-11-18 Secretory cargo destined to be secreted or to arrive at the plasma membrane (PM) leaves the ER via distinct exit sites. This cargo is destined for the Golgi apparatus. ACTIVATION GENE ONTOLOGYGO:0042392 Reactome Database ID Release 43428666 Reactome, http://www.reactome.org COPII (Coat Protein 2) Mediated Vesicle Transport Authored: Gillespie, ME, 2007-07-13 20:42:29 COPII components (known as Sec13p, Sec23p, Sec24p, Sec31p, and Sar1p in yeast) traffic cargo from the endoplasmic reticulum to the Golgi apparatus. COPII-coated vesicles were originally discovered in the yeast Saccharomyces cerevisiae using genetic approaches coupled with a cell-free assay. The mammalian counterpart of this pathway is represented here. Newly synthesized proteins destined for secretion are sorted into COPII-coated vesicles at specialized regions of the ER. These vesicles leave the ER, become uncoated and subsequently fuse with the Golgi apparatus membrane. Edited: Gillespie, ME, 2007-11-21 20:48:45 GENE ONTOLOGYGO:0048208 Pubmed11252894 Pubmed17316621 Reactome Database ID Release 43204005 Reactome, http://www.reactome.org ReactomeREACT_12507 Reviewed: Gagneux, P, 2010-11-18 ACTIVATION GENE ONTOLOGYGO:0017050 Reactome Database ID Release 43428281 Reactome, http://www.reactome.org N-glycan trimming and elongation in the cis-Golgi After the transport of the glycoprotein to the cis-Golgi, the pathway of N-glycosylation bifurcates. Some N-glycans can be moved to subsequent steps of the secretory pathway without further modifications, or alternatively, with the removal of a few mannoses (Oligo Mannoses pathway). In yeast and other unicellular species, a series of mannose residues are added (High Mannoses pathway). The presence of this modification is a major obstacle to the production of pharmaceutical drugs in yeast, where the HighMannose pathway must be inhibited or modified in order to avoid the presence of high mannose xenoglycans.<br>The first N-glycan modification step is the trimming of up to four mannoses by one of three mannosidase enzymes. Moreover, Glycoproteins that have not entered in the Calnexin/Calreticulin cycle or that have not had their glucose residues trimmed earlier in the ER, can enter the main pathway here due to the existence to an alternative route catalyzed by the enzyme Endomannosidase I (Schachter, 2000; Stanley et al, 2009)<br> Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-09-17 Pubmed11421343 Pubmed20301244 Reactome Database ID Release 43964739 Reactome, http://www.reactome.org ReactomeREACT_25210 Reviewed: Gagneux, P, 2010-11-18 ACTIVATION GENE ONTOLOGYGO:0042392 Reactome Database ID Release 43428693 Reactome, http://www.reactome.org Progressive trimming of alpha-1,2-linked mannose residues from Man9/8/7GlcNAc2 to produce Man5GlcNAc2 Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-09-17 In the cis-Golgi, Man7, Man8 or Man9 N-glycans are progressively trimmed to Man5 N-glycans. The reaction can be catalyzed by one of three known mannosidases, expressed in different tissues and with slightly different affinity. These enzymes trim the mannoses in a different order (Tremblay and Herscovics, 2000), but produce the same output with 5 mannoses.<br>A small confusion on the nomenclature of these genes coding for these enzymes is present in the literature: the standard HGNC symbols are MAN1A1, MAN1A2, MAN1C1, but MAN1A2 is also referred to as MAN1B in certain publications, while MAN1B1 is the enzyme acting in the ERQC compartment on unfolded glycoproteins. Moreover, the names do not correspond to a preference of these enzymes for which of the three mannose branches these trim first. Pubmed10915796 Reactome Database ID Release 43964827 Reactome, http://www.reactome.org ReactomeREACT_25396 Reviewed: Gagneux, P, 2010-11-18 N-glycan antennae elongation in the medial/trans-Golgi Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-09-30 In the latter compartments of the distal Golgi the N-Glycan is further modified, leading to the wide range of N-Glycans observed in multicellular organisms. The first step of N-Glycan elongation in the Golgi is the addition of a GlcNAc residue on the alpha 1,3 branch by the enzyme MGAT1 (GlcNAc-TI), which commits the elongation pathway to Complex or Hybrid N-Glycans from Oligomannose N-Glycans. At this point, the pathway bifurcates again to generate Complex or Hybrid N-Glycans. The addition of a GlcNAc in the middle of the two arms of the N-Glycan, catalyzed by MGAT3 (GNT-III), inhibits the removal of the mannoses on the alpha1,3 branches by MAN2 and the addition of a GlcNAc by MGAT2 (GlcNAc-TII), and commits the pathway toward the synthesis of hybrid N-Glycans. Alternatively, the removal of these mannoses and the action of MGAT2 leads to the synthesis of complex N-Glycans (Kornfeld and Kornfeld 1985).<br>The exact structure of the network of reactions leading to Complex or Hybrid N-Glycans is still not completely described and validated experimentally. Here we will annotate only one generic reaction for each of the enzymes known to participate in this process. For a better annotation on the reactions and genes involved in the synthesis of Complex and Hybrid N-Glycans we recommend the GlycoGene Database (Ito H. et al, 2010) (http://riodb.ibase.aist.go.jp/rcmg/ggdb/textsearch.jsp) for annotations on genes, and the Consortium for Functional Genomics (http://riodb.ibase.aist.go.jp/rcmg/ggdb/textsearch.jsp) for annotation of Glycan structures and reactions. Moreover, a computationally inferred prediction on the structure of this network is available through the software GlycoVis (Hossler P. et. al. 2006). Pubmed11421343 Pubmed16807922 Pubmed20816477 Pubmed3896128 Reactome Database ID Release 43975576 Reactome, http://www.reactome.org ReactomeREACT_25208 Reviewed: Gagneux, P, 2010-11-18 Reactions specific to the hybrid N-glycan synthesis pathway Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-09-30 Pubmed11421343 Pubmed9061364 Reactome Database ID Release 43975574 Reactome, http://www.reactome.org ReactomeREACT_25266 Reviewed: Gagneux, P, 2010-11-18 The transfer of a bisecting GlcNAc by MGAT3 commits the pathway toward the synthesis of hybrid glycans, because MAN2 is not able to operate on bisected oligosaccharides (Schachter et al 2000, Priatel JJ et al, 1997). The expression of MGAT3 over MGAT2 in a tissue can regulate the synthesis of hybrid toward complex N-glycans. The addition of a GlcNAc between the two arms also prevents the action of MGAT4, MGAT5 and FUT8. ACTIVATION GENE ONTOLOGYGO:0008117 Reactome Database ID Release 43428675 Reactome, http://www.reactome.org Reactions specific to the complex N-glycan synthesis pathway Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-09-30 If MAN2 acts before MGAT3, the pathway progresses to complex N-glycans, because MAN2 is not able to operate on bisected oligosaccharides (11421343, page 5). The expression of MAN2 over MGAT3 in a tissue can regulate the synthesis of hybrid or complex N-glycans. Reactome Database ID Release 43975578 Reactome, http://www.reactome.org ReactomeREACT_25302 Reviewed: Gagneux, P, 2010-11-18 ACTIVATION GENE ONTOLOGYGO:0004565 Reactome Database ID Release 431605789 Reactome, http://www.reactome.org N-Glycan antennae elongation Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-09-30 N-glycans are further modified after the commitment to Complex or Hybrid N-glycans. The exact structure of the network of metabolic reactions involved is complex and not yet validated experimentally. Here we will show a generic reaction for each of the genes known to be involved in N-Glycosylation.<br>For a better annotation of the reactions and genes involved in the synthesis of Complex and Hybrid N-glycans we recommend the GlycoGene Database (Ito H. et al, 2010) (http://riodb.ibase.aist.go.jp/rcmg/ggdb/textsearch.jsp) for annotations of genes, and the Consortium for Functional Genomics (http://riodb.ibase.aist.go.jp/rcmg/ggdb/textsearch.jsp) for annotation of Glycan structures and reactions. Moreover, a computationally inferred prediction for the structure of this network is available through the software GlycoVis (Hossler P. et. al. 2006). Pubmed16807922 Pubmed20816477 Reactome Database ID Release 43975577 Reactome, http://www.reactome.org ReactomeREACT_25085 Reviewed: Gagneux, P, 2010-11-18 ACTIVATION GENE ONTOLOGYGO:0070780 Reactome Database ID Release 43428691 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008117 Reactome Database ID Release 43428675 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008481 Reactome Database ID Release 43428215 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050291 Reactome Database ID Release 43428183 Reactome, http://www.reactome.org ER Quality Control Compartment (ERQC) Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-07-02 Proteins that are released from the CNX or CRT complex with folding defects accumulate in a compartment of the ER called ERQC (Kamhi-Nesher S et al 2001). Here, the enzymes UGGG1 or UGGG2 are able to recognize glycoproteins with minor folding process and re-add the glucose on the alpha,1,3 branch; this is a signal for the transport of these glycoproteins back to the ER, where they can interact again with CNX or CRT in order to achieve a correct folding. At the same time that the glycoprotein is in the ERQC, the enzyme ER mannosidase I progressively removes the mannoses in position 1A, 2A, B, C on the N-glycans; when the mannose on 1A is trimmed, UGGG1/UGGG2 is no longer able to re-add the glucose, and therefore the protein is destined for degradation.<br>For years it has been thought that the removal of the mannose in position B of the N-glycan was the signal to direct proteins to degradation. However, this mechanism has been described better by Avezov et al (Avezov V et al, 2008) and it has been demonstrated that even glycoproteins with Man8 or Man7 glycans can be re-glucosylated and interact again with CNX or CRT. For a review on this topic, see Lederkremer GZ, 2009 and Määttänen P et al, 2010. Pubmed11408579 Pubmed18003979 Pubmed19616933 Pubmed20347046 Reactome Database ID Release 43901032 Reactome, http://www.reactome.org ReactomeREACT_25091 Reviewed: Gagneux, P, 2010-11-18 Neuronal System Authored: Gillespie, ME, 2005-11-10 16:23:09 Edited: Gillespie, ME, 2005-11-10 16:23:09 GENE ONTOLOGYGO:0007268 Reactome Database ID Release 43112316 Reactome, http://www.reactome.org ReactomeREACT_13685 The human brain contains at least 100 billion neurons, each with the ability to influence many other cells. Clearly, highly sophisticated and efficient mechanisms are needed to enable communication among this astronomical number of elements. This communication occurs across synapses, the functional connection between neurons. Synapses can be divided into two general classes: electrical synapses and chemical synapses. Electrical synapses permit direct, passive flow of electrical current from one neuron to another. The current flows through gap junctions, specialized membrane channels that connect the two cells. Chemical synapses enable cell-to-cell communication using neurotransmitter release. Neurotransmitters are chemical agents released by presynaptic neurons that trigger a secondary current flow in postsynaptic neurons by activating specific receptor molecules. Neurotransmitter secretion is triggered by the influx of Ca2+ through voltage-gated channels, which gives rise to a transient increase in Ca2+ concentration within the presynaptic terminal. The rise in Ca2+ concentration causes synaptic vesicles (the presynaptic organelles that store neurotransmitters) to fuse with the presynaptic plasma membrane and release their contents into the space between the pre- and postsynaptic cells. Transmission across Electrical Synapses Authored: Joshi-Tope, G, 2004-04-22 09:35:00 Edited: Mahajan, SS, 2008-01-14 16:01:52 Electrical transmission across nerve cells is accomplished when the current generated in the upstream neuron spreads to the downstream neuron through a path of low electrical resistance. In neurons this is accomplished at gap junctions. Electrical synapses are found in neuronal tissue where the activity of neurons must be highly synchronized. The neurons responsible for hormone secretion from the mammalian hypothalamus are a class of highly synchronized electric neurons. Gap junctions connecting the presynaptic cell with the postsynaptic cell allow current generated in the presynaptic cell to flow directly into the postsynaptic cell. Transmission speed is dramatically increased in such a system. The junction itself is composed of two hemichannels, one each on the pre- and postsysnaptic cells. These channels are composed of members of the connexin family of proteins. Reactome Database ID Release 43112307 Reactome, http://www.reactome.org ReactomeREACT_16881 Reviewed: Rush, MG, 2008-01-11 00:00:00 Mitochondrial Protein Import A human mitochondrion contains about 1500 proteins, more than 99% of which are encoded in the nucleus, synthesized in the cytosol and imported into the mitochondrion. Proteins are targeted to four locations (outer membrane, intermembrane space, inner membrane, and matrix) and must be sorted accordingly (reviewed in Kutik et al. 2007, Milenkovic et al. 2007, Bolender et al. 2008, Endo and Yamano 2009). Newly synthesized proteins are transported from the cytosol across the outer membrane by the TOMM40:TOMM70 complex. Proteins that contain presequences first interact with the TOMM20 subunit of the complex while proteins that contain internal targeting elements first interact with the TOMM70 subunit. After initial interaction the protein is conducted across the outer membrane by TOMM40 subunits. In yeast some proteins such as Aco1, Atp1, Cit1, Idh1, and Atp2 have both presequences that interact with TOM20 and mature regions that interact with TOM70 (Yamamoto et al. 2009).<br>After passage across the outer membrane, proteins may be targeted to the outer membrane via the SAMM50 complex, to the inner membrane via the TIMM22 or TIMM23 complexes (reviewed in van der Laan et al. 2010), to the matrix via the TIMM23 complex (reviewed in van der Laan et al. 2010), or proteins may fold and remain in the intermembrane space (reviewed in Stojanovski et al. 2008, Deponte and Hell 2009, Sideris and Tokatlidis 2010). Presequences on matrix and inner membrane proteins cause interaction with TIMM23 complexes; internal targeting sequences cause outer membrane proteins to interact with the SAMM50 complex and inner membrane proteins to interact with the TIMM22 complex. While in the intermembrane space hydrophobic proteins are chaperoned by the TIMM8:TIMM13 complex and/or the TIMM9:TIMM10:FXC1 complex. Authored: May, B, 2011-05-03 Edited: May, B, 2011-05-03 GENE ONTOLOGYGO:0006626 Pubmed17696772 Pubmed17996737 Pubmed17998403 Pubmed18174896 Pubmed19453276 Pubmed19720617 Pubmed19767391 Pubmed20100523 Pubmed20214493 Reactome Database ID Release 431268020 Reactome, http://www.reactome.org ReactomeREACT_118595 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 Metabolism of Angiotensinogen to Angiotensins Angiotensinogen, a prohormone, is synthesized and secreted mainly by the liver but also from other tissues (reviewed in Fyhrquist and Saijonmaa 2008, Cat and Touyz 2011). Renin, an aspartyl protease specific for angiotensinogen, is secreted into the bloodstream by juxtaglomerular cells of the kidney in response to a drop in blood pressure. Renin cleaves angiotensinogen to yield a decapaptide, angiotensin I (angiotensin-1, angiotensin-(1-10)). Circulating renin can also bind the membrane-localized (pro)renin receptor (ATP6AP2) which increases its catalytic activity. After cleavage of angiotensinogen to angiotensin I by renin, two C-terminal amino acid residues of angiotensin I are removed by angiotensin-converting enzyme (ACE), located on the surface of endothelial cells, to yield angiotensin II (angiotensin-2, angiotensin-(1-8)), the active peptide that causes vasoconstriction, resorption of sodium and chloride, excretion of potassium, water retention, and aldosterone secretion.<br>More recently other, more tissue-localized pathways leading to angiotensin II and alternative derivatives of angiotensinogen have been identified (reviewed in Kramkowski et al. 2006, Kumar et al. 2007, Fyhrquist and Saijonmaa 2008, Becari et al. 2011). Chymase, cathepsin G, and cathepsin X (cathepsin Z) can each cleave angiotensin I to yield angiotensin II. Angiotensin-converting enzyme 2 (ACE2) cleaves 1 amino acid residue from angiotensin I (angiotensin-(1-10)) to yield angiotensin-(1-9), which can be cleaved by ACE to yield angiotensin-(1-7). ACE2 can also cleave angiotensin II to yield angiotensin-(1-7). Neprilysin can cleave either angiotensin-(1-9) or angiotensin I to yield angiotensin-(1-7). Angiotensin-(1-7) binds the MAS receptor (MAS1, MAS proto-oncogene) and, interestingly, produces effects opposite to those produced by angiotensin II.<br>Aminopeptidase A (APA, ENPEP) cleaves angiotensin II to yield angiotensin III (angiotensin-(2-8)), which is then cleaved by aminopeptidase N (APN, ANPEP) yielding angiotensin IV (angiotensin-(3-8)). Angiotensin IV binds the AT4 receptor (AT4R, IRAP, LNPEP, oxytocinase).<br>Inhibitors of renin (e.g. aliskiren) and ACE (e.g. lisinopril, ramipril) are currently used to treat hypertension (reviewed in Gerc et al. 2009, Verdecchia et al. 2010, Alreja and Joseph 2011). Authored: May, B, 2011-11-19 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed12676165 Pubmed17229979 Pubmed17509892 Pubmed18793332 Pubmed20380117 Pubmed20418269 Pubmed21499495 Pubmed21945916 Pubmed21956534 Pubmed22389749 Pubmed22410251 Reactome Database ID Release 432022377 Reactome, http://www.reactome.org ReactomeREACT_147707 Reviewed: Joseph, J, 2012-08-06 Depolarization of the Presynaptic Terminal Triggers the Opening of Calcium Channels Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 GENE ONTOLOGYGO:0051899 Reactome Database ID Release 43112308 Reactome, http://www.reactome.org ReactomeREACT_13606 Reviewed: Kavalali, E, 2008-04-24 16:31:34 The action potential travels down the axon and reaches the pre-synaptic terminal depolarizing the membrane in the pre-synaptic terminal. The depolarization causes the voltage-gated Ca2+ channels to open allowing the influx of Ca2+ that signals the release of neurotransmitter into the synaptic cleft. Neurotransmitter Release Cycle Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 GENE ONTOLOGYGO:0007269 Neurotransmitter is stored in the synaptic vesicle in the pre-synaptic terminal prior to its release in the synaptic cleft upon depolarization of the pre-synaptic membrane. The release of the neurotransmitter is a multi-step process that is controlled by electrical signals passing through the axons in form of action potential. Neurotransmitters include glutamate, acetylcholine, nor-epinephrine, dopamine and seratonin. Each of the neurotransmitter cycle is independently described. Pubmed15217342 Pubmed16819626 Pubmed16865347 Pubmed17880890 Reactome Database ID Release 43112310 Reactome, http://www.reactome.org ReactomeREACT_13723 Reviewed: Restituito, S, Kavalali, E, 2008-12-02 04:33:19 Electric Transmission Across Gap Junctions Authored: Joshi-Tope, G, 2004-04-22 09:35:00 Edited: Gillespie, ME, 2009-03-10 20:55:39 Electrical synapses are found in all nervous systems, including the human brain. The membranes of the two communicating neurons come extremely close at the synapse and are actually linked together by an intercellular specialization called a gap junction. Gap junctions contain precisely aligned, paired channels in the membrane of the pre- and postsynaptic neurons, such that each channel pair forms a pore. Electrical synapses thus work by allowing ionic current to flow passively through the gap junction pores from one neuron to another. Because passive current flow across the gap junction is virtually instantaneous, communication can occur without the delay that is characteristic of chemical synapses. Reactome Database ID Release 43112303 Reactome, http://www.reactome.org ReactomeREACT_16970 Reviewed: Rush, MG, 2008-01-11 00:00:00 Transmission across Chemical Synapses Authored: Mahajan, SS, 2008-01-14 16:01:52 Chemical synapses are specialized junctions that are used for communication between neurons, neurons and muscle or gland cells. The synapse involves a pre-synaptic neuron and a post-synaptic neuron, muscle cell or glad cell. The pre and the post-synaptic cell are separated by a gap of 20nm called the synaptic cleft. The signals pass in a unidirection from pre-synaptic to post-synaptic. The pre-synaptic neuron communicates via the release of neurotransmitter which bind the receptors on the post-synaptic cell. Edited: Mahajan, SS, 2008-01-14 16:01:52 GENE ONTOLOGYGO:0007268 Reactome Database ID Release 43112315 Reactome, http://www.reactome.org ReactomeREACT_13477 Reviewed: Restituito, S, Kavalali, E, 2008-12-02 04:33:19 Termination of O-glycan biosynthesis Authored: Jassal, B, 2010-10-15 Edited: Jassal, B, 2010-10-15 GENE ONTOLOGYGO:0016266 O-glycan biosynthesis can be terminated (or modified) by the addition of sialic acid residues on Core 1 and 2 glycoproteins by sialyltransferases (Varki et al, 2009). Pubmed20301246 Reactome Database ID Release 43977068 Reactome, http://www.reactome.org ReactomeREACT_115835 Reviewed: Ferrer, A, 2011-11-04 O-linked glycosylation of mucins Authored: Jassal, B, 2010-07-19 Edited: Jassal, B, 2010-07-19 GENE ONTOLOGYGO:0016266 Mucins are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most metazoa. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell signalling to forming chemical barriers. To date, there are approximately 20 genes that express mucins. Mature mucins are composed of two distinct regions:<br>(1) The amino- and carboxy-terminal regions are very lightly glycosylated, but rich in cysteines. The cysteine residues participate in establishing disulfide linkages within and among mucin monomers.<br>(2) A large central region rich in serine, threonine and proline residues called the variable number of tandem repeat (VNTR) region which can become heavily O-glycosylated with hundreds of O-GalNAc glycans.<br> N-acetyl-galactosamine (GalNAc) is the first glycan to be attached, forming the simplest mucin O-glycan. After this, several different pathways are possible generating "core" structures. Four core structures are commonly formed, several others are possible but infrequent. O-linked glycans are often capped by the addition of a sialic acid residue, terminating the addition of any more O-glycans (Brockhausen et al, 2009; Tarp and Clausen, 2008). Pubmed17988798 Pubmed20301232 Reactome Database ID Release 43913709 Reactome, http://www.reactome.org ReactomeREACT_115606 Reviewed: Ferrer, A, 2011-11-04 PKA catalytic subunits Converted from EntitySet in Reactome Protein Kinase A, catalytic subunits Reactome DB_ID: 111917 Reactome Database ID Release 43111917 Reactome, http://www.reactome.org ReactomeREACT_2480 cAMP-dependent protein kinase catalytic subunits ACTIVATION GENE ONTOLOGYGO:0036185 Reactome Database ID Release 432161822 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047977 Reactome Database ID Release 432161802 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051120 Reactome Database ID Release 432161887 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004301 Reactome Database ID Release 432161846 Reactome, http://www.reactome.org Dynamin-2 Converted from EntitySet in Reactome Reactome DB_ID: 535015 Reactome Database ID Release 43535015 Reactome, http://www.reactome.org ReactomeREACT_23256 ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 432161882 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43429674 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047560 Reactome Database ID Release 43428165 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 432162026 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 432161998 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 432161927 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 432161836 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0042284 Reactome Database ID Release 43428230 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017040 Reactome Database ID Release 43428257 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017040 Reactome Database ID Release 43428216 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0070774 Reactome Database ID Release 43428234 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033188 Reactome Database ID Release 43429800 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033188 Reactome Database ID Release 43429784 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004758 Reactome Database ID Release 43428142 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004722 Reactome Database ID Release 43429724 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43429721 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000170 Reactome Database ID Release 43428238 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0042626 Reactome Database ID Release 43266058 Reactome, http://www.reactome.org Presynaptic nicotinic acetylcholine receptors Authored: Mahajan, SS, 2010-04-01 Edited: Gillespie, ME, 2010-05-18 Presynaptic terminal acetylcholine receptors are located at or near nerve terminal and modulate the release of neurotransmitter such as glutamate, noradrenaline and dopamine. Activation of presynaptic acetylcholine receptors leads to influx of Ca2+ and sufficient increase in local Ca2+ concentrations which could be due to either direct or indirect Ca2+ entry. Direct Ca2+ entry through acetylcholine receptors containing alpha3 beta4 receptors is sufficient for the release of noradrenaline in hippocampus. Indirect Ca2+ increase could be due to Na+ dependent depolarization and activation of voltage dependent calcium channels (VDCC) as in the case of dopamine release. Local Ca2+ increase could also be due to an initial Ca2+ influx through acetlycholine homomeric receptors containing alpha7 subunits and further increase in Ca2+ is elicited due to Ca2+ induced Ca2+ release (CICR) that involves the ryanodine receptors in the ER and the IP3 receptors. This mechanism is used in hippocampal mossyfibre pathway. Nicotinic acetylcholine receptors may permit both sodium and calcium ions, however, the ratio of sodium and calcium influx makes these receptors either highly sodium permeable or highly calcium permeable. Pubmed9023878 Reactome Database ID Release 43622323 Reactome, http://www.reactome.org ReactomeREACT_22336 Reviewed: Cooper, E, 2010-05-24 ACTIVATION GENE ONTOLOGYGO:0003840 Reactome Database ID Release 43266030 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016805 Reactome Database ID Release 43266039 Reactome, http://www.reactome.org Postsynaptic nicotinic acetylcholine receptors Authored: Mahajan, SS, 2010-04-26 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholine receptors are found in the postsynaptic terminals and these receptors are responsible in mediating postsynaptic currents. Most common types of postsynaptic nicotinic acetylcholine receptors are homomeric alpha 7 containing acetylcholine receptors. The densities of acetylcholine receptors are found to be similar to NMDA and AMPA receptors at these sites. Nicotinic acetylcholine receptors may permit both sodium and calcium ions, however, the ratio of sodium and calcium influx makes the receptors either highly sodium permeable or highly calcium permeable. Pubmed12036180 Pubmed17009926 Pubmed17689497 Reactome Database ID Release 43622327 Reactome, http://www.reactome.org ReactomeREACT_22149 Reviewed: Cooper, E, 2010-05-24 Highly calcium permeable postsynaptic nicotinic acetylcholine receptors Authored: Mahajan, SS, 2010-04-26 Edited: Gillespie, ME, 2010-05-18 Postsynaptic acetylcholine receptors mediate Ca2+ currents that may be involved in the facilitation of long term potentiation (LTP). Pubmed14670366 Reactome Database ID Release 43629594 Reactome, http://www.reactome.org ReactomeREACT_22303 Reviewed: Cooper, E, 2010-05-24 Highly calcium permeable nicotinic acetylcholine receptors Authored: Mahajan, SS, 2010-04-22 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholine receptors exhibit high influx of Ca2+, the degree of Ca2+ permeability is dependent on the subunit composition; homomeric acetylcholine receptors containing aplha 7 subunits allow maximum Ca2+ influx followed by receptors containing alpha3 beta2 alpha5 or alpha3 beta4 alpha5. Pubmed14670366 Reactome Database ID Release 43629597 Reactome, http://www.reactome.org ReactomeREACT_22352 Reviewed: Cooper, E, 2010-05-24 Highly sodium permeable acetylcholine nicotinic receptors Authored: Mahajan, SS, 2010-04-26 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholne receptors that have low Ca2+ permeability allow the influx of Na+ which causes depolarization of the membrane initiating voltage dependent responses such as activation of voltage dependent opening of Ca2+ channels and thus eliciting an increase in Ca2+ and downstream signaling. These receptors could be found in both presynaptic and postsynaptic terminals. Pubmed9110108 Reactome Database ID Release 43629587 Reactome, http://www.reactome.org ReactomeREACT_22223 Reviewed: Cooper, E, 2010-05-24 Activation of AMPA receptors AMPA receptors are functionally either Ca permeable or Ca impermeable based on the subunit composition. Ca permeability is determined by GluR2 subunit which undergoes post-transcriptional RNA editing that changes glutamine (Q) at the pore to arginine (R). Incorporation of even a single subunit in the AMPA receptor confers Ca-limiting properties. Ca permeable AMPA receptors permit Ca and Na whereas Ca impermeable AMPA receptors permit only Na. In general, glutamatergic neurons contain Ca impermeable AMPA receptors and GABAergic interneurons contain Ca permeable AMPA receptors. However, some synapses do contain a mixture of Ca permeable and Ca impermeable AMPA receptors. GluR1-4 are encoded by four genes however, alternative splicing generates several functional subunits namely long and short forms of GluR1 and GluR2. GluR4 has long tail only and GluR3 has short tail only. Besides the differences in the tail length, flip/flop isoforms are generated by an interchangeable exon that codes the fourth membranous domain towards the C terminus. The fip/flop isoforms determine rate of desensitization/resensitization and the rate of channel closing. Receptors homomers or heteromers assembled from the combination of GluR1-4 subunits that vary in C tail length and flip/flop versions generates a whole battery of functionally distinct AMPA receptors. Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 Pubmed16723221 Pubmed17256974 Pubmed7973663 Reactome Database ID Release 43399710 Reactome, http://www.reactome.org ReactomeREACT_18338 Reviewed: Ziff, EB, 2009-05-15 16:23:37 ACTIVATION GENE ONTOLOGYGO:0097261 Reactome Database ID Release 432161978 Reactome, http://www.reactome.org Trafficking of GluR2-containing AMPA receptors Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 Pubmed18547676 Reactome Database ID Release 43416993 Reactome, http://www.reactome.org ReactomeREACT_18422 Reviewed: Ziff, EB, 2009-05-15 16:23:37 Trafficking of GluR2-containing receptors is governed by protein protein interactions that are regulated by phosphorylation events. GluR2 binds NSF and AP2 in the proximal C terminal region and binds PICK and GRIP1/2 in the extreme C terminal region. GluR2 interaction with NSF is necessary to maintain the synaptic levels of GluR2-containing AMPA receptors both at basal levels and under conditions of synaptic activity. GluR2 interaction with GRIP helps anchor AMPA receptors at the synapse. Phosphorylation of GluR2 at S880 disrupts GRIP interaction but allows binding of PICK. PICK is activated by Ca sensitive Protein kinase C (PKC). Under basal conditions, in hippocampal synapse, GluR2-containing AMPA receptors (GluR2/GluR3) constitutively recycle between the synapse and the endosome by endocytosis and exocytosis. GRIP anchors the receptors at the synapse while PICK interaction internalizes the receptors and NSF helps maintain the synaptic receptors. Cerebellar stellate cells mainly contain GluR3 homomers as Ca permeable receptors. The interaction of GluR3 and GRIP is disrupted by PICK interaction by phosphorylation of equivalent of S880 residue in GluR3. Under conditions of repetitive presynaptic activity, there is PICK dependent removal of GluR2-lacking AMPA receptors and selective incorporation of GluR2-containing AMPA receptors at the synapse. The GluR2-containing AMPA receptors are first delivered to the surface by PICK and mobilized to the synapse by NSF dependent mechanism (Liu SJ and Cull-Candy SG Nat Neurosci. 2005 Jun;8(6):768-75) ACTIVATION GENE ONTOLOGYGO:0097260 Reactome Database ID Release 432161993 Reactome, http://www.reactome.org Trafficking of AMPA receptors Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 Pubmed19217372 Reactome Database ID Release 43399719 Reactome, http://www.reactome.org ReactomeREACT_18307 Repetitive presynaptic activity causes long lasting changes in the postsynaptic transmission by changing the type and the number of AMPA receptors. These changes are brought about by trafficking mechanisms that are mainly controlled by activity dependent phosphorylation/desphosphorylation of the GluR1/GluR2 subunits. Reviewed: Ziff, EB, 2009-05-15 16:23:37 ACTIVATION GENE ONTOLOGYGO:0097263 Reactome Database ID Release 432161981 Reactome, http://www.reactome.org Glutamate Binding, Activation of AMPA Receptors and Synaptic Plasticity Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-01-14 16:01:52 Excitatory synaptic transmission in the brain is carried out by glutamate receptors through the activation of both ionotropic and metabotropic receptors. Ionotropic glutamate receptors are of three subtypes based on distinct physiologic properties and their differential binding of exogenous ligands namely NMDA (N-methyl D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and Kainate . The ionotropic receptors are glutamate gated ion channels that initiate signaling by influx of ions, and are comprised of subunits with distinct structures and distinguished based on their agonist binding. Even though all three types of receptors are found at the glutamatergic synapses yet they exhibit great diversity in the synaptic distribution. The metabotropic glutamate receptors are a family of G-protein coupled receptors that are slow acting. Fast excitatory synaptic transmission is carried out through AMPA receptors. Post-synaptic transmission involves binding of the ligand such as glutamate/AMPA to the AMPA receptor resulting in the Na influx which causes depolarization of the membrane. NMDA receptors are blocked by Mg at resting membrane potential. NMDA receptors are activated upon coincident depolarization and glutamate binding are activated following AMPA receptor activation.NMDA receptors are blocked by Mg at resting <br>membrane potential. NMDA receptors are Ca permeable and their activity leads to increase in Ca which, leads to upregulation of AMPA receptors at the synapse which causes the long lasting excitatory post-synaptic potential (EPSP) which forms the basis of long term potentiation (LTP). LTP is one form of synaptic plasticity wherein the strength of the synapses is enhanced by either change in the number, increase in the efficacy by phosphorylation or change in the type of receptors. Phosphorylation of AMPA receptors changes the localization of the receptors, increases the single channel conductance, and increases the probability of open channel. GluR1 has four phosphorylation sites; serine 818 (S818) is phosphorylated by PKC and is necessary for LTP, serine 831 (S831) is phosphorylated by CaMKII that increases the delivery of receptors to the synapse and also increased their single channel conductance, threonine (T840) is implicated in LTP. Serine 845 (S845) is phosphorylated by PKA which regulates open channel probability. Long term depression is another form of plasticity wherein the number of AMPA receptors is diminished by either phosphorylation of GluR2 at Ser880 or dephosphorylation of GluR1 by protein phosphatase1, protein phosphatase 2A and protein phosphatase 2B (calcineurin). Pubmed16713244 Pubmed16904750 Pubmed19217372 Reactome Database ID Release 43399721 Reactome, http://www.reactome.org ReactomeREACT_18347 Reviewed: Ziff, EB, 2009-05-15 16:23:37 ACTIVATION GENE ONTOLOGYGO:0097262 Reactome Database ID Release 432161784 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0097265 Reactome Database ID Release 432161975 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004602 Reactome Database ID Release 432161908 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004602 Reactome Database ID Release 432161937 Reactome, http://www.reactome.org Activation of NMDA receptor upon glutamate binding and postsynaptic events Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-11-19 NMDA receptors are a subtype of ionotropic glutamate receptors that are specifically activated by a glutamate agonist N-methyl-D-aspartate (NMDA). Activation of NMDA receptor involves opening of the ion channel that allows the influx of Ca2+. NMDA receptors are central to activity dependent changes in synaptic strength and are predominantly involved in the synaptic plasticity that pertain to learning and memory. A unique feature of NMDA receptor unlike other glutamate receptors is the requirement of dual activation of the NMDA receptor, which require both voltage dependent and ligand dependent activation. At resting membrane potential the NMDA receptors are blocked by Mg2+. The voltage dependent Mg2+ block is relieved upon depolarization of the post-synpatic membrane . The ligand dependent activation of the NMDA receptor requires co-activation by two ligands, namely glutamate and glycine. NMDA receptors are coincidence detector, and are activated only if there is simultaneous activation of both pre and post-synaptic cell. Upon activation NMDA receptors allow the influx of Ca2+ that initiates various molecular signaling cascades that are involved in the process of learning and memory. Pubmed18616423 Reactome Database ID Release 43442755 Reactome, http://www.reactome.org ReactomeREACT_20563 Reviewed: Tukey, D, 2009-11-17 ACTIVATION GENE ONTOLOGYGO:0050473 Reactome Database ID Release 432161832 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047034 Reactome Database ID Release 432161741 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050473 Reactome Database ID Release 432161919 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004052 Reactome Database ID Release 432161752 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004052 Reactome Database ID Release 432161926 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004602 Reactome Database ID Release 432161908 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004052 Reactome Database ID Release 432162014 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004602 Reactome Database ID Release 432161908 Reactome, http://www.reactome.org Dynamin-2 Converted from EntitySet in Reactome Reactome DB_ID: 196047 Reactome Database ID Release 43196047 Reactome, http://www.reactome.org ReactomeREACT_10524 ACTIVATION GENE ONTOLOGYGO:0016404 Reactome Database ID Release 432161623 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016702 Reactome Database ID Release 432161852 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016702 Reactome Database ID Release 432161852 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016702 Reactome Database ID Release 432161800 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004667 Reactome Database ID Release 432161729 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050220 Reactome Database ID Release 43265290 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050220 Reactome Database ID Release 432161577 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004667 Reactome Database ID Release 432161647 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050221 Reactome Database ID Release 432161655 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036132 Reactome Database ID Release 432161566 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008116 Reactome Database ID Release 4376495 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004796 Reactome Database ID Release 4376499 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036133 Reactome Database ID Release 432161726 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036131 Reactome Database ID Release 432161608 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016404 Reactome Database ID Release 432161623 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004051 Reactome Database ID Release 43265275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004051 Reactome Database ID Release 43265275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43429015 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036134 Reactome Database ID Release 432161594 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0097259 Reactome Database ID Release 432161683 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004464 Reactome Database ID Release 43266055 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0097258 Reactome Database ID Release 432161740 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0097259 Reactome Database ID Release 432161602 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0097257 Reactome Database ID Release 432161632 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050051 Reactome Database ID Release 432162138 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004463 Reactome Database ID Release 43266024 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003997 Reactome Database ID Release 43390231 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005324 Reactome Database ID Release 432046078 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016508 Reactome Database ID Release 43389989 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016508 Reactome Database ID Release 43389989 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008775 Reactome Database ID Release 432066786 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050632 Reactome Database ID Release 432066783 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003986 Reactome Database ID Release 43390301 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004467 Reactome Database ID Release 432046080 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016213 Reactome Database ID Release 432046082 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548806 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0045485 Reactome Database ID Release 432046077 Reactome, http://www.reactome.org PDK isoforms Converted from EntitySet in Reactome Reactome DB_ID: 203947 Reactome Database ID Release 43203947 Reactome, http://www.reactome.org ReactomeREACT_12749 ACTIVATION GENE ONTOLOGYGO:0005324 Reactome Database ID Release 432046078 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016213 Reactome Database ID Release 432046082 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548822 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 432046081 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004666 Reactome Database ID Release 43140354 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047498 Reactome Database ID Release 43111882 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004666 Reactome Database ID Release 432309772 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036130 Reactome Database ID Release 432161558 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008379 Reactome Database ID Release 432161731 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004601 Reactome Database ID Release 43140358 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004601 Reactome Database ID Release 432309777 Reactome, http://www.reactome.org KSPG(2) Converted from EntitySet in Reactome Keratan sulfate proteoglycan Reactome DB_ID: 2046288 Reactome Database ID Release 432046288 Reactome, http://www.reactome.org ReactomeREACT_125462 MMP1,7 Converted from EntitySet in Reactome Reactome DB_ID: 1604358 Reactome Database ID Release 431604358 Reactome, http://www.reactome.org ReactomeREACT_118956 MMP14 (16) Converted from EntitySet in Reactome Reactome DB_ID: 1629856 Reactome Database ID Release 431629856 Reactome, http://www.reactome.org ReactomeREACT_118920 ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 432046081 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016213 Reactome Database ID Release 432046082 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009922 Reactome Database ID Release 43548822 Reactome, http://www.reactome.org KSPG(2) Converted from EntitySet in Reactome Keratan sulfate proteoglycan Reactome DB_ID: 2046244 Reactome Database ID Release 432046244 Reactome, http://www.reactome.org ReactomeREACT_121812 CHST2,5,6 Converted from EntitySet in Reactome Reactome DB_ID: 2046158 Reactome Database ID Release 432046158 Reactome, http://www.reactome.org ReactomeREACT_123312 MMP3, cathepsin K, cathepsin L2 Converted from EntitySet in Reactome Reactome DB_ID: 2514830 Reactome Database ID Release 432514830 Reactome, http://www.reactome.org ReactomeREACT_150524 ST3GAL1-4,6 Converted from EntitySet in Reactome Reactome DB_ID: 2046170 Reactome Database ID Release 432046170 Reactome, http://www.reactome.org ReactomeREACT_121515 KSPG(1) Converted from EntitySet in Reactome Reactome DB_ID: 2046166 Reactome Database ID Release 432046166 Reactome, http://www.reactome.org ReactomeREACT_121901 partially sulfated Keratan sulfate proteoglycan G-beta subunit Converted from EntitySet in Reactome Reactome DB_ID: 164339 Reactome Database ID Release 43164339 Reactome, http://www.reactome.org ReactomeREACT_3420 Adenylate cyclase Converted from EntitySet in Reactome Reactome DB_ID: 379053 Reactome Database ID Release 43379053 Reactome, http://www.reactome.org ReactomeREACT_17141 G-gamma subunit Converted from EntitySet in Reactome Reactome DB_ID: 164340 Reactome Database ID Release 43164340 Reactome, http://www.reactome.org ReactomeREACT_2503 Keratan(4)-PG Converted from EntitySet in Reactome Reactome DB_ID: 2046203 Reactome Database ID Release 432046203 Reactome, http://www.reactome.org ReactomeREACT_123640 GAG core proteins Converted from EntitySet in Reactome Reactome DB_ID: 2054107 Reactome Database ID Release 432054107 Reactome, http://www.reactome.org ReactomeREACT_124694 KS core proteins Converted from EntitySet in Reactome Reactome DB_ID: 2105011 Reactome Database ID Release 432105011 Reactome, http://www.reactome.org ReactomeREACT_125390 KSPG(2) Converted from EntitySet in Reactome Keratan sulfate proteoglycan Reactome DB_ID: 2046191 Reactome Database ID Release 432046191 Reactome, http://www.reactome.org ReactomeREACT_123146 MMP1,3,8,13, PRSS2 Converted from EntitySet in Reactome Reactome DB_ID: 1606374 Reactome Database ID Release 431606374 Reactome, http://www.reactome.org ReactomeREACT_150610 MMP1,2,8,13, PRSS2 Converted from EntitySet in Reactome Reactome DB_ID: 1605826 Reactome Database ID Release 431605826 Reactome, http://www.reactome.org ReactomeREACT_151771 Cleaved collagen alpha-3(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2470419 Reactome Database ID Release 432470419 Reactome, http://www.reactome.org ReactomeREACT_150677 MMP1,2,3 Converted from EntitySet in Reactome Reactome DB_ID: 2470302 Reactome Database ID Release 432470302 Reactome, http://www.reactome.org ReactomeREACT_151170 MMP2,9,11 Converted from EntitySet in Reactome Reactome DB_ID: 2470215 Reactome Database ID Release 432470215 Reactome, http://www.reactome.org ReactomeREACT_151459 MMP2,9,10 Converted from EntitySet in Reactome Reactome DB_ID: 2470195 Reactome Database ID Release 432470195 Reactome, http://www.reactome.org ReactomeREACT_151890 MMP2,3,4,9,10,12 Converted from EntitySet in Reactome Reactome DB_ID: 1606378 Reactome Database ID Release 431606378 Reactome, http://www.reactome.org ReactomeREACT_151325 MMP1,8,9,13 Converted from EntitySet in Reactome Reactome DB_ID: 1606407 Reactome Database ID Release 431606407 Reactome, http://www.reactome.org ReactomeREACT_151454 Keratan(3)-PG Converted from EntitySet in Reactome Reactome DB_ID: 2046314 Reactome Database ID Release 432046314 Reactome, http://www.reactome.org ReactomeREACT_122716 proMT-MMPs Converted from EntitySet in Reactome Reactome DB_ID: 1604700 Reactome Database ID Release 431604700 Reactome, http://www.reactome.org ReactomeREACT_120167 Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits Authored: Mahajan, SS, 2010-11-08 Edited: D'Eustachio, P, 2010-11-24 GABA B receptors are coupled to Gproteins and function by increasing the K+ and decreasing the Ca2+ inside the cell. The increase in K+ increases the negative membrane potential of the cell thereby hyper polarizing the cell which inhibits the release of neurotransmitters. The decrease in Ca2+ also inhibits neurotransmitter in two ways; first by preventing the fusion of synaptic vesicles containing the neurotransmitter with the plasma membrane and second by decreasing the Ca2+ dependent recruitment of synaptic vesicles to the plasma membrane. In particular GABA B receptors inhibit voltage gated Ca2+ channels via the activity of Gbeta/Ggamma subunits of G proteins. Pubmed20655481 Pubmed20655490 Reactome Database ID Release 43997272 Reactome, http://www.reactome.org ReactomeREACT_25004 Reviewed: Restituito, S, 2008-11-27 12:38:49 GABA A (rho) receptor activation Authored: Mahajan, SS, 2010-11-08 Edited: D'Eustachio, P, 2010-11-24 GABA A (rho) receptors are highly expressed in the retina and are functional homopentamers of rho subunits. These receptors are formerly called GABA C receptors. Pubmed10637650 Pubmed17398006 Reactome Database ID Release 43977442 Reactome, http://www.reactome.org ReactomeREACT_25168 Reviewed: Restituito, S, 2008-11-27 12:38:49 Potassium Channels Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-22 Potassium channels are tetrameric ion channels that are widely distributed and are found in all cell types. Potassium channels control resting membrane potential in neurons, contribute to regulation of action potentials in cardiac muscle and help release of insulin form pancreatic beta cells.<br>Broadly K+ channels are classified into voltage gated K+ channels, Hyperpolarization activated cyclic nucleotide gated K+ channels (HCN), Tandem pore domain K+ channels, Ca2+ activated K+ channels and inwardly rectifying K+ channels. Pubmed1822292 Pubmed18413784 Pubmed18446619 Pubmed19584315 Pubmed20086079 Pubmed20213494 Pubmed20813163 Reactome Database ID Release 431296071 Reactome, http://www.reactome.org ReactomeREACT_75908 Reviewed: Jassal, B, 2010-09-23 Ca activated K+ channels Authored: Mahajan, SS, 2011-05-18 Ca2+ activated K+ channels Ca2+ activated potassium channels are expressed in neuronal and non-neuronal tissue such as smooth muscle, epithelial cell and sensory cells. Ca2+ activated potassium channels are activated when the Ca2+ ion concentration increased, The efflux of K+ via these channels leads to repolarization/hyperpolarization of the membrane potential which limits the Ca2+ influx though voltage activated Ca2+ channels (VGCC) thereby regulating the influx of Ca2+ flow via VGCC. Edited: Mahajan, SS, 2011-05-23 Pubmed19074509 Pubmed19149539 Pubmed20178789 Pubmed20859064 Reactome Database ID Release 431296052 Reactome, http://www.reactome.org ReactomeREACT_75896 Reviewed: Jassal, B, 2010-09-23 HCN channels Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Hyperpolarization-activated and cyclic nucleotide gated (HCN) channel are activated by membrane hyperpolarization and cAMP binding. HCN channels are homotetramers of four subunits HCN1-4. HCN channels conduct Na and K current with a permeability of 1:4. The current flowing through HCN channels is call funny current. HCN channels are involved in controlling the rhythmic activity of pacemaker current in autorythymic cells in heart and neuronal processes such as dendritic integration and synaptic transmission. Pubmed19584315 Pubmed20213494 Reactome Database ID Release 431296061 Reactome, http://www.reactome.org ReactomeREACT_75862 Reviewed: Jassal, B, 2010-09-23 Inwardly rectifying K+ channels Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Inwardly rectifying K+ channels (Kir channels) show an inward rather than outward (like the voltage gated K+ channels) flow of K+ thereby contributing to maintenance of resting membrane potential and regulation of action potential in excitable tissue. Kir channels are found in a variety of cell types such as cardiac myocytes, neurons, blood cells, osteoblasts, glial cells, epithelial cells, and oocytes. Kir channels can be functionally divided into ATP sensitive K+ channels (Kir 6.1 and Kir 6.2), classical kir channels (Kir 2.1, 2.2, 2.3, 2.4, 5.1) G protein gated K+ channels (Kir 3.1, 3.2, 3.3, 3.4) and K+ transport channels (Kir1.1, 7.1, 4.2, 4.1). Pubmed18087715 Pubmed18691387 Pubmed20086079 Reactome Database ID Release 431296065 Reactome, http://www.reactome.org ReactomeREACT_75918 Reviewed: Jassal, B, 2010-09-23 G protein gated Potassium channels Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Inwardly rectifying G protein activated K+ channels (GIRK) are tetrameric assemblies of Ki3 3 family subunits (Kir 3.1, 3.2 3.3 and 3.4). The activation of G protein coupled receptor by ligand results in the liberation of G alpha and G beta gamma subunits. Gbeta gamma subunits interact and activate GIRK channels. Pubmed20921230 Reactome Database ID Release 431296059 Reactome, http://www.reactome.org ReactomeREACT_75780 Reviewed: Jassal, B, 2010-09-23 Activation of G protein gated Potassium channels Activation of Kir 3 channels occurs after binding of G beta gamma subunits of GPCR. Activation of Kir3/GIRK leads to K+ efflux. The dissociation of GPCR into G alpha and G beta gamma subunits is activated by the activation of GABA B receptor by GABA binding. Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-22 Pubmed20655490 Reactome Database ID Release 431296041 Reactome, http://www.reactome.org ReactomeREACT_75831 Reviewed: Jassal, B, 2010-09-23 MMP13 intermediate form fragments Converted from EntitySet in Reactome Reactome DB_ID: 1604745 Reactome Database ID Release 431604745 Reactome, http://www.reactome.org ReactomeREACT_119990 Potassium transport channels Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-22 Inwardly rectifying potassium transport are tetrameric channels that are found in kidney in the nephron. Kir 1.1 works as a homotetramer, however, Kir 4.1 and 5.1 work as heterotetramers. These channels transport K+ from cytosol to the lumen of the tubules. Pubmed19221509 Reactome Database ID Release 431296067 Reactome, http://www.reactome.org ReactomeREACT_75815 Reviewed: Jassal, B, 2010-09-23 ATP sensitive Potassium channels ATP sensitive K+ channels couple intracellular metabolism with membrane excitability. These channels are inhibited by ATP so are open in low metabolic states and close in high metabolic states, resulting in membrane depolarization triggering responses such as insulin secretion, modulation of vascular smooth muscle and cardioprotection. The channel comprises four Kir6.x subunits and four regulatory sulphonylurea receptors (SUR) (Akrouh et al, 2009). Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Pubmed18258787 Pubmed19787700 Reactome Database ID Release 431296025 Reactome, http://www.reactome.org ReactomeREACT_75775 Reviewed: Jassal, B, 2010-09-23 MT-MMPs Converted from EntitySet in Reactome Reactome DB_ID: 1605821 Reactome Database ID Release 431605821 Reactome, http://www.reactome.org ReactomeREACT_118930 B3GNT1,2,3,4,7 Converted from EntitySet in Reactome Reactome DB_ID: 2046221 Reactome Database ID Release 432046221 Reactome, http://www.reactome.org ReactomeREACT_121781 Keratan(2)-PG Converted from EntitySet in Reactome Reactome DB_ID: 2046206 Reactome Database ID Release 432046206 Reactome, http://www.reactome.org ReactomeREACT_123317 Activation of Ca-permeable Kainate Receptor Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Kainate receptors that are assembled with subunits GRIK1-5, are Ca2+ permeable if GRIK1 and GRIK2 are not edited at the Q/R or other sites.<br>These channels permit Ca2+ upon activation by glutamate or other agonists. Pubmed10718099 Reactome Database ID Release 43451308 Reactome, http://www.reactome.org ReactomeREACT_21346 Reviewed: Tukey, D, 2009-11-17 Presynaptic function of Kainate receptors Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Kainate receptors in the presynaptic neuron are involved in modulating the release of neurotransmitters like glutamate and gamma amino butyric acid (GABA). This activity of Kainate receptors is independent of ionic fluxes through the channel. Homomeric kainate receptors containing GRIK3 are shown to be involved in this process. Kainate receptors in these neurons bind G-protein coupled receptors that activate phospholipase C which eventually triggers the release of Ca2+ from the intracellular stores. The released Ca2+ further initiates the fusion and release of vesicles containing the neurotransmitter. Pubmed20007474 Reactome Database ID Release 43500657 Reactome, http://www.reactome.org ReactomeREACT_21254 Reviewed: Tukey, D, 2009-11-17 Ionotropic activity of Kainate Receptors Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Kainate receptors are either Ca2+ permeable or impermeable depending on the composition of the receptor and the editing status of subunits GluR5 and GluR6 (GRIK1 and 2). Pubmed16847640 Reactome Database ID Release 43451306 Reactome, http://www.reactome.org ReactomeREACT_21322 Reviewed: Tukey, D, 2009-11-17 Activation of Na-permeable Kainate Receptors Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Kainate receptors that are formed by subunits GRIK1 and or GRIK2 that are edited at the Q/R and other editing sites in GRIK2 are Ca2+ impermeable. They permit the passage of Na+ ions. Glutamine in GRIK1 at position 636 is replaced by arginine by an editing step which occurs posttranscriptioanlly. GRIK2 is glutamine 621 is edited to arginine. GRIK2 is also edited at 571 (Y/C) where a tyrosine residue is changed to cysteine and 567 (I/V) where an isoleucine is changed to valine. All three sites are edited postranscriptionally. A fully edited GRIK2 at all three sites is impermeable to calcium ions. Pubmed16847640 Reactome Database ID Release 43451307 Reactome, http://www.reactome.org ReactomeREACT_21343 Reviewed: Tukey, D, 2009-11-17 GABA B receptor activation Authored: Mahajan, SS, 2010-11-08 Edited: D'Eustachio, P, 2010-11-24 Functional GABA B receptors are heteromers of GABA B1 and B2 subunits, complexed with G protein alpha-i, 0, beta, and gamma subunits. They function as metabotropic receptors. When GABA is bound to the B1 sub-unit, the B2 subunit undergoes a conformational change that releases the G alpha-i G0 dimer (which binds and inactivates cytosolic adenylate cyclase) and the G beta G gamma dimer (which activates the GIRK (KIR3) potassium channel) (Pinard et al. 2010). Pubmed20655485 Reactome Database ID Release 43977444 Reactome, http://www.reactome.org ReactomeREACT_25031 Reviewed: Restituito, S, 2008-11-27 12:38:49 MT-MMPs Converted from EntitySet in Reactome Reactome DB_ID: 1604727 Reactome Database ID Release 431604727 Reactome, http://www.reactome.org ReactomeREACT_119656 Activation of GABAB receptors Authored: Mahajan, SS, 2010-11-08 Edited: D'Eustachio, P, 2010-11-24 GABA B receptors are metabotropic receptors that are functionally linked to C type G protein coupled receptors.? GABA B receptors are activated upon ligand binding. The GABA B1 subunit binds ligand and GABA B2 subunit modulates the activity of adenylate cyclase via the intracellular loop.? GABA B receptors show inhibitory activity via Galpha/G0 subunits via the inhibition of adenylate cyclase or via the activity of Gbeta/gamma subunits that mediate the inhibition of voltage gated Ca2+ channels. Pubmed20655481 Reactome Database ID Release 43991365 Reactome, http://www.reactome.org ReactomeREACT_25330 Reviewed: Restituito, S, 2008-11-27 12:38:49 GABA receptor activation Authored: Mahajan, SS, 2010-11-08 Edited: D'Eustachio, P, 2010-11-24 Gamma aminobutyric acid (GABA) receptors are the major inhibitory receptors in human synapses. They are of two types. GABA A receptors are fast-acting ligand gated chloride ion channels that mediate membrane depolarization and thus inhibit neurotransmitter release (G Michels et al Crit Rev Biochem Mol Biol 42, 2007, 3-14). GABA B receptors are slow acting metabotropic Gprotein coupled receptors that act via the inhibitory action of their Galpha/Go subunits on adenylate cyclase to attenuate the actions of PKA. In addition, their Gbeta/gamma subunits interact directly with N and P/Q Ca2+ channels to decrease the release of Ca2+. GABA B receptors also interact with Kir3 K+ channels and increase the influx of K+, leading to cell membrane hyperpolarization and inhibition of channels such as NMDA receptors (A Pinard et al Adv Pharmacol, 58, 2010, 231-55). Pubmed11283747 Pubmed15269338 Pubmed17364682 Pubmed20655481 Pubmed20655485 Reactome Database ID Release 43977443 Reactome, http://www.reactome.org ReactomeREACT_25199 Reviewed: Restituito, S, 2008-11-27 12:38:49 GABA A receptor activation Authored: Mahajan, SS, 2010-11-08 Edited: D'Eustachio, P, 2010-11-24 GABA B receptors are G protein coupled receptors that are activated by GABA binding to the B1 subunit and B2 subunit alters the activity of adenylate cyclase by interacting with the G alpha i/alpha 0 subunit of the pertussis toxin sensitive G protein. The activation of GABA B receptors results in the inhibition of adenylate cyclase activity decreasing the levels of cyclic AMP production and hence the activity of Protein kinase A. Pubmed17364682 Pubmed18382465 Pubmed19828786 Reactome Database ID Release 43977441 Reactome, http://www.reactome.org ReactomeREACT_24987 Reviewed: Restituito, S, 2008-11-27 12:38:49 Inhibition of adenylate cyclase pathway Authored: Mahajan, SS, 2010-11-08 Edited: D'Eustachio, P, 2010-11-24 GABA B receptors are G protein coupled receptors that are activated by GABA binding to the B1 subunit and B2 subunit alters the activity of adenylate cyclase by interacting with the G alpha i/alpha 0 subunit of the pertussis toxin sensitive G protein. The activation of GABA B receptors results in the inhibition of adenylate cyclase activity decreasing the levels of cyclic AMP production and hence the activity of Protein kinase A. Pubmed8327893 Reactome Database ID Release 43997269 Reactome, http://www.reactome.org ReactomeREACT_25282 Reviewed: Restituito, S, 2008-11-27 12:38:49 Adenylate cyclase inhibitory pathway Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 GENE ONTOLOGYGO:0007193 Guanine nucleotide-binding protein G(i) alpha (Gi-alpha) inhibits adenylate cyclase, thus inhibiting the production of cAMP from ATP and ultimately decreasing the activity of cAMP-dependent protein kinase. Pubmed14993377 Reactome Database ID Release 43170670 Reactome, http://www.reactome.org ReactomeREACT_15333 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Keratan(1)-PG Converted from EntitySet in Reactome Reactome DB_ID: 2046187 Reactome Database ID Release 432046187 Reactome, http://www.reactome.org ReactomeREACT_124854 MMP1 (2, 3, 7, 10, 13) Converted from EntitySet in Reactome Reactome DB_ID: 1604697 Reactome Database ID Release 431604697 Reactome, http://www.reactome.org ReactomeREACT_119134 Unblocking of NMDA receptor, glutamate binding and activation At resting membrane potential the NMDA receptor is blocked by extracellular Mg2+ ions and therefore is not activated in this state by ligands (glutamate, glycine, NMDA). The voltage block is removed upon depolarization of the post-synaptic cell membrane by the influx of Na+ and efflux of K+ from the cell, Mg2+ is expelled from the NMDA receptor can now be activated by the ligands. The depolarization of the membrane maybe due to activation of Ca2+ impermeable AMPA receptors, which facilitates Na+ influx, contributing to the unblocking of NMDA receptors. Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-11-19 Pubmed9481670 Reactome Database ID Release 43438066 Reactome, http://www.reactome.org ReactomeREACT_20594 Reviewed: Tukey, D, 2009-11-17 Post NMDA receptor activation events Authored: Mahajan, SS, 2009-10-29 Ca2+ influx through the NMDA receptor initiates subsequent molecular pathways that have a defined role in establishing long-lasting synaptic changes. The molecular signaling initiated by a rise in Ca2+ within the spine leads to phosphorylation of Cyclic AMP Response Element binding protein (CREB) at serine 133 which is involved in the transcription of genes that results in long lasting changes in the synapse. The phosphorylation of CREB by increased Ca2+ can be brought about by distinct molecular pathways that may involve MAP kinase, activation of adenylate cyclase, activation of CaMKII and/or the activation of CaMKIV. Pubmed18616423 Reactome Database ID Release 43438064 Reactome, http://www.reactome.org ReactomeREACT_20593 Reviewed: Tukey, D, 2009-11-17 CREB phosphorylation through the activation of Ras Authored: Mahajan, SS, 2009-10-29 Ca2+ influx through the NMDA receptor initiates subsequent molecular pathways that have a defined role in establishing long-lasting synaptic changes. The molecular signaling initiated by a rise in Ca2+ within the spine leads to phosphorylation of Cyclic AMP Response Element binding protein (CREB) at serine 133 which is involved in the transcription of genes that results in long lasting changes in the synapse. The phosphorylation of CREB by increased Ca2+ can be brought about by distinct molecular pathways that may involve MAP kinase, activation of adenylate cyclase, activation of CaMKII and/or the activation of CaMKIV. Edited: Gillespie, ME, 2009-11-19 Pubmed12819448 Reactome Database ID Release 43442742 Reactome, http://www.reactome.org ReactomeREACT_20568 Reviewed: Tukey, D, 2009-11-17 CREB phosphorylation through the activation of CaMKK Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-11-19 Pubmed18817731 Reactome Database ID Release 43442717 Reactome, http://www.reactome.org ReactomeREACT_20661 Reviewed: Tukey, D, 2009-11-17 Transient increase in intracellular Ca2+ concentration after NMDA receptor activation leads to the activation of the CaMKIV via the activation of CaM-kinase kinase. CaM-kinase kinase and CaMKIV are both activated upon binding Ca2+/Calmodulin after Ca2+ influx through activated NMDA receptor. Activation of CaMK IV Authored: Mahajan, SS, 2009-10-29 CaMKIV is activated in a multi-step mechanism in an Ca2+/Calmodulin dependent manner. Edited: Gillespie, ME, 2009-11-19 Pubmed15769749 Reactome Database ID Release 43442745 Reactome, http://www.reactome.org ReactomeREACT_20652 Reviewed: Tukey, D, 2009-11-17 Activation of Kainate Receptors upon glutamate binding Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Kainate receptors are found both in the presynaptc terminals and the postsynaptic neurons. <br>Kainate receptor activation could lead to either ionotropic activity (influx of Ca2+ or Na+ and K+) in the postsynaptic neuron or coupling of the receptor with G proteins in the presynaptic and the postsynaptic neurons. <br>Kainate receptors are tetramers made from subunits GRIK1-5 or GluR5-7 and KA1-2. Activation of kainate receptors made from GRIK1 or KA2 release Ca2+ from the intracellular stores in a G protein-dependent manner. The G protein involved in this process is sensitive to pertussis toxin. Pubmed18793656 Reactome Database ID Release 43451326 Reactome, http://www.reactome.org ReactomeREACT_21312 Reviewed: Tukey, D, 2009-11-17 Ras activation uopn Ca2+ infux through NMDA receptor Authored: Mahajan, SS, 2009-10-29 Ca2+ influx through the NMDA receptor leads to the activation of Ras kinase via the activation of RasGRF. Edited: Gillespie, ME, 2009-11-19 Pubmed14622581 Reactome Database ID Release 43442982 Reactome, http://www.reactome.org ReactomeREACT_20546 Reviewed: Tukey, D, 2009-11-17 RSK activation Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-11-19 Pubmed18813292 Reactome Database ID Release 43444257 Reactome, http://www.reactome.org ReactomeREACT_20510 Reviewed: Tukey, D, 2009-11-17 Ribosomal S6 kinase has four isoforms in humans and each of the isoforms have sic conserved phosphorylation sites (S221, S363, S380,S749, T359,T573) out of which four are important for its activity (S221, S363, 380,T573).<br>Phosphorylation and activation of ribosomal S6 Kinase (RSK) occurs at the plasma membrane, cytoplasm and in the nucleus. Phosphorylation of RSK first occurs at residue T573 followed by S363 an S380 by activated MAPK/ERK . This form is then phosphorylated by PDK1, which is active in the plasm membrane by an autophosphorylation event. CREB phosphorylation through the activation of Adenylate Cyclase Authored: Mahajan, SS, 2009-10-29 Ca2+ signal generated through NMDA receptor in the post-synaptic neuron activates adenylate cyclase signal transduction, leading to the activation of PKA and phosphorylation and activation of CREB-induced transcription. The isoforms of adenylate cyclase that are activated by Ca2+ in the brain are I, III and IX. Edited: Gillespie, ME, 2009-11-19 Pubmed19244110 Reactome Database ID Release 43442720 Reactome, http://www.reactome.org ReactomeREACT_20625 Reviewed: Tukey, D, 2009-11-17 CREB phosphorylation through the activation of CaMKII Authored: Mahajan, SS, 2009-10-29 Ca2+ signal generated through NMDA receptor in the post-synaptic neuron activates adenylate cyclase signal transduction, leading to the activation of PKA and phosphorylation and activation of CREB-induced transcription. The isoforms of adenylate cyclase that are activated by Ca2+ in the brain are I, III and IX. Edited: Gillespie, ME, 2009-11-19 Pubmed16799259 Reactome Database ID Release 43442729 Reactome, http://www.reactome.org ReactomeREACT_20642 Reviewed: Tukey, D, 2009-11-17 MMP13 intermediate forms Converted from EntitySet in Reactome Reactome DB_ID: 1604714 Reactome Database ID Release 431604714 Reactome, http://www.reactome.org ReactomeREACT_119399 Alpha-1(V) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268765 Reactome Database ID Release 432268765 Reactome, http://www.reactome.org ReactomeREACT_123473 HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2130470 Reactome Database ID Release 432130470 Reactome, http://www.reactome.org ReactomeREACT_122217 HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2130690 Reactome Database ID Release 432130690 Reactome, http://www.reactome.org ReactomeREACT_125592 FGFR2c A315S mutant dimer Reactome DB_ID: 2071933 Reactome Database ID Release 432071933 Reactome, http://www.reactome.org ReactomeREACT_123893 has a Stoichiometric coefficient of 2 FGFR2c P253R mutant dimer Reactome DB_ID: 2011943 Reactome Database ID Release 432011943 Reactome, http://www.reactome.org ReactomeREACT_123000 has a Stoichiometric coefficient of 2 phosphorylated FGFR2b mutant dimers with enhanced ligand binding Converted from EntitySet in Reactome Reactome DB_ID: 2065923 Reactome Database ID Release 432065923 Reactome, http://www.reactome.org ReactomeREACT_124504 Activated FGFR2b mutants with enhanced ligand binding Reactome DB_ID: 2065931 Reactome Database ID Release 432065931 Reactome, http://www.reactome.org ReactomeREACT_122429 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 phosphorylated FGFR2b S252W mutant dimer Reactome DB_ID: 2011957 Reactome Database ID Release 432011957 Reactome, http://www.reactome.org ReactomeREACT_125259 has a Stoichiometric coefficient of 2 Alpha-2(XI) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268850 Reactome Database ID Release 432268850 Reactome, http://www.reactome.org ReactomeREACT_122707 phosphorylated FGFR2b P253R mutant dimer Reactome DB_ID: 2011962 Reactome Database ID Release 432011962 Reactome, http://www.reactome.org ReactomeREACT_122552 has a Stoichiometric coefficient of 2 FGFR2c mutant dimers with enhanced ligand-binding bound to FGFs Reactome DB_ID: 2065986 Reactome Database ID Release 432065986 Reactome, http://www.reactome.org ReactomeREACT_124172 has a Stoichiometric coefficient of 1 FGFR2b mutant-binding FGFs:FP-1039 Reactome DB_ID: 2077406 Reactome Database ID Release 432077406 Reactome, http://www.reactome.org ReactomeREACT_123321 has a Stoichiometric coefficient of 1 FGFR2c S252W mutant dimer Reactome DB_ID: 2011938 Reactome Database ID Release 432011938 Reactome, http://www.reactome.org ReactomeREACT_122070 has a Stoichiometric coefficient of 2 FGFR2c mutant dimers with enhanced ligand-binding Converted from EntitySet in Reactome Reactome DB_ID: 2065983 Reactome Database ID Release 432065983 Reactome, http://www.reactome.org ReactomeREACT_123526 phosphorylated FGFR2c A315T mutant dimer Reactome DB_ID: 2071948 Reactome Database ID Release 432071948 Reactome, http://www.reactome.org ReactomeREACT_121579 has a Stoichiometric coefficient of 2 phosphorylated FGFR2c mutant dimers with enhanced ligand-binding Converted from EntitySet in Reactome Reactome DB_ID: 2065987 Reactome Database ID Release 432065987 Reactome, http://www.reactome.org ReactomeREACT_124749 Activated FGFR2c mutants with enhanced ligand-binding Reactome DB_ID: 2065989 Reactome Database ID Release 432065989 Reactome, http://www.reactome.org ReactomeREACT_122590 has a Stoichiometric coefficient of 1 FGFR2c A315T mutant dimer Reactome DB_ID: 2071934 Reactome Database ID Release 432071934 Reactome, http://www.reactome.org ReactomeREACT_125274 has a Stoichiometric coefficient of 2 FGFR2c A314D mutant dimer Reactome DB_ID: 2071939 Reactome Database ID Release 432071939 Reactome, http://www.reactome.org ReactomeREACT_123355 has a Stoichiometric coefficient of 2 phosphorylated FGFR2c A314S mutant dimer Reactome DB_ID: 2071952 Reactome Database ID Release 432071952 Reactome, http://www.reactome.org ReactomeREACT_121629 has a Stoichiometric coefficient of 2 phosphorylated FGFR2c A315S mutant dimer Reactome DB_ID: 2071951 Reactome Database ID Release 432071951 Reactome, http://www.reactome.org ReactomeREACT_125531 has a Stoichiometric coefficient of 2 phosphorylated FGFR2c P253R mutant dimer Reactome DB_ID: 2011967 Reactome Database ID Release 432011967 Reactome, http://www.reactome.org ReactomeREACT_121811 has a Stoichiometric coefficient of 2 phosphorylated FGFR2c S252W mutant dimer Reactome DB_ID: 2011964 Reactome Database ID Release 432011964 Reactome, http://www.reactome.org ReactomeREACT_125197 has a Stoichiometric coefficient of 2 FGFR2c A314S mutant dimer Reactome DB_ID: 2071937 Reactome Database ID Release 432071937 Reactome, http://www.reactome.org ReactomeREACT_122148 has a Stoichiometric coefficient of 2 Activated FGFR2 mutants with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2033348 Reactome Database ID Release 432033348 Reactome, http://www.reactome.org ReactomeREACT_122016 FGFR2 K660M mutant dimer Reactome DB_ID: 2033327 Reactome Database ID Release 432033327 Reactome, http://www.reactome.org ReactomeREACT_124257 has a Stoichiometric coefficient of 2 Activated FGFR2 N549K mutant Reactome DB_ID: 2033316 Reactome Database ID Release 432033316 Reactome, http://www.reactome.org ReactomeREACT_122270 has a Stoichiometric coefficient of 2 Activated FGFR2 K660N mutant Reactome DB_ID: 2033312 Reactome Database ID Release 432033312 Reactome, http://www.reactome.org ReactomeREACT_123578 has a Stoichiometric coefficient of 2 FGFR2 N549K mutant dimer Reactome DB_ID: 2033329 Reactome Database ID Release 432033329 Reactome, http://www.reactome.org ReactomeREACT_123218 has a Stoichiometric coefficient of 2 FGFR2 K660N mutant dimer Reactome DB_ID: 2033331 Reactome Database ID Release 432033331 Reactome, http://www.reactome.org ReactomeREACT_123285 has a Stoichiometric coefficient of 2 FGFR2 K660E mutant dimer Reactome DB_ID: 2033339 Reactome Database ID Release 432033339 Reactome, http://www.reactome.org ReactomeREACT_125172 has a Stoichiometric coefficient of 2 FGFR2 N549H mutant dimer Reactome DB_ID: 2033341 Reactome Database ID Release 432033341 Reactome, http://www.reactome.org ReactomeREACT_125380 has a Stoichiometric coefficient of 2 Alpha-3(V) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268849 Reactome Database ID Release 432268849 Reactome, http://www.reactome.org ReactomeREACT_123981 phosphorylated FGFR2c A314D mutant dimer Reactome DB_ID: 2071955 Reactome Database ID Release 432071955 Reactome, http://www.reactome.org ReactomeREACT_123466 has a Stoichiometric coefficient of 2 FGFR2 mutant dimers with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2033349 Reactome Database ID Release 432033349 Reactome, http://www.reactome.org ReactomeREACT_125530 HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2130696 Reactome Database ID Release 432130696 Reactome, http://www.reactome.org ReactomeREACT_125620 Alpha-2(V) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268930 Reactome Database ID Release 432268930 Reactome, http://www.reactome.org ReactomeREACT_122052 HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2130459 Reactome Database ID Release 432130459 Reactome, http://www.reactome.org ReactomeREACT_124517 5-HT1A-F/5 receptor Converted from EntitySet in Reactome Reactome DB_ID: 390959 Reactome Database ID Release 43390959 Reactome, http://www.reactome.org ReactomeREACT_17644 HRH3, 4 Converted from EntitySet in Reactome Reactome DB_ID: 390872 Reactome Database ID Release 43390872 Reactome, http://www.reactome.org ReactomeREACT_17881 DRD2, 3, 4 Converted from EntitySet in Reactome Reactome DB_ID: 390818 Reactome Database ID Release 43390818 Reactome, http://www.reactome.org ReactomeREACT_18193 Beta adrenoceptor Converted from EntitySet in Reactome Reactome DB_ID: 390670 Reactome Database ID Release 43390670 Reactome, http://www.reactome.org ReactomeREACT_17735 DRD1, 5 Converted from EntitySet in Reactome Reactome DB_ID: 390836 Reactome Database ID Release 43390836 Reactome, http://www.reactome.org ReactomeREACT_17080 Alpha-1 adrenoceptor Converted from EntitySet in Reactome Reactome DB_ID: 390684 Reactome Database ID Release 43390684 Reactome, http://www.reactome.org ReactomeREACT_17980 M1/M3/M5 receptors Converted from EntitySet in Reactome Reactome DB_ID: 390660 Reactome Database ID Release 43390660 Reactome, http://www.reactome.org ReactomeREACT_17246 M2/M4 receptors Converted from EntitySet in Reactome Reactome DB_ID: 390686 Reactome Database ID Release 43390686 Reactome, http://www.reactome.org ReactomeREACT_17604 Neuromedin-U receptors Converted from EntitySet in Reactome Reactome DB_ID: 964805 Reactome Database ID Release 43964805 Reactome, http://www.reactome.org ReactomeREACT_26152 Melanin-concentrating hormone receptors Converted from EntitySet in Reactome Reactome DB_ID: 947667 Reactome Database ID Release 43947667 Reactome, http://www.reactome.org ReactomeREACT_26635 Urotensin 2, 2B Converted from EntitySet in Reactome Reactome DB_ID: 445115 Reactome Database ID Release 43445115 Reactome, http://www.reactome.org ReactomeREACT_21487 EP2/EP4 receptors Converted from EntitySet in Reactome Reactome DB_ID: 391921 Reactome Database ID Release 43391921 Reactome, http://www.reactome.org ReactomeREACT_19013 LTB4 receptors Converted from EntitySet in Reactome Reactome DB_ID: 416401 Reactome Database ID Release 43416401 Reactome, http://www.reactome.org ReactomeREACT_18655 GNRH ligands Converted from EntitySet in Reactome Reactome DB_ID: 873938 Reactome Database ID Release 43873938 Reactome, http://www.reactome.org ReactomeREACT_24377 GnRH receptor Converted from EntitySet in Reactome Reactome DB_ID: 391368 Reactome Database ID Release 43391368 Reactome, http://www.reactome.org ReactomeREACT_17831 Trace amine-associated receptor Converted from EntitySet in Reactome Reactome DB_ID: 391201 Reactome Database ID Release 43391201 Reactome, http://www.reactome.org ReactomeREACT_18228 5-HT4/6/7 receptor Converted from EntitySet in Reactome Reactome DB_ID: 390942 Reactome Database ID Release 43390942 Reactome, http://www.reactome.org ReactomeREACT_17859 5-HT2 receptor Converted from EntitySet in Reactome Reactome DB_ID: 391030 Reactome Database ID Release 43391030 Reactome, http://www.reactome.org ReactomeREACT_17926 ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376465 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43215063 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43215079 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030342 Reactome Database ID Release 43215644 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43215524 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008401 Reactome Database ID Release 43215605 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008401 Reactome Database ID Release 43215642 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008401 Reactome Database ID Release 43215633 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008401 Reactome Database ID Release 43216562 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43216595 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 43216569 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 43216599 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004499 Reactome Database ID Release 43114712 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 43217318 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004499 Reactome Database ID Release 43217265 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004497 Reactome Database ID Release 43216629 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008131 Reactome Database ID Release 43141714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004024 Reactome Database ID Release 4371694 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008131 Reactome Database ID Release 43141195 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008131 Reactome Database ID Release 43141714 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003979 Reactome Database ID Release 43173601 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003987 Reactome Database ID Release 4371734 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015020 Reactome Database ID Release 43174915 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005461 Reactome Database ID Release 43174365 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004029 Reactome Database ID Release 4371722 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004029 Reactome Database ID Release 4371690 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003987 Reactome Database ID Release 43449908 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015020 Reactome Database ID Release 43174934 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004781 Reactome Database ID Release 43174381 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004020 Reactome Database ID Release 43174366 Reactome, http://www.reactome.org Cysteinyl leukotriene receptors Converted from EntitySet in Reactome Reactome DB_ID: 416385 Reactome Database ID Release 43416385 Reactome, http://www.reactome.org ReactomeREACT_18826 ACTIVATION GENE ONTOLOGYGO:0008146 Reactome Database ID Release 43176520 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004062 Reactome Database ID Release 43176535 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004062 Reactome Database ID Release 43176524 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004062 Reactome Database ID Release 43176678 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004062 Reactome Database ID Release 43159347 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004062 Reactome Database ID Release 43158475 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004062 Reactome Database ID Release 43158475 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004062 Reactome Database ID Release 43158475 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004027 Reactome Database ID Release 43176510 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004027 Reactome Database ID Release 43176537 Reactome, http://www.reactome.org p-IRS1,2 Converted from EntitySet in Reactome Reactome DB_ID: 112322 Reactome Database ID Release 43112322 Reactome, http://www.reactome.org ReactomeREACT_4523 PKB regulator Converted from EntitySet in Reactome Reactome DB_ID: 162414 Reactome Database ID Release 43162414 Reactome, http://www.reactome.org ReactomeREACT_5778 Raptor Converted from EntitySet in Reactome Reactome DB_ID: 165671 Reactome Database ID Release 43165671 Reactome, http://www.reactome.org ReactomeREACT_7195 phospho-IRS Converted from EntitySet in Reactome Reactome DB_ID: 74687 Reactome Database ID Release 4374687 Reactome, http://www.reactome.org ReactomeREACT_4422 p-SHC Converted from EntitySet in Reactome Reactome DB_ID: 167016 Reactome Database ID Release 43167016 Reactome, http://www.reactome.org ReactomeREACT_12146 Alpha-1(XXVII) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268856 Reactome Database ID Release 432268856 Reactome, http://www.reactome.org ReactomeREACT_122638 IRS Converted from EntitySet in Reactome Reactome DB_ID: 74698 Reactome Database ID Release 4374698 Reactome, http://www.reactome.org ReactomeREACT_2507 FGFR1 K656E mutant dimer Reactome DB_ID: 2023412 Reactome Database ID Release 432023412 Reactome, http://www.reactome.org ReactomeREACT_122529 has a Stoichiometric coefficient of 2 FGFR1 N546K mutant dimer Reactome DB_ID: 2023414 Reactome Database ID Release 432023414 Reactome, http://www.reactome.org ReactomeREACT_122483 has a Stoichiometric coefficient of 2 FGFR1 R576W mutant dimer Reactome DB_ID: 2023419 Reactome Database ID Release 432023419 Reactome, http://www.reactome.org ReactomeREACT_124197 has a Stoichiometric coefficient of 2 Activated FGFR1 mutant dimers with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2023432 Reactome Database ID Release 432023432 Reactome, http://www.reactome.org ReactomeREACT_122042 FGFR1 mutant dimers with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2023433 Reactome Database ID Release 432023433 Reactome, http://www.reactome.org ReactomeREACT_121650 FGFR2 S267P mutant dimer Reactome DB_ID: 2033335 Reactome Database ID Release 432033335 Reactome, http://www.reactome.org ReactomeREACT_124600 has a Stoichiometric coefficient of 2 phosphorylated FGFR1 K656E mutant dimer Reactome DB_ID: 2023426 Reactome Database ID Release 432023426 Reactome, http://www.reactome.org ReactomeREACT_121806 has a Stoichiometric coefficient of 2 phosphorylated FGFR1 N546K mutant dimer Reactome DB_ID: 2023428 Reactome Database ID Release 432023428 Reactome, http://www.reactome.org ReactomeREACT_125119 has a Stoichiometric coefficient of 2 phosphorylated FGFR1 R576W mutant dimer Reactome DB_ID: 2023430 Reactome Database ID Release 432023430 Reactome, http://www.reactome.org ReactomeREACT_122613 has a Stoichiometric coefficient of 2 FGFR2 ligand-independent mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 2029952 Reactome Database ID Release 432029952 Reactome, http://www.reactome.org ReactomeREACT_124503 FGFR1 P252S mutant dimer Reactome DB_ID: 2011924 Reactome Database ID Release 432011924 Reactome, http://www.reactome.org ReactomeREACT_123237 has a Stoichiometric coefficient of 2 FGFR1 S252T mutant dimer Reactome DB_ID: 2011926 Reactome Database ID Release 432011926 Reactome, http://www.reactome.org ReactomeREACT_125191 has a Stoichiometric coefficient of 2 FGFR1 P252X mutant dimers bound to FGFs Reactome DB_ID: 2050638 Reactome Database ID Release 432050638 Reactome, http://www.reactome.org ReactomeREACT_124631 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR1 P252X mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 2050635 Reactome Database ID Release 432050635 Reactome, http://www.reactome.org ReactomeREACT_122247 phosphorylated FGFR1 P252T mutant dimer Reactome DB_ID: 2018773 Reactome Database ID Release 432018773 Reactome, http://www.reactome.org ReactomeREACT_123305 has a Stoichiometric coefficient of 2 phosphorylated FGFR1c P252R mutant dimer Reactome DB_ID: 2011960 Reactome Database ID Release 432011960 Reactome, http://www.reactome.org ReactomeREACT_124772 has a Stoichiometric coefficient of 2 phosphorylated FGFR1 P252X mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 2050627 Reactome Database ID Release 432050627 Reactome, http://www.reactome.org ReactomeREACT_123958 phosphorylated FGFR1 P252S mutant dimer Reactome DB_ID: 2011961 Reactome Database ID Release 432011961 Reactome, http://www.reactome.org ReactomeREACT_122450 has a Stoichiometric coefficient of 2 FGFR1c P252R mutant dimer Reactome DB_ID: 2011923 Reactome Database ID Release 432011923 Reactome, http://www.reactome.org ReactomeREACT_123201 has a Stoichiometric coefficient of 2 Activated FGFR1 P252X mutants Reactome DB_ID: 2050642 Reactome Database ID Release 432050642 Reactome, http://www.reactome.org ReactomeREACT_121913 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004013 Reactome Database ID Release 43174397 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047150 Reactome Database ID Release 431614655 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004478 Reactome Database ID Release 43174380 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008705 Reactome Database ID Release 43174360 Reactome, http://www.reactome.org Alpha-1(XI) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268808 Reactome Database ID Release 432268808 Reactome, http://www.reactome.org ReactomeREACT_125129 ACTIVATION GENE ONTOLOGYGO:0008891 Reactome Database ID Release 43389828 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047969 Reactome Database ID Release 43389855 Reactome, http://www.reactome.org Histone H3 with dimethylated lysine-4 Converted from EntitySet in Reactome Reactome DB_ID: 1214192 Reactome Database ID Release 431214192 Reactome, http://www.reactome.org ReactomeREACT_27589 ACTIVATION GENE ONTOLOGYGO:0030267 Reactome Database ID Release 43389805 Reactome, http://www.reactome.org Histone H3 with trimethylated lysine-4 Converted from EntitySet in Reactome Reactome DB_ID: 1214232 Reactome Database ID Release 431214232 Reactome, http://www.reactome.org ReactomeREACT_27357 ACTIVATION GENE ONTOLOGYGO:0004357 Reactome Database ID Release 43174398 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004122 Reactome Database ID Release 431614644 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004123 Reactome Database ID Release 431614601 Reactome, http://www.reactome.org Activated FGFR2c S372C mutant Reactome DB_ID: 2029911 Reactome Database ID Release 432029911 Reactome, http://www.reactome.org ReactomeREACT_122980 has a Stoichiometric coefficient of 2 Activated FGFR2b S373C mutant Reactome DB_ID: 2029906 Reactome Database ID Release 432029906 Reactome, http://www.reactome.org ReactomeREACT_124395 has a Stoichiometric coefficient of 2 Activated FGFR2b S376C mutant Reactome DB_ID: 2029909 Reactome Database ID Release 432029909 Reactome, http://www.reactome.org ReactomeREACT_125519 has a Stoichiometric coefficient of 2 Activated FGFR2 W290C mutant Reactome DB_ID: 2029905 Reactome Database ID Release 432029905 Reactome, http://www.reactome.org ReactomeREACT_121773 has a Stoichiometric coefficient of 2 Activated FGFR2c Y375C mutant Reactome DB_ID: 2029915 Reactome Database ID Release 432029915 Reactome, http://www.reactome.org ReactomeREACT_124805 has a Stoichiometric coefficient of 2 Activated FGFR2 L764fs*4STOP mutant Reactome DB_ID: 2071958 Reactome Database ID Release 432071958 Reactome, http://www.reactome.org ReactomeREACT_124669 has a Stoichiometric coefficient of 2 FGFR2b mutant dimers with enhanced ligand-binding bound to FGFs Reactome DB_ID: 2065929 Reactome Database ID Release 432065929 Reactome, http://www.reactome.org ReactomeREACT_124272 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR2b mutant dimers with enhanced ligand-binding Converted from EntitySet in Reactome Reactome DB_ID: 2065927 Reactome Database ID Release 432065927 Reactome, http://www.reactome.org ReactomeREACT_124116 FGFR2b S252W mutant dimer Reactome DB_ID: 2011931 Reactome Database ID Release 432011931 Reactome, http://www.reactome.org ReactomeREACT_123742 has a Stoichiometric coefficient of 2 FGFR2b P253R mutant dimer Reactome DB_ID: 2011934 Reactome Database ID Release 432011934 Reactome, http://www.reactome.org ReactomeREACT_121857 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004782 Reactome Database ID Release 431655436 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047822 Reactome Database ID Release 431655454 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016846 Reactome Database ID Release 431614528 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0080146 Reactome Database ID Release 431614529 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004180 Reactome Database ID Release 431258416 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047982 Reactome Database ID Release 431614534 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0080146 Reactome Database ID Release 431614529 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017172 Reactome Database ID Release 431614590 Reactome, http://www.reactome.org ERM Converted from EntitySet in Reactome Reactome DB_ID: 437353 Reactome Database ID Release 43437353 Reactome, http://www.reactome.org ReactomeREACT_22626 Alpha-1(XXIV) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268928 Reactome Database ID Release 432268928 Reactome, http://www.reactome.org ReactomeREACT_124151 ACTIVATION GENE ONTOLOGYGO:0070224 Reactome Database ID Release 431614554 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050313 Reactome Database ID Release 431614523 Reactome, http://www.reactome.org FGFR2c W290G mutant dimer Reactome DB_ID: 2029930 Reactome Database ID Release 432029930 Reactome, http://www.reactome.org ReactomeREACT_123031 has a Stoichiometric coefficient of 2 FGFR2b S373C mutant dimer Reactome DB_ID: 2029923 Reactome Database ID Release 432029923 Reactome, http://www.reactome.org ReactomeREACT_124973 has a Stoichiometric coefficient of 2 FGFR2c S372C mutant dimer Reactome DB_ID: 2029928 Reactome Database ID Release 432029928 Reactome, http://www.reactome.org ReactomeREACT_122774 has a Stoichiometric coefficient of 2 FGFR2c Y375C mutant dimer Reactome DB_ID: 2029936 Reactome Database ID Release 432029936 Reactome, http://www.reactome.org ReactomeREACT_124008 has a Stoichiometric coefficient of 2 FGFR2b Y376C mutant dimer Reactome DB_ID: 2029924 Reactome Database ID Release 432029924 Reactome, http://www.reactome.org ReactomeREACT_124469 has a Stoichiometric coefficient of 2 FGFR2 W290C mutant dimer Reactome DB_ID: 2029919 Reactome Database ID Release 432029919 Reactome, http://www.reactome.org ReactomeREACT_121506 has a Stoichiometric coefficient of 2 Activated FGFR2 S267C mutant Reactome DB_ID: 2033319 Reactome Database ID Release 432033319 Reactome, http://www.reactome.org ReactomeREACT_123544 has a Stoichiometric coefficient of 2 Activated FGFR2c W290G mutant Reactome DB_ID: 2029913 Reactome Database ID Release 432029913 Reactome, http://www.reactome.org ReactomeREACT_121872 has a Stoichiometric coefficient of 2 FGFR2 L764fs*4STOP mutant dimer Reactome DB_ID: 2071927 Reactome Database ID Release 432071927 Reactome, http://www.reactome.org ReactomeREACT_125471 has a Stoichiometric coefficient of 2 Activated FGFR2 ligand-independent mutants Converted from EntitySet in Reactome Reactome DB_ID: 2029948 Reactome Database ID Release 432029948 Reactome, http://www.reactome.org ReactomeREACT_124056 Dephosphorylated NFATC1/2/3 Converted from EntitySet in Reactome Reactome DB_ID: 2025852 Reactome Database ID Release 432025852 Reactome, http://www.reactome.org ReactomeREACT_119501 HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2130565 Reactome Database ID Release 432130565 Reactome, http://www.reactome.org ReactomeREACT_125689 ACTIVATION GENE ONTOLOGYGO:0004729 Reactome Database ID Release 43189420 Reactome, http://www.reactome.org Neutrophil CEACAMs affecting integrin binding to fibronectin Converted from EntitySet in Reactome Reactome DB_ID: 202719 Reactome Database ID Release 43202719 Reactome, http://www.reactome.org ReactomeREACT_12292 ACTIVATION GENE ONTOLOGYGO:0004418 Reactome Database ID Release 43189486 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004655 Reactome Database ID Release 43189415 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003870 Reactome Database ID Release 43189479 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008482 Reactome Database ID Release 431614541 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004109 Reactome Database ID Release 43189416 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004853 Reactome Database ID Release 43189412 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004853 Reactome Database ID Release 43189412 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004852 Reactome Database ID Release 43189468 Reactome, http://www.reactome.org p-FGFR1 fusion mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 1839020 Reactome Database ID Release 431839020 Reactome, http://www.reactome.org ReactomeREACT_124620 MYO18A-FGFR1 fusion mutant dimer MYO18A(1-1691)-FGFR1(429-822) fusion dimer Reactome DB_ID: 1637934 Reactome Database ID Release 431637934 Reactome, http://www.reactome.org ReactomeREACT_123595 has a Stoichiometric coefficient of 2 t(8;17) MYO18A-FGFR1 fusion dimer CEP110-p-FGFR1 CNTRL-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1838984 Reactome Database ID Release 431838984 Reactome, http://www.reactome.org ReactomeREACT_125255 has a Stoichiometric coefficient of 2 BCR-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1838980 Reactome Database ID Release 431838980 Reactome, http://www.reactome.org ReactomeREACT_123968 has a Stoichiometric coefficient of 2 CUX1-FGFR1 fusion mutant dimer CUX1(1-339)-FGFR1(429-822) fusion dimer Reactome DB_ID: 1637880 Reactome Database ID Release 431637880 Reactome, http://www.reactome.org ReactomeREACT_122687 has a Stoichiometric coefficient of 2 t(7;8) CUX1-FGFR1 fusion dimer ACTIVATION GENE ONTOLOGYGO:0016783 Reactome Database ID Release 431614551 Reactome, http://www.reactome.org TRIM24-FGFR1 fusion mutant dimer Reactome DB_ID: 1638017 Reactome Database ID Release 431638017 Reactome, http://www.reactome.org ReactomeREACT_123503 TRIM24(1-626)-FGFR1(429-822) fusion dimer has a Stoichiometric coefficient of 2 t(7;8) TRIM24-FGFR1 fusion dimer LRRFIP1-FGFR1 fusion mutant dimer LRRFIP1(1-249)-FGFR1(429-822) fusion dimer Reactome DB_ID: 1604541 Reactome Database ID Release 431604541 Reactome, http://www.reactome.org ReactomeREACT_123897 has a Stoichiometric coefficient of 2 t(2;8) LRRFIP1-FGFR1 fusion dimer CPSF6-FGFR1 fusion mutant dimer CPSF6(1-490)-FGFR1(429-822) fusion dimer Reactome DB_ID: 1637878 Reactome Database ID Release 431637878 Reactome, http://www.reactome.org ReactomeREACT_125376 has a Stoichiometric coefficient of 2 t(8:12) CPSF6-FGFR1 fusion dimer FGFR1OP2-FGFR1 fusion mutant dimer FGFR1OP(1-132)-FGFR1(429-822) fusion dimer Reactome DB_ID: 1637884 Reactome Database ID Release 431637884 Reactome, http://www.reactome.org ReactomeREACT_123249 has a Stoichiometric coefficient of 2 t(12;8) FGFR1OP2-FGFR1 fusion dimer Glycine receptor alpha subunits 1-4 Converted from EntitySet in Reactome Reactome DB_ID: 975405 Reactome Database ID Release 43975405 Reactome, http://www.reactome.org ReactomeREACT_26082 HTR3 receptors Converted from EntitySet in Reactome Reactome DB_ID: 975326 Reactome Database ID Release 43975326 Reactome, http://www.reactome.org ReactomeREACT_25982 ACTIVATION GENE ONTOLOGYGO:0015020 Reactome Database ID Release 43159159 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004074 Reactome Database ID Release 43189392 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43211893 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015020 Reactome Database ID Release 43159150 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376471 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004507 Reactome Database ID Release 43211941 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376372 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376372 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004325 Reactome Database ID Release 43189476 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004392 Reactome Database ID Release 43189379 Reactome, http://www.reactome.org HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2130321 Reactome Database ID Release 432130321 Reactome, http://www.reactome.org ReactomeREACT_123730 Procollagen N-proteinases Converted from EntitySet in Reactome Reactome DB_ID: 2002418 Reactome Database ID Release 432002418 Reactome, http://www.reactome.org ReactomeREACT_125184 ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376353 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376353 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376353 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43211869 Reactome, http://www.reactome.org Collagen alpha-1(I) chains Converted from EntitySet in Reactome Reactome DB_ID: 2089973 Reactome Database ID Release 432089973 Reactome, http://www.reactome.org ReactomeREACT_121971 ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43211871 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43211992 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43211888 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008389 Reactome Database ID Release 43211854 Reactome, http://www.reactome.org pY177-BCR1-p-FGFR1 mutant:GRB2:GAB2 Reactome DB_ID: 1839045 Reactome Database ID Release 431839045 Reactome, http://www.reactome.org ReactomeREACT_121944 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43211938 Reactome, http://www.reactome.org GRB2:GAB2 Reactome DB_ID: 912522 Reactome Database ID Release 43912522 Reactome, http://www.reactome.org ReactomeREACT_24714 has a Stoichiometric coefficient of 1 GRB2:pY-GAB2 Reactome DB_ID: 912528 Reactome Database ID Release 43912528 Reactome, http://www.reactome.org ReactomeREACT_24086 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0008389 Reactome Database ID Release 4376451 Reactome, http://www.reactome.org pY177-BCR-pY-FGFR1 mutant:GRB2:p-GAB2 Reactome DB_ID: 1839047 Reactome Database ID Release 431839047 Reactome, http://www.reactome.org ReactomeREACT_124181 has a Stoichiometric coefficient of 1 pY177-BCR-pY-FGFR1 mutant:GRB2:p-GAB1:PI3K Reactome DB_ID: 1839051 Reactome Database ID Release 431839051 Reactome, http://www.reactome.org ReactomeREACT_123413 has a Stoichiometric coefficient of 1 p-Y177-BCR-pY-FGFR1 mutant:GRB2:p-GAB2:PIK3R1 Reactome DB_ID: 1839048 Reactome Database ID Release 431839048 Reactome, http://www.reactome.org ReactomeREACT_122981 has a Stoichiometric coefficient of 1 p-FGFR1 fusion mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 1839023 Reactome Database ID Release 431839023 Reactome, http://www.reactome.org ReactomeREACT_123920 p-FGFR1 fusions that activate STAT5 Activated FGFR1 fusion mutants:p-PLCgamma Reactome DB_ID: 1839062 Reactome Database ID Release 431839062 Reactome, http://www.reactome.org ReactomeREACT_122284 has a Stoichiometric coefficient of 1 p-FGFR1 mutant fusions:PI3K Reactome DB_ID: 1839055 Reactome Database ID Release 431839055 Reactome, http://www.reactome.org ReactomeREACT_121575 has a Stoichiometric coefficient of 1 p-FGFR1 fusion mutant dimers:PIK3R1 Reactome DB_ID: 1839052 Reactome Database ID Release 431839052 Reactome, http://www.reactome.org ReactomeREACT_124249 has a Stoichiometric coefficient of 1 HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2130598 Reactome Database ID Release 432130598 Reactome, http://www.reactome.org ReactomeREACT_125028 ACTIVATION GENE ONTOLOGYGO:0008392 Reactome Database ID Release 43215088 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43213160 Reactome, http://www.reactome.org FGFR1OP-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1838997 Reactome Database ID Release 431838997 Reactome, http://www.reactome.org ReactomeREACT_121731 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43213146 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016712 Reactome Database ID Release 43212002 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43213161 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 43213172 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376353 Reactome, http://www.reactome.org LRRFIP1-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1839005 Reactome Database ID Release 431839005 Reactome, http://www.reactome.org ReactomeREACT_122658 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376353 Reactome, http://www.reactome.org CPSF6-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1838989 Reactome Database ID Release 431838989 Reactome, http://www.reactome.org ReactomeREACT_124500 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376353 Reactome, http://www.reactome.org CUX1-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1838992 Reactome Database ID Release 431838992 Reactome, http://www.reactome.org ReactomeREACT_123258 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376454 Reactome, http://www.reactome.org ZMYM2-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1839019 Reactome Database ID Release 431839019 Reactome, http://www.reactome.org ReactomeREACT_122249 has a Stoichiometric coefficient of 2 Activated FGFR1 fusion mutants:PLC-gamma Reactome DB_ID: 1839061 Reactome Database ID Release 431839061 Reactome, http://www.reactome.org ReactomeREACT_122191 has a Stoichiometric coefficient of 1 pY177-BCR-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1839043 Reactome Database ID Release 431839043 Reactome, http://www.reactome.org ReactomeREACT_125032 has a Stoichiometric coefficient of 2 FGFR1 fusion mutant dimers:TKIs Reactome DB_ID: 1839036 Reactome Database ID Release 431839036 Reactome, http://www.reactome.org ReactomeREACT_122131 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 MYO18A-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1839009 Reactome Database ID Release 431839009 Reactome, http://www.reactome.org ReactomeREACT_122132 has a Stoichiometric coefficient of 2 TRIM24-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1839015 Reactome Database ID Release 431839015 Reactome, http://www.reactome.org ReactomeREACT_123394 has a Stoichiometric coefficient of 2 FGFR1OP2-p-FGFR1 fusion mutant dimer Reactome DB_ID: 1839001 Reactome Database ID Release 431839001 Reactome, http://www.reactome.org ReactomeREACT_125384 has a Stoichiometric coefficient of 2 L-selectin ligands Converted from EntitySet in Reactome Reactome DB_ID: 198922 Reactome Database ID Release 43198922 Reactome, http://www.reactome.org ReactomeREACT_11759 LILR set Converted from EntitySet in Reactome Reactome DB_ID: 198894 Reactome Database ID Release 43198894 Reactome, http://www.reactome.org ReactomeREACT_11576 Activated overexpressed FGFR1c homodimer Reactome DB_ID: 1982036 Reactome Database ID Release 431982036 Reactome, http://www.reactome.org ReactomeREACT_123568 has a Stoichiometric coefficient of 2 Overexpressed FGFR1:TKIs Reactome DB_ID: 2023442 Reactome Database ID Release 432023442 Reactome, http://www.reactome.org ReactomeREACT_122320 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR1 fusion mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 1839026 Reactome Database ID Release 431839026 Reactome, http://www.reactome.org ReactomeREACT_122426 ZNF198-FGFR1 fusion dimer Reactome DB_ID: 1604545 Reactome Database ID Release 431604545 Reactome, http://www.reactome.org ReactomeREACT_123283 ZMYM2(1-913)-FGFR1(429-822) fusion dimer ZMYM2-FGFR1 fusion mutant dimer ZNF198(1-913)-FGFR1(429-822) fusion dimer has a Stoichiometric coefficient of 2 t(8;13) ZMYM2-FGFR1 fusion dimer t(8;13) ZNF198-FGFR1 fusion dimer FOP-FGFR1 fusion dimer FGFR1OP(2-163)-FGFR1(429-822) fusion dimer FGFR1OP-FGFR1 fusion mutant dimer Reactome DB_ID: 1604535 Reactome Database ID Release 431604535 Reactome, http://www.reactome.org ReactomeREACT_121665 has a Stoichiometric coefficient of 2 t(6;8) FGFR1OP-FGFR1 fusion dimer CNTRL-FGFR1 fusion mutant dimer CNTRL(1-808)-FGFR1(429-822) fusion dimer Reactome DB_ID: 1604531 Reactome Database ID Release 431604531 Reactome, http://www.reactome.org ReactomeREACT_122760 has a Stoichiometric coefficient of 2 t(8;9) CNTRL-FGFR1 fusion dimer BCR-FGFR1 fusion mutant dimer BCR(1-584)-FGFR1(419-822) fusion dimer Reactome DB_ID: 1604525 Reactome Database ID Release 431604525 Reactome, http://www.reactome.org ReactomeREACT_124707 has a Stoichiometric coefficient of 2 t(8:22) BCR-FGFR1 fusion dimer Duet Converted from EntitySet in Reactome Duo/Hapip KALRN Reactome DB_ID: 195061 Reactome Database ID Release 43195061 Reactome, http://www.reactome.org ReactomeREACT_10675 Collagen alpha-1(II) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127295 Reactome Database ID Release 432127295 Reactome, http://www.reactome.org ReactomeREACT_123680 Overexpressed FGFR1 homodimers Converted from EntitySet in Reactome Reactome DB_ID: 1982053 Reactome Database ID Release 431982053 Reactome, http://www.reactome.org ReactomeREACT_125009 Activated overexpressed FGFR1b homodimer Reactome DB_ID: 1982038 Reactome Database ID Release 431982038 Reactome, http://www.reactome.org ReactomeREACT_124709 has a Stoichiometric coefficient of 2 Activated overexpressed FGFR1 homodimers Converted from EntitySet in Reactome Reactome DB_ID: 1982041 Reactome Database ID Release 431982041 Reactome, http://www.reactome.org ReactomeREACT_125662 Collagen alpha-2(I) chains Converted from EntitySet in Reactome Reactome DB_ID: 2089983 Reactome Database ID Release 432089983 Reactome, http://www.reactome.org ReactomeREACT_123211 Phospho-BIM Converted from EntitySet in Reactome Reactome DB_ID: 217302 Reactome Database ID Release 43217302 Reactome, http://www.reactome.org ReactomeREACT_14475 NRIF Converted from EntitySet in Reactome Reactome DB_ID: 194338 Reactome Database ID Release 43194338 Reactome, http://www.reactome.org ReactomeREACT_14012 Ig Kappa Light Chain V Region Converted from EntitySet in Reactome Reactome DB_ID: 197037 Reactome Database ID Release 43197037 Reactome, http://www.reactome.org ReactomeREACT_10896 BIM Converted from EntitySet in Reactome Reactome DB_ID: 217313 Reactome Database ID Release 43217313 Reactome, http://www.reactome.org ReactomeREACT_14503 PPA2A (A:C):S112/S115 p-SPRY2 Reactome DB_ID: 1295605 Reactome Database ID Release 431295605 Reactome, http://www.reactome.org ReactomeREACT_111537 has a Stoichiometric coefficient of 1 Ub-Activated FGFR complex:Ub-p-FRS2alpha Reactome DB_ID: 1270445 Reactome Database ID Release 431270445 Reactome, http://www.reactome.org ReactomeREACT_111678 has a Stoichiometric coefficient of 1 PPA2A(A:C):SPRY2 PPA2A (A:C):Sprouty2 Reactome DB_ID: 1295593 Reactome Database ID Release 431295593 Reactome, http://www.reactome.org ReactomeREACT_111883 has a Stoichiometric coefficient of 1 PP2A (A:C) Reactome DB_ID: 934544 Reactome Database ID Release 43934544 Reactome, http://www.reactome.org ReactomeREACT_111802 has a Stoichiometric coefficient of 1 Activated FGFR:p-SHC1:GRB2:SOS1 Reactome DB_ID: 1268252 Reactome Database ID Release 431268252 Reactome, http://www.reactome.org ReactomeREACT_111709 has a Stoichiometric coefficient of 1 Activated FGFR:p-SHC1 Reactome DB_ID: 1268230 Reactome Database ID Release 431268230 Reactome, http://www.reactome.org ReactomeREACT_111736 has a Stoichiometric coefficient of 1 Activated FGFR:p-FRS2alpha:p-CBL:GRB2 Reactome DB_ID: 1580739 Reactome Database ID Release 431580739 Reactome, http://www.reactome.org ReactomeREACT_111661 has a Stoichiometric coefficient of 1 p-ERK dimer Converted from EntitySet in Reactome Reactome DB_ID: 1268261 Reactome Database ID Release 431268261 Reactome, http://www.reactome.org ReactomeREACT_111281 PP2A(A:C):SPRY2 PP2A (A:C):Sprouty 2 Reactome DB_ID: 934550 Reactome Database ID Release 43934550 Reactome, http://www.reactome.org ReactomeREACT_111668 has a Stoichiometric coefficient of 1 Collagen alpha-1(V) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127441 Reactome Database ID Release 432127441 Reactome, http://www.reactome.org ReactomeREACT_124841 Activated FGFR:SHC1 Reactome DB_ID: 1268225 Reactome Database ID Release 431268225 Reactome, http://www.reactome.org ReactomeREACT_111717 has a Stoichiometric coefficient of 1 p-MEK:p-ERK Converted from EntitySet in Reactome Reactome DB_ID: 1268207 Reactome Database ID Release 431268207 Reactome, http://www.reactome.org ReactomeREACT_111550 p-MEK:ERK Converted from EntitySet in Reactome Reactome DB_ID: 1268217 Reactome Database ID Release 431268217 Reactome, http://www.reactome.org ReactomeREACT_111738 S111/S120 p-SPRY2:B-RAF Reactome DB_ID: 1295587 Reactome Database ID Release 431295587 Reactome, http://www.reactome.org ReactomeREACT_111531 has a Stoichiometric coefficient of 1 SPRY2:B-RAF Reactome DB_ID: 1295598 Reactome Database ID Release 431295598 Reactome, http://www.reactome.org ReactomeREACT_111407 has a Stoichiometric coefficient of 1 Ub-(Y55/Y227)p-SPRY2 Reactome DB_ID: 1370875 Reactome Database ID Release 431370875 Reactome, http://www.reactome.org ReactomeREACT_111390 has a Stoichiometric coefficient of 1 Ub:Y55/Y227-pSPRY2:CBL Reactome DB_ID: 934572 Reactome Database ID Release 43934572 Reactome, http://www.reactome.org ReactomeREACT_111327 Ubiquitin:Y55/Y227-phospho Sprouty 2:CBL has a Stoichiometric coefficient of 1 Y55/Y227-pSPRY2:CBL Reactome DB_ID: 934576 Reactome Database ID Release 43934576 Reactome, http://www.reactome.org ReactomeREACT_111757 Y55/Y227-phospho Sprouty 2:CBL has a Stoichiometric coefficient of 1 PPA2A (A:C):Y55/Y227 p-SPRY2:GRB2 Reactome DB_ID: 1295625 Reactome Database ID Release 431295625 Reactome, http://www.reactome.org ReactomeREACT_111774 has a Stoichiometric coefficient of 1 PP2A(A:C):Y55/Y227-pSPRY2 PP2A (A:C):Y55/Y227-p-Sprouty 2 Reactome DB_ID: 934598 Reactome Database ID Release 43934598 Reactome, http://www.reactome.org ReactomeREACT_111410 has a Stoichiometric coefficient of 1 PP2A(A:C):S112/S121-pSPRY2 PP2A (A:C):S112/S121-phospho Sprouty 2 Reactome DB_ID: 934578 Reactome Database ID Release 43934578 Reactome, http://www.reactome.org ReactomeREACT_111444 has a Stoichiometric coefficient of 1 Collagen alpha-1(III) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127409 Reactome Database ID Release 432127409 Reactome, http://www.reactome.org ReactomeREACT_121539 FGFR2c short homodimer bound to FGF Reactome DB_ID: 192609 Reactome Database ID Release 43192609 Reactome, http://www.reactome.org ReactomeREACT_9545 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR3b homodimer bound to FGF Reactome DB_ID: 190232 Reactome Database ID Release 43190232 Reactome, http://www.reactome.org ReactomeREACT_9670 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR2c short homodimer Reactome DB_ID: 192586 Reactome Database ID Release 43192586 Reactome, http://www.reactome.org ReactomeREACT_9862 has a Stoichiometric coefficient of 2 FGFR3c homodimer bound to FGF Reactome DB_ID: 190234 Reactome Database ID Release 43190234 Reactome, http://www.reactome.org ReactomeREACT_9621 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR3b homodimer Reactome DB_ID: 190221 Reactome Database ID Release 43190221 Reactome, http://www.reactome.org ReactomeREACT_9649 has a Stoichiometric coefficient of 2 FGFR4 homodimer bound to FGF Reactome DB_ID: 190223 Reactome Database ID Release 43190223 Reactome, http://www.reactome.org ReactomeREACT_9679 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR3c homodimer Reactome DB_ID: 190235 Reactome Database ID Release 43190235 Reactome, http://www.reactome.org ReactomeREACT_9631 has a Stoichiometric coefficient of 2 FGF19 bound to BetaKlotho and FGFR4 Reactome DB_ID: 1307953 Reactome Database ID Release 431307953 Reactome, http://www.reactome.org ReactomeREACT_111259 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR4 homodimer Reactome DB_ID: 190224 Reactome Database ID Release 43190224 Reactome, http://www.reactome.org ReactomeREACT_9674 has a Stoichiometric coefficient of 2 FGF23 bound to Klotho and FGFR1c Reactome DB_ID: 190218 Reactome Database ID Release 43190218 Reactome, http://www.reactome.org ReactomeREACT_9730 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Collagen alpha-3(V) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127416 Reactome Database ID Release 432127416 Reactome, http://www.reactome.org ReactomeREACT_121974 Activated FGFR:p-FRS2beta Activated FGFR complexed with phosphorylated FRS2-beta Reactome DB_ID: 191483 Reactome Database ID Release 43191483 Reactome, http://www.reactome.org ReactomeREACT_111510 has a Stoichiometric coefficient of 1 Activated FGFR:pThr-FRS2alpha Reactome DB_ID: 1270463 Reactome Database ID Release 431270463 Reactome, http://www.reactome.org ReactomeREACT_76489 has a Stoichiometric coefficient of 1 Activated FGFR:FRS2beta Activated FGFR complexed with FRS2-beta Reactome DB_ID: 191480 Reactome Database ID Release 43191480 Reactome, http://www.reactome.org ReactomeREACT_111323 has a Stoichiometric coefficient of 1 Activated FGFR:FRS2alpha Activated FGFR complexed with FRS2-alpha Reactome DB_ID: 532643 Reactome Database ID Release 43532643 Reactome, http://www.reactome.org ReactomeREACT_21820 has a Stoichiometric coefficient of 1 Activated FGFR:p-FRS2:GRB2:SOS1 Reactome DB_ID: 1268251 Reactome Database ID Release 431268251 Reactome, http://www.reactome.org ReactomeREACT_111480 has a Stoichiometric coefficient of 1 Activated FGFR:p-FRS2:p-SHP2 Reactome DB_ID: 1268183 Reactome Database ID Release 431268183 Reactome, http://www.reactome.org ReactomeREACT_76410 has a Stoichiometric coefficient of 1 Activated FGFR:p-FRS2:SHP2 Reactome DB_ID: 1268152 Reactome Database ID Release 431268152 Reactome, http://www.reactome.org ReactomeREACT_76468 has a Stoichiometric coefficient of 1 Activated FGFR:p-FRS2 Converted from EntitySet in Reactome Reactome DB_ID: 1604520 Reactome Database ID Release 431604520 Reactome, http://www.reactome.org ReactomeREACT_117323 Activated FGFR bound to activated PLC gamma Reactome DB_ID: 190902 Reactome Database ID Release 43190902 Reactome, http://www.reactome.org ReactomeREACT_22036 has a Stoichiometric coefficient of 1 Activated FGFR bound to PLC gamma Reactome DB_ID: 190895 Reactome Database ID Release 43190895 Reactome, http://www.reactome.org ReactomeREACT_21704 has a Stoichiometric coefficient of 1 Collagen alpha-2(V) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127360 Reactome Database ID Release 432127360 Reactome, http://www.reactome.org ReactomeREACT_123075 AMPK-alpha2 Phosphorylates TBC1D1 Authored: May, B, 2011-07-15 EC Number: 2.7.11 Edited: May, B, 2011-07-15 In response to muscle contraction and insulin signaling, AMPK-alpha2 phosphorylates TBC1D1 on serine 237 and probably other residues (Frosig et al. 2010, Vichaiwong et al. 2010). As inferred from rat L6 muscle cells TBC1D1 colocalizes with perinuclear vesicles bearing GLUT4 and may be involved in an early step that mobilizes them (Chen et al. 2008). Human TBC1D1 appears cytosolic and is believed to be concentrated near vesicle membranes (Park et al. 2011). Pubmed17995453 Pubmed20701589 Pubmed20837646 Pubmed21454505 Reactome Database ID Release 431454699 Reactome, http://www.reactome.org ReactomeREACT_147871 Reviewed: Klip, Amira, 2012-08-21 MVB Vesicle Formation Authored: Gillespie, ME, 2010-08-10 ESCRT-III assembles into a highly ordered filament-like hetero-oligomer. Vps20 nucleates the homo-oligomerization of Snf7 that is capped by Vps24. Vps24 recruits Vps2 and initiates Vps4-dependent ESCRT-III disassembly. ESCRT-III is required for the last steps of MVB sorting, cargo sequestration, and MVB vesicle formation. Edited: Gillespie, ME, 2010-08-10 Pubmed16371348 Pubmed16973552 Pubmed19345195 Reactome Database ID Release 43917700 Reactome, http://www.reactome.org ReactomeREACT_27290 Reviewed: Rush, MG, 2008-01-11 00:00:00 Cargo Sequestration Authored: Gillespie, ME, 2010-08-10 ESCRT-0 recruits ESCRT-I and thereby initiates the MVB pathway. Cargo Sorting ESCRT-I is a heterotetramer consisting of Vps23, Vps28, Vps37, and Mvb12. The UEV domain of Vps23 binds ubiquitinated membrane proteins. Vps28 interacts with the GLUE domain of Vps36 in ESCRT-II. Cargo Sorting ESCRT-II is a heterotetramer formed of Vps36, Vps22, and two Vps25 molecules. The GLUE domain of Vps36 binds PI3P, Vps28, and ubiquitinated membrane proteins. Vps25 interacts with Vps20 of ESCRT-III. Edited: Gillespie, ME, 2010-08-10 Pubmed15218037 Pubmed19345195 Reactome Database ID Release 43917696 Reactome, http://www.reactome.org ReactomeREACT_27319 Reviewed: Rush, MG, 2008-01-11 00:00:00 Cargo Recognition And Sorting Authored: Gillespie, ME, 2010-08-10 Edited: Gillespie, ME, 2010-08-10 Initiation/Cargo Recognition is mediated by ESCRT-0, a heterodimer consisting of Vps27 and Hse1. ESCRT-0 binds Phosphatidyl inositol 3- phosphate (PI3P) on endosomes via a FVYE domain and ubiquitinated cargo via two UIM domains. Pubmed14624836 Pubmed15218037 Pubmed19345195 Reactome Database ID Release 43917730 Reactome, http://www.reactome.org ReactomeREACT_27272 Reviewed: Rush, MG, 2008-01-11 00:00:00 Closure of gap junction Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-17 10:03:12 Pubmed12907686 Reactome Database ID Release 43191656 Reactome, http://www.reactome.org ReactomeREACT_10125 The closure of Cx43 gap junction channels is observed following src-mediated Cx43 phosphorylation. 14-3-3 Binds Phosphorylated AS160 (TBC1D4) AS160 (TBC1D4) phosphorylated on serines 318, 341, 570, 588, and 751 and threonine 642 binds to all 14-3-3 proteins, although binding to 14-3-3 delta is comparatively low (Ramm et al. 2006, Howlett et al. 2007, Ngo et al. 2009, Treebak et al. 2009, Koumanov et al. 2011). As inferred from mouse, binding to 14-3-3 does not interfere with the interaction between AS160 and IRAP (LNPEP). Authored: May, B, 2011-07-07 Edited: May, B, 2011-07-07 Pubmed16880201 Pubmed17369524 Pubmed19013499 Pubmed19252894 Pubmed21454690 Reactome Database ID Release 431445149 Reactome, http://www.reactome.org ReactomeREACT_147698 Reviewed: Klip, Amira, 2012-08-21 AKT1/2 Phosphorylates AS160 (TBC1D4) As inferred from mouse, AKT2 and, to a lesser extent, AKT1 phosphorylate AS160 (TBC1D4) in response to insulin signaling (Howlett et al. 2007, Karlsson et al 2005). AS160, a RAB GTPase activating protein, interacts with IRAP (LNPEP) and is associated with cytoplasmic vesicles containing GLUT4. Authored: May, B, 2011-07-07 EC Number: 2.7.11 Edited: May, B, 2011-07-07 Pubmed15919790 Pubmed17369524 Reactome Database ID Release 431445144 Reactome, http://www.reactome.org ReactomeREACT_147770 Reviewed: Klip, Amira, 2012-08-21 has a Stoichiometric coefficient of 6 RAB4A:GTP Activates KIF3 As inferred from mouse adipocytes, insulin signals via PKC-lambda to cause Rab4 to load GTP and associate with Kif3, which then has higher affinity for microtubules. Motor activity of Kif3 along microtubules is believed to transport vesicles containing Glut4 across the cytosol to the cortical actin network. Authored: May, B, 2012-05-27 Edited: May, B, 2012-05-27 Reactome Database ID Release 432316347 Reactome, http://www.reactome.org ReactomeREACT_147824 Reviewed: Klip, Amira, 2012-08-21 ESCRT Disassembly Authored: Gillespie, ME, 2010-08-10 Disassembly Phase <br> The AAA-ATPase, Vps4 disassembles ESCRT-III and catalyzes the final step of the MVB pathway. The microtubule interacting and trafficking (MIT) domain of Vps4 interacts directly with the C-terminal region of Vps2 (MIM1) and Vps20 (MIM2). The association of Vta1, which contains two MIT domains, greatly enhances the activity of Vps4. Please note that the recomended names of the Vacuolar protein sorting-associated proteins (Vps) are Charged multivesicular body proteins or CHMPs. EC Number: 3.6.1.3 Edited: Gillespie, ME, 2010-08-10 Pubmed11563910 Pubmed15075231 Pubmed19345195 Reactome Database ID Release 43917693 Reactome, http://www.reactome.org ReactomeREACT_27184 Reviewed: Rush, MG, 2008-01-11 00:00:00 14-3-3 Binds Phosphorylated TBC1D1 Authored: May, B, 2011-07-15 Edited: May, B, 2011-07-15 Pubmed17995453 Pubmed20837646 Reactome Database ID Release 431454689 Reactome, http://www.reactome.org ReactomeREACT_147700 Reviewed: Klip, Amira, 2012-08-21 TBC1D1 phosphorylated on serine-237 binds 14-3-3 proteins in assays with yeast 14-3-3 proteins BMH1 and BMH2 (Chen et al. 2008, Frosig et al. 2010). Binding with human 14-3-3 proteins is inferred. RAB8A/10/13/14 Exchange GDP for GTP Authored: May, B, 2012-05-16 Edited: May, B, 2012-05-16 Pubmed20631154 Pubmed20937701 RAB8A/10/13/14 release GDP and bind GTP to yield the active complex. Guanine nucleotide exchange factors (GEFs) stimulate the reaction. GTPase-activating proteins (GAPs) oppose the reaction by stimulating the intrinsic GTPase activity of the RAB proteins. Reactome Database ID Release 432255343 Reactome, http://www.reactome.org ReactomeREACT_147746 Reviewed: Klip, Amira, 2012-08-21 c-src associates with Cx43 in gap junctions Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-17 10:03:12 Pubmed11124251 Pubmed15998870 Reactome Database ID Release 43191654 Reactome, http://www.reactome.org ReactomeREACT_9975 c-src has been shown to interact with Cx43 (Giepmans et al., 2001). Models describing v-src mediated Cx43 channel gating propose that the initial interaction between v-src and Cx43 may occur via a SH3 domain interaction (see Lau 2005). has a Stoichiometric coefficient of 12 Association of Cx43 with ZO-1 Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Connexin-interacting proteins appear to function in regulating gap junction formation and communication. ZO-1 has been shown to alter the membrane localization of Cx43 and plays a role in regulating Cx43-mediated gap junctional communication in osteoblastic cells (Laing et al. 2005). ZO-1 may function in the delivery of Cx43 from a lipid raft domain to gap junctional plaques, which may be an important regulatory step in gap junction formation. Edited: Matthews, L, 2007-01-07 14:51:44 Pubmed15855237 Reactome Database ID Release 43190541 Reactome, http://www.reactome.org ReactomeREACT_10060 Docking of connexons into junctional, double-membrane spanning channels Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Docking of Cx43 at the plasma membrane may involve ZO-1 as well as alpha- and beta-catenin (Shaw et al., 2007). The role of ZO-1 in regulating gap junction biology is unclear. Recent results indicate a role for ZO-1 in regulating gap junction plaque size (Hunter et al., 2007). Edited: Matthews, L, 2007-04-12 12:59:16 Pubmed16195341 Pubmed17289573 Reactome Database ID Release 43191737 Reactome, http://www.reactome.org ReactomeREACT_10108 Association of Golgi transport vesicles with microtubules Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-07 14:51:44 One mechanism of transport of connexon-containing vesicles involves movement along microtubules (Segretain and Falk, 2004). Such a transport system has been described for similar secretory vesicles (Toomre et al., 1999). Direct microtubule-dependent transport of connexons to GJ-assembly sites has recently been reported as well (Shaw et al., 2007). Pubmed12149451 Pubmed15033576 Pubmed17289573 Pubmed9841901 Reactome Database ID Release 43190520 Reactome, http://www.reactome.org ReactomeREACT_10011 Formation of junctional channels Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-12 12:57:50 Junctional channels are an assembly of two docked connexons on adjacent cells that permits direct communication of the cytoplasm in the two cells as shown below. Proteins associated with GJs such as catenins (Wu et al., 2003, Shaw et al., 2007) and L-CAM (Musil et al., 1990) might be required for connexon docking. Docking occurs through a tight interaction of the extracellular loops (Unger et al., 1999; Sosinsky and Nicholson, 2005). Intramolecular disulfide bridges between the two extracellular loops (E1 and E2) of connexin polypeptides are important for the correct three-dimensional structure of the extracellular loops (Foote et al., 1998) Pubmed10024245 Pubmed12577316 Pubmed15925321 Pubmed1850831 Pubmed2172261 Pubmed9490731 Reactome Database ID Release 43190788 Reactome, http://www.reactome.org ReactomeREACT_9990 has a Stoichiometric coefficient of 2 Insertion of connexons into the plasma membrane resulting in the formation of hemi-channels Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-12 12:59:16 Hemi-channels appear to play a role in isosmotic cell volume regulation (Quist et al., 2000), in apoptosis regulation (Contreras et al. 2002; John et al. 1999), and in the differentiation of different cell types (Boucher and Bennett 2003). Individual connexons have been observed dispersed around gap junction plaques. This observation suggests that there is a pool of connexons dispersed in the plasma membrane which can migrate to gap junction plaques (Benedetti et al. 2000; Hulser et al. 1997; Lauf et al. 2002; Gaietta et al. 2002). Insertion of a connexon into the cell membrane results in the formation of a hemi-channel. This channel permits direct exchanges between cell cytoplasm and extracellular matrix (Figure 3). Freeze-fracture electron microscopy studies have revealed that cytoplasmic vesicles can fuse with the plasma membrane to permit connexon insertion (Shivers and Bowman 1985). Pubmed10704454 Pubmed11001494 Pubmed11756680 Pubmed11964472 Pubmed12149451 Pubmed12692906 Pubmed15033576 Pubmed1680869 Pubmed3999183 Pubmed9194487 Pubmed9867835 Reactome Database ID Release 43190877 Reactome, http://www.reactome.org ReactomeREACT_10004 Dab2 is recruited to the junctional plaques Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Dab2 is recruited to Cx43-based GJs possibly through a direct interaction between its N-terminal phosphotyrosine binding (PTB) domain and a putative XPXY internalization motif found in the C-terminal tail of Cx43 as well as a number of other connexin family members (Piehl et al., 2007).The distal portion of Dab2 on its opposite end binds the globular N-terminal domain of clathrin heavy chains (Piehl et al., 2007). Edited: Matthews, L, 2007-04-17 13:55:45 Pubmed17108328 Reactome Database ID Release 43196026 Reactome, http://www.reactome.org ReactomeREACT_9951 Reviewed: Falk, MM, 2007-02-01 20:15:27 Assembly of gap junction plaques Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-03-27 16:29:06 Once transported to the plasma membrane, junctional channels aggregate into clusters forming gap junction plaques that may contain a few to many thousands of individual channels and that vary in size from a few square nanometers to many square micrometers (Bruzzone et al. 1996; Falk 2000; Severs et al. 2001). Gap junction plaques are involved in numerous processes including growth and differentiation (Loewenstein and Rose 1992), pathological cell proliferation (Roger et al. 2004; Segretain et al. 2003) and spermatogenesis (Juneja et al. 1999; Plum et al. 2000). The physiological importance of gap junction plaques is underscored by the diverse pathologies associated with connexin gene mutations (De Maio et al. 2002). An arbitrary number (10) of channels is shown as aggregating in this reaction but the actual number may be hundreds to thousands. Pubmed10208994 Pubmed10996788 Pubmed11058097 Pubmed11180622 Pubmed12012322 Pubmed14639657 Pubmed14743507 Pubmed1623203 Pubmed17200141 Pubmed8665925 Reactome Database ID Release 43190790 Reactome, http://www.reactome.org ReactomeREACT_10046 has a Stoichiometric coefficient of 10 Internalization of gap junction plaques Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-12 12:57:50 GJ plaques, clusters of GJ channels, can be internalized to form large, double-membrane vesicles (aka AGJs). Internalized AGJ vesicles subdivide into smaller vesicles that are subsequently degraded by endo/lysosomal pathways (Piehl et al., 2007). Pubmed17108328 Reactome Database ID Release 43190519 Reactome, http://www.reactome.org ReactomeREACT_9971 Reviewed: Falk, MM, 2007-02-01 20:15:27 Dynamin is recruited to the gap junction plaque Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-17 13:54:37 Pubmed17108328 Reactome Database ID Release 43196017 Reactome, http://www.reactome.org ReactomeREACT_9969 Reviewed: Falk, MM, 2007-02-01 20:15:27 The GTPase dynamin, which functions in the completion of vesicle budding localizes in Cx43-based GJs and especially invaginating plaques and AGJ vesicles (Piehl et al., 2007). Phosphorylation of Cx43 by c-src Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-17 13:50:09 Pubmed12506110 Reactome Database ID Release 43191636 Reactome, http://www.reactome.org ReactomeREACT_9997 c-Src phosphorylates Cx43 on Tyr 265. has a Stoichiometric coefficient of 12 Budding of connexon-containing transport vesicles from the Golgi Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Connexon-containing transport vesicles have been shown to emanate from the Golgi and deliver connexons to the plasma membrane (Lauf et al., 2002). Edited: Matthews, L, 2007-01-07 14:51:44 Pubmed12149451 Reactome Database ID Release 43190782 Reactome, http://www.reactome.org ReactomeREACT_10110 Microtubule-independent trafficking of connexons to the plasma membrane Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Connexons may also traffic using a microtubule-independent mechanism. A few studies suggest that rough ER membranes can directly transfer connexons to the plasma membrane (Martin et al. 2001; Bloom and Goldstein 1998). Other cytoskeletal components, such as actin filaments, might be involved in the delivery of connexons to gap junction plaques (Thomas et al. 2001; Gilleron et al. 2006). Edited: Matthews, L, 2007-04-12 12:57:50 Pubmed11719551 Pubmed12064594 Pubmed16823880 Pubmed9508761 Reactome Database ID Release 43451056 Reactome, http://www.reactome.org ReactomeREACT_21353 Connexin oligomerization in Trans-Golgi Network (TGN) A study using cultured cells demonstrated connexon oligomerization from Cx43 subunits inside the Trans-Golgi Network after exit from the ER (Musil and Goodenough 1993). Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-07 14:51:44 Pubmed7691412 Reactome Database ID Release 43190662 Reactome, http://www.reactome.org ReactomeREACT_9415 has a Stoichiometric coefficient of 6 Connexin oligomerization in ER-Golgi-Intermediate Compartment Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-07 14:51:44 Oligomerization of connexins Cx32 and Cx26 has also been observed in the ER-Golgi-intermediate compartment (ERGIC) (Diez et al. 1999). Heteromeric connexons containing both Cx32 and Cx26 have been observed. For the sake of simplicity, the connexon here is described as containing equal numbers of Cx26 and Cx32 subunits, although the ratio may vary. Pubmed10231375 Pubmed10646523 Reactome Database ID Release 43190687 Reactome, http://www.reactome.org ReactomeREACT_9520 has a Stoichiometric coefficient of 3 Melanocortin receptors Converted from EntitySet in Reactome Reactome DB_ID: 388601 Reactome Database ID Release 43388601 Reactome, http://www.reactome.org ReactomeREACT_18111 Connexin oligomerization in endoplasmic reticulum membrane Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-07 14:51:44 Pubmed10191254 Pubmed11985493 Pubmed9184217 Reactome Database ID Release 43190681 Reactome, http://www.reactome.org ReactomeREACT_9494 Studies using microsomes have revealed that oligomerization of connexins Cx26, Cx43, and Cx32 can occur after insertion of connexins in the ER membrane (Falk et al. 1997; Ahmad et al. 1999, Ahmad and Evans, 2002). has a Stoichiometric coefficient of 6 Transport of connexins to the Trans-Golgi Network (TGN) Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-07 14:51:44 Reactome Database ID Release 43190686 Reactome, http://www.reactome.org ReactomeREACT_9499 Transport of connexins along the secretory pathway (including transit from the Golgi to the TGN where Cx43 is predicted to oligomerize) occurs in vesicular transport containers. Transport of connexins to the ER-Golgi intermediate compartment Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-07 14:51:44 Reactome Database ID Release 43190698 Reactome, http://www.reactome.org ReactomeREACT_9503 Transport of connexins along the secretory pathway (including transit from the ER to the ERGIC where Cx32 is predicted to oligomerize) occurs in vesicular transport containers. MSH Converted from EntitySet in Reactome Melanocyte stimulating hormone Reactome DB_ID: 388597 Reactome Database ID Release 43388597 Reactome, http://www.reactome.org ReactomeREACT_17380 Vamp8 associated secretory vesicle to plasma membrane transport Authored: Gillespie, ME, 2009-08-27 Reactome Database ID Release 43376364 Reactome, http://www.reactome.org ReactomeREACT_14821 Reviewed: Rush, MG, 2008-01-11 00:00:00 The vamp8 associated vesicle docks and fuses with the plasma membrane. Vamp7 associated Lysosome to Plasma membrane transport Authored: Gillespie, ME, 2009-08-27 Pubmed11101518 Pubmed14993220 Reactome Database ID Release 43376357 Reactome, http://www.reactome.org ReactomeREACT_14778 Reviewed: Rush, MG, 2008-01-11 00:00:00 The lysosomal vesicle is targeted to and fused with the plasma membrane, releasing its contents into the extracellular space. Vamp2 associated secretory vesicle to plasma membrane transport Authored: Gillespie, ME, 2009-08-27 Pubmed11994746 Reactome Database ID Release 43376369 Reactome, http://www.reactome.org ReactomeREACT_14822 Reviewed: Rush, MG, 2008-01-11 00:00:00 The vamp2 associated vesicle docks and fuses with the plasma membrane. Endothelin receptor Converted from EntitySet in Reactome Reactome DB_ID: 388547 Reactome Database ID Release 43388547 Reactome, http://www.reactome.org ReactomeREACT_17602 trans-Golgi Network Lysosome Vesicle Destined Membrane Coat Assembly Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2008-05-21 20:31:35 Once the basic components of the docking complex are assembled with one end of AP-1 bound to cargo molecules, the other end binds to clathrin. Clathrin triskelions polymerize into hexagons and pentagons, forming a cage, which leads to membrane deformation. This polymerization step drives the sculpting of the lysosome vesicle. Here only 5 clathrin triskelions are represented, though in reality many more would be involved in sculpting an entire vesicle. Pubmed10394364 Pubmed11994746 Reactome Database ID Release 43432706 Reactome, http://www.reactome.org ReactomeREACT_19167 Reviewed: Simpson, JC, 2009-08-27 has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 52 Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture On Lysosome Vesicle Destined Golgi Membrane Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2008-05-21 20:31:35 Once AP-1 is recruited to the trans-Golgi Network membrane the complex of functional vesicle building proteins is joined by the cargo that will be within that vesicle. As with other types of vesicles the cargo itself is part of the vesicle development. Here the cargo is destined for the lysosome membrane. It is at this stage that a specific Synaptobrevin (Vamp) molecule also joins the complex. It should be noted that only certain Vamp molecules will be found with specific cargo molecules on the newly forming vesicles. However here we represent this reaction in bulk, without specific Vamp and cargo molecule pairings. Pubmed11694590 Pubmed11994746 Pubmed17116749 Reactome Database ID Release 43432712 Reactome, http://www.reactome.org ReactomeREACT_19371 Reviewed: Simpson, JC, 2009-08-27 trans-Golgi Network Derived Lysosomal Vesicle Uncoating Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2008-05-21 20:31:41 Pubmed11994746 Pubmed16155256 Pubmed17116749 Pubmed8374173 Pubmed8524399 Reactome Database ID Release 43432688 Reactome, http://www.reactome.org ReactomeREACT_19206 Reviewed: Simpson, JC, 2009-08-27 The heat shock protein Hsc70 and auxilin, a J-domain containing protein, are responsible for clathrin disassembly through an ATP-dependent reaction. This uncoating step may be a point in the pathway subject to regulation. This final step releases the vesicle from the clathrin cage. The vesicle still contatins a specific Vamp molecule, part of the targeting and fusion mechanism that delivers the vesicle to its ultimate destination. This vesicle also contains its cargo, membrane proteins embeded in the lysosome membrane. has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 52 trans-Golgi Network Lysosomal Vesicle Scission Authored: Gillespie, ME, 2009-08-27 Dynamin is recruited to the growing lysosome destined vesicle and, under conditions that interfere with its GTPase activity, dynamin forms a collar or ring around the neck of the budding vesicle. It is unclear whether dynamin acts as a mechanochemical transducer to generate fission or as a recruiter to attach other proteins that are directly responsible for the fission step. Lipid-modifying enzymes such as endophilin are also involved in vesicle formation. Endophilin is an acyltransferase that interacts with dynamin and that generates lysophosphatidic acid. The current view is that this reaction produces a negative curvature at the neck of the vesicle. EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Gillespie, ME, 2008-05-21 20:31:41 Pubmed11604418 Pubmed11994746 Pubmed8670264 Reactome Database ID Release 43432707 Reactome, http://www.reactome.org ReactomeREACT_19194 Reviewed: Simpson, JC, 2009-08-27 trans-Golgi Network Coat Assembly Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2008-05-21 20:31:35 Once the basic components of the docking complex are assembled with one end of AP-1 bound to cargo molecules, the other end binds to clathrin. Clathrin triskelions polymerize into hexagons and pentagons, forming a cage, which leads to membrane deformation. This polymerization step drives the sculpting of the vesicle. The number of clathrin triskelions required to sculpt a vesicle appears to be variable, but has been estimated to require 36 - 60 triskelions assocaited with 30 - 66 AP-1 complexes. Here a ~380 angstroms vesicle is represented with 48 clathrin triskelions and 52 AP-1 complexes. Pubmed10394364 Pubmed11994746 Pubmed17095010 Reactome Database ID Release 43421831 Reactome, http://www.reactome.org ReactomeREACT_19334 Reviewed: Simpson, JC, 2009-08-27 has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 52 Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2008-05-21 20:31:35 Once AP-1 is recruited to the trans-Golgi Network membrane the complex of functional vesicle building proteins is joined by the cargo that will be within that vesicle. As with other types of vesicles the cargo itself is part of the vesicle development. Here the cargo is destined for the Golgi-associated vesicle membrane. It is at this stage that a specific Synaptobrevin (Vamp) molecule also joins the complex. It should be noted that only certain Vamp molecules will be found with specific cargo molecules on the newly forming vesicles. However here we represent this reaction in bulk, without specific Vamp and cargo molecule pairings. Pubmed11694590 Pubmed11994746 Pubmed17116749 Reactome Database ID Release 43421833 Reactome, http://www.reactome.org ReactomeREACT_19391 Reviewed: Simpson, JC, 2009-08-27 trans-Golgi Network Vesicle Scission Authored: Gillespie, ME, 2009-08-27 Dynamin is recruited to the growing vesicle and, under conditions that interfere with its GTPase activity, dynamin forms a collar or ring around the neck of the budding vesicle. It is unclear whether dynamin acts as a mechanochemical transducer to generate fission or as a recruiter to attach other proteins that are directly responsible for the fission step. Lipid-modifying enzymes such as endophilin are also involved in vesicle formation. Endophilin is an acyltransferase that interacts with dynamin and that generates lysophosphatidic acid. The current view is that this reaction produces a negative curvature at the neck of the vesicle. EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Gillespie, ME, 2008-05-21 20:31:41 Pubmed11604418 Pubmed11994746 Pubmed8670264 Reactome Database ID Release 43421835 Reactome, http://www.reactome.org ReactomeREACT_19255 Reviewed: Simpson, JC, 2009-08-27 Cholecystokinin receptors Converted from EntitySet in Reactome Reactome DB_ID: 388518 Reactome Database ID Release 43388518 Reactome, http://www.reactome.org ReactomeREACT_17385 trans-Golgi Network Derived Vesicle Uncoating Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2008-05-21 20:31:41 Pubmed11994746 Pubmed16155256 Pubmed17116749 Pubmed8374173 Pubmed8524399 Reactome Database ID Release 43421836 Reactome, http://www.reactome.org ReactomeREACT_19124 Reviewed: Simpson, JC, 2009-08-27 The heat shock protein Hsc70 and auxilin, a J-domain containing protein, are responsible for clathrin disassembly through an ATP-dependent reaction. This uncoating step may be a point in the pathway subject to regulation. This final step releases the vesicle from the clathrin cage. The vesicle still contatins a specific Vamp molecule, part of the targeting and fusion mechanism that delivers the vesicle to its ultimate destination. This vesicle also contains its cargo, membrane proteins embeded in the Golgi-associated vesicle membrane. has a Stoichiometric coefficient of 48 has a Stoichiometric coefficient of 52 Recruitment Of Cytoplasmic Proteins To Vesicles Authored: Gillespie, ME, 2009-08-12 Cytosolic proteins are also recruited to the cyctoplasmic face of newly formed vesicles. Edited: Gillespie, ME, 2008-09-08 03:19:22 Pubmed17116749 Reactome Database ID Release 43434362 Reactome, http://www.reactome.org ReactomeREACT_19237 Reviewed: Simpson, JC, 2009-08-27 Endothelin Converted from EntitySet in Reactome Reactome DB_ID: 388544 Reactome Database ID Release 43388544 Reactome, http://www.reactome.org ReactomeREACT_17435 Formation Of Bloc-1 Complex Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2009-09-09 Pubmed15102850 Pubmed17116749 Reactome Database ID Release 43429815 Reactome, http://www.reactome.org ReactomeREACT_19390 Reviewed: Simpson, JC, 2009-08-27 The ubiquitously expressed protein complexes, named biogenesis of lysosome-related organelles complex or BLOC are required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules. Vasopressin receptor type 1 Converted from EntitySet in Reactome Reactome DB_ID: 388458 Reactome Database ID Release 43388458 Reactome, http://www.reactome.org ReactomeREACT_17773 Neurotensin receptor Converted from EntitySet in Reactome Reactome DB_ID: 388917 Reactome Database ID Release 43388917 Reactome, http://www.reactome.org ReactomeREACT_17215 NPY family of peptides Converted from EntitySet in Reactome Reactome DB_ID: 388902 Reactome Database ID Release 43388902 Reactome, http://www.reactome.org ReactomeREACT_17966 Neuropeptide Y receptors Converted from EntitySet in Reactome Reactome DB_ID: 388858 Reactome Database ID Release 43388858 Reactome, http://www.reactome.org ReactomeREACT_17692 prolactin-releasing peptide (PrRP) Converted from EntitySet in Reactome Reactome DB_ID: 388908 Reactome Database ID Release 43388908 Reactome, http://www.reactome.org ReactomeREACT_17709 Neuropeptide FF receptor Converted from EntitySet in Reactome Reactome DB_ID: 389406 Reactome Database ID Release 43389406 Reactome, http://www.reactome.org ReactomeREACT_18244 RALA Hydrolyzes GTP Authored: May, B, 2011-07-17 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: May, B, 2011-07-17 Pubmed8664345 RALA is a guanine nucleotide binding protein that hydrolyzes bound GTP to yield GDP and phosphate. RGC1 and RGC2 are GAPs (GTPase-activating proteins) that activate the GTPase activity of RALA. Insulin activates AKT, which phosphorylates RGC2, inactivating the GAP activity of RGC1:RGC2 and allowing RALA:GTP to accumulate. Reactome Database ID Release 431458485 Reactome, http://www.reactome.org ReactomeREACT_147722 Reviewed: Klip, Amira, 2012-08-21 AKT2 Phosphorylates Myosin 5A As inferred from mouse, AKT2 phosphorylates Myosin 5A on serine-1652. The phosphorylation promotes association of Myosin 5A with actin and ATPase activity of Myosin 5A. Authored: May, B, 2011-07-12 EC Number: 2.7.11 Edited: May, B, 2011-07-12 Reactome Database ID Release 431449597 Reactome, http://www.reactome.org ReactomeREACT_147884 Reviewed: Klip, Amira, 2012-08-21 Translocation of GLUT4 Vesicle and Docking at the Plasma Membrane As inferred from mouse, GLUT4 initially translocates from endosomes to insulin-responsive vesicles (IRVs, GSVs). RAB11 appears to play a role in this process. IRVs bearing GLUT4 are then translocated across the cortical actin network to the plasma membrane. Myosins 2A, 2B, 5A, and 5B contribute to translocation and are presumed to be involved in this step. Myosin 1C appears to act close to the plasma membrane and may facilitate fusion of the vesicle with the plasma membrane. RAB:GTP complexes coupled to the vesicles may interact with myosins to regulate their activity. Authored: May, B, 2012-05-27 Edited: May, B, 2012-05-27 Reactome Database ID Release 432316352 Reactome, http://www.reactome.org ReactomeREACT_147776 Reviewed: Klip, Amira, 2012-08-21 Fusion of GLUT4 Vesicle with the Plasma Membrane After docking at the membrane VAMP2 on the vesicle interacts with SYNTAXIN-4 and SNAP23 on the plasma membrane to catalyze fusion of the vesicle with the plasma membrane. STXBP3 (MUNC18C) bound to STX4 prevents fusion until STXBP3 is phosphorylated. Authored: May, B, 2011-07-12 Edited: May, B, 2011-07-12 Reactome Database ID Release 431449574 Reactome, http://www.reactome.org ReactomeREACT_147780 Reviewed: Klip, Amira, 2012-08-21 Proteinase-activated receptors Converted from EntitySet in Reactome Reactome DB_ID: 389458 Reactome Database ID Release 43389458 Reactome, http://www.reactome.org ReactomeREACT_17699 RAB8A/10/13/14 Hydrolyze GTP Authored: May, B, 2011-07-07 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: May, B, 2011-07-07 Pubmed15971998 RAB proteins have intrinsic weak GTPase activity that is enhanced by RAB-GTPase activating proteins (RAB-GAPs, Sano et al. 2007). The GTPase activity of RAB13 is inferred from other RAB proteins. AS160 (TBC1D4) and TBC1D1 are GAPs that activate the GTPase activity of RAB8A/10/13. Insulin signaling activates AKT, which phosphorylates and inactivates AS160 and TBC1D1, allowing GTP-bound (active) RABs to accumulate. Reactome Database ID Release 431445143 Reactome, http://www.reactome.org ReactomeREACT_147836 Reviewed: Klip, Amira, 2012-08-21 AKT2 Phosphorylates RGC2 As inferred from mouse, AKT2 (PKB-beta) phosphorylates RBC2 (RALGAPA2) on serine-486, serine-696, and threonine-715 in response to insulin. The phosphorylation prevents RBC1:RBC2 from activating RALA GTPase and allows RALA:GTP to accumulate. Authored: May, B, 2011-07-17 EC Number: 2.7.11 Edited: May, B, 2011-07-17 Reactome Database ID Release 431458463 Reactome, http://www.reactome.org ReactomeREACT_147852 Reviewed: Klip, Amira, 2012-08-21 has a Stoichiometric coefficient of 3 Activation of RALA Authored: May, B, 2012-05-16 Edited: May, B, 2012-05-16 Pubmed2550440 Pubmed8094051 RALA Exchanges GDP for GTP RALA releases GDP and binds GTP, producing the active form of RALA. The reaction is accelerated by guanine nucleotide exchange factors (GEFs) and opposed by GTPase-activating proteins (GAPs) which enhance the conversion of RALA:GTP back to RALA:GDP by activating the GTPase activity of RALA. Reactome Database ID Release 432255342 Reactome, http://www.reactome.org ReactomeREACT_147712 Reviewed: Klip, Amira, 2012-08-21 RALA:GTP Activates MYO1C As inferred from mouse, insulin causes phosphorylation and inactivation of the Ral GTPase activating complex RGC, causing RALA:GTP to accumulate and associate with the unconventional myosin MYO1C. MYO1C, with calmodulin as a light chain, motors across cortical actin and interacts with the exocyst complex to tether vesicles at the plasma membrane (Chen et al. 2007). Authored: May, B, 2012-05-27 Edited: May, B, 2012-05-27 Reactome Database ID Release 432316349 Reactome, http://www.reactome.org ReactomeREACT_147829 Reviewed: Klip, Amira, 2012-08-21 Galanin receptor Converted from EntitySet in Reactome Reactome DB_ID: 389011 Reactome Database ID Release 43389011 Reactome, http://www.reactome.org ReactomeREACT_17295 ACTIVATION GENE ONTOLOGYGO:0004766 Reactome Database ID Release 43351209 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004014 Reactome Database ID Release 43351211 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004145 Reactome Database ID Release 43351231 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016768 Reactome Database ID Release 43351216 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004586 Reactome Database ID Release 4370691 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008783 Reactome Database ID Release 43351161 Reactome, http://www.reactome.org FPRL2 ligands Converted from EntitySet in Reactome Reactome DB_ID: 444545 Reactome Database ID Release 43444545 Reactome, http://www.reactome.org ReactomeREACT_21470 ACTIVATION GENE ONTOLOGYGO:0052904 Reactome Database ID Release 43141347 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004145 Reactome Database ID Release 43351231 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052904 Reactome Database ID Release 43141347 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052901 Reactome Database ID Release 43266190 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008483 Reactome Database ID Release 431295495 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0010309 Reactome Database ID Release 431237139 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0043874 Reactome Database ID Release 431237084 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046570 Reactome Database ID Release 431237163 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046523 Reactome Database ID Release 431237154 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046523 Reactome Database ID Release 431237154 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017061 Reactome Database ID Release 431237143 Reactome, http://www.reactome.org NrCAM binds axonin-1 Authored: Garapati, P V, 2008-07-30 10:22:58 Axonin-1 expressed on the commissural axons interacts in trans with NrCAM expressed on floor plate. This interaction is required for commissural axons to enter the floor plate and cross the midline. Edited: Garapati, P V, 2008-07-30 10:22:58 Reactome Database ID Release 43445067 Reactome, http://www.reactome.org ReactomeREACT_22203 Reviewed: Maness, PF, 2010-02-16 Neurofascin interacts with syntenin-1 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed11152476 Reactome Database ID Release 43373738 Reactome, http://www.reactome.org ReactomeREACT_22139 Reviewed: Maness, PF, 2010-02-16 Syntenin-1 is an intracellular binding partner of neurofascin. Syntenin-1 contains two PDZ domains; the second one is a binding site for the COOH terminus of neurofascin. Doublecortin binds phosphorylated neurofascin Authored: Garapati, P V, 2008-07-30 10:22:58 Doublecortin is a microtubule associated protein expressed in neurons. Mutated doublecortin has been linked to the neuronal migration disorder X linked subcortical laminar heterotopia (double cortex)/lissencephaly. It binds neurofascin when the FIGQY motif of the latter protein is phosphorylated. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed12223548 Reactome Database ID Release 43437243 Reactome, http://www.reactome.org ReactomeREACT_22165 Reviewed: Maness, PF, 2010-02-16 NrCAM binds Ankyrin-G Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 NrCAM is expressed specifically at node of ranvier where it interacts with the cytoskeletal adaptor protein ankyrin-G with the conserved motif F1272IGQY. Reactome Database ID Release 43447030 Reactome, http://www.reactome.org ReactomeREACT_22306 Reviewed: Maness, PF, 2010-02-16 TRH Converted from EntitySet in Reactome Reactome DB_ID: 444529 Reactome Database ID Release 43444529 Reactome, http://www.reactome.org ReactomeREACT_21461 Thyrotropin releasing hormone Neurofascin binds contactin-1:CASPR complex Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Neurofascin, expressed at the paranodal loop might be the glial receptor for the paranodin/Caspr-contactin complex. Neurofascin-Caspr-contactin complex forms the core structure of paranodal junctions. Pubmed11839274 Reactome Database ID Release 43373733 Reactome, http://www.reactome.org ReactomeREACT_22413 Reviewed: Maness, PF, 2010-02-16 Trans-homodimerization of Neurofascin Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Interaction with ankyrins mediates the lateral oligomerization of neurofascin and this lateral oligomerization enhances its homophilic trans-adhesion. Pubmed9371782 Pubmed9804856 Reactome Database ID Release 43443774 Reactome, http://www.reactome.org ReactomeREACT_22248 Reviewed: Maness, PF, 2010-02-16 Neurofascin binds Ankyrin-G Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed9804856 Reactome Database ID Release 43373729 Reactome, http://www.reactome.org ReactomeREACT_22341 Reviewed: Maness, PF, 2010-02-16 The cytoplasmic domains of neurofascin contains a highly conserved sequence (F1315IGQY) that binds ankyrin. The membrane binding domain of ankyrin has two distinct binding sites for neurofascin and is proposed to form lateral complexes between ion channels and cell adhesion molecules as well as to couple these proteins to the spectrin based membrane skeleton. Phosphorylation of Neurofascin Authored: Garapati, P V, 2008-07-30 10:22:58 EC Number: 2.7.10 Edited: Garapati, P V, 2008-07-30 10:22:58 Reactome Database ID Release 43445091 Reactome, http://www.reactome.org ReactomeREACT_22202 Reviewed: Maness, PF, 2010-02-16 The highly conserved FIGQY motif in the cytoplasmic domain of neurofascin is phosphorylated by tyrosine kinases in response to external signals. Phosphorylation of the tyrosine in the FIGQY motif inhibits ankyrin binding. Neurofascin and NrCAM heterodimerization Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Neurofascin and NrCAM proteins undergo heterophilic interaction with one another with their extracellular Ig like domains and promote axon outgrowth. Pubmed8922386 Reactome Database ID Release 43373730 Reactome, http://www.reactome.org ReactomeREACT_22108 Reviewed: Maness, PF, 2010-02-16 Prokineticin receptors Converted from EntitySet in Reactome Reactome DB_ID: 444628 Reactome Database ID Release 43444628 Reactome, http://www.reactome.org ReactomeREACT_21481 CHL1 interacts with contactin-6 Authored: Garapati, P V, 2008-07-30 10:22:58 Close homolog of L1 (CHL1), associates with Contactin-6/NB-3, a member of the F3/contactin family of neural recognition molecules, and enhances its cell surface expression. CHL1 and NB3 may engage in a cis-interaction and form a coreceptor/adhesion complex on the neuronal surface.<br>CHL1/NB3 clustering activates protein tyrosine phosphatase alpha (PTP alpha), which dephosphorylates and activates Fyn. Both PTP alpha and Fyn are required for proper apical dendrite orientation of deep layer pyramidal neurons. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed18760361 Reactome Database ID Release 43443782 Reactome, http://www.reactome.org ReactomeREACT_22372 Reviewed: Maness, PF, 2010-02-16 ACTIVATION GENE ONTOLOGYGO:0004058 Reactome Database ID Release 43209894 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004511 Reactome Database ID Release 43209959 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016212 Reactome Database ID Release 43893618 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047102 Reactome Database ID Release 4371238 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004087 Reactome Database ID Release 4370552 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004042 Reactome Database ID Release 4370539 Reactome, http://www.reactome.org Prokineticin Converted from EntitySet in Reactome Reactome DB_ID: 444692 Reactome Database ID Release 43444692 Reactome, http://www.reactome.org ReactomeREACT_21551 ACTIVATION GENE ONTOLOGYGO:0004585 Reactome Database ID Release 4370559 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004055 Reactome Database ID Release 4370576 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004056 Reactome Database ID Release 4370572 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004053 Reactome Database ID Release 4370568 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004053 Reactome Database ID Release 43452020 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000064 Reactome Database ID Release 4370633 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050353 Reactome Database ID Release 4371103 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015068 Reactome Database ID Release 4371274 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008336 Reactome Database ID Release 4371111 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004028 Reactome Database ID Release 4371259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004372 Reactome Database ID Release 4371248 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004111 Reactome Database ID Release 43200365 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005309 Reactome Database ID Release 43200397 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008168 Reactome Database ID Release 4371283 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004111 Reactome Database ID Release 43200322 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008792 Reactome Database ID Release 43351146 Reactome, http://www.reactome.org Phosphorylation of R-SMAD2/3 by NODAL Receptor Authored: May, B, 2011-01-27 EC Number: 2.7.11 Edited: May, B, 2011-01-27 NODAL receptors signal by phosphorylating SMAD2 and SMAD3 (Bondestam et al. 2001, Kumar et al. 2001, DaCosta Byfield et al. 2004). As in TGF-beta signaling, Smad anchor for receptor activation (SARA) may bind and present SMAD2 and SMAD3 for phosphorylation but this has not yet been demonstrated in NODAL signaling. Pubmed11024047 Pubmed12063393 Pubmed14978253 Reactome Database ID Release 431181355 Reactome, http://www.reactome.org ReactomeREACT_111138 Reviewed: Peng, C, 2011-08-24 has a Stoichiometric coefficient of 2 Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXO3 Binds FoxO3a-binding Elements Authored: May, B, 2011-08-26 Edited: May, B, 2011-08-26 FOXO3 (FOXO3A) interacts with phospho-SMAD2 and phospho-SMAD3 complexed with CO-SMAD (SMAD4) at a promoter containing the FoxO3a-binding Element (Fu and Peng 20110). Pubmed21532621 Reactome Database ID Release 431535903 Reactome, http://www.reactome.org ReactomeREACT_111216 Reviewed: Peng, C, 2011-08-24 Larg Converted from EntitySet in Reactome Reactome DB_ID: 195099 Reactome Database ID Release 43195099 Reactome, http://www.reactome.org ReactomeREACT_10641 Type II Activin Receptor (ActRII/ACVR2) Phosphorylates Type I Activin Receptor (ActRIB/ACVR1B) in Response to NODAL As inferred from the response of the activin receptor to activin, the type II component of the NODAL receptor phosphorylates the type I component in response to NODAL binding. Experiments with human proteins in frog oocytes show NODAL can signal via the CRIPTO:ACVR1B(ALK4):ACVR2 complex (Yeo and Whitman 2001). Authored: May, B, 2011-01-23 EC Number: 2.7.11 Edited: May, B, 2011-01-23 Pubmed11389842 Reactome Database ID Release 431181156 Reactome, http://www.reactome.org ReactomeREACT_111131 Reviewed: Peng, C, 2011-08-24 has a Stoichiometric coefficient of 12 Type II Activin Receptor (ActRIIB/ACVR2B) Phosphorylates Type I Activin Receptor (ActRIC/ACVR1C) in Response to NODAL As inferred from the response of the activin receptor to activin, the type II component of the NODAL receptor phosphorylates the type I component in response to NODAL binding. As inferred from mouse and frog (Xenopus) NODAL can signal via the ACVR1C (ALK7) type I activin receptor (Reissman et al. 2001) though this may be dispensable for development in mouse (Jornvall et al. 2004). Authored: May, B, 2011-01-23 EC Number: 2.7.11 Edited: May, B, 2011-01-23 Pubmed11485994 Pubmed15485907 Pubmed21356369 Pubmed21383881 Reactome Database ID Release 431225894 Reactome, http://www.reactome.org ReactomeREACT_111130 Reviewed: Peng, C, 2011-08-24 has a Stoichiometric coefficient of 10 Fgd2 Converted from EntitySet in Reactome Reactome DB_ID: 195105 Reactome Database ID Release 43195105 Reactome, http://www.reactome.org ReactomeREACT_10936 PPARG:RXRA Heterodimer binds to PPARG corepressors Authored: May, B, 2009-05-15 01:16:49 Edited: May, B, 2009-05-15 01:16:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed17011499 Pubmed8970730 Reactome Database ID Release 43381290 Reactome, http://www.reactome.org ReactomeREACT_27280 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 The PPARG:RXRA heterodimer binds specific the PPRE element, two 6-bp DR-1 motifs separated by 1 nucleotide, in the promoters of target genes such as aP2/FABP4 even in the absence of fatty acid ligands that activate PPARG. When activating ligands of PPARG are absent PPARG:RXRA recruits corepressors such as NCoR2(SMRT), NCoR, and HDAC3 to maintain the target gene in an inactive state. PPARG:RXRA Heterodimer Binds to Fatty Acid-like Ligands Authored: May, B, 2009-05-15 01:16:49 Edited: May, B, 2009-05-15 01:16:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 PPARG can be activated in cell cultures by adding ligands such as polyunsaturated fatty acids and certain prostanoids (prostaglandins). Endogenous fatty acids are relatively poor activators. Which ligands are most responsible for PPARG activation in the body has not yet been established. Generally, oxidized fatty acids such as 9(S')-hydroxyoctadeca-10,12-dienoic acid (9(S')-HODE) and 13(S')-HODE are more effective activators than are endogenous fatty acids. The thiazolidinedione (TZD) class of antidiabetic drugs are agonist ligands for PPARG (Lambe and Tugwood 1996).<br>FABP4 delivers ligands to PPARG directly. Binding of activator ligands to PPARG causes loss of corepressors such as SMRT/NCoR2, NCoR1, and HDAC3 and gain of interactions with the basal transcription machinery (Yoo et al. 2006). The TRAP220/MED1/DRIP205 subunit of the TRAP/Mediator (DRIP) complex binds directly to the LXXLL motif of PPARG and TRAP/Mediator is necessary for full transcriptional activation of target genes (Ge et al. 2008). PPARG also interacts with the MED14 subunit of the Mediator complex (Grontved et al. 2010).<br>Other coactivators, including NCOA1/SRC-1, NCOA2/TIF2/GRIP1, CBP, HAT/p300, and PRIP, interact with PPARG in a ligand-dependent way and enhance transcription (Gellman et al. 1999, Wallberg et al. 2003, Yang et al. 2000, Ge et al. 2002, Puigserver et al. 1999, Bugge et al. 2009, Steger et al. 2010).<br>The target genes of PPARG encode proteins involved in adipocyte differentiation (PGAR/ANGPTL4, PLIN, and aP2/FABP4), carbohydrate metabolism (PEPCK-C), and fatty acid transport (FAT/CD36, LPL). Pubmed10075656 Pubmed17011499 Pubmed8706692 Pubmed8970730 Pubmed9065481 Reactome Database ID Release 43381309 Reactome, http://www.reactome.org ReactomeREACT_27257 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 LEFTY Binds the EGF-CFC Coreceptor in the NODAL Receptor Authored: May, B, 2011-01-27 Edited: May, B, 2011-01-27 LEFTY1 and LEFTY2 are able to inhibit NODAL signaling by binding the EGF-CFC coreceptor (CRIPTO or CRYPTIC) and thereby preventing the coreceptor from interacting with other components of the NODAL receptor. Reactome Database ID Release 431181351 Reactome, http://www.reactome.org ReactomeREACT_111240 Reviewed: Peng, C, 2011-08-24 Formation of PPARG:RXRA Heterodimer (ARF6 Complex) Authored: May, B, 2009-05-15 01:16:49 Edited: May, B, 2009-05-15 01:16:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 PPARG binds the Retinoic acid X Receptor RXRA to form a heterodimer that has transcriptional acivation activity. The complex was initially called ARF6 when discovered. PPARG binds RXRA via the C-terminus and AF-2 regions of PPARG. Pubmed17011499 Pubmed17980149 Pubmed19043829 Reactome Database ID Release 43381262 Reactome, http://www.reactome.org ReactomeREACT_27277 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 CERBERUS Binds NODAL As inferred from Xenopus (Piccolo 1999) CERBERUS binds NODAL and inhibits NODAL signaling. Authored: May, B, 2011-01-27 Edited: May, B, 2011-01-27 Pubmed10067895 Reactome Database ID Release 431181354 Reactome, http://www.reactome.org ReactomeREACT_111227 Reviewed: Peng, C, 2011-08-24 LEFTY Binds NODAL As inferred from mouse (Chen and Shen 2004) both LEFTY1 and LEFTY2 can bind NODAL and inhibit NODAL signaling. Authored: May, B, 2011-01-27 Edited: May, B, 2011-01-27 Pubmed15062104 Reactome Database ID Release 431181352 Reactome, http://www.reactome.org ReactomeREACT_111188 Reviewed: Peng, C, 2011-08-24 Dbl/MCF2 Converted from EntitySet in Reactome Reactome DB_ID: 194896 Reactome Database ID Release 43194896 Reactome, http://www.reactome.org ReactomeREACT_10193 Arf1 Activation by GBF1 Authored: Gillespie, ME, 2007-07-23 15:44:13 Pubmed10402461 Reactome Database ID Release 43199998 Reactome, http://www.reactome.org ReactomeREACT_11099 Reviewed: Rush, MG, 2008-01-11 00:00:00 The formation of the COPI coat requires membrane recruitment and activation of Arf1. Arf1 activation is normally mediated by guanine nucleotide exchange factors (GEFs) that convert Arf1 to its active GTP-bound state on the membrane. In this reaction that GEF is represented by GBF1. Coat Complex Formation Authored: Gillespie, ME, 2007-07-23 15:44:13 In models of COPI coat assembly and disassembly, after GBF1 activates Arf1 on membranes, the active form of Arf1 recruits coatomer complexes from the cytoplasm. Pubmed8599108 Reactome Database ID Release 43199990 Reactome, http://www.reactome.org ReactomeREACT_11243 Reviewed: Rush, MG, 2008-01-11 00:00:00 GAP Recruitment to the Coatomer:Arf1-GTP Complex Authored: Gillespie, ME, 2007-07-23 15:44:13 Once both coatomer and the active form of Arf1 have been recruited to the Golgi membrane surface, ArfGAP joins the complex. Pubmed8533093 Reactome Database ID Release 43200461 Reactome, http://www.reactome.org ReactomeREACT_11111 Reviewed: Rush, MG, 2008-01-11 00:00:00 Coatomer:Arf1-GTP:GAP lattice formation on golgi membrane Authored: Gillespie, ME, 2007-07-23 15:44:13 Edited: Gillespie, ME, 2007-07-18 23:13:28 Pubmed16956762 Reactome Database ID Release 43200462 Reactome, http://www.reactome.org ReactomeREACT_11126 Reviewed: Rush, MG, 2008-01-11 00:00:00 Together, the complex of coatomer, Arf1, and ArfGAP assembles into a lattice that concentrates cargo proteins and deforms the membrane. Eventually this membrane pocket forms into a bud that pinches off the membrane, and is released into the cytoplasm (Lippincott-Schwartz and Liu 2006). Smad7:SMURF1 complex binds XPO1 (CRM1) Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed12519765 Reactome Database ID Release 432169012 Reactome, http://www.reactome.org ReactomeREACT_121131 Reviewed: Huang, Tao, 2012-05-14 Smad7:SMURF1 complex, formed by exogenous expression of recombinant human SMURF1 and recombinant mouse Smad7 in COS7 cells, binds to XPO1 (CRM1). Recombinant XPO1 was also exogenously expressed in COS7 cells, and since the species origin of XPO1 is not specified in the paper by Tajima et al., it is assumed that XPO1 is of human origin (Tajima et al. 2003). trans-Golgi Network Coat Activation ARF1 helps to recruit AP-1 to Golgi membrane. AP-1 is not alone in this process of establishing a docking complex at the trans-Golgi Network. This section of the Golgi membrane will be where the new vesicle will be built and loaded. Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2008-05-21 20:31:41 Pubmed8810314 Pubmed9614177 Reactome Database ID Release 43350769 Reactome, http://www.reactome.org ReactomeREACT_14808 Reviewed: Rush, MG, 2008-01-11 00:00:00 Sculpting and pinching-off of Golgi vessicle All of the key components and regulators of the COPI coat (GBF1, Arf1, ArfGAP1 and coatomer) cycle on and off the Golgi membrane. This cycle is required for vesicle formation, but is uncoupled from the actual vesicle release. Continuous membrane binding and release of these molecules enables the COPI lattice to be dynamically modulated. Once the vesicle is released from the Golgi apparatus, this lattice is completely disassociated from the vesicle. Authored: Gillespie, ME, 2007-07-23 15:44:13 Pubmed12379802 Pubmed14654841 Reactome Database ID Release 43200516 Reactome, http://www.reactome.org ReactomeREACT_11138 Reviewed: Rush, MG, 2008-01-11 00:00:00 Hydrolysis of Arf1-GTP to Arf1-GDP Authored: Gillespie, ME, 2007-07-23 15:44:13 Pubmed15795316 Reactome Database ID Release 43200456 Reactome, http://www.reactome.org ReactomeREACT_11107 Reviewed: Rush, MG, 2008-01-11 00:00:00 The hydrolysis of Arf1-bound GTP is induced by the recruited ArfGAP. Diffusion of inactive Arf1-GDP from membrane Authored: Gillespie, ME, 2007-07-23 15:44:13 Inactive Arf1-GDP then diffuses away from the membrane, initiating the disassembly of the lattice. Pubmed15795316 Reactome Database ID Release 43200459 Reactome, http://www.reactome.org ReactomeREACT_11073 Reviewed: Rush, MG, 2008-01-11 00:00:00 Golgi vesicle lattice disassociation Authored: Gillespie, ME, 2007-07-23 15:44:13 Pubmed16956762 Reactome Database ID Release 43200604 Reactome, http://www.reactome.org ReactomeREACT_11078 Reviewed: Rush, MG, 2008-01-11 00:00:00 Ultimately the hydrolysis of Arf1-bound GTP, induced by the recruited ArfGAP, allows the inactive Arf1-GDP to diffuse away from the membrane, initiating disassembly of the lattice from the vesicle (Lippincott-Schwartz and Liu 2006). ACTIVATION GENE ONTOLOGYGO:0004500 Reactome Database ID Release 43209827 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004603 Reactome Database ID Release 43209780 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015111 Reactome Database ID Release 43209801 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004601 Reactome Database ID Release 43209956 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004601 Reactome Database ID Release 43209956 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016491 Reactome Database ID Release 43209848 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004601 Reactome Database ID Release 43209956 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016491 Reactome Database ID Release 43209848 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004601 Reactome Database ID Release 43209956 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004601 Reactome Database ID Release 43209956 Reactome, http://www.reactome.org NrCAM binds synapse-associated proteins Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 NrCAM is the only mammalian L1CAM family member containing a consensus PDZ binding motif. NrCAM interacts with the PDZ domain containing proteins SAP-102, SAP-95 and SAP-97 and recruits them to the cell membrane. These SAP family members are colocalized with NrCAM in photoreceptor cells of the mammalian retina. Pubmed16882004 Reactome Database ID Release 43376134 Reactome, http://www.reactome.org ReactomeREACT_22222 Reviewed: Maness, PF, 2010-02-16 NrCAM binds Neuropilin-2 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 NrCAM associates with NP2 and is required for Sema3B- and Sema3F-induced attractive and repulsive responses. Pubmed16202709 Reactome Database ID Release 43549060 Reactome, http://www.reactome.org ReactomeREACT_22402 Reviewed: Maness, PF, 2010-02-16 Bnip2 interacts with CDO complex Authored: Garapati, P V, 2008-08-11 10:36:48 Bnip-2 is a scaffold protein with a single recognizable motif, a BCH domain that spans its C-terminal half involved in the dynamic regulation of Cdc42 signaling. The CDO intracellular region binds Bnip-2 and this complex regulates Cdc42 activity. Edited: Garapati, P V, 2008-08-11 10:36:48 Pubmed18678706 Reactome Database ID Release 43376121 Reactome, http://www.reactome.org ReactomeREACT_21336 Reviewed: Krauss, RS, 2010-02-09 Interaction of Bnip-2 with Cdc42 Authored: Garapati, P V, 2008-08-11 10:36:48 Bnip-2 interacts with Cdc42 through its Bnip-2 and Cdc42GAP homology (BCH) domain and thus it acts as a linkage between the CDO receptor and the Cdc42 activity. Formation of a CDO-Bnip-2-Cdc42 complex stimulates Cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation. Edited: Garapati, P V, 2008-08-11 10:36:48 Pubmed18678706 Reactome Database ID Release 43376119 Reactome, http://www.reactome.org ReactomeREACT_21249 Reviewed: Krauss, RS, 2010-02-09 CDO binds BOC Authored: Garapati, P V, 2008-08-11 10:36:48 CDO and BOC form complexes in a cis fashion via association of both their ectodomains and their intracellular domains. CDO and BOC exert their effects as components of a receptor, in which the role of BOC is primarily extracellular and that of CDO includes intracellular signaling. Edited: Garapati, P V, 2008-08-11 10:36:48 Pubmed11782431 Pubmed9786951 Reactome Database ID Release 43375138 Reactome, http://www.reactome.org ReactomeREACT_21377 Reviewed: Krauss, RS, 2010-02-09 CDO binds promyogenic cadherins Authored: Garapati, P V, 2008-08-11 10:36:48 Edited: Garapati, P V, 2008-08-11 10:36:48 In myoblasts, CDO forms cis complexes with the cell–cell adhesion molecule N-cadherin, which is itself involved in regulation of myogenesis. These cadherin complexes contain beta- and alpha-catenins which are important for N-cadherin's effect in myoblast. When CDO binds with ligated cadherins, its intracellular region undergoes a change in conformation and/or posttranslational modi?cation that permits its stable association with Bnip-2 and JLP and, consequently, activation of p38. Pubmed12634428 Pubmed15520228 Pubmed20160094 Reactome Database ID Release 43375140 Reactome, http://www.reactome.org ReactomeREACT_21371 Reviewed: Krauss, RS, 2010-02-09 Interaction of p38 MAPK with JLP Authored: Garapati, P V, 2008-08-11 10:36:48 Edited: Garapati, P V, 2008-08-11 10:36:48 JLP is a p38 alpha/beta MAPK scaffold protein. p38 alpha/beta MAPK binds to two sites within JLP (amino acids 1-110 and 160-209), neither of which overlaps the CDO binding region. Reactome Database ID Release 43448957 Reactome, http://www.reactome.org ReactomeREACT_21282 Reviewed: Krauss, RS, 2010-02-09 Activation of p38 alpha/beta MAPK Authored: Garapati, P V, 2008-08-11 10:36:48 Edited: Garapati, P V, 2008-08-11 10:36:48 Reactome Database ID Release 43448951 Reactome, http://www.reactome.org ReactomeREACT_21301 Reviewed: Krauss, RS, 2010-02-09 has a Stoichiometric coefficient of 5 p38 alpha/beta MAPK is well established as a promyogenic kinase, but the mechanism by which it is activated during differentiation is not well understood. CDO, JLP and p38 form a ternary complex and it is anticipated that in its role as a scaffold, JLP brings additional components of the pathway, such as MKKs, to these complexes and cooperate to activate p38 alpha/beta MAPK pathway. p38 is activated by phosphorylation on a canonical TxY motif by dual specificity kinases MKK6 and MKK3. MKK6 is the most abundant in skeletal muscles and displays minimal substrate selectivity among all p38 isoforms. JLP interacts with CDO complex Authored: Garapati, P V, 2008-08-11 10:36:48 Edited: Garapati, P V, 2008-08-11 10:36:48 JLP is a scaffold protein for the p38 MAPK pathway. During myogenic differentiation JLP binds the intracellular region of CDO which in turn binds p38 leading to p38 activation. The major CDO-binding region of JLP resides between amino acids 465-647. Pubmed17074887 Reactome Database ID Release 43376117 Reactome, http://www.reactome.org ReactomeREACT_21386 Reviewed: Krauss, RS, 2010-02-09 Interaction of ABL1 with CDO complex ABL binds to the cytoplasmic tail of CDO and also to the p38 MAPK scaffold protein JLP. ABL binds a proline-rich motif in CDO via its SH3 domain, and ABL is necessary for full activation of p38 MAPK, during myogenic differentiation. Authored: Garapati, P V, 2008-08-11 10:36:48 Edited: Garapati, P V, 2008-08-11 10:36:48 Reactome Database ID Release 43449200 Reactome, http://www.reactome.org ReactomeREACT_21341 Reviewed: Krauss, RS, 2010-02-09 ACTIVATION GENE ONTOLOGYGO:0004800 Reactome Database ID Release 43350862 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004058 Reactome Database ID Release 43209894 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004059 Reactome Database ID Release 43209902 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004800 Reactome Database ID Release 43350898 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004510 Reactome Database ID Release 43209966 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003884 Reactome Database ID Release 43389825 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008453 Reactome Database ID Release 43389659 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008172 Reactome Database ID Release 43209807 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 43378987 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008453 Reactome Database ID Release 43904847 Reactome, http://www.reactome.org Nuclear translocation of p38 MAPK Authored: Garapati, P V, 2008-08-11 10:36:48 Edited: Garapati, P V, 2008-08-11 10:36:48 Pubmed10601328 Pubmed19564926 Reactome Database ID Release 43448958 Reactome, http://www.reactome.org ReactomeREACT_21288 Reviewed: Krauss, RS, 2010-02-09 p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors. Phosphorylation of E proteins by p38 MAPK Authored: Garapati, P V, 2008-08-11 10:36:48 EC Number: 2.7.11 Edited: Garapati, P V, 2008-08-11 10:36:48 Reactome Database ID Release 43448948 Reactome, http://www.reactome.org ReactomeREACT_21321 Reviewed: Krauss, RS, 2010-02-09 p38 MAPK plays a fundamental role in the transition of myoblasts to different myocytes. Activated p38 MAPK phosphorylates E12/E47, a member of the E protein subfamily of bHLH proteins. p38 MAPK in particular phosphorylates Ser140 of E47. Its been observed that phosphorylation of E47 improves its ability to form heterodimers with Myod transcription factor. Heterodimerization of E proteins with Myod Authored: Garapati, P V, 2008-08-11 10:36:48 Edited: Garapati, P V, 2008-08-11 10:36:48 MyoD is a basic helix loop helix (bHLH) myoblast specific transcription factor defined as a 'master switch' gene in that it can convert other cell types into muscles if the gene is active in them. bHLH proteins Myf5, Myogenin and MRF4/Myf6 are highly related to MyoD and these along with MyoD form the 'MyoD family' of transcription factors, also called the myogenic regulatory factors (MRFs). <br>MRFs form transcriptionally active heterodimers with the widely expressed E proteins, a distinct group of bHLH proteins including E12/E47, ITF-2 and HEB. Dimerization of these proteins juxtaposes their basic domains forming a functional DNA binding domain. MyoD/E protein heterodimers preferentially bind the DNA consensus sequence referred to as an E-box (CANNTG) in the control regions of muscle-specific genes and activate gene transcription of genes that are expressed in skeletal muscle. Reactome Database ID Release 43448962 Reactome, http://www.reactome.org ReactomeREACT_21420 Reviewed: Krauss, RS, 2010-02-09 Phosphorylation of MEF2 proteins by p38 Authored: Garapati, P V, 2008-08-11 10:36:48 EC Number: 2.7.11 Edited: Garapati, P V, 2008-08-11 10:36:48 Pubmed10330143 Pubmed10805738 Pubmed9069290 Pubmed9858528 Pubmed9988769 Reactome Database ID Release 43448955 Reactome, http://www.reactome.org ReactomeREACT_21276 Reviewed: Krauss, RS, 2010-02-09 The family of transcription factors myocyte enhancer factor-2 (MEF2) regulate myogenesis through combinatorial interactions with other transcription factors to the MEF2 site found in the promoter regions of numerous muscle specific genes. There are four members of the MEF2 family, MEF2A to D.<br>p38 MAPK plays a role in the regulation of the MEF2 family members and this is mediated by the phosphorylation of two or three (Thr312 and 319 in MEF2A and Thr 293, 300 and ser387 in MEF2C) amino acids in the C-terminal activation domain of MEF2 factors. MEF2A and MEF2C are preferred substrates for p38 compared with MEF2B and MEF2D. The phosphorylation of MEF2 members results in their increased transcriptional activity. has a Stoichiometric coefficient of 5 Interaction of MyoD:E protein with MEF2 Authored: Garapati, P V, 2008-08-11 10:36:48 Edited: Garapati, P V, 2008-08-11 10:36:48 MyoD-E protein heterodimers interact with MEF2 proteins to synergistically activate myogenesis. This interaction occurs via association of these two heterologous classes of transcription factors through their DNA-binding and dimerization motifs. The combinatorial associations of these two protein families appear to establish a transcriptional code specific for skeletal muscle gene activation. Together with the Mef2 proteins and E proteins, MyoD transcription factors are responsible for coordinating muscle-specific gene expression in the undifferentiated myoblast. MyoD activation leads to expression of myogenin, M-cadherin, myosin heavy and light chains, and muscle creatine kinase. Pubmed9418854 Reactome Database ID Release 43448963 Reactome, http://www.reactome.org ReactomeREACT_21369 Reviewed: Krauss, RS, 2010-02-09 Neogenin:Netrin-3 binds CDO complex Authored: Garapati, P V, 2008-08-11 10:36:48 CDO selectively binds to neogenin in a cis fashion and this interaction involves extracellular domains of both proteins. CDO is essential in mediating netrin-3-induced differentiation of myoblasts by neogenin. Neogenin and netrin-3 stimulate myotube formation and enhance myogenic bHLH-and NFAT-dependent transcription. Edited: Garapati, P V, 2008-08-11 10:36:48 Pubmed17137827 Reactome Database ID Release 43375141 Reactome, http://www.reactome.org ReactomeREACT_21315 Reviewed: Krauss, RS, 2010-02-09 AKT phosphorylates FOXO1A Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- EC Number: 2.7.11 Edited: D'Eustachio, P, 2008-05-12 21:43:33 One or more of the isoforms of AKT catalyzes the phosphorylation of FOXO1A protein at three sites, threonine-24, serine-256, and serine-319 (Zhang et al. 2002, 2006). This reaction occurs in the nucleoplasm, and thus is dependent on the phosphorylation and nuclear import of AKT in response to upstream regulatory factors (Burgering and Kops 2002). Pubmed12114024 Pubmed12228231 Pubmed16540465 Reactome Database ID Release 43211164 Reactome, http://www.reactome.org ReactomeREACT_12430 Reviewed: Jensen, J, 2008-05-12 21:46:53 has a Stoichiometric coefficient of 3 Phosphorylated FOXO1A is excluded from the nucleus Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Phosphorylated FOXO1A is transported from the nucleoplasm to the cytosol (Zhang et al. 2002). Pubmed12228231 Reactome Database ID Release 43211178 Reactome, http://www.reactome.org ReactomeREACT_13699 Reviewed: Jensen, J, 2008-05-12 21:46:53 Cleavage of NODAL Proprotein Authored: May, B, 2011-01-23 EC Number: 3.4.21 Edited: May, B, 2011-01-23 Either FURIN or PACE4 endoproteases cleave the 321 amino acid NODAL proprotein to yield the 110 amino acid NODAL mature protein. In cultured mouse cells the CRIPTO coreceptor at the plasma membrane recruits both NODAL proprotein and FURIN or PACE4 endoprotease. Reactome Database ID Release 431181152 Reactome, http://www.reactome.org ReactomeREACT_111228 Reviewed: Peng, C, 2011-08-24 The NODAL Receptor Binds NODAL Ligands Authored: May, B, 2011-01-23 Edited: May, B, 2011-01-23 NODAL binds a receptor comprising a type I activin receptor (ACVR1B or ACVR1C), a type II activin receptor (ACVR2 or ACVR2B), and a EGF-CFC coreceptor (CRIPTO or CRYPTIC). Though NODAL is able to signal via the ACVR1C (ALK7) receptor (Reissman et al. 2001), experiments in mouse indicate NODAL signaling via ALK7 is dispensable during embryogenesis (Jornvall et al. 2004). Pubmed15150278 Pubmed15485907 Pubmed15531507 Pubmed21229555 Pubmed21356369 Reactome Database ID Release 431181155 Reactome, http://www.reactome.org ReactomeREACT_111250 Reviewed: Peng, C, 2011-08-24 Vav3 Converted from EntitySet in Reactome Reactome DB_ID: 195062 Reactome Database ID Release 43195062 Reactome, http://www.reactome.org ReactomeREACT_10807 NBR Converted from EntitySet in Reactome Reactome DB_ID: 194999 Reactome Database ID Release 43194999 Reactome, http://www.reactome.org ReactomeREACT_10209 FGFR2b short homodimer Reactome DB_ID: 192612 Reactome Database ID Release 43192612 Reactome, http://www.reactome.org ReactomeREACT_9848 has a Stoichiometric coefficient of 2 FGFR2c homodimer bound to FGF Converted from EntitySet in Reactome Reactome DB_ID: 192594 Reactome Database ID Release 43192594 Reactome, http://www.reactome.org ReactomeREACT_9689 FGFR2c long homodimer bound to FGF Reactome DB_ID: 190225 Reactome Database ID Release 43190225 Reactome, http://www.reactome.org ReactomeREACT_9599 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR2c long homodimer Reactome DB_ID: 190231 Reactome Database ID Release 43190231 Reactome, http://www.reactome.org ReactomeREACT_9894 has a Stoichiometric coefficient of 2 FGFR1c homodimer bound to FGF Reactome DB_ID: 190233 Reactome Database ID Release 43190233 Reactome, http://www.reactome.org ReactomeREACT_9629 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR1c homodimer Reactome DB_ID: 190222 Reactome Database ID Release 43190222 Reactome, http://www.reactome.org ReactomeREACT_9800 has a Stoichiometric coefficient of 2 FGFR2b homodimer bound to FGF Converted from EntitySet in Reactome Reactome DB_ID: 192615 Reactome Database ID Release 43192615 Reactome, http://www.reactome.org ReactomeREACT_9654 FGFR2b long homodimer bound to FGF Reactome DB_ID: 190227 Reactome Database ID Release 43190227 Reactome, http://www.reactome.org ReactomeREACT_9806 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR2b long homodimer Reactome DB_ID: 190230 Reactome Database ID Release 43190230 Reactome, http://www.reactome.org ReactomeREACT_9871 has a Stoichiometric coefficient of 2 FGFR2b short homodimer bound to FGF Reactome DB_ID: 192591 Reactome Database ID Release 43192591 Reactome, http://www.reactome.org ReactomeREACT_9579 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Fgd4 Converted from EntitySet in Reactome Frabin Reactome DB_ID: 194997 Reactome Database ID Release 43194997 Reactome, http://www.reactome.org ReactomeREACT_10429 Intersectin1 Converted from EntitySet in Reactome Reactome DB_ID: 194990 Reactome Database ID Release 43194990 Reactome, http://www.reactome.org ReactomeREACT_10314 Ephexin1/Ngef Converted from EntitySet in Reactome Reactome DB_ID: 194973 Reactome Database ID Release 43194973 Reactome, http://www.reactome.org ReactomeREACT_10772 Collagen alpha-2(XI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192884 Reactome Database ID Release 432192884 Reactome, http://www.reactome.org ReactomeREACT_121792 IGF2BP3:RNA Complex Reactome DB_ID: 428310 Reactome Database ID Release 43428310 Reactome, http://www.reactome.org ReactomeREACT_23052 has a Stoichiometric coefficient of 1 FGFR1b homodimer bound to FGF Reactome DB_ID: 190226 Reactome Database ID Release 43190226 Reactome, http://www.reactome.org ReactomeREACT_9772 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 IGF2BP1:RNA Complex Reactome DB_ID: 428327 Reactome Database ID Release 43428327 Reactome, http://www.reactome.org ReactomeREACT_23009 has a Stoichiometric coefficient of 1 IGF2BP2:RNA Complex Reactome DB_ID: 428335 Reactome Database ID Release 43428335 Reactome, http://www.reactome.org ReactomeREACT_22864 has a Stoichiometric coefficient of 1 FGFR1b homodimer Reactome DB_ID: 190228 Reactome Database ID Release 43190228 Reactome, http://www.reactome.org ReactomeREACT_9721 has a Stoichiometric coefficient of 2 IGF:IGFBP-2 Complex Reactome DB_ID: 381473 Reactome Database ID Release 43381473 Reactome, http://www.reactome.org ReactomeREACT_17076 has a Stoichiometric coefficient of 1 IGF:IGFBP-5:ALS Complex Reactome DB_ID: 381423 Reactome Database ID Release 43381423 Reactome, http://www.reactome.org ReactomeREACT_15736 has a Stoichiometric coefficient of 1 IGF:IGFBP-6 Complex Reactome DB_ID: 381482 Reactome Database ID Release 43381482 Reactome, http://www.reactome.org ReactomeREACT_16051 has a Stoichiometric coefficient of 1 IGF:IGFBP-3:ALS Complex Reactome DB_ID: 381536 Reactome Database ID Release 43381536 Reactome, http://www.reactome.org ReactomeREACT_17086 has a Stoichiometric coefficient of 1 IGF:IGFBP-4 Complex Reactome DB_ID: 381509 Reactome Database ID Release 43381509 Reactome, http://www.reactome.org ReactomeREACT_15846 has a Stoichiometric coefficient of 1 Trio Converted from EntitySet in Reactome Reactome DB_ID: 195037 Reactome Database ID Release 43195037 Reactome, http://www.reactome.org ReactomeREACT_10311 Collagen alpha-1(XI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192881 Reactome Database ID Release 432192881 Reactome, http://www.reactome.org ReactomeREACT_122093 Tiam2 Converted from EntitySet in Reactome Reactome DB_ID: 195026 Reactome Database ID Release 43195026 Reactome, http://www.reactome.org ReactomeREACT_10996 PERK Homodimer Reactome DB_ID: 381126 Reactome Database ID Release 43381126 Reactome, http://www.reactome.org ReactomeREACT_18942 has a Stoichiometric coefficient of 2 IGF:IGFBP-1 Complex Reactome DB_ID: 381539 Reactome Database ID Release 43381539 Reactome, http://www.reactome.org ReactomeREACT_18201 has a Stoichiometric coefficient of 1 IRE1 homodimer Reactome DB_ID: 381200 Reactome Database ID Release 43381200 Reactome, http://www.reactome.org ReactomeREACT_18870 has a Stoichiometric coefficient of 2 IRE1 homodimer (phosphorylated) Reactome DB_ID: 381154 Reactome Database ID Release 43381154 Reactome, http://www.reactome.org ReactomeREACT_19024 has a Stoichiometric coefficient of 2 IRE1 homodimer (phosphorylated):ADP Reactome DB_ID: 381078 Reactome Database ID Release 43381078 Reactome, http://www.reactome.org ReactomeREACT_18755 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PERK:BiP Heterodimer Reactome DB_ID: 381216 Reactome Database ID Release 43381216 Reactome, http://www.reactome.org ReactomeREACT_18951 has a Stoichiometric coefficient of 1 Exocyst Complex Reactome DB_ID: 264974 Reactome Database ID Release 43264974 Reactome, http://www.reactome.org ReactomeREACT_15928 has a Stoichiometric coefficient of 1 ATF6-alpha:BiP Reactome DB_ID: 381168 Reactome Database ID Release 43381168 Reactome, http://www.reactome.org ReactomeREACT_18758 has a Stoichiometric coefficient of 1 BiP:Unfolded Protein Reactome DB_ID: 381062 Reactome Database ID Release 43381062 Reactome, http://www.reactome.org ReactomeREACT_18551 has a Stoichiometric coefficient of 1 IRE1:BiP Reactome DB_ID: 381202 Reactome Database ID Release 43381202 Reactome, http://www.reactome.org ReactomeREACT_18771 has a Stoichiometric coefficient of 1 Asef Converted from EntitySet in Reactome Reactome DB_ID: 195064 Reactome Database ID Release 43195064 Reactome, http://www.reactome.org ReactomeREACT_10424 Cathepsin Converted from EntitySet in Reactome Reactome DB_ID: 2130544 Reactome Database ID Release 432130544 Reactome, http://www.reactome.org ReactomeREACT_121862 Prex-1 Converted from EntitySet in Reactome Reactome DB_ID: 195059 Reactome Database ID Release 43195059 Reactome, http://www.reactome.org ReactomeREACT_10507 Obscurin Converted from EntitySet in Reactome Reactome DB_ID: 195053 Reactome Database ID Release 43195053 Reactome, http://www.reactome.org ReactomeREACT_10994 Insulin-Zinc-Calcium Complex Reactome DB_ID: 264931 Reactome Database ID Release 43264931 Reactome, http://www.reactome.org ReactomeREACT_15628 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 6 Proinsulin-Zinc-Calcium Complex (golgi) Reactome DB_ID: 264908 Reactome Database ID Release 43264908 Reactome, http://www.reactome.org ReactomeREACT_15839 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 6 Proinsulin-Zinc-Calcium Complex (granule) Reactome DB_ID: 265073 Reactome Database ID Release 43265073 Reactome, http://www.reactome.org ReactomeREACT_17973 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 6 Nucleosome (Deacetylated) Reactome DB_ID: 977585 Reactome Database ID Release 43977585 Reactome, http://www.reactome.org ReactomeREACT_76035 has a Stoichiometric coefficient of 2 Serum amyloid P-component pentamer:Double-stranded DNA Reactome DB_ID: 977223 Reactome Database ID Release 43977223 Reactome, http://www.reactome.org ReactomeREACT_76462 has a Stoichiometric coefficient of 1 Serum amyloid P decamer Reactome DB_ID: 976787 Reactome Database ID Release 43976787 Reactome, http://www.reactome.org ReactomeREACT_76463 has a Stoichiometric coefficient of 2 Chromatin Reactome DB_ID: 977584 Reactome Database ID Release 43977584 Reactome, http://www.reactome.org ReactomeREACT_76335 has a Stoichiometric coefficient of 1 Insulin Glulisine (Apidra) Reactome DB_ID: 429472 Reactome Database ID Release 43429472 Reactome, http://www.reactome.org ReactomeREACT_76638 has a Stoichiometric coefficient of 1 Amyloid fibrils Reactome DB_ID: 977084 Reactome Database ID Release 43977084 Reactome, http://www.reactome.org ReactomeREACT_76626 has a Stoichiometric coefficient of 1 Insulin Aspart (Novolog) Reactome DB_ID: 429352 Reactome Database ID Release 43429352 Reactome, http://www.reactome.org ReactomeREACT_76084 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0003842 Reactome Database ID Release 4370678 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004657 Reactome Database ID Release 4370669 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004334 Reactome Database ID Release 4371180 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016034 Reactome Database ID Release 4371172 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004411 Reactome Database ID Release 4371084 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003868 Reactome Database ID Release 4371162 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004838 Reactome Database ID Release 4371154 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004838 Reactome Database ID Release 4371154 Reactome, http://www.reactome.org Cathepsin Converted from EntitySet in Reactome Reactome DB_ID: 2130682 Reactome Database ID Release 432130682 Reactome, http://www.reactome.org ReactomeREACT_122689 Fgd3 Converted from EntitySet in Reactome Reactome DB_ID: 194924 Reactome Database ID Release 43194924 Reactome, http://www.reactome.org ReactomeREACT_10762 Rac1 Converted from EntitySet in Reactome Reactome DB_ID: 195345 Reactome Database ID Release 43195345 Reactome, http://www.reactome.org ReactomeREACT_10627 Dimers of ligand-responsive EGFR mutants sensitive to non-covalent TKIs Reactome DB_ID: 1181059 Reactome Database ID Release 431181059 Reactome, http://www.reactome.org ReactomeREACT_116384 has a Stoichiometric coefficient of 2 Dimers of EGF:Ligand-responsive EGFR mutants sensitive to non-covalent TKIs Reactome DB_ID: 1220571 Reactome Database ID Release 431220571 Reactome, http://www.reactome.org ReactomeREACT_117559 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0008124 Reactome Database ID Release 4371145 Reactome, http://www.reactome.org EGF:EGFR Dimer:irrevTKIs EGF:EGFR Dimer:Covalent EGFR TKIs Reactome DB_ID: 1225979 Reactome Database ID Release 431225979 Reactome, http://www.reactome.org ReactomeREACT_117215 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004155 Reactome Database ID Release 4371128 Reactome, http://www.reactome.org Resistant ligand-responsive EGFR mutants:Covalent EGFR TKIs Reactome DB_ID: 1220579 Reactome Database ID Release 431220579 Reactome, http://www.reactome.org ReactomeREACT_117723 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Serum amyloid P-component homopentamer Reactome DB_ID: 976776 Reactome Database ID Release 43976776 Reactome, http://www.reactome.org ReactomeREACT_76328 has a Stoichiometric coefficient of 10 has a Stoichiometric coefficient of 5 EGFR:Cetuximab Reactome DB_ID: 1248675 Reactome Database ID Release 431248675 Reactome, http://www.reactome.org ReactomeREACT_117571 has a Stoichiometric coefficient of 1 Insulin_Glargine Reactome DB_ID: 429348 Reactome Database ID Release 43429348 Reactome, http://www.reactome.org ReactomeREACT_76870 has a Stoichiometric coefficient of 1 Human Insulin Analogues Converted from EntitySet in Reactome Reactome DB_ID: 429407 Reactome Database ID Release 43429407 Reactome, http://www.reactome.org ReactomeREACT_76604 Insulin_Detemir(Levemir) Reactome DB_ID: 429349 Reactome Database ID Release 43429349 Reactome, http://www.reactome.org ReactomeREACT_76681 has a Stoichiometric coefficient of 1 Insulin_Humalog(Lispro) Reactome DB_ID: 429384 Reactome Database ID Release 43429384 Reactome, http://www.reactome.org ReactomeREACT_76787 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0000334 Reactome Database ID Release 4371096 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030429 Reactome Database ID Release 4371216 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016831 Reactome Database ID Release 4371222 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016212 Reactome Database ID Release 43893577 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004061 Reactome Database ID Release 43178109 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004502 Reactome Database ID Release 4371199 Reactome, http://www.reactome.org Subtilisin/kexin-like convertase Converted from EntitySet in Reactome Reactome DB_ID: 166569 Reactome Database ID Release 43166569 Reactome, http://www.reactome.org ReactomeREACT_10172 ACTIVATION GENE ONTOLOGYGO:0016212 Reactome Database ID Release 43901096 Reactome, http://www.reactome.org Dynactin Converted from EntitySet in Reactome Reactome DB_ID: 2029120 Reactome Database ID Release 432029120 Reactome, http://www.reactome.org ReactomeREACT_125297 ACTIVATION GENE ONTOLOGYGO:0004833 Reactome Database ID Release 4371187 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004833 Reactome Database ID Release 43198570 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004833 Reactome Database ID Release 43888607 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008442 Reactome Database ID Release 4370884 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008442 Reactome Database ID Release 4370884 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003860 Reactome Database ID Release 4370880 Reactome, http://www.reactome.org Lbc AKAP13/Brx Converted from EntitySet in Reactome Reactome DB_ID: 194961 Reactome Database ID Release 43194961 Reactome, http://www.reactome.org ReactomeREACT_10512 ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4370828 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016812 Reactome Database ID Release 4370905 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016153 Reactome Database ID Release 4370902 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004397 Reactome Database ID Release 4370898 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004491 Reactome Database ID Release 4370892 Reactome, http://www.reactome.org DLCs Converted from EntitySet in Reactome Dynein light chain Reactome DB_ID: 2029105 Reactome Database ID Release 432029105 Reactome, http://www.reactome.org ReactomeREACT_124963 ACTIVATION GENE ONTOLOGYGO:0004398 Reactome Database ID Release 43977296 Reactome, http://www.reactome.org Arhgef8/Net1 Converted from EntitySet in Reactome Reactome DB_ID: 194987 Reactome Database ID Release 43194987 Reactome, http://www.reactome.org ReactomeREACT_10819 ACTIVATION GENE ONTOLOGYGO:0030412 Reactome Database ID Release 4370917 Reactome, http://www.reactome.org Arhgef3 Converted from EntitySet in Reactome Reactome DB_ID: 194977 Reactome Database ID Release 43194977 Reactome, http://www.reactome.org ReactomeREACT_10479 DHCs Converted from EntitySet in Reactome Dynein Heavy chain Reactome DB_ID: 2029094 Reactome Database ID Release 432029094 Reactome, http://www.reactome.org ReactomeREACT_123810 DICs Converted from EntitySet in Reactome Dynein intermediate chains Reactome DB_ID: 2029119 Reactome Database ID Release 432029119 Reactome, http://www.reactome.org ReactomeREACT_123047 DLIs Converted from EntitySet in Reactome Dynein light intermediate chain Reactome DB_ID: 2029122 Reactome Database ID Release 432029122 Reactome, http://www.reactome.org ReactomeREACT_123519 ACTIVATION GENE ONTOLOGYGO:0004043 Reactome Database ID Release 43508540 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047131 Reactome Database ID Release 4370937 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047536 Reactome Database ID Release 4370950 Reactome, http://www.reactome.org GNRP Converted from EntitySet in Reactome Reactome DB_ID: 194946 Reactome Database ID Release 43194946 Reactome, http://www.reactome.org ReactomeREACT_10678 ACTIVATION GENE ONTOLOGYGO:0047536 Reactome Database ID Release 4370950 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0034602 Reactome Database ID Release 4369997 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015139 Reactome Database ID Release 43372492 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047312 Reactome Database ID Release 43893585 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004361 Reactome Database ID Release 4371044 Reactome, http://www.reactome.org Abr Converted from EntitySet in Reactome Reactome DB_ID: 194929 Reactome Database ID Release 43194929 Reactome, http://www.reactome.org ReactomeREACT_10625 ACTIVATION GENE ONTOLOGYGO:0004505 Reactome Database ID Release 4371074 Reactome, http://www.reactome.org HLA-C group-I-interacting KIRs Converted from EntitySet in Reactome Reactome DB_ID: 199540 Reactome Database ID Release 43199540 Reactome, http://www.reactome.org ReactomeREACT_11748 NKG2D ligand Converted from EntitySet in Reactome Reactome DB_ID: 198916 Reactome Database ID Release 43198916 Reactome, http://www.reactome.org ReactomeREACT_11351 ARP-1 Converted from EntitySet in Reactome Reactome DB_ID: 2228747 Reactome Database ID Release 432228747 Reactome, http://www.reactome.org ReactomeREACT_124999 ACTIVATION GENE ONTOLOGYGO:0047130 Reactome Database ID Release 4370934 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003829 Reactome Database ID Release 43976831 Reactome, http://www.reactome.org HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2130672 Reactome Database ID Release 432130672 Reactome, http://www.reactome.org ReactomeREACT_123431 ACTIVATION GENE ONTOLOGYGO:0008499 Reactome Database ID Release 43916826 Reactome, http://www.reactome.org Collagen alpha-1(XVI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192829 Reactome Database ID Release 432192829 Reactome, http://www.reactome.org ReactomeREACT_123898 ACTIVATION GENE ONTOLOGYGO:0003829 Reactome Database ID Release 43914007 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016263 Reactome Database ID Release 431964519 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004653 Reactome Database ID Release 43913697 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003836 Reactome Database ID Release 431022131 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003828 Reactome Database ID Release 431022136 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003835 Reactome Database ID Release 43975918 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003831 Reactome Database ID Release 43975894 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030144 Reactome Database ID Release 43975917 Reactome, http://www.reactome.org HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2130718 Reactome Database ID Release 432130718 Reactome, http://www.reactome.org ReactomeREACT_125425 Mitotic Prometaphase GENE ONTOLOGYGO:0000236 Reactome Database ID Release 4368877 Reactome, http://www.reactome.org ReactomeREACT_682 The dissolution of the nuclear membrane marks the beginning of the prometaphase. Kinetochores are created when proteins attach to the centromeres. Microtubules then attach at the kinetochores, and the chromosomes begin to move to the metaphase plate. Resolution of Sister Chromatid Cohesion Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed11509732 Pubmed14730319 Pubmed15339662 Pubmed15723797 Pubmed15737063 Pubmed16541025 Pubmed17112726 Pubmed17113138 Pubmed19696148 Pubmed21111234 Pubmed21878504 Pubmed21987589 Pubmed9649503 Reactome Database ID Release 432500257 Reactome, http://www.reactome.org ReactomeREACT_150425 Reviewed: Zhang, Nenggang, 2012-10-22 The resolution of sister chromatids in mitotic prometaphase involves removal of cohesin complexes from chromosomal arms, with preservation of cohesion at centromeres (Losada et al. 1998, Hauf et al. 2001, Hauf et al. 2005). <br><br> CDK1-mediated phosphorylation of cohesin-bound CDCA5 (Sororin) at threonine T159 provides a docking site for PLK1, enabling PLK1-mediated phosphorylation of cohesin subunits STAG2 (SA2) and RAD21 (Hauf et al. 2005, Dreier et al. 2011, Zhang et al. 2011). Further phosphorylation of CDCA5 by CDK1 results in dissociation of CDCA5 from cohesin complex, which restores the activity of WAPAL in removing STAG2-phosphorylated cohesin from chromosomal arms (Hauf et al. 2005, Gandhi et al. 2006, Kueng et al. 2006, Shintomi and Hirano 2006, Nishiyama et al. 2010, Zhang et al. 2011). <br><br> <br>At centromeres, kinetochore proteins shugoshins (SGOL1 and SGOL2) enable PP2A-B56 (also a kinetochore constituent) to dephosphorylate the STAG2 subunit of centromeric cohesin. Dephosphorylation of STAG2 enables maintenance of centromeric cohesion, thus preventing separation of sister chromatids until anaphase (Salic et al. 2004, Kitajima et al. 2004, Kitajima et al. 2005, Kitajima et al. 2006). Condensation of Prometaphase Chromosomes Authored: Orlic-Milacic, M, 2012-10-12 Edited: D'Eustachio, P, 2012-10-19 Edited: Matthews, L, 2012-10-18 Pubmed11136719 Pubmed14607834 Pubmed15146063 Pubmed15572404 Pubmed17066080 Pubmed17356064 Pubmed17525332 Pubmed18977199 Pubmed19481522 Pubmed19608861 Pubmed19915589 Pubmed20703077 Pubmed7954811 Pubmed9160743 Pubmed9288743 Pubmed9774278 Reactome Database ID Release 432514853 Reactome, http://www.reactome.org ReactomeREACT_150260 Reviewed: Kalitsis, Paul, 2012-11-12 The condensin I complex is evolutionarily conserved and consists of five subunits: two SMC (structural maintenance of chromosomes) family subunits, SMC2 and SMC4, and three non-SMC subunits, NCAPD2, NCAPH and NCAPG. The stoichiometry of the complex is 1:1:1:1:1 (Hirano and Mitchinson 1994, Hirano et al. 1997, Kimura et al. 2001). SMC2 and SMC4 subunits, shared between condensin I and condensin II, are DNA-dependent ATPases, and condensins are able to introduce positive supercoils into DNA in an ATP-dependent manner (Kimura and Hirano 1997). <br><br>Protein levels of condensin subunits are constant during the cell cycle, however condensins are enriched on mitotic chromosomes. Four of the five subunits, SMC4, NCAPD2, NCAPG and NCAPH, are phosphorylated in both mitotic and interphase HeLa cells, but on different sites (Takemoto et al. 2004). CDK1 (CDC2) in complex with CCNB (cyclin B) phosphorylates NCAPD2, NCAPG and NCAPH in mitosis (Kimura et al. 1998, Kimura et al. 2001, Takemoto et al. 2006, Murphy et al. 2008), but other mitotic kinases, such as PLK1 (St-Pierre et al. 2009), and other post-translational modifications, such as acetylation, may also be involved (reviewed by Bazile et al. 2010). Global proteomic analysis of human cell lines has identified N6-acetylation of lysine residues in condensin subunits SMC2, SMC4 and NCAPH (Choudhary et al. 2009). Another high throughput proteomic study showed that condensin I subunits NCAPD2 and NCAPH are phosphorylated upon DNA damage, probably by ATM or ATR kinase (Matsuoka et al. 2007).<br><br> As condensin I is cytosolic, it gains access to chromosomes only after the nuclear envelope breakdown at the start of prometaphase (Ono et al. 2004). Condensin I, activated by CDK1-mediated phosphorylation, promotes hypercondensation of chromosomes that were condensed in prophase through the action of condensin II (Hirota et al. 2004). AURKB may also regulate association of condensin I complex with chromatin (Lipp et al. 2007). Protein phosphatase PP2A acts independently of its catalytic activity to target condensin II complex to chromatin, but does not interact with condensin I (Takemoto et al. 2009). Full activation of condensin I requires dephosphorylation of sites modified by CK2 during interphase (Takemoto et al. 2006). Besides being essential for chromosome condensation in mitosis, condensin I may also contribute to cohesin removal from chromosome arms in prometaphase, but the exact mechanism is not known (Hirota et al. 2004). Mitotic Metaphase and Anaphase Metaphase is marked by the formation of the metaphase plate. The metaphase plate is formed when the spindle fibers align the chromosomes along the middle of the cell. Such an organization helps to ensure that later, when the chromosomes are separated, each new nucleus that is formed receives one copy of each chromosome. This pathway has not yet been annotated in Reactome.<br><br>The metaphase to anaphase transition during mitosis is triggered by the destruction of mitotic cyclins.<br><br>In anaphase, the paired chromosomes separate at the centromeres, and move to the opposite sides of the cell. The movement of the chromosomes is facilitated by a combination of kinetochore movement along the spindle microtubules and through the physical interaction of polar microtubules. Reactome Database ID Release 432555396 Reactome, http://www.reactome.org ReactomeREACT_150314 Mitotic Metaphase GENE ONTOLOGYGO:0000089 Metaphase is marked by the formation of the metaphase plate. The metaphase plate is formed when the spindle fibers align the chromosomes along the middle of the cell. Such an organization helps to ensure that later, when the chromosomes are separated, each new nucleus that is formed receives one copy of each chromosome. This pathway has not yet been annotated in Reactome. Reactome Database ID Release 4368879 Reactome, http://www.reactome.org ReactomeREACT_434 Mitotic Metaphase/Anaphase Transition GENE ONTOLOGYGO:0007091 Reactome Database ID Release 4368881 Reactome, http://www.reactome.org ReactomeREACT_1016 The metaphase to anaphase transition during mitosis is triggered by the destruction of mitotic cyclins. Mitotic Anaphase GENE ONTOLOGYGO:0000090 In anaphase, the paired chromosomes separate at the centromeres, and move to the opposite sides of the cell. The movement of the chromosomes is facilitated by a combination of kinetochore movement along the spindle microtubules and through the physical interaction of polar microtubules. Reactome Database ID Release 4368882 Reactome, http://www.reactome.org ReactomeREACT_1275 Separation of Sister Chromatids Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed10411507 Pubmed11081627 Pubmed11509732 Pubmed12070128 Pubmed12194817 Reactome Database ID Release 432467813 Reactome, http://www.reactome.org ReactomeREACT_150471 Reviewed: Zhang, Nenggang, 2012-10-22 While sister chromatids resolve in prometaphase, separating along chromosomal arms, the cohesion of sister centromeres persists until anaphase. At the anaphase onset, the anaphase promoting complex/cyclosome (APC/C) ubiquitinates PTTG1 (securin), targeting it for degradation (Hagting et al. 2002). PTTG1 acts as an inhibitor of ESPL1 (known as separin i.e. separase). Hence, PTTG1 removal initiated by APC/C, enables ESPL1 to become catalytically active (Zou et al. 1999, Waizenegger et al. 2002). ESPL1 undergoes autoleavage (Waizenegger et al. 2002) and also cleaves RAD21 subunit of centromeric cohesin (Hauf et al. 2001). RAD21 cleavage promotes dissociation of cohesin complexes from sister centromeres, leading to separation of sister chromatids. Subsequent movement of sister chromatids to opposite poles of the mitotic spindle segregates replicated chromosomes to two daughter cells (Waizenegger et al. 2000, Hauf et al. 2001, Waizenegger et al. 2002). cell division GENE ONTOLOGYGO:0000910 In this final phase of mitosis, new membranes are formed around two sets of chromatids and two daughter cells are formed. The chromosomes and the spindle fibers disperse, and the fiber ring around the center of the cell, composed of actin, contracts, pinching the cell into two daughter cells. Mitotic Telophase/Cytokinesis Reactome Database ID Release 4368884 Reactome, http://www.reactome.org ReactomeREACT_1932 Cohesin Loading onto Chromatin Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 In mitotic telophase, as chromosomes decondense, cohesin complex associated with PDS5 (PDS5A and PDS5B) and WAPAL (WAPL) proteins is loaded onto chromatin (Shintomi and Hirano, 2009, Kueng et al. 2006, Gandhi et al. 2006, Chan et al. 2012). Cohesin loading is facilitated by the complex of NIPBL (SCC2) and MAU2 (SCC4) proteins, which constitute an evolutionarily conserved cohesin loading complex. MAU2 depletion in HeLa cells results in 2-3-fold reduction in the amount of cohesin in the chromatin fraction (Watrin et al. 2006). NIPBL mutations are the cause of the Cornelia de Lange syndrome, a dominantly inherited disorder characterized by facial malformations, limb defects, and growth and cognitive retardation (Tonkin et al. 2004). Cornelia de Lange syndrome can also be caused by mutations in cohesin subunits SMC1A (Musio et al. 2006, Borck et al. 2007, Deardorff et al. 2007, Pie et al. 2010) and SMC3 (Deardorff et al. 2007). Pubmed15146185 Pubmed16604071 Pubmed16682347 Pubmed17112726 Pubmed17113138 Pubmed17221863 Pubmed17273969 Pubmed19696148 Pubmed20358602 Pubmed22901742 Reactome Database ID Release 432470946 Reactome, http://www.reactome.org ReactomeREACT_150421 Reviewed: Zhang, Nenggang, 2012-10-22 ACTIVATION GENE ONTOLOGYGO:0008454 Reactome Database ID Release 43975927 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008424 Reactome Database ID Release 431028794 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003830 Reactome Database ID Release 43975892 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003827 Reactome Database ID Release 43964758 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008455 Reactome Database ID Release 43975825 Reactome, http://www.reactome.org FCGR Converted from EntitySet in Reactome Fc-gamma receptor Reactome DB_ID: 1236898 Reactome Database ID Release 431236898 Reactome, http://www.reactome.org ReactomeREACT_111875 ACTIVATION GENE ONTOLOGYGO:0004572 Reactome Database ID Release 43975817 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004571 Reactome Database ID Release 43964728 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004569 Reactome Database ID Release 43964755 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004571 Reactome Database ID Release 43964728 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004571 Reactome Database ID Release 43964728 Reactome, http://www.reactome.org FCGR Converted from EntitySet in Reactome Fc-gamma receptor Reactome DB_ID: 1236905 Reactome Database ID Release 431236905 Reactome, http://www.reactome.org ReactomeREACT_111253 Regulation of APC/C activators between G1/S and early anaphase GENE ONTOLOGYGO:0051439 Pubmed10465783 Pubmed12049731 Pubmed12208841 Pubmed15678131 Pubmed16508672 Reactome Database ID Release 43176408 Reactome, http://www.reactome.org ReactomeREACT_6837 Reviewed: Peters, JM, 2006-03-27 22:55:09 The APC/C is activated by either Cdc20 or Cdh1. While both activators associate with the APC/C, they do so at different points in the cell cycle and their binding is regulated differently (see Zachariae and Nasmyth, 1999). Cdc20, whose protein levels increase as cells enter into mitosis and decrease upon mitotic exit, only associates with the APC/C during M phase. Cdh1 associates with the APC/C in G1. This interaction is inhibited at other times by Cdk1 phosphorylation. Phosphorylation of Emi1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Reactome Database ID Release 43176417 Reactome, http://www.reactome.org ReactomeREACT_6875 Reviewed: Peters, JM, 2006-03-27 22:55:09 The phosphorylation of Emi1, which is required for its degradation in mitosis, appears to involve both Plk1 and Cdk1. Regulation of mitotic cell cycle Edited: Matthews, L, 2010-01-19 Reactome Database ID Release 43453276 Reactome, http://www.reactome.org ReactomeREACT_21279 Reviewed: Manfredi, J, 0000-00-00 00:00:00 APC/C-mediated degradation of cell cycle proteins Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0031145 Pubmed10465783 Pubmed10733526 Pubmed11336713 Pubmed11340163 Pubmed11562348 Pubmed12049731 Pubmed12446569 Pubmed15678131 Pubmed15840442 Pubmed15949434 Pubmed16413484 Pubmed7985232 Reactome Database ID Release 43174143 Reactome, http://www.reactome.org ReactomeREACT_6828 Reviewed: Peters, JM, 2006-03-27 22:55:09 The Anaphase Promoting Complex or Cyclosome (APC/C) functions during mitosis to promote sister chromatid separation and mitotic exit through the degradation of mitotic cyclins and securin. This complex is also active in interphase insuring the appropriate length of the G1 phase (reviewed in Peters, 2002). The APC/C contains at least 12 subunits and functions as an ubiquitin-protein ligase (E3) promoting the multiubiquitination of its target proteins (see Gieffers et al., 2001). <br>In the ubiquitination reaction, ubiquitin is activated by the formation of a thioester bond with the (E1) ubiquitin activating enzyme then transferred to a cysteine residue within the ubiquitin conjugating enzyme (E2) and ultimately to a lysine residue within the target protein, with the aid of ubiquitin-protein ligase activity of the APC/C. The ubiquitin chains generated are believed to target proteins for destruction by the 26S proteasome (Reviewed in Peters, 1994 ) <br>The activity of the APC/C is highly periodic during the cell cycle and is controlled by a combination of regulatory events. The APC/C is activated by phosphorylation and the regulated recruitment of activating subunits and is negatively regulated by sequestration by kinetochore-associated checkpoint proteins. The Emi1 protein associates with Cdh1 and Cdc20, inhibiting the APC/C between G1/S and prophase. RSSA1 may play a similar role in ihibiting the APC during early mitosis.<br>Following phosphorylation of the APC/C core subunits by mitotic kinases, the activating subunit, Cdc20 is recruited to the APC/C and is responsible for mitotic activities, including the initiation of sister chromatid separation and the timing of exit from mitosis (See Zachariae and Nasmyth, 1999). Substrates of the Cdc20:APC/C complex, which are recognized by a motif known as the destruction box (D box) include Cyclin A, Nek2, Securin and Cyclin B. Degradation of Securin and Cyclin B does not occur until the mitotic spindle checkpoint has been satisfied (see Castro et al. 2005).<br>Cdc20 is degraded late in mitosis (Reviewed in Owens and Hoyt, 2005). At this time the activating subunit, Cdh1, previously maintained in an inactive phosphorylated state by mitotic kinases, is dephosphorylated and associates with and activates the APC/C. The APC/C:Cdh1 complex recognizes substrates containing a D box, a KEN box (Pfleger and Kirschner, 2000) or a D box activated (DAD) domain (Castro et al., 2002) sequence and promotes the ordered degration of mitotic cyclins and other mitotic proteins culminating with its own ubiquitin-conjugating enzyme (E2) subunit UbcH10 (Rape et al., 2006). This ordered degradation promotes the stability of Cyclin A at the end of G1. This stabilization, in turn, promotes the phosphorylation of Cdh1 and its abrupt dissociation from the APC/C, allowing accumulation of cyclins for the next G1/S transition (Sorensen et al., 2001). <br><br> Phosphorylation of the APC/C GENE ONTOLOGYGO:0051437 Phosphorylation of APC subunits is required for Cdc20 mediated activation by of the APC/C at the metaphase anaphase transition (Kramer et al., 2000). While the kinases responsible for phosphorylation in vivo have not been determined with certainty, both Plk1 and Cyclin B:Cdc2 have been implicated in this process. Pubmed10793135 Reactome Database ID Release 43176412 Reactome, http://www.reactome.org ReactomeREACT_6904 Reviewed: Peters, JM, 2006-03-27 22:55:09 APC/C:Cdc20 mediated degradation of mitotic proteins Following phosphorylation of the APC/C core subunits by mitotic kinases, the activating protein, Cdc20 is recruited to the APC and promotes the multiubiquitination and subsequent degradation of the mitotic cyclins (Cyclin A and Cyclin B) as well as the protein securin which functions in sister chromatid cohesion. Timely degradation of these proteins is essential for sister chromatid separation and the proper timing of exit from mitosis (See Zachariae and Nasmyth, 1999). Cdc20 is degraded late in mitosis (Reviewed in Owens and Hoyt, 2005) Pubmed10465783 Pubmed15949434 Reactome Database ID Release 43176409 Reactome, http://www.reactome.org ReactomeREACT_6781 Reviewed: Peters, JM, 2006-03-27 22:55:09 SCF-beta-TrCP mediated degradation of Emi1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 Emi1 destruction in early mitosis requires the SCFβTrCP ubiquitin ligase complex. Binding of βTrCP to Emi1 occurs in late prophase and requires phosphorylation at the DSGxxS consensus motif as well as Cdk mediated phosphorylation. A two-step mechanism has been proposed in which the phosphorylation of Emi1 by Cdc2 occurs after the G2-M transition followed soon after by binding of βTrCP to the DSGxxS phosphorylation sites. Emi1 is then poly-ubiquitinated and degraded by the 26S proteasome. GENE ONTOLOGYGO:0051437 Pubmed12791267 Reactome Database ID Release 43174113 Reactome, http://www.reactome.org ReactomeREACT_6821 Reviewed: Peters, JM, 2006-03-27 22:55:09 Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins APC/C:Cdc20 is first activated at the prometaphase/metaphase transition through phosphorylation of core subunits of the APC/C by mitotic kinases as well as recruitment of the APC/C activator protein Cdc20. APC/C:Cdc20 promotes the multiubiquitination and ordered degradation of Cyclin A and Nek2 degradation in prometaphase followed by Cyclin B and securin in metaphase (Reviewed in Castro et al., 2005). Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Pubmed15678131 Reactome Database ID Release 43176814 Reactome, http://www.reactome.org ReactomeREACT_6954 Reviewed: Peters, JM, 2006-03-27 22:55:09 APC/C:Cdc20 mediated degradation of Cyclin B Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0031145 Pubmed11285280 Pubmed12070128 Reactome Database ID Release 43174048 Reactome, http://www.reactome.org ReactomeREACT_6820 Reviewed: Peters, JM, 2006-03-27 22:55:09 The degradation of cyclin B1, which appears to occur at the mitotic spindle, is delayed until the metaphase /anaphase transition by the spindle assembly checkpoint and is required in order for sister chromatids to separate (Geley et al. 2001;Hagting et al, 2002). APC/C:Cdc20 mediated degradation of Securin Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0031145 Pubmed10827941 Pubmed12070128 Reactome Database ID Release 43174154 Reactome, http://www.reactome.org ReactomeREACT_6871 Reviewed: Peters, JM, 2006-03-27 22:55:09 The separation of sister chromatids in anaphase requires the destruction of the anaphase inhibitor, securin. Securin associates with and inactivates the protease, separase. Separase cleaves the cohesin subunit, Scc1 that is responsible for the cohesion of sister chromatids (reviewed in Nasmyth et al., 2000). Securin destruction begins at metaphase after the mitotic spindle checkpoint has been satisfied (Hagting et al., 2002). FCGRA Converted from EntitySet in Reactome Fc-gamma receptor alpha Reactome DB_ID: 1031694 Reactome Database ID Release 431031694 Reactome, http://www.reactome.org ReactomeREACT_26475 ACTIVATION GENE ONTOLOGYGO:0008236 Reactome Database ID Release 432022371 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0070573 Reactome Database ID Release 432065398 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0070573 Reactome Database ID Release 432022372 Reactome, http://www.reactome.org S Phase DNA synthesis occurs in the S phase, or the synthesis phase, of the cell cycle. The cell duplicates its hereditary material, and two copies of the chromosome are formed. As DNA replication continues, the E type cyclins shared by the G1 and S phases, are destroyed and the levels of the mitotic cyclins rise. GENE ONTOLOGYGO:0000084 Reactome Database ID Release 4369242 Reactome, http://www.reactome.org ReactomeREACT_899 Reviewed: Manfredi, J, 0000-00-00 00:00:00 E2F-enabled inhibition of pre-replication complex formation Authored: Gopinathrao, G, 2004-05-26 17:05:00 Pubmed11090133 Pubmed11231579 Reactome Database ID Release 43113507 Reactome, http://www.reactome.org ReactomeREACT_1321 Under specific conditions, Cyclin B, a mitotic cyclin, can inhibit the functions of pre-replicative complex. E2F1 activates Cdc25A protein which regulates Cyclin B in a positive manner. Cyclin B/Cdk1 function is restored which leads to the disruption of pre-replicative complex. This phenomenon has been demonstrated by Bosco et al (2001) in Drosophila. ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 431299486 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0032977 Reactome Database ID Release 431299485 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 431299486 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004190 Reactome Database ID Release 432065406 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004190 Reactome Database ID Release 432022410 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004190 Reactome Database ID Release 432022388 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008320 Reactome Database ID Release 431299479 Reactome, http://www.reactome.org Cyclin A:Cdk2-associated events at S phase entry Authored: Pagano, M, 2006-09-19 08:23:10 Cyclin A:Cdk2 plays a key role in S phase entry by phosphorylation of proteins including Cdh1, Rb, p21 and p27. During G1 phase of the cell cycle, cyclin A is synthesized and associates with Cdk2. After forming in the cytoplasm, the Cyclin A:Cdk2 complexes are translocated to the nucleus (Jackman et al.,2002). Prior to S phase entry, the activity of Cyclin A:Cdk2 complexes is negatively regulated through Tyr 15 phosphorylation of Cdk2 (Gu et al., 1995) and also by the association of the cyclin kinase inhibitors (CKIs), p27 and p21. Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK2 kinase activity (Aprelikova et al., 1995). The entry into S phase is promoted by the removal of inhibitory Tyr 15 phosphates from the Cdk2 subunit of Cyclin A:Cdk2 complex by the Cdc25 phosphatases (Blomberg and Hoffmann, 1999) and by SCF(Skp2)-mediated degradation of p27/p21 (see Ganoth et al., 2001). While Cdk2 is thought to play a primary role in regulating entry into S phase, recent evidence indicates that Cdk1 is equally capable of promoting entry into S phase and the initiation of DNA replication (see Bashir and Pagano, 2005). Thus, Cdk1 complexes may also play a significant role at this point in the cell cycle. Edited: Matthews, L, 2006-09-29 14:05:42 Pubmed10454565 Pubmed11231585 Pubmed11907280 Pubmed1396589 Pubmed15014502 Pubmed7629134 Reactome Database ID Release 4369656 Reactome, http://www.reactome.org ReactomeREACT_9029 Reviewed: Coqueret, O, 2006-10-06 08:59:06 G2 Phase GENE ONTOLOGYGO:0000085 Reactome Database ID Release 4368911 Reactome, http://www.reactome.org ReactomeREACT_1915 This is one of two 'gap' phases in the standard eukaryotic mitotic cell cycle. It is the interval between the completion of DNA synthesis and the beginning of mitosis. Protein synthesis occurs in this phase, following DNA replication in the S phase. This is the time when the cell stockpiles on the cytoplasmic contents, before mitosis and cytokinesis occur. G2/M Transition Cyclin A can also form complexes with Cdc2 (Cdk1). Together with three B-type cyclins, Cdc2 (Cdk1) regulates the transition from G2 into mitosis. These complexes are activated by dephosphorylation of T14 and Y15. Cyclin A, B - Cdc2 complexes phosphorylate several proteins involved in mitotic spindle structure and function, the breakdown of the nuclear envelope, and topological changes in chromosomes allowing resolution of their entanglement and condensation that is necessary for the ~2 meters of DNA to be segregated at mitosis. GENE ONTOLOGYGO:0000086 Reactome Database ID Release 4369275 Reactome, http://www.reactome.org ReactomeREACT_2203 Reviewed: Lorca, T, 2005-10-10 00:00:00 Cyclin A/B1 associated events during G2/M transition Cell cycle progression is regulated by cyclin-dependent protein kinases at both the G1/S and the G2/M transitions by cyclin-dependent protein kinases. The G2/M transition is regulated through the phosphorylation of nuclear lamins and histones (reviewed in Sefton, 2001). Pubmed18228324 Reactome Database ID Release 4369273 Reactome, http://www.reactome.org ReactomeREACT_1857 Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes Cyclin A:Cdc2 complexes are detected in the nucleus earlier that cyclin B1:Cdc2 complexes and may play a role in the initial events in prophase. Inactivation of Cdc25B by proteasome-mediated degradation is dependent upon cyclin A:Cdc2-mediated phosphorylation (Cans et al, 1999) Pubmed10363647 Reactome Database ID Release 43170145 Reactome, http://www.reactome.org ReactomeREACT_6362 Ubiquitin-dependent degradation of Cyclin D Cyclin D turnover is regulated by ubiquitination and proteasomal degradation which are positively regulated by cyclin D phosphorylation on threonine-286 (Diehl et al., 1997). Pubmed9136925 Reactome Database ID Release 4375815 Reactome, http://www.reactome.org ReactomeREACT_938 Ubiquitin-dependent degradation of Cyclin D1 After the Cyclin D serves the role of mediating reactions by Cdk4 and Cdk6, it is shuttled to the cytoplasm and degraded in a ubiquitin-dependent manner. Whether Cdk4 and Cdk6 are truly redundant is a topic still under investigation, although both the kinases are required for normal cell cycle progression.<p>Destruction of the D type cyclins accompanies the end of the G1 phase, and the E type cyclins are involved in transition of the cell from G1 to S phase. Reactome Database ID Release 4369229 Reactome, http://www.reactome.org ReactomeREACT_4 Establishment of Sister Chromatid Cohesion Authored: Orlic-Milacic, M, 2012-10-02 Edited: Gillespie, ME, 2012-10-05 Edited: Matthews, L, 2012-10-05 Pubmed15837422 Pubmed15958495 Pubmed16890534 Pubmed18614053 Pubmed21111234 Pubmed22101327 Reactome Database ID Release 432468052 Reactome, http://www.reactome.org ReactomeREACT_150266 Reviewed: Zhang, Nenggang, 2012-10-22 The cohesin complex loads onto chromatin in telophase, but its association with chromatin remains transient, dynamic until the S-phase of the cell cycle, presumably because the cohesin-bound NIPBL:MAU2 (SCC2:SCC4) complex promotes chromatin loading, while cohesin-bound WAPAL promotes dissociation from chromatin. Stable binding of cohesin complexes to chromatin, measured by a mean residence time on chromatin, is triggered by DNA replication in S-phase (Gerlich et al. 2006), consistent with establishment of sister chromatid cohesion. <br><br> In S-phase, acetyltransferases ESCO1 and ESCO2 acetylate the SMC3 cohesin subunit (Hou and Zou 2005, Zhang et al. 2008, Nishiyama et al. 2010, Whelan et al. 2012). The acetylation of SMC3, in addition to DNA replication and the presence of PDS5 on cohesin, facilitates the recruitment of CDCA5 (Sororin) to cohesin complexes, an essential step in the establishment of sister chromatid cohesion in mammalian cells (Rankin et al. 2005). CDCA5 (Sororin) displaces WAPAL from PDS5, thus preventing WAPAL to interfere with the establishment of sister chromatid cohesion (Nishiyama et al. 2010). The establishment and temporal regulation of sister chromatid cohesion is necessary for equal segregation of replicated chromosomes to daughter cells. Mitotic G2-G2/M phases Reactome Database ID Release 43453274 Reactome, http://www.reactome.org ReactomeREACT_21391 Reviewed: Manfredi, J, 0000-00-00 00:00:00 ACTIVATION GENE ONTOLOGYGO:0015035 Reactome Database ID Release 431307805 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008320 Reactome Database ID Release 431268023 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0032977 Reactome Database ID Release 431307806 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0032977 Reactome Database ID Release 431268024 Reactome, http://www.reactome.org Cyclin B2 mediated events Pubmed10395539 Pubmed11238451 Pubmed17533373 Pubmed7737117 Reactome Database ID Release 43157881 Reactome, http://www.reactome.org ReactomeREACT_2101 The two B-type cyclins localize to different regions within <br>the cell and and are thought to have specific roles as CDK1-activating subunits (see Bellanger et al., 2007). Cyclin B1 is primarily cytoplasmic during interphase and translocates into the nucleus at the onset of mitosis (Jackman et al., 1995; Hagting et al., 1999). Cyclin B2 colocalizes with the Golgi apparatus and contributes to its fragmentation during mitosis (Jackman et al., 1995; Draviam et al., 2001). ACTIVATION GENE ONTOLOGYGO:0003835 Reactome Database ID Release 43977229 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008378 Reactome Database ID Release 431964513 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008373 Reactome Database ID Release 43981807 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003835 Reactome Database ID Release 43977229 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047290 Reactome Database ID Release 43981821 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003836 Reactome Database ID Release 43981487 Reactome, http://www.reactome.org Polo-like kinase mediated events At mitotic entry, Plk1 phosphorylates and activates Cdc25C phosphatase, whereas it phosphorylates and down-regulates Wee1A. Plk1 also phosphorylates and inhibits Myt1 activity. Cyclin B1-bound Cdc2, which is the target of Cdc25C, Wee1A, and Myt1, functions in a feedback loop and phosphorylates the latter components (Cdc25C, Wee1A, Myt1). The Cdc2- dependent phosphorylation provides docking sites for the polo-box domain of Plk1, thus promoting the Plk1-dependent regulation of these components and, as a result, activation of Cdc2-Cyclin B1. Authored: Lee, KS, 2004-12-08 21:18:23 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0051726 Pubmed15070733 Pubmed15692562 Reactome Database ID Release 43156711 Reactome, http://www.reactome.org ReactomeREACT_1006 Centrosome maturation Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-24 13:58:10 Pubmed17178454 Pubmed18437411 Reactome Database ID Release 43380287 Reactome, http://www.reactome.org ReactomeREACT_15479 Reviewed: Merdes, A, 2008-11-17 13:55:29 The centrosome is the primary microtubule organizing center (MTOC) in vertebrate cells and plays an important role in orchestrating the formation of the mitotic spindle. Centrosome maturation is an early event in this process and involves a major reorganization of centrosomal material at the G2/M transition. During maturation, centrosomes undergo a dramatic increase in size and microtubule nucleating capacity. As part of this process, a number of proteins and complexes, including some that are required for microtubule nucleation and anchoring, are recruited to the centrosome while others that are required for organization of interphase microtubules and centrosome cohesion are lost (reviewed in Schatten, 2008; Raynaud-Messina and Merdes 2007). Golgi Cisternae Pericentriolar Stack Reorganization Authored: Gillespie, ME, 2005-04-04 01:40:57 Pubmed10679020 Pubmed11285137 Pubmed11408587 Pubmed11447294 Pubmed11739401 Pubmed12015985 Pubmed12695496 Pubmed12839990 Pubmed15232108 Pubmed15576368 Pubmed15678101 Pubmed16533948 Pubmed17182854 Pubmed17431394 Pubmed18385516 Pubmed18434598 Pubmed20083603 Pubmed20937827 Pubmed9458043 Pubmed9753325 Reactome Database ID Release 43162658 Reactome, http://www.reactome.org ReactomeREACT_1100 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Malhotra, Vivek, 2012-08-15 Reviewed: Wang, Yanzhuang, 2012-08-19 The pericentriolar stacks of Golgi cisternae undergo extensive fragmentation and reorganization in mitosis.<br> <br>In mammalian cells, Golgi apparatus consists of stacked cisternae that are connected by tubules to form a ribbon-like structure in the perinuclear region, in vicinity of the centrosome. Reorganization of the Golgi apparatus during cell division allows both daughter cells to inherit this organelle, and may play additional roles in the organization of the mitotic spindle. <br> <br>First changes in the structure of the Golgi apparatus likely start in G2 and are subtle, involving unlinking of the Golgi ribbon into separate stacks. These changes are required for the entry of mammalian cells into mitosis (Sutterlin et al. 2002). This initial unlinking of the Golgi ribbon depends on GRASP proteins and on CTBP1 (BARS) protein, which induces the cleavage of the tubular membranes connecting the stacks (Hidalgo Carcedo et al. 2004, Colanzi et al. 2007), but the exact mechanism is not known. Activation of MEK1/2 also contributes to unlinking of the Golgi ribbon in G2 (Feinstein and Linstedt 2007). <br> <br>From prophase to metaphase, Golgi cisternae undergo extensive fragmentation that is a consequence of unstacking of Golgi cisternae and cessation of transport through Golgi. At least three mitotic kinases, CDK1, PLK1 and MEK1, regulate these changes. CDK1 in complex with cyclin B phosphorylates GOLGA2 (GM130) and GORASP1 (GRASP65), constituents of a cis-Golgi membrane complex (Lowe et al. 1998, Preisinger et al. 2005). Phosphorylation of GOLGA2 prevents binding of USO1 (p115), a protein localizing to the membrane of ER (endoplasmic reticulum) to Golgi transport vesicles and cis-Golgi, thereby impairing fusion of these vesicles with cis-Golgi cisternae and stopping ER to Golgi transport (Lowe et al. 1998, Seeman et al. 2000, Moyer et al. 2001). Phosphorylation of GORASP1 by CDK1 enables further phosphorylation of GORASP1 by PLK1 (Sutterlin et al. 2001, Preisinger et al. 2005). Phosphorylation of GORASP1 by CDK1 and PLK1 impairs stacking of Golgi cisternae by interfering with formation of GORASP1 trans-oligomers that would normally link the Golgi cisternae together (Wang et al. 2003, Wang et al. 2005, Sengupta and Linstedt 2010). <br><br> In the median Golgi, GORASP2 (GRASP55), a protein that forms a complex with BLFZ1 (Golgin-45) and RAB2A GTPase and contributes to cisternae stacking and Golgi trafficking (Short et al. 2001), is also phosphorylated in mitosis. Phosphorylation of GORASP2 by MEK1/2-activated MAPK1 (ERK2) and/or MAPK3-3 (ERK1b in human, Erk1c in rat) contributes to Golgi unlinking in G2 and fragmentation of Golgi cisternae in mitotic prophase (Acharya et al. 1998, Jesch et al. 2001, Colanzi et al. 2003, Shaul and Seger 2006, Duran et al. 2008, Feinstein and Linstedt 2007, Feinstein and Linstedt 2008, Xiang and Wang 2010). MASTL Facilitates Mitotic Progression Authored: Orlic-Milacic, M, 2012-09-04 Edited: Gillespie, ME, 2012-09-14 Pubmed16600872 Pubmed20538976 Pubmed21164013 Pubmed21164014 Pubmed21444715 Pubmed22354989 Reactome Database ID Release 432465910 Reactome, http://www.reactome.org ReactomeREACT_150182 Reviewed: Burgess, A, 2012-09-28 Reviewed: Mochida, Satoru, 2012-09-26 The activity of MASTL, also known as the Greatwall kinase (GWL), is necessary for the entry and progression of mitosis. MASTL is activated by phosphorylation of several key residues during mitotic entry. Phosphorylation on the serine residue S875 (S883 in Xenopus), likely through autophosphorylation (Blake-Hodek et al. 2012) appears to be critical (Vigneron et al. 2011). Several other sites, including putative CDK1 targets T194, T207 and T741, contribute to the full activation of MASTL (Yu et al. 2006, Blake-Hodek et al. 2012). Other kinases, such as PLK1 (Vigneron et al. 2011) and other MASTL phosphorylation sites may also be functionally important (Yu et al. 2006, Blake-Hodek et al. 2012).<br><br>Activated MASTL phosphorylates ARPP19 and ENSA on serines S62 and S67, respectively, enabling them to bind to and inhibit the phosphatase activity of PP2A complexed with the regulatory subunit PPP2R2D (B55-delta). Inhibition of PP2A-PPP2R2D activity by ARPP19 or ENSA prevents dephosphorylation of CDK1 targets, hence allowing entry and maintenance of mitosis (Mochida et al. 2010, Gharbi-Ayachi et al. 2010, Burgess et al. 2010).<br><br> M Phase GENE ONTOLOGYGO:0000087 Mitosis, or the M phase, involves nuclear division and cytokinesis, where two identical daughter cells are produced. Mitosis involves prophase, prometaphase, metaphase, anaphase, and telophase. Finally, cytokinesis leads to cell division. The phase between two M phases is called the interphase; it encompasses the G1, S, and G2 phases of the cell cycle. Reactome Database ID Release 4368886 Reactome, http://www.reactome.org ReactomeREACT_910 Reviewed: Manfredi, J, 0000-00-00 00:00:00 Mitotic Prophase During prophase, the chromatin in the nucleus condenses, and the nucleolus disappears. Centrioles begin moving to the opposite poles or sides of the cell. Some of the fibers that extend from the centromeres cross the cell to form the mitotic spindle. GENE ONTOLOGYGO:0000088 Reactome Database ID Release 4368875 Reactome, http://www.reactome.org ReactomeREACT_765 Loss of proteins required for interphase microtubule organization from the centrosome Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-09 05:12:41 In addition to recruiting proteins and complexes necessary for increased microtubule nucleation, centrosomal maturation involves the loss of proteins involved in interphase microtubule organization and centrosome cohesion (Casenghi et al., 2003; Mayor et al., 2002). Pubmed11076968 Pubmed12140259 Pubmed12852856 Reactome Database ID Release 43380284 Reactome, http://www.reactome.org ReactomeREACT_15451 Reviewed: Merdes, A, 2008-11-17 13:55:29 Loss of Nlp from mitotic centrosomes Authored: Matthews, L, 2008-11-11 14:53:40 During interphase, Nlp interacts with gamma-tubulin ring complexes (gamma-TuRC), and is thought to contribute to the organization of interphase microtubules (Casenghi et al.,2003). Plk1 is activated at the onset of mitosis and phosphorylates Nlp triggering its displacement from the centrosome (Casenghi et al.,2003). Removal of Nlp appears to contribute to the establishment of a mitotic scaffold with enhanced microtubule nucleation activity. Edited: Matthews, L, 2008-11-09 05:12:41 Pubmed12852856 Reactome Database ID Release 43380259 Reactome, http://www.reactome.org ReactomeREACT_15364 Reviewed: Merdes, A, 2008-11-17 13:55:29 Recruitment of mitotic centrosome proteins and complexes Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-09 05:12:41 Pubmed17178454 Pubmed18437411 Reactome Database ID Release 43380270 Reactome, http://www.reactome.org ReactomeREACT_15296 Reviewed: Merdes, A, 2008-11-17 13:55:29 The mitotic spindle becomes established once centrosomes have migrated to opposite poles and the nuclear envelope has broken down. During this stage, interphase centrosomes mature into mitotic centrosomes recruiting additional gamma TuRC complexes and acquiring mitosis-associated centrosomal proteins including NuMA, Plk1 and CDK11p58 (reviewed in Schatten 2008; Raynaud-Messina and Merdes 2007). Recruitment of NuMA to mitotic centrosomes Authored: Matthews, L, 2008-11-11 14:53:40 Edited: Matthews, L, 2008-11-09 05:12:41 Pubmed10811826 Pubmed11163243 Pubmed11229403 Pubmed15561764 Pubmed7593190 Pubmed7962183 Pubmed8896597 Pubmed8898198 Pubmed9394013 Reactome Database ID Release 43380320 Reactome, http://www.reactome.org ReactomeREACT_15510 Reviewed: Merdes, A, 2008-11-17 13:55:29 The NuMA protein, which functions as a nuclear matrix protein in interphase (Merdes and Cleveland 1998), redistributes to the cytoplasm following nuclear envelope breakdown where it plays an essential role in formation and maintenance of the spindle poles (Gaglio, et al., 1995; Gaglio, et al., 1996; Merdes et al, 1996). The mitotic activation of NuMA involves Ran-GTP-dependent dissociation from importin (Nachury et al, 2001, Wiese et al, 2001). NuMA is transported to the mitotic poles where it forms an insoluble crescent around centrosomes tethering microtubules into the bipolar configuration of the mitotic apparatus (Merdes et al., 2000; Kisurina-Evgenieva et al, 2004). Although NuMA is not a bona fide constituent of the mitotic centrosome but rather a protein associated with microtubules at the spindle pole, specific splice variants of NuMA have been identified that associate with the centrosome during interphase (Tang et al, 1994). PDGF A isoforms Converted from EntitySet in Reactome Reactome DB_ID: 381933 Reactome Database ID Release 43381933 Reactome, http://www.reactome.org ReactomeREACT_17551 Signal regulatory protein (SIRP) family interactions Authored: Garapati, P V, 2009-02-12 18:17:40 Edited: Garapati, P V, 2009-02-12 18:17:40 Pubmed11792697 Pubmed12023008 Pubmed16339511 Pubmed16691243 Pubmed19144521 Reactome Database ID Release 43391160 Reactome, http://www.reactome.org ReactomeREACT_23916 Reviewed: Barclay, AN, 2010-05-20 Signal regulatory protein (SIRP)alpha, also known as SHPS-1 or SIRPA or CD172a, is a transmembrane protein expressed mostly on myeloid cells. CD47, a widely expressed transmembrane protein, is a ligand for SIRP alpha, with the two proteins constituting a cell-cell communication system. The interaction of SIRP alpha with CD47 is important for the regulation of migration and phagocytosis. SIRP alpha functions as a docking protein to recruit and activate SHP-1 or SHP-2 at the cell membrane in response to extracellular stimuli. SIRP alpha also binds other intracellular proteins including the adaptor molecules Src kinase-associated protein (SKAP2 SKAP55hom/R), Fyn-binding protein/SLP-76-associated phosphoprotein (FYB/SLAP-130) and the tyrosine kinase PYK2. SIRP alpha also binds the extracellular proteins, surfactant-A (SP-A) and surfactant-D (SP-D). <br>In addition to SIRP alpha there are two closely related proteins in the SIRP family namely SIRP beta and SIRP gamma. These three family proteins show high sequence similarity and similar extracellular structural topology, including three Ig domains, but their ligand binding topology might differ. SIRP beta is expressed on myeloid cells, including monocytes, granulocytes and DCs. A natural ligand for SIRP beta remains unknown; SIRP gamma can bind to CD47 but the binding affinity is lower than that of SIRP alpha. Type I hemidesmosome assembly Authored: Matthews, L, 2009-11-04 Edited: Matthews, L, 2009-11-04 GENE ONTOLOGYGO:0031581 Hemidesmosomes (HDs) are specialized multiprotein junctional complexes that connect the keratin cytoskeleton of epithelial cells to the extracellular matrix and play a critical role in the maintenance of tissue structure and integrity (reviewed in Litjens et al., 2006). HDs mediate adhesion of epithelial cells to the underlying basement membrane in stratified squamous, transitional and pseudostratified epithelia (Jones et al., 1994 ; Borradori and Sonnenberg, 1996). Classical Type I HDs are found in stratified and pseudo-stratified epithelia, such as the skin, and contain a6b4, plectin, tetraspanin CD151 and the bullous pemphigoid (BP) antigens BP180 and BP230 (reviewed in Litjens et al., 2006). While HDs function in promoting stable adhesion, they are highly dynamic structures that are able to disassemble quickly, for example, during cell division, differentiation, or migration (see Margadant et al, 2008). Pubmed16757171 Pubmed18583123 Pubmed8020577 Pubmed8939649 Reactome Database ID Release 43446107 Reactome, http://www.reactome.org ReactomeREACT_20537 Reviewed: Sonnenberg, A, 2009-11-15 DSCAM interactions Authored: Garapati, P V, 2010-01-05 DSCAM (Down syndrome cell adhesion molecule) is one of the members of the Ig superfamily CAMs with a domain architecture comprising 10 Ig domains, 6 fibronectin type III (FN) repeats, a single transmembrane and a C terminal cytoplasmic domain. DSCAM is implicated in Down syndrome (DS) due to the chromosomal location of the DSCAM gene, but no evidence supports a direct involvement of DSCAM with DS. It likely functions as a cell surface receptor mediating axon pathfinding. Besides these important implications, little is known about the physiological function or the molecular mechanism of DSCAM signal transduction in mammalian systems. A closely related DSCAM paralogue Down syndrome cell adhesion moleculelike protein 1 (DSCAML1) is present in humans. Both these proteins are involved in homophilic intercellular interactions. Edited: Garapati, P V, 2010-01-05 Pubmed10925149 Pubmed18585357 Reactome Database ID Release 43376172 Reactome, http://www.reactome.org ReactomeREACT_25299 Reviewed: Clemens, JC, 2010-08-10 Cell-cell junction organization Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-05-18 22:49:42 Edited: Matthews, L, 2009-08-26 Epithelial cell-cell contacts consist of three major adhesion systems: adherens junctions (AJs), tight junctions (TJs), and desmosomes. These adhesion systems differ in their function and composition. AJs play a critical role in initiating cell–cell contacts and promoting the maturation and maintenance of the contacts (reviewed in Ebnet, 2008; Hartsock and Nelson, 2008). TJs form physical barriers in various tissues and regulate paracellular transport of water, ions, and small water soluble molecules (reviewed in Rudini and Dejana, 2008; Ebnet, 2008; Aijaz et al., 2006; Furuse and Tsukit, 2006). Desmosomes mediate strong cell adhesion linking the intermediate filament cytoskeletons between cells and playing roles in wound repair, tissue morphogenesis, and cell signaling (reviewed in Holthöfer et al., 2007). Desmosomes will be covered in a later Reactome release. GENE ONTOLOGYGO:0045216 Pubmed1616050 Pubmed16487793 Pubmed16537104 Pubmed17854762 Pubmed17964922 Pubmed18365233 Pubmed19081036 Reactome Database ID Release 43421270 Reactome, http://www.reactome.org ReactomeREACT_19331 Reviewed: Ebnet, K, 2009-08-26 Nectin/Necl trans heterodimerization Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-08-26 Nectins and Nectin-like molecules (Necls) also undergo trans-heterophilic interactions to interact with other nectin or Necl family members. Besides these trans interactions among nectins and nectin-like family members, trans-homophilic interactions have also been described between nectins or Necls with other immunoglobulin-superfamily members like CD96, CD226 and CRTAM (Sakisaka et al., 2007; Takai et al., 2008). It should be noted that some of these interactions might not exist in epithelial cell-cell contacts but may occur in other cell-cell adhesion systems. Pubmed17942295 Pubmed18648374 Reactome Database ID Release 43420597 Reactome, http://www.reactome.org ReactomeREACT_19268 Reviewed: Ebnet, K, 2009-08-26 Adherens junctions interactions Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-04-21 15:39:06 GENE ONTOLOGYGO:0034332 Pubmed16025097 Pubmed17854762 Pubmed18365233 Pubmed19081036 Reactome Database ID Release 43418990 Reactome, http://www.reactome.org ReactomeREACT_19195 Reviewed: Ebnet, K, 2009-08-26 The adherens junctions (AJ) are multiprotein complexes that promote homotypic cell adhesion in nearly all types of tissue by linking membrane and cytoskeletal components at discrete contact regions (reviewed in Hartsock & Nelson 2008; Gumbiner 2005; Ebnet, 2008). The molecular constituents of adherens junctions form adhesive units which are organized into higher order junctional adhesions that create a zipper-like seal between adjacent cells. Junctional adhesions function in epithelial cell polarization and in the coupling of cytoskeletons in adjacent cells that allow coordinated movements. During embryonic development, AJs function in specifying adhesion between cells and contribute in the sorting of different cell types. AJs also regulate cell polarity and shape, promote cell-cell communication and help mediate contact inhibition of cell growth. This module covers transdimerization events involving AJ transmembrane proteins (cadherins and nectins) (Gumbiner 2005; Ebnet 2008; Hartsock & Nelson 2008). Cell-extracellular matrix interactions Authored: Matthews, L, 2009-10-12 Cell–extracellular matrix (ECM) interactions play a critical role in regulating a variety of cellular processes in multicellular organisms including motility, shape change, survival, proliferation and differentiation. Cell–ECM contact is mediated by transmembrane cell adhesion receptors, such as integrins, that interact with extracellular matrix proteins as well as a number of cytoplasmic adaptor proteins. Many of these adaptor proteins physically interact with the actin cytoskeleton or function in signal transduction. <br>Several protein complexes interact with the cytoplasmic tail of integrins and function in transducing bi-directional signals between the ECM and intracellular signaling pathways (reviewed in Sepulveda et al., 2005).<br>Early events that are triggered by interactions with ECM, such as formation/turnover of Focal Adhesions, regulation of actin dynamics and protrusion of lamellipodia to promote cellular spreading and motility are modulated by PINCH, ILK, parvin complexes (see Sepulveda et al., 2005). A number of partners of the PINCH-ILK-parvin complex components have been identified that regulate and/or mediate the functions of these complexes (reviewed in Wu, 2004). Interactions with some of these partners modulate cytoskeletal remodeling and cell spreading. Edited: Matthews, L, 2009-11-10 Pubmed15246679 Pubmed16314921 Reactome Database ID Release 43446353 Reactome, http://www.reactome.org ReactomeREACT_20649 Reviewed: Wu, C, 2009-11-12 Tight junction interactions Authored: Matthews, L, 2009-05-15 19:26:33 Edited: Matthews, L, 2009-05-12 19:53:20 Edited: Matthews, L, 2009-08-19 GENE ONTOLOGYGO:0070830 Pubmed11283726 Pubmed12612641 Pubmed16923393 Pubmed17452622 Pubmed18365233 Reactome Database ID Release 43420029 Reactome, http://www.reactome.org ReactomeREACT_19373 Reviewed: Ebnet, K, 2009-08-26 Tight junctions (TJs) are the most apical component of the epithelial junctional complex forming a belt-like structure at the cellular junction. When visualized by freeze-fracture electron microscopy they appear as a branched network of intramembrane strands that correspond to the sites of direct membrane contacts and that are composed of the integral membrane claudin proteins. The TJs act as a primary barrier to the diffusion of solutes through the paracellular space (barrier function) (Tsukita et al., 2001). They also prevent the intermixing of intramembrane proteins and lipids and thus create a boundary between the apical and the basolateral membrane domains of polarized epithelial cells (fence function) (Tsukita et al., 2001). Interestingly, the fence function seems not to depend on TJ strands (Umeda et al., 2006). Recents evidence indicates that the TJs also participate in signal transduction mechanisms which regulate cell proliferation and morphogenesis (Matter and Balda, 2003; Matter and Balda, 2007). This module describes the major molecular interactions responsible for the formation of TJ strands and for the rectruitment of the PAR-3–aPKC–PAR-6 and CRB3–Pals1–PATJ complexes that function in tight junction formation (Ebnet, 2008). Regulation of cytoskeletal remodeling and cell spreading by IPP complex components Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-10 Pubmed15246679 Reactome Database ID Release 43446388 Reactome, http://www.reactome.org ReactomeREACT_20580 Reviewed: Wu, C, 2009-11-12 The PINCH–ILK–Parvin complexes function in transducing diverse signals from ECM to intracellular effectors. Interacting partners for components of these complexes have been identified, a number of which regulate and/or mediate its functions in cytoskeletal remodeling and cell spreading (reviewed in Wu, 2004). Localization of the PINCH-ILK-PARVIN complex to focal adhesions Authored: Matthews, L, 2009-10-12 Edited: Matthews, L, 2009-11-10 Pubmed12432066 Pubmed15246679 Reactome Database ID Release 43446343 Reactome, http://www.reactome.org ReactomeREACT_20617 Reviewed: Wu, C, 2009-11-12 The interactions among ILK, PINCH, and parvins are necessary but not sufficient for localization of ILK to cell–ECM adhesions (Zhang et al., 2002). Additional proteins that interact with PINCH–ILK–parvin complex components likely participate in mediating its localization (reviewed in Wu, 2004). PDGF A isoforms Converted from EntitySet in Reactome Reactome DB_ID: 381929 Reactome Database ID Release 43381929 Reactome, http://www.reactome.org ReactomeREACT_17286 Cleaved fragments of PDGF A chain isoforms Converted from EntitySet in Reactome Reactome DB_ID: 389067 Reactome Database ID Release 43389067 Reactome, http://www.reactome.org ReactomeREACT_18169 Sodium/Proton exchangers Authored: Jassal, B, 2009-06-11 Edited: Jassal, B, 2009-06-11 Pubmed11279194 Pubmed12845533 Pubmed15522866 Reactome Database ID Release 43425986 Reactome, http://www.reactome.org ReactomeREACT_19314 Reviewed: He, L, 2009-08-24 The SLC9 gene family encode proteins (sodium/proton exchangers, NHE or NHX) which exchange sodium (influx) for protons (efflux) electroneutrally. This mechanism is important because many metabolic processes generate acids which need to be removed to maintain pH. This is the major proton extruding system in cells, driven by the inward sodium ion chemical gradient. To date, there are eleven NHE genes, NHE1-11. NHE1-5 exchange cations at the cell membrane. NHE6-9 exchange cations at endosomal membranes or the trans-golgi network membranes. Sodium/Calcium exchangers Authored: Jassal, B, 2009-06-05 Calcium ions are used by cells as ubiquitous signalling molecules that control diverse physiological events. Three mammalian gene families control Ca2+ transport across plasma membranes and intracellular compartments (Lytton J, 2007). They are the Na+/Ca2+ exchanger family designated NCX (SLC8) (three members NCX1-3) (Quednau BD et al, 2004), the Na+/Ca2+-K+ exchanger family designated NCKX (SLC24) (five members NCKX1-5) (Schnetkamp PP, 2004) and a Ca2+/cation exchanger (NCKX6, NCLX) whose physiological function remains unclear. Edited: Jassal, B, 2009-06-05 Pubmed12734757 Pubmed14770312 Pubmed17716241 Reactome Database ID Release 43425561 Reactome, http://www.reactome.org ReactomeREACT_19320 Reviewed: He, L, 2009-08-24 ABCA transporters in lipid homeostasis A defined subset of the ABC transporter superfamily, the ABCA transporters, are highly expressed in monocytes and macrophages and are regulated by cholesterol flux which may indicate their role in in chronic inflammatory diseases (Schmitz and Kaminski 2001, Schmitz et al. 2000). Authored: Jassal, B, 2011-07-04 Edited: Jassal, B, 2011-07-04 Pubmed11048892 Pubmed11229879 Reactome Database ID Release 431369062 Reactome, http://www.reactome.org ReactomeREACT_111158 Reviewed: D'Eustachio, P, 2011-08-23 ABC-family proteins mediated transport Authored: Gopinathrao, G, 2008-11-23 14:00:06 Edited: Gopinathrao, G, 2008-11-29 15:54:33 GENE ONTOLOGYGO:0055085 Pubmed11435397 Pubmed12045106 Pubmed15209530 Pubmed19234479 Reactome Database ID Release 43382556 Reactome, http://www.reactome.org ReactomeREACT_15480 Reviewed: D'Eustachio, P, 2011-08-23 Reviewed: Matthews, L, 2008-12-02 15:41:53 The ATP-binding cassette (ABC) superfamily of active transporters involves a large number of functionally diverse transmembrane proteins. They transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. These substrates include amino acids, lipids, inorganic ions, peptides, saccharides, peptides for antigen presentation, metals, drugs, and proteins. The ABC transporters not only move a variety of substrates into and out of the cell, but are also involved in intracellular compartmental transport. Energy derived from the hydrolysis of ATP is used to transport the substrate across the membrane against a concentration gradient. Human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease (Dean et al. 2001, Borst and Elferink 2002, Rees et al. 2009). Transmembrane transport of small molecules GENE ONTOLOGYGO:0055085 Reactome Database ID Release 43382551 Reactome, http://www.reactome.org ReactomeREACT_15518 Reviewed: Jassal, B, Matthews, L, Wright, EM, 2008-12-02 15:43:13 Nephrin interactions Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2010-03-01 Nephrin is a member of the Super-IgG-Molecule family and is most prominently expressed in kidney podocytes. It is a major if not the most important structural component of the slit diaphragm, a modified adherens junction in between these cells. Nephrin is composed of an extracellular domain with eight distal IgG like domains and one proximal fibronectin type III domain, a transmembrane domain and a short intracellular domain. Nephrin molecules show both homophilic and heterophilic interactions. Among heterophilic interaction partners slit diaphragm proteins such as NEPH1, NEPH2 and NEPH3 were shown to stabilize the slit diaphragm structure. Intracellularly Podocin, CD2 associated protein (CD2AP) and adherins junction associated proteins like IQGAP, MAGI, CASK and spectrins were all shown to interact with nephrin. Hence nephrin seems to play a major role in organizing the molecular structure of the slit diaphragm itself and via its binding partners links it to the actin cytoskeleton. Nephrin does not only fulfill static properties within the slit diaphragm but by tyrosine phosphorylation of its cytoplasmic tail by the Src kinase Fyn it initiates the PI3K AKT signaling cascade which seems to promote antiapoptotic signals. Pubmed10393930 Pubmed10541305 Pubmed12832477 Pubmed15821412 Pubmed15994232 Pubmed16571882 Pubmed17766183 Pubmed19649571 Reactome Database ID Release 43373753 Reactome, http://www.reactome.org ReactomeREACT_23832 Reviewed: Huber, TB, Grahammer, Florian, 2010--0-5- Bicarbonate transporters Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 GENE ONTOLOGYGO:0015701 Pubmed14722772 Pubmed19099540 Reactome Database ID Release 43425381 Reactome, http://www.reactome.org ReactomeREACT_19298 Respiratory oxidation in the mitochondria produces carbon dioxide (CO2) as a waste product. CO2 is in equilibrium with bicarbonate (HCO3-) and is the body's central pH buffering system. HCO3- is charged so cannot move across membranes unaided. The bicarbonate transport proteins move bicarbonate across the membrane. There are 14 genes which encode these transport proteins in mammals. Applying the Human Genome Organization's sytematic nomenclature to human genes, the bicarbonate transporters belong to the SLC4A and SLC26A families. Within SLC4A, there are two distinct subfamilies, functionally corresponding to the electroneutral Cl-/HCO3- exchangers and Na+-coupled HCO3- co-transporters (Romero MF et al, 2004; Cordat E and Casey JR, 2009). Reviewed: He, L, 2009-08-24 Transport of inorganic cations/anions and amino acids/oligopeptides Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 GENE ONTOLOGYGO:0006811 Pubmed12734757 Pubmed12739168 Pubmed12759754 Pubmed12845533 Pubmed16461757 Pubmed16955105 Pubmed17581921 Pubmed17693766 Pubmed18195086 Pubmed18400693 Pubmed18690016 Pubmed19164095 Reactome Database ID Release 43425393 Reactome, http://www.reactome.org ReactomeREACT_19397 Reviewed: He, L, 2009-08-24 Teleologically, one might argue that inorganic cation and anion transport would be evolutionarily among the oldest transport functions. Eight families comprise the group that transports exclusively inorganic cations and anions across membranes : SLC4 plays a pivotal role in mediating Na+- and/or Cl–-dependent transport of basic anions [e.g. HCO3–, (CO3)2–] in various tissues and cell types (in addition to pH regulation, specific members of this family also contribute to vectorial trans-epithelial base transport in several organ systems including the kidney, pancreas, and eye) (Pushkin A and Kurtz I, 2006); SLC8 is a group of Na+/Ca2+ exchangers (SLC8A1 is involved in cardiac contractility) (Quednau BD et al, 2004); SLC24 is a group of Na+/Ca2+ or Na+/K+ exchangers (Altimimi HF and Schnetkamp PP, 2007); SLC9 comprises Na+/H+ exchanger proteins involved in the electroneutral exchange of sodium ion and protons (Orlowski J and Grinstein S, 2004); SLC12 functions as Na+, K+ and Cl– ion electroneutral symporters (Hebert SC et al, 2004); SLC26 is the trans-epithelial multifunctional anion (e.g. sulfate, oxalate, HCO3–, Cl–) exchanger family, important in cartilage development, production of thyroid hormone, sound amplification in the cochlea etc (Sindic A et al, 2007; Dorwart MR et al, 2008; Ashmore J, 2008). SLC34 is an important Type II Na+/(HPO4)2– symporter (Forster IC et al, 2006; Virkki LV et al, 2007); SLC20 was originally identified as a viral receptor, and functions as a Type III Na+/(H2PO4)– symporter (Collins JF et al, 2004; Virkki LV et al, 2007). Eight SLC gene families are involved in the transport of amino acids and oligopeptides. SLC-mediated transmembrane transport Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 GENE ONTOLOGYGO:0055085 Proteins with transporting functions can be roughly classified into 3 categories: ATP-powered pumps, ion channels, and transporters. Pumps utilize the energy released by ATP hydrolysis to power the movement of the substrates across the membrane, against their electrochemical gradient. Channels at the open state can transfer the substrates (ions or water) down their electrochemical gradient, at an extremely high efficiency (up to 108 s-1). Transporters facilitate the movement of a specific substrate –either against or following their concentration gradient, at a lower speed (about 102 -104 s-1); as generally believed, conformational change of the transporter protein is involved in the transfer process.<br><br>According to the Human Genome Organization (HUGO) Gene Nomenclature Committee, all human transporters can be grouped into the solute-carrier (SLC) superfamily. Currently, there are 55 SLC families in the superfamily, with a total of at least 362 putatively functional protein-coding genes (Hediger et al, 2004; He et al., 2009). At least 20-25% amino-acid sequence identity is shared by members belonging to the same SLC family. No homology is shared between different SLC families. While the HUGO nomenclature system by definition only includes human genes, the nomenclature system has been informally extended to include rodent species through the use of lower cases letters (e.g., Slc1a1 denotes the rodent ortholog of the human SLC1A1 gene). And it's worthwhile to mention that pumps, channels and aquporins are not included in SLC superfamily. Pubmed14624363 Pubmed19164095 Reactome Database ID Release 43425407 Reactome, http://www.reactome.org ReactomeREACT_19118 Reviewed: He, L, 2009-08-24 Mitochondrial ABC transporters Authored: Jassal, B, 2011-07-04 Edited: Jassal, B, 2011-07-04 Mammalian ABC transporters are usually found on the plasma membrane and on organelles such as the ER and peroxisome but a small number are also located on the mitochondria. Here they are thought to play roles in heme biosynthesis and iron-sulphur cluster synthesis (Burke & Ardehali 2007). Pubmed17656326 Reactome Database ID Release 431369007 Reactome, http://www.reactome.org ReactomeREACT_111108 Reviewed: D'Eustachio, P, 2011-08-23 C3G Converted from EntitySet in Reactome Reactome DB_ID: 169863 Reactome Database ID Release 43169863 Reactome, http://www.reactome.org ReactomeREACT_12233 Telomere C-strand (Lagging Strand) Synthesis Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 Due to the antiparallel nature of DNA, DNA polymerization is unidirectional, and one strand is synthesized discontinuously. This strand is called the lagging strand. Although the polymerase switching on the lagging strand is very similar to that on the leading strand, the processive synthesis on the two strands proceeds quite differently. Short DNA fragments, about 100 bases long, called Okazaki fragments are synthesized on the RNA-DNA primers first. Strand-displacement synthesis occurs, whereby the primer-containing 5'-terminus of the adjacent Okazaki fragment is folded into a single-stranded flap structure. This flap structure is removed by endonucleases, and the adjacent Okazaki fragments are joined by DNA ligase. GENE ONTOLOGYGO:0032201 Pubmed15189140 Reactome Database ID Release 43174417 Reactome, http://www.reactome.org ReactomeREACT_7961 Reviewed: Price, C, 2006-07-13 18:33:38 Phospho-IRS1/2 (by TRKA) Converted from EntitySet in Reactome Reactome DB_ID: 198301 Reactome Database ID Release 43198301 Reactome, http://www.reactome.org ReactomeREACT_13223 Telomere Maintenance Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000723 Maintenance of Telomeres Pubmed14685173 Pubmed15189140 Pubmed16166375 Pubmed2342578 Pubmed2463488 Pubmed2780561 Pubmed2805070 Pubmed3413114 Pubmed3907856 Pubmed4507727 Pubmed4754905 Pubmed642006 Pubmed7544491 Pubmed9054505 Pubmed9110970 Pubmed9252327 Pubmed9353250 Reactome Database ID Release 43157579 Reactome, http://www.reactome.org ReactomeREACT_7970 Reviewed: Price, C, 2006-07-13 18:33:38 Telomeres are protein-DNA complexes at the ends of linear chromosomes that are important for genome stability. Telomeric DNA in humans, as in many eukaryotic organisms, consists of tandem repeats (Blackburn and Gall 1978; Moyzis et al. 1988; Meyne et al. 1989). The repeats at human telomeres are composed of TTAGGG sequences and stretch for several kilobase pairs. Another feature of telomeric DNA in many eukaryotes is a G-rich 3' single strand overhang, which in humans is estimated to be approximately 50-300 bases long (Makarov et al. 1997; Wright et al. 1997; Huffman et al. 2000). Telomeric DNA isolated from humans and several other organisms can form a lasso-type structure called a t-loop in which the 3' single-strand end is presumed to invade the double stranded telomeric DNA repeat tract (Griffith et al. 1999). Telomeric DNA is bound by multiple protein factors that play important roles in regulating telomere length and in protecting the chromosome end from recombination, non-homologous end-joining, DNA damage signaling, and unregulated nucleolytic attack (reviewed in de Lange 2005). <br><br><br>DNA attrition can occur at telomeres, which can impact cell viability. Attrition can occur owing to the "end-replication problem", a consequence of the mechanism of lagging-strand synthesis (Watson 1972; Olovnikov 1973). Besides incomplete replication, nucleolytic processing also likely contributes to telomere attrition (Huffman et al. 2000). If telomeres become critically shortened, replicative senescence can result (Harley et al. 1990). Thus, in order to undergo multiple divisions, cells need a mechanism to replenish the sequence at their chromosome ends.<br><br><br>The primary means for maintaining the sequence at chromosome ends in many eukaryotic organisms, including humans, is based on telomerase (Greider and Blackburn, 1985; Morin 1989). Telomerase is a ribonucleoprotein complex minimally composed of a conserved protein subunit containing a reverse transcriptase domain (telomerase reverse transcriptase, TERT) (Lingner et al. 1997; Nakamura et al. 1997) and a template-containing RNA (telomerase RNA component, TERC, TR, TER) (Greider and Blackburn, 1987; Feng et al 1995). Telomerase uses the RNA template to direct addition of multiple tandem repeats to the 3' G-rich single strand overhang. Besides extension by telomerase, maintenance of telomeric DNA involves additional activities, including C-strand synthesis, which fills in the opposing strand, and nucleolytic processing, which likely contributes to the generation of the 3' overhang.<br> Deposition of New CENPA-containing Nucleosomes at the Centromere Authored: May, B, 2010-04-15 Edited: May, B, 2010-04-15 Eukaryotic centromeres are marked by a unique form of histone H3, designated CENPA in humans. In human cells newly synthesized CENPA is deposited in nucleosomes at the centromere during late telophase/early G1 phase of the cell cycle. Once deposited, nucleosomes containing CENPA remain stably associated with the centromere and are partitioned equally to daughter centromeres during S phase. A current model proposes that pre-existing CENPA at the centromere drives recruitment of new CENPA, however this has not been proved.<br>The deposition process requires at least 3 complexes: the Mis18 complex, HJURP complex, and the RSF complex. HJURP binds newly synthesized CENPA-H4 tetramers before deposition and brings them to the centromere for deposition in new CENPA-containing nucleosomes. The exact mechanism of deposition remains unknown. GENE ONTOLOGYGO:0034080 Pubmed17339380 Pubmed19410539 Pubmed19410544 Pubmed19410545 Pubmed19590885 Pubmed19629040 Pubmed19660450 Pubmed20080577 Reactome Database ID Release 43606279 Reactome, http://www.reactome.org ReactomeREACT_22186 Reviewed: Almouzni-Pettinotti, G, Dunleavy, EM, 2010-05-30 Reviewed: Foltz, DR, 2010-06-14 Telomere Extension By Telomerase Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0007004 Humans, like most eukaryotic organisms, add direct repeats to the telomere using a specialized DNA polymerase called telomerase. Telomerase is a ribonucleoprotein (RNP) complex minimally composed of a conserved protein subunit containing a reverse transcriptase domain (human telomerase reverse transcriptase, hTERT) and a template-containing RNA (human telomerase RNA component, hTERC, or hTR, hTER). The primer for telomerase is the G-rich single-strand overhang at the chromosome end. <br><br><br>Telomerase can perform multiple rounds of repeat synthesis. The reaction cycle has been inferred from in vitro studies of telomerase from multiple organisms and can be described as having four events: 1) DNA primer recognition, 2) RNA template alignment, 3) elongation, and 4) translocation. Telomeric DNA is recognized in part by a presumed "anchor site" in hTERT, which preferentially binds G-rich DNA, and this interaction can affect elongation and translocation steps. This interaction occurs 5' of the alignment of the RNA template with the end nucleotides of the chromosome. RNA alignment positions the template adjacent to the chromosome terminus. During elongation, the template directs sequential addition of nucleotides to the telomere end. After synthesis of a repeat is completed, relative movement of telomerase and the primer, termed translocation, repositions telomerase at the end of the newly added sequence to allow initiation of another round of repeat addition. <br> Pubmed14685173 Pubmed15189140 Reactome Database ID Release 43171319 Reactome, http://www.reactome.org ReactomeREACT_7974 Reviewed: Price, C, 2006-07-13 18:33:38 IRS1,2 Converted from EntitySet in Reactome Reactome DB_ID: 198273 Reactome Database ID Release 43198273 Reactome, http://www.reactome.org ReactomeREACT_12744 Extension of Telomeres Pubmed15189140 Reactome Database ID Release 43180786 Reactome, http://www.reactome.org ReactomeREACT_8030 Reviewed: Price, C, 2006-07-13 18:33:38 Telomerase acts as reverse transcriptase in the elongation of telomeres (Smogorzewska and de Lange 2004). Autodegradation of Cdh1 by Cdh1:APC/C Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Cdh1 is degraded by the APC/C during in G1 and G0. This auto-regulation may contribute to reducing the levels of Cdh1 levels during G1 and G0 (Listovsky et al., 2004). Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0051436 Pubmed15029244 Reactome Database ID Release 43174084 Reactome, http://www.reactome.org ReactomeREACT_6785 Reviewed: Peters, JM, 2006-03-27 22:55:09 APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-01-30 00:00:00 From late mitosis through G1 phase APC/C:Cdh1 insures the continued degradation of the mitotic proteins and during mitotic exit and G1 its substrates include Cdc20, Plk1, Aurora A, Cdc6 and Geminin (see Castro et al., 2005). Rape et al. have recently demonstrated that the order in which APC/C targeted proteins are degraded is determined by the processivity of multiubiquitination of these substrates. Processive substrates acquire a polyubiquitin chain upon binding to the APC/C once and are degraded. Distributive substrates bind, dissociate and reassociate with the APC/C multiple times before acquiring an ubiquitin chain of sufficient length to insure degradation. In addition, distributive substrates that dissociate from the APC/C with short ubiquitin chains are targeted for deubiquitination (Rape et al., 2006). GENE ONTOLOGYGO:0031145 Pubmed15678131 Pubmed16413484 Reactome Database ID Release 43174178 Reactome, http://www.reactome.org ReactomeREACT_6761 Reviewed: Peters, JM, 2006-03-27 22:55:09 Nucleosome assembly Authored: Matthews, L, 2010-05-21 Edited: Matthews, L, 2010-05-24 GENE ONTOLOGYGO:0006334 Reactome Database ID Release 43774815 Reactome, http://www.reactome.org ReactomeREACT_22344 The formation of centromeric chromatin assembly outside the context of DNA replication involves the assembly of nucleosomes containing the histone H3 variant CenH3 (also called CENP-A). Chromosome Maintenance Authored: Gillespie, ME, 0000-00-00 00:00:00 Chromosome maintenance is critical for stable chromosome function in mammalian and other eukaryotic cells. Aspects of telomere maintenance and nucleosome assembly are covered here. Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Reactome Database ID Release 4373886 Reactome, http://www.reactome.org ReactomeREACT_22172 Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-02-17 00:35:21 GENE ONTOLOGYGO:0051439 Pubmed15678131 Reactome Database ID Release 43176407 Reactome, http://www.reactome.org ReactomeREACT_6867 Reviewed: Peters, JM, 2006-03-27 22:55:09 The activity of the APC/C must be appropriately regulated during the cell cycle to ensure the timely degradation of its substrates. Of particular importance is the conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase. Phosphorylation of both the APC/C complex and Cdh1 regulate this conversion. During mitosis, several APC/C subunits are phosphorylated increasing the activity of APC/C:Cdc20. However, phosphorylation of Cdh1 by mitotic Cyclin:Cdk complexes prevents it from activating the APC/C. Dephosphorylation of Cdh1 in late anaphase by Cdc14a results in the activation of APC/C:Cdh1 (reviewed in Castro et al, 2005). Phospho-STAT3 Converted from EntitySet in Reactome Reactome DB_ID: 198743 Reactome Database ID Release 43198743 Reactome, http://www.reactome.org ReactomeREACT_12279 STAT3 Converted from EntitySet in Reactome Reactome DB_ID: 198665 Reactome Database ID Release 43198665 Reactome, http://www.reactome.org ReactomeREACT_12309 Cell junction organization Edited: Matthews, L, 2009-11-17 GENE ONTOLOGYGO:0034329 Reactome Database ID Release 43446728 Reactome, http://www.reactome.org ReactomeREACT_20676 Cell-Cell communication Authored: Garapati, P V, 2011-08-23 Cell-to-Cell communication is crucial for multicellular organisms because it allows organisms to coordinate the activity of their cells. Some cell-to-cell communication requires direct cell-cell contacts and this is mediated by different receptors on their cell surfaces. Members of the immunoglobulin superfamily (IgSF) proteins are some of the cell surface receptors involved in cell-cell recognition, communication and many aspects of the axon guidance and synapse formation-the crucial processes during embryonal development (Rougon & Hobert 2003).<br>Cells interact with adjacent cells as well as with extracellular matrix in tissues and these interactions are supported by cell junctions. Cell junctions consists of protein complexes and include various cell adhesion molecules (CAMs). Cell junctions are more abundant in epithelial cells and there are three major types of cell junctions: adherens junctions (AJs), tight junctions (TJs), and desmosomes. Edited: Garapati, P V, 2011-08-23 Pubmed12598678 Pubmed1616050 Pubmed16691243 Pubmed17766183 Pubmed18837673 Pubmed20554646 Reactome Database ID Release 431500931 Reactome, http://www.reactome.org ReactomeREACT_111155 APC-Cdc20 mediated degradation of Nek2A Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Edited: Matthews, L, 2006-07-11 10:28:00 Like Cyclin A, NIMA-related kinase 2A (Nek2A) is degraded during pro-metaphase in a checkpoint-independent manner. Pubmed11742988 Pubmed16648845 Reactome Database ID Release 43179409 Reactome, http://www.reactome.org ReactomeREACT_8017 Reviewed: Peters, JM, 2006-03-27 22:55:09 Dephosphorylation of pChREBP by PP2A Reactome Database ID Release 43163362 Reactome, http://www.reactome.org ReactomeREACT_1919 Meiotic Synapsis Authored: May, B, 2011-02-25 Edited: May, B, 2011-02-25 Meiotic synapsis is the stable physical pairing of homologous chromosomes that begins in leptonema of prophase I and lasts until anaphase of prophase I. First, short segments of axial elements form along chromosomes. Telomeres then cluster at a region of the inner nuclear membrane and axial elements extend and fuse along the length of the chromosomes. Subsequent to the initiation of recombination transverse filaments of SYCP1 link axial/lateral elements to a central element containing SYCE1 and SYCE2, thus forming the synaptonemal complex (reviewed in Yang and Wang 2009).<br>Unsynapsed regions are silenced during pachynema by recruitment of BRCA1 and ATR, which phosphorylates histone H2AX (reviewed in Inagaki et al. 2010). Pubmed18948708 Pubmed20364103 Reactome Database ID Release 431221632 Reactome, http://www.reactome.org ReactomeREACT_75792 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Packaging Of Telomere Ends Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000723 Multiple steps, including C-strand resection, telomerase-mediated elongation, and C-strand synthesis are involved in processing and maintaining the telomere. Though this module posits a linear transit for the steps, in humans it is not well understood how these steps are coordinated and what other events may be involved.<br><br><br>Telomeric DNA can form higher order structures. Electron microscopy of telomeric DNA isolated from human cells provided evidence for lariat-type structures termed telomeric loops, or t-loops (Griffith et al., 1999). t-loops are proposed to result from the invasion of the 3' G-rich single strand overhang into the double stranded telomeric TTAGGG repeat tract. The function of the t-loop is presumed to be the masking of the 3' telomeric overhang. Multiple protein factors can bind telomeric DNA and likely contribute to dynamic, higher order structures.<br> Pubmed10338214 Reactome Database ID Release 43171306 Reactome, http://www.reactome.org ReactomeREACT_7963 Reviewed: Price, C, 2006-07-13 18:33:38 Removal of the Flap Intermediate from the C-strand Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed1671046 Reactome Database ID Release 43174437 Reactome, http://www.reactome.org ReactomeREACT_7999 Reviewed: Price, C, 2006-07-13 18:33:38 Two endonucleases, Dna2 and flap endonuclease 1 (FEN-1), are responsible for resolving the nascent flap structure (Tsurimoto and Stillman 1991). The Dna2 endonuclease/helicase in yeast is a monomer of approximately 172 kDa. Human FEN-1 is a single polypeptide of approximately 42 kDa. Replication Protein A regulates the switching of endonucleases during the removal of the displaced flap. Processive synthesis on the C-strand of the telomere Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Once polymerase switching from pol alpha to pol delta is complete the processive synthesis of a short run of DNA called an Okazaki fragment begins. DNA synthesis is discontinuous and as the extending Okazaki fragment reaches the RNA primer, this primer is folded into a single-stranded flap, which is removed by endonucleases. The process of extension is completed by the ligation of adjacent Okazaki fragments. Pubmed1671046 Reactome Database ID Release 43174414 Reactome, http://www.reactome.org ReactomeREACT_8027 Reviewed: Price, C, 2006-07-13 18:33:38 Polymerase switching on the C-strand of the telomere After the primers are synthesized on the G-Rich strand, Replication Factor C binds to the 3'-end of the initiator DNA to trigger polymerase switching. The non-processive nature of pol alpha catalytic activity and the tight binding of Replication Factor C to the primer-template junction presumably lead to the turnover of the pol alpha:primase complex. After the Pol alpha-primase primase complex is displaced from the primer, the proliferating cell nuclear antigen (PCNA) binds to form a "sliding clamp" structure. Replication Factor C then dissociates, and DNA polymerase delta binds and catalyzes the processive synthesis of DNA. Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 GENE ONTOLOGYGO:0000722 Pubmed1670772 Pubmed1671046 Pubmed1967833 Reactome Database ID Release 43174411 Reactome, http://www.reactome.org ReactomeREACT_7987 Reviewed: Price, C, 2006-07-13 18:33:38 Telomere C-strand synthesis initiation Authored: Blackburn, EH, Seidel, J, 2006-03-09 19:41:08 DNA polymerases are not capable of de novo DNA synthesis and require synthesis of a primer, usually by a DNA-dependent RNA polymerase (primase) to begin DNA synthesis. In eukaryotic cells, the primer is synthesized by DNA polymerase alpha:primase. First, the DNA primase portion of this complex synthesizes approximately 6-10 nucleotides of RNA primer and then the DNA polymerase portion synthesizes an additional 20 nucleotides of DNA. There have been reports that TRF1 inhibits this activity at telomeres, though the mechanism and physiological relevance of this inhibition remain to be elucidated. GENE ONTOLOGYGO:0000722 Pubmed11327863 Pubmed11395402 Pubmed6693436 Reactome Database ID Release 43174430 Reactome, http://www.reactome.org ReactomeREACT_7993 Reviewed: Price, C, 2006-07-13 18:33:38 XC1 ligands Converted from EntitySet in Reactome Reactome DB_ID: 373356 Reactome Database ID Release 43373356 Reactome, http://www.reactome.org ReactomeREACT_15007 CCL19,21 Converted from EntitySet in Reactome Reactome DB_ID: 373283 Reactome Database ID Release 43373283 Reactome, http://www.reactome.org ReactomeREACT_14912 CCR9 CC chemokine receptor 9 Converted from EntitySet in Reactome Reactome DB_ID: 373226 Reactome Database ID Release 43373226 Reactome, http://www.reactome.org ReactomeREACT_14914 CX3C1 receptor Converted from EntitySet in Reactome Reactome DB_ID: 373350 Reactome Database ID Release 43373350 Reactome, http://www.reactome.org ReactomeREACT_14957 CCL27,28 Converted from EntitySet in Reactome Reactome DB_ID: 373322 Reactome Database ID Release 43373322 Reactome, http://www.reactome.org ReactomeREACT_14942 Opioid receptors Converted from EntitySet in Reactome Reactome DB_ID: 374277 Reactome Database ID Release 43374277 Reactome, http://www.reactome.org ReactomeREACT_14921 Dynorphins Converted from EntitySet in Reactome Reactome DB_ID: 374372 Reactome Database ID Release 43374372 Reactome, http://www.reactome.org ReactomeREACT_14913 TAK1 Associated with the CBM Complex Phosphorylates IKKbeta Authored: May, B, 2010-12-18 EC Number: 2.7.11 Edited: May, B, 2010-12-18 Pubmed11460167 Pubmed14695475 Pubmed16301747 Pubmed19909372 Pubmed20449947 Reactome Database ID Release 431168641 Reactome, http://www.reactome.org ReactomeREACT_118689 Reviewed: Wienands, J, 2012-02-11 TAK1 phosphorylates IKK-beta (Wang et al. 2001). As inferred from chicken B cells, the reaction in human B cells may occur when TAK1 and the IKK complex are associated with the CARMA1:BCL10:MALT1 (CBM) complex. During T cell activation TAK1 forms a complex with TAB1 and TAB2, which binds K-63 conjugated polyubiquitin attached to TRAF6 associated with the CBM complex (Sun et al. 2004, reviewed in Shinohara et al. 2009). TRAF6 also polyubiquitinates IKK-gamma in T cells (Zhou et al. 2004). B cells contain functional TRAF6 and TRAF2 (Zhang et al. 2010) so the same mechanism may occur during activation of B cells. Neuropeptides B/W receptors Converted from EntitySet in Reactome Reactome DB_ID: 374798 Reactome Database ID Release 43374798 Reactome, http://www.reactome.org ReactomeREACT_15030 Phosphorylation of CARMA1 in B Cells Authored: May, B, 2010-12-18 CARMA1 is phosphorylated at serines 559, 644, and 652 by Protein Kinase C beta (PKC-beta) (Sommer et al. 2005). CARMA1 is constitutively oligomerized (Tanner et al. 2007) and most CARMA1 in unstimulated cells is cytosolic (Sommer et al. 2005, Tanner et al. 2007), though a portion is constitutively associated with the plasma membrane (Gaide et al. 2002, Sommer et al. 2005). After phosphorylation, CARMA1 is associated with lipid rafts in the plasma membrane (Sommer et al. 2005). Note that some publications refer to CARMA1 with a different N-terminal methionine that is 7 amino acids shorter. In this case the phosphorylated serines are 552, 537, and 645. EC Number: 2.7.11 Edited: May, B, 2010-12-18 Pubmed16356855 Reactome Database ID Release 431168635 Reactome, http://www.reactome.org ReactomeREACT_118598 Reviewed: Wienands, J, 2012-02-11 has a Stoichiometric coefficient of 6 Activation of Protein Kinase C beta (PKC-beta) Authored: May, B, 2010-12-09 Edited: May, B, 2010-12-09 Human Protein kinase C beta (PKC-beta) is activated by calcium ions, diacylglycerol, and binds phosphatidylserine (Kochs et al. 1991). Experiments in mice have shown that knocking out PKC-beta causes severe defects in B cells, leading to the conclusion that PKC-beta is the predominant signaling PKC in these cells (Leitges et al. 1996, Su et al. 2002, Saijo et al. 2002). Pubmed12070292 Pubmed12118249 Pubmed8387275 Pubmed8670417 Reactome Database ID Release 431168373 Reactome, http://www.reactome.org ReactomeREACT_118748 Reviewed: Wienands, J, 2012-02-11 has a Stoichiometric coefficient of 3 Calcium Influx via TRPC1 Authored: May, B, 2012-01-31 Edited: May, B, 2012-01-31 Pubmed17224452 Pubmed17486119 Pubmed18995841 Pubmed22210847 Reactome Database ID Release 432089943 Reactome, http://www.reactome.org ReactomeREACT_118688 Reviewed: Wienands, J, 2012-02-11 TRPC1 forms a channel that transports Ca2+ across the plasma membrane. TRPC1 is gated by STIM1 (Ong et al. 2007). STIM1 Binds TRPC1 Authored: May, B, 2012-01-31 Edited: May, B, 2012-01-31 Formation of STIM1:TRPC1 Complex Pubmed11901194 Pubmed16906149 Pubmed17224452 Pubmed17486119 Pubmed18326500 Pubmed18420269 Pubmed18843204 Pubmed18995841 Pubmed21408196 Pubmed22210847 Reactome Database ID Release 432089927 Reactome, http://www.reactome.org ReactomeREACT_118759 Reviewed: Wienands, J, 2012-02-11 The polybasic region of STIM1 interacts with 2 aspartate residues in the C-terminal region of TRPC1 (Zeng et al. 2008, Huang et al. 2006). The STIM1:TRPC1 complex can form a tenary complex with ORAI1 (Ong et al. 2007, Jardin et al. 2008) and ORAI participates in function of STIM1:TRPC1 channels (Cheng et al. 2008, Cheng et al. 2011). As inferred from chicken DT40 cells, TRPC1 (and possibly other TRP channels) participates in store-operated calcium influx during signaling by the B cell receptor (Mori et al. 2002). Oligomerization of STIM1 Authored: May, B, 2011-01-19 Edited: May, B, 2011-01-19 In the resting state the luminal domain of STIM1 binds Ca2+ ions within the endoplasmic reticulum and this binding prevents dimerization of STIM1 (Luik et al. 2008). Upon depletion of Ca2+ ions from the endoplasmic reticulum, STIM1 is no longer bound to Ca2+ and forms homodimers (Muik et al. 2008, Luik et al. 2008, Park et al. 2009). Pubmed18187424 Pubmed18596693 Pubmed19249086 Reactome Database ID Release 431168376 Reactome, http://www.reactome.org ReactomeREACT_118808 Reviewed: Wienands, J, 2012-02-11 has a Stoichiometric coefficient of 2 BLNK (SLP-65) Signalosome Generates Diacylglycerol and Inositol-1,4,5-trisphosphate Authored: May, B, 2011-01-19 Edited: May, B, 2011-01-19 Phospholipase C gamma (PLC-gamma) is activated by phosphorylation in response to antigen-binding by the B cell receptor (Carter et al. 1991, Roitman and Wang 1992, Rodriguez et al. 2001, Kim et al. 2004, Sekiya et al. 2004). Phospholipase C gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate and diacylglycerol (Carter et al. 1991, Kim et al. 2004). Human B cells contain both PLC-gamma1 and PLC-gamma2, with PLC-gamma2 predominating (Coggeshall et al. 1992). Pubmed12181444 Pubmed1374290 Pubmed1376928 Pubmed1599430 Pubmed1705565 Pubmed2011584 Pubmed3500860 Reactome Database ID Release 431112666 Reactome, http://www.reactome.org ReactomeREACT_118781 Reviewed: Wienands, J, 2012-02-11 CD19 Signalosome Generates PIP3 Authored: May, B, 2012-01-10 EC Number: 2.7.1.153 Edited: May, B, 2012-01-10 PI3K generates phosphoinositol-3,4,5-trisphosphate (PIP3) from PIP2 after activation of the BCR (Gold et al. 1992). Experiments in mice indicate that PI3K associated with CD19 is partly responsible for the activity (Buhl et al. 1997, Otero et al. 2001, Aiba et al. 2008). (PI3K associated with BCAP is also partly responsible (Aiba et al. 2008).) Pubmed11042164 Pubmed1372019 Pubmed18025150 Pubmed9235916 Pubmed9382888 Reactome Database ID Release 432076220 Reactome, http://www.reactome.org ReactomeREACT_118828 Reviewed: Wienands, J, 2012-02-11 BCAP Signalosome Generates PIP3 Authored: May, B, 2012-01-10 Edited: May, B, 2012-01-10 PI3K generates phosphoinositol-3,4,5-trisphosphate (PIP3) from PIP2 after activation of the BCR (Gold et al. 1992, Chantry et al. 1997). Experiments in mice indicate that PI3K associated with BCAP is partly responsible for the activity (Aiba et al. 2008). (PI3K associated with CD19 is also partly responsible (Aiba et al. 2008).) Pubmed1372019 Pubmed18025150 Pubmed9235916 Reactome Database ID Release 432045911 Reactome, http://www.reactome.org ReactomeREACT_118601 Reviewed: Wienands, J, 2012-02-11 CARMA1:BCL10:MALT1 Complex Recruits TAK1 and IKK Authored: May, B, 2010-12-18 Edited: May, B, 2010-12-18 Pubmed16301747 Pubmed16356855 Pubmed19909372 Reactome Database ID Release 431168637 Reactome, http://www.reactome.org ReactomeREACT_118585 Reviewed: Wienands, J, 2012-02-11 TAK1 and the IKK complex are observed to migrate from the cytosol to lipid rafts containing the CARMA1:BCL10:MALT1 (CBM) complex (Sommer et al. 2005, Shinohara et al. 2005 using chicken cells). By analogy with activation of NF-KappaB signaling in T cells, TAK1 in B cells may also be bound to TAB1 and TAB2 or TAB3, which bind K63-conjugated polyubiquitin on a TRAF protein bound to the CBM complex (reviewed in Shinohara et al. 2009). Formation of CBM Complex Authored: May, B, 2010-12-18 CARMA1 Recruits MALT1 and BCL10 to Form CBM Complex CARMA1 is phosphorylated and recruits BCL10 and MALT1 to the plasma membrane to form the CBM complex (Sommer et al. 2005, Tanner et al. 2007). Evidence from T cells (Jurkat cells) indicates that MALT1 and BCL10 oligomerize to activate the IKK complex (Zhou 2004). Edited: May, B, 2010-12-18 Pubmed14695475 Pubmed16356855 Pubmed17428801 Reactome Database ID Release 431168644 Reactome, http://www.reactome.org ReactomeREACT_118777 Reviewed: Wienands, J, 2012-02-11 has a Stoichiometric coefficient of 2 Cyclin E associated events during G1/S transition Reactome Database ID Release 4369202 Reactome, http://www.reactome.org ReactomeREACT_1574 The transition from the G1 to S phase is controlled by the Cyclin E:Cdk2 complexes. As the Cyclin E:Cdk2 complexes are formed, the Cdk2 is phosphorylated by the Wee1 and Myt1 kinases. This phosphorylation keeps the Cdk2 inactive. In yeast this control is called the cell size checkpoint control. The dephosphorylation of the Cdk2 by Cdc25A activates the Cdk2, and is coordinated with the cells reaching the proper size, and with the DNA synthesis machinery being ready. The Cdk2 then phosphorylates G1/S specific proteins, including proteins required for DNA replication initiation. The beginning of S-phase is marked by the first nucleotide being laid down on the primer during DNA replication at the early-firing origins G1/S Transition Cyclin E - Cdk2 complexes control the transition from G1 into S-phase. In this case, the binding of p21Cip1/Waf1 or p27kip1 is inhibitory. Important substrates for Cyclin E - Cdk2 complexes include proteins involved in the initiation of DNA replication. The two Cyclin E proteins are subjected to ubiquitin-dependent proteolysis, under the control of an E3 ubiquitin ligase known as the SCF. Cyclin A - Cdk2 complexes, which are also regulated by p21Cip1/Waf1 and p27kip1, are likely to be important for continued DNA synthesis, and progression into G2. An additional level of control of Cdk2 is reversible phosphorylation of Threonine-14 (T14) and Tyrosine-15 (Y15), catalyzed by the Wee1 and Myt1 kinases, and dephosphorylation by the three Cdc25 phosphatases, Cdc25A, B and C. GENE ONTOLOGYGO:0000082 Reactome Database ID Release 4369206 Reactome, http://www.reactome.org ReactomeREACT_1783 Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes Pubmed12851482 Reactome Database ID Release 4369200 Reactome, http://www.reactome.org ReactomeREACT_308 The G1/S transition is facilitated by Cyclin E:Cdk2-mediated phoshorylation of proteins including Rb and Cyclin Kinase Inhibitors (CKIs). SCF(Skp2)-mediated degradation of p27/p21 Authored: Pagano, M, 2006-09-19 08:23:10 During G1, the activity of cyclin-dependent kinases (CDKs) is kept in check by the CDK inhibitors (CKIs) p27 and p21, thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). These two CKIs are degraded in late G1 phase by the ubiquitin pathway (Pagano et al., 1995; Bloom et al., 2003) involving the ubiquitin ligase SCF(Skp2) (Tsvetkov et al., 1999; Carrano et al., 1999; Sutterluty et al., 1999, Bornstein et al., 2003) and the cell-cycle regulatory protein Cks1 (Ganoth et al., 2001; Spruck et al 2001; Bornstein et al., 2003). Recognition of p27 by SCF(Skp2) and its subsequent ubiquitination is dependent upon Cyclin E/A:Cdk2- mediated phosphorylation at Thr 187 of p27 (Montagnoli et al., 1999). There is evidence that Cyclin A/B:Cdk1 complexes can also bind and phosphorylate p27 on Th187 (Nakayama et al., 2004). Degradation of polyubiquitinated p27 by the 26S proteasome promotes the activity of CDKs in driving cells into S phase. (Montagnoli et al., 1999; Tsvetkov et al., 1999, Carrano et al 1999). The mechanism of SCF(Skp2)-mediated degradation of p21 is similar to that of p27 in terms of its requirements for the presence of Cks1 and of Cdk2/cyclin E/A (Bornstein et al.,2003; Wang et al., 2005). In addition, as observed for p27, p21 phosphorylation at a specific site (Ser130) stimulates its ubiquitination. In contrast to p27, however, ubiquitination of p21 can take place in the absence of phosphorylation, although with less efficiency (Bornstein et al.,2003). SCF(Skp2)-mediated degradation of p27/p21 continues from late G1 through M-phase. During G0 and from early G1 to G1/S, Skp2 is degraded by the anaphase promoting complex/Cyclosome and its activator Cdh1 [APC/C(Cdh1)] (Bashir et al, 2004; Wei et al, 2004). The tight regulation of APC/C(Cdh1) activity ensures the timely elimination Skp2 and, thus, plays a critical role in controlling the G1/S transition. APC/C(Cdh1) becomes active in late M-phase by the association of unphosphorylated Cdh1 with the APC/C. APC/C(Cdh1) remains active until the G1/S phase at which time it interacts with the inhibitory protein, Emi1 (Hsu et al., 2002). Inhibition of APC/C(Cdh1) activity results in an accumulation of cyclins, which leads to the phosphorylation and consequently to a further inactivation of Cdh1 at G1/S (Lukas et al., 1999). Finally, to make the inactivation of APC/C(Cdh1) permanent, Cdh1 and its E2, namely Ubc10, are eliminated in an auto-ubiquitination event (Listovsky et al., 2004; Rape and Kirschner, 2004). At G1/S, Skp2 reaccumulates as Cdh1 is inactivated, thus allowing the ubiquitination of p21 and p27 and resulting in a further increase in CDK activity. Edited: Matthews, L, 2006-09-19 08:32:00 Pubmed10323868 Pubmed10375532 Pubmed10548110 Pubmed10559916 Pubmed10559918 Pubmed11231585 Pubmed11463388 Pubmed11988738 Pubmed12730199 Pubmed14532004 Pubmed15014502 Pubmed15014503 Pubmed15029244 Pubmed15130491 Pubmed15558010 Pubmed16262255 Pubmed16600864 Pubmed7624798 Reactome Database ID Release 43187577 Reactome, http://www.reactome.org ReactomeREACT_9003 Reviewed: Coqueret, O, 2006-10-06 08:59:06 G1/S-Specific Transcription GENE ONTOLOGYGO:0000083 Reactome Database ID Release 4369205 Reactome, http://www.reactome.org ReactomeREACT_683 The E2F family of transcription factors regulate the transition from the G1 to the S phase in the cell cycle. E2F activity is regulated by members of the retinoblastoma protein (pRb) family, resulting in the tight control of the expression of E2F-responsive genes. Phosphorylation of pRb by cyclin D:CDK complexes releases pRb from E2F, inducing E2F-targeted genes such as cyclin E. Ubiquitin-Dependent Degradation of Cyclin E Failure to appropriately regulate cyclin E accumulation can lead to accelerated S phase entry, genetic instability, and tumorigenesis. The amount of cyclin E protein in the cell is controlled by ubiquitin-mediated proteolysis (see Woo, 2003).This pathway has not yet been annotated in Reactome. Pubmed12851482 Reactome Database ID Release 4369201 Reactome, http://www.reactome.org ReactomeREACT_926 Inhibition of replication initiation of damaged DNA by RB1/E2F1 Reactome Database ID Release 43113501 Reactome, http://www.reactome.org ReactomeREACT_329 E2F mediated regulation of DNA replication Authored: Gopinathrao, G, 2004-06-16 19:20:00 Progression through G1 and G1 to S-phase transition that initiates DNA synthesis involve many complexes that are regulated by RB1:E2F pathway. RB1:E2F pathway plays a key role in gene expression regulation in proliferating and differentiated cells. As a repressor, E2F remains bound to RB1; it can activate the expression of S-phase genes involved in DNA replication after the phosphorylation of RB1.<BR>E2F proteins regulate expression of genes involved in various processes thereby forming interlinks between cell cycle, DNA synthesis, DNA damage recognition etc.<BR>In this module, activation of replication related genes by E2F1 and two ways by which E2F1 regulates DNA replication initiation are annotated. Detailed connection between the E2F protein function and various pathways will be covered in future releases of Reactome. Pubmed12393009 Pubmed12473340 Pubmed12726857 Reactome Database ID Release 43113510 Reactome, http://www.reactome.org ReactomeREACT_471 The Immunoglobulin of the BCR Binds Antigen Authored: May, B, 2010-09-28 Edited: May, B, 2010-09-28 Mature, unstimulated B cells express IgM and IgD immunoglobulins on their surfaces (Fu et al. 1974, Fu et al. 1975, reviewed in Kunkel 1975). The immunoglobulins form B cell receptor (BCR) complexes with disulfide-linked heterodimers of Ig-alpha (CD79A) and Ig-beta (CD79B), which have cytoplasmic tails containing immunoreceptor tyrosine-based activation motifs (ITAMs) (van Noesel et al. 1992, Saouaf et al. 1995, inferred from mouse Hombach et al. 1990, Wienands et al. 1990). Upon binding of antigen to the immunoglobulin a chain of phosphorylation events is triggered (Nel et al. 1984, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Harwood and Batista 2010). Pubmed1081164 Pubmed1375264 Pubmed20192804 Pubmed2303036 Pubmed2304550 Pubmed4589993 Pubmed6335036 Pubmed7524079 Pubmed7592958 Pubmed7927516 Pubmed803528 Reactome Database ID Release 43983696 Reactome, http://www.reactome.org ReactomeREACT_118606 Reviewed: Wienands, J, 2012-02-11 The Immunoglobulin of the B Cell Receptor Binds Antigen Grb2 binds pBTLA Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed12796776 Pubmed16932752 Reactome Database ID Release 43389919 Reactome, http://www.reactome.org ReactomeREACT_19406 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 The sequence around Y226 in the BTLA cytoplasmic domain is a predicted recruitment site for Grb2. Despite the prediction there is no direct evidence of protein recruitment to this tyrosine motif. Recruitment of SYK to the Activated BCR Authored: May, B, 2010-10-31 Edited: May, B, 2010-10-31 Pubmed18818202 Pubmed7538118 Pubmed7592958 Pubmed8163536 Reactome Database ID Release 43983700 Reactome, http://www.reactome.org ReactomeREACT_118749 Recruitment of SYK to the Activated B Cell Receptor Reviewed: Wienands, J, 2012-02-11 The SYK protein tyrosine kinase binds specifically to phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Law et al. 1994, Saouaf et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding activates the kinase activity of SYK (Rowley et al. 1995, Tsang et al. 2008). Phosphorylation of ITAMs of Ig-alpha (CD79A) and Ig-beta (CD79B) Authored: May, B, 2010-09-28 EC Number: 2.7.10 Edited: May, B, 2010-09-28 Pubmed12453414 Pubmed1702903 Pubmed7524079 Pubmed7592958 Pubmed7688784 Pubmed7927516 Pubmed8306975 Reactome Database ID Release 43983709 Reactome, http://www.reactome.org ReactomeREACT_118716 Reviewed: Wienands, J, 2012-02-11 The B cell receptor (BCR) comprises an immunoglobulin complexed with a heterodimer of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29). After immunoglobulin IgM or IgD binds antigen the associated Ig-alpha and Ig-beta are each observed to be phosphorylated at two tyrosine residues in the cytoplasmic immunoreceptor tyrosine-activated motif (ITAM) (Sanchez et al. 1993, Hata et al. 1994, Saouaf et al. 1994, Saouaf et al. 1995). Saouaf et al. (1995) showed that the kinase Blk could phosphorylate both tyrosines of each ITAM and that the kinase SYK specifically bound phosphorylated but not unphosphorylated ITAMs. In mouse the kinase Lyn and other kinases phosphorylate one tyrosine and Syk is believed to phosphorylate the other (Yamanashi et al. 1991, Flaswinkel and Reth 1994, Rolli et al. 2002). has a Stoichiometric coefficient of 4 Dephosphorylation of CD3-zeta by PD-1 bound phosphatases Authored: Garapati, P V, 2008-12-16 11:12:19 EC Number: 3.1.3.48 Edited: Garapati, P V, 2008-12-16 11:12:19 PD-1 delivers inhibitory signals and downregulates antigen receptor signaling through direct dephosphorylation of signaling intermediates. The phosphatases SHP-1 and SHP-2 dephosphorylate CD3 zeta and inhibit the phosphorylation of ZAP-70 and PKC theta. Pubmed12947224 Pubmed15358536 Pubmed18173375 Pubmed18759926 Reactome Database ID Release 43389758 Reactome, http://www.reactome.org ReactomeREACT_19146 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 has a Stoichiometric coefficient of 12 HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2130380 Reactome Database ID Release 432130380 Reactome, http://www.reactome.org ReactomeREACT_121949 SHP-1 and SHP-2 bind pBTLA Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed12796776 Pubmed16932752 Reactome Database ID Release 43389941 Reactome, http://www.reactome.org ReactomeREACT_19365 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 The cytoplasmic tail of BTLA contains three tyrosine residues that are conserved in most organisms. The tyrosine residues Y257 and Y282 are both present in ITIM motif sequences. These tyrosine residues are phosphorylated after BTLA cross-linking, and both ITIM motifs recruit the tyrosine phosphatases SHP1 and SHP2. The targets of SHP1 and SHP2 recruited to BTLA are not known, although it is possible that they also have a role in dephosphorylating signaling intermediates downstream of antigen receptors in lymphocytes or in specifically targeting the PI3K-AKT pathway. BTLA interacts with HVEM Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed16932752 Reactome Database ID Release 43389523 Reactome, http://www.reactome.org ReactomeREACT_19395 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 The B and T lymphocyte attenuator, BTLA, is one of the co-inhibitory receptors of CD28 superfamily along with CTLA-4 and PD-1. BTLA differs from other CD28 members by having an extracellular Ig C-like domain, instead of a V-like one. Herpesvirus entry mediator (HVEM) is the external ligand for BTLA, providing the first example of a functional interaction between a TNFR and an Ig superfamily member. Binding of HVEM to BTLA delivers an inhibitory signal to T cells. Activated SYK Phosphorylates BLNK (SLP65) Authored: May, B, 2010-10-31 BLNK (SLP-65, BASH) forms a stable complex with GRB2, SOS1, and CIN85 in the cytosol. The complex is recruited to the plasma membrane where activated (phosphorylated) SYK phosphorylates BLNK at tyrosines 72, 84, 96, 178, and 189 (Fu et al. 1998, Chiu et al. 2002, inferred from mouse in Wienands et al. 1998, from chicken in Oellerich et al. 2009). Phosphorylated BLNK serves as a scaffold that binds effector molecules such as Phospholipase C. As inferred from mouse, BLNK interacts with phosphorylated tyrosines on CD79A (Ig-alpha) (Engels et al. 2001, Kabak et al. 2002). EC Number: 2.7.10 Edited: May, B, 2010-10-31 Pubmed11071869 Pubmed11449366 Pubmed11909947 Pubmed12456653 Pubmed19372136 Pubmed21822214 Pubmed9341187 Pubmed9697839 Pubmed9705962 Reactome Database ID Release 43983703 Reactome, http://www.reactome.org ReactomeREACT_118834 Reviewed: Wienands, J, 2012-02-11 has a Stoichiometric coefficient of 5 Autophosphorylation of SYK at the Activated BCR Authored: May, B, 2010-09-28 Autophosphorylation of SYK at the Activated B Cell Receptor EC Number: 2.7.10 Edited: May, B, 2010-09-28 Pubmed10648173 Pubmed16849466 Pubmed18006696 Pubmed18052078 Pubmed18818202 Pubmed21469132 Pubmed7538118 Pubmed8163536 Reactome Database ID Release 43983707 Reactome, http://www.reactome.org ReactomeREACT_118728 Reviewed: Wienands, J, 2012-02-11 The SYK protein tyrosine kinase autophosphorylates at tyrosines 131, 323, 348, 352, 525, and 526 (Law et al. 1994, Rowley et al. 1995, Baldock et al. 2000, Irish et al. 2006, Papp et al. 2007, Chen et al. 2008, Tsang et al. 2008). The autophosphorylation increases the kinase activity of SYK. SYK is also phosporylated on additional residues in response to BCR activation (Bohnenberger et al. 2011). has a Stoichiometric coefficient of 6 Assembly of Signalosomes at the Activated BCR Assembly of Signalosomes at the Activated B Cell Receptor Authored: May, B, 2010-10-31 EC Number: 2.7.1.153 EC Number: 2.7.10 Edited: May, B, 2010-10-31 Phosphorylated SYK phosphorylates BLNK (SLP-65, Fu et al. 1998, Chiu et al. 2002) and BCAP (inferred from mouse, Okada et al. 2000). Effector molecules are then recruited: phosphoinositol 3-kinase (PI3K), Phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.<br>As inferred from chicken DT40 cells and mouse B cells (Okada et al. 2000), phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates Phospholipase C gamma-2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004).<br>Phosphorylated BLNK recruits PLC gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002).<br>SYK phosphorylates SHC which then binds GRB2 (Saxton et al. 1994, Harmer and DeFranco 1997).<br>CD19 in a stable complex with VAV1 is phosphorylated by Src kinases (inferred from mouse, Xu et al. 2002) and possibly by LYN (inferred from mouse, Fujimoto et al. 2000) in response to BCR activation. Phosphorylated CD19 then binds PI3K (Roifman and Ke 1993, Chalupny et al. 1993, Uckun et al. 1993, Weng et al. 1994, Brooks et al. 2000, Brooks et al. 2004) and can bind PLC-gamma2, which competes with VAV1 for the same binding site on CD19 (Brooks et al. 2000, Brooks et al. 2004). Pubmed10706702 Pubmed10770799 Pubmed10933394 Pubmed11226282 Pubmed11606584 Pubmed12456653 Pubmed12471124 Pubmed1376928 Pubmed15161916 Pubmed15187135 Pubmed1550550 Pubmed15509800 Pubmed2011584 Pubmed7528218 Pubmed7687428 Pubmed7687539 Pubmed7691807 Pubmed7929028 Pubmed8021500 Pubmed8621483 Pubmed8918697 Pubmed9199344 Pubmed9341187 Pubmed9468499 Pubmed9697839 Reactome Database ID Release 43983704 Reactome, http://www.reactome.org ReactomeREACT_118566 Reviewed: Wienands, J, 2012-02-11 HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2130353 Reactome Database ID Release 432130353 Reactome, http://www.reactome.org ReactomeREACT_123741 SCF with beta-TrCP1 or beta-TrCP2 Binds NF-kappaB;phospho-IkB Authored: May, B, 2010-12-18 Edited: May, B, 2010-12-18 Pubmed10066435 Pubmed10230406 Pubmed10321728 Pubmed10514424 Pubmed9859996 Pubmed9990852 Reactome Database ID Release 431168642 Reactome, http://www.reactome.org ReactomeREACT_118856 Reviewed: Wienands, J, 2012-02-11 SKP:Cul:F-box (SCF) complexes containing F-box factors Beta-TrCP1 (BTRCP, E3RSIkappaB) or beta-TrCP2 (BTRCP2, FBXW11, HOS) bind IkappaB (Yaron et al. 1998, Fuchs et al. 1999, Suzuki et al. 1999, Tan et al. 1999, Winston et al. 1999, Wu and Ghosh 1999). Phosphorylation of I-kappaB by Activated IKK (B cell) Activated IKK complex phosphorylates the I-kappaB component of the cytoplasmic NF-kappaB complex (Zandi et al. 1998, Burke et al. 1999, Heilker et al. 1999). B cells contain I-kappaB-alpha, I-kappaB-beta, and I-kappaB-epsilon (Whiteside et al. 1997, Li and Nabel 1997). Authored: May, B, 2011-01-19 EC Number: 2.7.11 Edited: May, B, 2011-01-19 Pubmed10593898 Pubmed9135156 Pubmed9315679 Pubmed9721103 Pubmed9914500 Reactome Database ID Release 431168638 Reactome, http://www.reactome.org ReactomeREACT_118618 Reviewed: Wienands, J, 2012-02-11 has a Stoichiometric coefficient of 2 Degradation of Ubiquitinated IkB (B cell) Authored: May, B, 2010-12-18 Edited: May, B, 2010-12-18 Phosphorylated, ubiquitinated IkB is degraded by the proteasome (Miyamoto et al. 1994, Traenckner et al. 1994, Alkalay et al. 1995, DiDonato et al. 1995, Li et al. 1995, Lin et al. 1995, Scherer et al. 1995, Chen et al. 1995). IkB does not dissociate from NF-kB before it is proteolyzed (Miyamoto et al. 1994, Traenckner et al. 1994, DiDonato et al. 1995, Lin et al. 1995). Pubmed7479848 Pubmed7479976 Pubmed7575604 Pubmed7628694 Pubmed7809113 Pubmed7831327 Pubmed7862124 Pubmed7957109 Reactome Database ID Release 431168640 Reactome, http://www.reactome.org ReactomeREACT_118617 Reviewed: Wienands, J, 2012-02-11 Ubiquitination of IkB by SCF-beta-TrCP Authored: May, B, 2010-12-18 Edited: May, B, 2010-12-18 Pubmed10066435 Pubmed10230406 Pubmed10321728 Pubmed10514424 Pubmed9859996 Pubmed9990852 Reactome Database ID Release 431168643 Reactome, http://www.reactome.org ReactomeREACT_118619 Reviewed: Wienands, J, 2012-02-11 SKP:Cul:F-box (SCF) complexes containing F-box factors Beta-TrCP1 (BTRCP, E3RSIkappaB) or beta-TrCP2 (BTRCP2, FBXW11, HOS) catalyze the polyubiquitination of IkappaB (Yaron et al. 1998, Fuchs et al. 1999, Suzuki et al. 1999, Tan et al. 1999, Winston et al. 1999, Wu and Ghosh 1999). Activation of RasGRP1 and RasGRP3 by Recruitment to the Membrane and Phosphorylation Authored: May, B, 2011-01-03 Edited: May, B, 2010-12-09 Pubmed10222061 Pubmed11221888 Pubmed12730099 Pubmed15657177 Pubmed16301621 RasGRP1 and RasGRP3 translocate to the plasma membrane where they bind diacylglycerol (Lorenzo et al. 2001) and are phosphorylated (Teixeira et al. 2003, Zheng et al. 2005). Though RasGRP3 is phosphorylated in vitro and in some cell lines (e.g. Ramos cells) by protein kinase C theta (PKC-theta, Zheng et al. 2005), normal B cells do not contain PKC-theta (Meller et al. 1999). Both Rasgrp1 and Rasgrp3 participate in activating Ras in response to BCR signaling in mouse B cells (Coughlin et al. 2005). Reactome Database ID Release 431168374 Reactome, http://www.reactome.org ReactomeREACT_118733 Reviewed: Wienands, J, 2012-02-11 Translocation of NF-kappaB from the Cytosol to the Nucleus Authored: May, B, 2010-12-18 Edited: May, B, 2010-12-18 Nf-kappaB subunits contain nuclear localization sequences and, in the absence of IkB, are translocated to the nucleus (Bauerle and Baltimore 1988, Blank et al. 1991, Ghosh et al. 2008, Fagerlund et al. 2008). c-Rel binds to importins alpha5, alpha6, and alpha7; RelB binds to importins alpha5 and alpha6; p52 binds importin alpha3, alpha4, alpha5, and alpha6 (Fagerlund et al. 2008) Pubmed1756723 Pubmed18462924 Pubmed19066035 Pubmed3129195 Reactome Database ID Release 431168633 Reactome, http://www.reactome.org ReactomeREACT_118705 Reviewed: Wienands, J, 2012-02-11 E1 mediated ubiquitin activation Authored: Garapati, P V, 2010-10-29 EC Number: 6.3.2.19 Edited: Garapati, P V, 2010-10-29 Pubmed16595681 Pubmed18662542 Pubmed19352404 Reactome Database ID Release 43983153 Reactome, http://www.reactome.org ReactomeREACT_75782 Reviewed: Elliott, T, 2011-02-10 Ubiquitin is activated in an ATP-dependent manner, catalyzed by E1 ubiquitin-activating enzymes. In the first step of ubiquitin activation, the E1 enzyme binds ATP, Mg+2 and ubiquitin, and catalyses ubiquitin C-terminal acyl-adenylation (Ubiquitin-AMP). In the second step, the catalytic cystine in the E1 attacks the ubiquitin-adenylate (Ub-AMP) to form the activated ubiquitin-E1 thioester-bonded complex and an AMP leaving group. The intermediate reaction involving the formation of the ubiquitin-AMP complex is not represented here. Activation of RAS by RasGRP1 and RasGRP3 Authored: May, B, 2011-01-03 Edited: May, B, 2010-12-18 Pubmed10777492 Pubmed10835426 Pubmed10934204 Pubmed11221888 Pubmed17283063 RasGRP1 (Roose et al. 2007) and RasGRP3 (Ohba et al. 2000, Yamashita et al. 2000, Rebhun et al. 2000, Lorenzo et al. 2001) catalyze the exchange of GDP for GTP bound by RAS. Reactome Database ID Release 431168636 Reactome, http://www.reactome.org ReactomeREACT_118807 Reviewed: Wienands, J, 2012-02-11 Transfer of ubiquitin from E1 to E2 Activated ubiquitin is transferred from E1 to the active site cystine of ubiquitin conjugating enzymes (E2s) via a trans-esterification reaction. E2s catalyze covalent attachment of ubiquitin to target proteins. They all share an active-site ubiquitin-binding cysteine residue and are distinguished by the presence of a ubiquitin-conjugating catalytic (UBC) fold required for binding of distinct ubiquitin ligases or E3s. Once conjugated to ubiquitin, the E2 molecule binds one of several E3s (Glickman et al. 2002). Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed11917093 Pubmed19452197 Pubmed19851334 Pubmed19940261 Reactome Database ID Release 43983152 Reactome, http://www.reactome.org ReactomeREACT_75860 Reviewed: Elliott, T, 2011-02-10 Oligomerization of CARMA1 After the phosphorylation and activation CARMA1 undergoes oligomerization, likely through its CC domain. CARMA1 is thought to oligomerize first as a trimer which triggers downstream oligomerization cascade that is ultimately necessary for the subsequent activation of the IKK complex. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed15541657 Reactome Database ID Release 43202443 Reactome, http://www.reactome.org ReactomeREACT_12571 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 2 Interaction of Bcl10 to CARMA1 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Bcl10 is recruited to activated, oligomeric CARMA1 through a CARD-CARD interaction. Bcl10 is characterized by an N-terminal CARD motif and a C-terminal extension of ~130 amino acids rich in serine and threonine residues that serve as targets for multiple phosphorylation events. Pubmed15122200 Pubmed17468049 Reactome Database ID Release 43202466 Reactome, http://www.reactome.org ReactomeREACT_12574 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Translocation of CARMA1 to Plasma membrane Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 CARMA1 and Bcl10 are the possible link between PKC theta and IKK activation. PDK1 is also required for PKC theta mediated activation of IKK. CARMA1 has a N-terminal CARD motif, a coiled coiled region, a linker region, and a MAGUK-typical PDZ, SH3 and a GUK domains. The linker region is proposed to contain a hinge region and a CARD binding domain. CARMA1 exists in an inactive conformation in which the linker region binds to and blocks the accessibility of the CARD motif. CARMA1 is recruited to the plasma membrane by binding to the 'PxxP' motif of membrane bound PDK1 with its SH3 domain. Pubmed15122200 Pubmed15541657 Pubmed17468049 Reactome Database ID Release 43202394 Reactome, http://www.reactome.org ReactomeREACT_12609 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phosphorylation of CARMA1 Antigen receptor triggered PKC theta dependent linker phosphorylation of S552 residue is required to release this inhibition and expose the CARD motif for downstream Bcl10 recruitment. PDK1 and maybe other unknown adapter proteins bring PKC theta and CARMA1 into close proximity, facilitating PKC theta mediated CARMA1 phosphorylation and consequent activation. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.11 Pubmed16356853 Pubmed17468049 Reactome Database ID Release 43202437 Reactome, http://www.reactome.org ReactomeREACT_12573 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Interaction and oligomerization of MALT1 to Bcl10 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Oligomerized Bcl10 facilitates the association with MALT1 to form the CBM signalosome. MALT1 possesses one death domain (DD) and 2 immunoglobulin-like domains (Ig-like) in its N-terminal region and a caspase like domain (CLD) in its C-terminal region. The region between amino acids 107 and 119 of Bcl10 bind to the two Ig-like domains of MALT1. After binding to CARMA1 and Bcl10 complex, MALT1 also undergoes oligomerization. Only the oligomerized forms of Bcl10 and MALT1 are capable of activating IKK. Pubmed15125833 Reactome Database ID Release 43202478 Reactome, http://www.reactome.org ReactomeREACT_12563 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phosphorylation of Bcl10 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.11 Pubmed17468049 Reactome Database ID Release 43202459 Reactome, http://www.reactome.org ReactomeREACT_12619 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Upon interaction with CARMA1, Bcl10 undergoes phosphorylation and oligomerization. The oligomerized Bcl10 acts as a adaptor for the incoming MALT1 and TRAF6. Phosphorylation events of Bcl10 can both positively and negatively regulate the NF-kB pathway. Phosphorylation of Bcl10 that depends on the Ser/Thr kinase RIP2 and correlated with the physical association of Bcl10 with RIP2 has a activation effect on the NF-kB pathway. The target sites of RIP2-mediated phosphorylation has not yet been identified. Oligomerization of Bcl10 Association with RIP2 and its phosphorylation allows subsequent trimerization of Bcl10. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed15122200 Reactome Database ID Release 43202489 Reactome, http://www.reactome.org ReactomeREACT_12639 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 2 Change of PKC theta conformation Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 PKC theta localizes at the interface between T cells and antigen presenting cells. Upon the T cell activation and release of the second messengers Ca++ and DAG by PLC-gamma1, DAG binds to the C1 domain of the PKC theta thereby enhances the attachment to the plasma membrane. Upon membrane translocation, PKC theta is phosphorylated at tyrosine 90 in the C2 like domain. This phosphorylation is mediated by the tyrosine kinase Lck. These association and, most likely, other regulatory interactions, lead to a change in PKC theta conformation into an open, active state whereby it can now access its substrates and phosphorylate them. Pubmed12473184 Pubmed16978534 Reactome Database ID Release 43202307 Reactome, http://www.reactome.org ReactomeREACT_12566 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phosphorylation of PKC theta Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.11 Pubmed12473184 Pubmed16978534 Raft localized PKC theta is further phosphorylated and activated by PDK1. The threonine residue (T538) in the kinase domain is the potential target of PDK1. Phosphorylation of this site is critical for the PKC theta kinase activity, and its ability to activate NF-kB pathway. PKC theta is later trans-autophopshorylated on putative phosphorylation sites (S676, S695) for the fine-tuning of its kinase activity. Reactome Database ID Release 43202222 Reactome, http://www.reactome.org ReactomeREACT_12557 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 3 Translocation of PKC theta to plasma membrane Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 PKC theta is a member of the Ca++ independent and DAG dependent, novel PKC subfamily expressed mainly in T cells. It contains, N-term C2 like domain, a pseudosubstrate (PS), DAG binding (C1) domain and a C-term kinase domain. The PS sequence resembles an ideal substrate with the exception that it contains an alanine residue instead of a substrate serine residue, is bound to the kinase domain in the resting state. As a result, PKC theta is maintained in a closed inactive state, which is inaccessible to cellular substrates. Pubmed12473184 Pubmed16978534 Reactome Database ID Release 43202328 Reactome, http://www.reactome.org ReactomeREACT_12493 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Ubiquitination of NEMO by TRAF6 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Residues Lysine 321 and Lysine 326 may be few of the potent ubiquitination sites in NEMO. EC Number: 6.3.2.19 Pubmed17047224 Pubmed17728323 Reactome Database ID Release 43202534 Reactome, http://www.reactome.org ReactomeREACT_12553 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Activation of NF-kB complex Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.11 NF-kB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. NF-kB/Rel family include five members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kB1) and p52/p100 (NF-kB2), exist in unstimulated cells as homo or heterodimers. NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kB to translocate into nucleus and induces the expression of various genes. <br>The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkB-alpha) and subsequent degradation by the 26S proteasome. The K-48 ubiquitination is mediated by the E2 ubiquitin ligases (or SCFs) formed by three subunits: Skp1, Cul A (Cdc53), and one of many F-box proteins. Pubmed15145317 Pubmed15371334 Pubmed17363905 Pubmed9252186 Reactome Database ID Release 43202541 Reactome, http://www.reactome.org ReactomeREACT_12399 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 2 CD28 homodimer binds B7-1 homodimer A costimulatory signal involved in T cell activation is transmitted by CD28. This signal is delivered by the interaction of the CD28 receptor on T cells with its ligand B7-1 on the antigen-presenting cell and modulates T cell antigen recognition. Despite the homodimeric structure of CD28, it interacts with B7-1 as though it has a single binding site. The V-like domains of CD28 contains a strictly conserved MYPPPY sequence motif that maps to the CDR3-analogous loop and is critical for recognition of its ligands. B7-1 and B7-2 bind to overlapping but not identical sites on CD28 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed8609386 Pubmed8649453 Reactome Database ID Release 43388811 Reactome, http://www.reactome.org ReactomeREACT_19148 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 CD28 homodimer binds B7-2 monomer Authored: Garapati, P V, 2008-12-16 11:12:19 CD28 delivers the costimulatory signal by interacting with its ligand B7-2 on the antigen-presenting cell and modulates T cell antigen recognition. The V-like domains of CD28 contains a strictly conserved MYPPPY sequence motif that maps to the CDR3-analogous loop and is critical for recognition of its ligand B7-2. Engagement of CD28 with B7-1 and with B7-2 have different bilogical functions in-vivo. Rapid dissociation of B7-2 from CD28 may not permit the robust tyrosine phosphorylation that the prolonged binding of B7-1 induces. Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed8609386 Pubmed8649453 Reactome Database ID Release 43388808 Reactome, http://www.reactome.org ReactomeREACT_19240 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Phosphorylation of CD28 Authored: Garapati, P V, 2008-12-16 11:12:19 EC Number: 2.7.10 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed8946678 Pubmed9973466 Reactome Database ID Release 43388831 Reactome, http://www.reactome.org ReactomeREACT_19264 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 The interaction of CD28 with its ligands, B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells enhances a number of TCR-mediated responses like production of interleukins. CD28 mediated costimulation is dependent upon phosphorylation of tyrosine residue 191 of the CD28 cytoplasmic tail, present in a 'YMNM' motif. p56Lck and p59Fyn phosphorylate CD28 and the phosphorylated residue allows the recruitment of PI3K, growth factor receptor-bound protein 2 (GRB2) and Grb2-related adaptor downstream of SHC (GADS) via their src-homology region 2 (SH2) domains. has a Stoichiometric coefficient of 2 Gads binds CD28 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Gads (Grb2-related adaptor protein 2) is essential for CD28 mediated NF-kB activation. This signal is mediated by the binding of Gads to the CD28 YMNM motif. The CD28 cytoplasmic PxxP motif is also required for this association. Pubmed16818765 Reactome Database ID Release 43389381 Reactome, http://www.reactome.org ReactomeREACT_19159 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Translocation of TRAF6 to CBM complex Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed15125833 Reactome Database ID Release 43202472 Reactome, http://www.reactome.org ReactomeREACT_12448 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 TRAF6, which plays central role in innate immune responses, is implicated as proximal downstream effector of MALT1. TRAF6 is a member of the TRAF proteins. It contains an N-term RING domain, followed by several Zn finger domains and C-term MATH domain. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization and thereby activate the ubiquitin ligase activity of TRAF6 to polyubiquitinate itself and NEMO. has a Stoichiometric coefficient of 3 Auto-ubiquitination of TRAF6 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 6.3.2.19 Edited: Garapati, P V, 2010-11-08 Pubmed17135271 Reactome Database ID Release 43202453 Reactome, http://www.reactome.org ReactomeREACT_12595 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. has a Stoichiometric coefficient of 3 Activation of TAK1-TAB2 complex Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.11 Pubmed15125833 Pubmed16056267 Pubmed17496917 Reactome Database ID Release 43202510 Reactome, http://www.reactome.org ReactomeREACT_12518 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Ubiquitinated TRAF6 recruits TAB2 and activates the TAB2-associated TAK1 kianse by promoting the autophosphorylation of TAK1. TAB2 contains an N-term pseudophosphatase domain, which is indispensable for TAK1 activation, and a C-term domain that binds to and activates TAK1. The activation of TAK1/TAB2 complex requires a ubiquitination reaction catalysed by E1, Ubc13/Uev1A (E2) and TRAF6 (E3). TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 then phosphorylates and activates IKK beta. has a Stoichiometric coefficient of 2 Activation of IKK complex Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.11 Pubmed17047224 Reactome Database ID Release 43202500 Reactome, http://www.reactome.org ReactomeREACT_12581 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex. <br>IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on serine residues (S177 and S181) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation. has a Stoichiometric coefficient of 2 CCL19, CCL21, CCL25 Converted from EntitySet in Reactome Reactome DB_ID: 443985 Reactome Database ID Release 43443985 Reactome, http://www.reactome.org ReactomeREACT_21963 Activation of PAK by Rac1 and Cdc42 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-12-16 11:12:19 In its unbound state PAK is maintained in an inactive conformation through intra domain interactions. On stimulation PAK is translocated to the plasma membrane where it specifically interacts with Rho family GTP-binding proteins Rac1-GTP and Cdc42-GTP. All PAK isoforms are direct effectors of the Rac and Cdc42. Rac and Cdc42 bind to a highly conserved motif in the amino terminus of PAK known as p21-binding domain (PBD) or Cdc42/Rac interactive binding (CRIB) domain. This binding is thought to induce a conformational change in PAK that relieves autoinhibition of the catalytic carboxy terminal domain, thereby inducing autophosphorylation at several sites and enabling the phosphorylation of exogenous substrates. Pubmed10470034 Pubmed19513348 Reactome Database ID Release 43389788 Reactome, http://www.reactome.org ReactomeREACT_19246 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Somatostatin Converted from EntitySet in Reactome Reactome DB_ID: 374714 Reactome Database ID Release 43374714 Reactome, http://www.reactome.org ReactomeREACT_14924 Activation of Rac1 by pVav1 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed8990121 Pubmed9438848 Reactome Database ID Release 43389348 Reactome, http://www.reactome.org ReactomeREACT_19243 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Vav1, once activated by PIP3 binding and phosphorylation by Fyn, stimulates the GDP/GTP exchange activity of Rac. Vav1 is selective for Rac and catalyses exchange of bound GDP for GTP. Activation of Cdc42 by pVav1 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed9032261 Reactome Database ID Release 43389350 Reactome, http://www.reactome.org ReactomeREACT_19286 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Vav1 serves as a GEF for Cdc42-GTPase. It interacts with and activates Cdc42. The activated Cdc42 in turn transmits its signals through the downstream target, the PAK1 kinase. Somatostatin receptors Converted from EntitySet in Reactome Reactome DB_ID: 374746 Reactome Database ID Release 43374746 Reactome, http://www.reactome.org ReactomeREACT_15117 Translocation of Vav1 to CD28 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed10849438 Pubmed15886116 Pubmed18295596 Reactome Database ID Release 43389352 Reactome, http://www.reactome.org ReactomeREACT_19244 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Vav1 protein is a cytoplasmic guanine nucleotide exchange factor (GEF) for Rho-family GTPases. CD28 co-stimulation resulted in a prolonged and sustained phosphorylation and membrane localization of Vav1 in comparison to T-cell receptor activation alone. Vav1 contains a unique arrangement of signaling motifs a calponin homology domain, an acidic domain, a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain (CR), and a SH2 domain flanked by two proline-binding SH3 domains. Vav-1 may be recruited to the membrane through its PH domain by binding PI(3,4,5)P3 produced by CD28-bound PI3K and also by binding to CD28:Grb2 complexes by the dimerized SH3 domains in both the molecules. Activation of Vav1 Authored: Garapati, P V, 2008-12-16 11:12:19 EC Number: 2.7.10 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed10849438 Pubmed12670394 Pubmed15886116 Pubmed9822663 Reactome Database ID Release 43389354 Reactome, http://www.reactome.org ReactomeREACT_19316 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Vav1 exists in an auto-inhibitory state folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the CH domain to the C1 region. Activation of Vav may involve at least three different events to relieve this auto-inhibition. Phosphorylation of the tyrosines causes them to be displaced from the DH domain, binding of a ligand to the CH domain may cause it to release the C1 domain and PIP3 may bind to the PH domain, altering its conformation. Vav1 is phosphorylated on at least three tyrosines (Y142, Y160 and Y174) in the acidic domain, and this phosphorylation results in an increase in GEF activity. Fyn tyrosine kinase phosphorylates Vav1 after CD28 ligation. has a Stoichiometric coefficient of 3 p-S400-Cot phosphorylates NIK Authored: Garapati, P V, 2008-12-16 11:12:19 Cot functions upstream of NIK in the CD28-costimulation signaling pathway leading to activation of NF-kB. Cot binds avidly to NIK and induces NIK phosphorylation in vivo. EC Number: 2.7.11.25 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed18439422 Reactome Database ID Release 43392530 Reactome, http://www.reactome.org ReactomeREACT_19141 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Grb2 binds CD28 Authored: Garapati, P V, 2008-12-16 11:12:19 CD28 is capable of binding the Src homology 3 (SH3) domains of several proteins, including Grb2. The phospho-YMNM motif in CD28's cytoplasmic domain facilitates tandem SH2–SH3 domain binding. Grb-2 has been shown to bind to the CD28 YMNM motif with additional SH3 domain binding to the diproline motif in the C-terminal portion of the cytoplasmic domain of CD28. Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed7737275 Pubmed9694876 Reactome Database ID Release 43388814 Reactome, http://www.reactome.org ReactomeREACT_19254 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 CD28 bound PI3K phosphorylates PIP2 to PIP3 Authored: Garapati, P V, 2008-12-16 11:12:19 EC Number: 2.7.1.153 Edited: Garapati, P V, 2008-12-16 11:12:19 PI3K enzyme bound to co-stimulatory protein CD28 catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and PKB. Pubmed12660731 Reactome Database ID Release 43389158 Reactome, http://www.reactome.org ReactomeREACT_19274 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 AKT interacts and phosphorylates Cot Authored: Garapati, P V, 2008-12-16 11:12:19 Cot/Tpl 2 is a serine/threonine kinase of the mitogen activated protein kinase kinase kinase (MAP3K) family. Cot is observed as one of the downstream effectors of Akt. Based on in-vitro kinase assays and following overexpression in cell lines its been showed that AKT can phosphorylate Cot under non-physiological conditions. Akt and Cot physically interact through the amino terminus of Cot, and this interaction results in the phosphorylation of Cot on serine 400. Cot was shown to activate the IkB kinase (IKK) complex, possibly acting through NF kB inducing kinase (NIK). EC Number: 2.7.11 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed12138205 Reactome Database ID Release 43389756 Reactome, http://www.reactome.org ReactomeREACT_19232 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 PI3K binds CD28 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 PI3K inducibly associates with CD28: the SH2 domains of the PI3K p85 adaptor subunit interact with a cytoplasmic YMNM consensus motif at residues 173-176 of CD28. Pubmed12670391 Pubmed8621607 Reactome Database ID Release 43388832 Reactome, http://www.reactome.org ReactomeREACT_19212 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 PI3K binds ICOS Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed12538664 Reactome Database ID Release 43388830 Reactome, http://www.reactome.org ReactomeREACT_19171 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 The p85 unit of PI3K is the only signaling molecule identified so far that interacts with ICOS. ICOS contains several conserved motifs also found in CD28, including the YxxM motif in the cytoplasmic tail, which binds the lipid kinase phosphatidylinositol 3-kinase (PI3K) upon tyrosine phosphorylation after complex formation with ICOS. However, ICOS costimulation shows greater PI3K activity than CD28 in T cells. PD-1 binds B7DC and B7H1 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed12893276 Reactome Database ID Release 43388828 Reactome, http://www.reactome.org ReactomeREACT_19196 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 The Programmed cell death protein 1 (PD-1) is functionally similar to CTLA4 and exerts an inhibitory signal on T cell activation. PD-1 binds the ligands B7H1 and B7DC but with different affinities. Interaction of PD-1/B7DC exhibited a 2-6-fold higher affinity and had different association/dissociation kinetics compared with the interaction of PD-1/B7H1. Phosphorylation of PD-1 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed12947224 Pubmed18173375 Pubmed18759926 Reactome Database ID Release 43389762 Reactome, http://www.reactome.org ReactomeREACT_19312 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 The cytoplasmic domain of PD-1 has two tyrosine motifs, ITIM and ITSM. On engagement with B7 ligands B7DC and B7H1, PD-1 is phosphorylated on tyrosine residues 223 and 248 within these motifs. Kinases Lck and Csk also bind to these motifs and these kinases may be involved in the phosphorylation of PD-1. has a Stoichiometric coefficient of 2 Interaction of SHP-1 or SHP-2 with phospho PD-1 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Once phosphorylated, SH2-domain containing tyrosine phosphatases SHP-1 and SHP-2 bind to the ITIM and ITSM motifs of PD-1. The association between SHP-1 and PD-1 appears to be weaker than the interaction of PD-1 with SHP-2. Pubmed18173375 Pubmed18759926 Reactome Database ID Release 43389759 Reactome, http://www.reactome.org ReactomeREACT_19198 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Phosphorylation of CTLA-4 Authored: Garapati, P V, 2008-12-16 11:12:19 EC Number: 2.7.10 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed11994459 Pubmed9712716 Reactome Database ID Release 43388833 Reactome, http://www.reactome.org ReactomeREACT_19380 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Upon TCR-CTLA-4 complex formation, CTLA4 is tyrosine phosphorylated. Src family tyrosine kinases Fyn, Lyn, and Lck associate with CTLA-4 and phosphorylate both Y-165 and Y-182 that are mainly responsible for interaction with Fyn through its SH2 domain. Once tyrosine 165 is phosphorylated, PP2A is activated and disassociates from CTLA4; this correlates with T cell inactivation. has a Stoichiometric coefficient of 4 SHP2 phosphatase binds CTLA-4 Authored: Garapati, P V, 2008-12-16 11:12:19 CTLA4 associates with the SH2 domain containing tyrosine phosphatase SHP2 and this interaction is mediated through the YVKM motif of CTLA-4. Phosphorylation of tyrosine in the YVKM motif recruits SHP-2. <br>Still the association of SHP-2 with CTLA-4 is unclear and remains controversial. Several other studies have reported that CTLA-4 does not directly associate with SHP-2. The interaction between the phosphatase and CTLA-4 may be an indirect event, possibly mediated by PI3-kinase/SHP-2 binding. Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed10694513 Pubmed9712716 Reactome Database ID Release 43388829 Reactome, http://www.reactome.org ReactomeREACT_19203 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Dephosphorylation of AKT by PP2A Authored: Garapati, P V, 2008-12-16 11:12:19 EC Number: 3.1.3.4 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed16551244 Pubmed19405949 Reactome Database ID Release 43390329 Reactome, http://www.reactome.org ReactomeREACT_19209 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 When CTLA4 is engaged by B7 molecules, PP2A disassociates from CTLA4 in a phosphorylation dependent manner. Released PP2A acts downstream of early TCR and CD28 signaling, by inhibition of the PKB/Akt pathway. ICOS binds ICOSL/B7-H2 Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Inducible T cell co-stimulatory (ICOS) protein is the third member of the CD28 family that regulates T-cell activation and function. ICOS interacts with B7H2 (ICOSL, B7RP-1), a member of the B7 family expressed on the antigen-presenting cell. Pubmed15007255 Pubmed15870016 Reactome Database ID Release 43388817 Reactome, http://www.reactome.org ReactomeREACT_19418 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 PP2A binds CTLA4 homodimer Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Newly synthesized CTLA4 expressed on the transmembrane associates with PP2A, and under these conditions the inhibitory function of CTLA4 is inactive. CTLA4 homodimer has a PP2A trimer bound to each tail. The A subunit of PP2A binds the lysine-rich motif located at lysine residues 152, 155, and 156 of the juxtamembrane region of the CTLA-4 tail, and the C subunit binds the Y165 residue. Pubmed12876557 Pubmed16551244 Reactome Database ID Release 43389532 Reactome, http://www.reactome.org ReactomeREACT_19404 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 CTLA-4 binds B7-1/B7-2 Authored: Garapati, P V, 2008-12-16 11:12:19 CTLA4 binds with high affinity to the ligands B71 and B72. The interaction of B7 molecules with CTLA4 provides inhibitory signals required for downregulation of the TCR response. The interaction is mediated by the CDR3 analogous loop of CTLA4, composed of an MYPPY motif, with a concave surface on the B7 formed predominately by the G, F, C, C' and C" strands. Its also been demonstrated that B7 binding is not totally essential for CTLA-4 activity. Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed10799894 Pubmed11976720 Pubmed15142525 Reactome Database ID Release 43388809 Reactome, http://www.reactome.org ReactomeREACT_19129 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 CCR3,4,5 Converted from EntitySet in Reactome Reactome DB_ID: 373259 Reactome Database ID Release 43373259 Reactome, http://www.reactome.org ReactomeREACT_15214 CCR1,2,8 Converted from EntitySet in Reactome Reactome DB_ID: 373229 Reactome Database ID Release 43373229 Reactome, http://www.reactome.org ReactomeREACT_14910 Inactivation of Lck by Csk Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 Lck is a member of the Src family tyrosine kinases and these members have the following domains in common: N-terminal Myristoylation site for saturated fatty acid addition, a unique region, a Src-homology 3 (SH3) domain, an SH2 domain, a tyrosine kinase domain (SH1), and a C-terminal negative regulatory domain. Myristoylation engenders Lck with the ability to attach to cellular membranes. This interaction is mediated by both myristic acid and palmitic acid that are bound to the amino terminal glycine and Cys-3 and/or Cys-5. <br><br>The unique region of Lck is thought to be involved in the interaction with the cytoplasmic tails of coreceptors CD4 and CD8. The Lck/CD4 interaction require conserved cysteine motifs: a CxCP motif in CD4 and a CxxC motif in the Lck unique domain. The SH3 and SH2 domains of Lck are involved in intramolecular and intermolecular regulation by mediating protein-protein interactions via poly-proline and phosphotyrosine-specific interactions, respectively. <br><br>Lck adopts specific conformation that largely dictate its level of activity. The C-ter tail has an autoinhibitory phosphorylation site (tyr 505). When the Y505 is phosphorylated, Lck adopts a closed conformation, where the pY505 residue creates an intramolecular binding motif for the SH2 domain, effectively inactivating the kinase domain. The inactivating phosphorylation on Y505 is carried out by the Src-specific kinase Csk. Pubmed15489910 Pubmed15489916 Reactome Database ID Release 43202233 Reactome, http://www.reactome.org ReactomeREACT_12640 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Interaction of Csk with PAG Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Csk is a tyrosine kinase that phosphorylates the negative regulatory C-terminal tyrosine residue Y505 of Lck to maintain Lck in an inactive state. In resting T cells, Csk is targeted to lipid rafts through engagement of its SH2 domain with phosphotyrosine residue pY317 of PAG. PAG is expressed as a tyrosine phosphorylated protein in nonstimulated T-cells. This interaction of Csk and PAG allows activation of Csk and inhibition of Lck. Given that PAG-1 T cell knock out show a weak phenotype, some other protein may substitute in activating Csk. Pubmed10790433 Pubmed11827988 Pubmed12938237 Reactome Database ID Release 43203774 Reactome, http://www.reactome.org ReactomeREACT_12603 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Activation of Lck Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 Pubmed11827988 Pubmed15489916 Reactome Database ID Release 43202291 Reactome, http://www.reactome.org ReactomeREACT_12467 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The binding of CD4/CD8 to non-polymorphic regions of MHC brings Lck in to proximity with TCR subunits phosphorylation. Lck is further phosphorylated to promote the active conformation and to increase their catalytic activity. The C-term domain contain a regulatory activation loop, which is the site of activating Tyr 394 phosphorylation. This tyrosine is auto-phosphorylated to attain an active conformation on TCR stimulation. Now Lck through its kinase activity phosphorylates the ITAMs in TCR zeta and CD3 members. Dephosphorylation of Lck-pY505 by CD45 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 3.1.3.48 Pubmed11827988 Reactome Database ID Release 43202214 Reactome, http://www.reactome.org ReactomeREACT_12446 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 TCR stimulation induce the transient dephosphorylation of PAG thereby release the Csk from its plasma membrane anchor. The release of Csk from its proximity with Lck may serve to facilitate the activation of Lck. The inactive Lck is dephosphorylated by CD45 phosphatase. CD45 specifically dephosphorylates the Y505 residue of Lck and induce the active open conformation. Recruitment of ZAP-70 to phosphorylated ITAMs Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Phosphorylation of the ITAMs by Lck is followed by the recruitment of the ZAP-70 a member of Syk family PTK, to the receptor complex. ZAP-70 is exclusively expressed in T cells and NK cells. The dually phosphorylated ITAMs provide a high-affinity docking site for the tandem SH2-domains of the ZAP-70. Once recruited, ZAP-70 is activated by phosphorylation and will be responsible for the phosphorylation of further downstream molecules. Due to the presence of 10 ITAMs in the TCR complex, up to 10 ZAP-70 molecules may cluster on the fully phosphorylated receptors. Pubmed12485116 Pubmed8520027 Pubmed9850860 Reactome Database ID Release 43202344 Reactome, http://www.reactome.org ReactomeREACT_12642 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phosphorylation of ITAM motifs in CD3 complexes Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 Pubmed15084594 Pubmed16364187 Reactome Database ID Release 43202165 Reactome, http://www.reactome.org ReactomeREACT_12633 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The autophosphorylated, active Lck is now proximally positioned to phosphorylate specific tyrosine residues within ITAMs (immunoreceptor tyrosine-based activation motifs) located within the CD3 and the TCR zeta signaling chains of the TCR. ITAMs consist of evolutionarily conserved amino-acid sequence motifs of D/ExYxxLx(6-8)YxxL. Both the tyrosine residues in the motif are phosphorylated by Lck and the TCR complex include 10 ITAMs with one ITAM in each of the CD3 chains including the three tandem ITAMs in each zeta chains. has a Stoichiometric coefficient of 20 Activation of ZAP-70 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 Later ZAP-70 undergoes trans-autophosphorylation at Y315 and Y319. These sites appear to be positive regulatory sites. ZAP-70 achieve its full activation after the trans-autophosphorylation. Activated ZAP-70 phosphorylates T-cell-specific adaptors, such as LAT and SLP-76 leading to the recruitment and activation of other kinase families and enzymes, resulting in secondary messenger generation and culminating in T cell activation. Pubmed10202147 Pubmed8520027 Pubmed9850860 Reactome Database ID Release 43202174 Reactome, http://www.reactome.org ReactomeREACT_12394 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 CCBP2 ligands Converted from EntitySet in Reactome Reactome DB_ID: 443962 Reactome Database ID Release 43443962 Reactome, http://www.reactome.org ReactomeREACT_22045 Phosphorylation of ZAP-70 by Lck Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 In ZAP-70 there are multiple phosphorylation sites (Y292, Y315, Y319, Y492, Y493) which have both positive and negative regulatory effect on its catalytic activity. Tyrosine 493 is a conserved regulatory site found within the activation loop of the kinase domain. This site has shown to be a positive regulatory site required for ZAP-70 kinase activity and is phosphorylated by Lck. This phosphorylation contribute to the active conformation of the catalytic domain. Pubmed10202147 Pubmed8520027 Pubmed9850860 Reactome Database ID Release 43202168 Reactome, http://www.reactome.org ReactomeREACT_12538 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phosphorylation of TBSMs in LAT Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 Pubmed10811803 Pubmed11752630 Pubmed14510693 Reactome Database ID Release 43202245 Reactome, http://www.reactome.org ReactomeREACT_12421 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The adaptor molecule LAT (Linker for the Activation of T cells) is a membrane protein that links the TCR signal to the cell activation. It has a total 10 (Y36, Y45, Y64, Y110, Y156, Y161, Y200, Y220, and Y255) conserved TBSMs (tyrosine based signaling motifs) in its cytoplasmic region. These tyrosine residues are phosphorylated by the activated ZAP-70 upon TCR/CD3 complex engagement. Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2 and Gads, and indirectly binds SOS, Vav, SLP-76, and Itk. The residues Y200, Y220 and Y255 are responsible for Grb2 binding, Y200 and Y220 but not Y255, are necessary for Gads binding and Y161 for the PLC-gamma1 binding (numbering based on Uniprot isoform 1). has a Stoichiometric coefficient of 5 Recruitment of Gads to LAT Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Gads is a member of the Grb2 family containing SH2 and SH3 domains with the arrangement SH3-SH2-SH3. Gads binds to the tyrosine phosphorylated residues Y171 and Y191 of LAT through its SH2 domain. It plays a critical role in signaling from the T cell receptor by promoting the formation of a complex between SLP-76 and LAT. Pubmed11607830 Reactome Database ID Release 43202325 Reactome, http://www.reactome.org ReactomeREACT_12570 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Recruitment of SLP-76 to Gads Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed11607830 Reactome Database ID Release 43202241 Reactome, http://www.reactome.org ReactomeREACT_12489 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 SLP-76 is an adaptor protein that links proximal and distal T cell receptor signaling events through its function as a molecular scaffold in the assembly of multi molecular signaling complexes. SLP-76 consists of three domains that mediate interactions with many different signaling proteins: an N-terminal acidic domain containing three tyrosine phosphorylation sites, a large central proline-rich region, and a C-terminal SH2 domain. The function of SLP-76 is dependent on its association with Gads. SLP-76 constitutively binds through its 'RxxK' motif in the proline rich region to the SH3 domain of Gads upon TCR activation. CXCR3 Converted from EntitySet in Reactome Reactome DB_ID: 374193 Reactome Database ID Release 43374193 Reactome, http://www.reactome.org ReactomeREACT_15120 Collagen alpha-1(XXVIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2193037 Reactome Database ID Release 432193037 Reactome, http://www.reactome.org ReactomeREACT_122934 CXCR3 ligands Converted from EntitySet in Reactome Reactome DB_ID: 374233 Reactome Database ID Release 43374233 Reactome, http://www.reactome.org ReactomeREACT_15199 Translocation of PLC-gamma1 to PIP2 Activated PLA-gamma1 translocates to the plasmamembrane and interacts with the inositol ring of the membrane bound phosphatidylinositol 4,5-bisphosphate (PIP2) with its PH domain. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed11048639 Reactome Database ID Release 43202354 Reactome, http://www.reactome.org ReactomeREACT_12460 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Disassociation of PLC-gamma1 from SLP-76 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed11048639 Reactome Database ID Release 43213407 Reactome, http://www.reactome.org ReactomeREACT_12525 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The activated PLC-gamma1 detaches from its substrate SLP-76 and translocates to the membrane. Disassociation of PLC-gamma1 from LAT Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed11048639 Reactome Database ID Release 43213406 Reactome, http://www.reactome.org ReactomeREACT_12618 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The activated PLC-gamma1 detaches from its substrate LAT and translocates to the membrane. Phosphorylation of PLC-gamma1 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 Pubmed11048639 Reactome Database ID Release 43202248 Reactome, http://www.reactome.org ReactomeREACT_12498 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Three tyrosine residues at positions 771, 783 and 1254 in PLC-gamma1 have been identified as the sites of receptor tyrosine kinase phosphorylation. Of these Y783 and Y1254 are required for activation of PLC-gamma1. The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK. has a Stoichiometric coefficient of 3 Recruitment of PLC-gamma1 to LAT Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 PLC-gamma1 interacts with its SH2 domain to the pY132 residue of LAT. Pubmed11048639 Reactome Database ID Release 43202212 Reactome, http://www.reactome.org ReactomeREACT_12398 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Recruitment of PLC-gamma1 to SLP-76 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 PLC-gamma1 plays an important role in transducing the external signal in to second messengers by hydrolysing PIP2. PLC-gamma1 contains an N-term PH domain, a catalytic domain 'X' followed by two SH2 domains and an SH3 domain, a C-term catalytic domain 'Y' and a C2 domain (Ca++ binding). PLC-gamma1 interacts with both SLP-76 aswell as LAT. It interacts with its SH3 domain to the proline rich sequence of SLP-76. This interaction aids in localizing PLC-gamma1 to the membrane. This recruitment of PLC-gamma1 to LAT and SLP-76 is essential for its TCR induced tyrosine phosphorylation and activation. Pubmed11048639 Pubmed11390650 Reactome Database ID Release 43202331 Reactome, http://www.reactome.org ReactomeREACT_12506 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Recruitment of ITK to SLP-76 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 ITK is a member of the Tec protein tyrosine kinase family which forms a complex with SLP-76 after TCR activation. ITK has N-terminal pleckstrin homology (PH) domain, a Tec homology (TH) domain, a proline rich domain, a SH3 domain, an SH2 domain and a C-term kinase domain. The SH2 domain of ITK may interact with Y145 within the N-ter acidic domain of SLP-76 and the SH3 domain of the ITK binds the proline rich region of SLP-76. ITK plays an important role in phosphorylating and activating PLC-gamma-1, leading to the development of second-messenger molecules. Pubmed17652306 Reactome Database ID Release 43202375 Reactome, http://www.reactome.org ReactomeREACT_12604 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Phosphorylation of SLP-76 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.10 Once SLP-76 is recruited to Gads its rapidly phosphorylated on the tyrosine residues in the N-terminal acidic domain. This domain contains three tyrosine phosphorylation sites, Y113, Y128 and Y145. These tyrosine residues are phosphorylated by tyrosine kinase ZAP-70 and these phosphorylated tyrosine residues provide the binding site for the SH2 domains of the incoming signaling proteins like Vav, Itk and PLC-gamma1. Pubmed17652306 Reactome Database ID Release 43202216 Reactome, http://www.reactome.org ReactomeREACT_12615 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 3 PLC-gamma1 hydrolyses PIP2 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 3.1.4.11 On recruitment to plasma membrane PLC-gamma1 then hydrolyses PIP2 producing two second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 induces a transient increase in intracellular free Ca++, while DAG is a direct activator of protein kinase C (PKC theta). These process have been implicated in many cellular physiological functions like cell proliferation, cell growth and differentiation. Reactome Database ID Release 43202407 Reactome, http://www.reactome.org ReactomeREACT_12585 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 p-SLP-76:ADAP binds Ena/VASP ADAP (FYB) is an adaptor protein containing multiple binding motifs including an enabled protein vasodilator-stimulated phosphoprotein homology domain 1 (EVH1)-binding domain. This domain binds Ena-VASP family proteins that regulate actin dynamics. The Ena-VASP family member EVL is found in regions of dynamic actin polymerization, such as F-actin rich patches and the distal tips of microspikes. Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed10747096 Pubmed11943877 Reactome Database ID Release 43430201 Reactome, http://www.reactome.org ReactomeREACT_20624 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 p-SLP-76 binds ADAP Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed10671560 Pubmed10747096 Pubmed11113155 Pubmed11567141 Pubmed17003372 Pubmed9115214 Reactome Database ID Release 43430135 Reactome, http://www.reactome.org ReactomeREACT_20591 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 SLP-76 inducibly-associates with ADAP (also known as FYN-binding protein or SLAP-130) a hematopoietic-specific adapter protein. ADAP has been implicated in T cell migration and rearrangement of the actin cytoskeleton. In platelets, adhesion to fibrinogen stimulates the association of SLP-76 with ADAP and VASP (Obergfell et al. 2001). ADAP knockout mice exhibit mild thrombocytopenia (Kasirer-Friede et al. 2007). Hydrolysis of PIP3 to PI(3,4)P2 After the generation of PIP3 by PI3K, a part of it is further dephosphorylated to generate other forms of PI which are also involved in signaling. Two major routes for the degradation of PIP3 exists: dephosphorylation by the haematopoietic-specific SH2 domain-containing inositol 5' phosphatase SHIP-1 and dephosphorylation by the 3' phosphoinositide phosphatase PTEN. <br>SHIP-1 appears to set an activation threshold on T cell signaling. SHIP-1 phosphatase activity removes the 5' phosphate of PIP3 and generate phosphatidylinositol 3,4-bisphosphate. PI(3,4)P2 along with PIP3 preferentially binds to the PH domains of PKB and PDK1. Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 3.1.3.67 Pubmed10716940 Pubmed11884229 Reactome Database ID Release 43202237 Reactome, http://www.reactome.org ReactomeREACT_12405 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 PI3K phosphorylates PIP2 to PIP3 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 2.7.1.153 PI3K enzyme bound to adaptor protein TRIM, uses phosphatidylinositol 4,5-bisphosphate (PIP2) as its substrate and phosphorylates it to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and PKB. Pubmed12660731 Reactome Database ID Release 43202365 Reactome, http://www.reactome.org ReactomeREACT_12561 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Translocation of PDK1 to Plasma membrane Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 PDK1 is a Ser/Thr kinase with a N-term kinase domain and a C-term PH domain. PDK1 with its PH domain binds to PIP3 and PI(3,4)P2 and is translocated to the plasma membrane. PDK1 seems to exist in an active, phosphorylated configuration under basal conditions. PDK1 pays an important role in activating and phosphorylating the enzymes PKB and PKC theta. Pubmed10698680 Reactome Database ID Release 43202164 Reactome, http://www.reactome.org ReactomeREACT_12641 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Hydrolysis of PIP3 to PIP2 Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 EC Number: 3.1.3.67 PTEN dephosphorylates 3' position of PIP3 to generate PIP2 and negatively regulates the PI3K pathway and PKB activation. Reactome Database ID Release 43202371 Reactome, http://www.reactome.org ReactomeREACT_12545 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 CXCR4,7 Converted from EntitySet in Reactome Reactome DB_ID: 374120 Reactome Database ID Release 43374120 Reactome, http://www.reactome.org ReactomeREACT_15121 NCK binds PAK Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 NCK binds to PAK through its second SH3 domain. PAK interacts with NCK via the amino terminal SH3 binding domain. This interaction leads to the phosphorylation of NCK at multiple sites. Pubmed8798379 Pubmed8824201 Reactome Database ID Release 43430183 Reactome, http://www.reactome.org ReactomeREACT_20657 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 p-SLP-76 binds NCK Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed9846482 Reactome Database ID Release 43430190 Reactome, http://www.reactome.org ReactomeREACT_20599 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 SLP-76 interacts with the adaptor protein NCK1. This interaction involved the SH2 domain of NCK1, leaving 3 three SH3 domains free to interact with other proteins, notably PAK1, N-WASP and Sos. Recruitment of PI3K to plasmamembrane Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 In response to the TCR stimulation, phsophoinositides are phosphorylated on the 3-position of the inositol ring by PI3K to generate lipid second messengers that serve as membrane docking sites for a variety of downstream effector proteins such as PDK1 and PKB. PI3K is a heterodimer comprising a regulatory subunit p85 and a catalytic subunit p110 which associate constitutively and are activated upon interaction with tyrosine-phosphorylated proteins at the plasma membrane. The p85 subunit contains two SH2 domains and an SH3 domain. p85 subunit is involved in interaction with two phsophotyrosine residues of the adaptor protein TRIM with its two SH2 domains. This interaction is important in recruiting the p110 subunit to the plasma membrane and activate the p110 kinase activity, which is normally inhibited in the p85-p110 complex. Pubmed12660731 Pubmed16612002 Pubmed9687533 Reactome Database ID Release 43202203 Reactome, http://www.reactome.org ReactomeREACT_12486 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 NCK recruits WASP Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 Pubmed10679362 Pubmed7565724 Reactome Database ID Release 43430180 Reactome, http://www.reactome.org ReactomeREACT_20623 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 The second SH3 domain of NCK interacts with the carboxy-terminal SH3 domain of WASP. WASP family proteins bind the Arp2/3 complex, stimulating its ability to nucleate actin filaments and induce filament branching. ACTIVATION GENE ONTOLOGYGO:0016788 Reactome Database ID Release 43162708 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004168 Reactome Database ID Release 43449273 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003923 Reactome Database ID Release 43162847 Reactome, http://www.reactome.org Myelin component Converted from EntitySet in Reactome Reactome DB_ID: 194580 Reactome Database ID Release 43194580 Reactome, http://www.reactome.org ReactomeREACT_14289 ACTIVATION GENE ONTOLOGYGO:0004610 Reactome Database ID Release 43532213 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004343 Reactome Database ID Release 43449733 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004360 Reactome Database ID Release 43532207 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047874 Reactome Database ID Release 43449731 Reactome, http://www.reactome.org LINGO1 Converted from EntitySet in Reactome Reactome DB_ID: 358208 Reactome Database ID Release 43358208 Reactome, http://www.reactome.org ReactomeREACT_15166 Collagen alpha-1(XXII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192964 Reactome Database ID Release 432192964 Reactome, http://www.reactome.org ReactomeREACT_125161 ACTIVATION GENE ONTOLOGYGO:0004615 Reactome Database ID Release 43532558 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004476 Reactome Database ID Release 43532557 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003977 Reactome Database ID Release 43532209 Reactome, http://www.reactome.org G1 Phase Early cell cycle progression in G1 is under the control of the D-type cyclins together with Cdk4 and Cdk6. An important target for these CDKs is the Retinoblastoma (Rb) protein, which when phosphorylated promotes cell cycle progression by releasing E2F transcription factors that transactivate several important genes for later cell cycle events. The formation of Cyclin D - Cdk4/6 complexes is promoted by two proteins, p21Cip1/Waf1 and p27kip1, and their activity can be inhibited by the binding of several small CDK-inhibitory proteins (CKIs): p15INK4B, p16INK4A, p18INK4C and p19INK4D. GENE ONTOLOGYGO:0000080 Reactome Database ID Release 4369236 Reactome, http://www.reactome.org ReactomeREACT_1590 Cyclin D associated events in G1 Reactome Database ID Release 4369231 Reactome, http://www.reactome.org ReactomeREACT_821 Three D-type cyclins are essential for progression from G1 to S-phase. These D cyclins bind to and activate both CDK4 and CDK6. The formation of all possible complexes between the D-type cyclins and CDK4/6 is promoted by the proteins, p21(CIP1/WAF1) and p27(KIP1). The cyclin-dependent kinases are then activated due to phosphorylation by CAK. The cyclin dependent kinases phosphorylate the RB1 protein and RB1-related proteins p107 (RBL1) and p130 (RBL2). Phosphorylation of RB1 leads to release of activating E2F transcription factors (E2F1, E2F2 and E2F3). After repressor E2Fs (E2F4 and E2F5) dissociate from phosphorylated RBL1 and RBL2, activating E2Fs bind to E2F promoter sites, stimulating transcription of cell cycle genes, which then results in proper G1/S transition. The binding and sequestration of p27Kip may also contribute to the activation of CDK2 cyclin E/CDK2 cyclin A complexes at the G1/S transition (Yew et al., 2001). Mitotic G1-G1/S phases Edited: Matthews, L, 2010-01-19 Reactome Database ID Release 43453279 Reactome, http://www.reactome.org ReactomeREACT_21267 Reviewed: Grana, X, 2011-06-15 Reviewed: MacPherson, D, 2011-08-25 Reviewed: Manfredi, J, 0000-00-00 00:00:00 G0 and Early G1 Authored: Orlic-Milacic, Marija, 2011-08-26 In G0 and early G1 in quiescent cells, p130 (RBL2) bound to E2F4 or E2F5 and either DP1 or DP2, associates with the MuvB complex, forming an evolutionarily conserved DREAM complex, that represses transcription of cell cycle genes. During early G1 phase in actively cycling cells, p107 (RBL1) forms a complex with E2F4 and DP1 or DP2 and represses transcription of E2F target genes. Both p130 (RBL2) and p107 (RBL1) repress transcription of E2F targets through recruiting histone deacetylase HDAC1, possibly in complex with other chromatin modifying enzymes, to E2F-regulated promoters. Expression of p107 (RBL1) is cell cycle regulated, with its levels peaking in late G1 and S phase. Although p107 (RBL1) is phosphorylated by cyclin D assocaited kinases during late G1 phase, a small pool of p107 (RBL1) is thought to be present throughout G1 and S phase, and could be involved in fine tuning the transcription of S-phase genes. This is supported by studies showing that unlike RB1 and p130 (RBL2), which are able to induce G1 arrest when over-expressed, p107 (RBL1) over-expression can arrest the cell cycle in both G1 and S phase. For recent reviews on the function of p107, p130 and pocket proteins in general, please refer to Wirt and Sage, 2010, MacPherson 2008 and Cobrinik 2005. Pubmed15838516 Pubmed18489754 Pubmed20359370 Reactome Database ID Release 431538133 Reactome, http://www.reactome.org ReactomeREACT_111214 Reviewed: MacPherson, D, 2011-08-25 Inactivation of APC/C via direct inhibition of the APC/C complex Authored: Yen, T, 2004-05-05 00:00:00 In the direct inhibition model, the cytosolic Mitotic Checkpoint Complex, consisting of hBUBR1, hBUB3, Cdc20 and Mad2, directly inhibits APC/C by binding to it. Pubmed11535616 Pubmed14593737 Pubmed9637688 Reactome Database ID Release 43141430 Reactome, http://www.reactome.org ReactomeREACT_1072 Reviewed: Peters, JM, 2006-03-27 22:55:09 ACTIVATION GENE ONTOLOGYGO:0004475 Reactome Database ID Release 43532540 Reactome, http://www.reactome.org Cell Cycle, Mitotic Authored: O'Connell, M, Walworth, N, Bosco, G, 2005-01-01 14:12:30 Edited: Matthews, L, Gopinathrao, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0000278 Reactome Database ID Release 4369278 Reactome, http://www.reactome.org ReactomeREACT_152 Reviewed: Grana, X, 2011-06-15 Reviewed: MacPherson, D, 2011-08-25 Reviewed: Manfredi, J, 0000-00-00 00:00:00 The replication of the genome and the subsequent segregation of chromosomes into daughter cells are controlled by a series of events collectively known as the cell cycle. DNA replication is carried out during a discrete temporal period known as the S (synthesis)-phase, and chromosome segregation occurs during a massive reorganization to cellular architecture at mitosis. Two gap-phases separate these major cell cycle events: G1 between mitosis and S-phase, and G2 between S-phase and mitosis. In the development of the human body, cells can exit the cell cycle for a period and enter a quiescent state known as G0, or terminally differentiate into cells that will not divide again, but undergo morphological development to carry out the wide variety of specialized functions of individual tissues.<br>A family of protein serine/threonine kinases known as the cyclin-dependent kinases (CDKs) controls progression through the cell cycle. As the name suggests, the activity of the catalytic subunit is dependent on binding to a cyclin partner. The human genome encodes several cyclins and several CDKs, with their names largely derived from the order in which they were identified. The oscillation of cyclin abundance is one important mechanism by which these enzymes phosphorylate key substrates to promote events at the relevant time and place. Additional regulatory proteins and post-translational modifications ensure that CDK activity is precisely regulated, frequently confined to a narrow window of activity. ACTIVATION GENE ONTOLOGYGO:0004581 Reactome Database ID Release 43532215 Reactome, http://www.reactome.org Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal Authored: Yen, T, 2004-05-05 00:00:00 Pubmed14593737 Reactome Database ID Release 43141444 Reactome, http://www.reactome.org ReactomeREACT_491 The signal from unattached kinetochores is amplified through a Mad2 inhibitory signal that is propagated by the binding of Mad1 to the kinetochore, the association of Mad2 with Mad1, the conversion of Mad2 conformation to an inhibitory form through its association with Mad1 and finally the release of the inhibitory form of Mad2 from the kinetochore. ACTIVATION GENE ONTOLOGYGO:0003975 Reactome Database ID Release 43449231 Reactome, http://www.reactome.org Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components Authored: Yen, T, 2004-05-05 00:00:00 GENE ONTOLOGYGO:0051436 Pubmed14593737 Reactome Database ID Release 43141405 Reactome, http://www.reactome.org ReactomeREACT_1041 Reviewed: Peters, JM, 2006-03-27 22:55:09 The target of the mitotic checkpoint is the Anaphase Promoting Complex/Cyclosome (APC/C) an E3 ubiquitin ligase that targets proteins whose destruction is essential for mitotic exit. Currently, there are two proposed mechanism by which inhibition of the APC/C is achieved. These mechanisms differ depending on the mechanism of signal transduction. The APC/C may be inhibited directly by association with the Mitotic Checkpoint Complex (MCC) or through the sequestration of its activator, Cdc20. ACTIVATION GENE ONTOLOGYGO:0004577 Reactome Database ID Release 43449313 Reactome, http://www.reactome.org Amplification of signal from the kinetochores A single unattached kinetochore is capable of preventing cells from exiting mitosis. The mitotic checkpoint provides a way for a localized defect to affect the global biochemical status of the cell. In principle, the signal that is generated at an unattached kinetochore diffuses throughout the cell to affect its target. There are currently two models for how this is achieved. One model is based on the observation that the Mad2 checkpoint protein binds and is rapidly released from unattached kinetochores. The kinetochore is believed to act as a catalyst that converts Mad2 into an inhibitory state that diffuses throughout the cell upon its release from the kinetochore. A second model proposes that the signal is amplified by a kinase cascade much like a conventional signal transduction pathway. This kinase cascade is believed to be comprised of the checkpoint kinases, hBUBR1, hBUB1, hMPS1. Authored: Yen, T, 2004-05-05 00:00:00 Pubmed14593737 Reactome Database ID Release 43141424 Reactome, http://www.reactome.org ReactomeREACT_795 ACTIVATION GENE ONTOLOGYGO:0000033 Reactome Database ID Release 43449272 Reactome, http://www.reactome.org Mitotic Spindle Checkpoint Authored: Yen, T, 2004-05-05 00:00:00 GENE ONTOLOGYGO:0007094 Pubmed12360190 Pubmed14593737 Reactome Database ID Release 4369618 Reactome, http://www.reactome.org ReactomeREACT_2137 The mitotic checkpoint or spindle assembly checkpoint is an evolutionarily conserved mechanism that ensures that cells with misaligned chromosomes do not exit mitosis and divide to form aneuploid cells. As chromosome attachment to the spindle microtubules is a stochastic process, not all chromosomes achieve alignment at the spindle equator at the same time. It is therefore essential that even a single unaligned chromosome can prevent the onset of anaphase. The ability of the checkpoint to monitor the status of chromosome alignment is achieved by assigning checkpoint proteins to the kinetochore, a macromolecular complex that resides at centromeres of chromosomes that establishes connections with spindle microtubules. <P>The checkpoint proteins monitor, in an unknown way, the mechanical activities between kinetochore-associated proteins and microtubules. Defects in mechanical activities at kinetochores activate the resident checkpoint proteins to initiate a signal that is amplified throughout the cell that ultimately prevents the activation of the proteolytic process that is required for sister chromatid separation and the onset of anaphase. Kinetochores of unaligned chromosomes differ from those of aligned chromosomes in two ways. Kinetochores of aligned chromosomes are saturated with between 20 to 30 microtubules. In addition, poleward directed forces exerted at each sister kinetochore generates tension between them. Unaligned kinetochores on the other hand, are not saturated with microtubules and are not under tension. The mitotic checkpoint detects the presence of unattached kinetochores rather than monitoring for the presence of attached kinetochores. Consequently, unattached kinetochores emit an inhibitory signal that inhibits the biochemical events that are required to initiate the onset of anaphase. The mechanism by which this inhibitory signal is generated at unattached kinetochores has not precisely been determined but the signal is generated as a result of the lack of microtubule occupancy and kinetochore tension. A single unattached kinetochore is capable of preventing cells from exiting mitosis. The mitotic checkpoint provides a way for a localized defect to affect the global biochemical status of the cell. In principle, the signal that is generated at an unattached kinetochore diffuses throughout the cell to affect its target. There are currently two models for how this is achieved. One model is based on the observation that the Mad2 checkpoint protein binds and is rapidly released from unattached kinetochores. The kinetochore is believed to act as a catalyst that converts Mad2 into an inhibitory state that diffuses throughout the cell upon its release from the kinetochore. A second model proposes that the signal is amplified by a kinase cascade much like a conventional signal transduction pathway. This kinase cascade is believed to be comprised of the checkpoint kinases, hBUBR1, hBUB1, hMPS1. ACTIVATION GENE ONTOLOGYGO:0004578 Reactome Database ID Release 43449217 Reactome, http://www.reactome.org Histone deacetylase Converted from EntitySet in Reactome Reactome DB_ID: 205005 Reactome Database ID Release 43205005 Reactome, http://www.reactome.org ReactomeREACT_14591 ACTIVATION GENE ONTOLOGYGO:0000026 Reactome Database ID Release 43449259 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000009 Reactome Database ID Release 43449719 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000033 Reactome Database ID Release 43449317 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0034202 Reactome Database ID Release 43449213 Reactome, http://www.reactome.org Collagen alpha-1(XXVI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192941 Reactome Database ID Release 432192941 Reactome, http://www.reactome.org ReactomeREACT_121651 Transcriptional activation of cell cycle inhibitor p21 Both p53-independent and p53-dependent mechanisms of induction of p21 mRNA have been demonstrated. p21 is transcriptionally activated by p53 after DNA damage (el-Deiry et al., 1993). Pubmed8242752 Reactome Database ID Release 4369895 Reactome, http://www.reactome.org ReactomeREACT_346 ACTIVATION GENE ONTOLOGYGO:0004583 Reactome Database ID Release 43449636 Reactome, http://www.reactome.org p53-Independent G1/S DNA damage checkpoint Pubmed10827953 Reactome Database ID Release 4369613 Reactome, http://www.reactome.org ReactomeREACT_1208 The G1 arrest induced by DNA damage has been ascribed to the transcription factor and tumor suppressor protein p53. To be effective within minutes after DNA damage, induction of the G1 block should exploit transcription and protein synthesis independent mechanisms.<p>Upon exposure to ultraviolet light (UV) or ionizing radiation (IR), the abundance and activity of a protein, Cdc25A, rapidly decreases; this DNA damage response is not dependent on p53. The rapid destruction of Cdc25A phosphatase prevents entry of a cell into S-phase, by maintaining the CyclinE:Cdk2 complexes in their T14Y15 phosphorylated form. ACTIVATION GENE ONTOLOGYGO:0004583 Reactome Database ID Release 43449642 Reactome, http://www.reactome.org p53-Independent DNA Damage Response In response to DNA damage due to exposure to ultraviolet light or to ionizing radiation, Cdc25A is phosphorylated by Chk1 or Chk2. The phosphorylation of Cdc25A at ser-123, in response to DNA damage from ionizing radiation is a signal for ubiquitination and subsequent degradation of Cdc25A. The destruction of Cdc25A prevents the normal G1/S transition. Cdc25A is required for the activation of the Cyclin E:Cdk2 complexes via dephosphorylation.<p>Chk1 is activated in response to DNA damage due to uv light. However, the phosphorylation occurs at a different site. Pubmed11298456 Reactome Database ID Release 4369610 Reactome, http://www.reactome.org ReactomeREACT_2160 ACTIVATION GENE ONTOLOGYGO:0000030 Reactome Database ID Release 43449367 Reactome, http://www.reactome.org Ubiquitin Mediated Degradation of Phosphorylated Cdc25A Pubmed10828887 Reactome Database ID Release 4369601 Reactome, http://www.reactome.org ReactomeREACT_1614 cdc25A protein is degraded by the ubiquitin-proteasome machinery in both terminally differentiating and cycling cells (Bernardi et al. 2000). ACTIVATION GENE ONTOLOGYGO:0000026 Reactome Database ID Release 43449260 Reactome, http://www.reactome.org G2/M Checkpoints G2/M checkpoints include the checks for damaged DNA, unreplicated DNA, and checks that ensure that the genome is replicated once and only once per cell cycle. If cells pass these checkpoints, they follow normal transition to the M phase. However, if any of these checkpoints fail, mitotic entry is prevented by specific G2/M checkpoint events.<p>The G2/M checkpoints can fail due to the presence of unreplicated DNA or damaged DNA. In such instances, the cyclin-dependent kinase, Cdc2(Cdk1), is maintained in its inactive, phosphorylated state, and mitotic entry is prevented. Events that ensure that origins of DNA replication fire once and only once per cell cycle are also an example of a G2/M checkpoint.<p>In the event of high levels of DNA damage, the cells may also be directed to undergo apopotosis (not covered). Reactome Database ID Release 4369481 Reactome, http://www.reactome.org ReactomeREACT_828 G2/M DNA damage checkpoint Reactome Database ID Release 4369473 Reactome, http://www.reactome.org ReactomeREACT_897 Throughout the cell cycle, the genome is constantly monitored for damage, resulting either from errors of replication, by-products of metabolism or through extrinsic sources such as ultra-violet or ionizing radiation. The different DNA damage checkpoints act to inhibit or maintain the inhibition of the relevant CDK that will control the next cell cycle transition. The G2 DNA damage checkpoint prevents mitotic entry solely through T14Y15 phosphorylation of Cdc2 (Cdk1). Failure of the G2 DNA damage checkpoint leads to catastrophic attempts to segregate unrepaired chromosomes. ACTIVATION GENE ONTOLOGYGO:0000026 Reactome Database ID Release 43449260 Reactome, http://www.reactome.org Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex Authored: Matthews, L, 2003-08-05 01:10:00 DNA damage induced activation of the checkpoint kinases Chk1/Chk2(Cds1) results in the conversion and/or maintenance of CyclinB:Cdc2 complex in its Tyrosine 15 phosphorylated (inactive) state. Cdc2 activity is regulated by a balance between the phosphorylation and dephosphorylation by the Wee1/Myt1 kinase and Cdc25 phosphatase. Inactivation of the Cyclin B:Cdc2 complex likely involves both inactivation of Cdc25 and/or stimulation of Wee1/Myt1 kinase activity. Reactome Database ID Release 4375035 Reactome, http://www.reactome.org ReactomeREACT_407 G2/M DNA replication checkpoint Reactome Database ID Release 4369478 Reactome, http://www.reactome.org ReactomeREACT_1846 The G2/M DNA replication checkpoint ensures that mitosis is not initiated until DNA replication is complete. If replication is blocked, the DNA replication checkpoint signals to maintain Cyclin B - Cdc2 complexes in their T14Y15 phosphorylated and inactive state. This prevents the phosphorylation of proteins involved in G2/M transition, and prevents mitotic entry.<p>Failure of these checkpoints results in changes of ploidy: in the case of mitosis without completion of DNA replication, aneuploidy of <2C will result, and the opposite is true if DNA replication is completed more than once in a single cell cycle with an overall increase in ploidy. The mechanism by which unreplicated DNA is first detected by the cell is unknown. Activation of ATR in response to replication stress Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 GENE ONTOLOGYGO:0006260 Genotoxic stress caused by DNA damage or stalled replication forks can lead to genomic instability. To guard against such instability, genotoxically-stressed cells activate checkpoint factors that halt or slow cell cycle progression. Among the pathways affected are DNA replication by reduction of replication origin firing, and mitosis by inhibiting activation of cyclin-dependent kinases (Cdks). A key factor involved in the response to stalled replication forks is the ATM- and rad3-related (ATR) kinase, a member of the phosphoinositide-3-kinase-related kinase (PIKK) family. Rather than responding to particular lesions in DNA, ATR and its binding partner ATRIP (ATR-interacting protein) sense replication fork stalling indirectly by associating with persistent ssDNA bound by RPA. These structures would be formed, for example, by dissociation of the replicative helicase from the leading or lagging strand DNA polymerase when the polymerase encounters a DNA lesion that blocks DNA synthesis. Along with phosphorylating the downstream transducer kinase Chk1 and the tumor suppressor p53, activated ATR modifies numerous factors that regulate cell cycle progression or the repair of DNA damage. The persistent ssDNA also stimulates recruitment of the RFC-like Rad17–Rfc2-5 alternative clamp-loading complex, which subsequently loads the Rad9-Hus1-Rad1 complex onto the DNA. The latter '9-1-1' complex serves to facilitate Chk1 binding to the stalled replication fork, where Chk1 is phosphorylated by ATR and thereby activated. Upon activation, Chk1 can phosphorylate additional substrates including the Cdc25 family of phosphatases (Cdc25A, Cdc25B, and Cdc25C). These enzymes catalyze the removal of inhibitory phosphate residues from cyclin-dependent kinases (Cdks), allowing their activation. In particular, Cdc25A primarily functions at the G1/S transition to dephosphorylate Cdk2 at Thr 14 and Tyr 15, thus positively regulating the Cdk2-cyclin E complex for S-phase entry. Cdc25A also has mitotic functions. Phosphorylation of Cdc25A at Ser125 by Chk1 leads to Cdc25A ubiquitination and degradation, thus inhibiting DNA replication origin firing. In contrast, Cdc25B and Cdc25C regulate the onset of mitosis through dephosphorylation and activation of Cdk1-cyclin B complexes. In response to replication stress, Chk1 phosphorylates Cdc25B and Cdc25C leading to Cdc25B/C complex formation with 14-3-3 proteins. As these complexes are sequestered in the cytoplasm, they are unable to activate the nuclear Cdk1-cyclin B complex for mitotic entry.<p>These events are outlined in the figure. Persistent single-stranded DNA associated with RPA binds claspin (A) and ATR:ATRIP (B), leading to claspin phosphorylation (C). In parallel, the same single-stranded DNA:RPA complex binds RAD17:RFC (D), enabling the loading of RAD9:HUS1:RAD1 (9-1-1) complex onto the DNA (E). The resulting complex of proteins can then repeatedly bind (F) and phosphorylate (G) CHK1, activating multiple copies of CHK1. Pubmed12781359 Pubmed12791985 Pubmed15530773 Pubmed16314342 Reactome Database ID Release 43176187 Reactome, http://www.reactome.org ReactomeREACT_6769 Caspase-2 p18 subunit Converted from EntitySet in Reactome Reactome DB_ID: 204988 Reactome Database ID Release 43204988 Reactome, http://www.reactome.org ReactomeREACT_13876 Caspase-2 p12 subunit Converted from EntitySet in Reactome Reactome DB_ID: 205110 Reactome Database ID Release 43205110 Reactome, http://www.reactome.org ReactomeREACT_14363 Collagen alpha-1(XXI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192922 Reactome Database ID Release 432192922 Reactome, http://www.reactome.org ReactomeREACT_122271 ACTIVATION GENE ONTOLOGYGO:0033919 Reactome Database ID Release 43532675 Reactome, http://www.reactome.org Caspase-2 precursor Converted from EntitySet in Reactome Reactome DB_ID: 205030 Reactome Database ID Release 43205030 Reactome, http://www.reactome.org ReactomeREACT_14186 ACTIVATION GENE ONTOLOGYGO:0033919 Reactome Database ID Release 43532675 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004573 Reactome Database ID Release 43532670 Reactome, http://www.reactome.org Transcriptional activation of p53 responsive genes Pubmed7664346 Pubmed8242751 Pubmed8242752 Pubmed8259214 Reactome Database ID Release 4369560 Reactome, http://www.reactome.org ReactomeREACT_202 p53 causes G1 arrest by inducing the expression of a cell cycle inhibitor, p21 (El-Deiry et al, 1993; Harper et al, 1993; Xiong et al, 1993). P21 binds and inactivates Cyclin-Cdk complexes that mediate G1/S progression, resulting in lack of phosphorylation of Rb, E2F sequestration and cell cycle arrest at the G1/S transition. Mice with a homozygous deletion of p21 gene are deficient in their ability to undergo a G1/S arrest in response to DNA damage (Deng et al, 1995). ACTIVATION GENE ONTOLOGYGO:0004579 Reactome Database ID Release 43532535 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004583 Reactome Database ID Release 43449654 Reactome, http://www.reactome.org Role of DCC in regulating apoptosis Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 In the presence of Netrin1, DCC and UNC5 generate attractive and repulsive signals to growing axons. In the absence of Netrin-1, DCC induces cell death signaling initiated via caspase cleavage of DCC and the interaction of caspase-9. Recent reports have shown that UNC5 receptors similarly induce apoptosis in the absence of Netrin-1. These reactions proceed without a requirement for cytochrome c release from mitochondria or interaction with apoptotic protease activating factor 1 (APAF1). DCC thus regulates an apoptosome-independent pathway for caspase activation. DCC and UNC-5 are hence defined as dependence receptors. Dependence receptors exhibit dual functions depending on the availability of ligand. They create cellular states of dependence on their respective ligands by either inducing apoptosis when unoccupied by the ligand, or inhibiting apoptosis in the presence of the ligand. Pubmed10348349 Pubmed12011067 Pubmed12598906 Pubmed15310786 Reactome Database ID Release 43418889 Reactome, http://www.reactome.org ReactomeREACT_22128 Reviewed: Cooper, HM, 2010-02-16 ACTIVATION GENE ONTOLOGYGO:0004559 Reactome Database ID Release 43901026 Reactome, http://www.reactome.org Cell Cycle Edited: Matthews, L, 2011-10-10 Reactome Database ID Release 431640170 Reactome, http://www.reactome.org ReactomeREACT_115566 ACTIVATION GENE ONTOLOGYGO:0004559 Reactome Database ID Release 43901026 Reactome, http://www.reactome.org Regulation of activated PAK-2p34 by proteasome mediated degradation Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-03 20:50:13 Edited: Matthews, L, 2008-06-12 00:23:53 Pubmed12853446 Pubmed9786869 Reactome Database ID Release 43211733 Reactome, http://www.reactome.org ReactomeREACT_13464 Reviewed: Chang, E, 2008-05-21 00:05:41 Stimulation of cell death by PAK-2 requires the generation and stabilization of the caspase-activated form, PAK-2p34 (Walter et al., 1998;Jakobi et al., 2003). Levels of proteolytically activated PAK-2p34 protein are controlled by ubiquitin-mediated proteolysis. PAK-2p34 but not full-length PAK-2 is degraded by the 26 S proteasome (Jakobi et al., 2003). It is not known whether ubiquitination and degradation of PAK-2p34 occurs in the cytoplasm or in the nucleus. ACTIVATION GENE ONTOLOGYGO:0003980 Reactome Database ID Release 43548875 Reactome, http://www.reactome.org Regulation of PAK-2p34 activity by PS-GAP/RHG10 Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-03 20:50:13 Edited: Matthews, L, 2008-06-12 00:23:53 PS-GAP (RGH10) interacts specifically with caspase-activated PAK-2p34 reducing the ability of PAK-2p34 to induce cell death. This interaction  inhibits the kinase activity of  PAK-2p34 and changes the localization of PAK-2p34 from the nucleus to the perinuclear region (Koeppel et al., 2004).   Pubmed15471851 Reactome Database ID Release 43211728 Reactome, http://www.reactome.org ReactomeREACT_13528 Reviewed: Chang, E, 2008-05-21 00:05:41 ACTIVATION GENE ONTOLOGYGO:0051787 Reactome Database ID Release 431022135 Reactome, http://www.reactome.org p53-Dependent G1/S DNA damage checkpoint Authored: Khanna, K, 2003-06-05 08:03:38 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed1323840 Reactome Database ID Release 4369580 Reactome, http://www.reactome.org ReactomeREACT_85 The arrest at G1/S checkpoint is mediated by the action of a widely known tumor suppressor protein, p53. Loss of p53 functions, as a result of mutations in cancer prevent the G1/S checkpoint (Kuerbitz et al, 1992). P53 is rapidly induced in response to damaged DNA. A number of kinases, phosphatases, histone acetylases and ubiquitin-conjugating enzymes regulate the stability as well as transcriptional activity of p53 after DNA damage. p53-Dependent G1 DNA Damage Response GENE ONTOLOGYGO:0006977 Most of the damage-induced modifications of p53 are dependent on the ATM kinase. The first link between ATM and p53 was predicted based on the earlier studies that showed that AT cells exhibit a reduced and delayed induction of p53 following exposure to IR (Kastan et al, 1992 and Khanna and Lavin, 1993).<p>Under normal conditions, p53 is a short-lived protein. The MDM2 protein, usually interacts with p53 (Haupt et al, 1997 and Kubbutat et al, 1997), and by virtue of its E3 ubiquitin ligase activity, shuttles p53 to the cytoplasm and mediates its degradation by the ubiquitin-proteasome machinery. Upon detection of DNA damage, the ATM kinase mediates the phosphorylation of the Mdm2 protein to block its interaction with p53. Also, phosphorylation of p53 at multiple loci, by the ATM kinase and by other kinases activated by the ATM kinase, stabilizes and activates the p53 protein.<p>The p53 protein activates the transcription of cyclin-dependent kinase inhibitor, p21. p21 inactivates the CyclinE:Cdk2 complexes, and prevent entry of the cell into S phase, leading to G1 arrest. Under severe conditions, the cell may undergo apoptosis. Pubmed1423616 Pubmed8247533 Pubmed9153395 Pubmed9153396 Reactome Database ID Release 4369563 Reactome, http://www.reactome.org ReactomeREACT_1625 Reviewed: Manfredi, J, 0000-00-00 00:00:00 Cell Cycle Checkpoints A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.<p>Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs.<p>The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear. Authored: Hoffmann, I, Khanna, K, O'Connell, M, Walworth, N, Yen, TJ, 2005-01-01 00:00:00 Edited: Matthews, L, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0000075 Reactome Database ID Release 4369620 Reactome, http://www.reactome.org ReactomeREACT_1538 Reviewed: Sanchez, Y, Knudsen, E, Hardwick, KG, 0000-00-00 00:00:00 ACTIVATION GENE ONTOLOGYGO:0004559 Reactome Database ID Release 43901026 Reactome, http://www.reactome.org G1/S DNA Damage Checkpoints Authored: Hoffmann, I, Khanna, K, 2003-06-05 08:03:42 In the G1 phase there are two types of DNA damage responses, the p53-dependent and the p53-independent pathways. The p53-dependent responses inhibit CDKs through the up-regulation of genes encoding CKIs mediated by the p53 protein, whereas the p53-independent mechanisms inhibit CDKs through the inhibitory T14Y15 phosphorylation of Cdk2. Failure of DNA damage checkpoints in G1 leads to mutagenic replication of damaged templates and other replication defects. Reactome Database ID Release 4369615 Reactome, http://www.reactome.org ReactomeREACT_2254 ACTIVATION GENE ONTOLOGYGO:0004559 Reactome Database ID Release 43901026 Reactome, http://www.reactome.org Stabilization of p53 Edited: Matthews, L, 2008-05-12 13:48:33 Later studies pin-pointed that a single serine (Ser-15) was phosphorylated by ATM and phosphorylation of Ser-15 was rapidly-induced in IR-treated cells and this response was ATM-dependent (Canman et al, 1998; Banin et al, 1998 and Khanna et al, 1998). ATM also regulates the phosphorylation of p53 at other sites, especially Ser-20, by activating other serine/threonine kinases in response to IR (Chehab et al, 2000; Shieh et al, 2000; Hirao et al 2000). Phosphorylation of p53 at Ser-20 interferes with p53-MDM2 interaction. MDM2 is transcriptionally activated by p53 and is a negative regulator of p53 that targets it for degradation (Haupt et al, 1997; Kubbutat et al, 1997). In addition modification of MDM2 by ATM also affects p53 stabilization (Maya et al, 2001). Pubmed10673500 Pubmed10673501 Pubmed10710310 Pubmed11331603 Reactome Database ID Release 4369541 Reactome, http://www.reactome.org ReactomeREACT_309 Reviewed: Sanchez, Y, 2008-05-07 22:09:03 Autodegradation of the E3 ubiquitin ligase COP1 Authored: Matthews, L, 2008-06-12 21:09:06 COP1 is one of several E3 ubiquitin ligases responsible for the tight regulation of p53 abundance. Following DNA damage, COP1 dissociates from p53 and is inactivated by autodegradation via a pathway involving ATM phosphorylation of COP1 on Ser(387), autoubiquitination and proteasome mediated degradation. Destruction of COP1 results in abrogation of the ubiquitination and degradation of p53 (Dornan et al., 2006). Edited: Matthews, L, 2009-11-09 Pubmed16931761 Reactome Database ID Release 43349425 Reactome, http://www.reactome.org ReactomeREACT_20549 Reviewed: Dixit, VM, 2009-11-17 NRIF Converted from EntitySet in Reactome Reactome DB_ID: 216351 Reactome Database ID Release 43216351 Reactome, http://www.reactome.org ReactomeREACT_14593 ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43204006 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005537 Reactome Database ID Release 431017218 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43211500 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43203986 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 4369115 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 4368484 Reactome, http://www.reactome.org C3G Converted from EntitySet in Reactome Reactome DB_ID: 190074 Reactome Database ID Release 43190074 Reactome, http://www.reactome.org ReactomeREACT_12261 ACTIVATION GENE ONTOLOGYGO:0004520 Reactome Database ID Release 43109959 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43420756 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004843 Reactome Database ID Release 43420759 Reactome, http://www.reactome.org CRKL (SH3 domain) Converted from EntitySet in Reactome Reactome DB_ID: 190079 Reactome Database ID Release 43190079 Reactome, http://www.reactome.org ReactomeREACT_12190 ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 43109965 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43420756 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047057 Reactome Database ID Release 43159727 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43421861 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43421861 Reactome, http://www.reactome.org Collagen alpha-1(XIX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192888 Reactome Database ID Release 432192888 Reactome, http://www.reactome.org ReactomeREACT_123536 ACTIVATION GENE ONTOLOGYGO:0008488 Reactome Database ID Release 43159812 Reactome, http://www.reactome.org MAPKAP kinase Converted from EntitySet in Reactome Reactome DB_ID: 187699 Reactome Database ID Release 43187699 Reactome, http://www.reactome.org ReactomeREACT_12293 ACTIVATION GENE ONTOLOGYGO:0008488 Reactome Database ID Release 43159812 Reactome, http://www.reactome.org RIT/RIN Converted from EntitySet in Reactome Reactome DB_ID: 187719 Reactome Database ID Release 43187719 Reactome, http://www.reactome.org ReactomeREACT_12234 ACTIVATION GENE ONTOLOGYGO:0008488 Reactome Database ID Release 43159812 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008488 Reactome Database ID Release 43159812 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008488 Reactome Database ID Release 43159812 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008488 Reactome Database ID Release 43159812 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008488 Reactome Database ID Release 43159812 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008488 Reactome Database ID Release 43159812 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org Collagen alpha-1(XX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192901 Reactome Database ID Release 432192901 Reactome, http://www.reactome.org ReactomeREACT_123881 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0034038 Reactome Database ID Release 43204646 Reactome, http://www.reactome.org Intracellular Phosphorylated Trk receptor Converted from EntitySet in Reactome Reactome DB_ID: 187680 Reactome Database ID Release 43187680 Reactome, http://www.reactome.org ReactomeREACT_10421 ACTIVATION GENE ONTOLOGYGO:0019135 Reactome Database ID Release 43204618 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0034038 Reactome Database ID Release 43204646 Reactome, http://www.reactome.org SHC Converted from EntitySet in Reactome Reactome DB_ID: 167023 Reactome Database ID Release 43167023 Reactome, http://www.reactome.org ReactomeREACT_12338 Shc transforming protein ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43156993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004582 Reactome Database ID Release 43162705 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000225 Reactome Database ID Release 43162853 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008194 Reactome Database ID Release 43162711 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004376 Reactome Database ID Release 43162844 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016780 Reactome Database ID Release 43162883 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000030 Reactome Database ID Release 43162700 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016780 Reactome Database ID Release 43162802 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008374 Reactome Database ID Release 43162878 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000030 Reactome Database ID Release 43162859 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016780 Reactome Database ID Release 43162868 Reactome, http://www.reactome.org Collagen alpha-1(XVIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192854 Reactome Database ID Release 432192854 Reactome, http://www.reactome.org ReactomeREACT_122516 ACTIVATION GENE ONTOLOGYGO:0004376 Reactome Database ID Release 43162827 Reactome, http://www.reactome.org Intracellular Trk receptor Converted from EntitySet in Reactome Nerve Growth Factor receptor Neurotrophic tyrosine kinase receptor Reactome DB_ID: 187658 Reactome Database ID Release 43187658 Reactome, http://www.reactome.org ReactomeREACT_10478 ACTIVATION GENE ONTOLOGYGO:0004519 Reactome Database ID Release 43175587 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004519 Reactome Database ID Release 43175592 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004520 Reactome Database ID Release 43109958 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004519 Reactome Database ID Release 43109956 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43111307 Reactome, http://www.reactome.org HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2130483 Reactome Database ID Release 432130483 Reactome, http://www.reactome.org ReactomeREACT_125205 ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 4375926 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004520 Reactome Database ID Release 43109959 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 43109965 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 4369115 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 4368484 Reactome, http://www.reactome.org Dynamin Converted from EntitySet in Reactome Reactome DB_ID: 2213185 Reactome Database ID Release 432213185 Reactome, http://www.reactome.org ReactomeREACT_122824 ACTIVATION GENE ONTOLOGYGO:0003684 Reactome Database ID Release 43113683 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003684 Reactome Database ID Release 43113683 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003684 Reactome Database ID Release 43113683 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 43109965 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4383536 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4375225 Reactome, http://www.reactome.org HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2130392 Reactome Database ID Release 432130392 Reactome, http://www.reactome.org ReactomeREACT_122715 Collagen alpha-6(VI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127492 Reactome Database ID Release 432127492 Reactome, http://www.reactome.org ReactomeREACT_125324 Collagen alpha-1(XXIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192980 Reactome Database ID Release 432192980 Reactome, http://www.reactome.org ReactomeREACT_125383 AP-1 mu Converted from EntitySet in Reactome Reactome DB_ID: 2130503 Reactome Database ID Release 432130503 Reactome, http://www.reactome.org ReactomeREACT_124617 Collagen alpha-2(VI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127516 Reactome Database ID Release 432127516 Reactome, http://www.reactome.org ReactomeREACT_124774 AP-1 sigma Converted from EntitySet in Reactome Reactome DB_ID: 2130555 Reactome Database ID Release 432130555 Reactome, http://www.reactome.org ReactomeREACT_124521 Collagen alpha-1(XIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192718 Reactome Database ID Release 432192718 Reactome, http://www.reactome.org ReactomeREACT_125650 Thrombospondin Converted from EntitySet in Reactome Reactome DB_ID: 684997 Reactome Database ID Release 43684997 Reactome, http://www.reactome.org ReactomeREACT_23294 ACTIVATION GENE ONTOLOGYGO:0031545 Reactome Database ID Release 431234168 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0031545 Reactome Database ID Release 431234168 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431234157 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 431234182 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 43174219 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0031545 Reactome Database ID Release 431234168 Reactome, http://www.reactome.org Crk isoforms Converted from EntitySet in Reactome Reactome DB_ID: 381945 Reactome Database ID Release 43381945 Reactome, http://www.reactome.org ReactomeREACT_17492 ACTIVATION GENE ONTOLOGYGO:0031545 Reactome Database ID Release 431234180 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0031545 Reactome Database ID Release 431234180 Reactome, http://www.reactome.org PDGF receptor monomer Converted from EntitySet in Reactome Reactome DB_ID: 186792 Reactome Database ID Release 43186792 Reactome, http://www.reactome.org ReactomeREACT_18211 PDGF A and B chains with retention motif Converted from EntitySet in Reactome Reactome DB_ID: 381934 Reactome Database ID Release 43381934 Reactome, http://www.reactome.org ReactomeREACT_17714 HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2214376 Reactome Database ID Release 432214376 Reactome, http://www.reactome.org ReactomeREACT_123774 ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 431169248 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 431169248 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 431169203 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0031545 Reactome Database ID Release 431234180 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016706 Reactome Database ID Release 431234170 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 43204233 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 431169238 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 431168883 Reactome, http://www.reactome.org HLA II beta chain Converted from EntitySet in Reactome Reactome DB_ID: 2130388 Reactome Database ID Release 432130388 Reactome, http://www.reactome.org ReactomeREACT_122751 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431168900 Reactome, http://www.reactome.org VEGFB Converted from EntitySet in Reactome Reactome DB_ID: 195358 Reactome Database ID Release 43195358 Reactome, http://www.reactome.org ReactomeREACT_13378 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 431168897 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 431168926 Reactome, http://www.reactome.org VEGFA Converted from EntitySet in Reactome Reactome DB_ID: 194136 Reactome Database ID Release 43194136 Reactome, http://www.reactome.org ReactomeREACT_12932 ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 431112516 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004691 Reactome Database ID Release 43914181 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 431295532 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 431363334 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43914051 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43912642 Reactome, http://www.reactome.org VEGFR1 Converted from EntitySet in Reactome Reactome DB_ID: 195354 Reactome Database ID Release 43195354 Reactome, http://www.reactome.org ReactomeREACT_12746 HLA II alpha chain Converted from EntitySet in Reactome Reactome DB_ID: 2214383 Reactome Database ID Release 432214383 Reactome, http://www.reactome.org ReactomeREACT_123475 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43912324 Reactome, http://www.reactome.org NRP-1 Converted from EntitySet in Reactome Reactome DB_ID: 195380 Reactome Database ID Release 43195380 Reactome, http://www.reactome.org ReactomeREACT_12698 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43912315 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43904801 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43508440 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 43914083 Reactome, http://www.reactome.org PLGF Converted from EntitySet in Reactome Reactome DB_ID: 195357 Reactome Database ID Release 43195357 Reactome, http://www.reactome.org ReactomeREACT_13187 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43507940 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 43508253 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43453091 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43507928 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43451931 Reactome, http://www.reactome.org Glc,Gal-GlcNAc-Fuc-Pre-NOTCH Converted from EntitySet in Reactome Galactosylated FRINGE-modified pre-NOTCH Reactome DB_ID: 1911423 Reactome Database ID Release 431911423 Reactome, http://www.reactome.org ReactomeREACT_119453 Fringe family Converted from EntitySet in Reactome Reactome DB_ID: 1464792 Reactome Database ID Release 431464792 Reactome, http://www.reactome.org ReactomeREACT_119986 'BetaGamma [cytosol]' negatively regulates 'cyclase activity of Adenylate cyclase [integral to plasma membrane]' INHIBITION Reactome Database ID Release 43111929 Reactome, http://www.reactome.org ReactomeREACT_5958 'active Calmodulin [cytosol]' positively regulates 'calcium- and calmodulin-responsive adenylate cyclase activity of Adenylate cyclase [plasma membrane]' ACTIVATION Reactome Database ID Release 43111928 Reactome, http://www.reactome.org ReactomeREACT_6041 'iron (ferrous) [nucleoplasm]' is required for 'Damaged DNA binding activity of ABH2 protein [nucleoplasm]' ACTIVATION Reactome Database ID Release 43159944 Reactome, http://www.reactome.org ReactomeREACT_6032 'iron (ferrous) [nucleoplasm]' is required for 'Damaged DNA binding activity of ABH2 protein [nucleoplasm]' ACTIVATION Reactome Database ID Release 43159944 Reactome, http://www.reactome.org ReactomeREACT_6032 'iron (ferrous) [nucleoplasm]' is required for 'Damaged DNA binding activity of ABH3 protein [nucleoplasm]' ACTIVATION Reactome Database ID Release 43159943 Reactome, http://www.reactome.org ReactomeREACT_6000 'iron (ferrous) [nucleoplasm]' is required for 'Damaged DNA binding activity of ABH3 protein [nucleoplasm]' ACTIVATION Reactome Database ID Release 43159943 Reactome, http://www.reactome.org ReactomeREACT_6000 'iron (ferrous) [nucleoplasm]' is required for 'Damaged DNA binding activity of ABH3 protein [nucleoplasm]' ACTIVATION Reactome Database ID Release 43159943 Reactome, http://www.reactome.org ReactomeREACT_6000 MIB/NEURL Converted from EntitySet in Reactome Mindbomb/Neuralized Reactome DB_ID: 1911464 Reactome Database ID Release 431911464 Reactome, http://www.reactome.org ReactomeREACT_119394 DTX Converted from EntitySet in Reactome Protein deltex Reactome DB_ID: 1604454 Reactome Database ID Release 431604454 Reactome, http://www.reactome.org ReactomeREACT_119774 'ADP' positively regulates 'glutamate dehydrogenase (NAD(P)+) activity of glutamate dehydrogenase 1, homohexamer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370585 Reactome, http://www.reactome.org ReactomeREACT_6025 'arginine' positively regulates 'amino acid N-acetyltransferase activity of N-acetylglutamate synthetase' ACTIVATION Reactome Database ID Release 4370540 Reactome, http://www.reactome.org ReactomeREACT_5951 'GDP' positively regulates 'glutamate dehydrogenase (NAD(P)+) activity of glutamate dehydrogenase 1, homohexamer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370587 Reactome, http://www.reactome.org ReactomeREACT_6050 'GTP' positively regulates 'glutamate dehydrogenase (NAD(P)+) activity of glutamate dehydrogenase 1, homohexamer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370588 Reactome, http://www.reactome.org ReactomeREACT_6125 'N-acetyl glutamate' positively regulates 'carbamoyl-phosphate synthase (ammonia) activity of carbamoyl-phosphate synthetase I dimer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370553 Reactome, http://www.reactome.org ReactomeREACT_5969 'iron (ferrous) [nucleoplasm]' is required for 'Damaged DNA binding activity of ABH2 protein [nucleoplasm]' ACTIVATION Reactome Database ID Release 43159944 Reactome, http://www.reactome.org ReactomeREACT_6032 'ADP' positively regulates 'glutamate dehydrogenase (NAD(P)+) activity of glutamate dehydrogenase 1, homohexamer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370585 Reactome, http://www.reactome.org ReactomeREACT_6025 'ATP' positively regulates 'glutamate dehydrogenase (NAD(P)+) activity of glutamate dehydrogenase 1, homohexamer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370586 Reactome, http://www.reactome.org ReactomeREACT_5976 'GDP' positively regulates 'glutamate dehydrogenase (NAD(P)+) activity of glutamate dehydrogenase 1, homohexamer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370587 Reactome, http://www.reactome.org ReactomeREACT_6050 'GTP' positively regulates 'glutamate dehydrogenase (NAD(P)+) activity of glutamate dehydrogenase 1, homohexamer' ACTIVATION-ALLOSTERIC Reactome Database ID Release 4370588 Reactome, http://www.reactome.org ReactomeREACT_6125 ST3GAL3/4/6 Converted from EntitySet in Reactome Reactome DB_ID: 1499957 Reactome Database ID Release 431499957 Reactome, http://www.reactome.org ReactomeREACT_118994 Sialyl Transferase Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH Converted from EntitySet in Reactome Reactome DB_ID: 1911509 Reactome Database ID Release 431911509 Reactome, http://www.reactome.org ReactomeREACT_119543 Sialylated FRINGE-modified NOTCH receptor precursor TLE Converted from EntitySet in Reactome Reactome DB_ID: 212370 Reactome Database ID Release 43212370 Reactome, http://www.reactome.org ReactomeREACT_120154 Ligand binds to TLR10 Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2011-08-12 Microbal stimulation was shown to alter mRNA expression of TLR10 in human granulocytes, monocytes[Zarember KA and Godowski P 2002] and B cells[Bourke ED et al 2003]. However the natural ligand of TLR10 remains unknown. Pubmed11777946 Pubmed12689944 Pubmed15728506 Reactome Database ID Release 43168947 Reactome, http://www.reactome.org ReactomeREACT_9052 Reviewed: Gale M, Jr, 2006-10-31 16:45:01 Reviewed: Gillespie, ME, 2011-02-10 has a Stoichiometric coefficient of 2 TLR9 processing at neutral pH Authored: Shamovsky, V, 2011-10-19 EC Number: 3.4.22 Edited: Shamovsky, V, 2012-02-19 Pubmed21604257 Reactome Database ID Release 431678981 Reactome, http://www.reactome.org ReactomeREACT_118693 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28 TLR9 traffics to an endosomal vesicle where it is processed by cathepsin S at neural pH to generate an N-terminal product (TLR9 N-ter, aa 1-723). The N-terminal fragment of TLR9 also binds ligand, but in contrast to the C-terminal fragment it inhibits TLR9 signaling. Thus, a proper balance between the two proteolytic events probably regulates TLR9-mediated host responses. (Chockalingam A et al 2011). Endosomal TLRs pass through the Golgi Authored: Shamovsky, V, 2011-10-19 Edited: Shamovsky, V, 2012-02-19 Pubmed19079358 Pubmed21402738 Reactome Database ID Release 431678998 Reactome, http://www.reactome.org ReactomeREACT_118791 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28 TLRs traffic through the Golgi complex by the conventional secretory pathway and are routed to endolysosomes where they bind their ligands (Chockalingam A et al 2008, Ewald SE et al 2011). . Full-length TLR3/7/8/9 binds to UNC93B1 Authored: Shamovsky, V, 2011-10-19 Edited: Shamovsky, V, 2012-02-19 Mammalian UNC93B1, a multi-transmembrane protein, directly associates with transmembrane domains of TLR3, TLR7, TLR8 and TLR9 (and mouse TLR13) in the ER and facilitates their translocation to endolysosome compartments (Brinkmann et al 2007; Kim et al 2008; Itoh H et al 2011). Mutant mouse and human cells that lack functional UNC93B1 showed disrupted signaling via the endosomal TLRs (Taneda K et al 2006; Fukui et al 2009; Kim YM et al 2008; Qi R et al 2010; Koehn J et al 2007). Furthermore, defects in the human gene encoding UNC93B1 are associated with the increased susceptibility to herpes simplex encephalitis (HSE) in children (Casrouge A et al 2006).<p>TLR7 and TLR9 compete for UNC931-dependent trafficking and under normal circumstances TLR9 predominates over TLR7. This preference for TLR9 is mediated by an N-terminal domain in UNC93B1 and is reversed to TLR7 if UNC93B1 loses the preferential N-terminal binding site via mutation of aspartate at position 34. Loss of binding to TLR9 and preferential association with TLR7 resulted in hyperresponsiveness to RNA ligands (Fukui et al 2009).<p>TLR3 appears to translocate to the endosomal compartment with equal efficiency regardless of the presence or absence of the N-terminal domain that mediates preference for TLR9. Thus, endosomal TLR trafficking is orchestrated by UNC93B1 which determines how efficiently each TLR is able to move from the ER to the endolysosomes to initiate host responses. Pubmed16415873 Pubmed16973841 Pubmed17452530 Pubmed18082565 Pubmed18305481 Pubmed19451267 Pubmed20855885 Pubmed22164301 Reactome Database ID Release 431678921 Reactome, http://www.reactome.org ReactomeREACT_118802 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28 TLR processing at low pH Authored: Shamovsky, V, 2011-10-19 EC Number: 3.4.22 Edited: Shamovsky, V, 2012-02-19 Endosome maturation (acidification) is required for both the activation of TLR9 and TLR7 through proteolytic cleavage and the disassembly of pathogens, thereby releasing the TLR ligands within them. TLR7 and TLR9 are cleaved within their ectodomains by pH-sensitive cysteine endopeptidases. Cathepsins (CTS) B, K, L, and S, and asparagine endopeptidase (AEP, also known as legumain) have been implicated in endolysosomal TLR processing, however, several groups have reported somewhat controversial results on the role of specific proteases (Matsumoto F et al 2008, Park B et al 2008, Ewald SE et al 2008, Ewald SE et al 2011, Sepulveda FE et al 2009).<p>One study showed that TLR9 proteolysis is a multistep process with the initial cleavage that can be mediated by AEP or multiple members of the cathepsin family. The second event is mediated exclusively by cathepsins. TLR7 and TLR3 were reported to be cleaved in a similar manner (Ewald SE et al 2011). Cleavage of TLR3 is not shown in this reaction, since other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, suggesting that TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).</p> <p>Both full-length receptor and cleaved fragment corresponding to the C-terminal part of TLR9 were capable to bind ligand, however only the processed form (TLR9 C-ter, aa 471-1032) was shown to bind MyD88 and induce signaling in different mouse cells (Ewald SE et al 2008). Pubmed18166152 Pubmed18820679 Pubmed18931679 Pubmed21402738 Reactome Database ID Release 431678920 Reactome, http://www.reactome.org ReactomeREACT_118824 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28 UNC93B1 delivers endosomal full-length TLRs to endolysosome Authored: Shamovsky, V, 2011-10-19 Edited: Shamovsky, V, 2012-02-19 Pubmed14716310 Pubmed15226270 Pubmed16857668 Pubmed18305481 Pubmed21398612 Pubmed21402738 Pubmed9799232 Reactome Database ID Release 431678927 Reactome, http://www.reactome.org ReactomeREACT_118774 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28 TLR3, 7, 8 and 9 activation occurs within acidified endolysosomal compartments. Inhibition of endosome acidification with bafilomicin A or chloroquine abrogated TLR's-mediated responses to pathogen-derived nucleic acids (Hacker H et al 1998, Funami K et al 2004, Gibbard RJ et al 2006, Kuznik A et al 2011). Upon stimulation, TLR3, 7, and 9 (and possibly TLR8) are transported to the signaling endosomes by UNC93B1, whereby they become functional receptors and bind to their specific ligands (Kim et al 2008, Ewald et al 2011). Although UNC93B1 is critically involved in TLRs trafficking it was dispensable for ligand binding by these TLRs (Kim YM et al 2008). Rap1 sequesters Raf1 to inhibit ERK cascade Active Rap1 binds but does not activate Raf-1, preventing Raf-1 from participating in the Ras/ERK pathway. Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-09-01 Pubmed8253074 Pubmed9115221 Reactome Database ID Release 43392835 Reactome, http://www.reactome.org ReactomeREACT_23814 Reviewed: Heemskerk, JW, 2010-09-01 Rap1 signal termination by Rap1GAPs Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-09-01 Pubmed15632203 Pubmed16076873 Pubmed1846040 Pubmed9346962 Rap1 signalling is terminated by the hydrolysis of bound GTP to GDP. The intrinsic GTPase activity of Rap1 is greatly enhanced by GTP-ase activating proteins (GAPs). Reactome Database ID Release 43392513 Reactome, http://www.reactome.org ReactomeREACT_23811 Reviewed: Heemskerk, JW, 2010-09-01 Folded full-length TLR7/8/9 dissociates from the GP96:CNPY3 complex Authored: Shamovsky, V, 2011-10-19 Edited: Shamovsky, V, 2012-02-19 Folded TLR9 dissociates from GP96:CNPY3 complex (Liu B et al 2010) and translocates to the endolysosome with the aid of the membrane protein UNC93b. Here we assume that TLR7 and TLR8 behave in a similar manner. Pubmed20865800 Reactome Database ID Release 431678944 Reactome, http://www.reactome.org ReactomeREACT_118678 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28 has a Stoichiometric coefficient of 2 TLR folding by chaperones GP96 and CNPY3 Authored: Shamovsky, V, 2011-10-19 Edited: Shamovsky, V, 2012-02-19 GP96 (also known as GRP94, HSP90b1), a paralogue of HSP90 in the endoplasmic reticulum, acts as a chaperone for some integrines and Toll-like receptors. Macrophages or B-cells from gp96 knockout mice have abrogated function of TLR2, 4, 5, 7 and 9, but not TLR3 (Yang Y et al 2007, Liu B and Li Z 2008, Staron M et al 2010). GP96 interacts with TLRs and integrines via its C-terminal hydrophobic domain, formed by residues 652-678 (Wu S et al 2012). GP96 functions as a V-shaped dimer in ATP-dependent manner, however it remains unclear how ATP hydrolysis-dependent conformational changes of GP96 are regulated (Li Z and Srivastava PK 1993).<p>GP96 forms a complex with co-chaperone CNPY3, also known as PRAT4A. GP96-CNPY3 promotes the proper post-translational ectodomain folding of TLRs, but not TLR3 (Liu B et al 2010). Pubmed17275357 Pubmed18509083 Pubmed19965672 Pubmed20865800 Pubmed22223641 Pubmed8344253 Reactome Database ID Release 431678923 Reactome, http://www.reactome.org ReactomeREACT_118729 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28 has a Stoichiometric coefficient of 2 Poliovirus precursor binds CD226 Authored: de Bono, B, 2007-07-08 12:58:15 NK cells express adhesion molecules that allow interaction with their tumour targets, promoting their lysis.<p><p>For instance, the activating receptor CD226 is known to be involved in cytotoxic lymphocyte formation, as well as platelet adhesion to the endothelium. The cytoplasmic domain of CD226 contains binding motifs for members of the band 4.1 family of proteins, and for members of the membrane-associated guanylate kinase homolog (MAGUK) family. These proteins connect the CD226 receptor to the cytoskeleton and may promote clustering with LFA-1 integrin (also discussed in this pathway), which is known to participate in CD226's signaling cascade. CD226 plays a role in transendothelial migration, where it facilitates adherence to endothelial cells and migration between cell junctions. <p><p>Nectin-2 binds CD226. It is ubiquitously expressed in cells of various tissues, especially in epithelial cells, neurons and fibroblasts. Like many other nectin and Necl proteins, nectin-2 serves as a viral entry receptor for alpha-herpesviruses including herpes simplex virus (HSV-1 and HSV-2). The other CD226 ligand, Necl-5, was initially identified as a receptor for poliovirus.<p><p>CD96, another ligand for Necl-5, is strongly upregulated in activated NK cells.<p><p>CRTAM is similarly up-regulated, and has been shown to to bind Necl-2, promoting NK cell cytotoxicity towards otherwise poorly immunogenic targets. Pubmed15607800 Pubmed16904340 Reactome Database ID Release 43199131 Reactome, http://www.reactome.org ReactomeREACT_11239 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 Nectin 2 binds CD226 Authored: de Bono, B, 2007-07-08 12:58:15 NK cells express adhesion molecules that allow interaction with their tumour targets, promoting their lysis.<p><p>For instance, the activating receptor CD226 is known to be involved in cytotoxic lymphocyte formation, as well as platelet adhesion to the endothelium. The cytoplasmic domain of CD226 contains binding motifs for members of the band 4.1 family of proteins, and for members of the membrane-associated guanylate kinase homolog (MAGUK) family. These proteins connect the CD226 receptor to the cytoskeleton and may promote clustering with LFA-1 integrin (also discussed in this pathway), which is known to participate in CD226's signaling cascade. CD226 plays a role in transendothelial migration, where it facilitates adherence to endothelial cells and migration between cell junctions. <p><p>Nectin-2 binds CD226. It is ubiquitously expressed in cells of various tissues, especially in epithelial cells, neurons and fibroblasts. Like many other nectin and Necl proteins, nectin-2 serves as a viral entry receptor for alpha-herpesviruses including herpes simplex virus (HSV-1 and HSV-2). The other CD226 ligand, Necl-5, was initially identified as a receptor for poliovirus.<p><p>CD96, another ligand for Necl-5, is strongly upregulated in activated NK cells.<p><p>CRTAM is similarly up-regulated, and has been shown to to bind Necl-2, promoting NK cell cytotoxicity towards otherwise poorly immunogenic targets. Pubmed15607800 Pubmed16904340 Reactome Database ID Release 43199144 Reactome, http://www.reactome.org ReactomeREACT_11094 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 has a Stoichiometric coefficient of 2 Bombesin-like receptor Converted from EntitySet in Reactome Reactome DB_ID: 375362 Reactome Database ID Release 43375362 Reactome, http://www.reactome.org ReactomeREACT_14985 Epithelial cadherin binds to KLRG1 Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed16904340 Reactome Database ID Release 43199079 Reactome, http://www.reactome.org ReactomeREACT_11212 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 The lectin-like NK cell receptor KLRG1 binds to cadherins on epithelial cells and transmits inhibitory signals to the leukocyte. CRTAM binds to NECL2 Authored: de Bono, B, 2007-07-08 12:58:15 NK cells express adhesion molecules that allow interaction with their tumour targets, promoting their lysis.<p><p>For instance, the activating receptor CD226 is known to be involved in cytotoxic lymphocyte formation, as well as platelet adhesion to the endothelium. The cytoplasmic domain of CD226 contains binding motifs for members of the band 4.1 family of proteins, and for members of the membrane-associated guanylate kinase homolog (MAGUK) family. These proteins connect the CD226 receptor to the cytoskeleton and may promote clustering with LFA-1 integrin (also discussed in this pathway), which is known to participate in CD226's signaling cascade. CD226 plays a role in transendothelial migration, where it facilitates adherence to endothelial cells and migration between cell junctions. <p><p>Nectin-2 binds CD226. It is ubiquitously expressed in cells of various tissues, especially in epithelial cells, neurons and fibroblasts. Like many other nectin and Necl proteins, nectin-2 serves as a viral entry receptor for alpha-herpesviruses including herpes simplex virus (HSV-1 and HSV-2). The other CD226 ligand, Necl-5, was initially identified as a receptor for poliovirus.<p><p>CD96, another ligand for Necl-5, is strongly upregulated in activated NK cells.<p><p>CRTAM is similarly up-regulated, and has been shown to to bind Necl-2, promoting NK cell cytotoxicity towards otherwise poorly immunogenic targets. Pubmed15781451 Pubmed16091383 Pubmed16904340 Reactome Database ID Release 43199112 Reactome, http://www.reactome.org ReactomeREACT_11097 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 Ligands bind L-selectin Authored: de Bono, B, 2007-07-08 12:58:15 L-selectin plays a major role in leukocyte traffic through lymph node high endothelial venules.<p><p>Both MAdCAM and GlyCAM-1 are major L-selectin ligands produced by these venules and mediate leukocyte rolling, particularly in lymphocytes. They are also expressed in mammary tissue and play an important role in the transfer of immune cells into milk secretions.<p><p>The adhesive properties of CD34 and its potential role in homing lymphocytes to lymphoid tissues mimics the mechanims leukocytes adopt to travel to inflammatory sites. Pubmed12588680 Pubmed16846369 Pubmed9865468 Reactome Database ID Release 43199046 Reactome, http://www.reactome.org ReactomeREACT_11230 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 NKG2A-CD94 heterdimer interacts with HLA-E After interaction with its ligand HLA-E, which is expressed on normal cells, the C-type lectin inhibitory receptor CD94/NKG2A suppresses activation signaling processes. CD94/NKG2A receptors continuously recycle from the cell surface through endosomal compartments and back again in a process that requires energy and the cytoskeleton. This steady state process appears to be largely unaffected by exposure to ligand. Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed11513152 Pubmed15607803 Reactome Database ID Release 43199062 Reactome, http://www.reactome.org ReactomeREACT_11119 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 Apelin peptides Converted from EntitySet in Reactome Reactome DB_ID: 374317 Reactome Database ID Release 43374317 Reactome, http://www.reactome.org ReactomeREACT_15235 Fc gamma receptors interact with antigen-bound IgG Authored: de Bono, B, 2007-07-08 12:58:15 Most cells of the immune system express receptors for the Fc region of IgG. This heterogeneous family of molecules plays a critical role in immunity, by linking the humoral to the cellular responses. NK cells and B cells have been shown to express exclusively Fc-gamma RIIIa and RIIb respectively. Pubmed11955599 Pubmed15081612 Reactome Database ID Release 43199161 Reactome, http://www.reactome.org ReactomeREACT_11087 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 CD40 interacting with CD40L Authored: de Bono, B, 2007-07-08 12:58:15 CD40 is a member of the Tumour Necrosis Factor receptor family and its ligand CD40L is a type II transmembrane protein of the TNF superfamily. The latter is expressed preferentially on T-cells and platelets. In the immune system, CD40-CD40L interaction affects some key processes such as immune cell activation, differentiation, proliferation, and apoptosis. CD40-CD40L interaction also upregulates costimulatory molecules (ICAM-1, VCAM-1, E-selectin, LFA-3, B7.1, B7.2, class II MHC, and CD40 itself). Pubmed16893496 Reactome Database ID Release 43199404 Reactome, http://www.reactome.org ReactomeREACT_11241 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 has a Stoichiometric coefficient of 3 CD200 binds to CD200R Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed15187158 Pubmed16928187 Reactome Database ID Release 43199154 Reactome, http://www.reactome.org ReactomeREACT_11188 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 While not ubiquitously distributed, CD200 is expressed on a wide range of cell types including thymocytes, B-cells, activated T-cells, follicular dendritic cells, endothelium, CNS neurons in the central nervous system, cells in reproductive organs, keratinocytes and renal glomeruli. CD200R is a myeloid-inhibitory receptor, despite the absence of classical ITIMs in the cytoplasmic portion of the protein. Interestingly, CD200 is also expressed on neurons within the CNS and would be predicted to modulate activation of microglia through CD200R. MHC Class I interacts with CD160 Authored: de Bono, B, 2007-07-08 12:58:15 CD160 is a GPI-anchored lymphocyte surface receptor in which expression is mostly restricted to the highly cytotoxic NK cells. MHC class I molecules bind to CD160 receptors on circulating NK lymphocytes and this triggers their cytotoxic activity and cytokine production. NK cells stimulated by IL-15 secrete soluble CD160 protein that binds to MHC-I molecules, resulting in the inhibition of the cytotoxic CD8+ T lymphocyte activity and of the CD160-mediated NK cell cytotoxicity. Pubmed16129954 Pubmed17237375 Reactome Database ID Release 43199169 Reactome, http://www.reactome.org ReactomeREACT_11106 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 KIR3DL2 interacting with HLA-A3 A hallmark of human NK cells is the expression of HLA class I-specific killer-cell immunoglobulin-like receptors (KIR). KIRs are not only variably expressed on the level of single NK cells but they are also highly polymorphic and polygenic (i.e. the gene content of the KIR cluster varies from individual to individual).<p><p>There are 15 functional KIR genes known to date, 11 encoding receptors with two immunoglobulin domains (KIR2D genes) and 4 with three domains (KIR3D genes). Inhibitory KIR genes are characterized by long cytoplasmic tails featuring immunoreceptor tyrosine-based inhibitory motifs (ITIM), which upon engagement transmit inhibitory signals leading to the general shutdown of NK cell effector functions. There are six inhibitory KIRs with clearly defined specificities, all of the inhibitory kind and all for HLA class I allotypes: KIR2DL2 and KIR2DL3 for HLA-C group 1, KIR2DL1 for HLA-C group 2, KIR3DL1 for HLA-B (Bw4 epitope), KIR3DL2 with HLA-A3 and KIR2DL4 with HLA-G.<p><p>In contrast, stimulatory KIR have short cytoplasmic tails lacking ITIM, but have a charged amino acid in the transmembrane region that provides a docking site for the activating adapter molecule DAP12. KIR2DS1 is known to bind HLA-C group 2 and KIR2DS2 binds HLA-C group 1. Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed11861603 Pubmed11955593 Pubmed15580655 Reactome Database ID Release 43199576 Reactome, http://www.reactome.org ReactomeREACT_11124 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 KIR2DL4 interacting with HLA-G A hallmark of human NK cells is the expression of HLA class I-specific killer-cell immunoglobulin-like receptors (KIR). KIRs are not only variably expressed on the level of single NK cells but they are also highly polymorphic and polygenic (i.e. the gene content of the KIR cluster varies from individual to individual).<p><p>There are 15 functional KIR genes known to date, 11 encoding receptors with two immunoglobulin domains (KIR2D genes) and 4 with three domains (KIR3D genes). Inhibitory KIR genes are characterized by long cytoplasmic tails featuring immunoreceptor tyrosine-based inhibitory motifs (ITIM), which upon engagement transmit inhibitory signals leading to the general shutdown of NK cell effector functions. There are six inhibitory KIRs with clearly defined specificities, all of the inhibitory kind and all for HLA class I allotypes: KIR2DL2 and KIR2DL3 for HLA-C group 1, KIR2DL1 for HLA-C group 2, KIR3DL1 for HLA-B (Bw4 epitope), KIR3DL2 with HLA-A3 and KIR2DL4 with HLA-G.<p><p>In contrast, stimulatory KIR have short cytoplasmic tails lacking ITIM, but have a charged amino acid in the transmembrane region that provides a docking site for the activating adapter molecule DAP12. KIR2DS1 is known to bind HLA-C group 2 and KIR2DS2 binds HLA-C group 1. Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed11861603 Pubmed11955593 Pubmed15580655 Reactome Database ID Release 43199579 Reactome, http://www.reactome.org ReactomeREACT_11141 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 KIR2DS1 interacting with HLA-C group 2 (Cw4) A hallmark of human NK cells is the expression of HLA class I-specific killer-cell immunoglobulin-like receptors (KIR). KIRs are not only variably expressed on the level of single NK cells but they are also highly polymorphic and polygenic (i.e. the gene content of the KIR cluster varies from individual to individual).<p><p>There are 15 functional KIR genes known to date, 11 encoding receptors with two immunoglobulin domains (KIR2D genes) and 4 with three domains (KIR3D genes). Inhibitory KIR genes are characterized by long cytoplasmic tails featuring immunoreceptor tyrosine-based inhibitory motifs (ITIM), which upon engagement transmit inhibitory signals leading to the general shutdown of NK cell effector functions. There are six inhibitory KIRs with clearly defined specificities, all of the inhibitory kind and all for HLA class I allotypes: KIR2DL2 and KIR2DL3 for HLA-C group 1, KIR2DL1 for HLA-C group 2, KIR3DL1 for HLA-B (Bw4 epitope), KIR3DL2 with HLA-A3 and KIR2DL4 with HLA-G.<p><p>In contrast, stimulatory KIR have short cytoplasmic tails lacking ITIM, but have a charged amino acid in the transmembrane region that provides a docking site for the activating adapter molecule DAP12. KIR2DS1 is known to bind HLA-C group 2 and KIR2DS2 binds HLA-C group 1. Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed11861603 Pubmed11955593 Pubmed15580655 Reactome Database ID Release 43199587 Reactome, http://www.reactome.org ReactomeREACT_11077 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 KIR2DS2 interacting with HLA-C group 1 (Cw3) A hallmark of human NK cells is the expression of HLA class I-specific killer-cell immunoglobulin-like receptors (KIR). KIRs are not only variably expressed on the level of single NK cells but they are also highly polymorphic and polygenic (i.e. the gene content of the KIR cluster varies from individual to individual).<p><p>There are 15 functional KIR genes known to date, 11 encoding receptors with two immunoglobulin domains (KIR2D genes) and 4 with three domains (KIR3D genes). Inhibitory KIR genes are characterized by long cytoplasmic tails featuring immunoreceptor tyrosine-based inhibitory motifs (ITIM), which upon engagement transmit inhibitory signals leading to the general shutdown of NK cell effector functions. There are six inhibitory KIRs with clearly defined specificities, all of the inhibitory kind and all for HLA class I allotypes: KIR2DL2 and KIR2DL3 for HLA-C group 1, KIR2DL1 for HLA-C group 2, KIR3DL1 for HLA-B (Bw4 epitope), KIR3DL2 with HLA-A3 and KIR2DL4 with HLA-G.<p><p>In contrast, stimulatory KIR have short cytoplasmic tails lacking ITIM, but have a charged amino acid in the transmembrane region that provides a docking site for the activating adapter molecule DAP12. KIR2DS1 is known to bind HLA-C group 2 and KIR2DS2 binds HLA-C group 1. Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed11861603 Pubmed11955593 Pubmed15580655 Reactome Database ID Release 43199583 Reactome, http://www.reactome.org ReactomeREACT_11176 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 C3d-complexed antigen binds to complement receptor Authored: de Bono, B, 2007-07-08 12:58:15 CD19 is a lymphocyte cell surface molecule that functions as a general response regulator or rheostat, which defnes signalling thresholds. These responses are infuenced by signals transduced through a CD19-CD21 cell surface receptor complex, where the binding of complement C3d to CD21 links humoral immune responses with the innate immune system. The CD19-CD21 complex is composed of at least four non-covalently associated proteins: CD19, CD21(complement receptor 2),CD81 and CD225. Pubmed12196203 Pubmed14719373 Pubmed15778510 Pubmed17337780 Reactome Database ID Release 43199518 Reactome, http://www.reactome.org ReactomeREACT_11121 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 KIR2DL1 interacting with HLA-C group 2 (Cw3) A hallmark of human NK cells is the expression of HLA class I-specific killer-cell immunoglobulin-like receptors (KIR). KIRs are not only variably expressed on the level of single NK cells but they are also highly polymorphic and polygenic (i.e. the gene content of the KIR cluster varies from individual to individual).<p><p>There are 15 functional KIR genes known to date, 11 encoding receptors with two immunoglobulin domains (KIR2D genes) and 4 with three domains (KIR3D genes). Inhibitory KIR genes are characterized by long cytoplasmic tails featuring immunoreceptor tyrosine-based inhibitory motifs (ITIM), which upon engagement transmit inhibitory signals leading to the general shutdown of NK cell effector functions. There are six inhibitory KIRs with clearly defined specificities, all of the inhibitory kind and all for HLA class I allotypes: KIR2DL2 and KIR2DL3 for HLA-C group 1, KIR2DL1 for HLA-C group 2, KIR3DL1 for HLA-B (Bw4 epitope), KIR3DL2 with HLA-A3 and KIR2DL4 with HLA-G.<p><p>In contrast, stimulatory KIR have short cytoplasmic tails lacking ITIM, but have a charged amino acid in the transmembrane region that provides a docking site for the activating adapter molecule DAP12. KIR2DS1 is known to bind HLA-C group 2 and KIR2DS2 binds HLA-C group 1. Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed11861603 Pubmed11955593 Pubmed15580655 Reactome Database ID Release 43199558 Reactome, http://www.reactome.org ReactomeREACT_11140 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 KIR3DL1 interacting with HLA Bw4 A hallmark of human NK cells is the expression of HLA class I-specific killer-cell immunoglobulin-like receptors (KIR). KIRs are not only variably expressed on the level of single NK cells but they are also highly polymorphic and polygenic (i.e. the gene content of the KIR cluster varies from individual to individual).<p><p>There are 15 functional KIR genes known to date, 11 encoding receptors with two immunoglobulin domains (KIR2D genes) and 4 with three domains (KIR3D genes). Inhibitory KIR genes are characterized by long cytoplasmic tails featuring immunoreceptor tyrosine-based inhibitory motifs (ITIM), which upon engagement transmit inhibitory signals leading to the general shutdown of NK cell effector functions. There are six inhibitory KIRs with clearly defined specificities, all of the inhibitory kind and all for HLA class I allotypes: KIR2DL2 and KIR2DL3 for HLA-C group 1, KIR2DL1 for HLA-C group 2, KIR3DL1 for HLA-B (Bw4 epitope), KIR3DL2 with HLA-A3 and KIR2DL4 with HLA-G.<p><p>In contrast, stimulatory KIR have short cytoplasmic tails lacking ITIM, but have a charged amino acid in the transmembrane region that provides a docking site for the activating adapter molecule DAP12. KIR2DS1 is known to bind HLA-C group 2 and KIR2DS2 binds HLA-C group 1. Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed11861603 Pubmed11955593 Pubmed15580655 Reactome Database ID Release 43199566 Reactome, http://www.reactome.org ReactomeREACT_11223 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 Bombesin-like peptide Converted from EntitySet in Reactome Reactome DB_ID: 375360 Reactome Database ID Release 43375360 Reactome, http://www.reactome.org ReactomeREACT_15061 Bradykinin receptor Converted from EntitySet in Reactome Reactome DB_ID: 374323 Reactome Database ID Release 43374323 Reactome, http://www.reactome.org ReactomeREACT_15029 PKA/PKG phosphorylate Rap1GAP2 Authored: Akkerman, JW, 2009-06-03 EC Number: 2.7.11 Edited: Jupe, S, 2010-09-01 Pubmed15632203 Reactome Database ID Release 43913996 Reactome, http://www.reactome.org ReactomeREACT_23849 Reviewed: Heemskerk, JW, 2010-09-01 cGMP and cAMP dependent protein kinases (PKG and PKA respectively) phosphorylate the Rap1 GTPase activating RAP1GAP2 at serine 7 (Schultess et al. 2007). This reduces the binding of inhibitory 14-3-3 proteins to RAP1GAP2. 14-3-3 proteins beta and zeta bind and inhibit Rap1Gap2 Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-09-01 Pubmed15632203 Pubmed18039662 RAP1GAP2 binds 14-3-3 proteins beta and zeta, inhibiting its GAP activity for Rap1. This effect is diminished by Ser-7 phosphorylation of RAP1GAP2 by cGMP- and cAMP-dependent protein kinases (PKG and PKA respectively), which inhibits the binding of 14-3-3 proteins beta and zeta to Rap1GAP2. 14-3-3 binding does not appear to alter the GTPase-activating function of Rap1GAP2 in vitro, but attenuates Rap1GAP2 mediated inhibition of cell adhesion (Hoffmeister et al. 2008). Reactome Database ID Release 43913993 Reactome, http://www.reactome.org ReactomeREACT_23924 Reviewed: Heemskerk, JW, 2010-09-01 Activation of EPACs by cAMP Authored: Akkerman, JW, 2009-06-03 EPACs (exchange proteins directly activated by cAMP) are Rap1 GEFs that are activated by direct binding of cAMP (cyclic adenosine monophosphate). cAMP-GEFI (EPAC1) is widely expressed, while cAMP-GEFII (EPAC2) is enriched in brain and adrenal tissue. Both are selective for Rap1. A role of EPACs has been proposed for Rap1-dependent cell adhesion to laminin in both epithelial and red blood cells, and in the regulation of vascular endothelial barrier function. Edited: Jupe, S, 2010-09-01 Pubmed16076873 Pubmed9789079 Reactome Database ID Release 43392834 Reactome, http://www.reactome.org ReactomeREACT_23933 Reviewed: Heemskerk, JW, 2010-09-01 has a Stoichiometric coefficient of 2 Anaphylatoxin ligands of GPR77 Converted from EntitySet in Reactome Reactome DB_ID: 964782 Reactome Database ID Release 43964782 Reactome, http://www.reactome.org ReactomeREACT_26867 Recruitment of clathrin coated vesicle by Ii Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Plasma membrane-associated nonameric complexes (MHC II alpha/beta/Ii complex) are rapidly internalized and delivered to late endosomes (LEs) and lysosomes. The dileucine-based signal present in the cytoplasmic tail of Ii is required for sorting of the nonameric MHC II-Ii complex from the plasma membrane to peptide loading compartments. These signals promote rapid internalization by recognising and binding to clathrin adaptor AP-2, a scaffolding-protein complex that brings together components of the vesicle-formation machinery. AP-2 is an essential component of an endocytic clathrin coat and participates in initiation of coat assembly. The critical role of AP2 in delivering MHC II:Ii complex to antigen processing compartments came from RNA interference studies targeting clathrin and AP2. The knockout of AP2 profoundly inhibited MHC II:Ii complex internalization and resulted in the accumulation of Ii at the surface (Dugast et al. 2005, McCormick et al. 2005). Pubmed15749704 Pubmed15911768 Pubmed8397411 Reactome Database ID Release 432130640 Reactome, http://www.reactome.org ReactomeREACT_120771 Reviewed: Neefjes, Jacques, 2012-05-14 Internalization of MHC II:Ii clathrin coated vesicle Authored: Garapati, P V, 2012-02-21 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Garapati, P V, 2012-02-21 MHC II:Ii complexes are internalized in to the endocytic clathrin coated-pit. Dynamin, the GTPase involved in the scission of clathrin-coated vesicles from plasma membrane is observed to be involved in the effective endocytosis of MHC II:Ii complexes. Wang et al, demonstrated that overexpression of a dominant-negative mutant of the GTPase dynamin resulted in the cell surface accumulation of MHC II:Ii complex, supporting that endocytosis is required for delivery to antigen processing compartments (Wang et al, 1997). However, another study using the same dynamin mutant generated opposite conclusions (Davidson, 1999). This discrepancy may be caused by differences in experimental set-up and in the levels of expression of the dynamin mutant and MHC II chains (Dugast et al, 2005). Pubmed10480952 Pubmed15749704 Pubmed8397411 Pubmed9202021 Reactome Database ID Release 432130725 Reactome, http://www.reactome.org ReactomeREACT_120835 Reviewed: Neefjes, Jacques, 2012-05-14 Transport of MHC II:Ii complex to plasma membrane Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Pubmed10540230 Pubmed14731593 Pubmed15911768 Pubmed16824007 Pubmed8397411 Reactome Database ID Release 432130378 Reactome, http://www.reactome.org ReactomeREACT_121019 Reviewed: Neefjes, Jacques, 2012-05-14 The newly formed MHC II-Ii complex exits the TGN and ultimately is delivered to late-endosome/lysosome compartments. A proportion of the nonameric complex traffics directly from the TGN to these compartments, while a substantial population follow the indirect pathway involving transport from the TGN to the plasma membrane, followed by endocytic delivery to early endosomes, late endosomes, and finally lysosomes (McCormick et al. 2005). Transport carrier vesicles may traffic the cargo MHC II-Ii complex from the TGN to the plasma membrane. Insertion of MHC II:Ii complex in to the plasma membrane Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 On reaching the cell surface, transport carrier vesicles insert the cargo MHC II:Ii complex into the plasma membrane. Pubmed10540230 Pubmed8397411 Reactome Database ID Release 432130500 Reactome, http://www.reactome.org ReactomeREACT_121063 Reviewed: Neefjes, Jacques, 2012-05-14 Neuropeptides B/W Converted from EntitySet in Reactome Reactome DB_ID: 374796 Reactome Database ID Release 43374796 Reactome, http://www.reactome.org ReactomeREACT_14997 Initial proteolyis of Ii by aspartic proteases to lip22 Authored: Garapati, P V, 2012-02-21 EC Number: 3.4.22 Edited: Garapati, P V, 2012-02-21 Pubmed10631941 Pubmed18292509 Pubmed18582577 Pubmed8134367 Pubmed9843486 Reactome Database ID Release 432130336 Reactome, http://www.reactome.org ReactomeREACT_121251 Reviewed: Neefjes, Jacques, 2012-05-14 Within acidic endocytic compartments Ii is proteolytically cleaved, ultimately freeing the class II peptide-binding groove for loading of antigenic peptides. Ii is degraded in a stepwise manner by a combination of aspartyl and cysteine proteases, following a well defined path with intermediates lip22, lip10 and finally CLIP. The initial Ii cleavage has been ascribed to leupeptin-insensitive cysteine or aspartic proteases, which include aspartyl protease and asparagine endopeptidase (AEP) (Maric et al. 1994, Manoury et al. 2003, Costantino et al. 2008). These proteases generate 22 kDa fragments of Ii (lip22). The trimerization domain of human Ii (residues 134-208) has three possible AEP cleavage sites, Asn148, 165 and 171. Asn171, located at the C-terminal end of helix B, is the demonstrated cleavage site for AEP (Manoury et al. 2003, Jasanoff et al. 1998). This cleavage eliminates the C-terminal trimerization domain of Ii, which causes disassociation of the (MHC II:Ii)3 nonamer and exposes new cleavage sites in the MHC II:lip22 trimers (Villadangos et al. 1999, Guillaume et al. 2008). The residue numbering of Ii given above is based on Uniprot isoform 1. Cleavage of lip22 to lip10 Authored: Garapati, P V, 2012-02-21 EC Number: 3.4.22 Edited: Garapati, P V, 2012-02-21 Pubmed11684289 Pubmed12078484 Pubmed12748383 Pubmed8687433 Pubmed9254653 Reactome Database ID Release 432130504 Reactome, http://www.reactome.org ReactomeREACT_121306 Reviewed: Neefjes, Jacques, 2012-05-14 The cleavage of lip22 occurs in residues 115-125, closer to the C-terminus than CLIP (residues 81-105). The resulting lip10 fragment is approximately 100 residues long and extends just through the C-terminus of the Ii CLIP. The proteases responsible for generating lip10 in vivo are not determined. Cysteine proteases like cathepsin S (CatS) are capable of degrading lip22 to lip10 (Bania et al. 2003) but in the presence of LHVS, an inhibitor of CatS, lip22 degradation is still observed, suggesting that other proteases are involved (Villadangos et al. 1997), possibly aspartic proteinases such as cathepsins D and E (Kageyama et al. 1996). The degradation of lip22 may depend on cell type (Bania et al. 2003). The lip22 and lip10 intermediate forms are still maintained as a nonameric complex due to the existence of the last trimerisation domain in the transmembrane region. Uncoating of clathrin-coated vesicles and fusion with endosomes Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 MHC II:Ii complexes bound to clathrin-coated vesicles rapidly fuse with endosomes. Pubmed8397411 Reactome Database ID Release 432130486 Reactome, http://www.reactome.org ReactomeREACT_121177 Reviewed: Neefjes, Jacques, 2012-05-14 Trafficking of nonameric complex in the endocytic pathway Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Pubmed14731593 Pubmed19703008 Reactome Database ID Release 432213235 Reactome, http://www.reactome.org ReactomeREACT_120768 Reviewed: Neefjes, Jacques, 2012-05-14 The internalized nonameric complex passes through the endocytic pathway and finally reach the acidic late endosomal/lysosomal compartments, where the Ii component is progressively degraded by proteases. Proteolysis of Ii occurs through sequential cleavages from the lumenal (C-terminal) side, generating cleavage products of approximately 22 kDa (lip22) and 10 kDa (lip10), finally leaving only CLIP bound within the peptide binding groove of MHC II (Landsverk et al. 2009). CXCL8 Converted from EntitySet in Reactome Reactome DB_ID: 373816 Reactome Database ID Release 43373816 Reactome, http://www.reactome.org ReactomeREACT_15113 Generation of CLIP from lip10 Authored: Garapati, P V, 2012-02-21 EC Number: 3.4.22 Edited: Garapati, P V, 2012-02-21 Pubmed10072072 Pubmed10631941 Pubmed10748235 Pubmed11684289 Pubmed11853874 Pubmed12078484 Pubmed12748383 Pubmed7606781 Pubmed9545226 Reactome Database ID Release 432130349 Reactome, http://www.reactome.org ReactomeREACT_121107 Reviewed: Neefjes, Jacques, 2012-05-14 The lip10 fragments bound in the nonameric complex are processed leaving only the CLIP fragment (81-105) bound to the MHC II peptide binding groove. Three cysteine proteases have been shown to be capable of digesting lip10, each with a different expression pattern among different APC. Cathepsin (Cat) S digests Ii in B cells and dendritic cells, thymic epithelial cells use Cat L and Cat L, while Cat S and F are active in macrophages (Villadangos, 2001; Bryant et al, 2002). Cat S appears to be the major enzyme involved as demonstrated by the use of specific inhibitors and of knockout experiments (Stumptner-Cuvelette et al. 2002). Following lip10 digestion, the MHC-like molecule HLA-DM induces the exchange of CLIP fragment for a highly diverse array of antigens (Denzin & Cresswell. 1995). has a Stoichiometric coefficient of 3 Disassociation of CLIP from MHC II Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Pubmed10631952 Pubmed7481823 Pubmed7667286 Pubmed8046351 Pubmed9075930 Pubmed9311912 Pubmed9606180 Reactome Database ID Release 432213246 Reactome, http://www.reactome.org ReactomeREACT_121161 Reviewed: Neefjes, Jacques, 2012-05-14 To gain the capacity to activate antigen-specific T cells, MHC class II-associated CLIP must be exchanged for an antigenic peptide (Kropshofer et al. 1999). There are two CLIP variants in humans: CLIP(long) with 21-26 residues, and CLIP(short) with 14-19 residues. CLIP(long) disassociates rapidly from HLA-DR molecules at endosomal/lysosomal pH, whereas CLIP(short) displays a lower off-rate. The N-terminal 9 residues of CLIP (81-89) facilitate its rapid release (Urban et al. 1994, Kropshofer et al. 1995a, Kropshofer et al. 1995b). The non-classical MHC class II molecule HLA-DM (DM) functions as a mediator of peptide exchange by accelerating the removal of CLIP. DM mediated peptide release involves a direct interaction between DM and the class II molecule. In addition to peptide release, DM also acts as a chaperone for MHC class II molecules in endosomal/lysosomal compartments. It stabilizes the peptide-receptive empty MHC II molecules and prevents them from unfolding and also favors the generation of high-stability peptide-MHC class II complexes by promoting release of low-stability peptide ligands (Kropshofer et al. 1999, Kropshofer et al. 1997). Another non-classical MHC II molecule HLA-DO (DO), only expressed in B-cells and thymic epithelial cells, binds tightly to DM modulating DM activity both negatively and positively, depending on the amount of DO present in an APC. Heterotypic DR-DM-DO complexes are receptive for peptide loading, in these complexes DO does not appear to be inhibitory (Denzin et al. 1997, Kropshofer et al. 1998, Kropshofer et al. 1999). MHC class II antigen internalization Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 MHC II typically presents antigens derived from exogenous proteins internalized by APCs such as macrophages, B cells or dendritic cells. Different types of antigen use different routes of internalization. Endocytosis may be specific, mediated by a range of receptors expressed on APC, or may occur by nonspecific mechanisms such as phagocytosis, macropinocytosis or autophagy. Antigens are first loaded into endocytic vesicles and progress along the early endosomes (EE)-late endosomes (LE) lysosomal axis. Antigens are exposed to increasingly acidic, more denaturing and proteolytic conditions (Doherty & McMahon 2009, Underhill & Ozinsky 2002). Pubmed10092778 Pubmed11714749 Pubmed11861619 Pubmed19317650 Pubmed8970738 Reactome Database ID Release 432130627 Reactome, http://www.reactome.org ReactomeREACT_121145 Reviewed: Neefjes, Jacques, 2012-05-14 Reduction of disulphide bonds in MHC II antigens Authored: Garapati, P V, 2012-02-21 EC Number: 1.8 Edited: Garapati, P V, 2012-02-21 MHC class II epitopes require protein denaturation and removal of intra- and inter-chain disulphide bonds prior to proteolysis. The lysosomal thiol reductase gamma-IFN-inducible lysosomal thiol reductase (GILT) has been shown to facilitate MHC class II-restricted antigen (Ag) processing by breaking disulphide bonds. GILT is constitutively expressed in APCs. The reduction of disulphide bonds by mature GILT is optimal at acidic pH (Hastings et al. 2006, Arunachalam et al. 2000). Pubmed10639150 Pubmed17142755 Reactome Database ID Release 432213240 Reactome, http://www.reactome.org ReactomeREACT_121326 Reviewed: Neefjes, Jacques, 2012-05-14 MHC class II antigen processing Antigen processing and loading on to MHC class II molecules occurs in late endocytic/lysosomal vesicles, where epitopes which require extensive proteolytic processing are generated (Bryant & Ploegh 2003). These late endosome/lysosomal-like compartments are enriched in MHC II and are referred to as MIICs (MHC class II compartments) (Peters et al. 1991). A variety of lysosomal proteases like cathepsins S, D, B etc. and Asparaginyl endopeptidase (AEP) are suggested to be involved in the processing of antigens to generate CD4+ T cell epitopes (Deusing et al. 1998, Shi et al. 1999, Pluger et al. 2002, Watts et al. 2005). An initial cleavage by endopeptidases (AEP) would be necessary to unlock the antigen and allow further trimming of the ends by exopeptidases (Cathepsins). In the acidic environment of the lysosome, cathepsins are generally activated by autocatalytic cleavage of a propeptide which otherwise blocks the active site. Authored: Garapati, P V, 2012-02-21 EC Number: 3.4.22 Edited: Garapati, P V, 2012-02-21 Pubmed10072072 Pubmed10809954 Pubmed11813165 Pubmed12742663 Pubmed14734116 Pubmed16181339 Pubmed1847504 Pubmed9539769 Reactome Database ID Release 432130706 Reactome, http://www.reactome.org ReactomeREACT_120767 Reviewed: Neefjes, Jacques, 2012-05-14 has a Stoichiometric coefficient of 3 Loading of antigenic peptides Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 In the acidic compartments of MIICs the empty MHC II molecules are protected from unfolding and degradation by HLA-DM (DM). DM acts as a peptide editor, favouring the formation and presentation of long-lived MHC II peptide complexes on the surface of APCs. The intrinsic stability of a ligand determines whether a peptide is resistant or sensitive to DM-mediated release (Kropshofer et al. 1996, Weber et al. 1996). From X-ray structure analysis it is known that two types of forces contribute to the intrinsic stability of class II-peptide complexes: i) interactions of the anchor side chains of the peptides with specificity pockets of polymorphic residues of the peptide binding groove of MHC II and ii) hydrogen bonds between the peptide backbone and conserved residues of the peptide binding grooves (Stern et al. 1994, Kropshofer et al. 1999). Naturally-processed antigenic peptides 14-16 residues in length with many anchor residues and few destabilizing residues (glycine and proline) at non-anchor positions are the most resistant to DM-mediated release (Radrizzani et al. 1999, Kropshofer et al. 1999). Pubmed10064083 Pubmed10631952 Pubmed8145819 Pubmed8849454 Pubmed8947036 Reactome Database ID Release 432213244 Reactome, http://www.reactome.org ReactomeREACT_120805 Reviewed: Neefjes, Jacques, 2012-05-14 Transport of antigen loaded MHC II molecules to surface Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Once MHC class II-peptide complexes are formed, they must be transported back to the cell surface. It is unclear how this occurs. LEs/lysosomes with peptide loaded MHC II molecules may move in a bidirectional manner in a stop-and-go fashion along microtubules to the plasma membrane, driven by the activities of the oppositely-directed motor proteins dynein and kinesin (Wubbolts et al. 1996, 1999, Chow et al. 2002, Rocha & Neefjes 2007). Ultimately, LEs/lysosomes fuse to the plasma membrane delivering the MHC II-peptide complexes to the surface (Raposo et al. 1996, Rocha & Neefjes 2007). RAB7-GTP present on LEs/lysosome membrane interacts with Rab7-interacting lysosomal protein (RILP) and oxysterol-binding protein-related protein 1L (ORP1L) to form a tripartite RILP-Rab7-ORP1L complex. RILP binds to the p150 dynactin subunit to recruit the dynein or kinesin motor proteins. ORP1L recruits this complex to betaIII spectrin domains, which appears to be critical for dynein motor activation and transport of LEs/lysosome vesicles to the cell periphery (Johansson et al. 2007, Rocha & Neefjes 2008). Pubmed10036229 Pubmed12198549 Pubmed17283181 Pubmed18046453 Pubmed19564404 Pubmed8642258 Pubmed8909537 Reactome Database ID Release 432213248 Reactome, http://www.reactome.org ReactomeREACT_120995 Reviewed: Neefjes, Jacques, 2012-05-14 TCR complex interacts with peptide antigen-presenting MHC Class I Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed15136729 Pubmed15534202 Pubmed16551255 Reactome Database ID Release 43198955 Reactome, http://www.reactome.org ReactomeREACT_11080 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 T cells distinguish foreign material from self through presentation of fragments of the antigen by the MHC cell surface receptors. Only if an MHC molecule presents an appropriate antigenic peptide will a cellular immune response be triggered. The orchestration of recognition and signaling events, from the initial recognition of antigenic peptides to the lysis of the target cell, is performed in a localized environment on the T cell, called the immunological synapse, and requires the coordinated activities of several T-Cell Receptor (TCR)-associated molecules. This particular reaction depicts the interaction of the TCR with MHC Class I molecules on somatic cell, requiring the support of CD3 and CD8 proteins. KIR2DL2/3 interacting with HLA-C group 1 (Cw4) A hallmark of human NK cells is the expression of HLA class I-specific killer-cell immunoglobulin-like receptors (KIR). KIRs are not only variably expressed on the level of single NK cells but they are also highly polymorphic and polygenic (i.e. the gene content of the KIR cluster varies from individual to individual).<p><p>There are 15 functional KIR genes known to date, 11 encoding receptors with two immunoglobulin domains (KIR2D genes) and 4 with three domains (KIR3D genes). Inhibitory KIR genes are characterized by long cytoplasmic tails featuring immunoreceptor tyrosine-based inhibitory motifs (ITIM), which upon engagement transmit inhibitory signals leading to the general shutdown of NK cell effector functions. There are six inhibitory KIRs with clearly defined specificities, all of the inhibitory kind and all for HLA class I allotypes: KIR2DL2 and KIR2DL3 for HLA-C group 1, KIR2DL1 for HLA-C group 2, KIR3DL1 for HLA-B (Bw4 epitope), KIR3DL2 with HLA-A3 and KIR2DL4 with HLA-G.<p><p>In contrast, stimulatory KIR have short cytoplasmic tails lacking ITIM, but have a charged amino acid in the transmembrane region that provides a docking site for the activating adapter molecule DAP12. KIR2DS1 is known to bind HLA-C group 2 and KIR2DS2 binds HLA-C group 1. Authored: de Bono, B, 2007-07-08 12:58:15 Pubmed11861603 Pubmed11955593 Pubmed15580655 Reactome Database ID Release 43198958 Reactome, http://www.reactome.org ReactomeREACT_11210 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 NKG2D homodimer interacting with ligands Authored: de Bono, B, 2007-07-08 12:58:15 NKG2D is an activating immunoreceptor. By engaging NKG2D, HlA Class I-like molecules such as MICA, MICB, ULBP1-4 and RAE-1 provide powerful costimulation for NK cells and T-cells and can determine the magnitude and outcome of certain effector functions. NKG2D ligands are upregulated on the surfaces of cells under conditions of stress, for example infection or tumorigenesis, and therefore act as molecular flags to the immune system that something is wrong. Pubmed11858820 Pubmed11955595 Pubmed16698438 Pubmed16737824 Reactome Database ID Release 43198983 Reactome, http://www.reactome.org ReactomeREACT_11178 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 CD96 binds Nectin-like-5 Authored: de Bono, B, 2007-07-08 12:58:15 NK cells express adhesion molecules that allow interaction with their tumour targets, promoting their lysis.<p><p>For instance, the activating receptor CD226 is known to be involved in cytotoxic lymphocyte formation, as well as platelet adhesion to the endothelium. The cytoplasmic domain of CD226 contains binding motifs for members of the band 4.1 family of proteins, and for members of the membrane-associated guanylate kinase homolog (MAGUK) family. These proteins connect the CD226 receptor to the cytoskeleton and may promote clustering with LFA-1 integrin (also discussed in this pathway), which is known to participate in CD226's signaling cascade. CD226 plays a role in transendothelial migration, where it facilitates adherence to endothelial cells and migration between cell junctions. <p><p>Nectin-2 binds CD226. It is ubiquitously expressed in cells of various tissues, especially in epithelial cells, neurons and fibroblasts. Like many other nectin and Necl proteins, nectin-2 serves as a viral entry receptor for alpha-herpesviruses including herpes simplex virus (HSV-1 and HSV-2). The other CD226 ligand, Necl-5, was initially identified as a receptor for poliovirus.<p><p>CD96, another ligand for Necl-5, is strongly upregulated in activated NK cells.<p><p>CRTAM is similarly up-regulated, and has been shown to to bind Necl-2, promoting NK cell cytotoxicity towards otherwise poorly immunogenic targets. Pubmed15034010 Pubmed16904340 Reactome Database ID Release 43199014 Reactome, http://www.reactome.org ReactomeREACT_11207 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 LILRs interact with MHC Class I Authored: de Bono, B, 2007-07-08 12:58:15 Leukocyte immunoglobulin (Ig)-like receptors [LILRs, also known as Ig-like transcripts (ILTs)] are a family of inhibitory and stimulatory receptors encoded within the leukocyte receptor complex and are expressed by immune cell types of both myeloid and lymphoid lineage. Several members of the LILR family recognize major histocompatibility complex class I. The immunomodulatory role of LILR receptors indicates that they may exert an influence on signaling pathways of both innate and adaptive immune systems.<p><p>Signaling mechanisms are employed that are similar to the ones adopted by the closely related killer cell inhibitory receptors (KIRs). ITIMs recruit inhibitory phosphatases that dephosphorylate ITIM and ITAM domains in order to influence intracellular signaling cascades. In contrast, activating LILRs, which lack any signaling domains of their own, rely on association with an adaptor protein such as FceRI-gamma to transmit their signal through its intracellular ITAMs. Pubmed15304001 Reactome Database ID Release 43199043 Reactome, http://www.reactome.org ReactomeREACT_11127 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 Egress of internalized antigen into cytosol from early endosome Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Endocytosed antigens must leave the endocytic structure to enter into the MHC I pathway before exhaustive degradation within lysosomes. The canonical pathway is the transporter associated with antigen processing (TAP)-dependent cytosolic pathway, which involves the translocation of endocytosed antigens into the cytosol where they are degraded into antigenic peptides by the proteasome and transported to ER through TAP. This hypothesis comes from indirect evidences showing that proteasome inhibitors block cross presentation of certain antigens (Amigorena et al. 2010, Burgdorf et al. 2008) . According to this model antigens are translocated into the cytosol by an undefined mechanism. <br>There are less well-characterized mechanisms for the delivery of exogenous antigens into the cytosol. Certain peptides with highly positively charged sequences derived from HIV tat protein or the Antennapedia homeodomain (AntHD) protein seem to penetrate into the cytosol directly across the plasma membrane (Monu et al. 2007, Vendeville et al. 2004). It is also proposed that some exogenous antigens can be exchanged between neighboring cells through gap junctions, leading to cross presentation by the recipient cell (Monu et al. 2007, Neijssen et al. 2005).<br>Once internalized antigens are routed into the cytosol, they follow the conventional pathway of proteasome digestion and TAP mediated transport of peptides into the ER lumen. Pubmed10559964 Pubmed15020715 Pubmed15592474 Pubmed15744304 Pubmed15761154 Pubmed16530046 Pubmed16818754 Pubmed17157489 Pubmed18376402 Pubmed18425099 Pubmed20171863 Pubmed8752913 Pubmed9022030 Pubmed9257826 Reactome Database ID Release 431236968 Reactome, http://www.reactome.org ReactomeREACT_111203 Reviewed: Desjardins, M, English, L, 2011-05-13 Exogenous soluble antigen targeted to more stable early endosome Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Pubmed15592474 Reactome Database ID Release 431236940 Reactome, http://www.reactome.org ReactomeREACT_111150 Reviewed: Desjardins, M, English, L, 2011-05-13 Within the endosome the receptor and cargo separate and the receptor recycles back to the cell surface. Soluble antigens are targeted into the stable early endosome lumen for efficient cross presentation. Early endosomes are mildly acidic and relatively poor in proteases. Movement of clathrin coated vesicles into early endosome Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 GENE ONTOLOGYGO:0006898 Pubmed12061891 Pubmed19317650 Reactome Database ID Release 431236955 Reactome, http://www.reactome.org ReactomeREACT_111177 Reviewed: Desjardins, M, English, L, 2011-05-13 The antigen:receptor complex moves from clathrin-coated vesicles to the early endosome membrane. Internalization of receptor bound antigen into clathrin coted vesicles Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Pubmed12061891 Pubmed18249105 Pubmed19317650 Reactome Database ID Release 431236941 Reactome, http://www.reactome.org ReactomeREACT_111101 Receptor-bound exogenous antigens in coated pits on the cell surface are internalized into clathrin-coated vesicles. Reviewed: Desjardins, M, English, L, 2011-05-13 Interaction of exogenous soluble antigen with its corresponding receptor Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Pubmed16530046 Pubmed16709836 Pubmed17463291 Pubmed18249105 Pubmed18376402 Reactome Database ID Release 431236939 Reactome, http://www.reactome.org ReactomeREACT_111111 Reviewed: Desjardins, M, English, L, 2011-05-13 Soluble antigens are presented to dendritic cells (DCs) in some cases by receptor mediated endocytosis or fluid-phase endocytosis. Burgdorf et al. (2008) suggest that there are two different endocytic compartments for antigen processing: one dedicated to MHC class I (early endosomes) and the other one for MHC class II presentation (lysosomes). Sorting of cargo into these different compartments occurs at the plasma membrane and is likely to depend on the type of endocytic receptor the cargo is interacting with (Burgdorf et al. 2008, Zhuang et al. 2006). The mannose receptor (MR) is the best studied receptor that targets soluble antigens to early endosomes but not to lysosomes (Burgdorf et al. 2006). Antigens taken up by the MR are targeted towards a mildly acidic stable early endosomal compartment for exclusive presentation on MHC I molecules (Burgdorf et al. 2008). Translocation of peptide bound MHC class I complex to cell surface Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Peptide-loaded MHC class I complexes are transported by an undefined mechanism back to the cell surface for cross-presentation to T cells. Pubmed18268517 Pubmed18802471 Reactome Database ID Release 431236964 Reactome, http://www.reactome.org ReactomeREACT_111086 Reviewed: Desjardins, M, English, L, 2011-05-13 Loading of antigen peptide onto MHC class I molecule Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Peptides generated by Cathepsin S or IRAP-mediated proteolysis in the endosomes are loaded onto MHC class I molecules, which are internalized and transported to early and late endosomal compartments where antigenic peptides can be loaded. A fraction of the internalized cell surface class I molecules enter MHC class II compartments (MIICs) within endocytic vesicles (Gromme et al. 1999, Kleijmeer et al. 2001). Microscopic analysis has revealed that surface MHC-I molecules are internalized and transported to early and late endosomal compartments (Basha et al. 2008, Lizee et al. 2003). A tyrosine-based endocytic trafficking motif (YXXA) is required for the constitutive internalization of MHC-I molecules from the cell surface into early/late endosomes for peptide loading (Basha et al. 2008, Lizee et al. 2003). Upon entry in to these endosomal compartments the MHC class I complexes exchange their pre-bound peptides with exogenously derived antigenic peptides. Pubmed10468607 Pubmed11247303 Pubmed14566337 Pubmed18802471 Reactome Database ID Release 431236943 Reactome, http://www.reactome.org ReactomeREACT_111077 Reviewed: Desjardins, M, English, L, 2011-05-13 Trimming of peptides by IRAP in endocytic vesicles Authored: Garapati, P V, 2011-03-28 EC Number: 3.4.11 Edited: Garapati, P V, 2011-03-28 Pubmed19498108 Pubmed19918052 Reactome Database ID Release 431236954 Reactome, http://www.reactome.org ReactomeREACT_111222 Reviewed: Desjardins, M, English, L, 2011-05-13 While it is established that cathepsin S is involved in antigen processing in endocytotic vesicles, it is less certain whether other proteases present in endocytic vesicles are also involved in generating the peptide fragments. Insulin regulated aminopeptidase (IRAP) is an epitope-trimming zinc-dependent aminopeptidase closely related to ERAP1 and ERAP2. IRAP may be involved in vacuolar processing of the peptide fragments within endosomes (Saveanu et al. 2009, Segura et al. 2009). IRAP is detected predominantly in the early and recycling endosome fractions. Saveanu et al. (2009) observed the physical association of IRAP with internalized class I MHC molecules and suggested that this may favour a direct linkage between peptide trimming and MHC class I loading. They also showed that IRAP-dependent processing of antigens requires active proteasome but not lysosomal proteases, which suggests that this pathway utilizes cytosolic degradation followed by peptide transport into IRAP-containing endosomes. Antigen processing by cathepsin S in endosoytic vesicle Authored: Garapati, P V, 2011-03-28 EC Number: 3.4.22 Edited: Garapati, P V, 2011-03-28 Endocytic compartments contain many cysteine proteases such as cathepsin S that can generate cross-presented peptides. Cathepsins may participate in the generation of MHC class II-presentated peptides (Villadangos et al. 1999). Shen et al. (2004) demonstrated that cathepsin S contributes to TAP-independent cross-presentation in vivo, showing that ovalbumin was cross-presented by denritic cells (DCs) through both TAP-dependent and TAP-independent pathways. The TAP-independent pathway was sensitive to the cystine protease inhibitor leupeptin, but not to proteasome inhibitors. Further experiments with knockout mice showed that cathepsin S contributed to cross-presentation. DCs lacking cathepsin S lack the TAP-independent pathway (Khor et al. 2008, Shen et al. 2004). Pubmed10631941 Pubmed15308097 Pubmed18572095 Reactome Database ID Release 431236948 Reactome, http://www.reactome.org ReactomeREACT_111140 Reviewed: Desjardins, M, English, L, 2011-05-13 ARRB Beta-arrestin Converted from EntitySet in Reactome Reactome DB_ID: 1911410 Reactome Database ID Release 431911410 Reactome, http://www.reactome.org ReactomeREACT_119070 Export of peptide loaded MHC class I complex to PM Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Exogenous antigen loaded class I MHC molecules in phagosomes may be delivered to the surface by membrane recycling machinery. Pubmed14508490 Pubmed19217269 Reactome Database ID Release 431236965 Reactome, http://www.reactome.org ReactomeREACT_111215 Reviewed: Desjardins, M, English, L, 2011-05-13 HDAC Converted from EntitySet in Reactome Reactome DB_ID: 350066 Reactome Database ID Release 43350066 Reactome, http://www.reactome.org ReactomeREACT_119886 TBL1 Converted from EntitySet in Reactome Reactome DB_ID: 350064 Reactome Database ID Release 43350064 Reactome, http://www.reactome.org ReactomeREACT_120014 Translocation of TGN-lysosome vesicle to lysosome Authored: Garapati, P V, 2012-02-21 Budding vesicles loaded with the nonameric complex bud off from the TGN to reach the late-endosome/lysosome membrane. EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Garapati, P V, 2012-02-21 Pubmed10480952 Pubmed10593899 Pubmed2121367 Pubmed7592972 Pubmed7650016 Pubmed8939989 Pubmed9497313 Reactome Database ID Release 432130641 Reactome, http://www.reactome.org ReactomeREACT_120774 Reviewed: Neefjes, Jacques, 2012-05-14 TGN-lysosomal vesicle coat assembly Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Pubmed10480952 Pubmed10593899 Pubmed11520080 Pubmed11790530 Pubmed14731593 Pubmed15911768 Pubmed2121367 Pubmed7592972 Pubmed7650016 Pubmed8034737 Pubmed8177316 Pubmed8939989 Pubmed9497313 Reactome Database ID Release 432130619 Reactome, http://www.reactome.org ReactomeREACT_121003 Reviewed: Neefjes, Jacques, 2012-05-14 The trans-Golgi network (TGN) is the sorting and package centre for trafficking cargo to the endoplasmic reticulum, plasma membrane and endosomes. Signal peptides determine the sorting and trafficking of proteins to the endosomal-lysosomal pathway or to the cell surface. The main signals that mediate targeting of MHC-II molecules to the endocytic pathway are two dileucine-based motifs, Leu23-Ile24 and Pro31-Leu33 present in the short cytoplasmic tail of Ii (Odorizzi et al. 1994). These motifs bind both the adaptor proteins AP-1 and AP-2, which are components of clathrin coats associated with the TGN/endosomes and the plasma membrane, respectively (McCormick et al. 2005). The precise pathway of class II:Ii complex trafficking from TGN to endocytic pathway is not well understood. In one view MHC II:Ii complexes directly traffic from the TGN to lysosomes, possibly using AP-1 dependent endocytic vesicles (Peters et al. 1991, Amigorena et al. 1994). Alternatively trafficking occurs via transient expression on the cell surface followed by rapid internalization and delivery to endocytic compartments. Early immunoelectron microscopy data has shown the presence of MHC class II:Ii complex molecules primarily in TGN and lysosomes (Peters et al. 1991, Hiltbold & Roche 2002). This theory was further supported by a study examining the trafficking of sulphate-tagged class II molecules, which concluded that the rapid appearance of these molecules in lysosomes was consistent with their direct transport from the TGN to lysosomes (Hiltbold & Roche 2002, Davidson 1999). The transport of cargo MHC II:Ii complexes from the TGN to lysosomes may be mediated by small TGN vesicles coated with AP-1 and clathrin. The di-leucine-based sorting signal in the Ii cytoplasmic chain recruits AP-1 and clathrin from cytosol to TGN to form AP-1 clathrin-coated TGN-derived vesicles. This process is regulated by the small GTPase ARF-1 (Salamero et al. 1996). TGN-lysosome vesicle uncoating and release of nonameric complex to lysosome Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 On reaching the late endosomes/lysosomes the TGN-lysosome vesicle uncoats and fuses with the lysosome to releases the MHC II nonameric complex. Pubmed10480952 Pubmed7650016 Reactome Database ID Release 432213236 Reactome, http://www.reactome.org ReactomeREACT_120943 Reviewed: Neefjes, Jacques, 2012-05-14 Formation of COPII vesicle Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Immediately after assembly in the ER nonameric (alpha beta:Ii)3 complexes egress from ER, facilitated by the presence of Ii, and enter the Golgi complex (Wolf & Ploegh 1995, Geuze 1998). Incorrectly folded or oligomerized alpha, beta and Ii chains are retained in the ER and degraded. The Sec23/24-Sar1 pre-budding complex binds to the nonameric complex and then recruits Sec13/31 outer shell, which buds off from the membrane as a coat protein complex II (COPII) vesicle to be transported to the Golgi complex (Bickford et al. 2004). Pubmed11790530 Pubmed15093828 Pubmed19703008 Pubmed2391366 Pubmed8689559 Pubmed9639994 Reactome Database ID Release 432130731 Reactome, http://www.reactome.org ReactomeREACT_120802 Reviewed: Neefjes, Jacques, 2012-05-14 Formation of nonameric complex Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Progressive addition of two more preformed alpha beta dimers to the invariant chain trimer and alpha beta complex ((alpha beta)1:(Ii)3) forms the complete nonameric structure ((alpha beta:Ii)3). Calnexin then disassociates on egress of the nonameric complex from the ER. Pubmed16618111 Pubmed1956401 Pubmed9312039 Reactome Database ID Release 432213241 Reactome, http://www.reactome.org ReactomeREACT_120846 Reviewed: Neefjes, Jacques, 2012-05-14 has a Stoichiometric coefficient of 2 Translocation of MHC II:Ii complex to TGN Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Nonameric MHC II:Ii complex move through the various cisternae to reach the trans-golgi network (TGN), a tubulo-vesicular organelle located at the trans-face of Golgi stacks. From the TGN, MHC II:Ii complexes are targeted to the endocytic pathway for peptide loading. Pubmed10480952 Pubmed11529500 Pubmed11790530 Pubmed19703008 Reactome Database ID Release 432130393 Reactome, http://www.reactome.org ReactomeREACT_121309 Reviewed: Neefjes, Jacques, 2012-05-14 Transport of MHC II:Ii complex along Golgi to TGN Fusion of COPII vesicle with Golgi complex Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 Pubmed10480952 Pubmed11790530 Reactome Database ID Release 432213243 Reactome, http://www.reactome.org ReactomeREACT_121121 Reviewed: Neefjes, Jacques, 2012-05-14 The COPII vesicle uncoats and fuses with the cis-Golgi, releasing the MHC II:Ii complex into the Golgi. Proteasomal clevage of exogenous antigen Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Exogenous antigens are thought to be processed for cross-presentation in much the same manner as endogenous proteins once they enter the cytosolic pathway (Rock et al. 2010). Immunoproteasome components are the major proteases involved in generating the antigenic fragments. The precurssor peptides are further trimmed by cytosolic aminopeptidases and shuttled to ER through TAP for MHC class I loading. Pubmed16818754 Pubmed20028659 Reactome Database ID Release 431236970 Reactome, http://www.reactome.org ReactomeREACT_111172 Reviewed: Desjardins, M, English, L, 2011-05-13 Interaction of invariant chain trimer and MHC II alpha beta dimer Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 MHC II alpha beta dimers associate with a third polypeptide, the invariant chain (Ii), required for class II molecules to reach the endocytic pathway (Roche et al. 1991). The interaction of Ii with the MHC II alpha beta dimer serves multiple functions. It plays a role in assembly, folding, egress from the ER and transport through the Golgi. Ii exists as a trimer; residues 163-183 of the Ii lumenal domain are involved in covalent cross-linking. Residues 96-104 are critical for association with class II alpha beta dimers (Bijlmakers et al. 1994, Freisewinkel et al. 1993). Residues 89-104 known as CLIP (Class II-associated invariant chain peptide) are the part of the Ii chain that binds antigen binding MHC class II groove, remaining bound until the MHC receptor is completely assembled. This CLIP domain prevents the premature binding of self-peptide fragments present in ER prior to MHC II localization within the endosomal compartment. The ER-resident chaperone protein calnexin rapidly associates with newly synthesized alpha, beta and invariant chains, and remains associated until the final nonamer assembly. The stoichiometry of calnexin in this interaction and the dynamics of association-dissociation are not known. Calnexin may stabilize the free class II chains and regulate their intracellular transport by facilitating the production of transport competent molecules out of the ER (Anderson & Cresswell 1994, Schreiber et al. 1995). Pubmed1656276 Pubmed16618111 Pubmed1956401 Pubmed19703008 Pubmed21116285 Pubmed2190094 Pubmed7519244 Pubmed8148318 Pubmed8313912 Pubmed8415765 Pubmed8689559 Pubmed9312039 Reactome Database ID Release 432130478 Reactome, http://www.reactome.org ReactomeREACT_121334 Reviewed: Neefjes, Jacques, 2012-05-14 Formation of MHC II alpha beta heterodimer Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 MHC II alpha and beta chains translocate to the ER and associate noncovalently to form an alpha beta heterodimer (Roche et al. 1991). This heterodimer then associates with a preformed invariant (Ii) chain trimer. Pubmed16242130 Pubmed1956401 Pubmed8415765 Pubmed9312039 Reactome Database ID Release 432213239 Reactome, http://www.reactome.org ReactomeREACT_121116 Reviewed: Neefjes, Jacques, 2012-05-14 Transport of MHC heterotrimer to ER exit site Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed11163199 Pubmed14718384 Pubmed17056546 Pubmed19342655 Reactome Database ID Release 43983138 Reactome, http://www.reactome.org ReactomeREACT_75826 Reviewed: Elliott, T, 2011-02-10 When the loaded peptide is of a sufficiently high-affinity the trimeric complex is transported to a special ER exit site by a putative cargo receptor, B cell receptor-associated protein (BAP31), where it translocates to the cell surface, possibly by transport in COPII-coated vesicles. Loading of antigenic peptides on to class I MHC Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 MHC class I heterodimers are only stable in peptide bound form and only as a trimer (with bound peptide) present on the cell surface. Class I MHC molecules prefer nonapeptides, and less frequently use octa- or deca-peptides. The peptide binding groove in MHC class I molecules is formed by the intimate association of the alpha1 and alpha2 domains of the heavy chain. Structural studies have revealed that the alpha1:alpha2 domains form a single peptide binding groove consisting of 2 parallel helices on a floor of 8 beta-strands. Hydrogen bonding networks are established in the binding groove with the antigenic peptide main chain and terminal atoms that enable largely sequence independent ligation. Upon peptide binding the class I MHC molecule releases from the peptide loading complex (PLC) and clusters at ER exit sites and is finally exported to the cell surface.<br>MHC I molecules bound to low-affinity peptides are not transferred to the cell surface and are instead cycled back to ER. They can proceed to the cell surface only when they become bound to high-affinity peptide (Howe et al, 2009; Garstka et al, 2007). Calreticulin binds to these low-affinity peptide bound class I molecules and mediate the retrieval from golgi apparatus to ER and for effcient presentation of a model antigen (Howe et al, 2009). Pubmed16473882 Pubmed17656363 Pubmed19851281 Pubmed2038058 Pubmed21050182 Reactome Database ID Release 43983161 Reactome, http://www.reactome.org ReactomeREACT_75916 Reviewed: Elliott, T, 2011-02-10 Trimming of peptides in ER Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed12436109 Pubmed12436110 Pubmed17088086 Reactome Database ID Release 43983158 Reactome, http://www.reactome.org ReactomeREACT_75798 Reviewed: Elliott, T, 2011-02-10 Transporter associated with antigen processing (TAP) prefers peptides 8-16 residues long, slightly longer than the canonical 8-10 residue peptides that fit into class I MHC binding sites. These longer peptides are further trimmed at their N-termini by the ER-associated aminopeptidase (ERAP). ERAP trims peptides to a length of 8-10 residues, suitable for loading into the MHC class I binding groove. Transport of Antigen peptide in to ER Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed10600378 Pubmed12645939 Pubmed19261456 Pubmed8342042 Reactome Database ID Release 43983144 Reactome, http://www.reactome.org ReactomeREACT_75812 Reviewed: Elliott, T, 2011-02-10 Ttransporter associated with antigen processing (TAP) is a heterodimeric complex, composed of TAP1 and TAP2 proteins, members of the ATP-binding cassette (ABC) superfamily. TAP consists of two transmembrane domains (TMDs) and two cytosolic nucleotide-binding domains. Peptide binding to the cytosolic-facing cavity formed by the TMDs causes it to undergo a conformational change that induces ATP hydrolysis, forcing the opening of a pore and translocation of the peptide into the ER lumen. TAP transports peptides in the range of 8-16 amino acids into the ER, which is the peptide length typically generated by the immunoproteasome. has a Stoichiometric coefficient of 2 Disassembly of COPII coated vesicle Authored: Garapati, P V, 2010-10-29 Before the cargo vesicle can fuse with target membrane, the COPII protein coat must be disassembled and its components released into cytosol. This uncoating is triggered by hydrolysis of the bound GTP to produce Sar1p-GDP, which has decreased affinity for the vesicle membrane. Disassociation of Sar1p-GDP from the membrane is followed by the release of the other COPII subunits. EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Garapati, P V, 2010-10-29 Pubmed10825291 Pubmed10982397 Pubmed17316621 Reactome Database ID Release 43983422 Reactome, http://www.reactome.org ReactomeREACT_75799 Reviewed: Elliott, T, 2011-02-10 Budding of COPII coated vesicle Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Once the entire COPII coat has been assembled, the bud is separated from the ER membrane in the form of a COPII coated vesicle. Pubmed10825291 Pubmed10982397 Reactome Database ID Release 43983424 Reactome, http://www.reactome.org ReactomeREACT_75771 Reviewed: Elliott, T, 2011-02-10 Recruitment of Sec31p:Sec13p to prebudding complex and formation of COPII vesicle Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed10825291 Pubmed10982397 Pubmed17316621 Reactome Database ID Release 43983425 Reactome, http://www.reactome.org ReactomeREACT_75825 Reviewed: Elliott, T, 2011-02-10 Sec13-Sec31 binds the prebudding complex and this Sec13-Sec31 heterotetramer forms the outer structural scaffold of the coat. Sec13-Sec31 is likely to crosslink the prebudding complexes generating COPII-coated vesicles. Capturing cargo and formation of prebudding complex Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed10825291 Pubmed10982397 Pubmed11163199 Pubmed17316621 Reactome Database ID Release 43983426 Reactome, http://www.reactome.org ReactomeREACT_75836 Reviewed: Elliott, T, 2011-02-10 The cytoplasmic tails of MHC class I molecules do not possess any of the known ER export sequences. BAP31 acts as a cargo receptor by exporting peptide-loaded class I MHC molecules to the ER exit sites or ER/Golgi intermediate compartment. Sec24 of the Sec23-Sec24/Sar1-GTP complex catches cargo by direct contact, forming the prebudding complex. Sar1/Sec23-Sec24 can bring about curvature of the membrane in the formation of vesicle. The cargo (antigen-bound MHC) accumulates within the COPII vesicle by binding to the Sec24 polypeptide of the COPII coat. ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 43110379 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43110377 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43110367 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017108 Reactome Database ID Release 43110409 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110230 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110230 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004520 Reactome Database ID Release 43110358 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110209 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43110377 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003906 Reactome Database ID Release 43110374 Reactome, http://www.reactome.org Journey of cargo through Golgi complex Authored: Garapati, P V, 2010-10-29 Cargo must pass through the various compartments of the Golgi complex to reach the plasma membrane. This may occur through either of the two well known models, cisternal maturation or vesicular transport (Refer to review articles Glick et al. 2009, Jackson 2009, Nakano et al. 2010). Edited: Garapati, P V, 2010-10-29 Pubmed15927284 Pubmed19193869 Pubmed19575639 Pubmed20605430 Reactome Database ID Release 43983421 Reactome, http://www.reactome.org ReactomeREACT_75894 Reviewed: Elliott, T, 2011-02-10 Expression of peptide bound class I MHC on cell surface After passing through the Golgi complex, secretory cargo is packaged into post-Golgi transport intermediates (post-Golgi), which translocate plus-end directed along microtubules to the plasma membrane. Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed11163199 Pubmed19193869 Pubmed20605430 Reactome Database ID Release 43983427 Reactome, http://www.reactome.org ReactomeREACT_75781 Reviewed: Elliott, T, 2011-02-10 HEY Converted from EntitySet in Reactome Reactome DB_ID: 1911450 Reactome Database ID Release 431911450 Reactome, http://www.reactome.org ReactomeREACT_119350 Maturation of phagosome into phagolysosome Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Following fission of the phagosome vesicle from the plasma membrane, the phagosome undergoes maturation by a series of fusion and fission events, fusing with late endosomes and ultimately lysosomes, to form a phagolysosome. <br><br>fuses sequentially with sorting/early endosomes, late endosomes and finally lysosomes to acquire degradative capabilities. This process is referred to as phagosome maturation. Pubmed12061891 Pubmed18331591 Reactome Database ID Release 431236963 Reactome, http://www.reactome.org ReactomeREACT_111097 Reviewed: Desjardins, M, English, L, 2011-05-13 Engulfment of particulate antigen into phagocytic vesicle After internalization, F-actin is depolymerized from the phagosome, and the newly denuded vacuole membrane becomes accessible to early endosomes (Aderem & Underhill. 1999). Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Pubmed10358769 Pubmed18331591 Reactome Database ID Release 431236956 Reactome, http://www.reactome.org ReactomeREACT_111116 Reviewed: Desjardins, M, English, L, 2011-05-13 Partial proteolysis of antigen in phagolysosomes Authored: Garapati, P V, 2011-03-28 EC Number: 3 Edited: Garapati, P V, 2011-03-28 Phagocytosed particulate antigens are partially digested in the lumen of phagolysosomes by various lysosomal hydrolases. Pubmed19265109 Reactome Database ID Release 431236938 Reactome, http://www.reactome.org ReactomeREACT_111159 Reviewed: Desjardins, M, English, L, 2011-05-13 Alkalization of the phagosomal lumen by NOX2 After the fusion of phagosome and lysosome lumen acidity rises and the activity of lysosomal proteases increases, conferring proteolytic ability. However antigens must be spared from complete proteolytic destruction. Dendritic cells (DCs) achieve this by regulating the level of proteolysis and phagosomal acidification. DCs recruit the NADPH oxidase NOX2 to the phagosome and mediate sustained production of low levels of reactive oxygen species (ROS), causing active alkalization of the phagosomal lumen (Savina et al. 2006, Ramachandra et al. 2009). NOX2 consumes oxygen and protons (pumped by V-ATPase or other H+ voltage-gated channels) to produce ROS and this lowers phagosome acidity. This apparently reduces antigen proteolysis to a level that allows processing but does not fully destroy the antigenic peptides, favouring increased MHC-I cross presentation (Ramachandra et al. 2009). Rab27a controls the recruitment of NOX2 to DC phagosomes (Savina et al. 2007). Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Pubmed16839887 Pubmed17351642 Pubmed17850487 Pubmed18682599 Pubmed19217269 Pubmed20171863 Reactome Database ID Release 431236967 Reactome, http://www.reactome.org ReactomeREACT_111243 Reviewed: Desjardins, M, English, L, 2011-05-13 has a Stoichiometric coefficient of 2 Egress of internalized antigen to the cytosol via sec61 Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Fusion of the maturing phagosome with the ER mediates the exchange of materials resulting in the formation of a hybrid ER-phagosome compartment (Gagnon et al. 2002, Guermonprez et al. 2003, Houde et al. 2003, Ackerman et al. 2003, Blanchard et al. 2010). This hybrid contains the retrotranslocon factor Sec61 that mediates the access of proteasomes on the cytosolic surface of the phagosome. Using fluorescence imaging, Houde et al. (2003) provided evidence for the role of Sec61 in the retrotranslocation of internalized exogenous proteins from phagosomes to the cytoplasmic face of J774 macrophages. Sec61 factor is a heterotrimeric complex composed of alpha, beta and gamma subunits forming the core of the mammalian ER translocon (Greenfield et al. 1999). Oligomers of the Sec61 complex form a transmembrane channel involved in the retrotranslocation of misfolded proteins from ER to the cytosol for degradation, and thus it has been proposed that Sec61 might be involved in the translocation of proteins in phagosomes to the cytosol (Kasturi et al. 2008). Pubmed10212142 Pubmed14508490 Pubmed18425099 Pubmed20869317 Reactome Database ID Release 431236947 Reactome, http://www.reactome.org ReactomeREACT_111088 Reviewed: Desjardins, M, English, L, 2011-05-13 Escape of antigens from phagosome to cytosol Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Pubmed17157489 Pubmed7809629 Pubmed8612129 Reactome Database ID Release 431236972 Reactome, http://www.reactome.org ReactomeREACT_111122 Reviewed: Desjardins, M, English, L, 2011-05-13 Upon phagolysosomal proteolysis the phagocytosed proteins still need to gain access to the cytosol for proteasomal access, transport into the ER and loading onto MHC class I. The mechanism for this escape of phagocytosed antigens remain unknown. Translocation of antigenic peptides back to phagosomes via TAP After processing by the proteasome, some of the oligopeptides could be reinternalized to the phagosome lumen of the same phagosome through the TAP complex probably acquired during ER-phagosome fusion. Guermonprez et al. (2003) tested this model and observed abundant TAP complex in early phagosomes and its reduction over time. Electron microscopy analysis of purified phagosomes also showed the insertion of TAP2 into the phagosomal membrane. Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Pubmed14508489 Reactome Database ID Release 431236949 Reactome, http://www.reactome.org ReactomeREACT_111185 Reviewed: Desjardins, M, English, L, 2011-05-13 has a Stoichiometric coefficient of 2 Proteasomal cleavage of substrate Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Proteasomes are usually localized to the cytoplasm but are also present in the nucleus and ER. Houde et al. (2003) investigated the distribution of proteasomes in J774 macrophages and observed them on phagosomes. The proteasomes present on phagosomes may not come directly from ER, but instead assemble on phagosomes to play a function at a precise point during phagolysosomal biogenesis. Houde et al. also observed polyubiquitinated proteins on the cytoplasmic side of phagosomes and highlighted the link between the ubiquitination process and proteasomal degradation; translocated peptides are ubiquitinated and processed by the proteasome complex assembled on the cytoplasmic side of phagosomes, leading to the generation of MHC class I binding peptides. Reactome Database ID Release 431236935 Reactome, http://www.reactome.org ReactomeREACT_111104 Reviewed: Desjardins, M, English, L, 2011-05-13 ACTIVATION GENE ONTOLOGYGO:0003684 Reactome Database ID Release 43113678 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003684 Reactome Database ID Release 43113678 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003684 Reactome Database ID Release 43113678 Reactome, http://www.reactome.org Interaction of particulate antigens with dendritic cell receptors Authored: Garapati, P V, 2011-03-28 Dendritic cells (DCs) and macrophages recognize and phagocytose apoptotic cells/invading microorganisms using a variety of receptors including lectins, Mannose receptor (MR) (Stahl & Ezekowitz. 1998), CD36 (Savill 1997), CD14 (Devitt et al. 1998), scavenger receptor A (SR-A) (Platt et al. 1996) and integrin alphaVbeta5 (Savill et al. 1992, Savilli et al. 1990), then cross-present cell-associated antigens to CD8+ T cells. Ligands on apoptotic cell like sugars, phosphatidylserine and surface-bound thrombospondin (TSP) are recognized by these receptors and induce rearrangements in the actin cytoskeleton that lead to the internalization of the particle. Edited: Garapati, P V, 2011-03-28 Pubmed1383273 Pubmed1688647 Pubmed18268517 Pubmed18331591 Pubmed7678924 Pubmed8901603 Pubmed9523111 Pubmed9763615 Reactome Database ID Release 431236958 Reactome, http://www.reactome.org ReactomeREACT_111137 Reviewed: Desjardins, M, English, L, 2011-05-13 AGT receptor Converted from EntitySet in Reactome Reactome DB_ID: 374209 Reactome Database ID Release 43374209 Reactome, http://www.reactome.org ReactomeREACT_15028 ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43111299 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43110309 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 43109965 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003908 Reactome Database ID Release 43353355 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43110323 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43111300 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 43110318 Reactome, http://www.reactome.org Peptide loading on MHC class I in phagosome Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Peptides translocated back into the phagosomal lumen are loaded onto MHC class I molecules. Guermonprez et al. (2003) detected the components of the peptide loading complex (TAP, tapasin, calreticulin and ERp57) together with MHC class I in purified early phagosomes. They observed peptide loading in the presence of ATP in purified phagosomes expressing HLA-A2, incubated with iodinated S-9-L peptide. From these experiments they concluded that TAP-imported peptides can be loaded on MHC class I molecules in the lumen of phagosomes. Houde et al. (2003) also observed OVA peptide SIINFEKL:MHC-I complex in the phagosome lumen. Pubmed14508489 Pubmed14508490 Reactome Database ID Release 431236971 Reactome, http://www.reactome.org ReactomeREACT_111153 Reviewed: Desjardins, M, English, L, 2011-05-13 ACTIVATION GENE ONTOLOGYGO:0004190 Reactome Database ID Release 43157355 Reactome, http://www.reactome.org DAP12 dimer Reactome DB_ID: 548940 Reactome Database ID Release 43548940 Reactome, http://www.reactome.org ReactomeREACT_147960 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004190 Reactome Database ID Release 43157355 Reactome, http://www.reactome.org DAP12:TRIM2 complex Reactome DB_ID: 210245 Reactome Database ID Release 43210245 Reactome, http://www.reactome.org ReactomeREACT_19597 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0017018 Reactome Database ID Release 43445806 Reactome, http://www.reactome.org Sema7A:Plexin-C1 Reactome DB_ID: 434928 Reactome Database ID Release 43434928 Reactome, http://www.reactome.org ReactomeREACT_20419 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004190 Reactome Database ID Release 43157355 Reactome, http://www.reactome.org Plexin-A1:Sema6D:Trem2:DAP12 Reactome DB_ID: 416720 Reactome Database ID Release 43416720 Reactome, http://www.reactome.org ReactomeREACT_19554 has a Stoichiometric coefficient of 1 NCAM1 cis-homodimer Reactome DB_ID: 190988 Reactome Database ID Release 43190988 Reactome, http://www.reactome.org ReactomeREACT_19070 has a Stoichiometric coefficient of 2 Sema7A:Integrin alpha1beta1 Reactome DB_ID: 434927 Reactome Database ID Release 43434927 Reactome, http://www.reactome.org ReactomeREACT_20443 has a Stoichiometric coefficient of 1 NCAM1:FGFR-1 Reactome DB_ID: 419028 Reactome Database ID Release 43419028 Reactome, http://www.reactome.org ReactomeREACT_18900 has a Stoichiometric coefficient of 1 NCAM1:NCAM1 trans-homotetramer Reactome DB_ID: 375103 Reactome Database ID Release 43375103 Reactome, http://www.reactome.org ReactomeREACT_18931 has a Stoichiometric coefficient of 2 Sema5A:Plexin-B3 Reactome DB_ID: 416696 Reactome Database ID Release 43416696 Reactome, http://www.reactome.org ReactomeREACT_19434 has a Stoichiometric coefficient of 1 Sema6A:Plexin-A (2and 4) Reactome DB_ID: 416728 Reactome Database ID Release 43416728 Reactome, http://www.reactome.org ReactomeREACT_19923 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0008534 Reactome Database ID Release 43110241 Reactome, http://www.reactome.org Plexin-A1-Trem2-DAP12 Reactome DB_ID: 416707 Reactome Database ID Release 43416707 Reactome, http://www.reactome.org ReactomeREACT_20126 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110247 Reactome, http://www.reactome.org Alpha-1(II) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268922 Reactome Database ID Release 432268922 Reactome, http://www.reactome.org ReactomeREACT_123084 ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110247 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110247 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110245 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004190 Reactome Database ID Release 43157355 Reactome, http://www.reactome.org Metal ion SLC transporters Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 Pubmed12748861 Pubmed12827356 Pubmed12836025 Pubmed14530973 Pubmed15157936 Pubmed16675045 Pubmed16720382 Pubmed16825786 Pubmed16908340 Pubmed17215883 Pubmed17374385 Pubmed17439925 Pubmed19164095 Reactome Database ID Release 43425410 Reactome, http://www.reactome.org ReactomeREACT_20547 Reviewed: He, L, 2009-11-12 Six SLC gene families encode proteins which mediate transport of metals. The families are SLC11, SLC30, SLC31, SLC39, SLC40 and SLC41 (He L et al, 2009; Bressler JP et al, 2007). Fyn:NCAM1:RPTP-alpha Reactome DB_ID: 391845 Reactome Database ID Release 43391845 Reactome, http://www.reactome.org ReactomeREACT_18571 has a Stoichiometric coefficient of 1 Formation of peptide loading complex (PLC) Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed14718384 Pubmed15286279 Pubmed16465444 Pubmed19119025 Pubmed19361863 Pubmed19426129 Reactome Database ID Release 43983142 Reactome, http://www.reactome.org ReactomeREACT_75922 Reviewed: Elliott, T, 2011-02-10 Upon interaction of Beta-2-microglobin (B2M) with MHC class I Heavy Chain (HC), calnexin is fully replaced by its soluble ortholog calreticulin (CRT) and this complex is incorporated into the peptide loading complex (PLC). PLC is a multiprotein complex that includes CRT, ERp57 and the additional components tapasin, transporter associated with antigen processing (TAP) and Bap31. The stoichometry of components in PLC remains unclear. The PLC loads antigenic peptides onto MHC class I molecules; components of the PLC cooperate to stabilize the MHC class I complex and optimally load peptides. Tapasin is a type I transmembrane protein that interacts directly with TAP and tethers the MHC complex to it. TAP facilitates the transport of peptides from the cytosol to the ER lumen. B cell receptor–associated protein (Bap31), a putative cargo receptor, associates with HC and acts as a retrograde transporter, carrying peptide-loaded class I MHC molecules. Interaction of beta-2-microglobulin (B2M) chain with class I HC Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Interaction of calnexin (CNX) with MHC class I HC stabilizes it and facilitates the association of the beta2 microglobulin component (B2M). The two chains are linked noncovalently via interaction of B2M and the alpha3 domain of MHC HC. After formation of the HC:B2M heterodimer, the MHC complex dissociates from CNX. Pubmed10064069 Pubmed14681859 Pubmed2450918 Reactome Database ID Release 43983146 Reactome, http://www.reactome.org ReactomeREACT_75898 Reviewed: Elliott, T, 2011-02-10 Interaction of Erp57 with MHC class I HC Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Endoplasmic reticulum resident protein 57 (ERp57), is a member of the protein disulphide isomerase (PDI) family of thiol oxidoreducatases. It associates with Calnexin (CNX), and its soluble homolog calreticulin (CRT) and is recruited to MHC Class I Heavy Chain (HC). ERp57 is involved in the formation of HC disulphide bonds. Reactome Database ID Release 43983148 Reactome, http://www.reactome.org ReactomeREACT_75930 Reviewed: Elliott, T, 2011-02-10 Type II Na+/Pi cotransporters Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Pubmed12750889 Reactome Database ID Release 43427589 Reactome, http://www.reactome.org ReactomeREACT_19411 Reviewed: He, L, 2009-08-24 The SLC34 family of type II Na+/Pi cotransporters consist of three members; NaPi-IIa (SLC34A1), NaPi-IIb (SLC34A2) and NaPi-IIc (SLC34A3) (Murer H et al, 2004). They are expressed mainly in the kidney and small intestine, located at the apical sites of epithelial cells although other areas of the body express them to a lesser extent. NaPi-IIa and b cotransports divalent Pi (HPO4[2-]) with three Na+ ions (electrogenic transport) whereas NaPi-IIc cotransports divalent Pi with two Na+ ions (electroneutral transport). ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110209 Reactome, http://www.reactome.org pFAK (391) bound to NCAM1:pFyn Reactome DB_ID: 391841 Reactome Database ID Release 43391841 Reactome, http://www.reactome.org ReactomeREACT_18498 has a Stoichiometric coefficient of 1 Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 Hexoses like glucose, galactose and fructose serve as basic fuel molecules for eukaryotic cells. Indeed, glucose is the main energy source for mammalian cells. These sugars are unable to diffuse across cellular membranes, and require transporter proteins for entry into and exit out of cells. Four gene families encode hexose transporter proteins (He et al, 2009). SLC2 family contains 14 genes and encode facilitative glucose transporters (GLUTs) (Uldry M and Thorens B, 2004). SLC5 family contains 12 genes and encode Na+/glucose symporters (Wright EM and Turk E, 2004). SLC37 family contains 4 members and encode sugar-phosphate/phosphate exchangers (Bartoloni L and Antonarakis SE, 2004). SLC45 family has 4 members and encode putative sugar/H+ symporters. Pubmed12748858 Pubmed12750891 Pubmed12811562 Pubmed19164095 Reactome Database ID Release 43425366 Reactome, http://www.reactome.org ReactomeREACT_19305 Reviewed: He, L, 2009-08-24 ACTIVATION GENE ONTOLOGYGO:0004844 Reactome Database ID Release 43110214 Reactome, http://www.reactome.org NCAM:pFyn-Y420 Reactome DB_ID: 391843 Reactome Database ID Release 43391843 Reactome, http://www.reactome.org ReactomeREACT_18841 has a Stoichiometric coefficient of 1 Multifunctional anion exchangers Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Pubmed12759755 Pubmed18400693 Reactome Database ID Release 43427601 Reactome, http://www.reactome.org ReactomeREACT_19357 Reviewed: He, L, 2009-08-24 The human SLC26 gene family consists of eleven members which encode multifunctional anion exchangers.These exchangers are capable of transporting a variety of anions such as sulphate, bicarbonate, oxalate, hydroxyl, formate, iodide and chloride. SLC26 members can be grouped according to functional similiarities and three groups can be classified this way. Group 1 are selective sulphate transporters and include SLC26A1 and 2. Group 2 are Cl-/HCO3- exchangers and include SLC26A3, 4 and 6. Group 3 function as ion channels and include SLC26A7 and 9. ACTIVATION GENE ONTOLOGYGO:0004844 Reactome Database ID Release 43110214 Reactome, http://www.reactome.org NCAM1 complexed with pFyn-Y420 Reactome DB_ID: 391842 Reactome Database ID Release 43391842 Reactome, http://www.reactome.org ReactomeREACT_18470 has a Stoichiometric coefficient of 1 Sodium-coupled phosphate cotransporters Authored: Jassal, B, 2009-06-23 Edited: Jassal, B, 2009-06-23 Phosphorus is an essential element that is critical for structural and metabolic roles in all living organisms. Cells obtain phosphorus in the form of negatively-charged inorganic phosphate (Pi). Two SLC families transport phosphate in mammals; SLC34 (Murer H et al, 2004) and SLC20 (Collins JF et al, 2004). Both are secondary-active, Na+-coupled transporter systems which use the inward Na+ gradient (from the Na+-K+-ATPase) to drive phosphate influx into cells (Virkki LV et al, 2007). Pubmed12750889 Pubmed12759754 Pubmed17581921 Reactome Database ID Release 43427652 Reactome, http://www.reactome.org ReactomeREACT_19275 Reviewed: He, L, 2009-08-24 ACTIVATION GENE ONTOLOGYGO:0019104 Reactome Database ID Release 43110209 Reactome, http://www.reactome.org NCAM complexed with Fyn Reactome DB_ID: 391844 Reactome Database ID Release 43391844 Reactome, http://www.reactome.org ReactomeREACT_18690 has a Stoichiometric coefficient of 1 Na+-dependent glucose transporters Authored: Jassal, B, 2009-07-10 Edited: Jassal, B, 2009-07-10 Pubmed17222166 Reactome Database ID Release 43428808 Reactome, http://www.reactome.org ReactomeREACT_19165 Reviewed: He, L, 2009-08-24 Two gene families are responsible for glucose transport in humans. SLC2 (encoding GLUTs) and SLC5 (encoding SGLTs) families mediate glucose absorption in the small intestine, glucose reabsorption in the kidney, glucose uptake by the brain across the blood-brain barrier and glucose release by all cells in the body.<br><br>Na+-dependent glucose transporters (SGLTs) mediate secondary active glucose transport in the small intestine and kidney . They use the downhill Na+ gradient to transport glucose across intestinal and renal membranes. Three genes in the SLC5 family (SLC5A1, 2 and 9) encode proteins that transport glucose (and other substrates) with Na+ (Wright EM et al, 2007). Grb2:Sos:pFAK bound to NCAM1:pFyn Reactome DB_ID: 392045 Reactome Database ID Release 43392045 Reactome, http://www.reactome.org ReactomeREACT_18839 has a Stoichiometric coefficient of 1 Inositol transporters Authored: Jassal, B, 2009-07-17 Edited: Jassal, B, 2009-07-17 Myo-Inositol is a neutral cyclic polyol, abundant in mammalian tissues. It plays important roles; it is a precursor to phosphatidylinositols (PtdIns) and to the inositol phosphates (IP), which serve as second messengers and as key regulators of many cell functions. It can also serve as a compatible osmolyte during volume regulation in many tissues where cells are exposed to hyperosmotic conditions. Three members of the glucose transporter families are inositol transporters. Two (SMIT1 and SMIT2) couple myo-inositol transport with two Na+ ions. Unlike SMIT1, SMIT2 also transports D-chiro_inositol. The third transporter (HMIT), couples myo-inositol transport with a proton. Reactome Database ID Release 43429593 Reactome, http://www.reactome.org ReactomeREACT_19188 Reviewed: He, L, 2009-08-24 pFAK:Grb2 Reactome DB_ID: 392043 Reactome Database ID Release 43392043 Reactome, http://www.reactome.org ReactomeREACT_19019 has a Stoichiometric coefficient of 1 Facilitative Na+-independent glucose transporters Authored: Jassal, B, 2009-07-10 Edited: Jassal, B, 2009-07-10 Pubmed11780753 Pubmed12568659 Pubmed18660845 Reactome Database ID Release 43428790 Reactome, http://www.reactome.org ReactomeREACT_19343 Reviewed: He, L, 2009-08-24 Two gene families are responsible for glucose transport in humans. SLC2 (encoding GLUTs) and SLC5 (encoding SGLTs) families mediate glucose absorption in the small intestine, glucose reabsorption in the kidney, glucose uptake by the brain across the blood-brain barrier and glucose release by all cells in the body.<br><br>Glucose is the main energy source used by cells to make energy. Im mammals, blood glucose levels are tightly controlled and glucose is taken up from interstitial fluid by a passive, facilitative transport driven by the diffusion gradient of glucose (and other sugars) across the plasma membrane. This process is mediated by a family of Na+-independent, facilitative glucose transporters (GLUTs) encoded by the SLC2A gene family (Zhao FQ and Keating AF, 2007; Wood IS and Trayhurn P, 2003). There are 14 members belonging to this family (GLUT1-12, 14 and HMIT (H+/myo-inositol symporter)). The GLUT family can be subdivided into three subclasses (I-III) based on sequence similarity and characteristic sequence motifs (Joost HG and Thorens B, 2001). Grb2:pFAK bound to NCAM1:pFyn Reactome DB_ID: 392047 Reactome Database ID Release 43392047 Reactome, http://www.reactome.org ReactomeREACT_18783 has a Stoichiometric coefficient of 1 Class II GLUTs Authored: Jassal, B, 2009-07-10 Class II facilitative transporters consist of GLUT5, 7, 9 and 11 (Zhao FQ and Keating AF, 2007; Wood IS and Trayhurn P, 2003). Edited: Jassal, B, 2009-07-10 Pubmed12568659 Pubmed18660845 Reactome Database ID Release 43428776 Reactome, http://www.reactome.org ReactomeREACT_19281 Reviewed: He, L, 2009-08-24 ACTIVATION GENE ONTOLOGYGO:0008534 Reactome Database ID Release 43110241 Reactome, http://www.reactome.org Multiple phosphorylated FAK bound to NCAM:pFyn Reactome DB_ID: 391848 Reactome Database ID Release 43391848 Reactome, http://www.reactome.org ReactomeREACT_18768 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0000703 Reactome Database ID Release 43110222 Reactome, http://www.reactome.org NCAM-1:ATP Reactome DB_ID: 375093 Reactome Database ID Release 43375093 Reactome, http://www.reactome.org ReactomeREACT_18582 has a Stoichiometric coefficient of 1 NCAM1 complexed with Fyn Reactome DB_ID: 391847 Reactome Database ID Release 43391847 Reactome, http://www.reactome.org ReactomeREACT_18556 has a Stoichiometric coefficient of 1 Cation-coupled Chloride cotransporters Authored: Jassal, B, 2009-06-12 Edited: Jassal, B, 2009-06-12 Pubmed12739168 Pubmed15788703 Reactome Database ID Release 43426117 Reactome, http://www.reactome.org ReactomeREACT_19315 Reviewed: He, L, 2009-08-24 The cation-chloride cotransporter family (SLC12 gene family) are membrane proteins that cotranslocate chloride (Cl-) with either Na+, K+, or both cations electroneutrally. The general topology of these proteins feature 12 transmembrane domains flanked by hydrophilic NH2 and COOH-terminal domains. They are secondary transporters and movement of these cations is determined by gradients established by primary transporters such as Na+-K+-ATPase. Cotransporters that use Na+ as the driving force move Cl- into the cell because Na+ concentration is higher in the extracellular region. Conversely, cotransporters that use K+ as the driving force move Cl- out of the cell because K+ concentration is higher inside the cell.<br><br>The SLC12 gene family contains nine members, of which seven are clearly characterized genes and two are orphans. They encode cotransporter proteins which are 1) involved in Cl- homeostasis, 2) regulate cell volume, 3) involved in transepithelial ion movement (salt reabsorption in the kidney) and 4) involved in response to neurotransmitters such as GABA. <br><br>Three different cotransporter subtypes are expressed by the seven characterized genes; one thiazide-sensitive Na+/Cl- cotransporter, two loop diuretic-sensitive Na+, K+/2Cl- cotransporters and four K+/Cl- cotransporters (Gamba G, 2005; Hebert SC et al, 2004). ACTIVATION GENE ONTOLOGYGO:0000703 Reactome Database ID Release 43110222 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017065 Reactome Database ID Release 43110220 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000703 Reactome Database ID Release 43110222 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000703 Reactome Database ID Release 43110222 Reactome, http://www.reactome.org Alpha-1(III) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268794 Reactome Database ID Release 432268794 Reactome, http://www.reactome.org ReactomeREACT_125125 Trimming of N-ter extended precursor fragments by cytosolic aminopeptidases Authored: Garapati, P V, 2010-10-29 EC Number: 3.4.11 Edited: Garapati, P V, 2010-10-29 Pubmed11062501 Pubmed15224091 Pubmed15224092 Pubmed16849449 Pubmed9668046 Reactome Database ID Release 43983162 Reactome, http://www.reactome.org ReactomeREACT_75931 Reviewed: Elliott, T, 2011-02-10 Some peptides generated by the 26S proteasome are too long to bind to MHC class I molecules. These N-terminal extended precursor peptides may be trimmed by cytosolic aminopeptidases, such as Tripeptidyl peptidase II (TPP2), puromycin-sensitive aminopeptidase (PSA), bleomycin hydrolase (BH), and leucine aminopeptidase (LAP). Binding of newly synthesized MHC class I heavy chain (HC) with calnexin Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed10777614 Pubmed11160214 Pubmed11470776 Pubmed11514579 Pubmed12495737 Pubmed7642652 Pubmed7876241 Pubmed9605141 Reactome Database ID Release 43983145 Reactome, http://www.reactome.org ReactomeREACT_75754 Reviewed: Elliott, T, 2011-02-10 The newly synthesized MHC class I heavy chain (HC) translocates into the endoplasmic reticulum (ER) and binds rapidly to calnexin (CNX), a transmembrane calcium-dependent lectin with chaperone activity. CNX recognizes and binds to an N-linked monoglycosylated Glc1Man9GlcNAc2 carbohydrate group found attached to the conserved Asn-86 in the HC. Interaction of HC with CNX promotes the formation of intrachain disulfide bonds. Another candidate ER chaperon protein is immunoglobulin binding protein (BiP), found to associate with HC in the absence of CNX. These chaperones can cooperate in protein folding and prevention of aggregation. Release of E3 from polyubiquitinated substrate Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 K48 polyubiquitinated substrate dissociates from E3 to become a substrate for a multicatalytic complex called the 26S proteasome. Pubmed12646216 Pubmed16954532 Pubmed19489725 Reactome Database ID Release 43983147 Reactome, http://www.reactome.org ReactomeREACT_75928 Reviewed: Elliott, T, 2011-02-10 Cleaved novel PDGF fragments Converted from EntitySet in Reactome Reactome DB_ID: 389070 Reactome Database ID Release 43389070 Reactome, http://www.reactome.org ReactomeREACT_18041 Proteasomal cleavage of substrate Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed11350924 Pubmed14734113 Pubmed15224091 Pubmed15224092 Pubmed15571818 Pubmed9380723 Reactome Database ID Release 43983150 Reactome, http://www.reactome.org ReactomeREACT_75871 Reviewed: Elliott, T, 2011-02-10 The 26S proteasome complex consists of the 20S catalytic core particle which harbours the proteolytically active sites and the regulatory 19S particle which is responsible for substrate interaction. This process generates a vast number (perhaps hundreds) of different peptides, depending on the length and sequence of the substrate protein. Only a small fraction of these peptides (nearly 10%) form the exact length to be presented by class I MHC; most (approximately 70%) are too short to bind. The remaining proteasome products (10-20%) are N-terminally extended precursors that require additional cleavage by cytosolic aminopeptidases for presentation by MHC class I molecules. Transfer of Ub from E2 to substrate and release of E2 Authored: Garapati, P V, 2010-10-29 EC Number: 6.3.2.19 Edited: Garapati, P V, 2010-10-29 Interaction of E3 with both substrate and E2-Ub, brings them into proximity so that ubiquitin is transferred from E2 to the substrate. In most cases the transfer of ubiquitin is direct from E2 to substrate, but in a small subset of E3s, it occurs via a covalent E3-Ub thioester intermediate (Raymond et al. 2009). Pubmed12646216 Pubmed16954532 Pubmed19489725 Reactome Database ID Release 43983140 Reactome, http://www.reactome.org ReactomeREACT_75901 Reviewed: Elliott, T, 2011-02-10 Polyubiquitination of substrate Authored: Garapati, P V, 2010-10-29 EC Number: 6.3.2.19 Edited: Garapati, P V, 2010-10-29 Monoubiquitinated substrate acquires additional ubiquitin modifications in the form of multiple single attachments or a ubiquitin chain. Polyubiquitin chains added through K48 residue of ubiquitin typically targets the substrate for degradation (Raymond et al. 2009). Pubmed12646216 Pubmed16954532 Pubmed19489725 Pubmed19874575 Reactome Database ID Release 43983156 Reactome, http://www.reactome.org ReactomeREACT_75847 Reviewed: Elliott, T, 2011-02-10 has a Stoichiometric coefficient of 2 Interaction of E3 with substrate and E2-Ub complex Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed12646216 Pubmed16954532 Pubmed19489725 Reactome Database ID Release 43983157 Reactome, http://www.reactome.org ReactomeREACT_75856 Reviewed: Elliott, T, 2011-02-10 Ubiquitin E3 ligases confer specificity to ubiquitination by recognizing target substrates and mediating transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to substrate (Raymond et al. 2009). E3 ligases includes a large, diverse set of proteins characterized by several defining motifs which include a HECT (homologous to E6-associated C-terminus), RING (Really Interesting New Gene) and U-box domains. The E3 ligases can be multisubunit complexes rather than a single polypeptide. Presently three different kinds of E3 complexes have been described called SCF, APC, and VHL. E3 ligases binds to both substrate and an E2 thioesterified with ubiquitin (E2-Ub). pCdk5:p35 Reactome DB_ID: 421098 Reactome Database ID Release 43421098 Reactome, http://www.reactome.org ReactomeREACT_19834 has a Stoichiometric coefficient of 1 Fyn:pCdk5 Reactome DB_ID: 399838 Reactome Database ID Release 43399838 Reactome, http://www.reactome.org ReactomeREACT_19655 has a Stoichiometric coefficient of 1 Sema3A:Nrp-1:PlexinA:Fyn:Cdk5:pCRMP's Reactome DB_ID: 399867 Reactome Database ID Release 43399867 Reactome, http://www.reactome.org ReactomeREACT_19706 has a Stoichiometric coefficient of 1 CRMP's tetramers Reactome DB_ID: 399843 Reactome Database ID Release 43399843 Reactome, http://www.reactome.org ReactomeREACT_19835 has a Stoichiometric coefficient of 4 ACTIVATION GENE ONTOLOGYGO:0015101 Reactome Database ID Release 432161534 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008559 Reactome Database ID Release 432161515 Reactome, http://www.reactome.org PlexinA:Fyn:pCdk5 Reactome DB_ID: 399854 Reactome Database ID Release 43399854 Reactome, http://www.reactome.org ReactomeREACT_19497 has a Stoichiometric coefficient of 1 Nrp-1:PlexinA:Fyn:pCdk5 Reactome DB_ID: 399845 Reactome Database ID Release 43399845 Reactome, http://www.reactome.org ReactomeREACT_19966 has a Stoichiometric coefficient of 1 Collagen alpha-3(VI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192698 Reactome Database ID Release 432192698 Reactome, http://www.reactome.org ReactomeREACT_122939 ACTIVATION GENE ONTOLOGYGO:0016773 Reactome Database ID Release 432161189 Reactome, http://www.reactome.org Sema3A:Nrp-1:PlexinA:Fyn:pCdk5 Reactome DB_ID: 399868 Reactome Database ID Release 43399868 Reactome, http://www.reactome.org ReactomeREACT_20429 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004022 Reactome Database ID Release 432162089 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015020 Reactome Database ID Release 432162079 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008559 Reactome Database ID Release 432161511 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004550 Reactome Database ID Release 432162074 Reactome, http://www.reactome.org Nrp-1 complexed with PlexinA:Fyn Reactome DB_ID: 399846 Reactome Database ID Release 43399846 Reactome, http://www.reactome.org ReactomeREACT_20319 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0019201 Reactome Database ID Release 432162086 Reactome, http://www.reactome.org Plexin bound with Fyn Reactome DB_ID: 399847 Reactome Database ID Release 43399847 Reactome, http://www.reactome.org ReactomeREACT_20013 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0050146 Reactome Database ID Release 432161536 Reactome, http://www.reactome.org Sema3A:Nrp-1:PlexinA:Fyn Reactome DB_ID: 399869 Reactome Database ID Release 43399869 Reactome, http://www.reactome.org ReactomeREACT_20413 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004000 Reactome Database ID Release 432161186 Reactome, http://www.reactome.org Cdk5:p35 Reactome DB_ID: 421107 Reactome Database ID Release 43421107 Reactome, http://www.reactome.org ReactomeREACT_19863 has a Stoichiometric coefficient of 1 Sema4A:Plexin-D1 Reactome DB_ID: 416694 Reactome Database ID Release 43416694 Reactome, http://www.reactome.org ReactomeREACT_19803 has a Stoichiometric coefficient of 1 Sema3E bound to Plexin D1 receptor Reactome DB_ID: 209639 Reactome Database ID Release 43209639 Reactome, http://www.reactome.org ReactomeREACT_20367 has a Stoichiometric coefficient of 1 pCRMP's tertramers (Y499) Reactome DB_ID: 399863 Reactome Database ID Release 43399863 Reactome, http://www.reactome.org ReactomeREACT_19615 has a Stoichiometric coefficient of 4 Sema3A:NP-1:Plexin-A:Fes:CRMP Reactome DB_ID: 399860 Reactome Database ID Release 43399860 Reactome, http://www.reactome.org ReactomeREACT_20015 has a Stoichiometric coefficient of 1 pCRMP's tetramers (S522,S518,T509,T514) Reactome DB_ID: 399848 Reactome Database ID Release 43399848 Reactome, http://www.reactome.org ReactomeREACT_19910 has a Stoichiometric coefficient of 4 ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431475014 Reactome, http://www.reactome.org PlexinA:Fyn:Cdk5:pCRMP's (S522,S518,T509,T514) Reactome DB_ID: 399851 Reactome Database ID Release 43399851 Reactome, http://www.reactome.org ReactomeREACT_19864 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431475014 Reactome, http://www.reactome.org Nrp-1:PlexinA:Fyn:Cdk5:pCRMP's (S522,S518,T509,T514) Reactome DB_ID: 399853 Reactome Database ID Release 43399853 Reactome, http://www.reactome.org ReactomeREACT_20332 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431475013 Reactome, http://www.reactome.org Collagen alpha-1(VI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127497 Reactome Database ID Release 432127497 Reactome, http://www.reactome.org ReactomeREACT_123579 ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431475031 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431475013 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431237060 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431475031 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017018 Reactome Database ID Release 43390594 Reactome, http://www.reactome.org pCRMP's tetramers (S522) Reactome DB_ID: 399850 Reactome Database ID Release 43399850 Reactome, http://www.reactome.org ReactomeREACT_19675 has a Stoichiometric coefficient of 4 ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431237060 Reactome, http://www.reactome.org Sema3A:Nrp-1:PlexinA:Fyn:Cdk5:pCRMP's Reactome DB_ID: 399870 Reactome Database ID Release 43399870 Reactome, http://www.reactome.org ReactomeREACT_20425 has a Stoichiometric coefficient of 1 Nrp-1:PlexinA:Fyn:Cdk5:pCRMP's Reactome DB_ID: 399855 Reactome Database ID Release 43399855 Reactome, http://www.reactome.org ReactomeREACT_20341 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004687 Reactome Database ID Release 43445811 Reactome, http://www.reactome.org PlexinA:Fyn:Cdk5:pCRMP's Reactome DB_ID: 399852 Reactome Database ID Release 43399852 Reactome, http://www.reactome.org ReactomeREACT_19745 has a Stoichiometric coefficient of 1 Collagen alpha-1(XXV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2193027 Reactome Database ID Release 432193027 Reactome, http://www.reactome.org ReactomeREACT_124668 ACTIVATION GENE ONTOLOGYGO:0031071 Reactome Database ID Release 431362414 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009055 Reactome Database ID Release 432395510 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047962 Reactome Database ID Release 43159547 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015093 Reactome Database ID Release 431362410 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016410 Reactome Database ID Release 43177155 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016405 Reactome Database ID Release 43159441 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047962 Reactome Database ID Release 43159547 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016405 Reactome Database ID Release 43177146 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004364 Reactome Database ID Release 43176052 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016405 Reactome Database ID Release 43177146 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431237049 Reactome, http://www.reactome.org Collagen alpha-5(VI) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127458 Reactome Database ID Release 432127458 Reactome, http://www.reactome.org ReactomeREACT_122257 Alpha-1(I) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268797 Reactome Database ID Release 432268797 Reactome, http://www.reactome.org ReactomeREACT_122962 ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431237049 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005452 Reactome Database ID Release 431237040 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431475432 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035379 Reactome Database ID Release 431237058 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035379 Reactome Database ID Release 431237071 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035379 Reactome Database ID Release 431237058 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035379 Reactome Database ID Release 431237071 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004089 Reactome Database ID Release 431475432 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005452 Reactome Database ID Release 431237040 Reactome, http://www.reactome.org NCAM1-Contactin-2 Reactome DB_ID: 375108 Reactome Database ID Release 43375108 Reactome, http://www.reactome.org ReactomeREACT_19032 has a Stoichiometric coefficient of 1 Polysialylated NCAM Reactome DB_ID: 422441 Reactome Database ID Release 43422441 Reactome, http://www.reactome.org ReactomeREACT_18914 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 NCAM1:T- and L-type VDCC Reactome DB_ID: 525828 Reactome Database ID Release 43525828 Reactome, http://www.reactome.org ReactomeREACT_21777 has a Stoichiometric coefficient of 1 DCC:Netrin-1 Reactome DB_ID: 373667 Reactome Database ID Release 43373667 Reactome, http://www.reactome.org ReactomeREACT_22821 has a Stoichiometric coefficient of 1 NCAM-1:Neurocan Reactome DB_ID: 375100 Reactome Database ID Release 43375100 Reactome, http://www.reactome.org ReactomeREACT_18891 has a Stoichiometric coefficient of 1 NCAM-1:Collagen complex Reactome DB_ID: 375098 Reactome Database ID Release 43375098 Reactome, http://www.reactome.org ReactomeREACT_18833 has a Stoichiometric coefficient of 1 NCAM-1:Major prion protein Reactome DB_ID: 375105 Reactome Database ID Release 43375105 Reactome, http://www.reactome.org ReactomeREACT_18842 has a Stoichiometric coefficient of 1 NCAM-1:Agrin Reactome DB_ID: 375096 Reactome Database ID Release 43375096 Reactome, http://www.reactome.org ReactomeREACT_19071 has a Stoichiometric coefficient of 1 NCAM1:GFRalpha-1 Reactome DB_ID: 375101 Reactome Database ID Release 43375101 Reactome, http://www.reactome.org ReactomeREACT_18445 has a Stoichiometric coefficient of 1 NCAM1:GFRalpha-1:GDNF Reactome DB_ID: 375111 Reactome Database ID Release 43375111 Reactome, http://www.reactome.org ReactomeREACT_18598 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004060 Reactome Database ID Release 43158690 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019825 Reactome Database ID Release 4376372 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008441 Reactome Database ID Release 43176558 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004060 Reactome Database ID Release 43174964 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050294 Reactome Database ID Release 43176472 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004304 Reactome Database ID Release 43176657 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008146 Reactome Database ID Release 43176547 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008146 Reactome Database ID Release 43176547 Reactome, http://www.reactome.org pFAK:Grb2:Sos Reactome DB_ID: 392044 Reactome Database ID Release 43392044 Reactome, http://www.reactome.org ReactomeREACT_18636 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0050294 Reactome Database ID Release 43176602 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050294 Reactome Database ID Release 43176571 Reactome, http://www.reactome.org CDC42-GDP Reactome DB_ID: 418830 Reactome Database ID Release 43418830 Reactome, http://www.reactome.org ReactomeREACT_20401 has a Stoichiometric coefficient of 1 Nterin-1:pDCC oligomer:pFAK:Fyn:NCK1 Reactome DB_ID: 373663 Reactome Database ID Release 43373663 Reactome, http://www.reactome.org ReactomeREACT_23303 has a Stoichiometric coefficient of 1 Netrin:DCC oligomer:pFAK:Fyn:Nck-1:Rho GEFs DOCK/Trio Reactome DB_ID: 418829 Reactome Database ID Release 43418829 Reactome, http://www.reactome.org ReactomeREACT_23304 has a Stoichiometric coefficient of 1 Nterin-1:pDCC dimer:pFADK1 Reactome DB_ID: 418839 Reactome Database ID Release 43418839 Reactome, http://www.reactome.org ReactomeREACT_22544 has a Stoichiometric coefficient of 1 Netrin-1:pDCC dimer Reactome DB_ID: 418837 Reactome Database ID Release 43418837 Reactome, http://www.reactome.org ReactomeREACT_22829 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Netrin1:DCC oligomer:pFADK1:Fyn/src Reactome DB_ID: 418815 Reactome Database ID Release 43418815 Reactome, http://www.reactome.org ReactomeREACT_22915 has a Stoichiometric coefficient of 1 Netrin-1:pDCC dimer:pFAK:Src/Fyn Reactome DB_ID: 374551 Reactome Database ID Release 43374551 Reactome, http://www.reactome.org ReactomeREACT_23053 has a Stoichiometric coefficient of 1 FADK1:DCC oligomer:Netrin Reactome DB_ID: 373662 Reactome Database ID Release 43373662 Reactome, http://www.reactome.org ReactomeREACT_22770 has a Stoichiometric coefficient of 1 Nterin-1:DCC oligomer:pFADK1 Reactome DB_ID: 418822 Reactome Database ID Release 43418822 Reactome, http://www.reactome.org ReactomeREACT_23005 has a Stoichiometric coefficient of 1 Netrin:DCC oligomer Reactome DB_ID: 373678 Reactome Database ID Release 43373678 Reactome, http://www.reactome.org ReactomeREACT_23248 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0003840 Reactome Database ID Release 431247914 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003839 Reactome Database ID Release 431247932 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004364 Reactome Database ID Release 43158544 Reactome, http://www.reactome.org Alpha-2(I) -N propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268757 Reactome Database ID Release 432268757 Reactome, http://www.reactome.org ReactomeREACT_122973 ACTIVATION GENE ONTOLOGYGO:0008119 Reactome Database ID Release 43158629 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0018708 Reactome Database ID Release 43175985 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030760 Reactome Database ID Release 43175975 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016206 Reactome Database ID Release 43175988 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017168 Reactome Database ID Release 431247941 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003839 Reactome Database ID Release 431247932 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004363 Reactome Database ID Release 43174399 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004108 Reactome Database ID Release 4370974 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004146 Reactome Database ID Release 431497819 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004740 Reactome Database ID Release 43203942 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004741 Reactome Database ID Release 43204160 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050833 Reactome Database ID Release 43372338 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004738 Reactome Database ID Release 43450854 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015129 Reactome Database ID Release 43373866 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004459 Reactome Database ID Release 4370509 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004459 Reactome Database ID Release 4370509 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015129 Reactome Database ID Release 43373866 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003994 Reactome Database ID Release 4370969 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003994 Reactome Database ID Release 4370969 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004776 Reactome Database ID Release 4371774 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004775 Reactome Database ID Release 4370996 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008177 Reactome Database ID Release 4370993 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004333 Reactome Database ID Release 4370981 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004449 Reactome Database ID Release 4370966 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004450 Reactome Database ID Release 43450976 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008746 Reactome Database ID Release 43450969 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0034602 Reactome Database ID Release 4369997 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030060 Reactome Database ID Release 4370978 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047545 Reactome Database ID Release 43880037 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004333 Reactome Database ID Release 4370981 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047988 Reactome Database ID Release 43880047 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051990 Reactome Database ID Release 43880026 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0051990 Reactome Database ID Release 43880022 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047988 Reactome Database ID Release 43880047 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0009055 Reactome Database ID Release 43169261 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008137 Reactome Database ID Release 43164321 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008177 Reactome Database ID Release 43163955 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43354119 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43210268 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43372641 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43354090 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004143 Reactome Database ID Release 43426239 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004698 Reactome Database ID Release 43139850 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004174 Reactome Database ID Release 43169271 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43432183 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0045153 Reactome Database ID Release 43164660 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43939916 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004129 Reactome Database ID Release 43164322 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 43426035 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046933 Reactome Database ID Release 43164536 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047372 Reactome Database ID Release 43426275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015078 Reactome Database ID Release 43164850 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008509 Reactome Database ID Release 43166401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015078 Reactome Database ID Release 43170031 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004044 Reactome Database ID Release 4373791 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004637 Reactome Database ID Release 4373807 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004644 Reactome Database ID Release 4373808 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432482187 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004721 Reactome Database ID Release 432167886 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432485156 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 431852619 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 43157208 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 43157208 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008237 Reactome Database ID Release 43157208 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43162362 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004114 Reactome Database ID Release 43162426 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432176399 Reactome, http://www.reactome.org pPlexin-B1:Met Reactome DB_ID: 419623 Reactome Database ID Release 43419623 Reactome, http://www.reactome.org ReactomeREACT_20252 has a Stoichiometric coefficient of 1 Sema4D:pPlexin-B1:Met Reactome DB_ID: 419621 Reactome Database ID Release 43419621 Reactome, http://www.reactome.org ReactomeREACT_19905 has a Stoichiometric coefficient of 1 CNOT7 or CNOT8 Converted from EntitySet in Reactome Reactome DB_ID: 429868 Reactome Database ID Release 43429868 Reactome, http://www.reactome.org ReactomeREACT_20928 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4369014 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 4369115 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017108 Reactome Database ID Release 4369151 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43169514 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 43169510 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 43174240 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 432484978 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003909 Reactome Database ID Release 43109965 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008907 Reactome Database ID Release 43175070 Reactome, http://www.reactome.org Sema4D:pPlexin-B1:ErbB2:Rac1:Rnd1 Reactome DB_ID: 419626 Reactome Database ID Release 43419626 Reactome, http://www.reactome.org ReactomeREACT_19890 has a Stoichiometric coefficient of 1 Smooth muscle/non-muscle myosin II Reactome DB_ID: 419194 Reactome Database ID Release 43419194 Reactome, http://www.reactome.org ReactomeREACT_19969 has a Stoichiometric coefficient of 2 Sema4D:Plexin-B1:Rac-Rnd1:LARG/PDZ-RhoGEF Reactome DB_ID: 416580 Reactome Database ID Release 43416580 Reactome, http://www.reactome.org ReactomeREACT_20349 has a Stoichiometric coefficient of 1 Sema4D:pPlexin-B1:Met:RAC1-GTP Reactome DB_ID: 400679 Reactome Database ID Release 43400679 Reactome, http://www.reactome.org ReactomeREACT_20028 has a Stoichiometric coefficient of 1 Rnd1-GTP Reactome DB_ID: 421104 Reactome Database ID Release 43421104 Reactome, http://www.reactome.org ReactomeREACT_20300 has a Stoichiometric coefficient of 1 Sema4D:pPlexin-B1:Met:Rnd1 Reactome DB_ID: 416587 Reactome Database ID Release 43416587 Reactome, http://www.reactome.org ReactomeREACT_19721 has a Stoichiometric coefficient of 1 R-Ras-GDP Reactome DB_ID: 399866 Reactome Database ID Release 43399866 Reactome, http://www.reactome.org ReactomeREACT_20329 has a Stoichiometric coefficient of 1 Sema4D:Plexin-B1:p190RhoGAP:Rac:Rnd1 Reactome DB_ID: 416601 Reactome Database ID Release 43416601 Reactome, http://www.reactome.org ReactomeREACT_19579 has a Stoichiometric coefficient of 1 Plexin-B1:ErbB2 Reactome DB_ID: 419629 Reactome Database ID Release 43419629 Reactome, http://www.reactome.org ReactomeREACT_19954 has a Stoichiometric coefficient of 1 CNOT6 or CNOT6L Converted from EntitySet in Reactome Homologues of Ccr4 Reactome DB_ID: 429962 Reactome Database ID Release 43429962 Reactome, http://www.reactome.org ReactomeREACT_21088 SEMA4D:pPlexin-B1:ErbB2 complex Reactome DB_ID: 373695 Reactome Database ID Release 43373695 Reactome, http://www.reactome.org ReactomeREACT_20256 has a Stoichiometric coefficient of 1 pPlexin-B1:ErbB2 Reactome DB_ID: 419627 Reactome Database ID Release 43419627 Reactome, http://www.reactome.org ReactomeREACT_20079 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0016274 Reactome Database ID Release 43191843 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008173 Reactome Database ID Release 43192210 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4368401 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43159593 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 4368385 Reactome, http://www.reactome.org Sema3A:NRP-1:pPlexin-A:fyn Reactome DB_ID: 419622 Reactome Database ID Release 43419622 Reactome, http://www.reactome.org ReactomeREACT_20191 has a Stoichiometric coefficient of 1 Sema3A:NRP-1:pPlexin-A:Fyn:Fes Reactome DB_ID: 399859 Reactome Database ID Release 43399859 Reactome, http://www.reactome.org ReactomeREACT_19958 has a Stoichiometric coefficient of 1 NRP-1:PlexinA:Fyn Reactome DB_ID: 399841 Reactome Database ID Release 43399841 Reactome, http://www.reactome.org ReactomeREACT_19632 has a Stoichiometric coefficient of 1 Sema3A:Nrp-1:Plexin A:Fyn Reactome DB_ID: 399858 Reactome Database ID Release 43399858 Reactome, http://www.reactome.org ReactomeREACT_19816 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0003899 Reactome Database ID Release 4368509 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003887 Reactome Database ID Release 4368508 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016301 Reactome Database ID Release 43141607 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org Sema3A dimer Reactome DB_ID: 399861 Reactome Database ID Release 43399861 Reactome, http://www.reactome.org ReactomeREACT_19939 has a Stoichiometric coefficient of 2 Nrp-1 complexed with PlexinA:FARP2:Fyn Reactome DB_ID: 399837 Reactome Database ID Release 43399837 Reactome, http://www.reactome.org ReactomeREACT_20390 has a Stoichiometric coefficient of 1 Plexin-A:Fyn:FARP2 Reactome DB_ID: 421116 Reactome Database ID Release 43421116 Reactome, http://www.reactome.org ReactomeREACT_20044 has a Stoichiometric coefficient of 1 SEMA4D:CD45 complex Reactome DB_ID: 373689 Reactome Database ID Release 43373689 Reactome, http://www.reactome.org ReactomeREACT_19862 has a Stoichiometric coefficient of 1 Plexin-A:Fyn Reactome DB_ID: 399844 Reactome Database ID Release 43399844 Reactome, http://www.reactome.org ReactomeREACT_19507 has a Stoichiometric coefficient of 1 Phospho-activated smooth muscle/non-muscle myosin 2 Reactome DB_ID: 419195 Reactome Database ID Release 43419195 Reactome, http://www.reactome.org ReactomeREACT_19704 has a Stoichiometric coefficient of 2 SEMA4D:CD72 complex Reactome DB_ID: 373697 Reactome Database ID Release 43373697 Reactome, http://www.reactome.org ReactomeREACT_20194 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0003743 Reactome Database ID Release 4372620 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003743 Reactome Database ID Release 4372620 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 4372598 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004386 Reactome Database ID Release 4372599 Reactome, http://www.reactome.org pLIMK dimer:HSP-90 Reactome DB_ID: 419632 Reactome Database ID Release 43419632 Reactome, http://www.reactome.org ReactomeREACT_19543 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Sema3A:Nrp-1:PlexinA:Rac1-GTP:pPAK Reactome DB_ID: 399874 Reactome Database ID Release 43399874 Reactome, http://www.reactome.org ReactomeREACT_19495 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 43159651 Reactome, http://www.reactome.org pCofilin: Active LIMK-1 Reactome DB_ID: 399878 Reactome Database ID Release 43399878 Reactome, http://www.reactome.org ReactomeREACT_20103 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0000048 Reactome Database ID Release 43159645 Reactome, http://www.reactome.org Active LIMK1 Reactome DB_ID: 419630 Reactome Database ID Release 43419630 Reactome, http://www.reactome.org ReactomeREACT_19790 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265014 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019001 Reactome Database ID Release 43159619 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003743 Reactome Database ID Release 4372528 Reactome, http://www.reactome.org Sema3A:Nrp-1:PlexinA:Rac1-GTP:PAK Reactome DB_ID: 399876 Reactome Database ID Release 43399876 Reactome, http://www.reactome.org ReactomeREACT_20083 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43156822 Reactome, http://www.reactome.org FARP2:PIP5KIgamma Reactome DB_ID: 399839 Reactome Database ID Release 43399839 Reactome, http://www.reactome.org ReactomeREACT_19748 has a Stoichiometric coefficient of 1 eIF4A Converted from EntitySet in Reactome Reactome DB_ID: 429842 Reactome Database ID Release 43429842 Reactome, http://www.reactome.org ReactomeREACT_21151 PAK homodimer Reactome DB_ID: 399856 Reactome Database ID Release 43399856 Reactome, http://www.reactome.org ReactomeREACT_19479 has a Stoichiometric coefficient of 2 NRP-1:pPlexin-A:Fyn Reactome DB_ID: 419625 Reactome Database ID Release 43419625 Reactome, http://www.reactome.org ReactomeREACT_20331 has a Stoichiometric coefficient of 1 Sema3A:Nrp-1:pPlexinA:Fyn:Fes:Rac-1-GTP Reactome DB_ID: 399872 Reactome Database ID Release 43399872 Reactome, http://www.reactome.org ReactomeREACT_20187 has a Stoichiometric coefficient of 1 Sema3A:Nrp-1:pPlexinA:Fyn:Fes:Rac-1-GTP:Rnd1 Reactome DB_ID: 399877 Reactome Database ID Release 43399877 Reactome, http://www.reactome.org ReactomeREACT_19802 has a Stoichiometric coefficient of 1 PIP5K1gamma:Talin-1 Reactome DB_ID: 398218 Reactome Database ID Release 43398218 Reactome, http://www.reactome.org ReactomeREACT_19891 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004629 Reactome Database ID Release 43139824 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43434837 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004676 Reactome Database ID Release 43437273 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046934 Reactome Database ID Release 43437156 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43939267 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43354106 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004725 Reactome Database ID Release 43210705 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43442279 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43442283 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43442310 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004930 Reactome Database ID Release 43139932 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004930 Reactome Database ID Release 43139932 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43139890 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43453305 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 43437943 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 43453196 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43139843 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43870419 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003924 Reactome Database ID Release 432206199 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43432080 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43432078 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004715 Reactome Database ID Release 43870418 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43432134 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43432075 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43428962 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005388 Reactome Database ID Release 43427907 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015279 Reactome Database ID Release 43434796 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005432 Reactome Database ID Release 43425666 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005388 Reactome Database ID Release 43418310 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005261 Reactome Database ID Release 43426224 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005262 Reactome Database ID Release 43139849 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005262 Reactome Database ID Release 43139847 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004692 Reactome Database ID Release 43418433 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004692 Reactome Database ID Release 43418433 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047555 Reactome Database ID Release 43418559 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004383 Reactome Database ID Release 43392149 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004517 Reactome Database ID Release 43419299 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43432083 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004693 Reactome Database ID Release 432311326 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004222 Reactome Database ID Release 431251962 Reactome, http://www.reactome.org Cathepsin D dimer Reactome DB_ID: 2471622 Reactome Database ID Release 432471622 Reactome, http://www.reactome.org ReactomeREACT_152347 has a Stoichiometric coefficient of 1 Collagen alpha-6(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127391 Reactome Database ID Release 432127391 Reactome, http://www.reactome.org ReactomeREACT_123417 Cleaved collagen type XIII Reactome DB_ID: 2471865 Reactome Database ID Release 432471865 Reactome, http://www.reactome.org ReactomeREACT_151119 has a Stoichiometric coefficient of 3 Cathepsin B dimer Reactome DB_ID: 2471613 Reactome Database ID Release 432471613 Reactome, http://www.reactome.org ReactomeREACT_151626 has a Stoichiometric coefficient of 1 Fibrillins:MFAP2,MFAP5:Tropoelastin aggregate Reactome DB_ID: 2161254 Reactome Database ID Release 432161254 Reactome, http://www.reactome.org ReactomeREACT_151465 has a Stoichiometric coefficient of 1 Tropoelastin aggregate Reactome DB_ID: 2161342 Reactome Database ID Release 432161342 Reactome, http://www.reactome.org ReactomeREACT_150727 has a Stoichiometric coefficient of 10 Fibrilins:MFAP2,MFAP5 Reactome DB_ID: 2396329 Reactome Database ID Release 432396329 Reactome, http://www.reactome.org ReactomeREACT_151869 has a Stoichiometric coefficient of 1 Fibrilin-1:Fibrilin-binding integrins Reactome DB_ID: 2396200 Reactome Database ID Release 432396200 Reactome, http://www.reactome.org ReactomeREACT_151729 has a Stoichiometric coefficient of 1 Fibrilin-binding integrins Converted from EntitySet in Reactome Reactome DB_ID: 2396352 Reactome Database ID Release 432396352 Reactome, http://www.reactome.org ReactomeREACT_150923 Cleaved collagen type XXV Reactome DB_ID: 2473532 Reactome Database ID Release 432473532 Reactome, http://www.reactome.org ReactomeREACT_151359 has a Stoichiometric coefficient of 3 Cleaved collagen type XXIII Reactome DB_ID: 2473492 Reactome Database ID Release 432473492 Reactome, http://www.reactome.org ReactomeREACT_150891 has a Stoichiometric coefficient of 3 Collagen type XXIII Reactome DB_ID: 2172426 Reactome Database ID Release 432172426 Reactome, http://www.reactome.org ReactomeREACT_152282 has a Stoichiometric coefficient of 3 MMP14:TIMP2 Reactome DB_ID: 1604365 Reactome Database ID Release 431604365 Reactome, http://www.reactome.org ReactomeREACT_120170 has a Stoichiometric coefficient of 1 MMP14:TIMP2:proMMP2 Reactome DB_ID: 1604369 Reactome Database ID Release 431604369 Reactome, http://www.reactome.org ReactomeREACT_119067 has a Stoichiometric coefficient of 1 MMP14:TIMP2:MMP2 intermediate form Reactome DB_ID: 1604373 Reactome Database ID Release 431604373 Reactome, http://www.reactome.org ReactomeREACT_118865 has a Stoichiometric coefficient of 1 Cleaved collagen type XIV Reactome DB_ID: 2470788 Reactome Database ID Release 432470788 Reactome, http://www.reactome.org ReactomeREACT_151586 has a Stoichiometric coefficient of 3 Cleaved collagen type XII Reactome DB_ID: 2470728 Reactome Database ID Release 432470728 Reactome, http://www.reactome.org ReactomeREACT_151439 has a Stoichiometric coefficient of 3 Cathepsin L1 dimer Reactome DB_ID: 449862 Reactome Database ID Release 43449862 Reactome, http://www.reactome.org ReactomeREACT_150887 has a Stoichiometric coefficient of 1 Cleaved tropocollagen type XVI Reactome DB_ID: 2470823 Reactome Database ID Release 432470823 Reactome, http://www.reactome.org ReactomeREACT_151587 has a Stoichiometric coefficient of 3 Chymotrypsin B Reactome DB_ID: 1604751 Reactome Database ID Release 431604751 Reactome, http://www.reactome.org ReactomeREACT_119053 has a Stoichiometric coefficient of 1 MMP14:TIMP:MMP2 Reactome DB_ID: 1604349 Reactome Database ID Release 431604349 Reactome, http://www.reactome.org ReactomeREACT_119984 has a Stoichiometric coefficient of 1 Cleaved collagen type IX Reactome DB_ID: 2470424 Reactome Database ID Release 432470424 Reactome, http://www.reactome.org ReactomeREACT_151104 has a Stoichiometric coefficient of 1 Chymotrypsin B2 Reactome DB_ID: 1604683 Reactome Database ID Release 431604683 Reactome, http://www.reactome.org ReactomeREACT_119553 has a Stoichiometric coefficient of 1 Digestion of diacylglycerols by extracellular PTL:colipase Authored: D'Eustachio, P, 2007-02-02 21:43:49 EC Number: 3.1.1.23 Pancreatic lipase catalyzes the hydrolysis of extracellular dicylglycerols to yield monoacylglycerols and long-chain fatty acids. The enzyme is active only when complexed with colipase protein and plays a major role in the digestion of dietary diacylglycerols in the small intestine (Carriere et al. 2000; Giller et al. 1992). Pubmed11040182 Pubmed1379598 Reactome Database ID Release 43192434 Reactome, http://www.reactome.org ReactomeREACT_9457 Digestion of triacylglycerols by extracellular CEL (bile salt-dependent lipase) Authored: D'Eustachio, P, 2007-02-02 21:43:49 CEL (bile salt-dependent lipase) catalyzes the hydrolysis of extracellular monoacylglycerols to yield glycerol and a long-chain fatty acid. This reaction, in the lumen of the small intestine, is essential for the complete digestion of milk-derived triacylglycerols in the nursing infant (Bernback et al. 1990). Its importance in adult fat digestion is unclear.<p>While alternative splicing gives rise to two CEL isoforms, only the longer one encodes all of the residues that form the active site of the enzyme (Reue et al. 1991). In vitro, monomeric CEL protein is active even in the absence of bile salts. its activity is greatly increased when it is complexed with two molecules of cholate, chenodeoxycholate, or their glycine or taurine conjugates (Lombardo and Guy 1980), and the predominant form of the enzyme active on lipid micelles in the gut is a dimer of two such complexes (Aubert-Jousset et al. 2004).<p>CEL is synthesized in pancreatic acinar cells and released into the small intestine. It is also synthesized in the mammary gland and is a constituent of breast milk (Lombardo 2001; Bernback et al. 1990). EC Number: 3.1.1.23 Pubmed11514232 Pubmed15265857 Pubmed2066663 Pubmed2318975 Pubmed7350912 Pubmed7350913 Reactome Database ID Release 43192430 Reactome, http://www.reactome.org ReactomeREACT_9412 Digestion of cholesterol esters by extracellular CEL (bile salt-dependent lipase) Authored: D'Eustachio, P, 2007-02-02 21:43:49 CEL (bile salt-dependent lipase) catalyzes the hydrolysis of extracellular cholesterol esters to yield cholesterol and a long-chain fatty acid. This reaction, in the lumen of the small intestine, is part of the process of digestion of dietary fats.<p>While alternative splicing gives rise to two CEL isoforms, only the longer one encodes all of the residues that form the active site of the enzyme (Reue et al. 1991). In vitro, monomeric CEL protein is active even in the absence of bile salts. Its activity is greatly increased when it is complexed with two molecules of cholate, chenodeoxycholate, or their glycine or taurine conjugates (Lombardo and Guy 1980), and the predominant form of the enzyme active on lipid micelles in the gut is a dimer of two such complexes (Aubert-Jousset et al. 2004).<p>CEL is synthesized in pancreatic acinar cells and released into the small intestine. It is also synthesized in the mammary gland and is a constituent of breast milk. The milk CEL is thought to play a role in digestion of milk fat in newborn infants, whose own pancreatic synthesis of the enzyme is low (Lombardo 2001; Bernback et al. 1990). EC Number: 3.1.1.13 Pubmed11514232 Pubmed15265857 Pubmed2066663 Pubmed2318975 Pubmed7350913 Reactome Database ID Release 43192417 Reactome, http://www.reactome.org ReactomeREACT_9468 Digestion of monoacylglycerols by extracellular CEL (bile salt-dependent lipase) Authored: D'Eustachio, P, 2007-02-02 21:43:49 CEL (bile salt-dependent lipase) catalyzes the hydrolysis of extracellular monoacylglycerols to yield glycerol and a long-chain fatty acid. This reaction, in the lumen of the small intestine, is essential for the complete digestion of milk-derived triacylglycerols in the nursing infant (Bernback et al. 1990). Its importance in adult fat digestion is unclear.<p>While alternative splicing gives rise to two CEL isoforms, only the longer one encodes all of the residues that form the active site of the enzyme (Reue et al. 1991). In vitro, monomeric CEL protein is active even in the absence of bile salts. its activity is greatly increased when it is complexed with two molecules of cholate, chenodeoxycholate, or their glycine or taurine conjugates (Lombardo and Guy 1980), and the predominant form of the enzyme active on lipid micelles in the gut is a dimer of two such complexes (Aubert-Jousset et al. 2004).<p>CEL is synthesized in pancreatic acinar cells and released into the small intestine. It is also synthesized in the mammary gland and is a constituent of breast milk (Lombardo 2001; Bernback et al. 1990). EC Number: 3.1.1.23 Pubmed11514232 Pubmed15265857 Pubmed2066663 Pubmed2318975 Pubmed7350913 Reactome Database ID Release 43192425 Reactome, http://www.reactome.org ReactomeREACT_9502 Glc6P is isomerised to I3P by ISYNA1 in the cytosol Authored: Williams, MG, 2011-10-28 EC Number: 5.5.1.4 Edited: Williams, MG, 2011-10-28 Inositol-3-phosphate synthase 1 (ISYNA1) aka hIPS isomerises glucose 6-phosphate (Glc6P) to inositol 3-phosphate (I3P) (Ju et al. 2004). Pubmed15024000 Reactome Database ID Release 431855178 Reactome, http://www.reactome.org ReactomeREACT_150300 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I3P is dephosphorylated to Ins by IMPA1/2 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol monophosphatase 1 (IMPA1) and 2 (IMPA2) homodimers dephosphorylate inositol 3-phosphate (I3P) to inositol (Ins). In vitro, IMPA1 and 2 differ in their pH optima and IMPA1 has a significantly greater activity on IP4 than does IMPA2 (Ohnishi et al. 2007). Pubmed17068342 Reactome Database ID Release 431855210 Reactome, http://www.reactome.org ReactomeREACT_150231 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,3,4)P3 is dephosphorylated to I(3,4)P2 by INPP1 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol polyphosphate 1-phosphatase (INPP1) dephosphorylates inositol 1,3,4-trisphosphate (I(1,3,4)P3) to inositol 3,4-bisphosphate (I(3,4)P2) (York et al. 1993). Pubmed8390685 Reactome Database ID Release 431855232 Reactome, http://www.reactome.org ReactomeREACT_150176 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(3,4)P2 is dephosphorylated to I3P by INPP4A/B in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Pubmed7608176 Pubmed9295334 Reactome Database ID Release 431855202 Reactome, http://www.reactome.org ReactomeREACT_150323 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Type I (INPP4A) and type II inositol-3,4-bisphosphate 4-phosphatase (INPP4B) dephosphorylate inositol 3,4-bisphosphate (I(3,4)P2) to inositol 3-phosphate (I3P) (Norris et al. 1995, Norris et al. 1997). I1P is dephosphorylated to Ins by IMPA1/2 in the cytosol Authored: Williams, MG, 2011-10-28 EC Number: 3.1.3.25 Edited: Williams, MG, 2011-10-28 Inositol monophosphatase 1 (IMPA1) and 2 (IMPA2) homodimers dephosphorylate inositol 1-phosphate (I1P) to inositol (Ins). In vitro, IMPA1 and 2 differ in their pH optima and IMPA1 has a significantly greater activity on IP4 than does IMPA2 (McAllister et al. 1992, Ohnishi et al. 2007). Pubmed1377913 Pubmed17068342 Reactome Database ID Release 431855154 Reactome, http://www.reactome.org ReactomeREACT_150218 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,3,4)P3 is dephosphorylated to I(1,3)P2 by INPP4A/B in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Pubmed7608176 Pubmed9295334 Reactome Database ID Release 431855180 Reactome, http://www.reactome.org ReactomeREACT_150198 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Type I (INPP4A) and type II inositol-3,4-bisphosphate 4-phosphatase (INPP4B) dephosphorylate inositol 1,3,4-trisphosphate (I(1,3,4)P3) to inositol 1,3-bisphosphate (I(1,3)P2) (Norris et al. 1995, Norris et al. 1997). LAP3-binding integrins Converted from EntitySet in Reactome Reactome DB_ID: 2396408 Reactome Database ID Release 432396408 Reactome, http://www.reactome.org ReactomeREACT_151258 TGF-beta-1:LAP1:LAP1-binding integrins Reactome DB_ID: 2396201 Reactome Database ID Release 432396201 Reactome, http://www.reactome.org ReactomeREACT_150875 has a Stoichiometric coefficient of 1 Integrin alphaVbeta5 Reactome DB_ID: 1299497 Reactome Database ID Release 431299497 Reactome, http://www.reactome.org ReactomeREACT_111337 has a Stoichiometric coefficient of 1 LAP1 binding-integrins Converted from EntitySet in Reactome Reactome DB_ID: 2396176 Reactome Database ID Release 432396176 Reactome, http://www.reactome.org ReactomeREACT_151153 Elastic fibre with associated proteins Reactome DB_ID: 2161325 Reactome Database ID Release 432161325 Reactome, http://www.reactome.org ReactomeREACT_151681 has a Stoichiometric coefficient of 1 LTBPs:Fibrillin-1 Reactome DB_ID: 2396177 Reactome Database ID Release 432396177 Reactome, http://www.reactome.org ReactomeREACT_150481 has a Stoichiometric coefficient of 1 Fibrillins:BMP2,4,7,10,GF5 Reactome DB_ID: 2396217 Reactome Database ID Release 432396217 Reactome, http://www.reactome.org ReactomeREACT_152006 has a Stoichiometric coefficient of 1 TGF-beta-3:LAP3:LAP3-binding integrins Reactome DB_ID: 2396121 Reactome Database ID Release 432396121 Reactome, http://www.reactome.org ReactomeREACT_150873 has a Stoichiometric coefficient of 1 Plexin-B1:Met Reactome DB_ID: 419634 Reactome Database ID Release 43419634 Reactome, http://www.reactome.org ReactomeREACT_19866 has a Stoichiometric coefficient of 1 I4P is dephosphorylated to Ins by IMPA1/2 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol monophosphatase 1 (IMPA1) and 2 (IMPA2) homodimers dephosphorylate inositol 4-phosphate (I4P) to inositol (Ins). In vitro, IMPA1 and 2 differ in their pH optima and IMPA1 has a significantly greater activity on IP4 than does IMPA2 (Ohnishi et al. 2007). Pubmed17068342 Reactome Database ID Release 431855211 Reactome, http://www.reactome.org ReactomeREACT_150193 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 SEMA4D dimer Reactome DB_ID: 373690 Reactome Database ID Release 43373690 Reactome, http://www.reactome.org ReactomeREACT_19817 has a Stoichiometric coefficient of 2 IP6 transports from the nucleus to the ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,2,3,4,5,6-hexakisphosphate (IP6) translocates from the nucleus to the endoplasmic reticulum (ER) lumen (Caffrey et al. 1999). Pubmed9923613 Reactome Database ID Release 431855187 Reactome, http://www.reactome.org ReactomeREACT_150257 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,4,5)P3 is dephosphorylated to I(1,4)P2 by INPP5(4) in the cytosol A group of inositol phosphatases dephosphorylate inositol 1,4,5-trisphosphate (I(1,4,5)P3) to inositol 1,4-bisphosphate (I(1,4)P2). The group of inositol phosphatases involved are: inositol polyphosphate 5-phosphatase OCRL-1 (OCRL), phosphatidylinositol 4,5-bisphosphate 5-phosphatase A (INPP5J), and synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 (SYNJ1).<br><br>The following lists the above proteins with their corresponding literature references: OCRL (Zhang et al. 1995, Zhang et al. 1998, Schmid et al. 2004); INPP5J (Mochizuki & Thompson 1999); SYNJ1 (Schmid et al. 2004). Authored: Williams, MG, 2011-10-28 EC Number: 3.1.3.56 Edited: Williams, MG, 2011-10-28 Pubmed10593988 Pubmed15474001 Pubmed7761412 Pubmed9430698 Reactome Database ID Release 431855174 Reactome, http://www.reactome.org ReactomeREACT_150347 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,4,5)P3 is dephosphorylated to I(1,4)P2 by INPP5A/B at the plasma membrane Authored: Williams, MG, 2011-10-28 EC Number: 3.1.3.56 Edited: Williams, MG, 2011-10-28 Pubmed15474001 Pubmed1718960 Pubmed7721860 Pubmed8006039 Reactome Database ID Release 431855222 Reactome, http://www.reactome.org ReactomeREACT_150429 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Type I inositol-1,4,5-trisphosphate 5-phosphatase (INPP5A) and the Type II phosphatase (INPP5B) are isoprenylated to the plasma membrane and act as a lipid anchor. Here they dephosphorylate inositol 1,4,5-trisphosphate (I(1,4,5)P3) to inositol 1,4-bisphosphate I(1,4)P2. ).<br><br>The following lists the above proteins with their corresponding literature references: INPP5A (Laxminarayan et al. 1994); INPP5B (Jefferson & Majerus 1995, Ross et al. 1991, Schmid et al. 2004). I(1,4)P2 is dephosphorylated to I4P by INPP1 in the cytosol Authored: Williams, MG, 2011-10-28 EC Number: 3.1.3.57 Edited: Williams, MG, 2011-10-28 Inositol polyphosphate 1-phosphatase (INPP1) dephosphorylates inositol 1,4-bisphosphate (I(1,4)P2) to inositol 4-phosphate (I4P) (York et al. 1993). Pubmed8390685 Reactome Database ID Release 431855208 Reactome, http://www.reactome.org ReactomeREACT_150296 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,4,5)P3 transports from the ER lumen to the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,4,5-trisphosphate (I(1,4,5)P3) translocates from the endoplasmic reticulum (ER) lumen to the cytosol (Caffrey et al. 1999, Chi et al. 1999). Pubmed10087200 Pubmed9923613 Reactome Database ID Release 431855217 Reactome, http://www.reactome.org ReactomeREACT_150270 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,3,4,5,6)P5 transports from the ER lumen to the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,3,4,5,6-pentakisphosphate I(1,3,4,5,6)P5 translocates from the endoplasmic reticulum (ER) lumen to the cytosol (Nalaskowski et al. 2002, Ho et al. 2002, Brehm et al. 2007). Pubmed11909533 Pubmed12027805 Pubmed17705785 Reactome Database ID Release 431855155 Reactome, http://www.reactome.org ReactomeREACT_150404 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,4,5,6)P4 transports from the ER lumen to the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,4,5,6-tetrakisphosphate (I(1,4,5,6)P4) translocates from the endoplasmic reticulum (ER) lumen to the nucleus (Caffrey et al. 1999, Chi et al. 1999, Nalaskowski et al. 2002). Pubmed10087200 Pubmed12027805 Pubmed9923613 Reactome Database ID Release 431855189 Reactome, http://www.reactome.org ReactomeREACT_150284 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,3,4,5,6)P5 transports from the ER lumen to the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) translocates from the endoplasmic reticulum (ER) lumen to the nucleus (Verbsky et al. 2002, Brehm et al. 2007, Choi et al. 2007). Pubmed12084730 Pubmed17702752 Pubmed17705785 Reactome Database ID Release 431855160 Reactome, http://www.reactome.org ReactomeREACT_150233 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 IP6 is dephosphorylated to I(1,2,4,5,6)P5 by MINPP1 in the ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the endoplasmic reticulum (ER) lumen, multiple inositol polyphosphate phosphatase 1 (MINPP1) dephosphorylates 1,2,3,4,5,6-hexakisphosphate (IP6) to inositol 1,2,4,5,6-pentakisphosphate (I(1,2,4,5,6)P5) (Caffrey et al. 1999, Chi et al. 1999, Deleu et al. 2006, Nogimori et al. 1991). Pubmed10087200 Pubmed15979280 Pubmed1653239 Pubmed9923613 Reactome Database ID Release 431855225 Reactome, http://www.reactome.org ReactomeREACT_150382 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Elastic fibre Reactome DB_ID: 2161360 Reactome Database ID Release 432161360 Reactome, http://www.reactome.org ReactomeREACT_151836 has a Stoichiometric coefficient of 1 Elastic fibre:Fibulins Reactome DB_ID: 2395337 Reactome Database ID Release 432395337 Reactome, http://www.reactome.org ReactomeREACT_152532 has a Stoichiometric coefficient of 1 FBLN1, FBLN2:Fibronectin matrix Reactome DB_ID: 2537655 Reactome Database ID Release 432537655 Reactome, http://www.reactome.org ReactomeREACT_152335 has a Stoichiometric coefficient of 1 TGF betas:LAPs Converted from EntitySet in Reactome Reactome DB_ID: 2395330 Reactome Database ID Release 432395330 Reactome, http://www.reactome.org ReactomeREACT_150990 Elastic fibre:Fibulins:Emilins Reactome DB_ID: 2396077 Reactome Database ID Release 432396077 Reactome, http://www.reactome.org ReactomeREACT_151799 has a Stoichiometric coefficient of 1 TGF-beta-2:LAP2 Reactome DB_ID: 2395253 Reactome Database ID Release 432395253 Reactome, http://www.reactome.org ReactomeREACT_150813 has a Stoichiometric coefficient of 1 TGF-beta-1:LAP1 Reactome DB_ID: 2395236 Reactome Database ID Release 432395236 Reactome, http://www.reactome.org ReactomeREACT_151208 has a Stoichiometric coefficient of 1 I(1,3,4,5,6)P5 is dephosphorylated to I(1,4,5,6)P4 by MINPP1 in the ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the endoplasmic reticulum (ER) lumen, multiple inositol polyphosphate phosphatase 1 (MINPP1) dephosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 1,4,5,6-tetrakisphosphate (I(1,4,5,6)P4) (Caffrey et al. 1999, Chi et al. 1999). Pubmed10087200 Pubmed9923613 Reactome Database ID Release 431855163 Reactome, http://www.reactome.org ReactomeREACT_150329 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 LTBP1, LTBP3:TGF betas:LAPs Reactome DB_ID: 2395250 Reactome Database ID Release 432395250 Reactome, http://www.reactome.org ReactomeREACT_151500 has a Stoichiometric coefficient of 1 I(1,3,4,5)P4 is dephosphorylated to I(1,4,5)P3 by MINPP1 in the ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the endoplasmic reticulum (ER) lumen, multiple inositol polyphosphate phosphatase 1 (MINPP1) dephosphorylates inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,4,5-trisphosphate (I(1,4,5)P3) (Caffrey et al. 1999, Chi et al. 1999). Pubmed10087200 Pubmed9923613 Reactome Database ID Release 431855200 Reactome, http://www.reactome.org ReactomeREACT_150358 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 TGF-beta-3:LAP3 Reactome DB_ID: 2395241 Reactome Database ID Release 432395241 Reactome, http://www.reactome.org ReactomeREACT_151912 has a Stoichiometric coefficient of 1 LTBP4:TGF-beta-1:LAP1 Reactome DB_ID: 2395326 Reactome Database ID Release 432395326 Reactome, http://www.reactome.org ReactomeREACT_151063 has a Stoichiometric coefficient of 1 IP6 transports from the cytosol to the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,2,3,4,5,6-hexakisphosphate (IP6) translocates from the cytosol to the nucleus (Saiardi et al. 2001). Pubmed11502751 Reactome Database ID Release 431855188 Reactome, http://www.reactome.org ReactomeREACT_150151 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 (PP)2-IP4 is dephosphorylated to 1/3-PP-IP5 by NUDT(1) in the cytosol Authored: Williams, MG, 2011-10-28 Diphosphoinositol polyphosphate phosphohydrolases (DIPP), also known as nucleoside diphosphate-linked moiety X motif (NUDT) proteins, dephosphorylate inositol bisdiphospho-tetrakisphosphate ((PP)2-IP4) to inositol diphospho-pentakisphosphate (PP-IP5). The NUDT proteins involved are: nucleoside diphosphate-linked moiety X motif 3 (NUDT3), 4 (NUDT4), 10 (NUDT10), and 11 (NUDT11). The reactants consumed are: inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) and inositol 3,5-bisdiphospho-1,2,4,6-tetrakisphosphate (3,5-(PP)2-IP4). The products made are: inositol 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) and 3-diphospho-1,2,4,5,6-pentakisphosphate (3-PP-IP5).<br><br>The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002). Edited: Williams, MG, 2011-10-28 Pubmed10419486 Pubmed10585413 Pubmed10777568 Pubmed12105228 Pubmed12121577 Pubmed9822604 Reactome Database ID Release 432023973 Reactome, http://www.reactome.org ReactomeREACT_150371 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 1-PP-IP5 is phosphorylated to 1,5-(PP)2-IP4 by IP6K1/3 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) to form inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) (Saiardi et al. 2001, Mulugu et al. 2007). Pubmed11502751 Pubmed17412958 Reactome Database ID Release 431855194 Reactome, http://www.reactome.org ReactomeREACT_150348 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 (PP)2-IP4 is dephosphorylated to 5-PP-IP5 by NUDT(1) in the cytosol Authored: Williams, MG, 2011-10-28 Diphosphoinositol polyphosphate phosphohydrolases (DIPP), also known as nucleoside diphosphate-linked moiety X motif (NUDT) proteins, dephosphorylate inositol bisdiphospho-tetrakisphosphate ((PP)2-IP4) to inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5). The NUDT proteins involved are: nucleoside diphosphate-linked moiety X motif 3 (NUDT3), 4 (NUDT4), 10 (NUDT10), and 11 (NUDT11). The reactants consumed are: inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) and inositol 3,5-bisdiphospho-1,2,4,6-tetrakisphosphate (3,5-(PP)2-IP4).<br><br>The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002). Edited: Williams, MG, 2011-10-28 Pubmed10419486 Pubmed10585413 Pubmed10777568 Pubmed12105228 Pubmed12121577 Pubmed9822604 Reactome Database ID Release 431855165 Reactome, http://www.reactome.org ReactomeREACT_150184 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Tropocollagen type XI Reactome DB_ID: 2142910 Reactome Database ID Release 432142910 Reactome, http://www.reactome.org ReactomeREACT_123232 has a Stoichiometric coefficient of 1 IP6 transports from the cytosol to the ER lumen 1,2,3,4,5,6-hexakisphosphate (IP6) translocates from the cytosol to the endoplasmic reticulum (ER) lumen (Caffrey et al. 1999). Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Pubmed9923613 Reactome Database ID Release 431855164 Reactome, http://www.reactome.org ReactomeREACT_150393 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Tropocollagen alpha-3(V) Reactome DB_ID: 2127296 Reactome Database ID Release 432127296 Reactome, http://www.reactome.org ReactomeREACT_122288 has a Stoichiometric coefficient of 3 I(1,3,4,5,6)P5 transports from the cytosol to the ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,3,4,5,6-pentakisphosphate I(1,3,4,5,6)P5 translocates from the cytosol to the endoplasmic reticulum (ER) lumen (Caffrey et al. 1999, Chi et al. 1999). Pubmed10087200 Pubmed9923613 Reactome Database ID Release 431855195 Reactome, http://www.reactome.org ReactomeREACT_150140 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Tropocollagen alpha-1-3(V) Reactome DB_ID: 2127310 Reactome Database ID Release 432127310 Reactome, http://www.reactome.org ReactomeREACT_122400 has a Stoichiometric coefficient of 1 Collagen alpha-3(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127311 Reactome Database ID Release 432127311 Reactome, http://www.reactome.org ReactomeREACT_122940 I(1,3,4,5)P4 transports from the cytosol to the ER lumen Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) translocates from the cytosol to the endoplasmic reticulum (ER) lumen (Caffrey et al. 1999, Chi et al. 1999). Pubmed10087200 Pubmed9923613 Reactome Database ID Release 431855186 Reactome, http://www.reactome.org ReactomeREACT_150413 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Tropocollagen alpha-1(V)X2 alpha-2(V) Reactome DB_ID: 2127308 Reactome Database ID Release 432127308 Reactome, http://www.reactome.org ReactomeREACT_124349 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 1/3-PP-IP5 transports from the cytosol to the nucleus 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) and 3-diphospho-1,2,4,5,6-pentakisphosphate (3-PP-IP5) translocate from the cytosol to the nucleus (Saiardi et al. 2001, Mulugu et al. 2007). Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Pubmed11502751 Pubmed17412958 Reactome Database ID Release 431855212 Reactome, http://www.reactome.org ReactomeREACT_150212 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Tropocollagen type V Converted from EntitySet in Reactome Reactome DB_ID: 2127422 Reactome Database ID Release 432127422 Reactome, http://www.reactome.org ReactomeREACT_123314 5-PP-IP5 is phosphorylated to 1,5-(PP)2-IP4 by PPIP5K1/2 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1/2 (PPIP5K1) and 2 (PPIP5K2) phosphorylate inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) to inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) (Fridy et al. 2007, Mulugu et al. 2007, Choi et al. 2007, Lin et al. 2009). Pubmed17412958 Pubmed17690096 Pubmed17702752 Pubmed18981179 Reactome Database ID Release 431855182 Reactome, http://www.reactome.org ReactomeREACT_150291 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43139890 Reactome, http://www.reactome.org Collagen type VII dimer Reactome DB_ID: 2214316 Reactome Database ID Release 432214316 Reactome, http://www.reactome.org ReactomeREACT_150771 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43139890 Reactome, http://www.reactome.org Collagen type VII Reactome DB_ID: 2214323 Reactome Database ID Release 432214323 Reactome, http://www.reactome.org ReactomeREACT_152256 has a Stoichiometric coefficient of 3 1/3 PP-IP5 is dephosphorylated to IP6 by NUDT(1) in the cytosol Authored: Williams, MG, 2011-10-28 Diphosphoinositol polyphosphate phosphohydrolases, also known as nucleoside diphosphate-linked moiety X motif (NUDT) proteins, dephosphorylate inositol diphospho-pentakisphosphate (PP-IP5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6). The NUDT proteins involved are: nucleoside diphosphate-linked moiety X motif 3 (NUDT3), 4 (NUDT4), 10 (NUDT10), and 11 (NUDT11). The reactants consumed are: inositol 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) and 3-diphospho-1,2,4,5,6-pentakisphosphate (3-PP-IP5).<br><br>The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002). Edited: Williams, MG, 2011-10-28 Pubmed10419486 Pubmed10585413 Pubmed10777568 Pubmed12105228 Pubmed12121577 Pubmed9822604 Reactome Database ID Release 432023971 Reactome, http://www.reactome.org ReactomeREACT_150167 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 TLL2:PCPE1 Reactome DB_ID: 2002434 Reactome Database ID Release 432002434 Reactome, http://www.reactome.org ReactomeREACT_122653 has a Stoichiometric coefficient of 1 5-PP-IP5 is phosphorylated to 5-PPP-IP5 by IP6K1/3 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) to inositol 5-triphospho- 1,2,3,4,6-pentakisphosphate (5-PPP-IP5).<br><br>The following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Draskovic et al. 2008) and IP6K3 (Saiardi et al. 2001, Draskovic et al. 2008). Pubmed11502751 Pubmed18355727 Reactome Database ID Release 431855158 Reactome, http://www.reactome.org ReactomeREACT_150145 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0003810 Reactome Database ID Release 43140850 Reactome, http://www.reactome.org Collagen type VII hexamer Reactome DB_ID: 2127449 Reactome Database ID Release 432127449 Reactome, http://www.reactome.org ReactomeREACT_151144 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43140699 Reactome, http://www.reactome.org Tropocollagen type XXIV Reactome DB_ID: 2152372 Reactome Database ID Release 432152372 Reactome, http://www.reactome.org ReactomeREACT_124441 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158179 Reactome, http://www.reactome.org Tropocollagen type XXVII Reactome DB_ID: 2152344 Reactome Database ID Release 432152344 Reactome, http://www.reactome.org ReactomeREACT_122993 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43140663 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43139890 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43139890 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43139890 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158128 Reactome, http://www.reactome.org I(1,3,4,5,6)P5 is phosphorylated to IP6 by IPPK in the cytosol Authored: Williams, MG, 2011-10-28 EC Number: 2.7.1.158 Edited: Williams, MG, 2011-10-28 Inositolpentakisphosphate 2-kinase (IPPK), also known as IP52K, phosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6) (Verbski et al. 2002, Brehm et al. 2007, Choi et al. 2007). Pubmed12084730 Pubmed17702752 Pubmed17705785 Reactome Database ID Release 431855179 Reactome, http://www.reactome.org ReactomeREACT_150360 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Procollagen type XI -N Reactome DB_ID: 2268777 Reactome Database ID Release 432268777 Reactome, http://www.reactome.org ReactomeREACT_122120 has a Stoichiometric coefficient of 1 Procollagen alpha-3(V) -N trimer Reactome DB_ID: 2268882 Reactome Database ID Release 432268882 Reactome, http://www.reactome.org ReactomeREACT_121671 has a Stoichiometric coefficient of 3 PP-IP4 is dephosphorylated to I(1,3,4,5,6)P5 by NUDT4 in the cytosol Authored: Williams, MG, 2011-10-28 Diphosphoinositol polyphosphate phosphohydrolase 2, also known as nucleoside diphosphate-linked moiety X motif 4 (NUDT4), dephosphorylates diphospho- tetrakisphosphate (PP-IP4) to inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5). The products made are: inositol 5-diphospho-1,3,4,6-tetrakisphosphate (5-PP-IP4); inositol 1-diphospho-3,4,5,6-tetrakisphosphate (1-PP-IP4); and inositol 3-diphospho-1,4,5,6-tetrakisphosphate (3-PP-IP4).<br><br>The following lists the above protein with its corresponding literature references: NUDT4 (Saiardi et al. 2001, Saiardi et al. 2000). Edited: Williams, MG, 2011-10-28 Pubmed10827188 Pubmed11502751 Reactome Database ID Release 431855166 Reactome, http://www.reactome.org ReactomeREACT_150309 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,3,4,5,6)P5 is phosphorylated to 5-PP-IP4 by IP6K1/3 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 5-diphospho-(1,3,4,6)-tetrakisphosphate (5-PP-IP4) (Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008). Pubmed10827188 Pubmed11502751 Pubmed18355727 Reactome Database ID Release 431855223 Reactome, http://www.reactome.org ReactomeREACT_150450 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 IP6 is phosphorylated to 5-PP-IP5 by IP6K1/3 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate inositol 1,2,3,4,5,6-hexakisphosphate (IP6) to inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5).<br><br>The following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008; Lin et al. 2009) and IP6K3 (Saiardi et al. 2001, Draskovic et al. 2008). Pubmed11502751 Pubmed17412958 Pubmed18355727 Pubmed18981179 Reactome Database ID Release 431855227 Reactome, http://www.reactome.org ReactomeREACT_150153 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Procollagen type V -N Converted from EntitySet in Reactome Reactome DB_ID: 2268936 Reactome Database ID Release 432268936 Reactome, http://www.reactome.org ReactomeREACT_122787 1-PP-IP4 is phosphorylated to 1,5-(PP)2-IP3 by IP6K1/3 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol hexakisphosphate kinase 1 (IP6K1) and 3 (IP6K3) phosphorylate inositol 1-diphospho-3,4,5,6-tetrakisphosphate (1-PP-IP4) to form inositol 1,5-bisdiphospho-3,4,6-trisphosphate (1,5-(PP)2-IP3) (Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008). Pubmed10827188 Pubmed11502751 Pubmed18355727 Reactome Database ID Release 431855193 Reactome, http://www.reactome.org ReactomeREACT_150415 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Procollagen type III -N Reactome DB_ID: 2268745 Reactome Database ID Release 432268745 Reactome, http://www.reactome.org ReactomeREACT_124453 has a Stoichiometric coefficient of 3 IP6 is phosphorylated to 1-PP-IP5 by PPIP5K1/2 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1/2 (PPIP5K1) and 2 (PPIP5K2) phosphorylate inositol 1,2,3,4,5,6-hexakisphosphate (IP6) to inositol 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5)) (Fridy et al. 2007, Mulugu et al. 2007, Choi et al. 2007, Lin et al. 2009; Wang et al. 2011). Pubmed17412958 Pubmed17690096 Pubmed17702752 Pubmed18981179 Pubmed22119861 Reactome Database ID Release 431855216 Reactome, http://www.reactome.org ReactomeREACT_150370 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Procollagen alpha-1-3(V) propeptide -N trimer Reactome DB_ID: 2268898 Reactome Database ID Release 432268898 Reactome, http://www.reactome.org ReactomeREACT_124246 has a Stoichiometric coefficient of 1 5-PP-IP5 is dephosphorylated to IP6 by NUDT(1) in the cytosol Authored: Williams, MG, 2011-10-28 Diphosphoinositol polyphosphate phosphohydrolases (DIPP), also known as nucleoside diphosphate-linked moiety X motif (NUDT) proteins, dephosphorylate inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6). The NUDT proteins involved are: nucleoside diphosphate-linked moiety X motif 3 (NUDT3), 4 (NUDT4), 10 (NUDT10), and 11 (NUDT11).<br><br>The following lists the above proteins with their corresponding literature references: NUDT3 (Safrany et al. 1999, Safrany et al. 1998, Yang et al. 1999, Caffrey et al. 2000), NUDT4 (Caffrey et al. 2000), NUDT10 (Leslie et al. 2002, Hidaka et al. 2002) and NUDT11 (Leslie et al. 2002, Hidaka et al. 2002). Edited: Williams, MG, 2011-10-28 Pubmed10419486 Pubmed10585413 Pubmed10777568 Pubmed12105228 Pubmed12121577 Pubmed9822604 Reactome Database ID Release 431855198 Reactome, http://www.reactome.org ReactomeREACT_150467 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Procollagen alpha-1(V)X2 alpha-2(V) -N trimer Reactome DB_ID: 2268793 Reactome Database ID Release 432268793 Reactome, http://www.reactome.org ReactomeREACT_125288 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 5-PP-IP5 transports from the nucleus to the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) translocates from the nucleus to the cytosol (Fridy et al. 2007). Pubmed17690096 Reactome Database ID Release 431855203 Reactome, http://www.reactome.org ReactomeREACT_150150 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Procollagen type XXVII -N Reactome DB_ID: 2268803 Reactome Database ID Release 432268803 Reactome, http://www.reactome.org ReactomeREACT_125664 has a Stoichiometric coefficient of 3 (PP)2-IP4 transports from the nucleus to the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) and inositol 3,5-bisdiphospho-1,2,4,6-tetrakisphosphate (3,5-(PP)2-IP4) translocate from the nucleus to the cytosol (Leslie et al. 2002). Pubmed12121577 Reactome Database ID Release 431855220 Reactome, http://www.reactome.org ReactomeREACT_150419 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Tropocollagen type I Reactome DB_ID: 2089970 Reactome Database ID Release 432089970 Reactome, http://www.reactome.org ReactomeREACT_121825 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 I(1,3,4,5,6)P5 is dephosphorylated to I(3,4,5,6)P4 by ITPK1 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol-tetrakisphosphate 1-kinase (ITPK1) dephosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 3,4,5,6-tetrakisphosphate (I(3,4,5,6)P4) (Ho et al. 2002). Pubmed11909533 Reactome Database ID Release 431855219 Reactome, http://www.reactome.org ReactomeREACT_150330 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0004867 Reactome Database ID Release 43159020 Reactome, http://www.reactome.org Tropocollagen type II Reactome DB_ID: 2127377 Reactome Database ID Release 432127377 Reactome, http://www.reactome.org ReactomeREACT_123318 has a Stoichiometric coefficient of 3 I(3,4,5,6)P4 is phosphorylated to I(1,3,4,5,6)P5 by ITPK1 in the cytosol Authored: Williams, MG, 2011-10-28 EC Number: 2.7.1.134 Edited: Williams, MG, 2011-10-28 Inositoltetrakisphosphate 1-kinase (ITPK1) phosphorylates inositol 3,4,5,6-tetrakisphosphate (I(3,4,5,6)P4) to inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) (Yang & Shears 2000). Pubmed11042108 Reactome Database ID Release 431855162 Reactome, http://www.reactome.org ReactomeREACT_150321 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 ACTIVATION GENE ONTOLOGYGO:0004867 Reactome Database ID Release 43158919 Reactome, http://www.reactome.org Tropocollagen type III Reactome DB_ID: 2127436 Reactome Database ID Release 432127436 Reactome, http://www.reactome.org ReactomeREACT_123260 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0004867 Reactome Database ID Release 43158919 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158767 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158743 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158743 Reactome, http://www.reactome.org Procollagen type XXIV -N Reactome DB_ID: 2268921 Reactome Database ID Release 432268921 Reactome, http://www.reactome.org ReactomeREACT_121503 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158768 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43141025 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43141039 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43140869 Reactome, http://www.reactome.org Collagen alpha-4(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127328 Reactome Database ID Release 432127328 Reactome, http://www.reactome.org ReactomeREACT_122039 5-PP-IP4 transports from the nucleus to the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 5-diphospho-1,3,4,6-tetrakisphosphate (5-PP-IP4) translocates from the nucleus to the cytosol (Saiardi et al. 2001, Saiardi et al. 2000). Pubmed10827188 Pubmed11502751 Reactome Database ID Release 431855173 Reactome, http://www.reactome.org ReactomeREACT_150356 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 I(1,3,4,5,6)P5 transports from the nucleus to the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,3,4,5,6-pentakisphosphate I(1,3,4,5,6)P5 translocates from the nucleus to the cytosol (Nalaskowski et al. 2002; Ho et al. 2002, Brehm et al. 2007). Pubmed11909533 Pubmed12027805 Pubmed17705785 Reactome Database ID Release 431855161 Reactome, http://www.reactome.org ReactomeREACT_150342 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Collagen type I,II:XII,XIV fibrils Reactome DB_ID: 2220795 Reactome Database ID Release 432220795 Reactome, http://www.reactome.org ReactomeREACT_151645 has a Stoichiometric coefficient of 1 1-PP-IP5 is phosphorylated to 1,5-(PP)2-IP4 by IP6K1/2 in the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate 1-diphospho-2,3,4,5,6-pentakisphosphate (1-PP-IP5) to make inositol 1,5-bisdiphospho-2,3,4,6-tetrakisphosphate (1,5-(PP)2-IP4) (Saiardi et al. 2001, Mulugu et al. 2007). Pubmed11502751 Pubmed17412958 Reactome Database ID Release 431855157 Reactome, http://www.reactome.org ReactomeREACT_150168 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Collagen type II:type IX fibril Reactome DB_ID: 2220801 Reactome Database ID Release 432220801 Reactome, http://www.reactome.org ReactomeREACT_151242 has a Stoichiometric coefficient of 1 5-PP-IP5 is phosphorylated to 5-PPP-IP5 by IP6K1/2 in the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5) to inositol 5-triphospho- 1,2,3,4,6-pentakisphosphate (5-PPP-IP5) (Saiardi et al. 2001, Draskovic et al. 2008) and IP6K2 (Saiardi et al. 2001, Draskovic et al. 2008). While this reaction has been demonstrated to occur in vitro, the extent to which it occurs in vivo is less clear. Pubmed11502751 Pubmed18355727 Reactome Database ID Release 431855224 Reactome, http://www.reactome.org ReactomeREACT_150137 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Collagen type XI fibril:Collagen type II fibril Reactome DB_ID: 2413074 Reactome Database ID Release 432413074 Reactome, http://www.reactome.org ReactomeREACT_150897 has a Stoichiometric coefficient of 1 IP6 is phosphorylated to 5-PP-IP5 by IP6K1/2 in the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate inositol 1,2,3,4,5,6-hexakisphosphate (IP6) to inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (5-PP-IP5).<br><br>The following lists the above proteins with their corresponding literature references: IP6K1 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008) and IP6K2 (Saiardi et al. 2001, Mulugu et al. 2007, Draskovic et al. 2008). Pubmed11502751 Pubmed17412958 Pubmed18355727 Reactome Database ID Release 431855207 Reactome, http://www.reactome.org ReactomeREACT_150465 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 5-PP-IP4 is phosphorylated to 1,5-(PP)2-IP3 by IP6K1/2 in the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate5-diphospho-1,3,4,6-tetrakisphosphate (5-PP-IP4) to inositol 1,5-bisdiphospho-3,4,6-trisphosphate (1,5-(PP)2-IP3) (Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008). Pubmed10827188 Pubmed11502751 Pubmed18355727 Reactome Database ID Release 431855230 Reactome, http://www.reactome.org ReactomeREACT_150313 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Collagen type VII fibril:Laminin-332 Reactome DB_ID: 2220790 Reactome Database ID Release 432220790 Reactome, http://www.reactome.org ReactomeREACT_151770 has a Stoichiometric coefficient of 1 Collagen type XVII fibril:Integrin alpha6beta4 Reactome DB_ID: 2220788 Reactome Database ID Release 432220788 Reactome, http://www.reactome.org ReactomeREACT_151728 has a Stoichiometric coefficient of 1 I(1,3,4,5,6)P5 is phosphorylated to 5-PP-IP4 by IP6K1/2 in the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol hexakisphosphate kinase 1 (IP6K1) and 2 (IP6K2) phosphorylate inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 5-diphospho-(1,3,4,6)-tetrakisphosphate (5-PP-IP4) (Saiardi et al. 2001, Saiardi et al. 2000, Draskovic et al. 2008). Pubmed10827188 Pubmed11502751 Pubmed18355727 Reactome Database ID Release 431855181 Reactome, http://www.reactome.org ReactomeREACT_150336 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Collagen type X:type II fibrils Reactome DB_ID: 2220791 Reactome Database ID Release 432220791 Reactome, http://www.reactome.org ReactomeREACT_151731 has a Stoichiometric coefficient of 1 BPAG1e:Plectin Reactome DB_ID: 2220789 Reactome Database ID Release 432220789 Reactome, http://www.reactome.org ReactomeREACT_152489 has a Stoichiometric coefficient of 1 I(1,4,5,6)P4 is phosphorylated to I(1,3,4,5,6)P5 by IPMK in the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol polyphosphate multikinase (IPMK) phosphorylates inositol 1,4,5,6-tetrakisphosphate (I(1,4,5,6)P4) to inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) (Nalaskowski et al. 2002, Chang & Majerus 2006). Pubmed12027805 Pubmed16293229 Reactome Database ID Release 431855185 Reactome, http://www.reactome.org ReactomeREACT_150202 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Tryptase Reactome DB_ID: 1602485 Reactome Database ID Release 431602485 Reactome, http://www.reactome.org ReactomeREACT_120305 has a Stoichiometric coefficient of 4 I(1,3,4,5,6)P5 is phosphorylated to IP6 by IPPK (IP5-2K) in the nucleus Authored: Williams, MG, 2011-10-28 EC Number: 2.7.1.158 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol-pentakisphosphate 2-kinase (IPPK - also known as IP5-2K) phosphorylates inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) to inositol 1,2,3,4,5,6-hexakisphosphate (IP6) (Verbsky et al. 2002, Brehm et al. 2007, Choi et al. 2007). Pubmed12084730 Pubmed17702752 Pubmed17705785 Reactome Database ID Release 431855176 Reactome, http://www.reactome.org ReactomeREACT_150383 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 proMMP9:TIMP1 Reactome DB_ID: 1604377 Reactome Database ID Release 431604377 Reactome, http://www.reactome.org ReactomeREACT_119657 has a Stoichiometric coefficient of 1 I(1,3,4,5)P4 is phosphorylated to I(1,3,4,5,6)P5 by IPMK in the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol polyphosphate multikinase (IPMK) phosphorylates inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) (Nalaskowski et al. 2002, Chang & Majerus 2006). Pubmed12027805 Pubmed16293229 Reactome Database ID Release 431855206 Reactome, http://www.reactome.org ReactomeREACT_150254 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Type I hemidesmosome complex Reactome DB_ID: 2220800 Reactome Database ID Release 432220800 Reactome, http://www.reactome.org ReactomeREACT_152127 has a Stoichiometric coefficient of 1 I(1,3,4,6)P4 is phosphorylated to I(1,3,4,5,6)P5 by IPMK in the nucleus Authored: Williams, MG, 2011-10-28 EC Number: 2.7.1.140 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol polyphosphate multikinase (IPMK) phosphorylates inositol 1,3,4,6-tetrakisphosphate (I(1,3,4,6)P4) to inositol 1,3,4,5,6-pentakisphosphate (I(1,3,4,5,6)P5) (Chang et al. 2002, Chang & Majerus 2006). Pubmed12223481 Pubmed16293229 Reactome Database ID Release 431855228 Reactome, http://www.reactome.org ReactomeREACT_150368 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Cathepsin L1 Reactome DB_ID: 2228673 Reactome Database ID Release 432228673 Reactome, http://www.reactome.org ReactomeREACT_151571 has a Stoichiometric coefficient of 1 Collagen alpha-5(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127390 Reactome Database ID Release 432127390 Reactome, http://www.reactome.org ReactomeREACT_123868 I(1,3,4,5)P4 transports from the cytosol to the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) translocates from the cytosol to the nucleus (Dewaste et al. 2003, Nalaskowski et al. 2002). Pubmed12027805 Pubmed12747803 Reactome Database ID Release 431855168 Reactome, http://www.reactome.org ReactomeREACT_150307 Reviewed: Challiss, John, 2012-11-09 Lysyl oxidases:Cu2+ Reactome DB_ID: 2022132 Reactome Database ID Release 432022132 Reactome, http://www.reactome.org ReactomeREACT_151397 has a Stoichiometric coefficient of 1 I(1,4,5)P3 transports from the cytosol to the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,4,5-trisphosphate (I(1,4,5)P3) translocates from the cytosol to the nucleus (Dewaste et al. 2003, Nalaskowski et al. 2002). Pubmed12027805 Pubmed12747803 Reactome Database ID Release 431855190 Reactome, http://www.reactome.org ReactomeREACT_150402 Reviewed: Challiss, John, 2012-11-09 Anchoring fibril complex Reactome DB_ID: 2399659 Reactome Database ID Release 432399659 Reactome, http://www.reactome.org ReactomeREACT_151867 has a Stoichiometric coefficient of 1 I(1,4,5)P3 is phosphorylated to I(1,3,4,5)P4 by IPMK in the nucleus Authored: Williams, MG, 2011-10-28 EC Number: 2.7.1.127 Edited: Williams, MG, 2011-10-28 In the nucleus, inositol polyphosphate multikinase (IPMK) phosphorylates inositol 1,4,5-trisphosphate (I(1,4,5)P3) to inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) (Nalaskowski et al. 2002, Chang et al. 2002, Chang & Majerus 2006). Pubmed12027805 Pubmed12223481 Pubmed16293229 Reactome Database ID Release 431855233 Reactome, http://www.reactome.org ReactomeREACT_150392 Reviewed: Challiss, John, 2012-11-09 Reviewed: Wundenberg, Torsten, 2012-11-06 Collagen type I fibrils with deH-HLNL cross-links Reactome DB_ID: 2396268 Reactome Database ID Release 432396268 Reactome, http://www.reactome.org ReactomeREACT_151003 has a Stoichiometric coefficient of 1 I(1,3,4,6)P4 transports from the cytosol to the nucleus Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol 1,3,4,6-tetrakisphosphate (I(1,3,4,6)P4) translocates from the cytosol to the nucleus (Ho et al. 2002, Nalaskowski et al. 2002). Pubmed11909533 Pubmed12027805 Reactome Database ID Release 431855201 Reactome, http://www.reactome.org ReactomeREACT_150457 Reviewed: Challiss, John, 2012-11-09 Collagen type 1 fibrils cross-linked by dehydro-lysinonorleucine crosslinks Reactome DB_ID: 2396037 Reactome Database ID Release 432396037 Reactome, http://www.reactome.org ReactomeREACT_151642 has a Stoichiometric coefficient of 1 I(3,4,6)P3 is phosphorylated to I(1,3,4,6)P4 by ITPK1 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates inositol 3,4,6-trisphosphate (I(3,4,6)P3) to inositol 1,3,4,6-tetrakisphosphate (I(1,3,4,6)P4) (Ho et al. 2002). Pubmed11909533 Reactome Database ID Release 431855169 Reactome, http://www.reactome.org ReactomeREACT_150431 Reviewed: Challiss, John, 2012-11-09 I(1,3,4,6)P4 is dephosphorylated to I(1,3,4)P3 by ITPK1 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol-tetrakisphosphate 1-kinase (ITPK1) dephosphorylates inositol 1,3,4,6-tetrakisphosphate (I(1,3,4,6)P4) to inositol 1,3,4-trisphosphate (I(1,3,4)P3) (Ho et al. 2002). Pubmed11909533 Reactome Database ID Release 431855171 Reactome, http://www.reactome.org ReactomeREACT_150351 Reviewed: Challiss, John, 2012-11-09 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43140735 Reactome, http://www.reactome.org I(1,3,4,6)P4 is dephosphorylated to I(3,4,6)P3 by ITPK1 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol-tetrakisphosphate 1-kinase (ITPK1) dephosphorylates inositol 1,3,4,6-tetrakisphosphate (I(1,3,4,6)P4) to inositol 3,4,6-trisphosphate (I(3,4,6)P3) (Ho et al. 2002). Pubmed11909533 Reactome Database ID Release 431855159 Reactome, http://www.reactome.org ReactomeREACT_150200 Reviewed: Challiss, John, 2012-11-09 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43140735 Reactome, http://www.reactome.org Collagen type I fibrils with lysino-5-ketonorleucine cross-links Reactome DB_ID: 2447200 Reactome Database ID Release 432447200 Reactome, http://www.reactome.org ReactomeREACT_152495 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43140768 Reactome, http://www.reactome.org Collagen type I fibrils with hydroxylysino-5-ketonorleucine crosslinks Reactome DB_ID: 2396143 Reactome Database ID Release 432396143 Reactome, http://www.reactome.org ReactomeREACT_152262 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43140776 Reactome, http://www.reactome.org Collagen type I fibrils with lysyl-pyridinoline cross-links Reactome DB_ID: 2396051 Reactome Database ID Release 432396051 Reactome, http://www.reactome.org ReactomeREACT_152486 has a Stoichiometric coefficient of 2 I(1,3,4,5)P4 is dephosphorylated to I(1,3,4)P3 by INPP5[3]/ITPK1 in the cytosol A group of inositol phosphatases and the broad specificity enzyme inositol-tetrakisphosphate 1-kinase (ITPK1) dephosphorylate inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,3,4-trisphosphate (I(1,3,4)P3). The group of inositol phosphatases involved are: inositol polyphosphate 5-phosphatase OCRL-1 (OCRL), phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 (INPP5D) aka SHIP1, phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 (INPPL1) aka SHIP2, phosphatidylinositol 4,5-bisphosphate 5-phosphatase A (INPP5J) aka PIPP, and synaptic inositol-1,4,5-trisphosphate 5-phosphatase 1 (SYNJ1).<br><br>The following lists the above proteins with their corresponding literature references: OCRL (Chang et al. 2002, Zhang et al. 1995, Zhang et al. 1998, Schmid et al. 2004); INPP5D (Drayer et al. 1996, Kavanaugh et al. 1996); INPPL1 (Chi et al. 2004); INPP5J (Mochizuki & Thompson 1999); SYNJ1 (Schmid et al. 2004); ITPK1 (Ho et al. 2002). Authored: Williams, MG, 2011-10-28 EC Number: 3.1.3.56 Edited: Williams, MG, 2011-10-28 Pubmed10593988 Pubmed11909533 Pubmed12223481 Pubmed15316017 Pubmed15474001 Pubmed7761412 Pubmed8723348 Pubmed8769125 Pubmed9430698 Reactome Database ID Release 431855218 Reactome, http://www.reactome.org ReactomeREACT_150220 Reviewed: Challiss, John, 2012-11-09 ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158386 Reactome, http://www.reactome.org Collagen type I fibrils with hydroxylysyl-pyridinoline cross-links Reactome DB_ID: 2396133 Reactome Database ID Release 432396133 Reactome, http://www.reactome.org ReactomeREACT_151870 has a Stoichiometric coefficient of 2 I(1,3,4,5)P4 is dephosphorylated to I(1,3,4)P3 by INPP5B at the plasma membrane Authored: Williams, MG, 2011-10-28 EC Number: 3.1.3.56 Edited: Williams, MG, 2011-10-28 Pubmed15474001 Pubmed1718960 Pubmed7721860 Reactome Database ID Release 431855213 Reactome, http://www.reactome.org ReactomeREACT_150158 Reviewed: Challiss, John, 2012-11-09 Type II inositol-1,4,5-trisphosphate 5-phosphatase (INPP5B) is attached to the plasma membrane where it dephosphorylates inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,3,4-trisphosphate (I(1,3,4)P3 (Jefferson & Majerus 1995, Ross et al. 1991, Schmid et al. 2004). INPP5B is isoprenylated at its C-terminus for membrane attachment. ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158359 Reactome, http://www.reactome.org Collagen type I fibrils with lysyl-pyrrole cross-links Reactome DB_ID: 2396474 Reactome Database ID Release 432396474 Reactome, http://www.reactome.org ReactomeREACT_151712 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 I(1,3,4)P3 is phosphorylated to I(1,3,4,5)P4 by ITPK1 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Pubmed8662638 Reactome Database ID Release 431855172 Reactome, http://www.reactome.org ReactomeREACT_150236 Reviewed: Challiss, John, 2012-11-09 The broad-specificity enzyme inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates inositol 1,3,4-trisphosphate (I(1,3,4)P3) to inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) (Wilson & Majerus 1996). ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158359 Reactome, http://www.reactome.org Collagen type I fibrils with hydroxylysyl-pyrrole cross-links Reactome DB_ID: 2396060 Reactome Database ID Release 432396060 Reactome, http://www.reactome.org ReactomeREACT_151793 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 I(1,3,4)P3 is phosphorylated to I(1,3,4,6)P4 by ITPK1 in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates inositol 1,3,4-trisphosphate (I(1,3,4)P3) to inositol 1,3,4,6-tetrakisphosphate (I(1,3,4,6)P4) (Wilson & Majerus 1996, Yang & Shears 2000). Pubmed11042108 Pubmed8662638 Reactome Database ID Release 431855197 Reactome, http://www.reactome.org ReactomeREACT_150157 Reviewed: Challiss, John, 2012-11-09 ACTIVATION GENE ONTOLOGYGO:0004185 Reactome Database ID Release 43158252 Reactome, http://www.reactome.org Collagen type I fibrils with histidino-hydroxylysinoleucine cross-links Reactome DB_ID: 2399496 Reactome Database ID Release 432399496 Reactome, http://www.reactome.org ReactomeREACT_151494 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0015662 Reactome Database ID Release 43429152 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004698 Reactome Database ID Release 43139850 Reactome, http://www.reactome.org p21 RAS Converted from EntitySet in Reactome Reactome DB_ID: 109782 Reactome Database ID Release 43109782 Reactome, http://www.reactome.org ReactomeREACT_4582 PI3K-regulatory subunit Converted from EntitySet in Reactome Reactome DB_ID: 74688 Reactome Database ID Release 4374688 Reactome, http://www.reactome.org ReactomeREACT_3241 PI3K-catalytic subunit Converted from EntitySet in Reactome Reactome DB_ID: 74689 Reactome Database ID Release 4374689 Reactome, http://www.reactome.org ReactomeREACT_3915 Src family tyrosine kinases (SFKs) Converted from EntitySet in Reactome Reactome DB_ID: 211064 Reactome Database ID Release 43211064 Reactome, http://www.reactome.org ReactomeREACT_13328 Collagen alpha-1(VII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127505 Reactome Database ID Release 432127505 Reactome, http://www.reactome.org ReactomeREACT_124704 CD47-binding SIRPs Converted from EntitySet in Reactome Reactome DB_ID: 202788 Reactome Database ID Release 43202788 Reactome, http://www.reactome.org ReactomeREACT_12311 ACTIVATION GENE ONTOLOGYGO:0004348 Reactome Database ID Release 431605702 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004348 Reactome Database ID Release 431861763 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004767 Reactome Database ID Release 431606275 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004767 Reactome Database ID Release 431606279 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017040 Reactome Database ID Release 431606595 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004308 Reactome Database ID Release 431605760 Reactome, http://www.reactome.org Collagen alpha-2(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127329 Reactome Database ID Release 432127329 Reactome, http://www.reactome.org ReactomeREACT_121996 ACTIVATION GENE ONTOLOGYGO:0004308 Reactome Database ID Release 431605672 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004767 Reactome Database ID Release 431640163 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017040 Reactome Database ID Release 431606585 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004348 Reactome Database ID Release 431861757 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030290 Reactome Database ID Release 431861790 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004563 Reactome Database ID Release 431605773 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004308 Reactome Database ID Release 431605780 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004336 Reactome Database ID Release 431606568 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004098 Reactome Database ID Release 431606828 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004767 Reactome Database ID Release 431605754 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004563 Reactome Database ID Release 431605761 Reactome, http://www.reactome.org Collagen alpha-1(IV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2127294 Reactome Database ID Release 432127294 Reactome, http://www.reactome.org ReactomeREACT_122992 ACTIVATION GENE ONTOLOGYGO:0004565 Reactome Database ID Release 431605789 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016491 Reactome Database ID Release 431614322 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004557 Reactome Database ID Release 431605696 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43400498 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265205 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005355 Reactome Database ID Release 43500053 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43400498 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265205 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265014 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005245 Reactome Database ID Release 43265625 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005261 Reactome Database ID Release 43169682 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015207 Reactome Database ID Release 43187455 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005524 Reactome Database ID Release 43264517 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004773 Reactome Database ID Release 431606835 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0001729 Reactome Database ID Release 431638839 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008120 Reactome Database ID Release 431638095 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43749482 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0001733 Reactome Database ID Release 431638107 Reactome, http://www.reactome.org MERTK ligands Converted from EntitySet in Reactome Reactome DB_ID: 202771 Reactome Database ID Release 43202771 Reactome, http://www.reactome.org ReactomeREACT_12235 Selectin Converted from EntitySet in Reactome Reactome DB_ID: 203453 Reactome Database ID Release 43203453 Reactome, http://www.reactome.org ReactomeREACT_12297 ACTIVATION GENE ONTOLOGYGO:0004629 Reactome Database ID Release 43400007 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43400010 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43416526 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004016 Reactome Database ID Release 43381716 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43265014 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004692 Reactome Database ID Release 431475413 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003874 Reactome Database ID Release 431475060 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004692 Reactome Database ID Release 431475413 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003934 Reactome Database ID Release 431474128 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008474 Reactome Database ID Release 43203697 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016175 Reactome Database ID Release 431497778 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004517 Reactome Database ID Release 43203600 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0016409 Reactome Database ID Release 43203709 Reactome, http://www.reactome.org Platelet Factor 4 Converted from EntitySet in Reactome Reactome DB_ID: 203105 Reactome Database ID Release 43203105 Reactome, http://www.reactome.org ReactomeREACT_12205 ACTIVATION GENE ONTOLOGYGO:0003726 Reactome Database ID Release 4383527 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003726 Reactome Database ID Release 4383526 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004126 Reactome Database ID Release 4383524 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004482 Reactome Database ID Release 4372082 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004519 Reactome Database ID Release 4372175 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0001734 Reactome Database ID Release 4372094 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004484 Reactome Database ID Release 43111348 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004484 Reactome Database ID Release 4377051 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004651 Reactome Database ID Release 4377052 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004757 Reactome Database ID Release 431497839 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004757 Reactome Database ID Release 431497839 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004691 Reactome Database ID Release 43163671 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004691 Reactome Database ID Release 43163675 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004679 Reactome Database ID Release 43163694 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004672 Reactome Database ID Release 43164052 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000149 Reactome Database ID Release 43387385 Reactome, http://www.reactome.org Collagen alpha-2(VIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192734 Reactome Database ID Release 432192734 Reactome, http://www.reactome.org ReactomeREACT_123205 ACTIVATION GENE ONTOLOGYGO:0004016 Reactome Database ID Release 43164332 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005085 Reactome Database ID Release 43163619 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008195 Reactome Database ID Release 43163684 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008195 Reactome Database ID Release 43163698 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008195 Reactome Database ID Release 43163698 Reactome, http://www.reactome.org Na+/H+ exchanger proteins Converted from EntitySet in Reactome Reactome DB_ID: 425963 Reactome Database ID Release 43425963 Reactome, http://www.reactome.org ReactomeREACT_20090 Na+-driven Cl-/HCO3- exchanger proteins Converted from EntitySet in Reactome Reactome DB_ID: 425553 Reactome Database ID Release 43425553 Reactome, http://www.reactome.org ReactomeREACT_19659 Na+/K+/Ca2+ exchanger proteins Converted from EntitySet in Reactome Reactome DB_ID: 425657 Reactome Database ID Release 43425657 Reactome, http://www.reactome.org ReactomeREACT_20166 Collagen type XX Reactome DB_ID: 2152265 Reactome Database ID Release 432152265 Reactome, http://www.reactome.org ReactomeREACT_124965 has a Stoichiometric coefficient of 3 Collagen type XIX Reactome DB_ID: 2152272 Reactome Database ID Release 432152272 Reactome, http://www.reactome.org ReactomeREACT_122742 has a Stoichiometric coefficient of 3 Collagen type XVIII Reactome DB_ID: 2152295 Reactome Database ID Release 432152295 Reactome, http://www.reactome.org ReactomeREACT_123391 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0005313 Reactome Database ID Release 43428556 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015538 Reactome Database ID Release 43428636 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015321 Reactome Database ID Release 43428583 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008507 Reactome Database ID Release 43429651 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0046899 Reactome Database ID Release 431008260 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005314 Reactome Database ID Release 43428035 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015333 Reactome Database ID Release 43427987 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015333 Reactome Database ID Release 43428018 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0052725 Reactome Database ID Release 432267371 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0032454 Reactome Database ID Release 43997238 Reactome, http://www.reactome.org HGSNAT acetylates the terminal N-glucosamine in heparan sulfate Authored: Jassal, B, 2011-10-19 EC Number: 2.3.1.78 Edited: Jassal, B, 2011-10-19 Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) acetylates the non-reducing terminal alpha-glucosamine residue of heparan sulfate. This is a critical reaction for the degradation of heparan sulfate because there is no enzyme that can act on the unacetylated glucosamine molecule. The mechanism by which HGSNAT uses cytosolic acetyl-CoA to transfer the acetyl group to the lysosomal luminal substrate is unknown (Fan et al. 2006). A catalytically inactive 77kDa precursor is transported to the lysosome and is cleaved into a 29kDa N-terminal alpha-chain and a 48kDa C-terminal beta-chain, which are assembled into active 440kDa oligomers in the lysosomal membrane (Durand et al. 2010). Defects in HGSNAT cause mucopolysaccharidosis type IIIC (MPSIIIC, MIM:252930), also called Sanfilippo C syndrome (Fan et al. 2006, Hrebicek et al. 2006). Pubmed16960811 Pubmed17033958 Pubmed20650889 Reactome Database ID Release 431678660 Reactome, http://www.reactome.org ReactomeREACT_121010 Reviewed: D'Eustachio, P, 2012-03-28 Iduronate 2-sulfatase (IDS) hydrolyses sulfates from L-iduronate 2-sulfate units of heparan sulfate Authored: Jassal, B, 2011-10-19 EC Number: 3.1.6.13 Edited: Jassal, B, 2011-10-19 Iduronate 2sulfatase (IDS) hydrolyses 2-sulfate groups from Liduronate 2-sulfate units of heparan sulfate. Defects in IDS are the cause of mucopolysaccharidosis type II (MPSII, MIM:309900), also called Hunter syndrome (Wilson et al. 1990). Pubmed2122463 Reactome Database ID Release 431678650 Reactome, http://www.reactome.org ReactomeREACT_121160 Reviewed: D'Eustachio, P, 2012-03-28 Collagen type XXV Reactome DB_ID: 2152353 Reactome Database ID Release 432152353 Reactome, http://www.reactome.org ReactomeREACT_124506 has a Stoichiometric coefficient of 3 Alpha-N-acetylglucosaminidase (NAGLU) hydrolyses N-acetyl-D-glucosamine residues from heparan sulfate Alpha-N-acetylglucosaminidase (NAGLU) hydrolyses the non-reducing, terminal N-acetyl-D-glucosamine residue from heparan sulfate. The active form of the enzyme (77kDa) is derived from a 82kDa precursor (Weber et al. 1996). Defects in NAGLU cause of mucopolysaccharidosis type IIIB (MPSIIIB, MIM:252920) also known as Sanfilippo syndrome type B (Beesley et al. 2005). Authored: Jassal, B, 2011-10-19 EC Number: 3.2.1.50 Edited: Jassal, B, 2011-10-19 Pubmed16151907 Pubmed8776591 Reactome Database ID Release 431678742 Reactome, http://www.reactome.org ReactomeREACT_121018 Reviewed: D'Eustachio, P, 2012-03-28 Collagen type XXIII Reactome DB_ID: 2152345 Reactome Database ID Release 432152345 Reactome, http://www.reactome.org ReactomeREACT_125340 has a Stoichiometric coefficient of 3 N-sulphoglucosamine sulphohydrolase (SGSH) hydrolyses another sulfate from the N-sulphoglucosamine residue of heparan sulfate Alpha-N-acetylglucosaminidase (NAGLU) also hydrolyses another nonreducing, terminal N-acetyl-D-glucosamine residue from heparan sulfate. The active form of the enzyme (77kDa) is derived from an 82kDa precursor (Weber et al. 1996). Defects in NAGLU cause Mucopolysaccharidosis type IIIB (MPSIIIB, MIM:252920), also known as Sanfilippo syndrome type B (Beesley et al. 2005). Authored: Jassal, B, 2012-02-06 EC Number: 3.10.1.1 Edited: Jassal, B, 2012-02-06 Pubmed7493035 Pubmed9285796 Reactome Database ID Release 432090043 Reactome, http://www.reactome.org ReactomeREACT_121158 Reviewed: D'Eustachio, P, 2012-03-28 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0052726 Reactome Database ID Release 43994155 Reactome, http://www.reactome.org Procollagen type II -N Reactome DB_ID: 2268830 Reactome Database ID Release 432268830 Reactome, http://www.reactome.org ReactomeREACT_121905 has a Stoichiometric coefficient of 3 Alpha-L-iduronidase (IDUA) hydrolyses another unsulfated alpha-L-iduronosidic linkage in heparan sulfate An L-iduronic acid residue can be cleaved from either heparan sulfate or dermatan sulfate by the lysosomal enzyme alpha-L-iduronidase (IDUA) (Scott et al. 1991). Defects in IDUA are the cause of mucopolysaccharidosis type IH (MPS IH, Hurler syndrome, MIM:607014), mucopolysaccharidosis IH/S (MPSIH/S, HurlerScheie syndrome, MIM:607015) and mucopolysaccharidosis type IS (MPSIS, Scheie syndrome, MIM:607016) (LeeChen et al. 1999). Authored: Jassal, B, 2012-02-06 EC Number: 3.2.1.76 Edited: Jassal, B, 2012-02-06 Pubmed10466419 Pubmed1946389 Reactome Database ID Release 432090037 Reactome, http://www.reactome.org ReactomeREACT_121137 Reviewed: D'Eustachio, P, 2012-03-28 Procollagen type I -N Reactome DB_ID: 2268776 Reactome Database ID Release 432268776 Reactome, http://www.reactome.org ReactomeREACT_125013 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Alpha-N-acetylglucosaminidase (NAGLU) hydrolyses another N-acetyl-D-glucosamine residue from heparan Alpha-N-acetylglucosaminidase (NAGLU) also hydrolyses another non-reducing, terminal N-acetyl-D-glucosamine residue from heparan sulfate. The active form of the enzyme (77kDa) is derived from an 82kDa precursor (Weber et al. 1996). Defects in NAGLU cause Mucopolysaccharidosis type IIIB (MPSIIIB, MIM:252920), also known as Sanfilippo syndrome type B (Beesley et al. 2005). Authored: Jassal, B, 2012-02-06 EC Number: 3.2.1.50 Edited: Jassal, B, 2012-02-06 Pubmed16151907 Pubmed8776591 Reactome Database ID Release 432090038 Reactome, http://www.reactome.org ReactomeREACT_120723 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43210261 Reactome, http://www.reactome.org HGSNAT acetylates another terminal N-glucosamine in heparan Authored: Jassal, B, 2012-02-06 EC Number: 2.3.1.78 Edited: Jassal, B, 2012-02-06 Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) acetylates another non-reducing terminal alpha-glucosamine residue of heparan sulfate. This is a critical reaction for the degradation of heparan sulfate because there is no enzyme that can act on the unacetylated glucosamine molecule. The mechanism by which HGSNAT uses cytosolic acetyl-CoA to transfer the acetyl group to the lysosomal luminal substrate is unknown (Fan et al. 2006). A catalytically inactive 77kDa precursor is transported to the lysosome and is cleaved into a 29kDa N-terminal alpha-chain and a 48kDa C-terminal beta-chain, which are assembled into active 440kDa oligomers in the lysosomal membrane (Durand et al. 2010). Defects in HGSNAT cause mucopolysaccharidosis type IIIC (MPSIIIC, MIM:252930), also called Sanfilippo C syndrome (Fan et al. 2006, Hrebicek et al. 2006). Pubmed16960811 Pubmed17033958 Pubmed20650889 Reactome Database ID Release 432090085 Reactome, http://www.reactome.org ReactomeREACT_121194 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0047325 Reactome Database ID Release 43994161 Reactome, http://www.reactome.org Beta-galactosidase (GLB1) can cleave galactose from the linker chain Authored: Jassal, B, 2012-02-06 Beta-galactosidase (GLB1) can cleave terminal galactose residues from the linker chain sequence of glycosaminoglycans (Asp et al. 1969). Defects in GLB1 causes the lysosomal storage diseases GM1 gangliosidosis (Yoshida et al. 1991) and Morquio syndrome B (Oshima et al. 1991). EC Number: 3.2.1.23 Edited: Jassal, B, 2012-02-06 Pubmed1907800 Pubmed1928092 Pubmed5822067 Reactome Database ID Release 432090079 Reactome, http://www.reactome.org ReactomeREACT_121086 Reviewed: D'Eustachio, P, 2012-03-28 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004713 Reactome Database ID Release 43210866 Reactome, http://www.reactome.org Beta-glucuronidase (GUSB) hydrolyses glucuronate from the linker chain Authored: Jassal, B, 2011-10-19 EC Number: 3.2.1.31 Edited: Jassal, B, 2011-10-19 Pubmed11568288 Pubmed3468507 Reactome Database ID Release 431678854 Reactome, http://www.reactome.org ReactomeREACT_121353 Reviewed: D'Eustachio, P, 2012-03-28 The tetrameric lysosomal enzyme beta-glucuronidase hydrolyses glucuronate from heparan or the linker chain (Oshima et al. 1987). L-aspartic acid is an inhibitor of enzyme activity (Kreamer et al. 2001). ACTIVATION GENE ONTOLOGYGO:0005088 Reactome Database ID Release 43210973 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004867 Reactome Database ID Release 43158920 Reactome, http://www.reactome.org The addition of GalNAc to the terminal glucuronate residue forms chondroitin Authored: Jassal, B, 2011-11-04 Chondroitin sulfate N-acetylgalactosaminyltransferases 1 and 2 (CSGALNACT1 and 2) (Uyama et al. 2002, Gotoh et al. 2002) transfer N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the glucuronate (GlcA) residue of the linker sequence. This first addition to the linker determines this GAG to be chondroitin. Chondroitin is comprised of the repeating disaccharide unit GalNAc-GlcA. EC Number: 2.4.1.175 Edited: Jassal, B, 2011-11-04 Pubmed11788602 Pubmed12163485 Reactome Database ID Release 431971482 Reactome, http://www.reactome.org ReactomeREACT_120769 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0004867 Reactome Database ID Release 43158991 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158743 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158973 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004252 Reactome Database ID Release 43158953 Reactome, http://www.reactome.org Transmembrane collagens Converted from EntitySet in Reactome Reactome DB_ID: 2152290 Reactome Database ID Release 432152290 Reactome, http://www.reactome.org ReactomeREACT_123289 Collagen type XIII Reactome DB_ID: 2143423 Reactome Database ID Release 432143423 Reactome, http://www.reactome.org ReactomeREACT_123901 has a Stoichiometric coefficient of 3 Collagen type XVII Reactome DB_ID: 2152283 Reactome Database ID Release 432152283 Reactome, http://www.reactome.org ReactomeREACT_125367 has a Stoichiometric coefficient of 3 Collagen type XXI Reactome DB_ID: 2152270 Reactome Database ID Release 432152270 Reactome, http://www.reactome.org ReactomeREACT_125590 has a Stoichiometric coefficient of 3 Tropocollagen type XXII Reactome DB_ID: 2152375 Reactome Database ID Release 432152375 Reactome, http://www.reactome.org ReactomeREACT_124087 has a Stoichiometric coefficient of 3 A glucuronate moiety is added to chondroitin A glucuronate moiety is added to the chondroitin chain by dual-activity enzymes, the chondroitin sulfate synthases 1-3 (CHSY1, CHPF and CHSY3 respectively) (Kitagawa et al. 2001, Yada et al. 2003, Yada et al. 2003b). They possess both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity. These three enzymes require divalent metals as cofactors, manganese producing the highest activities. Another candidate enzyme, chondroitin sulfate glucuronyltransferase (CHPF2) possess only beta-1,3-glucuronic acid transferase activity (Izumikawa et al. 2008, Gotoh et al. 2002). Defects in CHSY1 cause Temtamy preaxial brachydactyly syndrome (TPBS) (MIM:605282) (Tian et al. 2010, Li et al. 2010). Authored: Jassal, B, 2011-11-04 EC Number: 2.4.1.226 Edited: Jassal, B, 2011-11-04 Pubmed11514575 Pubmed12145278 Pubmed12761225 Pubmed12907687 Pubmed18316376 Pubmed21129727 Pubmed21129728 Reactome Database ID Release 431971491 Reactome, http://www.reactome.org ReactomeREACT_120993 Reviewed: D'Eustachio, P, 2012-03-28 Tropocollagen type XXVI Reactome DB_ID: 2193012 Reactome Database ID Release 432193012 Reactome, http://www.reactome.org ReactomeREACT_123551 has a Stoichiometric coefficient of 3 GalNAc is added to chondroitin An N-acetylgalactosamine (GalNAc) moiety is added to the chondroitin chain by dual-activity enzymes, the chondroitin sulfate synthases 1-3 (CHSY1, CHPF and CHSY3 respectively) (Kitagawa et al. 2001, Yada et al. 2003, Yada et al. 2003b). They possess both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity, the latter activity used in this reaction. These three enzymes require divalent metals as cofactors, manganese producing the highest activities. The repeated disaccharide units of GlcA-GalNAc identify this glycosaminoglycan as chondroitin. Authored: Jassal, B, 2011-11-04 EC Number: 2.7.1.61 Edited: Jassal, B, 2011-11-04 Pubmed11514575 Pubmed12761225 Pubmed12907687 Reactome Database ID Release 431971487 Reactome, http://www.reactome.org ReactomeREACT_121192 Reviewed: D'Eustachio, P, 2012-03-28 Tropocollagen type XXVIII Reactome DB_ID: 2193047 Reactome Database ID Release 432193047 Reactome, http://www.reactome.org ReactomeREACT_125657 has a Stoichiometric coefficient of 3 DSPGs are secreted Authored: Jassal, B, 2011-11-25 Edited: Jassal, B, 2011-11-25 Pubmed12512856 Reactome Database ID Release 432022065 Reactome, http://www.reactome.org ReactomeREACT_121341 Reviewed: D'Eustachio, P, 2012-03-28 Various forms of dermatan sulfate are excreted from the cell once formed. The mechanism of transport is unknown but most likely involves the trans-golgi network (Silbert & Sugumaran 2002). ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352055 Reactome, http://www.reactome.org GalNAc is sulfated on position 4 once dermatan sulfate is formed Authored: Jassal, B, 2011-11-25 Edited: Jassal, B, 2011-11-25 Important functional domains in dermatan sulfate (DS) are generated by the action of an epimerase (which converts D-glucuronic acid into its epimer L-iduronic acid) together with 4-O-sulfation. These domains are named 4-O-sulfated iduronic acid blocks (Pachebo et al. 2009). Pubmed19661164 Reactome Database ID Release 432022063 Reactome, http://www.reactome.org ReactomeREACT_120903 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43351962 Reactome, http://www.reactome.org Dermatan sulfate can be further sulfated on position 2 of iduronate Authored: Jassal, B, 2011-11-25 EC Number: 2.8.2 Edited: Jassal, B, 2011-11-25 Pubmed10187838 Reactome Database ID Release 432022061 Reactome, http://www.reactome.org ReactomeREACT_120932 Reviewed: D'Eustachio, P, 2012-03-28 Uronyl 2-sulfotransferase (UST) catalyzes the transfer of sulfate from PAPS to position 2 of iduronyl residues in dermatan sulfate (Kobayashi et al. 1999). Dermatan-sulfate epimerase (DSE) converts chondroitin sulfate (CS) to dermatan sulfate (DS) Authored: Jassal, B, 2011-11-24 EC Number: 5.1.3.19 Edited: Jassal, B, 2011-11-24 Pubmed11414686 Pubmed16505484 Reactome Database ID Release 432022052 Reactome, http://www.reactome.org ReactomeREACT_120814 Reviewed: D'Eustachio, P, 2012-03-28 The glucuronate (GlcA) moiety of chondroitin sulfate (CS) can undergo C-5 epimerization to change into an iduronic acid (IdoA) moiety, thus changing the polymer composition and creating dermatan sulfate (DS). Dermatan-sulfate epimerase (DSE) mediates this reaction (Tiedemann et al. 2001). CSPG is secreted Authored: Jassal, B, 2011-12-01 Edited: Jassal, B, 2011-12-01 Once chondroitin sulfate proteoglycans (CSPGs) are formed (can be either C4S-PG, C6S-PG or CSE-PG), they are secreted out into the extracellular matrix (ECM) via the trans-golgi network (Fransson et al. 2000). Pubmed10963998 Reactome Database ID Release 432022911 Reactome, http://www.reactome.org ReactomeREACT_120998 Reviewed: D'Eustachio, P, 2012-03-28 Chondroitin can be sulfated on position 6 of GalNAc by CHST3,7 Authored: Jassal, B, 2011-11-24 Carbohydrate sulfotransferases 3 and 7 (CHST3 and 7) catalyse the transfer of sulfate from PAPS to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin (Tsutsumi et al. 1998, Kitagawa et al. 2000). EC Number: 2.8.2.17 Edited: Jassal, B, 2011-11-24 Pubmed10781596 Pubmed9883891 Reactome Database ID Release 432018682 Reactome, http://www.reactome.org ReactomeREACT_120725 Reviewed: D'Eustachio, P, 2012-03-28 Chondroitin 4-sulfate (C4S) can be further sulfated on position 6 by CHST15 Authored: Jassal, B, 2011-11-24 Carbohydrate sulfotransferase 15 (CHST15) catalyses the transfer of sulfate from PAPS to the C-6 hydroxyl group of the GalNAc 4-sulfate residue of chondroitin 4-sulfate (C4S) (Ohtake et al. 2003). EC Number: 2.8.2.33 Edited: Jassal, B, 2011-11-24 Pubmed12874280 Reactome Database ID Release 432018659 Reactome, http://www.reactome.org ReactomeREACT_120940 Reviewed: D'Eustachio, P, 2012-03-28 Chondroitin can be sulfated on position 4 of GalNAc by CHST9, 11, 12 and 13 Authored: Jassal, B, 2011-11-04 Carbohydrate sulfotransferase9, 11, 12 and 13 (CHST9, 11, 12 and 13) catalyse the transfer of sulfate from PAPS to position 4 of the N-acetylgalactosamine (GalNAc) residue of chondroitin (Kang et al. 2001, Okuda et al. 2000, Hiraoka et al. 2000, Kang et al. 2002 respectively). EC Number: 2.8.2.5 Edited: Jassal, B, 2011-11-04 Pubmed10781601 Pubmed11056388 Pubmed11139592 Pubmed12080076 Reactome Database ID Release 431971483 Reactome, http://www.reactome.org ReactomeREACT_121270 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352151 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352130 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352160 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352083 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352082 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43351984 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352062 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43351965 Reactome, http://www.reactome.org DS is cleaved from its proteoglycan Authored: Jassal, B, 2011-10-21 Dermatan sulfate (DS) is thought to be hydrolysed from its dermatan sulfate proteoglycan (DSPG) by an unknown human beta-xylosidase. The reaction shown here is based on studies of a rabbit lysosomal enzyme fraction assay (Takagaki et al. 1988). DSPG can have many DS chains attached to it; this example shows the hydrolysis of one DS chain from DSPG. EC Number: 3.2 Edited: Jassal, B, 2011-10-21 Pubmed3134052 Reactome Database ID Release 431793176 Reactome, http://www.reactome.org ReactomeREACT_121041 Reviewed: D'Eustachio, P, 2012-03-28 CS is cleaved from its proteoglycan Authored: Jassal, B, 2012-01-20 Chondroitin sulfate (CS) is hydrolysed from its chondroitin sulfate proteoglycan (CSPG) by an unknown human beta-xylosidase. The reaction shown here is based on studies of a rabbit lysosomal enzyme fraction assay (Takagaki et al. 1988). CSPG can have many CS chains attached to it; this example shows the hydrolysis of one CS chain from CSPG. EC Number: 3.2 Edited: Jassal, B, 2012-01-20 Pubmed3134052 Reactome Database ID Release 432065233 Reactome, http://www.reactome.org ReactomeREACT_121272 Reviewed: D'Eustachio, P, 2012-03-28 DSPG and CSPG translocate to the lysosome for degradation As part of the natural turnover of GAGs, extracellular KSPGs translocate to the lysosome to be degraded. The translocation process is unsure but could be either endocytosis from outside the cell or autophagy from inside the cell (Winchester 2005). Authored: Jassal, B, 2011-11-25 Edited: Jassal, B, 2011-11-25 Pubmed15647514 Reactome Database ID Release 432022056 Reactome, http://www.reactome.org ReactomeREACT_120855 Reviewed: D'Eustachio, P, 2012-03-28 Hyaluronidase 1 (HYAL1) hydrolyses 1-4 linkages between GalNAc and D-glucuronate residues in CS. Authored: Jassal, B, 2011-10-21 EC Number: 3.2.1.35 Edited: Jassal, B, 2011-10-21 Hyaluronidase 1 (HYAL1) hydrolyses 1-4 linkages between GalNAc and D-glucuronate residues in chondroitin (or dermatan). It also hydrolyses this linkage in hyaluronate, another glycosaminoglycan (GAG) composed of repeating disaccharide units but the only one which is non-sulfated (Frost et al. 1997). There are five human hyaluronidases (HYALs, endo-beta-acetyl-hexosaminidases), HYAL1-4, and PH-20 (Jedrzejas & Stern 2005). Pubmed16104017 Pubmed9223416 Reactome Database ID Release 431793209 Reactome, http://www.reactome.org ReactomeREACT_121345 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352086 Reactome, http://www.reactome.org Arylsulfatase B (ARSB) hydrolyses sulfate groups from GalNAc 4-sulfate units of CS Arylsulfatase B (ARSB) hydrolyses sulfate from N-acetylgalactosamine 4-sulfate (or 6-sulfate) units (GalNAc 4-sulfate or GalNAc 6-sulfate) within chondroitin sulfate (Gorham & Cantz 1978). The conversion to 3-oxoalanine (formylglycine, FGly) of a cysteine residue in eukaryotes, is critical for catalytic activity, based on similarity to the prototypical arylsulfatase ARSA (Chruszcz et al. 2003, Lukatela et al. 1998). Defects in ARSB are the cause of mucopolysaccharidosis type VI (MPSVI) (MIM:253200, also called Maroteaux-Lamy syndrome (Wicker et al. 1991). ARSB activity is defective in multiple sulfatase deficiency (MSD) (MIM:272200) (Schmidt et al. 1995). Authored: Jassal, B, 2011-10-21 EC Number: 3.1.6.12 Edited: Jassal, B, 2011-10-21 Pubmed12888274 Pubmed738706 Pubmed7628016 Pubmed9521684 Reactome Database ID Release 431793207 Reactome, http://www.reactome.org ReactomeREACT_120889 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352168 Reactome, http://www.reactome.org PI(4,5)P2 is hydrolysed to I(1,4,5)P3 and DAG by cytosolic PLC[2] at the plasma membrane At the plasma membrane, a group of phospholipase C (“PLC(bz))” proteins hydrolyse phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) to inositol 1,4,5 trisphosphate (I(1,4,5)P3) and diacylglycerol (DAG). This group of phospholipase C proteins lack a PH domain and so are is cytosolic. Their C2 domains bind to PI(4,5)P2 at the membrane. The PLC-beta proteins are thought to be responsible for the majority of PI(4,5)P2 hydrolysis.<br><br>The phospholipase C isoforms involved and their corresponding literature references are: phosphoinositide phospholipase C beta-1 (PLCB1) (Caricasole et al. 2000, Jhon et al. 1993, Park et al. 1992); beta-2 (PLCB2) (Jhon et al. 1993, Park et al. 1992); beta-3 (PLCB3) (Carozzi et al. 1992, Jhon et al. 1993); beta-4 (PLCB4) (Alvarez et al. 1995, Lee et al. 1993); and zeta-1 (PLCZ1) (Kouchi et al. 2005, Rogers et al. 2004). Authored: Williams, MG, 2011-10-28 EC Number: 3.1.4.11 Edited: Williams, MG, 2011-10-28 Pubmed11118617 Pubmed1333955 Pubmed15579586 Pubmed15790568 Pubmed1644792 Pubmed8407970 Pubmed8454637 Pubmed8530101 Reactome Database ID Release 431855177 Reactome, http://www.reactome.org ReactomeREACT_150328 Reviewed: Challiss, John, 2012-11-09 ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352092 Reactome, http://www.reactome.org Iduronate 2-sulfatase (IDS) hydrolyses sulfates from L-iduronate 2-sulfate units of dermatan sulfate Authored: Jassal, B, 2011-10-21 EC Number: 3.1.6.13 Edited: Jassal, B, 2011-10-21 Iduronate 2-sulfatase (IDS) hydrolyses 2-sulfate groups from L-iduronate 2-sulfate units of dermatan sulfate in the lysosome. Defects in IDS are the cause of mucopolysaccharidosis type II (MPSII, MIM:309900), also called Hunter syndrome (Wilson et al. 1990). Pubmed2122463 Reactome Database ID Release 431793182 Reactome, http://www.reactome.org ReactomeREACT_120781 Reviewed: D'Eustachio, P, 2012-03-28 Arylsulfatase B (ARSB) hydrolyses sulfate groups from GalNAc 4-sulfate units of DS Arylsulfatase B (ARSB) hydrolyses sulfate from N-acetylgalactosamine 4-sulfate units within dermatan sulfate (DS; Gorham & Cantz 1978). The conversion to 3-oxoalanine (formylglycine, FGly) of a cysteine residue in eukaryotes, is critical for catalytic activity, based on similarity to the prototypical arylsulfatase ARSA (Chruszcz et al. 2003, Lukatela et al. 1998). Defects in ARSB are the cause of mucopolysaccharidosis type VI (MPSVI) (MIM:253200, also called Maroteaux-Lamy syndrome (Wicker et al. 1991). ARSB activity is defective in multiple sulfatase deficiency (MSD) (MIM:272200) (Schmidt et al. 1995). Authored: Jassal, B, 2011-09-27 EC Number: 3.1.6.12 Edited: Jassal, B, 2011-09-27 Pubmed12888274 Pubmed738706 Pubmed7628016 Pubmed9521684 Reactome Database ID Release 431606789 Reactome, http://www.reactome.org ReactomeREACT_121276 Reviewed: D'Eustachio, P, 2012-03-28 Alpha-L-iduronidase (IDUA) hydrolyses the unsulfated alpha-L-iduronosidic linkage in DS Authored: Jassal, B, 2011-10-21 EC Number: 3.2.1.76 Edited: Jassal, B, 2011-10-21 Pubmed1946389 Pubmed8213840 Reactome Database ID Release 431793186 Reactome, http://www.reactome.org ReactomeREACT_121062 Reviewed: D'Eustachio, P, 2012-03-28 The lysosomal enzyme alpha-L-iduronidase (IDUA) hydrolyzes the nonreducing terminal iduronide glycosidic bond in heparan sulfate and dermatan sulfate (Scott et al. 1991). Defects in IDUA cause mucopolysaccharidosis type IH (MIM:607014, also called Hurler syndrome), mucopolysaccharidosis type IH/S (MIM:607015, also called HurlerScheie syndrome) and mucopolysaccharidosis type IS (MIM:607016, also called Scheie syndrome) (Scott et al. 1993). Beta-hexosaminidase A (BHEXA) cleaves the terminal GalNAc from DS Authored: Jassal, B, 2012-02-09 Beta-hexosaminidase A (bHEXA) cleaves the terminal N-acetyl galactosamine (GalNAc) from glucosaminoglycans (GAGs) and any other molecules containing a terminal GalNAc. There are two forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988). Defects in the two subunits cause lysosomal storage diseases marked by the accumulation of GM2 gangliosides in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991). EC Number: 3.2.1.52 Edited: Jassal, B, 2012-02-09 Pubmed1720305 Pubmed2970528 Pubmed2971395 Reactome Database ID Release 432105001 Reactome, http://www.reactome.org ReactomeREACT_121316 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0008028 Reactome Database ID Release 43429740 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005310 Reactome Database ID Release 43372844 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0022803 Reactome Database ID Release 43429741 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43375408 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43375415 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005310 Reactome Database ID Release 43372844 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0005276 Reactome Database ID Release 43936483 Reactome, http://www.reactome.org PI(4,5)P2 is hydrolysed to I(1,4,5)P3 and DAG by tethered PLC[1] at the plasma membrane A group of phospholipase C proteins (“PLC(degh)”) bind to the plasma membrane via their PH domains. These phospholipases hydrolyse phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) to inositol 1,4,5 trisphosphate (I(1,4,5)P3) and diacylglycerol (DAG). The C2 domains of the enzymes bind to PI(4,5)P2 at the membrane.<br><br>The phospholipase C isoforms involved and their corresponding literature references are: phosphoinositide phospholipase C delta-1(PLCD1) (Cheng et al. 1995); epsilon-1 (PLCE1) (Song et al. 2001, Lopez et al. 2001); delta-3 (PLCD3) (Pawelczyk & Matecki 1997); gamma-1 (PLCG1) (Harita et al. 2009, Baldassare et al. 1989); gamma-2 (PLCG2) (Banno et al. 1988); eta-1 (PLCH1) (Hwang et al. 2005); and eta-2 (PLCH2) (Zhou et al 2005). Authored: Williams, MG, 2011-10-28 EC Number: 3.1.4.11 Edited: Williams, MG, 2011-10-28 Pubmed11022047 Pubmed11022048 Pubmed15702972 Pubmed16107206 Pubmed19179337 Pubmed2550068 Pubmed2841328 Pubmed7890667 Pubmed9360711 Reactome Database ID Release 431855221 Reactome, http://www.reactome.org ReactomeREACT_150377 Reviewed: Challiss, John, 2012-11-09 PI(4,5)P2 is hydrolysed to I(1,4,5)P3 and DAG by PLCD4 at the ER membrane At the endoplasmic reticulum (ER) membrane, phosphoinositide phospholipase C delta-4 (PLCD4) hydrolyses phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to inositol 1,4,5-trisphosphate (I(1,4,5)P3) and diacylglycerol (DAG). PLCD4 (Leung et al. 2004, Lee et al. 2004) is attached to the ER membrane via its PH domain while its C2 domain binds to the PI(4,5)P2 in the membrane. Authored: Williams, MG, 2011-10-28 EC Number: 3.1.4.11 Edited: Williams, MG, 2011-10-28 Pubmed15037625 Pubmed15140260 Reactome Database ID Release 431855214 Reactome, http://www.reactome.org ReactomeREACT_150317 Reviewed: Challiss, John, 2012-11-09 I(1,4,5)P3 is phosphorylated to I(1,3,4,5)P4 by ITPKA/B/C in the cytosol Authored: Williams, MG, 2011-10-28 EC Number: 2.7.1.127 Edited: Williams, MG, 2011-10-28 Inositol-trisphosphate 3-kinase A (ITPKA), B (ITPKB), and C (ITPKC) phosphorylate inositol 1,4,5-trisphosphate (I(1,4,5)P3) to inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) (Dewaste et al. 2003). Pubmed12747803 Reactome Database ID Release 431855153 Reactome, http://www.reactome.org ReactomeREACT_150282 Reviewed: Challiss, John, 2012-11-09 I(1,3,4,5)P4 is dephosphorylated to I(1,4,5)P3 by PTEN in the cytosol Authored: Williams, MG, 2011-10-28 Edited: Williams, MG, 2011-10-28 Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) to inositol 1,4,5-trisphosphate (I(1,4,5)P3) (Maehama & Dixon 1998, Han et al. 2000). Pubmed10866302 Pubmed9593664 Reactome Database ID Release 431855205 Reactome, http://www.reactome.org ReactomeREACT_150242 Reviewed: Challiss, John, 2012-11-09 ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43379423 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43379413 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008508 Reactome Database ID Release 43433106 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43379445 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43375789 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43375782 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43378514 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43376185 Reactome, http://www.reactome.org Imidazoquinoline compounds Converted from EntitySet in Reactome Reactome DB_ID: 1216503 Reactome Database ID Release 431216503 Reactome, http://www.reactome.org ReactomeREACT_27809 ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43375796 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43375775 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43375486 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352388 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352388 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352361 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352361 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352361 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352361 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352154 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43375470 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015171 Reactome Database ID Release 43352233 Reactome, http://www.reactome.org TLR6:TLR2 recognized ligand Converted from EntitySet in Reactome Reactome DB_ID: 181407 Reactome Database ID Release 43181407 Reactome, http://www.reactome.org ReactomeREACT_8552 Imidazoquinoline compounds Converted from EntitySet in Reactome Reactome DB_ID: 188128 Reactome Database ID Release 43188128 Reactome, http://www.reactome.org ReactomeREACT_9276 NLRP3 elicitor small molecules Converted from EntitySet in Reactome Reactome DB_ID: 877245 Reactome Database ID Release 43877245 Reactome, http://www.reactome.org ReactomeREACT_76093 ACTIVATION GENE ONTOLOGYGO:0008028 Reactome Database ID Release 43434169 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015307 Reactome Database ID Release 43446610 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015137 Reactome Database ID Release 43433103 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015362 Reactome Database ID Release 43433132 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43445081 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 431181353 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004842 Reactome Database ID Release 432064880 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015382 Reactome Database ID Release 43433100 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015361 Reactome Database ID Release 43433125 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015382 Reactome Database ID Release 43433110 Reactome, http://www.reactome.org Further sulfation on galactose residues produces KSPG Authored: Jassal, B, 2011-12-01 Carbohydrate sulfotransferase 1 (CHST1, keratan sulfate Gal-6 sulfotransferase) mediates the sulfation of galactose (Gal) on position 6 in keratan sulfate proteoglycans (KSPGs) (Fukuta et al. 1997). EC Number: 2.8.2.21 Edited: Jassal, B, 2011-12-01 Pubmed9405439 Reactome Database ID Release 432046175 Reactome, http://www.reactome.org ReactomeREACT_121317 Reviewed: D'Eustachio, P, 2012-03-28 Collagen alpha-1(VIII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192731 Reactome Database ID Release 432192731 Reactome, http://www.reactome.org ReactomeREACT_123532 Beta-hexosaminidase A (BHEXA) cleaves the terminal GalNAc from keratan sulfate Authored: Jassal, B, 2011-10-05 Beta-hexosaminidase A (bHEXA) cleaves the terminal N-acetyl galactosamine (GalNAc) from glucosaminoglycans (GAGs) and any other molecules containing a terminal GalNAc. There are two forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988). Defects in the two subunits cause lysosomal storage diseases marked by the accumulation of GM2 gangliosides in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991). EC Number: 3.2.1.52 Edited: Jassal, B, 2011-10-05 Pubmed1720305 Pubmed2970528 Pubmed2971395 Reactome Database ID Release 431638053 Reactome, http://www.reactome.org ReactomeREACT_120972 Reviewed: D'Eustachio, P, 2012-03-28 Xylose is transferred to a serine residue on the core protein Authored: Jassal, B, 2011-10-31 EC Number: 2.4.2.26 Edited: Jassal, B, 2011-10-31 Pubmed11099377 Pubmed15294915 Pubmed15461586 Reactome Database ID Release 431878002 Reactome, http://www.reactome.org ReactomeREACT_120955 Reviewed: D'Eustachio, P, 2012-03-28 Xylosyltransferase 1 (XYLT1) catalyses the initial step in the tetrasaccharide linkage required for glycosaminoglycan biosynthesis. This reaction can take place in the Golgi apparatus and endoplasmic reticulum (not shown here). XYLT1 mediates the transfer of xylose from the active nucleotide sugar UDP-xylose to specific serine hydroxy groups in the core protein. A C-terminal DxD motif on the enzyme is thought to be critical for activity (Muller et al. 2005, Goetting et al. 2004). Xylosyltransferase 2 (XYLT2) belongs to the XYLT family, displaying 55% amino acid sequence homology to XYLT1, whose activity has yet to be demonstrated (Goetting et al. 2000). Beta-galactosidase (GLB1) can cleave galactose from a glycosaminoglycan Authored: Jassal, B, 2011-10-05 Beta-galactosidase (GLB1) can cleave terminal galactose residues from glycosaminoglycans such as keratan sulfate (KS) (Asp et al. 1969). Defects in GLB1 cause the lysosomal storage diseases GM1gangliosidosis (Yoshida et al. 1991) and Morquio syndrome type B (Oshima et al. 1991). EC Number: 3.2.1.23 Edited: Jassal, B, 2011-10-05 Pubmed1907800 Pubmed1928092 Pubmed5822067 Reactome Database ID Release 431630306 Reactome, http://www.reactome.org ReactomeREACT_120986 Reviewed: D'Eustachio, P, 2012-03-28 N-acetylglucosamine 6-sulfatase (GNS) hydrolyses 6-sulfate groups of the N-acetyl-D-glucosamine 6-sulfate units of keratan sulfate Authored: Jassal, B, 2011-10-05 EC Number: 3.1.6.14 Edited: Jassal, B, 2011-10-05 N-acetylglucosamine 6-sulfatase (GNS) is a lysosomal enzyme which degrades glycosaminoglycans such as heparan sulfate and keratan sulfate. GNS shows strong sequence similarity to other sulphatases such as the family of arylsulfatases and the conversion to 3-oxo-alanine (formylglycine, FGly) of a cysteine residue is critical for catalytic activity, based on this similarity (Robertson et al. 1992, Robertson et al. 1988). Defects in GNS are the cause of mucopolysaccharidosis type IIID (MPSIIID, MIM:252940), also called Sanfilippo D syndrome (Valstar et al. 2010). Pubmed1463457 Pubmed20232353 Pubmed3196333 Reactome Database ID Release 431638032 Reactome, http://www.reactome.org ReactomeREACT_120828 Reviewed: D'Eustachio, P, 2012-03-28 Keratan sulfate is cleaved from its proteoglycan by an unknown galactosidase Authored: Jassal, B, 2011-10-21 EC Number: 3.2.1.23 Edited: Jassal, B, 2011-10-21 Keratan sulfate (KS) is cleaved from its KS proteoglycan (KSPG) by an as yet unknown beta-galactosidase. It performs a similar function to beta-galactosidase GLB1 (Asp et al. 1969). A simplified version of KS is used to demonstrate cleavage reactions. Pubmed5822067 Reactome Database ID Release 431793217 Reactome, http://www.reactome.org ReactomeREACT_121072 Reviewed: D'Eustachio, P, 2012-03-28 N-acetylgalactosamine-6-sulfatase (GALNS) hydrolyses the sulfate groups of galactose 6-sulfate units of keratan sulfate Authored: Jassal, B, 2011-10-05 EC Number: 3.1.6.4 Edited: Jassal, B, 2011-10-05 N-acetylgalactosamine 6-sulfate sulfatase (GALNS) hydrolyses sulfate from galactose 6-sulfate units of keratan sulfate (KS, shown here) and sulfate from N-acetyl-D-galactosamine 6-sulfate units of chondroitin sulfate (CS, not shown) (Lim & Horwitz 1981, Masue et al. 1991). The conversion to 3-oxoalanine (C-formylglycine, FGly) of a cysteine residue in eukaryotes, is critical for catalytic activity, based on similarity to the prototypical arylsulfatase ARSA (Chruszcz et al. 2003, Lukatela et al. 1998). Defects in GALNS cause mucopolysaccharidosis type IVA (MPSIVA, MIM:253000), also called Morquio A syndrome, a lysosomal storage disease characterized by intracellular accumulation of KS and CS (Fukuda et al. 1992). Pubmed12888274 Pubmed1522213 Pubmed1794986 Pubmed7213753 Pubmed9521684 Reactome Database ID Release 431630304 Reactome, http://www.reactome.org ReactomeREACT_121094 Reviewed: D'Eustachio, P, 2012-03-28 KSPG is secreted from the cell Authored: Jassal, B, 2011-12-01 Edited: Jassal, B, 2011-12-01 Once formed, keratan sulfate proteoglycans (KSPGs) are secreted from the cell into the extracellular matrix (ECM) by an unknown translocation mechanism (Funderburgh 2000). KSPG can bind with many cell surface and extracellular proteins. Pubmed11030741 Reactome Database ID Release 432046180 Reactome, http://www.reactome.org ReactomeREACT_121178 Reviewed: D'Eustachio, P, 2012-03-28 Extracellular KSPG translocates to the lysosome for degradation As part of the natural turnover of GAGs, extracellular KSPGs translocate to the lysosome to be degraded. The translocation process is unsure but could be either endocytosis from outside the cell or autophagy from inside the cell (Winchester 2005). Authored: Jassal, B, 2012-01-11 Edited: Jassal, B, 2012-01-11 Pubmed15647514 Reactome Database ID Release 432046239 Reactome, http://www.reactome.org ReactomeREACT_121303 Reviewed: D'Eustachio, P, 2012-03-28 Procollagen type I Reactome DB_ID: 2268676 Reactome Database ID Release 432268676 Reactome, http://www.reactome.org ReactomeREACT_123566 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Collagens and tropocollagens:Serpin H1 Reactome DB_ID: 2187527 Reactome Database ID Release 432187527 Reactome, http://www.reactome.org ReactomeREACT_123739 has a Stoichiometric coefficient of 1 Collagen type VI tetramer Reactome DB_ID: 1614493 Reactome Database ID Release 431614493 Reactome, http://www.reactome.org ReactomeREACT_122747 has a Stoichiometric coefficient of 2 Collagen type VI dimer Reactome DB_ID: 1614447 Reactome Database ID Release 431614447 Reactome, http://www.reactome.org ReactomeREACT_123281 has a Stoichiometric coefficient of 2 Procollagen type V Converted from EntitySet in Reactome Reactome DB_ID: 2268660 Reactome Database ID Release 432268660 Reactome, http://www.reactome.org ReactomeREACT_121686 Sulfation of GlcNAc residues on Keratan-PG forms KSPG Authored: Jassal, B, 2011-12-01 Carbohydrate sulfotransferases 2, 5 and 6 (CHST2, 5 and 6) catalyse the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues within keratan-like molecules (Sakaguchi et al. 2000, Lee et al. 1999, Akama et al. 2002). Edited: Jassal, B, 2011-12-01 Pubmed10491328 Pubmed11042394 Pubmed12218059 Reactome Database ID Release 432046222 Reactome, http://www.reactome.org ReactomeREACT_121283 Reviewed: D'Eustachio, P, 2012-03-28 Procollagen type III Reactome DB_ID: 2268686 Reactome Database ID Release 432268686 Reactome, http://www.reactome.org ReactomeREACT_122703 has a Stoichiometric coefficient of 3 The keratan chain can be capped by N-acetylneuraminic acid Authored: Jassal, B, 2011-12-01 EC Number: 2.4.99.4 Edited: Jassal, B, 2011-12-01 Pubmed10206952 Pubmed10504389 Pubmed8333853 Pubmed8611500 Pubmed8920913 Reactome Database ID Release 432046285 Reactome, http://www.reactome.org ReactomeREACT_121285 Reviewed: D'Eustachio, P, 2012-03-28 The human genes ST3GAL1-4 and 6 encode for sialyltransferase1-4 and 6 respectively (Shang et al. 1999, Kim et al. 1996, Kitagawa and Paulson, 1993, Basu et al. 1993, Okajima et al. 1999). They add a sialyl residue to the growing keratan chain, blocking any further chain elongation. Procollagen type II Reactome DB_ID: 2268711 Reactome Database ID Release 432268711 Reactome, http://www.reactome.org ReactomeREACT_125177 has a Stoichiometric coefficient of 3 Collagen type VI Reactome DB_ID: 2060916 Reactome Database ID Release 432060916 Reactome, http://www.reactome.org ReactomeREACT_123415 has a Stoichiometric coefficient of 1 Collagen type XXV Reactome DB_ID: 2192641 Reactome Database ID Release 432192641 Reactome, http://www.reactome.org ReactomeREACT_123681 has a Stoichiometric coefficient of 3 Collagen type XXIII Reactome DB_ID: 2192639 Reactome Database ID Release 432192639 Reactome, http://www.reactome.org ReactomeREACT_122259 has a Stoichiometric coefficient of 3 B4GALTs add galactose to the N-glycan precursor Authored: Jassal, B, 2011-12-15 EC Number: 2.4.1.38 Edited: Jassal, B, 2011-12-15 Pubmed11588157 Pubmed11901181 Pubmed17021253 Pubmed1714903 Pubmed9597550 Reactome Database ID Release 432025723 Reactome, http://www.reactome.org ReactomeREACT_120962 Reviewed: D'Eustachio, P, 2012-03-28 The family of beta 4-galactosyltransferases (B4GALTs) is composed of at least six known members with different Km and acceptor specifities (Guo et al. 2001) that probably originated by gene duplication (Lo et al. 1998). They mediate the transfer of galactose to N-glycan structures which form the beginning of keratan sulfate biosynthesis. B4GALT1 is associated with Congenital Disorder of Glycosylation of type IId (Hansske et al. 2002), and is expressed as two splicing isoforms of which only one is localizated in the Golgi system (Lopez et al. 1991, Schaub et al. 2006). Collagen type XVI Reactome DB_ID: 2187502 Reactome Database ID Release 432187502 Reactome, http://www.reactome.org ReactomeREACT_122319 has a Stoichiometric coefficient of 3 B3GNT1,2,3,4,7 add GlcNAc to form Keratan-PG Authored: Jassal, B, 2011-12-15 EC Number: 2.4.1.149 Edited: Jassal, B, 2011-12-15 Pubmed11042166 Pubmed11283017 Pubmed11821425 Pubmed15486459 Pubmed15560372 Pubmed15620693 Pubmed9417100 Reactome Database ID Release 432025724 Reactome, http://www.reactome.org ReactomeREACT_121143 Reviewed: D'Eustachio, P, 2012-03-28 The UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase family (B3GNTs) consists of 9 members in humans (Kolbinger et al, 1998; Shiraishi et al, 2001; Togayachi et al, 2001; Iwai et al, 2002; Huang et al, 2004; Ishida et al, 2005; Zheng et al, 2004). Members 1,2,3,4 and 7 can catalyse the addition of N-acetylglucosamine (GlcNAc) to the galactosyl residue of the sachharide chain in a beta-1,3 linkage to form a structure called Keratan-proteoglycan (PG). B4GALTs add another galactose to the chain Authored: Jassal, B, 2011-12-01 EC Number: 2.4.1.38 Edited: Jassal, B, 2011-12-01 Pubmed11588157 Pubmed11901181 Pubmed17021253 Pubmed1714903 Pubmed9597550 Reactome Database ID Release 432046265 Reactome, http://www.reactome.org ReactomeREACT_120893 Reviewed: D'Eustachio, P, 2012-03-28 The family of beta 4-galactosyltransferases (B4GALTs) is composed by at least six known members with different Km and acceptor specifities (Guo et al. 2001) and probably originated by duplication (Lo et al. 1998). They mediate the transfer of galactose to N-glycan structures, either to begin, or in this case, to elongate keratan chains. B4GALT1 is associated with Congenital Disorder of Glycosylation of type IId (Hansske et al. 2002), and is expressed as two splicing isoforms of which only one is localizated in the Golgi system (Lopez et al. 1991, Schaub et al. 2006). B4GALTs can add galactose to a branch of keratan Authored: Jassal, B, 2011-12-01 EC Number: 2.4.1.38 Edited: Jassal, B, 2011-12-01 Pubmed11588157 Pubmed11901181 Pubmed17021253 Pubmed1714903 Pubmed9597550 Reactome Database ID Release 432046298 Reactome, http://www.reactome.org ReactomeREACT_120770 Reviewed: D'Eustachio, P, 2012-03-28 The family of beta 4-galactosyltransferases (B4GALTs) is composed by at least six known members with different Km and acceptor specifities (Guo et al. 2001) that probably originated by gene duplication (Lo et al. 1998). They mediate the transfer of galactose to N-glycan structures, in this case, to elongate a branched chain of keratan. B4GALT1 is associated with Congenital Disorder of Glycosylation of type IId (Hansske et al. 2002), and is expressed as two splicing isoforms of which only one is localizated in the Golgi system (Lopez et al. 1991, Schaub et al. 2006). Beta-glucuronidase (GUSB) hydrolyses glucuronate from HA tetrasaccharides Authored: Jassal, B, 2012-03-16 EC Number: 3.2.1.31 Edited: Jassal, B, 2012-03-16 Pubmed11568288 Pubmed3468507 Reactome Database ID Release 432162227 Reactome, http://www.reactome.org ReactomeREACT_121043 Reviewed: D'Eustachio, P, 2012-03-28 The tetrameric lysosomal enzyme beta-glucuronidase hydrolyses glucuronate from the HA tetrasaccharide (Oshima et al. 1987) resulting in the single sugars glucuronic acid and N-acetylglucosamine. These single sugars can exit the lysosome by an unknown mechanism. L-aspartic acid is an inhibitor of enzyme activity (Kreamer et al. 2001). Beta-hexosaminidase A (BHEXA) cleaves the terminal GalNAc from small HA fragments Authored: Jassal, B, 2012-03-16 Beta-hexosaminidase A (bHEXA) cleaves the terminal N-acetyl galactosamine (GalNAc) from glucosaminoglycans (GAGs) and any other molecules containing a terminal GalNAc. There are two forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988). Defects in the two subunits cause lysosomal storage diseases marked by the accumulation of GM2 gangliosides in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991). EC Number: 3.2.1.52 Edited: Jassal, B, 2012-03-16 Pubmed1720305 Pubmed2970528 Pubmed2971395 Reactome Database ID Release 432162225 Reactome, http://www.reactome.org ReactomeREACT_121200 Reviewed: D'Eustachio, P, 2012-03-28 Beta-glucuronidase (GUSB) hydrolyses glucuronate from the HA disaccharides Authored: Jassal, B, 2012-03-16 EC Number: 3.2.1.31 Edited: Jassal, B, 2012-03-16 Pubmed11568288 Pubmed3468507 Reactome Database ID Release 432162226 Reactome, http://www.reactome.org ReactomeREACT_120758 Reviewed: D'Eustachio, P, 2012-03-28 The tetrameric lysosomal enzyme beta-glucuronidase hydrolyses glucuronate from the HA disaccharide (Oshima et al. 1987) resulting in the single sugars glucuronic acid and N-acetylglucosamine. These single sugars can exit the lysosome by an unknown mechanism. L-aspartic acid is an inhibitor of enzyme activity (Kreamer et al. 2001). The single sugars GlcA and GlcNAc translocate from the lysosome to the cytosol Authored: Jassal, B, 2012-03-16 Edited: Jassal, B, 2012-03-16 Glucuronate and N-acetylglucosamine exit the lysosome into the cytosol, ready for reuse in GAG biosynthesis. The mechanism of translocation is unknown (for reviews see Stern 2004, Stern 2003). Pubmed14514708 Pubmed15503855 Reactome Database ID Release 432162229 Reactome, http://www.reactome.org ReactomeREACT_121138 Reviewed: D'Eustachio, P, 2012-03-28 Collagen type XXI Reactome DB_ID: 2192646 Reactome Database ID Release 432192646 Reactome, http://www.reactome.org ReactomeREACT_122209 has a Stoichiometric coefficient of 3 Tropocollagen type XX Reactome DB_ID: 2192645 Reactome Database ID Release 432192645 Reactome, http://www.reactome.org ReactomeREACT_122317 has a Stoichiometric coefficient of 3 Tropocollagen type XXVI Reactome DB_ID: 2192650 Reactome Database ID Release 432192650 Reactome, http://www.reactome.org ReactomeREACT_125272 has a Stoichiometric coefficient of 3 Tropocollagen type XXII Reactome DB_ID: 2192649 Reactome Database ID Release 432192649 Reactome, http://www.reactome.org ReactomeREACT_124010 has a Stoichiometric coefficient of 3 20kDa HA fragments are translocated to lysosomes Authored: Jassal, B, 2012-03-05 Edited: Jassal, B, 2012-03-05 Pubmed11827788 Pubmed22216413 Reactome Database ID Release 432160906 Reactome, http://www.reactome.org ReactomeREACT_121181 Reviewed: D'Eustachio, P, 2012-03-28 The smallest fragments HYAL2 can generate are 20kDa (approximately 50 disaccharide unit) HA fragments. These fragments are internalized and delivered to lysosomes (Knudson et al. 2002, Erickson & Stern 2012) where another hyalurindase, HYAL1, can degrade them further. Transmembrane collagens Converted from EntitySet in Reactome Reactome DB_ID: 2152293 Reactome Database ID Release 432152293 Reactome, http://www.reactome.org ReactomeREACT_124103 Hyaluronidase 2 (HYAL2) hydrolyses HA into 20kDa fragments Authored: Jassal, B, 2012-03-05 EC Number: 3.2.1.35 Edited: Jassal, B, 2012-03-05 In acidic conditions, hyaluronidase 2 (HYAL2), a membrane-anchored protein, hydrolyses high molecular weight HA into approximately 20kDa (50 disaccharide unit) fragments (Lepperdinger et al. 1998, Jedrzejas & Stern 2005). Pubmed16104017 Pubmed9712871 Reactome Database ID Release 432160892 Reactome, http://www.reactome.org ReactomeREACT_120971 Reviewed: D'Eustachio, P, 2012-03-28 Tropocollagen type XXVIII Reactome DB_ID: 2192651 Reactome Database ID Release 432192651 Reactome, http://www.reactome.org ReactomeREACT_122305 has a Stoichiometric coefficient of 3 Collagen type XVII Reactome DB_ID: 2187525 Reactome Database ID Release 432187525 Reactome, http://www.reactome.org ReactomeREACT_121881 has a Stoichiometric coefficient of 3 Hyaluronidase 1 (HYAL1) hydrolyses HA from 20kDa to 800Da fragments Authored: Jassal, B, 2012-03-05 EC Number: 3.2.1.35 Edited: Jassal, B, 2012-03-05 In the acid environment of the lysosome, hyaluronidase 1 (HYAL1) is able to hydrolyse large 20kDa HA fragments (approximately 50 disaccharide units) to 800 Da fragments (2 disaccharide units). Pubmed16104017 Reactome Database ID Release 432160874 Reactome, http://www.reactome.org ReactomeREACT_121183 Reviewed: D'Eustachio, P, 2012-03-28 Collagen type XIII Reactome DB_ID: 2187521 Reactome Database ID Release 432187521 Reactome, http://www.reactome.org ReactomeREACT_122350 has a Stoichiometric coefficient of 3 Collagen type XIX Reactome DB_ID: 2192648 Reactome Database ID Release 432192648 Reactome, http://www.reactome.org ReactomeREACT_125660 has a Stoichiometric coefficient of 3 Collagen type XVIII Reactome DB_ID: 2192647 Reactome Database ID Release 432192647 Reactome, http://www.reactome.org ReactomeREACT_124583 has a Stoichiometric coefficient of 3 HS3ST1 sulfates GlcN at C3 in heparan sulfate Authored: Jassal, B, 2012-01-27 EC Number: 2.8.2.23 Edited: Jassal, B, 2012-01-27 Heparan sulfate 3-O-sulfotransferase1 (HS3ST1) transfers sulfate to the 3-OH position on glucosamine (GlcN) residues of heparan sulfate (HS) to form 3-O-sulfated HS. HS3ST1 is the rate limiting enzyme for synthesis of anticoagulant heparan sulfate. Unlike the other members of the HS3ST family, it is probably located in the Golgi lumen (Shworak et al. 1997). Pubmed9346953 Reactome Database ID Release 432076383 Reactome, http://www.reactome.org ReactomeREACT_120741 Reviewed: D'Eustachio, P, 2012-03-28 GLCE epimerises more GlcA to IdoA as sulfate content rises As the sulfate content rises, so does the iduronic acid:glucuronic acid ratio. Once glucosamine is sulfated, glucuronic acid (GlcA) is epimerised to iduronic acid (IdoA). The enzyme glucuronyl C5-epimerase (GLCE) mediates this reaction, evidence of function and cellular location coming from mouse studies (Li et al. 2001, Crawford et al. 2001). The distinction between HS and heparin is fairly arbritary but generally, low-sulfated and GlcA-rich polysaccharides are called HS and high-sulfated and IdoA-rich polysaccharides are called heparin. It can be argued that this structure can now be called either heparan sulfate-PG or heparin-PG. Authored: Jassal, B, 2012-01-27 EC Number: 5.1.3.12 Edited: Jassal, B, 2012-01-27 Pubmed11274177 Pubmed11279150 Reactome Database ID Release 432076371 Reactome, http://www.reactome.org ReactomeREACT_120946 Reviewed: D'Eustachio, P, 2012-03-28 HS3STs sulfate GlcN at C3 in heparan sulfate Authored: Jassal, B, 2012-01-27 EC Number: 2.8.2.23 Edited: Jassal, B, 2012-01-27 Heparan sulfate 3-O-sulfotransferases (HS3ST2-6) transfer sulfate to the 3-OH position on glucosamine (GlcN) residues of heparan sulfate (HS) to form 3-O-sulfated HS (Shworak et al. 1999, Xia et al. 2002). HS3ST2-6 do not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate. Pubmed12138164 Pubmed9346953 Pubmed9988767 Reactome Database ID Release 432076611 Reactome, http://www.reactome.org ReactomeREACT_120839 Reviewed: D'Eustachio, P, 2012-03-28 HS-GAGs translocate to the lysosome for degradation As part of the natural turnover of GAGs, extracellular KSPGs translocate to the lysosome to be degraded. The translocation process is unsure but could be either endocytosis from outside the cell and/or autophagy from inside the cell (Winchester 2005). Authored: Jassal, B, 2011-12-14 Edited: Jassal, B, 2011-12-14 Pubmed15647514 Reactome Database ID Release 432024084 Reactome, http://www.reactome.org ReactomeREACT_121392 Reviewed: D'Eustachio, P, 2012-03-28 Heparanase (HPSE) cleaves heparan sulfate from its proteoglycan (lysosome) Authored: Jassal, B, 2011-12-14 Edited: Jassal, B, 2011-12-14 Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate (HS) from its HS proteoglycan (HSPG) (Toyoshima & Nakajima 1999). The formation of a heterodimer of 8kDa and 50kDa subunits cleaved from the 65kDa form is required for enzyme activity (Levy-Adam et al. 2003) and this proteolytic cleavage occurs in the lysosome (Goldshmidt et al. 2002). Acidic conditions within the lysosome optimises HPSE activity. Pubmed10446189 Pubmed12441129 Pubmed12927802 Reactome Database ID Release 431667005 Reactome, http://www.reactome.org ReactomeREACT_121335 Reviewed: D'Eustachio, P, 2012-03-28 HS6STs sulfate GlcN at C6 in heparan sulfate/heparin Authored: Jassal, B, 2012-01-27 Edited: Jassal, B, 2012-01-27 Heparan-sulfate 6-O-sulfotransferases 1 and 2 (HS3ST1-2) (Habuchi et al. 1998, Habuchi et al. 2003 respectively) catalyze the transfer of sulfate to C6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate. A third member HS3ST3 that may also mediate this reaction has been characterised in mouse (Habuchi et al. 2000) but remains uncharacterised in humans. It can be argued that this structure can now be called either heparan sulfate- or heparin-PG. Pubmed10644753 Pubmed12492399 Pubmed9535912 Reactome Database ID Release 432076419 Reactome, http://www.reactome.org ReactomeREACT_120849 Reviewed: D'Eustachio, P, 2012-03-28 Some HSPGs are secreted to the plasma membrane Authored: Jassal, B, 2011-12-14 Depending on the nature of the core protein HS-GAGs are attached to, they will either translocate to the cell surface or be secreted into the extracellular matrix (ECM). Here, HS-GAGs are shown to translocate to the cell surface (Kjellen & Lindahl, 1991). The mechanism of transfer from the Golgi apparatus to the cell surface and beyond is unknown but most likely involves the trans-Golgi network. Edited: Jassal, B, 2011-12-14 Pubmed10716625 Reactome Database ID Release 432024108 Reactome, http://www.reactome.org ReactomeREACT_121021 Reviewed: D'Eustachio, P, 2012-03-28 N-sulphoglucosamine sulphohydrolase (SGSH) hydrolyses sulfate from the N-sulphoglucosamine residue of heparan sulfate Authored: Jassal, B, 2011-10-19 EC Number: 3.10.1.1 Edited: Jassal, B, 2011-10-19 N-sulphoglucosamine sulphohydrolase (SGSH) hydrolyses the sulfate group from the terminal N-sulphoglucosamine residue of heparan sulfate (Scott et al. 1995). Defects in SGSH cause mucopolysaccharidosis type IIIA (MPSIIIA, MIM:252900), also called Sanfilippo syndrome A (Weber et al. 1997). Pubmed7493035 Pubmed9285796 Reactome Database ID Release 431678708 Reactome, http://www.reactome.org ReactomeREACT_121274 Reviewed: D'Eustachio, P, 2012-03-28 has a Stoichiometric coefficient of 2 Heparanase 2 (HPSE2) cleaves heparan sulfate from its proteoglycan (plasma membrane) Authored: Jassal, B, 2011-10-19 Edited: Jassal, B, 2011-10-19 Heparanase 2 (HPSE2) (McKenzie et al. 2000) is a membrane-bound endoglycosidase that cleaves heparan sulfate (HS) from its HS proteoglycan (HSPG), either in the extracellular matrix or the basement membranes of cells. Defects in HPSE2 are the cause of urofacial syndrome (UFS) (MIM:236730) (Daly et al. 2010, Pang et al. 2010). Pubmed11027606 Pubmed20560209 Pubmed20560210 Reactome Database ID Release 431678694 Reactome, http://www.reactome.org ReactomeREACT_120961 Reviewed: D'Eustachio, P, 2012-03-28 Tropocollagen alpha-1(IV)X2 alpha-2(IV) Reactome DB_ID: 2089993 Reactome Database ID Release 432089993 Reactome, http://www.reactome.org ReactomeREACT_124906 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Alpha-L-iduronidase (IDUA) hydrolyses the unsulfated alpha-L-iduronosidic linkage in heparan sulfate An L-iduronic acid residue can be cleaved from either heparan sulfate or dermatan sulfate by the lysosomal enzyme alpha-L-iduronidase (IDUA) (Scott et al. 1991). Defects in IDUA are the cause of mucopolysaccharidosis type IH (MPS IH, Hurler syndrome, MIM:607014), mucopolysaccharidosis IH/S (MPSIH/S, HurlerScheie syndrome, MIM:607015) and mucopolysaccharidosis type IS (MPSIS, Scheie syndrome, MIM:607016) (LeeChen et al. 1999). Authored: Jassal, B, 2011-10-19 EC Number: 3.2.1.76 Edited: Jassal, B, 2011-10-19 Pubmed10466419 Pubmed1946389 Reactome Database ID Release 431678716 Reactome, http://www.reactome.org ReactomeREACT_120763 Reviewed: D'Eustachio, P, 2012-03-28 Tropocollagen alpha-5(IV)X2 alpha-6(IV) Reactome DB_ID: 2090010 Reactome Database ID Release 432090010 Reactome, http://www.reactome.org ReactomeREACT_124721 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Collagen type XV Reactome DB_ID: 2187528 Reactome Database ID Release 432187528 Reactome, http://www.reactome.org ReactomeREACT_123758 has a Stoichiometric coefficient of 3 Collagen type XIV Reactome DB_ID: 2187514 Reactome Database ID Release 432187514 Reactome, http://www.reactome.org ReactomeREACT_125567 has a Stoichiometric coefficient of 3 Collagen type XII Reactome DB_ID: 2187508 Reactome Database ID Release 432187508 Reactome, http://www.reactome.org ReactomeREACT_122963 has a Stoichiometric coefficient of 3 Tropocollagen type X Reactome DB_ID: 2187506 Reactome Database ID Release 432187506 Reactome, http://www.reactome.org ReactomeREACT_121558 has a Stoichiometric coefficient of 3 Collagen type IX Reactome DB_ID: 2187515 Reactome Database ID Release 432187515 Reactome, http://www.reactome.org ReactomeREACT_124876 has a Stoichiometric coefficient of 1 Tropocollagen type VIII Reactome DB_ID: 2187512 Reactome Database ID Release 432187512 Reactome, http://www.reactome.org ReactomeREACT_123456 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Procollagen type VII Reactome DB_ID: 2060923 Reactome Database ID Release 432060923 Reactome, http://www.reactome.org ReactomeREACT_123108 has a Stoichiometric coefficient of 3 Tropocollagen type VI Reactome DB_ID: 2187500 Reactome Database ID Release 432187500 Reactome, http://www.reactome.org ReactomeREACT_124562 has a Stoichiometric coefficient of 1 Tropocollagen alpha-3(IV), alpha-4(IV), alpha-5(IV) Reactome DB_ID: 2090016 Reactome Database ID Release 432090016 Reactome, http://www.reactome.org ReactomeREACT_121931 has a Stoichiometric coefficient of 1 Collagen alpha-1(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2193049 Reactome Database ID Release 432193049 Reactome, http://www.reactome.org ReactomeREACT_123433 A second galactose is added in the tetrasaccharide linker Authored: Jassal, B, 2011-11-01 Beta-1,3-galactosyltransferase 6 (B3GALT6) transfers a second galactose to the tetrasaccharide linker. Although it can act on substrates with a terminal beta-linked galactose residue, it prefers galactose-beta-1,4-xylose (Bai et al. 2001). B3GALT6 requires manganese as a cofactor (Zhou et al. 1999). EC Number: 2.4.1.134 Edited: Jassal, B, 2011-11-01 Pubmed11551958 Pubmed9892646 Reactome Database ID Release 431889978 Reactome, http://www.reactome.org ReactomeREACT_121213 Reviewed: D'Eustachio, P, 2012-03-28 A glucuronate moiety is the fourth addition to the tetrasaccharide linker Authored: Jassal, B, 2011-11-01 B3GAT1 (Kitagawa et al. 1998), 2 (Marcos et al. 2002) and 3 (Ouzzine et al. 2000) transfer a glucuronate residue via a beta1,3-linkage to a terminal galactose. The B3GATs are homodimeric and require manganese as a cofactor (Kakuda et al. 2004, Ouzzine et al. 2000). The tetrasaccharide linker is now complete, ready to accept further hexosamine additions. The type of hexosamine added is critical in determining which glycosaminoglycan (GAG) is formed. EC Number: 2.4.1.135 Edited: Jassal, B, 2011-11-01 Pubmed10842173 Pubmed12522689 Pubmed14993226 Pubmed9506957 Reactome Database ID Release 431889955 Reactome, http://www.reactome.org ReactomeREACT_120897 Reviewed: D'Eustachio, P, 2012-03-28 The addition of GlcNAc to the terminal glucuronate residue creates heparan Authored: Jassal, B, 2011-12-01 EC Number: 2.4.1.224 Edited: Jassal, B, 2011-12-01 Exostosin1 and 2 (EXT1 and 2) are dual-specificity enzymes which catalyse the addition of N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to the GAG-protein linker sequence. Heparan is synthesized once GlcNAc is transferred to this sequence. EXT1 and 2 form a heterodimer which translocates to the Golgi apparatus from the ER membrane (McCormick et al. 2000). Defects in EXT1 or 2 cause the hereditary bone disorders multiple exostoses type 1 (MIM:133700) and 2 (MIM:133701) (Wuyts et al. 1998, Bernard et al. 2001). Pubmed10639137 Pubmed11169766 Pubmed9463333 Reactome Database ID Release 432022919 Reactome, http://www.reactome.org ReactomeREACT_121277 Reviewed: D'Eustachio, P, 2012-03-28 Glucuronate is added to the heparan chain Authored: Jassal, B, 2011-12-01 EC Number: 2.4.1.225 Edited: Jassal, B, 2011-12-01 Exostosin1 and 2 (EXT1 and 2) are dual-specificity enzymes which catalyse the addition of N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to the GAG-protein linker sequence. The next addition mediated by these enzymes is that of glucuronate. EXT1 and 2 form a heterodimer which translocates to the Golgi apparatus from the ER membrane (McCormick et al. 2000). Defects in EXT1 or 2 cause the hereditary bone disorders multiple exostoses type 1 (MIM:133700) and 2 (MIM:133701) (Wuyts et al. 1998, Bernard et al. 2001). Pubmed10639137 Pubmed11169766 Pubmed9463333 Reactome Database ID Release 432022856 Reactome, http://www.reactome.org ReactomeREACT_121320 Reviewed: D'Eustachio, P, 2012-03-28 Another GlcNAc addition extends the heparan chain Authored: Jassal, B, 2011-12-01 EC Number: 2.4.1.224 Edited: Jassal, B, 2011-12-01 Exostosin1 and 2 (EXT1 and 2) are dual-specificity enzymes which catalyse the addition of N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to the GAG-protein linker sequence. Heparan is synthesized once GlcNAc is transferred to this sequence. EXT1 and 2 form a heterodimer which translocates to the Golgi apparatus from the ER membrane (McCormick et al. 2000). Defects in EXT1 or 2 cause the hereditary bone disorders multiple exostoses type 1 (MIM:133700) and 2 (MIM:133701) (Wuyts et al. 1998, Bernard et al. 2001). Pubmed10639137 Pubmed11169766 Pubmed9463333 Reactome Database ID Release 432022851 Reactome, http://www.reactome.org ReactomeREACT_121050 Reviewed: D'Eustachio, P, 2012-03-28 Another GlcA addition extends the heparan chain Authored: Jassal, B, 2012-01-27 EC Number: 2.4.1.225 Edited: Jassal, B, 2012-01-27 Exostosin1 and 2 (EXT1 and 2) are dual-specificity enzymes which catalyse the addition of N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to the GAG-protein linker sequence. The next addition mediated by these enzymes is that of glucuronate. EXT1 and 2 form a heterodimer which translocates to the Golgi apparatus from the ER membrane (McCormick et al. 2000). Defects in EXT1 or 2 cause the hereditary bone disorders multiple exostoses type 1 (MIM:133700) and 2 (MIM:133701) (Wuyts et al. 1998, Bernard et al. 2001). Pubmed10639137 Pubmed11169766 Pubmed9463333 Reactome Database ID Release 432076392 Reactome, http://www.reactome.org ReactomeREACT_120936 Reviewed: D'Eustachio, P, 2012-03-28 L-Amino Acids Converted from EntitySet in Reactome Reactome DB_ID: 1225821 Reactome Database ID Release 431225821 Reactome, http://www.reactome.org ReactomeREACT_111268 NDST1-4 N-deacetylates GlcNAc residues in heparan Authored: Jassal, B, 2011-12-01 EC Number: 3.5.1.33 Edited: Jassal, B, 2011-12-01 Pubmed11087757 Pubmed16343444 Pubmed7601448 Pubmed9915799 Reactome Database ID Release 432022887 Reactome, http://www.reactome.org ReactomeREACT_121110 Reviewed: D'Eustachio, P, 2012-03-28 The bifunctional enzymes heparan sulfate N-deacetylase/N-sulfotransferase 1-4 (NDST1-4) catalyse both the N-deacetylation and the N-sulfation of N-acetylglucosamine (GlcNAc) of heparan (Dixon et al. 1995, Duncan et al. 2006, Aikawa & Esko 1999, Aikawa et al. 2001). The N-deacetylation of a GlcNAc residue to a glucosamine residue is shown here. Procollagen type I Reactome DB_ID: 2187498 Reactome Database ID Release 432187498 Reactome, http://www.reactome.org ReactomeREACT_124638 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 NDST1-4 can sulfate a glucosamine residue in heparan to form heparan sulfate (HS) Authored: Jassal, B, 2011-12-01 EC Number: 2.8.2.8 Edited: Jassal, B, 2011-12-01 Pubmed11087757 Pubmed16343444 Pubmed7601448 Pubmed9915799 Reactome Database ID Release 432022860 Reactome, http://www.reactome.org ReactomeREACT_120811 Reviewed: D'Eustachio, P, 2012-03-28 The bifunctional enzymes heparan sulfate N-deacetylases/N-sulfotransferases 1-4 (NDST1-4) catalyse both the N-deacetylation and the N-sulfation of N-acetylglucosamine (GlcNAc) of heparan (Dixon et al. 1995, Duncan et al. 2006, Aikawa & Esko 1999, Aikawa et al. 2001). Once GlcNAc is deacetylated to glucosamine, the NDST enzymes can sulfate it on position 2 (N). has a Stoichiometric coefficient of 2 Procollagen type II Reactome DB_ID: 2187509 Reactome Database ID Release 432187509 Reactome, http://www.reactome.org ReactomeREACT_124978 has a Stoichiometric coefficient of 3 GLCE epimerises GlcA to IdoA As the sulfate content rises, so does the iduronic acid:glucuronic acid ratio. Once glucosamine is sulfated, glucuronic acid (GlcA) is epimerised to iduronic acid (IdoA). The enzyme glucuronyl C5-epimerase (GLCE) mediates this reaction, evidence of function and cellular location coming from mouse studies (Li et al. 2001, Crawford et al. 2001). The distinction between HS and heparin is fairly arbritary but generally, low-sulfated and GlcA-rich polysaccharides are called HS and high-sulfated and IdoA-rich polysaccharides are called heparin. It can be argued that this structure can now be called either heparan sulfate-PG or heparin-PG. Authored: Jassal, B, 2011-12-14 EC Number: 5.1.3.12 Edited: Jassal, B, 2011-12-14 Pubmed11274177 Pubmed11279150 Reactome Database ID Release 432024100 Reactome, http://www.reactome.org ReactomeREACT_120794 Reviewed: D'Eustachio, P, 2012-03-28 Procollagen type III Reactome DB_ID: 2187513 Reactome Database ID Release 432187513 Reactome, http://www.reactome.org ReactomeREACT_123003 has a Stoichiometric coefficient of 3 HS2ST1 sulfates IdoA at C2 in heparan sulfate Authored: Jassal, B, 2012-01-27 Edited: Jassal, B, 2012-01-27 Human heparan sulfate L-iduronyl 2-O-sulfotransferase 1 (HS2ST1) mediates the transfer of sulfate from PAPS to the C2-position of iduronate (and glucuronate with lesser preference) (Smeds et al. 2010) residues in heparan sulfate chains (Rong et al. 2000). Pubmed10677367 Pubmed20554947 Reactome Database ID Release 432076508 Reactome, http://www.reactome.org ReactomeREACT_120904 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0000016 Reactome Database ID Release 43188991 Reactome, http://www.reactome.org Procollagen type XXIV Reactome DB_ID: 2187511 Reactome Database ID Release 432187511 Reactome, http://www.reactome.org ReactomeREACT_124258 has a Stoichiometric coefficient of 3 Galactose is the second sugar added in the tetrasaccharide linker Authored: Jassal, B, 2011-11-01 Beta-1,4-galactosyltransferase 7 (B4GALT7) adds galactose to beta-xyloside in a beta-1,4 linkage creating the second addition to the tetrasaccharide linker, the precursor required for glycosaminoglycan synthesis (Almeida et al. 1999). Defects in B4GALT7 cause Ehlers-Danlos syndrome progeroid type (EDSP) (MIM:130070) (Okajima et al. 1999). EC Number: 2.4.1.133 Edited: Jassal, B, 2011-11-01 Pubmed10473568 Pubmed10506123 Reactome Database ID Release 431889981 Reactome, http://www.reactome.org ReactomeREACT_121136 Reviewed: D'Eustachio, P, 2012-03-28 ACTIVATION GENE ONTOLOGYGO:0004575 Reactome Database ID Release 43189029 Reactome, http://www.reactome.org Procollagen type XI Reactome DB_ID: 2187501 Reactome Database ID Release 432187501 Reactome, http://www.reactome.org ReactomeREACT_122208 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004558 Reactome Database ID Release 43191113 Reactome, http://www.reactome.org Tropocollagen type IV Converted from EntitySet in Reactome Reactome DB_ID: 2060922 Reactome Database ID Release 432060922 Reactome, http://www.reactome.org ReactomeREACT_125638 ACTIVATION GENE ONTOLOGYGO:0004558 Reactome Database ID Release 43189007 Reactome, http://www.reactome.org Procollagen type XXVII Reactome DB_ID: 2187505 Reactome Database ID Release 432187505 Reactome, http://www.reactome.org ReactomeREACT_125415 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0004558 Reactome Database ID Release 43191113 Reactome, http://www.reactome.org Procollagen alpha-1(V)X2 alpha-2(V) Reactome DB_ID: 2187503 Reactome Database ID Release 432187503 Reactome, http://www.reactome.org ReactomeREACT_124152 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004558 Reactome Database ID Release 43189007 Reactome, http://www.reactome.org Procollagen type V Converted from EntitySet in Reactome Reactome DB_ID: 2187504 Reactome Database ID Release 432187504 Reactome, http://www.reactome.org ReactomeREACT_121906 ACTIVATION GENE ONTOLOGYGO:0004556 Reactome Database ID Release 43189018 Reactome, http://www.reactome.org Procollagen alpha-3(V) Reactome DB_ID: 2187517 Reactome Database ID Release 432187517 Reactome, http://www.reactome.org ReactomeREACT_123426 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0004558 Reactome Database ID Release 43189007 Reactome, http://www.reactome.org Procollagen alpha-1-3(V) Reactome DB_ID: 2187507 Reactome Database ID Release 432187507 Reactome, http://www.reactome.org ReactomeREACT_125585 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004556 Reactome Database ID Release 43189018 Reactome, http://www.reactome.org ATP + D-glyceraldehyde => ADP + D-glyceraldehyde 3-phosphate Cytosolic triokinase catalyzes the reaction of ATP and D-glyceraldehyde to form ADP and D-glyceraldehyde 3-phosphate. No human triokinase enzyme has been characterized, and this reaction is inferred from studies of guinea pig liver fractions enriched in triokinase activity (Hers and Kusaka 1953). EC Number: 2.7.1.28 Pubmed13093749 Reactome Database ID Release 4370349 Reactome, http://www.reactome.org ReactomeREACT_52 ACTIVATION GENE ONTOLOGYGO:0004555 Reactome Database ID Release 43189044 Reactome, http://www.reactome.org C-linked procollagen type XXII trimer Reactome DB_ID: 2179362 Reactome Database ID Release 432179362 Reactome, http://www.reactome.org ReactomeREACT_123957 has a Stoichiometric coefficient of 3 D-fructose 1-phosphate <=> D-glyceraldehyde + dihydroxyacetone phosphate Cytosolic aldolase B (ALDOB) catalyzes the reaction of D-fructose 1-phosphate to form dihydroxyacetone phosphate and D-glyceraldehyde (Sakakibara et al. 1989). The active form of the enzyme is a tetramer (Dalby et al. 2001). Deficiencies in the enzyme are associated with hereditary fructose intolerance in vivo (e.g., Tolan 1995). EC Number: 4.1.2.13 Pubmed11679716 Pubmed2649152 Pubmed8535439 Reactome Database ID Release 4370342 Reactome, http://www.reactome.org ReactomeREACT_2013 C-linked procollagen type XXI trimer Reactome DB_ID: 2179364 Reactome Database ID Release 432179364 Reactome, http://www.reactome.org ReactomeREACT_124860 has a Stoichiometric coefficient of 3 ATP + beta-D-fructose => ADP + D-fructose 1-phosphate Cytosolic ketohexokinase (KHK) catalyzes the reaction of D-fructose and ATP to form D-fructose 1-phosphate and ADP. Two isoforms of the enzyme are encoded by alternatively spliced forms of the gene; both form catalytically active dimers (Trinh et al. 2009). The physiological role of KHK has been established from metabolic and DNA sequencing studies of patients with essential fructosuria (Bonthron et al. 1994). EC Number: 2.7.1.3 Pubmed19237742 Pubmed7833921 Reactome Database ID Release 4370333 Reactome, http://www.reactome.org ReactomeREACT_1927 C-linked procollagen type XX trimer Reactome DB_ID: 2179372 Reactome Database ID Release 432179372 Reactome, http://www.reactome.org ReactomeREACT_125515 has a Stoichiometric coefficient of 3 D-Glucose 1-phosphate <=> alpha-D-Glucose 6-phosphate Cytosolic phosphoglucomutase (PGM) catalyzes the reversible conversion of glucose 1-phosphate to glucose 6-phosphate. Two PGM isoenzymes, both monomers, have been identified. PGM1 is the major form found in most tissues except erythrocytes, where PGM2 is abundant (March et al. 1993; Parrington et al. 1968; Putt et al. 1993). PGM2 also has substantial phosphopentomutase activity and its primary physiological in normal tissues in vivo is not clear. EC Number: 5.4.2.2 Pubmed7902568 Reactome Database ID Release 4370427 Reactome, http://www.reactome.org ReactomeREACT_605 C-linked procollagen type XIX trimer Reactome DB_ID: 2179379 Reactome Database ID Release 432179379 Reactome, http://www.reactome.org ReactomeREACT_122601 has a Stoichiometric coefficient of 3 poly((1,4)-alpha-glucosyl) glycogenin-2 + n orthophosphate => glycogenin-2 + n D-glucose 1-phosphate [PYGL] Authored: D'Eustachio, P, 2010-01-21 Pubmed10949035 Pubmed2667896 Reactome Database ID Release 43453339 Reactome, http://www.reactome.org ReactomeREACT_21313 The phosphorylated PYGL dimer (a form) of glycogen phosphorylase catalyzes the reaction of orthophosphate and poly((1,4)-alpha-glucosyl) glycogenin-2 to form D-glucose 1-phosphate and glycogenin-2. This reaction occurs on the surfaces of cytosolic glycogen granules. Non-phosphorylated PYGL dimers (b form) are catalytically inactive even in the presence of AMP. In the body, this reaction takes place in the liver where its dependence on hormonally stimulated PYGL phosphorylation (and lack of sensitivity to AMP) allow glucose mobilization in response to a demand for glucose from the rest of the body (Newgard et al. 1989; Rath et al. 2000). Collagen alpha-3(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2193016 Reactome Database ID Release 432193016 Reactome, http://www.reactome.org ReactomeREACT_124833 'Inhibition of JAK kinase activity by SOCS1/3' negatively regulates 'Phosphorylation of STAT2' INHIBITION Pubmed16311601 Reactome Database ID Release 43912708 Reactome, http://www.reactome.org ReactomeREACT_27119 'PTPs SHP1/2/PTP1B [cytosol]' negatively regulates 'Phosphorylation of STAT1' INHIBITION Protein tyrosine phosphatases SHP-1 and SHP-2 dephosphorylate JAK1 and STAT1 and suppress their signaling. Pubmed10022928 Pubmed8524272 Reactome Database ID Release 43912707 Reactome, http://www.reactome.org ReactomeREACT_27105 'dsRNA:RIG-I/MDA5:NLRC5 [cytosol]' negatively regulates 'RIG-I/MDA5 interacts with IPS-1' INHIBITION NLRC5 competes with IPS-1 for binding to the CARD domain of RIG-I/MDA5. NLRC5 specifically recognize the CARD domains of RIG-I/MDA5 when the CARD domains become accessible after viral infection, leading to dampened activation of IRF3. Pubmed20434986 Reactome Database ID Release 43992762 Reactome, http://www.reactome.org ReactomeREACT_27091 'IPS-1:NLRX1 [mitochondrial outer membrane]' negatively regulates 'RIG-I/MDA5 interacts with IPS-1' INHIBITION NLRX1 is a member of nucleotide-binding domain and leucine-rich repeat containing (NLR) protein family. NLRX1 competes with RIG-I for IPS-1 interaction and has been identified as a negative regulator of RLR signaling. NLRX1 resides at the outer mitochondrial membrane where IPS-1 is located and this interaction is mediated by the CARD region of IPS-1 and a putative nucleotide-binding domain (NBD) of NLRX1. This interaction between NLRX1 and IPS-1 prevents the association between RIG-1/MDA5 and IPS-1. Pubmed18200010 Reactome Database ID Release 43992760 Reactome, http://www.reactome.org ReactomeREACT_27079 'LGP2 [cytosol]' negatively regulates 'dsRNA binds to RIG-I' INHIBITION LGP2 acts as a natural negative regulator of dsRNA signaling. Several mechanisms may account for the LGP2 inhibitory effects. As a homolog of RIG-I, one attractive model is that LGP2 can sequester RNA ligands from recognition by RIG-I/MDA5. LGP2 has also been demonstrated to associate with RIG-I to inhibit its auto-oligomerizaton via the LGP2 C-terminal region comparable to the RIG-I repressor domain. In this model, dimerization of RIG-I by viral RNA, proposed to be an active form of RIG-I, is replaced by a RIG-I:LGP2 hetero-oligomer. Pubmed17190814 Reactome Database ID Release 43937345 Reactome, http://www.reactome.org ReactomeREACT_27108 'ISG15:RIG-I conjugate [cytosol]' negatively regulates 'dsRNA binds to RIG-I' INHIBITION ISG15 is a ubiquitin (Ub)-like protein which is conjugated to intracellular proteins via an isopeptide bond. Similar to ubiquitination, the conjugation of ISG15 (ISGylation) requires a three-step process, involving an E1 activating enzyme (UBE1L), an E2 conjugating enzyme (UbcM8/H8), and HERC5/Ceb1 an IFN-inducible ISG15-specific E3 ligase. ISG15 conjugation may play an important regulatory role in IFN-mediated antiviral responses. IFN induces ISG15 conjugation to RIG-I protein and lowers cellular levels of unconjugated RIG-I protein and, thus, negatively regulates RIG-I-mediated antiviral signaling. ISGylated RIG-I protein becomes subject to an irreversible biochemical process, such as proteolysis or proteasomeal degradation. Pubmed18057259 Reactome Database ID Release 43992763 Reactome, http://www.reactome.org ReactomeREACT_27115 'dsDNA:IFI16 [cytosol]' positively regulates 'STING recruits TBK1 and IRF3' ACTIVATION Reactome Database ID Release 432396008 Reactome, http://www.reactome.org ReactomeREACT_148664 'dsDNA:DAI:RIP1:RIP3 [cytosol]' positively regulates 'RIP1 facilitates IKK complex phosphorylation' ACTIVATION Reactome Database ID Release 431810459 Reactome, http://www.reactome.org ReactomeREACT_118020 ACTIVATION GENE ONTOLOGYGO:0005412 Reactome Database ID Release 43428653 Reactome, http://www.reactome.org RIP1 facilitates IKK activation ACTIVATION Reactome Database ID Release 43975228 Reactome, http://www.reactome.org ReactomeREACT_27104 ACTIVATION GENE ONTOLOGYGO:0005353 Reactome Database ID Release 43428655 Reactome, http://www.reactome.org 'ISGylated IRF3 [cytosol]' negatively regulates 'PIN1 mediated IRF3 degradation' INHIBITION Pubmed16914094 Pubmed20153823 Reactome Database ID Release 431176076 Reactome, http://www.reactome.org ReactomeREACT_27981 The transcription factor IRF3 is a target for ISGylation. Conjugation of ISG15 positively regulates IRF3 and thereby promotes induction of type I interferons. ISGylation of IRF3 prevents the binding of PIN1, a protein that promotes IRF3 ubiquitination and subsequent degradation. ACTIVATION GENE ONTOLOGYGO:0005355 Reactome Database ID Release 43352531 Reactome, http://www.reactome.org C-linked procollagen type XXIV trimer Reactome DB_ID: 2179375 Reactome Database ID Release 432179375 Reactome, http://www.reactome.org ReactomeREACT_121577 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0015149 Reactome Database ID Release 43211384 Reactome, http://www.reactome.org C-linked procollagen type XXV trimer Reactome DB_ID: 2179380 Reactome Database ID Release 432179380 Reactome, http://www.reactome.org ReactomeREACT_125424 has a Stoichiometric coefficient of 3 ((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl)glycogenin => poly{(1,4)-alpha-glucosyl} glycogenin + alpha-D-glucose At the beginning of this reaction, 1 molecule of '{(1,6)-alpha-glucosyl}poly{(1,4)-alpha-glucosyl}glycogenin-2' is present. At the end of this reaction, 1 molecule of 'alpha-D-glucose', and 1 molecule of 'poly{(1,4)-alpha-glucosyl}glycogenin-2' are present.<br><br> This reaction takes place in the 'cytoplasm' and is mediated by the 'amylo-alpha-1,6-glucosidase activity' of 'glycogen debranching enzyme'.<br> EC Number: 3.2.1.33 Pubmed2961257 Pubmed9691087 Reactome Database ID Release 4371593 Reactome, http://www.reactome.org ReactomeREACT_1433 ACTIVATION GENE ONTOLOGYGO:0004340 Reactome Database ID Release 4370419 Reactome, http://www.reactome.org poly((1,4)-alpha-glycosyl) glycogenin-1 + n orthophosphate => glycogenin-1 + n D-glucose 1-phosphate [PYGM,PYGB] Authored: D'Eustachio, P, 2010-01-21 Pubmed10949035 Pubmed2667896 Reactome Database ID Release 43453358 Reactome, http://www.reactome.org ReactomeREACT_21296 The PYGM and PYGB forms of glycogen phosphorylase catalyze the reaction of orthophosphate and poly((1,4) alpha glucosyl) glycogenin-1 to form D-glucose 1-phosphate and glycogenin-1. This reaction occurs on the surfaces of cytosolic glycogen granules. The phosphorylated forms of PYGM and PYGB dimers (a form) are catalytically active; the non-phosphorylated dimers (b form) become active when complexed with AMP. In the body, this reaction takes place in tissues other than the liver where its sensitivity to AMP allows glucose mobilization in response to acute energy needs of the individual cell, and hormonally mediated phosphorylation can stimulate increased glucose production, still for use by the individual producing cell, in response to stress signals. These reactions have not been characterized in detail but are inferred to occur from the very close similarity among PGYM, PGYB, and PGYL (Newgard et al. 1989; Rath et al. 2000). ACTIVATION GENE ONTOLOGYGO:0005355 Reactome Database ID Release 43211383 Reactome, http://www.reactome.org C-linked procollagen type XXIII trimer Reactome DB_ID: 2179378 Reactome Database ID Release 432179378 Reactome, http://www.reactome.org ReactomeREACT_124290 has a Stoichiometric coefficient of 3 'STING:c-di-GMP [cytosol]' positively regulates 'STING recruits TBK1 and IRF3' ACTIVATION Reactome Database ID Release 432395991 Reactome, http://www.reactome.org ReactomeREACT_148692 glycogen-glycogenin-2 + n orthophosphate => limit dextrin-glycogenin-2 + n D-glucose 1-phosphate [PYGL] Pubmed10949035 Pubmed2667896 Reactome Database ID Release 4371590 Reactome, http://www.reactome.org ReactomeREACT_1348 The phosphorylated PYGL dimer (a form) of glycogen phosphorylase catalyzes the reaction of orthophosphate and glycogen-glycogenin 1 to form D-glucose 1-phosphate and limit dextrin-glycogenin 1. This reaction occurs on the surfaces of cytosolic glycogen granules. Non-phosphorylated PYGL dimers (b form) are catalytically inactive even in the presence of AMP. In the body, this reaction takes place in the liver where its dependence on hormonally stimulated PYGL phosphorylation (and lack of sensitivity to AMP) allow glucose mobilization in response to a demand for glucose from the rest of the body (Newgard et al. 1989; Rath et al. 2000). ACTIVATION GENE ONTOLOGYGO:0015152 Reactome Database ID Release 43198473 Reactome, http://www.reactome.org C-linked procollagen type XXVIII trimer Reactome DB_ID: 2179377 Reactome Database ID Release 432179377 Reactome, http://www.reactome.org ReactomeREACT_122690 has a Stoichiometric coefficient of 3 limit dextrin-glycogenin => ((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl) glycogenin Cytosolic debranching enzyme associated with glycogen granules transfers 3-glucose blocks from branches to the main linear polyglucose chain of limit dextrin formed on glycogenin 1 or glycogenin 2 (Chen et al. 1988; Shen et al. 1996). EC Number: 2.4.1.25 Pubmed2961257 Pubmed8755644 Reactome Database ID Release 4371552 Reactome, http://www.reactome.org ReactomeREACT_1507 ACTIVATION GENE ONTOLOGYGO:0005487 Reactome Database ID Release 43450099 Reactome, http://www.reactome.org Collagen and procollagen triple helices:Serpin H1 Reactome DB_ID: 2187526 Reactome Database ID Release 432187526 Reactome, http://www.reactome.org ReactomeREACT_123463 has a Stoichiometric coefficient of 1 PGYM b dimer:AMP complex <=> PGYM dimer, b form + 2 AMP Authored: D'Eustachio, P, 2010-01-21 Cytosolic, non-phosphorylated PGYM dimers (b form) complexed with AMP can reversibly dissociate (Rath et al. 2000). Pubmed10949035 Reactome Database ID Release 43453338 Reactome, http://www.reactome.org ReactomeREACT_21291 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004347 Reactome Database ID Release 4370470 Reactome, http://www.reactome.org C-linked procollagen type XXVI trimer Reactome DB_ID: 2179370 Reactome Database ID Release 432179370 Reactome, http://www.reactome.org ReactomeREACT_124873 has a Stoichiometric coefficient of 3 glycogen-glycogenin-1 + n orthophosphate => limit dextrin-glycogenin-1 + n D-glucose 1-phosphate [PYGM,PYGB] Pubmed10949035 Pubmed2667896 Reactome Database ID Release 4371515 Reactome, http://www.reactome.org ReactomeREACT_1670 The PYGM and PYGB forms of glycogen phosphorylase catalyze the reaction of orthophosphate and glycogen-glycogenin 1 to form D-glucose 1-phosphate and limit dextrin-glycogenin 1. This reaction occurs on the surfaces of cytosolic glycogen granules. The phosphorylated forms of PYGM and PYGB dimers (a form) are catalytically active; the non-phosphorylated dimers (b form) become active when complexed with AMP. In the body, this reaction takes place in tissues other than the liver where its sensitivity to AMP allows glucose mobilization in response to acute energy needs of the individual cell, and hormonally mediated phosphorylation can stimulate increased glucose production, still for use by the individual producing cell, in response to stress signals. These reactions have not been characterized in detail but are inferred to occur from the very close similarity among PGYM, PGYB, and PGYL (Newgard et al. 1989; Rath et al. 2000). ACTIVATION GENE ONTOLOGYGO:0004346 Reactome Database ID Release 4371824 Reactome, http://www.reactome.org C-linked procollagen type XXVII trimer Reactome DB_ID: 2179367 Reactome Database ID Release 432179367 Reactome, http://www.reactome.org ReactomeREACT_123991 has a Stoichiometric coefficient of 3 PGYB dimer, b form + 2 AMP <=> PGYB b dimer:AMP complex Authored: D'Eustachio, P, 2010-01-21 Cytosolic, non-phosphorylated PGYB dimers (b form) can reversibly bind AMP. This reaction is inferred from the AMP-binding properties of human PGYL and closely homologous PGYM proteins from other species (Newgard et al. 1989; Rath et al. 2000). Pubmed10949035 Pubmed2667896 Reactome Database ID Release 43453356 Reactome, http://www.reactome.org ReactomeREACT_21380 has a Stoichiometric coefficient of 2 C-linked procollagen type IX trimer Reactome DB_ID: 2179360 Reactome Database ID Release 432179360 Reactome, http://www.reactome.org ReactomeREACT_123385 has a Stoichiometric coefficient of 1 glycogen phosphorylase (PYGL) dimer b + 2 ATP => glycogen phosphorylase (PYGL) dimer a + 2 ADP EC Number: 2.7.11.19 Pubmed10487978 Pubmed12825073 Pubmed12930917 Pubmed13115432 Pubmed5461220 Pubmed7847371 Pubmed8896567 Reactome Database ID Release 4371588 Reactome, http://www.reactome.org ReactomeREACT_1623 The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of glycogen phosphorylase (PYGL). Two forms of phosphorylase kinase complex have been described (Brushia and Walsh 1999). The one annotated here, consisting of four copies each of PHKA2 (alpha regulatory) (van den Berg et al. 1995), PHKB (beta regulatory) (Burwinkel et al. 2003a), PHKG2 (gamma catalytic) (Burwinkel et al. 2003b; Maichele et al. 2006) and CALM (calmodulin) subunits is abundant in liver and its action on the form of phosphorylase (PYGL) abundant in liver is described.<p>While initial studies of glycogen phosphorylase PGYM from rabbit muscle suggested that it is a homotetramer (Keller and Cori 1953), more recent work indicates that under physiological conditions the enzyme occurs as a homodimer (Huang and Graves 1970) and a dimeric structure for human PYGL enzyme is inferred here. has a Stoichiometric coefficient of 2 C-linked procollagen type VIII trimer Reactome DB_ID: 2179381 Reactome Database ID Release 432179381 Reactome, http://www.reactome.org ReactomeREACT_121440 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PGYM dimer, b form + 2 AMP <=> PGYM b dimer:AMP complex Authored: D'Eustachio, P, 2010-01-21 Cytosolic, non-phosphorylated PGYM dimers (b form) can reversibly bind AMP. This reaction is negatively regulated by ATP and glucose 6-phosphate and is the means by which high levels of these molecules repress PGYM activity (Rath et al. 2000). Pubmed10949035 Reactome Database ID Release 43453342 Reactome, http://www.reactome.org ReactomeREACT_21397 has a Stoichiometric coefficient of 2 C-linked procollagen type XI trimer Reactome DB_ID: 2179368 Reactome Database ID Release 432179368 Reactome, http://www.reactome.org ReactomeREACT_121897 has a Stoichiometric coefficient of 1 PGYB b dimer:AMP complex <=> PGYB dimer, b form + 2 AMP Authored: D'Eustachio, P, 2010-01-21 Cytosolic, non-phosphorylated PGYB dimers (b form) complexed with AMP can reversibly dissociate. This reaction is inferred from the AMP-binding properties of the closely homologous PGYM complex (Rath et al. 2000). Reactome Database ID Release 43453346 Reactome, http://www.reactome.org ReactomeREACT_21337 has a Stoichiometric coefficient of 2 C-linked procollagen type X trimer Reactome DB_ID: 2179376 Reactome Database ID Release 432179376 Reactome, http://www.reactome.org ReactomeREACT_122964 has a Stoichiometric coefficient of 3 C-linked procollagen type XII trimer Reactome DB_ID: 2179363 Reactome Database ID Release 432179363 Reactome, http://www.reactome.org ReactomeREACT_123862 has a Stoichiometric coefficient of 3 Collagen alpha-2(IX) chains Converted from EntitySet in Reactome Reactome DB_ID: 2193011 Reactome Database ID Release 432193011 Reactome, http://www.reactome.org ReactomeREACT_122151 'IRAK-M [cytosol]' negatively regulates 'TRAF6 binding leads to IRAK1:TRAF6 release' INHIBITION IRAKM prevents the dissociation of IRAK1 and IRAK4 from MYD88 thereby inhibiting the formation of IRAK1-TRAF6 complexes. Pubmed12150927 Reactome Database ID Release 43446965 Reactome, http://www.reactome.org ReactomeREACT_23405 'Beta-TrCP ubiquitinates then dissociates from p-NFKB p105' negatively regulates 'NFKB p105, TPL2 (COT) and ABIN2 form a stable complex' Degradation of NFKB p105 frees Tpl2 from p105 allowing it to activate MEK1. INHIBITION Reactome Database ID Release 43451645 Reactome, http://www.reactome.org ReactomeREACT_23412 'IL6:sIL6R:sgp130 [extracellular region]' negatively regulates 'IL6:sIL6R binds to JAKs:IL6RB (gp130)' INHIBITION Reactome Database ID Release 431164957 Reactome, http://www.reactome.org ReactomeREACT_28003 'IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2:SOCS-1/-3 [plasma membrane]' negatively regulates 'Transphosphorylation of JAK1' INHIBITION Reactome Database ID Release 43877306 Reactome, http://www.reactome.org ReactomeREACT_27100 'ISGF3 bound to ISRE promotor elements [nucleoplasm]' positively regulates 'Expression of IFN-induced genes' ACTIVATION Reactome Database ID Release 431031720 Reactome, http://www.reactome.org ReactomeREACT_27112 'GAF bound to GAS promoter element [nucleoplasm]' positively regulates 'Expression of IFNG-stimulated genes' ACTIVATION Reactome Database ID Release 431031722 Reactome, http://www.reactome.org ReactomeREACT_27116 'SHP-1 [cytosol]' negatively regulates 'Transphosphorylation of JAK1' INHIBITION Reactome Database ID Release 43877279 Reactome, http://www.reactome.org ReactomeREACT_27118 ACTIVATION GENE ONTOLOGYGO:0003872 Reactome Database ID Release 4370466 Reactome, http://www.reactome.org 'ISG15 [cytosol]' negatively regulates 'Monoubiquitination of N-myristoyl GAG (P12493) protein' INHIBITION Over expression of ISG15 inhibits the release of HIV -1 virions. ISG15 mainly inhibits the ubiquitination of viral GAG and host Tsg101 proteins and disrupts their interaction, thereby preventing assembly and release of virions. Pubmed16434471 Pubmed20153823 Reactome Database ID Release 431169312 Reactome, http://www.reactome.org ReactomeREACT_117958 ACTIVATION GENE ONTOLOGYGO:0003873 Reactome Database ID Release 43163768 Reactome, http://www.reactome.org 'ISGylated NS1 [cytosol]' negatively regulates 'Translocation of Influenza A virus nonstructural protein 1 (NS1A) into the nucleus' INHIBITION Pubmed20133869 Reactome Database ID Release 431176075 Reactome, http://www.reactome.org ReactomeREACT_118011 ACTIVATION GENE ONTOLOGYGO:0008195 Reactome Database ID Release 43163684 Reactome, http://www.reactome.org 'IL1B [cytosol]' negatively regulates 'p62:MEKK3 binds to TRAF6' INHIBITION Reactome Database ID Release 43507738 Reactome, http://www.reactome.org ReactomeREACT_23407 'NFkB Complex [nucleoplasm]' positively regulates 'Interleukin-1 family precursors are cleaved by caspase-1' ACTIVATION In the absence of TLR agonist 'priming', inflammasome dependent caspase-1 activation is observed but IL-1 beta secretion is minimal because pro-IL1 beta is not expressed in most cells until stimulated by proinflammatory signals such as TNF or LPS that activate NFkappaB. NFkappaB induces expression of pro-IL1beta but also expression of NLRP3 which may be a limiting component of the NLRP3 inflammasome complex. Pubmed19570822 Pubmed8413223 Reactome Database ID Release 43844659 Reactome, http://www.reactome.org ReactomeREACT_24894 poly((1,4)-alpha-D-glucosyl) glycogenin => glycogen-glycogenin Cytosolic glycogen branching enzyme associated with glycogen granules transfers terminal alpha(1,4) glucose blocks to form alpha(1,6) branches on growing glycogen molecules formed on glycogenin (Bao et al. 1996). EC Number: 2.4.1.18 Pubmed8613547 Reactome Database ID Release 4371610 Reactome, http://www.reactome.org ReactomeREACT_1560 ACTIVATION GENE ONTOLOGYGO:0004618 Reactome Database ID Release 4370485 Reactome, http://www.reactome.org glycogen phosphorylase (PYGB) dimer b + 2 ATP => glycogen phosphorylase (PYGB) dimer a + 2 ADP Authored: D'Eustachio, P, 2010-01-21 EC Number: 2.7.11.19 Pubmed2667896 Reactome Database ID Release 43453337 Reactome, http://www.reactome.org ReactomeREACT_21331 The phosphorylation of glycogen phosphorylase PYGB by the widely expressed form of the phosphorylase kinase complex is inferred from its activity on PGYM (Newgard et al. 1989). has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004365 Reactome Database ID Release 4370448 Reactome, http://www.reactome.org glycogen phosphorylase (PYGM) dimer b + 2 ATP => glycogen phosphorylase (PYGM) dimer a + 2 ADP EC Number: 2.7.11.19 Pubmed10487978 Pubmed12825073 Pubmed13115432 Pubmed5461220 Reactome Database ID Release 4371541 Reactome, http://www.reactome.org ReactomeREACT_848 The cytosolic phosphorylase kinase complex catalyzes the phosphorylation of the subunits of the glycogen phosphorylase (PYGM) dimer. Two forms of phosphorylase kinase complex have been described (Brushia and Walsh 1999). The one annotated here, consisting of four copies each of PHKA1 (alpha regulatory) (Burwinkel et al 2003), PHKB (beta regulatory) (Burwinkel et al. 2003), PHKG1 (gamma catalytic) (Burwinkel et al. 2003) and CALM (calmodulin) subunits is abundant in muscle and its action on the form of phosphorylase (PYGM) abundant in muscle is described.<p>While initial studies of PGYM from rabbit muscle suggested that it is a homotetramer (Keller and Cori 1953), more recent work indicates that under physiological conditions the enzyme occurs as a homodimer (Huang and Graves 1970) and a dimeric structure for the human enzyme is inferred here. has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004807 Reactome Database ID Release 4370453 Reactome, http://www.reactome.org C-linked procollagen type XIII trimer Reactome DB_ID: 2179357 Reactome Database ID Release 432179357 Reactome, http://www.reactome.org ReactomeREACT_121635 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0004332 Reactome Database ID Release 4371494 Reactome, http://www.reactome.org C-linked procollagen type XIV trimer Reactome DB_ID: 2179371 Reactome Database ID Release 432179371 Reactome, http://www.reactome.org ReactomeREACT_125293 has a Stoichiometric coefficient of 3 UTP + D-glucose 1-phosphate <=> pyrophosphate + UDP-glucose Cytosolic UDP-glucose pyrophosphorylase 2 (UGP2) catalyzes the reaction of UTP and glucose 1-phosphate to form UDP glucose and pyrophosphate (Knop and Hansen 1970; Duggleby et al. 1996). UGP2 is inferred to occur in the cell as a homooctamer from studies of its bovine homologue (Levine et al. 1969). EC Number: 2.7.7.9 Pubmed5348606 Pubmed5427280 Pubmed8631325 Reactome Database ID Release 4370286 Reactome, http://www.reactome.org ReactomeREACT_86 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 C-linked procollagen type XV trimer Reactome DB_ID: 2179369 Reactome Database ID Release 432179369 Reactome, http://www.reactome.org ReactomeREACT_122818 has a Stoichiometric coefficient of 3 8 UDP-glucose + glycogenin dimer => 8 UDP + {(1,4)-alpha-D-glucosyl}4 glycogenin dimer EC Number: 2.4.1.186 Glycogenin catalyzes its own reaction with UDP-glucose to synthesize an oligo (1,4)-alpha-D-glucosyl chain attached to itself (Mu et al. 1997; Mu and Roach 1998). The oligosaccharide is annotated here as containing four glucose residues. Glycogenin occurs as a homodimer associated with glycogen granules in the cytosol (Wilson et al. 2007).<p>Glycogenin proteins are encoded by two human genes, GYG1 and GYG2. Multiple isoforms of each protein due to alternative splicing have been described, but none of these isoforms has yet been associated with a distinctive function. GYG1 protein is abundant in skeletal muscle while GYG2 is abundant in liver. Human GYG2 has been characterized biochemically (Mu et al. 1997; Mu and Roach 1998) but while the role of human GYG1 in muscle glycogen metabolism during exercise has been studied (Wilson et al. 2007), details of its structure and catalytic activities are inferred from those of its rabbit homologue (e.g., Gibbons et al. 2002). Pubmed12051921 Pubmed17311895 Pubmed9346895 Pubmed9857012 Reactome Database ID Release 4370290 Reactome, http://www.reactome.org ReactomeREACT_1902 has a Stoichiometric coefficient of 8 ACTIVATION GENE ONTOLOGYGO:0004743 Reactome Database ID Release 4371669 Reactome, http://www.reactome.org C-linked procollagen type XVI trimer Reactome DB_ID: 2179374 Reactome Database ID Release 432179374 Reactome, http://www.reactome.org ReactomeREACT_122213 has a Stoichiometric coefficient of 3 8 UDP-glucose + ((1,4)-alpha-D-glucosyl}4 glycogenin => 8 UDP + ((1,4)-alpha-D-glucosyl)8 glycogenin [GYS I form] EC Number: 2.4.1.11 Glycogen synthase catalyzes the addition of glucose residues to the non-reducing end of a (1,4)-alpha-D-glucose multimer formed on glycogenin-1 or -2. (Here the addition of four glucose residues is annotated.) The enzyme is associated with glycogen granules in the cytosol.<p>Glycogen synthase proteins are encoded by two human genes, GYS1 and GYS2. GYS1 protein is abundant in skeletal muscle while GYS2 is abundant in liver. The cytosolic location and glycogen synthase activity of GYS1 protein has been demonstrated in studies of wild-type and mutant proteins expressed in cultured cells in vitro (Cid et al. 2000). Defects in GYS1 protein in vivo are associated with deficient muscle glycogen synthesis and exercise intolerance in vivo (Kollberg et al. 2007). The enzymatic activity of purified GYS2 protein has been characterized experimentally (Westphal and Nuttall 1992). Defects in GYS2 protein in vivo are associated with fasting hypoglycemia and defective glycogen synthesis in the liver (Orho et al. 1998).<p>Human GYS enzymes are inferred to be active as homotetramers, from detailed characterization of the homologous rabbit muscle enzyme (Soderling et al. 1970).<p>GYS activity is regulated by phosphorylation. In its non-phosphorylated “I” form, annotated here, the enzyme is active with no added cofactor.<br> Pubmed10924520 Pubmed1731614 Pubmed17928598 Pubmed4320836 Pubmed9691087 Reactome Database ID Release 4371602 Reactome, http://www.reactome.org ReactomeREACT_1169 has a Stoichiometric coefficient of 8 ACTIVATION GENE ONTOLOGYGO:0004634 Reactome Database ID Release 4371439 Reactome, http://www.reactome.org C-linked procollagen type XVII trimer Reactome DB_ID: 2179366 Reactome Database ID Release 432179366 Reactome, http://www.reactome.org ReactomeREACT_121809 has a Stoichiometric coefficient of 3 8 UDP-glucose + ((1,4)-alpha-D-glucosyl)4 glycogenin => 8 UDP + ((1,4)-alpha-D-glucosyl)8 glycogenin [GYS D form] EC Number: 2.4.1.11 Phosphorylated glycogen synthase catalyzes the addition of glucose residues to the non reducing end of a (1,4)-alpha-D-glucose multimer formed on glycogenin 1 or 2 when activated by glucose 6-phosphate. (Here the addition of four glucose residues is annotated.) The enzyme is associated with glycogen granules in the cytosol.<p>Glycogen synthase proteins are encoded by two human genes, GYS1 and GYS2. GYS1 protein is abundant in skeletal muscle while GYS2 is abundant in liver. The cytosolic location and glycogen synthase activity of GYS1 protein has been demonstrated in studies of wild-type and mutant proteins expressed in cultured cells in vitro (Cid et al. 2000). Defects in GYS1 protein in vivo are associated with deficient muscle glycogen synthesis and exercise intolerance in vivo (Kollberg et al. 2007). The enzymatic activity of purified GYS2 protein has been characterized experimentally (Westphal and Nuttall 1992). Defects in GYS2 protein in vivo are associated with fasting hypoglycemia and defective glycogen synthesis in the liver (Orho et al. 1998).<p>GYS activity is regulated by phosphorylation. In its phosphorylated “D” form, annotated here, enzyme activity requires the presence of glucose 6-phosphate. The structure and activity of phosphorylated human GYS protein tetramers are inferred from the properties of the rabbit GYS1 (skeletal muscle) protein which has been purified and characterized in detail (Soderling et al. 1970). Pubmed10924520 Pubmed1731614 Pubmed17928598 Pubmed4320836 Pubmed9691087 Reactome Database ID Release 4371574 Reactome, http://www.reactome.org ReactomeREACT_1053 has a Stoichiometric coefficient of 8 ACTIVATION GENE ONTOLOGYGO:0004619 Reactome Database ID Release 4371444 Reactome, http://www.reactome.org C-linked procollagen type XVIII trimer Reactome DB_ID: 2179373 Reactome Database ID Release 432179373 Reactome, http://www.reactome.org ReactomeREACT_122886 has a Stoichiometric coefficient of 3 D-ribose 5-phosphate + ATP => 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) + adenosine 5'-monophosphate Cytosolic phophoribosyl pyrophosphate synthetase catalyzes the reaction of D-ribose 5-phosphate and ATP to form 5-phospho-alpha-D-ribose and AMP. Three isoforms of the enzyme have been described. The first has been purified and characterized biochemically (Fox and Kelley 1971). The others are known only as inferred protein products of cloned genes; their catalytic properties have not been determined. EC Number: 2.7.6.1 Pubmed4328836 Reactome Database ID Release 4373580 Reactome, http://www.reactome.org ReactomeREACT_2023 addition of diphosphate (PP) to ribose 5-phosphate to form 5'-Phospho-alpha-D-ribose 1-diphosphate (PRPP) D-ribose 5-phosphate + 2'-deoxyadenosine 5'-triphosphate (dATP) => 5-Phospho-alpha-D-ribose 1-diphosphate (PRPP) + 2'-deoxyadenosine 5'-monophosphate Cytosolic phosphoribosyl pyrophosphate synthetase 1 catalyzes the reaction of D-ribose 5-phosphate and dATP to form 5-phospho-alpha-D-ribose 1-diphosphate and 2'-deoxyadenosine 5'-monophosphate. While phosphoribosyl pyrophosphate synthetase 1 works well with either ATP or dATP as a substrate in vitro, the extent of the dATP reaction in vivo is unclear, as cellular dATP concentrations are normally very low (Fox and Kelley 1971). EC Number: 2.7.6.1 Pubmed4328836 Reactome Database ID Release 43111215 Reactome, http://www.reactome.org ReactomeREACT_1781 PIP3, PI(3,4)P2 Converted from EntitySet in Reactome Reactome DB_ID: 202277 Reactome Database ID Release 43202277 Reactome, http://www.reactome.org ReactomeREACT_12804 ribose 5-phosphate <=> D-ribulose 5-phosphate EC Number: 5.3.1.6 Edited: D'Eustachio, P, 2006-04-05 13:59:09 Pubmed14988808 Reactome Database ID Release 43177784 Reactome, http://www.reactome.org ReactomeREACT_6907 The reversible interconversion of ribose 5-phosphate and ribulose 5-phosphate is catalyzed by cytosolic ribose 5-phosphate isomerase (Huck et al. 2004). C-linked procollagen type V trimers Converted from EntitySet in Reactome Reactome DB_ID: 2025764 Reactome Database ID Release 432025764 Reactome, http://www.reactome.org ReactomeREACT_122473 L-Amino Acids Converted from EntitySet in Reactome Reactome DB_ID: 983135 Reactome Database ID Release 43983135 Reactome, http://www.reactome.org ReactomeREACT_75988 C-linked procollagen alpha-3(IV), alpha-4(IV) alpha-5(IV) trimer Reactome DB_ID: 2025758 Reactome Database ID Release 432025758 Reactome, http://www.reactome.org ReactomeREACT_121961 has a Stoichiometric coefficient of 1 HYAL2 interacts with NHE1 to create an acidic environment Authored: Jassal, B, 2012-03-05 Edited: Jassal, B, 2012-03-05 Hyaluronidases are only active in acidic environments. HYAL2 can interact with the Na+-H+ exchanger NHE1 which can create an acidic microenvironment in the caveolae. Extracellular Na+ ions are exchanged for protons which creates the acidic conditions required for the activity of HYAL2. Pubmed15090545 Reactome Database ID Release 432160884 Reactome, http://www.reactome.org ReactomeREACT_120879 Reviewed: D'Eustachio, P, 2012-03-28 C-linked procollagen alpha-5(IV)X2 alpha-6(IV) trimer Reactome DB_ID: 2025751 Reactome Database ID Release 432025751 Reactome, http://www.reactome.org ReactomeREACT_124297 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Receptor-mediated uptake of HA Authored: Jassal, B, 2012-03-05 Edited: Jassal, B, 2012-03-05 HA receptors mediate the uptake of HA into cells. CD44 consists of four functional domains, the extracellular distal domain being the HA-binding region (Culty et al. 1990, Asher & Bignami 1992). The receptor for hyaluronan mediated motility (RHAMM, also called HMMR) can bind HA but not heparin or chondroitin sulfate (Assmann et al. 1998, Wang et al. 1996). Lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1) removes HA from the lymphatic system (Banerji et al. 1999). It is present mainly on lymphatic endothelial cells but also in liver sinusoids. Hyaluronan receptor for endocytosis (HARE, stabilin-2, STAB2) binds to and mediates endocytosis of HA (Harris et al. 2007, Harris et al. 2004). HARE can also bind other glycosaminoglycans such as heparin (Harris et al. 2008).<br>High molecular weight HA is tethered to the cell surface by HA receptors and the GPI-linked hyaluronidase 2 (HYAL2) to form a HA:HAR:HYAL2 complex in the plasma membrane that localizes to caveolae (invaginations of the plasma membrane composed of cholesterol and gangliosides and rich in caveolin and flotillin). Pubmed10037799 Pubmed1426053 Pubmed15208308 Pubmed1703543 Pubmed17145755 Pubmed18434317 Pubmed8890751 Pubmed9601098 Reactome Database ID Release 432160915 Reactome, http://www.reactome.org ReactomeREACT_120787 Reviewed: D'Eustachio, P, 2012-03-28 C-linked procollagen alpha-1(IV)X2 alpha-2(IV) trimer Reactome DB_ID: 2025749 Reactome Database ID Release 432025749 Reactome, http://www.reactome.org ReactomeREACT_125639 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Growing HA is extruded from the cell by ABCC5 As hyaluronan (HA) is synthesised, it is continually extruded from the cell by the ABC transporter C5 (ABCC5), also called multidrug resistance-associated protein 5 (MRP5) (Schulz et al. 2007). Authored: Jassal, B, 2012-02-24 Edited: Jassal, B, 2012-02-24 Pubmed17540771 Reactome Database ID Release 432142859 Reactome, http://www.reactome.org ReactomeREACT_121051 Reviewed: D'Eustachio, P, 2012-03-28 C-linked procollagen type IV trimers Converted from EntitySet in Reactome Reactome DB_ID: 2025771 Reactome Database ID Release 432025771 Reactome, http://www.reactome.org ReactomeREACT_121424 HAS1,2,3 mediate the polymerisation of HA Authored: Jassal, B, 2012-03-05 EC Number: 2.4.1.212 Edited: Jassal, B, 2012-03-05 Pubmed8798477 Pubmed8798544 Pubmed9083017 Reactome Database ID Release 432160851 Reactome, http://www.reactome.org ReactomeREACT_121109 Reviewed: D'Eustachio, P, 2012-03-28 The integral membrane dual-action glycosyltransferase proteins hyaluronan synthases 1-3 (HAS1-3) (Shyjan et al. 1996, Watanabe & Yamaguchi 1996, Spicer et al. 1997 respectively) mediate the polymerisation of glucuronic acid (GlcA) with N-acetylglucosamine (GlcNAc) to form hyaluronan (HA). The resulting polymer has the arrangement [-4GlcA-1,3GlcNAc-]n and can be as large as 10 miilion Da. C-linked procollagen type III trimer Reactome DB_ID: 2025766 Reactome Database ID Release 432025766 Reactome, http://www.reactome.org ReactomeREACT_124944 has a Stoichiometric coefficient of 3 Collagen alpha-1(XII) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192779 Reactome Database ID Release 432192779 Reactome, http://www.reactome.org ReactomeREACT_121523 ACTIVATION GENE ONTOLOGYGO:0030060 Reactome Database ID Release 4370978 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004736 Reactome Database ID Release 4370500 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004069 Reactome Database ID Release 4370595 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0030060 Reactome Database ID Release 43198512 Reactome, http://www.reactome.org D-glyceraldehyde 3-phosphate + D-fructose 6-phosphate <=> xylulose 5-phosphate + D-erythrose 4-phosphate Cytosolic transketolase catalyzes the reaction of D-glyceraldehyde 3-phosphate and D-fructose 6-phosphate to form D-erythrose 4-phosphate and D-xylulose 5-phosphate. The active transketolase enzyme is a homodimer with one molecule of thiamine pyrophosphate and magnesium bound to each monomer (Wang et al. 1997). EC Number: 2.2.1.1 Pubmed9357955 Reactome Database ID Release 43163751 Reactome, http://www.reactome.org ReactomeREACT_1730 ACTIVATION GENE ONTOLOGYGO:0015142 Reactome Database ID Release 43372450 Reactome, http://www.reactome.org C-linked procollagen type VI trimer Reactome DB_ID: 2025770 Reactome Database ID Release 432025770 Reactome, http://www.reactome.org ReactomeREACT_121449 has a Stoichiometric coefficient of 1 D-ribulose 5-phosphate <=> ribose 5-phosphate EC Number: 5.3.1.6 Edited: D'Eustachio, P, 2006-04-05 13:59:09 Pubmed14988808 Reactome Database ID Release 4371306 Reactome, http://www.reactome.org ReactomeREACT_2033 The reversible interconversion of ribulose 5-phosphate and ribose 5-phosphate is catalyzed by cytosolic ribose 5-phosphate isomerase (Huck et al. 2004). ACTIVATION GENE ONTOLOGYGO:0004613 Reactome Database ID Release 43372821 Reactome, http://www.reactome.org C-linked procollagen type VII trimer Reactome DB_ID: 2025759 Reactome Database ID Release 432025759 Reactome, http://www.reactome.org ReactomeREACT_121902 has a Stoichiometric coefficient of 3 D-fructose 6-phosphate + D-erythrose 4-phosphate <=> sedoheptulose 7-phosphate + D-glyceraldehyde 3-phosphate Cytosolic transaldolase (TALDO1) catalyzes the reversible reaction of D-erythrose 4-phosphate and D-fructose 6-phosphate to form D-glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate. Protein expressed from the cloned gene has been characterized biochemically (Banki et al. 1994) and transaldolase deficiency in a patient has been correlated with a mutation in the TALDO1 gene (Verhoeven et al. 2001). EC Number: 2.2.1.2 Pubmed11283793 Pubmed8300619 Reactome Database ID Release 43163764 Reactome, http://www.reactome.org ReactomeREACT_1272 C-linked procollagen alpha-1-3(V) propeptide trimer Reactome DB_ID: 2025772 Reactome Database ID Release 432025772 Reactome, http://www.reactome.org ReactomeREACT_121498 has a Stoichiometric coefficient of 1 xylulose 5-phosphate + D-erythrose 4-phosphate <=> D-glyceraldehyde 3-phosphate + D-fructose 6-phosphate Cytosolic transketolase catalyzes the reaction of D-erythrose 4-phosphate and D-xylulose 5-phosphate to form D-glyceraldehyde 3-phosphate and D-fructose 6-phosphate. The active transketolase enzyme is a homodimer with one molecule of thiamine pyrophosphate and magnesium bound to each monomer (Wang et al. 1997). EC Number: 2.2.1.1 Pubmed9357955 Reactome Database ID Release 4371335 Reactome, http://www.reactome.org ReactomeREACT_1811 C-linked procollagen alpha-3(V) trimer Reactome DB_ID: 2025768 Reactome Database ID Release 432025768 Reactome, http://www.reactome.org ReactomeREACT_125420 has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0015172 Reactome Database ID Release 43372473 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015367 Reactome Database ID Release 43198502 Reactome, http://www.reactome.org C-linked procollagen alpha-1(V)X2 alpha-2(V) trimer Reactome DB_ID: 2025752 Reactome Database ID Release 432025752 Reactome, http://www.reactome.org ReactomeREACT_122677 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004613 Reactome Database ID Release 4370496 Reactome, http://www.reactome.org Highly sulphated glycosaminoglycans Converted from EntitySet in Reactome Reactome DB_ID: 1604783 Reactome Database ID Release 431604783 Reactome, http://www.reactome.org ReactomeREACT_119236 ACTIVATION GENE ONTOLOGYGO:0004069 Reactome Database ID Release 4370580 Reactome, http://www.reactome.org Collagen alpha-1(X) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192782 Reactome Database ID Release 432192782 Reactome, http://www.reactome.org ReactomeREACT_124353 D-ribulose 5-phosphate <=> xylulose 5-phosphate Cytosolic ribulose-5-phosphate-3-epimerase (RPE) catalyzes the reversible interconversion of D-ribulose 5-phosphate and D-xylulose 5-phosphate (Bose and 1985). The electrophoretic properties of RPE activity detected in extracts of mouse-human somatic cell hybrids suggest that the active form of the enzyme is a homodimer (Spencer and Hopkinson 1980). EC Number: 5.1.3.1 Pubmed2581946 Pubmed7396409 Reactome Database ID Release 4371303 Reactome, http://www.reactome.org ReactomeREACT_1522 6-phospho-D-gluconate + NADP+ => D-ribulose 5-phosphate + CO2 + NADPH + H+ Cytosolic phosphogluconate dehydrogenase (PGD) catalyzes the reaction of 6-phospho-D-gluconate and NADP+ to form D-ribulose 5-phosphate, CO2, and NADPH + H+ (Beutler and Kuhl 1985; Rippa et al. 1998). The PGD enzyme is dimeric (Dallocchio et al. 1985). EC Number: 1.1.1.44 Pubmed3932573 Pubmed3994686 Pubmed9920387 Reactome Database ID Release 4371299 Reactome, http://www.reactome.org ReactomeREACT_611 ribose 5-phosphate + xylulose 5-phosphate <=> sedoheptulose 7-phosphate + D-glyceraldehyde 3-phosphate Cytosolic transketolase catalyzes the reversible reaction of D-xylulose 5-phosphate and D-ribose 5-phosphate to form D-glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate. The active transketolase enzyme is a homodimer with one molecule of thiamine pyrophosphate and magnesium bound to each monomer (Wang et al. 1997). EC Number: 2.2.1.1 Pubmed9357955 Reactome Database ID Release 4371324 Reactome, http://www.reactome.org ReactomeREACT_1629 xylulose 5-phosphate <=> D-ribulose 5-phosphate Cytosolic ribulose-5-phosphate-3-epimerase (RPE) catalyzes the reversible interconversion of D-xylulose 5-phosphate and D-ribulose 5-phosphate (Bose and 1985). The electrophoretic properties of RPE activity detected in extracts of mouse-human somatic cell hybrids suggest that the active form of the enzyme is a homodimer (Spencer and Hopkinson 1980). EC Number: 5.1.3.1 Pubmed2581946 Pubmed7396409 Reactome Database ID Release 43199803 Reactome, http://www.reactome.org ReactomeREACT_11118 sedoheptulose 7-phosphate + D-glyceraldehyde 3-phosphate <=> D-erythrose 4-phosphate + D-fructose 6-phosphate Cytosolic transaldolase (TALDO1) catalyzes the reversible reaction of D-glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate to form D-erythrose 4-phosphate and D-fructose 6-phosphate. Protein expressed from the cloned gene has been characterized biochemically (Banki et al. 1994) and transaldolase deficiency in a patient has been correlated with a mutation in the TALDO1 gene (Verhoeven et al. 2001). EC Number: 2.2.1.2 Pubmed11283793 Pubmed8300619 Reactome Database ID Release 4371334 Reactome, http://www.reactome.org ReactomeREACT_479 D-glyceraldehyde 3-phosphate + sedoheptulose 7-phosphate<=> xylulose 5-phosphate+ribose 5-phosphate Cytosolic transketolase catalyzes the reversible reaction of D-glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate to form D-xylulose 5-phosphate and D-ribose 5-phosphate. The active transketolase enzyme is a homodimer with one molecule of thiamine pyrophosphate and magnesium bound to each monomer (Wang et al. 1997). EC Number: 2.2.1.1 Pubmed9357955 Reactome Database ID Release 43163741 Reactome, http://www.reactome.org ReactomeREACT_1450 'NFkB Complex [nucleoplasm]' positively regulates 'The NLRP3 inflammasome' ACTIVATION In the absence of TLR agonist 'priming', inflammasome dependent caspase-1 activation is observed but IL-1 beta secretion is minimal. This is primarily because pro-IL1 beta is not expressed in most cells until stimulated by proinflammatory signals such as TNF or LPS that activate NFkappaB. NFkappaB induces expression of pro-IL1beta that can be activated by caspase-1. Pubmed19570822 Reactome Database ID Release 43844634 Reactome, http://www.reactome.org ReactomeREACT_76920 ACTIVATION GENE ONTOLOGYGO:0004807 Reactome Database ID Release 4370453 Reactome, http://www.reactome.org SIGRR decoys MyD88 interaction with Toll receptors INHIBITION Pubmed12925853 Pubmed14673019 Pubmed15866876 Pubmed15928677 Reactome Database ID Release 43188069 Reactome, http://www.reactome.org ReactomeREACT_9385 ACTIVATION GENE ONTOLOGYGO:0004365 Reactome Database ID Release 4370448 Reactome, http://www.reactome.org 'PLCG2 [cytosol]' positively regulates 'Endocytosis of TLR4:MD2:LPS:CD14' ACTIVATION Reactome Database ID Release 432201314 Reactome, http://www.reactome.org ReactomeREACT_125714 ACTIVATION GENE ONTOLOGYGO:0004618 Reactome Database ID Release 4370485 Reactome, http://www.reactome.org 'C-reactive protein pentamer:phosphocholine:C1Q [extracellular region]' positively regulates 'Activation of C1R' ACTIVATION Reactome Database ID Release 43977428 Reactome, http://www.reactome.org ReactomeREACT_27113 ACTIVATION GENE ONTOLOGYGO:0004619 Reactome Database ID Release 4371444 Reactome, http://www.reactome.org 'IRAK-M [cytosol]' negatively regulates 'Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:Mal:p-IRAK4 complex' INHIBITION Pubmed12150927 Reactome Database ID Release 43166139 Reactome, http://www.reactome.org ReactomeREACT_7936 ACTIVATION GENE ONTOLOGYGO:0004634 Reactome Database ID Release 4371439 Reactome, http://www.reactome.org Rab5 is required for PI3K class III docking to TLR9 ACTIVATION Reactome Database ID Release 43188013 Reactome, http://www.reactome.org ReactomeREACT_9387 'EEA1:EEA1 [endosome membrane]' positively regulates 'Engulfed CpG DNA binds to endosomal TLR9' ACTIVATION Pubmed16410796 Reactome Database ID Release 43187892 Reactome, http://www.reactome.org ReactomeREACT_9380 'Dynamin-1/2/3 [plasma membrane]' positively regulates 'Endocytosis of TLR4:MD2:LPS:CD14' ACTIVATION Reactome Database ID Release 432201303 Reactome, http://www.reactome.org ReactomeREACT_125703 'RP105:MD1 [plasma membrane]' negatively regulates 'Transfer of LPS onto TLR4' INHIBITION Pubmed15852007 Reactome Database ID Release 43166156 Reactome, http://www.reactome.org ReactomeREACT_7945 ATP + D-galactose => ADP + D-galactose 1-phosphate Cytosolic galactokinase (GALK1) catalyzes the reaction of ATP and D-galactose to form ADP and D-galactose 1-phosphate (Ai at al. 1995). EC Number: 2.7.1.6 Pubmed7542884 Reactome Database ID Release 4370355 Reactome, http://www.reactome.org ReactomeREACT_1246 Galactosyl-hydroxylysyl collagen propeptides:P4HB Reactome DB_ID: 2023003 Reactome Database ID Release 432023003 Reactome, http://www.reactome.org ReactomeREACT_123700 has a Stoichiometric coefficient of 1 D-galactose 1-phosphate + UDP-glucose <=> D-glucose 1-phosphate + UDP-galactose Authored: 2003-02-25 00:00:00 Cytosolic galactose-1-phosphate uridylyltransferase (GALT) catalyzes the reaction of alpha-D-galactose 1-phosphate and UDP glucose to form D-glucose 1-phosphate and UDP galactose (Reichardt et al. 1991). EC Number: 2.7.7.12 Pubmed1897530 Reactome Database ID Release 4370361 Reactome, http://www.reactome.org ReactomeREACT_2047 Glucosyl-galactosyl-hydroxylysyl collagen propeptides:P4HB Reactome DB_ID: 2023661 Reactome Database ID Release 432023661 Reactome, http://www.reactome.org ReactomeREACT_123070 has a Stoichiometric coefficient of 1 UDP-galactose <=> UDP-glucose Cytosolic UDP-galactose 4-epimerase catalyzes the interconversion of UDP-D-galactose and UDPglucose (Schulz et al. 2004). The active form of the enzyme is a homodimer with one molecule of bound NAD per monomer (Thoden et al. 2000). EC Number: 5.1.3.2 Pubmed10801319 Pubmed15175331 Reactome Database ID Release 4370369 Reactome, http://www.reactome.org ReactomeREACT_1315 C-linked procollagen type I trimer Reactome DB_ID: 2025669 Reactome Database ID Release 432025669 Reactome, http://www.reactome.org ReactomeREACT_125101 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 alpha-D-glucose 6-phosphate + NADP+ => D-glucono-1,5-lactone 6-phosphate + NADPH + H+ Cytosolic glucose-6-phosphate dehydrogenase (G6PD) catalyzes the reaction of glucose 6-phosphate and NADP+ to form D-glucono-1,5-lactone 6-phosphate and , and NADPH + H+. Biochemical studies indicate that both G6PD dimers and tetramers are catalytically active and capable or forming under physiological conditions in vivo (Au et al. 2000). Mutations that reduce the catalytic efficientcy of G6PD are remarkably common in human populations; these appear to have a protective effect against malaria (e.g., Luzzatto and Afolayan 1968). EC Number: 1.1.1.49 Pubmed10745013 Pubmed5666113 Reactome Database ID Release 4370377 Reactome, http://www.reactome.org ReactomeREACT_1868 ACTIVATION GENE ONTOLOGYGO:0004347 Reactome Database ID Release 4370470 Reactome, http://www.reactome.org C-linked procollagen type II trimer Reactome DB_ID: 2025762 Reactome Database ID Release 432025762 Reactome, http://www.reactome.org ReactomeREACT_123895 has a Stoichiometric coefficient of 3 D-glucono-1,5-lactone 6-phosphate + H2O => 6-phospho-D-gluconate Cytosolic 6-phosphogluconolactonase (PGLS) catalyzes the hydrolysis of D-glucono-1,5-lactone 6-phosphate to form 6-phospho-D-gluconate (Beutler and Kuhl 1985; Collard et al. 1999). EC Number: 3.1.1.31 Pubmed10518023 Pubmed3932573 Reactome Database ID Release 4371296 Reactome, http://www.reactome.org ReactomeREACT_2072 ACTIVATION GENE ONTOLOGYGO:0004331 Reactome Database ID Release 43177980 Reactome, http://www.reactome.org 'Factor H:Host cell surface [plasma membrane]' positively regulates 'Factor H binds to C3bBb' ACTIVATION Reactome Database ID Release 431006829 Reactome, http://www.reactome.org ReactomeREACT_120362 ACTIVATION GENE ONTOLOGYGO:0004691 Reactome Database ID Release 43163671 Reactome, http://www.reactome.org 'Factor H:Host cell surface [plasma membrane]' positively regulates 'Factor H binds to membrane-associated C3b' ACTIVATION Reactome Database ID Release 431006830 Reactome, http://www.reactome.org ReactomeREACT_120356 ACTIVATION GENE ONTOLOGYGO:0042132 Reactome Database ID Release 4370478 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004332 Reactome Database ID Release 4371494 Reactome, http://www.reactome.org Alpha-actinin Converted from EntitySet in Reactome Reactome DB_ID: 451402 Reactome Database ID Release 43451402 Reactome, http://www.reactome.org ReactomeREACT_24475 Collagen alpha-1(XIV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192781 Reactome Database ID Release 432192781 Reactome, http://www.reactome.org ReactomeREACT_123215 ABCA cholesterol transporters Converted from EntitySet in Reactome Reactome DB_ID: 383207 Reactome Database ID Release 43383207 Reactome, http://www.reactome.org ReactomeREACT_17258 PEX19 Converted from EntitySet in Reactome Reactome DB_ID: 382609 Reactome Database ID Release 43382609 Reactome, http://www.reactome.org ReactomeREACT_15871 ABCCs Converted from EntitySet in Reactome Reactome DB_ID: 1454912 Reactome Database ID Release 431454912 Reactome, http://www.reactome.org ReactomeREACT_111491 'Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:SOCS3 [plasma membrane]' negatively regulates 'Tyrosine phosphorylation of STATs by IL6 receptor' INHIBITION Pubmed12754505 Reactome Database ID Release 431112775 Reactome, http://www.reactome.org ReactomeREACT_28012 'GHBP:GHR [plasma membrane]' negatively regulates 'Growth hormone receptor dimerizes' Binding of GHBP to GHR produces 'unproductive' dimers that prevent formation of signaling-capable GHR dimers. INHIBITION Pubmed9058373 Reactome Database ID Release 431362495 Reactome, http://www.reactome.org ReactomeREACT_111906 Cl-/HCO3- exchanger proteins Converted from EntitySet in Reactome Reactome DB_ID: 425408 Reactome Database ID Release 43425408 Reactome, http://www.reactome.org ReactomeREACT_20076 Na+/HCO3- symporter proteins Converted from EntitySet in Reactome Reactome DB_ID: 425547 Reactome Database ID Release 43425547 Reactome, http://www.reactome.org ReactomeREACT_20393 Collagen alpha-1(XV) chains Converted from EntitySet in Reactome Reactome DB_ID: 2192816 Reactome Database ID Release 432192816 Reactome, http://www.reactome.org ReactomeREACT_123623 ABCA8/B1/B5 Converted from EntitySet in Reactome Reactome DB_ID: 1467470 Reactome Database ID Release 431467470 Reactome, http://www.reactome.org ReactomeREACT_111404 BP230 Converted from EntitySet in Reactome Reactome DB_ID: 447012 Reactome Database ID Release 43447012 Reactome, http://www.reactome.org ReactomeREACT_25566 Src kinases Src/FADK1 Converted from EntitySet in Reactome Reactome DB_ID: 548936 Reactome Database ID Release 43548936 Reactome, http://www.reactome.org ReactomeREACT_24388 SHP-2/SHP-1 Converted from EntitySet in Reactome Reactome DB_ID: 389744 Reactome Database ID Release 43389744 Reactome, http://www.reactome.org ReactomeREACT_20250 DSCAM/DSCAML1 Converted from EntitySet in Reactome Reactome DB_ID: 629650 Reactome Database ID Release 43629650 Reactome, http://www.reactome.org ReactomeREACT_25673 Platelet releasate (inferred) cytosolic proteins Converted from EntitySet in Reactome Reactome DB_ID: 482774 Reactome Database ID Release 43482774 Reactome, http://www.reactome.org ReactomeREACT_21781 Tropocollagen alpha-1(IV).alpha-1(IV).alpha-2(IV) Reactome DB_ID: 2127348 Reactome Database ID Release 432127348 Reactome, http://www.reactome.org ReactomeREACT_123604 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Collagen alpha-1(VII) trimer Reactome DB_ID: 2022124 Reactome Database ID Release 432022124 Reactome, http://www.reactome.org ReactomeREACT_125037 has a Stoichiometric coefficient of 3 Tropocollagen type VIII Reactome DB_ID: 2168043 Reactome Database ID Release 432168043 Reactome, http://www.reactome.org ReactomeREACT_124086 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Collagen type IX Reactome DB_ID: 2142899 Reactome Database ID Release 432142899 Reactome, http://www.reactome.org ReactomeREACT_121565 has a Stoichiometric coefficient of 1 Platelet releasate (inferred) cytosolic proteins Converted from EntitySet in Reactome Reactome DB_ID: 482764 Reactome Database ID Release 43482764 Reactome, http://www.reactome.org ReactomeREACT_21475 Tropocollagen alpha-3(IV).alpha-4(IV).alpha-5(IV) Reactome DB_ID: 2127428 Reactome Database ID Release 432127428 Reactome, http://www.reactome.org ReactomeREACT_123226 has a Stoichiometric coefficient of 1 Collagen type XVI Reactome DB_ID: 2143413 Reactome Database ID Release 432143413 Reactome, http://www.reactome.org ReactomeREACT_121586 has a Stoichiometric coefficient of 3 Tropocollagen type X Reactome DB_ID: 2142930 Reactome Database ID Release 432142930 Reactome, http://www.reactome.org ReactomeREACT_123978 has a Stoichiometric coefficient of 3 Collagen type XII Reactome DB_ID: 2142915 Reactome Database ID Release 432142915 Reactome, http://www.reactome.org ReactomeREACT_122636 has a Stoichiometric coefficient of 3 Collagen type XIV Reactome DB_ID: 2143434 Reactome Database ID Release 432143434 Reactome, http://www.reactome.org ReactomeREACT_123707 has a Stoichiometric coefficient of 3 Collagen type XV Reactome DB_ID: 2168060 Reactome Database ID Release 432168060 Reactome, http://www.reactome.org ReactomeREACT_123202 has a Stoichiometric coefficient of 3 MAP kinase p38 Converted from EntitySet in Reactome Reactome DB_ID: 171016 Reactome Database ID Release 43171016 Reactome, http://www.reactome.org ReactomeREACT_12350 Platelet releasate secretory granule proteins Converted from EntitySet in Reactome Reactome DB_ID: 482765 Reactome Database ID Release 43482765 Reactome, http://www.reactome.org ReactomeREACT_21850 Platelet releasate secretory granule proteins Converted from EntitySet in Reactome Reactome DB_ID: 482769 Reactome Database ID Release 43482769 Reactome, http://www.reactome.org ReactomeREACT_21832 Procollagen alpha-3(V) Reactome DB_ID: 2268712 Reactome Database ID Release 432268712 Reactome, http://www.reactome.org ReactomeREACT_125333 has a Stoichiometric coefficient of 3 Procollagen type XI Reactome DB_ID: 2268825 Reactome Database ID Release 432268825 Reactome, http://www.reactome.org ReactomeREACT_121467 has a Stoichiometric coefficient of 1 Procollagen alpha-1(V)X2 alpha-2(V) Reactome DB_ID: 2268645 Reactome Database ID Release 432268645 Reactome, http://www.reactome.org ReactomeREACT_124310 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Procollagen alpha-1-3(V) Reactome DB_ID: 2268659 Reactome Database ID Release 432268659 Reactome, http://www.reactome.org ReactomeREACT_122788 has a Stoichiometric coefficient of 1 Tropocollagen type IV Converted from EntitySet in Reactome Reactome DB_ID: 2127389 Reactome Database ID Release 432127389 Reactome, http://www.reactome.org ReactomeREACT_123301 Tropocollagen alpha-5(IV).alpha-5(IV).alpha-6(IV) Reactome DB_ID: 2127425 Reactome Database ID Release 432127425 Reactome, http://www.reactome.org ReactomeREACT_125671 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Tropocollagen type VI tetramer Reactome DB_ID: 1637811 Reactome Database ID Release 431637811 Reactome, http://www.reactome.org ReactomeREACT_123863 has a Stoichiometric coefficient of 2 Tropocollagen type VI dimer Reactome DB_ID: 1637802 Reactome Database ID Release 431637802 Reactome, http://www.reactome.org ReactomeREACT_122194 has a Stoichiometric coefficient of 2 Procollagen type XXIV Reactome DB_ID: 2268752 Reactome Database ID Release 432268752 Reactome, http://www.reactome.org ReactomeREACT_124379 has a Stoichiometric coefficient of 3 Procollagen type XXVII Reactome DB_ID: 2268847 Reactome Database ID Release 432268847 Reactome, http://www.reactome.org ReactomeREACT_123300 has a Stoichiometric coefficient of 3 NCK Converted from EntitySet in Reactome Reactome DB_ID: 381949 Reactome Database ID Release 43381949 Reactome, http://www.reactome.org ReactomeREACT_17190 NEPH2/NEPH3 Converted from EntitySet in Reactome Reactome DB_ID: 936056 Reactome Database ID Release 43936056 Reactome, http://www.reactome.org ReactomeREACT_24799 ROCK Converted from EntitySet in Reactome Reactome DB_ID: 419057 Reactome Database ID Release 43419057 Reactome, http://www.reactome.org ReactomeREACT_20281 RhoA/B/C Converted from EntitySet in Reactome Reactome DB_ID: 419160 Reactome Database ID Release 43419160 Reactome, http://www.reactome.org ReactomeREACT_20229 Olfactory Receptor Converted from EntitySet in Reactome Reactome DB_ID: 381741 Reactome Database ID Release 43381741 Reactome, http://www.reactome.org ReactomeREACT_17423 Myosin-binding protein C Converted from EntitySet in Reactome Reactome DB_ID: 390553 Reactome Database ID Release 43390553 Reactome, http://www.reactome.org ReactomeREACT_18240 Myosin Light Chain Converted from EntitySet in Reactome Reactome DB_ID: 390525 Reactome Database ID Release 43390525 Reactome, http://www.reactome.org ReactomeREACT_17591 RGS proteins active for G alpha (z) Converted from EntitySet in Reactome Reactome DB_ID: 921140 Reactome Database ID Release 43921140 Reactome, http://www.reactome.org ReactomeREACT_24027 PLC-beta Converted from EntitySet in Reactome Reactome DB_ID: 111854 Reactome Database ID Release 43111854 Reactome, http://www.reactome.org ReactomeREACT_15673 RGS proteins active for G alpha (q) Converted from EntitySet in Reactome Reactome DB_ID: 921123 Reactome Database ID Release 43921123 Reactome, http://www.reactome.org ReactomeREACT_24580 Trio family RhoGEFs Converted from EntitySet in Reactome Reactome DB_ID: 399963 Reactome Database ID Release 43399963 Reactome, http://www.reactome.org ReactomeREACT_20038 PathwayStep5111 PathwayStep5110 PathwayStep5113 PathwayStep5112 PathwayStep5115 PathwayStep5114 PDE 4 Converted from EntitySet in Reactome Reactome DB_ID: 111960 Reactome Database ID Release 43111960 Reactome, http://www.reactome.org ReactomeREACT_5541 Histone H3 Converted from EntitySet in Reactome Reactome DB_ID: 212293 Reactome Database ID Release 43212293 Reactome, http://www.reactome.org ReactomeREACT_20295 PDE7 Converted from EntitySet in Reactome Phosphodiesterase 7 Reactome DB_ID: 418540 Reactome Database ID Release 43418540 Reactome, http://www.reactome.org ReactomeREACT_20321 PDE8 Converted from EntitySet in Reactome Reactome DB_ID: 418541 Reactome Database ID Release 43418541 Reactome, http://www.reactome.org ReactomeREACT_19538 PathwayStep5105 PathwayStep5106 PathwayStep5107 PathwayStep5108 Nuclear ubiquitin ligase Converted from EntitySet in Reactome Reactome DB_ID: 173530 Reactome Database ID Release 43173530 Reactome, http://www.reactome.org ReactomeREACT_7541 Ubiquitin conjugating enzyme PathwayStep5109 PathwayStep5100 PathwayStep5104 PathwayStep5103 PathwayStep5102 PathwayStep5101 RGS proteins active for G alpha (i) Converted from EntitySet in Reactome Reactome DB_ID: 921124 Reactome Database ID Release 43921124 Reactome, http://www.reactome.org ReactomeREACT_24579 G-protein alpha (t) subunit Converted from EntitySet in Reactome Reactome DB_ID: 420878 Reactome Database ID Release 43420878 Reactome, http://www.reactome.org ReactomeREACT_18507 PathwayStep5129 PathwayStep5128 PathwayStep5127 Smooth Muscle Myosin Heavy Chain Converted from EntitySet in Reactome Reactome DB_ID: 445788 Reactome Database ID Release 43445788 Reactome, http://www.reactome.org ReactomeREACT_20779 Groups II and III Metabotropic glutamate receptors Converted from EntitySet in Reactome Reactome DB_ID: 420517 Reactome Database ID Release 43420517 Reactome, http://www.reactome.org ReactomeREACT_18623 Phosphorylated Smooth Muscle Myosin Light Chain Converted from EntitySet in Reactome Reactome DB_ID: 445770 Reactome Database ID Release 43445770 Reactome, http://www.reactome.org ReactomeREACT_21117 Group I Metabotropic glutamate receptors Converted from EntitySet in Reactome Reactome DB_ID: 420566 Reactome Database ID Release 43420566 Reactome, http://www.reactome.org ReactomeREACT_18910 PathwayStep5136 PathwayStep5137 PathwayStep5134 PathwayStep5135 PathwayStep5132 PathwayStep5133 PathwayStep5130 PathwayStep5131 p-2S-SMAD2/PAR-2S-SMAD3 Converted from EntitySet in Reactome Reactome DB_ID: 2187329 Reactome Database ID Release 432187329 Reactome, http://www.reactome.org ReactomeREACT_122527 PathwayStep5117 PathwayStep5116 PathwayStep5119 PathwayStep5118 SMAD2 Converted from EntitySet in Reactome Reactome DB_ID: 2176456 Reactome Database ID Release 432176456 Reactome, http://www.reactome.org ReactomeREACT_125589 Smooth Muscle Myosin Light Chain Converted from EntitySet in Reactome Reactome DB_ID: 445793 Reactome Database ID Release 43445793 Reactome, http://www.reactome.org ReactomeREACT_21113 VIP receptor Converted from EntitySet in Reactome Reactome DB_ID: 420267 Reactome Database ID Release 43420267 Reactome, http://www.reactome.org ReactomeREACT_18471 SMAD2 Converted from EntitySet in Reactome Reactome DB_ID: 2187393 Reactome Database ID Release 432187393 Reactome, http://www.reactome.org ReactomeREACT_121519 Alpha-actinin Converted from EntitySet in Reactome Reactome DB_ID: 390561 Reactome Database ID Release 43390561 Reactome, http://www.reactome.org ReactomeREACT_17381 PathwayStep5123 PathwayStep5124 PathwayStep5125 PathwayStep5126 PathwayStep5120 PathwayStep5121 PathwayStep5122 PathwayStep5149 FZDs Converted from EntitySet in Reactome Frizzled receptors Reactome DB_ID: 517388 Reactome Database ID Release 43517388 Reactome, http://www.reactome.org ReactomeREACT_22039 NCOR1 Converted from EntitySet in Reactome Reactome DB_ID: 349714 Reactome Database ID Release 43349714 Reactome, http://www.reactome.org ReactomeREACT_120212 NCOR2 Converted from EntitySet in Reactome Reactome DB_ID: 349713 Reactome Database ID Release 43349713 Reactome, http://www.reactome.org ReactomeREACT_119207 Tropomyosin Converted from EntitySet in Reactome Reactome DB_ID: 390545 Reactome Database ID Release 43390545 Reactome, http://www.reactome.org ReactomeREACT_18024 SKI/SKIL Converted from EntitySet in Reactome Reactome DB_ID: 2186620 Reactome Database ID Release 432186620 Reactome, http://www.reactome.org ReactomeREACT_122826 PathwayStep5150 PathwayStep5151 PathwayStep5154 PathwayStep5155 PathwayStep5152 PathwayStep5153 PathwayStep5158 PathwayStep5159 PathwayStep5156 PathwayStep5157 PathwayStep5139 PathwayStep5138 Troponin I Converted from EntitySet in Reactome Reactome DB_ID: 390541 Reactome Database ID Release 43390541 Reactome, http://www.reactome.org ReactomeREACT_17224 ubiquitin Converted from EntitySet in Reactome Reactome DB_ID: 113595 Reactome Database ID Release 43113595 Reactome, http://www.reactome.org ReactomeREACT_3316 Troponin C Converted from EntitySet in Reactome Reactome DB_ID: 390532 Reactome Database ID Release 43390532 Reactome, http://www.reactome.org ReactomeREACT_17803 EGF-7TMs Converted from EntitySet in Reactome Reactome DB_ID: 444765 Reactome Database ID Release 43444765 Reactome, http://www.reactome.org ReactomeREACT_24399 Troponin T Converted from EntitySet in Reactome Reactome DB_ID: 390546 Reactome Database ID Release 43390546 Reactome, http://www.reactome.org ReactomeREACT_17600 RNF111/SMURF2 Converted from EntitySet in Reactome Reactome DB_ID: 2186743 Reactome Database ID Release 432186743 Reactome, http://www.reactome.org ReactomeREACT_125485 PathwayStep5140 PathwayStep5141 PathwayStep5142 PathwayStep5143 PathwayStep5144 PathwayStep5145 PathwayStep5146 PathwayStep5147 PathwayStep5148 oxaloacetate + GTP => phosphoenolpyruvate + GDP + CO2 [mitochondrial matrix] Authored: D'Eustachio, P, 2008-09-12 21:47:19 EC Number: 4.1.1.32 Edited: D'Eustachio, P, 2008-09-12 21:47:19 PCK2 (phosphoenolcarboxykinase), located in the mitochondrial matrix, catalyzes the physiologically irreversible reaction of oxaloacetate and GTP to form phosphoenolpyruvate, GDP, and CO2 (Modaressi et al. 1996, 1998). Pubmed8645161 Pubmed9657976 Reactome Database ID Release 43372819 Reactome, http://www.reactome.org ReactomeREACT_14793 Reviewed: Harris, RA, 2008-09-10 18:47:12 Exchange of cytosolic citrate for mitochondrial phosphoenolpyruvate Authored: D'Eustachio, P, 2008-09-12 21:47:19 Edited: D'Eustachio, P, 2008-09-12 21:47:19 Pubmed11945784 Pubmed11946196 Pubmed4719206 Pubmed8666394 Pubmed9254007 Reactome Database ID Release 43372449 Reactome, http://www.reactome.org ReactomeREACT_14780 Reviewed: Harris, RA, 2008-09-10 18:47:12 SLC25A1, in the inner mitochondrial membrane, mediates the exchange of cytosolic citrate for mitochondrial phosphoenolpyruvate. The exchange is physiologically irreversible because of the potential of the inner mitochondrial membrane. The gene encoding human SLC25A1 has been cloned and its expression pattern has been characterized (Heisterkamp et al. 1995; Iacobazzi et al. 1997), but the biochemical details of the transport process are inferred from those worked out for the well-characterized rat system (Robinson 1971; Soling et al. 1971; Kleineke et al. 1973). phosphoenolpyruvate [mitochondrial matrix] + citrate [cytosol] => phosphoenolpyruvate [cytosol] + citrate [mitochondrial matrix] Ig Heavy Chain V Region Converted from EntitySet in Reactome Reactome DB_ID: 197042 Reactome Database ID Release 43197042 Reactome, http://www.reactome.org ReactomeREACT_10944 PathwayStep5179 PathwayStep5178 PathwayStep5177 PathwayStep5176 PathwayStep5175 PathwayStep5174 Presenilin Converted from EntitySet in Reactome Reactome DB_ID: 157335 Reactome Database ID Release 43157335 Reactome, http://www.reactome.org ReactomeREACT_5678 PathwayStep5173 PathwayStep5172 PathwayStep5171 PathwayStep5170 Nicastrin Converted from EntitySet in Reactome Reactome DB_ID: 157333 Reactome Database ID Release 43157333 Reactome, http://www.reactome.org ReactomeREACT_4122 Fructose 2,6-bisphosphate is hydrolyzed to form fructose-6-phosphate and orthophosphate EC Number: 3.1.3.46 Pubmed7574501 Reactome Database ID Release 4370262 Reactome, http://www.reactome.org ReactomeREACT_1084 Reviewed: Harris, RA, 2008-09-10 18:47:12 The fructose 2,6-bisphosphatase activity of cytosolic phosphofructokinase 2/fructose-2,6-bisphosphatase catalyzes the hydrolysis of fructose 2,6 bisphosphate to form fructose 6-phosphate. Fructose 2,6 bisphosphate is a key allosteric regulator of PFK1. In its absence the activity of PFK1 is reduced while fructose 1,6-bisphosphatase is activated, thus inhibiting glycolysis and favoring gluconeogenesis (Pilkis et al. 1995). D-fructose 6-phosphate <=> alpha-D-Glucose 6-phosphate EC Number: 5.3.1.9 ISBN0121227022 Pubmed13538944 Pubmed7989588 Reactome Database ID Release 4370475 Reactome, http://www.reactome.org ReactomeREACT_1690 Reviewed: Harris, RA, 2008-09-10 18:47:12 The reversible isomerization of fructose-6-phosphate to form glucose-6-phosphate is catalyzed by cytosolic phosphoglucose isomerase (Noltman 1972; Xu and Beutler 1994; Tsuboi et al. 1958). alpha-D-Glucose 6-phosphate <=> D-Glucose 1-phosphate Cytosolic phosphoglucomutase (PGM) catalyzes the reversible conversion of glucose 6-phosphate to glucose 1-phosphate (Drago et al. 1991). Two PGM isoenzymes, both monomers, have been identified. PGM1 is the major form found in most tissues except erythrocytes, where PGM2 is abundant (March et al. 1993; Parrington et al. 1968; Putt et al. 1993). PGM2 also has substantial phosphopentomutase activity and its primary physiological in normal tissues in vivo is not clear. EC Number: 5.4.2.2 Pubmed17804405 Pubmed1840235 Pubmed7902568 Pubmed8257433 Reactome Database ID Release 4370272 Reactome, http://www.reactome.org ReactomeREACT_2164 E2F4/5 Converted from EntitySet in Reactome Reactome DB_ID: 1226069 Reactome Database ID Release 431226069 Reactome, http://www.reactome.org ReactomeREACT_111318 Erk Converted from EntitySet in Reactome Reactome DB_ID: 997400 Reactome Database ID Release 43997400 Reactome, http://www.reactome.org ReactomeREACT_26117 PathwayStep5168 PathwayStep5167 PathwayStep5169 PathwayStep5164 PathwayStep5163 PathwayStep5166 PathwayStep5165 PathwayStep5160 dihydroxyacetone phosphate + D-glyceraldehyde 3-phosphate <=> D-fructose 1,6-bisphosphate EC Number: 4.1.2.13 In this freely reversible cytosolic reaction, dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate react to form D-fructose 1,6-bisphosphate. The active form of aldolase, the enzyme that catalyzes the reaction, is a homotetramer. Three aldolase isozymes have been identified which differ in their patterns of expression in various adult tissues and during development but are otherwise functionally indistinguishable (Ali and Cox 1995; Dunbar and Fothergill-Gilmore 1988). Pubmed3355497 Pubmed7717389 Reactome Database ID Release 4371495 Reactome, http://www.reactome.org ReactomeREACT_235 Reviewed: Harris, RA, 2008-09-10 18:47:12 D-glyceraldehyde 3-phosphate <=> dihydroxyacetone phosphate EC Number: 5.3.1.1 Pubmed6434534 Pubmed8571957 Reactome Database ID Release 4370481 Reactome, http://www.reactome.org ReactomeREACT_469 Reviewed: Harris, RA, 2008-09-10 18:47:12 The reversible conversion of glyceraldehyde-3-phosphate to dihydroxyacetone phosphate is catalyzed by cytosolic triose phosphate isomerase (Watanabe et al. 1996; Lu et al. 1984). PathwayStep5162 Phosphorylation of PF2K-Pase by PKA catalytic subunit Activated PKA (protein kinase A) phosphorylates serine 36 of the bifunctional 6-Phosphofructo-2-kinase /Fructose-2,6-bisphosphatase (PFKFB1) enzyme. This phosphorylation inhibits the enzyme's phosphofructokinase (PFK-2) activity while activating its phosphatase activity. As a result, cytosolic levels of Fructose-2,6-bisphosphate (F-2,6-P2) are reduced. F-2,6-P2 in turn is a key positive regulator of the committed step of glycolysis, so the net effect of this phosphorylation event is a reduced rate of glycolysis. Authored: Gopinathrao, G, 2005-05-11 18:49:22 EC Number: 2.7.11.11 Pubmed6281764 Reactome Database ID Release 43163773 Reactome, http://www.reactome.org ReactomeREACT_2128 has a Stoichiometric coefficient of 2 PathwayStep5161 D-fructose 1,6-bisphosphate + H2O => D-fructose 6-phosphate + orthophosphate Cytosolic fructose-1,6-bisphosphatase catalyzes the physiologically irreversible hydrolysis of fructose-1,6-bisphosphate to form fructose-6-phosphate and orthophosphate. In the body, two isoforms of the enzyme are expressed, one ubiquitous and one muscle-specific (Kikawa et al. 1997; Tillmann and Eschrich 1998). EC Number: 3.1.3.11 Pubmed9382095 Pubmed9678974 Reactome Database ID Release 4370479 Reactome, http://www.reactome.org ReactomeREACT_379 Reviewed: Harris, RA, 2008-09-10 18:47:12 DP1/2 Converted from EntitySet in Reactome Reactome DB_ID: 1362227 Reactome Database ID Release 431362227 Reactome, http://www.reactome.org ReactomeREACT_111844 2-Phospho-D-glycerate <=> 3-Phospho-D-glycerate Cytosolic phosphoglycerate mutase dimer catalyzes the reversible isomerisation of 2- and 3-phosphoglycerate. There are two isoforms of this enzyme, PGAM1 (isoform B) and PGAM2 (isoform M). In the body, erythrocytes express only PGAM1, while skeletal muscle expresses only PGAM2. Other tissues express both isoforms (Repiso et al. 2005; Tsujino et al. 1993). EC Number: 5.4.2.1 Pubmed15710582 Pubmed8447317 Reactome Database ID Release 4371445 Reactome, http://www.reactome.org ReactomeREACT_766 Reviewed: Harris, RA, 2008-09-10 18:47:12 Phosphoenolpyruvate + H2O <=> 2-Phospho-D-glycerate Cytosolic enolase dimer catalyzes the reversible reaction of phosphoenolpyruvate and water to form 2-phosphoglycerate. Three enolase isozymes have been purified and biochemically characterized. The alpha isoform is widely expressed (Giallongo et al. 1986). The beta isoform is expressed in muscle. Evidence for its function in vivo in humans comes from studies of a patient in whom a point mutation in the gene encoding the enzyme was associated specifically with reduced enolase activity in muscle extracts, and with other symptoms consistent with a defect in glycolysis (Comi et al. 2001). The gamma isoform of human enolase is normally expressed in neural tissue. It is not known to have distinctive biochemical functions, but is of possible clinical interest as a marker of some types of neuroendocrine and lung tumors (McAleese et al. 1988). Verma and Kurl (1993) identifed a possible fourth isoform, a "lung-specific" enolase whose expression is increased in response to dexamethasone treatment. The protein has not been biochemically characterized, however, nor have the levels of mRNA and protein in other tissues been examined. Thus, the observation that this protein is particularly similar in its predicted amino acid sequence to a duck crystallin (Wistow et al. 1988) raises the possibility that its normal function is unrelated to glycolysis. EC Number: 4.2.1.11 Pubmed11506403 Pubmed2462567 Pubmed3208766 Pubmed3529090 Pubmed7689884 Reactome Database ID Release 4370494 Reactome, http://www.reactome.org ReactomeREACT_2018 Reviewed: Harris, RA, 2008-09-10 18:47:12 1,3-bisphospho-D-glycerate + NADH + H+ <=> D-glyceraldehyde 3-phosphate + Orthophosphate + NAD+ EC Number: 1.2.1.12 Pubmed10714828 Pubmed183598 Pubmed3170585 Pubmed7144574 Reactome Database ID Release 4370482 Reactome, http://www.reactome.org ReactomeREACT_1593 Reviewed: Harris, RA, 2008-09-10 18:47:12 The reversible reduction of 1,3-bisphosphoglycerate to form glyceraldehyde-3-phosphate is catalyzed by cytosolic glyceraldehyde-3-phosphate dehydrogenase tetramer.<p>There are multiple human glyceraldehyde 3-phosphate dehydrogenase-like pseudogenes, but only one glyceraldehyde 3-phosphate dehydrogenase gene expressed in somatic tissue (Benham and Povey 1989). Consistent with this conclusion, the homogeneous enzymes purified from various human tissues had indistinguishable physical and immunochemical properties (Heinz and Freimuller 1982), and studies of human erythrocytes of various ages suggested that variant forms of the enzyme arise as a result of post-translational modifications (Edwards et al. 1976). There is, however, an authentic second isoform of glyceraldehyde 3-phosphate dehydrogenase whose expression is confined to spermatogenic cells of the testis (Welch et al. 2000). ATP + 3-Phospho-D-glycerate <=> ADP + 1,3-bisphospho-D-glycerate Cytosolic phosphoglycerate kinase complexed with magnesium catalyzes the reversible phosphorylation of 3-phosphoglycerate to form 1,3-bisphosphoglycerate (Huang et al. 1980a, 1980b). EC Number: 2.7.2.3 Pubmed6771269 Pubmed7391027 Reactome Database ID Release 4370486 Reactome, http://www.reactome.org ReactomeREACT_432 Reviewed: Harris, RA, 2008-09-10 18:47:12 PathwayStep5199 PathwayStep5198 PathwayStep5197 PathwayStep5196 PathwayStep5191 p-SMAD2/3 Converted from EntitySet in Reactome Phospho-R-SMAD Reactome DB_ID: 177105 Reactome Database ID Release 43177105 Reactome, http://www.reactome.org ReactomeREACT_7263 PathwayStep5190 PathwayStep5195 PathwayStep5194 PathwayStep5193 p-T-2S-SMAD2 Converted from EntitySet in Reactome Reactome DB_ID: 2179280 Reactome Database ID Release 432179280 Reactome, http://www.reactome.org ReactomeREACT_122819 PathwayStep5192 Smooth Muscle Actin Converted from EntitySet in Reactome Reactome DB_ID: 445782 Reactome Database ID Release 43445782 Reactome, http://www.reactome.org ReactomeREACT_21045 ubiquitin Converted from EntitySet in Reactome Reactome DB_ID: 68524 Reactome Database ID Release 4368524 Reactome, http://www.reactome.org ReactomeREACT_3995 UBIQ_HUMAN PathwayStep5186 PathwayStep5185 PathwayStep5188 PathwayStep5187 PathwayStep5189 PathwayStep5180 PathwayStep5182 PathwayStep5181 PathwayStep5184 TGIF Converted from EntitySet in Reactome Reactome DB_ID: 2186609 Reactome Database ID Release 432186609 Reactome, http://www.reactome.org ReactomeREACT_124484 PathwayStep5183 SLC1A5-mediated exchange of glutamine and alanine across the plasma membrane Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed10698697 Pubmed8702519 Reactome Database ID Release 43352385 Reactome, http://www.reactome.org ReactomeREACT_13611 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC1A5, associated with the plasma membrane, mediates the exchange of extracellular glutamine for cytosolic alanine (Broer et al. 2000). SLC6A14-mediated uptake of basic and neutral amino acids and of beta-alanine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed10446133 Pubmed18599538 Reactome Database ID Release 43375487 Reactome, http://www.reactome.org ReactomeREACT_14802 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC6A14, associated with the plasma membrane, mediates the uptake of multiple basic and nonpolar amino acids as well as beta-alanine. Uptake of one amino acid molecule is accompanied by uptake of two sodium ions and a chloride ion. As assessed by Northern blotting, SLC6A14 is expressed at high levels in lung but only at low levels, if at all, in intestine or kidney (Sloan and Mager 1999; Anderson et al. 2008). has a Stoichiometric coefficient of 2 SLC1A4-mediated exchange of extracellular threonine for cytosolic alanine, serine, or cysteine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed8101838 Pubmed8340364 Pubmed8910405 Reactome Database ID Release 43352371 Reactome, http://www.reactome.org ReactomeREACT_13531 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC1A4, associated with the plasma membrane, mediates the exchange of threonine and an extracellular sodium ion for a cytosolic sodium ion and any one of the four amino acids alanine, serine, threonine, or cysteine (Zerangue and Kavanaugh 1996). SLC1A5-mediated exchange of alanine and glutamine across the plasma membrane Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed10698697 Pubmed8702519 Reactome Database ID Release 43352379 Reactome, http://www.reactome.org ReactomeREACT_13419 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC1A5, associated with the plasma membrane, mediates the exchange of extracellular alanine for cytosolic glutamine (Broer et al. 2000). SLC6A19-mediated uptake of neutral amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed15286787 Pubmed15286788 Reactome Database ID Release 43375473 Reactome, http://www.reactome.org ReactomeREACT_14843 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC6A19, associated with the plasma membrane, mediates the uptake of neutral amino acids. Uptake of an amino acid molecule is accompanied by uptake of a sodium ion. The protein is abundant in cells in the small intestine and kidney. Its deficiency is associated with Hartnup disorder, the failure to take up neutral amino acids efficiently from the gut lumen and to reabsorb them in the proximal kidney tubule (Kleta et al. 2004; Seow et al, 2004). SLC7A2, isoform A (CAT-2A)-mediated uptake of cationic amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed18195088 Pubmed9174363 Reactome Database ID Release 43375790 Reactome, http://www.reactome.org ReactomeREACT_14848 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC7A2, isoform A, mediates the uptake of cationic amino acids across the plasma membranes of non-epithelial cells (Broer 2008; Closs et al. 1997). SLC7A1 (CAT-1)-mediated uptake of cationic amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed10485994 Pubmed12202949 Pubmed18195088 Pubmed9174363 Reactome Database ID Release 43375776 Reactome, http://www.reactome.org ReactomeREACT_14850 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC7A1 mediates the uptake of cationic amino acids across the plasma membranes of non-epithelial cells (Broer 2008; Closs et al. 1997; Furesz et al. 2002; Kamath et al. 1999). SLC7A11-mediated exchange of extracellular cysteine and cytosolic glutamate Authored: D'Eustachio, P, 2008-11-29 15:37:01 Edited: D'Eustachio, P, 2008-11-29 15:37:01 Pubmed11417227 Pubmed15151999 Reactome Database ID Release 43378513 Reactome, http://www.reactome.org ReactomeREACT_15324 Reviewed: Jassal, B, 2008-11-26 09:32:08 SLC7A11 as a heterodimer with SLC3A2 in the plasma membrane mediates the exchange of glutamate and cysteine. Under physiological conditions, cytosolic glutamate concentrations are high and cysteine concentrations are low, so glutamate is exported and cysteine imported. SLC7A11 is widely expressed in the body (Bassi et al. 2001; Gasol et al. 2004). SLC7A10-mediated uptake of small neutral amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed10863037 Reactome Database ID Release 43376200 Reactome, http://www.reactome.org ReactomeREACT_14851 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC7A10, complexed with SLC3A2 in the plasma membrane, mediates the uptake of small neutral amino acids. The process is Na+-independent. As measured by Northern blotting SLC7A10 is widely expressed in the body (Nakauchi et al. 2000). SLC7A3 (CAT-3)-mediated uptake of cationic amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed11591158 Reactome Database ID Release 43375770 Reactome, http://www.reactome.org ReactomeREACT_14813 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC7A3 mediates the uptake of cationic amino acids across the plasma membranes of non-epithelial cells (Vekony et al. 2001). SLC7A2, isoform B (CAT-2B)-mediated uptake of cationic amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed12202949 Pubmed18195088 Pubmed9174363 Reactome Database ID Release 43375768 Reactome, http://www.reactome.org ReactomeREACT_14845 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC7A2, isoform B, mediates the uptake of cationic amino acids across the plasma membranes of non-epithelial cells (Broer 2008; Closs et al. 1997; Furesz et al. 2002). SLC43A2 (LAT4)-mediated uptake of large neutral amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed15659399 Reactome Database ID Release 43352107 Reactome, http://www.reactome.org ReactomeREACT_13741 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC43A2 (LAT4), associated with the plasma membrane, mediates the uptake of isoleucine, leucine, methionine, phenylalanine, and valine in a biphasic and sodium ion-independent transport process. Northern blotting and in situ hybridization experiments indicate gene expression in kidney and intestine (Bodoy et al. 2005). SLC6A12 (BGT-1)-mediated uptake of GABA and betaine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed10358010 Pubmed7589472 Reactome Database ID Release 43352029 Reactome, http://www.reactome.org ReactomeREACT_13561 Reviewed: Jassal, B, 2008-06-03 13:06:01 The plasma membrane transport protein SLC6A12 (BGT-1) mediates the uptake of GABA (gamma-aminobutyrate) and betaine and, less efficiently, of diminobutyrate (DABA) and beta-alanine. Together with each amino acid molecule, 3 sodium ions and 2 chloride ions are taken up. In the body, SLC6A12 is expressed in the proximal tubules of the kidney and cells of the central nervous system (Rasola et al. 1995; Matskevitch et al. 1999). has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 SLC6A15-mediated amino acid uptake Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed16226721 Reactome Database ID Release 43352059 Reactome, http://www.reactome.org ReactomeREACT_13593 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC6A15, associated with the plasma membrane, mediates the uptake of a broad range of amino acids plus a sodium ion, transporting branched-chain amiono acids and methionine most efficiently. The human protein is expressed in the brain (Takanaga et al. 2005). SLC6A18-mediated glycine uptake Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed15121838 Pubmed16125675 Reactome Database ID Release 43351963 Reactome, http://www.reactome.org ReactomeREACT_13677 Reviewed: Jassal, B, 2008-06-03 13:06:01 The protein SLC6A18 was first identified as an amino acid transporter based on sequence similarity to other members of the SLC6 protein family (Hoglund et al. 2005). It is annotated here as mediating glycine uptake based on the phenotype of mice homozygous for a null mutation in the homologous gene (Quan et al. 2004). SLC6A20-mediated uptake of proline Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed15632147 Reactome Database ID Release 43352052 Reactome, http://www.reactome.org ReactomeREACT_13591 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC6A20, associated with the plasma membrane, mediates the uptake of proline plus a sodium ion. The human protein is expressed in the intestine and kidney (Takanaga et al. 2005). SLC6A6-mediated uptake of taurine and beta-alanine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed8010975 Reactome Database ID Release 43351987 Reactome, http://www.reactome.org ReactomeREACT_13704 Reviewed: Jassal, B, 2008-06-03 13:06:01 The plasma membrane transport protein SLC6A6 mediates the uptake of taurine and beta-alanine. Together with each amino acid molecule, 2 sodium ions and 1 chloride ion are taken up. SLC6A6 is widely expressed in the body (Ramamoorthy et al. 1994). has a Stoichiometric coefficient of 2 Platelet releasate cytosolic proteins Converted from EntitySet in Reactome Reactome DB_ID: 482771 Reactome Database ID Release 43482771 Reactome, http://www.reactome.org ReactomeREACT_21985 SLC7A5-mediated uptake of neutral amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed10049700 Pubmed10391915 Reactome Database ID Release 43352232 Reactome, http://www.reactome.org ReactomeREACT_13642 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC7A5, complexed with SLC3A2 in the plasma membrane, mediates the uptake of neutral amino acids. The process is Na+-independent and not coupled to H+ transport. As measured by Northern blotting SLC7A5 is widely expressed in the body. In situ hybridization studies indicate that the gene product is widely expressed in the body but not in the kidney (Pineda et al. 1999; Prasad et al. 1999). SLC1A4-mediated exchange of extracellular alanine for cytosolic serine, threonine, or cysteine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed8101838 Pubmed8340364 Pubmed8910405 Reactome Database ID Release 43352364 Reactome, http://www.reactome.org ReactomeREACT_13455 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC1A4, associated with the plasma membrane, mediates the exchange of alanine and an extracellular sodium ion for a cytosolic sodium ion and any one of the four amino acids alanine, serine, threonine, or cysteine (Zerangue and Kavanaugh 1996). SLC7A8-mediated uptake of neutral amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed10391915 Pubmed15918515 Reactome Database ID Release 43352191 Reactome, http://www.reactome.org ReactomeREACT_13482 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC7A8, complexed with SLC3A2 in the plasma membrane, mediates the uptake of neutral amino acids. The process is Na+-independent and not coupled to H+ transport. As measured by Northern blotting SLC7A8 is widely expressed in the body. In situ hybridization studies indicate that the gene product is abundant in kidney proximal tubules (Pineda et al. 1999; Park et al. 2005) SLC1A4-mediated exchange of extracellular serine for cytosolic alanine, threonine, or cysteine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed8101838 Pubmed8340364 Pubmed8910405 Reactome Database ID Release 43352347 Reactome, http://www.reactome.org ReactomeREACT_13745 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC1A4, associated with the plasma membrane, mediates the exchange of serine and an extracellular sodium ion for a cytosolic sodium ion and any one of the four amino acids alanine, serine, threonine, or cysteine (Zerangue and Kavanaugh 1996). SLC1A4-mediated exchange of extracellular cysteine for cytosolic alanine, serine, or threonine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed8101838 Pubmed8340364 Pubmed8910405 Reactome Database ID Release 43352354 Reactome, http://www.reactome.org ReactomeREACT_13618 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC1A4, associated with the plasma membrane, mediates the exchange of cysteine and an extracellular sodium ion for a cytosolic sodium ion and any one of the four amino acids alanine, serine, threonine, or cysteine (Zerangue and Kavanaugh 1996). SLC38A2 (ATA2)-mediated uptake of neutral amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed10930503 Reactome Database ID Release 43352108 Reactome, http://www.reactome.org ReactomeREACT_13449 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC38A2 (ATA2), associated with the plasma membrane, mediates the uptake of neutral amino acids, especially alanine, asparagine, glutamine, glycine, leucine, methionine, proline, and threonine in a sodium ion-dependent transport process. Northern blotting experiments indicate gene expression in placenta and heart, and at lower levels in other tissues including brain, lung, skeletal muscle, spleen, stomach, testis, kidney, and intestine (Hatanaka et al. 2000). Integrin alpha8beta1:Fibronectin Reactome DB_ID: 216009 Reactome Database ID Release 43216009 Reactome, http://www.reactome.org ReactomeREACT_13847 has a Stoichiometric coefficient of 1 Processed PDGF-B Converted from EntitySet in Reactome Reactome DB_ID: 381935 Reactome Database ID Release 43381935 Reactome, http://www.reactome.org ReactomeREACT_17313 Integrin alpha8beta1:Osteopontin Reactome DB_ID: 216006 Reactome Database ID Release 43216006 Reactome, http://www.reactome.org ReactomeREACT_13981 has a Stoichiometric coefficient of 1 SLC16A10-mediated uptake of aromatic amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed11278508 Pubmed11827462 Pubmed15918515 Reactome Database ID Release 43352158 Reactome, http://www.reactome.org ReactomeREACT_13410 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC16A10 mediates the reversible facilitated diffusion of phenylalanine, tyrosine, and tryptophan across the plasma membrane. The process is Na+-independent and not coupled to H+ transport. As measured by Northern blotting SLC16A10 is widely expressed in the body but especially abundant in kidney. In situ hybridization studies indicate that the gene product is abundant in kidney proximal tubules (Kim et al. 2001; Kim et al. 2002; Park et al. 2005). ACTIVATION GENE ONTOLOGYGO:0004788 Reactome Database ID Release 43196957 Reactome, http://www.reactome.org SLC38A1 (ATA1)-mediated uptake of neutral amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed10891391 Reactome Database ID Release 43352119 Reactome, http://www.reactome.org ReactomeREACT_13590 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC38A1 (ATA1), associated with the plasma membrane, mediates the uptake of neutral amino acids, especially alanine, asparagine, glutamine, methionine, and serine in a sodium ion-dependent transport process. Northern blotting experiments indicate gene expression in placenta and heart, and at lower levels in other tissues including brain, lung, skeletal muscle, spleen, stomach and testis, but not kidney or intestine (Wang et al. 2000). ACTIVATION GENE ONTOLOGYGO:0015234 Reactome Database ID Release 43199654 Reactome, http://www.reactome.org SLC36A1-mediated uptake of glycine, proline, and alanine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed12527723 Reactome Database ID Release 43375417 Reactome, http://www.reactome.org ReactomeREACT_14785 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC36A1 (PAT1), associated with the plasma membrane, mediates the uptake of glycine, alanine, and proline coupled to the uptake of a proton. Northern blotting experiments indicate gene expression principally in the intestine (Chen et al. 2003). Integrin alpha9beta1 Reactome DB_ID: 216011 Reactome Database ID Release 43216011 Reactome, http://www.reactome.org ReactomeREACT_14004 has a Stoichiometric coefficient of 1 SLC36A2-mediated uptake of glycine and proline Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-09-12 21:44:24 Pubmed12809675 Reactome Database ID Release 43375405 Reactome, http://www.reactome.org ReactomeREACT_14841 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC36A2 (PAT2), associated with the plasma membrane, has been shown in a limited set of tests in vitro to mediate the uptake of glycine and proline coupled to the uptake of a proton (Boll et al. 2003). PAT2 is most abundantly expressed in kidney and muscle. Integrin alpha9beta1:Osteopontin Reactome DB_ID: 216005 Reactome Database ID Release 43216005 Reactome, http://www.reactome.org ReactomeREACT_14228 has a Stoichiometric coefficient of 1 malate [mitochondrial matrix] + orthophosphate [cytosol] <=> malate [cytosol] + orthophosphate [mitochondrial matrix] Authored: D'Eustachio, P, 2008-09-12 21:47:19 Edited: D'Eustachio, P, 2008-09-12 21:47:19 Pubmed10585886 Reactome Database ID Release 43372843 Reactome, http://www.reactome.org ReactomeREACT_14803 Reviewed: Harris, RA, 2008-09-10 18:47:12 SLC25A10, the mitochondrial dicarboxylate carrier protein in the inner mitochondrial membrane, mediates the reversible exchange of mitochondrial malate for cytosolic phosphate (Fiermonte et al. 1999). Tenascin hexamer Reactome DB_ID: 216010 Reactome Database ID Release 43216010 Reactome, http://www.reactome.org ReactomeREACT_14068 has a Stoichiometric coefficient of 6 APH-1 Converted from EntitySet in Reactome Reactome DB_ID: 157341 Reactome Database ID Release 43157341 Reactome, http://www.reactome.org ReactomeREACT_2545 Vesicular inhibitory amino acid transport Authored: Jassal, B, 2009-07-06 Edited: Jassal, B, 2009-07-06 Gamma-Aminobutyric acid (GABA) is the major inhibitory<br>transmitter of the vertebrate retina. The gene SLC32A1 encodes the vesicular inhibitory amino acid transporter (VIAAT, also called vesicular GABA transporter VGAT) (Jellali A et al, 2002). VIAAT is a proton-coupled amino acid antiporter, uptaking the inhibitory neurotransmitters GABA and glycine into synaptic vesicles in exchange for protons. This process is driven by the H+-ATPase, providing the driving force for uptake of these neurotransmitters. The protein is expressed throughout the terminal ends of horizontal cells of the retina.<br> Pubmed12115694 Reactome Database ID Release 43428625 Reactome, http://www.reactome.org ReactomeREACT_19142 Reviewed: He, L, 2009-08-24 Integrin alpha8beta1:Tenascin Reactome DB_ID: 216008 Reactome Database ID Release 43216008 Reactome, http://www.reactome.org ReactomeREACT_14604 has a Stoichiometric coefficient of 1 Vascular endothelial growth factor Converted from EntitySet in Reactome Reactome DB_ID: 139884 Reactome Database ID Release 43139884 Reactome, http://www.reactome.org ReactomeREACT_5049 SLC43A1 (LAT3)-mediated uptake of large neutral amino acids Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed12930836 Reactome Database ID Release 43352103 Reactome, http://www.reactome.org ReactomeREACT_13479 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC43A1 (LAT3), associated with the plasma membrane, mediates the uptake of isoleucine, leucine, methionine, phenylalanine, and valine in a biphasic and sodium ion-independent transport process. Northern blotting experiments indicate gene expression in liver, pancreas, and skeletal muscle, and at lower levels in many tissues including kidney and intestine (Babu et al. 2003). ACTIVATION GENE ONTOLOGYGO:0004551 Reactome Database ID Release 43196942 Reactome, http://www.reactome.org Integrin alpha7beta1:Laminin-2 Reactome DB_ID: 215995 Reactome Database ID Release 43215995 Reactome, http://www.reactome.org ReactomeREACT_14652 has a Stoichiometric coefficient of 1 SLC38A5-mediated uptake of glutamine, histidine, asparagine, and serine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed11243884 Reactome Database ID Release 43352182 Reactome, http://www.reactome.org ReactomeREACT_13564 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC38A5 (SN2), associated with the plasma membrane, mediates the uptake of asparagine, glutamine, histidine, serine and, with lower efficiency, alanine and glycine. Indirect assays suggest that amino acid uptake is coupled to the uptake of sodium ion(s) and the export of H+. Northern blotting experiments indicate gene expression in brain and stomach, and at lower levels in liver, lung, and intestine (Nakanishi et al. 2001). ACTIVATION GENE ONTOLOGYGO:0003993 Reactome Database ID Release 43196922 Reactome, http://www.reactome.org Merosin Laminin-2 Laminin-211 Reactome DB_ID: 216003 Reactome Database ID Release 43216003 Reactome, http://www.reactome.org ReactomeREACT_13824 has a Stoichiometric coefficient of 1 SLC38A4 (ATA3)-mediated uptake of arginine and lysine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed11342143 Reactome Database ID Release 43352136 Reactome, http://www.reactome.org ReactomeREACT_13736 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC38A4 (ATA3), associated with the plasma membrane, mediates the sodium-independent uptake of arginine and lysine. SLC38A4 was first identified on the basis of its similarity to SLC38A1 and SLC38A2. Like those two transporters, it can mediate the sodium-dependent uptake of neutral amino acids in cultured cells transfected with an expression vector, but it does so very inefficiently and its role, if any, in neutral amino acid uptake in vivo is unclear. By Northern blotting, SLC38A4 is abundant in liver and undetectable in all other tissues tested, including heart, placenta, kidney, and intestine (Hatanaka et al. 2001). ACTIVATION GENE ONTOLOGYGO:0008523 Reactome Database ID Release 43199212 Reactome, http://www.reactome.org Integrin alpha7beta1:Laminin-1 Reactome DB_ID: 216000 Reactome Database ID Release 43216000 Reactome, http://www.reactome.org ReactomeREACT_14098 has a Stoichiometric coefficient of 1 SLC38A3-mediated uptake of glutamine, histidine, asparagine, and alanine Authored: D'Eustachio, P, 2008-06-02 20:10:30 Edited: D'Eustachio, P, 2008-06-02 20:10:30 Pubmed10823827 Pubmed11243884 Reactome Database ID Release 43352174 Reactome, http://www.reactome.org ReactomeREACT_13659 Reviewed: Jassal, B, 2008-06-03 13:06:01 SLC38A3 (SN1), associated with the plasma membrane, mediates the uptake of glutamine, histidine, and, with lower efficiency, alanine and asparagine. Uptake of one molecule of amino acid is coupled to the uptake of two sodium ions and the export of one H+. Northern blotting experiments indicate gene expression in liver and kidney, and at much lower levels in brain, lung, skeletal muscle, spleen, stomach, testis, kidney, and intestine (Fei et al. 2000; Nakanishi et al. 2001). has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004594 Reactome Database ID Release 43196799 Reactome, http://www.reactome.org Integrin alpha7beta1 Reactome DB_ID: 215998 Reactome Database ID Release 43215998 Reactome, http://www.reactome.org ReactomeREACT_14603 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0050331 Reactome Database ID Release 43997383 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0050333 Reactome Database ID Release 43964942 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008531 Reactome Database ID Release 43196939 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003919 Reactome Database ID Release 43196924 Reactome, http://www.reactome.org Integrin alpha8beta1 Reactome DB_ID: 216012 Reactome Database ID Release 43216012 Reactome, http://www.reactome.org ReactomeREACT_14156 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0044717 Reactome Database ID Release 432532779 Reactome, http://www.reactome.org Alpha actinins Converted from EntitySet in Reactome Reactome DB_ID: 349778 Reactome Database ID Release 43349778 Reactome, http://www.reactome.org ReactomeREACT_14456 Integrin alpha4beta7 Reactome DB_ID: 198927 Reactome Database ID Release 43198927 Reactome, http://www.reactome.org ReactomeREACT_11974 has a Stoichiometric coefficient of 1 Integrin alpha4beta7:MADCAM1 Reactome DB_ID: 198925 Reactome Database ID Release 43198925 Reactome, http://www.reactome.org ReactomeREACT_11447 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Integrin alpha5beta1:Ostepontin Reactome DB_ID: 265411 Reactome Database ID Release 43265411 Reactome, http://www.reactome.org ReactomeREACT_14080 has a Stoichiometric coefficient of 1 Integrin alpha6beta1:Laminin-1 Reactome DB_ID: 215996 Reactome Database ID Release 43215996 Reactome, http://www.reactome.org ReactomeREACT_14563 has a Stoichiometric coefficient of 1 Integrin alpha6beta4:Laminin-5 Reactome DB_ID: 216002 Reactome Database ID Release 43216002 Reactome, http://www.reactome.org ReactomeREACT_14260 has a Stoichiometric coefficient of 1 Ig Lambda C region Converted from EntitySet in Reactome Immunoglobulin Lambda C Region Reactome DB_ID: 983681 Reactome Database ID Release 43983681 Reactome, http://www.reactome.org ReactomeREACT_26049 Ig Lamda Light Chain V Region Converted from EntitySet in Reactome Reactome DB_ID: 197028 Reactome Database ID Release 43197028 Reactome, http://www.reactome.org ReactomeREACT_10476 ACTIVATION GENE ONTOLOGYGO:0045174 Reactome Database ID Release 43198791 Reactome, http://www.reactome.org Passive I- efflux mediated by SMCT1 Authored: Jassal, B, 2009-07-21 Edited: Jassal, B, 2009-07-21 Pubmed12107270 Reactome Database ID Release 43429767 Reactome, http://www.reactome.org ReactomeREACT_19251 Reviewed: He, L, 2009-08-24 SLC5A8 encodes for the apical iodide transporter, AIT (also known as SMCT1). As well as functioning as a Na+-dependent monocarboxylate co-transporter, AIT also mediates iodide transport from the thyrocyte into the colloid lumen through the apical membrane (Rodriguez AM et al, 2002). AIT, together with NIS (see previous reaction), mediates iodide transfer from blood to the colloid lumen of thyrocytes. ACTIVATION GENE ONTOLOGYGO:0004033 Reactome Database ID Release 43198774 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004128 Reactome Database ID Release 43198863 Reactome, http://www.reactome.org Sulfate is exported to the cytosol in exchange for dicarboxylate Authored: Stephan, R, 2010-10-24 Edited: Jassal, B, 2011-09-29 Pubmed10585886 Pubmed4441366 Reactome Database ID Release 431614546 Reactome, http://www.reactome.org ReactomeREACT_115667 Reviewed: D'Eustachio, P, 2011-10-13 Sulfate leaves the mitochondrion with the help of the dicarboxylate carrier, via antiport with malate (Crompton et al. 1974, Fiemont et al. 1999) ACTIVATION GENE ONTOLOGYGO:0033300 Reactome Database ID Release 43198847 Reactome, http://www.reactome.org Na+-dependent monocarboxylate transport by SMCT Authored: Jassal, B, 2009-07-21 Edited: Jassal, B, 2009-07-21 Pubmed14966140 Pubmed15090606 Reactome Database ID Release 43429749 Reactome, http://www.reactome.org ReactomeREACT_19245 Reviewed: He, L, 2009-08-24 The human tumour suppressor gene SLC5A8 encodes for a sodium-coupled monocarboxylate transporter 1, SMCT1 (also called AIT) and is abundantly expressed in the colon (Coady MJ et al, 2004; Myauchi S et al, 2004). When the human protein is expressed in Xenopus oocytes, it was found to transport small monocarboxylates, co-transporting Na+ ions electrogenically (3 Na+ ions co-transported with 1 carboxylate). has a Stoichiometric coefficient of 3 ACTIVATION GENE ONTOLOGYGO:0015229 Reactome Database ID Release 43198796 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047631 Reactome Database ID Release 432393952 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047631 Reactome Database ID Release 432393912 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0097383 Reactome Database ID Release 432509802 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0090450 Reactome Database ID Release 432509812 Reactome, http://www.reactome.org Integrin alphaVbeta3:Tenascin Reactome DB_ID: 265412 Reactome Database ID Release 43265412 Reactome, http://www.reactome.org ReactomeREACT_14164 has a Stoichiometric coefficient of 1 Integrin alphaVbeta3:Fibronectin Reactome DB_ID: 216016 Reactome Database ID Release 43216016 Reactome, http://www.reactome.org ReactomeREACT_14178 has a Stoichiometric coefficient of 1 Integrin alphaVbeta3:Vitronectin Reactome DB_ID: 216017 Reactome Database ID Release 43216017 Reactome, http://www.reactome.org ReactomeREACT_14620 has a Stoichiometric coefficient of 1 Glucose is secreted across the plasma membrane Authored: D'Eustachio, P, 2009-12-11 Edited: D'Eustachio, P, 2010-02-18 GLUT2 (glucose transporter) homotetramers associated with the plasma membrane mediate the facilitated diffusion of glucose between the cytosol and the extracellular space, so glucose will leave cells when its intracellular concentration exceeds the extracellular one (Colville et al. 1993; Santer et al. 1997; Wu et al. 1998). In the body, such glucose export is a normal feature of liver cells when gluconeogenesis or glycogen breakdown is underway. Pubmed8457197 Pubmed9354798 Pubmed9751501 Reactome Database ID Release 43450095 Reactome, http://www.reactome.org ReactomeREACT_21316 Reviewed: Jassal, B, 2010-02-26 alpha-D-glucose (cytosol) <=> alpha-D-glucose (extracellular) Integrin alphaVbeta3:Bone sialoprotein 2 Reactome DB_ID: 265408 Reactome Database ID Release 43265408 Reactome, http://www.reactome.org ReactomeREACT_14050 has a Stoichiometric coefficient of 1 LFA-1:ICAM 1-4 Reactome DB_ID: 198200 Reactome Database ID Release 43198200 Reactome, http://www.reactome.org ReactomeREACT_11942 has a Stoichiometric coefficient of 1 Integrin alphaXbeta2:fibrin multimer Reactome DB_ID: 216032 Reactome Database ID Release 43216032 Reactome, http://www.reactome.org ReactomeREACT_13854 has a Stoichiometric coefficient of 1 Integrin alphaVbeta8:Vitronectin Reactome DB_ID: 216311 Reactome Database ID Release 43216311 Reactome, http://www.reactome.org ReactomeREACT_14549 has a Stoichiometric coefficient of 1 Integrin alphaVbeta8 Reactome DB_ID: 216307 Reactome Database ID Release 43216307 Reactome, http://www.reactome.org ReactomeREACT_14042 has a Stoichiometric coefficient of 1 cytosolic GCK1:GKRP complex <=> glucokinase (GCK1) + glucokinase regulatory protein (GKRP) Edited: D'Eustachio, P, 2006-02-20 18:39:56 Pubmed10601273 Pubmed14627435 Reactome Database ID Release 43170799 Reactome, http://www.reactome.org ReactomeREACT_6920 The cytosolic glucokinase (GCK1):glucokinase regulatory protein (GKRP) complex dissociates.However, while GCK1:GKRP complex formation is reversible (Brocklehurst et al. 2004) the major fate of these complexes in vivo appears to be transport to the nucleus (Shiota et al. 1999). GCK1:GKRP [cytosol] => GCK1:GKRP [nucleoplasm] Edited: D'Eustachio, P, 2006-02-20 18:39:56 Pubmed10601273 Reactome Database ID Release 43170796 Reactome, http://www.reactome.org ReactomeREACT_6938 The complex of glucokinase (GCK1) and glucokinase regulatory protein (GKRP) is translocated to the nucleus via the nuclear pore (Shiota et al. 1999). Transport of glucokinase (GCK1):GKRP complex to the nucleus alpha-D-Glucose + ATP => alpha-D-glucose 6-phosphate + ADP Cytosolic glucokinase and the three isoforms of hexokinase catalyze the irreversible reaction of glucose and ATP to form glucose 6 phosphate and ADP. In the body glucokinase is found only in hepatocytes and pancreatic beta cells. Glucokinase and the hexokinase enzymes differ in that glucokinase has a higher Km than the hexokinases and is less readily inhibited by the reaction product. As a result, glucokinase should be inactive in the fasting state when glucose concentrations are low but in the fed state should have an activity proportional to glucose concentration. These features are thought to enable efficient glucose uptake and retention in the liver, and to function as a sensor of glucose concentration coupled to insulin release in pancreatic beta cells (Thorens 2001). Glucokinase mutations are associated with MODY2, a heritable early onset form of type II diabetes (Tanizawa et al. 1991; Takeda et al. 1993). Three human hexokinase enzymes have been characterized, HK1 (Aleshin et al. 1998), HK2 (Lehto et al. 1995), and HK3 (Rijksen at al. 1982). EC Number: 2.7.1.2 Pubmed11780755 Pubmed1871135 Pubmed7150652 Pubmed8325892 Pubmed8786021 Pubmed9493266 Reactome Database ID Release 4370420 Reactome, http://www.reactome.org ReactomeREACT_1827 glucokinase (GCK1) + glucokinase regulatory protein (GKRP) <=> GCK1:GKRP complex Edited: D'Eustachio, P, 2006-02-20 18:39:56 Glucokinase (GCK1) reversibly binds glucokinase regulatory protein (GKRP) to form an inactive complex. Binding is stimulated by fructose 6-phosphate and sorbitol 6-phosphate (hence high concentrations of these molecules tend to reduce GCK1 activity) and inhibited by fructose 1-phosphate (hence a high concentration of this molecule tends to increase GCK1 activity) (Brocklehurst et al. 2004). Pubmed14627435 Reactome Database ID Release 43170824 Reactome, http://www.reactome.org ReactomeREACT_6771 transport of cytosolic alpha-D-glucose 6-phosphate into the endoplasmic reticulum Authored: D'Eustachio, P, 2007-06-22 14:17:01 Pubmed9428641 Reactome Database ID Release 43198513 Reactome, http://www.reactome.org ReactomeREACT_11151 Reviewed: Harris, RA, 2008-09-10 18:47:12 The SLC37A4 transport protein in the endoplasmic reticulum membrane mediates the translocation of glucose-6-phosphate from the cytosol into the lumen of the endoplasmic reticulum. Defects in this transporter are associated with glycogen storage disease type Ib (Gerin et al. 1997). alpha-D-glucose 6-phosphate [cytosol] => alpha-D-glucose 6-phosphate [endoplasmic reticulum lumen] Integrin alphaVbeta6:Fibronectin Reactome DB_ID: 216022 Reactome Database ID Release 43216022 Reactome, http://www.reactome.org ReactomeREACT_14046 has a Stoichiometric coefficient of 1 alpha-D-Glucose 6-phosphate + H2O => alpha-D-Glucose + Orthophosphate EC Number: 3.1.3.9 Glucose-6-phosphatase associated with the inner face of the endoplasmic reticulum membrane catalyzes the hydrolysis of glucose-6-phosphate to glucose and orthophosphate (reviewed by Van Scaftingen and Gerin 2002). This reaction is essentially irreversible. Defects in glucose-6-phosphatase are the cause of glycogen storage disease type 1a (Lei et al. 1995; Guionie et al, 2003; Petrolonis et al, 2004). Pubmed11879177 Pubmed12965222 Pubmed14722102 Pubmed7573034 Reactome Database ID Release 4371825 Reactome, http://www.reactome.org ReactomeREACT_1682 Reviewed: Harris, RA, 2008-09-10 18:47:12 Dissociation of the nucleoplasmic GCK1:GKRP complex Edited: D'Eustachio, P, 2006-02-20 18:39:56 In the presence of high glucose concentrations, the complex of nucleoplasmic glucokinase (GCK1) and glucokinase regulatory protein (GKRP) dissociates (Shiota et al. 1999). Pubmed10601273 Reactome Database ID Release 43170810 Reactome, http://www.reactome.org ReactomeREACT_6899 nucleoplasmic GCK1:GKRP complex => glucokinase (GCK1) + glucokinase regulatory protein (GKRP) Integrin alphaVbeta5:Vitronectin Reactome DB_ID: 216021 Reactome Database ID Release 43216021 Reactome, http://www.reactome.org ReactomeREACT_14045 has a Stoichiometric coefficient of 1 glucokinase [nucleoplasm] => glucokinase [cytosol] Edited: D'Eustachio, P, 2006-02-20 18:39:56 Free glucokinase (GCK1) leaves the nucleus via the nuclear pore. While the GCK1 protein contains a nuclear export sequence motif, the molecular details of the GCK1 export process remain to be worked out (Shiota et al. 1999). Pubmed10601273 Reactome Database ID Release 43170825 Reactome, http://www.reactome.org ReactomeREACT_6714 Integrin alphaVbeta6 Reactome DB_ID: 216024 Reactome Database ID Release 43216024 Reactome, http://www.reactome.org ReactomeREACT_14276 has a Stoichiometric coefficient of 1 GLUT1 + ATP <=> GLUT1:ATP Authored: D'Eustachio, P, 2009-12-11 Cytosolic ATP reversibly associates with GLUT1. This association inhibits GLUT1 glucose transport (Blodgett et al. 2007). Edited: D'Eustachio, P, 2010-02-18 Pubmed17635959 Reactome Database ID Release 43450088 Reactome, http://www.reactome.org ReactomeREACT_21271 Reviewed: Graves, L, Rush, MG, 0000-00-00 00:00:00 Na+/H+ exchanger proteins 7/8 Converted from EntitySet in Reactome Reactome DB_ID: 426005 Reactome Database ID Release 43426005 Reactome, http://www.reactome.org ReactomeREACT_20455 GLUT1:ATP <=> GLUT1 + ATP Authored: D'Eustachio, P, 2009-12-11 Edited: D'Eustachio, P, 2010-02-18 GLUT1:ATP complexes reversibly dissociate, restoring the glucose transport activity of GLUT1 glucose transport, with the result that depletion of cellular ATP leads to increased glucose uptake (Blodgett et al. 2007). Pubmed17635959 Reactome Database ID Release 43450092 Reactome, http://www.reactome.org ReactomeREACT_21378 maltotriose + H2O => maltose + D-glucose (sucrase-isomaltase) Authored: D'Eustachio, P, 2006-11-03 14:36:07 Digestion of maltotriose by sucrase-isomaltase to yield maltose and glucose EC Number: 3.2.1.20 ISBN0079130356 Maltotriose is representative of linear glucose oligomers containing more than two residues. The 1-4 linkages of extracellular maltotriose are hydrolyzed to yield maltose and glucose in a reaction catalyzed by the exoglucosidase activity of sucrase-isomaltase (Nichols et al. 1998; Semenza et al. 2001). In the body, this enzyme is found as a dimer on the external face of enterocytes in microvilli of the small intestine (Hauri et al. 1985), and acts on maltotriose derived directly from the diet and from the hydrolysis of starch, although with lower activity than maltase-glucoamylase. Pubmed12547908 Pubmed3897250 Reactome Database ID Release 43191101 Reactome, http://www.reactome.org ReactomeREACT_9479 Reviewed: Nichols, BL, 2007-01-15 21:51:24 Integrin alphaVbeta1 Reactome DB_ID: 216015 Reactome Database ID Release 43216015 Reactome, http://www.reactome.org ReactomeREACT_13937 has a Stoichiometric coefficient of 1 maltotriose + H2O => maltose + D-glucose (maltase-glucoamylase) Authored: D'Eustachio, P, 2006-11-03 14:36:07 Digestion of maltotriose by maltase-glucomylase to yield maltose and glucose EC Number: 3.2.1.20 ISBN0079130356 Maltotriose is representative of linear glucose oligomers containing more than two residues. The 1-4 linkages of extracellular maltotriose are hydrolyzed to yield maltose and glucose in a reaction catalyzed by the exoglucosidase activity of maltase-glucoamylase (Nichols et al. 1998; Semenza et al. 2001). In the body, this enzyme is found as a dimer on the external face of enterocytes in microvilli of the small intestine (Hauri et al. 1985), and acts on maltotriose derived directly from the diet and from the hydrolysis of starch. This reaction can also be catalyzed by sucrase-isomaltase, but maltase-glucoamylase is about a hundredfold more active. Pubmed12547908 Pubmed3897250 Reactome Database ID Release 43191116 Reactome, http://www.reactome.org ReactomeREACT_9506 Reviewed: Nichols, BL, 2007-01-15 21:51:24 Integrin alphaDbeta2:fibrin multimer:Mg++ Reactome DB_ID: 216027 Reactome Database ID Release 43216027 Reactome, http://www.reactome.org ReactomeREACT_14528 has a Stoichiometric coefficient of 1 Integrin alphaVbeta5 Reactome DB_ID: 216019 Reactome Database ID Release 43216019 Reactome, http://www.reactome.org ReactomeREACT_13993 has a Stoichiometric coefficient of 1 Integrin alphaVbeta1:FN1 dimer Integrin alphaVbeta1:Fibronectin dimer Reactome DB_ID: 216013 Reactome Database ID Release 43216013 Reactome, http://www.reactome.org ReactomeREACT_13983 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Integrin alpha11beta1 Reactome DB_ID: 215990 Reactome Database ID Release 43215990 Reactome, http://www.reactome.org ReactomeREACT_14514 has a Stoichiometric coefficient of 1 Integrin alphaDbeta2 Reactome DB_ID: 216026 Reactome Database ID Release 43216026 Reactome, http://www.reactome.org ReactomeREACT_14521 has a Stoichiometric coefficient of 1 Alpha 11 beta 1 integrin: Collagen type-I:Mg++ complex Reactome DB_ID: 215988 Reactome Database ID Release 43215988 Reactome, http://www.reactome.org ReactomeREACT_13934 has a Stoichiometric coefficient of 1 KCC cotransporters Converted from EntitySet in Reactome Reactome DB_ID: 426109 Reactome Database ID Release 43426109 Reactome, http://www.reactome.org ReactomeREACT_19723 maltose + H2O => 2 D-glucose (sucrase-isomaltase) Authored: D'Eustachio, P, 2006-11-03 14:36:07 Digestion of maltose by sucrase-isomaltase to yield glucose EC Number: 3.2.1.20 Pubmed12547908 Pubmed3897250 Reactome Database ID Release 43191108 Reactome, http://www.reactome.org ReactomeREACT_9426 Reviewed: Nichols, BL, 2007-01-15 21:51:24 The alpha-1,4 linkages of extracellular maltose are hydrolyzed to yield glucose in a reaction catalyzed by sucrase-maltase (Nichols et al. 1998; Semenza et al. 2001). In the body, this enzyme is found as a dimer on the external face of enterocytes in microvilli of the small intestine (Hauri et al. 1985), and acts on maltose derived directly from the diet and from the hydrolysis of starch. has a Stoichiometric coefficient of 2 lactose + H2O => D-glucose + D-galactose Authored: D'Eustachio, P, 2006-11-03 14:36:07 Digestion of lactose to yield glucose and galactose EC Number: 3.2.1.108 Extracellular lactose is hydrolyzed to yield molecules of glucose and galactose, in a reaction catalyzed by the lactase activity of lactase-phlorizin hydrolase associated with the plasma membrane. In the body, lactase-phlorzin hydrolase is found on the external face of enterocytes in microvilli of the small intestine (Hauri et al. 1985). Expression of the enzyme is developmentally regulated and subject to a genetic polymorphism: enzyme levels fall after weaning but the extent of the fall varies sharply between human populations (Grand et al. 2003; Swallow 2003). The lactase-phlorizin hydrolase polypeptide undergoes dimerization and two rounds of proteolytic cleavage in the course of its maturation and transport to the cell surface (Grunberg and Sterchi 1995; Wuthrich et al. 1996). Pubmed12692040 Pubmed14616060 Pubmed3897250 Pubmed7487100 Pubmed8951031 Reactome Database ID Release 43189062 Reactome, http://www.reactome.org ReactomeREACT_9455 Reviewed: Nichols, BL, 2007-01-15 21:51:24 sucrose + H2O => glucose + fructose Authored: D'Eustachio, P, 2006-11-03 14:36:07 Digestion of sucrose to yield glucose and fructose EC Number: 3.2.1.26 EC Number: 3.2.1.48 Extracellular sucrose is hydrolyzed to yield glucose and fructose in a reaction catalyzed by the sucrase domain of sucrase-isomaltase (Conklin et al. 1975). In the body, this enzyme is found on the external face of enterocytes in microvilli of the small intestine (Hauri et al. 1985). The sucrase-isomaltase polypeptide is cleaved into its sucrase and isomaltase domains, which remain associated and, by analogy to the corresponding pig enzyme, are thought to dimerize (Cowell et al. 1986). Pubmed3800897 Pubmed3897250 Pubmed807575 Reactome Database ID Release 43189069 Reactome, http://www.reactome.org ReactomeREACT_9409 Reviewed: Nichols, BL, 2007-01-15 21:51:24 trehalose + H2O => 2 D-glucose Authored: D'Eustachio, P, 2006-11-03 14:36:07 Digestion of trehalose to yield glucose EC Number: 3.2.1.28 Extracellular trehalose, a disaccharide, is cleaved by trehalase associated with the plasma membrane to yield two molecules of glucose. Trehalase has been purified to homogeneity from rabbit intestine and shown to be a monomer attached to the plasma membrane by a GPI anchor (Galand 1984; Ruf et al. 1990). A human cDNA encoding a closely homologous protein has been cloned and the protein product of the clone has been shown to have trehalase activity in vitro (Ishihara et al. 1997). The human enzyme has not been characterized further, and so both the posttranslational modifications of the human enzyme and its activity in vivo have been inferred from the properties of the well studied rabbit enzyme. Pubmed1697585 Pubmed6466686 Pubmed9427547 Reactome Database ID Release 43188985 Reactome, http://www.reactome.org ReactomeREACT_9425 Reviewed: Nichols, BL, 2007-01-15 21:51:24 has a Stoichiometric coefficient of 2 Transport (influx) of fructose by GLUT5 Authored: D'Eustachio, P, 2006-11-03 14:36:07 Edited: D'Eustachio, P, 2006-11-04 20:44:47 Pubmed1550217 Pubmed1634504 Reactome Database ID Release 43189222 Reactome, http://www.reactome.org ReactomeREACT_9449 Reviewed: Wright, EM, 2007-01-15 21:00:45 The reversible transport of extracellular fructose into the cytosol is mediated by GLUT5. In the small intestine, GLUT5 is localized on the lumenal surfaces of enterocytes (Davidson et al. 1992) and thus mediates the uptake of dietary fructose, which can be released into the circulation in a separate transport step mediated by basolaterally localized GLUT2. The specificity of GLUT5 has been worked out by studying sugar transport in Xenopus oocytes expressing recombinant human GLUT5 protein (Burant et al. 1992). extracellular fructose => cytosolic fructose Integrin alpha9beta1:VCAM-1 Reactome DB_ID: 265410 Reactome Database ID Release 43265410 Reactome, http://www.reactome.org ReactomeREACT_14331 has a Stoichiometric coefficient of 1 NKCC cotransporters Converted from EntitySet in Reactome Reactome DB_ID: 426153 Reactome Database ID Release 43426153 Reactome, http://www.reactome.org ReactomeREACT_20085 Transport (influx) of glucose, galactose, and sodium ions by SGLT1 Authored: D'Eustachio, P, 2006-11-03 14:36:07 Edited: D'Eustachio, P, 2006-11-04 20:44:47 Pubmed12885248 Pubmed15546855 Pubmed8563765 Reactome Database ID Release 43189208 Reactome, http://www.reactome.org ReactomeREACT_9525 Reviewed: Wright, EM, 2007-01-15 21:00:45 The transport of extracellular glucose and galactose into the cytosol, coupled to the uptake of two sodium ions for each hexose transported is mediated by SGLT1. In the small intestine, SGLT1 is localized on the lumenal surfaces of enterocytes and thus mediates the uptake of dietary glucose and galactose, which can be released into the circulation in a separate transport step mediated by basolaterally localized GLUT2 (Wright et al. 2004). The specificity of SGLT1 has been worked out by studying sugar transport in plasma membrane vesicles containing recombinant human SGLT1 protein (Quick et al. 2003). Consistent with these in vitro results, children lacking functional SGLT1 protein fail to absord dietary glucose and galactose (Martin et al. 1996). has a Stoichiometric coefficient of 2 Integrin alpha9beta1:Tenascin Reactome DB_ID: 216014 Reactome Database ID Release 43216014 Reactome, http://www.reactome.org ReactomeREACT_14395 has a Stoichiometric coefficient of 1 Transport (efflux) of fructose, galactose, and glucose by GLUT2 Authored: D'Eustachio, P, 2006-11-03 14:36:07 Edited: D'Eustachio, P, 2006-11-04 20:44:47 Pubmed1701966 Pubmed8457197 Pubmed9354798 Pubmed9751501 Reactome Database ID Release 43189242 Reactome, http://www.reactome.org ReactomeREACT_9458 Reviewed: Wright, EM, 2007-01-15 21:00:45 The reversible facilitated diffusion of fructose, galactose, and glucose from the cytosol to the extracellular space is mediated by the GLUT2 transporter in the plasma membrane. In the epithelial cells of the small intestine, the basolateral localization of GLUT2 (Thorens et al. 1990) enables hexose sugars derived from the diet and taken up by the action of the SGLT1 and GLUT5 transporters to be released into the circulation. The specificity of the GLUT2 transporter has been established directly through biochemical assays of purified recombinant proteins (Colville et al. 1993; Wu et al. 1998) and indirectly through studies of patients deficient in GLUT2 transporter protein (Santer et al. 1997). cytosolic fructose, galactose, or glucose => extracellular fructose, galactose, or glucose Integrin alpha10beta1 Reactome DB_ID: 215987 Reactome Database ID Release 43215987 Reactome, http://www.reactome.org ReactomeREACT_13998 has a Stoichiometric coefficient of 1 alpha-D-glucose (extracellular) <=> alpha-D-glucose (cytosol) GLUT (glucose transporter) homotetramers associated with the plasma membrane mediate the facilitated diffusion of glucose between the extracellular space and the cytosol. Four human GLUT isoforms have been identified, members of a larger family of transporter proteins (Joost et al. 2002), encoded by the SCLC2A1, 2, 3, and 4 genes. Conserved sequence motifs in the GLUT proteins suggest the existence of shared structural features confirmed by in situ labeling and mutagenesis studies. Each GLUT protein has twelve membrane spanning domains organized to form an aqueous channel. While monomeric protein can form such a channel and transport glucose, kinetic studies suggest that the functional form of the protein is a homotetramer.<p>Different GLUT proteins are expressed in different tissues. GLUT1 is expressed by many cell types, notably endothelial cells, red blood cells and cells of the brain. Its low Km for glucose (~1 mM) relative to normal blood glucose concentration (~5 mM) allows these cells to take up glucose independent of changes in blood glucose levels. Its abundance in red blood cells has allowed it to be purified and biochemically characterized (Hruz and Mueckler 2001; Liu et al. 2001). Cytosolic ATP associates with GLUT1 and inhibits its glucose transporter activity. GLUT2 is expressed on hepatocytes and pancreatic beta cells. Because of its high Km for glucose (~15-20 mM), GLUT2-mediated glucose uptake normally occurs only in the fed state, when its rate is proportional to blood glucose concentration. This feature of the transporter is thought to enable efficient uptake of large amounts of glucose by the liver in the fed state, and to allow it to function as part of a glucose sensor coupled to insulin release in pancreatic beta cells (Thorens 2001). GLUT2 also mediates glucose export from liver cells when gluconeogenesis is underway (Colville et al. 1993; Santer et al. 1997; Wu et al. 1998). GLUT3 is expressed by cells of the brain and possibly other cell types with a high constitutive requirement for glucose. Its low Km for glucose (~1.5 mM) allows these cells to import glucose independent of fluctuations in blood glucose levels (Colville et al. 1993). GLUT4, like GLUT1 and 3, has a high affinity for glucose. GLUT4 is abundant in cells of skeletal muscle and adipose tissue. GLUT4 molecules are translocated from an intracellular store to the cell surface in response to increased insulin levels (Bryant et al. 2002; Fukumoto et al. 1989).<br> Glucose is taken up across the plasma membrane by a glucose transport protein (GLUT) Pubmed11425315 Pubmed11681785 Pubmed11780755 Pubmed11882521 Pubmed11994746 Pubmed2656669 Pubmed8457197 Pubmed9354798 Pubmed9477959 Pubmed9751501 Reactome Database ID Release 4370403 Reactome, http://www.reactome.org ReactomeREACT_1338 Integrin alpha10beta1:Collagen type-II:Mg++ Reactome DB_ID: 215994 Reactome Database ID Release 43215994 Reactome, http://www.reactome.org ReactomeREACT_13948 has a Stoichiometric coefficient of 1 Sulfate transporters Converted from EntitySet in Reactome Reactome DB_ID: 427632 Reactome Database ID Release 43427632 Reactome, http://www.reactome.org ReactomeREACT_19980 maltose + H2O => 2 D-glucose (maltase-glucoamylase) Authored: D'Eustachio, P, 2006-11-03 14:36:07 Digestion of maltose by maltase-glucoamylase to yield glucose EC Number: 3.2.1.20 Pubmed12547908 Pubmed3897250 Reactome Database ID Release 43189102 Reactome, http://www.reactome.org ReactomeREACT_9424 Reviewed: Nichols, BL, 2007-01-15 21:51:24 The alpha-1,4 linkages of extracellular maltose are hydrolyzed to yield glucose in a reaction catalyzed by maltase-glucoamylase (Nichols et al. 1998; Semenza et al. 2001). In the body, this enzyme is found as a dimer on the external face of enterocytes in microvilli of the small intestine (Hauri et al. 1985), and acts on maltose derived directly from the diet and from the hydrolysis of starch. has a Stoichiometric coefficient of 2 autophosphorylated IGF1R Reactome DB_ID: 2404188 Reactome Database ID Release 432404188 Reactome, http://www.reactome.org ReactomeREACT_152507 has a Stoichiometric coefficient of 2 IGF1/2:p-IGF1R Reactome DB_ID: 2404189 Reactome Database ID Release 432404189 Reactome, http://www.reactome.org ReactomeREACT_150608 has a Stoichiometric coefficient of 1 Platelet releasate cytosolic proteins Converted from EntitySet in Reactome Reactome DB_ID: 482768 Reactome Database ID Release 43482768 Reactome, http://www.reactome.org ReactomeREACT_21997 IGF1/2:p-IGF1R:IRS2 Reactome DB_ID: 2428931 Reactome Database ID Release 432428931 Reactome, http://www.reactome.org ReactomeREACT_151257 has a Stoichiometric coefficient of 1 IGF1/2:p-IGF1R:IRS1/4 Reactome DB_ID: 2428923 Reactome Database ID Release 432428923 Reactome, http://www.reactome.org ReactomeREACT_151270 has a Stoichiometric coefficient of 1 IGF1/2:p-IGF1R:p-SHC1 Reactome DB_ID: 2404190 Reactome Database ID Release 432404190 Reactome, http://www.reactome.org ReactomeREACT_151817 has a Stoichiometric coefficient of 1 IGF1/2:p-IGF1R:SHC1 Reactome DB_ID: 2404185 Reactome Database ID Release 432404185 Reactome, http://www.reactome.org ReactomeREACT_151215 has a Stoichiometric coefficient of 1 Activin AB INHBA:INHBB Reactome DB_ID: 2470491 Reactome Database ID Release 432470491 Reactome, http://www.reactome.org ReactomeREACT_151029 has a Stoichiometric coefficient of 1 FBXW7 mediates ubiquitination of phosphorylated NICD1 A recombinant mouse NICD1 was shown to be ubiquitinated upon binding to recombinant human FBXW7 (Oberg et al. 2001), which is followed by NICD1 degradation (Fyer et al. 2004). Ubiquitination and degradation of NICD1 by FBXW7 is dependent on PEST sequence in Notch. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 6.3.2.19 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed11461910 Pubmed15546612 Reactome Database ID Release 432064883 Reactome, http://www.reactome.org ReactomeREACT_118847 Reviewed: Haw, R, 2012-02-06 Activin A/AB/B Converted from EntitySet in Reactome INHBA:INHBA/INHBA:INHBB/INHBB:INHBB Reactome DB_ID: 2470494 Reactome Database ID Release 432470494 Reactome, http://www.reactome.org ReactomeREACT_151143 Thrombopoietin binds the thrombopoietin receptor Authored: Akkerman, JW, 2009-09-04 Edited: Jupe, S, 2010-06-08 Pubmed15518238 Pubmed16673285 Pubmed7492761 Pubmed8073287 Pubmed8202154 Reactome Database ID Release 43443942 Reactome, http://www.reactome.org ReactomeREACT_23983 Reviewed: Kunapuli, SP, 2010-06-07 Thrombopoietin (TPO) is a primary regulator of megakaryocytopoiesis. Binding of TPO to its receptor TPOR (c-Mpl) mediates pleiotropic effects on megakaryocyte development leading to significant increase in circulating platelet numbers. TPOR knockout mice show a marked reduction in bone marrow megakaryocytes and blood platelets. Although thrombopoietin (TPO) by itself has little or no effect on platelet aggregation, pretreatment of platelets with TPO augments the aggregation induced by various agonists such as ADP, thrombin, collagen, and adrenaline. IGF1/2:p-IGF1R:p-IRS1/2/4 Reactome DB_ID: 2445094 Reactome Database ID Release 432445094 Reactome, http://www.reactome.org ReactomeREACT_151884 has a Stoichiometric coefficient of 1 MCTs mediate proton-coupled transport of monocarboxylates and ketone bodies Authored: Jassal, B, 2009-08-25 Edited: Jassal, B, 2009-08-21 Four members of the SLC16A gene family encode classical monocarboxylate transporters, MCT1-4. They all function as proton-dependent transporters of monocarboxylic acids such as lactate and pyruvate and ketone bodies such as acetacetate and beta-hydroxybutyrate. These processes are crucial in the regulation of energy metabolism and acid-base homeostasis.<br><br>SLC16A1 encodes MCT1, a ubiquitiously expressed protein (Garcia CK et al, 1994). Defects in SLC16A1 are the cause of symptomatic deficiency in lactate transport (SDLT), resulting in an acidic intracellular environment and muscle degeneration (Merezhinskaya N et al, 2000). Another defect in SLC16A1 causes exercise-induced hyperinsulinism (EIHI), a dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load (Otonkoski T et al, 2000). SLC16A7 encodes MCT2, a high affinity pyruvate transporter highly expressed in testis (Lin RY et al, 1998). SLC16A8 encodes MCT3 (Yoon H et al, 1999).<br><br>Human RPE (retinal pigment epithelial) cells express two proton-coupled monocarboxylate transporters: MCT1 in the apical membrane and MCT3 in the basolateral membrane. This suggested that the coordinated activities of these two transporters could facilitate the transepithelial transport of lactate from the retina to the choroid. (Philip NJ et al, 2003). Pubmed10493836 Pubmed10590411 Pubmed12657613 Pubmed17701893 Pubmed8124722 Pubmed9786900 Reactome Database ID Release 43433698 Reactome, http://www.reactome.org ReactomeREACT_20553 Reviewed: He, L, 2009-11-12 IGF1/2:p-IGF1R:IRS1/2/4 Reactome DB_ID: 2428921 Reactome Database ID Release 432428921 Reactome, http://www.reactome.org ReactomeREACT_150878 has a Stoichiometric coefficient of 1 Digestion of branched starch (amylopectin) by extracellular amylase Authored: D'Eustachio, P, 2006-11-03 14:36:07 EC Number: 3.2.1.1 ISBN0079130356 Pubmed10769135 Pubmed15299664 Pubmed2452973 Pubmed8368500 Reactome Database ID Release 43191114 Reactome, http://www.reactome.org ReactomeREACT_9475 Reviewed: Nichols, BL, 2007-01-15 21:51:24 The 1-4 linkages of extracellular amylopectin starch, a glucose polymer containing linear segments formed by alpha-1,4 linkages and a smaller number of alpha-1,6 linkages forming branch points, are digested by the endoglucosidase activity of alpha-amylases, yielding maltose, maltotriose, and longer maltosides from the alpha-1,4 linear segments and alpha-limit dextrins from the branch points (Semenza et al. 2001). Alpha-limit dextrins are glucose (G) oligomers linked by 1-4 and 1-6 bonds. 1-6 branch points make up about 5% of all amylopectin glucose bonds - the exact fraction depends on the source of the starch. Mass spectroscopic analysis of alpha-limit dextrin shows it to be a mixture of maltosides and isomaltosides containing two to forty G residues, but the most common contain fewer than seven. Maltose (G2) is the shortest 1-4 maltoside produced by alpha-amylase. Isomaltose (G2) is the shortest 1-6 isomaltoside.<p>The human genome contains five functional alpha-amylase genes, encoding structurally closely related isoenzymes (Gumucio et al. 1988). Three of these genes encode proteins synthesized in the parotid glands and released into the saliva (amylase 1A, B, and C), and the other two encode proteins synthesized in the exocrine pancreas and released into the small intestine (amylase 2A and B). In the human body, starch digestion thus commences in the mouth, mediated by salivary amylases, and is continued in the small intestine, mediated by the pancreatic ones.<p>X-ray crystallographic studies of amylase 1A and 2A proteins show them to be monomers, complexed with single calcium and chloride ions (Ramasubbu et al. 1996; Brayer et al. 2000). Biochemical characterization of amylase 2A indicates that the enzyme efficiently cleaves poly-glucose chains so as to release maltose - a glucose disaccharide - from the reducing end of the chain (Braun et al. 1993; Brayer et al. 2000). Digestion of 1-6 linkages of limit dextrins to yield maltose, maltotriose, longer maltosides, and glucose Authored: D'Eustachio, P, 2006-11-03 14:36:07 EC Number: 3.2.1.20 Edited: D'Eustachio, P, 2006-11-03 14:39:28 ISBN0079130356 Pubmed3897250 Pubmed807575 Pubmed9446624 Reactome Database ID Release 43189053 Reactome, http://www.reactome.org ReactomeREACT_9414 Reviewed: Nichols, BL, 2007-01-15 21:51:24 The 1-6 linkages in extracellular limit dextrins are hydrolyzed by sucrase-isomaltase to yield maltose, maltotriose, longer maltosides, and glucose (Conklin et al. 1975; Nichols et al. 1998; Semenza et al. 2001). In the body, this enzyme is found on the external face of enterocytes in microvilli of the small intestine (Hauri et al. 1985), and acts on limit dextrins generated by the hydrolysis of amylopectin starch. SOCS binding to Ghr Edited: Jupe, S, 2011-06-10 Pubmed10551777 Pubmed10585430 Pubmed17666591 Reactome Database ID Release 431169195 Reactome, http://www.reactome.org ReactomeREACT_111181 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 Supprossor of Cytokine Signaling (SOCS)1-3, and the related Cytokine-inducible SH2-containing protein (CIS) all bind tyrosine-phosphorylated GHR (Ram & Waxman 1999, Hansen et al. 1999). SOCS3 binding has been mapped to phosphorylated tyrosines Y338, Y333 (Ram & Waxman 1999), and Y487 (Hansen et al. 1999) in the membrane proximal region of the receptor. SOCS2 and CIS bind to residues Y487 and Y595 (Uyttendaele et al. 2007). IGF1/2:IGF1R Reactome DB_ID: 2404186 Reactome Database ID Release 432404186 Reactome, http://www.reactome.org ReactomeREACT_151821 has a Stoichiometric coefficient of 1 Digestion of linear starch (amylose) by extracellular amylase Authored: D'Eustachio, P, 2006-11-03 14:36:07 EC Number: 3.2.1.1 Extracellular amylose starch, linear polymers of glucose joined by alpha-1,4 linkages, is digested by the endoglucosidase activity of alpha-amylases, yielding maltose, maltotriose, and longer maltosides (Semenza et al. 2001). The human genome contains five functional alpha-amylase genes, encoding structurally closely related isoenzymes (Gumucio et al. 1988). Three of these genes encode proteins synthesized in the parotid glands and released into the saliva (amylase 1A, B, and C), and the other two encode proteins synthesized in the exocrine pancreas and released into the small intestine (amylase 2A and B). In the human body, starch digestion thus commences in the mouth, mediated by salivary amylases, and is continued in the small intestine, mediated by the pancreatic ones.<p>X-ray crystallographic studies of amylase 1A and 2A proteins show them to be monomers, complexed with single calcium and chloride ions (Ramasubbu et al. 1996; Brayer et al. 2000). Biochemical characterization of amylase 2A indicates that the enzyme efficiently cleaves poly-glucose chains so as to release maltose - a glucose disaccharide - from the reducing end of the chain (Braun et al. 1993; Brayer et al. 2000). ISBN0079130356 Pubmed10769135 Pubmed15299664 Pubmed2452973 Pubmed8368500 Reactome Database ID Release 43188979 Reactome, http://www.reactome.org ReactomeREACT_9403 Reviewed: Nichols, BL, 2007-01-15 21:51:24 Phosphorylation of L1 by p90rsk Authored: Garapati, P V, 2008-07-30 10:22:58 EC Number: 2.7.11 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed10608864 Pubmed8663493 Reactome Database ID Release 43445066 Reactome, http://www.reactome.org ReactomeREACT_22101 Reviewed: Maness, PF, 2010-02-16 p90rsk associates with the internalized L1 in the endosomes and phosphorylates it at Ser1152. This phosphorylation may regulate the interactions of L1 and intracellular signaling cascades or cytoskeletal elements involved in neurite outgrowth on specific substrates. TGFBR2 phosphorylates Pard6a Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed15761148 Reactome Database ID Release 432161165 Reactome, http://www.reactome.org ReactomeREACT_121319 Reviewed: Huang, Tao, 2012-05-14 TGFBR2, recruited to tight junctions, phosphorylates mouse FLAG-tagged Pard6a exogenously expressed in human embryonic kidney cell line, HEK293 (Ozdamar et al. 2005). has a Stoichiometric coefficient of 13 Smad7 recruits NEDD4L to activated TGF-beta receptor complex Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 In an affinity cross-linking assay performed in COS7 cells transfected with recombinant mouse Smad7 and recombinant human NEDD4L, TGFBR2 and TGFBR1, NEDD4L is coimmunoprecipitated with the activated TGF-beta receptor complex in the presence of Smad7 (Kuratomi et al. 2005). Pubmed15496141 Reactome Database ID Release 432176431 Reactome, http://www.reactome.org ReactomeREACT_121030 Reviewed: Huang, Tao, 2012-05-14 Phosphorylation of Smad2 by Nodal Receptor Authored: May, B, 2011-03-03 Binding of Nodal to the Nodal receptor causes the type I component of the receptor to phosphorylate Smad2 (Yeo and Whitman 2001). EC Number: 2.7.11 Edited: May, B, 2011-03-03 Pubmed11389842 Reactome Database ID Release 431181349 Reactome, http://www.reactome.org ReactomeREACT_111058 Reviewed: Peng, C, 2011-08-24 Integrin alphaEbeta7 Reactome DB_ID: 265415 Reactome Database ID Release 43265415 Reactome, http://www.reactome.org ReactomeREACT_13938 has a Stoichiometric coefficient of 1 Integrin alphaIIbbeta3:Fibronectin Reactome DB_ID: 349592 Reactome Database ID Release 43349592 Reactome, http://www.reactome.org ReactomeREACT_14637 has a Stoichiometric coefficient of 1 Integrin alphaEbeta7:Cadherin-1 Reactome DB_ID: 265418 Reactome Database ID Release 43265418 Reactome, http://www.reactome.org ReactomeREACT_14442 has a Stoichiometric coefficient of 1 fibrin multimer Reactome DB_ID: 139934 Reactome Database ID Release 43139934 Reactome, http://www.reactome.org ReactomeREACT_5429 has a Stoichiometric coefficient of 3 Integrin alpha IIb beta 3:Fibrin complex Reactome DB_ID: 114559 Reactome Database ID Release 43114559 Reactome, http://www.reactome.org ReactomeREACT_4777 has a Stoichiometric coefficient of 1 SLC7A7 (y+LAT1)-mediated exchange of extracellular leucine for cytosolic arginine Authored: D'Eustachio, P, 2008-11-29 15:37:01 Edited: D'Eustachio, P, 2008-11-29 15:37:01 Pubmed9878049 Reactome Database ID Release 43379415 Reactome, http://www.reactome.org ReactomeREACT_15441 Reviewed: Jassal, B, 2008-11-26 09:32:08 SLC7A7 as a heterodimer with SLC3A2 in the plasma membrane mediates the exchange of arginine for leucine and a sodium ion. The physiological concentrations of arginine and leucine are expected to favor arginine export. By the criterion of Northern blotting, SLC7A6 is predominantly expressed in the kidney (Pfeiffer et al. 2000). Integrin alphaIIbbeta3:VWF multimer Reactome DB_ID: 216031 Reactome Database ID Release 43216031 Reactome, http://www.reactome.org ReactomeREACT_14499 has a Stoichiometric coefficient of 1 SLC7A6 (y+LAT2)-mediated exchange of extracellular leucine for cytosolic arginine Authored: D'Eustachio, P, 2008-11-29 15:37:01 Edited: D'Eustachio, P, 2008-11-29 15:37:01 Pubmed10903140 Reactome Database ID Release 43379426 Reactome, http://www.reactome.org ReactomeREACT_15318 Reviewed: Jassal, B, 2008-11-26 09:32:08 SLC7A6 as a heterodimer with SLC3A2 in the plasma membrane mediates the exchange of arginine for leucine and a sodium ion. The physiological concentrations of arginine and leucine are expected to favor arginine export. By the criterion of Northern blotting, SLC7A6 is expressed in a variety of tissues (Broer et al. 2000). fibrin monomer Reactome DB_ID: 140919 Reactome Database ID Release 43140919 Reactome, http://www.reactome.org ReactomeREACT_5693 has a Stoichiometric coefficient of 2 NEDD4L ubiquitinates Smad7 and TGFBR1 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 NEDD4L, recruited to the activated TGF-beta receptor complex by Smad7, ubiquitinates TGFBR1. Ubiquitination of Smad7 by NEDD4L has not been examined in this context (Kuratomi et al. 2005). Pubmed15496141 Reactome Database ID Release 432176427 Reactome, http://www.reactome.org ReactomeREACT_121321 Reviewed: Huang, Tao, 2012-05-14 has a Stoichiometric coefficient of 2 IGF1R Reactome DB_ID: 2404182 Reactome Database ID Release 432404182 Reactome, http://www.reactome.org ReactomeREACT_152174 has a Stoichiometric coefficient of 2 SLC7A9-mediated exchange of extracellular arginine, lysine, or cystine for cytosolic leucine Authored: D'Eustachio, P, 2008-11-29 15:37:01 Edited: D'Eustachio, P, 2008-11-29 15:37:01 Pubmed11318953 Reactome Database ID Release 43379432 Reactome, http://www.reactome.org ReactomeREACT_15542 Reviewed: Jassal, B, 2008-11-26 09:32:08 SLC7A9 as a heterodimer with SLC3A1 in the plasma membrane mediates the exchange of arginine, lysine, or cystine for leucine. The physiological concentrations of these amino acids favor leucine export and arginine / lysine / cystine import. Defects in SLC7A9 and SLC3A1 are associated with cystinuria. In the body, this transport process is prominent in the kidney (Mizoguchi et al. 2001). Integrin alphaIIbbeta3:Thrombospondin 1 Reactome DB_ID: 349605 Reactome Database ID Release 43349605 Reactome, http://www.reactome.org ReactomeREACT_14140 has a Stoichiometric coefficient of 1 NaDC1 co-transports dicarboxylic acids and a sodium ion Authored: Jassal, B, 2009-08-21 Edited: Jassal, B, 2009-08-21 Mammalian sodium/dicarboxylate cotransporters (transport succinate and other Krebs cycle intermediates) fall into two categories based on their substrate affinity. The human gene SLC13A2 encodes a low-affinity sodium/dicarboxlate co-transporter, NaDC1. NaDC1 is highly expressed in the brush-border membranes of kidney and intestinal cells and reabsorbs Krebs cycle intermediates, such as succinate and citrate, from the glomerular filtrate (Pajor AM, 1996). Pubmed8967342 Reactome Database ID Release 43433131 Reactome, http://www.reactome.org ReactomeREACT_20534 Reviewed: He, L, 2009-11-12 Integrin alphaVbeta3:Fibrillin-1 Reactome DB_ID: 265416 Reactome Database ID Release 43265416 Reactome, http://www.reactome.org ReactomeREACT_13939 has a Stoichiometric coefficient of 1 NaDC3 co-transports the dicarboxylic acid succinate and three sodium ion Authored: Jassal, B, 2009-08-21 Edited: Jassal, B, 2009-08-21 Mammalian sodium/dicarboxylate cotransporters (transport succinate and other Krebs cycle intermediates) fall into two categories based on their substrate affinity. The human gene SLC13A3 encodes a high-affinity sodium/dicarboxlate co-transporter, NaDC3. NaDC3 is expressed in the basolateral membrane of renal proximal tubular epithelial cells, sinusoidal membrane of hepatocytes, and brain synaptosomes. Kinetic studies in human retinal pigment epithelial (HRPE) cells suggest three sodium ions co-transported with every divalent succinate (Wang H et al, 2000). Pubmed10794676 Reactome Database ID Release 43433101 Reactome, http://www.reactome.org ReactomeREACT_20618 Reviewed: He, L, 2009-11-12 has a Stoichiometric coefficient of 3 Integrin alphaVbeta3:VWF multimer Reactome DB_ID: 265414 Reactome Database ID Release 43265414 Reactome, http://www.reactome.org ReactomeREACT_14672 has a Stoichiometric coefficient of 1 NACT co-transports trivalent citrate and a sodium ion Authored: Jassal, B, 2009-08-21 Edited: Jassal, B, 2009-08-21 Pubmed12445824 Reactome Database ID Release 43433104 Reactome, http://www.reactome.org ReactomeREACT_20529 Reviewed: He, L, 2009-11-12 The human SLC13A5 gene encodes a sodium-coupled citrate transporter, NACT. This gene is expressed mainly in the liver, with lower levels in brain and testis. NACT has a preference for trivalent citrate (Inoue K et al, 2002). MATEs mediate extrusion of xenobiotics Authored: Jassal, B, 2009-09-02 Edited: Jassal, B, 2009-08-21 Pubmed16330770 Pubmed16807400 Pubmed17509534 Reactome Database ID Release 43434650 Reactome, http://www.reactome.org ReactomeREACT_20650 Reviewed: He, L, 2009-11-12 The human gene family SLC47 encodes 2 multidrug and toxin extrusion (MATE) proteins. Mammalian MATE-type transporters are responsible for the final step in the excretion of metabolic waste and xenobiotic organic cations in the kidney and liver through electroneutral exchange of H(+).<br> MATE1 is primarily expressed in the kidney and liver, where it is localized to the luminal membranes of the urinary tubules and bile canaliculi. When expressed in HEK293 cells, MATE1 mediates H(+)-coupled electroneutral exchange of various drugs (Otsuka M et al, 2005). MATE2 is a human kidney-specific H+/organic cation antiporter that is responsible for the tubular secretion of cationic drugs across the brush border membranes (Masuda S et al, 2006). Substrates for both MATEs include tetraethylammonium, 1-methyl-4-phenylpyridinium, cimetidine, metformin, creatinine, guanidine and procainamide (Tanihara Y et al, 2007). SOAT can transport taurolithocholate-3-sulphate Authored: Jassal, B, 2009-08-21 Edited: Jassal, B, 2009-08-21 Pubmed17491011 Reactome Database ID Release 43433089 Reactome, http://www.reactome.org ReactomeREACT_20626 Reviewed: He, L, 2009-11-12 The human SLC10A6 gene encodes a sodium-dependant organic anion transporter, SOAT. Highest expressions of the gene are in testis, placenta and pancreas. Unlike the other SLC10A gene products, SOAT shows no affinity for binding bile acids. However, SOAT is able to transport sulpho-conjugated bile acids such as taurolithocholate 3-sulphate (Geyer J et al, 2007). It can also transport the structurally similar sulphated steroids (not shown here), thus SOAT may play a role in delivery of these prohormones to testis, pancreas and placenta. NaS1 co-transports sulphate and a sodium ion Authored: Jassal, B, 2009-08-21 Edited: Jassal, B, 2009-08-21 Pubmed11161786 Reactome Database ID Release 43433114 Reactome, http://www.reactome.org ReactomeREACT_20504 Reviewed: He, L, 2009-11-12 The human gene SLC13A1 encodes a sodium/sulphate co-transporter NaS1 (Lee A et al, 2000). NaS1 is almost exclusively expressed in the kidney and mediates sulphate reabsorption there. NaS2 co-transports sulphate and two sodium ions Authored: Jassal, B, 2009-08-21 Edited: Jassal, B, 2009-08-21 Pubmed10535998 Pubmed15607730 Reactome Database ID Release 43433099 Reactome, http://www.reactome.org ReactomeREACT_20550 Reviewed: He, L, 2009-11-12 The human gene SLC13A4 encodes a sodium/sulphate co-transporter NaS2 (Girard JP et al, 1999). NaS2 is highly expressed in placenta and testis, mainly in high endothelial venules. Kinetic experiments suggest two sodium ions co-transported for every sulphate ion (Markovich D et al, 2005). has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004353 Reactome Database ID Release 4370584 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004356 Reactome Database ID Release 4370605 Reactome, http://www.reactome.org GLUT6/8/10/12 Converted from EntitySet in Reactome Reactome DB_ID: 429047 Reactome Database ID Release 43429047 Reactome, http://www.reactome.org ReactomeREACT_20110 ACTIVATION GENE ONTOLOGYGO:0004587 Reactome Database ID Release 4370653 Reactome, http://www.reactome.org BMAL1:CLOCK/NPAS2:CRY Reactome DB_ID: 549449 Reactome Database ID Release 43549449 Reactome, http://www.reactome.org ReactomeREACT_25684 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004587 Reactome Database ID Release 4370653 Reactome, http://www.reactome.org CRY:PER:Kinase Reactome DB_ID: 421287 Reactome Database ID Release 43421287 Reactome, http://www.reactome.org ReactomeREACT_26725 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004069 Reactome Database ID Release 4370595 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004069 Reactome Database ID Release 4370580 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004353 Reactome Database ID Release 4370584 Reactome, http://www.reactome.org Syk:Vav1 Reactome DB_ID: 446294 Reactome Database ID Release 43446294 Reactome, http://www.reactome.org ReactomeREACT_24660 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004066 Reactome Database ID Release 4370598 Reactome, http://www.reactome.org BMAL1:CLOCK/NPAS2 ARNTL:CLOCK/NPAS2 Reactome DB_ID: 400360 Reactome Database ID Release 43400360 Reactome, http://www.reactome.org ReactomeREACT_26547 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004735 Reactome Database ID Release 4370663 Reactome, http://www.reactome.org BMAL2:CLOCK Reactome DB_ID: 879827 Reactome Database ID Release 43879827 Reactome, http://www.reactome.org ReactomeREACT_26482 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0017084 Reactome Database ID Release 43508035 Reactome, http://www.reactome.org Glucocorticoid receptor:Dexamethasone Complex Reactome DB_ID: 879850 Reactome Database ID Release 43879850 Reactome, http://www.reactome.org ReactomeREACT_26089 has a Stoichiometric coefficient of 1 Spectrin heterodimer Reactome DB_ID: 391839 Reactome Database ID Release 43391839 Reactome, http://www.reactome.org ReactomeREACT_19000 has a Stoichiometric coefficient of 1 NCAM:pFyn(Y531) Reactome DB_ID: 833624 Reactome Database ID Release 43833624 Reactome, http://www.reactome.org ReactomeREACT_23015 has a Stoichiometric coefficient of 1 NCAM:Fyn:RPTP-alpha:Spectrin Reactome DB_ID: 420361 Reactome Database ID Release 43420361 Reactome, http://www.reactome.org ReactomeREACT_19048 has a Stoichiometric coefficient of 1 NCAM:Fyn Reactome DB_ID: 420374 Reactome Database ID Release 43420374 Reactome, http://www.reactome.org ReactomeREACT_18586 has a Stoichiometric coefficient of 1 Vascular endothelial growth factor Converted from EntitySet in Reactome Reactome DB_ID: 139882 Reactome Database ID Release 43139882 Reactome, http://www.reactome.org ReactomeREACT_5385 ACTIVATION GENE ONTOLOGYGO:0004021 Reactome Database ID Release 4370522 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004021 Reactome Database ID Release 43507754 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004021 Reactome Database ID Release 43507754 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0070283 Reactome Database ID Release 43947552 Reactome, http://www.reactome.org Activin A/AB/B:FST Activin:Follistatin Reactome DB_ID: 2473196 Reactome Database ID Release 432473196 Reactome, http://www.reactome.org ReactomeREACT_150737 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0016783 Reactome Database ID Release 43947580 Reactome, http://www.reactome.org FOXH1:DRAP1 Reactome DB_ID: 1226031 Reactome Database ID Release 431226031 Reactome, http://www.reactome.org ReactomeREACT_111401 has a Stoichiometric coefficient of 1 hZIP1-4 Converted from EntitySet in Reactome Reactome DB_ID: 442327 Reactome Database ID Release 43442327 Reactome, http://www.reactome.org ReactomeREACT_20986 ACTIVATION GENE ONTOLOGYGO:0031071 Reactome Database ID Release 43947571 Reactome, http://www.reactome.org Activin A/AB/B:FSTL3 Reactome DB_ID: 2473219 Reactome Database ID Release 432473219 Reactome, http://www.reactome.org ReactomeREACT_152075 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0016740 Reactome Database ID Release 43947533 Reactome, http://www.reactome.org Activin:ACVR2A/B:p-ACVR1B/C Converted from EntitySet in Reactome Reactome DB_ID: 2470484 Reactome Database ID Release 432470484 Reactome, http://www.reactome.org ReactomeREACT_150543 ACTIVATION GENE ONTOLOGYGO:0030366 Reactome Database ID Release 43947528 Reactome, http://www.reactome.org SMAD2/3:SMAD4:FOXH1:Activin Response Element Reactome DB_ID: 1225870 Reactome Database ID Release 431225870 Reactome, http://www.reactome.org ReactomeREACT_111692 SMAD2/3:SMAD4:FAST1 Complex Bound to Activin Response Element has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004021 Reactome Database ID Release 4370522 Reactome, http://www.reactome.org Activin A/AB/B:ACVR2A/B:p-ACVR1B Reactome DB_ID: 1549500 Reactome Database ID Release 431549500 Reactome, http://www.reactome.org ReactomeREACT_111303 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0008265 Reactome Database ID Release 43947545 Reactome, http://www.reactome.org Activin AB/B:ACVR2A/B:p-ACVR1C Reactome DB_ID: 2470475 Reactome Database ID Release 432470475 Reactome, http://www.reactome.org ReactomeREACT_150570 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Processed PDGF-B Converted from EntitySet in Reactome Reactome DB_ID: 387074 Reactome Database ID Release 43387074 Reactome, http://www.reactome.org ReactomeREACT_17727 Activin AB/B Converted from EntitySet in Reactome INHBA:INHBB/INHBB:INHBB Reactome DB_ID: 2470478 Reactome Database ID Release 432470478 Reactome, http://www.reactome.org ReactomeREACT_152049 Activin AB/B:ACVR2A/B:ACVR1C Reactome DB_ID: 2470469 Reactome Database ID Release 432470469 Reactome, http://www.reactome.org ReactomeREACT_151591 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activin A/AB/B:ACVR2A/B:ACVR1B Reactome DB_ID: 1549493 Reactome Database ID Release 431549493 Reactome, http://www.reactome.org ReactomeREACT_111481 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 phosphoenolpyruvate + ADP => pyruvate + ATP Authored: D'Eustachio, P, 2004-09-21 15:25:22 Cytosolic pyruvate kinase catalyzes the transfer of a high-energy phosphate from phosphoenolpyruvate to ADP, forming pyruvate and ATP. This reaction, an instance of substrate-level phosphorylation, is essentially irreversible under physiological conditions.<p>Four isozymes of human pyruvate kinase have been described, L, R, M1 and M2. Isozymes L and R are encoded by alternatively spliced transcripts of the PKLR gene; isozymes M1 and M2 are encoded by alternatively spliced transcripts of PKM2. In the body, L pyruvate kinase is found in liver (Tani et al. 1988), R in red blood cells (Kanno et al. 1991), M1 in muscle, heart and brain (Takenaka et al. 1991), and M2 in early fetal tissues and tumors (e.g., Lee et al. 2008). In all cases, the active form of the enzyme is a homotetramer, activated by fructose 1,6-bisphosphate (Valentini et al. 2002; Dombrauckas et al. 2005). Mutations in PKLR have been associated with hemolytic anemias (e.g., Zanella et al. 2005). EC Number: 2.7.1.40 Pubmed11960989 Pubmed15982340 Pubmed15996096 Pubmed18191611 Pubmed1896471 Pubmed2040271 Pubmed3126495 Reactome Database ID Release 4371670 Reactome, http://www.reactome.org ReactomeREACT_1524 Electrogenic Na+/Pi cotransporters Converted from EntitySet in Reactome Reactome DB_ID: 427640 Reactome Database ID Release 43427640 Reactome, http://www.reactome.org ReactomeREACT_20196 2-Phospho-D-glycerate <=> Phosphoenolpyruvate + H2O Authored: D'Eustachio, P, 2004-09-21 15:25:22 Cytosolic enolase catalyzes the reversible reaction of 2 phosphoglycerate to form phosphoenolpyruvate and water, elevating the transfer potential of the phosphoryl group.<p>Enolase is a homodimer and requires Mg++ for activity. Three isozymes have been purified and biochemically characterized. The alpha isoform is expressed in many normal human tissues (Giallongo et al. 1986). The beta isoform is expressed in muscle. Evidence for its function in vivo in humans comes from studies of a patient in whom a point mutation in the gene encoding the enzyme was associated specifically with reduced enolase activity in muscle extracts and with other symptoms consistent with a defect in glycolysis (Comi et al. 2001). The gamma isoform of human enolase is normally expressed in neural tissue and is of possible clinical interest as a marker of some types of neuroendocrine and lung tumors (McAleese et al. 1988). Biochemical studies of the homologous rat proteins indicate that both homo- and heterodimers of enolase form and are enzymatically active (Rider and Taylor 1974). EC Number: 4.2.1.11 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed11506403 Pubmed2462567 Pubmed3208766 Pubmed3529090 Pubmed4413246 Reactome Database ID Release 4371660 Reactome, http://www.reactome.org ReactomeREACT_1400 Oxaloacetate + NADH + H+ <=> (S)-Malate + NAD+ EC Number: 1.1.1.37 Mitochondrial malate dehydrogenase catalyzes the reversible reaction of oxaloacetate and NADH + H+ to form malate and NAD+ (Luo et al. 2006). Unpublished crystallographic data indicate that the protein is a dimer (PDB 3E04). Pubmed16740313 Pubmed9792106 Reactome Database ID Release 4371783 Reactome, http://www.reactome.org ReactomeREACT_11169 Reviewed: Harris, RA, 2008-09-10 18:47:12 Pyruvate + CO2 + ATP => ADP + Orthophosphate + Oxaloacetate EC Number: 6.4.1.1 Pubmed10229653 Pubmed12437512 Pyruvate, CO2, and ATP react to form oxaloacetate, ADP, and orthophosphate Reactome Database ID Release 4370501 Reactome, http://www.reactome.org ReactomeREACT_1895 Reviewed: Harris, RA, 2008-09-10 18:47:12 The carboxylation of pyruvate to form oxaloacetate, catalyzed by mitochondrial pyruvate carboxylase, is an irreversible and allosterically regulated reaction (Jitrapakdee and Wallace 1999). Cl-/HCO3- exchanger proteins (SLC26) Converted from EntitySet in Reactome Reactome DB_ID: 427587 Reactome Database ID Release 43427587 Reactome, http://www.reactome.org ReactomeREACT_20307 oxaloacetate + GTP => phosphoenolpyruvate + GDP + CO2 [cytosol] EC Number: 4.1.1.32 Oxaloacetate and GTP react to form phosphoenolpyruvate, CO2, and GDP [cytosol] Pubmed11851336 Reactome Database ID Release 4370241 Reactome, http://www.reactome.org ReactomeREACT_259 Reviewed: Harris, RA, 2008-09-10 18:47:12 The transfer of a high-energy phosphate bond from GTP to oxaloacetate, to form phosphoenolpyruvate, GDP, and CO2, is catalyzed by cytosolic phosphoenolpyruvate carboxykinase (Dunten et al. 2002). This reaction is irreversible under physiological conditions. aspartate + alpha-ketoglutarate <=> oxaloacetate + glutamate [GOT1] Cytosolic aspartate aminotransferase (glutamate oxaloacetate transaminase 1 - GOT1) catalyzes the reversible reaction of aspartate and 2-oxoglutarate (alpha-ketoglutarate) to form oxaloacetate and glutamate (Doyle et al. 1990). Unpublished crystallographic data (PBD 3IIO) suggest the enzyme is a homodimer). EC Number: 2.6.1.1 Pubmed2241899 Reactome Database ID Release 4370592 Reactome, http://www.reactome.org ReactomeREACT_1558 Reviewed: Harris, RA, 2008-09-10 18:47:12 SLC26 chloride transporters Converted from EntitySet in Reactome Reactome DB_ID: 429630 Reactome Database ID Release 43429630 Reactome, http://www.reactome.org ReactomeREACT_19871 oxaloacetate + glutamate <=> aspartate + alpha-ketoglutarate [GOT2] EC Number: 2.6.1.1 Mitochondrial aspartate aminotransferase catalyzes the reversible reaction of oxaloacetate and glutamate to form aspartate and 2-oxoglutarate (alpha-ketoglutarate) (Martini et al. 1985). The active form of the enzyme is inferred to be a dimer with one molecule of pyridoxal phosphate associated with each monomer. Pubmed4052435 Reactome Database ID Release 4370613 Reactome, http://www.reactome.org ReactomeREACT_1632 Reviewed: Harris, RA, 2008-09-10 18:47:12 malate + NAD+ <=> oxaloacetate + NADH + H+ (S)-malate + NAD+ <=> oxaloacetate + NADH + H+ Authored: D'Eustachio, P, 2007-06-22 14:17:01 Cytosolic malate dehydrogenase catalyzes the reaction of malate and NAD+ to form oxaloacetate and NADH + H+ (Lo et al. 2005). The dimeric structure of the human dehydrogenase is inferred from that established for its well-studied pig homolog (Birktoft et al. 1989). EC Number: 1.1.1.37 Pubmed15565635 Pubmed2775751 Reactome Database ID Release 43198508 Reactome, http://www.reactome.org ReactomeREACT_11216 Reviewed: Harris, RA, 2008-09-10 18:47:12 Exchange of cytosolic glutamate and mitochondrial aspartate Authored: D'Eustachio, P, 2008-09-12 21:47:19 Edited: D'Eustachio, P, 2008-09-12 21:47:19 Pubmed10369257 Pubmed10642534 Pubmed11566871 Reactome Database ID Release 43372448 Reactome, http://www.reactome.org ReactomeREACT_14830 Reviewed: Harris, RA, 2008-09-10 18:47:12 SLC25A12 and SLC25A13, located in the inner mitochondrial membrane, each mediate the exchange of cytosolic aspartate and mitochondrial glutamate. The exchange is physiologically irreversible because of the potential across the inner mitochondrial membrane (positive outside, negative inside). In the body, SLC25A12 (ARALAR1) is found mainly in heart, skeletal muscle, and brain, while SCL25A13 (CITRIN) is widely expressed but most abundant in liver (del Arco et al. 2000; Palmieri et al. 2001). Defects in SLC25A13 are associated with type II citrullinemia (Kobayashi et al. 1999). aspartate [mitochondrial matrix] + glutamate [cytosol] => aspartate [cytosol] + glutamate [mitochondrial matrix] Exchange of malate and alpha-ketoglutarate (2-oxoglutarate) across the inner mitochondrial membrane Authored: D'Eustachio, P, 2007-06-22 14:17:01 Edited: D'Eustachio, P, 2008-09-12 22:05:52 Pubmed16920706 Pubmed4687397 Pubmed8597574 Reactome Database ID Release 43198440 Reactome, http://www.reactome.org ReactomeREACT_11181 Reviewed: Harris, RA, 2008-09-10 18:47:12 The SLC25A11 transport protein in the inner mitochondrial membrane mediates the reversible exchange of mitochondrial malate and cytosolic alpha-ketoglutarate (2-oxoglutarate). Qualitative evidence for this process comes from studies of the human protein (Kabe et al. 2006); kinetic details are inferred from stdies of rat mitochondria under conditions in which only the one transport protein appears to be active (Sluse et al. 1973). The dimeric state of the transport protein is inferred from studies of its bovine homologue (Bisaccia et al. 1996). malate [mitochondrial matrix] + alpha-ketoglutarate [cytosol] <=> malate [cytosol] + alpha-ketoglutarate [mitochondrial matrix] ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4370857 Reactome, http://www.reactome.org Lysyl hydroxylases Converted from EntitySet in Reactome Reactome DB_ID: 1981125 Reactome Database ID Release 431981125 Reactome, http://www.reactome.org ReactomeREACT_121594 ACTIVATION GENE ONTOLOGYGO:0003985 Reactome Database ID Release 4370842 Reactome, http://www.reactome.org PLOD1:Fe2+ dimer Reactome DB_ID: 1981140 Reactome Database ID Release 431981140 Reactome, http://www.reactome.org ReactomeREACT_125619 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4370835 Reactome, http://www.reactome.org PLOD2:Fe2+ dimer Reactome DB_ID: 1981144 Reactome Database ID Release 431981144 Reactome, http://www.reactome.org ReactomeREACT_124773 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0003857 Reactome Database ID Release 4370835 Reactome, http://www.reactome.org PLOD3:Fe2+ dimer Reactome DB_ID: 1981148 Reactome Database ID Release 431981148 Reactome, http://www.reactome.org ReactomeREACT_124739 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004300 Reactome Database ID Release 4370828 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003995 Reactome Database ID Release 4370798 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004490 Reactome Database ID Release 4370783 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004485 Reactome Database ID Release 4370771 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004485 Reactome Database ID Release 4370771 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008470 Reactome Database ID Release 4370743 Reactome, http://www.reactome.org Prolyl 4-hydroxylases Reactome DB_ID: 1650765 Reactome Database ID Release 431650765 Reactome, http://www.reactome.org ReactomeREACT_123477 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 3,4-Hyp collagen propeptides:P4HB Reactome DB_ID: 2022426 Reactome Database ID Release 432022426 Reactome, http://www.reactome.org ReactomeREACT_122180 has a Stoichiometric coefficient of 1 Prolyl 3-hydroxylases:Fe2+ Reactome DB_ID: 1981160 Reactome Database ID Release 431981160 Reactome, http://www.reactome.org ReactomeREACT_122904 has a Stoichiometric coefficient of 1 LEPRE1:PPIB:CRTAP Reactome DB_ID: 1980234 Reactome Database ID Release 431980234 Reactome, http://www.reactome.org ReactomeREACT_122694 has a Stoichiometric coefficient of 1 Lysyl hydroxylae procollagen substrates:P4HB Reactome DB_ID: 2023011 Reactome Database ID Release 432023011 Reactome, http://www.reactome.org ReactomeREACT_125301 has a Stoichiometric coefficient of 1 Lysyl hydroxylated collagen propeptides:P4HB Reactome DB_ID: 2022428 Reactome Database ID Release 432022428 Reactome, http://www.reactome.org ReactomeREACT_123631 has a Stoichiometric coefficient of 1 Dephosphorylation of phosphoPFKFB1 by PP2A complex At the beginning of this reaction, 1 molecule of 'pPF2K-Pase complex' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'PF2K-Pase1 homodimer' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.<br> EC Number: 3.1.3.4 Reactome Database ID Release 43163750 Reactome, http://www.reactome.org ReactomeREACT_1347 has a Stoichiometric coefficient of 2 alpha-D-glucose 6-phosphate <=> D-fructose 6-phosphate Cytosolic phosphoglucose isomerase catalyzes the reversible interconversion of glucose 6-phosphate and fructose 6-phosphate (Tsuboi et al. 1958; Noltmann 1972; Bloxham and Lardy 1973). The active form of the enzyme is a homodimer (Read et al. 2001). Mutations in the enzyme are associated with hemolytic anemia (Xu and Beutler 1994). EC Number: 5.3.1.9 Glucose 6-phosphate is isomerized to form fructose-6-phosphate ISBN0121227022 Pubmed11371164 Pubmed13538944 Pubmed7989588 Reactome Database ID Release 4370471 Reactome, http://www.reactome.org ReactomeREACT_1255 Efflux of glucose from the endoplasmic reticulum Authored: D'Eustachio, P, 2007-06-22 14:17:01 Edited: D'Eustachio, P, 2008-09-12 21:47:19 Glucose generated within the endoplasmic reticulum is exported from the cell. Several mechanisms for this transport process have been proposed but experimental data remain incomplete and contradictory (e.g., Hosokawa and Thorens 2002; Fehr et al. 2005; Van Schaftingen and Gerin 2002). Pubmed11879177 Pubmed11882499 Pubmed16314530 Reactome Database ID Release 43198458 Reactome, http://www.reactome.org ReactomeREACT_11189 Reviewed: Harris, RA, 2008-09-10 18:47:12 3-Phospho-D-glycerate <=> 2-Phospho-D-glycerate Cytosolic phosphoglycerate mutase catalyzes the reversible isomerisation of 3- and 2-phosphoglycerate. The active form of the enzyme is a dimer. There are two isoforms of this enzyme, PGAM1 (isoform B, widely expressed in non-muscle tissue) and PGAM2 (isoform M, expressed in muscle) (Blouquit et al. 1988; Omenn and Cheung 1974; Repiso et al. 2005; Tsujino et al. 1993). EC Number: 5.4.2.1 Pubmed15710582 Pubmed2846554 Pubmed4827367 Pubmed8447317 Reactome Database ID Release 4371654 Reactome, http://www.reactome.org ReactomeREACT_576 Type III Na+/Pi cotransporters Converted from EntitySet in Reactome Reactome DB_ID: 427584 Reactome Database ID Release 43427584 Reactome, http://www.reactome.org ReactomeREACT_19685 1,3-bisphospho-D-glycerate + ADP <=> 3-phospho-D-glycerate + ADP 1,3-Bisphosphoglycerate and ADP react to form 3-phosphoglycerate and ATP Cytosolic phosphoglycerate kinase catalyzes the reaction of ADP and 1,3-bisphosphoglycerate to form D glyceraldehyde 3-phosphate and ATP. The active form of the enzyme is a monomer and requires Mg++ (Yoshida and Watanabe 1972; Huang et al. 1980a,b). This is the first substrate level phosphorylation reaction in glycolysis. EC Number: 2.7.2.3 Pubmed5009693 Pubmed6771269 Pubmed7391027 Reactome Database ID Release 4371850 Reactome, http://www.reactome.org ReactomeREACT_1186 D-glyceraldehyde 3-phosphate + orthophosphate + NAD+ <=> 1,3-bisphospho-D-glycerate + NADH + H+ Cytosolic glyceraldehyde 3-phosphate dehydrogenase catalyzes the reversible reaction of glyceraldehyde 3-phosphate, orthophosphate, and NAD+ to form NADH + H+ and 1,3-bisphosphoglycerate, the first energy rich intermediate of glycolysis. The biochemical details of this reaction were worked out by C and G Cori and their colleagues (Taylor et al. 1948; Cori et al. 1948).<p>While there are multiple human glyceraldehyde 3-phosphate dehydrogenase-like pseudogenes, there is only one glyceraldehyde 3-phosphate dehydrogenase gene expressed in somatic tissue (Benham and Povey 1989; Heinz and Freimuller 1982; Ercolani et al. 1988), and studies of aged human erythrocytes suggest that variant forms of the enzyme arise as a result of post-translational modifications (Edwards et al. 1976). There is, however, an authentic second isoform of glyceraldehyde 3-phosphate dehydrogenase whose expression is confined to spermatogenic cells of the testis (Welch et al. 2000). EC Number: 1.2.1.12 Glyceraldehyde 3 phosphate, NAD+, and orthophosphate react to form 1,3 bisphosphoglycerate and NADH + H+ Pubmed10714828 Pubmed183598 Pubmed2793178 Pubmed3170585 Pubmed7144574 Reactome Database ID Release 4370449 Reactome, http://www.reactome.org ReactomeREACT_1847 dihydroxyacetone phosphate <=> D-glyceraldehyde 3-phosphate Cytosolic triose phosphate isomerase catalyzes the freely reversible interconversion of dihydroxyacetone phosphate and glyceraldehyde 3-phosphate (Lu et al. 1984). The active form of the enzyme is a homodimer (Kinoshita et al. 2005). EC Number: 5.3.1.1 Pubmed16511037 Pubmed6434534 Reactome Database ID Release 4370454 Reactome, http://www.reactome.org ReactomeREACT_775 ACTIVATION GENE ONTOLOGYGO:0003826 Reactome Database ID Release 4370029 Reactome, http://www.reactome.org D-fructose 1,6-bisphosphate <=> dihydroxyacetone phosphate + D-glyceraldehyde 3-phosphate Cytosolic aldolase catalyzes the cleavage of D-fructose 1,6-bisphosphate to yield dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate. The active form of aldolase is a homotetramer. Three aldolase isozymes have been identified which differ in their patterns of expression in various adult tissues and during development but are otherwise functionally indistinguishable (Ali and Cox 1995; Freemont et al. 1984, 1988). EC Number: 4.1.2.13 Pubmed3355497 Pubmed6696436 Pubmed7717389 Reactome Database ID Release 4371496 Reactome, http://www.reactome.org ReactomeREACT_1602 GLUT7/11 Converted from EntitySet in Reactome Reactome DB_ID: 429107 Reactome Database ID Release 43429107 Reactome, http://www.reactome.org ReactomeREACT_19472 D-fructose 6-phosphate + ATP => D-fructose 1,6-bisphosphate + ADP Cytosolic phosphofructokinase 1 catalyzes the reaction of fructose 6-phosphate and ATP to form fructose 1,6-bisphosphate and ADP. This reaction, irreversible under physiological conditions, is the rate limiting step of glycolysis. Phosphofructokinase 1 activity is allosterically regulated by ATP, citrate, and fructose 2,6-bisphosphate.<p>Phosphofructokinase 1 is active as a tetramer (although higher order multimers, not annotated here, may form in vivo). Two isoforms of phosphofructokinase 1 monomer, L and M, are widely expressed in human tissues. Different tissues can contain different homotetramers or heterotetramers: L4 in liver, M4 in muscle, and all possible heterotetramers, L4, L3M, L2M2, LM3, and M4, in red blood cells, for example (Raben et al. 1995; Vora et al. 1980, 1987; Vora 1981). A third isoform, P, is abundant in platelets, where it is found in P4, P3L, P2L2, and PL3 tetramers (Eto et al. 1994; Vora et al. 1987). EC Number: 2.7.1.11 Pubmed2960695 Pubmed6444721 Pubmed6451249 Pubmed7825568 Pubmed8117307 Reactome Database ID Release 4370467 Reactome, http://www.reactome.org ReactomeREACT_736 Class I GLUTs Converted from EntitySet in Reactome Reactome DB_ID: 428789 Reactome Database ID Release 43428789 Reactome, http://www.reactome.org ReactomeREACT_20111 D-fructose 6-phosphate + ATP => D-fructose 2,6-bisphosphate + ADP EC Number: 2.7.1.105 Fructose 6-phosphate and ATP react to form fructose 2,6-bisphosphate and ADP Pubmed10095107 Pubmed15896703 Pubmed2837207 Pubmed3052289 Pubmed7574501 Pubmed9464277 Reactome Database ID Release 4371802 Reactome, http://www.reactome.org ReactomeREACT_291 The 6-phosphofructo-2-kinase activity of cytosolic PFKFB (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase) homodimer catalyzes the reaction of fructose 6-phosphate and ATP to form fructose 2,6-bisphosphate and ADP (Pilkis et al. 1988). Fructose 2,6-bisphosphate is not itself on the pathway of glycolysis. Rather, it acts as a positive allosteric effector of phosphofructokinase 1, greatly increasing the rate of synthesis of fructose 1,6-bisphosphate and hence the overall rate of glycolysis. The conversion of PFKFB between its dephosphorylated form, which catalyzes the synthesis of fructose 2,6-bisphosphate as described here, and its phosphorylated form, which catalyzes the hydrolysis of fructose 2,6-bisphosphate to fructose 6-phosphate and orthophosphate plays a central role in the short-term regulation of glycolysis (Pilkis et al. 1995).<p>Four isoforms of PFKFB protein encoded by four different genes exhibit tissue-specific expression patterns. PFKFB1 is expressed in the liver (Algaier and Uyeda 1988), PFKFB2 is expressed in the heart (Hirata et al. 1998), PFKFB3 is ubiquitously expressed (Manes and el-Maghrabi 2005), and PFKFB4, originally described as a testis-specific gene product (Manzano et al. 1999), may also be expressed in several kinds of tumors. ACTIVATION GENE ONTOLOGYGO:0004084 Reactome Database ID Release 4370700 Reactome, http://www.reactome.org Smad7:NEDD4L Reactome DB_ID: 2176426 Reactome Database ID Release 432176426 Reactome, http://www.reactome.org ReactomeREACT_124588 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004084 Reactome Database ID Release 4370700 Reactome, http://www.reactome.org Collagen propeptides and chains:P4HB Reactome DB_ID: 2022120 Reactome Database ID Release 432022120 Reactome, http://www.reactome.org ReactomeREACT_122651 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004084 Reactome Database ID Release 4370711 Reactome, http://www.reactome.org MEF2C/D:PPARGC1A Reactome DB_ID: 1605560 Reactome Database ID Release 431605560 Reactome, http://www.reactome.org ReactomeREACT_120029 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004084 Reactome Database ID Release 4370711 Reactome, http://www.reactome.org polyubiquitinated PAK-2p34 Reactome DB_ID: 212918 Reactome Database ID Release 43212918 Reactome, http://www.reactome.org ReactomeREACT_14496 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004617 Reactome Database ID Release 43977334 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0047945 Reactome Database ID Release 43893579 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004647 Reactome Database ID Release 43977341 Reactome, http://www.reactome.org 4-Hyp collagen propeptides:P4HB Reactome DB_ID: 2022076 Reactome Database ID Release 432022076 Reactome, http://www.reactome.org ReactomeREACT_122514 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004648 Reactome Database ID Release 43977342 Reactome, http://www.reactome.org p-CRY:p-PER:Kinase Reactome DB_ID: 421296 Reactome Database ID Release 43421296 Reactome, http://www.reactome.org ReactomeREACT_26285 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004359 Reactome Database ID Release 4370608 Reactome, http://www.reactome.org Beta-TrCP1:PER Reactome DB_ID: 400368 Reactome Database ID Release 43400368 Reactome, http://www.reactome.org ReactomeREACT_27062 has a Stoichiometric coefficient of 1 FBXL3:CRY Reactome DB_ID: 400351 Reactome Database ID Release 43400351 Reactome, http://www.reactome.org ReactomeREACT_25657 has a Stoichiometric coefficient of 1 p-CRY:p-PER:Kinase Reactome DB_ID: 400277 Reactome Database ID Release 43400277 Reactome, http://www.reactome.org ReactomeREACT_25528 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 BMAL1:CLOCK/NPAS2:CRY:PER ARNTL:CLOCK/NPAS2:CRY:PER Reactome DB_ID: 400273 Reactome Database ID Release 43400273 Reactome, http://www.reactome.org ReactomeREACT_26318 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0003952 Reactome Database ID Release 43197281 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000309 Reactome Database ID Release 43200494 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000309 Reactome Database ID Release 43197217 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0000309 Reactome Database ID Release 43200481 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008936 Reactome Database ID Release 43197239 Reactome, http://www.reactome.org Urea transporters Converted from EntitySet in Reactome Reactome DB_ID: 444114 Reactome Database ID Release 43444114 Reactome, http://www.reactome.org ReactomeREACT_20946 ACTIVATION GENE ONTOLOGYGO:0003951 Reactome Database ID Release 43197237 Reactome, http://www.reactome.org TGF beta Converted from EntitySet in Reactome Reactome DB_ID: 114657 Reactome Database ID Release 43114657 Reactome, http://www.reactome.org ReactomeREACT_5047 Carnitine transporters Converted from EntitySet in Reactome Reactome DB_ID: 597614 Reactome Database ID Release 43597614 Reactome, http://www.reactome.org ReactomeREACT_22929 ACTIVATION GENE ONTOLOGYGO:0008523 Reactome Database ID Release 43199212 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004514 Reactome Database ID Release 43197214 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004733 Reactome Database ID Release 43965270 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004733 Reactome Database ID Release 43965270 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004140 Reactome Database ID Release 43196818 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004595 Reactome Database ID Release 43196830 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008897 Reactome Database ID Release 43199214 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015291 Reactome Database ID Release 43199228 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008478 Reactome Database ID Release 43965111 Reactome, http://www.reactome.org OAT1-3 Converted from EntitySet in Reactome Reactome DB_ID: 561087 Reactome Database ID Release 43561087 Reactome, http://www.reactome.org ReactomeREACT_22994 ACTIVATION GENE ONTOLOGYGO:0008478 Reactome Database ID Release 43965111 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008478 Reactome Database ID Release 43965111 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004594 Reactome Database ID Release 43199185 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004632 Reactome Database ID Release 43196734 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004633 Reactome Database ID Release 43196842 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004477 Reactome Database ID Release 43200745 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004486 Reactome Database ID Release 43200717 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004372 Reactome Database ID Release 4371248 Reactome, http://www.reactome.org ZIP6/ZIP14 Converted from EntitySet in Reactome Reactome DB_ID: 442330 Reactome Database ID Release 43442330 Reactome, http://www.reactome.org ReactomeREACT_21222 ACTIVATION GENE ONTOLOGYGO:0004489 Reactome Database ID Release 43200678 Reactome, http://www.reactome.org Alpha actinins Converted from EntitySet in Reactome Reactome DB_ID: 349780 Reactome Database ID Release 43349780 Reactome, http://www.reactome.org ReactomeREACT_14060 ACTIVATION GENE ONTOLOGYGO:0004486 Reactome Database ID Release 43200717 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004372 Reactome Database ID Release 4371248 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004329 Reactome Database ID Release 43200692 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004477 Reactome Database ID Release 43200745 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008517 Reactome Database ID Release 43200687 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004326 Reactome Database ID Release 43200730 Reactome, http://www.reactome.org MagT1/2 Converted from EntitySet in Reactome Reactome DB_ID: 442654 Reactome Database ID Release 43442654 Reactome, http://www.reactome.org ReactomeREACT_20757 ACTIVATION GENE ONTOLOGYGO:0008517 Reactome Database ID Release 43200687 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0033560 Reactome Database ID Release 43197966 Reactome, http://www.reactome.org GLYT Converted from EntitySet in Reactome Reactome DB_ID: 444088 Reactome Database ID Release 43444088 Reactome, http://www.reactome.org ReactomeREACT_21204 ACTIVATION GENE ONTOLOGYGO:0033560 Reactome Database ID Release 43197966 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004326 Reactome Database ID Release 43197957 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004326 Reactome Database ID Release 43197957 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004516 Reactome Database ID Release 43197236 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008517 Reactome Database ID Release 43200706 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008517 Reactome Database ID Release 43200706 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008517 Reactome Database ID Release 43200705 Reactome, http://www.reactome.org VMAT1/2 Converted from EntitySet in Reactome Reactome DB_ID: 444147 Reactome Database ID Release 43444147 Reactome, http://www.reactome.org ReactomeREACT_21239 ACTIVATION GENE ONTOLOGYGO:0047280 Reactome Database ID Release 43197240 Reactome, http://www.reactome.org RNF111 binds SMAD7 Authored: Orlic-Milacic, M, 2012-04-04 E3 ubiquitin ligase RNF111 (Arkadia) binds SMAD7 in the nucleus (Koinuma et al. 2003). Edited: Jassal, B, 2012-04-10 Pubmed14657019 Reactome Database ID Release 432186771 Reactome, http://www.reactome.org ReactomeREACT_121185 Reviewed: Huang, Tao, 2012-05-14 RNF111 ubiquitinates SMAD7 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed14657019 RNF111 (Arkadia) polyubiquitinates SMAD7 (Koinuma et al. 2003). This was inferred from studies using recombinant mouse Smad7 and recombinant mouse Rnf111 expressed in human embryonic kidney cell line HEK293. Reactome Database ID Release 432186785 Reactome, http://www.reactome.org ReactomeREACT_120848 Reviewed: Huang, Tao, 2012-05-14 SMAD2/3:SMAD4 heterotrimer forms a complex with RBL1, E2F4/5 and DP1/2 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 In response to TGF-beta stimulation, a complex composed of SMAD2/3:SMAD4 heterotrimer and RBL1 (p107), E2F4/5 and DP1/2 can be detected in the nucleus. Formation of this complex was confirmed by both co-immunoprecipitation of the endogenous complex from the human keratinocyte cell line HaCat and by protein interaction studies using tagged recombinant proteins. It is possible that cells contain pre-assembled cytosolic complexes of SMAD2/3, RBL1 (p107) and E2F4/5, that translocate to the nucleus after TGF-beta stimulation, when phosphorylated SMAD2/3 recruit SMAD4. The MH2 domain of SMAD3 establishes independent contacts with the N-termini of E2F4 (or E2F5) and unphosphorylated RBL1 (p107). RBL2 (p130), RB1 and E2F1 do not interact with SMAD2/3 (Chen et al. 2002). Pubmed12150994 Reactome Database ID Release 432127257 Reactome, http://www.reactome.org ReactomeREACT_121097 Reviewed: Huang, Tao, 2012-05-14 Parathyroid hormone receptors Converted from EntitySet in Reactome Reactome DB_ID: 420554 Reactome Database ID Release 43420554 Reactome, http://www.reactome.org ReactomeREACT_18822 MYC trancscription is negatively regulated by SMAD2/3:SMAD4:RBL1:E2F4/5:DP1/2 complex Authored: Orlic-Milacic, M, 2012-04-04 Complex formed by RBL1 (p107), E2F4/5, DP1/2 and a trimer of phosphorylated R-SMADs (SMAD2/3) and SMAD4 (Co-SMAD) cooperatively binds to TIE (TGF-beta inhibitory element) and E2F sites in the MYC promoter and promotes cell-cycle independent inhibition of MYC transcription in response to TGF-beta stimulation (Chen et al. 2002). Edited: Jassal, B, 2012-04-10 Pubmed12150994 Reactome Database ID Release 431484099 Reactome, http://www.reactome.org ReactomeREACT_121295 Reviewed: Huang, Tao, 2012-05-14 WWTR1:SMAD stimulates transcription of SERPINE1 while TGIF:SMAD inhibits it Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Knocking down WWTR1 (TAZ) expression by siRNA treatment inhibits TGF-beta-dependent transcription of SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) in hepatocellular carcinoma cell line Hep G2. Chromatin immunoprecipitation (ChIP) confirmed binding of both WWTR1 and SMAD2/3 to the promoter of SERPINE1 gene in response to TGF-beta stimulation (Varelas et al. 2008). Binding of TGIF1 or TGIF2 to SMAD2/3:SMAD4 heterotrimer negatively regulates transcription of SERPINE1 (Wotton et al. 1999, Melhuish et al. 2001). Pubmed18568018 Reactome Database ID Release 432106586 Reactome, http://www.reactome.org ReactomeREACT_120967 Reviewed: Huang, Tao, 2012-05-14 SKI/SKIL binds SMAD complex, suppressing TGF-beta signaling Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-02-10 14:02:35 Edited: Jassal, B, 2012-04-10 Pubmed10485843 Pubmed10531062 Pubmed10535941 Pubmed10549282 Pubmed11389444 Reactome Database ID Release 43173481 Reactome, http://www.reactome.org ReactomeREACT_6887 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 SKI and SKIL (SNO) are able to recruit NCOR and possibly other transcriptional repressors to SMAD2/3:SMAD4 complex, inhibiting SMAD2/3:SMAD4-mediated transcription (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Experimental findings suggest that SMAD2 and SMAD3 may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001), and that the ratio of SMAD2/3 and SKI/SKIL determines the outcome (inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL). SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex. PACAP peptides Converted from EntitySet in Reactome Reactome DB_ID: 420080 Reactome Database ID Release 43420080 Reactome, http://www.reactome.org ReactomeREACT_19059 SMAD2/3:SMAD4 heterotrimer binds SP1 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11013220 Reactome Database ID Release 432187309 Reactome, http://www.reactome.org ReactomeREACT_120838 Reviewed: Huang, Tao, 2012-05-14 TGF-beta (TGFB1) stimulates formation of a complex of SP1 transcription factor and SMAD2/3:SMAD4 heterotrimer. SMAD2 and SMAD4 bind to SP1 directly, through their C- and N-terminus, respectively (Feng et al. 2000). SMAD2/3:SMAD4:SP1 complex stimulates transcription of CDKN2B Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11013220 Reactome Database ID Release 432187303 Reactome, http://www.reactome.org ReactomeREACT_120757 Reviewed: Huang, Tao, 2012-05-14 SMAD2/3:SMAD4:SP1 complex binds SP1 and SMAD promoter elements of CDKN2B (p15-INK4B) gene and stimulates transcription of CDKN2B. CDKN2B inhibits the action of cyclin-dependent kinases CDK4 and CDK6 and may be an effector of TGF-beta induced cell cycle arrest (Feng et al. 2000). MEN1 binds SMAD2/3:SMAD4 heterotrimer Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, binds SMAD2/3:SMAD4 heterotrimer through interaction with SMAD3. MEN1 likely acts as a trancriptional cofactor for SMAD2/3:SMAD4 and may be involved in transcriptional regulation of some SMAD2/3:SMAD4 target genes (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012). Pubmed11274402 Pubmed15150273 Pubmed22275377 Reactome Database ID Release 432186643 Reactome, http://www.reactome.org ReactomeREACT_120994 Reviewed: Huang, Tao, 2012-05-14 SMAD2/3:SMAD4 complex positively regulates JUNB transcription Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed10022869 Reactome Database ID Release 432187293 Reactome, http://www.reactome.org ReactomeREACT_121406 Reviewed: Huang, Tao, 2012-05-14 SMAD2/3:SMAD4 heterotrimer binds SMAD binding site in the promoter of JUNB transcription factor and in cooperation with AP-1 transcription factors, which bind to an adjacent promoter element, stimulates transcription of JUNB gene (Wong et al. 1999). MIR150 Reactome DB_ID: 1852607 Reactome Database ID Release 431852607 Reactome, http://www.reactome.org ReactomeREACT_119290 has a fragment starting at 16 and ending at 37 miR-150 microRNA 150 MIR206 Reactome DB_ID: 1614232 Reactome Database ID Release 431614232 Reactome, http://www.reactome.org ReactomeREACT_119177 has a fragment starting at 53 and ending at 74 miR-206 microRNA 206 MIR181C Reactome DB_ID: 1852600 Reactome Database ID Release 431852600 Reactome, http://www.reactome.org ReactomeREACT_119564 miR-181C microRNA 181c MIR302A Reactome DB_ID: 1852592 Reactome Database ID Release 431852592 Reactome, http://www.reactome.org ReactomeREACT_119679 has a fragment starting at 44 and ending at 66 miR-302A microRNA 302a MIR449C Reactome DB_ID: 1606506 Reactome Database ID Release 431606506 Reactome, http://www.reactome.org ReactomeREACT_119325 has a fragment starting at 17 and ending at 41 miR-449C WWTR1 (TAZ), TBX5, and PCAF form a complex Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind the TBX5 transcription factor and PCAF (KAT2B) histone acetyltransferase to form a complex. The stoichiometry of this complex is unknown (Murakami et al. 2005). Pubmed16332960 Reactome Database ID Release 432032794 Reactome, http://www.reactome.org ReactomeREACT_118620 Reviewed: Sudol, M, 2012-02-03 WWTR1 (TAZ) binds RUNX2 Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-19 In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind the RUNX2 transcription factor to form a complex. This interaction has not been experimentally characterized in human cells but is inferred from properties of the homologous mouse proteins. The stoichiometry of this complex is unknown (Cui et al. 2003). Pubmed12529404 Reactome Database ID Release 432064932 Reactome, http://www.reactome.org ReactomeREACT_118717 Reviewed: Sudol, M, 2012-02-03 WWTR1 (TAZ) binds TEAD Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind any one of the four TEAD transcription factors to form a complex. The stoichiometry of this complex is unknown (Chan et al. 2009; Zhang et al. 2009). Pubmed19324876 Pubmed19324877 Reactome Database ID Release 432032781 Reactome, http://www.reactome.org ReactomeREACT_118805 Reviewed: Sudol, M, 2012-02-03 YAP1 binds TEAD Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 In the nucleus the YAP1 transcriptional coactivator can bind any one of the four TEAD transcription factors to form a complex. The stoichiometry of this complex is unknown (Chan et al. 2009). Pubmed19324876 Reactome Database ID Release 432032775 Reactome, http://www.reactome.org ReactomeREACT_118835 Reviewed: Sudol, M, 2012-02-03 Patched homologs Converted from EntitySet in Reactome Reactome DB_ID: 445134 Reactome Database ID Release 43445134 Reactome, http://www.reactome.org ReactomeREACT_21754 Parathyroid hormone-type ligands Converted from EntitySet in Reactome Reactome DB_ID: 420569 Reactome Database ID Release 43420569 Reactome, http://www.reactome.org ReactomeREACT_18854 WWTR1:SMAD translocates to the nucleus Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed18568018 Reactome Database ID Release 432106579 Reactome, http://www.reactome.org ReactomeREACT_121015 Reviewed: Huang, Tao, 2012-05-14 TGF-beta-dependent nuclear accumulation of SMAD2/3 and SMAD4 is mediated by WWTR1 (TAZ). WWTR1 does not affect phosphorylation of SMAD2/3 or the formation of SMAD2/3:SMAD4 trimers. WWTR1:SMAD stimulates transcription of SMAD7 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Knocking down WWTR1 (TAZ) expression by siRNA treatment inhibits TGF-beta-dependent transcription of SMAD7 in human hepatocellular carcinoma cell line Hep G2. Chromatin immunoprecipitation (ChIP) confirmed binding of both WWTR1 and SMAD2/3 to the promoter of SMAD7 gene in response to TGF-beta stimulation (Varelas et al. 2008). Pubmed18568018 Reactome Database ID Release 432106591 Reactome, http://www.reactome.org ReactomeREACT_120803 Reviewed: Huang, Tao, 2012-05-14 Phosphorylation of SMAD2 and SMAD3 linker regions by CDK8 or CDK9 Authored: Orlic-Milacic, M, 2012-04-04 CDK8 in complex with cyclin C (CDK8:CCNC) and CDK9 in complex with cyclin T (CDK9:CCNT) are able to phosphorylate the linker region of SMAD2 and SMAD3. In SMAD3, CDK8/CDK9 preferentially targets threonine residue T179, although serine residues S208 and S213 can also be phosphorylated. In SMAD2, CDK8/9 preferentially targets threonine residue T220 (corresponds to T190 in the short isoform of SMAD2, SMAD2-2). Phosphorylation of serine residues that correspond to serines S208 and S213 of SMAD3 has not been examined. Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8/CDK9 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes SMAD2 and SMAD3 for ubiquitination and subsequent degradation (Alarcon et al. 2009). EC Number: 2.7.11 Edited: Jassal, B, 2012-04-10 Pubmed19914168 Reactome Database ID Release 432176475 Reactome, http://www.reactome.org ReactomeREACT_121336 Reviewed: Huang, Tao, 2012-05-14 has a Stoichiometric coefficient of 2 WWTR1 binds SMAD2/3:SMAD4 heterotrimer Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 In the cytosol of human embryonic stem cells, WWTR1 (TAZ) binds heterotrimer composed of two R-SMADs (SMAD2 and/or SMAD3) and SMAD4. This interaction involves the C-terminus of WWTR1 (TAZ) and the MH1 domain of SMAD proteins. Pubmed18568018 Reactome Database ID Release 432031355 Reactome, http://www.reactome.org ReactomeREACT_121368 Reviewed: Huang, Tao, 2012-05-14 Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-01-18 10:19:52 Edited: Jassal, B, 2012-04-10 Pubmed11779503 Pubmed11779505 Pubmed15350224 Pubmed9311995 Pubmed9670020 Reactome Database ID Release 43170847 Reactome, http://www.reactome.org ReactomeREACT_6760 Reviewed: Chen, Ye-Guang, 2012-11-14 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif. has a Stoichiometric coefficient of 2 The SMAD2/3:SMAD4 complex transfers to the nucleus Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-02-10 14:02:35 Pubmed10934479 Pubmed11294908 Pubmed12592392 Pubmed16260601 Pubmed19114992 Pubmed20694664 Reactome Database ID Release 43173488 Reactome, http://www.reactome.org ReactomeREACT_6726 Reviewed: Chen, Ye-Guang, 2012-11-14 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 The phosphorylated R-SMAD:CO-SMAD complex rapidly translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003) where it binds directly to DNA and interacts with a plethora of transcription co-factors. Regulation of target gene expression can be either positive or negative. A classic example of a target gene of the pathway are the genes encoding for I-SMADs. Thus, TGF-beta/SMAD signaling induces the expression of the negative regulators of the pathway (negative feedback loop). MIR34B Reactome DB_ID: 1606694 Reactome Database ID Release 431606694 Reactome, http://www.reactome.org ReactomeREACT_119625 has a fragment starting at 50 and ending at 71 miR-34B MIR34C Reactome DB_ID: 1606687 Reactome Database ID Release 431606687 Reactome, http://www.reactome.org ReactomeREACT_120087 has a fragment starting at 13 and ending at 35 miR-34C MIR34 Converted from EntitySet in Reactome Reactome DB_ID: 1606690 Reactome Database ID Release 431606690 Reactome, http://www.reactome.org ReactomeREACT_119468 miR-34 MIR34A Reactome DB_ID: 1606699 Reactome Database ID Release 431606699 Reactome, http://www.reactome.org ReactomeREACT_119105 has a fragment starting at 22 and ending at 43 miR-34A MIR200C Reactome DB_ID: 1606774 Reactome Database ID Release 431606774 Reactome, http://www.reactome.org ReactomeREACT_119299 has a fragment starting at 44 and ending at 66 miR-200C microRNA 200c MIR449 Converted from EntitySet in Reactome Reactome DB_ID: 1606508 Reactome Database ID Release 431606508 Reactome, http://www.reactome.org ReactomeREACT_119918 miR-449 MIR200B/C Converted from EntitySet in Reactome Reactome DB_ID: 1614240 Reactome Database ID Release 431614240 Reactome, http://www.reactome.org ReactomeREACT_118864 miR-200B/C MIR200B Reactome DB_ID: 1606776 Reactome Database ID Release 431606776 Reactome, http://www.reactome.org ReactomeREACT_119352 has a fragment starting at 57 and ending at 78 miR-200B microRNA 200b MIR449A Reactome DB_ID: 1606491 Reactome Database ID Release 431606491 Reactome, http://www.reactome.org ReactomeREACT_119505 has a fragment starting at 16 and ending at 37 miR-449A MIR449B Reactome DB_ID: 1606503 Reactome Database ID Release 431606503 Reactome, http://www.reactome.org ReactomeREACT_120149 has a fragment starting at 16 and ending at 37 miR-449B CPT1 converts palmitoyl-CoA to palmitoyl carnitine Authored: Gopinathrao, G, 2007-07-29 21:03:03 Carnitine palmitoyl transferase 1 (CPT1) associated with the inner mitochondrial membrane, catalyzes the reaction of palmitoyl-CoA from the cytosol with carnitine in the mitochondrial intermembrane space to form palmitoylcarnitine and CoASH. Two CPT1 isoforms exist, encoded by two different genes. In the body, CPT1A is most abundant in liver while CPT1B is abundant in muscle. Both CPT1A and CPT1B are inhibited by malonyl-CoA (Morillas et al. 2002, 2004; Zammit et al. 2001; Zhu et al. 1997). Mutations in CPT1A are associated with defects in fatty acid metabolism and fasting intoilerance, consistent with the role assigned to CPT1 from studies in vitro and in animal models (IJlst et al. 1998; Gobin et al. 2003). EC Number: 2.3.1.21 Pubmed11356169 Pubmed11790793 Pubmed14517221 Pubmed14711372 Pubmed9344464 Pubmed9691089 Reactome Database ID Release 43200406 Reactome, http://www.reactome.org ReactomeREACT_11185 Reviewed: D'Eustachio, P, 2007-07-31 18:50:15 palmitoyl-CoA + carnitine => palmitoylcarnitine + CoASH Exchange of palmitoylcarnitine and carnitine across the inner mitochondrial membrane Authored: Gopinathrao, G, 2007-07-29 21:03:03 Pubmed9399886 Reactome Database ID Release 43200424 Reactome, http://www.reactome.org ReactomeREACT_11180 Reviewed: D'Eustachio, P, 2007-07-31 18:50:15 The carnitine-acylcarnitine transporter (SLC25A20 / CACT), embedded in the inner mitochondrial membrane, mediates the exchange of palmitoyl-carnitine (and other acylcarnitine esters) and carnitine across the inner mitochondrial membrane (Huizing et al., 1997). CPT2 converts palmitoyl carnitine to palmitoyl-CoA Authored: Gopinathrao, G, 2007-07-29 21:03:03 CPT2, associated with the inner mitochondrial membrane, catalyzes the reaction of palmitoylcarnitine and CoASH to form palmitoyl-CoA and carnitine (Verderio et al. 1995). EC Number: 2.3.1.21 Pubmed7711730 Reactome Database ID Release 43200410 Reactome, http://www.reactome.org ReactomeREACT_11133 Reviewed: D'Eustachio, P, 2007-07-31 18:50:15 palmitoylcarnitine + CoASH => palmitoyl-CoA + carnitine Activated human P2Y purinoceptor 1 binds mouse G-protein Gq Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-11-03 P2Y1 is coupled to the Gq family of G protein alpha subunits, causing increases in intracellular calcium concentration through stimulation of PLC. Pubmed14742685 Reactome Database ID Release 43428715 Reactome, http://www.reactome.org ReactomeREACT_20602 Reviewed: Harper, MT, 2009-11-02 Reviewed: Jones, ML, 2009-11-02 Reviewed: Poole, AW, 2009-11-02 Formation of ARC coactivator complex ARC co-activator complex and assembly<br><br>The ARC co-activator complex is a subset of 18 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes in human cells. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).<br><br>The ARC complex was originally identified and named as a co-activator complex associated with transcription activator proteins (reviewed in Malik, 2005 and references therein). It was subsequently determined that many of the components of the ARC complex are also in the DRIP complex, and in the TRAP complex..<br><br>The ARC complex contains the following 14 proteins, which also are common to the DRIP and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC. <br><br>The ARC complex also contains 4 additional, ARC-specific components, which are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004).<br><br>The order of addition of the ARC proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, ARC complex assembly is represented as a single reaction event, in which all 19 components assemble simultaneously into the ARC co-activator complex.<br><br> Pubmed10235266 Pubmed15175151 Pubmed15896744 Pubmed16719718 Pubmed2163759 Pubmed9637681 Pubmed9653119 Reactome Database ID Release 43212352 Reactome, http://www.reactome.org ReactomeREACT_12480 Reviewed: Freedman, LP, 2008-02-25 20:35:15 Hedgehog protein N product Converted from EntitySet in Reactome Reactome DB_ID: 445153 Reactome Database ID Release 43445153 Reactome, http://www.reactome.org ReactomeREACT_21921 Formation of DRIP coactivator complex DRIP co-activator complex and assembly<br><br>The DRIP co-activator complex is a subset of 14 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).<br><br>The DRIP complex was originally identified and named as a co-activator complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). It was later determined that all of the components of the DRIP complex were also in the TRAP complex, and the ARC complex.<br><br>The DRIP complex contains the following 14 proteins, which also are common to the ARC and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC. <br><br>All of the DRIP adapter complex components are present in the ARC adapter complex, but the ARC complex also has 4 additional components (Rachez, 1999). These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).<br><br>Similarly, all 14 of the DRIP adapter complex components are present in the TRAP adapter complex, but the TRAP complex also has 4 additional components (Bourbon, 2004), These TRAP-specific components are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme.<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex identified in yeast, first identified by Kornberg and colleagues (Kelleher, 1990).<br><br> Pubmed10235266 Pubmed11395415 Pubmed15175151 Pubmed16719718 Pubmed2163759 Pubmed9637681 Pubmed9653119 Reactome Database ID Release 43212432 Reactome, http://www.reactome.org ReactomeREACT_12379 Reviewed: Freedman, LP, 2008-02-25 20:35:15 Formation of TRAP coactivator complex Pubmed10235266 Pubmed15175151 Pubmed2163759 Pubmed9637681 Pubmed9653119 Reactome Database ID Release 43212380 Reactome, http://www.reactome.org ReactomeREACT_12410 Reviewed: Freedman, LP, 2008-02-25 20:35:15 TRAP co-activator complex and assembly<br><br>The TRAP co-activator complex is a subset of 18 proteins from the set of at least 31 Mediator proteins that, in different combinations and in different contexts, form specific co-activator or "Adapter" complexes in human cells. These complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).<br><br>The TRAP complex was originally identified and named as a co-activator complex associated with the Thyroid Hormone Receptor member of the nuclear receptor family of transcription factors (Yuan, 1998). It was later determined that many of the components of the TRAP complex are also in the DRIP complex, and in the ARC complex.<br><br>The TRAP complex contains the following 14 proteins, which also are common to the DRIP and ARC complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.<br><br>The TRAP complex also contains 4 additional components, which are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme (Bourbon, 2004).<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004).<br><br>The order of addition of the TRAP proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, TRAP co-activator complex assembly is represented as a single reaction event, in which all 18 components assemble simultaneously into the TRAP co-activator complex.<br><br> Formation of CSL-NICD coactivator complex Authored: Caudy, M, 2008-09-05 23:43:34 Mammalian CSL Coactivator Complexes: Upon activation of Notch signaling, cleavage of the transmembrane Notch receptor releases the Notch Intracellular Domain (NICD), which translocates to the nucleus, where it binds to CSL and displaces the corepressor complex from CSL (reviewed in Mumm, 2000 and Kovall, 2007). The resulting CSL-NICD "binary complex" then recruits an additional coactivator, Mastermind (Mam), to form a ternary complex. The ternary complex then recruits additional, more general coactivators, such as CREB Binding Protein (CBP), or the related p300 coactivator, and a number of Histone Acetytransferase (HAT) proteins, including GCN5 and PCAF (Fryer, 2002). There is evidence that Mam also can subsequently recruit specific kinases that phosphorylate NICD, to downregulate its function and turn off Notch signaling (Fryer, 2004). Reactome Database ID Release 43212356 Reactome, http://www.reactome.org ReactomeREACT_14814 Reviewed: Baker, N, 2008-06-05 07:19:32 Formation of NR-MED1 Coactivator Complex <b>THE NUCLEAR RECEPTOR-MED1 REACTION</b>: The Nuclear Receptor (NR) proteins are a highly conserved family of DNA-binding transcription factors that bind certain hormones, vitamins, and other small, diffusible signaling molecules. The non-liganded NRs recruit specific corepressor complexes of the NCOR/SMRT type, to mediate transcriptional repression of the target genes to which they are bound. During signaling, ligand binding to a specific domain in the NR proteins induces a conformational change that results in the exchange of the associated corepressor complex, and its replacement by a specific coactivator complex of either the TRAP/DRIP/Mediator type, or the p160/SRC type. The Mediator coactivator complexes typically nucleate around the MED1 coactivator protein, which is directly bound to the NR transcription factor (reviewed in Freedman, 1999; Malik, 2005).<br><br> A general feature of the NR proteins is that they each contain a specific protein interaction domain (PID), or domains, that mediates the specific binding interactions with the MED1 proteins. In the ligand-bound state, NRs each take part in an NR-MED1 binding reaction to form an NR-MED1 complex. The bound MED1 then functions to nucleate the assembly of additional specific coactivator proteins, depending on the cell and DNA context, such as what specific target gene promoter or enhancer they are bound to, and in what cell type.<br><br> The formation of specific MED1-containing coactivator complexes on specific NR proteins has been well-characterized for a number of the human NR proteins. For example, binding of Vitamin D to the human Vitamin D3 Receptor was found to result in the recruitment of a specific complex of D Receptor Interacting Proteins - the DRIP coactivator complex (Rachez, 1998). Within the DRIP complex, the DRIP205 subunit was later renamed human "MED1", based on sequence similarities with yeast MED1 (reviewed in Bourbon, 2004).<br><br> Similarly, binding of thyroid hormone (TH) to the human TH Receptor (THRA or THRB) was found to result in the recruitment of a specific complex of Thyroid Receptor Associated Proteins - the TRAP coactivator complex (Yuan, 1998). The TRAP220 subunit was later identified to be the Mediator 1 (MED1) homologue (summarized in Bourbon, et al., 2004; Table 1).<br><br> The 48 human NR proteins each contain the PID(s) known to mediate interaction with the human MED1 protein. Direct NR-MED1 protein-protein interactions have been shown for a number of the NR proteins. The MED1-interacting PIDs are conserved in all of the human NRs. Therefore, each of the human NRs is known or expected to interact with MED1 in the appropriate cell context, depending on the cell type, the cell state, and the target gene regulatory region involved. Authored: Caudy, M, 2008-11-20 05:11:03 Edited: Caudy, M, 2009-05-26 21:05:28 Pubmed10235266 Pubmed10542397 Pubmed11865025 Pubmed15175151 Pubmed15896744 Pubmed16751179 Pubmed9653119 Reactome Database ID Release 43376419 Reactome, http://www.reactome.org ReactomeREACT_19207 Reviewed: Freedman, LP, 2009-08-29 Wnts Converted from EntitySet in Reactome Reactome DB_ID: 517409 Reactome Database ID Release 43517409 Reactome, http://www.reactome.org ReactomeREACT_21532 KRAB-ZNF / KAP Interaction <p>Formation of the KRAB ZNF / KAP1 Corepressor Complex: </p> <p>Transcription factors which contain tandem copies of the C2H2 zinc finger DNA binding motif (ZNFs) are the most abundant class of TFs in the human proteome, comprising more than 1000 members. The KRAB ZNF proteins are the largest subset of these (with 423 members) and are defined by having an additional conserved domain, the KRAB domain (Bellefroid,1991, Margolin, 1994, Urrutia, 2003, Huntley, 2006). The Kruppel Associated Box (KRAB) domain is a transcription repression domain (Margolin, 1994) which mediates the recruitment of a specific and dedicated co repressor protein for the KRAB-ZNF family - KAP1 - which is required for transcriptional repression and gene silencing (Friedman, 1996). </p> <p>The larger family of ZNF transcription factors are present in almost all metazoans and generally their DNA binding specificities and transcription regulation functions are conserved from Drosophila to humans. Although the biological functions of most ZNF TFs is not known, they often function biochemically as sequence specific DNA binding proteins and can be activators, or more oftenly observed, repressors of transcription, depending on cellular context. Transcriptional repression is mediated via specific protein protein interaction surfaces in the ZNF that function as repression domains, by recruiting specific co repressors, such as KAP1 in humans (Friedman, 1996), and dCTBP in Drosophila (Nibu, 1998). </p> <p>In contrast to the larger ZNF family, the KRAB-ZNFs only appear much later in vertebrate evolution: genes encoding the primordial KRAB ZNF subfamily first arose in tetrapods and the family has been greatly expanded in numbers and complexity in mammals. Interestingly,a large fraction of KRAB-ZNFs are found only in primates. In addition to their rapid and dynamic evolutionary history, comparative genomics and expression studies of primate KRAB-ZNFs suggest that these genes have played a significant role in shaping primate specific traits (Huntley, 2006, Nowick, 2009). </p> <p>The biochemical pathway utilized by KRAB-ZNFs is well defined and probably nearly identical for each member: All KRAB-ZNF proteins which have been studied in detail are repressors and utilize the KRAB domain to bind the KAP1 co-repressor. This interaction is direct, of high affinity, and is obligate for the KRAB-ZNF to function as a repressor when bound to DNA in vivo (Peng, 2000a,b).. The KAP1co-repressor appears to function as a scaffold protein to assemble and coordinate multiple enzymes (histone de-acetylases, histone methyltransferases and heterochromatin proteins) which target and modify chromatin structure thus leading to a compacted, silent state (Lechner, 2000; Schultz, 2001 Schultz, 2002 , Ayyanathan, 2003). The post-translational modification of KAP1 by SUMO controls its ability to assemble the enzymatic apparatus in chromatin (Ivanov, 2007; Zeng, 2008). It is formally possible that some KRAB ZNF proteins may have additional functional domains that recruit coactivators in specific contexts, given that such bifunctionality is common for many classes of DNA binding transcription factors,. However, there is no experimental evidence for this yet. </p> <p>There also is good evidence that the KRAB ZNF-KAP1 complex proteins can have long range gene silencing functions, by nucleating chromatin complexes that inactivate transcription of large numbers of genes over large distances by assembling silent heterochromatin (Ayyanathan, 2003). Although KAP1 was originally identified as a mediator of specific gene transcription repression, subsequent studies have shown that KAP1 also is involved in the recruitment of homologues of the HP1 protein family (Ryan, 1999, Ayyanathan, 2003; Lechner, 2000). These nonhistone heterochromatin associated proteins were first shown to have an epigenetic gene silencing function in Drosophila and more recently in mammalian cells . These studies suggest that KRAB ZNF proteins and KAP1 may also be involved in large scale chromatin regulation and gene silencing, not just in gene specific transcriptional repression. Whether this is a general property of most or all KRAB ZNF proteins will require additional studies. </p> <p>Finally, several KRAB containing ZNFs in mammals also contain a conserved SCAN domain which, like the KRAB domain also functions as a protein protein interaction domain. (Edelstein, 2005, Peng, 2000a,b). The SCAN domain does not participate in KAP1 binding but rather functions to mediate homodimerization, or selective heterodimerization with other SCAN containing proteins. However, the biochemical and biological functions of the SCAN domain in KRAB-ZNF mediated repression are not known. </p> <p>Remaining Questions: The single most important unanswered question for KRAB-ZNFDs is to determine their biological functions. While the mechanism utilized by the KRAB ZNF / KAP1 protein complex to mediate gene specific transcription repression is well understood , much less known about the specific biological pathways they control. Preliminary evidence from recent whole genome analysis of the target genes for the KRAB- ZNF263 protein suggest that it can have both positive and negative effects on transcriptional regulation of its target genes (Frietze, 2010). Presumably, each KRAB-ZNF, via its array of zinc fingers can bind to specific DNA recognition sequences in target promoters. This, combined with highly tissue specific expression of each gene, makes the potential transcriptome controlled by the 423 KRAB-ZNFs extremely large.</p> Authored: Caudy, M, 2010-09-22 Edited: D'Eustachio, P, 2010-11-27 Pubmed10330177 Pubmed14519192 Pubmed16139965 Pubmed16606702 Pubmed18082607 Pubmed19887448 Pubmed20007773 Pubmed2023909 Pubmed8183939 Pubmed8769649 Pubmed9843507 Reactome Database ID Release 43975040 Reactome, http://www.reactome.org ReactomeREACT_27218 Reviewed: Rauscher, F, 2011-02-15 CD44 mRNA isoform 204 Reactome DB_ID: 428345 Reactome Database ID Release 43428345 Reactome, http://www.reactome.org ReactomeREACT_22599 CD44 mRNA isoform 205 Reactome DB_ID: 428290 Reactome Database ID Release 43428290 Reactome, http://www.reactome.org ReactomeREACT_22625 H19 noncoding RNA Reactome DB_ID: 428386 Reactome Database ID Release 43428386 Reactome, http://www.reactome.org ReactomeREACT_22936 RNA molecules bound by IGF2BP2 (IMP2/VICKZ2) Converted from EntitySet in Reactome Reactome DB_ID: 428328 Reactome Database ID Release 43428328 Reactome, http://www.reactome.org ReactomeREACT_23078 RNA molecules bound by IGF2BP3 (IMP3/VICKZ3) Converted from EntitySet in Reactome Reactome DB_ID: 428384 Reactome Database ID Release 43428384 Reactome, http://www.reactome.org ReactomeREACT_22455 Telomerase RNA Component (TERC) Reactome DB_ID: 163077 Reactome Database ID Release 43163077 Reactome, http://www.reactome.org ReactomeREACT_8394 NOTCH1 mRNA Reactome DB_ID: 1606559 Reactome Database ID Release 431606559 Reactome, http://www.reactome.org ReactomeREACT_119985 has a fragment starting at 1 and ending at 9371 NOTCH2 mRNA Reactome DB_ID: 1911477 Reactome Database ID Release 431911477 Reactome, http://www.reactome.org ReactomeREACT_119279 has a fragment starting at 1 and ending at 11389 NOTCH3 mRNA Reactome DB_ID: 1911478 Reactome Database ID Release 431911478 Reactome, http://www.reactome.org ReactomeREACT_120201 has a fragment starting at 1 and ending at 8070 NOTCH4 mRNA Reactome DB_ID: 1911475 Reactome Database ID Release 431911475 Reactome, http://www.reactome.org ReactomeREACT_119534 has a fragment starting at 1 and ending at 6745 Recognition of AAUAAA sequence by CPSF Authored: Wahle, E, 2003-06-05 08:30:31 Edited: Gillespie, ME, 0000-00-00 00:00:00 Poly(A) polymerase has no specificity for any particular RNA sequence, as well as a very low affinity for the RNA. Under physiological conditions, the activity of poly(A) polymerase depends on two auxiliary factors, both of which bind to specific RNA sequences and recruit the poly(A) polymerase by a direct contact. One of these proteins is the heterotetrameric CPSF, which binds the AAUAAA sequence and is also essential for 3' cleavage. Pubmed2408761 Reactome Database ID Release 4377589 Reactome, http://www.reactome.org ReactomeREACT_1652 Recruitment of CstF to the CPSF Bound Pre-mRNA Authored: Wahle, E, 2003-06-05 08:30:31 Edited: Gillespie, ME, 0000-00-00 00:00:00 Endonucleolytic cleavage separates the pre-mRNA into an upstream fragment destined to become the mature mRNA and a downstream fragment that is rapidly degraded. Polyadenylation and cleavage occur concurrently, with complexes co-assembling, cleavage depends on two signals in the RNA, a highly conserved hexanucleotide, AAUAAA, 10 to 30 nucleotides upstream of the cleavage site, and a poorly conserved GU- or U-rich downstream element. Additional sequences, often upstream of AAUAAA, can enhance the efficiency of the reaction. Cleavage occurs most often after a CA dinucleotide. A single gene can have more than one 3' processing site.<p> Cleavage is preceded by the assembly of a large processing complex, the composition of which is poorly defined. ATP, but not its hydrolysis, is required for assembly. Cleavage depends on a number of protein factor. CPSF, a heterotetramer, binds specifically to the AAUAAA sequence. The heterotrimer CstF binds the GU- or U-rich downstream element. Pubmed10371034 Reactome Database ID Release 4377590 Reactome, http://www.reactome.org ReactomeREACT_336 Cleavage of Intronless Pre-mRNA at 3'-end Authored: Wahle, E, 2003-06-05 08:30:31 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed10371034 Reactome Database ID Release 4377592 Reactome, http://www.reactome.org ReactomeREACT_460 The polypeptide catalyzing the hydrolysis of the phosphodiester bond remains to be identified. Cleavage produces a 3'-OH on the upstream fragment and a 5'-phosphate on the downstream fragment. At some unknown point after cleavage, the downstream fragment, CstF, CF I and CF II are thought to be released, whereas CPSF and poly(A) polymerase remain to carry out polyadenylation. rDll1 binds NOTCH1 in cis Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Mammalian cell lines were constructed that allow for independent modulation of the levels of cis- and trans-Delta and quantitative monitoring of the transcriptional response of a Noth reporter gene (Citrine fluorescent protein cDNA fused to a Notch responsive promoter). Cell lines stably expressed recombinant human NOTCH1 and contained a DNA encoding a doxycycline-inducible recombinant rat Dll1 (cis-Dll1). Cell lines were grown on plates containing different concentrations of adsorbed recombinant Dll1 (trans-Dll1). In the absence of cis-Dll1 (no doxycycline added), NOTCH1 activation is proportional to the concentration of trans-Delta. Induction of cis-Dll1 expression blocks NOTCH1 activation, and the response to cis-Dll1 is sharp and switch-like. Pubmed20418862 Reactome Database ID Release 432076711 Reactome, http://www.reactome.org ReactomeREACT_118597 Reviewed: Haw, R, 2012-02-06 Binding of Cleavage factors and Poly(A)Polymerase to the CstF:CPSF:Pre-mRNA Complex Authored: Wahle, E, 2003-06-05 08:30:31 CF I, which appears to be composed of two subunits, one of several related larger polypeptides and a common smaller one, also binds RNA, but with unknown specificity. RNA recognition by these proteins is cooperative. Cleavage also requires CF II, composed of at least two subunits, and poly(A) polymerase, the enzyme synthesizing the poly(A) tail in the second step of the reaction. Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed10371034 Reactome Database ID Release 4377591 Reactome, http://www.reactome.org ReactomeREACT_1724 Cleavage and polyadenylation of Intronless Pre-mRNA Authored: Wahle, E, 2003-06-05 08:30:31 Edited: Gillespie, ME, 0000-00-00 00:00:00 Pubmed10371034 Reactome Database ID Release 4377593 Reactome, http://www.reactome.org ReactomeREACT_45 The nuclear poly(A) binding protein (PABPN1), which binds the growing poly(A) tails once it has reached a length of about ten nucleotides. Stimulation of poly(A) polymerase by both CPSF and PABPN1 is synergistic and results in processive elongation of the RNA (the polymerase adds AMP residues without dissociating from the RNA). The processive reaction is terminated when the tail has reached a length of about 250 nucleotides. pAMPK inactivates ACC2 inhibiting malonyl-CoA synthesis Authored: Gopinathrao, G, 2007-07-29 21:03:03 Pubmed15060529 Reactome Database ID Release 43200423 Reactome, http://www.reactome.org ReactomeREACT_11110 Reviewed: D'Eustachio, P, 2007-07-31 18:50:15 The phosphorylated AMPK inactivates ACC2 in muscle cells by phophorylation. This results in decreased levels of malonyl CoA. Conversion of palmitic acid to palmitoyl-CoA Authored: Gopinathrao, G, 2007-07-29 21:03:03 EC Number: 6.2.1.3 Membrane-associated acyl-CoA synthetase long-chain family member 1 (ACSL1) catalyzes the reaction of palmitate, CoASH, and ATP to form palmitoyl-CoA, AMP, pyrophosphate, and water. Human ACSL1 has not been characterized in detail, but available data suggest that it is associated specifically with the membrane of the endoplasmic reticulum and that it can act on oleic acid as well as on palmitic acid (Malhotra et al. 1999). Pubmed10548543 Reactome Database ID Release 43201035 Reactome, http://www.reactome.org ReactomeREACT_11137 Reviewed: D'Eustachio, P, 2007-07-31 18:50:15 palmitate + CoASH + ATP => palmitoyl-CoA + AMP + pyrophosphate + H2O [ACSL1] Formation of Malonyl-CoA from Acetyl-CoA (muscle) Authored: Gopinathrao, G, 2007-07-29 21:03:03 Cytosolic acetyl-CoA carboxylase 1 (ACACA) catalyzes the reaction of bicarbonate, ATP, and acetyl-CoA to form malonyl-CoA, ADP, and orthophosphate. The reaction is positively regulated by citrate. The human ACACA cDNA has been cloned (Abu-Elheiga et al. 1995) and the biochemical properties of the human enzyme have recently been described (Cheng et al. 2007; Locke et al. 2008). Four ACACA isoforms generated by alternative splicing have been identified as mRNAs - the protein product of the first has been characterized experimentally. EC Number: 6.4.1.2 Pubmed10677481 Pubmed17223360 Pubmed9099716 Reactome Database ID Release 4375851 Reactome, http://www.reactome.org ReactomeREACT_590 Reviewed: D'Eustachio, P, 2007-07-31 18:50:15 Activation of cytosolic AMPK by phosphorylation Authored: Gopinathrao, G, 2007-07-29 21:03:03 EC Number: 2.7.11 Edited: Jassal, B, 2009-11-20 Pubmed11018120 Pubmed11797013 Pubmed14511394 Pubmed14614828 Pubmed14985505 Pubmed15579580 Pubmed16054041 Pubmed8779952 Reactome Database ID Release 43200421 Reactome, http://www.reactome.org ReactomeREACT_11183 Reviewed: Zheng, B, 2009-10-20 The cytosolic AMPK complex is activated by phosphorylation. LKB1 phosphorylates AMPK heterotrimer on Thr174 of the alpha 1 subunit (or Thr172 on alpha 2 subunit) leading to activation of AMPK (if cellular AMP/ATP ratio is high) (Hawley SA et al, 2003; Woods A et al, 2003; Shaw RJ et al, 2004). Signals leading to this phosphorylation event can be mediated by exercise, leptin and adiponectin, the hypothalamic-sympathetic nervous system (SNS), and alpha adrenergic receptors, as demonstrated in studies of rat and human skeletal muscle (Minoksohi et al, 2002, Kahn et al, 2005). The details of AMPK activation in response to these stimuli will be annotated in the future. Nuclear AMPK may well be a substrate for LKB1 but, to date, there is no clear evidence for this. Light-sensing opsins Converted from EntitySet in Reactome Reactome DB_ID: 419811 Reactome Database ID Release 43419811 Reactome, http://www.reactome.org ReactomeREACT_18720 Niacin receptors Converted from EntitySet in Reactome Reactome DB_ID: 444698 Reactome Database ID Release 43444698 Reactome, http://www.reactome.org ReactomeREACT_21774 pH sensing receptors Converted from EntitySet in Reactome Reactome DB_ID: 444736 Reactome Database ID Release 43444736 Reactome, http://www.reactome.org ReactomeREACT_21755 ACTIVATION GENE ONTOLOGYGO:0004550 Reactome Database ID Release 43110637 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004550 Reactome Database ID Release 43110637 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004550 Reactome Database ID Release 43482613 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004550 Reactome Database ID Release 43482613 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004362 Reactome Database ID Release 4371681 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004791 Reactome Database ID Release 4373533 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004748 Reactome Database ID Release 43111796 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0015038 Reactome Database ID Release 43499937 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036175 Reactome Database ID Release 4373641 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036175 Reactome Database ID Release 4373641 Reactome, http://www.reactome.org CGRP ligands Converted from EntitySet in Reactome Reactome DB_ID: 419795 Reactome Database ID Release 43419795 Reactome, http://www.reactome.org ReactomeREACT_18962 ACTIVATION GENE ONTOLOGYGO:0044715 Reactome Database ID Release 432532781 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0044714 Reactome Database ID Release 432532794 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0044713 Reactome Database ID Release 432395832 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035539 Reactome Database ID Release 432395845 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035539 Reactome Database ID Release 432395882 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0017110 Reactome Database ID Release 432395875 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0044715 Reactome Database ID Release 432395887 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036220 Reactome Database ID Release 432509830 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0035870 Reactome Database ID Release 432509845 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0036222 Reactome Database ID Release 432509849 Reactome, http://www.reactome.org ADM/ADM2 Converted from EntitySet in Reactome Reactome DB_ID: 420061 Reactome Database ID Release 43420061 Reactome, http://www.reactome.org ReactomeREACT_18746 CRHR Converted from EntitySet in Reactome Reactome DB_ID: 420140 Reactome Database ID Release 43420140 Reactome, http://www.reactome.org ReactomeREACT_18750 Formation of stem-loop structure in ApoB mRNA Authored: Gopinathrao, G, 2003-12-05 16:34:53 It is predicted that the target RNA could form secondary structures including stem-loop confirmation prior to the formation of editosome.<BR> Reactome Database ID Release 4377607 Reactome, http://www.reactome.org ReactomeREACT_208 Binding of ACF to stem-looped RNA ACF protein is cytosolic in origin and is translocated to nucleus where it binds to the target RNA. The order of events in the formation of editosomes, namely, binding of ACF and APOBEC-1 are not will elucidated in human cells.<BR> Authored: Gopinathrao, G, 2003-12-05 16:34:53 Reactome Database ID Release 4377608 Reactome, http://www.reactome.org ReactomeREACT_1850 PathwayStep5029 Activation of GT At the beginning of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex' is present. At the end of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex with activated GT' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4377068 Reactome, http://www.reactome.org ReactomeREACT_893 PathwayStep5028 RNA Polymerase II CTD (phosphorylated) binds to CE At the beginning of this reaction, 1 molecule of 'mRNA capping enzyme', and 1 molecule of 'Pol II transcription complex with (ser5) phosphorylated CTD containing extruded transcript to +30' are present. At the end of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4377069 Reactome, http://www.reactome.org ReactomeREACT_2233 SPT5 subunit of Pol II binds the RNA triphosphatase (RTP) Authored: Buratowski, S, 2003-10-15 15:18:41 Reactome Database ID Release 4377073 Reactome, http://www.reactome.org ReactomeREACT_423 The capping enzyme interacts with the Spt5 subunit of transcription elongation factor DSIF. This interaction may couple the capping reaction with promoter escape or elongation, thereby acting as a “checkpoint” to assure that capping has occurred before the polymerase proceeds to make the rest of the transcript. PathwayStep5033 PathwayStep5034 PathwayStep5031 PathwayStep5032 Binding of ADAR1 homodimer to dsRNA duplex At the beginning of this reaction, 1 molecule of 'dsRNA duplex', and 1 molecule of 'ADAR1 homodimer ' are present. At the end of this reaction, 1 molecule of 'Editosome (ADAR1) complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375090 Reactome, http://www.reactome.org ReactomeREACT_970 PathwayStep5037 Formation of ADAR1 homodimer At the beginning of this reaction, 2 molecules of 'ADAR1 protein' is present. At the end of this reaction, 1 molecule of 'ADAR1 homodimer ' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43111237 Reactome, http://www.reactome.org ReactomeREACT_186 has a Stoichiometric coefficient of 2 PathwayStep5038 Formation of dsRNA structure by looping Authored: Gopinathrao, G, 2003-12-05 16:34:53 Reactome Database ID Release 4377612 Reactome, http://www.reactome.org ReactomeREACT_1276 Site-specific A to I conversion requires dsRNA structures present around the editing site. These structures can be formed by exonic sequences and neighboring intronic sequences. An editing-site complementary sequence (ECS) has been identified in mice. Although minimal requirements for A to I editing have been identified, detailed mechanisms describing the individual steps are not yet well studied in humans.<BR> PathwayStep5035 C4 deamination of cytidine Authored: Gopinathrao, G, 2003-12-05 16:34:53 EC Number: 3.5.4.5 Hydrolytic deamination of cytidine leads to uridine. Ammonia is presumed to be released during this reaction.<BR> Pubmed11718896 Pubmed8208612 Reactome Database ID Release 4383677 Reactome, http://www.reactome.org ReactomeREACT_869 PathwayStep5036 Binding of APOBEC-1 to form editosome APOBEC-1 binds to ACF:stem-looped mRNA complex forming the editosome.<BR> Authored: Gopinathrao, G, 2003-12-05 16:34:53 Reactome Database ID Release 4377609 Reactome, http://www.reactome.org ReactomeREACT_99 PathwayStep5030 PathwayStep5018 PathwayStep5017 PathwayStep5019 PathwayStep5020 PathwayStep5021 PathwayStep5022 PathwayStep5023 PathwayStep5024 PathwayStep5025 PathwayStep5026 PathwayStep5027 Cannabinoid receptors Converted from EntitySet in Reactome Reactome DB_ID: 419398 Reactome Database ID Release 43419398 Reactome, http://www.reactome.org ReactomeREACT_18496 PathwayStep5009 PathwayStep5008 PathwayStep5007 PathwayStep5006 PathwayStep5015 PathwayStep5016 PathwayStep5013 PathwayStep5014 PathwayStep5011 PathwayStep5012 PathwayStep5010 A1/A3 receptors Converted from EntitySet in Reactome Reactome DB_ID: 418922 Reactome Database ID Release 43418922 Reactome, http://www.reactome.org ReactomeREACT_18478 A2a/A2b receptors Converted from EntitySet in Reactome Reactome DB_ID: 418907 Reactome Database ID Release 43418907 Reactome, http://www.reactome.org ReactomeREACT_18766 S1P-binding EDG receptors Converted from EntitySet in Reactome Reactome DB_ID: 419401 Reactome Database ID Release 43419401 Reactome, http://www.reactome.org ReactomeREACT_18823 PathwayStep5002 PathwayStep5003 PathwayStep5004 PathwayStep5005 PathwayStep5000 PathwayStep5001 Melatonin receptors Converted from EntitySet in Reactome Reactome DB_ID: 419423 Reactome Database ID Release 43419423 Reactome, http://www.reactome.org ReactomeREACT_18452 LPA-binding EDG receptors Converted from EntitySet in Reactome Reactome DB_ID: 419369 Reactome Database ID Release 43419369 Reactome, http://www.reactome.org ReactomeREACT_18675 Recruitment of U7 snRNP:ZFP100 complex to the Histone Pre-mRNA Authored: Marzluff, WF, 2003-08-22 00:29:39 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008334 Pubmed3022153 Reactome Database ID Release 43111438 Reactome, http://www.reactome.org ReactomeREACT_1591 The U7 snRNP. This particle contains the U7 snRNA, the smallest of the snRNAs which varies from 57-70 nts long depending on the species. The 5’ end of U7 snRNA binds to a sequence 3’ of the stemloop, termed the histone downstream element (HDE). There are a number of proteins found in the U7 snRNP. There are 7 Sm proteins, as are present in the spliceosomal snRNP. Five of these proteins are the same as ones found in the spliceosomal snRNPs and there are 2, Lsm10 and Lsm11 that are unique to U7 snRNP. Cleavage of the 3'-end of Replication Dependent Histone Pre-mRNA Authored: Marzluff, WF, 2003-08-22 00:29:39 Edited: Gillespie, ME, 0000-00-00 00:00:00 Processing is initiated once the SLBP (bound to the stem loop) and the U7 snRNP (bound to the HDE) are both loaded onto the pre-mRNA. The pre-mRNA HDE makes base-pairing contacts with the 5′ end of U7 snRNA. Binding of the U7 snRNP to the pre-mRNA is stabilized by interactions between a U7 snRNP protein, hZFP100 and SLBP. It should be noted that there must be other trans-acting factors, including the factor that catalyzes the cleavage reaction, which have yet to be defined. The cleavage occurs in the presence of EDTA as does the cleavage reaction in polyadenylation, it is likely that this reaction is catalyzed by a protein. There may well be additional proteins associated with the U7 snRNP, and since in some conditions in vitro processing occurs in the absence of SLBP, it is possible that all the other factors required for processing are associated with the active form of the U7 snRNP. Pubmed8479907 Reactome Database ID Release 4377586 Reactome, http://www.reactome.org ReactomeREACT_888 Recruitment of U7 snRNP:ZFP100 complex to the SLBP Bound Pre-mRNA Authored: Gillespie, ME, 2004-03-13 15:04:49 GENE ONTOLOGYGO:0008334 Pubmed3022153 Reactome Database ID Release 4377585 Reactome, http://www.reactome.org ReactomeREACT_967 The U7 snRNP. This particle contains the U7 snRNA, the smallest of the snRNAs which varies from 57-70 nts long depending on the species. The 5’ end of U7 snRNA binds to a sequence 3’ of the stemloop, termed the histone downstream element (HDE). There are a number of proteins found in the U7 snRNP. There are 7 Sm proteins, as are present in the spliceosomal snRNP. Five of these proteins are the same as ones found in the spliceosomal snRNPs and there are 2, Lsm10 and Lsm11 that are unique to U7 snRNP. A third protein joins the U7 snRNP, ZFP100, a large zinc finger protein. ZFP100 interacts with SLBP bound to the histone pre-mRNA and with Lsm11 and likely plays a critical role in recruiting U7 snRNP to the histone pre-mRNA. Binding of SLBP to Replication-Dependent Histone Pre-mRNA Authored: Marzluff, WF, 2003-08-22 00:29:39 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008334 Pubmed10207079 Pubmed8957003 Pubmed9049306 Reactome Database ID Release 4377584 Reactome, http://www.reactome.org ReactomeREACT_706 The 32 kDa stem-loop binding protein (SLBP), also termed hairpin binding protein (HBP) is likely the first protein that binds to the histone pre-mRNA as it is being transcribed. Release of the Mature intronless derived mRNA, TAP, and Aly/Ref from the NPC Authored: Gillespie, ME, 2005-01-26 20:24:54 GENE ONTOLOGYGO:0006405 Reactome Database ID Release 43158447 Reactome, http://www.reactome.org ReactomeREACT_1334 The cytoplasmic 3' polyadenylated, capped intronless mRNA and TAP are released from the NPC into the cytosol. Cytosolic TAP will be recycled to the nucleous, while the 3' polyadenylated, capped intronless mRNA is bound by eIF4E and destined for translation. Transport of the Mature intronless transcript derived mRNA:TAP:Aly/Ref Complex through the NPC Authored: Gillespie, ME, 2005-01-26 20:24:54 GENE ONTOLOGYGO:0006405 Reactome Database ID Release 43158441 Reactome, http://www.reactome.org ReactomeREACT_1004 The nucleoplasmic 3' polyadenylated, capped intronless mRNA and TAP are transported through the NPC to the cyotplasmic side of the pore. Docking of the Mature intronless derived transcript derived mRNA, TAP and Aly/Ref at the NPC Authored: Gillespie, ME, 2005-01-26 20:24:54 GENE ONTOLOGYGO:0006406 Reactome Database ID Release 4377594 Reactome, http://www.reactome.org ReactomeREACT_1897 The polyadenylated, capped transcript and TAP dock at the nucleoplasmic side of the NPC. The Cap Binding Complex (CBC) and CPSF complexes are released back into the nucleoplasm. Release of the SLBP independent Histone mRNA from the NPC At some point eIF4E binds the mature mRNA. While TAP and Aly/Ref are released and will be reycled back to the nucleoplasm. Authored: Gillespie, ME, 2005-01-27 17:31:58 GENE ONTOLOGYGO:0006406 Reactome Database ID Release 43158484 Reactome, http://www.reactome.org ReactomeREACT_1356 Transport of the Mature Intronless Transcript Derived Histone mRNA:TAP:Aly/Ref Complex through the NPC Authored: Gillespie, ME, 2005-01-27 17:31:58 GENE ONTOLOGYGO:0006405 Reactome Database ID Release 43158481 Reactome, http://www.reactome.org ReactomeREACT_904 The mature SLBP independent intronless histone mRNA is transported through the nucler pore to the cytoplasmic side. PathwayStep5070 PathwayStep5074 PathwayStep5073 PathwayStep5072 PathwayStep5071 PathwayStep5078 PathwayStep5077 PathwayStep5076 PathwayStep5075 Cleavage of the 3'-end of the Histone Pre-mRNA Authored: Marzluff, WF, 2003-08-22 00:29:39 Edited: Gillespie, ME, 0000-00-00 00:00:00 Processing is initiated once the U7 snRNP is loaded onto the pre-mRNA. The pre-mRNA HDE makes base-pairing contacts with the 5′ end of U7 snRNA. Binding of the U7 snRNP to the pre-mRNA is stabilized by interactions between a U7 snRNP protein, hZFP100 and other trans-acting factors, including the factor that catalyzes the cleavage reaction, which have yet to be defined. The cleavage occurs in the presence of EDTA as does the cleavage reaction in polyadenylation, it is likely that this reaction is catalyzed by a protein. There may well be additional proteins associated with the U7 snRNP, since the in vitro processing occurs in the absence of SLBP, it is possible that all the other factors required for processing are associated with the active form of the U7 snRNP. Pubmed8479907 Reactome Database ID Release 43111437 Reactome, http://www.reactome.org ReactomeREACT_1222 PathwayStep5079 Release from the NPC and Disassembly of the mRNP At the beginning of this reaction, 1 molecule of 'eIF4E', and 1 molecule of 'Export Receptor bound mature mRNA Complex' are present. At the end of this reaction, 1 molecule of 'THOC4(Aly/Ref)', 1 molecule of 'Mature mRNP Complex', 1 molecule of 'SRm160', and 1 molecule of 'TAP' are present.<br><br> This reaction takes place in the 'cytoplasm'.<br> GENE ONTOLOGYGO:0006406 Reactome Database ID Release 4375098 Reactome, http://www.reactome.org ReactomeREACT_1228 Transport of the export-competent complex through the NPC GENE ONTOLOGYGO:0006406 In this reaction, 1 molecule of 'Export Receptor bound mature mRNA Complex' is translocated from nucleoplasm to cytosol.<br><br>This reaction takes place in the 'nuclear envelope'.<br> Reactome Database ID Release 4375097 Reactome, http://www.reactome.org ReactomeREACT_2104 Transport of the Mature IntronlessTranscript Derived Histone mRNA:SLBP:TAP:Aly/Ref complex through the NPC Authored: Gillespie, ME, 2005-03-13 17:31:37 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006406 Once the transport complex is fully assembled the mature mRNA can be translocated from the nucleoplasm to the cytoplasm. The assembled complex starts at the nucleoplasmic basket, travels through the pore, and ends it journey at the cytoplasmic face of the nuclear pore complex. Reactome Database ID Release 43159046 Reactome, http://www.reactome.org ReactomeREACT_1799 Docking of Mature Replication Dependent Histone mRNA with the NPC Authored: Marzluff, WF, 2003-08-22 00:29:39 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006406 Histone mRNAs are exported by a mechanism that requires TAP, the key factor requires for transport of polyadenylated mRNAs. How TAP is recruited to the histone mRNAs is not known, but it is clear that transport can occur in the absence of either the stemloop or of SLBP. The stemloop and SLBP enhance the rate of transport of histone mRNAs in Xenopus oocytes, but are not essential for transport Pubmed2017161 Reactome Database ID Release 4377587 Reactome, http://www.reactome.org ReactomeREACT_1604 mRNA polyadenylation EC Number: 2.7.7.19 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed10357856 Pubmed2408761 Reactome Database ID Release 4372185 Reactome, http://www.reactome.org ReactomeREACT_1162 The upstream fragment generated by 3' cleavage of the pre-mRNA receives a poly(A) tail of approximately 250 AMP residues in a reaction depending on the AAUAAA sequence 10 to 30 nucleotides upstream of the 3' end. Polyadenylation is carried out by three proteins: Poly(A) polymerase carries the catalytic activity. The enzyme has no specificity for any particular RNA sequence, and it also has a very low affinity for the RNA.<p>Under physiological conditions, the activity of poly(A) polymerase thus depends on two auxiliary factors, both of which bind to specific RNA sequences and recruit the enzyme by a direct contact. One of these proteins is the heterotetrameric CPSF, which binds the AAUAAA sequence and is also essential for 3' cleavage. The second is the nuclear poly(A) binding protein (PABPN1), which binds the growing poly(A) tails once this has reached a length of about ten nucleotides. Stimulation of poly(A) polymerase by both proteins is synergistic and results in processive elongation of the RNA, i.e. the polymerase adds AMP residues without dissociating from the RNA. The processive reaction is terminated when the tail has reached a length of about 250 nucleotides. Cleavage of mRNA at the 3'-end Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Endonucleolytic cleavage separates the pre-mRNA into an upstream fragment destined to become the mature mRNA, and a downstream fragment that is rapidly degraded. Cleavage depends on two signals in the RNA, a highly conserved hexanucleotide, AAUAAA, 10 to 30 nucleotides upstream of the cleavage site, and a poorly conserved GU- or U-rich downstream element. Additional sequences, often upstream of AAUAAA, can enhance the efficiency of the reaction. Cleavage occurs most often after a CA dinucleotide. A single gene can have more than one 3' processing site.<p>Cleavage is preceded by the assembly of a large processing complex, the composition of which is poorly defined. ATP, but not its hydrolysis, is required for assembly. Cleavage at the 3'-end of mRNAs depends on a number of protein factors. CPSF, a heterotetramer, binds specifically to the AAUAAA sequence. The heterotrimer CstF binds the downstream element. CF I, which appears to be composed of two subunits, one of several related larger polypeptides and a common smaller one, also binds RNA, but with unknown specificity. RNA recognition by these proteins is cooperative. Cleavage also requires CF II, composed of at least two subunits, and poly(A) polymerase, the enzyme synthesizing the poly(A) tail in the second step of the reaction. The polypeptide catalyzing the hydrolysis of the phosphodiester bond remains to be identified.<p>Cleavage produces a 3'-OH on the upstream fragment and a 5'-phosphate on the downstream fragment. At some unknown point after cleavage, the downstream RNA fragment, CstF, CF I and CF II are thought to be released, whereas CPSF and poly(A) polymerase remain to carry out polyadenylation. Pubmed10357856 Pubmed10371034 Reactome Database ID Release 4372180 Reactome, http://www.reactome.org ReactomeREACT_1914 Docking of the TAP:EJC Complex with the NPC At the beginning of this reaction, 1 molecule of 'TAP:3'-polyadenylated, capped mRNA complex' is present. At the end of this reaction, 1 molecule of 'SRp55', 1 molecule of 'U2AF 65 kDa subunit', 1 molecule of 'SR9 / SRp30', 1 molecule of 'hTra2', 1 molecule of 'hPrp16', 1 molecule of 'SR 11/ p54', 1 molecule of 'hPrp22', 1 molecule of 'SRp40', 1 molecule of 'hPrp17', 1 molecule of 'SF2/ASF/SFRS1', 1 molecule of 'hSLU7', 1 molecule of 'Export Receptor bound mature mRNA Complex', 1 molecule of 'U2AF 35 kDa subunit', 1 molecule of 'SR2 / SC35', 1 molecule of 'hPrp43', 1 molecule of 'SRp20', 1 molecule of 'SR7/ 9G8 protein', 1 molecule of 'hPrp18', and 1 molecule of 'SR4 / SRp75' are present.<br><br> This reaction takes place in the 'nucleoplasm'.<br> GENE ONTOLOGYGO:0006406 Reactome Database ID Release 4375096 Reactome, http://www.reactome.org ReactomeREACT_138 Recruitment of TAP to the EJC Aly/Ref recruits TAP to the Exon Junction Complex. This makes the mRNP complex ready for export to the cytoplasm. Authored: Joshi-Tope, G, 2005-02-17 16:25:28 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006405 Reactome Database ID Release 43159101 Reactome, http://www.reactome.org ReactomeREACT_53 Histone H3 dimethylated at lysine-9 Converted from EntitySet in Reactome Reactome DB_ID: 427406 Reactome Database ID Release 43427406 Reactome, http://www.reactome.org ReactomeREACT_20454 PathwayStep5061 PathwayStep5060 PathwayStep5063 PathwayStep5062 PathwayStep5065 PathwayStep5064 PathwayStep5067 PathwayStep5066 PathwayStep5069 Release of the Mature intronless transcript derived Histone mRNA:SLBP:eIF4E Complex At some point eIF4E binds the mature mRNA. While TAP and Aly/Ref are released and will be reycled back to the nucleoplasm. Authored: Gillespie, ME, 2005-01-27 17:31:58 GENE ONTOLOGYGO:0006406 Reactome Database ID Release 43159050 Reactome, http://www.reactome.org ReactomeREACT_1044 PathwayStep5068 Docking of Mature Histone mRNA complex:TAP at the NPC Authored: Marzluff, WF, 2003-08-22 00:29:39 Edited: Gillespie, ME, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006406 Histone mRNAs are exported by a mechanism that requires TAP, the key factor requires for transport of polyadenylated mRNAs. How TAP is recruited to the histone mRNAs is not known, but it is clear that transport can occur in the absence of either the stemloop or of SLBP. The mature transcript docks at the NPC, in the course of transport CBC will be lost from the mRNA cap, and remain in the nucleous. Pubmed2017161 Reactome Database ID Release 43111439 Reactome, http://www.reactome.org ReactomeREACT_696 Lariat Formation and 5'-Splice Site Cleavage Authored: Krainer, AR, 2003-06-05 08:30:23 In the first catalytic step of mRNA splicing, the 2' OH group of the bulged A at the branch site performs a nucleophilic attack on the 5' splice site phosphodiester bond, resulting in cleavage of the bond between the 5' exon and the 5' end of the intron, and formation of a new bond between the 5' end of the intron and the branch site A. This results in a lariat-shaped intermediate, with the intron still attached to the 3' exon. The branch site A has a 2'-5' phosphodiester bond with the G at the beginning of the intron, in addition to the usual 5'-3' and 3'-5'phosphodiester bonds. Pubmed6088074 Pubmed6206566 Reactome Database ID Release 4372143 Reactome, http://www.reactome.org ReactomeREACT_1935 Formation of the active Spliceosomal C complex Pubmed11991638 Pubmed12176931 Reactome Database ID Release 4372139 Reactome, http://www.reactome.org ReactomeREACT_1554 The active C complex is formed due to a conformational change in the intermediate C complex. After formation of the active C complex, the splicing reactions occur very rapidly. Formation of an intermediate Spliceosomal C complex Authored: Krainer, AR, 2003-06-05 08:30:23 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed11991638 Pubmed12176931 Reactome Database ID Release 4372130 Reactome, http://www.reactome.org ReactomeREACT_625 The spliceosomal C complex is a very short-lived intermediate; the splicing intermediates are rapidly converted to splicing products. Also, the spliced products are released very rapidly, and no complex containing both the splicing products has been isolated. Conversion of the spliceosomal B complex to the spliceosomal C complex requires ATP. The extensive base-pairing between the U4 and U6 snRNAs is disrupted during the formation of the C complex, which is thought to require helicase-type activity associated with the DEAD box factors. Formation of AT-AC B Complex Authored: Joshi-Tope, G, 2003-10-27 22:47:00 Reactome Database ID Release 4375081 Reactome, http://www.reactome.org ReactomeREACT_1253 The U4atac/U6atac enters the spliceosome and U6atac snRNA forms base pairing interactions with the 5' ss and also forms base pairing interactions with U12 and U4atac is partially displaced. U5 snRNP, the only snRNP common to both the major and minor splicing pathways, also joins the spliceosome to form the B complex and interacts with nucleotides within the 3' end of the exon flanking the 5' ss. Formation of AT-AC A complex Authored: Joshi-Tope, G, 2003-10-27 22:47:00 Reactome Database ID Release 4375080 Reactome, http://www.reactome.org ReactomeREACT_864 U12-type AT-AC introns are distinguished from the major U2-type introns by the consensus sequences of their highly conserved splicing signals. U12 introns have the 5' ss consensus sequence (G/A)TATCCTTT, the branchpoint sequence TTTCCTTAACT and the 3' ss (C/T)AG. Initial recognition of AT-AC introns involves interaction of U12 snRNP with the branch-point sequence and U11 with the 5' ss. Unlike the major splicing pathway, U11 and U12 are in a complex and interact with the pre-mRNA simultaneously, binding in an ATP-dependent manner as a di-snRNP complex and likely bridging the 5' ss and 3' ss region.<p>Twenty proteins have been identified in the U11/U12 di-snRNP complex including the snRNP Sm proteins B’, B, D3, D2, D1, E, F, and G which are identical to the major splicing pathway Sm proteins. A U2 snRNP core protein complex, SF3b is also found in the U11/U12 di-snRNP, including p14, a protein that interacts with the branchpoint adenosine.<p>SR proteins are required for formation of A complex in AT-AC splicing. The same SR proteins involved in splicing of the major introns are also active in splicing of AT-AC introns, though, as in the major pathway, there is substrate specificity. Cleavage at the 3'-Splice Site and Exon Ligation Reactome Database ID Release 4372160 Reactome, http://www.reactome.org ReactomeREACT_1331 The second step of the splicing reaction results in cleavage of the transcript at the 3'splice site, and results in ligation of the two exons and excision of the intron. Formation of Exon Junction Complex At the beginning of this reaction, 1 molecule of 'Magoh-Y14 complex', and 1 molecule of 'Spliceosomal active C complex with lariat containing, 5'-end cleaved pre-mRNP:CBC complex' are present. At the end of this reaction, 1 molecule of 'Exon Junction Complex' is present.<br><br> This reaction takes place in the 'nucleoplasm'.<br> Pubmed11118221 Pubmed11532962 Pubmed12414731 Reactome Database ID Release 43156661 Reactome, http://www.reactome.org ReactomeREACT_774 RPC7/RPC7-like Converted from EntitySet in Reactome Reactome DB_ID: 1964432 Reactome Database ID Release 431964432 Reactome, http://www.reactome.org ReactomeREACT_117732 PathwayStep5052 PathwayStep5051 PathwayStep5050 ATAC spliceosome mediated 3' splice site cleavage, exon ligation At the beginning of this reaction, 1 molecule of 'ATAC C Complex with lariat containing 5'-end cleaved mRNA' is present. At the end of this reaction, 1 molecule of 'U6 ATAC snRNP', 1 molecule of 'post exon ligation complex', 1 molecule of 'U12 snRNP', 1 molecule of 'U11 snRNP', and 1 molecule of 'U5 snRNP' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375083 Reactome, http://www.reactome.org ReactomeREACT_1494 PathwayStep5059 PathwayStep5058 Formation of AT-AC C complex At the beginning of this reaction, 1 molecule of 'ATAC B Complex' is present. At the end of this reaction, 1 molecule of 'U4 ATAC snRNP', and 1 molecule of 'ATAC C Complex' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375079 Reactome, http://www.reactome.org ReactomeREACT_1615 PathwayStep5057 ATAC spliceosome mediated Lariat formation,5' splice site cleavage At the beginning of this reaction, 1 molecule of 'ATAC C Complex' is present. At the end of this reaction, 1 molecule of 'ATAC C Complex with lariat containing 5'-end cleaved mRNA' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375082 Reactome, http://www.reactome.org ReactomeREACT_2241 PathwayStep5056 PathwayStep5055 PathwayStep5054 PathwayStep5053 Binding of ADAR2 homodimer to dsRNA duplex At the beginning of this reaction, 1 molecule of 'dsRNA duplex', and 1 molecule of 'ADAR2 homodimer' are present. At the end of this reaction, 1 molecule of 'Editosome (ADAR2) complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4377613 Reactome, http://www.reactome.org ReactomeREACT_621 Formation of ADAR2 homodimer At the beginning of this reaction, 2 molecules of 'ADAR2 protein' is present. At the end of this reaction, 1 molecule of 'ADAR2 homodimer' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43111238 Reactome, http://www.reactome.org ReactomeREACT_990 has a Stoichiometric coefficient of 2 PathwayStep5039 Deamination at C6 position of adenosine in Editosome (ADAR2) At the beginning of this reaction, 1 molecule of 'H2O', and 1 molecule of 'Editosome (ADAR2) complex' are present. At the end of this reaction, 1 molecule of 'NH3', and 1 molecule of 'A to I edited RNA:Editosome (ADAR2) complex' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'double-stranded RNA adenosine deaminase activity' of 'ADAR2 homodimer'.<br> Reactome Database ID Release 4377615 Reactome, http://www.reactome.org ReactomeREACT_365 Deamination at C6 position of adenosine in Editosome (ADAR1) At the beginning of this reaction, 1 molecule of 'Editosome (ADAR1) complex', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of 'A to I edited RNA:Editosome (ADAR1) complex', and 1 molecule of 'NH3' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'double-stranded RNA adenosine deaminase activity' of 'ADAR1 homodimer '.<br> Reactome Database ID Release 4377614 Reactome, http://www.reactome.org ReactomeREACT_1105 Formation of pre-mRNPs After the nascent pre-mRNA undergoes the initial capping and methylation reactions, it gets associated with numerous factors, including the various heterogeneous nuclear ribonucleoproteins (hnRNPS), the nuclear Cap-Binding Complex, and many splicing factors that make the pre-mRNA a substrate for splicing, 3'-end processing, and in some cases editing. Reactome Database ID Release 4372103 Reactome, http://www.reactome.org ReactomeREACT_1877 Internal Methylation of mRNA Edited: Joshi-Tope, G, 0000-00-00 00:00:00 In addition to the methylation of the 5'-cap, there is methylation of internal nucleotides in the mRNA. This methylation can occur in translated and untranslated regions. One to three methyl groups have been seen per mRNA molecule, but methylation is non-stoichiometric. The most frequent methylation observed is at the N6 position of adenosine. The function of mRNA internal methylation, if any, is unknown. Pubmed9409616 Reactome Database ID Release 4372095 Reactome, http://www.reactome.org ReactomeREACT_1720 PathwayStep5041 PathwayStep5040 PathwayStep5047 Formation of the Spliceosomal E complex Pre-mRNA transcripts become rapidly associated with many RNA-binding proteins, including hnRNP proteins, cap-binding proteins, SR proteins, etc; in the test tube this binding does not require splice sites or ATP. The E complex, or early complex, is the first detectable functional intermediate in spliceosome assembly in vitro. It is an ATP-independent complex. When a functional 5' splice site is present, it is bound by the U1 snRNP. The splicing factor U2AF (65 and 35 kDa subunits) binds to the polypyrimidine tract (Y)n and the AG dinucleotide at the 3' splice site, respectively. SF1/mBBP binds to the branch site. Binding of many of these factors is cooperative; e.g., SR proteins and U2AF apparently interact with each other, facilitating their binding to the pre-mRNA. In the presence of ATP, the E complex is converted to the first ATP-dependent spliceosomal complex, namely the A complex. Pubmed12176931 Pubmed12477934 Reactome Database ID Release 4372107 Reactome, http://www.reactome.org ReactomeREACT_222 PathwayStep5046 Formation of the Spliceosomal A Complex Pubmed12176931 Pubmed12477934 Reactome Database ID Release 4372124 Reactome, http://www.reactome.org ReactomeREACT_788 The A complex is the first ATP-dependent complex in spliceosome assembly. U2AF recruits the U2 snRNP to bind to the branch site in the E complex in an ATP-dependent fashion, to form the A complex. The U2 snRNA base-pairs with the branch site, causing the branch-site adenosine to bulge out, which later positions it for nucleophilic attack at the 5' splice site. The A complex serves as a substrate for formation of the B complex. PathwayStep5049 Formation of the Spliceosomal B Complex Authored: Krainer, AR, 2003-06-05 08:30:23 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Pubmed12176931 Pubmed12477934 Reactome Database ID Release 4372127 Reactome, http://www.reactome.org ReactomeREACT_48 The formation of the B complex is ATP-dependent, and both the 5' and 3' splice sites are essential for B complex assembly. The U4 and U6 snRNPS are extensively base-paired, and this U4:U6 complex associates with the U5 snRNP to form a tri-snRNP particle. This tri-snRNP particle then binds to the spliceosomal A complex, to form the spliceosomal B complex. PathwayStep5048 Formation of the Cleavage and Polyadenylation Complex Edited: Joshi-Tope, G, 0000-00-00 00:00:00 Reactome Database ID Release 4372231 Reactome, http://www.reactome.org ReactomeREACT_1184 PathwayStep5043 PathwayStep5042 PathwayStep5045 PathwayStep5044 Histone H2B Converted from EntitySet in Reactome Reactome DB_ID: 181911 Reactome Database ID Release 43181911 Reactome, http://www.reactome.org ReactomeREACT_8092 PathwayStep5088 PathwayStep5089 PathwayStep5086 PathwayStep5087 PathwayStep5080 VLA-4 binds JAM-B Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed12070135 Pubmed17525755 Reactome Database ID Release 43202706 Reactome, http://www.reactome.org ReactomeREACT_12040 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Several key IgSF cell adhesion molecules engage integrin and in so doing impact on the multi-step paradigm of leukocyte emigration. The interaction between JAM-B and VLA-4 is facilitated by prior engagement of JAM-B with JAM-C. PathwayStep5081 JAM-A homodimerises Authored: Ouwehand, W.H., 2007-11-12 16:45:54 JAM-A is the most widely expressed member of the family, and has been shown to be expressed on endothelial and epithelial cells, on platelets, and on a number of leukocyte subsets. In endothelial cells, JAM-A locates to the tight junctions, where it appears to engage in homophilic binding to JAM-A on adjacent cells, an interaction that is considered to play a critical role in angiogenesis. Pubmed16783819 Pubmed17505016 Pubmed17525755 Pubmed17615384 Reactome Database ID Release 43202726 Reactome, http://www.reactome.org ReactomeREACT_11999 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 has a Stoichiometric coefficient of 2 Histone H2A Converted from EntitySet in Reactome Reactome DB_ID: 181899 Reactome Database ID Release 43181899 Reactome, http://www.reactome.org ReactomeREACT_8447 MAC1 binds JAM-C Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed17379836 Pubmed17525755 Reactome Database ID Release 43202727 Reactome, http://www.reactome.org ReactomeREACT_12035 Recruitment of monocytic cells to the vessel wall by platelets is mediated via CD11b/CD18 (Mac-1) and platelet JAM-C. In the case of dendritic cells, this interaction leads to their activation and platelet phagocytosis. This process may be of importance for progression of atherosclerotic lesions. Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 JAM-B binds JAM-C Authored: Ouwehand, W.H., 2007-11-12 16:45:54 JAM-B and -C bind each other and are strongly expressed by endothelial cells of high endothelial venules, the predominant site of leukocyte extravasation. JAM-B and -C also bind to the leukocyte integrins VLA-4 and Mac-1 respectively. Pubmed16297198 Pubmed17525755 Reactome Database ID Release 43202721 Reactome, http://www.reactome.org ReactomeREACT_12053 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 PathwayStep5084 PathwayStep5085 PathwayStep5082 LFA1 binds JAM-A Authored: Ouwehand, W.H., 2007-11-12 16:45:54 JAM-A plays a key role in leukocyte transmigration and inflammatory extravasation. Transmigration of human leukocytes has been shown to involve heterophilic interactions of JAM-A with its integrin receptor LFA-1. Pubmed11812992 Pubmed15528364 Pubmed15681301 Pubmed17525755 Reactome Database ID Release 43202718 Reactome, http://www.reactome.org ReactomeREACT_12042 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 PathwayStep5083 Integrin alphaXbeta2 binds JAM-C Although JAM-C is better known for its interaction with MAC-1, an interaction with CD11c/CD18 (known as alpha X beta 2), has also been described. Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed12208882 Pubmed17525755 Pubmed17625065 Reactome Database ID Release 43202704 Reactome, http://www.reactome.org ReactomeREACT_12064 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 MERTK receptor binds ligands (Gas6 or Protein S) Authored: Ouwehand, W.H., 2007-11-12 16:45:54 MerTK appears to be required for ingestion of apoptotic cells by professional phagocytes such as monocytes/macrophages, retinal pigment epithelial cells and dendritic cells. Mer appears to be able to induce the cytoskeletal remodelling that is required for engulfment during phagocytosis. For instance, a deletion in the MERTK gene was identified as the underlying cause for retinal dystrophy which involves an impairment in the ingestion of shed photoreceptor cell fragments by retinal pigment epithelial cells. <p> The biological ligands for MerTK are two highly similar vitamin K-dependent proteins, Gas6 and protein S (PS), a negative regulator of blood coagulation. Both proteins are composed an N-terminal region containing multiple post-translationally modified gamma-carboxyglutamic acid residues (Gla). The Gla region possesses the ability to interact in a conformationally specific manner with negatively charged membrane phospholipids, which is thought to mediate the binding of both Gas6 and PS to apoptotic cells. In this way, they are thought to act as recognition bridges between apoptotic cells and the phagocyte cell that ingest them. Pubmed16737840 Pubmed17064312 Pubmed17442946 Reactome Database ID Release 43202710 Reactome, http://www.reactome.org ReactomeREACT_12060 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 Alpha-1(V) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268693 Reactome Database ID Release 432268693 Reactome, http://www.reactome.org ReactomeREACT_122022 JAM-C homodimerises Authored: Ouwehand, W.H., 2007-11-12 16:45:54 JAM-C has been detected in epithelial-cell desmosomes. JAM-C homodimers are prominently located in endothelial-cell tight junctions. Pubmed17099249 Pubmed17525755 Reactome Database ID Release 43202731 Reactome, http://www.reactome.org ReactomeREACT_12029 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 has a Stoichiometric coefficient of 2 JAM-B homodimerises Apart from its well-established interaction with VLA-4, JAM-B is also known to homodimerize. Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed17525755 Reactome Database ID Release 43202709 Reactome, http://www.reactome.org ReactomeREACT_11994 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 has a Stoichiometric coefficient of 2 P-selectin binds P-selectin ligand Authored: Ouwehand, W.H., 2007-11-12 16:45:54 PSGL-1 is expressed as a homodimer of two 120-kDa subunits that binds all three selectins, with the highest affinity for P-selectin, and is known to be constitutively expressed on the surface of platelets and most types of leukocytes. Besides playing a critical role in the inflammatory response by mediating leukocyte-leukocyte and leukocyte-endothelium interactions, PSGL-1 also participates in the hemostatic process by mediating leukocyte-platelet interactions. Pubmed14615387 Pubmed17322099 Reactome Database ID Release 43202724 Reactome, http://www.reactome.org ReactomeREACT_12081 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 has a Stoichiometric coefficient of 2 CD84 homodimerises Authored: Ouwehand, W.H., 2007-11-12 16:45:54 CD84 is a homophilic receptor expressed on T cells, B cells, dendritic cells, monocytes, macrophages, eosinophils, mast cells, granulocytes, and platelets. CD84 expression increases following activation of T cells, B cells, and dendritic cells. CD84 homophilic engagement is known to induce platelet stimulation. Pubmed11564780 Pubmed17563375 Reactome Database ID Release 43202713 Reactome, http://www.reactome.org ReactomeREACT_12027 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 PathwayStep5097 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43450501 Reactome, http://www.reactome.org PathwayStep5098 ACTIVATION GENE ONTOLOGYGO:0004175 Reactome Database ID Release 4368824 Reactome, http://www.reactome.org PathwayStep5099 ACTIVATION GENE ONTOLOGYGO:0004521 Reactome Database ID Release 43426499 Reactome, http://www.reactome.org PathwayStep5090 ACTIVATION GENE ONTOLOGYGO:0003724 Reactome Database ID Release 4372645 Reactome, http://www.reactome.org PathwayStep5091 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43450388 Reactome, http://www.reactome.org PathwayStep5092 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43450427 Reactome, http://www.reactome.org PathwayStep5093 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43187724 Reactome, http://www.reactome.org PathwayStep5094 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43450501 Reactome, http://www.reactome.org PathwayStep5095 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43429015 Reactome, http://www.reactome.org PathwayStep5096 ACTIVATION GENE ONTOLOGYGO:0004674 Reactome Database ID Release 43429015 Reactome, http://www.reactome.org Alpha-2(V) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268700 Reactome Database ID Release 432268700 Reactome, http://www.reactome.org ReactomeREACT_123726 plasminogen:histidine-rich glycoprotein -> plasmin + histidine-rich glycoprotein (uPA [two-chain] catalyst) Authored: D'Eustachio, P, 2005-02-14 18:06:15 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Plasminogen, tethered to the cell surface by its association with histidine-rich glycoprotein, is rapidly cleaved and activated to plasmin by the action of urokinase plasminogen activator(two-chain form) bound to uPAR, its cell-surface receptor. The association of both substrate and enzyme with the cell surface is necessary for the reaction to proceed efficiently (Ellis et al. 1989, 1991). Pubmed1829461 Pubmed2521625 Reactome Database ID Release 43158925 Reactome, http://www.reactome.org ReactomeREACT_598 urokinase plasminogen activator (one-chain):uPAR -> urokinase plasminogen activator (two-chain):uPAR Authored: D'Eustachio, P, 2005-02-14 18:06:15 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed2935528 Pubmed3023326 Reactome Database ID Release 43158942 Reactome, http://www.reactome.org ReactomeREACT_547 The small amount of plasmin generated by the activity of the one-chain form of urokinase plasminogen activator in turn cleaves urokinase plasminogen activator, converting it to its substantially more active two-chain form (Cubellis et al. 1986; Lijnen et al. 1991). urokinase plasminogen activator (two-chain):uPAR + plasminogen activator inhibitor 2 (PAI-2) -> PAI-2:urokinase plasminogen activator (two-chain):uPAR Activated (two-chain) urokinase plasminogen activator binds plasminogen activator inhibitor 2, a serpin, to form a stable, inactive complex that remains associated with uPAR on the plasma membrane (Estreicher et al. 1990; Kruithof et al. 1986). Authored: D'Eustachio, P, 2005-02-14 18:10:49 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed2166055 Pubmed3090045 Reactome Database ID Release 43159001 Reactome, http://www.reactome.org ReactomeREACT_142 urokinase plasminogen activator (two-chain):uPAR + plasminogen activator inhibitor 1 (PAI-1) -> PAI-1:urokinase plasminogen activator (two-chain):uPAR Activated (two-chain) urokinase plasminogen activator binds plasminogen activator inhibitor 1, a serpin, to form a stable, inactive complex that remains associated with uPAR on the plasma membrane (Cubellis et al. 1989). Authored: D'Eustachio, P, 2005-02-14 18:10:49 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed2544876 Reactome Database ID Release 43159005 Reactome, http://www.reactome.org ReactomeREACT_863 G-protein alpha:GDP Reactome DB_ID: 111864 Reactome Database ID Release 43111864 Reactome, http://www.reactome.org ReactomeREACT_17952 has a Stoichiometric coefficient of 1 G protein alpha:GTP complex Reactome DB_ID: 167438 Reactome Database ID Release 43167438 Reactome, http://www.reactome.org ReactomeREACT_17389 has a Stoichiometric coefficient of 1 G protein-GTP Reactome DB_ID: 167439 Reactome Database ID Release 43167439 Reactome, http://www.reactome.org ReactomeREACT_15745 has a Stoichiometric coefficient of 1 Opioid:MOR:G protein-GTP complex Reactome DB_ID: 167426 Reactome Database ID Release 43167426 Reactome, http://www.reactome.org ReactomeREACT_15831 has a Stoichiometric coefficient of 1 Sos-mediated nucleotide exchange of Ras (Tie2 receptor:Grb2:Sos) Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Reactome Database ID Release 43210977 Reactome, http://www.reactome.org ReactomeREACT_12516 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Sos-1 bound to Grb2:Tie2 complex promotes the exchange of inactive Ras-GDP to active Ras-GTP. Phosphorylated (T34) DARPP-32:PP1A Reactome DB_ID: 180025 Reactome Database ID Release 43180025 Reactome, http://www.reactome.org ReactomeREACT_17348 has a Stoichiometric coefficient of 1 Interaction of SOS-1 to Tie2 bound Grb2 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Grb2 binds directly to autophosphorylated Tie2 receptor. GRB2 also contains two SH3 domains, which bring various ligands to the sites of active signaling. One of the SH3 domains on Tie2-bound Grb2 recruits SOS1, an activating nucleotide exchange factor for Ras. This interaction of Sos1 to Grb2 brings Sos1 towards Ras molecules leading to Ras activation. Ras is implicated in the MAP kinase cascade, a pathway in cell growth stimulation, migration and differentiation. Pubmed11191051 Pubmed7478529 Pubmed8479541 Reactome Database ID Release 43210974 Reactome, http://www.reactome.org ReactomeREACT_12504 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 G alpha-olf:GDP:Adenylate cyclase (active) complex Reactome DB_ID: 170679 Reactome Database ID Release 43170679 Reactome, http://www.reactome.org ReactomeREACT_15796 has a Stoichiometric coefficient of 1 Interaction of Tie2 and Grb2 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Pubmed10521483 Pubmed11191051 Pubmed14749497 Pubmed7478529 Reactome Database ID Release 43204871 Reactome, http://www.reactome.org ReactomeREACT_12511 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Tie2/Tek provide mitogenic signals to endothelial cells by promoting the association of Grb2 to one of their phosphotyrosines. Grb2 is an adaptor protein that has been linked to activation of Ras and mitogen activated protein kinase (MAPK) cell growth signaling pathways. Grb2 also binds to the Y1102 of the kinase domain of Tie2 with one of its SH2 doamins. G alpha-olf:GTP:Adenylate cyclase (active) complex Reactome DB_ID: 170655 Reactome Database ID Release 43170655 Reactome, http://www.reactome.org ReactomeREACT_17212 has a Stoichiometric coefficient of 1 Interaction of Tie2 and p85 of PI3K Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Edited: Garapati, P V, 2009-03-16 17:55:42 Pubmed10521483 Pubmed9632797 Reactome Database ID Release 43204798 Reactome, http://www.reactome.org ReactomeREACT_12475 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase) associates with Tie2, most likely at phosphotyrosine 1102. This association leads on to the activation of Akt/PKB, a process linked to cell survival and antiapoptosis, and that may in part account for Tie2's role in vascular growth and maintenance. Activated PLC beta 1/4 Reactome DB_ID: 111856 Reactome Database ID Release 43111856 Reactome, http://www.reactome.org ReactomeREACT_15568 has a Stoichiometric coefficient of 1 Heterotrimeric G-protein Reactome DB_ID: 167441 Reactome Database ID Release 43167441 Reactome, http://www.reactome.org ReactomeREACT_17846 has a Stoichiometric coefficient of 1 Interaction of Tie2 and Grb7 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Edited: Garapati, P V, 2009-03-16 17:55:42 Grb7 was initially identified as an EGF receptor binding protein and thereafter many binding partners have been reported. Grb7 interacts with Tie2/Tek in a phosphotyrosine-dependent manner through its SH2 domain. Pubmed10521483 Pubmed11607834 Reactome Database ID Release 43204773 Reactome, http://www.reactome.org ReactomeREACT_16914 Reviewed: Trowsdale, J, 2009-02-13 11:51:02 Interaction of Tie2 and Grb14 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Edited: Garapati, P V, 2009-03-16 17:55:42 Grb14 is also one of the signaling partners of Tie2. The SH2 domain of Grb2 mediates binding to Tie2. It binds residues Y816, Y1108 and Y1113 respectively, in the C-terminal tail region of Tie2/Tek. Pubmed10521483 Pubmed11607834 Reactome Database ID Release 43204813 Reactome, http://www.reactome.org ReactomeREACT_16885 Reviewed: Trowsdale, J, 2009-02-13 11:51:02 Interaction of Tie2 and Ang4 Ang4 represents a third protein of the Ang family that binds to the Tie2 receptor. The mouse Ang3 and human Ang4 are interspecies orthologs. Ang4 acts as an activating ligand and induces phosphorylation in Tie2. Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Pubmed10051567 Pubmed11969368 Pubmed15284220 Reactome Database ID Release 43204824 Reactome, http://www.reactome.org ReactomeREACT_12598 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Opioid:MOR:G protein-GDP complex Reactome DB_ID: 167403 Reactome Database ID Release 43167403 Reactome, http://www.reactome.org ReactomeREACT_15815 has a Stoichiometric coefficient of 1 Interaction of Tie2 and Shp2 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Edited: Garapati, P V, 2009-03-16 17:55:42 Pubmed10521483 Pubmed9764820 Reactome Database ID Release 43204873 Reactome, http://www.reactome.org ReactomeREACT_16906 Reviewed: Trowsdale, J, 2009-02-13 11:51:02 Shp2 interact with Tyr816 in the juxtamembrane region and Tyr1108 and Tyr1113, respectively, in the C-terminal tail region of Tie2/Tek. Opioid:MOR:G-protein complex Reactome DB_ID: 167436 Reactome Database ID Release 43167436 Reactome, http://www.reactome.org ReactomeREACT_15585 has a Stoichiometric coefficient of 1 Interaction of Tie2 and Dok-2 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Dok-2 is a member of a docking proteins class, termed the DOK family. The DOK family members are characterized by an N-terminal pleckstrin homology (PH) domain followed by a central PTB domain and a proline- and tyrosine-rich C-terminal tail. Dok-2 is recruited to activated Tie2 via its PTB domain, which results in its subsequent tyrosine phosphorylation, thereby establishing binding sites for the small GTPase-activating protein for Ras, p120RasGAP (RasGAP) and the adapter protein Nck. The binding of DOK to the receptor leads to Nck recruitment and subsequent phosphorylation. Binding of Pak to Nck follows. this brings about the Ang-1-dependent phosphorylation of Pak in endothelial cells. Pubmed11689432 Pubmed12665569 Pubmed9764820 Reactome Database ID Release 43204850 Reactome, http://www.reactome.org ReactomeREACT_12575 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 OAT2/4 Converted from EntitySet in Reactome Reactome DB_ID: 561077 Reactome Database ID Release 43561077 Reactome, http://www.reactome.org ReactomeREACT_23320 Interaction of Tie2 with Ang2 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Pubmed15893672 Pubmed16895971 Reactome Database ID Release 43204863 Reactome, http://www.reactome.org ReactomeREACT_12547 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The major ligands for Tie2 are Ang1 and Ang2. Ang1 has been considered as the primary activating ligand of Tie2 whereas role of Ang2 remains controversial. Ang2 acts as stimulating in some studies and inhibiting in others. The activity of Ang2 is concentration dependent. Ang2 possesses similar receptor affinity to Ang1 and they both share the same binding site on Tie2. The Ang2 fibrinogen domain is solely responsible for receptor recognition and binding, the coiled-coil motif mediates its oligomerization. Interaction of Tie2 and Shc1 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Edited: Garapati, P V, 2009-03-16 17:55:42 Pubmed14665640 Reactome Database ID Release 43204861 Reactome, http://www.reactome.org ReactomeREACT_12409 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 ShcA, an SH2-containing adapter protein, acts as a scaffold for the assembly of signaling proteins involved in the activation of the Ras-MAPK pathway, and potentially other signaling pathways. <br>ShcA is one of the binding partners of endogenous Tie2 receptor on vascular endothelial cells. After Tie2 stimulation by Ang-1 interaction, ShcA associates with Tie2 and becomes tyrosine-phosphorylated. ShcA interacts with the cytoplasmic domain of Tie2 and Y1102 of Tie2 was identified as the primary binding site for the SH2 domain of ShcA. ShcA leads to a reduction of tyrosine phosphorylation of p85 subunit of PI3-kinase and is involved in the inhibition of endothelial cell migration and survival. G-protein alpha (12/13):GDP Converted from EntitySet in Reactome Reactome DB_ID: 418570 Reactome Database ID Release 43418570 Reactome, http://www.reactome.org ReactomeREACT_19591 Integrin alpha 5 beta 1 binds fibronectin Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed16258728 Pubmed17167768 Pubmed8314844 Reactome Database ID Release 43202723 Reactome, http://www.reactome.org ReactomeREACT_12043 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 Tenacious binding of free fibronectin to cells leads to enhanced fibronectin matrix assembly and the formation of a polymerized fibronectin "cocoon" around the cells. This process is enhanced in the presence of CEACAM molecules. G-protein alpha (12/13):LARG:Plexin B1 Reactome DB_ID: 398146 Reactome Database ID Release 43398146 Reactome, http://www.reactome.org ReactomeREACT_19937 has a Stoichiometric coefficient of 1 G Protein Trimer Complex (olfactory) Reactome DB_ID: 380924 Reactome Database ID Release 43380924 Reactome, http://www.reactome.org ReactomeREACT_15768 has a Stoichiometric coefficient of 1 G-protein beta-gamma:PI3K gamma Reactome DB_ID: 392293 Reactome Database ID Release 43392293 Reactome, http://www.reactome.org ReactomeREACT_20226 has a Stoichiometric coefficient of 1 CD47 binds SIRP Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Integrin-associated protein (IAP or CD47) is a receptor for thrombospondin family members, a ligand for the transmembrane signaling protein SIRP-alpha and -gamma, and a component of a supramolecular complex containing specific integrins, heterotrimeric G proteins and cholesterol. Pubmed16691243 Reactome Database ID Release 43202703 Reactome, http://www.reactome.org ReactomeREACT_12068 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 Opioid:MOR Reactome DB_ID: 112039 Reactome Database ID Release 43112039 Reactome, http://www.reactome.org ReactomeREACT_15680 has a Stoichiometric coefficient of 1 CD177 binds PECAM-1 Authored: Ouwehand, W.H., 2007-11-12 16:45:54 CD177 is a 58- to 64-kDa glycosylphosphatidylinositol-anchored glycoprotein expressed exclusively by neutrophils, neutrophilic metamyelocytes, and myelocytes, but not by any other blood cells. It has been shown that neutrophil-specific CD177 is a heterophilic binding partner of PECAM-1, constituting a novel pathway that promotes neutrophil transmigration. Pubmed17116209 Pubmed17580308 Reactome Database ID Release 43202702 Reactome, http://www.reactome.org ReactomeREACT_12006 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 OR - G Protein Trimer Complex Reactome DB_ID: 381747 Reactome Database ID Release 43381747 Reactome, http://www.reactome.org ReactomeREACT_17238 has a Stoichiometric coefficient of 1 CD58 binds CD2 Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed14529530 Pubmed17172599 Reactome Database ID Release 43202714 Reactome, http://www.reactome.org ReactomeREACT_12031 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 The crystal structure of the human CD2-CD58 complex also shows that most of the residues at the interface between these two proteins are charged and form several inter-protein salt bridges. G protein alpha:GDP complex Reactome DB_ID: 167410 Reactome Database ID Release 43167410 Reactome, http://www.reactome.org ReactomeREACT_17462 has a Stoichiometric coefficient of 1 CD48 binds CD244 Authored: Ouwehand, W.H., 2007-11-12 16:45:54 CD2, CD48, CD84, CD244 and CD58 have a similar extracellular domain arichitecture consisting of two IgSF domains. CD244 is closely related to CD84 in having a long cytoplasmic tail with tyrosine-based motifs (TxYxxI/V) resembling immunoreceptor tyrosine-based inhibitory motifs (ITIMs). CD2 has a cytoplasmic domain with proline-rich regions which recruit an Src homology 3 (SH3)- containing protein called CD2-associated protein (CD2AP). CD48 is glycosyl-phosphatidyl-inositol (GPI)-anchored to the membrane.<p> CD244 is known to be activated by binding to CD48 in humans. Pubmed10764623 Pubmed16585556 Reactome Database ID Release 43202722 Reactome, http://www.reactome.org ReactomeREACT_12018 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 G protein-GDP complex Reactome DB_ID: 167418 Reactome Database ID Release 43167418 Reactome, http://www.reactome.org ReactomeREACT_15793 has a Stoichiometric coefficient of 1 FATP1/4/6 Converted from EntitySet in Reactome Reactome DB_ID: 879582 Reactome Database ID Release 43879582 Reactome, http://www.reactome.org ReactomeREACT_24174 Platelet-derived TREM-1 ligand binds to TREM-1 Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed17452516 Pubmed18192027 Reactome Database ID Release 43203156 Reactome, http://www.reactome.org ReactomeREACT_12047 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 The triggering receptor expressed on myeloid cells 1 (TREM-1) plays an important role in the innate immune response related to severe infections and sepsis. Although the identity and occurrence of the natural TREM-1 ligands are so far unknown, the presence of a ligand for TREM-1 on human platelets has been established. It has been suggested that TREM1 recognizes soluble proteins or cell-surface proteins which are upregulated as a result of inflammation and/or tissue damage and also bacterial LPS (Tessarz & Cerwenka 2008). RhoA/B/C:GTP Reactome DB_ID: 419161 Reactome Database ID Release 43419161 Reactome, http://www.reactome.org ReactomeREACT_19589 has a Stoichiometric coefficient of 1 Interaction of Tie2 with Ang1 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Pubmed11191051 Pubmed11447223 Pubmed11566266 Pubmed11969368 Pubmed8980223 Reactome Database ID Release 43204779 Reactome, http://www.reactome.org ReactomeREACT_12523 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Tie receptors and their angiopoietin ligands play a critical role in angiogenesis or blood vessel formation. They are considered to control numerous signaling pathways that are involved in diverse cellular processes, such as cell migration, proliferation, survival and reorganization of the actin cytoskeleton. <br><br>Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) represents a class of receptor tyrosine kinases (RTKs) that are predominately expressed by vascular endothelial cells. The angiopoietins are a family of growth factors that are largely specific for endothelium and they bind to Tie2/Tek RTKs.<br><br>Tie2 signaling initially involves the activation of Tie2 by the interaction of angiopoietin 1. Angiopoietin interacts with the Tie2 receptor with its fibrinogen like domain (FLD). This interaction leads to the dimerization of both the receptor and the ligand, and later initiate the trans-phosphorylation of Tie2. Activated ROCK:RhoA/B/C:GTP Reactome DB_ID: 422483 Reactome Database ID Release 43422483 Reactome, http://www.reactome.org ReactomeREACT_19928 has a Stoichiometric coefficient of 1 Dimerization of Tie2/Ang1 complex Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 Pubmed11080633 Pubmed14749497 Reactome Database ID Release 43210881 Reactome, http://www.reactome.org ReactomeREACT_12431 Receptor tyrosine kinase activation and signaling are typically initiated via dimerization of the receptors through homo-oligomeric ligand binding. <br><br>Angiopoietin1 may form homotrimers, but in most cases it assembles into higher-order multimers. This oligomerization is mediated by the N-ter coiled coil domain (CCD). <br>The binding of Ang1 oligomers to Tie2 promotes the dimerization of Tie2, which is further assisted by the interaction between the kinase domains of the receptors. Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 2 G-protein alpha (12/13):LARG Reactome DB_ID: 398145 Reactome Database ID Release 43398145 Reactome, http://www.reactome.org ReactomeREACT_19624 has a Stoichiometric coefficient of 1 Trans-phosphorylation of Tie2 Authored: Garapati, P V, de Bono, B, 2008-03-05 10:26:56 EC Number: 2.7.10 Pubmed12665569 Pubmed14749497 Pubmed9632797 Reactome Database ID Release 43210872 Reactome, http://www.reactome.org ReactomeREACT_12496 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The dimerization of Tie2 leads to autophosphorylation and activation of its kinase domain. There are multiple tyrosine phosphorylation sites in the Tie2 kinase domain. The phosphorylated tyrosine residues provide the interaction site for the SH2 domains of other downstream signaling molecules like PI3K, Grb2, SHP2 etc. has a Stoichiometric coefficient of 12 CXADR binds to AMICA1 Authored: Ouwehand, W.H., 2007-11-12 16:45:54 JAM members, such as JAML, bind coxsackie and adenovirus receptor (CXADR) on epithelial and endothelial cells. Pubmed15800062 Pubmed16904340 Reactome Database ID Release 43199093 Reactome, http://www.reactome.org ReactomeREACT_11154 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 OLR1 binds to oxidized LDL Authored: Ouwehand, W.H., 2007-11-12 16:45:54 Pubmed11256994 Pubmed15000751 Pubmed9052782 Pubmed9693095 Pubmed9763524 Reactome Database ID Release 43203130 Reactome, http://www.reactome.org ReactomeREACT_12039 Reviewed: Zwaginga, JJ, 2007-11-12 16:47:00 The lectin-like oxidized low density lipoprotein receptor- 1 (Lox-1) mediates the recognition and internalization of oxidatively modified low density lipoprotein. This interaction results in a number of pro-atherogenic cellular responses that probably play a significant role in the pathology of atherosclerosis. has a Stoichiometric coefficient of 2 RhoA,B,C:GDP Reactome DB_ID: 419164 Reactome Database ID Release 43419164 Reactome, http://www.reactome.org ReactomeREACT_20118 has a Stoichiometric coefficient of 1 Activated Rac1:PI3K alpha Reactome DB_ID: 114540 Reactome Database ID Release 43114540 Reactome, http://www.reactome.org ReactomeREACT_5860 has a Stoichiometric coefficient of 1 Basigin binds to integrins Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Basigin is a widely distributed cell-surface protein with two immunoglobulin domains and has shown to associate with both the integrins alpha3beta1 and alpha6beta1. Pubmed9360995 Reactome Database ID Release 43204434 Reactome, http://www.reactome.org ReactomeREACT_13430 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 G13-activated p115-RhoGEF Reactome DB_ID: 114527 Reactome Database ID Release 43114527 Reactome, http://www.reactome.org ReactomeREACT_3301 has a Stoichiometric coefficient of 1 Basigin binds Mannose-carrying cell recognition molecules Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Based on in vitro affinity chromatography study, basigin was found to bind to high mannose-carrying cell recognition molecules, such as myelin-associated glycoprotein, L1 and the beta2-subunit of Na+/K+-ATPase. Edited: Garapati, P V, 2009-03-16 17:55:42 Pubmed12558975 Reactome Database ID Release 43375133 Reactome, http://www.reactome.org ReactomeREACT_16975 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Ligand:GPCR complexes that activate G12/13:Heterotrimeric G-protein G12/13 (active). Reactome DB_ID: 751015 Reactome Database ID Release 43751015 Reactome, http://www.reactome.org ReactomeREACT_22602 has a Stoichiometric coefficient of 1 Ligand:GPCR complexes that activate G12/13:Heterotrimeric G-protein G12/13 (inactive). Reactome DB_ID: 750994 Reactome Database ID Release 43750994 Reactome, http://www.reactome.org ReactomeREACT_23035 has a Stoichiometric coefficient of 1 Ligand:GPCR complexes that activate G12/13 Converted from EntitySet in Reactome Reactome DB_ID: 751003 Reactome Database ID Release 43751003 Reactome, http://www.reactome.org ReactomeREACT_22808 G-protein alpha (q/11):PI3K alpha Reactome DB_ID: 416356 Reactome Database ID Release 43416356 Reactome, http://www.reactome.org ReactomeREACT_20202 has a Stoichiometric coefficient of 1 Basigin binds MCT1, MCT3 and MCT4 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Edited: Garapati, P V, 2009-03-16 17:55:42 Proton-coupled monocarboxylate transporters (MCT) MCT1, MCT3, and MCT4 form heterodimeric complexes with the cell surface glycoprotein CD147 and exhibit tissue-specific polarized distributions that are essential for maintaining lactate and pH homeostasis. Pubmed10921872 Pubmed11719518 Pubmed16260747 Reactome Database ID Release 43204392 Reactome, http://www.reactome.org ReactomeREACT_16882 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 2 Thyroid hormone transporting SLCOs Converted from EntitySet in Reactome Reactome DB_ID: 879625 Reactome Database ID Release 43879625 Reactome, http://www.reactome.org ReactomeREACT_24523 RAD51B:RAD51C binds single-stranded DNA Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Pubmed10915877 Pubmed11751636 Reactome Database ID Release 43983218 Reactome, http://www.reactome.org ReactomeREACT_25328 Reviewed: Ouwehand, WH, 2010-11-12 The complex of Rad51B and Rad51C binds single-stranded DNA and hydrolyses ATP (Sigurdsson et al. 2001). Rad51B and Rad51C are both required for recombination and DNA double-strand break repair in vivo. The complex cannot substitute for RPA but enhances Rad51/RPA mediated repair. The proposed mechanism for this is that Rad51b:Rad51C partially overcomes the suppressive effect of RPA on Rad51-catalyzed DNA pairing and strand exchange; RPA is an important accessory factor for Rad51-mediated homologous DNA pairing and strand exchange, but it can also compete with Rad51 for binding sites on the ssDNA template, which, when allowed to occur, suppresses pairing and strand exchange efficiency markedly (Sung et al. 2000). Dual-specific AKAPs bind type I and II PKA regulatory subunits Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Protein kinase A (PKA) refers to a family of multimeric enzyme complexes whose activity is dependent on the level of cyclic AMP (cAMP), hence PKA is also known as cAMP-dependent protein kinase (EC 2.7.11.11). PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. PKA is a holoenzyme complex consisting of two regulatory and two catalytic subunits. When cAMP levela are low the holoenzyme remains intact and is inactive. When the concentration of cAMP rises (e.g. as a result of adenylate cyclase activation by G protein-coupled receptors coupled to Gs, or inhibition of phosphodiesterases that degrade cAMP) cAMP binds to two binding sites on the regulatory subunits, leading to the release and activation of the catalytic subunits. The regulatory subunits of PKA are also important for localizing the kinase inside the cell. A-kinase anchor proteins (AKAPs) bind to the regulatory subunits and to cytoskeletal structures or membranes, anchoring the enzyme complex to a particular subcellular compartment. Dual-specificity A kinase-anchoring proteins (AKAP1/D-AKAP1) and (AKAP10/D-AKAP2) interact with the type I and type II regulatory subunits of PKA (Huang et al. 1997). AKAP10 additionally has two regulator of G-protein signaling (RGS) domains, giving it the potential to coordinate a signaling complex that links cAMP signaling with G-protein-coupled receptor (GPCR) signaling (Burns-Hamuro et al. 2004). Pubmed11788480 Pubmed15488188 Pubmed9065479 Pubmed9326583 Reactome Database ID Release 43992708 Reactome, http://www.reactome.org ReactomeREACT_24992 Reviewed: Ouwehand, WH, 2010-11-12 Basigin binds CD98 complex Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 CD97hc is a multifunctional glycoprotein with a single transmembrane domain, is highly expressed on proliferating cells, and functions as a chaperone for transporters. CD98hc forms disulfide-bonded heterodimers with at least seven different light chains (SLC7A5-11) that serve as amino acid transporters. Covalent cross-linking, mass spectrometric protein identification, and co-immunoprecipitation shows selective CD147 association with CD98hc complex. Edited: Garapati, P V, 2009-03-16 17:55:42 Pubmed15901826 Reactome Database ID Release 43375131 Reactome, http://www.reactome.org ReactomeREACT_16988 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 RAD51B binds RAD51C Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Pubmed11744692 Pubmed12427746 Pubmed15902993 Reactome Database ID Release 43983285 Reactome, http://www.reactome.org ReactomeREACT_24936 Reviewed: Ouwehand, WH, 2010-11-12 The Rad51-like proteins Rad51B and Rad51C form a highly stable complex. This complex assists Rad51 in the early stages of homologous recombination. IRF1 binds the promoters of Interferon alpha and beta Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Interferon regulatory factor-1 (IRF-1) is a positive transcription factor for genes involved in immune response, cell growth regulation and apoptosis in mammalian cells. Many agents such as viruses, interferon (IFN), double-stranded RNA (dsRNA), and proinflammatory cytokines induce IRF-1 transcription. IRF-1 transcriptionally activates many IRF-1-regulated genes during normal physiological and pathological conditions, including interferon-beta and alpha (Escalante et al. 1998, Harada et al. 1990), iNOS, COX-2, VCAM-1, IL-12, IL-15, CIITA, Caspase-1 and Caspase-7 (Upreti & Rath 2005). Pubmed16022283 Pubmed2208287 Pubmed3409321 Pubmed9422515 Reactome Database ID Release 43994020 Reactome, http://www.reactome.org ReactomeREACT_25334 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 G-protein alpha (q/11):Trio family RhoGEFs Reactome DB_ID: 400608 Reactome Database ID Release 43400608 Reactome, http://www.reactome.org ReactomeREACT_19870 has a Stoichiometric coefficient of 1 IRF2 binds the promoters of Interferon alpha and beta Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Interferon regulatory factor 2 (IRF-2) represses the action of IRF-1 on type I interferon genes (Harada et al, 1989, 1990; Palombella & Maniatis, 1992) by competing with IRF-1 for binding at the PRDI site. Pubmed1630448 Pubmed2475256 Reactome Database ID Release 43994038 Reactome, http://www.reactome.org ReactomeREACT_25232 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 PLC beta:G alpha (q/11) Reactome DB_ID: 398158 Reactome Database ID Release 43398158 Reactome, http://www.reactome.org ReactomeREACT_17363 has a Stoichiometric coefficient of 1 Mitofusins trans-interact linking mitochondria prior to fusion Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Mitochondria frequently fuse and divide (Bereiter-Hahn & Voth 1994); these processes affect morphology and are important for normal mitochondrial functions such as respiration, development and apoptosis. Mitofusins (MFNs) are mitochondrial GTPases that mediate mitochondrial outer membrane fusion. Mammals have two mitofusins; Mfn1-null or Mfn2-null mouse embryonic fibroblast cells show predominantly fragmented mitochondria and have greatly reduced mitochondrial fusion in vivo (Chen et al. 2003, 2005). MFNs acts in trans to bring mitochondria into close proximity prior to fusion (Koshiba et al. 2004). They also tether the endoplasmic reticulum (ER) to mitochondria, cross-linking MFNs expressed on the mitochondrial outer membrane and ER membrane (de Brito & Scorrano 2008). Pubmed11950885 Pubmed12527753 Pubmed15297672 Pubmed15899901 Pubmed17331506 Pubmed19052620 Pubmed8204911 Reactome Database ID Release 43992703 Reactome, http://www.reactome.org ReactomeREACT_25188 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 G-protein alpha (q):GRK2 Reactome DB_ID: 416515 Reactome Database ID Release 43416515 Reactome, http://www.reactome.org ReactomeREACT_19587 has a Stoichiometric coefficient of 1 p53, SIN3A and MYB form a complex Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Pubmed10378697 Pubmed14761981 Pubmed15509555 Pubmed16597594 Pubmed1709592 Pubmed19252138 Pubmed20599537 Pubmed2413449 Pubmed8710361 Reactome Database ID Release 43992696 Reactome, http://www.reactome.org ReactomeREACT_25138 Reviewed: Ouwehand, WH, 2010-11-12 The DNA-binding domain of c-Myb binds the co-repressor protein SIN3A (Nomura et al. 2004). The tumor repressor p53 also binds MYB directly (Tanikawa et al. 2004), promoting formation of a trimeric SIN3A:c-Myb:p53 complex. This does not affect the ability of c-Myb to bind to DNA, but may represent the mechanism that allows p53 to to regulate specific Myb target genes. <br>c-Myb (gene symbol MYB) is highly conserved in all vertebrates and some invertebrate species (Lipsick 1996). It plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells (Duprey & Boettiger 1985); Down-regulation of c-Myb is believed to be critical for the commitment of cells to terminal differentiation (Oh & Reddy, 1999). c-Myb interacts with many other transcription factors including CBP, several CCAAT binding protein (c/EBP) family members, and Ets family proteins such as Ets-2 (Oh & Reddy, 1999). <br>Loss of c-Myb function results in embryonic lethality due to failure of fetal hepatic hematopoiesis (Mucenski et al. 1991). G-protein alpha (q):GRK5 Reactome DB_ID: 416517 Reactome Database ID Release 43416517 Reactome, http://www.reactome.org ReactomeREACT_19592 has a Stoichiometric coefficient of 1 Interaction of integrin alphaVbeta3 with PECAM-1 Alpha v beta 3 integrin is one of the potential heterophilic ligands of PECAM-1 that is involved in down-regulation of T-cell responses. The heterophilic interaction of alpha v beta 3 integrin on endothelial cells with PEACAM-1 on leukocytes increases the adhesive function of beta integrins on T cells, monocytes, neutrophils and NK cells suggesting that leukocyte PEACAM-1 act as a signaling molecule. Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Pubmed7542249 Pubmed8838667 Reactome Database ID Release 43210304 Reactome, http://www.reactome.org ReactomeREACT_12468 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Gastrin:CCKBR Reactome DB_ID: 870262 Reactome Database ID Release 43870262 Reactome, http://www.reactome.org ReactomeREACT_24587 has a Stoichiometric coefficient of 1 Trans-homophilic interaction of PECAM-1 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 PECAM-mediated adhesion is complex, because it is capable of binding both to itself (homophilic adhesion) and to non-PECAM ligands (heterophilic adhesion). The trans-homophilic interaction between the two PECAM-1 molecules is mediated by their NH2-terminal membrane distal Ig homology domains 1 and 2 plus the proper spacing formed by the six Ig-homology domains. Pubmed10425179 Pubmed9252369 Reactome Database ID Release 43210285 Reactome, http://www.reactome.org ReactomeREACT_12419 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 2 Type 1 angiotensin II receptor:Angiotensin II Reactome DB_ID: 389874 Reactome Database ID Release 43389874 Reactome, http://www.reactome.org ReactomeREACT_17354 has a Stoichiometric coefficient of 1 Ligand:GPCR complexes that activate Gq/11:Heterotrimeric G-protein Gq (active) Reactome DB_ID: 749447 Reactome Database ID Release 43749447 Reactome, http://www.reactome.org ReactomeREACT_22589 has a Stoichiometric coefficient of 1 Phoshorylation of PECAM-1 by Fyn or Lyn or c-Src Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 EC Number: 2.7.10 PECAM-1 is capable of transmitting information into the cell following its engagement and becomes tyrosine-phosphorylated during the platelet aggregation process. The Src family of tyrosine kinases (more specifically, Src, Lyn, and c-src) has been widely implicated in the phosphorylation of PECAM-1. Conserved tyrosine residues (Tyr663 and Tyr686) within the PECAM-1 cytoplasmic ITIM motif have been shown to become phosphorylated. Tyrosine phosphorylation of PECAM-1 prompts its association with intracellular signal transduction molecules. Pubmed10858437 Pubmed9624175 Reactome Database ID Release 43210291 Reactome, http://www.reactome.org ReactomeREACT_12408 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 4 Ligand:GPCR complexes that activate Gq/11:Heterotrimeric G-protein Gq (inactive) Reactome DB_ID: 749451 Reactome Database ID Release 43749451 Reactome, http://www.reactome.org ReactomeREACT_22865 has a Stoichiometric coefficient of 1 Ligand:GPCR complexes that activate Gq/11 Converted from EntitySet in Reactome Reactome DB_ID: 380110 Reactome Database ID Release 43380110 Reactome, http://www.reactome.org ReactomeREACT_18247 p(S27)-G protein alpha (z):GTP Reactome DB_ID: 804940 Reactome Database ID Release 43804940 Reactome, http://www.reactome.org ReactomeREACT_22530 has a Stoichiometric coefficient of 1 Interaction of PECAM-1 and SHIP Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 PECAM/CD31 is a member of the immunoglobulin superfamily (IgSF) and has been implicated to mediate the adhesion and trans-endothelial migration of T-lymphocytes into the vascular wall, T cell activation and angiogenesis. It has six Ig homology domains within its extracellularly and an ITIM motif within its cytoplasmic region. <br>PECAM-mediated adhesion is complex, because it is capable of binding both to itself (homophilic adhesion) and to non-PECAM ligands (heterophilic adhesion). The trans-homophilic interaction between the two PECAM-1 molecules is mediated by their NH2-terminal membrane distal Ig homology domains 1 and 2 plus the proper spacing formed by the six Ig-homology domains. Pubmed10350061 Reactome Database ID Release 43210290 Reactome, http://www.reactome.org ReactomeREACT_12476 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Interaction of PECAM-1 and PLC gamma1 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Like SHP-1 and SHP-2, PLC-gamma 1 also interacts with PECAM-1. PLC-gamma 1 binds with both the tyrosine residues (Y663 and Y686). Unlike the N-SH2 domain, the C-SH2 domain on PLC-gamma 1 can only bind phosphotyrosine 663. The engagement of PECAM-1 with PLC-gamma 1 may lead to PLC-gamma 1 activation and subsequent calcium influx. Pubmed10350061 Reactome Database ID Release 43210283 Reactome, http://www.reactome.org ReactomeREACT_12540 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 CyP60 chaperones Basigin Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Basigin serves as a signaling receptor for extracellular cyclophilins. Its been reported that cyclophilin 60 (Cyp60), a distinct member of the cyclophilin family is involved in the regulation of intracellular transport of basigin. The mechanism of this activity involves interaction of Cyp60 with the proline-containing region within or adjacent to the predicted transmembrane domain basigin. Cyp60 is co-localized with basigin at the plasma membrane suggesting that Cyp60 may function as a chaperone escorting basigin through the secretory pathway. Pubmed15946952 Reactome Database ID Release 43204500 Reactome, http://www.reactome.org ReactomeREACT_12550 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Basigin homodimerises Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Basigin (Bsg) is a highly glycosylated transmembrane protein belonging to the Ig superfamily with two Ig domains. Bsg forms homo-oligomers on the plasma membrane in a cis-dependent manner. The N-terminal Ig-like domain is functionally important in oligomer formation. <br> Pubmed10880960 Reactome Database ID Release 43204600 Reactome, http://www.reactome.org ReactomeREACT_12593 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 has a Stoichiometric coefficient of 2 Caveolin-1 binds Basigin Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Pubmed14707126 Pubmed15201341 Reactome Database ID Release 43204549 Reactome, http://www.reactome.org ReactomeREACT_12637 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Stromal fibroblasts secrete multiple matrix metalloproteinases (MMP)1 that can promote tumor cell growth, survival, invasion, angiogenesis, and metastasis. Basigin on the surface of carcinoma cells, stimulates production of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), and MMP-3 (stromelysin). Basigin has been shown to co-immunoprecipitate with caveolin-1. The second Ig domain of Basigin is required for this association, which leads to decreased Besigin self-association on the cell surface. Therefore, caveolin-1 is a negative regulator of CD147 self-association, and its MMP-inducing activity. Basigin binds CyPA Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Cyclophilin A (CyPA)1 is an intracellular protein belonging to the immunophilin family and is recognized as the major target for the potent immunosuppressive drug cyclosporin A. CD147 is the natural cell surface receptor for CyPA. It is demonstrated that CD147 is an essential component in the CyPA-initiated signaling cascade that culminates in ERK activation. Pubmed11943775 Reactome Database ID Release 43204485 Reactome, http://www.reactome.org ReactomeREACT_12497 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Basigin interacts with CD43 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 CD43, a major leukocyte cell surface sialoglycoprotein, interacts directly with Basigin. Edited: Garapati, P V, 2009-02-13 13:45:38 Pubmed17996943 Reactome Database ID Release 43204465 Reactome, http://www.reactome.org ReactomeREACT_16931 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Basigin binds Matrix metalloproteinase-1 Authored: de Bono, B, Garapati, P V, 2008-02-26 12:30:30 Basigin expressed on the surface of most tumor cells, stimulates stromal cells to produce elevated levels of several matrix metalloproteinases (MMP), including interstitial collagenase (MMP-1). MMPs have been implicated in several aspects of tumor progression, including invasion through basement membranes and interstitial matrices, angiogenesis, and tumor cell growth. Basigin not only stimulates the production of MMP-1 but also forms a complex with MMP-1 at the tumor cell surface and this interaction may be important in modifying the tumor cell pericellular matrix to promote invasion. Edited: Garapati, P V, 2009-03-16 17:55:42 Pubmed10706100 Reactome Database ID Release 43375135 Reactome, http://www.reactome.org ReactomeREACT_16941 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Cables1 links CDK2 and WEE1 Authored: Ouwehand, WH, 2010-11-12 CDK5 and ABL1 enzyme substrate 1 (Cables1) is a negative regulator of cell proliferation. Loss of Cables1 function can lead to uncontrolled growth in vivo, observed in many human cancers, such as colon, lung and gynecological malignancies including ovarian and endometrial cancers (Sakamoto et al. 2008). Cables1 is up-regulated by progesterone and down-regulated by estrogen (Zukerberg et al. 2004). Cables1 is predominantly located in the nucleus of proliferating cells (Zukerberg et al. 2000, Wu et al. 2001) but some fully differentiated cells such as mature neurons have a significant proportion in the cytoplasm. Cables1 interacts with cyclin-dependent kinases (Cdk) 2, 3 and 5 (Wu et al. 2001, Matsuoka et al. 2000, Zukerberg et al. 2000). In proliferating cells, Cables1 links Cdk2 and Wee1, a dual specificity kinase. Phosphorylation of Cdk2 on tyrosine-15 by Wee-1 leads to decreased Cdk2 activity; Cables1 enhances this inhibitory phosphorylation (Wu et al. 2001). Cables1 has also been shown to interact with two regulators of apoptosis, p53 and p73. The physiological relevance of this interaction is not fully understood, but Cables1 augments p53-induced apoptosis in human osteosarcoma cells (Tsuji et al. 2002). Cables2 interacts with Cdk3, Cdk5 and c-Abl (Sato et al. 2002). Edited: Jupe, S, 2010-11-24 Pubmed10873625 Pubmed10896159 Pubmed11585773 Pubmed11706030 Pubmed11955625 Pubmed14729625 Pubmed18059193 Reactome Database ID Release 431013881 Reactome, http://www.reactome.org ReactomeREACT_25027 Reviewed: Akkerman, JW, 2010-10-29 Cables link CDK5 and ABL1 Authored: Ouwehand, WH, 2010-11-12 CDK5 and ABL1 enzyme substrate 1 (Cables1) is a negative regulator of cell proliferation. Loss of Cables1 function can lead to uncontrolled growth in vivo, observed in many human cancers, such as colon, lung and gynecological malignancies including ovarian and endometrial cancers (Sakamoto et al. 2008). Cables1 is up-regulated by progesterone and down-regulated by estrogen (Zukerberg et al. 2004). Cables1 is predominantly located in the nucleus of proliferating cells (Zukerberg et al. 2000, Wu et al. 2001) but some fully differentiated cells such as mature neurons have a significant proportion in the cytoplasm. Cables1 interacts with cyclin-dependent kinases (Cdk) 2, 3 and 5 (Wu et al. 2001, Matsuoka et al. 2000, Zukerberg et al. 2000). In neurons, Cables1 links Cdk5 and c-Abl, enhancing Cdk5 tyrosine-15 phosphorylation which results in increased Cdk5 activity, important in neurite outgrowth (Zukerberg et al. 2000). In proliferating cells, Cables1 links Cdk2 and Wee1, a dual specificity kinase. Phosphorylation of Cdk2 on tyrosine-15 by Wee-1 leads to decreased Cdk2 activity, Cables1 enhances this inhibitory phosphorylation (Wu et al. 2001). Cables1 has also been shown to interact with two regulators of apoptosis, p53 and p73. The physiological relevance of this interaction is not fully understood, but Cables1 augments p53-induced apoptosis in human osteosarcoma cells (Tsuji et al. 2002). Cables2 interacts with Cdk3, Cdk5 and c-Abl (Sato et al. 2002). Edited: Jupe, S, 2010-11-12 Pubmed10873625 Pubmed10896159 Pubmed11585773 Pubmed11706030 Pubmed11955625 Pubmed14729625 Pubmed18059193 Reactome Database ID Release 431013833 Reactome, http://www.reactome.org ReactomeREACT_25197 Reviewed: Akkerman, JW, 2010-10-29 Kinesin-1 is a heterotetramer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kinesin-1 is a heterotetramer of two heavy chains (HCs) and two light chains (LCs). The HC tail binds microtubules and inhibits ATPase activity by interacting with the enzymatic HC heads. LCs regulate the head and microtubule-binding activities of the HC tail by reducing the affinity of the head-tail interaction over tenfold. By a separate mechanism LCs inhibit microtubule binding. Pubmed1607388 Pubmed20547877 Pubmed3130248 Pubmed3134048 Reactome Database ID Release 43983194 Reactome, http://www.reactome.org ReactomeREACT_25083 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 EHD proteins interact with Rabenosyn-5 Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-12 Pubmed15020713 Pubmed16155252 Pubmed17233914 Pubmed9303539 Reactome Database ID Release 431011576 Reactome, http://www.reactome.org ReactomeREACT_25249 Reviewed: Akkerman, JW, 2010-10-29 The four human EH domain-containing proteins (EHD1-4) are a distinct highly-homologous subfamily of the Eps15-homology (EH) domain family. They are distinct from most other EH family members in having the EH-domain at the C-terminus (Naslavsky & Caplan 2005). EH domains interact with other proteins; peptides containing Asp-Pro-Phe (NPF) motifs are major targets for EH-domain binding (Salcini et al. 1997). EH domain family proteins have regulatory roles in endocytic membrane transport events (Naslavsky & Caplan 2005); the EHD subfamily is believed to regulate endocytic recycling (George et al. 2007). All four human EHD proteins can rescue the vacuolated intestinal phenotype observed when the C. elegans orthologue rme-1 is mutated (George et al. 2007). Over 20 interaction partners have been reported for the C-terminal EHD proteins including clathirin, syndaptins and Arp2/3 (see Naslavsky & Caplan 2005). EHD1-3 all interact with Rabenosyn-5 (Rab5), a Rab5 effector (Naslavsky et al. 2004). Alpha-1(XXVII) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268919 Reactome Database ID Release 432268919 Reactome, http://www.reactome.org ReactomeREACT_122372 Expression of globin genes under control of the beta globin control region Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-16 Pubmed11895428 Pubmed2649166 Reactome Database ID Release 431008220 Reactome, http://www.reactome.org ReactomeREACT_25336 Reviewed: Akkerman, JW, 2010-10-29 The human beta-globin locus consists of five genes encoding the beta globin gene but also delta, gamma-A, gamma-G and epsilon globin. All of these genes are controlled by the beta globin locus control region. DOCKs bind to RhoGEFs Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-12 Members of the Dedicator of cytokinesis (DOCK) family, also known as the Dock180 superfamily, are Rho GTPase guanine nucleotide exchange factors (GEFs), modulating Rho GTPase activity (Cote & Vuori 2002). All eleven human members share the presence of two evolutionarily conserved protein domains, termed DHR-1 and DHR-2 (Cote & Vuori 2007). The DHR-2 domains of several DOCKs interact with the nucleotide-free forms of Rho GTPases, intermediates in the catalytic reaction leading to the exchange of GDP for GTP. DHR-2 domains have been shown necessary and sufficient to promote specific guanine nucleotide exchange on various Rho GTPases, both in vitro and in vivo. Inactivation of the DHR-2 domain in DOCK1 (Dock180) has been shown to block Rac activation, cell migration and phagocytosis (Brugnera et al. 2002, Grimsley et al. 2004, Cote & Vuori 2002). The DHR-1 domain of DOCK1 was shown to mediate a specific interaction with PIP2 and PIP3 signaling lipids in vitro and in cells (Cote et al. 2005). Mutations of the DOCK1 DHR-1 domain blocked Rac-dependent cell elongation and cell migration suggesting that the role of DHR-1 is to position DOCK1 at sites of PIP3 production by PI3-kinase, coupling this to Rac signaling (Cote & Vuori 2007). Pubmed12134158 Pubmed12432077 Pubmed14638695 Pubmed15247287 Pubmed15710388 Pubmed16025104 Pubmed17027967 Pubmed17196961 Pubmed17765544 Reactome Database ID Release 431011598 Reactome, http://www.reactome.org ReactomeREACT_25140 Reviewed: Akkerman, JW, 2010-10-29 ACTIVATION GENE ONTOLOGYGO:0003883 Reactome Database ID Release 43504051 Reactome, http://www.reactome.org Rabenosyn-5 connects Rab5 to VPS-45 Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-24 Pubmed10559924 Pubmed10811830 Pubmed11062261 Reactome Database ID Release 431011600 Reactome, http://www.reactome.org ReactomeREACT_24949 Reviewed: Akkerman, JW, 2010-10-29 The small GTPase Rab5 regulates membrane traffic into and between early endosomes by specifically recruiting cytosolic effector proteins to their site of action on early endosomal membranes. Rab5 occupies a restricted membrane subdomain on endosomes that has distinct biochemical features when compared with neighboring subcompartments (Sonnichsen et al. 2000). Rab5 is believed to form this subdomain by recruiting the specific PI3 kinase VPS-45, causing localized production of PI-3-phosphate (PI-3P) (Christoforidis et al. 1999). Rabenosyn-5 is a Rab5 effector, recruited in a phosphatidylinositol-3-kinase dependent fashion to early endosomes where it serves as a molecular link between VPS-45 and Rab5. Adenylate Kinase 3 is a GTP-AMP phosphotransferase Authored: Ouwehand, WH, 2010-11-12 EC Number: 2.7.4.10 Edited: Jupe, S, 2010-11-12 GTP-AMP phosphotransferase, also called Adenylate kinase 3 catalyzes phosphate transfer from GTP to AMP (EC 2.7.4.10). A crystal structure is available (Choe et al. 2005). Pubmed218813 Reactome Database ID Release 431008248 Reactome, http://www.reactome.org ReactomeREACT_25345 Reviewed: Akkerman, JW, 2010-10-29 NFE2 binds the beta globin locus control region Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-24 Pubmed8816476 Reactome Database ID Release 431008200 Reactome, http://www.reactome.org ReactomeREACT_25340 Reviewed: Akkerman, JW, 2010-10-29 The human beta-globin locus control region (LCR) controls expression of the beta-globin gene family. It consists of four erythroid-cell-specific DNase I hypersensitive sites, HS1-4. DNAse I HS sites are thought to represent nucleosome-free regions of DNA which are available to trans-acting factors. NF-E2 binds two tandem AP1-like sites in HS2 which form the core of its enhancer activity. Interaction of NF-E2 with HS2 allows a second erythroid factor, GATA-1, to bind its nearby sites. NFE2 is a heterodimer Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-12 NF-E2 is a heterodimer consisting of a hematopoietic-specific subunit NFE2-p45, a member of the cap and collar (CNC) family, and a more widely expressed small subunit which can be any of the three small members of the Maf protein family MafF, MafG OR MafK (Motohashi et al. 1997). MafG and MafK are the predominant small Maf molecules in erythroid cells and megakaryocytes (Shavit et al. 1998). NF-E2 binds to an extended AP-1-like element, TGCTGA(G/C)TCA, which is found in the locus control regions (LCRs) of the alpha- and beta-globin genes and in the promoters of several heme biosynthetic enzyme genes (see Motohashi et al. 1997). NF-E2 binding sites in the DNase I hypersensitive site 2 (HS2) of the beta-globin LCR are essential for its enhancer activity (Ney et al. 1990, Talbot & Grosveld 1991). NFE2-p45 null mice have a mild defect in globin gene expression, suggesting that other members of the CNC protein family can substitute for function in vivo (Shivdasani & Orkin 1995). Pubmed1902783 Pubmed2116990 Pubmed2235483 Pubmed7567998 Pubmed9224592 Pubmed9679061 Reactome Database ID Release 431008240 Reactome, http://www.reactome.org ReactomeREACT_25294 Reviewed: Akkerman, JW, 2010-10-29 ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 43110088 Reactome, http://www.reactome.org p-STK3/N dimer Reactome DB_ID: 2028677 Reactome Database ID Release 432028677 Reactome, http://www.reactome.org ReactomeREACT_118971 has a Stoichiometric coefficient of 2 p-MST2/N dimer p-STK4/N:p-SAV1 Reactome DB_ID: 2028698 Reactome Database ID Release 432028698 Reactome, http://www.reactome.org ReactomeREACT_120272 has a Stoichiometric coefficient of 1 p-STK4/N dimer Reactome DB_ID: 2028671 Reactome Database ID Release 432028671 Reactome, http://www.reactome.org ReactomeREACT_119885 has a Stoichiometric coefficient of 2 p-MST1/N dimer KIBRA:LATS Reactome DB_ID: 2038402 Reactome Database ID Release 432038402 Reactome, http://www.reactome.org ReactomeREACT_119048 has a Stoichiometric coefficient of 1 NPHP4:LATS Reactome DB_ID: 2059920 Reactome Database ID Release 432059920 Reactome, http://www.reactome.org ReactomeREACT_119950 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0003883 Reactome Database ID Release 4373537 Reactome, http://www.reactome.org LATS:p-MOB Reactome DB_ID: 2028543 Reactome Database ID Release 432028543 Reactome, http://www.reactome.org ReactomeREACT_119861 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0050145 Reactome Database ID Release 4373499 Reactome, http://www.reactome.org p-LATS:p-MOB Reactome DB_ID: 2028550 Reactome Database ID Release 432028550 Reactome, http://www.reactome.org ReactomeREACT_118982 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0050145 Reactome Database ID Release 4373499 Reactome, http://www.reactome.org YAP1:ZO-2 Reactome DB_ID: 2064400 Reactome Database ID Release 432064400 Reactome, http://www.reactome.org ReactomeREACT_119487 YAP1:TJP2 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0050145 Reactome Database ID Release 4373495 Reactome, http://www.reactome.org YAP1:ZO-2 Reactome DB_ID: 2064401 Reactome Database ID Release 432064401 Reactome, http://www.reactome.org ReactomeREACT_118921 YAP1:TJP2 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0050145 Reactome Database ID Release 4373495 Reactome, http://www.reactome.org AMOT:YAP1 Reactome DB_ID: 2028720 Reactome Database ID Release 432028720 Reactome, http://www.reactome.org ReactomeREACT_119692 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004385 Reactome Database ID Release 4374189 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004385 Reactome Database ID Release 4374189 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 43110088 Reactome, http://www.reactome.org ATP6V0A Converted from EntitySet in Reactome Reactome DB_ID: 912594 Reactome Database ID Release 43912594 Reactome, http://www.reactome.org ReactomeREACT_24539 SH2B proteins bind JAK2 Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-12 Pubmed15121872 Pubmed16914724 Pubmed18618018 Pubmed19293402 Pubmed9831170 Reactome Database ID Release 43997237 Reactome, http://www.reactome.org ReactomeREACT_25338 Reviewed: Akkerman, JW, 2010-10-29 The SH2B family has 3 members sharing a common domain structure, including a dimerization domain, a pleckstrin homology (PH) region, and a SH2 domain. The SH2 domain binds phosphotyrosines of various signal-transducing proteins such as c-Kit, MPL, EpoR. All are able to bind JAK2 phosphorylated at Tyr-813 (Bersenev et al. 2008, Kurzer et al. 2004, 2006), inhibiting JAK2 proliferative signaling (Gery et al. 2009). JMJD1C demethylates H3K9 mono- and di-methylation Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-12 JMJD1C specifically demethylates histone H3K9 mono- and di-methylation, thereby mediating transcriptional activation. Pubmed20526338 Pubmed20530532 Reactome Database ID Release 43997263 Reactome, http://www.reactome.org ReactomeREACT_25371 Reviewed: Akkerman, JW, 2010-10-29 ZFPM proteins bind GATA proteins Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-12 Pubmed12700765 Pubmed15659346 Pubmed9230307 Pubmed9927674 Reactome Database ID Release 43996755 Reactome, http://www.reactome.org ReactomeREACT_25215 Reviewed: Akkerman, JW, 2010-10-29 The Friend of GATA (FOG) family of proteins are a highly-conserved family of large multitype zinc finger cofactors that bind to the amino zinc finger of GATA transcription factors, modulating their activity. GATA proteins are named for the DNA consensus sequence they recognize, (T/A)GATA(A/G). FOG/GATA protein interactions are essential for the development of many tissues. All six GATA family members are capable of interacting with both FOG-1 and FOG-2 (Tsang et al. 1997, Tevosian et al. 1999). Mutations that disrupt binding of GATA-1 to FOG-1 are associated with a syndrome of severe X-linked macrothrombocytopenia (Cantor & Orkin 2005) and in some cases dyserythropoietic anemia (Nichols et al. 2000). In addition to binding GAG proteins, FOGs interact with complexes containing the co-repressor C-terminal binding protein (CtBP) that are thought to coordinate histone modifications leading to a transcriptionally repressed state (Shi et al. 2003). REST recruits the BHC complex Authored: Ouwehand, WH, 2010-11-12 Edited: Jupe, S, 2010-11-12 Pubmed12032298 Pubmed16079794 Pubmed16150588 Reactome Database ID Release 43996727 Reactome, http://www.reactome.org ReactomeREACT_25101 Reviewed: Akkerman, JW, 2010-10-29 The BHC (BRAF-HDAC) complex is involved in the repression of neuronal-specific genes during development. It is recruited by RE1-silencing transcription factor (REST) to mediate the repression of REST-responsive genes. The BHC complex includes histone deacetylases (HDACs) 1 and 2, and the histone demethylase KDM1A (also knowns as BHC110, LSD1 or AOF2). KDM1A demethylates both Lys-4 (H3K4me) and Lys-9 (H3K9me) of histone H3, acting as a coactivator or a corepressor, depending on the context. Corepressor for element-1-silencing transcription factor (CoREST) is an essential component of the BHC complex, enhancing the association with nucleosomes (Lee et al. 2005). <br> <br>REST is a modular transcriptional regulator that recruits CoREST and other regulatory cofactors to activate or repress transcription through dynamic epigenetic mechanisms (Ballas & Mandel 2005). F-actin capping protein binds to the barbed end of elongating F-actin Actin capping protein (CP) was named for its ability to bind the barbed ends of actin filaments. CP inhibits the addition and loss of actin subunits at the barbed end and is important for the dynamics of actin filament assembly, and therefore important for the control of cell shape and movement. CP was called beta-actinin when first characterized and purified from muscle (Maruyama 1966). Actin polymerization is controlled by a large cellular excess of capping proteins which bind to the barbed end of actin filaments preventing elongation. Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Pubmed18544499 Pubmed5971860 Reactome Database ID Release 43994169 Reactome, http://www.reactome.org ReactomeREACT_25135 Reviewed: Ouwehand, WH, 2010-11-12 ACTIVATION GENE ONTOLOGYGO:0004017 Reactome Database ID Release 43110089 Reactome, http://www.reactome.org Alpha-1(XXIV) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268772 Reactome Database ID Release 432268772 Reactome, http://www.reactome.org ReactomeREACT_123632 F-actin capping protein is a heterodimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-16 F-actin-capping protein binds in a Ca2+-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits. Unlike other capping proteins (such as gelsolin and severin), they do not sever actin filaments. Pubmed9331217 Reactome Database ID Release 43879459 Reactome, http://www.reactome.org ReactomeREACT_25363 Reviewed: Ouwehand, WH, 2010-11-12 ACTIVATION GENE ONTOLOGYGO:0004017 Reactome Database ID Release 43110089 Reactome, http://www.reactome.org LRRC16A binds F-actin capping protein Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Leucine rich repeat-containing protein 16A (CARMIL homolog) binds F-actin capping protein (CP) with high affinity, significantly decreasing the affinity of CP for actin barbed ends. Actin polymerization occurs at the barbed end; proteins like CP that cap the barbed end inhibit elongation. Inhibition of CP therefore enhances the rate of barbed-end actin polymerization. In cells, GFP-LRRC16A was seen to be concentrated in lamellipodia and increased the fraction of cells with large lamellipodia. Decreasing LRRC16A levels with siRNA lowered F-actin levels, decreased lamellipodia protrusion and slowed cell migration. Pubmed16054028 Pubmed20625546 Reactome Database ID Release 43994148 Reactome, http://www.reactome.org ReactomeREACT_25319 Reviewed: Ouwehand, WH, 2010-11-12 ATP6V0D Converted from EntitySet in Reactome Reactome DB_ID: 912580 Reactome Database ID Release 43912580 Reactome, http://www.reactome.org ReactomeREACT_24190 ITPK1 converts Ins-1,3,4-P3 to Ins-1,3,4,6-P4 Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates Ins(1,3,4)P3 on O-6 to form Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway. Pubmed11042108 Pubmed18272466 Reactome Database ID Release 432267372 Reactome, http://www.reactome.org ReactomeREACT_120737 Reviewed: Ouwehand, WH, 2010-11-12 ATP6V0E Converted from EntitySet in Reactome Reactome DB_ID: 912581 Reactome Database ID Release 43912581 Reactome, http://www.reactome.org ReactomeREACT_24719 ITPK1 converts Ins-1,3,4-P3 to Ins-1,3,4,5-P4 Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates Ins(1,3,4)P3 on O-5 to form Ins(1,3,4,5)P4. Pubmed11042108 Pubmed18272466 Reactome Database ID Release 43994140 Reactome, http://www.reactome.org ReactomeREACT_25214 Reviewed: Ouwehand, WH, 2010-11-12 ITPK1 converts Ins-3,4,5,6-P4 to Ins-1,3,4,5,6-P5 Authored: Akkerman, JW, 2010-10-29 EC Number: 2.7.1.134 Edited: Jupe, S, 2010-11-12 Inositol-tetrakisphosphate 1-kinase (ITPK1) can phosphorylate inositol polyphosphates Ins(3,4,5,6)P4 at position 1 to form Ins(1,3,4,5,6)P5. This reaction is thought to have regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca2+-activated Cl- channels. Pubmed17616525 Pubmed18272466 Pubmed8662638 Reactome Database ID Release 43994137 Reactome, http://www.reactome.org ReactomeREACT_25076 Reviewed: Ouwehand, WH, 2010-11-12 p-STK3:p-SAV1 Reactome DB_ID: 2028261 Reactome Database ID Release 432028261 Reactome, http://www.reactome.org ReactomeREACT_119188 has a Stoichiometric coefficient of 1 p-SAV1 dimer Reactome DB_ID: 2028281 Reactome Database ID Release 432028281 Reactome, http://www.reactome.org ReactomeREACT_119796 has a Stoichiometric coefficient of 2 phosphorylated salvador dimer STK3 dimer MST2 dimer Reactome DB_ID: 2028270 Reactome Database ID Release 432028270 Reactome, http://www.reactome.org ReactomeREACT_119433 has a Stoichiometric coefficient of 2 SAV1 dimer Reactome DB_ID: 2028279 Reactome Database ID Release 432028279 Reactome, http://www.reactome.org ReactomeREACT_119077 has a Stoichiometric coefficient of 2 salvador dimer ACTIVATION GENE ONTOLOGYGO:0047305 Reactome Database ID Release 43909768 Reactome, http://www.reactome.org STK4 dimer MST1 dimer Reactome DB_ID: 2028264 Reactome Database ID Release 432028264 Reactome, http://www.reactome.org ReactomeREACT_119251 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0003837 Reactome Database ID Release 4373466 Reactome, http://www.reactome.org p-STK4:p-SAV1 Reactome DB_ID: 2028266 Reactome Database ID Release 432028266 Reactome, http://www.reactome.org ReactomeREACT_120086 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004017 Reactome Database ID Release 4373829 Reactome, http://www.reactome.org p-STK3 dimer Reactome DB_ID: 2028277 Reactome Database ID Release 432028277 Reactome, http://www.reactome.org ReactomeREACT_118902 has a Stoichiometric coefficient of 2 p-MST2 dimer ACTIVATION GENE ONTOLOGYGO:0004017 Reactome Database ID Release 4373829 Reactome, http://www.reactome.org STK4:SAV1 Reactome DB_ID: 2028286 Reactome Database ID Release 432028286 Reactome, http://www.reactome.org ReactomeREACT_119056 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0016223 Reactome Database ID Release 43909784 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003837 Reactome Database ID Release 4373466 Reactome, http://www.reactome.org HP1 alpha binds Histone H3K9(me)3 Authored: Akkerman, JW, 2010-10-29 Chromobox (CBX) genes encode members of the Heterochromatin Protein (HP) family. HP1 was discovered in Drosophila as a dominant suppressor of position-effect variegation and a major component of heterochromatin. The HP1 family is evolutionarily conserved, with members in fungi, plants and animals. Most animal species have several HP1 isoforms; humans have HP alpha, beta and gamme encoded by the genes CBX5, CBX1 and CBX3 respectively. <br>The HP1 amino-terminal chromodomain binds methylated lysine-9 of histone H3, causing transcriptional repression (Lachner et al. 2001). A crystal structure of human HP1 alpha in complex with H3K9(me)3 peptide is available (Amaya et al. 2008). The highly-conserved carboxy-terminal chromoshadow domain enables dimerization and also serves as a docking site for proteins involved in a wide variety of nuclear functions, from transcription to nuclear architecture.<br> Edited: Jupe, S, 2010-11-12 Pubmed11242053 Pubmed17224041 Reactome Database ID Release 43994106 Reactome, http://www.reactome.org ReactomeREACT_25059 Reviewed: Ouwehand, WH, 2010-11-12 ACTIVATION GENE ONTOLOGYGO:0004157 Reactome Database ID Release 4373469 Reactome, http://www.reactome.org p-STK4 dimer Reactome DB_ID: 2028260 Reactome Database ID Release 432028260 Reactome, http://www.reactome.org ReactomeREACT_119219 has a Stoichiometric coefficient of 2 p-MST1 dimer ACTIVATION GENE ONTOLOGYGO:0017113 Reactome Database ID Release 4373530 Reactome, http://www.reactome.org p-STK3/N:p-SAV1 Reactome DB_ID: 2028690 Reactome Database ID Release 432028690 Reactome, http://www.reactome.org ReactomeREACT_119801 has a Stoichiometric coefficient of 1 Vesicular glutamate transport Authored: Jassal, B, 2009-06-30 Edited: Jassal, B, 2009-06-30 Pubmed11698620 Pubmed12151341 Pubmed8632143 Reactome Database ID Release 43428052 Reactome, http://www.reactome.org ReactomeREACT_19233 Reviewed: He, L, 2009-08-24 There are two classes of glutamate transporters; the excitatory amino acid transporters (EAATs) which depend on an electrochemical gradient of Na+ ions and vesicular glutamate transporters (VGLUTs) which don't. Together, these transporters uptake and release glutamate to mediate this neurotransmitter's excitatory signal and are part of the glutamate-gluatamine cycle.<br><br>Three members of the SLC17A gene family (7, 6 and 8) encode VGLUTs 1-3 respectively (Ni B et al, 1996; Takamori S et al, 2001; Takamori S et al, 2002 respectively). VGLUT1 (brain-specific Na+-dependent phopshate transporter, BNPI) and VGLUT2 (differentiation-associated Na+-dependent phosphate transporter, DNPI) were identified first and originally characterized as phosphate transporters. However, they are localized to synaptic vesicles, not the plasma membrane (like EAATs) and transport the organic anion glutamate into synaptic vesicles. This uptake is thought to be coupled to the proton electrochemical gradient generated by a vacuolar type H+-ATPase. They are all expressed in the CNS in neuron-rich areas but VGLUT3 is also expressed on astrocytes and in liver and kidney. ACTIVATION GENE ONTOLOGYGO:0004157 Reactome Database ID Release 4373469 Reactome, http://www.reactome.org Proton-coupled histidine and di-peptide cotransport A bioinformatics approach identified two further human transporters, PHT1 and PHT2 (Botka CW et al, 2000). These two transporters may be located on the lysosomal membrane for the proton-coupled export of histidine and di-peptides from lysosomal protein degradation. Authored: Jassal, B, 2009-06-30 Edited: Jassal, B, 2009-06-30 Pubmed11741232 Reactome Database ID Release 43428007 Reactome, http://www.reactome.org ReactomeREACT_19377 Reviewed: He, L, 2009-08-24 Type I Na+-coupled phosphate co-transport Authored: Jassal, B, 2009-07-06 Edited: Jassal, B, 2009-07-06 Four SLC17 genes are thought to encode type I Na+-dependent phosphate co-transporters in humans. SLC17A1 (NPT1) encodes Na+-dependent phosphate co-transporter 1 (Na/Pi-4). It is abundant in human kidney cortex, liver and brain and is important for the resorption of phosphate by the kidney. It does this by actively transporting phosphate into cells via Na+ cotransport in the renal brush border membrane (Chong SS et al, 1993).<br><br>Three close relatives of NPT1 have been identified through genomic analysis and designated NPT3 (SLC17A2), NPT4 (SLC17A3) and a putative small intestine sodium-dependent phosphate co-transporter (SLC17A4). None of these three proteins have been functionally characterized yet. Pubmed8288239 Reactome Database ID Release 43428609 Reactome, http://www.reactome.org ReactomeREACT_19157 Reviewed: He, L, 2009-08-24 ACTIVATION GENE ONTOLOGYGO:0016763 Reactome Database ID Release 4373611 Reactome, http://www.reactome.org Proton-coupled sialic acid co-transport Authored: Jassal, B, 2009-07-06 Edited: Jassal, B, 2009-07-06 Pubmed10581036 Pubmed10947946 Pubmed11751519 Reactome Database ID Release 43428585 Reactome, http://www.reactome.org ReactomeREACT_19297 Reviewed: He, L, 2009-08-24 SLC17A5 encodes a lysosomal sialic acid transporter, Sialin (AST, membrane glycoprotein HP59) (Verheijen FW et al, 1999; Fu C et al, 2001). Lysosomes export sialic acid which is derived from the degradation of glycosylated membrane proteins. This export is dependent in the proton electrochemical gradient across the lysosomal membrane. It is present in the pathological tumor vasculature of the lung, breast, colon, and ovary, but not in the normal vasculature, suggesting that the protein may be critical to pathological angiogenesis. Sialin is not expressed in a variety of normal tissues, but is significantly expressed in human fetal lung. Defects in SLC17A5 cause Salla disease (SD) and infantile sialic acid storage disorder (ISSD, also called N-acetylneuraminic acid storage disease (NSD)). Both are sialic acid storage diseases (SASDs) which are autosomal recessive neurodegenerative disorders characterized by hypotonia, cerebellar ataxia and mental retardation in very young infants (Verheijen FW et al, 1999; Aula N et al, 2000). ACTIVATION GENE ONTOLOGYGO:0017113 Reactome Database ID Release 4373530 Reactome, http://www.reactome.org Ferritin Complex Chains Converted from EntitySet in Reactome Reactome DB_ID: 434356 Reactome Database ID Release 43434356 Reactome, http://www.reactome.org ReactomeREACT_20324 Na+/I- cotransport (influx) by the Na+/I- symporter Authored: Jassal, B, 2009-07-17 Edited: Jassal, B, 2009-07-17 Human SLC5A5 encodes a Na+/I- symporter, NIS (Smanik PA et al, 1996). NIS is localized in the basolateral membrane facing the bloodstream and mediates iodide accumulation into thyrocytes.Defects in SLC5A5 cause congenital hypothyroidism due to dyshormonogenesis type 1 (CHDH1) (Fujiwara H et al, 1997). NIS, together with AIT (see next reaction), mediates iodide transfer from blood to the colloid lumen of thyrocytes. Pubmed8806637 Pubmed9171822 Reactome Database ID Release 43429591 Reactome, http://www.reactome.org ReactomeREACT_19340 Reviewed: He, L, 2009-08-24 Kinesin-14 is a dimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kinesin-14 proteins have a C-terminal motor domain. At least four members of the group (Dm Ncd, Sc KAR3, Cg CHO2, At KCBP) have been demonstrated to be minus-end directed motors (Walker et al. 1990), in contrast to the usual plus-end directed motility of other kinesin proteins. <br><br>During spindle formation, Kinesin-14 cross-links antiparallel microtubules and slides them together (thereby generating inward forces) to balance the outward forces generated by plus-end-directed kinesins of the Kinesin-5 family. Kinesin-14 family members also gather microtubule minus-ends and focus them into spindle poles. Mutation or inhibition of Kinesin-14 family members often results in disordered or splayed meiotic spindle poles (Ambrose et al. 2005). Pubmed15659646 Pubmed2146510 Reactome Database ID Release 43990478 Reactome, http://www.reactome.org ReactomeREACT_25242 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 Kinesins move along microtubules consuming ATP Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kinesins consume ATP to power the motor which allows them to move along microtubules. The motor region contains highly conserved Switch 1 (SSRSH) and 2 (DLAGSE) motifs which change conformation during ATP hydrolysis (Rice et al. 1999). These form a salt-bridge that, in myosin, closes the nucleotide-binding cleft, enabling the motor to hydrolyze ATP (Geeves & Holmes 1999). This closed conformation has now been seen by cryo-electron microscopy in human conventional kinesin (Sindelar & Downing 2010) and in a crystal structure of the frog kinesin-5 Eg5 (Parke et al. 2010). Pubmed10617199 Pubmed10872464 Pubmed12368902 Pubmed20018897 Pubmed20160108 Pubmed2142332 Pubmed8602245 Reactome Database ID Release 43983259 Reactome, http://www.reactome.org ReactomeREACT_24947 Reviewed: Ouwehand, WH, 2010-11-12 Kinesins bind microtubules All kinesins contain a motor domain or head, the position varies but it is structurally highly conserved (Kull et al. 1996, Sablin et al. 1996). The microtubule-binding site includes structural elements which interact with tubulin and undergo movement between the ADP and ATP bound states. The highly conserved switch I (SSRSH) and II (DLAGSE) motifs, which change in conformation during the ATP hydrolysis cycle, form a salt-bridge that, in myosin, closes the nucleotide-binding cleft, enabling the motor to hydrolyze ATP (Geeves & Holmes 1999). This closed conformation has now been seen in a crystal structure of the frog kinesin-5 Eg5 (Parke et al. 2010). Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Pubmed10872464 Pubmed15326200 Pubmed1607388 Pubmed16262723 Pubmed19116309 Pubmed20018897 Pubmed2521221 Pubmed2522352 Pubmed7929562 Pubmed8606779 Pubmed8606780 Reactome Database ID Release 43983266 Reactome, http://www.reactome.org ReactomeREACT_25309 Reviewed: Ouwehand, WH, 2010-11-12 Proton-coupled di- and tri-peptide cotransport Authored: Jassal, B, 2009-06-30 Edited: Jassal, B, 2009-06-30 Pubmed7756356 Pubmed7896779 Pubmed9299407 Reactome Database ID Release 43427998 Reactome, http://www.reactome.org ReactomeREACT_19313 Reviewed: He, L, 2009-08-24 The prototypical transporters of the SLC15 gene family are PEPT1 and PEPT2, which mediate the uptake of every possible di- and tri-peptide. PEPT1 (PTR1) is expressed mainly in the intestine (Liang R et al, 1995; Saito H et al, 1997) while PEPT2 (PTR2) is expressed in the kidney (Liu W et al, 1995). Sarco/endoplasmic reticulum Ca2+ ATPases (SERCAs) Converted from EntitySet in Reactome Reactome DB_ID: 418312 Reactome Database ID Release 43418312 Reactome, http://www.reactome.org ReactomeREACT_26227 Glutamate transport Authored: Jassal, B, 2009-06-30 Edited: Jassal, B, 2009-06-30 Pubmed16116111 Pubmed7521911 Pubmed7791878 Pubmed7859077 Pubmed9108121 Reactome Database ID Release 43428015 Reactome, http://www.reactome.org ReactomeREACT_19362 Reviewed: He, L, 2009-08-24 There are two classes of glutamate transporters; the excitatory amino acid transporters (EAATs) which depend on an electrochemical gradient of Na+ ions and vesicular glutamate transporters (VGLUTs) which don't. Together, these transporters uptake and release glutamate to mediate this neurotransmitter's excitatory signal and are part of the glutamate-gluatamine cycle.<br><br>The SLC1 gene family includes five high-affinity glutamate transporters encoded by SLC1, 2, 3, 6 and 7. These transporters can mediate transport of L-Glutamate, L-Aspartate and D-Aspartate with cotransport of 3 Na+ ions and H+ and antiport of a K+ ion. This mechanism allows glutamate into cells against a concentration gradient. This is a crucial factor in the protection of neurons against glutamate excitotoxicity in the CNS.<br><br>SLC1A1 encodes an excitatory amino-acid carrier 1 (EAAC1, also called EAAT3) (Shashidharan P et al, 1994; Arriza JL et al, 1994) and is abundant particularly in brain but also in liver, muscle, ovary, testis and in retinoblastoma cell lines. In the kidney, EAAC1 is present at apical membranes of proximal tubes. Defects in SLC1A1 may be a cause of dicarboxylicamino aciduria (glutamate-aspartate transport defect in the kidney and intestine). SLC1A2 encodes the glial-type high affinity glutamate transporter (GLT1, EAAT2) (Arriza JL et al, 1994). GLT1 is expressed mainly in the brain and is essential for terminating the postsynaptic action of glutamate by rapidly removing released glutamate from the synaptic cleft.<br><br>SLC1A3 encodes a sodium-dependent glutamate/aspartate transporter 1 (GLAST1, EAAT1). It is particularly abundant in the cerebellum and, like GLT1, plays a role in terminating the postsynaptic action of glutamate (Arriza JL et al, 1994). Defects in SLC1A3 are the cause of episodic ataxia type 6 (EA6), characterized by episodic ataxia, seizures, migraine and alternating hemiplegia (Jen JC et al, 2005).<br><br>SLC1A6 encodes an excitatory amino-acid transporter 4 (EAAT4) (Fairman WA et al, 1995) and is predominantly expressed in cerebellar Purkinje cells. SLC1A7 encodes an excitatory amino acid transporter 5 (EAAT5, retinal glutamate transporter) (Arriza JL et al, 1997) which is highly expressed in the retina. has a Stoichiometric coefficient of 3 p-T41,S45-beta-catenin:Axin:GSK3:CK1alpha:APC:PP2A:FAM123B complex Reactome DB_ID: 195313 Reactome Database ID Release 43195313 Reactome, http://www.reactome.org ReactomeREACT_10844 has a Stoichiometric coefficient of 1 FRAT1/FRAT2:GSK3beta Complex Reactome DB_ID: 1226052 Reactome Database ID Release 431226052 Reactome, http://www.reactome.org ReactomeREACT_76688 has a Stoichiometric coefficient of 1 p-S37,T41,S45-beta-catenin:Axin,GSK3:CK1alpha:APC:PP2A:FAM123B complex Reactome DB_ID: 195305 Reactome Database ID Release 43195305 Reactome, http://www.reactome.org ReactomeREACT_10861 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109273 Reactome, http://www.reactome.org ubiquitinated phospho-beta-catenin:SCF:beta-TrCP1 complex Reactome DB_ID: 195303 Reactome Database ID Release 43195303 Reactome, http://www.reactome.org ReactomeREACT_10202 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109498 Reactome, http://www.reactome.org Axin:CK1alpha:GSK3B:phospho-APC (20 aa repeat region):PP2A:FAM123B complex Reactome DB_ID: 196222 Reactome Database ID Release 43196222 Reactome, http://www.reactome.org ReactomeREACT_10381 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004126 Reactome Database ID Release 4373463 Reactome, http://www.reactome.org STK3:SAV1 Reactome DB_ID: 2028275 Reactome Database ID Release 432028275 Reactome, http://www.reactome.org ReactomeREACT_118889 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004850 Reactome Database ID Release 4373557 Reactome, http://www.reactome.org p-S33,S37,T41,S45-beta-catenin:Axin:GSK3:CK1alpha:APC:PP2A:FAM123B complex Reactome DB_ID: 195282 Reactome Database ID Release 43195282 Reactome, http://www.reactome.org ReactomeREACT_10610 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109469 Reactome, http://www.reactome.org p-S33,S37,T41,S45-beta-catenin:Axin:CK1alpha:GSK3B:phospho-APC (20 aa repeat region):PP2A:FAM123B complex Reactome DB_ID: 195297 Reactome Database ID Release 43195297 Reactome, http://www.reactome.org ReactomeREACT_10660 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109365 Reactome, http://www.reactome.org p-S33,S37,T41,S45-beta-catenin:Axin:CK1alpha:GSK3B:phospho-APC (20 aa repeat region):PP2A:FAM123B complex Reactome DB_ID: 195322 Reactome Database ID Release 43195322 Reactome, http://www.reactome.org ReactomeREACT_10886 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109441 Reactome, http://www.reactome.org SCF-beta-TrCP1 complex associated with phosphorylated beta-catenin Reactome DB_ID: 195311 Reactome Database ID Release 43195311 Reactome, http://www.reactome.org ReactomeREACT_10593 has a Stoichiometric coefficient of 1 ATP1A Converted from EntitySet in Reactome Reactome DB_ID: 936779 Reactome Database ID Release 43936779 Reactome, http://www.reactome.org ReactomeREACT_26744 Sodium/potassium-transporting ATPase subunit alpha Kinesin-9 is a dimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 KIF9 has the coiled-coil domain typical of the dimeric kinesins and is believed to function as a dimer. Reactome Database ID Release 43984775 Reactome, http://www.reactome.org ReactomeREACT_24934 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 43109900 Reactome, http://www.reactome.org ATP1B Converted from EntitySet in Reactome Reactome DB_ID: 936820 Reactome Database ID Release 43936820 Reactome, http://www.reactome.org ReactomeREACT_25792 Sodium/potassium-transporting ATPase subunit beta Kinesin-8 is a dimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kinesin-8 is a plus-end-directed dimeric kinesin with an internal motor domain (Loughlin et al. 2008) that can depolymerize stable microtubuless specifically at their plus-ends (Pereira et al. 1997) in a length-dependent manner (Varga et al. 2006). Human kinesin-8 KIF18A is believed to promote chromosome congression by attenuating chromosome oscillation magnitudes (Stumpff et al. 2008). Pubmed16906145 Pubmed17346968 Pubmed18267093 Pubmed18692476 Pubmed9060472 Reactome Database ID Release 43984609 Reactome, http://www.reactome.org ReactomeREACT_25182 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 4373502 Reactome, http://www.reactome.org Kinesin-7 is a dimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Human kinesin-7, or CENP-E was one of the first kinesins to be discovered (Yen et al. 1991). It is essential for mammalian development, having a role in stabilizing kinetochore-microtubule capture (Putkey et al. 2002), CENP-E is an integral component of kinetochore corona fibers that link centromeres to spindle microtubules and localizes to kinetochores throughout all phases of mitotic chromosome movement (early premetaphase through anaphase A). Though originally reported to be minus-end-directed it is now believed to be a plus-end-directed dimeric kinesin (Espeut et al. 2008). It is sequestered in the cytoplasm until nuclear envelope breakdown and then localizes to its chromosomal cargo at the kinetochores (Brown et al. 1996). Pubmed12361599 Pubmed18342609 Pubmed2022189 Pubmed8743943 Reactome Database ID Release 43984689 Reactome, http://www.reactome.org ReactomeREACT_25390 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 43109753 Reactome, http://www.reactome.org Kinesin-6 and RACGAP1 form the heterotetrameric complex centralspindlin Authored: Akkerman, JW, 2010-10-29 Cytokinesis requires the central spindle, which forms during anaphase by the bundling of antiparallel nonkinetochore microtubules. Microtubule bundling and completion of cytokinesis require MKLP1, a kinesin-6 family member, and RACGAP1 (MgcRacGap), which contains a RhoGAP domain. These form a heterotetrameric complex known as centralspindlin. Centralspindlin, but not its individual components, strongly promotes microtubule bundling in vitro. Edited: Jupe, S, 2010-11-15 Pubmed11782313 Pubmed1406973 Reactome Database ID Release 43984648 Reactome, http://www.reactome.org ReactomeREACT_25259 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 4373517 Reactome, http://www.reactome.org ATP2C1/2 Converted from EntitySet in Reactome Reactome DB_ID: 936887 Reactome Database ID Release 43936887 Reactome, http://www.reactome.org ReactomeREACT_26912 Kinesin-13 is a dimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kinesin-13 proteins are homodimeric with the kinesin motor in the middle of the amino acid sequence. They induce microtubule depolymerization by disassembling tubulin subunits from the polymer end (Desai et al. 1999). Pubmed17538014 Pubmed7822426 Pubmed9989498 Reactome Database ID Release 43990489 Reactome, http://www.reactome.org ReactomeREACT_25381 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 Kinesin-12 is a dimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kif15 (human kinesin-12) is by analogy with orthologous proteins believed to be a plus-end-directed motor. It cooperates with kinesin-5 to promote bipolar spindle assembly during cell division (Tanenbaum et al. 2009), with a mechanism that is distinct from that of kinesin-5 (Vanneste et al. 2009). Pubmed19818618 Pubmed19818619 Reactome Database ID Release 43984821 Reactome, http://www.reactome.org ReactomeREACT_25172 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 PP1A(Fe and Mn cofactors) Reactome DB_ID: 180029 Reactome Database ID Release 43180029 Reactome, http://www.reactome.org ReactomeREACT_17956 has a Stoichiometric coefficient of 1 Kinesin-5 is a homotetramer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kinesin-5 motors are bipolar homotetramers with two motor domains at each end, separated by a stalk/tail region (Cole et al. 1994). During mitosis, Kinesin-5 motors function near the spindle midzone to maintain pole to pole distance. Motor domains attach to microtubules from opposite poles and translocate towards the plus ends, thereby pushing the spindle poles apart (Kapitein et al. 2005). Kinesin-5 is also involved in axon growth (Myers & Baas 2007). Pubmed15875026 Pubmed17846176 Pubmed8083185 Pubmed8548803 Reactome Database ID Release 43984606 Reactome, http://www.reactome.org ReactomeREACT_25074 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 4 Chromokinesins form dimers Authored: Akkerman, JW, 2010-10-29 Chromokinesins consist of the kinesin-4 and kinesin-10 families.They act in various steps of mitosis, including chromosome condensation, metaphase alignment, chromosome segregation and cytokinesis (Mazumdar & Misteli 2005). Both families consist of homodimeric microtubule-based plus-end directed motor proteins (Sekine et al. 1994, Yajima et al. 2003). Edited: Jupe, S, 2010-11-15 Pubmed12606572 Pubmed15326200 Pubmed15946846 Pubmed7929562 Pubmed8599929 Reactome Database ID Release 43984671 Reactome, http://www.reactome.org ReactomeREACT_25110 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 Kinesin-3 is a dimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kinesin-3 drives the transport of synaptic vesicle precursors to axon terminals. Loss of the Caenorhabditis elegans protein Unc104, eqivalent to human KIF1A, results in decreased synaptic vesicles in axonal growth cones. In mice loss of KIF1A caused severe motor and sensory abnormalities associated with neuronal cell death (Yonekawa et al. 1998). Kinesin-3 is often described as monomeric, but has recently been shown to be functionally dimeric (Hammond et al. 2009). Pubmed19338388 Pubmed7528108 Pubmed7539720 Pubmed9548721 Reactome Database ID Release 43984733 Reactome, http://www.reactome.org ReactomeREACT_25043 Reviewed: Ouwehand, WH, 2010-11-12 has a Stoichiometric coefficient of 2 Kinesin-2 is a heterotrimer Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-15 Kinesin-2 is a heterotrimer with two different motor subunits and an accessory protein that is believed to interact with the cargo, or possibly regulate motor activity (Marszalek & Goldstein 2002). The motor domain interacts with microtubules and contains the ATPase used to translocate the holoenzyme along the microtubule. The coiled-coil stalk is where the two motor subunits interact with each other to form a stable heterodimer. The tail domains interact with the KAP3 non-motor accessory subunit. Kinesin-2 is a plus-end directed kinesin involved in photoreceptor cell function (Jimeno et al. 2006) and normal steady-state localization of late endosomes/lysosomes (Brown et al. 2005). Pubmed10722883 Pubmed16262723 Pubmed16337628 Reactome Database ID Release 43984708 Reactome, http://www.reactome.org ReactomeREACT_25360 Reviewed: Ouwehand, WH, 2010-11-12 p-T75-DARPP32s:PRKACA Reactome DB_ID: 180050 Reactome Database ID Release 43180050 Reactome, http://www.reactome.org ReactomeREACT_17157 has a Stoichiometric coefficient of 1 PP2B catalytic (Fe3+, Zn2+) Reactome DB_ID: 201779 Reactome Database ID Release 43201779 Reactome, http://www.reactome.org ReactomeREACT_18243 has a Stoichiometric coefficient of 1 beta-catenin:destruction complex Reactome DB_ID: 195301 Reactome Database ID Release 43195301 Reactome, http://www.reactome.org ReactomeREACT_10837 beta-catenin:Axin:GSK3:CK1alpha:APC:PP2A:FAM123B complex has a Stoichiometric coefficient of 1 pS45-beta-catenin:destruction complex Reactome DB_ID: 195277 Reactome Database ID Release 43195277 Reactome, http://www.reactome.org ReactomeREACT_10809 has a Stoichiometric coefficient of 1 pS45-beta-catenin:Axin:GSK3:CK1alpha:APC:PP2A:FAM123B complex ACTIVATION GENE ONTOLOGYGO:0004170 Reactome Database ID Release 43142075 Reactome, http://www.reactome.org GRB2:SOS1:HB-EGF:p-6Y-EGFR Reactome DB_ID: 2179409 Reactome Database ID Release 432179409 Reactome, http://www.reactome.org ReactomeREACT_124650 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004132 Reactome Database ID Release 4373593 Reactome, http://www.reactome.org destruction complex Axin:GSK3:CK1alpha:APC:PP2A:FAM123B complex Reactome DB_ID: 195250 Reactome Database ID Release 43195250 Reactome, http://www.reactome.org ReactomeREACT_10218 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004850 Reactome Database ID Release 4373557 Reactome, http://www.reactome.org HB-EGF:p-6Y-EGFR dimer Reactome DB_ID: 2179410 Reactome Database ID Release 432179410 Reactome, http://www.reactome.org ReactomeREACT_123414 has a Stoichiometric coefficient of 2 ACTIVATION GENE ONTOLOGYGO:0004799 Reactome Database ID Release 4373520 Reactome, http://www.reactome.org HB-EGF:p-6Y-EGFR Reactome DB_ID: 2179388 Reactome Database ID Release 432179388 Reactome, http://www.reactome.org ReactomeREACT_124369 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 4373505 Reactome, http://www.reactome.org PP2B catalytic (Fe3+, Zn2+):Active Calmodulin Reactome DB_ID: 201762 Reactome Database ID Release 43201762 Reactome, http://www.reactome.org ReactomeREACT_17373 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0016763 Reactome Database ID Release 4373611 Reactome, http://www.reactome.org PP2B complex Reactome DB_ID: 201788 Reactome Database ID Release 43201788 Reactome, http://www.reactome.org ReactomeREACT_17149 has a Stoichiometric coefficient of 1 K+-transporting ATPase alpha Converted from EntitySet in Reactome Reactome DB_ID: 937304 Reactome Database ID Release 43937304 Reactome, http://www.reactome.org ReactomeREACT_26795 ACTIVATION GENE ONTOLOGYGO:0004590 Reactome Database ID Release 4373492 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004588 Reactome Database ID Release 4373491 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004152 Reactome Database ID Release 4373535 Reactome, http://www.reactome.org Probable phospholipid-transporting ATPases Converted from EntitySet in Reactome Reactome DB_ID: 939735 Reactome Database ID Release 43939735 Reactome, http://www.reactome.org ReactomeREACT_26376 ACTIVATION GENE ONTOLOGYGO:0004151 Reactome Database ID Release 4373460 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004070 Reactome Database ID Release 4373459 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004096 Reactome Database ID Release 4376030 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004088 Reactome Database ID Release 4373458 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004855 Reactome Database ID Release 4374246 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004602 Reactome Database ID Release 4371675 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004855 Reactome Database ID Release 4374246 Reactome, http://www.reactome.org Alpha-3(V) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268631 Reactome Database ID Release 432268631 Reactome, http://www.reactome.org ReactomeREACT_124164 ACTIVATION GENE ONTOLOGYGO:0008892 Reactome Database ID Release 4374254 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004731 Reactome Database ID Release 4374238 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109365 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109412 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004731 Reactome Database ID Release 4374238 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109469 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004422 Reactome Database ID Release 4374210 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003920 Reactome Database ID Release 43514632 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109273 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0008253 Reactome Database ID Release 43109324 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004000 Reactome Database ID Release 432161186 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003876 Reactome Database ID Release 4376587 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 4374206 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0019206 Reactome Database ID Release 4373517 Reactome, http://www.reactome.org Alpha-1(XI) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268779 Reactome Database ID Release 432268779 Reactome, http://www.reactome.org ReactomeREACT_122384 ACTIVATION GENE ONTOLOGYGO:0003999 Reactome Database ID Release 4374212 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004731 Reactome Database ID Release 4374238 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004731 Reactome Database ID Release 4374238 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004000 Reactome Database ID Release 4374234 Reactome, http://www.reactome.org VLA-4:Osteopontin complex Reactome DB_ID: 265417 Reactome Database ID Release 43265417 Reactome, http://www.reactome.org ReactomeREACT_14112 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004001 Reactome Database ID Release 4376547 Reactome, http://www.reactome.org VLA-4:Thrombospondin-1 complex Reactome DB_ID: 265419 Reactome Database ID Release 43265419 Reactome, http://www.reactome.org ReactomeREACT_14539 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004018 Reactome Database ID Release 4373799 Reactome, http://www.reactome.org VLA-4:VCAM-1 Reactome DB_ID: 198199 Reactome Database ID Release 43198199 Reactome, http://www.reactome.org ReactomeREACT_11750 has a Stoichiometric coefficient of 1 Integrin alpha3beta1:Laminin-5 Reactome DB_ID: 216004 Reactome Database ID Release 43216004 Reactome, http://www.reactome.org ReactomeREACT_14028 has a Stoichiometric coefficient of 1 Alpha2beta1 complex with Laminin-5 Reactome DB_ID: 349628 Reactome Database ID Release 43349628 Reactome, http://www.reactome.org ReactomeREACT_14426 has a Stoichiometric coefficient of 1 VLA-4:Fibronectin complex Reactome DB_ID: 216035 Reactome Database ID Release 43216035 Reactome, http://www.reactome.org ReactomeREACT_14684 has a Stoichiometric coefficient of 1 Integrin alpha3beta1:Thrombospondin-1 Reactome DB_ID: 265407 Reactome Database ID Release 43265407 Reactome, http://www.reactome.org ReactomeREACT_14479 has a Stoichiometric coefficient of 1 Integrin alpha1beta1:Type IV collagen:Mg++ Reactome DB_ID: 215986 Reactome Database ID Release 43215986 Reactome, http://www.reactome.org ReactomeREACT_14130 has a Stoichiometric coefficient of 1 Integrin alpha1beta1:Laminin-1:Mg++ Reactome DB_ID: 215991 Reactome Database ID Release 43215991 Reactome, http://www.reactome.org ReactomeREACT_14643 has a Stoichiometric coefficient of 1 Laminin-1 Laminin-111 Reactome DB_ID: 215989 Reactome Database ID Release 43215989 Reactome, http://www.reactome.org ReactomeREACT_14571 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004639 Reactome Database ID Release 4373801 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004638 Reactome Database ID Release 4373802 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004643 Reactome Database ID Release 4373796 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004018 Reactome Database ID Release 4373799 Reactome, http://www.reactome.org Alpha-2(XI) propeptides Converted from EntitySet in Reactome Reactome DB_ID: 2268780 Reactome Database ID Release 432268780 Reactome, http://www.reactome.org ReactomeREACT_123397 ACTIVATION GENE ONTOLOGYGO:0003938 Reactome Database ID Release 4373793 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003937 Reactome Database ID Release 4373795 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0004019 Reactome Database ID Release 43111492 Reactome, http://www.reactome.org ACTIVATION GENE ONTOLOGYGO:0003921 Reactome Database ID Release 4373785 Reactome, http://www.reactome.org Integrin alpha1beta1 Reactome DB_ID: 215982 Reactome Database ID Release 43215982 Reactome, http://www.reactome.org ReactomeREACT_14015 has a Stoichiometric coefficient of 1 p-WWTR1:YWHAE Reactome DB_ID: 2028649 Reactome Database ID Release 432028649 Reactome, http://www.reactome.org ReactomeREACT_119876 has a Stoichiometric coefficient of 1 ACTIVATION GENE ONTOLOGYGO:0004642 Reactome Database ID Release 4373811 Reactome, http://www.reactome.org p-TAZ:DVL2 Reactome DB_ID: 2066300 Reactome Database ID Release 432066300 Reactome, http://www.reactome.org ReactomeREACT_120163 has a Stoichiometric coefficient of 1 p-WWTR1:DVL2 ACTIVATION GENE ONTOLOGYGO:0004641 Reactome Database ID Release 4373809 Reactome, http://www.reactome.org AMOT:WWTR1 (TAZ) Reactome DB_ID: 2028723 Reactome Database ID Release 432028723 Reactome, http://www.reactome.org ReactomeREACT_120141 has a Stoichiometric coefficient of 1 TAZ:ZO-2 Reactome DB_ID: 2064405 Reactome Database ID Release 432064405 Reactome, http://www.reactome.org ReactomeREACT_119772 TAZ:TJP2 WWTR1:TJP2 WWTR1:ZO-2 has a Stoichiometric coefficient of 1 TAZ:ZO-1 Reactome DB_ID: 2064404 Reactome Database ID Release 432064404 Reactome, http://www.reactome.org ReactomeREACT_119540 TAZ:TJP1 WWTR1:TJP1 WWTR1:ZO-1 has a Stoichiometric coefficient of 1 p-YAP1:YWHAB Reactome DB_ID: 2028630 Reactome Database ID Release 432028630 Reactome, http://www.reactome.org ReactomeREACT_119234 has a Stoichiometric coefficient of 1 YWHAB dimer Reactome DB_ID: 2028645 Reactome Database ID Release 432028645 Reactome, http://www.reactome.org ReactomeREACT_120053 has a Stoichiometric coefficient of 2 p-LATS2:p-MOB1 Reactome DB_ID: 2028584 Reactome Database ID Release 432028584 Reactome, http://www.reactome.org ReactomeREACT_120047 has a Stoichiometric coefficient of 1 p-LATS1:p-MOB1 Reactome DB_ID: 2028559 Reactome Database ID Release 432028559 Reactome, http://www.reactome.org ReactomeREACT_119829 has a Stoichiometric coefficient of 1 RAC:GDP Reactome DB_ID: 217287 Reactome Database ID Release 43217287 Reactome, http://www.reactome.org ReactomeREACT_14026 has a Stoichiometric coefficient of 1 Sia-Gal-GlcNAc-NOTCH4 Fringe-modified NOTCH4 Reactome DB_ID: 1911526 Reactome Database ID Release 431911526 Reactome, http://www.reactome.org ReactomeREACT_120105 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:NRAGE:CHE1 Reactome DB_ID: 205048 Reactome Database ID Release 43205048 Reactome, http://www.reactome.org ReactomeREACT_14340 has a Stoichiometric coefficient of 1 Sia-Gal-GlcNAc-NOTCH3 Fringe-modified NOTCH3 Reactome DB_ID: 1911527 Reactome Database ID Release 431911527 Reactome, http://www.reactome.org ReactomeREACT_120294 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:NRIF Reactome DB_ID: 205100 Reactome Database ID Release 43205100 Reactome, http://www.reactome.org ReactomeREACT_14508 has a Stoichiometric coefficient of 1 CNTN1:NOTCH1:DTX Contactin-1:Notch1 complex Reactome DB_ID: 373658 Reactome Database ID Release 43373658 Reactome, http://www.reactome.org ReactomeREACT_119728 has a Stoichiometric coefficient of 1 RAC:GTP Reactome DB_ID: 217289 Reactome Database ID Release 43217289 Reactome, http://www.reactome.org ReactomeREACT_14200 has a Stoichiometric coefficient of 1 NOTCH1:DTX Reactome DB_ID: 1852570 Reactome Database ID Release 431852570 Reactome, http://www.reactome.org ReactomeREACT_119931 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:NRIF:TRAF6 Reactome DB_ID: 204977 Reactome Database ID Release 43204977 Reactome, http://www.reactome.org ReactomeREACT_13913 has a Stoichiometric coefficient of 1 DNER:NOTCH1:DTX Reactome DB_ID: 1911551 Reactome Database ID Release 431911551 Reactome, http://www.reactome.org ReactomeREACT_119486 has a Stoichiometric coefficient of 1 TRAF6 homotrimer Reactome DB_ID: 421373 Reactome Database ID Release 43421373 Reactome, http://www.reactome.org ReactomeREACT_18543 has a Stoichiometric coefficient of 3 NICD1:DTX Reactome DB_ID: 1911468 Reactome Database ID Release 431911468 Reactome, http://www.reactome.org ReactomeREACT_119443 has a Stoichiometric coefficient of 1 Ubiquitinated NRIF Reactome DB_ID: 204965 Reactome Database ID Release 43204965 Reactome, http://www.reactome.org ReactomeREACT_14387 has a Stoichiometric coefficient of 1 Ub-NOTCH1:DTX:ARRB Reactome DB_ID: 1911542 Reactome Database ID Release 431911542 Reactome, http://www.reactome.org ReactomeREACT_118876 has a Stoichiometric coefficient of 1 K63 linked polyubiquitin chain Reactome DB_ID: 204940 Reactome Database ID Release 43204940 Reactome, http://www.reactome.org ReactomeREACT_14648 has a Stoichiometric coefficient of 63 NOTCH1:DTX:ARRB Reactome DB_ID: 1911487 Reactome Database ID Release 431911487 Reactome, http://www.reactome.org ReactomeREACT_119850 has a Stoichiometric coefficient of 1 pro-beta NGF:p75NTR:sortilin Reactome DB_ID: 193678 Reactome Database ID Release 43193678 Reactome, http://www.reactome.org ReactomeREACT_14400 has a Stoichiometric coefficient of 1 mature NGF homodimer:p75NTR Reactome DB_ID: 205123 Reactome Database ID Release 43205123 Reactome, http://www.reactome.org ReactomeREACT_14458 has a Stoichiometric coefficient of 1 NGF:p75NTR:NRAGE Reactome DB_ID: 205059 Reactome Database ID Release 43205059 Reactome, http://www.reactome.org ReactomeREACT_14388 has a Stoichiometric coefficient of 1 NOTCH1:DLL/JAG Reactome DB_ID: 1980055 Reactome Database ID Release 431980055 Reactome, http://www.reactome.org ReactomeREACT_119924 has a Stoichiometric coefficient of 1 mature beta-NGF homodimer Reactome DB_ID: 187017 Reactome Database ID Release 43187017 Reactome, http://www.reactome.org ReactomeREACT_10730 has a Stoichiometric coefficient of 2 Ub-NOTCH1 Reactome DB_ID: 1911534 Reactome Database ID Release 431911534 Reactome, http://www.reactome.org ReactomeREACT_119360 has a Stoichiometric coefficient of 1 pro-beta-NGF homodimer Reactome DB_ID: 187028 Reactome Database ID Release 43187028 Reactome, http://www.reactome.org ReactomeREACT_11017 has a Stoichiometric coefficient of 2 Ub-NOTCH1:NUMB:ITCH Reactome DB_ID: 1911544 Reactome Database ID Release 431911544 Reactome, http://www.reactome.org ReactomeREACT_119624 has a Stoichiometric coefficient of 1 pro-beta-NGF homodimer Reactome DB_ID: 166554 Reactome Database ID Release 43166554 Reactome, http://www.reactome.org ReactomeREACT_10374 has a Stoichiometric coefficient of 2 NOTCH1:NUMB:ITCH Reactome DB_ID: 1604458 Reactome Database ID Release 431604458 Reactome, http://www.reactome.org ReactomeREACT_119510 has a Stoichiometric coefficient of 1 NOTCH1:DLK1 Reactome DB_ID: 1911561 Reactome Database ID Release 431911561 Reactome, http://www.reactome.org ReactomeREACT_119507 has a Stoichiometric coefficient of 1 p75NTR:sortilin complex Reactome DB_ID: 193698 Reactome Database ID Release 43193698 Reactome, http://www.reactome.org ReactomeREACT_13954 has a Stoichiometric coefficient of 1 NOTCH1 Coactivator Complex:CDK8:CCNC Reactome DB_ID: 1604463 Reactome Database ID Release 431604463 Reactome, http://www.reactome.org ReactomeREACT_119042 has a Stoichiometric coefficient of 1 mature beta-NGF homodimer Reactome DB_ID: 187031 Reactome Database ID Release 43187031 Reactome, http://www.reactome.org ReactomeREACT_10239 has a Stoichiometric coefficient of 2 HES1:TLE Reactome DB_ID: 1911448 Reactome Database ID Release 431911448 Reactome, http://www.reactome.org ReactomeREACT_119912 has a Stoichiometric coefficient of 1 pro-beta-NGF homodimer Reactome DB_ID: 187029 Reactome Database ID Release 43187029 Reactome, http://www.reactome.org ReactomeREACT_10895 has a Stoichiometric coefficient of 2 NCOR:HDAC:TBL1 Reactome DB_ID: 1911465 Reactome Database ID Release 431911465 Reactome, http://www.reactome.org ReactomeREACT_120282 has a Stoichiometric coefficient of 1 Subtilisin/kexin convertase (Calcium dependant) Reactome DB_ID: 166611 Reactome Database ID Release 43166611 Reactome, http://www.reactome.org ReactomeREACT_10851 has a Stoichiometric coefficient of 1 CSL NCOR corepressor complex RBPJ:NCOR corepressor complex Reactome DB_ID: 350052 Reactome Database ID Release 43350052 Reactome, http://www.reactome.org ReactomeREACT_119627 has a Stoichiometric coefficient of 1 insulin Reactome DB_ID: 77385 Reactome Database ID Release 4377385 Reactome, http://www.reactome.org ReactomeREACT_3655 has a Stoichiometric coefficient of 1 insulin receptor Reactome DB_ID: 74706 Reactome Database ID Release 4374706 Reactome, http://www.reactome.org ReactomeREACT_3854 has a Stoichiometric coefficient of 2 activated insulin receptor Reactome DB_ID: 74702 Reactome Database ID Release 4374702 Reactome, http://www.reactome.org ReactomeREACT_4836 has a Stoichiometric coefficient of 1 DTX:ITCH Reactome DB_ID: 1604453 Reactome Database ID Release 431604453 Reactome, http://www.reactome.org ReactomeREACT_119862 has a Stoichiometric coefficient of 1 phospho-insulin receptor Reactome DB_ID: 77384 Reactome Database ID Release 4377384 Reactome, http://www.reactome.org ReactomeREACT_3809 has a Stoichiometric coefficient of 2 Ub-DTX:ITCH Reactome DB_ID: 1911536 Reactome Database ID Release 431911536 Reactome, http://www.reactome.org ReactomeREACT_120238 has a Stoichiometric coefficient of 1 PathwayStep3014 PathwayStep3013 PathwayStep3012 NGF:p75NTR:RIP2 Reactome DB_ID: 209578 Reactome Database ID Release 43209578 Reactome, http://www.reactome.org ReactomeREACT_14436 has a Stoichiometric coefficient of 1 NICD1:HIF1A Reactome DB_ID: 1911469 Reactome Database ID Release 431911469 Reactome, http://www.reactome.org ReactomeREACT_119980 has a Stoichiometric coefficient of 1 PathwayStep3011 PRDM4:Histone deacetylase Reactome DB_ID: 205111 Reactome Database ID Release 43205111 Reactome, http://www.reactome.org ReactomeREACT_14535 has a Stoichiometric coefficient of 1 Ub-p-NICD1 Reactome DB_ID: 1852621 Reactome Database ID Release 431852621 Reactome, http://www.reactome.org ReactomeREACT_119109 has a Stoichiometric coefficient of 1 PathwayStep3010 NGF ligand:p75NTR:Phospho-IRAK1:TRAF6 Reactome DB_ID: 209569 Reactome Database ID Release 43209569 Reactome, http://www.reactome.org ReactomeREACT_14600 has a Stoichiometric coefficient of 1 C5a receptor:C5a Reactome DB_ID: 375354 Reactome Database ID Release 43375354 Reactome, http://www.reactome.org ReactomeREACT_15215 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:Phospho-IRAK1:MYD88:TRAF6 Reactome DB_ID: 209574 Reactome Database ID Release 43209574 Reactome, http://www.reactome.org ReactomeREACT_13833 has a Stoichiometric coefficient of 1 Anaphylatoxin ligands of GPR77:GPR77 Reactome DB_ID: 964812 Reactome Database ID Release 43964812 Reactome, http://www.reactome.org ReactomeREACT_26791 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:Phospho-IRAK1:polyubiquitinated TRAF6:p62 Reactome DB_ID: 209542 Reactome Database ID Release 43209542 Reactome, http://www.reactome.org ReactomeREACT_14488 has a Stoichiometric coefficient of 1 DARC-1:CXCL8 Reactome DB_ID: 374123 Reactome Database ID Release 43374123 Reactome, http://www.reactome.org ReactomeREACT_14958 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:Phospho-IRAK1:TRAF6:p62 Reactome DB_ID: 209577 Reactome Database ID Release 43209577 Reactome, http://www.reactome.org ReactomeREACT_13898 has a Stoichiometric coefficient of 1 C3a receptor:C3a Reactome DB_ID: 444688 Reactome Database ID Release 43444688 Reactome, http://www.reactome.org ReactomeREACT_21565 has a Stoichiometric coefficient of 1 MYD88 homodimer Reactome DB_ID: 193932 Reactome Database ID Release 43193932 Reactome, http://www.reactome.org ReactomeREACT_14253 has a Stoichiometric coefficient of 2 Apelin receptor:apelin peptides Reactome DB_ID: 374316 Reactome Database ID Release 43374316 Reactome, http://www.reactome.org ReactomeREACT_15042 has a Stoichiometric coefficient of 1 IRAK1:MYD88 Reactome DB_ID: 193874 Reactome Database ID Release 43193874 Reactome, http://www.reactome.org ReactomeREACT_14310 has a Stoichiometric coefficient of 1 Angiotensin II receptor:Angiotensin II Reactome DB_ID: 389876 Reactome Database ID Release 43389876 Reactome, http://www.reactome.org ReactomeREACT_17732 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:Phospho-IRAK1:MYD88 Reactome DB_ID: 209572 Reactome Database ID Release 43209572 Reactome, http://www.reactome.org ReactomeREACT_14491 has a Stoichiometric coefficient of 1 Bradykinin receptor:Bradykinin Reactome DB_ID: 374321 Reactome Database ID Release 43374321 Reactome, http://www.reactome.org ReactomeREACT_14940 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:IRAK1:MYD88 Reactome DB_ID: 209570 Reactome Database ID Release 43209570 Reactome, http://www.reactome.org ReactomeREACT_13877 has a Stoichiometric coefficient of 1 Bombesin-like receptor:bombesin-like peptide Reactome DB_ID: 375359 Reactome Database ID Release 43375359 Reactome, http://www.reactome.org ReactomeREACT_15082 has a Stoichiometric coefficient of 1 NGF:p75NTR:PRDM4 Reactome DB_ID: 204972 Reactome Database ID Release 43204972 Reactome, http://www.reactome.org ReactomeREACT_14414 has a Stoichiometric coefficient of 1 p-NICD1:FBXW7:SKP1:CUL1:RBX1 Reactome DB_ID: 1604468 Reactome Database ID Release 431604468 Reactome, http://www.reactome.org ReactomeREACT_119071 has a Stoichiometric coefficient of 1 PathwayStep3008 PathwayStep3009 PathwayStep3006 PathwayStep3007 PathwayStep3004 PathwayStep3005 PathwayStep3001 K63 linked polyubiquitin chain Reactome DB_ID: 205097 Reactome Database ID Release 43205097 Reactome, http://www.reactome.org ReactomeREACT_13971 has a Stoichiometric coefficient of 63 Nociceptin receptor:Nociceptin Reactome DB_ID: 374725 Reactome Database ID Release 43374725 Reactome, http://www.reactome.org ReactomeREACT_15076 has a Stoichiometric coefficient of 1 PathwayStep3000 Neuropeptides B/W receptor:neuropeptides B/W Reactome DB_ID: 374779 Reactome Database ID Release 43374779 Reactome, http://www.reactome.org ReactomeREACT_15065 has a Stoichiometric coefficient of 1 PathwayStep3003 GPER:Estrogen Reactome DB_ID: 374150 Reactome Database ID Release 43374150 Reactome, http://www.reactome.org ReactomeREACT_14862 has a Stoichiometric coefficient of 1 PathwayStep3002 NGF ligand:p75NTR:NADE:14-3-3epsilon Reactome DB_ID: 205018 Reactome Database ID Release 43205018 Reactome, http://www.reactome.org ReactomeREACT_14418 has a Stoichiometric coefficient of 1 YWHAE dimer 14-3-3E homodimer Reactome DB_ID: 194364 Reactome Database ID Release 43194364 Reactome, http://www.reactome.org ReactomeREACT_14118 has a Stoichiometric coefficient of 2 Chemokine XC receptor 1: XC1 ligands Reactome DB_ID: 373357 Reactome Database ID Release 43373357 Reactome, http://www.reactome.org ReactomeREACT_15008 has a Stoichiometric coefficient of 1 Caspase-3 heterodimer Reactome DB_ID: 350888 Reactome Database ID Release 43350888 Reactome, http://www.reactome.org ReactomeREACT_14608 has a Stoichiometric coefficient of 1 CX3C receptor:fractalkine Reactome DB_ID: 373352 Reactome Database ID Release 43373352 Reactome, http://www.reactome.org ReactomeREACT_15045 has a Stoichiometric coefficient of 1 Active Caspase-3 heterotetramer Reactome DB_ID: 350870 Reactome Database ID Release 43350870 Reactome, http://www.reactome.org ReactomeREACT_14435 has a Stoichiometric coefficient of 2 CCR9:CCL25 Reactome DB_ID: 373329 Reactome Database ID Release 43373329 Reactome, http://www.reactome.org ReactomeREACT_15263 has a Stoichiometric coefficient of 1 active Caspase-2 Reactome DB_ID: 205098 Reactome Database ID Release 43205098 Reactome, http://www.reactome.org ReactomeREACT_14251 has a Stoichiometric coefficient of 1 CCR7:CCL19,21 Reactome DB_ID: 373319 Reactome Database ID Release 43373319 Reactome, http://www.reactome.org ReactomeREACT_15131 has a Stoichiometric coefficient of 1 Avtive Caspase-2 heterotetramer Reactome DB_ID: 350852 Reactome Database ID Release 43350852 Reactome, http://www.reactome.org ReactomeREACT_14323 has a Stoichiometric coefficient of 2 CCR6:CCL20 Reactome DB_ID: 373235 Reactome Database ID Release 43373235 Reactome, http://www.reactome.org ReactomeREACT_15252 has a Stoichiometric coefficient of 1 active Caspase2/3 Converted from EntitySet in Reactome Reactome DB_ID: 205013 Reactome Database ID Release 43205013 Reactome, http://www.reactome.org ReactomeREACT_14578 CCR10:CCL27,28 Reactome DB_ID: 373236 Reactome Database ID Release 43373236 Reactome, http://www.reactome.org ReactomeREACT_15017 has a Stoichiometric coefficient of 1 NGF:p75NTR:NADE Reactome DB_ID: 204978 Reactome Database ID Release 43204978 Reactome, http://www.reactome.org ReactomeREACT_14270 has a Stoichiometric coefficient of 1 Opioid receptor:opioid ligand Reactome DB_ID: 374302 Reactome Database ID Release 43374302 Reactome, http://www.reactome.org ReactomeREACT_15064 has a Stoichiometric coefficient of 1 Ubiquitinated NRIF:Sequestosome Reactome DB_ID: 205035 Reactome Database ID Release 43205035 Reactome, http://www.reactome.org ReactomeREACT_14383 has a Stoichiometric coefficient of 1 Ubiquitinated NRIF:Sequestosome Reactome DB_ID: 210946 Reactome Database ID Release 43210946 Reactome, http://www.reactome.org ReactomeREACT_14087 has a Stoichiometric coefficient of 1 CXCR4,7:CXCL12 Reactome DB_ID: 374203 Reactome Database ID Release 43374203 Reactome, http://www.reactome.org ReactomeREACT_15088 has a Stoichiometric coefficient of 1 CXCR5:CXCL13 Reactome DB_ID: 444551 Reactome Database ID Release 43444551 Reactome, http://www.reactome.org ReactomeREACT_21433 has a Stoichiometric coefficient of 1 CXCR6:CXCL16 Reactome DB_ID: 373797 Reactome Database ID Release 43373797 Reactome, http://www.reactome.org ReactomeREACT_15130 has a Stoichiometric coefficient of 1 CCR1,2,8:CCL16 Reactome DB_ID: 373268 Reactome Database ID Release 43373268 Reactome, http://www.reactome.org ReactomeREACT_14934 has a Stoichiometric coefficient of 1 CCR3,4,5:CCL5 Reactome DB_ID: 373299 Reactome Database ID Release 43373299 Reactome, http://www.reactome.org ReactomeREACT_15094 has a Stoichiometric coefficient of 1 CCBP2:CCBP2 ligands Reactome DB_ID: 443988 Reactome Database ID Release 43443988 Reactome, http://www.reactome.org ReactomeREACT_21521 has a Stoichiometric coefficient of 1 PathwayStep3031 PathwayStep3032 PathwayStep3030 PathwayStep3035 CXCR1:CXCR1 ligands Reactome DB_ID: 373801 Reactome Database ID Release 43373801 Reactome, http://www.reactome.org ReactomeREACT_15234 has a Stoichiometric coefficient of 1 PathwayStep3036 CXCL4 homotetramer Reactome DB_ID: 373835 Reactome Database ID Release 43373835 Reactome, http://www.reactome.org ReactomeREACT_14905 has a Stoichiometric coefficient of 4 PathwayStep3033 CXCR2:CXCR2 ligands Reactome DB_ID: 373773 Reactome Database ID Release 43373773 Reactome, http://www.reactome.org ReactomeREACT_14863 has a Stoichiometric coefficient of 1 PathwayStep3034 CXCR3:CXCR3 ligands Reactome DB_ID: 374141 Reactome Database ID Release 43374141 Reactome, http://www.reactome.org ReactomeREACT_15140 has a Stoichiometric coefficient of 1 PathwayStep3029 PathwayStep3028 PathwayStep3027 PathwayStep3026 Phospho-IKK-beta homdimer Reactome DB_ID: 193888 Reactome Database ID Release 43193888 Reactome, http://www.reactome.org ReactomeREACT_14544 has a Stoichiometric coefficient of 2 CCK:Cholecystokinin receptors Reactome DB_ID: 388532 Reactome Database ID Release 43388532 Reactome, http://www.reactome.org ReactomeREACT_17106 has a Stoichiometric coefficient of 1 IkB(alpha):NF-kB complex Reactome DB_ID: 193938 Reactome Database ID Release 43193938 Reactome, http://www.reactome.org ReactomeREACT_12767 has a Stoichiometric coefficient of 1 Endothelin:Endothelin receptor Reactome DB_ID: 388546 Reactome Database ID Release 43388546 Reactome, http://www.reactome.org ReactomeREACT_17601 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:Phospho-IRAK1:TRAF6:p62:IKK-beta Reactome DB_ID: 209533 Reactome Database ID Release 43209533 Reactome, http://www.reactome.org ReactomeREACT_14101 has a Stoichiometric coefficient of 1 Vasopressin receptor type 1:AVP Reactome DB_ID: 388502 Reactome Database ID Release 43388502 Reactome, http://www.reactome.org ReactomeREACT_17712 has a Stoichiometric coefficient of 1 NGF ligand:p75NTR:Phospho-IRAK1:TRAF6:p62:Phospho-IKK-beta Reactome DB_ID: 209565 Reactome Database ID Release 43209565 Reactome, http://www.reactome.org ReactomeREACT_14473 has a Stoichiometric coefficient of 1 Oxytocin:Oxytocin receptor Reactome DB_ID: 388495 Reactome Database ID Release 43388495 Reactome, http://www.reactome.org ReactomeREACT_18108 has a Stoichiometric coefficient of 1 NF-kB complex Reactome DB_ID: 194047 Reactome Database ID Release 43194047 Reactome, http://www.reactome.org ReactomeREACT_12775 has a Stoichiometric coefficient of 1 NF-kB complex Reactome DB_ID: 194043 Reactome Database ID Release 43194043 Reactome, http://www.reactome.org ReactomeREACT_12832 has a Stoichiometric coefficient of 1 MSH:Melanocortin receptors Reactome DB_ID: 388602 Reactome Database ID Release 43388602 Reactome, http://www.reactome.org ReactomeREACT_17748 has a Stoichiometric coefficient of 1 Ubiquitinated phospho-IkB Reactome DB_ID: 209535 Reactome Database ID Release 43209535 Reactome, http://www.reactome.org ReactomeREACT_14136 has a Stoichiometric coefficient of 1 CCR11:CCL19,21,25 Reactome DB_ID: 443970 Reactome Database ID Release 43443970 Reactome, http://www.reactome.org ReactomeREACT_21839 has a Stoichiometric coefficient of 1 PathwayStep3020 PathwayStep3021 PathwayStep3022 NGF ligand:p75NTR:Phospho-IRAK1:TRAF6:p62:aPKCi Reactome DB_ID: 209558 Reactome Database ID Release 43209558 Reactome, http://www.reactome.org ReactomeREACT_14236 has a Stoichiometric coefficient of 1 Substance K receptor:Neurokinin A peptide Reactome DB_ID: 383351 Reactome Database ID Release 43383351 Reactome, http://www.reactome.org ReactomeREACT_17342 has a Stoichiometric coefficient of 1 PathwayStep3023 IKK-beta homdimer Reactome DB_ID: 193897 Reactome Database ID Release 43193897 Reactome, http://www.reactome.org ReactomeREACT_13835 has a Stoichiometric coefficient of 2 Neuromedin K receptor:Neurokinin B peptide Reactome DB_ID: 383372 Reactome Database ID Release 43383372 Reactome, http://www.reactome.org ReactomeREACT_17561 has a Stoichiometric coefficient of 1 PathwayStep3024 Somatostatin receptor:somatostatin Reactome DB_ID: 374763 Reactome Database ID Release 43374763 Reactome, http://www.reactome.org ReactomeREACT_15046 has a Stoichiometric coefficient of 1 PathwayStep3025 Poly-ubiquitinated TRAF6 Reactome DB_ID: 205343 Reactome Database ID Release 43205343 Reactome, http://www.reactome.org ReactomeREACT_13062 has a Stoichiometric coefficient of 1 Substance P receptor:Substance P peptide Reactome DB_ID: 380119 Reactome Database ID Release 43380119 Reactome, http://www.reactome.org ReactomeREACT_17872 has a Stoichiometric coefficient of 1 PathwayStep3016 PathwayStep3015 PathwayStep3018 PathwayStep3017 PathwayStep3019 PathwayStep3050 Thrombin:Proteinase-activated receptors Reactome DB_ID: 389470 Reactome Database ID Release 43389470 Reactome, http://www.reactome.org ReactomeREACT_17427 has a Stoichiometric coefficient of 1 Orexin 1 receptor:Orexin A Reactome DB_ID: 389441 Reactome Database ID Release 43389441 Reactome, http://www.reactome.org ReactomeREACT_18037 has a Stoichiometric coefficient of 1 Orexin 2 receptor:Orexin B Reactome DB_ID: 389449 Reactome Database ID Release 43389449 Reactome, http://www.reactome.org ReactomeREACT_18148 has a Stoichiometric coefficient of 1 Neuropeptide FF receptor:Neuropeptide FF Reactome DB_ID: 389459 Reactome Database ID Release 43389459 Reactome, http://www.reactome.org ReactomeREACT_17284 has a Stoichiometric coefficient of 1 PathwayStep3057 NPY peptides:NPY receptors Reactome DB_ID: 388866 Reactome Database ID Release 43388866 Reactome, http://www.reactome.org ReactomeREACT_18251 has a Stoichiometric coefficient of 1 PathwayStep3058 Neurotensin:Neurotensin receptor Reactome DB_ID: 388920 Reactome Database ID Release 43388920 Reactome, http://www.reactome.org ReactomeREACT_17641 has a Stoichiometric coefficient of 1 PathwayStep3055 Galanin:Galanin receptor Reactome DB_ID: 389042 Reactome Database ID Release 43389042 Reactome, http://www.reactome.org ReactomeREACT_17234 has a Stoichiometric coefficient of 1 PathwayStep3056 Metastin:KiSS1R Reactome DB_ID: 389016 Reactome Database ID Release 43389016 Reactome, http://www.reactome.org ReactomeREACT_17482 has a Stoichiometric coefficient of 1 PathwayStep3053 PathwayStep3054 PathwayStep3051 Corticotropin:Melanocortin receptor 2 Reactome DB_ID: 388603 Reactome Database ID Release 43388603 Reactome, http://www.reactome.org ReactomeREACT_17097 has a Stoichiometric coefficient of 1 PathwayStep3052 PrRP:GRP10 Reactome DB_ID: 388889 Reactome Database ID Release 43388889 Reactome, http://www.reactome.org ReactomeREACT_17575 has a Stoichiometric coefficient of 1 PathwayStep3049 PathwayStep3048 Relaxin-2 Reactome DB_ID: 444853 Reactome Database ID Release 43444853 Reactome, http://www.reactome.org ReactomeREACT_21631 has a Stoichiometric coefficient of 1 Prokineticin receptors:prokineticin Reactome DB_ID: 444730 Reactome Database ID Release 43444730 Reactome, http://www.reactome.org ReactomeREACT_21880 has a Stoichiometric coefficient of 1 Relaxins 2 and 3 Converted from EntitySet in Reactome Reactome DB_ID: 444858 Reactome Database ID Release 43444858 Reactome, http://www.reactome.org ReactomeREACT_21742 PathwayStep3044 TRH:TRHR Reactome DB_ID: 444479 Reactome Database ID Release 43444479 Reactome, http://www.reactome.org ReactomeREACT_21699 has a Stoichiometric coefficient of 1 PathwayStep3045 NPS:NPSR Reactome DB_ID: 444726 Reactome Database ID Release 43444726 Reactome, http://www.reactome.org ReactomeREACT_21948 has a Stoichiometric coefficient of 1 PathwayStep3046 FPRL1:FPRL1 ligands Reactome DB_ID: 416459 Reactome Database ID Release 43416459 Reactome, http://www.reactome.org ReactomeREACT_18658 has a Stoichiometric coefficient of 1 PathwayStep3047 FPRL2:FPRL2 ligands Reactome DB_ID: 444553 Reactome Database ID Release 43444553 Reactome, http://www.reactome.org ReactomeREACT_21978 has a Stoichiometric coefficient of 1 PathwayStep3040 Motilin receptor:Motilin Reactome DB_ID: 444197 Reactome Database ID Release 43444197 Reactome, http://www.reactome.org ReactomeREACT_21682 has a Stoichiometric coefficient of 1 PathwayStep3041 FPR:fMet-Leu-Phe Reactome DB_ID: 444509 Reactome Database ID Release 43444509 Reactome, http://www.reactome.org ReactomeREACT_21972 has a Stoichiometric coefficient of 1 PathwayStep3042 PathwayStep3043 QRFP receptor:QRFP Reactome DB_ID: 389407 Reactome Database ID Release 43389407 Reactome, http://www.reactome.org ReactomeREACT_17289 has a Stoichiometric coefficient of 1 PathwayStep3038 PathwayStep3037 PathwayStep3039 The Ligand:GPCR:Gq complex dissociates Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43749452 Reactome, http://www.reactome.org ReactomeREACT_22263 Reviewed: D'Eustachio, P, 2010-05-21 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (q) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). G alpha (q) auto-inactivates by hydrolysing GTP to GDP Authored: Jupe, S, 2009-04-24 10:43:00 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jupe, S, 2009-09-09 Pubmed7937899 Reactome Database ID Release 43418582 Reactome, http://www.reactome.org ReactomeREACT_19186 Reviewed: Akkerman, JW, 2009-06-03 When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region. Inactive G alpha (q) reassociates with G beta:gamma Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed15951850 Pubmed16923326 Reactome Database ID Release 43750993 Reactome, http://www.reactome.org ReactomeREACT_22425 Reviewed: D'Eustachio, P, 2010-05-21 The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active G alpha (q) subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (q):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates. G alpha (q) inhibits PI3K alpha Authored: Jupe, S, 2009-03-26 17:21:12 Edited: Jupe, S, 2009-09-09 Phospholipase C activation is the classical signalling route for G alpha (q) but an additional mechanism is an inhibitory interaction between G alpha (q) and phosphatidylinositol 3-kinase alpha (PI3K alpha). There are several PI3K subtypes but only the p85 alpha/p110 alpha subtype (PI3K alpha) is a G alpha (q) effector (PMID: 18515384). Activated G alpha (q) inhibits PI3K alpha directly, in a GTP-dependent manner. G alpha(q) binding of PI3K competes with Ras, a PI3K activator (PMID: 16268778). Pubmed16268778 Pubmed18515384 Reactome Database ID Release 43416358 Reactome, http://www.reactome.org ReactomeREACT_19172 Reviewed: Akkerman, JW, 2009-06-03 PLC beta-mediated PIP2 hydrolysis Edited: Jupe, S, 2009-09-09 Phospholipase C (PLC) isozymes are a group of related proteins that cleave the polar head group from inositol phospholipids, typically in response to signals from cell surface receptors. They hydrolyze the highly phosphorylated lipid phosphatidylinositol 4,5-bisphosphate (PIP2) generating two products: inositol 1,4,5-trisphosphate (IP3), a universal calcium-mobilizing second messenger, and diacylglycerol (DAG), an activator of protein kinase C. PLC-beta isoforms are regulated by heterotrimeric GTP-binding proteins. PLC-beta 1 and 3 are widely expressed, with the highest concentrations found in (differing) specific regions of the brain. PLC-beta 2 is expressed at highest levels in cells of hematopoeitic origin; it is involved in leukocyte signaling and host defense. PLC-beta 4 is highly concentrated in cerebellar Purkinje and granule cells, the median geniculate body, whose axons terminate in the auditory cortex, and the lateral geniculate nucleus, where most retinal axons terminate in a visuotopic representation of each half of the visual field. Pubmed11015615 Pubmed2841328 Reactome Database ID Release 43114688 Reactome, http://www.reactome.org ReactomeREACT_960 G alpha (q) binds to Trio family RhoGEFs Authored: Jupe, S, 2009-03-24 18:05:59 Edited: Jupe, S, 2009-09-09 Pubmed17942708 Pubmed18936096 Reactome Database ID Release 43400586 Reactome, http://www.reactome.org ReactomeREACT_19301 Reviewed: Akkerman, JW, 2009-06-03 The Trio family of RhoA guanine nucleotide exchange factors (RhoGEFs) are directly activated by G alpha (q), possibly within a Gq:Trio:RhoA signalling complex, thereby linking Gq to RhoA-mediated processes such as cell migration, proliferation, and contraction. Like most other RhoGEFs, they have a tandem motif consisting of a Dbl homology (DH) and a pleckstrin homology (PH) domain. Trio and Duet have a number of other domains including an immunoglobin domains that may be involved in interacting with Rho, but the considerably smaller GEFT (p63RhoGEF) does not have any identifiable additional domains yet appears to be sufficient to mediate the activation of RhoA by G alpha (q). The structure represented by GEFT is proposed to represent the core of an ancient signal transduction pathway. PLC beta is activated by G alpha (q) Authored: Jupe, S, 2009-06-03 Edited: Jupe, S, 2009-09-09 Pubmed11753430 Pubmed15705797 Pubmed16182515 Reactome Database ID Release 43398188 Reactome, http://www.reactome.org ReactomeREACT_19270 Reviewed: Akkerman, JW, 2009-06-03 The active form of G protein alpha subunit q (Gq-alpha) was found to activate phospholipase C beta-1 (PLC-beta1), in investigations using bovine membranes. Subsequently, all 4 human isoforms have been shown to be activated by Gq, though activation of PLCbeta-4 is limited. In recombinant assays, several activated rat G alpha q family members were found to stimulate human PLC-beta isoforms with the same rank order of decreasing potency. PLC-beta1 stimulation was slightly more than for PLC-beta3; PLC-beta3 stimulation was 10-fold greater than for beta-2. PLC-beta2 is expressed specifically in hematopoietic cells. PLC-beta acts directly on Gq to accelerate hydrolysis of bound GTP, thus PLC-betas are GTPase activating proteins (GAPs). The crystal structure of the C-terminal region from Turkey PLC-beta, revealed a novel fold composed almost entirely of three long helices forming a coiled-coil that dimerizes along its long axis in an antiparallel orientation. The extent of the dimer interface and gel exclusion chromatography data suggest that PLC-betas are functionally dimeric. GRK2 sequesters activated Gq Authored: Jupe, S, 2009-03-27 16:14:26 Edited: Jupe, S, 2009-09-09 GRK2 can inhibit GPCR signaling via phosphorylation-independent sequestration of Gq/11/14 subunits utilising its RGS homology (RH) domain. GRK2 may be an effector of activated Gq, initiating signalling cascades other than the classical PLC beta signalling associated with Gq. Pubmed10567430 Pubmed16339447 Pubmed18936096 Reactome Database ID Release 43416516 Reactome, http://www.reactome.org ReactomeREACT_19213 Reviewed: Akkerman, JW, 2009-06-03 GRK5 sequesters activated Gq Authored: Jupe, S, 2009-03-27 16:14:26 Edited: Jupe, S, 2009-09-09 GRKs are serine/threonine kinases that phosphorylate GPCRs leading to receptor desensitization. GRK5 appears to be the predominant regulator of PAR1 desensitization in endothelial cells. Pubmed10861009 Reactome Database ID Release 43416510 Reactome, http://www.reactome.org ReactomeREACT_19325 Reviewed: Akkerman, JW, 2009-06-03 PathwayStep3074 PathwayStep3073 PathwayStep3076 PathwayStep3075 PathwayStep3078 PathwayStep3077 PathwayStep3079 Liganded G12/13-activating GPCRs bind inactive heterotrimeric G-protein G12/13 About 25 receptors are reported to couple to the G12/13 G protein subtype (Riobo & Manning, 2005).Direct assay methods have not identified a receptor that only couples with G12. At least one receptor (5-HT4) only couples with G13, but most other receptors are reported to couple with both G12 and G13. Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed12433842 Pubmed15749160 Pubmed18374420 Reactome Database ID Release 43751027 Reactome, http://www.reactome.org ReactomeREACT_22424 Reviewed: D'Eustachio, P, 2010-05-21 PathwayStep3070 PathwayStep3072 PathwayStep3071 Liganded G12/13-activating GPCR acts as a GEF for G12/13 Authored: Jupe, S, 2009-02-26 15:51:29 Edited: Jupe, S, 2010-05-26 Pubmed19212140 Pubmed3086311 Pubmed3113327 Pubmed9032437 Reactome Database ID Release 43751029 Reactome, http://www.reactome.org ReactomeREACT_22370 Reviewed: D'Eustachio, P, 2010-05-21 The liganded receptor undergoes a conformational change, generating a signal that is propagated in a manner that is not completely understood to the the G-protein. This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. The Ligand:GPCR:G12/13 complex dissociates Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed18577758 Reactome Database ID Release 43751019 Reactome, http://www.reactome.org ReactomeREACT_22264 Reviewed: D'Eustachio, P, 2010-05-21 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (12/13) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). has a Stoichiometric coefficient of 2 ROCK activation by Rho Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2009-05-20 09:50:28 Pubmed12778124 Pubmed8617235 Pubmed9920927 Reactome Database ID Release 43419049 Reactome, http://www.reactome.org ReactomeREACT_19389 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Rho-associated, coiled-coil containing protein kinases (ROCKs) are primarily known as downstream effectors of Rho, but they can also be activated by arachidonic acid, which binds to the pleckstrin homology domain, releasing an autoinhibitory loop within ROCK allowing catalytic activity. Multiple targets of ROCK contribute to the stabilization of actin filaments and the generation of actin-myosin contractile force. LARG activation by G alpha 12/13 Authored: Jupe, S, 2009-03-18 10:07:56 Edited: Jupe, S, 2009-09-09 Leukemia-associated RhoGEF (LARG) serves as a G alpha responsive RhoGEF for G alpha 12, 13 and possibly G alpha q. G alpha 12 activity appears to depend on LARG tyrosine phosphorylation by Tec-family kinases (Suzuki et al. 2003) or FAK (Chikumi et al. 2002). The involvement of LARG may be specific to particular receptor signalling pathways; RNAi-mediated knockdown of LARG specifically inhibited thrombin signaling via PAR1 but not LPA receptors (Wang et al 2004). Pubmed11799111 Pubmed12515866 Pubmed12771155 Pubmed15143072 Pubmed15951850 Reactome Database ID Release 43398184 Reactome, http://www.reactome.org ReactomeREACT_19158 Reviewed: Akkerman, JW, 2009-06-03 PathwayStep3059 LARG binds plexin B1 Authored: Jupe, S, 2009-03-18 10:07:56 Edited: Jupe, S, 2009-09-09 LARG binds plexin-B1, a transmembrane receptor for the semaphorin Sema4D. Binding of Sema4D to plexin-B1 stimulates RhoA activation. Pubmed12123608 Pubmed15951850 Reactome Database ID Release 43398185 Reactome, http://www.reactome.org ReactomeREACT_19360 Reviewed: Akkerman, JW, 2009-06-03 G alpha (12/13) auto-inactivates by hydrolysing GTP to GDP Authored: Jupe, S, 2009-04-24 08:15:10 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jupe, S, 2009-09-09 Pubmed7937899 Reactome Database ID Release 43418574 Reactome, http://www.reactome.org ReactomeREACT_19123 Reviewed: Akkerman, JW, 2009-06-03 When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region. G alpha (13) activates Rho guanine nucleotide exchange factor 1 (p115-RhoGEF) Edited: Jupe, S, 2009-09-09 Pubmed11313914 Pubmed15951850 Reactome Database ID Release 43114548 Reactome, http://www.reactome.org ReactomeREACT_56 p115-RhoGEF is a potent GTPase activating protein (GAP) for both G alpha 12 and G alpha 13 subunits. More importantly, the interaction between activated G alpha 13 (but not G alpha 12) triggers p115-RhoGEF activity. While this pathway may important in vivo, in prostate-derived PC-3 cells RNAi mediated knockdown of p115-RhoGEF levels had no effect on the response to thrombin (PMID: 15143072). p115-RhoGEF activation of Rac1 At the beginning of this reaction, 1 molecule of 'GTP', and 1 molecule of 'Deactivated RAC1' are present. At the end of this reaction, 1 molecule of 'Activated RAC1', and 1 molecule of 'GDP' are present.<br><br> This reaction is mediated by the 'guanyl-nucleotide exchange factor activity' of 'Activated 115Rho GEF'.<br> Edited: Jupe, S, 2009-09-09 Pubmed10648409 Reactome Database ID Release 43114544 Reactome, http://www.reactome.org ReactomeREACT_1214 Rac1 activation of PI3K Edited: Jupe, S, 2009-09-09 PIP3 produced by PI3K activity is essential for receptor-driven stimulation of Rac activation, but PI3K also lies downstream of Rac, as Rac1 can form a complex with PI3K alpha leading to its activation. Pubmed11803464 Pubmed7627555 Pubmed7744773 Pubmed8645157 Reactome Database ID Release 43114542 Reactome, http://www.reactome.org ReactomeREACT_754 GEFs activate RhoA,B,C Authored: Jupe, S, 2009-04-29 09:05:05 Edited: Jupe, S, 2009-09-09 Guanine nucleotide exchange factors (GEFs) activate GTPases by enhancing the exchange of bound GDP for GTP. Much evidence points to GEFs being critical mediators of Rho GTPase activation (Schmidt and Hall, 2002). Many GEFs are known to be highly specific for a particular GTPase, e.g. Fgd1/Cdc42 and p115RhoGEF/Rho (Hart et al., 1996, Zheng et al., 1996). Others have a broader spectrum and activate several GTPases, e.g. Vav1 for Rac, Rho, and Cdc42 (Hart et al, 1994). Pubmed12101119 Pubmed16212495 Pubmed8276860 Pubmed8810315 Pubmed9308960 Reactome Database ID Release 43419166 Reactome, http://www.reactome.org ReactomeREACT_19216 Reviewed: Akkerman, JW, 2009-06-03 PathwayStep3065 PathwayStep3064 PathwayStep3063 PathwayStep3062 PathwayStep3069 PathwayStep3068 PathwayStep3067 PathwayStep3066 PathwayStep3061 PathwayStep3060 Gbeta:gamma recruits PI3K gamma Authored: Jupe, S, 2009-03-02 16:20:47 Edited: Jupe, S, 2009-09-09 G beta:gamma recruits PI3K gamma from the cytosol to the plasma membrane by interacting with the p101 regulatory subunit. G beta:gamma activates PI3Kgamma via interactions with the catalytic p110 subunit. Pubmed12507995 Reactome Database ID Release 43392295 Reactome, http://www.reactome.org ReactomeREACT_19289 Reviewed: Akkerman, JW, 2009-06-03 G beta:gamma activated PI3Kgamma converts PIP2 to PIP3 Authored: Jupe, S, 2009-03-02 16:22:24 Biochemical and cellular studies have shown that the p101/p110 form of PI3K gamma is substantially activated by G beta:gamma in a manner that is dependent on p101. EC Number: 2.7.1.153 Edited: Jupe, S, 2009-09-09 Pubmed7624799 Reactome Database ID Release 43392300 Reactome, http://www.reactome.org ReactomeREACT_19310 Reviewed: Akkerman, JW, 2009-06-03 Inactive G alpha (12/13) reassociates with G beta:gamma Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed15951850 Pubmed16923326 Reactome Database ID Release 43751039 Reactome, http://www.reactome.org ReactomeREACT_22368 Reviewed: D'Eustachio, P, 2010-05-21 The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active alpha subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (12/13):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates into the inactive heterotrimeric G-protein. has a Stoichiometric coefficient of 2 G Protein trimer formation (olfactory) Authored: Caudy, M, 2009-03-02 00:28:58 Edited: Caudy, M, 2009-04-28 19:52:59 Pubmed14983052 Pubmed17509148 Pubmed17873857 Pubmed17973576 Pubmed18043707 Pubmed1840504 Pubmed9459443 Reactome Database ID Release 43381749 Reactome, http://www.reactome.org ReactomeREACT_15416 Reviewed: Vosshall, L, 2008-12-02 23:19:16 The heterotrimeric guanine nucleotide-binding proteins (G-proteins) function to transduce signals from this vast panoply of receptors to effector systems including ion channels and enzymes that alter the rate of production, release or degradation of intracellular second messengers. GPCRs activate the G-proteins, which consist of an alpha-subunit that binds and hydrolyses guanosine triphosphate (GTP), a beta and a gamma subunit. Olfactory Receptor - G Protein olfactory trimer complex formation Authored: Caudy, M, 2009-03-02 01:45:35 Edited: Caudy, M, 2009-02-28 23:58:34 Edited: Caudy, M, 2009-04-28 19:52:59 Edited: Caudy, M, 2009-05-26 21:05:28 Olfactory receptors (ORs) have diverse protein sequences but can be assigned to subfamilies on the basis of sequence relationships. Odorants and pheromones bind to these seven transmembrane domain G-protein-coupled receptors that permit signal transduction. These receptors are encoded by large multigene families that evolved in mammal species in function of specific olfactory needs. Members of the same subfamily have related sequences and are likely to recognize structurally related odorants. <br> Of the 960 human OR genes and pseudogenes, there is experimental evidence which indicates that at least 437 actually are expressed in human olfactory epithelium; this includes 357 OR genes, and 80 OR pseudogenes (Zhang, 2007). These 357 olfactory-expressed OR genes are therefore expected to be functional in the Olfactory Signaling Pathway, and to interact directly with human G alpha olf in human olfactory cells.<p>(Note: A subset of 200 of these 357 OR genes are shown as components of OR-G Protein reaction. The others will be added to Reactome later.)<br> Pubmed14983052 Pubmed17509148 Pubmed17873857 Pubmed17973576 Pubmed18043707 Pubmed1840504 Pubmed9459443 Reactome Database ID Release 43381750 Reactome, http://www.reactome.org ReactomeREACT_15515 Reviewed: Vosshall, L, 2008-12-02 23:19:16 Reviewed: Vosshall, L, 2010-02-22 Gbeta:gamma activation of PLC beta Authored: Jupe, S, 2009-03-16 10:02:22 Edited: Jupe, S, 2009-09-09 G beta:gamma engages the PH domain of Phospholipase C beta, stimulating phospholipase activity, resulting in increased PIP2 hydrolysis. Pubmed15611108 Pubmed17115053 Reactome Database ID Release 43398040 Reactome, http://www.reactome.org ReactomeREACT_19150 Reviewed: Akkerman, JW, 2009-06-03 PLC beta-mediated PIP2 hydrolysis Authored: Jupe, S, 2009-03-18 10:07:56 Edited: Jupe, S, 2009-09-09 Phospholipase C (PLC) isozymes are a group of related proteins that cleave the polar head group from inositol phospholipids, typically in response to signals from cell surface receptors. They hydrolyze the highly phosphorylated lipid phosphatidylinositol 4,5-bisphosphate (PIP2) generating two products: inositol 1,4,5-trisphosphate (IP3), a universal calcium-mobilizing second messenger, and diacylglycerol (DAG), an activator of protein kinase C. PLC-beta isoforms are regulated by heterotrimeric GTP-binding proteins. PLC-beta 1 and 3 are widely expressed, with the highest concentrations found in (differing) specific regions of the brain. PLC-beta 2 is expressed at highest levels in cells of hematopoeitic origin; it is involved in leukocyte signaling and host defense. PLC-beta 4 is highly concentrated in cerebellar Purkinje and granule cells, the median geniculate body, whose axons terminate in the auditory cortex, and the lateral geniculate nucleus, where most retinal axons terminate in a visuotopic representation of each half of the visual field. Pubmed11015615 Pubmed2841328 Reactome Database ID Release 43398193 Reactome, http://www.reactome.org ReactomeREACT_19319 Reviewed: Akkerman, JW, 2009-06-03 The receptor:G-protein complex releases GDP Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 G proteins are inactive in the GDP-bound state. The ternary complex neurotransmitter:receptor:G-protein releases GDP. Pubmed16892066 Reactome Database ID Release 43167419 Reactome, http://www.reactome.org ReactomeREACT_15549 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Opioid binds MOR Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed7905839 Reactome Database ID Release 43112042 Reactome, http://www.reactome.org ReactomeREACT_15473 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The binding of an opiate peptide to the mu opiate receptor stabilises the receptor conformation in a state of high affinity, both for the ligand itself, and for the G-protein. The high affinity receptor complex binds to G-protein Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed10215864 Pubmed11786497 Pubmed16415903 Pubmed9544801 Reactome Database ID Release 43167408 Reactome, http://www.reactome.org ReactomeREACT_15298 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The high affinity complex beta-endorphin:mu opioid receptor binds to the heterotrimeric G-protein. This binding stabilises a conformation of the G-protein alpha i subunit presenting a low affinity for GDP, but a high affinity for GTP PathwayStep3099 PathwayStep3096 PathwayStep3095 PathwayStep3098 PathwayStep3097 PathwayStep3092 PathwayStep3091 PathwayStep3094 PathwayStep3093 PathwayStep3090 The receptor:G-protein complex binds GTP Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed16892066 Reactome Database ID Release 43167429 Reactome, http://www.reactome.org ReactomeREACT_15491 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The ternary complex neurotransmitter:receptor:G-protein binds GTP, resulting in activation of G protein. The receptor:G-protein complex dissociates Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed8208289 Reactome Database ID Release 43112271 Reactome, http://www.reactome.org ReactomeREACT_15336 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The ternary complex neurotransmitter:receptor:G-protein dissociates. Both the alpha-i subunit and beta:gamma complex become active, by conformational transition and surface exposure, and both are free to activate downstream effectors. G-protein alpha subunit is inactivated Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed7937899 Pubmed8073283 Reactome Database ID Release 43167415 Reactome, http://www.reactome.org ReactomeREACT_15316 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Slow intrisinc GTPase activity results in an inactivation of the alpha-i subunit by hydrolyzing GTP to GDP. G-protein beta-gamma subunits rebind the alpha-GDP subunit Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Gbetagamma rebinds Galpha-olfactory:GDP, stopping its activity Pubmed8521505 Reactome Database ID Release 43167433 Reactome, http://www.reactome.org ReactomeREACT_15387 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Opioid dissociates from MOR Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Different ligands of the MOR receptor can promote MOR phosphorylation, uncoupling, endocytosis or inactivation. For example, the endogenous peptide ligands at the MOR induce rapid desensitization, endocytosis and rapid receptor recycling. By contrast, morphine induces little to no endocytosis, tolerance and dependence. The agonist-dependent phosphorylation of opioid receptors changes the receptor conformation and increases the affinity of the receptors for cytosolic beta-arrestin proteins. This results in an uncoupling of G protein signalling and recruitment of the endocytotic machinery leading to receptor internalization and rapid resensitization. By contrast, PKC phosphorylation by non internalizing opioid ligands (e.g., morphine) cause receptors to remain inactivated in the plasma membrane, leading to signaling desensitization and opioid tolerance. In this case receptors appear to require activity of a phosphatase to be resensitized. Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed15272312 Pubmed16682505 Reactome Database ID Release 43167427 Reactome, http://www.reactome.org ReactomeREACT_15388 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Activation of PLC beta-1/4 Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed11753430 Pubmed15705797 Pubmed16182515 Reactome Database ID Release 43111870 Reactome, http://www.reactome.org ReactomeREACT_15402 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The active form of G protein alpha subunit q (Gq-alpha) was found to activate phospholipase C beta-1 (PLC-beta1), in investigations using bovine membranes. Subsequently, all 4 human isoforms have been shown to be activated by Gq, though activation of PLCbeta-4 is limited. In recombinant assays, several activated rat G alpha q family members were found to stimulate human PLC-beta isoforms with the same rank order of decreasing potency. PLC-beta1 stimulation was slightly more than for PLC-beta3; PLC-beta3 stimulation was 10-fold greater than for beta-2. PLC-beta2 is expressed specifically in hematopoietic cells. PLC-beta acts directly on Gq to accelerate hydrolysis of bound GTP, thus PLC-betas are GTPase activating proteins (GAPs). The crystal structure of the C-terminal region from Turkey PLC-beta, revealed a novel fold composed almost entirely of three long helices forming a coiled-coil that dimerizes along its long axis in an antiparallel orientation. The extent of the dimer interface and gel exclusion chromatography data suggest that PLC-betas are functionally dimeric. PIP2 hydrolysis Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 3.1.4.11 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed11118617 Reactome Database ID Release 43111879 Reactome, http://www.reactome.org ReactomeREACT_15353 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The phospholipase C (PLC) family of enzymes is both diverse and complex. The isoforms beta, gamma and delta (each have subtypes) make up the members of this family. One type, PLC-beta1, hydrolyzes phosphatidylinositol bisphosphate (PIP2) into two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores while DAG activates protein kinase C isoforms which are involved in regulatory functions. Inactivation of PLC beta Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 PLC-beta1 is a GTPase-activating protein (GAP) for Gq-alpha, exchanging GTP for GDP and releasing the alpha subunit to cycle back to the membrane and reassociate with the beta-gamma subunits. Between itself and the receptor, they regulate the amplitude of the PLC signal and the rates of signal initiation and termination. Pubmed1322796 Reactome Database ID Release 43112037 Reactome, http://www.reactome.org ReactomeREACT_15301 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Phosphorylation of cPLA2 by ERK-2 Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 ERK2 phosphorylates cPLA2, increasing enzymatic activity. The site of cPLA2 phosphorylation by ERK2 is Ser-505, the major site of cPLA2 phosphorylation observed in phorbol ester-treated cells. Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed8381049 Reactome Database ID Release 43111898 Reactome, http://www.reactome.org ReactomeREACT_23990 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 has a Stoichiometric coefficient of 2 Phospho-cPLA2 translocates to membranes when intracellular calcium levels increase Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed11375391 Pubmed1904318 Pubmed9468497 Reactome Database ID Release 43111881 Reactome, http://www.reactome.org ReactomeREACT_15311 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The 85kDa cytosolic phospholipase A2 (cPLA2 - PLA2G4A) is involved in cell signalling processes and inflammatory response and is regulated by phosphorylation and calcium concentrations. cPLA2 is phosphorylated at Ser727 and by a MAPK at Ser505. When phosphorylation is coupled with an influx of calcium ions, PLA2 becomes stimulated and translocates to the membrane where it releases arachidonic acid (AA) from membrane phospholipids. Calcium does not itself activate cPLA2. cPLA2 contains an N-terminal calcium-dependent phospholipid binding domain (CaLB) which shares homology with C2 domains (plays roles in signal transduction and membrane trafficking) and binds it to the membrane. Arachidonic acid is both a signalling molecule and the precursor for other signalling molecules termed eicosanoids (e.g., prostaglandins, leukotrienes and platelet-activating factor). A strict regulation of the activity of phospholipase enzyme is essential. Cations Converted from EntitySet in Reactome Reactome DB_ID: 426219 Reactome Database ID Release 43426219 Reactome, http://www.reactome.org ReactomeREACT_24030 PathwayStep3089 PathwayStep3088 PathwayStep3087 PathwayStep3086 PathwayStep3085 Cations Converted from EntitySet in Reactome Reactome DB_ID: 426221 Reactome Database ID Release 43426221 Reactome, http://www.reactome.org ReactomeREACT_24868 PathwayStep3084 PathwayStep3083 PathwayStep3082 PathwayStep3081 PathwayStep3080 Glucagon-like receptor 2 binds GLP2 Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Glucagon-like peptide 2 (GLP-2) (Drucker DJ 1999) is a 33-aa proglucagon-derived peptide produced by intestinal enteroendocrine cells. GLP-2 stimulates intestinal growth. The effects of GLP-2 are mediated by the GLP2 receptor (Munroe DG et al, 1999), which can couple with G protein alpha s subunit that activates adenylyl cyclase (Koehler JA et al, 2005). Pubmed10322410 Pubmed15471943 Pubmed9990065 Reactome Database ID Release 43420123 Reactome, http://www.reactome.org ReactomeREACT_18322 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 GIP receptor binds gastric inhibitory peptide Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Gastric inhibitory polypeptide (GIP, glucose-dependent insulinotropic peptide) (Moody AJ et al, 1984) is a member of the secretin family of hormones. It is synthesized and secreted from endocrine cells in the small intestine. GIP induces insulin secretion, which is primarily stimulated by hyperosmolarity of glucose in the duodenum. Gastric inhibitory polypeptide receptors are found on beta-cells in the pancreas (Volz A et al, 1995). Their effects are mediated by coupling to the G protein alpha s subunit, which stimulates adenylyl cyclase which can increase intracellular cAMP levels (Bollag RJ et al, 2000). Pubmed10698200 Pubmed6745415 Pubmed7589426 Reactome Database ID Release 43420274 Reactome, http://www.reactome.org ReactomeREACT_18392 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Corticotropin-releasing hormone receptor can bind CRH Authored: Jassal, B, 2009-05-11 13:30:54 Corticotropin-releasing hormone (CRH), originally named corticotropin-releasing factor (CRF), is a polypeptide hormone and neurotransmitter involved in the stress response (Shibahara S et al, 1983). The corticotropin-releasing hormone receptors (CRHR), (corticotropin-releasing factor receptors) are a G protein-coupled receptor family that binds corticotropin-releasing hormone (CRH). There are two receptors in the family (type I and 2), each encoded by a separate gene (CRHR1 and CRHR2 respectively) (Chen R et al, 1993; Liaw CW et al, 1996). The activity of these receptors is mediated by coupling to the G protein alpha s subunit, which stimulates adenylyl cyclase which can increase intracellular cAMP levels (Donaldson CJ et al, 1996). Edited: Jassal, B, 2009-05-11 13:30:54 Pubmed6605851 Pubmed7692441 Pubmed8536644 Reactome Database ID Release 43420173 Reactome, http://www.reactome.org ReactomeREACT_18384 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The adrenomedullin receptor can bind adrenomedullin and intermedin Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Intermedin (AM2) (Roh J et al, 2004) and adrenomedullin (AM) (Kitamura K et al, 1993) belong to the calcitonin peptide hormone family and are important for cardiovascular and respiratory regulation. The functional adrenomedullin receptor AM1 is composed of the calcitonin gene-related peptide receptor (CGPR) and receptor activity modifying protein 2 (RAMP2) (Kamitani S et al, 1999). AM1 receptor can bind either of these peptide hormones and its activity is mediated by coupling with the G protein alpha s subunit which stimulates adenylyl cyclase and increases intracellular cAMP levels (Aiyar N et al, 2001). The function of the AM2 receptor (formed by the combination of CGPR and RAMP3) is very similar to that of AM1. Pubmed10217420 Pubmed11693189 Pubmed14615490 Pubmed8387282 Pubmed9620797 Reactome Database ID Release 43420214 Reactome, http://www.reactome.org ReactomeREACT_18386 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 CGRP receptor can bind calcitonin gene-related peptides Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Pubmed14722252 Pubmed2177866 Pubmed2985435 Pubmed6609312 Pubmed8626685 Reactome Database ID Release 43420127 Reactome, http://www.reactome.org ReactomeREACT_18360 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The calcitonin gene-related peptides alpha-CGRP and beta-CGRP (Morris HR et al, 1984, Steenbergh PH et al, 1985 respectively) are members of the calcitonin family of peptides and are produced in both peripheral and central neurons. They are the most potent peptide vasodilators and can function in the transmission of pain. Their effects are mediated by binding to the CGRP1 receptor (CL) (Aiyar N et al, 1996). CGRP receptors are complexes between CL and receptor activity modifying protein 1 (RAMP1) (Kuwasako K et al, 2004). The activity of the receptor is mediated by coupling to the G protein alpha s subunit, which stimulates adenylyl cyclase which can increase intracellular cAMP levels (Van Valen et al, 1990). Patched binds Smoothened Authored: Jupe, S, 2009-10-27 Edited: Jupe, S, 2010-03-01 Pubmed10021362 Pubmed10966113 Pubmed15104233 Pubmed15803137 Pubmed17094938 Pubmed8906787 Reactome Database ID Release 43445124 Reactome, http://www.reactome.org ReactomeREACT_21260 Reviewed: D'Eustachio, P, 2009-12-11 Smoothened (Smo) is usually classified with family B GPCRs based on homology. There are indications that it can signal via G-proteins Gi and G12/13 (Ruiz-Gomez, 2007) but this role is poorly understood. It's better characterised physiological role is as the transducer of hedgehog (HH) signaling. In this capacity Smo is not acting as a receptor, but as part of a signaling cascade. <br> <br> The Hedgehog(HH)/Smo signalling pathway was identified as a key component of Drosophila development and subsequently found to be conserved in all meatazoans. Most of the functions attributed to Smo are associated with development such as digit patterning in the chick limb bud and left–right asymmetry of vertebrate embryos. In addition, Smo appears to be involved in homeostasis; deregulated Smo signaling is implicated in tumorogenesis (Ruiz-Gomez, 2007). <br> <br> The ligand of the 12 transmembrane-domain receptor Patched (Ptc) is Hedgehog(HH) but in the absence of HH, Ptc binds Smo (Stone et al. 1996) which consequently becomes internalised into endosomes, where it associates with Costal-2 (Cos2), and lysosomes, where it is degraded. This 'inactivates' Smo by preventing the formation of an active Smo signaling complex at the plasma membrane. Internalised Smo:Cos2 forms a complex with protein kinase A (PKA), casein kinase I (CKI) glycogen synthase kinase-3 (GSK3) and Cucurbitus interruptus (Ci), a transcriptional regulator, enabling phosphorylation of Ci and subsequent processing to a transcriptional repressor form (CiR). When HH binds to Ptc, it does not bind Smo, allowing Smo to undergo a conformational change, exposing a new surface in its cytoplasmic tail. This causes PKA, CKI and GSK3 to dissociate from Smo:Cos2 complexes, so that Ci is no longer phosphorylated or processed to CiR. Accumulating Smo is phosphorylated instead and assumes a third conformational state. Phosphorylated Smo trafficks to the plasma membrane (Denef et al. 2000) and assembles into a signalling complex that promotes the phosphorylation of Fused (Fu) and Cos2. Phosphorylated Cos2 dissociates from membranes and recruits Fu to Sufu (Suppressor of Fused), which produces the activated form of Ci (CiA), probably through phosphorylation of Sufu (Hooper & Scott, 2005). Secretin receptor binds secretin Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Pubmed11060443 Pubmed7700244 Reactome Database ID Release 43420202 Reactome, http://www.reactome.org ReactomeREACT_18292 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Secretin (SCT) (Whitmore TE et al, 2000) is a peptide hormone belonging to the glucagon peptide hormone family and is produced in the duodenum. Its primary effect is to regulate the pH of the duodenal contents via the control of gastric acid secretion and buffering with bicarbonate. These effects are mediated by the SCT receptor (Patel DR et al, 1995). The receptor activity is mediated by coupling to G protein alpha s subunits, which stimulate adenylyl cyclase which increases intracellular cAMP levels (Patel DR et al, 1995). Parathyroid hormone receptor can bind parathyroid hormone Authored: Jassal, B, 2009-05-12 14:18:01 Edited: Jassal, B, 2009-05-12 14:18:01 Parathyroid hormone (PTH) (Hendy GN et al, 1981), parathyroid hormone-related protein (PTHrP) (Suva LJ et al, 1987) and tuberoinfundibular peptide of thirty-nine residues (TIP39) (Hansen IA et al, 2002; Della Penna K et al, 2003) are endogenous ligands for the parathyroid hormone 1 and 2 receptors. These peptide hormones play a key role in controlling blood Ca(2+) concentration and endochondral bone formation. PTH1 is the classical PTH receptor 1 (Schipani E et al, 1993; Schneider H et al, 1993) and is expressed in high levels in bone and kidney. It regulates calcium ion homeostasis through activation of adenylate cyclase and phospholipase C. PTH receptor 2 (Usdin TB et al, 1995) is most abundant in brain and testes and potently activated by PTH. The activity of these receptors is mediated by G proteins which activate adenylyl cyclase (Schneider H et al, 1994; Offermanns S et al, 1996; Behar V et al, 1996). Pubmed12098667 Pubmed12559132 Pubmed3616618 Pubmed6950381 Pubmed7797535 Pubmed8082781 Pubmed8386612 Pubmed8397094 Pubmed8732687 Pubmed8770894 Reactome Database ID Release 43420489 Reactome, http://www.reactome.org ReactomeREACT_18314 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 GHRH receptor binds GHRH Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Growth hormone-releasing hormone (GHRH, somatocrinin, growth hormone-releasing factor) (Gubler U et al, 1983) is released from neurosecretory cells in the hypothalamus and along with the inhibitory peptide, somatostatin, mediates the neuroendocrine regulation of pituitary growth hormone synthesis and secretion. The GHRH receptor (Gaylinn BD et al, 1993) is expressed in the pituitary gland and mediates the activity of GHRH. Downstream signalling is mediated by coupling to the G protein alpha s subunit, which stimulates adenylyl cyclase which increases intracellular cAMP levels (Mayo KE, 1992). Pubmed1333056 Pubmed6192430 Pubmed7680413 Reactome Database ID Release 43420243 Reactome, http://www.reactome.org ReactomeREACT_18354 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The PACAP receptor binds PACAP Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Pubmed1739432 Pubmed7902709 Reactome Database ID Release 43420131 Reactome, http://www.reactome.org ReactomeREACT_18424 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The pituitary adenylate cyclase-activating peptide (PACAP) (Ohkubo S et al, 1992) is a peptide hormone similar to vasoactive intestinal peptide (VIP). PACAP functions as a hypophysiotropic hormone, neurotransmitter and neuromodulator. Three active peptides are cleaved from the precursor protein; PACAP-related peptide, PACAP-27 and PACAP-38. The effects of the PACAP peptides are mediated by the PACAP receptor (Ogi K et al, 1993). This receptor is predominantly expressed in the CNS. The activity of the receptor is mediated by coupling with the G protein alpha s subunit, which stimulates adenylyl cyclase which increases intracellular cAMP levels (Ogi K et al, 1993). Metabotropic glutamate receptors bind glutamate Authored: Jassal, B, 2008-07-14 12:08:56 Edited: Jassal, B, 2008-07-14 12:08:56 Pubmed1329206 Pubmed7476890 Pubmed7617140 Pubmed7620613 Pubmed7623957 Pubmed7908515 Pubmed8887960 Pubmed9131252 Pubmed9144651 Pubmed9473604 Reactome Database ID Release 43373075 Reactome, http://www.reactome.org ReactomeREACT_18380 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The metabotropic glutamate receptors (mGluRs) are members of the group C family of G-protein-coupled receptors (GPCRs) (Pin JP et al, 1995; Conn PJ and Pin JP, 1997). Metabotropic glutamate receptors are characterized by a large N-terminal extracellular domain of approximately 560 amino acids which possesses the glutamate binding domain and confers selectivity for agonists. There are eight mGluRs, 1-8 (Desai MA et al, 1995; Flor PJ et al, 1995; Emile L. et al, 1996; Flor PJ et al, 1995b; Minakami R et al, 1994; Laurie DJ et al, 1997; Wu S et al, 1998 respectively). They can be subdivided into 'groups' according to their sequence homology, signal transduction mechanisms and pharmacological properties. Group I contains mGluR1 and 5; Group II contains mGluR2 and 3; Group III contains mGluR4,6,7 and 8 (Nakanishi S, 1992). Group I receptors activate PLC downstream via coupling to Gq/11. Groups II and III inhibit adenylyl cyclase via coupling to Gi.<br>Like all glutamate receptors, mGluRs bind to glutamate, an amino acid that functions as an excitatory neurotransmitter. Glutamate is the most abundant excitatory neurotransmitter in the mammalian nervous system. CD97 binds CD55 Authored: Jupe, S, 2010-06-16 CD55 (or Decay Accelerating Factor; DAF) is a member of the regulators of complement activation (RCA) family. It protects host cells from complement system attack by binding to C3b and C4b preventing formation of the membrane attack complex. CD97 is a member of the Adhesion class or LNB subfamily of family B GPCRs, characterized by long N-terminal regions containing domains contain multiple tandem epidermal growth factor (EGF)-like repeats in their N-termini (Foord et al. 2002). CD97 is constitutively expressed on granulocytes and monocytes and is rapidly up-regulated on activated T and B cells. It is known to have many splice forms containing different numbers of EGF domains, consequently binding CD55 with differing affinities. The highest affinity variant has three EGF domains. The leukocyte-restricted expression pattern of CD97, and the presence of both CD97 and CD55 in arthritic joints suggest a possible role in adhesion and signaling within the inflammatory and immune responses (Lin et al. 2001). Edited: Jupe, S, 2010-11-18 Pubmed11297558 Pubmed12196118 Pubmed9064337 Reactome Database ID Release 43879674 Reactome, http://www.reactome.org ReactomeREACT_25290 Reviewed: Jassal, B, 2010-10-11 GPRC6A can bind L-alpha amino acids and calcium Authored: Jassal, B, 2009-05-13 14:32:46 Edited: Jassal, B, 2009-05-13 14:32:46 G-protein coupled receptor family C group 6 member A (GPRC6A, GPCR33) (Wellendorph P and Brauner-Osborne H, 2004) is a receptor that functions as a sensor for both L-amino acids and extracellular concentration of calcium ions. GPRC6A is a promiscuous L-alpha-amino acid receptor but has preference for the basic amino-acids L-Arg, L-Lys and L-ornithine (Wellendorph P et al, 2005). The effects of this receptor are mediated by coupling to the G protein alpha q/11 subunit, which activates a phosphatidylinositol-calcium second messenger system. Pubmed15194188 Pubmed15576628 Reactome Database ID Release 43420739 Reactome, http://www.reactome.org ReactomeREACT_18362 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Calcium-sensing receptor binds calcium Authored: Jassal, B, 2009-05-13 14:32:46 Edited: Jassal, B, 2009-05-13 14:32:46 Pubmed11208605 Pubmed7759551 Pubmed9144337 Reactome Database ID Release 43420724 Reactome, http://www.reactome.org ReactomeREACT_18402 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The parathyroid glands play a role in ion homeostasis by sensing small changes in extracellular Ca2+ ion concentration. These glands express a cell surface receptor, calcium-sensing receptors (CaR) (Garrett JE et al, 1995) that is activated by increases in the concentration of extracellular calcium and by a variety of other cations. CaR serves as the primary physiological regulator of parathyroid hormone secretion. CaR contributes to regulation of systemic calcium homeostasis by activation of Gq- (Kifor O et al, 1997) and Gi-linked (Kifor O et al, 2001) signaling pathways in the parathyroid glands, kidney and intestine. EGF-TM7 receptors bind chondroitin sulphate Authored: Jupe, S, 2009-10-23 Edited: Jupe, S, 2010-06-16 Pubmed12829604 Pubmed14647991 Pubmed15498814 Reactome Database ID Release 43444773 Reactome, http://www.reactome.org ReactomeREACT_23776 Reviewed: D'Eustachio, P, 2010-05-26 The EGF-TM7 receptors are within the family B Adhesion (LNB) receptor subclass. They are characterised by long N-teminal extracellular domains containing multiple epidermal growth factor (EGF)-like domains. CD97 and EMR2 interact with the glycosaminoglycan chondroitin sulfate (CS). Frizzled receptors bind Wnts Authored: Jupe, S, 2010-02-18 Edited: Matthews, L, 2007-09-10 12:45:35 Pubmed10097073 Pubmed10557084 Pubmed11029007 Pubmed14977548 Pubmed15862553 Pubmed16602827 Pubmed9389482 Reactome Database ID Release 43201708 Reactome, http://www.reactome.org ReactomeREACT_21361 Reviewed: D'Eustachio, P, 2009-12-11 The highly conserved Wnt signaling proteins play critical roles in guiding pattern formation, cell fate decision, and morphogenetic movement during animal development. They bind to the Frizzled (FZD) family of seven-pass transmembrane proteins and initiate at least three different intracellular signaling pathways. Historically they were considered to be family B GPCRs but more recent phylogenetic classifications put them into a class of their own (e.g. Schioth & Fredriksson 2005). FZD members have been demonstrated to signal via Gi/o (Slusarski et al. 1997) but this is not considered to be the primary signaling mechanism for these receptors (Hsieh 2004). Instead they signal through the canonical/beta-catenin pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. The canonical/beta-catenin pathway requires a co-receptor protein known as LDL5 or LDL6 (Tamai et al. 2000). <br>Most Wnt signaling has been attributed to the activation of FZD receptors but there is evidence of FZD-independent signaling (Mikels & Nusse 2006). Much Wnt research has used indirect evidence to infer the involvement of FZD receptors (e.g. Gazit et al. 1999) but there is some direct evidence of Wnt-FZD binding (Hsieh et al. 1999; Mikels & Nusse 2006). T1R1/T1R3 dimer is the umami taste receptor Authored: Jupe, S, 2009-10-23 Dimers of the T1R1 and T1R3 receptors responds to the umami taste stimulus L-glutamate. Edited: Jupe, S, 2010-03-01 Pubmed11917125 Reactome Database ID Release 43444705 Reactome, http://www.reactome.org ReactomeREACT_21256 Reviewed: D'Eustachio, P, 2009-12-11 T1R2/T1R3 dimer is a sweet taste receptor A dimer of T1R2 and T1R3 receptors responds to diverse stimuli associated with the human sense of sweet taste, such as sucrose, d-tryptophan, aspartame, and saccharin. Authored: Jupe, S, 2009-10-23 Edited: Jupe, S, 2010-03-01 Pubmed11917125 Reactome Database ID Release 43444606 Reactome, http://www.reactome.org ReactomeREACT_21366 Reviewed: D'Eustachio, P, 2009-12-11 Liganded Gs-activating GPCRs bind inactive heterotrimeric Gs Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed12036966 Reactome Database ID Release 43744887 Reactome, http://www.reactome.org ReactomeREACT_22234 Reviewed: D'Eustachio, P, 2010-05-21 The role of the guanine nucleotide-binding protein G alpha-s subunit (G alpha-s) (Kozasa T et al, 1988) is to activate adenylate cyclase, which, in turn, produces cAMP, which, in turn, activates cAMP-dependent protein kinase. Liganded Gs-activating GPCR acts as a GEF for Gs Authored: Jassal, B, 2009-02-13 11:37:11 Edited: Jassal, B, 2009-02-13 11:37:11 Pubmed12106601 Pubmed12860470 Pubmed2553705 Pubmed3086311 Pubmed3113327 Pubmed3127824 Pubmed9032437 Pubmed9651336 Reactome Database ID Release 43379044 Reactome, http://www.reactome.org ReactomeREACT_17008 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The liganded receptor undergoes a conformational change, generating a signal that is propagated in a manner that is not completely understood to the the G-protein. This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. cAMP degradation by Phosphodiesterases Authored: Jupe, S, 2009-04-23 15:40:54 Cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes that regulate signal transduction by the second messenger molecules cAMP and cGMP. Some PDEs are cAMP selective (PDE4, 7 and 8), some cGMP selective (PDE5, 6 and 9) while others can hydrolyse cAMP and cGMP (PDE1, 2, 3, 10 and 11). PDEs are important as drug targets: Sildenafil (Viagra) is an inhibitor of PDE5; Cilostazol (Pletal) inhibits PDE3, increasing the flexibility of erythrocytes. Edited: Jupe, S, 2009-09-09 Pubmed15769620 Pubmed15798894 Reactome Database ID Release 43418553 Reactome, http://www.reactome.org ReactomeREACT_19387 Reviewed: Akkerman, JW, 2009-06-03 Adenylate cyclase converts ATP to 3',5'-cyclic AMP (cAMP) and pyrophosphate Authored: Jupe, S, 2009-05-22 13:10:56 EC Number: 4.6.1.1 Edited: Jupe, S, 2009-09-09 Pubmed13549488 Pubmed14993377 Reactome Database ID Release 43392129 Reactome, http://www.reactome.org ReactomeREACT_19249 Reviewed: Akkerman, JW, 2009-06-03 The activation of adenylyl (adenylate) cyclase (AC) results in the production of adenosine-3',5'-monophosphate i.e. cyclic AMP. Humans have 9 genes encoding membrane-associated AC and one encoding a soluble AC. Two of the classes of heterotrimeric G-proteins are named according to their effect on AC; Gs stimulates all membrane-bound ACs (the s in Gs denotes AC stimulatory); the Gi class inhibits some AC isoforms, particularly 5 and 6. Beta-gamma subunits of heterotrimeric G-proteins can also regulate AC. Ca2+/Calmodulin activates some AC isoforms (1, 8 and 3) but is inhibitory to others (5 and 6). The Ligand:GPCR:Gs complex dissociates Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43744886 Reactome, http://www.reactome.org ReactomeREACT_22268 Reviewed: D'Eustachio, P, 2010-05-21 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). Liganded Gi-activating GPCR acts as a GEF for Gi Authored: Jassal, B, 2008-11-07 12:17:32 Pubmed2534964 Pubmed2748346 Pubmed2834384 Pubmed3086311 Pubmed3113327 Pubmed8015379 Pubmed8406495 Pubmed9032437 Reactome Database ID Release 43380073 Reactome, http://www.reactome.org ReactomeREACT_15538 Reviewed: D'Eustachio, P, 2008-11-29 18:33:05 The liganded receptor undergoes a conformational change, generating a signal that is propagated in a manner that is not completely understood to the the G-protein. This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Many unrelated GPCRs couple with the Gi G-protein subtype. The G-alpha (i) subunit inhibits the production of cAMP from ATP. In turn, this results in decreased activity of cAMP-dependent protein kinase. There are 8 types of G-alpha (i) known to date:G(i)1, G(i)2, G(i)3, G(i)o, G(i)z, G(i)gust (gustducin) and two G(i)t (retinal transducin) (Downes GB and Gautam N, 1999). Once GDP is exchanged for GTP on the alpha subunit, it dissociates from the G-beta-gamma subunit. Pubmed10644457 Pubmed2834384 Reactome Database ID Release 43749456 Reactome, http://www.reactome.org ReactomeREACT_22289 Reviewed: D'Eustachio, P, 2010-05-21 Inactive G alpha (s) reassociates with G beta:gamma Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed14671004 Pubmed15951850 Pubmed16923326 Reactome Database ID Release 43751013 Reactome, http://www.reactome.org ReactomeREACT_22138 Reviewed: D'Eustachio, P, 2010-05-21 The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active alpha subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (s):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates into the inactive heterotrimeric G-protein. G alpha (s) auto-inactivates by hydrolysing GTP to GDP Authored: Gopinathrao, G, 2005-05-18 22:14:39 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jupe, S, 2009-09-09 Reactome Database ID Release 43164381 Reactome, http://www.reactome.org ReactomeREACT_348 Reviewed: Jupe, S, 2009-03-10 09:59:17 When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region. G alpha (i) auto-inactivates by hydrolysing GTP to GDP Authored: Jupe, S, 2009-02-27 15:59:25 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jupe, S, 2009-09-09 Pubmed7937899 Reactome Database ID Release 43392212 Reactome, http://www.reactome.org ReactomeREACT_19219 Reviewed: Akkerman, JW, 2009-06-03 When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region. The Ligand:GPCR:Gi complex dissociates Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43749454 Reactome, http://www.reactome.org ReactomeREACT_22239 Reviewed: D'Eustachio, P, 2010-05-21 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (i) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). Opsins that act as GEFs for G alpha-t Authored: Jassal, B, 2009-05-14 14:29:50 Edited: Jassal, B, 2009-05-14 14:29:50 Pubmed16634148 Pubmed2534964 Pubmed8406495 Reactome Database ID Release 43420883 Reactome, http://www.reactome.org ReactomeREACT_18400 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Transducin (Gt) is a heterotrimeric G protein encoded by GNAT genes and is naturally expressed in vertebrate retina rods and cones. There are two types, alpha-1 chain (expressed in rods by GNAT1) (Lerea CL et al, 1989) and alpha-2 chain (expressed in cones by GNAT2) (Morris TA and Fong SL, 1993). Activation of the Gt alpha subunit results in the "vertebrate phototransduction cascade" (Chen CK, 2005). Cyclic GMP Phosphodiesterase is activated which lowers cGMP levels (an intracellular second messenger molecule). Lower cGMP levels can then lead to the closure of cGMP-regulated Na+ and Ca2+ ion channels and a hyperpolarized membrane potential.<br> Liganded Gz-activating GPCRs bind inactive heterotrimeric G-protein Gz Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Gz is predominantly expressed in the nervous system and platelets. Gz interacts with receptors for many neurotransmitters and neuropeptides, including the adenosine A1, alpha2-adrenergic, dopamine D2, 5-HT1A, muscarinic M2, substance P, and all types of opioid receptors. In addition, Gz is capable of transducing signals from receptors such as the C5a and formyl peptide receptors. All these receptors can also signal via Gi. (Ho & Wong 2001). Pubmed10954748 Pubmed11313909 Reactome Database ID Release 43749446 Reactome, http://www.reactome.org ReactomeREACT_22150 Reviewed: D'Eustachio, P, 2010-05-21 Inactive G alpha (i) reassociates with G beta:gamma Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed15951850 Pubmed16923326 Reactome Database ID Release 43751001 Reactome, http://www.reactome.org ReactomeREACT_22335 Reviewed: D'Eustachio, P, 2010-05-21 The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active G alpha (i) subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (i):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates. The Ligand:GPCR:Gz complex dissociates Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed18577758 Pubmed8736705 Reactome Database ID Release 43751024 Reactome, http://www.reactome.org ReactomeREACT_22170 Reviewed: D'Eustachio, P, 2010-05-21 The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (z) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008). Liganded Gz-activating GPCR acts as a GEF for Gz Authored: Jupe, S, 2009-02-26 15:51:29 Edited: Jupe, S, 2010-05-26 Pubmed11313909 Pubmed3086311 Pubmed3113327 Pubmed9032437 Reactome Database ID Release 43749453 Reactome, http://www.reactome.org ReactomeREACT_22380 Reviewed: D'Eustachio, P, 2010-05-21 The liganded receptor undergoes a conformational change, generating a signal that is propagated in a manner that is not completely understood to the the G-protein. This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein. Gz is a substrate for PKC Authored: Jupe, S, 2010-05-18 EC Number: 2.7.11.13 Edited: Jupe, S, 2010-05-24 G alpha z (Lounsbury et al. 1991) and G alpha 12 (Kozasa & Gilman, 1996) are excellent in vitro substrates for all three subtypes of protein kinase C (PKC). Activation of PKC in intact platelets by agents such as thrombin, thromboxane A2 (TXA2) analogues and phorbol esters leads to rapid and near-stoichiometric phosphorylation of G alpha z (Carlson et al. 1989). The primary site of G alpha z phosphorylation is Ser-27 (Lounsbury et al. 1993). This phosphorylation blocks the interaction of G alpha z with Gbeta:gamma suggesting that it is a regulatory mechanism for attenuating signalling by preventing subunit reassociation. Pubmed1939224 Pubmed2502548 Pubmed8429024 Pubmed8647866 Reactome Database ID Release 43751040 Reactome, http://www.reactome.org ReactomeREACT_22249 Reviewed: D'Eustachio, P, 2010-05-21 G alpha (z) inhibits adenylate cyclase Authored: Jupe, S, 2009-02-26 14:43:12 Edited: Jupe, S, 2009-09-09 G-proteins in the Gi class inhibit adenylate cyclase activity, decreasing the production of cAMP from ATP, which has many consequences but classically results in decreased activity of Protein Kinase A (PKA). cAMP also activates the cyclic nucleotide-gated ion channels, a process that is particularly important in olfactory cells. Experimental data for this reaction was obtained in vitro using rat G alpha (i) and dog Adenylate Cyclase. Pubmed1347957 Pubmed7595566 Pubmed8327893 Reactome Database ID Release 43392064 Reactome, http://www.reactome.org ReactomeREACT_19147 Reviewed: Akkerman, JW, 2009-06-03 Inactive G alpha (z) reassociates with G beta:gamma Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Pubmed15951850 Pubmed16923326 Reactome Database ID Release 43750988 Reactome, http://www.reactome.org ReactomeREACT_22135 Reviewed: D'Eustachio, P, 2010-05-21 The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active G alpha (z) subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (z):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates. G alpha (z) auto-inactivates by hydrolysing GTP to GDP Authored: Jupe, S, 2009-02-27 15:59:25 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jupe, S, 2009-09-09 Reactome Database ID Release 43392133 Reactome, http://www.reactome.org ReactomeREACT_19178 Reviewed: Akkerman, JW, 2009-06-03 When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region. Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq Authored: Jupe, S, 2010-05-18 Edited: Jupe, S, 2010-05-26 Numerous functionally unrelated GPCRs couple with the Gq G-protein subtype. Pubmed16754659 Reactome Database ID Release 43749448 Reactome, http://www.reactome.org ReactomeREACT_22436 Reviewed: D'Eustachio, P, 2010-05-21 Liganded Gq/11-activating GPCRs act as GEFs for Gq/11 Authored: Jassal, B, 2008-11-07 12:17:32 Edited: Jupe, S, 2010-05-26 G alpha q protein (or Gq/11) consists of four family members (G-alpha 11, -alpha 14, -alpha 15 and -alpha q). It activates phospholipase C (PLC) (Dowal L et al, 2006). PLC hydrolyzes phosphatidylinositol (PIP2) to diacyl glycerol (DAG) and inositol triphosphate (IP3). DAG acts as a second messenger that activates protein kinase C (PKC) and IP3 can bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). Calcium flow causes the cytosolic concentration of calcium to increase, causing a cascade of intracellular changes and activity. Pubmed10191087 Pubmed16754659 Pubmed1905813 Pubmed3086311 Pubmed8664309 Reactome Database ID Release 43379048 Reactome, http://www.reactome.org ReactomeREACT_15291 Reviewed: D'Eustachio, P, 2008-11-29 18:33:05 PathwayStep5243 GRB2:SOS1 binds to HBEGF:p-Y-EGFR Authored: Jassal, B, Tripathi, S, 2012-04-04 Cytoplasmic target proteins containing the SH2 domain can bind to activated EGFR. One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 autophosphorylation sites on the receptor (Batzer et al. 1994, Okutani et al. 1994). Edited: Jassal, B, Tripathi, S, 2012-04-04 Pubmed7518560 Pubmed7527043 Reactome Database ID Release 432179415 Reactome, http://www.reactome.org ReactomeREACT_121250 Reviewed: D'Eustachio, P, 2012-04-23 PathwayStep5242 Mature HBEGF binds to EGFR, triggering dimerisation and autophosphorylation of the receptor Authored: Jassal, B, Tripathi, S, 2012-04-04 Edited: Jassal, B, Tripathi, S, 2012-04-04 Pubmed1840698 Pubmed9135143 Reactome Database ID Release 432179387 Reactome, http://www.reactome.org ReactomeREACT_121381 Reviewed: D'Eustachio, P, 2012-04-23 The heparin-binding EGF growth factor (HBEGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor EGFR/ErbB1 and ErbB4 (not shown here) (Higashiyama et al. 1991, Elenius et al. 1997). The details which describe receptor dimerisation on ligand binding and autophosphorylation from experiments in mice have been omitted here. PathwayStep5241 Active MMP3 can cleave pro-HBEGF to form active HBEGF Authored: Jassal, B, Tripathi, S, 2012-04-04 EC Number: 3.4.24 Edited: Jassal, B, Tripathi, S, 2012-04-04 Gastrin can induce cleavage of pro-HBEGF via MMP3, releasing mature HBEGF. This event is based on evidence from mouse experiments (Suzuki et al. 1997). Pubmed9395517 Reactome Database ID Release 432179402 Reactome, http://www.reactome.org ReactomeREACT_121027 Reviewed: D'Eustachio, P, 2012-04-23 PathwayStep5240 Gastrin binds to CCK-B receptor Authored: Jassal, B, Tripathi, S, 2012-04-04 Edited: Jassal, B, Tripathi, S, 2012-04-04 Gastrin receptors (gastric cholecystokinin B receptor, CCK-BR) mediate acid secretion from parietal cells, release of histamine from enterochromaffin-like (ECL) cells and contraction of smooth muscle (Ito et al. 1993).The hormone gastrin is the central regulator of gastric acid secretion and in addition, plays a prominent role in regulation of growth and differentiation of gastric and colonic mucosa. Pubmed8349705 Reactome Database ID Release 43870269 Reactome, http://www.reactome.org ReactomeREACT_121113 Reviewed: D'Eustachio, P, 2012-04-23 PathwayStep5247 PathwayStep5246 Association of beta-catenin with the destruction complex Beta-catenin associates with the destruction complex through an interaction with Axin and or APC. This association may also involve interactions with the 15 aa repeats in APC (Spink et al., 2001) or the third APC 20aa repeat and its N-terminal flanking residues (Ha et al., 2004, Xing et al., 2004; Liu et al., 2006). Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed11707392 Pubmed15327768 Pubmed15327769 Pubmed16753179 Reactome Database ID Release 43195304 Reactome, http://www.reactome.org ReactomeREACT_10111 Reviewed: Pagano, M, 2007-04-27 13:02:18 PathwayStep5245 Assembly of the destruction complex Authored: Kimelman, D, 2007-04-03 12:34:14 Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed10092233 Pubmed12554650 Pubmed17143292 Pubmed17510365 Reactome Database ID Release 43195251 Reactome, http://www.reactome.org ReactomeREACT_10134 Reviewed: Pagano, M, 2007-04-27 13:02:18 The exact composition of the destruction complex is not known. A number of components appear to form a core complex, while others may associate with the complex transiently when a Wnt signal is present (reviewed in Kimelman and Xu, 2006). The core components include Axin, glycogen synthase kinase 3 (GSK-3), Casein kinase 1 (CKI) alpha, beta-catenin, Protein phosphatase 2A (PP2A) and Adenomatous Polyposis Coli (APC). CK1 epsilon, Diversin and PP1 may also be components of the complex. PathwayStep5244 SOS1-mediated nucleotide exchange of RAS (HB-EFG-initiated) Authored: Jassal, B, Tripathi, S, 2012-04-04 Edited: Jassal, B, Tripathi, S, 2012-04-04 Pubmed8493579 Reactome Database ID Release 432179407 Reactome, http://www.reactome.org ReactomeREACT_121377 Reviewed: D'Eustachio, P, 2012-04-23 SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP) (Chardin et al. 1993). PathwayStep5239 PathwayStep5237 PathwayStep5238 High-affinity glutamate transporter ligands Converted from EntitySet in Reactome Reactome DB_ID: 428027 Reactome Database ID Release 43428027 Reactome, http://www.reactome.org ReactomeREACT_20284 Inactive catalytic PP2B is activated by the binding of calmodulin Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 PP2B (calcineurin) is a calcium-dependent, calmodulin-stimulated protein phosphatase. It comprises of two components; a catalytic subunit and a regulatory subunit which confers calcium sensitivity to the complex. PP2B is in equilibrium between active and inactive forms. Because the affinity of calmodulin for the active form is higher than for the inactive form, it stabilises PP2B. Reactome Database ID Release 43201783 Reactome, http://www.reactome.org ReactomeREACT_15299 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 DARPP-32 is dephosphorylated on Thr34 by PP2B Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Calcineurin has been identified as a Ca2+- and calmodulin-dependent phosphoprotein phosphatase. The concentration of the enzyme is relatively high in mammalian brain. Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed6330098 Reactome Database ID Release 43201787 Reactome, http://www.reactome.org ReactomeREACT_15494 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 DARPP-32 is dephosphorylated on Thr75 by PP2A Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 PP2A is ubiquitously expressed in eukaryotic cells, existing as a heterotrimeric enzyme composed of a 36-kDa catalytic C subunit, a 64-kDa scaffolding A subunit, and multiple regulatory B subunits. The B subunits are thought to influence enzyme activity, substrate specificity, and subcellular localization. PKA phosphorylates PP2A thereby activating the enzyme and is responsible for dopamine/cAMP-dependent dephosphorylation of Thr-75 of DARPP-32. Pubmed12065642 Pubmed17535922 Reactome Database ID Release 43201790 Reactome, http://www.reactome.org ReactomeREACT_15438 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PathwayStep5252 The G alpha-olf:GDP:Adenylate cyclase complex dissociates Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Once the intrinsic GTPase hydrolyzes GTP to GDP, Galpha-olf dissociates from adenylate cyclase, allowing it to re-associate with G-beta-gamma and starting a new cycle. Pubmed7937899 Reactome Database ID Release 43170677 Reactome, http://www.reactome.org ReactomeREACT_15547 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PathwayStep5251 Adenylaye cyclase increases the GTPase activity of G alpha-olf Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jassal, B, 2008-11-06 10:17:49 G proteins can deactivate themselves via their intrinsic GTPase activity, which hydrolyzes GTP to GDP. Effectors such as adenylate cyclase can increase the G protein GTPase rate, acting like GTPase-activating proteins (GAPs). Pubmed7937899 Reactome Database ID Release 43170685 Reactome, http://www.reactome.org ReactomeREACT_15449 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PathwayStep5254 cAMP hydrolysis by PDE 4 Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 PDE4 hydrolyzes cAMP to AMP. Pubmed9371714 Reactome Database ID Release 43111962 Reactome, http://www.reactome.org ReactomeREACT_1257 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PathwayStep5253 PKA phosphorylates PDE4B Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 2.7.11.11 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed8663227 Pubmed9099992 Reactome Database ID Release 43177284 Reactome, http://www.reactome.org ReactomeREACT_15519 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The phosphorylation of the phosphodiesterase increases its activity, forming a negative feedback loop of the cAMP signal. PathwayStep5256 DARPP-32 phosphorylated on T34 binds to PP1, inhibiting its function Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) on a single threonine residue, Thr34, resulting in its conversion into a potent inhibitor of protein phosphatase-1. Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed6087160 Reactome Database ID Release 43180038 Reactome, http://www.reactome.org ReactomeREACT_15496 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PathwayStep5255 PKA phosphorylates DARPP-32 on Thr34 Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) on a single threonine residue, Thr34, resulting in its conversion into a potent inhibitor of protein phosphatase-1. EC Number: 2.7.11.11 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed6296685 Pubmed6501302 Reactome Database ID Release 43177275 Reactome, http://www.reactome.org ReactomeREACT_15529 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PathwayStep5258 DARPP-32 phosphorylated on Thr75 binds to PKA, inhibiting its function Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 DARPP-32 is converted into an inhibitor of protein kinase A (PKA) when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5) in brain cells. Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed10604473 Reactome Database ID Release 43180073 Reactome, http://www.reactome.org ReactomeREACT_15540 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PathwayStep5257 CDK5 phosphorylates DARPP-32 on Thr75 Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 2.7.11.22 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed10604473 Reactome Database ID Release 43180047 Reactome, http://www.reactome.org ReactomeREACT_15365 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The amino-acid sequence of DARPP-32 contains consensus phosphorylation sites for proline-directed kinases, including Cdk5, a cyclin-dependent kinase family member which is present in post-mitotic neurons expressing high levels of DARPP-32. PathwayStep5250 PathwayStep5248 PathwayStep5249 Galpha-olf:GTP binds to adenylate cyclase and activates it Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 G alpha-olf:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it. GENE ONTOLOGYGO:0007190 Pubmed11832410 Pubmed8243272 Reactome Database ID Release 43170672 Reactome, http://www.reactome.org ReactomeREACT_15385 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Adenylate cyclase converts ATP into cyclic AMP Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 4.6.1.1 Edited: Jassal, B, 2008-11-06 10:17:49 Once activated, adenylate cyclase utilizes one molecule of ATP to synthesize one molecule of cyclic AMP and pyrophosphate. Pubmed8663304 Reactome Database ID Release 43170676 Reactome, http://www.reactome.org ReactomeREACT_15399 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PathwayStep5269 PathwayStep5268 PathwayStep5267 PathwayStep5266 Phosphorylation of MOB1A and B by p-STK3 (p-MST2) Authored: D'Eustachio, P, 2012-02-03 Cytosolic MOB1A and MOB1B are phosphorylated by phospho-STK3 (p-MST2). Phosphorylated (active) STK3 (p-MST2) and SAV1 are known to form a complex and that complex is annotated as the catalyst of this reaction. Threonine residues 12 and 35 have been experimentally identifed as the targets of MOB1A phosphorylation; the homologous residues of MOB1B are inferred likewise to be targets (Praskova et al. 2008). EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed18328708 Reactome Database ID Release 432028635 Reactome, http://www.reactome.org ReactomeREACT_118698 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 PathwayStep5265 Phosphorylation of LATS1 and 2 by p-STK4(MST1)/N Authored: D'Eustachio, P, 2012-02-03 Cytosolic LATS1 and LATS2 are phosphorylated by phospho-STK4(MST1)/N (Graves et al. 1998; Lee et al. 2001). LATS proteins are known to form complexes with MOB1 proteins and this reaction is annotated with LATS:MOB1 complexes as its substrate. Serine-909 and threonine-1097 have been identified as LATS1 residues phosphorylated by STK4 (MST1) kinase. The target residues of LATS2 have not been identified experiemntally but are inferred to be serine-871 and threonine-1041 based on sequence similarity. EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed11278283 Pubmed9545236 Reactome Database ID Release 432028679 Reactome, http://www.reactome.org ReactomeREACT_118609 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 PathwayStep5264 Phosphorylation of LATS1 and 2 by p-STK4 (p-MST1) Authored: D'Eustachio, P, 2012-02-03 Cytosolic LATS1 and LATS2 are phosphorylated by phospho-STK4 (p-MST1). LATS proteins are known to form complexes with MOB1 proteins and this reaction is annotated with LATS:MOB1 complexes as its substrate. Likewise, phosphorylated (active) STK4 (p-MST1) and SAV1 are known to form a complex and that complex is annotated as the catalyst of this reaction. Serine-909 and threonine-1097 have been identified as LATS1 residues phosphorylated by STK4 (MST1) kinase. The target residues of LATS2 have not been identified experimentally but are inferred to be serine-871 and threonine-1041 based on sequence similarity (Chan et al. 2005). EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed15688006 Reactome Database ID Release 432028555 Reactome, http://www.reactome.org ReactomeREACT_118786 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 PathwayStep5263 Phosphorylation of LATS1 and 2 by p-STK3 (MST2)/N Authored: D'Eustachio, P, 2012-02-03 Cytosolic LATS1 and LATS2 are phosphorylated by phospho-STK3 (MST2)/N (Lee et al. 2001). LATS proteins are known to form complexes with MOB1 proteins and this reaction is annotated with LATS:MOB1 complexes as its substrate. Serine-909 and threonine-1097 have been identified as LATS1 residues phosphorylated by STK4 (MST1) kinase; STK3(MST2)/N is inferred to act similarly. The target residues of LATS2 have not been identified experimentally but are inferred to be serine-871 and threonine-1041 based on sequence similarity. EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed11278283 Reactome Database ID Release 432028673 Reactome, http://www.reactome.org ReactomeREACT_118858 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 PathwayStep5262 Phosphorylation of LATS1 and 2 by p-STK3 (p-MST2) Authored: D'Eustachio, P, 2012-02-03 Cytosolic LATS1 and LATS2 are phosphorylated by phospho-STK3 (p-MST2). LATS proteins are known to form complexes with MOB1 proteins and this reaction is annotated with LATS:MOB1 complexes as its substrate. Likewise, phosphorylated (active) STK3 (p-MST2) and SAV1 are known to form a complex and that complex is annotated as the catalyst of this reaction. Serine-909 and threonine-1097 have been identified as LATS1 residues phosphorylated by STK4 kinase (MST1); STK3 (MST2) is inferred to act similarly. The target residues of LATS2 have not been identified experimentally but are inferred to be serine-871 and threonine-1041 based on sequence similarity (Chan et al. 2005). EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed15688006 Reactome Database ID Release 432028589 Reactome, http://www.reactome.org ReactomeREACT_118669 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 PathwayStep5261 PathwayStep5260 KIBRA (WWC1) binds LATS proteins Authored: D'Eustachio, P, 2012-02-03 Cytosolic KIBRA (WWC1) binds LATS proteins. The stoichiometry of the resulting complex is unlnown. The interaction of KIBRA with LATS directly or indirectly stimulates the phosphorylation of the latter proteins, so this interaction may promote LATS activation and, ultimately, YAP1 and TAZ sequestration in vivo (Xiao et al. 2011). Edited: D'Eustachio, P, 2012-01-09 Pubmed21233212 Reactome Database ID Release 432038398 Reactome, http://www.reactome.org ReactomeREACT_118857 Reviewed: Sudol, M, 2012-02-03 NPHP4 protein binds LATS proteins Authored: D'Eustachio, P, 2012-02-03 Cytosolic NPHP4 protein binds LATS proteins to form a complex. The stoiciometry of the resulting complex is unknown. When bound to NPHP4, LATS is unable to phosphorylate YAP1 and WWTR1 (TAZ) proteins, so the effect of NPHP4 binding is to antagonize this aspect of the Hippo cascade (Habbig et al. 2011). Edited: D'Eustachio, P, 2012-01-18 Pubmed21555462 Reactome Database ID Release 432059926 Reactome, http://www.reactome.org ReactomeREACT_118831 Reviewed: Sudol, M, 2012-02-03 Cleavage of p-STK3 (p-MST2) by caspase 3 Authored: D'Eustachio, P, 2012-02-03 Cytosolic caspase 3 cleaves p-STK3 (p-MST2) to yield an active animo-terminal fragment (p-STK3/N) and a carboxy-terminal fragment (p-STK3/C) (Lee et al. 2001). The association of p-STK3 (p-MST2) with other proteins at the time of its cleavage by caspase has not been studied experimentally. Here, it is inferred to be dimerized and in a complex with SAV1 because that is the form of the molecule that becomes phosphorylated and phosphorylation appears normally to precede caspase cleavage. The effect of the cleavage is to increase the kinase activity of p-STK3 (p-MST2). EC Number: 3.4.22 Edited: D'Eustachio, P, 2011-12-30 Pubmed11278283 Reactome Database ID Release 432028697 Reactome, http://www.reactome.org ReactomeREACT_118640 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 Cleavage of p-STK4 (p-MST1) by caspase 3 Authored: D'Eustachio, P, 2012-02-03 Cytosolic caspase 3 cleaves p-STK4 (p-MST1) to yield an active animo-terminal fragment (p-STK4/N) and a carboxy-terminal fragment (p-STK4/C) (Graves et al. 1998; Lee et al. 2001). The association of p-STK4 (p-MST1) with other proteins at the time of its cleavage by caspase has not been studied experimentally. Here, it is inferred to be dimerized and in a complex with SAV1 because that is the form of the molecule that becomes phosphorylated and phosphorylation appears normally to precede caspase cleavage. The effect of the cleavage is to increase the kinase activity of p-STK4 (p-MST1). EC Number: 3.4.22 Edited: D'Eustachio, P, 2011-12-30 Pubmed11278283 Pubmed9545236 Reactome Database ID Release 432028692 Reactome, http://www.reactome.org ReactomeREACT_118582 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 Phosphorylation of STK4 (MST1) and SAV1 by STK4 Authored: D'Eustachio, P, 2012-02-03 EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed15109305 Pubmed16930133 Pubmed8702870 Reactome Database ID Release 432028284 Reactome, http://www.reactome.org ReactomeREACT_118842 Reviewed: Sudol, M, 2012-02-03 The serine/threonine kinase STK4 (MST1) catalyzes its own autophosphorylation as well as the phosphorylation of SAV1. These two reactions are annotated here as a single concerted process that takes place in a tetrameric complex containing two STK4 (MST1) subunits and two SAV1 subunits, based on the observations that STK4 (MST1) can catalyze both phosphorylation reactions in vitro, as well as the observations that each protein dimerizes and that STK4 (MST1) and SAV1 associate to form a complex. The order in which the various components associate, the stoichiometry of the complex ultimately formed, and the point(s) in this association process at which phosphoryltion occurs have not been established in vitro or in vivo, however (Callus et al. 2006; Creasy et al. 1996; Praskova et al. 2004). has a Stoichiometric coefficient of 4 PathwayStep5259 PathwayStep5278 Phosphorylation of STK3 (MST2) and SAV1 by STK3 Authored: D'Eustachio, P, 2012-02-03 EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed15109305 Pubmed15688006 Pubmed16930133 Reactome Database ID Release 432028591 Reactome, http://www.reactome.org ReactomeREACT_118652 Reviewed: Sudol, M, 2012-02-03 The serine/threonine kinase STK3 (MST2) catalyzes its own autophosphorylation as well as the phosphorylation of SAV1. These two reactions are annotated here as a single concerted process that takes place in a tetrameric complex containing two STK3 (MST2) subunits and two SAV1 subunits, based on the observations that STK3 (MST2) can catalyze both phosphorylation reactions in vitro, as well as the observations that each protein dimerizes and that STK3 (MST2) and SAV1 associate to form a complex. The order in which the various components associate, the stoichiometry of the complex ultimately formed, and the point(s) in this association process at which phosphoryltion occurs have not been established in vitro or in vivo, however (Callus et al. 2006; Praskova et al. 2004). has a Stoichiometric coefficient of 4 PathwayStep5277 Degradation of ubiquitinated -beta catenin by the proteasome Authored: Matthews, L, 2007-04-03 12:38:03 Edited: Matthews, L, 2007-04-19 13:48:27 Pubmed17183061 Reactome Database ID Release 43195298 Reactome, http://www.reactome.org ReactomeREACT_10017 Reviewed: Pagano, M, 2007-04-27 13:02:18 Ubiquitinated beta-catenin is degraded by the proteasome. has a Stoichiometric coefficient of 4 PathwayStep5279 PathwayStep5274 Dissociation of beta-catenin from Axin and association of beta catenin with phospho-(20 aa) APC in the detruction complex Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed15327768 Pubmed15327769 Pubmed16753179 Reactome Database ID Release 43195280 Reactome, http://www.reactome.org ReactomeREACT_10127 Reviewed: Pagano, M, 2007-04-27 13:02:18 The phosphorylation of the 20 aa repeats in APC results in an increase in affinity for beta-catenin (Ha et al., 2004, Xing et al., 2004; Liu et al., 2006). The binding site of phospho -(20 aa) APC on beta-catenin, overlaps the binding site of Axin on beta catenin. In addition, phosphorylated APC prevents the association of Axin with beta-catenin (Ha et al., 2004, Xing et al., 2004). In this model, phosphorylated APC may compete with Axin for beta-catenin binding, resulting in dissociation of the Axin:beta-catenin interaction in the destruction complex (see Kimelman and Xu 2006). PathwayStep5273 Phosphorylation of APC component of the destruction complex APC is phosphorylated on the 20 aa repeats by CK1 and potentially GSK-3. This significantly increases the binding affinity of the APC 20 aa repeats for beta-catenin, causing one of them to bind b-catenin in the same region as beta-catenin binds Axin, thus displacing beta-catenin from Axin ( Step 5 above) (Reviewed in Kimelman, 2006). Authored: Kimelman, D, 2007-04-03 12:34:14 Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed11707392 Pubmed12628243 Pubmed15327769 Pubmed16753179 Pubmed17143292 Reactome Database ID Release 43195275 Reactome, http://www.reactome.org ReactomeREACT_9983 Reviewed: Pagano, M, 2007-04-27 13:02:18 PathwayStep5276 Multi-ubiquitination of phospho-beta-catenin by SCF-beta-TrCP1 Authored: Kimelman, D, 2007-04-03 12:34:14 Beta-catenin is ubiquitinated by the SCF-B-TrCP1 complex. Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed12820959 Reactome Database ID Release 43195279 Reactome, http://www.reactome.org ReactomeREACT_10082 Reviewed: Pagano, M, 2007-04-27 13:02:18 has a Stoichiometric coefficient of 4 PathwayStep5275 Association of beta-catenin with the SCF-beta-TrCP1 ubiquitin ligase complex B-TrCP associates with phosphorylated beta-catenin through the B-TrCP WD40 repeat region. Currently, it is unclear whether the ubiquitin ligase binds beta-catenin after it leaves the complex. It is equally possible that it binds beta-catenin while beta-catenin is still bound to Axin. Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed10023660 Pubmed9990852 Reactome Database ID Release 43195285 Reactome, http://www.reactome.org ReactomeREACT_9977 Reviewed: Pagano, M, 2007-04-27 13:02:18 PathwayStep5270 PathwayStep5272 PathwayStep5271 High-affinity glutamate transporter ligands Converted from EntitySet in Reactome Reactome DB_ID: 427997 Reactome Database ID Release 43427997 Reactome, http://www.reactome.org ReactomeREACT_19595 Phosphorylation of beta-catenin at Ser45 by CK1 alpha Authored: Kimelman, D, 2007-04-03 12:34:14 CK1a binds to Axin and phosphorylates beta-catenin at Ser45 priming GSK3 mediated phosphorylation at the more N-terminal residues (Amit et al., 2002; Liu et al., 2002; Yanagawa et al., 2002). Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed12000790 Reactome Database ID Release 43195318 Reactome, http://www.reactome.org ReactomeREACT_9978 Reviewed: Pagano, M, 2007-04-27 13:02:18 Phosphorylation of phospho-(Ser45 ) at Thr 41 by GSK-3 Authored: Kimelman, D, 2007-04-03 12:34:14 Edited: Matthews, L, 2007-04-03 12:38:03 Following CKI-mediated phosphorylation at Ser45, beta-catenin is phosphorylated by GSK3 at Thr41. Pubmed11955436 Reactome Database ID Release 43195287 Reactome, http://www.reactome.org ReactomeREACT_9955 Reviewed: Pagano, M, 2007-04-27 13:02:18 Phosphoryation of phospho- (Ser45, Thr41) beta-catenin at Ser37 by GSK-3 Authored: Kimelman, D, 2007-04-03 12:34:14 Edited: Matthews, L, 2007-04-03 12:38:03 Phospho-(Ser45, Thr41) beta-catenin is phosphorylated by GSK3 at Ser37. Pubmed11955436 Reactome Database ID Release 43195283 Reactome, http://www.reactome.org ReactomeREACT_9959 Reviewed: Pagano, M, 2007-04-27 13:02:18 Phosphorylation of phospho-(Ser45,Thr41,Ser37) at Ser33 by GSK-3 Authored: Kimelman, D, 2007-04-03 12:34:14 Beta-catenin is then phosphorylated at Ser33. Phosphorylated S37 and S33 together with neighboring residues constitute the recognition motif for beta-TrCP. Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed11955436 Reactome Database ID Release 43195300 Reactome, http://www.reactome.org ReactomeREACT_9987 Reviewed: Pagano, M, 2007-04-27 13:02:18 L-Amino Acids Converted from EntitySet in Reactome Reactome DB_ID: 428009 Reactome Database ID Release 43428009 Reactome, http://www.reactome.org ReactomeREACT_19825 PathwayStep5282 PathwayStep5283 PathwayStep5280 PathwayStep5281 Catecholamine Converted from EntitySet in Reactome Reactome DB_ID: 390627 Reactome Database ID Release 43390627 Reactome, http://www.reactome.org ReactomeREACT_17411 PathwayStep5286 PathwayStep5287 PathwayStep5284 PathwayStep5285 PathwayStep5288 PathwayStep5289 Integrin binding divalent cations Converted from EntitySet in Reactome Reactome DB_ID: 377604 Reactome Database ID Release 43377604 Reactome, http://www.reactome.org ReactomeREACT_18138 PathwayStep5290 PathwayStep5291 PathwayStep5292 PathwayStep5293 PathwayStep5294 PathwayStep5295 PathwayStep5296 PathwayStep5297 PathwayStep5298 PathwayStep5299 Platelet dense granule content Converted from EntitySet in Reactome Reactome DB_ID: 481030 Reactome Database ID Release 43481030 Reactome, http://www.reactome.org ReactomeREACT_21516 Platelet dense granule content Converted from EntitySet in Reactome Reactome DB_ID: 481002 Reactome Database ID Release 43481002 Reactome, http://www.reactome.org ReactomeREACT_21949 ABCC4 transported dense granule content Converted from EntitySet in Reactome Reactome DB_ID: 429153 Reactome Database ID Release 43429153 Reactome, http://www.reactome.org ReactomeREACT_24476 ABCC4 transported dense granule content Converted from EntitySet in Reactome Reactome DB_ID: 429160 Reactome Database ID Release 43429160 Reactome, http://www.reactome.org ReactomeREACT_24718 RasGRP1/3 Converted from EntitySet in Reactome RasGRP1 and RasGRP3 Reactome DB_ID: 1169462 Reactome Database ID Release 431169462 Reactome, http://www.reactome.org ReactomeREACT_119242 p-RasGRP1/3 Converted from EntitySet in Reactome Phosphorylated RasGRP1 and phosphorylated RasGRP3 Reactome DB_ID: 1169483 Reactome Database ID Release 431169483 Reactome, http://www.reactome.org ReactomeREACT_120296 Activating enzymes E1 Converted from EntitySet in Reactome Reactome DB_ID: 947695 Reactome Database ID Release 43947695 Reactome, http://www.reactome.org ReactomeREACT_76728 Ubiquitin activating E1 enzymes Acyl ghrelin:GHSR Reactome DB_ID: 947644 Reactome Database ID Release 43947644 Reactome, http://www.reactome.org ReactomeREACT_26440 has a Stoichiometric coefficient of 1 Alpha-1 adrenoceptor:Catecholamine Reactome DB_ID: 390633 Reactome Database ID Release 43390633 Reactome, http://www.reactome.org ReactomeREACT_17767 has a Stoichiometric coefficient of 1 M1/M3/M5:acetylcholine Reactome DB_ID: 390676 Reactome Database ID Release 43390676 Reactome, http://www.reactome.org ReactomeREACT_17800 has a Stoichiometric coefficient of 1 DRD1, 5:dopamine Reactome DB_ID: 390847 Reactome Database ID Release 43390847 Reactome, http://www.reactome.org ReactomeREACT_18099 has a Stoichiometric coefficient of 1 Beta adrenoceptor:catecholamine Reactome DB_ID: 390643 Reactome Database ID Release 43390643 Reactome, http://www.reactome.org ReactomeREACT_17476 has a Stoichiometric coefficient of 1 Neuromedin-U:Neuromedin receptors Reactome DB_ID: 964802 Reactome Database ID Release 43964802 Reactome, http://www.reactome.org ReactomeREACT_26703 has a Stoichiometric coefficient of 1 MCH:Melanin-concentrating hormone receptors Reactome DB_ID: 947670 Reactome Database ID Release 43947670 Reactome, http://www.reactome.org ReactomeREACT_26243 has a Stoichiometric coefficient of 1 M2/M4:acetylcholine Reactome DB_ID: 390685 Reactome Database ID Release 43390685 Reactome, http://www.reactome.org ReactomeREACT_17077 has a Stoichiometric coefficient of 1 Neuromedin-S:Neuromedin-U receptor 2 Reactome DB_ID: 981831 Reactome Database ID Release 43981831 Reactome, http://www.reactome.org ReactomeREACT_25984 has a Stoichiometric coefficient of 1 DRD2, 3, 4:dopamine Reactome DB_ID: 390849 Reactome Database ID Release 43390849 Reactome, http://www.reactome.org ReactomeREACT_17750 has a Stoichiometric coefficient of 1 IKB alpha/beta/epsilon Converted from EntitySet in Reactome NF-kappaB Inhibitor (IkBalpha, IkBbeta, IkBepsilon) Reactome DB_ID: 1168604 Reactome Database ID Release 431168604 Reactome, http://www.reactome.org ReactomeREACT_118907 p-IKB alpha/beta/epsilon Converted from EntitySet in Reactome Reactome DB_ID: 1168607 Reactome Database ID Release 431168607 Reactome, http://www.reactome.org ReactomeREACT_120112 ub-p-IKB alpha/beta/epsilon Converted from EntitySet in Reactome Reactome DB_ID: 1168599 Reactome Database ID Release 431168599 Reactome, http://www.reactome.org ReactomeREACT_120214 Ubiquitinated Phospho-NF-kappaB Inhibitor (IkBalpha, IkBbeta, IkBepsilon) Insulin-like peptide 5 Reactome DB_ID: 444898 Reactome Database ID Release 43444898 Reactome, http://www.reactome.org ReactomeREACT_22037 has a Stoichiometric coefficient of 1 Relaxin-3 receptor 2 ligands Converted from EntitySet in Reactome Reactome DB_ID: 444889 Reactome Database ID Release 43444889 Reactome, http://www.reactome.org ReactomeREACT_21586 Relaxin-3 receptor 1:Relaxin-3 Reactome DB_ID: 444847 Reactome Database ID Release 43444847 Reactome, http://www.reactome.org ReactomeREACT_21763 has a Stoichiometric coefficient of 1 Relaxin receptor 2: Relaxin receptor 2 ligands Reactome DB_ID: 444892 Reactome Database ID Release 43444892 Reactome, http://www.reactome.org ReactomeREACT_21450 has a Stoichiometric coefficient of 1 Insulin-like peptide 3 Reactome DB_ID: 444887 Reactome Database ID Release 43444887 Reactome, http://www.reactome.org ReactomeREACT_21451 has a Stoichiometric coefficient of 1 Relaxin receptor 2 ligands Converted from EntitySet in Reactome Reactome DB_ID: 444902 Reactome Database ID Release 43444902 Reactome, http://www.reactome.org ReactomeREACT_21674 Relaxin receptor 1: Relaxins 2 and 3 Reactome DB_ID: 444839 Reactome Database ID Release 43444839 Reactome, http://www.reactome.org ReactomeREACT_21925 has a Stoichiometric coefficient of 1 Relaxin-3 Reactome DB_ID: 444822 Reactome Database ID Release 43444822 Reactome, http://www.reactome.org ReactomeREACT_21424 has a Stoichiometric coefficient of 1 Active N-SMase:Mg2+ Reactome DB_ID: 194354 Reactome Database ID Release 43194354 Reactome, http://www.reactome.org ReactomeREACT_13925 has a Stoichiometric coefficient of 1 UTS2R:Urotensin 2, 2B Reactome DB_ID: 445119 Reactome Database ID Release 43445119 Reactome, http://www.reactome.org ReactomeREACT_22067 has a Stoichiometric coefficient of 1 Relaxin-3 receptor 2:relaxin-3 receptor 2 ligands Reactome DB_ID: 444907 Reactome Database ID Release 43444907 Reactome, http://www.reactome.org ReactomeREACT_21723 has a Stoichiometric coefficient of 1 RHOA:RHO-GDIalpha Reactome DB_ID: 194533 Reactome Database ID Release 43194533 Reactome, http://www.reactome.org ReactomeREACT_14266 has a Stoichiometric coefficient of 1 RhoA (Mg cofactor):GDP Reactome DB_ID: 194489 Reactome Database ID Release 43194489 Reactome, http://www.reactome.org ReactomeREACT_13852 has a Stoichiometric coefficient of 1 RHOA:RHO-GDIalpha:p75NTR Reactome DB_ID: 194466 Reactome Database ID Release 43194466 Reactome, http://www.reactome.org ReactomeREACT_14502 has a Stoichiometric coefficient of 1 RhoA:Rho-GDIalpha:p75NTR:NGF Reactome DB_ID: 194506 Reactome Database ID Release 43194506 Reactome, http://www.reactome.org ReactomeREACT_14392 has a Stoichiometric coefficient of 1 p75NTR:NgR Reactome DB_ID: 194513 Reactome Database ID Release 43194513 Reactome, http://www.reactome.org ReactomeREACT_14205 has a Stoichiometric coefficient of 1 p75NTR:NgR:LINGO1 Reactome DB_ID: 194583 Reactome Database ID Release 43194583 Reactome, http://www.reactome.org ReactomeREACT_14153 has a Stoichiometric coefficient of 1 p75NTR:NgR:LINGO1:myelin component Reactome DB_ID: 194499 Reactome Database ID Release 43194499 Reactome, http://www.reactome.org ReactomeREACT_14145 has a Stoichiometric coefficient of 1 RHOA:RHO-GDI:p75NTR:NgR:myelin component Reactome DB_ID: 194481 Reactome Database ID Release 43194481 Reactome, http://www.reactome.org ReactomeREACT_14139 has a Stoichiometric coefficient of 1 RHO-GDI:p75NTR:NgR:myelin component Reactome DB_ID: 194528 Reactome Database ID Release 43194528 Reactome, http://www.reactome.org ReactomeREACT_14519 has a Stoichiometric coefficient of 1 ADAM 17 metalloprotease (Zn cofactor) Reactome DB_ID: 194538 Reactome Database ID Release 43194538 Reactome, http://www.reactome.org ReactomeREACT_14091 has a Stoichiometric coefficient of 1 RhoA (Mg cofactor):GTP Reactome DB_ID: 194545 Reactome Database ID Release 43194545 Reactome, http://www.reactome.org ReactomeREACT_14306 has a Stoichiometric coefficient of 1 beta-NGF homodimer Reactome DB_ID: 167057 Reactome Database ID Release 43167057 Reactome, http://www.reactome.org ReactomeREACT_10974 has a Stoichiometric coefficient of 2 beta-NGF dimer:TrkA receptor dimer Reactome DB_ID: 166543 Reactome Database ID Release 43166543 Reactome, http://www.reactome.org ReactomeREACT_10135 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PLC gamma1/2 Converted from EntitySet in Reactome Phospholipase C gamma1 and Phospholipase C gamma2 Reactome DB_ID: 1169089 Reactome Database ID Release 431169089 Reactome, http://www.reactome.org ReactomeREACT_120292 NF-kB:p75NTR ICD:TRAF6 Reactome DB_ID: 197481 Reactome Database ID Release 43197481 Reactome, http://www.reactome.org ReactomeREACT_13901 has a Stoichiometric coefficient of 1 beta-NGF dimer:TrkA receptor Reactome DB_ID: 166537 Reactome Database ID Release 43166537 Reactome, http://www.reactome.org ReactomeREACT_10893 has a Stoichiometric coefficient of 1 beta-NGF homodimer Reactome DB_ID: 190067 Reactome Database ID Release 43190067 Reactome, http://www.reactome.org ReactomeREACT_10850 has a Stoichiometric coefficient of 2 Adenosine:Adenosine A2a receptor Reactome DB_ID: 187653 Reactome Database ID Release 43187653 Reactome, http://www.reactome.org ReactomeREACT_11028 has a Stoichiometric coefficient of 1 Activated TrkA receptor complex Reactome DB_ID: 166540 Reactome Database ID Release 43166540 Reactome, http://www.reactome.org ReactomeREACT_10696 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated TrkA receptor complex Reactome DB_ID: 190083 Reactome Database ID Release 43190083 Reactome, http://www.reactome.org ReactomeREACT_10757 has a Stoichiometric coefficient of 1 p-PLC gamma1/2 Converted from EntitySet in Reactome Phosphorylated Phospholipase C gamma1 and Phosphorylated Phospholipase C gamma2 Reactome DB_ID: 1169086 Reactome Database ID Release 431169086 Reactome, http://www.reactome.org ReactomeREACT_119455 Activated TrkA receptor:p-SHC Reactome DB_ID: 167015 Reactome Database ID Release 43167015 Reactome, http://www.reactome.org ReactomeREACT_12114 has a Stoichiometric coefficient of 1 Activated TrkA receptor:SHC Reactome DB_ID: 167020 Reactome Database ID Release 43167020 Reactome, http://www.reactome.org ReactomeREACT_12103 has a Stoichiometric coefficient of 1 PACAP:PACAP type 1 receptor Reactome DB_ID: 187656 Reactome Database ID Release 43187656 Reactome, http://www.reactome.org ReactomeREACT_10139 has a Stoichiometric coefficient of 1 RALA-GTP Reactome DB_ID: 170990 Reactome Database ID Release 43170990 Reactome, http://www.reactome.org ReactomeREACT_12110 has a Stoichiometric coefficient of 1 RAL-GTP Converted from EntitySet in Reactome Reactome DB_ID: 170998 Reactome Database ID Release 43170998 Reactome, http://www.reactome.org ReactomeREACT_12304 RALB-GTP Reactome DB_ID: 171017 Reactome Database ID Release 43171017 Reactome, http://www.reactome.org ReactomeREACT_12281 has a Stoichiometric coefficient of 1 RAL-GDP Converted from EntitySet in Reactome Reactome DB_ID: 170994 Reactome Database ID Release 43170994 Reactome, http://www.reactome.org ReactomeREACT_12274 Ras-GTP:RalGDS complex Reactome DB_ID: 171020 Reactome Database ID Release 43171020 Reactome, http://www.reactome.org ReactomeREACT_12340 has a Stoichiometric coefficient of 1 RALB-GDP Reactome DB_ID: 171005 Reactome Database ID Release 43171005 Reactome, http://www.reactome.org ReactomeREACT_12220 has a Stoichiometric coefficient of 1 RALA-GDP Reactome DB_ID: 171002 Reactome Database ID Release 43171002 Reactome, http://www.reactome.org ReactomeREACT_12294 has a Stoichiometric coefficient of 1 RIT/RIN-GDP Reactome DB_ID: 187734 Reactome Database ID Release 43187734 Reactome, http://www.reactome.org ReactomeREACT_12139 has a Stoichiometric coefficient of 1 Active TrkA receptor complex:RIT/RIN-GDP Reactome DB_ID: 187690 Reactome Database ID Release 43187690 Reactome, http://www.reactome.org ReactomeREACT_12112 has a Stoichiometric coefficient of 1 Active Trk receptor complex:RIT/RIN-GTP Reactome DB_ID: 187701 Reactome Database ID Release 43187701 Reactome, http://www.reactome.org ReactomeREACT_12211 has a Stoichiometric coefficient of 1 RIT/RIN-GTP Reactome DB_ID: 187722 Reactome Database ID Release 43187722 Reactome, http://www.reactome.org ReactomeREACT_12109 has a Stoichiometric coefficient of 1 PathwayStep5200 PathwayStep5201 PathwayStep5202 PathwayStep5203 PathwayStep5207 PathwayStep5206 PathwayStep5205 PathwayStep5204 PathwayStep5209 PathwayStep5208 Active TrkA receptor:p-FRS2:CRKL complex Reactome DB_ID: 190081 Reactome Database ID Release 43190081 Reactome, http://www.reactome.org ReactomeREACT_12126 has a Stoichiometric coefficient of 1 Active TrkA receptor:PLCG1 complex Reactome DB_ID: 167687 Reactome Database ID Release 43167687 Reactome, http://www.reactome.org ReactomeREACT_12180 has a Stoichiometric coefficient of 1 Active TrkA receptor:p-FRS2 complex Reactome DB_ID: 190073 Reactome Database ID Release 43190073 Reactome, http://www.reactome.org ReactomeREACT_12171 has a Stoichiometric coefficient of 1 Active TrkA receptor:FRS2 complex Reactome DB_ID: 190068 Reactome Database ID Release 43190068 Reactome, http://www.reactome.org ReactomeREACT_12147 has a Stoichiometric coefficient of 1 Active Trk receptor complex:RIT/RIN-GTP:B-RAF Reactome DB_ID: 187750 Reactome Database ID Release 43187750 Reactome, http://www.reactome.org ReactomeREACT_12347 has a Stoichiometric coefficient of 1 B-RAF Reactome DB_ID: 189845 Reactome Database ID Release 43189845 Reactome, http://www.reactome.org ReactomeREACT_12124 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 B-Raf complex Reactome DB_ID: 190075 Reactome Database ID Release 43190075 Reactome, http://www.reactome.org ReactomeREACT_12219 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Rap1-GTP:B-Raf complex Reactome DB_ID: 190082 Reactome Database ID Release 43190082 Reactome, http://www.reactome.org ReactomeREACT_12223 has a Stoichiometric coefficient of 1 Rap1-GDP Reactome DB_ID: 190077 Reactome Database ID Release 43190077 Reactome, http://www.reactome.org ReactomeREACT_12111 has a Stoichiometric coefficient of 1 Rap1-GTP Reactome DB_ID: 190069 Reactome Database ID Release 43190069 Reactome, http://www.reactome.org ReactomeREACT_12189 has a Stoichiometric coefficient of 1 Active TrkA receptor:Phospho-Frs2:CrkL:C3G complex Reactome DB_ID: 190070 Reactome Database ID Release 43190070 Reactome, http://www.reactome.org ReactomeREACT_12337 has a Stoichiometric coefficient of 1 PathwayStep5210 PathwayStep5213 PathwayStep5214 PathwayStep5211 PathwayStep5212 PathwayStep5219 PathwayStep5216 PathwayStep5215 PathwayStep5218 PathwayStep5217 Active TrkA receptor:ARMS:Crk complex Reactome DB_ID: 169871 Reactome Database ID Release 43169871 Reactome, http://www.reactome.org ReactomeREACT_12251 has a Stoichiometric coefficient of 1 ARMS:Crk Reactome DB_ID: 169872 Reactome Database ID Release 43169872 Reactome, http://www.reactome.org ReactomeREACT_12089 has a Stoichiometric coefficient of 1 Phospho-ARMS:Crk Reactome DB_ID: 169854 Reactome Database ID Release 43169854 Reactome, http://www.reactome.org ReactomeREACT_12208 has a Stoichiometric coefficient of 1 Active TrkA receptor:Phospho-ARMS:Crk complex Reactome DB_ID: 169865 Reactome Database ID Release 43169865 Reactome, http://www.reactome.org ReactomeREACT_12282 has a Stoichiometric coefficient of 1 Active TrkA receptor:Phospho-ARMS:Crk:C3G complex Reactome DB_ID: 169857 Reactome Database ID Release 43169857 Reactome, http://www.reactome.org ReactomeREACT_12225 has a Stoichiometric coefficient of 1 Rap1-GDP Reactome DB_ID: 169860 Reactome Database ID Release 43169860 Reactome, http://www.reactome.org ReactomeREACT_12289 has a Stoichiometric coefficient of 1 Rap1-GTP Reactome DB_ID: 169866 Reactome Database ID Release 43169866 Reactome, http://www.reactome.org ReactomeREACT_12362 has a Stoichiometric coefficient of 1 Active TrkA:Phospho-ARMS:Crk:C3G:Rap1-GTP complex Reactome DB_ID: 169874 Reactome Database ID Release 43169874 Reactome, http://www.reactome.org ReactomeREACT_12359 has a Stoichiometric coefficient of 1 B-Raf complex Reactome DB_ID: 170966 Reactome Database ID Release 43170966 Reactome, http://www.reactome.org ReactomeREACT_12300 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Active TrkA:Phospho-ARMS:Crk:C3G:Rap1:Phospho-B-Raf complex Reactome DB_ID: 169882 Reactome Database ID Release 43169882 Reactome, http://www.reactome.org ReactomeREACT_12169 has a Stoichiometric coefficient of 1 Phospho-B-Raf Reactome DB_ID: 169877 Reactome Database ID Release 43169877 Reactome, http://www.reactome.org ReactomeREACT_12150 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5222 PathwayStep5223 PathwayStep5224 PathwayStep5225 PathwayStep5220 PathwayStep5221 PathwayStep5229 PathwayStep5228 PathwayStep5227 PathwayStep5226 Activated TrkA receptor:Phospho-IRS1/2:PI3K(p85:p110) Reactome DB_ID: 213135 Reactome Database ID Release 43213135 Reactome, http://www.reactome.org ReactomeREACT_12678 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated TrkA receptor:Phospho-IRS1/2 Reactome DB_ID: 198299 Reactome Database ID Release 43198299 Reactome, http://www.reactome.org ReactomeREACT_13002 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated TrkA receptor:IRS1/2 Reactome DB_ID: 198307 Reactome Database ID Release 43198307 Reactome, http://www.reactome.org ReactomeREACT_13110 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Active TrkA receptor:Phospho-PLCG1 complex Reactome DB_ID: 167681 Reactome Database ID Release 43167681 Reactome, http://www.reactome.org ReactomeREACT_12153 has a Stoichiometric coefficient of 1 Activated TrkA receptor complex:Clathrin-coated vesicle Reactome DB_ID: 177506 Reactome Database ID Release 43177506 Reactome, http://www.reactome.org ReactomeREACT_13141 has a Stoichiometric coefficient of 1 Activated TrkA receptor complex:Clathrin-coated vesicle Activated TrkA receptor complex:Clathrin-coated vesicle:Endophilin Reactome DB_ID: 177490 Reactome Database ID Release 43177490 Reactome, http://www.reactome.org ReactomeREACT_13349 has a Stoichiometric coefficient of 1 PIP3:RhoA Reactome DB_ID: 202676 Reactome Database ID Release 43202676 Reactome, http://www.reactome.org ReactomeREACT_12649 has a Stoichiometric coefficient of 1 PDGF A-chain precursor dimer Reactome DB_ID: 381927 Reactome Database ID Release 43381927 Reactome, http://www.reactome.org ReactomeREACT_17221 has a Stoichiometric coefficient of 2 PDGF B-chain precursor dimer Reactome DB_ID: 381938 Reactome Database ID Release 43381938 Reactome, http://www.reactome.org ReactomeREACT_18022 has a Stoichiometric coefficient of 2 Activated TrkA receptor complex:Clathrin-coated vesicle:dynein:dynactin complex Reactome DB_ID: 177507 Reactome Database ID Release 43177507 Reactome, http://www.reactome.org ReactomeREACT_13375 has a Stoichiometric coefficient of 1 PDGF precursor dimers (AA, BB, A/B, CC, DD) Converted from EntitySet in Reactome Reactome DB_ID: 381936 Reactome Database ID Release 43381936 Reactome, http://www.reactome.org ReactomeREACT_17541 PathwayStep5235 PathwayStep5236 PathwayStep5233 PathwayStep5234 PathwayStep5231 PathwayStep5232 PathwayStep5230 GPR39:Zn++ Reactome DB_ID: 444575 Reactome Database ID Release 43444575 Reactome, http://www.reactome.org ReactomeREACT_23186 has a Stoichiometric coefficient of 1 N-arachidonyl glycine receptor:NAGly Reactome DB_ID: 517528 Reactome Database ID Release 43517528 Reactome, http://www.reactome.org ReactomeREACT_21829 has a Stoichiometric coefficient of 1 Calcitonin receptor:Calcitonin Reactome DB_ID: 419848 Reactome Database ID Release 43419848 Reactome, http://www.reactome.org ReactomeREACT_18940 has a Stoichiometric coefficient of 1 pH sensing receptors:H+ Reactome DB_ID: 444739 Reactome Database ID Release 43444739 Reactome, http://www.reactome.org ReactomeREACT_22012 has a Stoichiometric coefficient of 1 FFAR3:Carboxylate ligands Reactome DB_ID: 444048 Reactome Database ID Release 43444048 Reactome, http://www.reactome.org ReactomeREACT_21693 has a Stoichiometric coefficient of 1 G-protein coupled bile acid receptor: Bile acids Reactome DB_ID: 444843 Reactome Database ID Release 43444843 Reactome, http://www.reactome.org ReactomeREACT_21728 has a Stoichiometric coefficient of 1 Niacin receptors:niacin Reactome DB_ID: 444663 Reactome Database ID Release 43444663 Reactome, http://www.reactome.org ReactomeREACT_21888 has a Stoichiometric coefficient of 1 PathwayStep3135 Opsins:photon Reactome DB_ID: 419779 Reactome Database ID Release 43419779 Reactome, http://www.reactome.org ReactomeREACT_19008 has a Stoichiometric coefficient of 1 PathwayStep3134 PathwayStep3133 FFAR2:Carboxylate ligands Reactome DB_ID: 444174 Reactome Database ID Release 43444174 Reactome, http://www.reactome.org ReactomeREACT_21889 has a Stoichiometric coefficient of 1 PathwayStep3132 Melanospin:photon Reactome DB_ID: 419842 Reactome Database ID Release 43419842 Reactome, http://www.reactome.org ReactomeREACT_18512 has a Stoichiometric coefficient of 1 PathwayStep3131 PathwayStep3130 PathwayStep3129 PathwayStep3127 PathwayStep3128 PathwayStep3125 PathwayStep3126 Phospho PDGF beta receptor: PDGF chain B homodimer Reactome DB_ID: 389074 Reactome Database ID Release 43389074 Reactome, http://www.reactome.org ReactomeREACT_17403 has a Stoichiometric coefficient of 1 PDGF beta receptor:PDGF chain B homodimer Reactome DB_ID: 389078 Reactome Database ID Release 43389078 Reactome, http://www.reactome.org ReactomeREACT_17457 has a Stoichiometric coefficient of 1 Beta receptor homodimer Reactome DB_ID: 186799 Reactome Database ID Release 43186799 Reactome, http://www.reactome.org ReactomeREACT_17291 has a Stoichiometric coefficient of 2 AM2 receptor Reactome DB_ID: 420109 Reactome Database ID Release 43420109 Reactome, http://www.reactome.org ReactomeREACT_18730 has a Stoichiometric coefficient of 1 Alpha-Beta receptor heterodimer Reactome DB_ID: 186791 Reactome Database ID Release 43186791 Reactome, http://www.reactome.org ReactomeREACT_17278 has a Stoichiometric coefficient of 1 AM1 receptor Reactome DB_ID: 420232 Reactome Database ID Release 43420232 Reactome, http://www.reactome.org ReactomeREACT_18575 has a Stoichiometric coefficient of 1 Alpha receptor homodimer Reactome DB_ID: 186817 Reactome Database ID Release 43186817 Reactome, http://www.reactome.org ReactomeREACT_17302 has a Stoichiometric coefficient of 2 Adrenomedullin receptor Converted from EntitySet in Reactome Reactome DB_ID: 420118 Reactome Database ID Release 43420118 Reactome, http://www.reactome.org ReactomeREACT_18795 PDGF receptor dimer Converted from EntitySet in Reactome Reactome DB_ID: 186770 Reactome Database ID Release 43186770 Reactome, http://www.reactome.org ReactomeREACT_17877 CGRP1 receptor:CGRP Reactome DB_ID: 420236 Reactome Database ID Release 43420236 Reactome, http://www.reactome.org ReactomeREACT_18642 has a Stoichiometric coefficient of 1 PDGF:PDGF receptor dimer Reactome DB_ID: 186766 Reactome Database ID Release 43186766 Reactome, http://www.reactome.org ReactomeREACT_18025 has a Stoichiometric coefficient of 1 CGRP receptor Reactome DB_ID: 419782 Reactome Database ID Release 43419782 Reactome, http://www.reactome.org ReactomeREACT_18682 has a Stoichiometric coefficient of 1 PDGF A and B chains:ECM complex Reactome DB_ID: 381952 Reactome Database ID Release 43381952 Reactome, http://www.reactome.org ReactomeREACT_17710 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 AMY receptors:Amylin Reactome DB_ID: 420147 Reactome Database ID Release 43420147 Reactome, http://www.reactome.org ReactomeREACT_19065 has a Stoichiometric coefficient of 1 PathwayStep3122 Tropocollagen type VI Reactome DB_ID: 381923 Reactome Database ID Release 43381923 Reactome, http://www.reactome.org ReactomeREACT_18009 has a Stoichiometric coefficient of 1 AMY3 receptor Reactome DB_ID: 420172 Reactome Database ID Release 43420172 Reactome, http://www.reactome.org ReactomeREACT_18950 has a Stoichiometric coefficient of 1 PathwayStep3121 Collagen type IX Reactome DB_ID: 375076 Reactome Database ID Release 43375076 Reactome, http://www.reactome.org ReactomeREACT_17546 has a Stoichiometric coefficient of 1 AMY2 receptor Reactome DB_ID: 420186 Reactome Database ID Release 43420186 Reactome, http://www.reactome.org ReactomeREACT_18997 has a Stoichiometric coefficient of 1 PathwayStep3124 AMY1 receptor Reactome DB_ID: 420212 Reactome Database ID Release 43420212 Reactome, http://www.reactome.org ReactomeREACT_18527 has a Stoichiometric coefficient of 1 PathwayStep3123 AMY receptors Converted from EntitySet in Reactome Reactome DB_ID: 420237 Reactome Database ID Release 43420237 Reactome, http://www.reactome.org ReactomeREACT_18958 PathwayStep3120 PathwayStep3118 PathwayStep3119 PathwayStep3114 PathwayStep3115 PathwayStep3116 PathwayStep3117 Procollagen type V alpha-1X2 alpha-2 Reactome DB_ID: 375080 Reactome Database ID Release 43375080 Reactome, http://www.reactome.org ReactomeREACT_17987 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PDGF-C chain dimer Reactome DB_ID: 381941 Reactome Database ID Release 43381941 Reactome, http://www.reactome.org ReactomeREACT_18174 has a Stoichiometric coefficient of 2 P2RY2:ATP Reactome DB_ID: 417866 Reactome Database ID Release 43417866 Reactome, http://www.reactome.org ReactomeREACT_19036 has a Stoichiometric coefficient of 1 Active PDGF dimers (CC, DD) Converted from EntitySet in Reactome Reactome DB_ID: 381939 Reactome Database ID Release 43381939 Reactome, http://www.reactome.org ReactomeREACT_17802 P2RY1:ADP Reactome DB_ID: 417920 Reactome Database ID Release 43417920 Reactome, http://www.reactome.org ReactomeREACT_18780 has a Stoichiometric coefficient of 1 Procollagen type II Reactome DB_ID: 215983 Reactome Database ID Release 43215983 Reactome, http://www.reactome.org ReactomeREACT_14196 has a Stoichiometric coefficient of 3 P2RY5:LPA Reactome DB_ID: 417887 Reactome Database ID Release 43417887 Reactome, http://www.reactome.org ReactomeREACT_18493 has a Stoichiometric coefficient of 1 PDGF-D chain dimer Reactome DB_ID: 381930 Reactome Database ID Release 43381930 Reactome, http://www.reactome.org ReactomeREACT_17287 has a Stoichiometric coefficient of 2 P2RY4:UTP Reactome DB_ID: 417869 Reactome Database ID Release 43417869 Reactome, http://www.reactome.org ReactomeREACT_18831 has a Stoichiometric coefficient of 1 Type IV collagen Converted from EntitySet in Reactome Reactome DB_ID: 215993 Reactome Database ID Release 43215993 Reactome, http://www.reactome.org ReactomeREACT_14341 P2RY9:LPA Reactome DB_ID: 418023 Reactome Database ID Release 43418023 Reactome, http://www.reactome.org ReactomeREACT_19068 has a Stoichiometric coefficient of 1 Procollagen type III Reactome DB_ID: 375077 Reactome Database ID Release 43375077 Reactome, http://www.reactome.org ReactomeREACT_17422 has a Stoichiometric coefficient of 3 P2RY6:UDP Reactome DB_ID: 417868 Reactome Database ID Release 43417868 Reactome, http://www.reactome.org ReactomeREACT_19085 has a Stoichiometric coefficient of 1 Collagen alpha-3(IV):Collagen alpha-4(IV):Collagen alpha-5(IV) triple helix Reactome DB_ID: 215984 Reactome Database ID Release 43215984 Reactome, http://www.reactome.org ReactomeREACT_14476 has a Stoichiometric coefficient of 1 P2RY11 :ATP Reactome DB_ID: 417836 Reactome Database ID Release 43417836 Reactome, http://www.reactome.org ReactomeREACT_18925 has a Stoichiometric coefficient of 1 Collagen alpha-1(IV):Collagen alpha-2(IV) Reactome DB_ID: 215992 Reactome Database ID Release 43215992 Reactome, http://www.reactome.org ReactomeREACT_13960 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 P2RY10:LPA Reactome DB_ID: 418019 Reactome Database ID Release 43418019 Reactome, http://www.reactome.org ReactomeREACT_18593 has a Stoichiometric coefficient of 1 PathwayStep3113 PathwayStep3112 PathwayStep3111 PDGF-D chain precursor dimer Reactome DB_ID: 381944 Reactome Database ID Release 43381944 Reactome, http://www.reactome.org ReactomeREACT_17154 has a Stoichiometric coefficient of 2 OXE receptor:5-oxo-ETE Reactome DB_ID: 416461 Reactome Database ID Release 43416461 Reactome, http://www.reactome.org ReactomeREACT_18684 has a Stoichiometric coefficient of 1 PathwayStep3110 PathwayStep3105 PathwayStep3106 PathwayStep3103 PathwayStep3104 PathwayStep3109 PathwayStep3107 PathwayStep3108 Novel PDGF precursor dimers (CC, DD) Converted from EntitySet in Reactome Reactome DB_ID: 381947 Reactome Database ID Release 43381947 Reactome, http://www.reactome.org ReactomeREACT_17162 Cysteinyl leukotriene receptors:Cysteinyl leukotrienes Reactome DB_ID: 416423 Reactome Database ID Release 43416423 Reactome, http://www.reactome.org ReactomeREACT_18752 has a Stoichiometric coefficient of 1 PDGF-C chain precursor dimer Reactome DB_ID: 381943 Reactome Database ID Release 43381943 Reactome, http://www.reactome.org ReactomeREACT_18218 has a Stoichiometric coefficient of 2 GPR17:cysLTs Reactome DB_ID: 416381 Reactome Database ID Release 43416381 Reactome, http://www.reactome.org ReactomeREACT_18619 has a Stoichiometric coefficient of 1 PDGF A/B-chain precursor hetero dimer Reactome DB_ID: 380751 Reactome Database ID Release 43380751 Reactome, http://www.reactome.org ReactomeREACT_18157 has a Stoichiometric coefficient of 1 Cannabinoid receptor:2-AG Reactome DB_ID: 419404 Reactome Database ID Release 43419404 Reactome, http://www.reactome.org ReactomeREACT_18651 has a Stoichiometric coefficient of 1 PDGF B-chain precursor dimer Reactome DB_ID: 380748 Reactome Database ID Release 43380748 Reactome, http://www.reactome.org ReactomeREACT_17456 has a Stoichiometric coefficient of 2 A2a/A2b receptor:Adenosine Reactome DB_ID: 418926 Reactome Database ID Release 43418926 Reactome, http://www.reactome.org ReactomeREACT_18473 has a Stoichiometric coefficient of 1 PDGF A-chain precursor dimer Reactome DB_ID: 380749 Reactome Database ID Release 43380749 Reactome, http://www.reactome.org ReactomeREACT_18117 has a Stoichiometric coefficient of 2 A1/A3 receptor:Adenosine Reactome DB_ID: 418897 Reactome Database ID Release 43418897 Reactome, http://www.reactome.org ReactomeREACT_19006 has a Stoichiometric coefficient of 1 PDGF precursor dimers (AA, BB, A/B, CC, DD) Converted from EntitySet in Reactome Reactome DB_ID: 381926 Reactome Database ID Release 43381926 Reactome, http://www.reactome.org ReactomeREACT_17912 GPR17:UDP Reactome DB_ID: 418945 Reactome Database ID Release 43418945 Reactome, http://www.reactome.org ReactomeREACT_18488 has a Stoichiometric coefficient of 1 Novel PDGF precursor dimers (CC, DD) Converted from EntitySet in Reactome Reactome DB_ID: 381942 Reactome Database ID Release 43381942 Reactome, http://www.reactome.org ReactomeREACT_17079 S1P-binding EDG receptors: S1P Reactome DB_ID: 419346 Reactome Database ID Release 43419346 Reactome, http://www.reactome.org ReactomeREACT_18907 has a Stoichiometric coefficient of 1 Classical PDGF precursor dimers (AA, AB, BB) Converted from EntitySet in Reactome Reactome DB_ID: 186822 Reactome Database ID Release 43186822 Reactome, http://www.reactome.org ReactomeREACT_17671 LPA-binding EDG receptors: LPA Reactome DB_ID: 419353 Reactome Database ID Release 43419353 Reactome, http://www.reactome.org ReactomeREACT_18853 has a Stoichiometric coefficient of 1 PDGF-C chain precursor dimer Reactome DB_ID: 381928 Reactome Database ID Release 43381928 Reactome, http://www.reactome.org ReactomeREACT_17940 has a Stoichiometric coefficient of 2 Melatonin receptors:melatonin Reactome DB_ID: 419365 Reactome Database ID Release 43419365 Reactome, http://www.reactome.org ReactomeREACT_18621 has a Stoichiometric coefficient of 1 PDGF-D chain precursor dimer Reactome DB_ID: 381948 Reactome Database ID Release 43381948 Reactome, http://www.reactome.org ReactomeREACT_17794 has a Stoichiometric coefficient of 2 PAF receptor:PAF Reactome DB_ID: 419364 Reactome Database ID Release 43419364 Reactome, http://www.reactome.org ReactomeREACT_18643 has a Stoichiometric coefficient of 1 PathwayStep3100 P2RY14:UDP-glucose Reactome DB_ID: 417863 Reactome Database ID Release 43417863 Reactome, http://www.reactome.org ReactomeREACT_18577 has a Stoichiometric coefficient of 1 P2RY13:ADP Reactome DB_ID: 417853 Reactome Database ID Release 43417853 Reactome, http://www.reactome.org ReactomeREACT_18440 has a Stoichiometric coefficient of 1 PathwayStep3102 PathwayStep3101 PDGF AB precursor heterodimer Reactome DB_ID: 392712 Reactome Database ID Release 43392712 Reactome, http://www.reactome.org ReactomeREACT_17432 has a Stoichiometric coefficient of 1 PDGF-D chain precursor dimer Reactome DB_ID: 381925 Reactome Database ID Release 43381925 Reactome, http://www.reactome.org ReactomeREACT_17867 has a Stoichiometric coefficient of 2 P2RY12:ADP Reactome DB_ID: 417834 Reactome Database ID Release 43417834 Reactome, http://www.reactome.org ReactomeREACT_18716 has a Stoichiometric coefficient of 1 PDGF-C chain precursor dimer Reactome DB_ID: 381931 Reactome Database ID Release 43381931 Reactome, http://www.reactome.org ReactomeREACT_18219 has a Stoichiometric coefficient of 2 PathwayStep3178 Ligand:GPCR complexes that activate Gs:Heterotrimeric G-protein Gs (inactive) Reactome DB_ID: 744885 Reactome Database ID Release 43744885 Reactome, http://www.reactome.org ReactomeREACT_22796 has a Stoichiometric coefficient of 1 PathwayStep3179 GPCR:ligand complexes that act on Gs:Heterotrimeric G-protein Gs (active) Reactome DB_ID: 744890 Reactome Database ID Release 43744890 Reactome, http://www.reactome.org ReactomeREACT_22953 has a Stoichiometric coefficient of 1 PathwayStep3176 G-protein alpha (z):GTP:Adenylate cyclase Reactome DB_ID: 392049 Reactome Database ID Release 43392049 Reactome, http://www.reactome.org ReactomeREACT_19687 has a Stoichiometric coefficient of 1 PathwayStep3177 G-protein alpha (z):GTP Reactome DB_ID: 392003 Reactome Database ID Release 43392003 Reactome, http://www.reactome.org ReactomeREACT_20258 has a Stoichiometric coefficient of 1 PathwayStep3174 PathwayStep3175 Ligand:GPCR complexes that activate Gs Converted from EntitySet in Reactome Reactome DB_ID: 391181 Reactome Database ID Release 43391181 Reactome, http://www.reactome.org ReactomeREACT_17498 PathwayStep3172 CGRP receptor:CGRP ligands Reactome DB_ID: 419784 Reactome Database ID Release 43419784 Reactome, http://www.reactome.org ReactomeREACT_18446 has a Stoichiometric coefficient of 1 PathwayStep3173 VIP receptor:VIP Reactome DB_ID: 420213 Reactome Database ID Release 43420213 Reactome, http://www.reactome.org ReactomeREACT_18982 has a Stoichiometric coefficient of 1 PathwayStep3170 PathwayStep3171 Ligand:GPCR complexes that activate Gi Converted from EntitySet in Reactome Reactome DB_ID: 380091 Reactome Database ID Release 43380091 Reactome, http://www.reactome.org ReactomeREACT_17461 Type 2 angiotensin II receptor:Angiotensin II Reactome DB_ID: 389873 Reactome Database ID Release 43389873 Reactome, http://www.reactome.org ReactomeREACT_17107 has a Stoichiometric coefficient of 1 Ligand:GPCR complexes that activate Gi:Heterotrimeric G-protein Gi (inactive) Reactome DB_ID: 749455 Reactome Database ID Release 43749455 Reactome, http://www.reactome.org ReactomeREACT_22813 has a Stoichiometric coefficient of 1 PathwayStep3169 PathwayStep3165 Ligand:GPCR complexes that activate Gz Converted from EntitySet in Reactome Reactome DB_ID: 392855 Reactome Database ID Release 43392855 Reactome, http://www.reactome.org ReactomeREACT_23082 PathwayStep3166 Ligand:GPCR complexes that activate Gz:Heterotrimeric G-protein Gz (inactive) Reactome DB_ID: 749450 Reactome Database ID Release 43749450 Reactome, http://www.reactome.org ReactomeREACT_23143 has a Stoichiometric coefficient of 1 PathwayStep3167 Heterotrimeric G-protein Gz (inactive) Reactome DB_ID: 391985 Reactome Database ID Release 43391985 Reactome, http://www.reactome.org ReactomeREACT_22728 has a Stoichiometric coefficient of 1 PathwayStep3168 G-protein alpha (z):GDP Reactome DB_ID: 392006 Reactome Database ID Release 43392006 Reactome, http://www.reactome.org ReactomeREACT_20097 has a Stoichiometric coefficient of 1 PathwayStep3161 G-alpha(t)-GDP Reactome DB_ID: 420882 Reactome Database ID Release 43420882 Reactome, http://www.reactome.org ReactomeREACT_18975 has a Stoichiometric coefficient of 1 PathwayStep3162 G-alpha(t)-GTP Reactome DB_ID: 420891 Reactome Database ID Release 43420891 Reactome, http://www.reactome.org ReactomeREACT_18710 has a Stoichiometric coefficient of 1 PathwayStep3163 Ligand:GPCR complexes that activate Gi:Heterotrimeric G-protein Gi (active) Reactome DB_ID: 749445 Reactome Database ID Release 43749445 Reactome, http://www.reactome.org ReactomeREACT_23190 has a Stoichiometric coefficient of 1 PathwayStep3164 G-alpha(t)-GDP:G-beta-gamma Reactome DB_ID: 420877 Reactome Database ID Release 43420877 Reactome, http://www.reactome.org ReactomeREACT_18859 has a Stoichiometric coefficient of 1 PathwayStep3160 Ligand:GPCR complexes that activate Gz:Heterotrimeric G-protein Gz (active) Reactome DB_ID: 751030 Reactome Database ID Release 43751030 Reactome, http://www.reactome.org ReactomeREACT_22976 has a Stoichiometric coefficient of 1 Heterotrimeric G-protein Gz (active) Reactome DB_ID: 392005 Reactome Database ID Release 43392005 Reactome, http://www.reactome.org ReactomeREACT_23379 has a Stoichiometric coefficient of 1 PathwayStep3159 PathwayStep3158 PathwayStep3152 PathwayStep3153 PathwayStep3150 PathwayStep3151 Adrenomedullin receptor:AM/AM2 Reactome DB_ID: 420062 Reactome Database ID Release 43420062 Reactome, http://www.reactome.org ReactomeREACT_19018 has a Stoichiometric coefficient of 1 PathwayStep3156 CRH receptor:CRH Reactome DB_ID: 420105 Reactome Database ID Release 43420105 Reactome, http://www.reactome.org ReactomeREACT_18567 has a Stoichiometric coefficient of 1 PathwayStep3157 Gastric inhibitory polypeptide receptor:Gastric inhibitory polypeptide Reactome DB_ID: 420229 Reactome Database ID Release 43420229 Reactome, http://www.reactome.org ReactomeREACT_18909 has a Stoichiometric coefficient of 1 PathwayStep3154 GLPR2:GLP2 Reactome DB_ID: 420087 Reactome Database ID Release 43420087 Reactome, http://www.reactome.org ReactomeREACT_18838 has a Stoichiometric coefficient of 1 PathwayStep3155 GHRH receptor:GHRH Reactome DB_ID: 420258 Reactome Database ID Release 43420258 Reactome, http://www.reactome.org ReactomeREACT_18607 has a Stoichiometric coefficient of 1 PACAP receptor:PACAP peptides Reactome DB_ID: 420103 Reactome Database ID Release 43420103 Reactome, http://www.reactome.org ReactomeREACT_18461 has a Stoichiometric coefficient of 1 Secretin receptor:secretin Reactome DB_ID: 420082 Reactome Database ID Release 43420082 Reactome, http://www.reactome.org ReactomeREACT_18782 has a Stoichiometric coefficient of 1 Parathyroid hormone receptors:parathyroid hormone-type ligands Reactome DB_ID: 420503 Reactome Database ID Release 43420503 Reactome, http://www.reactome.org ReactomeREACT_18736 has a Stoichiometric coefficient of 1 Patched:Smoothened Reactome DB_ID: 445147 Reactome Database ID Release 43445147 Reactome, http://www.reactome.org ReactomeREACT_21759 has a Stoichiometric coefficient of 1 Patched:Hedgehog Reactome DB_ID: 445151 Reactome Database ID Release 43445151 Reactome, http://www.reactome.org ReactomeREACT_21511 has a Stoichiometric coefficient of 1 IP receptor can bind prostacyclin Authored: Jassal, B, 2009-04-02 10:56:26 Edited: Jassal, B, 2009-04-02 10:56:26 Prostacyclin (PGI2) prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation) and is an effective vasodilator. Binding to its receptor, IP (Boie Y et al, 1994), allows coupling to and activation of the G protein alpha s subunit, which leads to activation of cAMP and increase in protein kinase A (PKA) activity (Schwaner I et al, 1995). Pubmed7512962 Pubmed7532011 Reactome Database ID Release 43391942 Reactome, http://www.reactome.org ReactomeREACT_18432 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 FP receptor can bind PGF2-alpha Authored: Jassal, B, 2009-04-02 10:56:26 Edited: Jassal, B, 2009-04-02 10:56:26 Prostaglandin F receptor (FP) is a GPCR for Prostaglandin F2alpha and is encoded by the PTGFR gene (Abramovitz M et al, 1994). Main effects of prostaglandin binding to the receptor are uterine contraction and bronchoconstriction. These effects are mediated by coupling with the G protein alpha q/11 subunit which activates a phosphatidylinositol-calcium second messenger system (Carrasco MP et al, 1997). Pubmed8300593 Pubmed9462300 Reactome Database ID Release 43416929 Reactome, http://www.reactome.org ReactomeREACT_18276 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 DP2 receptor can bind PGD2 Authored: Jassal, B, 2009-04-02 10:56:26 Edited: Jassal, B, 2009-04-02 10:56:26 G protein-coupled receptor 44 (GPR44) is a GPCR that has recently been found to belong to the prostanoid receptor family and named DP2 (CRTH2) (Marchese A et al, 1999). The effects of PGD2 bound to the receptor are mediated by coupling with the G protein alpha i/o subunit which inhibits cAMP production (Sawyer N et al, 2002). Pubmed10036181 Pubmed12466225 Reactome Database ID Release 43391934 Reactome, http://www.reactome.org ReactomeREACT_18415 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 DP1 receptor can bind PGD2 Authored: Jassal, B, 2009-04-02 10:56:26 DP1 is a G-protein-coupled receptor encoded by the PTGDR gene (Boie Y et al, 1995). Its activity is mainly mediated by the G protein alpha s subunit that stimulates adenylate cyclase resulting in an elevation of intracellular cAMP and Ca2+ (Seiler S et al, 1990). Edited: Jassal, B, 2009-04-02 10:56:26 Pubmed2171039 Pubmed7642548 Reactome Database ID Release 43391935 Reactome, http://www.reactome.org ReactomeREACT_18313 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 P2Y2 receptor binds ATP and UTP Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed12458155 Pubmed8159738 Pubmed9364473 Reactome Database ID Release 43417927 Reactome, http://www.reactome.org ReactomeREACT_18310 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y2 receptor (Parr CE et al, 1994) is responsive to both adenosine and uridine nucleotides. It may participate in control of the cell cycle of endometrial carcinoma cells. Three transcript variants encoding the same protein have been identified for this gene. The effects of P2Y2 are mediated by coupling with the G protein alpha Gq/11 subunits (Schachter JB et al, 1997). P2Y2 is a potential drug target for treating cystic fibrosis (Kellerman D et al, 2002). PathwayStep3149 P2Y1 receptor can bind to ADP Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed8666290 Pubmed9364473 Reactome Database ID Release 43417908 Reactome, http://www.reactome.org ReactomeREACT_18297 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y1 receptor can bind ADP (Leon C et al, 1996). In platelets, binding to ADP leads to coupling with the G protein alpha q/11 subunits resulting in mobilization of intracellular calcium ions via activation of phospholipase C, a change in platelet shape, and probably to platelet aggregation (Schachter JB et al, 1997). PathwayStep3148 PathwayStep3147 CysLT receptors can bind cysteinyl leukotrienes Authored: Jassal, B, 2009-03-26 15:30:13 Edited: Jassal, B, 2009-03-26 15:30:13 Pubmed10391245 Pubmed10462554 Pubmed10851239 Reactome Database ID Release 43391943 Reactome, http://www.reactome.org ReactomeREACT_18346 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The cysteinyl-leukotrienes (cys-LTs) are potent smooth muscle contractile agents mediating bronchoconstriction. Examples are LTC4, LTD4 and LTE4. There are two human cys-LT receptors, 1 (Lynch KR et al, 1999) and 2 (Heise CE et al, 2000). They mediate their effects via coupling to the G protein alpha q/11 subunit (Sarau HM et al, 1999). BLT receptors can bind LTB4 Authored: Jassal, B, 2009-03-26 15:30:13 Edited: Jassal, B, 2009-03-26 15:30:13 Pubmed10934230 Pubmed2548477 Pubmed9177352 Reactome Database ID Release 43391941 Reactome, http://www.reactome.org ReactomeREACT_18361 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The dihydroxy-leukotriene, leukotriene B4 (LTB4) stimulates neutrophil chemotaxis and secretion. Chemotaxis, the principal effects of LTB4 and related dihydroxy-acids on leukocytes, occurs via activation of BLT (1 and 2) receptors (Yokomizo T et al, 1997; Yokozimo T et al, 2000). BLT2 is expressed ubiquitously, in contrast to BLT1, which is expressed predominantly in leukocytes. These receptors mediate their actions by coupling to G protein alpha q/11 subunits (McLeish KR et al, 1989) which activate a phosphatidylinositol-calcium second messenger system. Oxoeicosanoid receptor can bind oxoeicosanoid Authored: Jassal, B, 2009-03-26 15:30:13 Edited: Jassal, B, 2009-03-26 15:30:13 Oxoeicosanoids are a family of biologically active arachidonic acid derivatives that are associated with cellular migration. These mediators are potent chemotaxins for eosinophils, monocytes and polymorphonuclear neutrophils. They act via the OXE receptor (Hosoi T et al, 2002), expressed principally in kidney, liver as well as in eosinophils, neutrophils, and lung macrophages. The most potent ligand is 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). Activation of the receptor leads to calcium mobilization and the receptor was shown to be coupled to the G alpha i subunit (Jones CE et al, 2003). Pubmed12065583 Pubmed12606753 Reactome Database ID Release 43391905 Reactome, http://www.reactome.org ReactomeREACT_18371 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 UDP/CysLT receptor can bind cysteinyl leukotrienes Authored: Jassal, B, 2009-03-26 15:30:13 Edited: Jassal, B, 2009-03-26 15:30:13 In general, nucleotides and cysteinyl-leukotrienes (CysLTs) are unrelated signaling molecules inducing multiple effects via separate G-protein-coupled receptors: the purinoceptors and CysLT receptors. However, GPR17, an orphan receptor at intermediate phylogenetic position between P2Y and CysLT receptors, is specifically activated by both families of endogenous ligands. The orphan receptor GRR17 has been identified as a dual uracil nucleotide/cysteinyl-leukotriene receptor (Ciana P et al, 2006). Here, the ligands cys-LTs bind with the receptor and their effects are mediated by coupling to the G protein alpha i subunit (Ciana P et al, 2006). Pubmed16990797 Reactome Database ID Release 43391937 Reactome, http://www.reactome.org ReactomeREACT_18268 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Frizzled receptors:Wnts Reactome DB_ID: 517468 Reactome Database ID Release 43517468 Reactome, http://www.reactome.org ReactomeREACT_21725 has a Stoichiometric coefficient of 1 PathwayStep3140 EGF-7TMs:Chondroitin sulfate Reactome DB_ID: 444754 Reactome Database ID Release 43444754 Reactome, http://www.reactome.org ReactomeREACT_24408 has a Stoichiometric coefficient of 1 PathwayStep3141 PathwayStep3142 PathwayStep3143 CASR:Calcium Reactome DB_ID: 420743 Reactome Database ID Release 43420743 Reactome, http://www.reactome.org ReactomeREACT_18984 has a Stoichiometric coefficient of 1 PathwayStep3144 GPRC6A receptor:GPRC6A ligands Reactome DB_ID: 420722 Reactome Database ID Release 43420722 Reactome, http://www.reactome.org ReactomeREACT_18802 has a Stoichiometric coefficient of 1 PathwayStep3145 CD55:CD97 Reactome DB_ID: 879676 Reactome Database ID Release 43879676 Reactome, http://www.reactome.org ReactomeREACT_25409 has a Stoichiometric coefficient of 1 PathwayStep3146 Metabotropic glutamate receptors:L-Glutamate Reactome DB_ID: 420519 Reactome Database ID Release 43420519 Reactome, http://www.reactome.org ReactomeREACT_19054 has a Stoichiometric coefficient of 1 Sweet taste receptor Reactome DB_ID: 444621 Reactome Database ID Release 43444621 Reactome, http://www.reactome.org ReactomeREACT_21789 has a Stoichiometric coefficient of 1 Sweet taste receptor:sweet taste stimuli Reactome DB_ID: 444662 Reactome Database ID Release 43444662 Reactome, http://www.reactome.org ReactomeREACT_21680 has a Stoichiometric coefficient of 1 Umami taste receptor Reactome DB_ID: 444633 Reactome Database ID Release 43444633 Reactome, http://www.reactome.org ReactomeREACT_21797 has a Stoichiometric coefficient of 1 Umami taste receptor:L-glutamate Reactome DB_ID: 444655 Reactome Database ID Release 43444655 Reactome, http://www.reactome.org ReactomeREACT_21577 has a Stoichiometric coefficient of 1 P2Y10 receptor can bind to LPA Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed11004484 Pubmed18466763 Reactome Database ID Release 43417842 Reactome, http://www.reactome.org ReactomeREACT_18420 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y10 receptor is expressed during myeloid differentiation of HL60 cells (Adrian K et al, 2000) and is the first dual lysophospholipid receptor, able to bind both sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) (Murakami M et al, 2008). The effects of this receptor are mediated by coupling with the G protein alpha q/11 subunit. P2Y9 receptor can bind to LPA Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed17166850 Pubmed9223435 Reactome Database ID Release 43417820 Reactome, http://www.reactome.org ReactomeREACT_18317 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The human form of the receptor was cloned and sequenced as GPR23 (Janssens R et al, 1997). P2Y9 has been reported to bind lysophosphatidic acid (LPA) as a ligand and elicit numerous effects via multiple G proteins (Lee CW et al, 2007). P2Y6 receptor can bind to UDP Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed8670200 Pubmed9405388 Reactome Database ID Release 43417896 Reactome, http://www.reactome.org ReactomeREACT_18284 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y6 receptor (Communi D et al, 1996) is responsive to UDP, partially responsive to UTP and ADP, and not responsive to ATP. Four transcript variants encoding the same isoform have been identified for this gene. The effects of P2Y6 are mediated by coupling to stimulation of both the phosphoinositide and adenylyl cyclase pathways, a unique feature among the P2Y family (Communi D et al,1997). P2Y5 receptor can bind to LPA Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed16774927 Pubmed18297070 Reactome Database ID Release 43417890 Reactome, http://www.reactome.org ReactomeREACT_18359 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y5 receptor (Lee CW et al, 2006) binds lysophosphatidic acid (LPA). Its effects are mediated by coupling with the G protein alpha G q/11 and G12/13 subunits (Lee CW et al, 2006). Mutations in the P2RY5 gene cause a rare, inherited form of hair loss called Hypotrichosis simplex. It is the first receptor in humans known to play a role in hair growth (Pasternack SM et al, 2008). P2Y4 receptor can bind to UTP Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed8537336 Reactome Database ID Release 43417898 Reactome, http://www.reactome.org ReactomeREACT_18287 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y4 receptor (Communi D et al, 1995) is responsive to uridine nucleotides, partially responsive to ATP, and not responsive to ADP. PathwayStep3137 PathwayStep3136 PathwayStep3139 PathwayStep3138 The UDP/CysLT (P2Y17) receptor can bind UTP Authored: Jassal, B, 2009-04-27 14:38:30 Edited: Jassal, B, 2009-04-27 14:38:30 GPR17, an orphan receptor at intermediate phylogenetic position between P2Y and CysLT receptors, is specifically activated by both families of endogenous ligands, leading to both adenylyl cyclase inhibition and intracellular calcium increases. In this example, GPR17 binds to UDP. The UDP-bound receptor couples with Gq/11 and leads to intracellular calcium increases (Ciana P et al, 2006). Pubmed16990797 Reactome Database ID Release 43418918 Reactome, http://www.reactome.org ReactomeREACT_18396 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 P2Y14 receptor can bind to UDP-glucose Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed10753868 Pubmed19339661 Reactome Database ID Release 43417858 Reactome, http://www.reactome.org ReactomeREACT_18318 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Uridine 5'-diphosphoglucose (UDP-glucose) has a well established biochemical role as a glycosyl donor in the enzymatic biosynthesis of glycogen and polysaccharides. UDP-glucose may also possess pharmacological activity and is found to activate the orphan receptor P2Y14 (KIAA0001) (Chambers JK et al, 2000). Nucleotides known to activate P2Y receptors were inactive towards P2Y14. This receptor's actions are mediated by coupling with the G protein alpha Gi/o which inhibits adenylyl cyclase and thus, reduces cAMP accumulation (Fricks IP et al, 2009). P2Y13 receptor can bind ADP Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed11546776 Reactome Database ID Release 43417843 Reactome, http://www.reactome.org ReactomeREACT_18419 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y13 receptor is closely related to P2Y12 and displays a high affinity for ADP (Communi D et al, 2001). P2Y12 receptor can bind to ADP Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed11196645 Pubmed12560222 Pubmed14573771 Reactome Database ID Release 43417829 Reactome, http://www.reactome.org ReactomeREACT_18281 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y12 receptor (Bodor ET et al, 2003) is found on the surface of blood platelet cells and is an important regulator in blood clotting. Its preferred ligand is ADP. The platelet anticoagulant drug clopidogrel binds to this receptor (Hollopeter G et al, 2001). P2Y11 receptor can bind to ATP Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed11156592 Pubmed9405388 Reactome Database ID Release 43417825 Reactome, http://www.reactome.org ReactomeREACT_18351 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The P2Y11 receptor (Communi D et al, 1997) can bind adenosine nucleotides but not uridine nucleotides. This receptor is coupled to the stimulation of both the phosphoinositide (Gq/11) and adenylyl cyclase (Gs) pathways (Qi AD et al, 2001). D1-like dopamine receptors bind to dopamine Authored: Jassal, B, 2009-02-10 10:07:58 Dopamine receptors 1 (Dearry A et al, 1990) and 5 (Sunahara RK et al, 1991) are members of the D1-like dopamine receptor family. Once activated, they couple to the G protein alpha-s subtype which can activate adenylate cyclase. This increases the intracellular concentration of cAMP, which, in neurons, is typically excitatory. Edited: Jassal, B, 2009-02-10 10:07:58 Pubmed1826762 Pubmed2144334 Reactome Database ID Release 43390835 Reactome, http://www.reactome.org ReactomeREACT_17033 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 D2-like dopamine receptors bind to dopamine Authored: Jassal, B, 2009-02-10 10:07:58 Dopamine receptors 2 (Grandy DK et al, 1989), 3 (Giros B et al, 1990) and 4 (Van Tol HH et al, 1991) are members of the D2-like dopamine receptor family. Once activated, these receptors couple with the G protein alpha-i subtype which directly inhibits cAMP formation by inhibition of the enzyme adeylate cyclase. Edited: Jassal, B, 2009-02-10 10:07:58 Pubmed1840645 Pubmed2129115 Pubmed2532362 Reactome Database ID Release 43390846 Reactome, http://www.reactome.org ReactomeREACT_16959 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Alpha-1 adrenoceptors bind catecholamines Authored: Jassal, B, 2009-02-10 10:07:58 Edited: Jassal, B, 2009-02-10 10:07:58 Pubmed1328250 Pubmed7746284 Pubmed8396931 Reactome Database ID Release 43390641 Reactome, http://www.reactome.org ReactomeREACT_16992 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The alpha-1 adrenoceptors are involved in smooth muscle contraction. This is achieved by the receptor-ligand complex coupling with the G protein alpha-q/11 subtype, which results in increased intracellular calcium and thus muscle contraction. There are 3 subtypes of the alpha-1 adrenoceptor; 1a (Hirasawa A et al, 1993), 1b (Ramarao CS et al, 1992) and 1d (Esbenshade TA et al, 1995). Beta adrenoceptors bind catecholamines Authored: Jassal, B, 2009-02-10 10:07:58 Beta adrenoceptors couple with G protein alpha-s subtype (Wenzel-Seifert K et al, 2002), increasing cAMP activity resulting in heart muscle contraction, smooth muscle relaxation and glycogenolysis. There are three subtypes in humans; beta1 (Frielle T et al, 1987), beta2 (Kobilka BK et al, 1987) and beta 3 (Emorine LJ et al, 1989). Edited: Jassal, B, 2009-02-10 10:07:58 Pubmed12106601 Pubmed2570461 Pubmed2825170 Pubmed3025863 Reactome Database ID Release 43390674 Reactome, http://www.reactome.org ReactomeREACT_16893 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 H3 and H4 receptors binds histamine Authored: Jassal, B, 2009-02-11 13:39:02 Edited: Jassal, B, 2009-02-11 13:39:02 Histamine H3 receptor (Lovenberg TW et al, 1999) is predominantly expressed in the CNS and is involved in decreasing the release of neurotransmitters such as histamine, acetylcholine, norepinephrine and serotonin. There are currently at least six isoforms of the H3 receptor in humans of which isoforms 1,2 and 4 encode functional proteins (Wellendorph P et al, 2002).<br>Histamine H4 receptor (Nakamura T et al, 2000) is highly expressed in bone marrow and white blood cells. It is also found in other tissues such as colon, liver, lungs and thymus. The H4 receptor mediates mast cell chemotaxis. Both the H3 and H4 receptors mediate their actions by coupling with the G protein alpha-i subtype, thus decreasing intracellular cAMP. Pubmed10347254 Pubmed11118334 Pubmed12069903 Reactome Database ID Release 43390886 Reactome, http://www.reactome.org ReactomeREACT_17028 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 5-HT1 and 5A receptors can bind serotonin 5-HT1 receptors, once bound to serotonin (5-HT), act on the CNS where they induce neuronal and presynaptic inhibition and behavioural effects. In humans, there are five subtypes of the 5-HT1 receptor, designated 1A-1F (there is no 1C type) (Stam NJ et al, 1992; Hamblin MW et al, 1992; Weinshank RL et al, 1992; Zgombick JM et al, 1992; Adham N et al, 1993). 5-HT5A is expressed in human brain (Rees S et al, 1994) and has an inhibitory effect like 5-HT1 receptors. Both these subtypes mediate their actions by coupling with the G protein alpha-i/o subtype (Lin SL et al, 2002; Francken BJ et al, 1998), inhibiting adenylate cyclase activity and thus decreasing celular cAMP levels. Authored: Jassal, B, 2009-02-12 10:33:32 Edited: Jassal, B, 2009-02-12 10:33:32 Pubmed12145108 Pubmed1315531 Pubmed1330647 Pubmed1513320 Pubmed1565658 Pubmed8380639 Pubmed9865521 Reactome Database ID Release 43390929 Reactome, http://www.reactome.org ReactomeREACT_16978 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 H1 receptor binds histamine Authored: Jassal, B, 2009-02-11 13:39:02 Edited: Jassal, B, 2009-02-11 13:39:02 Pubmed2155607 Pubmed8280179 Reactome Database ID Release 43390912 Reactome, http://www.reactome.org ReactomeREACT_16945 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The histamine H1 receptor (De Backer MD et al, 1993) is found on smooth muscle, endothelium and the CNS. Histamine released from neurons binds to the H1 receptor and causes systemic vasodilation and increased endothelial cell permeability. The effects are modulated by the activated receptor binding to the G protein alpha-q/11 subtype which can activate phospholipase C and the phosphatidylinositol (PIP2) signaling pathway (Tilly BC et al, 1990). The classical antihistamines (histamine H1 receptor antagonists) were developed in the early 1930s and were shown to reduce the effects of histamine on many tissues. H2 receptor binds histamine Authored: Jassal, B, 2009-02-11 13:39:02 Edited: Jassal, B, 2009-02-11 13:39:02 Histamine H2 receptors (Gantz I et al, 1991) are primarily located on parietal cells (oxyntic cells) which are the stomach epithelium cells that secrete gastric acid in response to histamine. This action is modulated by coupling of the activated receptor with the G protein alpha-s subtype which can stimulate adenylate cyclase (Mitsuhashi M et al, 1989). Through a separate mechanism, the activated receptor can also couple with the G protein alpha-q/11 to stimulate phospholipase C (Mitsuhashi M et al, 1989). H2-receptor antagonists (H2RA) are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells.They are used in the treatment of dyspepsia. Pubmed1714721 Pubmed2553705 Reactome Database ID Release 43390909 Reactome, http://www.reactome.org ReactomeREACT_17005 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 M2 and M4 receptors bind acetylcholine Authored: Jassal, B, 2009-02-10 10:07:58 Edited: Jassal, B, 2009-02-10 10:07:58 M2 muscarinic receptors (Peralta EG et al, 1987) are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after stimulatory actions of the sympathetic nervous system. This is achieved by slowing the speed of depolarization. M4 muscarinic receptors are expressed in the CNS (Peralta EG et al, 1987). Both receptors act via Gi proteins, causing a decrease in cAMP in the cell and generally leading to inhibitory-type effects (Bräuner-Osborne H and Brann MR, 1996). Pubmed3443095 Pubmed8925880 Reactome Database ID Release 43390673 Reactome, http://www.reactome.org ReactomeREACT_16955 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 M1, M3 and M5 receptors bind acetylcholine Authored: Jassal, B, 2009-02-10 10:07:58 Edited: Jassal, B, 2009-02-10 10:07:58 Pubmed3272174 Pubmed3443095 Pubmed8925880 Reactome Database ID Release 43390649 Reactome, http://www.reactome.org ReactomeREACT_16947 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The M1 receptor (Peralta EG et al, 1987) is found in exocrine glands and the CNS. It mediates slow excitatory postsynaptic potential (EPSP) at the ganglion in the postganglionic nerve. The M3 receptor (Peralta EG et al, 1987) is found in smooth muscle of the blood vessels and in the lungs. M3 mediates vascular relaxation (by activating vascular endothelial cells causing increased NO synthesis) and lung constriction (by coupling to Gq protein causing increased intracellular calcium). The location of the M5 receptor is not well known but thought to be in the CNS.<br>All of these three receptors couple with Gq/11 protein which use the upregulation of phospholipase C and therefore inositol trisphosphate and intracellular calcium as a signaling mechanism (Bräuner-Osborne H and Brann MR, 1996). Processing of Capped Intron-Containing Pre-mRNA Authored: Carmichael, GG, Hammarskjold, ML, Hastings, M, Krainer, AR, Marzluff, WF, Wahle, E, Zhang, Z, 2003-06-05 08:30:31 Co-transcriptional pre-mRNA splicing is not obligatory. Pre-mRNA splicing begins co-transcriptionally and often continues post-transcriptionally. Human genes contain an average of nine introns per gene, which cannot serve as splicing substrates until both 5' and 3' ends of each intron are synthesized. Thus the time that it takes for pol II to synthesize each intron defines a minimal time and distance along the gene in which splicing factors can be recruited. The time that it takes for pol II to reach the end of the gene defines the maximal time in which splicing could occur co-transcriptionally. Thus, the kinetics of transcription can affect the kinetics of splicing.Any covalent change in a primary (nascent) mRNA transcript is mRNA Processing. For successful gene expression, the primary mRNA transcript needs to be converted to a mature mRNA prior to its translation into polypeptide. Eucaryotic mRNAs undergo a series of complex processing reactions; these begin on nascent transcripts as soon as a few ribonucleotides have been synthesized during transcription by RNA Polymerase II, through the export of the mature mRNA to the cytoplasm, and culminate with mRNA turnover in the cytoplasm. Edited: Gillespie, ME, Gopinathrao, G, Joshi-Tope, G, 0000-00-00 00:00:00 Reactome Database ID Release 4372203 Reactome, http://www.reactome.org ReactomeREACT_125 Reviewed: Nilsen, TW, 0000-00-00 00:00:00 mRNA Capping GENE ONTOLOGYGO:0006370 Pubmed10395561 Pubmed11017188 Pubmed11909521 Pubmed3326038 Reactome Database ID Release 4372086 Reactome, http://www.reactome.org ReactomeREACT_1470 The 5'-ends of all eukaryotic pre-mRNAs studied thus far are converted to cap structures. The cap is thought to influence splicing of the first intron, and is bound by 'cap-binding' proteins, CBP80 and CBP20, in the nucleus. The cap is important for translation initiation, and it also interacts with the poly(A)terminus, via proteins, resulting in circularization of the mRNA to facilitate multiple rounds of translation. The cap is also important for mRNA stability, protecting it from 5' to 3' nucleases, and is required for mRNA export to the cytoplasm.<BR>The capping reaction usually occurs very rapidly on nascent transcripts; after the synthesis of only a few nucleotides by RNA polymerase II. The capping reaction involves the conversion of the 5'-end of the nascent transcript from a triphosphate to a diphosphate by a RNA 5'-triphosphatase, followed by the addition of a guanosine monophosphate by the mRNA guanylyltransferase, to form a 5'-5'-triphosphate linkage. This cap is then methylated by 2'-O-methyltransferases.<P> mRNA Processing Authored: Carmichael, GG, Hammarskjold, ML, Hastings, M, Krainer, AR, Marzluff, WF, Wahle, E, Zhang, Z, 2003-06-05 08:30:31 Edited: Gillespie, ME, Gopinathrao, G, Joshi-Tope, G, 0000-00-00 00:00:00 Processing of mRNA encompasses the capping of mRNA, processing of mRNAs with and without introns, and also modification of mRNA, as in mRNA editing. Reactome Database ID Release 4375071 Reactome, http://www.reactome.org ReactomeREACT_1675 Reviewed: Nilsen, TW, Krainer, AR, 0000-00-00 00:00:00 mRNA Editing: C to U Conversion GENE ONTOLOGYGO:0016554 Pubmed11072063 Pubmed11092837 Pubmed12446660 Pubmed12683974 Reactome Database ID Release 4372200 Reactome, http://www.reactome.org ReactomeREACT_167 The best characterized case of C to U editing is in the intestinal apolipoprotein B transcript, where the editing event creates a premature translation stop codon and consequently leads to a shorter form of the protein. In the liver, C to U editing is important in the expression of specific isoforms of the apolipoprotein B enzyme. ApoB mRNA editing is a posttranscriptional, nuclear process that can be initiated after splicing, at the time of polyadenylation and is completed by the time pre-mRNA matures fully (reviewed by Blanc and Davidson, 2003).<BR>This editing event is a simple hydrolytic cytidine deamination to uridine, and is carried out by the Apobec-1 enzyme, along with the Apobec-1 complementing factor, ACF. The editing of apo-B mRNA involves the site-specific deamination of (C6666 to U), which converts codon 2153 from a glutamine codon, CAA, to a premature stop codon, UAA. As ACF is distributed in a variety of tissues, and these genes contain multiple family members, it is possible that editing events in additional targets will be found.<BR>The cis-acting regulatory elements for C to U editing include: 22 nt editing site within ApoB mRNA, 5’ tripartite motif with an enhancer element adjacent to the target cytidine, a spacer element and mooring sequence both 3’ to the cytidine (reviewed by Smith et al., 1997). The editing complex can be represented as:<BR> mRNA Editing After transcription, some RNA molecules are altered to contain bases not encoded in the genome. Most often this involves the editing or modification of one base to another, but in some organisms can involve the insertion or deletion of a base. Such editing events alter the coding properties of mRNA.<BR>RNA editing can be generally defined as the co- or post transcriptional modification of the primary sequence of RNA from that encoded in the genome through nucleotide deletion, insertion, or base modification mechanisms.<BR>There are two pathways of RNA editing: the substitution/conversion pathway and the insertion/deletion pathway. The insertion/deletion editing occurs in protozoans like Trypanosoma, Leishmania; in slime molds like Physarum spp., and in some viral categories like paramyxoviruses, Ebola virus etc. To date, the substitution/conversion pathway has been observed in human along with other mammals, Drosophila, and some plants. The RNA editing processes are known to create diversity in proteins involved in various pathways like lipid transport, metabolism etc. and may act as potential targets for therapeutic intervention (Smith et al., 1997).<BR>The reaction mechanisms of cytidine and adenosine deaminases is represented below. In both these reactions, NH3 is presumed to be released:<BR> Authored: Carmichael, GG, 2003-08-22 09:59:54 Edited: Gopinathrao, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0016556 Pubmed11092837 Pubmed12139607 Reactome Database ID Release 4375072 Reactome, http://www.reactome.org ReactomeREACT_1757 mRNA Editing: A to I Conversion Authored: Carmichael, GG, 2003-08-22 09:59:54 GENE ONTOLOGYGO:0006382 In humans the deamination of adenosines to inosines is the most common editing event. It is particularly prevalent in the brain, where it leads to amino acid changes that affect the conductance of several ion channels. Inosines are recognized by the translation machinery as if they were guanosines.<BR>ADARs (Adenosine Deaminases Acting on RNA) modify pre-mRNA, acting as single peptides and recognize structural determinants in the RNA. To date 3 members of this deaminase family are known: ADAR 1, ADAR 2, and ADAR 3 that share a common modular domain structure. ADAR 1 and 2 contain a catalytic deaminase domain, a double-stranded RNA binding domain and exhibit RNA editing activity. ADAR1 activity is found in various mammalian tissues with the highest concentration in brain.<BR>An increasing number of mammalian genes have been found to undergo deamination by ADARs. Deamination by editing in pre-mRNAs encoding subunits of ionotropic glutamate receptors (GluRs) is another well studied example. An editing event at the Q/R site of the GluR2 (GluRB) subunit of AMPA –receptors converts a Gln codon CAG to an Arg codon CIG rendering the heteromeric receptor impermeable to Ca 2+ ions. Another example is the editing of 5-HT2C subtype serotonin receptor mRNA resulting in receptor isoforms with reduced G-protein coupling efficiency (reviewed by Gerber and Keller, 2001).<BR>In mice, the editosomes with ADAR proteins require some cis-acting elements like an intronic 'editing-site complementary sequence (ECS)'. Although evolutionarily conserved, the actual role of ECS is not yet elucidated in humans. The editing complex can be generally represented as:<BR> Pubmed11406411 Pubmed12045112 Pubmed12446660 Pubmed1747369 Pubmed8943218 Reactome Database ID Release 4375064 Reactome, http://www.reactome.org ReactomeREACT_18 Formation of the Editosome Authored: Gopinathrao, G, 2003-12-05 16:34:53 Reactome Database ID Release 4375094 Reactome, http://www.reactome.org ReactomeREACT_1390 The editosome for C to U editing in mammals consist of a member of cytidine deaminase family of enzymes, apoB mRNA editig catalytic polypeptide 1 (APOBEC-1) and a complementing specificity factor (ACF) in addition to the target mRNA. C6 deamination of adenosine Authored: Gopinathrao, G, 2003-12-05 16:34:53 Hydrolytic deamination of adenosine leads to inosine. Ammonia is presumed to be released during this reaction.<BR> Pubmed7565688 Pubmed9111310 Reactome Database ID Release 4375102 Reactome, http://www.reactome.org ReactomeREACT_1231 Formation of editosomes by ADAR proteins Authored: Gopinathrao, G, 2003-12-05 16:34:53 It is still unclear how ADAR 1 and ADAR 2 proteins form the editosomes with the target RNA. Other components of these editosomes for A to I editing are unknown. <BR> Reactome Database ID Release 4377042 Reactome, http://www.reactome.org ReactomeREACT_1966 Follicle-stimulating hormone receptor can bind FSH Authored: Jassal, B, 2009-02-23 11:19:01 Edited: Jassal, B, 2009-02-23 11:19:01 Follicle-stimulating hormone (FSH) is a dimeric glycoprotein hormone synthesized and secreted by gonadotropes in the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the human body. The actions of FSH are mediated by the FSH receptor (Minegishi T et al, 1991), found in the ovaries, testes and uterus.<br>Once activated, the receptor mediates its action by coupling to the G protein alpha-s subunit (Timossi C et al, 2002), which activates adenylate cyclase and increases intracellular cAMP levels.<br> Pubmed12039074 Pubmed1709010 Reactome Database ID Release 43391378 Reactome, http://www.reactome.org ReactomeREACT_17031 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Gonadotropin-releasing hormone receptors can bind GNRH I and II Authored: Jassal, B, 2009-02-23 11:19:01 Edited: Jassal, B, 2009-02-23 11:19:01 Luteinizing hormone releasing hormone (LHRH, also termed gonadotropin releasing hormone GnRH), is a decapeptide involved in the control of human reproduction. There are two genes, LHRH I and II which encode two hormones (Seeburg PH and Adelman JP, 1984; White RB et al, 1998). They are produced by hypothalamic neurones and mediates the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from gonadotropic cells in the anterior pituitary. Their effects are mediated by binding to the gonadotropin-releasing hormone receptors 1 and 2 (GnRHR) (Kakar SS et al, 1992; Faurholm B et al, 2001) which couple with the G protein alpha-q/11 subunit. Pubmed11707068 Pubmed1333190 Pubmed6090951 Pubmed9419371 Reactome Database ID Release 43391372 Reactome, http://www.reactome.org ReactomeREACT_17010 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Luteinizing hormone receptor can bind LH Authored: Jassal, B, 2009-02-23 11:19:01 Edited: Jassal, B, 2009-02-23 11:19:01 Luteininzing hormone (LH, lutropin) is a dimeric glycoprotein synthesized in the anterior pituitary gland. It triggers ovulation in females and stimulates Leydig cell production of testosterone in males. It mediates its action by binding to the LH receptor (Minegishi T et al, 1990, Jia XC et al, 1991), which is found in the ovary, testes and uterus. The activated receptor couples to the G protein alpha-s subunit (Gilchrist RL et al, 1996) which activates adenylate cyclase and increases intracellular cAMP levels. Pubmed1922095 Pubmed2244890 Pubmed8702611 Reactome Database ID Release 43391377 Reactome, http://www.reactome.org ReactomeREACT_17047 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Thyroid-stimulating hormone receptor can bind TSH Authored: Jassal, B, 2009-02-23 11:19:01 Edited: Jassal, B, 2009-02-23 11:19:01 Pubmed2558651 Pubmed8188646 Reactome Database ID Release 43391375 Reactome, http://www.reactome.org ReactomeREACT_16966 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Thyroid-stimulating hormone (TSH, thyrotropin) is a dimeric glycoprotein synthesized and secreted by thyrotrope cells in the anterior pituitary gland. TSH regulates the endocrine function of the thyroid gland, mediating the release of the hormones thyroxine (T4) and triiodothyronine (T3). These effects are mediated by the TSH receptor (Nagayama Y et al, 1989), found primarily on thyroid follicular cells. The activated receptor couples with the G protein alpha-s subunit (Allgeier A et al ,1994) which activates adeylate cyclase and increases intracellular cAMP levels. EP1 receptor can bind PGE2 Authored: Jassal, B, 2009-04-02 10:56:26 Edited: Jassal, B, 2009-04-02 10:56:26 Pubmed8253813 Reactome Database ID Release 43391936 Reactome, http://www.reactome.org ReactomeREACT_18421 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The EP1 protein (Funk CD et al, 1993) is one of four receptors identified for prostaglandin E2 (PGE2). The effects of PGE2 are mediated through the G protein g alpha q/11 subunits and the subsequent phosphatidylinositol-calcium second messenger system (Funk CD et al, 1993). Acids transported by SMCT1 Converted from EntitySet in Reactome Reactome DB_ID: 429739 Reactome Database ID Release 43429739 Reactome, http://www.reactome.org ReactomeREACT_20122 EP2 and EP4 receptors can bind PGE2 Authored: Jassal, B, 2009-04-02 10:56:26 Edited: Jassal, B, 2009-04-02 10:56:26 Once activated by PGE2, the EP2 (Regan JW et al, 1994) receptor:ligand complex can mediate downstream effects by coupling to the G protein alpha s subunit and activate adenylyl cyclase (Schwaner I et al, 1995). EP4 receptors (Bastien L et al, 1994) are present on smooth muscle cells and their effects are mediated via coupling to G protein alpha s subunit and subsequent stimulation of adenylate cyclase (Wilson RJ et al, 2004). Pubmed15464062 Pubmed7532011 Pubmed8078484 Pubmed8163486 Reactome Database ID Release 43391940 Reactome, http://www.reactome.org ReactomeREACT_18298 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 EP3 receptor can bind PGE2 Authored: Jassal, B, 2009-04-02 10:56:26 EP3 receptor mRNA are subject to alternative splicing at their 3'-ends and, to date, six expressed protein isoforms have been found in man (Yang J et al, 1994; Schmid A et al, 1995). These isoforms (not annotated here) differ in their G-protein coupling thereby contributing to the wide spectrum of EP3 actions: contraction of smooth muscle, enhancement of platelet aggregation, inhibition of autonomic neurotransmitter release, inhibition of gastric acid secretion, and inhibition of fat cell lipolysis. Edited: Jassal, B, 2009-04-02 10:56:26 Pubmed7532011 Pubmed7883006 Pubmed8117308 Reactome Database ID Release 43391933 Reactome, http://www.reactome.org ReactomeREACT_18345 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 5-HT2 receptor can bind serotonin Authored: Jassal, B, 2009-02-12 10:33:32 Edited: Jassal, B, 2009-02-12 10:33:32 Pubmed1330647 Pubmed7895773 Pubmed8078486 Pubmed8143856 Pubmed8809227 Reactome Database ID Release 43390930 Reactome, http://www.reactome.org ReactomeREACT_16879 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The 5-HT-2 receptors mediate many of the central and peripheral physiologic functions of serotonin. There are three subtypes; 2A (Stam NJ et al, 1992), 2B (Kursar JD et al, 1994; Schmuck K et al, 1994) and 2C (Stam NJ et al, 1994). The actions of these receptors are mediated by coupling with the G protein alpha-q/11 subtype which activates phospholipase C, increasing cellular levels of inositol trisphosphate (IP3) and diacylglycerol (DAG) (Lucaites VL et al, 1996). 5-HT4, 6 and 7 receptors can bind serotonin Authored: Jassal, B, 2009-02-12 10:33:32 Edited: Jassal, B, 2009-02-12 10:33:32 Pubmed12860470 Pubmed8522988 Pubmed9303561 Pubmed9349523 Pubmed9603189 Pubmed9651336 Reactome Database ID Release 43390931 Reactome, http://www.reactome.org ReactomeREACT_17039 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The 5-HT4 receptor (Van den Wyngaert I et al, 1997) is located in the alimentary tract, bladder, heart and adrenal gland as well as the central nervous system (CNS). It modulates the release of various neurotransmitters. Multiple transcripts encode proteins with distinct C-terminal sequences, but the full-length nature of some transcript variants has not been determined (Blondel O et al, 1998). The 5-HT6 receptor (Kohen R et al, 1996) is primarily expressed in the brain and is involved in glutamatergic and cholinergic neuronal activity. The 5-HT7 receptor (Stam NJ et al, 1997) plays a role in vasculature smooth muscle relaxation and in the GI tract. It is involved in thermoregulation, circadian rhythm, learning and memory, and sleep.<br>All these receptor types mediate their actions by coupling to the G protein alpha-s subtype, which increases cellular cAMP levels (Baker LP et al, 1998; Zhang JY et al, 2003).<br><br><br><br> Trace amine-associated receptors can bind trace amines Authored: Jassal, B, 2009-02-13 11:37:11 Edited: Jassal, B, 2009-02-13 11:37:11 Pubmed11459929 Pubmed11723224 Pubmed15718104 Pubmed17218486 Reactome Database ID Release 43391211 Reactome, http://www.reactome.org ReactomeREACT_16878 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Trace amines, such as para-tyramine, beta-phenylethylamine (beta-PEA) and tryptamine are endogenous sympathomimetics. They are related to classical biogenic amines such as histamine, serotonin and catecholamines. The trace amine receptor TAR1 was identified in rat (Borowsky et al. 2001; Bunzow et al. 2001) and recognized to be a member of a family of trace amine-associated receptors (TAARs). Humans have seven subtypes plus a number of pseudogenes (TAAR1,2,3,5,6,8 and 9). Only one of these has been demonstrated to respond to trace amines, TAAR1. These receptors mediate their actions by coupling with the G protein alpha-s subtype, which activates adenylate cyclase and elevates cellular cAMP levels. Beta-PEA is the trace amine used as an example in this annotation. Acids transported by SMCT1 Converted from EntitySet in Reactome Reactome DB_ID: 429748 Reactome Database ID Release 43429748 Reactome, http://www.reactome.org ReactomeREACT_19944 FPRL1 receptor binds a wide range of ligands Authored: Jassal, B, 2009-03-26 15:30:13 Edited: Jassal, B, 2009-03-26 15:30:13 FPRL1 has been reported to respond to numerous ligand with a broad range of structural diversity. It was originally identified as a low-affinity receptor for fMLF, but has greater affinity for many ligands including lipoxin A4, annexin-1, the truncated chemokine sCKbeta8-1 and humanin. Pubmed12368905 Pubmed1374236 Pubmed14662730 Pubmed15153530 Pubmed17084101 Pubmed8006586 Reactome Database ID Release 43391913 Reactome, http://www.reactome.org ReactomeREACT_18373 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 FPRL2 receptor binds a wide range of ligands Authored: Jupe, S, 2009-08-13 Edited: Jupe, S, 2010-03-01 FPRL2 is activated by the neuroprotective peptide humanin, also an agonist of FPRL1. The peptide F2L is the only reported specific agonist of FPRL2. This is an N-terminal fragment of heme-binding protein. The mechanism of cleavage and secretion of F2L is unknown. Pubmed12368905 Pubmed15153530 Pubmed15623572 Pubmed17084101 Reactome Database ID Release 43444476 Reactome, http://www.reactome.org ReactomeREACT_21406 Reviewed: D'Eustachio, P, 2009-12-11 MLNR (GPR38) is a receptor for motilin Authored: Jupe, S, 2009-10-21 Edited: Jupe, S, 2010-03-01 Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. The receptor protein is known as motilin receptor, derived from the gene MLNR (first identified as GPR38). Pubmed10381885 Pubmed9441746 Reactome Database ID Release 43444208 Reactome, http://www.reactome.org ReactomeREACT_21410 Reviewed: D'Eustachio, P, 2009-12-11 FPR is a receptor for formyl peptides Authored: Jupe, S, 2009-10-22 Edited: Jupe, S, 2010-03-01 Pubmed17084101 Pubmed2161213 Reactome Database ID Release 43444527 Reactome, http://www.reactome.org ReactomeREACT_21390 Reviewed: D'Eustachio, P, 2009-12-11 The formyl peptide receptor (FPR) is activated by small peptides derived from bacterial and mitochondrial proteins, often with a formylated N terminal methionine and usually a hydrophobic amino acid at the carboxy terminal end. Formyl-MetLeuPhe is the most commonly used peptide ligand, leading to a widespread use of the name fMetLeuPhe receptor. <br> Formyl peptides are produced by the degradation of either bacterial or host cells. They have a wide range of biological activities including the stimulation of chemotaxis and secretory activities of leukocytes, particularly neutrophils and monocytes. Formyl peptide receptors are involved in mediating immune cell responses to infection. Two NPFF receptors can bind neuropeptide FF Authored: Jassal, B, 2009-01-07 14:37:24 Edited: Jassal, B, 2009-01-07 14:37:24 Pubmed11024015 Pubmed9224703 Reactome Database ID Release 43389491 Reactome, http://www.reactome.org ReactomeREACT_17045 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The 8 residue neuropeptide FF (NPFF, morphine-modulating peptide) (Perry SJ et al, 1997) is believed to play a role in pain modulation and opiate tolerance. Two G protein-coupled receptors bind NPFF; NPFF1 and NPFF2 (Bonini JA et al, 2000). These receptors share the highest amino acid sequence homology with members of the orexin, NPY, and cholecystokinin families, which have been implicated in feeding. This may be a potential role for NPFF1/2. These receptors mediate the action of NPFF by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The orphan QRFP receptor can bind neuropeptide QRFP Authored: Jassal, B, 2009-01-07 14:37:24 Edited: Jassal, B, 2009-01-07 14:37:24 Pubmed11030716 Pubmed11574155 Pubmed12714592 Reactome Database ID Release 43389424 Reactome, http://www.reactome.org ReactomeREACT_16886 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The orphan QRFP receptor (SP9155) (Lee DK et al, 2001) shares a high sequence homology with the neuropeptide FF receptor. It mediates the activity of neuropeptide QRFP (Jiang Y et al, 2003), which is suspected to have orexigenic activity, via the G alpha-q/11 subunit (Langmead CJ et al, 2000). Orexin 1 receptor can bind orexin-A neuropeptide Authored: Jassal, B, 2009-01-07 14:37:24 Edited: Jassal, B, 2009-01-07 14:37:24 Pubmed10364220 Pubmed16429482 Pubmed9491897 Reactome Database ID Release 43389481 Reactome, http://www.reactome.org ReactomeREACT_16987 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The orexin (hypocretin) neuropeptides (A and B) both derive from a 131 residue precursor, prepro-orexin peptide (Sakurai T et al, 1999). Orexin A (Takai T et al, 2006) binds preferentially to the orphan GPCR orexin 1 receptor (Sakurai T et al, 1998). This activated complex can transduce its signal via the Gq class of G protein. Orexin 2 receptor can bind orexin-B neuropeptide Authored: Jassal, B, 2009-01-07 14:37:24 Edited: Jassal, B, 2009-01-07 14:37:24 Pubmed10364220 Pubmed10583376 Pubmed9491897 Reactome Database ID Release 43389487 Reactome, http://www.reactome.org ReactomeREACT_16895 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The orexin (hypocretin) neuropeptides (A and B) both derive from a 131 residue precursor, prepro-orexin peptide (Sakurai T et al, 1999). Orexin B (Lee JH et al, 1999) binds preferentially to the orphan GPCR orexin 2 receptor (Sakurai T et al, 1998). This activated complex can transduce its signal via the Gq class of G protein. Orexin deficiency is inferred in narcolepsy and regulation of feeding behaviour. PathwayStep3191 PathwayStep3190 PathwayStep3193 PathwayStep3192 PathwayStep3195 L-Amino Acids Converted from EntitySet in Reactome Reactome DB_ID: 427988 Reactome Database ID Release 43427988 Reactome, http://www.reactome.org ReactomeREACT_20219 PathwayStep3194 PathwayStep3197 PathwayStep3196 PathwayStep3199 PathwayStep3198 L-Amino Acids Converted from EntitySet in Reactome Reactome DB_ID: 400144 Reactome Database ID Release 43400144 Reactome, http://www.reactome.org ReactomeREACT_20059 Neuropeptide S receptor binds neuropeptide S Authored: Jupe, S, 2009-10-23 Edited: Jupe, S, 2010-03-01 Neuropeptide S receptor (NPSR) is also called G protein-coupled receptor for asthma susceptibility (GPRA) and GPR154. NPSR is activated by neuropeptide S (NPS), a bioactive peptide that modulates stress and arousal. NPSR is thought to be Gs and Gq coupled (Gupte et al. 2004). Pubmed14757815 Pubmed15312648 Pubmed15941840 Pubmed15947423 Pubmed17613937 Reactome Database ID Release 43444620 Reactome, http://www.reactome.org ReactomeREACT_21295 Reviewed: D'Eustachio, P, 2009-12-11 Thyrotropin-releasing hormone receptor binds thyrotropin Authored: Jupe, S, 2009-10-22 Edited: Jupe, S, 2010-03-01 Pubmed8395824 Reactome Database ID Release 43444498 Reactome, http://www.reactome.org ReactomeREACT_21417 Reviewed: D'Eustachio, P, 2009-12-11 Thyrotropin-releasing hormone receptor (TRHR) binds the tripeptide thyrotropin releasing hormone (TRH or thyroliberin). Urotensin-2 receptor binds urotensin-2 and 2B Authored: Jupe, S, 2009-10-27 Edited: Jupe, S, 2010-03-01 Pubmed10499587 Pubmed14550283 Reactome Database ID Release 43445113 Reactome, http://www.reactome.org ReactomeREACT_21287 Reviewed: D'Eustachio, P, 2009-12-11 Urotensin-II (U2) is a vasoactive 'somatostatin-like' cyclic peptide originally isolated from fish spinal cords. It was found to activate GPR14 later renamed Urotensin II receptor (U2R). <br> U2 is the most potent known vasoconstrictor. A second ligand for U2R, urotensin-related peptide or Urotensin 2B, was identified as an extract from rat brains, and shown to activate rat and human U2R. GHSR is a receptor for ghrelin Authored: Jupe, S, 2010-06-18 Edited: Jupe, S, 2010-06-18 Ghrelin is a 27 or 28 residue long peptide that is the ligand of Growth hormone secretagogue receptor type 1 (GHSR). O-octanoylation or O-decanoylation is essential for ghrelin activity. GHSR activation induces the release of growth hormone from the pituitary. It has an appetite-stimulating effect, induces adiposity and stimulates gastric acid secretion. Involved in growth regulation. Pubmed10604470 Pubmed11306336 Pubmed11322507 Reactome Database ID Release 43947647 Reactome, http://www.reactome.org ReactomeREACT_25028 Reviewed: Jassal, B, 2010-06-09 Melanin-concentrating hormone receptors bind MCH Authored: Jupe, S, 2010-09-10 Edited: Jupe, S, 2010-09-10 Pubmed10421367 Pubmed10421368 Pubmed11562423 Pubmed12036292 Reactome Database ID Release 43947673 Reactome, http://www.reactome.org ReactomeREACT_25247 Reviewed: Jassal, B, 2010-06-09 Two Melanin-concentrating hormone receptors have been characterized in humans. Many non-human species (rat, mouse, hamster, guinea pig and rabbit) do not have a functional MCHR2 receptor, or encode a nonfunctional MCHR2 pseudogene (Tan et al. 2002). The receptors bind melanin concentrating hormone, a cyclic peptide predominantly expressed in the hypothalamus that functions as a neurotransmitter controlling a range of functions. A major role of MCH is thought to be in the regulation of feeding: injection of MCH into rat brains stimulates feeding; expression of MCH is upregulated in the hypothalamus of obese and fasting mice; and mice lacking MCH are lean and eat less. MCH and alpha melanocyte-stimulating hormone (alpha-MSH) have antagonistic effects on a number of physiological functions. Alpha-MSH darkens pigmentation in fish and reduces feeding in mammals, whereas MCH increases feeding. Neuromedin-U receptors bind neuromedins U, S Authored: Jupe, S, 2010-09-10 Edited: Jupe, S, 2010-09-10 Pubmed10899166 Reactome Database ID Release 43964800 Reactome, http://www.reactome.org ReactomeREACT_25350 Reviewed: Jassal, B, 2010-06-09 The neuromedin-U receptors bind the neuropeptides neuromedin-U and neuromedin-S. Neuromedin U is an agonist at both the NMUR1 and NMUR2 subtypes, while neuromedin S is selective for NMUR2, and is a more potent agonist for NMUR2 than neuromedin-U. Relaxin receptor 1 binds relaxin 2 and 3 Authored: Jupe, S, 2009-10-26 Edited: Jupe, S, 2010-03-01 Pubmed11809971 Pubmed12506116 Pubmed17293890 Pubmed20138959 Reactome Database ID Release 43444838 Reactome, http://www.reactome.org ReactomeREACT_21318 Relaxin receptor 1 (RXFP1 or LGR7) was identified as a receptor for porcine relaxin and subsequently shown to bind human relaxin-2 and relaxin-3. Reviewed: D'Eustachio, P, 2009-12-11 Relaxin receptor 2 binds relaxin 2 and INSL3 Authored: Jupe, S, 2009-10-26 Edited: Jupe, S, 2010-03-01 Pubmed12114498 Pubmed12506116 Pubmed17293890 Reactome Database ID Release 43444879 Reactome, http://www.reactome.org ReactomeREACT_21332 Relaxin receptor 2 (RXFP2 or LGR8) is activated by porcine relaxin, human relaxin-2 and insulin-like peptide-3 (INSL3). Relaxin affinity is lower than for Relaxin receptor 1, suggesting that this receptor functions as an INSL3 receptor. Reviewed: D'Eustachio, P, 2009-12-11 Relaxin 3 receptor 1 binds relaxin 3 Authored: Jupe, S, 2009-10-26 Edited: Jupe, S, 2010-03-01 Pubmed14522968 Pubmed17293890 Reactome Database ID Release 43444848 Reactome, http://www.reactome.org ReactomeREACT_21392 Relaxin-3 receptor 1 (RXFP3, GPCR135 or SALPR) is activated by relaxin-3. Reviewed: D'Eustachio, P, 2009-12-11 Relaxin 3 receptor 2 binds relaxin 3 and INSL5 Authored: Jupe, S, 2009-10-26 Edited: Jupe, S, 2010-03-01 Pubmed14522967 Pubmed15525639 Pubmed17293890 Reactome Database ID Release 43444859 Reactome, http://www.reactome.org ReactomeREACT_21349 Relaxin-3 receptor 2 (RXFP4 or GPR100) is activated by relaxin-3 and by INSL5. Because of overlapping expression patterns between ligand and receptor Relaxin-3 receptor 2 is considered to be a high affinity INSL5 receptor. Reviewed: D'Eustachio, P, 2009-12-11 Prokineticin receptors bind prokineticin Authored: Jupe, S, 2009-10-23 Edited: Jupe, S, 2010-03-01 Prokineticin receptors 1 and 2 are receptors for the bioactive peptides Prokineticin 1 and prokineticin 2 (PK1 and PK2). Both PKs have 10 conserved cysteines and about 40% amino acid identity with each other. PKs potently contract gastrointestinal smooth muscle. Pubmed11259612 Pubmed12054613 Pubmed12427552 Reactome Database ID Release 43444691 Reactome, http://www.reactome.org ReactomeREACT_21289 Reviewed: D'Eustachio, P, 2009-12-11 PathwayStep3182 PathwayStep3181 PathwayStep3180 PathwayStep3186 PathwayStep3185 PathwayStep3184 PathwayStep3183 PathwayStep3189 NMUR2 binds neuromedin-S Authored: Jupe, S, 2010-05-26 Edited: Jupe, S, 2010-05-26 Neuromedin-U receptor 2 binds the neuromedin-U and neuromedin-S. While neuromedin-U is an agonist at both the NMUR1 and NMUR2 subtypes, neuromedin-S is selective for NMUR2, and a more potent agonist for NMUR2 than neuromedin-U. Pubmed10899166 Reactome Database ID Release 43981832 Reactome, http://www.reactome.org ReactomeREACT_25159 Reviewed: Jassal, B, 2010-10-11 PathwayStep3188 PathwayStep3187 Receptors CCR3, 4 and 5 bind CCL5 ligand Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed7622448 Pubmed7642634 Pubmed8639485 Reactome Database ID Release 43373061 Reactome, http://www.reactome.org ReactomeREACT_14847 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Three receptors have a common CC chemokine CCL5 that can signal through them. CCR3 (Combadiere C et al, 1995) is highly expressed in eosinophils and basophils and also found in airway epithelial cells, thus implicating this receptor in allergic reactions. CCR4 (Power CA et al, 1995) is expressed in Th2 T lymphocytes and upregulated by T-cell receptor activation. CCR5 (Samson M et al, 1996) mediates the recruitment of cells involved in immune and inflammatory processes. Receptors CCR1, 2 and 8 bind CCL16 ligand Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed7679328 Pubmed8048929 Pubmed9207005 Reactome Database ID Release 43373073 Reactome, http://www.reactome.org ReactomeREACT_14854 Reviewed: Bockaert, J, 2008-09-01 12:04:13 These three receptors can all bind the CC chemokine CCL16. CCR1 was the first CC chemokine receptor identified (Neote K et al, 1993) and can bind multiple chemokines. CCR1 is found on blood lymphocytes and monocytes. CCR2 is found on monocytes, B cells, activated memory T cells and basophils (Yamagami S et al, 1994). CCR8 is found mainly in the thymus (Tiffany HL et al, 1997). Tachykinin receptor 1 (NK1) binds to substance P Authored: Jassal, B, 2008-11-24 14:25:55 Edited: Jassal, B, 2008-11-24 14:25:55 Pubmed1718267 Pubmed3770210 Reactome Database ID Release 43380076 Reactome, http://www.reactome.org ReactomeREACT_16928 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Substance P (Harmar AJ et al, 1986) is an neuropeptide, 11 amino-acids in length, that acts as a neurotransmitter for pain response neurons. It does this by binding to its endogenous receptor neurokinin 1 (NK1R, substance P receptor) which belongs to the tachykinin receptor sub-family of GPCRs (Takeda Y et al, 1991). Somatostatin receptors bind somatostatin Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed1337145 Pubmed1346068 Pubmed6126875 Pubmed7792934 Pubmed8373420 Reactome Database ID Release 43374758 Reactome, http://www.reactome.org ReactomeREACT_14807 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Somatostatin (growth hormone inhibiting hormone, GHIH; somatotropin release-inhibiting factor, SRIF) (Shen LP et al, 1992) is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with somatostatin receptors 1-5 (Hoyer D et al, 1995). Somatostatin has two active forms produced by alternative cleavage of the single preproprotein and named according to the number of amino acids in the chain; Somatostatin-28 and somatostatin-14. The 5 receptors known to date all couple with pertussis toxin-sensitive G proteins to inhibit adenylate cyclase after ligand binding. They were classified according to the dates they were discovered; SSTR1 and 2 (Yamada Y et al, Jan. 1992), SSTR3 (Yamada Y et al, Dec. 1992) and SSTR4 and SSTR5 (Yamada Y et al, Sep. 1993). Receptor CCR11 binds CCL19, CCL21 & CCL25 Authored: Jupe, S, 2009-10-19 CCR11 binds CCL19, CCL21, and CCL25 but calcium signalling is low level, consequently it is regarded by some as a scavenger receptor (Comerford et al. 2006). Edited: Jupe, S, 2010-03-01 Pubmed10706668 Pubmed16791897 Reactome Database ID Release 43443978 Reactome, http://www.reactome.org ReactomeREACT_21379 Reviewed: D'Eustachio, P, 2009-12-11 Receptor CCBP2 binds most inflammatory CC chemokines Authored: Jupe, S, 2009-10-19 CC binding protein 2 (CCBP2) is a promiscuous chemokine receptor which has no known signalling function and is therefore considered to be a 'silent' or 'scavenger' receptor. CCBP2 negatively regulates inflammatory responses by binding CC chemokines, targeting them for degradation following receptor internalization. Pubmed12594248 Pubmed15067078 Reactome Database ID Release 43443986 Reactome, http://www.reactome.org ReactomeREACT_21265 Vasopressin receptor type 1 bind vasopressin Authored: Jassal, B, 2008-12-12 10:43:13 Edited: Jassal, B, 2008-12-12 10:43:13 In humans there are three main arginine vasopressin (AVP) receptors; AVPR1A, 1B and 2. AVPR1A (Thibonnier M et al, 1994) and AVPR1B (Sugimoto T et al, 1994) act as receptors for AVP (Mohr E et al, 1985; Sausville E et al, 1985) and are expressed mainly in the brain. The 1A and 1B forms use G protein alpha q/11 subunits as their second messenger system. Pubmed2991279 Pubmed4065330 Pubmed7929452 Pubmed8106369 Reactome Database ID Release 43388468 Reactome, http://www.reactome.org ReactomeREACT_16934 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Oxytocin receptor bind oxytocin Authored: Jassal, B, 2008-12-12 10:43:13 Edited: Jassal, B, 2008-12-12 10:43:13 Oxytocin is a nonapetide closely related to vasopressin (Mohr E et al, 1985; Sausville E et al, 1985). It is best known for its roles in female reproduction: it is released in large amounts during labour facilitating birth and afterwards, breastfeeding. It also acts as a neurotransmitter in the brain. The actions of oxytocin via the oxytocin receptor (Kimura T et al, 1992) are mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. Pubmed1313946 Pubmed2991279 Pubmed4065330 Reactome Database ID Release 43388503 Reactome, http://www.reactome.org ReactomeREACT_16898 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Tachykinin receptor 2 (NK2) binds to nuerokinin A Authored: Jassal, B, 2008-11-24 14:25:55 Edited: Jassal, B, 2008-11-24 14:25:55 Neurokinin A (substance K) (Gerard NP et al, 1990) is a peptide neurotransmitter of the tachykinin family which can act as a mediator in human airway and gastrointestinal tissues. Neurokinin A acts via the substance K receptor (NK-2 receptor) (Harmar AJ et al, 1986), believed to be localized on smooth muscle cells and pharmacologically coupled to a GTP-binding protein. Pubmed2173708 Pubmed3770210 Reactome Database ID Release 43383363 Reactome, http://www.reactome.org ReactomeREACT_17046 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Tachykinin receptor 3 (NK3) binds to neurokinin B Authored: Jassal, B, 2008-11-24 14:25:55 Edited: Jassal, B, 2008-11-26 10:37:44 Neurokinin B peptide (NKB) (Torricelli M et al, 2007) is a tachykinin-related neuropeptide that is highly expressed in the placenta.It can bind to its receptor, NK3 (Huang RR et al, 1992), which is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. Elevated levels of NKB in early pregnancy may be an indicator of hypertension and pre-eclampsia (Page NM et al, 2000), and treatment with certain neurokinin receptor antagonists may be useful in alleviating the symptoms. Pubmed10866201 Pubmed1374246 Pubmed17561251 Reactome Database ID Release 43383373 Reactome, http://www.reactome.org ReactomeREACT_16953 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 5-HT4/6/7 receptor:serotonin Reactome DB_ID: 390972 Reactome Database ID Release 43390972 Reactome, http://www.reactome.org ReactomeREACT_17532 has a Stoichiometric coefficient of 1 Trace amine-associated receptor:beta-PEA Reactome DB_ID: 391202 Reactome Database ID Release 43391202 Reactome, http://www.reactome.org ReactomeREACT_18231 has a Stoichiometric coefficient of 1 5-HT1A-F/5 receptor:serotonin Reactome DB_ID: 390955 Reactome Database ID Release 43390955 Reactome, http://www.reactome.org ReactomeREACT_17662 has a Stoichiometric coefficient of 1 5-HT2 receptor:Serotonin Reactome DB_ID: 390951 Reactome Database ID Release 43390951 Reactome, http://www.reactome.org ReactomeREACT_17445 has a Stoichiometric coefficient of 1 HRH2:histamine Reactome DB_ID: 390881 Reactome Database ID Release 43390881 Reactome, http://www.reactome.org ReactomeREACT_17806 has a Stoichiometric coefficient of 1 HRH3, 4:histamine Reactome DB_ID: 390876 Reactome Database ID Release 43390876 Reactome, http://www.reactome.org ReactomeREACT_18195 has a Stoichiometric coefficient of 1 HRH1:Histamine Reactome DB_ID: 390885 Reactome Database ID Release 43390885 Reactome, http://www.reactome.org ReactomeREACT_18109 has a Stoichiometric coefficient of 1 GnRH receptor:GNRH ligands Reactome DB_ID: 391379 Reactome Database ID Release 43391379 Reactome, http://www.reactome.org ReactomeREACT_17472 has a Stoichiometric coefficient of 1 FSH receptor:FSH Reactome DB_ID: 391365 Reactome Database ID Release 43391365 Reactome, http://www.reactome.org ReactomeREACT_17096 has a Stoichiometric coefficient of 1 LH receptor:LH Reactome DB_ID: 391367 Reactome Database ID Release 43391367 Reactome, http://www.reactome.org ReactomeREACT_17353 has a Stoichiometric coefficient of 1 Cholecystokinin receptors bind cholecystokinin Authored: Jassal, B, 2008-12-12 14:37:44 Cholecystokinin (CCK, previously called pancreozymin) (Takahashi Y et al,1985) is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. CCK is synthesized by I-cells in the small intestine and secreted in the duodenum, causing the release of digestive enzymes and bile from the pancreas and gall-bladder respectively. It also acts as a hunger suppressant. CCK receptors bind CCK. In humans, there are two receptor types, A (Ulrich CD et al, 1993) and B (Pisegna JR et al, 1992). The A type are primarily distributed in the GI tract whereas the B type are primarily in the CNS. In the CNS, type B receptors modulate anxiety, analgesia, arousal, and neuroleptic activity.These receptors mediates the action of CCK by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Edited: Jassal, B, 2008-12-12 14:37:44 Pubmed1280419 Pubmed3856870 Pubmed8503909 Reactome Database ID Release 43388529 Reactome, http://www.reactome.org ReactomeREACT_16965 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Melanocortin receptors bind melanocortins Authored: Jassal, B, 2008-12-16 10:33:44 Edited: Jassal, B, 2008-12-16 10:33:44 Melanocortins are a group of pituitary peptide hormones that include corticotropin (ACTH) and the alpha, beta and gamma melanocyte-stimulating hormones (MSH) derived from the prohormone proopiomelanocortin (Takahashi H et al, 1981). Melanocortins can act through multiple melanocortin receptors (MC1R-MC5R) (Mountjoy KG et al, 1992). The majority of melanocortin receptors (MC1R, MC3R, MC4R and MC5R) are semi-selective in their ability to bind multiple melanocortins (MSH and ACTH). MSH regulates pigmentation. Pubmed1325670 Pubmed6274691 Reactome Database ID Release 43388596 Reactome, http://www.reactome.org ReactomeREACT_16884 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Endothelin receptors bind endothelin Authored: Jassal, B, 2008-12-12 14:37:44 Edited: Jassal, B, 2008-12-12 14:37:44 Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium that play a key role in vascular homeostasis. An imbalance and over-expression of endothelins can contribute to hypertension (high blood pressure). Endothelins are implicated in vascular diseases of several organ systems, including the heart, general circulation and brain. There are 3 isoforms designated ET1, ET2 and ET3 (Inoue A et al, 1989).<br><br>These bind to two receptors, designated ETA (Adachi M et al, 1991) and ETB (Nakamuta M et al, 1991). ETA receptors are primarily located in smooth muscle of blood vessels. Endothelin binding to ETA causes vasoconstriction and sodium retention, leading to increased blood pressure. ETB are primarily located on endothelial cells lining the internal walls of vasculature. Endothelin binding to ETB leads to the release of NO (nitric oxide) which is a strong vasodilator. Pubmed1710450 Pubmed1719979 Pubmed2649896 Pubmed8440682 Reactome Database ID Release 43388560 Reactome, http://www.reactome.org ReactomeREACT_17040 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Prolactin-releasing hormone receptor binds PRH Authored: Jassal, B, 2008-12-17 14:36:56 Edited: Jassal, B, 2008-12-17 14:36:56 Pubmed10498338 Pubmed8666380 Pubmed9607765 Reactome Database ID Release 43388855 Reactome, http://www.reactome.org ReactomeREACT_16922 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The prolactin-releasing peptide receptor (PrRP; GRP10) (Marchese A et al, 1995) is expressed in the pituitary gland (Fujii R et al, 1999) and binds prolactin-releasing peptide (PrRP) (Hinuma S et al, 1998). PrRP is implicated in lactation, regulation of food intake and pain-signal processing. ACTH specifically binds with melanocortin receptor 2 Authored: Jassal, B, 2008-12-16 10:33:44 Edited: Jassal, B, 2008-12-16 10:33:44 MC2R (Gantz I et al, 1993) is also known as the ACTH receptor since it selectively binds ACTH (corticotropin) (Lee TH et al, 1961). ACTH regulates adrenal cortical function via the G protein alpha-s subunit. Pubmed1325670 Pubmed14463577 Pubmed8463333 Reactome Database ID Release 43388605 Reactome, http://www.reactome.org ReactomeREACT_16933 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Neurotensin receptors can bind neurotensins Authored: Jassal, B, 2008-12-17 14:36:56 Edited: Jassal, B, 2008-12-17 14:36:56 Neurotensin (Dong Z et al, 1998) is a 13-amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release. It also has significant interaction with the dopaminergic system. Neurotensin is synthesized as part of a precursor protein that also contains the related neuropeptide neuromedin N. The neurotensin receptor binds neurotensin. There are two transmembrane receptors encoded by the NTSR1 (Vita N et al, 1993) and NTSR2 (Vita N et al, 1998) genes. Pubmed8381365 Pubmed9530155 Pubmed9851594 Reactome Database ID Release 43388900 Reactome, http://www.reactome.org ReactomeREACT_17061 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Neuropeptide Y receptors can bind neuropeptide Y-related peptides At least four neuropeptide Y receptor subtypes each with specific affinities to neuropeptide Y peptides, serve as regulators of mucosal function, gastrointestinal motility and secretion. Four receptors have been characterized to date; NPY1R (Larhammar D et al, 1992), NPY2R (Gerald C et al, 1995), NPY4R (Bard JA et al, 1995) and NPY5R (Parker EM and Xia L, 1999).<br><br> Neuropeptide Y peptides are also implicated as mediators in the pathogenesis of many gastrointestinal disorders, including malabsorption, short gut, inflammatory bowel diseases, and forms of pancreatitis. The three peptides are neuropeptide Y (NPY) (Minth CD et al, 1984), peptide YY (PYY) (Tatemoto K et al, 1988) and pancreatic peptide (PP) (Boel E et al, 1984). <br><br>Although each peptide can bind to any of the four receptors, they each have preferred receptors. NPY binds preferentially to NPY1R, PYY to NYP2R and PP to NYP4R. Authored: Jassal, B, 2008-12-17 14:36:56 Edited: Jassal, B, 2008-12-17 14:36:56 Pubmed10461880 Pubmed1317848 Pubmed3202875 Pubmed6373251 Pubmed6589611 Pubmed7592910 Pubmed7592911 Reactome Database ID Release 43388863 Reactome, http://www.reactome.org ReactomeREACT_16924 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Galanin receptors can bind galanin Authored: Jassal, B, 2008-12-18 15:01:49 Edited: Jassal, B, 2008-12-18 15:01:49 Galanin is a 30-amino acid inhibitory neuropeptide encoded by the GAL gene (Schmidt WE et al, 1991; Bersani M et al, 1991). It is involved in a number of physiological processes such as regulation of food intake, metabolism and reproduction and regulation of neurotransmitter and hormone release. These actions are mediated via the galanin receptor which binds galanin. Three receptor subtypes exist; GALR1 (Habert-Ortoli E et al, 1994), GALR2 (Fathi Z et al, 1998; Kolakowski LF et al, 1998) and GALR3 (Smith KE et al, 1998; Kolakowski LF et al, 1998). These receptors are found throughtout the PNS, CNS and the endocrine system. Pubmed1710578 Pubmed1722333 Pubmed7524088 Pubmed9685625 Pubmed9722565 Pubmed9832121 Reactome Database ID Release 43389026 Reactome, http://www.reactome.org ReactomeREACT_17036 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The Kiss receptor GPR54 binds kisspeptin Authored: Jassal, B, 2008-12-18 15:01:49 Edited: Jassal, B, 2008-12-18 15:01:49 Pubmed10100623 Pubmed11385580 Pubmed11457843 Pubmed14573733 Reactome Database ID Release 43388981 Reactome, http://www.reactome.org ReactomeREACT_16911 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The KiSS1-derived peptide receptor, GPR54 is a galanin-like GPCR (Lee DK et al, 1999) that can bind kisspeptin-54 (metastin), a natural ligand of the receptor (Kotani M et al, 2001). The GPR54 gene appears to be essential for normal puberty and gonadotropin-released hormone physiology (Seminara SB et al, 2003). Metastin is encoded by the KiSS-1 metastasis suppressor gene, a 54-amino acid peptide that suppresses metastases of human melanomas and breast carcinomas without affecting tumorigenicity (Ohtaki T et al, 2001). Proteinase-activated receptors can bind thrombin Authored: Jassal, B, 2009-01-07 14:37:24 Edited: Jassal, B, 2009-01-07 14:37:24 Pubmed10079109 Pubmed8615752 Pubmed873923 Reactome Database ID Release 43389463 Reactome, http://www.reactome.org ReactomeREACT_16939 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Thrombin (Butkowski RJ et al, 1977) plays a vital role in blood homeostasis, inflammation and wound healing. Thrombin (which cleaves bonds after arginine and lysine) converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII. Complexed with thrombomodulin it can also activate protein C. It performs these functions by binding to four proteinase-activated receptors (PAR1-4) (Kahn ML, et al, 1999; Bohm SK et al, 1996). These complexes couple to G proteins which stimulate phosphoinositide hydrolysis. FP receptor:PGF2-alpha Reactome DB_ID: 391931 Reactome Database ID Release 43391931 Reactome, http://www.reactome.org ReactomeREACT_18639 has a Stoichiometric coefficient of 1 DP1 receptor:PGD2 Reactome DB_ID: 416920 Reactome Database ID Release 43416920 Reactome, http://www.reactome.org ReactomeREACT_18665 has a Stoichiometric coefficient of 1 DP2 receptor:PGD2 Reactome DB_ID: 416875 Reactome Database ID Release 43416875 Reactome, http://www.reactome.org ReactomeREACT_19057 has a Stoichiometric coefficient of 1 LTB4 receptors:LTB4 Reactome DB_ID: 416435 Reactome Database ID Release 43416435 Reactome, http://www.reactome.org ReactomeREACT_18933 has a Stoichiometric coefficient of 1 TSH receptor:TSH Reactome DB_ID: 391374 Reactome Database ID Release 43391374 Reactome, http://www.reactome.org ReactomeREACT_17143 has a Stoichiometric coefficient of 1 EP1 receptor:PGE2 Reactome DB_ID: 391920 Reactome Database ID Release 43391920 Reactome, http://www.reactome.org ReactomeREACT_18947 has a Stoichiometric coefficient of 1 EP2/4 receptor:PGE2 Reactome DB_ID: 416880 Reactome Database ID Release 43416880 Reactome, http://www.reactome.org ReactomeREACT_18721 has a Stoichiometric coefficient of 1 EP3 receptor:PGE2 Reactome DB_ID: 391924 Reactome Database ID Release 43391924 Reactome, http://www.reactome.org ReactomeREACT_19004 has a Stoichiometric coefficient of 1 DARC is a non-specific receptor for many chemokines Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed12956774 Pubmed49254 Pubmed8248172 Reactome Database ID Release 43374251 Reactome, http://www.reactome.org ReactomeREACT_14786 Reviewed: Bockaert, J, 2008-09-01 12:04:13 The Duffy blood group system consists of two antigens defining four phenotypes (Marsh WL, 1975). Duffy antigen/receptor for chemokines (DARC) (Chaudhuri A et al, 1993) carries the Duffy (Fy) blood group and acts as a widely expressed promiscuous chemokine receptor. The chemokine interleukin-8 is one example shown here. C3a receptor binds anaphylatoxin C3a Authored: Jupe, S, 2009-10-23 Edited: Jupe, S, 2010-03-01 Pubmed19601884 Pubmed8702752 Reactome Database ID Release 43444647 Reactome, http://www.reactome.org ReactomeREACT_21294 Reviewed: D'Eustachio, P, 2009-12-11 The complement component 3a receptor (C3AR) binds C3a, a 77-amino acid anaphylatoxin generated during activation of the complement cascade. C3a is involved in mediation of a variety of inflammatory responses. C5a receptor binds C5a anaphylatoxin Authored: Jassal, B, 2008-08-21 14:07:16 C5a (Fernandez HN and Hugli TE, 1978) is a protein fragment released from complement component C5. C5a is a potent anaphylatoxin, causing the release of histamine from mast cells and also being an effective leukocyte attractant. The C5a receptor (complement component 5a receptor 1, C5AR1; Cluster of Differentiation 88, CD88) (Gerard NP and Gerard C, 1991) mediates the pro-inflammatory and chemotactic actions of C5a. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed1847994 Pubmed690134 Reactome Database ID Release 43375395 Reactome, http://www.reactome.org ReactomeREACT_14799 Reviewed: Bockaert, J, 2008-09-01 12:04:13 GPR77 binds anaphylatoxins and thier desArginated derivatives Authored: Jupe, S, 2010-09-10 Edited: Jupe, S, 2010-09-10 GPR77 (C5L2) has been described as a receptor for the chemotactic and inflammatory peptides anaphylatoxin C5a, C4a and C3a and even their des-arginated derivatives. Highest binding affinity was for C3a-desArg, also called Acylation Stimulating Protein (ASP), produced from C3a following arginine removal by carboxypeptidases. Binding of C3a and its derivatives has been disputed (Johswich et al. 2006) leading to suggestions that this receptor may be a C5a scavenger. It is weakly coupled to G(i)-mediated signaling pathways and believed to function primarily as a decoy receptor though it can interact with beta arrestin (Van Lith et al. 2009). Pubmed11773063 Pubmed12540846 Pubmed17068344 Pubmed19641221 Reactome Database ID Release 43964811 Reactome, http://www.reactome.org ReactomeREACT_24998 Reviewed: Jassal, B, 2010-10-01 Receptor CCR10 binds CCL27 and 28 ligands Authored: Jassal, B, 2008-08-21 14:07:16 CCR10 (previously known as GPR2) (Jarmin DI et al, 2000) is implicated in skin inflammation and recruits regulatory T cells to mucosal layers. CCR10 binds both CCL27 (ESkine, CTACK) (Homey B et al, 2000) and CCL28 (Mucosae-associated epithelial chemokine, MEC) (Wang W et al, 2000) and signal transduction is via increase of intracellular calcium levels. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed10725696 Pubmed10725697 Pubmed10781587 Reactome Database ID Release 43373086 Reactome, http://www.reactome.org ReactomeREACT_14831 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Receptor CCR6 binds CCL20 ligand Authored: Jassal, B, 2008-08-21 14:07:16 CCR6 (Baba M et al, 1997) is expressed on inactive memory T-cells and on Th17 cells. CCR6 is down-regulated in activated T-cells. CCL20 (macrophage inflammatory protein 3-alpha, MIP 3-alpha) binds and activates CCR6 and it does not share the binding site of CCR6 with any other chemokine. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed12149255 Pubmed9169459 Reactome Database ID Release 43373087 Reactome, http://www.reactome.org ReactomeREACT_14829 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Nociceptin receptor binds to nociceptin Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed8137918 Pubmed8710928 Pubmed9521323 Reactome Database ID Release 43374723 Reactome, http://www.reactome.org ReactomeREACT_14801 Reviewed: Bockaert, J, 2008-09-01 12:04:13 The orphan nociceptin (ORL1) receptor (Mollereau C et al, 1994) is most closely related to opioid receptors on structural (sequence) and functional grounds but is not a typical opioid receptor. It may play a role in instinctive behaviours and emotions. Its natural ligand is nociceptin (orphanin FQ) (Mollereau C et al, 1996), a 17 amino acid neuropeptide which acts as a potent anti-analgesic. Both receptor and ligand are widely expressed in the CNS. Opioid receptors bind opioid peptides Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed195688 Pubmed6128656 Pubmed6274691 Pubmed6281660 Pubmed7057924 Pubmed7624359 Pubmed7905839 Pubmed8201839 Pubmed9422738 Reactome Database ID Release 43374298 Reactome, http://www.reactome.org ReactomeREACT_14795 Reviewed: Bockaert, J, 2008-09-01 12:04:13 There are three well-characterized families of opioid peptides produced by the body: endorphins, enkephalins and dynorphins. Endorphins are processed from the precursor proopiomelanocortin (POMC) (Takahashi H et al, 1981), which can also be processed to yield adrenocorticotropic hormone (ACTH) and alpha- and gamma-melanocyte stimulating hormone (MSH). Beta-endorphin (Dragon N et al, 1977) is a 31 amino acid peptide found in neurons of the hypothalamus and pituitary gland. It is released into the blood (from the pituitary gland) and into the spinal cord and brain from hypothalamic neurons during vigourous exercise, excitement and orgasm. Beta-endorphin binds with the highest affinity to the mu-opioid receptor but it also possesses some affinity towards the delta- and kappa-opioid receptors. Once bound, it acts as an analgesic in the body by dulling pain. It does this by breaking down bradykinins which are peptides which accumulate in response to injury. The mu-opioid receptor (MOR) (Wang JB et al, 1994) possesses high affinity for enkephalins and beta-endorphin but low affinity for dynorphins.<br>The enkephalins are endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. There are two forms of enkephalin, one containing leucine ("leu"), while the other contains methionine ("met"). The met-enkephalin peptide sequence is coded by the POMC gene whereas leu-enkephalin is coded by both POMC and dynorphin genes. Enkephalins are pentapeptides involved in regulating pain and nociception in the body. Their action is mediated through the delta-opioid receptor (DOR) (Knapp RJ et al, 1994).<br>Dynorphins constitute a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released, amongst which are dynorphin A, dynorphin B, big-dyn and alpha/beta-neoendorphin (Day R et al, 1998). Dynorphins primarily exert their effects through the kappa-opioid receptor (KOR), a G-protein coupled receptor (Simonin F et al, 1995). Two subtypes of KORs have been identified: K1 and K2. Although KOR is the primary receptor for all dynorphins (James IF et al, 1982), the peptides do have some affinity for MOR and DOR. G protein-coupled estrogen receptor 1 binds estrogen non-classically Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 G protein-coupled estrogen receptor 1 (GPER; CEPR; G-protein coupled receptor 30, GPR30) (Feng Y and Gregor P, 1997) has a ubiquitous tissue distribution. This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). This suggests a role for GPCRs in nonclassical steroid hormone actions. Pubmed15539556 Pubmed9070864 Reactome Database ID Release 43374207 Reactome, http://www.reactome.org ReactomeREACT_14791 Reviewed: Bockaert, J, 2008-09-01 12:04:13 GPCR neuropeptide receptor binds neuropeptides B and W Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed12719537 Pubmed7590751 Reactome Database ID Release 43374787 Reactome, http://www.reactome.org ReactomeREACT_14856 Reviewed: Bockaert, J, 2008-09-01 12:04:13 The structurally related (70% identity) orphan G-protein-coupled receptors, neuropeptides B/W receptor 1 and 2 (GPR7 and GPR8 respectively) (O'Dowd BF et al, 1995), are wideley expressed in the central nervous system of humans. Natural ligands identified for these receptors are involved in the regulation of feeding. Neuropeptide B is cleaved into two chains; NPB23 (L7) and NPB29 (L7C). Neuropeptide W is also cleaved into two chains; NPW23 (L8) and NPW30 (L8C) (Tanaka H et al, 2003). Both these peptides can bind to either GPR7 or 8 to elicit their effects downstream. Receptor CX3C1 binds CX3CL1 Authored: Jassal, B, 2008-08-21 14:07:16 CX3CL1 (fractalkine) is a member of the chemokine superfamily and functions as a human leukocyte chemoattractant protein (Bazan JF et al, 1997). Unlike other human chemokines, the chemokine domain of fractalkine has three amino acids between two conserved cysteines, referred to as the CX3C motif. This molecule can exist in two forms: either membrane-anchored or as a shed 95K glycoprotein. The soluble form has potent chemoattractant activity for T-cells and monocytes, and the membrane-bound protein, which is induced on activated primary endothelial cells, promotes strong adhesion of those leukocytes. The seven-transmembrane high-affinity receptor for fractalkine, termed CX3C1, mediates both the adhesive and migratory functions of fractalkine (Imai T et al, 1997). Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed9024663 Pubmed9390561 Reactome Database ID Release 43373342 Reactome, http://www.reactome.org ReactomeREACT_14810 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Receptor CCR9 binds CCL25 ligand Authored: Jassal, B, 2008-08-21 14:07:16 CCR9 (previously called orphan receptor GPR 9-6) is highly expressed in the thymus on both mature and immature T-cells. It is also abundant in T-cells of the intestine but is lowly expressed in lymph nodes and the spleen. Alternative splicing produces two receptors, called CCR9A and CCR9B, CCR9A containing 12 additional amino acids at its N terminus as compared with CCR9B (Yu CR et al, 2000). The A and B forms of the receptor were expressed at a ratio of approximately 10:1. CCR9 has a specific ligand in CCL25 (Thymus-expressed chemokine, TECK) (Zaballos A et al, 1999) and transduces the signal by intracellular calcium mobilization. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed10229797 Pubmed10640743 Reactome Database ID Release 43373074 Reactome, http://www.reactome.org ReactomeREACT_14836 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Receptor CXCR1 binds CXCL6 and CXCL8 ligands Authored: Jassal, B, 2008-08-21 14:07:16 CXCR1 (high affinity interleukin-8 receptor A) (Holmes WE et al, 1991) is closely related to CXCR2. They recognize CXC chemokines that possess an E-L-R amino acid motif immediately adjacent to their CXC motif. CXCL8 (interleukin-8, IL-8) (Matsushima K et al, 1988) and CXCL6 (Rovai LE et al, 1997) can both bind CXCR1 in humans and elicit various effects. CXCL8 attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. CXCL6 is a chemotactic factor for neutrophil granulocytes. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed1840701 Pubmed3260265 Pubmed9164944 Reactome Database ID Release 43373791 Reactome, http://www.reactome.org ReactomeREACT_14782 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Receptor CXC1 binds to the ligands lymphotactin and cytokine SCM-1 beta Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed7602097 Pubmed7875320 Pubmed8849694 Reactome Database ID Release 43373339 Reactome, http://www.reactome.org ReactomeREACT_14858 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Single C motif-1 (SCM-1; lymphotactin, CXC1) is a member of the chemokine receptor family (Yoshida T et al, 1995). CXC differs from the CC chemokines by one amino acid separating two of the four conserved cysteine residues (to give the motif CXC) whereas two adjacent cysteines denote CC. In humans, there are two highly conserved SCM-1 genes, SCYC1 and 2, which encode two SCM-1 proteins, SCM1-alpha and beta (Yoshida T et al, 1996). These proteins act as specific ligands for the CXC1 receptor. This receptor is highly expressed in placenta but lowly in spleen and thymus. Receptor CCR7 binds CCL19 and 21 ligands Authored: Jassal, B, 2008-08-21 14:07:16 CCR7 (Epstein-Barr virus-induced gene 1, EBI1) (Birkenbach M, 1993; Schweickart VL et al, 1994) plays an important role in the trafficking of B and T lymphocytes and dendritic cells across high endothelial venules. Both CCL19 (Macrophage inflammatory protein 3 beta, MIP-3-beta; EBI1-ligand chemokine, ELC) (Yoshida R et al, 1997) and CCL21 (Secondary lymphoid-tissue chemokine, SLC; Beta chemokine exodus-2) (Yoshida R et al, 1998) bind specifically to CCR7. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed7851893 Pubmed8383238 Pubmed9153236 Pubmed9507024 Reactome Database ID Release 43373071 Reactome, http://www.reactome.org ReactomeREACT_14781 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Receptor CXCR6 binds CXCL16 ligand Authored: Jassal, B, 2008-08-21 14:07:16 CXCR6 (formerly called STRL33, BONZO, and TYMSTR) was assigned this name based on its chromosomal location (within the chemokine receptor cluster on human chromosome 3p21) and its similarity to other chemokine receptors in its gene sequence (Liao F et al, 1997). CXCR6 is structurally more closely related to CC chemokine receptors than to other CXC chemokine receptors. It is expressed in lymphoid tissues and activated T cells and is induced in activated peripheral blood lymphocytes. CXCR6 binds the ligand CXCL16 (Shimaoka T et al, 2000) which acts as a scavenger receptor on macrophages. It specifically binds to oxidized low density lipoprotein, suggesting that it may be involved in pathophysiology such as atherogenesis. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed11060282 Pubmed9166430 Reactome Database ID Release 43373358 Reactome, http://www.reactome.org ReactomeREACT_14777 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Receptor CXCR2 binds ligands CXCL1 to 7 Authored: Jassal, B, 2008-08-21 14:07:16 CXCR2 (High affinity interleukin-8 receptor B) (Murphy PM and Tiffany HL, 1991) is closely related to CXCR1 and binding of IL-8 to the receptor causes activation of neutrophils. Other ELR-positive chemokines (CXCL1 to CXCL7) can also bind with CXCR2 to cause various effects as described below.<br>CXCL1 (previously known as GRO1 oncogene; NAP-3; MSGA-alpha) (Richmond A et al, 1988) is expressed by neutrophils, macrophages and epithelial cells and possesses neutrophil chemoattractant activity. It is secreted by melanoma cells and is implicated in melanoma pathogenesis. CXCL2 (MIP2-alpha;Gro-beta;Gro-2) (Iida N and Grotendorst GR, 1990; Haskill S et al, 1990) is closely related to CXCL1 (90% amino acid sequence). It is secreted by monocytes and macrophages and attracts polymorphonuclear leukocytes and hematopoietic stem cells. CXCL3 (GRO3; GROg; MIP2-beta) (Haskill S et al, 1990) controls the migration and adhesion of monocytes.<br>CXCL4 (platelet factor 4, PF4) (Poncz M et al, 1987) is released from platelets during aggregation and promotes blood coagulation by neutralization of heparin-like molecules. It is chemotactic for neutrophils, fibroblasts and monocytes. Due to all these roles, CXCL4 is implicated in wound repair and inflammation. CXCL5 (ENA-78) (Walz A et al, 1991) is produced by cells which have been stimulated by interleulin-1 or tumor necrosis factor-alpha. CXCL7 (pro-platelet basic protein, PPBP) (Holt JC et al, 1986) is released from platelets once they are activated. It can stimulate various processes including glucose metabolism, mitogenesis and syntheses of plasminogen activator and extracellular matrix. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed1744577 Pubmed1891716 Pubmed2078213 Pubmed2217207 Pubmed2423119 Pubmed2970963 Pubmed3098319 Reactome Database ID Release 43373813 Reactome, http://www.reactome.org ReactomeREACT_14784 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Receptor CXCR3 binds ligands CXCL9 to 11 Authored: Jassal, B, 2008-08-21 14:07:16 CXCR3 (Loetscher M et al, 1996) is predominantly expressed on T lymphocytes, and on other lymphocytes (some B cells and NK cells). It is highly induced following cell activation. There are three isoforms, CXCR3-A, CXCR3-B and CXCR3-alt. CXCR3 binds to three highly related ligands in mammals, CXCL9, CXCL10 and CXCL11 (Xanthou G et al, 2003). The ligands then elicit their chemoattractant functions. CXCL9 (CMK; monokine induced by gamma-interferon, MIG; SCYB9) is a T cell chemoattractant (Farber JM, 1993). CXCL10 (IP-10) (Booth V et al, 2002) is secreted by monocytes, endothelial cells and fibroblasts in response to gamma-interferon. It can act as a chemoattractant for monocytes, macrophages, T cells, NK cells and dendritic cells, promote T cell adhesion to endothelial cells and inhibit angiogenesis and bone marrow colony formation. CXCL11 (I-TAC,; iIP-9) (Cole KE et al, 1998) is highly expressed in peripheral blood leukocytes, pancreas and liver. It is regulated by interferon and has potent chemoattractant activity for interleukin-2-activated T cells. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed12173928 Pubmed12884299 Pubmed8476424 Pubmed9064356 Pubmed9625760 Reactome Database ID Release 43374248 Reactome, http://www.reactome.org ReactomeREACT_14787 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Receptors CXCR4 and 7 bind CXCL12 ligand Authored: Jassal, B, 2008-08-21 14:07:16 CXCL12 (stromal cell-derived factor-1, SDF-1) (Shirozu M et al, 1995) is produced in two forms, CXCL12alpha and CXCL12beta, by alternate splicing of the same gene (De La Luz Sierra M et al, 2004). It is a chemoattractant for T-lymphocytes and monocytes, but not neutrophils. In adult humans it plays an important role in angiogenesis by recruiting endothelial progenitor cells from the bone morrow through a CXCR4-dependent mechanism. CXCR4 (fusin) (Herzog H et al, 1993) is the receptor for CXCL12 and, like CCR5, is utilized by HIV-1 to gain entry into target cells. This receptor has a wide cellular distribution, with expression on most immature and mature hematopoietic cell types and also on vascular endothelial cells and neuronal/nerve cells. CXCR7 (RDC-1) (Infantino S et al, 2006) is expressed in monocytes, basophils and B cells and was originally an orphan receptor. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed14525775 Pubmed16107333 Pubmed16455976 Pubmed7490086 Pubmed8329116 Pubmed9618518 Reactome Database ID Release 43374214 Reactome, http://www.reactome.org ReactomeREACT_14783 Reviewed: Bockaert, J, 2008-09-01 12:04:13 CXCR5 binds CXCL13 Authored: Jupe, S, 2009-10-22 CXC-Chemokine receptor 5 (CXCR5) was originally called Burkitts Lymphoma receptor 1 after the source tissue. The primary ligand for this receptor is CXCL13 (B-cell attracting chemokine 1 also known as B-lymphocyte chemoattractant). Edited: Jupe, S, 2010-03-01 Pubmed9463416 Reactome Database ID Release 43444523 Reactome, http://www.reactome.org ReactomeREACT_21335 Reviewed: D'Eustachio, P, 2009-12-11 PathwayStep5382 PathwayStep5381 PathwayStep5380 PathwayStep5389 PathwayStep5388 Amylin receptors can bind Amylin Amylin (islet amyloid polypeptide, diabetes associated peptide) is a 37 amino acid peptide first purified from amyloid deposits in the pancreatic islets of type 2 diabetic patients (Nishi M et al, 1989). It is a product of the islet B-cell, along with insulin and probably has a hormonal role in the regulation of nutrient intake. Amylin receptors are multimeric complexes, formed by CT receptor (Gorn AH et al, 1992) interaction with receptor activity modifying proteins (RAMPs) (McLatchie LM et al, 1998). The CT receptor interacts with the three RAMPs, generating multiple subtypes of amylin receptor (AMY1-3). Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Pubmed1331173 Pubmed2608057 Pubmed9620797 Reactome Database ID Release 43420265 Reactome, http://www.reactome.org ReactomeREACT_18391 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 PathwayStep5387 Calcitonin receptor binds calcitonin Authored: Jassal, B, 2009-05-07 08:25:16 Edited: Jassal, B, 2009-05-07 08:25:16 Pubmed1331173 Pubmed6148938 Reactome Database ID Release 43419843 Reactome, http://www.reactome.org ReactomeREACT_18403 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The CALC1 gene produces a prepropeptide from which calcitonin (CT) is a cleavage product (Nelkin BD et al, 1984). CT is a polypeptide hormone that is produced in the thyroid gland. It acts to reduce blood calcium, opposing the effects of parathyroid hormone. The CT receptor (Gorn AH et al, 1992) binds CT and mediates its actions. The ligand:receptor complex couples to the G protein alpha s subunit, which stimulates adenylyl cyclase and increases intracellular cAMP levels (Gorn AH et al, 1992). PathwayStep5386 Zinc is an agonist of GPR39 Authored: Jupe, S, 2009-10-21 Edited: Jupe, S, 2010-03-01 Pubmed18588883 Reactome Database ID Release 43444572 Reactome, http://www.reactome.org ReactomeREACT_22251 Reviewed: D'Eustachio, P, 2009-12-11 Zn2+ is a potent and effective agonist of GPR39. PathwayStep5385 N-arachidonyl glycine receptor GPR18 binds N-arachidonyl glycine Authored: Jupe, S, 2010-02-19 Edited: Jupe, S, 2010-03-01 GPR18 (GPRW) is a receptor for the biologically active anandamide derivative n-arachidonyl glycine. Pubmed16844083 Reactome Database ID Release 43517536 Reactome, http://www.reactome.org ReactomeREACT_21253 Reviewed: D'Eustachio, P, 2009-12-11 PathwayStep5384 G-protein coupled bile acid receptor binds lithocholic acid Authored: Jupe, S, 2009-10-23 Edited: Jupe, S, 2010-03-01 Pubmed10334992 Pubmed12524422 Pubmed1591235 Reactome Database ID Release 43444654 Reactome, http://www.reactome.org ReactomeREACT_21388 Reviewed: D'Eustachio, P, 2009-12-11 The G-protein coupled bile acid receptor (GPBAR1) responds to several bile acids the most potent being lithocholic acid. Primary bile acids are acidic sterols synthesized from cholesterol in the liver where they are conjugated with glycine or taurine. Following synthesis bile acids are stored in the gall bladder and secreted into the duodenum where they facilitate solubilization and absorption of lipid-soluble vitamins and dietary fats. Bile acids can also regulate expression of various transport proteins and enzymes through the binding and activation of nuclear receptors, particularly FXR. PathwayStep5383 Niacin receptors bind niacin Authored: Jupe, S, 2009-10-23 Edited: Jupe, S, 2010-03-01 Niacin receptor 1 (GPR109A) and Niacin receptor 2 (GPR109B) are activated by niacin (nicotinic acid). GPR109A can also be activated by (D)-beta-Hydroxybutyrate. Pubmed12522134 Pubmed15929991 Reactome Database ID Release 43444661 Reactome, http://www.reactome.org ReactomeREACT_21396 Reviewed: D'Eustachio, P, 2009-12-11 GPR120 is a receptor for unsaturated long-chain free fatty acids Authored: Jupe, S, 2009-10-21 Edited: Jupe, S, 2010-03-01 GPR120 is a receptor for many unsaturated long-chain free fatty acids (FFAs) with carbon chains 16-22 in length, the most potent tested being alpha-linolenic acid. Pubmed15619630 Reactome Database ID Release 43444191 Reactome, http://www.reactome.org ReactomeREACT_21408 Reviewed: D'Eustachio, P, 2009-12-11 GPR4, GPR65, GPR132 and OGR1 are pH sensing receptors Authored: Jupe, S, 2009-10-23 Edited: Jupe, S, 2010-03-01 Pubmed12955148 Pubmed15280385 Pubmed15326175 Pubmed17118800 Pubmed17462861 Reactome Database ID Release 43444731 Reactome, http://www.reactome.org ReactomeREACT_21323 Reviewed: D'Eustachio, P, 2009-12-11 The subfamily of G protein-coupled receptors comprising GPR4, OGR1, TDAG8, and G2A was originally characterized as a group of proteins mediating biological responses to the lipid messengers sphingosylphosphorylcholine (SPC), lysophosphatidylcholine (LPC), and psychosine. This was later replaced by reports that OGR1 and GPR4 sense acidic pH. GPR4, OGR1, and TDAG8 are now considered as proton-sensing receptors. Receptor FFAR2 binds carboxylates Authored: Jupe, S, 2009-10-19 Edited: Jupe, S, 2010-03-01 Free fatty acid receptor 2 (FFAR2/GPR43) is activated by carboxylate ligands, with relative potencies as follows: acetate = propionate = butyrate > pentanoate > hexanoate = formate. Pubmed12496283 Reactome Database ID Release 43444171 Reactome, http://www.reactome.org ReactomeREACT_21370 Reviewed: D'Eustachio, P, 2009-12-11 Receptor FFAR3 binds carboxylates Authored: Jupe, S, 2009-10-19 Edited: Jupe, S, 2010-03-01 Free fatty acid receptor 3 (FFAR3/GPR41) is activated by carboxylate anion ligands with a rank order of potency: propionate = pentanoate = butyrate > acetate > formate. Pubmed12496283 Reactome Database ID Release 43444047 Reactome, http://www.reactome.org ReactomeREACT_21363 Reviewed: D'Eustachio, P, 2009-12-11 PathwayStep5391 PathwayStep5390 PathwayStep5393 PathwayStep5392 PathwayStep5399 Melanospin is stimulated by light Authored: Jassal, B, 2009-05-07 08:25:16 Edited: Jassal, B, 2009-06-03 Melanopsin (Opsin-4) (Provencio I et al, 2000) is a member of the opsin family encoded by the OPN4 gene. It is found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary light reflex, and other non-visual responses to light. Melanopsin is expressed only in the retina and there, only in 1-2% of the ganglion cells. The effects of melanopsin are mediated by coupling to Gq/11 proteins which results in increased intracellular calcium levels (Qiu X et al, 2005). Pubmed10632589 Pubmed15674243 Reactome Database ID Release 43419861 Reactome, http://www.reactome.org ReactomeREACT_18262 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 PathwayStep5398 Light stimulates opsin receptors Authored: Jassal, B, 2009-05-07 08:25:16 Edited: Jassal, B, 2009-06-03 Pubmed10234000 Pubmed10581022 Pubmed1302020 Pubmed14623103 Pubmed1531728 Pubmed1557123 Pubmed2937147 Pubmed6589631 Pubmed7947717 Pubmed9275222 Reactome Database ID Release 43419841 Reactome, http://www.reactome.org ReactomeREACT_18363 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Rhodopsin (encoded by the human gene OPN2) (Nathans J and Hogness DS, 1984) is expressed in rod photoreceptor cells used in night vision. In humans, three opsins are expressed in cone cells used for colour vision. The opsin 1 gene OPN1MW encodes a protein called green cone photopigment or medium-wave-sensitive opsin (Nathans J et al, 1986). Defects in OPN1MW are the cause of partial colorblindness called deuteranopia (Winderickx J et al, 1992).<br>The opsin 1 gene OPN1LW encodes a protein called red cone photopigment or long-wavelength sensitive opsin (Nathans J et al, 1986). Defects in this gene are the cause of partial colorblindness (protanopia) (Winderickx J et al, 1992). The opsin 1 gene OPN1SW encodes for blue-sensitive opsins (BOP) (Nathans J et al, 1986). A deficiency in function or numbers (or both) of BOP results in a selective deficiency of blue spectral sensitivity. This is called Tritanopia, an autosomal dominant genetic disorder of human vision (Weitz CJ et al, 1992).<br>The human gene OPN3 encodes opsin 3 (encephalopsin, panopsin) (Blackshaw S and Snyder SH, 1999). It is strongly expressed in brain and testis with features of a classical photoreceptive opsin. The human gene OPN5 encodes opsin 5, which is expressed in the eye, brain, testes, and spinal cord (Tarttelin EE et al, 2003).<br>The visual pigment-like receptor peropsin (RRH) is found only in the eye, where it is localized to the retinal pigment epithelium (RPE) (Sun H et al, 1997). In the RPE, it is localized to the microvilli that surround the photoreceptor outer segments. It may play a role in RPE physiology, either by detecting light directly or by monitoring the concentration of retinoids or other photoreceptor-derived compounds.<br>The putative RPE-retinal G protein coupled receptor (RGR) (Shen D et al, 1994) covalently binds both all-trans- and 11-cis-retinal after reduction by sodium borohydride. The 32-kDa receptor binds all-trans-retinal preferentially, rather than the 11-cis isomer. Defects in RGR are a cause of autosomal recessive retinitis pigmentosa (ARRP). RP leads to degeneration of retinal photoreceptor cells (Morimura H et al, 1999).<br>Transducin (also called Gt) is a heterotrimeric G protein that is naturally expressed in vertebrate retina rods and cones and couple with these opsins to mediate the stimulation of cGMP hydrolysis. Receptor FFAR1 binds free fatty acids Authored: Jupe, S, 2009-10-19 Edited: Jupe, S, 2010-03-01 Free fatty acid receptor 1 (FFAR1/GPR40) is activated by many medium-length fatty acids. In recombinant assays the most potent saturated fatty acids had carbon chain lengths of 15-16; the most potent unsaturated fatty acid tested was 5,8,11-Eicosatriynoic Acid (C20). Pubmed12496284 Reactome Database ID Release 43444202 Reactome, http://www.reactome.org ReactomeREACT_21412 Reviewed: D'Eustachio, P, 2009-12-11 PathwayStep5395 Melatonin receptors can bind melatonin Authored: Jassal, B, 2009-04-30 13:38:16 Edited: Jassal, B, 2009-04-30 13:38:16 Melatonin (N-acetyl-5-methoxytryptamine) is a natural hormone produced by the pineal gland that is involved in the regulation of circadian rhythms. These actions are mediated by melatonin receptors. Melatonin can also function as a powerful antioxidant in the protection of nuclear and mitochondrial DNA.There are two melatonin receptors in humans, MT1 (Mel1a, MTNR1A) and MT2 (Mel1b, MTNR1B). Their actions are mediated by coupling with the G protein alpha i/o subunits to inhibit adenylyl cyclase (Reppert SM et al, 1994: Reppert SM et al, 1995). Pubmed7568007 Pubmed7946354 Reactome Database ID Release 43419334 Reactome, http://www.reactome.org ReactomeREACT_18412 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 PathwayStep5394 PAF receptor binds platelet activating factor Authored: Jassal, B, 2009-04-30 13:38:16 Edited: Jassal, B, 2009-04-30 13:38:16 Platelet-activating factor (PAF, AGEPC, acetyl-glyceryl-ether-phosphorylcholine) is a potent phospholipid activator and mediator of many leukocyte functions, including platelet aggregation, inflammation, and anaphylaxis. It is an important mediator of bronchoconstriction. It causes platelets to aggregate and blood vessels to dilate so is important to the process of hemostasis. The PAF receptor (Ye RD et al, 1991) shows structural characteristics of the rhodopsin gene family and binds platelet-activating factor (PAF). The activity of this receptor is mediated by coupling with the G protein alpha q subunit which stimulates PLC-beta which can cleave PIP2 to form secondary messengers (Deo DD et al, 2004). Pubmed14617636 Pubmed1656963 Reactome Database ID Release 43419351 Reactome, http://www.reactome.org ReactomeREACT_18369 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 PathwayStep5397 S1P-binding receptors bind S1P Authored: Jassal, B, 2009-04-30 13:38:16 Edited: Jassal, B, 2009-04-30 13:38:16 Five EDG-encoded receptors can all bind sphingolipid-1-phosphate (S1P), a second messenger implicated in cell survival, cell migration, and inflammation. The five genes encoding the receptors are EDG1, 3, 5, 6 and 8.<br>EDG1 is a human gene which encodes a GPCR which binds S1P. Hence this receptor is also known as S1PR1 (Hla T, Maciag T, 1990). S1PR1 seems to couple with Gi proteins (Lee MJ et al, 1996).<br>EDG5 encodes the GPCR known as S1PR2 (An S et al, 2000). This protein participates in S1P-induced cell proliferation, survival, and transcriptional activation, effects mediated by coupling to Gi and Gq proteins (Windh RT et al, 1999).<br>EDG3 encodes a GPCR known as S1PR3 (Yamaguchi F et al, 1996). This protein contributes to the regulation of angiogenesis and vascular endothelial cell function. These effects are mediated by coupling with Gi, Gq/11 and G12/13 proteins (Windh RT et al, 1999).<br>EDG6 encodes the GPCR known as S1PR4 (Graler MH et al, 1998). This EDG receptor gene is intronless and is specifically expressed in the lymphoid tissue. It's actions are mediated by coupling with Gi/o proteins to inhibit adenylyl cyclase (Van Brocklyn JR et al, 2000).<br>EDG8 encodes the GPCR known as S1PR5 (Kothapalli R et al, 2002). Its actions are mediated by coupling with Gi/o proteins to inhibit adenylyl cyclase (Im DS et al, 2000). Pubmed10488065 Pubmed10617617 Pubmed10753843 Pubmed10799507 Pubmed12427546 Pubmed2160972 Pubmed8626678 Pubmed8878560 Reactome Database ID Release 43419428 Reactome, http://www.reactome.org ReactomeREACT_18416 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 PathwayStep5396 LPA-binding receptors bind LPA Authored: Jassal, B, 2009-04-30 13:38:16 Edited: Jassal, B, 2009-04-30 13:38:16 Pubmed10488122 Pubmed10727522 Pubmed9070858 Pubmed9525886 Pubmed9804623 Reactome Database ID Release 43419389 Reactome, http://www.reactome.org ReactomeREACT_18285 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The LPA-binding EDG receptors all bind to the ligand lysophosphatidic acid (LPA), a phospholipid derivative that acts as a potent signaling molecule.<br>EDG2 is a human gene encoding a GPCR, LPA1 (as this receptor binds LPA) (An S et al, 1997). Downstream effects such as inhibition of adenylyl cyclase are mediated by binding to Gi proteins (An S et al, 1998).<br>EDG4 is a human gene which encodes the GPCR known as LPA2 (An S et al, 1998). This protein contributes towards Ca2+ mobilization, a critical cellular response to LPA in cells, through association with Gi and Gq proteins (An S et al, 1998).<br>EDG7 encodes the GPCR LPA3. This receptor binds LPA and mediates LPA-evoked calcium mobilization. This receptor couples predominantly to Gq/11 alpha proteins (Im DS et al, 2000). A1 and A3 receptors bind adenosine Authored: Jassal, B, 2009-04-27 14:38:30 Edited: Jassal, B, 2009-04-27 14:38:30 Pubmed10029519 Pubmed1530647 Pubmed8234299 Reactome Database ID Release 43418904 Reactome, http://www.reactome.org ReactomeREACT_18300 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The A1 receptor (Libert F et al, 1992) has an inhibitory function on most of the tissues in which it is expressed. In the brain, it slows metabolic activity and also decreases heart rate. The A1, together with A2a receptors, are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow.<br>The A3 receptor (Salvatore CA et al, 1993) mediates a sustained cardioprotective function during cardiac ischemia and it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury.<br> Both the A1 and A3 receptors mediate their effects by coupling with the G protein alpha i subunit which inhibits adenylyl cyclase (Wise A et al, 1999). A2a and A2b receptors bind adenosine A2b receptors (Peterfreund RA et al, 1996) are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. The A2A receptor is responsible for regulating myocardial blood flow by vasodilation of the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. Just as in A1 receptors, this normally serves as a protective mechanism. A2b receptor work (Pierce KD et al, 1992) has lagged behind research in the other adenosine receptors.<br>Both A2 receptors mediate their actions by coupling with the G protein alpha s subunit which activates adenylyl cyclase and increases intracellular cAMP concentrations (Cooper JA et al, 1995; Linden J et al, 1999). Authored: Jassal, B, 2009-04-27 14:38:30 Edited: Jassal, B, 2009-04-27 14:38:30 Pubmed10496952 Pubmed1325798 Pubmed8522976 Pubmed8527267 Reactome Database ID Release 43418925 Reactome, http://www.reactome.org ReactomeREACT_18299 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Cannabinoid receptors can bind cannabinoids Authored: Jassal, B, 2009-04-30 13:38:16 Edited: Jassal, B, 2009-04-30 13:38:16 Pubmed12037135 Pubmed17876302 Pubmed18845565 Pubmed2263478 Pubmed7498464 Pubmed7689702 Pubmed7775459 Reactome Database ID Release 43419426 Reactome, http://www.reactome.org ReactomeREACT_18279 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The cannabinoid receptors are a class of receptors within the G-protein coupled receptor superfamily. Their ligands are known as cannabinoids or endocannabinoids depending on whether they come from external or internal (endogenous) sources, respectively (Howlett AC et al, 2002). Endocannabinoids serve as intercellular lipid messengers, signaling molecules that are released from one cell and activate the cannabinoid receptors present on other cells. <br>Cannabinoid type 1 (CB1) receptors (Gerrard C et al, 1990) are thought to be the most widely expressed G-protein coupled receptors in the brain, lungs, liver and kidneys. Endocannabinoids released from the depolarized neuron bind to CB1 receptors in the pre-synaptic neuron and cause a reduction in GABA release.<br>CB2 receptors (Munro S et al, 1993) are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. Current research suggests that these receptors play a role in nociception, or the perception of pain.<br>Both receptors' activity is mediated by coupling to the G protein alpha i/o subunit, which inhibits adenylyl cyclase (Bouaboula M et al, 1995; Bayewitch M et al, 1995).<br>GPR55 is activated by plant cannabinoids and the endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide, leading to suggestions that it shold be renamed CB3. However GPR55 has also been reported as a receptor for LPI and its derivative 2-Arachidonoyl-sn-glycero-3-phosphoinositol. <br> 2-AG binds to the CB1 and CB2 receptors with similar affinity, acting as a full agonist. PathwayStep5360 PathwayStep5364 PathwayStep5363 PathwayStep5362 PathwayStep5361 PathwayStep5368 PathwayStep5367 PathwayStep5366 PathwayStep5365 ligands of SLC7A8 Converted from EntitySet in Reactome Reactome DB_ID: 352190 Reactome Database ID Release 43352190 Reactome, http://www.reactome.org ReactomeREACT_14072 ligands of SLC7A8 Converted from EntitySet in Reactome Reactome DB_ID: 352193 Reactome Database ID Release 43352193 Reactome, http://www.reactome.org ReactomeREACT_14264 alanine, serine, threonine, or cysteine Converted from EntitySet in Reactome Reactome DB_ID: 352359 Reactome Database ID Release 43352359 Reactome, http://www.reactome.org ReactomeREACT_14477 PathwayStep5358 alanine, serine, threonine, or cysteine Converted from EntitySet in Reactome Reactome DB_ID: 352355 Reactome Database ID Release 43352355 Reactome, http://www.reactome.org ReactomeREACT_14614 PathwayStep5359 ligands of SLC6A14 Converted from EntitySet in Reactome Reactome DB_ID: 375459 Reactome Database ID Release 43375459 Reactome, http://www.reactome.org ReactomeREACT_15206 ligands of SLC6A14 Converted from EntitySet in Reactome Reactome DB_ID: 375468 Reactome Database ID Release 43375468 Reactome, http://www.reactome.org ReactomeREACT_15161 ligands of SLC6A19 Converted from EntitySet in Reactome Reactome DB_ID: 375481 Reactome Database ID Release 43375481 Reactome, http://www.reactome.org ReactomeREACT_15227 ligands of SLC6A19 Converted from EntitySet in Reactome Reactome DB_ID: 375458 Reactome Database ID Release 43375458 Reactome, http://www.reactome.org ReactomeREACT_15160 ligands of SLC7A5 Converted from EntitySet in Reactome Reactome DB_ID: 352227 Reactome Database ID Release 43352227 Reactome, http://www.reactome.org ReactomeREACT_14158 ligands of SLC7A5 Converted from EntitySet in Reactome Reactome DB_ID: 352229 Reactome Database ID Release 43352229 Reactome, http://www.reactome.org ReactomeREACT_14292 PathwayStep5371 PathwayStep5370 PathwayStep5373 PathwayStep5372 PathwayStep5375 PathwayStep5374 PathwayStep5377 PathwayStep5376 PathwayStep5379 PathwayStep5378 ligands of SLC6A15 Converted from EntitySet in Reactome Reactome DB_ID: 352048 Reactome Database ID Release 43352048 Reactome, http://www.reactome.org ReactomeREACT_14097 PathwayStep5369 ligands of SLC6A15 Converted from EntitySet in Reactome Reactome DB_ID: 352051 Reactome Database ID Release 43352051 Reactome, http://www.reactome.org ReactomeREACT_13883 ligands of SLC6A6 Converted from EntitySet in Reactome Reactome DB_ID: 352019 Reactome Database ID Release 43352019 Reactome, http://www.reactome.org ReactomeREACT_14671 ligands of SLC6A6 Converted from EntitySet in Reactome Reactome DB_ID: 352024 Reactome Database ID Release 43352024 Reactome, http://www.reactome.org ReactomeREACT_14486 ligands of SLC6A12 (BGT-1) Converted from EntitySet in Reactome Reactome DB_ID: 351982 Reactome Database ID Release 43351982 Reactome, http://www.reactome.org ReactomeREACT_14644 ligands of SLC43A1 and SLC43A2 Converted from EntitySet in Reactome Reactome DB_ID: 352114 Reactome Database ID Release 43352114 Reactome, http://www.reactome.org ReactomeREACT_13952 ligands of SLC6A12 (BGT-1) Converted from EntitySet in Reactome Reactome DB_ID: 352007 Reactome Database ID Release 43352007 Reactome, http://www.reactome.org ReactomeREACT_14225 ligands of SLC43A1 and SLC43A2 Converted from EntitySet in Reactome Reactome DB_ID: 352101 Reactome Database ID Release 43352101 Reactome, http://www.reactome.org ReactomeREACT_14610 ligands of SLC38A5 Converted from EntitySet in Reactome Reactome DB_ID: 352175 Reactome Database ID Release 43352175 Reactome, http://www.reactome.org ReactomeREACT_13843 ligands of SLC38A5 Converted from EntitySet in Reactome Reactome DB_ID: 352178 Reactome Database ID Release 43352178 Reactome, http://www.reactome.org ReactomeREACT_14636 ligands of SLC38A4 Converted from EntitySet in Reactome Reactome DB_ID: 352128 Reactome Database ID Release 43352128 Reactome, http://www.reactome.org ReactomeREACT_14058 ligands of SLC38A4 Converted from EntitySet in Reactome Reactome DB_ID: 352135 Reactome Database ID Release 43352135 Reactome, http://www.reactome.org ReactomeREACT_14105 ligands of SLC38A3 Converted from EntitySet in Reactome Reactome DB_ID: 352186 Reactome Database ID Release 43352186 Reactome, http://www.reactome.org ReactomeREACT_13991 ligands of SLC38A3 Converted from EntitySet in Reactome Reactome DB_ID: 352169 Reactome Database ID Release 43352169 Reactome, http://www.reactome.org ReactomeREACT_14234 ligands of SLC38A2 Converted from EntitySet in Reactome Reactome DB_ID: 352091 Reactome Database ID Release 43352091 Reactome, http://www.reactome.org ReactomeREACT_13984 ligands of SLC38A2 Converted from EntitySet in Reactome Reactome DB_ID: 352088 Reactome Database ID Release 43352088 Reactome, http://www.reactome.org ReactomeREACT_14296 ligands of SLC38A1 Converted from EntitySet in Reactome Reactome DB_ID: 352105 Reactome Database ID Release 43352105 Reactome, http://www.reactome.org ReactomeREACT_14092 ligands of SLC16A10 Converted from EntitySet in Reactome Reactome DB_ID: 352161 Reactome Database ID Release 43352161 Reactome, http://www.reactome.org ReactomeREACT_14064 ligands of SLC36A2 Converted from EntitySet in Reactome Reactome DB_ID: 375414 Reactome Database ID Release 43375414 Reactome, http://www.reactome.org ReactomeREACT_15209 ligands of SLC38A1 Converted from EntitySet in Reactome Reactome DB_ID: 352123 Reactome Database ID Release 43352123 Reactome, http://www.reactome.org ReactomeREACT_14635 ligands of SLC16A10 Converted from EntitySet in Reactome Reactome DB_ID: 352139 Reactome Database ID Release 43352139 Reactome, http://www.reactome.org ReactomeREACT_14325 Inhibitory amino acids Converted from EntitySet in Reactome Reactome DB_ID: 428632 Reactome Database ID Release 43428632 Reactome, http://www.reactome.org ReactomeREACT_19773 ligands of SLC36A1 Converted from EntitySet in Reactome Reactome DB_ID: 375400 Reactome Database ID Release 43375400 Reactome, http://www.reactome.org ReactomeREACT_14867 ligands of SLC36A1 Converted from EntitySet in Reactome Reactome DB_ID: 375411 Reactome Database ID Release 43375411 Reactome, http://www.reactome.org ReactomeREACT_15239 ligands of SLC36A2 Converted from EntitySet in Reactome Reactome DB_ID: 375409 Reactome Database ID Release 43375409 Reactome, http://www.reactome.org ReactomeREACT_15066 Inhibitory amino acids Converted from EntitySet in Reactome Reactome DB_ID: 428592 Reactome Database ID Release 43428592 Reactome, http://www.reactome.org ReactomeREACT_19986 PathwayStep5300 PathwayStep5302 PathwayStep5301 PathwayStep5309 PathwayStep5307 PathwayStep5308 PathwayStep5305 PathwayStep5306 PathwayStep5303 PathwayStep5304 PathwayStep5313 PathwayStep5312 PathwayStep5311 PathwayStep5310 PathwayStep5337 PathwayStep5336 PathwayStep5339 PathwayStep5338 PathwayStep5343 PathwayStep5344 PathwayStep5345 PathwayStep5346 PathwayStep3200 PathwayStep5340 PathwayStep3201 PathwayStep5341 PathwayStep5342 PathwayStep3203 PathwayStep3202 PathwayStep3205 PathwayStep3204 PathwayStep3207 PathwayStep5349 PathwayStep3206 PathwayStep5348 PathwayStep3209 PathwayStep5347 PathwayStep3208 PathwayStep5356 PathwayStep5357 PathwayStep5354 PathwayStep5355 PathwayStep5352 PathwayStep5353 PathwayStep3210 PathwayStep5350 PathwayStep3211 PathwayStep5351 PathwayStep3212 PathwayStep5315 PathwayStep5314 PathwayStep5317 PathwayStep5316 PathwayStep5319 PathwayStep5318 PathwayStep5320 PathwayStep5321 PathwayStep5322 PathwayStep5323 PathwayStep5324 PathwayStep5328 PathwayStep5327 PathwayStep5326 PathwayStep5325 PathwayStep5329 PathwayStep5330 PathwayStep5331 PathwayStep5334 PathwayStep5335 PathwayStep5332 PathwayStep5333 PathwayStep3269 PathwayStep3268 Necl-3 dimer Reactome DB_ID: 433735 Reactome Database ID Release 43433735 Reactome, http://www.reactome.org ReactomeREACT_19876 has a Stoichiometric coefficient of 2 Nectin-1 cis homodimer Reactome DB_ID: 420607 Reactome Database ID Release 43420607 Reactome, http://www.reactome.org ReactomeREACT_19460 has a Stoichiometric coefficient of 2 NRG1/2:p-10Y-ERBB3:p-ERBB2:RNF41 Reactome DB_ID: 1358734 Reactome Database ID Release 431358734 Reactome, http://www.reactome.org ReactomeREACT_116551 has a Stoichiometric coefficient of 1 Nectin-1:Nectin-3 trans heterodimer Reactome DB_ID: 420601 Reactome Database ID Release 43420601 Reactome, http://www.reactome.org ReactomeREACT_20025 has a Stoichiometric coefficient of 1 NRG1/2:Ub-p-10Y-ERBB3:p-ERBB2 Reactome DB_ID: 1358729 Reactome Database ID Release 431358729 Reactome, http://www.reactome.org ReactomeREACT_117753 has a Stoichiometric coefficient of 1 Nectin-4 cis homodimer Reactome DB_ID: 420606 Reactome Database ID Release 43420606 Reactome, http://www.reactome.org ReactomeREACT_20206 has a Stoichiometric coefficient of 2 Ub-ERBB2:ERBB2IP:Ub-HSP90:CDC37 Reactome DB_ID: 1918083 Reactome Database ID Release 431918083 Reactome, http://www.reactome.org ReactomeREACT_116767 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Nectin-1:Nectin-4 trans heterodimer Reactome DB_ID: 420609 Reactome Database ID Release 43420609 Reactome, http://www.reactome.org ReactomeREACT_20421 has a Stoichiometric coefficient of 1 Ub-ERBB2:ERBB2IP:HSP90:CDC37 Reactome DB_ID: 1918081 Reactome Database ID Release 431918081 Reactome, http://www.reactome.org ReactomeREACT_116340 has a Stoichiometric coefficient of 1 Nectin-2 cis homodimer Reactome DB_ID: 420575 Reactome Database ID Release 43420575 Reactome, http://www.reactome.org ReactomeREACT_20053 has a Stoichiometric coefficient of 2 Phosphorylated ERBB2 heterodimers:MATK Reactome DB_ID: 1963590 Reactome Database ID Release 431963590 Reactome, http://www.reactome.org ReactomeREACT_117768 has a Stoichiometric coefficient of 1 PathwayStep3270 Nectin-2:Nectin-3 transheterodimer Reactome DB_ID: 420605 Reactome Database ID Release 43420605 Reactome, http://www.reactome.org ReactomeREACT_20370 has a Stoichiometric coefficient of 1 NRGs/EGFLs:ERBB4 Converted from EntitySet in Reactome NRGs/EGF-like ligands:ERBB4 Reactome DB_ID: 1236393 Reactome Database ID Release 431236393 Reactome, http://www.reactome.org ReactomeREACT_117478 Necl-1:Nectin-1 trans heterodimer Reactome DB_ID: 420585 Reactome Database ID Release 43420585 Reactome, http://www.reactome.org ReactomeREACT_19689 has a Stoichiometric coefficient of 1 NRGs/EGF-like ligands:ERBB4jmAcyt1 Reactome DB_ID: 1258437 Reactome Database ID Release 431258437 Reactome, http://www.reactome.org ReactomeREACT_117297 has a Stoichiometric coefficient of 1 Necl-1:Nectin-3 trans heterodimer Reactome DB_ID: 420577 Reactome Database ID Release 43420577 Reactome, http://www.reactome.org ReactomeREACT_19782 has a Stoichiometric coefficient of 1 NRGs/EGF-like ligands:ERBB4jmBcyt1 Reactome DB_ID: 1258439 Reactome Database ID Release 431258439 Reactome, http://www.reactome.org ReactomeREACT_117381 has a Stoichiometric coefficient of 1 PathwayStep3273 PathwayStep3274 PathwayStep3271 PathwayStep3272 PathwayStep3277 PathwayStep3278 PathwayStep3275 Necl-1/Necl-2/Necl-3 trans homodimer Reactome DB_ID: 420594 Reactome Database ID Release 43420594 Reactome, http://www.reactome.org ReactomeREACT_19789 has a Stoichiometric coefficient of 2 Ub-RNF41 Reactome DB_ID: 1358737 Reactome Database ID Release 431358737 Reactome, http://www.reactome.org ReactomeREACT_117273 Ub-NRDP1 has a Stoichiometric coefficient of 1 PathwayStep3276 Nectin-3 cis homodimer Reactome DB_ID: 420590 Reactome Database ID Release 43420590 Reactome, http://www.reactome.org ReactomeREACT_19940 has a Stoichiometric coefficient of 2 Ub-RNF41:p-USP8 Reactome DB_ID: 1358740 Reactome Database ID Release 431358740 Reactome, http://www.reactome.org ReactomeREACT_117304 Ub-NRDP1:P-USP8 has a Stoichiometric coefficient of 1 PathwayStep3258 PathwayStep3257 PathwayStep3259 Multiubiquitinated Nek2A Reactome DB_ID: 179414 Reactome Database ID Release 43179414 Reactome, http://www.reactome.org ReactomeREACT_8451 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Nek2A:MCC:APC/C complex Reactome DB_ID: 179413 Reactome Database ID Release 43179413 Reactome, http://www.reactome.org ReactomeREACT_8246 has a Stoichiometric coefficient of 1 Nectin:afadin complex Reactome DB_ID: 419013 Reactome Database ID Release 43419013 Reactome, http://www.reactome.org ReactomeREACT_20350 has a Stoichiometric coefficient of 1 ERBB4:ERBB3 heterodimer Reactome DB_ID: 1977955 Reactome Database ID Release 431977955 Reactome, http://www.reactome.org ReactomeREACT_117805 has a Stoichiometric coefficient of 1 Nectin cis-homodimer Reactome DB_ID: 433730 Reactome Database ID Release 43433730 Reactome, http://www.reactome.org ReactomeREACT_19521 has a Stoichiometric coefficient of 2 SHC1:p-ERBB4 Reactome DB_ID: 1250359 Reactome Database ID Release 431250359 Reactome, http://www.reactome.org ReactomeREACT_116475 has a Stoichiometric coefficient of 1 Cadherin:Catenin complex Reactome DB_ID: 418976 Reactome Database ID Release 43418976 Reactome, http://www.reactome.org ReactomeREACT_20065 has a Stoichiometric coefficient of 1 ERBB4jmAcyt2 homodimer Reactome DB_ID: 1250321 Reactome Database ID Release 431250321 Reactome, http://www.reactome.org ReactomeREACT_117734 has a Stoichiometric coefficient of 2 Afadin:F-actin Reactome DB_ID: 433726 Reactome Database ID Release 43433726 Reactome, http://www.reactome.org ReactomeREACT_19820 has a Stoichiometric coefficient of 1 ERBB4:EGFR heterodimer Reactome DB_ID: 1977956 Reactome Database ID Release 431977956 Reactome, http://www.reactome.org ReactomeREACT_116654 has a Stoichiometric coefficient of 1 Necl-1 dimer Reactome DB_ID: 433733 Reactome Database ID Release 43433733 Reactome, http://www.reactome.org ReactomeREACT_20051 has a Stoichiometric coefficient of 2 p-ERBB4 JM-A homodimers Converted from EntitySet in Reactome Phosphorylated homodimers of ERBB4 JM-A isoforms Reactome DB_ID: 1843077 Reactome Database ID Release 431843077 Reactome, http://www.reactome.org ReactomeREACT_116984 Necl-2 dimer Reactome DB_ID: 433737 Reactome Database ID Release 43433737 Reactome, http://www.reactome.org ReactomeREACT_19471 has a Stoichiometric coefficient of 2 Nectin trans homodimer Reactome DB_ID: 418972 Reactome Database ID Release 43418972 Reactome, http://www.reactome.org ReactomeREACT_19779 has a Stoichiometric coefficient of 2 p-Y349,350-SHC1:p-ERBB4 Reactome DB_ID: 1250343 Reactome Database ID Release 431250343 Reactome, http://www.reactome.org ReactomeREACT_117460 has a Stoichiometric coefficient of 1 Necl-1/Necl-2/Necl-3 homodimer Converted from EntitySet in Reactome Reactome DB_ID: 420583 Reactome Database ID Release 43420583 Reactome, http://www.reactome.org ReactomeREACT_19578 GRB2:SOS1:p-Y349,350-SHC1:p-ERBB4 Reactome DB_ID: 1250382 Reactome Database ID Release 431250382 Reactome, http://www.reactome.org ReactomeREACT_116366 has a Stoichiometric coefficient of 1 PathwayStep3260 PathwayStep3261 PathwayStep3262 PathwayStep3263 PathwayStep3264 ERBB4jmAcyt1 homodimer Reactome DB_ID: 1258441 Reactome Database ID Release 431258441 Reactome, http://www.reactome.org ReactomeREACT_117799 has a Stoichiometric coefficient of 2 PathwayStep3265 Cadherin trans-homodimer Reactome DB_ID: 418999 Reactome Database ID Release 43418999 Reactome, http://www.reactome.org ReactomeREACT_19942 has a Stoichiometric coefficient of 2 ERBB4jmBcyt1 homodimer Reactome DB_ID: 1258436 Reactome Database ID Release 431258436 Reactome, http://www.reactome.org ReactomeREACT_116468 has a Stoichiometric coefficient of 2 PathwayStep3266 PathwayStep3267 ERBB4cyt1 homodimers Converted from EntitySet in Reactome Reactome DB_ID: 1250318 Reactome Database ID Release 431250318 Reactome, http://www.reactome.org ReactomeREACT_116527 PathwayStep5502 PathwayStep5501 PathwayStep5504 PathwayStep5503 PathwayStep5506 PathwayStep5505 PathwayStep5508 PathwayStep5507 PathwayStep5509 PathwayStep3291 Integrin alpha6beta4 Reactome DB_ID: 215997 Reactome Database ID Release 43215997 Reactome, http://www.reactome.org ReactomeREACT_14337 has a Stoichiometric coefficient of 1 STAT5A homodimer Reactome DB_ID: 507927 Reactome Database ID Release 43507927 Reactome, http://www.reactome.org ReactomeREACT_24376 has a Stoichiometric coefficient of 2 PathwayStep3292 Integrin alpha 6:beta 4:Plectin complex Reactome DB_ID: 445996 Reactome Database ID Release 43445996 Reactome, http://www.reactome.org ReactomeREACT_21067 has a Stoichiometric coefficient of 1 ERBB4s80:STAT5A Reactome DB_ID: 1254284 Reactome Database ID Release 431254284 Reactome, http://www.reactome.org ReactomeREACT_117283 has a Stoichiometric coefficient of 1 PathwayStep3290 PARVB:alpha actinin Reactome DB_ID: 446335 Reactome Database ID Release 43446335 Reactome, http://www.reactome.org ReactomeREACT_21104 has a Stoichiometric coefficient of 1 TAB2:NCOR1 Reactome DB_ID: 1253304 Reactome Database ID Release 431253304 Reactome, http://www.reactome.org ReactomeREACT_117587 has a Stoichiometric coefficient of 1 MIG-2:MIGFILIN Reactome DB_ID: 430295 Reactome Database ID Release 43430295 Reactome, http://www.reactome.org ReactomeREACT_21097 has a Stoichiometric coefficient of 1 ERBB4s80:WWOX Reactome DB_ID: 1253344 Reactome Database ID Release 431253344 Reactome, http://www.reactome.org ReactomeREACT_116574 has a Stoichiometric coefficient of 1 Migfilin:Filamin A:F-actin Reactome DB_ID: 430323 Reactome Database ID Release 43430323 Reactome, http://www.reactome.org ReactomeREACT_20733 has a Stoichiometric coefficient of 1 ERBB4s80:YAP1 Reactome DB_ID: 1253341 Reactome Database ID Release 431253341 Reactome, http://www.reactome.org ReactomeREACT_116244 has a Stoichiometric coefficient of 1 MIGFILIN:VASP Reactome DB_ID: 446308 Reactome Database ID Release 43446308 Reactome, http://www.reactome.org ReactomeREACT_21228 has a Stoichiometric coefficient of 1 ERBB4s80:YAP1 Reactome DB_ID: 1253347 Reactome Database ID Release 431253347 Reactome, http://www.reactome.org ReactomeREACT_117816 has a Stoichiometric coefficient of 1 PathwayStep3299 PARVA:Paxillin Reactome DB_ID: 446326 Reactome Database ID Release 43446326 Reactome, http://www.reactome.org ReactomeREACT_21170 has a Stoichiometric coefficient of 1 ADAM17 Reactome DB_ID: 1251963 Reactome Database ID Release 431251963 Reactome, http://www.reactome.org ReactomeREACT_116419 has a Stoichiometric coefficient of 1 ParvB/Affixin:Alpha-Pix Reactome DB_ID: 446035 Reactome Database ID Release 43446035 Reactome, http://www.reactome.org ReactomeREACT_20814 has a Stoichiometric coefficient of 1 TAB2:NCOR1 Reactome DB_ID: 1253312 Reactome Database ID Release 431253312 Reactome, http://www.reactome.org ReactomeREACT_116523 has a Stoichiometric coefficient of 1 PathwayStep3297 Rsu-1:Pinch1 complex Reactome DB_ID: 446302 Reactome Database ID Release 43446302 Reactome, http://www.reactome.org ReactomeREACT_20937 has a Stoichiometric coefficient of 1 ERBB4s80:TAB2:NCOR1 Reactome DB_ID: 1253326 Reactome Database ID Release 431253326 Reactome, http://www.reactome.org ReactomeREACT_117347 has a Stoichiometric coefficient of 1 PathwayStep3298 PARVA:TESK1 Reactome DB_ID: 446404 Reactome Database ID Release 43446404 Reactome, http://www.reactome.org ReactomeREACT_21038 has a Stoichiometric coefficient of 1 ERBB4s80:TAB2:NCOR1 Reactome DB_ID: 1253328 Reactome Database ID Release 431253328 Reactome, http://www.reactome.org ReactomeREACT_117194 has a Stoichiometric coefficient of 1 PathwayStep3295 PathwayStep3296 PathwayStep5510 PathwayStep3293 PathwayStep5511 PathwayStep3294 PathwayStep3279 ILK:Integrin beta-1 Reactome DB_ID: 446408 Reactome Database ID Release 43446408 Reactome, http://www.reactome.org ReactomeREACT_20766 has a Stoichiometric coefficient of 1 PathwayStep3280 CRB3:PALS1:PATJ complex Reactome DB_ID: 420663 Reactome Database ID Release 43420663 Reactome, http://www.reactome.org ReactomeREACT_20032 has a Stoichiometric coefficient of 1 PRLR:JAK2 dimer Reactome DB_ID: 1364076 Reactome Database ID Release 431364076 Reactome, http://www.reactome.org ReactomeREACT_117889 has a Stoichiometric coefficient of 2 PathwayStep3281 PINCH-ILK-parvin complex Reactome DB_ID: 432932 Reactome Database ID Release 43432932 Reactome, http://www.reactome.org ReactomeREACT_20853 has a Stoichiometric coefficient of 1 JAM-A:PAR-aPKC complex Reactome DB_ID: 420006 Reactome Database ID Release 43420006 Reactome, http://www.reactome.org ReactomeREACT_20246 has a Stoichiometric coefficient of 1 ERBB4jmAcyt2s80 dimer Reactome DB_ID: 1254391 Reactome Database ID Release 431254391 Reactome, http://www.reactome.org ReactomeREACT_116619 has a Stoichiometric coefficient of 2 Par3:Par6:aPKC complex Reactome DB_ID: 419984 Reactome Database ID Release 43419984 Reactome, http://www.reactome.org ReactomeREACT_20424 has a Stoichiometric coefficient of 1 PRLR:JAK2 Reactome DB_ID: 1302663 Reactome Database ID Release 431302663 Reactome, http://www.reactome.org ReactomeREACT_111285 has a Stoichiometric coefficient of 1 claudin trans-homodimer Reactome DB_ID: 421252 Reactome Database ID Release 43421252 Reactome, http://www.reactome.org ReactomeREACT_20391 has a Stoichiometric coefficient of 2 E4ICD Converted from EntitySet in Reactome ERBB4s80 Reactome DB_ID: 1254403 Reactome Database ID Release 431254403 Reactome, http://www.reactome.org ReactomeREACT_116484 Par3:Par6:aPKC complex Reactome DB_ID: 419976 Reactome Database ID Release 43419976 Reactome, http://www.reactome.org ReactomeREACT_19423 has a Stoichiometric coefficient of 1 ERBB4jmAcyt1s80 dimer Reactome DB_ID: 1254379 Reactome Database ID Release 431254379 Reactome, http://www.reactome.org ReactomeREACT_116425 has a Stoichiometric coefficient of 2 PathwayStep3286 Nectin-3:Necl-2 trans heterodimer Reactome DB_ID: 420578 Reactome Database ID Release 43420578 Reactome, http://www.reactome.org ReactomeREACT_19977 has a Stoichiometric coefficient of 1 ESR1 homodimer Reactome DB_ID: 1254384 Reactome Database ID Release 431254384 Reactome, http://www.reactome.org ReactomeREACT_117483 has a Stoichiometric coefficient of 2 PathwayStep3287 Necl-5:Nectin-3 trans heterodimer Reactome DB_ID: 420579 Reactome Database ID Release 43420579 Reactome, http://www.reactome.org ReactomeREACT_19715 has a Stoichiometric coefficient of 1 ERBB4s80:ESR1 Reactome DB_ID: 1254397 Reactome Database ID Release 431254397 Reactome, http://www.reactome.org ReactomeREACT_117209 has a Stoichiometric coefficient of 1 PathwayStep3288 STAT5A homodimer Reactome DB_ID: 507996 Reactome Database ID Release 43507996 Reactome, http://www.reactome.org ReactomeREACT_24679 has a Stoichiometric coefficient of 2 PathwayStep3289 Necl-1:Necl-2 trans heterodimer Reactome DB_ID: 420587 Reactome Database ID Release 43420587 Reactome, http://www.reactome.org ReactomeREACT_20182 has a Stoichiometric coefficient of 1 ESR1:estrogen Reactome DB_ID: 1254381 Reactome Database ID Release 431254381 Reactome, http://www.reactome.org ReactomeREACT_117017 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep3282 PathwayStep5500 PathwayStep3283 ERBB4s80:STAT5A Reactome DB_ID: 1254288 Reactome Database ID Release 431254288 Reactome, http://www.reactome.org ReactomeREACT_116515 has a Stoichiometric coefficient of 1 PathwayStep3284 PathwayStep3285 Nucleosome Reactome DB_ID: 181921 Reactome Database ID Release 43181921 Reactome, http://www.reactome.org ReactomeREACT_8671 has a Stoichiometric coefficient of 2 Shelterin complex Reactome DB_ID: 174898 Reactome Database ID Release 43174898 Reactome, http://www.reactome.org ReactomeREACT_8593 has a Stoichiometric coefficient of 1 Extended And Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Reactome DB_ID: 176703 Reactome Database ID Release 43176703 Reactome, http://www.reactome.org ReactomeREACT_8626 has a Stoichiometric coefficient of 1 Extended And Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order Structure Reactome DB_ID: 182751 Reactome Database ID Release 43182751 Reactome, http://www.reactome.org ReactomeREACT_8525 has a Stoichiometric coefficient of 1 Extended And Processed Telomere End Folded Into Higher Order Structure Reactome DB_ID: 182752 Reactome Database ID Release 43182752 Reactome, http://www.reactome.org ReactomeREACT_8171 has a Stoichiometric coefficient of 1 PathwayStep3226 PathwayStep3227 PathwayStep3224 PathwayStep3225 PathwayStep3228 PathwayStep3229 PathwayStep3230 PathwayStep3234 PathwayStep3233 PathwayStep3232 PathwayStep3231 Axial/Lateral Element of Synaptonemal Complex Reactome DB_ID: 912338 Reactome Database ID Release 43912338 Reactome, http://www.reactome.org ReactomeREACT_76597 has a Stoichiometric coefficient of 1 Meiotic Cohesin Complex Reactome DB_ID: 912384 Reactome Database ID Release 43912384 Reactome, http://www.reactome.org ReactomeREACT_76256 has a Stoichiometric coefficient of 1 Synaptonemal Complex Reactome DB_ID: 912422 Reactome Database ID Release 43912422 Reactome, http://www.reactome.org ReactomeREACT_76002 has a Stoichiometric coefficient of 1 Telomere Bouquet Reactome DB_ID: 912372 Reactome Database ID Release 43912372 Reactome, http://www.reactome.org ReactomeREACT_76658 Telomere Attachment Plate has a Stoichiometric coefficient of 1 Central Element of Synaptonemal Complex Reactome DB_ID: 912489 Reactome Database ID Release 43912489 Reactome, http://www.reactome.org ReactomeREACT_76183 has a Stoichiometric coefficient of 1 Transverse Filament of Synaptonemal Complex Reactome DB_ID: 912437 Reactome Database ID Release 43912437 Reactome, http://www.reactome.org ReactomeREACT_76868 has a Stoichiometric coefficient of 1 Processive complex loaded on telomere Reactome DB_ID: 174453 Reactome Database ID Release 43174453 Reactome, http://www.reactome.org ReactomeREACT_8041 has a Stoichiometric coefficient of 1 Processive complex loaded on telomere:Okazaki fragment complex Reactome DB_ID: 174435 Reactome Database ID Release 43174435 Reactome, http://www.reactome.org ReactomeREACT_8837 has a Stoichiometric coefficient of 1 RFC Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end duplex:PCNA homotrimer Reactome DB_ID: 174449 Reactome Database ID Release 43174449 Reactome, http://www.reactome.org ReactomeREACT_8208 has a Stoichiometric coefficient of 1 RNA primer-DNA primer:G-strand extended telomere:PCNA Reactome DB_ID: 174450 Reactome Database ID Release 43174450 Reactome, http://www.reactome.org ReactomeREACT_8843 has a Stoichiometric coefficient of 1 Processive complex loaded on telomere:Okazaki fragment:Flap Reactome DB_ID: 174431 Reactome Database ID Release 43174431 Reactome, http://www.reactome.org ReactomeREACT_8956 has a Stoichiometric coefficient of 1 Processive complex loaded on telomere:Okazaki fragment:Flap:RPA heterotrimer Reactome DB_ID: 174436 Reactome Database ID Release 43174436 Reactome, http://www.reactome.org ReactomeREACT_8468 has a Stoichiometric coefficient of 1 PathwayStep3213 PathwayStep3214 PathwayStep3215 PathwayStep3216 PathwayStep3217 PathwayStep3218 PathwayStep3219 PathwayStep3221 PathwayStep3220 PathwayStep3223 PathwayStep3222 Processive complex loaded on telomere:Okazaki fragment:Flap:RPA heterotrimer:dna2 Reactome DB_ID: 174442 Reactome Database ID Release 43174442 Reactome, http://www.reactome.org ReactomeREACT_8321 has a Stoichiometric coefficient of 1 Extended And Processed Telomere End Reactome DB_ID: 176706 Reactome Database ID Release 43176706 Reactome, http://www.reactome.org ReactomeREACT_8288 has a Stoichiometric coefficient of 1 Processive complex loaded on telomere:ligated C-strand Okazaki fragments Reactome DB_ID: 176394 Reactome Database ID Release 43176394 Reactome, http://www.reactome.org ReactomeREACT_8541 has a Stoichiometric coefficient of 1 Processive complex loaded on telomere:nicked DNA from adjacent Okazaki fragments Reactome DB_ID: 174432 Reactome Database ID Release 43174432 Reactome, http://www.reactome.org ReactomeREACT_8309 has a Stoichiometric coefficient of 1 Processive complex loaded on telomere:Okazaki fragments:Remaining Flap Reactome DB_ID: 174440 Reactome Database ID Release 43174440 Reactome, http://www.reactome.org ReactomeREACT_8363 has a Stoichiometric coefficient of 1 IL3RB:Jak2 Reactome DB_ID: 879918 Reactome Database ID Release 43879918 Reactome, http://www.reactome.org ReactomeREACT_24818 has a Stoichiometric coefficient of 1 Smad7:SMURF2 Reactome DB_ID: 2167867 Reactome Database ID Release 432167867 Reactome, http://www.reactome.org ReactomeREACT_122075 has a Stoichiometric coefficient of 1 Tight Junction Complex:TGFBR1:Pard6a:RHOA Reactome DB_ID: 2161145 Reactome Database ID Release 432161145 Reactome, http://www.reactome.org ReactomeREACT_122482 has a Stoichiometric coefficient of 1 PathwayStep3248 PathwayStep3249 PathwayStep3246 PathwayStep3247 PathwayStep3256 PathwayStep3255 PathwayStep3254 PathwayStep3253 PathwayStep3252 PathwayStep3251 PathwayStep3250 RBPJ:SNW1 Reactome DB_ID: 1911412 Reactome Database ID Release 431911412 Reactome, http://www.reactome.org ReactomeREACT_119151 has a Stoichiometric coefficient of 1 xNICD1:RBPJ:SNW1 Reactome DB_ID: 2064909 Reactome Database ID Release 432064909 Reactome, http://www.reactome.org ReactomeREACT_120309 has a Stoichiometric coefficient of 1 Elastin:Fibulin-5:Emilin1 Reactome DB_ID: 2426553 Reactome Database ID Release 432426553 Reactome, http://www.reactome.org ReactomeREACT_152130 has a Stoichiometric coefficient of 1 Elastin:Fbln5 Reactome DB_ID: 2426508 Reactome Database ID Release 432426508 Reactome, http://www.reactome.org ReactomeREACT_151693 has a Stoichiometric coefficient of 1 Myb:SIN3A:p53 Reactome DB_ID: 992690 Reactome Database ID Release 43992690 Reactome, http://www.reactome.org ReactomeREACT_27056 has a Stoichiometric coefficient of 1 TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-Smad7:Uchl5 Reactome DB_ID: 2179308 Reactome Database ID Release 432179308 Reactome, http://www.reactome.org ReactomeREACT_123737 has a Stoichiometric coefficient of 1 xNOTCH1 Coactivator Complex Reactome DB_ID: 2064911 Reactome Database ID Release 432064911 Reactome, http://www.reactome.org ReactomeREACT_119397 has a Stoichiometric coefficient of 1 xNOTCH1 Chimeric Coactivator Complex:CDK8:CCNC Reactome DB_ID: 2064914 Reactome Database ID Release 432064914 Reactome, http://www.reactome.org ReactomeREACT_119497 has a Stoichiometric coefficient of 1 Synaptonemal:BRCA1 Complex Reactome DB_ID: 912476 Reactome Database ID Release 43912476 Reactome, http://www.reactome.org ReactomeREACT_76427 has a Stoichiometric coefficient of 1 Synaptonemal:BRCA1:ATR Complex Reactome DB_ID: 912463 Reactome Database ID Release 43912463 Reactome, http://www.reactome.org ReactomeREACT_75938 has a Stoichiometric coefficient of 1 Unsynapsed Chromatin Reactome DB_ID: 975778 Reactome Database ID Release 43975778 Reactome, http://www.reactome.org ReactomeREACT_76872 has a Stoichiometric coefficient of 1 Nucleosome containing Histone H2A.x Reactome DB_ID: 975775 Reactome Database ID Release 43975775 Reactome, http://www.reactome.org ReactomeREACT_27840 has a Stoichiometric coefficient of 2 PathwayStep3239 PathwayStep3235 PathwayStep3236 PathwayStep3237 PathwayStep3238 PathwayStep3243 PathwayStep3242 PathwayStep3245 PathwayStep3244 PathwayStep3241 PathwayStep3240 Ras:GTP Reactome DB_ID: 1250491 Reactome Database ID Release 431250491 Reactome, http://www.reactome.org ReactomeREACT_116365 has a Stoichiometric coefficient of 1 Ras:GDP Reactome DB_ID: 1250493 Reactome Database ID Release 431250493 Reactome, http://www.reactome.org ReactomeREACT_116245 has a Stoichiometric coefficient of 1 GRB2:Sos1:P-Erbb2mut Reactome DB_ID: 1250478 Reactome Database ID Release 431250478 Reactome, http://www.reactome.org ReactomeREACT_117259 has a Stoichiometric coefficient of 1 P-Erbb2mut dimer Reactome DB_ID: 1250496 Reactome Database ID Release 431250496 Reactome, http://www.reactome.org ReactomeREACT_117223 has a Stoichiometric coefficient of 2 GRB2:Sos1 Reactome DB_ID: 1250499 Reactome Database ID Release 431250499 Reactome, http://www.reactome.org ReactomeREACT_116348 has a Stoichiometric coefficient of 1 Nucleosome containing Histone gamma-H2A.x Reactome DB_ID: 975776 Reactome Database ID Release 43975776 Reactome, http://www.reactome.org ReactomeREACT_27348 has a Stoichiometric coefficient of 2 Unsynapsed Chromatin containing gamma-H2A.x Reactome DB_ID: 975781 Reactome Database ID Release 43975781 Reactome, http://www.reactome.org ReactomeREACT_75943 has a Stoichiometric coefficient of 1 Formation of lysyl-pyrrole cross-links Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed12211432 Pubmed1567360 Pubmed18442706 Reactome Database ID Release 432250301 Reactome, http://www.reactome.org ReactomeREACT_150410 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Trivalent collagen cross-links can also form as pyrroles. Lysyl-Pyrrole (L-Pyrrole) is formed when Lysino-ketonorleucine (LKNL) reacts with Hydroxylysino-norleucine (deH-HLNL) (Eyre et al. 2008), with structures based on a 3-hydroxypyrrole, believed to be the core structure of the pyrrole cross-links in bone collagen, rather than a pyrrole lacking a hydroxyl on the ring as depicted earlier. Formation of lysyl-pyridinoline cross-links Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Lysyl-pyridinoline (L-Pyr) cross-links are formed from two hydroxylysine residues and a lysine residue (LKNL plus a further hydroxyallysine contributed by HLKNL), found mostly in calcified tissues (Bailey et al. 1998). Pubmed6129847 Reactome Database ID Release 432395322 Reactome, http://www.reactome.org ReactomeREACT_150249 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Formation of hydroxylysyl-pyridinoline cross-links Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Hydroxylysyl-pyridinoline (HL-Pyr) is formed from three hydroxylysine residues, (HLKNL plus a further hydroxyallysine donated by a second HLKNL). It predominates in highly hydroxylated collagens such as type II collagen in cartilage. Pubmed1484505 Pubmed3595596 Pubmed641035 Reactome Database ID Release 432395223 Reactome, http://www.reactome.org ReactomeREACT_150258 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 has a Stoichiometric coefficient of 2 Formation of hydroxylysino-5-ketonorleucine cross-links Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Hydroxyallysine and hydroxylysine can react forming the Schiff base, which spontaneously undergoes an Amadori rearrangement resulting in the ketoimine cross-link hydroxylysino-5-ketonorleucine (HLKNL). This is much more stable than the aldimine crosslinks (Bailey et al. 1998). Pubmed1348714 Pubmed3992061 Pubmed9883973 Reactome Database ID Release 432395302 Reactome, http://www.reactome.org ReactomeREACT_150322 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Formation of lysino-5-ketonorleucine cross-links Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 ISBN978-0-12-088562-6 In bone, cross-links are formed between telopeptide hydroxallysine residues and helical lysines (Robins & Bailey 1975). The resulting Schiff base undergoes Amadori rearrangement to form lysino-5-ketonorleucine (LKNL). Pubmed1237296 Reactome Database ID Release 432395314 Reactome, http://www.reactome.org ReactomeREACT_150373 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Formation of dehydro-hydroxylysino-norleucine cross-links Allysine residues condense with hydroxylysine residues to form the aldimine dehydro-hydroxylysino-norleucine (deH-HLNL), first identified by Bailey & Peach (1968). Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed5723342 Reactome Database ID Release 432395257 Reactome, http://www.reactome.org ReactomeREACT_150325 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Formation of dehydro-lysinonorleucine cross-links Allysine residues can condense with lysine residues forming dehydro-lysinonorleucine (deH-LNL) cross-links. In this representative reaction, all allysine residues are shown as converted to deH-LNL though partial conversion, or conversion to other cross-linked forms is possible (Reiser et al. 1992, Bailey & Peach 1968). Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed1348714 Pubmed5723342 Reactome Database ID Release 432243931 Reactome, http://www.reactome.org ReactomeREACT_150460 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Formation of hydroxyallysine by LOX Authored: Jupe, S, 2012-04-30 EC Number: 1.4.3.13 Edited: Jupe, S, 2012-11-12 Hydroxylysines residues can be converted to hydroxyallysines by lysyl oxidase. In this representative reaction a single hydroxylysine residue in each collagen chain is shown as converted to hydroxyallysine (Pinnell et al. 1968, Siegel 1979). Pubmed41816 Pubmed5246001 Reactome Database ID Release 432395340 Reactome, http://www.reactome.org ReactomeREACT_150172 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Formation of allysine by LOX Authored: Jupe, S, 2012-04-30 EC Number: 1.4.3.13 Edited: Jupe, S, 2012-11-12 Lysine residues can be converted to allysine by lysyl oxidase. In this representative reaction a single lysine residue in each collagen chain is shown as converted to allysine (Pinnell et al. 1968). Pubmed5246001 Reactome Database ID Release 432002466 Reactome, http://www.reactome.org ReactomeREACT_150131 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 has a Stoichiometric coefficient of 2 Prolysyl oxidase activation Authored: Jupe, S, 2012-04-30 EC Number: 3.4.24 Edited: Jupe, S, 2012-11-12 Lysyl oxidase (LOX) is secreted to the extracellular space in an inactive, proenzyme form (proLOX). This is proteolytically cleaved between Gly168 and Asp169 generating the mature 32-kDa enzyme. The activating proteinase is Bone morphogenetic protein 1 (BMP1), also called Procollagen C-proteinase (Cronshaw et al. 1995, Panchenko et al. 1996). Other extracellular proteases, including the BMP1 variant mammalian tolloid, tolloid-like (TLL) 1 and TLL2 proteases cleave proLOX at the correct physiological site but with lower efficiency (Uzel et al. 2001). Pubmed11313359 Pubmed7864821 Pubmed8636146 Reactome Database ID Release 432022141 Reactome, http://www.reactome.org ReactomeREACT_150462 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Release of endostatin-like peptides Authored: Jupe, S, 2012-04-30 Collagens XV and XVIII are basement membrane associated collagens that can be cleaved to generate the antiangiogenic peptides restin (endostatin-XV) and endostatin (endostatin-XVIII), respectively (O'Reilly et al. 1997, Ramachandran et al. 1997, Sasaki et al. 2000). Endostatin fragments of differing molecular size (14-30 kDa) have been identified in vivo. Furthermore the C-terminal domains of several other collagens (IV, VIII, XIX) have anti-angiogenic and anti-tumoral activities (Ricard-Blum & Ballut 2011). Several proteases are able to generate endostatin from collagen XVIII including MMP-3, -7, -9, -13 and -20 and cathepsins B, V, S and L (Heljasvaara et al. 2005, Ma et al. 2007, Veillard et al. 2011). Endostatin inhibits proliferation of endothelial cells, angiogenesis and tumor growth in vivo (O'Reilly et al. 1997). Edited: Jupe, S, 2012-11-12 Pubmed10049780 Pubmed10966814 Pubmed12690120 Pubmed15950618 Pubmed17251461 Pubmed21196195 Pubmed21896479 Pubmed9008168 Reactome Database ID Release 432213200 Reactome, http://www.reactome.org ReactomeREACT_150219 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 has a Stoichiometric coefficient of 18 Initial activation of proMMP1 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 ProMMP1 has several activators including plasmin (Eeckhout & Vaes 1977, Werb et al. 1977, Santala et al. 1999), trypsin (Grant et al. 1987, Saunders et al. 2005), plasma kallikrein (Nagase et al. 1982, Saunders et al. 2005), chymase (Saarinen et al. 1994, Suzuki et al. 1995, Saunders et al. 2005), tryptase (Gruber et al. 1989, Suzuki et al. 1995, Saunders et al. 2005), neutrophil elastase, cathepsin G (Saunders et al. 2005) and trypsin-2 (Moilanen et al. 2003). Concanavalin A (ConA) was the first cellular treatment that yielded active MMPs in culture, inducing the cellular activation of MMP1 likely through MMP14 activity (Overall and Sodek 1990).Trypsin-like serine proteinases are believed to remove 34-36 residues from the N-terminus of the secreted pro-enzyme, equivalent to positions 53-55 of the UniProt cannonical sequence which includes a signal peptide. Removal of this region is sufficient to destabilize the Cys92-Zn2+ stabilizing bond (numbered according to the Uniprot canonical sequence, Cys73 when numbered from the N terminus of the secreted peptide as typically represented in the literature) and partially activate enzyme activity. This intermediate form then undergoes autocatalysis at Thr83-Leu84 producing an MMP1 with about 20% of full collagenase activity (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100. When first reported, considerable debate surrounded the activation of this archetypical MMP. Divergence of opinion resulted when competing groups studied activation in vitro using chemicals (organomercurials such as aminophenylmecuricacetate), which yield a different autolytic cleavage site in the protease susceptible loop when compared with the site cut by serine proteases such as trypsin. Different specific activities result, but in general the final autolytic cleavage site for all MMPs is the homologous Phe or Tyr at position 100 or 101. When the active enzyme commences here, full activity is realised due to the salt bridge forming between the N-terminal primary amine of the conserved Phe or Tyr with an Asp on helix C that in turn salt bridges to the active site Glu. Termini either side of this position do not result in full activity. Pubmed10567688 Pubmed12731883 Pubmed15870107 Pubmed197917 Pubmed2174435 Pubmed2176865 Pubmed2553780 Pubmed3032947 Pubmed6279161 Pubmed66627 Pubmed7826345 Pubmed8027075 Reactome Database ID Release 431592316 Reactome, http://www.reactome.org ReactomeREACT_118608 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Type XII and XIV collagens associate with type I and type II fibrils. Authored: Jupe, S, 2012-04-30 Certain fibril-associated collagens with interrupted triple helices (FACITs) associate with the surface of collagen fibrils, where they may serve to limit fibril fusion and thereby regulate fibril diameter (Ansorge et al. 2009, Gordon & Hahn 2010). Type XII and XIV colalgens are found in association with type I (Walchli et al. 1994) and type II (Watt et al. 1992, Eyre 2002). Edited: Jupe, S, 2012-11-12 Pubmed1400327 Pubmed19136672 Pubmed19693541 Pubmed8207089 Reactome Database ID Release 432213205 Reactome, http://www.reactome.org ReactomeREACT_150286 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Collagen IX is cross-linked to the surface of collagen type II fibrils Authored: Jupe, S, 2012-04-30 Certain fibril-associated collagens with interrupted triple helices (FACITs) associate with the surface of collagen fibrils, where they may serve to limit fibril fusion and thereby regulate fibril diameter (Gordon & Hahn 2010, Ricard-Blum et al. 2011). Collagen IX cross-linked to the surface of collagen type II fibrils is thought to both regulate fibril diameter and stabilize interfibrillar connections (Eyre et al. 2004). An alternative model suggests that collagen II and XI form a biological alloy (Blaschke et al. 2000). Edited: Jupe, S, 2012-11-12 Pubmed14602708 Pubmed19693541 Pubmed21421911 Reactome Database ID Release 432213210 Reactome, http://www.reactome.org ReactomeREACT_150424 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Hemidesmosome formation Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed10637308 Pubmed11884516 Pubmed12482924 Pubmed15265795 Pubmed15561712 Pubmed18474082 Pubmed19736524 Pubmed19945617 Pubmed9856810 Reactome Database ID Release 432213192 Reactome, http://www.reactome.org ReactomeREACT_150217 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Type XVII collagen is a component of hemidesmosomes (HDs) (Has & Kern 2010). It associates with integrin alpha6beta4 (a6b4) (Hopkinson et al. 1999). The extracellular region of a6b4 extends from the cell membrane into the basement membrane to bind laminins, with a preference for laminin-332 (Hopkinson & Jones 2000, Sugawara et al. 2008), which is a component of anchoring fibrils. Laminins are complex glycoproteins, consisting of alpha, beta and gamma chains bound into a cross-shaped molecule. Laminin-332 is a complex of alpha-3, beta-2 and gamma-2 subunits. The cytoplasmic domain of integrin beta-4 interacts with other hemidesmosomal components, plectrin and BPAG1. The interaction of a6b4 and plectrin is likely to be the initial step in HD formation (de Pereda et al. 2009). The cytoplasmic domain of collagen type XVII (BP180) binds to integrin beta-4, plectin and BPAG1 (Hopkinson & Jones 2000, Koster et al. 2003). The transmembrane protein CD151 (tetraspanin-24) associates with a6b4 (Sterk et al. 2002) and is essential for the correct assembly of basement membranes in human kidney and skin, possibly having a role in integrin alpha-3 maturation and cell surface expression (Karamatic Crew et al. 2003). Type X collagen associates with collagen type II fibrils Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 In vivo type X collagen is found associated with cartilage fibrils in the form of fine filaments (Schmidt & Linsenmayer 1990), which may represent hexagonal lattices that have collapsed during sample preparation (Gordon & Hahn 2010). Pubmed19693541 Pubmed2307289 Reactome Database ID Release 432213208 Reactome, http://www.reactome.org ReactomeREACT_150398 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Formation of histidino-hydroxylysinonorleucine cross-links Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Histidino-hydroxylysinonorleucine (HHL) cross-links, formed when deH-HLNL reacts with a histidine residue, have been identified in skin and cornea (Yamauchi et al. 1987, 1996, Okada et al. 1997). Pubmed3624221 Pubmed8604983 Pubmed9470928 Reactome Database ID Release 432243926 Reactome, http://www.reactome.org ReactomeREACT_150362 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Formation of hydroxylysyl-pyrrole cross-links Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed12211432 Pubmed1567360 Pubmed18442706 Pubmed9883973 Reactome Database ID Release 432395324 Reactome, http://www.reactome.org ReactomeREACT_150389 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Trivalent collagen cross-links can form as pyrroles. Hydroxylysyl-Pyrrole (HL-Pyrrole) is formed when Hydroxylysino-ketonorleucine (HLKNL) reacts with hydroxylysino-norleucine (deH-HLNL) (Eyre et al. 2008). The mechanism of pyrrole cross-links has been revised to a structure based on 3-hydroxypyrrole, rather than a pyrrole lacking a hydroxyl on the ring as depicted earlier (Bailey et al. 1998). Collagen XI cross-links with collagen II Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed10744725 Pubmed14602708 Pubmed17083085 Pubmed7642541 Pubmed7919525 Reactome Database ID Release 432299620 Reactome, http://www.reactome.org ReactomeREACT_150444 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Type XI collagen molecules are cross-linked by lysyl oxidase-mediated bonds (Wu & Eyre 1995) primarily in a head-to-tail manner (Eyre et al. 2006). Homopolymers of type XI collagen can form in vitro (Bruckner & van der Rest 1994, Blaschke et al. 2000). Type XI collagen molecules can cross-link with type II collagen forming heterofibrils (Eyre & Wu 2004, 2005). Formation of collagen fibres Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Fibrils are components of larger suprafibrillar structures, fibres. The organisation of fibrils varies between tissues; in the cornea fibrils are arranged in parallel within layers but layers have different orientations. In articular cartilage, fibrils are arranged in mostly parallel layers (Wess 2005). Interactions between fibrils are thought to be largely mediated by surface-associated macromolecules, such as anionic glycosaminoglycans (GAGs) and small leucine-rich proteoglycans such as decorin. ISBN978-3-642-16555-9 Pubmed15837520 Reactome Database ID Release 432213201 Reactome, http://www.reactome.org ReactomeREACT_150338 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Initial activation of proMMP3 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 ISBN0 19 850268 0 Pubmed1783204 Pubmed2383557 Pubmed3058116 Pubmed7826345 Reactome Database ID Release 431592371 Reactome, http://www.reactome.org ReactomeREACT_118776 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 proMMP3 is activated in a similar manner to pro MMP1 but by a large number of proteinases, including bacterial thermolysin, all cleaving within the region residues 51-56 (Woessner & Nagase 2000). This initiates autocatalysis and cleavage of the His99-Phe100 bond (Nagase et al. 1990, 1991). Residue numbering given here is based on the UniProt canonical sequence. MMP14:TIMP2 binds proMMP2 Authored: Jupe, S, 2011-09-09 Edited: Jupe, S, 2012-02-21 Pubmed10947989 Pubmed11325829 Pubmed12374789 Pubmed18974156 Pubmed9182583 Pubmed9422744 Pubmed9632662 Pubmed9685420 Pubmed9933646 Reactome Database ID Release 431604350 Reactome, http://www.reactome.org ReactomeREACT_118860 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 The MMP14:TIMP2 complex can efficiently bind proMMP2. Physiological concentrations of TIMP2 enhance proMMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that while MMP14:TIMP2 complexes bind proMMP2, local free MMP14 cleaves the TIMP-bound proMMP2 in the prodomain, leading to autoactivation between Asn109 Tyr110. In vivo the majority of MMP14 (MT1-MMP) is bound to TIMP2 and therefore functions as a receptor for proMMP2 (Nishida et al. 2008). Binding of TIMP-2 to proMMP2 occurs via interaction of the TIMP2 C domain (McQuibban et al. 2000) and the MMP2 hemopexin domain between hemopexin blades III and IV (Overall et al. 1999) in an interaction that is highly dependant upon the nature of the C-tail of the TIMP (Kai et al. 2002). TIMP-4 also binds the proMMP2 hemopexin domain (Bigg et al. 1997) to prevent activation by MMP14 (Bigg et al. 2001). An alternative cell surface localization mechanism exists that inhibits MMP2 activation: Cell surface Beta1 integrin binds native type I collagen, which in turn is bound by the fibronectin type II modules of MMP2 to prevent activation by MMP14 (Steffensen et al. 1998). MMP14 (MT1-MMP) binds TIMP2 Authored: Jupe, S, 2011-09-09 Edited: Jupe, S, 2012-02-21 MMP14 (MT1-MMP) binds tissue inhibitor of metalloproteinases 2 (TIMP2) and has been isolated as a complex from the plasma membrane of HT-1080 cells (Strongin et al. 1995). This complex in turn binds proMMP2 via an interaction of the C-termini of proMMP2 and TIMP2 (Itoh et al. 1998, Butler et al. 1998). Formation of this ternary complex is critical for the subsequent activation of proMMP2. Pubmed10947989 Pubmed10991943 Pubmed7890645 Pubmed9422744 Pubmed9733724 Reactome Database ID Release 431592349 Reactome, http://www.reactome.org ReactomeREACT_118709 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 proMMP9 binds TIMP1 Authored: Jupe, S, 2011-09-09 Edited: Jupe, S, 2012-02-21 ProMMP9 binds Tissue Inhibitor of Metalloproteinases 1 (TIMP1) (Wilheim et al. 1989). By homology with the binding of TIMP2 to the MMP2 hemopexin domain, TIMP1 is thought to binds via its C domain to the MMP9 hemopexin domain. This is a two-way potential regulatory mechanism as the interaction does not prevent the free N-terminal inhibitory domain of TIMP1 from inhibiting other MMPs (Murthpy et al. 1991) while it may prevent the activation of proMMP9. Pubmed1868085 Pubmed2551898 Reactome Database ID Release 431602454 Reactome, http://www.reactome.org ReactomeREACT_118611 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Full activation of MMP1 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed1480033 Pubmed1660474 Pubmed2169257 Pubmed2548603 Pubmed7896811 Pubmed7981201 Pubmed8340372 Reactome Database ID Release 431592297 Reactome, http://www.reactome.org ReactomeREACT_118610 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 The 42 kDa intermediate form of MMP1 is fully activated by cleavage of the Gln99-Phe100 bond, producing a 41 kDa protein. MMP2 (Crabbe et al. 1994), MMP3 (Suzuki et al. 1990, Nagase et al. 1992), MMP7 (Imai et al. 1995), MMP10 (Nicholson et al. 1989) and MMP11 (Murphy et al. 1993) are able to convert the 42 kDa intermediate to fully activated 41 kDa form though they are not able to initiate activation of proMMP1 effectively (Nagase et al. 1992). MMP3 regulates MMP1 collagenase activity in human rheumatoid synovial fibroblasts (Unemori et al. 1991). Autocatalytic activation of bound proMMP2 Authored: Jupe, S, 2011-09-09 Cleavage of the Asn66-Leu67 bond of MMP2 activates it sufficiently to allow autocleavage of the Asn109-Tyr110 bond (Okada et al. 1990, Strongin et al. 1993, Crabbe et al. 1994a, Atkinson et al. 1995, Sang et al. 1996). Residue numbering here refers to the UniProt canonical sequence. EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed2269296 Pubmed7981201 Pubmed8314771 Pubmed8530478 Pubmed8804571 Reactome Database ID Release 431604368 Reactome, http://www.reactome.org ReactomeREACT_118723 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Autocatalytic activation of proMMP2 Authored: Jupe, S, 2011-09-09 Cleaving the Asn66-Leu67 bond of MMP2 activates it sufficiently to allow autocleavage of the Asn109-Tyr110 bond (Okada et al. 1990, Strongin et al. 1993, Crabbe et al. 1994a, Atkinson et al. 1995, Sang et al. 1996). This activation is inhibited by endostatin (Nyberg et al. 2003). Residue numbering here refers to the UniProt canonical sequence. EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed12690120 Pubmed2269296 Pubmed7981201 Pubmed8314771 Pubmed8530478 Pubmed8804571 Reactome Database ID Release 431592278 Reactome, http://www.reactome.org ReactomeREACT_118573 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Initial activation of proMMP2 by MMP14 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 MMP2 is activated by the MT-MMPs MMP14 (Sato et al. 1994), MMP15 (Butler et al. 1997) and MMP16 (Takino et al. 1995). MMP14 (MT1-MMP) initially cleaves the Asn66-Leu67 bond of MMP2, followed by autocleavage of the Asn109-Tyr110 bond (Strongin et al. 1993, Atkinson et al. 1995). Residue numbering here refers to the UniProt canonical sequence.<br><br>MMP2 processing by MMP14 or MMP16 is very inefficient unless the MT-MMP has pre-bound TIMP2, which in turn binds MMP2. Physiological concentrations of TIMP2 enhance MMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that MT-MMP:TIMP2 complexes bind MMP2, but local free MT-MMP subsequently cleaves the TIMP-bound proMMP2. In vivo the majority of MMP14 is bound to TIMP2 and functions as a receptor for proMMP2 (Nishida et al. 2008). In contrast, activation of proMMP2 by MMP15 occurs in a TIMP independent manner, with TIMP2 inhibiting activation at all concentrations (Morrison et al. 2001). Native type I collagen binds to the hemopexin C domain of MMP14, and following clustering of the enzyme together enhances proMMP2 activation (Tam et al. 2002). However, proMMP2 also binds the cell via cell surface Beta1 integrin, which binds native type I collagen which in turn is bound by the fibronectin type II modules of MMP2, preventing activation by MMP14 (Steffensen et al. 1998). ConA is the only known stimulator of cells to induce proMMP2 activation by MMP14 (Overall & Sodek 1990). Pubmed11584019 Pubmed12145314 Pubmed18974156 Pubmed2174435 Pubmed7559440 Pubmed8015608 Pubmed8314771 Pubmed8530478 Pubmed9119036 Pubmed9422744 Pubmed9632662 Pubmed9685420 Reactome Database ID Release 431604360 Reactome, http://www.reactome.org ReactomeREACT_118593 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Initial activation of proMMP2 by MMP1, 7 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 MMP2 can be activated by MMP1 (Crabbe et al. 1994a, Sang et al. 1996) and MMP7 (Crabbe et al. 1994b, Sang et al. 1996). MMP1 initially cleaves either Pro33-Ile34 or Asn66-Leu67. This is followed by autolytic cleavage at Asn109-Tyr110 (Crabbe et al. 1994a, Okada et al. 1990, Sang et al. 1996). MMP1 and MMP7 are not efficient activators of MMP2; significant physiological activation of proMMP2 is performed by the MT-MMPs MMP14 (Sato et al. 1994), MMP15 (Butler et al. 1997, Morrison et al. 2001) and MMP16 (Takino et al. 1995). Residue numbering here refers to the UniProt canonical sequence. Pubmed11584019 Pubmed2269296 Pubmed7559440 Pubmed7981201 Pubmed8015608 Pubmed8194591 Pubmed8804571 Pubmed9119036 Reactome Database ID Release 431604359 Reactome, http://www.reactome.org ReactomeREACT_118726 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Autocatalytic activation of MMP1 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Following initiating proteolytic cleavage by serine proteases the Cys92-Zn2+ bond is destabilized allowing autocleavage at Thr83-Leu84, generating a 42 kDa active form of MMP1 with about 20% of the activity of the 41 kDa form (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100. Pubmed2176865 Reactome Database ID Release 431602473 Reactome, http://www.reactome.org ReactomeREACT_118790 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Autocatalytic activation of MMP7 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Once cleaved at Lys50-Asn51 MMP7 undergoes autocatalysis (Crabbe et al. 1992). Highly sulfated glycosaminoglycans (GAG), such as heparin, chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhance (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin (Ra et al. 2009). Pubmed1390635 Pubmed19654318 Reactome Database ID Release 431604763 Reactome, http://www.reactome.org ReactomeREACT_118658 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Initial activation of proMMP7 by trypsin Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed1390635 Pubmed19654318 Reactome Database ID Release 431604712 Reactome, http://www.reactome.org ReactomeREACT_118565 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 proMMP7 (proMatrilysin-1) activation by trypsin occurs via an intermediate cleaved at Lys50-Asn51 which undergoes autocatalysis (Crabbe et al. 1992). Leukocyte elastase and plasmin partially activate MMP7 by an uncharacterized mechanism. Highly sulfated glycosaminoglycans (GAG), such as heparin, chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhance (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin (Ra et al. 2009). Initial activation of proMMP9 by MMPs Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 MMP1 (Sang et al. 1995), MMP2 (Fridman et al. 1995), MMP3 (Goldberg et al. 1992, Ogata et al. 1992, Okada et al. 1992), MMP7 (Imai et al. 1995, Sang et al. 1995), MMP10 (Nakamura et al. 1998) and MMP13 (Knauper et al. 1997) activate MMP9 by a stepwise mechanism but the second cleavage is apparently not an autocatalytic event as is the case for MMP1 (Okada et al. 1992). The first site is the Glu59-Met60 bond, generating an inactive 85-86 kDa intermediate (O'Connell et al. 1994), followed by cleavage of the Arg106-Phe107 peptide bond producing the fullly active 82 kDa form of MMP9 (Okada et al. 1992, Fridman et al. 1995). Pubmed1311314 Pubmed1371271 Pubmed1400481 Pubmed7669817 Pubmed7780967 Pubmed7896811 Pubmed8195131 Pubmed9346290 Pubmed9578462 Reactome Database ID Release 431592436 Reactome, http://www.reactome.org ReactomeREACT_118800 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Activation of proMMP8 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed2159879 Pubmed2546891 Reactome Database ID Release 431592398 Reactome, http://www.reactome.org ReactomeREACT_118600 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 proMMP8 is activated by tissue kallikrein, leukocyte elastase, trypsin and cathepsin G (Capodici et al. 1989, Knauper et al. 1990) probably at the predicted bait region, residues 30-36. Activation of proMMP9 by proteases Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed12690120 Pubmed2557753 Pubmed4216367 Pubmed6263256 Pubmed8253870 Pubmed9261109 Reactome Database ID Release 431604722 Reactome, http://www.reactome.org ReactomeREACT_118561 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 proMMP9 can be activated by trypsin and chymotrypsin (Sopata & Dancewicz 1974), tissue kallikrein (Tschesche et al. 1989, Desrivieres et al. 1993), cathepsin G (Murphy et al. 1980), and trypsin-2 (Sorsa et al. 1997). This appears to be a one-step activation; the single peptide bond cleaved by trypsin-2 in proMMP-9 is Arg106-Phe107. Modes of activation by other proteases are unclear. Activation is inhibited by endostatin (Nyberg et al. 2003). Activation of MMP9 intermediate form by MMPs Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed1371271 Pubmed7780967 Reactome Database ID Release 431604690 Reactome, http://www.reactome.org ReactomeREACT_118742 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 The intermediate form of MMP9 is activated by cleavage of the Arg106-Phe107 peptide bond producing the fullly active 82-kDa MMP-9 species (Ogata et al. 1992, Fridman et al. 1995). Activation of proMMP11 by FURIN Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed7746327 Pubmed8645182 Reactome Database ID Release 431602484 Reactome, http://www.reactome.org ReactomeREACT_118812 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 proMMP11 has a furin recognition sequence and is activated by furin in the Golgi (Pei & Weiss 1996, Santavicca et al. 1996). Activation of proMMP10 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 ISBN0 19 850268 0 Reactome Database ID Release 431602458 Reactome, http://www.reactome.org ReactomeREACT_118769 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 proMMP10 is similar in sequence to proMMP3 with just one residue difference in the bait region. The activation mechanism is believed to be similar, namely cleavage in the N-terminal bait region, followed by autocatalytic cleavage at His81-Phe82 (Woessner & Nagasse 2000). proMMP10 is activated by plasmin, trypsin and chymotrypsin. Activation of proMMP7 by MMP3 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 MMP3 activates MMP7 by cleavage of Glu94-Tyr95 (Imai et al. 1997). Pubmed7896811 Reactome Database ID Release 431592362 Reactome, http://www.reactome.org ReactomeREACT_118765 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Autocatalytic activation of MMP3 After the initial cleavage of the N-terminus, MMP3 undergoes autocatalysis and cleavage of the His99-Phe100 bond (Nagase et al. 1990, 1991). Residue numbering given here is based on the UniProt canonical sequence. Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed1783204 Pubmed2383557 Reactome Database ID Release 431604731 Reactome, http://www.reactome.org ReactomeREACT_118625 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Integrin alpha6:beta4:Plectin:BP180 complex Reactome DB_ID: 445993 Reactome Database ID Release 43445993 Reactome, http://www.reactome.org ReactomeREACT_21046 has a Stoichiometric coefficient of 1 Integrin alpha 6:beta 4:Plectin:BP180:Laminin-322 complex Reactome DB_ID: 445997 Reactome Database ID Release 43445997 Reactome, http://www.reactome.org ReactomeREACT_20915 has a Stoichiometric coefficient of 1 Laminin-5 Laminin-332 Reactome DB_ID: 216001 Reactome Database ID Release 43216001 Reactome, http://www.reactome.org ReactomeREACT_14602 has a Stoichiometric coefficient of 1 CD151:BP230:BP180:Plectin:Integrin alpha 6 beta 4: Laminin Reactome DB_ID: 446066 Reactome Database ID Release 43446066 Reactome, http://www.reactome.org ReactomeREACT_21118 has a Stoichiometric coefficient of 1 BP230:BP180:Plectin:integrin alpha 6 beta 4:Laminin 332 Reactome DB_ID: 446010 Reactome Database ID Release 43446010 Reactome, http://www.reactome.org ReactomeREACT_20979 has a Stoichiometric coefficient of 1 SIRP alpha:CD47 Reactome DB_ID: 391111 Reactome Database ID Release 43391111 Reactome, http://www.reactome.org ReactomeREACT_24285 has a Stoichiometric coefficient of 1 Type II hemidesmosome Reactome DB_ID: 446086 Reactome Database ID Release 43446086 Reactome, http://www.reactome.org ReactomeREACT_20848 has a Stoichiometric coefficient of 1 SHP2/SHP1:pSIRP alpha:CD47 Reactome DB_ID: 391110 Reactome Database ID Release 43391110 Reactome, http://www.reactome.org ReactomeREACT_24824 has a Stoichiometric coefficient of 1 pSIRP alpha:CD47 Reactome DB_ID: 391115 Reactome Database ID Release 43391115 Reactome, http://www.reactome.org ReactomeREACT_24659 has a Stoichiometric coefficient of 1 pSIRP alpha:CD47:SCAP2 Reactome DB_ID: 391118 Reactome Database ID Release 43391118 Reactome, http://www.reactome.org ReactomeREACT_24452 has a Stoichiometric coefficient of 1 Collagen type II degradation by MMP14 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed8999957 Reactome Database ID Release 431474196 Reactome, http://www.reactome.org ReactomeREACT_150221 Reviewed: Sorsa, Timo, 2012-10-08 The membrane-type MMP MMP14 (MT1-MMP) is a fibrillar collagenase. MMP14 is able to degrade collagen types I, II and III (Ohuchi et al. 1997). Collagen type VII degradation by MMP1,2,3 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed10652000 Pubmed1704217 Pubmed2537292 Reactome Database ID Release 431564120 Reactome, http://www.reactome.org ReactomeREACT_150453 Reviewed: Sorsa, Timo, 2012-10-08 Type VII collagen is the major collagen component of anchoring fibrils, which are essential for the attachment of the epidermis to the dermis. It is degraded by MMP1 (Seltzer et al. 1989), MMP2 (Seltzer et al. 1989, Sawamura et al. 1991, Karelina et al. 2000) and MMP3 (Sawamura et al. 1991). MMP2 is 3000-fold more active than MMP1 (Seltzer et al. 1989). Collagen type III degradation by MMP10 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 MMP10 (Stromelysin-2) is able to degrade collagen type III (Nicholson et al. 1989). Pubmed2548603 Reactome Database ID Release 432485111 Reactome, http://www.reactome.org ReactomeREACT_150170 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type III degradation by MMP14 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed8999957 Reactome Database ID Release 431474210 Reactome, http://www.reactome.org ReactomeREACT_150213 Reviewed: Sorsa, Timo, 2012-10-08 The membrane-type MMP MMP14 (MT1-MMP) is a fibrillar collagenase able to degrade collagen types I, II and III (Ohuchi et al. 1997). Collagen type II degradation by MMP15 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed12801404 Pubmed16825197 Pubmed8999957 Reactome Database ID Release 432473594 Reactome, http://www.reactome.org ReactomeREACT_150211 Reviewed: Sorsa, Timo, 2012-10-08 The membrane-type MMP MMP15 (MT2-MMP) is a fibrillar collagenase. MMP15 is able to degrade collagen type I (Morrison & Overall 2006) and believed able to degrade types II and III (Somerville et al. 2003). Collagen type III degradation by MMP1,8,9,13 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996, Mitchell et al. 1996), called collagenases I, II and III respectively, are all able to cleave the intrahelical bonds of collagen type III, cleaving between amino acids Gly948 and Ile949 of the Uniprot canonical sequence. MMP9 (Bigg et al. Veidal et al. 2010) and MMP10 (Stromelysin-2) are able to degrade collagen type III (Nicholson et al. 1989). Pubmed15257288 Pubmed17298441 Pubmed20666994 Pubmed2548603 Pubmed3038863 Pubmed6270089 Pubmed8576151 Pubmed8609233 Pubmed8999957 Reactome Database ID Release 431474213 Reactome, http://www.reactome.org ReactomeREACT_150222 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type V degradation by MMP2,9,10 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed10796876 Pubmed14623400 Pubmed15383546 Pubmed22382088 Pubmed2548603 Pubmed3346334 Pubmed6285893 Pubmed7041891 Pubmed8037728 Pubmed8305481 Pubmed8314909 Pubmed9425231 Reactome Database ID Release 431564164 Reactome, http://www.reactome.org ReactomeREACT_150374 Reviewed: Sorsa, Timo, 2012-10-08 Type V collagen is a fibril-forming collagen forming a group with collagen types I, II, III and XI (Gelse et al. 2003). Three different alpha chains exist that can combine in three distinct trimers. Collagen V forms fibrils that are associated with type I and to a lesser extent III collagen, as a minor but critical component of bone matrix, corneal stroma and the interstitial matrix of muscle, liver, lung and placenta (Birk et al. 1988). COL5A1-/- mice have an almost complete lack of collagen fibrils reflecting a central role in fibrillogenesis (Wenstrup et al. 2004). Type V collagen mutation results in a range of connective tissue diseases including Ehlers-Danlos syndrome (EDS), which is a heterogeneous group of disorders characterized by joint hypermobility and skin hyperextensibility, thinness and fragility. These result from mutations in the COL5A1 and COL5A2 genes (Michalickova et al. 1998, Schwarze et al. 2000). Type V collagen is digested by MMP2 (Murphy et al. 1981, Veidal et al. 2011), MMP10 (Nicholson et al. 1989), and MMP9 (Murphy et al. 1982, Watanabe et al. 1993, Pourmotabbed et al. 1994, Niyibizi et al. 1994, Veidal et al. 2011). Collagen type VI degradation by MMP2,9,11 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed14623400 Pubmed1544908 Pubmed18622425 Pubmed21935455 Pubmed6432530 Pubmed8862926 Pubmed9183676 Pubmed9334230 Reactome Database ID Release 431564112 Reactome, http://www.reactome.org ReactomeREACT_150235 Reviewed: Sorsa, Timo, 2012-10-08 Type VI collagen aggregates into distinctive microfibrils known as beaded filaments that form an independent microfibrillar network in virtually all connective tissues except for bone (von der Mark et al. 1984). It plays a role in the maintenance of tissue integrity since it participates in both cell-matrix and matrix-matrix interactions, interacting with many other ECM proteins including fibronectin (Chang et al. 1997), type IV collagen (Kuo et al. 1997), type II collagen, decorin and biglycan (Bidanset et al. 1992). Collagen type VI has been described as a connecting protein (Gelse et al. 2003). <br><br>Collagen type VI is resistant to digestion by many MMPs but is cleaved by MMP2 (Myint et al. 1996, Veidal et al. 2011), MMP9 (Veidal et al. 2011) and MMP11 (Motrescu et al. 2008). Collagen type III degradation by MMP15 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed12801404 Pubmed16825197 Reactome Database ID Release 432473584 Reactome, http://www.reactome.org ReactomeREACT_150439 Reviewed: Sorsa, Timo, 2012-10-08 The membrane-type MMP MMP15 (MT2-MMP) is a fibrillar collagenase able to degrade collagen type I (Morrison & Overall 2006) and believed able to degrade collagen types II and III (Somerville et al. 2002). Collagen type IV degradation by MMP2,3,4,9,10,12 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed11025665 Pubmed11375996 Pubmed1379048 Pubmed1649600 Pubmed17088321 Pubmed2169335 Pubmed2253219 Pubmed2430974 Pubmed2548603 Pubmed3095317 Pubmed3223920 Pubmed3477804 Pubmed3997977 Pubmed6258630 Pubmed6298220 Pubmed8314909 Pubmed8920930 Reactome Database ID Release 431564142 Reactome, http://www.reactome.org ReactomeREACT_150293 Reviewed: Sorsa, Timo, 2012-10-08 Type IV collagen is the most abundant structural basement membrane (BM) component, providing a scaffold for other major BM proteins such as laminin (Charonis et al. 1985, 1986). There are six different genes encoding type IV collagen chains, alpha-1 to alpha-6(IV) with distinct tissue distributions. Three alpha chains fold to form the triple helical unit of collagen IV. Three chain combinations have been identified, alpha-1X2 alpha-2(IV), alpha-3,alpha-4, alpha-5(IV) and alpha-5X2, alpha-6(IV) (Borza et al. 2001). The first is the major form, found in all basement membranes, the other types have more restricted distributions. <br><br>Collagen IV forms a lattice network rather than extended fibrils. It can be digested by MMP2 (Liotta et al. 1981, Salo et al. 1983, Bergers et al. 2000, Monaco et al. 2006), MMP3 (Okada et al. 1986, Wilhelm et al. 1987, Bejarano et al. 1988, Nicholson et al. 1989), MMP7 (Miyazaki et al. 1990, Murphy et al. 1991), MMP9 (Moll et al. 1990, Morodomi et al. 1992, Murphy et al. 1991, Watanabe et al. 1993, Bergers et al. 2000), MMP10 (Nicholson et al. 1989) and MMP12 (Chandler et al. 1996). Collagen type I degradation by MMP15 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed12801404 Pubmed16825197 Reactome Database ID Release 432473596 Reactome, http://www.reactome.org ReactomeREACT_150199 Reviewed: Sorsa, Timo, 2012-10-08 The membrane-type MMP MMP15 (MT2-MMP) is a fibrillar collagenase able to degrade collagen type I (Morrison and Overall 2006) and believed able to degrade types II and III (Somerville et al. 2003). Collagen type II degradation by MMP1,3,8,13,PRSS2 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996, Mitchell et al. 1996, Billinghurst et al. 1997) known in the literature as collagenases I, II and III respectively are able to digest the intrahelical bonds of collagen type II, cleaving between amino acids Gly975 and Leu976 of the Uniprot canonical sequence. Human trypsin-2 is also capable of cleaving the triple helix of human cartilage collagen type II (Stenman et al. 2005). Pubmed16192646 Pubmed2005102 Pubmed3038863 Pubmed6270089 Pubmed8576151 Pubmed8609233 Pubmed9119997 Reactome Database ID Release 431474197 Reactome, http://www.reactome.org ReactomeREACT_150223 Reviewed: Sorsa, Timo, 2012-10-08 Initial activation of proMMP13 by plasmin and trypsin Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed8663255 Reactome Database ID Release 431602488 Reactome, http://www.reactome.org ReactomeREACT_118634 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 proMMP13 can be activated by plasmin and trypsin initially cleaving at Lys57-Glu58 followed by autoproteolysis at Glu103-Tyr104 (Knauper et al. 1996a). Initial activation of proMMP13 by MMP3 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 MMP3 initially cleaves proMMP13 at Gly76-Leu77 followed by autoprocessing at Glu103-Tyr104 (Knauper et al. 1996). Pubmed8576151 Reactome Database ID Release 431604752 Reactome, http://www.reactome.org ReactomeREACT_118681 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Initial activation of proMMP13 by MMP14 (MT1-MMP) Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 MMP14 (MT1-MMP) initially cleaves MMP13 at Gly54-Ile55 (Knauper et al. 1996a, 1996b) followed by autoprocessing at Glu103-Tyr104. Pubmed8663255 Reactome Database ID Release 431604741 Reactome, http://www.reactome.org ReactomeREACT_118861 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 Autocatalytic activation of proMMP13 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Following initial activation autoproteolysis occurs at Glu103-Tyr104 (Knauper et al. 1996a,1996b). This is inhibited by endostatin (Nyberg et al. 2003). Pubmed12690120 Pubmed8576151 Pubmed8663255 Reactome Database ID Release 431604732 Reactome, http://www.reactome.org ReactomeREACT_118628 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 has a Stoichiometric coefficient of 3 Activation of MT-MMPs by FURIN Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 Pubmed10567400 Pubmed10888676 Pubmed11830519 Pubmed16103082 Pubmed22367194 Pubmed8621565 Pubmed8804434 Reactome Database ID Release 431602466 Reactome, http://www.reactome.org ReactomeREACT_118665 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 The membrane-type MMPs (MT-MMPs) MMP14 (MT1-MMP) (Pei et al. 1996, Sato et al. 1996) and MMP16 (MT3-MMP) (Kang et al. 2002) are processed to an active form by furin (Yana & Weiss 2000) and PACE4 (Bassi et al. 2005) within the golgi before secretion. The other MT-MMPs MMP15 (MT2-MMP), MMP17 (MT4-MMP) (Itoh et al. 1999), MMP24 (MT5-MMP) and MMP25 (MT6-MMP) (Starr et al. 2012) are believed to undergo similar processing before membrane association. MT-MMPs are sorted to the plasma membrane Authored: Jupe, S, 2011-09-09 Edited: Jupe, S, 2012-02-21 Pubmed10036228 Pubmed11773076 Pubmed11830519 Pubmed8621565 Pubmed8804434 Reactome Database ID Release 431605825 Reactome, http://www.reactome.org ReactomeREACT_118753 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 The process that targets activated MT-MMPs to the plasma membrane is unclear but presumed to involve standard golgi transport mechanisms. The cytoplasmic domain of MT1-MMP is critical for the localization to discrete regions of the cell surface (Urena et al. 1999) and involved in internalization which has a regulatory role. The cytoplasmic domain mediates interactions with specific cell-surface proteins such as C1Q binding protein which may serve to direct the MMP from the golgi to the cell surface (Rozanov et al. 2002). Collagen type I degradation by MMP1,2,8,13, PRSS2 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996) known in the literature as collagenases I, II and III respectively are able to digest the intrahelical bonds of collagen type I. MMP2, also known as Gelatinase-A, was found to cleave collagen type I fibrils (Aimes & Quigley 1995). Though this was disputed (Seltzre & Eisen 1999) there is a structural explanation for the apparent discrepancies in experimental data (Patterson et al. 2001). In addition trypsin-2 is able to degrade native soluble type I collagen (Moilanen et al. 2003). Degradation is represented here at a theoretical end point where every alpha strand has been cleaved. Pubmed10383752 Pubmed11513874 Pubmed12731883 Pubmed15257288 Pubmed3038863 Pubmed6270089 Pubmed7790374 Pubmed7890717 Pubmed8576151 Reactome Database ID Release 431454822 Reactome, http://www.reactome.org ReactomeREACT_150397 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type I degradation by MMP14 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed8999957 Reactome Database ID Release 431458433 Reactome, http://www.reactome.org ReactomeREACT_150364 Reviewed: Sorsa, Timo, 2012-10-08 The membrane-type MMP MMP14 (MT1-MMP) is a fibrillar collagenase able to degrade collagen types I, II and III (Ohuchi et al. 1997). Collagen type XVII ectodomain shedding Authored: Jupe, S, 2011-07-12 Collagen type XVII, identified as the 180-kDa bullous pemphigoid antigen or BP180, is a transmembrane protein forming a family with collagen type XIII. It is an important structural component of hemidesmosomes, complexes found in the dermal-epidermal basement membrane zone that mediate adhesion of keratinocytes to the underlying membrane (Franzke et al. 2005). The intracellular ligands of collagen XVII include Beta 4-integrins, plectin and BP230 in the hemidesmosomal plaque (Koster et al. 2003). Extracellular ligands include alpha 6-integrin and laminin-5 in anchoring filaments (Hopkinson et al. 1995, Tasanen et al. 2004). Mutations in the human collagen XVII gene COL17A1 lead to diminished epidermal adhesion and skin blistering in response to minimal shearing forces, a disorder called junctional epidermolysis bullosa (JEB).<br><br>A soluble ectodomain form of collagen type XVII referred to as LAD-1 is generated by proteolytic processing of the full length form (Hirako et al. 1988, Schäcke et al. 1998). Collagen XVII has a furin consensus sequence but is cleaved by proteinases of the ADAM family rather than furin convertases. ADAM-17 (TACE) appears to be the major physiologically-relevant sheddase for collagen XVII, though ADAM-9 and -10 may substitute (Franzke et al. 2002). These proteinases are activated by furin (Franzke et al. 2005). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed12356719 Pubmed12482924 Pubmed15161638 Pubmed15561712 Pubmed7790367 Pubmed9545306 Pubmed9748270 Reactome Database ID Release 432168960 Reactome, http://www.reactome.org ReactomeREACT_150324 Reviewed: Sorsa, Timo, 2012-10-08 has a Stoichiometric coefficient of 3 Collagen type XIII ectodomain shedding Authored: Jupe, S, 2011-07-12 Edited: Jupe, S, 2012-11-12 Pubmed10713152 Pubmed10722741 Pubmed11013208 Pubmed11223332 Pubmed11956183 Pubmed15005656 Pubmed16091016 Pubmed20844119 Pubmed9624150 Reactome Database ID Release 432167942 Reactome, http://www.reactome.org ReactomeREACT_150341 Reviewed: Sorsa, Timo, 2012-10-08 Type XIII is a non-fibril-forming type II transmembrane protein with a large amino terminal NC1 domain. This domain has a hydrophobic membrane-spanning segment that anchors the molecule to the plasma membrane and a large extracellular, mostly collagenous carboxyterminal domain (Hägg et al. 1998). Recombinant type XIII collagen can form homotrimers with triple-helical collagenous domains (Snellman et al. 2000a). It is detected at low levels in all connective tissue-producing cells; in cultured cells it is localized in focal adhesions (Hägg et al. 2001). The extracellular region has an adhesion-related function (Hägg et al. 2001) that is involved in formation of the neuromuscular junction (Latvanlehto et al. 2010). The purified protein has been shown to interact with Integrin alpha1beta1 (Nykvist et al. 2000). An N-terminal ectodomain portion of type XIII collagen is cleaved in culture medium by a furin-like protease (Snellman et al. 2000b, Väisänen et al. 2004). This ectodomain interacts with fibronectin, nidogen-2 and perlecan (Tu et al. 2002, Väisänen et al. 2006). has a Stoichiometric coefficient of 3 Collagen type XVIII endostatin release Authored: Jupe, S, 2011-07-12 Collagen type XVIII is a heparan sulfate proteoglycan associated with the basement membranes of almost all epithelia and endothelia. It has a large C-terminal noncollagenous domain. Mouse knockouts suggest that it may have a role in maintaining the structural integrity of the extracellular matrix (Utriainen et al. 2004). <br><br>Proteolytic cleavage of the C-terminal noncollagenous domain by matrix metalloproteinases (Heljasvaara et al. 2005) releases 18 to 38 kDa C-terminal proteolytic fragments, collectively named endostatin. They have anti-angiogenic activity (O'Reilly et al. 1997, Ständker et al. 1997) and suppress primary tumor and metastasis growth in experimental animal models (Ortega & Werb 2002). It is not clear whether this collagen subtype forms supramolecular assemblies (Myllyharju & Kivirikko, 2004) but thought likely, via a similar mechanism to the related collagen XV (Hurskainen et al. 2010).<br><br>Endostatin-like fragments are released from collagen type XVIII by MMP 7 (Lin et al. 2001), 3, 9, 12, 13 (Ferreras et al. 2000) and 20 (Heljasvaara et al. 2005). Several cathepsins and elastase can bring about endostatin release (Ferreras et al. 2000, Felbor et al. 2000). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed10716919 Pubmed11119712 Pubmed11581192 Pubmed12376553 Pubmed14698617 Pubmed15254016 Pubmed15950618 Pubmed20040604 Pubmed9008168 Pubmed9459295 Reactome Database ID Release 432168923 Reactome, http://www.reactome.org ReactomeREACT_150437 Reviewed: Sorsa, Timo, 2012-10-08 Tropoelastin forms aggregate globules Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed15172035 Pubmed16192266 Pubmed16906757 Pubmed21081222 Reactome Database ID Release 432161293 Reactome, http://www.reactome.org ReactomeREACT_150175 Reviewed: Muiznieks, Lisa, 2012-11-02 The core protein representing ~90% of the mass of elastic fibres is elastin, a highly insoluble protein. It is secreted as soluble protein monomers referred to as tropoelastin, which have alternating hydrophobic and cross linking domains. The self-assembly of tropoelastin into a fibrillar elastin matrix is a multi step process. The first step is the self-association of secreted monomers via hydrophobic domains, in a process known as coacervation. This process concentrates monomers and may align residues in the correct register for subsequent cross linking (Yeo et al. 2011). Under physiological conditions the ~15 nm monomers phase-separate and coalesce into spherical packages 2-6 micrometers in diameter (Clarke et al. 2006, Kozel et al. 2004). This process is represented here by the association of an arbitrary 10 tropoelastin monomers. While they grow, coacervate packages are tethered to the cell surface. The binding interactions between tropoelastin and the cell surface are not fully understood but possible partners include integrins and glycosaminoglycans (Broekelmann et al. 2005). Extracellular fibrillin microfibrils act as a scaffold for the deposition of tropoelastin globules as part of elastic fibre formation (Kozel et al. 2004). has a Stoichiometric coefficient of 10 Fibrillin microfibril assembly Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Fibrillin microfibril assembly is a cell regulated process, independent of tropoelastin. Distinct microfibril populations have been identified, suggesting that the cellular environment plays a role in regulating microfibril fate (Kielty et al. 2002). Fibrillin 1 may undergo limited assembly into dimers or trimers in the secretory pathway (Ashworth et al. 1999, Trask et al. 1999) but the formation of large microfibril polymers is extracellular. Microfibrils assemble close to the cell surface in a process that may require cell surface receptors. Fibrillins interact with several integrins (Sakamoto et al. 1996, Jovanovic et al. 2008) suggesting an assembly mechanism with similarities to fibronectin matrix formation. Heparan sulphate proteoglycans (HSPGs) and chondroitin sulfate containing proteoglycans (CSPGs) have also been proposed to have a role in assembly (Tiedemann et al. 2001). Fibrillin polymerization into fibres further requires the formation of disulfide bonds between fibrillins (Reinhardt et al. 2000), initially via calcium-binding epidermal growth factor domains at the C-terminus (Hubmacher et al. 2008), and transglutaminase cross-links (Kielty et al. 2002). Pubmed10359653 Pubmed10504303 Pubmed10636927 Pubmed10936461 Pubmed11461921 Pubmed12082143 Pubmed18363569 Pubmed18448684 Pubmed8617764 Reactome Database ID Release 432129362 Reactome, http://www.reactome.org ReactomeREACT_150349 Reviewed: Muiznieks, Lisa, 2012-11-02 MFAP2, MFAP5 bind microfibrils Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Microfibrils are composed largely of fibrillin but also contain covalently-linked microfibril associated glycoproteins MAGP-1 (MFAP2) and MAGP-2 (MFAP5). MFAP2 is a structural component of almost all vertebrate microfibrils (Gibson et al. 1989, Trask et al. 2000, Jensen et al. 2001). It appears to be important for tissue development and/or homeostasis, including regulation of bone remodelling and deposition of tissue fat (Weinbaum et al. 2008). The C-terminal half of MFAP2 is rich in cysteines and contains a matrix-binding domain that facilitates interactions with fibrillin (Weinbaum et al. 2008). The related MFAP5 similarly binds to microfibrils (Gibson et al. 1998) but with a restricted expression profile. Pubmed10793130 Pubmed11481325 Pubmed18625713 Pubmed2647740 Pubmed9671438 Reactome Database ID Release 432129385 Reactome, http://www.reactome.org ReactomeREACT_150448 Reviewed: Muiznieks, Lisa, 2012-11-02 Fibrillin C-terminal processing Authored: Jupe, S, 2012-04-30 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Extracellular deposition of fibrillin requires removal of the C-terminus, which can be cleaved in vitro by several furin/PACE family convertases (Raghunath et al. 1999, Ritty et al. 1999) in a process that is inhibited by N-glycosylation and calreticulin (Ashworth et al. 1999). Furin (PACE) is a transmembrane protein, synthesized as a 100 kDa protein, which rapidly undergoes autocatalytic cleavage to a 94 kDa protein in the endoplasmic reticulum (ER). The propeptide remains bound as an auto-inhibitor. Propeptide release occurs in the acidic pH of the trans-golgi-network (TGN)/endosomal compartment, activating furin. Though furin is primarily localized to the TGN a proportion of furin molecules are found on the cell surface (Teuchert et al. 1999). Profibrillin-1 processing does not occur in the TGN, where it is bound by two ER-resident molecular chaperones, BiP and GRP94. Instead activation by furin occurs as profibrillin-1 is secreted, or immediately after secretion (Wallis et al. 2003). Pubmed10085138 Pubmed10198291 Pubmed10547375 Pubmed10593987 Pubmed14523997 Reactome Database ID Release 432129357 Reactome, http://www.reactome.org ReactomeREACT_150177 Reviewed: Muiznieks, Lisa, 2012-11-02 Fibrillin-1 binds integrins Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Fibrillin-1 splice variants that include the RGD sequence located in the fourth 8-cysteine domain mediate cell adhesion, binding integrin alphaVbeta3 (Pfaff et al. 1996), alpha5beta1 (Bax et al. 2003) and alphaVbeta6 (Jovanovic et al. 2008). AlphaVbeta3 has the highest affinity for fibrillin-1. Pubmed12807887 Pubmed18363569 Pubmed8617364 Reactome Database ID Release 432328037 Reactome, http://www.reactome.org ReactomeREACT_150256 Reviewed: Muiznieks, Lisa, 2012-11-02 Collagen type XXIII ectodomain shedding Authored: Jupe, S, 2011-07-12 Collagen type XXIII is a type II transmembrane collagen with a relatively small ectodomain. It exists in a membrane-bound form and a shed form, cleaved by furin (Veit et al. 2007). Both forms can bind alpha2beta1 integrin via the ectodomain, stimulating the formation of focal adhesion plaques (Veit et al. 2011). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed17627939 Pubmed21652699 Reactome Database ID Release 432172405 Reactome, http://www.reactome.org ReactomeREACT_150339 Reviewed: Sorsa, Timo, 2012-10-08 has a Stoichiometric coefficient of 3 Collagen type XXV ectomain shedding Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Identified as a component of amyloid plaques in Alzheimer's brain, the ectodomain of type XXV collagen (known as CLAC) is released by furin convertase activity (Hashimoto et al. 2002). The presence of CLAC leads to Abeta fibril bundles that have an increased resistance to proteases (Söderberg et al. 2005). Pubmed11927537 Pubmed15615705 Pubmed15853808 Reactome Database ID Release 432471842 Reactome, http://www.reactome.org ReactomeREACT_150355 Reviewed: Sorsa, Timo, 2012-10-08 has a Stoichiometric coefficient of 3 Collagen type VIII degradation by ELANE Authored: Jupe, S, 2011-07-12 Collagen type VIII is a short chain, network-forming collagen,thought to play a role in tissue remodeling and repair (Shuttleworth 1997, Weitkamp et al. 1999). There are two alpha chain subtypes, found in a ratio of two alpha-1 to one alpha-2 chains (Mann et al. 1990) in the typical collagen heterotrimer. Studies suggest that type VIII collagen is a major component of the hexagonal lattice seen in Descemet’s membrane (Mann et al. 1990). Mutations in both alpha chains have been associated with Fuchs endothelial corneal dystrophy (FECD), a degenerative disease of the corneal endothelium (Jun et al. 2012). Collagen type VIII can be degraded by neutrophil elastase (ELANE, ELA2; Kittelberger et al. 1992). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed10428768 Pubmed1515454 Pubmed22002996 Pubmed2226849 Pubmed9438378 Reactome Database ID Release 432482180 Reactome, http://www.reactome.org ReactomeREACT_150332 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type VIII degradation by MMP1 Authored: Jupe, S, 2011-07-12 Collagen type VIII is a short chain, network-forming collagen,thought to play a role in tissue remodeling and repair (Shuttleworth 1997, Weitkamp et al. 1999). There are two alpha chain subtypes, found in a ratio of two alpha-1 to one alpha-2 chains (Mann et al. 1990) in the typical collagen heterotrimer. Studies suggest that type VIII collagen is a major component of the hexagonal lattice seen in Descemet's membrane (Mann et al. 1990). Mutations in both alpha chains have been associated with Fuchs endothelial corneal dystrophy (FECD), a degenerative disease of the corneal endothelium (Jun et al. 2012).<br><br> Collagen type VIII can be degraded by MMP1 (Sage et al. 1983, 1984). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed10428768 Pubmed22002996 Pubmed2226849 Pubmed6630235 Pubmed6694361 Pubmed9438378 Reactome Database ID Release 431564169 Reactome, http://www.reactome.org ReactomeREACT_150162 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type XII degradation by MMP12 Authored: Jupe, S, 2011-07-12 Collagen type XII is a member of the fibril-associated collagens with interrupted triple helices (FACIT) group, thought to be bound to the surface of interstitial collagen fibrils (Keene et al.1991). It has only one alpha chain type, with two collagenous (Col1 and Col2) and three noncollagenous domains (NC1-NC3). Whereas the collagenous and the NC1 and NC2 regions are short, the NHE-terminal NC3 is a huge trimeric domain (Yamagata et al. 1991, Wälchli et al. 1993). Collagen XII may enhance the stability of connective tissues by bridging collagen fibrils (Nishiyama et al. 1994, Bader et al. 2009). It may be a stress response molecule, directly influenced by stretch and shear stress. Expression of COL12A1 is directly stimulated by mechanical forces (Flück et al. 2003, Jin et al. 2003, Arai et al. 2008). Expression is predominantly in bone, suggesting involvement of type XII collagen in the regulation of osteoblasts and cell interactions. Transgenic type XII collagen-null mice have skeletal abnormalities. They have decreased bone matrix deposition and delayed maturation. Compared with controls, Col12a knockout osteoblasts are disorganized, being less polarized with disrupted cell-cell interactions, decreased connexin43 expression and impaired gap junction function (Izu et al. 2011).<br><br>MMP12 can cleave collagen XII (Didangelos et al. 2011). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed12581868 Pubmed12890494 Pubmed18957791 Pubmed18983916 Pubmed1918137 Pubmed2026656 Pubmed21593211 Pubmed21670218 Pubmed7961756 Pubmed8207089 Reactome Database ID Release 432168046 Reactome, http://www.reactome.org ReactomeREACT_150466 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type XIV degradation by MMP9,13 Authored: Jupe, S, 2011-07-12 Collagen type XIV is a member of the fibril-associated collagens with interrupted triple helices (FACIT) family, expressed in most mesenchymal tissues. The non-collagenous domain at the N-terminus of collagen XIV is extremely large, nearly 80% of the entire polypeptide. This domain is composed of eight fibronectin type III repeats, two von Willebrand factor A-like (vWFA) domains and one non-collagenous domain 4 (NC4 domain) related to collagen type IX. Collagen XIV is expressed in most mesenchymal tissues where it appears to interact with collagen type VI, glycosaminoglycans, proteoglycans and matrix receptors (Brown et al. 1993, Imhof & Trueb 1998). It has been implicated as a regulator of fibrillogenesis. Collagen type XIV deficient mice have a grossly normal phenotype but their skin has altered mechanical properties. Tendons were seen to be enlarged at postnatal day 4 though mature tendons appeared normal. Tendons from postnatal day 7 KO mice had reduced strength but by 60 days were comparable with wild-type (Ansorge et al. 2009). Adult Col14a1 mice have defects in ventricular morphogenesis (Tao et al. 2012).<br><br>Collagen type XIV is degraded by MMP9 (Sires et al. 1995) and MMP13 (Knauper et al. 1997). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed19136672 Pubmed7836360 Pubmed8421066 Pubmed9065415 Pubmed9827571 Reactome Database ID Release 431564117 Reactome, http://www.reactome.org ReactomeREACT_150248 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type XV restin release Authored: Jupe, S, 2011-07-12 Collagens type XV and XVIII are closely related non-fibrillar collagens that define the multiplexin (multiple triple helix domains with interruptions) subfamily of collagens. Both are homotrimers characterized by highly interrupted collagenous domains flanked by large globular domains with attached glycosaminoglycan chains. Collagen XV is localized in the outermost layer of the basement membrane (BM) and in the fibrillar matrix. Collagen type XV is the only collagen able to self-assemble into higher-order cruciform structures with intermolecular binding sites (Myers et al. 2007). The interaction is mediated by interactions between triple helical regions (Hurskainen et al. 2010). It is predominantly located in the basement membranes of microvessels, and cardiac and skeletal myocytes (Hägg et al. 1997), where it binds basement membrane and microfibrillar components such as fibulin-2, nidogen-2, vitronectin, laminin, and fibronectin (Sasaki et al. 2000, Hurskainen et al. 2010). It may form a bridge between fibrillar collagens and the basement membrane (Amenta et al. 2005), acting as a molecular shock absorber to stabilize and enhance resilience to compressive and expansive forces (Myers et al. 2007). Lack of Collagen type XV in Col15a1-null mice resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes (Rasi et al. 2010a). Col15a1 knockout also leads to loosely packed axons in C-fibers and polyaxonal myelination. Simultaneous knockout with laminin alpha-4 leads to severely impaired radial sorting and myelination (Rasi et al. 2010b).<br><br>The C-terminal non-collagenous region of collagen type XV is known as restin because it resembles endostatin, having antiangiogenic effects (Ramchandran et al. 1999, Sasaki et al. 2000). Edited: Jupe, S, 2012-11-12 Pubmed10049780 Pubmed10966814 Pubmed15684329 Pubmed17355226 Pubmed20040604 Pubmed20847313 Pubmed20980607 Pubmed9176399 Reactome Database ID Release 432168038 Reactome, http://www.reactome.org ReactomeREACT_150289 Reviewed: Sorsa, Timo, 2012-10-08 has a Stoichiometric coefficient of 3 Collagen type XVI degradation by MMP9 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed10429949 Pubmed12782140 Pubmed15165854 Pubmed16754661 Pubmed7836360 Pubmed8650669 Reactome Database ID Release 432168982 Reactome, http://www.reactome.org ReactomeREACT_150173 Reviewed: Sorsa, Timo, 2012-10-08 Type XVI collagen is a member of the FACIT collagen family (fibril-associated collagens with interrupted helices). During early mouse development, it occurs in many tissues and is co-distributed with the major fibrillar collagens (Lai & Chu 1996). In skin, collagen XVI preferentially occurs in narrow zones near basement membranes at the dermo-epidermal junction (DEJ) of blood vessels (Grässel et al., 1999). In papillary dermis, the protein unexpectedly does not occur in banded collagen fibrils, but is a component of specialized fibrillin-1-containing microfibrils. However, in cartilage matrix it does not aggregate with fibrillin-1, rather it exists as a discrete population of thin, weakly banded collagen fibrils in association with collagens II and XI (Kassner et al. 2003, 2004). Collagen XVI induces the recruitment of integrins alpha1 beta1 and alpha1 beta 2 into focal adhesion plaques, a principal step in integrin signaling (Eble et al. 2006), allowing cells to affect the architecture of the ECM networks by binding and moving ECM proteins.<br><br>Collagen type XVI is cleaved by MMP9 (Sires et al. 1995). Collagen type IX degradation by MMP3,13 Authored: Jupe, S, 2011-07-12 EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed11212149 Pubmed2005102 Pubmed2027130 Pubmed2920840 Pubmed3609327 Pubmed9065415 Pubmed9363632 Reactome Database ID Release 431564184 Reactome, http://www.reactome.org ReactomeREACT_150281 Reviewed: Sorsa, Timo, 2012-10-08 Type IX collagen interacts covalently with type II collagen fibril surfaces, suggesting that it represents a macromolecular bridge between fibrils and other cartilage matrix components (Eyre et al. 1987, Olsen 1997). Degradation of type IX (and type II) collagen is seen at the onset of inflammatory arthritis (Kojima et al. 2001). <br><br>Collagen type IX is cleaved by MMP3 (Okada et al. 1989, Eyre et al. 1991, Wu et al. 1991) and MMP13 (Knauper et al. 1997). Collagen type X degradation by MMP1,2 Authored: Jupe, S, 2011-07-12 Collagen X is thought to form extended hexagonal networks (Kwan et al. 1991, Jacenko et al. 2001). It's distribution is limited to regions of hypertrophic cartilage destined for degradation during endochondral ossification (Schmid & Conrad 1982). It is also found in areas of surface fibrillation and osteophyte formation during the development of osteoarthritic lesions in articular cartilage (von der Mark et al. 1992). In Timp3 knockout mice type X collagen was observed mostly in areas of articular cartilage that stained strongly for collagen cleavage products, suggesting that deposition of type X collagen might be a damage repair mechanism (Sahebjam et al. 2007). Mutations in the gene COL10A1 are associated with Schmid/Japanese type metaphyseal chondrodysplasia (SMCD) (Warman et al. 1993, Ho et al. 2007, Woelfle et al. 2011).<br><br>Type X collagen is degraded by MMP1 (Schmid et al. 1986, Welgus et al. 1990, Cole et al. 1993), MMP2 (Cole et al. 1993, Welgus et al. 1990), MMP3 (Wu et al. 1991), MMP13 (Knauper et al. 1997) and neutrophil elastase (Kittelberger et al. 1992). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed11733375 Pubmed1515454 Pubmed1622419 Pubmed17328064 Pubmed17403716 Pubmed1860888 Pubmed2005102 Pubmed21360259 Pubmed2166034 Pubmed3005323 Pubmed7118949 Pubmed8220429 Pubmed8405676 Pubmed9065415 Reactome Database ID Release 431564143 Reactome, http://www.reactome.org ReactomeREACT_150197 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type X degradation by MMP3, 13 Authored: Jupe, S, 2011-07-12 Collagen X forms extended hexagonal networks (Kwan et al. 1991, Jacenko et al. 2001). It's distribution is limited to regions of hypertrophic cartilage destined for degradation during endochondral ossification (Schmid & Conrad 1982). It is also found in areas of surface fibrillation and osteophyte formation during the development of osteoarthritic lesions in articular cartilage (von der Mark et al. 1992). In Timp3 knockout mice type X collagen was observed mostly in areas of articular cartilage that stained strongly for collagen cleavage products, suggesting that deposition of type X collagen might be a damage repair mechanism (Sahebjam et al. 2007). Mutations in the gene COL10A1 are associated with Schmid/Japanese type metaphyseal chondrodysplasia (SMCD) (Warman et al. 1993, Ho et al. 2007, Woelfle et al. 2011).<br><br>Type X collagen is degraded by MMP1 (Schmid et al. 1986, Welgus et al. 1990, Cole et al. 1993), MMP2 (Cole et al. 1993, Welgus et al. 1990), MMP3 (Wu et al. 1991), MMP13 (Knauper et al. 1997) and ELANE (neutrophil elastase - Kittelberger et al. 1992). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed11733375 Pubmed1515454 Pubmed1622419 Pubmed17328064 Pubmed17403716 Pubmed1860888 Pubmed2005102 Pubmed21360259 Pubmed2166034 Pubmed3005323 Pubmed7118949 Pubmed8220429 Pubmed8405676 Pubmed9065415 Reactome Database ID Release 432484882 Reactome, http://www.reactome.org ReactomeREACT_150432 Reviewed: Sorsa, Timo, 2012-10-08 Collagen type XI degradation by MMP1,2,3,9 Authored: Jupe, S, 2011-07-12 Collagen type XI has 3 types of alpha chain. The alpha1(XI) and alpha2(XI) chains are distinct gene products unique to collagen XI, while alpha3(XI) is a hyperglycosylated form of the alpha1 chain for collagen II (Burgeson & Hollister 1979, Morris & Bächinger 1987). Collagen type XI is a fibril-forming collagen found in conjunction with collagens type II and IX in cartilage fibrils (Miller & Gay 1987, Mendler et al. 1989). It is thought to be the structural equivalent of collagen V in connective tissue collagen fibrils. The formation of cartilage collagen fibrils requires collagen XI, suggesting a regulatory function (Li et al. 1995, Wu & Eyre 1995). <br><br>Mutations in COL11A1 result in fibrochondrogenesis, a severe, autosomal-recessive, short-limbed skeletal dysplasia (Tompson et al. 2010). Variations in COL11A1, COL11A2 and COL2A1 are associated with the inherited chondrodysplasias Marshall and Stickler syndromes (Annunen et al. 1999).<br><br>Collagen type XI is degraded by MMP1 (Eyre et al. 1984), MMP2 (Yu et al. 1990, Smith et al. 1991, Brown et al. 1996), MMP3 (Wu et al. 1991) and MMP9 (Hirose et al. 1992, Pormotabbed et al. 1994). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed10486316 Pubmed1317454 Pubmed1851245 Pubmed2005102 Pubmed21035103 Pubmed2173606 Pubmed2463256 Pubmed3112157 Pubmed3306286 Pubmed465027 Pubmed6322761 Pubmed7642541 Pubmed7859283 Pubmed8305481 Pubmed8670744 Reactome Database ID Release 431564179 Reactome, http://www.reactome.org ReactomeREACT_150259 Reviewed: Sorsa, Timo, 2012-10-08 Fibrillin-1 binds latent TGF-beta Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed10646116 Pubmed12429738 Pubmed15307633 Pubmed18585707 Pubmed19349279 Pubmed19513754 Pubmed8756760 Reactome Database ID Release 432328033 Reactome, http://www.reactome.org ReactomeREACT_150295 Reviewed: Muiznieks, Lisa, 2012-11-02 TGF-beta is released from cells as a latent complex of three proteins: TGF-beta (which is encoded by three human genes), the processed TGF-beta propeptide (latency-associated peptide LAP), and a member of the latent TGF-beta binding protein (LTBP) family. LTBPs are microfibril (fibrillin)-associated proteins that bind LAP, tethering latent TGF-beta to microfibrils in the ECM (Taipale et al. 1996, Hyytiainen et al. 2004). LTBP1 and LTBP4 incorporation into ECM requires fibrillin-1 (Ono et al. 2009). The protein–protein interaction sites between LTBPs and fibrillins have been determined using recombinant protein fragments and surface plasmon resonance (Ono et al. 2009). LTBP4 binds to the first hybrid domain of fibrillin-1 (Hyb1), whereas LTBP1 binds to a site involving both Hyb1 and adjacent EGF-like domains 2 and 3. Previous studies showed that the carboxyl terminus of LTBP1 binds to fibrillin-1, whereas the amino terminus of LTBPs is mainly responsible for binding ECM components made in cell culture generally, and fibronectin specifically (Kantola et al. 2008). PathwayStep5479 Active Rac1 interacts with Plexin-B1:Sema4D Active Rac1 interacts with Plexin-B1:Sema4A Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed11035813 Pubmed11937491 Reactome Database ID Release 43400682 Reactome, http://www.reactome.org ReactomeREACT_19354 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 The cytoplasmic tails of plexins have two domains, C1 and C2, which are highly conserved and act as GAP for small GTPases like Rac1. Active Rac1 binds directly to a binding domain of Plexin-B1 in the linker region between C1 and C2. The functional consequence of the plexin-B1/Rac interaction is not understood but this binding might sequester Rac1 away from p21-activated kinase (PAK). Plexin-B1 can compete with PAK for binding to active Rac and this competition results in the ability of plexin-B1 to inhibit Rac-induced PAK activation. Rnd1 interacts with Plexin-B1:Sema4D Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed12730235 Reactome Database ID Release 43400677 Reactome, http://www.reactome.org ReactomeREACT_19382 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Rnd1 is constitutively active and stably associates with Plexin-B1 and regulates the R-Ras GAP activity of the C1 and C2 domains of the Plexin-B1 cytoplasmic tail. These domains interact with each other and in this closed conformation cannot associate with active R-Ras-GTP. Rnd1 binds to the region between C1 and C2 domains and disrupts this interaction, allowing the receptor to associate with GTP-bound R-Ras. Elastic fibres bind associated proteins Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Other proteins found associated with elastic fibres include vitronectin (Dahlback et al. 1989,1990, Hintner et al. 1991) and and a structurally unrelated group of proteins collectively termed microfibrillar-associated proteins (MFAPs) (Gibson et al. 1996, 2000, Abrams et al. 1995, Toyashima et al. 1999). The significance of these interactions is not well understood. Vitronectin is present in plasma, extracellular matrix, and the alpha granules of blood platelets. It has been implicated as a regulator of many processes including coagulation, fibrinolysis, pericellular proteolysis, complement dependent immune response, cell attachment and spreading (Zhuang et al. 1996). It interacts with integrins alphaVbeta1 (Marshall et al. 1995), alphaVbeta3 (Pytela et al. 1985), alphaVbeta5 (Panetti & McKeown Longo 1993) and alphaIIbBeta3 (Pytela et al. 1986) through Arg Gly Asp (RGD) cell binding sequences. The MFAPs are not a structurally related family but grouped due to their localization with microfibrils. MFAP1 was originally called 'associated microfibril protein' (AMP). It is a 54 kDa protein, processed to 32 kDa, localizing to fibrillin-containing microfibrils in several tissues including zonule fibers (Horrigan et al. 1992). MFAP3 is a 41 kDa serine-rich protein localized to zonular microfibrils, found in extracts of developing nuchal ligament, also expressed in fetal aorta and lung (Abrams et al. 1995). MFAP4 is a 29 kDa protein localized to fibrillin-containing microfibrils surrounding elastic fibers in aorta, skin and spleen (Toyoshima et al. 1999). Pubmed10424889 Pubmed1374398 Pubmed1689758 Pubmed1708799 Pubmed2412224 Pubmed2420006 Pubmed2469736 Pubmed7542669 Pubmed7685013 Pubmed7782085 Pubmed8557636 Pubmed8663084 Reactome Database ID Release 432161282 Reactome, http://www.reactome.org ReactomeREACT_150335 Reviewed: Muiznieks, Lisa, 2012-11-02 SEMA4D interacts with Plexin-B1:Met Authored: Garapati, P V, 2009-03-23 09:59:28 EC Number: 2.7.10 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed12198496 Pubmed18025083 Reactome Database ID Release 43419646 Reactome, http://www.reactome.org ReactomeREACT_19398 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema4D binds Plexin-B1 to induce repulsive or attractive effects in neuronal and nonneuronal cells. Plexins constitute a large family of transmembrane proteins that function as receptors for semaphorins and their interaction governs cell adhesion and migration in a variety of tissues. All B-class plexins can interact with the receptor tyrosine kinases Met and ErbB2. The binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase activity of Met, leading to the phosphorylation of both Plexin-B1 and Met. The phosphorylation of the plexin-B1/Met complex induced by Sema4D is crucial for epithelial cell migration and invasive growth. Sequence alignment reveals the presence of 13 conserved tyrosine residues (highly conserved sites 1918, 1953, 2038), but the specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified. PathwayStep5485 SEMA4D interacts with Plexin-B1:ErbB2 Authored: Garapati, P V, 2009-03-23 09:59:28 EC Number: 2.7.10 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed15210733 Pubmed18025083 Reactome Database ID Release 43373750 Reactome, http://www.reactome.org ReactomeREACT_19381 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema4D binds Plexin-B1 to induce repulsive or attractive effects in neuronal and nonneuronal cells. Plexins constitute a large family of transmembrane proteins that function as receptors for semaphorins and their interaction governs cell adhesion and migration in a variety of tissues. All B-class plexins can interact with the receptor tyrosine kinases Met and ErbB2. Upon binding of Sema4D to plexin-B1, the kinase activity of ErbB2 is increased resulting in tyrosine phosphorylation of both Plexin-B1 and ErbB2. ErbB2 has been shown to mediate Sema4D-induced growth cone collapse in hippocampal neurons by the activation of RhoA via plexinB1 and PDZRhoGEF/LARG.<br>Sequence alignment reveals the presence of 13 conserved tyrosine residues (highly conserved sites 1918, 1953, 2038) but the specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified. PathwayStep5484 Inactivation of Rho-GTP by p190RhoGAP Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed16188938 Reactome Database ID Release 43416559 Reactome, http://www.reactome.org ReactomeREACT_19242 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 p190RhoGAP complexed with Plexin-B1 stimulates GTP hydrolysis by RhoA. The resulting lower levels of Rho-GTP may account for F-actin depolymerization and cytoskeletal rearrangements. PathwayStep5483 p190RhoGAP binds Plexin-B1 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Plexin-B1 can mediate inhibition of RhoA via the Sema4D-dependent recruitment of p190RhoGAP into the semaphorin receptor complex. Pubmed16188938 Reactome Database ID Release 43416562 Reactome, http://www.reactome.org ReactomeREACT_19356 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 PathwayStep5482 Inactivation of R-Ras by Sema4D-Plexin-B1 GAP activity Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Plexin-B1 functions as an R-Ras GTPase-activating protein (GAP) and directly and specifically down regulates R-Ras activity in response to Sema4D, inducing growth cone collapse. R-Ras inactivation promotes PI3K and Akt inactivation followed by GSK-3beta activation and CRMP inactivation. R-Ras inactivation also inhibits cell migration by regulating beta1 integrin activity. <br> Pubmed16702230 Pubmed16799460 Reactome Database ID Release 43416546 Reactome, http://www.reactome.org ReactomeREACT_19120 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 PathwayStep5489 PathwayStep5488 PathwayStep5487 PathwayStep5486 LARG and PDZ-RhoGEF binds to Plexin-B1 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Plexin-B1 activates RhoA and induces growth cone collapse and and cytoskeletal reorganization through Rho-specific guanine nucleotide exchange factors PDZ-RhoGEF and leukemia-associated RhoGEF (LARG). Plexin-B1 directly interacts with PDZ-RhoGEF through its c-terminal PDZ domain binding motif. It has been suggested that Rnd1, which binds to the cytoplasmic part of plexin-B1, can promote the interaction between plexin-B1 and PDZ-RhoGEF. The PDZ domain of LARG is directly involved in the interaction with the c-terminal sequence of Plexin-B1. Pubmed12196628 Pubmed12220504 Pubmed12730235 Pubmed15210733 Reactome Database ID Release 43416594 Reactome, http://www.reactome.org ReactomeREACT_19153 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 PathwayStep5481 PathwayStep5480 Tropoelastin associates with microfibrils Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Elastin, the highly insoluble core protein of elastic fibers, is secreted as a soluble protein monomer referred to as tropoelastin. Under physiological conditions the monomers phase separate and coalesce into spherical packages (Clarke et al. 2006), a process known as coacervation. Packages of accumulated elastin are delivered to fibrillin-based fibres in a mechanism that is correlated with cell migration during embryonic development (Czirok et al. 2006). A transglutaminase cross-link between domain 4 of tropoelastin and domain 16 of fibrillin-1 may stabilize initial deposition (Clarke et al. 2005). Elastin is subsequently cross linked by members of the lysyl oxidase family via lysine residues, resulting in mature, insoluble fibres (Sato et al. 2007, Wise & Weiss 2009). Pubmed16042404 Pubmed16331676 Pubmed16906757 Pubmed17459412 Pubmed18468477 Reactome Database ID Release 432129353 Reactome, http://www.reactome.org ReactomeREACT_150146 Reviewed: Muiznieks, Lisa, 2012-11-02 Elastin cross-linking by lysyl oxidase Authored: Jupe, S, 2012-04-30 EC Number: 1.4.3.13 Edited: Jupe, S, 2012-11-12 Pubmed16906757 Pubmed16909208 Pubmed6123066 Reactome Database ID Release 432129375 Reactome, http://www.reactome.org ReactomeREACT_150459 Reviewed: Muiznieks, Lisa, 2012-11-02 Soluble monomers of tropoelastin are cross-linked by the oxidative deamination of lysine residues, catalyzed by lysyl oxidase (LOX). The first step in the cross linking reaction is the oxidative formation of the delta-aldehyde, known as alpha aminoadipic semialdehyde or allysine (Partridge 1963). Subsequent spontaneous reactions lead to the formation of cross-links through dehydrolysinonorleucine and allysine aldol, a trifunctional cross-link dehydromerodesmosine and two tetrafunctional cross-links desmosine and isodesmosine (Lucero & Kagan 2006), which are unique to elastin. FBLN1, FBLN2 bind fibronectin Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Fibulin-1 and -2 bind fibronectin Fibulins are a family of 7 extracellular calcium binding proteins that have developmental roles (Twal et al. 2001). Fibulins 1-5 are found in association with elastic fibers. Fibulin-1 binds fibronectin (Balbona et al. 1992, Tran et al. 1997) suppressing fibronectin-mediated inhibitory effects on cell attachment and spreading (Twal et al. 2001). Fibulin-2 also binds fibronectin (Sasaki et al. 1995). Pubmed11792823 Pubmed1400330 Pubmed7500359 Pubmed9278415 Reactome Database ID Release 432537665 Reactome, http://www.reactome.org ReactomeREACT_150469 Reviewed: Muiznieks, Lisa, 2012-11-02 Fibulin binds elastic fibres Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Fibulins are a family of 7 genes encoding calcium binding glycoproteins with distinct roles in elastogenesis. They are essential for elastic fibre formation, having a role in regulating and organising tropoelastin formation (Yanagisawa & Davis 2010). Fibulins 1-5 all bind elastin (Roark et al. 1995, Sasaki et al. 1999, Kobayashi et al. 2007). Fibulins 2, 4, 5 and 7 also bind fibrillin (Reinhardt et al. 1996, El Hallous et al. 2007, de Vega et al. 2007). Fibulin 6 has a role in the formation of the cleavage furrow during cytokinesis but its binding partners are unclear (Xu & Vogel 2011). Pubmed10544250 Pubmed17255108 Pubmed17324935 Pubmed17699513 Pubmed20236620 Pubmed21966563 Pubmed7534784 Pubmed8702639 Reactome Database ID Release 431592387 Reactome, http://www.reactome.org ReactomeREACT_150243 Reviewed: Muiznieks, Lisa, 2012-11-02 PathwayStep5494 LTBP1, LTBP3 bind TGF-Beta Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed10646116 Pubmed10930463 Pubmed12429738 Pubmed15307633 Pubmed18585707 Pubmed19349279 Pubmed19513754 Pubmed21900405 Pubmed8756760 Reactome Database ID Release 432395328 Reactome, http://www.reactome.org ReactomeREACT_150269 Reviewed: Muiznieks, Lisa, 2012-11-02 Transforming growth factor (TGF) beta (TGF-beta) is a family of three cytokine ‘isoforms’ (encoded by three separate human genes) that control proliferation, cellular differentiation and other functions. TGF-beta originally referred to the founding member TGF-beta-1, now it is often used as a collective term for all three. TGF-beta is secreted from cells in latent form as part of a complex that includes two other proteins: the cleaved propeptide of TGF beta, known as latency associated peptide (LAP), and a member of the latent TGF beta binding protein (LTBP) family. LTBPs are members of the fibrillin/LTBP superfamily, characterised by the presence of unique TGF-binding protein (TB) domains, also known as 8 cys domains as they contain eight characteristic cysteines (Ramirez & Sakai 2010). LTBPs are microfibril-associated, proteins that tether latent complexes of TGF-beta to microfibrils in the ECM (Taipale et al. 1996, Dallas et al. 2000, Isogai et al. 2003, Hyytiainen et al. 2004, Ono et al. 2009, Munger & Sheppard 2011). LTBP1 and 3 bind all three isoforms of latent TGF-beta, while LTBP4 only weakly binds TGF-beta1 (Saharinen & Keski Oja 2000). LTBP2 does not bind TGF-beta and is a structural component of fibrillin microfibrils. The carboxyl terminus of LTBP1 binds to fibrillin-1. LTBP1 and LTBP4 incorporation into the ECM is abolished in fibrillin-1 null mice (Ono et al. 2009). The amino terminus of LTBPs binds ECM components such as collagen (Taipale et al. 1996) and fibronectin (Kantola et al. 2008). Fibulins compete for the LTBP sites in fibrillin (Ono et al. 2009). PathwayStep5493 Emilin is found in elastic fibres Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Elastin microfibril interface located protein (EMILIN)-1 is localized to the microfibril-elastin interface (Bressan et al. 1993). It can bind elastin and fibulin-5 (Zanetti et al. 2004). Emilin1 knockout mice have ultrastructural alterations of the elastic fibers in aorta and skin, abnormal cell morphology and anchorage of endothelial and smooth muscle cells to elastic lamellae, and abnormal elastic fibers in cultured embryonic fibroblasts. Pubmed14701737 Pubmed8458869 Reactome Database ID Release 432328048 Reactome, http://www.reactome.org ReactomeREACT_150187 Reviewed: Muiznieks, Lisa, 2012-11-02 PathwayStep5496 Latent TGF-beta-1 binds integrins Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed10025398 Pubmed11970960 Pubmed12358597 Pubmed12415008 Pubmed16877343 Pubmed9725916 Reactome Database ID Release 432395320 Reactome, http://www.reactome.org ReactomeREACT_150434 Reviewed: Muiznieks, Lisa, 2012-11-02 The LAPs of TGF beta-1 and TGF beta-3 contain RGD sequences near the carboxyl termini that are bound by RGD binding integrins. The TGF beta-1 form of LAP (LAP1) binds the integrins alphaVBeta1 (Munger et al. 1998), alphaVBeta3 (Ludbrook et al. 2003), alphaVBeta5 (Munger et al. 1998), alphaVBeta6 (Munger et al. 1999, Araya et al. 2006), alphaVBeta8 (Mu et al. 2002, Araya et al. 2006) and alpha8Beta1 (Lu et al. 2002). Binding to integrins alphaVBeta6 and alphaVBeta8 leads to TGF beta activation. PathwayStep5495 LTBP4 binds TGF-Beta-1 Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed10646116 Pubmed10930463 Pubmed12429738 Pubmed15307633 Pubmed18585707 Pubmed19349279 Pubmed19513754 Pubmed21900405 Pubmed8756760 Reactome Database ID Release 432395364 Reactome, http://www.reactome.org ReactomeREACT_150240 Reviewed: Muiznieks, Lisa, 2012-11-02 Transforming growth factor (TGF) beta (TGF-beta) is a family of three cytokine 'isoforms' (encoded by three separate human genes) that control proliferation, cellular differentiation and other functions. TGF-beta originally referred to the founding member TGF-beta-1, now it is often used as a collective term for all three. TGF-beta is secreted from cells in latent form as part of a complex that includes two other proteins: the cleaved propeptide of TGF beta, known as latency associated peptide (LAP), and a member of the latent TGF beta binding protein (LTBP) family. LTBPs are members of the fibrillin/LTBP superfamily, characterised by the presence of unique TGF-binding protein (TB) domains, also known as 8 cys domains as they contain eight characteristic cysteines (Ramirez & Sakai 2010). LTBPs are microfibril-associated, proteins that tether latent complexes of TGF-beta to microfibrils in the ECM (Taipale et al. 1996, Dallas et al. 2000, Isogai et al. 2003, Hyytiainen et al. 2004, Ono et al. 2009, Munger & Sheppard 2011). LTBP1 and 3 bind all three isoforms of latent TGF-beta, while LTBP4 only weakly binds TGF-beta1 (Saharinen & Keski Oja 2000). LTBP2 does not bind TGF-beta and is a structural component of fibrillin microfibrils. The carboxyl terminus of LTBP1 binds to fibrillin-1. LTBP1 and LTBP4 incorporation into the ECM is abolished in fibrillin-1 null mice (Ono et al. 2009). The amino terminus of LTBPs binds ECM components such as collagen (Taipale et al. 1996) and fibronectin (Kantola et al. 2008). Fibulins compete for the LTBP sites in fibrillin (Ono et al. 2009). PathwayStep5498 Fibrillins bind BMPs Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Fibrillins can bind the prodomains of TGF-beta superfamily members bone morphogenic factor (BMP) 2, 4, 7, 10, and growth and differentiation factor (GDF) 5 (Sengle et al. 2008). Prodomain binding by ECM constituents may be a targeting mechanism for TGF family members (Sengle et al. 2011). Pubmed18339631 Pubmed21135108 Reactome Database ID Release 432396399 Reactome, http://www.reactome.org ReactomeREACT_150165 Reviewed: Muiznieks, Lisa, 2012-11-02 PathwayStep5497 Latent TGF-beta-3 binds integrins Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed12358597 Pubmed21646718 Reactome Database ID Release 432396029 Reactome, http://www.reactome.org ReactomeREACT_150337 Reviewed: Muiznieks, Lisa, 2012-11-02 The LAPs of TGF-beta1 and TGF-beta3 contain RGD sequences near the carboxyl termini that are bound by RGD-binding integrins. LAP3 binds alphaVBeta1, 3, 5 and 6 (Ludbrook et al. 2003) and 8 (Kitamura et al. 2011). Binding to integrins alphaVBeta6 and alphaVBeta8 leads to TGF-beta activation. PathwayStep5499 PathwayStep5490 PathwayStep5492 PathwayStep5491 Phosphorylation of LIMK-1 by PAK Authored: Garapati, P V, 2009-03-23 09:59:28 EC Number: 2.7.11 Edited: Garapati, P V, 2009-03-23 10:00:07 LIM-kinase is responsible for the tight regulation of the activity of cofilin (a protein that depolymerizes actin filaments) and thus maintains the balance between actin assembly and disassembly. LIMK is one of the downstream targets of PAK1 and is activated through phosphorylation by PAK1 on T508 within its activation loop. Pubmed10559936 Pubmed11276226 Reactome Database ID Release 43399952 Reactome, http://www.reactome.org ReactomeREACT_19221 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Dimerization of LIMK1 by Hsp90 After phosphorylation on Thr 508, LIMK undergoes homodimerization. Homodimer formation is promoted by the binding of heat shock protein 90 (Hsp90) to a short sequence in the kinase domain of LIMKs. LIMKs are further phosphorylated after homodimer formation and transphosphorylation of the kinase domain. Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed16641196 Pubmed17188549 Reactome Database ID Release 43419645 Reactome, http://www.reactome.org ReactomeREACT_19307 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 has a Stoichiometric coefficient of 2 Activation of PAK by Rac1 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Plexin-bound Rac1 binds to and stimulates the kinase activity of PAK. PAK dimers are arranged in head-to-tail fashion, in which the catalytic domain binds the kinase inhibitory (KI) domain and is supported by associated PAK-interacting exchange factor (PIX) dimers. Upon Rac1 binding the kinase undergoes conformational change that allows autophosphorylation. Phosphorylation of serine residues disables the KI-domain-kinase interaction and thereby reduces the affinity of PIX. Pubmed11604131 Pubmed15548136 Reactome Database ID Release 43399930 Reactome, http://www.reactome.org ReactomeREACT_19269 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Autophosphorylation of PAK Authored: Garapati, P V, 2009-03-23 09:59:28 EC Number: 2.7.11 Edited: Garapati, P V, 2009-03-23 10:00:07 PAK is autophosphorylated at several sites but S-144 flanking the kinase inhibitor region and T-423 (S-141/T-402 in PAK-gamma) within the catalytic domain are the two conserved sites that regulate the catalytic activity. Pubmed10075701 Pubmed11278486 Reactome Database ID Release 43399939 Reactome, http://www.reactome.org ReactomeREACT_19197 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 has a Stoichiometric coefficient of 2 Inactivation of R-Ras by Sema3A-Plexin-A GAP activity Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Plexin-A's are GAPs for the Ras family GTPase R-Ras. On stimulation with Rnd-1, plexin-A directly and specifically down regulates R-Ras activity. R-Ras activity is critical for PI3K activation and ECM-mediated beta1 integrin activation and cell migration. Inactivation of R-Ras by Sema3A/Plexin-A1 reduces integrin-mediated adhesions. It has been suggested that the final step in the Sema3A repulsive signaling pathway is inhibition of integrin activity. Reduced integrin activity allows detachment from the substratum and subsequent cell retraction. Reactome Database ID Release 43399935 Reactome, http://www.reactome.org ReactomeREACT_19117 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Inhibition of integrin activation by sequestering PIP5KIgamma Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed10934324 Pubmed12422220 Pubmed16286926 Pubmed16930978 Reactome Database ID Release 43399936 Reactome, http://www.reactome.org ReactomeREACT_19403 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema3A also mediates integrin inhibition by a mechanism involving PIPKI gamma 661, a phosphatidylinositol kinase that participates in integrin mediated focal adhesion assembly. The binding of talin to beta-integrin is required for integrin activation and is strengthened by PtdIns(4,5)P(2). PIPKI gamma 661, an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. Sema3A induced dissociation of FARP2 from Plexin-A1 stimulates an interaction between FARP2 and PIPKI gamma 661. FARP2 inhibits PIPK gamma 661's kinase activity, and thus inhibits integrin mediated adhesion. Recruitment of Rnd1 to Plexin A Authored: Garapati, P V, 2009-03-23 09:59:28 Binding of Sema3A to the Neuropilin-1-Plexin-A receptor complex results in the recruitment of Rnd1 to the cytoplasmic linker region of Plexin-A. Rnd1 activates the cytoplasmic GTPase signaling domain of Plexin-A. Edited: Garapati, P V, 2009-03-23 10:00:07 Reactome Database ID Release 43399928 Reactome, http://www.reactome.org ReactomeREACT_19337 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Activation of Fyn Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 PlexinA1 and A2 are constitutively bound to the src family tyrosine kinase, Fyn. Stimulation with Sema3A causes Fyn activation and leads to the recruitment of Cdk5 into the complex. Reactome Database ID Release 43399931 Reactome, http://www.reactome.org ReactomeREACT_19368 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Phosphorylation of cofilin by LIMK-1 Authored: Garapati, P V, 2009-03-23 09:59:28 Cofilin is a member of the ADF (actin-depolymerizing factor) protein family, that is involved in regulating actin dynamics in the growth cone. It binds to actin in a one-to-one molar ratio, and stimulates both the severing of actin filaments and depolymerization of actin subunits from the actin filament end. <br>Activated LIMK phosphorylates cofilin on conserved serine 3 (Ser3/S3), located near the actin binding site. After phosphorylation cofilin is inactive and looses its affinity for actin and releases from G-actin monomers. Now the ADP-actin monomers are free and can exchange ADP with cytoplasmic ATP and they are ready for reincorporation at the barbed end of the a growing filament. EC Number: 2.7.11 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed12593985 Pubmed12642619 Reactome Database ID Release 43399950 Reactome, http://www.reactome.org ReactomeREACT_19276 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Transphosphorylation of pLIMK1 Authored: Garapati, P V, 2009-03-23 09:59:28 Binding of Hsp90 to the LIMK proteins protects them from degradation and promotes their dimer formation and transphosphorylation. It is estimated that LIMK1 contains at least 5 phospho-amino acids primarily phospho-serines, in its kinase domain. The positions of these serine residues are not known. Transphosphorylation of these serine residues in LIMK1 increases its stability. EC Number: 2.7.11 Edited: Garapati, P V, 2009-03-23 09:59:28 Pubmed16641196 Pubmed17188549 Pubmed7848918 Reactome Database ID Release 43419644 Reactome, http://www.reactome.org ReactomeREACT_19168 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 LIM kinase phosphorylation by ROCK Authored: Akkerman, JW, 2009-06-03 EC Number: 2.7.11 Edited: Jupe, S, 2009-04-28 12:55:15 Pubmed10652353 Pubmed11018042 Pubmed12778124 Pubmed16219803 ROCK I phosphorylates LIMK1 at Thr508 and LIMK2 at Thr505, enhancing the ability of LIMKs to phosphorylate cofilin. Reactome Database ID Release 43419087 Reactome, http://www.reactome.org ReactomeREACT_19282 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 SEMA4D interacts with CD72 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 In the immune system, Sema4D/CD100 binds CD72 to mediate B-cell-B-cell, B-cell-T-cell and T-cell-dendritic cell interactions and there by regulates B-cell and T-cell activation. In B-cells, this interaction directs the dissociation of SHP-1 from the CD72 cytoplasmic domain and enhances their activation.<br> Pubmed11114375 Pubmed12882840 Reactome Database ID Release 43373748 Reactome, http://www.reactome.org ReactomeREACT_19336 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 SEMA4D interacts with CD45 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed10648410 Pubmed8955171 Reactome Database ID Release 43373746 Reactome, http://www.reactome.org ReactomeREACT_19295 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 SEMA4D also associates with CD45, a cell surface protein tyrosine phosphatase (PTP) considered a key molecule in the T-cell receptor (TCR) activation process. Plexin-A binds to neuropilin-1 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed10520994 Reactome Database ID Release 43399942 Reactome, http://www.reactome.org ReactomeREACT_19128 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 The best characterized receptors for mediating semaphorin signaling are members of the neuropilin and plexin families of transmembrane proteins. Neuropilins form complexes with Plexin-A which in turn can act as a signaling moiety. Also, when complexed with neuropilin-1, plexin-A1 can associate directly with the FERM domain containing guanine nucleotide exchange factor (GEF) FARP2. FARP2 exerts GEF activity for Rac but not Cdc42 and Rho. Activation of Rho by LARG and PDZ-RhoGEF Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed12220504 Pubmed12730235 Pubmed15210733 Reactome Database ID Release 43416588 Reactome, http://www.reactome.org ReactomeREACT_19137 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 The RhoGEFs LARG and PDZ-RhoGEF complexed with Plexin-B1 stimulate the exchange of GDP for GTP on RhoA through their DH and PH domains. Myosin regulatory light chain phosphorylation by ROCK Authored: Akkerman, JW, 2009-06-03 EC Number: 2.7.11 Edited: Jupe, S, 2009-05-20 09:50:28 Nonmuscle myosin II (NMM2) is an actin-based motor protein that plays a crucial role in a variety of cellular processes, including cell migration, polarity formation, and cytokinesis. NMM2 consists of two myosin heavy chains encoded by MYH9, MYH10 or MYH14 (NMHC-IIA, B and C), two copies of MYL6 essential light chain protein, and two regulatory light chains (MRLCs), MYL9 and MYLC2B. Myosin II activity is stimulated by phosphorylation of MRLC. Diphosphorylation at Thr-19 and Ser-20 increases both actin-activated Mg2+ ATPase activity and the stability of myosin II filaments; monophosphorylation at Ser-20 is less effective. Kinases responsible for the phosphorylation include myosin light chain kinase (MLCK), ROCK kinase, citron kinase, myotonic dystrophy kinase-related CDC42-binding protein kinase, and Zipper-interacting protein (ZIP) kinase. ROCK activity has been shown to regulate MRLC phosphorylation by directly mono- (Amano et al., 1996) or di- (Ueda et al., 2002) phosphorylating MRLC. Pubmed12778124 Pubmed17151359 Pubmed8702756 Reactome Database ID Release 43419197 Reactome, http://www.reactome.org ReactomeREACT_19191 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Phosphorylation of Plexin-A Authored: Garapati, P V, 2009-03-23 09:59:28 EC Number: 2.7.10 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed12093729 Pubmed18660749 Reactome Database ID Release 43399934 Reactome, http://www.reactome.org ReactomeREACT_19420 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema3A binding to Neuropilin-1:Plexin-A complex results in conformational change of plexin-A and this conformational change permits Fes nonreceptor tyrosine kinase to bind and phosphorylate Plexin-A. The specific tyrosine residues phosphorylated in the cytoplasmic domain of plexins in response to semaphorin stimulation have not yet been identified. Sema3A binds Nrp-1 bound to PlexinA Although neuropilin-1 is required for Sema-3A action, it is incapable of transmitting a Sema-3A signal to the growth cone interior. The function of Sema-3A is mediated by Plexins. Sema-3A binds with high affinity to Plexin when the latter is complexed with Neuropilin-1. <br>Plexin-A1 is known to act as an R-Ras GAP (GTPase activating protein) when bound by Sema-3A. Plexin's GAP activity is regulated by FARP2 mediated Rac1 activation. Sema-3A binding to neuropilin-1/Plexin-A1 seems to induce a conformational change of plexin-A1 necessary for releasing FARP2. This suggests that neuropilin1 is required not only for ligand binding, but also for signaling, by modulating the interaction of FARP2 with plexin-A1. Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed10679438 Pubmed16286926 Reactome Database ID Release 43399933 Reactome, http://www.reactome.org ReactomeREACT_19173 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Rac1 binds PlexinA Active Rac1 associates directly with Plexin-A1 in the linker region separating Plexin-A1's cytoplasmic GAP domains. Rac1 association relieves an inhibitory intramolecular interaction between the two Plexin-A1 GAP domains C1 and C2. Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed15187088 Reactome Database ID Release 43399941 Reactome, http://www.reactome.org ReactomeREACT_19160 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Activation of Rac1 by FARP2 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed16286926 Pubmed17607942 Reactome Database ID Release 43399938 Reactome, http://www.reactome.org ReactomeREACT_19363 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema3A-mediated dissociation of FARP2 from Plexin-A is followed by activation of Rac1 by the GEF activity of released FARP2.<br>FARP2 is critical for Sema3A-mediated axonal repulsion through two independent downstream signaling pathways. Sema3A mediated disassociation of FARP2 from Plexin-A is followed by activation of Rac by GEF activity of released FARP2, binding of Rnd1 to plexin-A and down regulation of R-Ras by GAP activity of plexin-A. p-2S-SMAD1/5/8:SMAD4:SKI Phospho-r-SMAD1/5/8:Co-SMAD:SKI Reactome DB_ID: 201427 Reactome Database ID Release 43201427 Reactome, http://www.reactome.org ReactomeREACT_12184 has a Stoichiometric coefficient of 1 PathwayStep3300 BMP2:BMP type II receptor:Phospho-BMP type I receptor:I-SMAD Reactome DB_ID: 201446 Reactome Database ID Release 43201446 Reactome, http://www.reactome.org ReactomeREACT_117029 has a Stoichiometric coefficient of 1 PathwayStep5440 Pre-TGFB1 complex Reactome DB_ID: 171260 Reactome Database ID Release 43171260 Reactome, http://www.reactome.org ReactomeREACT_7332 TGF-beta 1 precursor complex has a Stoichiometric coefficient of 2 PathwayStep5441 PathwayStep5442 BMP:p-BMPR:Endofin BMP2:BMP type II receptor:Phospho-BMP type I receptor:Endofin Reactome DB_ID: 201647 Reactome Database ID Release 43201647 Reactome, http://www.reactome.org ReactomeREACT_12142 has a Stoichiometric coefficient of 1 PathwayStep5443 I-SMAD:p-2S-SMAD1/5/8 I-Smad:Phospho-R-Smad1/5/8 Reactome DB_ID: 202644 Reactome Database ID Release 43202644 Reactome, http://www.reactome.org ReactomeREACT_12285 has a Stoichiometric coefficient of 1 PathwayStep5444 p-2S-SMAD1/5/8:SMAD4 Phospho-r-SMAD1/5/8:Co-SMAD Reactome DB_ID: 201419 Reactome Database ID Release 43201419 Reactome, http://www.reactome.org ReactomeREACT_12276 has a Stoichiometric coefficient of 1 PathwayStep5445 p-2S-SMAD1/5/8:SMAD4 Phospho-r-SMAD1/5/8:Co-SMAD complex Reactome DB_ID: 201450 Reactome Database ID Release 43201450 Reactome, http://www.reactome.org ReactomeREACT_12149 has a Stoichiometric coefficient of 1 PathwayStep5436 I-SMAD:SMURF Reactome DB_ID: 178185 Reactome Database ID Release 43178185 Reactome, http://www.reactome.org ReactomeREACT_12212 has a Stoichiometric coefficient of 1 PathwayStep5435 PathwayStep5438 BMP:p-BMPR:Endofin:p-2S-SMAD1/5/8 BMP2:BMP type II receptor:Phospho-BMP type I receptor:Endofin:Phospho-R-SMAD1/5/8 Reactome DB_ID: 201467 Reactome Database ID Release 43201467 Reactome, http://www.reactome.org ReactomeREACT_12310 has a Stoichiometric coefficient of 1 PathwayStep5437 BMP:p-BMPR:I-SMAD:SMURF BMP2:BMP type II receptor:Phospho-BMP type I receptor:I-SMAD:SMURF Reactome DB_ID: 201841 Reactome Database ID Release 43201841 Reactome, http://www.reactome.org ReactomeREACT_12352 has a Stoichiometric coefficient of 1 PathwayStep5439 pSIRP-A:PYK2 Reactome DB_ID: 391113 Reactome Database ID Release 43391113 Reactome, http://www.reactome.org ReactomeREACT_24348 has a Stoichiometric coefficient of 1 pSIRP-A:Grb2 Reactome DB_ID: 391112 Reactome Database ID Release 43391112 Reactome, http://www.reactome.org ReactomeREACT_24616 has a Stoichiometric coefficient of 1 pSIRP alpha:CD47:SCAP2:FYB Reactome DB_ID: 391116 Reactome Database ID Release 43391116 Reactome, http://www.reactome.org ReactomeREACT_24378 has a Stoichiometric coefficient of 1 PathwayStep5451 p-4S-BMPRI dimer Phospho-BMP type I receptor dimer Reactome DB_ID: 201447 Reactome Database ID Release 43201447 Reactome, http://www.reactome.org ReactomeREACT_12122 has a Stoichiometric coefficient of 2 PathwayStep5452 BMP:p-BMPR:Endofin:SMAD1/5/8 BMP2:BMP type II receptor:Phospho-BMP type I receptor:Endofin:R-SMAD1/5/8 Reactome DB_ID: 201477 Reactome Database ID Release 43201477 Reactome, http://www.reactome.org ReactomeREACT_12351 has a Stoichiometric coefficient of 1 PathwayStep3310 BMP:BMPR BMP:BMPRII:BMPRI Dimeric BMP2:BMP type II:type I receptor complex Reactome DB_ID: 201459 Reactome Database ID Release 43201459 Reactome, http://www.reactome.org ReactomeREACT_12213 has a Stoichiometric coefficient of 1 PathwayStep5450 PathwayStep3311 BMP:BMPRII:P-BMPRI BMP:BMPRII:p-4S-BMPRI Dimeric BMP2:BMP type II receptor:Phospho-BMP type I receptor complex Reactome DB_ID: 201426 Reactome Database ID Release 43201426 Reactome, http://www.reactome.org ReactomeREACT_12127 has a Stoichiometric coefficient of 1 PathwayStep5455 BMPRI dimer BMP type I receptor dimer BMPR1A homodimer Reactome DB_ID: 201428 Reactome Database ID Release 43201428 Reactome, http://www.reactome.org ReactomeREACT_12210 has a Stoichiometric coefficient of 2 PathwayStep5456 BMPRII:BMPRI BMPR tetramer Heteromeric BMP receptor complex Reactome DB_ID: 202640 Reactome Database ID Release 43202640 Reactome, http://www.reactome.org ReactomeREACT_12094 has a Stoichiometric coefficient of 1 PathwayStep5453 Ligand Trap:BMP2 Reactome DB_ID: 201806 Reactome Database ID Release 43201806 Reactome, http://www.reactome.org ReactomeREACT_12298 has a Stoichiometric coefficient of 1 PathwayStep5454 BMPRII dimer BMP type II receptor dimer Reactome DB_ID: 201465 Reactome Database ID Release 43201465 Reactome, http://www.reactome.org ReactomeREACT_12254 has a Stoichiometric coefficient of 2 PathwayStep5449 PathwayStep3306 Dimeric BMP2 Reactome DB_ID: 201463 Reactome Database ID Release 43201463 Reactome, http://www.reactome.org ReactomeREACT_12151 has a Stoichiometric coefficient of 2 PathwayStep5448 PathwayStep3305 RhoGTPase:GDP Reactome DB_ID: 194900 Reactome Database ID Release 43194900 Reactome, http://www.reactome.org ReactomeREACT_10889 has a Stoichiometric coefficient of 1 PathwayStep5447 PathwayStep3308 PathwayStep5446 PathwayStep3307 PathwayStep3302 PathwayStep3301 PathwayStep3304 PathwayStep3303 PathwayStep3309 RAC1-GTP Reactome DB_ID: 442641 Reactome Database ID Release 43442641 Reactome, http://www.reactome.org ReactomeREACT_21594 has a Stoichiometric coefficient of 1 DSCAM:pPAK(S144):Rac1-GTP Reactome DB_ID: 376009 Reactome Database ID Release 43376009 Reactome, http://www.reactome.org ReactomeREACT_26061 has a Stoichiometric coefficient of 1 MAP kinase p38 (Mg2+ cofactor) Reactome DB_ID: 189828 Reactome Database ID Release 43189828 Reactome, http://www.reactome.org ReactomeREACT_12099 has a Stoichiometric coefficient of 1 Nephrin dimer Reactome DB_ID: 373670 Reactome Database ID Release 43373670 Reactome, http://www.reactome.org ReactomeREACT_24735 has a Stoichiometric coefficient of 2 PathwayStep5464 PathwayStep5465 PathwayStep5466 PathwayStep5467 PathwayStep5460 PathwayStep3321 PathwayStep5461 PathwayStep3322 PathwayStep5462 PathwayStep5463 PathwayStep3320 PathwayStep3315 PathwayStep3314 PathwayStep3313 PathwayStep3312 PathwayStep5458 PathwayStep3319 PathwayStep5457 PathwayStep3318 PathwayStep3317 PathwayStep5459 PathwayStep3316 SIRP beta1:DAP12 Reactome DB_ID: 210222 Reactome Database ID Release 43210222 Reactome, http://www.reactome.org ReactomeREACT_24726 has a Stoichiometric coefficient of 1 SIRP alpha:SP-A/SP-D Reactome DB_ID: 391109 Reactome Database ID Release 43391109 Reactome, http://www.reactome.org ReactomeREACT_24481 has a Stoichiometric coefficient of 1 DSCAM/DSCAML1 homodimers Reactome DB_ID: 376016 Reactome Database ID Release 43376016 Reactome, http://www.reactome.org ReactomeREACT_26416 has a Stoichiometric coefficient of 2 SIRP gamma:CD47 Reactome DB_ID: 391166 Reactome Database ID Release 43391166 Reactome, http://www.reactome.org ReactomeREACT_24053 has a Stoichiometric coefficient of 1 DSCAM:netrin Reactome DB_ID: 376019 Reactome Database ID Release 43376019 Reactome, http://www.reactome.org ReactomeREACT_26451 has a Stoichiometric coefficient of 1 DSCAM:DCC Reactome DB_ID: 451355 Reactome Database ID Release 43451355 Reactome, http://www.reactome.org ReactomeREACT_26311 has a Stoichiometric coefficient of 1 pPAK(S144):Rac1-GTP Reactome DB_ID: 451352 Reactome Database ID Release 43451352 Reactome, http://www.reactome.org ReactomeREACT_26868 has a Stoichiometric coefficient of 1 PathwayStep5470 NEPH1:p-Nephrin:Fyn:NCK:N-WASP Reactome DB_ID: 532605 Reactome Database ID Release 43532605 Reactome, http://www.reactome.org ReactomeREACT_24683 has a Stoichiometric coefficient of 1 PI3K:CD2AP:p-Nephrin:Fyn:NEPH1 Reactome DB_ID: 451720 Reactome Database ID Release 43451720 Reactome, http://www.reactome.org ReactomeREACT_24519 has a Stoichiometric coefficient of 1 Nephrin dimer:CASK Reactome DB_ID: 373681 Reactome Database ID Release 43373681 Reactome, http://www.reactome.org ReactomeREACT_24544 has a Stoichiometric coefficient of 1 Podocin:p-Nephrin:Fyn:NEPH1 Reactome DB_ID: 373691 Reactome Database ID Release 43373691 Reactome, http://www.reactome.org ReactomeREACT_24571 has a Stoichiometric coefficient of 1 CD2AP:p-Nephrin:Fyn:NEPH1 Reactome DB_ID: 373680 Reactome Database ID Release 43373680 Reactome, http://www.reactome.org ReactomeREACT_24742 has a Stoichiometric coefficient of 1 PathwayStep5477 PathwayStep5478 PathwayStep5475 PathwayStep5476 PathwayStep5473 PathwayStep3330 PathwayStep5474 PathwayStep3331 PathwayStep5471 PathwayStep3332 PathwayStep5472 PathwayStep3333 PathwayStep3324 PathwayStep3323 PathwayStep3326 PathwayStep3325 PathwayStep3328 PathwayStep3327 PathwayStep5469 PathwayStep5468 PathwayStep3329 NEPH1:p-Nephrin:Nephrin Reactome DB_ID: 451430 Reactome Database ID Release 43451430 Reactome, http://www.reactome.org ReactomeREACT_24428 has a Stoichiometric coefficient of 1 NEPH1:p-Nephrin:Fyn Reactome DB_ID: 374555 Reactome Database ID Release 43374555 Reactome, http://www.reactome.org ReactomeREACT_24538 has a Stoichiometric coefficient of 1 Nephrin dimer:NEPH2/NEPH3 Reactome DB_ID: 451719 Reactome Database ID Release 43451719 Reactome, http://www.reactome.org ReactomeREACT_24383 has a Stoichiometric coefficient of 1 Nephrin dimer:NEPH1 Reactome DB_ID: 373679 Reactome Database ID Release 43373679 Reactome, http://www.reactome.org ReactomeREACT_24342 has a Stoichiometric coefficient of 1 NEPH1:p-Nephrin:Fyn:NCK Reactome DB_ID: 373677 Reactome Database ID Release 43373677 Reactome, http://www.reactome.org ReactomeREACT_24581 has a Stoichiometric coefficient of 1 p-Nephrin:Nephrin Reactome DB_ID: 451723 Reactome Database ID Release 43451723 Reactome, http://www.reactome.org ReactomeREACT_24623 has a Stoichiometric coefficient of 1 Activated Growth Hormone Receptor:JAK2 Reactome DB_ID: 1168397 Reactome Database ID Release 431168397 Reactome, http://www.reactome.org ReactomeREACT_111855 has a Stoichiometric coefficient of 1 Activated Growth Hormone Receptor:JAK2 dimer Reactome DB_ID: 1168387 Reactome Database ID Release 431168387 Reactome, http://www.reactome.org ReactomeREACT_111547 has a Stoichiometric coefficient of 2 Growth Hormone: Activated Growth Hormone Receptor- p(Y1007)-JAK2 dimer Reactome DB_ID: 1168856 Reactome Database ID Release 431168856 Reactome, http://www.reactome.org ReactomeREACT_111571 has a Stoichiometric coefficient of 1 Activated cytokine-like hormone receptors, p(Y1007)-JAK2 Converted from EntitySet in Reactome Reactome DB_ID: 1364054 Reactome Database ID Release 431364054 Reactome, http://www.reactome.org ReactomeREACT_111453 PRLR ligands:Activated PRLR:JAK2 dimer:SH2B1 beta Reactome DB_ID: 1675475 Reactome Database ID Release 431675475 Reactome, http://www.reactome.org ReactomeREACT_116998 has a Stoichiometric coefficient of 1 PathwayStep5401 Growth Hormone: Activated Growth Hormone Receptor-JAK2 dimer Reactome DB_ID: 1168384 Reactome Database ID Release 431168384 Reactome, http://www.reactome.org ReactomeREACT_111254 has a Stoichiometric coefficient of 1 PathwayStep5400 Activated cytokine-like hormone receptors Converted from EntitySet in Reactome Reactome DB_ID: 1364055 Reactome Database ID Release 431364055 Reactome, http://www.reactome.org ReactomeREACT_111865 Activated Growth Hormone Receptor:p(Y1007)-JAK2 Reactome DB_ID: 1168869 Reactome Database ID Release 431168869 Reactome, http://www.reactome.org ReactomeREACT_111775 has a Stoichiometric coefficient of 1 Activated Growth Hormone Receptor:p(Y1007)-JAK2 dimer Reactome DB_ID: 1168860 Reactome Database ID Release 431168860 Reactome, http://www.reactome.org ReactomeREACT_111784 has a Stoichiometric coefficient of 2 PRLR ligands:Activated PRLR:p(Y1007)-JAK2 dimer Reactome DB_ID: 1671683 Reactome Database ID Release 431671683 Reactome, http://www.reactome.org ReactomeREACT_117043 has a Stoichiometric coefficient of 1 p(S349)-PRLR:JAK2 dimer Reactome DB_ID: 1675474 Reactome Database ID Release 431675474 Reactome, http://www.reactome.org ReactomeREACT_116400 has a Stoichiometric coefficient of 2 PRLR ligands:p(S349)-PRLR:JAK2 dimer Reactome DB_ID: 1977946 Reactome Database ID Release 431977946 Reactome, http://www.reactome.org ReactomeREACT_116992 has a Stoichiometric coefficient of 1 SCF beta-TrCP complex Reactome DB_ID: 206748 Reactome Database ID Release 43206748 Reactome, http://www.reactome.org ReactomeREACT_22981 beta-TrCP:Skp1:Cul1:Rbx1 has a Stoichiometric coefficient of 1 PRLR ligands:p(S349)- PRLR:JAK2 dimer:SCF beta-TrCP complex Reactome DB_ID: 1369085 Reactome Database ID Release 431369085 Reactome, http://www.reactome.org ReactomeREACT_117494 has a Stoichiometric coefficient of 1 PathwayStep5412 PRLR ligands:PRLR:JAK2 dimer Reactome DB_ID: 1671652 Reactome Database ID Release 431671652 Reactome, http://www.reactome.org ReactomeREACT_116278 has a Stoichiometric coefficient of 1 PathwayStep5411 Placental lactogen Reactome DB_ID: 1172022 Reactome Database ID Release 431172022 Reactome, http://www.reactome.org ReactomeREACT_111825 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5410 Activated PRLR:JAK2 Reactome DB_ID: 1977936 Reactome Database ID Release 431977936 Reactome, http://www.reactome.org ReactomeREACT_116912 has a Stoichiometric coefficient of 1 Activated PRLR:JAK2 dimer Reactome DB_ID: 1671734 Reactome Database ID Release 431671734 Reactome, http://www.reactome.org ReactomeREACT_117772 has a Stoichiometric coefficient of 2 PRLR ligands:Activated PRLR:JAK2 dimer Reactome DB_ID: 976956 Reactome Database ID Release 43976956 Reactome, http://www.reactome.org ReactomeREACT_111809 has a Stoichiometric coefficient of 1 p(S349)-PRLR:JAK2 Reactome DB_ID: 1370506 Reactome Database ID Release 431370506 Reactome, http://www.reactome.org ReactomeREACT_116463 has a Stoichiometric coefficient of 1 PathwayStep5404 PathwayStep5405 PathwayStep5402 PathwayStep5403 PathwayStep5408 PathwayStep5409 PathwayStep5406 PathwayStep5407 PathwayStep5421 ERBB4/m80/s80:WWP1/ITCH Reactome DB_ID: 1253284 Reactome Database ID Release 431253284 Reactome, http://www.reactome.org ReactomeREACT_117195 has a Stoichiometric coefficient of 1 PathwayStep5420 p(S349)-PRLR:JAK2 Reactome DB_ID: 2002374 Reactome Database ID Release 432002374 Reactome, http://www.reactome.org ReactomeREACT_116547 has a Stoichiometric coefficient of 1 PathwayStep5423 ERBB4jmAcyt1s80:NEDD4 Reactome DB_ID: 1973959 Reactome Database ID Release 431973959 Reactome, http://www.reactome.org ReactomeREACT_116714 has a Stoichiometric coefficient of 1 PathwayStep5422 Ub-ERBB4:WWP1/ITCH Reactome DB_ID: 1253293 Reactome Database ID Release 431253293 Reactome, http://www.reactome.org ReactomeREACT_116798 has a Stoichiometric coefficient of 1 RhoGTPase:GDP Reactome DB_ID: 194915 Reactome Database ID Release 43194915 Reactome, http://www.reactome.org ReactomeREACT_10155 has a Stoichiometric coefficient of 1 Ub-ERBB4jmAcyt1s80:NEDD4 Reactome DB_ID: 1977297 Reactome Database ID Release 431977297 Reactome, http://www.reactome.org ReactomeREACT_117572 has a Stoichiometric coefficient of 1 RhoGTPase:GTP:Effectors complex Reactome DB_ID: 194875 Reactome Database ID Release 43194875 Reactome, http://www.reactome.org ReactomeREACT_10149 has a Stoichiometric coefficient of 1 RhoGTPase:GTP Reactome DB_ID: 194890 Reactome Database ID Release 43194890 Reactome, http://www.reactome.org ReactomeREACT_10731 has a Stoichiometric coefficient of 1 Inactivated RhoGTPase:GDP:GDI complex Reactome DB_ID: 194912 Reactome Database ID Release 43194912 Reactome, http://www.reactome.org ReactomeREACT_10882 has a Stoichiometric coefficient of 1 PathwayStep5417 PathwayStep5418 PathwayStep5419 PathwayStep5413 PathwayStep5414 PathwayStep5415 PathwayStep5416 p(S349)-PRLR:JAK2 dimer Reactome DB_ID: 2002375 Reactome Database ID Release 432002375 Reactome, http://www.reactome.org ReactomeREACT_116470 has a Stoichiometric coefficient of 2 PathwayStep5434 p(Y611)-PRLR:p(Y1007)-JAK2 dimer Reactome DB_ID: 1977945 Reactome Database ID Release 431977945 Reactome, http://www.reactome.org ReactomeREACT_116477 has a Stoichiometric coefficient of 2 PathwayStep5433 PRLR ligands:p(Y611)-PRLR:p(Y1007)-JAK2 dimer Reactome DB_ID: 1369125 Reactome Database ID Release 431369125 Reactome, http://www.reactome.org ReactomeREACT_117024 has a Stoichiometric coefficient of 1 PathwayStep5432 Activated PRLR:p(Y1007)-JAK2 Reactome DB_ID: 1364053 Reactome Database ID Release 431364053 Reactome, http://www.reactome.org ReactomeREACT_111356 has a Stoichiometric coefficient of 1 PathwayStep5431 Activated PRLR:p(Y1007)-JAK2 dimer Reactome DB_ID: 1364075 Reactome Database ID Release 431364075 Reactome, http://www.reactome.org ReactomeREACT_111309 has a Stoichiometric coefficient of 2 PathwayStep5430 PRLR ligands:p(Y611)-PRLR:p(Y1007)-JAK2 dimer:SHP2 Reactome DB_ID: 1369118 Reactome Database ID Release 431369118 Reactome, http://www.reactome.org ReactomeREACT_117717 has a Stoichiometric coefficient of 1 PRLR ligands:p(Y611)-PRLR:p(Y1007)-JAK2 dimer:p-STAT5 Reactome DB_ID: 1671696 Reactome Database ID Release 431671696 Reactome, http://www.reactome.org ReactomeREACT_117210 has a Stoichiometric coefficient of 1 PRLR ligands:p(Y611)-PRLR:p(Y1007)-JAK2:STAT5 Reactome DB_ID: 1369095 Reactome Database ID Release 431369095 Reactome, http://www.reactome.org ReactomeREACT_116867 has a Stoichiometric coefficient of 1 p(Y611)-PRLR:p(Y1007)-JAK2 Reactome DB_ID: 1369079 Reactome Database ID Release 431369079 Reactome, http://www.reactome.org ReactomeREACT_117543 has a Stoichiometric coefficient of 1 PRLR ligands:p(S349)- PRLR:JAK2 dimer:SCF beta-TrCP complex Reactome DB_ID: 1370498 Reactome Database ID Release 431370498 Reactome, http://www.reactome.org ReactomeREACT_117721 has a Stoichiometric coefficient of 1 PRLR ligands:p(Y611)-PRLR:p(Y1007)-JAK2 dimer:p-SHP2 Reactome DB_ID: 1369127 Reactome Database ID Release 431369127 Reactome, http://www.reactome.org ReactomeREACT_117018 has a Stoichiometric coefficient of 1 PathwayStep5428 PathwayStep5429 PathwayStep5426 PathwayStep5427 PathwayStep5424 PathwayStep5425 IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation Although IRAK-1 was originally thought to be a key mediator of TRAF6 activation in the IL1R/TLR signaling (Dong W et al. 2006), recent studies showed that IRAK-2, but not IRAK-1, led to TRAF6 polyubiquitination (Keating SE et al 2007). IRAK-2 loss-of-function mutants, with mutated TRAF6-binding motifs, could no longer activate NF-kB and could no longer stimulate TRAF-6 ubiquitination (Keating SE et al 2007). Furthermore, the proxyvirus protein A52 - an inhibitor of all IL-1R/TLR pathways to NF-kB activation, was found to interact with both IRAK-2 and TRAF6, but not IRAK-1. Further work showed that A52 inhibits IRAK-2 functions, whereas association with TRAF6 results in A52-induced MAPK activation. The strong inhibition effect of A52 was also observed on the TLR3-NFkB axis and this observation led to the discovery that IRAK-2 is recruited to TLR3 to activate NF-kB (Keating SE et al 2007). Thus, A52 possibly inhibits MyD88-independent TLR3 pathways to NF-kB via targeting IRAK-2 as it does for other IL-1R/TLR pathways, although it remains unclear how IRAK-2 is involved in TLR3 signaling.<p>IRAK-2 was shown to have two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 Pubmed12140561 Pubmed16831874 Pubmed17878161 Reactome Database ID Release 43975163 Reactome, http://www.reactome.org ReactomeREACT_25018 Reviewed: Gillespie, ME, 2010-10-29 IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 Pubmed12856330 Pubmed14625308 Pubmed14661019 Pubmed15695821 Pubmed15767370 Pubmed16477006 Pubmed18276832 Pubmed18347055 Reactome Database ID Release 43975144 Reactome, http://www.reactome.org ReactomeREACT_25354 Reviewed: Gillespie, ME, 2010-10-29 The role of IRAK1 kinase activity in the activation of NF-kappa-B by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK1 mutants can still activate NF-kappa-B. Furthermore, stimulation of IRAK1-deficient I1A 293 cells with LMP1 (latent membrane protein 1- a known viral activator of NF-kappa-B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK1 enhances p65 Ser536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NF-kappa-B dependent target genes [Liu G et al 2008].<p> IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B. </p><p>Upon IL-1/TLR stimulation IRAK1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003]. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2010-11-15 In plasmacytoid dendritic cell induction of type I IFNs critically depends on IFN regulatory factor 7 in TLR7 and 9 signaling (Honda et al 2005). IRF-7, but not IRF3, interacts with MyD88, TRAF6, and IRAKs and translocates to the nucleus upon phosphorylation (Kawai et al 2004; Uematsu et al 2005).<p> TLR7/8 signaling was shown to induce IRF5 activation along with IRF7 [Schoenemeyer et al 2005], while IRF8 [Tsujimura H et al 2004] and IRF1 were reported to be implicated in TLR9 signaling. Pubmed11070172 Pubmed15153500 Pubmed15361868 Pubmed15767370 Pubmed16214811 Pubmed16497588 Reactome Database ID Release 43975110 Reactome, http://www.reactome.org ReactomeREACT_25120 Reviewed: Gillespie, ME, 2010-10-29 Toll Like Receptor 7/8 (TLR7/8) Cascade Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2010-11-15 Pubmed14976262 RNA can serve as a danger signal, both in its double-stranded form (that is associated with viral infection), as well as single-stranded RNA (ssRNA). Specifically, guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus-1 (HIV-1), for example, stimulate dendritic cells (DC) and macrophages to secrete interferon-alpha and proinflammatory, as well as regulatory, cytokines. This has been found to be mediated by TLR7, as well as TLR8. Separate studies showed that imidazoquinoline compounds (e.g. imiquimod and R-848, low-molecular-weight immune response modifiers that can induce the synthesis of interferon-alpha) also exert their effects in a MyD88-dependent fashion independently through TLR7 and 8 (Heil et al. 2004). Reactome Database ID Release 43168181 Reactome, http://www.reactome.org ReactomeREACT_9020 Reviewed: Gale M, Jr, 2006-10-31 16:45:01 Reviewed: Gillespie, ME, 2010-10-29 Toll Like Receptor 5 (TLR5) Cascade Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2011-08-12 ISBN0781735149 Pubmed11323673 Pubmed11489966 Reactome Database ID Release 43168176 Reactome, http://www.reactome.org ReactomeREACT_9061 Reviewed: Gale M, Jr, 2006-10-31 16:45:01 Reviewed: Gillespie, ME, 2011-02-10 TLR5 is the receptor for flagellin, the protein that forms bacterial flagella. Unlike most other Pathogen-Associated Molecular Patterns (PAMPs), flagellin does not undergo any posttranslational modifications that would distinguish it from cellular proteins. However, flagellin is extremely conserved at its amino- and carboxyl-termini, which presumably explains why it was selected as a ligand for innate immune recognition. TLR5 is expressed on epithelial cells as well as on macrophages and dendritic cells. Expression of TLR5 on intestinal epithelium is polarized such that TLR5 is expressed only on the basolateral side of the cell, as pathogenic but not commensal microbes cross the epithelial barrier. This ensures that innate immune responses are confined to pathogenic but not commensal microbes (Paul 2004; Hayashi et al. 2001; Gewirtz et al. 2001). TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation Authored: Shamovsky, V, 2010-08-25 Edited: Shamovsky, V, 2010-11-15 Pubmed18794297 Pubmed22511786 Reactome Database ID Release 43975138 Reactome, http://www.reactome.org ReactomeREACT_25024 Reviewed: Gillespie, ME, 2010-10-29 TRAF6 mediates NFkB activation via canonical phosphorylation of IKK complex by TAK1. TRAF6 and TAK1 also regulate MAPK cascades leading to the activation of AP-1. MyD88 dependent cascade initiated on endosome Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2010-11-15 Pubmed15276183 Pubmed16497588 Pubmed18652679 Pubmed20237413 Reactome Database ID Release 43975155 Reactome, http://www.reactome.org ReactomeREACT_25222 Reviewed: Gillespie, ME, 2010-10-29 Upon binding of their ligands, TLR7/8 and TLR9 recruit a cytoplasmic adaptor MyD88 and IRAKs, downstream of which the signaling pathways are divided to induce either inflammatory cytokines or type I IFNs. PathwayStep5623 IKK complex recruitment mediated by RIP1 Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 Pubmed14530355 Pubmed16115877 Pubmed16603398 Reactome Database ID Release 43937041 Reactome, http://www.reactome.org ReactomeREACT_25374 Receptor-interacting protein 1 (RIP1) mediates the activation of proinflammatory cytokines via intermediate induction of IKK complex in NFkB pathways [Ea et al. 2006]. Poly(I-C) treatment stimulated the recruitment of RIP1, TRAF6, and TAK1 to the TLR3 receptor complex in human embryonic kidney HEK293 transfected with FLAG-tagged TLR3 [Cusson-Hermance et al. 2005]. RIP1 was shown to be dispensable for TRIF-dependent activation of IRF3, which occurs in a TRIF/TBK1/IKKi-dependent manner [Cusson-Hermance et al. 2005, Sato et al. 2003] Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 PathwayStep5622 PathwayStep5625 TRAF6 mediated induction of TAK1 complex Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 GENE ONTOLOGYGO:0007249 In human, together with ubiquitin-conjugating E2-type enzymes UBC13 and UEV1A (also known as UBE2V1), TRAF6 catalyses Lys63-linked ubiquitination. It is believed that auto polyubiquitination and oligomerization of TRAF6 is followed by binding the ubiquitin receptors of TAB2 or TAB3 (TAK1 binding protein 2 and 3), which stimulates phosphorylation and activation of TGF beta-activated kinase 1(TAK1).<p>TAK1 phosphorylates IKK alpha and IKK beta, which in turn phosphorylate NF-kB inhibitors - IkB and eventually results in IkB degradation and NF-kB translocation to the nucleus. Also TAK1 mediates JNK and p38 MAP kinases activation by phosphorylating MKK4/7 and MKK3/6 respectivly resulting in the activation of many transcription factors. <p>The role of TRAF6 is somewhat controversial and probably cell type specific. TRAF6 autoubiquitination was found to be dispensable for TRAF6 function to activate TAK1 pathway. These findings are consistent with the new mechanism of TRAF6-mediated NF-kB activation that was suggested by Xia et al. (2009). TRAF6 generates unanchored Lys63-linked polyubiquitin chains that bind to the regulatory subunits of TAK1 (TAB2 or TAB3) and IKK(NEMO), leading to the activation of the kinases.<p> Xia et al. (2009) demonstrated in vitro that unlike polyubiquitin chains covalently attached to TRAF6 or IRAK, TAB2 and NEMO-associated ubiquitin chains were found to be unanchored and susceptible to N-terminal ubiquitin cleavage. Only K63-linked polyubiquitin chains, but not monomeric ubiquitin, activated TAK1 in a dose-dependent manner. Optimal activation of the IKK complex was achieved using ubiquitin polymers containing both K48 and K63 linkages.<p>Furthermore, the authors proposed that the TAK1 complexes might be brougt in close proximity by binding several TAB2/3 to a single polyubiquitin chain to facilitate TAK1 kinase trans-phosphorylation. Alternativly, the possibility that polyUb binding promotes allosteric activation of TAK1 complex should be considered (Walsh et al 2008). Pubmed19112497 Pubmed19675569 Reactome Database ID Release 43937072 Reactome, http://www.reactome.org ReactomeREACT_25351 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 PathwayStep5624 TRIF-mediated programmed cell death Authored: Shamovsky, V, 2012-05-15 Edited: Shamovsky, V, 2012-11-19 Pubmed12181749 Pubmed14739303 Pubmed15814722 Pubmed20019748 Pubmed21737329 Pubmed21737330 Pubmed22421964 Reactome Database ID Release 432562578 Reactome, http://www.reactome.org ReactomeREACT_150361 Reviewed: Fitzgerald, Katherine A, 2012-11-13 TLR3 and -4 trigger TRIF-dependent programmed cell death in various human and mouse cells [Kalai M et al 2002; Han KJ et al 2004; Kaiser WJ and Offermann MK 2005; Estornes Y et al 2012; He S et al 2011]. Apoptosis is a prevalent form of programmed cell death and is mediated by the activation of a set of caspases. In addition to apoptosis, TLR3/TLR4 activation induces RIP3-dependent necroptosis. These two programmed cell-death pathways may suppress each other. When the caspase activity is impaired or inhibited, certain cell types switch the apoptotic death program to necroptosis in response to various stimuli (TNF, Fas, viral infection and other stress stimuli) [Kalai M et al 2002; Weber A et al 2010; Feoktistova M et al 2011, Tenev et al 2011]. PathwayStep5627 PathwayStep5626 PathwayStep5629 PathwayStep5628 NOTCH1 Coactivator Complex Reactome DB_ID: 1604462 Reactome Database ID Release 431604462 Reactome, http://www.reactome.org ReactomeREACT_119935 has a Stoichiometric coefficient of 1 NICD1:RBPJ:SNW1 Reactome DB_ID: 1604460 Reactome Database ID Release 431604460 Reactome, http://www.reactome.org ReactomeREACT_119914 has a Stoichiometric coefficient of 1 NOTCH3 Coactivator Complex Reactome DB_ID: 2248837 Reactome Database ID Release 432248837 Reactome, http://www.reactome.org ReactomeREACT_121818 has a Stoichiometric coefficient of 1 miR-34 RISC Converted from EntitySet in Reactome Reactome DB_ID: 1606685 Reactome Database ID Release 431606685 Reactome, http://www.reactome.org ReactomeREACT_118950 miR-34-induced Silencing Complex PathwayStep5630 PathwayStep5631 PathwayStep5632 E2F1/3:DP1/2 Reactome DB_ID: 2248825 Reactome Database ID Release 432248825 Reactome, http://www.reactome.org ReactomeREACT_124495 has a Stoichiometric coefficient of 1 NOTCH1 mRNA:miR-34 RISC Reactome DB_ID: 1606698 Reactome Database ID Release 431606698 Reactome, http://www.reactome.org ReactomeREACT_119152 has a Stoichiometric coefficient of 1 miR-34 Endonucleolytic RISC Reactome DB_ID: 1606684 Reactome Database ID Release 431606684 Reactome, http://www.reactome.org ReactomeREACT_119418 has a Stoichiometric coefficient of 1 miR-34 Endonucleolytic Minimal RISC Argonaute2: miR-34 (single-stranded) Reactome DB_ID: 1606688 Reactome Database ID Release 431606688 Reactome, http://www.reactome.org ReactomeREACT_119027 has a Stoichiometric coefficient of 1 miR-34 Nonendonucleolytic RISC Reactome DB_ID: 1606692 Reactome Database ID Release 431606692 Reactome, http://www.reactome.org ReactomeREACT_120055 has a Stoichiometric coefficient of 1 Argonaute1/3/4: miR-34 Reactome DB_ID: 1606686 Reactome Database ID Release 431606686 Reactome, http://www.reactome.org ReactomeREACT_119678 has a Stoichiometric coefficient of 1 miR-34 Nonendonucleolytic Minimal RISC PathwayStep5619 PathwayStep5614 PathwayStep5613 PathwayStep5612 PathwayStep5611 PathwayStep5618 PathwayStep5617 PathwayStep5616 PathwayStep5615 P-Shc1:P-Erbb2mut Reactome DB_ID: 1250490 Reactome Database ID Release 431250490 Reactome, http://www.reactome.org ReactomeREACT_116531 has a Stoichiometric coefficient of 1 Argonaute1/3/4: miR-200B/C Reactome DB_ID: 1614234 Reactome Database ID Release 431614234 Reactome, http://www.reactome.org ReactomeREACT_120264 has a Stoichiometric coefficient of 1 miR-200B/C Nonendonucleolytic Minimal RISC GRB2:Sos1:P-Shc1:P-Erbb2mut Reactome DB_ID: 1250487 Reactome Database ID Release 431250487 Reactome, http://www.reactome.org ReactomeREACT_117901 has a Stoichiometric coefficient of 1 NOTCH1 mRNA:miR-200B/C RISC Reactome DB_ID: 1911483 Reactome Database ID Release 431911483 Reactome, http://www.reactome.org ReactomeREACT_119797 has a Stoichiometric coefficient of 1 FKBP1A:Tacrolimus Reactome DB_ID: 2026019 Reactome Database ID Release 432026019 Reactome, http://www.reactome.org ReactomeREACT_120070 has a Stoichiometric coefficient of 1 miR-200B/C Endonucleolytic Minimal RISC Argonaute2: miR-200B/C (single-stranded) Reactome DB_ID: 1614235 Reactome Database ID Release 431614235 Reactome, http://www.reactome.org ReactomeREACT_119561 has a Stoichiometric coefficient of 1 Cyclophilin A:Cyclosporin A Reactome DB_ID: 2026008 Reactome Database ID Release 432026008 Reactome, http://www.reactome.org ReactomeREACT_119713 has a Stoichiometric coefficient of 1 miR-200B/C Nonendonucleolytic RISC Reactome DB_ID: 1614236 Reactome Database ID Release 431614236 Reactome, http://www.reactome.org ReactomeREACT_119936 has a Stoichiometric coefficient of 1 PathwayStep5620 miR-200B/C RISC Converted from EntitySet in Reactome Reactome DB_ID: 1614237 Reactome Database ID Release 431614237 Reactome, http://www.reactome.org ReactomeREACT_119264 miR-200B/C-induced Silencing Complex PathwayStep5621 miR-200B/C Endonucleolytic RISC Reactome DB_ID: 1614231 Reactome Database ID Release 431614231 Reactome, http://www.reactome.org ReactomeREACT_120288 has a Stoichiometric coefficient of 1 PRDM9:DNA Complex Reactome DB_ID: 912415 Reactome Database ID Release 43912415 Reactome, http://www.reactome.org ReactomeREACT_27470 has a Stoichiometric coefficient of 1 Nucleosome with Histone H3 Dimethylated at Lysine-4 Reactome DB_ID: 1214200 Reactome Database ID Release 431214200 Reactome, http://www.reactome.org ReactomeREACT_27650 has a Stoichiometric coefficient of 2 ERM:PIP2 Reactome DB_ID: 443660 Reactome Database ID Release 43443660 Reactome, http://www.reactome.org ReactomeREACT_22835 has a Stoichiometric coefficient of 1 miR-449 Endonucleolytic Minimal RISC Argonaute2: miR-449 (single-stranded) Reactome DB_ID: 1606549 Reactome Database ID Release 431606549 Reactome, http://www.reactome.org ReactomeREACT_119133 has a Stoichiometric coefficient of 1 L1:ANK_RAT Reactome DB_ID: 443050 Reactome Database ID Release 43443050 Reactome, http://www.reactome.org ReactomeREACT_22908 has a Stoichiometric coefficient of 1 miR-449 Nonendonucleolytic RISC Reactome DB_ID: 1606554 Reactome Database ID Release 431606554 Reactome, http://www.reactome.org ReactomeREACT_119658 has a Stoichiometric coefficient of 1 L1 trans-homodimer Reactome DB_ID: 191438 Reactome Database ID Release 43191438 Reactome, http://www.reactome.org ReactomeREACT_22570 has a Stoichiometric coefficient of 1 miR-449 RISC Converted from EntitySet in Reactome Reactome DB_ID: 1606557 Reactome Database ID Release 431606557 Reactome, http://www.reactome.org ReactomeREACT_120304 miR-449-induced Silencing Complex pL1:Ezrin Reactome DB_ID: 374575 Reactome Database ID Release 43374575 Reactome, http://www.reactome.org ReactomeREACT_22884 has a Stoichiometric coefficient of 1 miR-449 Endonucleolytic RISC Reactome DB_ID: 1606551 Reactome Database ID Release 431606551 Reactome, http://www.reactome.org ReactomeREACT_120124 has a Stoichiometric coefficient of 1 PathwayStep5609 PathwayStep5608 PathwayStep5605 PathwayStep5604 PathwayStep5607 PathwayStep5606 PathwayStep3389 PathwayStep5601 PathwayStep5600 PathwayStep5603 PathwayStep5602 PathwayStep3394 PathwayStep3395 PathwayStep3392 PathwayStep5610 PathwayStep3393 PathwayStep3398 PathwayStep3399 Tf:TfR1 complex Reactome DB_ID: 917833 Reactome Database ID Release 43917833 Reactome, http://www.reactome.org ReactomeREACT_25753 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 Reactome DB_ID: 2169047 Reactome Database ID Release 432169047 Reactome, http://www.reactome.org ReactomeREACT_125417 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep3396 Ferritin Complex Reactome DB_ID: 434350 Reactome Database ID Release 43434350 Reactome, http://www.reactome.org ReactomeREACT_19855 has a Stoichiometric coefficient of 24 TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7:UCHL5/USP15 Reactome DB_ID: 2179287 Reactome Database ID Release 432179287 Reactome, http://www.reactome.org ReactomeREACT_124446 has a Stoichiometric coefficient of 1 PathwayStep3397 ATP2C1/2:Mg2+ Reactome DB_ID: 936921 Reactome Database ID Release 43936921 Reactome, http://www.reactome.org ReactomeREACT_27002 has a Stoichiometric coefficient of 1 TGFB1:TGFBR2:p-TGFBR1:Ub-SMAD7 Reactome DB_ID: 2179328 Reactome Database ID Release 432179328 Reactome, http://www.reactome.org ReactomeREACT_122134 has a Stoichiometric coefficient of 1 Na+/K+-transporting ATPase trimer Reactome DB_ID: 936770 Reactome Database ID Release 43936770 Reactome, http://www.reactome.org ReactomeREACT_26819 has a Stoichiometric coefficient of 1 SMAD2:SMURF2 Reactome DB_ID: 2176457 Reactome Database ID Release 432176457 Reactome, http://www.reactome.org ReactomeREACT_122626 has a Stoichiometric coefficient of 1 K+-transporting ATPase heterodimer Reactome DB_ID: 937301 Reactome Database ID Release 43937301 Reactome, http://www.reactome.org ReactomeREACT_26485 has a Stoichiometric coefficient of 1 Ub-SMAD2 Reactome DB_ID: 2176443 Reactome Database ID Release 432176443 Reactome, http://www.reactome.org ReactomeREACT_121470 has a Stoichiometric coefficient of 1 HTR3 receptor heteropentamer:serotonin Reactome DB_ID: 975348 Reactome Database ID Release 43975348 Reactome, http://www.reactome.org ReactomeREACT_25951 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 5 SMAD3:STUB1 Reactome DB_ID: 2187365 Reactome Database ID Release 432187365 Reactome, http://www.reactome.org ReactomeREACT_124835 has a Stoichiometric coefficient of 1 Glycine receptor heteropentamer:glycine Reactome DB_ID: 975385 Reactome Database ID Release 43975385 Reactome, http://www.reactome.org ReactomeREACT_26060 has a Stoichiometric coefficient of 1 Ub-SMAD3 Reactome DB_ID: 2187371 Reactome Database ID Release 432187371 Reactome, http://www.reactome.org ReactomeREACT_123646 has a Stoichiometric coefficient of 1 PathwayStep3390 TGFB1:p-TGFBR:Ub-Smad7 Reactome DB_ID: 2179330 Reactome Database ID Release 432179330 Reactome, http://www.reactome.org ReactomeREACT_125673 has a Stoichiometric coefficient of 1 p-2S-SMAD2/3:PMEPA1 Reactome DB_ID: 2187343 Reactome Database ID Release 432187343 Reactome, http://www.reactome.org ReactomeREACT_122643 has a Stoichiometric coefficient of 1 PathwayStep3391 Dimeric TGFB1:TGFBR2 homodimer Dimeric TGF-beta1:type II receptor complex Reactome DB_ID: 170865 Reactome Database ID Release 43170865 Reactome, http://www.reactome.org ReactomeREACT_7218 has a Stoichiometric coefficient of 1 SMAD2/3:PMEPA1 Reactome DB_ID: 2187341 Reactome Database ID Release 432187341 Reactome, http://www.reactome.org ReactomeREACT_121843 has a Stoichiometric coefficient of 1 CEACAM heterodimer Reactome DB_ID: 202716 Reactome Database ID Release 43202716 Reactome, http://www.reactome.org ReactomeREACT_12134 has a Stoichiometric coefficient of 2 p-2S-SMAD2/3:MTMR4 Reactome DB_ID: 2187399 Reactome Database ID Release 432187399 Reactome, http://www.reactome.org ReactomeREACT_123224 has a Stoichiometric coefficient of 1 Cytochrome b reductase 1 Reactome DB_ID: 917916 Reactome Database ID Release 43917916 Reactome, http://www.reactome.org ReactomeREACT_25782 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep3379 PathwayStep3378 PathwayStep3381 PathwayStep3382 PathwayStep3383 PathwayStep3384 PathwayStep3385 holo-Serotransferrin Reactome DB_ID: 917889 Reactome Database ID Release 43917889 Reactome, http://www.reactome.org ReactomeREACT_26297 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Tight Junction Complex:TGFBR1:PARD6A:RHOA Reactome DB_ID: 2134509 Reactome Database ID Release 432134509 Reactome, http://www.reactome.org ReactomeREACT_124021 has a Stoichiometric coefficient of 1 PathwayStep3386 TfR1 dimer Reactome DB_ID: 917784 Reactome Database ID Release 43917784 Reactome, http://www.reactome.org ReactomeREACT_26822 has a Stoichiometric coefficient of 2 Tight Junction Complex:TGFB1:TGFBR2:TGFBR1:PARD6A:RHOA Reactome DB_ID: 2134522 Reactome Database ID Release 432134522 Reactome, http://www.reactome.org ReactomeREACT_122365 has a Stoichiometric coefficient of 1 PathwayStep3387 Tight Junction Complex:PARD6A:RHOA Reactome DB_ID: 2134514 Reactome Database ID Release 432134514 Reactome, http://www.reactome.org ReactomeREACT_121703 has a Stoichiometric coefficient of 1 PathwayStep3388 PARD3:PARD6A:PRKCZ Reactome DB_ID: 2133770 Reactome Database ID Release 432133770 Reactome, http://www.reactome.org ReactomeREACT_124676 has a Stoichiometric coefficient of 1 holo-Serotransferrin Reactome DB_ID: 918029 Reactome Database ID Release 43918029 Reactome, http://www.reactome.org ReactomeREACT_26872 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PARD3:p-PARD6A:PRKCZ Reactome DB_ID: 2134528 Reactome Database ID Release 432134528 Reactome, http://www.reactome.org ReactomeREACT_125201 has a Stoichiometric coefficient of 1 TfR1 dimer Reactome DB_ID: 917971 Reactome Database ID Release 43917971 Reactome, http://www.reactome.org ReactomeREACT_26380 has a Stoichiometric coefficient of 2 Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA:SMURF1 Reactome DB_ID: 2160929 Reactome Database ID Release 432160929 Reactome, http://www.reactome.org ReactomeREACT_121985 has a Stoichiometric coefficient of 1 hTf:TfR1 complex Reactome DB_ID: 917834 Reactome Database ID Release 43917834 Reactome, http://www.reactome.org ReactomeREACT_26372 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:RHOA Reactome DB_ID: 2134534 Reactome Database ID Release 432134534 Reactome, http://www.reactome.org ReactomeREACT_124952 has a Stoichiometric coefficient of 1 hTf:TfR1 complex Reactome DB_ID: 917799 Reactome Database ID Release 43917799 Reactome, http://www.reactome.org ReactomeREACT_26531 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Tight Junction Complex:p-PARD6A:RHOA Reactome DB_ID: 2134529 Reactome Database ID Release 432134529 Reactome, http://www.reactome.org ReactomeREACT_125212 has a Stoichiometric coefficient of 1 ATP6V0C hexamer Reactome DB_ID: 912571 Reactome Database ID Release 43912571 Reactome, http://www.reactome.org ReactomeREACT_24155 has a Stoichiometric coefficient of 6 Tf:TfR1 complex Reactome DB_ID: 917912 Reactome Database ID Release 43917912 Reactome, http://www.reactome.org ReactomeREACT_26824 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 V-ATPase Reactome DB_ID: 912600 Reactome Database ID Release 43912600 Reactome, http://www.reactome.org ReactomeREACT_24332 has a Stoichiometric coefficient of 1 Tight Junction Complex:TGFB1:TGFBR2:p-TGFBR1:p-PARD6A:Ub-RHOA:SMURF1 Reactome DB_ID: 2160934 Reactome Database ID Release 432160934 Reactome, http://www.reactome.org ReactomeREACT_122343 has a Stoichiometric coefficient of 1 PathwayStep3380 ATP6V0 Reactome DB_ID: 912585 Reactome Database ID Release 43912585 Reactome, http://www.reactome.org ReactomeREACT_24590 has a Stoichiometric coefficient of 1 CCND1:CREBBP Reactome DB_ID: 2247939 Reactome Database ID Release 432247939 Reactome, http://www.reactome.org ReactomeREACT_124278 has a Stoichiometric coefficient of 1 PathwayStep3369 PathwayStep3367 PathwayStep3368 AQP6 tetramer Aquaporin-6 tetramer Reactome DB_ID: 432253 Reactome Database ID Release 43432253 Reactome, http://www.reactome.org ReactomeREACT_24861 has a Stoichiometric coefficient of 4 AQP3/7/9/10 AQP3, AQP7, AQP9, AQP10 Aqauporins that transport glycerol across the plasma membrane. Aquaporin-3, Aquaporin-7, Aquaporin-9, Aquaporin-10 Converted from EntitySet in Reactome Reactome DB_ID: 507882 Reactome Database ID Release 43507882 Reactome, http://www.reactome.org ReactomeREACT_24387 p-S256-AQP2 Phosphorylated Aquaporin-2 tetramer Reactome DB_ID: 432217 Reactome Database ID Release 43432217 Reactome, http://www.reactome.org ReactomeREACT_24418 has a Stoichiometric coefficient of 4 TGFB1:p-TGFBR:STRAP Reactome DB_ID: 2127564 Reactome Database ID Release 432127564 Reactome, http://www.reactome.org ReactomeREACT_125338 has a Stoichiometric coefficient of 1 AQP2 tetramer Aquaporin-2 tetramer Reactome DB_ID: 432228 Reactome Database ID Release 43432228 Reactome, http://www.reactome.org ReactomeREACT_24078 has a Stoichiometric coefficient of 4 TGFB1:p-TGFBR:I-SMAD7 Reactome DB_ID: 173476 Reactome Database ID Release 43173476 Reactome, http://www.reactome.org ReactomeREACT_7842 TGF-beta 1:type II receptor:Phospho-type I receptor:I-SMAD7 complex TGFB1:TGFBR2:p-5S-T185-TGFBR1:I-SMAD7 has a Stoichiometric coefficient of 1 RAB11A:GTP Reactome DB_ID: 1458542 Reactome Database ID Release 431458542 Reactome, http://www.reactome.org ReactomeREACT_120028 has a Stoichiometric coefficient of 1 TGFB1:p-TGFBR:STRAP:SMAD7 Reactome DB_ID: 2128993 Reactome Database ID Release 432128993 Reactome, http://www.reactome.org ReactomeREACT_122595 has a Stoichiometric coefficient of 1 MYO5B:RABFIP2:RAB11A Reactome DB_ID: 2028701 Reactome Database ID Release 432028701 Reactome, http://www.reactome.org ReactomeREACT_119400 has a Stoichiometric coefficient of 1 TGFBR:STRAP Reactome DB_ID: 2127608 Reactome Database ID Release 432127608 Reactome, http://www.reactome.org ReactomeREACT_122598 TGFB1:TGFBR2:TGFBR1 has a Stoichiometric coefficient of 1 G-alpha(s):GDP:G-beta:G-gamma Heterotrimeric G-alpha(s): GDP:G-beta: G-gamma Complex Reactome DB_ID: 432200 Reactome Database ID Release 43432200 Reactome, http://www.reactome.org ReactomeREACT_24149 has a Stoichiometric coefficient of 1 TGFB1:p-TGFBR:SARA:SMAD2/3 Reactome DB_ID: 171266 Reactome Database ID Release 43171266 Reactome, http://www.reactome.org ReactomeREACT_7757 TGF-beta 1:type II receptor:Phospho-type I receptor:SARA:R-SMAD complex TGFB1:TGFBR2:p-5S-T185-TGFBR1:SARA:SMAD2/3 has a Stoichiometric coefficient of 1 Vasopressin receptor type 2:AVP Reactome DB_ID: 392261 Reactome Database ID Release 43392261 Reactome, http://www.reactome.org ReactomeREACT_17670 has a Stoichiometric coefficient of 1 TGFBR1:FKBP1A Reactome DB_ID: 2187279 Reactome Database ID Release 432187279 Reactome, http://www.reactome.org ReactomeREACT_122814 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 AVPR2:AVP:G-alpha(s):GTP:G-beta:G-gamma Reactome DB_ID: 432187 Reactome Database ID Release 43432187 Reactome, http://www.reactome.org ReactomeREACT_24244 Vasopressin Receptor Type 2:AVP: Heterotrimeric G-protein:GTP Complex has a Stoichiometric coefficient of 1 TGFB1:p-TGFBR:SARA Reactome DB_ID: 171173 Reactome Database ID Release 43171173 Reactome, http://www.reactome.org ReactomeREACT_7772 TGF-beta 1:type II receptor:Phospho-type I receptor:SARA complex TGFB1:TGFBR2:p-5S-T185-TGBR1:SARA has a Stoichiometric coefficient of 1 AVPR2:AVP:G-alpha(s):GDP:G-beta:G-gamma Reactome DB_ID: 432197 Reactome Database ID Release 43432197 Reactome, http://www.reactome.org ReactomeREACT_24450 Vasopressin Receptor Type 2:AVP: Heterotrimeric G-protein:GDP Complex has a Stoichiometric coefficient of 1 TGFB1:p-TGFBR:SARA:p-2S-SMAD2/3 Reactome DB_ID: 171180 Reactome Database ID Release 43171180 Reactome, http://www.reactome.org ReactomeREACT_6989 TGF-beta 1:type II receptor:Phospho-type I receptor:SARA:Phospho-R-SMAD complex TGFB1:TGFBR2:p-5S-T185-TGFBR1:SARA:p-S465/423,467/425-SMAD2/3 TGFB1:p-TGFBR:SARA:p-S465/423,467/425-SMAD2/3 has a Stoichiometric coefficient of 1 PathwayStep3377 PathwayStep3376 PathwayStep3375 AQP9/10 AQP9, AQP10 Aquaporin-9, Aquaporin-10 Aquaporins that transport urea Converted from EntitySet in Reactome Reactome DB_ID: 507881 Reactome Database ID Release 43507881 Reactome, http://www.reactome.org ReactomeREACT_24403 Large latent complex of TGFB1 Large latent complex of TGF-beta 1 Reactome DB_ID: 177102 Reactome Database ID Release 43177102 Reactome, http://www.reactome.org ReactomeREACT_7797 has a Stoichiometric coefficient of 2 PathwayStep3374 PathwayStep3373 PathwayStep3372 PathwayStep3371 PathwayStep3370 PathwayStep3356 PathwayStep3357 PathwayStep3358 PathwayStep3359 Lens fiber major intrinsic protein (AQP0) tetramer Reactome DB_ID: 432251 Reactome Database ID Release 43432251 Reactome, http://www.reactome.org ReactomeREACT_24156 has a Stoichiometric coefficient of 4 MTP1:Ceruloplasmin (copper complex) Reactome DB_ID: 904825 Reactome Database ID Release 43904825 Reactome, http://www.reactome.org ReactomeREACT_24142 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 GADD34:PP1 Reactome DB_ID: 2162158 Reactome Database ID Release 432162158 Reactome, http://www.reactome.org ReactomeREACT_124291 has a Stoichiometric coefficient of 1 AQP0/1/2/3/4/5/7/8/9/10 AQP0 (MIP), AQP1, p-AQP2, AQP3, AQP4, AQP5, AQP7, AQP8, AQP9, AQP10 Aquaporin-0, Aquaporin-1, Phospho-Aquaporin-2, Aquaporin-3, Aquaporin-4, Aquaporin-5, Aquaporin-7, Aquaporin-8, Aquaporin-9, Aquaporin-10 Aquaporins that transport water across the plasma membrane. Converted from EntitySet in Reactome Reactome DB_ID: 507884 Reactome Database ID Release 43507884 Reactome, http://www.reactome.org ReactomeREACT_24033 AQP10 tetramer Aquaporin-10 tetramer Reactome DB_ID: 432247 Reactome Database ID Release 43432247 Reactome, http://www.reactome.org ReactomeREACT_24728 has a Stoichiometric coefficient of 4 TGFB1:TGFBR2:p-TGFBR1:SMAD7:SMURF/NEDD4L Reactome DB_ID: 2169025 Reactome Database ID Release 432169025 Reactome, http://www.reactome.org ReactomeREACT_123560 has a Stoichiometric coefficient of 1 AQP9 tetramer Aquaporin-9 tetramer Reactome DB_ID: 432249 Reactome Database ID Release 43432249 Reactome, http://www.reactome.org ReactomeREACT_24736 has a Stoichiometric coefficient of 4 SMAD7:SMURF/NEDD4L Reactome DB_ID: 2169026 Reactome Database ID Release 432169026 Reactome, http://www.reactome.org ReactomeREACT_123020 has a Stoichiometric coefficient of 1 Aquaporin-8 tetramer Reactome DB_ID: 432244 Reactome Database ID Release 43432244 Reactome, http://www.reactome.org ReactomeREACT_124437 has a Stoichiometric coefficient of 4 SMAD7:NEDD4L Reactome DB_ID: 2176419 Reactome Database ID Release 432176419 Reactome, http://www.reactome.org ReactomeREACT_124391 has a Stoichiometric coefficient of 1 AQP7 tetramer Aquaporin-7 tetramer Reactome DB_ID: 432243 Reactome Database ID Release 43432243 Reactome, http://www.reactome.org ReactomeREACT_24294 has a Stoichiometric coefficient of 4 SMAD7:NEDD4L Reactome DB_ID: 2176418 Reactome Database ID Release 432176418 Reactome, http://www.reactome.org ReactomeREACT_125398 has a Stoichiometric coefficient of 1 AQP5 tetramer Aquaporin-5 tetramer Reactome DB_ID: 432245 Reactome Database ID Release 43432245 Reactome, http://www.reactome.org ReactomeREACT_24404 has a Stoichiometric coefficient of 4 SMAD7:SMURF1 Reactome DB_ID: 2167927 Reactome Database ID Release 432167927 Reactome, http://www.reactome.org ReactomeREACT_122445 has a Stoichiometric coefficient of 1 AQP4 tetramer Aquaporin-4 tetramer Reactome DB_ID: 432252 Reactome Database ID Release 43432252 Reactome, http://www.reactome.org ReactomeREACT_24757 has a Stoichiometric coefficient of 4 SMAD7:SMURF1:XPO1 Reactome DB_ID: 2167923 Reactome Database ID Release 432167923 Reactome, http://www.reactome.org ReactomeREACT_122262 has a Stoichiometric coefficient of 1 AQP3 tetramer Aquaporin-3 tetramer Reactome DB_ID: 432250 Reactome Database ID Release 43432250 Reactome, http://www.reactome.org ReactomeREACT_24542 has a Stoichiometric coefficient of 4 SMAD7:SMURF1 Reactome DB_ID: 2167913 Reactome Database ID Release 432167913 Reactome, http://www.reactome.org ReactomeREACT_124389 has a Stoichiometric coefficient of 1 p-S256-AQP2 Phosphorylated Aquaporin-2 tetramer Reactome DB_ID: 432226 Reactome Database ID Release 43432226 Reactome, http://www.reactome.org ReactomeREACT_24265 has a Stoichiometric coefficient of 4 SMAD7:SMURF2 Reactome DB_ID: 2167883 Reactome Database ID Release 432167883 Reactome, http://www.reactome.org ReactomeREACT_124286 has a Stoichiometric coefficient of 1 PathwayStep3364 SMAD7:SMURF2 Reactome DB_ID: 2167870 Reactome Database ID Release 432167870 Reactome, http://www.reactome.org ReactomeREACT_121453 has a Stoichiometric coefficient of 1 PathwayStep3363 TGFB1:p-TGFBR:I-SMAD7:GADD34:PP1:SARA Reactome DB_ID: 2167884 Reactome Database ID Release 432167884 Reactome, http://www.reactome.org ReactomeREACT_122135 has a Stoichiometric coefficient of 1 PathwayStep3366 PathwayStep3365 PathwayStep3360 PathwayStep3362 PathwayStep3361 PathwayStep3347 PathwayStep3348 PathwayStep3345 PathwayStep3346 PathwayStep3349 ABCD1/2/3 dimers Converted from EntitySet in Reactome Reactome DB_ID: 1456465 Reactome Database ID Release 431456465 Reactome, http://www.reactome.org ReactomeREACT_111783 ABCD1:ABCD2 Reactome DB_ID: 1456457 Reactome Database ID Release 431456457 Reactome, http://www.reactome.org ReactomeREACT_111345 has a Stoichiometric coefficient of 1 ABCD1:ABCD3 Reactome DB_ID: 1456460 Reactome Database ID Release 431456460 Reactome, http://www.reactome.org ReactomeREACT_111838 has a Stoichiometric coefficient of 1 ABCD2:ABCD3 Reactome DB_ID: 1456454 Reactome Database ID Release 431456454 Reactome, http://www.reactome.org ReactomeREACT_111594 has a Stoichiometric coefficient of 1 ABCG4 dimer Reactome DB_ID: 1454940 Reactome Database ID Release 431454940 Reactome, http://www.reactome.org ReactomeREACT_111598 has a Stoichiometric coefficient of 2 ABC7 dimer Reactome DB_ID: 1369041 Reactome Database ID Release 431369041 Reactome, http://www.reactome.org ReactomeREACT_111663 has a Stoichiometric coefficient of 2 Heme transporters Converted from EntitySet in Reactome Reactome DB_ID: 1369030 Reactome Database ID Release 431369030 Reactome, http://www.reactome.org ReactomeREACT_111880 mABC1 dimer Reactome DB_ID: 1369073 Reactome Database ID Release 431369073 Reactome, http://www.reactome.org ReactomeREACT_111815 has a Stoichiometric coefficient of 2 mABC2 dimer Reactome DB_ID: 1368989 Reactome Database ID Release 431368989 Reactome, http://www.reactome.org ReactomeREACT_111739 has a Stoichiometric coefficient of 2 MTP1:Hephaestin (copper complex) Reactome DB_ID: 904821 Reactome Database ID Release 43904821 Reactome, http://www.reactome.org ReactomeREACT_24553 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 MTABC3 dimer Reactome DB_ID: 1368982 Reactome Database ID Release 431368982 Reactome, http://www.reactome.org ReactomeREACT_111504 has a Stoichiometric coefficient of 2 PathwayStep3351 PathwayStep3350 PathwayStep3355 PathwayStep3354 PathwayStep3353 PathwayStep3352 PathwayStep3334 PathwayStep3335 PathwayStep3336 PathwayStep3337 PathwayStep3338 PathwayStep3339 TGFB1:TGFBR2:TGFBR1:Strap Reactome DB_ID: 2128989 Reactome Database ID Release 432128989 Reactome, http://www.reactome.org ReactomeREACT_124928 has a Stoichiometric coefficient of 1 mNICD1 Chimeric Enhancer Complex Reactome DB_ID: 2065276 Reactome Database ID Release 432065276 Reactome, http://www.reactome.org ReactomeREACT_119161 has a Stoichiometric coefficient of 1 Nephrin dimer:IQGAP1 Reactome DB_ID: 451398 Reactome Database ID Release 43451398 Reactome, http://www.reactome.org ReactomeREACT_24686 has a Stoichiometric coefficient of 1 Nephrin dimer:adherins junction-associated proteins Reactome DB_ID: 451387 Reactome Database ID Release 43451387 Reactome, http://www.reactome.org ReactomeREACT_24676 has a Stoichiometric coefficient of 1 ABCA7-1:ApoA1 complex Reactome DB_ID: 382558 Reactome Database ID Release 43382558 Reactome, http://www.reactome.org ReactomeREACT_17496 has a Stoichiometric coefficient of 1 ABCD1/2/3 dimers Converted from EntitySet in Reactome Reactome DB_ID: 382604 Reactome Database ID Release 43382604 Reactome, http://www.reactome.org ReactomeREACT_15669 PEX19:ABCD1/2/3 Reactome DB_ID: 382586 Reactome Database ID Release 43382586 Reactome, http://www.reactome.org ReactomeREACT_15838 has a Stoichiometric coefficient of 1 ABCD2:ABCD3 Reactome DB_ID: 1456467 Reactome Database ID Release 431456467 Reactome, http://www.reactome.org ReactomeREACT_111357 has a Stoichiometric coefficient of 1 ABCD1:ABCD3 Reactome DB_ID: 1456463 Reactome Database ID Release 431456463 Reactome, http://www.reactome.org ReactomeREACT_111625 has a Stoichiometric coefficient of 1 ABCD1:ABCD2 Reactome DB_ID: 1456464 Reactome Database ID Release 431456464 Reactome, http://www.reactome.org ReactomeREACT_111664 has a Stoichiometric coefficient of 1 ALDP ABCD1:ABCD1 Reactome DB_ID: 382584 Reactome Database ID Release 43382584 Reactome, http://www.reactome.org ReactomeREACT_17771 has a Stoichiometric coefficient of 2 PathwayStep3340 PathwayStep3342 PathwayStep3341 PathwayStep3344 PathwayStep3343 MADCAM interacts with Integrin alpha4beta7 Authored: de Bono, B, 2007-07-08 12:58:15 Mucosal addressin cell adhesion molecule (MADCAM1) is present in the endothelium of mucosa, and binds alpha-4 beta-7 integrin and L-selectin, regulating both the passage and retention of leukocytes in mucosal tissues. MADCAM1 has been shown to be present as a homodimer. Pubmed11807247 Pubmed9700512 Reactome Database ID Release 43199032 Reactome, http://www.reactome.org ReactomeREACT_11199 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 has a Stoichiometric coefficient of 2 Interaction of integrin alpha5beta1 with Osteopontin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Osteopontin (OPN) is expressed by numerous cell types and is involved in normal tissue remodeling processes such as in bone resorption, angiogenesis, wound healing and tissue injury. OPN is a ligand for a number of integrins including alpha5beta1. Alpha5beta1 interacts with the cryptic RGD site present in the thrombin cleaved fragment of OPN. Pubmed10673366 Reactome Database ID Release 43265431 Reactome, http://www.reactome.org ReactomeREACT_13682 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Interaction of integrin alpha3beta1 with Thrombospondin-1 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed10982388 Reactome Database ID Release 43265429 Reactome, http://www.reactome.org ReactomeREACT_13576 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The alpha3beta1 integrin is localized in cell-cell junctions of endothelial cells and this integrin is involved in regulating angiogenesis by interacting with thrombospondin-1 (TSP1). Interaction of integrin alpha3beta1 with Laminin-5 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed11964076 Reactome Database ID Release 43216048 Reactome, http://www.reactome.org ReactomeREACT_13569 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The alpha3beta1 (VLA-3) is known as a promiscuous receptor, as it functions as a receptor for various ECM proteins including laminins, fibronectin and collagen and for intercellular adhesion through interaction with other integrins. The alpha3beta1 is of particular interest, as its expression is associated with melanoma progression. Among the laminin isoforms Laminin-5 binds to VLA-3 with high affinity and promotes melanoma cell migration. Interaction of integrin alpha2beta1 with Lamini-5 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Colonic epithelial cells use integrin alpha2beta1 to adhere to Laminin-5. Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed9645947 Reactome Database ID Release 43349626 Reactome, http://www.reactome.org ReactomeREACT_13693 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Interaction of integrin alpha1beta1 with Laminin-1 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Laminins are a group of large, adhesive glycoproteins found in all basement membranes. Laminins contribute to the structure, stability and physical characteristics of basement membrane and also induce a multitude of cellular responses, including migration, cell polarization and influence cell proliferation and differentiation. The alpha1beta1 integrin is one of the laminin-1 (EHS-laminin) receptors that link the ECM to the cell interior and can activate several pathways. Pubmed16847051 Pubmed8773297 Pubmed9427390 Reactome Database ID Release 43216041 Reactome, http://www.reactome.org ReactomeREACT_13529 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 VCAM-1interacts with VLA-4 Authored: de Bono, B, 2007-07-08 12:58:15 Integrins play a central role in mediating lymphocyte adhesion to a number of surfaces. LFA-1 interacts with ICAMs 1-3 that are typically expressed on other immune system cells. ICAM-4 also interacts with LFA-1, and is known to be expressed on telencepahlic neurons.<p><p>VCAM-1 regulates lymphocyte adhesion to activated endothelial cells via Very Late Antigen-4 (VLA-4).<p><p>To function in a circulating mode, leukocytes express LFA-1 and VLA-4 in a low ligand binding capacity. When leukocytes reach sites of imflammation, these integrins are switched to a higher binding state to guide the complex process of transmigration, tethering, rolling, arrest, adhesion and shape change.<p><p>Signal cascades between LFA-1 and VLA-4 may cross-talk affecting binding affinities in a reciprocal fashion. Pubmed11857637 Pubmed7531291 Reactome Database ID Release 43198941 Reactome, http://www.reactome.org ReactomeREACT_11161 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 Interaction of integrin alpha4beta1 with Osteopontin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Osteopontin (OPN) provides an adhesive matrix for endothelial and smooth muscle cells during remodeling of the vascular wall following injury. The alpha4beta1 integrin is expressed on leukocytes, differentiated vascular smooth muscle cells and tumor cells. The alpha4beta1 integrin has been shown to mediate leukocyte attachment to OPN. Pubmed9547293 Reactome Database ID Release 43265424 Reactome, http://www.reactome.org ReactomeREACT_13810 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Interaction of integrin alpha4beta1 with Thrombospondin-1 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed11980922 Pubmed15292271 Reactome Database ID Release 43265421 Reactome, http://www.reactome.org ReactomeREACT_13516 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Thrombospondin-1 (TSP1) is an extracellular matrix glycoprotein that modulates cell adhesion, growth, motility, differentiation, and survival. TSP1 interacts with cells via a number of receptors, including several integrins. Alpha4beta1 integrin binds to the N-terminal pentraxin modules of TSP1 and stimulates chemotaxis and modulates T cell behavior both positively and negatively. Interaction of integrin alpha4beta1 with Fibronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed1588291 Pubmed9858236 Reactome Database ID Release 43216050 Reactome, http://www.reactome.org ReactomeREACT_13818 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The alpha4beta1 (VAL-4) integrin has been suggested to play an important role in haemopoiesis. Fibronectin and VCAM-1 are the main ligands for VLA-4. The H1 region present in all FN isoforms represents the binding site for VLA-4. Interaction of integrin alpha9beta1 with tenascin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed9565552 Reactome Database ID Release 43216068 Reactome, http://www.reactome.org ReactomeREACT_13633 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The integrin alpha 9 subunit forms a single heterodimer, alpha9beta1 that mediates cell adhesion to a site within the third fibronectin type III repeat of tenascin-C. Cellular responses to stress Authored: Matthews, L, 2012-05-20 Cells are subject to external molecular and physical stresses such as foreign molecules that perturb metabolic or signaling processes, and changes in temperature or pH. The ability of cells and tissues to modulate molecular processes in response to such external stresses is essential to the maintenance of tissue homeostasis (Kultz 2005). Edited: Matthews, L, 2012-05-20 GENE ONTOLOGYGO:0033554 Pubmed15709958 Reactome Database ID Release 432262752 Reactome, http://www.reactome.org ReactomeREACT_120956 Reviewed: D'Eustachio, P, 2012-05-20 Cellular response to hypoxia Authored: May, B, 2012-05-20 Edited: Matthews, L, 2012-05-20 GENE ONTOLOGYGO:0071456 Oxygen plays a central role in the functioning of human cells: it is both essential for normal metabolism and toxic. To begin the annotation of stress responses in Reactome, we have annotated one aspect of cellular responses to oxygen (Semenza 2004), the role of hypoxia-inducible factor in regulating cellular transcriptional responses to changes in oxygen availability. Pubmed15304631 Reactome Database ID Release 432262749 Reactome, http://www.reactome.org ReactomeREACT_121311 Reviewed: D'Eustachio, P, 2012-05-20 Interaction of integrin alpha6beta1 with Laminin-1 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed11170142 Pubmed16219796 Reactome Database ID Release 43216051 Reactome, http://www.reactome.org ReactomeREACT_13405 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The alpha6beta1 integrin is one of the major platelet receptor for laminin-1 and plays an important role in supporting platelet adhesion under arterial rates of flow. PLC-mediated hydrolysis of PIP2 Edited: Jupe, S, 2009-09-09 Reactome Database ID Release 43139943 Reactome, http://www.reactome.org ReactomeREACT_2080 Interaction of integrin alpha7beta1 with Laminin-1 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Of the 12 alpha integrin subunits associated with beta1 integrin, mainly alpha7, alpha3 and alphaV are present in skeletal muscles. The alpha7beta1 integrin is a laminin receptor that serves as a transmembrane link and signal transduction mechanism between the extracellular matrix and muscle fiber. The alpha7beta1 integrin plays an important role in vascular development and also in the recruitment of cerebral vascular smooth muscles cells. Alpha7beta1 binds to laminin-1, which is one of the major laminin isoforms expressed in the developing and adult vasculature. Pubmed10910772 Pubmed11054877 Pubmed16003770 Pubmed17901369 Reactome Database ID Release 43216054 Reactome, http://www.reactome.org ReactomeREACT_13613 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Cdc20:Phospho-APC/C mediated degradation of Cyclin A Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00 Cyclin A, functions in mitosis as well as DNA replication and is degraded in the interim by the APC/C to permit normal chromosome segregation, cell division, and the onset of S phase (see Lukas and Bartek, 2004). Cyclin A is initially degraded early in mitosis by APC/C:Cdc20 when the spindle checkpoint is still active and degradation of securin and cyclin B is inhibited. Edited: Matthews, L, 2006-01-30 00:00:00 GENE ONTOLOGYGO:0031145 Pubmed11285280 Pubmed15577895 Reactome Database ID Release 43174184 Reactome, http://www.reactome.org ReactomeREACT_6850 Reviewed: Peters, JM, 2006-03-27 22:55:09 Interaction of integrin alpha6beta4 with Laminin-5 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed16581764 Reactome Database ID Release 43216056 Reactome, http://www.reactome.org ReactomeREACT_13774 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The alpha6beta4 plays an important role in the formation and stabilization of functional adhesion complexes called hemidesmosomes (HDs), as well as in the regulation of a variety of signaling processes. Alpha6beta4, like alpha6beta1, can interact with different laminin isoforms, its preferred ligand is laminin-5. Among the integrin beta-subunits beta4-subunit has unusually long cytoplasmic domain of over 1000 amino acid residues. Interaction of integrin alpha8beta1 with Fibronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Integrins can influence cell survival in several ways. The integrin alpha8 subunit forms a heterodimer exclusively with beta1 subunit and is expressed in mesenchymal cells. Alpha8beta1 recognizes the tripeptide sequence RGD in several ECM proteins including fibronectin, tenascin and vitronectin. Alpha8beta1 integrin promotes cell survival through adhesion to fibronectin and may play a role in the continued survival of matrix producing cells during fibrosis mediated by PI3 kinase pathway. Pubmed15721307 Pubmed7626807 Reactome Database ID Release 43216059 Reactome, http://www.reactome.org ReactomeREACT_13465 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Interaction of integrin alpha7beta1 with Laminin-2 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Laminins are a major ECM component of basement membrane in striated muscle and are critically important for myodifferentiation. The laminin variants 2 and 4 also called as merosin, are the prevalent laminin isoforms in developing and adult muscle, and are important for muscle cell survival. Alpha7beta1 is one of the most abundant integrins in differentiated muscle fibers and the predominant laminin binding integrin present in the adult skeletal muscle. Pubmed11054877 Reactome Database ID Release 43216058 Reactome, http://www.reactome.org ReactomeREACT_13716 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Oxygen-dependent Asparagine Hydroxylation of Hypoxia-inducible Factor Alpha Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 HIF1AN (FIH, FIH-1) forms a homodimer that hydroxylates an asparagine residue on HIF1A and HIF2A (Hewitson et al. 2002, Lando et al. 2002, Metzen et al. 2003, Lancaster et al. 2004). The hydroxylation of the asparagine interferes with the interaction between HIF1A/HIF2A and p300, a histone acetylase, and therefore inhibits the ability of HIF1A/2A to activate transcription of target genes (Lando et al. 2002). Because molecular oxygen is a substrate of the reaction, hypoxia is a negative regulator of this reaction and thereby increases transcriptional activation of target genes by HIF1A/2A. Pubmed11823643 Pubmed12042299 Pubmed12080085 Pubmed14701857 Pubmed15239670 Reactome Database ID Release 431234162 Reactome, http://www.reactome.org ReactomeREACT_121226 Reviewed: Rantanen, Krista, 2012-05-19 Interaction of integrin alpha8beta1 with Tenascin-c Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed7541634 Pubmed7559467 Reactome Database ID Release 43216064 Reactome, http://www.reactome.org ReactomeREACT_13568 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Tenascin-C (TN-C) and its isoforms are multidomain extracellular matrix (ECM) proteins that are believed to be involved in the regulation of stromal-epithelial interactions. Some of the interactions between TN-C and cells are mediated by integrins. Alpha8beta1 integrin interacts with the third FN type III repeats which contains an RGD sequence in tenascin-c. Regulation of Hypoxia-inducible Factor (HIF) by Oxygen Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 GENE ONTOLOGYGO:0061418 In the presence of oxygen members of the transcription factor family HIF-alpha, comprising HIF1A, HIF2A (EPAS1), and HIF3A, are hydroxylated on proline residues by PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) and on asparagine residues by HIF1AN (FIH) (reviewed in Pouyssegur et al. 2006, Semenza 2007, Kaelin and Ratcliffe 2008, Nizet and Johnson 2009, Brahimi-Horn and Pouyssegur 2009, Majmundar et al. 2010, Loenarz and Schofield 2011). Both types of reaction require molecular oxygen as a substrate and it is probable that at least some HIF-alpha molecules carry both hydroxylated asparagine and hydroxylated proline (Tian et al. 2011).<br>Hydroxylated asparagine interferes with the ability of HIF-alpha to interact with p300 and CBP while hydroxylated proline facilitates the interaction of HIF-alpha with the E3 ubiquitin ligase VHL, causing ubiquitination and proteolysis of HIF-alpha. Hypoxia inhibits both types of hydroxylation, resulting in the stabilization of HIF-alpha, which then enters the nucleus, binds HIF-beta, and recruits p300 and CBP to activate target genes such as EPO and VEGF. Pubmed16724055 Pubmed17916722 Pubmed18498744 Pubmed19339544 Pubmed19704417 Pubmed20728359 Pubmed20965423 Pubmed21335549 Reactome Database ID Release 431234174 Reactome, http://www.reactome.org ReactomeREACT_120815 Reviewed: Rantanen, Krista, 2012-05-19 Interaction of integrin alpha8beta1 with Osteopontin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Osteopontin (OPN) is a soluble secreted basement phosphoprotein that binds with high affinity to integrin alpha8beta1. The alpha8beta1 recognizes an RGD domain that is present within the N-terminal region of osteopontin. This interaction plays an important role in kidney morphogenesis. Pubmed12811645 Pubmed9614184 Reactome Database ID Release 43216061 Reactome, http://www.reactome.org ReactomeREACT_13733 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Regulation of Gene Expression by Hypoxia-inducible Factor Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 HIF-alpha (HIF1A, HIF2A (EPAS1), HIF3A) is translocated to the nucleus, possibly by two pathways: importin 4/7 (Chachami et al. 2009) and importin alpha/beta (Depping et al. 2008). Once in the nucleus HIF-alpha heterodimerizes with HIF-beta (ARNT) (Wang et al. 1995, Jiang et al. 1996, Tian et al. 1997, Gu et al. 1998, Erbel et al. 2003) and recruits CBP and p300 to promoters of target genes (Ebert and Bunn 1998, Kallio et al. 1998, Ema et al. 1999, Gu et al. 2001, Dames et al. 2002, Freedman et al. 2002). Pubmed10202154 Pubmed11063749 Pubmed11959977 Pubmed11959990 Pubmed14668441 Pubmed18187047 Pubmed19788888 Pubmed7539918 Pubmed8663540 Pubmed9000051 Pubmed9632793 Pubmed9822602 Pubmed9840812 Reactome Database ID Release 431234158 Reactome, http://www.reactome.org ReactomeREACT_121092 Reviewed: Rantanen, Krista, 2012-05-19 Interaction of integrin alpha9beta1 with VCAM-1 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Integrin alpha9beta1 is widely expressed on smooth muscle, epithelial cells, and highly and specifically expressed on neutrophils. VCAM-1 is one of the effective ligands for the integrin alpha9beta1. This interaction mediates the neutrophile migration on VCAM-1 and extravasation of neutrophils at sites of acute inflammation. Pubmed10209034 Reactome Database ID Release 43265428 Reactome, http://www.reactome.org ReactomeREACT_13603 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Oxygen-dependent Proline Hydroxylation of Hypoxia-inducible Factor Alpha Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 HIF-alpha subunits, comprising HIF1A (Bruick and McKnight 2001, Ivan et al. 2001, Jaakkola et al. 2001), HIF2A (Percy et al. 2008, Furlow et al. 2009), and HIF3A (Maynard et al. 2003), are hydroxylated at proline residues by the prolyl hydroxylases PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) (Bruick and McKnight 2001, Berra et al. 2003, Hirsila et al. 2003, Metzen et al. 2003, Tuckerman et al. 2004, Appelhoff et al. 2004, Fedulova et al. 2007, Tian et al. 2011). The reaction requires molecular oxygen as a substrate and so it is inhibited by hypoxia. PHD2 (EGLN1) is predominantly cytosolic (Metzen et al. 2003) and is the key determinant in the regulation of HIF-alpha subunits by oxygen (Berra et al. 2003).<br>HIF-alpha subunits hydroxylated at proline residues are bound by VHL, an E3 ubiquitin ligase in a complex containing ElonginB, Elongin C, CUL2, and RBX1. VHL ubiquitinates HIF-alpha, resulting in destruction of HIF-alpha by proteolysis. Hypoxia inhibits proline hydroxylation and interaction with VHL, stabilizing HIF-alpha, which transits to the nucleus and activates gene expression. Pubmed11292861 Pubmed11292862 Pubmed11598268 Pubmed12351678 Pubmed12538644 Pubmed12615973 Pubmed12788921 Pubmed12912907 Pubmed15247232 Pubmed15474027 Pubmed17434750 Pubmed18184961 Pubmed19208626 Pubmed21335549 Reactome Database ID Release 431234176 Reactome, http://www.reactome.org ReactomeREACT_120916 Reviewed: Rantanen, Krista, 2012-05-19 Interaction of integrin alpha9beta1 with Osteopontin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Osteopontin is involved in cell adhesion, chemoattraction and immunomodulation. Osteopontin contains several interesting structural domains. Several integrin receptors interact with the RGD domain. There are two conserved thrombin cleavage sites in osteopontin and the adhesive interactions may be regulated by the thrombin cleavage. The thrombin cleaved NH3-terminal fragment of osteopontin containing the RGD domain acts as a ligand for integrin alpha9beta1. Unlike the most of the integrin receptors alpha9beta1 does not bind the RGD domain but interacts with a sequence ‘SVVYGLR’ in the N-terminal fragment of osteopontin. Pubmed10593924 Pubmed8910476 Reactome Database ID Release 43216066 Reactome, http://www.reactome.org ReactomeREACT_13751 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Phosphorylation of YAP by LATS1 Authored: D'Eustachio, P, 2012-02-03 Cytosolic phospho-LATS1, complexed with MOB1, catalyzes the phosphorylation of YAP on five serine residues (Hao et al. 2008). EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed18158288 Reactome Database ID Release 432028598 Reactome, http://www.reactome.org ReactomeREACT_118711 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 5 Interleukin-1 processing Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10233156 Pubmed11728343 Pubmed12626557 Pubmed15530394 Pubmed1574116 Pubmed17284521 Pubmed2328723 Reactome Database ID Release 43448706 Reactome, http://www.reactome.org ReactomeREACT_23950 Reviewed: Pinteaux, E, 2010-09-06 The IL-1 family of cytokines that interact with the Type 1 IL-1R include IL-1 Alpha (IL1A), IL-1 Beta (IL1B) and the IL-1 receptor antagonist protein (IL1RAP). IL1RAP is synthesized with a signal peptide and secreted as a mature protein via the classical secretory pathway. IL1A and IL1B are synthesised as cytoplasmic precursors (pro-IL1A and pro-IL1B) in activated cells. They have no signal sequence, precluding secretion via the classical ER-Golgi route (Rubartelli et al. 1990). Processing of pro-IL1B to the active form requires caspase-1 (Thornberry et al. 1992), which is itself activated by a molecular scaffold termed the inflammasome (Martinon et al. 2002). Processing and release of IL1B are thought to be closely linked, because mature IL1B is only seen inside inflammatory cells just prior to release (Brough et al. 2003). It has been reported that in monocytes a fraction of cellular IL1B is released by the regulated secretion of late endosomes and early lysosomes, and that this may represent a cellular compartment where caspase-1 processing of pro-IL1B takes place (Andrei et al. 1999). Shedding of microvesicles from the plasma membrane has also been proposed as a mechanism of secretion (MacKenzie et al. 2001). These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered. However, there is evidence in the literature that supports all of these mechanisms and there is still controversy over how IL1B exits from cells (Brough & Rothwell 2007). A calpain-like potease has been reported to be important for the processing of pro-IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology. Phosphorylation of YAP by LATS2 Authored: D'Eustachio, P, 2012-02-03 Cytosolic phospho-LATS2, complexed with MOB1, catalyzes the phosphorylation of YAP on serine residue 127 (and possibly other serine residues) (Zhao et al. 2007). This reaction is positively regulated by the angiomotin proteins AMOT (130 kd form), AMOTL1, and AMOTL2, which may function by physically bridging LATS2 and YAP (Paramasivam et al. 2011; Zhao et al. 2011). EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed17974916 Pubmed21205866 Pubmed21832154 Reactome Database ID Release 432028583 Reactome, http://www.reactome.org ReactomeREACT_118829 Reviewed: Sudol, M, 2012-02-03 Translocation of YAP1:ZO-2 (TJP2) to the nucleus Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-18 Pubmed20868367 Reactome Database ID Release 432064406 Reactome, http://www.reactome.org ReactomeREACT_118822 Reviewed: Sudol, M, 2012-02-03 The YAP1:ZO-2 (TJP2) complex can translocate to the nucleus (Oka et al. 2010). AMOT proteins bind YAP1 AMOT (130 KDa isoform), AMOTL1, and AMOTL2 can each bind YAP1 and sequester it in the cytosol. This interaction is not dependent on YAP1 phosphorylation and may thus be a means of negatively regulating YAP activity in addition to the ones dependent on Hippo pathway-dependent phosphorylation. AMOT - YAP1 binding is dependent on sequence motifs in the amino terminal portions of the AMOT proteins (and that are absent from the AMOT 80 KDa isoform, which does not bind YAP1) (Wang et al. 2010; Chan et al. 2011). Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 Pubmed21187284 Pubmed21224387 Reactome Database ID Release 432028724 Reactome, http://www.reactome.org ReactomeREACT_118701 Reviewed: Sudol, M, 2012-02-03 Amine compound SLC transporters Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 Five SLC gene families encode proteins that mediate transport of amines (neurotransmitters, biogenic amines, ammonium and choline). They are SLC6, SLC14, SLC18, SLC42. The fifth family, SLC22, will appear in a later release (He L et al, 2009). Pubmed19164095 Reactome Database ID Release 43425428 Reactome, http://www.reactome.org ReactomeREACT_20679 Reviewed: He, L, 2009-11-12 Interleukin-3, 5 and GM-CSF signaling Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Pubmed10450743 Pubmed10851052 Pubmed11312115 Pubmed1590989 Pubmed18692472 Pubmed19436055 Pubmed19819937 Pubmed7567993 Pubmed7896837 Pubmed8007942 Pubmed9766809 Pubmed9794243 Reactome Database ID Release 43512988 Reactome, http://www.reactome.org ReactomeREACT_23837 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains.<br><br> IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).<br><br> All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).<br><br> The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).<br><br><br><br>Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed. YAP1 binds ZO-2 (TJP2) Authored: D'Eustachio, P, 2012-02-03 Cytosolic ZO-2 (TJP2) binds YAP1 to form a complex (Oka et al. 2010). The phosphorylation state of the YAP1 protein involved in this interaction has not been determined experimentally; it is inferred to be unphosphorylated. Edited: D'Eustachio, P, 2012-01-18 Pubmed20868367 Reactome Database ID Release 432064421 Reactome, http://www.reactome.org ReactomeREACT_118825 Reviewed: Sudol, M, 2012-02-03 Interleukin receptor SHC signaling Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Phosphorylation of Shc at three tyrosine residues, 239, 240 (Gotoh et al. 1996) and 317 (Salcini et al. 1994) involves unidentified tyrosine kinases presumed to be part of the activated receptor complex. These phosphorylated tyrosines subsequently bind SH2 signaling proteins such as Grb2, Gab2 and SHIP that are involved in the regulation of different signaling pathways. Grb2 can associate with the guanosine diphosphate-guanosine triphosphate exchange factor Sos1, leading to Ras activation and regulation of cell proliferation. Downstream signals are mediated via the Raf-MEK-Erk pathway.Grb2 can also associate through Gab2 with PI3K and with SHIP.<br><br>Figure reproduced from Gu, H. et al. 2000. Mol. Cell. Biol. 20(19):7109-7120<br>Copyright American Society for Microbiology. All Rights Reserved. Pubmed10982827 Pubmed8084588 Pubmed8294403 Pubmed8947042 Reactome Database ID Release 43912526 Reactome, http://www.reactome.org ReactomeREACT_23891 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Translocation of YAP1 to the nucleus Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 In its unphosphorylated state, the YAP1 transcriptional coactivator moves freely into the nucleus. Phosphorylated YAP1, in contrast, is sequestered in the cytosol (Hao et al. 2008). Pubmed18158288 Reactome Database ID Release 432032770 Reactome, http://www.reactome.org ReactomeREACT_118592 Reviewed: Sudol, M, 2012-02-03 Interleukin-2 signaling Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Interleukin-2 (IL-2) is a cytokine that is produced by T cells in response to antigen stimulation. Originally, IL-2 was discovered because of its potent growth factor activity on activated T cells in vitro and was therefore named 'T cell growth factor' (TCGF). However, the generation of IL-2- and IL-2 receptor-deficient mice revealed that IL-2 also plays a regulatory role in the immune system by suppressing autoimmune responses. Two main mechanisms have been identified that explain this suppressive function: (1) IL-2 sensitizes activated T cells for activation-induced cell death (AICD) and (2) IL-2 is critical for the survival and function of regulatory T cells (Tregs), which possess potent immunosuppressive properties.<br><br>IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c). The tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells. Pubmed12525482 Pubmed1545122 Pubmed17936914 Pubmed18062768 Pubmed18817510 Pubmed19543225 Pubmed3095922 Pubmed3098894 Pubmed3116143 Pubmed6815536 Pubmed6975347 Reactome Database ID Release 43451927 Reactome, http://www.reactome.org ReactomeREACT_27283 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Phosphorylated MOB1A proteins associate with LATS proteins Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2011-12-30 Phosphoylated MOB1A proteins are able to associate with LATS proteins (Praskova et al. 2008). Pubmed18328708 Reactome Database ID Release 432028626 Reactome, http://www.reactome.org ReactomeREACT_118627 Reviewed: Sudol, M, 2012-02-03 Interleukin-1 signaling Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Interleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL1R1), the only signaling-capable IL1 receptor. This is a single chain type 1 transmembrane protein comprising an extracellular ligand binding domain and an intracellular region called the Toll/Interleukin-1 receptor (TIR) domain that is structurally conserved and shared by other members of the two families of receptors (Xu et al. 2000). This domain is also shared by the downstream adapter molecule MyD88. IL1 binding to IL1R1 leads to the recruitment of a second receptor chain termed the IL1 receptor accessory protein (IL1RAP or IL1RAcP) enabling the formation of a high-affinity ligand-receptor complex that is capable of signal transduction. Intracellular signaling is initiated by the recruitment of MyD88 to the IL-1R1/IL1RAP complex. IL1RAP is only recruited to IL1R1 when IL1 is present; it is believed that a TIR domain signaling complex is formed between the receptor and the adapter TIR domains. The recruitment of MyD88 leads to the recruitment of Interleukin-1 receptor-associated kinase (IRAK)-1 and -4, probably via their death domains. IRAK4 then activates IRAK1, allowing IRAK1 to autophosphorylate. Both IRAK1 and IRAK4 then dissociate from MyD88 (Brikos et al. 2007) which remains stably complexed with IL-1R1 and IL1RAP. They in turn interact with Tumor Necrosis Factor Receptor (TNFR)-Associated Factor 6 (TRAF6), which is an E3 ubiquitin ligase (Deng et al. 2000). TRAF6 is then thought to auto-ubiquinate, attaching K63-polyubiquitin to itself with the assistance of the E2 conjugating complex Ubc13/Uev1a. K63-pUb-TRAF6 recruits Transforming Growth Factor (TGF) beta-activated protein kinase 1 (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (Ninomiya-Tsuji et al. 1999). This activates TAK1, which then activates inhibitor of NF-kappaB (IkappaB) kinase 2 (IKK2 or IKKB) within the IKK complex, the kinase responsible for phosphorylation of IkappaB. The IKK complex also contains the scaffold protein NF-kappa B essential modulator (NEMO). TAK1 also couples to the upstream kinases for p38 and c-jun N-terminal kinase (JNK). IRAK1 undergoes K63-linked polyubiquination; Pellino E3 ligases are important in this process. (Butler et al. 2007; Ordureau et al. 2008). The activity of these proteins is greatly enhanced by IRAK phosphorylation (Schauvliege et al. 2006), leading to K63-linked polyubiquitination of IRAK1. This recruits NEMO to IRAK1, with NEMO binding to polyubiquitin (Conze et al. 2008).<br><br>TAK1 activates IKKB (and IKK), resulting in phosphorylation of the inhibitory IkB proteins and enabling translocation of NFkB to the nucleus; IKKB also phosphorylates NFkB p105, leading to its degradation and the subsequent release of active TPL2 that triggers the extracellular-signal regulated kinase (ERK)1/2 MAPK cascade. TAK1 can also trigger the p38 and JNK MAPK pathways via activating the upstream MKKs3, 4 and 6. The MAPK pathways activate a number of downstream kinases and transcription factors that co-operate with NFkB to induce the expression of a range of TLR/IL-1R-responsive genes. There are reports suggesting that IL1 stimulation increases nuclear localization of IRAK1 (Bol et al. 2000) and that nuclear IRAK1 binds to the promoter of NFkB-regulated gene and IkBa, enhancing binding of the NFkB p65 subunit to NFkB responsive elements within the IkBa promoter. IRAK1 is required for IL1-induced Ser-10 phosphorylation of histone H3 in vivo (Liu et al. 2008). However, details of this aspect of IRAK1 signaling mechanisms remain unclear. Pubmed10094049 Pubmed10899313 Pubmed11057907 Pubmed11081518 Pubmed16884718 Pubmed17507369 Pubmed17675297 Pubmed17997719 Pubmed18276832 Pubmed18347055 Pubmed19022706 Pubmed19161412 Pubmed19302047 Reactome Database ID Release 43446652 Reactome, http://www.reactome.org ReactomeREACT_22442 Reviewed: Pinteaux, E, 2010-05-17 Phosphorylation of MOB1A and B by p-STK4(MST1)/N Authored: D'Eustachio, P, 2012-02-03 Cytosolic MOB1A and MOB1B are phosphorylated by phospho-STK4(MST1)/N (Graves et al. 1998; Lee et al. 2001). Threonine residues 12 and 35 have been experimentally identifed as the targets of MOB1A phosphorylation; the homologous residues of MOB1B are inferred likewise to be targets. EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed11278283 Pubmed9545236 Reactome Database ID Release 432028670 Reactome, http://www.reactome.org ReactomeREACT_118559 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 Growth hormone receptor signaling Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 GENE ONTOLOGYGO:0060397 Growth hormone (Somatotropin or GH) is a key factor in determining lean body mass, stimulating the growth and metabolism of muscle, bone and cartilage cells, while reducing body fat. It has many other roles; it acts to regulate cell growth, differentiation, apoptosis, and reorganisation of the cytoskeleton, affecting diverse processes such as cardiac function, immune function, brain function, and aging. GH also has insulin-like effects such as stimulating amino acid transport, protein synthesis, glucose transport, and lipogenesis. The growth hormone receptor (GHR) is a a member of the cytokine receptor family. When the dimeric receptor binds GH it undergoes a conformational change which leads to phosphorylation of key tyrosine residues in its cytoplasmic domains and activation of associated tyrosine kinase JAK2. This leads to recruitment of signaling molecules such as STAT5 and Src family kinases such as Lyn leading to ERK activation. The signal is attenuated by association of Suppressor of Cytokine Signaling (SOCS) proteins and SHP phosphatases which bind to or dephosphorylate specific phosphorylated tyrosines on GHR/JAK. The availability of GHR on the cell surface is regulated by at least two processes; internalization and cleavage from the suface by metalloproteases. Pubmed15601831 Pubmed17488973 Pubmed20664532 Pubmed8548048 Reactome Database ID Release 43982772 Reactome, http://www.reactome.org ReactomeREACT_111133 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 Phosphorylation of MOB1A and B by p-STK4 (p-MST1) Authored: D'Eustachio, P, 2012-02-03 Cytosolic MOB1A and MOB1B are phosphorylated by phospho-STK4 (p-MST1). Phosphorylated (active) STK4 (p-MST1) and SAV1 are known to form a complex and that complex is annotated as the catalyst of this reaction. Threonine residues 12 and 35 have been experimentally identifed as the targets of MOB1A phosphorylation; the homologous residues of MOB1B are inferred likewise to be targets (Praskova et al. 2008). EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed18328708 Reactome Database ID Release 432028629 Reactome, http://www.reactome.org ReactomeREACT_118768 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 Interleukin-7 signaling Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2011-05-06 Interleukin-7 (IL7) is produced primarily by T zone fibroblastic reticular cells found in lymphoid organs, and also expressed by non-hematopoietic stromal cells present in other tissues including the skin, intestine and liver. It is an essential survival factor for lymphocytes, playing a key anti-apoptotic role in T-cell development, as well as mediating peripheral T-cell maintenance and proliferation. This dual function is reflected in a dose-response relationship that distinguishes the survival function from the proliferative activity; low doses of IL7 (<1 ng/ml) sustain only survival, higher doses (>1 ng/ml) promote survival and cell cycling (Kittipatarin et al. 2006, Swainson et al. 2007).<br><br>The IL7 receptor is a heterodimeric complex of the the common cytokine-receptor gamma chain (IL2RG, CD132, or Gc) and the IL7-receptor alpha chain (IL7RA, IL7R, CD127). Both chains are members of the type 1 cytokine family. Neither chain is unique to the IL7 receptor as IL7RA is utilized by the receptor for thymic stromal lymphopoietin (TSLP) while Gc is shared with the receptors for IL2, IL4, IL9, IL15 and IL21. Gc consists of a single transmembrane region and a 240aa extracellular region that includes a fibronectin type III (FNIII) domain thought to be involved in receptor complex formation. It is expressed on most lymphocyte populations. Null mutations of Gc in humans cause X-linked severe combined immunodeficiency (X-SCID), which has a phenotype of severely reduced T-cell and natural killer (NK) cell populations, but normal numbers of B cells. In addition to reduced T- and NK-cell numbers Gc knockout mice also have dramatically reduced B-cell populations suggesting that Gc is more critical for B-cell development in mice than in humans. Patients with severe combined immunodeficiency (SCID) phenotype due to IL7RA mutations (see Puel & Leonard 2000), or a partial deficiency of IL7RA (Roifman et al. 2000) have markedly reduced circulating T cells, but normal levels of peripheral blood B cells and NK cells, similar to the phenotype of Gc mutations, highlighting a requirement for IL7 in T cell lymphopoiesis. It has been suggested that IL7 is essential for murine, but not human B cell development, but recent studies indicate that IL7 is essential for human B cell production from adult bone marrow and that IL7-induced expansion of the progenitor B cell compartment is increasingly critical for human B cell production during later stages of development (Parrish et al. 2009).<br><br>IL7 has been shown to induce rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, and concomitantly tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7RA was shown to directly induce the activation of JAKs and STATs by van der Plas et al. (1996). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).<br><br>The role of STAT5 in IL7 signaling has been studied largely in mouse models. Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and activation of JAK/STAT5 and PI3k/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine residue. STAT5 seems to enhance proliferation of multiple cell lineages in mouse models but it remains unclear whether STAT5 is required solely for survival signaling or also for the induction of proliferative activity (Kittipatarin & Khaled, 2007).<br><br>The model for IL7 receptor signaling is presumed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor, where IL2RB binds constitutively to JAK1 while JAK3 is pre-associated uniquely with the Gc chain. Extending this model to IL7 suggests a similar series of events: IL7RA constitutively associated with JAK1 binds IL7, the resulting trimer recruits Gc:JAK3, bringing JAK1 and JAK3 into proximity. The association of both chains of the IL7 receptor orients the cytoplasmic domains of the receptor chains so that their associated kinases (Janus and phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). JAKs have low intrinsic enzymatic activity, but after mutual phosphorylation acquire much higher activity, leading to phosphorylation of the critical Y449 site on IL7RA. This site binds STAT5 and possibly other signaling adapters, they in turn become phosphorylated by JAK1 and/or JAK3. Phosphorylated STATs translocate to the nucleus and trigger the transcriptional events of their target genes.<br><br>The role of the PI3K/AKT pathway in IL7 signaling is controversial. It is a potential T-cell survival pathway because in many cell types PI3K signaling regulates diverse cellular functions such as cell cycle progression, transcription, and metabolism. The ERK/MAPK pathway does not appear to be involved in IL7 signaling (Crawley et al. 1996).<br><br>It is not clear how IL7 influences cell proliferation. In the absence of a proliferative signal such as IL7 or IL3, dependent lymphocytes arrest in the G0/G1 phase of the cell cycle. To exit this phase, cells typically activate specific G1 Cyclin-dependent kinases/cyclins and down regulate cell cycle inhibitors such as Cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27kip1). There is indirect evidence suggesting a possible role for IL7 stimulated activation of PI3K/AKT signaling, obtained from transformed cell lines and thymocytes, but not confirmed by observations using primary T-cells (Kittipatarin & Khaled, 2007). IL7 withdrawal results in G1/S cell cycle arrest and is correlated with loss of cdk2 activity (Geiselhart et al. 2001), both events which are known to be regulated by the dephosphorylating activity of Cdc25A. Expression of a p38 MAPK-resistant Cdc25A mutant in an IL-7-dependent T-cell line as well as in peripheral, primary T-cells was sufficient to sustain cell survival and promote cell cycling for several days in the absence of IL-7 (Khaled et al. 2005). Cdkn1b is a member of the CIP/KIP family of cyclin-dependent cell cycle inhibitors (CKIs) that negatively regulates the G1/S transition. In IL7 dependent T-cells, the expression of Cdkn1b was sufficient to cause G1 arrest in the presence of IL7. Withdrawal of IL7 induced the upregulation of Cdkn1b and arrested cells in G1 while siRNA knockout of Cdkn1b enhanced cell cycle progression. However, adoptive transfer of Cdkn1b-deficient lymphocytes into IL7 deficient mice indicated that loss of Cdkn1b could only partially compensate for the IL7 signal needed by T-cells to expand in a lymphopenic environment (Li et al. 2006), so though Cdkn1b may be involved in negative regulation of the cell cycle through an effect on cdk2 activity, its absence is not sufficient to fully induce cell cycling under lymphopenic conditions.<br><br> Pubmed10367898 Pubmed10899029 Pubmed11023514 Pubmed11207251 Pubmed15226449 Pubmed15928203 Pubmed15996891 Pubmed16492801 Pubmed16628013 Pubmed17023582 Pubmed17325202 Pubmed17768066 Pubmed19299724 Pubmed7481769 Pubmed7489741 Pubmed8709637 Pubmed8921960 Pubmed9590172 Reactome Database ID Release 431266695 Reactome, http://www.reactome.org ReactomeREACT_115529 Reviewed: Puck, J, 2011-11-03 Phosphorylation of MOB1A and B by p-STK3(MST2)/N Authored: D'Eustachio, P, 2012-02-03 Cytosolic MOB1A and MOB1B are phosphorylated by phospho-STK3(MST2)/N (Lee et al. 2001). Threonine residues 12 and 35 have been experimentally identifed as the targets of MOB1A phosphorylation; the homologous residues of MOB1B are inferred likewise to be targets. EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed11278283 Reactome Database ID Release 432028675 Reactome, http://www.reactome.org ReactomeREACT_118615 Reviewed: Sudol, M, 2012-02-03 has a Stoichiometric coefficient of 2 Interleukin-6 signaling Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep. It is the founding member of a family of IL-6-related cytokines such as IL-11, IL-27 leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF) and oncostatin M. <br><br>The IL-6 receptor (IL6R) consists of an alpha subunit that specifically binds IL-6 and a beta subunit, IL6RB or gp130, which is the signaling component of all the receptors for cytokines related to IL-6. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL-6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL-6 activities<br><br>IL6R signal transduction is mediated by two pathways:the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras-MAPK (mitogen-activated protein kinase) pathway. Negative regulators of IL-6 signaling include SOCS (suppressor of cytokine signals) and SHP2. Within the last few years different antibodies have been developed to inhibit IL-6 activity, and the first such antibodies have been introduced into the clinic for the treatment of inflammatory diseases (Kopf et al. 2010). Pubmed18490707 Pubmed20410258 Pubmed20811382 Reactome Database ID Release 431059683 Reactome, http://www.reactome.org ReactomeREACT_27307 Reviewed: Rose-John, S, 2011-02-11 Regulation of signaling by CBL Authored: Ray, KP, 2010-05-17 Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl negatively regulates PI3K via this mechanism (Dufour et al. 2008). The binding of Cbl to the p85 subunit of PI3K is mediated at least in part by tyrosine phosphorylation at Y731 (Dufour et al. 2008). Fyn and the related kinases Hck and Lyn are known to be associated with Cbl (Anderson et al. 1997, Hunter et al. 1999). Fyn is proven capable of Cbl Y731 phosphorylation (Hunter et al. 1999).The association of Fyn and Cbl has been described as constitutive (Hunter et al. 1999). CBL further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this also described as constitutive and mediated by the SH3 domain of p85. Binding of the SH2 domain of p85 to a specific phosphorylation site in Cbl is postulated to explain the the increase in Cbl/p85 association seen in activated cells (Panchamoorthy et al 1996) which negatively regulates PI3K activity (Fang et al. 2001). The negative effect of increased Cbl-PI3K interaction is mediated by Y731 of Cbl. Cbl binding increases PI3K ubiquitination and proteasome degradation (Dufour et al. 2008).<br><br><br>Cbl is constitutively associated with Grb in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain binds the adaptor protein CRKL. Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). Cbl is tyrosine phosphorylated in response to many cytokines including IL-3, IL-2 (Gesbert et al. 1998) and IL-4 (Ueno et al. 1998). Edited: Jupe, S, 2010-08-06 Pubmed11526404 Pubmed11994499 Pubmed18374639 Pubmed7537740 Pubmed7629144 Pubmed8621719 Pubmed8995358 Pubmed9414268 Pubmed9461587 Pubmed9590251 Pubmed9890970 Reactome Database ID Release 43912631 Reactome, http://www.reactome.org ReactomeREACT_23787 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 DVL2 binds phosphorylated WWTR1 (TAZ) Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-19 Phosphorylated WWTR1 (TAZ) and DVL interact to form a complex in the cytosol. Thus sequestered, DVL2 is unable to undergo phosphorylation by casein kinase, inhibiting its role in WNT signaling. WWTR1 - DLV interaction thus appears to link the Hippo and WNT signaling processes (Varelas et al. 2010). The stoichiometry of the WWTR1:DVL complex is unknown. Pubmed20412773 Reactome Database ID Release 432066299 Reactome, http://www.reactome.org ReactomeREACT_118667 Reviewed: Sudol, M, 2012-02-03 YWHAE (14-3-3 epsilon) dimer binds phosphorylated WWTR1 (TAZ) Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2011-12-30 Pubmed11118213 Pubmed17085597 Pubmed18227151 Reactome Database ID Release 432028651 Reactome, http://www.reactome.org ReactomeREACT_118843 Reviewed: Sudol, M, 2012-02-03 YWHAE (14-3-3 epsilon) binds phosphorylated WWTR1 (TAZ), sequestering it in the cytosol. Structural studies indicate that the active form of YWHAE (14-3-3 epsilon) is a homodimer (Yang et al. 2006); the stoichiometry of its complex with WWTR1 (TAZ) is unknown and has been annotated arbitrarily here to involve one WWTR1 (TAZ) molecule and a YWHAE(14-3-3 epsilon) dimer. Phosphorylation of serine residue 127 of WWTR1 (TAZ) appears to be critical for YWHAE (14-3-3 epsilon) binding (Kanai et al. 2000; Lei et al. 2008). Interaction of integrin alpha1beta1 with Type IV collagen Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed10963992 Pubmed15451466 Pubmed16623929 Pubmed17603494 Reactome Database ID Release 43216040 Reactome, http://www.reactome.org ReactomeREACT_13656 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The alpha1/beta1 integrin, also known as very late antigen (VLA)-1, is mostly expressed on smooth muscle cells and are also found on fibroblasts, osteoblasts, chondrocytes, endothelial cells and lymphocytes. They have a specific inserted domain or I domain as a part of their alpha subunit. This I domain is responsible for the recognition and interaction with collagen molecules in the extracellular matrix (ECM). VLA-1 primarily binds to type IV but also to type I collagen. By outside-in transmembranal signaling to the interior of the cell, it mediates adhesion, migration, proliferation, remodeling of the ECM, and cytokine secretion by endothelial cells, mesangial cells, fibroblasts, and immunocytes. Signaling by Interleukins Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-26 Interleukins are low molecular weight proteins that bind to cell surface receptors and act in an autocrine and/or paracrine fashion. They were first identified as factors produced by leukocytes but are now known to be produced by many other cells throughout the body. They have pleiotropic effects on cells which bind them, impacting processes such as tissue growth and repair, hematopoietic homeostasis, and multiple levels of the host defense against pathogens where they are an essential part of the immune system. Pubmed12445398 Pubmed19302047 Reactome Database ID Release 43449147 Reactome, http://www.reactome.org ReactomeREACT_22232 Reviewed: Pinteaux, E, 2010-05-17 ISG15 antiviral mechanism Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 Interferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (Ubl) family. It is strongly induced upon exposure to type I Interferons (IFNs), viruses, bacterial LPS, and other stresses. Once released the mature ISG15 conjugates with an array of target proteins, a process termed ISGylation. ISGylation utilizes a mechanism similar to ubiquitination, requiring a three-step enzymatic cascade. UBE1L is the ISG15 E1 activating enzyme which specifically activates ISG15 at the expense of ATP. ISG15 is then transfered from E1 to the E2 conjugating enzyme UBCH8 and then to the target protein with the aid of an ISG15 E3 ligase, such as HERC5 and EFP. Hundreds of target proteins for ISGylation have been identified. Several proteins that are part of antiviral signaling pathways, such as RIG-I, MDA5, Mx1, PKR, filamin B, STAT1, IRF3 and JAK1, have been identified as targets for ISGylation. ISG15 also conjugates some viral proteins, inhibiting viral budding and release. ISGylation appears to act either by disrupting the activity of a target protein and/or by altering its localization within the cell. Pubmed12582176 Pubmed15970528 Pubmed16009940 Pubmed20153823 Pubmed20946978 Reactome Database ID Release 431169408 Reactome, http://www.reactome.org ReactomeREACT_115831 Reviewed: Zhang, DE, 2011--0-2- Cytokine Signaling in Immune system Authored: Jupe, S, Garapati, P V, Ray, K, 2011-05-22 Cytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted in response to immune stimuli, and usually act briefly, locally, at very low concentrations. Cytokines bind to specific membrane receptors, which then signal the cell via second messengers, to regulate cellular activity. Edited: Jupe, S, Garapati, P V, Ray, K, 2011-05-22 Pubmed12613569 Reactome Database ID Release 431280215 Reactome, http://www.reactome.org ReactomeREACT_75790 Reviewed: Pinteaux, E, Abdul-Sater, AA, Schindler, C, 2011-05-28 AMOT proteins bind WWTR1 (TAZ) AMOT (130 KDa isoform) and AMOTL1 can each bind WWTR1 (TAZ) and sequester it in the cytosol. AMOTL2 - WWTR1 binding has not been studied but is inferred to occur from the presence of key binding sequence motifs in AMOTL2 protein and from its known binding activity with YAP1, a WWTR1 homolog. These interactions are not dependent on WWTR1 phosphorylation and may thus be a means of negatively regulating WWTR1 activity in addition to the ones dependent on Hippo pathway-dependent phosphorylation. AMOT - WWTR1 binding is dependent on sequence motifs in the amino terminal portions of the AMOT proteins (and that are absent from the AMOT 80 KDa isoform) (Chan et al. 2011). Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 Pubmed21224387 Reactome Database ID Release 432028735 Reactome, http://www.reactome.org ReactomeREACT_118821 Reviewed: Sudol, M, 2012-02-03 DAP12 signaling Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 In response to receptor ligation, the tyrosine residues in DAP12's immunoreceptor tyrosine-based activation motif (ITAM) are phosphorylated by Src family kinases. These phosphotyrosines form the docking site for the protein tyrosine kinase SYK in myeloid cells and SYK and ZAP70 in NK cells. DAP12-bound SYK autophosphorylates and phosphorylates the scaffolding molecule LAT, recruiting the proximal signaling molecules phosphatidylinositol-3-OH kinase (PI3K), phospholipase-C gamma (PLC-gamma), GADS (GRB2-related adapter downstream of SHC), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), GRB2:SOS (Growth factor receptor-bound protein 2:Son of sevenless homolog 1) and VAV. All of these intermediate signalling molecules result in the recruitment and activation of kinases AKT, CBL (Casitas B-lineage lymphoma) and ERK (extracellular signal-regulated kinase), and rearrangement of the actin cytoskeleton (actin polymerization) finally leading to cellular activation. PLC-gamma generates the secondary messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsP3), leading to activation of protein kinase C (PKC) and calcium mobilization, respectively (Turnbull & Colonna 2007, Klesney-Tait et al. 2006). Pubmed15884055 Pubmed17110943 Pubmed17220916 Reactome Database ID Release 432424491 Reactome, http://www.reactome.org ReactomeREACT_147814 Reviewed: Lanier, Lewis L, 2012-08-09 WWTR1 (TAZ) binds ZO-2 (TJP2) Authored: D'Eustachio, P, 2012-02-03 Cytosolic ZO-2 (TJP2) binds WWTR1 (TAZ) to form a complex. This event may play a role in sequestering WWTR1 in the cytosol (Remue et al. 2010). The phosphorylation state of the WWTR1 protein involved in this interaction has not been determined experimentally; it is inferred to be unphosphorylated. Edited: D'Eustachio, P, 2012-01-18 Pubmed20850437 Reactome Database ID Release 432064418 Reactome, http://www.reactome.org ReactomeREACT_118797 Reviewed: Sudol, M, 2012-02-03 Interferon alpha/beta signaling Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 GENE ONTOLOGYGO:0060337 Pubmed17969444 Pubmed8605876 Pubmed8621447 Pubmed8702790 Reactome Database ID Release 43909733 Reactome, http://www.reactome.org ReactomeREACT_25162 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Type I interferons (IFNs) are composed of various genes including IFN alpha (IFNA), beta (IFNB), omega, epsilon, and kappa. In humans the IFNA genes are composed of more than 13 subfamily genes, whereas there is only one IFNB gene. The large family of IFNA/B proteins all bind to a single receptor which is composed of two distinct chains: IFNAR1 and IFNAR2. The IFNA/B stimulation of the IFNA receptor complex leads to the formation of two transcriptional activator complexes: IFNA-activated-factor (AAF), which is a homodimer of STAT1 and IFN-stimulated gene factor 3 (ISGF3), which comprises STAT1, STAT2 and a member of the IRF family, IRF9/P48. AAF mediates activation of the IRF-1 gene by binding to GAS (IFNG-activated site), whereas ISGF3 activates several IFN-inducible genes including IRF3 and IRF7. Phosphorylation of WWTR1 (TAZ) by LATS2 Authored: D'Eustachio, P, 2012-02-03 Cytosolic phospho-LATS2, complexed with MOB1, catalyzes the phosphorylation of WWTR1 (TAZ) on serine residue 89 (Lei et al. 2008). This reaction is positively regulated by the angiomotin proteins AMOT (130 kd form), AMOTL1, and AMOTL2, which may function by physically bridging LATS2 and YAP (Zhao et al. 2011). EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed18227151 Pubmed21205866 Reactome Database ID Release 432028661 Reactome, http://www.reactome.org ReactomeREACT_118702 Reviewed: Sudol, M, 2012-02-03 Interferon Signaling Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 GENE ONTOLOGYGO:0019221 Interferons (IFNs) are cytokines that play a central role in initiating immune responses, especially antiviral and antitumor effects. There are three types of IFNs:Type I (IFN-alpha, -beta and others, such as omega, epsilon, and kappa), Type II (IFN-gamma) and Type III (IFN-lamda). In this module we are mainly focusing on type I IFNs alpha and beta and type II IFN-gamma. Both type I and type II IFNs exert their actions through cognate receptor complexes, IFNAR and IFNGR respectively, present on cell surface membranes. Type I IFNs are broadly expressed heterodimeric receptors composed of the IFNAR1 and IFNAR2 subunits, while the type II IFN receptor consists of IFNGR1 and IFNGR2. Type III interferon lambda has three members: lamda1 (IL-29), lambda2 (IL-28A), and lambda3 (IL-28B) respectively. IFN-lambda signaling is initiated through unique heterodimeric receptor composed of IFN-LR1/IF-28Ralpha and IL10R2 chains. <br>Type I IFNs typically recruit JAK1 and TYK2 proteins to transduce their signals to STAT1 and 2; in combination with IRF9 (IFN-regulatory factor 9), these proteins form the heterotrimeric complex ISGF3. In nucleus ISGF3 binds to IFN-stimulated response elements (ISRE) to promote gene induction. <br>Type II IFNs in turn rely upon the activation of JAKs 1 and 2 and STAT1. Once activated, STAT1 dimerizes to form the transcriptional regulator GAF (IFNG activated factor) and this binds to the IFNG activated sequence (GAS) elements and initiate the transcription of IFNG-responsive genes. <br>Like type I IFNs, IFN-lambda recruits TYK2 and JAK1 kinases and then promote the phosphorylation of STAT1/2, and induce the ISRE3 complex formation. Pubmed14525967 Pubmed15607020 Pubmed15864272 Pubmed18929502 Pubmed19059436 Reactome Database ID Release 43913531 Reactome, http://www.reactome.org ReactomeREACT_25229 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Phosphorylation of WWTR1 (TAZ) by LATS1 Authored: D'Eustachio, P, 2012-02-03 Cytosolic phospho-LATS1, complexed with MOB1, catalyzes the phosphorylation of WWTR1 (TAZ) on serine residue 89. This activity of human LATS1 protein has not been demonstrated experimentally but is inferred from the activity of human paralogue LATS2 and of mouse homologue LATS1 (Varelas et al. 2010). EC Number: 2.7.11 Edited: D'Eustachio, P, 2011-12-30 Pubmed20412773 Reactome Database ID Release 432060328 Reactome, http://www.reactome.org ReactomeREACT_118649 Reviewed: Sudol, M, 2012-02-03 Interferon gamma signaling Authored: Garapati, P V, 2010-06-08 Edited: Garapati, P V, 2010-06-08 GENE ONTOLOGYGO:0060333 Interferon-gamma (IFN-gamma) belongs to the type II interferon family and is secreted by activated immune cells-primarily T and NK cells, but also B-cells and APC. INFG exerts its effect on cells by interacting with the specific IFN-gamma receptor (IFNGR). IFNGR consists of two chains, namely IFNGR1 (also known as the IFNGR alpha chain) and IFNGR2 (also known as the IFNGR beta chain). IFNGR1 is the ligand binding receptor and is required but not sufficient for signal transduction, whereas IFNGR2 do not bind IFNG independently but mainly plays a role in IFNG signaling and is generally the limiting factor in IFNG responsiveness. Both IFNGR chains lack intrinsic kinase/phosphatase activity and thus rely on other signaling proteins like Janus-activated kinase 1 (JAK1), JAK2 and Signal transducer and activator of transcription 1 (STAT-1) for signal transduction. IFNGR complex in its resting state is a preformed tetramer and upon IFNG association undergoes a conformational change. This conformational change induces the phosphorylation and activation of JAK1, JAK2, and STAT1 which in turn induces genes containing the gamma-interferon activation sequence (GAS) in the promoter. Pubmed14525967 Pubmed18929502 Pubmed9143700 Pubmed9462485 Reactome Database ID Release 43877300 Reactome, http://www.reactome.org ReactomeREACT_25078 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 YWHAB (14-3-3 beta/alpha) dimer binds phosphorylated YAP1 Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2011-12-30 Pubmed17085597 Pubmed17974916 Reactome Database ID Release 432028644 Reactome, http://www.reactome.org ReactomeREACT_118801 Reviewed: Sudol, M, 2012-02-03 YWHAB (14-3-3 beta/alpha) binds phosphorylated YAP1 proteins, sequestering them in the cytosol. Structural studies indicate that the active form of YWHAB (14-3-3 beta/alpha) is a homodimer (Yang et al. 2006); the stoichiometry of its complex with YAP1 is unknown and has been annotated arbitrarily here to involve one YAP1 molecule and a YWHAB (14-3-3 beta/alpha) dimer. While YAP1 can be phosphorylated on several serine residues, phosphorylation of serine-127 appears to be critical for YWHAB(14-3-3 beta/alpha) binding (Zhao et al. 2007). Regulation of IFNA signaling Authored: Garapati, P V, 2010-07-07 Edited: Garapati, P V, 2010-07-07 GENE ONTOLOGYGO:0060338 Pubmed10526574 Pubmed16311601 Pubmed16710296 Reactome Database ID Release 43912694 Reactome, http://www.reactome.org ReactomeREACT_25216 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 There are several proteins and mechanisms involved in controlling the extent of ligand stimulation of IFNA/B signaling. These mechanisms can effect every step of the IFNA/B cascade. Dephosphorylation of JAK and STAT by SHP protein phosphatases, inhibition of STAT function in the nucleus by protein inhibitors of activated STATs (PIAS) proteins, inhibition of tyrosine kinase activity of JAKs by SOCS as well as inhibition of JAK and IFNAR2 interaction by UBP43 are few of the negative regulation mechanisms in controling type I IFN signaling. Antiviral mechanism by IFN-stimulated genes Authored: Garapati, P V, 2011-01-18 Edited: Garapati, P V, 2011-01-18 Reactome Database ID Release 431169410 Reactome, http://www.reactome.org ReactomeREACT_115676 Reviewed: Zhang, DE, 2011--0-2- The ISG proteins generated by IFN pathways plays key roles in the induction of innate and adaptive immune responses. WWTR1 (TAZ) binds ZO-1 (TJP1) Authored: D'Eustachio, P, 2012-02-03 Cytosolic ZO-1 (TJP1) binds WWTR1 (TAZ) to form a complex. This event may play a role in sequestering WWTR1 in the cytosol (Remue et al. 2010). The phosphorylation state of the WWTR1 protein involved in this interaction has not been determined experimentally; it is inferred to be unphosphorylated. Edited: D'Eustachio, P, 2012-01-18 Pubmed20850437 Reactome Database ID Release 432064417 Reactome, http://www.reactome.org ReactomeREACT_118750 Reviewed: Sudol, M, 2012-02-03 Regulation of IFNG signaling At least three different classes of negative regulators exist to control the extent of INFG stimulation and signaling. These include the feedback inhibitors belonging to protein family suppressors of cytokine signaling (SOCS), the Scr-homology 2 (SH2)-containing protein tyrosine phosphatases (SHPs), and the protein inhibitors of activated STATs (PIAS). The induction of these regulators seems to be able to stop further signal transduction by inhibiting various steps in IFNG cascade. Authored: Garapati, P V, 2010-06-08 Edited: Garapati, P V, 2010-06-08 GENE ONTOLOGYGO:0060334 Pubmed10526574 Pubmed12645661 Pubmed18031232 Reactome Database ID Release 43877312 Reactome, http://www.reactome.org ReactomeREACT_24980 Reviewed: Abdul-Sater, AA, Schindler, C, 2010-08-17 Translocation of WWTR1 (TAZ) to the nucleus Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2012-01-06 In its unphosphorylated state, the WWTR1 (TAZ) transcriptional coactivator moves freely into the nucleus. Phosphorylated WWTR1 (TAZ), in contrast, is sequestered in the cytosol (Lei et al. 2008). Pubmed18227151 Reactome Database ID Release 432032768 Reactome, http://www.reactome.org ReactomeREACT_118676 Reviewed: Sudol, M, 2012-02-03 DAI mediated induction of type I IFNs Authored: Shamovsky, V, 2011-09-21 DNA-dependent activator of IFN-regulatory factors (DAI), also known as Z-DNA-binding protein-1 (ZBP-1), was reported to initiate innate immune responses in murine L929 cells upon stimulation by multiple types of exogenously added DNA (Takaoka A et al 2007). Human cytomegalovirus (HCMV) was shown to stimulate DAI-mediated induction of IRF3 in human foreskin (DeFilippis VR et al 2010). DAI was also implicated in activation of NF-kappaB pathways in human embryonic kidney HEK293T cells (Kaiser WJ et al 2008, Rebsamen M et al 2009). However, the role and importance of DAI as dsDNA sensor remain controversial, since knocking down DAI expression in other human or murine cell types by siRNA had very little effect on cellular responses to cytosolic DNA, suggesting the presence of alternative pathway (Wang ZC et al 2008, Lippmann J et al 2008). Tissue-specific expression of human DAI also suggests that DAI may function in cell-type specific way (Rothenburg S et al 2002).<br> Edited: Shamovsky, V, 2012-02-23 Pubmed11842111 Pubmed17618271 Pubmed18375758 Pubmed18771559 Pubmed18941233 Pubmed19590578 Pubmed19846511 Reactome Database ID Release 431606322 Reactome, http://www.reactome.org ReactomeREACT_118764 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- IRF3 mediated activation of type 1 IFN Authored: Shamovsky, V, 2011-09-21 Edited: Shamovsky, V, 2012-02-23 Interferon regulatory factors (IRF) IRF-3 and IRF-7 are the major modulators of IFN gene expression in response to pathogenic molecules. The relative contribution of IRF3 and IRF7 depends on the signaling pathway that is activated. Type I IFN production in cytosolic DNA-sensing pathway is mediated predominantly by IRF3 and partially by IRF7, since DNA-stimulated IFN-beta and IFN-alpha4 mRNA induction was strongly inhibited in IRF3-deficient mouse embryonic fibroblasts (MEFs), while remained normal (IFN-beta) or reduced (IFN-alpha4) in IRF7-deficient MEFs (Takaoke A et al 2007). IRF3 activation in response to B-DNA stimulation occurs via its co-recruitment with serine/threonine kinase TANK-binding kinase 1 (TBK1) or inducible IkB kinase (IKKi/IKKepsilon) to the C-terminal region of DAI. Pubmed16413926 Pubmed17618271 Pubmed18375758 Pubmed19846511 Reactome Database ID Release 431606341 Reactome, http://www.reactome.org ReactomeREACT_118811 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- Beta defensins Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Humans have 38 beta-defensin genes plus 9-10 pseudogenes (details available on the HGNC website at http://www.genenames.org/genefamilies/DEFB). Many beta-defensins are encoded by recently duplicated genes giving rise to identical transcripts. Nomenclature is confusing and currently in transition. Uniprot recommended names are used throughout this pathway.<br>Many beta-defensins show expression that correlates with infection (Sahl et al. 2005, Pazgier et al. 2006). All so far characterized beta-defensins, i.e. beta-defensin 1 (hBD1), 4A (hBD2), 103 (hBD3), 104 (hBD4), 106 (hBD6), 118 (hBD18) and 128 (hBD28) have antimicrobial properties (Pazgier et al. 2006). For beta-defensins 4A, 103 and 118 (hBD2, 3, and 18) this has been shown to correlate with membrane permeabilization effects (Antcheva et al. 2004, Sahl et al. 2005, Yenugu et al. 2004). Electrostatic interaction and disruption of microbial membranes is widely believed to the primary mechanism of action for beta-defensins. Two models explain how membrane disruption takes place, the 'pore model' which postulates that beta-defensins form transmembrane pores in a similar manner to alpha-defensins, and the 'carpet model', which suggests that beta-defensins act as detergents. Beta-defensins contain 6 conserved cysteine residues that in beta-defensins 1, 4A and 103 (hBD1-3) are experimentally confirmed to be cross-linked 1-5, 2-4, 3-6. The canonical sequence for beta-defensins is x2-10Cx5-6(G/A)xCX3-4Cx9-13Cx4-7CCxn. Structurally they are similar to alpha-defensins but with much shorter pre-regions. Though dimerization of some beta-defensins has been reported this is not the case for all and it is unclear whether it is required for function. The majority of functional studies have focused on beta-defensin 103 (hBD3), which has the most significant antimicrobial activity at physiological salt concentrations (Harder et al. 2001). Beta-defensin 103 is highly cationic with a net charge of +11 e0. It exhibits broad-spectrum antimicrobial activity against gram-positive bacteria and some gram-negative bacteria (Harder et al. 2001), though some species are highly resistant (Sahly et al. 2003). Sensitivity correlates with lipid composition of the membrane, with more negatively-charged lipids correlating with larger beta-defensin 103-induced changes in membrane capacitance (Bohling et al. 2006). Though membrane disruption is widely believed to be the primary mechanism of action of beta-defensins they have other antimicrobial properties, such as inhibition of cell wall biosynthesis (Sass et al. 2010), and chemoattractant effects (Yang et al. 1999, Niyonsaba et al. 2002, 2004). The chemotactic activity of beta-defensins 1, 4A and 103 (hBD1-3) for memory T cells and immature DCs is mediated through binding to the chemokine receptor CCR6 and probably another unidentified Gi-coupled receptor (Yang et al. 1999, 2000). <br> <br>Like defensins, the human cathelicidin LL37 peptide is rich in positively-charged residues (Lehrer & Ganz 2002).<br>Expression of certain beta-defensins can be induced in response to various signals, such as bacteria, pathogen-associated molecular patterns (PAMPs), or proinflammatory cytokines (Ganz 2003, Yang et al. 2004). Like the alpha-defensins, copy number variation has been reported for DEFB4, DEFB103 and DEFB104 with individuals having 2-12 copies per diploid genome. In contrast DEFB1 does not show such variation but exhibits a number of SNPs (Hollox et al. 2003, Linzmier & Ganz 2005). Pubmed10521347 Pubmed10914484 Pubmed11085990 Pubmed11753073 Pubmed11934878 Pubmed12709350 Pubmed12916016 Pubmed12949495 Pubmed14742239 Pubmed15009427 Pubmed15032578 Pubmed15033915 Pubmed15582982 Pubmed16039093 Pubmed16634647 Pubmed16710608 Pubmed20385753 Reactome Database ID Release 431461957 Reactome, http://www.reactome.org ReactomeREACT_115897 Reviewed: McDermott, AM, 2011-11-03 Cytosolic sensors of pathogen-associated DNA Authored: Shamovsky, V, 2011-09-21 Edited: Shamovsky, V, 2012-02-23 GENE ONTOLOGYGO:0032481 Presence of pathogen-associated DNA in cytosol induces type I IFN production. Several intracellular receptors have been implicated to some degree. These include DNA-dependent activator of interferon (IFN)-regulatory factors (DAI) (also called Z-DNA-binding protein 1, ZBP1), absent in melanoma 2 (AIM2), RNA polymerase III (Pol III), leucine-rich repeat flightless interacting protein-1 (Lrrfip1), DExD/H box helicases (DHX9 and DHX36), and the IFN-inducible protein IFI16.<p>Detection of cytosolic DNA requires multiple and possibly redundant sensors leading to activation of the transcription factor NF-kappaB and TBK1-mediated phosphorylation of the transcription factor IRF3. Cytosolic DNA also activates caspase-1-dependent maturation of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-18. This pathway is mediated by AIM2. Pubmed21533068 Reactome Database ID Release 431834949 Reactome, http://www.reactome.org ReactomeREACT_118823 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- Defensins Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Pubmed10521347 Pubmed10914484 Pubmed12021776 Pubmed12949495 Pubmed15032578 Pubmed15372083 Pubmed15703760 Pubmed15908936 Pubmed19024344 Pubmed21573784 Pubmed21617811 Reactome Database ID Release 431461973 Reactome, http://www.reactome.org ReactomeREACT_115846 Reviewed: McDermott, AM, 2011-11-03 The defensins are a family of antimicrobial cationic peptide molecules which in mammals have a characteristic beta-sheet-rich fold and framework of six disulphide-linked cysteines (Selsted & Ouellette 2005, Ganz 2003). Human defensin peptides have two subfamilies, alpha- and beta-defensins, differing in the length of peptide chain between the six cysteines and the order of disulphide bond pairing between them. A third subfamily, the theta defensins, is derived from alpha-defensins prematurely truncated by a stop codon between the third and fourth cysteine residues. The translated products are shortened to nonapeptides, covalently dimerized by disulfide linkages, and cyclized via new peptide bonds between the first and ninth residues. Humans have one pseudogene but no translated representatives of the theta class.<br>In solution most alpha and beta defensins are monomers but can form dimers and higher order structures. The primary cellular sources of defensins are neutrophils, epithelial cells and intestinal Paneth cells.Those expressed in neutrophils and the gut are predominantly constitutive, while those in epithelial tissues such as skin are often inducible by proinflammatory stimuli such as LPS or TNF-alpha. Defensins are translated as precursor polypeptides that include a typical signal peptide or prepiece that is cleaved in the Golgi body, and a propiece, cleaved by differing mechanisms to produce the mature defensin. Mature defensin peptides can be further processed by removal of individual N-terminal residues (Yang et al. 2004). This may be a mechanism to broaden the activity profile of defensins (Ghosh et al. 2002). Defensins have direct antimicrobial effects and kill a wide range of Gram-positive and negative bacteria, fungi and some viruses. The primary antimicrobial action of defensins is permeabilization of microbial target membranes but several additional mechanisms have been suggested (Brogden 2005, Wilmes et al. 2011). Defensins and related antimicrobial peptides such as cathelicidin bridge the innate and acquired immune responses. In addition to their antimicrobial properties, cathelicidin and several defensins show receptor-mediated chemotactic activity for immune cells such as monocytes, T cells or immature DCs, induce cytokine production by monocytes and epithelial cells, modulate angiogenesis and stimulate wound healing (Yang et al. 1999, 2000, 2004, Rehaume & Hancock 2008, Yeung et al. 2011). Alpha-defensins Authored: Jupe, S, 2011-04-28 Edited: Jupe, S, 2011-07-27 Humans have 7 alpha defensin genes plus 5 pseudogenes (see HGNC at http://www.genenames.org/genefamilies/DEFA). Alpha-defensins have six cysteines linked 1-6, 2-4, 3-5. The canonical sequence of alpha-defensins in humans is x1-2CXCRx2-3Cx3Ex3GxCx3Gx5CCx1-4, where x represents any amino acid residue. <br>Human alpha-defensins 1-4 are often called human neutrophil peptides (HNP1-4) as they were initially identified in neutrophil primary (azurophilic) granules. Alpha-defensins 5 and 6 (HD5, HD6) are products of Paneth cells. HNP-1 and -3 peptides are 30 residues long, differing only in the first amino acid. They are encoded by the genes DEFA1 and DEFA3 respectively. These exhibit copy number polymorphism, with some individuals having 4-14 copies per diploid genome, while 10-37% of individuals have no copies of DEFA3 (Aldred et al. 2005, Linzmier & Ganz 2005, Ballana et al. 2007). HNP-4, encoded by DEFA4, is 33 amino acids long of which 22 differ from the other HNPs (Wilde et al. 1989). It is a minor component of neutrophil granules compared to HNP1-3. In contrast to DEFA1 and DEFA3, the genes for HNP-4, HD-5 and HD-6 are only found as two copies per diploid genome (Linzmeier & Ganz 2005). HNP-2 is 29 amino acids in length and is the proteolytic product of cleavage of the N-terminal amino acid from either HNP-1 and/or HNP-3 (Selsted et al. 1985). Pubmed12949495 Pubmed15944200 Pubmed16039093 Pubmed17214878 Pubmed2500436 Pubmed4056036 Reactome Database ID Release 431462054 Reactome, http://www.reactome.org ReactomeREACT_115574 Reviewed: McDermott, AM, 2011-11-03 Negative regulators of RIG-I/MDA5 signaling As with other cytokine systems, production of type I IFN is a transient process, and can be hazardous to the host if unregulated, resulting in chronic cellular toxicity or inflammatory and autoimmune diseases. RIG-I-mediated production of IFN can, in turn, increase the transcription of RIG-I itself, thus setting into motion an IFN amplification loop, which if left unchecked, could become deleterious to the host. This module mainly focuses on the endogenous negative regulation of the RIG-I-like receptor (RLR) family proteins RIG-I and MDA5. Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 GENE ONTOLOGYGO:0032480 Pubmed18549796 Pubmed18703349 Reactome Database ID Release 43936440 Reactome, http://www.reactome.org ReactomeREACT_25271 Reviewed: Kawai, T, Akira, S, 2010-10-30 DAP12 interactions Authored: Garapati, P V, 2012-05-25 DNAX activation protein of 12kDa (DAP12) is an immunoreceptor tyrosine-based activation motif (ITAM)-bearing adapter molecule that transduces activating signals in natural killer (NK) and myeloid cells. It mediates signalling for multiple cell-surface receptors expressed by these cells, associating with receptor chains through complementary charged transmembrane amino acids that form a salt-bridge in the context of the hydrophobic lipid bilayer (Lanier et al. 1998). DAP12 homodimers associate with a variety of receptors expressed by macrophages, monocytes and myeloid cells including TREM2, Siglec H and SIRP-beta, as well as activating KIR, LY49 and the NKG2C proteins expressed by NK cells. DAP12 is expressed at the cell surface, with most of the protein lying on the cytoplasmic side of the membrane (Turnbull & Colonna 2007, Tessarz & Cerwenka 2008). Edited: Garapati, P V, 2012-05-25 Pubmed15884055 Pubmed17220916 Pubmed18192027 Pubmed19120482 Pubmed9490415 Reactome Database ID Release 432172127 Reactome, http://www.reactome.org ReactomeREACT_147694 Reviewed: Lanier, Lewis L, 2012-08-09 RIP-mediated NFkB activation via DAI Authored: Shamovsky, V, 2011-09-21 Edited: Shamovsky, V, 2012-02-23 Overexpression of human or murine DAI in human embryonic kidney 293T cells (HEK293T) activated NF-kB-dependent promoter in a dose-dependent manner. Two RHIM-contaning kinases RIP1 and RIP3 are implicated in DAI-induced NFkB activation (Rebsamen M et al 2009; Kaiser WJ et al 2008). Pubmed18941233 Pubmed19590578 Reactome Database ID Release 431810476 Reactome, http://www.reactome.org ReactomeREACT_118563 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- STING mediated induction of type 1 IFN Authored: Shamovsky, V, 2012-07-09 GENE ONTOLOGYGO:0032481 Pubmed18724357 Pubmed19433799 Pubmed19776740 Pubmed19926846 Pubmed20107183 Pubmed20871604 Pubmed20890285 Pubmed21820332 Pubmed21892174 Pubmed21947006 Pubmed22394562 Pubmed22607800 Pubmed22706339 Reactome Database ID Release 431834941 Reactome, http://www.reactome.org ReactomeREACT_147841 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 STING (stimulator of IFN genes; also known as MITA/ERIS/MPYS/TMEM173) is an endoplasmic reticulum (ER) resident, which is required for effective type I IFN production in response to nucleic acids. Indeed, select pathogen-derived DNA or RNA were shown to activate STING in human and mouse cells [Ishikawa H and Barber GN 2008; Ishikawa H et al 2009; Sun W et al 2009; Prantner D et al 2010]. Importantly, in vitro studies have shown that STING is essential for Mycobacterium tuberculosis [Manzanillo PS et al 2012], Plasmodium falciparum [Sharma S et al 2011] and human immunodeficiency virus (HIV) induced type I IFN production [Yan N et al 2010]. Mycobacterium tuberculosis, plasmodium falciparum and HIV are three deadliest pathogens, which kill millions of people each year worldwide.<p>STING has been also implicated in type I IFN response which was stimulated by fusion of viral and target-cell membrane in a manner independent of DNA, RNA and viral capsid [Holm CK et al 2012].<p>Under steady state conditions, STING is positioned at the translocon complex within the ER membrane. However upon stimulation with intracellular DNA it translocates from ER to perinuclear vesicles via the Golgi by mechanisms that remain unclear [Ishikawa H and Barber GN 2008; Sun W et al 2009; Ishikawa H et al 2009; Saitoh T et al 2009]. Mouse Sting trafficking in dsDNA-stimulated mouse embryonic fibroblasts (MEF) cells was found to depend on autophagy-related gene 9a (Atg9a) [Saitoh T et al 2009].<p>STING was reported to function as a signaling adaptor or coreceptor in response to cytosolic dsDNA [Unterholzner L et al 2010; Zhang Z et al 2011]. Additionally, STING is thought to function as a direct sensor of cyclic dinucleotides. STING was shown to interact directly with c-di-GMP in human embryonic kidney HEK293T cell lysates and [Burdette DL et al 2011]. Once STING is stimulated, its C-terminus serves as a signaling scaffold to recruit IRF3 and TBK1, which leads to TBK1-dependent phosphorylation of IRF3 [Tanaka Y and Chen ZJ 2012]. The IPAF inflammasome Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed11390368 Pubmed15190255 Pubmed16444259 Pubmed16648853 Pubmed18724372 Pubmed20133635 Pubmed20303873 Reactome Database ID Release 43844623 Reactome, http://www.reactome.org ReactomeREACT_75892 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The IPAF (NLRC4) inflammasome can be activated by several stimuli, most notably by Gram-negative bacteria with either type III or type IV secretion systems that result in cytosolic flagellin, which is recognized by the IPAF inflammasome (Miao et al. 2006). IPAF also recognizes the rod-component of the type III secretion system which shares a sequence motif with flagellin that is essential for detection (Miao et al. 2010). Detection of Legionella and/or flagellin may also involve NAIP5 (Zamboni et al. 2006, Lightfield et al. 2008). IPAF contains a CARD domain and can interact directly with procaspase-1 (Poyet et al. 2001) but ASC increases the maximal activation of caspase-1 in response to S. typhimurium (Mariathasan et al. 2004), S. flexneri, and P. aeruginosa suggesting a possible collaboration with a PYD-containing NLRP for responses to these pathogens (Schroder & Tschopp, 2010). IPAF mediated caspase-1 activation can lead to a particular type of cell death called 'pyroptosis' (see Schroder & Tschopp 2010). The AIM2 inflammasome AIM2 is a member of the PYHIN or HIN200 family. It has a C-terminal HIN domain which can bind double-stranded DNA (dsDNA) and a PYD domain that can bind ASC via a PYD-PYD interaction. In cells expressing procaspase-1, The interaction of AIM2 with ASC leads to recruitment of procaspase-1 forming the ASC pyroptosome which induces pyroptotic cell death by generating active caspase-1. Data from AIM2 deficient mice indicates that the AIM2 inflammasome is a nonredundant sensor for dsDNA that regulates the caspase-1-dependent maturation of IL-1beta and IL-18 (Rathinam et al. 2010, Hornung & Latz, 2009). Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed20098460 Pubmed20303873 Pubmed20351692 Reactome Database ID Release 43844615 Reactome, http://www.reactome.org ReactomeREACT_75777 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Advanced glycosylation endproduct receptor signaling Advanced Glycosylation End- product-specific Receptor (AGER) also known as Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand membrane receptor belonging to the immunoglobulin superfamily. It is considered to be a Pattern Recognition Receptor (Liliensiek et al. 2004). It recognizes a large variety of modified proteins known as advanced glycation/glycosylation endproducts (AGEs), a heterogenous group of structures that are generated by the Maillard reaction, a consequence of long-term incubation of proteins with glucose (Ikeda et al. 1996). Their accumulation is associated with diabetes, atherosclerosis, renal failure and ageing (Schmidt et al. 1999). The most prevalent class of AGE in vivo are N(6)-carboxymethyllysine (NECML) adducts (Kislinger et al. 1991). In addition to AGEs, AGER is a signal transduction receptor for amyloid-beta peptide (Ab) (Yan et al. 1996), mediating Ab neurotoxicity and promoting Ab influx into the brain. AGER also responds to the proinflammatory S100/calgranulins (Hofmann et al. 1999) and High mobility group protein B1 (HMGB1/Amphoterin/DEF), a protein linked to neurite outgrowth and cellular motility (Hori et al. 1995).<br><br>The major inflammatory pathway stimulated by AGER activation is NFkappaB. Though the signaling cascade is unclear, several pieces of experimental data suggest that activation of AGER leads to sustained activation and upregulation of NFkappaB, measured as NFkappaB translocation to the nucleus, and increased levels of de novo synthesized NFkappaB (Bierhaus et al. 2001). As this is clearly an indirect effect it is represented here as positive regulation of NFkappaB translocation to the nucleus. AGER can bind ERK1/2 and thereby activate the MAPK and JNK cascades (Bierhaus et al. 2005). Authored: Jupe, S, 2010-06-01 Edited: Jupe, S, 2010-09-01 Pubmed10399917 Pubmed10531386 Pubmed11723063 Pubmed15173891 Pubmed16133426 Pubmed7592757 Pubmed8672512 Pubmed8751438 Reactome Database ID Release 43879415 Reactome, http://www.reactome.org ReactomeREACT_25195 Reviewed: Yan, SD, 2010-11-09 RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed15208624 Pubmed16214811 Pubmed17395582 Pubmed17683970 Pubmed17942531 Pubmed18701081 Pubmed18989317 RIG-I-like helicases (RLHs) the retinoic acid inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) are RNA helicases that recognize viral RNA present within the cytoplasm. Functionally RIG-I and MDA5 positively regulate the IFN genes in a similar fashion, however they differ in their response to different viral species. RIG-I is essential for detecting influenza virus, Sendai virus, VSV and Japanese encephalitis virus (JEV), whereas MDA5 is essential in sensing encephalomyocarditis virus (EMCV), Mengo virus and Theiler's virus, all of which belong to the picornavirus family. RIG-I and MDA5 signalling results in the activation of IKK epsilon and (TKK binding kinase 1) TBK1, two serine/threonine kinases that phosphorylate interferon regulatory factor 3 and 7 (IRF3 and IRF7). Upon phosphorylation, IRF3 and IRF7 translocate to the nucleus and subsequently induce interferon alpha (IFNA) and interferon beta (IFNB) gene transcription. Reactome Database ID Release 43168928 Reactome, http://www.reactome.org ReactomeREACT_25359 Reviewed: Kawai, T, Akira, S, 2010-10-30 The NLRP3 inflammasome Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 Pubmed11607846 Pubmed12766759 Pubmed15075209 Pubmed16498449 Pubmed17036048 Pubmed18604214 Pubmed19501527 Pubmed20303873 Reactome Database ID Release 43844456 Reactome, http://www.reactome.org ReactomeREACT_75808 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The NLRP3 (Cryopyrin) inflammasome is currently the best characterized. It consists of NLRP3, ASC (PYCARD) and procaspase-1; CARD8 (Cardinal) is also suggested to be a component. It is activated by a number of pathogens and bacterial toxins as well as diverse PAMPs, danger-associated molecular patterns (DAMPS) such as hyaluronan and uric acid, and exogenous irritants such as silica and asbestos (see Table S1 Schroder & Tschopp, 2010).<br> Mutations in NLRP3 which lead to constitutive activation are linked to the human diseases Muckle-Wells syndrome, familial cold autoinflammatory syndrome and NOMID (Ting et al. 2006), characterized by skin rashes and other symptoms associated with generalized inflammation. The cause of these symptoms is uncontrolled IL-1 beta production. Multiple studies have shown that activation of the NLRP3 inflammasome by particulate activators (e.g. Hornung et al. 2008) requires phagocytosis, but this is not required for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006). Direct binding of activators to NLRP3 has not been demonstrated and the exact process of activation is unclear, though it is speculated to involve changes in conformation that free the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003). The NLRP1 inflammasome Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 NLRP1 is activated by MDP (Faustin et al. 2007). The NLRP1 inflammasome was the first to be characterized. It was described as a complex containing NALP1, ASC, caspase-1 and caspase-5 (Martinon et al. 2002). Unlike NLRP3, NLRP1 has a C-terminal extension containing a CARD domain, which has been reported to interact directly with procaspase-1, obviating a requirement for ASC (Faustin et al. 2007), though ASC was found to augment the interaction. Mouse NLRP1 has no PYD domain and would therefore not be expected to interact directly with procaspase-1. Like the NLRP3 inflammasome, K+ efflux appears to be essential for caspase-1 activation (Wickliffe et al. 2008). Ribonucleoside triphosphates (NTPs) are required for NALP1-mediated caspase-1 activation with ATP being the most efficient, Mg2+ was also required (Faustin et al. 2007). The human NLRP1 gene has 3 paralogues in mouse that are highly polymorphic. Differences between mouse strains underlie susceptibility to anthrax lethal toxin (Boyden & Dietrich 2006). Pubmed12191486 Pubmed16429160 Pubmed17349957 Pubmed17850338 Reactome Database ID Release 43844455 Reactome, http://www.reactome.org ReactomeREACT_75927 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 TRAF3-dependent IRF activation pathway Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 IPS-1/MAVS/Cardif/VISA with its TRAF-interaction motif (TIM) directly interacts with TRAF3 and recruits TRAF3 to the RIG-I/MDA5 signaling complex. TRAF3 acts as a scaffold for the assembly of a signaling complex composed of IKK epsilon/TBK1, leading to the activation of transcription factors IRF3/IRF7. Pubmed16306936 Pubmed17190786 Reactome Database ID Release 43918233 Reactome, http://www.reactome.org ReactomeREACT_25026 Reviewed: Kawai, T, Akira, S, 2010-10-30 NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Fas-associateddeathdomain (FADD) and receptor interacting protein 1 (RIP1) are death domain containing molecules that interact with the C-terminal portion of IPS-1 and induce NF-kB through interaction and activation of initiator caspases (caspase-8 and -10). Caspases are usually involved in apoptosis and inflammation but they also exhibit nonapoptotic functions. These nonapoptotic caspase functions involve prodomain-mediated activation of NF-kB. Processed caspases (caspase-8/10) encoding the DED (death effector domain)starongly activate NF-kB. The exact mechanism by which caspases mediate NF-kB activation is unclear but the prodomains of caspase-8/10 may act as scaffolding and allow the recruitment of IKK complex in proximity with other signaling molecules. Pubmed12884866 Pubmed16127453 Pubmed16585540 Pubmed16618810 Reactome Database ID Release 43933543 Reactome, http://www.reactome.org ReactomeREACT_25039 Reviewed: Kawai, T, Akira, S, 2010-10-30 TRAF6 mediated IRF7 activation Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed19479062 Reactome Database ID Release 43933541 Reactome, http://www.reactome.org ReactomeREACT_24938 Reviewed: Kawai, T, Akira, S, 2010-10-30 TRAF6 is crucial for both RIG-I- and MDA5-mediated antiviral responses. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of type I IFNs and IL6 after infection with RNA virus. Activation of NF-kB and IRF7, but not that of IRF3, was significantly impaired during RIG-like helicases (RLHs) signaling in the absence of TRAF6. TRAF6-induced activation of IRF is likely to be specific for IRF7, while TRAF3 is thought to activate both IRF3 and IRF7. These results strongly suggest that the TRAF6- and TRAF3-dependent pathways are likely to bifurcate at IPS-1, but to converge later at IRF7 in order to co-operatively induce sufficient production of type I IFNs during RLH signaling. TRAF6 mediated NF-kB activation Authored: Garapati, P V, 2010-08-02 Edited: Garapati, P V, 2010-08-02 Pubmed18984593 Reactome Database ID Release 43933542 Reactome, http://www.reactome.org ReactomeREACT_24969 Reviewed: Kawai, T, Akira, S, 2010-10-30 The TRAF6/TAK1 signal activates a canonical IKK complex, resulting in the activation of NF-kB as well as MAPK cascades leading to the activation of AP-1. Although TRAF6/TAK1 has been implicated in Tool like receptor (TLR) mediated cytokine production, the involvement of these molecules in the regulation of type I IFN induction mediated by RIG-I/MDA5 pathway is largely unknown. According to the study done by Yoshida et al RIG-I/IPS-1 pathway requires TRAF6 and MAP3K, MEKK1 to activate NF-kB and MAP Kinases for optimal induction of type I IFNs. ICAMs 1-4 bind to Integrin LFA-1 Authored: de Bono, B, 2007-07-08 12:58:15 Integrins play a central role in mediating lymphocyte adhesion to a number of surfaces. LFA-1 interacts with ICAMs 1-3 that are typically expressed on other immune system cells. ICAM-4 also interacts with LFA-1, and is known to be expressed on telencepahlic neurons.<p><p>VCAM-1 regulates lymphocyte adhesion to activated endothelial cells via Very Late Antigen-4 (VLA-4).<p><p>To function in a circulating mode, leukocytes express LFA-1 and VLA-4 in a low ligand binding capacity. When leukocytes reach sites of imflammation, these integrins are switched to a higher binding state to guide the complex process of transmigration, tethering, rolling, arrest, adhesion and shape change.<p><p>Signal cascades between LFA-1 and VLA-4 may cross-talk affecting binding affinities in a reciprocal fashion. Pubmed11857637 Reactome Database ID Release 43199050 Reactome, http://www.reactome.org ReactomeREACT_11173 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 Creation of C4 and C2 activators Authored: de Bono, B, 2004-08-04 09:17:50 Pubmed11044372 Pubmed12396008 Pubmed70787 Reactome Database ID Release 43166786 Reactome, http://www.reactome.org ReactomeREACT_8012 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Two pathways lead to a complex capable of activating C4 and C2. The classical pathway is triggered by activation of the C1-complex (C1q, 2X C1r and 2X C1s, thus forming C1qr2s2). This occurs when C1q binds to IgM or IgG complexed with antigens, a single IgM can initiate the pathway while multiple IgGs are needed, or when C1q binds directly to the surface of the pathogen. Binding leads to conformational changes in C1q, activating the serine protease activity of C1r, which then cleaves C1s, another serine protease. The C1r2s2 component is now capable of splitting C4 and C2 to produce the classical C3-convertase C4b2a. C1r and C1s are additionally controlled by C1-inhibitor. The lectin pathway is similar in operation but has different components. Mannose-binding lectin (MBL) initiates the lectin pathway cascade by binding to specific carbohydrate patterns on pathogenic cell surfaces. MASPs associated with MBL become activated and capable of C4 and C2 cleavage, giving rise to the same C3 convertase C4b-C2a as the classical pathway. Interaction of integrin alphaVbeta3 with Bone sialoprotein 2 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Integrin alphaVbeta3 receptor has been implicated in various physiological and pathological responses, including bone density, angiogenesis, apoptosis, tumor growth and metastasis. <br>Bone sialoprotein (BSP) is a significant component of the bone extracellular matrix and plays an important role in bone resorption and osteoclast formation. BSP is considered as an important physiological ligand of alphaVbeta3 for osteoclast adhesion in bone development and mineralization. Pubmed10640428 Reactome Database ID Release 43265427 Reactome, http://www.reactome.org ReactomeREACT_13402 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Interaction of integrin alphaVbeta8 with vitronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed14644171 Pubmed7525578 Pubmed7559467 Reactome Database ID Release 43216315 Reactome, http://www.reactome.org ReactomeREACT_13719 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 alphaVbeta8 acts as a fibrin receptor and mediates the attachment of cells to fibrin. This attachment involves the RGD-containing sequence within the fibrin Interaction of integrin alphaXbeta2 with fibrin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Integrin alphaXbeta2 serves as a cell surface receptor for fibrinogen and plays an important role in leuckocyte functions including phagocytosis and migration. Pubmed10543983 Pubmed17339034 Reactome Database ID Release 43216082 Reactome, http://www.reactome.org ReactomeREACT_13612 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Alternative complement activation Authored: de Bono, B, 2004-08-04 09:17:50 Edited: Jupe, S, 2010-11-17 GENE ONTOLOGYGO:0006957 ISBN0781735149 Pubmed162484 Reactome Database ID Release 43173736 Reactome, http://www.reactome.org ReactomeREACT_8001 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 The proteins participating in alternative pathway activation are C3 (and C3b), the factors B, D, and properdin. In the first place, alternative pathway activation is a positive feedback mechanism to increase C3b. When C3b binds covalently to sugars on a cell surface, it can become protected. Then Factor B binds to C3b. In the presence of Factor D, bound Factor B is cleaved to Ba and Bb. Bb contains the active site for a C3 convertase. Properdin then binds to C3bBb to stabilize the C3bBb convertase on cell surface leading to cleavage of C3. Finally, a C3bBb3b complex forms and this is a C5 convertase. Interaction of integrin alphaVbeta5 with vitronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed9443892 Reactome Database ID Release 43216077 Reactome, http://www.reactome.org ReactomeREACT_13540 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The beta5 integrin subunit has been reported to only pair with the alphaV subunit. The integrin alphaVbeta5 receptor interact with vitronectin and promote cell spreading and motility on this ligand. Terminal pathway of complement After cleavage of C5, C5b undergoes conformational changes and exposes a binding site for C6. C5b6 binds C7 resulting in the exposure of membrane binding sites and incorporation into target membranes. The membrane-bound C5b-7 complex can then bind C8. C5b-8 acts as a polymerizing agent for C9. The first C9 bound to C5b-8 undergoes major structural changes enabling formation of an elongated molecule and allows binding of additional C9 molecules and insertion of C9 cylinders into the target membrane. The number of C9 molecules varies from 1-12 in the membrane, although polymers containing up to fifteen C9 molecules are also possible. Authored: de Bono, B, 2004-08-04 09:17:50 ISBN0781735149 Reactome Database ID Release 43166665 Reactome, http://www.reactome.org ReactomeREACT_8028 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Interaction of integrin alphaVbeta6 with Fibronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Fibronectin serves as the main ligand for the integrin alphaVbeta6 however it is not used as a primary fibronectin receptor. Pubmed1532572 Pubmed16260650 Reactome Database ID Release 43216080 Reactome, http://www.reactome.org ReactomeREACT_13742 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Lectin pathway of complement activation Authored: de Bono, B, 2004-08-04 09:17:50 GENE ONTOLOGYGO:0001867 Mannose-binding lectin (MBL), a Ca-dependent (C-type) lectin, initiates the complement cascade after binding to specific carbohydrate patterns on pathogenic cell surfaces. The MBL polypeptide chain consists of a short N-terminal cysteine-rich region, a collagen-like region comprising 19 Gly-X-Y triplets, a 34-residue hydrophobic stretch, and a C-terminal C-type lectin domain. MBL monomers associate via their cysteine-rich and collagen-like regions to form homotrimers, and these in turn associate into oligomers. The predominant oligomers found in human serum contain three (MBL-I) or four (MBL-II) homotrimers (Fujita et al. 2004; Teillet et al. 2005). These oligomers are associated with homodimers of the MASP2 serine protease (Fujita et al. 2004; Hajela et al. 2002). MBL-II is associated with one or two MASP homodimers (Chen and Wallis 2001, 2004). The carbohydrate recognition domain (CRD) of MBL binds carbohydrates with 3- and 4- OH groups in the pyranose ring, such as mannose and N-acetyl-D-glucosamine, in the presence of Ca2+. This binding results in a change in conformation of the MBL and activation of MASP by cleavage (Fujita et al. 2004). MASP2a cleaves C4 to generate C4a and C4b. C4b binds to the bacterial or foreign cell surface via its thioester bond (Law and Dodds 1997) and binds circulating C2. Bound C2 is then cleaved by MASP2 to yield the C3 convertase C4b-C2a. MASP1, a serine protease encoded by an alternatively spliced transcript of the same gene that encodes MASP2, can also be activated by binding of the MBL complex to carbohydrate patterns. MASP-1a cleaves fibrinogen to yield fibrinopeptide B, and cleaves and activates factor XIII. While MASP1 can also cleave C2, it is not thought to mediate the initial cleavage and activation of C2 in vivo (Chen and Wallis 2004). MASP-1a may have a role in cleavage of 'dead C3', i.e. C3(H2O) (Hajela et al. 2002). Pubmed11337510 Pubmed11532276 Pubmed12396008 Pubmed15060079 Pubmed15199963 Pubmed15728497 Pubmed9041627 Reactome Database ID Release 43166662 Reactome, http://www.reactome.org ReactomeREACT_7964 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Interaction of integrin alphaDbeta2 with fibrin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Integrin alphaDbeta2 is a member of the beta2 family. It is expressed poorly on peripheral blood leukocytes but strongly on macrophages. alphaDbeta2 has the ability to interact with multiple ligands, including many ECM proteins. The interaction of beta2 integrins with ligands is mediated by their I-domains of the alpha subunits. The alphaD I-domain mediates the interaction with the ECM protein fibrinogen. Pubmed10438935 Pubmed16239428 Reactome Database ID Release 43216069 Reactome, http://www.reactome.org ReactomeREACT_13787 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Classical antibody-mediated complement activation Authored: de Bono, B, 2004-08-04 09:17:50 C1, the first component of complement is a complex containing three protein species, C1q, C1r, and C1s. C1q is assembled from six identical subunits each of which consists of three homologous chains (A, B, and C). These chains form a globular domain at the C-terminus, followed by the "neck" and a coil in the "stalk." The six subunits are held together by the collagenous stalk parts (giving rise to the comparison of C1q with a "bunch of six tulips"). The stalks also interact with the [C1r:C1s]x2 tetramer assembled in a linear chain. Binding of an antigen to an antibody of the IgM or IgG class induces a conformational change in the Fc domain of the antibody that allows it to bind to the C1q component of C1. C1 activation requires interaction with two separate Fc domains, so pentavalent IgM antibody is far more efficient at complement activation than IgG antibody. Antibody binding results in a conformational change in the C1r component of the C1 complex and a proteolytic cleavage of C1r, activating it. Active C1r then cleaves and activates the C1s component of the C1 complex (Muller-Eberhard 1988). GENE ONTOLOGYGO:0006958 Pubmed12788922 Pubmed3052276 Pubmed9777414 Reactome Database ID Release 43173623 Reactome, http://www.reactome.org ReactomeREACT_7956 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Interaction of integrin alphaVbeta1 with Fibronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed10801899 Pubmed11997396 Pubmed1677003 Pubmed19285555 Pubmed20690820 Pubmed2380248 Reactome Database ID Release 43216314 Reactome, http://www.reactome.org ReactomeREACT_13423 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The alphaV integrin subfamily has five members, all recognize components of the ECM. AlphaVbeta1 integrin binds fibronectin (FN1). In solution FN1 occurs as a dimer. Binding to alpha5beta1 integrin stimulates FN1 self-association; blocking the RGD-cell binding domain of FN1 blocks fibril formation (Fogerty et al. 1990). FN1 binding is believed to induce integrin clustering, which promotes FN1-FN1 interactions. Integrin clustering is mediated by association between integrins and intracellular actin stress fibers (Calderwood et al. 2000). Binding of integrins to each of the monomers in the FN1 dimer pair is thought to trigger a conformational change in FN1 that exposes 'cryptic' FN1 binding sites that allow additional fibronectin dimers to bind without the requirement for preassociation with integrins (Singh et al. 2010). This non-covalent interaction may involve interactions with fibrillin (Ohashi & Erickson 2009). I1-5 functions as a unit that is the primary FN matrix assembly domain (Sottile et al. 1991) but other units are likely to be involved (Singh et al. 2010), the process is not fully understood. has a Stoichiometric coefficient of 2 Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 GENE ONTOLOGYGO:0035872 Pubmed12830145 Pubmed15967716 Pubmed17875812 Pubmed18446235 Pubmed18928408 Pubmed21245903 Reactome Database ID Release 43168643 Reactome, http://www.reactome.org ReactomeREACT_75913 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 The innate immune system is the first line of defense against invading microorganisms, a broad specificity response characterized by the recruitment and activation of phagocytes and the release of anti-bacterial peptides. The receptors involved recognize conserved molecules present in microbes called pathogen-associated molecular patterns (PAMPs), and/or molecules that are produced as a result of tissue injury, the damage associated molecular pattern molecules (DAMPs). PAMPs are essential to the pathogen and therefore unlikely to vary. Examples are lipopolysaccharide (LPS), peptidoglycans (PGNs) and viral RNA. DAMPs include intracellular proteins, such as heat-shock proteins and extracellular matrix proteins released by tissue injury, such as hyaluronan fragments. Non-protein DAMPs include ATP, uric acid, heparin sulfate and dsDNA. The receptors for these factors are referred to collectively as pathogen- or pattern-recognition receptors (PRRs). The best studied of these are the membrane-associated Toll-like receptor family. Less well studied but more numerous are the intracellular nucleotide-binding domain, leucine rich repeat containing receptors (NLRs) also called nucleotide binding oligomerization domain (NOD)-like receptors, a family with over 20 members in humans and over 30 in mice. These recognise PAMPs/DAMPs from phagocytosed microorganisms or from intracellular infections (Kobayashi et al. 2003, Proell et al. 2008, Wilmanski et al. 2008). Some NLRs are involved in process unrelated to pathogen detection such as tissue homeostasis, apoptosis, graft-versus-host disease and early development (Kufer & Sansonetti 2011). <br><br><br>Structurally NLRs can be subdivided into the caspase-recruitment domain (CARD)-containing NLRCs (NODs) and the pyrin domain (PYD)-containing NLRPs (NALPs), plus outliers including ice protease (caspase-1) activating factor (IPAF) (Martinon & Tschopp, 2005). In practical terms, NLRs can be divided into the relatively well characterized NOD1/2 which signal via RIP2 primarily to NFkappaB, and the remainder, some of which participate in macromolecular structures called Inflammasomes that activate caspases. Mutations in several members of the NLR protein family have been linked to inflammatory diseases, suggesting these molecules play important roles in maintaining host-pathogen interactions and inflammatory responses.<br><br><br>Most NLRs have a tripartite structure consisting of a variable amino-terminal domain, a central nucleotide-binding oligomerization domain (NOD or NACHT) that is believed to mediate the formation of self oligomers, and a carboxy-terminal leucine-rich repeat (LRR) that detects PAMPs/DAMPs. In most cases the amino-terminal domain includes protein-interaction modules, such as CARD or PYD, some harbour baculovirus inhibitor repeat (BIR) or other domains. For most characterised NLRs these domains have been attributed to downstream signaling<br><br>Under resting conditions, NLRs are thought to be present in an autorepressed form, with the LRR folded back onto the NACHT domain preventing oligomerization. Accessory proteins may help maintain the inactive state. PAMP/DAMP exposure is thought to triggers conformational changes that expose the NACHT domain enabling oligomerization and recruitment of effectors, though it should be noted that due to the lack of availability of structural data, the mechanistic details of NLR activation remain largely elusive.<br><br>New terminology for NOD-like receptors was adopted by the Human Genome Organization (HUGO) in 2008 to standardize the nomenclature of NLRs. The acronym NLR, once standing for NOD-like receptor, now is an abbreviation of 'nucleotide-binding domain, leucine-rich repeat containing' protein. The term NOD-like receptor is officially outdated and replaced by NLRC where the C refers to the CARD domain. However the official gene symbols for NOD1 and NOD2 still contain NOD and this general term is still widely used. Interaction of integrin alpha10beta1 with Collagen-II Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed15713743 Pubmed17581134 Reactome Database ID Release 43216043 Reactome, http://www.reactome.org ReactomeREACT_13784 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The integrin alpha10beta1 is a collagen type II-binding integrin on chondrocytes. This integrin is of great importance during chondrogenesis. alpha10 binds the collagen-II with its I domain displaying similar binding properties as alpha1 I domain. NOD1/2 Signaling Pathway Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 GENE ONTOLOGYGO:0070423 NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells (Inohara et al. 2005). NOD1 and NOD2 activation induces transcription of immune response genes, predominantly mediated by the proinflammatory transcriptional factor NFkappaB but also by AP-1 and Elk-1 (Inohara et al. 2005). NFkappaB translocates to the nucleus following release from IkappaB proteins. NOD1 and NOD2 signaling involves an interaction between their caspase-recruitment domain (CARD) and the CARD of the kinase RIPK2 (RIP2/RICK). This leads to the activation of the NFkappaB pathway and MAPK pathways (Windheim et al. 2007).<br>Activated NODs oligomerize via their NACHT domains, inducing physical proximity of RIP2 proteins that is believed to trigger their K63-linked polyubiquitination, facilitating recruitment of the TAK1 complex. RIP2 also recruits NEMO, bringing the TAK1 and IKK complexes into proximity, leading to NF-kappaB activation and activation of MAPK signaling. Recent studies have demonstrated that K63-linked regulatory ubiquitination of RIP2 is essential for the recruitment of TAK1 (Hasegawa et al. 2008, Hitosumatsu et al. 2008). As observed for toll-like receptor (TLR) signaling, ubiquitination can be removed by the deubiquitinating enzyme A20, thereby dampening NOD1/NOD2-induced NF-kappaB activation. NOD1 and NOD2 both induce K63-linked ubiquitination of RIP2, but NOD2-signaling appears to preferentially utilize the E3 ligase TRAF6, while TRAF2 and TRAF5 were shown to be important for NOD1-mediated signaling. In both cases, activation of NF-kappaB results in the upregulated transcription and production of inflammatory mediators. Pubmed15952891 Pubmed17348859 Pubmed18079694 Pubmed18342009 Pubmed18414735 Pubmed18585455 Pubmed18928408 Reactome Database ID Release 43168638 Reactome, http://www.reactome.org ReactomeREACT_75776 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Interaction of integrin alpha11beta1 with Collagen-I Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed11518510 Pubmed12496264 Reactome Database ID Release 43216045 Reactome, http://www.reactome.org ReactomeREACT_13663 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The integrin alpha11beta1 along with alpha1beta1, alpha2beta1 and alpha10beta1 are referred as a collagen receptor subgroup of the integrin family. Alpha11beta1 mediates cell adhesion to collagens I and IV (with preference to collagen-I) and form focal contacts on collagens. Activation of C3 and C5 Authored: de Bono, B, 2004-08-04 09:17:50 Edited: Jupe, S, 2010-11-17 GENE ONTOLOGYGO:0006956 Pubmed15199963 Pubmed458145 Reactome Database ID Release 43174577 Reactome, http://www.reactome.org ReactomeREACT_7972 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 The 3 pathways of complement activation converge on the cleavage of C3 by C3 convertases. C3 convertase cleaves C3 into C3a and C3b - a central step of complement activation. C3a remains in the fluid phase and acts as an anaphylatoxin, whereas C3b can bind to C3 convertases to form C5 convertase, can act as an opsonin, or is degraded into fragments which cannot form an active convertase. Regulation of Complement cascade Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 GENE ONTOLOGYGO:0030449 Pubmed15476920 Pubmed16011850 Pubmed18197169 Pubmed19730437 Pubmed20720586 Pubmed21979047 Reactome Database ID Release 43977606 Reactome, http://www.reactome.org ReactomeREACT_118707 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Two inherent features of complement activation make its regulation very important: <br>1. There is an inherent positive feedback loop because the product of C3 activation forms part of an enzyme that causes more C3 activation.<br>2. There is continuous low-level activation of the alternative pathway (see Spontaneous hydrolysis of C3 thioester).<br><br>Complement cascade activation is regulated by a family of related proteins termed the regulators of complement activation (RCA). These are expressed on healthy host cells. Most pathogens do not express RCA proteins on their surface, but many have have found ways to evade the complement system by stably binding the RCA that circulates in human plasma (Lambris et al. 2008); trapping RCA is by far the most widely employed strategy for avoiding the complement response. RCA recruitment is common in bacteria such as E. coli and streptococci (Kraiczy & Würzner 2006) and has also been described for viruses, fungi and parasites. RCA deposition and the complement system also have an important role in tissue homeostasis, clearing dead cells and debris, and preventing damage from oxidative stress (Weismann et al. 2011).<br><br>RCA proteins control complement activation in two different ways; by promoting the irreversible dissociation (decay acceleration) of complement convertases and by acting as cofactors for Complement factor I (CFI)-mediated cleavage of C3b and C4b.<br>Decay accelerating factor (DAF, CD55), Complement factor H (FH), Membrane Cofactor Protein (MCP) and Complement receptor 1 (CR1) are composed of arrays of tandem globular domains termed CCPs (complement control protein repeats) or SCRs (short consensus repeats). CR1, MCP and FH are cofactors for the CFI-mediated cleavage of C3b, generating iC3b. CR1 and MCP are also cofactors for C4b cleavage.<br>C4BP is an additional cofactor for the CFI-mediated cleavage of C4b. Inflammasomes Authored: Jupe, S, 2010-04-22 Edited: Jupe, S, 2011-04-28 In contrast to NOD1/2 some NLRPs function as large macromolecular complexes called 'Inflammasomes'. These multiprotein platforms control activation of the cysteinyl aspartate protease caspase-1 and thereby the subsequent cleavage of pro-interleukin 1B (pro-IL1B) into the active proinflammatory cytokine IL1B. Activation of caspase-1 is essential for production of IL1B and IL18, which respectively bind and activate the IL1 receptor (IL1R) and IL18 receptor (IL18R) complexes. IL1R and IL18R activate NFkappaB and other signaling cascades.<br><br>As the activation of inflammasomes leads to caspase-1 activation, inflammasomes can be considered an upstream step of the IL1R and IL18R signaling cascades, linking intracellular pathogen sensing to immune response pathways mediated by Toll-Like Receptors (TLRs). Monocytes and macrophages do not express pro-IL1B until stimulated, typically by TLRs (Franchi et al. 2009). The resulting pro-IL1B is not converted to IL1B unless a second stimulus activates an inflammasome. This requirement for two distinct stimuli allows tight regulation of IL1B/IL18 production, necessary because excessive IL-1B production is associated with numerous inflammatory diseases such as gout and rheumatoid arthritis (Masters et al. 2009).<br><br>There are at least four subtypes of the inflammasome, characterized by the NLRP. In addition the protein AIM2 can form an inflammasome. All activate caspase-1. NLRP1 (NALP1), NLRP3 (Cryopyrin, NALP3), IPAF (CARD12, NLRC4) and AIM2 inflammasomes all have clear physiological roles in vivo. NLRP2, NLRP6, NLRP7, NLRP10 and NLRP12 have been demonstrated to modulate caspase-1 activity in vitro but the significance of this is unclear (Mariathasan and Monack, 2007).<br><br>NLRP3 and AIM2 bind the protein 'apoptosis-associated speck-like protein containing a CARD' (ASC, also called PYCARD), via a PYD-PYD domain interaction. This in turn recruits procaspase-1 through a CARD-CARD interaction. NLRP1 and IPAF contain CARD domains and can bind procaspase-1 directly, though both are stimulated by ASC. Oligomerization of NLRPs is believed to bring procaspases into close proximity, leading to 'induced proximity' auto-activation (Boatright et al. 2003). This leads to formation of the active caspase tetramer. NLRPs are generally considered to be cytoplasmic proteins, but there is evidence for cytoplasmic-nuclear shuttling of the family member CIITA (LeibundGut-Landmann et al. 2004) and tissue/cell dependent NALP1 expression in the nucleus of neurons and lymphocytes (Kummer et al. 2007); the significance of this remains unclear. Pubmed12620239 Pubmed15162420 Pubmed17164409 Pubmed17186029 Pubmed19120479 Pubmed19120480 Pubmed19302049 Pubmed20303873 Reactome Database ID Release 43622312 Reactome, http://www.reactome.org ReactomeREACT_75900 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 Adhesion of integrin alphaIIbbeta3 to fibrin network At the beginning of this reaction, 1 molecule of 'fibrin multimer', and 1 molecule of 'Alpha IIb Beta 3 Integrin' are present. At the end of this reaction, 1 molecule of 'Integrin alpha IIb beta 3:Fibrin complex' is present.<br><br> <br> Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Pubmed10605720 Reactome Database ID Release 43114560 Reactome, http://www.reactome.org ReactomeREACT_726 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Interaction of integrin alphaIIbbeta3 with von Willebrand factor Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Integrin alphaIIbbeta3 (glycoprotein IIb-IIIa, GP IIb-IIIa) is one of the major platelet receptor that is involved in aggregation and adhesion of platelets. In resting stage alphaIIbbeta3 is inactive and does not interact with its ligands but upon activation or vascular injury it binds to the ECM protein von Willebrand factor (vWf) and stimulate the platelet aggregation. Pubmed11713259 Pubmed12585966 Reactome Database ID Release 43216072 Reactome, http://www.reactome.org ReactomeREACT_13780 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Interaction of integrin alphaIIb beta 3 with Thrombospondin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed2010551 Reactome Database ID Release 43349603 Reactome, http://www.reactome.org ReactomeREACT_13616 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Thrombospondin-1 (TSP-1) secreated from platelet alpha granules on thombin activation associates with actin cytoskeleton. This association of TSP-1 with actin skytoskeleton is mediated by the membrane receptor alphaIIbbeta3. Toll Like Receptor 9 (TLR9) Cascade Authored: Luo, F, 2005-11-10 11:23:18 CpG DNA is an unusual Pathogen-Associated Molecular Pattern (PAMP). Cytosine methylation exists in mammalian but not bacterial cells, and most (but not all) CpG in the mammalian genome is methylated. Therefore, unmethylated CpG DNA may signal the presence of microbial infection. Evidence of CpG recognition by TLR9 was demonstrated both in human and mouse, and this type of signaling requires its internalization into late endosomal/lysosomal compartments. TLR9 has been reported to be able to discern different types of CpG motifs, and therefore that it presumably recognizes CpG DNA directly. It appears that over evolutionary periods, TLR9 molecules expressed by different species have diverged. This has led to differences in the precise sequence motif (CpG dinucleotide plus flanking regions) that optimally stimulate the innate immune system of different animals. Edited: Shamovsky, V, 2010-11-15 ISBN0781735149 Pubmed11130078 Pubmed11470918 Pubmed11564765 Pubmed14751759 Pubmed7700380 Pubmed9799232 Reactome Database ID Release 43168138 Reactome, http://www.reactome.org ReactomeREACT_9047 Reviewed: Gale M, Jr, 2006-10-31 16:45:01 Reviewed: Gillespie, ME, 2010-10-29 Interaction of integrin alphaVbeta3 with Fibrillin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Fibrillins are the main constituents of the extracellular microfibrils that form a template for tropoelastin during elastic fibrillogenesis. Fibrillins polymerize extracellularly as parallel bundles of head-to-tail monomers. The integrin receptor alphaVbeta3 is the major receptor for the fibrillin ligands and influences cell shape and migration, focal complex formation, signaling and ECM deposition. Pubmed12807887 Reactome Database ID Release 43265423 Reactome, http://www.reactome.org ReactomeREACT_13566 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Toll Like Receptor 4 (TLR4) Cascade Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2010-11-15 GENE ONTOLOGYGO:0008063 Reactome Database ID Release 43166016 Reactome, http://www.reactome.org ReactomeREACT_6894 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Toll-like Receptor 4 is a Microbe Associated Molecular Pattern receptor well known for it's sensitivity to Bacterial Lipopolysaccharides (LPS). LPS is assembled within diverse Gram-negative bacteria, many of which are human or plant pathogens. It is a component of the outer membrane of Gram-negative bacteria and consists of lipid A, a core polysaccharide and an O-polysaccharide of variable length (often more than 50 monosaccharide units). LPS is a potent activator of the innate immune response in humans, causing reactions including fever, headache, nausea, diarrhoea, changes in leukocyte and platelet counts, disseminated intravascular coagulation, multiorgan failure, shock and death. All these reactions are induced by cytokines and other endogenous mediators which are produced after interaction of LPS with the humoral and cellular targets of the host. In macrophages and dendritic cells, LPS-mediated activation of TLR4 triggers the biosynthesis of diverse mediators of inflammation, such as TNF-alpha and IL6, and activates the production of co-stimulatory molecules required for the adaptive immune response. In mononuclear and endothelial cells, LPS also stimulates tissue factor production. These events are desirable for clearing local infections, but when these various mediators and clotting factors are overproduced, they can damage small blood vessels and precipitate shock accompanied by disseminated intravascular coagulation and multiple organ failure. Interaction of integrin alphaVbeta3 with von Willbrand Factor Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Integrin alphaVbeta3 interacts with von Willebrand factor (vWF) on the RGD motif (1744-1746 residues) present on the mature vWF subunit. Pubmed7505120 Reactome Database ID Release 43265425 Reactome, http://www.reactome.org ReactomeREACT_13697 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Transfer of LPS from LBP carrier to CD14 Authored: de Bono, B, 2005-08-16 10:54:15 Edited: de Bono, B, 2005-08-16 10:54:15 LBP delivers LPS from bacteria (or bacterial membrane fragments) to CD14 on the surfaces of phagocytes, where it is recognised by the MD2:TLR4 complex . Thus, LBP is an opsonin and CD14 is an opsonic receptor for complexes of LPS (or LPS-containing particles such as bacteria) and LBP. CD14 exists as two isoforms. CD14 can be either secreted into the extracellular compartment, or it can be anchored to the plasma membrane via its GPI module. Pubmed9665271 Reactome Database ID Release 43166020 Reactome, http://www.reactome.org ReactomeREACT_6822 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 Interaction of integrin alphaEbeta7 with Cadherin-1 Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 E-cadherin, memeber of the cadherin superfamily is a calcium-dependent cell adhesion protein expressed on the epithelial cells. The integrin alphaEbeta7 is selectively expressed on intestinal intraepithelial T lymphocytes and CD8+ T lymphocytes in inflammatory lesions near epithelial cells. E-cadherin undergoes both homophilic and heterophilic interactions. It is the only binding partner for alphaEbeta7. This interaction plays a key role in the proliferation of intrathymic T cell populations, T lymphocyte development and damage of target epithelia. Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed15330449 Pubmed16002701 Reactome Database ID Release 43265422 Reactome, http://www.reactome.org ReactomeREACT_13535 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Activated TLR4 signalling Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 GENE ONTOLOGYGO:0034142 Pubmed14556004 Pubmed15276183 Pubmed15588429 Pubmed15596121 Pubmed15845500 Pubmed18222170 Pubmed18297073 Pubmed22078883 Reactome Database ID Release 43166054 Reactome, http://www.reactome.org ReactomeREACT_6890 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 TLR4 is unique among the TLR family in its ability to recruit four adapters to activate two distinct signaling pathways. One pathway is activated by the pair of the adapters Mal or TIRAP (Toll/interleukin-1-receptor (TIR)-domain-containing adapter protein) and MyD88, which leads to the NFkB activation and the induction of pro-inflammatory cytokines. The second pathway is activated by the adapters TRIF (TIR-domain-containing adapter protein inducing interferon-beta) and TRAM (TRIF-related adapter molecule). The combined use of TRIF and TRAM adapters is specific for TLR4 signaling pathway and leads to the induction of type I interferons and delayed activation of NFkB.<p>The previous model of TLR4 signaling pathway described the simultaneous activation of these two signaling pathways at the plasma membrane, however the later studies suggested that upon activation TLR4 first induces TIRAP-MyD88 signaling at the plasma membrane and is then endocytosed and activates TRAM-TRIF signaling from the early endosome [Kagan JC et al 2008; Tanimura N et al 2008; Zanoni I et al 2011]. Interaction of integrin alphaIIbbeta3 with Fibronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Fibronectin plays a role in cell adhesion and cell migration. It mediates platelet adhesion in the vasculature by interacting with integrin alphaIIbbeta3. Pubmed16933105 Reactome Database ID Release 43349593 Reactome, http://www.reactome.org ReactomeREACT_13452 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 MyD88:Mal cascade initiated on plasma membrane Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-05 GENE ONTOLOGYGO:0002755 Pubmed15276183 Reactome Database ID Release 43166058 Reactome, http://www.reactome.org ReactomeREACT_6788 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects. Toll Like Receptor 2 (TLR2) Cascade Authored: D'Eustachio, P, Gay, NJ, Gale M, Jr, Zwaginga, JJ, 2006-04-19 04:09:58 Edited: Shamovsky, V, 2010-11-16 GENE ONTOLOGYGO:0034134 Pubmed10820283 Reactome Database ID Release 43181438 Reactome, http://www.reactome.org ReactomeREACT_7980 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 TLR2 is involved in recognition of peptidoglycan from gram-positive bacteria, bacterial lipoproteins, mycoplasma lipoprotein and mycobacterial products. It is quite possible that recognition of at least some other TLR2 ligands may be assisted by additional accessory proteins, particularly in association with TLR1 or TLR6. TLR2 is expressed constitutively on macrophages, dendritic cells, and B cells, and can be induced in some other cell types, including epithelial cells. TLR1 and TLR6, on the other hand, are expressed almost ubiquitously (Muzio et al. 2000). TLR2 may be a sensor and inductor of specific defense processes, including oxidative stress and cellular necrosis initially spurred by microbial compounds. Interaction of integrin alphaVbeta3 with vitronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Integrin alphaVbeta3 a vitronectin receptor is highly expressed on the osteoclasts, bone resorbing cells and is upregulated during vascular damage, during angiogenesis and also in certain type of malignancies. It binds to vitronectin by recognizing the conserved RGD sequence with in the N-ter region of vitronectin. This integrin plays an important role in signal transduction and regulating osteoclast function. Pubmed17968485 Pubmed9251239 Reactome Database ID Release 43216076 Reactome, http://www.reactome.org ReactomeREACT_13634 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Toll Like Receptor TLR1:TLR2 Cascade Authored: D'Eustachio, P, Gay, NJ, Gale M, Jr, Zwaginga, JJ, 2006-04-19 04:09:58 Edited: Shamovsky, V, 2012-11-06 GENE ONTOLOGYGO:0034130 Pubmed12975352 Reactome Database ID Release 43168179 Reactome, http://www.reactome.org ReactomeREACT_8005 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 TLR1 is expressed by monocytes. TLR1 and TLR2 cotranslationally form heterodimeric complexes on the cell surface and in the cytosol. The TLR2:TLR1 complex recognizes Neisserial PorB and Mycobacterial triacylated lipoproteins and peptides, amongst others, triggering up-regulation of nuclear factor-kappaB production and apoptotic cascades. Such cooperation between TLR1 and TLR2 on the cell surface of normal human peripheral blood mononuclear cells, for instance, leads to the activation of pro-inflammatory cytokine secretion (Sandor et al. 2003). Interaction of integrin alphaVbeta3 with Fibronectin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed11495705 Pubmed15687337 Pubmed15795319 Pubmed8969861 Reactome Database ID Release 43216073 Reactome, http://www.reactome.org ReactomeREACT_13520 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The alphaVbeta3 integrin is expressed on the surface of a variety of cell types, including platelets, endothelial cells, vascular smooth muscle cells, osteoclasts, and tumor cells. This integrin plays a key role in numerous physiological processes such as angiogenesis, apoptosis, and bone resorption. <br>alphaVbeta3 interacts with various RGD-containing proteins including fibronectin, fibrinogen and vitronectin. Upon stimuli alphaVbeta3 in the presence of Mn++ binds the FN7-FN10 domains of fibronectin. This interaction activates the Ras/ERK/Raf-1 and the Ca+2/CaMKII pathways. Toll Like Receptor TLR6:TLR2 Cascade Authored: D'Eustachio, P, Gay, NJ, Gale M, Jr, Zwaginga, JJ, 2006-04-19 04:09:58 Edited: Shamovsky, V, 2012-11-19 GENE ONTOLOGYGO:0002224 Pubmed14977973 Reactome Database ID Release 43168188 Reactome, http://www.reactome.org ReactomeREACT_8006 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 TLR2 and TLR4 recognize different bacterial cell wall components. While TLR4 is trained onto Gram-negative lipopolysaccharide components, TLR2 - in combination with TLR6 - plays a major role in recognizing peptidoglycan wall products from Gram-positive bacteria, as well as Mycobacterial diacylated lipopeptides. In particular, TLR6 appears to participate in discriminating the subtle differences between dipalmitoyl and tripalmitoyl cysteinyl residues (Okusawa et al. 2004). Interaction of integrin alphaVbeta3 with Tenascin Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed8798654 Reactome Database ID Release 43265426 Reactome, http://www.reactome.org ReactomeREACT_13495 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 Tenascin, an extracellular matrix protein acts as a ligand to multiple integrin receptors including alphaVbeta3. Integrin alphaVbeta3 binds to the third fibronectin type III repeat in tenascin (Tnfn3) and induces the cell proliferation. Complement cascade Authored: de Bono, B, 2004-08-04 09:17:50 Edited: Jupe, S, 2010-11-11 ISBN0781735149 Pubmed11044372 Pubmed11213801 Pubmed14698228 Pubmed15476920 Pubmed3052276 Reactome Database ID Release 43166658 Reactome, http://www.reactome.org ReactomeREACT_6932 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 The complement system is a biochemical cascade, so named because it 'complements' the ability of antibodies to clear pathogens. It is part of the innate immune system. Complement system proteins circulate in the blood as inactive precursors (pro-proteins). When triggered by the presence of microbes, complement proteases cleave complement proteins, initiating a cascade of further cleavages. The end-result of this activation is the activation of the Membrane Attack Complex and cell lysis. The C3 and C5 components also lead to phagocytosis by leukocytes.<br><br>There are three branches that lead to activation of the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway. Complement proteins are always present in the blood and a small percentage spontaneously activate. Innapropriate activation leads to host cell damage, so the activation process is tightly controlled by several regulatory mechanisms. N.B. Originally the larger fragment of Complement Factor 2 (C2) was designated C2a. However, complement scientists decided that the smaller of all C fragments should be designated with an 'a', the larger with a 'b', changing the nomenclature for C2. Recent literature may use the updated nomenclature and refer to the larger C2 fragment as C2b, and refer to the classical C3 convertase as C4bC2b. Throughout this pathway Reactome adheres to the original convention to agree with the current (Feb 2012) Uniprot names for C2 fragments. Initial triggering of complement Authored: de Bono, B, 2004-08-04 09:17:50 Complement activation is due to a cascade of proteolytic steps, performed by serine protease domains in some of the components. Three different pathways of activation are distinguished triggered by target-bound antibody (the classical pathway); microbial polysaccharide structures (the lectin pathway); or recognition of other "foreign" surface structures (the alternative pathway) by C3b. All three merge in the pivotal activation of C3 and, subsequently, of C5 by highly specific enzymatic complexes, the so-called C3/C5 convertases. A complement system with three C3 activation pathways and a common lytic pathway is found only in jawed vertebrates. Edited: Jupe, S, 2010-11-17 GENE ONTOLOGYGO:0006956 ISBN0781735149 Reactome Database ID Release 43166663 Reactome, http://www.reactome.org ReactomeREACT_8024 Reviewed: D'Eustachio, P, 2006-07-03 21:35:13 Phosphorylation of SMAD2/3 by Activin:Activin Receptor Activin receptors containing the type II receptors ACVR2A/B (ActRIIA, ActRIIB) and the type I receptors ACVR1B/C (ALK4, ALK7) signal through SMAD2 and SMAD3. The phosphorylated type I receptor (ACVR1B/C) phosphorylates SMAD2 or SMAD3. Homodimers or heterodimers of SMAD2 and SMAD3 bind the co-Smad SMAD4 and the ternary complex (SMAD2/3:SMAD2/3:SMAD4) enters the nucleus and activates expression of target genes. Authored: May, B, 2011-08-28 EC Number: 2.7.11 Edited: May, B, 2011-08-28 Pubmed15087470 Pubmed16140969 Pubmed17906079 Pubmed18166170 Pubmed18951876 Reactome Database ID Release 431549526 Reactome, http://www.reactome.org ReactomeREACT_150345 Reviewed: Chen, Ye-Guang, 2012-11-14 has a Stoichiometric coefficient of 2 ACVR2A/B (ActRIIA/B) Phosphorylates ACVR1C (ActRIC, ALK7) in Response to Activin As inferred from mouse, upon binding Activin AB (INHBA:INHBB) or Activin B (INHBB:INHBB), the type II component of the activin receptor (ACVR2A or ACVR2B) phosphorylates the type I component ACVR1C (ALK7) at multiple serine and threonine residues within the GS domain. Authored: May, B, 2011-01-23 EC Number: 2.7.11 Edited: May, B, 2011-03-03 Reactome Database ID Release 432470508 Reactome, http://www.reactome.org ReactomeREACT_150380 Reviewed: Chen, Ye-Guang, 2012-11-14 has a Stoichiometric coefficient of 10 ROCK1 activates LIM kinase 2 (rat) Authored: Akkerman, JW, 2009-06-03 EC Number: 2.7.11 Edited: Jupe, S, 2009-05-20 11:38:59 Pubmed10652353 Pubmed11018042 Pubmed12778124 Pubmed16219803 ROCK I phosphorylates LIMK1 at Thr508 and LIMK2 at Thr505, enhancing the ability of LIMKs to phosphorylate cofilin. Reactome Database ID Release 43421733 Reactome, http://www.reactome.org ReactomeREACT_19311 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Dephosphorylation of NCAM1 bound pFyn Authored: Garapati, P V, 2009-02-24 10:31:15 EC Number: 3.1.3.48 Edited: Garapati, P V, 2009-02-24 10:58:20 Pubmed12743109 Pubmed15623578 Reactome Database ID Release 43420388 Reactome, http://www.reactome.org ReactomeREACT_18414 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- The homophilic NCAM1:NCAM1 interaction redistributes these molecules and leads to the formation of clusters within lipid rafts. Spectrin, an NCAM1 binding cytoskeletal protein, colocalizes with NCAM1 and codistribute to lipid rafts. Spectrin associates with RPTP-alpha, linking it to the cytoplasmic NCAM1 domain and causing its coredistribution to lipid rafts on NCAM1 clustering. The receptor tyrosine phosphatase RPTP-alpha is an activator of all kinases of the Src family, including Fyn kinase.<p>The interaction of RPTP-alpha and the SH2 domain of Fyn induces an interaction of Fyn Tyr531 with the D1 domain of RPTP-alpha. This induces dephosphorylation of Tyr531 and activates Fyn. Smad7:SMURF1 binds phosphorylated TGFBR1 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11278251 Reactome Database ID Release 432169036 Reactome, http://www.reactome.org ReactomeREACT_120745 Reviewed: Huang, Tao, 2012-05-14 Smad7 recruits SMURF1 to TGF-beta (TGFB1)-activated TGF-beta receptor complex. In this study, recombinant mouse Smad7 and recombinant human SMURF1, TGFBR2 and TGFBR1 were exogenously expressed in COS7 cells (Ebisawa et al. 2001). FBXW7 binds phosphorylated NICD1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed11461910 Pubmed11585921 Pubmed15546612 Reactome Database ID Release 432064853 Reactome, http://www.reactome.org ReactomeREACT_118775 Reviewed: Haw, R, 2012-02-06 The E3 ubiquitin ligase FBXW7, a homologue of C. elegans sel-10, binds to Notch1 intracellular domain NICD1. This interaction was demonstrated by co-immunoprecipitation of the human recombinant FBXW7 and mouse recombinant NICD1 (Oberg et al. 2001). FBXW7 binds phosphorylated intracellular domain of Notch proteins, as shown for mouse NICD1 (Fryer et al. 2004) and mouse NICD4 (Wu et al. 2001). Follistatin (FST) binds Activin Authored: May, B, 2012-09-21 Edited: May, B, 2012-09-21 Pubmed12697670 Pubmed1592877 Pubmed16198295 Pubmed7678220 Pubmed8033815 Reactome Database ID Release 432473184 Reactome, http://www.reactome.org ReactomeREACT_150395 Reviewed: Chen, Ye-Guang, 2012-11-14 Two molecules of Follistatin (FST) bind an Activin dimer in serum or follicular fluid (Schneyer et al. 1992, Krummen et al. 1993, Schneyer et al. 1994, Thompson et al. 2005). FST has been experimentally shown to bind Activin A and Activin B (Schneyer et al. 2003). Binding of FST to Activin AB is inferred. has a Stoichiometric coefficient of 2 Ubiquitination of SKI/SKIL by Rnf11 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed17510063 Pubmed17591695 Reactome Database ID Release 432186755 Reactome, http://www.reactome.org ReactomeREACT_121269 Recombinant mouse Rnf111 (Arkadia), recruited to recombinant human SKI/SKIL bound to TGF-beta-activated SMAD2/3, ubiquitinates SKI/SKIL transcriptional repressors (Levy et al. 2007, Nagano et al. 2007). Reviewed: Huang, Tao, 2012-05-14 Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXH1 Binds Activin Response Element Authored: May, B, 2011-02-13 Edited: May, B, 2011-02-13 Pubmed10473623 Pubmed10822381 Pubmed8878477 Pubmed9288972 Pubmed9702198 Reactome Database ID Release 431225919 Reactome, http://www.reactome.org ReactomeREACT_111132 Reviewed: Chen, Ye-Guang, 2012-11-14 Reviewed: Peng, C, 2011-08-24 SMAD2 and SMAD3 do not bind DNA efficiently. They must interact with DNA-binding proteins to activate transcription. FOXH1 interacts with phospho-SMAD2 and phospho-SMAD3 complexed with CO-SMAD (SMAD4) at promoters containing the Activin Response Element (Zhou et al. 1998, Yanagisawa et al. 2000, inferred from Xenopus in Chen et al. 1996, Chen et al. 1997, Yeo et al. 1999). Follicle-stimulating hormone beta subunit (FSHB) and the Lim1 homeobox gene (LXH1) are examples of genes regulated by Activin. FSTL3 binds Activin Authored: May, B, 2012-09-21 Edited: May, B, 2012-09-21 Pubmed11459787 Pubmed11956142 Pubmed12697670 Pubmed18768470 Reactome Database ID Release 432473186 Reactome, http://www.reactome.org ReactomeREACT_150306 Reviewed: Chen, Ye-Guang, 2012-11-14 Two molecules of FSTL3 bind an Activin dimer (Sidis et al. 2002, Stamler et al. 2008). FSTL3 has been experimentally shown to bind Activin A and Activin B (Schneyer et al. 2003). Binding of FSTL3 to Activin AB is inferred. A portion of FSTL3 is also located in the nucleus (Tortoriello et al. 2001), however FSTL3:Activin complexes have not been demonstrated in the nucleus. has a Stoichiometric coefficient of 2 IGF1/2 binds IGF1R Authored: May, B, 2012-07-07 Edited: May, B, 2012-07-07 Either IGF1 (IGF-I) or IGF2 (IGF-II) can bind the type 1 insulin-like growth factor receptor (IGF1R) (Casella et al. 1986, LeBon et al. 1986, Maly and Luthi 1986, Cacieri et al. 1988, Steele-Perkins et al. 1988, Burgisser et al. 1991, Germain-Lee et al. 1992, Keyhanfar et al. 2007, Alvino et al. 2009, Alvino et al. 2011). IGF1R has similar affinities for IGF1 and IGF2 (Casella et al. 1986, Steele-Perkins et al. 1988). The binding sites for IGF1 and IGF2 are in a similar location on the alpha peptide of IGF1R but there are some differences in which residues of IGF1R interact with IGF1 vs. IGF2 (Keyhanfar et al. 2007, Alvino et al. 2009, Alvino et al. 2011). Pubmed1310594 Pubmed16981855 Pubmed1845984 Pubmed19139090 Pubmed22140443 Pubmed2839228 Pubmed2969892 Pubmed3011795 Pubmed3013881 Pubmed3019338 Reactome Database ID Release 432404200 Reactome, http://www.reactome.org ReactomeREACT_150464 Reviewed: Holzenberger, Martin, 2012-11-09 IGF1/2:p-IGF1R binds IRS2 Authored: May, B, 2012-08-06 Edited: May, B, 2012-08-06 IRS2 binds the NPEY-juxtamembrane motif of phosphorylated IGF1R (He et al. 1996, Kim et al. 1998). IRS2 is cytosolic while IRS1 and IRS4 are located in the plasma membrane. Pubmed8662806 Pubmed9852124 Reactome Database ID Release 432428922 Reactome, http://www.reactome.org ReactomeREACT_150340 Reviewed: Holzenberger, Martin, 2012-11-09 IGF1/2:p-IGF1R phosphorylates IRS1/2/4 Authored: May, B, 2012-08-06 EC Number: 2.7.10 Edited: May, B, 2012-08-06 Phosphorylated IGF1R phosphorylates IRS1 (Siemeister et al. 1995, Xu et al. 1995, Takahashi et al. 1997, Rakatzi et al. 2006), IRS2 (Kim et al. 1998, Kim et al. 2004), and IRS4 (Fantin et al.1998, Karas et al. 2001, Cuevas et al. 2007) on numerous tyrosine residues. IRS4 is phosphorylated by IGF1R in HEK cells but not in primary muscle cells (Fantin et al. 1998, Schreyer et al. 2003). The phosphotyrosine resideus create binding sites for downstream effectors such as GRB2:SOS and PI3K. Pubmed11316748 Pubmed12639902 Pubmed14712218 Pubmed16754202 Pubmed17408801 Pubmed7876259 Pubmed8530377 Pubmed9003010 Pubmed9553137 Pubmed9832424 Pubmed9852124 Reactome Database ID Release 432428926 Reactome, http://www.reactome.org ReactomeREACT_150135 Reviewed: Holzenberger, Martin, 2012-11-09 Activin A/AB/B Binds Activin Receptor ACVR2A/B:ACVR1B Activin binds the Activin receptor composed of a type II receptor (ACVR2A/B) and a type I receptor, in this case ACVR1B (ALK4) (Attisano et al. 1996, Zhou et al. 2000). Activin appears to interact initially with the type II receptor component (Attisano et al. 1996). It is unclear if the type II and type I receptors are associated before binding Activin. Any of Activin A (INHBA:INHBA), Activin AB (INHBA:INHBB), and Activin B (INHBB:INHBB) can bind and signal via an activin receptor containing the ACVR1B (ALK4) type I receptor. Authored: May, B, 2011-01-23 Edited: May, B, 2011-01-23 Pubmed11117535 Pubmed8196624 Pubmed8622651 Pubmed9032295 Reactome Database ID Release 431181153 Reactome, http://www.reactome.org ReactomeREACT_150161 Reviewed: Chen, Ye-Guang, 2012-11-14 has a Stoichiometric coefficient of 2 Activin AB/B Binds Activin Receptor ACVR2A/B:ACVR1C As inferred from mouse, Activin binds the Activin receptor composed of a type II receptor (ACVR2A/B) and a type I receptor, in this case ACVR1C (ALK7). It is unclear if the type II receptor and the type I receptor are associated before binding Activin, Activin AB (INHBA:INHBB) and Activin B (INHBB:INHBB), but not Activin A (INHBA:INHBA) can bind and signal via an activin receptor containing the ACVR1C (ALK7) type I receptor. Authored: May, B, 2012-09-13 Edited: May, B, 2012-09-13 Reactome Database ID Release 432470483 Reactome, http://www.reactome.org ReactomeREACT_150244 Reviewed: Chen, Ye-Guang, 2012-11-14 has a Stoichiometric coefficient of 2 Autophosphorylation of IGF1R Authored: May, B, 2012-07-07 EC Number: 2.7.10 Edited: May, B, 2012-07-07 Pubmed1697749 Pubmed22140443 Pubmed3011795 Pubmed3015966 Pubmed7493944 Reactome Database ID Release 432404199 Reactome, http://www.reactome.org ReactomeREACT_150288 Reviewed: Holzenberger, Martin, 2012-11-09 The beta peptide of the type 1 insulin-like growth factor (IGF1R) spans the plasma membrane and trans-autophosphorylates tyrosine residues in response to binding of either IGF1 or IGF2 by the extracellular alpha peptide (LeBon et al. 1986, Yu et al. 1986, Doronio et al. 1990, Hernandez-Sanchez et al. 1995, Alvino et al. 2001). has a Stoichiometric coefficient of 6 Binding of SHC1 by phosphorylated IGF1R Authored: May, B, 2012-07-07 Edited: May, B, 2012-07-07 Pubmed7559507 Pubmed8033892 Reactome Database ID Release 432404195 Reactome, http://www.reactome.org ReactomeREACT_150430 Reviewed: Holzenberger, Martin, 2012-11-09 SHC1 binds the NPEY-juxtamembrane motif of the phosphorylated insulin-like growth factor receptor (IGF1R) (Giorgetti et al. 1994, Tartare-Deckert et al. 1995). Phosphorylation of SHC1 by IGF1R Authored: May, B, 2012-07-07 EC Number: 2.7.10 Edited: May, B, 2012-07-07 Pubmed7493944 Pubmed8033892 Pubmed9852124 Reactome Database ID Release 432404193 Reactome, http://www.reactome.org ReactomeREACT_150227 Reviewed: Holzenberger, Martin, 2012-11-09 The phosphorylated IGF1R phosphorylates SHC1 (Giorgetti et al. 1994, Hernandez-Sanchez et al. 1995, Kim et al. 1998). Phosphorylation of SHC1 is sustained whereas phosphorylation of IRS2 by IGF1R is transient (Kim et al. 1998). has a Stoichiometric coefficient of 3 IGF1/2:p-IGF1R binds IRS1/4 Authored: May, B, 2012-08-06 Edited: May, B, 2012-08-06 IRS1 binds the NPEY-juxtamembrane motif of phosphorylated IGF1R (Craparo et al. 1995, He et al. 1995, Huang et al. 2001). IRS4 is also involved in signaling by IGF1R and is presumed to bind phosphorylated IGF1R in the same way as IRS1 (Qu et al. 1999, Cuevas et al. 2007). IRS1 and IRS4 are located at the plasma membrane (Karlsson et al. 2004, Fantin et al. 1998). Pubmed10531310 Pubmed11557037 Pubmed15182363 Pubmed17408801 Pubmed7541045 Pubmed7559478 Pubmed9553137 Reactome Database ID Release 432428930 Reactome, http://www.reactome.org ReactomeREACT_150315 Reviewed: Holzenberger, Martin, 2012-11-09 ACVR2A/B (ActRIIA/B) Phosphorylates ACVR1B (ActRIB, ALK4) in Response to Activin Authored: May, B, 2011-01-23 EC Number: 2.7.11 Edited: May, B, 2011-03-03 Pubmed11117535 Pubmed15123686 Pubmed8622651 Pubmed8721982 Pubmed9459292 Reactome Database ID Release 431181149 Reactome, http://www.reactome.org ReactomeREACT_111068 Reviewed: Chen, Ye-Guang, 2012-11-14 Reviewed: Peng, C, 2011-08-24 Upon binding Activin A (INHBA:INHBA), Activin AB (INHBA:INHBB), or Activin B (INHBB:INHBB), the type II component of the activin receptor (ACVR2A or ACVR2B) phosphorylates the type I component ACVR1B (ALK4) at multiple serine and threonine residues within the GS domain (Attisano et al. 1996, Willis et al. 1996, Willis and Mathews 1997, Zhou et al. 2000). has a Stoichiometric coefficient of 12 MyD88-independent cascade Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2012-11-06 GENE ONTOLOGYGO:0002756 MyD88-independent signaling route utilizes TRAM and TRIF adapters, that are essential for production of both type 1 interferons(IFNs) and pro-inflammatory cytokines. TRAM is thought to bridge between activated TLR4 and TRIF. Pubmed12855817 Pubmed14556004 Pubmed15276183 Pubmed18222170 Pubmed18297073 Reactome Database ID Release 43166166 Reactome, http://www.reactome.org ReactomeREACT_6809 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Formation of collagen fibrils Authored: Jupe, S, 2011-08-05 Collagen fibrils are the principal tensile element of the extracellular matrix in a wide range of animal connective tissues. They have a 67 nm axial periodicity in most tissues, 65 nm in vertebrate skin, and are near-circular in transverse section. Fibril diameter depends both on tissue type and stage of development, covering a range of 20-500 nm in vertebrates. Fibril length is less well characterised but fibrils with lengths in the range 1-100 micrometres have been isolated.<br><br>Fibril formation is spontaneous (Fallas et al. 2010, Birk & Brückner 2011), but influenced by developmental state and the cellular environment. Several models have been proposed including the simple surface nucleation and propagation (SNAP) model (Trotter et al. 2000) but the mechanism of fibril assembly and regulation of fibril diameter and length are not completely understood (Holmes et al. 2001, Banos et al. 2008). Fibrils frequently contain more than one type of collagen, and the outer surface of fibrils frequently interacts with proteoglycans, fine-tuning its structural and signaling properties (Wess 2005, Kalamajski & Oldberg 2010, Ricard-Blum et al. 2011).<br><br>Individual fibril-forming collagen molecules are around 300nm in length. Complete fibrils exhibit a 67 nm periodicity, seen with many different imaging methods. This is due to a staggered overlap of molecules which leads to regions where fewer molecules overlap with a periodicity of 67 nm (Hodge & Petruska 1963, Wess 2005). Laterally, molecules are believed to be packed into a quasi-hexagonal structure (Trus & Piez 1980) resulting in locally ordered crystalline regions interspersed with disordered regions across the lateral plane of the fibril (Hulmes 2002). Interactions between molecules stabilize the fibril, including the formation of divalent and subsequently trivalent crosslinks, unique to collagen, that involve lysine or hydroxylysine residues. Edited: Jupe, S, 2012-11-12 ISBN978-3-642-16555-9 Pubmed10596943 Pubmed10884349 Pubmed12064927 Pubmed15837520 Pubmed18773462 Pubmed20080181 Pubmed20385142 Pubmed20676409 Pubmed7402317 Reactome Database ID Release 431474266 Reactome, http://www.reactome.org ReactomeREACT_150299 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 TRIF-mediated TLR3/TLR4 signaling Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2010-11-15 GENE ONTOLOGYGO:0035666 Pubmed12855817 Pubmed14739303 Pubmed15814722 Reactome Database ID Release 43937061 Reactome, http://www.reactome.org ReactomeREACT_25281 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 TRIF was shown to induce IRF3/7 and NF-?B activation and apoptosis through distinct intracellular signaling pathways [Han KJ et al 2004; Kaiser WJ and Offermann MK et al 2005]. TRIF consists of an N-terminal region (1-234), a TIR domain (235-500), and a C-terminal region (501-680).<p> The N-terminal region of TRIF harbors TRAF (TNF receptor associated factor) family proteins and forms complexes containing IRF-3 and/or NFkB -activating kinases. The C-terminal region of TRIF can recruit receptor-interacting protein-1 (RIP-1), and this event is followed by the activation of IKK complex. Formation of collagen networks Authored: Jupe, S, 2012-04-30 Collagens IV, VI, VIII and X form open networks. Type IV networks are irregular. Type VIII and X form hexagonal networks. Type VI collagen forms tetramers which aggregate linearly to form beaded filaments, but also associates laterally through the globular domains so forming a network (Baldock et al. 2003, Knupp et al. 2006, ). Type IV collagen is the predominant collagen type in basement membranes (Parkin et al. 2011). It assembles into three distinct networks with differing combinations of alpha chains, namely alpha1.alpha1.alpha2, alpha3.alpha4.alpha5 and alpha1.alpha2.alpha5.alpha6, (Siebold et al. 1988, Gunwar et al. 1998, Borza et al. 2001), the last of these forms through the association of alpha5.alpha5.alpha6 triple-helical protomers and alpha1.alpha1.alpha2 protomers, interacting tail-to-tail at the retained NC1 domains. Further associations are formed by tetramerization of the 7S domain at the N terminus (Timpl et al. 1981, Siebold et al. 1987). These interactions are the most significant for network formation, but a third interaction occurs whereby type IV collagen dimers interact through lateral association (Yurchenco & Furthmayr 1984, Yurchenco & Ruben 1987, Yurchenko & Patton 2009). Collagen type VI forms tetramers and subsequently several types of higher-order structure (Ball et al. 2001, Beecher et al. 2011) that are probably influenced by the association of other matrix constituents such as hyaluronan (Kielty et al. 1992), fibrillin (Ueda & Yue 2003), biglycan and decorin (Wiberg et al. 2001). <br><br>Type VIII collagen forms a hexagonal lattice in Descemet's membrane (Shuttleworth 1997). These are thought to be derived from tetrahedral structures that form when 4 type VIII molecules associate via hydrophobic patches on their C-termini, which then associate via their N-terminals (Stephan et al. 2004). Type X collagen is very similar to type VIII and in vitro forms hexagonal arrays, believed to arise from interactions of the globular domains (Kwan et al. 1991, Jacenko et al. 2001). In vivo type X collagen is found associated with cartilage fibrils in the form of fine filaments (Schmidt & Linsenmayer 1990), which may represent hexagonal lattices that have collapsed during sample preparation (Gordon & Hahn 2010). Edited: Jupe, S, 2012-11-12 Pubmed11036066 Pubmed11375996 Pubmed11733375 Pubmed12354766 Pubmed12823969 Pubmed1323568 Pubmed14578398 Pubmed14990571 Pubmed16713302 Pubmed1860888 Pubmed19355968 Pubmed19693541 Pubmed21280145 Pubmed21908605 Pubmed2307289 Pubmed2844531 Pubmed3117548 Pubmed3693393 Pubmed6274634 Pubmed6722126 Pubmed9438378 Pubmed9535854 Reactome Database ID Release 432213207 Reactome, http://www.reactome.org ReactomeREACT_150311 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 IRAK2 mediated activation of TAK1 complex Although IRAK-1 was originally thought to be a key mediator of TRAF6 activation in the IL1R/TLR signaling (Dong W et al. 2006), recent studies showed that IRAK-2, but not IRAK-1, led to TRAF6 polyubiquitination (Keating SE et al 2007). IRAK-2 loss-of-function mutants, with mutated TRAF6-binding motifs, could no longer activate NF-kB and could no longer stimulate TRAF-6 ubiquitination (Keating SE et al 2007). Furthermore, the proxyvirus protein A52 - an inhibitor of all IL-1R/TLR pathways to NF-kB activation, was found to interact with both IRAK-2 and TRAF6, but not IRAK-1. Further work showed that A52 inhibits IRAK-2 functions, whereas association with TRAF6 results in A52-induced MAPK activation. The strong inhibition effect of A52 was also observed on the TLR3-NFkB axis and this observation led to the discovery that IRAK-2 is recruited to TLR3 to activate NF-kB (Keating SE et al 2007). Thus, A52 possibly inhibits MyD88-independent TLR3 pathways to NF-kB via targeting IRAK-2 as it does for other IL-1R/TLR pathways, although it remains unclear how IRAK-2 is involved in TLR3 signaling.<p>IRAK-2 was shown to have two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 Pubmed12140561 Pubmed16831874 Pubmed17878161 Pubmed21606490 Reactome Database ID Release 43937042 Reactome, http://www.reactome.org ReactomeREACT_25380 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 Removal of fibrillar collagen N-propeptides Authored: Jupe, S, 2010-07-20 EC Number: 3.4.24 Edited: Jupe, S, 2012-05-14 Fibrillar collagen is synthesized in the ER as procollagen with N- and C-terminal propeptides flanking the collagenous domain (Bellamy & Bornstein 1971). These propeptides, particularly the C-propeptide, inhibit fibril formation (Kadler et al. 1987). Propeptide removal and self-assembly of collagen into fibrils can be studied in vitro (Kadler et al. 1987). Early studies of propeptide processing identified enzymes in the medium of cultured cells (Kerwar et al. 1973, Layman & Ross 1973). The removal of propeptides is generally described as an extracellular process, but accumulating evidence suggests that fibril assembly can begin in the secretory pathway and at the plasma membrane (Canty & Kadler 2005). Procollagen processing in tendon fibroblasts was initiated within the secretory pathway, with the N-propetides removed first in the ER or an intermediate between the ER and Golgi. The C peptides were removed later, probably at the cell membrane-ECM interface (Canty-Laird et al. 2012). <br><br>Processing of procollagens I, II, and III results in an almost complete removal of both the N- and C-propeptides. Procollagen type I-III N-propeptides are removed by disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family members -2, -3 and 14*. These are themselves synthesized as proenzymes and activated by the removal of an inhibitory prodomain, probably by furin-like convertases (Wang et al. 2003). Type V collagen N-propeptide removal is partial, and reported to be mediated by BMP-1 which cleaves between the proline/arginine-rich protein domain and the variable domain of the alpha1 chain and between the small and the large collagenous domain of alpha3 chain (refs. in Colige et al. 2005). The retention of some N-propeptides occurs in a tissue specific manner and may be a mechanism to inhibit lateral fibril growth (Silver et al. 2003).<br><br><br>*ADAMTS2 is active against collagen types I (Lapière et al. 1971), II (Colige et al. 1995) and III (Wang et al. 2003 types I-III). ADAMTS3 has activity against type I (Le Goff 2006) and II collagen (Fernandes et al. 2001). ADAMTS14 has activity against type I collagen (Colige et al. 2002). Pubmed10417273 Pubmed11408482 Pubmed11741898 Pubmed12646579 Pubmed14499302 Pubmed15788652 Pubmed16046392 Pubmed16556917 Pubmed21967573 Pubmed3316206 Pubmed4351174 Pubmed4730803 Pubmed4942180 Pubmed5289249 Pubmed7622483 Reactome Database ID Release 432002428 Reactome, http://www.reactome.org ReactomeREACT_121172 Reviewed: Canty-Laird, EG, 2012-05-24 Toll Like Receptor 3 (TLR3) Cascade Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2011-08-12 GENE ONTOLOGYGO:0034138 Pubmed15031527 Pubmed15733829 Pubmed18202435 Pubmed19627256 Reactome Database ID Release 43168164 Reactome, http://www.reactome.org ReactomeREACT_6783 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Toll-like receptor 3 (TLR3) as was shown for mammals is expressed on myeloid dendritic cells, respiratory epithelium, macrophages, and appears to play a central role in mediating the antiviral and inflammatory responses of the innate immunity in combating viral infections.<p>Mammalian TLR3 recognizes dsRNA, and that triggers the receptor to induce the activation of NF-kappaB and the production of type I interferons (IFNs). dsRNA-stimulated phosphorylation of two specific TLR3 tyrosine residues (Tyr759 and Tyr858) is essential for initiating TLR3 signaling pathways. Removal of fibrillar collagen C-propeptides Authored: Jupe, S, 2010-07-20 EC Number: 3.4.24 Edited: Jupe, S, 2012-05-14 Fibrillar collagen is synthesized in the ER as procollagen with N- and C- terminal propeptides flanking the collagenous domain (Bellamy & Bornstein 1971). These propeptides, particularly the C-propeptide, inhibit fibril formation (Kadler et al. 1987). Removal of propeptides is generally described as an extracellular process but can occur within the cell. Procollagen processing in tendon fibroblasts was initiated within the secretory pathway with the N-propetides removed first, in the ER or an intermediate between the ER and Golgi. The C peptides were removed later, probably at the cell membrane-ECM interface (Canty-Laird et al. 2012). <br><br>Collagen C-propeptides are cleaved by the tolloid family metalloproteinases bone morphogenic protein 1 (BMP1)/mammalian tolloid (mTLD), tolloid-like 1 (TLL1) and TLL2.<br><br>Procollagen types I-III are cleaved by BMP1/mTLD (Chicken types I and II, human type III, by chicken enzyme, Hojima et al. 1985, human types I, II, human enzyme, Scott et al. 1999), TLL-1 (human types I, II, human enzyme, Scott et al. 1999), and TLL-2 in the presence of PCOLCE (PCPE-1, Pappano et al. 2003, Petropoulou et al. 2005). Type V C-propeptide removal is mediated by furin-like proprotein convertases and/or BMP-1 depending on the chain type (Kessler et al. 2005). Pubmed10479448 Pubmed11358968 Pubmed12808086 Pubmed15817489 Pubmed21967573 Pubmed3316206 Pubmed3905801 Pubmed4942180 Reactome Database ID Release 432002440 Reactome, http://www.reactome.org ReactomeREACT_121108 Reviewed: Canty-Laird, EG, 2012-05-24 Secretion of collagens Authored: Jupe, S, 2010-07-20 Collagen precursors are co-translated into the ER, where post-translational modifications occur that are essential for oligomerization and stabilization, the latter thought to involve Serpin H1 (HSP47). Trimers are exported from the ER and trafficked through the Golgi network before secretion into the extracellular space and organization into higher order structures. The precise route and mechanism of secretion for collagen is unclear (Canty & Kadler 2005). In the conventional protein secretion pathway cargo is collected at ER exits sites and loaded into small membrane vesicles that are generated by a set of highly conserved proteins called the coat protein complex II (COPII) (Jensen & Schekman 2011). However, these small vesicles of 60-90 nm diameter are too small for collagens some of which assemble in the ER into 300-400 nm rod-like structures. Collagen secretion appears to involve a modification of the COPII process involving TANGO1 and cTAGE5 which form a dimer at ER exit sites (Malhotra & Erlmann 2011). TANGO1-null mice die at birth and are defective in the secretion of a number of different collagens (Wilson et al. 2011). Another recent study suggests that ubiquitination of one of the COPII complex proteins, SEC31, is sufficient to allow formation of vesicles that are large enough to hold procollagen (Jin et al. 2012). Edited: Jupe, S, 2012-05-14 Pubmed15788652 Pubmed21172817 Pubmed21606205 Pubmed21878990 Pubmed21967573 Pubmed22358839 Reactome Database ID Release 432089971 Reactome, http://www.reactome.org ReactomeREACT_121366 Reviewed: Canty-Laird, EG, 2012-05-24 Secretion of transmembrane collagens Authored: Jupe, S, 2010-07-20 Edited: Jupe, S, 2012-05-14 Pubmed19693541 Reactome Database ID Release 432152276 Reactome, http://www.reactome.org ReactomeREACT_120755 Reviewed: Canty-Laird, EG, 2012-05-24 Secretion of transmembrane collagens is presumably similar to the secretion of extracellular forms except that they are trafficked to the plasma membrane rather than the extracellular space. Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon Authored: Shamovsky, V, 2010-06-01 Cell stimulation with viral ds RNA leads to the activation of two IKK-related serine/threonine kinases, TBK1 and IKK-i which directly phosphorylate IRF3 and IRF7 promoting their dimerization and translocation into the nucleus. Although both kinases show structural and functional similarities, it seems that TBK1 and IKK-i differ in their regulation of downstream signaling events of TLR3.<p>IRF3 activation and IFN-b production by poly(I:C) are decreased in TBK1-deficient mouse fibroblasts, whereas normal activation was observed in the IKK-i-deficient fibroblasts. However, in double-deficient mouse fibroblasts, the activation of IRF3 is completely abolished, suggesting a partially redundant functions of TBK1 and IKK-i [Hemmi et al 2004].<p>TLR3 recruits and activates PI3 kinase (PI3K), which activates the downstream kinase, Akt, leading to full phosphorylation and activation of IRF-3 [Sarkar SN et al 2004]. When PI3K is not recruited to TLR3 or its activity is blocked, IRF-3 is only partially phosphorylated and fails to bind the promoter of the target gene. Edited: Shamovsky, V, 2010-11-16 GENE ONTOLOGYGO:0035666 Pubmed14679297 Pubmed15210742 Pubmed15502848 Pubmed17332413 Reactome Database ID Release 43936964 Reactome, http://www.reactome.org ReactomeREACT_25148 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Gillespie, ME, 2010-11-30 Toll Receptor Cascades Authored: de Bono, B, Gillespie, ME, Luo, F, Gay, NJ, 0000-00-00 00:00:00 In human, ten members of the Toll-like receptor (TLR) family (TLR1-TLR10) have been identified (TLR11 has been found in mouse, but not in human). All TLRs have a similar Toll/IL-1 receptor (TIR) domain in their cytoplasmic region and an Ig-like domain in the extracellular region, where each is enriched with a varying number of leucine-rich repeats (LRRs). Each TLR can recognize specific microbial pathogen components. The binding pathogens component of the TLRs initializes signaling pathways that lead to induction of Interferon alpha/beta. There are three main signaling pathways: the first is a MyD88-dependent pathway that is common to all TLRs, except TLR3; the second is a TRAM-dependent pathway that is peculiar to TLR3 and TLR4 and is mediated by TRIF and RIP1; and the third is a TRAF6-mediated pathway peculiar to TLR3 (Takeda & Akira 2004; Akira 2003; Takeda & Akira 2005; Kawai 2005; Heine & Ulmer 2005). Pubmed12893815 Pubmed14751757 Pubmed15585605 Pubmed15950447 Pubmed15976490 Reactome Database ID Release 43168898 Reactome, http://www.reactome.org ReactomeREACT_6966 Reviewed: D'Eustachio, P, Gale M, Jr, Gay, NJ, 2006-10-31 16:43:59 IRAK1 recruits IKK complex Authored: Shamovsky, V, 2010-06-01 Edited: Shamovsky, V, 2012-11-06 GENE ONTOLOGYGO:0043123 Pubmed12856330 Pubmed14625308 Pubmed14661019 Pubmed15695821 Pubmed15767370 Pubmed16477006 Pubmed18276832 Pubmed18347055 Reactome Database ID Release 43937039 Reactome, http://www.reactome.org ReactomeREACT_24918 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Napetschnig, Johanna, 2012-11-16 The role of IRAK1 kinase activity in the activation of NF-kappa-B by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK1 mutants can still activate NF-kappa-B. Furthermore, stimulation of IRAK1-deficient I1A 293 cells with LMP1 (latent membrane protein 1- a known viral activator of NF-kappa-B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK1 enhances p65 Ser536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NF-kappa-B dependent target genes [Liu G et al 2008].<p> IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B. </p><p>Upon IL-1/TLR stimulation IRAK1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003]. Collagen type VII binds laminin-322 and collagen IV Anchoring fibrils are structures in skin that consist largely of collagen VII. They extend from the epidermal basement membrane to the dermal stroma where they connect with reticular fibre bundles, largely composed of collagen III (Fleischmajer et al. 1980). The long loop region of collagen VII entraps fibrillar collagens in the papillary dermis (Burgeson 1993). Type VII collagen binds laminin-332 (laminin-5) through the beta3 short arm, and also binds both type IV collagen and interstitial banded collagen fibrils - represented here by their major constituent, collagen I (Nakishima et al. 2005, Brittingham et al. 2006, Villone et al. 2008). Mutations of collagen VII are a cause of dystrophic epidermolysis bullosa, a blistering skin disease where separation occurs in the dermis at the level of anchoring fibrils (Chung & Uitto 2010, Uitto et al. 2010). Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed16272566 Pubmed16563355 Pubmed18599485 Pubmed19945621 Pubmed20393479 Pubmed7410886 Pubmed8370960 Reactome Database ID Release 432396234 Reactome, http://www.reactome.org ReactomeREACT_150470 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 MyD88 cascade initiated on plasma membrane Authored: Shamovsky, V, 2010-10-06 Edited: Shamovsky, V, 2011-08-12 GENE ONTOLOGYGO:0002755 Mammalian myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays crucial role in TLR signaling. All TLRs, with only one exception of TLR3, can initiate downstream signaling trough MyD88. In the MyD88 - dependent pathway, once the adaptor is bound to TLR it leads to recruitment of IL1 receptor associated kinase family – IRAK which is followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6) . TRAF6 is an ubiquitin E3 ligase which in turn induces TGF-beta activating kinase 1 (TAK1) auto phosphorylation. Once activated TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides. Pubmed10435584 Pubmed15728506 Pubmed16239509 Pubmed9430229 Reactome Database ID Release 43975871 Reactome, http://www.reactome.org ReactomeREACT_27215 Reviewed: Gillespie, ME, 2011-02-10 Reviewed: Li, L, 2011-08-04 Formation of anchoring fibrils Authored: Jupe, S, 2012-04-30 Collagen VII forms anchoring fibrils, composed of antiparallel dimers that connect the dermis to the epidermis (Bruckner-Tuderman 2009). During fibrillogenesis, the nascent type VII procollagen molecules dimerize in an antiparallel manner. The C-propeptides are then removed by bone morphogenetic protein 1 (Rattenholl et al. 2002) and the processed antiparallel dimers laterally aggregate (Gordon & Hahn 2010). Edited: Jupe, S, 2012-11-12 Pubmed11986329 Pubmed19116634 Pubmed19693541 Reactome Database ID Release 432213195 Reactome, http://www.reactome.org ReactomeREACT_150357 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Toll Like Receptor 10 (TLR10) Cascade Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2011-08-12 Little is known about TLR10 ligands. It has been established that the receptor homodimerizes upon binding and signals in an MyD88-dependent manner (Hasan U et al 2005; Nyman T et al 2008). It may also heterodimerize with TLRs 1 and 2. It is expressed in a restricted fashion as a highly N-glycosylated protein detectable in B cells and dendritic cells. Pubmed15728506 Pubmed18332149 Reactome Database ID Release 43168142 Reactome, http://www.reactome.org ReactomeREACT_9027 Reviewed: Gale M, Jr, 2006-10-31 16:45:01 Reviewed: Gillespie, ME, 2011-02-10 Cleavage of collagen VII NC2 region by BMP1 Authored: Jupe, S, 2012-04-30 Bone morphogenetic protein-1 (BMP1) cleaves the C-terminal propeptide from human procollagen VII within the NC2 domain at the BMP1 consensus cleavage site SYAA|DTAG. Mammalian tolloid-like (mTLL)-1 and -2 can substitute for BMP1 (Ratttenholl et al. 2002). EC Number: 3.4.21 Edited: Jupe, S, 2012-11-12 Pubmed11986329 Reactome Database ID Release 432214330 Reactome, http://www.reactome.org ReactomeREACT_150316 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 has a Stoichiometric coefficient of 6 Trafficking and processing of endosomal TLR Authored: Shamovsky, V, 2011-10-19 Edited: Shamovsky, V, 2012-02-19 Mammalian TLR3, TLR7, TLR8, TLR9 are endosomal receptors that sense nucleic acids that have been released from endocytosed/phagocytosed bacteria, viruses or parasites. These TLRs have a ligand-recognition domain that faces the lumen of the endosome (which is topologically equivalent to the outside of the cell), a transmembrane domain, and a signaling domain that faces the cytosol.<p>Under normal conditions, self nucleic acids are not recognized by TLRs due to multiple levels of regulation including receptor compartmentalization, trafficking and proteolytic processing (Barton GM et al 2006, Ewald SE et al 2008). At steady state TLR3, TLR7, TLR8, TLR9 reside primarily in the endoplasmic reticulum (ER), however, their activation by specific ligands only occurs within acidified endolysosomal compartments (Hacker H et al 1998, Funami K et al 2004, Gibbard RJ et al 2006). Several chaperon proteins associate with TLRs in the ER to provide efficient translocation to endolysosome. Upon reaching endolysosomal compartments the ectodomains of TLR7 and TLR9 are proteolytically cleaved by cysteine endoproteases. Both full-length and cleaved C-terminus of TLR9 bind CpG-oligodeoxynucleotides, however it has been proposed that only the processed receptor is functional.<p> Although similar cleavage of TLR3 has been reported by Ewald et al 2011, other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, thus TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).<p> There are no data on TLR8 processing, although the cell biology of TLR8 is probably similar to TLR9 and TLR7 (Gibbard RJ et al 2006, Wei T et al 2009). Pubmed15226270 Pubmed16144834 Pubmed16341217 Pubmed16857668 Pubmed18420935 Pubmed18776324 Pubmed18820679 Pubmed19521997 Pubmed21402738 Pubmed9799232 Reactome Database ID Release 431679131 Reactome, http://www.reactome.org ReactomeREACT_118632 Reviewed: Gillespie, ME, 2012-02-09 Reviewed: Leifer, CA, Rose II, WA, 2012-02-28 Collagen type VII dimerization Authored: Jupe, S, 2012-04-30 Collagen VII triple-helices form an anti-parallel dimer, associating through disulfide bonds formed in a 60-nm overlap (NC2 domain) of the amino terminal triple helical ends. A portion of this region is proteolytically removed (Morris et al. 1986, Chen et al. 2001) prior to aggregation of dimers into anchoring fibrils (Lundstrum et al. 1986). Edited: Jupe, S, 2012-11-12 Pubmed11274208 Pubmed11986329 Pubmed3013874 Pubmed3082888 Reactome Database ID Release 432214324 Reactome, http://www.reactome.org ReactomeREACT_150302 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 has a Stoichiometric coefficient of 2 Collagen prolyl 3-hydroxylase converts proline to 3-hydroxyproline Authored: Jupe, S, 2010-07-20 Collagen contains (2S,3S)-3-hydroxyproline (3-Hyp), though much less abundantly than 4-Hyp (Rhodes and Miller 1978). The 3-Hyp content of collagen is much more variable than that of 4-Hyp, varying between collagen types, tissues, developmental stages and pathological states (Kivirikko et al. 1992). It is more prevalent in type IV and V collagens at 10-15 3-Hyp residues (Bentz et al. 1983) than in Type I-III fibrillar collagens which have a single 3-Hyp residue per chain; the alpha-1 chain of type I collagen has 3-Hyp at residue 986 (Fietzek et al. 1972, Marini et al. 2007). 3-Hyp is formed from Pro in the Xaa position of Xaa-Hyp-Gly triplets (Gryder et al. 1975, Kivirikko et al. 1992). It is likely that 4-Hyp is a requirement at the second position of the triplet as 4-Hyp rich substrates are more active than 4-Hyp poor (Adams & Frank 1980). 3-Hyp has a modest effect on triple-helix stability (Jenkins et al. 2003; Mizuno et al. 2008). 3-Hyp may adjust the stability of basement membranes to enable formation of the meshwork structure, or serve as a ligand for other proteins. It is suggested to have a role in the self-assembly of collagen supramolecular structures (Weis et al. 2010). <br>3-Hyp is formed by prolyl 3-hydroxylase (P3H; EC 1.14.11.7), which has 3 isoforms in vertebrates. All contain an ER-retention signal but vary in their tissue expression (Vranka et al. 2009). P3H can hydroxylate prolines that precede 4-Hyp residues (Tryggvason et al. 1976) but not those that precede an unhydroxylated proline (Kivirikko & Myllla 1982, Myllyharju 2005). Like P4H, P3H requires molecular oxygen, alpha-ketoglutarate, iron(II), and ascorbate for activity. P3H1 is homologous to mammalian leprecan or growth suppressor 1 (Gros1), and forms a 3-prolyl hydroxylation complex with cartilage-associated protein (CRTAP) and a peptidyl-prolyl cis-trans isomerase, cyclophilin B (CypB), which is encoded by the PPIB gene (Vranka et al. 2004). Lack of 3-Hyp in Type I and II collagens leads to an osteogenesis imperfecta (OI)-like disease, as demonstrated by CRTAP and PPIB knock-out mice (Morello et al. 2006, Choi et al. 2009) and by mutations in human LEPRE1 (which encodes P3H1), CRTAP, and PPIB (Barnes et al. 2006, Cabral et al. 2007, van Dijk et al. 2009). The P3H1/CRTAP/CypB complex has also been shown to have chaperone activity (Ishikawa et al. 2009). P3H2 hydroxylates peptides derived from Type IV collagen more efficiently than Type I peptides and is localized to tissues that are rich in basement membrane (Tiainen et al. 2008). The effect of prolyl 3-hydroxylation on basement membrane collagens remains unknown.<br><br> In this generalized reaction, all collagen subtypes are represented as having one 3-Hyp residue. EC Number: 1.14.11.7 Edited: Jupe, S, 2012-05-14 ISBN3-540-23272-9 Pubmed12785781 Pubmed15044469 Pubmed164442 Pubmed17055431 Pubmed17192541 Pubmed17277775 Pubmed17630507 Pubmed18487197 Pubmed19021759 Pubmed19419969 Pubmed194596 Pubmed19652424 Pubmed19781681 Pubmed19940144 Pubmed19997487 Pubmed4343807 Pubmed6210830 Pubmed6250440 Pubmed6574478 Pubmed687595 Reactome Database ID Release 431980233 Reactome, http://www.reactome.org ReactomeREACT_120853 Reviewed: Canty-Laird, EG, 2012-05-24 Procollagen lysyl hydrolases convert lysine to 5-hydroxylysine Authored: Jupe, S, 2010-07-20 EC Number: 1.14.11.4 Edited: Jupe, S, 2012-05-14 ISBN978-0444007995 Lysyl hydroxylase (LH) (E.C. 1.14.11.4) is a dimeric enzyme that catalyzes the formation of (2S,5R)-5-hydroxylysyl residues (5-Hyl) in proteins (reviewed in Myllyharju & Kivirikko 2001) within a peptide linkage at the Y position of the repeating X-Y-Gly sequence motif. The extent of 5-Hyl formation is much more variable than that of hydroxyproline. It varies between collagen types, tissues and by physiological state (Miller 1984). 5-Hyl content also differs between the helical and telopeptide domains. This and the observation that purified lysyl hydroxylase failed to hydroxylate Lys in the telopeptide domains has led to speculation that there are separate enzymes responsible for Lys hydroxylation in the helical and telopeptide domains (Royce & Barnes 1985, Gerriets et al. 1993). The LH2b isoform may be the telopeptide-specific form (Pornprasertsuk et al. 2004).<br>In human type I collagen, there are 38 residues of Lys in each alpha-1 chain (36 in the helical domain, 1 each in the C- and N-telopeptide domains) and 31 in each alpha-2 chain (30 in the helical domain,1 in the N-telopeptide and none in the C-telopeptide domains) (Yamauchi & Shiiba 2002). <br><br>LH requires ferrous iron, oxygen, 2-oxoglutarate, and ascorbate. The hydroxylation reaction occurs during collagen biosynthesis in the ER as a co- and post-translational event, before triple helix formation. Three LH isoforms have been characterized in humans, encoded by the genes PLOD1-3. The isoforms appear to have preferences for certain collagen types, e.g. LH3 preferentially binds collagen types IV, VI, XI and XII (Myllyla et al. 2007). LH3 has galactosyltransferase and glucosyltransferase activities in addition to its lysyl hydroxylase activity (Heikkinen et al. 2000, Wang et al. 2002), a multifunctionality also seen in the single C. elegans orthologue (Wang et al. 2002a, b). Hydroxylysine residues can form stable intermolecular cross-links between collagen molecules in fibrils and also represent sites for glucosyl- and galactosyl- carbohydrate attachment. <br><br>In this reaction all collagen subtypes are represented as having a single hydroxylysine. Pubmed10934207 Pubmed11310942 Pubmed11896059 Pubmed12029842 Pubmed12475640 Pubmed15231023 Pubmed1577494 Pubmed17516569 Pubmed3931636 Pubmed6809411 Pubmed8244992 Pubmed9054364 Pubmed9582318 Reactome Database ID Release 431981104 Reactome, http://www.reactome.org ReactomeREACT_120884 Reviewed: Canty-Laird, EG, 2012-05-24 Galactosylation of collagen propeptide hydroxylysines by procollagen galactosyltransferases 1, 2. Authored: Jupe, S, 2010-07-20 EC Number: 2.4.1.50 Edited: Jupe, S, 2012-05-14 Hydroxylysine glycosides are specific to collagen. Collagen glycosylation takes place in the endoplasmic reticulum before triple-helix formation. Either galactose or glucose-galactose are attached to approximately one third of hydroxylysine residues by specific transferases, beta(1-O)galactosyl- and alpha(1-2)glucosyltransferase, forming galactosyl hydroxylysine (Gal-Hyl) and glucosyl-galactosyl hydroxylysine (Glu-Gal-Hyl) respectively. The genes GLT25D1 and GLT25D2 encode galactosyltransferases that are active with various types of collagen and the serum mannose-binding lectin MBL, which also contains a collagen domain. GLT25D1 gene is constitutively expressed in human tissues, whereas the GLT25D2 gene was found to be expressed only at low levels in the nervous system. These galactosyltransferases convert 5-hydroxylysine to 5-galactosyl hydroxylysine (Gal-Hyl). The extent of hydroxylysine galactosylation is variable between collagen types and locations; it is particularly common in bone type I collagen (Al-Dehaimi et al. 1999). Although the fraction of hydroxylysine residues that are glycosylated does not differ between skin and bone (the major sources of type I collagen) the pattern of hydroxylysine glycosylation is different. Glu-Gal-Hyl predominates in skin, where the Glu-Gal-Hyl/Gal-Hyl ratio is approximately 2 (Pinnell et al. 1971), whereas Gal-Hyl predominates in bone, where the Glu-Gal-Hyl/Gal-Hyl ratio is 0.47 (Krane et al. 1977). Pubmed10222355 Pubmed19075007 Pubmed20470363 Pubmed404321 Pubmed5101159 Reactome Database ID Release 431981120 Reactome, http://www.reactome.org ReactomeREACT_121077 Reviewed: Canty-Laird, EG, 2012-05-24 Galactosylation of collagen propeptide hydroxylysines by PLOD3 Authored: Jupe, S, 2010-07-20 EC Number: 2.4.1.50 Edited: Jupe, S, 2012-05-14 Pubmed10934207 Pubmed12475640 Pubmed19075007 Reactome Database ID Release 431981128 Reactome, http://www.reactome.org ReactomeREACT_120777 Reviewed: Canty-Laird, EG, 2012-05-24 The ER membrane-associated enzyme PLOD3 has collagen galactosyltransferase activity (Heikkinen et al. 2000, Wang et al. 2002) though the biological significance of this has been questioned (Schegg et al. 2009). Collagen prolyl 4-hydroxylase converts proline to 4-hydroxyproline Authored: Jupe, S, 2010-07-20 Collagen was for many years considered the only source of 4-hydroxyproline (4-Hyp) in animals. Though it is now known that other proteins such as C1q and elastin also contain 4-Hyp, collagen is by far the major source (Adams & Frank 1980). 4-Hyp is required for collagen stability at physiological temperatures. The abundance of Hyp in animal proteins is ~4%, making it more abundant than the amino-acids Cys, Gln, His, Met, Phe, Trp and Tyr (McCaldon & Argos 1988). In collagen Hyp abundance is much higher at ~38% (Ramshaw et al. 1998). Full collagen proline hydroxylation significantly raises the melting temperature (Tm) by stabilizing the collagen triple helix (Berg & Prockop 1973a), a process that has been studied extensively using synthetic collagen peptides (Sakakibara et al. 1973, Holmgren et al. 1998) and is well understood at the structural level (Shoulders & Raines 2009). Collagen 4-Hyp content is relatively stable, with small differences between collagen types. Collagen type I has approximately 1 4-Hyp for every 10 residues, roughly 50% of available prolines (Kivirikko et al. 1992). Conversion of Pro to (2S,4R)-4-hydroxyproline (4-Hyp) is the most prevalent posttranslational modification in humans, catalyzed by prolyl 4-hydroxylase (P4H). Mammalian prolyl 4-hydroxylase is an alpha2 beta2 tetramer (Berg & Prockop 1973b). The 59-kDa alpha subunit contains the substrate-binding domain and the enzymic active site (Helaakoski et al. 1989). Humans and most other vertebrates have three isoforms of the alpha subunit, isoform alpha-1 is the most prevalent. The pair of alpha subunits can be any of the three isoforms (Gorres & Raines 2010). The 55-kDa beta subunit is protein disulphide isomerase (PDI), which has additional functions in collagen formation. As part of P4H it retains the tetramer in the ER lumen and maintains the otherwise insoluble alpha subunit in an active form (Vuori et al. 1992, Nietfeld & Kemp 1981). P4H is a member of the non-heme iron(II), alpha-ketoglutarate-dependent dioxygenase family. Molecular oxygen (O2), 2-oxoglutarate (alpha-ketoglutarate) and iron(II) are required for its activity (Hutton & Udenfriend 1966). During the reaction, alpha-ketoglutarate is oxidatively decarboxylated producing succinate and CO2 (Rhoads & Udenfriend 1968, Gorres & Raines 2010). Ascorbate is required as a cofactor but not consumed (Kivirikko et al 1989). The minimum substrate required for hydroxylation is an Xaa-Pro-Gly tripeptide, with Pro preferred in the Xaa position, though hydroxylation can occur at lower rates with a variety of residues at this position (Kivirikko et al. 1972). A number of other peptides, notably elastin, are substrates for P4H (Bhatnagar 1978).<br><br>For brevity, all forms of collagen propeptide are shown as having 3X 4-Hyp residues following the action of P4H. EC Number: 1.14.11.2 Edited: Jupe, S, 2012-05-14 Pubmed1323838 Pubmed16591531 Pubmed19160570 Pubmed19344236 Pubmed20199358 Pubmed214345 Pubmed2537773 Pubmed2543975 Pubmed3227018 Pubmed4346946 Pubmed4702003 Pubmed4712181 Pubmed5046811 Pubmed5244754 Pubmed5965224 Pubmed6057106 Pubmed6250440 Pubmed6260196 Pubmed9565027 Pubmed9724608 Reactome Database ID Release 431650808 Reactome, http://www.reactome.org ReactomeREACT_121152 Reviewed: Canty-Laird, EG, 2012-05-24 Tetramerization of procollagen VI Authored: Jupe, S, 2010-07-20 Collagen VI dimers combine to form tetramers before secretion (Furthmayr et al. 1983, von der Mark et al. 1984, Engel et al. 1985, Engvall et al. 1986, Colombatti et al. 1987). Collagen type VI chains are extensively post translationally modifed by the hydroxylation of proline and lysine residues (Myllyharju & Kivirikko 2004) and subsequent glycosylation of hydroxylysine, thought to be essential for tetramer formation and secretion (Sipila et al. 2007). Edited: Jupe, S, 2012-05-14 Pubmed14698617 Pubmed17873278 Pubmed3117786 Pubmed3456350 Pubmed3938630 Pubmed6307276 Pubmed6432530 Reactome Database ID Release 431614461 Reactome, http://www.reactome.org ReactomeREACT_121234 Reviewed: Canty-Laird, EG, 2012-05-24 has a Stoichiometric coefficient of 2 Association of procollagen chains Authored: Jupe, S, 2010-07-20 Edited: Jupe, S, 2012-05-14 Pubmed171650 Pubmed1867713 Pubmed22001560 Pubmed710449 Pubmed710450 Reactome Database ID Release 432002401 Reactome, http://www.reactome.org ReactomeREACT_121254 Reviewed: Canty-Laird, EG, 2012-05-24 The C-propeptides are essential for the association of three alpha chains into a trimeric non-helical procollagen. Alignment determines the composition of the trimer, brings the individual chains into the correct register and initiates formation of the triple helix at the C-terminus, which then proceeds to the N-terminus in a zipper-like fashion (Engel & Prockop 1991). Most early refolding studies were performed with collagen type III which contains a disulfide linkage at the C-terminus of its triple helix (Bächinger et al. 1978, Bruckner et al. 1978) that acts as a permanent linker even after removal of the non-collagenous domains. <br><br>Mutations within the C-propeptides further suggest that they are crucial for the correct interaction of the three polypeptide chains and for subsequent correct folding (refs. in Boudko et al. 2011). Glucosylation of collagen propeptide hydroxylysines Authored: Jupe, S, 2010-07-20 EC Number: 2.4.1.66 Edited: Jupe, S, 2012-05-14 Pubmed10934207 Pubmed12475640 Pubmed19075007 Reactome Database ID Release 431981157 Reactome, http://www.reactome.org ReactomeREACT_120743 Reviewed: Canty-Laird, EG, 2012-05-24 The glucosyltransferase activity of PLOD3 adds glucose to procollagen galactosyl hydroxylysyl residues. Dimerization of procollagen type VI Authored: Jupe, S, 2010-07-20 Collagen type VI forms dimers and tetramers before secretion (Furthmayr et al. 1983, von der Mark et al. 1984, Engel et al. 1985, Colombatti et al. 1987). The monomers associate in antiparallel with a 30nm axial shift, intertwining 4 or 5 times (Furthmayr et al. 1983). These associate laterally to form tetramers (Furthmayr et al. 1983, von der Mark et al. 1984)The tetramers associate to form microfibrils in a non-covalent manner, presumed to be mediated through A domain interactions (Baldock et al. 2003). Collagen type VI chains are extensively post translationally modifed by the hydroxylation of proline and lysine residues (Myllyharju & Kivirikko 2004) and subsequent glycosylation of hydroxylysine, thought to be essential for tetramer formation and secretion (Sipila et al. 2007). Edited: Jupe, S, 2012-05-14 Pubmed12473679 Pubmed12823969 Pubmed14698617 Pubmed17873278 Pubmed3117786 Pubmed3938630 Pubmed6307276 Pubmed6432530 Reactome Database ID Release 431614460 Reactome, http://www.reactome.org ReactomeREACT_121253 Reviewed: Canty-Laird, EG, 2012-05-24 has a Stoichiometric coefficient of 2 Procollagen triple helix formation Alignment of the C-terminal prodomains initiates triple helix formation, which propagates in a zipper-like fashion in the C-to-N direction. This occurs in the rough endoplasmic reticulum (Engel & Prockop 1991). Compared with the folding of globular proteins and coiled-coil structures, the concentration-independent folding steps of collagen are extremely slow (Bächinger et al. 1980). Triple helix formation combines a fast process, interpreted as the folding of regions devoid of cis residues, and a slow process, limited by the slow kinetics of cis to trans prolyl-isomerization (Bächinger et al. 1978). Triple-helix formation in regions devoid of cis-prolyl bonds is 3-4 times faster than formation limited by prolyl isomerization reactions (Bachmann et al. 2005). Conversion to trans is required as only trans-peptide bonds can be incorporated into the collagen triple helix (Zeng et al. 1998). Efficient helix folding requires the presence of the 3-prolyl hydroxylation complex. This trimer of Prolyl 3-hydroxylase 1 (LEPRE1), Cyclophilin B (CyPB), also called Peptidyl-prolyl cis-trans isomerase B (PPIB) and CRTAP has 3-prolyl hydroxylase, PPIase and procollagen chaperone properties (Ishikawa et al. 2009, van Dijk et al. 2009). Efficient folding involves additional collagen-specific chaperones such as Serpin H1 (HSP47 - Smith et al. 1995). CyPB belongs to the cyclophilins, a conserved class of intracellular and/or secreted proteins originally identified as cellular binding proteins for the immunosuppressive drug cyclosporin A. They are peptidyl-prolyl cis-trans isomerases (PPIases), which catalyze the cis-trans isomerisation of peptide bonds. CyPB localises to the rough ER but is also secreted extracellularly. It directly interacts with procollagen and is believed to be responsible for converting procollagen cis- to trans-conformers (Zeng et al. 1998). CyPB and Serpin H1 are also involved in procollagen export and secretion. Results obtained with collagen peptides suggest that variations in the Gly-X-Y sequence are likely to result in a non-uniform helical twist along the length of a collagen fibril. Sequences poor in imino acids will have a symmetry close to 10 tripeptide units for every 3 turns of the triple helix (10/3), while stretches of Gly-Pro-Hyp units may have 7/2 symmetry (Brodsky & Persikov 2005). Authored: Jupe, S, 2010-07-20 EC Number: 5.2.1.8 Edited: Jupe, S, 2012-05-14 Pubmed15837519 Pubmed16172389 Pubmed1867713 Pubmed18786928 Pubmed19419969 Pubmed19781681 Pubmed20484404 Pubmed710450 Pubmed7398630 Pubmed7629154 Pubmed9461498 Reactome Database ID Release 432022073 Reactome, http://www.reactome.org ReactomeREACT_120939 Reviewed: Canty-Laird, EG, 2012-05-24 Antigen processing: Ubiquitination & Proteasome degradation Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 GENE ONTOLOGYGO:0000209 Intracellular foreign or aberrant host proteins are cleaved into peptide fragments of a precise size, such that they can be loaded on to class I MHC molecules and presented externally to cytotoxic T cells. The ubiquitin-26S proteasome system plays a central role in the generation of these class I MHC antigens. <br>Ubiquitination is the mechanism of adding ubiquitin to lysine residues on substrate protein leading to the formation of a polyubiquitinated substrate. This process involves three classes of enzyme, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase. Polyubiquitination through lysine-48 (K48) generally targets the substrate protein for proteasomal destruction. The protease responsible for the degradation of K48-polyubiquitinated proteins is the 26S proteasome. This proteasome is a two subunit protein complex composed of the 20S (catalytic core) and 19S (regulatory) proteasome complexes. The proteasome eliminates most of the foreign and non-functional proteins from the cell by degrading them into short peptides; only a small fraction of the peptides generated are of the correct length to be presented by the MHC class I system. It has been calculated that between 994 and 3122 protein molecules have to be degraded for the formation of a single, stable MHC class I complex at the cell surface, with an average effciency of 1 in 2000 (Kloetzel et al. 2004, Princiotta et al. 2003). Pubmed11917093 Pubmed12648452 Pubmed14734113 Pubmed17145306 Pubmed19489725 Pubmed20351195 Reactome Database ID Release 43983168 Reactome, http://www.reactome.org ReactomeREACT_75842 Reviewed: Elliott, T, 2011-02-10 Activation of RAS in B Cells Authored: May, B, 2011-01-03 Edited: May, B, 2011-01-03 Pubmed10777492 Pubmed10835426 Pubmed10934204 Pubmed11221888 Pubmed12730099 Pubmed15657177 Pubmed17283063 RasGRP1 and RasGRP3 bind diacylglycerol at the plasma membrane (Lorenzo et al. 2001) and are phosphorylated by protein kinase C (Teixeira et al. 2003, Zheng et al. 2005). Phosphorylated RasGRP1 (Roose et al. 2007) and RasGRP3 (Ohba et al. 2000, Yamashita et al. 2000, Rebhun et al. 2000, Lorenzo et al. 2001) then catalyze the exchange of GDP for GTP bound by RAS, thereby activating RAS. Reactome Database ID Release 431169092 Reactome, http://www.reactome.org ReactomeREACT_118778 Reviewed: Wienands, J, 2012-02-11 Class I MHC mediated antigen processing & presentation Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 GENE ONTOLOGYGO:0002474 Major histocompatibility complex (MHC) class I molecules play an important role in cell mediated immunity by reporting on intracellular events such as viral infection, the presence of intracellular bacteria or tumor-associated antigens. They bind peptide fragments of these proteins and presenting them to CD8+ T cells at the cell surface. This enables cytotoxic T cells to identify and eliminate cells that are synthesizing abnormal or foreign proteins. MHC class I is a trimeric complex composed of a polymorphic heavy chain (HC or alpha chain) and an invariable light chain, known as beta2-microglobulin (B2M) plus an 8-10 residue peptide ligand. Represented here are the events in the biosynthesis of MHC class I molecules, including generation of antigenic peptides by the ubiquitin/26S-proteasome system, delivery of these peptides to the endoplasmic reticulum (ER), loading of peptides to MHC class I molecules and display of MHC class I complexes on the cell surface. Pubmed12495737 Pubmed17055423 Pubmed17145306 Pubmed18243674 Pubmed18641646 Pubmed18926908 Pubmed19261456 Pubmed8717519 Reactome Database ID Release 43983169 Reactome, http://www.reactome.org ReactomeREACT_75820 Reviewed: Elliott, T, 2011-02-10 Downstream Signaling Events Of B Cell Receptor (BCR) Authored: May, B, 2010-12-09 Edited: May, B, 2010-12-09 Pubmed17052215 Pubmed19909372 Reactome Database ID Release 431168372 Reactome, http://www.reactome.org ReactomeREACT_118638 Reviewed: Wienands, J, 2012-02-11 Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidyinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS via RasGRP proteins, NF-AT via calcineurin, and AKT via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006). Ubiquitination of PER Proteins Authored: May, B, 2009-05-17 22:04:50 EC Number: 6.3.2.19 Edited: May, B, 2009-06-02 00:51:49 Edited: May, B, 2010-02-20 Polyubiquitination of PER proteins is directed by the Beta-TrCP1 component of SCF E3 ubiquitin ligase. The polyubiquitinated PER proteins are recognized and degraded by the 26S proteasome. Degradation of PER proteins occurs during the night and is necessary to allow new transcription of BMAL1:CLOCK/NPAS2 targets in the morning during the circadian cycle. Reactome Database ID Release 43400267 Reactome, http://www.reactome.org ReactomeREACT_25143 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Activation of NF-kappaB in B Cells Authored: May, B, 2011-01-03 DAG and calcium activate protein kinase C beta (PKC-beta, Kochs et al. 1991) which phosphorylates CARMA1 and other proteins (Sommer et al. 2005). Phosphorylated CARMA1 recruits BCL10 and MALT1 to form the CBM complex (Sommer et al. 2005, Tanner et al. 2007) which, in turn, recruits the kinase TAK1 and the IKK complex (Sommer et al. 2005, Shinohara et al. 2005 using chicken cells). TAK1 phosphorylates the IKK-beta subunit, activating it (Wang et al. 2001). The IKK complex then phosphorylates IkB complexed with NF-kappaB dimers in the cytosol (Zandi et al. 1998, Burke et al. 1999, Heilker et al. 1999), resulting in the degradation of IkB (Miyamoto et al. 1994, Traenckner et al. 1994, Alkalay et al. 1995, DiDonato et al. 1995, Li et al. 1995, Lin et al. 1995, Scherer et al. 1995, Chen et al. 1995). NF-kappaB dimers are thereby released and are translocated to the nucleus where they activate transcription (Baeuerle and Baltimore 1988, Blank et al. 1991, Ghosh et al. 2008, Fagerlund et al. 2008). Edited: May, B, 2011-01-03 Pubmed10593898 Pubmed11460167 Pubmed16301747 Pubmed16356855 Pubmed17428801 Pubmed1756723 Pubmed18462924 Pubmed19066035 Pubmed3129195 Pubmed7479848 Pubmed7479976 Pubmed7575604 Pubmed7628694 Pubmed7809113 Pubmed7831327 Pubmed7862124 Pubmed7957109 Pubmed8387275 Pubmed9721103 Pubmed9914500 Reactome Database ID Release 431169091 Reactome, http://www.reactome.org ReactomeREACT_118656 Reviewed: Wienands, J, 2012-02-11 Formation of ROR-alpha Coactivator Complex As inferred from mouse, RORA binds DNA and recruits the coactivators PGC-1alpha (PPARGC1A) and p300 (EP300, a histone acetylase). Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Reactome Database ID Release 431368087 Reactome, http://www.reactome.org ReactomeREACT_118616 Reviewed: Delaunay, F, 2012-01-28 B Cell Activation Authored: May, B, 2010-09-28 Edited: May, B, 2010-09-28 Mature B cells express IgM and IgD immunoglobulins which are complexed at the plasma membrane with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesel et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010).<br>The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Baldock et al. 2000, Irish et al. 2006, Tsang et al. 2008, reviewed in Bradshaw 2010).<br>Activated SYK and other kinases phosphorylate BLNK (SLP-65), BCAP, and CD19 which serve as scaffolds for the assembly of large complexes, the signalosomes, by recruiting phosphoinositol 3-kinase (PI3K), phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.<br>PLC-gamma associated with BLNK hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of calcium ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels in the plasma membrane, resulting in an influx of extracellular calcium ions (Muik et al. 2008, Luik et al. 2008, Park et al. 2009, Mori et al. 2002). PI3K associated with BCAP and CD19 phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyinositol 3,4,5-trisphosphate.<br>Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidylinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS is activated via RasGRP proteins, NF-AT is activated via calcineurin, and AKT (PKB) is activated via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006). Pubmed10648173 Pubmed1081164 Pubmed11901194 Pubmed1375264 Pubmed1376928 Pubmed15489917 Pubmed15509800 Pubmed16849466 Pubmed1702903 Pubmed17052215 Pubmed18187424 Pubmed18596693 Pubmed18818202 Pubmed19065780 Pubmed19249086 Pubmed19909372 Pubmed2011584 Pubmed20192804 Pubmed20206686 Pubmed4589993 Pubmed6335036 Pubmed7524079 Pubmed7538118 Pubmed7592958 Pubmed7688784 Pubmed7927516 Pubmed803528 Pubmed8163536 Pubmed8306975 Pubmed8580068 Reactome Database ID Release 43983705 Reactome, http://www.reactome.org ReactomeREACT_118773 Reviewed: Wienands, J, 2012-02-11 Signaling by the B Cell Receptor (BCR) Binding of FBXL3 to Phosphorylated CRY proteins Authored: May, B, 2009-05-17 22:04:50 Edited: May, B, 2009-06-02 00:51:49 FBXL3 is an F-box type component of a particular SKP/CUL/F-Box E3 ubiquitin ligase. FBXL3 interacts specifically with CRY1 and CRY2 in the cytosol to direct the polyubiquitination of CRY1 and CRY2. It is unknown if FBXL3 requires phosphorylation or other modification of CRY proteins in order to bind and ubiquitinate them. Phosphorylation of CRY by Adenosine monophosphate-dependent kinase increases degradation of CRY, apparently by increasing association of CRY with FBXL3 Polyubiquitination of CRY proteins directs them to the 26S proteasome for degradation. Reactome Database ID Release 43400272 Reactome, http://www.reactome.org ReactomeREACT_25106 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Antigen Activates B Cell Receptor Leading to Generation of Second Messengers Authored: May, B, 2010-09-28 Edited: May, B, 2010-09-28 Mature B cells express IgM and IgD immunoglobulins which are complexed with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesal et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010). The protein kinase SYK may also be involved in phosphorylating the ITAMs.<br>The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Irish et al. 2006, Baldock et al. 2008, Tsang et al. 2008, reviewed in Bradshaw 2010).<br>Activated SYK and other kinases phosphorylate BLNK (SLP-65, BASH) and BCAP. LYN and FYN phosphorylate CD19. Phosphorylated BLNK, BCAP, and CD19 serve as scaffolds which recruit effectors to the plasma membrane and assemble large complexes, the signalosomes. BCAP and CD19 recruit phosphoinositol 3-kinase (PI3K). BLNK recruits phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.<br>Phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). Phosphorylated CD19 likewise recruits PIP3K. PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) to the plasma membrane via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates PLC-gamma2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004). Phosphorylated BLNK recruits PLC-gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002).<br>PLC-gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of Ca2+ ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels (and possibly other TRP channels) in the plasma membrane, resulting in an influx of extracellular calcium ions (Mori et al. 2002, Muik et al. 2008, Luik et al. 2008, Park et al. 2009). Pubmed10648173 Pubmed10770799 Pubmed1081164 Pubmed11226282 Pubmed11606584 Pubmed11901194 Pubmed12456653 Pubmed1375264 Pubmed1376928 Pubmed15161916 Pubmed15489917 Pubmed1550550 Pubmed15509800 Pubmed16849466 Pubmed1702903 Pubmed18187424 Pubmed18596693 Pubmed18818202 Pubmed19065780 Pubmed19249086 Pubmed2011584 Pubmed20192804 Pubmed20206686 Pubmed4589993 Pubmed6335036 Pubmed7524079 Pubmed7538118 Pubmed7592958 Pubmed7688784 Pubmed7927516 Pubmed7929028 Pubmed803528 Pubmed8163536 Pubmed8306975 Pubmed8580068 Pubmed8918697 Pubmed9341187 Pubmed9468499 Pubmed9697839 Reactome Database ID Release 43983695 Reactome, http://www.reactome.org ReactomeREACT_118700 Reviewed: Wienands, J, 2012-02-11 Ubiquitination of CRY Proteins Authored: May, B, 2009-05-17 22:04:50 Edited: May, B, 2009-06-02 00:51:49 Edited: May, B, 2010-02-20 Polyubiquitination of CRY proteins is directed by the FBXL3 component of SCF E3 ubiquitin ligase. The polyubiquitinated CRY proteins are recognized and degraded by the 26S proteasome. Degradation of CRY proteins occurs during the night and is necessary to allow new transcription of BMAL1:CLOCK/NPAS2 targets in the morning during the circadian cycle. Reactome Database ID Release 43400282 Reactome, http://www.reactome.org ReactomeREACT_25378 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 PD-1 signaling Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed18173375 Pubmed18759926 Reactome Database ID Release 43389948 Reactome, http://www.reactome.org ReactomeREACT_19324 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 The Programmed cell death protein 1 (PD-1) is one of the negative regulators of TCR signaling. PD-1 may exert its effects on cell differentiation and survival directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2. PD-1 ligation inhibits the induction of the cell survival factor Bcl-xL and the expression of transcription factors associated with effector cell function, including GATA-3, Tbet, and Eomes. PD-1 exerts its inhibitory effects by bringing phosphatases SHP-1 and SHP-2 into the immune synapse, leading to dephosphorylation of CD3-zeta chain, PI3K and AKT. Translocation of Smad7:NEDD4L complex to the cytosol Authored: Orlic-Milacic, M, 2012-04-04 Co-transfection of recombinant mouse Smad7 and recombinant human NEDD4L in HepG2 cells, COS7 cells of HEK293 cells, results in the mainly cytoplasmic localization of Smad7. In the absensce of NEDD4L, Smad7 is predominantly found in the nucleus (Kuratomi et al. 2005). Edited: Jassal, B, 2012-04-10 Pubmed15496141 Reactome Database ID Release 432176428 Reactome, http://www.reactome.org ReactomeREACT_120978 Reviewed: Huang, Tao, 2012-05-14 CTLA4 inhibitory signaling Authored: Garapati, P V, 2008-12-16 11:12:19 CTLA4 is one of the best studied inhibitory receptors of the CD28 superfamily. CTLA4 inhibits Tcell activation by reducing IL2 production and IL2 expression, and by arresting T cells at the G1 phase of the cell cycle. CTLA-4 expressed by a T cell subpopulation exerts a dominant control on the proliferation of other T cells, which limits autoreactivity. CTLA4 also blocks CD28 signals by competing for the ligands B71 and B72 in the limited space between T cells and antigenpresenting cells. Though the mechanism is obscure, CTLA4 may also propagate inhibitory signals that actively counter those produced by CD28. CTLA4 can also function in a ligand-independent manner.?<br>CTLA-4 regulates the activation of pathogenic T cells by directly modulating T cell receptor signaling (i.e. TCR-zeta chain phosphorylation) as well as downstream biochemical signals (i.e. ERK activation). The cytoplasmic region of CTLA4 contains a tyrosine motif YVKM and a proline rich region. After TCR stimulation, it undergoes tyrosine phosphorylation by src kinases, inducing surface retention. Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed10374692 Pubmed11905831 Pubmed12876557 Pubmed16551244 Reactome Database ID Release 43389513 Reactome, http://www.reactome.org ReactomeREACT_19405 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Gap repair completes provirus integration Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed16175173 Pubmed16291214 Pubmed1760846 Reactome Database ID Release 43164506 Reactome, http://www.reactome.org ReactomeREACT_9001 Reviewed: Bushman, FD, 2006-10-30 22:19:13 The mechanism by which the integration reaction is completed has not been fully clarified. Unfolding of the integration intermediate resulting from the IN-catalyzed transesterification produces a branched DNA molecule. Denaturation of the host DNA between the points of joining produces DNA gaps at each host-virus DNA junction. How these gaps are repaired is unclear. Well studied host cell gap repair enzymes can carry out this repair step on model virus-host DNA junctions in vitro, providing candidate enzymes. However, efforts to show importance in vivo are complicated by the fact that the functions are either redundant or lethal when mutated.<p>Because the strand transfer complex formed at the completion of integration is quite stable, there may be a requirement for a disassembly step to remove integrase and potentially other proteins to allow access of the gap repair machinery.<br>In order to complete the last stages of integration, the viral proteins must be removed, and the gaps at the host virus DNA junctions repaired. The sequence in which the dissembly of PIC occus is not yet understood. has a Stoichiometric coefficient of 2 CD28 dependent Vav1 pathway Authored: Garapati, P V, 2008-12-16 11:12:19 CD28 binds to several intracellular proteins including PI3 kinase, Grb-2, Gads and ITK. Grb-2 specifically co-operates with Vav-1 in the up-regulation of NFAT/AP-1 transcription. CD28 costimulation resulted in a prolonged and sustained phosphorylation and membrane localization of Vav1 in comparison to T-cell receptor activation alone. Tyrosine-phosphorylated Vav1 is an early point of integration between the signaling routes triggered by the T-cell receptor and CD28.<br>Vav1 transduces TCR and co-stimulatory signals to multiple biochemical pathways and several cytoskeleton-dependent processes. The products of Vav1 activation, Rac1 and Cdc42, in turn activate the mitogen-activated protein kinases JNK and p38. Vav1 is also required for TCR-induced calcium flux, activation of the ERK MAP kinase pathway, activation of the NF-kB transcription factor, inside-out activation of the integrin LFA-1, TCR clustering, and polarisation of the T cell. Edited: Garapati, P V, 2008-12-16 11:12:19 Pubmed10849438 Pubmed12670394 Pubmed15886116 Reactome Database ID Release 43389359 Reactome, http://www.reactome.org ReactomeREACT_19238 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Ras guanyl-nucleotide exchange mediated by Sos1 bound to GRB2 in complex with P-Shc1:P-Erbb2mut Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed8530511 Reactome Database ID Release 431250472 Reactome, http://www.reactome.org ReactomeREACT_115858 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Sos1 bound to exogenously expressed human GRB2 in complex with phosphorylated mouse Shc1 and phosphorylated rat oncoprotein Erbb2mut catalyzes guanyl-nucleotide exchange on endogenous Ras in mouse fibroblasts. Proteasome mediated degradation of PAK-2p34 Authored: Jakobi, R, 2008-02-05 11:04:14 Edited: Matthews, L, 2008-02-03 20:50:13 Proteolytically activated PAK-2p34, but not full-length PAK-2, is degraded rapidly by the proteasome (Jakobi et al., 2003). Here, degradation of PAK-2p34 is described as occurring in the cytosol. However, to date it is not known whether this occurs in the nucleus or in the cytoplasm. Pubmed12853446 Reactome Database ID Release 43212917 Reactome, http://www.reactome.org ReactomeREACT_13505 Reviewed: Chang, E, 2008-05-21 00:05:41 PDI is a chaperone for collagen peptides As the collagen peptide chain is translocated across the membrane of the endoplasmic reticulum, intrachain disulfide bonds are formed within the N- and C-propeptides. This allows the triple helical domain to form a nucleation point at its C-terminal end and ensures correct alignment of the chains (Engel & Prockop 1991). Protein disulfide isomerase (P4HB) catalyzes the formation of both intra- (Bulleid & Freedman 1988) and inter-chain disulfide bonds (Koivu & Myllylä 1987). In addition, PDI acts as a molecular chaperone, interacting with monomeric collagen propeptide chains to prevent premature assembly or aggregation (Wilson et al. 1998). Authored: Jupe, S, 2010-07-20 Edited: Jupe, S, 2012-05-14 Pubmed1867713 Pubmed3173483 Pubmed3571251 Pubmed9545296 Pubmed9560306 Reactome Database ID Release 432002460 Reactome, http://www.reactome.org ReactomeREACT_120881 Reviewed: Canty-Laird, EG, 2012-05-24 MAML recruits CDK8:CCNC to xNICD1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15546612 Reactome Database ID Release 432064916 Reactome, http://www.reactome.org ReactomeREACT_118645 Recruitment of CDK8 and cyclin C (CDK8:CCNC) by MAML, a constituent of the NOTCH1 coactivator complex, was studied in HeLa cells in which tagged human MAML, CDK8 and CCNC proteins were expressed together with a tagged Xenopus NICD1 (xNICD1). Reviewed: Haw, R, 2012-02-06 Rap1 signalling Authored: Akkerman, JW, 2009-06-03 Edited: Jupe, S, 2010-09-01 Pubmed16076873 Rap1 (Ras-proximate-1) is a small G protein in the Ras superfamily. Like all G proteins, Rap1 is activated when bound GDP is exchanged for GTP. Rap1 is targeted to lipid membranes by the covalent attachment of lipid moieties to its carboxyl terminus. Movement of Rap1 from endosomal membranes to the plasma membrane upon activation has been reported in several cell types including Jurkat T cells and megakaryocytes. On activation, Rap1 undergoes conformational changes that facilitate recruitment of a variety of effectors, triggering it's participation in integrin signaling, ERK activation, and others. Reactome Database ID Release 43392517 Reactome, http://www.reactome.org ReactomeREACT_23898 Reviewed: Heemskerk, JW, 2010-09-01 Innate Immune System GENE ONTOLOGYGO:0045087 Innate immunity encompases the nonspecific part of immunity tha are part of an individual's natural biologic makeup Reactome Database ID Release 43168249 Reactome, http://www.reactome.org ReactomeREACT_6802 Endosomal/Vacuolar pathway Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 GENE ONTOLOGYGO:0002480 Pubmed15308097 Pubmed18376401 Reactome Database ID Release 431236977 Reactome, http://www.reactome.org ReactomeREACT_111168 Reviewed: Desjardins, M, English, L, 2011-05-13 Some antigens are cross-presented through a vacuolar mechanism that involves generation of antigenic peptides and their loading on to MHC-I molecules within the endosomal compartment in a proteasome and TAP-independent manner. Antigens within the endosome are processed by cathepsin S and other proteases into antigenic peptides. Loading of these peptides onto MHC-I molecules occurs directly within early and late endosomal compartments. Why certain antigens are cross-presented exclusively by the cytosolic pathway while others use the vacuolar pathway is unknown. It may be because some epitopes cannot be generated by endosomal proteolysis, or are completely destroyed. Alternatively, the physical form of the antigen may influence its accessibility to the endosomal or vacuolar pathways (Shen et al. 2004). Cross-presentation of soluble exogenous antigens (endosomes) Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 Exogenous soluble antigens are cross-presented by dendritic cells, albeit with lower efficiency than for particulate substrates. Soluble antigens destined for cross-presentation are taken up by distinct endocytosis mechanisms which route them into stable early endosomes and then to the cytoplasm for proteasomal degradation and peptide loading. GENE ONTOLOGYGO:0002479 Pubmed15592474 Pubmed17157489 Pubmed20171863 Reactome Database ID Release 431236978 Reactome, http://www.reactome.org ReactomeREACT_111056 Reviewed: Desjardins, M, English, L, 2011-05-13 Syk phosphorylates Vav1 Authored: Akkerman, JW, 2009-09-04 EC Number: 2.7.10.2 Edited: Jupe, S, 2009-06-08 Pubmed11007481 Pubmed11262396 Pubmed17054426 Pubmed8986718 Reactome Database ID Release 43437938 Reactome, http://www.reactome.org ReactomeREACT_121246 Reviewed: Kunapuli, SP, 2010-06-07 Tyrosine phosphorylateion is believed to be a general activation mechansim for the Vav family. VAV1 Tyr-174 binds to the Dbl homology region, inhibiting GEF activity. Phosphorylation of this residue by Syk relieves inhibition, activating Vav1. In Jurkat cells T-cell receptor activation leads to increased Vav2 tyrosine phosphorylation; the expression of Lck, Fyn, Zap70, or Syk stimulated this phosphorylation. Vav is regulated downstream of the thrombin and thrombopoietin receptors (Miyakawa et al. 1997) and integrins, including the major platelet integrin alphaIIbbeta3. Vav family proteins are involved in filopodia and lamellipodia formation; mouse platelets deficient in Vav1 and Vav3 exhibit reduced filopodia and lamellipodia formation during spreading on fibrinogen. This is accompanied by reduced alphaIIbbeta3-mediated PLCgamma2 tyrosine phosphorylation and reduced Ca(2+) mobilization (Pearce et al. 2007). MHC class II antigen presentation Antigen presenting cells (APCs) such as B cells, dendritic cells (DCs) and monocytes/macrophages express major histocompatibility complex class II molecules (MHC II) at their surface and present exogenous antigenic peptides to CD4+ T helper cells. CD4+ T cells play a central role in immune protection. On their activation they stimulate differentiation of B cells into antibody-producing B-cell blasts and initiate adaptive immune responses. MHC class II molecules are transmembrane glycoprotein heterodimers of alpha and beta subunits. Newly synthesized MHC II molecules present in the endoplasmic reticulum bind to a chaperone protein called invariant (Ii) chain. The binding of Ii prevents the premature binding of self antigens to the nascent MHC molecules in the ER and also guides MHC molecules to endocytic compartments. In the acidic endosomal environment, Ii is degraded in a stepwise manner, ultimately to free the class II peptide-binding groove for loading of antigenic peptides. Exogenous antigens are internalized by the APC by receptor mediated endocytosis, phagocytosis or pinocytosis into endocytic compartments of MHC class II positive cells, where engulfed antigens are degraded in a low pH environment by multiple acidic proteases, generating MHC class II epitopes. Antigenic peptides are then loaded into the class II ligand-binding groove. The resulting class II peptide complexes then move to the cell surface, where they are scanned by CD4+ T cells for specific recognition (Berger & Roche 2009, Zhou & Blum 2004, Watts 2004, Landsverk et al. 2009). Authored: Garapati, P V, 2012-02-21 Edited: Garapati, P V, 2012-02-21 GENE ONTOLOGYGO:0019886 Pubmed11684289 Pubmed15224094 Pubmed15531770 Pubmed19092054 Pubmed19217269 Pubmed19703008 Pubmed8689559 Pubmed9316394 Reactome Database ID Release 432132295 Reactome, http://www.reactome.org ReactomeREACT_121399 Reviewed: Neefjes, Jacques, 2012-05-14 Formation of BMAL1:CLOCK/NPAS2 Heterodimer Authored: May, B, 2009-05-17 22:04:50 BMAL1 (ARNTL), CLOCK, and NPAS2 are basic helix-loop-helix transcription factors. In humans BMAL1 has been demonstrated to form a heterodimer with CLOCK. In mouse, BMAL1 can form a heterodimer with either CLOCK or NPAS2. By analogy with other basic helix-loop-helix proteins the basic domain binds DNA, in this case the E-box motif, and the helix-loop-helix domains interact to form the heterodimer. BMAL1 and CLOCK/NPAS2 are codependently phosphorylated by unknown kinases after dimerization. The phosphorylation enhances transactivation activity and is inhibited by PER:CRY complexes. Both CLOCK and NPAS2 are expressed in the suprachiasmatic nucleus of the hypothalamus and act redundantly there. The tissue distributions of CLOCK and NPAS2 do not entirely overlap, however. For example, NPAS2 but not CLOCK is found in forebrain. Edited: May, B, 2009-06-02 00:51:49 Pubmed11441146 Pubmed11441147 Pubmed9576906 Pubmed9616112 Reactome Database ID Release 43400228 Reactome, http://www.reactome.org ReactomeREACT_25402 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell A number of receptors and cell adhesion molecules play a key role in modifying the response of cells of lymphoid origin (such as B-, T- and NK cells) to self and tumor antigens, as well as to pathogenic organisms.<p><p>Molecules such as KIRs and LILRs form part of a crucial surveillance system that looks out for any derangement, usually caused by cancer or viral infection, in MHC Class I presentation. Somatic cells are also able to report internal functional impairment by displaying surface stress markers such as MICA. The presence of these molecules on somatic cells is picked up by C-lectin NK immune receptors.<p><p>Lymphoid cells are able to regulate their location and movement in accordance to their state of activation, and home in on tissues expressing the appropriate complementary ligands. For example, lymphoid cells may fine tune the presence and concentration of adhesion molecules belonging to the IgSF, Selectin and Integrin class that interact with a number of vascular markers of inflammation.<p><p>Furthermore, there are a number of avenues through which lymphoid cells may interact with antigen. This may be presented directly to a specific T-cell receptor in the context of an MHC molecule. Antigen-antibody complexes may anchor to the cell via a small number of lymphoid-specific Fc receptors that may, in turn, influence cell function further. Activated complement factor C3d binds to both antigen and to cell surface receptor CD21. In such cases, the far-reaching influence of CD19 on B-lymphocyte function is tempered by its interaction with CD21. Authored: de Bono, B, 2007-07-08 12:58:15 GENE ONTOLOGYGO:0050776 Pubmed11244041 Pubmed16603343 Pubmed16616474 Pubmed17218381 Reactome Database ID Release 43198933 Reactome, http://www.reactome.org ReactomeREACT_11152 Reviewed: Trowsdale, J, 2007-08-06 19:33:04 Phosphorylation and Nuclear Translocation of the BMAL1:CLOCK/NPAS2 Heterodimer Authored: May, B, 2009-05-17 22:04:50 Edited: May, B, 2009-06-02 00:51:49 In mouse, BMAL1, CLOCK, and NPAS2 are phosphorylated by unknown kinases. The phosphorylation is dependent on the heterodimerization of BMAL1 with CLOCK or NPAS2. Phosphorylated BMAL1:CLOCK/NPAS2 is a much stronger transactivator of gene expression than is unphosphorylated BMAL1:CLOCK/NPAS2. Reactome Database ID Release 43421320 Reactome, http://www.reactome.org ReactomeREACT_25029 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Antigen processing-Cross presentation Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 GENE ONTOLOGYGO:0042590 MHC class I molecules generally present peptide antigens derived from proteins synthesized by the cell itself to CD8+ T cells. However, in some circumstances, antigens from extracellular environment can be presented on MHC class I to stimulate CD8+ T cell immunity, a process termed cross-presentation (Rock & Shen. 2005). Cross-presentation/cross-priming is the ability of antigen presenting cells (APCs) to present exogenous antigens on MHC class I molecules to CD8+ T lymphocytes. Among all the APCs, Dendritic cells (DC) are the dominant antigen cross presenting cell types in vivo, although macrophages and B cells appear to cross present model antigens in vitro with a low degree of efficiency (Amigorena & Savina. 2010, Ackermann & Peter Cresswell. 2004). Compared to macrophages, DCs have low levels of lysosomal proteases and exhibit limited lysosomal degradation (Delamarre et al. 2005). This limited proteolysis of internalized antigens by DCs might contribute to their high efficiency for cross presentation (Monua & Trombetta. 2007). APCs acquire the exogenous antigens through endocytic mechanisms, especially phagosomes for particulate/cell-associated antigens and endosomes for soluble protein antigens. There does not seem to be a unique pathway for cross-presentation but rather different potential mechanisms of cross-presentation have been proposed. These proposed pathways can be classified according to the location where two key events occur: 1) processing of the antigenic protein and 2) loading of the processed peptide on to MHC I molecule (Blanchard & Shastri. 2010). Based on the requirement for TAP and cytosolic proteases two mechanisms have been described, a cytosolic pathway (TAP-dependent and proteasome-dependent) or a vacuolar pathway (TAP- and proteasome-independent) (Blanchard & Shastri. 2010, Amigorena & Savina. 2010). Regarding peptide-loading, MHC I could be loaded in the ER or in the phagosome and recycled to cell surface (Blanchard & Shastri. 2010). Exogenous soluble antigens are cross-presented by dendritic cells, albeit with lower efficiency than for particulate substrates. Soluble antigens destined for cross-presentation are taken up by distinct endocytosis mechanisms which route them into stable early endosomes and then to the cytoplasm for proteasomal degradation and peptide loading. The outcome of the cross presentation can be either tolerance or immunity (Rock & Shen. 2005). Pubmed15761154 Pubmed16181333 Pubmed16181335 Pubmed17157489 Pubmed19218463 Pubmed20171863 Reactome Database ID Release 431236975 Reactome, http://www.reactome.org ReactomeREACT_111119 Reviewed: Desjardins, M, English, L, 2011-05-13 Stabilization of Unphosphorylated BMAL1:CLOCK/NPAS2 Heterodimer by CRY Proteins Authored: May, B, 2010-03-19 CRY1 and CRY2 bind the unphosphorylated BMAL1:CLOCK heterodimer (and by homology the BMAL1:NPAS2 heterodimer) and prolong its half-life. The unphosphorylated BMAL1:CLOCK heterodimer only weakly activates transcription and is therefore believed to competitively reduce transcription by phosphorylated BMAL1:CLOCK heterodimer. The complex of unphosphorylated BMAL1:CLOCK with CRY may contain additional components and may traffic into the nucleus. Edited: May, B, 2010-03-19 Reactome Database ID Release 43549355 Reactome, http://www.reactome.org ReactomeREACT_25234 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Antigen Presentation: Folding, assembly and peptide loading of class I MHC Authored: Garapati, P V, 2010-10-29 Edited: Garapati, P V, 2010-10-29 Pubmed12495737 Pubmed15224092 Pubmed18641646 Pubmed18926908 Pubmed19178136 Reactome Database ID Release 43983170 Reactome, http://www.reactome.org ReactomeREACT_75795 Reviewed: Elliott, T, 2011-02-10 Unlike other glycoproteins, correct folding of MHC class I molecules is not sufficient to trigger their exit from the ER, they exit only after peptide loading. Described here is the process of antigen presentation which consists of the folding, assembly, and peptide loading of MHC class I molecules. The newly synthesized MHC class I Heavy Chain (HC) is initially folded with the help of several chaperones (calnexin, BiP, ERp57) and then binds with Beta-2-microglobulin (B2M). This MHC:B2M heterodimer enters the peptide loading complex (PLC), a multiprotein complex that includes calreticulin, endoplasmic reticulum resident protein 57 (ERp57), transporter associated with antigen processing (TAP) and tapasin. Peptides generated from Ub-proteolysis are transported into the ER through TAP. These peptides are further trimmed by ER-associated aminopeptidase (ERAP) and loaded on to MHC class I molecules. Stable MHC class I trimers with high-affinity peptide are transported from the ER to the cell surface by the Golgi apparatus. NR1D1 (REV-ERBA) Binds Heme and Corepressors Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 NR1D1 (REV-ERBA) binds heme. The REV-ERBA:heme complex is then able to recruit the corepressors NCoR and HDAC3. Corepressors do not bind REV-ERBA in the absence of heme. Pubmed15761026 Pubmed18006707 Pubmed18037887 Pubmed20581824 Reactome Database ID Release 431368069 Reactome, http://www.reactome.org ReactomeREACT_118766 Reviewed: Delaunay, F, 2012-01-28 ER-Phagosome pathway Authored: Garapati, P V, 2011-03-28 Edited: Garapati, P V, 2011-03-28 GENE ONTOLOGYGO:0002479 Pubmed12151002 Pubmed12669019 Pubmed14508489 Pubmed14508490 Pubmed14561893 Pubmed15728715 Pubmed15845646 Pubmed16213220 Pubmed17027300 Pubmed18006660 Pubmed18802471 Pubmed20171863 Reactome Database ID Release 431236974 Reactome, http://www.reactome.org ReactomeREACT_111178 Reviewed: Desjardins, M, English, L, 2011-05-13 The other TAP-dependent cross-presentation mechanism in phagocytes is the endoplasmic reticulum (ER)-phagosome model. Desjardins proposed that ER is recruited to the cell surface, where it fuses with the plasma membrane, underneath phagocytic cups, to supply membrane for the formation of nascent phagosomes (Gagnon et al. 2002). Three independent studies simultaneously showed that ER contributes to the vast majority of phagosome membrane (Guermonprez et al. 2003, Houde et al. 2003, Ackerman et al. 2003). The composition of early phagosome membrane contains ER-resident proteins, the components required for cross-presentation. This model is similar to the phagosome-to-cytosol model in that Ag is translocated to cytosol for proteasomal degradation, but differs in that antigenic peptides are translocated back into the phagosome (instead of ER) for peptide:MHC-I complexes. ER fusion with phagosome introduces molecules that are involved in Ag transport to cytosol (Sec61) and proteasome-generated peptides back into the phagosome (TAP) for loading onto MHC-I. <br>Through extensive biochemical assays, fluorescent imaging and electron microscopy-based experiments, most of the evidence in favor of ER-phagocytosis has been challenged (Touret et al. 2005a/b). Using quantitative proteomics Roger and Foster have shown that the percentage of PM and ER membranes on phagosomes 10 min after internalization was approximately 10% and 0.2% (Rogers et al. 2007). They concluded that ER contributes only a small part of phagosomal membranes.<br>Although the ER-phagosome pathway is controversial, the concept remains attractive as it explains how peptide-receptive MHC-I molecules could intersect with a relatively high concentration of exogenous antigens, presumably a crucial prerequisite for efficient cross-presentation (Basha et al. 2008). Phosphorylation of CRY and PER Proteins Authored: May, B, 2009-05-17 22:04:50 EC Number: 2.7.11 Edited: May, B, 2009-06-02 00:51:49 In the cytosol the kinases CSNK1D (casein kinase I delta) and CSNK1E (casein kinase I epsilon) phosphorylate PER1, PER2, CRY1, and CRY2 at multiple sites. Evidence indicates that PER:CRY complexes form a stable ternary complex with either CSNK1E or CSNK1D. Both kinases are able to bind and phosphorylate PER proteins. CSNK1E has been shown to phosphorylate CRY proteins only when they are complexed with PER proteins.<br>PER proteins contain a nuclear localization sequence and a nuclear export sequence allowing their movement into and out of the nucleus. Phosphorylation is required for transit of PER:CRY:kinase complexes into the nucleus and for interaction of PER proteins with the ubiquitin-mediated degradation process in the cytoplasm.<br>A mutation at Serine662 of PER2 is responsible for familial advanced phase sleep syndrome, however the particular kinase responsible for phosphorylating Serine662 is unknown. Pubmed10790862 Pubmed11165242 Pubmed11232563 Pubmed14750904 Pubmed15800623 Pubmed15917222 Pubmed17218255 Pubmed19805222 Reactome Database ID Release 43400382 Reactome, http://www.reactome.org ReactomeREACT_25125 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Cross-presentation of particulate exogenous antigens (phagosomes) Authored: Garapati, P V, 2011-03-28 Dendritic cells (DCs) take up and process exogenous particulate or cell-associated antigens such as microbes or tumor cells for MHC-I cross-presentation. Particulate antigens have been reported to be more efficiently cross-presented than soluble antigens by DCs (Khor et al. 2008). Particulate antigens are internalized by phagosomes. There are two established models that explain the mechanism by which exogenous particulate antigens are presented through MHC I; the cytosolic pathway where internalized antigens are somehow translocated from phagosomes into cytosol for proteasomal degradation and the vacuolar pathway (Lin et al. 2008, Amigorena et al. 2010). Edited: Garapati, P V, 2011-03-28 GENE ONTOLOGYGO:0002479 Pubmed18268517 Pubmed18572095 Pubmed20028659 Pubmed20171863 Reactome Database ID Release 431236973 Reactome, http://www.reactome.org ReactomeREACT_111174 Reviewed: Desjardins, M, English, L, 2011-05-13 Formation of CRY:PER:Kinase Complex Authored: May, B, 2011-10-29 CRYPTOCHROME, PERIOD, and a kinase (CKIepsilon or CKIdelta) form a ternary complex in the cytosol. Edited: May, B, 2011-10-29 Pubmed10790862 Pubmed11165242 Reactome Database ID Release 431856948 Reactome, http://www.reactome.org ReactomeREACT_115943 Reviewed: Albrecht, U, 2010-06-23 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Binding of CRY:PER Heterodimer to the BMAL1:CLOCK/NPAS2 Heterodimer Authored: May, B, 2009-05-17 22:04:50 CRY (CRY1 and CRY2) and PER (PER1, PER2, PER3) proteins form complex in the cytoplasm where they are phosphorylated by CSNK1D and CSNK1E kinases. CRY:PER complexes appear to form stable complexes with a kinase. Because of the nuclear localization signals of PER and CRY, the complexes are translocated to the nucleus where they bind BMAL1:CLOCK/NPAS2 heterodimers and inhibit the transactivation activity of BMAL1:CLOCK/NPAS2.<br>CRY and PER proteins are themselves transcriptionally activated by BMAL1:CLOCK/NPAS2 thus they participate in a negative loop inhibiting their own synthesis and the synthesis of other targets of BMAL1:CLOCK/NPAS2.<br>Experiments with two-hybrid interactions and in vitro associations show that CRY1, CRY2, and PER2 bind BMAL1 at two different sites on BMAL1. PER2 but not CRY1 or CRY2 binds CLOCK. Different combinations of PER and CRY proteins in PER:CRY complexes have different inhibitory activities. Edited: May, B, 2009-06-02 00:51:49 Pubmed10531061 Pubmed16474406 Reactome Database ID Release 43400256 Reactome, http://www.reactome.org ReactomeREACT_25061 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Translocation of CRY:PER:Kinase Ternary Complex into the Nucleus Authored: May, B, 2010-03-19 Edited: May, B, 2010-03-19 Reactome Database ID Release 43549385 Reactome, http://www.reactome.org ReactomeREACT_25049 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 The ternary complex containing phosphorylated CRY and PER proteins with a kinase (CSNK1D or CSNK1E) is translocated to the nucleus. Phosphorylation controls transfer to the nucleus and retention in the nucleus. Binding of Beta-TrCP1 to phosphorylated PER proteins Authored: May, B, 2009-05-17 22:04:50 Beta-TrCP1 is an F-box type component of a particular SKP/CUL/F-Box (SCF) E3 ubiquitin ligase. Beta-TrCP1 interacts specifically with phosphorylated PER proteins and directs their polyubiquitination. Edited: May, B, 2009-06-02 00:51:49 Pubmed15917222 Reactome Database ID Release 43400219 Reactome, http://www.reactome.org ReactomeREACT_25088 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 PathwayStep5585 PathwayStep5586 PathwayStep5587 PathwayStep5588 PathwayStep5581 PathwayStep3442 PathwayStep5582 PathwayStep3443 PathwayStep5583 PathwayStep3440 PathwayStep5584 PathwayStep3441 PathwayStep5580 Rheb:GDP Reactome DB_ID: 165191 Reactome Database ID Release 43165191 Reactome, http://www.reactome.org ReactomeREACT_7464 has a Stoichiometric coefficient of 1 Rheb:GTP Reactome DB_ID: 165189 Reactome Database ID Release 43165189 Reactome, http://www.reactome.org ReactomeREACT_7765 has a Stoichiometric coefficient of 1 Activated mTORC1 Reactome DB_ID: 165678 Reactome Database ID Release 43165678 Reactome, http://www.reactome.org ReactomeREACT_7770 has a Stoichiometric coefficient of 1 eIF4E:4E-BP1-P Reactome DB_ID: 165697 Reactome Database ID Release 43165697 Reactome, http://www.reactome.org ReactomeREACT_7838 has a Stoichiometric coefficient of 1 p-AMPK heterotrimer:AMP Reactome DB_ID: 380931 Reactome Database ID Release 43380931 Reactome, http://www.reactome.org ReactomeREACT_21851 has a Stoichiometric coefficient of 1 fl-TLR9:unmethylated CpG DNA Reactome DB_ID: 187884 Reactome Database ID Release 43187884 Reactome, http://www.reactome.org ReactomeREACT_9181 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PI3K class III Reactome DB_ID: 188015 Reactome Database ID Release 43188015 Reactome, http://www.reactome.org ReactomeREACT_9166 has a Stoichiometric coefficient of 1 GRB2 and GAB1 bound to activated FGFR and FRS2-alpha Reactome DB_ID: 190399 Reactome Database ID Release 43190399 Reactome, http://www.reactome.org ReactomeREACT_21915 has a Stoichiometric coefficient of 1 Activated FGFR bound to PI3K Reactome DB_ID: 190928 Reactome Database ID Release 43190928 Reactome, http://www.reactome.org ReactomeREACT_21751 has a Stoichiometric coefficient of 1 TSC1:Inhibited TSC2-1-P Reactome DB_ID: 165180 Reactome Database ID Release 43165180 Reactome, http://www.reactome.org ReactomeREACT_7650 has a Stoichiometric coefficient of 1 TSC1:TSC2 Reactome DB_ID: 165175 Reactome Database ID Release 43165175 Reactome, http://www.reactome.org ReactomeREACT_7850 has a Stoichiometric coefficient of 1 PathwayStep3436 PathwayStep3435 PathwayStep3434 PathwayStep3433 PathwayStep5579 PathwayStep5578 PathwayStep3439 PathwayStep3438 PathwayStep3437 PathwayStep5598 PathwayStep5599 PathwayStep5596 PathwayStep5597 PathwayStep3450 PathwayStep5594 PathwayStep3451 PathwayStep5595 PathwayStep3452 PathwayStep5592 PathwayStep3453 PathwayStep5593 PathwayStep3454 PathwayStep5590 GRB2:phospho-SHC Reactome DB_ID: 109799 Reactome Database ID Release 43109799 Reactome, http://www.reactome.org ReactomeREACT_2584 has a Stoichiometric coefficient of 1 PathwayStep5591 GRB2:IRS-P Reactome DB_ID: 109801 Reactome Database ID Release 43109801 Reactome, http://www.reactome.org ReactomeREACT_5160 has a Stoichiometric coefficient of 1 Crk:IRS-P Reactome DB_ID: 109812 Reactome Database ID Release 43109812 Reactome, http://www.reactome.org ReactomeREACT_4822 has a Stoichiometric coefficient of 1 GRB10:INSR Reactome DB_ID: 110010 Reactome Database ID Release 43110010 Reactome, http://www.reactome.org ReactomeREACT_5054 has a Stoichiometric coefficient of 1 Crk:SOS:IRS-P Reactome DB_ID: 109811 Reactome Database ID Release 43109811 Reactome, http://www.reactome.org ReactomeREACT_2957 has a Stoichiometric coefficient of 1 Crk:SOS Reactome DB_ID: 109810 Reactome Database ID Release 43109810 Reactome, http://www.reactome.org ReactomeREACT_3418 has a Stoichiometric coefficient of 1 PIP3:AKT2 complex Reactome DB_ID: 109696 Reactome Database ID Release 43109696 Reactome, http://www.reactome.org ReactomeREACT_4871 has a Stoichiometric coefficient of 1 PKB:PKB Regulator Reactome DB_ID: 162401 Reactome Database ID Release 43162401 Reactome, http://www.reactome.org ReactomeREACT_4747 has a Stoichiometric coefficient of 1 PIP3:PDK1 complex Reactome DB_ID: 109697 Reactome Database ID Release 43109697 Reactome, http://www.reactome.org ReactomeREACT_5409 has a Stoichiometric coefficient of 1 TSC1:p-S1387-TSC2 Reactome DB_ID: 381855 Reactome Database ID Release 43381855 Reactome, http://www.reactome.org ReactomeREACT_21675 has a Stoichiometric coefficient of 1 GRB2:SOS:IRS-P Reactome DB_ID: 109800 Reactome Database ID Release 43109800 Reactome, http://www.reactome.org ReactomeREACT_3414 has a Stoichiometric coefficient of 1 PathwayStep3445 PathwayStep3444 PathwayStep3447 PathwayStep3446 PathwayStep3449 PathwayStep3448 PathwayStep5589 PathwayStep3420 PathwayStep5560 PathwayStep3421 PathwayStep5561 PathwayStep5562 PathwayStep5563 PathwayStep5564 PathwayStep5565 PathwayStep5566 Cleaved Meiotic Holliday Junction Reactome DB_ID: 913201 Reactome Database ID Release 43913201 Reactome, http://www.reactome.org ReactomeREACT_27914 has a Stoichiometric coefficient of 1 MutL gamma MLH1:MLH3 Heterodimer Reactome DB_ID: 914134 Reactome Database ID Release 43914134 Reactome, http://www.reactome.org ReactomeREACT_27457 has a Stoichiometric coefficient of 1 Insulin receptor Reactome DB_ID: 74675 Reactome Database ID Release 4374675 Reactome, http://www.reactome.org ReactomeREACT_5691 has a Stoichiometric coefficient of 2 HOP2(TBPIP):MND1 Complex Reactome DB_ID: 913509 Reactome Database ID Release 43913509 Reactome, http://www.reactome.org ReactomeREACT_27766 has a Stoichiometric coefficient of 1 Meiotic D-loop Complex Reactome DB_ID: 912484 Reactome Database ID Release 43912484 Reactome, http://www.reactome.org ReactomeREACT_27539 has a Stoichiometric coefficient of 1 MSH4:MSH5 Heterodimer Reactome DB_ID: 914109 Reactome Database ID Release 43914109 Reactome, http://www.reactome.org ReactomeREACT_27543 has a Stoichiometric coefficient of 1 Meiotic Holliday Junction Reactome DB_ID: 912428 Reactome Database ID Release 43912428 Reactome, http://www.reactome.org ReactomeREACT_27566 has a Stoichiometric coefficient of 1 SPO11 Covalently Attached to Oligonucleotide Reactome DB_ID: 912381 Reactome Database ID Release 43912381 Reactome, http://www.reactome.org ReactomeREACT_27423 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 SPO11 Covalently Attached to Double-strand Break Reactome DB_ID: 912365 Reactome Database ID Release 43912365 Reactome, http://www.reactome.org ReactomeREACT_27482 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Meiotic Single-stranded DNA Complex Reactome DB_ID: 912507 Reactome Database ID Release 43912507 Reactome, http://www.reactome.org ReactomeREACT_27879 has a Stoichiometric coefficient of 1 PathwayStep3419 MRN:CtIP Complex MRE11:RAD50:NBS1:CtIP Complex MRE11:RAD50:NBS1:RBBP8 Complex Reactome DB_ID: 981776 Reactome Database ID Release 43981776 Reactome, http://www.reactome.org ReactomeREACT_27850 has a Stoichiometric coefficient of 1 PathwayStep5557 PathwayStep3418 PathwayStep5556 PathwayStep3417 PathwayStep5559 PathwayStep3416 PathwayStep5558 PathwayStep3415 PathwayStep3414 PathwayStep3413 PathwayStep3412 PathwayStep3411 PathwayStep5572 PathwayStep5573 PathwayStep3430 PathwayStep5570 PathwayStep3431 PathwayStep5571 PathwayStep3432 PathwayStep5576 PathwayStep5577 PathwayStep5574 PathwayStep5575 Activated PI3K Converted from EntitySet in Reactome Reactome DB_ID: 188019 Reactome Database ID Release 43188019 Reactome, http://www.reactome.org ReactomeREACT_9165 activated TLR9:PI3K class III Reactome DB_ID: 188017 Reactome Database ID Release 43188017 Reactome, http://www.reactome.org ReactomeREACT_9357 has a Stoichiometric coefficient of 1 phospho-IRS:activated insulin receptor Reactome DB_ID: 74695 Reactome Database ID Release 4374695 Reactome, http://www.reactome.org ReactomeREACT_4013 has a Stoichiometric coefficient of 1 phospho-IRS:PI3K Reactome DB_ID: 74694 Reactome Database ID Release 4374694 Reactome, http://www.reactome.org ReactomeREACT_3175 has a Stoichiometric coefficient of 1 IRS:activated insulin receptor Reactome DB_ID: 74699 Reactome Database ID Release 4374699 Reactome, http://www.reactome.org ReactomeREACT_3393 has a Stoichiometric coefficient of 1 GRB2:SOS:Phospho-SHC Reactome DB_ID: 109798 Reactome Database ID Release 43109798 Reactome, http://www.reactome.org ReactomeREACT_2380 has a Stoichiometric coefficient of 1 phospho-SHC: activated insulin receptor Reactome DB_ID: 74685 Reactome Database ID Release 4374685 Reactome, http://www.reactome.org ReactomeREACT_4738 has a Stoichiometric coefficient of 1 SHC:activated insulin receptor Reactome DB_ID: 74681 Reactome Database ID Release 4374681 Reactome, http://www.reactome.org ReactomeREACT_3791 has a Stoichiometric coefficient of 1 phospho-insulin receptor Reactome DB_ID: 74671 Reactome Database ID Release 4374671 Reactome, http://www.reactome.org ReactomeREACT_4536 has a Stoichiometric coefficient of 2 Aminoacyl-tRNA Converted from EntitySet in Reactome Reactome DB_ID: 37001 Reactome Database ID Release 4337001 Reactome, http://www.reactome.org ReactomeREACT_4792 activated insulin receptor Reactome DB_ID: 74678 Reactome Database ID Release 4374678 Reactome, http://www.reactome.org ReactomeREACT_3057 has a Stoichiometric coefficient of 1 insulin:insulin receptor Reactome DB_ID: 74703 Reactome Database ID Release 4374703 Reactome, http://www.reactome.org ReactomeREACT_3518 has a Stoichiometric coefficient of 1 PathwayStep3427 PathwayStep5569 PathwayStep3426 PathwayStep5568 PathwayStep3429 PathwayStep5567 PathwayStep3428 PathwayStep3423 PathwayStep3422 PathwayStep3425 PathwayStep3424 PathwayStep5542 Sia-Gal-GlcNAc-NOTCH1 FRINGE-modified NOTCH1 Reactome DB_ID: 1911513 Reactome Database ID Release 431911513 Reactome, http://www.reactome.org ReactomeREACT_120236 has a Stoichiometric coefficient of 1 PathwayStep5541 Sia-Gal-GlcNAc-NOTCH Converted from EntitySet in Reactome FRINGE-modified NOTCH Reactome DB_ID: 1911547 Reactome Database ID Release 431911547 Reactome, http://www.reactome.org ReactomeREACT_118888 PathwayStep5544 Sia-Gal-GlcNAc-NOTCH3 FRINGE-modified NOTCH3 Reactome DB_ID: 1911525 Reactome Database ID Release 431911525 Reactome, http://www.reactome.org ReactomeREACT_120139 has a Stoichiometric coefficient of 1 PathwayStep5543 Sia-Gal-GlcNAc-NOTCH2 FRINGE-modified NOTCH2 Reactome DB_ID: 1911529 Reactome Database ID Release 431911529 Reactome, http://www.reactome.org ReactomeREACT_119198 has a Stoichiometric coefficient of 1 NOTCH Converted from EntitySet in Reactome NTM:NEC heterodimer Reactome DB_ID: 1911474 Reactome Database ID Release 431911474 Reactome, http://www.reactome.org ReactomeREACT_119110 Sia-Gal-GlcNAc-NOTCH4 FRINGE-modified NOTCH4 Reactome DB_ID: 1911530 Reactome Database ID Release 431911530 Reactome, http://www.reactome.org ReactomeREACT_119273 has a Stoichiometric coefficient of 1 PathwayStep5540 Sia-Gal-GlcNAc-NOTCH2 Fringe-modified NOTCH2 Reactome DB_ID: 1911528 Reactome Database ID Release 431911528 Reactome, http://www.reactome.org ReactomeREACT_119411 has a Stoichiometric coefficient of 1 Sia-Gal-GlcNAc-NOTCH Converted from EntitySet in Reactome Fringe-modified NOTCH Reactome DB_ID: 1911550 Reactome Database ID Release 431911550 Reactome, http://www.reactome.org ReactomeREACT_120243 PathwayStep5538 PathwayStep5539 PathwayStep5534 PathwayStep5535 PathwayStep5536 NOTCH3 NTM3:NEC3 heterodimer Reactome DB_ID: 157061 Reactome Database ID Release 43157061 Reactome, http://www.reactome.org ReactomeREACT_5620 has a Stoichiometric coefficient of 1 PathwayStep5537 NOTCH4 NTM4:NEC4 heterodimer Reactome DB_ID: 157054 Reactome Database ID Release 43157054 Reactome, http://www.reactome.org ReactomeREACT_4796 has a Stoichiometric coefficient of 1 NOTCH2 NTM2:NEC2 heterodimer Reactome DB_ID: 157037 Reactome Database ID Release 43157037 Reactome, http://www.reactome.org ReactomeREACT_5420 has a Stoichiometric coefficient of 1 SPO11 Dimer Reactome DB_ID: 912393 Reactome Database ID Release 43912393 Reactome, http://www.reactome.org ReactomeREACT_27627 has a Stoichiometric coefficient of 2 Nucleosome with Histone H3 Trimethylated at Lysine-4 Reactome DB_ID: 1214169 Reactome Database ID Release 431214169 Reactome, http://www.reactome.org ReactomeREACT_27602 has a Stoichiometric coefficient of 2 PathwayStep5555 miR-302A Nonendonucleolytic RISC Reactome DB_ID: 1852593 Reactome Database ID Release 431852593 Reactome, http://www.reactome.org ReactomeREACT_120206 has a Stoichiometric coefficient of 1 PathwayStep5554 miR-302A Endonucleolytic Minimal RISC Argonaute2: miR-302A (single-stranded) Reactome DB_ID: 1852595 Reactome Database ID Release 431852595 Reactome, http://www.reactome.org ReactomeREACT_118906 has a Stoichiometric coefficient of 1 PathwayStep5553 miR-302A Endonucleolytic RISC Reactome DB_ID: 1852597 Reactome Database ID Release 431852597 Reactome, http://www.reactome.org ReactomeREACT_119058 has a Stoichiometric coefficient of 1 PathwayStep5552 miR-302A RISC Converted from EntitySet in Reactome Reactome DB_ID: 1852598 Reactome Database ID Release 431852598 Reactome, http://www.reactome.org ReactomeREACT_120131 miR-302A-induced Silencing Complex PathwayStep5551 NOTCH1 NTM1:NEC1 heterodimer Reactome DB_ID: 157091 Reactome Database ID Release 43157091 Reactome, http://www.reactome.org ReactomeREACT_5481 has a Stoichiometric coefficient of 1 PathwayStep5550 NOTCH Converted from EntitySet in Reactome NTM:NEC heterodimer Reactome DB_ID: 1911472 Reactome Database ID Release 431911472 Reactome, http://www.reactome.org ReactomeREACT_119526 PathwayStep3410 NOTCH4 mRNA:miR-302A RISC Reactome DB_ID: 1911500 Reactome Database ID Release 431911500 Reactome, http://www.reactome.org ReactomeREACT_118905 has a Stoichiometric coefficient of 1 Argonaute1/3/4: miR-302A Reactome DB_ID: 1852594 Reactome Database ID Release 431852594 Reactome, http://www.reactome.org ReactomeREACT_119694 has a Stoichiometric coefficient of 1 miR-302A Nonendonucleolytic Minimal RISC PathwayStep3400 PathwayStep3401 PathwayStep5549 PathwayStep3402 PathwayStep3403 PathwayStep5547 PathwayStep3404 PathwayStep5548 PathwayStep3405 NOTCH4 mRNA:miR-181C RISC Reactome DB_ID: 1911502 Reactome Database ID Release 431911502 Reactome, http://www.reactome.org ReactomeREACT_119872 has a Stoichiometric coefficient of 1 PathwayStep5545 PathwayStep3406 PathwayStep5546 PathwayStep3407 PathwayStep3408 PathwayStep3409 Argonaute1/3/4: miR-181C Reactome DB_ID: 1852602 Reactome Database ID Release 431852602 Reactome, http://www.reactome.org ReactomeREACT_120224 has a Stoichiometric coefficient of 1 miR-181C Nonendonucleolytic Minimal RISC miR-181C Nonendonucleolytic RISC Reactome DB_ID: 1852606 Reactome Database ID Release 431852606 Reactome, http://www.reactome.org ReactomeREACT_119005 has a Stoichiometric coefficient of 1 miR-181C RISC Converted from EntitySet in Reactome Reactome DB_ID: 1852604 Reactome Database ID Release 431852604 Reactome, http://www.reactome.org ReactomeREACT_119531 miR-181C-induced Silencing Complex NOTCH3 mRNA:miR-206 RISC Reactome DB_ID: 1911498 Reactome Database ID Release 431911498 Reactome, http://www.reactome.org ReactomeREACT_120083 has a Stoichiometric coefficient of 1 miR-181C Endonucleolytic Minimal RISC Argonaute2: miR-181C (single-stranded) Reactome DB_ID: 1852601 Reactome Database ID Release 431852601 Reactome, http://www.reactome.org ReactomeREACT_119080 has a Stoichiometric coefficient of 1 miR-181C Endonucleolytic RISC Reactome DB_ID: 1852605 Reactome Database ID Release 431852605 Reactome, http://www.reactome.org ReactomeREACT_119972 has a Stoichiometric coefficient of 1 PathwayStep5520 miR-206 Endonucleolytic Minimal RISC Argonaute2: miR-206 (single-stranded) Reactome DB_ID: 1614233 Reactome Database ID Release 431614233 Reactome, http://www.reactome.org ReactomeREACT_119622 has a Stoichiometric coefficient of 1 miR-206 Endonucleolytic RISC Reactome DB_ID: 1614241 Reactome Database ID Release 431614241 Reactome, http://www.reactome.org ReactomeREACT_119736 has a Stoichiometric coefficient of 1 PathwayStep5522 Argonaute1/3/4: miR-206 Reactome DB_ID: 1614239 Reactome Database ID Release 431614239 Reactome, http://www.reactome.org ReactomeREACT_119410 has a Stoichiometric coefficient of 1 miR-206 Nonendonucleolytic Minimal RISC PathwayStep5521 miR-206 Nonendonucleolytic RISC Reactome DB_ID: 1614230 Reactome Database ID Release 431614230 Reactome, http://www.reactome.org ReactomeREACT_119735 has a Stoichiometric coefficient of 1 PathwayStep5512 PathwayStep5513 PathwayStep5514 PathwayStep5515 PathwayStep5516 PathwayStep5517 PathwayStep5518 PathwayStep5519 miR-206 RISC Converted from EntitySet in Reactome Reactome DB_ID: 1614243 Reactome Database ID Release 431614243 Reactome, http://www.reactome.org ReactomeREACT_120082 miR-206-induced Silencing Complex NOTCH3 mRNA:miR-150 RISC Reactome DB_ID: 1911497 Reactome Database ID Release 431911497 Reactome, http://www.reactome.org ReactomeREACT_119485 has a Stoichiometric coefficient of 1 Argonaute1/3/4: miR-150 Reactome DB_ID: 1852614 Reactome Database ID Release 431852614 Reactome, http://www.reactome.org ReactomeREACT_120205 has a Stoichiometric coefficient of 1 miR-150 Nonendonucleolytic Minimal RISC miR-150 Nonendonucleolytic RISC Reactome DB_ID: 1852611 Reactome Database ID Release 431852611 Reactome, http://www.reactome.org ReactomeREACT_118913 has a Stoichiometric coefficient of 1 miR-150 Endonucleolytic Minimal RISC Argonaute2: miR-150 (single-stranded) Reactome DB_ID: 1852610 Reactome Database ID Release 431852610 Reactome, http://www.reactome.org ReactomeREACT_119602 has a Stoichiometric coefficient of 1 miR-150 Endonucleolytic RISC Reactome DB_ID: 1852609 Reactome Database ID Release 431852609 Reactome, http://www.reactome.org ReactomeREACT_119118 has a Stoichiometric coefficient of 1 miR-150 RISC Converted from EntitySet in Reactome Reactome DB_ID: 1852612 Reactome Database ID Release 431852612 Reactome, http://www.reactome.org ReactomeREACT_119440 miR-150-induced Silencing Complex PathwayStep5533 NOTCH2 mRNA:miR-34 RISC Reactome DB_ID: 1911490 Reactome Database ID Release 431911490 Reactome, http://www.reactome.org ReactomeREACT_120101 has a Stoichiometric coefficient of 1 PathwayStep5532 NOTCH1 mRNA:miR-449 RISC Reactome DB_ID: 1606562 Reactome Database ID Release 431606562 Reactome, http://www.reactome.org ReactomeREACT_119337 has a Stoichiometric coefficient of 1 PathwayStep5531 Argonaute1/3/4: miR-449 Reactome DB_ID: 1606553 Reactome Database ID Release 431606553 Reactome, http://www.reactome.org ReactomeREACT_120222 has a Stoichiometric coefficient of 1 miR-449 Nonendonucleolytic Minimal RISC PathwayStep5530 PathwayStep5525 PathwayStep5526 PathwayStep5523 PathwayStep5524 PathwayStep5529 PathwayStep5527 PathwayStep5528 Ac-Cohesin:PDS5:WAPAL:Centromere Reactome DB_ID: 2473149 Reactome Database ID Release 432473149 Reactome, http://www.reactome.org ReactomeREACT_152186 has a Stoichiometric coefficient of 1 Sister Chromosomal Arms:Ac-Cohesin:PDS5:CDCA5:WAPAL Reactome DB_ID: 1638802 Reactome Database ID Release 431638802 Reactome, http://www.reactome.org ReactomeREACT_150576 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Ac-Cohesin:PDS5:CDCA5:WAPAL Ac-Cohesin:PDS5:Sororin:WAPAL Reactome DB_ID: 2468165 Reactome Database ID Release 432468165 Reactome, http://www.reactome.org ReactomeREACT_150483 has a Stoichiometric coefficient of 1 Ac-Cohesin Complex Reactome DB_ID: 1638788 Reactome Database ID Release 431638788 Reactome, http://www.reactome.org ReactomeREACT_151419 has a Stoichiometric coefficient of 1 Sister Centromeres:Ac-Cohesin:PDS5:CDCA5:WAPAL Reactome DB_ID: 1638799 Reactome Database ID Release 431638799 Reactome, http://www.reactome.org ReactomeREACT_151874 has a Stoichiometric coefficient of 1 Centromere:Ac-Cohesin:PDS5:CDCA5:WAPAL Reactome DB_ID: 2473148 Reactome Database ID Release 432473148 Reactome, http://www.reactome.org ReactomeREACT_151335 has a Stoichiometric coefficient of 1 Ac-Cohesin:PDS5:CDCA5:WAPAL Ac-Cohesin:PDS5:Sororin:WAPAL Reactome DB_ID: 2574847 Reactome Database ID Release 432574847 Reactome, http://www.reactome.org ReactomeREACT_152022 has a Stoichiometric coefficient of 1 Ac-Cohesin Complex Acetylated Cohesin Complex Reactome DB_ID: 2466014 Reactome Database ID Release 432466014 Reactome, http://www.reactome.org ReactomeREACT_151065 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdk2(Thr160):E2F1/E2F3 complex Reactome DB_ID: 187932 Reactome Database ID Release 43187932 Reactome, http://www.reactome.org ReactomeREACT_9177 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdk2(Thr160):phospho-E2F1/E2F2 complex Reactome DB_ID: 187944 Reactome Database ID Release 43187944 Reactome, http://www.reactome.org ReactomeREACT_9267 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdc2(Thr 14) Reactome DB_ID: 170090 Reactome Database ID Release 43170090 Reactome, http://www.reactome.org ReactomeREACT_6613 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdc2(Thr 14, Thr 161) Reactome DB_ID: 170092 Reactome Database ID Release 43170092 Reactome, http://www.reactome.org ReactomeREACT_6673 has a Stoichiometric coefficient of 1 Cyclin A:Cdc2 Reactome DB_ID: 170091 Reactome Database ID Release 43170091 Reactome, http://www.reactome.org ReactomeREACT_6461 has a Stoichiometric coefficient of 1 phospho-Cdc2(Thr 14):Cyclin A Reactome DB_ID: 170085 Reactome Database ID Release 43170085 Reactome, http://www.reactome.org ReactomeREACT_6681 has a Stoichiometric coefficient of 1 Cyclin A1:phospho-Cdc2(Thr161) Reactome DB_ID: 68892 Reactome Database ID Release 4368892 Reactome, http://www.reactome.org ReactomeREACT_4408 has a Stoichiometric coefficient of 1 Cyclin A2:phospho-Cdc2(Thr 161) Reactome DB_ID: 68906 Reactome Database ID Release 4368906 Reactome, http://www.reactome.org ReactomeREACT_4651 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdc2(Thr 161, Thr 14, Tyr 15) Reactome DB_ID: 170147 Reactome Database ID Release 43170147 Reactome, http://www.reactome.org ReactomeREACT_6620 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdc2(Thr 161) Reactome DB_ID: 170146 Reactome Database ID Release 43170146 Reactome, http://www.reactome.org ReactomeREACT_6644 has a Stoichiometric coefficient of 1 cytoplasmic Cyclin B1:Cdc2 complexes Converted from EntitySet in Reactome Reactome DB_ID: 170079 Reactome Database ID Release 43170079 Reactome, http://www.reactome.org ReactomeREACT_6372 Cyclin B1:phospho-Cdc2 ( Thr 14) Reactome DB_ID: 170048 Reactome Database ID Release 43170048 Reactome, http://www.reactome.org ReactomeREACT_6406 has a Stoichiometric coefficient of 1 FRS2 binds to active TrkA receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 FRS2 binds to TRKA through the same motif (NPXY) around the TRKA phospho-tyrosine residue Y496 to which SHC proteins bind. The competition between SHC proteins and FRS2 for binding to NGF-activated TRKA may provide a novel mechanism by which proliferation and differentiation may be regulated in response to neurotrophin stimulation. Tyrosine phosphorylation of FRS2 occurs within 2 min of NGF stimulation. Pubmed10629055 Reactome Database ID Release 43170964 Reactome, http://www.reactome.org ReactomeREACT_12010 Reviewed: Greene, LA, 2007-11-08 15:39:37 RIT/RIN-GTP binds B-RAF Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Once activated by RIT or RIN, B-RAF activates, through MEK, the p38 MAP kinase. Whereas RIN appears to activate p38 (specifically the p38-alpha isoform) but not the ERKs, RIN was described to activate ERK1/ ERK2 as well, although to a much lower extent than p38. RIN signaling gives rise to sustained activation of p38 MAP kinase. Reactome Database ID Release 43187698 Reactome, http://www.reactome.org ReactomeREACT_12000 Reviewed: Greene, LA, 2007-11-08 15:39:37 p-FRS2 binds CRKL Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Besides CRK, FRS2 also binds GRB2, the cyclin-dependent kinase substrate p13(SUC1), and the SH3 domain of SRC. There is also evidence for a C3G/CRK/SHP2/GAB2 complex, which is trafficked to the endosome, where C3G interacts with RAP1, triggering sustained RAP1 activation and prolonged B-RAF/MEK1/MAPK signalling. Crk-L is the predominant CRK isoform that interacts with C3G in several cell types; it is abundant in PC12 cells. PC12 cells also express high levels of Crk-II and low, but detectable, levels of Crk-I. Activation of Elk-1 by NGF was potently increased by cotransfection of exogenous Crk-II and Crk-L, but only weakly by Crk-I. In the absence of NGF, the expression of CRK isoforms activated Elk-1 minimally. Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43170975 Reactome, http://www.reactome.org ReactomeREACT_12023 Reviewed: Greene, LA, 2007-11-08 15:39:37 FRS2 is phosphorylated by active TrkA receptor Activated TrkA induces the tyrosine phosphorylation of the lipid-anchored docking protein, FRS2. FRS2 is an adapter protein that links NGF receptors to downstream signaling pathways. It is involved in the activation of MAP kinases. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.10.1 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed9182757 Reactome Database ID Release 43170977 Reactome, http://www.reactome.org ReactomeREACT_12063 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 6 (Frs2)C3G stimulates nucleotide exchange on Rap1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Rap1 is a small G protein, necessary for prolonged ERK activity in PC12 cells. In such cells, NGF triggers a program of neuronal differentiation through the activation of a Rap1:B-RAF:ERK module Rap1 is activated by NGF, but not by epidermal growth factor (EGF), although both growth factors cause transient activation of RAS. Activation of Rap1 by NGF requires internalization of TRKA to intracellular vesicles, mostly endosomes, containing Rap1, B-RAF, MEK and ERKs. Rap1 does not co-localize with RAS. Therefore, the ability of Rap1 to bind RAF-1 without activating it might sequester RAF-1 from RAS. Activation of GEFs that couple to Rap1 as well as RAS might provide a mechanism to limit signals to RAS. Reactome Database ID Release 43170979 Reactome, http://www.reactome.org ReactomeREACT_12083 Reviewed: Greene, LA, 2007-11-08 15:39:37 Phospho-Frs2:CrkL engages C3G Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 C3G is a guanine nucleotide exchange factor for Rap1, which is recruited by Crk adaptor proteins. Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed7806500 Reactome Database ID Release 43170978 Reactome, http://www.reactome.org ReactomeREACT_12015 Reviewed: Greene, LA, 2007-11-08 15:39:37 ARMS:Crk complex binds to active TrkA receptor Ankyrin-Rich Membrane Spanning protein (ARMS or Kidins220) is a specific target of Trk receptor tyrosine phosphorylation. The ARMS/Kidins220:Crk complex is an upstream component of the C3G-Rap1-MAP kinase cascade and is SH3 dependent. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43169891 Reactome, http://www.reactome.org ReactomeREACT_11996 Reviewed: Greene, LA, 2007-11-08 15:39:37 (Frs2)Rap1-GTP binds to and activates B-Raf Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Rap1 binds to B-RAF; as a consequence, B-RAF is recruited to endosomes. The binding event of Rap1 to B-RAF is thought to be very similar to the binding of RAS to RAF-1. In neuronal cells that express B-Raf, NGF induced activation of Rap1 promotes a sustained activation of ERKs and is required for the induction of electrical excitability and a subset of neuron-specific genes. As regards morphological differentiation (e. g. neurite outgrowth in PC12 cells), things are more complex. The transient activation of ERKs via RAS is not sufficient for neurite outgrowth in the absence of additional signals. On the contrary, constitutive activation of Rap1 is sufficient to trigger neurite outgrowth, but it is not necessary for this response.<br>Clearly, morphological differentiation of PC12 cells involves the activation of multiple pathways by NGF. Rap1 activates B-Raf, but inhibits RAF-1. Consequently, Rap1 could have two opposing functions: to limit ERK activation in B-RAF-negative cells and to increase ERK activation in B-Raf-positive cells. Reactome Database ID Release 43170965 Reactome, http://www.reactome.org ReactomeREACT_12050 Reviewed: Greene, LA, 2007-11-08 15:39:37 ARMS is phosphorylated by active TrkA receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.10.1 Edited: Jassal, B, 2006-10-10 09:20:18 Phosphorylation of ARMS by Trk receptor (on tyrosine 1096) enables ARMS to recruit Crk via it's SH2 domain and freeing the SH3 domain. The SH3 domain of Crk is then free to bind C3G for MAP kinase activation. Pubmed16284401 Reactome Database ID Release 43169905 Reactome, http://www.reactome.org ReactomeREACT_12066 Reviewed: Greene, LA, 2007-11-08 15:39:37 phospho-cyclin B1(CRS):phosph-Cdc2(Thr 161) Reactome DB_ID: 170047 Reactome Database ID Release 43170047 Reactome, http://www.reactome.org ReactomeREACT_6436 has a Stoichiometric coefficient of 1 Crk's SH3 domain engages C3G Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 C3G is a guanine nucleotide exchange factor for Rap1, which is recruited by Crk adaptor proteins. Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed16284401 Reactome Database ID Release 43169895 Reactome, http://www.reactome.org ReactomeREACT_11995 Reviewed: Greene, LA, 2007-11-08 15:39:37 nuclear Cyclin B1:Cdc2 complexes Converted from EntitySet in Reactome Reactome DB_ID: 170051 Reactome Database ID Release 43170051 Reactome, http://www.reactome.org ReactomeREACT_6641 nuclear Cyclin B1:phospho-Cdc2 ( Thr 14) complexes Reactome DB_ID: 170056 Reactome Database ID Release 43170056 Reactome, http://www.reactome.org ReactomeREACT_6390 has a Stoichiometric coefficient of 1 phospho-Cyclin B1:phospho-Cdc2(Thr 161) Reactome DB_ID: 170081 Reactome Database ID Release 43170081 Reactome, http://www.reactome.org ReactomeREACT_6510 has a Stoichiometric coefficient of 1 Cyclin B1:phospho-Cdc2(Thr 161, Thr 14, Tyr 15) Reactome DB_ID: 170068 Reactome Database ID Release 43170068 Reactome, http://www.reactome.org ReactomeREACT_6566 has a Stoichiometric coefficient of 1 Cyclin B2:phospho-Cdc2(Thr 14, Thr 161) Reactome DB_ID: 170152 Reactome Database ID Release 43170152 Reactome, http://www.reactome.org ReactomeREACT_6445 has a Stoichiometric coefficient of 1 Cyclin B1:phospho-Cdc2(Thr 161) Reactome DB_ID: 157456 Reactome Database ID Release 43157456 Reactome, http://www.reactome.org ReactomeREACT_3166 has a Stoichiometric coefficient of 1 Phospho-Cyclin B1 (CRS):phospho-Cdc2(Thr 161) Reactome DB_ID: 170121 Reactome Database ID Release 43170121 Reactome, http://www.reactome.org ReactomeREACT_6578 has a Stoichiometric coefficient of 1 phospho-Cyclin B1(CRS):phospho-Cdc2 (Thr 161) Reactome DB_ID: 170127 Reactome Database ID Release 43170127 Reactome, http://www.reactome.org ReactomeREACT_6646 has a Stoichiometric coefficient of 1 active nuclear Cyclin B1:Cdc2 complexes Converted from EntitySet in Reactome Reactome DB_ID: 170168 Reactome Database ID Release 43170168 Reactome, http://www.reactome.org ReactomeREACT_6519 Phospho-Shc dissociates from the TrkA receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Once Shc is phosphorylated, it dissociates from the receptor. Reactome Database ID Release 43167217 Reactome, http://www.reactome.org ReactomeREACT_12019 Reviewed: Greene, LA, 2007-11-08 15:39:37 TAT protein Converted from EntitySet in Reactome Reactome DB_ID: 175673 Reactome Database ID Release 43175673 Reactome, http://www.reactome.org ReactomeREACT_7504 SHC, complexed with TrkA, is tyrosine-phosphorylated Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.10.1 Edited: Jassal, B, 2006-10-10 09:20:18 Phosphorylation of Shc adapter proteins, and the concomitant recruitment of GRB2/SOS, results in the RAS-dependent, transient activation of ERKs, which is correlated with mitogenic and proliferative cell signalling. Prolonged activation of ERKs is instead regulated by a parallel pathway, involving CRK/C3G-dependent activation of the RAS-like GTPase RAP-1, and takes place in early endosomes. Reactome Database ID Release 43167019 Reactome, http://www.reactome.org ReactomeREACT_12003 Reviewed: Greene, LA, 2007-11-08 15:39:37 SHC binds to the activated TrkA receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43167056 Reactome, http://www.reactome.org ReactomeREACT_12017 Reviewed: Greene, LA, 2007-11-08 15:39:37 SHC proteins (SHC 1, 2, 3) are signalling adapters, able to interact with phosphorylated Y496 of TRKA. SHC2 and SHC3 appear to be the primary SHC adaptor proteins in neurons as they are expressed in both the developing and adult nervous system. SHC1 is expressed embryonically but not in the adult brain, whereas SHC3 expression is lower in the embryonic brain and increases post-natally. Pi-Y496 of TrkA can also be bound by FRS2. The competitive binding between Frs2 and SHC at this phospho-tyrosine residue contributes to a cellular switch between cell cycle progression (SHC recruitment) and cell cycle arrest/differentiation (Frs2 recruitment). Binding and activation of MAP Kinase Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.10 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43171011 Reactome, http://www.reactome.org ReactomeREACT_12016 Reviewed: Greene, LA, 2007-11-08 15:39:37 The NGF activation of p38 MAP kinase is transient, being maximal at 10 min and declining to near control levels by 30 min. T180 and Y182 are two sites that become newly phosphorylated as p38 MAPK becomes activated. has a Stoichiometric coefficient of 2 Activation of SRC by RAL-GTP Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.10 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43170991 Reactome, http://www.reactome.org ReactomeREACT_12030 Reviewed: Greene, LA, 2007-11-08 15:39:37 The active form of RAL, RAL-GTP, activates SRC tyrosine kinase. Guanine nucleotide exchange on RAL Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43171026 Reactome, http://www.reactome.org ReactomeREACT_12041 Reviewed: Greene, LA, 2007-11-08 15:39:37 The Ras-related protein, RAL becomes activated once GDP is replaced by GTP. Ral-GDS binds to Ras-GTP Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Besides the RAF kinase, RAS can activate several ral guanine nucleotide dissociation stimulators (RALGDSs). Binding of RALGDS with RAS competes with RAF binding to RAS. Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed7972015 Reactome Database ID Release 43170986 Reactome, http://www.reactome.org ReactomeREACT_12001 Reviewed: Greene, LA, 2007-11-08 15:39:37 PSIP1 Converted from EntitySet in Reactome Reactome DB_ID: 180114 Reactome Database ID Release 43180114 Reactome, http://www.reactome.org ReactomeREACT_8576 RIT/RIN are activated Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 RIT and RIN are activated by neurotrophins through unknown exchange factors. Activation reaches a maximal level between 5 and 15 min after NGF stimulation and remains elevated for at least 2 h. RIN, which is neuron-specific, might function as a component of a neuron specific B-RAF signalosome complex, in which RIN provides spatial and/or substrate specificity to the B-RAF-MEK kinase cascade to direct stimulation of p38 signaling. Reactome Database ID Release 43187746 Reactome, http://www.reactome.org ReactomeREACT_12071 Reviewed: Greene, LA, 2007-11-08 15:39:37 NuMA homodimer Reactome DB_ID: 380486 Reactome Database ID Release 43380486 Reactome, http://www.reactome.org ReactomeREACT_15940 has a Stoichiometric coefficient of 2 centrosome-nucleated microtubules Reactome DB_ID: 379273 Reactome Database ID Release 43379273 Reactome, http://www.reactome.org ReactomeREACT_16122 has a Stoichiometric coefficient of 1 MAP kinase activates MAPKAPK2, MAPKAPK3 and MSK1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed8846784 Reactome Database ID Release 43187688 Reactome, http://www.reactome.org ReactomeREACT_12032 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 2 p38 MAPK is known to activate the Ser/Thr protein kinase MAPKAP kinase 2 and a closely related kinase, MAPKAP kinase 3, through phosphorylation at multiple sites. According to some authors, NGF does not induce any significant activation of MAPKAPK2 activity in PC12 cells. Potential p38 signaling effectors include transcription factors, such as cAMP-response element-binding protein and MEF2, cytoskeleton modulators, and a number of protein kinases. After activation, MAPKAP kinase 2 and 3 move to the nucleus. Centrosomes containing recruited CDK11p58 Reactome DB_ID: 380453 Reactome Database ID Release 43380453 Reactome, http://www.reactome.org ReactomeREACT_17657 has a Stoichiometric coefficient of 1 TRKA recruits RIT and RIN Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43187697 Reactome, http://www.reactome.org ReactomeREACT_12036 Reviewed: Greene, LA, 2007-11-08 15:39:37 TrkA can bind the Ras subfamly members RIT and RIN. Centrosome associated Plk1 Reactome DB_ID: 380288 Reactome Database ID Release 43380288 Reactome, http://www.reactome.org ReactomeREACT_18209 has a Stoichiometric coefficient of 1 HMG1/Y Converted from EntitySet in Reactome Reactome DB_ID: 174979 Reactome Database ID Release 43174979 Reactome, http://www.reactome.org ReactomeREACT_8214 Cyclin B2:phospho-Cdc2(Thr 161) Reactome DB_ID: 68898 Reactome Database ID Release 4368898 Reactome, http://www.reactome.org ReactomeREACT_4066 has a Stoichiometric coefficient of 1 centrosome Reactome DB_ID: 380268 Reactome Database ID Release 43380268 Reactome, http://www.reactome.org ReactomeREACT_15979 has a Stoichiometric coefficient of 1 centrosome-associated NuMA Reactome DB_ID: 380503 Reactome Database ID Release 43380503 Reactome, http://www.reactome.org ReactomeREACT_15920 has a Stoichiometric coefficient of 1 NuMA-bound microtubules Reactome DB_ID: 380495 Reactome Database ID Release 43380495 Reactome, http://www.reactome.org ReactomeREACT_18043 has a Stoichiometric coefficient of 1 gamma-tubulin complex Reactome DB_ID: 379277 Reactome Database ID Release 43379277 Reactome, http://www.reactome.org ReactomeREACT_15704 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 6 gamma-TuSC Reactome DB_ID: 380447 Reactome Database ID Release 43380447 Reactome, http://www.reactome.org ReactomeREACT_15756 has a Stoichiometric coefficient of 1 p-RAB1:GTP Reactome DB_ID: 2311336 Reactome Database ID Release 432311336 Reactome, http://www.reactome.org ReactomeREACT_148082 has a Stoichiometric coefficient of 1 p-T216,S274,S373-GRASP65:p-S37-GM130:p-RAB1:GTP Reactome DB_ID: 2172185 Reactome Database ID Release 432172185 Reactome, http://www.reactome.org ReactomeREACT_148500 has a Stoichiometric coefficient of 1 p-T216,S274,S373-GORASP1:p-S37-GOLGA2:p-RAB1:GTP p-T216,S274,S373-GORASP1:p-S37-GOLGA2:p-RAB1:GTP:PLK1 Reactome DB_ID: 2172193 Reactome Database ID Release 432172193 Reactome, http://www.reactome.org ReactomeREACT_148515 has a Stoichiometric coefficient of 1 Mature centrosomes enriched in gamma-TURC complexes Reactome DB_ID: 380440 Reactome Database ID Release 43380440 Reactome, http://www.reactome.org ReactomeREACT_15605 has a Stoichiometric coefficient of 1 centrosome containing phosphorylated Nlp Reactome DB_ID: 380704 Reactome Database ID Release 43380704 Reactome, http://www.reactome.org ReactomeREACT_17093 has a Stoichiometric coefficient of 1 cNAP-1 depleted centrosome Reactome DB_ID: 380698 Reactome Database ID Release 43380698 Reactome, http://www.reactome.org ReactomeREACT_17186 has a Stoichiometric coefficient of 1 GRASP65:GM130:p115:RAB1:GTP GORASP1:GOLGA2:USO1:RAB1:GTP Reactome DB_ID: 2172177 Reactome Database ID Release 432172177 Reactome, http://www.reactome.org ReactomeREACT_148011 has a Stoichiometric coefficient of 1 Nlp-depleted centrosome Reactome DB_ID: 380705 Reactome Database ID Release 43380705 Reactome, http://www.reactome.org ReactomeREACT_18075 has a Stoichiometric coefficient of 1 USO1 homodimer Reactome DB_ID: 2311342 Reactome Database ID Release 432311342 Reactome, http://www.reactome.org ReactomeREACT_148109 has a Stoichiometric coefficient of 2 USO1 homodimer Reactome DB_ID: 2311335 Reactome Database ID Release 432311335 Reactome, http://www.reactome.org ReactomeREACT_148122 has a Stoichiometric coefficient of 2 bile salts and acids Converted from EntitySet in Reactome Reactome DB_ID: 192483 Reactome Database ID Release 43192483 Reactome, http://www.reactome.org ReactomeREACT_9533 sterols Converted from EntitySet in Reactome Reactome DB_ID: 265784 Reactome Database ID Release 43265784 Reactome, http://www.reactome.org ReactomeREACT_13962 cholesterol and phytosterols sterols Converted from EntitySet in Reactome Reactome DB_ID: 265781 Reactome Database ID Release 43265781 Reactome, http://www.reactome.org ReactomeREACT_14321 cholesterol and phytosterols Vif Converted from EntitySet in Reactome Reactome DB_ID: 173125 Reactome Database ID Release 43173125 Reactome, http://www.reactome.org ReactomeREACT_8158 Viral Infectivity Factor Interaction of Src family kinases with p-KIT Authored: Garapati, P V, 2011-07-11 Binding of SCF to KIT induces the activation and rapid increase in kinase activity of multiple Src family kinases (SFK), including Src, Lck, Tec, Fyn, and Lyn (Timokhina et al. 1998, Krystal et al. 1998, Linnekin et al. 1997, Lennartsson et al. 1999, Tang et al. 1994, Samayawardhena et al. 2007). The tyrosine residues Y568 and Y570 in KIT juxtamembrane region are involved in the association of SFKs (Price et al. 1997). <br>SFKs recruited to KIT induce proliferation and chemotaxis in primary hematopoietic progenitor cells or bone marrow derived mast cells (O'Laughlin-Bunner et al. 2001). SCF activated SFKs also mediate a critical signal for lymphocyte development (Agosti et al. 2004). Timokhina et al. demonstrated that Src kinase and PI3-kinase signalling pathways converge to activate Rac1 and JNK after SCF stimulation in BMMC, promoting cell proliferation (Timokhina et al., 1998, Reber et al. 2006 ). Edited: Garapati, P V, 2011-07-11 Pubmed16483568 Pubmed9799234 Reactome Database ID Release 43205205 Reactome, http://www.reactome.org ReactomeREACT_111251 Reviewed: Rönnstrand, L, 2011-08-22 Activation of RAC1 Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed8990121 Pubmed9799234 Reactome Database ID Release 431433415 Reactome, http://www.reactome.org ReactomeREACT_111195 Reviewed: Rönnstrand, L, 2011-08-22 Vav1, once activated by PIP3 binding and phosphorylation by Src kinases, stimulates the GDP/GTP exchange activity of Rac. Vav1 is selective for Rac and catalyses exchange of bound GDP for GTP. Phosphorylation and activation of VAV1 Authored: Garapati, P V, 2011-07-11 EC Number: 2.7.10 Edited: Garapati, P V, 2011-07-11 Pubmed12829242 Pubmed1381360 Pubmed9799234 Reactome Database ID Release 431433542 Reactome, http://www.reactome.org ReactomeREACT_111072 Reviewed: Rönnstrand, L, 2011-08-22 The Src and PI3-kinase signaling pathways converge to activate Rac1 and JNK after c-Kit activation, promoting mast cell proliferation but not for suppression of apoptosis (Timokhina et al. 1998). PI3K and Src are considered mediators of c-Kit induced Rac1 activation via the guanine nucleotide exchange factor (GEF) VAV1. Stimulation of c-Kit receptor results in rapid tyrosine phosphorylation of VAV1 (Timokhina et al. 1998). <br>VAV1 exists in an auto-inhibitory state folded in such a way as to inhibit the GEF activity of its Dbl homology domain (DH) domain. PI3K is thought to modulate the activation of VAV1 by influencing its degree of tyrosine phosphorylation and its recruitment to membrane. VAV1 is recruited to membrane by binding to PtdIns(3,4,5)P3 (PIP3) and this interaction relieves an intramolecular interaction between pleckstrin homology (PH) and DH domains, thus facilitating tyrosine phosphorylation on Y174 and so further opening of the DH/PH domains, binding of Rac-GDP and catalysis (Welch et al, 2003). In VAV1, tyrosine 174 (Y174) binds to the DH domain and inhibits its GEF activity. Src kinases phosphorylate this Y174 and this causes the tyrosine to move away from the DH domain thereby reliving the auto-inhibition. has a Stoichiometric coefficient of 3 Synthesis of PIP3 from PIP2 by PI3K Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 PI3 kinases catalyze the production of phosphatidylinositol-3, 4, 5-triphosphate (PIP3) by phosphorylating phosphatidylinositol-4, 5-bisphosphate (PIP2). PIP3 bound to the inner lipid bilayer of the plasma membrane promotes the recruitment and activation of AKT. Active AKT subsequently phosphorylates the pro-apoptotic factor Bad at Ser136 which leads to it binding 14-3-3 protein and sequestering from the anti-apoptotic molecules Bcl-XL therby reducing antiapoptotic events and promoting cell survival. The alternative route for c-Kit mediated survival is through AKT-mediated phosphorylation and incativation of the forkhead transcription factor (FoxO3a) (Engstrom et al, 2003; Lennartson et al , 2005). Pubmed11395417 Pubmed12660731 Pubmed12691919 Pubmed15526160 Pubmed16483568 Pubmed9651683 Reactome Database ID Release 431433514 Reactome, http://www.reactome.org ReactomeREACT_111081 Reviewed: Rönnstrand, L, 2011-08-22 Direct recruitment of PI3K to p-KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed11520784 Pubmed15526160 Pubmed16129412 Pubmed16483568 Reactome Database ID Release 43205262 Reactome, http://www.reactome.org ReactomeREACT_111146 Reviewed: Rönnstrand, L, 2011-08-22 The regulatory subunit (p85) of PI3K interacts directly with phosphorylated Y721 of KIT via one of its SH2 domains. This binding leads to the activation of the catalytic domain (p110) of PI3K. SCF-induced PI3K recruitment mediates AKT activation through phospholipids at the membrane and to subsequent phosphorylation of the pro-apoptotic factor Bad as well as Fox3a.<br>PI3K activation mediates SCF-induced cell proliferation, survival, differentiation, adhesion, secretion and actin cytoskeletal organization. Autophosphorylation of KIT Authored: Garapati, P V, 2011-07-11 EC Number: 2.7.10 Edited: Garapati, P V, 2011-07-11 Pubmed10377264 Pubmed12824176 Pubmed16129412 Pubmed20147452 Pubmed7509796 Pubmed9038210 Reactome Database ID Release 43205289 Reactome, http://www.reactome.org ReactomeREACT_111103 Reviewed: Rönnstrand, L, 2011-08-22 The cytoplasmic domain of KIT contains a bipartite kinase domain separated by 77 residues. The first part of the catalytic domain contains the ATP binding region while the second part contains an activation loop. Both parts of the domain have a number of possible autophosphorylation sites. In contrast to many other tyrosine kinases, autophosphorylation of the activation loop does not seem to be involved in the activation of the kinase activity nor it is required for full kinase activity (DiNitto et al. 2010). Instead, phosphorylation sites in the juxtamembrane region are important for activation of the kinase activity. The dimerized KIT acts as both enzyme and substrate for itself and autophosphorylates these specific tyrosine residues with in the kinases domains in trans as well as tyrosine residues outside the kinase domain. The resulting phosphotyrosine residues serve as docking sites for a number of signal transduction molecules containing Src-homology 2 (SH2) and phosphotyrosine-binding (PTB) domains. A majority of the autophosphorylation sites reside outside the kinase domain. has a Stoichiometric coefficient of 14 Phosphorylation of SHP2 by SFKs Authored: Garapati, P V, 2011-07-11 EC Number: 2.7.10 Edited: Garapati, P V, 2011-07-11 Following association with KIT, Tauchi et al. had observed phosphorylation of SHP2 (Tauchi et al. 1994). Tyrosine residues Y546 and Y584 (usually referred to as Y542 and Y580 in literature based on the short isoform) are the major sites of SHP2 tyrosyl phosphorylation. Src family kinases (SFKs) are candidates for this phosphorylation (Araki et al. 2003). The phosphorylated tyrosine residues on SHP2 can recruit the adapter protein GRB2 (Tauchi et al. 1994), but it is unclear whether GRB2 binding to SHP2 is important for KIT mediated SHP2 signaling or whether the effect of SHP2 on the RAS/ERK pathway goes through its catalytic activity. Pubmed12923167 Pubmed7523381 Reactome Database ID Release 431433488 Reactome, http://www.reactome.org ReactomeREACT_111152 Reviewed: Rönnstrand, L, 2011-08-22 has a Stoichiometric coefficient of 2 SHP2 interacts with p-KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed15526160 Pubmed18588518 Pubmed7523381 Pubmed9038210 Pubmed9528781 Reactome Database ID Release 43205238 Reactome, http://www.reactome.org ReactomeREACT_111049 Reviewed: Rönnstrand, L, 2011-08-22 SHP2 is a protein tyrosine phosphatase (PTP) with two NH2-terminal SH2 domains, a PTP domain, a -COOH tail with two tyrosyl phosphorylation sites at Y546 and Y584, and an interposed proline-rich domain. SHP2 binds to activated KIT on tyrosine-568 in the juxtamembrane region, which also constitutes the docking site for a number of other signal transduction molecules, such as SFKs, Csk homologous kinase (CHK), CBL, LNK and Adapter protein with PH and SH2 domains (APS) (Kozlowski et al. 1998, Price et al. 1997, Gueller et al. 2008). GRB2:SOS interacts with p-KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 GRB2 is an adapter protein with one SH2 domain and two SH3 domains. It exists in part as a preformed complex with the RAS GDP/GTP exchanger SOS. GRB2 with its SH2 domain binds directly to activated KIT on autophosphorylated sites Y703 and Y936 (Thommes et al. 1999). GRB2 can also be recruited indirectly to KIT by binding KIT downstream signal transduction molecules such as SHP 2, SHC1, GAB1 and GAB2 (Rönnstrand 2004, Linnekin 1999). GRB2:SOS complex bound to KIT then activates the small GTPase protein RAS. It should be noted that not all GRB2 interactions with KIT involves an activation of RAS, but it can also act as an adapter protein for recruiting both GAB2 (Sun et al. 2008) and CBL (Sun et al. 2007) to KIT. Pubmed10377264 Pubmed10582339 Pubmed15526160 Pubmed16129412 Pubmed17904548 Pubmed18697750 Pubmed8950973 Reactome Database ID Release 43205286 Reactome, http://www.reactome.org ReactomeREACT_111200 Reviewed: Rönnstrand, L, 2011-08-22 Phosphorylation of p-KIT on Y900 by Src kinases Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed12878163 Reactome Database ID Release 431472121 Reactome, http://www.reactome.org ReactomeREACT_111042 Reviewed: Rönnstrand, L, 2011-08-22 Src family of tyrosine kinases phosphorylate KIT on Y900 located in the second part of the tyrosine kinase domain. This phosphorylated tyrosine acts as a docking site for p85alpha regulatory subunit of PI3K and the adapter protein CRKII. CRKII does not interact directly with KIT but is recruited indirectly by binding to p85alpha subunit of PI3K. Thus, in this case the p85 subunit acts as an adapter between KIT and CRKII, and not to recruit PI3-kinase. (Lennartsson et al. 2003). has a Stoichiometric coefficient of 2 VEGF-A,C,D,E bind to VEGFR2 leading to receptor dimerization Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 Pubmed11004490 Pubmed11387210 Pubmed12881528 Pubmed1417831 Pubmed15585754 Pubmed16336962 Pubmed16835467 Pubmed7824266 Pubmed8617204 Pubmed9207067 Pubmed9435229 Reactome Database ID Release 43194310 Reactome, http://www.reactome.org ReactomeREACT_12440 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 VEGFR-2 binds VEGF-A, -C, -D, and -E homodimers. VEGFR-2 is the primary mediator of the physiological effects of VEGF-A in angiogenesis, including microvascular permeability, endothelial cell proliferation, invasion, migration, and survival. In endothelial cells, these effects are mediated via activation of a phospholipase gamma-protein kinase C-Raf-MAPK signaling pathway for proliferation and PI3K and focal adhesion kinase for survival and migration. VEGFR-2 is the important receptor among VEGFR protiens and its activation and signaling may be positively or negatively regulated by co-expression and activation of various factors and other VEGF receptors like VEGFR-1 (Hicklin and Ellis 2005).The regulatory events of this receptor will be annotated in subsequent modules. has a Stoichiometric coefficient of 2 VEGF-A,B,PLGF bind to VEGFR1 leading to receptor dimerization Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 Pubmed11387210 Pubmed12871269 Pubmed14764923 Pubmed15585754 Pubmed16336962 Pubmed2479986 Pubmed8637916 Pubmed9207067 Pubmed9722576 Reactome Database ID Release 43194311 Reactome, http://www.reactome.org ReactomeREACT_12556 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 VEGFR-1 binds VEGF-A, VEGF-B, and PLGF homodimers. This interaction is required for normal angiogenesis and hematopoiesis, although many of the detailed molecular steps from binding to these physiological consequences remain unclear (Hickins and Ellis, 2005). VEGFR-1 is made up of 1338 aa and has three regions: an extracellular region consisting of 7 immunoglobin-like domains, a transmembrane (TM) domain and a cytosolic tyrosine kinase (TK) domain. An alternatively spliced form, soluble VEGFR-1 (sVEGFR1), also binds VEGF proteins and may serve in the body to down-regulate VEGF activation of membrane-bound receptors. Overexpression of sVEGFR1 (VEGF121) is associated with preeclampsia, a major disorder of pregnancy (Shibuya and Claesson-Welsh 2006; Levine et al. 2004). has a Stoichiometric coefficient of 2 NRP-1 forms a ternary complex with VEGF165 and VEGFR1 Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 Plasma membrane-associated Neuropilin-1 (NRP1) binds vascular endothelial growth factor (VEGF) family members. NRP1 has three distinct extracellular domains, a1a2, b1b2, and c but lacks a distinct intracellular domain. VEGF165 mediates the formation of complexes containing VEGFR-2 and NRP-1, enhancing VEGF165-receptor binding on the endothelial cell membrane (Soker et al. 2002). The role of heparin, a critical component of NRP-1 interactions with VEGF proteins, will annotated in detail in future. Pubmed10842181 Pubmed11756651 Pubmed11948691 Pubmed11986311 Pubmed16763549 Reactome Database ID Release 43195408 Reactome, http://www.reactome.org ReactomeREACT_12494 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 has a Stoichiometric coefficient of 2 VEGF-C,D bind to VEGFR3 leading to receptor dimerization Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 Pubmed11532940 Pubmed12881528 Pubmed15585754 Pubmed8617204 Pubmed8700872 Pubmed9435229 Reactome Database ID Release 43194308 Reactome, http://www.reactome.org ReactomeREACT_12533 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 VEGFR-3 preferentially binds VEGF-C and -D. Mutations of the VEGFR-3 tyrosine kinase domain are seen in human lymphedema. VEGFR-3 expression has been correlated with transient lymphangiogenesis in wound healing and may modulate VEGFR-2 signaling in maintaining vascular integrity (Hicklin and Ellis 2005). has a Stoichiometric coefficient of 2 Homodimerization of VEGF proteins Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 Pubmed16633338 Pubmed16835467 Reactome Database ID Release 43195378 Reactome, http://www.reactome.org ReactomeREACT_12588 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 VEGF proteins bind their receptors as homodimers. Heterodimers with PLGF and among different VEGF proteins have been observed but have no known function. has a Stoichiometric coefficient of 2 Dimerization of KIT upon SCF binding Authored: Garapati, P V, 2011-07-11 Binding of the SCF dimer to KIT rapidly triggers KIT dimerization and autophosphorylation. It is thought that one SCF dimer binds simultaneously to two KIT monomers. The fourth Ig-like domain of KIT contains the dimerisation site; deletion of this domain completely abolishes KIT dimerisation and subsequent downstream signaling (Edling et al. 2007, Blechman et al. 1995). KIT dimerization is a crucial initial step in the SCF signal transduction process. Edited: Garapati, P V, 2011-07-11 Pubmed17255936 Pubmed17350321 Pubmed17662946 Pubmed7529140 Pubmed8636116 Pubmed9045650 Pubmed9446650 Reactome Database ID Release 43205231 Reactome, http://www.reactome.org ReactomeREACT_111210 Reviewed: Rönnstrand, L, 2011-08-22 Processing of SCF isoform 1 Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed12062105 Pubmed15526160 Pubmed17344430 Pubmed9256427 Reactome Database ID Release 431433374 Reactome, http://www.reactome.org ReactomeREACT_111098 Reviewed: Rönnstrand, L, 2011-08-22 SCF exists as two alternatively spliced variants, a soluble form and a membrane-bound form differing in one exon (exon 6). Both isoforms are initially membrane bound with an extracellular domain, a transmembrane segment and an intracellular region. The longer isoform is rapidly cleaved to generate a 165 aa soluble protein knows as sSCF. The SCF transcript that lacks exon 6 encodes a glycoprotein that remains membrane-bound (mSCF). Both mSCF and sSCF are bioactive but different in their efficacy in c-kit activation.<br>Proteases including matrix metalloprotease-9 (Heissig et al., 2002), Chymase-1 (Longley et al., 1997) and several members of the ADAMs family (Kawaguchi et al, 2007; Amour et al, 2002; Chesneau et al, 2003; Mohan et al, 2002; Roghani et al, 1999; Zou et al, 2004) have been suggested to have a role in the processing of sSCF. NRP-2 associates with VEGFR1 forming complexes on cell surface Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 NRP-2 associates with VEGFR-1 on the plasma membrane. As NRP-2 lacks an intracellular domain, this association may be the means by which NRP-2 participates in VEGF-induced signaling. This interaction requires VEGF to bridge between NRP and the receptor. Pubmed10748121 Pubmed11278319 Reactome Database ID Release 43195418 Reactome, http://www.reactome.org ReactomeREACT_12600 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 has a Stoichiometric coefficient of 2 Interaction of KIT and sSCF Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed10523834 Pubmed10884405 Pubmed12824176 Pubmed1375232 Pubmed16737840 Pubmed1714377 Pubmed17662946 Pubmed7506952 Pubmed7680037 Pubmed8636116 Pubmed8695790 Pubmed8774734 Pubmed9045650 Reactome Database ID Release 43205321 Reactome, http://www.reactome.org ReactomeREACT_111051 Reviewed: Rönnstrand, L, 2011-08-22 Two human isoforms of KIT have been identified, resulting from alternative splicing. They are characterized by the presence or absence of a tetrapeptide sequence (GNNK 510-513 aa) in the extracellular part of the juxtamembrane region and designated GNNK+ (Kit) or GNNK- (KitA) (Piao et al. 1994). The isoforms are co-expressed in most tisuues, with the GNNK- form predominating (Reith et al. 1991). No difference in ligand affinity was observed (Caruana et al. 1999). <br>KIT belongs to the type III tyrosine kinase receptor family, with five extracellular immunoglobulin (Ig)-like domains, a single transmembrane region, an inhibitory cytoplasmic juxtamembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment and a cytoplasmic tail (Mol et al. 2003). <br>Signaling by KIT occurs following SCF binding. SCF homodimers binds to the first three Ig-like domains of KIT in the regions between aa L104-D122 and R146-D153 (Mendiaz et al. 1996, Matous et al. 1996) which leads to dimerization which is further stabilized by Ig-like domains 3-4 (Yuzawa et al., 2007). Dimerization of sSCF Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed10884405 Pubmed8636116 Reactome Database ID Release 431433395 Reactome, http://www.reactome.org ReactomeREACT_111044 Reviewed: Rönnstrand, L, 2011-08-22 has a Stoichiometric coefficient of 2 sSCF exists as noncovalently associated homodimer composed of two monomers interacting head-to-head to form an elongated, slightly bent dimer. Dimerization of sSCF is a dynamic process and it may play a regulatory role in the dimerization and activation of KIT (Zhang et al, 2000; Philo et al, 1996). PKC alpha interacts with and phosphorylates KIT Authored: Garapati, P V, 2011-07-11 EC Number: 2.7.11 Edited: Garapati, P V, 2011-07-11 Protein kinase C (PKC) alpha phosphorylates and regulates the activity of several receptor tyrosine kinases including KIT. PKC alpha is involved in a negative feedback loop regulating SCF induced proliferation by phosphorylating and inhibiting the kinase activity of KIT (Blume-Jensen et al. 1994, 1995). PKC alpha phosphorylates KIT on S741 and S746 of the kinase insert (Blume-Jensen et al. 1995). This serine phosphorylation inhibits KIT kinase activity and reduces the capacity of multiple SH2 containing signaling components to associate with KIT (Linnekin 1999). Pubmed10582339 Pubmed16483568 Pubmed7520444 Pubmed7539802 Reactome Database ID Release 431433508 Reactome, http://www.reactome.org ReactomeREACT_111196 Reviewed: Rönnstrand, L, 2011-08-22 has a Stoichiometric coefficient of 2 Disassociation and translocation of STATs to the nucleus After dimerization STAT dimers release from the receptor complex and migrate to the nucleus for DNA binding. STAT5s/STAT1alpha heterodimeric complexes specifically recognize beta-casein promoter region (PIE) (Brizzi et al. 1999). c-Kit dependent JAK/STAT activation is associated with the growth and differentiation of fetal liver haematopoietic progenitor cells (Rönnstrand 2004, Reber et al. 2006). Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed10358045 Pubmed15526160 Pubmed16483568 Reactome Database ID Release 431470012 Reactome, http://www.reactome.org ReactomeREACT_111242 Reviewed: Rönnstrand, L, 2011-08-22 Dimerization of STATs Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Phosphorylation on a tyrosine residues immediately distal to the SH2 domain induces STATs homo- or heterodimerization through phosphotyrosine-SH2 interactions. Pubmed10358045 Reactome Database ID Release 431470010 Reactome, http://www.reactome.org ReactomeREACT_111182 Reviewed: Rönnstrand, L, 2011-08-22 Phosphorylation of STATs Authored: Garapati, P V, 2011-07-11 EC Number: 2.7.10 Edited: Garapati, P V, 2011-07-11 JAK2 activation results in the phosphorylation and activation of STAT1alpha, STAT3, STAT5A and STAT5B (Deberry et al. 1997, Brizzi et al. 1999, Ning et al. 2001, Ronnstrand 2004). STAT family members can be activated by JAK kinases, receptor tyrosine kinases or SFKs. LYN kinase has been identified to have role in SCF-induced phosphorylation of STAT3 (Shivakrupa & Linnekin 2005). Pubmed10358045 Pubmed15451030 Pubmed15526160 Pubmed9355737 Reactome Database ID Release 431470009 Reactome, http://www.reactome.org ReactomeREACT_111244 Reviewed: Rönnstrand, L, 2011-08-22 has a Stoichiometric coefficient of 8 Phosphorylation of APS APS bound to KIT is phosphorylated by tyrosine kinases in response to SCF stimulation (Wollberg et al, 2003). The C-terminal tyrosine 629 may be the target site of phosphorylation in APS (Wakioka et al, 1999). Authored: Garapati, P V, 2011-07-11 EC Number: 2.7.10 Edited: Garapati, P V, 2011-07-11 Pubmed10374881 Pubmed12444928 Reactome Database ID Release 431433506 Reactome, http://www.reactome.org ReactomeREACT_111112 Reviewed: Rönnstrand, L, 2011-08-22 Interaction of APS and p-KIT APS adapter protein has been identified as a KIT binding partner using yeast two-hybrid screening. APS contains a PH domain and an SH2 domain. The SH2 domain interacts with c-Kit phosphotyrosine residues Y568 and Y936 (Wollberg et al. 2003). Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed12444928 Reactome Database ID Release 43205319 Reactome, http://www.reactome.org ReactomeREACT_111199 Reviewed: Rönnstrand, L, 2011-08-22 SOCS1 as a regulator of KIT signaling Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed10022833 Pubmed15526160 Reactome Database ID Release 431433410 Reactome, http://www.reactome.org ReactomeREACT_111100 Reviewed: Rönnstrand, L, 2011-08-22 SOCS1 has been identified as a KIT binding partner from the yeast two-hybrid system (Sepulveda et al, 1999). SOCS1 expression is induced upon KIT activation. It associates with KIT via its SH2 domain. SOCS1 does not inhibit KIT kinase activity directly, instead it binds to GRB2 and VAV1, and selectively inhibits SCF-induced proliferation, while not effecting survival signal (Sepulveda et al, 1999). It has been proposed that SOCS1 may interrupt signal transduction pathways downstream of JAK2 (Sepulveda et al, 1999). Interaction of SHP1 and KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed16129412 Pubmed7684496 Pubmed9528781 Reactome Database ID Release 43205306 Reactome, http://www.reactome.org ReactomeREACT_111223 Reviewed: Rönnstrand, L, 2011-08-22 The protein tyrosine phosphatase SHP-1 negatively regulates KIT signaling through binding to phosphorylated Y570. It is unclear whether SHP1 directly dephosphorylates KIT or elicits dephosphorylation of the receptor indirectly by dephosphorylating and inhibiting cytosolic PTKs that act on KIT. SHP-1 may also compete with and displace SFKs or other proteins that dock to phosphorylated Y570 (Kozlowski et al, 1998). Downregulation of c-Kit signaling by SOCS6 Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed14707129 Reactome Database ID Release 431470011 Reactome, http://www.reactome.org ReactomeREACT_111230 Reviewed: Rönnstrand, L, 2011-08-22 SOCS6 protein interacts with the phosphorylated Y568 in the juxtamembrane domain of c-Kit following SCF-stimulated tyrosine phosphorylation. Binding of SOCS6 to Y568 may mask this docking site for Src family kinases and this may inhibit the phosphorylation of p38 and ERK. This negatively regulates c-Kit receptor proliferation signal but not SCF-induced chemotaxis (Bayle et al. 2004, Zadjali et al 2011). Binding of SOCS6 mediates recruitment of elongin B and C to form a ubiquitin E3 ligase complex that leads to ubiquitination of KIT and its degradation (Zadjali et al 2011). Recruitment of CBL to KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed11994499 Pubmed12444928 Pubmed16780420 Pubmed17904548 Reactome Database ID Release 43205244 Reactome, http://www.reactome.org ReactomeREACT_111179 Reviewed: Rönnstrand, L, 2011-08-22 The phosphotyrosine residue in APS creates a putative binding site for CBL. CBL is an ubiquitin E3 ligase that attaches ubiquitin to KIT leading to KIT's ubiquitination followed by internalization and degradation. GRB2 in addition to its role in positive signaling via RAS/ERK pathway also mediates negative regulation of KIT by recruiting CBL (Sun et al, 2007). CBL has also been shown to bind directly to both Y568 and Y936 in KIT (Masson et al. 2006). CBL bound to KIT ubiquitinates KIT and targets it to lysosomal degradation (Masson et al. 2006) 1/3-PP-IP5 Converted from EntitySet in Reactome Reactome DB_ID: 2023974 Reactome Database ID Release 432023974 Reactome, http://www.reactome.org ReactomeREACT_152042 Mg2+/Mn2+ Converted from EntitySet in Reactome Reactome DB_ID: 1500648 Reactome Database ID Release 431500648 Reactome, http://www.reactome.org ReactomeREACT_151505 Cyclin D:phospho-CDK4/6:p21/p27 Reactome DB_ID: 69212 Reactome Database ID Release 4369212 Reactome, http://www.reactome.org ReactomeREACT_3625 has a Stoichiometric coefficient of 1 1/3-PP-IP5 Converted from EntitySet in Reactome Reactome DB_ID: 2023944 Reactome Database ID Release 432023944 Reactome, http://www.reactome.org ReactomeREACT_151826 Rb-E2F1/2/3:DP-1 complex Reactome DB_ID: 68644 Reactome Database ID Release 4368644 Reactome, http://www.reactome.org ReactomeREACT_4483 has a Stoichiometric coefficient of 1 DP-1:E2F1/2/3 Reactome DB_ID: 1227905 Reactome Database ID Release 431227905 Reactome, http://www.reactome.org ReactomeREACT_76628 has a Stoichiometric coefficient of 1 E2F4:DP1/2 Reactome DB_ID: 1362228 Reactome Database ID Release 431362228 Reactome, http://www.reactome.org ReactomeREACT_111631 has a Stoichiometric coefficient of 1 Cdk4/6:INK4A complex Reactome DB_ID: 182579 Reactome Database ID Release 43182579 Reactome, http://www.reactome.org ReactomeREACT_8076 has a Stoichiometric coefficient of 1 Cyclin D:Cdk4/6:p21/p27 Reactome DB_ID: 141298 Reactome Database ID Release 43141298 Reactome, http://www.reactome.org ReactomeREACT_2453 has a Stoichiometric coefficient of 1 PathwayStep5708 GRB2 is indirectly recruited to p-KIT through SHP2 Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 GRB2 can be recruited indirectly to KIT through SHP2 (Tauchi et al. 1994). Y279, Y304, Y546 and Y584 (usually referred to as Y542 and Y580 in literature based on the SHP2 short isoform) are the potential sites of SHP2 tyrosyl phosphorylation and that Y546 is the major GRB2 binding site (Feng, et al. 1993, Araki, et al. 2003). This brings Grb2:SOS1 into proximity with the plasma membrane, where it can activate Ras. Pubmed10523831 Pubmed11707405 Pubmed7523381 Reactome Database ID Release 431433428 Reactome, http://www.reactome.org ReactomeREACT_111069 Reviewed: Rönnstrand, L, 2011-08-22 PathwayStep5707 Phosphorylation of GAB2 by SFKs Authored: Garapati, P V, 2011-07-11 EC Number: 2.7.10 Edited: Garapati, P V, 2011-07-11 GAB2 bound to GRB2 on KIT is then phosphorylated on a number of tyrosine residues through the action of Src family kinases (SFKs). Pubmed18697750 Reactome Database ID Release 431433454 Reactome, http://www.reactome.org ReactomeREACT_111186 Reviewed: Rönnstrand, L, 2011-08-22 PathwayStep5709 Indirect recruitment of GAB2 to p-KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed16873377 Pubmed18697750 Reactome Database ID Release 43205234 Reactome, http://www.reactome.org ReactomeREACT_111237 Reviewed: Rönnstrand, L, 2011-08-22 The scaffolding adapter GAB2 plays a role in KIT dependent PI3K/AKT activation. GAB2 interacts with KIT indirectly via the adapter protein GRB2 which is bound to KIT on phosphorylated Y703 and Y936 (Sun et al. 2008, Yu et al. 2006). Activation of RAS by p-KIT bound SOS1 Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Once recruited to the membrane in response to c-Kit stimulation, Son of sevenless (SOS1) activates the small GTPase protein Ras. SOS1 is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases. SOS1 activates Ras by binding which induces a conformational change that causes the exchange of GDP with GTP. Ras proteins are membrane-bound GTPases that regulate crucial cellular processes such as growth, proliferation and differentiation. Active Ras-GTP stimulates multiple effector proteins such as Raf-1, which induce a variety of cellular responses, including initiation of mitogen activated protein kinase (MAPK) cascade signaling. Pubmed1371879 Pubmed16129412 Pubmed16483568 Pubmed17052120 Pubmed1721591 Reactome Database ID Release 431433471 Reactome, http://www.reactome.org ReactomeREACT_111091 Reviewed: Rönnstrand, L, 2011-08-22 Indirect recruitment of PI3K to KIT via p(Y)-GAB2 Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Phosphorylated GAB2 recruits the p85 subunit of the PI3K complex and activates the PI3K/AKT pathway. This is one of two mechanisms described for the recruitment of PI3K to KIT. Pubmed18697750 Reactome Database ID Release 431562641 Reactome, http://www.reactome.org ReactomeREACT_111036 Reviewed: Rönnstrand, L, 2011-08-22 Interaction of other adapter proteins with p-KIT Adapter proteins GADS, GRAP, GRB7 and GRB10 interact with activated KIT (Liu & McGlade 1998, Feng et al. 1996, Thömmes et al. 1999, Jahn et al. 2002). Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed10377264 Pubmed11809791 Pubmed16129412 Pubmed8647802 Pubmed9872323 Reactome Database ID Release 431433501 Reactome, http://www.reactome.org ReactomeREACT_111192 Reviewed: Rönnstrand, L, 2011-08-22 Interaction of other tyrosine kinases with p-KIT Authored: Garapati, P V, 2011-07-11 Cytoplasmic tyrosine kinases such as CHK1 (Csk homologous kinase or MATK), FER and FES associate with p-KIT upon SCF stimulation (Price et al, 19997; Jhun et al, 1995; Craig AW, Greer PA, 2002). TEC has been demonstrated to associate with KIT constitutively and is activated by ligand stimulation (Tang et a l. 1994). Edited: Garapati, P V, 2011-07-11 Pubmed10679268 Pubmed12192036 Pubmed16129412 Pubmed7526158 Pubmed7536744 Pubmed9038210 Reactome Database ID Release 43205328 Reactome, http://www.reactome.org ReactomeREACT_111221 Reviewed: Rönnstrand, L, 2011-08-22 PathwayStep5700 Phosphorylation of JAK2 Authored: Garapati, P V, 2011-07-11 EC Number: 2.7.10 Edited: Garapati, P V, 2011-07-11 Pubmed15143187 Pubmed20304997 Pubmed8611693 Pubmed9111318 Reactome Database ID Release 431433418 Reactome, http://www.reactome.org ReactomeREACT_111070 Reviewed: Rönnstrand, L, 2011-08-22 SCF induces rapid and transient autophosphorylation of JAK2 bound to c-KIT. JAKs bound to activated, dimerized receptors cross-phosphorylate and thereby activate each other. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity (Feng et al 1997, Argetsinger et al. 2004, 2010). Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only the critical tyrosine 1007 is represented in the reaction. has a Stoichiometric coefficient of 2 JAK2 binds to p-KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Janus kinase 2 (JAK2) plays an important role in SCF induced proliferation (Radosevic et al. 2004). JAK2 was observed to pre-associate with KIT, with increased association after SCF stimulation of KIT (Weiler et al. 1996). Pubmed15102475 Pubmed8611693 Reactome Database ID Release 431433451 Reactome, http://www.reactome.org ReactomeREACT_111205 Reviewed: Rönnstrand, L, 2011-08-22 has a Stoichiometric coefficient of 2 PathwayStep5702 PathwayStep5701 Recruitment of STATs Activation of KIT mediates the recruitment of and association with STAT1alpha, STAT3, STAT5A and STAT5B (Deberry et al. 1997, Brizzi et al. 1999, Rönnstrand 2004). Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed10358045 Pubmed11494148 Pubmed9355737 Reactome Database ID Release 431433456 Reactome, http://www.reactome.org ReactomeREACT_111136 Reviewed: Rönnstrand, L, 2011-08-22 has a Stoichiometric coefficient of 2 PathwayStep5704 PathwayStep5703 PathwayStep5706 PathwayStep5705 Cyclin E:Cdk2 complex Reactome DB_ID: 157594 Reactome Database ID Release 43157594 Reactome, http://www.reactome.org ReactomeREACT_3296 has a Stoichiometric coefficient of 1 Ub-P-p130 Reactome DB_ID: 1363324 Reactome Database ID Release 431363324 Reactome, http://www.reactome.org ReactomeREACT_111808 Ub-p-T401,S672,1035-RBL2 has a Stoichiometric coefficient of 1 P-p130:SCF(Skp2):Cks1 Reactome DB_ID: 1363326 Reactome Database ID Release 431363326 Reactome, http://www.reactome.org ReactomeREACT_111614 has a Stoichiometric coefficient of 1 p-T401,S672,1035-RBL2:SCF(Skp2):Cks1 Cyclin E/A:Cdk2:multiubiquitinated phospho-p27/p21:SCF(Skp2):Cks1 complex Reactome DB_ID: 187568 Reactome Database ID Release 43187568 Reactome, http://www.reactome.org ReactomeREACT_9266 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Cyclin E/A:Cdk2:phospho-p27/p21:SCF(Skp2):Cks1 complex Reactome DB_ID: 187565 Reactome Database ID Release 43187565 Reactome, http://www.reactome.org ReactomeREACT_9193 has a Stoichiometric coefficient of 1 Cyclin E/A:Cdk2:phospho-p27/p21 Reactome DB_ID: 187522 Reactome Database ID Release 43187522 Reactome, http://www.reactome.org ReactomeREACT_9321 has a Stoichiometric coefficient of 1 Cyclin E/A:Cdk2:p27/p21 complex Reactome DB_ID: 187516 Reactome Database ID Release 43187516 Reactome, http://www.reactome.org ReactomeREACT_9314 has a Stoichiometric coefficient of 1 PathwayStep5720 PathwayStep5716 Extracellular processing of novel PDGFs Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 During the extracellular proteolytic activation of PDGF-C and PDGF-D chains, the CUB domains is removed and plasmin protease has been shown to proteolytically cleave within the hinge regions, and thus releasing the corresponding growth factor domains. In addition the protease tissue-type plasminogen activator (tPA) is also involved in the activation of PDGF-CC but not able to cleave and activate PDGF-DD. EC Number: 3.4.21 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed15207811 Reactome Database ID Release 43382061 Reactome, http://www.reactome.org ReactomeREACT_16891 Reviewed: Heldin, CH, 2008-11-23 19:29:34 has a Stoichiometric coefficient of 2 PathwayStep5717 PDGF binds to extracellular matrix proteins Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed10508235 Pubmed1311092 Pubmed1639841 Pubmed8900172 Pubmed9334164 Reactome Database ID Release 43382054 Reactome, http://www.reactome.org ReactomeREACT_16880 Reviewed: Heldin, CH, 2008-11-23 19:29:34 The long splice version of the PDGF-A chain as well as the COOH-terminal part of the PDGF-B precursor contain C-terminal protein motifs that confer retention of the secreted factors. In both the PDGF A- and B-chains, exon 6 encodes a basic sequence that mediates interaction with components of the extracellular matrix. PDGF binds to various types of collagens, thrombospondin and osteopontin; however, the major component of the matrix involved in PDGF binding is likely to be haparan sulphate. The negatively charged sulfate groups on the disaccharide building blocks of heparan sulfate (HS) polysaccharide chains provide binding sites for positively charged amino acid sequence motifs. <br>The precursor of the B-chain may be retained in the matrix; after maturation when the COOH-terminal retention sequence has been cleaved off, the molecule may become more diffusible. has a Stoichiometric coefficient of 2 PathwayStep5714 Processing of classical PDGFs After dimerization of the PDGF-A and PDGF-B chains in the ER of producing cells, the dimers are proteolytically cleaved in the trans-Golgi network during protein maturation and secretion. The dibasic-specific proprotein convertase, furin, or related convertases are involved in the conversion of proPDGF forms to active PDGF forms. Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 EC Number: 3.4.21 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed15207811 Pubmed1639841 Reactome Database ID Release 43186785 Reactome, http://www.reactome.org ReactomeREACT_17059 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5715 Release of novel PDGFs as latent factors Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Novel PDGFs both PDGF-CC and PDGF-DD dimers are secreted as latent factors without removal of the N-terminal CUB domain. These require further activation by extracellular proteolysis. Pubmed15207811 Reactome Database ID Release 43382057 Reactome, http://www.reactome.org ReactomeREACT_17022 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5712 Axonal transport of NGF:Trk complexes Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0007018 Of the internalized NGF:TRK complexes, many undergo recycling and/or proteolysis. Only a small fraction is retrogradely transported. Vesicles containing neurotrophin, activated receptors and downstream kinases are transported through axons by the action of dynein, which produces a force towards the end of microtubules. Pubmed11157096 Reactome Database ID Release 43177479 Reactome, http://www.reactome.org ReactomeREACT_12385 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep5713 Translocation of PDGF from ER to Golgi All the newly synthesized PDGF chains are dimerized in the ER and thereafter transferred to the Golgi complex for proteolytic processing. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed15207811 Pubmed1639841 Reactome Database ID Release 43382053 Reactome, http://www.reactome.org ReactomeREACT_17051 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5710 Formation of clathrin-coated vesicle Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Both BDNF and NGF treatment recruits clathrin and AP2 (adaptor protein 2) proteins to the plasma membrane. Clathrin is the major protein of the polyhedral coat of vesicles. The AP2 complex mediates both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43177491 Reactome, http://www.reactome.org ReactomeREACT_12559 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep5711 Endocytosis (internalization) of clathrin-coated vesicle Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Dynamin is a microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. It is involved in vesicle trafficking processes and is necessary for endocytosis. Dynamins are large GTPases that bind to PIP2-containing membranes, several SH3-domain containing proteins and cytoskeletal modifiers. They self-polymerize in a GTP dependent manner, catalyzing the scission of invaginating membranes during endocytosis (Praefcke & McMahon, 2004). There are three dynamins in humans: dynamin I is neuron-specific; dynamin II shows ubiquitous expression; dynamin III is expressed in testis, brain, lung and blood platelets. EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed15040446 Reactome Database ID Release 43177501 Reactome, http://www.reactome.org ReactomeREACT_12397 Reviewed: Greene, LA, 2007-11-08 15:39:37 ERK5 is activated Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11.24 Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase family. ERK5 is twice the size of the ERK1/2, containing a conserved amino terminal kinase domain that is 53% identical to ERK1/2, and a unique carboxyterminal region which contains potential binding sites for signalling molecules such as CRK, PI3 kinase and SRC. The second proline-rich region may interact with actin, targeting the kinase to a specific location in the cell. In contrast to ERK1 and ERK2, which are activated by neurotrophins (NTs), cAMP, and neuronal activity in neurons, ERK5 appears to be activated only by neurotrophins. The small GTPase Rap1 and the MEKK2 or MEKK3 kinases are critical upstream signaling molecules mediating neurotrophin stimulation of ERK5 in neurons. MEKK2 or MEKK3 activate MEK5, which appears to be localised in intracellular vesicles. MEK5 then activates ERK5. Once phosphorylated, ERK5 translocates to the nucleus. Reactome Database ID Release 43198733 Reactome, http://www.reactome.org ReactomeREACT_12075 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 2 SCF(Skp2):Cks1 complex Reactome DB_ID: 187547 Reactome Database ID Release 43187547 Reactome, http://www.reactome.org ReactomeREACT_9182 has a Stoichiometric coefficient of 1 ERK5 translocates to the nucleus Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 On phosphorylation, ERK5 translocates to the nucleus. Reactome Database ID Release 43198714 Reactome, http://www.reactome.org ReactomeREACT_12055 Reviewed: Greene, LA, 2007-11-08 15:39:37 SCF(Skp2) complex Reactome DB_ID: 187541 Reactome Database ID Release 43187541 Reactome, http://www.reactome.org ReactomeREACT_9339 has a Stoichiometric coefficient of 1 PP2A PP2A with regulatory subunit B alpha or B" beta Reactome DB_ID: 1363265 Reactome Database ID Release 431363265 Reactome, http://www.reactome.org ReactomeREACT_111771 has a Stoichiometric coefficient of 1 E2F4/5:DP1/2 Reactome DB_ID: 1226072 Reactome Database ID Release 431226072 Reactome, http://www.reactome.org ReactomeREACT_111584 has a Stoichiometric coefficient of 1 PathwayStep5718 PathwayStep5719 Cyclin E2:Cdk2 complex Reactome DB_ID: 68368 Reactome Database ID Release 4368368 Reactome, http://www.reactome.org ReactomeREACT_5296 has a Stoichiometric coefficient of 1 Cyclin E1:phospho-Cdk2 complex Reactome DB_ID: 68371 Reactome Database ID Release 4368371 Reactome, http://www.reactome.org ReactomeREACT_2714 has a Stoichiometric coefficient of 1 Myc/Max heterodimer Reactome DB_ID: 188378 Reactome Database ID Release 43188378 Reactome, http://www.reactome.org ReactomeREACT_9233 has a Stoichiometric coefficient of 1 Cyclin E2:phospho-Cdk2 complex Reactome DB_ID: 68372 Reactome Database ID Release 4368372 Reactome, http://www.reactome.org ReactomeREACT_3967 has a Stoichiometric coefficient of 1 Cyclin E:Phospho-Cdk2(Thr160):Rb complex Reactome DB_ID: 188373 Reactome Database ID Release 43188373 Reactome, http://www.reactome.org ReactomeREACT_9136 has a Stoichiometric coefficient of 1 Cyclin E:Phosho-Cdk2 (Thr 160) Reactome DB_ID: 188362 Reactome Database ID Release 43188362 Reactome, http://www.reactome.org ReactomeREACT_9167 has a Stoichiometric coefficient of 1 RNA primer-DNA primer:origin duplex with DNA damage Reactome DB_ID: 113656 Reactome Database ID Release 43113656 Reactome, http://www.reactome.org ReactomeREACT_2843 has a Stoichiometric coefficient of 1 Cyclin E:phospho-Cdk2 (Thr 160):phospho-Rb Reactome DB_ID: 188391 Reactome Database ID Release 43188391 Reactome, http://www.reactome.org ReactomeREACT_9190 has a Stoichiometric coefficient of 1 PathwayStep5731 MA Converted from EntitySet in Reactome Matrix Reactome DB_ID: 173120 Reactome Database ID Release 43173120 Reactome, http://www.reactome.org ReactomeREACT_8346 PathwayStep5730 STAT3 activation Activation of TRKA by NGF triggers STAT3 phosphorylation at Ser-727, and enhances the DNA binding and transcriptional activities of STAT3. Ser-727 phosphorylation of STAT3 begins within 5 min, and the levels of Ser(P) STAT3 remain elevated up to 30 min of NGF stimulation. Ser(P) STAT3 was localized to the cytoplasm, nuclei, and growth cones of neurites. Although the mechanisms by which STAT3 is activated by neurotrophins remaines unknown, phosphorylation of STAT3 at serine 727 might function as a convergent point for several signaling pathways triggered by Trk activation. Inhibition of STAT3 expression was found to attenuate NGF-induced transcription of immediate early genes, to suppress NGF-induced cyclin D1 expression, and to decrease BDNF-promoted neurite outgrowth in hippocampal neurons. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: 2007-07-10 08:01:57 Reactome Database ID Release 43198732 Reactome, http://www.reactome.org ReactomeREACT_12057 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep5725 TRKA phosphorylates IRS Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.10.1 IRS1 and IRS2 are tyrosine phosphorylated at multiple YXXM motifs by the active TRKA kinase. Reactome Database ID Release 43198295 Reactome, http://www.reactome.org ReactomeREACT_12434 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep5726 Active IRS recruits PI3K to the plasma membrane and activates it Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Reactome Database ID Release 43198315 Reactome, http://www.reactome.org ReactomeREACT_12384 Reviewed: Greene, LA, 2007-11-08 15:39:37 The PI3K regulatory subunit p85 binds to IRS1 or IRS2, tyrosine-phosphorylated at YXXM motifs, through its SH2 domain.<br>As the p85 subunt is constitutively associated with the p110 catalytic subunit, the outcome is that the whole PI3K complex is recruited to the membrane. The interaction at the plasma membrane of the p85 regulatory subunit with the p110 catalytic subunit of PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) causes a conformational change, resulting in activation of the catalytic subunit. PathwayStep5727 PI3K produces PIP3 and other phosphatidyl inositides Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.1.153 PI3-kinase phosphorylates several phosphatidyl-inositides (phospholipids) at the plasma membrane: the most relevant is PtdIns(3,4,5)P3, also named PIP3. Pubmed12167717 Reactome Database ID Release 43198266 Reactome, http://www.reactome.org ReactomeREACT_12624 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep5728 PIP3 binds to RhoA and activates it Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Reactome Database ID Release 43202692 Reactome, http://www.reactome.org ReactomeREACT_12577 Reviewed: Greene, LA, 2007-11-08 15:39:37 Several guanine exchange factors (GEFs) for the Rho family of GTPases contain PH domains that bind to PIP3. RhoA protein activation is a mechanism whereby PI3K acts independently of AKT. PathwayStep5721 (ARMS)Rap1-GTP binds and activates B-Raf Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Rap1 binds to B-RAF; as a consequence, B-RAF is recruited to endosomes. The binding event of Rap1 to B-RAF is thought to be very similar to the binding of RAS to RAF-1. In neuronal cells that express B-Raf, NGF induced activation of Rap1 promotes a sustained activation of ERKs and is required for the induction of electrical excitability and a subset of neuron-specific genes. As regards morphological differentiation (e. g. neurite outgrowth in PC12 cells), things are more complex. The transient activation of ERKs via RAS is not sufficient for neurite outgrowth in the absence of additional signals. On the contrary, constitutive activation of Rap1 is sufficient to trigger neurite outgrowth, but it is not necessary for this response.<br>Clearly, morphological differentiation of PC12 cells involves the activation of multiple pathways by NGF. Rap1 activates B-Raf, but inhibits RAF-1. Consequently, Rap1 could have two opposing functions: to limit ERK activation in B-RAF-negative cells and to increase ERK activation in B-Raf-positive cells. Reactome Database ID Release 43169901 Reactome, http://www.reactome.org ReactomeREACT_12046 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep5722 Binding of PLCG1 to active TrkA receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43167674 Reactome, http://www.reactome.org ReactomeREACT_11998 Reviewed: Greene, LA, 2007-11-08 15:39:37 The PLC-gamma 1 docking site in Trk receptor (Y785) is important for initiation and maintenance of hippocampal LTP (long term potentiation); this residue in TrkA receptor also binds to CHK tyrosine kinase, which participates in MAPK pathway activation and is involved in PC12 cells neurite outgrowth in response to NGF. PLC-gamma 1 activation results in long term induction of a sodium channel gene (PN1). PathwayStep5723 Active PLCG1 dissociates from TrkA receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Once phosphorylated, PLC-gamma dissociates from the receptor Reactome Database ID Release 43167684 Reactome, http://www.reactome.org ReactomeREACT_12061 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep5724 Active TRKA binds IRS1/2 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 IRS1 and IRS2 bind directly to TRK receptors phosphorylated at Y490, through their phosphotyrosine- binding (PTB) domains. Reactome Database ID Release 43198211 Reactome, http://www.reactome.org ReactomeREACT_12502 Reviewed: Greene, LA, 2007-11-08 15:39:37 26S proteasome Reactome DB_ID: 177750 Reactome Database ID Release 43177750 Reactome, http://www.reactome.org ReactomeREACT_7467 has a Stoichiometric coefficient of 1 Cyclin E:phospho-Cdk2 Complex Reactome DB_ID: 68377 Reactome Database ID Release 4368377 Reactome, http://www.reactome.org ReactomeREACT_4112 has a Stoichiometric coefficient of 1 Cyclin E1:Cdk2 complex Reactome DB_ID: 68378 Reactome Database ID Release 4368378 Reactome, http://www.reactome.org ReactomeREACT_4601 has a Stoichiometric coefficient of 1 C3G stimulates nucleotide exchange on Rap1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed16284401 Rap1 is a small G protein, necessary for prolonged ERK activity in PC12 cells. In such cells, NGF triggers a program of neuronal differentiation through the activation of a Rap1:B-RAF:ERK module Rap1 is activated by NGF, but not by epidermal growth factor (EGF), although both growth factors cause transient activation of RAS. Activation of Rap1 by NGF requires internalization of TRKA to intracellular vesicles, mostly endosomes, containing Rap1, B-RAF, MEK and ERKs. Rap1 does not co-localize with RAS. Therefore, the ability of Rap1 to bind RAF-1 without activating it might sequester RAF-1 from RAS. Activation of GEFs that couple to Rap1 as well as RAS might provide a mechanism to limit signals to RAS. Reactome Database ID Release 43169904 Reactome, http://www.reactome.org ReactomeREACT_12037 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep5729 Cyclin A:Cdk2:phosphorylated substrate complex Reactome DB_ID: 187965 Reactome Database ID Release 43187965 Reactome, http://www.reactome.org ReactomeREACT_9299 has a Stoichiometric coefficient of 1 Cyclin A:Cdk2:phospho-p27/p21 complex Reactome DB_ID: 187912 Reactome Database ID Release 43187912 Reactome, http://www.reactome.org ReactomeREACT_9145 has a Stoichiometric coefficient of 1 Cyclin A:Cdk2:p21/p27 complex Reactome DB_ID: 187926 Reactome Database ID Release 43187926 Reactome, http://www.reactome.org ReactomeREACT_9335 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdk2(Tyr 15) Reactome DB_ID: 187907 Reactome Database ID Release 43187907 Reactome, http://www.reactome.org ReactomeREACT_9202 has a Stoichiometric coefficient of 1 Cyclin A:Cdk2 complex Reactome DB_ID: 141608 Reactome Database ID Release 43141608 Reactome, http://www.reactome.org ReactomeREACT_4932 has a Stoichiometric coefficient of 1 Cyclin A:Cdk2 complex Reactome DB_ID: 187501 Reactome Database ID Release 43187501 Reactome, http://www.reactome.org ReactomeREACT_9350 has a Stoichiometric coefficient of 1 ORC:origin:cyclin B:cdk1 complex Reactome DB_ID: 113637 Reactome Database ID Release 43113637 Reactome, http://www.reactome.org ReactomeREACT_4235 has a Stoichiometric coefficient of 1 Cyclin B:Cdk1 complex Reactome DB_ID: 75032 Reactome Database ID Release 4375032 Reactome, http://www.reactome.org ReactomeREACT_4583 has a Stoichiometric coefficient of 1 Aborted replication complex Reactome DB_ID: 113648 Reactome Database ID Release 43113648 Reactome, http://www.reactome.org ReactomeREACT_2817 has a Stoichiometric coefficient of 1 PathwayStep5742 PathwayStep5741 PathwayStep5740 PathwayStep5734 Crk binds to the active PDGF receptor Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Crk family of adaptor molecules consists of CrkI with one SH2 and one SH3 domains and CrkII and CrkL with one SH2 and two SH3 domains each. They bind to Tyr762 of the PDGF alpha-receptor and represent the only known SH2-domain containing molecule which binds with significantly higher affinity to the alpha-receptor than to the beta-receptor. Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed10508235 Pubmed9546424 Pubmed9739761 Reactome Database ID Release 43382056 Reactome, http://www.reactome.org ReactomeREACT_16940 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5735 p130Cas and C3G bind PDGFR bound Crk Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed9546424 Pubmed9739761 Reactome Database ID Release 43382052 Reactome, http://www.reactome.org ReactomeREACT_16951 Reviewed: Heldin, CH, 2008-11-23 19:29:34 The presence of both SH2 and SH3 domains in Crk proteins is of crucial importance for their function as adaptor molecules. Crk forms complex with Cas, an SH3 domain-containing docking protein which has been shown to be phosphorylated after PDGF-stimulation of cells, and C3G, a nucleotide exchange protein which has been linked to the activation of JNK. PathwayStep5732 Sos-mediated nucleotide exchange of Ras (PDGF receptor:Grb2:Sos) Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed8388543 Pubmed9739761 Reactome Database ID Release 43186834 Reactome, http://www.reactome.org ReactomeREACT_16923 Reviewed: Heldin, CH, 2008-11-23 19:29:34 SOS is the guanine nucleotide exchange factor (GEF) for Ras. SOS activates Ras nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP).<br> PathwayStep5733 STAT binds to the active receptor Among the seven members of the Stat family, Stat1, Stat3, Stat5 alpha and -beta, and Stat6 have been shown to bind to the activated PDGF beta-receptor and to be phosphorylated after PDGF stimulation; binding also occurs to the alpha-receptor, albeit only weakly. Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed8657151 Pubmed9484840 Pubmed9739761 Reactome Database ID Release 43380782 Reactome, http://www.reactome.org ReactomeREACT_16982 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5738 PathwayStep5739 PathwayStep5736 Nck binds to the active PDGF receptor Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Nck is a widely expressed protein consisting exclusively of SH2 and SH3 domains. With its SH2 doamin Nck interacts with Tyr571 of the PDGF beta-receptor and it also interacts with the alpha-receptor, but the sites of interaction has not been determined. Nck is involved in the activation of the JNK serine/threonine kinase through interaction with the serine/threonine kinases PAK1 and NIK. Pubmed10508235 Pubmed7692233 Pubmed9739761 Reactome Database ID Release 43382058 Reactome, http://www.reactome.org ReactomeREACT_16997 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5737 Grb7 binds to the active PDGF receptor Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Grb7 an adapter protein contains a single SH2 domain, a pleckstrin homology (PH) domain, and a proline-rich region. Similar to Grb2, Grb7 interacts with phosphorylated tyrosines in pYXNX motifs, including Tyr716 and Tyr775 of the PDGF beta-receptor. Pubmed10508235 Pubmed8940081 Pubmed9739761 Reactome Database ID Release 43382055 Reactome, http://www.reactome.org ReactomeREACT_17063 Reviewed: Heldin, CH, 2008-11-23 19:29:34 GAP binds to PDGF-beta receptors only Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 GTPase-activating protein (GAP) has two SH2 domains which bind only to PDGF beta-receptors on Tyr771. GAP does not bind the alpha-receptor. GAP converts Ras-GTP to Ras-GDP, deactivating Ras. Pubmed1314164 Pubmed1375321 Pubmed9739761 Reactome Database ID Release 43186798 Reactome, http://www.reactome.org ReactomeREACT_16950 Reviewed: Heldin, CH, 2008-11-23 19:29:34 Grb2/Sos1 complex binds to the active receptor Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Grb2 is an adaptor molecule containing one SH2 domain and two SH3 domains. The SH2 domain of Grb2 binds directly to autophosphorylated PDGF receptors and with its SH3 domain it forms a complex with Sos1. The binding of Grb2/Sos1 to the PDGF receptor juxtaposes the complex towards Ras molecules leading to Ras activation. Ras is implicated in the MAP kinase cascade, a pathway in cell growth stimulation, migration and differentiation.<br> Pubmed7935391 Pubmed8388543 Pubmed9739761 Reactome Database ID Release 43186826 Reactome, http://www.reactome.org ReactomeREACT_16901 Reviewed: Heldin, CH, 2008-11-23 19:29:34 Activation of Src Activation of Src kinases involves displacement of Tyr527 from the SH2 domain and phosphorylation of other tyrosine residues in the kinase domain. Src activation appears to be important for the mitogenic response of PDGF. Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 EC Number: 2.7.10 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed8647855 Pubmed9739761 Reactome Database ID Release 43380780 Reactome, http://www.reactome.org ReactomeREACT_16991 Reviewed: Heldin, CH, 2008-11-23 19:29:34 Rb1:RNA primer-DNA primer:origin duplex with DNA damage Reactome DB_ID: 113646 Reactome Database ID Release 43113646 Reactome, http://www.reactome.org ReactomeREACT_3869 has a Stoichiometric coefficient of 1 SHP2 binds to the active receptor Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Protein-tyrosine phosphatase 2C (SHP2) is ubiquitously expressed and has two SH2 domains, both of which need to be bound to phosphorylated tyrosine residues for full activation of catalytic activity. SHP-2 binds with high affinity to Tyr 1009 of the PDGF beta-receptor and with lower affinity to Tyr 763; it also binds to the alpha-receptor and Tyr 720 in the interkinase domain has been implicated in this binding. <br>The phosphatase is able to dephosphorylate autophosphorylated PDGF receptors and substrates for PDGF receptors so SHP2 can be thought of as a negative regulator of signaling from PDGF receptors. SHP2 may be involved in positive signaling by binding Grb2/Sos1 and dephosphorylating the COOH-terminal tyrosine of Src, factors important for Src activation. Pubmed7691811 Pubmed9739761 Reactome Database ID Release 43186778 Reactome, http://www.reactome.org ReactomeREACT_16960 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PP2A PP2A complex (containing PPP2R3B) Reactome DB_ID: 1362456 Reactome Database ID Release 431362456 Reactome, http://www.reactome.org ReactomeREACT_111616 Serine/threonine-protein phosphatase 2A complex with regulatory subunit PPP2R3B has a Stoichiometric coefficient of 1 DBP:Calcidiol Reactome DB_ID: 209892 Reactome Database ID Release 43209892 Reactome, http://www.reactome.org ReactomeREACT_14039 has a Stoichiometric coefficient of 1 vitamin D Binding Protein:calcidiol Ac-Cohesin:PDS5:WAPAL Reactome DB_ID: 2468047 Reactome Database ID Release 432468047 Reactome, http://www.reactome.org ReactomeREACT_150942 has a Stoichiometric coefficient of 1 Ac-Cohesin:PDS5:WAPAL:Chromosomal Arm Reactome DB_ID: 2473153 Reactome Database ID Release 432473153 Reactome, http://www.reactome.org ReactomeREACT_151929 has a Stoichiometric coefficient of 1 Cohesin:PDS5:WAPAL:Centromere Reactome DB_ID: 2545177 Reactome Database ID Release 432545177 Reactome, http://www.reactome.org ReactomeREACT_151885 has a Stoichiometric coefficient of 1 Ac-Cohesin Complex Reactome DB_ID: 2468048 Reactome Database ID Release 432468048 Reactome, http://www.reactome.org ReactomeREACT_151202 has a Stoichiometric coefficient of 1 Cubilin:DBP:Calcidiol Reactome DB_ID: 350085 Reactome Database ID Release 43350085 Reactome, http://www.reactome.org ReactomeREACT_14090 has a Stoichiometric coefficient of 1 Cohesin:PDS5:WAPAL:Chromosomal Arm Reactome DB_ID: 2545179 Reactome Database ID Release 432545179 Reactome, http://www.reactome.org ReactomeREACT_150643 has a Stoichiometric coefficient of 1 DBP:Calcidiol Reactome DB_ID: 350130 Reactome Database ID Release 43350130 Reactome, http://www.reactome.org ReactomeREACT_13868 has a Stoichiometric coefficient of 1 multi-ubiquitinated phospho-(T286) Cyclin D1 Reactome DB_ID: 177997 Reactome Database ID Release 43177997 Reactome, http://www.reactome.org ReactomeREACT_7367 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Cubilin:DBP:Calcidiol Reactome DB_ID: 350092 Reactome Database ID Release 43350092 Reactome, http://www.reactome.org ReactomeREACT_14699 has a Stoichiometric coefficient of 1 Cohesin Complex Reactome DB_ID: 1641505 Reactome Database ID Release 431641505 Reactome, http://www.reactome.org ReactomeREACT_117037 has a Stoichiometric coefficient of 1 CUBN:DBP:calcidiol Cubilin:vitamin D Binding Protein:Calcidiol Reactome DB_ID: 350115 Reactome Database ID Release 43350115 Reactome, http://www.reactome.org ReactomeREACT_14197 has a Stoichiometric coefficient of 1 Cohesin:PDS5:WAPAL Reactome DB_ID: 2468042 Reactome Database ID Release 432468042 Reactome, http://www.reactome.org ReactomeREACT_151612 has a Stoichiometric coefficient of 1 phospho(T286)-Cyclin D1:Cdk4 Reactome DB_ID: 75814 Reactome Database ID Release 4375814 Reactome, http://www.reactome.org ReactomeREACT_4903 has a Stoichiometric coefficient of 1 phospho(T286)-Cyclin D1:Cdk4 Reactome DB_ID: 75812 Reactome Database ID Release 4375812 Reactome, http://www.reactome.org ReactomeREACT_5446 has a Stoichiometric coefficient of 1 PathwayStep5751 PathwayStep5750 PathwayStep5753 p6 protein Converted from EntitySet in Reactome Reactome DB_ID: 173114 Reactome Database ID Release 43173114 Reactome, http://www.reactome.org ReactomeREACT_8911 PathwayStep5752 PathwayStep5743 Autophosphorylation of PDGF alpha/beta receptors Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 EC Number: 2.7.10 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed9739761 Reactome Database ID Release 43389086 Reactome, http://www.reactome.org ReactomeREACT_17034 Receptor dimerisation is key event in PDGF receptor activation. The intracellular parts of the receptors are juxtaposed which allows trans-phosphorylation between the two receptors in the complex.<br>The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites Reviewed: Heldin, CH, 2008-11-23 19:29:34 has a Stoichiometric coefficient of 23 PathwayStep5744 PI3-kinase binds to the active receptor Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Phosphatidylinositol 3'-kinases (PI3Ks) are a family of enzymes which can phosphorylate phosphoinositides. These bind to and are activated by PDGF receptors. Tyr 740 and tyr 751 in PDGF beta-receptor, and tyr 731 and tyr 742 in PDGF alpha-receptor have been shown to be autophosphorylation sites and to bind PI3-kinase. <br> Pubmed1374684 Pubmed2466336 Pubmed9739761 Reactome Database ID Release 43186780 Reactome, http://www.reactome.org ReactomeREACT_17052 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5745 PI3K catalyses the phosphorylation of PIP2 to PIP3 Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 EC Number: 2.7.1.153 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 PI3K's preferred substrate is phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] which is phosphorylated to the trisphosphate [PI(3,4,5)P3]. PI3-kinase and its products have been found to be of importance in PDGF-stimulated actin reorganization, and directed cell movement, as well as in the stimulation of cell growth and inhibition of apoptosis. Pubmed2466336 Pubmed9739761 Reactome Database ID Release 43186800 Reactome, http://www.reactome.org ReactomeREACT_16877 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5746 PLC-gamma binds to the active receptor Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 PLC-gamma 1 has been shown to bind to phosphorylated Tyr 1021 of the PDGF beta-receptor with high affinity and to Tyr 1009 with low affinity. In the alpha-receptor, Tyr 988 and Tyr 1018 bind PLC-gamma1. Association of PLC-gamma1 with the activated PDGF receptor has been shown to be necessary for its activation.<br> Pubmed1396585 Pubmed8443409 Pubmed9739761 Reactome Database ID Release 43186765 Reactome, http://www.reactome.org ReactomeREACT_16998 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5747 Phosphorylation of PLCgamma by PDGFR Authored: Rothfels, K, 2011-08-24 EC Number: 2.7.10 Pubmed10579907 Pubmed2472219 Reactome Database ID Release 431524186 Reactome, http://www.reactome.org ReactomeREACT_111134 Reviewed: Heldin, CH, 2008-11-23 19:29:34 The activated PDGF receptor phosphorylates PLCgamma on tyrosine residues 472,771,783 and 1254, activating the enzyme. PathwayStep5748 Activated PLC gamma dissociates from the PDGF receptor Authored: Rothfels, K, 2011-08-24 Once phosphorylated, PLCgamma dissociates from the receptor. The active enzyme promotes intracelllular signaling by catalysing the hydrolysis of PIP2 to generate the second messengers IP3 and DAG. Pubmed10579907 Reactome Database ID Release 431524182 Reactome, http://www.reactome.org ReactomeREACT_111066 Reviewed: Heldin, CH, 2008-11-23 19:29:34 PathwayStep5749 SH2 domain of Src binds to the active receptor Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed10508235 Pubmed7685273 Pubmed9488729 Pubmed9739761 Reactome Database ID Release 43186819 Reactome, http://www.reactome.org ReactomeREACT_17048 Reviewed: Heldin, CH, 2008-11-23 19:29:34 The Src family of tyrosine kinases are characterized by a SH3 and a SH2 domain in addition to the kinase domain.Src is activated when the SH2 domain binds to autophosphorylation sites on PDGF receptors (Tyr579 and 581 in the beta-receptor, Tyr572 and 574 in the alpha receptor), in conjuction with dephosporylation of the COOH-terminal phosphorylated tyrosine 527. Cyclin D1:Cdk4 Reactome DB_ID: 113844 Reactome Database ID Release 43113844 Reactome, http://www.reactome.org ReactomeREACT_2478 has a Stoichiometric coefficient of 1 PDGF dimer binds two receptors simultaneously Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 PDGF dimer binds two receptors simultaneously. The receptors dimerise on binding and this is key to receptor autophosphorylation. Pubmed9739761 Reactome Database ID Release 43186773 Reactome, http://www.reactome.org ReactomeREACT_16905 Reviewed: Heldin, CH, 2008-11-23 19:29:34 has a Stoichiometric coefficient of 2 Autophosphorylation of PDGF beta receptors Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 EC Number: 2.7.10 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed9739761 Reactome Database ID Release 43186786 Reactome, http://www.reactome.org ReactomeREACT_16926 Receptor dimerisation is key event in PDGF receptor activation. The intracellular parts of the receptors are juxtaposed which allows trans-phosphorylation between the two receptors in the complex.<br>The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites Reviewed: Heldin, CH, 2008-11-23 19:29:34 has a Stoichiometric coefficient of 24 Autophosphorylation of PDGF alpha receptors Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 EC Number: 2.7.10 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed9739761 Reactome Database ID Release 43389083 Reactome, http://www.reactome.org ReactomeREACT_16993 Receptor dimerisation is key event in PDGF receptor activation. The intracellular parts of the receptors are juxtaposed which allows trans-phosphorylation between the two receptors in the complex.<br>The autophosphorylation site Y857 located inside the kinase domain of beta-receptor is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (Y849 ) and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors ; 11 out of 15 tyrosine residues in the intracellular, non-catalytic part of the beta-receptor are autophosphorylation sites Reviewed: Heldin, CH, 2008-11-23 19:29:34 has a Stoichiometric coefficient of 22 PathwayStep5647 PathwayStep5646 PathwayStep5645 PathwayStep5644 PathwayStep5649 PathwayStep5648 PathwayStep5650 PathwayStep5653 PathwayStep5654 PathwayStep5651 PathwayStep5652 DECR1 tetramer 2,4-dienoyl-CoA reductase, mitochondrial precursor (EC 1.3.1.34) (2,4- dienoyl-CoA reductase (NADPH)) (4-enoyl-CoA reductase (NADPH)) Homotetramer Reactome DB_ID: 110061 Reactome Database ID Release 43110061 Reactome, http://www.reactome.org ReactomeREACT_4894 has a Stoichiometric coefficient of 4 PCCA:PCCB complex Reactome DB_ID: 71026 Reactome Database ID Release 4371026 Reactome, http://www.reactome.org ReactomeREACT_3520 has a Stoichiometric coefficient of 6 propionyl-CoA carboxylase dodecamer propionyl-CoA carboxylase protomer Reactome DB_ID: 71025 Reactome Database ID Release 4371025 Reactome, http://www.reactome.org ReactomeREACT_5676 has a Stoichiometric coefficient of 1 propionyl-CoA carboxylase alpha chain, holoprotein Reactome DB_ID: 71022 Reactome Database ID Release 4371022 Reactome, http://www.reactome.org ReactomeREACT_3001 has a Stoichiometric coefficient of 1 MUT dimer Reactome DB_ID: 70999 Reactome Database ID Release 4370999 Reactome, http://www.reactome.org ReactomeREACT_2476 has a Stoichiometric coefficient of 2 methylmalonyl-CoA mutase, homodimer ACAT1 tetramer Reactome DB_ID: 70839 Reactome Database ID Release 4370839 Reactome, http://www.reactome.org ReactomeREACT_4071 acetyl-CoA acetyltransferase tetramer has a Stoichiometric coefficient of 4 PathwayStep5634 PathwayStep5633 PathwayStep5636 PathwayStep5635 PathwayStep5638 PathwayStep5637 PathwayStep5639 PathwayStep5640 PathwayStep5641 PathwayStep5642 PathwayStep5643 PPARG:Fatty Acid Ligand Reactome DB_ID: 2026077 Reactome Database ID Release 432026077 Reactome, http://www.reactome.org ReactomeREACT_119596 has a Stoichiometric coefficient of 1 Activated PPARG:RXRA Reactome DB_ID: 2026078 Reactome Database ID Release 432026078 Reactome, http://www.reactome.org ReactomeREACT_119652 has a Stoichiometric coefficient of 1 Mediator Complex (consensus) Reactome DB_ID: 556786 Reactome Database ID Release 43556786 Reactome, http://www.reactome.org ReactomeREACT_27330 has a Stoichiometric coefficient of 1 PathwayStep5669 PathwayStep5668 PathwayStep5667 PathwayStep5666 PathwayStep5675 PathwayStep5676 PathwayStep5673 PathwayStep5674 PathwayStep5671 PathwayStep5672 PathwayStep5670 NR1D1 (REV-ERBA):heme:Corepressor Reactome DB_ID: 1368079 Reactome Database ID Release 431368079 Reactome, http://www.reactome.org ReactomeREACT_111441 has a Stoichiometric coefficient of 1 NR1D1 (REV-ERBA):heme Reactome DB_ID: 1368127 Reactome Database ID Release 431368127 Reactome, http://www.reactome.org ReactomeREACT_111759 has a Stoichiometric coefficient of 1 p-BMAL1:p-CLOCK/NPAS2:DNA Reactome DB_ID: 421315 Reactome Database ID Release 43421315 Reactome, http://www.reactome.org ReactomeREACT_25790 has a Stoichiometric coefficient of 1 p-ARNTL:p-CLOCK/NPAS2:DNA PHYH:Fe++ Reactome DB_ID: 389634 Reactome Database ID Release 43389634 Reactome, http://www.reactome.org ReactomeREACT_17895 has a Stoichiometric coefficient of 1 phytanoyl-CoA dioxygenase:iron complex ROR-alpha:Coactivator Reactome DB_ID: 1368124 Reactome Database ID Release 431368124 Reactome, http://www.reactome.org ReactomeREACT_111748 has a Stoichiometric coefficient of 1 SREBP1A/1C/2:NF-Y:SP1:FDFT1 gene Reactome DB_ID: 2426135 Reactome Database ID Release 432426135 Reactome, http://www.reactome.org ReactomeREACT_148107 SREBF1A/1C/2:NF-Y:SP1:FDFT1 gene has a Stoichiometric coefficient of 1 SREBP1A/1C/2 Dimer Reactome DB_ID: 1655744 Reactome Database ID Release 431655744 Reactome, http://www.reactome.org ReactomeREACT_117119 SREBF1A/1C/2 Dimer has a Stoichiometric coefficient of 2 SREBP1A/1C/2:NF-Y:HMGCS1 gene Reactome DB_ID: 2426129 Reactome Database ID Release 432426129 Reactome, http://www.reactome.org ReactomeREACT_148333 SREBF1A/1C/2:NF-Y:HMGCS1 gene has a Stoichiometric coefficient of 1 PPARA:RXRA Heterodimer Reactome DB_ID: 400138 Reactome Database ID Release 43400138 Reactome, http://www.reactome.org ReactomeREACT_20362 has a Stoichiometric coefficient of 1 OXCT1 dimer 3-oxoacid CoA-transferase homodimer Reactome DB_ID: 74318 Reactome Database ID Release 4374318 Reactome, http://www.reactome.org ReactomeREACT_5536 has a Stoichiometric coefficient of 2 BDH1 tetramer D-beta-hydroxybutyrate dehydrogenase tetramer Reactome DB_ID: 74280 Reactome Database ID Release 4374280 Reactome, http://www.reactome.org ReactomeREACT_3781 has a Stoichiometric coefficient of 4 HMGCL dimer Reactome DB_ID: 74264 Reactome Database ID Release 4374264 Reactome, http://www.reactome.org ReactomeREACT_4784 has a Stoichiometric coefficient of 2 hydroxymethylglutaryl-CoA lyase homodimer PathwayStep5659 PathwayStep5656 PathwayStep5655 PathwayStep5658 PathwayStep5657 PathwayStep5662 PathwayStep5663 PathwayStep5664 PathwayStep5665 PathwayStep5660 PathwayStep5661 ALAS1 gene:NRF1:PPARGC1B NRF1:PGC-1beta:ALAS1 gene Reactome DB_ID: 2466384 Reactome Database ID Release 432466384 Reactome, http://www.reactome.org ReactomeREACT_151863 has a Stoichiometric coefficient of 1 PPARG:Fatty Acid:RXRA:Mediator:Coactivator Complex Reactome DB_ID: 381367 Reactome Database ID Release 43381367 Reactome, http://www.reactome.org ReactomeREACT_27768 has a Stoichiometric coefficient of 1 NF-Y Reactome DB_ID: 381204 Reactome Database ID Release 43381204 Reactome, http://www.reactome.org ReactomeREACT_26721 has a Stoichiometric coefficient of 1 SREBP1A/2 Dimer Reactome DB_ID: 2065551 Reactome Database ID Release 432065551 Reactome, http://www.reactome.org ReactomeREACT_119740 SREBF1A/2 Dimer has a Stoichiometric coefficient of 2 FABP1:Ligands of PPARA Reactome DB_ID: 2026984 Reactome Database ID Release 432026984 Reactome, http://www.reactome.org ReactomeREACT_119390 has a Stoichiometric coefficient of 1 SREBP1A/2:NF-Y:HMGCR gene Reactome DB_ID: 2426128 Reactome Database ID Release 432426128 Reactome, http://www.reactome.org ReactomeREACT_148301 SREBF1A/2:NF-Y:HMGCR gene has a Stoichiometric coefficient of 1 PPARA:RXRA Repressor Complex Reactome DB_ID: 400196 Reactome Database ID Release 43400196 Reactome, http://www.reactome.org ReactomeREACT_19814 has a Stoichiometric coefficient of 1 PathwayStep5688 PathwayStep5689 IDH1 dimer Reactome DB_ID: 389559 Reactome Database ID Release 43389559 Reactome, http://www.reactome.org ReactomeREACT_17471 has a Stoichiometric coefficient of 2 IDI1 or 2 Isopentenyl-diphosphate delta-isomerase (Mg2+ cofactor) Reactome DB_ID: 191397 Reactome Database ID Release 43191397 Reactome, http://www.reactome.org ReactomeREACT_9627 has a Stoichiometric coefficient of 1 MVD dimer Diphosphomevalonate decarboxylase homodimer Reactome DB_ID: 191341 Reactome Database ID Release 43191341 Reactome, http://www.reactome.org ReactomeREACT_9808 has a Stoichiometric coefficient of 2 holo-FDPS dimer Reactome DB_ID: 981570 Reactome Database ID Release 43981570 Reactome, http://www.reactome.org ReactomeREACT_26509 has a Stoichiometric coefficient of 2 prenyltransferase Converted from EntitySet in Reactome Reactome DB_ID: 981567 Reactome Database ID Release 43981567 Reactome, http://www.reactome.org ReactomeREACT_26922 PathwayStep5690 holo-GGPS1 hexamer Reactome DB_ID: 981569 Reactome Database ID Release 43981569 Reactome, http://www.reactome.org ReactomeREACT_26473 has a Stoichiometric coefficient of 6 FDPS:3Mg++ Reactome DB_ID: 981562 Reactome Database ID Release 43981562 Reactome, http://www.reactome.org ReactomeREACT_26436 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 FDFT (Mg2+ cofactor) Reactome DB_ID: 191320 Reactome Database ID Release 43191320 Reactome, http://www.reactome.org ReactomeREACT_9885 has a Stoichiometric coefficient of 1 GGPS1:3Mg++ Reactome DB_ID: 981557 Reactome Database ID Release 43981557 Reactome, http://www.reactome.org ReactomeREACT_26879 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep5694 PathwayStep5693 PathwayStep5692 PathwayStep5691 PathwayStep5698 PathwayStep5697 PathwayStep5696 MVK dimer Mevalonate kinase homodimer Reactome DB_ID: 191285 Reactome Database ID Release 43191285 Reactome, http://www.reactome.org ReactomeREACT_9683 has a Stoichiometric coefficient of 2 PathwayStep5695 HMGCR dimer Hydroxymethyl glutaryl CoA reductase homodimer Reactome DB_ID: 191277 Reactome Database ID Release 43191277 Reactome, http://www.reactome.org ReactomeREACT_9875 has a Stoichiometric coefficient of 2 PathwayStep5677 PathwayStep5678 PathwayStep5679 HACL1 tetramer Reactome DB_ID: 389616 Reactome Database ID Release 43389616 Reactome, http://www.reactome.org ReactomeREACT_17962 has a Stoichiometric coefficient of 4 HACL1 holoenzyme monomer Reactome DB_ID: 389627 Reactome Database ID Release 43389627 Reactome, http://www.reactome.org ReactomeREACT_17150 has a Stoichiometric coefficient of 1 Class I MHC heavy chain (MHC HC) Converted from EntitySet in Reactome Reactome DB_ID: 1236901 Reactome Database ID Release 431236901 Reactome, http://www.reactome.org ReactomeREACT_111574 ACOX1 dimer Reactome DB_ID: 390232 Reactome Database ID Release 43390232 Reactome, http://www.reactome.org ReactomeREACT_18252 has a Stoichiometric coefficient of 2 ALDP ABCD1 homodimer Reactome DB_ID: 382579 Reactome Database ID Release 43382579 Reactome, http://www.reactome.org ReactomeREACT_15606 has a Stoichiometric coefficient of 2 HSD17B4 dimer Peroxisomal multifunctional enzyme type 2 dimer Reactome DB_ID: 389999 Reactome Database ID Release 43389999 Reactome, http://www.reactome.org ReactomeREACT_17840 has a Stoichiometric coefficient of 2 ACOX3:FAD Acyl-CoA oxidase 3 (FAD cofactor) Reactome DB_ID: 389905 Reactome Database ID Release 43389905 Reactome, http://www.reactome.org ReactomeREACT_17430 has a Stoichiometric coefficient of 1 IDH1 dimer Reactome DB_ID: 389557 Reactome Database ID Release 43389557 Reactome, http://www.reactome.org ReactomeREACT_17197 has a Stoichiometric coefficient of 2 AGPS:FAD Reactome DB_ID: 390407 Reactome Database ID Release 43390407 Reactome, http://www.reactome.org ReactomeREACT_17522 has a Stoichiometric coefficient of 1 GNPAT:AGPS complex Reactome DB_ID: 76165 Reactome Database ID Release 4376165 Reactome, http://www.reactome.org ReactomeREACT_2259 has a Stoichiometric coefficient of 1 ACOX1:FAD complex Reactome DB_ID: 390237 Reactome Database ID Release 43390237 Reactome, http://www.reactome.org ReactomeREACT_17900 has a Stoichiometric coefficient of 1 PathwayStep5681 PathwayStep5680 PathwayStep5683 PathwayStep5682 PathwayStep5685 ACOX2:FAD Acyl-CoA oxidase 2 (FAD cofactor) Reactome DB_ID: 192320 Reactome Database ID Release 43192320 Reactome, http://www.reactome.org ReactomeREACT_10603 has a Stoichiometric coefficient of 1 PathwayStep5684 PathwayStep5687 PathwayStep5686 SREBP1A/1C:ACACB gene Reactome DB_ID: 2426125 Reactome Database ID Release 432426125 Reactome, http://www.reactome.org ReactomeREACT_148190 SREBF1A/1C:ACACB gene has a Stoichiometric coefficient of 1 SREBP1A/1C:ACACA gene Reactome DB_ID: 2426141 Reactome Database ID Release 432426141 Reactome, http://www.reactome.org ReactomeREACT_148537 SREBF1A/1C:ACACA gene has a Stoichiometric coefficient of 1 SREBP1A/1C/2:Importin beta-1 Reactome DB_ID: 2065543 Reactome Database ID Release 432065543 Reactome, http://www.reactome.org ReactomeREACT_148551 SREBF1A/1C/2:Importin beta-1 has a Stoichiometric coefficient of 1 SREBP1A/1C/2:Importin beta-1 Reactome DB_ID: 2065556 Reactome Database ID Release 432065556 Reactome, http://www.reactome.org ReactomeREACT_148461 has a Stoichiometric coefficient of 1 SREBP1A/1C Dimer Reactome DB_ID: 2065537 Reactome Database ID Release 432065537 Reactome, http://www.reactome.org ReactomeREACT_148003 SREBF1A/1C Dimer has a Stoichiometric coefficient of 2 Importin-beta:Ran GTP complex Reactome DB_ID: 180719 Reactome Database ID Release 43180719 Reactome, http://www.reactome.org ReactomeREACT_9883 has a Stoichiometric coefficient of 1 SREBP1A/1C/2:SCAP Reactome DB_ID: 1655742 Reactome Database ID Release 431655742 Reactome, http://www.reactome.org ReactomeREACT_148317 SREBF1A/1C/2:SCAP has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 SREBP1A/1C/2:SCAP:Cop II Coat Reactome DB_ID: 1655765 Reactome Database ID Release 431655765 Reactome, http://www.reactome.org ReactomeREACT_147983 SREBF1A/1C/2:SCAP:Cop II Coat has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 SREBP1A/1C/2 Dimer Reactome DB_ID: 2065548 Reactome Database ID Release 432065548 Reactome, http://www.reactome.org ReactomeREACT_148157 SREBF1A/1C/2 Dimer has a Stoichiometric coefficient of 2 SCAP tetramer Reactome DB_ID: 1655737 Reactome Database ID Release 431655737 Reactome, http://www.reactome.org ReactomeREACT_147962 has a Stoichiometric coefficient of 4 PathwayStep5699 Sar1b:GTP Complex Reactome DB_ID: 204003 Reactome Database ID Release 43204003 Reactome, http://www.reactome.org ReactomeREACT_12713 has a Stoichiometric coefficient of 1 Sec23p:Sec24p Complex Reactome DB_ID: 204007 Reactome Database ID Release 43204007 Reactome, http://www.reactome.org ReactomeREACT_12818 has a Stoichiometric coefficient of 1 Sar1b:GTP:Sec23p:Sec24p Reactome DB_ID: 203997 Reactome Database ID Release 43203997 Reactome, http://www.reactome.org ReactomeREACT_13151 has a Stoichiometric coefficient of 1 SREBP1A/1C/2:SCAP:INSIG:oxysterol Reactome DB_ID: 2317522 Reactome Database ID Release 432317522 Reactome, http://www.reactome.org ReactomeREACT_148296 SREBF1A/1C/2:SCAP:INSIG:oxysterol has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 INSIG:oxysterol Reactome DB_ID: 2317517 Reactome Database ID Release 432317517 Reactome, http://www.reactome.org ReactomeREACT_148530 has a Stoichiometric coefficient of 1 SCAP:cholesterol Reactome DB_ID: 1655741 Reactome Database ID Release 431655741 Reactome, http://www.reactome.org ReactomeREACT_148629 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 SREBP1A/1C/2:SCAP:cholesterol:INSIG Reactome DB_ID: 1655766 Reactome Database ID Release 431655766 Reactome, http://www.reactome.org ReactomeREACT_147991 SREBF1A/1C/2:SCAP:cholesterol:INSIG has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 SCAP tetramer Reactome DB_ID: 1655748 Reactome Database ID Release 431655748 Reactome, http://www.reactome.org ReactomeREACT_148041 has a Stoichiometric coefficient of 4 SREBP1A/1C/2:SCAP Reactome DB_ID: 2317520 Reactome Database ID Release 432317520 Reactome, http://www.reactome.org ReactomeREACT_148494 SREBF1A/1C/2:SCAP has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 SQLE:FAD Reactome DB_ID: 191413 Reactome Database ID Release 43191413 Reactome, http://www.reactome.org ReactomeREACT_9686 Squalene monooxygenase (FAD cofactor) has a Stoichiometric coefficient of 1 SREBP1A/2:NF-Y:SP1:MVK gene Reactome DB_ID: 2426127 Reactome Database ID Release 432426127 Reactome, http://www.reactome.org ReactomeREACT_148095 SREBF1A/2:NF-Y:SP1:MVK gene has a Stoichiometric coefficient of 1 SREBP1A/2:NF-Y:SP1:PMVK gene Reactome DB_ID: 2426139 Reactome Database ID Release 432426139 Reactome, http://www.reactome.org ReactomeREACT_148481 SREBF1A/2:NF-Y:SP1:PMVK gene has a Stoichiometric coefficient of 1 SREBP1A/1C/2:NF-Y:FDPS gene Reactome DB_ID: 2426134 Reactome Database ID Release 432426134 Reactome, http://www.reactome.org ReactomeREACT_148195 SREBF1A/1C/2:NF-Y:FDPS gene has a Stoichiometric coefficient of 1 CH25H (Fe2+ cofactor) Reactome DB_ID: 192180 Reactome Database ID Release 43192180 Reactome, http://www.reactome.org ReactomeREACT_10164 has a Stoichiometric coefficient of 1 SREBP1A/2:SQLE gene Reactome DB_ID: 2426136 Reactome Database ID Release 432426136 Reactome, http://www.reactome.org ReactomeREACT_148275 SREBF1A/2:SQLE gene has a Stoichiometric coefficient of 1 SREBP1A/1C/2:ELOVL6 gene Reactome DB_ID: 1655762 Reactome Database ID Release 431655762 Reactome, http://www.reactome.org ReactomeREACT_148436 SREBF1A/1C/2:ELOVL6 gene has a Stoichiometric coefficient of 1 albumin:bile salt complex Reactome DB_ID: 194125 Reactome Database ID Release 43194125 Reactome, http://www.reactome.org ReactomeREACT_10145 has a Stoichiometric coefficient of 1 albumin:bile salt and acid (OATP-A) complex Reactome DB_ID: 194110 Reactome Database ID Release 43194110 Reactome, http://www.reactome.org ReactomeREACT_10829 has a Stoichiometric coefficient of 1 bile salts and acids complexed with FABP6 Reactome DB_ID: 194191 Reactome Database ID Release 43194191 Reactome, http://www.reactome.org ReactomeREACT_10401 has a Stoichiometric coefficient of 1 bile salts and acids complexed with albumin Reactome DB_ID: 194165 Reactome Database ID Release 43194165 Reactome, http://www.reactome.org ReactomeREACT_10309 has a Stoichiometric coefficient of 1 SREBP1A/1C/2:NF-Y:TM7SF2 gene Reactome DB_ID: 1655714 Reactome Database ID Release 431655714 Reactome, http://www.reactome.org ReactomeREACT_148435 SREBF1A/1C/2:NF-Y:TM7SF2 gene has a Stoichiometric coefficient of 1 SREBP1A/1C:NF-Y:GPAM gene Reactome DB_ID: 2426131 Reactome Database ID Release 432426131 Reactome, http://www.reactome.org ReactomeREACT_148505 SREBF1A/1C:NF-Y:GPAM gene has a Stoichiometric coefficient of 1 SREBP1A/1C:NF-Y:SP1:FASN gene Reactome DB_ID: 1655738 Reactome Database ID Release 431655738 Reactome, http://www.reactome.org ReactomeREACT_116518 SREBF1A/1C:NF-Y:SP1:FASN gene has a Stoichiometric coefficient of 1 SREBP1A/2:LSS gene Reactome DB_ID: 2426137 Reactome Database ID Release 432426137 Reactome, http://www.reactome.org ReactomeREACT_148445 SREBF1A/2:LSS gene has a Stoichiometric coefficient of 1 SREBP1A/2:MVD gene Reactome DB_ID: 2426130 Reactome Database ID Release 432426130 Reactome, http://www.reactome.org ReactomeREACT_148564 SREBF1A/2:MVD gene has a Stoichiometric coefficient of 1 SREBP1A/2:NF-Y:SC5DL gene Reactome DB_ID: 2426140 Reactome Database ID Release 432426140 Reactome, http://www.reactome.org ReactomeREACT_148446 SREBF1A/2:NF-Y:SC5DL gene has a Stoichiometric coefficient of 1 SREBP1A/2:NF-Y:SP1:CYP51A1 gene Reactome DB_ID: 2426132 Reactome Database ID Release 432426132 Reactome, http://www.reactome.org ReactomeREACT_148151 SREBF1A/2:NF-Y:SP1:CYP51A1 gene has a Stoichiometric coefficient of 1 SREBP1A/2:NF-Y:SP1:DHCR7 gene Reactome DB_ID: 2426124 Reactome Database ID Release 432426124 Reactome, http://www.reactome.org ReactomeREACT_148543 SREBF1A/2:NF-Y:SP1:DHCR7 gene has a Stoichiometric coefficient of 1 SREBP1A/2:NF-Y:SP1:GGPS1 gene Reactome DB_ID: 2426126 Reactome Database ID Release 432426126 Reactome, http://www.reactome.org ReactomeREACT_147937 SREBF1A/2:NF-Y:SP1:GGPS1 gene has a Stoichiometric coefficient of 1 SREBP1A/2:NF-Y:SP1:IDI1 gene Reactome DB_ID: 2426138 Reactome Database ID Release 432426138 Reactome, http://www.reactome.org ReactomeREACT_148432 SREBF1A/2:NF-Y:SP1:IDI1 gene has a Stoichiometric coefficient of 1 3-beta-HSD 3-beta-hydroxysteroid dehydrogenase/isomerase Converted from EntitySet in Reactome HSD2B1 or HSD3B2 dimer Reactome DB_ID: 196357 Reactome Database ID Release 43196357 Reactome, http://www.reactome.org ReactomeREACT_10470 HSD3B1 homodimer Reactome DB_ID: 196351 Reactome Database ID Release 43196351 Reactome, http://www.reactome.org ReactomeREACT_10210 has a Stoichiometric coefficient of 2 HSD3B2 homodimer Reactome DB_ID: 196336 Reactome Database ID Release 43196336 Reactome, http://www.reactome.org ReactomeREACT_10397 has a Stoichiometric coefficient of 2 HSD11B1 dimer 11beta-HSD homodimer Reactome DB_ID: 193980 Reactome Database ID Release 43193980 Reactome, http://www.reactome.org ReactomeREACT_10331 has a Stoichiometric coefficient of 2 albumin:cholate bile salt complex Reactome DB_ID: 194104 Reactome Database ID Release 43194104 Reactome, http://www.reactome.org ReactomeREACT_10265 has a Stoichiometric coefficient of 1 cholesterol:StAR-related protein Reactome DB_ID: 196124 Reactome Database ID Release 43196124 Reactome, http://www.reactome.org ReactomeREACT_10388 has a Stoichiometric coefficient of 1 cholesterol:STAR Reactome DB_ID: 196090 Reactome Database ID Release 43196090 Reactome, http://www.reactome.org ReactomeREACT_10256 has a Stoichiometric coefficient of 1 Lutropin Reactome DB_ID: 378969 Reactome Database ID Release 43378969 Reactome, http://www.reactome.org ReactomeREACT_17811 has a Stoichiometric coefficient of 1 HSD17B1 dimer Reactome DB_ID: 804966 Reactome Database ID Release 43804966 Reactome, http://www.reactome.org ReactomeREACT_27045 has a Stoichiometric coefficient of 2 DBP:vitamin D3 Reactome DB_ID: 352339 Reactome Database ID Release 43352339 Reactome, http://www.reactome.org ReactomeREACT_14420 has a Stoichiometric coefficient of 1 SEC61 alpha Converted from EntitySet in Reactome Reactome DB_ID: 1236910 Reactome Database ID Release 431236910 Reactome, http://www.reactome.org ReactomeREACT_111871 Class I MHC heavy chain (MHC HC) Converted from EntitySet in Reactome Reactome DB_ID: 1236902 Reactome Database ID Release 431236902 Reactome, http://www.reactome.org ReactomeREACT_111740 Telomerase RNP:Telomeric Chromosome End with an Additional single Stranded Telomere repeat Reactome DB_ID: 163098 Reactome Database ID Release 43163098 Reactome, http://www.reactome.org ReactomeREACT_8663 has a Stoichiometric coefficient of 1 Telomerase Holoenzyme Base-paired to the Telomeric Chromosome End with an Additional single Stranded Telomere repeat Reactome DB_ID: 164684 Reactome Database ID Release 43164684 Reactome, http://www.reactome.org ReactomeREACT_8180 has a Stoichiometric coefficient of 1 Telomerase Holoenzyme:Telomeric RNP End with Two Additional Single Stranded Telomere Repeats Reactome DB_ID: 164619 Reactome Database ID Release 43164619 Reactome, http://www.reactome.org ReactomeREACT_8055 has a Stoichiometric coefficient of 1 DNA polymerase alpha:primase:DNA polymerase alpha:G-strand extended telomere end Reactome DB_ID: 174473 Reactome Database ID Release 43174473 Reactome, http://www.reactome.org ReactomeREACT_8177 has a Stoichiometric coefficient of 1 Centromeric Chromatin:CENPH-I:Centromeric Nucleosome:RSF Complex Reactome DB_ID: 606323 Reactome Database ID Release 43606323 Reactome, http://www.reactome.org ReactomeREACT_23201 has a Stoichiometric coefficient of 1 Telomerase RNP Reactome DB_ID: 163101 Reactome Database ID Release 43163101 Reactome, http://www.reactome.org ReactomeREACT_8548 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Telomerase RNP Bound to the Telomeric Chromosome End Reactome DB_ID: 163088 Reactome Database ID Release 43163088 Reactome, http://www.reactome.org ReactomeREACT_8788 has a Stoichiometric coefficient of 1 Telomerase RNP Bound and base-paired to the Telomeric Chromosome End Reactome DB_ID: 164683 Reactome Database ID Release 43164683 Reactome, http://www.reactome.org ReactomeREACT_8909 has a Stoichiometric coefficient of 1 HJURP Complex (without CENPA-H4 tetramer) Reactome DB_ID: 606330 Reactome Database ID Release 43606330 Reactome, http://www.reactome.org ReactomeREACT_22542 has a Stoichiometric coefficient of 1 RSF Complex Reactome DB_ID: 606288 Reactome Database ID Release 43606288 Reactome, http://www.reactome.org ReactomeREACT_22664 has a Stoichiometric coefficient of 1 Cdc20:phospho-APC/C:Cyclin B:Cdc2 complex Reactome DB_ID: 174095 Reactome Database ID Release 43174095 Reactome, http://www.reactome.org ReactomeREACT_7019 has a Stoichiometric coefficient of 1 multiubiquitinated Cyclin B:Cdc2:Cdc20:phospho-APC/C complex Reactome DB_ID: 174131 Reactome Database ID Release 43174131 Reactome, http://www.reactome.org ReactomeREACT_7475 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 phospho-APC/C:Cdh1 complex Reactome DB_ID: 174181 Reactome Database ID Release 43174181 Reactome, http://www.reactome.org ReactomeREACT_7510 has a Stoichiometric coefficient of 1 cell cycle proteins:phospho-APC/C:Cdh1 complex Reactome DB_ID: 174107 Reactome Database ID Release 43174107 Reactome, http://www.reactome.org ReactomeREACT_7411 has a Stoichiometric coefficient of 1 multiubiquitinated cell cycle protein:APC/C:Cdh1 complex Reactome DB_ID: 174248 Reactome Database ID Release 43174248 Reactome, http://www.reactome.org ReactomeREACT_7822 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 multiubiquitinated Skp2:phospho-APC/C:Cdh1 complex Reactome DB_ID: 188192 Reactome Database ID Release 43188192 Reactome, http://www.reactome.org ReactomeREACT_9140 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 SCF-beta-TrCP:phospho-Emi1 complexes Reactome DB_ID: 174138 Reactome Database ID Release 43174138 Reactome, http://www.reactome.org ReactomeREACT_7039 has a Stoichiometric coefficient of 1 SCF-associated multiubiquitinated Emi1complexes Reactome DB_ID: 174061 Reactome Database ID Release 43174061 Reactome, http://www.reactome.org ReactomeREACT_7461 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 anaphase promoting complex (APC/C) Reactome DB_ID: 174091 Reactome Database ID Release 43174091 Reactome, http://www.reactome.org ReactomeREACT_7825 has a Stoichiometric coefficient of 1 hBUBR1:hBUB3:MAD2* complex Reactome DB_ID: 174196 Reactome Database ID Release 43174196 Reactome, http://www.reactome.org ReactomeREACT_7493 has a Stoichiometric coefficient of 1 Centromeric Chromatin:CENPH-I:Mis18:HJURP:CENPA Complex Reactome DB_ID: 606282 Reactome Database ID Release 43606282 Reactome, http://www.reactome.org ReactomeREACT_23362 has a Stoichiometric coefficient of 1 Centromeric Chromatin: New CENPA Nucleosome:Mis18:HJURP Complex Reactome DB_ID: 606328 Reactome Database ID Release 43606328 Reactome, http://www.reactome.org ReactomeREACT_23327 has a Stoichiometric coefficient of 1 HJURP:CENPA Complex Reactome DB_ID: 606319 Reactome Database ID Release 43606319 Reactome, http://www.reactome.org ReactomeREACT_22554 has a Stoichiometric coefficient of 1 CENPA:H4 Tetramer Reactome DB_ID: 606291 Reactome Database ID Release 43606291 Reactome, http://www.reactome.org ReactomeREACT_22693 has a Stoichiometric coefficient of 2 Centromeric Nucleosome Reactome DB_ID: 606295 Reactome Database ID Release 43606295 Reactome, http://www.reactome.org ReactomeREACT_22498 has a Stoichiometric coefficient of 2 multiubiquitinated Cdh1 associated with APC/C Reactome DB_ID: 174068 Reactome Database ID Release 43174068 Reactome, http://www.reactome.org ReactomeREACT_7295 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Centromeric Chromatin:CENPH-I Complex Reactome DB_ID: 606340 Reactome Database ID Release 43606340 Reactome, http://www.reactome.org ReactomeREACT_22632 has a Stoichiometric coefficient of 1 Centromeric Chromatin:CENPH-I: Mis18 Complex Reactome DB_ID: 606342 Reactome Database ID Release 43606342 Reactome, http://www.reactome.org ReactomeREACT_22736 has a Stoichiometric coefficient of 1 phospho-Cdh1:phospho-APC/C Reactome DB_ID: 174213 Reactome Database ID Release 43174213 Reactome, http://www.reactome.org ReactomeREACT_7125 has a Stoichiometric coefficient of 1 Mis18 Complex Reactome DB_ID: 606346 Reactome Database ID Release 43606346 Reactome, http://www.reactome.org ReactomeREACT_22768 has a Stoichiometric coefficient of 1 Ligands of PPARG Converted from EntitySet in Reactome Reactome DB_ID: 381235 Reactome Database ID Release 43381235 Reactome, http://www.reactome.org ReactomeREACT_27432 Nup107-160 complex Reactome DB_ID: 377883 Reactome Database ID Release 43377883 Reactome, http://www.reactome.org ReactomeREACT_15280 has a Stoichiometric coefficient of 1 Chromosome passenger complex Reactome DB_ID: 377879 Reactome Database ID Release 43377879 Reactome, http://www.reactome.org ReactomeREACT_14945 has a Stoichiometric coefficient of 1 CENP-(H,I, K) complex Reactome DB_ID: 377884 Reactome Database ID Release 43377884 Reactome, http://www.reactome.org ReactomeREACT_15119 has a Stoichiometric coefficient of 1 CENP-O complex Reactome DB_ID: 377886 Reactome Database ID Release 43377886 Reactome, http://www.reactome.org ReactomeREACT_14902 has a Stoichiometric coefficient of 1 Mitotic checkpoint complex Reactome DB_ID: 377882 Reactome Database ID Release 43377882 Reactome, http://www.reactome.org ReactomeREACT_15078 has a Stoichiometric coefficient of 1 CCAN network Reactome DB_ID: 377738 Reactome Database ID Release 43377738 Reactome, http://www.reactome.org ReactomeREACT_14870 has a Stoichiometric coefficient of 1 PathwayStep5812 PathwayStep5811 NF-kB migrates to the nucleus and turns on transcription Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Once dissociated from IkB, NF-kB moves to the nucleus. Once in the nucleus, NF-kB binds DNA at promoters of target genes. This entails transcription of several genes including the two HLH transcriptional regulators HES1 and HES5. HES1 and HES5 transcription can also be activated via NOTCH signalling. Increased production of HES1 and HES5 reduces the number of primary dendrites and promotes dendrite elongation. Pubmed15496460 Reactome Database ID Release 43193691 Reactome, http://www.reactome.org ReactomeREACT_13816 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 PathwayStep5810 IkB is ubiquitinated and degraded Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Once dissociated from NF-kB, the phosphorylated IkB protein is ubiquitinated at lysines 21 and 22, and degraded by the proteosome. Reactome Database ID Release 43209536 Reactome, http://www.reactome.org ReactomeREACT_13676 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 IKKbeta phosphorylates IkB causing NF-kB to dissociate Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Edited: Jassal, B, 2008-05-20 12:26:36 IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits. A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). NGF stimulates the activity of the IkB kinase IKK-beta, and, possibly, IKK-alpha as well. Once IkB is phosphorylated, the IkB:NF-kB complex dissociates. Pubmed9252186 Reactome Database ID Release 43193705 Reactome, http://www.reactome.org ReactomeREACT_13502 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 has a Stoichiometric coefficient of 2 PathwayStep5816 PathwayStep5815 PathwayStep5814 PathwayStep5813 p62 is recruited and forms a complex with TRAF6 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NGF binding to p75NTR induces recruitment of the atypical PKC interacting protein, p62, necessary for coupling IKKbeta with p75NTR. The kinase activity of IRAK1 is necessary for p62 (sequestosome-1) recruitment. IRAK1 interaction with TRAF6 precedes (1 min) its interaction with p62 (5 min). p62 has two protein interaction domains, named UBA and PB1. The UBA domain binds non-covalently to polyubiquitin chains. The PB1 domain has structural homology with the UbL (ubiquitin like) domain, and is able to interact with the 26S proteasome subunit Rpt1. Other protein interaction domains also exist within p62, suggesting that it may have a role in the formation of multimeric signalling complexes.p62 forms a complex with TRAF6, which involves the two domains PB1 at the p62 C-terminal end, and UBA, at the N-terminus. Pubmed10747026 Pubmed11244088 Reactome Database ID Release 43193694 Reactome, http://www.reactome.org ReactomeREACT_13754 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 PathwayStep5819 MYD88 dissociates After recruiting IRAK, MYD88 leaves the receptor complex. The amount of MYD88 that associates with p75 peaks at 1 min of NGF treatment and declines thereafter. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed9575168 Reactome Database ID Release 43193665 Reactome, http://www.reactome.org ReactomeREACT_13439 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 PathwayStep5818 IRAK interacts with TRAF6 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Neurotrophin binding to p75NTR leads to recruitment of TRAF6. This protein is an E3 ubiquitin ligase, which, together with an E2 Ubiquitin conjugating enzyme, mediates the assembly of lysine 63-linked polyubiquitin chains and their attachment to a lysine of a substrate protein. Activation of IRAK1 promotes recruitment of TRAF6. TRAF6 is able to bind to p75NTR (juxtamembrane region, residues 113-128), IRAK1 (N-terminal residues 1-198 and C-terminal residues 523-618), and MYD88. It might be recruited through the MYD88:IRAK1 complex. Pubmed9915784 Reactome Database ID Release 43193695 Reactome, http://www.reactome.org ReactomeREACT_13584 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 PathwayStep5817 RZZ complex Reactome DB_ID: 377885 Reactome Database ID Release 43377885 Reactome, http://www.reactome.org ReactomeREACT_15105 has a Stoichiometric coefficient of 1 IKKbeta is activated Atypical PKC isoforms phosphorylate the beta subunit of the IKK complex (on Serines 177 and 181) thereby serving as an IKK kinase. TRAF6 and p62 as well appear to have a role in IKK activation. TRAF6 mediates the assembly of K63-linked poly-Ub chains required for IKK activation. The ubiquitin binding property of p62 may also be relevant in regulating IKK activation. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed10022904 Reactome Database ID Release 43193703 Reactome, http://www.reactome.org ReactomeREACT_13726 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 has a Stoichiometric coefficient of 4 Kinetochore Reactome DB_ID: 375305 Reactome Database ID Release 43375305 Reactome, http://www.reactome.org ReactomeREACT_14970 has a Stoichiometric coefficient of 1 IKK-beta is recruited Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NGF stimulation results in recruitment of IKK-beta (Inhibitor of nuclear factor kappa-B kinase subunit beta) to the p75NTR receptor complex. IKK-beta recruitment involves p62. Reactome Database ID Release 43193641 Reactome, http://www.reactome.org ReactomeREACT_13512 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p-S62-ARPP19/p-S67-ENSA:PP2A-PPP2R2D Reactome DB_ID: 2430556 Reactome Database ID Release 432430556 Reactome, http://www.reactome.org ReactomeREACT_150546 has a Stoichiometric coefficient of 1 p62 recruits an atypical PKC Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed11244088 Reactome Database ID Release 43193684 Reactome, http://www.reactome.org ReactomeREACT_13586 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The atypical protein kinase C-iota isoform (aPKC-i) is recruited to the p75NTR receptor complex by p62 and becomes active. p62 recruits aPKC both via TRAF6 and RIP2. PP2A-PPP2R2D PP2A complex (containing PPP2R2D) Reactome DB_ID: 2430554 Reactome Database ID Release 432430554 Reactome, http://www.reactome.org ReactomeREACT_150946 Serine/threonine-protein phosphatase 2A complex with regulatory subunit PPP2R3D has a Stoichiometric coefficient of 1 TRAF6 is auto-ubiquitinated Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed15465037 Reactome Database ID Release 43209566 Reactome, http://www.reactome.org ReactomeREACT_13753 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The activity of TRAF6 is regulated by autoubiquitination. This process, in turn, is regulated by p62. Cells devoid of p62 exhibit low basal TRAF6 polyubiquitination. When p62 is expressed, auto-ubiquitination of TRAF6 is enhanced. The details curated in this event represent the ubiquitination of TRAF6, even as ubiquitin is shown as 1 stoichiometrically. p-Y204-ERK1b homodimer Reactome DB_ID: 2422444 Reactome Database ID Release 432422444 Reactome, http://www.reactome.org ReactomeREACT_148368 has a Stoichiometric coefficient of 2 p-Y204-ERK1-3 homodimer p-Y204-MAPK3-3 homodimer p-STAG2,RAD21-Ac-Cohesin:PDS5:p-CDCA5:WAPAL Reactome DB_ID: 2484814 Reactome Database ID Release 432484814 Reactome, http://www.reactome.org ReactomeREACT_150555 has a Stoichiometric coefficient of 1 p-SA2,RAD21-Ac-Cohesin:PDS5:p-Sororin:WAPAL p-STAG2,RAD21-Ac-Cohesin Reactome DB_ID: 1638794 Reactome Database ID Release 431638794 Reactome, http://www.reactome.org ReactomeREACT_152379 has a Stoichiometric coefficient of 1 p-Ac-Cohesin:PDS5:WAPAL Reactome DB_ID: 2484812 Reactome Database ID Release 432484812 Reactome, http://www.reactome.org ReactomeREACT_151851 has a Stoichiometric coefficient of 1 p-Ac-Cohesin Reactome DB_ID: 2484807 Reactome Database ID Release 432484807 Reactome, http://www.reactome.org ReactomeREACT_151516 has a Stoichiometric coefficient of 1 Sister Chromosomal Arms:Ac-Cohesin:PDS5:p-CDCA5:WAPAL Reactome DB_ID: 2468274 Reactome Database ID Release 432468274 Reactome, http://www.reactome.org ReactomeREACT_151061 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Ac-Cohesin:PDS5:p-CDCA5:WAPAL Ac-Cohesin:PDS5:p-Sororin:WAPAL Reactome DB_ID: 2468272 Reactome Database ID Release 432468272 Reactome, http://www.reactome.org ReactomeREACT_151560 has a Stoichiometric coefficient of 1 Sister Chromosomal Arms:p-STAG2,RAD21-Ac-Cohesin:PDS5:p-CDCA5:WAPAL Reactome DB_ID: 1638805 Reactome Database ID Release 431638805 Reactome, http://www.reactome.org ReactomeREACT_151301 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5830 PathwayStep5821 p75NTR interacts with RIP2 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed11487608 Reactome Database ID Release 43193656 Reactome, http://www.reactome.org ReactomeREACT_13404 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The RIP2 (receptor-interacting protein-2) kinase is a mediator of NGF-dependent NF-kB activity. It contains a serine/threonine kinase domain and a caspase recruitment domain (CARD) at the C terminus. It binds to the death domain of p75NTR via its CARD domain in an NGF-dependent manner. RIP2 may also bind TRAF proteins, suggesting the existence of complexes of TRAF and RIP2 proteins with the p75 receptor. RIP2 is also able to interact with p62. It is highly expressed in Schwann cells. PathwayStep5820 PRDM4 inhibits cyclin E transcription Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Reactome Database ID Release 43205056 Reactome, http://www.reactome.org ReactomeREACT_13434 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Within the nucleus, PRDM4 is found in a complex with HDACs (histone deacetylases) 1, 2, and 3. It interacts with the regulatory regions of the cyclin E gene, strongly inhibiting transcription. It was also shown to weakly affect cyclib B transcription. PRDM4 is believed to interact with regulatory regions of other genes, which are unknown. PathwayStep5823 IRAK is activated Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Edited: Jassal, B, 2008-05-20 12:26:36 Reactome Database ID Release 43193647 Reactome, http://www.reactome.org ReactomeREACT_13775 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Upon recruitment to p75NTR, Interleukin-1 receptor-associated kinase (IRAK) is rapidly phosphorylated and activated by an unknown mechanism and protein. has a Stoichiometric coefficient of 2 PathwayStep5822 p75NTR interacts with IRAK:MYD88 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Reactome Database ID Release 43193686 Reactome, http://www.reactome.org ReactomeREACT_13503 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The serine/threonine kinase IRAK (interleukin-1 receptor-associated kinase) is necessary for NF-kB activation. Under basal conditions, IRAK is not bound to the p75 receptor, and stays inactive in the cytoplasm. It associates with p75NTR following neurotrophin binding. MYD88 functions as an adapter, by recruiting IRAK to the p75 receptor. Upon stimulation with NGF, a MYD88: IRAK1 complex quickly forms that is recruited to p75NTR. PathwayStep5825 PathwayStep5824 PathwayStep5827 PathwayStep5826 PathwayStep5829 PathwayStep5828 p75NTR binds to NADE Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed10764727 Pubmed11830582 Reactome Database ID Release 43193650 Reactome, http://www.reactome.org ReactomeREACT_13536 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The NADE protein interacts with p75NTR to mediate cell death. The interaction is mediated by NADE NES (nuclear export signal), also responsible for self-association of NADE (Mukai J et al, 2002). Polyubiquitinated NRIF migrates to the nucleus Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NRIF polyubiquitination is necessary for nuclear translocation. The carboxyl terminus of NRIF mediates nuclear localization, whereas the amino terminus prevents it. Once in the nucleus, NRIF regulates gene expression, acting as a transcriptional repressor. Pubmed16630834 Reactome Database ID Release 43204947 Reactome, http://www.reactome.org ReactomeREACT_13601 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 14-3-3epsilon attentuates NADE-related apoptosis Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NADE forms a complex with the 14-3-3epsilon isoform. The last one interacts with caspase 3 through its C terminal region. The NADE:4-3-3epsilon complex negatively regulates p75NTR-mediated apoptosis, probably by down regulating caspase activity. Pubmed11278287 Reactome Database ID Release 43204981 Reactome, http://www.reactome.org ReactomeREACT_13657 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 NDC80 complex Reactome DB_ID: 375444 Reactome Database ID Release 43375444 Reactome, http://www.reactome.org ReactomeREACT_15005 has a Stoichiometric coefficient of 1 p75NTR:NADE promotes caspase2/3 activation Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Once bound to the NGF:p75NTR complex, NADE contributes to cell death signalling by promoting activation of caspases 2 and 3. It is unclear whether JNK activation is involved. The apoptotic function of NADE was observed in oligodendrocytes (Mukai et al. 2002). Pubmed11830582 Reactome Database ID Release 43205117 Reactome, http://www.reactome.org ReactomeREACT_13533 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 KMN network Reactome DB_ID: 377745 Reactome Database ID Release 43377745 Reactome, http://www.reactome.org ReactomeREACT_14928 has a Stoichiometric coefficient of 1 PRDM4 translocates to the nucleus Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 PRDM4 is found in the cytoplasm. Following binding of NGF to p75NTR, after 1 hour of NGF treatment, PRDM4 is redistributed from the cytoplasm to the nucleus. The relocalisation of PRDM4 appears to be specific for NGF, as it is not affected by BDNF or NT3. Reactome Database ID Release 43193661 Reactome, http://www.reactome.org ReactomeREACT_13744 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Microtubule-bound kinetochore Reactome DB_ID: 375303 Reactome Database ID Release 43375303 Reactome, http://www.reactome.org ReactomeREACT_15175 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 15 PRDM4 (SC1) binds to p75NTR Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 PRDM4, usually named SC1, for Schwann Cell factor 1, is a zinc finger protein that functions as a repressor of transcription. It is present in many tissues, and abundant in brain. It interacts with the NGF:p75NTR complex to signal cell cycle arrest. It is unclear whether it already forms a complex with p75NTR before NGF binding to p75. Reactome Database ID Release 43193643 Reactome, http://www.reactome.org ReactomeREACT_13469 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Mis12 complex Reactome DB_ID: 375441 Reactome Database ID Release 43375441 Reactome, http://www.reactome.org ReactomeREACT_15104 has a Stoichiometric coefficient of 1 Polyubiquitinated NRIF binds to p62 (Sequestosome) Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Binding of NRIF to p62 (Sequestosome) is suspected to modulate NRIF transcriptional activity. Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed16252010 Reactome Database ID Release 43205008 Reactome, http://www.reactome.org ReactomeREACT_13460 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 TRAF6 polyubiquitinates NRIF Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 6.3.2.19 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed16252010 Reactome Database ID Release 43205118 Reactome, http://www.reactome.org ReactomeREACT_13488 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 TRAF6 attaches a lysine 63-linked polyubiquitin chain to lysine 19 of NRIF. Mutation of NRIF lysine 19 prevents p75-mediated apoptosis. p75NTR cleavage by gamma-secretase is required for NRIF ubiquitination. gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 3.4 Edited: Jassal, B, 2008-05-20 12:26:36 Neurotrophin or proneurotrophin signalling promotes p75NTR cleavage by gamma-secretase, allowing the release of p75 ICD and NRIF. This mechanism was shown in sympathetic neurons.<br>Gamma-secretase can be activated in a number of ways, including signalling via p75NTR. The phorbol esther PMA induces p75 cleavage, followed by NRIF nuclear translocation, after 30 min. Neurotrophin binding to p75, instead, triggers the same events only after 12 h. Pubmed16630834 Reactome Database ID Release 43205112 Reactome, http://www.reactome.org ReactomeREACT_13710 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 NRIF and TRAF6 may activate JNK Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NRIF and TRAF6 appear to cooperate in JNK activation. TRAF6 is involved both in JNK activation and in NF-kB activation. Although the NRIF:TRAF6 interaction enhances by threefold the TRAF6-mediated activation of JNK, it only modestly affects TRAF6-mediated activation of NF-kB. Reactome Database ID Release 43204949 Reactome, http://www.reactome.org ReactomeREACT_13422 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 has a Stoichiometric coefficient of 2 TRAF6 binds to p75NTR:NRIF Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed14960584 Reactome Database ID Release 43193669 Reactome, http://www.reactome.org ReactomeREACT_13785 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Upon neurotrophin stimulation, p75NTR interacts with the ubiquitin 3 ligase TRAF6 (TNF receptor-associated factor 6). It is unclear whether TRAF6 binds to p75NTR directly, or whether it needs to be recruited through an adaptor protein such as MyD88.Recruitment of NRIF and TRAF6 to p75NTR is followed by an interaction between the two cytoplasmic proteins, It is possible that the NRIF:TRAF6 interaction promotes formation of a multimeric signalling complex. TRAF6 appears to promote NRIF release from p75NTR NRIF binds to p75NTR Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NRIF is a ubiquitously expressed zinc finger protein of the Kruppel family that may transduce cell death signals during development and functions in association with TRAF6 to induce activation of JNK. NRIF-induced cell death through p75NTR requires p53 and NRIF nuclear translocation, which is modulated by TRAF6-mediated polyubiquitination of NRIF at lysine 63. Reactome Database ID Release 43193677 Reactome, http://www.reactome.org ReactomeREACT_13687 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Active JNK moves to the nucleus and phosphorylates different transcription factors Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12097334 Reactome Database ID Release 43193666 Reactome, http://www.reactome.org ReactomeREACT_13632 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The different molecules listed (NRAGE, NRIF, NADE, TRAF6) mediate, through unclear mechanisms, JNK activation by threonine and tyrosine phosphorylation. While active JNK does move to the nucleus and phosphorylates and activate transcription factors such as c-JUN and ATF2, these have not been implicated in p75-mediated cell death, but rather the direct activation of the cell death machinery by JNK has been implicated. p75 activates the intrinsic caspase pathway (involving mitochondrial release of cytochrome c, Apaf-1, and caspases-9) rather than the extrinsic (caspase-8) pathway activated by most other death receptors. JNK phosphorylates BIM, BAD and other targets Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Once activated, JNK phosphorylates targets in cytoplasm, including BIM and BAD that promote the release of cytochrome c and activation of caspases 9, 6 and 3. Pubmed14673001 Pubmed15470142 Reactome Database ID Release 43205075 Reactome, http://www.reactome.org ReactomeREACT_13777 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 has a Stoichiometric coefficient of 2 GTP-bound RAC contributes to JNK activation Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed9520479 RAC activation was described as essential for p75NTR to induce JNK and apoptosis in cortical oligodendrocytes. The simultaneous activation of TRKA counteracts the apoptotic action of p75, by modulating the kinetics of p75-mediated RAC activation. Reactome Database ID Release 43205136 Reactome, http://www.reactome.org ReactomeREACT_13538 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 has a Stoichiometric coefficient of 2 p75NTR indirectly activates RAC and Cdc42 via a guanyl-nucleotide exchange factor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Following NGF binding, p75NTR activates the RAC (Ras-related C3 botulinum toxin substrate) GTPase. Pubmed11756498 Reactome Database ID Release 43205039 Reactome, http://www.reactome.org ReactomeREACT_13694 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p-T216,S189,S274,S373-GORASP1:p-S37-GOLGA2:p-RAB1:GTP:PLK1 Reactome DB_ID: 2314414 Reactome Database ID Release 432314414 Reactome, http://www.reactome.org ReactomeREACT_148029 has a Stoichiometric coefficient of 1 GORASP2:BLZF1:RAB2A:GTP Reactome DB_ID: 2422429 Reactome Database ID Release 432422429 Reactome, http://www.reactome.org ReactomeREACT_148276 has a Stoichiometric coefficient of 1 RAB2A:GTP Reactome DB_ID: 2422449 Reactome Database ID Release 432422449 Reactome, http://www.reactome.org ReactomeREACT_148087 has a Stoichiometric coefficient of 1 p-T222,225-GORASP2:BLZF1:RAB2A:GTP Reactome DB_ID: 2422951 Reactome Database ID Release 432422951 Reactome, http://www.reactome.org ReactomeREACT_148269 has a Stoichiometric coefficient of 1 p-ERK1b/p-ERK2 homodimer Converted from EntitySet in Reactome Reactome DB_ID: 2422450 Reactome Database ID Release 432422450 Reactome, http://www.reactome.org ReactomeREACT_148329 p-Y204-MAPK3-3/p-T185,Y187-MAPK1 homodimer PathwayStep5803 NRAGE activates JNK Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Reactome Database ID Release 43205132 Reactome, http://www.reactome.org ReactomeREACT_13427 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The NGF:p75:NRAGE complex promotes threonine and tyrosine phosphorylation, and activation of JNK, by an unknown mechanism. has a Stoichiometric coefficient of 2 PathwayStep5802 NRAGE sequesters CHE1 in the cytoplasm Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 CHE1, also named AATF, is an Apoptosis Antagonizing Transcription Factor in cortical neurons. NRAGE binds to CHE1, inhibiting its nuclear localization by sequestering it in the cytoplasm, and, consequently, antagonizes its anti-apoptotic function. Edited: Jassal, B, 2008-05-20 12:26:36 Reactome Database ID Release 43204958 Reactome, http://www.reactome.org ReactomeREACT_13683 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 PathwayStep5805 PathwayStep5804 Binding of pro-NGF to p75NTR:sortilin Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed11729324 Pubmed14985763 Pubmed16855103 Reactome Database ID Release 43193642 Reactome, http://www.reactome.org ReactomeREACT_13684 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Sortilin is a membrane protein that acts as co-receptor for p75NTR. Superior cervical ganglion (SCG) neurons, vascular smooth muscle (SM-11) cells, oligodendrocytes and CNS neurons (including basal forebrain neurons) (Volosin et al, 2006) express significant levels of sortilin and p75NTR. Schwann cells, instead, do not express sortilin. It is expressed during embryogenesis in areas where NGF and proNGF have well-characterized effects. It is important for proNGF signalling, but has little or no role on mature NGF initiated signalling. ProNGF preferentially binds to a p75NTR:sortilin complex, whereas mature NGF preferentially binds p75NTR alone. ProNGF binds to p75NTR with a dissociation constant (Kd) ~15-20 nM, and to sortilin with a Kd ~5 nM. In the presence of sortilin, proNGF binds to p75NTR with a Kd 0.2 nM. In contrast, mature NGF binds to p75NTR with a Kd of 1-2 nM, whereas it binds sortilin very weakly (Kd ~ 90 nM). Therefore, in the presence of sortilin, p75NTR binds more strongly to proNGF than to NGF, and proNGF signalling predominates. In the absence of sortilin, NGF binding is stronger than proNGF, and it is the mature NGF signalling that prevails. proNGF interacts with sortilin via its pro-domain, whereas the interaction with p75NTR is mediated by the mature domain. Pro-beta-NGF and mature beta-NGF are secreted Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Both mature neurotrophin and pro-neurotrophin are released extracellularly and are biologically active. The precursor proNGF, instead of mNGF (mature NGF), is the molecular form preferentially released by neurons in an activity-dependent manner. Neurotrophins are secreted in low amounts from several tissues, mainly from target tissues of innervating neurons. In the nervous system, they are secreted by neurons, astrocytes and microglia. Neurotrophin secretion can be both constitutive and regulated. Constitutive release is observed in cells lacking a regulated pathway, and additional stimulus-dependent regulated secretion is evident in those cells where this route is available. Secretion is regulated by a number of stimuli, including neurotrophins themselves. In neurons, regulated secretion appears to be the prevalent pathway. NGF is secreted from the cell soma and the dendrites, while it is unclear whether it can also be secreted by axons. Constitutive secretion of NGF is observed only from the soma and the most proximal dendrites. Similar considerations hold for the other neurotrophins as well. Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed12787574 Reactome Database ID Release 43187035 Reactome, http://www.reactome.org ReactomeREACT_10024 PathwayStep5801 NGF:p75NTR complex binds to NRAGE Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NRAGE (neurotrophin receptor-interacting MAGE homolog), a member of the MAGE family of proteins, is a cytoplasmic protein that mediates neurotrophin-induced cell death. NRAGE binding is stimulated following NGF (or proNGF) binding to p75NTR. Some studies indicate that NRAGE expression is limited to proliferative neural populations, whereas others indicate its presence in differentiated neurons in hippocampus. Another MAGE protein, Necdin, was reported to interact with p75NTR and affect cell death. Reactome Database ID Release 43205115 Reactome, http://www.reactome.org ReactomeREACT_13480 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 PathwayStep5800 NGF homodimer binds to p75NTR Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed15131306 Pubmed17196528 Pubmed8120051 Reactome Database ID Release 43193653 Reactome, http://www.reactome.org ReactomeREACT_13649 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p75NTR exists in a multimeric form both in presence or absence of NGF. In the NGF:p75NTR complex, a single p75 molecule is asymmetrically bound to a NGF homodimer, along the homodimeric interface of NGF. This causes an allosteric conformational change, which disables the NGF symmetry-related second p75 binding site. Therefore, it is possible that NGF has to perturb or alter the preformed p75 dimer orientation in order to initiate intracellular signalling. NGF:p75NTR complexes are not so long living as the NGF:TRKA complexes. This is due, at least in part, to the fact that TRKA homodimers are internalized, and continue signalling in endosomes.<br>Contrary to what is commonly believed, NGF bind to p75NTR and TRKA, individually, with a similar equilibrium binding constant (Kd ~ 1-2 nM). As a matter of fact, the association constant for NGF binding to p75NTR (k+1 = 8x10 to power of 6 M-1 s-1) is faster than for TRKA (k+1 = 8x10 to power of 5 M-1 s-1). On the other hand, the off rate of the NGF:TRKA complex ( k-1 = 7.2x10 to power of -5 s-1) is much slower than the NGF:p75NTR complex (k-1 = 1x10 to power of -3 s-1) . p75NTR and TRK receptors functionally interact, but the precise means by which this occurs has remained unresolved. This could result from a direct physical interaction or be explained by convergent signalling of these two receptors. Co-expression of both p75NTR and TRKA at the cell surface appears to result in the formation of a “high-affinity” binding site that has an accelerated rate of NGF association and a 30- to 100-fold higher affinity for NGF (Kd ~ 1-3 x 10 to power of -11 M) than either receptor alone.<br>The high-affinity binding sites appear to constitute 10%–15% of the total NGF binding sites. The nature of such high affinity binding sites is still unclear. They could be due to a multimeric complex of p75:TRKA proteins. Alternatively, NGF might first rapidly bind to p75NTR and then be presented to TRKA in a conformation that lowers its TRKA association rate. Some authors even question the existence of these high affinity sites. Structural data on NGF complexes with p75NTR and TRKA extracellular domains suggest that formation of a ternary complex TRKA:NGF:p75NTR in a 1:2:1 ration is theoretically possible, although unlikely. However, biochemical data so far failed to show that this complex forms. pro-beta-NGF dimerizes Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43167047 Reactome, http://www.reactome.org ReactomeREACT_10027 Reviewed: Greene, LA, 2007-11-08 15:39:37 The pro-neurotrophin (pro-NGF: 27 kDa) spontaneously forms stable, non-covalent dimers directly in the ER. The homodimer is associated by noncovalent forces, with an equilibrium dissociation constant of 10 pM. The neurotrophin pro- domain is important for proper folding and intracellular sorting. Heterodimers of different neurotrophin monomers can also be generated at the ER.<br> has a Stoichiometric coefficient of 2 The signal peptide is excised from beta-NGF pre-pro-precursor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Pre-pro- precursors of the neurotrophins NGF, BDNF, NT-3, NT-4/5 are synthesized in various cell types by endoplasmic reticulum (ER) attached ribosomes, leading to sequestration of the newly formed polypeptide chain into the ER. The mouse NGF gene gives rise to two major transcripts that contain NGF (12.5 kDa) at the C-terminus and differ by alternative splicing of an N-terminal exon, so that the large precursor (34 kDa) has 67 amino acids upstream of an internal signal peptide and the smaller precursor (27 kDa) has this signal peptide at its N-terminus. The transcript for the large precursor predominates in the submaxillary gland, whereas the transcript for the smaller precursor predominates in virtually all other tissues.<br>The signal peptide is cleaved off immediately after sequestration into the ER. Therefore, expression of either NGF transcript gives rise to an apparently identical intracellular glycosylated precursor formed by cleavage of the primary gene product after the signal peptide. Reactome Database ID Release 43187045 Reactome, http://www.reactome.org ReactomeREACT_10114 Reviewed: Greene, LA, 2007-11-08 15:39:37 Part of pro-beta-NGF is processed to mature beta-NGF Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 3.4.21 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed16025106 Pubmed18204444 Pubmed8615794 Reactome Database ID Release 43187020 Reactome, http://www.reactome.org ReactomeREACT_10058 The pro-neurotrophins are rapidly cleaved intra-cellularly by furin or the pro-protein convertases at a highly conserved site, to produce the mature protein of 12-14 kDa in size (mature NGF or beta-NGF: 12.5 kDa). Furin, PACE4 and PC7 belong to the constitutive secretory pathway; NEC1/PC1, NEC2/PC2, PC4 and PC5 are instead targeted to regulated secretory granules. Furin is expressed ubiquitously in all tissues, whereas NEC1 and NEC2 are the dominant pro-protein convertases in neurons. The mature neurotrophins can be stored within neurons and released extra-cellularly upon stimulation.<br>Cells, however, appear to have a limited capacity to process pro-neurotrophins, a capacity that may be exhausted when they are produced in excess (Matsumoto T et al, 2008). In this case, the proforms of NGF and BDNF are secreted and cleaved extracellularly by the serine protease plasmin and by selective matrix metalloproteinases (MMPs). The signalling capacities of pro-neurotrophins and mature neurotrophins are markedly different. The pro-neurotrophins are high affinity ligands for p75NTR and can induce p75NTR dependent apoptosis in cultured neurons with minimal activation of TRK receptor mediated differentiation or survival. The biological action of neurotrophins may thus be regulated by proteolytic cleavage, with proforms preferentially activating p75NTR to mediate apoptosis and mature forms activating TRK receptors to promote survival.<br>It is possible that pro-neurotrophins may somehow be released during development and eliminate neurons in a p75NTR dependent fashion. Substantial quantities of proNGF are found in the cerebrospinal fluid of adult rodents after brain injury, perhaps following NGF expression by inflammatory cells that may not efficiently process pro-neurotrophins. When proBDNF is added as recombinant protein, activation of p75NTR by proBDNF facilitates hippocampal long-term depression (LTD; Woo NH et al, 2005). However, it is unclear whether proBDNF plays any role in LTD under physiological conditions. pro-beta-NGF homodimer transits to the golgi apparatus Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 From the endoplasmic reticulum, the pro-neurotrophins transit to the golgi apparatus, most likely via intermediate non-clathrin-coated transport vesicles, and finally accumulate in the trans-golgi network (TGN). In the TGN, two different types of secretory vesicles can be generated and filled with neurotrophins: regulated and constitutive secretory vesicles. Reactome Database ID Release 43167014 Reactome, http://www.reactome.org ReactomeREACT_10040 PathwayStep5807 PathwayStep5806 PathwayStep5809 PathwayStep5808 Cohesin Complex Reactome DB_ID: 2545214 Reactome Database ID Release 432545214 Reactome, http://www.reactome.org ReactomeREACT_152002 has a Stoichiometric coefficient of 1 PDGF:phospho-PDGF receptor dimer:STAT Reactome DB_ID: 380766 Reactome Database ID Release 43380766 Reactome, http://www.reactome.org ReactomeREACT_17883 has a Stoichiometric coefficient of 1 Cleaved Cohesin Reactome DB_ID: 2467802 Reactome Database ID Release 432467802 Reactome, http://www.reactome.org ReactomeREACT_151089 has a Stoichiometric coefficient of 1 PDGF:Phospho-PDGF receptor dimer:Grb2:Sos1 Reactome DB_ID: 186827 Reactome Database ID Release 43186827 Reactome, http://www.reactome.org ReactomeREACT_18248 has a Stoichiometric coefficient of 1 Phospho-beta receptor homodimer:GAP Reactome DB_ID: 186830 Reactome Database ID Release 43186830 Reactome, http://www.reactome.org ReactomeREACT_17783 has a Stoichiometric coefficient of 1 PDGF:Phospho-PDGF receptor dimer:SHP2 Reactome DB_ID: 186839 Reactome Database ID Release 43186839 Reactome, http://www.reactome.org ReactomeREACT_17654 has a Stoichiometric coefficient of 1 PathwayStep5863 PathwayStep5862 PathwayStep5861 PathwayStep5860 Cyclin A:phospho-Cdk2(Thr 160):phospho-Cdh1:phospho-APC/C complex Reactome DB_ID: 188387 Reactome Database ID Release 43188387 Reactome, http://www.reactome.org ReactomeREACT_9272 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdk(Thr 160):Cdh1:phosho-APC/C complex Reactome DB_ID: 188374 Reactome Database ID Release 43188374 Reactome, http://www.reactome.org ReactomeREACT_9153 has a Stoichiometric coefficient of 1 ceramide:CERT:PPM1L:VAPA/B trimer Reactome DB_ID: 429705 Reactome Database ID Release 43429705 Reactome, http://www.reactome.org ReactomeREACT_20363 has a Stoichiometric coefficient of 1 phosphorylated anaphase promoting complex (APC/C) Reactome DB_ID: 174109 Reactome Database ID Release 43174109 Reactome, http://www.reactome.org ReactomeREACT_7542 has a Stoichiometric coefficient of 1 VEGFA,B,PLGF Converted from EntitySet in Reactome Reactome DB_ID: 195389 Reactome Database ID Release 43195389 Reactome, http://www.reactome.org ReactomeREACT_12921 VEGFA,B and PLGF homodimers Cdh1:phospho-APC/C complex Reactome DB_ID: 174250 Reactome Database ID Release 43174250 Reactome, http://www.reactome.org ReactomeREACT_7373 has a Stoichiometric coefficient of 1 VEGF homodimer Reactome DB_ID: 195376 Reactome Database ID Release 43195376 Reactome, http://www.reactome.org ReactomeREACT_12721 has a Stoichiometric coefficient of 2 multiphospho-CERT:PPM1L:VAPA/B trimer Reactome DB_ID: 429726 Reactome Database ID Release 43429726 Reactome, http://www.reactome.org ReactomeREACT_20055 has a Stoichiometric coefficient of 1 Cohesin:PDS5:WAPAL:NIPBL:MAU2:Chromosomal Arm Reactome DB_ID: 2470928 Reactome Database ID Release 432470928 Reactome, http://www.reactome.org ReactomeREACT_152392 has a Stoichiometric coefficient of 1 PDGF:Phospho-PDGF receptor dimer:Grb7 Reactome DB_ID: 381956 Reactome Database ID Release 43381956 Reactome, http://www.reactome.org ReactomeREACT_17607 has a Stoichiometric coefficient of 1 ceramide:CERT Reactome DB_ID: 429706 Reactome Database ID Release 43429706 Reactome, http://www.reactome.org ReactomeREACT_20304 has a Stoichiometric coefficient of 1 Cohesin:PDS5:WAPAL:NIPBL:MAU2:Centromere Reactome DB_ID: 2470943 Reactome Database ID Release 432470943 Reactome, http://www.reactome.org ReactomeREACT_151329 has a Stoichiometric coefficient of 1 PDGF:Phospho-PDGFR receptor dimer:Nck Reactome DB_ID: 381954 Reactome Database ID Release 43381954 Reactome, http://www.reactome.org ReactomeREACT_17490 has a Stoichiometric coefficient of 1 SPTLC1:SPTLC2 Reactome DB_ID: 428140 Reactome Database ID Release 43428140 Reactome, http://www.reactome.org ReactomeREACT_19643 has a Stoichiometric coefficient of 1 serine palmitoyltransferase 2 complex Cohesin:PDS5:WAPAL:NIPBL:MAU2:Chromatin Converted from EntitySet in Reactome Reactome DB_ID: 2537688 Reactome Database ID Release 432537688 Reactome, http://www.reactome.org ReactomeREACT_152029 PDGF:Phospho-PDGF receptor dimer:Crk:p130Cas:C3G Reactome DB_ID: 381957 Reactome Database ID Release 43381957 Reactome, http://www.reactome.org ReactomeREACT_17351 has a Stoichiometric coefficient of 1 SPTLC 2 or 3 complexes Converted from EntitySet in Reactome Reactome DB_ID: 428174 Reactome Database ID Release 43428174 Reactome, http://www.reactome.org ReactomeREACT_19691 serine palymitoyltransferase SCC2:SCC4 Cohesin Loading Complex NIPBL:MAU2 Reactome DB_ID: 2470930 Reactome Database ID Release 432470930 Reactome, http://www.reactome.org ReactomeREACT_151219 has a Stoichiometric coefficient of 1 PDGF:Phospho-PDGF receptor dimer:Crk Reactome DB_ID: 381955 Reactome Database ID Release 43381955 Reactome, http://www.reactome.org ReactomeREACT_17941 has a Stoichiometric coefficient of 1 ALOX12B:Fe2+ Reactome DB_ID: 2142822 Reactome Database ID Release 432142822 Reactome, http://www.reactome.org ReactomeREACT_152080 has a Stoichiometric coefficient of 1 ALOX12/15 Converted from EntitySet in Reactome Reactome DB_ID: 2161958 Reactome Database ID Release 432161958 Reactome, http://www.reactome.org ReactomeREACT_151613 ALOX12:Fe2+ Reactome DB_ID: 2142793 Reactome Database ID Release 432142793 Reactome, http://www.reactome.org ReactomeREACT_152143 has a Stoichiometric coefficient of 1 EPHX2 dimer Reactome DB_ID: 2142777 Reactome Database ID Release 432142777 Reactome, http://www.reactome.org ReactomeREACT_151689 has a Stoichiometric coefficient of 2 SOS phosphorylation and dissociation (SHC) At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'GRB2:SOS:SHC-P' are present. At the end of this reaction, 1 molecule of 'GRB2:SHC-P', 1 molecule of 'phospho-SOS', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.<br> Pubmed7739560 Reactome Database ID Release 43109822 Reactome, http://www.reactome.org ReactomeREACT_1420 CERT:PPM1L:VAPA/B trimer Reactome DB_ID: 429672 Reactome Database ID Release 43429672 Reactome, http://www.reactome.org ReactomeREACT_19603 has a Stoichiometric coefficient of 1 SOS phosphorylation and dissociation (IRS) At the beginning of this reaction, 4 molecules of 'ATP', and 1 molecule of 'GRB2:SOS:IRS-P' are present. At the end of this reaction, 1 molecule of 'GRB2:IRS-P', 1 molecule of 'phospho-SOS', and 4 molecules of 'ADP' are present.<br><br> This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.<br> Pubmed7739560 Pubmed8816480 Reactome Database ID Release 43109823 Reactome, http://www.reactome.org ReactomeREACT_169 has a Stoichiometric coefficient of 4 PPM1L:VAPA/B dimer Reactome DB_ID: 429703 Reactome Database ID Release 43429703 Reactome, http://www.reactome.org ReactomeREACT_19722 has a Stoichiometric coefficient of 1 Cleaved Cohesin:PDS5:WAPAL Reactome DB_ID: 2467805 Reactome Database ID Release 432467805 Reactome, http://www.reactome.org ReactomeREACT_150591 has a Stoichiometric coefficient of 1 De-phosphorylation of SHC At the beginning of this reaction, 1 molecule of 'phospho-SHC' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'SHC transforming protein' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase'.<br> EC Number: 3.1.3.48 Reactome Database ID Release 4374748 Reactome, http://www.reactome.org ReactomeREACT_1411 PathwayStep5855 Internalisation of the insulin receptor Almost concomitantly a second effect resulting from the tyrosine phosphorylation of the insulin receptor begins to occur. The phosphorylation of the tyrosine in the NPEY sequence found in the juxtamembrane is also a signal for endocytosis to occur. Whilst invagination of the plasma membrane commences the receptor tyrosine kinase activity continues unabated as does substrate phosphorylation.<p>As the invagination continues certain proteins are concentrated in the area of invagination. In addition to the insulin receptor itself there is a recruitment of insulin-specific protein tyrosine phosphatases (PTPs). This process takes less than one minute. (The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.)<p>The formation of the endosome containing the activated ligand-receptor complex is completed within two minutes following ligand presentation at the plasma membrane and is maximal by five minutes. Endocytosis of activated receptors has the dual effect of concentrating receptors within endosomes and allowing the insulin receptor tyrosine kinase to phosphorylate substrates that are spatially distinct from those accessible at the plasma membrane. The endosome also contains other proteins crucial to the signal transduction process. These include a proton pump and the insulin degrading activity. It is not certain how these proteins arrive in the endosome since it could be via the endosome maturation or fusion pathways. Authored: Bevan, AP, 2003-07-31 08:01:55 Pubmed18406720 Pubmed8760075 Pubmed9609114 Reactome Database ID Release 4374718 Reactome, http://www.reactome.org ReactomeREACT_599 PathwayStep5856 Endosome acidification Authored: Bevan, AP, 2003-07-31 08:01:55 Edited: Jassal, B, 2010-08-09 Pubmed3061785 Pubmed8682206 Pubmed9793760 Reactome Database ID Release 4374723 Reactome, http://www.reactome.org ReactomeREACT_2002 Reviewed: He, L, 2010-08-09 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome. The net effect of this is to lower the pH of the lumen from pH 7.4 (the pH at the plasma membrane) to pH 6.0 (documented with studies using FITC-labeled insulin - a pH dependent fluorescence marker). PathwayStep5853 SOS phosphorylation and dissociation (IRS, Crk) At the beginning of this reaction, 4 molecules of 'ATP', and 1 molecule of 'Crk:SOS:IRS-P' are present. At the end of this reaction, 1 molecule of 'Crk:IRS-P', 1 molecule of 'phospho-SOS', and 4 molecules of 'ADP' are present.<br><br> This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.<br> Pubmed8810325 Pubmed8816480 Reactome Database ID Release 43109827 Reactome, http://www.reactome.org ReactomeREACT_26 has a Stoichiometric coefficient of 4 PathwayStep5854 Binding of Grb10 to the insulin receptor At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'GRB10' are present. At the end of this reaction, 1 molecule of 'GRB10:INSR' is present.<br><br> This reaction takes place on the 'internal side of plasma membrane'.<br> Pubmed12493740 Pubmed14615605 Reactome Database ID Release 43110011 Reactome, http://www.reactome.org ReactomeREACT_509 PathwayStep5859 Re-integration of insulin receptor into plasma membrane Authored: Bevan, AP, 2003-07-31 08:01:55 Pubmed2986535 Reactome Database ID Release 4374734 Reactome, http://www.reactome.org ReactomeREACT_490 The endosome fuses with the plasma membrane allowing the insulin receptor to re-integrate there. Any degraded insulin remnants which remained in the endosome are also expelled (The majority having been excreted into the cytoplasm and secreted out of the cell via other mechanisms).<p>The cycle is complete with the dephosphorylated receptor now back in the plasma membrane available to bind the next insulin molecule presented to it. There is some insulin receptor degradation over time when damaged insulin receptors are not recycled but fuse instead with the lysosomes where they are degraded. However the majority of insulin receptors are recycled back to the plasma membrane with greater than 95% efficiency. PathwayStep5857 Dissociation of insulin from insulin receptor As the endosomal lumen acidifies the insulin dissociates from the insulin receptor making it available for degradation by the insulin degrading activity (IDA) present in the endosomal membrane. Authored: Bevan, AP, 2003-07-31 08:01:55 Pubmed3061785 Pubmed8682206 Pubmed9793760 Reactome Database ID Release 4374726 Reactome, http://www.reactome.org ReactomeREACT_134 PathwayStep5858 Insulin receptor de-phosphorylation Authored: Bevan, AP, 2003-07-31 08:01:55 EC Number: 3.1.3.48 Pubmed18406720 Pubmed9609117 Reactome Database ID Release 4374733 Reactome, http://www.reactome.org ReactomeREACT_453 With insulin dissociated from its receptor the signal to sustain the receptor kinase's activity is also removed. Thus endosomally-associated protein tyrosine phosphatases (PTPs) are able to dephosphorylate the receptor which now can not rephosphorylate themselves since insulin is removed and the receptor is in the inactive protein conformation. (The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.)<p>The dephosphorylation of the receptor is also a signal for the receptor to recycle back to the plasma membrane. has a Stoichiometric coefficient of 12 phospho-Cdh1:phospho-APC/C complex Reactome DB_ID: 174167 Reactome Database ID Release 43174167 Reactome, http://www.reactome.org ReactomeREACT_7124 has a Stoichiometric coefficient of 1 PDGF alpha receptor: PDGF dimers Reactome DB_ID: 389079 Reactome Database ID Release 43389079 Reactome, http://www.reactome.org ReactomeREACT_17393 has a Stoichiometric coefficient of 1 PathwayStep5870 Emi1:Cdc20 complex Reactome DB_ID: 174186 Reactome Database ID Release 43174186 Reactome, http://www.reactome.org ReactomeREACT_7552 has a Stoichiometric coefficient of 1 PDGF alpha/beta:PDGF AB and BB dimers Reactome DB_ID: 389077 Reactome Database ID Release 43389077 Reactome, http://www.reactome.org ReactomeREACT_17544 has a Stoichiometric coefficient of 1 Emi1:Cdh1 complex Reactome DB_ID: 174247 Reactome Database ID Release 43174247 Reactome, http://www.reactome.org ReactomeREACT_7054 has a Stoichiometric coefficient of 1 Phospho PDGF alpha receptor:PDGF dimers Reactome DB_ID: 389073 Reactome Database ID Release 43389073 Reactome, http://www.reactome.org ReactomeREACT_17261 has a Stoichiometric coefficient of 1 PathwayStep5872 PathwayStep5871 PathwayStep5874 PathwayStep5873 GLA dimer Reactome DB_ID: 1605744 Reactome Database ID Release 431605744 Reactome, http://www.reactome.org ReactomeREACT_116236 has a Stoichiometric coefficient of 2 phospho-Emi1(Ser 145, Ser 149):Cdc20/Cdh1 complexes Reactome DB_ID: 177318 Reactome Database ID Release 43177318 Reactome, http://www.reactome.org ReactomeREACT_7621 has a Stoichiometric coefficient of 1 PDGF:Phospho-PDGF receptor dimer:Src Reactome DB_ID: 186831 Reactome Database ID Release 43186831 Reactome, http://www.reactome.org ReactomeREACT_18132 has a Stoichiometric coefficient of 1 bHEXB Reactome DB_ID: 1605749 Reactome Database ID Release 431605749 Reactome, http://www.reactome.org ReactomeREACT_116222 beta-hexosaminidase B has a Stoichiometric coefficient of 2 phospho-Emi1(Ser 182):Cdc20/Cdh1:complexes Reactome DB_ID: 177328 Reactome Database ID Release 43177328 Reactome, http://www.reactome.org ReactomeREACT_7631 has a Stoichiometric coefficient of 1 PDGF:p-PDGFR dimer:p-PLCgamma Reactome DB_ID: 1524184 Reactome Database ID Release 431524184 Reactome, http://www.reactome.org ReactomeREACT_111673 has a Stoichiometric coefficient of 1 SCF-beta-TrCP1 complex Reactome DB_ID: 174155 Reactome Database ID Release 43174155 Reactome, http://www.reactome.org ReactomeREACT_6992 has a Stoichiometric coefficient of 1 PDGF:Phospho-PDGF receptor dimer:phospho-Src Reactome DB_ID: 380768 Reactome Database ID Release 43380768 Reactome, http://www.reactome.org ReactomeREACT_17206 has a Stoichiometric coefficient of 1 SMPD2,3:Mg2+ Reactome DB_ID: 1606266 Reactome Database ID Release 431606266 Reactome, http://www.reactome.org ReactomeREACT_117063 has a Stoichiometric coefficient of 1 Phospho-Emi1(Ser 182):Cdc20/Cdh1 complexes Reactome DB_ID: 186975 Reactome Database ID Release 43186975 Reactome, http://www.reactome.org ReactomeREACT_9362 has a Stoichiometric coefficient of 1 Phospho PDGF alpha-beta dimer:PDGF AB or BB dimers Reactome DB_ID: 389076 Reactome Database ID Release 43389076 Reactome, http://www.reactome.org ReactomeREACT_17875 has a Stoichiometric coefficient of 1 active ARSA:Ca2+ Reactome DB_ID: 1606814 Reactome Database ID Release 431606814 Reactome, http://www.reactome.org ReactomeREACT_117367 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Emi1:Cdc20/Cdh1 complex Reactome DB_ID: 188679 Reactome Database ID Release 43188679 Reactome, http://www.reactome.org ReactomeREACT_9334 has a Stoichiometric coefficient of 1 PDGF AB or BB homodimers Converted from EntitySet in Reactome Reactome DB_ID: 389071 Reactome Database ID Release 43389071 Reactome, http://www.reactome.org ReactomeREACT_17191 active ARSA:Ca2+ Reactome DB_ID: 1614355 Reactome Database ID Release 431614355 Reactome, http://www.reactome.org ReactomeREACT_117040 has a Stoichiometric coefficient of 1 phospho-Emi1:Cdc20/Cdh1 complexes Converted from EntitySet in Reactome Reactome DB_ID: 177332 Reactome Database ID Release 43177332 Reactome, http://www.reactome.org ReactomeREACT_7348 PDGF:Phospho-PDGF receptor dimer:PLC-gamma Reactome DB_ID: 186795 Reactome Database ID Release 43186795 Reactome, http://www.reactome.org ReactomeREACT_17327 has a Stoichiometric coefficient of 1 ARSA dimer Reactome DB_ID: 1614339 Reactome Database ID Release 431614339 Reactome, http://www.reactome.org ReactomeREACT_122323 has a Stoichiometric coefficient of 1 phospho-Emi1(Ser 145, Ser 149):Cdc20/Cdh1 complexes Reactome DB_ID: 176446 Reactome Database ID Release 43176446 Reactome, http://www.reactome.org ReactomeREACT_7571 has a Stoichiometric coefficient of 1 PDGF:Phospho-PDGF receptor dimer Reactome DB_ID: 186811 Reactome Database ID Release 43186811 Reactome, http://www.reactome.org ReactomeREACT_17756 has a Stoichiometric coefficient of 1 multienzyme complex Reactome DB_ID: 1605684 Reactome Database ID Release 431605684 Reactome, http://www.reactome.org ReactomeREACT_117655 has a Stoichiometric coefficient of 1 CTSA dimer Reactome DB_ID: 1605630 Reactome Database ID Release 431605630 Reactome, http://www.reactome.org ReactomeREACT_117036 has a Stoichiometric coefficient of 1 SPTLC1:SPTLC3 Reactome DB_ID: 428177 Reactome Database ID Release 43428177 Reactome, http://www.reactome.org ReactomeREACT_19819 has a Stoichiometric coefficient of 1 serine palmitoyltransferase 3 complex GM2A:GM2 Reactome DB_ID: 1605600 Reactome Database ID Release 431605600 Reactome, http://www.reactome.org ReactomeREACT_117099 has a Stoichiometric coefficient of 1 Phosphorylated AMPK binds AMP Authored: Katajisto, P, Makela, T, Wu, J, 2008--1-1- Edited: Jassal, B, 2008-11-19 15:14:38 If AMP:ATP ratio rises, AMP (instead of ATP) is bound by the AMPK-gamma subunit, which inhibits the dephosphorylation of the AMPK-alpha subunit resulting in activation of AMPK. It is not clear, as of yet, whether AMP binds to unphosphorylated AMPK. Pubmed16943194 Pubmed8549768 Reactome Database ID Release 43380930 Reactome, http://www.reactome.org ReactomeREACT_21293 Reviewed: Zheng, B, 2009-10-20 bHEX Converted from EntitySet in Reactome Reactome DB_ID: 1605607 Reactome Database ID Release 431605607 Reactome, http://www.reactome.org ReactomeREACT_116264 beta-hexosaminidases AMPK phosphorylates Raptor Activated AMPK (phosphorylated on Thr172/Thr174 and AMP bound) phosphorylates Raptor on Ser 722 and Ser 792. These phosphorylations are required for inhibition of mTORC1 activity in response to energy stress (Gwinn DM et al, 2008). Authored: Katajisto, P, Makela, T, Wu, J, 2010-02-03 Edited: Jassal, B, 2009--1-1- Pubmed18439900 Reactome Database ID Release 43447074 Reactome, http://www.reactome.org ReactomeREACT_21413 Reviewed: Zheng, B, 2009-10-20 has a Stoichiometric coefficient of 2 PathwayStep5864 Phosphorylated AMPK phosphorylates TSC2 Activated AMPK (phosphorylated on the alpha subunit and AMP bound) phosphorylates TSC2 on Ser1387, thereby activating the GAP activity of the TSC complex via an unknown mechanism. Authored: Katajisto, P, Makela, T, Wu, J, 2008--1-1- Edited: Jassal, B, 2008-11-19 15:14:38 Pubmed14651849 Reactome Database ID Release 43380927 Reactome, http://www.reactome.org ReactomeREACT_21348 Reviewed: Zheng, B, 2009-10-20 PathwayStep5865 TSC2 activates intrinsic GTPase activity of Rheb Authored: Katajisto, P, Makela, T, Wu, J, 2008--1-1- Edited: Jassal, B, 2008-11-19 15:14:38 Pubmed12869586 Pubmed12906785 Reactome Database ID Release 43380979 Reactome, http://www.reactome.org ReactomeREACT_21261 Reviewed: Zheng, B, 2009-10-20 TSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of a small G-protein Rheb. This results in the conversion of Rheb-GTP into Rheb-GDP and in the inhibition of the mTOR activation by GTP-bound Rheb (Inoki K et al, 2003; Tee AR et al, 2003). PathwayStep5866 PDK1 attachment to plasma membrane At the beginning of this reaction, 1 molecule of '3-phosphoinositide dependent protein kinase-1 ', and 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate' are present. At the end of this reaction, 1 molecule of 'PIP3:PDK complex [plasma membrane]' is present.<br><br> This reaction takes place in the 'cell'.<br> Reactome Database ID Release 43109701 Reactome, http://www.reactome.org ReactomeREACT_260 PathwayStep5867 PKB attachment to plasma membrane At the beginning of this reaction, 1 molecule of 'PKB:PKB Regulator', and 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate' are present. At the end of this reaction, 1 molecule of 'PKB regulator', and 1 molecule of 'PIP3:PKB complex ' are present.<br><br> This reaction takes place in the 'cell'.<br> Pubmed11598301 Pubmed12791994 Pubmed8645147 Pubmed9445477 Reactome Database ID Release 43109700 Reactome, http://www.reactome.org ReactomeREACT_1622 PathwayStep5868 Phosphorylation of AKT2 by PDK1 At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'PIP3:PKB complex ' are present. At the end of this reaction, 1 molecule of 'PIP3:Phosphorylated PKB complex', and 2 molecules of 'ADP' are present.<br><br> This reaction takes place on the 'plasma membrane' and is mediated by the 'kinase activity' of 'PIP3:PDK complex [plasma membrane]'.<br> Pubmed9094314 Pubmed9228007 Reactome Database ID Release 43109702 Reactome, http://www.reactome.org ReactomeREACT_908 has a Stoichiometric coefficient of 2 PathwayStep5869 GRB2:SOS binds IRS-P Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Inactive p21ras-GDP is found anchored to the plasma membrane by a farnesyl residue.<br>Insulin stimulation results in phosphorylation of IRS1/2 on tyrosine residues (Y). GRB2 binds the phosphotyrosine residues of IRS via its SH2 domain. As IRS is phosphorylated by the insulin receptor near to the plasma membrane, the SOS-GRB2:IRS interaction brings the SOS enzyme into close proximity to p21ras. Pubmed8316835 Pubmed8530377 Pubmed8621421 Pubmed8810325 Pubmed9003010 Pubmed9832424 Pubmed9852124 Reactome Database ID Release 4374736 Reactome, http://www.reactome.org ReactomeREACT_646 SOS mediated nucleotide exchange of RAS (IRS) Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Reactome Database ID Release 43109817 Reactome, http://www.reactome.org ReactomeREACT_1672 SOS promotes the formation of GTP-bound RAS, thus activating this protein. RAS activation results in activation of the protein kinases RAF1, B-Raf, and MAP-ERK kinase kinase (MEKK), and the catalytic subunit of PI3K, as well as of a series of RALGEFs. The activation cycle of RAS GTPases is regulated by their interaction with specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs promote activation by inducing the release of GDP, whereas GAPs inactivate RAS-like proteins by stimulating their intrinsic GTPase activity. NGF-induced RAS activation via SHC-GRB2-SOS is maximal at 2 min but it is no longer detected after 5 min. Therefore, the transient activation of RAS obtained through SHC-GRB2-SOS is insufficient for the prolonged activation of ERKs found in NGF-treated cells.<br> De-phosphorylation of IRS At the beginning of this reaction, 1 molecule of 'phospho-IRS' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'IRS' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase'.<br> EC Number: 3.1.3.48 Reactome Database ID Release 4374747 Reactome, http://www.reactome.org ReactomeREACT_1810 PathwayStep5841 PathwayStep5840 AMPK is dephosphorylated Authored: Katajisto, P, Makela, T, Wu, J, 2008--1-1- Edited: Jassal, B, 2008-11-19 15:14:38 Normally under low AMP:ATP conditions, the active AMPK is dephosphorylated (possibly by PP2C), and thus inactivated. Pubmed16943194 Pubmed8549768 Reactome Database ID Release 43380949 Reactome, http://www.reactome.org ReactomeREACT_21418 Reviewed: Zheng, B, 2009-10-20 p-STAG2,RAD21-Ac-Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules Reactome DB_ID: 1638796 Reactome Database ID Release 431638796 Reactome, http://www.reactome.org ReactomeREACT_150708 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Ac-Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules Reactome DB_ID: 2468282 Reactome Database ID Release 432468282 Reactome, http://www.reactome.org ReactomeREACT_152183 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Sister Centromere:Kinetochore Reactome DB_ID: 2484816 Reactome Database ID Release 432484816 Reactome, http://www.reactome.org ReactomeREACT_151570 has a Stoichiometric coefficient of 1 Ac-Cohesin:PDS5:WAPAL:Centromere:Kinetochore Reactome DB_ID: 2484817 Reactome Database ID Release 432484817 Reactome, http://www.reactome.org ReactomeREACT_150918 has a Stoichiometric coefficient of 1 Condensin I Reactome DB_ID: 1638143 Reactome Database ID Release 431638143 Reactome, http://www.reactome.org ReactomeREACT_151162 SMC2:SMC4:NCAPD2:NCAPH:NCAPG has a Stoichiometric coefficient of 1 p-RAD21-Ac-Cohesin Reactome DB_ID: 2500251 Reactome Database ID Release 432500251 Reactome, http://www.reactome.org ReactomeREACT_152037 has a Stoichiometric coefficient of 1 p-RAD21-Ac-Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules Reactome DB_ID: 2500242 Reactome Database ID Release 432500242 Reactome, http://www.reactome.org ReactomeREACT_151499 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-STAG2,RAD21-Ac-Cohesin Reactome DB_ID: 2484809 Reactome Database ID Release 432484809 Reactome, http://www.reactome.org ReactomeREACT_151715 has a Stoichiometric coefficient of 1 Ac-Cohesin:PDS5:CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules Reactome DB_ID: 2484819 Reactome Database ID Release 432484819 Reactome, http://www.reactome.org ReactomeREACT_151019 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 30 Formation of active mTORC1 complex Pubmed15755954 Reactome Database ID Release 43165680 Reactome, http://www.reactome.org ReactomeREACT_6851 mTOR forms a functional protein complex with at least two proteins: Raptor (Regulated Associated Protein of mTOR) and mLst8. This complex is called mammalian TOR complex 1 (mTORC1). Raptor serves as a scaffolding protein to bridge the interaction between mTOR and its substrates. mLst8 enhances the association of mTOR with Raptor. [Rheb:GTP] binds and activates mTORC1. Besides binding directly to mTOR, Rheb can also bind to Raptor and mLst8 (PMIDs 15854902, 15755954 and 12150926). p-Cohesin:PDS5:WAPAL Reactome DB_ID: 2545249 Reactome Database ID Release 432545249 Reactome, http://www.reactome.org ReactomeREACT_151704 has a Stoichiometric coefficient of 1 p-Cohesin Reactome DB_ID: 2545252 Reactome Database ID Release 432545252 Reactome, http://www.reactome.org ReactomeREACT_151967 has a Stoichiometric coefficient of 1 PathwayStep5839 PathwayStep5837 Dissociation of phosphorylated 4EBP1 from eIF4E At the beginning of this reaction, 1 molecule of 'eIF4E:4E-BP1-P' is present. At the end of this reaction, 1 molecule of '4E-BP1-P', and 1 molecule of 'eIF4E' are present.<br><br> This reaction takes place in the 'cytosol'.<br> Pubmed15809305 Reactome Database ID Release 43165708 Reactome, http://www.reactome.org ReactomeREACT_6742 PathwayStep5838 LKB1 forms a trimeric complex with STRAD and MO25 Authored: Katajisto, P, Makela, T, Wu, J, 2008--1-1- Edited: Jassal, B, 2008-11-19 15:14:38 Pubmed12805220 Pubmed14517248 Reactome Database ID Release 43380942 Reactome, http://www.reactome.org ReactomeREACT_21345 Reviewed: Zheng, B, 2009-10-20 Upon complex formation with STRAD and MO25, LKB1 (also known as serine/threonine kinase 11, STK11) is mostly cytosolic. LKB1 attains 20x activity towards the substrates belonging to the subfamily of AMPK-like kinases (5'AMP-activated protein kinases). PathwayStep5835 Phosphorylation and activation of eIF4B by activated S6K1 Pubmed15314020 Reactome Database ID Release 43165777 Reactome, http://www.reactome.org ReactomeREACT_6778 eIF4B is a physiologically relevant target of S6K1. Once phosphorylated and activated by S6K1, eIF4B specifically stimulates the ATPase and RNA helicase activities of eIF4A. PathwayStep5836 Phosphorylation of 4E-BP1 by activated mTORC1 At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'eIF4E:4E-BP' are present. At the end of this reaction, 1 molecule of 'eIF4E:4E-BP1-P', and 2 molecules of 'ADP' are present.<br><br> This reaction is mediated by the 'kinase activity' of 'Activated mTORC1'.<br> Pubmed12150926 Pubmed15809305 Reactome Database ID Release 43165692 Reactome, http://www.reactome.org ReactomeREACT_6873 has a Stoichiometric coefficient of 2 PathwayStep5833 Phosphorylation and inactivation of eEF2K by activated S6K1 Phosphorylation of eEF2 kinase by S6K1-P results in decreased activity of this kinase. eEF2 kinase normally phosphorylates and deactivates eEF2, preventing its binding to the ribosome. Pubmed15809305 Reactome Database ID Release 43165758 Reactome, http://www.reactome.org ReactomeREACT_6883 PathwayStep5834 Phosphorylation and activation of eIF4G by activated S6K1 At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'eIF4G' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'eIF4G-P' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'kinase activity' of 'S6K1-P'.<br> Pubmed15314020 Reactome Database ID Release 43165766 Reactome, http://www.reactome.org ReactomeREACT_6870 has a Stoichiometric coefficient of 3 PathwayStep5831 Activation of S6K1 Pubmed15809305 Reactome Database ID Release 43165718 Reactome, http://www.reactome.org ReactomeREACT_6948 S6K1 contains a TOS motif. mTORC1 requires an intact TOS motif to bind and phosphorylate S6K1 (PMID 15809305). has a Stoichiometric coefficient of 2 PathwayStep5832 Phosphorylation of Ribosomal protein S6 by activated S6K1 Once phosphorylated, S6K1-P phosphorylates and activates ribosomal protein S6 (rpS6), which in turn selectively increases the translation of 5’TOP mRNAs. These mRNAs encode exclusively for components of the translation machinery (PMID 15809305). Pubmed15809305 Reactome Database ID Release 43165726 Reactome, http://www.reactome.org ReactomeREACT_6912 has a Stoichiometric coefficient of 5 PathwayStep5850 PathwayStep5852 PathwayStep5851 GTP loading by Rheb Pubmed15951850 Reactome Database ID Release 43165195 Reactome, http://www.reactome.org ReactomeREACT_6895 Rheb is a GTP binding protein that exhibits GTPase activity. GDP is exchanged for GTP in the [Rheb:GDP] complex to form [Rheb:GTP], which binds and activates the mTORC1 complex. This exchange is catalysed by an as yet unidentified guanine exchange factor (GEF) (PMIDs 15951850 and 15755954). Phosphorylation of complexed TSC2 by PKB At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'TSC1:TSC2' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'TSC1:Inhibited TSC2-1-P' are present.<br><br> This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.<br> Pubmed15314020 Reactome Database ID Release 43165182 Reactome, http://www.reactome.org ReactomeREACT_6952 has a Stoichiometric coefficient of 3 CDK1 Phosphorylated Condensin I Reactome DB_ID: 2520845 Reactome Database ID Release 432520845 Reactome, http://www.reactome.org ReactomeREACT_150472 SMC2:SMC4:p-T1339,1384,1389-NCAPD2:p-NCAPH:p-T308,332-NCAPG has a Stoichiometric coefficient of 1 ALOX15B:Fe2+ Reactome DB_ID: 2142760 Reactome Database ID Release 432142760 Reactome, http://www.reactome.org ReactomeREACT_150731 has a Stoichiometric coefficient of 1 CDC20:p-APC/C:PTTG1 Cdc20:phosph-APC/C:Securin complex Reactome DB_ID: 174212 Reactome Database ID Release 43174212 Reactome, http://www.reactome.org ReactomeREACT_7642 has a Stoichiometric coefficient of 1 ALOX15/15B Converted from EntitySet in Reactome Reactome DB_ID: 2161783 Reactome Database ID Release 432161783 Reactome, http://www.reactome.org ReactomeREACT_150783 CDC20:p-APC/C CDC20:Phospho-APC/C Reactome DB_ID: 174081 Reactome Database ID Release 43174081 Reactome, http://www.reactome.org ReactomeREACT_7165 has a Stoichiometric coefficient of 1 GPX2 tetramer Reactome DB_ID: 2142735 Reactome Database ID Release 432142735 Reactome, http://www.reactome.org ReactomeREACT_150670 glutathione peroxidase tetramer has a Stoichiometric coefficient of 4 PTTG1:ESPL1 Reactome DB_ID: 2467796 Reactome Database ID Release 432467796 Reactome, http://www.reactome.org ReactomeREACT_152196 Securin:Separase Securin:Separin has a Stoichiometric coefficient of 1 GPX1 tetramer Reactome DB_ID: 71674 Reactome Database ID Release 4371674 Reactome, http://www.reactome.org ReactomeREACT_2935 glutathione peroxidase tetramer has a Stoichiometric coefficient of 4 CDC20:p-APC/C:Ub-PTTG1 Reactome DB_ID: 174215 Reactome Database ID Release 43174215 Reactome, http://www.reactome.org ReactomeREACT_7079 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 multiubiquitinated Securin in complex with CDC20:phospho-APC/C Cleaved Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules Reactome DB_ID: 2467806 Reactome Database ID Release 432467806 Reactome, http://www.reactome.org ReactomeREACT_152233 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 30 ESPL1 Autocleaved Reactome DB_ID: 2467770 Reactome Database ID Release 432467770 Reactome, http://www.reactome.org ReactomeREACT_150534 Separase Autocleaved Separin Autocleaved has a Stoichiometric coefficient of 1 Sister Centromere:Kinetochore:Microtubules Reactome DB_ID: 2484902 Reactome Database ID Release 432484902 Reactome, http://www.reactome.org ReactomeREACT_151809 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 15 Cleaved Cohesin Reactome DB_ID: 2467801 Reactome Database ID Release 432467801 Reactome, http://www.reactome.org ReactomeREACT_150824 has a Stoichiometric coefficient of 1 CK2 Phosphorylated Condensin I Reactome DB_ID: 2529014 Reactome Database ID Release 432529014 Reactome, http://www.reactome.org ReactomeREACT_151678 has a Stoichiometric coefficient of 1 CK2 Casein kinase II Reactome DB_ID: 201711 Reactome Database ID Release 43201711 Reactome, http://www.reactome.org ReactomeREACT_23098 has a Stoichiometric coefficient of 1 PathwayStep5846 Dissociation of IRS-P from insulin receptor At the beginning of this reaction, 1 molecule of 'phospho-IRS:activated insulin receptor' is present. At the end of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'phospho-IRS' are present.<br><br> This reaction takes place on the 'internal side of plasma membrane'.<br> Reactome Database ID Release 4374712 Reactome, http://www.reactome.org ReactomeREACT_562 PathwayStep5847 PI3K activation Authored: 2003-07-28 10:05:14 IRS1, IRS2 and IRS3 are all known to bind the regulatory subunit of PI3K via its SH2 domain, an interaction that itself activates the kinase activity of the PI3K catalytic subunit. Reactome Database ID Release 4374737 Reactome, http://www.reactome.org ReactomeREACT_537 PathwayStep5848 PIP2 conversion to PIP3 At the beginning of this reaction, 1 molecule of 'Phosphatidyl-myo-inositol 4,5-bisphosphate', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'cell' and is mediated by the 'kinase activity' of 'phospho-IRS:PI3K'.<br> Authored: de Bono, B, 2007-01-10 10:27:18 Edited: Jupe, S, 2010-02-03 Pubmed12660731 Reactome Database ID Release 43109699 Reactome, http://www.reactome.org ReactomeREACT_244 Reviewed: Mohammadi, M, 2007-02-06 21:44:35 PathwayStep5849 Phosphorylation of TSC2 by PKB At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'TSC2-1' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'Inhibited TSC2-1-P at Ser 939, 1130 and Thr 1462' are present.<br><br> This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.<br> Pubmed15314020 Reactome Database ID Release 43165162 Reactome, http://www.reactome.org ReactomeREACT_6725 has a Stoichiometric coefficient of 3 PathwayStep5842 GRB2:SOS binds to SHC-P Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Pubmed8810325 Reactome Database ID Release 4374746 Reactome, http://www.reactome.org ReactomeREACT_176 Reviewed: Greene, LA, 2007-11-08 15:39:37 Tyrosine receptor kinase stimulation phosphorylates Shc which recruits the SH2 domain of the adaptor protein GRB2, which is complexed with SOS, an exchange factor for p21ras and RAC, through its SH3 domain. Besides SOS, the GRB2 SH3 domain can associate with other intracellular targets, including GAB1. Erk and Rsk mediated phosphorylation results in dissociation of the SOS-GRB2 complex. This may explain why Erk activation through Shc and SOS-GRB2 is transient. Inactive p21ras-GDP is found anchored to the plasma membrane by a farnesyl residue. As Shc is phosphorylated by the the stimulated receptor near to the plasma membrane, the SOS-GRB2:Shc interaction brings the SOS enzyme into close proximity to p21ras. PathwayStep5843 SOS mediated nucleotide exchange of RAS (SHC) Authored: Charalambous, M, 2005-01-07 11:17:43 Edited: Schmidt, EE, 0000-00-00 00:00:00 Pubmed9690470 Reactome Database ID Release 43109807 Reactome, http://www.reactome.org ReactomeREACT_2010 Reviewed: Greene, LA, 2007-11-08 15:39:37 SOS promotes the formation of GTP-bound RAS, thus activating this protein. RAS activation results in activation of the protein kinases RAF1, B-Raf, and MAP-ERK kinase kinase (MEKK), and the catalytic subunit of PI3K, as well as of a series of RALGEFs. The activation cycle of RAS GTPases is regulated by their interaction with specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs promote activation by inducing the release of GDP, whereas GAPs inactivate RAS-like proteins by stimulating their intrinsic GTPase activity. NGF-induced RAS activation via SHC-GRB2-SOS is maximal at 2 min but it is no longer detected after 5 min. Therefore, the transient activation of RAS obtained through SHC-GRB2-SOS is insufficient for the prolonged activation of ERKs found in NGF-treated cells.<br> PathwayStep5844 Binding of IRS to insulin receptor At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'IRS' are present. At the end of this reaction, 1 molecule of 'IRS:activated insulin receptor' is present.<br><br> This reaction takes place on the 'internal side of plasma membrane'.<br> Reactome Database ID Release 4374707 Reactome, http://www.reactome.org ReactomeREACT_2120 PathwayStep5845 Phosphorylation of IRS At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'IRS:activated insulin receptor' are present. At the end of this reaction, 1 molecule of 'phospho-IRS:activated insulin receptor', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'transmembrane receptor protein tyrosine kinase activity' of 'IRS:activated insulin receptor'.<br> EC Number: 2.7.10.1 Pubmed16814735 Reactome Database ID Release 4374711 Reactome, http://www.reactome.org ReactomeREACT_342 PathwayStep5789 PathwayStep5788 PathwayStep5787 PCYT1A dimer Reactome DB_ID: 1524108 Reactome Database ID Release 431524108 Reactome, http://www.reactome.org ReactomeREACT_124084 has a Stoichiometric coefficient of 2 PCYT1 dimer Converted from EntitySet in Reactome Reactome DB_ID: 1524125 Reactome Database ID Release 431524125 Reactome, http://www.reactome.org ReactomeREACT_125243 PC:PITPNB Reactome DB_ID: 1524110 Reactome Database ID Release 431524110 Reactome, http://www.reactome.org ReactomeREACT_125308 has a Stoichiometric coefficient of 1 p(Y)-GAB2:GRB2:p-SHP2:p-KIT complex Reactome DB_ID: 1562560 Reactome Database ID Release 431562560 Reactome, http://www.reactome.org ReactomeREACT_111870 has a Stoichiometric coefficient of 1 CDS1:Mg2+ Reactome DB_ID: 1500651 Reactome Database ID Release 431500651 Reactome, http://www.reactome.org ReactomeREACT_123471 has a Stoichiometric coefficient of 1 CDIPT:Mg2+/Mn2+ Reactome DB_ID: 1500647 Reactome Database ID Release 431500647 Reactome, http://www.reactome.org ReactomeREACT_122002 has a Stoichiometric coefficient of 1 GRB2:p-SHP2:p-KIT complex GRB2:p-SHP2:SFKs:p-7Y-KIT:sSCF dimer:p-7Y-KIT Reactome DB_ID: 1433549 Reactome Database ID Release 431433549 Reactome, http://www.reactome.org ReactomeREACT_111665 has a Stoichiometric coefficient of 1 HADH octamer Reactome DB_ID: 1524100 Reactome Database ID Release 431524100 Reactome, http://www.reactome.org ReactomeREACT_121411 has a Stoichiometric coefficient of 4 GAB2:GRB2:p-SHP2:p-KIT complex Reactome DB_ID: 1433545 Reactome Database ID Release 431433545 Reactome, http://www.reactome.org ReactomeREACT_111599 has a Stoichiometric coefficient of 1 CHPT1:Mg2+/Mn2+ Reactome DB_ID: 1500652 Reactome Database ID Release 431500652 Reactome, http://www.reactome.org ReactomeREACT_125323 has a Stoichiometric coefficient of 1 PI:PITPNB Reactome DB_ID: 1524117 Reactome Database ID Release 431524117 Reactome, http://www.reactome.org ReactomeREACT_122202 has a Stoichiometric coefficient of 1 PI:PITPNB Reactome DB_ID: 1524150 Reactome Database ID Release 431524150 Reactome, http://www.reactome.org ReactomeREACT_121494 has a Stoichiometric coefficient of 1 PC:PITPNB Reactome DB_ID: 1524122 Reactome Database ID Release 431524122 Reactome, http://www.reactome.org ReactomeREACT_122197 has a Stoichiometric coefficient of 1 PathwayStep5796 RAC1-GDP Reactome DB_ID: 445010 Reactome Database ID Release 43445010 Reactome, http://www.reactome.org ReactomeREACT_22018 has a Stoichiometric coefficient of 1 PathwayStep5797 SFKs:p-8Y-KIT:sSCF dimer:p-8Y-KIT Reactome DB_ID: 1472120 Reactome Database ID Release 431472120 Reactome, http://www.reactome.org ReactomeREACT_111437 has a Stoichiometric coefficient of 1 PathwayStep5794 PathwayStep5795 PCYT1B dimer Reactome DB_ID: 1524111 Reactome Database ID Release 431524111 Reactome, http://www.reactome.org ReactomeREACT_123403 has a Stoichiometric coefficient of 2 SFKs:p-KIT complex Reactome DB_ID: 205271 Reactome Database ID Release 43205271 Reactome, http://www.reactome.org ReactomeREACT_111322 SFKs:p-7Y-KIT:sSCF dimer:p-7Y-KIT has a Stoichiometric coefficient of 1 PathwayStep5792 SHP2:SFKs:p-KIT:sSCF dimer:p-KIT Reactome DB_ID: 205267 Reactome Database ID Release 43205267 Reactome, http://www.reactome.org ReactomeREACT_111414 has a Stoichiometric coefficient of 1 PathwayStep5793 p-SHP2:p-KIT complex Reactome DB_ID: 1433530 Reactome Database ID Release 431433530 Reactome, http://www.reactome.org ReactomeREACT_111317 has a Stoichiometric coefficient of 1 p-SHP2:SFKs:p-7Y-KIT:sSCF dimer:p-7Y-KIT PathwayStep5790 p-8Y-KIT:sSCF dimer:p-8Y-KIT Reactome DB_ID: 1472119 Reactome Database ID Release 431472119 Reactome, http://www.reactome.org ReactomeREACT_111812 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5791 GRB2:SOS1:p-KIT complex GRB2:SOS1:p-KIT:sSCF dimer:p-KIT Reactome DB_ID: 205202 Reactome Database ID Release 43205202 Reactome, http://www.reactome.org ReactomeREACT_111435 has a Stoichiometric coefficient of 1 PathwayStep5777 PathwayStep5776 PathwayStep5779 PathwayStep5778 CEPT1/EPT1 Converted from EntitySet in Reactome Reactome DB_ID: 1500592 Reactome Database ID Release 431500592 Reactome, http://www.reactome.org ReactomeREACT_123588 LPIN3:Mg2+ Reactome DB_ID: 1500638 Reactome Database ID Release 431500638 Reactome, http://www.reactome.org ReactomeREACT_121972 has a Stoichiometric coefficient of 1 LPIN2:Mg2+ Reactome DB_ID: 1500641 Reactome Database ID Release 431500641 Reactome, http://www.reactome.org ReactomeREACT_124464 has a Stoichiometric coefficient of 1 ACHE tetramer Reactome DB_ID: 1524053 Reactome Database ID Release 431524053 Reactome, http://www.reactome.org ReactomeREACT_117400 has a Stoichiometric coefficient of 4 p-STAT dimer Reactome DB_ID: 1469975 Reactome Database ID Release 431469975 Reactome, http://www.reactome.org ReactomeREACT_111270 has a Stoichiometric coefficient of 2 CHK dimer Converted from EntitySet in Reactome Reactome DB_ID: 1524078 Reactome Database ID Release 431524078 Reactome, http://www.reactome.org ReactomeREACT_122518 p-STAT dimers Reactome DB_ID: 1566924 Reactome Database ID Release 431566924 Reactome, http://www.reactome.org ReactomeREACT_111683 has a Stoichiometric coefficient of 2 PLA2G3:Ca2+ Reactome DB_ID: 1602411 Reactome Database ID Release 431602411 Reactome, http://www.reactome.org ReactomeREACT_123638 has a Stoichiometric coefficient of 1 ACHE dimer Reactome DB_ID: 1524054 Reactome Database ID Release 431524054 Reactome, http://www.reactome.org ReactomeREACT_116661 has a Stoichiometric coefficient of 2 PISD:Pyruvoyl Reactome DB_ID: 1500656 Reactome Database ID Release 431500656 Reactome, http://www.reactome.org ReactomeREACT_121720 has a Stoichiometric coefficient of 1 PLA2(16) Converted from EntitySet in Reactome Reactome DB_ID: 1602354 Reactome Database ID Release 431602354 Reactome, http://www.reactome.org ReactomeREACT_122442 CEPT1:Mg2+/Mn2+ Reactome DB_ID: 1500587 Reactome Database ID Release 431500587 Reactome, http://www.reactome.org ReactomeREACT_123267 has a Stoichiometric coefficient of 1 EPT1:Mg2+/Mn2+ Reactome DB_ID: 1500584 Reactome Database ID Release 431500584 Reactome, http://www.reactome.org ReactomeREACT_123678 has a Stoichiometric coefficient of 1 PathwayStep5783 P13K:p(Y)-GAB2:GRB2:p-SHP2:p-KIT complex Reactome DB_ID: 1562561 Reactome Database ID Release 431562561 Reactome, http://www.reactome.org ReactomeREACT_111874 has a Stoichiometric coefficient of 1 PathwayStep5784 Tyrosine kinases:p-KIT complex Reactome DB_ID: 205201 Reactome Database ID Release 43205201 Reactome, http://www.reactome.org ReactomeREACT_111354 has a Stoichiometric coefficient of 1 PathwayStep5785 Adapter proteins:p-KIT complex Reactome DB_ID: 1433538 Reactome Database ID Release 431433538 Reactome, http://www.reactome.org ReactomeREACT_111421 has a Stoichiometric coefficient of 1 PathwayStep5786 JAK2:SFKS:p-KIT complex Reactome DB_ID: 1433493 Reactome Database ID Release 431433493 Reactome, http://www.reactome.org ReactomeREACT_111373 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-JAK2:SFKs:p-KIT complex Reactome DB_ID: 1433552 Reactome Database ID Release 431433552 Reactome, http://www.reactome.org ReactomeREACT_111294 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5780 p-JAK2:SFKs:p-KIT complex:STATs Reactome DB_ID: 1433527 Reactome Database ID Release 431433527 Reactome, http://www.reactome.org ReactomeREACT_111888 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5781 p-JAK2:SFKs:p-KIT complex:p-STATs Reactome DB_ID: 1470000 Reactome Database ID Release 431470000 Reactome, http://www.reactome.org ReactomeREACT_111763 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5782 p-JAK2:SFKs:p-KIT complex:p-STAT dimers Reactome DB_ID: 1469999 Reactome Database ID Release 431469999 Reactome, http://www.reactome.org ReactomeREACT_111313 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5768 PathwayStep5767 PathwayStep5766 PathwayStep5765 PathwayStep5769 PLA2G10:Ca2+ Reactome DB_ID: 1602425 Reactome Database ID Release 431602425 Reactome, http://www.reactome.org ReactomeREACT_123818 has a Stoichiometric coefficient of 1 PLA2G5:Ca2+ Reactome DB_ID: 1500668 Reactome Database ID Release 431500668 Reactome, http://www.reactome.org ReactomeREACT_125666 has a Stoichiometric coefficient of 1 MGLL dimer Reactome DB_ID: 1500601 Reactome Database ID Release 431500601 Reactome, http://www.reactome.org ReactomeREACT_122974 has a Stoichiometric coefficient of 2 PLA2G12A:Ca2+ Reactome DB_ID: 1602352 Reactome Database ID Release 431602352 Reactome, http://www.reactome.org ReactomeREACT_124213 has a Stoichiometric coefficient of 1 CHKA:CHKA CHKA dimer CHKA homodimer Reactome DB_ID: 1500612 Reactome Database ID Release 431500612 Reactome, http://www.reactome.org ReactomeREACT_122983 has a Stoichiometric coefficient of 2 CHKB:CHKB CHKB dimer CHKB homodimer Reactome DB_ID: 1500611 Reactome Database ID Release 431500611 Reactome, http://www.reactome.org ReactomeREACT_121951 has a Stoichiometric coefficient of 2 Reactome DB_ID: 215139 Reactome Database ID Release 43215139 Reactome, http://www.reactome.org ReactomeREACT_13060 VEGFR2:VEGFA,C,D,E has a Stoichiometric coefficient of 1 CHKA:CHKB CHKA:CHKB heterodimer Reactome DB_ID: 1500617 Reactome Database ID Release 431500617 Reactome, http://www.reactome.org ReactomeREACT_124432 has a Stoichiometric coefficient of 1 PHOSPHO1:Mg2+ Reactome DB_ID: 1500633 Reactome Database ID Release 431500633 Reactome, http://www.reactome.org ReactomeREACT_124361 has a Stoichiometric coefficient of 1 VEGFD homodimer Reactome DB_ID: 195355 Reactome Database ID Release 43195355 Reactome, http://www.reactome.org ReactomeREACT_12803 has a Stoichiometric coefficient of 2 PCYT2 dimer Reactome DB_ID: 1500642 Reactome Database ID Release 431500642 Reactome, http://www.reactome.org ReactomeREACT_123639 has a Stoichiometric coefficient of 2 VEGFE homodimer Reactome DB_ID: 195386 Reactome Database ID Release 43195386 Reactome, http://www.reactome.org ReactomeREACT_12722 has a Stoichiometric coefficient of 2 LPIN Converted from EntitySet in Reactome Reactome DB_ID: 1500636 Reactome Database ID Release 431500636 Reactome, http://www.reactome.org ReactomeREACT_121465 VEGFA,C,D,E Converted from EntitySet in Reactome Reactome DB_ID: 195393 Reactome Database ID Release 43195393 Reactome, http://www.reactome.org ReactomeREACT_12894 LPIN1:Mg2+ Reactome DB_ID: 1500637 Reactome Database ID Release 431500637 Reactome, http://www.reactome.org ReactomeREACT_124186 has a Stoichiometric coefficient of 1 VEGFC homodimer Reactome DB_ID: 195360 Reactome Database ID Release 43195360 Reactome, http://www.reactome.org ReactomeREACT_13010 has a Stoichiometric coefficient of 2 PathwayStep5770 Reactome DB_ID: 195396 Reactome Database ID Release 43195396 Reactome, http://www.reactome.org ReactomeREACT_12847 VEGFR1:VEGFA,B,PGLF has a Stoichiometric coefficient of 1 PathwayStep5771 VEGFR1 dimer Reactome DB_ID: 195398 Reactome Database ID Release 43195398 Reactome, http://www.reactome.org ReactomeREACT_13036 has a Stoichiometric coefficient of 2 VEGFA homodimer Reactome DB_ID: 195364 Reactome Database ID Release 43195364 Reactome, http://www.reactome.org ReactomeREACT_12819 has a Stoichiometric coefficient of 2 VEGFB homodimer Reactome DB_ID: 195367 Reactome Database ID Release 43195367 Reactome, http://www.reactome.org ReactomeREACT_12791 has a Stoichiometric coefficient of 2 PathwayStep5774 PathwayStep5775 PLGF homodimer Reactome DB_ID: 195352 Reactome Database ID Release 43195352 Reactome, http://www.reactome.org ReactomeREACT_12855 has a Stoichiometric coefficient of 2 PathwayStep5772 PathwayStep5773 PathwayStep5755 PathwayStep5754 PathwayStep5757 PathwayStep5756 PathwayStep5759 PathwayStep5758 PLA2G4A:Ca2+ Reactome DB_ID: 1500626 Reactome Database ID Release 431500626 Reactome, http://www.reactome.org ReactomeREACT_123983 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 RBP2:atRAL CRBP II:all-trans-retinal Reactome DB_ID: 975639 Reactome Database ID Release 43975639 Reactome, http://www.reactome.org ReactomeREACT_25547 has a Stoichiometric coefficient of 1 BCMO1:Fe2+ Reactome DB_ID: 975642 Reactome Database ID Release 43975642 Reactome, http://www.reactome.org ReactomeREACT_26746 has a Stoichiometric coefficient of 1 RBP2:atROL RBP2:all-trans-retinol Reactome DB_ID: 975626 Reactome Database ID Release 43975626 Reactome, http://www.reactome.org ReactomeREACT_25941 has a Stoichiometric coefficient of 1 PLA2G2A:Ca2+ Reactome DB_ID: 1500630 Reactome Database ID Release 431500630 Reactome, http://www.reactome.org ReactomeREACT_123992 has a Stoichiometric coefficient of 1 PLA2(15) Converted from EntitySet in Reactome Reactome DB_ID: 1602359 Reactome Database ID Release 431602359 Reactome, http://www.reactome.org ReactomeREACT_124046 PLA2G1B:Ca2+ Reactome DB_ID: 1602365 Reactome Database ID Release 431602365 Reactome, http://www.reactome.org ReactomeREACT_123709 has a Stoichiometric coefficient of 1 PLA2G2E:Ca2+ Reactome DB_ID: 1602386 Reactome Database ID Release 431602386 Reactome, http://www.reactome.org ReactomeREACT_125506 has a Stoichiometric coefficient of 1 KIT:sSCF dimer Reactome DB_ID: 205166 Reactome Database ID Release 43205166 Reactome, http://www.reactome.org ReactomeREACT_111507 has a Stoichiometric coefficient of 1 PLA2G2F:Ca2+ Reactome DB_ID: 1602383 Reactome Database ID Release 431602383 Reactome, http://www.reactome.org ReactomeREACT_123615 has a Stoichiometric coefficient of 1 KIT:sSCF dimer:KIT Reactome DB_ID: 205208 Reactome Database ID Release 43205208 Reactome, http://www.reactome.org ReactomeREACT_111669 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PLA2G2A:Ca2+ Reactome DB_ID: 1602363 Reactome Database ID Release 431602363 Reactome, http://www.reactome.org ReactomeREACT_122437 has a Stoichiometric coefficient of 1 p-KIT (S741,746):PKC alpha Reactome DB_ID: 1433473 Reactome Database ID Release 431433473 Reactome, http://www.reactome.org ReactomeREACT_111348 has a Stoichiometric coefficient of 1 PLA2G2D:Ca2+ Reactome DB_ID: 1602360 Reactome Database ID Release 431602360 Reactome, http://www.reactome.org ReactomeREACT_122166 has a Stoichiometric coefficient of 1 p-VAV1:PIP3 Reactome DB_ID: 1433526 Reactome Database ID Release 431433526 Reactome, http://www.reactome.org ReactomeREACT_111383 has a Stoichiometric coefficient of 1 Reactome DB_ID: 215140 Reactome Database ID Release 43215140 Reactome, http://www.reactome.org ReactomeREACT_12751 VEGFR3:VEGF-C, and D has a Stoichiometric coefficient of 1 VEGFR3 dimer Reactome DB_ID: 195405 Reactome Database ID Release 43195405 Reactome, http://www.reactome.org ReactomeREACT_13161 has a Stoichiometric coefficient of 2 NRP1:VERGF165:VERGFR2 Reactome DB_ID: 195419 Reactome Database ID Release 43195419 Reactome, http://www.reactome.org ReactomeREACT_12681 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5760 NRP-2:VEGFR1 Reactome DB_ID: 195427 Reactome Database ID Release 43195427 Reactome, http://www.reactome.org ReactomeREACT_13266 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PathwayStep5761 PathwayStep5762 PathwayStep5763 VEGFR2 dimer Reactome DB_ID: 195403 Reactome Database ID Release 43195403 Reactome, http://www.reactome.org ReactomeREACT_13085 has a Stoichiometric coefficient of 2 PathwayStep5764 VEGF-C,D Converted from EntitySet in Reactome Reactome DB_ID: 195391 Reactome Database ID Release 43195391 Reactome, http://www.reactome.org ReactomeREACT_12875 EGF:EGFR:p-Y877-ERBB2 Reactome DB_ID: 1810434 Reactome Database ID Release 431810434 Reactome, http://www.reactome.org ReactomeREACT_117276 has a Stoichiometric coefficient of 1 NRG1/2:ERBB3:p-Y877-ERBB2 Reactome DB_ID: 1810433 Reactome Database ID Release 431810433 Reactome, http://www.reactome.org ReactomeREACT_117363 has a Stoichiometric coefficient of 1 ERBB2:ERBB4cyt2 heterodimer Reactome DB_ID: 1250312 Reactome Database ID Release 431250312 Reactome, http://www.reactome.org ReactomeREACT_116924 has a Stoichiometric coefficient of 1 PTGS2:celecoxib Reactome DB_ID: 2309778 Reactome Database ID Release 432309778 Reactome, http://www.reactome.org ReactomeREACT_151321 has a Stoichiometric coefficient of 1 NRGs/EGFLs:p-ERBB4:p-7Y-ERBB2 Converted from EntitySet in Reactome Reactome DB_ID: 1368190 Reactome Database ID Release 431368190 Reactome, http://www.reactome.org ReactomeREACT_117121 PTGS2 dimer PGHS2 dimer Reactome DB_ID: 140491 Reactome Database ID Release 43140491 Reactome, http://www.reactome.org ReactomeREACT_2322 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-Y877-ERBB2:ERBB4cyt2 heterodimer Reactome DB_ID: 1810437 Reactome Database ID Release 431810437 Reactome, http://www.reactome.org ReactomeREACT_116253 has a Stoichiometric coefficient of 1 Ac-PTGS1 dimer Reactome DB_ID: 2314695 Reactome Database ID Release 432314695 Reactome, http://www.reactome.org ReactomeREACT_151604 has a Stoichiometric coefficient of 1 p-Y877-ERBB2:ERBB4cyt1 heterodimers Reactome DB_ID: 1810431 Reactome Database ID Release 431810431 Reactome, http://www.reactome.org ReactomeREACT_117120 has a Stoichiometric coefficient of 1 COX1 PGHS1 homodimer PTGS1 dimer Reactome DB_ID: 428986 Reactome Database ID Release 43428986 Reactome, http://www.reactome.org ReactomeREACT_19925 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 NRGs/EGFLs:ERBB4:p-Y877-ERBB2 Converted from EntitySet in Reactome NRGs/EGF-like ligands:ERBB4:p-Y877-ERBB2 Reactome DB_ID: 1810435 Reactome Database ID Release 431810435 Reactome, http://www.reactome.org ReactomeREACT_116851 p-Y877-ERBB2:ERBB4 heterodimers NRGs/EGFLs:p-ERBB4cyt2:p-6Y-ERBB2 Reactome DB_ID: 1250329 Reactome Database ID Release 431250329 Reactome, http://www.reactome.org ReactomeREACT_117552 has a Stoichiometric coefficient of 1 Active PLA2:phosphatidylcholine Reactome DB_ID: 111860 Reactome Database ID Release 43111860 Reactome, http://www.reactome.org ReactomeREACT_15631 has a Stoichiometric coefficient of 1 NRGs/EGFLs:p-ERBB4:p-6Y-ERBB2 Converted from EntitySet in Reactome Reactome DB_ID: 1963594 Reactome Database ID Release 431963594 Reactome, http://www.reactome.org ReactomeREACT_117881 NRGs/EGFLs:p-ERBB4cyt2:p-7Y-ERBB2 Reactome DB_ID: 1963567 Reactome Database ID Release 431963567 Reactome, http://www.reactome.org ReactomeREACT_116989 has a Stoichiometric coefficient of 1 ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 2237880 Reactome Database ID Release 432237880 Reactome, http://www.reactome.org ReactomeREACT_124491 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PTGES trimer Prostaglandin E synthase homotrimer Reactome DB_ID: 2142686 Reactome Database ID Release 432142686 Reactome, http://www.reactome.org ReactomeREACT_151526 has a Stoichiometric coefficient of 3 RFC Heteropentamer:RNA primer-DNA primer:G-strand extended telomere end Reactome DB_ID: 174454 Reactome Database ID Release 43174454 Reactome, http://www.reactome.org ReactomeREACT_8972 has a Stoichiometric coefficient of 1 Ac-PTGS2 dimer Reactome DB_ID: 2314687 Reactome Database ID Release 432314687 Reactome, http://www.reactome.org ReactomeREACT_151020 has a Stoichiometric coefficient of 1 RNA primer-DNA primer:G-strand extended telomere Reactome DB_ID: 174433 Reactome Database ID Release 43174433 Reactome, http://www.reactome.org ReactomeREACT_8560 has a Stoichiometric coefficient of 1 HPGD dimer Reactome DB_ID: 2142778 Reactome Database ID Release 432142778 Reactome, http://www.reactome.org ReactomeREACT_152047 has a Stoichiometric coefficient of 2 RNA primer:G-strand extended telomere end:DNA polymerase alpha:primase complex Reactome DB_ID: 174434 Reactome Database ID Release 43174434 Reactome, http://www.reactome.org ReactomeREACT_8504 has a Stoichiometric coefficient of 1 HPGDS dimer Reactome DB_ID: 2142683 Reactome Database ID Release 432142683 Reactome, http://www.reactome.org ReactomeREACT_150558 has a Stoichiometric coefficient of 2 DNA polymerase epsilon:G-strand extended telomere end Reactome DB_ID: 174471 Reactome Database ID Release 43174471 Reactome, http://www.reactome.org ReactomeREACT_8099 has a Stoichiometric coefficient of 1 SHC1:Phosphorylated ERBB2 heterodimers Reactome DB_ID: 1248746 Reactome Database ID Release 431248746 Reactome, http://www.reactome.org ReactomeREACT_116413 has a Stoichiometric coefficient of 1 p-Y349,350-SHC1:Phosphorylated ERBB2 heterodimers Reactome DB_ID: 1250194 Reactome Database ID Release 431250194 Reactome, http://www.reactome.org ReactomeREACT_117006 has a Stoichiometric coefficient of 1 GRB2:SOS1:p-Y349,350-SHC1:Phosphorylated ERBB2 heterodimers Reactome DB_ID: 1250479 Reactome Database ID Release 431250479 Reactome, http://www.reactome.org ReactomeREACT_116174 has a Stoichiometric coefficient of 1 GRB2:SOS1:P-ERBB2:P-EGFR EGF:p-EGFR:p-ERBB2:GRB2:SOS1 Reactome DB_ID: 1250505 Reactome Database ID Release 431250505 Reactome, http://www.reactome.org ReactomeREACT_116273 has a Stoichiometric coefficient of 1 PIP4K2A:PIP4K2A Reactome DB_ID: 1806252 Reactome Database ID Release 431806252 Reactome, http://www.reactome.org ReactomeREACT_122397 has a Stoichiometric coefficient of 2 GRB2:SOS1:P-ERBB2:P-ERBB4 NRGs/EGFLs:p-ERBB4:p-ERBB2:GRB2:SOS1 Reactome DB_ID: 1306947 Reactome Database ID Release 431306947 Reactome, http://www.reactome.org ReactomeREACT_116478 has a Stoichiometric coefficient of 1 PIK3C2B:Ca2+/Mg2+/Mn2+ Reactome DB_ID: 1604663 Reactome Database ID Release 431604663 Reactome, http://www.reactome.org ReactomeREACT_121700 has a Stoichiometric coefficient of 1 Phosphorylated ERBB2:ERBB4cyt2 heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963591 Reactome Database ID Release 431963591 Reactome, http://www.reactome.org ReactomeREACT_117814 PIK3CG:PIK3R6 Reactome DB_ID: 1806192 Reactome Database ID Release 431806192 Reactome, http://www.reactome.org ReactomeREACT_124520 has a Stoichiometric coefficient of 1 NRG1/2:p-10Y-ERBB3:p-ERBB2:GRB7 Reactome DB_ID: 1306951 Reactome Database ID Release 431306951 Reactome, http://www.reactome.org ReactomeREACT_116889 has a Stoichiometric coefficient of 1 PIK3CG:PIK3R5 Reactome DB_ID: 1806236 Reactome Database ID Release 431806236 Reactome, http://www.reactome.org ReactomeREACT_122119 has a Stoichiometric coefficient of 1 EGF:p-EGFR:p-ERBB2:PLCG1 EGF:p-6Y-EGFR:p-6Y-ERBB2:PLCG1 Phospholipase C gamma 1:P-ERBB2:P-EGFR Reactome DB_ID: 1251942 Reactome Database ID Release 431251942 Reactome, http://www.reactome.org ReactomeREACT_116869 has a Stoichiometric coefficient of 1 Ub-ERBB3 Reactome DB_ID: 1358735 Reactome Database ID Release 431358735 Reactome, http://www.reactome.org ReactomeREACT_117196 has a Stoichiometric coefficient of 1 ERBB3:RNF41 ERBB3:NRDP1 Reactome DB_ID: 1358732 Reactome Database ID Release 431358732 Reactome, http://www.reactome.org ReactomeREACT_116975 has a Stoichiometric coefficient of 1 ACSL1 Reactome DB_ID: 2046075 Reactome Database ID Release 432046075 Reactome, http://www.reactome.org ReactomeREACT_123297 has a Stoichiometric coefficient of 1 PIKFYVE:VAC14:FIG4 Reactome DB_ID: 1806187 Reactome Database ID Release 431806187 Reactome, http://www.reactome.org ReactomeREACT_122721 has a Stoichiometric coefficient of 1 PIKFYVE:VAC14:FIG4 Reactome DB_ID: 1806169 Reactome Database ID Release 431806169 Reactome, http://www.reactome.org ReactomeREACT_124411 has a Stoichiometric coefficient of 1 PIP4K2A/B Converted from EntitySet in Reactome Reactome DB_ID: 1806229 Reactome Database ID Release 431806229 Reactome, http://www.reactome.org ReactomeREACT_125440 PIP4K2B:PIP4K2B Reactome DB_ID: 1806168 Reactome Database ID Release 431806168 Reactome, http://www.reactome.org ReactomeREACT_121711 has a Stoichiometric coefficient of 2 PIP4K2A:PIP4K2B Reactome DB_ID: 1806183 Reactome Database ID Release 431806183 Reactome, http://www.reactome.org ReactomeREACT_124592 has a Stoichiometric coefficient of 1 p75NTR and RHOA-GDI interact Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12692556 Pubmed9195882 Reactome Database ID Release 43193668 Reactome, http://www.reactome.org ReactomeREACT_13771 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p75NTR directly complexes with RHO-GDI (RHO-GDP Dissociation Inhibitor). RHO-GDI inhibits the dissociation of GDP and the subsequent binding of GTP to RHOA, thus preventing formation of active RHOA. Once bound to p75NTR, RHOA-GDI is less active. p75NTR acts on RHOB in a similar mechanism. NGF binding to p75NTR inactivates RHOA Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Neurotrophin (NGF or BDNF) binding to p75NTR increases RHO-GDI activity, possibly by loosening the grip of p75NTR on RHO-GDI, which prevents the dissociation of GDP thus allowing axonal growth to occur (Gehler et al. 2004). Pubmed15128850 Reactome Database ID Release 43193646 Reactome, http://www.reactome.org ReactomeREACT_13555 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Sphingomyelinase is activated by the NGF:p75NTR complex Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NGF binding to p75NTR activates N-SMase (Neutral sphingomyelinase), and possibly A-SMase (acid sphingomyelinase), an enzyme that converts sphingomyelin to ceramide. The mode and mechanism of interaction between p75 and N-SMase have not been determined but is thought to involve the recruitment of Mg2+ to the active site of the enzyme. Reactome Database ID Release 43193672 Reactome, http://www.reactome.org ReactomeREACT_13625 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Production of ceramide which can activate JNK and other targets Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 3.1.4.12 Edited: Jassal, B, 2008-05-20 12:26:36 Reactome Database ID Release 43193706 Reactome, http://www.reactome.org ReactomeREACT_13752 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Sphingomyielinase promotes the conversion of sphingomyelin to ceramide. Ceramide can activate JNK and other targets. The molecular details of the p75NTR-activated ceramide signalling cascade are only partially understood. Myelin components can interact with p75NTR:NgR:LINGO1 A group of myelin components named MDGIs (myelin-derived growth-inhibitors), bind to NgR and inhibit neurite outgrowth. Examples of such components are NOGO, OMGP (oligodendrocyte myelin glycoprotein) and MAG (myelin-associated glycoprotein). The amino-terminal region of NgR, covering eight leucine-rich repeats (LRR) and the LRR carboxy-terminal domain (LRRCT) is sufficient to interact with MAG, OMGP and NOGO. Their binding to NgR enhances the NgR-p75 interaction.These inhibitors bind to a receptor complex made up of the NOGO receptor, NgR, and p75NTR. Such complexes then activate RHOA, thereby inhibiting axonal growth. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12426574 Reactome Database ID Release 43193655 Reactome, http://www.reactome.org ReactomeREACT_13496 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The p75NTR:NgR:MDGI complex reduces RHOA-GDI activity, displacing RHOA Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12692556 Reactome Database ID Release 43193696 Reactome, http://www.reactome.org ReactomeREACT_13732 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The p75NTR:RHO-GDI complex appears to be strengthened in presence of a GMDI (MAG, NOGO or OMGP) bound to a NgR:p75 complex. When in a complex with MDGIs and NgR, p75NTR restrains the activity of RHO-GDI (GDP Dissociation Inhibitor). This facilitates the displacement of RHO-GDI from RHOA. p75NTR interacts with the NOGO receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed11201742 Reactome Database ID Release 43193636 Reactome, http://www.reactome.org ReactomeREACT_13497 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The p75NTR extracellular domain interacts with NOGO receptor (NgR), a glycosyl phosphatidylinositol (GPI)-anchored protein present as a homomultimer at the cell surface. As NgR lacks an intracellular domain, it utilizes p75NTR as a co-receptor for intracellular signalling. p75NTR:NgR complex interacts with the axonal inhibitor LINGO1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed14966521 Reactome Database ID Release 43209573 Reactome, http://www.reactome.org ReactomeREACT_13493 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The NgR1:p75NTR complex also interacts with LINGO1, a nervous system-specific transmembrane protein. LINGO1 is a potent axonal inhibitor of oligodendrocyte differentiation and myelination, and is regulated by NGF and its receptor TRKA . SHP-1:p-c-Kit complex Reactome DB_ID: 205181 Reactome Database ID Release 43205181 Reactome, http://www.reactome.org ReactomeREACT_111525 has a Stoichiometric coefficient of 1 RhoA is activated by nucleotide exchange and inhibits axonal growth Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12692556 Reactome Database ID Release 43194518 Reactome, http://www.reactome.org ReactomeREACT_13808 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 RhoA is activated by guanine nucleotide exchange factors (RhoGEF), exchanging GDP for GTP. RHOA, activated following binding of MDGIs to the NgR:p75NTR complex, rigidifies the actin cytoskeleton, thereby inhibiting axonal elongation and causing growth cone collapse. MHC Class I Converted from EntitySet in Reactome Reactome DB_ID: 198889 Reactome Database ID Release 43198889 Reactome, http://www.reactome.org ReactomeREACT_11401 alpha-secretase cleaves the p75NTR extracellular domain Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12843241 Pubmed12913006 Pubmed15701642 Reactome Database ID Release 43193679 Reactome, http://www.reactome.org ReactomeREACT_13658 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 alpha-secretase (ADAM17) is a metalloprotese that has the ability to cleave the p75NTR extracellular domain, in proximity of the transmembrane region. The cleaved extracellular domain is shed from the cell membrane, whereas the rest of the protein, the C-terminal fragment, stays anchored to the membrane. The released extracellular domain represents a binding protein for many potential ligands, including neurotrophins, pro-neurotrophin precursors, beta-amyloid. Shedding of the p75NTR extracellular region can be both constituve and stimulated. The constitutive shedding is dependent on signalling via the p38 MAP kinase. Shedding can be stimulated by the phorbol ester PMA, acting through protein kinase C and ERK activation, and by a tyrosine phosphatase inhibitor. Activation of TRKA by NGF (or TRKB by BDNF) also induces release of the p75NTR extracellular domain. The alpha-secretase cleavage is required for the subsequent cleavage by gamma-secretase. SOCS6:p-c-Kit:sSCF dimer:p-c-Kit Reactome DB_ID: 1470001 Reactome Database ID Release 431470001 Reactome, http://www.reactome.org ReactomeREACT_111256 has a Stoichiometric coefficient of 1 CBL:Grb2/p-APS:p-c-Kit complex Reactome DB_ID: 205200 Reactome Database ID Release 43205200 Reactome, http://www.reactome.org ReactomeREACT_111310 has a Stoichiometric coefficient of 1 Grb2:SOS:p-c-Kit/p-APS:p-c-Kit complex Converted from EntitySet in Reactome Reactome DB_ID: 1433400 Reactome Database ID Release 431433400 Reactome, http://www.reactome.org ReactomeREACT_111576 p-APS dimer Reactome DB_ID: 1433375 Reactome Database ID Release 431433375 Reactome, http://www.reactome.org ReactomeREACT_111305 has a Stoichiometric coefficient of 2 PIK3C(1) Converted from EntitySet in Reactome Reactome DB_ID: 1806233 Reactome Database ID Release 431806233 Reactome, http://www.reactome.org ReactomeREACT_121556 p-APS dimer:p-KIT complex Reactome DB_ID: 1433276 Reactome Database ID Release 431433276 Reactome, http://www.reactome.org ReactomeREACT_111587 has a Stoichiometric coefficient of 1 APS dimer:p-c-Kit:SFKs complex Reactome DB_ID: 205257 Reactome Database ID Release 43205257 Reactome, http://www.reactome.org ReactomeREACT_111288 has a Stoichiometric coefficient of 1 PIK3CA:PIK3R2 Reactome DB_ID: 1806270 Reactome Database ID Release 431806270 Reactome, http://www.reactome.org ReactomeREACT_125153 has a Stoichiometric coefficient of 1 APS dimer Reactome DB_ID: 1433305 Reactome Database ID Release 431433305 Reactome, http://www.reactome.org ReactomeREACT_111367 has a Stoichiometric coefficient of 2 PIK3CA:PIK3R1 Reactome DB_ID: 1806218 Reactome Database ID Release 431806218 Reactome, http://www.reactome.org ReactomeREACT_122807 has a Stoichiometric coefficient of 1 SOCS1:p-KIT complex Reactome DB_ID: 1433442 Reactome Database ID Release 431433442 Reactome, http://www.reactome.org ReactomeREACT_111392 has a Stoichiometric coefficient of 1 PIK3CB:PIK3R1 Reactome DB_ID: 1806184 Reactome Database ID Release 431806184 Reactome, http://www.reactome.org ReactomeREACT_125235 has a Stoichiometric coefficient of 1 PIK3CA:PIK3R3 Reactome DB_ID: 1806182 Reactome Database ID Release 431806182 Reactome, http://www.reactome.org ReactomeREACT_123115 has a Stoichiometric coefficient of 1 PIK3CB:PIK3R3 Reactome DB_ID: 1806237 Reactome Database ID Release 431806237 Reactome, http://www.reactome.org ReactomeREACT_123589 has a Stoichiometric coefficient of 1 PIK3CB:PIK3R2 Reactome DB_ID: 1806272 Reactome Database ID Release 431806272 Reactome, http://www.reactome.org ReactomeREACT_122233 has a Stoichiometric coefficient of 1 The p75NTR C-terminal fragment enters endosomes Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Most of the p75NTR C-terminal fragment resulting from alpha-secretase cleavage enters the early/recycling endosomal compartment. Pubmed12843241 Reactome Database ID Release 43209532 Reactome, http://www.reactome.org ReactomeREACT_13772 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 PIK3CD:PIK3R2 Reactome DB_ID: 1806210 Reactome Database ID Release 431806210 Reactome, http://www.reactome.org ReactomeREACT_125458 has a Stoichiometric coefficient of 1 PIK3CD:PIK3R1 Reactome DB_ID: 1806213 Reactome Database ID Release 431806213 Reactome, http://www.reactome.org ReactomeREACT_119537 has a Stoichiometric coefficient of 1 PIK3CD:PIK3R3 Reactome DB_ID: 1806256 Reactome Database ID Release 431806256 Reactome, http://www.reactome.org ReactomeREACT_122918 has a Stoichiometric coefficient of 1 LNK:p-7Y-KIT:sSCF dimer:p-7Y-KIT Reactome DB_ID: 1562562 Reactome Database ID Release 431562562 Reactome, http://www.reactome.org ReactomeREACT_111280 has a Stoichiometric coefficient of 1 gamma-secretase cleaves the p75NTR transmembrane domain Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12843241 Reactome Database ID Release 43193682 Reactome, http://www.reactome.org ReactomeREACT_13609 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Within early endosomes, p75NTR C-Terminal Fragment undergoes processing by gamma-secretase, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such a minimal complex is sufficient for secretase activity, although other components may exist. The p75NTR cleavage by gamma-secretase gives rise to a 20-kD ICD (IntraCellular Domain) fragment, and to a small peptide, the significance of which is unknown but that is analogous to the A-beta peptides generated from amyloid precursor protein. p75NTR ICD may have cytoplasmic and nuclear signalling functions and it is unstable. p75NTR ICD signals to NF-kB Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12843241 Reactome Database ID Release 43193700 Reactome, http://www.reactome.org ReactomeREACT_13446 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The p75NTR ICD has the potential to bind many intracellular proteins, including TRAF6, SC1, NADE, NRAGE, and RHOA. It may bring these proteins to function in different cellular compartments. p75NTR ICD was shown to activate NF-kB via TRAF6. Part of the ICD migrates to the nucleus A portion of the p75NTR ICD produced by gamma-secretase cleavage moves to the nucleus where it may participate in transcriptional regulation. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed12843241 Reactome Database ID Release 43193702 Reactome, http://www.reactome.org ReactomeREACT_13669 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 PLA2G4A:Ca2+ Reactome DB_ID: 1524095 Reactome Database ID Release 431524095 Reactome, http://www.reactome.org ReactomeREACT_122109 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 beta-NGF dimer binds to TrkA receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Neurotrophin dimer binding to TRK receptors causes receptor dimerization. Although the dissociation constants of NGF for TRK and p75NTR are very similar, the binding kinetics are quite different: NGF associates with and dissociates from p75NTR much more rapidly than from TRKA. p75NTR regulates the affinity and specificity of TRK receptor activation by neurotrophins is regulated. Its presence is required to observe high affinity binding to TRK receptors, since it increases the rate of neurotrophin association with TRK proteins. The major ligand binding domain in TRK receptors is the membrane-proximal Ig-C2-like domain (named Ig2 domain or domain 5), although other regions in in the TRK extracellular domains are also important for ligand binding.<br>The N termini of neurotrophins are important in controlling binding specificity, and the structure of this region is reorganized upon binding to a TRK receptor. In some neurons, TRK receptors are localized to intracellular vesicles in the absence of signals. Electrical activity, cAMP, and Ca2+ stimulate TRK insertion into the cell surface by exocytosis of cytoplasmic membrane vesicles containing TRK. At axon terminals, TRK receptors undergo ligand-dependent endocytosis upon ligand binding. The internalized neurotrophin-TRK complex is then sorted and enters either recycling or retrograde transport pathways.<br> Pubmed10490030 Pubmed1849459 Pubmed1850549 Reactome Database ID Release 43166542 Reactome, http://www.reactome.org ReactomeREACT_10088 The bound receptor dimerizes Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed10490030 Pubmed1849459 Reactome Database ID Release 43166538 Reactome, http://www.reactome.org ReactomeREACT_10014 The binding of neurotrotrophin to TrkA receptors induce their dimerization to form receptor homodimers. TrkA receptor autophosphorylates Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.10.1 Edited: Jassal, B, 2006-10-10 09:20:18 NGF binding induces a conformational change in TRKA, which entails the activation of the receptor kinase domain. TRK receptor activation results in phosphorylation of several of ten evolutionary conserved tyrosines present in the cytoplasmic domain of each receptor. Phosphorylation of the three tyrosines in the activation loop of the kinase domain (Y670, Y674, and Y675 in TRKA) enhances tyrosine kinase activity. Phosphorylation of TRKA Y490 and Y785 creates docking sites for proteins containing SH2 or PTB domains: Y490 is the docking site for SHC, FRS2 and IRS1/2, Y785 interacts with PLC-gamma-1. Three other tyrosine residues are important for signalling but it is not clear how. It is possible that they play a structural role in the receptor. Therefore, full activity of TRKA receptor requires eight tyrosine residues.<br>Human TRKA comes in two isoforms, named TRKA- I (790 a.a long) and TRKA- II (796 a.a. long). The tyrosine phosphorylation site numbering refers to TRKA- I. The site numbering in TRK-II is equal to TRK- I numbering + 6 (that is: Y490 in TRK- I corresponds to Y496 in TRK- II, and so on).The same modifications occur at the homologous sites of rat TrkA, which also comes in the two isoforms I and II.<br> Reactome Database ID Release 43166544 Reactome, http://www.reactome.org ReactomeREACT_9962 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 10 Activated TrkA receptor internalizes to endosomes Reactome Database ID Release 43190065 Reactome, http://www.reactome.org ReactomeREACT_10033 TRKA at the plasma membrane typically results in rapid endocytosis and subsequent passage of the receptors through a network of endosomal compartments. TRKA activation by adenosine A2a receptor Adenosine, acting through A2A receptors can induce TrkA activation. The mechanism of this activation is not understood. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Reactome Database ID Release 43187661 Reactome, http://www.reactome.org ReactomeREACT_9980 PathwayStep5798 TRKA activation by PACAP type 1 receptor Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that acts through type 1 PACAP receptor, a G protein-coupled receptor. PACAP exerts its trophic effects using TrkA receptors and utilizing tyrosine kinase signaling pathways. The mechanism of activation is still poorly understood. Reactome Database ID Release 43187678 Reactome, http://www.reactome.org ReactomeREACT_10128 PathwayStep5799 PTPRO:KIT Reactome DB_ID: 1433419 Reactome Database ID Release 431433419 Reactome, http://www.reactome.org ReactomeREACT_111289 has a Stoichiometric coefficient of 1 NRG1/2:ERBB3 Reactome DB_ID: 1247495 Reactome Database ID Release 431247495 Reactome, http://www.reactome.org ReactomeREACT_117375 has a Stoichiometric coefficient of 1 NRG1/2:ERBB3:ERBB2 ERBB2:ERBB3 heterodimer Reactome DB_ID: 1247502 Reactome Database ID Release 431247502 Reactome, http://www.reactome.org ReactomeREACT_117748 has a Stoichiometric coefficient of 1 EGF:EGFR:ERBB2 ERBB2:EGFR heterodimer ERBB2:HSP90:CDC37:EGF:EGFR Reactome DB_ID: 1227939 Reactome Database ID Release 431227939 Reactome, http://www.reactome.org ReactomeREACT_117594 has a Stoichiometric coefficient of 1 ERBB2:ERBB4cyt1 heterodimers Reactome DB_ID: 1250328 Reactome Database ID Release 431250328 Reactome, http://www.reactome.org ReactomeREACT_117163 has a Stoichiometric coefficient of 1 NRGs/EGFLs:ERBB4:ERBB2 Converted from EntitySet in Reactome ERBB2:ERBB4 heterodimers NRGs/EGF-like ligands:ERBB4:ERBB2 Reactome DB_ID: 1250224 Reactome Database ID Release 431250224 Reactome, http://www.reactome.org ReactomeREACT_116375 ARF1:GTP Reactome DB_ID: 1806286 Reactome Database ID Release 431806286 Reactome, http://www.reactome.org ReactomeREACT_123187 has a Stoichiometric coefficient of 1 NRGs/EGF-like ligands:ERBB4cyt1 Reactome DB_ID: 1250304 Reactome Database ID Release 431250304 Reactome, http://www.reactome.org ReactomeREACT_116219 has a Stoichiometric coefficient of 1 ARF1/3:GTP Converted from EntitySet in Reactome Reactome DB_ID: 1806258 Reactome Database ID Release 431806258 Reactome, http://www.reactome.org ReactomeREACT_123090 Ligand-Activated EGFR/ERBB3/ERBB4 Converted from EntitySet in Reactome Reactome DB_ID: 1963571 Reactome Database ID Release 431963571 Reactome, http://www.reactome.org ReactomeREACT_116645 ERBB2:ERBB2IP:HSP90:CDC37 Reactome DB_ID: 1227970 Reactome Database ID Release 431227970 Reactome, http://www.reactome.org ReactomeREACT_117260 has a Stoichiometric coefficient of 1 NRGs/EGF-like ligands:ERBB4jmAcyt2 Reactome DB_ID: 1250317 Reactome Database ID Release 431250317 Reactome, http://www.reactome.org ReactomeREACT_117739 has a Stoichiometric coefficient of 1 PIK3C3:Mn2+:PIK3R4:Mn2+ Reactome DB_ID: 1806266 Reactome Database ID Release 431806266 Reactome, http://www.reactome.org ReactomeREACT_124134 has a Stoichiometric coefficient of 1 PIK3C2A/3 Converted from EntitySet in Reactome Reactome DB_ID: 1806185 Reactome Database ID Release 431806185 Reactome, http://www.reactome.org ReactomeREACT_122283 ARF1/3:GTP:PI4KB Reactome DB_ID: 1806287 Reactome Database ID Release 431806287 Reactome, http://www.reactome.org ReactomeREACT_124176 has a Stoichiometric coefficient of 1 ARF3:GTP Reactome DB_ID: 1806265 Reactome Database ID Release 431806265 Reactome, http://www.reactome.org ReactomeREACT_122520 has a Stoichiometric coefficient of 1 PIKFYVE:VAC14:FIG4 Reactome DB_ID: 1806269 Reactome Database ID Release 431806269 Reactome, http://www.reactome.org ReactomeREACT_122161 has a Stoichiometric coefficient of 1 PIK3C2A:Ca2+/Mg2+ Reactome DB_ID: 1604655 Reactome Database ID Release 431604655 Reactome, http://www.reactome.org ReactomeREACT_125646 has a Stoichiometric coefficient of 1 PIK3C3:Mn2+ Reactome DB_ID: 1604673 Reactome Database ID Release 431604673 Reactome, http://www.reactome.org ReactomeREACT_123069 has a Stoichiometric coefficient of 1 PIK3R4:Mn2+ Reactome DB_ID: 1604644 Reactome Database ID Release 431604644 Reactome, http://www.reactome.org ReactomeREACT_124565 has a Stoichiometric coefficient of 1 Class I MHC heavy chain (MHC HC) Converted from EntitySet in Reactome Reactome DB_ID: 983410 Reactome Database ID Release 43983410 Reactome, http://www.reactome.org ReactomeREACT_76898 GGT1/5 dimer Converted from EntitySet in Reactome Reactome DB_ID: 2162130 Reactome Database ID Release 432162130 Reactome, http://www.reactome.org ReactomeREACT_124519 GGT1 dimer Gamma-glutamyltransferase 1 Reactome DB_ID: 1247898 Reactome Database ID Release 431247898 Reactome, http://www.reactome.org ReactomeREACT_76337 has a Stoichiometric coefficient of 1 GGT5 dimer Gamma-glutamyltransferase 5 Reactome DB_ID: 265314 Reactome Database ID Release 43265314 Reactome, http://www.reactome.org ReactomeREACT_15599 has a Stoichiometric coefficient of 1 ALOX15:Fe2+ Reactome DB_ID: 2142744 Reactome Database ID Release 432142744 Reactome, http://www.reactome.org ReactomeREACT_152517 has a Stoichiometric coefficient of 1 p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 265277 Reactome Database ID Release 43265277 Reactome, http://www.reactome.org ReactomeREACT_16091 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ALOX5:FLAP:LTC4S ALOX5:ALOX5AP:LTC4S Reactome DB_ID: 2318764 Reactome Database ID Release 432318764 Reactome, http://www.reactome.org ReactomeREACT_148198 has a Stoichiometric coefficient of 1 LTC4S trimer LTC4 synthase homotrimer Reactome DB_ID: 2142729 Reactome Database ID Release 432142729 Reactome, http://www.reactome.org ReactomeREACT_121552 has a Stoichiometric coefficient of 3 p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 2318769 Reactome Database ID Release 432318769 Reactome, http://www.reactome.org ReactomeREACT_148349 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FLAP trimer ALOX5AP trimer Reactome DB_ID: 2318770 Reactome Database ID Release 432318770 Reactome, http://www.reactome.org ReactomeREACT_147922 has a Stoichiometric coefficient of 3 LTA4H:Zn2+ LTA4 hydrolase (Zinc cofactor) Reactome DB_ID: 266038 Reactome Database ID Release 43266038 Reactome, http://www.reactome.org ReactomeREACT_15887 has a Stoichiometric coefficient of 1 Activated FGFR4 Y367C mutant Reactome DB_ID: 2011990 Reactome Database ID Release 432011990 Reactome, http://www.reactome.org ReactomeREACT_121910 has a Stoichiometric coefficient of 2 FGFR4 Y367C mutant dimer Reactome DB_ID: 2011955 Reactome Database ID Release 432011955 Reactome, http://www.reactome.org ReactomeREACT_123822 has a Stoichiometric coefficient of 2 FGFR4 N535K mutant dimer Reactome DB_ID: 2038928 Reactome Database ID Release 432038928 Reactome, http://www.reactome.org ReactomeREACT_124454 has a Stoichiometric coefficient of 2 FGFR4 enhanced kinase mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 2038942 Reactome Database ID Release 432038942 Reactome, http://www.reactome.org ReactomeREACT_124830 FGFR4 V550E mutant dimer Reactome DB_ID: 2038926 Reactome Database ID Release 432038926 Reactome, http://www.reactome.org ReactomeREACT_122910 has a Stoichiometric coefficient of 2 Overexpressed FGFR3 mutant dimer Reactome DB_ID: 2038364 Reactome Database ID Release 432038364 Reactome, http://www.reactome.org ReactomeREACT_123082 has a Stoichiometric coefficient of 2 Activated FGFR3 795fs*139STOP mutant Reactome DB_ID: 2038362 Reactome Database ID Release 432038362 Reactome, http://www.reactome.org ReactomeREACT_125078 has a Stoichiometric coefficient of 2 Activated FGFR3 t(4;14) translocation mutants Converted from EntitySet in Reactome Reactome DB_ID: 2038377 Reactome Database ID Release 432038377 Reactome, http://www.reactome.org ReactomeREACT_125581 FGFR3 mutant dimers:TKIs Reactome DB_ID: 2077417 Reactome Database ID Release 432077417 Reactome, http://www.reactome.org ReactomeREACT_125258 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated overexpressed FGFR3 Reactome DB_ID: 2038367 Reactome Database ID Release 432038367 Reactome, http://www.reactome.org ReactomeREACT_125439 has a Stoichiometric coefficient of 2 Activated FGFR mutants:p-FRS2alpha Reactome DB_ID: 1982059 Reactome Database ID Release 431982059 Reactome, http://www.reactome.org ReactomeREACT_122898 has a Stoichiometric coefficient of 1 Activated FGFR mutants:FRS2alpha Reactome DB_ID: 1982058 Reactome Database ID Release 431982058 Reactome, http://www.reactome.org ReactomeREACT_124658 has a Stoichiometric coefficient of 1 FGFR4 mutant dimers with enhanced kinase activity:PD173074 Reactome DB_ID: 2046360 Reactome Database ID Release 432046360 Reactome, http://www.reactome.org ReactomeREACT_121721 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 activated FGFR4 V550L mutant Reactome DB_ID: 2038936 Reactome Database ID Release 432038936 Reactome, http://www.reactome.org ReactomeREACT_122407 has a Stoichiometric coefficient of 2 FGFR4 V550L mutant dimer Reactome DB_ID: 2038929 Reactome Database ID Release 432038929 Reactome, http://www.reactome.org ReactomeREACT_123242 has a Stoichiometric coefficient of 2 FGFR4 N535D mutant dimer Reactome DB_ID: 2038930 Reactome Database ID Release 432038930 Reactome, http://www.reactome.org ReactomeREACT_121900 has a Stoichiometric coefficient of 2 activated FGFR4 N535D mutant Reactome DB_ID: 2038938 Reactome Database ID Release 432038938 Reactome, http://www.reactome.org ReactomeREACT_123909 has a Stoichiometric coefficient of 2 activated FGFR4 V550E mutant Reactome DB_ID: 2038937 Reactome Database ID Release 432038937 Reactome, http://www.reactome.org ReactomeREACT_122839 has a Stoichiometric coefficient of 2 activated FGFR4 N535K mutant Reactome DB_ID: 2038939 Reactome Database ID Release 432038939 Reactome, http://www.reactome.org ReactomeREACT_124990 has a Stoichiometric coefficient of 2 Activated FGFR4 enhanced kinase mutants Converted from EntitySet in Reactome Reactome DB_ID: 2038945 Reactome Database ID Release 432038945 Reactome, http://www.reactome.org ReactomeREACT_122869 PIK3R1 mutants:PIK3CA Reactome DB_ID: 2399558 Reactome Database ID Release 432399558 Reactome, http://www.reactome.org ReactomeREACT_148038 has a Stoichiometric coefficient of 1 PIK3R1:PIK3CA mutants Reactome DB_ID: 2394005 Reactome Database ID Release 432394005 Reactome, http://www.reactome.org ReactomeREACT_148433 has a Stoichiometric coefficient of 1 AKT1 E17K mutant:PIP2 Reactome DB_ID: 2219527 Reactome Database ID Release 432219527 Reactome, http://www.reactome.org ReactomeREACT_148412 has a Stoichiometric coefficient of 1 SMAD7 binds to SMURF1 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2012-04-10 Pubmed11278251 Pubmed12519765 Pubmed20937913 Reactome Database ID Release 432167917 Reactome, http://www.reactome.org ReactomeREACT_121065 Reviewed: Huang, Tao, 2012-05-14 SMAD7 binds to SMURF1 in the nucleus (Ebisawa et al. 2001, Tajima et al. 2003). SMURF1 domains WW1 and WW2, highly similar to WW2 and WW3 domains of SMURF2, are involved in SMAD7 binding. SMURF1 has two splicing isoforms. The shorter splicing isoform of SMURF1 has an inter-WW domain linker of the same length as the WW2-WW3 domain linker of SMURF2. The longer isoform of SMURF1 has a longer WW1-WW2 domain linker, resulting in decreased affinity of the longer SMURF1 isoform for SMAD7 (Chong et al. 2010). This is based on experiments with recombinant mouse Smad7 and recombinant human SMURF1. Activated FGFR mutants bound to activated PLC gamma Reactome DB_ID: 2077383 Reactome Database ID Release 432077383 Reactome, http://www.reactome.org ReactomeREACT_122024 has a Stoichiometric coefficient of 1 arginine, cystine, lysine Converted from EntitySet in Reactome Reactome DB_ID: 379430 Reactome Database ID Release 43379430 Reactome, http://www.reactome.org ReactomeREACT_17488 SMAD7:SMURF2 complex translocates to the cytosol After forming a complex in the nucleus, SMAD7:SMURF2 traffics to the cytosol (Kavsak et al. 2000). This was inferred from experiments that used a recombinant mouse Smad7 and recombinant human SMURF2. Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11163210 Reactome Database ID Release 432167876 Reactome, http://www.reactome.org ReactomeREACT_120957 Reviewed: Huang, Tao, 2012-05-14 Activated FGFR mutants bound to PLC-gamma Reactome DB_ID: 2077381 Reactome Database ID Release 432077381 Reactome, http://www.reactome.org ReactomeREACT_123449 has a Stoichiometric coefficient of 1 ligands of SLC7A10 Converted from EntitySet in Reactome Reactome DB_ID: 376196 Reactome Database ID Release 43376196 Reactome, http://www.reactome.org ReactomeREACT_15265 SMAD7:SMURF1 complex is exported to the cytosol After SMAD7:SMURF1 complex binds to XPO1 (CRM1) through the nuclear export signal (NES) in the C-terminus of SMURF1, XPO1 enables transport of SMAD7:SMURF1 to the cytosol (Suzuki et al. 2002, Tajima et al. 2003). A recombinant mouse Smad7 and recombinant human SMURF1 were used in these experiments. Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2012-04-10 Pubmed12151385 Pubmed12519765 Reactome Database ID Release 43178215 Reactome, http://www.reactome.org ReactomeREACT_120910 Reviewed: Huang, Tao, 2012-05-14 PI3K mutants Converted from EntitySet in Reactome Reactome DB_ID: 2394006 Reactome Database ID Release 432394006 Reactome, http://www.reactome.org ReactomeREACT_148388 SMAD7:SMURF1 complex binds XPO1 (CRM1) Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed12519765 Reactome Database ID Release 432167924 Reactome, http://www.reactome.org ReactomeREACT_121148 Reviewed: Huang, Tao, 2012-05-14 SMAD7:SMURF1 complex binds to XPO1 (CRM1) through a nuclear export signal (NES) located in the C-terminus of SMURF1 (Tajima et al. 2003). Recombinant mouse Smad7 and recombinant human SMURF1 were used in this study. L-amino acid oxidase Reactome DB_ID: 2160485 Reactome Database ID Release 432160485 Reactome, http://www.reactome.org ReactomeREACT_123633 has a Stoichiometric coefficient of 1 FGFR mutants:p-FRS2alpha:GRB2:SOS1 Reactome DB_ID: 1982061 Reactome Database ID Release 431982061 Reactome, http://www.reactome.org ReactomeREACT_125060 has a Stoichiometric coefficient of 1 Activated FGFR mutants:p-FRS2alpha:GRB2:GAB1:PI3K Reactome DB_ID: 1986641 Reactome Database ID Release 431986641 Reactome, http://www.reactome.org ReactomeREACT_122297 has a Stoichiometric coefficient of 1 arginine, cystine, lysine Converted from EntitySet in Reactome Reactome DB_ID: 379440 Reactome Database ID Release 43379440 Reactome, http://www.reactome.org ReactomeREACT_17929 Activated FGFR mutants:p-FRS2alpha:GRB2:GAB1:PIK3R1 Reactome DB_ID: 1986638 Reactome Database ID Release 431986638 Reactome, http://www.reactome.org ReactomeREACT_125545 has a Stoichiometric coefficient of 1 STRAP binds phosphorylated TGF-beta receptor complex Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed9856985 Reactome Database ID Release 432127562 Reactome, http://www.reactome.org ReactomeREACT_120862 Reviewed: Huang, Tao, 2012-05-14 STRAP (serine-threonine kinase receptor-associated protein) binds to the activated TGF-beta receptor complex. In in vitro studies, STRAP is able to bind both TGFBR1 and TGFBR2 (Datta et al. 1998). This was deduced from experiments in which a recombinant mouse Strap and recombinant human TGFBR1 and TGFBR2 were expressed in COS1 cells. STRAP binds unphosphorylated TGF-beta receptor complex Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed9856985 Reactome Database ID Release 432127609 Reactome, http://www.reactome.org ReactomeREACT_120784 Reviewed: Huang, Tao, 2012-05-14 STRAP (serine-threonine kinase receptor-associated protein) is able to bind the unphosphorylated TGF-beta receptor complex. In addition, in in vitro studies, STRAP was shown to interact individually with both TGFBR1 and TGFBR2 in the absence of TGF-beta stimulation (Datta et al. 1998). This was inferred from experiments using recombinant mouse Strap with recombinant human TGF-beta receptors. STRAP stabilizes interaction of activated TGF-beta receptor complex with SMAD7 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed10757800 Reactome Database ID Release 432128994 Reactome, http://www.reactome.org ReactomeREACT_121338 Reviewed: Huang, Tao, 2012-05-14 STRAP binds both TGF-beta receptor and SMAD7, and stabilizes interaction of phosphorylated TGF-beta receptor complex with SMAD7.This reaction may involve oligomerization of STRAP. STRAP and SMAD7 act synergistically to inhibit the transcription of TGF-beta target genes by preventing SMAD2 and SMAD3 from binding phosphorylated TGFBR1. SMAD7 recruits GADD34:PP1 to phosphorylated TGFBR Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2012-04-10 Pubmed14718519 Reactome Database ID Release 43178189 Reactome, http://www.reactome.org ReactomeREACT_121211 Reviewed: Huang, Tao, 2012-05-14 SMAD7 recruits protein phosphatase 1 (PP1) to TGF-beta receptor complex by binding to the PP1 regulatory subunit PPP1R15A (GADD34). SARA stabilizes the complex by directly interacting with PP1 catalytic subunit, and presumably TGF-beta receptor complex (Shi et al. 2004). This was deduced based on experiments involving recombinant mouse Smad7 and recombinant human PPP1R15A, TGFBR1, TGFBR2 and SARA. PP1 dephosphorylates TGFBR1 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 EC Number: 3.1.3.16 Edited: Jassal, B, 2012-04-10 PP1 dephosphorylates TGF-beta receptor-1 (TGFBR1), thereby inhibiting TGF-beta signaling. It has not been precisely examined whether PP1 dephosphorylates all TGFBR1 serine and threonine residues phosphorylated by TGFBR2 (Shi et al. 2004). This was inferred from experiments that used a recombinant mouse Smad7 and recombinant human TGFBR1, TGFBR2 and PP1. Pubmed14718519 Reactome Database ID Release 43178178 Reactome, http://www.reactome.org ReactomeREACT_121355 Reviewed: Huang, Tao, 2012-05-14 has a Stoichiometric coefficient of 6 SMAD7 binds to SMURF2 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2012-04-10 Pubmed11163210 Pubmed16061177 Reactome Database ID Release 43178208 Reactome, http://www.reactome.org ReactomeREACT_121124 Reviewed: Huang, Tao, 2012-05-14 SMURF2, an E3 ubiquitin protein ligase, binds to SMAD7 in the nucleus. WW2 and WW3 domains of SMURF2 are both required for binding PY motif (PPXY sequence) of SMAD7. Endogenous human SMAD7 and SMURF2 were shown to form a complex in human U4A/Jak1 cells, derived from a sarcoma cell line 2fTGH. The interaction was studied in more detail by expressing tagged recombinant human SMURF2 and mouse Smad7 in human embryonic kidney cell line HEK293 (Kavsak et al. 2000, Ogunjimi et al. 2005). ligands of SLC7A10 Converted from EntitySet in Reactome Reactome DB_ID: 376201 Reactome Database ID Release 43376201 Reactome, http://www.reactome.org ReactomeREACT_15039 FASL:FAS Receptor Trimer:FADD:pro-Caspase-10 Reactome DB_ID: 141315 Reactome Database ID Release 43141315 Reactome, http://www.reactome.org ReactomeREACT_4528 has a Stoichiometric coefficient of 1 FASL:FAS Receptor Trimer:FADD:pro-Caspase-8 DISC Reactome DB_ID: 75114 Reactome Database ID Release 4375114 Reactome, http://www.reactome.org ReactomeREACT_2430 has a Stoichiometric coefficient of 1 ligands of SLC7A1 and SLC7A2 isoform B Converted from EntitySet in Reactome Reactome DB_ID: 375765 Reactome Database ID Release 43375765 Reactome, http://www.reactome.org ReactomeREACT_17674 Phosphorylated SMAD2/3 dissociates from TGFBR Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-01-18 10:19:52 Pubmed15350224 Pubmed8980228 Pubmed9311995 Pubmed9346966 Reactome Database ID Release 43170850 Reactome, http://www.reactome.org ReactomeREACT_6744 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 Upon phosphorylation of the R-SMAD (SMAD2/3), the conformation of the C-terminal (MH2) domain of the R-SMAD changes, lowering its affinity for the type I receptor and SARA. As a result, the phosphorylated R-SMAD dissociates from the activated receptor complex (TGFBR). FASL:FAS Receptor Trimer:FADD complex Reactome DB_ID: 43124 Reactome Database ID Release 4343124 Reactome, http://www.reactome.org ReactomeREACT_4500 has a Stoichiometric coefficient of 1 Activated type I receptor phosphorylates SMAD2/3 directly Activated type I receptor kinase directly phosphorylates two of the C-terminal serine residues of SMAD2 or SMAD3. Binding of these R-SMADs to the L45 loop of the type I receptor is critical for this event. Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-01-18 10:19:52 Pubmed11100470 Reactome Database ID Release 43170868 Reactome, http://www.reactome.org ReactomeREACT_6879 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 has a Stoichiometric coefficient of 2 FASL:FAS Receptor Trimer Reactome DB_ID: 76195 Reactome Database ID Release 4376195 Reactome, http://www.reactome.org ReactomeREACT_5688 has a Stoichiometric coefficient of 3 ligands of SLC7A1 and SLC7A2 isoform B Converted from EntitySet in Reactome Reactome DB_ID: 375781 Reactome Database ID Release 43375781 Reactome, http://www.reactome.org ReactomeREACT_15195 An anchoring protein, SARA, recruits SMAD2/3 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-01-18 10:19:52 Pubmed9865696 Reactome Database ID Release 43170835 Reactome, http://www.reactome.org ReactomeREACT_6923 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 The activated TGF-beta receptor complex is internalized by clathrin-mediated endocytosis into early endosomes. SARA resides in the membrane of early endosomes. Crystallographic studies suggest that dimeric SARA in the early endosome coordinates two R-SMAD molecules (SMAD2 and/or SMAD3) per one receptor complex. FASL:FAS Receptor monomer Reactome DB_ID: 76564 Reactome Database ID Release 4376564 Reactome, http://www.reactome.org ReactomeREACT_3459 has a Stoichiometric coefficient of 1 TGFBR2 phosphorylates TGFBR1 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-01-18 10:19:52 Formation of the hetero-tetrameric TGF-beta-1 receptor complex induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. The constitutively active type II receptor kinase (which auto-phosphorylates in the absence of ligand), trans-phosphorylates specific serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of the type I receptor (Wrana et al. 1994, Souchelnytskyi et al. 1996).<br><br>In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta-1 stimulation. Sumoylation enhances TGFBR1 function by facilitating recruitment and phosphorylation of SMAD3 (Kang et al. 2008). Pubmed8047140 Pubmed8947046 Reactome Database ID Release 43170843 Reactome, http://www.reactome.org ReactomeREACT_6816 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 Type II receptor phosphorylates type I receptor has a Stoichiometric coefficient of 12 Smad7:SMURF1:XPO1 Reactome DB_ID: 2169005 Reactome Database ID Release 432169005 Reactome, http://www.reactome.org ReactomeREACT_124157 has a Stoichiometric coefficient of 1 ligands of SLC7A2, isoform A Converted from EntitySet in Reactome Reactome DB_ID: 375764 Reactome Database ID Release 43375764 Reactome, http://www.reactome.org ReactomeREACT_15006 AKT inhibitors:AKT Reactome DB_ID: 2400006 Reactome Database ID Release 432400006 Reactome, http://www.reactome.org ReactomeREACT_148070 has a Stoichiometric coefficient of 1 ligands of SLC7A2, isoform A Converted from EntitySet in Reactome Reactome DB_ID: 375795 Reactome Database ID Release 43375795 Reactome, http://www.reactome.org ReactomeREACT_15174 PI3K Inhibitors:PI3K Reactome DB_ID: 2400008 Reactome Database ID Release 432400008 Reactome, http://www.reactome.org ReactomeREACT_148204 has a Stoichiometric coefficient of 1 ligands of SLC7A3 Converted from EntitySet in Reactome Reactome DB_ID: 375794 Reactome Database ID Release 43375794 Reactome, http://www.reactome.org ReactomeREACT_15247 PDPK1:p-S473-AKT1 E17K mutant:PIP2 Reactome DB_ID: 2243941 Reactome Database ID Release 432243941 Reactome, http://www.reactome.org ReactomeREACT_148312 has a Stoichiometric coefficient of 1 ligands of SLC7A3 Converted from EntitySet in Reactome Reactome DB_ID: 375791 Reactome Database ID Release 43375791 Reactome, http://www.reactome.org ReactomeREACT_15019 I-SMAD competes with SMAD2/3 for type I receptor (TGFBR1) Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-02-10 14:02:35 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0030512 I-SMADs (SMAD6 and SMAD7) reside in the nucleus presumably to be sequestered from the TGF-beta receptor complex and thus avoid inappropriate silencing of the signaling pathway. Upon activation of the signaling pathway, I-SMADs exit the nucleus and are recruited to the signaling TGF-beta receptor complex. I-SMADs directly bind to the so-called L45 loop of the type I receptor, the site of binding of R-SMADs. Thus, I-SMADs competitively inhibit the activation/phosphorylation of R-SMADs. Pubmed9215638 Pubmed9335507 Reactome Database ID Release 43173512 Reactome, http://www.reactome.org ReactomeREACT_6909 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 p-S473-AKT1 E17K mutant:PIP2 Reactome DB_ID: 2243943 Reactome Database ID Release 432243943 Reactome, http://www.reactome.org ReactomeREACT_148525 has a Stoichiometric coefficient of 1 PathwayStep5900 I-Smad competes with R-Smad1/5/8 for type I receptor Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Edited: Jassal, B, 2007-08-13 08:42:05 I-SMADs reside in the nucleus presumably to be sequestered from the BMP2:receptor complex and thus avoid inappropriate silencing of the signalling pathway. Upon activation of the signalling pathway, I-SMADs exit the nucleus and are recruited to the signalling BMP2:receptor complex. I-SMADs directly bind to the so-called L45 loop of the type I receptor, the site of binding of R-SMADs. Thus, I-SMADs competitively inhibit the activation/phosphorylation of R-SMADs. Pubmed12519765 Pubmed12857866 Reactome Database ID Release 43201475 Reactome, http://www.reactome.org ReactomeREACT_115888 Reviewed: Heldin, CH, 2007--1-1- PathwayStep5903 Dimeric TGFB1 binds to TGFBR2 homodimer Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Dimeric TGF-beta-1 binds to the receptor Edited: Jassal, B, 2006-01-18 10:19:52 Pubmed1333888 Pubmed7693660 Pubmed8242743 Reactome Database ID Release 43170861 Reactome, http://www.reactome.org ReactomeREACT_6872 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 The mature dimeric TGF-beta-1 (TGFB1) binds with high affinity to its signaling receptor, the type II receptor serine/threonine kinase (TGFBR2). The type II receptor is known to form dimeric complexes even in the absence of TGF-beta-1. PathwayStep5904 TGFBR2 recruits TGFBR1 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-01-18 10:19:52 Edited: Jassal, B, 2012-04-10 Pubmed1333888 Pubmed7693660 Pubmed8242743 Pubmed9233797 Reactome Database ID Release 43170846 Reactome, http://www.reactome.org ReactomeREACT_6945 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 The protein complex of dimeric TGF-beta-1 with the type II receptor dimer (Dimeric TGFB1:TGFBR2 homodimer) recruits the low affinity receptor, type I receptor (TGFBR1), which is also known to pre-exist in a dimeric form, thus forming a hetero-tetrameric receptor bound to the dimeric ligand on the extracellular face of the plasma membrane (TGFB1:TGFBR2:TGFBR1). FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase, forms a complex with TGFBR1 and prevents phosphorylation of TGFBR1 by TGFBR2 in the absence of ligand. FKBP1A dissociates from TGFBR1 after it forms a complex with ligand-activated TGFBR2. Type II receptor recruits type I receptor has a Stoichiometric coefficient of 2 PathwayStep5901 Latent TGF-beta-1 is cleaved by furin Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 EC Number: 3.4.21 Edited: Jassal, B, 2006-01-18 10:19:52 In the Golgi apparatus, TGF-beta-1 (TGFB1) is activated by furin protease cleavage of the N-terminal pro-peptide portion. This leads to the formation of the N-terminal disulphide-linked dimeric pro-peptides, also known as latency-associated proteins (LAPs) and the C-terminal mature disulphide-linked dimeric TGF-beta-1. However, the N- and C-terminal polypeptides do not physically separate. Rather they stay in one complex. In addition, the LAP forms disulphide links with separate secreted proteins, the Latent TGF-beta binding proteins (LTBPs). LTBPs-linked to LAP and the non-covalently linked mature TGF-beta-1 remain together and form the large latent complex (LLC) Pubmed12482908 Pubmed7737999 Reactome Database ID Release 43170844 Reactome, http://www.reactome.org ReactomeREACT_6931 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 PathwayStep5902 Secretion and activation of the latent large complex of TGF-beta-1 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-03-22 11:41:32 Pubmed12482908 Pubmed15564041 Reactome Database ID Release 43177107 Reactome, http://www.reactome.org ReactomeREACT_6888 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 The large latent complex (LLC) of TGF-beta-1 (TGFB1) is secreted by exocytosis to the extracellular region. TGF-beta-1 in the LLC cannot interact with the receptors and for this reason we say that it requires "activation". This means release from the LLC. This release is achieved by many mechanisms: proteolytic cleavage of the LTBPs, thrombospondin-1 binding to the LLC, integrin alphaV-beta6 binding to the LLC, reactive oxygen species and low pH. The release of mature dimeric TGF-beta-1 is essentially a mechanical process that demands cleavage and opening of the LLC structure so that the caged mature C-terminal TGF-beta-1 polypeptide is released to reach the receptor. PathwayStep5907 PathwayStep5908 PathwayStep5905 PathwayStep5906 PathwayStep5909 SMURF1 ubiquitinates RHOA Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed14657501 Pubmed15761148 Reactome Database ID Release 432160935 Reactome, http://www.reactome.org ReactomeREACT_121146 Reviewed: Huang, Tao, 2012-05-14 SMURF1, recruited to tight junctions through association with phosphorylated PARD6A, ubiquitinates RHOA, leading to RHOA degradation and disassembly of tight junctions (Ozdamar et al. 2005). Disassembly of tight junctions is an important step in epithelial to mesenchymal transition. SMURF1, but not SMURF2, decreases RHOA level, and this effect is proteasome dependent (Wang et al. 2003). MATE substrates Converted from EntitySet in Reactome Reactome DB_ID: 446597 Reactome Database ID Release 43446597 Reactome, http://www.reactome.org ReactomeREACT_20849 Disassembly of tight junctions Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed15761148 Reactome Database ID Release 432160931 Reactome, http://www.reactome.org ReactomeREACT_120890 Reviewed: Huang, Tao, 2012-05-14 Ubiquitination of RHOA by SMURF1 leads to disassembly of tight junctions, an important step in epithelial to mesenchymal transition. Overexpressed FGFR2:TKIs Reactome DB_ID: 2029966 Reactome Database ID Release 432029966 Reactome, http://www.reactome.org ReactomeREACT_125625 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Overexpressed FGFR2 homodimers:GP369 Reactome DB_ID: 2067714 Reactome Database ID Release 432067714 Reactome, http://www.reactome.org ReactomeREACT_123175 has a Stoichiometric coefficient of 1 FGFR3 cysteine mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 2012041 Reactome Database ID Release 432012041 Reactome, http://www.reactome.org ReactomeREACT_125342 FGFR3 R248C mutant dimer Reactome DB_ID: 2011948 Reactome Database ID Release 432011948 Reactome, http://www.reactome.org ReactomeREACT_124840 has a Stoichiometric coefficient of 2 FGFR3b S249C mutant dimer Reactome DB_ID: 1226110 Reactome Database ID Release 431226110 Reactome, http://www.reactome.org ReactomeREACT_124615 has a Stoichiometric coefficient of 2 FGFR3 G370C mutant dimer Reactome DB_ID: 2011945 Reactome Database ID Release 432011945 Reactome, http://www.reactome.org ReactomeREACT_121521 has a Stoichiometric coefficient of 2 FGFR3 S371C mutant dimer Reactome DB_ID: 2038352 Reactome Database ID Release 432038352 Reactome, http://www.reactome.org ReactomeREACT_125361 has a Stoichiometric coefficient of 2 FGFR3 Y373C mutant dimer Reactome DB_ID: 2038353 Reactome Database ID Release 432038353 Reactome, http://www.reactome.org ReactomeREACT_124738 has a Stoichiometric coefficient of 2 Activated FGFR3 cysteine mutants Converted from EntitySet in Reactome Reactome DB_ID: 2012020 Reactome Database ID Release 432012020 Reactome, http://www.reactome.org ReactomeREACT_121642 Activated overexpressed FGFR2 Reactome DB_ID: 2029916 Reactome Database ID Release 432029916 Reactome, http://www.reactome.org ReactomeREACT_125621 has a Stoichiometric coefficient of 2 phosphorylated FGFR2b C3 variant dimer Reactome DB_ID: 2029932 Reactome Database ID Release 432029932 Reactome, http://www.reactome.org ReactomeREACT_124656 has a Stoichiometric coefficient of 2 Mg2+/Mn2+ Converted from EntitySet in Reactome Reactome DB_ID: 1524087 Reactome Database ID Release 431524087 Reactome, http://www.reactome.org ReactomeREACT_122642 TGFBR2 is recruited to tight junctions after TGF-beta stimulation After TGF-beta stimulation, TGFBR2 binds TGFBR1 anchored to tight junctions through association with PARD6A (Ozdamar et al. 2005). FKBP1A (FKBP12) prevents phosphorylation of TGFBR1 by TGFBR2 in the absence of ligand. FKBP1A dissociates from TGFBR1 after it forms a complex with ligand-activated TGFBR2 (Chen et al. 1997). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 and TGFBR2 were studied in the context of endogenous mouse tight junctions. Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed15761148 Pubmed9233797 Reactome Database ID Release 432134519 Reactome, http://www.reactome.org ReactomeREACT_121305 Reviewed: Huang, Tao, 2012-05-14 has a Stoichiometric coefficient of 2 TGFBR1 is recruited to tight junctions by PARD6A Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed10877843 Pubmed11447115 Pubmed12953056 Pubmed15761148 Pubmed21258369 Reactome Database ID Release 432134506 Reactome, http://www.reactome.org ReactomeREACT_121029 Reviewed: Huang, Tao, 2012-05-14 TGFBR1 binds to PARD6A, a component of tight junctions, and localizes to tight junctions irrespective of TGF-beta stimulation. The N-terminus of PARD6A, containing a PB1 domain necessary for interactions with PRKCZ, is necessary for binding to TGFBR1 (Ozdamar et al. 2005).<br>PARD6A, bound to PARD3 and PRKCZ, is associated with tight junctions through JAM-A (Ebnet et al. 2001), which is bound to CGN (cingulin) (Bazzoni et al. 2000). CGN binds ARHGEF18 (p114RhoGEF), and ARHGEF18 recruits RHOA to tight junctions. Other components of the tight junction structure are not shown in this context (Terry et al. 2011). <br>Junctional RHOA activity is required for maintenance of junctional integrity through regulation of actinomyosin cytoskeleton organization (Terry et al. 2011). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 were studied in the context of endogenous mouse tight junctions. SMURF1 binds phosphorylated PARD6A Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed15761148 Reactome Database ID Release 432160932 Reactome, http://www.reactome.org ReactomeREACT_121150 Reviewed: Huang, Tao, 2012-05-14 SMURF1 ubiquitin ligase is recruited to tight junctions by binding to phosphorylated PARD6A (Ozdamar et al. 2005). TGFBR2 phosphorylates TGFBR1 and PARD6A Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed15761148 Reactome Database ID Release 432134532 Reactome, http://www.reactome.org ReactomeREACT_121038 Reviewed: Huang, Tao, 2012-05-14 TGFBR2 recruited to tight junctions after TGF-beta stimulation phosphorylates PARD6A on serine residue S345, and it also phosphorylates TGFBR1 (Ozdamar et al. 2005). This was inferred from experiments in which a recombinant mouse Pard6a and recombinant human TGFBR1 and TGFBR2 were used. has a Stoichiometric coefficient of 13 PMEPA1 sequesters unphosphorylated SMAD2/3 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 PMEPA1 binds unphosphorylated SMAD2 and SMAD3 and prevents their phosphorylation in response to TGF-beta stimulation (Watanabe et al. 2010). Pubmed20129061 Reactome Database ID Release 432187358 Reactome, http://www.reactome.org ReactomeREACT_121239 Reviewed: Huang, Tao, 2012-05-14 PMEPA1 sequesters phosphorylated SMAD2/3 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 PMEPA1 binds phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers (Watanabe et al. 2010). Pubmed20129061 Reactome Database ID Release 432187355 Reactome, http://www.reactome.org ReactomeREACT_120812 Reviewed: Huang, Tao, 2012-05-14 MTMR4 dephosphorylates SMAD2/3 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 MTMR4 protein phosphatase dephosphorylates SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers and inhibiting transmission of TGF-beta signal to the nucleus (Yu et al. 2010). Pubmed20061380 Reactome Database ID Release 432187401 Reactome, http://www.reactome.org ReactomeREACT_120908 Reviewed: Huang, Tao, 2012-05-14 MTMR4 binds phosphorylated SMAD2/3 A protein phosphatase MTMR4, residing in the early endosome membrane, binds phosphorylated SMAD2 and SMAD3 (Yu et al. 2010). Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed20061380 Reactome Database ID Release 432187405 Reactome, http://www.reactome.org ReactomeREACT_120991 Reviewed: Huang, Tao, 2012-05-14 MATE substrates Converted from EntitySet in Reactome Reactome DB_ID: 446589 Reactome Database ID Release 43446589 Reactome, http://www.reactome.org ReactomeREACT_21070 STUB1 (CHIP) ubiquitinates SMAD3 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed14701756 Pubmed15781469 Reactome Database ID Release 432187368 Reactome, http://www.reactome.org ReactomeREACT_120732 Reviewed: Huang, Tao, 2012-05-14 STUB1 (CHIP) ubiquitinates SMAD3 in the absence of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005). Activated FGFR3b S249C mutant Reactome DB_ID: 1226875 Reactome Database ID Release 431226875 Reactome, http://www.reactome.org ReactomeREACT_123323 has a Stoichiometric coefficient of 2 Activated FGFR3 G370C mutant Reactome DB_ID: 2011980 Reactome Database ID Release 432011980 Reactome, http://www.reactome.org ReactomeREACT_122790 has a Stoichiometric coefficient of 2 SMURF2 ubiquitinates SMAD2 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 EC Number: 6.3.2.19 Edited: Jassal, B, 2006-02-14 10:42:31 Pubmed11158580 Reactome Database ID Release 43173542 Reactome, http://www.reactome.org ReactomeREACT_6786 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 SMAD2 is polyubiquitinated by SMURF2 and targeted for proteasome-mediated degradation. Dicarboxylates transported by NaDC1 Converted from EntitySet in Reactome Reactome DB_ID: 433124 Reactome Database ID Release 43433124 Reactome, http://www.reactome.org ReactomeREACT_20685 SMAD3 binds STUB1 (CHIP) Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed14701756 Pubmed15781469 Reactome Database ID Release 432187375 Reactome, http://www.reactome.org ReactomeREACT_120728 Reviewed: Huang, Tao, 2012-05-14 STUB1 (CHIP), an E3 ubiquitin ligase, binds SMAD3 irrespective of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005). FGFR3 point mutant dimers with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2033383 Reactome Database ID Release 432033383 Reactome, http://www.reactome.org ReactomeREACT_122137 FGFR3 G380R mutant dimer Reactome DB_ID: 2033337 Reactome Database ID Release 432033337 Reactome, http://www.reactome.org ReactomeREACT_123420 has a Stoichiometric coefficient of 2 Activated FGFR3 S371C mutant dimer Reactome DB_ID: 2011985 Reactome Database ID Release 432011985 Reactome, http://www.reactome.org ReactomeREACT_121668 has a Stoichiometric coefficient of 2 Activated FGFR3 Y373C mutant dimer Reactome DB_ID: 2011986 Reactome Database ID Release 432011986 Reactome, http://www.reactome.org ReactomeREACT_123510 has a Stoichiometric coefficient of 2 FGFR3 K650M mutant dimer Reactome DB_ID: 2033324 Reactome Database ID Release 432033324 Reactome, http://www.reactome.org ReactomeREACT_125163 has a Stoichiometric coefficient of 2 FGFR3 K650N mutant dimer Reactome DB_ID: 2033336 Reactome Database ID Release 432033336 Reactome, http://www.reactome.org ReactomeREACT_124020 has a Stoichiometric coefficient of 2 FGFR3 G382D mutant dimer Reactome DB_ID: 2033325 Reactome Database ID Release 432033325 Reactome, http://www.reactome.org ReactomeREACT_123882 has a Stoichiometric coefficient of 2 FGFR3 K650E mutant dimer Reactome DB_ID: 2033332 Reactome Database ID Release 432033332 Reactome, http://www.reactome.org ReactomeREACT_121425 has a Stoichiometric coefficient of 2 Activated FGFR3 R248C mutant dimer Reactome DB_ID: 2011982 Reactome Database ID Release 432011982 Reactome, http://www.reactome.org ReactomeREACT_123275 has a Stoichiometric coefficient of 2 SMURF2 binds SMAD2 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11158580 Reactome Database ID Release 432176445 Reactome, http://www.reactome.org ReactomeREACT_121290 Reviewed: Huang, Tao, 2012-05-14 SMURF2 binds SMAD2 irrespective of TGF-beta signaling (Zhang et al. 2001). UCHL5 or USP15 deubiquitinates TGFBR1 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 3.1.2.15 Edited: Jassal, B, 2012-04-10 Pubmed16027725 Pubmed22344298 Reactome Database ID Release 432179291 Reactome, http://www.reactome.org ReactomeREACT_120959 Reviewed: Huang, Tao, 2012-05-14 Ubiquitin C-terminal hydrolase UCHL5 (UCH37) deubiquitinates TGFBR1, stabilizing TGF-beta receptor complex and prolonging TGF-beta receptor signaling. Deubiqutination of SMAD7 by UCHL5 has not been examined in this context (Wicks et al. 2005). Ubiquitin peptidase USP15 also deubiquitinates and stabilizes TGFBR1, leading to enhanced signaling by TGF-beta receptor complex. USP15 does not affect the ubiquitination status of SMAD7. Amplification of USP15 has recently been reported in glioblastoma, breast and ovarian cancer. In advanced glioblastoma, TGF-beta receptor signaling acts as an oncogenic factor, and USP15-mediated upregulation of TGF-beta receptor signaling may be a key factor in glioblastoma pathogenesis (Eichhorn et al. 2012). The role of UCHL5 was inferred from experiments using recombinant mouse Uchl5 and Smad7 with recombinant human TGF-beta receptors. The role of USP15 was established by experiments using human proteins. has a Stoichiometric coefficient of 2 UCHL5 binds SMAD7 in complex with ubiquitinated TGFBR1 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed16027725 Pubmed22344298 Reactome Database ID Release 432179293 Reactome, http://www.reactome.org ReactomeREACT_120979 Reviewed: Huang, Tao, 2012-05-14 Ubiquitin C-terminal hydrolase UCHL5 (UCH37) strongly binds to SMAD7 and is thereby recruited to TGF-beta receptor complex (Wicks et al. 2005). Another ubiquitin peptidase, USP15, has recently been found to associate with ubiquitinated TGFBR1 through SMAD7 (Eichhorn et al. 2012). The role of UCHL5 was inferred from experiments using recombinant mouse Uchl5 and Smad7 with recombinant human TGF-beta receptors. The role of USP15 was established by experiments with human proteins. Dicarboxylates transported by NaDC1 Converted from EntitySet in Reactome Reactome DB_ID: 433111 Reactome Database ID Release 43433111 Reactome, http://www.reactome.org ReactomeREACT_21161 SMURFs/NEDD4L ubiquitinate phosphorylated TGFBR1 and SMAD7 Authored: Orlic-Milacic, M, 2012-04-04 EC Number: 6.3.2.19 Edited: Jassal, B, 2012-04-10 Pubmed11163210 Pubmed11278251 Pubmed15496141 Reactome Database ID Release 432169050 Reactome, http://www.reactome.org ReactomeREACT_121128 Reviewed: Huang, Tao, 2012-05-14 SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) ubiquitin ligases, recruited to TGF-beta receptor complex through interaction with SMAD7, ubiquitinate both SMAD7 and/or TGF-beta receptor I (TGFBR1), targeting the complex for degradation. This was inferred from experiments using a recombinant mouse Smad7 with recombinant human ubiquitin ligases and TGF-beta receptors. has a Stoichiometric coefficient of 2 SMAD7:SMURF complex binds to phosphorylated TGFBR1 Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2012-04-10 Pubmed11163210 Pubmed11278251 Pubmed15496141 Reactome Database ID Release 43178218 Reactome, http://www.reactome.org ReactomeREACT_121080 Reviewed: Huang, Tao, 2012-05-14 SMAD7 binds to phosphorylated TGFBR1 (TGF-beta receptor I), thereby recruiting SMURF1 (Ebisawa et al. 2001), SMURF2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) ubiquitin ligases to the activated TGF-beta receptor complex. This is based on experiments in which recombinant mouse Smad7 was used together with recombinant human ubiquitin ligases and TGF-beta receptors. SMAD7:NEDD4L complex translocates to the cytosol Authored: Orlic-Milacic, M, 2012-04-04 Binding of NEDD4L promotes translocation of SMAD7 to the cytosol (Kuratomi et al. 2005). This is based on experiments using recombinant mouse Smad7 and recombinant human NEDD4L. Edited: Jassal, B, 2012-04-10 Pubmed15496141 Reactome Database ID Release 432176417 Reactome, http://www.reactome.org ReactomeREACT_120817 Reviewed: Huang, Tao, 2012-05-14 NEDD4L ubiquitin ligase binds SMAD7 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 NEDD4L ubiquitin ligase, structurally similar to SMURF ubiquitin ligases, binds SMAD7 (Kuratomi et al. 2005). This was inferred from experiments that used recombinant mouse Smad7 and recombinant human NEDD4L. Pubmed15496141 Reactome Database ID Release 432176416 Reactome, http://www.reactome.org ReactomeREACT_121293 Reviewed: Huang, Tao, 2012-05-14 FGFR3 K650Q mutant dimer Reactome DB_ID: 2033343 Reactome Database ID Release 432033343 Reactome, http://www.reactome.org ReactomeREACT_124193 has a Stoichiometric coefficient of 2 CYP3A5 oxidises aflatoxin B1 to aflatoxin-8,9-oxide Aflatoxins are produced by the fungal molds Aspergillus flavus and Aspergillus parasiticus. Dietary contamination accounts for adverse health problems including liver cancer therby classifying aflatoxins as a Group 1 carcinogen in humans.Aflatoxin B1 (AFB1) is especially carcinogenic in a number of species including humans.<br>AFB1 requires microsomal oxidation to produce epoxides which are the cause of their toxic and carcinogenic effects. In humans, both CYP3A4 and CYP3A5 are able to produce epoxide stereoisomers of AFB1, the most potent being aflatoxin exo-8,9-oxide (AFBO). Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed15454734 Reactome Database ID Release 43213175 Reactome, http://www.reactome.org ReactomeREACT_13734 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 FGFR3 K650T mutant dimer Reactome DB_ID: 2033328 Reactome Database ID Release 432033328 Reactome, http://www.reactome.org ReactomeREACT_123761 has a Stoichiometric coefficient of 2 FGFR3b G697C mutant dimer Reactome DB_ID: 2033342 Reactome Database ID Release 432033342 Reactome, http://www.reactome.org ReactomeREACT_123026 has a Stoichiometric coefficient of 2 CYP2F1 dehydrogenates 3-methylindole 3-methylindole (3MI) is a fermentation product of tryptophan. It is usually formed in the rumen of goats and cattle and in the large intestine of humans. CYP2F1 shows the highest activity towards the dehydrogenation of 3MI to form a methylene imine-reactive intermediate. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed10383923 Reactome Database ID Release 43212005 Reactome, http://www.reactome.org ReactomeREACT_13671 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP3A4 can N-demethylate loperaminde Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed15365656 Reactome Database ID Release 43211948 Reactome, http://www.reactome.org ReactomeREACT_13765 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The CYP3A family are the most abundantly expressed P450s in human liver, accounting for around 50% of xenobiotic drug metabolism. CYP3A4 is the most abundant member of the family and possesses broad specificity to a range of xenobiotics. Loperamide (LOP), an antidiarrheal, is mainly metabolized to desmethylloperamide (DLOP) through the N-demethylation pathway. This initial N-demethylation is carried out by CYP3A4. O-atom dealkylation of dextromethorphan At the beginning of this reaction, 1 molecule of 'H+', 1 molecule of 'Dextromethorphan', 1 molecule of 'Oxygen', and 1 molecule of 'NADPH' are present. At the end of this reaction, 1 molecule of 'NADP+', 1 molecule of 'Dextrorphan', 1 molecule of 'Formaldehyde', and 1 molecule of 'H2O' are present.<br><br> This reaction takes place in the 'smooth endoplasmic reticulum' and is mediated by the 'oxygen binding activity' of 'Cytochrome P450 2D6 '.<br> Reactome Database ID Release 4376456 Reactome, http://www.reactome.org ReactomeREACT_323 CYP2D6 4-hydroxylates debrisoquine Authored: Jassal, B, 2008-05-19 12:57:01 CYP2D6 (debrisoquine 4-hydroxylase) has a wide substrate specificity and is an important cytochrme P450 in drug metabolism. It has extensive genetic polymorphism (called the debrisoquine/sparteine oxidation polymorphism) that influences its expression and function.The polymorphism is responsible for populations being poor metabolizers (PM) or extensive metabolizers (EM, normal). Approximately 10% of Caucasians and less than 1% of Asians lack the CYP2D6 protein because of two null alleles which do not encode the functional product. Further polymorphisms discovered recently have identified ultrarapid metabolizers (PM) (alleles with multiple gene copies) and intermediate metabolizers (IM) (deficiency in their metabolism capacity) (Zanger UM et al, 2004). EC Number: 1.14.14 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed14618296 Pubmed6220203 Pubmed7903454 Reactome Database ID Release 43211966 Reactome, http://www.reactome.org ReactomeREACT_13478 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Activated FGFR3 K650E mutant Reactome DB_ID: 2033333 Reactome Database ID Release 432033333 Reactome, http://www.reactome.org ReactomeREACT_124807 has a Stoichiometric coefficient of 2 Activated FGFR3 K650M mutant Reactome DB_ID: 2033334 Reactome Database ID Release 432033334 Reactome, http://www.reactome.org ReactomeREACT_121555 has a Stoichiometric coefficient of 2 Activated FGFR3 K650N mutant Reactome DB_ID: 2033380 Reactome Database ID Release 432033380 Reactome, http://www.reactome.org ReactomeREACT_121775 has a Stoichiometric coefficient of 2 FGFR3 A319E mutant dimer Reactome DB_ID: 2065831 Reactome Database ID Release 432065831 Reactome, http://www.reactome.org ReactomeREACT_124736 has a Stoichiometric coefficient of 2 Activated FGFR3 mutants with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2033358 Reactome Database ID Release 432033358 Reactome, http://www.reactome.org ReactomeREACT_124455 Activated FGFR3 G380R mutant Reactome DB_ID: 2033320 Reactome Database ID Release 432033320 Reactome, http://www.reactome.org ReactomeREACT_123071 has a Stoichiometric coefficient of 2 Activated FGFR3 G382D mutant Reactome DB_ID: 2033323 Reactome Database ID Release 432033323 Reactome, http://www.reactome.org ReactomeREACT_124979 has a Stoichiometric coefficient of 2 MIR181C microRNA binds 3'UTR of NOTCH4 mRNA Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed20080834 Reactome Database ID Release 431912364 Reactome, http://www.reactome.org ReactomeREACT_118737 Reviewed: Haw, R, 2012-02-06 miR-181C microRNA inhibits translation of NOTCH4 mRNA by binding to its 3'UTR. miR181c is a candidate tumor suppressor in gastric cancer. Mg2+/Mn2+ Converted from EntitySet in Reactome Reactome DB_ID: 1500591 Reactome Database ID Release 431500591 Reactome, http://www.reactome.org ReactomeREACT_123902 MIR206 microRNA binds 3'UTR of NOTCH3 mRNA Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed19723635 Reactome Database ID Release 431912366 Reactome, http://www.reactome.org ReactomeREACT_118736 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH3 mRNA is inhibited by microRNA miR-206 which binds to the 3'UTR of NOTCH3 mRNA. Vinyl chloride is oxidized to 2-Chloroethylene oxide Authored: Jassal, B, 2008-05-19 12:57:01 CYP2E1 can catalyze the oxidation of the vinyl halide vinyl chloride to the epoxide 2-chloroethylene oxide. The epoxide is very unstable and rearranges quickly to 2-chloroacetaldehyde. Both these products can interact with DNA and proteins. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed1664256 Pubmed497175 Reactome Database ID Release 4376354 Reactome, http://www.reactome.org ReactomeREACT_1750 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 NOTCH1 mRNA translation controlled by miRNAs Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed19714243 Pubmed19773441 Pubmed20805998 Pubmed21602795 Reactome Database ID Release 431912412 Reactome, http://www.reactome.org ReactomeREACT_118745 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH1 mRNA is negatively regulated by microRNAs miR-200B and miR200C (Kong et al. 2010), miR-34 (Li et al. 2009, Ji et al. 2009) and miR-449 (Marcet et al. 2011). These miRNAs bind and cause degradation of NOTCH1 mRNA, resulting in decreased level of NOTCH1 protein product. MEOS oxidizes ethanol to acetaldehyde Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed3675576 Pubmed409715 Pubmed8627510 Pubmed9028626 Pubmed9884161 Reactome Database ID Release 43143468 Reactome, http://www.reactome.org ReactomeREACT_499 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The MEOS (microsomal ethanol oxidizing system) is an accessory pathway in the liver which increases in activity on chronic alcohol induction. The MEOS utilizes a cytochrome P450 which has since been deciphered to be CYP2E1, an ethanol-inducible form of P450. CYP2E1 also increases acetaldehyde formation and free radicals which can initiate lipid peroxidation. CYP2E1 can also activate many over-the-counter medicines and solvents to toxic metabolites and deplete retinoids resulting in their depletion and deletrious effects. This is because, being a cytochrome P450 and using NADPH and oxygen, it has the ability to biotransform drugs when it has been induced by ethanol. has a Stoichiometric coefficient of 2 MIR302A microRNA binds 3'UTR of NOTCH4 mRNA Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 MicroRNA miR-302A, upregulated in melanoma, binds the 3'UTR of NOTCH4, resulting in inhibition of NOTCH4 mRNA translation. Pubmed20495621 Reactome Database ID Release 431912368 Reactome, http://www.reactome.org ReactomeREACT_118819 Reviewed: Haw, R, 2012-02-06 Dehalogenation of the poly-halogenated hydrocarbon Halothane to form the acylhalide Trifluoroacetlychloride and hydrogen bromide Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0042197 Pubmed8637342 Pubmed9103523 Reactome Database ID Release 4376475 Reactome, http://www.reactome.org ReactomeREACT_305 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The volatile anesthetic halothane can undergo CYP2E1-catalyzed oxidation to form a reactive intermediate which can acetylate liver proteins. These proteins can then stimulate an immune reaction that mediates severe hepatic necrosis ("halothane hepatitis"). NOTCH3 mRNA translation controlled by miRNAs Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed19723635 Pubmed21551231 Reactome Database ID Release 431912409 Reactome, http://www.reactome.org ReactomeREACT_118714 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH3 mRNA is negatively regulated by miR-150 (Ghisi et al. 2011) and miR-206 microRNAs (Song et al. 2009). These miRNAs bind and cause degradation of NOTCH3 mRNA, resulting in decreased level of NOTCH3 protein product. Dehalogenation of carbon tetrachloride to form a free radical Authored: Jassal, B, 2008-05-19 12:57:01 Carbon tetrachloride (CCl4) has been widely used as a dry-cleaning agent, in fire extinguishers and in the manufacture of other halogenated hydrocarbons. At toxic doses, CCl4 exposure can damage the liver and kidneys. This toxicity results from CYP2E1-dependant reduction of CCl4 to the reactive trichloromethyl radical (CCl3.). Dehalogenation of the haloalkane CCl4 to form CCl3. free radical Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0018885 Pubmed10731522 Reactome Database ID Release 4376434 Reactome, http://www.reactome.org ReactomeREACT_122 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 NOTCH2 mRNA translation controlled by miRNAs Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed19773441 Reactome Database ID Release 431912413 Reactome, http://www.reactome.org ReactomeREACT_118612 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH2 mRNA is negatively regulated by miR-34 microRNAs (Li et al. 2009). miR-34 miRNAs bind and cause degradation of NOTCH2 mRNA, resulting in decreased level of NOTCH2 protein product. Benzene is hydroxylated to phenol Authored: Jassal, B, 2008-05-19 12:57:01 Benzene + O<sub>2</sub> + NADPH + H<sup>+</sup> -> Phenol + H<sub>2</sub>O + NADP<sup>+</sup> Benzene is an occupational and environmental toxicant and is implicated in myelogenous leukemia. For toxicity to occur, benzene is oxidised to phenol and subsequently to catechol and hydroquinone. CYP2E1 is the enzyme responsible for oxidation of benzene to phenol. Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0018910 Pubmed11701230 Reactome Database ID Release 4376416 Reactome, http://www.reactome.org ReactomeREACT_228 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Fucosylation of Pre-NOTCH by POFUT1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 2.4.1.221 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 In the endoplasmic reticulum, NOTCH receptor precursors are fucosylated on conserved serine and threonine residues in their EGF repeats. The consensus fucosylation site sequence is C2-X(4-5)-S/T-C3, where C2 and C3 are the second and third cysteine residue within the EGF repeat, and X(4-5) is four to five amino acid residues of any type. Only those fucosylation sites that are conserved between human, mouse and rat NOTCH isoforms are annotated. Two additional potential fucosylation sites exist in human NOTCH1, on threonine 194 and threonine 1321, but since they are not conserved between all three species, they are not shown. Fucosylation is performed by the endoplasmic reticulum resident O-fucosyl transferase (POFUT1). Fucosylation by POFUT1 is considered to be essential for NOTCH folding/processing and production of a fully functional receptor. In addition to Notch fucosylation, Drosophila Pofut1 (o-fut1) acts as a Notch chaperone, playing an important role in Notch trafficking (Okajima et al. 2005). The chaperone role of POFUT1 may not be conserved in mammals (Stahl et al. 2008). Pubmed11524432 Pubmed12486116 Pubmed15692013 Pubmed18347015 Pubmed21464368 Reactome Database ID Release 431912349 Reactome, http://www.reactome.org ReactomeREACT_118694 Reviewed: Haw, R, 2012-02-06 has a Stoichiometric coefficient of 70 NOTCH4 mRNA translation controlled by miRNAs Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed20080834 Pubmed20495621 Reactome Database ID Release 431912410 Reactome, http://www.reactome.org ReactomeREACT_118578 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH4 mRNA is negatively regulated by miR-181c (Hashimoto et al. 2010) and miR-302A microRNAs (Costa et al. 2009). These miRNAs bind and cause degradation of NOTCH4 mRNA, resulting in decreased level of NOTCH4 protein product. Transport of NOTCH precursor to Golgi Authored: Jassal, B, 2004-12-15 13:08:03 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH receptor precursors (Pre-NOTCH) traffic from the endoplasmic reticulum to the Golgi. Endoplasmic reticulum calcium ATPases are required for maintenance of high levels of calcium and positively regulate NOTCH trafficking, perhaps by ensuring proper NOTCH folding. Exit of NOTCH precursors from the endoplasmic reticulum is negatively regulated by SEL1L (Li et al. 2010, Sundaram et al. 1993), an endoplasmic reticulum membrane protein that is part of the ERAD (endoplasmic reticulum associated degradation) system, which performs quality control and triggers degradation of misfolded proteins (Francisco et al. 2010). NOTCH trafficking through the Golgi and trans-Golgi network is positively regulated by RAB6, a Golgi membrane GTPase. Pubmed10459009 Pubmed10545110 Pubmed1295745 Pubmed1764995 Pubmed20170518 Pubmed20197277 Pubmed7918097 Pubmed8293978 Pubmed8681805 Pubmed9244302 Reactome Database ID Release 431912374 Reactome, http://www.reactome.org ReactomeREACT_118577 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 Glucosylation of Pre-NOTCH by POGLUT1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 In addition to fucosylation of NOTCH receptor precursors, glucosylation represents another crucial NOTCH processing reaction, required for full receptor function. Endoplasmic reticulum O-glucosyl transferase, POGLUT1, adds a glucosyl group to conserved serine residues within the EGF repeats of NOTCH. The consensus sequence of POGLUT1 glucosylation sites is C1-X-S-X-P-C2, where C1 and C2 are the first and second cysteine residue in the EGF repeat, respectively, while X represents any amino acid. Only those glucosylation sites that are conserved between human, mouse and rat isoforms are shown. In human NOTCH1, the consensus glucosylation site on serine at position 951 was not annotated since it is not conserved in rat NOTCH1. In human NOTCH4, glucosylation at serine 398 was not annotated because this site is not conserved in rat, and glucosylation at serine 936 was not annotated because this site is not conserved in mouse. Glucosylation of NOTCH4 serine 773 was not annotated because a proline at position 775 is not conserved in either mouse or rat. Pubmed18243100 Pubmed21490058 Reactome Database ID Release 431912353 Reactome, http://www.reactome.org ReactomeREACT_118657 Reviewed: Haw, R, 2012-02-06 has a Stoichiometric coefficient of 53 CYP2C19 5-hydroxylates omeprazole Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Omeprazole is a potent long-acting inhibitor of gastric acid secretion by irreversible binding to the proton pump (H+,K+) ATPase in the gastric parietal cell. CYP2C19 is the major P450 which involved in 5-hydroxylation of omeprazole. Pubmed8647857 Reactome Database ID Release 43211929 Reactome, http://www.reactome.org ReactomeREACT_13761 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Activated FGFR3b G967C Reactome DB_ID: 2033340 Reactome Database ID Release 432033340 Reactome, http://www.reactome.org ReactomeREACT_124348 has a Stoichiometric coefficient of 2 Acetaminophen oxidised to N-acetylbenzoquinoneimine (NAPQI) Authored: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0017144 N-acetyl-p-benzoquinone imine (NAPQI) is the reactive intermediate of the analgesic and antipyretic, acetaminophen (INN, paracetamol). At usual doses, NAPQI is quickly detoxified by conjugation but in overdose situations, NAPQI is extremely toxic to liver tissue. Pubmed10741631 Reactome Database ID Release 4376397 Reactome, http://www.reactome.org ReactomeREACT_163 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Activated FGFR3 A391E mutant Reactome DB_ID: 2065834 Reactome Database ID Release 432065834 Reactome, http://www.reactome.org ReactomeREACT_124456 has a Stoichiometric coefficient of 2 MIR150 microRNA binds 3'UTR of NOTCH3 mRNA Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed21551231 Reactome Database ID Release 431912362 Reactome, http://www.reactome.org ReactomeREACT_118686 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH3 mRNA is inhibited by miR-150 microRNA which binds to the 3'UTR of NOTCH3 mRNA. miR-150 is involved in regulation of differentiation of B-cells and T-cells. Activated FGFR3 K650Q mutant Reactome DB_ID: 2033330 Reactome Database ID Release 432033330 Reactome, http://www.reactome.org ReactomeREACT_122446 has a Stoichiometric coefficient of 2 MCT substrates Converted from EntitySet in Reactome Reactome DB_ID: 433686 Reactome Database ID Release 43433686 Reactome, http://www.reactome.org ReactomeREACT_20996 Activated FGFR3 K650T mutant Reactome DB_ID: 2033326 Reactome Database ID Release 432033326 Reactome, http://www.reactome.org ReactomeREACT_122761 has a Stoichiometric coefficient of 2 Cyclophosphamide is 4-hydroxylated by CYP2B6 Authored: Jassal, B, 2008-05-19 12:57:01 Cyclophosphamide (CPA) is an alkylating agent used in cancer chemotherapy and an immunosuppressant. CYP2B6 converts CPA to the active metabolite 4-hydroxy-CPA. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed12629583 Reactome Database ID Release 43211991 Reactome, http://www.reactome.org ReactomeREACT_13515 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP2C8 inactivates paclitaxel by 6alpha-hydroxylation Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Paclitaxel (Taxol) is a naturally occurring member of the taxane family of antitumor drugs. It acts by stabilizing microtubules. Paclitaxel is inactivated in human liver by CYP2C8, which catalyzes 6alpha-hydroxylation of paclitaxel. Pubmed9842986 Reactome Database ID Release 43211910 Reactome, http://www.reactome.org ReactomeREACT_13651 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP2C9 inactivates tolbutamide by 4methyl-hydroxylation Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed2025243 Reactome Database ID Release 43211988 Reactome, http://www.reactome.org ReactomeREACT_13607 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Tolbutamide is an oral hypoglycemic agent whose action is terminated by hydroxylation of the tolylsulfonyl methyl moiety. The reaction is catalyzed by CYP2C9. CYP2C18 initiates bioactivation of phenytoin by 4-hydroxylation Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Phenytoin is a widely used anti-epileptic drug which can be hydroxylated by several P450s including CYP2C18 to its major metabolite, (5-(4-hydroxyphenyl)-phenylhydantoin (HPPH). Pubmed16359177 Reactome Database ID Release 43212004 Reactome, http://www.reactome.org ReactomeREACT_13729 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 FGFR3 (4;14) translocation mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 2038375 Reactome Database ID Release 432038375 Reactome, http://www.reactome.org ReactomeREACT_124823 FGFR3 795fs*139STOP mutant dimer Reactome DB_ID: 2038350 Reactome Database ID Release 432038350 Reactome, http://www.reactome.org ReactomeREACT_124184 has a Stoichiometric coefficient of 2 Activated FGFR3c P250R mutant Reactome DB_ID: 2011989 Reactome Database ID Release 432011989 Reactome, http://www.reactome.org ReactomeREACT_123091 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 phosphorylated FGFR3c P250R mutant dimer Reactome DB_ID: 2011968 Reactome Database ID Release 432011968 Reactome, http://www.reactome.org ReactomeREACT_123671 has a Stoichiometric coefficient of 2 FGFR3c P250R mutant dimer bound to FGF Reactome DB_ID: 2011952 Reactome Database ID Release 432011952 Reactome, http://www.reactome.org ReactomeREACT_123540 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FGFR3c P250R mutant dimer Reactome DB_ID: 2011951 Reactome Database ID Release 432011951 Reactome, http://www.reactome.org ReactomeREACT_121776 has a Stoichiometric coefficient of 2 NOTCH1 gene transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH1 was cloned as a chromosome 9 gene involved in translocation t(7;9)(q34;q34.3) in several T-cell acute lymphoblastic leukemia (T-ALL) patients. The gene was found to be highly homologous to the Drosophila gene Notch and was initially named TAN-1 (translocation-associated Notch homolog). Transcripts of NOTCH1 were detected in many fetal and adult human and mouse tissues, with the highest abundance in lymphoid tissues. The translocation t(7;9)(q34;q34.3) found in a small fraction of T-ALL patients puts NOTCH1 transcription under the control of the T-cell receptor-beta (TCRB) locus, which results in expression of truncated peptides that lack the extracellular ligand binding domain and are constitutively active (reviewed by Grabher et al. 2006). Activating NOTCH1 point mutations, mainly affecting the extracellular heterodimerization domain and/or the C-terminal PEST domain, are found in more than 50% of human T-ALLs (Weng et al. 2004).<br><br>Studies of mouse Rbpj knockout embryos and zebrafish Mib (mindbomb) mutants indicate that the NOTCH1 coactivator complex positively regulates NOTCH1 transcription. The RBPJ-binding site(s) that the NOTCH1 coactivator complex normally binds have not been found in the NOTCH1 promoter, however, so this effect may be indirect and its mechanism is unknown (Del Monte et al. 2007). <br><br>CCCND1 (cyclin D1) forms a complex with CREBBP and binds to the NOTCH1 promoter, stimulating NOTCH1 transcription. The involvement of CCND1 in transcriptional regulation of NOTCH1 was established in mouse retinas and the rat retinal precursor cell line R28 (Bienvenu et al. 2010).<br><br> E2F1 and E2F3 are able to bind to the NOTCH1 promoter and activate NOTCH1 transcription (Viatour et al. 2011).<br><br> NOTCH1 promoter possesses two putative p53-binding sites. Chromatin immunoprecipitation (ChIP) assays of human primary keratinocytes showed binding of endogenous p53 protein to both sites. Experiments in which p53 was downregulated or overexpressed implicate p53 as a positive regulator of NOTCH1 expression in primary human keratinocytes. It is likely that p53-mediated regulation of NOTCH1 expression involves interplay with other cell-type specific determinants of gene expression (Lefort et al. 2007). In lymphoid cells, NOTCH1 expression may be negatively regulated by p53 (Laws and Osborne 2004). Other proteins implicated in the negative regulation of NOTCH1 transcription are KLF9 (Ying et al. 2011), JARID2 (Mysliwiec et al. 2011, Mysliwiec et al. 2012), KLF4 and SP3 (Lambertini et al. 2010), and p63 (Yugawa et al. 2010). Pubmed14991602 Pubmed15472075 Pubmed16612405 Pubmed17344417 Pubmed17685488 Pubmed1831692 Pubmed20090754 Pubmed20442293 Pubmed20442780 Pubmed21280156 Pubmed21402699 Pubmed21875955 Pubmed22110129 Reactome Database ID Release 431912416 Reactome, http://www.reactome.org ReactomeREACT_118626 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 N-hydroxylation of 4-aminobiphenyl Authored: Jassal, B, 2008-05-19 12:57:01 Heterocyclic and aromatic amines require metabolic activation to convert them to genotoxic metabolites.The initial step is N-hydroxylation and cytochrome P450 1A2 can carry out the catalysis. Pubmed1934265 Pubmed9111224 Reactome Database ID Release 4376373 Reactome, http://www.reactome.org ReactomeREACT_1437 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 p53 positively regulates transcription of MIR34 microRNAs Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed17540598 Pubmed17540599 Pubmed17554337 Pubmed17823410 Reactome Database ID Release 431912406 Reactome, http://www.reactome.org ReactomeREACT_118576 Reviewed: Haw, R, 2012-02-06 Transcription of microRNA MIR34A is directly induced by the tumor suppressor p53, which binds to the conserved p53 binding site located in the vicinity of the MIR34A transcription start (Chang et al. 2007, Raver-Shapira et al. 2007). Genomic loss of the chromosomal band 1p36, harboring the MIR34A gene, is a frequent event in pancreatic cancer, and MIR34A is considered to act as a tumor suppressor. Conserved p53 binding sites were also mapped to the promoter of clustered MIR34B and MIR34C genes, and the transcription of MIR34B and MIR34C microRNAs was shown to be positively regulated by p53 (He et al. 2007, Corney et al. 2007). The steps involved in processing of pri-microRNA into pre-microRNA have been omitted in this event - please refer to the diagram of Regulatory RNA Pathways for details. N-atom dealkylation of caffeine Authored: Jassal, B, 2008-05-19 12:57:01 Caffeine is one of the world's most frequently consumed xenobiotic. The major source of caffeine comes from tea and coffee. Caffeine is extensively metabolized in humans with at least 17 metabolites formed in its biotransformation. CYP1A2 is a prominent enzyme in the formation of an important metabolite of caffeine (paraxanthine) by N3-demethylation. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed8553685 Reactome Database ID Release 4376426 Reactome, http://www.reactome.org ReactomeREACT_1165 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 NOTCH4 gene transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15684396 Pubmed9693032 Reactome Database ID Release 431912401 Reactome, http://www.reactome.org ReactomeREACT_118639 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 The NOTCH4 gene maps to the short arm of human chromosome 6. High levels of NOTCH4 transcript are detectable in adult heart. NOTCH4 mRNA is also found in lung and placenta, and at low levels in liver, skeletal muscle, kidney, pancreas, spleen, thymus, lymph nodes and bone marrow (Li et al. 1998).<br><br>In vascular endothelium, NOTCH4 transcription is activated by c-JUN (AP-1) transcription factor. JUN, likely in complex with other transcription factors, binds AP-1 motif(s) in the NOTCH4 promoter and possibly within the first intron (Wu et al. 2005). Coumarin is 7-hydroxylated by CYP2A13 Authored: Jassal, B, 2008-05-19 12:57:01 CYP2A13 can also 7-hydroxylate coumarin. It shares a 93.5% identity with CYP2A6 in the amino acid sequence but it is only about one-tenth as active as CYP2A6 in catalyzing coumarin 7-hydroxylation. Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0009804 Pubmed15196988 Reactome Database ID Release 43211881 Reactome, http://www.reactome.org ReactomeREACT_13492 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 NOTCH3 gene transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed19150886 Pubmed8878478 Reactome Database ID Release 431912415 Reactome, http://www.reactome.org ReactomeREACT_118757 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 The NOTCH3 gene maps to human chromosome 19. NOTCH3 transcript is ubiquitously expressed in fetal and adult human tissues. Mutations in NOTCH3 are found in cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an autosomal dominant progressive disorder of small arterial vessels of the brain characterized by migraines, strokes, and white matter lesions, with the onset in early adulthood (Joutel et al. 1996).<br><br>NOTCH3 gene transcription is stimulated by the NOTCH3 coactivator complex but it is not known whether this effect is direct, or indirect (Liu et al. 2009). Coumarin is 7-hydroxylated by CYP2A6 Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0009804 Pubmed15665333 Reactome Database ID Release 4376453 Reactome, http://www.reactome.org ReactomeREACT_572 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The 7-hydroxylation of coumarin is used as an assay of P450 activity in animal and human liver microsomes. CYP2A6 is the major coumarin 7-hydroxylase in human liver. NOTCH2 gene transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed11187898 Pubmed16773578 Pubmed7698746 Reactome Database ID Release 431912407 Reactome, http://www.reactome.org ReactomeREACT_118827 Reviewed: Haw, R, 2012-02-06 The NOTCH2 gene maps to human chromosome 1. NOTCH2 gene expression is differentially regulated during human B-cell development, with NOTCH2 transcripts appearing at late developmental stages. NOTCH2 mutations are a rare cause of Alagille syndrome. Alagille syndrome is a dominant multisystem disorder mainly characterized by hepatic bile duct abnormalities, and is predominantly caused by mutations in JAG1, a NOTCH2 ligand. MIR34 microRNAs bind 3'UTR of NOTCH2 mRNA Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed19773441 Reactome Database ID Release 431912367 Reactome, http://www.reactome.org ReactomeREACT_118850 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH2 mRNA is inhibited by MIR34 microRNAs (MIR34A, MIR34B and MIR34C), which bind to the 3'UTR of NOTCH2 mRNA. MIR449 microRNAs bind 3'UTR of NOTCH1 mRNA Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed21602795 Reactome Database ID Release 431606561 Reactome, http://www.reactome.org ReactomeREACT_118755 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH1 mRNA is negatively regulated by MIR449 microRNAs (MIR449A, MIR449B and MIR449C), which bind to the 3'UTR of NOTCH1. Downregulation of NOTCH1 signaling by the MIR449 cluster appears to be an evolutionarily conserved mechanism involved in regulation of vertebrate multiciliogenesis. DLL1 mRNA is also a target of the MIR449 cluster. MIR200B/C microRNAs bind NOTCH1 mRNA Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed20805998 Reactome Database ID Release 431912363 Reactome, http://www.reactome.org ReactomeREACT_118670 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH1 mRNA is inhibited by microRNAs miR-200B and miR-200C, which bind to the 3'UTR of NOTCH1 mRNA. Levels of miR-200B and miR-200C are decreased in pancreatic cancer cells with an EMT (epithelial to mesenchymal transition) phenotype, and the EMT phenotype is reversed by exogenous overexpression of miR-200B/C microRNAs, suggesting that miR-200B and mir-200C may be acting as tumor suppressors. MCT substrates Converted from EntitySet in Reactome Reactome DB_ID: 433683 Reactome Database ID Release 43433683 Reactome, http://www.reactome.org ReactomeREACT_21125 MIR34 microRNAs bind 3'UTR of NOTCH1 mRNA Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed17540598 Pubmed17540599 Pubmed19714243 Pubmed19773441 Pubmed20351093 Reactome Database ID Release 431606682 Reactome, http://www.reactome.org ReactomeREACT_118599 Reviewed: Haw, R, 2012-02-06 Translation of NOTCH1 mRNA is inhibited by MIR34 microRNAs (MIR34A, MIR34B and MIR34C), which bind to the 3'UTR of NOTCH1 mRNA. Expression of MIR34 microRNAs is directly regulated by the p53 (TP53) tumor suppressor gene (Chang et al. 2007, Raver-Shapira et al. 2007), and MIR34-mediated downregulation of NOTCH1 signaling is thought to negatively regulate cell survival, motility and maintenance of an undifferentiated state. PathwayStep5958 PathwayStep5959 PathwayStep5956 ARRB mediates NOTCH1 ubiquitination Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 6.3.2.19 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed16284625 Reactome Database ID Release 431980118 Reactome, http://www.reactome.org ReactomeREACT_118655 Reviewed: Haw, R, 2012-02-06 Ubiquitination of NOTCH1 mediated by DTX-recruited beta-arrestins (ARRB) has not been directly studied in mammals. Non-visual beta arrestins ARRB1 and ARRB2 are known to facilitate ubiquitination and downregulation of GPCRs and IGF1R. PathwayStep5957 ITCH binds DTX Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Genetic studies in Drosophila identified deltex as a positive regulator of Notch signaling, while the Drosophila homologue of ITCH (AIP4) was identified as a negative regulator of Notch signaling and named suppressor of deltex. ITCH and DTX1 interact and form a complex, as determined by co-immunoprecipitaion experiments in human embryonic kidney cell line HEK293 in which tagged recombinant human DTX1 and ITCH were expressed. It is not known whether this complex involves other proteins, but its formation is NOTCH-independent. Both DTX1 and ITCH are ubiquitin ligases. DTX1 is a RING-type ubiquitin ligase, while ITCH is a HECT-type ubiquitin ligase. The ubiquitin ligase activity of either protein is not needed for the formation of the DTX1:ITCH complex, and the inactive ITCH mutant co-immunoprecipitates more DTX1 than the wild-type ITCH, implicating the ubiquitin ligase activity of ITCH in DTX1 degradation. Pubmed17028573 Reactome Database ID Release 431980125 Reactome, http://www.reactome.org ReactomeREACT_118690 Reviewed: Haw, R, 2012-02-06 PathwayStep5954 Cleavage of DNER:NOTCH1 complex releases NICD1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Binding of DNER to NOTCH1 induces gamma-secretase dependent cleavage of NOTCH1 at the S3 cleavage site and releases NOTCH1 intracellular domain into the cytosol. Cleavage of NOTCH1 at the S2 cleavage site by ADAM10/17, which should precede cleavage at the S3 site, has not been studied in the context of DNER-mediated NOTCH1 activation. Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15965470 Reactome Database ID Release 431980112 Reactome, http://www.reactome.org ReactomeREACT_118830 Reviewed: Haw, R, 2012-02-06 PathwayStep5955 DTX recruits beta-arrestin (ARRB) to NOTCH Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Formation of a complex involving NOTCH, Deltex (DTX) and non-visual beta-arrestin (ARRB) has not been directly studied in mammalian cells. The mammalian non-visual beta-arrestins ARRB1 and ARRB2 play a major role in desensitization and endocytosis of G-protein-coupled receptors (GPCRs), and their interaction with GPCRs involves N-terminal beta-arrestin sequences that are homologous to the Deltex-binding N-terminus of Drosophila Kurtz (Mukherjee et al. 2005). Shrub, a core component of the ESCRT-III complex, was recently identified as an important modulator of non-visual beta-arrestin-mediated downregulation of Notch in Drosophila (Hori et al. 2011). Pubmed16284625 Pubmed22162134 Reactome Database ID Release 431980123 Reactome, http://www.reactome.org ReactomeREACT_118816 Reviewed: Haw, R, 2012-02-06 PathwayStep5952 Cleavage of CNTN1:NOTCH1 complex releases NICD1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Binding of NOTCH1 to CNTN1 (contactin-1) is followed by gamma-secretase mediated cleavage of NOTCH1 at the S3 cleavage site and accumulation of NICD1 in the nucleus. Cleavage of NOTCH1 by ADAM10/17 at the S2 cleavage site, which should precede the S3 cleavage by gamma-secretase, has not been studied in the context of NOTCH1 activation by CNTN1. NOTCH activation by CNTN1 is deltex-dependent, but the exact mechanism for action of the NOTCH:DTX complex has not yet been elucidated. Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed14567914 Reactome Database ID Release 431980109 Reactome, http://www.reactome.org ReactomeREACT_118761 Reviewed: Haw, R, 2012-02-06 PathwayStep5953 NOTCH1 binds DNER Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 DNER is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. DNER has ten extracellular EGF repeats highly homologous to EGF repeats of Notch and Delta proteins, but does not contain a typical DSL domain. DNER binds NOTCH1 and this interaction involves the first and second EGF repeat of DNER. Activation of NOTCH1 signaling by DNER requires the presence of deltex (DTX1, DTX2 and/or DTX4). The interaction of DNER and NOTCH may be playing an important role in the development of the central nervous system by influencing the differentiation of astrocytes, based on mouse studies. Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15965470 Reactome Database ID Release 431912398 Reactome, http://www.reactome.org ReactomeREACT_118704 Reviewed: Haw, R, 2012-02-06 DTX binds NOTCH1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Deltex (DTX) protein family in mammals includes four proteins: DTX1, DTX2, DTX3 and DTX4. Human DTX1 interacts with cdc10/ankyrin repeats of the intracellular domain of NOTCH1 and NOTCH2, similar to the interaction of Drosophila deltex and notch proteins (Matsuno et al. 1998). Studies on mouse deltex proteins showed that the N-terminal region of Dtx1, homologous to the Drosophila deltex domain I, is necessary and sufficient to bind the ankyrin repeats of Notch. Besides Dtx1, this Notch-interacting region is conserved in Dtx2 and Dtx4. Dtx3 lacks most of the N-terminal sequence homologous to Drosophila deltex domain I and cannot bind ankyrin repeats of mouse Notch1, while Dtx1, Dtx2 and Dtx4 bind to it strongly. Dtx3 also has a different class of RING finger domain than the other three deltex proteins (Kishi et al. 2001). While deltex colocalizes with Notch at the plasma membrane and in the cytosol, there is no colocalization between NICD and deltex in the nucleus, suggesting that DTX does not mediate NOTCH signaling by direct interaction with nuclear NICD (Matsuno et al. 1998). Recent studies in Drosophila indicate that Deltex, acting as an E3 ubiquitin ligase, may activate ligand independent Notch proteolysis and signaling by shunting Notch into an endocytic pathway that involves HOPS and AP-3 complexes (Wiklin et al. 2008). Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed11226752 Pubmed19000840 Pubmed9590294 Reactome Database ID Release 431980122 Reactome, http://www.reactome.org ReactomeREACT_118679 Reviewed: Haw, R, 2012-02-06 Contactin-1 (CNTN1) binds NOTCH1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Contactin-1 (CNTN1) is composed of six Ig domains followed by four FNIII repeats and is anchored to the membrane via a glycosyl-phosphatidylinositol (GPI) tail. It is expressed transiently during CNS and PNS development both as GPI-anchored and soluble forms. CNTN1 is a physiological ligand of NOTCH, shown to bind and activate NOTCH1 and NOTCH2 in trans. The activation of NOTCH signaling by CNTN1 is Deltex (DTX)-dependent and promotes oligodendrocyte maturation and myelination. Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed14567914 Reactome Database ID Release 43373706 Reactome, http://www.reactome.org ReactomeREACT_118762 Reviewed: Haw, R, 2012-02-06 NOTCH1 binds JAG2 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH1 is activated by JAG2 ligand expressed on a neighboring cell. When the mouse myoblast cell line C2C12 expressing exogenous human NOTCH1 is grown with NIH3T3 cells expressing exogenous human JAG2, myogenic differentiation is inhibited and a NOTCH1 polypeptide that corresponds to the NOTCH intracellular domain appears (Luo et al. 1997). Pubmed11006133 Pubmed9315665 Reactome Database ID Release 431980044 Reactome, http://www.reactome.org ReactomeREACT_118746 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 6.3.2.19 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH ligands DLL1, DLL4, JAG1 or JAG2 undergo ubiqutination and endocytosis after binding NOTCH1 in trans. In Drosophila, ubiquitination of Delta and Serrate ligands is performed by either Mindbomb or Neuralized ubiquitin ligase. In mammals, there are two Mindbomb homologues, MIB1 and MIB2 and two Neuralized homologues, NEURL (also known as NEUR1) and NEURL1B (also known as NEUR2). Although both Mib1 and Mib2 ubiquitinate Delta (Koo et al. 2005), only Mib1 was shown to be essential for normal development in mice, with Mib1 deficient mice exhibiting typical Notch deficiency phenotypes (Koo et al. 2007). This could be due to different expression patterns of Mib1 and Mib2. While Mib1 is abundantly expressed in embryos and adult tissues, Mib2 expression is limited to adult tissues only (Koo et al. 2005). Mouse Neurl was directly shown to ubiquitinate Jag1 but not other Notch ligands in vitro. N-terminal myristoylation targets Neurl to the plasma membrane and this is a prerequisite for Jag1 internalization (Koutelou et al. 2008). Mouse Neurl1b was shown to directly bind and ubiquitinate recombinant Xenopus Delta and to cooperate with Mib1 in Delta endocytosis (Song et al. 2006). Ubiquitination of NOTCH ligands by MIB and NEURL ubiquitin ligases triggers ligand endocytosis. Drosophila Neuralized needs to interact with membrane phosphoinositides through its phosphoinositide-binding motif to trigger endocytosis of ubiquitinated Delta (Skwarek et al. 2007). Endocytosis of ubiquitinated Notch ligands is thought to mechanically stretch the ligand-bound Notch receptor, exposing the S2 cleavage site and resulting in Notch receptor cleavage by ADAM10 and/or ADAM17 metalloproteases (Itoh et al. 2003). Pubmed11740940 Pubmed12530964 Pubmed15760269 Pubmed15824097 Pubmed15829515 Pubmed16093323 Pubmed17003037 Pubmed18043734 Pubmed18077452 Reactome Database ID Release 431980074 Reactome, http://www.reactome.org ReactomeREACT_118653 Reviewed: Haw, R, 2012-02-06 PathwayStep5962 PathwayStep5961 PathwayStep5960 PathwayStep5967 NOTCH1 binds DLL1 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15574878 Pubmed18296446 Pubmed9819428 Reactome Database ID Release 431980039 Reactome, http://www.reactome.org ReactomeREACT_118603 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 The NOTCH1 receptor is activated by binding a Delta-like 1 ligand (DLL1), presented on the plasma membrane of a neighboring cell (Jarriault et al. 1998). EGF repeat 12 (EGF12) in the extracellular domain of NOTCH1 appears to be particularly important for interaction of NOTCH1 with DLL1 (Cordle et al. 2008). The affinity of NOTCH1 for DLL1 is increased when NOTCH1 is glycosylated by fringe enzymes (Yang et al 2005). PathwayStep5968 NOTCH1 binds DLL4 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH1 is activated by DLL4 ligand expressed on a neighboring cell. The interaction of NOTCH1 and DLL4 is enhanced when NOTCH1 is glycosylated by fringe-enzymes. Based on mouse studies, activation of NOTCH1 by DLL4 may be important in angiogenesis (Benedito et al. 2009). DLL4 may also be involved in T-cell development. Mouse Dll4 is expressed on thymic epithelial cells and its interaction with Notch1 expressed on hematopoietic progenitors is necessary for T-cell lineage commitment (Koch et al. 2008, Hozumi et al. 2008). Pubmed18824583 Pubmed18824585 Pubmed19524514 Reactome Database ID Release 431980041 Reactome, http://www.reactome.org ReactomeREACT_118643 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 PathwayStep5969 NOTCH1 binds JAG1 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH1 is activated by JAG1 ligand expressed on a neighboring cell. Based on mouse studies, activation of NOTCH1 by JAG1 may be important in angiogenesis (Benedito et al. 2009). In addition, human JAG1 was shown to inhibit granulocytic differentiation of 32D mouse myeloid progenitors expressing Notch1 (Li et al. 1998). Pubmed19524514 Pubmed9462510 Reactome Database ID Release 431980042 Reactome, http://www.reactome.org ReactomeREACT_118661 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 PathwayStep5963 Sialylation of Pre-NOTCH Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 2.4.99.4 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Mature fringe-modified NOTCH usually has a tetrasaccharide attached to conserved fucosylated serine and threonine residues in EGF repeats. The chemical structure of these tetrasaccharides is Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). The identity of sialyltransferase(s) that add sialic acid to galactose remains unknown in this context. Based on the type of chemical bonds in the tetrasaccharide, there are three known Golgi membrane sialyltransferases that could perform this function: ST3GAL3, ST3GAL4, ST3GAL6 (Harduin-Lepers et al. 2001). Pubmed10935626 Pubmed11530204 Reactome Database ID Release 431912378 Reactome, http://www.reactome.org ReactomeREACT_118739 Reviewed: Haw, R, 2012-02-06 PathwayStep5964 Fringe-modified Pre-NOTCH is cleaved by FURIN Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Cleavage of fringe-modified NOTCH by FURIN has not been examined directly, but since mature, plasma membrane-anchored NOTCH receptors are typically cleaved by FURIN (Blaumueller et al. 1997) and fringe-modified NOTCH functions at the cell surface (Moloney et al. 2000), it is expected that fringe-modified NOTCH is processed by FURIN cleavage. The exact order of fringe-mediated glycosylation and FURIN cleavage has not been experimentally established, but since FURIN localizes to the trans-Golgi network -TGN (Teuchert et al. 1999), while fringe has not been associated with TGN, it is likely that modification of NOTCH by fringe enzymes precedes FURIN-mediated cleavage. EC Number: 3.4.21 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed10075724 Pubmed10935626 Pubmed9244302 Reactome Database ID Release 431912372 Reactome, http://www.reactome.org ReactomeREACT_118767 Reviewed: Haw, R, 2012-02-06 PathwayStep5965 Mature NOTCH heterodimer traffics to the plasma membrane Authored: Jassal, B, 2004-12-15 13:08:03 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Mature NOTCH translocates from the Golgi to plasma membrane. In Caenorhabditis elegans, a Golgi membrane protein sel-9, a homolog of mammalian TMED2, acts as a quality controller and prevents misfolded lin-12, a NOTCH homolog, to reach the cell surface. Pubmed10366590 Pubmed11135303 Pubmed9244302 Reactome Database ID Release 431912382 Reactome, http://www.reactome.org ReactomeREACT_118747 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 PathwayStep5966 Transport of fringe-modified NOTCH to plasma membrane Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Fringe-modified NOTCH functions at the plasma membrane. The transport of fringe-modified NOTCH to the plasma membrane from Golgi has not been studied directly, but is assumed to share properties of transport of mature NOTCH receptors that are not modified by fringe. Pubmed10935626 Reactome Database ID Release 431912379 Reactome, http://www.reactome.org ReactomeREACT_118708 Reviewed: Haw, R, 2012-02-06 NOTCH precursor cleaved to form mature NOTCH Authored: Jassal, B, 2004-12-15 13:08:03 EC Number: 3.4.21 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed10669757 Pubmed12049766 Pubmed19701457 Pubmed9244302 Pubmed9653148 Pubmed9727485 Reactome Database ID Release 431912369 Reactome, http://www.reactome.org ReactomeREACT_118833 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 The NOTCH receptor is synthesized as a precursor polypeptide (approx. 300 kDa) associated with the endoplasmic reticulum membrane. The mature NOTCH receptor is produced by proteolytic cleavage to form a heterodimer. The enzyme responsible is a furin-like convertase which cleaves the full-length precursor into a transmembrane fragment (NTM) of approximate size 110 kDa and an extracellular fragment (NEC) of approximate size 180 kDa. The mature NOTCH receptor is reassembled as a heterodimer (Blaumueller et al. 1997, Logeat et al. 1998). Both disulfide bonds and calcium-mediated ionic interactions stabilize the heterodimer (Rand et al. 2000, Gordon et al. 2009). This process takes place in the trans-Golgi network . Mammalian NOTCH is predominantly presented as a heterodimer on the cell surface. Although FURIN-mediated cleavage is evolutionarily conserved, it may not be mandatory for Drosophila Notch function (Kidd et al. 2002). Glycosylation of Pre-NOTCH by FRINGE Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 2.4.1.222 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed10935626 Pubmed10935637 Pubmed21097675 Pubmed9187150 Pubmed9207795 Reactome Database ID Release 431912355 Reactome, http://www.reactome.org ReactomeREACT_118594 Reviewed: Haw, R, 2012-02-06 The Fringe family of glycosyl transferases in mammals includes LFNG (lunatic fringe), MFNG (manic fringe) and RFNG (radical fringe). Fringe enzymes function in the Golgi apparatus where they initiate the elongation of O linked fucose on fucosylated peptides by the addition of a beta 1,3 N acetylglucosaminyl group (Moloney et al. 2000). Fringe enzymes (LFNG, MNFG and RFNG) elongate conserved O fucosyl residues conjugated to EGF repeats of NOTCH, resulting in formation of disaccharide chains on NOTCH (GlcNAc beta1,3 fucitol). Fringe enzymes modulate NOTCH activity (Cohen et al. 1997, Johnston et al. 1997) by decreasing the affinity of NOTCH extracellular domain for JAG ligands (Brückner et al. 2000). In developing mouse thymocytes, Lfng enhances Notch1 activation by Dll4, resulting in prolonged Notch1 signaling that promotes self-renewal of TCR-beta-expressing progenitors (Yuan et al. 2011). Since the exact preference, if any, of fringe enzymes for NOTCH O fucose sites is not known, the extension of an O fucosyl residue at an unknown position is shown. Galactosylation of Pre-NOTCH Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Beta-1,4-galactosyltransferase 1 (B4GALT1) is a Golgi membrane enzyme responsible for galactosylation of N-acetylglucosaminyl group added by fringe enzymes to O-linked fucosyl residues on NOTCH. This results in formation of trisaccharide chains on NOTCH (Gal-beta1,4-GlcNAc-beta1,3-fucitol), and is a necessary step for fringe-mediated modulation of NOTCH signaling. EC Number: 2.4.1.38 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed10935626 Pubmed11707585 Reactome Database ID Release 431912352 Reactome, http://www.reactome.org ReactomeREACT_118855 Reviewed: Haw, R, 2012-02-06 PathwayStep5971 PathwayStep5970 PathwayStep5973 PathwayStep5972 PathwayStep5976 Bombesin-like receptors bind bombesin homologues Authored: Jassal, B, 2008-08-21 14:07:16 Bombesin-like receptors are widely distributed in the CNS as well as in the GI tract where they modulate smooth-muscle contraction, exocrine and endocrine processes, metabolism, and behaviour through the binding of bombesin-like peptides. They include gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R) (Corjay MH et al, 1991) and bombesin-like receptor-3 (BRS-3) (Fathi Z et al, 1993). BRS-3 binds bombesin peptides with low affinity and is often classed as an orphan receptor. There are two homologues of bombesin-like peptides; Gastrin-releasing peptide (GRP) (Sausville EA et al, 1986) and Neuromedin-B (NMB) (Krane IM et al, 1988). GRP regulates gastric acid secretion and motor function and is a negative feedback operator regulating fear. NMB is involved in the regulation of many functions such as cell growth, body temperature and blood pressure and glucose levels. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed1655761 Pubmed2458345 Pubmed3003116 Pubmed8383682 Reactome Database ID Release 43375384 Reactome, http://www.reactome.org ReactomeREACT_14812 Reviewed: Bockaert, J, 2008-09-01 12:04:13 PathwayStep5977 Bradykinin receptors B1 and B2 bind to bradykinin Authored: Jassal, B, 2008-08-21 14:07:16 Bradykinin (Rocha e Silva M, et al, 1949) is a 9 amino-acid peptide belonging to the kinin group of proteins. It causes blood vessel dilation via the release of prostacyclin, nitric oxide and endothelial-derived hyperpolarizing factor, resulting in lower blood pressure. It is also involved in the pain mechanism. Bradykinin exerts its effects through two receptors, bradykinin receptor B1 and 2 (B1R and B2R respectively). B1R (Menke JG et al, 1994) is synthesized de novo following tissue injury and receptor binding leads to an increase in cytosolic calcium concentration, resulting in chronic and acute inflammatory responses. Unlike B1R, B2R (Hess JF et al, 1992) is ubiquitously and constitutively expressed in healthy tissues. It also increase cytosolic calcium concentration and stimulates the mitogen-activated protein kinase pathways. Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed1314587 Pubmed18127230 Pubmed3366244 Pubmed8063797 Reactome Database ID Release 43374331 Reactome, http://www.reactome.org ReactomeREACT_14852 Reviewed: Bockaert, J, 2008-09-01 12:04:13 PathwayStep5974 Angiotensin II binds to angiotensin II receptor (types 1 and 2) Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed1567413 Pubmed8185599 Reactome Database ID Release 43374173 Reactome, http://www.reactome.org ReactomeREACT_14853 Reviewed: Bockaert, J, 2008-09-01 12:04:13 The cardiovascular and other actions of the vasoconstricting peptide angiotensin II are mediated by the type 1 and type 2 angiotensin II receptors (AT1 and AT2), which are seven transmembrane glycoproteins with 30% sequence similarity. AT1 receptors (Bergsma DJ et al, 1992) couple to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. The AT2 receptor (Tsuzuki S et al, 1994) is expressed mainly during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A2, nitric oxide, and cyclic guanosine monophosphate. The AT2 receptor counteracts several of the growth responses initiated by the AT1 and growth factor receptors. <br> PathwayStep5975 Apelin receptor binds to apelin Apelin (Tatemoto K et al, 1998) is an endogenous ligand for the apelin (APJ) receptor (O'Dowd BF et al, 1993) and is widely expressed in the human body including the heart and brain. Apelin is one of the most potent stimulators of cardiac contractility and mediates blood pressure and blood flow. Several active peptides can be produced by proteolytic processing of the peptide precursor (apelin-36, 31, 28 and 13). APJ is related to the angiotensin receptor (40-50% identity) and couples to G proteins that inhibit adenylate cyclase activity. It is an alternative coreceptor with CD4 for HIV-1 infection. Binding of apelin to its receptor inhibits HIV-1 entry in cells coexpressing CD4 and APJ. Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed8294032 Pubmed9792798 Reactome Database ID Release 43374337 Reactome, http://www.reactome.org ReactomeREACT_14804 Reviewed: Bockaert, J, 2008-09-01 12:04:13 PathwayStep5978 PathwayStep5979 Phosphorylated NICD1 binds FBXW7 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed11461910 Pubmed15546612 Pubmed18094723 Reactome Database ID Release 431912385 Reactome, http://www.reactome.org ReactomeREACT_118662 Reviewed: Haw, R, 2012-02-06 The E3 ubiquitin ligase FBXW7, a homologue of C. elegans sel-10, binds phosphorylated NOTCH1 intracellular domain, p-NICD1 (Oberg et al. 2001, Fryer et al. 2004, Wu et al. 2001). FBXW7 is a substrate recognition component of an E3 ubiquitin-protein ligase complex that also contains SKP1, CUL1 and RBX1. FBXW7 has three transcriptional isoforms, known as FBXW7 alpha, FBXW7 beta and FBXWT gamma. While FBXW7 beta is cytosolic, FBXW7 alpha and gamma are nuclear, with FBXW7 gamma localizing to the nucleolus. FBXW7 alpha is the most abundant isoform and the one directly shown to interact with NICD1 (Welcker and Clurman 2008). Ubiquitination of NICD1 by FBWX7 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 6.3.2.19 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Once bound to FBXW7, phosphorylated NICD1 is ubiquitinated, which leads to degradation of NICD1 and downregulation of NOTCH1 signaling. FBXW7-mediated ubiquitination and degradation of NOTCH1 depend on the C-terminally located PEST domain of NOTCH1 (Fryer et al. 2004, Oberg et al. 2001, Wu et al. 2001). The PEST domain in NOTCH1 and the substrate binding WD40 domain in FBXW7 are frequent targets of mutations in T-cell acute lymphoblastic leukemia - T-ALL (Welcker and Clurman 2008). Pubmed11461910 Pubmed11585921 Pubmed15546612 Pubmed18094723 Reactome Database ID Release 431852623 Reactome, http://www.reactome.org ReactomeREACT_118587 Reviewed: Haw, R, 2012-02-06 Class I MHC heavy chain (MHC HC) Converted from EntitySet in Reactome Reactome DB_ID: 983117 Reactome Database ID Release 43983117 Reactome, http://www.reactome.org ReactomeREACT_26784 Notch 3 heterodimer binds with a Notch ligand in the extracellular space Pubmed10079256 Pubmed10958687 Pubmed12794186 Reactome Database ID Release 43157644 Reactome, http://www.reactome.org ReactomeREACT_452 The NOTCH3 receptor is activated by binding a Delta-like (DLL) or Jagged (JAG) ligand presented on the plasma membrane of a neighbouring cell. Notch 4 heterodimer binds with a Notch ligand in the extracellular space Pubmed10079256 Pubmed10958687 Pubmed12794186 Reactome Database ID Release 43157633 Reactome, http://www.reactome.org ReactomeREACT_1381 The NOTCH4 receptor is activated by binding a Delta-like (DLL) or Jagged (JAG) ligand presented on the plasma membrane of a neighbouring cell. NICD1 binds HIF1A Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed16256737 Reactome Database ID Release 431912396 Reactome, http://www.reactome.org ReactomeREACT_118646 Reviewed: Haw, R, 2012-02-06 When the oxygen supply is low, hypoxia-inducible factor 1-alpha (HIF1A) accumulates in the nucleus where it binds and prolongs the half-life of NICD1, resulting in increased NICD1-mediated transcription and consequent inhibition of cellular differentiation. Notch 2 heterodimer binds with a Notch ligand in the extracellular space Pubmed10079256 Pubmed10958687 Pubmed12794186 Reactome Database ID Release 43157651 Reactome, http://www.reactome.org ReactomeREACT_515 The NOTCH2 receptor is activated by binding a Delta-like (DLL) or Jagged (JAG) ligand presented on the plasma membrane of a neighbouring cell. Chaperones calnexin/BiP Converted from EntitySet in Reactome Reactome DB_ID: 983129 Reactome Database ID Release 43983129 Reactome, http://www.reactome.org ReactomeREACT_76291 PathwayStep5980 PathwayStep5984 PathwayStep5983 PathwayStep5982 PathwayStep5981 PathwayStep5985 NICD1 displaces co-repressor complex from RBPJ (CSL) Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 In the absence of NICD1, RBPJ (CSL) is bound to a co-repressor complex that includes NCOR proteins, NCOR1 and/or NCOR2 (also known as SMRT) and HDAC histone deacetylases. Both NCOR and HDAC proteins interact with RBPJ (CSL) through a repression domain in RBPJ. When bound to the co-repressor complex, RBPJ (CSL) represses transcription of NOTCH target genes (Kao et al. 1998). The co-repressor complex also contains SNW1 (SKIP), which interacts with RBPJ (CSL) in a repression-domain independent way (Zhou et al. 2000), TBL1X (TBL1) and TBL1XR1 (TBLR1) (Perissi et al. 2004). NICD1 binds to RBPJ (CSL) and SNW1 (SKIP) and displaces NCOR and HDAC proteins (Kao et al. 1998). TBL1X and TBL1XR1 facilitate displacement of NCOR and HDAC and positively regulated NOTCH-mediated transcription probably by recruiting the ubiquitin/19S proteasome complex that degrades transcriptional repressors (Perissi et al. 2004, Perissi et al. 2008). SNW1 facilitates NICD1 interaction with RBPJ and NOTCH-mediated transcription (Zhou et al. 2000). It is possible that the co-repressor complex contains additional proteins not described here. Loss-of-function mutations in RBPJ typically result in phenotypes associated with reduced NOTCH function, suggesting that RBPJ activation complex (i.e. NOTCH coactivator complex) is more important than RBPJ repressor complex in control of normal development and homeostasis (Oka et al. 1995). Pubmed10713164 Pubmed14980219 Pubmed18374649 Pubmed7588063 Pubmed9694793 Reactome Database ID Release 431912388 Reactome, http://www.reactome.org ReactomeREACT_118848 Reviewed: Haw, R, 2012-02-06 PathwayStep5986 NICD1 in complex with RBPJ (CSL) recruits MAML Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed12050117 Pubmed12391150 Pubmed16530044 Reactome Database ID Release 431912394 Reactome, http://www.reactome.org ReactomeREACT_118683 Reviewed: Haw, R, 2012-02-06 The minimal functional NOTCH coactivator complex that activates transcription from NOTCH regulatory elements is a heterotrimer composed of MAML (mastermind-like), NICD (NOTCH intracellular domain) and RBPJ (CSL) (Fryer et al. 2002). Structural studies indicate that NOTCH:RBPJ complexes can be pre-assembled on promoters of NOTCH-target genes and that MAML binds to a composite groove created by RBPJ and the NOTCH ankyrin domain (Nam et al. 2006). MAML is able to interact directly with a histone acetyltransferases EP300 (p300) and CREBBP. The presence of EP300 strongly activates NOTCH1 coactivator complex-mediated transcription and this positive effect is blocked by Lys-CoA, a selective inhibitor of EP300 histone acetyltransferase activity (Fryer et al. 2002). NICD1:RBPJ:MAML-mediated transcription increases threefold in the presence of both EP300 and PCAF, in comparison with the presence of EP300 alone (Wallberg et al. 2002). PathwayStep5987 HES1 binds TLE Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Enhancer of split, a Drosophila orthologue of HES, is a basic-helix-loop-helix (bHLH) protein that represses transcription during Drosophila nervous system development. Groucho, the Drosophila homologue of TLE proteins, binds to the WRPW motif of Enhancer of split, resulting in the formation of a transcriptional co-repressor involved in the regulation of neurogenesis, segmentation and sex determination (Paroush et al. 1994). The interaction of HES1 and TLE proteins is conserved in mammals and the WRPW motif of HES1 plays the key role in the formation of HES1:TLE complex (Fisher et al. 1996, Grbavec and Stifani 1996). Pubmed8001118 Pubmed8649374 Pubmed8687460 Reactome Database ID Release 431912359 Reactome, http://www.reactome.org ReactomeREACT_118574 Reviewed: Haw, R, 2012-02-06 PathwayStep5988 MAML in complex with NICD1 recruits CDK8 After a NOTCH1 coactivator complex is assembled on a NOTCH-target promoter, MAML (mastermind-like) recruits CDK8 in complex with cyclin C (CDK:CCNC). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15546612 Reactome Database ID Release 431912393 Reactome, http://www.reactome.org ReactomeREACT_118772 Reviewed: Haw, R, 2012-02-06 PathwayStep5989 NICD1 is phosphorylated by CDK8 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 CDK8 phosphorylates conserved serine residues in the TAD and PEST domains of NICD1. Phosphorylation targets NICD1 for ubiquitination and degradation, ultimately terminating transcriptional activity of NOTCH1. EC Number: 2.7.11.22 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15546612 Reactome Database ID Release 431912391 Reactome, http://www.reactome.org ReactomeREACT_118660 Reviewed: Haw, R, 2012-02-06 IFN gamma stimulated aminopeptidases Converted from EntitySet in Reactome Reactome DB_ID: 983128 Reactome Database ID Release 43983128 Reactome, http://www.reactome.org ReactomeREACT_75974 ITCH ubiquitinates DTX Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 6.3.2.19 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 ITCH ubiquitinates DTX, targeting it for degradation. Pubmed17028573 Reactome Database ID Release 431912357 Reactome, http://www.reactome.org ReactomeREACT_118581 Reviewed: Haw, R, 2012-02-06 NOTCH1 binds DLL/JAG ligand in cis Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Binding of NOTCH1 to DLL/JAG ligands expressed in the same cells (in cis) blocks NOTCH1 activation by DLL/JAG ligands expressed on neighboring cells (in trans). Cis-inhibiton of NOTCH signaling can amplify small differences in NOTCH and DLL/JAG levels between neighboring cells. Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed18660822 Pubmed20418862 Reactome Database ID Release 431980138 Reactome, http://www.reactome.org ReactomeREACT_118804 Reviewed: Haw, R, 2012-02-06 NOTCH1 binds DLK1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 DLK1 is a Delta-like transmembrane protein with six extracellular EGF repeats and a short intracellular tail. DLK1 is encoded by a paternally imprinted gene and, based on mouse studies, is implicated in many developmental processes, such as adipogenesis, hematopoiesis, differentiation of adrenal gland and other neuroendocrine cells, as well as development of the central nervous system. Mice lacking Dlk1 exhibit growth retardation and obesity. Based on studies done in mice and flies, NOTCH1 and DLK1 interact to form a complex, most likely in cis, which results in the inhibition of NOTCH1 signaling by preventing NOTCH1 interaction with DLL and JAG ligands (Baladron et al. 2005, Bray et al. 2008). Besides its inhibitory role, DLK1 may function as a coactivator for NOTCH receptors. DLK1 possesses a Delta and OSM-11 motif (DOS), which has been found in C. elegans proteins that facilitate Notch activation in trans by DSL family ligands. The mammalian DLK1 can substitute for OSM-11 protein in C. elegans development (Komatsu et al. 2008). Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Pubmed15652348 Pubmed18237417 Pubmed18700817 Reactome Database ID Release 431980130 Reactome, http://www.reactome.org ReactomeREACT_118570 Reviewed: Haw, R, 2012-02-06 NOTCH1 associates with negative regulators NUMB and ITCH Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Genetic studies in Drosophila have identified Numb as an inhibitor of Notch signaling during development of the peripheral and central nervous systems as well as muscle cell differentiation. Both Drosophila and mammalian Numb are asymmetrically localized in dividing precursor cells, ensuring that cells adopt distinct cell fates through suppression of Notch signaling in one daughter cell (Rhyu et al. 1994). NUMB recruits E3 ubiquitin ligase ITCH (AIP4) to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009). Pubmed19567869 Pubmed8313469 Reactome Database ID Release 431980128 Reactome, http://www.reactome.org ReactomeREACT_118622 Reviewed: Haw, R, 2012-02-06 Ubiquitination of NOTCH1 by ITCH in the absence of ligand Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 EC Number: 6.3.2.19 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 ITCH, recruited to NOTCH1 indirectly through association with NUMB, ubiquitinates NOTCH1 and targets it for degradation. Pubmed18628966 Pubmed19567869 Reactome Database ID Release 431912386 Reactome, http://www.reactome.org ReactomeREACT_118754 Reviewed: Haw, R, 2012-02-06 FGFR2b C3 variant dimer Reactome DB_ID: 2029921 Reactome Database ID Release 432029921 Reactome, http://www.reactome.org ReactomeREACT_122584 has a Stoichiometric coefficient of 2 Overexpressed FGFR2 homodimers Converted from EntitySet in Reactome Reactome DB_ID: 2029963 Reactome Database ID Release 432029963 Reactome, http://www.reactome.org ReactomeREACT_122797 Activated overexpressed FGFR2 dimers Converted from EntitySet in Reactome Reactome DB_ID: 2029940 Reactome Database ID Release 432029940 Reactome, http://www.reactome.org ReactomeREACT_124614 Overexpressed FGFR2 dimer Reactome DB_ID: 2029938 Reactome Database ID Release 432029938 Reactome, http://www.reactome.org ReactomeREACT_124922 has a Stoichiometric coefficient of 2 Activated FGFR2 K660E mutant Reactome DB_ID: 2033308 Reactome Database ID Release 432033308 Reactome, http://www.reactome.org ReactomeREACT_122029 has a Stoichiometric coefficient of 2 Activated FGFR2 N549H mutant Reactome DB_ID: 2033315 Reactome Database ID Release 432033315 Reactome, http://www.reactome.org ReactomeREACT_125065 has a Stoichiometric coefficient of 2 FGFR2 point mutant dimers:TKIs Reactome DB_ID: 2077404 Reactome Database ID Release 432077404 Reactome, http://www.reactome.org ReactomeREACT_124758 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Activated FGFR2 K660M mutant Reactome DB_ID: 2033310 Reactome Database ID Release 432033310 Reactome, http://www.reactome.org ReactomeREACT_122744 has a Stoichiometric coefficient of 2 PathwayStep5991 PathwayStep5990 PathwayStep5993 PathwayStep5992 PathwayStep5995 PathwayStep5994 PathwayStep5919 PathwayStep5918 PathwayStep5917 PathwayStep5916 PathwayStep5915 PathwayStep5914 PathwayStep5913 PathwayStep5912 PathwayStep5911 PathwayStep5910 PathwayStep5928 PathwayStep5927 PathwayStep5929 PathwayStep5924 PathwayStep5923 PathwayStep5926 PathwayStep5925 PathwayStep5920 PathwayStep5922 PathwayStep5921 PathwayStep5939 PathwayStep5938 Ca2+/Mg2+/Mn2+ Converted from EntitySet in Reactome Reactome DB_ID: 1604565 Reactome Database ID Release 431604565 Reactome, http://www.reactome.org ReactomeREACT_122314 PathwayStep5933 PathwayStep5932 PathwayStep5931 PathwayStep5930 PathwayStep5937 PathwayStep5936 PathwayStep5935 PathwayStep5934 PathwayStep5940 PathwayStep5949 PathwayStep5942 PathwayStep5941 PathwayStep5944 PathwayStep5943 PathwayStep5946 PathwayStep5945 PathwayStep5948 Ca2+/Mg2+ Converted from EntitySet in Reactome Reactome DB_ID: 1604564 Reactome Database ID Release 431604564 Reactome, http://www.reactome.org ReactomeREACT_121450 PathwayStep5947 PathwayStep5950 PathwayStep5951 enolase 3 dimer, (beta, muscle) Reactome DB_ID: 71434 Reactome Database ID Release 4371434 Reactome, http://www.reactome.org ReactomeREACT_4845 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 enolase 2 dimer, (gamma, neuronal) Reactome DB_ID: 71430 Reactome Database ID Release 4371430 Reactome, http://www.reactome.org ReactomeREACT_3268 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 pyruvate kinase M1 complex Reactome DB_ID: 450663 Reactome Database ID Release 43450663 Reactome, http://www.reactome.org ReactomeREACT_21685 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 pyruvate kinase tetramer Converted from EntitySet in Reactome Reactome DB_ID: 450668 Reactome Database ID Release 43450668 Reactome, http://www.reactome.org ReactomeREACT_21766 pyruvate kinase complex, liver and RBC Reactome DB_ID: 70098 Reactome Database ID Release 4370098 Reactome, http://www.reactome.org ReactomeREACT_2785 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 pyruvate kinase M2 complex Reactome DB_ID: 71668 Reactome Database ID Release 4371668 Reactome, http://www.reactome.org ReactomeREACT_2859 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 malate dehydrogenase 2 dimer Reactome DB_ID: 198511 Reactome Database ID Release 43198511 Reactome, http://www.reactome.org ReactomeREACT_11471 has a Stoichiometric coefficient of 2 pyruvate carboxylase holoenzyme Reactome DB_ID: 70499 Reactome Database ID Release 4370499 Reactome, http://www.reactome.org ReactomeREACT_5297 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PathwayStep22 PathwayStep21 PathwayStep20 PathwayStep18 Oxidation of protoporphyrinogen IX to protoporphyrin IX Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 EC Number: 1.3.3.4 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Pubmed8771201 Reactome Database ID Release 43189423 Reactome, http://www.reactome.org ReactomeREACT_9418 Reviewed: Sassa, S, 2007-01-24 10:18:36 Six electrons are oxidized in proto'gen IX to form the planar macrocycle protoporphyrin IX (proto IX). This reaction is performed by the enzyme protoporphyrinogen oxidase (PPO). PPO functions as a homodimer containing one non-covalently-bound FAD. The protein resides on the outer surface of the inner mitochondrial membrane. PPO deficiency is associated with variegate porphyria in vivo. has a Stoichiometric coefficient of 3 PathwayStep19 PathwayStep16 PathwayStep17 PathwayStep14 Uroporphyrinogen III is decarboxylated to form coproporphyrinogen III Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Cytosolic uroporphyrinogen decarboxylase (UROD) catalyzes the sequntial removal of four carboxylic groups from the acetic acid side chains of uroporphyrinogen III (uro'gen III) to form coproporphyrinogen III (copro'gen III) (de Verneuil et al. 1983). Human UROD is a dimer (Whitby et al. 1998). Heterogenous and homogenous deficiencies of UROD are associated with porphyria cutanea tarda and hepatoerythropoietic porphyria respectively in vivo (Moran-Jiminez et al. 1996). EC Number: 4.1.1.37 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Pubmed6822570 Pubmed8644733 Pubmed9564029 Reactome Database ID Release 43189425 Reactome, http://www.reactome.org ReactomeREACT_9422 Reviewed: Sassa, S, 2007-01-24 10:18:36 has a Stoichiometric coefficient of 4 PathwayStep15 Uroporphyrinogen I is decarboxylated to form coproporphyrinogen I Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Cytosolic uroporphyrinogen decarboxylase (UROD) catalyzes the sequential removal of four carboxylic groups from the acetic acid side chains of uroporphyrinogen I (uro'gen I) to form coproporphyrinogen I (copro'gen I). UROD catalyzes this reaction less efficiently than the decarboxylation of uroporphyrinogen III (de Verneuil et al. 1983). EC Number: 4.1.1.37 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Pubmed6822570 Pubmed8644733 Pubmed9564029 Reactome Database ID Release 43190182 Reactome, http://www.reactome.org ReactomeREACT_9436 Reviewed: Sassa, S, 2007-01-24 10:18:36 has a Stoichiometric coefficient of 4 PathwayStep12 Translocation of coproporphyrinogen III from the cytosol to the mitochondrial intermembrane space Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Coproporpyrinogen III enters the mitochondrial intermembrane space from the cytosol. It is not known whether this process is facilitated by a transporter. Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Reactome Database ID Release 43189467 Reactome, http://www.reactome.org ReactomeREACT_9945 Reviewed: Sassa, S, 2007-01-24 10:18:36 PathwayStep13 Conversion of coproporphyrinogen III to protoporphyrinogen IX Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 EC Number: 1.3.3.3 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 O2-dependent coproporpyrinogen oxidase (CPO) catalyzes the conversion of coproporphyrinogen III to protoporphyrinogen IX. The localization of the human enzyme to the mitochondrial intermembrane space is inferred from studies of the homologous rat enzyme (Elder and Evans 1978). The human enzyme functions as a homodimer (Lee et al. 2005). Enzyme deficiency is associated with hereditary coproporphyria in vivo. Pubmed16176984 Pubmed16258391 Pubmed666752 Reactome Database ID Release 43189421 Reactome, http://www.reactome.org ReactomeREACT_9421 Reviewed: Sassa, S, 2007-01-24 10:18:36 has a Stoichiometric coefficient of 2 Two molecules of ALA condense to form porphobilinogen (PBG) 5-Aminolevulinic acid dehydratase (ALAD), also known as porphobilinogen synthase (PBGS), catalyzes the asymmetric condensation of two molecules of ALA to form porphobilinogen. The substrate that becomes the acetyl side chain-containing half of PBG is called A-side ALA; the half that becomes the propionyl side chains and the pyrrole nitrogen is called P-ALA (Jaffe 2004). Porphobilinogen (PBG) is the first pyrrole formed, the precursor to all tetrapyrrole pigments such as heme and chlorophyll. There are at least eight bonds that are made or broken during this reaction. The active form of the ALAD enzyme is an octamer complexed with eight Zn++ ions, four that are strongly bound and four that are weakly bound. The four weakly bound ones are dispensible for enzyme activity in vitro (Bevan et al. 1980; Mitchell et al. 2001).<br>Deficiencies of ALAD enzyme in vivo are associated with 5-aminolevulinate dehydratase-deficient porphyria (e.g., Akagi et al. 2000). Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 EC Number: 4.2.1.24 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Pubmed10706561 Pubmed11032836 Pubmed11032841 Pubmed15381398 Pubmed7354072 Reactome Database ID Release 43189439 Reactome, http://www.reactome.org ReactomeREACT_9430 Reviewed: Sassa, S, 2007-01-24 10:18:36 has a Stoichiometric coefficient of 2 Four PBGs combine through deamination to form hydroxymethylbilane (HMB) Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Cytosolic porphobilinogen deaminase catalyzes the polymerization of four molecules of porphobilinogen (PBG) to generate hydroxymethylbilane (HMB), an unstable tetrapyrrole. This reaction is the first step in the formation of the tetrapyrrole macrocycle. Two isoforms of porphobilinogen deaminase are generated by alternative splicing, one expresssed in erythroid tissues and one ubiquitously expressed in the body. Deficiencies of both forms of PBG deaminase are associated with acute intermittent porphyria. EC Number: 2.5.1.61 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Pubmed12773194 Pubmed7354069 Reactome Database ID Release 43189406 Reactome, http://www.reactome.org ReactomeREACT_9446 Reviewed: Sassa, S, 2007-01-24 10:18:36 has a Stoichiometric coefficient of 4 Conversion of HMB to uroporphyrinogen III Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Cytosolic uroporphyrinogen III synthase (URO3S) catalyzes the conversion of HMB (hydroxymethylbilane) to uroporphyrinogen III, a reaction involving ring closure and intramolecular rearrangement. Uroporphyrinogen III represents a branch point for the pathways leading to formation of heme, chlorophyll and corrins. HMB is rapidly converted from a linear tetrapyrrole to the cyclic form. Deficiencies of URO3S in vivo are associated with congenital erythropoietic porphyria. EC Number: 4.2.1.75 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Pubmed3805019 Pubmed7592565 Reactome Database ID Release 43189488 Reactome, http://www.reactome.org ReactomeREACT_9526 Reviewed: Sassa, S, 2007-01-24 10:18:36 Spontaneous conversion of HMB to uroporphyrinogen I Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Hydroxymethybilane (HMB) can spontaneously cyclize and rearrange to form uroporphyrinogen I. Pubmed3805019 Reactome Database ID Release 43190168 Reactome, http://www.reactome.org ReactomeREACT_9408 Reviewed: Sassa, S, 2007-01-24 10:18:36 ALAD octamer associates with Pb++, forming a catalytically inactive complex Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Lead binds to ALAD enzyme displacing zinc ions essential for its catalytic activity and inactivating it. Lead is a major environmental toxin and this enzyme is one of its principal molecular targets (Jaffe et al. 2001). Pubmed11032836 Reactome Database ID Release 43190141 Reactome, http://www.reactome.org ReactomeREACT_9437 Reviewed: Sassa, S, 2007-01-24 10:18:36 has a Stoichiometric coefficient of 4 PathwayStep11 PathwayStep10 Class I MHC heavy chain (MHC HC) Converted from EntitySet in Reactome Reactome DB_ID: 983408 Reactome Database ID Release 43983408 Reactome, http://www.reactome.org ReactomeREACT_76754 11-deoxycorticosterone is oxidised to corticosterone by CYP11B2 Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.14.15.4 Edited: Jassal, B, 2008-05-19 12:57:01 P450 11B2 (steroid 11 beta-hydroxylase) is a mitochondrial cytochrome P-450 enzyme necessary for cortisol biosynthesis.The synthesis of the most important glucocorticoid and mineralocorticoid hormones in humans (cortisol and aldosterone, respectively), take place in the adrenal gland. The 11?- and 18-hydroxylation of the substrate 11-deoxycorticosterone (DOC) leads to corticosterone (B)band 18-hydroxycorticosterone (18-OH-B), whose 18-oxidation yields aldosterone. CYP11B1 is also able to produce corticosterone from 11-deoxycorticosterone but it cannot convert corticosterone into aldosterone. Pubmed11856349 Pubmed2592361 Reactome Database ID Release 43211955 Reactome, http://www.reactome.org ReactomeREACT_13700 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Ethylene oxidized to Ethylene oxide A simple example of epoxidation is the oxidation of an alkene (olefin) to the epoxide (oxirane), catalysed by CYP1A1. Even the simplest of epoxides (ethylene oxide) can react with DNA and amino groups in a protein. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Ethylene is oxidized to Ethylene oxide by CYP1A1 GENE ONTOLOGYGO:0009692 Pubmed12464245 Pubmed7217086 Reactome Database ID Release 4376472 Reactome, http://www.reactome.org ReactomeREACT_1447 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Bilirubin monoglucuronide is conjugated to bilirubin diglucuronide Authored: Jassal, B, 2005-02-23 15:02:50 EC Number: 2.4.1.17 Edited: Jassal, B, 2010-05-27 Pubmed3082969 Pubmed4639028 Pubmed6654901 Pubmed6796486 Reactome Database ID Release 43159179 Reactome, http://www.reactome.org ReactomeREACT_22319 Reviewed: D'Eustachio, P, 2010-05-08 The principal conjugate of bilirubin in bile is bilirubin diglucuronide. The monmeric form of UGT1A1 (Bilirubin UDP-glucuronyltransferase) only conjugates the first step of bilirubin conjugation to form the monoglucuronide. A tetrameric form of UGT1A1 can convert bilirubin to both the monoglucuronide and the diglucuronide. bilirubin monoglucuronide + UDP-glucuronic acid => bilirubin diglucuronide + UDP CYP1B1 4-hydroxylates estradiol-17beta Authored: Jassal, B, 2008-05-19 12:57:01 Cytochrome P450 1B1 (CYP1B1) can oxidize a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. CYP1B1 can also activate a range of procarcinogens. A specific substrate is the female sex hormone estradiol-17beta which is hydroxylated at position 4. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed11555828 Reactome Database ID Release 43211951 Reactome, http://www.reactome.org ReactomeREACT_13668 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Bilirubin translocates from the cytosol to the ER lumen Reactome Database ID Release 43189381 Reactome, http://www.reactome.org ReactomeREACT_22403 Reviewed: Sassa, S, 2007-01-24 10:18:36 The enzyme which catalyzes the conjugation of bilirubin (UGT1A1) is found in the ER. Bilirubin translocates here to be eliminated from the body. Bilirubin forms a monoglucuronide Authored: Jassal, B, 2005-02-23 15:02:50 Bilirubin is a breakdown product of heme, causing death if allowed to accumulate in the blood. It is highly lipophilic and thus requires conjugation to become more water soluble to aid excretion. UGT1A1 is the only enzyme that converts bilirubin to either a monoglucuronide or diglucuronide. Mutations of the UGT1A1 gene cause complete loss or partial activity for bilirubin glucuronidation. EC Number: 2.4.1.17 Edited: Jassal, B, 2010-05-27 GENE ONTOLOGYGO:0006789 Pubmed3082969 Pubmed8027054 Reactome Database ID Release 43159194 Reactome, http://www.reactome.org ReactomeREACT_22274 Reviewed: D'Eustachio, P, 2010-05-08 bilirubin + UDP-glucuronic acid => bilirubin monoglucuronide + UDP The heme ring is cleaved by heme oxygenase EC Number: 1.14.99.3 Heme oxygenase (HO) cleaves the heme ring at the alpha-methene bridge to form bilverdin. This reaction forms the only endogenous source of carbon monoxide. HO-1 is inducible and is thought to have an antioxidant role as it's activated in virtually all cell types and by many types of "oxidative stress" (Poss and Tonegawa, 1997). HO-2 is non-inducible. Pubmed9380736 Reactome Database ID Release 43189398 Reactome, http://www.reactome.org ReactomeREACT_22100 Reviewed: Sassa, S, 2007-01-24 10:18:36 has a Stoichiometric coefficient of 3 Biliverdin is reduced to bilirubin Bilirubin is the breakdown product of heme, causing death if allowed to accumulate in the blood. It is highly lipophilic thus requires conjugation to become more water soluble to aid excretion. EC Number: 1.3.1.24 Reactome Database ID Release 43189384 Reactome, http://www.reactome.org ReactomeREACT_22177 Reviewed: Sassa, S, 2007-01-24 10:18:36 Protoporphyrin IX is transported from the mitochondrial intermembrane space into the mitochondrial matrix Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Protoporphyrin IX is transported into the mitochondrial matrix where it becomes available for the last step in the heme biosynthetic pathway. The transporter that mediates this event is unknown. Reactome Database ID Release 43189457 Reactome, http://www.reactome.org ReactomeREACT_9393 Reviewed: Sassa, S, 2007-01-24 10:18:36 ERAP1/2 Converted from EntitySet in Reactome Reactome DB_ID: 983125 Reactome Database ID Release 43983125 Reactome, http://www.reactome.org ReactomeREACT_76495 Ferrous iron is inserted into protoporphyrin IX to form heme Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 EC Number: 4.99.1.1 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Ferrochelatase (FECH) catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. The enzyme functions as a homodimer with each monomer containing a nitric oxide-sensitive 2Fe-2S cluster. Enzyme deficiency is associated with erythropoietic protoporphyria in vivo, and inhibition of ferrochelatase activity is a clinically important consequence of lead poisoning (Piomelli et al. 1987). Pubmed11175906 Pubmed3327432 Reactome Database ID Release 43189465 Reactome, http://www.reactome.org ReactomeREACT_9461 Reviewed: Sassa, S, 2007-01-24 10:18:36 has a Stoichiometric coefficient of 2 poly((1,4)-alpha-glucosyl) glycogenin-2 dimer Reactome DB_ID: 453216 Reactome Database ID Release 43453216 Reactome, http://www.reactome.org ReactomeREACT_21621 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 poly((1,4)-alpha-glucosyl) glycogenin-1 dimer Reactome DB_ID: 453217 Reactome Database ID Release 43453217 Reactome, http://www.reactome.org ReactomeREACT_21883 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 GYS1 tetramer, I form Reactome DB_ID: 71566 Reactome Database ID Release 4371566 Reactome, http://www.reactome.org ReactomeREACT_5856 glycogen synthase 1 tetramer, I form has a Stoichiometric coefficient of 4 GYS tetramers I form Converted from EntitySet in Reactome GYS1 tetramer, GYS2 tetramer I forms Reactome DB_ID: 453227 Reactome Database ID Release 43453227 Reactome, http://www.reactome.org ReactomeREACT_21494 glycogen synthase tetramers, I form oligo((1,4)-alpha-glucosyl) glycogenin 1 dimer Reactome DB_ID: 453124 Reactome Database ID Release 43453124 Reactome, http://www.reactome.org ReactomeREACT_22046 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 oligo((1,4)-alpha-glucosyl) glycogenin dimer Converted from EntitySet in Reactome Reactome DB_ID: 453135 Reactome Database ID Release 43453135 Reactome, http://www.reactome.org ReactomeREACT_21856 poly((1,4)-alpha-glucosyl) glycogenin dimer Converted from EntitySet in Reactome Reactome DB_ID: 453224 Reactome Database ID Release 43453224 Reactome, http://www.reactome.org ReactomeREACT_21858 oligo((1,4)-alpha-glucosyl) glycogenin 2 dimer Reactome DB_ID: 453120 Reactome Database ID Release 43453120 Reactome, http://www.reactome.org ReactomeREACT_21849 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 glycogenin-2 dimer Reactome DB_ID: 70214 Reactome Database ID Release 4370214 Reactome, http://www.reactome.org ReactomeREACT_8601 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 glycogenin-1 dimer Reactome DB_ID: 70203 Reactome Database ID Release 4370203 Reactome, http://www.reactome.org ReactomeREACT_8800 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 GYG1, GYG2 Converted from EntitySet in Reactome Reactome DB_ID: 453144 Reactome Database ID Release 43453144 Reactome, http://www.reactome.org ReactomeREACT_21526 glycogenin 1 dimer, glycogenin 2 dimer glycogenin dimer UGP2 octamer Reactome DB_ID: 70281 Reactome Database ID Release 4370281 Reactome, http://www.reactome.org ReactomeREACT_4057 UDP-glucose pyrophosphorylase 2 octamer has a Stoichiometric coefficient of 8 PGM2:Mg++ Reactome DB_ID: 453137 Reactome Database ID Release 43453137 Reactome, http://www.reactome.org ReactomeREACT_21907 has a Stoichiometric coefficient of 1 PGM1:Mg++ Reactome DB_ID: 70218 Reactome Database ID Release 4370218 Reactome, http://www.reactome.org ReactomeREACT_3911 has a Stoichiometric coefficient of 1 PGM1, PGM2 Converted from EntitySet in Reactome Reactome DB_ID: 453132 Reactome Database ID Release 43453132 Reactome, http://www.reactome.org ReactomeREACT_24113 phosphoglucomutase FBP2 tetramer Reactome DB_ID: 2267351 Reactome Database ID Release 432267351 Reactome, http://www.reactome.org ReactomeREACT_124511 has a Stoichiometric coefficient of 4 FBP1 tetramer Reactome DB_ID: 70477 Reactome Database ID Release 4370477 Reactome, http://www.reactome.org ReactomeREACT_2768 fructose-1,6-bisphosphatase 1 complex has a Stoichiometric coefficient of 4 FBP tetramer Converted from EntitySet in Reactome Reactome DB_ID: 372874 Reactome Database ID Release 43372874 Reactome, http://www.reactome.org ReactomeREACT_15171 fructose-1,6-bisphosphatase isoforms GOT1 dimer Reactome DB_ID: 70579 Reactome Database ID Release 4370579 Reactome, http://www.reactome.org ReactomeREACT_2612 has a Stoichiometric coefficient of 2 SLC25A11 homodimer Reactome DB_ID: 376856 Reactome Database ID Release 43376856 Reactome, http://www.reactome.org ReactomeREACT_15258 has a Stoichiometric coefficient of 2 malate dehydrogenase 1 dimer Reactome DB_ID: 198437 Reactome Database ID Release 43198437 Reactome, http://www.reactome.org ReactomeREACT_11548 has a Stoichiometric coefficient of 2 GOT2 dimer Reactome DB_ID: 70594 Reactome Database ID Release 4370594 Reactome, http://www.reactome.org ReactomeREACT_5721 aspartate aminotransferase, mitochondrial, holoenzyme has a Stoichiometric coefficient of 2 PathwayStep5891 PathwayStep5892 PathwayStep5890 PathwayStep5895 PathwayStep5896 PathwayStep5893 PathwayStep5894 PathwayStep5889 PathwayStep5888 PathwayStep5887 PathwayStep5886 PathwayStep5880 PathwayStep5881 PathwayStep5882 PathwayStep5883 PathwayStep5884 PathwayStep5885 PathwayStep5876 PathwayStep5875 PathwayStep5878 PathwayStep5877 PathwayStep5879 PathwayStep5898 PathwayStep5897 PathwayStep5899 galactose, glucose Converted from EntitySet in Reactome Reactome DB_ID: 189254 Reactome Database ID Release 43189254 Reactome, http://www.reactome.org ReactomeREACT_9575 hexoses transported by SGLT1 Agmatine + H2O <=> putrescine + urea As it hydrolyzes a guanidino group within agmatine and also contains signature amino acid residues that act as ligand binding sites for the potential Mn(++) cofactor, agmatinase is classified as a member of the arginase superfamily (Morris, 2003). Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 3.5.3.11 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed11804860 Pubmed11914032 Pubmed15028567 Reactome Database ID Release 43350604 Reactome, http://www.reactome.org ReactomeREACT_14815 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 galactose, glucose Converted from EntitySet in Reactome Reactome DB_ID: 189227 Reactome Database ID Release 43189227 Reactome, http://www.reactome.org ReactomeREACT_9887 hexoses transported by SGLT1 ornithine => putrescine + CO2 Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 4.1.1.17 Edited: Gopinathrao, G, 2006-04-27 13:13:48 ISBN0079130356 L-ornithine is converted into putrescine by ODC holoenzyme complex.Putrescine is subsequent used for polyamine synthesis. Reactome Database ID Release 4370692 Reactome, http://www.reactome.org ReactomeREACT_1211 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Creatine transport across the plasma membrane Authored: D'Eustachio, P, 2007-07-18 14:33:15 Pubmed12889669 Pubmed7945388 Reactome Database ID Release 43200396 Reactome, http://www.reactome.org ReactomeREACT_11191 The SLC6A8 transport protein associated with the plasma membrane mediates the uptake of extracellular creatine and a sodium ion (Sora et al. 1994). Molecular and biochemical studies of patients deficient in SLC6A8 protein confirm this function in vivo (e.g., Salomons et al. 2003). Arginine<=>Agmatine+CO2 Agmatine is polyamine formed by decarboxylation of L-arginine by arginine decarboxylase (ADC). Human ADC is a 460-amino acid protein that shows about 48% identity to mammalian ornithine decarboxylase (ODC) but has no ODC activity. Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 4.1.1.19 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed14738999 Reactome Database ID Release 43350598 Reactome, http://www.reactome.org ReactomeREACT_14806 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 fructose, galactose, glucose Converted from EntitySet in Reactome Reactome DB_ID: 189219 Reactome Database ID Release 43189219 Reactome, http://www.reactome.org ReactomeREACT_9596 hexoses transported by GLUT2 fructose, galactose, glucose Converted from EntitySet in Reactome Reactome DB_ID: 189246 Reactome Database ID Release 43189246 Reactome, http://www.reactome.org ReactomeREACT_9838 hexoses transported by GLUT2 phosphocreatine + H2O => creatinine + orthophosphate Authored: D'Eustachio, P, 2007-07-18 14:33:15 Cytosolic phosphocreatine spontaneously hydrolyzes to yield creatinine and orthophosphate (Borsook and Dubnoff 1947). Creatinine cannot be metabolized further and is excreted from the body in the urine. Creatinine formation proceeds at a nearly constant rate and the amount produced by an individual is a function of muscle mass, so urinary creatinine output is clinically useful as a normalization factor in assays of urinary output of other molecules. Iyengar et al. (1985) have suggested that an alternative reaction sequence, proceeding via phosphocreatinine but also spontaneous, may contribute to creatinine formation. Pubmed20238607 Pubmed3997888 Reactome Database ID Release 4371287 Reactome, http://www.reactome.org ReactomeREACT_808 PLCB2:Ca2+ Reactome DB_ID: 1604651 Reactome Database ID Release 431604651 Reactome, http://www.reactome.org ReactomeREACT_151512 has a Stoichiometric coefficient of 1 PLCB1:Ca2+ Reactome DB_ID: 1604622 Reactome Database ID Release 431604622 Reactome, http://www.reactome.org ReactomeREACT_150673 has a Stoichiometric coefficient of 1 EXT1:EXT2 Reactome DB_ID: 2022878 Reactome Database ID Release 432022878 Reactome, http://www.reactome.org ReactomeREACT_122567 has a Stoichiometric coefficient of 1 B3GAT3 dimer Reactome DB_ID: 1889995 Reactome Database ID Release 431889995 Reactome, http://www.reactome.org ReactomeREACT_122845 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 B3GAT2 dimer Reactome DB_ID: 1889973 Reactome Database ID Release 431889973 Reactome, http://www.reactome.org ReactomeREACT_121908 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 N-acetylated spermidine (cytosol)=>N-acetylated spermidine (peroxisomal) Authored: Gopinathrao, G, 2008-05-21 15:52:50 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Reactome Database ID Release 43351201 Reactome, http://www.reactome.org ReactomeREACT_14857 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Transport and peroxisomal processing of specific polyamines will be annotated in future Reactome releases. B3GAT1 dimer Reactome DB_ID: 1889998 Reactome Database ID Release 431889998 Reactome, http://www.reactome.org ReactomeREACT_124247 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Spermidine => N-acetylated spermidine Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 2.3.1.57 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed1985966 Pubmed8360194 Reactome Database ID Release 43351208 Reactome, http://www.reactome.org ReactomeREACT_14817 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Spermidine/spermine N1-acetyltransferase (Spd/Spm acetyltransferase) is the rate-limiting enzyme in the catabolism of polyamines. Defects in SAT1 may be the cause of keratosis follicularis spinulosa decalvans (KFSD). PLCbz Converted from EntitySet in Reactome Reactome DB_ID: 2023864 Reactome Database ID Release 432023864 Reactome, http://www.reactome.org ReactomeREACT_151954 dc-Adenosyl methionine + Spermidine => Spermine + 5'-methylthioadenosine Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 2.5.1.22 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed7546290 Reactome Database ID Release 43351210 Reactome, http://www.reactome.org ReactomeREACT_14825 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 The protein encoded by this gene belongs to the spermidine/spermine synthases family. This gene encodes an ubiquitous enzyme of polyamine metabolism. Defects in SMS are the cause of Snyder-Robinson syndrome (SRS). ARSB:Ca2+ Reactome DB_ID: 1606792 Reactome Database ID Release 431606792 Reactome, http://www.reactome.org ReactomeREACT_122486 has a Stoichiometric coefficient of 1 Putrescine + dc-Adenosyl methionine => Spermidine + 5'-methylthioadenosine Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 2.5.1.16 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed2069720 Reactome Database ID Release 43351215 Reactome, http://www.reactome.org ReactomeREACT_14788 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Spermidine synthase is one of four enzymes in the polyamine-biosynthetic pathway and carries out the final step of spermidine biosynthesis. This enzyme catalyzes the conversion of putrescine to spermidine using decarboxylated S-adenosylmethionine as the cofactor. IDS dimer Reactome DB_ID: 1678638 Reactome Database ID Release 431678638 Reactome, http://www.reactome.org ReactomeREACT_121563 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 S-Adenosyl methionine <=> Decarboxylated-Adenosyl methionine + CO2 Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 4.1.1.50 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed10029540 Pubmed11583147 Reactome Database ID Release 43351222 Reactome, http://www.reactome.org ReactomeREACT_14840 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 S-Adenosylmethionine decarboxylase belongs to a small class of amino acid decarboxylases that use a covalently bound pyruvate as a prosthetic group. It is an essential enzyme for polyamine biosynthesis and provides an important target for the design of anti-parasitic and cancer chemotherapeutic agents. It catalyzes the formation of the aminopropyl group donor in the biosynthesis of the polyamines spermidine and spermine. These pyruvoyl-dependent decarboxylases also form amines such as histamine, decarboxylated S-adenosylmethionine, phosphatidylethanolamine (a component of membrane phospholipids), and -alanine (a precursor of coenzyme A), which are all of critical importance in cellular physiology and provide important targets for drug design. HPSE dimer Reactome DB_ID: 1666976 Reactome Database ID Release 431666976 Reactome, http://www.reactome.org ReactomeREACT_122933 has a Stoichiometric coefficient of 1 N-acetylated spermine (cytosol)=>N-acetylated spermine (peroxisomal) Authored: Gopinathrao, G, 2008-05-21 15:52:50 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Reactome Database ID Release 43351229 Reactome, http://www.reactome.org ReactomeREACT_14846 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Transport and peroxisomal processing of specific polyamines will be annotated in future Reactome releases. N-acetylspermine is oxidised to spermidine Acetylated spermine is oxidized by the flavoenzyme polyamine oxidase (PAO) to produce spermidine. PAO is involved in the back-conversion of polyamines and thus the regulation of their intracellular concentrations.<br> Authored: Gopinathrao, G, 2008-05-21 15:52:50 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed12477380 Reactome Database ID Release 43141351 Reactome, http://www.reactome.org ReactomeREACT_2231 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Spermine is oxidized to spermidine Authored: Gopinathrao, G, 2008-05-21 15:52:50 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed11454677 Pubmed12141946 Pubmed12727196 Reactome Database ID Release 43141341 Reactome, http://www.reactome.org ReactomeREACT_2194 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Spermine oxidase (SMOX/PAOh1/SMO) is a polyamine oxidase flavoenzyme which catalyzes the oxidation of spermine to spermidine. It plays an important role in the regulation of endogenous polyamine intracellular concentration. Five different isozymes are produced by alternative splicing with isozyme 3 being the major isoform and possessing the highest affinity for spermine. It is highly inducible by specific antitumor polyamine analogues (Wang et al., 2001). MTA is cleaved and phosphorylated Authored: Stephan, R, 2010-10-24 EC Number: 2.4.2.28 Edited: Jassal, B, 2011-03-30 MTA phosphorylase catalyzes the cleavage of adenine from S-methylthioadenosine (MTA) and subsequent phosphorylation of the product, yielding 5'-methylthio ribose-1-phosphate (Kamatani et al. 1981). The active form of the enzyme is a homotrimer (Della Ragione et al. 1985). Mutations in the gene are associated with a rare bone dysplasia and cancer syndrome, DMS-MFH (Camacho-Vanegas et al. 2012). Pubmed22464254 Pubmed3091600 Pubmed6785752 Reactome Database ID Release 431237160 Reactome, http://www.reactome.org ReactomeREACT_75786 Reviewed: D'Eustachio, P, 2011-05-23 PathwayStep89 N-acetylspermidine is oxidized to putrescine Acetylated spermidine is oxidized by the flavoenzyme polyamine oxidase (PAO) to produce putrescine. PAO is involved in the back-conversion of polyamines and thus the regulation of their intracellular concentrations.<br> Authored: Gopinathrao, G, 2008-05-21 15:52:50 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed12477380 Reactome Database ID Release 43141348 Reactome, http://www.reactome.org ReactomeREACT_1548 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Spermine => N-acetylated spermine Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 2.3.1.57 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed15784477 Pubmed1985966 Reactome Database ID Release 43351207 Reactome, http://www.reactome.org ReactomeREACT_14811 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 Spermidine/spermine N1-acetyltransferase (Spd/Spm acetyltransferase) is the rate-limiting enzyme in the catabolism of polyamines. Defects in SAT1 may be the cause of keratosis follicularis spinulosa decalvans (KFSD). PathwayStep91 B4GALT6 homodimer Reactome DB_ID: 1015817 Reactome Database ID Release 431015817 Reactome, http://www.reactome.org ReactomeREACT_26218 has a Stoichiometric coefficient of 2 PathwayStep90 B4GALT5 homodimer Reactome DB_ID: 1015827 Reactome Database ID Release 431015827 Reactome, http://www.reactome.org ReactomeREACT_25503 has a Stoichiometric coefficient of 2 B3GAT dimers Converted from EntitySet in Reactome Reactome DB_ID: 1889954 Reactome Database ID Release 431889954 Reactome, http://www.reactome.org ReactomeREACT_122746 PathwayStep99 GUSB tetramer Reactome DB_ID: 1678867 Reactome Database ID Release 431678867 Reactome, http://www.reactome.org ReactomeREACT_125084 has a Stoichiometric coefficient of 4 PathwayStep98 PathwayStep97 B4GALT1-6 homodimers Converted from EntitySet in Reactome Reactome DB_ID: 975898 Reactome Database ID Release 43975898 Reactome, http://www.reactome.org ReactomeREACT_26591 PathwayStep96 bHEXA Reactome DB_ID: 1605656 Reactome Database ID Release 431605656 Reactome, http://www.reactome.org ReactomeREACT_117569 beta-hexosaminidase A has a Stoichiometric coefficient of 1 PathwayStep95 Methylthio-ribulose-P = Methylthio-ribose-P Authored: Jassal, B, 2011-05-23 EC Number: 5.3.1.23 Edited: Jassal, B, 2011-05-23 Equilibrium between 5'-methylthio ribose-1-phosphate and 5'-methylthio ribulose-1-phosphate is catalyzed by 5'-methylthio ribose-1-phosphate isomerase. (Kabuyama et al, 2009) Pubmed19620624 Reactome Database ID Release 431299507 Reactome, http://www.reactome.org ReactomeREACT_75840 Reviewed: D'Eustachio, P, 2011-05-23 B4GALT2 homodimer Reactome DB_ID: 975923 Reactome Database ID Release 43975923 Reactome, http://www.reactome.org ReactomeREACT_25724 has a Stoichiometric coefficient of 2 PathwayStep94 Methylthio-ribose-P = Methylthio-ribulose-P Authored: Stephan, R, 2010-10-24 EC Number: 5.3.1.23 Edited: Jassal, B, 2011-03-30 Equilibrium between 5'-methylthio ribose-1-phosphate and 5'-methylthio ribulose-1-phosphate is catalyzed by 5'-methylthio ribose-1-phosphate isomerase. (Kabuyama et al, 2009) Pubmed19620624 Reactome Database ID Release 431237096 Reactome, http://www.reactome.org ReactomeREACT_75853 Reviewed: D'Eustachio, P, 2011-05-23 B4GALT1 homodimer Reactome DB_ID: 975900 Reactome Database ID Release 43975900 Reactome, http://www.reactome.org ReactomeREACT_26670 has a Stoichiometric coefficient of 2 PathwayStep93 Acireductone is created Acireductone synthase (also: enolase-phosphatase E1) catalyzes the dephosphorylation and conversion to enolate of 2,3-dioxo-5'-methylthiopentane-1-phosphate, yielding acireductone. (Wang et al, 2005) Authored: Stephan, R, 2010-10-24 EC Number: 3.1.3.77 Edited: Jassal, B, 2011-03-30 Pubmed15843022 Reactome Database ID Release 431237129 Reactome, http://www.reactome.org ReactomeREACT_75868 Reviewed: D'Eustachio, P, 2011-05-23 has a Stoichiometric coefficient of 2 B4GALT4 homodimer Reactome DB_ID: 975909 Reactome Database ID Release 43975909 Reactome, http://www.reactome.org ReactomeREACT_26881 has a Stoichiometric coefficient of 2 PathwayStep92 Dehydration of methylthio-ribulose-P Authored: Stephan, R, 2010-10-24 EC Number: 4.2.1.109 Edited: Jassal, B, 2011-03-30 GENE ONTOLOGYGO:0019509 Reactome Database ID Release 431237140 Reactome, http://www.reactome.org ReactomeREACT_75828 Reviewed: D'Eustachio, P, 2011-05-23 The human enzyme with 5'-methylthio ribulose-1-phosphate isomerase activity is probably produced from the APIP gene, according to its orthology with the yeast Mde1p enzyme. B4GALT3 homodimer Reactome DB_ID: 975924 Reactome Database ID Release 43975924 Reactome, http://www.reactome.org ReactomeREACT_26131 has a Stoichiometric coefficient of 2 PathwayStep78 Transamination of MOB to methionine Authored: Stephan, R, 2010-10-24 EC Number: 2.6.1 Edited: Jassal, B, 2011-03-30 GENE ONTOLOGYGO:0019509 In the last step MOB gets transaminated to methionine. The reaction was confirmed in yeast, where several transaminases catalyze it, which appears to be also the case in rat. At the moment, the human enzymes involved are unknown but due to homology to the respective enzyme in the parasite <i>Crithidia fasciculata</i> we feel supported to state that human GOT is probably one of the involved transaminases. (Berger et al, 2001) Pubmed11443076 Reactome Database ID Release 431237102 Reactome, http://www.reactome.org ReactomeREACT_75811 Reviewed: D'Eustachio, P, 2011-05-23 PathwayStep79 Antizyme OAZ binds to Ornithine decarboxylase Antizyme is a non-competitive inhibitor of ODC that is synthesized in response to an increase in polyamine concentration. Tight binding of the antizyme to the ODC monomer forming a heterodimer prevents enzymatic activity. The region of antizyme interacting with ODC is contained in a section involving residues 106–212 in the COOH-terminal half of the antizyme molecule. The induction of antizyme thus leads to a loss of active ODC protein (Pegg, 2006 and references cited in that review). <br> Authored: Gopinathrao, G, 2008-05-19 18:50:15 Pubmed12359729 Pubmed12660156 Pubmed16459331 Pubmed7811704 Pubmed9132164 Reactome Database ID Release 43350567 Reactome, http://www.reactome.org ReactomeREACT_13759 Reviewed: D'Eustachio, P, 2008-06-12 17:57:32 Acireductone is oxidized to MOB Acireducone (1,2-Dihydroxy-3-oxo-5'-methylthiopentene) is oxidized using acireductone dioxygenase and dioxygen. There are two reactions possible, dependent on the metal cofactor: the alternative product 3-methylthiopropionate using nickel was confirmed in <i>Klebsiella</i>. In eukaryotes using iron(II) the result is 4-methylthio-2-oxobutanoate (MOB). (Ju et al, 2006) Authored: Stephan, R, 2010-10-24 EC Number: 1.13.11.54 Edited: Jassal, B, 2011-03-30 Pubmed17786183 Reactome Database ID Release 431237119 Reactome, http://www.reactome.org ReactomeREACT_75861 Reviewed: D'Eustachio, P, 2011-05-23 NQO1 interaction with ODC A novel pathway has been described for ODC degradation during oxidative stress, which is regulated by NAD(P)H quinone oxidoreductase (NQO1). In this pathway, the 20S proteasome has been shown to degrade unfolded ODC monomers. This event does not require the COOH-terminal domain. NQO1 binds to ODC and stabilizes it. If this interaction is disrupted with dicoumarol, it sensitizes ODC monomers to degradation by the 20S proteasome independent of both antizyme and ubiquitin. The details of the role of this pathway remains to be determined, but it could be involved in the nascent ODC chain turnover. Authored: Gopinathrao, G, 2008-05-19 18:50:15 Pubmed12653649 Pubmed15749015 Pubmed16205122 Pubmed16459331 Reactome Database ID Release 43350578 Reactome, http://www.reactome.org ReactomeREACT_13453 Reviewed: D'Eustachio, P, 2008-06-12 17:57:32 Tyrosine is hydroxylated to dopa Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.16.2 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed10691773 Pubmed2575455 Pubmed8101641 Reactome Database ID Release 43209823 Reactome, http://www.reactome.org ReactomeREACT_15366 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Tyrosine hydroxylase (TH) is the first enzyme in catecholamine biosynthesis, as well as being the rate-limiting enzyme in that process. TH requires tetrahydrobiopterin and uses iron as a cofactor in the 3,4-hydroxylation of tyrosine to produce dopa. Four isoforms of TH are expressed in the human brain and all have enzymatic activity (Nagatsu, T, 1989; Lewis, DA et al, 1993). 26S proteosome degrades ODC holoenzyme complex Authored: Gopinathrao, G, 2008-05-19 18:50:15 Pubmed11265248 Pubmed12660156 Pubmed16205122 Pubmed16223706 Pubmed16459331 Pubmed7864793 Reactome Database ID Release 43353125 Reactome, http://www.reactome.org ReactomeREACT_13491 Reviewed: D'Eustachio, P, 2008-06-12 17:57:32 The rapid turnover of ODC is brought about by the 26S proteasome. Proteolytic processing of ODC is highly unusual in that ubiquitination is not required for this degradation. Instead, a non-covalent association with antizyme directs ODC to the proteasome. Antizyme increases the degradation of ODC by enhancing its interaction with the proteasome (Pegg, 2006). Antizyme inhibitor binds to OAZ and stablizes ODC complex Antizyme inhibitor blocks the effects of antizyme on ODC. It has substantial similarity to ODC itself but has no ODC activity. It binds to antizyme more tightly than ODC displacing ODC from the antizyme-ODC complex. Recent studies have shown that antizyme inhibitor is able to disrupt the interaction between all forms of mammalian antizyme and ODC (Murakami et al., 1996, Nilsson et al., 2000, Mangold and Leberer, 2005). Authored: Gopinathrao, G, 2008-05-19 18:50:15 Pubmed10698696 Pubmed15355308 Pubmed15491992 Pubmed17900240 Pubmed8631929 Pubmed9349715 Pubmed9426243 Reactome Database ID Release 43350600 Reactome, http://www.reactome.org ReactomeREACT_13578 Reviewed: D'Eustachio, P, 2008-06-12 17:57:32 PathwayStep80 PathwayStep82 PathwayStep81 Dopamine is oxidised to noradrenaline Authored: Jassal, B, 2008-10-01 13:18:42 Dopamine beta-hydroxylase (DBH; dopamine beta-monooxygenase) is a copper-containing glycoprotein consisting of four identical subunits and catalyzes the oxidation of dopamine to norepinephrine. It requires ascorbic acid as an electron donor. DBH is localized in the norepinephrinergic and epinephrinergic neurons in the central nervous system. The enzyme exists in the secretory vesicles as both soluble and membrane-bound forms. The soluble form is secreted with catecholamines by exocytosis whereas the membrane-bound form is recycled into the vesicles. EC Number: 1.14.17.1 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed1857555 Pubmed3443096 Pubmed7961964 Reactome Database ID Release 43209891 Reactome, http://www.reactome.org ReactomeREACT_15372 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep84 Dopamine translocates to a secretory vesicle Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed16339215 Reactome Database ID Release 43351596 Reactome, http://www.reactome.org ReactomeREACT_15424 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 While dopamine is synthesized in the cytosol, its conversion to noradrenaline is mediated by a vesicle-associated enzyme. The process by which dopamine is transported across the vesicle membrane has not been elucidated yet, however. PathwayStep83 Dopa is decarboxylated to dopamine Aromatic L-amino acid decarboxylase (AADC, dopa decarboxylase) decarboxylates dopa to form dopamine. EC Number: 4.1.1.28 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed10691773 Pubmed1540578 Pubmed2590185 Reactome Database ID Release 43209924 Reactome, http://www.reactome.org ReactomeREACT_15382 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep86 PathwayStep85 PathwayStep88 PathwayStep87 PathwayStep69 Noradrenaline translocates to the cytosol Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed16047163 Reactome Database ID Release 43351604 Reactome, http://www.reactome.org ReactomeREACT_15392 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 While noradrenaline is synthesized in the secretory vesicle, its conversion to adrenaline is mediated by a cytosolic enzyme. The process by which noradrenaline is transported across the vesicle membrane has not been worked out, however. Noradrenaline is converted to adrenaline Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 2.1.1.28 Edited: Jassal, B, 2008-01-08 13:51:41 Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme in catecholamine biosynthesis. It performs transmethylation of noradrenaline to adrenaline using S-adenosyl L-methionine (SAM) as the methyl donor. Pubmed3372503 Reactome Database ID Release 43209903 Reactome, http://www.reactome.org ReactomeREACT_15442 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep67 Iodide is taken up by thyroid epithelial cells Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-01-08 13:51:41 Iodide (I-) is transported from blood serum into the thyroid cell by the Na+/I- symporter (sodium/iodide). This intrinsic membrane protein uses energy from the inward movement of Na+ to drive the process and accumulate I- in the cell, maintaining a cellular concentration 30-40 times that of the serum concentration. This process, also called the iodide trap, is stimulated by TSH (thyroid stimulating hormone) and is saturable by large amounts of I-. Pubmed8806637 Reactome Database ID Release 43209910 Reactome, http://www.reactome.org ReactomeREACT_15327 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 has a Stoichiometric coefficient of 2 PathwayStep68 Iodide is organified Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.11.1.7 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed1722671 Reactome Database ID Release 43350901 Reactome, http://www.reactome.org ReactomeREACT_15539 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The first step in the biogenesis of thyroid hormones is the oxidation of iodide (I-) by H2O2/peroxidase after being taken up by the thyroid gland. This event is known as organification. has a Stoichiometric coefficient of 2 PLCB3:Ca2+ Reactome DB_ID: 1604618 Reactome Database ID Release 431604618 Reactome, http://www.reactome.org ReactomeREACT_150548 has a Stoichiometric coefficient of 1 Tyrosine is monoiodinated Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.11.1.7 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed67547 Reactome Database ID Release 43209815 Reactome, http://www.reactome.org ReactomeREACT_15445 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Tyrosines can be iodinated in thyroglobulin to produce precursors for thyroid hormone synthesis. Monoiodinated tyrosine can be deiodinated Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed16910871 Reactome Database ID Release 43209921 Reactome, http://www.reactome.org ReactomeREACT_15389 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The human iodotyrosine dehalogenase 1 (DEHAL1) gene is composed of six exons. Two isoforms (DEHAL1 and DEHAL1B) have been published, both of which have a nitroreductase domain and arise from differential splicing in exon 5. The DEHAL1 isoform is a transmembrane protein that catalyzes the NADPH-dependent deiodination of monoiodotyrosine (MIT) and diiodotyrosine (DIT). Tyrosine is diiodinated Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.11.1.7 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed67547 Reactome Database ID Release 43209973 Reactome, http://www.reactome.org ReactomeREACT_15455 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Tyrosines can be iodinated in thyroglobulin to produce precursors for thyroid hormone synthesis. has a Stoichiometric coefficient of 2 Diiodinated tyrosine can be deiodinated Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed16910871 Reactome Database ID Release 43209960 Reactome, http://www.reactome.org ReactomeREACT_15410 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The human iodotyrosine dehalogenase 1 (DEHAL1) gene is composed of six exons. Two isoforms (DEHAL1 and DEHAL1B) have been published, both of which have a nitroreductase domain and arise from differential splicing in exon 5. The DEHAL1 isoform is a transmembrane protein that catalyzes the NADPH-dependent deiodination of monoiodotyrosine (MIT) and diiodotyrosine (DIT). has a Stoichiometric coefficient of 2 PLCH1:Ca2+ Reactome DB_ID: 2023879 Reactome Database ID Release 432023879 Reactome, http://www.reactome.org ReactomeREACT_151964 has a Stoichiometric coefficient of 1 PathwayStep73 Two DITs combine to form thyroxine Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.11.1.7 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed67547 Reactome Database ID Release 43209840 Reactome, http://www.reactome.org ReactomeREACT_15430 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Thyroxine (T4) can be formed by the combination of two diiodotyrosines. The hormone thyrotropin can stimulate the production of T3 and T4. has a Stoichiometric coefficient of 2 PLCD3:Ca2+ Reactome DB_ID: 2023852 Reactome Database ID Release 432023852 Reactome, http://www.reactome.org ReactomeREACT_151307 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep72 DIT and MIT combine to form triiodothyronine Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.11.1.7 Edited: Jassal, B, 2008-01-08 13:51:41 Mono- and di-iodinated tyrosine can combine to form tri-iodothyronine (T3). The hormone thyrotropin can stimulate the production of T3 and T4. Pubmed67547 Reactome Database ID Release 43209925 Reactome, http://www.reactome.org ReactomeREACT_15360 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PLCE1:Ca2+ Reactome DB_ID: 2023865 Reactome Database ID Release 432023865 Reactome, http://www.reactome.org ReactomeREACT_151530 has a Stoichiometric coefficient of 1 PathwayStep71 PLCG2:Ca2+ Reactome DB_ID: 2023881 Reactome Database ID Release 432023881 Reactome, http://www.reactome.org ReactomeREACT_152328 has a Stoichiometric coefficient of 1 PathwayStep70 PLCG1:Ca2+ Reactome DB_ID: 2023858 Reactome Database ID Release 432023858 Reactome, http://www.reactome.org ReactomeREACT_150497 has a Stoichiometric coefficient of 1 PathwayStep77 PLCZ1:Ca2+ Reactome DB_ID: 1604629 Reactome Database ID Release 431604629 Reactome, http://www.reactome.org ReactomeREACT_152073 has a Stoichiometric coefficient of 1 PathwayStep76 PLCB4:Ca2+ Reactome DB_ID: 1604664 Reactome Database ID Release 431604664 Reactome, http://www.reactome.org ReactomeREACT_151216 has a Stoichiometric coefficient of 1 PathwayStep75 PLCD1:Ca2+ Reactome DB_ID: 2023873 Reactome Database ID Release 432023873 Reactome, http://www.reactome.org ReactomeREACT_151861 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 PathwayStep74 PLCdegh Converted from EntitySet in Reactome Reactome DB_ID: 2023861 Reactome Database ID Release 432023861 Reactome, http://www.reactome.org ReactomeREACT_151148 Thyroxine is deiodinated to triiodothyronine Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.97.1.10 Edited: Jassal, B, 2008-01-08 13:51:41 Iodothyronine deiodinases 1 and 2 (DIO1/2) are the vertebrate enzymes responsible for the deiodination of the prohormone thyroxine (T4; 3,5,3',5'-tetraiodothyronine) into the biologically active hormone T3 (3,5,3'-triiodothyronine). DIO1/2 activity is critical for appropriate T3 levels in the brain during development. Pubmed1400883 Reactome Database ID Release 43209772 Reactome, http://www.reactome.org ReactomeREACT_15469 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Luteinizing hormone is a heterodimer Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-11-17 10:09:58 Luteinizing hormone (LH, lutropin) is a hormone produced by the anterior pituitary gland. In females it can trigger ovulation whereas in males it stimulates testosterone production. Like other glycoproteins, lutropin is composed of a common alpha subunit bound to a unique beta subunit (Sairam MR and Li CH, 1975). The beta subunit is responsible for lutropin's interaction with the LH receptor. Pubmed1191677 Reactome Database ID Release 43378956 Reactome, http://www.reactome.org ReactomeREACT_15460 Reviewed: D'Eustachio, P, 2008-11-29 15:53:45 Human chorionic gonadotropin (hCG) is a heterodimer Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-11-17 10:09:58 Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced in pregnancy. Its role is to maintain progesterone production by preventing the disintegration of the corpus luteum of the ovary and thus sustain the growing foetus. hCG is made up of a common alpha subunit and a unique beta subunit, bound by six intrachain disulfide bonds, required for dimer formation (Beebe JS et al, 1990) Pubmed1688430 Reactome Database ID Release 43378978 Reactome, http://www.reactome.org ReactomeREACT_15432 Reviewed: D'Eustachio, P, 2008-11-29 15:53:45 Corticotropin cleavage from POMC Authored: Jassal, B, 2008-10-01 13:18:42 Corticotropin (adrenocorticotropic hormone, ACTH) is a 39-amino acid polypeptide hormone produced and secreted by the pituitary gland. It is often produced in response to biological stress (along with corticotropin-releasing hormone). Its principal effects are increased production of androgens and cortisol. Corticotropin is processed from the precursor pro-opiomelanocortin (POMC). The enzyme that performs the cleavage of POMC to corticotropin is prohormone convertase 1 (PC1). In addition to corticotropin, POMC is processed into other small, biologically active fragments. These include lipotropins, melanocyte-stimulating hormone and endorphins. Edited: Jassal, B, 2008-11-17 10:09:58 Pubmed14463577 Pubmed9207799 Reactome Database ID Release 43265301 Reactome, http://www.reactome.org ReactomeREACT_15476 Reviewed: D'Eustachio, P, 2008-11-29 15:53:45 Methylation of N-acetyl-5-HT to form melatonin Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-05-28 09:06:10 Hydroxyindole-O-methyltransferase (HIOMT) catalyzes the last step in the synthesis of melatonin. Melatonin is synthesized and released by the pineal gland and is thought to control circadian rhythms. HIOMT has 3 isoforms and utilizes S-adenosyl-L-methionine (SAM) as the methyl donor in the conversion of N-acetyl-5HT to melatonin. Pubmed7989373 Reactome Database ID Release 43209821 Reactome, http://www.reactome.org ReactomeREACT_15383 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep57 N-acetylation of serotonin Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 2.3.1.87 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed8661026 Reactome Database ID Release 43209792 Reactome, http://www.reactome.org ReactomeREACT_15290 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Serotonin N-acetyltransferase (AANAT) catalyzes the N-acetylation of serotonin to form N-acetylserotonin. AANAT utilizes acetyl-CoA as the donor of the acetyl group. PathwayStep56 Decarboxylation of 5-hydroxytryptophan forms serotonin Aromatic L-amino acid decarboxylase (AADC) catalyzes the decarboxylation of both dopa and 5-hydroxytryptophan to dopamine and serotonin, respectively. AADC functions as a homodimer, utilizing pyridoxal phosphate as a cofactor. EC Number: 4.1.1.28 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed1540578 Pubmed2590185 Reactome Database ID Release 43209859 Reactome, http://www.reactome.org ReactomeREACT_15546 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep59 Tryptophan is hydroxylated Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.14.16.4 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed10872454 Pubmed12379098 Pubmed12511643 Reactome Database ID Release 43209828 Reactome, http://www.reactome.org ReactomeREACT_15352 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The first and rate limiting step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase. The enzyme requires iron(II), tetrahydrobiopterin, and dioxygen cofactors for the hydroxylation of L-tryptophan to 5-hydroxytryptophan. Tryptophan hydroxylase belongs to a small family of monooxygenases that utilize tetrahydrobiopterins. Other members are phenylalanine hydroxylase and tyrosine hydroxylase (Fitzpatrick, PF, 1999; Walther et al, 2003). PathwayStep58 Thyroxine is deiodinated to reverse triiodothyronine (RT3) Authored: Jassal, B, 2008-10-01 13:18:42 EC Number: 1.97.1.10 Edited: Jassal, B, 2008-01-08 13:51:41 Pubmed12419801 Pubmed7593630 Reactome Database ID Release 43350869 Reactome, http://www.reactome.org ReactomeREACT_15528 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Type III iodothyronine deiodinase (DIO3) is an integral membrane protein (Baqui M et al, 2003) and catalyzes the conversion of T4 (3,5,3',5'-tetraiodothyronine) into RT3 (3,3',5'-triiodothyronine) and T3 (3,5,3'-triiodothyronine) into T2 (3,3'-diiodothyronine). Both RT3 and T2 are inactive metabolites. It is thought DIO3 plays an essential role for regulation of thyroid hormone inactivation during embryological development. PathwayStep63 PathwayStep64 PathwayStep65 PathwayStep66 PGYL dimer b form Reactome DB_ID: 71581 Reactome Database ID Release 4371581 Reactome, http://www.reactome.org ReactomeREACT_3862 glycogen phosphorylase, liver form, dimer b has a Stoichiometric coefficient of 2 PathwayStep60 PGYL dimer a form Reactome DB_ID: 71586 Reactome Database ID Release 4371586 Reactome, http://www.reactome.org ReactomeREACT_5810 glycogen phosphorylase, liver form, dimer a has a Stoichiometric coefficient of 2 PathwayStep61 Thyrotropin is a heterodimer Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-11-17 10:09:58 Reactome Database ID Release 43378952 Reactome, http://www.reactome.org ReactomeREACT_15498 Reviewed: D'Eustachio, P, 2008-11-29 15:53:45 Thyroid-stimulating hormone (TSH, thyrotropin) is a glycopeptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland which regulates the endocrine function of the thyroid gland. Like other glycoprotein hormones, TSH consists of a common alpha subunit and a beta subunit unique to TSH which determines its specificty. TSH binds to TSH receptor to stimulate the release of the hormones thyroxine (T4) and triiodothyronine (T3). PGYM dimer, b form Reactome DB_ID: 71538 Reactome Database ID Release 4371538 Reactome, http://www.reactome.org ReactomeREACT_4634 glycogen phosphorylase, muscle form, dimer b has a Stoichiometric coefficient of 2 PathwayStep62 PGYM dimer a form Reactome DB_ID: 71513 Reactome Database ID Release 4371513 Reactome, http://www.reactome.org ReactomeREACT_4945 glycogen phosphorylase, muscle form, dimer a has a Stoichiometric coefficient of 2 PGYM b dimer:AMP Reactome DB_ID: 453344 Reactome Database ID Release 43453344 Reactome, http://www.reactome.org ReactomeREACT_21931 has a Stoichiometric coefficient of 2 limit dextrin-glycogenin-1 dimer Reactome DB_ID: 453345 Reactome Database ID Release 43453345 Reactome, http://www.reactome.org ReactomeREACT_21422 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 phosphorylase kinase complex (PHKL) Reactome DB_ID: 71534 Reactome Database ID Release 4371534 Reactome, http://www.reactome.org ReactomeREACT_4025 has a Stoichiometric coefficient of 4 PGYB b dimer:AMP Reactome DB_ID: 453332 Reactome Database ID Release 43453332 Reactome, http://www.reactome.org ReactomeREACT_21818 has a Stoichiometric coefficient of 2 active PYGM and PYGB dimers Converted from EntitySet in Reactome Reactome DB_ID: 453340 Reactome Database ID Release 43453340 Reactome, http://www.reactome.org ReactomeREACT_21554 limit dextrin-glycogenin-2 dimer Reactome DB_ID: 453330 Reactome Database ID Release 43453330 Reactome, http://www.reactome.org ReactomeREACT_22054 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Synthesis of glyoxylate from hydroxyproline Authored: D'Eustachio, P, 2009-01-11 19:48:01 Biochemical studies of rat and bovine liver extracts suggest that conversion of hydroxyproline to glyoxylate takes place in the mitochondria in four steps. The human enzymes that catalyze these reactions have not been identified (Adams and Frank 1980; Adams and Goldstone 1960; Valle et al. 1979; Scholtz and Schuster 1986). In addition, transport processes must exist to enable initially cytosolic hydroxyproline to enter the mitochondria, and to enable the mitochondrial glyoxylate to move to peroxisomes. Edited: D'Eustachio, P, 2009-03-03 14:28:53 Pubmed13681370 Pubmed3942759 Pubmed500817 Pubmed6250440 Reactome Database ID Release 43389859 Reactome, http://www.reactome.org ReactomeREACT_16896 Reviewed: Jassal, B, 2009-03-03 14:29:24 Follitropin is a heterodimer Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-11-17 10:09:58 Follicle-stimulating hormone (FSH, follitropin) is a hormone synthesized and secreted by gonadotropes in the anterior pituitary gland. FSH regulates the reproductive processes of the human body. FSH and Luteinizing hormone (LH) act synergistically in reproduction. In the female ovary, FSH stimulates the growth of immature Graafian follicles to maturation. In males, FSH enhances the production of androgen-binding protein, required for spermatogenesis. Like the other glycoprotein hormones, FSH consists of a common alpha subunit and a unique beta subunit.<br>Inhibins and activins are two closely related complexes which inhibit and activate respectively, FSH synthesis and secretion (Bilezikjian et al, 2006). Pubmed16885530 Pubmed6774759 Reactome Database ID Release 43378975 Reactome, http://www.reactome.org ReactomeREACT_15378 Reviewed: D'Eustachio, P, 2008-11-29 15:53:45 Conversion of glyoxylate to oxalate Authored: D'Eustachio, P, 2009-01-11 19:48:01 EC Number: 1.2.3.5 Edited: D'Eustachio, P, 2009-03-03 14:28:53 Peroxisomal hydroxyacid oxidase 1 catalyzes the reaction of glyoxylate to form oxalate. The active form of the enzyme is associated with FMN and is a tetramer (Jones et al. 2000; Murray et al. 2008; Vignaud et al. 2007; Williams et al. 2000). Pubmed10777549 Pubmed10978532 Pubmed17669354 Pubmed18215067 Reactome Database ID Release 43389862 Reactome, http://www.reactome.org ReactomeREACT_16979 Reviewed: Jassal, B, 2009-03-03 14:29:24 TNF-alpha:TNF-R1 complex Reactome DB_ID: 74277 Reactome Database ID Release 4374277 Reactome, http://www.reactome.org ReactomeREACT_5140 has a Stoichiometric coefficient of 1 glycolate + O2 => glyoxylate + H2O2 Authored: D'Eustachio, P, 2009-01-11 19:48:01 Edited: D'Eustachio, P, 2009-03-03 14:28:53 Peroxisomal hydroxyacid oxidase 1 catalyzes the reaction of glycolate and O2 to form glyoxylate and H2O2. The active form of the enzyme is associated with FMN and is a tetramer (Jones et al. 2000; Murray et al. 2008; Vignaud et al. 2007; Williams et al. 2000). Pubmed10777549 Pubmed10978532 Pubmed17669354 Pubmed18215067 Reactome Database ID Release 43389842 Reactome, http://www.reactome.org ReactomeREACT_17020 Reviewed: Jassal, B, 2009-03-03 14:29:24 Methionine is reformed Cytosolic methionine synthase catalyzes the reaction of 5-methyltetrahydrofolate polyglutamate and homocysteine to form L-methionine and tetrahydrofolate polyglutamate (Leclerc et al. 1996). EC Number: 2.1.1.13 Pubmed8968737 Reactome Database ID Release 43174374 Reactome, http://www.reactome.org ReactomeREACT_6739 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep49 SAM is sythesized from methionine's reaction with ATP Authored: Gopinathrao, G, 2008-05-21 15:52:50 EC Number: 2.5.1.6 Edited: Gopinathrao, G, 2006-04-27 13:13:48 Pubmed12163696 Pubmed9175157 Reactome Database ID Release 43174391 Reactome, http://www.reactome.org ReactomeREACT_6819 Reviewed: D'Eustachio, P, 2008-06-12 14:43:38 S-adenosylmethionine (SAM) is an essential metabolite in all cells. SAM is a precursor in the synthesis of polyamines. Methionine adenosyltransferase (MAT; EC 2.5.1.6) catalyzes the only known SAM biosynthetic reaction from methionine and ATP. In mammalian tissues, three different forms of MAT (MAT I, MAT III and MAT II) have been identified that are the product of two different genes (MAT1A and MAT2A). A third gene MAT2B has been identified and is known to be a part of MAT II heterotetramer complex. PathwayStep48 glyoxylate + alanine => glycine + pyruvate [peroxisome] Alanine-glyoxylate transaminase (AGXT) catalyzes the irreversible reaction of glyoxylate and alanine to form glycine and pyruvate (Danpure and Jennings 1988). The active form of the enzyme is a homodimer (Zhang et al. 2003) with one molecule of pyridoxal phosphate bound to each subunit (Coulter-Mackie et al. 2005). Mutations in this enzyme are associated with primary hyperoxaluria type I. Mutant alleles encode both catalytically inactive proteins and active ones that are mis-localized to mitochondria (Purdue et al. 1990; Takada et al. 1990). Authored: D'Eustachio, P, 2009-01-11 19:48:01 EC Number: 2.6.1.44 Edited: D'Eustachio, P, 2009-03-03 14:28:53 Pubmed12899834 Pubmed15802217 Pubmed1703535 Pubmed2363689 Pubmed3416563 Reactome Database ID Release 43389684 Reactome, http://www.reactome.org ReactomeREACT_16972 Reviewed: Jassal, B, 2009-03-03 14:29:24 PathwayStep47 glycine + O2 => glyoxylate + H2O2 + NH4+ Authored: D'Eustachio, P, 2009-01-11 19:48:01 EC Number: 1.4.3.3 Edited: D'Eustachio, P, 2009-03-03 14:28:53 Peroxisomal D-amino-acid oxidase catalyzes the reaction of glycine, water, and O2 to form glyoxylate, H2O2, and NH4+. The active form of the enzyme is a homodimer and has FAD as a cofactor (Kawazoe et al. 2006; Molla et al. 2006). Pubmed16616139 Pubmed17088322 Reactome Database ID Release 43389821 Reactome, http://www.reactome.org ReactomeREACT_17049 Reviewed: Jassal, B, 2009-03-03 14:29:24 PathwayStep46 glyoxylate + NADPH + H+ => glycolate + NADP+ Authored: D'Eustachio, P, 2009-01-11 19:48:01 EC Number: 1.1.1.79 Edited: D'Eustachio, P, 2009-03-03 14:28:53 Peroxisomal GRHPR catalyzes the reaction of glyoxylate and NADPH + H+ to form glycolate and NADP+. The active form of the enzyme is a monomer (Rumsby and Cregeen 1999); mutations in it are associated with primary hyperoxaluria type II (Cramer et al. 1999). Pubmed10484776 Pubmed10524214 Reactome Database ID Release 43389826 Reactome, http://www.reactome.org ReactomeREACT_16910 Reviewed: Jassal, B, 2009-03-03 14:29:24 PathwayStep45 glyoxylate + alanine => glycine + pyruvate [mitochondrial matrix] Authored: D'Eustachio, P, 2010-07-05 EC Number: 2.6.1.44 Edited: D'Eustachio, P, 2010-07-05 Mitochondrial AGXT2 (alanine-glyoxylate transaminase 2) catalyzes the irreversible reaction of glyoxylate and alanine to form glycine and pyruvate (Rodionov et al. 2010). The active form of the enzyme is inferred to be a homotetramer from the properties of the homologous rat protein, which has been purified and characterized in vitro (Tamaki et al.990). Most conversion of glyoxylate to glycine in vivo appears to occur in the peroxisome, catalyzed by AGXT, and the physiological role of the AGXT2 reaction is unclear. Pubmed20018850 Pubmed2158891 Reactome Database ID Release 43904864 Reactome, http://www.reactome.org ReactomeREACT_25087 Reviewed: Jassal, B, 2010-11-09 PathwayStep54 TRAIL:TRAIL receptor-2:FADD complex Reactome DB_ID: 141137 Reactome Database ID Release 43141137 Reactome, http://www.reactome.org ReactomeREACT_5875 has a Stoichiometric coefficient of 1 PathwayStep55 TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-8 precursor complex Reactome DB_ID: 141133 Reactome Database ID Release 43141133 Reactome, http://www.reactome.org ReactomeREACT_4420 has a Stoichiometric coefficient of 1 PathwayStep52 TRAIL receptor-2:TRAIL complex Reactome DB_ID: 141118 Reactome Database ID Release 43141118 Reactome, http://www.reactome.org ReactomeREACT_5556 has a Stoichiometric coefficient of 1 PathwayStep53 TRAIL receptor-2:TRAIL Trimer Reactome DB_ID: 141126 Reactome Database ID Release 43141126 Reactome, http://www.reactome.org ReactomeREACT_4466 has a Stoichiometric coefficient of 3 PathwayStep50 TRAF2:TRADD:RIP1:FADD Reactome DB_ID: 140977 Reactome Database ID Release 43140977 Reactome, http://www.reactome.org ReactomeREACT_3905 has a Stoichiometric coefficient of 1 PathwayStep51 GYS2 tetramer, I form Reactome DB_ID: 71600 Reactome Database ID Release 4371600 Reactome, http://www.reactome.org ReactomeREACT_4895 glycogen synthase 2 tetramer, I form has a Stoichiometric coefficient of 4 TRADD:TRAF2:RIP1:FADD:Caspase-8 Complex Reactome DB_ID: 140976 Reactome Database ID Release 43140976 Reactome, http://www.reactome.org ReactomeREACT_4646 has a Stoichiometric coefficient of 1 GYS tetramers D form Converted from EntitySet in Reactome GYS1 tetramer, GYS2 tetramer, D forms Reactome DB_ID: 453225 Reactome Database ID Release 43453225 Reactome, http://www.reactome.org ReactomeREACT_21974 glycogen synthase tetramers, D form phosphorylated GYS tetramers TNF-alpha:TNF-R1:TRAPP:RIP1:TRAF2 Complex Reactome DB_ID: 140946 Reactome Database ID Release 43140946 Reactome, http://www.reactome.org ReactomeREACT_2659 has a Stoichiometric coefficient of 1 GYS1 tetramer, D form Reactome DB_ID: 71571 Reactome Database ID Release 4371571 Reactome, http://www.reactome.org ReactomeREACT_4101 glycogen synthase 1 tetramer, D form has a Stoichiometric coefficient of 4 phosphorylated GYS1 tetramer TRAF2:TRADD:RIP1 Complex Reactome DB_ID: 140935 Reactome Database ID Release 43140935 Reactome, http://www.reactome.org ReactomeREACT_3424 has a Stoichiometric coefficient of 1 GYS2 tetramer, D form Reactome DB_ID: 71605 Reactome Database ID Release 4371605 Reactome, http://www.reactome.org ReactomeREACT_3071 glycogen synthase 2 tetramer, D form has a Stoichiometric coefficient of 4 phosphorylated GYS2 tetramer glycogen-glycogenin dimer Converted from EntitySet in Reactome Reactome DB_ID: 453241 Reactome Database ID Release 43453241 Reactome, http://www.reactome.org ReactomeREACT_21802 glycogen-glycogenin-1 dimer Reactome DB_ID: 453239 Reactome Database ID Release 43453239 Reactome, http://www.reactome.org ReactomeREACT_21555 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 glycogen-glycogenin-2 dimer Reactome DB_ID: 453240 Reactome Database ID Release 43453240 Reactome, http://www.reactome.org ReactomeREACT_21523 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 PGYB dimer b form Reactome DB_ID: 71863 Reactome Database ID Release 4371863 Reactome, http://www.reactome.org ReactomeREACT_21896 glycogen phosphorylase, brain form, dimer b has a Stoichiometric coefficient of 2 PGYB dimer a form Reactome DB_ID: 71869 Reactome Database ID Release 4371869 Reactome, http://www.reactome.org ReactomeREACT_21430 glycogen phosphorylase, brain form, tetramer a has a Stoichiometric coefficient of 2 phosphorylase kinase complex (PHKM) Reactome DB_ID: 71520 Reactome Database ID Release 4371520 Reactome, http://www.reactome.org ReactomeREACT_5518 has a Stoichiometric coefficient of 4 TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-10 precursor complex Reactome DB_ID: 141304 Reactome Database ID Release 43141304 Reactome, http://www.reactome.org ReactomeREACT_4656 has a Stoichiometric coefficient of 1 Cystathionine is formed from homocysteine and serine Authored: Stephan, R, 2010-10-24 EC Number: 4.2.1.22 Edited: Jassal, B, 2011-09-29 Pubmed11524006 Reactome Database ID Release 431614524 Reactome, http://www.reactome.org ReactomeREACT_115874 Reviewed: D'Eustachio, P, 2011-10-13 The first step of homocysteine conversion to cysteine is catalyzed by cystathionine beta-lyase, which adds a serine molecule to the substrate. The enzyme is a tetramer with two heme molecules as cofactor (Janosik et al. 2001). Remethylation of homocysteine via betaine degradation Authored: Stephan, R, 2010-10-24 EC Number: 2.1.1.5 Edited: Jassal, B, 2011-09-29 Pubmed18457970 Reactome Database ID Release 431614654 Reactome, http://www.reactome.org ReactomeREACT_115861 Remethylation of homocysteine to methionine can also happen using betaine as a methyl donor. This reaction is also part of choline catabolism (Li et al. 2008). Reviewed: D'Eustachio, P, 2011-10-13 S-adenoylhomocysteine is hydrolyzed At the beginning of this reaction, 1 molecule of 'S-adenosylhomocysteine', and 1 molecule of 'H2O' are present. At the end of this reaction, 1 molecule of 'adenosine', and 1 molecule of 'Homocysteine' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'adenosylhomocysteinase activity' of 'SAH hydrolase homotetramer'.<br> EC Number: 3.3.1.1 Reactome Database ID Release 43174401 Reactome, http://www.reactome.org ReactomeREACT_6756 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 PathwayStep35 Homocysteine is degraded to oxobutanoate and H2S Authored: Stephan, R, 2010-10-24 EC Number: 4.4.1.2 Edited: Jassal, B, 2011-09-29 Excess homocysteine will change the enzymatic activity of CBS such that other reactions than transsulfuration take place. In these reactions, oxobutanoate, lanthionine, and homolanthionine are produced by cystathionine gamma-lyase (CTH) (Chiku et al. 2009, Steegborn et al. 1999) Pubmed10212249 Pubmed19261609 Reactome Database ID Release 431614631 Reactome, http://www.reactome.org ReactomeREACT_116033 Reviewed: D'Eustachio, P, 2011-10-13 PathwayStep34 A dipeptidase cleaves cysteinylglycine A cytosolic, non-specific peptidase can hydrolyze cysteinylglycine to release cysteine and glycine (Tuefel et al, 2003). Authored: Jassal, B, 2011-04-08 Edited: Jassal, B, 2011-04-08 Pubmed12473676 Reactome Database ID Release 431247910 Reactome, http://www.reactome.org ReactomeREACT_75845 Reviewed: D'Eustachio, P, 2011-05-23 PathwayStep37 Glutamate and cysteine combine Authored: Jassal, B, 2006-02-17 10:30:46 EC Number: 6.3.2.2 Edited: Jassal, B, 2011-04-08 Pubmed7826375 Pubmed9675072 Reactome Database ID Release 43174367 Reactome, http://www.reactome.org ReactomeREACT_6970 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The first step in the formation of glutathione is the ligation of glutamate with cysteine, catalyzed by the dimeric protein glutamate-cysteine ligase (Gipp et al, 1995; Misra and Griffith, 1998). PathwayStep36 Cleavage of cystathionine into cysteine Authored: Stephan, R, 2010-10-24 Cystathionine is cleaved to cysteine, oxobutanoate, and ammonia by the alpha,gamma-elimination activity of cystathionine gamma-lyase (CTH) (Chiku et al. 2009, Steegborn et al. 1999). EC Number: 4.4.1.1 Edited: Jassal, B, 2011-09-29 Pubmed10212249 Pubmed19261609 Reactome Database ID Release 431614583 Reactome, http://www.reactome.org ReactomeREACT_116098 Reviewed: D'Eustachio, P, 2011-10-13 PathwayStep39 PathwayStep38 CSAD decarboxylates 3-sulfinoalanine to hypotaurine Authored: Jassal, B, 2011-10-12 Cysteine sulfinic acid decarboxylase (CSAD) mediates the decarboxylase of 3-sulfinoalanine to produce hypotuarine. CSAD functions as a homodimer and requires pyridoxal phosphate as a cofactor. Purification, characterisation and activity of CSAD has been determined from rat liver (Guion-Rain et al. 1975). EC Number: 4.1.1.29 Edited: Jassal, B, 2011-10-12 Pubmed236774 Reactome Database ID Release 431655443 Reactome, http://www.reactome.org ReactomeREACT_115820 Reviewed: D'Eustachio, P, 2011-10-13 Cysteine is oxidized Authored: Stephan, R, 2010-10-24 EC Number: 1.13.11.20 Edited: Jassal, B, 2011-09-29 GENE ONTOLOGYGO:0019448 Oxidation of the thiol moiety of cysteine yields sulfinoalanine, which itself is processed to hypotaurine by an as of yet uncharacterized enzyme in humans . Whether further oxidation of hypotaurine to taurine needs an enzyme is unknown at present (Ye et al. 2007). Pubmed17135237 Reactome Database ID Release 431614645 Reactome, http://www.reactome.org ReactomeREACT_115785 Reviewed: D'Eustachio, P, 2011-10-13 Cysteine is degraded to serine and H2S Authored: Stephan, R, 2010-10-24 EC Number: 4.4.1.1 Edited: Jassal, B, 2011-09-29 Pubmed10212249 Pubmed19261609 Reactome Database ID Release 431614614 Reactome, http://www.reactome.org ReactomeREACT_115816 Reviewed: D'Eustachio, P, 2011-10-13 alpha,beta-elimination activity of cystathionine-gamma-lyase (CTH) replaces the sulfur in cysteine with oxygen from water, resulting in serine and toxic hydrogen sulfide, which is further oxidized in mitochondria (Chiku et al. 2009, Steegborn et al. 1999). phosphoribosyl pyrophosphate synthetase 1 holoenzyme Reactome DB_ID: 73485 Reactome Database ID Release 4373485 Reactome, http://www.reactome.org ReactomeREACT_3747 has a Stoichiometric coefficient of 2 phosphoribosyl pyrophosphate synthetase holoenzyme Converted from EntitySet in Reactome Reactome DB_ID: 189812 Reactome Database ID Release 43189812 Reactome, http://www.reactome.org ReactomeREACT_9780 RPE dimer Reactome DB_ID: 467361 Reactome Database ID Release 43467361 Reactome, http://www.reactome.org ReactomeREACT_21583 has a Stoichiometric coefficient of 2 PathwayStep40 transketolase dimer Reactome DB_ID: 71322 Reactome Database ID Release 4371322 Reactome, http://www.reactome.org ReactomeREACT_3387 has a Stoichiometric coefficient of 2 PathwayStep41 G6PD tetramer Reactome DB_ID: 70375 Reactome Database ID Release 4370375 Reactome, http://www.reactome.org ReactomeREACT_2745 glucose-6-phosphate 1-dehydrogenase tetramer has a Stoichiometric coefficient of 4 PathwayStep42 PGD dimer Reactome DB_ID: 467365 Reactome Database ID Release 43467365 Reactome, http://www.reactome.org ReactomeREACT_21603 has a Stoichiometric coefficient of 2 PathwayStep43 PathwayStep44 HA:HAR:HYAL2 Reactome DB_ID: 2160889 Reactome Database ID Release 432160889 Reactome, http://www.reactome.org ReactomeREACT_124024 has a Stoichiometric coefficient of 1 HA:HAR:HYAL2:SLC9A1 Reactome DB_ID: 2160891 Reactome Database ID Release 432160891 Reactome, http://www.reactome.org ReactomeREACT_124260 has a Stoichiometric coefficient of 1 phosphoriboyl pyrophosphate synthetase 1-like 1 putative holoenzyme Reactome DB_ID: 189817 Reactome Database ID Release 43189817 Reactome, http://www.reactome.org ReactomeREACT_9888 has a Stoichiometric coefficient of 2 phosphoriboyl pyrophosphate synthetase 2 putative holoenzyme Reactome DB_ID: 189814 Reactome Database ID Release 43189814 Reactome, http://www.reactome.org ReactomeREACT_9582 has a Stoichiometric coefficient of 2 Excess homocysteine yields homolanthionine and H2S Authored: Stephan, R, 2010-10-24 EC Number: 4.4 Edited: Jassal, B, 2011-09-29 Excess homocysteine will change the enzymatic activity of CBS such that other reactions than transsulfuration take place. In these reactions, oxobutanoate, lanthionine, and homolanthionine are produced by cystathionine gamma-lyase (CTH) (Chiku et al. 2009, Steegborn et al. 1999) Pubmed10212249 Pubmed19261609 Reactome Database ID Release 431614567 Reactome, http://www.reactome.org ReactomeREACT_115918 Reviewed: D'Eustachio, P, 2011-10-13 has a Stoichiometric coefficient of 2 Oxidation of hypotaurine to taurine EC Number: 1.8.1.3 Pubmed16680400 Reactome Database ID Release 431655453 Reactome, http://www.reactome.org ReactomeREACT_115982 Reviewed: D'Eustachio, P, 2011-10-13 The as yet uncharacterised human enzyme hypotaurine dehydrogenase mediates the oxidation of hypotaurine to produce taurine. All studies to date have been performed predominantly in rat (Nakamura et al. 2006). SQR oxidizes sulfide to bound persulfide Authored: Stephan, R, 2010-10-24 Edited: Jassal, B, 2011-09-29 Pubmed12832624 Pubmed18494801 Reactome Database ID Release 431614665 Reactome, http://www.reactome.org ReactomeREACT_115885 Reviewed: D'Eustachio, P, 2011-10-13 When SQR is in the oxidized state, it can bind hydrogen sulfide as persulfide to one of its own cysteine residue, the electrons being transferred to ubiquinone. After that the additional sulfur is dioxygenated by another enzyme (ETHE1). The activity of human SQR was deduced from the orthologue in <i>Arenicola marina</i> (Theissen et al. 2003, Hildebrandt & Grieshaber 2008). has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Excess cysteine yields lanthionine and H2S Authored: Stephan, R, 2010-10-24 EC Number: 4.4.1.1 Edited: Jassal, B, 2011-09-29 Excess homocysteine will change the enzymatic activity of CBS such that other reactions than transsulfuration take place. In these reactions, oxobutanoate, lanthionine, and homolanthionine are produced by cystathionine gamma-lyase (CTH) (Chiku et al. 2009, Steegborn et al. 1999) Pubmed10212249 Pubmed19261609 Reactome Database ID Release 431614591 Reactome, http://www.reactome.org ReactomeREACT_116121 Reviewed: D'Eustachio, P, 2011-10-13 has a Stoichiometric coefficient of 2 PathwayStep26 Persulfide sulfur is transferred onto sulfite Authored: Stephan, R, 2010-10-24 EC Number: 2.8.1 Edited: Jassal, B, 2011-09-29 Pubmed18494801 Reactome Database ID Release 431614618 Reactome, http://www.reactome.org ReactomeREACT_115702 Reviewed: D'Eustachio, P, 2011-10-13 The main reaction catalyzed by rhodanase is not the name-giving detoxification of cyanide to thiocyanate, but the transfer of a sulfur atom from SQR-S-SH onto sulfite yielding thiosulfate during sulfide oxidation. The activity of human rhodanase was inferred from the rat orthologue by Hildebrandt & Grieshaber, 2008. has a Stoichiometric coefficient of 2 PathwayStep25 Persulfide sulfur is dioxygenated Authored: Stephan, R, 2010-10-24 EC Number: 1.13.11.18 Edited: Jassal, B, 2011-09-29 Pubmed19136963 Reactome Database ID Release 431614605 Reactome, http://www.reactome.org ReactomeREACT_115730 Reviewed: D'Eustachio, P, 2011-10-13 The sulfur dioxygenase ETHE1 converts persulfides to sulfite. Loss of this activity leads to the rare ethylmalonyl encephalopathy where the body can no longer detoxify H2S (Tiranti et al, 2009). has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 PathwayStep24 Sulfite is oxidized to sulfate Authored: Stephan, R, 2010-10-24 EC Number: 1.8.3.1 Edited: Jassal, B, 2011-09-29 Pubmed16475804 Pubmed17459792 Reactome Database ID Release 431614544 Reactome, http://www.reactome.org ReactomeREACT_116081 Reviewed: D'Eustachio, P, 2011-10-13 Sulfite oxidase oxidizes sulfite to sulfate which is among the most important macronutrients in cells and the fourth most abundant anion in human plasma (300 micromolar). The enzyme has a molybdenum-molybdopterin cofactor (MoCo) bound (Wilson et al. 2006, Feng et al. 2007). PathwayStep23 Thiosulfate can transfer its sulfate to glutathione Pubmed6361026 Reactome Database ID Release 431655879 Reactome, http://www.reactome.org ReactomeREACT_115851 Reviewed: D'Eustachio, P, 2011-10-13 Thiosulfate is able to transfer its sulfur atom to glutathione, a reaction investigated in yeast (Chauncey & Westley 1983). No human enzyme has been characterised yet for this reaction. has a Stoichiometric coefficient of 2 ALA is transported from the mitochondrial matrix to the cytosol 5-aminolevulinate is transported from the mitochondrial matrix to the cytosol. The transporter that enables it to cross the inner mitochondrial membrane is unknown. Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Reactome Database ID Release 43189456 Reactome, http://www.reactome.org ReactomeREACT_9454 Reviewed: Sassa, S, 2007-01-24 10:18:36 PathwayStep29 Succinyl CoA and glycine condense to form 5-aminolevulinate (ALA) Authored: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 EC Number: 2.3.1.37 Edited: Jassal, B, D'Eustachio, P, 2007-01-24 10:19:49 Pubmed16121195 Pubmed1939222 Reactome Database ID Release 43189442 Reactome, http://www.reactome.org ReactomeREACT_9463 Reviewed: Sassa, S, 2007-01-24 10:18:36 The committed step for porphyrin synthesis is the formation of 5-aminolevulinate (ALA) by condensation of glycine (from the general amino acid pool) and succinyl-CoA (from the TCA cycle), in the mitochondrial matrix. The reaction is catalyzed by two different ALA synthases, one expressed ubiquitously (ALAS1) and the other only expressed in erythroid precursors (ALAS2). Both enzymes are expressed as homodimers and require pyridoxal 5-phosphate as a cofactor.<br>No disease-causing mutations of ALAS1 have been recognised in humans. Mutations in ALAS2 cause X-linked sideroblastic anaemia (XLSA), characterised by a microcytic hypochromic anaemia. PathwayStep28 PathwayStep27 ((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl)glycogenin dimer Converted from EntitySet in Reactome Reactome DB_ID: 453350 Reactome Database ID Release 43453350 Reactome, http://www.reactome.org ReactomeREACT_21510 ((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl)glycogenin-1 dimer Reactome DB_ID: 453360 Reactome Database ID Release 43453360 Reactome, http://www.reactome.org ReactomeREACT_21540 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ((1,6)-alpha-glucosyl)poly((1,4)-alpha-glucosyl)glycogenin-2 dimer Reactome DB_ID: 453365 Reactome Database ID Release 43453365 Reactome, http://www.reactome.org ReactomeREACT_21903 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 KHK dimers Converted from EntitySet in Reactome Reactome DB_ID: 469698 Reactome Database ID Release 43469698 Reactome, http://www.reactome.org ReactomeREACT_21853 ketohexokinase dimers PathwayStep32 PathwayStep33 PathwayStep30 PathwayStep31 limit dextrin-glycogenin dimer Converted from EntitySet in Reactome Reactome DB_ID: 453336 Reactome Database ID Release 43453336 Reactome, http://www.reactome.org ReactomeREACT_21493 G6PD dimer Reactome DB_ID: 70373 Reactome Database ID Release 4370373 Reactome, http://www.reactome.org ReactomeREACT_4080 glucose-6-phosphate 1-dehydrogenase dimer has a Stoichiometric coefficient of 2 KHK, isoform A, dimer Reactome DB_ID: 469699 Reactome Database ID Release 43469699 Reactome, http://www.reactome.org ReactomeREACT_22042 has a Stoichiometric coefficient of 2 ketohexokinase, isoform A, dimer KHK, isoform C, dimer Reactome DB_ID: 469715 Reactome Database ID Release 43469715 Reactome, http://www.reactome.org ReactomeREACT_21574 has a Stoichiometric coefficient of 2 ketohexokinase, isoform C, dimer GALE dimer Reactome DB_ID: 70363 Reactome Database ID Release 4370363 Reactome, http://www.reactome.org ReactomeREACT_3698 has a Stoichiometric coefficient of 2 G6PD dimer and tetramer Converted from EntitySet in Reactome Reactome DB_ID: 464971 Reactome Database ID Release 43464971 Reactome, http://www.reactome.org ReactomeREACT_21436 RBL1:Cyclin E/A:CDK2 Reactome DB_ID: 1363310 Reactome Database ID Release 431363310 Reactome, http://www.reactome.org ReactomeREACT_111400 has a Stoichiometric coefficient of 1 p107:Cyclin E/A:CDK2 Cyclin E/A:Cdk2 Reactome DB_ID: 187496 Reactome Database ID Release 43187496 Reactome, http://www.reactome.org ReactomeREACT_9091 has a Stoichiometric coefficient of 1 RBL2:Cyclin E/A:CDK2 Reactome DB_ID: 1363301 Reactome Database ID Release 431363301 Reactome, http://www.reactome.org ReactomeREACT_111575 has a Stoichiometric coefficient of 1 p130:Cyclin E/A:CDK2 RBL1:E2F4:DP1/2:Cyclin E/A:CDK2 Reactome DB_ID: 1363307 Reactome Database ID Release 431363307 Reactome, http://www.reactome.org ReactomeREACT_111813 has a Stoichiometric coefficient of 1 p107:E2F4:DP1/2:Cyclin E/A:CDK2 RBL1:E2F4:DP1/2 Reactome DB_ID: 1226088 Reactome Database ID Release 431226088 Reactome, http://www.reactome.org ReactomeREACT_111376 has a Stoichiometric coefficient of 1 p107:E2F4:DP1/2 DREAM complex Reactome DB_ID: 1362264 Reactome Database ID Release 431362264 Reactome, http://www.reactome.org ReactomeREACT_111426 has a Stoichiometric coefficient of 1 HDAC1:RBL2:E2F4/5:DP1/2 HDAC1:p130:E2F4/5:DP1/2 Reactome DB_ID: 1227666 Reactome Database ID Release 431227666 Reactome, http://www.reactome.org ReactomeREACT_111840 has a Stoichiometric coefficient of 1 HDAC1:RBL1:E2F4:DP1/2 HDAC1:p107:E2F4:DP1/2 Reactome DB_ID: 1227668 Reactome Database ID Release 431227668 Reactome, http://www.reactome.org ReactomeREACT_111485 has a Stoichiometric coefficient of 1 Cyclin D:CDK4/6:p21/p27 complex Reactome DB_ID: 69210 Reactome Database ID Release 4369210 Reactome, http://www.reactome.org ReactomeREACT_2341 has a Stoichiometric coefficient of 1 RBL2:E2F4/5:DP1/2:Cyclin E/A:CDK2 Reactome DB_ID: 1363300 Reactome Database ID Release 431363300 Reactome, http://www.reactome.org ReactomeREACT_111339 has a Stoichiometric coefficient of 1 p130:E2F4/5:DP1/2:Cyclin E/A:CDK2 15k-PGD2/E2/F2a Converted from EntitySet in Reactome Reactome DB_ID: 2161597 Reactome Database ID Release 432161597 Reactome, http://www.reactome.org ReactomeREACT_151444 PGD2/E2/F2a Converted from EntitySet in Reactome Reactome DB_ID: 2161661 Reactome Database ID Release 432161661 Reactome, http://www.reactome.org ReactomeREACT_150622 Cyclin B:phospho-Cdc2(Thr 14) Reactome DB_ID: 170069 Reactome Database ID Release 43170069 Reactome, http://www.reactome.org ReactomeREACT_6524 has a Stoichiometric coefficient of 1 Cyclin B:Cdc2 complex Reactome DB_ID: 170077 Reactome Database ID Release 43170077 Reactome, http://www.reactome.org ReactomeREACT_6447 has a Stoichiometric coefficient of 1 ATR-ATRIP-RPA-ssDNA signaling complex Reactome DB_ID: 176281 Reactome Database ID Release 43176281 Reactome, http://www.reactome.org ReactomeREACT_7037 has a Stoichiometric coefficient of 1 RPA-ssDNA complex RPA complexed to ssDNA Reactome DB_ID: 176293 Reactome Database ID Release 43176293 Reactome, http://www.reactome.org ReactomeREACT_7172 has a Stoichiometric coefficient of 1 Rad17-RFC complex bound to DNA Reactome DB_ID: 176204 Reactome Database ID Release 43176204 Reactome, http://www.reactome.org ReactomeREACT_7502 has a Stoichiometric coefficient of 1 Rad17-RFC complex Reactome DB_ID: 176353 Reactome Database ID Release 43176353 Reactome, http://www.reactome.org ReactomeREACT_7804 has a Stoichiometric coefficient of 1 Rad9-Hus1-Rad1 bound to DNA Reactome DB_ID: 176256 Reactome Database ID Release 43176256 Reactome, http://www.reactome.org ReactomeREACT_7267 has a Stoichiometric coefficient of 1 9-1-1 complex Rad9-Hus1-Rad1 complex Reactome DB_ID: 176312 Reactome Database ID Release 43176312 Reactome, http://www.reactome.org ReactomeREACT_7593 has a Stoichiometric coefficient of 1 Activated claspin bound to DNA replication fork Cdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complex Reactome DB_ID: 176182 Reactome Database ID Release 43176182 Reactome, http://www.reactome.org ReactomeREACT_7262 has a Stoichiometric coefficient of 1 claspin bound to DNA replication fork Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complex Reactome DB_ID: 176229 Reactome Database ID Release 43176229 Reactome, http://www.reactome.org ReactomeREACT_7273 has a Stoichiometric coefficient of 1 Kinetochore:Mad1:MAD2* Complex Reactome DB_ID: 141432 Reactome Database ID Release 43141432 Reactome, http://www.reactome.org ReactomeREACT_5238 has a Stoichiometric coefficient of 1 Kinetochore:Mad1:MAD2 Complex Reactome DB_ID: 141427 Reactome Database ID Release 43141427 Reactome, http://www.reactome.org ReactomeREACT_4828 has a Stoichiometric coefficient of 1 Mad1:kinetochore complex Reactome DB_ID: 141441 Reactome Database ID Release 43141441 Reactome, http://www.reactome.org ReactomeREACT_5632 has a Stoichiometric coefficient of 1 15k-PGE2/F2a Converted from EntitySet in Reactome Reactome DB_ID: 2161650 Reactome Database ID Release 432161650 Reactome, http://www.reactome.org ReactomeREACT_151621 MCC:APC/C complex Reactome DB_ID: 141410 Reactome Database ID Release 43141410 Reactome, http://www.reactome.org ReactomeREACT_3955 has a Stoichiometric coefficient of 1 phosphorylated anaphase promoting complex (APC/C) Reactome DB_ID: 174191 Reactome Database ID Release 43174191 Reactome, http://www.reactome.org ReactomeREACT_7058 has a Stoichiometric coefficient of 1 hBUBR1:hBUB3:MAD2*:CDC20 complex Reactome DB_ID: 141440 Reactome Database ID Release 43141440 Reactome, http://www.reactome.org ReactomeREACT_5836 has a Stoichiometric coefficient of 1 MAD2*CDC20 complex Reactome DB_ID: 141408 Reactome Database ID Release 43141408 Reactome, http://www.reactome.org ReactomeREACT_2295 has a Stoichiometric coefficient of 1 RBL2:E2F4/5:DP1/2 Reactome DB_ID: 1226089 Reactome Database ID Release 431226089 Reactome, http://www.reactome.org ReactomeREACT_111674 has a Stoichiometric coefficient of 1 p130:E2F4/5:DP1/2 p-MuvB complex Reactome DB_ID: 1362259 Reactome Database ID Release 431362259 Reactome, http://www.reactome.org ReactomeREACT_111785 has a Stoichiometric coefficient of 1 MuvB complex LIN9:LIN37:LIN52:LIN54:RBBP4 Reactome DB_ID: 1362248 Reactome Database ID Release 431362248 Reactome, http://www.reactome.org ReactomeREACT_111706 has a Stoichiometric coefficient of 1 dhk-PGE2/F2a Converted from EntitySet in Reactome Reactome DB_ID: 2161684 Reactome Database ID Release 432161684 Reactome, http://www.reactome.org ReactomeREACT_150521 TGFB1:TGFBR2:p-TGFBR1:Smad7:SMURF2 Reactome DB_ID: 2169039 Reactome Database ID Release 432169039 Reactome, http://www.reactome.org ReactomeREACT_124881 has a Stoichiometric coefficient of 1 Smad7:SMURF2 Reactome DB_ID: 2167863 Reactome Database ID Release 432167863 Reactome, http://www.reactome.org ReactomeREACT_123096 has a Stoichiometric coefficient of 1 DCC:DIP13alpha:Caspase-9 Reactome DB_ID: 373664 Reactome Database ID Release 43373664 Reactome, http://www.reactome.org ReactomeREACT_22628 has a Stoichiometric coefficient of 1 Unc5B with death domain:DAPK Reactome DB_ID: 418842 Reactome Database ID Release 43418842 Reactome, http://www.reactome.org ReactomeREACT_23335 has a Stoichiometric coefficient of 1 UNC5A:NRAGE Reactome DB_ID: 374596 Reactome Database ID Release 43374596 Reactome, http://www.reactome.org ReactomeREACT_23063 has a Stoichiometric coefficient of 1 p-2S-SMAD2/3:SMAD4:SKI/SKIL:Rnf11 Reactome DB_ID: 2186742 Reactome Database ID Release 432186742 Reactome, http://www.reactome.org ReactomeREACT_122477 has a Stoichiometric coefficient of 1 ERBB4 binds NRGs or EGF-like ligands All three ERBB4 isoforms are activated by binding of neuregulins (NRG1, NRG2, NRG3 and NRG4) or EGF like growth factors (betacellulin, epiregulin, HB EGF) to their extracellular domain. Authored: Orlic-Milacic, M, 2011-11-04 ERBB4 binds neuregulins or EGF-like ligands Edited: Matthews, L, 2011-11-07 NRGs/EGF-like ligands + ERBB4 => NRGs/EGF-like ligands:ERBB4 Pubmed17545517 Pubmed7929212 Pubmed9135143 Pubmed9168115 Pubmed9275162 Pubmed9556621 Reactome Database ID Release 431236398 Reactome, http://www.reactome.org ReactomeREACT_115812 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 has a Stoichiometric coefficient of 3 polyubiquitinated PAK-2p34 Reactome DB_ID: 211768 Reactome Database ID Release 43211768 Reactome, http://www.reactome.org ReactomeREACT_13958 has a Stoichiometric coefficient of 1 PAK-2p34:RHG10 complex Reactome DB_ID: 211701 Reactome Database ID Release 43211701 Reactome, http://www.reactome.org ReactomeREACT_14362 has a Stoichiometric coefficient of 1 perinuclear PAK-2p34:RHG10 complex Reactome DB_ID: 211729 Reactome Database ID Release 43211729 Reactome, http://www.reactome.org ReactomeREACT_14389 has a Stoichiometric coefficient of 1 DCC:DIP13alpha Reactome DB_ID: 373668 Reactome Database ID Release 43373668 Reactome, http://www.reactome.org ReactomeREACT_23064 has a Stoichiometric coefficient of 1 Ubiquitinated RNF41 binds P-USP8 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed17210635 Reactome Database ID Release 431358797 Reactome, http://www.reactome.org ReactomeREACT_116151 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Ubiquitinated RNF41 binds deubiquitinating enzyme USP8, previously activated by phosphorylation on threonine residue T945. Phosphorylation of USP8 by P-AKT Activated AKT phosphorylates USP8, thereby stabilizing it and allowing it to deubiquitinate NRDP1, which results in increased NRDP1 level and downregulation of ERBB3. This represents a negative feedback loop in ERBB3-mediated signaling. Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.11 Edited: Matthews, L, 2011-11-07 Pubmed17210635 Reactome Database ID Release 431358791 Reactome, http://www.reactome.org ReactomeREACT_116065 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 RNF41 binds neuregulin-activated ERBB3 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 In addition to regulating the level of unstimulated ERBB3, ubiquitin ligase RNF41 is able to interact with neuregulin-activated ERBB3. Pubmed17210635 Reactome Database ID Release 431358798 Reactome, http://www.reactome.org ReactomeREACT_116128 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Deubiquitination of RNF41 by P-USP8 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Phosphorylated USP8 deubiquitinates RNF41 and increases RNF41 level in the cell. Pubmed17210635 Reactome Database ID Release 431358795 Reactome, http://www.reactome.org ReactomeREACT_115763 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 CHIP (STUB1) mediates ubiquitination of ERBB2 Authored: Orlic-Milacic, M, 2011-11-04 E3 ubiquitin ligase CHIP (STUB1) mediates ERBB2 ubiquitination by associating with the ERBB2 indirectly, through the chaperone protein HSP90. CHIP (STUB1) ubiquitinates both ERBB2 and HSP90, leading to their proteasome-dependent degradation. Ubiquitination of ERBB2 by CHIP (STUB1) is independent of ERBB2 activation. EC Number: 6.3.2.19 Edited: Matthews, L, 2011-11-07 Pubmed12239347 Reactome Database ID Release 431918092 Reactome, http://www.reactome.org ReactomeREACT_116015 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 has a Stoichiometric coefficient of 2 RNF41 ubiquitinates activated ERBB3 Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 6.3.2.19 Edited: Matthews, L, 2011-11-07 Pubmed17210635 RNF41 ubiquitinates activated ERBB3, thereby downregulating ERBB3-mediated signaling. This reaction is part of a negative feedback loop in ERBB2:ERBB3 signaling. Reactome Database ID Release 431358792 Reactome, http://www.reactome.org ReactomeREACT_115599 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Chondroitin chains Converted from EntitySet in Reactome Reactome DB_ID: 2065257 Reactome Database ID Release 432065257 Reactome, http://www.reactome.org ReactomeREACT_121412 MATK (CSK homologous kinase) binds phosphorylated ERBB2 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 MATK (also known as CHK or CSK homologous kinase) binds to ERBB2 through phosphorylated tyrosine residue Y1253 in the C-tail of ERBB2 and, through an unknown mechanism, inhibits ERBB2 downstream signaling. Pubmed9461599 Reactome Database ID Release 431963563 Reactome, http://www.reactome.org ReactomeREACT_115602 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 CUL5 mediates ubiquitination of ERBB2 Authored: Orlic-Milacic, M, 2011-11-04 E3 ubiquitin ligase Cullin-5 (CUL5) is recruited to the ERBB2 site at the plasma membrane and ubiquitinates ERBB2 in an HSP90-dependent way, targeting it for degradation. Ubiquitination of ERBB2 by CUL5 appears to be independent of CUL5 adaptor proteins ElonginB and ElonginC. EC Number: 6.3.2.19 Edited: Matthews, L, 2011-11-07 Pubmed19933325 Reactome Database ID Release 431918095 Reactome, http://www.reactome.org ReactomeREACT_115557 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Self-ubiquitination of RNF41 Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 6.3.2.19 Edited: Matthews, L, 2011-11-07 Pubmed12411582 RNF41 is able to self-ubiquitinate, which keeps its levels low when ERBB3 is unstimulated. Reactome Database ID Release 431358789 Reactome, http://www.reactome.org ReactomeREACT_115963 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Cyclin B1:phospho-Cdc2(Thr 161, Thr 14, Tyr 15) Reactome DB_ID: 170065 Reactome Database ID Release 43170065 Reactome, http://www.reactome.org ReactomeREACT_6704 has a Stoichiometric coefficient of 1 phospho-Cdc25C:14-3-3 protein complex Reactome DB_ID: 75005 Reactome Database ID Release 4375005 Reactome, http://www.reactome.org ReactomeREACT_4474 has a Stoichiometric coefficient of 1 Cyclin B1:phospho-Cdc2 (Thr 14, Thr 161) Reactome DB_ID: 170073 Reactome Database ID Release 43170073 Reactome, http://www.reactome.org ReactomeREACT_6474 has a Stoichiometric coefficient of 1 Ubiquitinated Phospho-Cdc25A Reactome DB_ID: 69589 Reactome Database ID Release 4369589 Reactome, http://www.reactome.org ReactomeREACT_4164 has a Stoichiometric coefficient of 1 ATR-ATRIP ATM- and rad3-related (ATR) ATR-interacting protein (ATRIP) Reactome DB_ID: 176269 Reactome Database ID Release 43176269 Reactome, http://www.reactome.org ReactomeREACT_7002 has a Stoichiometric coefficient of 1 Cyclin E:Cdk2 complexes Reactome DB_ID: 68374 Reactome Database ID Release 4368374 Reactome, http://www.reactome.org ReactomeREACT_5247 has a Stoichiometric coefficient of 1 Cyclin E:Cdk2:p21/p27 complex Reactome DB_ID: 68376 Reactome Database ID Release 4368376 Reactome, http://www.reactome.org ReactomeREACT_3804 has a Stoichiometric coefficient of 1 ERBB3 binds RNF41 ubiquitin ligase Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed17210635 RNF41 ubiquitin ligase is able to bind unstimulated ERBB3. Reactome Database ID Release 431358801 Reactome, http://www.reactome.org ReactomeREACT_115643 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 p53 tetramer Reactome DB_ID: 349474 Reactome Database ID Release 43349474 Reactome, http://www.reactome.org ReactomeREACT_20792 has a Stoichiometric coefficient of 4 RNF41 ubiquitinates ERBB3 Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 6.3.2.19 Edited: Matthews, L, 2011-11-07 Pubmed17210635 RNF41 ubiquitinates unstimulated ERBB3, targeting it for degradation and regulating ERBB3 level in the cell. Reactome Database ID Release 431358790 Reactome, http://www.reactome.org ReactomeREACT_115952 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 ubiquitinated phospho-COP1(ser-387) Reactome DB_ID: 349433 Reactome Database ID Release 43349433 Reactome, http://www.reactome.org ReactomeREACT_21146 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Phospho-COP1(Ser-387):p53 complex Reactome DB_ID: 349420 Reactome Database ID Release 43349420 Reactome, http://www.reactome.org ReactomeREACT_21189 has a Stoichiometric coefficient of 1 Recruitment of catalytic PI3K subunit p110 (PIK3CA) by PIK3R1 bound to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR Authored: Orlic-Milacic, M, 2011-11-04 Catalytic subunit p110 of PI3K (PIK3CA) is recruited by the regulatory p85 subunit of PI3K (PIK3R1) bound to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR. Edited: Matthews, L, 2011-11-07 Pubmed15059917 Reactome Database ID Release 431306966 Reactome, http://www.reactome.org ReactomeREACT_115734 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Binding of PI3K subunit p85 (PIK3R1) to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR. Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed15059917 Reactome Database ID Release 431306965 Reactome, http://www.reactome.org ReactomeREACT_115532 Regulatory subunit p85 of PI3K (PIK3R1) binds GAB1 in complex with GRB2 and phosphorylated ERBB2:EGFR heterodimer. Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Binding of GRB2:GAB1 to p-ERBB2:p-EGFR Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 GAB1 in complex with GRB2 is recruited to activated ERBB2:EGFR heterodimer through phosphorylated tyrosine residues that serve as docking sites for GRB2. Pubmed15059917 Reactome Database ID Release 431306963 Reactome, http://www.reactome.org ReactomeREACT_116087 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 PIP2 to PIP3 conversion by PI3K bound to phosphorylated heterodimer of ERBB2 and ERBB4 CYT1 Active PI3K in complex with phosphorylated ERBB2:ERBB4cyt1 heterodimer phosphorylates PIP2 into PIP3, leading to activation of AKT signaling. Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.1.153 Edited: Matthews, L, 2011-11-07 Pubmed10722704 Reactome Database ID Release 431306979 Reactome, http://www.reactome.org ReactomeREACT_116057 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 GRB7 binds phosphorylated heterodimer of ERBB2 and ERBB3 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Phosphorylated tyrosine residues Y1199 and Y1262 of ERBB3 in complex with ERBB2 are docking sites for GRB7 binding. Pubmed9516479 Reactome Database ID Release 431306953 Reactome, http://www.reactome.org ReactomeREACT_115703 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 PLCG1 phosphorylation by p-EGFR:p-ERBB2 Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: Matthews, L, 2011-11-07 Phospholipase C gamma 1 (PLCG1) is phosphorylated by phosphorylated EGFR:ERBB2 heterodimer. Pubmed1672440 Pubmed8940074 Reactome Database ID Release 431251922 Reactome, http://www.reactome.org ReactomeREACT_115882 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 has a Stoichiometric coefficient of 4 PLCG1 binds to p-ERBB2:p-EGFR Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Phospholipase C gamma 1 (PLCG1) binds to phosphorylated ERBB2:EGFR heterodimer Phospholipase C gamma 1 (PLCG1) binds to phosphorylated tyrosine Y1023 of ERBB2 or phosphorylated tyrosines Y992 and Y1173 of EGFR. Pubmed10473558 Pubmed1672440 Pubmed8940074 Reactome Database ID Release 431251944 Reactome, http://www.reactome.org ReactomeREACT_115579 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 C4S/C6S chains Converted from EntitySet in Reactome Reactome DB_ID: 2065251 Reactome Database ID Release 432065251 Reactome, http://www.reactome.org ReactomeREACT_122110 PIP2 to PIP3 conversion by PI3K bound to GRB2:GAB1 in complex with phosphorylated heterodimer of ERBB2 and EGFR Active PI3K in complex with p-EGFR:p-ERBB2:GRB2:GAB1 phosphorylates PIP2 into PIP3, leading to activation of AKT signaling. Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.1.153 Edited: Matthews, L, 2011-11-07 Pubmed15059917 Reactome Database ID Release 431306957 Reactome, http://www.reactome.org ReactomeREACT_115673 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 active caspase-6 Reactome DB_ID: 352255 Reactome Database ID Release 43352255 Reactome, http://www.reactome.org ReactomeREACT_14257 has a Stoichiometric coefficient of 1 Caspase-8 dimer Reactome DB_ID: 351836 Reactome Database ID Release 43351836 Reactome, http://www.reactome.org ReactomeREACT_13946 has a Stoichiometric coefficient of 1 active caspase-7 Reactome DB_ID: 351937 Reactome Database ID Release 43351937 Reactome, http://www.reactome.org ReactomeREACT_14263 has a Stoichiometric coefficient of 1 DFF45:DFF40 complex Reactome DB_ID: 211192 Reactome Database ID Release 43211192 Reactome, http://www.reactome.org ReactomeREACT_14626 has a Stoichiometric coefficient of 2 importin-alpha:importin-beta Reactome DB_ID: 350277 Reactome Database ID Release 43350277 Reactome, http://www.reactome.org ReactomeREACT_13986 has a Stoichiometric coefficient of 1 DFF:associated with the importin-alpha:importin-beta complex Reactome DB_ID: 350304 Reactome Database ID Release 43350304 Reactome, http://www.reactome.org ReactomeREACT_14680 has a Stoichiometric coefficient of 1 DFF:associated with the importin-alpha:importin-beta complex Reactome DB_ID: 350287 Reactome Database ID Release 43350287 Reactome, http://www.reactome.org ReactomeREACT_14003 has a Stoichiometric coefficient of 1 DFF45:DFF40 complex Reactome DB_ID: 211225 Reactome Database ID Release 43211225 Reactome, http://www.reactome.org ReactomeREACT_12695 has a Stoichiometric coefficient of 2 PIP2 to PIP3 conversion by PI3K bound to phosphorylated heterodimer of ERBB2 and ERBB3 Activated PI3K complex directly bound to phosphorylated heterodimer of ERBB2 and ERBB3 phosphorylates PIP2 and converts it into PIP3, leading to activation of AKT signaling. Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.1.153 Edited: Matthews, L, 2011-11-07 Pubmed19411071 Reactome Database ID Release 431250462 Reactome, http://www.reactome.org ReactomeREACT_116116 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Binding of p85 subunit of PI3K (PIK3R1) to p-ERBB2:p-ERBB4 CYT-1 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed18721752 Pubmed8617750 Reactome Database ID Release 431250346 Reactome, http://www.reactome.org ReactomeREACT_115895 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 p85 subunit of PI3K (PIK3R1) directly binds to any of the two phosphorylated ERBB4 CYT1 isoforms in complex with ERBB2 through interaction with a phosphorylated tyrosine residue in the C-tail of ERBB4 CYT1 (Y1056 in ERBB4 JM-A CYT1; Y1046 in ERBB4 JM-B CYT1). Recruitment of PI3K subunit p110 (PIK3CA) by PIK3R1bound to ERBB2:ERBB4cyt1 heterodimer. Authored: Orlic-Milacic, M, 2011-11-04 Catalytic subunit p110 of PI3K (PIK3CA) is recruited by the regulatory p85 subunit of PI3K (PIK3R1) directly bound to phosphorylated ERBB2:ERBB4cyt1 heterodimer, resulting in the assembly of an active PI3K complex. Edited: Matthews, L, 2011-11-07 Pubmed10722704 Reactome Database ID Release 431306980 Reactome, http://www.reactome.org ReactomeREACT_115622 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 active caspase-6 Reactome DB_ID: 350324 Reactome Database ID Release 43350324 Reactome, http://www.reactome.org ReactomeREACT_14343 has a Stoichiometric coefficient of 1 active caspase 3 Reactome DB_ID: 202920 Reactome Database ID Release 43202920 Reactome, http://www.reactome.org ReactomeREACT_12262 has a Stoichiometric coefficient of 1 RAS guanyl nucleotide exchange mediated by SOS1 bound to GRB2 in complex with phosphorylated ERBB4:ERBB2 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed8622888 Reactome Database ID Release 431306972 Reactome, http://www.reactome.org ReactomeREACT_115675 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 SOS1 bound to GRB2 in complex with any of the phosphorylated ERBB2:ERBB4 heterodimers catalyzes guanyl-nucleotide exchange on RAS, leading to the activation of the MAP kinase cascade. GRB2:SOS1 complex binds phosphorylated ERBB4:ERBB2 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 GRB2:SOS1 complex binds to phosphorylated tyrosine residue Y1139 of ERBB2 in complex with ERBB4. Pubmed8622888 Reactome Database ID Release 431306969 Reactome, http://www.reactome.org ReactomeREACT_116140 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Recruitment of PI3K subunit p110 (PIK3CA) by PIK3R1 bound to phosphorylated heterodimer of ERBB2 and ERBB3. Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 PI3K subunit p85 (PIK3R1) bound to ERBB2:p-ERBB3 recruits PI3K subunit p110 (PIK3CA) to form an active PI3K complex. Pubmed19411071 Reactome Database ID Release 431250466 Reactome, http://www.reactome.org ReactomeREACT_116108 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Binding of PI3K subunit p85 (PIK3R1) to ERBB2:P-ERBB3 heterodimer Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Membrane associated p85 subunit of PI3K (PIK3R1) binds to phosphorylated tyrosine residues of ERBB3 (Y1054, Y1197, Y1222, Y1224, Y1276 and Y1289) in complex with ERBB2. Pubmed17652160 Reactome Database ID Release 431250189 Reactome, http://www.reactome.org ReactomeREACT_115880 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and p-SHC1:Phosphorylated ERBB2 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed8530511 Reactome Database ID Release 431250463 Reactome, http://www.reactome.org ReactomeREACT_116041 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 SOS1, bound to GRB2 in complex with phosphorylated SHC1 and phosphorylated ERBB2 dimers, catalyzes guanyl-nucleotide exchange on RAS. RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and phosphorylated EGFR:ERBB2 heterodimers. Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed7970720 Reactome Database ID Release 431250498 Reactome, http://www.reactome.org ReactomeREACT_115771 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 SOS1 bound to GRB2 in complex with phosphorylated ERBB2:EGFR heterodimer catalyzes guanyl-nucleotide exchange on RAS, leading to activation of the MAP kinase cascade. GRB2:SOS1 complex binds phosphorylated EGFR:ERBB2 heterodimer Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Phosphorylated ERBB2:EGFR heterodimer recruits GRB2:SOS1 complex through phosphorylated tyrosine residues on either ERBB2 or EGFR that serve as direct docking sites for GRB2. Pubmed8530511 Reactome Database ID Release 431250488 Reactome, http://www.reactome.org ReactomeREACT_116115 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 caspase 3/caspase 7 Converted from EntitySet in Reactome Reactome DB_ID: 202877 Reactome Database ID Release 43202877 Reactome, http://www.reactome.org ReactomeREACT_12368 Histone H1 bound chromatin DNA Reactome DB_ID: 211238 Reactome Database ID Release 43211238 Reactome, http://www.reactome.org ReactomeREACT_14129 has a Stoichiometric coefficient of 1 DFF40 associated with chromatin Reactome DB_ID: 211253 Reactome Database ID Release 43211253 Reactome, http://www.reactome.org ReactomeREACT_14402 has a Stoichiometric coefficient of 1 caspase-3-cleaved DFF45 (117,224):DFF40 complex Reactome DB_ID: 211196 Reactome Database ID Release 43211196 Reactome, http://www.reactome.org ReactomeREACT_13244 has a Stoichiometric coefficient of 2 DFF40 homodimer Reactome DB_ID: 350273 Reactome Database ID Release 43350273 Reactome, http://www.reactome.org ReactomeREACT_14622 has a Stoichiometric coefficient of 2 ubiquitinated PAK-2p34 Reactome DB_ID: 213047 Reactome Database ID Release 43213047 Reactome, http://www.reactome.org ReactomeREACT_14454 has a Stoichiometric coefficient of 1 HMGB1/HMGB2- bound chromatin Reactome DB_ID: 266207 Reactome Database ID Release 43266207 Reactome, http://www.reactome.org ReactomeREACT_14370 has a Stoichiometric coefficient of 1 DFF cleaved DNA Reactome DB_ID: 211254 Reactome Database ID Release 43211254 Reactome, http://www.reactome.org ReactomeREACT_14657 has a Stoichiometric coefficient of 1 SHC1 phosphorylation by ERBB2 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: Matthews, L, 2011-11-07 Once bound to ERBB2 heterodimers, SHC1 is phosphorylated on tyrosine residues by the tyrosine kinase activity of either ERBB2 or its heterodimerization partners EGFR and ERBB4. Pubmed8036006 Pubmed8101647 Reactome Database ID Release 431250195 Reactome, http://www.reactome.org ReactomeREACT_115850 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 has a Stoichiometric coefficient of 2 active caspase-3 Reactome DB_ID: 211223 Reactome Database ID Release 43211223 Reactome, http://www.reactome.org ReactomeREACT_13159 has a Stoichiometric coefficient of 1 Recruitment of GRB2:SOS1 to p-SHC1 in complex with phosphorylated ERBB2 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Phosphorylated SHC1 bound to phosphorylated ERBB2 dimers recruits GRB2:SOS1 complex. Pubmed8530511 Reactome Database ID Release 431250486 Reactome, http://www.reactome.org ReactomeREACT_116127 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Caspase cleaved DFF45 (117) Reactome DB_ID: 211208 Reactome Database ID Release 43211208 Reactome, http://www.reactome.org ReactomeREACT_13101 has a Stoichiometric coefficient of 2 Trans-autophosphorylation of ERBB2 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Dimers of ERBB2 and EGF-bound EGFR trans-autophosphorylate on six EGFR tyrosine residues and six ERBB2 tyrosine residues to form phosphorylated heterodimers that activate downstream signaling cascades (Ricci et al. 1995, Pinkas-Kramarski et al. 1996, Walton et al. 1990, Margolis et al. 1989, Hazan et al. 1990, Helin et al. 1991). <br><br> In heterodimers of ERBB2 and neuregulin-stimulated ERBB3, ERBB2 phosphorylates ERBB3 on tyrosine residues that serve as docking sites for p85 subunit of PI3K (Y1054, Y1197, Y1222, Y1224, Y1260, Y1276 and Y1289), as well as SHC1 (Y1328) and GRB7 (Y1199 and Y1262). Since ERBB3 lacks catalytic activity, it cannot phosphorylate ERBB2. Hovewer, since ERBB2:ERBB3 heterodimers usually oligomerize on the cell surface, ERBB2 can become trans-autophosphorylated by and adjacent ERBB2 protein. It is not known if ERBB2 in the ERBB2:ERBB3 hetero-oligomer is phosphorylated on all conserved tyrosine residues and if the phosphorylation status of ERBB2 in the ERBB2:ERBB3 hetero-oligoimer significantly affects signaling (Li et al. 2007, Pinkas-Kramarski et al. 1996, Prigent et al. 1994, Vijapurkar et al. 2003, Wallasch et al. 1995). <br><br> Heterodimers of ERBB2 and ERBB4 trans-autophosphorylate on tyrosine residues that serve as docking sites for PLC-gamma, GRB2 and SHC1, as well as p85 subunit of PI3K (PIK3R1) in the case of ERBB2 heterodimers with ERBB4 CYT1 isoforms (ERBB4cyt1) - ERBB4 JM-A CYT1 and ERBB4 JM-B-CYT1 (Li et al. 2007, Kaushansky et al. 2008, Hazan et al. 1990, Cohen et al. 1996). EC Number: 2.7.10 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Pubmed12651161 Pubmed1688559 Pubmed16978839 Pubmed1706616 Pubmed18721752 Pubmed2022652 Pubmed2543678 Pubmed7478576 Pubmed7556068 Pubmed8026468 Pubmed8617750 Pubmed8665853 Reactome Database ID Release 431963582 Reactome, http://www.reactome.org ReactomeREACT_116044 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 has a Stoichiometric coefficient of 43 SHC1 binds phosphorylated ERBB2 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed18721752 Pubmed8617750 Pubmed8665853 Reactome Database ID Release 431963578 Reactome, http://www.reactome.org ReactomeREACT_116025 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 SHC1 binds phosphorylated ERBB2:EGFR heterodimers through phosphorylated tyrosine residues on either ERBB2 (Y1196, Y1221, Y1222 and Y1248) or EGFR (Y1148 and Y1173). Heterodimers of ERBB2 and ERBB3 recruit SHC1 through a phosphorylated tyrosine residue Y1328 in the C-tail of ERBB3. Heterodimers of ERBB2 and ERBB4 isoforms recruit SHC1 through phosphorylated tyrosines in the C-tail of etiher ERBB2 (Y1196, Y1221, Y1222 and Y1248) or ERBB4 (Y1188 and Y1242 in ERBB4 JM-A CYT1 isoform; Y1178 and Y1232 in ERBB4 JM-B CYT1 isoform; Y1172 and Y1226 in ERBB4 JM-A CYT2 isoform). Association of SHC1 with ERBB2:EGFR and ERBB2:ERBB3 heterodimers was demonstrated in engineered mouse 32D cells in which human ERBB2, EGFR and ERBB3 were expressed. Therefore, these experiments showed association of human ERBB receptor dimers and mouse Shc1. In the case of ERBB2:ERBB4 heterodimers, direct evidence, involving human proteins only, is available. importin-alpha:importin-beta complex Reactome DB_ID: 350267 Reactome Database ID Release 43350267 Reactome, http://www.reactome.org ReactomeREACT_13922 has a Stoichiometric coefficient of 1 Trans-autophosphorylation of p-Y877-ERBB2 heterodimers Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: D'Eustachio, P, 2011-10-25 Phosphorylation of ERBB2 on tyrosine residue Y877 by SRC family kinases significantly increases trans-autophosphorylation rate of ERBB2 heterodimers, presumably by enabling the kinase domain of ERBB2 to achieve a conformation that positively affects ERBB2 kinase activity. The downstream signaling of phosphorylated ERBB2 heterodimers that are phosphorylated on Y877 of ERBB2, in addition to the known trans-autophosphorylation sites, has not been studied extensively; it is assumed that the behavior of Y877-phosphorylated ERBB2 heterodimers is qualitatively similar to the behavior of trans-autophosphorylated ERBB2 heterodimers which do not harbor this modification. Pubmed17030621 Reactome Database ID Release 431963581 Reactome, http://www.reactome.org ReactomeREACT_115659 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 has a Stoichiometric coefficient of 43 SRC family kinases phosphorylate ERBB2 Authored: Orlic-Milacic, M, 2011-11-04 Dissociation of HSP90 from ERBB2 upon formation of ERBB2 heterodimers (with either EGFR, ERBB3 or ERBB4) enables phosphorylation of ERBB2 on the tyrosine residue Y877, mediated by one of SRC family kinases - SRC, FYN or YES1. Although not a mandatory prerequisite of ERBB2 catalytic activity, the phosphorylation at Y877 significantly increases the kinase activity of ERBB2. EC Number: 2.7.10 Edited: D'Eustachio, P, 2011-11-07 Pubmed17030621 Reactome Database ID Release 431963586 Reactome, http://www.reactome.org ReactomeREACT_115797 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 ERBB2 forms heterodimers with ligand-activated ERBB receptors: EGFR, ERBB3 and ERBB4 Authored: Orlic-Milacic, M, 2011-11-04 ERBB2, which does not bind any known ligand, is activated through formation of a heterodimer with another ligand-activated ERBB family member. ERBB2 heterodimerization partners are EGF-stimulated EGFR (Wada et al. 1990, Karunagaran et al. 1996), ERBB3 stimulated by neuregulins NRG1 or NRG2 (Pinkas-Kramarski et al. 1996), and ERBB4 stimulated by neuregulins or EGF-like ligands (Li et al. 2007). In the process of dimerization, ERBB2 dissociates from chaperone proteins HSP90 and CDC37 (Xu et al 2001, Citri et al. 2004). Activated ERBB2 also dissociates from ERBB2IP, the protein reponsible for proper localization of ERBB2 to basolateral membranes of epithelial cells (Borg et al. 2000). Edited: Matthews, L, 2011-11-07 Pubmed10878805 Pubmed11071886 Pubmed15568014 Pubmed15643424 Pubmed16978839 Pubmed1973074 Pubmed8617201 Pubmed8665853 Reactome Database ID Release 431963589 Reactome, http://www.reactome.org ReactomeREACT_115761 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 has a Stoichiometric coefficient of 4 ERBB3 binds neuregulins Authored: Orlic-Milacic, M, 2011-11-04 ERBB3 becomes activated by binding either neuregulin 1 (NRG1) or neuregulin 2 (NRG2). Edited: Matthews, L, 2011-11-07 Pubmed7929212 Reactome Database ID Release 431247497 Reactome, http://www.reactome.org ReactomeREACT_115637 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 PTP-RO interacts with p-c-Kit complex Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed10397721 Reactome Database ID Release 431433423 Reactome, http://www.reactome.org ReactomeREACT_111127 Reviewed: Rönnstrand, L, 2011-08-22 Tyrosine phosphatase PTPRO associates constitutively with c-Kit independently of SCF stimulation. PTPRO undergoes phosphorylation upon SCF stimulation. The PTPRO binding site on c-Kit and the molecular mechanism by which c-Kit signaling is regulated by PTPRO have not been determined. LNK binds to p-KIT and inhibit downstream signaling Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed18588518 Reactome Database ID Release 431562640 Reactome, http://www.reactome.org ReactomeREACT_111099 Reviewed: Rönnstrand, L, 2011-08-22 The adaptor protein LNK with its SH2 domain binds to the juxtamembrane domain (amino acids 544-577) of KIT on Y568 and inhibit the downstream signalling (Gueller et al. 2008). JAK2 phosphorylation Authored: Jupe, S, 2010-10-14 Edited: Jupe, S, 2011-06-10 Pubmed10828073 Pubmed11445442 Pubmed12456871 Pubmed12479803 Pubmed15143188 Pubmed16174768 Pubmed20304997 Pubmed20664532 Pubmed7508935 Pubmed7515493 Pubmed8007942 Pubmed8188682 Pubmed8343952 Pubmed9111318 Reactome Database ID Release 43982810 Reactome, http://www.reactome.org ReactomeREACT_111076 Reviewed: Herington, AC, 2011-06-13 Reviewed: Waters, MJ, 2011-06-23 Similar models explain JAK activation by the cytokine-like hormone receptors (GHR and PRLR) and interleukin receptors. JAK2 activation is believed to occur as mutual transactivation whereby JAK2 bound to one receptor chain phosphorylates JAK2 bound to the other receptor chain in the dimeric receptor. Transactivation is widely accepted (Herrington & Carter-Su 2001) having been originally proposed in the 1990's (Quelle et al. 1994, Hou et al. 2002). JAK phosphorylation is thought to lock the kinase domain in an active state; prior to this JAK2 is held in an inactive state by interactions between its kinase and pseudokinase domains (Giordanetto & Kroemer 2002). Although there are structures of JAK kinase domains (e.g. Lucet et al. 2006), no complete JAK structures are available and the activation mechanism remains poorly understood (Brooks & Waters 2010). The trigger for JAK activation is believed to be a conformational change in the receptor when ligand is bound, leading to a rotation of the cytoplasmic regions which brings the catalytic domains of bound JAK2 molecules into close proximity and frees them from inhibition by the pseudokinase domains. Supporting observations for cytokine-like hormone receptors include: JAK2 becomes tyrosine phosphorylated as a consequence of GHR activation by GH (Argetsinger et al. 1993); JAK2 is activated following PRLR activation (Campbell et al. 1994, Rui et al. 1994); forced dimerization of GH receptor domains is sufficient to activate signaling (Behncken et al. 2000); phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006); JAK autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the Y1007 phosphorylation is represented in this reaction. has a Stoichiometric coefficient of 4 PRLR-bound STAT5 is phosphorylated Authored: Jupe, S, 2011-06-13 Co-immunoprecipitation of rat Stat5 and Prlrs mutated to have a single intracellular tyrosine suggests that phosphorylation of these tyrosines is required for Stat5 binding and leads to Stat5 tyrosine phosphorylation (Pezet et al. 1997). STAT1 and STAT3 have both been reported to be activated by PRLR (DaSilva et al. 1996), but the region(s) of PRLR required for activation of these Stats remains poorly documented. EC Number: 2.7.10 Edited: Jupe, S, 2011-10-17 Pubmed8737372 Pubmed9312112 Reactome Database ID Release 431671691 Reactome, http://www.reactome.org ReactomeREACT_115938 Reviewed: Goffin, V, 2011-11-08 has a Stoichiometric coefficient of 2 phospho-dynein(DLC2) on microtubules Reactome DB_ID: 140530 Reactome Database ID Release 43140530 Reactome, http://www.reactome.org ReactomeREACT_5554 has a Stoichiometric coefficient of 1 PRLR binds SHP2 (PTPN11) Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Pubmed10991949 Reactome Database ID Release 431369114 Reactome, http://www.reactome.org ReactomeREACT_115782 Reviewed: Goffin, V, 2011-11-08 Tyrosine-phosphorylated PRLR can bind the protein-tyrosine Phosphatase SHP2 (PTPN11) via its C-terminal SH2 Domain. This binding does not occur when the most C-terminal PRLR tyrosine residue (residue 611 in the human canonical Uniprot sequence, equivalent to 587 in the mature protein with signal peptide removed) is mutated to alanine (Ali & Ali 2000). Tyrosine phosphorylation of PRLR Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Pubmed7537382 Pubmed9312112 Reactome Database ID Release 431364043 Reactome, http://www.reactome.org ReactomeREACT_116161 Reviewed: Goffin, V, 2011-11-08 The model for PRL-induced PRLR activation suggests that JAK2 phosphorylates PRLR on specific tyrosine residues. Consistent with this, JAK2 and PRLR are phosphorylated in response to activating ligand (Lebrun et al. 1994) and PRLR tyrosine phosphorylation is required for subsequent Stat signaling (Pezet et al. 1997). Though this evidence is consistent with a role for JAK2, it has not been formally demonstrated that JAK2 is the kinase responsible for PRLR tyrosine phosphorylation. has a Stoichiometric coefficient of 2 phospho-dynein(DLC1) on microtubules Reactome DB_ID: 140526 Reactome Database ID Release 43140526 Reactome, http://www.reactome.org ReactomeREACT_2522 has a Stoichiometric coefficient of 1 PRLR binds STAT5 Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 PRLRs contain intracellular phosphorylated tyrosine residues that are able to bind and activate STATs, demonstrated by the co-immunoprecipitation of rat Stat5 and Prlrs mutated to have a single intracellular tyrosine (Pezet et al. 1997). Prlr mutants with a single tyrosine residue at positions 599, 498 or 492 (reported according to their position in the mature peptide as 580, 479 or 473 in Pezet et al. 1997) were all able to activate Stat5; Y599 gave a much stronger response. Short forms of PRLR lacking these tyrosines did not bind STAT5. The equivalent human tyrosine residues are Y509 and Y611; Y492 is not conserved in humans.<br>Activation of STAT1 and STAT3 by PRLR has been reported (Da Silva et al. 1996) but the interaction has been suggested to be indirect and possibly mediated by JAK2. Pubmed8737372 Pubmed9312112 Reactome Database ID Release 431369080 Reactome, http://www.reactome.org ReactomeREACT_116156 Reviewed: Goffin, V, 2011-11-08 BMF sequestered to dynein (DLC2) Reactome DB_ID: 140528 Reactome Database ID Release 43140528 Reactome, http://www.reactome.org ReactomeREACT_3065 has a Stoichiometric coefficient of 1 PRLR binds SCF beta-TrCP complex Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Phosphorylation of PRLR on Ser-349 by an unidentified kinase enables recruitment of the SCF beta-TrCP ubiquitin ligase complex, which catalyzes ubiquitination of the receptor (Li et al. 2004). This downregulation mechanism is impaired in some forms of breast cancer (Li et al. 2006). Pubmed15082796 Pubmed16278670 Reactome Database ID Release 431370500 Reactome, http://www.reactome.org ReactomeREACT_115790 Reviewed: Goffin, V, 2011-11-08 Prolactin receptor is internalized Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 PRLR is regulated by ubiquitination of the activated receptor, leading to lysosomal degradation (Djiane et al. 1981, 1982, Lu et al. 2002). Recruitment of the SCFbeta-TrCP ubiquitin ligase complex enables receptor ubiquitination and internalization (Li et al. 2004). This limits the duration and intensity of receptor signaling. Deregulation of this negative control lead to pathological conditions including cancer (Swaminathan et al. 2008). Pubmed12403840 Pubmed15082796 Pubmed18204982 Pubmed6275396 Pubmed6276249 Reactome Database ID Release 431170539 Reactome, http://www.reactome.org ReactomeREACT_115907 Reviewed: Goffin, V, 2011-11-08 SHP2 is phosphorylated Authored: Jupe, S, 2011-06-13 EC Number: 2.7.10.2 Edited: Jupe, S, 2011-10-17 Prolactin stimulation leads to tyrosine phosphorylation of the C-terminal SH2 domain of SHP2 and requires JAK2 (Ali et al. 1996). This has a positive regulatory influence on PRLR signaling. SHP2 has a number of signaling-capable interactors such as signal regulatory proteins (SIRPs, Kharitonenkov et al. 1997), SH2-containing inositol phosphatase (SHIP, Liu et al. 1997), insulin receptor substrates 1 and 2 (Myers et al. 1998), JAK2 (Jiao et al. 1996) and GRB2 associated binder 2 (GAB2) an adaptor protein that links activated receptor tyrosine kinase and cytokine receptors to downstream signaling molecules. PRL stimulation leads to SHP2-GAB2 association, GAB2 tyrosine phosphorylation, and GAB2-PI3K p85 subunit association, though it is not clear that this is the order of events, nor that SHP2 serves as a link between PRLR and GAB2 (Ali & Ali 2000). Pubmed10991949 Pubmed8598196 Pubmed8943354 Pubmed9009077 Pubmed9062191 Pubmed9756938 Reactome Database ID Release 431369115 Reactome, http://www.reactome.org ReactomeREACT_115719 Reviewed: Goffin, V, 2011-11-08 PRLR is phosphorylated at Ser-349 Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Pubmed12403840 Pubmed15082796 Pubmed16278670 Pubmed6275396 Pubmed6276249 Reactome Database ID Release 431370505 Reactome, http://www.reactome.org ReactomeREACT_115844 Reviewed: Goffin, V, 2011-11-08 The PRL responsiveness of target cells is negatively regulated by receptor internalization, ubiquitination and degradation, which limit the duration and intensity of receptor signaling (Djiane et al. 1981, 1982, Lu et al. 2002). The PRLR is phosphorylated on Ser-349 by an unidentified kinase (Li et al. 2006) enabling subsequent recruitment of the SCF beta-TrCP ubiquitin ligase complex (Li et al. 2004). has a Stoichiometric coefficient of 2 ERBB4 binds WWP1/ITCH ubiquitin ligases Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Intact ERBB4 isoforms and their membrane bound and cytosolic cleavage products, m80 and s80, bind NEDD4 family E3 ubiquitin ligases WWP1 and ITCH through WW-binding motifs in the C-tail. This interaction is independent of ligand binding and ERBB4 phosphorylation. CYT1 isoforms of ERBB4 have three WW-binding motifs: PY1, PY2 and PY3. PY2 motif is unique to CYT1 isoforms and overlaps with the PIK3R1 binding site. CYT2 isoform of ERBB4 has two WW-binding motifs: PY1 and PY3. While both CYT1 and CYT2 isoforms of ERBB4 all bind WWP1, CYT1 intracellular domain exhibits higher affinity for WWP1. Based on co-immunoprecipitation experiments in which individual WW-binding motifs of ERBB4 were mutated, Feng et al. established that PY2 had the highest affinity for WWP1, followed by PY3, while PY1 showed the lowest affinity. Pubmed17463226 Pubmed19047365 Reactome Database ID Release 431253300 Reactome, http://www.reactome.org ReactomeREACT_116036 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Cytochrome C:Apaf-1:ATP:Procaspase-9 Reactome DB_ID: 114255 Reactome Database ID Release 43114255 Reactome, http://www.reactome.org ReactomeREACT_5647 has a Stoichiometric coefficient of 1 Apaf-1:Cytochrome C Reactome DB_ID: 114253 Reactome Database ID Release 43114253 Reactome, http://www.reactome.org ReactomeREACT_4880 has a Stoichiometric coefficient of 1 Active oligomeric BAK Reactome DB_ID: 114262 Reactome Database ID Release 43114262 Reactome, http://www.reactome.org ReactomeREACT_4956 has a Stoichiometric coefficient of 2 tBID bound to inactive BAK Reactome DB_ID: 168847 Reactome Database ID Release 43168847 Reactome, http://www.reactome.org ReactomeREACT_6608 has a Stoichiometric coefficient of 1 Activated BAX Reactome DB_ID: 114269 Reactome Database ID Release 43114269 Reactome, http://www.reactome.org ReactomeREACT_2560 has a Stoichiometric coefficient of 2 tBID bound to inactive BAX Reactome DB_ID: 168850 Reactome Database ID Release 43168850 Reactome, http://www.reactome.org ReactomeREACT_6691 has a Stoichiometric coefficient of 1 Bcl-XL:BH3-only protein complex Reactome DB_ID: 508159 Reactome Database ID Release 43508159 Reactome, http://www.reactome.org ReactomeREACT_21559 has a Stoichiometric coefficient of 1 Bcl2:BH3-only protein complex Reactome DB_ID: 508158 Reactome Database ID Release 43508158 Reactome, http://www.reactome.org ReactomeREACT_21874 has a Stoichiometric coefficient of 1 ERBB4s80 binds STAT5A Authored: Orlic-Milacic, M, 2011-11-04 ERBB4s80 binds STAT5A through STAT5A SH2 domain. This interaction likely depends on STAT5A activation induced by prolactin and mediated by JAK2. Heterodimers of prolactin receptor (PRLR) and JAK2 are activated by prolactin binding, resulting in STAT5 recruitment and phosphorylation, and subsequent formation of phosphorylated STAT5 homodimers. There is evidence that ERBB4 may be part of the PRLR:JAK2 complex and that it may be activated by JAK2-mediated phosphorylation, in the absence of ERBB4 growth factors (Muraoka-Cook et al. 2008). Edited: Matthews, L, 2011-11-07 Pubmed15534001 Pubmed18653779 Reactome Database ID Release 431254291 Reactome, http://www.reactome.org ReactomeREACT_115793 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Apoptosome Cytochrome C:Apaf-1:Caspase-9 Reactome DB_ID: 114258 Reactome Database ID Release 43114258 Reactome, http://www.reactome.org ReactomeREACT_3569 has a Stoichiometric coefficient of 1 E2 Ubiquitin-conjugating enzyme Converted from EntitySet in Reactome Reactome DB_ID: 947628 Reactome Database ID Release 43947628 Reactome, http://www.reactome.org ReactomeREACT_76170 ERBB4s80:STAT5A complex translocates to the nucleus Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Formation of cytosolic complex of ERBB4s80 and STAT5A promotes translocation of STAT5A to the nucleus, with ERBB4s80 acting as a nuclear chaperone of STAT5A. Pubmed15534001 Pubmed18653779 Reactome Database ID Release 431254285 Reactome, http://www.reactome.org ReactomeREACT_115942 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Cleaved Caspase-9 Reactome DB_ID: 141640 Reactome Database ID Release 43141640 Reactome, http://www.reactome.org ReactomeREACT_5782 has a Stoichiometric coefficient of 1 ERBB4s80 forms a complex with estrogen receptor ESR1 Authored: Orlic-Milacic, M, 2011-11-04 ERBB4s80 forms a complex with activated estrogen receptor ESR1 in the nucleus and acts as a transcriptional co-factor for ESR1. Edited: Matthews, L, 2011-11-07 Pubmed16912174 Reactome Database ID Release 431254386 Reactome, http://www.reactome.org ReactomeREACT_116083 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Transcription of NR3C3 and CXCL12 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed16912174 Reactome Database ID Release 431254392 Reactome, http://www.reactome.org ReactomeREACT_115653 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 The complex of ERBB4s80 and activated estrogen receptor ESR1 promotes transcription of estrogen regulated genes NR3C3 (coding for progesterone receptor) and CXCL12 (SDF1). Translocation of cytosolic ERBB4s80 to mitochondrial matrix Authored: Orlic-Milacic, M, 2011-11-04 Cytosolic ERBB4s80 is able to translocate to mitochondria where its BH3 domain, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor. Edited: Matthews, L, 2011-11-07 Pubmed16778220 Reactome Database ID Release 431254376 Reactome, http://www.reactome.org ReactomeREACT_115552 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 PRLR associates with JAK2 Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 PRLR has no intrinsic kinase activity but associates with Janus kinase 2 (JAK2) (Lebrun et al. 1994, 1995, Campbell et al. 1994, Rui et al. 1994). PRLR to JAK2 binding has been described as constitutive but a recent computational model suggests that roughly half of dimerized Growth Hormone receptors are bound with JAK2 (Barua et al. 2009), a model that may apply to other receptors that promote JAK2 trans-activation. The box 1 region of PRLR is a membrane proximal proline-rich region in the intracellular domain, conserved in all members of the growth hormone rereptor family. This region is critical for JAK2 association; deletion of box 1 virtually abolishes PRLR signaling (Edery et al. 1994). Alanine substitutions of individual residues within box 1 of rat PRLR have shown that the most C-terminal proline (P269 in the Uniprot canonical sequence, 250 in the mature peptide) is critical for association with and subsequent activation of JAK2 (Pezet et al. 1997). It is not known whether the interaction of JAK2 with PRLR is direct or involves an adaptor protein.<br><br>When the receptor is activated by ligand binding JAK2 (receptor pre-bound or recruited after ligand binding) becomes activated and phosphorylates the dimerized receptor preferentially at Y611 (position 587 in the mature peptide), a consensus tyrosine phosphorylation site. This is followed by the phosphorylation, dimerization and nuclear translocation of STAT5. There are nine other tyrosines in the cytoplasmic domain, some of which may undergo phosphorylation and may participate in signal transduction. Pubmed10912517 Pubmed19381268 Pubmed7508935 Pubmed7515493 Pubmed7537736 Pubmed7926272 Pubmed8188682 Pubmed9202403 Reactome Database ID Release 431302698 Reactome, http://www.reactome.org ReactomeREACT_116102 Reviewed: Goffin, V, 2011-11-08 PRLR:JAK2 dimerizes Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Pubmed16840534 Pubmed20053995 Reactome Database ID Release 431364044 Reactome, http://www.reactome.org ReactomeREACT_115881 Reviewed: Goffin, V, 2011-11-08 The prolactin receptor (PRLR) peptide is a single transmembrane domain protein that functions as a dimer. Recent reports suggest that like many other cytokine receptors, the prolactin receptor (PRLR) pre-assembles at the plasma membrane in the absence of ligand (Gadd & Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in the preformed receptor dimer (Broutin et al. 2010). has a Stoichiometric coefficient of 2 Prolactin receptor ligands bind the prolactin receptor Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Human PRLR binds at least 3 related peptide ligands namely prolactin, placental lactogen (PL) and growth hormone (GH). In non primates, GH is not able to bind the PRLR. Human GH binding to the PRLR is zinc-dependent (Cunningham et al. 1990). All three ligands bind the extracellular domain and have apparently identical actions. Two disulfide-linked cysteines in the D1 subdomain are involved in ligand binding while the WSXWS motif in the D2 subdomain is probably required for folding and cellular trafficking. Pubmed16546209 Pubmed2270485 Reactome Database ID Release 43976991 Reactome, http://www.reactome.org ReactomeREACT_116060 Reviewed: Goffin, V, 2011-11-08 PRLR activation Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Ligand binding activates the PRLR, probably by causing a subtle conformational change (Broutin et al. 2010). Pubmed20053995 Reactome Database ID Release 431671687 Reactome, http://www.reactome.org ReactomeREACT_115800 Reviewed: Goffin, V, 2011-11-08 SH2B binds JAK2 Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Pubmed15767667 Pubmed19381268 Reactome Database ID Release 431675473 Reactome, http://www.reactome.org ReactomeREACT_115792 Reviewed: Goffin, V, 2011-11-08 The SH2 domains of SH2B beta (Uniprot isoform Q9NRF2-2) binds JAK2 at Tyr813. SH2B beta is able to homodimerize while bound to JAK2 molecules, suggesting that SH2B binding and dimerization may help induce JAK2 transactivation (Nishi et al. 2005). Computational modeling suggests that SH2B beta can enhance Jak2 activation (Barua et al. 2009). The relevance of this for PRLR signalling has yet to be demonstrated. active caspase-3 Reactome DB_ID: 141647 Reactome Database ID Release 43141647 Reactome, http://www.reactome.org ReactomeREACT_2467 has a Stoichiometric coefficient of 1 XIAP:Caspase-9 Reactome DB_ID: 114317 Reactome Database ID Release 43114317 Reactome, http://www.reactome.org ReactomeREACT_4334 has a Stoichiometric coefficient of 1 SMAC:XIAP:Caspase-7 Reactome DB_ID: 114353 Reactome Database ID Release 43114353 Reactome, http://www.reactome.org ReactomeREACT_3355 has a Stoichiometric coefficient of 1 SMAC:XIAP Reactome DB_ID: 114391 Reactome Database ID Release 43114391 Reactome, http://www.reactome.org ReactomeREACT_5204 has a Stoichiometric coefficient of 1 SMAC:XIAP:Caspase-9 Reactome DB_ID: 114318 Reactome Database ID Release 43114318 Reactome, http://www.reactome.org ReactomeREACT_4472 has a Stoichiometric coefficient of 1 XIAP:Caspase-3 Reactome DB_ID: 114304 Reactome Database ID Release 43114304 Reactome, http://www.reactome.org ReactomeREACT_2704 has a Stoichiometric coefficient of 1 active caspase-7 Reactome DB_ID: 141643 Reactome Database ID Release 43141643 Reactome, http://www.reactome.org ReactomeREACT_3366 has a Stoichiometric coefficient of 1 XIAP:Caspase-7 Reactome DB_ID: 114308 Reactome Database ID Release 43114308 Reactome, http://www.reactome.org ReactomeREACT_2853 has a Stoichiometric coefficient of 1 SMAC:XIAP:Caspase-3 Reactome DB_ID: 114305 Reactome Database ID Release 43114305 Reactome, http://www.reactome.org ReactomeREACT_5281 has a Stoichiometric coefficient of 1 Cleavage of P-ERBB4jmA isoforms by ADAM17 Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 3.4.24 Edited: Matthews, L, 2011-11-07 Phosphorylated ligand-bound homodimers of ERBB4 JM-A isoforms are cleaved by ADAM17 metalloproteinase to yield ligand-bound ERBB4 extracellular domain and membrane bound ERBB4 fragment of 80 kDa (ERBB4m80). Pubmed10744726 Pubmed12869563 Reactome Database ID Release 431251992 Reactome, http://www.reactome.org ReactomeREACT_115618 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Cleavage of ERBB4m80 by gamma-scretase complex After ERBB4 is cleaved by ADAM17, gamma-secretase complex performs additional cleavage in the transmembrane region of the m80 ERBB4 fragment, releasing the soluble ERBB4 intracellular domain of 80 kDa, known as s80 or E4ICD. Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed11679632 Reactome Database ID Release 431251997 Reactome, http://www.reactome.org ReactomeREACT_115913 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Conversion of PIP2 into PIP3 by PI3K bound to p-ERBB4cyt1 homodimers Activated PI3K bound to phosphorylated ERBB4 CYT-1 homodimers converts PIP2 into PIP3, which leads to activation of AKT signaling. Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.1.153 Edited: Matthews, L, 2011-11-07 Pubmed10722704 Reactome Database ID Release 431250370 Reactome, http://www.reactome.org ReactomeREACT_115712 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Translocation of ERBB4s80:YAP1 complex to the nucleus Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed12807903 Pubmed15023535 Pubmed16061658 Reactome Database ID Release 431254248 Reactome, http://www.reactome.org ReactomeREACT_115819 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Upon formation of ERBB4s80:YAP1 complex in the cytosol, the complex translocates to the nucleus, where it may act as a regulator of transcription. WWOX binds ERBB4s80 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed16061658 Pubmed19047365 Reactome Database ID Release 431253343 Reactome, http://www.reactome.org ReactomeREACT_115707 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 WWOX binds to ERBB4s80 through WW-domain binding motifs in the C-tail of ERBB4. Formation of ERBB4s80:WWOX complex competes with the formation of ERBB4:YAP1 complex and prevents translocation of ERBB4s80 to the nucleus. Feng et al. established that WWOX binds with the same affinity to s80CYT1 and s80CYT2, and identified PY3 as the most important WW-domain binding motif for WWOX binding. ERBB4s80 binds YAP1 Authored: Orlic-Milacic, M, 2011-11-04 ERBB4s80 interacts with a co-transcriptional activator YAP1 through its WW-domain binding motifs in the C-tail. Feng et al. established that the PY2 motif, present in CYT1 isoforms of ERBB4 only, has the highest affinity for YAP1 binding. PY1 and PY3 motifs, shared between CYT1 and CYT2 isoforms, have lower binding affinity for YAP1, with PY1 motif being the least important for YAP1 interaction. Edited: Matthews, L, 2011-11-07 Pubmed12807903 Pubmed15023535 Pubmed19047365 Reactome Database ID Release 431254251 Reactome, http://www.reactome.org ReactomeREACT_116068 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 ERBB4:TAB2:NCOR1 complex translocates to the nucleus Authored: Orlic-Milacic, M, 2011-11-04 ERBB4s80 (E4ICD) bound to cytosolic TAB2:NCOR1 complex mediates the translocation of this complex to the nucleus. Edited: Matthews, L, 2011-11-07 Pubmed17018285 Reactome Database ID Release 431253319 Reactome, http://www.reactome.org ReactomeREACT_115674 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Transcription of GFAP and S100B Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed17018285 Reactome Database ID Release 431253321 Reactome, http://www.reactome.org ReactomeREACT_115713 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Transcription of GFAP and S100B genes, involved in astrocyte differentiation, is inhibited by ERBB4s80:TAB2:NCOR1 complex which binds promoters of GFAP and S100B. Translocation of ERBB4s80 to the nucleus Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed11679632 Reactome Database ID Release 431252013 Reactome, http://www.reactome.org ReactomeREACT_115558 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 The soluble intracellular domain of ERBB4 s80 (E4ICD) is able to translocate from the cytosol to the nucleus. ERBB4s80 binds TAB2:NCOR1 complex Authored: Orlic-Milacic, M, 2011-11-04 ERBB4s80 (E4ICD) binds cytosolic TAB2:NCOR1 complex through direct interaction with TAB2. Edited: Matthews, L, 2011-11-07 Pubmed17018285 Reactome Database ID Release 431253325 Reactome, http://www.reactome.org ReactomeREACT_115862 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Homodimerization of ERBB4 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Ligand stimulated ERBB4 forms homodimers. Pubmed10867024 Reactome Database ID Release 431250220 Reactome, http://www.reactome.org ReactomeREACT_115969 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 has a Stoichiometric coefficient of 2 Trans-autophosphorylation of ERBB4 homodimers Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: Matthews, L, 2011-11-07 Homodimers of ERBB4 CYT 1 isoforms trans autophosphorylate on six tyrosine residues (three on each monomer) that serve as docking sites for SHC1 (tyrosines Y1188 and 1242 in the isoform ERBB4 JM-A CYT1; tyrosines Y1178 and Y1232 in the isoform ERBB4 JM-B CYT1) and the p85 subunit of PI3K (tyrosine Y1056 in the isoform ERBB4 JM-A CYT1; tyrosine Y1046 in the isoform ERBB4 JM-B CYT1), while ERBB4 CYT2 isoform homodimer trans-autophosphorylates on four SHC1 binding tyrosines (two on each monomer - tyrosines Y1172 and Y1226). Pubmed18721752 Pubmed8617750 Reactome Database ID Release 431250315 Reactome, http://www.reactome.org ReactomeREACT_115989 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 has a Stoichiometric coefficient of 16 Recruitment of GRB2:SOS1 to phosphorylated SHC1 in complex with phosphorylated ERBB4 homodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Phosphorylated SHC1 bound to phosphorylated ERBB4 homodimers recruits GRB2:SOS1 complex. Pubmed10722704 Reactome Database ID Release 431250380 Reactome, http://www.reactome.org ReactomeREACT_116037 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and p-Y349,350-SHC1:p-ERBB4 Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed10722704 Reactome Database ID Release 431250383 Reactome, http://www.reactome.org ReactomeREACT_115999 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 SOS1 in complex with GRB2 and p-Y349,350-SHC1:p-ERBB4 activates RAS by mediating guanyl nucleotide exchange, which results in the activation of RAF/MAP kinase cascade. Binding of p85 subunit of PI3K (PIK3R1) to p-ERBB4cyt1 homodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed18721752 Pubmed8617750 Reactome Database ID Release 431250353 Reactome, http://www.reactome.org ReactomeREACT_115722 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 p85 subunit of PI3K (PIK3R1) directly binds to phosphorylated ERBB4 CYT1 homodimers through docking tyrosine residues on either ERBB4 JM A CYT1 (tyrosine Y1056) or ERBB4 JM B CYT1 (tyrosine Y1046) isoform. Recruitment of PI3K subunit p110 (PIK3CA) to PI3K subunit p85 (PIK3R1) bound to p-ERBB4cyt1 homodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 PI3K subunit p110 (PIK3CA) is recruited by PI3K subunit p85 (PIK3R1) bound to phosphorylated P-ERBB4cyt1 homodimers to form active PI3K. Pubmed10722704 Reactome Database ID Release 431250372 Reactome, http://www.reactome.org ReactomeREACT_115570 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 ERBB4 forms heterodimers with EGFR Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Ligand-stimulated ERBB4 was shown to form heterodimers with ligand-stimulated EGFR when human ERBB4 and EGFR were exogenously expressed in mouse fibroblast cell line. Heterodimers of ERBB4 and EGFR undergo trans-autophosphorylation, but the exact phosphorylation pattern, downstream signaling and physiological significance of these heterodimers have not been studied. Pubmed8617750 Reactome Database ID Release 431977959 Reactome, http://www.reactome.org ReactomeREACT_116135 Reviewed: Harris, RC, 2011-11-11 Reviewed: Zeng, F, 2011-11-11 ERBB4 forms heterodimers with ERBB3 Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Ligand-stimulated ERBB4 was shown to form heterodimers with ligand-stimulated ERBB3 when human ERBB4 and ERBB3 were exogenously expressed in mouse pro-B-lymphocyte cell line. Heterodimers of ERBB4 and ERBB3 undergo trans-autophosphorylation, but the exact phosphorylation pattern, downstream signaling and physiological significance of these heterodimers have not been studied. Pubmed7565730 Reactome Database ID Release 431977958 Reactome, http://www.reactome.org ReactomeREACT_115947 Reviewed: Harris, RC, 2011-11-11 Reviewed: Zeng, F, 2011-11-11 SHC1 binds P-ERBB4 isoform dimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Phosphorylated tyrosine residues in the C-tail of phosphorylated ERBB4 isoform dimers P-ERBB4jmAcyt1, P-ERBB4jmAcyt2 and P-ERBB4jmBcyt1 recruit SHC1. Pubmed18721752 Pubmed8617750 Pubmed8665853 Reactome Database ID Release 431250357 Reactome, http://www.reactome.org ReactomeREACT_115908 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Phosphorylation of SHC1 by ERBB4 homodimers After binding ERBB4 homodimers, SHC1 gets phosphorylated on tyrosine residues Y349 and Y350. Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: Matthews, L, 2011-11-07 Pubmed10722704 Reactome Database ID Release 431250348 Reactome, http://www.reactome.org ReactomeREACT_115935 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 has a Stoichiometric coefficient of 2 Caspase-8 dimer Reactome DB_ID: 139950 Reactome Database ID Release 43139950 Reactome, http://www.reactome.org ReactomeREACT_4185 has a Stoichiometric coefficient of 1 Calcineurin B complex Reactome DB_ID: 140202 Reactome Database ID Release 43140202 Reactome, http://www.reactome.org ReactomeREACT_4613 has a Stoichiometric coefficient of 1 143B:phospo-BAD complex Reactome DB_ID: 139904 Reactome Database ID Release 43139904 Reactome, http://www.reactome.org ReactomeREACT_5737 has a Stoichiometric coefficient of 1 BAD:BCL-2 Reactome DB_ID: 114268 Reactome Database ID Release 43114268 Reactome, http://www.reactome.org ReactomeREACT_3232 has a Stoichiometric coefficient of 1 tBID:BCL-2 Reactome DB_ID: 114339 Reactome Database ID Release 43114339 Reactome, http://www.reactome.org ReactomeREACT_5048 has a Stoichiometric coefficient of 1 BIM sequestered to dynein (DLC1) Reactome DB_ID: 140524 Reactome Database ID Release 43140524 Reactome, http://www.reactome.org ReactomeREACT_3567 has a Stoichiometric coefficient of 1 DP-1:E2F1 complex Reactome DB_ID: 68653 Reactome Database ID Release 4368653 Reactome, http://www.reactome.org ReactomeREACT_5400 has a Stoichiometric coefficient of 1 6t/6t,12epi-LTB4 Converted from EntitySet in Reactome Reactome DB_ID: 2161801 Reactome Database ID Release 432161801 Reactome, http://www.reactome.org ReactomeREACT_150956 SKI complexes with the Smad complex, suppressing BMP2 signalling Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Pubmed10485843 Pubmed10531062 Pubmed10535941 Pubmed10549282 Pubmed11121043 Pubmed11389444 Reactome Database ID Release 43201423 Reactome, http://www.reactome.org ReactomeREACT_12007 Reviewed: Heldin, CH, 2007--1-1- SKI and SKIL (SNO) are able to recruit NCOR and possibly other transcriptional repressors to SMAD2/3:SMAD4 complex, inhibiting SMAD2/3:SMAD4-mediated transcription (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Experimental findings suggest that SMAD2 and SMAD3 may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001), and that the ratio of SMAD2/3 and SKI/SKIL determines the outcome (inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL). SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex. The phospho-R-Smad1/5/8:Co-Smad transfers to the nucleus Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Pubmed11509558 Pubmed12592392 Pubmed12821673 Reactome Database ID Release 43201472 Reactome, http://www.reactome.org ReactomeREACT_12067 Reviewed: Heldin, CH, 2007--1-1- The phosphorylated-r-SMAD1/5/8:Co-SMAD complex rapidly translocates to the nucleus where it binds directly to DNA and interacts with a plethora of transcription co-factors. Regulation of target gene expression can be either positive or negative. A classic example of a target gene of the pathway are the genes encoding for i-SMADs. Thus, BMP2/SMAD signalling induces the expression of the negative regulators of the pathway (a negative feedback loop). Phospho-R-Smad1/5/8 forms a complex with Co-Smad Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Pubmed11779505 Pubmed15350224 Pubmed8893010 Pubmed9311995 Pubmed9670020 Reactome Database ID Release 43201422 Reactome, http://www.reactome.org ReactomeREACT_12080 Reviewed: Heldin, CH, 2007--1-1- The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif. I-Smad competes with Co-Smad for R-Smad1/5/8 Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 I-SMAD selectively antagonizes BMP-activated Smad1/5/9 by acting as a CO-SMAD decoy. Pubmed9436979 Reactome Database ID Release 43202626 Reactome, http://www.reactome.org ReactomeREACT_12028 Reviewed: Heldin, CH, 2007--1-1- Phospho-R-Smad1/5/8 dissociates from the receptor complex Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Pubmed15350224 Pubmed17356069 Pubmed8893010 Pubmed8980228 Pubmed9136927 Pubmed9311995 Pubmed9346966 Reactome Database ID Release 43201453 Reactome, http://www.reactome.org ReactomeREACT_12069 Reviewed: Heldin, CH, 2007--1-1- Upon phosphorylation of the R-SMAD (SMAD2/3), the conformation of the C-terminal (MH2) domain of the R-SMAD changes, lowering its affinity for the type I receptor and SARA. As a result, the phosphorylated R-SMAD dissociates from the activated receptor complex (TGFBR). Activated type I receptor phosphorylates R-Smad1/5/8 directly Activated type I receptor kinase directly phosphorylates two of the C-terminal serine residues of SMAD2 or SMAD3. Binding of these R-SMADs to the L45 loop of the type I receptor is critical for this event. Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Pubmed11100470 Pubmed8653785 Pubmed9136927 Reactome Database ID Release 43201476 Reactome, http://www.reactome.org ReactomeREACT_12052 Reviewed: Heldin, CH, 2007--1-1- has a Stoichiometric coefficient of 2 I-Smad binds to type I receptor, preventing Smad1/5/8 from being activated Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Pubmed11278251 Pubmed12151385 Pubmed12857866 Reactome Database ID Release 43201821 Reactome, http://www.reactome.org ReactomeREACT_12013 Reviewed: Heldin, CH, 2007--1-1- Smad6 and Smad7, the two I-Smads, bind directly to the BMP type I receptors and recruit the ubiquitin ligase Smurf1. This reaction leads to competitive inhibition of R-Smad binding to the type I receptor and activating phosphorylation by the receptor, and also leads to BMP receptor ubiquitination and degradation. An anchoring protein, Endofin, recruits R-Smad1/5/8 Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Endofin is a FYVE domain-containing protein that strongly resembles SARA, the Smad anchor for receptor activation that facilitates TGF-beta signalling. Endofin acts in a similar manner as SARA, it binds to BMP-specific R-Smads, it localizes in early endosomes and it facilitates their phosphorylation, thus promoting signal transduction by the BMP receptors. However, it should be noted that endofin has also been reported to bind to the Co-Smad, Smad4, and to the TGF-beta type receptor, thus enhancing TGF-beta signalling. Since Smad4 is a common Smad that operates in the BMP-specific pathways, the latter observation might imply that endofin could regulate both TGF-beta and BMP signalling, a hypothesis still open for investigation. Pubmed17356069 Reactome Database ID Release 43201648 Reactome, http://www.reactome.org ReactomeREACT_12054 Reviewed: Heldin, CH, 2007--1-1- Type II receptor phosphorylates type I receptor Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Formation of the hetero-tetrameric BMP2:receptor complex induces receptor rotation, so that their cytoplasmic kinase domains face each other in a catalytically favourable configuration. The constitutively active type II receptor kinase (which auto-phosphorylates in the absence of ligand), trans-phosphorylates specific serine residues at the conserved Gly-Ser-rich juxtapositioned domain of the type I receptor. It is not known if exactly 8 ATPs are required for the phosphorylation of type I receptor, there could be more or less than this number. Pubmed7644468 Pubmed7791754 Reactome Database ID Release 43201443 Reactome, http://www.reactome.org ReactomeREACT_12070 Reviewed: Heldin, CH, 2007--1-1- has a Stoichiometric coefficient of 8 BMP2 binds to the receptor complex Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 Reactome Database ID Release 43201457 Reactome, http://www.reactome.org ReactomeREACT_12011 Reviewed: Heldin, CH, 2007--1-1- The mature dimeric BMP2 binds with high affinity to its signalling receptor, the type II receptor serine/threonine kinase. The type II receptor is known to form dimeric complexes even in the absence of BMP2. Dissociation of Rho GTP:GDP from GDI complex Authored: Van Aelst, L, 2007-04-28 21:26:24 Edited: Gopinathrao, G, 2007-04-02 21:35:36 GDIs sequester the inactive GTPases, preventing the dissociation of GDP and interactions with regulatory and effector molecules. They maintain Rho GTPases as soluble cytosolic proteins by forming high affinity complexes. In these complexes, the geranylgeranyl membrane targeting moiety present at the C terminus of the Rho GTPases is shielded from the solvent by its insertion into the hydrophobic pocket formed by the immunoglobulin like beta sandwich of the GDI (DerMardirossian and Bokoch, 2005).<p>Rho proteins, when released from the sequestering cytosolic GDIs, insert into the lipid bilayer of the plasma membrane with their isoprenylated C termini. The membrane bound GEFs activate these free RhoGTPases and thereby trigger the downstream signaling events via respective effector proteins on the membrane (Robbe et al., 2003). Detailed annotation of the activities of farnesyltransferase / geranylgeranyltransferases on prenylation of Rho GTPases thereby enabling their subsequent localization to plasma membrane will be available in future releases. Pubmed10655614 Pubmed10676816 Pubmed12471028 Pubmed15921909 Pubmed9194563 Reactome Database ID Release 43195146 Reactome, http://www.reactome.org ReactomeREACT_10051 Reviewed: Bernards, A, 2007-04-28 21:27:12 GDIs block activation of Rho GTPase:GDP Authored: Van Aelst, L, 2007-04-28 21:26:24 Edited: Gopinathrao, G, 2007-04-02 21:35:36 GDP dissociation inhibitors or GDIs confer an additional but important layer of Rho GTPase regulation along with GEFs and GAPs. GDIs mainly inhibit the dissociation of bound guanine nucleotide (usually GDP) from their partner GTPases. So far, three human GDIs with proven biological functions have been found: RhoGDI/GDIalpha/GDI1, hematopoietic cell selective Ly/D4GDI/GDIbeta/GDI2, and Rho GDIgamma/GDI3 (DerMardirossian and Bokoch, 2005). Three specific biochemical functions of GDIs have been established: inhibiting the dissociation of GDP from Rho proteins, maintaining the GTPases in an inactive form, and preventing GTPase activation by GEFs (Olofsson, 1999). Detailed annotations of GDIs will be available in future releases. Pubmed10433515 Pubmed10655614 Pubmed10676816 Pubmed1439791 Pubmed15292224 Pubmed15921909 Pubmed16190977 Pubmed7543319 Pubmed7824266 Pubmed9113980 Pubmed9194563 Reactome Database ID Release 43194854 Reactome, http://www.reactome.org ReactomeREACT_10055 Reviewed: Bernards, A, 2007-04-28 21:27:12 Formation of a heteromeric BMP receptor complex Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 BMP receptors, unlike TGF-beta receptors are known to form hetero-oligomeric complexes in the endoplasmic reticulum and are transported as oligomers to the plasma membrane where they bind ligand. However, evidence for ligand-induced heteromeric BMP receptor complexes on the cell surface has also been published, leading to a model where both pre-formed and ligand-induced receptor oligomers are encountered on the plasma membrane. Based on the latter, a theory has been formulated that suggests that the signaling outcome from pre-formed and ligand-induced BMP receptor complexes is different. The mechanism that might explain this theory must involve different ways of internalization and trafficking of the BMP receptor complexes. Pubmed10712517 Pubmed11714695 Pubmed16672363 Reactome Database ID Release 43202604 Reactome, http://www.reactome.org ReactomeREACT_12009 Reviewed: Heldin, CH, 2007--1-1- The ligand trap binds the ligand BMP2, blocking BMP signalling Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 BMP ligand traps are cystine-knot containing proteins which bind BMPs and antagonise their actions. They are active during organ development and morphogenesis. Different BMP ligand traps show specific spatio-temporal expression during development, and selective activity against specific BMP ligands. Pubmed17029022 Reactome Database ID Release 43201810 Reactome, http://www.reactome.org ReactomeREACT_12026 Reviewed: Heldin, CH, 2007--1-1- GEFs activate Rho GTPase:GDP Authored: Van Aelst, L, 2007-04-28 21:26:24 Edited: Gopinathrao, G, 2007-04-02 21:35:36 Guanine nucleotide exchange factors (GEFs) activate GTPases by enhancing the exchange of bound GDP for GTP. Much evidence points to GEFs being critical mediators of Rho GTPase activation (Schmidt and Hall, 2002). Many GEFs are known to be highly specific for a particular GTPase, e.g. Fgd1/Cdc42 and p115RhoGEF/Rho (Hart et al., 1996, Zheng et al., 1996). Others have a broader spectrum and activate several GTPases, e.g. Vav1 for Rac, Rho, and Cdc42 (Hart et al, 1994). Pubmed10559246 Pubmed12101119 Pubmed16212495 Pubmed7478592 Pubmed7954831 Pubmed8276860 Pubmed8810315 Pubmed8969170 Pubmed9308960 Pubmed9857026 Reactome Database ID Release 43194913 Reactome, http://www.reactome.org ReactomeREACT_10098 Reviewed: Bernards, A, 2007-04-28 21:27:12 NEDD4 ubiquitinates ERBB4jmAcyt1s80 dimer Authored: Orlic-Milacic, M, 2011-11-04 E3 ubiquitin ligase NEDD4 mediates ubiquitination of ERBB4 JM-A CYT-1 intracellular domain s80 (ERBB4jmAcyt1s80) produced by ERBB4 cleavage. This induces degradation of ERBB4jmAcyt1s80, and decreases the amount of ERBB4jmAcyt1s80 that reaches the nucleus. EC Number: 6.3.2.19 Edited: Matthews, L, 2011-11-07 Pubmed19193720 Reactome Database ID Release 431977296 Reactome, http://www.reactome.org ReactomeREACT_115889 Reviewed: Harris, RC, 2011-11-11 Reviewed: Zeng, F, 2011-11-11 GAPs inactivate Rho GTPase:GTP by hydrolysis Authored: Van Aelst, L, 2007-04-28 21:26:24 Edited: Gopinathrao, G, 2007-04-02 21:35:36 Pubmed11431473 Pubmed11804589 Pubmed12015138 Pubmed17222083 Pubmed2825022 Pubmed8288572 Pubmed9605766 Reactome Database ID Release 43194922 Reactome, http://www.reactome.org ReactomeREACT_9982 Reviewed: Bernards, A, 2007-04-28 21:27:12 The human genome includes approximately 70 genes that are predicted to encode Rho-specific GTPase Activating Proteins (RhoGAPs). As in the case of GEFs, some RhoGAPs are believed to be highly specific, whereas others are more promiscuous with respect to their target GTPases. Increasing evidence suggests that GAPs are also regulated by external cues in addition to being signal terminators leading to Rho GTPase inactivation. These proteins play important role in many Rho mediated signaling pathways.<p>Some known GAPs include p190 A, cdGAP, ARAP3, MgcRacGAP, Chimaerin, Nadrin, TCGAP, DLC 1, 2, ArhGAP6, Myosin IXA. These and other GAPs have been implicated in many processes, such as exocytosis, endocytosis, cytokinesis, cell differentiation, migration, neuronal morphogenesis, angiogenesis and tumor suppression. Detailed annotations of the biological role of GAPs in Rho mediated signaling will be available in future releases. Rho GTPase:GTP activates downstream effectors Authored: Van Aelst, L, 2007-04-28 21:26:24 Edited: Gopinathrao, G, 2007-04-02 21:35:36 Pubmed10360578 Pubmed11130076 Pubmed11157984 Pubmed11738596 Pubmed12423633 Pubmed12429845 Pubmed12504591 Pubmed15260990 Pubmed15611088 Pubmed15630019 Pubmed15821030 Pubmed9308960 Reactome Database ID Release 43194894 Reactome, http://www.reactome.org ReactomeREACT_10126 Reviewed: Bernards, A, 2007-04-28 21:27:12 To transduce signals, the activated, GTP-bound Rho GTPases interact with specific effector molecules. It has been observed that GEFs contribute to the signaling specificity of their downstream target GTPase via association with scaffolding molecules that link them and the GTPase to specific GTPase effectors (Govek et al., 2005). Some of the effector molecules implicated in actin and microtubule dynamics include diaphanous-related formins, Toca 1, WIP, WASP, Pak, p35/Cdk5, Wave, Nap125, MLCK, MLC, IRSp53. Detailed annotations of the downstream events stimulated by activated, GTP bound Rho GTPases will be available in future releases. NEDD4 binds ERBB4jmAcyt1s80 dimer Authored: Orlic-Milacic, M, 2011-11-04 E3 ubiquitin ligase NEDD4 binds intracellular domain of ERBB4 isoform JM-A CYT1 (ERBB4jmAcyt1s80) produced by ERBB4 cleavage. Edited: Matthews, L, 2011-11-07 Pubmed19193720 Reactome Database ID Release 431973956 Reactome, http://www.reactome.org ReactomeREACT_115758 Reviewed: Harris, RC, 2011-11-11 Reviewed: Zeng, F, 2011-11-11 ERBB4 ubiquitination by WWP1/ITCH Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 6.3.2.19 Edited: Matthews, L, 2011-11-07 Pubmed17463226 Pubmed19047365 Reactome Database ID Release 431253282 Reactome, http://www.reactome.org ReactomeREACT_116054 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Upon binding to ERBB4 or its cleavage products m80 and s80, NEDD4 family ligases WWP1 and ITCH ubiquitinate intact and cleaved ERBB4 and target it for degradation. chylomicron remnant:apoE:LDLR complex Reactome DB_ID: 174749 Reactome Database ID Release 43174749 Reactome, http://www.reactome.org ReactomeREACT_7910 has a Stoichiometric coefficient of 1 chylomicron remnant Reactome DB_ID: 174797 Reactome Database ID Release 43174797 Reactome, http://www.reactome.org ReactomeREACT_7303 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 50 Stem-looped mRNA Reactome DB_ID: 77601 Reactome Database ID Release 4377601 Reactome, http://www.reactome.org ReactomeREACT_4094 chylomicron remnant:apoE complex Reactome DB_ID: 174659 Reactome Database ID Release 43174659 Reactome, http://www.reactome.org ReactomeREACT_7312 has a Stoichiometric coefficient of 1 Nascent pre-mRNA with hydrolysed 5'-end Reactome DB_ID: 111341 Reactome Database ID Release 43111341 Reactome, http://www.reactome.org ReactomeREACT_5790 chylomicron remnant:apoE:LDLR complex Reactome DB_ID: 174658 Reactome Database ID Release 43174658 Reactome, http://www.reactome.org ReactomeREACT_7115 has a Stoichiometric coefficient of 1 DNA Deoxyribonucleic Acid Reactome DB_ID: 29428 Reactome Database ID Release 4329428 Reactome, http://www.reactome.org ReactomeREACT_3913 ApoB-48:TG:PL complex Reactome DB_ID: 174746 Reactome Database ID Release 43174746 Reactome, http://www.reactome.org ReactomeREACT_7389 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 40 has a Stoichiometric coefficient of 60 nascent pre-mRNA transcript Reactome DB_ID: 72084 Reactome Database ID Release 4372084 Reactome, http://www.reactome.org ReactomeREACT_5393 template DNA:30 nt transcript hybrid Reactome DB_ID: 111260 Reactome Database ID Release 43111260 Reactome, http://www.reactome.org ReactomeREACT_4724 chylomicron remnant:apoE complex Reactome DB_ID: 174698 Reactome Database ID Release 43174698 Reactome, http://www.reactome.org ReactomeREACT_7032 has a Stoichiometric coefficient of 1 mRNA with spliced exons Reactome DB_ID: 72156 Reactome Database ID Release 4372156 Reactome, http://www.reactome.org ReactomeREACT_2708 chylomicron remnant:apoE:LDLR complex Reactome DB_ID: 174816 Reactome Database ID Release 43174816 Reactome, http://www.reactome.org ReactomeREACT_7091 has a Stoichiometric coefficient of 1 capped pre-mRNA Reactome DB_ID: 72085 Reactome Database ID Release 4372085 Reactome, http://www.reactome.org ReactomeREACT_3987 ApoB-48:TG:PL complex Reactome DB_ID: 174666 Reactome Database ID Release 43174666 Reactome, http://www.reactome.org ReactomeREACT_7813 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 40 has a Stoichiometric coefficient of 60 Nascent pre-mRNA with 5'-GMP dissociated from CE Reactome DB_ID: 111345 Reactome Database ID Release 43111345 Reactome, http://www.reactome.org ReactomeREACT_3793 chylomicron remnant Reactome DB_ID: 174649 Reactome Database ID Release 43174649 Reactome, http://www.reactome.org ReactomeREACT_7478 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 50 Nascent pre-mRNA with 5'-GMP associated with CE Reactome DB_ID: 111344 Reactome Database ID Release 43111344 Reactome, http://www.reactome.org ReactomeREACT_5463 chylomicron remnant:apoE complex Reactome DB_ID: 174787 Reactome Database ID Release 43174787 Reactome, http://www.reactome.org ReactomeREACT_7161 has a Stoichiometric coefficient of 1 2-amino-3-carboxymuconate semialdehyde => 2-aminomuconate semialdehyde + CO2 At the beginning of this reaction, 1 molecule of '2-Amino-3-carboxymuconate semialdehyde' is present. At the end of this reaction, 1 molecule of 'CO2', and 1 molecule of '2-Aminomuconate semialdehyde' are present.<br><br> This reaction takes place in the 'cytoplasm' and is mediated by the 'carboxy-lyase activity' of '2-amino-3-carboxymuconate-6-semialdehyde decarboxylase homodimer'.<br> Authored: D'Eustachio, P, 2005-07-20 13:46:37 EC Number: 4.1.1 Edited: D'Eustachio, P, 2005-07-20 13:46:37 Pubmed12140278 Reactome Database ID Release 4371223 Reactome, http://www.reactome.org ReactomeREACT_333 2-aminomuconate semialdehyde + NAD+ + H2O => aminomuconate + NADH + H+ Authored: D'Eustachio, P, 2005-07-20 13:46:37 EC Number: 1.2.1.32 Edited: D'Eustachio, P, 2005-07-20 13:46:37 Pubmed14275130 Reactome Database ID Release 4371239 Reactome, http://www.reactome.org ReactomeREACT_1425 This reaction has been characterized in vitro using enzyme partially purified from cat liver (Ichiyama et al. 1965). The human event is inferred from the cat one. Neither the cat nor the human protein has been fully purified or sequenced. kynurenine + 2-oxoglutarate => 4-(2-aminophenyl)-2,4-dioxobutanoic acid + glutamate AADAT dimer localized in the mitochondrial matrix catalyzes the reaction of kynurenine and 2-oxoglutarate to form 4-(2-aminophenyl)-2,4-dioxobutanoate and glutamate (Han et al. 2008). Biochemical studies of kynurenine transamination in vitro invariably measure kynurenic acid, not 4-(2-aminophenyl)-2,4-dioxobutanoate, the expected transamination product. As noted by Miller et al. (1953), "The keto acid assumed to be formed prior to ring closure in the conversion of kynurenine to kynurenic acid has not yet been detected. In principle, such detection should be possible, since it is sufficiently stable to have been synthesized. It also remains to be established whether ring closure is spontaneous, enzymatic, or both. The formation of kynurenic acid from L-kynurenine by the L-amino acid oxidase of Neurospora suggests, however, that ring closure can be spontaneous, unless the somewhat improbable assumption is made that Neurospora filtrate contained the ring-closing enzyme." Authored: D'Eustachio, P, 2005-07-20 13:46:37 EC Number: 2.6.1.7 Edited: D'Eustachio, P, 2005-07-20 13:46:37 Pubmed13069505 Pubmed18056995 Reactome Database ID Release 43893583 Reactome, http://www.reactome.org ReactomeREACT_25131 Reviewed: Jassal, B, 2010-11-09 4-(2-aminophenyl)-2,4-dioxobutanoate => kynurenate + H2O [mitochondrial] 4-(2-aminophenyl)-2,4-dioxobutanoate => kynurenic acid + H2O [mitochondrial] Authored: D'Eustachio, P, 2010-07-01 Edited: D'Eustachio, P, 2010-07-01 Mitochondrial 4-(2-aminophenyl)-2,4-dioxobutanoate is thought to spontaneously condense with the elimination of water to form kynurenic acid (kynurenate).<p>Biochemical studies of kynurenine transamination in vitro invariably measure kynurenic acid, not 4-(2-aminophenyl)-2,4-dioxobutanoate, the expected transamination product. The reaction annotated here has not been demonstrated directly. As noted by Miller et al. (1953), "The keto acid assumed to be formed prior to ring closure in the conversion of kynurenine to kynurenic acid has not yet been detected. In principle, such detection should be possible, since it is sufficiently stable to have been synthesized. It also remains to be established whether ring closure is spontaneous, enzymatic, or both. The formation of kynurenic acid from L-kynurenine by the L-amino acid oxidase of Neurospora suggests, however, that ring closure can be spontaneous, unless the somewhat improbable assumption is made that Neurospora filtrate contained the ring-closing enzyme." Pubmed13069505 Reactome Database ID Release 43893597 Reactome, http://www.reactome.org ReactomeREACT_25181 Reviewed: Jassal, B, 2010-11-09 glutamate + acetyl CoA => N-acetyl glutamate + CoA Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 2.3.1.1 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Mitochondrial N acetylglutamate synthetase (NAGS) catalyzes the reaction of glutamate and acetyl-CoA to form N-acetylglutamate and CoA. NAGS is activated by arginine and the N-acetylglutamate produced in the reaction in turn is required to activate carbamoyl synthetase I. Consistent with this regulatory role in urea synthesis, NAGS mutations in humans are associated with hyperammonemia (Caldovic et al. 2002; Morizono et al. 2004). Pubmed12459178 Pubmed15050968 Reactome Database ID Release 4370542 Reactome, http://www.reactome.org ReactomeREACT_2139 2 ATP + NH4+ + HCO3- => 2 ADP + orthophosphate + carbamoyl phosphate 2 ATP + NH4+ + HCO3- => 2 ADP + orthophosphate + carbamoyl phosphate [mitochondrial] At the beginning of this reaction, 1 molecule of 'NH4+', 1 molecule of 'HCO3-', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'Carbamoyl phosphate', 1 molecule of 'ADP', and 1 molecule of 'Orthophosphate' are present.<br><br> This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'carbamoyl-phosphate synthase (ammonia) activity' of 'carbamoyl-phosphate synthetase I dimer'.<br> Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 6.3.4.16 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed6249820 Reactome Database ID Release 4370555 Reactome, http://www.reactome.org ReactomeREACT_1701 has a Stoichiometric coefficient of 2 carbamoyl phosphate + ornithine => citrulline + orthophosphate Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 2.1.3.3 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Mitochondrial ornithine transcarbamoylase (OTC) catalyzes the reaction of ornithine and carbamoyl phosphate to form citrulline (Horwich et al. 1984). The enzyme is a homotrimer (Shi et al. 2001). Pubmed11237854 Pubmed6372096 Reactome Database ID Release 4370560 Reactome, http://www.reactome.org ReactomeREACT_801 ATP + aspartate + citrulline <=> argininosuccinate + AMP + pyrophosphate Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic argininosuccinate synthase catalyzes the reaction of aspartate, citrulline, and ATP to form argininosuccinate, AMP, and pyrophosphate. The function of the human enzyme in vivo is inferred from the hypercitrullinemia observed in patients with defective forms of the enzyme (e.g., Engel et al. 2009). The enzyme is active as a homotetramer (O’Brien 1980; Karlberg et al. 2008). EC Number: 6.3.4.5 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed18323623 Pubmed19006241 Pubmed518841 Reactome Database ID Release 4370577 Reactome, http://www.reactome.org ReactomeREACT_482 argininosuccinate <=> fumarate + arginine Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic argininosuccinate lyase (ASL) catalyzes the reversible reaction of argininosuccinate to form fumarate and arginine. The enzyme is a homotetramer (Turner et al. 1997). The function of the human enzyme in vivo is inferred from the defective argininosuccinate lyase enzyme activity observed in patients with mutant forms of the ASL gene (e.g., Walker et al. 1990). EC Number: 4.3.2.1 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed2263616 Pubmed9256435 Reactome Database ID Release 4370573 Reactome, http://www.reactome.org ReactomeREACT_1378 arginine + H2O => ornithine + urea [ARG1] Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic Arginase 1 (ARG1) trimer catalyzes the hydrolysis of arginine to yield ornithine and urea (DiCostanzo et al. 2005). Patients expressing mutated forms of the enzyme with diminished in vitro arginase activity can accumulate arginine to pathogenic levels in the blood (e.g., Uchino et al. 1995). EC Number: 3.5.3.1 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed16141327 Pubmed7649538 Reactome Database ID Release 4370569 Reactome, http://www.reactome.org ReactomeREACT_394 spherical HDL:apoC-II:apoC-III:apoE Reactome DB_ID: 174643 Reactome Database ID Release 43174643 Reactome, http://www.reactome.org ReactomeREACT_6983 has a Stoichiometric coefficient of 1 ApoB-48:TG:PL complex Reactome DB_ID: 174729 Reactome Database ID Release 43174729 Reactome, http://www.reactome.org ReactomeREACT_7119 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 40 has a Stoichiometric coefficient of 60 chylomicron remnant:apoE complex Reactome DB_ID: 174792 Reactome Database ID Release 43174792 Reactome, http://www.reactome.org ReactomeREACT_7274 has a Stoichiometric coefficient of 1 spherical HDL:apoA-I:apoA-II:apoA-IV:apoC-II:apoC-III Reactome DB_ID: 174769 Reactome Database ID Release 43174769 Reactome, http://www.reactome.org ReactomeREACT_7030 has a Stoichiometric coefficient of 1 chylomicron remnant Reactome DB_ID: 174807 Reactome Database ID Release 43174807 Reactome, http://www.reactome.org ReactomeREACT_7202 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 50 LPL:LPL Reactome DB_ID: 174592 Reactome Database ID Release 43174592 Reactome, http://www.reactome.org ReactomeREACT_7876 has a Stoichiometric coefficient of 2 lipoprotein lipase dimer HSPG:LPL:LPL HSPG-bound lipoprotein lipase Reactome DB_ID: 174691 Reactome Database ID Release 43174691 Reactome, http://www.reactome.org ReactomeREACT_7472 has a Stoichiometric coefficient of 1 TG-depleted chylomicron Reactome DB_ID: 174798 Reactome Database ID Release 43174798 Reactome, http://www.reactome.org ReactomeREACT_7393 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 50 mature CM Reactome DB_ID: 174697 Reactome Database ID Release 43174697 Reactome, http://www.reactome.org ReactomeREACT_7446 chylomicron has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 spherical HDL Reactome DB_ID: 265523 Reactome Database ID Release 43265523 Reactome, http://www.reactome.org ReactomeREACT_14247 has a Stoichiometric coefficient of 140 has a Stoichiometric coefficient of 160 has a Stoichiometric coefficient of 20 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 40 mature high-density lipoprotein spherical high-density lipoprotein ornithine (cytosolic) + citrulline (mitochondrial) => ornithine (mitochondrial) + citrulline (cytosolic) Authored: D'Eustachio, P, 2003-06-24 00:00:00 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed10369256 Pubmed12807890 Pubmed12948741 Reactome Database ID Release 4370634 Reactome, http://www.reactome.org ReactomeREACT_151 The mitochondrial ornithine transporters SLC25A15 and SLC25A2 mediate the exchange of cytosolic ornithine for citrulline from the mitochondrial matrix. SLC25A15 was the first protein shown to have this function, identified because mutations in the protein are associated with elevated levels of ammonia, ornithine, and citrulline in affected individuals (Camacho et al. 1999). The second transporter, SLC25A2, identified later, is also expressed in normal cells and their apparently partly redundant function may explain the relatively mild symptoms associated with SLC25A15 deficiency compared to other defects of the urea cycle (Fiermonte et al. 2003). trimethyllysine + alpha-ketoglutarate + O2 => beta-hydroxy-trimethyllysine + succinate + CO2 EC Number: 1.14.11.8 Pubmed11431483 Reactome Database ID Release 4371241 Reactome, http://www.reactome.org ReactomeREACT_1814 Trimethyllysine dioxygenase dimer (TMLHE) in the mitochondrial matrix catalyzes the reaction of oxygen, 2-oxoglutarate, and 'N6,N6,N6-Trimethyl-L-lysine to form CO2, 3-Hydroxy-N6,N6,N6-trimethyl-L-lysine, and succinate (Vaz et al. 2001). arginine + H2O => ornithine + urea [ARG2] Arginase 2 (ARG2) trimer catalyzes the hydrolysis of arginine to form urea and ornithine (Cama et al. 2003). ARG2 is localized to the mitochondrion (Gotoh ea 1996). The enzyme is expressed in many tissues in addition to liver and while its function appears to mitigate the effects of ARG1 deficiency on urea synthesis, its normal physiological roles have not been fully defined (Iyer et al. 1998). Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 3.5.3.1 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed12859189 Pubmed8898077 Pubmed9686347 Reactome Database ID Release 43452036 Reactome, http://www.reactome.org ReactomeREACT_21325 gamma-butyrobetaine + alpha-ketoglutarate + O2 => carnitine + succinate + CO2 Cytosolic gamma-butyrobetaine hydroxylase dimer (BBOX1) catalyzes the reaction of oxygen, 4-trimethylammoniobutanoate, and 2-oxoglutarate to form C)2, succinate, and carnitine (Lindstedt and Nordin 1984; Vaz et al. 1998). EC Number: 1.14.11.1 Pubmed6497835 Pubmed9753662 Reactome Database ID Release 4371261 Reactome, http://www.reactome.org ReactomeREACT_417 arginine + glycine => ornithine + guanidoacetate EC Number: 2.1.4.1 Glycine amindinotransferase, localized to the mitochondrial intermembrane space, catalyzes the reaction of arginine and glycine to form guanidinoacetate and ornithine. The active form of the enzyme is a dimer (Humm et al. 1997 {EMBO J]; Humm et al 1997 [Biochem J]). Its function in vivo has been confirmed by molecular and biochemical studies of patients deficient in the enzyme (Item et al. 2001). Pubmed11555793 Pubmed9148748 Pubmed9218780 Reactome Database ID Release 4371275 Reactome, http://www.reactome.org ReactomeREACT_396 beta-hydroxy-trimethyllysine => gamma-butyrobetaine aldehyde + glycine Cytosolic serine hydroxymethyltransferase tetramer (SHMT1) catalyzes the reaction of 3-Hydroxy-N6,N6,N6-trimethyl-L-lysine to form glycine and 4-trimethylammoniobutanal (Hulse et al. 1978). EC Number: 2.1.2.1 Pubmed627563 Reactome Database ID Release 4371249 Reactome, http://www.reactome.org ReactomeREACT_1345 nascent chylomicron Reactome DB_ID: 174791 Reactome Database ID Release 43174791 Reactome, http://www.reactome.org ReactomeREACT_7358 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 gamma-butyrobetaine semialdehyde + NAD+ => gamma-butyrobetaine + NADH + H+ Cytosolic 4-trimethylaminobutyraldehyde dehydrogenase tetramer (ALDH9A1) catalyzes the reaction of NAD+', and 4-trimethylammoniobutanal to form 4-Trimethylammoniobutanoate and NADH + H+ (Kurys et al. 1989; Vaz et al. 2000). Pubmed10702312 Pubmed2925663 Reactome Database ID Release 4371260 Reactome, http://www.reactome.org ReactomeREACT_220 creatine + ATP => phosphocreatine + ADP [CK octamer] Authored: D'Eustachio, P, 2007-07-18 14:33:15 Creatine kinase octamers associated with the inner mitochondrial membrane catalyze the reaction of creatine and ATP to form phosphocreatine and ADP. Two mitochondrial creatine kinase proteins have been identified, one encoded by CKMT1A and B that is found in many tissues and one encoded by CKMT2 that is found in sarcomeres (Haas et al. 1988; Haas and Straus 1990). Studies of sarcomeric creatine kinase octamers suggest that their organization and association with phospholipids in the inner mitochondrial membrane may facilitate energy transfer from ATP generated in the mitochondrial matrix to cytosolic phosphocreatine (Khuchua et al. 1998; Schlattner et al. 2004). EC Number: 2.7.3.2 Pubmed15044463 Pubmed2324105 Pubmed2914937 Pubmed9722522 Reactome Database ID Release 43200326 Reactome, http://www.reactome.org ReactomeREACT_11155 guanidinoacetate + S-adenosylmethionine => creatine + S-adenosylhomocysteine Cytosolic guanidinoacetate methyltransferase catalyzes the reaction of S-adenosylmethionine and guanidinoacetate to form S-adenosylhomocysteine and creatine (Stockler et al. 1996). EC Number: 2.1.1 Pubmed8651275 Reactome Database ID Release 4371286 Reactome, http://www.reactome.org ReactomeREACT_2094 creatine + ATP => phosphocreatine + ADP [CKB,CKM] Authored: D'Eustachio, P, 2007-07-18 14:33:15 Cytosolic creatine kinase catalyzes the reaction of creatine and ATP to form phosphocreatine and ADP. The active form of the enzyme is a dimer. Monomers of the cytosolic enzyme occur in two isoforms, B and M, so called because of their abundance in brain and muscle respectively. The enzyme is widely expressed in the body and many tissues express both isoforms. Both homo- (BB, MM) and heterodimers (BM) are catalytically active. EC Number: 2.7.3.2 Pubmed16981706 Reactome Database ID Release 43200318 Reactome, http://www.reactome.org ReactomeREACT_11156 dimerized CEL:bile salt complex Reactome DB_ID: 192480 Reactome Database ID Release 43192480 Reactome, http://www.reactome.org ReactomeREACT_9547 has a Stoichiometric coefficient of 2 PNLIP:CLPS Reactome DB_ID: 192466 Reactome Database ID Release 43192466 Reactome, http://www.reactome.org ReactomeREACT_9829 has a Stoichiometric coefficient of 1 pancreatic lipase:colipase complex CEL:bile salt complex Reactome DB_ID: 192452 Reactome Database ID Release 43192452 Reactome, http://www.reactome.org ReactomeREACT_9624 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ABCG5:ABCG8 heterodimer Reactome DB_ID: 265452 Reactome Database ID Release 43265452 Reactome, http://www.reactome.org ReactomeREACT_14030 has a Stoichiometric coefficient of 1 NPC1L1:ezetimibe complex Reactome DB_ID: 265464 Reactome Database ID Release 43265464 Reactome, http://www.reactome.org ReactomeREACT_13878 has a Stoichiometric coefficient of 1 MTP:PDI:lipid complex Reactome DB_ID: 174681 Reactome Database ID Release 43174681 Reactome, http://www.reactome.org ReactomeREACT_7657 has a Stoichiometric coefficient of 1 ApoB-48:TG:PL complex Reactome DB_ID: 174630 Reactome Database ID Release 43174630 Reactome, http://www.reactome.org ReactomeREACT_7033 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 40 has a Stoichiometric coefficient of 60 nascent chylomicron Reactome DB_ID: 174626 Reactome Database ID Release 43174626 Reactome, http://www.reactome.org ReactomeREACT_7057 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 100 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 ApoB-48:TG:PL complex Reactome DB_ID: 174756 Reactome Database ID Release 43174756 Reactome, http://www.reactome.org ReactomeREACT_7014 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 40 has a Stoichiometric coefficient of 60 q-dihydrobiopterin + NADH + H+ => tetrahydrobiopterin + NAD+ Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic dihydropteridine reductase (QDPR) catalyzes the reaction of q-dihydrobiopterin with NADH + H+to form tetrahydrobiopterin and NAD+. The enzyme is a homodimer (Lockyer et al. 1987; Su et al. 1993). EC Number: 1.5.1.34 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed3033643 Pubmed8262916 Reactome Database ID Release 4371130 Reactome, http://www.reactome.org ReactomeREACT_1925 IMPA2:Mg2+ Reactome DB_ID: 1604574 Reactome Database ID Release 431604574 Reactome, http://www.reactome.org ReactomeREACT_151246 has a Stoichiometric coefficient of 1 tyrosine + alpha-ketoglutarate <=> p-hydroxyphenylpyruvate + glutamate Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic tyrosine aminotransferase (TAT) catalyzes the reversible reaction of tyrosine and alpha-keto (2-oxo) glutarate to form 3-(4-hydroxyphenyl)pyruvate and glutamate (Mitchell et al. 2001). The enzymatic activity of the protein encoded by the cloned human TAT cDNA is inferred from the biochemical properties of its rat homologue. Unpublished crystallographic studies (PDB 3DYD) have shown TAT to be a homodimer with a pyridoxal phosphate moity attached to lysine-280 in each monomer. EC Number: 2.6.1.5 Edited: D'Eustachio, P, 2003-06-24 00:00:00 ISBN0079130356 Reactome Database ID Release 4371155 Reactome, http://www.reactome.org ReactomeREACT_690 ISYNA1:NAD+ Reactome DB_ID: 2024052 Reactome Database ID Release 432024052 Reactome, http://www.reactome.org ReactomeREACT_150931 has a Stoichiometric coefficient of 1 p-hydroxyphenylpyruvate + glutamate <=> tyrosine + alpha-ketoglutarate Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic tyrosine aminotransferase (TAT) catalyzes the reversible reaction of 3-(4-hydroxyphenyl)pyruvate and glutamate to form tyrosine and alpha-keto (2-oxo) glutarate (Mitchell et al. 2001). The enzymatic activity of the protein encoded by the cloned human TAT cDNA is inferred from the biochemical properties of its rat homologue. Unpublished crystallographic studies (PDB 3DYD) have shown TAT to be a homodimer with a pyridoxal phosphate moity attached to lysine-280 in each monomer. EC Number: 2.6.1.5 Edited: D'Eustachio, P, 2003-06-24 00:00:00 ISBN0079130356 Reactome Database ID Release 43517444 Reactome, http://www.reactome.org ReactomeREACT_21382 p-hydroxyphenylpyruvate + O2 => homogentisate + CO2 Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic 4-hydroxyphenylpyruvate dioxygenase (HPD) catalyzes the reaction of 3-(4-Hydroxyphenyl)pyruvate with molecular oxygen to form homogentisate and CO2 (Ruetschi et al. 2000). Unpublished crystallographic data indicate that the enzyme is a homodimer (PDB 3ISQ). EC Number: 1.13.11.27 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed10942115 Reactome Database ID Release 4371163 Reactome, http://www.reactome.org ReactomeREACT_1145 L-1-pyrroline-5-carboxylate <=> L-glutamate gamma-semialdehyde Authored: D'Eustachio, P, 2003-06-24 00:00:00 Edited: D'Eustachio, P, 2003-06-24 00:00:00 ISBN0079130356 Reactome Database ID Release 4370667 Reactome, http://www.reactome.org ReactomeREACT_892 The interconversion of (S)-1-pyrroline-5-carboxylate and glutamate 5-semialdehyde is a spontaneous reaction. L-glutamate gamma-semialdehyde + NAD+ => glutamate + NADH + H+ Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 1.5.1.12 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Mitochondrial delta-1-pyrroline-5-carboxylate dehydrogenase (ALDH4A1) catalyzes the reaction of L-glutamate gamma-semialdehyde and NAD+ to form glutamate and NADH + H+ (Hu et al. 1996). The enzyme is a dimer (Forte-McRobbie and Pietruszko 1986). ALDH4A1 mutations cause type II hyperprolinemia in vivo (Geraghty et al. 1998). Pubmed3944130 Pubmed8621661 Pubmed9700195 Reactome Database ID Release 4370679 Reactome, http://www.reactome.org ReactomeREACT_2180 homogentisate + O2 => maleylacetoacetate Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic homogentisate 1,2-dioxygenase (HGD) catalyzes the reaction of homogentisate and molecular oxygen to form 4-maleylacetoacetate. The activity of human HGD is inferred from the phenotype of alkaptonuria patients, in whom HGD activity is defective (Fernandez-Canon et al. 1996). HGD is a homohexamer (Titus et al. 2000). EC Number: 1.13.11.5 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed10876237 Pubmed8782815 Reactome Database ID Release 4371164 Reactome, http://www.reactome.org ReactomeREACT_557 maleylacetoacetate => fumarylacetoacetate Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic maleylacetoacetic acid isomerase (GSTZ1) catalyzes the conversion of 4-maleylacetoacetate to 4-fumarylacetoacetate. The enzyme is a homodimer (Polekhina et al. 2001). EC Number: 5.2.1.2 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed11327815 Reactome Database ID Release 4371173 Reactome, http://www.reactome.org ReactomeREACT_1466 fumarylacetoacetate => fumarate + acetoacetate Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic fumarylacetoacetase catalyzes the hydrolysis of 4-fumarylacetoacetate to form fumarate and acetoacetate (Labelle et al. 1993). EC Number: 3.7.1.2 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed8364576 Reactome Database ID Release 4371181 Reactome, http://www.reactome.org ReactomeREACT_1297 proline => L-1-pyrroline-5-carboxylate Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 1.5.99.8 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed15662599 Reactome Database ID Release 4370670 Reactome, http://www.reactome.org ReactomeREACT_1563 The dehydrogenation of proline to L-1-pyrroline-5-carboxylate coupled to the conversion of FAD to FADH2 is the first step in proline breakdown (Bender et al. 2005). Proline dehydrogenase (PRODH), the enzyme that catalyzes this reaction, is found in liver, kidney, and brain cells, where it is tightly bound to the inner mitochondrial membrane. INPP1:Mg2+ Reactome DB_ID: 1604578 Reactome Database ID Release 431604578 Reactome, http://www.reactome.org ReactomeREACT_150912 has a Stoichiometric coefficient of 1 NUDT11:Mg2+/Mn2+ Reactome DB_ID: 1604636 Reactome Database ID Release 431604636 Reactome, http://www.reactome.org ReactomeREACT_152443 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 NUDT10:Mg2+/Mn2+ Reactome DB_ID: 1604659 Reactome Database ID Release 431604659 Reactome, http://www.reactome.org ReactomeREACT_150764 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 NUDT3:Mg2+ Reactome DB_ID: 1604627 Reactome Database ID Release 431604627 Reactome, http://www.reactome.org ReactomeREACT_151468 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 IMPA2 dimer Reactome DB_ID: 2024023 Reactome Database ID Release 432024023 Reactome, http://www.reactome.org ReactomeREACT_150928 has a Stoichiometric coefficient of 2 IMPA1:Mg2+ Reactome DB_ID: 1604570 Reactome Database ID Release 431604570 Reactome, http://www.reactome.org ReactomeREACT_151396 has a Stoichiometric coefficient of 1 IMPA1 dimer Reactome DB_ID: 2024021 Reactome Database ID Release 432024021 Reactome, http://www.reactome.org ReactomeREACT_151585 has a Stoichiometric coefficient of 2 IMPA1/2 Converted from EntitySet in Reactome Reactome DB_ID: 2024024 Reactome Database ID Release 432024024 Reactome, http://www.reactome.org ReactomeREACT_151896 N-formylkynurenine + H2O => kynurenine + formate Authored: D'Eustachio, P, 2005-07-20 13:46:37 Cytosolic arylformamidase (AFMID) catalyzes the hydrolysis of formylkynurenine to yield formate and L-kynurenine. Human AFMID has been identified only as an open reading frame; its activity is inferred from that of its well-characterized mouse homologue (Pabarcus and Casida 2002). EC Number: 3.5.1.9 Edited: D'Eustachio, P, 2005-07-20 13:46:37 Pubmed12007602 Reactome Database ID Release 4371189 Reactome, http://www.reactome.org ReactomeREACT_1804 DIPP Converted from EntitySet in Reactome NUDT(1) Reactome DB_ID: 2023957 Reactome Database ID Release 432023957 Reactome, http://www.reactome.org ReactomeREACT_151416 kynurenine + pyruvate => 4-(2-aminophenyl)-2,4-dioxobutanoic acid + alanine [CCBL1] Authored: D'Eustachio, P, 2010-07-01 CCBL1 (KAT 1) catalyzes the reaction of kynurenine and pyruvate to form 4-(2-aminophenyl)-2,4-dioxobutanoate and alanine. The active form of CCBL1 is a homodimer with one molecule of pyridoxal phosphate bound to each monomer (Baran et al. 1994; Han et al. 2009; Rossi et al. 2004). The enzyme's cytosolic localization is inferred from that of recombinant protein overexpressed in transfected cells (Perry et al. 1995). The pH optimum observed for CCBL1 in vitro is 9.5 - 10.0, so its role in kynurenine metabolism in vivo is not clear (Baran et al. 1994).<p>Biochemical studies of CCBL1 activity in vitro (e.g., Baren et al. 1994) invariably measure kynurenic acid as the reaction product, not 4-(2-aminophenyl)-2,4-dioxobutanoate, the product to be expected from transamination of kynurenine. The condensation of 4-(2-aminophenyl)-2,4-dioxobutanoate and elimination of a water molecule to form kynurenic acid has not been demonstrated directly. As noted by Miller et al. (1953), discussing their characterization of a bacterial form of the enzyme, "The keto acid assumed to be formed prior to ring closure in the conversion of kynurenine to kynurenic acid has not yet been detected. In principle, such detection should be possible, since it is sufficiently stable to have been synthesized. It also remains to be established whether ring closure is spontaneous, enzymatic, or both. The formation of kynurenic acid from L-kynurenine by the L-amino acid oxidase of Neurospora suggests, however, that ring closure can be spontaneous, unless the somewhat improbable assumption is made that Neurospora filtrate contained the ring-closing enzyme." EC Number: 2.6.1.7 Edited: D'Eustachio, P, 2010-07-01 Pubmed13069505 Pubmed15364907 Pubmed19338303 Pubmed7883047 Pubmed8294935 Reactome Database ID Release 43893596 Reactome, http://www.reactome.org ReactomeREACT_25349 Reviewed: Jassal, B, 2010-11-09 tryptophan + O2 => N-formylkynurenine [IDO] Authored: D'Eustachio, P, 2007-06-22 18:24:32 Cytosolic indoleamine 2,3-dioxygenase (IDO) catalyzes the conversion of L-tryptophan and oxygen to formylkynurenine. The structure and catalytic properties of the human enzyme have been analyzed directly (Sugimoto et al. 2006); the subcellular location and monomeric state of the active form of the enzyme are inferred from the properties of its rabbit ortholog (Shimizu et al. 1976). In the body, IDO is ubiquitously expressed and is induced by interferon. These properties, together with IDO's broad substrate specificity, are consistent with the hypothesis that the enzyme functions functions in anti bacterial and inflammatory processes (Taylor and Feng 1991). EC Number: 1.13.11.11 Edited: D'Eustachio, P, 2007-06-22 18:24:32 Pubmed16477023 Pubmed1907934 Pubmed26687 Reactome Database ID Release 43198563 Reactome, http://www.reactome.org ReactomeREACT_11113 ITPK1:Mg2+ Reactome DB_ID: 1604601 Reactome Database ID Release 431604601 Reactome, http://www.reactome.org ReactomeREACT_150860 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 F-box proteins Converted from EntitySet in Reactome Reactome DB_ID: 976085 Reactome Database ID Release 43976085 Reactome, http://www.reactome.org ReactomeREACT_76131 substrate recognition component of a SCF E3 ligase complex tryptophan + O2 => N-formylkynurenine [IDO2] Authored: D'Eustachio, P, 2010-07-01 Cytosolic indoleamine 2,3-dioxygenase 2 (IDO2) catalyzes the conversion of L-tryptophan and oxygen to formylkynurenine. The catalytic properties of the human enzyme have been analyzed directly; the subcellular location and monomeric state of the active form of the enzyme are inferred from the properties of its rabbit ortholog. In the body, IDO2 mRNA can be detected in a variety of cells, including dendritic cells, consistent with a normal role in immune function and a pathological one in tumor progression. Two IDO2 variants common in human populations encode enzymatically inactive protiens, suggesting that absence of IDO2 activity may be common in humans (Metz et al. 2007). EC Number: 1.13.11.11 Edited: D'Eustachio, P, 2010-07-01 Pubmed17671174 Reactome Database ID Release 43888614 Reactome, http://www.reactome.org ReactomeREACT_23860 NUDT4:Mg2+/Mn2+ Reactome DB_ID: 1604660 Reactome Database ID Release 431604660 Reactome, http://www.reactome.org ReactomeREACT_151588 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 tryptophan + O2 => N-formylkynurenine [TDO] Authored: D'Eustachio, P, 2005-07-20 13:46:37 Cytosolic tryptophan 2,3-dioxygenase (TDO) tetramer catalyzes the conversion of L-tryptophan and oxygen to formylkynurenine. The structure and catalytic properties of the human enzyme are inferred from the close similarity of its predicted amino acid sequence (Comings et al. 1995) to that of the well-studied rat enzyme (Dick et al. 2001). In the body, TDO is found predominantly in the liver and is induced by metabolites such as tryptophan and histidine, and by glucocorticoids. These properties, together with TDO's narrow substrate specificity, are consistent with the hypothesis that the enzyme functions functions primarily in tryptophan catabolism and NAD biosynthesis (Taylor and Feng 1991). EC Number: 1.13.11.11 Edited: D'Eustachio, P, 2005-07-20 13:46:37 Pubmed11469796 Pubmed1907934 Pubmed8666386 Reactome Database ID Release 4371188 Reactome, http://www.reactome.org ReactomeREACT_1007 BTB proteins BTB members of E3 ligase complex Converted from EntitySet in Reactome Reactome DB_ID: 976145 Reactome Database ID Release 43976145 Reactome, http://www.reactome.org ReactomeREACT_76750 3-hydroxyanthranilate + O2 => 2-amino-3-carboxymuconate semialdehyde Authored: D'Eustachio, P, 2005-07-20 13:46:37 Cytosolic 3-hydroxyanthranilate oxygenase catalyzes the reaction of 3-hydroxyanthranilate and O2 to form 2-amino-3-carboxymuconate semialdehyde. EC Number: 1.13.11.6 Edited: D'Eustachio, P, 2005-07-20 13:46:37 Pubmed7514594 Reactome Database ID Release 4371218 Reactome, http://www.reactome.org ReactomeREACT_612 kynurenine + O2 + NADPH + H+ => 3-hydroxykynurenine + NADP+ + H2O Authored: D'Eustachio, P, 2005-07-20 13:46:37 Cytosolic kynurenine 3-monooxygenase catalyzes the reaction of L-kynurenine, NADPH + H+, and O2 to form 3-hydroxy-L-kynurenine, NADP+, and H2O. EC Number: 1.14.13.9 Edited: D'Eustachio, P, 2005-07-20 13:46:37 Pubmed10672018 Reactome Database ID Release 4371200 Reactome, http://www.reactome.org ReactomeREACT_927 3-hydroxykynurenine + H2O => 3-hydroxyanthranilate + alanine Authored: D'Eustachio, P, 2005-07-20 13:46:37 Cytosolic kynureninase catalyzes the hydrolysis of 3-hydroxy-L-kynurenine to form L-alanine and 3-hydroxyanthranilate. EC Number: 3.7.1.3 Edited: D'Eustachio, P, 2005-07-20 13:46:37 Pubmed9180257 Reactome Database ID Release 4371217 Reactome, http://www.reactome.org ReactomeREACT_2234 kynurenine + pyruvate => 4-(2-aminophenyl)-2,4-dioxobutanoic acid + alanine [CCBL2] Authored: D'Eustachio, P, 2010-07-01 CCBL2 (KAT 3) catalyzes the reaction of kynurenine and pyruvate to form 4-(2-aminophenyl)-2,4-dioxobutanoate and alanine. CCBL2 is known only as the predicted protein product of a cloned human gene closely homologous to CCBL1 (Yu et al. 2006) and all of the structural and catalytic properties annotated here are inferred from those of CCBL1. EC Number: 2.6.1.7 Edited: D'Eustachio, P, 2010-07-01 Pubmed16376499 Reactome Database ID Release 43901097 Reactome, http://www.reactome.org ReactomeREACT_25310 Reviewed: Jassal, B, 2010-11-09 4-(2-aminophenyl)-2,4-dioxobutanoate => kynurenate + H2O [cytosolic] 4-(2-aminophenyl)-2,4-dioxobutanoate => kynurenic acid + H2O [cytosolic] Authored: D'Eustachio, P, 2010-07-01 Cytosolic 4-(2-aminophenyl)-2,4-dioxobutanoate is thought to spontaneously condense with the elimination of water to form kynurenic acid (kynurenate).<p>Biochemical studies of kynurenine transamination in vitro invariably measure kynurenic acid, not 4-(2-aminophenyl)-2,4-dioxobutanoate, the expected transamination product. The reaction annotated here has not been demonstrated directly. As noted by Miller et al. (1953), "The keto acid assumed to be formed prior to ring closure in the conversion of kynurenine to kynurenic acid has not yet been detected. In principle, such detection should be possible, since it is sufficiently stable to have been synthesized. It also remains to be established whether ring closure is spontaneous, enzymatic, or both. The formation of kynurenic acid from L-kynurenine by the L-amino acid oxidase of Neurospora suggests, however, that ring closure can be spontaneous, unless the somewhat improbable assumption is made that Neurospora filtrate contained the ring-closing enzyme." Edited: D'Eustachio, P, 2010-07-01 Pubmed13069505 Reactome Database ID Release 43893609 Reactome, http://www.reactome.org ReactomeREACT_25044 Reviewed: Jassal, B, 2010-11-09 ITPKA:Ca2+:CALM1 Reactome DB_ID: 2023885 Reactome Database ID Release 432023885 Reactome, http://www.reactome.org ReactomeREACT_150888 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 ITPKB:Ca2+:CALM1 Reactome DB_ID: 2023849 Reactome Database ID Release 432023849 Reactome, http://www.reactome.org ReactomeREACT_151354 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 ITPKC:Ca2+:CALM1 Reactome DB_ID: 2023848 Reactome Database ID Release 432023848 Reactome, http://www.reactome.org ReactomeREACT_151228 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 PTEN:Mg2+ PTEN (Mg2+ cofactor) Reactome DB_ID: 199426 Reactome Database ID Release 43199426 Reactome, http://www.reactome.org ReactomeREACT_12877 has a Stoichiometric coefficient of 1 PLCH2:Ca2+ Reactome DB_ID: 2023868 Reactome Database ID Release 432023868 Reactome, http://www.reactome.org ReactomeREACT_150800 has a Stoichiometric coefficient of 1 PLCD4:Ca2+ Reactome DB_ID: 2023869 Reactome Database ID Release 432023869 Reactome, http://www.reactome.org ReactomeREACT_151453 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 ITPKA/B/C Converted from EntitySet in Reactome Reactome DB_ID: 2023867 Reactome Database ID Release 432023867 Reactome, http://www.reactome.org ReactomeREACT_150733 ASB family Converted from EntitySet in Reactome Reactome DB_ID: 975431 Reactome Database ID Release 43975431 Reactome, http://www.reactome.org ReactomeREACT_76095 SOCS-1 and SOCS-3 Converted from EntitySet in Reactome Reactome DB_ID: 877267 Reactome Database ID Release 43877267 Reactome, http://www.reactome.org ReactomeREACT_25587 PathwayStep5997 PathwayStep5996 PathwayStep5999 PathwayStep5998 Transfer of sulfur from MOCS3-S-S onto MOCS2A Authored: Stephan, R, 2010-09-05 EC Number: 2.8.1 Edited: Jassal, B, 2010-09-08 Pubmed18650437 Reactome Database ID Release 43947538 Reactome, http://www.reactome.org ReactomeREACT_25006 Reviewed: D'Eustachio, P, 2010-11-05 Sulfur transfer onto MOCS2A is closely preceded by its adenylylation and deadenylylation. After release of MOCS2A-CO-S(1-), two cysteines on MOCS3 form a disulfide bridge. This means that MOCS3 has to be reduced to be able to participate in the next round. The reducing agent is not known (Marelja et al, 2008). Sulfhydrylation and ring cleavage of precursor Z After the MOCS2A dimer is loaded with two sulfur atoms, their sequential deposition on the precursor Z molecule, with ring cleavage, is catalyzed by the MOCS2B half of the MOCS2 tetramer (Leimkuhler et al, 2003; Wuebbens & Rajagopalan, 2002). Authored: Stephan, R, 2010-09-05 Edited: Jassal, B, 2010-09-08 Pubmed12571226 Pubmed12732628 Reactome Database ID Release 43947541 Reactome, http://www.reactome.org ReactomeREACT_25353 Reviewed: D'Eustachio, P, 2010-11-05 alanine + alpha-ketoglutarate <=> pyruvate + glutamate [GPT] Cytosolic glutamic-pyruvate transaminase (alanine aminotransferase) (GPT) catalyzes the reversible reaction of alanine and 2-oxoglutarate (alpha-ketoglutarate) to form pyruvate and glutamate (Sohocki et al. 1997; Yang et al. 2002). The active form of the enzyme is a dimer (Ishiguro et al. 1991) and is inferred to have a molecule of pyridoxal phosphate associated with each monomer. This reaction allows the synthesis of alanine from intermediates of glucose metabolism in a well-fed person. Under fasting conditions, alanine, derived from protein breakdown, can be converted to pyruvate and used to synthesize glucose via the gluconeogenic pathway in liver, or fully oxidized via the TCA cycle in other tissues. EC Number: 2.6.1.2 Pubmed11863375 Pubmed1931970 Pubmed9119391 Reactome Database ID Release 4370523 Reactome, http://www.reactome.org ReactomeREACT_196 pyruvate + glutamate <=> alanine + alpha-ketoglutarate [GPT] Cytosolic glutamic-pyruvate transaminase (alanine aminotransferase) (GPT) catalyzes the reversible reaction of pyruvate and glutamate to form alanine and 2-oxoglutarate (alpha-ketoglutarate) (Sohocki et al. 1997; Yang et al. 2002). The active form of the enzyme is a dimer (Ishiguro et al. 1991) and is inferred to have a molecule of pyridoxal phosphate associated with each monomer. This reaction allows the synthesis of alanine from intermediates of glucose metabolism in a well-fed person. Under fasting conditions, alanine, derived from protein breakdown, can be converted to pyruvate and used to synthesize glucose via the gluconeogenic pathway in liver, or fully oxidized via the TCA cycle in other tissues. EC Number: 2.6.1.2 Pubmed11863375 Pubmed1931970 Pubmed9119391 Reactome Database ID Release 4370524 Reactome, http://www.reactome.org ReactomeREACT_356 Molybdenum ion transfer onto molybdopterin Authored: Stephan, R, 2010-09-05 EC Number: 2 Edited: Jassal, B, 2010-09-08 Gephyrin, which stabilizes receptors on neuronal membranes, also catalyzes the transfer of a molybdenum ion onto the cofactor. The mechanism was elucidated in plants but, as the pathway is highly conserved, human gephyrin can complement missing plant proteins. Doubts remain about the actual molybdenum donor, probably molybdate, and whether a copper ion is possibly bound and removed (Stallmeyer et al, 1999). Pubmed9990024 Reactome Database ID Release 43947531 Reactome, http://www.reactome.org ReactomeREACT_25050 Reviewed: D'Eustachio, P, 2010-11-05 Exchange of oxygen with sulfur in MoCo Authored: Stephan, R, 2010-09-07 Edited: Jassal, B, 2010-09-08 Pubmed11302742 Reactome Database ID Release 43947499 Reactome, http://www.reactome.org ReactomeREACT_25122 Reviewed: D'Eustachio, P, 2010-11-05 While the biosynthesis of the molybdenum cofactor for sulfite oxidase is finished after molybdenum ion insertion, human xanthine oxidase and aldehyde oxidase will only show activity with this cofactor when one of the oxygens bound to molybdenum is replaced with sulfur. The exchange is catalyzed by the MOCOS cysteine desulfurase (Ichida et al, 2001). aspartate + alpha-ketoglutarate <=> oxaloacetate + glutamate [GOT2] EC Number: 2.6.1.1 Mitochondrial glutamate oxaloacetate transaminase 2 (aspartate aminotransferase 2 - GOT2) catalyzes the reversible reaction of aspartate and 2-oxoglutarate (alpha-ketoglutarate) to form oxaloacetate and glutamate (Martini et al. 1985). The active form of the enzyme is inferred to be a dimer with one molecule of pyridoxal phosphate associated with each monomer. Pubmed4052435 Reactome Database ID Release 4370596 Reactome, http://www.reactome.org ReactomeREACT_280 oxaloacetate + glutamate <=> aspartate + alpha-ketoglutarate [GOT1] Cytosolic aspartate aminotransferase (glutamate oxaloacetate transaminase 1 - GOT1) catalyzes the reversible reaction of oxaloacetate and glutamate to form aspartate and 2-oxoglutarate (alpha-ketoglutarate) (Doyle et al. 1990). Unpublished crystallographic data (PBD 3IIO) suggest the enzyme is a homodimer. EC Number: 2.6.1.1 Pubmed2241899 Reactome Database ID Release 4370581 Reactome, http://www.reactome.org ReactomeREACT_2078 pyruvate + glutamate <=> alanine + alpha-ketoglutarate [GPT2] Authored: D'Eustachio, P, 2010-02-18 EC Number: 2.6.1.2 Edited: D'Eustachio, P, 2010-02-18 Glutamic-pyruvate transaminase 2 (alanine aminotransferase 2) (GPT2) catalyzes the reversible reaction of pyruvate and glutamate to form alanine and 2-oxoglutarate (alpha-ketoglutarate) (Yang et al. 2002). Unpublished crystallographic data are consistent with a homodimeric structure for the enzyme with one molecule of pyridoxal phosphate associated with each monomer (PDB 3IHJ). Recent studies of organelles purified from cultured human muscle cells suggest that GPT2 is localized to mitochondria (Glinghammar et al. 2009). Pubmed11863375 Pubmed19360321 Reactome Database ID Release 43507749 Reactome, http://www.reactome.org ReactomeREACT_21311 Reviewed: Jassal, B, 2010-02-26 alanine + alpha-ketoglutarate <=> pyruvate + glutamate [GPT2] Authored: D'Eustachio, P, 2010-02-18 EC Number: 2.6.1.2 Edited: D'Eustachio, P, 2010-02-18 Glutamic-pyruvate transaminase 2 (alanine aminotransferase 2) (GPT2) catalyzes the reversible reaction of alanine and 2-oxoglutarate (alpha-ketoglutarate) to form pyruvate and glutamate (Yang et al. 2002). Unpublished crystallographic data are consistent with a homodimeric structure for the enzyme with one molecule of pyridoxal phosphate associated with each monomer (PDB 3IHJ). Recent studies of organelles purified from cultured human muscle cells suggest that GPT2 is localized to mitochondria (Glinghammar et al. 2009). Pubmed11863375 Pubmed19360321 Reactome Database ID Release 43507775 Reactome, http://www.reactome.org ReactomeREACT_21263 Reviewed: Jassal, B, 2010-02-26 ornithine + alpha-ketoglutarate <=> glutamate + L-glutamate gamma-semialdehyde [OAT] EC Number: 2.6.1.13 ISBN0079130356 Mitochondrial ornithine aminotransferase (OAT) catalyzes the reversible reaction of ornithine and alpha-ketoglutarate to form glutamate semialdehyde and glutamate (Ohura et al. 1982). The active enzyme is a hexamer (Shen et al. 1998). Inherited OAT deficiency leads to ornithine accumulation in vivo and gyrate atrophy of the choroid and retina (Brody et al. 1992; Valle and Simell 2001). Pubmed1737786 Pubmed6819292 Pubmed9514741 Reactome Database ID Release 4370654 Reactome, http://www.reactome.org ReactomeREACT_14 glutamate + L-glutamate gamma-semialdehyde <=> ornithine + alpha-ketoglutarate [OAT] EC Number: 2.6.1.13 ISBN0079130356 Mitochondrial ornithine aminotransferase (OAT) catalyzes the reversible reaction of glutamate semialdehyde and glutamate to form ornithine and alpha-ketoglutarate (Ohura et al. 1982). The active enzyme is a hexamer (Shen et al. 1998). Inherited OAT deficiency leads to ornithine accumulation in vivo and gyrate atrophy of the choroid and retina (Brody et al. 1992; Vallee and Simell 2001). Pubmed1737786 Reactome Database ID Release 4370666 Reactome, http://www.reactome.org ReactomeREACT_189 glutamate + ATP + NADPH + H+ => L-glutamate gamma-semialdehyde + NADP+ + ADP + orthophosphate [P5CS] Authored: D'Eustachio, P, 2010-02-18 Delta-1-pyrroline-5-carboxylate synthetase associated with the inner mitochondrial membrane catalyzes the two-step reaction that converts glutamate, ATP, and NADPH + H+ to L-glutamate gamma-semialdehyde, NADP+, ADP, and orthophosphate. Two P5CS isoforms have been identified; both are active when expressed in enzyme-deficient cells in culture (Hu et al. 1999). Unpublished crystallographic data (PDB 2H5G) indicate that the enzyme is a dimer. Edited: D'Eustachio, P, 2010-02-18 Pubmed10037775 Reactome Database ID Release 43508040 Reactome, http://www.reactome.org ReactomeREACT_21319 Reviewed: Jassal, B, 2010-02-26 L-glutamate gamma-semialdehyde <=> L-1-pyrroline-5-carboxylate ISBN0079130356 Reactome Database ID Release 4370655 Reactome, http://www.reactome.org ReactomeREACT_1764 The interconversion of glutamate 5-semialdehyde and (S)-1-pyrroline-5-carboxylate is a spontaneous reaction. L-1-pyrroline-5-carboxylate + NADPH + H+ => proline + NADP+ EC Number: 1.5.1.2 ISBN0079130356 Pubmed19648921 Pubmed2722838 Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the reaction of (S)-1-pyrroline-5-carboxylate with NADPH + H+ to form proline and NADP+ (Merrill et al. 1989). The active enzyme is a homodecamer (Meng et al. 2006). Recent immunofluoresence studies show that PYCR1 colocalizes with mitochondrial markers including pyrroline 5-carboxylate synthase in cultured human fibroblasts (Reversade et al. 2009). Reactome Database ID Release 4370664 Reactome, http://www.reactome.org ReactomeREACT_119 aspartate + glutamine + ATP <=> asparagine + glutamate + AMP + pyrophosphate [ASNS] Cytosolic asparagine synthase (ASNS) catalyzes the reaction of aspartate, glutamine, and ATP to form asparagine, glutamate, AMP, and pyrophosphate. Studies of the recombinant protein expressed in E. coli suggest that the active form of the enzyme is a dimer (Van Heeke and Schuster 1989). EC Number: 6.3.5.4 Pubmed2564390 Reactome Database ID Release 4370599 Reactome, http://www.reactome.org ReactomeREACT_277 alpha-ketoglutarate + NH4+ + NAD(P)H + H+ <=> glutamate + NAD(P)+ [GLUD1] EC Number: 1.4.1.3 Mitochondrial glutamate dehydrogenase 1 (GLUD1) catalyzes the reversible reaction of 2-oxoglutarate, NAD(P)H + H+, and ammonia to form glutamate and NAD(P)+ (Fang et al. 2002). Mature GLUD1 protein lacks the 53 aminoterminal residues of the nascent protein (Julliard and Smith 1979), which function as a mitochondrial import signal. The active form of the enzyme is a hexamer, allosterically activated by ADP and inhibited by GTP (Fang et al. 2002; Smith et al. 2002). Pubmed11903050 Pubmed12054821 Pubmed429360 Reactome Database ID Release 4370589 Reactome, http://www.reactome.org ReactomeREACT_1896 glutamate + NH4+ + ATP => glutamine + ADP + orthophosphate [GLUL] Cytosolic glutamine synthetase (glutamate-ammonia ligase - GLUL) catalyzes the reaction of glutamate, ammonia, and ATP to form glutamine, ADP, and orthophosphate. The enzyme is a decamer (Krajewski et al. 2008). Mutations in the gene encoding GLUL cause glutamine deficiency in vivo (Haberle et al. 2005). EC Number: 6.3.1.2 EC Number: mate-ammonia Pubmed16267323 Pubmed18005987 Reactome Database ID Release 4370606 Reactome, http://www.reactome.org ReactomeREACT_1171 glutamate + NAD(P)+ => alpha-ketoglutarate + NH4+ + NAD(P)H + H+ [GLUD1] EC Number: 1.4.1.3 Mitochondrial glutamate dehydrogenase 1 (GLUD1) catalyzes the reversible reaction of glutamate and NAD(P)+ to form 2-oxoglutarate, NAD(P)H + H+, and ammonia (Fang et al. 2002). Mature GLUD1 protein lacks the 53 aminoterminal residues of the nascent protein (Julliard and Smith 1979), which function as a mitochondrial import signal. The active form of the enzyme is a hexamer, allosterically activated by ADP and inhibited by GTP (Fang et al. 2002; Smith et al. 2002). Pubmed11903050 Pubmed12054821 Pubmed429360 Reactome Database ID Release 4370600 Reactome, http://www.reactome.org ReactomeREACT_710 glutamine + H2O => glutamate + NH4+ [GLS] EC Number: 3.5.1.2 Mitochondrial glutaminase (GLS) catalyzes the hydrolysis of glutamine to yield glutamate and ammonia. Two GLS enzymes have been identified, one abundantly expressed in the liver (GLS - Elgadi et al. 1999) and one abundantly expressed in kidney (GLS2 - Gomez-Fabre et al. 2000). Their biochemical properties are similar. The enzymes are inferred to function as dimers based on unpublished crystallographic data for GLS (PDB 3CZD) and studies of glutaminase enzyme purified from Ehrlich Ascites cells (Quesada et al. 1988). Pubmed10620514 Pubmed11015561 Pubmed3214421 Reactome Database ID Release 4370609 Reactome, http://www.reactome.org ReactomeREACT_1700 (PP)2-IP4 Converted from EntitySet in Reactome Reactome DB_ID: 2023936 Reactome Database ID Release 432023936 Reactome, http://www.reactome.org ReactomeREACT_151687 (PP)2-IP4 Converted from EntitySet in Reactome Reactome DB_ID: 2023968 Reactome Database ID Release 432023968 Reactome, http://www.reactome.org ReactomeREACT_151108 DGAT1 tetramer Reactome DB_ID: 200109 Reactome Database ID Release 43200109 Reactome, http://www.reactome.org ReactomeREACT_11651 has a Stoichiometric coefficient of 4 PP-IP4 Converted from EntitySet in Reactome Reactome DB_ID: 2023943 Reactome Database ID Release 432023943 Reactome, http://www.reactome.org ReactomeREACT_150700 GPD1L dimer Glycerol-3-phosphate dehydrogenase 1-like homodimer Reactome DB_ID: 1500615 Reactome Database ID Release 431500615 Reactome, http://www.reactome.org ReactomeREACT_119633 has a Stoichiometric coefficient of 2 Trifunctional Protein Reactome DB_ID: 77267 Reactome Database ID Release 4377267 Reactome, http://www.reactome.org ReactomeREACT_5142 has a Stoichiometric coefficient of 2 ACADVL dimer Reactome DB_ID: 77279 Reactome Database ID Release 4377279 Reactome, http://www.reactome.org ReactomeREACT_2285 VLCAD acyl-CoA dehydrogenase homodimer has a Stoichiometric coefficient of 4 ECHS1 hexamer Reactome DB_ID: 71048 Reactome Database ID Release 4371048 Reactome, http://www.reactome.org ReactomeREACT_5859 enoyl-CoA hydratase hexamer has a Stoichiometric coefficient of 6 ACADL tetramer LCAD acyl-CoA dehydrogenase homotetramer Reactome DB_ID: 77258 Reactome Database ID Release 4377258 Reactome, http://www.reactome.org ReactomeREACT_5750 has a Stoichiometric coefficient of 4 ACADM tetramer MCAD acyl-CoA dehydrogenase homotetramer Reactome DB_ID: 77335 Reactome Database ID Release 4377335 Reactome, http://www.reactome.org ReactomeREACT_4772 has a Stoichiometric coefficient of 4 HADH dimer Reactome DB_ID: 71052 Reactome Database ID Release 4371052 Reactome, http://www.reactome.org ReactomeREACT_2262 has a Stoichiometric coefficient of 2 short chain 3-hydroxyacyl-CoA dehydrogenase homodimer DCI dimer 3,2-trans-enoyl-CoA isomerase Homodimer Reactome DB_ID: 110060 Reactome Database ID Release 43110060 Reactome, http://www.reactome.org ReactomeREACT_2924 has a Stoichiometric coefficient of 2 ACADS tetramer Reactome DB_ID: 77316 Reactome Database ID Release 4377316 Reactome, http://www.reactome.org ReactomeREACT_5531 SCAD acyl-CoA dehydrogenase homotetramer has a Stoichiometric coefficient of 4 urocanate + H2O => 4-imidazolone-5-propionate Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic urocanate hydratase (UROC1) catalyzes the hydrolysis of urocanate to form 4-imidazolone-5-propanoate. Human UROC1 was first identified in surveys of genes differentially expressed in hepatoblastoma (Yamamda et al. 2004). Recent biochemical and molecular studies of UROC1 protein and cDNA from a patient with urocanic aciduria has confirmed the function of UROC1 in vivo (Espinos et al. 2009). EC Number: 4.2.1.49 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed15221005 Pubmed19304569 Reactome Database ID Release 4370903 Reactome, http://www.reactome.org ReactomeREACT_1166 histidine => urocanate + NH4+ Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic histidine ammonia lyase (HAL) catalyzes the reaction of histidine to form urocanate and NH4+ (Kawai et al. 2005). EC Number: 4.3.1.3 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed15806399 Reactome Database ID Release 4370899 Reactome, http://www.reactome.org ReactomeREACT_1225 methylmalonate semialdehyde + NAD+ + CoA => propionyl-CoA + CO2 + NADH + H+ EC Number: 1.2.1.27 Mitochondrial methylmalonate semialdehyde dehydrogenase (ALDH6A1) catalyzes the reaction of methylmalonate semialdehyde, NAD+, and CoA to form propionyl-CoA, CO2, and NADH + H+. A human ALDH6A1 gene has been cloned. Its sequence is closely homologous to that of the better-characterized rat enzyme (Kedishvili et al. 1992) and a missense mutation in a normally well-conserved codon has been found in the allele of the gene from a patient with a defect in methylmalonic semialdehyde dehydrogenase activity (Chambliss et al. 2000). Pubmed10947204 Pubmed1527093 Reactome Database ID Release 4370893 Reactome, http://www.reactome.org ReactomeREACT_1077 methylmalonyl semialdehyde + NADH + H+ <=> beta-hydroxyisobutyrate + NAD+ Authored: D'Eustachio, P, 2010-02-18 EC Number: 1.1.1.31 Edited: D'Eustachio, P, 2010-02-18 Mitochondrial 3-hydroxyisobutyrate dehydrogenase (HIBADH) catalyzes the reversible reaction of methylmalonyl semialdehyde and NADH + H+ to form beta-hydroxyisobutyrate and NAD+. The biochemical properties of human HIBADH are inferred from those of its better-studied porcine homologue (Robinson and Coon 1957). Unpublished crystallographic studies (PDB 2GF2) have shown the active enzyme to be a tetramer of HIBADH polypeptides whose aminoterminal 40 residues, a mitochondrial targeting sequence, have been removed. Pubmed13416257 Reactome Database ID Release 43508473 Reactome, http://www.reactome.org ReactomeREACT_21400 Reviewed: Jassal, B, 2010-02-26 lysine + alpha-ketoglutarate +NADPH + H+ => saccharopine + NADP+ + H2O Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 1.5.1.8 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed10775527 Pubmed6434529 Reactome Database ID Release 4370938 Reactome, http://www.reactome.org ReactomeREACT_75 The saccharopine dehydrogenase activity of lysine-ketoglutarate reductase / saccharopine dehydrogenase homotetramer in the mitochondrial matrix catalyzes the reaction of lysine, alpha-ketoglutarate, and NADPH + H+ to form saccharopine, NADP+, and H2O (Markovitz et al. 1984; Sacksteder et al. 2001). Histidine is decarboxylated to histamine Authored: Stephan, R, 2010-10-15 Decarboxylation of L-Histidine happens analogously to other decarboxylations of amino acids. It uses the cofactor pyridoxal phosphate and is catalyzed by histidine decarboxylase (Mamune-Sato et al, 1992). EC Number: 4.1.1.22 Edited: Jassal, B, 2010-10-18 GENE ONTOLOGYGO:0001694 Pubmed1425659 Reactome Database ID Release 43977301 Reactome, http://www.reactome.org ReactomeREACT_115661 Reviewed: D'Eustachio, P, 2011-10-26 N-formiminoglutamate + tetrahydrofolate => glutamate + 5-formiminotetrahydrofolate Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic formimidoyltransferase-cyclodeaminase (FTCD) catalyzes the reaction of N-formiminoglutamate and tetrahydrofolate to form glutamate and 5-formiminotetrahydrofolate. The gene encoding the human enzyme has beeen cloned and its sequence can encode a protein homologous the the biochemically characterized porcine protein (Solans et al. 2000; Murley et al. 1993). The function of FTCD in vivo was established by identification of missense mutations that reduce enzyme activity in patients with glutamate formiminotransferase deficiency (Hilton et al. 2003). Human FTCD is inferred to be an octamer by homology to the porcine enzyme (Murley et al. 1993). EC Number: 4.3.1.4 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed10773664 Pubmed12815595 Pubmed7901203 Reactome Database ID Release 4370920 Reactome, http://www.reactome.org ReactomeREACT_485 4-imidazolone-5-propionate + H2O => N-formiminoglutamate + 2H+ Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic imidazolonepropionase catalyzes the hydrolysis of 4-imidazolone-5-propanoate to form N-Formimino-L-glutamate. While evidence from many experimental systems indicates that this reaction occurs, existence of the human enzyme is inferred only from high-throughput screening studies (e.g., Yamada et al. 2004). EC Number: 3.5.2 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed15221005 Reactome Database ID Release 4370906 Reactome, http://www.reactome.org ReactomeREACT_573 has a Stoichiometric coefficient of 2 beta-hydroxyisobutyrate + NAD+ <=> methylmalonyl semialdehyde + NADH + H+ EC Number: 1.1.1.31 Mitochondrial 3-hydroxyisobutyrate dehydrogenase (HIBADH) catalyzes the reversible reaction of beta-hydroxyisobutyrate and NAD+ to form methylmalonyl semialdehyde and NADH + H+. The biochemical properties of human HIBADH are inferred from those of its better-studied porcine homologue (Robinson and Coon 1957). Unpublished crystallographic studies (PDB 2GF2) have shown the active enzyme to be a tetramer of HIBADH polypeptides whose aminoterminal 40 residues, a mitochondrial targeting sequence, have been removed. Pubmed13416257 Reactome Database ID Release 4370885 Reactome, http://www.reactome.org ReactomeREACT_1514 Reviewed: Jassal, B, 2010-02-26 beta-hydroxyisobutyryl-CoA + H2O => beta-hydroxyisobutyrate + CoA EC Number: 3.1.2.4 Mitochondrial 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) catalyzes the hydrolysis of beta-hydroxyisobutyryl-CoA to form beta-hydroxyisobutyrate (3-hydroxy-2-methylpropanoate) and CoA (Hawes et al. 1996). Pubmed8824301 Reactome Database ID Release 4370881 Reactome, http://www.reactome.org ReactomeREACT_919 GPD1 dimer Glycerol-3-phosphate dehydrogenase homodimer Reactome DB_ID: 76117 Reactome Database ID Release 4376117 Reactome, http://www.reactome.org ReactomeREACT_5493 has a Stoichiometric coefficient of 2 FAS dimer FASN dimer Reactome DB_ID: 77380 Reactome Database ID Release 4377380 Reactome, http://www.reactome.org ReactomeREACT_5280 has a Stoichiometric coefficient of 2 GPD1/GPD1L homodimer Converted from EntitySet in Reactome Reactome DB_ID: 1500610 Reactome Database ID Release 431500610 Reactome, http://www.reactome.org ReactomeREACT_119910 phosphorylated HSL dimer:FABP4 complex Reactome DB_ID: 163535 Reactome Database ID Release 43163535 Reactome, http://www.reactome.org ReactomeREACT_4442 has a Stoichiometric coefficient of 1 Citrate lyase homotetramer Reactome DB_ID: 76188 Reactome Database ID Release 4376188 Reactome, http://www.reactome.org ReactomeREACT_3160 has a Stoichiometric coefficient of 4 perilipin:CGI-58 complex Reactome DB_ID: 163495 Reactome Database ID Release 43163495 Reactome, http://www.reactome.org ReactomeREACT_5654 has a Stoichiometric coefficient of 1 phosphorylated HSL dimer Reactome DB_ID: 163435 Reactome Database ID Release 43163435 Reactome, http://www.reactome.org ReactomeREACT_2496 has a Stoichiometric coefficient of 2 LDL Reactome DB_ID: 171082 Reactome Database ID Release 43171082 Reactome, http://www.reactome.org ReactomeREACT_7732 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1500 has a Stoichiometric coefficient of 170 has a Stoichiometric coefficient of 670 has a Stoichiometric coefficient of 690 low-density lipoprotein complex phosphorylated HSL dimer Reactome DB_ID: 163513 Reactome Database ID Release 43163513 Reactome, http://www.reactome.org ReactomeREACT_4459 has a Stoichiometric coefficient of 2 LDL Reactome DB_ID: 171044 Reactome Database ID Release 43171044 Reactome, http://www.reactome.org ReactomeREACT_7419 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1500 has a Stoichiometric coefficient of 170 has a Stoichiometric coefficient of 670 has a Stoichiometric coefficient of 690 low-density lipoprotein complex Exchange of cytosolic 2-oxoadipate for mitochondrial 2-oxoglutarate 2-oxoglutarate [mitochondrial matrix] + 2-oxoadipate [cytosol] <=> 2-oxoglutarate [cytosol] + 2-oxoadipate [mitochondrial matrix] Authored: D'Eustachio, P, 2008-09-12 21:47:19 Edited: D'Eustachio, P, 2008-09-12 21:47:19 Pubmed11083877 Reactome Database ID Release 43372480 Reactome, http://www.reactome.org ReactomeREACT_14838 SLC25A21, the mitochondrial 2-oxodicarboxylate carrier, mediates the exchange of 2-oxoadipate and 2-oxoglutarate across the inner mitochondrial membrane. While the exchange is reversible, under physiological conditions it proceeds in the direction of 2-oxoadipate import into the mitochondrial matrix and 2-oxoglutarate export (Fiermonte et al. 2001). alpha-ketoadipate + glutamate <=> alpha-aminoadipate + alpha-ketoglutarate Authored: D'Eustachio, P, 2010-02-18 EC Number: 2.6.1.39 Edited: D'Eustachio, P, 2010-02-18 Kynurenine/alpha-aminoadipate aminotransferase (AADAT) catalyzes the reversible reaction of alpha-ketoadipate and glutamate to form alpha-aminoadipate and alpha-ketoglutarate. Crystallographic studies have demonstrated that active AADAT enzyme is a homodimer with a pyridoxal phosphate moiety covalently attached to each monomer (Han et al. 2008; Rossi et al. 2008). The enzyme is inferred to be located within the mitochondrion because of a mitochondrial localization sequence motif at the aminoterminal end of the AADAT polypeptide (Goh et al. 2002). Pubmed12126930 Pubmed18056995 Pubmed18056996 Reactome Database ID Release 43508561 Reactome, http://www.reactome.org ReactomeREACT_21297 glutaryl-CoA + FAD => crotonyl-CoA + FADH2 + CO2 Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 1.3.99.7 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Mitochondrial glutaryl-CoA dehydrogenase (GCDH) catalyzes the reaction of glutaryl-CoA and FAD to form crotonyl-CoA, FADH2, and CO2. The active enzyme is a tetramer of GCDH polypeptides lacking a 44-residue aminoterminal mitochondrial targeting sequence. Mutations in GCDH cause glutaric aciduria type 1 in vivo (Fu et al. 2004; Keyser et al. 2008). Pubmed15274622 Pubmed18775954 Reactome Database ID Release 4371046 Reactome, http://www.reactome.org ReactomeREACT_1409 alpha-ketoadipate + CoASH + NAD+ => glutaryl-CoA + CO2 + NADH + H+ Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 1.2.1.52 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Oxidative decarboxylation of alpha-ketoadipate to glutaryl CoA by alpha-ketoglutarate dehydrogenase Pubmed11752427 Pubmed15946682 Pubmed2188967 Pubmed9727038 Reactome Database ID Release 4371037 Reactome, http://www.reactome.org ReactomeREACT_1865 The mitochondrial alpha-ketoglutarate dehydrogenase complex catalyzes the reaction of alpha-ketoadipate, CoASH, and NAD+ to form glutaryl-CoA, CO2, and NADH. The enzyme complex contains multiple copies of three different proteins, E1 (OGDH), E2 (DLST), and E3 (DLD), each with distinct catalytic activities (Reed and Hackert 1990; Zhou et al 2001). The reaction starts with the oxidative decarboxylation of alpha-ketoadipate catalyzed by E1alpha and beta (alpha ketoglutarate dehydrogenase). Lipoamide cofactor associated with E1 is reduced at the same time. Next, the glutaryl group derived from alpha ketoglutarate is transferred to coenzyme A in two steps catalyzed E2 (dihydrolipolyl transacetylase). Finally, the oxidized form of lipoamide is regenerated and electrons are transferred to NAD+ in two steps catalyzed by E3 (dihydrolipoyl dehydrogenase). The biochemical details of this reaction have been worked out with alpha ketoglutarate dehydrogenase complex and subunits purified from bovine tissue (McCartney et al. 1998). While all of the human proteins are known as predicted protein products of cloned genes, direct experimental evidence for their functions is available only for E3 (DLD) (Brautigam et al. 2005). phenylalanine + tetrahydrobiopterin + O2 => tyrosine + 4a-hydroxytetrahydrobiopterin + H2O Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic phenylalanine hydroxylase (PAH) catalyzes the reaction of phenylalanine, molecular oxygen and tetrahydrobiopterin to form tyrosine, water, and 4 alpha-hydroxytetrahydrobiopterin. The active form of the enzyme is a homotetramer (Fusetti et al. 1998). EC Number: 1.14.16.1 Edited: D'Eustachio, P, 2003-06-24 00:00:00 ISBN0079130356 Pubmed9642259 Reactome Database ID Release 4371118 Reactome, http://www.reactome.org ReactomeREACT_2 phenylalanine + pyruvate => 3-(indol-3-yl)pyruvate + alanine Authored: D'Eustachio, P, 2003-06-24 00:00:00 CCBL1 (KAT 1) catalyzes the reaction of phenylalanine and pyruvate to form 3-(indol-3-yl)pyruvate and alanine. The active form of CCBL1 is a homodimer with one molecule of pyridoxal phosphate bound to each monomer (Baran et al. 1994; Han et al. 2009; Rossi et al. 2004). The enzyme's cytosolic localization is inferred from that of recombinant protein overexpressed in transfected cells (Perry et al. 1995). EC Number: 2.6.1.58 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed15364907 Pubmed19338303 Pubmed7883047 Pubmed8294935 Reactome Database ID Release 43893593 Reactome, http://www.reactome.org ReactomeREACT_25224 Reviewed: Jassal, B, 2010-11-09 4a-hydroxytetrahydrobiopterin => q-dihydrobiopterin + H2O Authored: D'Eustachio, P, 2003-06-24 00:00:00 Cytosolic pterin-4-alpha-carbinolamine dehydratase (PCDB1) catalyzes the reaction of 4a-hydroxytetrahydrobiopterin to form q-dihydrobiopterin and water (Hauer et al. 1993. The active enzyme is a homotetramer (Ficner et al. 1995); mutations in the PCDB1 gene are associated with mild hyperphenylalanemia in vivo (Citron et al. 1993). EC Number: 4.2.1.96 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed7744010 Pubmed8352282 Pubmed8444860 Reactome Database ID Release 4371146 Reactome, http://www.reactome.org ReactomeREACT_2236 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of ABCA1' ACTIVATION Pubmed11135616 Pubmed19710929 Reactome Database ID Release 431989820 Reactome, http://www.reactome.org ReactomeREACT_117927 'IRF2:promoters of INF alpha, INF beta [nucleoplasm]' negatively regulates 'Expression of Interferon-alpha and beta' INHIBITION Reactome Database ID Release 43994052 Reactome, http://www.reactome.org ReactomeREACT_27125 'VAF/pIRF7:CBP/p300 bound to type I IFN gene promoter [nucleoplasm]' positively regulates 'Expression of Interferon-alpha and beta' ACTIVATION Reactome Database ID Release 431028813 Reactome, http://www.reactome.org ReactomeREACT_27084 saccharopine + NAD+ + H2O => alpha-aminoadipic semialdehyde + glutamate + NADH + H+ Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 1.5.1.9 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed10775527 Pubmed6434529 Reactome Database ID Release 4370940 Reactome, http://www.reactome.org ReactomeREACT_2132 The saccharopine dehydrogenase activity of lysine-ketoglutarate reductase / saccharopine dehydrogenase homotetramer in the mitochondrial matrix catalyzes the reaction of saccharopine (N6-(L-1,3-Dicarboxypropyl)-L-lysine), H2O, and NAD+ to form 'L-2-Aminoadipate 6-semialdehyde, glutamate, and NADH + H+ (Markovitz et al. 1984; Sacksteder et al. 2001). 'IRF1:Promotors of IFN alpha, IFN beta [nucleoplasm]' positively regulates 'Expression of Interferon-alpha and beta' ACTIVATION Reactome Database ID Release 43994043 Reactome, http://www.reactome.org ReactomeREACT_27109 'Transcription factor E2F [nucleoplasm]' positively regulates 'Cdc6 protein is synthesized under the control of E2F transcription factors' ACTIVATION Reactome Database ID Release 4368679 Reactome, http://www.reactome.org ReactomeREACT_5979 alpha-aminoadipate + alpha-ketoglutarate <=> alpha-ketoadipate + glutamate Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 2.6.1.39 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Kynurenine/alpha-aminoadipate aminotransferase (AADAT) catalyzes the reversible reaction of alpha-aminoadipate and alpha-ketoglutarate to form alpha-ketoadipate and glutamate. Crystallographic studies have demonstrated that active AADAT enzyme is a homodimer with a pyridoxal phosphate moiety covalently attached to each monomer (Han et al. 2008; Rossi et al. 2008). The enzyme is inferred to be located within the mitochondrion because of a mitochondrial localization sequence motif at the aminoterminal end of the AADAT polypeptide (Goh et al. 2002). Pubmed12126930 Pubmed18056995 Pubmed18056996 Reactome Database ID Release 4370952 Reactome, http://www.reactome.org ReactomeREACT_2065 'TBX5:WWTR1:PCAF [nucleoplasm]' positively regulates 'Expression of NPPA (ANF)' ACTIVATION Reactome Database ID Release 432032803 Reactome, http://www.reactome.org ReactomeREACT_120330 alpha-aminoadipic semialdehyde + NAD+ => alpha-aminoadipate + NADH + H+ Alpha-aminoadipic semialdehyde dehydrogenase (ALDH7A1) catalyzes the reaction of alpha-aminoadipic semialdehyde and NAD+ to form alpha-aminoadipate and NADH + H+ (Mills et al. 2006). Unpublished crystallographic data (PDB 2J6L) indicate that the enzyme is a homodimer. Recent immunofluorescence studies of both endogenous and GFP-tagged ALDH7A1 proteins in cultured human embryonic kidney cells indicate that the protein is present in both mitochondria and the cytosol (Wong et al. 2010). Authored: D'Eustachio, P, 2003-06-24 00:00:00 EC Number: 1.2.1.31 Edited: D'Eustachio, P, 2003-06-24 00:00:00 Pubmed16491085 Pubmed19885858 Reactome Database ID Release 4370941 Reactome, http://www.reactome.org ReactomeREACT_1540 'PPARA:RXRA Coactivator Complex [nucleoplasm]' positively regulates 'Expression of CTGF' ACTIVATION Pubmed20110263 Reactome Database ID Release 431989784 Reactome, http://www.reactome.org ReactomeREACT_118050 'TEAD:WWTR1(TAZ) [nucleoplasm]' positively regulates 'Expression of CTGF' ACTIVATION Reactome Database ID Release 432032783 Reactome, http://www.reactome.org ReactomeREACT_120312 'TEAD:YAP1 [nucleoplasm]' positively regulates 'Expression of CTGF' ACTIVATION Reactome Database ID Release 432032788 Reactome, http://www.reactome.org ReactomeREACT_120346 LDL Reactome DB_ID: 171112 Reactome Database ID Release 43171112 Reactome, http://www.reactome.org ReactomeREACT_7890 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1500 has a Stoichiometric coefficient of 170 has a Stoichiometric coefficient of 670 has a Stoichiometric coefficient of 690 low-density lipoprotein complex LDL:LDLR complex Reactome DB_ID: 171108 Reactome Database ID Release 43171108 Reactome, http://www.reactome.org ReactomeREACT_7278 has a Stoichiometric coefficient of 1 LDL Reactome DB_ID: 171156 Reactome Database ID Release 43171156 Reactome, http://www.reactome.org ReactomeREACT_7069 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 1500 has a Stoichiometric coefficient of 170 has a Stoichiometric coefficient of 670 has a Stoichiometric coefficient of 690 low-density lipoprotein complex LDL:LDLR complex Reactome DB_ID: 171056 Reactome Database ID Release 43171056 Reactome, http://www.reactome.org ReactomeREACT_7533 has a Stoichiometric coefficient of 1 apoA-I:CUBN:AMN complex Reactome DB_ID: 264851 Reactome Database ID Release 43264851 Reactome, http://www.reactome.org ReactomeREACT_14546 has a Stoichiometric coefficient of 1 LDL:cholesterol ester complex Reactome DB_ID: 266339 Reactome Database ID Release 43266339 Reactome, http://www.reactome.org ReactomeREACT_14115 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Lp(a) Reactome DB_ID: 176866 Reactome Database ID Release 43176866 Reactome, http://www.reactome.org ReactomeREACT_7145 apolipoprotein(a):LDL complex has a Stoichiometric coefficient of 1 LDL:LDLR complex Reactome DB_ID: 171100 Reactome Database ID Release 43171100 Reactome, http://www.reactome.org ReactomeREACT_7628 has a Stoichiometric coefficient of 1 spherical HDL Reactome DB_ID: 349644 Reactome Database ID Release 43349644 Reactome, http://www.reactome.org ReactomeREACT_14142 has a Stoichiometric coefficient of 140 has a Stoichiometric coefficient of 160 has a Stoichiometric coefficient of 20 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 40 mature high-density lipoprotein spherical high-density lipoprotein CUBN:AMN complex Reactome DB_ID: 264830 Reactome Database ID Release 43264830 Reactome, http://www.reactome.org ReactomeREACT_14330 has a Stoichiometric coefficient of 1 a-ketoisocaproate, a-keto-b-methylvalerate, or a-ketoisovalerate + glutamate <=> leu, ile, or val + alpha-ketoglutarate [BCAT2] Authored: D'Eustachio, P, 2010-02-18 EC Number: 2.6.1.42 Edited: D'Eustachio, P, 2010-02-18 Mitochondrial branched-chain-amino-acid aminotransferase (BCAT2) catalyzes the reversible reactions of alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or a-ketoisovalerate with glutamate to form leucine, isoleucine, or valine, respectively, and alpha-ketoglutarate (Bledsoe et al. 1997). The active enzyme is a homodimer (Yennawar et al. 2001, 2002). In the body, this enzyme is widely expressed but is especially abundant in muscle tissue. Pubmed11264579 Pubmed12269802 Pubmed9165094 Reactome Database ID Release 43508179 Reactome, http://www.reactome.org ReactomeREACT_21409 Reviewed: Jassal, B, 2010-02-26 leu, ile, or val + alpha-ketoglutarate <=> a-ketoisocaproate, a-keto-b-methylvalerate, or a-ketoisovalerate + glutamate [BCAT2] EC Number: 2.6.1.42 Mitochondrial branched-chain-amino-acid aminotransferase (BCAT2) catalyzes the reversible reactions of leucine, isoleucine, or valine with alpha-ketoglutarate (2-oxoglutarate) to form alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or a-ketoisovalerate, respectively, and glutamate (Bledsoe et al. 1997). The active enzyme is a homodimer (Yennawar et al. 2001, 2002). In the body, this enzyme is widely expressed but is especially abundant in muscle tissue. Pubmed11264579 Pubmed12269802 Pubmed9165094 Reactome Database ID Release 4370724 Reactome, http://www.reactome.org ReactomeREACT_2034 a-ketoisocaproate, a-keto-b-methylvalerate, or a-ketoisovalerate + glutamate <=> leu, ile, or val + alpha-ketoglutarate [BCAT1] Authored: D'Eustachio, P, 2010-02-18 Cytosolic branched-chain-amino-acid aminotransferase (BCAT1) catalyzes the reversible reactions of alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or a-ketoisovalerate with glutamate to form leucine, isoleucine, or valine, respectively, and alpha-ketoglutarate (2-oxoglutarate). The active enzyme is a homodimer (Goto et al. 2005). EC Number: 2.6.1.42 Edited: D'Eustachio, P, 2010-02-18 Pubmed16141215 Reactome Database ID Release 43508189 Reactome, http://www.reactome.org ReactomeREACT_21283 Reviewed: Jassal, B, 2010-02-26 leu, ile, or val + alpha-ketoglutarate <=> a-ketoisocaproate, a-keto-b-methylvalerate, or a-ketoisovalerate + glutamate [BCAT1] Cytosolic branched-chain-amino-acid aminotransferase (BCAT1) catalyzes the reversible reactions of leucine, isoleucine, or valine with alpha-ketoglutarate (2-oxoglutarate) to form alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, or a-ketoisovalerate, respectively, and glutamate. The active enzyme is a homodimer. Hutson and colleagues have argues that cytosolic BCAT1 plays a major role in the generation of glutamate involved in synaptic transmission in neural tissue (Goto et al. 2005). EC Number: 2.6.1.42 Pubmed16141215 Reactome Database ID Release 4370723 Reactome, http://www.reactome.org ReactomeREACT_1136 phosphoserine is dephosphorylated Authored: Stephan, R, 2010-10-16 Dephosphorylation of O-phospho-L-serine to L-serine proceeds through a phospho-enzyme intermediate of the catalysing phosphatase PSP (Collet et al. 1997). EC Number: 3.1.3.3 Edited: Jassal, B, 2010-10-18 Pubmed9188776 Reactome Database ID Release 43977324 Reactome, http://www.reactome.org ReactomeREACT_115834 Reviewed: D'Eustachio, P, 2011-10-26 3-phosphonooxypyruvic acid + L-glutamate = O-phospho-L-serine + 2-oxoglutarate Authored: Stephan, R, 2010-10-16 EC Number: 2.6.1.52 Edited: Jassal, B, 2010-10-18 Pubmed12633500 Reactome Database ID Release 43977333 Reactome, http://www.reactome.org ReactomeREACT_116056 Reviewed: D'Eustachio, P, 2011-10-26 The amino group needed for serine biosynthesis comes from glutamate. Its transfer onto 3-phosphonooxpyruvate is catalysed by the PSAT1 dimer which needs pyridoxal phosphate as cofactor. (Baek et al. 2003) 3-phosphoglycerate is dehydrogenated Authored: Stephan, R, 2010-10-16 EC Number: 1.1.1.95 Edited: Jassal, B, 2010-10-18 Pubmed19235232 Reactome Database ID Release 43977348 Reactome, http://www.reactome.org ReactomeREACT_116077 Reviewed: D'Eustachio, P, 2011-10-26 Serine biosynthesis starts from 3-phosphoglycerate, a glycolysis intermediate. Its dehydrogenation is catalysed by tetrameric phosphoglycerate dehydrogenase PHGDH. (Tabatabaie et al. 2009). glutamine + pyruvate => 2-oxoglutaramate + alanine Authored: D'Eustachio, P, 2010-07-01 CCBL1 (KAT 1) catalyzes the reaction of glutamine and pyruvate to form 2-oxoglutaramate and alanine. The active form of CCBL1 is a homodimer with one molecule of pyridoxal phosphate bound to each monomer (Baran et al. 1994; Han et al. 2009; Rossi et al. 2004). The enzyme's cytosolic localization is inferred from that of recombinant protein overexpressed in transfected cells (Perry et al. 1995). EC Number: 2.6.1.15 Edited: D'Eustachio, P, 2010-07-01 Pubmed15364907 Pubmed19338303 Pubmed7883047 Pubmed8294935 Reactome Database ID Release 43893616 Reactome, http://www.reactome.org ReactomeREACT_25034 Reviewed: Jassal, B, 2010-11-09 CETP:cholesterol ester complex Reactome DB_ID: 266340 Reactome Database ID Release 43266340 Reactome, http://www.reactome.org ReactomeREACT_14432 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 CETP:spherical HDL:torcetrapib complex Reactome DB_ID: 349410 Reactome Database ID Release 43349410 Reactome, http://www.reactome.org ReactomeREACT_14120 has a Stoichiometric coefficient of 1 CETP:triacylglycerol complex Reactome DB_ID: 266351 Reactome Database ID Release 43266351 Reactome, http://www.reactome.org ReactomeREACT_14006 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 spherical HDL:triacylglycerol complex Reactome DB_ID: 266348 Reactome Database ID Release 43266348 Reactome, http://www.reactome.org ReactomeREACT_14054 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 spherical HDL:SR-BI complex Reactome DB_ID: 349649 Reactome Database ID Release 43349649 Reactome, http://www.reactome.org ReactomeREACT_13961 has a Stoichiometric coefficient of 1 ABCG1 dimer Reactome DB_ID: 194222 Reactome Database ID Release 43194222 Reactome, http://www.reactome.org ReactomeREACT_14301 has a Stoichiometric coefficient of 2 albumin:2-lysophosphatidylcholine complex Reactome DB_ID: 264677 Reactome Database ID Release 43264677 Reactome, http://www.reactome.org ReactomeREACT_13885 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 LCAT:spherical HDL complex Reactome DB_ID: 266308 Reactome Database ID Release 43266308 Reactome, http://www.reactome.org ReactomeREACT_14401 has a Stoichiometric coefficient of 1 Oxidative decarboxylation of branched-chain alpha-keto acids ISBN0079130356 Pubmed10745006 Pubmed11839747 Pubmed15946682 Pubmed2188967 Pubmed7918575 Reactome Database ID Release 4370713 Reactome, http://www.reactome.org ReactomeREACT_1813 The mitochondrial nranched-chain alpha-ketoacid dehydrogenase (BKCD) complex catalyzes the reactions of alpha-ketoisocaproate, alpha-keto beta-methylvalerate, or aalpha-ketoisovalerate with CoA and NAD+ to form isovaleryl-CoA, a-methylbutyryl-CoA, or isobuyryl-CoA, respectively, and CO2 and NADH (Chuang and Shih 2001). While bovine and microbial BCKD complexes have been characterized most extensively (Reed and Hackert 1990), structural studies of individual components and subcomplexes of human BKCD have confirmed their structures and roles in the overall oxidative carboxylation process, and have related these features to the disruptive effects of mutations on branched-chain amino acid metabolism in vivo: E1a and E1b components - AEvarsson et al. 2000; E2 - Chang et al. 2002; E3- Brautigam et al. 2005. In addition, structural studies have confirmed the lipoylation of lysine residue 44 in E2 protein (Chang et al. 2002) and the loss of an aminoterminal mitochondrial transport sequence from mature E3 protein (Bruatigam et al. 2005). Loss of mitochondrial transport sequences from proteins E1a, E1b, and E2 has been domstrated by sequence analysis (Wynn et al. 1999). a-ketoisocaproate, a-keto b-methylvalerate, or a-ketoisovalerate + CoA + NAD+ => isovaleryl-CoA, a-methylbutyryl-CoA, or isobuyryl-CoA + CO2 + NADH + H+ discoidal HDL:cholesterol Reactome DB_ID: 266083 Reactome Database ID Release 43266083 Reactome, http://www.reactome.org ReactomeREACT_13978 has a Stoichiometric coefficient of 1 isovaleryl-CoA + FAD => beta-methylcrotonyl-CoA + FADH2 EC Number: 1.3.99.10 Mitochondrial isovaleryl dehydrogenase (IVD) catalyzes the reaction of isovaleryl-CoA and FAD to form beta-methylcrotonyl-CoA and FADH2 (Finocchiaro et al. 1978; Rhead and Tanaka 1980). Crystallographic studies demonstrated the existene of a tetramer of IVD polypeptides lacking an aminoterminal mitochondrial targeting sequence (Tiffany et al. 1997). Pubmed3597357 Pubmed6928646 Pubmed9214289 Reactome Database ID Release 4370745 Reactome, http://www.reactome.org ReactomeREACT_1586 LCAT:discoidal HDL complex LCAT:small nascent HDL complex Reactome DB_ID: 264684 Reactome Database ID Release 43264684 Reactome, http://www.reactome.org ReactomeREACT_14597 has a Stoichiometric coefficient of 1 alpha-methylacetoacetyl-CoA + NADH + H+ <=> alpha-methyl-beta-hydroxybutyryl-CoA + NAD+ Authored: D'Eustachio, P, 2010-02-18 EC Number: 1.1.1.35 Mitochondrial 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10; HADH2) catalyzes the reversible reaction of alpha-methylacetoacetyl-CoA and NADH + H+ to form alpha-methyl-beta-hydroxybutyryl-CoA and NAD+ (Ofman et al. 2003). Crystallographic data indicate that the enzyme is a homotetramer (Kissinger et al. 2004). Pubmed12696021 Pubmed15342248 Reactome Database ID Release 43508369 Reactome, http://www.reactome.org ReactomeREACT_21320 alpha-methyl-beta-hydroxybutyryl-CoA + NAD+ <=> alpha-methylacetoacetyl-CoA + NADH + H+ EC Number: 1.1.1.35 Mitochondrial 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10; HADH2) catalyzes the reversible reaction of alpha-methyl-beta-hydroxybutyryl-CoA and NAD+ to form alpha-methylacetoacetyl-CoA and NADH + H+ (Ofman et al. 2003). Crystallographic data indicate that the enzyme is a homotetramer (Kissinger et al. 2004). Pubmed12696021 Pubmed15342248 Reactome Database ID Release 4370837 Reactome, http://www.reactome.org ReactomeREACT_457 isobutyryl-CoA + FAD => methacrylyl-CoA + FADH2 EC Number: 1.3.99.3 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction of isobutyryl-CoA and FAD to form methacrylyl-CoA and FADH2 (Roe et al. 1999; Nguyen et al. 2002). Crystallographic studies have shown the active enzyme to be a tetramer of ACAD8 polypeptides whose aminoterminal 23 residues, a mitochondrial targeting sequence, have been removed (Bataille et al. 2004). Pubmed12359132 Pubmed14752098 Pubmed9889013 Reactome Database ID Release 4370859 Reactome, http://www.reactome.org ReactomeREACT_630 alpha-methyl-acetoacetyl-CoA + CoA => propionyl-CoA + acetyl-CoA EC Number: 2.3.1.9 Mitochondrial acetyl-CoA acetyltransferase (ACAT1) catalyzes the reaction of alpha-methyl-acetoacetyl-CoA and CoA to form propionyl-CoA and acetyl-CoA. Structural studies have shown the active enzyme to be a tetramer of ACAT1 polypeptides whose aminoterminal 34 residues, a mitochondrial targeting sequence, have been removed (Haapalainen et al. 2007). Pubmed17371050 Reactome Database ID Release 4370844 Reactome, http://www.reactome.org ReactomeREACT_1478 beta-methylglutaconyl-CoA + H2O <=> beta-hydroxy-beta-methylglutaryl-CoA EC Number: 4.2.1.18 Mitochondrial ethylglutaconyl-CoA hydratase (AUH) catalyzes the hydrolysis of beta-methylglutaconyl-CoA to yield beta-hydroxy-beta-methylglutaryl-CoA (IJlst et al. 2002; Narisawa et al. 1986). Crystallographic studies have shown the active enzyme to be a hexamer of AUH polypeptides whose aminoterminal 67 residues, a mitochondrial targeting sequence, have been removed ((Kurimoto et al. 2001). Pubmed11738050 Pubmed12434311 Pubmed3082934 Reactome Database ID Release 4370785 Reactome, http://www.reactome.org ReactomeREACT_1157 beta-methylglutaconyl-CoA + ADP + orthophosphate + H2O <=> beta-methylcrotonyl-CoA + ATP + CO2 [MCCA] Authored: D'Eustachio, P, 2010-02-18 EC Number: 6.4.1.4 Methylcrotonyl CoA carboxylase (MCCA) catalyzes the reversible reaction of beta-methylglutaconyl-CoA, ADP, orthophosphate, and H2O to form beta-methylcrotonyl-CoA, ATP, and CO2. Active MCCA is composed of two polypeptides, MCCA1 and MCCA2 (Baumgartner et al. 2001; Holzinger et al. 2001). The enzyme has been purified from fibroblast mitochondria. By analogy to the more thoroughly studied bovine homologue, MCCA is thought to be a hexamer of six MCCA1:MCCA2 dimers, and the MCCA1 polypeptides are thought to have biotin moieties covalently bound to a lysine residue at position 681 in the polypeptide chain. Mitochondrial import of MCCA1 and 2 is associated with removal of aminoterminal mitochondrial targeting sequences but the exact lengths of these sequences have not been determined. Pubmed11181649 Pubmed11406611 Reactome Database ID Release 43508308 Reactome, http://www.reactome.org ReactomeREACT_21275 tiglyl-CoA + H2O <=> alpha-methyl-beta-hydroxybutyryl-CoA EC Number: 4.2.1.17 ISBN0079130356 Mitochondrial tiglyl-CoA is hydrolyzed to form alpha-methyl-beta-hydroxybutyryl-CoA. While crude extracts of human liver cells have been shown to catalyze the reaction, the specific enzyme responsible for it has not been identified (Sweetman and Williams 2001). Reactome Database ID Release 4370830 Reactome, http://www.reactome.org ReactomeREACT_1582 alpha-methylbutyryl-CoA + FAD => tiglyl-CoA + FADH2 EC Number: 1.3.99.3 Mitochondrial 2-methyl branched chain acyl-CoA dehydrogenase (ACADSB) catalyzes the reaction of alpha-methylbutyryl-CoA and FAD to form 'tiglyl-CoA and FADH2 (Andresen et al. 2000; Gibson et al. 2000). Unpublished crystallographic data (PDB 2JIF) indicate that the enzyme is a tetramer of ACADSB polypeptides whose aminoterminal 51 residues, a mitochondrial targeting sequence, have been removed. Pubmed10832746 Pubmed11013134 Reactome Database ID Release 4370800 Reactome, http://www.reactome.org ReactomeREACT_1285 beta-methylcrotonyl-CoA + ATP + CO2 <=> beta-methylglutaconyl-CoA + ADP + orthophosphate + H2O [MCCA] EC Number: 6.4.1.4 Methylcrotonyl CoA carboxylase (MCCA) catalyzes the reversible reaction of beta-methylcrotonyl-CoA, ATP, and CO2 to form beta-methylglutaconyl-CoA, ADP, orthophosphate, and H2O. Active MCCA is composed of two polypeptides, MCCA1 and MCCA2 (Baumgartner et al. 2001; Holzinger et al. 2001). The enzyme has been purified from fibroblast mitochondria. By analogy to the more thoroughly studied bovine homologue, MCCA is thought to be a hexamer of six MCCA1:MCCA2 dimers, and the MCCA1 polypeptide is thought to have a biotin moiety covalently bound to lysine residue 681. Localization of the complex to the mitochondrial inner membrane is inferred from studies of the bovine homologue (Hector et al. 1980). Mitochondrial import of MCCA1 and 2 is associated with removal of aminoterminal mitochondrial targeting sequences (Stadler et al. 2005). Pubmed11181649 Pubmed11406611 Pubmed16023992 Pubmed7356336 Reactome Database ID Release 4370773 Reactome, http://www.reactome.org ReactomeREACT_1553 ApoB-48:TG:PL complex Reactome DB_ID: 174593 Reactome Database ID Release 43174593 Reactome, http://www.reactome.org ReactomeREACT_7228 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 40 has a Stoichiometric coefficient of 60 BMP1:Zn++ Reactome DB_ID: 264759 Reactome Database ID Release 43264759 Reactome, http://www.reactome.org ReactomeREACT_14259 has a Stoichiometric coefficient of 1 ABCA1 tetramer Reactome DB_ID: 216753 Reactome Database ID Release 43216753 Reactome, http://www.reactome.org ReactomeREACT_14510 has a Stoichiometric coefficient of 4 ABCA1:apoA-I complex Reactome DB_ID: 216758 Reactome Database ID Release 43216758 Reactome, http://www.reactome.org ReactomeREACT_14334 has a Stoichiometric coefficient of 1 pre-beta HDL Reactome DB_ID: 216752 Reactome Database ID Release 43216752 Reactome, http://www.reactome.org ReactomeREACT_13947 apoA-1:phospholipid:cholesterol discoidal HDL has a Stoichiometric coefficient of 10 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 25 small nascent HDL pre-beta HDL Reactome DB_ID: 349645 Reactome Database ID Release 43349645 Reactome, http://www.reactome.org ReactomeREACT_13956 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 lipid-poor apoA-I methacrylyl-CoA + H2O <=> beta-hydroxyisobutyryl-CoA EC Number: 4.2.1.17 ISBN0079130356 Reactome Database ID Release 4370870 Reactome, http://www.reactome.org ReactomeREACT_297 The reversible reaction of methacrylyl-CoA and water to form beta-hydroxybutyryl-CoA takes place in the mitochondrial matrix. While crude extracts of human fibroblasts and liver cells have been shown to catalyze the reaction, the specific human enzyme responsible for it has not been identified. chylomicron remnant Reactome DB_ID: 174795 Reactome Database ID Release 43174795 Reactome, http://www.reactome.org ReactomeREACT_7233 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 50 ApoB-48:TG:PL complex Reactome DB_ID: 174799 Reactome Database ID Release 43174799 Reactome, http://www.reactome.org ReactomeREACT_7722 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 40 has a Stoichiometric coefficient of 60 chylomicron remnant:apoE complex Reactome DB_ID: 174594 Reactome Database ID Release 43174594 Reactome, http://www.reactome.org ReactomeREACT_7201 has a Stoichiometric coefficient of 1 chylomicron remnant Reactome DB_ID: 174805 Reactome Database ID Release 43174805 Reactome, http://www.reactome.org ReactomeREACT_7230 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 50 PathwayStep3916 PathwayStep3917 PathwayStep3914 PathwayStep3915 PathwayStep3918 PathwayStep3919 PathwayStep3912 PathwayStep3913 PathwayStep3910 PathwayStep3911 PathwayStep3925 PathwayStep3926 PathwayStep3927 PathwayStep3928 PathwayStep3929 PathwayStep3920 PathwayStep3921 PathwayStep3922 PathwayStep3923 PathwayStep3924 Displacement of hSMUG1 glycosylase by APE1 at the AP site At the beginning of this reaction, 1 molecule of 'DNA containing an hSMUG1-bound apurinic/apyrimidinic site', and 1 molecule of 'APE1' are present. At the end of this reaction, 1 molecule of 'hSMUG1 glycosylase', and 1 molecule of 'DNA containing an APE1-bound AP site' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110351 Reactome, http://www.reactome.org ReactomeREACT_1148 Displacement of hNTH1 glycosylase by APE1 at the AP site At the beginning of this reaction, 1 molecule of 'DNA containing a hNTH1-bound apurinic/apyrimidinic site', and 1 molecule of 'APE1' are present. At the end of this reaction, 1 molecule of 'hNTH1', and 1 molecule of 'DNA containing an APE1-bound AP site' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110352 Reactome, http://www.reactome.org ReactomeREACT_2097 Displacement of UNG2 glycosylase by APE1 at the AP site At the beginning of this reaction, 1 molecule of 'DNA containing UNG2-bound apurinic/apyrimidinic site', and 1 molecule of 'APE1' are present. At the end of this reaction, 1 molecule of 'DNA containing an APE1-bound AP site', and 1 molecule of 'UNG2' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110349 Reactome, http://www.reactome.org ReactomeREACT_1588 Displacement of TDG glycosylase by APE1 at the AP site At the beginning of this reaction, 1 molecule of 'DNA containing a TDG-bound apurinic/apyrimidinic site', and 1 molecule of 'APE1' are present. At the end of this reaction, 1 molecule of 'DNA containing an APE1-bound AP site', and 1 molecule of 'G/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110350 Reactome, http://www.reactome.org ReactomeREACT_1239 APE1 mediated endonucleolytic cleavage at the 5' side of the base-free deoxyribose residue At the beginning of this reaction, 1 molecule of 'DNA containing an APE1-bound AP site' is present. At the end of this reaction, 1 molecule of 'APE1-bound DNA strand break containing an incision 5' to an AP site' is present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'endodeoxyribonuclease activity' of 'APE1'.<br> Pubmed9724657 Pubmed9804798 Reactome Database ID Release 43110359 Reactome, http://www.reactome.org ReactomeREACT_1964 Recruitment of POL Beta to the AP site At the beginning of this reaction, 1 molecule of 'APE1-bound DNA strand break containing an incision 5' to an AP site', and 1 molecule of 'DNA polymerase beta (EC 2.7.7.7)' are present. At the end of this reaction, 1 molecule of 'POL Beta: APE1-bound DNA strand break containing incision 5' to AP site ' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed9207062 Reactome Database ID Release 43110360 Reactome, http://www.reactome.org ReactomeREACT_344 Displacement of MYH glycosylase by APE1 at the AP site At the beginning of this reaction, 1 molecule of 'DNA containing an MYH-bound apurinic/apyrimidinic site', and 1 molecule of 'APE1' are present. At the end of this reaction, 1 molecule of 'MYH glycosylase', and 1 molecule of 'DNA containing an APE1-bound AP site' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110355 Reactome, http://www.reactome.org ReactomeREACT_1894 Displacement of MPG glycosylase by APE1 at the AP site At the beginning of this reaction, 1 molecule of 'DNA containing an MPG-bound apurinic/apyrimidinic site', and 1 molecule of 'APE1' are present. At the end of this reaction, 1 molecule of 'MPG glycosylase', and 1 molecule of 'DNA containing an APE1-bound AP site' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110356 Reactome, http://www.reactome.org ReactomeREACT_1527 Displacement of MBD4 glycosylase by APE1 at the AP site At the beginning of this reaction, 1 molecule of 'DNA containing an MBD4-bound apurinic/apyrimidinic site', and 1 molecule of 'APE1' are present. At the end of this reaction, 1 molecule of 'MBD4 glycosylase', and 1 molecule of 'DNA containing an APE1-bound AP site' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110353 Reactome, http://www.reactome.org ReactomeREACT_1057 Displacement of hOGG1 glycosylase by APE1 at the AP site At the beginning of this reaction, 1 molecule of 'DNA containing an hOGG1-bound apurinic/apyrimidinic site', and 1 molecule of 'APE1' are present. At the end of this reaction, 1 molecule of 'hOGG1 glycosylase', and 1 molecule of 'DNA containing an APE1-bound AP site' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110354 Reactome, http://www.reactome.org ReactomeREACT_54 PathwayStep3907 PathwayStep3908 Cleavage of uracil by TDG glycosylase At the beginning of this reaction, 1 molecule of 'TDG glycosylase:uracil complex' is present. At the end of this reaction, 1 molecule of 'DNA containing a TDG-bound apurinic/apyrimidinic site', and 1 molecule of 'Uracil' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed10583946 Reactome Database ID Release 43110218 Reactome, http://www.reactome.org ReactomeREACT_921 PathwayStep3909 Cleavage of thymine by TDG glycosylase At the beginning of this reaction, 1 molecule of 'TDG glycosylase:thymine complex' is present. At the end of this reaction, 1 molecule of 'DNA containing a TDG-bound apurinic/apyrimidinic site', and 1 molecule of 'Thymine' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'G/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)'.<br> Pubmed10583946 Reactome Database ID Release 43110219 Reactome, http://www.reactome.org ReactomeREACT_92 Cleavage of uracil by hSMUG1 glycosylase At the beginning of this reaction, 1 molecule of 'hSMUG1glycosylase:uracil complex' is present. At the end of this reaction, 1 molecule of 'Uracil', and 1 molecule of 'DNA containing an hSMUG1-bound apurinic/apyrimidinic site' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'single-strand selective uracil DNA N-glycosylase activity' of 'hSMUG1 glycosylase'.<br> Pubmed10583946 Reactome Database ID Release 43110221 Reactome, http://www.reactome.org ReactomeREACT_2205 PathwayStep3903 PathwayStep3904 PathwayStep3905 PathwayStep3906 Cleavage of uracil by MBD4 glycosylase At the beginning of this reaction, 1 molecule of 'MBD4 glycosylase:uracil complex' is present. At the end of this reaction, 1 molecule of 'Uracil', and 1 molecule of 'DNA containing an MBD4-bound apurinic/apyrimidinic site' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'MBD4 glycosylase'.<br> Reactome Database ID Release 43110231 Reactome, http://www.reactome.org ReactomeREACT_303 PathwayStep3900 Cleavage of thymine by MBD4 glycosylase At the beginning of this reaction, 1 molecule of 'MBD4 glycosylase:thymine complex' is present. At the end of this reaction, 1 molecule of 'DNA containing an MBD4-bound apurinic/apyrimidinic site', and 1 molecule of 'Thymine' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'MBD4 glycosylase'.<br> Reactome Database ID Release 43110232 Reactome, http://www.reactome.org ReactomeREACT_840 PathwayStep3901 Cleavage of ethenocytosine by TDG glycosylase At the beginning of this reaction, 1 molecule of 'TDG glycosylase:ethenocytosine complex' is present. At the end of this reaction, 1 molecule of 'DNA containing a TDG-bound apurinic/apyrimidinic site', and 1 molecule of 'ethenocytosine' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'G/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)'.<br> Reactome Database ID Release 43110234 Reactome, http://www.reactome.org ReactomeREACT_1229 PathwayStep3902 Cleavage of thymine glycol by hNTH1 glycosylase At the beginning of this reaction, 1 molecule of 'hNTH1 glycosylase:thymine glycol' is present. At the end of this reaction, 1 molecule of 'Thymine glycol', and 1 molecule of 'DNA containing a hNTH1-bound apurinic/apyrimidinic site' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'pyrimidine-specific oxidized base lesion DNA N-glycosylase activity' of 'hNTH1'.<br> Pubmed10583946 Reactome Database ID Release 43110224 Reactome, http://www.reactome.org ReactomeREACT_2255 Cleavage of cytosine glycol by hNTH1 glycosylase At the beginning of this reaction, 1 molecule of 'hNTH1 glycosylase:cytosine glycol complex' is present. At the end of this reaction, 1 molecule of 'cytosine glycol', and 1 molecule of 'DNA containing a hNTH1-bound apurinic/apyrimidinic site' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'pyrimidine-specific oxidized base lesion DNA N-glycosylase activity' of 'hNTH1'.<br> Pubmed10583946 Reactome Database ID Release 43110226 Reactome, http://www.reactome.org ReactomeREACT_2021 Cleavage of dihydrouracil by hNTH1 glycosylase At the beginning of this reaction, 1 molecule of 'hNTH1 glycosylase:dihydrouracil complex' is present. At the end of this reaction, 1 molecule of 'DNA containing a hNTH1-bound apurinic/apyrimidinic site', and 1 molecule of '5,6-Dihydrouracil' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'pyrimidine-specific oxidized base lesion DNA N-glycosylase activity' of 'hNTH1'.<br> Reactome Database ID Release 43110227 Reactome, http://www.reactome.org ReactomeREACT_2157 Cleavage of formamidopyrimidine by hNTH1 glycosylase At the beginning of this reaction, 1 molecule of 'hNTH1 glycosylase: foramidopyrimidine complex' is present. At the end of this reaction, 1 molecule of 'formamidopyrimidine', and 1 molecule of 'DNA containing a hNTH1-bound apurinic/apyrimidinic site' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'pyrimidine-specific oxidized base lesion DNA N-glycosylase activity' of 'hNTH1'.<br> Reactome Database ID Release 43110229 Reactome, http://www.reactome.org ReactomeREACT_890 PathwayStep3960 PathwayStep3953 hNTH1 glycosylase mediated recognition and binding of dihydrouracil At the beginning of this reaction, 1 molecule of 'hNTH1', and 1 molecule of 'Double-strand DNA containing a dihydrouracil' are present. At the end of this reaction, 1 molecule of 'hNTH1 glycosylase:dihydrouracil complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110212 Reactome, http://www.reactome.org ReactomeREACT_218 PathwayStep3952 hNTH1 glycosylase mediated recognition and binding of cytosine glycol At the beginning of this reaction, 1 molecule of 'hNTH1', and 1 molecule of 'Double-strand DNA containing a cytosine glycol' are present. At the end of this reaction, 1 molecule of 'hNTH1 glycosylase:cytosine glycol complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110208 Reactome, http://www.reactome.org ReactomeREACT_1999 PathwayStep3951 MBD4 glycosylase mediated recognition and binding of an uracil opposite to a guanine at CpG sequences At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing an uracil opposite to a guanine at CpG sequences', and 1 molecule of 'MBD4 glycosylase' are present. At the end of this reaction, 1 molecule of 'MBD4 glycosylase:uracil complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110171 Reactome, http://www.reactome.org ReactomeREACT_276 PathwayStep3950 MBD4 glycosylase mediated recognition and binding of a thymine opposite to a guanine at CpG sequences At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing a thymine opposite to a guanine at CpG sequences', and 1 molecule of 'MBD4 glycosylase' are present. At the end of this reaction, 1 molecule of 'MBD4 glycosylase:thymine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110172 Reactome, http://www.reactome.org ReactomeREACT_458 PathwayStep3957 Cleavage of 5-hydroxyluracil by UNG2 glycosylase At the beginning of this reaction, 1 molecule of 'UNG2 glycosylase:5-hydroxyuracil complex' is present. At the end of this reaction, 1 molecule of 'DNA containing UNG2-bound apurinic/apyrimidinic site', and 1 molecule of '5-hydroxyuracil' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'uracil DNA N-glycosylase activity' of 'UNG2'.<br> Pubmed10583946 Reactome Database ID Release 43110217 Reactome, http://www.reactome.org ReactomeREACT_1015 PathwayStep3956 Cleavage of uracil by UNG2 glycosylase At the beginning of this reaction, 1 molecule of 'UNG2 glycosylase:uracil complex' is present. At the end of this reaction, 1 molecule of 'DNA containing UNG2-bound apurinic/apyrimidinic site', and 1 molecule of 'Uracil' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'uracil DNA N-glycosylase activity' of 'UNG2'.<br> Pubmed10583946 Reactome Database ID Release 43110215 Reactome, http://www.reactome.org ReactomeREACT_239 PathwayStep3955 hNTH1 glycosylase mediated recognition and binding of thymine glycol At the beginning of this reaction, 1 molecule of 'hNTH1', and 1 molecule of 'Double-strand DNA containing a thymine glycol ' are present. At the end of this reaction, 1 molecule of 'hNTH1 glycosylase:thymine glycol' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110211 Reactome, http://www.reactome.org ReactomeREACT_2070 PathwayStep3954 hNTH1 glycosylase mediated recognition and binding of formamidopyrimidine At the beginning of this reaction, 1 molecule of 'hNTH1', and 1 molecule of 'Double-strand DNA containing a formamidopyrimidine ' are present. At the end of this reaction, 1 molecule of 'hNTH1 glycosylase: foramidopyrimidine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110213 Reactome, http://www.reactome.org ReactomeREACT_38 PathwayStep3959 PathwayStep3958 hSMUG1 glycosylase mediated recognition and binding of uracil within single-stranded DNA At the beginning of this reaction, 1 molecule of 'hSMUG1 glycosylase', and 1 molecule of 'single-stranded DNA containing an uracil' are present. At the end of this reaction, 1 molecule of 'hSMUG1glycosylase:uracil complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110164 Reactome, http://www.reactome.org ReactomeREACT_301 TDG glycosylase mediated recognition and binding of an uracil opposite to a guanine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing an uracil opposite to a guanine', and 1 molecule of 'G/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)' are present. At the end of this reaction, 1 molecule of 'TDG glycosylase:uracil complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110159 Reactome, http://www.reactome.org ReactomeREACT_1131 TDG glycosylase mediated recognition and binding of an thymine opposite to a guanine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing a thymine opposite to a guanine', and 1 molecule of 'G/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)' are present. At the end of this reaction, 1 molecule of 'TDG glycosylase:thymine complex' is present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'G/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)'.<br> Reactome Database ID Release 43110158 Reactome, http://www.reactome.org ReactomeREACT_1600 PathwayStep3970 PathwayStep3971 PathwayStep3962 Cleavage of ethenoadenine by MPG glycosylase At the beginning of this reaction, 1 molecule of 'MPG glycosylase:ethenoadenine complex' is present. At the end of this reaction, 1 molecule of 'DNA containing an MPG-bound apurinic/apyrimidinic site', and 1 molecule of 'ethenoadenine' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'MPG glycosylase'.<br> Pubmed10583946 Reactome Database ID Release 43110250 Reactome, http://www.reactome.org ReactomeREACT_909 PathwayStep3961 Cleavage of 3-methyladenine by MPG glycosylase At the beginning of this reaction, 1 molecule of 'MPG glycosylase:3-methyladenine complex' is present. At the end of this reaction, 1 molecule of 'DNA containing an MPG-bound apurinic/apyrimidinic site', and 1 molecule of '3-Methyladenine' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'MPG glycosylase'.<br> Pubmed10583946 Reactome Database ID Release 43110248 Reactome, http://www.reactome.org ReactomeREACT_924 PathwayStep3964 Cleavage of 8-oxo guanine by hOGG1 glycosylase At the beginning of this reaction, 1 molecule of 'hOGG1 glycosylase:8-oxo guanine complex' is present. At the end of this reaction, 1 molecule of '8-oxoguanine', and 1 molecule of 'DNA containing an hOGG1-bound apurinic/apyrimidinic site' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'purine-specific oxidized base lesion DNA N-glycosylase activity' of 'hOGG1 glycosylase'.<br> EC Number: 3.2.2.23 Pubmed10583946 Reactome Database ID Release 43110243 Reactome, http://www.reactome.org ReactomeREACT_1737 PathwayStep3963 Cleavage of hypoxanthine by MPG glycosylase At the beginning of this reaction, 1 molecule of 'MPG glycosylase:hypoxanthine complex' is present. At the end of this reaction, 1 molecule of 'Hypoxanthine', and 1 molecule of 'DNA containing an MPG-bound apurinic/apyrimidinic site' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'MPG glycosylase'.<br> Pubmed10583946 Reactome Database ID Release 43110251 Reactome, http://www.reactome.org ReactomeREACT_492 PathwayStep3966 UNG glycosylase mediated recognition and binding of a 5-hydroxyuracil opposite to a guanine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing 5-hydroxyuracil opposite to a guanine', and 1 molecule of 'UNG2' are present. At the end of this reaction, 1 molecule of 'UNG2 glycosylase:5-hydroxyuracil complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110157 Reactome, http://www.reactome.org ReactomeREACT_1630 PathwayStep3965 Cleavage of formamidopyrimidine by hOGG1 glycosylase At the beginning of this reaction, 1 molecule of 'hOGG1 glycosylase: formamidopyrimidine complex' is present. At the end of this reaction, 1 molecule of 'DNA containing an hOGG1-bound apurinic/apyrimidinic site', and 1 molecule of 'formamidopyrimidine' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'purine-specific oxidized base lesion DNA N-glycosylase activity' of 'hOGG1 glycosylase'.<br> EC Number: 3.2.2.23 Pubmed10583946 Reactome Database ID Release 43110244 Reactome, http://www.reactome.org ReactomeREACT_1013 PathwayStep3968 TDG glycosylase mediated recognition and binding of an ethenocytosine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing an ethenocytosine', and 1 molecule of 'G/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)' are present. At the end of this reaction, 1 molecule of 'TDG glycosylase:ethenocytosine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110210 Reactome, http://www.reactome.org ReactomeREACT_1674 PathwayStep3967 UNG glycosylase mediated recognition and binding of an uracil opposite to a guanine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing an uracil opposite to a guanine', and 1 molecule of 'UNG2' are present. At the end of this reaction, 1 molecule of 'UNG2 glycosylase:uracil complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110156 Reactome, http://www.reactome.org ReactomeREACT_1000 PathwayStep3969 Cleavage 8-oxo guanine by MYH glycosylase At the beginning of this reaction, 1 molecule of 'MYH glycosylase:adenine complex' is present. At the end of this reaction, 1 molecule of 'DNA containing an MYH-bound apurinic/apyrimidinic site', and 1 molecule of '8-oxoguanine' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA N-glycosylase activity' of 'MYH glycosylase'.<br> Pubmed10583946 Reactome Database ID Release 43110246 Reactome, http://www.reactome.org ReactomeREACT_818 hOGG1 glycosylase mediated recognition and binding of an 8-oxo guanine opposite to a cytosine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing an 8-oxo guanine opposite to a cytosine', and 1 molecule of 'hOGG1 glycosylase' are present. At the end of this reaction, 1 molecule of 'hOGG1 glycosylase:8-oxo guanine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110235 Reactome, http://www.reactome.org ReactomeREACT_1765 hOGG1 glycosylase mediated recognition and binding of a formamidopyrimidine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing a formamidopyrimidine ', and 1 molecule of 'hOGG1 glycosylase' are present. At the end of this reaction, 1 molecule of 'hOGG1 glycosylase: formamidopyrimidine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110236 Reactome, http://www.reactome.org ReactomeREACT_1843 PathwayStep3935 MYH glycosylase mediated recognition and binding of an adenine opposite to an 8-oxo guanine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing an adenine opposite to an 8-oxo guanine', and 1 molecule of 'MYH glycosylase' are present. At the end of this reaction, 1 molecule of 'MYH glycosylase:adenine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110237 Reactome, http://www.reactome.org ReactomeREACT_313 PathwayStep3934 MPG glycosylase mediated recognition and binding of hypoxanthine At the beginning of this reaction, 1 molecule of 'MPG glycosylase', and 1 molecule of 'Double-strand DNA containing a hypoxanthine' are present. At the end of this reaction, 1 molecule of 'MPG glycosylase:hypoxanthine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110240 Reactome, http://www.reactome.org ReactomeREACT_512 PathwayStep3933 MPG glycosylase mediated recognition and binding of ethenoadenine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing an ethenoadenine ', and 1 molecule of 'MPG glycosylase' are present. At the end of this reaction, 1 molecule of 'MPG glycosylase:ethenoadenine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110239 Reactome, http://www.reactome.org ReactomeREACT_213 PathwayStep3932 MPG glycosylase mediated recognition and binding of 3-methyladenine At the beginning of this reaction, 1 molecule of 'Double-strand DNA containing a 3-methyladenine', and 1 molecule of 'MPG glycosylase' are present. At the end of this reaction, 1 molecule of 'MPG glycosylase:3-methyladenine complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110238 Reactome, http://www.reactome.org ReactomeREACT_1436 PathwayStep3931 NEXT4 is cleaved to produce NICD4 EC Number: 3.4.23 NEXT4 fragment of NOTCH4 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD4 into the cytosol. Pubmed10206645 Pubmed12209127 Pubmed9620803 Reactome Database ID Release 43157648 Reactome, http://www.reactome.org ReactomeREACT_965 PathwayStep3930 NEXT3 is cleaved to produce NICD3 EC Number: 3.4.23 NEXT3 fragment of NOTCH3 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD3 into the cytosol. Pubmed10206645 Pubmed12209127 Pubmed9620803 Reactome Database ID Release 43157659 Reactome, http://www.reactome.org ReactomeREACT_1803 NEXT2 is cleaved to produce NICD2 Authored: Jassal, B, 2004-12-15 13:08:03 EC Number: 3.4.23 NEXT2 fragment of NOTCH2 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD2 into the cytosol. Pubmed10206645 Pubmed11518718 Pubmed12209127 Pubmed9620803 Reactome Database ID Release 43157640 Reactome, http://www.reactome.org ReactomeREACT_1306 NEXT1 is cleaved to produce NICD1 Authored: Jassal, B, 2004-12-15 13:08:03 EC Number: 3.4.23 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NEXT1 fragment of NOTCH1 is further cleaved at S3 by the presenilin-1 (PSEN1) containing gamma-secretase complex, which releases the intracellular domain NICD1 into the cytosol (Schroeter et al. 1998, De Strooper et al. 1999, Huppert et al. 2000, Fortini et al. 2002). PIN1, a prolyl isomerase, was recently found to bind phosphorylated Ser/Thr-Pro motifs in the cytoplasmic domain of NOTCH1 and potentiate NEXT1 cleavage by gamma-secretase. This generates a positive loop in NOTCH1 signaling since PIN1 is a transcriptional target of NICD1 (Rustighi et al. 2009). Pubmed10206645 Pubmed10879540 Pubmed12209127 Pubmed19151708 Pubmed9620803 Reactome Database ID Release 43157353 Reactome, http://www.reactome.org ReactomeREACT_1784 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 PathwayStep3939 PathwayStep3938 PathwayStep3937 PathwayStep3936 NICD4 traffics to the nucleus Reactome Database ID Release 43157941 Reactome, http://www.reactome.org ReactomeREACT_857 The cytosolic NICD4 translocates to the nucleus. AGER binds rat ERK1/2 A membrane-proximal cytoplasmic region of the advanced glycation end-products receptor (AGER) is responsible for binding to extracellular signal-regulated protein kinase-1 and -2 (ERK1/2 or MAPK3/1). This region is similar to the D-domain, an ERK docking site which is conserved in some ERK substrates (Ishihara et al. 2003). Authored: Jupe, S, 2010-06-17 Edited: Jupe, S, 2010-11-09 Pubmed12935895 Reactome Database ID Release 43997411 Reactome, http://www.reactome.org ReactomeREACT_25032 Reviewed: Yan, SD, 2010-11-09 Target DNA binding Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 How the PIC finds favored sites on target DNA has not been fully clarified. Active genes are favored for integration, and favored sequences at the site of integration also influence the reaction. Studies of cells depeleted in PSIP1/LEDGF/p75 suggest that this protein acts as a tethering factor binding HIV PICs near integration target DNA. Access of PICs to sites on chromosomes may be significant, since centromeric alphoid repeats are disfavored for integration, perhaps due to wrapping in compact centromeric heterochromatin. Nucleosomes bound to the integration template also affect target site selection and integration complex binding. Pubmed12202041 Pubmed15314653 Pubmed15677323 Pubmed15802467 Pubmed16175173 Pubmed16260736 Pubmed16291214 Pubmed16311605 Pubmed1760846 Pubmed9557688 Reactome Database ID Release 43175108 Reactome, http://www.reactome.org ReactomeREACT_9054 Reviewed: Bushman, FD, 2006-10-30 22:19:13 PathwayStep3944 NICD1 traffics to the nucleus Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Cytosolic NICD1 translocates to the nucleus. Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed9604939 Pubmed9651681 Reactome Database ID Release 43157926 Reactome, http://www.reactome.org ReactomeREACT_2109 Reviewed: Jensen, J, 2008-05-12 21:46:53 PathwayStep3943 mNICD1 binds HIF1A Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Hypoxia inhibits myogenic differentiation of the mouse cell line C2C12 and primary mouse satellite cells, and also inhibits neuronal differentiation of primary neuronal stem cells derived from the embryonic rat cortex. The inhibitory effect of hypoxia on cellular differentiation is dependent on hypoxia-inducible factor 1-alpha (Hif1a) and transcriptional activity of the Notch intracellular domain, NICD. The half-life of NICD1 is prolonged by hypoxia, and this increased stability of NICD1 is dependent on Hif1a. A recombinant mouse NICD1 (mNICD1) and a recombinant human HIF1A interact in vitro. Cotransfection of mNICD1 and HIF1A into mouse embryonic teratocarcinoma cell line P19 results in increased transcription from a Notch target promoter. Pubmed16256737 Reactome Database ID Release 432065560 Reactome, http://www.reactome.org ReactomeREACT_118840 Reviewed: Haw, R, 2012-02-06 PathwayStep3946 NICD3 traffics to the nucleus Reactome Database ID Release 43157937 Reactome, http://www.reactome.org ReactomeREACT_1135 The cytosolic NICD3 translocates to the nucleus. PathwayStep3945 NICD2 traffics to the nucleus Authored: Jassal, B, 2004-12-15 13:08:03 Reactome Database ID Release 43157933 Reactome, http://www.reactome.org ReactomeREACT_1091 The cytosolic NICD2 translocates to the nucleus. PathwayStep3940 ATP Hydrolysis By Myosin Authored: Gillespie, ME, 2003-07-01 00:00:00 Edited: Gillespie, ME, 2009-03-10 20:55:39 Once ATP is bound, myosin, which is an ATPase, uses the energy from the cleavage of the terminal phosphate to pivot the myosin head back, away from the actin filamentous chain. This change in conformation "resets" the myosin molecule, leaving it ready to bind the actin filament once more and slide the myosin filament along the actin filament, continuing the contractile cycle. Pubmed2526655 Pubmed3780718 Reactome Database ID Release 43445699 Reactome, http://www.reactome.org ReactomeREACT_20548 Reviewed: Rush, MG, 2008-01-11 00:00:00 has a Stoichiometric coefficient of 2 PathwayStep3942 PLK1 binds phosphorylated Gorasp1 Authored: Orlic-Milacic, M, 2012-07-20 Edited: Gillespie, ME, 2012-08-07 Human PLK1 from HeLa cell extracts binds recombinant rat Gorasp1 that was previously phosphorylated by CDK1 (Preisinger et al. 2005). Pubmed15678101 Reactome Database ID Release 432423781 Reactome, http://www.reactome.org ReactomeREACT_147820 Reviewed: Colanzi, Antonino, 2012-08-21 Reviewed: Wang, Yanzhuang, 2012-08-19 PathwayStep3941 Shc1 binds phosphorylated ERBB2:EGFR heterodimers Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Pubmed8665853 Reactome Database ID Release 431248744 Reactome, http://www.reactome.org ReactomeREACT_115568 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Shc1 binds phosphorylated ERBB2:EGFR heterodimers in engineered mouse 32D cells. PathwayStep3948 PathwayStep3947 PathwayStep3949 PathwayStep3994 PathwayStep3995 PathwayStep3996 PathwayStep3997 PathwayStep3998 PathwayStep3999 ferrous CYB5A CYB5A:ferroheme Reactome DB_ID: 198808 Reactome Database ID Release 43198808 Reactome, http://www.reactome.org ReactomeREACT_11661 has a Stoichiometric coefficient of 1 CYB5R3:FAD Reactome DB_ID: 198850 Reactome Database ID Release 43198850 Reactome, http://www.reactome.org ReactomeREACT_11367 has a Stoichiometric coefficient of 1 ferric CYB5A CYB5A:ferriheme Reactome DB_ID: 198772 Reactome Database ID Release 43198772 Reactome, http://www.reactome.org ReactomeREACT_11821 has a Stoichiometric coefficient of 1 ALG13:ALG14 complex Converted from EntitySet in Reactome Reactome DB_ID: 449326 Reactome Database ID Release 43449326 Reactome, http://www.reactome.org ReactomeREACT_22489 Phospho-IRS1/2 (by TRKA) Converted from EntitySet in Reactome Reactome DB_ID: 198369 Reactome Database ID Release 43198369 Reactome, http://www.reactome.org ReactomeREACT_13148 Riboflavin kinase (Mg2+) Reactome DB_ID: 196954 Reactome Database ID Release 43196954 Reactome, http://www.reactome.org ReactomeREACT_11696 has a Stoichiometric coefficient of 1 THTPA-Mg++ Reactome DB_ID: 964948 Reactome Database ID Release 43964948 Reactome, http://www.reactome.org ReactomeREACT_26403 has a Stoichiometric coefficient of 1 Nucleotide pyrophosphatase homodimer Reactome DB_ID: 196965 Reactome Database ID Release 43196965 Reactome, http://www.reactome.org ReactomeREACT_11259 has a Stoichiometric coefficient of 2 P-ERBB4cyt1 Converted from EntitySet in Reactome Reactome DB_ID: 1250325 Reactome Database ID Release 431250325 Reactome, http://www.reactome.org ReactomeREACT_117345 GSTO2 homodimer Reactome DB_ID: 198820 Reactome Database ID Release 43198820 Reactome, http://www.reactome.org ReactomeREACT_11325 has a Stoichiometric coefficient of 2 GSTO homodimers Converted from EntitySet in Reactome Reactome DB_ID: 198809 Reactome Database ID Release 43198809 Reactome, http://www.reactome.org ReactomeREACT_11879 TPK1 homodimer (Mg2+) Reactome DB_ID: 196971 Reactome Database ID Release 43196971 Reactome, http://www.reactome.org ReactomeREACT_11433 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 GSTO1 homodimer Reactome DB_ID: 198825 Reactome Database ID Release 43198825 Reactome, http://www.reactome.org ReactomeREACT_11608 has a Stoichiometric coefficient of 2 SIN1 Converted from EntitySet in Reactome Reactome DB_ID: 198596 Reactome Database ID Release 43198596 Reactome, http://www.reactome.org ReactomeREACT_13355 ALG10 homologue Converted from EntitySet in Reactome Reactome DB_ID: 449652 Reactome Database ID Release 43449652 Reactome, http://www.reactome.org ReactomeREACT_22988 p-S-AKT Converted from EntitySet in Reactome Reactome DB_ID: 2317317 Reactome Database ID Release 432317317 Reactome, http://www.reactome.org ReactomeREACT_147928 ribonucleotide reductase M2B (TP53 inducible) dimer Reactome DB_ID: 111794 Reactome Database ID Release 43111794 Reactome, http://www.reactome.org ReactomeREACT_4497 has a Stoichiometric coefficient of 2 ribonucleotide reductase M1 polypeptide dimer Reactome DB_ID: 111790 Reactome Database ID Release 43111790 Reactome, http://www.reactome.org ReactomeREACT_2566 has a Stoichiometric coefficient of 2 GSK3 Converted from EntitySet in Reactome Reactome DB_ID: 198358 Reactome Database ID Release 43198358 Reactome, http://www.reactome.org ReactomeREACT_13050 PathwayStep3976 PathwayStep3977 PathwayStep3978 PathwayStep3979 PathwayStep3972 PathwayStep3973 PathwayStep3974 PathwayStep3975 PathwayStep3980 PathwayStep3982 PathwayStep3981 glutathione reductase holoenzyme Reactome DB_ID: 71680 Reactome Database ID Release 4371680 Reactome, http://www.reactome.org ReactomeREACT_3184 has a Stoichiometric coefficient of 2 nucleotide diphosphate kinase hexamer Converted from EntitySet in Reactome Reactome DB_ID: 482610 Reactome Database ID Release 43482610 Reactome, http://www.reactome.org ReactomeREACT_21664 thioredoxin reductase holoenzyme Reactome DB_ID: 73532 Reactome Database ID Release 4373532 Reactome, http://www.reactome.org ReactomeREACT_3043 Thioredoxin reductase-FAD complex has a Stoichiometric coefficient of 2 nucleoside diphosphate kinase 2A:4B heterohexamer Reactome DB_ID: 482614 Reactome Database ID Release 43482614 Reactome, http://www.reactome.org ReactomeREACT_21994 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 nucleoside diphosphate kinase 1A:5B heterohexamer Reactome DB_ID: 482626 Reactome Database ID Release 43482626 Reactome, http://www.reactome.org ReactomeREACT_21578 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 5 nucleoside diphosphate kinase 4A:2B heterohexamer Reactome DB_ID: 482623 Reactome Database ID Release 43482623 Reactome, http://www.reactome.org ReactomeREACT_21800 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 p-AKT Active AKT Converted from EntitySet in Reactome Reactome DB_ID: 202074 Reactome Database ID Release 43202074 Reactome, http://www.reactome.org ReactomeREACT_13319 nucleoside diphosphate kinase 3A:3B heterohexamer Reactome DB_ID: 74193 Reactome Database ID Release 4374193 Reactome, http://www.reactome.org ReactomeREACT_2860 has a Stoichiometric coefficient of 3 nucleoside diphosphate kinase A hexamer Reactome DB_ID: 73542 Reactome Database ID Release 4373542 Reactome, http://www.reactome.org ReactomeREACT_4458 has a Stoichiometric coefficient of 6 THEM4/TRIB3 Converted from EntitySet in Reactome Reactome DB_ID: 2400007 Reactome Database ID Release 432400007 Reactome, http://www.reactome.org ReactomeREACT_148496 nucleoside diphosphate kinase 5A:1B heterohexamer Reactome DB_ID: 482611 Reactome Database ID Release 43482611 Reactome, http://www.reactome.org ReactomeREACT_21841 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 5 nucleoside diphosphate kinase B hexamer Reactome DB_ID: 110576 Reactome Database ID Release 43110576 Reactome, http://www.reactome.org ReactomeREACT_4586 has a Stoichiometric coefficient of 6 PathwayStep3989 PathwayStep3987 PathwayStep3988 PathwayStep3985 PathwayStep3986 PathwayStep3983 PathwayStep3984 PathwayStep3993 PathwayStep3992 PathwayStep3991 PathwayStep3990 ITPA dimer Reactome DB_ID: 2509833 Reactome Database ID Release 432509833 Reactome, http://www.reactome.org ReactomeREACT_152122 has a Stoichiometric coefficient of 2 NME4 hexamer Reactome DB_ID: 110636 Reactome Database ID Release 43110636 Reactome, http://www.reactome.org ReactomeREACT_5889 has a Stoichiometric coefficient of 6 nucleoside diphosphate kinase D, mitochondrial hexamer NUDT1p22:Mg2+ Reactome DB_ID: 2395816 Reactome Database ID Release 432395816 Reactome, http://www.reactome.org ReactomeREACT_151324 has a Stoichiometric coefficient of 1 NUDT1p21:Mg2+ Reactome DB_ID: 2395844 Reactome Database ID Release 432395844 Reactome, http://www.reactome.org ReactomeREACT_152376 has a Stoichiometric coefficient of 1 NUDT1p18:Mg2+ Reactome DB_ID: 2395829 Reactome Database ID Release 432395829 Reactome, http://www.reactome.org ReactomeREACT_150480 has a Stoichiometric coefficient of 1 NUDT1 Converted from EntitySet in Reactome Reactome DB_ID: 2395830 Reactome Database ID Release 432395830 Reactome, http://www.reactome.org ReactomeREACT_151234 NUDT9 Reactome DB_ID: 2393951 Reactome Database ID Release 432393951 Reactome, http://www.reactome.org ReactomeREACT_151956 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-S9/21-GSK3 Converted from EntitySet in Reactome Phospho-GSK3 Reactome DB_ID: 198373 Reactome Database ID Release 43198373 Reactome, http://www.reactome.org ReactomeREACT_13164 NUDT5 dimer Reactome DB_ID: 2393948 Reactome Database ID Release 432393948 Reactome, http://www.reactome.org ReactomeREACT_151423 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 6 NUDT16 dimer Reactome DB_ID: 2509818 Reactome Database ID Release 432509818 Reactome, http://www.reactome.org ReactomeREACT_152365 has a Stoichiometric coefficient of 2 NUDT1p26:Mg2+ Reactome DB_ID: 2395842 Reactome Database ID Release 432395842 Reactome, http://www.reactome.org ReactomeREACT_151575 has a Stoichiometric coefficient of 1 p-T-CDKN1A/B Converted from EntitySet in Reactome Phospho-CDK inhibitor Reactome DB_ID: 198605 Reactome Database ID Release 43198605 Reactome, http://www.reactome.org ReactomeREACT_12999 p-CDK inhibitor p-T145-CDKN1A/p-T157-CDKN1B p21/p27 CDK inhibitor CDKN1A/B CDKN1A/CDKN1B Converted from EntitySet in Reactome Reactome DB_ID: 198625 Reactome Database ID Release 43198625 Reactome, http://www.reactome.org ReactomeREACT_13380 Forkhead box transcription factor Converted from EntitySet in Reactome Reactome DB_ID: 199272 Reactome Database ID Release 43199272 Reactome, http://www.reactome.org ReactomeREACT_13013 Active AKT Converted from EntitySet in Reactome Reactome DB_ID: 202072 Reactome Database ID Release 43202072 Reactome, http://www.reactome.org ReactomeREACT_13116 P-AKT Converted from EntitySet in Reactome Phospho-AKT Reactome DB_ID: 202084 Reactome Database ID Release 43202084 Reactome, http://www.reactome.org ReactomeREACT_12669 p-T-AKT Phospho-Forkhead box transcription factor Converted from EntitySet in Reactome Reactome DB_ID: 199269 Reactome Database ID Release 43199269 Reactome, http://www.reactome.org ReactomeREACT_13209 Nonendonucleolytic Argonaute Converted from EntitySet in Reactome Reactome DB_ID: 210613 Reactome Database ID Release 43210613 Reactome, http://www.reactome.org ReactomeREACT_118909 PHLPP Converted from EntitySet in Reactome Reactome DB_ID: 2327836 Reactome Database ID Release 432327836 Reactome, http://www.reactome.org ReactomeREACT_148256 FGFR2c-binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 189957 Reactome Database ID Release 43189957 Reactome, http://www.reactome.org ReactomeREACT_9904 FGFR2b-binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 189967 Reactome Database ID Release 43189967 Reactome, http://www.reactome.org ReactomeREACT_9755 Sec24 Converted from EntitySet in Reactome Reactome DB_ID: 204017 Reactome Database ID Release 43204017 Reactome, http://www.reactome.org ReactomeREACT_12645 PSPH:Mg++ dimer Reactome DB_ID: 977344 Reactome Database ID Release 43977344 Reactome, http://www.reactome.org ReactomeREACT_117715 has a Stoichiometric coefficient of 2 BCAT2 dimer Reactome DB_ID: 70704 Reactome Database ID Release 4370704 Reactome, http://www.reactome.org ReactomeREACT_4953 branched-chain amino acid aminotransferase, mitochondrial, holoenzyme has a Stoichiometric coefficient of 2 BCAT1 dimer Reactome DB_ID: 70699 Reactome Database ID Release 4370699 Reactome, http://www.reactome.org ReactomeREACT_2441 has a Stoichiometric coefficient of 2 branched-chain alpha-ketoacid dehydrogenase E1 complex Reactome DB_ID: 70016 Reactome Database ID Release 4370016 Reactome, http://www.reactome.org ReactomeREACT_2643 has a Stoichiometric coefficient of 2 MAN1A1/A2/C1 Converted from EntitySet in Reactome Reactome DB_ID: 964764 Reactome Database ID Release 43964764 Reactome, http://www.reactome.org ReactomeREACT_25706 branched-chain alpha-ketoacid dehydrogenase complex Reactome DB_ID: 70019 Reactome Database ID Release 4370019 Reactome, http://www.reactome.org ReactomeREACT_3604 has a Stoichiometric coefficient of 12 has a Stoichiometric coefficient of 24 has a Stoichiometric coefficient of 6 GLS dimers Converted from EntitySet in Reactome Reactome DB_ID: 507859 Reactome Database ID Release 43507859 Reactome, http://www.reactome.org ReactomeREACT_21656 GLS dimer Reactome DB_ID: 507860 Reactome Database ID Release 43507860 Reactome, http://www.reactome.org ReactomeREACT_21726 has a Stoichiometric coefficient of 2 GLS2 dimer Reactome DB_ID: 507858 Reactome Database ID Release 43507858 Reactome, http://www.reactome.org ReactomeREACT_21657 has a Stoichiometric coefficient of 2 CCBL1 dimer Reactome DB_ID: 893603 Reactome Database ID Release 43893603 Reactome, http://www.reactome.org ReactomeREACT_25474 has a Stoichiometric coefficient of 2 PHGHD tetramer Reactome DB_ID: 977346 Reactome Database ID Release 43977346 Reactome, http://www.reactome.org ReactomeREACT_116228 has a Stoichiometric coefficient of 4 PSAT1 dimer Reactome DB_ID: 977345 Reactome Database ID Release 43977345 Reactome, http://www.reactome.org ReactomeREACT_117177 has a Stoichiometric coefficient of 2 FGFR1c-binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 189953 Reactome Database ID Release 43189953 Reactome, http://www.reactome.org ReactomeREACT_9777 GLUL decamer Reactome DB_ID: 70604 Reactome Database ID Release 4370604 Reactome, http://www.reactome.org ReactomeREACT_3307 glutamine synthetase homodecamer has a Stoichiometric coefficient of 10 GLUD1 hexamer Reactome DB_ID: 70583 Reactome Database ID Release 4370583 Reactome, http://www.reactome.org ReactomeREACT_5112 glutamate dehydrogenase 1, homohexamer has a Stoichiometric coefficient of 6 ASNS dimer Reactome DB_ID: 507865 Reactome Database ID Release 43507865 Reactome, http://www.reactome.org ReactomeREACT_21861 has a Stoichiometric coefficient of 2 PYCR1 decamer Reactome DB_ID: 70662 Reactome Database ID Release 4370662 Reactome, http://www.reactome.org ReactomeREACT_2465 has a Stoichiometric coefficient of 10 pyrroline-5-carboxylate reductase homomultimer GPT2 dimer Reactome DB_ID: 507753 Reactome Database ID Release 43507753 Reactome, http://www.reactome.org ReactomeREACT_21918 has a Stoichiometric coefficient of 2 OAT hexamer Reactome DB_ID: 70639 Reactome Database ID Release 4370639 Reactome, http://www.reactome.org ReactomeREACT_3827 has a Stoichiometric coefficient of 6 ornithine aminotransferase homohexamer MOCOS holoenzyme Reactome DB_ID: 947511 Reactome Database ID Release 43947511 Reactome, http://www.reactome.org ReactomeREACT_26664 has a Stoichiometric coefficient of 1 GPT dimer Reactome DB_ID: 70521 Reactome Database ID Release 4370521 Reactome, http://www.reactome.org ReactomeREACT_5396 has a Stoichiometric coefficient of 2 P5CS short isoform, dimer Reactome DB_ID: 508091 Reactome Database ID Release 43508091 Reactome, http://www.reactome.org ReactomeREACT_21567 has a Stoichiometric coefficient of 2 P5CS dimers ALDH18A1 dimers Converted from EntitySet in Reactome Reactome DB_ID: 508070 Reactome Database ID Release 43508070 Reactome, http://www.reactome.org ReactomeREACT_21892 delta-1-pyrroline-5-carboxylate synthetase dimers P5CS long isoform, dimer Reactome DB_ID: 508067 Reactome Database ID Release 43508067 Reactome, http://www.reactome.org ReactomeREACT_21899 has a Stoichiometric coefficient of 2 Lck/Fyn Converted from EntitySet in Reactome Reactome DB_ID: 389329 Reactome Database ID Release 43389329 Reactome, http://www.reactome.org ReactomeREACT_20035 Active platelet-derived growth factor A chain isoforms Converted from EntitySet in Reactome Reactome DB_ID: 381940 Reactome Database ID Release 43381940 Reactome, http://www.reactome.org ReactomeREACT_18205 MOCS2 tetramer Reactome DB_ID: 947569 Reactome Database ID Release 43947569 Reactome, http://www.reactome.org ReactomeREACT_25714 has a Stoichiometric coefficient of 2 Mucins Converted from EntitySet in Reactome Reactome DB_ID: 913666 Reactome Database ID Release 43913666 Reactome, http://www.reactome.org ReactomeREACT_117488 Gephyrin(Mg++) Reactome DB_ID: 947500 Reactome Database ID Release 43947500 Reactome, http://www.reactome.org ReactomeREACT_25665 has a Stoichiometric coefficient of 1 Gephyrin(Mg++) trimer Reactome DB_ID: 947576 Reactome Database ID Release 43947576 Reactome, http://www.reactome.org ReactomeREACT_26924 has a Stoichiometric coefficient of 3 ST8SIAs Converted from EntitySet in Reactome Reactome DB_ID: 1022134 Reactome Database ID Release 431022134 Reactome, http://www.reactome.org ReactomeREACT_25611 MOCS3(Zn++)-S-S(1-) Reactome DB_ID: 947584 Reactome Database ID Release 43947584 Reactome, http://www.reactome.org ReactomeREACT_25705 has a Stoichiometric coefficient of 1 NFS1 holoenzyme Reactome DB_ID: 947509 Reactome Database ID Release 43947509 Reactome, http://www.reactome.org ReactomeREACT_26174 has a Stoichiometric coefficient of 2 MOCS3(Zn++) (ox.) Reactome DB_ID: 947568 Reactome Database ID Release 43947568 Reactome, http://www.reactome.org ReactomeREACT_26398 has a Stoichiometric coefficient of 1 MOCS2-CO-S(1-) tetramer Reactome DB_ID: 947582 Reactome Database ID Release 43947582 Reactome, http://www.reactome.org ReactomeREACT_25716 has a Stoichiometric coefficient of 2 SHMT1 tetramer Reactome DB_ID: 71243 Reactome Database ID Release 4371243 Reactome, http://www.reactome.org ReactomeREACT_3102 has a Stoichiometric coefficient of 4 serine hydroxymethyltransferase tetramer MTHFR dimer Reactome DB_ID: 200713 Reactome Database ID Release 43200713 Reactome, http://www.reactome.org ReactomeREACT_11644 has a Stoichiometric coefficient of 2 MOCS1 holoenzyme Reactome DB_ID: 947498 Reactome Database ID Release 43947498 Reactome, http://www.reactome.org ReactomeREACT_26979 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 MOCS3(Zn++) (red.) Reactome DB_ID: 947543 Reactome Database ID Release 43947543 Reactome, http://www.reactome.org ReactomeREACT_27010 has a Stoichiometric coefficient of 1 FGFR3b-binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 189964 Reactome Database ID Release 43189964 Reactome, http://www.reactome.org ReactomeREACT_9651 FGFR3c-binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 189955 Reactome Database ID Release 43189955 Reactome, http://www.reactome.org ReactomeREACT_9844 FGFR4-binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 189959 Reactome Database ID Release 43189959 Reactome, http://www.reactome.org ReactomeREACT_9577 MGAT4s Converted from EntitySet in Reactome Reactome DB_ID: 975913 Reactome Database ID Release 43975913 Reactome, http://www.reactome.org ReactomeREACT_26701 MTHFD1 dimer Reactome DB_ID: 200667 Reactome Database ID Release 43200667 Reactome, http://www.reactome.org ReactomeREACT_11452 has a Stoichiometric coefficient of 2 Nicotinate phosphoribosyltransferase homodimer Reactome DB_ID: 389377 Reactome Database ID Release 43389377 Reactome, http://www.reactome.org ReactomeREACT_17164 has a Stoichiometric coefficient of 2 NMNAT3 tetramer Reactome DB_ID: 200487 Reactome Database ID Release 43200487 Reactome, http://www.reactome.org ReactomeREACT_11927 has a Stoichiometric coefficient of 4 NADSYN1 homohexamer Reactome DB_ID: 197192 Reactome Database ID Release 43197192 Reactome, http://www.reactome.org ReactomeREACT_11254 has a Stoichiometric coefficient of 6 NMNAT1 hexamer Reactome DB_ID: 200489 Reactome Database ID Release 43200489 Reactome, http://www.reactome.org ReactomeREACT_11954 has a Stoichiometric coefficient of 6 NMNAT2 (Mg2+) Reactome DB_ID: 197266 Reactome Database ID Release 43197266 Reactome, http://www.reactome.org ReactomeREACT_11885 has a Stoichiometric coefficient of 1 PDXK holoenzyme Reactome DB_ID: 965005 Reactome Database ID Release 43965005 Reactome, http://www.reactome.org ReactomeREACT_26520 has a Stoichiometric coefficient of 2 PNPO holoenzyme Reactome DB_ID: 964943 Reactome Database ID Release 43964943 Reactome, http://www.reactome.org ReactomeREACT_26517 has a Stoichiometric coefficient of 2 PPC synthase homodimer Reactome DB_ID: 196775 Reactome Database ID Release 43196775 Reactome, http://www.reactome.org ReactomeREACT_11296 has a Stoichiometric coefficient of 2 PPCDC homotrimer (FMN cofactor) Reactome DB_ID: 196828 Reactome Database ID Release 43196828 Reactome, http://www.reactome.org ReactomeREACT_11983 has a Stoichiometric coefficient of 3 NAD+ kinase homotetramer (Zn2+) Reactome DB_ID: 197222 Reactome Database ID Release 43197222 Reactome, http://www.reactome.org ReactomeREACT_11972 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 ALDH9A1 tetramer 4-trimethylaminobutyraldehyde dehydrogenase tetramer Reactome DB_ID: 71258 Reactome Database ID Release 4371258 Reactome, http://www.reactome.org ReactomeREACT_2391 has a Stoichiometric coefficient of 4 BBOX1 dimer Reactome DB_ID: 71107 Reactome Database ID Release 4371107 Reactome, http://www.reactome.org ReactomeREACT_5804 gamma-butyrobetaine hydroxylase dimer has a Stoichiometric coefficient of 2 GATM dimer Reactome DB_ID: 71268 Reactome Database ID Release 4371268 Reactome, http://www.reactome.org ReactomeREACT_2836 glycine amidinotransferase dimer has a Stoichiometric coefficient of 2 Tn antigens Converted from EntitySet in Reactome N-acetyl-D-galactosaminyl-mucins Reactome DB_ID: 913659 Reactome Database ID Release 43913659 Reactome, http://www.reactome.org ReactomeREACT_117289 CKB, CKM Converted from EntitySet in Reactome Reactome DB_ID: 200343 Reactome Database ID Release 43200343 Reactome, http://www.reactome.org ReactomeREACT_11575 creatine kinase dimer creatine kinase BB dimer Reactome DB_ID: 200341 Reactome Database ID Release 43200341 Reactome, http://www.reactome.org ReactomeREACT_11428 has a Stoichiometric coefficient of 2 creatine kinase BM dimer Reactome DB_ID: 200374 Reactome Database ID Release 43200374 Reactome, http://www.reactome.org ReactomeREACT_11514 has a Stoichiometric coefficient of 1 creatine kinase MM dimer Reactome DB_ID: 200359 Reactome Database ID Release 43200359 Reactome, http://www.reactome.org ReactomeREACT_11453 has a Stoichiometric coefficient of 2 CK octamers Converted from EntitySet in Reactome Reactome DB_ID: 200373 Reactome Database ID Release 43200373 Reactome, http://www.reactome.org ReactomeREACT_11971 creatine kinase octamers TMLHE dimer Reactome DB_ID: 71098 Reactome Database ID Release 4371098 Reactome, http://www.reactome.org ReactomeREACT_2511 has a Stoichiometric coefficient of 2 trimethyllysine dioxygenase dimer ARG2 trimer Reactome DB_ID: 452013 Reactome Database ID Release 43452013 Reactome, http://www.reactome.org ReactomeREACT_21733 arginase 2 homotrimer has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 6 ARG1 trimer Reactome DB_ID: 70567 Reactome Database ID Release 4370567 Reactome, http://www.reactome.org ReactomeREACT_4055 arginase 1 homotrimer has a Stoichiometric coefficient of 3 has a Stoichiometric coefficient of 6 KYNU dimer Reactome DB_ID: 71202 Reactome Database ID Release 4371202 Reactome, http://www.reactome.org ReactomeREACT_3262 has a Stoichiometric coefficient of 2 kynureninase dimer HAAO 3-hydroxyanthranilate oxygenase holoenzyme Reactome DB_ID: 71086 Reactome Database ID Release 4371086 Reactome, http://www.reactome.org ReactomeREACT_2694 has a Stoichiometric coefficient of 1 IDO2 Reactome DB_ID: 888612 Reactome Database ID Release 43888612 Reactome, http://www.reactome.org ReactomeREACT_24419 has a Stoichiometric coefficient of 1 indoleamine 2,3-dioxygenase 2:heme CCBL2 dimer Reactome DB_ID: 901094 Reactome Database ID Release 43901094 Reactome, http://www.reactome.org ReactomeREACT_26578 has a Stoichiometric coefficient of 2 ASS1 tetramer Reactome DB_ID: 70575 Reactome Database ID Release 4370575 Reactome, http://www.reactome.org ReactomeREACT_3887 argininosuccinate synthase homotetramer has a Stoichiometric coefficient of 4 ASL tetramer Reactome DB_ID: 70571 Reactome Database ID Release 4370571 Reactome, http://www.reactome.org ReactomeREACT_5742 argininosuccinate lyase tetramer has a Stoichiometric coefficient of 4 ACMSD dimer 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase homodimer Reactome DB_ID: 71221 Reactome Database ID Release 4371221 Reactome, http://www.reactome.org ReactomeREACT_4212 has a Stoichiometric coefficient of 2 OTC trimer Reactome DB_ID: 70558 Reactome Database ID Release 4370558 Reactome, http://www.reactome.org ReactomeREACT_2460 has a Stoichiometric coefficient of 3 ornithine transcarbamylase homotrimer IDO1 Reactome DB_ID: 198580 Reactome Database ID Release 43198580 Reactome, http://www.reactome.org ReactomeREACT_11571 has a Stoichiometric coefficient of 1 indoleamine 2,3-dioxygenase:heme TDO2 tetramer Reactome DB_ID: 71186 Reactome Database ID Release 4371186 Reactome, http://www.reactome.org ReactomeREACT_2731 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 tryptophan 2,3-dioxygenase tetramer ALDH4A1 dimer P5C dehydrogenase homodimer Reactome DB_ID: 70674 Reactome Database ID Release 4370674 Reactome, http://www.reactome.org ReactomeREACT_4273 has a Stoichiometric coefficient of 2 HPD dimer 4-hydroxyphenylpyruvate dioxygenase holoenzyme dimer Reactome DB_ID: 71161 Reactome Database ID Release 4371161 Reactome, http://www.reactome.org ReactomeREACT_5126 has a Stoichiometric coefficient of 2 HGD hexamer Reactome DB_ID: 71076 Reactome Database ID Release 4371076 Reactome, http://www.reactome.org ReactomeREACT_3888 has a Stoichiometric coefficient of 6 homogentisic acid oxidase hexamer GSTZ1 dimer Reactome DB_ID: 71166 Reactome Database ID Release 4371166 Reactome, http://www.reactome.org ReactomeREACT_3027 has a Stoichiometric coefficient of 2 maleylacetoacetic acid isomerase dimer FAH dimer Reactome DB_ID: 71175 Reactome Database ID Release 4371175 Reactome, http://www.reactome.org ReactomeREACT_4468 fumarylacetoacetate hydrolase dimer has a Stoichiometric coefficient of 2 GALNTs Converted from EntitySet in Reactome Reactome DB_ID: 913644 Reactome Database ID Release 43913644 Reactome, http://www.reactome.org ReactomeREACT_116270 PCBD1 tetramer Reactome DB_ID: 71132 Reactome Database ID Release 4371132 Reactome, http://www.reactome.org ReactomeREACT_5671 has a Stoichiometric coefficient of 4 pterin-4-alpha-carbinolamine dehydratase homotetramer QDPR dimer Reactome DB_ID: 71120 Reactome Database ID Release 4371120 Reactome, http://www.reactome.org ReactomeREACT_3771 dihydropteridine reductase homodimer has a Stoichiometric coefficient of 2 TAT dimer Reactome DB_ID: 71153 Reactome Database ID Release 4371153 Reactome, http://www.reactome.org ReactomeREACT_4161 has a Stoichiometric coefficient of 2 AADAT dimer Reactome DB_ID: 508545 Reactome Database ID Release 43508545 Reactome, http://www.reactome.org ReactomeREACT_21987 has a Stoichiometric coefficient of 2 ALDH7A1 tetramer Reactome DB_ID: 508564 Reactome Database ID Release 43508564 Reactome, http://www.reactome.org ReactomeREACT_22031 antiquitin tetramer has a Stoichiometric coefficient of 4 PAH tetramer Reactome DB_ID: 71068 Reactome Database ID Release 4371068 Reactome, http://www.reactome.org ReactomeREACT_5262 has a Stoichiometric coefficient of 4 phenylalanine hydroxylase holoenzyme tetramer GCDH tetramer Reactome DB_ID: 71040 Reactome Database ID Release 4371040 Reactome, http://www.reactome.org ReactomeREACT_4566 glutaryl-CoA dehydrogenase tetramer has a Stoichiometric coefficient of 4 HDC dimer Reactome DB_ID: 977300 Reactome Database ID Release 43977300 Reactome, http://www.reactome.org ReactomeREACT_117836 has a Stoichiometric coefficient of 2 AASS tetramer Reactome DB_ID: 70925 Reactome Database ID Release 4370925 Reactome, http://www.reactome.org ReactomeREACT_2695 has a Stoichiometric coefficient of 4 lysine-ketoglutarate reductase /saccharopine dehydrogenase homotetramer UROC1 Reactome DB_ID: 70901 Reactome Database ID Release 4370901 Reactome, http://www.reactome.org ReactomeREACT_3579 has a Stoichiometric coefficient of 1 urocanase urocanate hydratase FTCD octamer Reactome DB_ID: 70908 Reactome Database ID Release 4370908 Reactome, http://www.reactome.org ReactomeREACT_3643 has a Stoichiometric coefficient of 8 ACAD8 tetramer Reactome DB_ID: 70856 Reactome Database ID Release 4370856 Reactome, http://www.reactome.org ReactomeREACT_5431 has a Stoichiometric coefficient of 4 isobutyryl-CoA dehydrogenase, holoenzyme HIBADH tetramer 3-hydroxyisobutyrate dehydrogenase, tetramer Reactome DB_ID: 70883 Reactome Database ID Release 4370883 Reactome, http://www.reactome.org ReactomeREACT_4988 has a Stoichiometric coefficient of 4 HADH2 tetramer HSD17B10 tetramer Reactome DB_ID: 508381 Reactome Database ID Release 43508381 Reactome, http://www.reactome.org ReactomeREACT_22038 has a Stoichiometric coefficient of 4 ACADSB tetramer 2-methyl branched chain acyl-CoA dehydrogenase tetramer Reactome DB_ID: 70797 Reactome Database ID Release 4370797 Reactome, http://www.reactome.org ReactomeREACT_5830 has a Stoichiometric coefficient of 4 AUH hexamer Reactome DB_ID: 508309 Reactome Database ID Release 43508309 Reactome, http://www.reactome.org ReactomeREACT_21548 has a Stoichiometric coefficient of 6 methylcrotonyl-CoA carboxylase complex 3-methylcrotonyl-CoA carboxylase complex Reactome DB_ID: 70770 Reactome Database ID Release 4370770 Reactome, http://www.reactome.org ReactomeREACT_3783 has a Stoichiometric coefficient of 6 IVD tetramer Reactome DB_ID: 70730 Reactome Database ID Release 4370730 Reactome, http://www.reactome.org ReactomeREACT_5405 has a Stoichiometric coefficient of 4 isovaleryl-CoA dehydrogenase tetramer Association of RPA complexes with ssDNA Authored: Matthews, L, 2003-09-10 06:00:00 Human replication protein A (RPA) is a single-stranded DNA (ssDNA) binding protein required for DNA replication, recombination, and repair. RPA is a stable heterotrimer consisting of subunits with molecular masses of 14, 32 and 70 kDa (p14, p32 and p70, respectively). Association of RPA with ssDNA is thought to contribute to both the protection and removal of secondary structure from single-stranded DNA. Pubmed11080452 Reactome Database ID Release 4375994 Reactome, http://www.reactome.org ReactomeREACT_2149 Association of RAD51 with BRCA2 Authored: Matthews, L, 2003-11-23 12:20:00 BRCA2 and RAD51 interact directly through the highly conserved BRC repeats in BRCA2 (Venkitaraman, 2002). Pubmed12606939 Reactome Database ID Release 4383648 Reactome, http://www.reactome.org ReactomeREACT_1612 BRCA1 associates with 53BP1at the site of DNA double-strand break At the beginning of this reaction, 1 molecule of '53BP1:H2AX complex at site of double-strand break', and 1 molecule of 'Breast cancer type 1 susceptibility protein' are present. At the end of this reaction, 1 molecule of 'BRCA1:53BP1 complex at site of DNA double-strand break' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11756551 Pubmed12364621 Pubmed12778123 Reactome Database ID Release 4383570 Reactome, http://www.reactome.org ReactomeREACT_1259 Resection of double-strand break ends Authored: Matthews, L, 2003-08-11 05:43:00 GENE ONTOLOGYGO:0000729 In order for repair of the double-strand break to occur, the 5' ends of the break must first be resected to produce single-strands that invade homologous duplex DNA. Although the enzymatic activities responsible for end-processing in humans are not known with certainty, the MRE11-RAD50-NBS1 (MRN) complex has been implicated in this process (Thompson and Schild, 2001). The MRN complex may function as a bridge between double-strand break ends through interactions between the coiled-coil domains of RAD50 (Hoptner et al., 2002). Pubmed11139606 Pubmed11376695 Pubmed12152085 Pubmed9705271 Reactome Database ID Release 4383897 Reactome, http://www.reactome.org ReactomeREACT_172 Association of RAD50:MRE11 complex with NBS1 via MRE11 interaction At the beginning of this reaction, 1 molecule of 'RAD50:MRE11 complex', and 1 molecule of 'NBS1' are present. At the end of this reaction, 1 molecule of 'MRE11:RAD50:NBS1 complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375174 Reactome, http://www.reactome.org ReactomeREACT_730 Association of MRN with sites of DSB At the beginning of this reaction, 1 molecule of 'MRE11:RAD50:NBS1 complex', and 1 molecule of 'gamma-H2AX:NBS1 complex at the site of double-strand break' are present. At the end of this reaction, 1 molecule of 'DNA double-strand break ends: MRN complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4375176 Reactome, http://www.reactome.org ReactomeREACT_1232 Association of RAD51 with RAD52:DNA double-strand break ends Authored: Matthews, L, 2003-11-23 12:20:00 Binding of the RAD51:RAD52 complex to ssDNA may provide nucleation sites promoting the association of free RAD51 with the growing nucleoprotein filament. This interaction may also play a role in stimulating the strand transfer reactions mediated by RAD51 (Baumann, 1999). Pubmed10438626 Reactome Database ID Release 4383642 Reactome, http://www.reactome.org ReactomeREACT_674 Association of RAD52 with ssDNA at resected ends of double-strand break At the beginning of this reaction, 1 molecule of '3' overhanging DNA at resected DSB ends', and 1 molecule of 'RAD52' are present. At the end of this reaction, 1 molecule of 'RAD52:DNA double-strand break' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed10921897 Reactome Database ID Release 43109779 Reactome, http://www.reactome.org ReactomeREACT_772 Association of RAD52 with the RPA complex At the beginning of this reaction, 1 molecule of 'RAD52', and 1 molecule of 'RPA heterotrimer' are present. At the end of this reaction, 1 molecule of 'RAD52:RPA complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 4383644 Reactome, http://www.reactome.org ReactomeREACT_1465 Formation of RAD52 heptameric ring structure complexes on ssDNA Authored: Matthews, L, 2003-09-10 06:00:00 Pubmed10438626 Pubmed10744977 Pubmed10921897 Pubmed12191481 Pubmed12370410 Pubmed9837724 RAD52 interacts with ssDNA forming heptameric ring structure complexes. The conformation of the RAD52-ssDNA complex is thought to place the ssDNA on an exposed surface of the protein, in a configuration that may promote the DNA-DNA annealing of complementary DNA strands. Reactome Database ID Release 4375998 Reactome, http://www.reactome.org ReactomeREACT_1316 has a Stoichiometric coefficient of 7 DNA repair synthesis Authored: Matthews, L, 2003-11-23 12:20:00 Following branch migration, the invading 3’ resected ends of the double-strand break act as primers for repair DNA synthesis using the complementary strand of the invaded duplex as a template. GENE ONTOLOGYGO:0000731 Reactome Database ID Release 4376011 Reactome, http://www.reactome.org ReactomeREACT_973 Ligation of DNA and formation of Holliday structures following repair synthesis Authored: Matthews, L, 2003-08-11 05:43:00 Ligation of the crossed-strand intermediate results in the formation of Holliday structures with two crossovers. In humans, the identity of this ligase activity involved in this process is not known. Reactome Database ID Release 4375227 Reactome, http://www.reactome.org ReactomeREACT_819 Cleavage of Holliday junctions Authored: Matthews, L, 2003-09-10 06:00:00 Reactome Database ID Release 4373949 Reactome, http://www.reactome.org ReactomeREACT_1568 The enzymatic activities that cleave Holliday junctions have not yet been identified in human. Resolution of the D-loop through cleavage of the two Holliday junctions in the same orientation (i.e.: sites a and b or c and c) results in non-recombinant chromatids. Cleavage in opposite orientation (a and c or b and d) does not produce recombinants. Dissociation of the extended strands Authored: Matthews, L, 2003-11-23 12:20:00 Following repair synthesis, the extended strands may disassociate from their compliments within the duplex DNA and reanneal with their original complimentary strands through sequence acquired in repair synthesis . GENE ONTOLOGYGO:0000732 Reactome Database ID Release 4383663 Reactome, http://www.reactome.org ReactomeREACT_287 Association of RAD51 with the RPA complex Authored: Matthews, L, 2003-11-23 12:20:00 Pubmed9826763 Reactome Database ID Release 4383638 Reactome, http://www.reactome.org ReactomeREACT_1106 The binding of RAD51 to ssDNA may be facilitated by association with RPA (Golub et al., 1998). Association of RAD51 with the resected ends of the DNA double-strand break At the beginning of this reaction, 1 molecule of 'RAD51', and 1 molecule of '3' overhanging DNA at resected DSB ends' are present. At the end of this reaction, 1 molecule of 'RAD51:resected ends of DNA double-strand break' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed11080452 Reactome Database ID Release 43109780 Reactome, http://www.reactome.org ReactomeREACT_240 Strand exchange/Branch migration Authored: Matthews, L, 2003-11-23 12:20:00 Branch migration or strand exchange occurs as the complimentary duplex DNA strand is progressively taken up into the nucleoprotein filament to base pair with the invading single-strand sequence (Sung et al., 2003). Pubmed12912992 Reactome Database ID Release 4373947 Reactome, http://www.reactome.org ReactomeREACT_882 Association of Ku heterodimer with ends of DNA double-strand break Authored: Matthews, L, 2003-09-07 08:47:00 Ionizing radiation (IR) induces single-strand breaks i.e. cleavage of the phosphodiester backbone. When two single-strand breaks occur within approximately 10 base pairs, a DNA double-strand break results. IR-induced DSBs are complex DNA damage lesions, containing base damage and frequently containing 5'-OH groups and 3'-hydroxy or phosphoglycolate groups that must be removed prior to ligation in the final step of NHEJ (Friedberg et al, 1995; Nikjoo et al, 2001; Valerie and Povirk, 2003). The Ku70/80 heterodimer (Walker et al., 2001) binds to the ends of the double-strand break. Ku can translocate inwards from the site of the break in an ATP-independent manner (reviewed in Dynan and Yoo, 1998). Pubmed11493912 Pubmed11604075 Pubmed12947387 Pubmed9512523 Reactome Database ID Release 4375917 Reactome, http://www.reactome.org ReactomeREACT_1854 Fill-in DNA synthesis Authored: Matthews, L, 2003-11-23 12:20:00 DNA synthesis occurs to fill in remaining single-stranded gaps present in the reannealed DNA duplex. Reactome Database ID Release 4383665 Reactome, http://www.reactome.org ReactomeREACT_797 Association of DNA-PKcs with Ku-bound ends of DNA double-strand breaks Authored: Matthews, L, 2003-09-07 08:47:00 DNA-PKcs is recruited to the Ku-DNA end complex (Gottlieb and Jackson, 1993), causing Ku to translocate inwards (away from the break) approximately 10 bp (Yoo and Dynan, 1999). This forms the DNA-PK complex (DNA-PKcs plus Ku70/Ku80) at each end of the DNA double strand break. Pubmed10572166 Pubmed8422676 Reactome Database ID Release 4375916 Reactome, http://www.reactome.org ReactomeREACT_1989 MGMT/hAGT mediated DNA Damage Reversal Authored: Pegg, A, 2004-02-04 15:50:05 EC Number: 2.1.1.63 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0006307 Pubmed8434121 Reactive cellular catabolites can cause DNA damage by 6-O-methylation of guanine. 6-O-methylguanine can pair ambiguously with both C and T, and can cause transition mutations. Active reversal of such damage can be facilitated by proteins having 6-O-methylguanine-DNA methyltransferase (MGMT) activity.<p> MGMT removes the methyl group from the guanine and transfers it to the cysteine residue at position 145 on the protein itself. MGMT thus methylated is not regenerated, as the S-methylcysteine is very stable. This is an energetically expensive approach to DNA repair as one entire protein molecule is sacrificed per lesion that is corrected in this manner (Yang et al. 2011). Reactome Database ID Release 4373892 Reactome, http://www.reactome.org ReactomeREACT_1876 Oxidative demethylation of 1-MeA damaged DNA By ABH2 At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of '2-Oxoglutarate', and 1 molecule of 'Alkylated DNA with 1-methyladenine' are present. At the end of this reaction, 1 molecule of 'Formaldehyde', 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', and 1 molecule of 'Succinate' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH2 protein'.<br> Pubmed12486230 Reactome Database ID Release 43112118 Reactome, http://www.reactome.org ReactomeREACT_1696 Formation of Pol zeta complex At the beginning of this reaction, 1 molecule of 'HREV7', and 1 molecule of 'HREV3' are present. At the end of this reaction, 1 molecule of 'Pol zeta complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110322 Reactome, http://www.reactome.org ReactomeREACT_1544 Elongation by Pol zeta complex At the beginning of this reaction, 1 molecule of 'dNTP', and 1 molecule of 'Pol zeta:damaged DNA template complex' are present. At the end of this reaction, 1 molecule of 'Pol zeta complex', and 1 molecule of 'Elongated DNA template with bypassed lesion' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed DNA polymerase activity' of 'Pol zeta:damaged DNA template complex'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43110324 Reactome, http://www.reactome.org ReactomeREACT_1324 Oxidative demethylation of 3-MeC damaged DNA By ABH3 At the beginning of this reaction, 1 molecule of 'Alkylated DNA with 3-methylcytosine', 1 molecule of 'Oxygen', and 1 molecule of '2-Oxoglutarate' are present. At the end of this reaction, 1 molecule of 'Formaldehyde', 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', and 1 molecule of 'Succinate' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH3 protein'.<br> Pubmed12486230 Reactome Database ID Release 43112124 Reactome, http://www.reactome.org ReactomeREACT_1435 Oxidative demethylation of 1-MeA damaged DNA By ABH3 At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of '2-Oxoglutarate', and 1 molecule of 'Alkylated DNA with 1-methyladenine' are present. At the end of this reaction, 1 molecule of 'Formaldehyde', 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', and 1 molecule of 'Succinate' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH3 protein'.<br> Pubmed12486230 Reactome Database ID Release 43112123 Reactome, http://www.reactome.org ReactomeREACT_462 Oxidative demethylation of 1-EtA damaged DNA By ABH2 At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of 'Alkylated DNA with 1-ethyladenine', and 1 molecule of '2-Oxoglutarate' are present. At the end of this reaction, 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', 1 molecule of 'Succinate', and 1 molecule of 'Acetaldehyde' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH2 protein'.<br> Pubmed12486230 Reactome Database ID Release 43112121 Reactome, http://www.reactome.org ReactomeREACT_783 Oxidative demethylation of 3-MeC damaged DNA By ABH2 At the beginning of this reaction, 1 molecule of 'Alkylated DNA with 3-methylcytosine', 1 molecule of 'Oxygen', and 1 molecule of '2-Oxoglutarate' are present. At the end of this reaction, 1 molecule of 'Formaldehyde', 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', and 1 molecule of 'Succinate' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH2 protein'.<br> Pubmed12486230 Reactome Database ID Release 43112120 Reactome, http://www.reactome.org ReactomeREACT_2185 Intermolecular autophosphorylation of ATM within dimeric ATM complexes ATM is present in unirradiated cells as a dimer or higher-order multimer. Following irradiation, ATM undergoes rapid intermolecular autophosphorylation of serine 1981. Authored: Matthews, L, 2003-11-18 00:00:00 GENE ONTOLOGYGO:0046777 Pubmed12556884 Reactome Database ID Release 4375147 Reactome, http://www.reactome.org ReactomeREACT_1116 has a Stoichiometric coefficient of 2 Oxidative demethylation of 1-EtA damaged DNA By ABH3 At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of 'Alkylated DNA with 1-ethyladenine', and 1 molecule of '2-Oxoglutarate' are present. At the end of this reaction, 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', 1 molecule of 'Succinate', and 1 molecule of 'Acetaldehyde' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH3 protein'.<br> Pubmed12486230 Reactome Database ID Release 43112125 Reactome, http://www.reactome.org ReactomeREACT_1934 Dissociation of dimeric phospho-ATM complexes Authored: Matthews, L, 2003-12-10 03:30:00 Autophosphorylation of ATM results in the dissociation of the dimeric/multimeric ATM complex and initiation of ATM kinase activity. Autophosphorylation does not directly regulate ATM kinase activity. Instead, it is the resulting dissociation of ATM oligomers that allows substrates access to the ATM kinase domain. Pubmed12556884 Reactome Database ID Release 4383895 Reactome, http://www.reactome.org ReactomeREACT_1167 has a Stoichiometric coefficient of 2 Phosphorylation of histone H2AX at Serine-139 by ATM at the site of DSB Authored: Matthews, L, 2003-08-11 05:43:00 H2AX phosphorylation (producing the gamma-H2AX protein form) occurs within 1-3 minutes of DNA damage (Rogakou et al,1998) and is promoted by MDC1/NFBD1 (Stewart et al., 2003). gamma H2AX is one of the first proteins to appear at the site of damage, localizing to a region of about 2 Mbp surrounding the site of the double-strand break (Rogakou et al,1998). gamma-H2AX appears to play an essential role in recruiting other repair proteins including Rad50, Rad51 and BRCA1(Paull et al., 2000) (Stewart et al., 2003). Pubmed10959836 Pubmed12607005 Pubmed9488723 Reactome Database ID Release 4375242 Reactome, http://www.reactome.org ReactomeREACT_1517 Phosphorylation of BRCA1 at multiple sites by ATM ATM mediated phosphorylation of BRCA1 at Ser 1189, Ser 1542 and Ser 1524 (Cortez et al., 1999) is regulated by MDC1 (Lou et al., 2003). BRCA1 plays an important role in the response to double-strand breaks, participating in genome surveillance, DNA repair, and cell cycle checkpoint arrests. BRCA1 is required for ATM-dependent phosphorylation of NBS1 following exposure to ionizing radiation (Foray et al., 2003). BRCA1 also interacts with the MRE11-RAD50-NBS1 complex which has been implicated early in HRR during resection of the double-strand break. Authored: Matthews, L, 2003-11-18 00:00:00 Pubmed10550055 Pubmed12773400 Reactome Database ID Release 4375239 Reactome, http://www.reactome.org ReactomeREACT_937 has a Stoichiometric coefficient of 3 Phosphorylation of NBS1 by ATM Authored: Matthews, L, 2003-11-18 00:00:00 NSB1 is a component of the MRE11/RAD50/NBS1 complex which acts early in HRR during resection of the double-strand break. In addition, NBS1 is required for activation of the S-phase checkpoint in response to ionizing radiation (IR), ATM-dependent activation of CHK2 and cell survival after exposure to IR. Pubmed12861053 Reactome Database ID Release 4375241 Reactome, http://www.reactome.org ReactomeREACT_2009 Phosphorylation of MDC1/NFBD1 by ATM (within 2 c-term BRCT domains) ATM mediated phosphorylation of MDC1/NFBD1 may be involved in the rapid relocalization of MDC1/NFBD1 to nuclear foci that contain the MRE11 complex, phosphorylated histone H2AX and 53BP1 (Goldberg et al., 2003). NFBD1 may also function in recruiting DNA checkpoint signaling and repair proteins to the sites of DNA damage (Xu and Stern., 2003 and Stewart et al.,2003). Authored: Matthews, L, 2003-11-18 00:00:00 Pubmed12607003 Pubmed12607005 Pubmed14519663 Reactome Database ID Release 4375245 Reactome, http://www.reactome.org ReactomeREACT_1782 phospho-ATM (Serine 1981) associates with DNA at the site of double-strand breaks At the beginning of this reaction, 1 molecule of 'MDC1/NFBD1:gamma-H2AX complex', and 1 molecule of 'phospho-ATM (Ser 1981)' are present. At the end of this reaction, 1 molecule of 'ATM associated with DNA double-strand break ends' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed12556884 Reactome Database ID Release 4383592 Reactome, http://www.reactome.org ReactomeREACT_1304 MDC1/NFBD1associates with gamma H2AX at nuclear foci Authored: Matthews, L, 2003-11-18 00:00:00 Pubmed12607003 Pubmed12607005 Reactome Database ID Release 4383560 Reactome, http://www.reactome.org ReactomeREACT_1809 Recruitment of MDC1 to nuclear foci is mediated by H2AX. MDC1 forms complexes with phosphorylated H2AX, promotes efficient phosphorylation of H2AX and controls the formation of BRCA1 and MRN foci (Stewart et al.,2003). Association of gamma-H2AX with NBS1 Authored: Matthews, L, 2003-08-11 05:43:00 NBS1 binds to H2AX and functions in the relocalization of MRE11/RAD50 nuclease complex to the double-strand break (Kobayashi, J. et al., 2002). Pubmed12419185 Reactome Database ID Release 4375191 Reactome, http://www.reactome.org ReactomeREACT_1800 53BP1 associates with gamma H2AX at nuclear foci At the beginning of this reaction, 1 molecule of '53BP1', and 1 molecule of 'gamma H2AX:MDC1/NFBD1 complex at site of DNA double-strand break' are present. At the end of this reaction, 1 molecule of '53BP1:H2AX complex at site of double-strand break' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed12556884 Reactome Database ID Release 43110404 Reactome, http://www.reactome.org ReactomeREACT_1508 Formation of RAD50:MRE11 complex Authored: Matthews, L, 2003-08-11 05:43:00 MRE11 has both manganese dependent ss DNA 3'-5' exonuclease and endonuclease activities. MRE11 associates with RAD50 resulting in increased 3'-5' exonuclease activity. Reactome Database ID Release 4375172 Reactome, http://www.reactome.org ReactomeREACT_516 Recruitment of LIG3:XRRC1 complex to the site of repair by POL Beta At the beginning of this reaction, 1 molecule of 'POL Beta-bound DNA strand break containing gap left by excised residue', and 1 molecule of 'LIG3:XRRC1 complex ' are present. At the end of this reaction, 1 molecule of 'LIG3:XRCC1:POL Beta complex at site of base repair' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed8978692 Reactome Database ID Release 43110376 Reactome, http://www.reactome.org ReactomeREACT_1402 Excision of the abasic sugar phosphate (dRP) residue at the strand break At the beginning of this reaction, 1 molecule of 'POL Beta: APE1-bound DNA strand break containing incision 5' to AP site ' is present. At the end of this reaction, 1 molecule of 'POL Beta-bound DNA strand break containing gap left by excised residue', 1 molecule of 'APE1', and 1 molecule of 'Sugar phosphate' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-(apurinic or apyrimidinic site) lyase activity' of 'DNA polymerase beta (EC 2.7.7.7)'.<br> EC Number: 4.2.99.18 GENE ONTOLOGYGO:0006286 Reactome Database ID Release 43110375 Reactome, http://www.reactome.org ReactomeREACT_1215 TRAP homodimer Reactome DB_ID: 196946 Reactome Database ID Release 43196946 Reactome, http://www.reactome.org ReactomeREACT_11966 has a Stoichiometric coefficient of 2 tartrate-resistant acid phosphatase homodimer Interaction of APE1 with DNA ligase I At the beginning of this reaction, 1 molecule of 'APE1', and 1 molecule of 'DNA ligase I ' are present. At the end of this reaction, 1 molecule of 'APE1:DNA ligase I complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110371 Reactome, http://www.reactome.org ReactomeREACT_1688 Interaction of APE1 with FEN1 At the beginning of this reaction, 1 molecule of 'APE1', and 1 molecule of 'Flap endonuclease-1 ' are present. At the end of this reaction, 1 molecule of 'APE1:FEN1complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110410 Reactome, http://www.reactome.org ReactomeREACT_1114 POL delta associates with AP site displacing POL Beta At the beginning of this reaction, 1 molecule of 'POL Beta: APE1-bound 5' incised DNA strand break containing first resynthesized base ', and 1 molecule of 'DNA Polymerase delta tetramer' are present. At the end of this reaction, 1 molecule of 'DNA polymerase beta (EC 2.7.7.7)', and 1 molecule of 'POL Delta:APE1-bound 5' incised DNA strand break containing first resynthesized nucleotide' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Pubmed10559261 Reactome Database ID Release 43110361 Reactome, http://www.reactome.org ReactomeREACT_2121 DNA strand displacement synthesis At the beginning of this reaction, 1 molecule of 'POL Delta:APE1-bound 5' incised DNA strand break containing first resynthesized nucleotide', and 1 molecule of 'Deoxynucleoside triphosphate' are present. At the end of this reaction, 1 molecule of 'pyrophosphate', and 1 molecule of 'single-stranded DNA flap structure at the site of damaged residue' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed DNA polymerase activity' of 'DNA Polymerase delta tetramer'.<br> EC Number: 2.7.7.7 Pubmed10460157 Pubmed12200445 Reactome Database ID Release 43110368 Reactome, http://www.reactome.org ReactomeREACT_41 Dissociation of LIG3:XRCC1 complex from site of BER At the beginning of this reaction, 1 molecule of 'LIG3:XRRC1-bound DNA strand containing the ligated residue' is present. At the end of this reaction, 1 molecule of 'LIG3:XRRC1 complex ', and 1 molecule of 'DNA strand containing replaced ligated residue' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110380 Reactome, http://www.reactome.org ReactomeREACT_381 POL Beta mediated incorporation of the first replacement nucleotide At the beginning of this reaction, 1 molecule of 'dNTP', and 1 molecule of 'POL Beta: APE1-bound DNA strand break containing incision 5' to AP site ' are present. At the end of this reaction, 1 molecule of 'pyrophosphate', and 1 molecule of 'POL Beta: APE1-bound 5' incised DNA strand break containing first resynthesized base ' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'beta DNA polymerase activity' of 'DNA polymerase beta (EC 2.7.7.7)'.<br> EC Number: 2.7.7.7 Pubmed11250913 Reactome Database ID Release 43111253 Reactome, http://www.reactome.org ReactomeREACT_2224 Resynthesis of excised residue Authored: Matthews, L, 2004-01-29 18:52:00 DNA polymerase Beta mediates DNA synthesis that fills the gap left by the excised residue using the undamaged strand as a template. EC Number: 2.7.7.7 Pubmed8978692 Reactome Database ID Release 4373932 Reactome, http://www.reactome.org ReactomeREACT_292 DNA ligation via the single-nucleotide replacement pathway At the beginning of this reaction, 1 molecule of 'LIG3:XRCC1:POL Beta:DNA strand break containing replaced unligated residue' is present. At the end of this reaction, 1 molecule of 'LIG3:XRRC1-bound DNA strand containing the ligated residue' is present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA ligase activity' of 'DNA ligase III '.<br> GENE ONTOLOGYGO:0006288 Pubmed8978692 Reactome Database ID Release 4373931 Reactome, http://www.reactome.org ReactomeREACT_1659 Interaction between FEN1 and PCNA At the beginning of this reaction, 1 molecule of 'PCNA', and 1 molecule of 'Flap endonuclease-1 ' are present. At the end of this reaction, 1 molecule of 'FEN1:PCNA complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110364 Reactome, http://www.reactome.org ReactomeREACT_1288 Ligation of DNA at sites of patch replacement At the beginning of this reaction, 1 molecule of 'DNA containing unligated replacement-synthesized patch' is present. At the end of this reaction, 1 molecule of 'Ligated patch-repaired DNA' is present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA ligase activity' of 'DNA ligase I '.<br> GENE ONTOLOGYGO:0006288 Pubmed10559261 Reactome Database ID Release 43110370 Reactome, http://www.reactome.org ReactomeREACT_1247 Cleavage of flap structures Authored: Matthews, L, 2004-01-29 18:52:00 FEN1 cleaves the dRp group at the AP site and the 3'-adjacent nucleotide(s). Pubmed10460157 Pubmed10559261 Pubmed9214649 Reactome Database ID Release 43110363 Reactome, http://www.reactome.org ReactomeREACT_2189 Insertion of correct bases opposite to the lesion by Pol eta At the beginning of this reaction, 1 molecule of 'Pol eta:damaged DNA template complex' is present. At the end of this reaction, 1 molecule of 'Pol eta:lesioned DNA template inserted with correct base complement' is present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'eta DNA polymerase activity' of 'Pol eta:damaged DNA template complex'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43110317 Reactome, http://www.reactome.org ReactomeREACT_2016 Elongation by Pol eta At the beginning of this reaction, 1 molecule of 'Pol eta:lesioned DNA template inserted with correct base complement' is present. At the end of this reaction, 1 molecule of 'Pol eta protein', and 1 molecule of 'Elongated DNA template with bypassed lesion' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'eta DNA polymerase activity' of 'Pol eta:lesioned DNA template inserted with correct base complement'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43110319 Reactome, http://www.reactome.org ReactomeREACT_1479 Binding of Pol zeta to lesioned DNA template At the beginning of this reaction, 1 molecule of 'damaged DNA substrate ', and 1 molecule of 'Pol zeta complex' are present. At the end of this reaction, 1 molecule of 'Pol zeta:damaged DNA template complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110321 Reactome, http://www.reactome.org ReactomeREACT_1918 Binding of HREV1 to lesioned DNA template At the beginning of this reaction, 1 molecule of 'damaged DNA substrate ', and 1 molecule of 'HREV1 protein' are present. At the end of this reaction, 1 molecule of 'HREV1:damaged DNA template complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110307 Reactome, http://www.reactome.org ReactomeREACT_1502 Misinsertion of bases opposite to the lesion by HREV1 At the beginning of this reaction, 1 molecule of 'HREV1:damaged DNA template complex' is present. At the end of this reaction, 1 molecule of 'HREV1:lesioned DNA template with misinserted bases' is present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed DNA polymerase activity' of 'HREV1:damaged DNA template complex'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43110308 Reactome, http://www.reactome.org ReactomeREACT_2214 Elongation by HREV1 protein At the beginning of this reaction, 1 molecule of 'HREV1:lesioned DNA template with misinserted bases' is present. At the end of this reaction, 1 molecule of 'HREV1 protein', and 1 molecule of 'Elongated DNA template with bypassed lesion' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed DNA polymerase activity' of 'HREV1:lesioned DNA template with misinserted bases'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43110311 Reactome, http://www.reactome.org ReactomeREACT_867 Binding of Pol eta to lesioned DNA template At the beginning of this reaction, 1 molecule of 'damaged DNA substrate ', and 1 molecule of 'Pol eta protein' are present. At the end of this reaction, 1 molecule of 'Pol eta:damaged DNA template complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43110316 Reactome, http://www.reactome.org ReactomeREACT_504 Sec24 Converted from EntitySet in Reactome Reactome DB_ID: 203991 Reactome Database ID Release 43203991 Reactome, http://www.reactome.org ReactomeREACT_12982 EDEM Converted from EntitySet in Reactome Reactome DB_ID: 1022113 Reactome Database ID Release 431022113 Reactome, http://www.reactome.org ReactomeREACT_27025 UGGT1/2 Converted from EntitySet in Reactome Reactome DB_ID: 548881 Reactome Database ID Release 43548881 Reactome, http://www.reactome.org ReactomeREACT_26186 calreticulin/calnexin Converted from EntitySet in Reactome Reactome DB_ID: 901048 Reactome Database ID Release 43901048 Reactome, http://www.reactome.org ReactomeREACT_24126 Cleavage of 5-oxoproline to form glutamate 5-oxoprolinase catalyzes the cleavage of 5-oxoproline to form L-glutamate, coupled to the hydrolysis of ATP to ADP and inorganic phosphate (Chen et al, 1998). Authored: Jassal, B, 2011-04-08 EC Number: 3.5.2.9 Edited: Jassal, B, 2011-04-08 Pubmed9516961 Reactome Database ID Release 431247935 Reactome, http://www.reactome.org ReactomeREACT_75909 Reviewed: D'Eustachio, P, 2011-05-23 has a Stoichiometric coefficient of 2 Pyridine can be N-methylated EC Number: 2.1.1.87 Pyridine is a typical substrate for Nicotinamide N-methyltransferase Reactome Database ID Release 43175987 Reactome, http://www.reactome.org ReactomeREACT_6930 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 3,4-dihydroxybenzoate can be O-methylated Dihydroxybenzoate is a typical substrate for Catechol O-methyltransferase EC Number: 2.1.1.6 Pubmed8968737 Reactome Database ID Release 43175983 Reactome, http://www.reactome.org ReactomeREACT_6885 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 6-mercaptopurine can be S-methylated EC Number: 2.1.1.67 Methylation is the major biotransformation route of thiopurine drugs such as 6-mercaptopurine (6MP), used in the treatment of inflammatory diseases such as rheumatoid arthritis and childhood acute lymphoblastic leukemia. 6MP and it's thioguanine nucleotide metabolites are principally inactivated by thiopurine methyltransferase (TPMT)-catalyzed S-methylation. <br>TPMT exhibits an autosomal co-dominant trait: About one in 300 Caucasian, African, African-American, and Asian populations are TPMT deficient. Approximately 6-10% of these populations inherit intermediate TPMT activity and are heterozygous at the TPMT locus. The rest are homozygous for the wild-type allele and have high levels of TPMT activity. Low or undetectable levels of TPMT results in patients having this trait being at risk to thiopurine drug-induced toxicity such as myelosuppression.<br>6-MP is a typical substrate for TPMT as shown in this example. Pubmed10331075 Pubmed13981612 Pubmed15788214 Pubmed16267626 Reactome Database ID Release 43158609 Reactome, http://www.reactome.org ReactomeREACT_6779 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 2-mercaptoethanol can be S-methylated 2-mercaptoethanol is a typical substrate for Thiol S-methyltransferase. EC Number: 2.1.1.9 Edited: Jassal, B, 2008-05-19 12:57:01 Reactome Database ID Release 43175976 Reactome, http://www.reactome.org ReactomeREACT_6752 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 NAT2 acetylation EC Number: 2.3.1.5 Reactome Database ID Release 43174967 Reactome, http://www.reactome.org ReactomeREACT_6944 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Typical NAT 2 substrates were chosen as examples. They are paraxanthine, isoniazid and N-hydroxy 4-aminobiphenyl. S-atom dealkylation of 6-methylmercaptopurine At the beginning of this reaction, 1 molecule of 'H+', 1 molecule of '6-Methylmercaptopurine', 1 molecule of 'Oxygen', and 1 molecule of 'NADPH' are present. At the end of this reaction, 1 molecule of 'NADP+', 1 molecule of '6-Mercaptopurine', 1 molecule of 'Formaldehyde', and 1 molecule of 'H2O' are present.<br><br> This reaction takes place in the 'smooth endoplasmic reticulum' and is mediated by the 'oxygen binding activity' of 'Cytochrome P450 1A2 '.<br> Reactome Database ID Release 4376386 Reactome, http://www.reactome.org ReactomeREACT_1995 The acetyl group from acetyl-CoA is transferred to the NAT2 Authored: Jassal, B, 2005-02-09 10:26:12 N-acetylation occurs in two sequential steps via a <i>ping-pong Bi-Bi mechanism</i>. In the first step, the acetyl group from acetyl-CoA is transferred to a conserved cysteine residue (position 68) in the active site of NAT, with consequent release of coenzyme-A. In the second step, the acetyl group is transferred to the acceptor substrate and the enzyme returns to its initial state. Pubmed1559981 Reactome Database ID Release 43158832 Reactome, http://www.reactome.org ReactomeREACT_6755 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 NAT1 acetylation EC Number: 2.3.1.5 Reactome Database ID Release 43174963 Reactome, http://www.reactome.org ReactomeREACT_6832 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Typical NAT 1 substrates were chosen as examples. They are sulfanilamide, 4-aminosalicylate, 4-aminobenzoate and N-hydroxy 4-aminobiphenyl. The acetyl group from acetyl-CoA is transferred to the NAT1 Authored: Jassal, B, 2005-02-09 10:26:12 N-acetylation occurs in two sequential steps via a <i>ping-pong Bi-Bi mechanism</i>. In the first step, the acetyl group from acetyl-CoA is transferred to a conserved cysteine residue (position 68) in the active site of NAT, with consequent release of coenzyme-A. In the second step, the acetyl group is transferred to the acceptor substrate and the enzyme returns to its initial state. Pubmed1559981 Reactome Database ID Release 43174959 Reactome, http://www.reactome.org ReactomeREACT_6831 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 beta-estradiol + PAPS => beta-estradiol 3-sulfate + PAP EC Number: 2.8.2.15 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed7779757 Reactome Database ID Release 43176521 Reactome, http://www.reactome.org ReactomeREACT_6949 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Sulfonation of beta-estradiol is catalyzed by SULT1E1 (Falany et al. 1995). lithocholate + PAPS => lithocholate sulfate + PAP EC Number: 2.8.2 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed2268288 Reactome Database ID Release 43176588 Reactome, http://www.reactome.org ReactomeREACT_6770 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Sulfonation of lithocholate is catalyzed by SULT2A1 (Radominska et al. 1990). taurolithocholate + PAPS => taurolithocholate sulfate + PAP EC Number: 2.8.2 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed2268288 Reactome Database ID Release 43176604 Reactome, http://www.reactome.org ReactomeREACT_6814 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Sulfonation of taurolithocholate is catalyzed by SULT2A1 (Radominska et al. 1990). Adenosine 3',5'-bisphosphate (PAP) + H2O => AMP + orthophosphate EC Number: 3.1.3.7 Edited: D'Eustachio, P, 2006-03-11 18:40:17 GENE ONTOLOGYGO:0050427 PAP is generated as a byproduct of sulfonation reactions in vivo; its hydrolysis to AMP and orthophosphate returns its constituents to the pool of molecules available for cytosolic nucleotide metabolism. Bisphosphate 3'-nucleotidase 1catalyzes this reaction efficiently in vitro; whether other nucleotidases also play a role in PAP breakdown in vivo is unknown. Pubmed10224133 Reactome Database ID Release 43176606 Reactome, http://www.reactome.org ReactomeREACT_6763 27-hydroxycholesterol + PAPS => 27-hydroxycholesterol 3-sulfate + PAP EC Number: 2.8.2.2 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed11416019 Reactome Database ID Release 43176494 Reactome, http://www.reactome.org ReactomeREACT_6881 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The sulfonation of 27-hydroxycholesterol is catalyzed by both the a and b isoforms of SULT2B1 (Javitt et al. 2001). pregnenolone + PAPS => pregnenolone sulfate + PAP EC Number: 2.8.2.15 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed11457664 Pubmed12145317 Reactome Database ID Release 43176517 Reactome, http://www.reactome.org ReactomeREACT_6805 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The sulfonation of pregnenolone is catalyzed by both the a and b isoforms of SULT2B1, although the a isoform is more active in assays in vitro (Fuda et al. 2002; Meloche and Falany 2001). estrone + PAPS => estrone 3-sulfate + PAP EC Number: 2.8.2.4 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed7678732 Pubmed7779757 Pubmed8185618 Reactome Database ID Release 43176664 Reactome, http://www.reactome.org ReactomeREACT_6874 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Sulfonation of estrone is catalyzed by SULT1E1 (Aksoy et al. 1994; Falany et al. 1995), and also by SULT2A1 (Comer et al. 1993), although the efficiency of SULT2A1 catalysis is unknown. dehydroepiandrosterone (DHEA) + PAPS => DHEA sulfate + PAP EC Number: 2.8.2.15 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed11457664 Pubmed2268288 Pubmed8185618 Reactome Database ID Release 43176631 Reactome, http://www.reactome.org ReactomeREACT_6969 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Sulfonation of dehydroepiandrosterone (DHEA) is catalyzed by SULT1E1 (Aksoy et al. 1994), SULT2A1 (Radominska et al. 1990) and the a and b isoforms of SULT2B1 (Meloche and Falany 2001). N-hydroxy-2-acetylaminofluorene + PAPS => 2-acetylaminofluorene-N-sulfate + PAP EC Number: 2.8.2 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed11154739 Pubmed9852044 Reactome Database ID Release 43176669 Reactome, http://www.reactome.org ReactomeREACT_6925 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Sulfonation of the xenobiotic N-hydroxy-2-acetylaminofluorene converts it to a potent carcinogen. SULT1A2 (Glatt 2000) and SULT1C1 and 1C2 (Sakakibara et al. 1998) catalyze this reaction. cholesterol + PAPS => cholesterol sulfate + PAP EC Number: 2.8.2.2 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed11416019 Pubmed12145317 Pubmed12730293 Reactome Database ID Release 43176609 Reactome, http://www.reactome.org ReactomeREACT_6957 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The 3-hydroxyl groups of a number of sterols can undergo sulfonation. Cholesterol sulfate is particularly abundant in the body, and may have both regulatory and biosynthetic functions (Strott and Higashi 2003). Its synthesis is catalyzed by the b isoform of SULT2B1 (Fuda et al. 2002; Javitt et al. 2001). Transfer of Electrons from FDXR to FDX1/1L Authored: Lill, R, 2012-09-24 Authored: May, B, 2011-06-04 Edited: May, B, 2012-06-29 Pubmed20547883 Pubmed22101253 Reactome Database ID Release 432395512 Reactome, http://www.reactome.org ReactomeREACT_150196 Reviewed: Rouault, TA, 2012-10-11 Reviewed: Tong, Wing-Hang, 2012-10-11 Two electrons are transferred from reduced ferredoxin reductase (FDXR, adrenodoxin reductase) to two ferredoxin-1 or ferredoxin-1L (FDX1, FDX1L) molecules, each of which binds one electron. Two protons are released during the reaction. has a Stoichiometric coefficient of 2 FXN:NFS1:ISD11:ISCU Synthesizes Iron-Sulfur Cluster Authored: Lill, R, 2012-09-24 Authored: May, B, 2011-06-04 EC Number: 2.8.1.7 Edited: May, B, 2011-06-04 Iron-sulfur clusters are assembled on the scaffold, ISCU. Based on homology with bacterial IscU:IscS complexes (reviewed in Johnson et al. 2005), one molecule of ISCU is bound to each subunit of a NFS1 dimer (Marinoni et al. 2012). A single complex may thus be capable of assembling two 2Fe-2S clusters. Sulfide is provided by desulfuration of cysteine by NFS1:ISD11 (Biederbick et al. 2006, Shi et al. 2009, Tsai and Barondeau 2010). It has been proposed that ferrous iron is delivered by FXN (Gerber et al. 2003, Yoon and Cowan 2003, Schmucker et al. 2011) bound to ISCU (inferred from yeast, Wang and Craig 2008), although more recent studies suggested that FXN functions as an allosteric effector to stimulate sulfide transfer (Tsai et al. 2010). Holo-ISCU (ISCU bound to a newly synthesized 2Fe-2S cluster) transiently interacts with a dedicated HSP70 chaperone system including Mortalin (GRP75) and HSP20 and GLRX5 (GRX5). Electrons supplied by FDXL1 (FDX2) are required and may reduce the sulfur from S0 to S2-. NFU1 binds an Fe-S cluster (Tong et al. 2003, inferred from bacteria Yuvaniyama et al. 2000) and, from biochemical studies of bacterial NFU1 homologues, is proposed to be an intermediate Fe-S cluster carrier (Bandyopadhy et al. 2008). Mutations in human NFU1 affect only a subset of Fe-S proteins (Navarro-Sastre et al. 2011). Pubmed10639125 Pubmed12785837 Pubmed12886008 Pubmed12947415 Pubmed12970193 Pubmed15952888 Pubmed16847322 Pubmed17331979 Pubmed18319250 Pubmed18339629 Pubmed19454487 Pubmed20873749 Pubmed21944046 Pubmed22077971 Pubmed22101253 Pubmed22306468 Pubmed22352884 Pubmed22511353 Reactome Database ID Release 431362408 Reactome, http://www.reactome.org ReactomeREACT_150385 Reviewed: Rouault, TA, 2012-10-11 Reviewed: Tong, Wing-Hang, 2012-10-11 has a Stoichiometric coefficient of 4 Frataxin Binds Iron Authored: Lill, R, 2012-09-24 Authored: May, B, 2011-06-04 Edited: May, B, 2011-06-04 Frataxin (FXN) specifically binds 2 atoms of ferrous iron per monomer (reviewed in Stemmler et al. 2010). Iron bound to Frataxin may (Yoon and Cowan 2003, Gerber et al. 2003) or may not (Schmucker et al. 2011) enhance the interaction of Frataxin with NFS1, ICSU, and ISD11. Frataxin was shown to stimulate the cysteine desulfurase activity of NFS1 and was proposed to be a regulator of sulfur production (Tsai et al. 2010). The formation of sulfide by NFS1 is most efficiently observed when NFS1 is in complex with ISD11, ISCU, and FXN in the presence of cysteine and iron. This means that only the complete system of NFS1, ISD11, ISCU, FXN, cysteine, and iron is fully active as a desulfurase. FXN therefore seems to be a regulator of the cysteine desulfurase permitting sulfide production only when all components needed for Fe-S cluster synthesis are present and the ISCU-bound Fe-S cluster can be formed. Pubmed11823441 Pubmed12785837 Pubmed15509595 Pubmed18425540 Pubmed20522547 Pubmed20873749 Pubmed21298097 Pubmed21776984 Reactome Database ID Release 431362416 Reactome, http://www.reactome.org ReactomeREACT_150163 Reviewed: Rouault, TA, 2012-10-11 Reviewed: Tong, Wing-Hang, 2012-10-11 has a Stoichiometric coefficient of 4 Transfer of Electrons from NADPH to FDXR Authored: Lill, R, 2012-09-24 Authored: May, B, 2011-06-04 Edited: May, B, 2012-06-29 Pubmed1567230 Reactome Database ID Release 432395517 Reactome, http://www.reactome.org ReactomeREACT_150376 Reviewed: Rouault, TA, 2012-10-11 Reviewed: Tong, Wing-Hang, 2012-10-11 Two electrons and one proton are transferred from NADPH to the FAD moiety of ferredoxin reductase. A proton from the medium is also taken up by ferredoxin reductase. H2O + CO2 -> H+ + HCO3- Authored: May, B, 2011-03-24 Carbonic Anhydrase IV Hydrates Carbon Dioxide to Form a Proton and Bicarbonate Carbonic anhydrase IV (CA4) anchored to extracellular face of the plasma membrane (Wistrand et al. 1999) hydrates carbon dioxide (CO2) to yield bicarbonate (HCO3-) and a proton (H+) (Zhu & Sly 1990, Okayuma et al. 1992, Baird et al. 1997, Innocenti et al. 2004). During the reaction a hydroxyl group bound by the zinc ion (Zn2+) of CA4 attacks the CO2 molecule to directly form HCO3- (reviewed in Lindskog 1997). The HCO3- is displaced by water, which is then deprotonated by a histidine residue to recreate the Zn2+:hydroxyl group. Depending on the concentrations of reactants the reaction is reversible. EC Number: 4.2.1.1 Edited: May, B, 2011-03-24 Pubmed10090333 Pubmed1311094 Pubmed15501038 Pubmed2111324 Pubmed9054574 Pubmed9336012 Reactome Database ID Release 431237047 Reactome, http://www.reactome.org ReactomeREACT_120847 Reviewed: Jassal, B, 2012-04-27 Synthesis of phenylacetyl CoA from phenylacetate and Coenzyme A Edited: D'Eustachio, P, 2006-03-23 15:51:01 Phenylacetate and ATP react with coenzyme A to form phenylacetyl CoA, AMP, and pyrophosphate (Vessey et al. 1999). Two human CoA ligases have been characterized that catalyze this reaction efficiently in vitro: acyl-CoA synthetase medium-chain family member 1 (BUCS1) (Fujino et al. 2001) and xenobiotic/medium-chain fatty acid:CoA ligase (Vessey et al. 2003). Their relative contributions to phenylacetate metabolism in vivo are unknown. Pubmed10434065 Pubmed11470804 Pubmed12616642 Reactome Database ID Release 43177157 Reactome, http://www.reactome.org ReactomeREACT_6751 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 phenylacetate + Coenzyme A + ATP => phenylacetyl-CoA + AMP + pyrophosphate Salicylate-CoA forms an amide bond with glycine EC Number: 2.3.1.71 Pubmed7802672 Pubmed931988 Reactome Database ID Release 43159574 Reactome, http://www.reactome.org ReactomeREACT_6950 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Salicylate CoA and glycine react to form salicyluric acid and Coenzyme A (Mawal and Qureshi 1994). salicylate-CoA + glycine => salicyluric acid + Coenzyme A Mitoferrin Transports Iron Across the Mitochondrial Inner Membrane As inferred from biochemical studies in yeast and phenotypic studies in mouse, Mitoferrin-1 (SLC25A37) and Mitoferrin-2 (SLC25A28) transport ferrous iron across the inner mitochondrial membrane. Mitoferrin-1 is essential for maintaining mitochondrial iron uptake in developing erythroid cells; mitoferrin-2 is ubiquitously expressed. Defects in Mitoferrin-1 and Mitoferrin-2 cause a reduction in mitochondrial iron acquisition and biogenesis of iron-sulfur clusters and heme. Authored: Lill, R, 2012-09-24 Authored: May, B, 2011-06-04 Edited: May, B, 2011-06-04 Reactome Database ID Release 431362417 Reactome, http://www.reactome.org ReactomeREACT_150305 Reviewed: Rouault, TA, 2012-10-11 Reviewed: Tong, Wing-Hang, 2012-10-11 phenylacetyl-CoA + glutamine => phenylacetyl glutamine + Coenzyme A Edited: D'Eustachio, P, 2006-03-23 15:51:01 Phenylacetyl CoA and glutamine react to form phenylacetyl glutamine and Coenzyme A. The enzyme that catalyzes this reaction has been purified from human liver mitochondria and shown to be a distinct polypeptide species from glycine-N-acyltransferase (Webster et al. 1976). This human glutamine-N-acyltransferase activity has not been characterized by sequence analysis at the protein or DNA level, however, and thus cannot be associated with a known human protein in the annotation of phenylacetate conjugation. Pubmed931988 Reactome Database ID Release 43177160 Reactome, http://www.reactome.org ReactomeREACT_6927 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Synthesis of phenylacetyl glutamine from phenylacetyl-CoA and glutamine Salicylic acid and Coenzyme A react to form salicylate-CoA thioester Authored: Jassal, B, 2005-03-11 11:56:39 Pubmed12616642 Pubmed5862532 Reactome Database ID Release 43159567 Reactome, http://www.reactome.org ReactomeREACT_6790 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Salicylate and ATP react with coenzyme A to form salicylate CoA, AMP, and pyrophosphate in a reaction catalyzed by xenobiotic/medium-chain fatty acid:CoA ligase (Vessey et al. 2003). salicylic acid + Coenzyme A + ATP => salicylate-CoA + AMP + pyrophosphate Cysteinylglycine and gamma-glutamate:AA are imported into the cell Authored: Jassal, B, 2011-04-08 Edited: Jassal, B, 2011-04-08 Pubmed31622 Pubmed3997870 Reactome Database ID Release 431247939 Reactome, http://www.reactome.org ReactomeREACT_75773 Reviewed: D'Eustachio, P, 2011-05-23 The hydrolysis products of glutathione are transported back into the cell to replenish the precursor resevoir for the resynthesis of glutathione. The exact mechanism of uptake is unknown (Bridges and Meister, 1985; Griffith et al, 1978). 5-oxoproline can be formed from gamma-glutamyl-AA products Authored: Jassal, B, 2011-04-08 EC Number: 2.3.2.4 Edited: Jassal, B, 2011-04-08 Gamma-glutamylcyclotransferase (GGCT) homodimer (Bae et al, 2008) can catalyzes the formation of 5-oxoproline from gamma-glutamyl-amino acid products and thus can play a role in glutathione homeostasis (Oakley et al, 2008). Pubmed17932939 Pubmed18515354 Reactome Database ID Release 431247912 Reactome, http://www.reactome.org ReactomeREACT_75867 Reviewed: D'Eustachio, P, 2011-05-23 Glutathione conjugation of luminal substrates EC Number: 2.5.1.18 Reactome Database ID Release 43176059 Reactome, http://www.reactome.org ReactomeREACT_6947 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Typical substrates are chosen as examples for which the majority of the GST isozymes act on. Glutathione conjugation of cytosolic substrates EC Number: 2.5.1.18 Reactome Database ID Release 43176054 Reactome, http://www.reactome.org ReactomeREACT_6854 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Typical substrates are chosen as examples for which the majority of the GST isozymes act on. Benzoate and Coenzyme A react to form benzoyl-CoA thioester Authored: Jassal, B, 2005-03-10 15:37:26 Benzoate and ATP react with coenzyme A to form benzoyl CoA, AMP, and pyrophosphate (Vessey et al. 1999, 2003). Two human CoA ligases have been characterized that catalyze this reaction efficiently in vitro: acyl-CoA synthetase medium-chain family member 1 (BUCS1) (Fujino et al. 2001) and xenobiotic/medium-chain fatty acid:CoA ligase (Vessey et al. 2003). Their relative contributions to benzoate metabolism in vivo are unknown. Pubmed10434065 Pubmed11470804 Pubmed12616642 Reactome Database ID Release 43159443 Reactome, http://www.reactome.org ReactomeREACT_6972 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 benzoate + Coenzyme A + ATP => benzoyl-CoA + AMP + pyrophosphate Benzoyl-CoA forms an amide bond with glycine Benzoyl CoA and glycine react to form benzoyl glycine (hippuric acid) and Coenzyme A (Mawal and Qureshi 1994). EC Number: 2.3.1.71 Pubmed7802672 Pubmed931988 Reactome Database ID Release 43159566 Reactome, http://www.reactome.org ReactomeREACT_6953 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 benzoyl-CoA + glycine => benzoyl glycine (hippuric acid) + Coenzyme A Formation of 5-oxoproline from gamma-glutamylcysteine Authored: Jassal, B, 2011-04-08 EC Number: 2.3.2.4 Edited: Jassal, B, 2011-04-08 Gamma-glutamylcyclotransferase (GGCT) homodimer (Bae et al, 2008) catalyzes the formation of 5-oxoproline from gamma-glutamylcysteine and thus, may play a role in glutathione homeostasis (Oakley et al, 2008). Pubmed17932939 Pubmed18515354 Reactome Database ID Release 431247922 Reactome, http://www.reactome.org ReactomeREACT_75929 Reviewed: D'Eustachio, P, 2011-05-23 gamma-glutamylcysteine combines with glycine to form glutathione EC Number: 6.3.2.3 Edited: Jassal, B, 2011-04-08 In the second step in the formation of glutathione, gamma-glutamylcysteine ligates with glycine to form glutathione (Gali and Board, 1995; ). Pubmed7646467 Reactome Database ID Release 43174394 Reactome, http://www.reactome.org ReactomeREACT_6886 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Export of glutathione to the extracellular space Authored: Jassal, B, 2011-04-08 Edited: Jassal, B, 2011-04-08 Glutathione is exported out of the cell to be made available for membrane-bound gamma-glutamyl transpeptidases (GGTs). Cells that have GGTs can utilize translocated glutathione. The exact transport mechanism is uncertain (Griffith and Meister, 1979; Griffith et al, 1979). Pubmed34150 Pubmed42913 Reactome Database ID Release 431247915 Reactome, http://www.reactome.org ReactomeREACT_75882 Reviewed: D'Eustachio, P, 2011-05-23 Glutathione is hydrolyzed Authored: Jassal, B, 2011-04-08 EC Number: 2.3.2.2 Edited: Jassal, B, 2011-04-08 Extracellular glutathione can be hydrolyzed to give cysteinylglycine (Cys-Gly) and gamma glutamate, which, in the presence of amino acids, can form a gamma-glutamate:AA product (Heisterkamp et al, 2008). This hydrolysis provides cells with a cysteine supply and contributes to the maintainance of intracellular glutathione levels (Tate and Ross, 1977; Pawlak et al, 1989). Pubmed18357469 Pubmed19463 Pubmed2573352 Reactome Database ID Release 431247927 Reactome, http://www.reactome.org ReactomeREACT_75920 Reviewed: D'Eustachio, P, 2011-05-23 Oxidative deamination of 5-Hydroxytryptamine by MAOA At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of 'H2O', and 1 molecule of '5-Hydroxytryptamine' are present. At the end of this reaction, 1 molecule of 'NH3', 1 molecule of '5-Hydroxyindoleacetaldehyde', and 1 molecule of 'H2O2' are present.<br><br> This reaction takes place in the 'mitochondrial outer membrane' and is mediated by the 'amine oxidase activity' of 'MAOA-FAD complex'.<br> Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.4.3.21 EC Number: 1.4.3.22 EC Number: 1.4.3.4 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed6408492 Reactome Database ID Release 43141186 Reactome, http://www.reactome.org ReactomeREACT_1795 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 FMO3 N-oxidizes the tertiary amine trimethylamine Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.14.13.8 Edited: Jassal, B, 2008-05-14 09:43:11 Pubmed4195988 Pubmed5048998 Reactome Database ID Release 43139970 Reactome, http://www.reactome.org ReactomeREACT_236 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Trimethylamine (TMA) is present in the diet (in fish) but primarily formed in vivo from the breakdown of choline. It is N-oxidized by FMO3 in the liver, the major isoform active towards TMA Trimethylaminuria (“fish-odour syndrome”) is a human genetic disorder characterized by an impaired ability to convert the malodourous TMA to its odourless N-oxide. Trimethylamine N-oxidised to Trimethylamine-N-oxide Dietary tyramine is oxidatively deaminated to an aldehyde by MAOB Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.4.3.21 EC Number: 1.4.3.22 EC Number: 1.4.3.4 Edited: Jassal, B, 2008-05-19 12:57:01 Monoamine oxidases (MAO-A/B), present in the outer mitochondrial membrane, catalyze the oxidation of biogenic amines, releasing hydrogen peroxide (H2O2). H2O2 produced during the oxidative deamination of these amines appears to be involved in the progress of neurodegenerative disorders such as Parkinson disease, presumably via oxidative damage to the mitochondrial membrane. Pubmed4016087 Reactome Database ID Release 43141202 Reactome, http://www.reactome.org ReactomeREACT_1260 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 FMO2 S-oxidizes the antithyroid drug methimazole Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Methimazole is a drug used to treat hyperthyroidism, a condition arising when the thyroid gland is producing too much thyroid hormone. FMO2 is able to the S-oxidized form of methimazole. Pubmed11744609 Reactome Database ID Release 43217258 Reactome, http://www.reactome.org ReactomeREACT_13821 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 FMO1 N-oxidizes the anti-cancer drug tamoxifen Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.14.13.8 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed15987777 Reactome Database ID Release 43217255 Reactome, http://www.reactome.org ReactomeREACT_13805 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Tamoxifen (TAM) is an antiestrogen and currently used extensively for breast cancer therapy. FMOs, especially FMO1 can N-oxidze TAM to tamoxifen N-oxide (TNO). TNO can be reduced back to TAM by the P450 system. TNO appears to be just as potent as TAM but with fewer side-effects so this metabolic cycling could play a part in the use of TNO in the treatment of breast cancer. CYP4F11 omega-hydroxylates 3-hydroxypalmitate Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Long-chain 3-hydroxy fatty acids (3-OHFAs) are omega-hydroxylated to form 3-hydroxydicarboxylic acid (3-OHDCAs) precursors in human liver. These products may be implicated in pathological states where fatty acid mobilzation or impairment of mitochondrial fatty acid beta-oxidation increases 3-OHFA levels. CYP4A11, an orphan P450, has been shown to omega-hydroxylate 3-hydroxystearate and 3-hydroxypalmitate; the latter is shown here. Pubmed18065749 Reactome Database ID Release 43211962 Reactome, http://www.reactome.org ReactomeREACT_13511 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP3A43 catalyzes the 6beta-hydroxylation of testosterone Authored: Jassal, B, 2008-05-19 12:57:01 CYP3A43 belongs to the CYP3A family, of which CYP3A4 is the most active member in the biotransformation of xenobiotics. Testosterone metabolites are a major determinant of prostate growth and differentiation. CYP3A43, which is expressed in the prostate, exhibits minor 6-beta-hydroxylation activity towards testosterone. Thus, CYP3A43 may be involved in the etiology of prostate cancer. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed11160876 Pubmed15548719 Reactome Database ID Release 43211959 Reactome, http://www.reactome.org ReactomeREACT_13740 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP2W1 can oxidize indole Authored: Jassal, B, 2008-05-19 12:57:01 CYP2W1 is a so-called "ophan P450", a P450 which has no defined function or endogenous/xenobiotic substrates. CYP2W1 has recently been shown to be selectively expressed in some forms of cancers and, with the low expression in normal tissues, could be rendered as a possible drug target during cancer therapy (Karlgren M, Ingelman-Sundberg M, 2007). CYP2W1 can bioactivate several procarcinogens but at lower levels than other P450s (Wu, ZL et al, 2006). CYP2W1 also shows monooxygenase activity towards the pigment indole, an ingredient of perfumes and coal tar. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed16551781 Pubmed16677611 Pubmed17150034 Reactome Database ID Release 43211968 Reactome, http://www.reactome.org ReactomeREACT_13592 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP2U1 can omega-hydroxylate arachidonate A novel cytochrome P450, CYP2U1, may play an important role in modulating the arachidonic acid signaling pathway. It was discovered by searching the human EST database for homology to existing CYPs and subsequent cloning and expression to obtain the enzyme. CYP2U1 was found to be highly expressed in the thymus and the brain (cerebellum) and found to metabolize arachidonic acid to 19- and 20-hydroxy-modified arachidonic acids. It is thought that CYP2U1 plays an important physiological role in fatty acid signaling processes in both the cerebellum and thymus. The omega-hydroxylation (19) example is provided here. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed14660610 Reactome Database ID Release 43211960 Reactome, http://www.reactome.org ReactomeREACT_13412 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP2S1 can deactivate all-trans-retinoic acid Authored: Jassal, B, 2008-05-19 12:57:01 CYP2S1 is a recently discovered cytochrome P450 enzyme on the basis of homology searches of databases and was found to be homologous to the CYP2 family of enzymes that are known to metabolize xenobiotics (Rylander T et al, 2001). CYP2S1 is expressed in skin cells and is inducible by UV radiation, coal tar and all-trans retinoate, the latter also serving as a substrate for the enzyme. Expression of CYP2S1 was significantly higher in psoriatic plaque than in normal skin. Psoriasis is a chronic hyperproliferative and inflammatory disorder. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed11181079 Pubmed12711469 Reactome Database ID Release 43211874 Reactome, http://www.reactome.org ReactomeREACT_13626 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP24A1 catalyzes the initial step in the deactivation of the hormonally active form of vitamin D3 Authored: Jassal, B, 2008-05-19 12:57:01 Catabolic inactivation of the active, hormonal form of vitamin D3 (1,25-dihydroxyvitamin D3) is initially carried out by 24-hydroxylation, mediated by CYP24A1 (1,25-dihydroxyvitamin D3 24-hydroxylase). The product formed is eventually transformed to calcitroic acid, the major water-soluble metabolite that can be excreted in bile. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed11012668 Pubmed17646648 Pubmed8679605 Reactome Database ID Release 43211950 Reactome, http://www.reactome.org ReactomeREACT_13822 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP26A1 breaks down all-trans-retinoic acid by 4-hydroxylation Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed9716180 Reactome Database ID Release 43212007 Reactome, http://www.reactome.org ReactomeREACT_13572 Retinoic acid (RA) is a biologically active analogue of vitamin A (retinol). RA plays an important role in regulating cell growth and differentiation.CYP26A1 is involved in the metabolic breakdown of RA by 4-hydroxylation. CYP26A1-mediated 4-hydroxylation is specific for all-trans-RA but not for the isomers 13-cis-RA and 9-cis-RA. Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP26B1 also deactivates all-trans-retinoic acid by 4-hydroxylation Authored: Jassal, B, 2008-05-19 12:57:01 CYP26B1 can also deactivate all-trans-retinoic acid by 4-hydroxylation. High expression levels in the cerebellum and pons of human brain suggests a protective role of specific tissues against retinoid damage.<br> Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed10823918 Reactome Database ID Release 43211930 Reactome, http://www.reactome.org ReactomeREACT_13550 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP26C1 deactivates 9-cis-retinoic acid by 4-hydroxylation Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Endogenous retinoic acids (RA) which play a role in gene regulation exist as either cis or trans isomers. While CYP26C1 can also hydroxylate the trans form, it is unique in hydroxylating the 9-cis isomer of RA. Pubmed14532297 Reactome Database ID Release 43211923 Reactome, http://www.reactome.org ReactomeREACT_13793 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP4B1 can 12-hydroxylate arachidonic acid Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Injury to the eye's surface provokes an inflammatory response, mediated, in part, by 12-hydroxyeicosanoids. CYP4B1 catalyzes the 12-hydroxylation of arachidonic acid to 12-HETE and 12-HETrE (12-hydroxy-5,8,10,14-eicosatetraenoic acid and 12-hydroxy-5,8,14-eicosatrienoic acid respectively). Both these metabolites possess potent inflammatory and angiogenic properties. The example of 12-HETE formation only is shown here. Pubmed15006160 Reactome Database ID Release 43211924 Reactome, http://www.reactome.org ReactomeREACT_13615 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP4A11 omega-hydroxylates laurate Authored: Jassal, B, 2008-05-19 12:57:01 Dodecanoic acid (Lauric acid) is a medium-chain fatty acid which serves as a model substrate for studying the CYP4A gene subfamily of cytochrome P450s. CYP4A11 and CYP2E1 are the principal isozymes involved in omega-hydroxylation and omega-1 hydroxylation respectively of dodecanoic acid. Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0006631 Pubmed8914854 Reactome Database ID Release 4376466 Reactome, http://www.reactome.org ReactomeREACT_98 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 dodecanoic acid + O<sub>2</sub> + NADPH + H<sup>+</sup> -> 12-hydroxydodecanoic acid + H<sub>2</sub>O + NADP<sup>+</sup> CYP4F8 hydroxylates prostaglandin H2 19-hydroxyprostaglandins E1 and E2 (19-OH PGE1/2) are major components of human seminal fluid. The initial step in their formation is the 19-hydroxylation of prostaglandin H1 and H2 (PGH1/2). CYP4F8 performs this initial conversion. The example of PGH2 is used here. Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed10405341 Pubmed10791960 Reactome Database ID Release 43211919 Reactome, http://www.reactome.org ReactomeREACT_13624 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP4F12 hydroxylates arachidonic acid Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Human CYP4F12 is involved in metabolism of endogenous compounds such as inflammatory mediators (arachidonic acid and prostaglandin H2) as well as xenobiotics like terfenadine (an antihistaminic drug). The omega-hydroxylation of arachidonic acid is shown here as an example. Pubmed11162607 Reactome Database ID Release 43211904 Reactome, http://www.reactome.org ReactomeREACT_13485 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP2J2 epoxygenates arachidonic acid Activation of phospholipases releases free arachidonic acid (AA) from phospholipid bilayers which can then be metabolized to biologically active eicosanoids (signaling molecules which exert effects in inflammation and immunity). The cytochrome P450 enzyme CYP2J2 (arachidonic acid epoxygenase) is mainly expressed in human heart and can metabolize AA to epoxyeicosatrienoic acid (EET). Four cis-EETs can be produced: 5,6-, 8,9-, 11,12- and 14,15-EET. Each of these can be formed as the R,S or the S,R enantiomer (Zeldin DC, 2001). The most abundant regioisomer in human heart is 14,15-EET although 11,12-EET possesses the most potent anti-inflammatory effect (Wu et al, 1996). Authored: Jassal, B, 2008-05-19 12:57:01 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed11451964 Pubmed8631948 Pubmed8913342 Reactome Database ID Release 43211983 Reactome, http://www.reactome.org ReactomeREACT_13525 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 CYP3A7 can 6beta-hydroxylate testosterone Authored: Jassal, B, 2008-05-19 12:57:01 CYP3A7 is only expressed in fetal liver and not in adults. It has lower biotransformation capability than other members of the CYP3A family such as 3A4 or 3A5 but possesses a similar broad specificity. CYP3A7 plays a major role in fetal steroid hydroxylation, an example being the 6beta-hydroxylation of testosterone. Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed9644715 Reactome Database ID Release 43211882 Reactome, http://www.reactome.org ReactomeREACT_13670 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 p-nitrophenol + PAPS => p-nitrophenol sulfate + PAP EC Number: 2.8.2.1 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed12039030 Pubmed8697101 Pubmed9566739 Pubmed9852044 Reactome Database ID Release 43176646 Reactome, http://www.reactome.org ReactomeREACT_6855 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The sulfonation of the xenobiotic p-nitrophenol (4-nitrophenol) can be catalyzed by five well-characterized SULT enzymes, 1A1 (Brix et al. 1998), 1A2 (Brix et al. 1998; Zhu et al. 1996), 1C2 (Sakakibara et al. 1998), and 4A1 (Sakakibara et al. 2002). Formation of N-glucuronides EC Number: 2.4.1.17 Pubmed12433823 Pubmed14570768 Pubmed15135306 Reactome Database ID Release 43174916 Reactome, http://www.reactome.org ReactomeREACT_6956 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Typical N-centred substrates were chosen as examples for these isozymes. N-hydroxy-4-aminobiphenyl can form a sulfate conjugate At the beginning of this reaction, 1 molecule of 'PAPS', and 1 molecule of 'N-Hydroxy-4-aminobiphenyl' are present. At the end of this reaction, 1 molecule of 'N-hydroxy-4-aminobiphenyl O-sulfate', and 1 molecule of 'PAP' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'aryl sulfotransferase activity' of 'SULT1A1 homodimer'.<br> EC Number: 2.8.2.1 Pubmed10503886 Pubmed12372849 Pubmed9034160 Reactome Database ID Release 43158860 Reactome, http://www.reactome.org ReactomeREACT_6868 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Acetaminophen can form an O- sulfate conjugate At the beginning of this reaction, 1 molecule of 'Acetaminophen (TN TYLENOL)', and 1 molecule of 'PAPS' are present. At the end of this reaction, 1 molecule of 'PAP', and 1 molecule of 'Acetaminophen O-sulfate conjugate' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'aryl sulfotransferase activity' of 'SULT1A1 homodimer'.<br> EC Number: 2.8.2.1 Pubmed10503886 Pubmed12372849 Reactome Database ID Release 43158468 Reactome, http://www.reactome.org ReactomeREACT_6765 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 adenylyl sulfate (APS) + ATP => PAPS + ADP APS reacts with another ATP molecule to form PAPS EC Number: 2.7.1.25 In the second step of PAPS biosynthesis, adenylyl sulfate is phosphorylated. This reaction is energetically favorable, and makes the overall PAPS synthesis energetically favorable as well. Pubmed9576487 Pubmed9668121 Pubmed9771708 Reactome Database ID Release 43174389 Reactome, http://www.reactome.org ReactomeREACT_6792 Activation of inorganic sulfate forms APS ATP + sulfate => adenylyl sulfate (APS) + pyrophosphate EC Number: 2.7.7.4 In the first step of PAPS biosynthesis, ATP and sulfate react to form adenylyl sulfate and pyrophosphate. Even accounting for the free energy realized from the subsequent hydrolysis of the pyrophosphate, this reaction is energetically unfavorable. Pubmed9576487 Pubmed9668121 Pubmed9771708 Reactome Database ID Release 43174392 Reactome, http://www.reactome.org ReactomeREACT_6767 3,5,3'-triiodothyronine + PAPS => 3,5,3'-triiodothyronine 4-sulfate + PAP 3,5,3'-Triiodothyronine (T3) 4-sulfate is a major metabolite of T3 in humans (LoPresti and Nicoloff 1994), and seven SULT enzymes, SULT1A1 (Li et al. 2001), 1A3 (Kester, Kaptein et al. 1999), 1B1 (Wang et al. 1998), 1C1 (Li et al. 2000), 1E1 (Li and Anderson 1999; Kester, van Dijk et al. 1999), 2A1 (Li and Anderson 1999), and 4A1 (Sakakibara et al. 2002) can catalyze this reaction in vitro or in tissue culture model systems. All of these enzymes except SULT4A1 also catalyze the sulfonation of 3,3'-diiodothyronine (T2). EC Number: 2.8.2.1 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed10199779 Pubmed10512730 Pubmed11077054 Pubmed11739018 Pubmed12039030 Pubmed8126143 Pubmed9463486 Reactome Database ID Release 43176585 Reactome, http://www.reactome.org ReactomeREACT_6961 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 3,3'-diiodothyronine + PAPS => 3,3'-diiodothyronine 4-sulfate + PAP EC Number: 2.8.2.1 Edited: D'Eustachio, P, 2006-03-11 18:40:17 Pubmed10199779 Pubmed10512730 Pubmed11077054 Pubmed11739018 Pubmed9463486 Reactome Database ID Release 43176474 Reactome, http://www.reactome.org ReactomeREACT_6722 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Six SULT enzymes, SULT1A1 (Li et al. 2001), 1A3 (Kester, Kaptein et al. 1999), 1B1 (Wang et al. 1998), 1C1 (Li et al. 2000), 1E1 (Li and Anderson 1999; Kester, van Dijk et al. 1999), and 2A1 (Li and Anderson 1999), can catalyze the sulfonation of 3,3'-diiodothyronine (T2) in vitro or in tissue culture model systems. These six enzymes also catalyze the sulfonation of 3,5,3'-triiodothyronine (T3). Dopamine can form an O-sulfate conjugate Authored: Jassal, B, 2005-03-03 15:41:40 EC Number: 2.8.2.1 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed6139755 Pubmed6770210 Reactome Database ID Release 43159358 Reactome, http://www.reactome.org ReactomeREACT_6740 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The catecholamine neurotransmitter dopamine (DA) is predominantly (>95%) conjugated with sulfate in human blood circulation. Human SULT1A3 is the major sulfotransferase that sulfonates DA. Phenol can form a sulfate conjugate At the beginning of this reaction, 1 molecule of 'PAPS', and 1 molecule of 'Phenol' are present. At the end of this reaction, 1 molecule of 'Phenyl sulfate', and 1 molecule of 'PAP' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'aryl sulfotransferase activity' of 'SULT1A1 homodimer'.<br> EC Number: 2.8.2.1 Pubmed12372849 Pubmed9034160 Reactome Database ID Release 43158849 Reactome, http://www.reactome.org ReactomeREACT_6897 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 UDP-glucuronate transport from the cytosol to ER lumen Authored: Jassal, B, 2006-02-17 10:30:46 Edited: Jassal, B, 2006-02-17 10:30:46 Pubmed11322953 Reactome Database ID Release 43174368 Reactome, http://www.reactome.org ReactomeREACT_6892 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 The human gene SLC35D1 encodes the UDP-glucuronic acid transporter which transports both UDP-glucuronic acid (UDP-GlcA) and UDP-N-acetylgalactosamine (UDP-GalNAc) from the cytoplasm into the endoplasmic reticulum lumen. Formation of O-glucuronides EC Number: 2.4.1.17 Pubmed8687483 Reactome Database ID Release 43174931 Reactome, http://www.reactome.org ReactomeREACT_6815 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Typical O-centred substrates were chosen as examples for these isozymes. ethanol + NAD+ => acetaldehyde + NADH + H+ Authored: Jassal, B, 2008-05-19 12:57:01 Cytosolic alcohol dehydrogenase catalyzes the reaction of ethanol and NAD+ to form acetaldehyde and NADH + H+. The active form of the enzyme is a dimer with one zinc ion bound to each protein subunit. In the body, alcohol dehydrogenase is present in the liver, kidney, lung and gastric mucosa.<p>Six genes encode proteins active in ethanol oxidation: ADH1A, ADH1B, ADH1C, ADH4, ADH6, and ADH7 (Lange et al. 1976; Yin et al. 1985; Li et al. 1978; Bosron et al. 1979; Moreno and Pares 1991; Yokoyama et al. 1994; Chen and Yoshida 1991). ADH1A, B and C proteins can associate to form homodimers or heterodimers; ADH4, 6, and 7 proteins each form homodimers. Expression of ADH1A, B and C is developmentally regulated: ADH1A protein is abundant in the fetus, but expressed only at low levels in adulthood, when ADH1B and C proteins are abundant (Edenberg 2000). The various dimers differ substantially in the efficiency with which they oxidize ethanol. The ADH1B homodimer and heterodimers containing at least one 1B monomer are the most active towards ethanol (Yin et al. 1985). In addition, common polymorphic variants of ADH1B and C proteins differ substantially in this respect (Murray and Price 1972). Edited: Jassal, B, 2008-05-19 12:57:01 Ethanol is oxidized by NAD+ to form acetaldehyde, NADH, and H+ Pubmed10441588 Pubmed10697413 Pubmed1755855 Pubmed1985938 Pubmed270680 Pubmed427099 Pubmed4504607 Pubmed4748759 Pubmed6395883 Pubmed8074657 Pubmed9982 Reactome Database ID Release 4371707 Reactome, http://www.reactome.org ReactomeREACT_1431 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 Oxidative deamination of Phenyethylamine by MAOB At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of 'H2O', and 1 molecule of '2-Phenylethylamine' are present. At the end of this reaction, 1 molecule of 'NH3', 1 molecule of 'H2O2', and 1 molecule of 'Phenylacetaldehyde' are present.<br><br> This reaction takes place in the 'mitochondrial outer membrane' and is mediated by the 'amine oxidase activity' of 'MAOB-FAD complex'.<br> Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.4.3.21 EC Number: 1.4.3.22 EC Number: 1.4.3.4 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed6788990 Reactome Database ID Release 43141200 Reactome, http://www.reactome.org ReactomeREACT_980 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 acetaldehyde + NAD+ => acetate + NADH + H+ [mitochondrial] ALDH2 (aldehyde dehydrogenase) in the mitochondrial matrix catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ (Greenfield and Pietruszko 1977; Hempel et al. 1985). The active form of the enzyme is a tetramer (Ni et al. 1999). Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.2.1.3 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed10631996 Pubmed18196 Pubmed4065146 Reactome Database ID Release 4371723 Reactome, http://www.reactome.org ReactomeREACT_1080 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 acetaldehyde [cytosolic] => acetaldehyde [mitochondrial] Authored: D'Eustachio, P, 2009-12-09 Cytosolic acetaldehyde crosses the mitochondrial inner membrane and enters the mitochondrial matrix. Physiological studies have provided indirect evidence for acetaldehyde uptake by mitochondria (Lemasters 2007) but its molecular mechanism is unknown. Edited: D'Eustachio, P, 2010-02-18 Pubmed17567461 Reactome Database ID Release 43449872 Reactome, http://www.reactome.org ReactomeREACT_21302 Reviewed: Jassal, B, 2010-02-26 acetaldehyde + NAD+ => acetate + NADH + H+ [cytosolic] ALDH1A1 (aldehyde dehydrogenase) in the cytosol catalyzes the reaction of acetaldehyde and NAD+ to form acetate and NADH + H+ (Inoue et al. 1979). The active form of the enzyme is a tetramer (Ni et al. 1999). Authored: Jassal, B, 2008-05-19 12:57:01 EC Number: 1.2.1.3 Edited: Jassal, B, 2008-05-19 12:57:01 Pubmed10631996 Pubmed224930 Reactome Database ID Release 4371691 Reactome, http://www.reactome.org ReactomeREACT_2127 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 acetate + CoA + ATP => acetyl-CoA + AMP + pyrophosphate [mitochondrial] ACSS1 (acyl-CoA synthetase short-chain family member 1) in the mitochondrial matrix catalyzes the reaction of acetate, coenzyme A, and ATP to form acetyl-CoA, AMP, and pyrophosphate (Schwer et al. 2006). Authored: D'Eustachio, P, 2009-12-09 EC Number: 6.2.1.1 Edited: D'Eustachio, P, 2010-02-18 Pubmed16788062 Reactome Database ID Release 43449911 Reactome, http://www.reactome.org ReactomeREACT_21284 Reviewed: Jassal, B, 2010-02-26 UDP-glucose is oxidised to UDP-glucuronate Authored: Jassal, B, 2006-02-14 15:20:00 EC Number: 1.1.1.22 Edited: Jassal, B, 2006-02-14 15:20:00 Pubmed15044486 Reactome Database ID Release 43173597 Reactome, http://www.reactome.org ReactomeREACT_6876 Reviewed: D'Eustachio, P, 2008-05-28 08:30:54 UDP-glucose dehydrogenase (UGDH) catalyzes the conversion of UDP-glucose to UDP-glucuronic acid. The cytosolic enzyme is active as a hexamer and performs two successive oxidations to convert the 6'-hydroxyl of UDP-glucose to a carboxylate with concurrent reduction of 2 mol of NAD+ to NADH. has a Stoichiometric coefficient of 2 acetate + CoA + ATP => acetyl-CoA + AMP + pyrophosphate [cytosolic] Authored: Jassal, B, 2008-05-19 12:57:01 Cytosolic ACSS2 (acetyl-coenzyme A synthetase) catalyzes the reaction of acetate, coenzyme A, and ATP to form acetyl-CoA, AMP, and pyrophosphate (Luong et al. 2000). EC Number: 6.2.1.1 Pubmed10843999 Reactome Database ID Release 4371735 Reactome, http://www.reactome.org ReactomeREACT_553 creatine kinase, sarcomeric, octamer Reactome DB_ID: 200339 Reactome Database ID Release 43200339 Reactome, http://www.reactome.org ReactomeREACT_11583 has a Stoichiometric coefficient of 8 APIP:Zn++ Reactome DB_ID: 1237083 Reactome Database ID Release 431237083 Reactome, http://www.reactome.org ReactomeREACT_76345 has a Stoichiometric coefficient of 1 MTAP trimer Reactome DB_ID: 1237147 Reactome Database ID Release 431237147 Reactome, http://www.reactome.org ReactomeREACT_76563 has a Stoichiometric coefficient of 3 ARD:Fe++ Reactome DB_ID: 1237173 Reactome Database ID Release 431237173 Reactome, http://www.reactome.org ReactomeREACT_76515 has a Stoichiometric coefficient of 1 E1:Mg++ Reactome DB_ID: 1237166 Reactome Database ID Release 431237166 Reactome, http://www.reactome.org ReactomeREACT_76317 has a Stoichiometric coefficient of 1 AZIN1 bound OAZ:ODC complex Reactome DB_ID: 353105 Reactome Database ID Release 43353105 Reactome, http://www.reactome.org ReactomeREACT_14023 has a Stoichiometric coefficient of 1 ODC:OAZ complex Reactome DB_ID: 353118 Reactome Database ID Release 43353118 Reactome, http://www.reactome.org ReactomeREACT_14017 has a Stoichiometric coefficient of 1 ODC:NQO1 complex Reactome DB_ID: 353103 Reactome Database ID Release 43353103 Reactome, http://www.reactome.org ReactomeREACT_14566 has a Stoichiometric coefficient of 1 AZIN1 bound OAZ Reactome DB_ID: 353108 Reactome Database ID Release 43353108 Reactome, http://www.reactome.org ReactomeREACT_14681 has a Stoichiometric coefficient of 1 PAO-FAD complex Reactome DB_ID: 141346 Reactome Database ID Release 43141346 Reactome, http://www.reactome.org ReactomeREACT_3389 has a Stoichiometric coefficient of 1 creatine kinase, ubiquitous, octamer Reactome DB_ID: 200358 Reactome Database ID Release 43200358 Reactome, http://www.reactome.org ReactomeREACT_11820 has a Stoichiometric coefficient of 8 TrxA/B1 Converted from EntitySet in Reactome Reactome DB_ID: 1243096 Reactome Database ID Release 431243096 Reactome, http://www.reactome.org ReactomeREACT_121610 beta tubulin Converted from EntitySet in Reactome Reactome DB_ID: 392803 Reactome Database ID Release 43392803 Reactome, http://www.reactome.org ReactomeREACT_18029 alpha tubulin Converted from EntitySet in Reactome Reactome DB_ID: 190587 Reactome Database ID Release 43190587 Reactome, http://www.reactome.org ReactomeREACT_10584 MEK Converted from EntitySet in Reactome Reactome DB_ID: 112398 Reactome Database ID Release 43112398 Reactome, http://www.reactome.org ReactomeREACT_2275 Protein kinase C (alpha, gamma, delta) Converted from EntitySet in Reactome Reactome DB_ID: 112001 Reactome Database ID Release 43112001 Reactome, http://www.reactome.org ReactomeREACT_16126 FGFR1b-binding FGFs Converted from EntitySet in Reactome Reactome DB_ID: 189963 Reactome Database ID Release 43189963 Reactome, http://www.reactome.org ReactomeREACT_9541 ADAM metalloprotease Converted from EntitySet in Reactome Reactome DB_ID: 179832 Reactome Database ID Release 43179832 Reactome, http://www.reactome.org ReactomeREACT_9817 TrxA/B1 (ox.) Converted from EntitySet in Reactome Reactome DB_ID: 1243098 Reactome Database ID Release 431243098 Reactome, http://www.reactome.org ReactomeREACT_124277 PKC-delta/epsilon Converted from EntitySet in Reactome Reactome DB_ID: 198276 Reactome Database ID Release 43198276 Reactome, http://www.reactome.org ReactomeREACT_12301 Phospho-PKC-delta/epsilon Converted from EntitySet in Reactome Reactome DB_ID: 198265 Reactome Database ID Release 43198265 Reactome, http://www.reactome.org ReactomeREACT_12203 holo-SUOX Reactome DB_ID: 1614636 Reactome Database ID Release 431614636 Reactome, http://www.reactome.org ReactomeREACT_117350 has a Stoichiometric coefficient of 2 ETHE1:2Zn++ Reactome DB_ID: 1614521 Reactome Database ID Release 431614521 Reactome, http://www.reactome.org ReactomeREACT_117593 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ALAS1 homodimer (pyridoxal phosphate cofactor) Reactome DB_ID: 189446 Reactome Database ID Release 43189446 Reactome, http://www.reactome.org ReactomeREACT_9612 has a Stoichiometric coefficient of 2 ALAS homodimer Converted from EntitySet in Reactome Reactome DB_ID: 189429 Reactome Database ID Release 43189429 Reactome, http://www.reactome.org ReactomeREACT_9546 ATP6V1G Converted from EntitySet in Reactome Reactome DB_ID: 912574 Reactome Database ID Release 43912574 Reactome, http://www.reactome.org ReactomeREACT_24820 EIF5A(Hyp) Converted from EntitySet in Reactome Reactome DB_ID: 204658 Reactome Database ID Release 43204658 Reactome, http://www.reactome.org ReactomeREACT_12952 ATP6V1B Converted from EntitySet in Reactome Reactome DB_ID: 912593 Reactome Database ID Release 43912593 Reactome, http://www.reactome.org ReactomeREACT_24732 CDO1:Fe2+ Reactome DB_ID: 1614609 Reactome Database ID Release 431614609 Reactome, http://www.reactome.org ReactomeREACT_116910 has a Stoichiometric coefficient of 1 CSAD dimer Reactome DB_ID: 1655430 Reactome Database ID Release 431655430 Reactome, http://www.reactome.org ReactomeREACT_116175 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 SQR:FAD Reactome DB_ID: 1614651 Reactome Database ID Release 431614651 Reactome, http://www.reactome.org ReactomeREACT_117047 has a Stoichiometric coefficient of 1 CBS tetramer Reactome DB_ID: 1614610 Reactome Database ID Release 431614610 Reactome, http://www.reactome.org ReactomeREACT_116567 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 CTH tetramer:PXLP Reactome DB_ID: 1625212 Reactome Database ID Release 431625212 Reactome, http://www.reactome.org ReactomeREACT_116949 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 GCL Reactome DB_ID: 174377 Reactome Database ID Release 43174377 Reactome, http://www.reactome.org ReactomeREACT_7452 gamma-glutamylcysteine ligase gamma-glutamylcysteine synthase has a Stoichiometric coefficient of 1 CNDP2 CNDP2 homodimer Reactome DB_ID: 1258421 Reactome Database ID Release 431258421 Reactome, http://www.reactome.org ReactomeREACT_76091 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 BHMT tetramer Reactome DB_ID: 1614565 Reactome Database ID Release 431614565 Reactome, http://www.reactome.org ReactomeREACT_117610 has a Stoichiometric coefficient of 4 ATP6V1E Converted from EntitySet in Reactome Reactome DB_ID: 912576 Reactome Database ID Release 43912576 Reactome, http://www.reactome.org ReactomeREACT_24870 SAH hydrolase (NAD cofactor) Reactome DB_ID: 174357 Reactome Database ID Release 43174357 Reactome, http://www.reactome.org ReactomeREACT_7076 has a Stoichiometric coefficient of 1 EIF5A(Dhp) Converted from EntitySet in Reactome Reactome DB_ID: 204642 Reactome Database ID Release 43204642 Reactome, http://www.reactome.org ReactomeREACT_12917 SAH hydrolase homotetramer Reactome DB_ID: 174358 Reactome Database ID Release 43174358 Reactome, http://www.reactome.org ReactomeREACT_7827 has a Stoichiometric coefficient of 4 EIF5A Converted from EntitySet in Reactome Reactome DB_ID: 204659 Reactome Database ID Release 43204659 Reactome, http://www.reactome.org ReactomeREACT_12783 ATP6V1C Converted from EntitySet in Reactome Reactome DB_ID: 912577 Reactome Database ID Release 43912577 Reactome, http://www.reactome.org ReactomeREACT_24777 MAT II homodimer Reactome DB_ID: 174371 Reactome Database ID Release 43174371 Reactome, http://www.reactome.org ReactomeREACT_7749 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 MAT III homodimer Reactome DB_ID: 174395 Reactome Database ID Release 43174395 Reactome, http://www.reactome.org ReactomeREACT_7093 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 MAT I/III (Mg, K cofactors) Reactome DB_ID: 174402 Reactome Database ID Release 43174402 Reactome, http://www.reactome.org ReactomeREACT_7654 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 MAT II heterotetramer Reactome DB_ID: 353576 Reactome Database ID Release 43353576 Reactome, http://www.reactome.org ReactomeREACT_14298 has a Stoichiometric coefficient of 4 MAT homomultimer Converted from EntitySet in Reactome Reactome DB_ID: 174383 Reactome Database ID Release 43174383 Reactome, http://www.reactome.org ReactomeREACT_7868 MAT I homotetramer Reactome DB_ID: 174405 Reactome Database ID Release 43174405 Reactome, http://www.reactome.org ReactomeREACT_7431 has a Stoichiometric coefficient of 4 HAO1 tetramer Hydroxyacid oxidase 1 homotetramer Reactome DB_ID: 389845 Reactome Database ID Release 43389845 Reactome, http://www.reactome.org ReactomeREACT_18016 has a Stoichiometric coefficient of 4 HAO1:FMN complex Hydroxyacid oxidase 1:Flavin mononucleotide complex Reactome DB_ID: 389810 Reactome Database ID Release 43389810 Reactome, http://www.reactome.org ReactomeREACT_17387 has a Stoichiometric coefficient of 1 alcohol dehydrogenase 1 (class I), alpha/beta dimer Reactome DB_ID: 71696 Reactome Database ID Release 4371696 Reactome, http://www.reactome.org ReactomeREACT_4842 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ADH1A dimer Reactome DB_ID: 71693 Reactome Database ID Release 4371693 Reactome, http://www.reactome.org ReactomeREACT_5753 alcohol dehydrogenase 1 (class I), alpha/alpha dimer has a Stoichiometric coefficient of 2 alcohol dehydrogenase 1 (class I), beta/beta dimer Reactome DB_ID: 71698 Reactome Database ID Release 4371698 Reactome, http://www.reactome.org ReactomeREACT_3480 has a Stoichiometric coefficient of 2 alcohol dehydrogenase 1 (class I), alpha/gamma dimer Reactome DB_ID: 71701 Reactome Database ID Release 4371701 Reactome, http://www.reactome.org ReactomeREACT_5355 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 alcohol dehydrogenase 1 (class I), gamma/gamma dimer Reactome DB_ID: 71705 Reactome Database ID Release 4371705 Reactome, http://www.reactome.org ReactomeREACT_2620 has a Stoichiometric coefficient of 2 alcohol dehydrogenase 1 (class I), beta/gamma dimer Reactome DB_ID: 71703 Reactome Database ID Release 4371703 Reactome, http://www.reactome.org ReactomeREACT_3444 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FMO2 (FAD, Mg2+ cofactors) Reactome DB_ID: 217317 Reactome Database ID Release 43217317 Reactome, http://www.reactome.org ReactomeREACT_14675 has a Stoichiometric coefficient of 1 FMO3 (FAD cofactor) Reactome DB_ID: 217276 Reactome Database ID Release 43217276 Reactome, http://www.reactome.org ReactomeREACT_14498 has a Stoichiometric coefficient of 1 MAOB-FAD complex Reactome DB_ID: 141326 Reactome Database ID Release 43141326 Reactome, http://www.reactome.org ReactomeREACT_4664 has a Stoichiometric coefficient of 1 MAOA-FAD complex Reactome DB_ID: 141332 Reactome Database ID Release 43141332 Reactome, http://www.reactome.org ReactomeREACT_5113 has a Stoichiometric coefficient of 1 alcohol dehydrogenase complex Converted from EntitySet in Reactome Reactome DB_ID: 449883 Reactome Database ID Release 43449883 Reactome, http://www.reactome.org ReactomeREACT_21845 PPO homodimer (FAD cofactor) Reactome DB_ID: 189469 Reactome Database ID Release 43189469 Reactome, http://www.reactome.org ReactomeREACT_9681 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FMO1 (FAD cofactor) Reactome DB_ID: 217261 Reactome Database ID Release 43217261 Reactome, http://www.reactome.org ReactomeREACT_14390 has a Stoichiometric coefficient of 1 Tetrameric UGT1A1 Reactome DB_ID: 159191 Reactome Database ID Release 43159191 Reactome, http://www.reactome.org ReactomeREACT_22998 has a Stoichiometric coefficient of 4 Biliverdin reductase A:Zn2+ Reactome DB_ID: 189378 Reactome Database ID Release 43189378 Reactome, http://www.reactome.org ReactomeREACT_22999 has a Stoichiometric coefficient of 1 FECH homodimer (2Fe-2S cluster) Reactome DB_ID: 189402 Reactome Database ID Release 43189402 Reactome, http://www.reactome.org ReactomeREACT_9592 has a Stoichiometric coefficient of 2 ALAD homooctamer (Pb and Zn bound) Reactome DB_ID: 190145 Reactome Database ID Release 43190145 Reactome, http://www.reactome.org ReactomeREACT_9852 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 Porphobilinogen deaminase (dipyrromethane cofactor) Reactome DB_ID: 189426 Reactome Database ID Release 43189426 Reactome, http://www.reactome.org ReactomeREACT_9578 has a Stoichiometric coefficient of 1 ALAS2 homodimer (pyridoxal phosphate cofactor) Reactome DB_ID: 189443 Reactome Database ID Release 43189443 Reactome, http://www.reactome.org ReactomeREACT_9658 has a Stoichiometric coefficient of 2 ALAD homooctamer (Zinc cofactor) Reactome DB_ID: 189400 Reactome Database ID Release 43189400 Reactome, http://www.reactome.org ReactomeREACT_9587 has a Stoichiometric coefficient of 8 UROD homodimer Reactome DB_ID: 189454 Reactome Database ID Release 43189454 Reactome, http://www.reactome.org ReactomeREACT_9830 has a Stoichiometric coefficient of 2 CPO homodimer Reactome DB_ID: 189485 Reactome Database ID Release 43189485 Reactome, http://www.reactome.org ReactomeREACT_9811 has a Stoichiometric coefficient of 2 PMM1/2 Converted from EntitySet in Reactome Reactome DB_ID: 532532 Reactome Database ID Release 43532532 Reactome, http://www.reactome.org ReactomeREACT_22680 SULT1C2 homodimer Reactome DB_ID: 176597 Reactome Database ID Release 43176597 Reactome, http://www.reactome.org ReactomeREACT_7386 has a Stoichiometric coefficient of 2 SULT enzymes active on N-hydroxy-2-acetylaminofluorene Converted from EntitySet in Reactome Reactome DB_ID: 176572 Reactome Database ID Release 43176572 Reactome, http://www.reactome.org ReactomeREACT_7184 SULT2B1 b isoform homodimer Reactome DB_ID: 176484 Reactome Database ID Release 43176484 Reactome, http://www.reactome.org ReactomeREACT_7680 has a Stoichiometric coefficient of 2 SULT enzymes active on 27-hydroxycholesterol Converted from EntitySet in Reactome Reactome DB_ID: 176569 Reactome Database ID Release 43176569 Reactome, http://www.reactome.org ReactomeREACT_7691 SULT enzymes active on 3,5,3'-Triiodothyronine (T3) Converted from EntitySet in Reactome Reactome DB_ID: 176599 Reactome Database ID Release 43176599 Reactome, http://www.reactome.org ReactomeREACT_7526 GMPPA/B Converted from EntitySet in Reactome Reactome DB_ID: 532536 Reactome Database ID Release 43532536 Reactome, http://www.reactome.org ReactomeREACT_22600 SULT4A1 homodimer Reactome DB_ID: 176540 Reactome Database ID Release 43176540 Reactome, http://www.reactome.org ReactomeREACT_7008 has a Stoichiometric coefficient of 2 SULT enzymes active on p-nitrophenol Converted from EntitySet in Reactome Reactome DB_ID: 176479 Reactome Database ID Release 43176479 Reactome, http://www.reactome.org ReactomeREACT_7800 SULT1A2 homodimer Reactome DB_ID: 176613 Reactome Database ID Release 43176613 Reactome, http://www.reactome.org ReactomeREACT_7003 has a Stoichiometric coefficient of 2 SULT1E1 homodimer Reactome DB_ID: 176645 Reactome Database ID Release 43176645 Reactome, http://www.reactome.org ReactomeREACT_7163 has a Stoichiometric coefficient of 2 SULT1C1 homodimer Reactome DB_ID: 176514 Reactome Database ID Release 43176514 Reactome, http://www.reactome.org ReactomeREACT_7339 has a Stoichiometric coefficient of 2 SULT2A1 homodimer Reactome DB_ID: 176648 Reactome Database ID Release 43176648 Reactome, http://www.reactome.org ReactomeREACT_7457 has a Stoichiometric coefficient of 2 SULT enzymes active on 3,3'-Triiodothyronine (T2) Converted from EntitySet in Reactome Reactome DB_ID: 176650 Reactome Database ID Release 43176650 Reactome, http://www.reactome.org ReactomeREACT_7818 SULT1B1 homodimer Reactome DB_ID: 176495 Reactome Database ID Release 43176495 Reactome, http://www.reactome.org ReactomeREACT_7497 has a Stoichiometric coefficient of 2 SULT1A1 homodimer Phenol sulfotransferase (1A1) homodimer Reactome DB_ID: 158473 Reactome Database ID Release 43158473 Reactome, http://www.reactome.org ReactomeREACT_7821 has a Stoichiometric coefficient of 2 SULT1A3 homodimer Reactome DB_ID: 159361 Reactome Database ID Release 43159361 Reactome, http://www.reactome.org ReactomeREACT_7873 TL phenol transferase 1A3 homodimer has a Stoichiometric coefficient of 2 UDP-glucose dehydrogenase hexamer Reactome DB_ID: 173600 Reactome Database ID Release 43173600 Reactome, http://www.reactome.org ReactomeREACT_7430 has a Stoichiometric coefficient of 6 UDP-glucuronate transporter homohexamer Reactome DB_ID: 174388 Reactome Database ID Release 43174388 Reactome, http://www.reactome.org ReactomeREACT_7361 has a Stoichiometric coefficient of 6 GFPT1/2 Converted from EntitySet in Reactome Reactome DB_ID: 532205 Reactome Database ID Release 43532205 Reactome, http://www.reactome.org ReactomeREACT_22587 aldehyde dehydrogenase 1A1 tetramer Reactome DB_ID: 71689 Reactome Database ID Release 4371689 Reactome, http://www.reactome.org ReactomeREACT_5868 has a Stoichiometric coefficient of 4 aldehyde dehydrogenase, mitochondrial, tetramer Reactome DB_ID: 71721 Reactome Database ID Release 4371721 Reactome, http://www.reactome.org ReactomeREACT_2466 has a Stoichiometric coefficient of 4 alcohol dehydrogenase 7 (class IV), mu or sigma dimer Reactome DB_ID: 71754 Reactome Database ID Release 4371754 Reactome, http://www.reactome.org ReactomeREACT_5649 has a Stoichiometric coefficient of 2 alcohol dehydrogenase 6 (class V) complex Reactome DB_ID: 71748 Reactome Database ID Release 4371748 Reactome, http://www.reactome.org ReactomeREACT_5779 has a Stoichiometric coefficient of 1 alcohol dehydrogenase 4 (class II), pi dimer Reactome DB_ID: 71714 Reactome Database ID Release 4371714 Reactome, http://www.reactome.org ReactomeREACT_4786 has a Stoichiometric coefficient of 2 MsrA/B Converted from EntitySet in Reactome Reactome DB_ID: 1243099 Reactome Database ID Release 431243099 Reactome, http://www.reactome.org ReactomeREACT_122534 GGT7 dimer Gamma-glutamyltransferase 7 Reactome DB_ID: 1247950 Reactome Database ID Release 431247950 Reactome, http://www.reactome.org ReactomeREACT_76314 has a Stoichiometric coefficient of 1 SULT enzymes active on estrone Converted from EntitySet in Reactome Reactome DB_ID: 176621 Reactome Database ID Release 43176621 Reactome, http://www.reactome.org ReactomeREACT_7647 GGCT Gamma-glutamylcyclotransferase homodimer Reactome DB_ID: 1247905 Reactome Database ID Release 431247905 Reactome, http://www.reactome.org ReactomeREACT_76786 has a Stoichiometric coefficient of 2 GSS Glutathione synthase homodimer (Mg2+) Reactome DB_ID: 174382 Reactome Database ID Release 43174382 Reactome, http://www.reactome.org ReactomeREACT_7662 has a Stoichiometric coefficient of 2 SULT enzymes active on DHEA Converted from EntitySet in Reactome Reactome DB_ID: 176574 Reactome Database ID Release 43176574 Reactome, http://www.reactome.org ReactomeREACT_7609 OPLAH OPLAH homodimer Reactome DB_ID: 1247926 Reactome Database ID Release 431247926 Reactome, http://www.reactome.org ReactomeREACT_76319 has a Stoichiometric coefficient of 2 GGT2 dimer Gamma-glutamyltransferase 2 Reactome DB_ID: 1247921 Reactome Database ID Release 431247921 Reactome, http://www.reactome.org ReactomeREACT_76109 has a Stoichiometric coefficient of 1 GGT6 dimer Gamma-glutamyltransferase 6 Reactome DB_ID: 1247906 Reactome Database ID Release 431247906 Reactome, http://www.reactome.org ReactomeREACT_76441 has a Stoichiometric coefficient of 1 gamma-glutamyl-AA Reactome DB_ID: 1247917 Reactome Database ID Release 431247917 Reactome, http://www.reactome.org ReactomeREACT_76217 has a Stoichiometric coefficient of 1 GGT Converted from EntitySet in Reactome GGT dimer Reactome DB_ID: 1247946 Reactome Database ID Release 431247946 Reactome, http://www.reactome.org ReactomeREACT_76598 SULT enzymes active on pregnenolone Converted from EntitySet in Reactome Reactome DB_ID: 176567 Reactome Database ID Release 43176567 Reactome, http://www.reactome.org ReactomeREACT_7762 SULT2B1 a isoform homodimer Reactome DB_ID: 176659 Reactome Database ID Release 43176659 Reactome, http://www.reactome.org ReactomeREACT_7841 has a Stoichiometric coefficient of 2 Passive Transport of Carbon Dioxide into the Cell by RhAG Authored: May, B, 2011-03-24 Edited: May, B, 2011-03-24 Pubmed16563834 Pubmed17712059 Pubmed19273840 Reactome Database ID Release 431237069 Reactome, http://www.reactome.org ReactomeREACT_120886 Reviewed: Jassal, B, 2012-04-27 The Rhesus blood group type A glycoprotein (RhAG) passively transports carbon dioxide (CO2) across the plasma membrane according to the concentration gradient (Endeward et al. 2006, Endeward et al. 2008, Musa-Aziz et al. 2009). Carbonic Anhydrase I/II Hydrates Carbon Dioxide Authored: May, B, 2011-08-07 Carbonic anhydrase I (CA1, Khalifah 1971, Pesando 1975, Simonsson et al. 1982, Ren & Lindskog 1992) and carbonic anhydrase II (CA2, Tibell et al. 1984, Jones & Shaw 1983, Ghannam et al. 1986) hydrate carbon dioxide (CO2) to yield bicarbonate (HCO3-) and a proton (H+). During the reaction a hydroxyl group bound by the zinc ion (Zn2+) attacks the CO2 molecule in the active site to directly form HCO3- (reviewed in Lindskog 1997). The HCO3- is displaced by water, which is then deprotonated by a histidine residue to recreate the Zn2+:hydroxyl group. Depending on the concentrations of reactants the reaction is reversible. EC Number: 4.2.1.1 Edited: May, B, 2011-08-07 Pubmed1554744 Pubmed234739 Pubmed3080418 Pubmed4994926 Pubmed6407977 Pubmed6433979 Pubmed6819139 Pubmed9336012 Reactome Database ID Release 431475435 Reactome, http://www.reactome.org ReactomeREACT_121371 Reviewed: Jassal, B, 2012-04-27 Passive Transport of Carbon Dioxide into the Cell by AQP1 Aquaporin-1 (AQP1) passively transports carbon dioxide (CO2) across the plasma membrane according to the concentration gradient (Nakhoul et al. 1998, Blank & Ehmke et al. 2003, Endeward et al. 2006, Musa-Aziz et al. 2009). The pore in AQP1 that conducts CO2 may be distinct from the pore that conducts water. Authored: May, B, 2011-03-24 Edited: May, B, 2011-03-24 Pubmed12754312 Pubmed16563834 Pubmed17012249 Pubmed19273840 Pubmed9486145 Reactome Database ID Release 431237042 Reactome, http://www.reactome.org ReactomeREACT_120843 Reviewed: Jassal, B, 2012-04-27 Exchange of Cytosolic Chloride for Extracellular Bicarbonate by Band 3 Anion Exchanger (AE1, SLC4A1) Authored: May, B, 2011-04-04 Edited: May, B, 2011-04-04 Pubmed11606574 Pubmed12933803 Pubmed8972395 Reactome Database ID Release 431247665 Reactome, http://www.reactome.org ReactomeREACT_120922 Reviewed: Jassal, B, 2012-04-27 The band 3 anion exchange protein (AE1, SLC4A1) exchanges chloride (Cl-) for bicarbonate (HCO3-) across the plasma membrane according to the concentration gradients of the anions (Knauf et al. 1996, Dahl et al. 2003). SLC4A1 may be part of a complex ("metabolon") with carbonic anhydrase II (CA2) which would facilitate the transport of HCO3- (Sterling et al. 2001). Haldane Effect Authored: May, B, 2011-04-04 Edited: May, B, 2011-04-04 Hemoglobin A Binds Oxygen and Releases Protons and Carbon Dioxide Pubmed1395 Pubmed16994616 Pubmed20162361 Pubmed2506737 Pubmed3119859 Pubmed3938604 Pubmed4203704 Pubmed4514311 Pubmed4975618 Pubmed6417382 Pubmed7541176 Reactome Database ID Release 431247668 Reactome, http://www.reactome.org ReactomeREACT_120816 Reviewed: Jassal, B, 2012-04-27 The binding of oxygen (O2) to hemoglobin (HbA) decreases the affinity of HbA for protons (H+) bound at histidine residues and carbon dioxide (CO2) bound chemically as a carbamate at the N-terminus of the HbA (Ferguson and Roughton 1934, Kernohan & Roughton 1968, Klocke 1973, Morrow et al. 1973, Morrow et al. 1976, Tazawa et al. 1983, Kraan & Rispens 1985, Doyle et al. 1987, Mertzlufft & Brandt 1989, Kalhoff et al.1994, Dash & Bassingthwaighte 2010, reviewed in Jensen 2004). This property of HbA is known as the Haldane Effect and facilitates the exchange of CO2 for O2 in the lungs. Bohr Effect Authored: May, B, 2011-03-30 Edited: May, B, 2011-03-30 Protonation and Carbamation of Hemoglobin A Causes Release of Oxygen Pubmed10529219 Pubmed1395 Pubmed14958 Pubmed16992238 Pubmed16994616 Pubmed17990881 Pubmed20162361 Pubmed20230836 Pubmed21041929 Pubmed3136125 Pubmed4514311 Pubmed4647257 Pubmed4975618 Pubmed5656372 Pubmed8300612 Reactome Database ID Release 431237325 Reactome, http://www.reactome.org ReactomeREACT_121267 Reviewed: Jassal, B, 2012-04-27 The Bohr effect refers to the observation that carbon dioxide (CO2) decreases the affinity of hemoglobin (HbA) for oxygen (O2) (Rossi-Bernardi & Roughton 1967, Kwant et al. 1988, Dash & Bassingthwaighte 2010). The Bohr effect has two components: protonation of histidines in HbA (Chatake et al. 2007, Kovalevsky et al. 2010, Fang et al. 1999) and chemical reaction (carbamation) of the N-terminal valines of HbA by CO2 (Ferguson & Roughton 1934, Forster et al. 1968, Bauer & Schroder 1972, Morrow et al. 1973, Morrow et al. 1976, Mathew et al. 1977, Acharya et al. 1994). The protons (H+) for this reaction are produced by carbonic anhydrase acting on water and CO2 to produce bicarbonate (HCO3-) and H+ (Kernohan & Roughton 1968). Exchange of Cytosolic Bicarbonate for Extracellular Chloride by Band 3 Anion Exchanger (AE1, SLC4A1) Authored: May, B, 2011-03-24 Edited: May, B, 2011-03-24 Pubmed11606574 Pubmed12933803 Pubmed8972395 Reactome Database ID Release 431237038 Reactome, http://www.reactome.org ReactomeREACT_121292 Reviewed: Jassal, B, 2012-04-27 The band 3 anion exchange protein (AE1, SLC4A1) exchanges chloride (Cl-) for bicarbonate (HCO3-) across the plasma membrane according to the concentration gradients of the anions (Knauf et al. 1996, Dahl et al. 2003). SLC4A1 may be part of a complex ("metabolon") with carbonic anhydrase II (CA2) which would facilitate the transport of HCO3- (Sterling et al. 2001). Passive Transport of Carbon Dioxide out of the Cell by RhAG Authored: May, B, 2011-04-04 Edited: May, B, 2011-04-04 Pubmed16563834 Pubmed17712059 Pubmed19273840 Reactome Database ID Release 431247645 Reactome, http://www.reactome.org ReactomeREACT_121236 Reviewed: Jassal, B, 2012-04-27 The Rhesus blood group type A glycoprotein (RhAG) passively transports carbon dioxide (CO2) across the plasma membrane according to the concentration gradient (Endeward et al. 2006, Endeward et al. 2008, Musa-Aziz et al. 2009). Passive Transport of Carbon Dioxide out of the Cell by AQP1 Aquaporin-1 (AQP1) passively transports carbon dioxide (CO2) across the plasma membrane according to the concentration gradient (Nakhoul et al. 1998, Blank & Ehmke et al. 2003, Endeward et al. 2006, Musa-Aziz et al. 2009). The pore in AQP1 that conducts CO2 may be distinct from the pore that conducts water. Authored: May, B, 2011-04-04 Edited: May, B, 2011-04-04 Pubmed12754312 Pubmed16563834 Pubmed17012249 Pubmed19273840 Pubmed9486145 Reactome Database ID Release 431247649 Reactome, http://www.reactome.org ReactomeREACT_121218 Reviewed: Jassal, B, 2012-04-27 Carbonic Anhydrase I/II Dehydrates Bicarbonate Authored: May, B, 2011-08-07 Carbonic anhydrase I (CA1, Khalifah 1971, Pesando 1975, Simonsson et al. 1982, Ren & Lindskog 1992) and carbonic anhydrase II (CA2, Tibell et al. 1984, Jones & Shaw 1983, Ghannam et al. 1986) hydrate carbon dioxide (CO2) to yield bicarbonate (HCO3-) and a proton (H+). During the reaction a hydroxyl group bound by the zinc ion (Zn2+) attacks the CO2 molecule in the active site to directly form HCO3- (reviewed in Lindskog 1997). The HCO3- is displaced by water, which is then deprotonated by a histidine residue to recreate the Zn2+:hydroxyl group. Depending on the concentrations of reactants the reaction is reversible. EC Number: 4.2.1.1 Edited: May, B, 2011-08-07 Pubmed1554744 Pubmed234739 Pubmed3080418 Pubmed4994926 Pubmed6407977 Pubmed6433979 Pubmed6819139 Pubmed9336012 Reactome Database ID Release 431475436 Reactome, http://www.reactome.org ReactomeREACT_120912 Reviewed: Jassal, B, 2012-04-27 H+ + HCO3- -> H2O + CO2 Authored: May, B, 2011-03-24 Carbonic Anhydrase IV Dehydrates Bicarbonate to Yield Water and Carbon Dioxide Carbonic anhydrase IV (CA4) located on the extracellular face of the plasma membrane (Wistrand et al. 1999) dehydrates bicarbonate (HCO3--) to yield water and carbon dioxide (CO2) (Zhu & Sly 1990, Okayuma et al. 1992, Baird et al. 1997, Innocenti et al. 2004, reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible. EC Number: 4.2.1.1 Edited: May, B, 2011-03-24 Pubmed10090333 Pubmed1311094 Pubmed15501038 Pubmed2111324 Pubmed9054574 Pubmed9336012 Reactome Database ID Release 431237059 Reactome, http://www.reactome.org ReactomeREACT_120877 Reviewed: Jassal, B, 2012-04-27 abacavir [extracellular] => abacavir [cytosol] Authored: D'Eustachio, P, 2012-03-14 Edited: D'Eustachio, P, 2012-03-16 OCT (organic cation transporter)-mediated abacavir uptake Organic cation transporters 1 (OCT1, SLC22A1), 2 (OCT2, SLC22A2) and 3 (OCT3, SLC22A3) associated with the plasma membrane all mediate the influx of abacavir. The three transporters have similar affinities for abacavir (Minuesa et al. 2009) but differ in the tissues in which they are expressed and in their distributions on the surfaces of polarized cells (reviewed by Klaasen and Aleksunes 2010). Pubmed19141712 Pubmed20103563 Reactome Database ID Release 432161500 Reactome, http://www.reactome.org ReactomeREACT_121207 Reviewed: Jassal, B, 2012-03-16 ABCG2-mediated abacavir efflux ATP-binding cassette sub-family G member 2 (ABCG2), associated with the plasma membrane, mediates the ATP-dependent efflux of abacavir (Doyle et al. 1998). The active form of ABCG2 is a homodimer stabilized by an interchain disulfide bond (Wakabayashi et al. 2007). The abacavir specificity of the human ABCG2 transporter is inferred from studies of the corresponding mouse protein (Pan et al. 2007). Authored: D'Eustachio, P, 2012-03-14 EC Number: 3.6.3.44 Edited: D'Eustachio, P, 2012-03-16 Pubmed17437964 Pubmed17686774 Pubmed9861027 Reactome Database ID Release 432161506 Reactome, http://www.reactome.org ReactomeREACT_121056 Reviewed: Jassal, B, 2012-03-16 abacavir [cytosol] + ATP + H2O => abacavir[extracellular] + ADP + phosphate ABCB1-mediated abacavir efflux Authored: D'Eustachio, P, 2012-03-14 EC Number: 3.6.3.44 Edited: D'Eustachio, P, 2012-03-16 Pubmed17709369 Reactome Database ID Release 432161538 Reactome, http://www.reactome.org ReactomeREACT_120947 Reviewed: Jassal, B, 2012-03-16 The ABCB1 transporter associated with the plasma membrane mediates the ATP-dependent efflux of a variety of xenobiotic molecules. Its ability to transport abacavir is inferred from studies of the corresponding mouse protein (Shaik et al. 2007). abacavir [cytosol] + ATP + H2O => abacavir[extracellular] + ADP + phosphate Oxidation of abacavir to abacavir 5'-carboxylate Authored: D'Eustachio, P, 2012-03-14 Cytosolic ADH alpha dimer catalyzes the reaction of abacavir and NAD to form abacavir 5'-carboxylate and NADH + H+. Abacavir 5'-carboxylate is one of the major forms in which abacavir is excreted from the body. Studies with purified enzymes in vitro indicate that only the alpha isoform of ADH has this activity. These studies also suggest that the reaction proceeds in two steps via an unstable aldehyde intermediate (Walsh et al. 2002). Whether conversion of the aldehyde to the carboxylate is spontaneous or also catalyzed by ADH has not been established. EC Number: 1.1.1.1 Edited: D'Eustachio, P, 2012-03-16 Pubmed12399160 Reactome Database ID Release 432162078 Reactome, http://www.reactome.org ReactomeREACT_121302 Reviewed: Jassal, B, 2012-03-16 abacavir + 2 NAD+ => abacavir 5'-carboxylate + 2 NADH + 2 H+ has a Stoichiometric coefficient of 2 Glucuronidation of abacavir A member of the UDPGT (UDP-glucuronosyltransferase) enzyme family is thought to catalyze the reaction of abacavir and UDP-glucuronate to form UDP and abacavir-5'-glucuronate, one of the major forms in which abacavir is excreted from the body (McDowell et al. 1999; Ravitch and Moseley 2001). The specific UDPGT family enzyme family member or members that catalyze this reaction have not been identified. Authored: D'Eustachio, P, 2012-03-14 EC Number: 2.4.1.17 Edited: D'Eustachio, P, 2012-03-16 Pubmed10582871 Pubmed11678376 Reactome Database ID Release 432162099 Reactome, http://www.reactome.org ReactomeREACT_120923 Reviewed: Jassal, B, 2012-03-16 abacavir + UDP-glucuronate => abacavir 5'-glucuronide + UDP Deamination of abacavir monophosphate to form carbovir monophosphate Authored: D'Eustachio, P, 2012-03-14 Cytosolic ADAL (Adenosine DeAminase-Like) catalyzes the reaction of abacavir monophosphate and water to form carbovir monophosphate and cyclopropylamine. The active form of the enzyme is a protein monomer complexed with a zinc ion (Murakami et al. 2011). EC Number: 3.5.4.4 Edited: D'Eustachio, P, 2012-03-16 Pubmed21755941 Reactome Database ID Release 432161195 Reactome, http://www.reactome.org ReactomeREACT_121193 Reviewed: Jassal, B, 2012-03-16 abacavir monophosphate + H2O => carbovir monophosphate + cyclopropylamine Phosphorylation of abacavir Authored: D'Eustachio, P, 2012-03-14 Cytosolic adenosine phosphotransferase catalyzes the reaction of abacavir and AMP to form abacavir monophosphate and adenosine (Faletto et al. 1997). This enzymatic activity has been purified from human placenta and is distinct from known human kinases (Garvey and Krenitsky 1992) but has not been associated with a known human gene. EC Number: 2.7.1 Edited: D'Eustachio, P, 2012-03-16 Pubmed1605627 Pubmed9145876 Reactome Database ID Release 432161193 Reactome, http://www.reactome.org ReactomeREACT_120830 Reviewed: Jassal, B, 2012-03-16 abacavir + AMP => abacavir monophosphate + adenosine Phosphorylation of carbovir monophosphate Authored: D'Eustachio, P, 2012-03-14 Cytosolic GUK1 (guanylate kinase 1) catalyzes the reaction of carbovir monophosphate and ATP to form carbovir diphosphate and ADP. The activity of human GUK1 is inferred from that of the corresponding pig protein (Miller et al. 1992). Edited: D'Eustachio, P, 2012-03-16 Pubmed1383219 Reactome Database ID Release 432162092 Reactome, http://www.reactome.org ReactomeREACT_120913 Reviewed: Jassal, B, 2012-03-16 carbovir monophosphate + ATP => carbovir diphosphate + ADP Conversion of carbovir to carbovir monophosphate Authored: D'Eustachio, P, 2012-03-14 EC Number: 2.7.1.77 Edited: D'Eustachio, P, 2012-03-16 NT5C2 catalyzes the reaction of carbovir and IMP to form carbovir monophosphate and inosine (Johnson and Fridland 1989; Miller et al. 1992). The enzyme was originally identified as a high-Km soluble 5'-nucleotidase most active on IMP and GMP (Spychala et al. 1988). Its active form is a tetramer (Wallden et al. 2007). Pubmed1383219 Pubmed17405878 Pubmed2549385 Pubmed2848805 Reactome Database ID Release 432162066 Reactome, http://www.reactome.org ReactomeREACT_120749 Reviewed: Jassal, B, 2012-03-16 carbovir + IMP => carbovir monophosphate + inosine Carbonic Anhydrase Hydrates Carbon Dioxide (plasma membrane) Authored: May, B, 2011-08-06 Carbonic anhydrase IV (CA4, Zhu and Sly 1990, Okuyama et al. 1992, Baird et al. 1997, Innocenti et al. 2004), carbonic anhydrase IX (CA9, Wingo et al. 2001, Hilvo et al. 2008), carbonic anhydrase XII (CA12, Ulmasov et al. 2000, Pastorekova et al. 2008), and carbonic anhydrase XIV (CA14Ozensoy et al. 2005, Temperini et al. 2008) are membrane-bound enzymes that hydrate extracellular carbon dioxide to yield bicarbonate and a proton.Carbonic anhydrase deprotonates water to yield a zinc-hydroxyl group and a proton which is transferred to external buffer molecules via histidine or glutamate residues in carbonic anhydrase. The hydroxyl group reacts with carbon dioxide in the active site to yield bicarbonate. A water molecule displaces the bicarbonate and the reaction cycle begins again (reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible.<br>CA4 has high catalytic activity. CA9, CA12, and CA14 have moderate activity. CA4 is anchored to the extracellular face of the plasma membrane by glycosylphosphatidylinositol. CA9, CA12, and CA14 are single-pass transmembrane proteins. CA4 is found on the extracellular face of capillaries in kidney, lung, and muscle where it maintains the gradient of carbon dioxide between tissue and blood. CA9 and CA12 are found on basolateral membranes of epithelia. CA9 is inducible by Hypoxia-inducible factor 1 alpha (HIF1alpha) and acidifies the extracellular environment of tumors. In rodents CA15 is membrane anchored and has low activity; in primates CA15 is a pseudogene. EC Number: 4.2.1.1 Edited: May, B, 2011-08-06 Pubmed11121027 Pubmed11676494 Pubmed15501038 Pubmed16006130 Pubmed18162396 Pubmed18294854 Pubmed18703501 Pubmed2111324 Pubmed7625839 Pubmed9054574 Pubmed9336012 Reactome Database ID Release 431475025 Reactome, http://www.reactome.org ReactomeREACT_121310 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 Carbonic Anhydrase Dehydrates Bicarbonate (plasma membrane) Authored: May, B, 2011-08-06 Carbonic anhydrase IV (CA4, Zhu and Sly 1990, Okuyama et al. 1992, Baird et al. 1997, Innocenti et al. 2004), carbonic anhydrase IX (CA9, Wingo et al. 2001, Hilvo et al. 2008), carbonic anhydrase XII (CA12, Ulmasov et al. 2000, Pastorekova et al. 2008), and carbonic anhydrase XIV (CA14, Ozensoy et al. 2005, Temperini et al. 2008) are membrane-bound enzymes that dehydrate bicarbonate to yield water and carbon dioxide. Depending on the concentrations of reactants the reaction is reversible.<br>CA4 has high catalytic activity. CA9, CA12, and CA14 have moderate activity. CA4 is anchored to the extracellular face of the plasma membrane by glycosylphosphatidylinositol. CA9, CA12, and CA14 are single-pass transmembrane proteins. CA4 is found on the extracellular face of capillaries in kidney, lung, and muscle where it maintains the gradient of carbon dioxide between tissue and blood. CA9 and CA12 are found on basolateral membranes of epithelia. CA9 is inducible by Hypoxia-inducible factor 1 alpha (HIF1alpha) and acidifies the extracellular environment of tumors. In rodents CA15 is membrane anchored and has low activity; in primates CA15 is a pseudogene. EC Number: 4.2.1.1 Edited: May, B, 2011-08-06 Pubmed11121027 Pubmed11676494 Pubmed15501038 Pubmed16006130 Pubmed18162396 Pubmed18294854 Pubmed18703501 Pubmed2111324 Pubmed7625839 Pubmed9054574 Pubmed9336012 Reactome Database ID Release 431475017 Reactome, http://www.reactome.org ReactomeREACT_120844 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 Carbonic Anhydrase Hydrates Carbon Dioxide (cytosol) Authored: May, B, 2011-08-06 Carbonic anhydrase I (CA1, Khalifah 1971, Simonsson et al. 1982, Ren and Lindskog 1992), carbonic anyhydrase II (CA2, Tibell et al. 1984, Jones and Shaw 1983, Pesando 1975, Ghannam et al. 1986), carbonic anhydrase III (CA3, Carter et al. 1979, Tu et al. 1990, Tu et al. 1994, Tu et al. 1998, Silverman et al. 1993), carbonic anhydrase VII (CA7, Bootorabi et al. 2010, Gitto et al. 2010) hydrate carbon dioxide to yield bicarbonate and a proton. Carbonic anhydrase deprotonates water to yield a zinc-hydroxyl group and a proton which is transferred to external buffer molecules via histidine or glutamate residues in carbonic anhydrase. The hydroxyl group reacts with carbon dioxide in the active site to yield bicarbonate. A water molecule displaces the bicarbonate and the reaction cycle begins again (reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible.<br>CA2 and CA7 have high catalytic activity, CA1 has low activity (10% of the activity of CA2), and CA3 has very low activity (1% of the activity of CA2). CA1 and CA2 are found in erythrocytes. CA2 is also found in kidney, lung, and white muscle where it facilitates diffusion of carbon dioxide. CA3 is found in red muscle where it participates in resistance against oxidative stress. EC Number: 4.2.1.1 Edited: May, B, 2011-08-06 Pubmed120192 Pubmed1554744 Pubmed17427958 Pubmed20349499 Pubmed20493921 Pubmed20578724 Pubmed21282642 Pubmed2169869 Pubmed22001224 Pubmed234739 Pubmed3080418 Pubmed4994926 Pubmed6407977 Pubmed6433979 Pubmed6819139 Pubmed8083199 Pubmed8399223 Pubmed9336012 Pubmed9635771 Reactome Database ID Release 431475026 Reactome, http://www.reactome.org ReactomeREACT_120951 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 Carbonic Anhydrase Dehydrates Bicarbonate (cytosol) Authored: May, B, 2011-08-06 Carbonic anhydrase I (CA1, Khalifah 1971, Simonsson et al. 1982, Ren and Lindskog 1992), carbonic anyhydrase II (CA2, Tibell et al. 1984, Jones and Shaw 1983, Pesando 1975, Ghannam et al. 1986), carbonic anhydrase III (CA3, Carter et al. 1979, Tu et al. 1990, Tu et al. 1994, Tu et al. 1998, Silverman et al. 1993), carbonic anhydrase VII (CA7, Bootorabi et al. 2010, Gitto et al. 2010) dehydrate cytosolic bicarbonate to yield water and carbon dioxide (reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible.<br>CA2 and CA7 have high catalytic activity, CA1 has low activity (10% of the activity of CA2), and CA3 has very low activity (1% of the activity of CA2). CA1 and CA2 are found in erythrocytes. CA2 is also found in kidney, lung, and white muscle where it facilitates diffusion of carbon dioxide. CA3 is found in red muscle where it participates in resistance against oxidative stress. EC Number: 4.2.1.1 Edited: May, B, 2011-08-06 Pubmed120192 Pubmed1554744 Pubmed17427958 Pubmed20349499 Pubmed20493921 Pubmed20578724 Pubmed21282642 Pubmed2169869 Pubmed22001224 Pubmed234739 Pubmed3080418 Pubmed4994926 Pubmed6407977 Pubmed6433979 Pubmed6819139 Pubmed8083199 Pubmed8399223 Pubmed9336012 Pubmed9635771 Reactome Database ID Release 431475022 Reactome, http://www.reactome.org ReactomeREACT_120719 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 Phosphorylation of carbovir diphosphate Authored: D'Eustachio, P, 2012-03-14 Cytosolic PCK1 (phosphoenolpyruvate carboxykinase 1) catalyzes the reaction of carbovir diphosphate and ATP to form carbovir triphosphate and ADP. The activity of human PCK1 and relative inactivity of human nucleoside diphosphate kinase are inferred from the properties of the purified rat and bovine enzymes in vitro (Miller et al. 1992). EC Number: 2.7.4.6 Edited: D'Eustachio, P, 2012-03-16 Pubmed1383219 Reactome Database ID Release 432162096 Reactome, http://www.reactome.org ReactomeREACT_120894 Reviewed: Jassal, B, 2012-03-16 carbovir diphosphate + ATP => carbovir triphosphate + ADP Doublecortin binds phosphorylated neurofascin Authored: Garapati, P V, 2008-07-30 10:22:58 Doublecortin is a microtubule associated protein expressed in neurons. Mutated doublecortin has been linked to the neuronal migration disorder X linked subcortical laminar heterotopia (double cortex)/lissencephaly. It binds neurofascin when the FIGQY motif of the latter protein is phosphorylated. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed12223548 Reactome Database ID Release 43443772 Reactome, http://www.reactome.org ReactomeREACT_22218 Reviewed: Maness, PF, 2010-02-16 H+ + HCO3- -> H2O + CO2 Authored: May, B, 2011-03-24 Carbonic Anhydrase VI Dehydrates Bicarbonate to Yield Water and Carbon Dioxide Carbonic anhydrase VI (CA6) dehydrates bicarbonate to yield water and carbon dioxide (Thatcher et al. 1998, Nishimori et al. 2007). Depending on the concentrations of reactants the reaction is reversible. CA6 is a major protein of saliva and is also known as gustin. EC Number: 4.2.1.1 Edited: May, B, 2011-03-24 Pubmed17228881 Pubmed17499996 Pubmed9336012 Pubmed9784398 Reactome Database ID Release 431237081 Reactome, http://www.reactome.org ReactomeREACT_120791 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 H2O + CO2 -> H+ + HCO3- Authored: May, B, 2011-03-24 Carbonic Anhydrase VI Hydrates Carbon Dioxide to Form a Proton and Bicarbonate Carbonic anhydrase VI (CA6) hydrates carbon dioxide to yield bicarbonate and a proton (Thatcher et al. 1998, Nishimori et al. 2007).Carbonic anhydrase deprotonates water to yield a zinc-hydroxyl group and a proton which is transferred to external buffer molecules via histidine or glutamate residues in carbonic anhydrase. The hydroxyl group reacts with carbon dioxide in the active site to yield bicarbonate. A water molecule displaces the bicarbonate and the reaction cycle begins again (reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible. CA6 is a major protein of saliva and is also known as gustin. EC Number: 4.2.1.1 Edited: May, B, 2011-03-24 Pubmed17228881 Pubmed17499996 Pubmed9336012 Pubmed9784398 Reactome Database ID Release 431237045 Reactome, http://www.reactome.org ReactomeREACT_120867 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 Carbonic Anhydrase Dehydrates Bicarbonate (mitochondria) Authored: May, B, 2011-08-06 Carbonic anhydrase VA (CA5A, Nagao et al. 1993, Franchi et al. 2003, Nishimori et al. 2007) and carbonic anhydrase VB (CA5B, Fujikawa-Adachi et al. 1999, Nishimori et al. 2005, Nishimori et al. 2007) dehydrate bicarbonate in mitochondria to yield water and carbon dioxide (reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible. EC Number: 4.2.1.1 Edited: May, B, 2011-08-06 Pubmed10409679 Pubmed14611844 Pubmed16302824 Pubmed17761422 Pubmed8356065 Pubmed9336012 Reactome Database ID Release 431475028 Reactome, http://www.reactome.org ReactomeREACT_120942 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 Carbonic Anhydrase Hydrates Carbon Dioxide (mitochondria) Authored: May, B, 2011-08-06 Carbonic anhydrase VA (CA5A, Nagao et al. 1993, Franchi et al. 2003, Nishimori et al. 2007) and carbonic anhydrase VB (CA5B, Fujikawa-Adachi et al. 1999, Nishimori et al. 2005, Nishimori et al. 2007) hydrate carbon dioxide in mitochondria to yield bicarbonate and a proton. Carbonic anhydrase deprotonates water to yield a zinc-hydroxyl group and a proton which is transferred to external buffer molecules via histidine or glutamate residues in carbonic anhydrase. The hydroxyl group reacts with carbon dioxide in the active site to yield bicarbonate. A water molecule displaces the bicarbonate and the reaction cycle begins again (reviewed in Lindskog 1997). Depending on the concentrations of reactants the reaction is reversible. EC Number: 4.2.1.1 Edited: May, B, 2011-08-06 Pubmed10409679 Pubmed14611844 Pubmed16302824 Pubmed17761422 Pubmed8356065 Pubmed9336012 Reactome Database ID Release 431475032 Reactome, http://www.reactome.org ReactomeREACT_120901 Reviewed: Jassal, B, 2012-05-16 Reviewed: Silverman, DN, 2012-05-16 ATP Hydrolysis By Myosin Authored: Gillespie, ME, 2003-07-01 00:00:00 Edited: Gillespie, ME, 2009-03-10 20:55:39 Pubmed10747208 Reactome Database ID Release 43390593 Reactome, http://www.reactome.org ReactomeREACT_16995 Reviewed: Rush, MG, 2008-01-11 00:00:00 The cleft closes like a clam shell around the ATP molecule, triggering a large shape change that causes the myosin head to release actin and be displaced along the actin filament by a distance of about 5 nm. Hydrolysis of ATP occurs, but the ADP remains tightly bound to the protein. has a Stoichiometric coefficient of 2 Release Of ADP From Myosin Authored: Gillespie, ME, 2003-07-01 00:00:00 Edited: Gillespie, ME, 2009-03-10 20:55:39 Pubmed10747208 Reactome Database ID Release 43390597 Reactome, http://www.reactome.org ReactomeREACT_17057 Reviewed: Rush, MG, 2008-01-11 00:00:00 The weak binding of the myosin head to the new site on the actin filament causes release of the inorganic phosphate produced by ATP hydrolysis, concomitantly with the tight binding of the head to actin. This release triggers the power stroke, a force-generating change in the shape during which the head regains its original conformation. In the course of the power stroke, the head loses its bound ADP, thereby returning to the start of a new cycle. has a Stoichiometric coefficient of 2 Calcium binds calmodulin Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Calmodulin is activated upon binding at least two, and up to four, calcium ions. For our purposes, we assume 4 calcium ions bound produces full activation of calmodulin. Edited: Jassal, B, 2008-11-06 10:17:49 Reactome Database ID Release 4374448 Reactome, http://www.reactome.org ReactomeREACT_12602 Reviewed: Rush, MG, 2008-01-11 00:00:00 has a Stoichiometric coefficient of 4 MLCK Active Calmodulin Binding Authored: Gillespie, ME, 2009-02-10 05:04:11 Edited: Gillespie, ME, 2009-11-18 Once calcium influx occurs, calmodulin is activated by the binding of calcium. The active calmodulin complex binds and activated the smooth muscle myosin light chain kinase. Pubmed14627618 Reactome Database ID Release 43445797 Reactome, http://www.reactome.org ReactomeREACT_20521 Reviewed: Rush, MG, 2008-01-11 00:00:00 Calcium Binds Troponin-C At the start of the cycle a myosin head lacking a bound nucleotide is locked tightly onto an actin filament in a rigor conformation. Troponin-C has bound four calcium ions. In an actively contracting muscle this state is very short-lived, being rapidly terminated by the binding of a molecule of ATP. Authored: Gillespie, ME, 2003-07-01 00:00:00 Edited: Gillespie, ME, 2009-03-10 20:55:39 Pubmed10747208 Reactome Database ID Release 43390595 Reactome, http://www.reactome.org ReactomeREACT_16935 Reviewed: Rush, MG, 2008-01-11 00:00:00 has a Stoichiometric coefficient of 4 Myosin Binds ATP A molecule of ATP binds to the large cleft on the side of the myosin head farthest from the actin filament and immediately causes a slight change in the conformation of the domains that make up the actin-binding site. This reduces the affinity of the myosin head for actin and allows it to move along the filament. Authored: Gillespie, ME, 2003-07-01 00:00:00 Edited: Gillespie, ME, 2009-03-10 20:55:39 Pubmed10747208 Reactome Database ID Release 43390598 Reactome, http://www.reactome.org ReactomeREACT_16902 Reviewed: Rush, MG, 2008-01-11 00:00:00 has a Stoichiometric coefficient of 2 Calcium Binds Caldesmon Authored: Gillespie, ME, 2003-07-01 00:00:00 Caldesmon functions in an analogous fashion to troponin in striated muscle. Once calcium has entered the smooth muscle cell, calcium levels slowly rise. Caldesmon binds calcium, freeing tropomyosin, allowing the tropomyosin to move exposing the active sites on actin for myosin binding. Edited: Gillespie, ME, 2009-03-10 20:55:39 Pubmed11457814 Pubmed1930128 Reactome Database ID Release 43445704 Reactome, http://www.reactome.org ReactomeREACT_20643 Reviewed: Rush, MG, 2008-01-11 00:00:00 Phosphorylation of Smooth Muscle Myosin Light Chains Authored: Gillespie, ME, 2009-11-18 EC Number: 2.7.11.18 Edited: Gillespie, ME, 2009-11-18 Pubmed2526655 Pubmed2764880 Pubmed3780718 Reactome Database ID Release 43445813 Reactome, http://www.reactome.org ReactomeREACT_20597 Reviewed: Rush, MG, 2008-01-11 00:00:00 The smooth muscle light chain kinase phosphorylates the smooth muscle light chains. This phosphorylation activates the myosin lights chains, effectively allowing contraction to begin. Myosin Binds ATP Authored: Gillespie, ME, 2003-07-01 00:00:00 Edited: Gillespie, ME, 2009-03-10 20:55:39 Pubmed2526655 Pubmed2764880 Pubmed3780718 Reactome Database ID Release 43445700 Reactome, http://www.reactome.org ReactomeREACT_20663 Reviewed: Rush, MG, 2008-01-11 00:00:00 With the expulsion of ADP from the nucleotide binding pocket, ATP, if available will immediately bind. has a Stoichiometric coefficient of 2 Release Of ADP From Myosin As soon as the actin and myosin filaments become competent for contraction, the swiveling head of myosin pulls itself along the actin filament. This movement changes the shape of the pocket to which ADP is bound, freeing the ADP molecule. Authored: Gillespie, ME, 2003-07-01 00:00:00 Edited: Gillespie, ME, 2009-03-10 20:55:39 Pubmed2526655 Pubmed3780718 Reactome Database ID Release 43445705 Reactome, http://www.reactome.org ReactomeREACT_20613 Reviewed: Rush, MG, 2008-01-11 00:00:00 has a Stoichiometric coefficient of 2 INHBA dimer Reactome DB_ID: 206893 Reactome Database ID Release 43206893 Reactome, http://www.reactome.org ReactomeREACT_111651 has a Stoichiometric coefficient of 2 homoINHB Converted from EntitySet in Reactome Reactome DB_ID: 1449699 Reactome Database ID Release 431449699 Reactome, http://www.reactome.org ReactomeREACT_111563 INHIB INHIBIN Reactome DB_ID: 1449688 Reactome Database ID Release 431449688 Reactome, http://www.reactome.org ReactomeREACT_111497 has a Stoichiometric coefficient of 1 Follitropin Reactome DB_ID: 378947 Reactome Database ID Release 43378947 Reactome, http://www.reactome.org ReactomeREACT_15789 has a Stoichiometric coefficient of 1 heteroINHB Reactome DB_ID: 1449698 Reactome Database ID Release 431449698 Reactome, http://www.reactome.org ReactomeREACT_111638 has a Stoichiometric coefficient of 2 INHBE dimer Reactome DB_ID: 1449697 Reactome Database ID Release 431449697 Reactome, http://www.reactome.org ReactomeREACT_111469 has a Stoichiometric coefficient of 2 INHBC dimer Reactome DB_ID: 1449705 Reactome Database ID Release 431449705 Reactome, http://www.reactome.org ReactomeREACT_111604 has a Stoichiometric coefficient of 2 INHBB dimer Reactome DB_ID: 1449672 Reactome Database ID Release 431449672 Reactome, http://www.reactome.org ReactomeREACT_111752 has a Stoichiometric coefficient of 2 DAO dimer Reactome DB_ID: 389849 Reactome Database ID Release 43389849 Reactome, http://www.reactome.org ReactomeREACT_17927 has a Stoichiometric coefficient of 2 D-amino-acid oxidase:FAD complex Reactome DB_ID: 389816 Reactome Database ID Release 43389816 Reactome, http://www.reactome.org ReactomeREACT_17155 has a Stoichiometric coefficient of 1 AGXT dimer Alanine-glyoxylate aminotransferase homodimer Reactome DB_ID: 389671 Reactome Database ID Release 43389671 Reactome, http://www.reactome.org ReactomeREACT_17733 has a Stoichiometric coefficient of 2 DDC dimer Dopa decarboxylase homodimer (pyridoxal phosphate cofactor) Reactome DB_ID: 209895 Reactome Database ID Release 43209895 Reactome, http://www.reactome.org ReactomeREACT_15591 has a Stoichiometric coefficient of 2 TH:Fe++ Reactome DB_ID: 209926 Reactome Database ID Release 43209926 Reactome, http://www.reactome.org ReactomeREACT_15832 Tyrosine 3-monooxygenase (Fe2+ cofactor) has a Stoichiometric coefficient of 1 DEHAL1:FMN Reactome DB_ID: 209777 Reactome Database ID Release 43209777 Reactome, http://www.reactome.org ReactomeREACT_15960 has a Stoichiometric coefficient of 1 DBH tetramer Dopamine beta-oxygenase homotetramer (PQQ, copper cofactors) Reactome DB_ID: 209957 Reactome Database ID Release 43209957 Reactome, http://www.reactome.org ReactomeREACT_16014 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 DIO dimer Converted from EntitySet in Reactome Reactome DB_ID: 350846 Reactome Database ID Release 43350846 Reactome, http://www.reactome.org ReactomeREACT_17253 Thyrotropin Reactome DB_ID: 378994 Reactome Database ID Release 43378994 Reactome, http://www.reactome.org ReactomeREACT_17813 has a Stoichiometric coefficient of 1 DIO2 homodimer Reactome DB_ID: 350855 Reactome Database ID Release 43350855 Reactome, http://www.reactome.org ReactomeREACT_17240 has a Stoichiometric coefficient of 2 DIO1 homodimer Reactome DB_ID: 350886 Reactome Database ID Release 43350886 Reactome, http://www.reactome.org ReactomeREACT_18235 has a Stoichiometric coefficient of 2 PC1:calcium cofactor Reactome DB_ID: 378974 Reactome Database ID Release 43378974 Reactome, http://www.reactome.org ReactomeREACT_17306 has a Stoichiometric coefficient of 1 TPH:Fe++ Reactome DB_ID: 976249 Reactome Database ID Release 43976249 Reactome, http://www.reactome.org ReactomeREACT_26756 has a Stoichiometric coefficient of 1 Gonadotropin Reactome DB_ID: 378941 Reactome Database ID Release 43378941 Reactome, http://www.reactome.org ReactomeREACT_15610 has a Stoichiometric coefficient of 1 Sar1p Activation And Membrane Binding Authored: Gillespie, ME, 2007-07-13 20:42:29 Edited: Jassal, B, 2010-11-10 Pubmed10825291 Pubmed10982397 Reactome Database ID Release 43203977 Reactome, http://www.reactome.org ReactomeREACT_12554 Reviewed: Gagneux, P, 2010-11-18 Sar1p-GDP is recruited to the ER membrane by the transmembrane GEF (Guanine nucleotide exchange factor) Sec12, where it is converted to Sar1p-GTP. Transport of glycoproteins with Man8 (or Man9) N-glycans to the Golgi Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-09-15 Pubmed12717434 Pubmed12727195 Reactome Database ID Release 43947991 Reactome, http://www.reactome.org ReactomeREACT_25176 Reviewed: Gagneux, P, 2010-11-18 The LMAN1(also known as ERGIC-53)/MCFD2 complex recognizes Man8 and Man9 N-glycans released by the Calnexin/Calreticulin cycle and mediate their transport to the Golgi (Nyefeler B et al, 2003; Zhang B et al, 2003). Man8 glycan transfer is shown here. NS1 mRNA Reactome DB_ID: 192969 Reactome Database ID Release 43192969 Reactome, http://www.reactome.org ReactomeREACT_9770 Correctly folded glycoproteins translocate to the Golgi Authored: Dall'Olio, GM, 2009-11-10 Correctly folded proteins, after being released from the Calnexin/Calreticulin cycle, are translocated to the Golgi (Hauri H et al, 2000; Hauri HP et al, 2002; Molinari, 2007). Edited: Jassal, B, 2010-07-28 Pubmed10878245 Pubmed12655775 Pubmed17510649 Reactome Database ID Release 43915148 Reactome, http://www.reactome.org ReactomeREACT_23986 Reviewed: Gagneux, P, 2010-11-18 NP mRNA Reactome DB_ID: 192986 Reactome Database ID Release 43192986 Reactome, http://www.reactome.org ReactomeREACT_9607 Glycoproteins with lesser folding defects get transported back to the ER and the CNX/CRT complex Authored: Dall'Olio, GM, 2010-11-18 Edited: Jassal, B, 2010-11-16 Glycoproteins with lesser folding defects get transported back to the ER and the CNX/CRT complex (Lederkremer, 2009). Pubmed19616933 Reactome Database ID Release 431017228 Reactome, http://www.reactome.org ReactomeREACT_25057 Reviewed: Gagneux, P, 2010-11-18 Glycoproteins with major folding defects are sent to degradation by EDEMs Authored: Dall'Olio, GM, 2010-11-18 Edited: Jassal, B, 2010-11-16 Proteins with major folding defects are extracted from futile folding cycles in the calnexin chaperone system and the ER Quality Control Compartment, and are translocated back to the citosol for degradation. The N-glycan is used as a signal to distinguish proteins to be degraded, upon recognition by EDEM1, EDEM2 and EDEM3, three ER-stress-induced members of the glycosyl hydrolase 47 family (see Olivari S, Molinari M 2007 for a review) and OS9 (Mikami K, 2010; Hosokawa N, 2009).<br><br> Pubmed17499246 Reactome Database ID Release 431018376 Reactome, http://www.reactome.org ReactomeREACT_25207 Reviewed: Gagneux, P, 2010-11-18 Re-addition of a glucose on the alpha 1,3 branch Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-03-15 Pubmed10694380 Pubmed12913004 Pubmed18426978 Reactome Database ID Release 43548884 Reactome, http://www.reactome.org ReactomeREACT_25264 Reviewed: Gagneux, P, 2010-11-18 The enzymes UGGT1 and UGGT2 are able to distinguish proteins with minor folding defects in the ERQC and reglucosylate them, by adding a glucose on the alpha 1,3 branch (Arnold SM et al, 2000; Arnold SM et al, 2003). The major affinity of these enzymes for proteins with minor folding defects has been demonstrated, but the exact mechanism that enable them to distinguish proteins with major and minor defects is still unknown (Pearse BR et al, 2008). Trimming of the second mannose on the A branch Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.24 Edited: Jassal, B, 2010-07-02 Pubmed12829701 Reactome Database ID Release 43901036 Reactome, http://www.reactome.org ReactomeREACT_25313 Removal of the second mannose on the alpha 1,3 branch (Frenzel Z et al, 2003). Reviewed: Gagneux, P, 2010-11-18 Trimming of the first mannose on the A branch Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.24 Edited: Jassal, B, 2010-07-02 Pubmed12829701 Pubmed16431915 Reactome Database ID Release 43901024 Reactome, http://www.reactome.org ReactomeREACT_25093 Reviewed: Gagneux, P, 2010-11-18 The enzyme ER Man I can slowly trim up to four of the mannoses on the N-glycan on unfolded proteins accumulated in the ER. This step describes the removal of the mannose in the A position (Hirao et al, 2006; Frenkel et al, 2003). MIR26A1 Reactome DB_ID: 2318732 Reactome Database ID Release 432318732 Reactome, http://www.reactome.org ReactomeREACT_148207 has a fragment starting at 10 and ending at 31 miR-26A1 microRNA 26A1 Trimming of the terminal mannose on the C branch Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.24 Edited: Jassal, B, 2010-07-02 Pubmed16431915 Reactome Database ID Release 43901039 Reactome, http://www.reactome.org ReactomeREACT_25126 Reviewed: Gagneux, P, 2010-11-18 The enzyme ER Man I can slowly trim up to four of the mannoses on the N-glycan on unfolded proteins accumulated in the ER. This step describes the removal of the mannose in the C position (Hirao et al, 2006). miR-26A Converted from EntitySet in Reactome Reactome DB_ID: 2318743 Reactome Database ID Release 432318743 Reactome, http://www.reactome.org ReactomeREACT_148458 Trimming of the terminal mannose on the B branch Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.24 Edited: Jassal, B, 2010-07-02 Pubmed10409699 Pubmed16431915 Reactome Database ID Release 43901074 Reactome, http://www.reactome.org ReactomeREACT_24995 Reviewed: Gagneux, P, 2010-11-18 The enzyme ER Man I can slowly trim up to four of the mannoses on the N-glycan on unfolded proteins accumulated in the ER. This step describes the removal of the mannose in the B position (Gonzalez et al, 1999: Hirao et al, 2006). PTEN mRNA Reactome DB_ID: 2318746 Reactome Database ID Release 432318746 Reactome, http://www.reactome.org ReactomeREACT_147967 has a fragment starting at 1 and ending at 9027 MIR26A2 Reactome DB_ID: 2318734 Reactome Database ID Release 432318734 Reactome, http://www.reactome.org ReactomeREACT_148569 has a fragment starting at 10 and ending at 31 miR-26A2 microRNA 26A2 PA mRNA Reactome DB_ID: 192985 Reactome Database ID Release 43192985 Reactome, http://www.reactome.org ReactomeREACT_9783 PB1 mRNA Reactome DB_ID: 192983 Reactome Database ID Release 43192983 Reactome, http://www.reactome.org ReactomeREACT_9734 vRNA (genomic) Converted from EntitySet in Reactome Reactome DB_ID: 196484 Reactome Database ID Release 43196484 Reactome, http://www.reactome.org ReactomeREACT_10723 PB2 mRNA Reactome DB_ID: 192993 Reactome Database ID Release 43192993 Reactome, http://www.reactome.org ReactomeREACT_9567 RNA molecules bound by IGF2BP1 (IMP1/CRD-BP/ZBP1/VICKZ1) Converted from EntitySet in Reactome Reactome DB_ID: 428308 Reactome Database ID Release 43428308 Reactome, http://www.reactome.org ReactomeREACT_23171 Binding of calnexin/calreticulin to the unfolded protein Authored: Dall'Olio, GM, 2009-11-10 Calnexin (membrane protein) and calreticulin (soluble in ER) are two lectins (proteins that can bind a glycan) which recognize the mono-glucosylated form of the N-glycan and mediate the folding of the glycoproteins to which they are attached to (Ou WJ et al, 1993; Nauseef Wm et al, 1995). Calmegin is another chaperone with the same role expressed only in testis (van Lith M et al, 2007). These lectins act as chaperons, providing a protected environment where the unfolded glycoprotein can fold without forming interactions with other proteins or components in the ER. The unfolded protein can loop between these two steps multiple time, therefore this process is called the 'calnexin/calreticulin cycle'. If the protein achieves correct folding, it is modified by Mannosidase I and then moved to the cis-Golgi where the glycan is further processed. Edited: Jassal, B, 2010-03-05 Pubmed17507649 Pubmed7876246 Pubmed8102790 Reactome Database ID Release 43535717 Reactome, http://www.reactome.org ReactomeREACT_23778 Reviewed: Gagneux, P, 2010-08-17 Xbp1 mRNA (spliced) Reactome DB_ID: 425925 Reactome Database ID Release 43425925 Reactome, http://www.reactome.org ReactomeREACT_22580 Removal of the second glucose by glucosidase II A second glucose is removed from the N-linked glycan. The removal of an alpha1,3 glucose moiety is catalyzed by glucosidase II, a complex composed of an alpha subunit (GANAB) with catalytic activity and a beta subunit (GLU2B; PRKCSH), probably with regulatory and recruitment function (Pelletier MF et al, 2000). GANAB can exist in two different isoforms, but both are able to catalyze both of the reactions catalyzed by glucosidase II (Pelletier MF et al, 2000). Defects in PRKCSH are a cause of polycystic liver disease (PCLD). Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.84 Edited: Jassal, B, 2010-03-02 Pubmed10929008 Reactome Database ID Release 43532667 Reactome, http://www.reactome.org ReactomeREACT_23850 Reviewed: Gagneux, P, 2010-08-17 Xbp1 mRNA (unspliced) Reactome DB_ID: 425921 Reactome Database ID Release 43425921 Reactome, http://www.reactome.org ReactomeREACT_22687 Removal of the third glucose by glucosidase II and release from the chaperone Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.84 Edited: Jassal, B, 2010-03-15 Pubmed10929008 Reactome Database ID Release 43548890 Reactome, http://www.reactome.org ReactomeREACT_23791 Reviewed: Gagneux, P, 2010-08-17 While the protein is bound to the chaperone complex, the glycan is still accessible to glucosidase II, which eventually removes the last remaining glucose residue. This also results in breaking the interaction between the chaperone and the glycoprotein, independently of whether the latter has achieved proper folding (Pelletier MF et al, 2000). This has been interpreted as a 'timing mechanism', in which a protein has only a limited period of time to achieve correct folding when bound to the chaperone, to avoid the scenario where proteins that take too long to fold would block the availability of CNX or CRT. Proteins with folding defects get transported to the Endoplasmic Reticulum Quality Control Compartment, while proteins with correct folding are transported to the cis-Golgi where the glycan is further modified. Binding of ERp57 Authored: Dall'Olio, GM, 2009-11-10 ERp57/ERp27 is a thiol-oxidoreductase that interacts with calnexin and mediates the formation of disulfide bonds in the unfolded glycoprotein (Alanen HI et al, 2006). Edited: Jassal, B, 2010-07-02 Pubmed16940051 Reactome Database ID Release 43901047 Reactome, http://www.reactome.org ReactomeREACT_23831 Reviewed: Gagneux, P, 2010-08-17 Transfer of N-glycan to the protein Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.119 Edited: Jassal, B, 2009-11-10 Pubmed11470266 Pubmed14514716 Pubmed16317064 Pubmed19835842 Reactome Database ID Release 43446209 Reactome, http://www.reactome.org ReactomeREACT_22208 Reviewed: Gagneux, P, 2010-04-16 The 14-sugar N-glycan precursor, synthesized in the previous reactions, is attached in a single step to a nascent protein, releasing the dolichyl phosphate anchor and the as yet unfolded glycoprotein. The reaction occurs cotranslationally as the growing peptide chain leaves a ribosome associated with the ER membrane and enters the ER lumen. This reaction is catalyzed by the OST complex, composed of at least seven proteins; DAD1, DDOST (OST48 in yeast), RPN1 (ribophorin 1), RPN2 (ribophorin 2), OST4, TUSC3 (N33), and either STT3A or STT3B, which contain the catalytic domain (Kelleher DJ and Gilmore R, 2006). A mutation in RPN2 is associated with CDG-Ix (Vleugels W et al, 2009).<br>The signal for glycosylation is the consensus sequence Asn - X - Thr/Ser, where the first amino acid is always Asn, the second can be any amino acid except for Pro, and the third position may be Thr, Ser or Cys, with a preference for the first (Breuer W et al, 2001). Not all Asn - X - Thr/Ser sites are modified in vivo (Petrescu AJ et al, 2004).<br> Addition of a third glucose to the N-glycan precursor by an ALG10 homologue Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed15710750 Pubmed9597543 Reactome Database ID Release 43446194 Reactome, http://www.reactome.org ReactomeREACT_22406 Reviewed: Gagneux, P, 2010-04-16 The last glucose is added to the N-glycan precursor. This reaction occurs inside the ER lumen and uses Dol-P-Glc as the glucose donor. In yeast, this reaction is catalyzed by ALG10 (Burda P and Aebi M,1998); however, this gene is duplicated in primates (Ciccarelli FD et al, 2005; Table 1), leading to two homologues, ALG10A and ALG10B, and to date there is no clear evidence to say which of these two paralogues (or both) is responsible for catalyzing this reaction in humans. No Congenital Disorders of Glycosylations are known to be associated with either gene.<br> Binding of Malectin A recently discovered protein called malectin is known to recognize the Glc(2)Man(9)GlcNAc(2) glycan (Schallus T et al, 2008). The exact role of this interaction is not clear but malectin is thought to regulate the availability of this substrate to glucosidase II, or to act as a chaperone to stabilize the unfolded protein. Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-07-02 Pubmed18524852 Reactome Database ID Release 43901006 Reactome, http://www.reactome.org ReactomeREACT_23783 Reviewed: Gagneux, P, 2010-08-17 Trimming of the first glucose by glucosidase I After the glycosylated precursor is attached to the protein, the outer alpha-1,2-linked glucose is removed by glucosidase I (MOGS, GCS1 in yeast). This is a mandatory step for the protein folding control and glycan extension, and defects in MOGS are associated with congenital disorder of glycosylation type IIb (CDGIIb) (De Praeter CM et al, 2000; Völker C et al, 2002). Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.106 Edited: Jassal, B, 2010-03-02 Pubmed10788335 Pubmed12145188 Reactome Database ID Release 43532678 Reactome, http://www.reactome.org ReactomeREACT_23855 Reviewed: Gagneux, P, 2010-08-17 CD44 mRNA isoform 203 Reactome DB_ID: 428370 Reactome Database ID Release 43428370 Reactome, http://www.reactome.org ReactomeREACT_23208 CD44 mRNA isoform 202 Reactome DB_ID: 428347 Reactome Database ID Release 43428347 Reactome, http://www.reactome.org ReactomeREACT_23160 Addition of a second glucose to the N-glycan precursor by ALG8 Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed15235028 Pubmed16007612 Reactome Database ID Release 43446189 Reactome, http://www.reactome.org ReactomeREACT_22158 Reviewed: Gagneux, P, 2010-04-16 The second glucose (supplied from the donor dolichol-phosphate-glucose) is added to the N-glycan precursor, mediated by ALG8 (Schollen E et al, 2004). Defects in ALG8 are the cause of congenital disorder of glycosylation type 1H (CDG1H) (Schollen E et al, 2004; Sun L et al, 2005). CD44 mRNA isoform 201 Reactome DB_ID: 428379 Reactome Database ID Release 43428379 Reactome, http://www.reactome.org ReactomeREACT_23086 MYC mRNA isoform 201 Reactome DB_ID: 428380 Reactome Database ID Release 43428380 Reactome, http://www.reactome.org ReactomeREACT_22931 Beta-actin mRNA isoform 001 Reactome DB_ID: 428322 Reactome Database ID Release 43428322 Reactome, http://www.reactome.org ReactomeREACT_22790 IGF2-002 mRNA Insulin-like Growth Factor-2 mRNA isoform 002 Reactome DB_ID: 428307 Reactome Database ID Release 43428307 Reactome, http://www.reactome.org ReactomeREACT_22643 IGF2-001 mRNA Insulin-like Growth Factor-2 mRNA isoform 001 Reactome DB_ID: 428362 Reactome Database ID Release 43428362 Reactome, http://www.reactome.org ReactomeREACT_23368 Incorrectly folded glycoproteins translocate to the ERQC Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2010-07-08 Proteins with folding defects get transported to the Endoplasmic Reticulum Quality Control Compartment (Molinari, 2007). Pubmed17510649 Reactome Database ID Release 43912291 Reactome, http://www.reactome.org ReactomeREACT_23773 Reviewed: Gagneux, P, 2010-08-17 viral RNA template extensively digested except in PPT region 3'-polypurine tract (3'-PPT) Reactome DB_ID: 173819 Reactome Database ID Release 43173819 Reactome, http://www.reactome.org ReactomeREACT_9367 central polypurine tract (cPPT) AMPK heterotrimer (inactive) Reactome DB_ID: 163679 Reactome Database ID Release 43163679 Reactome, http://www.reactome.org ReactomeREACT_3733 has a Stoichiometric coefficient of 1 HIV-1 mRNA Reactome DB_ID: 165533 Reactome Database ID Release 43165533 Reactome, http://www.reactome.org ReactomeREACT_6408 viral RNA template degraded by RNase-H (initial) 3'-Repeated (R) sequence Reactome DB_ID: 173829 Reactome Database ID Release 43173829 Reactome, http://www.reactome.org ReactomeREACT_9342 central polypurine tract (cPPT) viral RNA template being digested by RNase-H (extensive) 3'-Repeated (R) sequence 3'-polypurine tract (3'-PPT) Reactome DB_ID: 173794 Reactome Database ID Release 43173794 Reactome, http://www.reactome.org ReactomeREACT_9271 G-beta:G-gamma dimer Reactome DB_ID: 164386 Reactome Database ID Release 43164386 Reactome, http://www.reactome.org ReactomeREACT_3447 has a Stoichiometric coefficient of 1 Adenylate cyclase (Mg2+ cofactor) Reactome DB_ID: 170665 Reactome Database ID Release 43170665 Reactome, http://www.reactome.org ReactomeREACT_17689 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 HIV-1 mRNA Reactome DB_ID: 165555 Reactome Database ID Release 43165555 Reactome, http://www.reactome.org ReactomeREACT_6617 Gs-activated adenylate cyclase Reactome DB_ID: 163622 Reactome Database ID Release 43163622 Reactome, http://www.reactome.org ReactomeREACT_2537 has a Stoichiometric coefficient of 1 HIV-1 unspliced RNA Reactome DB_ID: 187209 Reactome Database ID Release 43187209 Reactome, http://www.reactome.org ReactomeREACT_9274 Inactive PP2A-ABdeltaC complex Reactome DB_ID: 165992 Reactome Database ID Release 43165992 Reactome, http://www.reactome.org ReactomeREACT_4092 has a Stoichiometric coefficient of 1 insulin Reactome DB_ID: 74674 Reactome Database ID Release 4374674 Reactome, http://www.reactome.org ReactomeREACT_5828 has a Stoichiometric coefficient of 1 Core SNARE Complex Reactome DB_ID: 387383 Reactome Database ID Release 43387383 Reactome, http://www.reactome.org ReactomeREACT_16105 has a Stoichiometric coefficient of 1 unfolded actin/tubulin Converted from EntitySet in Reactome Reactome DB_ID: 390445 Reactome Database ID Release 43390445 Reactome, http://www.reactome.org ReactomeREACT_17525 Glucagon:GCGR Reactome DB_ID: 163627 Reactome Database ID Release 43163627 Reactome, http://www.reactome.org ReactomeREACT_3602 has a Stoichiometric coefficient of 1 G-protein with G(s) alpha:GDP Reactome DB_ID: 164384 Reactome Database ID Release 43164384 Reactome, http://www.reactome.org ReactomeREACT_5026 has a Stoichiometric coefficient of 1 Frizzled receptors Converted from EntitySet in Reactome Reactome DB_ID: 517514 Reactome Database ID Release 43517514 Reactome, http://www.reactome.org ReactomeREACT_21716 Insulin-Zinc-Calcium Complex Reactome DB_ID: 265168 Reactome Database ID Release 43265168 Reactome, http://www.reactome.org ReactomeREACT_15636 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 6 other viral genomic RNA Reactome DB_ID: 173808 Reactome Database ID Release 43173808 Reactome, http://www.reactome.org ReactomeREACT_9211 HIV-1 RNA template LTR domain Primer-binding domain (PBS) in minus strand Reactome DB_ID: 173654 Reactome Database ID Release 43173654 Reactome, http://www.reactome.org ReactomeREACT_8927 HIV-1 RNA Reactome DB_ID: 175178 Reactome Database ID Release 43175178 Reactome, http://www.reactome.org ReactomeREACT_8207 Spliceosome snRNAs Converted from EntitySet in Reactome Reactome DB_ID: 191819 Reactome Database ID Release 43191819 Reactome, http://www.reactome.org ReactomeREACT_10158 Genomic RNA Segment 7 Reactome DB_ID: 188828 Reactome Database ID Release 43188828 Reactome, http://www.reactome.org ReactomeREACT_9210 Genomic RNA Segment 2 Reactome DB_ID: 188838 Reactome Database ID Release 43188838 Reactome, http://www.reactome.org ReactomeREACT_9206 Genomic RNA Segment 6 Reactome DB_ID: 188829 Reactome Database ID Release 43188829 Reactome, http://www.reactome.org ReactomeREACT_9080 Genomic RNA Segment 6 Reactome DB_ID: 189133 Reactome Database ID Release 43189133 Reactome, http://www.reactome.org ReactomeREACT_9194 Genomic RNA Segment 7 Reactome DB_ID: 189163 Reactome Database ID Release 43189163 Reactome, http://www.reactome.org ReactomeREACT_9312 Genomic RNA Segment 5 Reactome DB_ID: 188840 Reactome Database ID Release 43188840 Reactome, http://www.reactome.org ReactomeREACT_9100 Genomic RNA Segment 1 Reactome DB_ID: 188872 Reactome Database ID Release 43188872 Reactome, http://www.reactome.org ReactomeREACT_9112 Genomic RNA Segment 4 Reactome DB_ID: 188876 Reactome Database ID Release 43188876 Reactome, http://www.reactome.org ReactomeREACT_9237 Genomic RNA Segment 8 Reactome DB_ID: 188833 Reactome Database ID Release 43188833 Reactome, http://www.reactome.org ReactomeREACT_9325 Genomic RNA Segment 3 Reactome DB_ID: 188859 Reactome Database ID Release 43188859 Reactome, http://www.reactome.org ReactomeREACT_9235 GLUT1 and GLUT2 (Pancreatic Beta Cell) Converted from EntitySet in Reactome Reactome DB_ID: 500048 Reactome Database ID Release 43500048 Reactome, http://www.reactome.org ReactomeREACT_21462 ANT homodimer ADP/ATP translocase dimer Adenine nucleotide translocator homodimer Converted from EntitySet in Reactome Reactome DB_ID: 187453 Reactome Database ID Release 43187453 Reactome, http://www.reactome.org ReactomeREACT_9306 ADP/ATP translocase 1 homodimer Reactome DB_ID: 77445 Reactome Database ID Release 4377445 Reactome, http://www.reactome.org ReactomeREACT_3875 has a Stoichiometric coefficient of 2 ADP/ATP translocase 2 homodimer Reactome DB_ID: 77447 Reactome Database ID Release 4377447 Reactome, http://www.reactome.org ReactomeREACT_2754 has a Stoichiometric coefficient of 2 ADP/ATP translocase 3 homodimer Reactome DB_ID: 77449 Reactome Database ID Release 4377449 Reactome, http://www.reactome.org ReactomeREACT_3614 has a Stoichiometric coefficient of 2 Inward Rectifying Potassium Channel (open) Reactome DB_ID: 265734 Reactome Database ID Release 43265734 Reactome, http://www.reactome.org ReactomeREACT_17204 has a Stoichiometric coefficient of 4 Inward Rectifying Potassium Channel (closed) Reactome DB_ID: 265746 Reactome Database ID Release 43265746 Reactome, http://www.reactome.org ReactomeREACT_18063 has a Stoichiometric coefficient of 4 GPR119:Fatty Acid Complex Reactome DB_ID: 400482 Reactome Database ID Release 43400482 Reactome, http://www.reactome.org ReactomeREACT_24051 has a Stoichiometric coefficient of 1 GPR120: Fatty Acid Complex Reactome DB_ID: 400543 Reactome Database ID Release 43400543 Reactome, http://www.reactome.org ReactomeREACT_21753 has a Stoichiometric coefficient of 1 Gustducin Complex (alpha, beta, gamma subunits) Reactome DB_ID: 400532 Reactome Database ID Release 43400532 Reactome, http://www.reactome.org ReactomeREACT_24604 has a Stoichiometric coefficient of 1 U4 snRNA Reactome DB_ID: 191882 Reactome Database ID Release 43191882 Reactome, http://www.reactome.org ReactomeREACT_10456 Insulin:Zinc:Calcium Complex in docked granule Reactome DB_ID: 386977 Reactome Database ID Release 43386977 Reactome, http://www.reactome.org ReactomeREACT_17297 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 6 U5 snRNA Reactome DB_ID: 191871 Reactome Database ID Release 43191871 Reactome, http://www.reactome.org ReactomeREACT_10487 Insulin Reactome DB_ID: 264998 Reactome Database ID Release 43264998 Reactome, http://www.reactome.org ReactomeREACT_17772 has a Stoichiometric coefficient of 1 U6 snRNA Reactome DB_ID: 191802 Reactome Database ID Release 43191802 Reactome, http://www.reactome.org ReactomeREACT_10677 IP3 receptor homotetramer Reactome DB_ID: 169686 Reactome Database ID Release 43169686 Reactome, http://www.reactome.org ReactomeREACT_12247 has a Stoichiometric coefficient of 4 IP3 receptor:IP3 complex Reactome DB_ID: 169696 Reactome Database ID Release 43169696 Reactome, http://www.reactome.org ReactomeREACT_12249 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 7SL RNA (ENST00000410707) Reactome DB_ID: 445243 Reactome Database ID Release 43445243 Reactome, http://www.reactome.org ReactomeREACT_20790 Spliceosome snRNAs Converted from EntitySet in Reactome Reactome DB_ID: 191872 Reactome Database ID Release 43191872 Reactome, http://www.reactome.org ReactomeREACT_10154 U1 snRNA Reactome DB_ID: 191863 Reactome Database ID Release 43191863 Reactome, http://www.reactome.org ReactomeREACT_10206 Syntaxin-1A-Unc18-1 Complex Reactome DB_ID: 265191 Reactome Database ID Release 43265191 Reactome, http://www.reactome.org ReactomeREACT_16057 has a Stoichiometric coefficient of 1 U2 snRNA Reactome DB_ID: 191831 Reactome Database ID Release 43191831 Reactome, http://www.reactome.org ReactomeREACT_10793 SNARE Complex Reactome DB_ID: 265202 Reactome Database ID Release 43265202 Reactome, http://www.reactome.org ReactomeREACT_15643 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 Voltage-gated Calcium Channel, P/Q-type 2.1 Reactome DB_ID: 265601 Reactome Database ID Release 43265601 Reactome, http://www.reactome.org ReactomeREACT_17903 has a Stoichiometric coefficient of 1 Voltage-gated Calcium Channel, R-type 2.3 Reactome DB_ID: 265728 Reactome Database ID Release 43265728 Reactome, http://www.reactome.org ReactomeREACT_17554 has a Stoichiometric coefficient of 1 SUR1-ATP Complex Reactome DB_ID: 265692 Reactome Database ID Release 43265692 Reactome, http://www.reactome.org ReactomeREACT_17502 has a Stoichiometric coefficient of 1 Voltage-gated Calcium Channels (pancreatic beta cell) Converted from EntitySet in Reactome Reactome DB_ID: 265569 Reactome Database ID Release 43265569 Reactome, http://www.reactome.org ReactomeREACT_17848 5.8S rRNA Reactome DB_ID: 72496 Reactome Database ID Release 4372496 Reactome, http://www.reactome.org ReactomeREACT_3174 7SL RNA (ENST00000410687) Reactome DB_ID: 445250 Reactome Database ID Release 43445250 Reactome, http://www.reactome.org ReactomeREACT_21013 7SL RNA Converted from EntitySet in Reactome Reactome DB_ID: 445238 Reactome Database ID Release 43445238 Reactome, http://www.reactome.org ReactomeREACT_20822 nucleases removing 3' phosphoglycolate Converted from EntitySet in Reactome Reactome DB_ID: 175597 Reactome Database ID Release 43175597 Reactome, http://www.reactome.org ReactomeREACT_7333 GLP-1R: Heterotrimeric G(s): GDP Reactome DB_ID: 422314 Reactome Database ID Release 43422314 Reactome, http://www.reactome.org ReactomeREACT_18624 has a Stoichiometric coefficient of 1 PKA:AKAP79:IQGAP1 Complex Reactome DB_ID: 381635 Reactome Database ID Release 43381635 Reactome, http://www.reactome.org ReactomeREACT_18813 has a Stoichiometric coefficient of 1 Activated Adenylate Cyclase Adenylate cyclase: G-protein alpha (s): GTP Complex Reactome DB_ID: 422306 Reactome Database ID Release 43422306 Reactome, http://www.reactome.org ReactomeREACT_19025 has a Stoichiometric coefficient of 1 NS1 mRNA Reactome DB_ID: 192982 Reactome Database ID Release 43192982 Reactome, http://www.reactome.org ReactomeREACT_9795 cAMP:PKA regulatory subunit Reactome DB_ID: 111923 Reactome Database ID Release 43111923 Reactome, http://www.reactome.org ReactomeREACT_4571 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 NP mRNA Reactome DB_ID: 192973 Reactome Database ID Release 43192973 Reactome, http://www.reactome.org ReactomeREACT_9738 cAMP:PKA:AKAP79:IQGAP1 Complex Reactome DB_ID: 381615 Reactome Database ID Release 43381615 Reactome, http://www.reactome.org ReactomeREACT_18785 has a Stoichiometric coefficient of 1 GLP-1:GLP-1R GLP-1 bound to GLP-1 Receptor Reactome DB_ID: 381656 Reactome Database ID Release 43381656 Reactome, http://www.reactome.org ReactomeREACT_18936 has a Stoichiometric coefficient of 1 GLP-1: GLP-1R: Heterotrimeric G(s): GDP Reactome DB_ID: 422310 Reactome Database ID Release 43422310 Reactome, http://www.reactome.org ReactomeREACT_18821 has a Stoichiometric coefficient of 1 G-alpha(s):GTP:G-beta:G-gamma Heterotrimeric G-alpha(s): GTP:G-beta: G-gamma Complex Reactome DB_ID: 422322 Reactome Database ID Release 43422322 Reactome, http://www.reactome.org ReactomeREACT_18711 has a Stoichiometric coefficient of 1 GLP-1: GLP-1R: Heterotrimeric G(s): GTP Reactome DB_ID: 422311 Reactome Database ID Release 43422311 Reactome, http://www.reactome.org ReactomeREACT_18812 has a Stoichiometric coefficient of 1 vRNA (genomic) Converted from EntitySet in Reactome Reactome DB_ID: 192849 Reactome Database ID Release 43192849 Reactome, http://www.reactome.org ReactomeREACT_9646 Elongating viral mRNA Converted from EntitySet in Reactome Reactome DB_ID: 192984 Reactome Database ID Release 43192984 Reactome, http://www.reactome.org ReactomeREACT_9870 Genomic RNA Segment 2 Reactome DB_ID: 188827 Reactome Database ID Release 43188827 Reactome, http://www.reactome.org ReactomeREACT_9251 Genomic RNA Segment 7 Reactome DB_ID: 188863 Reactome Database ID Release 43188863 Reactome, http://www.reactome.org ReactomeREACT_9174 M2 mRNA Reactome DB_ID: 192994 Reactome Database ID Release 43192994 Reactome, http://www.reactome.org ReactomeREACT_9773 Protein Kinase C, alpha type: Diacylglycerol Complex Reactome DB_ID: 422275 Reactome Database ID Release 43422275 Reactome, http://www.reactome.org ReactomeREACT_18539 has a Stoichiometric coefficient of 1 NA mRNA Reactome DB_ID: 192965 Reactome Database ID Release 43192965 Reactome, http://www.reactome.org ReactomeREACT_9602 FFAR1:fatty acid Free fatty acid receptor 1:fatty acid complex Reactome DB_ID: 400420 Reactome Database ID Release 43400420 Reactome, http://www.reactome.org ReactomeREACT_19781 has a Stoichiometric coefficient of 1 HA mRNA Reactome DB_ID: 192981 Reactome Database ID Release 43192981 Reactome, http://www.reactome.org ReactomeREACT_9740 M1 mRNA Reactome DB_ID: 192990 Reactome Database ID Release 43192990 Reactome, http://www.reactome.org ReactomeREACT_9759 IP3-gated Ca-channel type 2 Reactome DB_ID: 112290 Reactome Database ID Release 43112290 Reactome, http://www.reactome.org ReactomeREACT_18733 has a Stoichiometric coefficient of 4 IP3-gated Ca-channel type 1 Reactome DB_ID: 112288 Reactome Database ID Release 43112288 Reactome, http://www.reactome.org ReactomeREACT_19033 has a Stoichiometric coefficient of 4 hTCF-4:Beta-catenin Reactome DB_ID: 201922 Reactome Database ID Release 43201922 Reactome, http://www.reactome.org ReactomeREACT_24275 has a Stoichiometric coefficient of 1 NA mRNA Reactome DB_ID: 192972 Reactome Database ID Release 43192972 Reactome, http://www.reactome.org ReactomeREACT_9544 Epac2:cAMP Complex Reactome DB_ID: 381680 Reactome Database ID Release 43381680 Reactome, http://www.reactome.org ReactomeREACT_18747 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Epac1:cAMP Complex Reactome DB_ID: 381702 Reactome Database ID Release 43381702 Reactome, http://www.reactome.org ReactomeREACT_18906 has a Stoichiometric coefficient of 1 IP3-gated Ca-channel type 3 (open) Reactome DB_ID: 112291 Reactome Database ID Release 43112291 Reactome, http://www.reactome.org ReactomeREACT_18794 has a Stoichiometric coefficient of 4 IP3-gated Ca-channel type 2 (open) Reactome DB_ID: 112289 Reactome Database ID Release 43112289 Reactome, http://www.reactome.org ReactomeREACT_18731 has a Stoichiometric coefficient of 4 IP3-gated Ca-channel type 1 (open) Reactome DB_ID: 112287 Reactome Database ID Release 43112287 Reactome, http://www.reactome.org ReactomeREACT_18847 has a Stoichiometric coefficient of 4 Ca-channel (open) Converted from EntitySet in Reactome Reactome DB_ID: 111873 Reactome Database ID Release 43111873 Reactome, http://www.reactome.org ReactomeREACT_18978 IP3-gated Ca-channel type 3 Reactome DB_ID: 112292 Reactome Database ID Release 43112292 Reactome, http://www.reactome.org ReactomeREACT_18481 has a Stoichiometric coefficient of 4 P1 mRNA Reactome DB_ID: 192977 Reactome Database ID Release 43192977 Reactome, http://www.reactome.org ReactomeREACT_9540 PA mRNA Reactome DB_ID: 192995 Reactome Database ID Release 43192995 Reactome, http://www.reactome.org ReactomeREACT_9750 viral mRNA Converted from EntitySet in Reactome Reactome DB_ID: 192988 Reactome Database ID Release 43192988 Reactome, http://www.reactome.org ReactomeREACT_9782 M2 mRNA Reactome DB_ID: 192914 Reactome Database ID Release 43192914 Reactome, http://www.reactome.org ReactomeREACT_9847 NS2 mRNA Reactome DB_ID: 192996 Reactome Database ID Release 43192996 Reactome, http://www.reactome.org ReactomeREACT_9827 viral mRNA Converted from EntitySet in Reactome Reactome DB_ID: 192803 Reactome Database ID Release 43192803 Reactome, http://www.reactome.org ReactomeREACT_9819 HA mRNA Reactome DB_ID: 192987 Reactome Database ID Release 43192987 Reactome, http://www.reactome.org ReactomeREACT_9676 Ca-channel (closed) Converted from EntitySet in Reactome Reactome DB_ID: 111877 Reactome Database ID Release 43111877 Reactome, http://www.reactome.org ReactomeREACT_18712 M1 mRNA Reactome DB_ID: 192712 Reactome Database ID Release 43192712 Reactome, http://www.reactome.org ReactomeREACT_9604 NS2 mRNA Reactome DB_ID: 192966 Reactome Database ID Release 43192966 Reactome, http://www.reactome.org ReactomeREACT_9835 Adrenaline/Noradrenaline:Alpha-2A/2C Adrenergic Receptor Complex Reactome DB_ID: 400090 Reactome Database ID Release 43400090 Reactome, http://www.reactome.org ReactomeREACT_18594 has a Stoichiometric coefficient of 1 G-protein alpha i/o:GDP Complex Reactome DB_ID: 400036 Reactome Database ID Release 43400036 Reactome, http://www.reactome.org ReactomeREACT_18857 has a Stoichiometric coefficient of 1 G-protein i/o alpha:GDP:G-protein beta:G-protein gamma Complex Reactome DB_ID: 400088 Reactome Database ID Release 43400088 Reactome, http://www.reactome.org ReactomeREACT_18744 has a Stoichiometric coefficient of 1 Genomic RNA Segment 6 Reactome DB_ID: 196479 Reactome Database ID Release 43196479 Reactome, http://www.reactome.org ReactomeREACT_10243 G-protein i/o alpha:GTP:G-protein beta:G-protein gamma Complex Reactome DB_ID: 400031 Reactome Database ID Release 43400031 Reactome, http://www.reactome.org ReactomeREACT_18596 has a Stoichiometric coefficient of 1 Genomic RNA Segment 5 Reactome DB_ID: 196499 Reactome Database ID Release 43196499 Reactome, http://www.reactome.org ReactomeREACT_10499 G-beta:G-gamma (candidates) G-protein beta gamma Complex (candidates) Reactome DB_ID: 400034 Reactome Database ID Release 43400034 Reactome, http://www.reactome.org ReactomeREACT_18827 has a Stoichiometric coefficient of 1 Genomic RNA Segment 8 Reactome DB_ID: 188874 Reactome Database ID Release 43188874 Reactome, http://www.reactome.org ReactomeREACT_9345 Voltage-gated Calcium Channels Type Cav1 (open) Converted from EntitySet in Reactome Reactome DB_ID: 400055 Reactome Database ID Release 43400055 Reactome, http://www.reactome.org ReactomeREACT_18725 Genomic RNA Segment 7 Reactome DB_ID: 196477 Reactome Database ID Release 43196477 Reactome, http://www.reactome.org ReactomeREACT_10987 G-protein alpha i/o:GTP Complex Reactome DB_ID: 400076 Reactome Database ID Release 43400076 Reactome, http://www.reactome.org ReactomeREACT_18504 has a Stoichiometric coefficient of 1 Genomic RNA Segment 5 Reactome DB_ID: 189179 Reactome Database ID Release 43189179 Reactome, http://www.reactome.org ReactomeREACT_9213 SMPD4:Mg2+ Reactome DB_ID: 1606289 Reactome Database ID Release 431606289 Reactome, http://www.reactome.org ReactomeREACT_116988 has a Stoichiometric coefficient of 1 Genomic RNA Segment 3 Reactome DB_ID: 189162 Reactome Database ID Release 43189162 Reactome, http://www.reactome.org ReactomeREACT_9359 GBA:SAPC Reactome DB_ID: 1605675 Reactome Database ID Release 431605675 Reactome, http://www.reactome.org ReactomeREACT_117082 has a Stoichiometric coefficient of 1 Genomic RNA Segment 2 Reactome DB_ID: 189174 Reactome Database ID Release 43189174 Reactome, http://www.reactome.org ReactomeREACT_9326 ASAH1 Reactome DB_ID: 1606584 Reactome Database ID Release 431606584 Reactome, http://www.reactome.org ReactomeREACT_117617 has a Stoichiometric coefficient of 1 Genomic RNA Segment 1 Reactome DB_ID: 189169 Reactome Database ID Release 43189169 Reactome, http://www.reactome.org ReactomeREACT_9243 active STS dimer Reactome DB_ID: 1606803 Reactome Database ID Release 431606803 Reactome, http://www.reactome.org ReactomeREACT_117262 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Genomic RNA Segment 8 Reactome DB_ID: 189167 Reactome Database ID Release 43189167 Reactome, http://www.reactome.org ReactomeREACT_9349 Genomic RNA Segment 4 Reactome DB_ID: 189146 Reactome Database ID Release 43189146 Reactome, http://www.reactome.org ReactomeREACT_9363 ATR monomer Converted from EntitySet in Reactome Reactome DB_ID: 176111 Reactome Database ID Release 43176111 Reactome, http://www.reactome.org ReactomeREACT_7227 SMURF1 Converted from EntitySet in Reactome Reactome DB_ID: 2167910 Reactome Database ID Release 432167910 Reactome, http://www.reactome.org ReactomeREACT_124462 G beta:G gamma Reactome DB_ID: 399993 Reactome Database ID Release 43399993 Reactome, http://www.reactome.org ReactomeREACT_18681 has a Stoichiometric coefficient of 1 G(q) alpha 11/14/15/Q:GDP:G beta:G gamma G(q):GDP: G beta: G gamma Complex (pancreatic beta cell) Reactome DB_ID: 399992 Reactome Database ID Release 43399992 Reactome, http://www.reactome.org ReactomeREACT_18540 has a Stoichiometric coefficient of 1 Muscarinic Acetylcholine Receptor M3:Acetylcholine Complex Reactome DB_ID: 400013 Reactome Database ID Release 43400013 Reactome, http://www.reactome.org ReactomeREACT_18706 has a Stoichiometric coefficient of 1 Adenylate cyclase type V or VI: G-protein beta gamma Complex Reactome DB_ID: 400038 Reactome Database ID Release 43400038 Reactome, http://www.reactome.org ReactomeREACT_18486 has a Stoichiometric coefficient of 1 Genomic RNA Segment 5 Reactome DB_ID: 188858 Reactome Database ID Release 43188858 Reactome, http://www.reactome.org ReactomeREACT_9081 PLC beta1/2/3:G(q) alpha:GTP Phospholipase C Beta: G(q) Complex Reactome DB_ID: 400011 Reactome Database ID Release 43400011 Reactome, http://www.reactome.org ReactomeREACT_18449 has a Stoichiometric coefficient of 1 Genomic RNA Segment 6 Reactome DB_ID: 188868 Reactome Database ID Release 43188868 Reactome, http://www.reactome.org ReactomeREACT_9195 G(q) alpha 11/14/15/Q:GTP G(q) alpha: GTP Complex (pancreatic beta cell) Reactome DB_ID: 400008 Reactome Database ID Release 43400008 Reactome, http://www.reactome.org ReactomeREACT_18564 has a Stoichiometric coefficient of 1 G(q) alpha 11/14/15/Q:G beta:G gamma G(q) alpha:GTP: G beta: G gamma Complex (pancreatic beta cell) Reactome DB_ID: 399987 Reactome Database ID Release 43399987 Reactome, http://www.reactome.org ReactomeREACT_18484 has a Stoichiometric coefficient of 1 Genomic RNA Segment 1 Reactome DB_ID: 188875 Reactome Database ID Release 43188875 Reactome, http://www.reactome.org ReactomeREACT_9275 G(q) alpha 11/14/15/Q:GDP G(q) alpha: GDP Complex (pancreatic beta cell) Reactome DB_ID: 749499 Reactome Database ID Release 43749499 Reactome, http://www.reactome.org ReactomeREACT_23125 has a Stoichiometric coefficient of 1 Genomic RNA Segment 2 Reactome DB_ID: 196492 Reactome Database ID Release 43196492 Reactome, http://www.reactome.org ReactomeREACT_10334 Voltage-gated Calcium Channels Type Cav1 (closed) Converted from EntitySet in Reactome Reactome DB_ID: 400095 Reactome Database ID Release 43400095 Reactome, http://www.reactome.org ReactomeREACT_19083 Genomic RNA Segment 3 Reactome DB_ID: 188826 Reactome Database ID Release 43188826 Reactome, http://www.reactome.org ReactomeREACT_9332 Genomic RNA Segment 8 Reactome DB_ID: 188839 Reactome Database ID Release 43188839 Reactome, http://www.reactome.org ReactomeREACT_9171 Voltage-gated Calcium Channel, L-type 1.2 Reactome DB_ID: 265697 Reactome Database ID Release 43265697 Reactome, http://www.reactome.org ReactomeREACT_17757 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Genomic RNA Segment 4 Reactome DB_ID: 188867 Reactome Database ID Release 43188867 Reactome, http://www.reactome.org ReactomeREACT_9356 Voltage-gated Calcium Channel, L-type, 1.3 Reactome DB_ID: 265559 Reactome Database ID Release 43265559 Reactome, http://www.reactome.org ReactomeREACT_17193 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Genomic RNA Segment 1 Reactome DB_ID: 196480 Reactome Database ID Release 43196480 Reactome, http://www.reactome.org ReactomeREACT_10306 Genomic RNA Segment 4 Reactome DB_ID: 188856 Reactome Database ID Release 43188856 Reactome, http://www.reactome.org ReactomeREACT_9137 Genomic RNA Segment 3 Reactome DB_ID: 196489 Reactome Database ID Release 43196489 Reactome, http://www.reactome.org ReactomeREACT_10406 Wnts Converted from EntitySet in Reactome Reactome DB_ID: 517512 Reactome Database ID Release 43517512 Reactome, http://www.reactome.org ReactomeREACT_21964 p-SPR dimer Reactome DB_ID: 1497817 Reactome Database ID Release 431497817 Reactome, http://www.reactome.org ReactomeREACT_111842 has a Stoichiometric coefficient of 2 SPR dimer Reactome DB_ID: 1497791 Reactome Database ID Release 431497791 Reactome, http://www.reactome.org ReactomeREACT_111821 has a Stoichiometric coefficient of 2 lactate dehydrogenase complex Converted from EntitySet in Reactome Reactome DB_ID: 184549 Reactome Database ID Release 43184549 Reactome, http://www.reactome.org ReactomeREACT_8212 DHFR dimer Reactome DB_ID: 1497822 Reactome Database ID Release 431497822 Reactome, http://www.reactome.org ReactomeREACT_111516 has a Stoichiometric coefficient of 2 unfolded CCT/TriC substrate candidates Converted from EntitySet in Reactome Reactome DB_ID: 391287 Reactome Database ID Release 43391287 Reactome, http://www.reactome.org ReactomeREACT_17372 lactate dehydrogenase A2B2 complex Reactome DB_ID: 70513 Reactome Database ID Release 4370513 Reactome, http://www.reactome.org ReactomeREACT_3502 has a Stoichiometric coefficient of 2 lactate dehydrogenase A3B complex Reactome DB_ID: 70504 Reactome Database ID Release 4370504 Reactome, http://www.reactome.org ReactomeREACT_5380 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 lactate dehydrogenase A4 complex Reactome DB_ID: 70508 Reactome Database ID Release 4370508 Reactome, http://www.reactome.org ReactomeREACT_4780 has a Stoichiometric coefficient of 4 lactate dehydrogenase AB3 complex Reactome DB_ID: 70506 Reactome Database ID Release 4370506 Reactome, http://www.reactome.org ReactomeREACT_3717 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 lactate dehydrogenase B4 complex Reactome DB_ID: 70516 Reactome Database ID Release 4370516 Reactome, http://www.reactome.org ReactomeREACT_3017 has a Stoichiometric coefficient of 4 MPC1:MPC2 Reactome DB_ID: 2512902 Reactome Database ID Release 432512902 Reactome, http://www.reactome.org ReactomeREACT_151201 has a Stoichiometric coefficient of 1 pyruvate dehydrogenase complex Reactome DB_ID: 70070 Reactome Database ID Release 4370070 Reactome, http://www.reactome.org ReactomeREACT_5500 has a Stoichiometric coefficient of 12 has a Stoichiometric coefficient of 20 has a Stoichiometric coefficient of 22 has a Stoichiometric coefficient of 6 palmitoylated, myristoylated eNOS dimer Reactome DB_ID: 535006 Reactome Database ID Release 43535006 Reactome, http://www.reactome.org ReactomeREACT_23116 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 eNOS:Caveolin-1 Reactome DB_ID: 535005 Reactome Database ID Release 43535005 Reactome, http://www.reactome.org ReactomeREACT_22537 has a Stoichiometric coefficient of 1 eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASP Reactome DB_ID: 203648 Reactome Database ID Release 43203648 Reactome, http://www.reactome.org ReactomeREACT_12814 has a Stoichiometric coefficient of 1 eNOS:Caveolin-1:NOSTRIN:dynamin-2:N-WASP Reactome DB_ID: 203629 Reactome Database ID Release 43203629 Reactome, http://www.reactome.org ReactomeREACT_13117 has a Stoichiometric coefficient of 1 NOSTRIN homotrimer Reactome DB_ID: 535013 Reactome Database ID Release 43535013 Reactome, http://www.reactome.org ReactomeREACT_23019 has a Stoichiometric coefficient of 3 GCH1 decamer Reactome DB_ID: 1474144 Reactome Database ID Release 431474144 Reactome, http://www.reactome.org ReactomeREACT_111358 has a Stoichiometric coefficient of 5 GCH1 dimer Reactome DB_ID: 1474143 Reactome Database ID Release 431474143 Reactome, http://www.reactome.org ReactomeREACT_111567 has a Stoichiometric coefficient of 2 PTPS hexamer Reactome DB_ID: 1497879 Reactome Database ID Release 431497879 Reactome, http://www.reactome.org ReactomeREACT_111768 has a Stoichiometric coefficient of 6 p-PTPS hexamer Reactome DB_ID: 1475058 Reactome Database ID Release 431475058 Reactome, http://www.reactome.org ReactomeREACT_111591 has a Stoichiometric coefficient of 6 2GCHFR:GCH1 Reactome DB_ID: 1474149 Reactome Database ID Release 431474149 Reactome, http://www.reactome.org ReactomeREACT_111854 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 alpha-tubulin folding intermediate Converted from EntitySet in Reactome Reactome DB_ID: 391247 Reactome Database ID Release 43391247 Reactome, http://www.reactome.org ReactomeREACT_17069 GCHFR pentamer Reactome DB_ID: 1474155 Reactome Database ID Release 431474155 Reactome, http://www.reactome.org ReactomeREACT_111549 has a Stoichiometric coefficient of 5 eNOS:NOSIP Reactome DB_ID: 203595 Reactome Database ID Release 43203595 Reactome, http://www.reactome.org ReactomeREACT_12699 has a Stoichiometric coefficient of 1 myristoylated eNOS dimer Reactome DB_ID: 203969 Reactome Database ID Release 43203969 Reactome, http://www.reactome.org ReactomeREACT_13272 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 p-S1177-eNOS:CaM:HSP90:p-AKT1:BH2 Reactome DB_ID: 1497889 Reactome Database ID Release 431497889 Reactome, http://www.reactome.org ReactomeREACT_111290 has a Stoichiometric coefficient of 1 p-S1177-eNOS:CaM:HSP90:p-AKT1:BH4 Reactome DB_ID: 1497830 Reactome Database ID Release 431497830 Reactome, http://www.reactome.org ReactomeREACT_111579 has a Stoichiometric coefficient of 1 APT1 homodimer Reactome DB_ID: 203655 Reactome Database ID Release 43203655 Reactome, http://www.reactome.org ReactomeREACT_13023 has a Stoichiometric coefficient of 2 myristoylated eNOS dimer Reactome DB_ID: 203619 Reactome Database ID Release 43203619 Reactome, http://www.reactome.org ReactomeREACT_12833 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 palmitoylated, myristoylated eNOS dimer Reactome DB_ID: 203808 Reactome Database ID Release 43203808 Reactome, http://www.reactome.org ReactomeREACT_23059 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 NOSTRIN homotrimer Reactome DB_ID: 203678 Reactome Database ID Release 43203678 Reactome, http://www.reactome.org ReactomeREACT_12963 has a Stoichiometric coefficient of 3 eNOS:Caveolin-1:NOSTRIN complex Reactome DB_ID: 203758 Reactome Database ID Release 43203758 Reactome, http://www.reactome.org ReactomeREACT_13185 has a Stoichiometric coefficient of 1 eNOS:Caveolin-1:NOSTRIN:Dynamin-2 Reactome DB_ID: 203696 Reactome Database ID Release 43203696 Reactome, http://www.reactome.org ReactomeREACT_12737 has a Stoichiometric coefficient of 1 eNOS:NOSIP Reactome DB_ID: 203623 Reactome Database ID Release 43203623 Reactome, http://www.reactome.org ReactomeREACT_13282 has a Stoichiometric coefficient of 1 eNOS:Caveolin-1:CaM:HSP90 Reactome DB_ID: 202130 Reactome Database ID Release 43202130 Reactome, http://www.reactome.org ReactomeREACT_12971 has a Stoichiometric coefficient of 1 Ca(4)CaM Active Calmodulin Reactome DB_ID: 534997 Reactome Database ID Release 43534997 Reactome, http://www.reactome.org ReactomeREACT_23058 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 eNOS:Caveolin-1:CaM Reactome DB_ID: 202116 Reactome Database ID Release 43202116 Reactome, http://www.reactome.org ReactomeREACT_12757 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 eNOS:Caveolin-1 Reactome DB_ID: 202128 Reactome Database ID Release 43202128 Reactome, http://www.reactome.org ReactomeREACT_12997 has a Stoichiometric coefficient of 1 palmitoylated, myristoylated eNOS dimer Reactome DB_ID: 203639 Reactome Database ID Release 43203639 Reactome, http://www.reactome.org ReactomeREACT_13093 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ChREBP:MLX Reactome DB_ID: 163700 Reactome Database ID Release 43163700 Reactome, http://www.reactome.org ReactomeREACT_2382 has a Stoichiometric coefficient of 1 PP2A-ABdeltaC complex Reactome DB_ID: 165970 Reactome Database ID Release 43165970 Reactome, http://www.reactome.org ReactomeREACT_2369 has a Stoichiometric coefficient of 1 p-S1177-eNOS:CaM:HSP90:p-AKT1 Reactome DB_ID: 202121 Reactome Database ID Release 43202121 Reactome, http://www.reactome.org ReactomeREACT_12662 has a Stoichiometric coefficient of 1 p-S1177-eNOS dimer Reactome DB_ID: 203564 Reactome Database ID Release 43203564 Reactome, http://www.reactome.org ReactomeREACT_12967 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 eNOS:CaM:HSP90 Reactome DB_ID: 202105 Reactome Database ID Release 43202105 Reactome, http://www.reactome.org ReactomeREACT_12871 has a Stoichiometric coefficient of 1 eNOS:CaM:HSP90:p-AKT1 Reactome DB_ID: 202113 Reactome Database ID Release 43202113 Reactome, http://www.reactome.org ReactomeREACT_12902 has a Stoichiometric coefficient of 1 Alternative endo-mannosidase I route Authored: Dall'Olio, GM, 2009-11-10 Cells exposed to castanospermine or 1-deoxynojirimycin (inhibitors of the glucosidase enzymes GCS1 and GANAB), are still able to carry out glycosylation and produce complex glycans. This is due to the existence of an alternative route catalyzed by the enzyme endomannosidase (Moore and Spiro, 1990).<br>Glycoproteins that pass through this route probably skip or have a reduced interaction with the Calnexin/Calreticulin cycle, and are transported to the cis-golgi through a route that has not been described yet (probably through the general ER to Golgi flow). Here, the Endomannosidase enzyme, which resides on the Golgi membrane (Hardt et al 2005; Hamilton et al 2005) is able to remove the tri-, di-, or mono-glucose substituted mannose on branch A, leading to a deglucosylated N-glycan structure (Lubas and Spiro, 1988). EC Number: 3.2.1.130 Edited: Jassal, B, 2010-09-17 Pubmed15677381 Pubmed15760709 Pubmed2165493 Pubmed3346233 Reactome Database ID Release 43964759 Reactome, http://www.reactome.org ReactomeREACT_25136 Reviewed: Gagneux, P, 2010-11-18 has a Stoichiometric coefficient of 3 Adaptor protein complex 2 (AP-2) large adaptins Converted from EntitySet in Reactome Reactome DB_ID: 182144 Reactome Database ID Release 43182144 Reactome, http://www.reactome.org ReactomeREACT_11491 Vesicle Uncoating Authored: Gillespie, ME, 2007-07-13 20:42:29 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jupe, S, 2010-11-12 Pubmed10825291 Pubmed10982397 Pubmed17316621 Reactome Database ID Release 43203996 Reactome, http://www.reactome.org ReactomeREACT_12456 Reviewed: Gagneux, P, 2010-11-18 Vesicle uncoating is triggered by Sar1p-GTP hydrolysis leaving only the vesicle cargo and the v-SNARE to target the vesicle to the Golgi membrane. Progressive trimming of alpha-1,2-linked mannose residues from Man8GlcNAc2 to produce Man5GlcNAc2 Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.113 Edited: Jassal, B, 2010-09-17 In the cis-Golgi, Man7, Man8 or Man9 N-glycans are progressively trimmed to Man5 N-glycans. The reaction can be catalyzed by one of three known mannosidases, expressed in different tissues and with slightly different affinity. These enzymes trim the mannoses in a different order (Tremblay and Herscovics, 2000), but produce the same output with 5 mannoses.<br>A small confusion on the nomenclature of these genes coding for these enzymes is present in the literature: the standard HGNC symbols are MAN1A1, MAN1A2, MAN1C1, but MAN1A2 is also referred to as MAN1B in certain publications, while MAN1B1 is the enzyme acting in the ERQC compartment on unfolded glycoproteins. Moreover, the names do not correspond to a preference of these enzymes for which of the three mannose branches these trim first. Pubmed10915796 Reactome Database ID Release 43964825 Reactome, http://www.reactome.org ReactomeREACT_25205 Reviewed: Gagneux, P, 2010-11-18 has a Stoichiometric coefficient of 3 Progressive trimming of alpha-1,2-linked mannose residues from Man9GlcNAc2 to produce Man5GlcNAc2 Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.113 Edited: Jassal, B, 2010-09-17 In the cis-Golgi, Man7, Man8 or Man9 N-glycans are progressively trimmed to Man5 N-glycans. The reaction can be catalyzed by one of three known mannosidases, expressed in different tissues and with slightly different affinity. These enzymes trim the mannoses in a different order (Tremblay and Herscovics, 2000), but produce the same output with 5 mannoses.<br>A small confusion on the nomenclature of these genes coding for these enzymes is present in the literature: the standard HGNC symbols are MAN1A1, MAN1A2, MAN1C1, but MAN1A2 is also referred to as MAN1B in certain publications, while MAN1B1 is the enzyme acting in the ERQC compartment on unfolded glycoproteins. Moreover, the names do not correspond to a preference of these enzymes for which of the three mannose branches these trim first. Pubmed10915796 Reactome Database ID Release 43964737 Reactome, http://www.reactome.org ReactomeREACT_25341 Reviewed: Gagneux, P, 2010-11-18 has a Stoichiometric coefficient of 4 Loss of Sar1b GTPase Authored: Gillespie, ME, 2007-07-13 20:42:29 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Gillespie, ME, 2007-11-21 20:48:45 Pubmed10825291 Pubmed10982397 Pubmed17316621 Reactome Database ID Release 43203971 Reactome, http://www.reactome.org ReactomeREACT_12396 Reviewed: Gagneux, P, 2010-11-18 Sar1p-GTP hydrolysis is increased 15-30-fold by Sec23p. Sar1p-GDP is released as a result of this hydrolysis and used in further vesicle sculpting cycles. Sar1p-GTP hydrolysis occurs at two critical points during the cycle, first (as represented here) as a proofreading step, insuring that the cargo is loaded. Later in the cycle Sar1p-GTP hydrolysis triggers the uncoating of the budded vesicle. Coat Assembly Authored: Gillespie, ME, 2007-07-13 20:42:29 Pubmed10825291 Pubmed10982397 Reactome Database ID Release 43203979 Reactome, http://www.reactome.org ReactomeREACT_12393 Reviewed: Gagneux, P, 2010-11-18 Sar1p-GTP recruits the cytoplasmic Sec23p-Sec24p complex. Though not represented in the subsequent steps, Sec23p-Sec24p would bind to members of the p24 protein family of possible cargo receptors, and together with Sar1p bind the appropiate v-SNARE, and Rab-GTP. Vesicle Budding Authored: Gillespie, ME, 2007-07-13 20:42:29 Edited: Jassal, B, 2010-11-18 Once loaded the vesicles become fully sculpted, pinch off from the ER and bud into the cytosol. Pubmed10825291 Pubmed10982397 Reactome Database ID Release 43203973 Reactome, http://www.reactome.org ReactomeREACT_12610 Reviewed: Gagneux, P, 2010-11-18 Cargo, Sec31p:Sec13p, and v-SNARE recruitment Authored: Gillespie, ME, 2007-07-13 20:42:29 Cytosolic Sec13p-Sec31p complexes bind to pre-bound Sec23p-Sec24p complexes. Edited: Jassal, B, 2010-11-17 Pubmed10825291 Pubmed10982397 Reactome Database ID Release 43204008 Reactome, http://www.reactome.org ReactomeREACT_12422 Reviewed: Gagneux, P, 2010-11-18 Addition of GlcNAc to the glycan on the A arm Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.101 Edited: Jassal, B, 2010-09-17 Pubmed1702225 Pubmed1827260 Reactome Database ID Release 43964768 Reactome, http://www.reactome.org ReactomeREACT_25236 Reviewed: Gagneux, P, 2010-11-18 This is the first committed step in the synthesis of complex and hybrid N-glycans and is specific to multicellular organisms (Kumar et al, 1990; Hull et al, 1991). Hybri N-glycans are important for inter-cellular interactions and therefore during embryonic development of multicellular organisms, and it is probable that these pathways have evolved just before the emergence of multicellular organisms. Support for this hypothesis is provided by the phenomena of CDG and by the effects of null mutations in C.elegans. AMPK heterotrimer:AMP Reactome DB_ID: 163747 Reactome Database ID Release 43163747 Reactome, http://www.reactome.org ReactomeREACT_4802 has a Stoichiometric coefficient of 1 Progressive trimming of alpha-1,2-linked mannose residues from Man7GlcNAc2 to produce Man5GlcNAc2 Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.113 Edited: Jassal, B, 2010-09-17 In the cis-Golgi, Man7, Man8 or Man9 N-glycans are progressively trimmed to Man5 N-glycans. The reaction can be catalyzed by one of three known mannosidases, expressed in different tissues and with slightly different affinity. These enzymes trim the mannoses in a different order (Tremblay and Herscovics, 2000), but produce the same output with 5 mannoses.<br>A small confusion on the nomenclature of these genes coding for these enzymes is present in the literature: the standard HGNC symbols are MAN1A1, MAN1A2, MAN1C1, but MAN1A2 is also referred to as MAN1B in certain publications, while MAN1B1 is the enzyme acting in the ERQC compartment on unfolded glycoproteins. Moreover, the names do not correspond to a preference of these enzymes for which of the three mannose branches these trim first. Pubmed10915796 Reactome Database ID Release 43964830 Reactome, http://www.reactome.org ReactomeREACT_25217 Reviewed: Gagneux, P, 2010-11-18 has a Stoichiometric coefficient of 2 Activated AMPK heterotrimer Reactome DB_ID: 163736 Reactome Database ID Release 43163736 Reactome, http://www.reactome.org ReactomeREACT_5306 has a Stoichiometric coefficient of 1 AMPK gamma2:AMP Reactome DB_ID: 164188 Reactome Database ID Release 43164188 Reactome, http://www.reactome.org ReactomeREACT_4963 has a Stoichiometric coefficient of 1 Addition of a bifurcating GlcNAc to the N-glycan by MGAT3 Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.144 Edited: Jassal, B, 2010-10-08 Pubmed12417419 Pubmed20395209 Reactome Database ID Release 43975926 Reactome, http://www.reactome.org ReactomeREACT_25005 Reviewed: Gagneux, P, 2010-11-18 The addition of a bisecting GlcNAc to a complex N-glycan by MGAT3 is one of the most important regulatory steps in N-glycosylation, directing the pathway toward the synthesis of complex and hybrid N-glycans. This addition changes the structure of the N-glycan and inhibits further modification by MGAT2, MGAT4, MGAT5A/B and FUT8. Defects in MGAT3 have been shown to be associated with predisposition to cancer and several developmental defects (Song et al 2010; Stanley 2002). Addition of alpha-2,8-sialic acid to N-glycan over a galactose by ST8SIAs Addition of sialic acid to galactose-containing N-glycan. Sialic acid is usually found at terminal positions of the N-glycan. This imparts a negative charge at neutral pH this adds a negative charge which affects the chemico-physical and biological properties of the N-glycans (for a review, see Schauer R 2000); moreover, this modification can lead to the addition of extraordinarily long antennae such as polysialic acid (hundreds of sials) or poly lactosamine repeats (dozens of disaccharide repeats) (Harduin-Lepers A, 2001), while the number of modifications on the antennae of N-glycans is usually lower.<br>There are over 20 sialyltransferases known in humans, 5 of which are known to act on N-glycans. ST6Gal I (ST6GAL1) is the only alpha-2,6-sialyltransferase known to transfer sialic acid to galactose on N-Glycans (Dall'Olio F, 2000). A second beta-Galactoside alpha-2,6-sialyltransferase has been characterized, but this enzyme acts mainly on oligosaccharides (Krzewinski-Recchi MA et al 2003). Sialic acids can also be added via an alpha-2,3-linkage to galactose on N-glycans by ST3GalIV(ST3GAL4) (Ellies et al 2002). ST8Sia II (ST8SIA2), ST8Sia III (ST8SIA3), and ST8Sia IV (ST8SIA6) have alpha-2,8-activity (Angata K et al 1997; Angata et al 2000; Angata K, Fuduka M 2003). Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.99.8 Edited: Jassal, B, 2010-10-08 Pubmed10766765 Pubmed11421344 Pubmed11425186 Pubmed11530204 Pubmed12097641 Pubmed12603328 Pubmed12765789 Pubmed9054414 Reactome Database ID Release 431022133 Reactome, http://www.reactome.org ReactomeREACT_25115 Reviewed: Gagneux, P, 2010-11-18 Addition of alpha-2,6-sialic acid to terminal galactose of N-glycans by ST6GAL1 Addition of sialic acid to galactose-containing N-glycan. Sialic acid is usually found at terminal positions of the N-glycan. This imparts a negative charge at neutral pH this adds a negative charge which affects the chemico-physical and biological properties of the N-glycans (for a review, see Schauer R 2000); moreover, this modification can lead to the addition of extraordinarily long antennae such as polysialic acid (hundreds of sials) or poly lactosamine repeats (dozens of disaccharide repeats) (Harduin-Lepers A, 2001), while the number of modifications on the antennae of N-glycans is usually lower.<br>There are over 20 sialyltransferases known in humans, 5 of which are known to act on N-glycans. ST6Gal I (ST6GAL1) is the only alpha-2,6-sialyltransferase known to transfer sialic acid to galactose on N-Glycans (Dall'Olio F, 2000). A second beta-Galactoside alpha-2,6-sialyltransferase has been characterized, but this enzyme acts mainly on oligosaccharides (Krzewinski-Recchi MA et al 2003). Sialic acids can also be added via an alpha-2,3-linkage to galactose on N-glycans by ST3GalIV(ST3GAL4) (Ellies et al 2002). ST8Sia II (ST8SIA2), ST8Sia III (ST8SIA3), and ST8Sia IV (ST8SIA6) have alpha-2,8-activity (Angata K et al 1997; Angata et al 2000; Angata K, Fuduka M 2003). Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.99.1 Edited: Jassal, B, 2010-10-08 Pubmed10766765 Pubmed11421344 Pubmed11425186 Pubmed11530204 Pubmed12097641 Pubmed12603328 Pubmed12765789 Pubmed9054414 Reactome Database ID Release 43975902 Reactome, http://www.reactome.org ReactomeREACT_24990 Reviewed: Gagneux, P, 2010-11-18 Addition of galactose by beta 4-galactosyltransferases Addition of a galactose residue on N-acetylglucosamine. The family of beta 4-galactosyltransferases is composed by at least six known members with different K(m) and acceptor specifities (Guo S et al, 2001) and probably originated by duplication (Lo NW et al, 1998). B4GALT1 is associated with Congenital Disorder of Glycosylation of type IId (Hansske B et al, 2002), and is expressed as two splicing isoforms of which only one is localizated in the Golgi system (Lopez LC et al, 1991; Schaub BE et al, 2006). B4GALT2 is key in the regulation of proteins involved in neuronal development (Sasaki N et <br>al, 2005). Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.38 Edited: Jassal, B, 2010-10-08 Pubmed11588157 Pubmed11901181 Pubmed15939404 Pubmed17021253 Pubmed1714903 Pubmed9597550 Reactome Database ID Release 43975919 Reactome, http://www.reactome.org ReactomeREACT_25178 Reviewed: Gagneux, P, 2010-11-18 Addition of GlcNAc to position 5 by MGAT5 Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.155 Edited: Jassal, B, 2010-10-08 N-acetylglucosaminyltransferase (GnT)-V catalyzes the addition of GlcNAc beta 1,4 on the GlcNAc beta1,2 Man,alpha1,6 arm of complex type N-Glycans (Park C et al, 1999; Granowski M et al, 2000; Wang L et al, 2007). The activity of MGAT5 competes with MGAT3 (Pinho SS et al, 2009) and is associated with gastric cancer (Tian H et al, 2008) and multiple sclerosis (Brynedal B et al, 2010). Pubmed10395745 Pubmed10700233 Pubmed16924681 Pubmed18931531 Pubmed19403558 Pubmed20117844 Reactome Database ID Release 43975916 Reactome, http://www.reactome.org ReactomeREACT_25314 Reviewed: Gagneux, P, 2010-11-18 Addition of GlcNAc to position 4 by N-acetylglucosaminyltransferase (GnT)-IV Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.145 Edited: Jassal, B, 2010-10-08 N-acetylglucosaminyltransferase (GnT)-IV catalyzes the addition of GlcNAc beta,1,4 on the GlcNAc beta1,2 Man,alpha1,3 arm of both complex and hybrid N-glycans (Oguri S et al, 2006). Two human GnT-IV isozymes have been characterized (MGAT4A, MGAT4B) , plus a putative MGAT4C on chromosome 2 (Furukawa T et al, 1999). Aberrant expression of MGAT4A or MGAT4B is associated with pancreatic cancer (Ide Y et al, 2006; Kudo T et al , 2007) Pubmed10570912 Pubmed16434023 Pubmed17006639 Pubmed17488527 Reactome Database ID Release 43975903 Reactome, http://www.reactome.org ReactomeREACT_25009 Reviewed: Gagneux, P, 2010-11-18 Addition of alpha 1,6 fucose to the first GlcNAc of the N-glycan Addition of a fucose moiety as an alpha 1-6 linkage to the first GlcNAc <br>residue of the N-glycan (Clarke JL, Watkins WM 1999; Yamaguchi Y et <br>al, 1999; Yamaguchi Y et al 2000). Authored: Dall'Olio, GM, 2010-11-18 EC Number: 2.4.1.68 Edited: Jassal, B, 2010-11-18 Pubmed10343104 Pubmed10814706 Pubmed9949196 Reactome Database ID Release 431028788 Reactome, http://www.reactome.org ReactomeREACT_25399 Reviewed: Gagneux, P, 2010-11-18 Addition of a GlcNAc on the alpha 1,4 branch by MGAT2 Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.143 Edited: Jassal, B, 2010-10-04 Pubmed12417412 Pubmed7635144 Pubmed8808595 Reactome Database ID Release 43975829 Reactome, http://www.reactome.org ReactomeREACT_25253 Reviewed: Gagneux, P, 2010-11-18 The addition of a GlcNAc on the alpha,1,6 mannose on the alpha,1,4 branch is required for the synthesis of complex N-glycans (Tan J et al, 1995). Defects in this gene are associated with Congenital Disorder of Glycosylation type IIa (Tan J et al, 1996; Wang Y et al, 2002). Trimming of mannoses on the alpha1,6 arm by MAN2A1 Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.2.1.114 Edited: Jassal, B, 2010-10-04 Pubmed16754854 Pubmed17466984 Pubmed8524845 Reactome Database ID Release 43975814 Reactome, http://www.reactome.org ReactomeREACT_25047 Reviewed: Gagneux, P, 2010-11-18 The removal of mannoses on the alpha,1,6 arm by MAN2A1 or MAN2A2 is required for efficient formation of complex-type N-glycans (Misago M et al, 1995; Crispin M et al, 2007). These two enzymes carry out the same function and the disruption of both inhibits the formation of complex N-glycans in vivo (Akama TO et al, 2006). has a Stoichiometric coefficient of 2 AP-1 mu Converted from EntitySet in Reactome Reactome DB_ID: 167716 Reactome Database ID Release 43167716 Reactome, http://www.reactome.org ReactomeREACT_11565 Addition of alpha-2,3-sialic acid to N-glycan over a galactose by ST3GAL4 Addition of sialic acid to galactose-containing N-glycan. Sialic acid is usually found at terminal positions of the N-glycan. This imparts a negative charge at neutral pH this adds a negative charge which affects the chemico-physical and biological properties of the N-glycans (for a review, see Schauer R 2000); moreover, this modification can lead to the addition of extraordinarily long antennae such as polysialic acid (hundreds of sials) or poly lactosamine repeats (dozens of disaccharide repeats) (Harduin-Lepers A, 2001), while the number of modifications on the antennae of N-glycans is usually lower.<br>There are over 20 sialyltransferases known in humans, 5 of which are known to act on N-glycans. ST6Gal I (ST6GAL1) is the only alpha-2,6-sialyltransferase known to transfer sialic acid to galactose on N-Glycans (Dall'Olio F, 2000). A second beta-Galactoside alpha-2,6-sialyltransferase has been characterized, but this enzyme acts mainly on oligosaccharides (Krzewinski-Recchi MA et al 2003). Sialic acids can also be added via an alpha-2,3-linkage to galactose on N-glycans by ST3GalIV(ST3GAL4) (Ellies et al 2002). ST8Sia II (ST8SIA2), ST8Sia III (ST8SIA3), and ST8Sia IV (ST8SIA6) have alpha-2,8-activity (Angata K et al 1997; Angata et al 2000; Angata K, Fuduka M 2003). Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.99.4 Edited: Jassal, B, 2010-10-08 Pubmed10766765 Pubmed11421344 Pubmed11425186 Pubmed11530204 Pubmed12097641 Pubmed12603328 Pubmed12765789 Pubmed9054414 Reactome Database ID Release 431022129 Reactome, http://www.reactome.org ReactomeREACT_25121 Reviewed: Gagneux, P, 2010-11-18 unfolded alpha/beta tubulin Converted from EntitySet in Reactome Reactome DB_ID: 390461 Reactome Database ID Release 43390461 Reactome, http://www.reactome.org ReactomeREACT_18238 beta-tubulin folding intermediate Converted from EntitySet in Reactome Reactome DB_ID: 391244 Reactome Database ID Release 43391244 Reactome, http://www.reactome.org ReactomeREACT_17996 VPU protein Converted from EntitySet in Reactome Reactome DB_ID: 180531 Reactome Database ID Release 43180531 Reactome, http://www.reactome.org ReactomeREACT_9099 bile salts Converted from EntitySet in Reactome Reactome DB_ID: 193416 Reactome Database ID Release 43193416 Reactome, http://www.reactome.org ReactomeREACT_10276 Renin Hydrolyzes Angiotensinogen to Yield Angiotensin I Authored: May, B, 2011-11-19 EC Number: 3.4.23 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed12045255 Pubmed12927775 Pubmed20380117 Pubmed22193701 Pubmed4289389 Pubmed4322712 Pubmed4330891 Pubmed4360430 Reactome Database ID Release 432022412 Reactome, http://www.reactome.org ReactomeREACT_147869 Renin Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10) Renin in the bloodstream hydrolyzes angiotensinogen to yield angiotensin-(1-10) (angiotensin I). Renin is produced in the juxtaglomerular cells of the kidney in response to reduced blood pressure. Aliskiren, a drug used clinically to treat hypertension, inhibits this reaction (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009). Reviewed: Joseph, J, 2012-08-06 bile salts Converted from EntitySet in Reactome Reactome DB_ID: 193448 Reactome Database ID Release 43193448 Reactome, http://www.reactome.org ReactomeREACT_10834 Renin:Prorenin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10) Authored: May, B, 2011-11-19 EC Number: 3.4.23 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed12045255 Pubmed12927775 Pubmed22193701 Reactome Database ID Release 432022403 Reactome, http://www.reactome.org ReactomeREACT_147891 Renin Bound to Renin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin I Renin bound to the (pro)renin receptor (ATP6AP2) hydrolyzes angiotensinogen to yield angiotensin-(1-10) (angiotensin I) (Nguyen et al. 2002). Binding to the (pro)renin receptor increases the catalytic efficiency of renin 4-fold (Nguyen et al. 2002). Aliskiren, a drug used clinically to treat hypertension, inhibits cleavage of angiotensinogen by renin (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009). Reviewed: Joseph, J, 2012-08-06 MPP Cleaves Presequence of Matrix Precursors As inferred from yeast, the alpha subunit of the mitochondrial processing peptidase (MPP) binds presequences of mitochondrial precursors and the beta subunit cleaves the presequence. After cleavage, proteins destined for the matrix are drawn into the matrix by ATP-dependent interaction with mtHSP70 (HSPA9, homolog of yeast SSC1) of the PAM complex. Authored: May, B, 2011-05-21 EC Number: 3.4.24 Edited: May, B, 2011-05-21 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431299478 Reactome, http://www.reactome.org ReactomeREACT_118803 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 TIMM23 PAM Imports Proteins to Mitochondrial Matrix As inferred from the yeast TIM23 complex, the human TIMM23 complex transports precursor proteins across the inner membrane and into the matrix. As in yeast, subunits TIMM50, TIMM17, and TIMM23 are probably necessary for initiating translocation while the PAM complex with mtHSP70 (HSPA9, yeast SSC1) provides the motive force that drives the transport. mtHSP70 binding to the precursor pulls the protein into the matrix in a reaction requiring ATP hydrolysis. The yeast reaction appears to use a Brownian ratchet mechanism (Yamano et al. 2008).<br>In yeast experimentally verified substrates of TIM23 PAM include Hsp60 (HSP60 in human) and Yfh1 (Frataxin, FXN in human). Many other matrix proteins are believed to be substrates of the TIMM23 complex Authored: May, B, 2011-05-21 Edited: May, B, 2011-05-21 Pubmed18174896 Pubmed18678864 Pubmed19453276 Reactome Database ID Release 431299475 Reactome, http://www.reactome.org ReactomeREACT_118696 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 TIMM23 SORT Inserts Proteins into Inner Membrane As inferred from the yeast TIM23 complex, the human TIMM23 complex resides in the inner membrane of the mitochondrion and transfers precursor proteins to the inner membrane. The presequences of proteins targeted to the inner membrane are transferred to the matrix where they are cleaved. Sequences in the mature regions of the proteins then interact with the TIMM23 complex to halt transfer across the inner membrane and the proteins are released laterally into the inner membrane. TIMM21 is required.<br>In yeast experimentally verified substrates of the TIM23 complex targeted to the inner membrane include CYB2, DLD (LDHD in human), ATP9 (ATP5G1 in human), COQ2, TIM54 (TIMM54 in human), COX4, COX5A, and ATP2 (ATP5B in human). Many other inner membrane proteins are believed to be substrates of the TIMM23 complex. Authored: May, B, 2011-05-21 Edited: May, B, 2011-05-21 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431299482 Reactome, http://www.reactome.org ReactomeREACT_118571 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 Precursor Proteins Enter TIMM23 PAM As inferred from the yeast TIM23 complex, the human TIMM23 complex resides in the inner membrane of the mitochondrion and transfers precursor proteins to the matrix. The TIMM23 complex appears to adopt different configurations (and perhaps different subunit compositions) depending on whether the substrate is destined for the inner membrane or the matrix. Here we refer to the TIMM23 PAM complex as the configuration that delivers inner membrane proteins. The PAM17 subcomplex is required for this activity. The N-terminal presequence of precursors first interacts with TIMM50 and TIMM23. The TIMM17 and TIMM23 subunits form a channel and are required to initiate translocation of precursors.<br> In yeast experimentally verified substrates of TIM23:PAM include Hsp60 (HSP60 in human) and Yfh1 (Frataxin, FXN in human). Many other matrix proteins are believed to be substrates of the TIMM23 complex. Authored: May, B, 2011-05-21 Edited: May, B, 2011-05-21 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431299480 Reactome, http://www.reactome.org ReactomeREACT_118832 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 MPP Cleaves Presequence of Inner Membrane Precursors As inferred from yeast, the alpha subunit of the mitochondrial processing peptidase (MPP) binds presequences of mitochondrial precursors and the beta subunit cleaves the presequence. After cleavage, proteins destined for the inner membrane are released laterally from TIMM23 SORT into the membrane. Authored: May, B, 2011-05-21 EC Number: 3.4.24 Edited: May, B, 2011-05-21 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431299476 Reactome, http://www.reactome.org ReactomeREACT_118813 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 Precursor Proteins Enter TIMM23 SORT As inferred from the yeast TIM23 complex, the human TIMM23 complex resides in the inner membrane of the mitochondrion and transfers precursor proteins to the inner membrane. The TIMM23 complex appears to adopt different configurations (and perhaps different subunit compositions) depending on whether the substrate is destined for the inner membrane or the matrix. Here we refer to the TIMM23 SORT complex as the configuration that delivers inner membrane proteins. The TIMM21 subunit is required for this activity. In yeast, the N-terminal presequences of precursors first interact with TIM50 and TIM23 (TIMM50 and TIMM23 in human). The TIM17 and TIM23 subunits (TIMM17 and TIMM23 in human) form a channel and are required to initiate translocation of precursors.<br>In yeast experimentally verified substrates of the TIM23 SORT complex targeted to the inner membrane include CYB2, DLD (LDHD in human), ATP9 (ATP5G1 in human), COQ2, TIM54 (TIMM54 in human), COX4, COX5A, and ATP2 (ATP5B in human). Many other inner membrane proteins are believed to be substrates of the TIMM23 complex. Authored: May, B, 2011-05-21 Edited: May, B, 2011-05-21 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431299487 Reactome, http://www.reactome.org ReactomeREACT_118623 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 TIMM22 Inserts Proteins into Inner Membrane As inferred from the yeast TIM22 complex, human TIMM22 inserts precursor proteins into the inner membrane of the mitochondrion. The precursors are hydrophobic and may be chaperoned to TIMM22 by small TIM proteins (TIMM10, TIMM12) of the intermembrane space. In yeast, experimentally verified substrates of the TIM22 complex include AAC (ADP/ATP translocase 1, ANT, SLC25A4 in human), PIC, TIM22 (TIMM22 in human), and TIM23 (TIMM23 in human). Many other inner membrane proteins are anticipated to be substrates ofthe TIMM22 complex. Authored: May, B, 2011-05-23 Edited: May, B, 2011-05-23 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431307803 Reactome, http://www.reactome.org ReactomeREACT_118820 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 SAM50 Complex Inserts Proteins into Mitochondrial Outer Membrane As inferred from the yeast SAM50 complex, the human SAMM50 Complex (SAM50 complex, TOB55 complex) inserts mainly beta-barrel proteins into the outer membrane after they have passed from the cytosol, through the TOMM40:TOMM70 complex, and into the intermembrane space.<br>In yeast, experimentally verified substrates of the SAM50 complex include TOM40 (TOMM40 in human), MDM10, Porin1 (VDAC1 in human), and TOM22 (TOMM22 in human). In humans, TOMM40 (Humphries et al. 2005) and VDAC1 (Kozjak-Pavlovic et al. 2007, homologous to yeast Porin1) have been shown to be substrates. Many other mitochondrial proteins are anticipated to be substrates of the SAMM50 complex. Authored: May, B, 2011-05-03 Edited: May, B, 2011-05-03 Pubmed15644312 Pubmed17510655 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431268025 Reactome, http://www.reactome.org ReactomeREACT_118792 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 chenodeoxycholate bile salts Converted from EntitySet in Reactome Reactome DB_ID: 193453 Reactome Database ID Release 43193453 Reactome, http://www.reactome.org ReactomeREACT_10485 Neprilysin Hydrolyzes Angiotensin I to Yield Angiotensin-(1-7) Authored: May, B, 2011-11-19 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Neprilysin Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-7) Neprilysin hydrolyzes angiotensin-(1-10) (angiotensin I) directly to angiotensin-(1-7) (Rice et al. 2004). Pubmed15283675 Reactome Database ID Release 432022396 Reactome, http://www.reactome.org ReactomeREACT_147787 Reviewed: Joseph, J, 2012-08-06 Cathepsin Z (Cathepsin X) Hydrolyzes Angiotensin I to Yield Angiotensin II Authored: May, B, 2011-11-19 Cathepsin Z (Cathepsin X) Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8) Cathepsin Z (cathepsin X) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Nagler et al. 2010). Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed19800993 Reactome Database ID Release 432022381 Reactome, http://www.reactome.org ReactomeREACT_147799 Reviewed: Joseph, J, 2012-08-06 ACE2 Hydrolyzes Angiotensin I to Yield Angiotensin-(1-9) ACE2 Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-9) Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-9) (Donoghue et al. 2000, Tipnis et al. 2000, Vickers et al. 2002, Rice t al. 2004). The activity of ACE2 on angiotensin I is weak (Rice et al. 2004), being 400-fold lower than the activity of ACE2 on angiotensin II (Vickers et al. 2002). Authored: May, B, 2011-11-19 EC Number: 3.4.17 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed10924499 Pubmed10969042 Pubmed11815627 Pubmed15283675 Reactome Database ID Release 432022378 Reactome, http://www.reactome.org ReactomeREACT_147733 Reviewed: Joseph, J, 2012-08-06 ACE Hydrolyzes Angiotensin-(1-9) to Yield Angiotensin-(1-7) Angiotensin-converting enzyme (ACE) hydrolyzes angiotensin-(1-9) to yield angiotensin-(1-7) (Rice et al. 2004). Authored: May, B, 2011-11-19 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed15283675 Reactome Database ID Release 432022398 Reactome, http://www.reactome.org ReactomeREACT_147855 Reviewed: Joseph, J, 2012-08-06 Neprilysin Hydrolyzes Angiotensin-(1-9) to Yield Angiotensin-(1-7) Authored: May, B, 2011-11-19 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Neprilysin hydrolyzes angiotensin-(1-9) to yield angiotensin-(1-7) (Rice et al. 2004). The hydrolysis of angiotensin-(1-9) catalyzed by neprilysin is more efficient than that catalyzed by angiotensin-converting enzyme (ACE) (Rice et al. 2004). Pubmed15283675 Reactome Database ID Release 432022368 Reactome, http://www.reactome.org ReactomeREACT_147762 Reviewed: Joseph, J, 2012-08-06 Secreted ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8) Authored: May, B, 2011-11-19 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed10536878 Pubmed12540854 Pubmed1848554 Pubmed1851160 Pubmed2558510 Pubmed3017438 Pubmed6269175 Pubmed6270633 Reactome Database ID Release 432065355 Reactome, http://www.reactome.org ReactomeREACT_147705 Reviewed: Joseph, J, 2012-08-06 Secreted Angiotensin-converting Enzyme Hydrolyzes Angiotensin I to Yield Angiotensin II Secreted angiotensin-converting enzyme (ACE) cleaves 2 amino acid residues from the C-terminus of angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Wei et al. 1991). This reaction is inhibited by drugs used to treat hypertension (angiotensin converting enzyme inhibitors, ACEI) including captopril (Gronhagen-Riska and Fyhrquist 1980, Stewart et al. 1981, Ehlers et al. 1986, Hayakari et al. 1989, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), enalaprilat (metablized from the prodrug enalapril, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), lisinopril ( Ehlers et al. 1991, Natesh et al. 2003), and ramiprilat (metabolized from the prodrug ramipril, Baudin and Beneteau-Burnat 1999). ACE is secreted ("shed") from membranes of endothelial cells by cleavage in the C-terminal region that removes the membrane anchor. ACE Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8) Angiotensin-converting Enzyme Hydrolyzes Angiotensin I to Yield Angiotensin II Angiotensin-converting enzyme (ACE) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Ehlers and Kirsch 1988). ACE is found at the plasma membrane of endothelial cells. This reaction is inhibited by drugs used to treat hypertension (angiotensin converting enzyme inhibitors, ACEI) including captopril (Gronhagen-Riska and Fyhrquist 1980, Stewart et al. 1981, Ehlers et al. 1986, Hayakari et al. 1989, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), enalaprilat (metablized from the prodrug enalapril, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), lisinopril ( Ehlers et al. 1991, Natesh et al. 2003), and ramiprilat (metabolized from the prodrug ramipril, Baudin and Beneteau-Burnat 1999). Authored: May, B, 2011-11-19 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed10536878 Pubmed12540854 Pubmed1668266 Pubmed1848554 Pubmed1851160 Pubmed2558510 Pubmed2846041 Pubmed3017438 Pubmed6269175 Pubmed6270633 Reactome Database ID Release 432022405 Reactome, http://www.reactome.org ReactomeREACT_147747 Reviewed: Joseph, J, 2012-08-06 Cathepsin G Hydrolyzes Angiotensin I to Yield Angiotensin II Authored: May, B, 2011-11-19 Cathepsin G Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-8) Cathepsin G hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Reilly et al. 1982, Owen and Campbell 1998, Raymond et al. 2010). Cathepsin bound to the plasma membrane of neutrophils has a higher activity than does soluble cathepsin G (Owen and Campbell 1998). EC Number: 3.4.21 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed20889553 Pubmed6807977 Pubmed9570564 Reactome Database ID Release 432022411 Reactome, http://www.reactome.org ReactomeREACT_147744 Reviewed: Joseph, J, 2012-08-06 bile salts Converted from EntitySet in Reactome Reactome DB_ID: 193479 Reactome Database ID Release 43193479 Reactome, http://www.reactome.org ReactomeREACT_11011 Chymase Hydrolyzes Angiotensin I to Yield Angiotensin II Authored: May, B, 2011-11-19 Chymase Hydrolyzes Angiotensin-(1-10) to Yields Angiotensin-(1-8) Chymase hydrolyzes angiotensin-(1-10) (angiotensin) to yield angiotensin-(1-8) (angiotensin II) at a higher rate than does angiotensin-converting enzyme (Reilly et al. 1982, Urata et al. 1990, Caughey et al. 2000, Richard et al. 2001). Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed10899625 Pubmed11502696 Pubmed2266130 Pubmed6807977 Reactome Database ID Release 432022383 Reactome, http://www.reactome.org ReactomeREACT_147760 Reviewed: Joseph, J, 2012-08-06 Prorenin:Prorenin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin-(1-10) Authored: May, B, 2011-11-19 EC Number: 3.4.23 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Prorenin Bound to Renin Receptor Hydrolyzes Angiotensinogen to Yield Angiotensin I Pubmed12045255 Pubmed12927775 Pubmed22193701 Reactome Database ID Release 432065357 Reactome, http://www.reactome.org ReactomeREACT_147720 Reviewed: Joseph, J, 2012-08-06 The binding of prorenin to the (pro)renin receptor activates the protease activity of prorenin, which can then hydrolyze angiotensinogen to yield angiotensin-(1-10) (angiotensin I) (Nguyen et al. 2002). Prorenin is inactive when not bound to the (pro)renin receptor. Aliskiren, a drug used clinically to treat hypertension, inhibits the cleavage of angiotensinogen by renin (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009). Addition of GlcNAc to Core 3 forms a Core 4 glycoprotein Authored: Jassal, B, 2010-07-19 EC Number: 2.4.1.102 Edited: Jassal, B, 2010-07-19 Pubmed9915862 Pubmed9988682 Reactome Database ID Release 43914018 Reactome, http://www.reactome.org ReactomeREACT_115554 Reviewed: Ferrer, A, 2011-11-04 The glycosyltransferase GCNT3 mediates core 2 and core 4 O-glycan branching (Yeh et al, 1999; Schwientek et al, 1999). Addition of GlcNAc to the Tn antigen via an alpha-1,3 linkage forms a Core 5 glycoprotein An unknown N-acetylglucosaminyltransferase mediates the transfer of GlcNAc to Tn antigens via an alpha-1,3 linkage to create Core 5 mucins (Brockhausen et al. 2009). Authored: Jassal, B, 2010-07-19 Edited: Jassal, B, 2010-07-19 ISBN9780879697709 Reactome Database ID Release 43914005 Reactome, http://www.reactome.org ReactomeREACT_115664 Reviewed: Ferrer, A, 2011-11-04 Addition of GlcNAc to the T antigen forms a Core 2 glycoprotein Authored: Jassal, B, 2010-07-19 EC Number: 2.4.1.102 Edited: Jassal, B, 2010-07-19 Pubmed10753916 Pubmed1329093 Pubmed9915862 Reactome Database ID Release 43914012 Reactome, http://www.reactome.org ReactomeREACT_115905 Reviewed: Ferrer, A, 2011-11-04 The human gene GCNT encodes beta-1,6-N-acetylglucosaminyltransferase which mediates core 2 O-glycan branching by the addition of N-acetylgalactosamine, an important step in mucin-type biosynthesis. There are 3 defined members in humans, 1, 3 and 4 (Bierhuizen and Fukuda, 1992; Yeh et al, 1999; Schwientek et al, 2000). Two members (6 and 7) may be part of the family based on sequence similarity. Addition of GlcNAc to the Tn antigen forms a Core 3 glycoprotein Authored: Jassal, B, 2010-07-19 Edited: Jassal, B, 2010-07-19 Pubmed11042166 Pubmed11283017 Pubmed11821425 Pubmed15486459 Pubmed15560372 Pubmed15620693 Pubmed17113861 Pubmed9417100 Reactome Database ID Release 43914010 Reactome, http://www.reactome.org ReactomeREACT_116000 Reviewed: Ferrer, A, 2011-11-04 The UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase family (B3GNTs) consists of 9 members in humans (Kolbinger et al, 1998; Shiraishi et al, 2001; Togayachi et al, 2001; Iwai et al, 2002; Huang et al, 2004; Ishida et al, 2005; Zheng et al, 2004). They catalyse the addition of N-acetylglucosamine to the T antigen to form the Core 3 glycoprotein (Togayachi et al, 2006). Thie reaction occurs in the Golgi. Addition of GalNAc to the Tn antigen via an alpha-1,6 linkage forms a Core 7 glycoprotein An unknown N-acetylgalactosaminyltransferase mediates the transfer of GalNAc is transferred to Tn antigens via an alpha-1,6 linkage to create Core 7 mucins (Brockhausen et al. 2009). Authored: Jassal, B, 2010-07-19 Edited: Jassal, B, 2010-07-19 ISBN9780879697709 Reactome Database ID Release 43914017 Reactome, http://www.reactome.org ReactomeREACT_116107 Reviewed: Ferrer, A, 2011-11-04 Addition of galactose to the Tn antigen via an alpha-1,3 linkage forms a Core 8 glycoprotein An unknown galactosyltransferase mediates the transfer of galactose is transferred to Tn antigens via an alpha-1,3 linkage to create Core 8 mucins (Brockhausen et al. 2009). Authored: Jassal, B, 2010-07-19 Edited: Jassal, B, 2010-07-19 ISBN9780879697709 Reactome Database ID Release 43914006 Reactome, http://www.reactome.org ReactomeREACT_116089 Reviewed: Ferrer, A, 2011-11-04 Addition of GlcNAc to the Tn antigen via a beta-1,6 linkage forms a Core 6 glycoprotein An unknown N-acetylglucosaminyltransferase mediates the transfer of GlcNAc to Tn antigens via an beta-1,6 linkage to create Core 6 mucins (Brockhausen et al. 2009). Authored: Jassal, B, 2010-07-19 Edited: Jassal, B, 2010-07-19 ISBN9780879697709 Reactome Database ID Release 43914008 Reactome, http://www.reactome.org ReactomeREACT_116104 Reviewed: Ferrer, A, 2011-11-04 Addition of galactose to Core 6 glycoprotein Beta-1,4-galactosyltransferase 5 (B4GALT5) mediates the transfer of galactose from UDP-galactose to Core 6 glycoproteins (Sato et al. 1998). Pubmed9435216 Reactome Database ID Release 431964501 Reactome, http://www.reactome.org ReactomeREACT_116069 Reviewed: Ferrer, A, 2011-11-04 C1GALT1 transfers galactose to the Tn antigen forming Core 1 glycoproteins (T antigens) Authored: Jassal, B, 2010-07-19 EC Number: 2.4.1.122 Edited: Jassal, B, 2010-07-19 Glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 (C1GALT1) (Ju et al. 2002) mediates the transfer of galactose from UDP-galactose to Tn antigens to form Core 1 mucins. C1GALT1 is acitve when in complex with the molecular chaperone COSMC (C1GALT1C1) (Ju & Cummings 2002). Pubmed11677243 Pubmed12464682 Reactome Database ID Release 431964505 Reactome, http://www.reactome.org ReactomeREACT_116072 Reviewed: Ferrer, A, 2011-11-04 Addition of GalNAc to mucins to form the Tn antigen Authored: Jassal, B, 2010-07-19 EC Number: 2.4.1.41 Edited: Jassal, B, 2010-07-19 Pubmed12464682 Pubmed9295285 Pubmed9394011 Reactome Database ID Release 43913675 Reactome, http://www.reactome.org ReactomeREACT_115586 Reviewed: Ferrer, A, 2011-11-04 The family of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (GalNAc-transferases, GALNTs) carry out the addition of N-acetylgalactosamine on serine or threonine residues of proteins, especially mucins (Wandall et al, 1997). This reaction takes place in the Golgi apparatus (Röttger et al, 1998). There are 20 members of the GALNTs, 15 of which have been characterised and 5 candidate members which are thought to belong to this family based on sequence similarity. The molecular chaperone C1GALT1-specific chaperone (COSMC) is thought to be required for N-acetylgalactosaminyltransferase activity (Yu and Cummings, 2002). cholate bile salts Converted from EntitySet in Reactome Reactome DB_ID: 193404 Reactome Database ID Release 43193404 Reactome, http://www.reactome.org ReactomeREACT_10914 glycocholate; taurocholate ST3GAL1-4 can add a sialic acid to the T antigen at the alpha 3 position Authored: Jassal, B, 2010-10-15 EC Number: 2.4.99.4 Edited: Jassal, B, 2010-10-15 Pubmed10504389 Pubmed8333853 Pubmed8611500 Pubmed8920913 Reactome Database ID Release 43981497 Reactome, http://www.reactome.org ReactomeREACT_116038 Reviewed: Ferrer, A, 2011-11-04 The human genes ST3GAL1-4 encode for sialyltransferases1-4 respectively (Shang et al, 1999; Kim et al, 1996; Kitagawa and Paulson, 1993; Basu et al, 1993). They add a sialyl residue onto the T antigen forming an alpha-3-sialyl O-glycan. ST6GALNAC3/4 can add a sialic acid to the sialyl T antigen to form the disialyl T antigen Authored: Jassal, B, 2010-10-15 EC Number: 2.4.99.7 Edited: Jassal, B, 2010-10-15 Pubmed11062056 Reactome Database ID Release 43981809 Reactome, http://www.reactome.org ReactomeREACT_115974 Reviewed: Ferrer, A, 2011-11-04 The human genes ST6GALNAC3 and 4 encode GalNAc alpha-2,6-sialyltransferase III and IV respectively which can add a sialic acid residue to sialyl T antigen to produce a disialyl T antigen. ST6GALNAC4 is characterised (Harduin-Lepers et al, 2000) while ST6GALNAC3 is thought to perform a similar function based on sequence similarity. TOMM40 Complex Transports Proteins Across the Outer Mitochondrial Membrane As inferred from the yeast TOM40:TOM70 complex, the human TOMM40:TOMM70 complex transports precursor proteins from the cytosol, across the outer membrane of the mitochondrion, and into the intermembrane space from where they may be targeted to all locations within the mitochondrion. As inferred from yeast, TOMM40, TOMM22, TOMM5, TOMM6, and TOMM7 probably form the general import pore across the membrane. On the cytosolic side TOMM20 and TOMM22 interact with presequences on mitochondrial precursors while TOMM70 interacts with hydrophobic sequences in mature internal regions of mitochondrial proteins.<br>In yeast, experimentally verified substrates of the TOM40:TOM70 complex include ATP1 (ATP5A1 in human), ATP2 (ATP5B in human), ATP9 (ATP5G1 in human), TOM40 (TOMM40 in human), SSC1 (mtHsp70, HSPA9 in human), CIT1 (CS in human), ACO1 (ACO2 in human), IDH1 (IDH3G in human), BCS1 (BCS1L in human), CYT1 (CYC1 in human), TIM54 (TIMM54 in human), TIM22 (TIMM22 in human), AAC (ADP/ATP translocase 1, ANT, SLC25A4 in human), HSP60, and CYB2. In humans, TOMM40 has been shown to be a substrate (Humphries et al. 2005). In yeast some proteins such as ACO1, ATP1, CIT1, IDH1, and ATP2 contain both presequences that interact with TOM20 and mature regions that interact with TOM70 (Yamamoto et al. 2009). Most proteins imported into mitochondria are anticipated to be transported through the TOMM40:TOMM70 complex. Authored: May, B, 2011-05-03 Edited: May, B, 2011-05-03 Pubmed15644312 Pubmed18174896 Pubmed19453276 Pubmed19767391 Reactome Database ID Release 431268022 Reactome, http://www.reactome.org ReactomeREACT_118675 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 MIA40:ERV1 (CHCHD4:GFER) Catalyzes Formation of Disulfide Bonds As inferred from the yeast MIA40:ERV1 complex, human CHCHD4 (MIA40 homolog) catalyzes the oxidation of cysteine residues in precursor proteins in the intermembrane space to form cystine bonds. The electrons from the cysteine residues are transferred to CHCHD4, then to GFER (ERV1 homolog), and eventually to the respiratory chain. The interaction between yeast MIA40 and ERV1 is transitory.<br>In yeast, experimentally verified substrates of MIA40:ERV1 include COX17, COX19, CMC2, CMC3, CMC4, TIM13 (TIMM13 in human), TIM9 (TIMM9 in human), TIM10 (TIMM10 in human), CCS1 (CCS in human), TIM8 (TIMM8 in human), and ERV1 (GFER in human). Many other mitochondrial proteins are anticipated to be substrates of the MIA40:ERV1 complex. Authored: May, B, 2011-05-23 Edited: May, B, 2011-05-23 Pubmed15683237 Pubmed16185709 Pubmed18174896 Pubmed19409522 Pubmed19453276 Pubmed20593814 Reactome Database ID Release 431307802 Reactome, http://www.reactome.org ReactomeREACT_118849 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 TIMM8:TIMM13 Chaperones Hydrophobic Proteins As inferred from the yeast TIM8:TIM13 complex, the human TIMM8:TIMM13 complex chaperones hydrophobic membrane proteins in the intermembrane space until their insertion into the inner or outer membrane. In yeast experimentally verified substrates of the TIM8:TIM13 complex include TIM23 (TIMM23 in human) and TOM40 (TOMM40 in human). Many other mitochondrial proteins are anticipated to be chaperoned by the TIMM8:TIMM13 complex. Authored: May, B, 2011-05-21 Edited: May, B, 2011-05-21 Pubmed15254020 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431299484 Reactome, http://www.reactome.org ReactomeREACT_118838 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 TIMM9:TIMM10 Binds Hydrophobic Proteins As inferred from the yeast TIM9:TIM10 complex, the human TIMM9:TIMM10:FXC1 complex chaperones hydrophobic membrane proteins in the intermembrane space until their insertion into the inner or outer membrane. Whereas the yeast TIM9:TIM10 complex is soluble in the intermembrane space, the human TIMM9:TIMM10 complex is associated with the outer surface of the inner membrane (Muhlebein et al. 2004).<br>Experimentally verified substrates of the yeast TIM9:TIM10 complex include AAC (ADP/ATP translocase 1, ANT, SLC25A4 in human), TIM17 (TIMM17 in human), TOM40 (TOMM40 in human), TIM23 (TIMM23 in human), TIM22 (TIMM22 in human), and Tafazzin (Tafazzin, TAZ in human). Many other mitochondrial proteins are anticipated to be chaperoned by the TIMM9:TIMM10 complex. Authored: May, B, 2011-05-21 Edited: May, B, 2011-05-21 Pubmed14726512 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431299481 Reactome, http://www.reactome.org ReactomeREACT_118732 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 TIMM9:TIMM10 Delivers Proteins to TIMM22 Authored: May, B, 2011-11-03 Edited: May, B, 2011-11-03 Pubmed14726512 Pubmed18174896 Pubmed19453276 Reactome Database ID Release 431955380 Reactome, http://www.reactome.org ReactomeREACT_118697 Reviewed: D'Eustachio, P, 2011-11-01 Reviewed: Endo, T, 2012-02-12 TIMM9:TIMM10 with bound substrate protein interacts with FXC1 (TIMM9B, TIMM10B) and TIMM22 at the inner membrane (Muhlenbein et al. 2004). It is believed that TIMM22 then inserts the protein into the inner membrane and TIMM9:TIMM10 and FXC1 are released. glycine; taurine Converted from EntitySet in Reactome Reactome DB_ID: 193463 Reactome Database ID Release 43193463 Reactome, http://www.reactome.org ReactomeREACT_10219 Sialyltransferase I can add sialic acid to the Tn antigen at the alpha 6 position Authored: Jassal, B, 2010-10-15 Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) transfers a sialic acid from the donor CMP-sialic acid to galactose-containing acceptor substrates such as the Tn antigen (Stamenkovic et al, 1990). EC Number: 2.4.99.1 Edited: Jassal, B, 2010-10-15 Pubmed2373995 Reactome Database ID Release 43977071 Reactome, http://www.reactome.org ReactomeREACT_115991 Reviewed: Ferrer, A, 2011-11-04 GalNAc alpha-2,6-sialyltransferase II can add a sialic acid to the T antigen at the alpha 6 position Authored: Jassal, B, 2010-10-15 Edited: Jassal, B, 2010-10-15 Pubmed10742600 Reactome Database ID Release 43981814 Reactome, http://www.reactome.org ReactomeREACT_115996 Reviewed: Ferrer, A, 2011-11-04 The huma gene ST6GALNAC2 encodes GalNAc alpha-2,6-sialyltransferase II which mediates the transfer of a sialic acid onto the T antigen (Samyn-Petit et al, 2000). Sialyltransferase I can add sialic acid to the T antigen at the alpha 6 position Authored: Jassal, B, 2010-10-15 Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) transfers a sialic acid from the donor CMP-sialic acid to the T antigen (Stamenkovic et al, 1990). EC Number: 2.4.99.1 Edited: Jassal, B, 2010-10-15 Pubmed2373995 Reactome Database ID Release 43977228 Reactome, http://www.reactome.org ReactomeREACT_115891 Reviewed: Ferrer, A, 2011-11-04 Re-acidification of the clathrin sculpted acetylcholine transport vesicle Authored: Mahajan, SS, 2008-01-14 16:01:52 Pubmed7401925 Reactome Database ID Release 43349520 Reactome, http://www.reactome.org ReactomeREACT_13770 The proton gradient for the acetylcholine uptake is provided by vH+ type ATPase pump located in the acetylcholine vesicular membrane. Transport of Choline Authored: Mahajan, SS, 2008-01-14 16:01:52 Choline transporter symports Na ion and Choline from the extracellular region into the cytosol. The choline transporters are located in the nerve terminals of cholinergic neurons. Pubmed11068039 Reactome Database ID Release 43264632 Reactome, http://www.reactome.org ReactomeREACT_15552 Dopamine synaptic vesicle docking and priming Authored: Mahajan, SS, 2008-10-17 21:22:46 Dopamine loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasmamembrane. The docking brings the vesicles in close proximity to the release site to fascilitate the release of dopamine. Some of the molecules involved in the docking process are Munc 18, Rab3a, Rab 3 interacting molecule (RIM). The priming reaction brings docked but unprimed synaptic vesicles into a releaseable pool. Priming involes formation of the trimeric SNARE complex between two plasmamembrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2. Edited: Gillespie, ME, 2009-11-19 Pubmed15935055 Pubmed17989281 Pubmed18617632 Pubmed9701566 Reactome Database ID Release 43380574 Reactome, http://www.reactome.org ReactomeREACT_15517 Reviewed: Restituito, S, 2008-11-27 12:38:49 Release of docked dopamine loaded synaptic vesicle Authored: Mahajan, SS, 2008-06-26 19:01:12 Edited: Gillespie, ME, 2009-11-19 Pubmed12519779 Pubmed17478680 Pubmed17891149 Reactome Database ID Release 43380869 Reactome, http://www.reactome.org ReactomeREACT_15533 Reviewed: Restituito, S, 2008-11-27 12:38:49 The trimeric complex formed between V-SNARE (VAMP) and the T-SNAREs (syntaxin and SNAP 25) after priming step is called transSNARE complex because the members of each group lie on the opposide side of the membrane, plasmamembrane side and the vesicular membrane side. Ca2+ influx through the Voltage gated Calcium Channels (VGCC) initaites the process of fusion of the synaptic vesicle in the presynaptic cell. The rise in Ca2+ leads to the activation of Protein Kinase A through rise in cAMP. Synaptotagmin, a Ca2+ sensor proetin also plays a role in the fusion process. Following fusion the members of V and T SNARES lie on the same membrane formin the cis-SNARES. The fusion of release causes the release of the neurotransmitter into the synaptic cleft. has a Stoichiometric coefficient of 2 release of L-Glutamate at the synapse Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Gillespie, ME, 2009-11-19 Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the glutamate into the synaptic cleft. Pubmed12519779 Pubmed16990140 Pubmed17478680 Pubmed17891149 Reactome Database ID Release 43210430 Reactome, http://www.reactome.org ReactomeREACT_12411 Reviewed: Kavalali, E, 2008-04-24 16:31:34 L-Glutamate uptake by neurons Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Gillespie, ME, 2009-11-19 Excess L-Glutamate released by the pre-synaptic neuron in the synaptic cleft is cleared by high affinity transporters called the excitatory amino acid transporters (EAATs) to terminate synaptic actions of the neurotransmitter and to recycle these molecules. Five types of EAATs have been identified EAAT1-EAAT5 in the mammalian CNS. EAAT1 and EAAT2 are mainly expressed by astrocytes whereas EAAT3 and EAAT4 are predominantly neuronal. EAAT3 are expressed throughout the CNS however, EAAT4 is predominantly localized to purkinje cells. EAAT5 are expressed rod photoreceptor and bipolar cells of retina. Astrocytic EAATs are expressed in astrocytes in close apposition to the synapses and neuronal EAATs are expressed in the extra-synaptic or peri-synaptic locations on the neurons. Astrocytic EAATs are responsible for majority of the glutamate uptake, neuronal transporters are responsible for glutamate clearance in specialized synapses in cerebellum where the spatial relationship between the glutamate receptors and EAATs is altered and glutamate receptors are expressed in the peri-synaptic region. Pubmed16212990 Reactome Database ID Release 43210404 Reactome, http://www.reactome.org ReactomeREACT_13574 Reviewed: Jassal, B, 2008-06-03 13:06:01 L-Glutamate loading of synaptic vesicle Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Gillespie, ME, 2009-11-19 Nascent synaptic vesicles are loaded with glutamate by VGLUT1 to form glutamate containing synaptic vesicles. This process occurs while the synaptic vesicle is in the cytosol. Pubmed11001057 Pubmed18215623 Reactome Database ID Release 43210444 Reactome, http://www.reactome.org ReactomeREACT_12503 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Glutamate synaptic vesicle docking and priming Authored: Mahajan, SS, 2008-01-14 16:01:52 Docking occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.<br> Edited: Gillespie, ME, 2009-11-19 Pubmed10440375 Pubmed15935055 Pubmed17301226 Pubmed17989281 Pubmed9701566 Reactome Database ID Release 43210426 Reactome, http://www.reactome.org ReactomeREACT_12617 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Transport of L-Glutamine (cytosol) to mitochondrial matrix Authored: Mahajan, SS, 2008-01-14 16:01:52 Glutamine in neurons is transported into mitochondrial matrix by an unknown transporter. Because this enzyme is not yet identified, it is represented as a black box event. Reactome Database ID Release 43212651 Reactome, http://www.reactome.org ReactomeREACT_13703 Tranport of L-Glutamate (mitochondrial matrix) to cytosol Authored: Mahajan, SS, 2008-01-14 16:01:52 Glutamate from the mitochondrial matrix is transported back into the cytosol, to be loaded into synaptic vesicles. Solute carrier 25 is a mitochondrial glutamate transporter known to transport glutamate, but it is unclear if this protein is involved in the transport of glutamate in neurons. Reactome Database ID Release 43212658 Reactome, http://www.reactome.org ReactomeREACT_13790 Conversion of GABA to Succinate Semialdehyde Authored: Mahajan, SS, 2010-06-29 EC Number: 2.6.1.19 Edited: Mahajan, SS, 2010-08-03 GABA is converted to succinate semialdehyde by 4-aminobutyrate aminotransferase Pubmed7851425 Reactome Database ID Release 43916855 Reactome, http://www.reactome.org ReactomeREACT_23980 Reviewed: Restituito, S, 2008-11-27 12:38:49 Loading of acetylcholine in synaptic vesicle Acetylcholine is actively transported from the cytosol to the lumen of the clathrin sculpted synaptic vesicle by vesicular acetylcholine transporter. Two protons are exchanged for 1 molecule of acetylcholine. The vesicular acetylcholine transporter is located in the membrane of the clathrin sculpted synaptic vesicle. Authored: Mahajan, SS, 2008-01-14 16:01:52 Pubmed8071310 Reactome Database ID Release 43264615 Reactome, http://www.reactome.org ReactomeREACT_15317 has a Stoichiometric coefficient of 2 Loading of GABA into clathrin sculpted GABA transport vesicle lumen Authored: Mahajan, SS, 2010-06-29 Edited: Mahajan, SS, 2010-08-03 GABA is loaded into the synaptic vesicle by inihibitory amino acid transport, VIAAT or VGAT. Pubmed12750892 Reactome Database ID Release 43888592 Reactome, http://www.reactome.org ReactomeREACT_23968 Reviewed: Restituito, S, 2008-11-27 12:38:49 GABA loaded synaptic vesicle Docking and Priming Authored: Mahajan, SS, 2010-08-02 Edited: Mahajan, SS, 2010-08-03 GABA loaded synaptic vesicles are docked at the presynaptic terminal membrane by a number of proteins including Rab3a, RIM (Rab3a interaction protein) and Munc 13. The docked GABA vesicles are primed by the SNARE complex that includes synaptobrevin, SNAP 25 and syntaxin1. Pubmed16722236 Reactome Database ID Release 43917744 Reactome, http://www.reactome.org ReactomeREACT_23973 Reviewed: Restituito, S, 2008-11-27 12:38:49 Release of GABA at the synapse Authored: Mahajan, SS, 2010-06-29 Edited: Mahajan, SS, 2010-08-03 GABA synaptic vesicles are fused to the presynaptic terminal membrane with the help of SNARE complex proteins, synaptobrevin located in the synaptic vesicle, SNAP 25 and syntaxin located in the plasma membrane. Complexin optimizes partially assembled SNARES for Ca2+ dependent exocytosis. Fusion of the synaptic vesicle is triggered by the influx of Ca2+ through N, P/Q Ca2+ channels, which binds to synaptobrevin on the synaptic vesicles triggering a series of steps leading to fusion of the synaptic vesicle to the presynatic terminal membrane and release of GABA. Pubmed11017172 Pubmed12750892 Pubmed19375301 Reactome Database ID Release 43888589 Reactome, http://www.reactome.org ReactomeREACT_23813 Reviewed: Restituito, S, 2008-11-27 12:38:49 GAT1-3 mediate Na+/Cl- dependent GABA transport Authored: Jassal, B, 2009-10-20 Edited: Jassal, B, 2009-08-21 Four transporters mediate GABA uptake in the brain, GAT1-3 and BGT1. They terminates the action of GABA by high affinity sodium-dependent reuptake into presynaptic terminals. Transport of GABA by GAT1-3 is proposed to be accompanied by 2Na+ ions and 1 Cl- ion (Loo DD et al, 2000).<br><br>SLC6A1 encodes a sodium- and chloride-dependent GABA transporter 1, GAT1, which is the predominant GABA transporter in brain. It is widely distributed in the brain and co-localized to GABAergic neurons (Nelson H et al, 1990). SLC6A13 encodes a sodium- and chloride-dependent GABA transporter 2, GAT2, which is localized to GABAergic neurons in the brain. It is also found in retina, liver and kidney (Christiansen B et al, 2007). SLC6A11 encodes a sodium- and chloride-dependent GABA transporter 3, GAT3. It is expressed in the brain and localizes to GABAergic neurons (Borden LA et al, 1994). Pubmed10973981 Pubmed17502375 Pubmed2387399 Pubmed7874447 Reactome Database ID Release 43444007 Reactome, http://www.reactome.org ReactomeREACT_20659 Reviewed: He, L, 2009-11-12 has a Stoichiometric coefficient of 2 Acetylcholine synaptic vesicle docking and priming Authored: Mahajan, SS, 2008-01-14 16:01:52 Docking and priming of clathrin sculpted acetylcholine loaded transport vesicle occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The details of the docking and priming reaction have been worked out using synaptic vesicles loaded with glutamate and similar reactions may occur during the transport cycle of acetylcholine. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.<br> Edited: Gillespie, ME, 2009-11-19 Pubmed10440375 Pubmed15935055 Pubmed17301226 Pubmed17989281 Pubmed9701566 Reactome Database ID Release 43372505 Reactome, http://www.reactome.org ReactomeREACT_15483 Reviewed: Restituito, S, 2008-11-27 12:38:49 Release of acetylcholine at the synapse Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Gillespie, ME, 2009-11-19 Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the acetylcholine into the synaptic cleft. Pubmed12519779 Pubmed16990140 Pubmed17478680 Pubmed17891149 Reactome Database ID Release 43372529 Reactome, http://www.reactome.org ReactomeREACT_15404 Reviewed: Restituito, S, 2008-11-27 12:38:49 Synthesis of GABA by GAD1 Authored: Mahajan, SS, 2010-06-29 EC Number: 4.1.1.15 Edited: Mahajan, SS, 2010-08-03 GAD1 or GAD67 is evenly spread throghout the neuronal cytoplasm and is invoved in GABA synthesis that is used for synaptogenesis, in protection against neural injury and as energy source through GABA shunt. Pubmed16759710 Pubmed17767149 Reactome Database ID Release 43888572 Reactome, http://www.reactome.org ReactomeREACT_23937 Reviewed: Restituito, S, 2008-11-27 12:38:49 Synthesis of GABA by GAD2 Authored: Mahajan, SS, 2010-06-29 EC Number: 4.1.1.15 Edited: Mahajan, SS, 2010-08-03 GAD65 or GAD2 is concentrated in the nerve terminal region in the neurons and is involved in the synthesis of GABA which is used as a neurotransmitter. Pubmed14691540 Reactome Database ID Release 43888577 Reactome, http://www.reactome.org ReactomeREACT_23866 Reviewed: Restituito, S, 2008-11-27 12:38:49 Ca2+ influx through voltage gated Ca2+ channels Authored: Mahajan, SS, 2008-01-14 16:01:52 Ca2+ influx from the extracellular space into the presynaptic neuron through the Voltage Gated Ca2+ Channels (VGCC), is dependant on the arrival of an action potential at the synaptic bulb. The vesicle fusion and subsequent release of glutamate into the synapse is triggered by this influx of Ca2+. The VGCCs involved here could be of the N, P/Q or R type.<p>Hyperpolarization of the cell membrane due to KIR3 potassium channel activity inhibits this influx of Ca2+. Edited: Gillespie, ME, 2009-11-19 Pubmed8825650 Reactome Database ID Release 43210420 Reactome, http://www.reactome.org ReactomeREACT_12594 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Pannexin 1/Pannexin2 mediated neuronal gap junction communication Authored: Gillespie, ME, 2009-02-22 22:24:27 Edited: Gillespie, ME, 2009-03-10 20:55:39 In this electrical synapse the current generated in the presynaptic cell spreads to the postsynaptic cell through an ion channel composed of two hemi-channels composed of six Pannexin 1 proteins on one hemi-channel and six Pannexin 2 proteins on the second. Pubmed14597722 Reactome Database ID Release 43375339 Reactome, http://www.reactome.org ReactomeREACT_16954 Reviewed: Rush, MG, 2008-01-11 00:00:00 Connexin 62 mediated neuronal gap junction communication Authored: Gillespie, ME, 2009-02-22 22:24:27 Edited: Gillespie, ME, 2009-03-10 20:55:39 In this electrical synapse the current generated in the presynaptic cell spreads to the postsynaptic cell through an ion channel composed of two hemi-channels composed of six Connexin 62 proteins each. Pubmed12881038 Reactome Database ID Release 43375340 Reactome, http://www.reactome.org ReactomeREACT_17030 Reviewed: Rush, MG, 2008-01-11 00:00:00 Connexin 45/Connexin 36 mediated neuronal gap junction communication Authored: Gillespie, ME, 2009-02-22 22:24:27 Edited: Gillespie, ME, 2009-03-10 20:55:39 In this electrical synapse the current generated in the presynaptic cell spreads to the postsynaptic cell through an ion channel composed of two hemi-channels composed of six Connexin 45 proteins on one hemi-channel and six Connexin 36 proteins on the second. Reactome Database ID Release 43375330 Reactome, http://www.reactome.org ReactomeREACT_16989 Reviewed: Rush, MG, 2008-01-11 00:00:00 ENPEP Hydrolyzes Angiotensin II to Yield Angiotensin III Aminopeptidase A (APA, ENPEP) hydrolyzes the N-terminal amino acid of angiotensin-(1-8) (angiotensin II) to yield angiotensin-(2-8) (angiotensin III) (Goto et al. 2006). The catalysis is more specific and efficient in the presence of calcium ions (Goto et al. 2006). Authored: May, B, 2011-11-19 ENPEP Hydrolyzes Angiotensin-(1-8) to Yield Angiotensin-(2-8) Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed16790432 Reactome Database ID Release 432022399 Reactome, http://www.reactome.org ReactomeREACT_147872 Reviewed: Joseph, J, 2012-08-06 ANPEP Hydrolyzes Angiotensin III to Yield Angiotensin IV ANPEP Hydrolyzes Angiotensin-(2-8) to Yield Angiotensin-(3-8) Aminopeptidase N (APN, ANPEP, aminopeptidase M, alanyl aminopeptidase) hydrolyzes angiotensin-(2-8) (angiotensin III) to yield angiotensin-(3-8) (angiotensin IV) (see the positive control reactions in Diaz-Perales et al. 2005). Aminopeptidase O (AOPEP) also hydrolyzes angiotensin-(2-8) to angiotensin-(3-8) in vitro (Diaz-Perales et al. 2005) but AOPEP is located in the nucleolus in vivo (Axton et al. 2008) and angiotensin-(2-8) has not been observed in the nucleus. Authored: May, B, 2011-11-19 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed15687497 Pubmed17803194 Reactome Database ID Release 432022393 Reactome, http://www.reactome.org ReactomeREACT_147767 Reviewed: Joseph, J, 2012-08-06 ERBB4s80 binds Tab2:Ncor1 complex Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Exogenously expressed human ERBB4s80 binds mouse Tab2:Ncor1 complex through direct interaction with Tab2. Pubmed17018285 Reactome Database ID Release 431253318 Reactome, http://www.reactome.org ReactomeREACT_115929 Reviewed: Harris, RC, 2011-11-11 Reviewed: Zeng, F, 2011-11-11 Connexin 36 mediated neuronal gap junction communication Authored: Gillespie, ME, 2009-02-22 22:24:27 Edited: Gillespie, ME, 2009-03-10 20:55:39 In this electrical synapse the current generated in the presynaptic cell spreads to the postsynaptic cell through an ion channel composed of two hemi-channels composed of six Connexin 36 proteins each. Pubmed10462698 Reactome Database ID Release 43375342 Reactome, http://www.reactome.org ReactomeREACT_16981 Reviewed: Rush, MG, 2008-01-11 00:00:00 ACE2 Hydrolyzes Angiotensin II to Yield Angiotensin-(1-7) ACE2 Hydrolyzes Angiotensin-(1-8) to Yield Angiotensin-(1-7) Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin-(1-8) (angiotensin II) to yield angiotensin-(1-7) (Vickers et al. 2002, Rice et al. 2004). The activity of ACE2 on angiotensin-(1-8) is 400-fold higher than on angiotensin-(1-10) (Vickers et al. 2002). Authored: May, B, 2011-11-19 EC Number: 3.4.17 Edited: May, B, 2011-11-19 GENE ONTOLOGYGO:0002003 Pubmed11815627 Pubmed15283675 Reactome Database ID Release 432022379 Reactome, http://www.reactome.org ReactomeREACT_147889 Reviewed: Joseph, J, 2012-08-06 Mast Cell Carboxypeptidase Hydrolyzes Angiotensin I to Yield Angiotensin-(1-9) Authored: May, B, 2011-12-23 EC Number: 3.4.17 Edited: May, B, 2011-12-23 GENE ONTOLOGYGO:0002003 Mast Cell Carboxypeptidase Hydrolyzes Angiotensin-(1-10) to Yield Angiotensin-(1-9) Mast cell carboxypeptidase (CPA3) hydrolyzes a single amino acid residue from the C-terminus of angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-9). Pubmed2443571 Pubmed2708524 Reactome Database ID Release 432028294 Reactome, http://www.reactome.org ReactomeREACT_147882 Reviewed: Joseph, J, 2012-08-06 Release of docked serotonin loaded synaptic vesicle Authored: Mahajan, SS, 2008-06-26 19:01:12 Edited: Gillespie, ME, 2009-11-19 Pubmed12519779 Pubmed17478680 Pubmed17891149 Reactome Database ID Release 43380901 Reactome, http://www.reactome.org ReactomeREACT_15503 Reviewed: Restituito, S, 2008-11-27 12:38:49 The trimeric complex formed between V-SNARE (VAMP) and the T-SNAREs (syntaxin and SNAP 25) after priming step is called transSNARE complex because the members of each group lie on the opposide side of the membrane, plasmamembrane side and the vesicular membrane side. Ca2+ influx through the Voltage gated Calcium Channels (VGCC) initaites the process of fusion of the synaptic vesicle in the presynaptic cell. The rise in Ca2+ leads to the activation of Protein Kinase A through rise in cAMP. Synaptotagmin, a Ca2+ sensor proetin also plays a role in the fusion process. Following fusion the members of V and T SNARES lie on the same membrane formin the cis-SNARES. The fusion of release causes the release of the neurotransmitter into the synaptic cleft. Serotonin loaded synaptic vesicle docking and priming Authored: Mahajan, SS, 2008-10-30 16:17:49 Edited: Gillespie, ME, 2009-11-19 Pubmed15935055 Pubmed17989281 Pubmed9701566 Reactome Database ID Release 43380905 Reactome, http://www.reactome.org ReactomeREACT_15338 Reviewed: Restituito, S, 2008-11-27 12:38:49 Serotonin loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasmamembrane. The docking brings the vesicles in close proximity to the release site to fascilitate the release of serotonin. Some of the molecules involved in the docking process are Munc 18, Rab3a, Rab 3 interacting molecule (RIM). The priming reaction brings docked but unprimed synaptic vesicles into a releaseable pool. Priming involes formation of the trimeric SNARE complex between two plasmamembrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2. L-Glutamine transport into neurons Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Gillespie, ME, 2009-11-19 Glutamine uptake in neurons is carried out by Na+-dependant system A neutral amino acid transporter (Melone et al. 2006). Pubmed11756489 Pubmed16616430 Reactome Database ID Release 43212642 Reactome, http://www.reactome.org ReactomeREACT_13763 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Re-acidification of clathrin sculpted monoamine tranport vesicle lumen Authored: Mahajan, SS, 2008-06-26 18:29:42 Edited: Gillespie, ME, 2009-11-19 Loading of the monoamine vesicle is preceded by acidifcation of the vesicle by ATPAse. Pubmed10864948 Reactome Database ID Release 43374916 Reactome, http://www.reactome.org ReactomeREACT_15379 Reviewed: Restituito, S, 2008-11-27 12:38:49 Loading of dopamine into synaptic veiscles Authored: Mahajan, SS, 2008-06-26 18:29:42 Dopamine is transported from the cytosol into the reacidified clathrin sculpted monoamine transport vesicle by membranous vesicular monoamine transporter Edited: Gillespie, ME, 2009-11-19 Pubmed17766642 Pubmed8095030 Reactome Database ID Release 43372542 Reactome, http://www.reactome.org ReactomeREACT_15524 Reviewed: Restituito, S, 2008-11-27 12:38:49 Noradrenalin synaptic vesicle docking and priming Authored: Mahajan, SS, 2008-06-26 18:29:42 Docking and priming of clathrin sculpted Noradrenaline loaded transport vesicle occurs once the synaptic vesicle has moved from the cytoplasm to a region apposed to the plasma membrane. The details of the docking and priming recation have been worked out using synaptic vesicle loaded with glutamate and similar reactions may occur during the transport cycle of noradrenaline. The vesicle is held in close apposition to the plasma membrane by several proteins that bridge the synaptic vesicle to the plasma membrane. Some of these proteins are in the plasma membrane while others are in the synaptic vesicle. Vesicle fusion is preceded by a priming event where molecular interactions between the docked vesicle and the plasma membrane undergo changes. The molecules in the docking and the priming process are known, however, the exact sequence and the precise molecular changes involved in docking and priming are not well dissected. In this reaction the process of docking and priming has been condensed. It is known that Munc18 along with its interactors is critical for membrane docking and fusion events while Munc 13 along with its interacting proteins is central to priming. Munc 13 could act as a positive regulator for the priming recation. Finally the primed fusion complex is clamped in the pre-fusion form by a Complexin. Complexins are Ca2+ independent cytosolic proteins that bind to partly or fully assembled SNARE complexes. Complexins play both a positive and a negative role in the release process.<br> Edited: Gillespie, ME, 2009-11-19 Pubmed15935055 Pubmed17301226 Pubmed9701566 Reactome Database ID Release 43374922 Reactome, http://www.reactome.org ReactomeREACT_15411 Reviewed: Restituito, S, 2008-11-27 12:38:49 Release of noradrenaline at the synapse Authored: Mahajan, SS, 2008-06-26 18:29:42 Edited: Gillespie, ME, 2009-11-19 Once vesicles are docked, primed and ready to be released fusion of the synaptic vesicle with the plasma membrane can be triggered by an influx of Ca2+ through the voltage gated Ca2+ channels (N, P/Q and R type). Ca2+ influx initiates a cascade of events in which the Ca2+ sensing protein, synaptotagmin-1 (sty-1) is central. Sty-1 promotes the membrane fusion between the synaptic vesicle and the plasma membrane by Ca2+ dependant induction of membrane curvature. Synaptotagmin competes with SNARE complex binding in a Ca2+ dependent manner thereby displacing complexin-1 and causing membrane curvature and fusion of the synaptic vesicle with the plasma membrane. The fusion is characterized by the formation of a trans SNARE complex in which SNAP 25, syntaxin and synaptobrevin along with VGLUT1, the glutamate transporter, synaptotagmin, and Rab3a either become a part of the plasma membrane or membrane delimited in the vesicular membrane. Vesicle fusion ultimately results in the release of the noradrenalin into the synaptic cleft. Pubmed12519779 Pubmed16990140 Pubmed17478680 Pubmed17891149 Reactome Database ID Release 43374899 Reactome, http://www.reactome.org ReactomeREACT_15448 Reviewed: Restituito, S, 2008-11-27 12:38:49 Metabolism of Noradrenaline Authored: Mahajan, SS, 2008-06-26 18:29:42 EC Number: 1.4.3.21 EC Number: 1.4.3.22 EC Number: 1.4.3.4 Edited: Gillespie, ME, 2009-11-19 GENE ONTOLOGYGO:0042133 Noradrenaline is degraded by Monoamine oxidase A, which contains FAD as a cofactor. Monoamine oxidase is located in the outer mitochondrial membrane facing the cytoplasmic site. Monoamine xoidase functions as a monomer and is functional both is astrocyes and neurons. Pubmed8211186 Reactome Database ID Release 43374909 Reactome, http://www.reactome.org ReactomeREACT_15390 Uptake of Noradrenaline Authored: Mahajan, SS, 2008-08-05 20:29:44 Edited: Jassal, B, 2009-08-21 Noradrenaline is cleared from the synaptic cleft by Noaradrenaline uptake transporter. This reaction is carried out by neurons as well as astrocytes. Pubmed9260930 Reactome Database ID Release 43374896 Reactome, http://www.reactome.org ReactomeREACT_15472 Reviewed: He, L, 2009-11-12 loading of Serotonin in synaptic vesicles Authored: Mahajan, SS, 2008-08-05 20:29:44 Edited: Gillespie, ME, 2009-11-19 Reactome Database ID Release 43380586 Reactome, http://www.reactome.org ReactomeREACT_15486 Reviewed: Restituito, S, 2008-11-27 12:38:49 Serotonin is loaded into the clathrin sculpted monoamine transport vesicle by vesicular monoamine transporter. Formation of ERCC1-XPF heterodimeric complex At the beginning of this reaction, 1 molecule of 'ERCC1, DNA excision repair protein', and 1 molecule of 'XPF protein' are present. At the end of this reaction, 1 molecule of 'ERCC1:XPF complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43109955 Reactome, http://www.reactome.org ReactomeREACT_1438 RNA Pol II is blocked by the lesion leading to reduced transcription At the site of damage, the Pol II complex is arrested resulting in reduced levels of transcription. Several models have been proposed to explain the mechanism of this transcriptional downregulation. These include a. hyperphosphorylation of Pol II resulting in aborted entry to new pre-initiation complexes b. sequestration of TATA-binding proteins (TBP) c. enhanced use of TFIIH complexes for repair purposes precluding their use in transcription.<BR> Authored: Gopinathrao, G, 2004-02-02 17:30:34 GENE ONTOLOGYGO:0000716 Reactome Database ID Release 43109972 Reactome, http://www.reactome.org ReactomeREACT_1947 Formation of active Pol II complex with lesioned DNA template An active Pol II complex consisting mainly of the Pol II holoenzyme transcribes the damaged DNA template. <BR> Authored: Gopinathrao, G, 2004-02-02 17:30:34 Reactome Database ID Release 43110301 Reactome, http://www.reactome.org ReactomeREACT_1453 Ligation of newly synthesized repair patch to incised DNA in GG-NER Authored: Gopinathrao, G, 2004-02-02 17:30:34 DNA Ligase 1 ligates the newly synthesized fragment to the gap in the template DNA. <BR> Reactome Database ID Release 4374968 Reactome, http://www.reactome.org ReactomeREACT_2181 Repair synthesis of patch ~27-30 bases long by DNA Pol Delta At the beginning of this reaction, 1 molecule of 'dNTP', 1 molecule of 'incised DNA without lesion', 1 molecule of 'RPA heterotrimer', 1 molecule of 'PCNA homotrimer', 1 molecule of 'RFC Heteropentamer', and 1 molecule of 'DNA Polymerase delta tetramer' are present. At the end of this reaction, 1 molecule of 'incised DNA without lesion', 1 molecule of 'RPA heterotrimer', 1 molecule of 'PCNA homotrimer', 1 molecule of 'RFC Heteropentamer', 1 molecule of 'newly synthesized DNA fragment ', and 1 molecule of 'DNA Polymerase delta tetramer' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'delta DNA polymerase activity' of 'DNA Polymerase delta tetramer'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43109969 Reactome, http://www.reactome.org ReactomeREACT_465 Repair synthesis of ~27-30 bases long patch by DNA Pol Epsilon At the beginning of this reaction, 1 molecule of 'dNTP', 1 molecule of 'incised DNA without lesion', 1 molecule of 'RPA heterotrimer', 1 molecule of 'PCNA homotrimer', 1 molecule of 'RFC Heteropentamer', and 1 molecule of 'DNA polymerase epsilon' are present. At the end of this reaction, 1 molecule of 'incised DNA without lesion', 1 molecule of 'RPA heterotrimer', 1 molecule of 'PCNA homotrimer', 1 molecule of 'RFC Heteropentamer', 1 molecule of 'newly synthesized DNA fragment ', and 1 molecule of 'DNA polymerase epsilon' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed DNA polymerase activity' of 'DNA polymerase epsilon'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43109968 Reactome, http://www.reactome.org ReactomeREACT_353 5'-incision of DNA by ERCC1-XPF in GG-NER Authored: Joshi-Tope, G, 2003-07-14 15:01:00 GENE ONTOLOGYGO:0006296 Pubmed10214908 Reactome Database ID Release 4373939 Reactome, http://www.reactome.org ReactomeREACT_1311 The cleavage of the damaged strand of DNA 5' to the site of damage occurs at the junction of single-stranded DNA and double-stranded DNA that is formed when the DNA duplex is unwound. The incision is carried out by ERCC1-XPF complex.<BR> 3'- incision of DNA by XPG in GG-NER Authored: Joshi-Tope, G, 2003-07-14 15:01:00 GENE ONTOLOGYGO:0006295 Pubmed10214908 Reactome Database ID Release 4373938 Reactome, http://www.reactome.org ReactomeREACT_1124 The cleavage of the damaged strand of DNA 3' to the site of damage occurs at the junction of single-stranded DNA and double-stranded DNA that is formed when the DNA duplex is unwound. The incision is carried out by XPG.<BR> Binding of ERCC1-XPF to preincision complex Authored: Gopinathrao, G, 2004-02-02 17:30:34 ERCC1-XPF complex with 5’ endonuclease activity binds to this pre-incision complex around the bubble structure to form an active incision complex.<BR> GENE ONTOLOGYGO:0006293 Pubmed10214908 Reactome Database ID Release 43109953 Reactome, http://www.reactome.org ReactomeREACT_2163 Assembly of repair proteins at the site of Pol II blockage A proper assembly of repair complex may require displacement of Pol II from the damage site exposing a significant length of the corresponding template DNA with the lesions. Speculations on the mode of this displacement of Pol II are available from experimental evidences: a. CSB mediated dissociation of Pol II b. degradation of Pol II c. CSB mediated remodeling of damaged DNA-RNA PII interface etc.<BR>The TC-repair complex now consists of damaged DNA template: nascent mRNA hybrid. The damage site needs to be exposed to subsequent endonuclease activities.<BR> Authored: Gopinathrao, G, 2004-01-29 18:08:32 Reactome Database ID Release 43109973 Reactome, http://www.reactome.org ReactomeREACT_1584 Removal of repair proteins and ligation of the processed ends of the DNA double-strand break Authored: Matthews, L, 2003-09-07 08:47:00 Presumably the proteins must be released from the DNA prior to end joining but precisely when this step occurs is not known. Mg-ATP and the protein kinase activity of DNA-PKcs are required for repair of DNA double strand breaks (Kurimasa et al, 1999; Kienker et al, 2000; Baumann and West, 1998). In vitro, DNA-PK undergoes autophosphorylation which correlates with loss of protein kinase activity and disruption of the DNA-PKcs-Ku-DNA complex (Chan and Lees-Miller, 1996; Douglas et al, 2001; 2002; Merkle et al, 2002). Moreover, autophosphorylation of DNA-PKcs is required for NHEJ in vivo (Chan et al, 2002; Ding et al, 2003), suggesting that autophosphorylation may serve as a mechanism to remove DNA-PKcs from DNA prior to end joining. Pubmed10207111 Pubmed10908332 Pubmed11376007 Pubmed12186630 Pubmed12231622 Pubmed12379113 Pubmed12897153 Pubmed8621537 Pubmed9826654 Reactome Database ID Release 4375928 Reactome, http://www.reactome.org ReactomeREACT_12 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 Association of the XRCC4:DNA ligase IV complex with the DNA-PK:DNA synaptic complex A complex consisting of XRCC4 and DNA ligase IV is recruited to the DNA-PK-DNA complex (Critchlow and Jackson, 1997; Leber et al., 1998). Authored: Matthews, L, 2003-09-07 08:47:00 Pubmed9259561 Pubmed9430729 Reactome Database ID Release 4375922 Reactome, http://www.reactome.org ReactomeREACT_657 XPC:HR23B complex binds to damaged DNA site with lesion Authored: Gopinathrao, G, 2004-02-02 17:30:34 Disruption of normal Watson-Crick base pairing and altered chemistry in the damaged strand involving bases may act as signals of damage that are recognized by XPC:HR23B complex.<BR> Reactome Database ID Release 43109949 Reactome, http://www.reactome.org ReactomeREACT_1987 XPC binds to HR23B forming a heterodimeric complex Authored: Gopinathrao, G, 2004-01-29 18:08:32 Reactome Database ID Release 43109948 Reactome, http://www.reactome.org ReactomeREACT_1984 XPC is mutated in individuals with xeroderma pigmentosum from genetic Complementation Group C (XP-C). It forms a tight heterodimeric complex with human Rad 23B homolog, HR23B and is thought to bind to the damaged site with lesion first triggering subsequent reactions<BR> Synapsis, or interaction between two DNA-PK:DNA complexes at opposing ends of DNA DSB Authored: Matthews, L, 2003-09-07 08:47:00 Pubmed12065431 Reactome Database ID Release 4375920 Reactome, http://www.reactome.org ReactomeREACT_1971 Two DNA-PK-DNA complexes, one on either side of the break, interact to bring the DNA ends together in synaptic complex (DeFazio et al., 2002). has a Stoichiometric coefficient of 2 Autophosphorylation of DNA-PKcs Authored: Matthews, L, 2003-10-06 11:54:00 Autophosphorylation of DNA-PKcs is required for NHEJ in vivo (Chan et al, 2002; Ding et al, 2003). Pubmed12231622 Pubmed12897153 Reactome Database ID Release 4376303 Reactome, http://www.reactome.org ReactomeREACT_215 Removal of 3'-phosphate moiety from DSB ends At the beginning of this reaction, 1 molecule of 'DNA-PK synaptic complex' is present. At the end of this reaction, 1 molecule of 'DNA-PK:DNA synaptic complex with ligatable ends' is present.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'endonuclease activity' of 'unknown endonuclease'.<br> Authored: Lees-Miller, S, 2003-07-14 15:03:25 Reactome Database ID Release 43175585 Reactome, http://www.reactome.org ReactomeREACT_6746 Removal of 3'-phosphoglycolate (PG) moiety from DSB ends At the beginning of this reaction, 1 molecule of 'DNA-PK synaptic complex' is present. At the end of this reaction, 1 molecule of 'DNA-PK:DNA synaptic complex with ligatable ends' is present.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'endonuclease activity' of 'nucleases removing 3' phosphoglycolate'.<br> Authored: Lees-Miller, S, 2003-07-14 15:03:25 Pubmed12023295 Reactome Database ID Release 43175588 Reactome, http://www.reactome.org ReactomeREACT_6774 Recruitment of repair factors to form preincision complex Authored: Joshi-Tope, G, 2003-07-14 15:01:00 GENE ONTOLOGYGO:0006294 Pubmed10526214 Pubmed11511374 Reactome Database ID Release 4373936 Reactome, http://www.reactome.org ReactomeREACT_1492 Transcription factor II H (TFIIH) and XPG are added to the damaged site on the DNA to form a pre-incision complex along with lesioned DNA template.<BR> Formation of open bubble structure in DNA by helicases Authored: Joshi-Tope, G, 2003-07-14 15:01:00 GENE ONTOLOGYGO:0000717 Reactome Database ID Release 4373934 Reactome, http://www.reactome.org ReactomeREACT_1033 Two DNA helicases XPG and XPD, which are part of TFIIH, unwind DNA duplex around this lesion to form an open bubble structure that exposes the damaged site.<BR> Phosphorylation of FANCD2 by ATR/ATM ATR and ATM dependent phosphorylation of FANCD2 promotes the monoubiquitination of FANCD2 stimulating the FA pathway (Andreassen et al., 2004; Ho et al., 2006). Authored: Matthews, L, 2009-05-02 17:26:55 EC Number: 2.7.11 Edited: Matthews, L, 2009-05-20 15:51:04 Pubmed15314022 Pubmed16943440 Reactome Database ID Release 43420770 Reactome, http://www.reactome.org ReactomeREACT_18293 Reviewed: Huang, TT, 2009-05-20 17:48:24 FANCD2 deubiquitination by USP1/UAF1 Authored: Matthews, L, 2009-05-02 17:26:55 Edited: Matthews, L, 2009-05-20 15:51:04 Pubmed15694335 Pubmed18082604 Reactome Database ID Release 43419525 Reactome, http://www.reactome.org ReactomeREACT_18350 Reviewed: Huang, TT, 2009-05-20 17:48:24 The FA pathway is negatively regulated through the USP1/UAF1 mediated deubiquitination of FANCD2 (Nijman et al., 2005) UAF1 forms a complex with and activates USP1 (Cohn et al., 2007). Formation of the BRCA1-PALB2-BRCA2 complex Authored: Matthews, L, 2009-11-09 BRCA2 plays a critical role in the initiation of DNA repair by loading the repair protein RAD51 onto single-stranded DNA for homologous recombination (HR) (Reviewed in Lord and Ashworth, 2007). PALB2 associates with BRCA2 and also functions in the loading of the the BRCA2-RAD51 repair complex onto DNA (Xia et al., 2006 ). BRCA1, through its direct interaction with PALB2, may regulate recombinational repair partly by modulating the PALB2- dependent loading of the BRCA2-RAD51 repair machinery at the sites of DNA breaks (Sy et al., 2009). Edited: Matthews, L, 2010-02-26 Pubmed16793542 Pubmed17549079 Pubmed19369211 Reactome Database ID Release 43446345 Reactome, http://www.reactome.org ReactomeREACT_21405 Reviewed: Huang, TT, 2009-11-05 unfolded actin/tubulin associates with prefoldin Authored: Matthews, L, 2008-12-01 04:46:41 During the synthesis of actin and tubulin, the nascent ribosome-associated chains bind to the heteromeric chaperone protein, prefoldin (PFD) (Hansen et al., 1999). Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed10209023 Reactome Database ID Release 43389980 Reactome, http://www.reactome.org ReactomeREACT_16892 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Frizzled receptors bind Wnts Authored: Jupe, S, 2010-02-18 Edited: Jupe, S, 2010-03-01 Pubmed10097073 Pubmed10557084 Pubmed11029007 Pubmed14977548 Pubmed15862553 Pubmed16602827 Pubmed9389482 Reactome Database ID Release 43517516 Reactome, http://www.reactome.org ReactomeREACT_21306 Reviewed: D'Eustachio, P, 2009-12-11 The highly conserved Wnt signaling proteins play critical roles in guiding pattern formation, cell fate decision, and morphogenetic movement during animal development. They bind to the Frizzled (FZD) family of seven-pass transmembrane proteins and initiate at least three different intracellular signaling pathways. Historically they were considered to be family B GPCRs but more recent phylogenetic classifications put them into a class of their own (e.g. Schioth & Fredriksson 2005). FZD members have been demonstrated to signal via Gi/o (Slusarski et al. 1997) but this is not considered to be the primary signaling mechanism for these receptors (Hsieh 2004). Instead they signal through the canonical/beta-catenin pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. The canonical/beta-catenin pathway requires a co-receptor protein known as LDL5 or LDL6 (Tamai et al. 2000). <br>Most Wnt signaling has been attributed to the activation of FZD receptors but there is evidence of FZD-independent signaling (Mikels & Nusse 2006). Much Wnt research has used indirect evidence to infer the involvement of FZD receptors (e.g. Gazit et al. 1999) but there is some direct evidence of Wnt-FZD binding (Hsieh et al. 1999; Mikels & Nusse 2006). Smad7 binds SMURF1 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed11278251 Pubmed12519765 Reactome Database ID Release 432169004 Reactome, http://www.reactome.org ReactomeREACT_120980 Recombinant mouse Smad7 exogenously expressed in COS7 or HEK293 cells binds exogenously expressed recombinant human SMURF1 (Ebisawa et al. 2001, Tajima et al. 2003). Reviewed: Huang, Tao, 2012-05-14 Phosphorylation of FANCI by ATM/ATR Authored: Matthews, L, 2009-05-02 17:26:55 EC Number: 2.7.11 Edited: Matthews, L, 2009-05-20 15:51:04 FANCI phosphorylation may function as a molecular switch to turn on the Fanconi anemia pathway in response to DNA damage or replication fork stress (Ishiai et al., 2008). Multiple phosphorylation sites within FANCI are functionally important for inducing monoubiquitination of FANCD2. Several lines of evidence support the notion that the ATR kinase is involved in this phosphorylation (Ishiai et al., 2008). Pubmed18931676 Reactome Database ID Release 43420769 Reactome, http://www.reactome.org ReactomeREACT_18335 Reviewed: Huang, TT, 2009-05-20 17:48:24 Hydrolysis of ATP and release of tubulin folding intermediate from CCT/TriC Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Group II chaperonins enclose substrate proteins following substrate binding through the formation of a "built- in" lid over the central cavity. Upon ATP binding, lid formation is triggered by the transition state of ATP hydrolysis (Meyer, et al., 2003). In the case of CCT-mediated tubulin folding, one or more rounds of ATP hydrolysis are likely required before the association of non-exchangeable GTP with chaperonin-bound alpha tubulin. Pubmed12732144 Reactome Database ID Release 43389954 Reactome, http://www.reactome.org ReactomeREACT_17032 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 has a Stoichiometric coefficient of 8 ADP is exchanged for ATP in the (ADP:CCT/TriC):tubulin complex Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed7909354 Pubmed9153422 Reactome Database ID Release 43389961 Reactome, http://www.reactome.org ReactomeREACT_16909 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 The interaction between CCT and unfolded target proteins is thought to occur when CCT is in its ADP-bound state. ADP is then exchanged for ATP in CCT. has a Stoichiometric coefficient of 8 Actin/tubulin:prefoldin complex associates with CCT/TriC Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed8104191 Reactome Database ID Release 43389970 Reactome, http://www.reactome.org ReactomeREACT_16961 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Unfolded actins and tubulins compete efficiently for binding to TriC/CCT and their chaperonin binding sites appear to be at least in part overlapping (Melki et al., 1993). 3' incision of the lesioned strand of DNA in TC-NER At the beginning of this reaction, 1 molecule of 'Transcription-coupled (TC) repair complex', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid' are present. At the end of this reaction, 1 molecule of 'Transcription-coupled (TC) repair complex', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid with 3' incision' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'endodeoxyribonuclease activity' of 'Transcription-coupled (TC) repair complex'.<br> Pubmed11313499 Reactome Database ID Release 43109975 Reactome, http://www.reactome.org ReactomeREACT_1274 Displacement of stalled Pol II from the lesion site At the beginning of this reaction, 1 molecule of 'Transcription-coupled (TC) repair complex', and 1 molecule of 'Stalled Pol II complex with damaged DNA hybrid' are present. At the end of this reaction, 1 molecule of 'Transcription-coupled (TC) repair complex', 1 molecule of 'Stalled Pol II in TC-NER', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43109974 Reactome, http://www.reactome.org ReactomeREACT_1284 Repair synthesis for gap-filling by DNA pol delta in TC-NER At the beginning of this reaction, 1 molecule of 'dNTP', 1 molecule of 'RPA heterotrimer', 1 molecule of 'PCNA homotrimer', 1 molecule of 'RFC Heteropentamer', 1 molecule of 'DNA Polymerase delta tetramer', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid with dual incisions' are present. At the end of this reaction, 1 molecule of 'RPA heterotrimer', 1 molecule of 'PCNA homotrimer', 1 molecule of 'RFC Heteropentamer', 1 molecule of 'newly synthesized DNA fragment ', 1 molecule of 'DNA Polymerase delta tetramer', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid with dual incisions' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'delta DNA polymerase activity' of 'DNA Polymerase delta tetramer'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43110305 Reactome, http://www.reactome.org ReactomeREACT_1196 5' incision leading to excision of DNA fragment with lesion in TC-NER At the beginning of this reaction, 1 molecule of 'Transcription-coupled (TC) repair complex', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid with 3' incision' are present. At the end of this reaction, 1 molecule of 'Transcription-coupled (TC) repair complex', 1 molecule of 'excised DNA fragment with lesion', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid with dual incisions' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'endodeoxyribonuclease activity' of 'Transcription-coupled (TC) repair complex'.<br> Pubmed11313499 Reactome Database ID Release 43109976 Reactome, http://www.reactome.org ReactomeREACT_811 Ligation of newly synthesized repair patch to incised DNA in TC-NER At the beginning of this reaction, 1 molecule of 'newly synthesized DNA fragment ', 1 molecule of 'DNA ligase I ', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid with dual incisions' are present. At the end of this reaction, 1 molecule of 'repaired DNA template:nascent mRNA hybrid', and 1 molecule of 'DNA ligase I ' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA ligase activity' of 'DNA ligase I '.<br> Reactome Database ID Release 43109978 Reactome, http://www.reactome.org ReactomeREACT_527 Repair synthesis for gap-filling by DNA pol epsilon in TC-NER At the beginning of this reaction, 1 molecule of 'dNTP', 1 molecule of 'RPA heterotrimer', 1 molecule of 'PCNA homotrimer', 1 molecule of 'RFC Heteropentamer', 1 molecule of 'DNA polymerase epsilon', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid with dual incisions' are present. At the end of this reaction, 1 molecule of 'RPA heterotrimer', 1 molecule of 'PCNA homotrimer', 1 molecule of 'RFC Heteropentamer', 1 molecule of 'newly synthesized DNA fragment ', 1 molecule of 'DNA polymerase epsilon', and 1 molecule of 'damaged DNA substrate:nascent mRNA hybrid with dual incisions' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed DNA polymerase activity' of 'DNA polymerase epsilon'.<br> EC Number: 2.7.7.7 Reactome Database ID Release 43110306 Reactome, http://www.reactome.org ReactomeREACT_677 Monoubiquitination of FANCD2 by the FA ubiquitin ligase complex Authored: Matthews, L, 2009-05-02 17:26:55 EC Number: 6.3.2.19 Edited: Matthews, L, 2009-05-20 15:51:04 Lysine 561 of FANCD2 is monoubiquitinated by FANCL, a component of the FA core complex with ubiquitin ligase activity (Garcia Higuera et al., 2001). UBE2T binds to FANCL, and is required for the monoubiquitination of FANCD2 (Machida et al., 2006). Monoubiquitination of FANCD2 in turn is necessary for its localization to chromatin and for the formation of nuclear foci in response to DNA damage. FANCD2 ubiquitination requires the presence of FANCI although the molecular role of FANCI in FANCD2 ubiquitination is unknown. Pubmed11239454 Pubmed16916645 Reactome Database ID Release 43419534 Reactome, http://www.reactome.org ReactomeREACT_18429 Reviewed: Huang, TT, 2009-05-20 17:48:24 Resumption of transcription after TC-NER At the beginning of this reaction, 1 molecule of 'Stalled Pol II in TC-NER', and 1 molecule of 'repaired DNA template:nascent mRNA hybrid' are present. At the end of this reaction, 1 molecule of 'Active Pol II complex with repaired DNA template:mRNA hybrid' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Reactome Database ID Release 43109980 Reactome, http://www.reactome.org ReactomeREACT_551 Translocation of ub-FANCD2 and ub-FANCI to chromatin Authored: Matthews, L, 2009-05-02 17:26:55 Edited: Matthews, L, 2009-05-20 15:51:04 Monoubiquitinated FANCD2 and FANCI are targeted to chromatin (Wang et al., 2004; Smogorzewska et al., 2007). Pubmed15199141 Pubmed17412408 Reactome Database ID Release 43420781 Reactome, http://www.reactome.org ReactomeREACT_18327 Reviewed: Huang, TT, 2009-05-20 17:48:24 Monoubiquitination of FANCI by the FA ubiquitin ligase complex Authored: Matthews, L, 2009-05-02 17:26:55 EC Number: 6.3.2.19 Edited: Matthews, L, 2009-05-20 15:51:04 FANCI is monoubiquitinated on lysine 523 in an FA core-complex-dependent manner (Sims et al., 2007; Smogorzewska et al. 2007). FANCD2 and FANCI are mutually dependent on each other for their respective monoubiquitination. However, multiple phosphorylation of FANCI but not monoubiquitination is crucial for FANCD2 activation following DNA damage (Ishiai et al., 2008). Pubmed17412408 Pubmed17460694 Pubmed18931676 Reactome Database ID Release 43419539 Reactome, http://www.reactome.org ReactomeREACT_18367 Reviewed: Huang, TT, 2009-05-20 17:48:24 ETF (reduced) Electron Transfer Flavoprotein (reduced) Reactome DB_ID: 169268 Reactome Database ID Release 43169268 Reactome, http://www.reactome.org ReactomeREACT_6568 has a Stoichiometric coefficient of 1 Cytochrome c-Fe3+ Cytochrome c (oxidized) Ferric cytochrome c Reactome DB_ID: 352607 Reactome Database ID Release 43352607 Reactome, http://www.reactome.org ReactomeREACT_13953 has a Stoichiometric coefficient of 1 Cytochrome c-Fe2+ Cytochrome c (reduced) Ferrous cytochrome c Reactome DB_ID: 352609 Reactome Database ID Release 43352609 Reactome, http://www.reactome.org ReactomeREACT_13858 has a Stoichiometric coefficient of 1 Complex III Reactome DB_ID: 164317 Reactome Database ID Release 43164317 Reactome, http://www.reactome.org ReactomeREACT_6527 Ubiquinol-cytochrome c reductase cytochrome b-c1 complex has a Stoichiometric coefficient of 1 Complex III - Rieske protein-2Fe-2S cluster complex Reactome DB_ID: 164304 Reactome Database ID Release 43164304 Reactome, http://www.reactome.org ReactomeREACT_6690 has a Stoichiometric coefficient of 1 cytochrome b-heme complex Reactome DB_ID: 164662 Reactome Database ID Release 43164662 Reactome, http://www.reactome.org ReactomeREACT_6552 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Complex III - cytochrome c1-heme complex Reactome DB_ID: 164584 Reactome Database ID Release 43164584 Reactome, http://www.reactome.org ReactomeREACT_6582 has a Stoichiometric coefficient of 1 Complex IV Cytochrome c oxidase Reactome DB_ID: 164316 Reactome Database ID Release 43164316 Reactome, http://www.reactome.org ReactomeREACT_6661 has a Stoichiometric coefficient of 1 Complex IV - Cytochrome c oxidase subunit 2-Cu complex Reactome DB_ID: 164303 Reactome Database ID Release 43164303 Reactome, http://www.reactome.org ReactomeREACT_6380 has a Stoichiometric coefficient of 1 ATPase complex Reactome DB_ID: 74186 Reactome Database ID Release 4374186 Reactome, http://www.reactome.org ReactomeREACT_4862 has a Stoichiometric coefficient of 1 APOBEC3G Converted from EntitySet in Reactome Reactome DB_ID: 180578 Reactome Database ID Release 43180578 Reactome, http://www.reactome.org ReactomeREACT_9891 AP-1 sigma Converted from EntitySet in Reactome Reactome DB_ID: 167713 Reactome Database ID Release 43167713 Reactome, http://www.reactome.org ReactomeREACT_11809 phosphorylated pyruvate dehydrogenase complex Reactome DB_ID: 210342 Reactome Database ID Release 43210342 Reactome, http://www.reactome.org ReactomeREACT_12644 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 12 has a Stoichiometric coefficient of 20 has a Stoichiometric coefficient of 21 has a Stoichiometric coefficient of 6 pyruvate dehydrogenase E1 complex Reactome DB_ID: 69968 Reactome Database ID Release 4369968 Reactome, http://www.reactome.org ReactomeREACT_5341 has a Stoichiometric coefficient of 2 PDP complex Converted from EntitySet in Reactome Reactome DB_ID: 204219 Reactome Database ID Release 43204219 Reactome, http://www.reactome.org ReactomeREACT_13240 Inactive PDHE1 complex Inactive pyruvate dehydrogenase E1 complex Reactome DB_ID: 204168 Reactome Database ID Release 43204168 Reactome, http://www.reactome.org ReactomeREACT_13173 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 phosphorylated pyruvate dehydrogenase E1 complex PDPr:FAD Reactome DB_ID: 210347 Reactome Database ID Release 43210347 Reactome, http://www.reactome.org ReactomeREACT_12723 has a Stoichiometric coefficient of 1 PDP1 complex Reactome DB_ID: 204162 Reactome Database ID Release 43204162 Reactome, http://www.reactome.org ReactomeREACT_13359 has a Stoichiometric coefficient of 1 Citrate Synthase Holoenzyme Reactome DB_ID: 70973 Reactome Database ID Release 4370973 Reactome, http://www.reactome.org ReactomeREACT_3312 has a Stoichiometric coefficient of 2 PDP2 complex Reactome DB_ID: 204218 Reactome Database ID Release 43204218 Reactome, http://www.reactome.org ReactomeREACT_12911 has a Stoichiometric coefficient of 1 alpha-keto acid dehydrogenase E3 homodimer Reactome DB_ID: 69980 Reactome Database ID Release 4369980 Reactome, http://www.reactome.org ReactomeREACT_5578 has a Stoichiometric coefficient of 2 alpha-keto acid dehydrogenase E3 holoenzyme Reactome DB_ID: 69979 Reactome Database ID Release 4369979 Reactome, http://www.reactome.org ReactomeREACT_3390 has a Stoichiometric coefficient of 1 pyruvate dehydrogenase E2 trimer Reactome DB_ID: 69971 Reactome Database ID Release 4369971 Reactome, http://www.reactome.org ReactomeREACT_2909 has a Stoichiometric coefficient of 3 alpha-ketoglutarate dehydrogenase E1 holoenzyme Reactome DB_ID: 69982 Reactome Database ID Release 4369982 Reactome, http://www.reactome.org ReactomeREACT_2520 has a Stoichiometric coefficient of 1 alpha-ketoglutarate dehydrogenase E1 homodimer Reactome DB_ID: 69992 Reactome Database ID Release 4369992 Reactome, http://www.reactome.org ReactomeREACT_2420 has a Stoichiometric coefficient of 2 alpha-ketoglutarate dehydrogenase E2 holoenzyme Reactome DB_ID: 69995 Reactome Database ID Release 4369995 Reactome, http://www.reactome.org ReactomeREACT_4133 has a Stoichiometric coefficient of 1 alpha-ketoglutarate dehydrogenase complex Reactome DB_ID: 69996 Reactome Database ID Release 4369996 Reactome, http://www.reactome.org ReactomeREACT_5646 has a Stoichiometric coefficient of 12 has a Stoichiometric coefficient of 24 has a Stoichiometric coefficient of 6 Succinate dehydrogenase flavoprotein (subunit A), oxidised Reactome DB_ID: 70984 Reactome Database ID Release 4370984 Reactome, http://www.reactome.org ReactomeREACT_5368 has a Stoichiometric coefficient of 1 Succinate dehydrogenase complex (oxidised) Reactome DB_ID: 70990 Reactome Database ID Release 4370990 Reactome, http://www.reactome.org ReactomeREACT_3127 has a Stoichiometric coefficient of 1 Succinyl-CoA synthetase heterodimer (ADP-forming) Reactome DB_ID: 156625 Reactome Database ID Release 43156625 Reactome, http://www.reactome.org ReactomeREACT_5440 has a Stoichiometric coefficient of 1 Succinyl-CoA synthetase heterodimer (GDP-forming) Reactome DB_ID: 156627 Reactome Database ID Release 43156627 Reactome, http://www.reactome.org ReactomeREACT_5345 has a Stoichiometric coefficient of 1 NNT dimer Reactome DB_ID: 451008 Reactome Database ID Release 43451008 Reactome, http://www.reactome.org ReactomeREACT_21826 has a Stoichiometric coefficient of 2 IDH3 complex Isocitrate Dehydrogenase Holoenzyme (mitochondrial, NAD+) Reactome DB_ID: 70965 Reactome Database ID Release 4370965 Reactome, http://www.reactome.org ReactomeREACT_3944 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 IDH2 dimer Reactome DB_ID: 450982 Reactome Database ID Release 43450982 Reactome, http://www.reactome.org ReactomeREACT_21933 has a Stoichiometric coefficient of 2 FP sub-complex FlavoProtein fraction Reactome DB_ID: 163932 Reactome Database ID Release 43163932 Reactome, http://www.reactome.org ReactomeREACT_6488 has a Stoichiometric coefficient of 1 Complex I - NADH:Ubiquinone oxidoreductase Reactome DB_ID: 163924 Reactome Database ID Release 43163924 Reactome, http://www.reactome.org ReactomeREACT_6533 has a Stoichiometric coefficient of 1 IP sub-complex Iron-Sulfur Protein fraction Reactome DB_ID: 163928 Reactome Database ID Release 43163928 Reactome, http://www.reactome.org ReactomeREACT_6489 has a Stoichiometric coefficient of 1 Complex I - 51 kDa subunit-FMN-4Fe-4S cluster complex Reactome DB_ID: 164291 Reactome Database ID Release 43164291 Reactome, http://www.reactome.org ReactomeREACT_6466 has a Stoichiometric coefficient of 1 IDH1 R132C dimer Reactome DB_ID: 880029 Reactome Database ID Release 43880029 Reactome, http://www.reactome.org ReactomeREACT_26369 has a Stoichiometric coefficient of 2 IDH1 R132H dimer Reactome DB_ID: 880043 Reactome Database ID Release 43880043 Reactome, http://www.reactome.org ReactomeREACT_26474 has a Stoichiometric coefficient of 2 IDH1 R132S dimer Reactome DB_ID: 880038 Reactome Database ID Release 43880038 Reactome, http://www.reactome.org ReactomeREACT_25740 has a Stoichiometric coefficient of 2 IDH1 R132L dimer Reactome DB_ID: 880001 Reactome Database ID Release 43880001 Reactome, http://www.reactome.org ReactomeREACT_26241 has a Stoichiometric coefficient of 2 IDH1 R132mutant dimers Converted from EntitySet in Reactome Reactome DB_ID: 880004 Reactome Database ID Release 43880004 Reactome, http://www.reactome.org ReactomeREACT_25808 FH tetramer Reactome DB_ID: 451041 Reactome Database ID Release 43451041 Reactome, http://www.reactome.org ReactomeREACT_21885 fumarate hydratase tetramer has a Stoichiometric coefficient of 4 Succinate dehydrogenase Iron Sulphur (subunit B) Reactome DB_ID: 70987 Reactome Database ID Release 4370987 Reactome, http://www.reactome.org ReactomeREACT_5347 has a Stoichiometric coefficient of 1 ETF Electron Transfer Flavoprotein (cofactors FAD, AMP) Reactome DB_ID: 169267 Reactome Database ID Release 43169267 Reactome, http://www.reactome.org ReactomeREACT_6490 has a Stoichiometric coefficient of 1 Succinate dehydrogenase flavoprotein (subunit A) Reactome DB_ID: 165640 Reactome Database ID Release 43165640 Reactome, http://www.reactome.org ReactomeREACT_6576 has a Stoichiometric coefficient of 1 Succinate dehydrogenase complex (reduced) Reactome DB_ID: 165631 Reactome Database ID Release 43165631 Reactome, http://www.reactome.org ReactomeREACT_6402 has a Stoichiometric coefficient of 1 Complex I - 39 kDa subunit-FAD cofactor Reactome DB_ID: 164289 Reactome Database ID Release 43164289 Reactome, http://www.reactome.org ReactomeREACT_6473 has a Stoichiometric coefficient of 1 Complex I - 23 kDa subunit-2 x 4Fe-4S cluster complex Reactome DB_ID: 164295 Reactome Database ID Release 43164295 Reactome, http://www.reactome.org ReactomeREACT_6655 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Complex I - 20 kDa subunit-4Fe-4S cluster complex Reactome DB_ID: 164293 Reactome Database ID Release 43164293 Reactome, http://www.reactome.org ReactomeREACT_6486 has a Stoichiometric coefficient of 1 Complex I - 42 kDa subunit-FAD cofactor Reactome DB_ID: 164294 Reactome Database ID Release 43164294 Reactome, http://www.reactome.org ReactomeREACT_6386 has a Stoichiometric coefficient of 1 HP subcomplex Hydrophobic Protein fraction Reactome DB_ID: 163929 Reactome Database ID Release 43163929 Reactome, http://www.reactome.org ReactomeREACT_6454 has a Stoichiometric coefficient of 1 Complex I - 49 kDa subunit-4Fe-4S cluster complex Reactome DB_ID: 164288 Reactome Database ID Release 43164288 Reactome, http://www.reactome.org ReactomeREACT_6557 has a Stoichiometric coefficient of 1 Complex I - 75 kDa subunit-2Fe-2S cluster-4Fe- 2 x 4S cluster complex Reactome DB_ID: 164297 Reactome Database ID Release 43164297 Reactome, http://www.reactome.org ReactomeREACT_6508 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 XDH dimer Reactome DB_ID: 74244 Reactome Database ID Release 4374244 Reactome, http://www.reactome.org ReactomeREACT_2870 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 NT5C1A tetramer 5'-nucleotidase cytosolic 1A holoenzyme Reactome DB_ID: 109363 Reactome Database ID Release 43109363 Reactome, http://www.reactome.org ReactomeREACT_3192 has a Stoichiometric coefficient of 4 NT5C2 tetramer 5'-nucleotidase cytosolic II holoenzyme Reactome DB_ID: 109318 Reactome Database ID Release 43109318 Reactome, http://www.reactome.org ReactomeREACT_3347 has a Stoichiometric coefficient of 4 Guanine deaminase homodimer Reactome DB_ID: 74253 Reactome Database ID Release 4374253 Reactome, http://www.reactome.org ReactomeREACT_3879 has a Stoichiometric coefficient of 2 NT5C dimer Reactome DB_ID: 109468 Reactome Database ID Release 43109468 Reactome, http://www.reactome.org ReactomeREACT_2580 has a Stoichiometric coefficient of 2 Vpr protein Converted from EntitySet in Reactome Reactome DB_ID: 180893 Reactome Database ID Release 43180893 Reactome, http://www.reactome.org ReactomeREACT_8078 CAD hexamer Reactome DB_ID: 73457 Reactome Database ID Release 4373457 Reactome, http://www.reactome.org ReactomeREACT_2898 carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase hexamer has a Stoichiometric coefficient of 6 DHOdeHase-Fe-FMN complex Reactome DB_ID: 73534 Reactome Database ID Release 4373534 Reactome, http://www.reactome.org ReactomeREACT_5835 dihydroorotate dehydrogenase holoenzyme has a Stoichiometric coefficient of 1 UMPS dimer Reactome DB_ID: 419512 Reactome Database ID Release 43419512 Reactome, http://www.reactome.org ReactomeREACT_18920 has a Stoichiometric coefficient of 2 DCTD hexamer Reactome DB_ID: 500740 Reactome Database ID Release 43500740 Reactome, http://www.reactome.org ReactomeREACT_21568 has a Stoichiometric coefficient of 6 CAT tetramer Reactome DB_ID: 76028 Reactome Database ID Release 4376028 Reactome, http://www.reactome.org ReactomeREACT_2912 catalase holoenzyme tetramer has a Stoichiometric coefficient of 4 catalase holoenzyme monomer Reactome DB_ID: 76027 Reactome Database ID Release 4376027 Reactome, http://www.reactome.org ReactomeREACT_4030 has a Stoichiometric coefficient of 1 APRT homodimer Reactome DB_ID: 74211 Reactome Database ID Release 4374211 Reactome, http://www.reactome.org ReactomeREACT_2360 has a Stoichiometric coefficient of 2 NP trimer PNPase homotrimer Reactome DB_ID: 74237 Reactome Database ID Release 4374237 Reactome, http://www.reactome.org ReactomeREACT_3950 has a Stoichiometric coefficient of 3 nucleoside phosphorylase homotrimer ADAL:Zn Reactome DB_ID: 2161178 Reactome Database ID Release 432161178 Reactome, http://www.reactome.org ReactomeREACT_122370 has a Stoichiometric coefficient of 1 AMPD3 tetramer AMP deaminase isoform E tetramer Reactome DB_ID: 76601 Reactome Database ID Release 4376601 Reactome, http://www.reactome.org ReactomeREACT_5840 has a Stoichiometric coefficient of 4 AMPD2 tetramer AMP deaminase isoform L tetramer Reactome DB_ID: 76586 Reactome Database ID Release 4376586 Reactome, http://www.reactome.org ReactomeREACT_2993 has a Stoichiometric coefficient of 4 AMPD1 tetramer AMP deaminase isoform M tetramer Reactome DB_ID: 76595 Reactome Database ID Release 4376595 Reactome, http://www.reactome.org ReactomeREACT_2471 has a Stoichiometric coefficient of 4 GMPR2 tetramer Reactome DB_ID: 514630 Reactome Database ID Release 43514630 Reactome, http://www.reactome.org ReactomeREACT_22008 has a Stoichiometric coefficient of 4 5'-nucleotidase, ecto (CD73) holoenzyme Reactome DB_ID: 109266 Reactome Database ID Release 43109266 Reactome, http://www.reactome.org ReactomeREACT_4453 has a Stoichiometric coefficient of 2 GMPR tetramers Converted from EntitySet in Reactome Reactome DB_ID: 514620 Reactome Database ID Release 43514620 Reactome, http://www.reactome.org ReactomeREACT_22032 GMPR tetramer Reactome DB_ID: 514628 Reactome Database ID Release 43514628 Reactome, http://www.reactome.org ReactomeREACT_21827 has a Stoichiometric coefficient of 4 HGPRT homotetramer Reactome DB_ID: 74208 Reactome Database ID Release 4374208 Reactome, http://www.reactome.org ReactomeREACT_5640 has a Stoichiometric coefficient of 4 has a Stoichiometric coefficient of 8 3-ureidopropionase-Zn complex Reactome DB_ID: 73465 Reactome Database ID Release 4373465 Reactome, http://www.reactome.org ReactomeREACT_4599 has a Stoichiometric coefficient of 1 Dihydropyriminidase-Zn complex Reactome DB_ID: 73468 Reactome Database ID Release 4373468 Reactome, http://www.reactome.org ReactomeREACT_3991 has a Stoichiometric coefficient of 4 AGXT2 tetramer Reactome DB_ID: 904854 Reactome Database ID Release 43904854 Reactome, http://www.reactome.org ReactomeREACT_26949 has a Stoichiometric coefficient of 4 HREV1 Converted from EntitySet in Reactome Reactome DB_ID: 350783 Reactome Database ID Release 43350783 Reactome, http://www.reactome.org ReactomeREACT_14374 AK5 dimer Reactome DB_ID: 500061 Reactome Database ID Release 43500061 Reactome, http://www.reactome.org ReactomeREACT_21864 has a Stoichiometric coefficient of 2 dTMP kinase-Mg complex Reactome DB_ID: 73497 Reactome Database ID Release 4373497 Reactome, http://www.reactome.org ReactomeREACT_5195 deoxythymidylate kinase (thymidylate kinase) holoenzyme has a Stoichiometric coefficient of 2 bile salts and acids Converted from EntitySet in Reactome Reactome DB_ID: 194156 Reactome Database ID Release 43194156 Reactome, http://www.reactome.org ReactomeREACT_10768 CTPS tetramer Reactome DB_ID: 504052 Reactome Database ID Release 43504052 Reactome, http://www.reactome.org ReactomeREACT_21439 has a Stoichiometric coefficient of 4 CTPS2 tetramer Reactome DB_ID: 504058 Reactome Database ID Release 43504058 Reactome, http://www.reactome.org ReactomeREACT_21501 has a Stoichiometric coefficient of 1 ribonucleotide reductase Reactome DB_ID: 73640 Reactome Database ID Release 4373640 Reactome, http://www.reactome.org ReactomeREACT_3377 has a Stoichiometric coefficient of 1 ribonucleosidePP reductase ribonucleotide reductase M2 polypeptide dimer Reactome DB_ID: 111737 Reactome Database ID Release 43111737 Reactome, http://www.reactome.org ReactomeREACT_2953 has a Stoichiometric coefficient of 2 ribonucleotide reductase M1 polypeptide dimer Reactome DB_ID: 111735 Reactome Database ID Release 43111735 Reactome, http://www.reactome.org ReactomeREACT_5777 has a Stoichiometric coefficient of 2 ribonucleotide reductase M2B (TP53 inducible) variant Reactome DB_ID: 111795 Reactome Database ID Release 43111795 Reactome, http://www.reactome.org ReactomeREACT_2633 has a Stoichiometric coefficient of 1 TYMP dimer Reactome DB_ID: 74363 Reactome Database ID Release 4374363 Reactome, http://www.reactome.org ReactomeREACT_4588 has a Stoichiometric coefficient of 2 thymidine phosphorylase dimer UPP1 dimer Reactome DB_ID: 112267 Reactome Database ID Release 43112267 Reactome, http://www.reactome.org ReactomeREACT_8490 has a Stoichiometric coefficient of 2 TS dimer Reactome DB_ID: 73519 Reactome Database ID Release 4373519 Reactome, http://www.reactome.org ReactomeREACT_3137 has a Stoichiometric coefficient of 2 DUT trimer Reactome DB_ID: 500745 Reactome Database ID Release 43500745 Reactome, http://www.reactome.org ReactomeREACT_21950 has a Stoichiometric coefficient of 3 bile salts and acids (OATP-A) Converted from EntitySet in Reactome Reactome DB_ID: 194131 Reactome Database ID Release 43194131 Reactome, http://www.reactome.org ReactomeREACT_10444 bile salts and acids (OATP-A) Converted from EntitySet in Reactome Reactome DB_ID: 194092 Reactome Database ID Release 43194092 Reactome, http://www.reactome.org ReactomeREACT_10215 myristoylated Nef Protein (numerous variants) Converted from EntitySet in Reactome Reactome DB_ID: 167560 Reactome Database ID Release 43167560 Reactome, http://www.reactome.org ReactomeREACT_11427 choloyl-CoA; chenodeoxycholoyl-CoA Converted from EntitySet in Reactome Reactome DB_ID: 194073 Reactome Database ID Release 43194073 Reactome, http://www.reactome.org ReactomeREACT_10852 cholate; chenodeoxycholate Converted from EntitySet in Reactome Reactome DB_ID: 194096 Reactome Database ID Release 43194096 Reactome, http://www.reactome.org ReactomeREACT_10869 cholate bile salts Converted from EntitySet in Reactome Reactome DB_ID: 194097 Reactome Database ID Release 43194097 Reactome, http://www.reactome.org ReactomeREACT_10246 glycocholate; taurocholate cholate bile salts Converted from EntitySet in Reactome Reactome DB_ID: 194117 Reactome Database ID Release 43194117 Reactome, http://www.reactome.org ReactomeREACT_10400 glycocholate; taurocholate UCK2 tetramer Reactome DB_ID: 500801 Reactome Database ID Release 43500801 Reactome, http://www.reactome.org ReactomeREACT_21701 has a Stoichiometric coefficient of 4 glycine; taurine Converted from EntitySet in Reactome Reactome DB_ID: 194069 Reactome Database ID Release 43194069 Reactome, http://www.reactome.org ReactomeREACT_10925 TK1 tetramer Reactome DB_ID: 73501 Reactome Database ID Release 4373501 Reactome, http://www.reactome.org ReactomeREACT_2934 has a Stoichiometric coefficient of 4 thymidine kinase 1, soluble holoenzyme UCK1 tetramer Reactome DB_ID: 73504 Reactome Database ID Release 4373504 Reactome, http://www.reactome.org ReactomeREACT_2881 has a Stoichiometric coefficient of 4 NT5C3 holoenzyme 5'-nucleotidase, cytosolic III holoenzyme Reactome DB_ID: 109433 Reactome Database ID Release 43109433 Reactome, http://www.reactome.org ReactomeREACT_5077 has a Stoichiometric coefficient of 1 DPYD dimer DHUdehydrogenase-Fe-2FAD-2FMN complex Reactome DB_ID: 73529 Reactome Database ID Release 4373529 Reactome, http://www.reactome.org ReactomeREACT_4541 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 CDA tetramer Reactome DB_ID: 73462 Reactome Database ID Release 4373462 Reactome, http://www.reactome.org ReactomeREACT_4232 cytidine deaminase-Zn complex tetramer has a Stoichiometric coefficient of 4 NT5M dimer 5',3'-nucleotidase, mitochondrial holoenzyme Reactome DB_ID: 109497 Reactome Database ID Release 43109497 Reactome, http://www.reactome.org ReactomeREACT_4913 has a Stoichiometric coefficient of 2 ATPase CF(0) Reactome DB_ID: 74185 Reactome Database ID Release 4374185 Reactome, http://www.reactome.org ReactomeREACT_5736 has a Stoichiometric coefficient of 1 ATPase CF(1) Reactome DB_ID: 74184 Reactome Database ID Release 4374184 Reactome, http://www.reactome.org ReactomeREACT_3000 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 3 IMP (inosine monophosphate) dehydrogenase 1 tetramer Reactome DB_ID: 111583 Reactome Database ID Release 43111583 Reactome, http://www.reactome.org ReactomeREACT_3496 has a Stoichiometric coefficient of 4 IMP (inosine monophosphate) dehydrogenase 2 tetramer Reactome DB_ID: 111591 Reactome Database ID Release 43111591 Reactome, http://www.reactome.org ReactomeREACT_3429 has a Stoichiometric coefficient of 4 ADSS, ADSSL1 dimers Converted from EntitySet in Reactome Reactome DB_ID: 500310 Reactome Database ID Release 43500310 Reactome, http://www.reactome.org ReactomeREACT_21425 adenylosuccinate synthetase like 1 holoenzyme dimer Reactome DB_ID: 111484 Reactome Database ID Release 43111484 Reactome, http://www.reactome.org ReactomeREACT_4907 has a Stoichiometric coefficient of 2 adenylosuccinate synthetase like 1 holoenzyme Reactome DB_ID: 111483 Reactome Database ID Release 43111483 Reactome, http://www.reactome.org ReactomeREACT_4225 has a Stoichiometric coefficient of 1 adenylosuccinate synthetase holoenzyme dimer Reactome DB_ID: 111482 Reactome Database ID Release 43111482 Reactome, http://www.reactome.org ReactomeREACT_4496 has a Stoichiometric coefficient of 2 adenylosuccinate synthetase holoenzyme Reactome DB_ID: 111481 Reactome Database ID Release 43111481 Reactome, http://www.reactome.org ReactomeREACT_5410 has a Stoichiometric coefficient of 1 DCK dimer Reactome DB_ID: 73516 Reactome Database ID Release 4373516 Reactome, http://www.reactome.org ReactomeREACT_5285 deoxycytidine kinase holoenzyme has a Stoichiometric coefficient of 2 adenosine kinase holoenzyme Reactome DB_ID: 76542 Reactome Database ID Release 4376542 Reactome, http://www.reactome.org ReactomeREACT_5322 has a Stoichiometric coefficient of 1 Nef Protein (numerous variants) Converted from EntitySet in Reactome Reactome DB_ID: 165607 Reactome Database ID Release 43165607 Reactome, http://www.reactome.org ReactomeREACT_117900 AMPD tetramers Converted from EntitySet in Reactome Reactome DB_ID: 500235 Reactome Database ID Release 43500235 Reactome, http://www.reactome.org ReactomeREACT_22007 deoxyguanosine kinase holoenzyme Reactome DB_ID: 74205 Reactome Database ID Release 4374205 Reactome, http://www.reactome.org ReactomeREACT_4527 has a Stoichiometric coefficient of 2 UCP dimer Reactome DB_ID: 166389 Reactome Database ID Release 43166389 Reactome, http://www.reactome.org ReactomeREACT_6463 has a Stoichiometric coefficient of 2 FA anion:UCP dimer "head-in" complex Reactome DB_ID: 166218 Reactome Database ID Release 43166218 Reactome, http://www.reactome.org ReactomeREACT_6679 has a Stoichiometric coefficient of 1 ATPase-ADP and Pi complex Reactome DB_ID: 164838 Reactome Database ID Release 43164838 Reactome, http://www.reactome.org ReactomeREACT_2435 has a Stoichiometric coefficient of 1 ATPase-ATP complex Reactome DB_ID: 164835 Reactome Database ID Release 43164835 Reactome, http://www.reactome.org ReactomeREACT_3945 has a Stoichiometric coefficient of 1 PPAT tetramer ATASE-(4Fe-4S) Reactome DB_ID: 73789 Reactome Database ID Release 4373789 Reactome, http://www.reactome.org ReactomeREACT_3180 has a Stoichiometric coefficient of 2 phosphoribosyl pyrophosphate amidotransferase tetramer PAICS octamer Reactome DB_ID: 419271 Reactome Database ID Release 43419271 Reactome, http://www.reactome.org ReactomeREACT_18852 has a Stoichiometric coefficient of 8 FA anion:UCP dimer "head-out" complex Reactome DB_ID: 166385 Reactome Database ID Release 43166385 Reactome, http://www.reactome.org ReactomeREACT_6437 has a Stoichiometric coefficient of 1 PPAT dimer ATASE-(4Fe-4S)-(PRPP-Glutamine) reactive complex Reactome DB_ID: 73790 Reactome Database ID Release 4373790 Reactome, http://www.reactome.org ReactomeREACT_3790 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 phosphoribosyl pyrophosphate amidotransferase dimer IMPDH tetramers Converted from EntitySet in Reactome Reactome DB_ID: 500309 Reactome Database ID Release 43500309 Reactome, http://www.reactome.org ReactomeREACT_21890 ATIC dimer 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase dimer Reactome DB_ID: 111428 Reactome Database ID Release 43111428 Reactome, http://www.reactome.org ReactomeREACT_3222 has a Stoichiometric coefficient of 2 adenylosuccinate lyase tetramer Reactome DB_ID: 111408 Reactome Database ID Release 43111408 Reactome, http://www.reactome.org ReactomeREACT_2355 has a Stoichiometric coefficient of 4 Association of CCT/TriC with other substrates during biosynthesis (unknown chaperone) A combination of proteomic and bioinformatics analyses of TRiC substrates has revealed that they have complex topologies that are slow folding and aggregation prone (Yam et al., 2008). These substrates are also enriched in proteins that belong to oligomeric assemblies suggesting that TRiC plays a role in promoting complex assembly (Yam et al., 2008). Two possible mechanisms describing the role of TriC have been suggested (Yam et al., 2008). The processes of TRiC-mediated folding and assembly could be directly coupled, or TRiC could fold monomeric subunits and hold them in an assembly-competent state until they associate with the appropriate partner subunits. The complete list of TriC subsrates is not yet known. Many of its substrates that are targeted during biosynthesis are conserved between mammals and yeast (Yam et al. 2008). Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed19011634 Reactome Database ID Release 43390470 Reactome, http://www.reactome.org ReactomeREACT_16984 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Beta-tubulin:GTP + Cofactor A -> Beta-tubulin:GTP: Cofactor A Authored: Matthews, L, 2008-12-01 04:46:41 Beta-tubulin folding intermediates generated via ATP-dependent interaction with TriC/CCT are captured by cofactors A and D (Tian et al., 1996; Tian et al., 1997) in a reversible reaction forming tubulin intermediate/cofactor complexes Factor A:beta tubulin or Factor D:beta tubulin. Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed8706133 Pubmed9265649 Reactome Database ID Release 43389956 Reactome, http://www.reactome.org ReactomeREACT_16994 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Hydrolysis of ATP and release of folded actin from CCT/TriC Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed12732144 Pubmed1351421 Reactome Database ID Release 43390453 Reactome, http://www.reactome.org ReactomeREACT_16915 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 TriC/CCT-mediated beta-actin folding involves rapid ATP-independent formation of a binary complex, followed by a slower ATP-dependent release of the native product (Gao et al., 1992). Group II chaperonins enclose substrate proteins following substrate binding through the formation of a "built- in" lid over the central cavity. Upon ATP binding, lid formation is triggered by the transition state of ATP hydrolysis (Meyer, et al., 2003). has a Stoichiometric coefficient of 8 Association of CCT/TriC with sphingosine kinase 1 Authored: Matthews, L, 2008-12-01 04:46:41 CCT/TRiC facilitates folding of newly translated SK1 into its mature active form (Zebol et al., 2008) Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed18775504 Reactome Database ID Release 43391266 Reactome, http://www.reactome.org ReactomeREACT_16980 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 alpha-tubulin:GTP + Cofactor B -> alpha-tubulin:GTP: Cofactor B Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed7592580 Pubmed9265649 Quasi-native alpha-tubulin folding intermediates generated via ATP-dependent interaction with CCT (Tian et al., 1995) are captured in a reversible reaction by cofactors B and/or E (Tian et al., 1997), forming the tubulin intermediate/cofactor complexes Factor B:alpha tubulin or Factor E:alpha tubulin. Reactome Database ID Release 43389972 Reactome, http://www.reactome.org ReactomeREACT_16900 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 atREs Converted from EntitySet in Reactome Reactome DB_ID: 2534423 Reactome Database ID Release 432534423 Reactome, http://www.reactome.org ReactomeREACT_150876 all-trans-retinyl esters alpha-tubulin:GTP + Cofactor E -> alpha-tubulin:GTP:Cofactor E Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed7592580 Pubmed9265649 Quasi-native alpha-tubulin folding intermediates generated via ATP-dependent interaction with CCT (Tian et al., 1995) are captured in a reversible reaction by cofactors B and/or E (Tian et al., 1997), forming the tubulin intermediate/cofactor complexes Factor B:alpha tubulin or Factor E:alpha tubulin. Reactome Database ID Release 43389978 Reactome, http://www.reactome.org ReactomeREACT_17027 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Beta-tubulin:GTP + Cofactor D -> Beta-tubulin:GTP: Cofactor D Authored: Matthews, L, 2008-12-01 04:46:41 Beta-tubulin folding intermediates generated via ATP-dependent interaction with TriC/CCT are captured by cofactors A and D (Tian et al., 1996; Tian et al., 1997) in a reversible reaction forming tubulin intermediate/cofactor complexes Factor A:beta tubulin or Factor D:beta tubulin. Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed8706133 Pubmed9265649 Reactome Database ID Release 43389969 Reactome, http://www.reactome.org ReactomeREACT_17024 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Beta-tubulin:GTP: Cofactor A+ Cofactor D -> Beta-tubulin:GTP:Cofactor D + Cofactor A Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Factor A:beta tubulin complex act as a reservoir capable of accepting or delivering its target tubulin protein to cofactor D (Tian et al., 1997). In the reverse reaction, Cofactor A may displace cofactor D in a cofactor D:beta tubulin complex. Pubmed9265649 Reactome Database ID Release 43389955 Reactome, http://www.reactome.org ReactomeREACT_16986 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 alpha-tubulin:GTP:Cofactor B +Cofactor E -> alpha-tubulin:GTP: Cofactor E +Cofactor B Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed9265649 Reactome Database ID Release 43389963 Reactome, http://www.reactome.org ReactomeREACT_16937 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 The factor B:alpha tubulin complex act as a reservoir capable of accepting or delivering alpha tubulin to cofactor E (Tian et al., 1997). In the reverse reaction, cofactor B may displace cofactor E in the cofactor E:alpha tubulin complex. fatty acyl groups Converted from EntitySet in Reactome Reactome DB_ID: 2534426 Reactome Database ID Release 432534426 Reactome, http://www.reactome.org ReactomeREACT_150811 Exchange of ADP for ATP in CCT/TriC:actin complex Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed7909354 Pubmed9153422 Reactome Database ID Release 43390459 Reactome, http://www.reactome.org ReactomeREACT_17011 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 The interaction between CCT and unfolded target proteins is thought to occur when CCT is in its ADP-bound state. ADP is then exchanged for ATP in CCT. has a Stoichiometric coefficient of 8 Beta-tubulin:GTP:Cofactor D:alpha-tubulin:GTP:Cofactor E:Cofactor C-> Beta-tubulin:GDP :alpha-tubulin:GTP heterodimer +Cofactor E+ Cofactor D+ Cofactor C+ Pi Authored: Matthews, L, 2008-12-01 04:46:41 Beta tubulin within the active (Factor E:alpha tubulin: Factor D:beta tubulin:Factor C )-supercomplex hydrolyzes GTP. This results in the dissociation of the complex and the release of the native tubulin heterodimer (Tian et al., 1997). Edited: Matthews, L, 2009-02-21 05:37:28 Pubmed9265649 Reactome Database ID Release 43389974 Reactome, http://www.reactome.org ReactomeREACT_16958 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 vitamin K epoxide -> vitamin K hydroquinone Authored: D'Eustachio, P, 2005-03-17 16:24:57 EC Number: 1.1.4.1 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed14765176 Pubmed14765194 Pubmed14765195 Pubmed3932474 Reactome Database ID Release 43159790 Reactome, http://www.reactome.org ReactomeREACT_950 The regeneration of reduced vitamin K (vitamin K hydroquinone) from vitamin K epoxide is catalyzed by vitamin K epoxide reductase (VKORC1) (Sadler 2004). This enzyme is the target of the anticoagulant drug warfarin. Two important features of this reaction remain unclear. First, dithiothreitol functions efficiently as a reductant in vitro (Wallin and Martin 1985), but the in vivo reductant remains unknown. Second, while people homozygous for mutations in VKORC1 protein lack epoxide reductase activity (Rost et al. 2004) and cultured insect cells transfected with the cloned human VKORC1 gene express vitamin K epoxide reductase activity (Li et al. 2004), the possibility that the active form of the enzyme is a complex with other proteins cannot be formally excluded. has a Stoichiometric coefficient of 2 pro-factor IX, uncarboxylated + 12 CO2 + 12 O2 + 12 vitamin K hydroquinone -> pro-factor IX + 12 H2O + 12 vitamin K epoxide At the beginning of this reaction, 12 molecules of 'Oxygen', 12 molecules of 'vitamin K hydroquinone', 12 molecules of 'CO2', and 1 molecule of 'pro-factor IX, uncarboxylated' are present. At the end of this reaction, 12 molecules of 'H2O', 12 molecules of 'vitamin K epoxide', and 1 molecule of 'pro-factor IX' are present.<br><br> This reaction takes place in the 'endoplasmic reticulum membrane' and is mediated by the 'gamma-glutamyl carboxylase activity' of 'vitamin K-dependent gamma-carboxylase'.<br> Pubmed10068650 Pubmed10917896 Pubmed11513608 Pubmed2738071 Pubmed8530480 Reactome Database ID Release 43159803 Reactome, http://www.reactome.org ReactomeREACT_2045 has a Stoichiometric coefficient of 12 pro-factor VII, uncarboxylated + 10 CO2 + 10 O2 + 10 vitamin K hydroquinone -> pro-factor VII + 10 H2O + 10 vitamin K epoxide At the beginning of this reaction, 10 molecules of 'Oxygen', 10 molecules of 'vitamin K hydroquinone', 10 molecules of 'CO2', and 1 molecule of 'pro-factor VII, uncarboxylated' are present. At the end of this reaction, 1 molecule of 'pro-factor VII', 10 molecules of 'H2O', and 10 molecules of 'vitamin K epoxide' are present.<br><br> This reaction takes place in the 'endoplasmic reticulum membrane' and is mediated by the 'gamma-glutamyl carboxylase activity' of 'vitamin K-dependent gamma-carboxylase'.<br> Pubmed10068650 Pubmed10917896 Pubmed11513608 Pubmed8530480 Reactome Database ID Release 43159761 Reactome, http://www.reactome.org ReactomeREACT_1969 has a Stoichiometric coefficient of 10 pro-factor X, uncarboxylated + 11 CO2 + 11 O2 + 11 vitamin K hydroquinone -> pro-factor X + 11 H2O + 11 vitamin K epoxide At the beginning of this reaction, 11 molecules of 'Oxygen', 1 molecule of 'pro-factor X, uncarboxylated', 11 molecules of 'vitamin K hydroquinone', and 11 molecules of 'CO2' are present. At the end of this reaction, 1 molecule of 'pro-factor X', 11 molecules of 'H2O', and 11 molecules of 'vitamin K epoxide' are present.<br><br> This reaction takes place in the 'endoplasmic reticulum membrane' and is mediated by the 'gamma-glutamyl carboxylase activity' of 'vitamin K-dependent gamma-carboxylase'.<br> Pubmed10068650 Pubmed10917896 Pubmed11513608 Pubmed8530480 Reactome Database ID Release 43159819 Reactome, http://www.reactome.org ReactomeREACT_1565 has a Stoichiometric coefficient of 11 pro-prothrombin, uncarboxylated + 10 CO2 + 10 O2 + 10 vitamin K hydroquinone -> pro-prothrombin + 10 H2O + 10 vitamin K epoxide At the beginning of this reaction, 10 molecules of 'Oxygen', 10 molecules of 'vitamin K hydroquinone', 10 molecules of 'CO2', and 1 molecule of 'pro-prothrombin (factor II), uncarboxylated' are present. At the end of this reaction, 1 molecule of 'pro-prothrombin (factor II)', 10 molecules of 'H2O', and 10 molecules of 'vitamin K epoxide' are present.<br><br> This reaction takes place in the 'endoplasmic reticulum membrane' and is mediated by the 'gamma-glutamyl carboxylase activity' of 'vitamin K-dependent gamma-carboxylase'.<br> Pubmed10068650 Pubmed10917896 Pubmed11513608 Pubmed8530480 Reactome Database ID Release 43159826 Reactome, http://www.reactome.org ReactomeREACT_903 has a Stoichiometric coefficient of 10 pro-protein C, uncarboxylated + 8 CO2 + 8 O2 + 8 vitamin K hydroquinone -> pro-protein C + 8 H2O + 8 vitamin K epoxide At the beginning of this reaction, 8 molecules of 'Oxygen', 8 molecules of 'vitamin K hydroquinone', 8 molecules of 'CO2', and 1 molecule of 'pro-protein C, uncarboxylated' are present. At the end of this reaction, 8 molecules of 'H2O', 8 molecules of 'vitamin K epoxide', and 1 molecule of 'pro-protein C' are present.<br><br> This reaction takes place in the 'endoplasmic reticulum membrane' and is mediated by the 'gamma-glutamyl carboxylase activity' of 'vitamin K-dependent gamma-carboxylase'.<br> Pubmed10068650 Pubmed10917896 Pubmed11513608 Pubmed8530480 Reactome Database ID Release 43159795 Reactome, http://www.reactome.org ReactomeREACT_913 has a Stoichiometric coefficient of 8 pro-protein S, uncarboxylated + 11 CO2 + 11 O2 + 11 vitamin K hydroquinone -> pro-protein S + 11 H2O + 11 vitamin K epoxide At the beginning of this reaction, 11 molecules of 'Oxygen', 11 molecules of 'vitamin K hydroquinone', 11 molecules of 'CO2', and 1 molecule of 'pro-protein S, uncarboxylated' are present. At the end of this reaction, 1 molecule of 'pro-protein S', 11 molecules of 'H2O', and 11 molecules of 'vitamin K epoxide' are present.<br><br> This reaction takes place in the 'endoplasmic reticulum membrane' and is mediated by the 'gamma-glutamyl carboxylase activity' of 'vitamin K-dependent gamma-carboxylase'.<br> Pubmed10068650 Pubmed10917896 Pubmed11513608 Pubmed8530480 Reactome Database ID Release 43159752 Reactome, http://www.reactome.org ReactomeREACT_1307 has a Stoichiometric coefficient of 11 Beta-tubulin:GTP:Cofactor D:alpha-tubulin:GTP:Cofactor E+ Cofactor C-> Beta-tubulin:GTP:Cofactor D:alpha-tubulin:GTP:Cofactor E:Cofactor C Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Entry of cofactor C to the factor E:alpha tubulin: factor D:beta tubulin complex generates the active alpha:beta-supercomplex (Tian et al., 1997). Pubmed9265649 Reactome Database ID Release 43389964 Reactome, http://www.reactome.org ReactomeREACT_17016 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Beta-tubulin:GTP:Cofactor D+alpha-tubulin:GTP:Cofactor E-> Beta-tubulin:GTP:Cofactor D:alpha-tubulin:GTP:Cofactor E Authored: Matthews, L, 2008-12-01 04:46:41 Edited: Matthews, L, 2009-02-21 05:37:28 Factor E:alpha tubulin and Factor D:beta tubulin interact with each other in a reversible reaction to form the complex (Factor E alpha tubulin:Factor D:beta tubulin) (Tian et al., 1997). Pubmed9265649 Reactome Database ID Release 43389976 Reactome, http://www.reactome.org ReactomeREACT_17060 Reviewed: Cowan, NJ, 2009-01-21 16:47:24 Pro-GAS6 is transported from the endoplasmic reticulum to the Golgi apparatus In this reaction, 1 molecule of 'pro-GAS6' is translocated from endoplasmic reticulum lumen to Golgi lumen.<br><br>This reaction takes place in the 'ER to Golgi transport vesicle'.<br> Reactome Database ID Release 43163809 Reactome, http://www.reactome.org ReactomeREACT_1 Pro-protein S is transported from the endoplasmic reticulum to the Golgi apparatus In this reaction, 1 molecule of 'pro-protein S' is translocated from endoplasmic reticulum membrane to Golgi membrane.<br><br>This reaction takes place in the 'ER to Golgi transport vesicle'.<br> Reactome Database ID Release 43159729 Reactome, http://www.reactome.org ReactomeREACT_199 Pro-protein Z is transported from the endoplasmic reticulum to the Golgi apparatus In this reaction, 1 molecule of 'pro-protein Z' is translocated from endoplasmic reticulum lumen to Golgi lumen.<br><br>This reaction takes place in the 'ER to Golgi transport vesicle'.<br> Reactome Database ID Release 43163825 Reactome, http://www.reactome.org ReactomeREACT_1864 Pro-prothrombin is transported from the endoplasmic reticulum to the Golgi apparatus In this reaction, 1 molecule of 'pro-prothrombin (factor II)' is translocated from endoplasmic reticulum lumen to Golgi lumen.<br><br>This reaction takes place in the 'ER to Golgi transport vesicle'.<br> Reactome Database ID Release 43159843 Reactome, http://www.reactome.org ReactomeREACT_46 Pro-protein C is transported from the endoplasmic reticulum to the Golgi apparatus In this reaction, 1 molecule of 'pro-protein C' is translocated from endoplasmic reticulum lumen to Golgi lumen.<br><br>This reaction takes place in the 'ER to Golgi transport vesicle'.<br> Reactome Database ID Release 43159762 Reactome, http://www.reactome.org ReactomeREACT_1103 Pro-factor VII is transported from the endoplasmic reticulum to the Golgi apparatus In this reaction, 1 molecule of 'pro-factor VII' is translocated from endoplasmic reticulum lumen to Golgi lumen.<br><br>This reaction takes place in the 'ER to Golgi transport vesicle'.<br> Reactome Database ID Release 43159783 Reactome, http://www.reactome.org ReactomeREACT_1743 Pro-factor X is transported from the endoplasmic reticulum to the Golgi apparatus In this reaction, 1 molecule of 'pro-factor X' is translocated from endoplasmic reticulum lumen to Golgi lumen.<br><br>This reaction takes place in the 'ER to Golgi transport vesicle'.<br> Reactome Database ID Release 43159757 Reactome, http://www.reactome.org ReactomeREACT_968 Pro-factor IX is transported from the endoplasmic reticulum to the Golgi apparatus In this reaction, 1 molecule of 'pro-factor IX' is translocated from endoplasmic reticulum lumen to Golgi lumen.<br><br>This reaction takes place in the 'ER to Golgi transport vesicle'.<br> Reactome Database ID Release 43159836 Reactome, http://www.reactome.org ReactomeREACT_618 pro-GAS6, uncarboxylated + 11 CO2 + 11 O2 + 11 vitamin K hydroquinone -> pro-GAS6 + 11 H2O + 11 vitamin K epoxide Authored: D'Eustachio, P, 2005-05-07 21:30:29 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed8336730 Reactome Database ID Release 43163810 Reactome, http://www.reactome.org ReactomeREACT_1290 The details of the gamma-carboxylation of GAS6 have not been determined directly, but are inferred from those worked out for protein S (Manfioletti et al. 1993). has a Stoichiometric coefficient of 11 pro-protein Z, uncarboxylated + 13 CO2 + 13 O2 + 13 vitamin K hydroquinone -> pro-protein Z + 13 H2O + 13 vitamin K epoxide At the beginning of this reaction, 1 molecule of 'pro-protein Z, uncarboxylated', 13 molecules of 'Oxygen', 13 molecules of 'vitamin K hydroquinone', and 13 molecules of 'CO2' are present. At the end of this reaction, 1 molecule of 'pro-protein Z', 13 molecules of 'H2O', and 13 molecules of 'vitamin K epoxide' are present.<br><br> This reaction takes place in the 'endoplasmic reticulum membrane' and is mediated by the 'gamma-glutamyl carboxylase activity' of 'vitamin K-dependent gamma-carboxylase'.<br> Pubmed10068650 Pubmed10917896 Pubmed11513608 Pubmed8530480 Reactome Database ID Release 43163820 Reactome, http://www.reactome.org ReactomeREACT_124 has a Stoichiometric coefficient of 13 EIF5A + spermidine <=> EIF5A(Dhp) + 1,3-diaminopropane Authored: Johansson, HE, 2007-11-28 23:26:30 Cytosolic deoxyhypusine synthase catalyzes the reaction of EIF5A protein, spermidine, and NAD+ to convert lysine-50 of EIF5A to deoxyhypusine, generating 1,3-diaminopropane and NADH + H+ in the process (Park 2006). Although the reaction is reversible, the reverse reaction is probably minimized under physiological conditions by the rapid, irreversible conversion of EIF5A(Dhp) to EIF5A(Hyp). EC Number: 2.5.1.46 Edited: D'Eustachio, P, 2007-11-28 23:33:46 Pubmed14622290 Pubmed16452303 Pubmed7673224 Pubmed9188485 Reactome Database ID Release 43204647 Reactome, http://www.reactome.org ReactomeREACT_12551 Reviewed: Jassal, B, 2008-01-28 15:51:00 EIF5A(Dhp) + 1,3-diaminopropane <=> EIF5A + spermidine Authored: Johansson, HE, 2007-11-28 23:26:30 EC Number: 2.5.1.46 Edited: D'Eustachio, P, 2007-11-28 23:33:46 Pubmed16452303 Reactome Database ID Release 43204617 Reactome, http://www.reactome.org ReactomeREACT_12481 Reviewed: Jassal, B, 2008-01-28 15:51:00 The reaction of EIF5A, spermidine, and NAD+ to form EIF5A(Dhp), 1,3-diaminopropane, and NADH + H+ is reversible in vitro. Under physiological conditions, the reverse reaction is probably minimized by the rapid, irreversible conversion of FIF5A(Dhp) to EIF5A(Hyp). pro-protein C -> protein C + protein C propeptide At the beginning of this reaction, 1 molecule of 'pro-protein C' is present. At the end of this reaction, 1 molecule of 'protein C', and 1 molecule of 'protein C light chain propeptide' are present.<br><br> This reaction takes place in the 'Golgi lumen' and is mediated by the 'furin activity' of 'furin'.<br> EC Number: 3.4.21 Reactome Database ID Release 43159771 Reactome, http://www.reactome.org ReactomeREACT_2146 pro-protein S -> protein S + protein S propeptide At the beginning of this reaction, 1 molecule of 'pro-protein S' is present. At the end of this reaction, 1 molecule of 'protein S propeptide', and 1 molecule of 'protein S' are present.<br><br> This reaction takes place in the 'Golgi lumen' and is mediated by the 'furin activity' of 'furin'.<br> EC Number: 3.4.21 Reactome Database ID Release 43159773 Reactome, http://www.reactome.org ReactomeREACT_1860 pro-protein Z -> protein Z + protein Z propeptide At the beginning of this reaction, 1 molecule of 'pro-protein Z' is present. At the end of this reaction, 1 molecule of 'protein Z propeptide', and 1 molecule of 'protein Z' are present.<br><br> This reaction takes place in the 'Golgi lumen' and is mediated by the 'furin activity' of 'furin'.<br> EC Number: 3.4.21 Reactome Database ID Release 43163798 Reactome, http://www.reactome.org ReactomeREACT_1535 pro-GAS6 -> GAS6 + GAS6 propeptide Authored: D'Eustachio, P, 2005-05-07 21:30:29 EC Number: 3.4.21 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed8336730 Reactome Database ID Release 43163843 Reactome, http://www.reactome.org ReactomeREACT_1117 The details of the gamma-carboxylation of GAS6 have not been determined directly, but are inferred from those worked out for protein S (Manfioletti et al. 1993). pro-factor VII -> factor VII + factor VII propeptide At the beginning of this reaction, 1 molecule of 'pro-factor VII' is present. At the end of this reaction, 1 molecule of 'factor VII', and 1 molecule of 'factor VII propeptide' are present.<br><br> This reaction takes place in the 'Golgi membrane' and is mediated by the 'furin activity' of 'furin'.<br> EC Number: 3.4.21 Reactome Database ID Release 43159868 Reactome, http://www.reactome.org ReactomeREACT_1423 pro-factor IX -> factor IX + factor IX propeptide At the beginning of this reaction, 1 molecule of 'pro-factor IX' is present. At the end of this reaction, 1 molecule of 'factor IX', and 1 molecule of 'factor IX propeptide' are present.<br><br> This reaction takes place in the 'Golgi membrane' and is mediated by the 'furin activity' of 'furin'.<br> EC Number: 3.4.21 Reactome Database ID Release 43159796 Reactome, http://www.reactome.org ReactomeREACT_420 pro-prothrombin -> prothrombin + prothrombin propeptide At the beginning of this reaction, 1 molecule of 'pro-prothrombin (factor II)' is present. At the end of this reaction, 1 molecule of 'prothrombin (factor II) propeptide', and 1 molecule of 'prothrombin (factor II)' are present.<br><br> This reaction takes place in the 'Golgi membrane' and is mediated by the 'furin activity' of 'furin'.<br> EC Number: 3.4.21 Reactome Database ID Release 43159728 Reactome, http://www.reactome.org ReactomeREACT_1065 pro-factor X -> factor X + factor X propeptide At the beginning of this reaction, 1 molecule of 'pro-factor X' is present. At the end of this reaction, 1 molecule of 'factor X light chain propeptide', and 1 molecule of 'factor X' are present.<br><br> This reaction takes place in the 'Golgi membrane' and is mediated by the 'furin activity' of 'furin'.<br> EC Number: 3.4.21 Reactome Database ID Release 43159733 Reactome, http://www.reactome.org ReactomeREACT_1644 glucosaminyl-acyl-PI + dolichol phosphate D-mannose -> mannose(al1-4)glucosaminyl-acyl-PI + dolichol phosphate Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In the fifth step of GPI synthesis, a mannose residue is added to glucosaminyl-acyl-PI. The reaction takes place at the lumenal surface of the endoplasmic reticulum membrane. It is catalyzed by a complex of at least two components, PIG-M and PIG-X (Maeda et al. 2001; Ashida et al. 2005). Pubmed11226175 Pubmed15635094 Reactome Database ID Release 43162830 Reactome, http://www.reactome.org ReactomeREACT_1018 glucosaminyl-PI + fatty acyl-CoA -> glucosaminyl-acyl-PI + CoA-SH Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In the fourth step of GPI synthesis, an acyl group (typically palmitate) is transferred from acyl CoA to glucosaminyl-PI. Mutagenesis and cloning studies suggest that a single protein, PIG-W, catalyzes this reaction (Murakami et al. 2003). Pubmed14517336 Reactome Database ID Release 43162683 Reactome, http://www.reactome.org ReactomeREACT_1049 Reorientation of glucosaminyl-acyl-PI in the endoplasmic reticulum membrane Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 GPI moieties are synthesized anchored to dolichol phosphate in the membrane of the endoplasmic reticulum. The first two steps of the synthetic pathway, leading to the production of glucosaminyl-PI, occur on the cytosolic face of the membrane, while addition of an acyl group (step 4) and all subsequent steps occur on the lumenal face (Murakami et al. 2003). No mutant cell lines defective in the reorientation step have been identified, and the mechanism by which it occurs is unknown. Pubmed11102867 Pubmed14517336 Reactome Database ID Release 43162840 Reactome, http://www.reactome.org ReactomeREACT_1526 N-acetylglucosaminyl-PI + H2O -> glucosaminyl-PI + acetate Authored: D'Eustachio, P, 2005-04-04 21:01:34 EC Number: 3.5.1.89 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In the second step of GPI synthesis, N-acetylglucosaminyl-PI is hydrolyzed to yield glucosaminyl-PI and acetate. The phosphatidylinositol (PI) derivatives involved in this reaction are located in the endoplasmic reticulum membrane, as is the PIG-L enzyme that catalyzes it (Sharma et al. 1999; Pottekat and Menon 2004). Pubmed10089216 Pubmed14742432 Reactome Database ID Release 43162857 Reactome, http://www.reactome.org ReactomeREACT_779 mannose(a1-4)glucosaminyl-acyl-PI + phosphatidylethanolamine -> (ethanolamineP) mannose(al1-4)glucosaminyl-acyl-PI + diacylglycerol Authored: D'Eustachio, P, 2005-04-04 21:01:34 EC Number: 2.7.8 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In the sixth step of GPI synthesis, a phosphoethanolamine group is transferred from phosphatidylethanolamine onto the first mannose of the GPI precursor. The human protein that catalyzes this reaction was first identified because it could complement a yeast mutant strain defective for GPI synthesis (Gaynor et al. 1999); its specific function in phosphoethanolamine transfer is inferred from functional studies of the homologous mouse protein (Hong et al. 1999). The reaction is annotated here with phosphatidylethanolamine as the donor of the phosphoethanolamine group on the basis of studies in yeast (Imhof et al. 2000). Pubmed10069808 Pubmed10574991 Pubmed11159918 Reactome Database ID Release 43162798 Reactome, http://www.reactome.org ReactomeREACT_464 EIF5A(Dhp) + O2 => EIF5A(Hyp) Authored: Johansson, HE, 2007-11-28 23:26:30 Cytosolic deoxyhypusine hydroxylase catalyzes the irreversible conversion of peptidyl-deoxyhypusine to peptidyl-hypusine. The only known substrate for this enzyme is the modified lysine at residue 50 of eIF5A (Kang et al. 2007; Kim et al. 2006). EC Number: 1.14.99.29 Edited: D'Eustachio, P, 2007-11-28 23:33:46 Pubmed14622290 Pubmed16533814 Pubmed17213197 Reactome Database ID Release 43204662 Reactome, http://www.reactome.org ReactomeREACT_12479 Reviewed: Jassal, B, 2008-01-28 15:51:00 Reorientation of dolichyl phosphate D-mannose in the endoplasmic reticulum membrane Authored: Dall'Olio, GM, 2009-11-10 Dolichyl phosphate D-mannose is flipped in the endoplasmic reticulum membrane so that its mannose moiety is oriented inwards, towards the endoplasmic reticulum lumen, where it is accessible to transferases catalyzing the synthesis of glycolipids and glycoproteins (Kinoshita and Inoue 2000). Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed11102867 Reactome Database ID Release 43162715 Reactome, http://www.reactome.org ReactomeREACT_652 Reviewed: Gagneux, P, 2010-04-16 phosphatidylinositol + UDP-N-acetyl-D-glucosamine -> N-acetylglucosaminyl-PI + UDP Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10944123 Pubmed8900170 Pubmed9463366 Reactome Database ID Release 43162730 Reactome, http://www.reactome.org ReactomeREACT_1240 The first step of GPI synthesis is the transfer of N-acetylglucosamine from cytosolic UDP-N-acetylglucosamine to phosphatidyl inositol (PI) in the endoplasmic reticulum membrane. The reaction is catalyzed by a multimeric enzyme, also localized to the endoplasmic reticulum membrane, six components of which have been identified to date by mutagenesis studies in cultured cells and by co-recipitation studies in vitro (Watanabe et al. 1996, 1998, 2000). SUMF2 inhibits SUMF1-mediated activation of arylsulfatases Authored: Jassal, B, 2011-09-28 Edited: Jassal, B, 2011-09-28 Pubmed15708861 Pubmed15962010 Reactome Database ID Release 431614336 Reactome, http://www.reactome.org ReactomeREACT_121184 Reviewed: D'Eustachio, P, 2012-05-14 Sulfatase-modifying factor 2 (SUMF2, also called C-alpha-formylglycine-generating enzyme 2, pFGE) is the paralogue of SUMF1. While SUMF1 can modify a critical residue on arylsulfatases to confer activity to them, SUMF2 lacks this ability (Mariappan et al. 2005) and instead, SUMF2 can inhibit the action of SUMF1 by dimerising with it (Zito et al. 2005). SUMF2 can interact with sulfatases with and without SUMF1 (Zito et al. 2005). dolichyl phosphate + GDP-alpha-D-mannose -> dolichyl phosphate D-mannose Authored: Dall'Olio, GM, 2009-11-10 Cytosolic GDP-mannose reacts with dolichyl phosphate in the endoplasmic reticulum membrane to form dolichyl phosphate D-mannose. The reaction is catalyzed by dolichyl-phosphate mannosyltransferase, a heterotrimeric protein embedded in the endoplasmic reticulum membrane. The first subunit of the heterotrimer appears to be the actual catalyst, and the other two subunits appear to stabilize it (Maeda et al. 2000). EC Number: 2.4.1.83 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10835346 Reactome Database ID Release 43162721 Reactome, http://www.reactome.org ReactomeREACT_2036 Reviewed: Gagneux, P, 2010-04-16 Phosphorylation of dolichol Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.7.1.108 Edited: Jassal, B, 2009-11-10 Pubmed12213788 Pubmed17273964 Reactome Database ID Release 43446195 Reactome, http://www.reactome.org ReactomeREACT_22276 Reviewed: Gagneux, P, 2010-04-16 The phosphorylation of a dolichol residue of the ER membrane is a starting step in the N-glycan biosynthesis pathway (Fernandez F et al, 2002). Defects in DOLK are the cause of congenital disorder of glycosylation type 1M (CDG1M), also known as dolichol kinase deficiency (Kranz C et al, 2007). uPAR-acyl-GPI + H2O -> uPAR + long-chain fatty acid Authored: D'Eustachio, P, 2005-04-04 21:01:34 EC Number: 3.1 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed14734546 Reactome Database ID Release 43162729 Reactome, http://www.reactome.org ReactomeREACT_1978 The fatty acid group added to inositol in the fourth step of GPI biosynthsis is removed from GPI-conjugated uPAR. This hydrolysis event occurs in the endoplasmic reticulum and appears to be associated with efficient transport of the conjugated protein from the endoplasmic reticulum to the Golgi apparatus (Tanaka et al. 2004). Formation of glucosamine 6-phosphate from fructose 6-phosphate and glutamine Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.6.1.16 Edited: Jassal, B, 2009-12-07 Glucosamine-fructose 6-phosphate aminotransferase (GFAT) is the first and rate-limiting enzyme in the hexosamine synthesis pathway, and thus formation of hexosamines like N-acetylglucosamine (GlcNAc). This enzyme probably plays a role in limiting the availability of substrates for the N- and O- linked glycosylation of proteins. Two isoforms, GFAT 1 and 2, have been identified (McKnight GL et al, 1992; Oki T et al, 1999). GFAT is required normal functioning of neuromuscular synaptic transmission. Defects in the gene expressing this protein leads to altered muscle fiber morphology and impaired neuromuscular junction development (Senderek et al, 2011). Pubmed10198162 Pubmed1460020 Pubmed21310273 Reactome Database ID Release 43449715 Reactome, http://www.reactome.org ReactomeREACT_22115 Reviewed: Gagneux, P, 2010-04-16 Dephosphorylation of dolichyl diphosphate Authored: Dall'Olio, GM, 2009-11-10 EC Number: 3.6.1.43 Edited: Jassal, B, 2009-11-10 In the last step of the N-glycan precursor biosynthesis pathway, the mature N-glycan (Glc3Man9GlcNAc2) is removed from the dolichyl diphosphate molecule upon which it has been synthesized, and attached to a nascent protein. In this process, a dolichyl diphosphate molecule is released and once de-phosphorylated by dolichyl diphosphatase 1 (DOLPP1) to obtain dolichyl phosphate, it can be used as a substrate for the synthesis of another N-glycan oligosaccharide (Wedgwood JF and Strominger JL, 1980). Pubmed6243292 Reactome Database ID Release 43446200 Reactome, http://www.reactome.org ReactomeREACT_22114 Reviewed: Gagneux, P, 2010-04-16 (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI + dolichol phosphate D-mannose -> mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI + dolichol phosphate Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In the seventh reaction of GPI synthesis, a second mannose residue is added to the glycolipid on the lumenal face of the endoplasmic reticulum membrane. PIG-V was identified as the catylyst, or a component of the catalyst, of this reaction, on the basis of its ability to correct the metabolic defects of yeast and mammalian mutant cells arrested at this stage of the GPI synthetic process (Fabre et al. 2005; Kang et al. 2005). Pubmed15623507 Pubmed15720390 Reactome Database ID Release 43162873 Reactome, http://www.reactome.org ReactomeREACT_1848 mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI + dolichol phosphate D-mannose -> mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI + dolichol phosphate Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In the eighth reaction of GPI synthesis, a third mannose residue is added, catalyzed by PIG-B (Takahashi et al. 1996). Pubmed8861954 Reactome Database ID Release 43162821 Reactome, http://www.reactome.org ReactomeREACT_1308 mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI + phosphatidylethanolamine -> (ethanolamineP) mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI (acyl-GPI) + diacylglycerol Authored: D'Eustachio, P, 2005-04-04 21:01:34 EC Number: 2.7.8 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10781593 Pubmed8463218 Reactome Database ID Release 43163069 Reactome, http://www.reactome.org ReactomeREACT_2043 The final step in the main pathway for the synthesis of GPI moieties in human cells is the addition of an ethanolamine phosphate to the third mannose residue of the glycolipid, donated by phosphatidylethanolamine. This reaction has been experimentally characterized in the mouse, where studies with mutated cell lines defective in GPI biosynthesis have established the role of two proteins, PIG-F and PIG-O, in this reaction (Hong et al. 2000). While a human PIG-F protein has been identified and shown to be involved in this event (Inoue et al. 1993), the human event has not been fully characterized and is therefore annotated here as inferred from studies of the mouse event. mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI -> mannose (a1) mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Most human GPI anchors are thought to contain three mannose residues, while most yeast GPI anchors contain four. Recently, a human homologue of the yeast enzyme responsible for addition of the fourth mannose residue to GPI molecules was identified and shown to mediate synthesis of human GPI molecules with four mannose residues. While the mannose donor and the nature of the bond linking the third and fourth mannose residues have not been established directly in studies with the human enzyme, these features are known for yeast and the normal human gene restores GPI synthesis in mutant yeast. This observation, tegether with the sequence similarities among PIG-B and SMP3, it is reasonable to infer that the human enzyme uses dolichol-P-mannose as a donor. The functional distinction between GPI anchors with three and four mannose residues is unknown, although the latter appear to be abundant in many human tissues (Tauron et al. 2004). Pubmed15208306 Reactome Database ID Release 43162797 Reactome, http://www.reactome.org ReactomeREACT_2179 (ethanolamineP) mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI -> (ethanolamineP) mannose (a1-2) (ethanolamineP) mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI Authored: D'Eustachio, P, 2005-04-04 21:01:34 EC Number: 2.7.8 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Most human GPI anchors have ethanolamine phosphate groups attached to their first and third mannose residues, but GPI anchors with ethanolamine phosphates attached to all three mannose residues have also been identified. Addition of the third ethanolamine phosphate can be catalyzed by a complex of PIG-F and a newly described human protein, GPI7. The donor of the ethanolamine phosphate for this reaction is unknown (Shishioh et al. 2005). Pubmed15632136 Reactome Database ID Release 43162742 Reactome, http://www.reactome.org ReactomeREACT_155 uPAR precursor + acyl-GPI -> uPAR-acyl-GPI + uPAR propeptide Authored: D'Eustachio, P, 2005-04-04 21:01:34 Edited: D'Eustachio, P, 0000-00-00 00:00:00 In the endoplasmic reticulum, the precursor form of urokinase plasminogen activator receptor is transamidated at residue 305, replacing the 30 carboxyterminal residues of the protein with an acylated glucosylphosphatidylinositol (acyl-GPI) moiety. The released carboxyterminal propeptide has no known function. The reaction is catalyzed by GPI transamidase, a complex of at least five proteins associated with the lumenal surface of the endoplasmic reticulum membrane (Yu et al. 1997; Ohishi et al. 2001; Hong et al. 2003). Pubmed11483512 Pubmed12802054 Pubmed9356492 Reactome Database ID Release 43162836 Reactome, http://www.reactome.org ReactomeREACT_1777 Nucleolar phosphoprotein B23 Converted from EntitySet in Reactome Reactome DB_ID: 180716 Reactome Database ID Release 43180716 Reactome, http://www.reactome.org ReactomeREACT_9807 ADP/ATP translocase monomer (generic) Converted from EntitySet in Reactome Reactome DB_ID: 164858 Reactome Database ID Release 43164858 Reactome, http://www.reactome.org ReactomeREACT_8605 Addition of the second N-acetyl-glucosamine to the N-glycan precursor A second N-acetylglucosamine is added to the N-glycan precursor via a beta-1,4 linkage. This reaction is catalyzed by the ALG13:ALG14 complex, in which ALG13 functions as the catalyst and ALG14 functions as a membrane anchor which recruits ALG13 to the cytosolic face of ER (Gao XD et al, 2005). Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.141 Edited: Jassal, B, 2009-11-10 Pubmed16100110 Reactome Database ID Release 43446207 Reactome, http://www.reactome.org ReactomeREACT_22332 Reviewed: Gagneux, P, 2010-04-16 Nucleolar phosphoprotein B23 Converted from EntitySet in Reactome Reactome DB_ID: 180735 Reactome Database ID Release 43180735 Reactome, http://www.reactome.org ReactomeREACT_9856 Addition of N-acetyl-D-glucosamine to Dolichyl phosphate Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.7.8.15 Edited: Jassal, B, 2009-11-10 In the first step of N-glycan precursor (LLO) synthesis, N-acetylglucosamine is added, via an alpha-1,3 linkage, to a molecule of dolichyl phosphate, producing N-acetyl-D-glucosaminyl-diphosphodolichol (Eckert V et al, 1998). This reaction is catalyzed by DPAGT1 (ALG7 in yeast), mutations in which are associated with CDG disorder type I-J (Wu X et al, 2003). The dolichyl phosphate acts as an anchor for the LLO, so the following sugar-addition reactions take place on a sugar anchored in the ER membrane. Pubmed12872255 Pubmed9451016 Reactome Database ID Release 43446191 Reactome, http://www.reactome.org ReactomeREACT_22147 Reviewed: Gagneux, P, 2010-04-16 Flipping of dolichyl-phosphate-glucose into the ER lumen Authored: Dall'Olio, GM, 2009-11-10 Dolichyl-phosphate-glucose is flipped toward the luminal side of the ER membrane (Imbach T et al, 1999). The exact mechanism and proteins involved in this step are not clear yet, but it is known that it must be carried out by a different flippase than the one that catalyzes the flipping of the N-glycan precursor (Sanyal S et al, 2008). Edited: Jassal, B, 2009-11-10 Pubmed10359825 Pubmed18597486 Reactome Database ID Release 43446211 Reactome, http://www.reactome.org ReactomeREACT_22245 Reviewed: Gagneux, P, 2010-04-16 Mannose-1-phosphate converted to GDP-Mannose Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.7.7.13 Edited: Jassal, B, 2009-11-10 Mannose 1-phosphate is converted to GDP-Mannose by mannose-1-phosphate guanyltransferase alpha and beta forms (GMPPA/B). This enzyme had originally been characterized from rat and bovine sources (Verachtert H et al, 1966) and more recently from pig (Ning B and Elbein AD, 2000). Pubmed11082198 Pubmed5946626 Reactome Database ID Release 43446221 Reactome, http://www.reactome.org ReactomeREACT_22254 Reviewed: Gagneux, P, 2010-04-16 Synthesis of dolichyl-phosphate-glucose Authored: Dall'Olio, GM, 2009-11-10 Dolichyl-phosphate beta-glucosyltransferase (ALG5) associated with the endoplasmic reticulum (ER) membrane catalyzes the reaction of cytosolic UDP-glucose with dolichyl phosphate exposed on the cytosolic face of the ER membrane to form Dolichyl-P-glucose with its glucose moiety oriented toward the cytosol (Imbach T et al, 1999). EC Number: 2.4.1.117 Edited: Jassal, B, 2009-11-10 Pubmed10359825 Reactome Database ID Release 43446214 Reactome, http://www.reactome.org ReactomeREACT_22143 Reviewed: Gagneux, P, 2010-04-16 Fructose 6-phosphate isomerizes to Mannose 6-phosphate Authored: Dall'Olio, GM, 2009-11-10 EC Number: 5.3.1.8 Edited: Jassal, B, 2010-03-01 Mannose-6-phosphate isomerase (MPI) converts Fructose 6-phosphate to Mannose 6-phosphate (Proudfoot AE et al, 1994). Defects in this gene are associated with congenital disorder of glycosylation type 1B (CDG1B). Oral administration of mannose is an efficient therapy against this defect (Schollen E et al, 2000). Pubmed10980531 Pubmed8307007 Reactome Database ID Release 43532549 Reactome, http://www.reactome.org ReactomeREACT_22388 Reviewed: Gagneux, P, 2010-04-16 Mannose 6-phosphate isomerizes to Mannose 1-phosphate Authored: Dall'Olio, GM, 2009-11-10 EC Number: 5.4.2.8 Edited: Jassal, B, 2009-11-10 Phosphomannomutase 1 and 2 (PMM1 and PMM2) catalyze the isomerization of Mannose 6-phosphate to Mannose 1-phosphate (Wada Y and Sakamoto M et al, 1997; Matthijs G et al, February 1997). Mutations in the PMM2 gene are one of the causes of Jaeken syndrome. a disease of glycosylation, type CDGIa. (Matthijs G et al, May 1997). Pubmed9070917 Pubmed9119384 Pubmed9140401 Reactome Database ID Release 43446201 Reactome, http://www.reactome.org ReactomeREACT_22437 Reviewed: Gagneux, P, 2010-04-16 Isomerization of GlcNAc6P to GlcNAc1P Authored: Dall'Olio, GM, 2009-11-10 Cytosolic PGM3 catalyzes the isomerization of N-acetyl-D-glucosamine 6-phosphate (GlcNAc6P) to form N-acetyl-D-glucosamine 1-phosphate (GlcNAc1P) (Pang H et al, 2002). EC Number: 5.4.2.3 Edited: Jassal, B, 2009-11-10 Pubmed12174217 Reactome Database ID Release 43446185 Reactome, http://www.reactome.org ReactomeREACT_22269 Reviewed: Gagneux, P, 2010-04-16 GlcNAc1P is dephosphorylated to UDP-N-acetyl-glucosamine Authored: Dall'Olio, GM, 2009-11-10 Cytosolic UAP1 catalyzes the reaction of N-acetyl-D-glucosamine 1-phosphate (GlcNAc1P) and UTP to for UDP-N-acetyl-D-glucosamine and pyrophosphate. Structural studies indicate that the active form of the enzyme is a dimer (Peneff C et al, 2001) EC Number: 2.7.7.23 Edited: Jassal, B, 2009-11-10 Pubmed11707391 Reactome Database ID Release 43446204 Reactome, http://www.reactome.org ReactomeREACT_22397 Reviewed: Gagneux, P, 2010-04-16 Acetylation of glucosamine 6-phosphate to GlcNAc6P Authored: Dall'Olio, GM, 2009-11-10 Cytosolic GNPNAT1 catalyzes the reaction of glucosamine 6-phosphate and acetyl-CoA to form N-acetyl-glucosamine 6-phosphate (GlcNAc6P) and CoA-SH. Structural studies indicate that the active form of the enzyme is a dimer (Wang J et al, 2008). EC Number: 2.3.1.4 Edited: Jassal, B, 2009-12-07 Pubmed18675810 Reactome Database ID Release 43449734 Reactome, http://www.reactome.org ReactomeREACT_22233 Reviewed: Gagneux, P, 2010-04-16 Addition of the first glucose to the N-glycan precursor by ALG6 Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed10359825 Pubmed16007612 Reactome Database ID Release 43446202 Reactome, http://www.reactome.org ReactomeREACT_22194 Reviewed: Gagneux, P, 2010-04-16 The first glucose is added to the N-glycan precursor, mediated by ALG6. Defects in ALG6 are associated with CDG-Ic disorder (Imbach T et al, 1999; Sun L et al, 2005). The donor is a dolichol-phosphate-glucose (synthesized by ALG5). Addition of the last mannose to the N-glycan precursor by ALG3, inside the ER lumen. Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed12030331 Pubmed15148656 Pubmed15945070 Pubmed16859551 Reactome Database ID Release 43446216 Reactome, http://www.reactome.org ReactomeREACT_22307 Reviewed: Gagneux, P, 2010-04-16 The last mannose is added to the N-glycan precursor. This reaction occurs in the ER lumen, uses Dolichyl phosphate D-mannose as the mannose donor, and is catalyzed by ALG9. Defects in ALG9 are the cause of congenital disorder of glycosylation type 1L (CDG1L) (Frank CG et al, 2004; Weinstein M et al, 2005). For many years ALG9 was thought to be involved in bipolar affective disorder (Baysal BE et al, 2002), but this hypothesis has been proven wrong (Baysal BE et al, 2006). Flipping of the N-glycan precursor to inside the ER Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed11807558 Pubmed18313027 Pubmed18597486 Reactome Database ID Release 43446212 Reactome, http://www.reactome.org ReactomeREACT_22262 Reviewed: Gagneux, P, 2010-04-16 The precursor of the N-glycan sugar, now in the form of (GlcNAc)2 (Man)5 (PP-Dol), is flipped across the ER membrane, moving it from the cytosolic side into the ER lumen. The exact mechanism of this translocation is not well understood: the protein RFT1 is known to be involved (Helenius et al, 2002), along with an unknown flippase, which is distinct from the one that flips the Dol-P linked precursors (Dol-P-Mannose and Dol-P-glucose) (Sanyal et al, 2008). Defects in RFT1 are associated with Congenital Disorder of Glycosylation 1N (CDG1N) (Haeuptle MA et al, 2008). Addition of the sixth mannose to the N-glycan precursor by ALG3. Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed12200473 Pubmed15840742 Reactome Database ID Release 43446188 Reactome, http://www.reactome.org ReactomeREACT_22415 Reviewed: Gagneux, P, 2010-04-16 The sixth mannose is added to the N-glycan precursor. This reaction occurs in the ER lumen and uses a different mannose donor (dolichyl phosphate D-mannose) than the previous steps. It has been proposed that ALG3, along with all the mannosyl- and glucosyl transferases in the N-glycan biosynthesis pathway that use dolichyl phosphate D-mannose or dolichyl phosphate D-glucose as donor, derive from duplications of a common ancestral enzyme (Oriol R et al, 2002). Defects in ALG3 are associated with Congenital Disorder of Glycosylation 1D (CDG1D) (Sun L et al, 2005). Addition of the seventh mannose to the N-glycan precursor by ALG9, inside the ER lumen Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed12030331 Pubmed15148656 Pubmed15945070 Pubmed16859551 Reactome Database ID Release 43446215 Reactome, http://www.reactome.org ReactomeREACT_22123 Reviewed: Gagneux, P, 2010-04-16 The seventh mannose is added to the N-glycan precursor. This reaction occurs in the ER lumen and uses dolichyl phosphate D-mannose as the mannose donor with ALG9 mediating the reaction. Defects in ALG9 are the cause of congenital disorder of glycosylation type 1L (CDG1L) (Frank CG et al, 2004; Weinstein M et al, 2005). For many years ALG9 has been thought to be involved in bipolar affective disorder (Baysal BE et al, 2002), but this hypothesis has been proven wrong (Baysal BE et al, 2006). Addition of the eighth mannose to the N-glycan precursor by ALG12, inside the ER lumen Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed11983712 Reactome Database ID Release 43446198 Reactome, http://www.reactome.org ReactomeREACT_22117 Reviewed: Gagneux, P, 2010-04-16 The eighth mannose is added to the N-glycan precursor. This reaction occurs in the ER lumen and uses dolichyl phosphate D-mannose as a mannose donor. Defects in ALG12 are the cause of congenital disorder of glycosylation type 1G (CDG1G) (Chantret I et al, 2002). Addition of the first mannose to the N-glycan precursor by ALG13/14 A mannose is added to the N-glycan precursor via a beta-1,4 linkage. The reaction is catalyzed by ALG1 (Takahashi T et al, 2000). Defects in ALG1 lead to congenital disorder of glycosylation type 1K (CDG1K) (Schwarz M et al, 2004; Kranz C et al, 2004; Grubenmann CE et al, 2004). Authored: Dall'Olio, GM, 2009-11-10 EC Number: 2.4.1.142 Edited: Jassal, B, 2009-11-10 Pubmed10704531 Pubmed14709599 Pubmed14973778 Pubmed14973782 Reactome Database ID Release 43446218 Reactome, http://www.reactome.org ReactomeREACT_22214 Reviewed: Gagneux, P, 2010-04-16 Addition of a second mannose to the N-glycan precursor by ALG2 A second mannose is added to the N-glycan precursor via an alpha-1,3 linkage. The reaction is catalyzed by the mannosyltransferase ALG2. This is a bifunctional enzyme with both alpha 1,3- and alpha 1,6-mannosyltransferase activities. In humans, only the alpha 1,3 activity used in this reaction has been elucidated (Thiel C et al, 2003). Defects in ALG2 are the cause of CDG1I (Thiel C et al, 2003). Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed12684507 Reactome Database ID Release 43446208 Reactome, http://www.reactome.org ReactomeREACT_22347 Reviewed: Gagneux, P, 2010-04-16 Addition of a third mannose to the N-glycan precursor by ALG2 A third mannose is added to the N-glycan precursor by ALG2 using its alpha1,6-mannosyltransferase activity. This has been demonstrated experimentally in yeast (O'Reilly MK et al, 2006; Kämpf M et al, 2009); the human reaction is inferred by homology. Defects in ALG2 are the cause for CDG1I (Thiel C et al, 2003). Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-12-07 Pubmed12684507 Pubmed16878994 Pubmed19282279 Reactome Database ID Release 43449718 Reactome, http://www.reactome.org ReactomeREACT_22383 Reviewed: Gagneux, P, 2010-04-16 Addition of a fourth and fifth mannose to the N-glycan precursor by ALG11 A fourth mannose is added to the N-glycan precursor by ALG11. The addition of the fifth mannose, also by ALG11, is the last step occurring on the cytosolic side of the ER membrane (Cipollo JF et al, 2001). Both these reactions are alpha1,2 mannose additions. There are no known associations between ALG11 and CDG disorders to date. Authored: Dall'Olio, GM, 2009-11-10 Edited: Jassal, B, 2009-11-10 Pubmed11278778 Reactome Database ID Release 43446187 Reactome, http://www.reactome.org ReactomeREACT_22156 Reviewed: Gagneux, P, 2010-04-16 has a Stoichiometric coefficient of 2 PathwayStep3529 PathwayStep3524 PathwayStep3523 PathwayStep3522 PathwayStep3521 PathwayStep3528 PathwayStep3527 PathwayStep3526 PathwayStep3525 PathwayStep3530 PathwayStep3531 FGFR2b mutants with enhanced ligand binding Converted from EntitySet in Reactome Reactome DB_ID: 2033371 Reactome Database ID Release 432033371 Reactome, http://www.reactome.org ReactomeREACT_122026 FGFR2c mutants with enhanced ligand binding Converted from EntitySet in Reactome Reactome DB_ID: 2033375 Reactome Database ID Release 432033375 Reactome, http://www.reactome.org ReactomeREACT_125347 PathwayStep3519 PathwayStep3518 PathwayStep3511 PathwayStep3510 PathwayStep3513 PathwayStep3512 PathwayStep3515 PathwayStep3514 PathwayStep3517 PathwayStep3516 PathwayStep3520 PathwayStep3509 PathwayStep3508 PathwayStep3507 PathwayStep3506 PathwayStep3505 PathwayStep3504 PathwayStep3503 PathwayStep3502 PathwayStep3501 PathwayStep3500 PathwayStep3567 PathwayStep3568 PathwayStep3565 PathwayStep3566 PathwayStep3569 PathwayStep3571 PathwayStep3570 PathwayStep3575 PathwayStep3574 PathwayStep3573 PathwayStep3572 PathwayStep3554 PathwayStep3555 PathwayStep3556 PathwayStep3557 PathwayStep3558 PathwayStep3559 PathwayStep3560 PathwayStep3562 PathwayStep3561 PathwayStep3564 PathwayStep3563 PathwayStep3549 PathwayStep3547 PathwayStep3548 PathwayStep3545 PathwayStep3546 PathwayStep3543 PathwayStep3544 PathwayStep3553 PathwayStep3552 PathwayStep3551 PathwayStep3550 PathwayStep3536 PathwayStep3537 PathwayStep3538 PathwayStep3539 PathwayStep3532 PathwayStep3533 PathwayStep3534 PathwayStep3535 PathwayStep3540 PathwayStep3542 PathwayStep3541 SHC-related events triggered by IGF1R Authored: May, B, 2012-08-06 Edited: May, B, 2012-08-06 Phosphorylated IGF1R binds and phosphorylates SHC1 (reviewed in Pavelic et al. 2007, Chitnis et al. 2008, Maki et al. 2010, Parrella et al. 2010, Siddle et al. 2012). Phosphorylated SHC then binds GRB:SOS, which activates RAS-RAF-MAPK signaling. Pubmed17598937 Pubmed18927274 Pubmed20098959 Pubmed20975071 Pubmed22649417 Reactome Database ID Release 432428933 Reactome, http://www.reactome.org ReactomeREACT_150139 Reviewed: Holzenberger, Martin, 2012-11-09 Antagonism of Activin by Follistatin Authored: May, B, 2012-09-21 Both Follistatin (FST) and Follistatin-like-3 (FSTL3) irreversibly bind Activin dimers and prevent Activin from interacting with its receptor (reviewed in Schneyer et al. 2004 ,Xia and Schneyer 2009). Though functionally similar in vitro, FST and FSTL3 do not function identically in vivo. Mice lacking FST die shortly after birth due to defects in muscle and bone (Matzuk et al. 1995); mice lacking FSTL3 are viable but have altered glucose metabolism (Mukherjee et al. 2007). Edited: May, B, 2012-09-21 Pubmed15451564 Pubmed17229845 Pubmed19273500 Pubmed7885475 Reactome Database ID Release 432473224 Reactome, http://www.reactome.org ReactomeREACT_150276 Reviewed: Chen, Ye-Guang, 2012-11-14 Mitotic M-M/G1 phases Reactome Database ID Release 43453277 Reactome, http://www.reactome.org ReactomeREACT_21300 Reviewed: Manfredi, J, 0000-00-00 00:00:00 IRS-related events triggered by IGF1R Authored: May, B, 2012-08-06 Edited: May, B, 2012-08-06 Pubmed17598937 Pubmed18927274 Pubmed20098959 Pubmed20975071 Pubmed21042815 Pubmed22649417 Reactome Database ID Release 432428928 Reactome, http://www.reactome.org ReactomeREACT_150203 Reviewed: Holzenberger, Martin, 2012-11-09 The phosphorylated type 1 insulin-like growth factor receptor phosphorylates IR1, IRS2, IRS4 and possibly other IRS/DOK family members (reviewed in Pavelic et al. 2007, Chitnis et al. 2008, Maki et al. 2010, Parrella et al. 2010, Siddle et al. 2012). The phosphorylated IRS proteins serve as scaffolds that bind the effector molecules PI3K and GRB2:SOS. PI3K then activates PKB (AKT) signaling while GRB2:SOS activates RAS-RAF-MAPK signaling. Signaling by Activin Activin was initially discovered as an activator of follicle stimulating hormone in the pituitary gland. It has since been shown to be an important participant in the differentiation of embryonic cells into mesodermal and endodermal layers. Activin binds the Activin receptor and triggers downstream events: phosphorylation of SMAD2 and SMAD3 followed by activation of gene expression (reviewed in Attisano et al. 1996, Willis et al. 1996, Chen et al. 2006, Hinck 2012). Activins are dimers comprising activin A (INHBA:INHBA), activin AB (INHBA:INHBB), and activin B (INHBB:INHBB). Activin first binds the type II receptor (ACVR2A, ACVR2B) and this complex then interacts with the type I receptor (ACVR1B, ACVR1C) (Attisano et al. 1996). The type II receptor phosphorylates the type I receptor and then the phosphorylated type I receptor phosphorylates SMAD2 and SMAD3. Dimers of phosphorylated SMAD2/3 bind SMAD4 and the resulting ternary complex enters the nucleus and activates target genes. Authored: May, B, 2011-08-23 Edited: May, B, 2011-08-23 Pubmed16636301 Pubmed22651914 Pubmed8622651 Pubmed8721982 Reactome Database ID Release 431502540 Reactome, http://www.reactome.org ReactomeREACT_150238 Reviewed: Chen, Ye-Guang, 2012-11-14 PP2A (Calpha/Cbeta) Converted from EntitySet in Reactome Reactome DB_ID: 934615 Reactome Database ID Release 43934615 Reactome, http://www.reactome.org ReactomeREACT_111409 MIR34B gene Reactome DB_ID: 1852582 Reactome Database ID Release 431852582 Reactome, http://www.reactome.org ReactomeREACT_119216 MIR34C gene Reactome DB_ID: 1852583 Reactome Database ID Release 431852583 Reactome, http://www.reactome.org ReactomeREACT_119348 RORA Activates Circadian Expression As inferred from mouse, RORA binds ROR elements (ROREs) in DNA and recruits the coactivators PPARGC1A (PGC-1alpha) and p300 (EP300, a histone acetylase) to activate transcription. Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Pubmed7926749 Reactome Database ID Release 431368082 Reactome, http://www.reactome.org ReactomeREACT_118659 Reviewed: Delaunay, F, 2012-01-28 Circadian Repression of Expression by REV-ERBA Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Pubmed18037887 Pubmed20581824 REV-ERBA binds DNA elements very similar to those bound by the transcription activator RORA. RORAREV-ERBA bound to DNA and heme recruits the corepressors NCoR and HDAC3 to repress transcription. Thus REV-ERBA and RORA appear to compete to repress or activate genes, repectively. Reactome Database ID Release 431368071 Reactome, http://www.reactome.org ReactomeREACT_118789 Reviewed: Delaunay, F, 2012-01-28 BMAL1:CLOCK/NPAS2 Activates Circadian Expression As inferred from mouse, BMAL1:CLOCK and BMAL1:NPAS2 heterodimers bind to sequence elements (E boxes) in the promoters of target genes and enhance transcription (Gekakis et al. 1998, reviewed in Munoz and Baler 2003). Authored: May, B, 2011-06-22 Edited: May, B, 2011-06-22 Pubmed12868535 Pubmed9616112 Reactome Database ID Release 431368108 Reactome, http://www.reactome.org ReactomeREACT_111118 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Circadian Clock At the center of the mammalian circadian clock is a negative transcription/translation-based feedback loop: The BMAL1:CLOCK/NPAS2 heterodimer transactivates CRY and PER genes by binding E-box elements in their promoters; the CRY and PER proteins then inhibit transactivation by BMAL1:CLOCK/NPAS2. BMAL1:CLOCK/NPAS2 activates transcription of CRY, PER, and several other genes in the morning. Levels of PER and CRY proteins rise during the day and inhibit expression of CRY, PER, and other BMAL1:CLOCK/NPAS2-activated genes in the afternoon and evening. During the night CRY and PER proteins are targeted for degradation by phosphorylation and polyubiquitination, allowing the cycle to commence again in the morning. <br>Transcription of the BMAL1 (ARNTL) gene is controlled by ROR-alpha and REV-ERBA, both of which are targets of BMAL1:CLOCK/NPAS2 in mice and both of which compete for the same element (RORE) in the BMAL1 promoter. ROR-alpha activates transcription of BMAL1; REV-ERBA represses transcription of BMAL1. This mutual control forms a secondary, reinforcing loop of the circadian clock. REV-ERBA shows strong circadian rhythmicity and confers circadian expression on BMAL1. <br>BMAL1 can form heterodimers with either CLOCK or NPAS2, which act redundantly but show different tissue specificity. The BMAL1:CLOCK and BMAL1:NPAS2 heterodimers activate a set of genes that possess E-box elements (consensus CACGTG) in their promoters. This confers circadian expression on the genes. The PER genes (PER1, PER2, PER3) and CRY genes (CRY1, CRY2) are among those activated by BMAL1:CLOCK and BMAL1:NPAS2. PER and CRY mRNA accumulates during the morning and the proteins accumulate during the afternoon. PER and CRY proteins form complexes in the cytosol and these are bound by either CSNK1D or CSNK1E kinases which phosphorylate PER and CRY. The phosphorylated PER:CRY:kinase complex is translocated into the nucleus due to the nuclear localization signal of PER and CRY. Within the nucleus the PER:CRY complexes bind BMAL1:CLOCK and BMAL1:NPAS2, inhibiting their transactivation activity and their phosphorylation. This reduces expression of the target genes of BMAL1:CLOCK and BMAL1:NPAS2 during the afternoon and evening. <br>PER:CRY complexes also traffic out of the nucleus into the cytosol due to the nuclear export signal of PER. During the night PER:CRY complexes are polyubiquitinated and degraded, allowing the cycle to begin again. Phosphorylated PER is bound by Beta-TrCP1, a cytosolic F-box type component of some SCF E3 ubiquitin ligases. CRY is bound by FBXL3, a nucleoplasmic F-box type component of some SCF E3 ubiquitin ligases. Phosphorylation of CRY1 by Adenosine monophosphate-activated kinase (AMPK) enhances degradation of CRY1. PER and CRY are subsequently polyubiquitinated and proteolyzed by the 26S proteasome.<br>The circadian clock is cell-autonomous and some, but not all cells of the body exhibit circadian rhythms in metabolism, cell division, and gene transcription. The suprachiasmatic nucleus (SCN) in the hypothalamus is the major clock in the body and receives its major input from light (via retinal neurons) and a minor input from nutrient intake. The SCN and other brain tissues determine waking and feeding cycles and influence the clocks in other tissues by hormone secretion and nervous stimulation. Independently of the SCN, other tissues such as liver receive inputs from signals from the brain and from nutrients. Authored: May, B, 2009-05-17 22:04:50 Edited: May, B, 2009-05-17 22:04:50 Pubmed16987893 Pubmed18775307 Pubmed18786386 Pubmed18802415 Reactome Database ID Release 43400253 Reactome, http://www.reactome.org ReactomeREACT_24941 Reviewed: Albrecht, U, 2010-06-23 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Delaunay, F, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Steroid hormones Active steroid hormones are produced from the precursor cholesterol.The steps involved in the biosynthesis of the adrenal steroid hormones, corticosterone, cortisol, and aldosterone; and the gonadal steroid hormones, progesterone, estradiol, and testosterone are annotated here. The enzymes that catalyze these reactions fall into two major classes of proteins: the cytochrome P450 heme-containing proteins and the hydroxysteroid dehydrogenases. Authored: Jassal, B, 2008-10-01 13:18:42 Edited: Jassal, B, 2008-11-17 10:09:58 Pubmed15583024 Reactome Database ID Release 43209943 Reactome, http://www.reactome.org ReactomeREACT_15493 Reviewed: D'Eustachio, P, 2008-11-29 15:53:45 DARPP-32 events Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified as a major target for dopamine and protein kinase A (PKA) in striatum. Recent advances now indicate that regulation DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr34, converting DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr75 by Cdk5, converting DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA. Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed14744247 Pubmed2908293 Reactome Database ID Release 43180024 Reactome, http://www.reactome.org ReactomeREACT_15334 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Gastrin-CREB signalling pathway via PKC and MAPK Authored: Jassal, B, Tripathi, S, 2012-04-04 Edited: Jassal, B, Tripathi, S, 2012-04-04 Gastrin is a hormone whose main function is to stimulate secretion of hydrochloric acid by the gastric mucosa, which results in gastrin formation inhibition. This hormone also acts as a mitogenic factor for gastrointestinal epithelial cells. Gastrin has two biologically active peptide forms, G34 and G17.Gastrin gene expression is upregulated in both a number of pre-malignant conditions and in established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical gastrin cholecystokinin B receptor CCK-BR, its isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion (Wank 1995, de Weerth et al. 1999, Grabowska & Watson 2007) Pubmed10413847 Pubmed17698287 Pubmed7491953 Reactome Database ID Release 43881907 Reactome, http://www.reactome.org ReactomeREACT_120966 Reviewed: D'Eustachio, P, 2012-04-23 EGFR Transactivation by Gastrin Authored: Jassal, B, Tripathi, S, 2012-04-04 Edited: Jassal, B, Tripathi, S, 2012-04-04 Gastrin, through the action of diacylglycerol produced from downstream G alpha (q) events, transactivates EGFR via a PKC-mediated pathway by activation of MMP3 (Matrix Metalloproteinase 3) which allows formation of mature HBEGF (heparin-binding epidermal growth factor) by cleaving pro-HBEGF. Mature HBEGF is then free to bind the EGFR, resulting in EGFR activation (Dufresne et al. 2006, Liebmann 2011). Pubmed16816139 Pubmed20398727 Reactome Database ID Release 432179392 Reactome, http://www.reactome.org ReactomeREACT_121096 Reviewed: D'Eustachio, P, 2012-04-23 Signaling by Wnt Authored: Kimelman, D, 2007-04-03 12:34:14 Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed17143292 Pubmed19619488 Reactome Database ID Release 43195721 Reactome, http://www.reactome.org ReactomeREACT_11045 The beta-catenin destruction complex plays a key role in the canonical Wnt signaling pathway. In the absence of Wnt signaling, this complex controls the levels of cytoplamic beta-catenin. Beta-catenin associates with and is phosphorylated by the destruction complex. Phosphorylated beta-catenin is recognized and ubiquitinated by the SCF-beta TrCP ubiquitin ligase complex and is subsequently degraded by the proteasome (reviewed in Kimelman and Xu, 2006). NOTCH4 gene Reactome DB_ID: 1911501 Reactome Database ID Release 431911501 Reactome, http://www.reactome.org ReactomeREACT_119723 MIR34A gene Reactome DB_ID: 1852580 Reactome Database ID Release 431852580 Reactome, http://www.reactome.org ReactomeREACT_120202 MIR34 genes Converted from EntitySet in Reactome Reactome DB_ID: 1852586 Reactome Database ID Release 431852586 Reactome, http://www.reactome.org ReactomeREACT_119280 MVK gene Reactome DB_ID: 2393995 Reactome Database ID Release 432393995 Reactome, http://www.reactome.org ReactomeREACT_148520 PMVK gene Reactome DB_ID: 2393994 Reactome Database ID Release 432393994 Reactome, http://www.reactome.org ReactomeREACT_148307 SQLE gene Reactome DB_ID: 2393973 Reactome Database ID Release 432393973 Reactome, http://www.reactome.org ReactomeREACT_148363 ELOVL6 gene Reactome DB_ID: 2393996 Reactome Database ID Release 432393996 Reactome, http://www.reactome.org ReactomeREACT_148581 SHC1 p46/p52 Converted from EntitySet in Reactome Reactome DB_ID: 1169480 Reactome Database ID Release 431169480 Reactome, http://www.reactome.org ReactomeREACT_111758 SHC1 p46 and p52 FDPS gene Reactome DB_ID: 2393989 Reactome Database ID Release 432393989 Reactome, http://www.reactome.org ReactomeREACT_148106 NOTCH1 gene Reactome DB_ID: 1911481 Reactome Database ID Release 431911481 Reactome, http://www.reactome.org ReactomeREACT_119316 NOTCH2 gene Reactome DB_ID: 1911484 Reactome Database ID Release 431911484 Reactome, http://www.reactome.org ReactomeREACT_118878 p-SHC1 p46/p52 Converted from EntitySet in Reactome Phosphorylated SHC1 p46 and p52 Reactome DB_ID: 1169534 Reactome Database ID Release 431169534 Reactome, http://www.reactome.org ReactomeREACT_111325 NOTCH3 gene Reactome DB_ID: 1911492 Reactome Database ID Release 431911492 Reactome, http://www.reactome.org ReactomeREACT_119591 Beta-catenin phosphorylation cascade Authored: Kimelman, D, 2007-04-03 12:34:14 Degradation of beta-catenin is initiated following amino-terminal serine/threonine phosphorylation. Phosphorylation of B-catenin at S45 by CK1 alpha primes the subsequent sequential GSK-3-mediated phosphorylation at Thr41, Ser37 and Ser33 (Amit et al., 2002 ; Lui et al., 2002). Edited: Matthews, L, 2007-04-19 08:07:52 Pubmed11955436 Pubmed12000790 Reactome Database ID Release 43196299 Reactome, http://www.reactome.org ReactomeREACT_11065 Reviewed: Pagano, M, 2007-04-27 13:02:18 Degradation of beta-catenin by the destruction complex Authored: Kimelman, D, 2007-04-03 12:34:14 Edited: Matthews, L, 2007-04-03 12:38:03 Pubmed17143292 Reactome Database ID Release 43195253 Reactome, http://www.reactome.org ReactomeREACT_11063 Reviewed: Pagano, M, 2007-04-27 13:02:18 The beta-catenin destruction complex plays a key role in the canonical Wnt signaling pathway. In the absence of Wnt signaling, this complex controls the levels of cytoplamic beta-catenin. Beta-catenin associates with and is phosphorylated by the destruction complex. Phosphorylated beta-catenin is recognized and ubiquitinated by the SCF-beta TrCP ubiquitin ligase complex and is subsequently degraded by the proteasome (reviewed in Kimelman and Xu, 2006). Integrin cell surface interactions Authored: Geiger, B, Horwitz, R, 2008-05-07 08:30:32 Edited: Garapati, P V, 2008-03-11 10:20:45 Pubmed12231361 Pubmed15147720 Pubmed8866399 Reactome Database ID Release 43216083 Reactome, http://www.reactome.org ReactomeREACT_13552 Reviewed: Yamada, K, Humphries, MJ, Hynes, R, 2008-05-07 08:53:37 The extracellular matrix (ECM) is a network of macro-molecules that underlies all epithelia and endothelia and that surrounds all connective tissue cells. This matrix provides the mechanical strength and also influences the behavior and differentiation state of cells in contact with it. The ECM are diverse in composition, but they generally comprise a mixture of fibrillar proteins, polysaccharides synthesized, secreted and organized by neighboring cells. Collagens, fibronectin, and laminins are the principal components involved in cell matrix interactions; other components, such as vitronectin, thrombospondin, and osteopontin, although less abundant, are also important adhesive molecules.<br>Integrins are the receptors that mediate cell adhesion to ECM. Integrins consists of one alpha and one beta subunit forming a noncovalently bound heterodimer. 18 alpha and 8 beta subunits have been identified in humans that combine to form 24 different receptors. <br>The integrin dimers can be broadly divided into three families consisting of the beta1, beta2/beta7, and beta3/alphaV integrins. beta1 associates with 12 alpha-subunits and can be further divided into RGD-, collagen-, or laminin binding and the related alpha4/alpha9 integrins that recognise both matrix and vascular ligands. beta2/beta7 integrins are restricted to leukocytes and mediate cell-cell rather than cell-matrix interactions, although some recognize fibrinogen. The beta3/alphaV family members are all RGD receptors and comprise aIIbb3, an important receptor on platelets, and the remaining b-subunits, which all associate with alphaV. It is the collagen receptors and leukocyte-specific integrins that contain alpha A-domains. Signaling by Hippo Authored: D'Eustachio, P, 2012-02-03 Edited: D'Eustachio, P, 2011-12-30 GENE ONTOLOGYGO:0035329 Hippo signaling cascade Human Hippo signaling is a network of reactions that regulates cell proliferation and apoptosis, centered on a three-step kinase cascade. The cascade was discovered by analysis of Drosophila mutations that lead to tissue overgrowth, and human homologues of its components have since been identified and characterized at a molecular level. Data from studies of mice carrying knockout mutant alleles of the genes as well as from studies of somatic mutations in these genes in human tumors are consistent with the conclusion that in mammals, as in flies, the Hippo cascade is required for normal regulation of cell proliferation and defects in the pathway are associated with cell overgrowth and tumorigenesis (Oh and Irvine 2010; Pan 2010; Zhao et al. 2010). This group of reactions is also notable for its abundance or protein:protein interactions mediated by WW domains and PPxY sequence motifs (Sudol and Harvey 2010).<p>There are two human homologues of each of the three Drosophila kinases, whose functions are well conserved: expression of human proteins rescues fly mutants. The two members of each pair of human homologues have biochemically indistinguishable functions. Autophosphorylated STK3 (MST2) and STK4 (MST1) (homologues of Drosophila Hippo) catalyze the phosphorylation and activation of LATS1 and LATS2 (homologues of Drosophila Warts) and of the accessory proteins MOB1A and MOB1B (homologues of Drosophila Mats). LATS1 and LATS2 in turn catalyze the phosphorylation of the transcriptional co-activators YAP1 and WWTR1 (TAZ) (homologues of Drosophila Yorkie).<p>In their unphosphorylated states, YAP1 and WWTR1 freely enter the nucleus and function as transcriptional co-activators. In their phosphorylated states, however, YAP1 and WWTR1 are instead bound by 14-3-3 proteins, YWHAB and YWHAE respectively, and sequestered in the cytosol.<p>Several accessory proteins are required for the three-step kinase cascade to function. STK3 (MST2) and STK4 (MST1) each form a complex with SAV1 (homologue of Drosophila Salvador), and LATS1 and LATS2 form complexes with MOB1A and MOB1B (homologues of Drosophila Mats).<p>In Drosophila a complex of three proteins, Kibra, Expanded, and Merlin, can trigger the Hippo cascade. A human homologue of Kibra, WWC1, has been identified and indirect evidence suggests that it can regulate the human Hippo pathway (Xiao et al. 2011). A molecular mechanism for this interaction has not yet been worked out and the molecular steps that trigger the Hippo kinase cascade in humans are unknown.<p>Four additional processes related to human Hippo signaling, although incompletely characterized, have been described in sufficient detail to allow their annotation. All are of physiological interest as they are likely to be parts of mechanisms by which Hippo signaling is modulated or functionally linked to other signaling processes. First, the caspase 3 protease cleaves STK3 (MST2) and STK4 (MST1), releasing inhibitory carboxyterminal domains in each case, leading to increased kinase activity and YAP1 / TAZ phosphorylation (Lee et al. 2001). Second, cytosolic AMOT (angiomotin) proteins can bind YAP1 and WWTR1 (TAZ) in their unphosphorylated states, a process that may provide a Hippo-independent mechanism to down-regulate the activities of these proteins (Chan et al. 2011). Third, WWTR1 (TAZ) and YAP1 bind ZO-1 and 2 proteins (Remue et al. 2010; Oka et al. 2010). Fourth, phosphorylated WWTR1 (TAZ) binds and sequesters DVL2, providing a molecular link between Hippo and Wnt signaling (Varelas et al. 2010). Pubmed11278283 Pubmed20412773 Pubmed20439427 Pubmed20452772 Pubmed20598891 Pubmed20850437 Pubmed20868367 Pubmed20951342 Pubmed21224387 Pubmed21233212 Reactome Database ID Release 432028269 Reactome, http://www.reactome.org ReactomeREACT_118607 Reviewed: Sudol, M, 2012-02-03 IGF1R signaling cascade After autophosphorylation the type 1 insulin-like growth factor receptor (IGF1R) binds and phosphorylates scaffold proteins, IRS1/2/4 and SHC1, which in turn bind effectors possessing enzymatic activity (recently reviewed in Pavelic et al. 2007, Chitnis et al. 2008, Maki et al. 2010, Parrella et al. 2010, and Siddle et al. 2012). IRS1/2/4 can bind both PI3K (via the p85 subunit of PI3K) and the GRB2:SOS complex. PI3K activates PKB (AKT, AKT1) signaling. GRB:SOS stimulates RAS to exchange GDP for GTP leading to activation of RAF and MAPK. Authored: May, B, 2012-08-06 Edited: May, B, 2012-08-06 Pubmed17598937 Pubmed18927274 Pubmed20098959 Pubmed20975071 Pubmed21042815 Pubmed22649417 Reactome Database ID Release 432428924 Reactome, http://www.reactome.org ReactomeREACT_150210 Reviewed: Holzenberger, Martin, 2012-11-09 Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) Authored: May, B, 2012-07-07 Binding of IGF1 (IGF-I) or IGF2 (IGF-II) to the extracellular alpha peptides of the type 1 insulin-like growth factor receptor (IGF1R) triggers the activation of two major signaling pathways: the SOS-RAS-RAF-MAPK (ERK) pathway and the PI3K-PKB (AKT) pathway (recently reviewed in Pavelic et al. 2007, Chitnis et al. 2008, Maki et al. 2010, Parella et al. 2010, Annunziata et al. 2011, Siddle et al. 2012, Holzenberger 2012). Edited: May, B, 2012-07-07 Pubmed17598937 Pubmed18927274 Pubmed20098959 Pubmed20975071 Pubmed21042815 Pubmed22044904 Pubmed22649417 Reactome Database ID Release 432404192 Reactome, http://www.reactome.org ReactomeREACT_150359 Reviewed: Holzenberger, Martin, 2012-11-09 G beta:gamma signalling through PLC beta Authored: Jupe, S, 2009-04-17 08:59:54 Edited: Jupe, S, 2009-09-09 Phospholipase C beta (PLCbeta) isoforms are activated  by G-protein beta:gamma in the order PLCB3 > PLCB2 > PLCB1. Gbeta:gamma binds to the pleckstrin homology domain of PLC beta, increasing phospholipase activity and leading to increased hydrolysis of PIP2 to DAG and IP3. Pubmed8383116 Reactome Database ID Release 43418217 Reactome, http://www.reactome.org ReactomeREACT_19145 Reviewed: Akkerman, JW, 2009-06-03 Olfactory Signaling Pathway Authored: Caudy, M, 2008-11-21 02:39:06 Mammalian Olfactory Receptor (OR) genes were discoved in rats by Linda Buck and Richard Axel, who predicted that odorants would be detected by a large family of G protein-coupled receptors (GPCRs) that are selectively expressed in the olfactory epithelium. This prediction was based on previous biochemical evidence that cAMP levels increased in olfactory neurons upon odor stimulation. These predictions proved to be true, and Buck and Axel received a Nobel Prize for this and subsequent work (reviewed in Keller, 2008).<br><br>Subsequent work in mice and other vertebrates has confirmed that OR genes are comprised of a very large family of G Protein-Coupled Receptors (GPCRs) that are selectively-expressed in olfactory epithelium. Although some OR are also expressed selectively in one or a few other tissues, their expression in olfactory-epithelium generally indicates a functional role in mediating olfaction, where they couple binding by odorant ligands with intracellular olfactory signaling. (Note: the other subclasses of GPCR signaling pathways are described under "GPCR Signaling".)<br><br>The ligands for ORs are diverse, ranging from chemical compounds to peptides. Intracellular signaling by OR proteins in mice and other mammalian systems is known to be mediated via direct interactions of OR proteins with an olfactory specific heterotrimeric G Protein, that contains an olfactory-specific G alpha protein: G alpha S OLPH (also named "GNAL").<p>There are two models for GPCR-G Protein interactions: 1) ligand-GPCR binding first, then binding to G Proteins; 2) "Pre-coupling" of GPCRs and G Proteins before ligand binding {reviewed in (Oldham, 2008)}. Both models may be true for certain GPCRs in different contexts. Pre-coupling is likely to be functionally important, as pre-coupling of receptor and G Protein allows much more rapid kinetic response once ligand is bound, because the ligand-bound receptor is immediately able to transduce the signal, rather than having to diffuse around within the plasma membrane until it encounters a G Protein to interact with (Oldham, 2008).<p>The pre-coupling model is used here to characterise the reaction of the human ORs with G Proteins in the absence of ligand, because the ligands in humans are almost completely undocumented experimentally.<p>In model genetic systems such as mice, many candidate OR genes have been shown experimentally to function in olfactory signaling {reviewed in (Keller, 2008)}. For the human OR genes, experimental analysis has been much more limited, although some specific OR genes, such as OR7D4 and OR11H7P have been confirmed to mediate olfactory response and signaling in humans for specific chemical odorants (Keller, 2007; Abbafy, 2007). Mice and other rodents are believed to have about 1000 functional OR genes, as well as many additional pseudogenes. Based on sequence similarities, there are 960 human OR genes, but approximately half of these are pseudogenes {reviewed in (Keller, 2008)}. In mice, essentially all olfactory signaling requires G-alpha-S (OLF), since mouse G-OLF knockouts have been shown to lack essentially all olfactory responses (Belluscio, 1998). Thus, bona fide human OR genes identified by sequence similarity (i.e., not pseudogenes with function-blocking mutations) which are known to be expressed in olfactory epithelium are expected to interact with G alpha S OLF containing G Protein trimers. Therefore, we can model the human ORs which are expressed in human olfactory epithelium as each signaling via interactions with human G-alpha-S-OLF (GNAL).<br><br>Of the 960 human OR genes and pseudogenes, there is experimental evidence which indicates that at least 437 actually are expressed in human olfactory epithelium; this includes 357 OR genes, and 80 OR pseudogenes (Zhang, 2007). These 357 olfactory-expressed OR genes are therefore expected to be functional in the Olfactory Signaling Pathway, and to interact directly with human G alpha olf in human olfactory cells.<p>(Note: A subset of 200 of these 357 OR genes are shown as components of OR-G Protein reaction. The others will be added to Reactome later.)<br> Pubmed14983052 Pubmed16402120 Pubmed17509148 Pubmed17873857 Pubmed17973576 Pubmed18043707 Pubmed1840504 Pubmed18938244 Pubmed9459443 Reactome Database ID Release 43381753 Reactome, http://www.reactome.org ReactomeREACT_15488 Reviewed: Vosshall, L, 2008-12-02 23:19:16 G beta:gamma signalling through PI3Kgamma Authored: Jupe, S, 2009-03-04 10:18:49 Edited: Jupe, S, 2009-09-09 PI3K gamma (PI3KG) is a heterodimer consisting of a p110 catalytic subunit associated with a regulatory p101 or p84 subunit. PI3KG is most highly expressed in neutrophils, where the p101 form predominates (approximately 95%). G beta:gamma recruits PI3KG to the plasma membrane, both activating PI3KG and providing access to its substrate PIP2, which is converted to PIP3. Pubmed17041586 Pubmed17916723 Reactome Database ID Release 43392451 Reactome, http://www.reactome.org ReactomeREACT_19290 Reviewed: Akkerman, JW, 2009-06-03 IDI1 gene Reactome DB_ID: 2393982 Reactome Database ID Release 432393982 Reactome, http://www.reactome.org ReactomeREACT_148290 GGPS1 gene Reactome DB_ID: 2393998 Reactome Database ID Release 432393998 Reactome, http://www.reactome.org ReactomeREACT_148298 SC5DL gene Reactome DB_ID: 2394001 Reactome Database ID Release 432394001 Reactome, http://www.reactome.org ReactomeREACT_148085 CYP51A1 gene Reactome DB_ID: 2393988 Reactome Database ID Release 432393988 Reactome, http://www.reactome.org ReactomeREACT_148353 LSS gene Reactome DB_ID: 2393967 Reactome Database ID Release 432393967 Reactome, http://www.reactome.org ReactomeREACT_148155 MVD gene Reactome DB_ID: 2393981 Reactome Database ID Release 432393981 Reactome, http://www.reactome.org ReactomeREACT_148507 GPAM gene Reactome DB_ID: 2393968 Reactome Database ID Release 432393968 Reactome, http://www.reactome.org ReactomeREACT_148135 FASN gene Reactome DB_ID: 2393979 Reactome Database ID Release 432393979 Reactome, http://www.reactome.org ReactomeREACT_148051 ACACB gene Reactome DB_ID: 2393980 Reactome Database ID Release 432393980 Reactome, http://www.reactome.org ReactomeREACT_148319 TM7SF2 gene Reactome DB_ID: 2393984 Reactome Database ID Release 432393984 Reactome, http://www.reactome.org ReactomeREACT_148529 Adenylate cyclase activating pathway Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 GENE ONTOLOGYGO:0007189 Pubmed14993377 Reactome Database ID Release 43170660 Reactome, http://www.reactome.org ReactomeREACT_15312 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Stimulatory G proteins activate adenylate cyclase, which drives the conversion of cAMP from ATP and in turn activates cAMP-dependent protein kinase and subsequent kinase pathways. phospho-PLA2 pathway Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Phospholipase A2 (PLA2) enzymes hydrolyze arachidonic acid (AA) from the sn-2 position of phospholipids. AA is a precursor of eicosanoids, lipid mediators involved in inflammtory responses. PLA2 enzymes function as regulators of phospholipid acyl turnover, either as housekeepers for membrane repair or for the production of imflammatory lipid mediators. There are diverse forms of PLA2 enyzmes including secretory (sPLA2), calcium-independent and cytosolic (cPLA2). The cPLA2 form which mediates arachidonic acid release is annotated here. Pubmed9201969 Reactome Database ID Release 43111995 Reactome, http://www.reactome.org ReactomeREACT_15466 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Ca-dependent events Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Calcium, as the ion Ca2+, is essential in many biological processes. The majority of Ca2+ in many organisms is bound to phosphates which form skeletal structures and also buffer Ca2+ levels in extracellular fluids (typically 1 millimolar). Intracellular free Ca2+, by contrast, is 10,000 times lower than the outside of the cell (typically 10 micromolar). This concentration gradient is used to import Ca2+ into cells where it acts as a second messenger. Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed11162741 Pubmed16076488 Pubmed17697045 Pubmed18083096 Reactome Database ID Release 43111996 Reactome, http://www.reactome.org ReactomeREACT_15307 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 PLC beta mediated events Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed1335363 Pubmed16183910 Pubmed9218123 Reactome Database ID Release 43112043 Reactome, http://www.reactome.org ReactomeREACT_15426 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The phospholipase C (PLC) family of enzymes is both diverse and complex. The isoforms beta, gamma and delta (each have subtypes) make up the members of this family. PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) into two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores while DAG activates protein kinase C isoforms which are involved in regulatory functions. G-protein mediated events Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed9218123 Pubmed9422713 Reactome Database ID Release 43112040 Reactome, http://www.reactome.org ReactomeREACT_15526 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 When dissociated Galpha-GTP and Gbeta-gamma can activate or inhibit different signalling cascades and effector proteins. The precise pathways depends on the identity of the alpha and beta/gamma subtypes. DHCR7 gene Reactome DB_ID: 2393971 Reactome Database ID Release 432393971 Reactome, http://www.reactome.org ReactomeREACT_148281 G-protein activation Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed12184727 Pubmed15294442 Pubmed9218123 Reactome Database ID Release 43202040 Reactome, http://www.reactome.org ReactomeREACT_15457 Receptor activated heterotrimeric G proteins consist of the Galpha and the tightly associated Gbeta-gamma subunits. When a ligand binds to a G protein-coupled receptor, it stabilises a conformation with an high affinity for the G-protein bound to GDP. GDP is then exchanged for GTP on the Galpha subunit. This exchange triggers the dissociation of the Galpha subunit from the Gbeta-gamma dimer and the receptor. Galpha-GTP and Gbeta-gamma, can then modulate different signalling cascades and effector proteins, while the receptor is able to activate another G protein, resulting in an amplification cascade. The Galpha subunit will eventually hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to reassociate with Gbeta-gamma and start a new cycle. Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Opioid Signalling Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Schmidt, EE, 0000-00-00 00:00:00 Opioids are chemical substances similar to opiates, the active substances found in opium (morphine, codeine etc.). Opioid action is mediated by the receptors for endogenous opioids; peptides such as the enkephalins, the endorphins or the dynorphins. Opioids possess powerful analgesic and sedative effects, and are widely used as pain-killers. Their main side-effect is the rapid establishment of a strong addiction. Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP). Pubmed16612131 Pubmed9218123 Pubmed9422713 Reactome Database ID Release 43111885 Reactome, http://www.reactome.org ReactomeREACT_15295 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Calcitonin-like ligand receptors Authored: Jassal, B, 2009-05-07 08:25:16 Edited: Jassal, B, 2009-05-07 08:25:16 Pubmed10519914 Pubmed12037140 Pubmed14706825 Pubmed3317417 Pubmed8387282 Pubmed9646295 Reactome Database ID Release 43419812 Reactome, http://www.reactome.org ReactomeREACT_18290 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The calcitonin peptide family comprises calcitonin, amylin, calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and intermedin (AM2). Calcitonin is a 32 amino acid peptide, involved in bone homeostasis (Sexton PM et al, 1999). Amylin is a product of the islet beta-cell (Cooper GJ et al, 1987), along with insulin and probably has a hormonal role in the regulation of nutrient intake (Young A and Denaro M, 1998). Adrenomedullin (AM) is a ubiquitously expressed peptide initially isolated from phaechromocytoma (a tumour of the adrenal medulla) (Kitamura K et al, 1993). Both AM and AM2 (Takei Y et al, 2004) belong to a family of calcitonin-related peptide hormones important for regulating diverse physiologic functions and the chemical composition of fluids and tissues.<br>The receptor family for these peptides consists of two class B GPCRs, the calcitonin receptor (CT) and calcitonin receptor-like receptor (CL) (Poyner DR er al, 2002). Whilst the receptor for calcitonin is a conventional class B GPCR, the receptors for CGRP, AM and amylin require additional proteins, called the receptor activity modifying proteins (RAMPs). There are three RAMPs in mammals; they interact with the CT receptor to convert it to receptors for amylin. For CGRP and AM, the related CL interacts with RAMP1 to give a CGRP receptor and RAMP2 or 3 to give AM receptors. CL by itself will bind no known endogenous ligand. Glucagon-type ligand receptors Authored: Jassal, B, 2009-05-11 13:30:54 Edited: Jassal, B, 2009-05-11 13:30:54 Pubmed12529935 Pubmed12615957 Pubmed16174875 Reactome Database ID Release 43420092 Reactome, http://www.reactome.org ReactomeREACT_18377 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The glucagon hormone family regulates the activity of GPCRs from the secretin receptor subfamily in Class II/B (Mayo KE et al, 2003). IL17RD Converted from EntitySet in Reactome Reactome DB_ID: 1268209 Reactome Database ID Release 431268209 Reactome, http://www.reactome.org ReactomeREACT_111672 Phospho-MEK Converted from EntitySet in Reactome Reactome DB_ID: 169287 Reactome Database ID Release 43169287 Reactome, http://www.reactome.org ReactomeREACT_111532 ACACA gene Reactome DB_ID: 2393997 Reactome Database ID Release 432393997 Reactome, http://www.reactome.org ReactomeREACT_148334 FGFR1 fusion mutants Converted from EntitySet in Reactome Reactome DB_ID: 1839029 Reactome Database ID Release 431839029 Reactome, http://www.reactome.org ReactomeREACT_122479 G alpha (q) signalling events Authored: Jupe, S, 2009-03-09 15:04:20 Edited: Jupe, S, 2009-03-09 15:04:20 Pubmed16102047 Pubmed19212139 Pubmed9296496 Reactome Database ID Release 43416476 Reactome, http://www.reactome.org ReactomeREACT_18283 Reviewed: Akkerman, JW, 2009-06-03 The classic signalling route for G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinase cassettes and other proteins that mediate cellular responses ranging from granule secretion, integrin activation, and aggregation in platelets. Gq participates in many other signalling events including direct interaction with RhoGEFs that stimulate RhoA activity and inhibition of PI3K. Both in vitro and in vivo, the G-protein Gq seems to be the predominant mediator of the activation of platelets. G alpha (z) signalling events Authored: Jupe, S, 2009-04-24 08:15:10 Edited: Jupe, S, 2009-09-09 Pubmed10954748 Pubmed11313909 Pubmed1908722 Pubmed2491850 Pubmed9032437 Reactome Database ID Release 43418597 Reactome, http://www.reactome.org ReactomeREACT_19333 Reviewed: Akkerman, JW, 2009-06-03 The heterotrimeric G protein Gz, is a member of the Gi family. Unlike other Gi family members it lacks an ADP ribosylation site cysteine four residues from the carboxyl terminus and is thus pertussis toxin-insensitive. It inhibits adenylyl cyclase types I, V and VI. G alpha (z) interacts with the Rap1 GTPase activating protein (Rap1GAP) to attenuate Rap1 signaling. Like all G-proteins Gz has an intrinsic GTPase activity, but this activity tends to be lower for the pertussis toxin insensitive G-proteins, most strikingly so for Gz, whose kcat value for GTP hydrolysis is 200-fold lower than those of Gs or Gi (Grazziano et al. 1989). Gz knockout mice have disrupted platelet aggregation at physiological concentrations of epinephrine and responses to several neuroactive drugs are altered (Yang et al. 2000). G-protein beta:gamma signalling Authored: Jupe, S, 2009-03-13 10:42:02 Edited: Jupe, S, 2009-09-09 Pubmed18834311 Reactome Database ID Release 43397795 Reactome, http://www.reactome.org ReactomeREACT_19388 Reviewed: Akkerman, JW, 2009-06-03 The classical role of the G-protein beta/gamma dimer was believed to be the inactivation of the alpha subunit, Gbeta/gamma was viewed as a negative regulator of Galpha signalling. It is now known that Gbeta/gamma subunits can directly modulate many effectors, including some also regulated by G alpha. G alpha (12/13) signalling events Authored: Jupe, S, 2009-03-18 10:29:41 Edited: Jupe, S, 2009-03-27 13:06:35 Pubmed12588974 Pubmed16102047 Pubmed18814923 Pubmed19212140 Pubmed7559569 Reactome Database ID Release 43416482 Reactome, http://www.reactome.org ReactomeREACT_18407 Reviewed: Akkerman, JW, 2009-06-03 The G12/13 family is probably the least well characterized subtype, partly because G12/13 coupling is difficult to determine when compared with the other subtypes which predominantly rely on assay technologies that measure intracellular calcium. The G12/13 family are best known for their involvement in the processes of cell proliferation and morphology, such as stress fiber and focal adhesion formation. Interactions with Rho guanine nucleotide exchange factors (RhoGEFs) are thought to mediate many of these processes. (Buhl et al.1995, Sugimoto et al. 2003). Activation of Rho or the regulation of events through Rho is often taken as evidence of G12/13 signaling. Receptors that are coupled with G12/13 invariably couple with one or more other G protein subtypes, usually Gq. GPCR downstream signaling Authored: Jupe, S, 2009-03-26 09:39:59 Edited: Jupe, S, 2009-09-10 G protein-coupled receptors (GPCRs) are classically defined as the receptor, G-protein and downstream effectors, the alpha subunit of the G-protein being the primary signaling molecule. However, it has become clear that this greatly oversimplifies the complexities of GPCR signaling (see Gurevich & Gurevich, 2008). The beta:gamma G-protein dimer is also involved in downstream signaling (Smrcka, 2008), and some receptors form part of metastable complexes of receptor and accessory proteins such as the arrestins. GPCRs are involved in many diverse signaling events (Kristiansen 2004), using a variety of pathways that include modulation of adenylyl cyclase, phospholipase C, the mitogen activated protein kinases (MAPKs), extracellular signal regulated kinase (ERK) c-Jun-NH2-terminal kinase (JNK) and p38 MAPK. Pubmed12040175 Pubmed13679574 Pubmed15251227 Pubmed18240029 Pubmed18488142 Pubmed18515421 Pubmed19935667 Reactome Database ID Release 43388396 Reactome, http://www.reactome.org ReactomeREACT_19184 Reviewed: Akkerman, JW, 2009-06-03 Class C/3 (Metabotropic glutamate/pheromone receptors) Authored: Jassal, B, 2009-05-12 14:18:01 Edited: Jassal, B, 2009-05-12 14:18:01 Pubmed12782243 Pubmed17266540 Reactome Database ID Release 43420499 Reactome, http://www.reactome.org ReactomeREACT_18319 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The class C G-protein-coupled receptors are a class of G-protein coupled receptors that include the metabotropic glutamate receptors and several additional receptors (Bräuner-Osborne H et al, 2007). Family C GPCRs have a large extracellular N-terminus which binds the orthosteric (endogenous) ligand. The shape of this domain is often likened to a clam. Several allosteric ligands to these receptors have been identified and these bind within the seven transmembrane region. G alpha (i) signalling events Authored: Jupe, S, 2009-05-01 15:23:43 Edited: Jupe, S, 2009-05-01 15:23:43 Pubmed3113327 Pubmed9278091 Reactome Database ID Release 43418594 Reactome, http://www.reactome.org ReactomeREACT_19231 Reviewed: Akkerman, JW, 2009-06-03 The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase. Decreased production of cAMP from ATP results in decreased activity of cAMP-dependent protein kinases. G alpha (s) signalling events Authored: Jupe, S, 2009-04-23 16:22:25 Edited: Jupe, S, 2009-09-09 Pubmed12036966 Reactome Database ID Release 43418555 Reactome, http://www.reactome.org ReactomeREACT_19327 Reviewed: Akkerman, JW, 2009-06-03 The general function of the G alpha (s) subunit (Gs) is to activate adenylate cyclase, which in turn produces cAMP, leading to the activation of cAMP-dependent protein kinases (often referred to collectively as Protein Kinase A). The signal from the ligand-stimulated GPCR is amplified because the receptor can activate several Gs heterotrimers before it is inactivated. STAT5 Converted from EntitySet in Reactome Reactome DB_ID: 452094 Reactome Database ID Release 43452094 Reactome, http://www.reactome.org ReactomeREACT_24211 STAT1,3 Converted from EntitySet in Reactome Reactome DB_ID: 1888196 Reactome Database ID Release 431888196 Reactome, http://www.reactome.org ReactomeREACT_124378 p-STAT5 Converted from EntitySet in Reactome Reactome DB_ID: 507929 Reactome Database ID Release 43507929 Reactome, http://www.reactome.org ReactomeREACT_24299 pY-STAT1,3 Converted from EntitySet in Reactome Reactome DB_ID: 1888197 Reactome Database ID Release 431888197 Reactome, http://www.reactome.org ReactomeREACT_122394 FGFR2 ligand-independent mutants Converted from EntitySet in Reactome Reactome DB_ID: 2029955 Reactome Database ID Release 432029955 Reactome, http://www.reactome.org ReactomeREACT_123679 FGFR1 P252X mutants Converted from EntitySet in Reactome Reactome DB_ID: 2012029 Reactome Database ID Release 432012029 Reactome, http://www.reactome.org ReactomeREACT_121561 Assembly of collagen fibrils and other multimeric structures Authored: Jupe, S, 2011-08-05 Collagen trimers in triple-helical form, referred to as procollagen or collagen molecules, are exported from the ER and trafficked through the Golgi network before secretion into the extracellular space. For fibrillar collagens namely types I, II, III, V, XI, XXIV and XXVII (Gordon & Hahn 2010, Ricard-Blum 2011) secretion is concomitant with processing of the N and C terminal collagen propeptides. These processed molecules are known as tropocollagens, considered to be the units of higher order collagen structures. They form within the extracellular space via a process that can proceed spontaneously, but in the cellular environment is regulated by many collagen binding proteins such as the FACIT (Fibril Associated Collagens with Interrupted Triple helices) family collagens and Small Leucine-Rich Proteoglycans (SLRPs). The architecture formed ultimately depends on the collagen subtype and the cellular conditions. Structures include the well-known fibrils and fibres formed by the major structural collagens type I and II plus several different types of supramolecular assembly (Bruckner 2010). The mechanical and physical properties of tissues depend on the spatial arrangement and composition of these collagen-containing structures (Kadler et al. 1996, Shoulders & Raines 2009, Birk & Bruckner 2011).<br><br>Fibrillar collagen structures are frequently heterotypic, composed of a major collagen type in association with smaller amounts of other types, e.g. type I collagen fibrils are associated with types III and V, while type II fibrils frequently contain types IX and XI (Wess 2005). Fibres composed exclusively of a single collagen type probably do not exist, as type I and II fibrils require collagens V and XI respectively as nucleators (Kadler et al. 2008, Wenstrup et al. 2011). Much of the structural understanding of collagen fibrils has been obtained with fibril-forming collagens, particularly type I, but some central features are believed to apply to at least the other fibrillar collagen subtypes (Wess 2005). Fibril diameter and length varies considerably, depending on the tissue and collagen types (Fang et al. 2012). The reasons for this are poorly understood (Wess 2005).<br><br>Some tissues such as skin have fibres that are approximately the same diameter while others such as tendon or cartilage have a bimodal distribution of thick and thin fibrils. Mature type I collagen fibrils in tendon are up to 1 cm in length, with a diameter of approx. 500 nm. An individual fibrillar collagen triple helix is less than 1.5 nm in diameter and around 300 nm long; collagen molecules must assemble to give rise to the higher-order fibril structure, a process known as fibrillogenesis, prevented by the presence of C-terminal propeptides (Kadler et al. 1987). In electron micrographs, fibrils have a banded appearance, due to regular gaps where fewer collagen molecules overlap, which occur because the fibrils are aligned in a quarter-stagger arrangement (Hodge & Petruska 1963). Collagen microfibrils are believed to have a quasi-hexagonal unit cell, with tropocollagen arranged to form supertwisted, right-handed microfibrils that interdigitate with neighbouring microfibrils, leading to a spiral-like structure for the mature collagen fibril (Orgel et al. 2006, Holmes & Kadler 2006).<br><br>Neighbouring tropocollagen monomers interact with each other and are cross-linked covalently by lysyl oxidase (Orgel et al. 2000, Mäki 2006). Mature collagen fibrils are stabilized by lysyl oxidase-mediated cross-links. Hydroxylysyl pyridinoline and lysyl pyridinoline cross-links form between (hydroxy) lysine and hydroxylysine residues in bone and cartilage (Eyre et al. 1984). Arginoline cross-links can form in cartilage (Eyre et al. 2010); mature bovine articular cartilage contains roughly equimolar amounts of arginoline and hydroxylysyl pyridinoline based on peptide yields. Mature collagen fibrils in skin are stabilized by the lysyl oxidase-mediated cross-link histidinohydroxylysinonorleucine (Yamauch et al. 1987). Due to the quarter-staggered arrangement of collagen molecules in a fibril, telopeptides most often interact with the triple helix of a neighbouring collagen molecule in the fibril, except for collagen molecules in register staggered by 4D from another collagen molecule. Fibril aggregation in vitro can be unipolar or bipolar, influenced by temperature and levels of C-proteinase, suggesting a role for the N- and C- propeptides in regulation of the aggregation process (Kadler et al. 1996). In vivo, collagen molecules at the fibril surface may retain their N-propeptides, suggesting that this may limit further accretion, or alternatively represents a transient stage in a model whereby fibrils grow in diameter through a cycle of deposition, cleavage and further deposition (Chapman 1989).<br><br>In vivo, fibrils are often composed from more than one type of collagen. Type III collagen is found associated with type I collagen in dermal fibrils, with the collagen III on the periphery, suggesting a regulatory role (Fleischmajer et al. 1990). Type V collagen associates with type I collagen fibrils, where it may limit fibril diameter (Birk et al. 1990, White et al. 1997). Type IX associates with the surface of narrow diameter collagen II fibrils in cartilage and the cornea (Wu et al. 1992, Eyre et al. 2004). Highly specific patterns of crosslinking sites suggest that collagen IX functions in interfibrillar networking (Wess 2005). Type XII and XIV collagens are localized near the surface of banded collagen I fibrils (Nishiyama et al. 1994). Certain fibril-associated collagens with interrupted triple helices (FACITs) associate with the surface of collagen fibrils, where they may serve to limit fibril fusion and thereby regulate fibril diameter (Gordon & Hahn 2010). Collagen XV, a member of the multiplexin family, is almost exclusively associated with the fibrillar collagen network, in very close proximity to the basement membrane. In human tissues collagen XV is seen linking banded collagen fibers subjacent to the basement membrane (Amenta et al. 2005). Type XIV collagen, SLRPs and discoidin domain receptors also regulate fibrillogenesis (Ansorge et al. 2009, Kalamajski et al. 2010, Flynn et al. 2010).<br><br>Collagen IX is cross-linked to the surface of collagen type II fibrils (Eyre et al. 1987). Type XII and XIV collagens are found in association with type I (Walchli et al. 1994) and type II (Watt et al. 1992, Eyre 2002) fibrils in cartilage. They are thought to associate non-covalently via their COL1/NC1 domains (Watt et al. 1992, Eyre 2002). <br><br>Some non-fibrillar collagens form supramolecular assemblies that are distinct from typical fibrils. Collagen VII forms anchoring fibrils, composed of antiparallel dimers that connect the dermis to the epidermis (Bruckner-Tuderman 2009). During fibrillogenesis, the nascent type VII procollagen molecules dimerize in an antiparallel manner. The C-propeptides are then removed by Bone morphogenetic protein 1 (Rattenholl et al. 2002) and the processed antiparallel dimers aggregate laterally. Collagens VIII and X form hexagonal networks and collagen VI forms beaded filament (Gordon & Hahn 2010, Ricard-Blum et al. 2011). Edited: Jupe, S, 2012-11-12 ISBN978-3-642-16555-9 Pubmed10673433 Pubmed11879535 Pubmed11986329 Pubmed12354766 Pubmed1323568 Pubmed1400327 Pubmed1429648 Pubmed14578398 Pubmed14602708 Pubmed14990571 Pubmed15561712 Pubmed15684329 Pubmed15837520 Pubmed16751282 Pubmed17088555 Pubmed1860888 Pubmed18640274 Pubmed19116634 Pubmed19136672 Pubmed19283672 Pubmed19344236 Pubmed19693541 Pubmed19756756 Pubmed19900459 Pubmed20080181 Pubmed20363745 Pubmed2100147 Pubmed21182410 Pubmed21421911 Pubmed21467034 Pubmed2307289 Pubmed23083115 Pubmed2384532 Pubmed2752095 Pubmed2844531 Pubmed3117548 Pubmed3316206 Pubmed3609327 Pubmed3624221 Pubmed3693393 Pubmed6148038 Pubmed6274634 Pubmed6307276 Pubmed6722126 Pubmed7961756 Pubmed8207089 Pubmed8645190 Pubmed9438378 Pubmed9512886 Reactome Database ID Release 432022090 Reactome, http://www.reactome.org ReactomeREACT_150180 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Collagen biosynthesis and modifying enzymes Authored: Jupe, S, 2010-07-20 Edited: Jupe, S, 2012-05-14 Pubmed12064927 Pubmed1409713 Pubmed1466761 Pubmed14698617 Pubmed15788652 Pubmed171650 Pubmed17550969 Pubmed182083 Pubmed18845531 Pubmed3722183 Pubmed3956164 Pubmed4366267 Pubmed5046811 Pubmed710449 Pubmed710450 Pubmed7398630 Pubmed8428977 Pubmed8535602 Pubmed8694764 Pubmed8910551 Pubmed9401 Pubmed9724611 Reactome Database ID Release 431650814 Reactome, http://www.reactome.org ReactomeREACT_121139 Reviewed: Canty-Laird, EG, 2012-05-24 The biosynthesis of collagen is a multistep process. Collagen propeptides are cotranslationally translocated into the ER lumen. Propeptides undergo a number of post-translational modifications. Proline and lysine residues may be hydroxylated by prolyl 3-, prolyl 4- and lysyl hydroxylases. 4-hydroxyproline is essential for intramolecular hydrogen bonding and stability of the triple helical collagenous domain. In fibril forming collagens approximately 50% of prolines are 4-hydroxylated; the extent of this and of 3-hydroxyproline and lysine hydroxylation varies between tissues and collagen types (Kivirikko et al. 1972, 1992). Hydroxylysine molecules can form cross-links between collagen molecules in fibrils, and are sites for glycosyl- and galactosylation. Collagen peptides all have non-collagenous domains; collagens within the subclasses have common chain structures. These non-collagenous domains have regulatory functions; some are biologically active when cleaved from the main peptide chain. Fibrillar collagens all have a large triple helical domain (COL1) bordered by N and C terminal extensions, called the N and C propeptides, which are cleaved prior to formation of the collagen fibril. The C propeptide, also called the NC1 domain, is highly conserved. It directs chain association during intracellular assembly of the procollagen molecule from three collagen propeptide alpha chains (Hulmes 2002). The N-propeptide has a short linker (NC2) connecting the main triple helix to a short minor one (COL2) and a globular N-terminal region NC3. NC3 domains are variable both in size and the domains they contain.<br><br>Collagen propeptides typically undergo a number of post-translational modifications. Proline and lysine residues are hydroxylated by prolyl 3-, prolyl 4- and lysyl hydroxylases. 4-hydroxyproline is essential for intramolecular hydrogen bonding and stability of the triple helical collagenous domain. Prolyl 4-hydroxylase may also have a role in alpha chain association as no association of the C-propeptides of type XII collagen was seen in the presence of prolyl 4-hydroxylase inhibitors (Mazzorana et al. 1993, 1996). In fibril forming collagens approximately 50% of prolines are 4-hydroxylated; the extent of this is species dependent, lower hydroxylation correlating with lower ambient temperature and thermal stability (Cohen-Solal et al. 1986, Notbohm et al. 1992). Similarly the extent of 3-hydroxyproline and lysine hydroxylation varies between tissues and collagen types (Kivirikko et al. 1992). Hydroxylysine molecules can form cross-links between collagen molecules in fibrils, and are sites for glycosyl- and galactosylation.<br><br>Collagen molecules fold and assemble through a series of distinct intermediates (Bulleid 1996). Individual collagen polypeptide chains are translocated co-translationally across the membrane of the endoplasmic reticulum (ER). Intra-chain disulfide bonds are formed within the N-propeptide, and hydroxylation of proline and lysine residues occurs within the triple helical domain (Kivirikko et al. 1992). When the peptide chain is fully translocated into the ER lumen the C-propeptide folds, the conformation being stabilized by intra-chain disulfide bonds (Doege and Fessler 1986). Pro alpha-chains associate via the C-propeptides (Byers et al. 1975, Bächinger et al. 1978), or NC2 domains for FACIT family collagens (Boudko et al. 2008) to form an initial trimer which can be stabilized by the formation of inter-chain disulfide bonds (Schofield et al. 1974, Olsen et al. 1976), though these are not a prerequisite for further folding (Bulleid et al. 1996). The triple helix then nucleates and folds in a C- to N- direction. The association of the individual chains and subsequent triple helix formation are distinct steps (Bächinger et al. 1980). The N-propeptides associate and in some cases form inter-chain disulfide bonds (Bruckner et al., 1978). Procollagen is released via carriers into the exracellular space (Canty & Kadler 2005). Fibrillar procollagens undergo removal of the C- and N-propeptides by procollagen C and N proteinases respectively, both Zn2+ dependent metalloproteinases. Propeptide processing is a required step for normal collagen I and III fibril formation, but collagens can retain some or all of their non-collagenous propeptides. Retained collagen type V and XI N-propeptides contribute to the control of fibril growth by sterically limiting lateral molecule addition (Fichard et al. 1995). Processed fibrillar procollagen is termed tropocollagen, which is considered to be the unit of higher order fibrils and fibres. Tropocollagens of the fibril forming collagens I, II, III, V and XI sponteneously aggregate in vitro in a manner that has been compared with crystallization, commencing with a nucleation event followed by subsequent organized aggregation (Silver et al. 1992, Prockop & Fertala 1998). Fibril formation is stabilized by lysyl oxidase catalyzed crosslinks between adjacent molecules (Siegel & Fu 1976). Crosslinking of collagen fibrils After removal of the N- and C-procollagen propeptides, fibrillar collagen molecules aggregate into microfibrillar arrays, stabilized by covalent intermolecular cross-links. These depend on the oxidative deamination of specific lysine or hydroxylysine residues in the telopeptide region by lysyl oxidase (LOX) with the subsequent spontaneous formation of covalent intermolecular cross-links (Pinnell & Martin 1968, Siegel et al. 1970, 1974, Mäki 2009, Nishioka et al. 2012). Hydroxylysine is formed intracellularly by lysine hydroxylases (LH). There are different forms of LH responsible for hydroxylation of helical and telopeptide lysines (Royce & Barnes 1985, Knott et al.1997, Takaluoma et al. 2007, Myllylä 2007). The chemistry of the cross-links formed depends on whether lysines or hydroxylysines are present in the telopeptides (Barnes et al. 1974), which depends on the proportion of collagen lysines post-translationally converted to hydroxylysine by LH. The lysine pathway predominates in adult skin, cornea and sclera while the hydroxylysine pathway occurs primarily in bone, cartilage, ligament, tendons, embryonic skin and most connective tissues (Eyre 1987, Eyre & Wu 2005, Eyre et al. 2008). Oxidative deamination of lysine or hydroxylysine residues by LOX generates the allysine and hydroxyallysine aldehydes respectively. These can spontaneously react with either another aldehyde to form an aldol condensation product (intramolecular cross-link), or with an unmodified lysine or hydroxylysine residue to form intermolecular cross-links.<br><br>The pathway of cross-linking is regulated primarily by the hydroxylation pattern of telopeptide and triple-helix domain lysine residues. When lysine residues are the source of aldehydes formed by lysyl oxidase the allysine cross-linking pathway leads to the formation of aldimine cross-links (Eyre & Wu 2005). These are stable at physiological conditions but readily cleaved at acid pH or elevated temperature. When hydroxylysine residues are the source of aldehydes formed by lysyl oxidase the hydroxyallysine cross-linking pathway leads to the formation of more stable ketoimine cross-links. <br><br>Telopeptide lysine residues can be converted by LOX to allysine, which can react with a helical hydroxylysine residue forming the lysine aldehyde aldimine cross-link dehydro hydroxylysino norleucine (deHHLNL) (Bailey & Peach 1968, Eyre et al. 2008). If the telopeptide residue is hydroxylysine, the hydroxyallysine formed by LOX can react with a helical hydroxylysine forming the Schiff base, which spontaneously undergoes an Amadori rearrangement resulting in the ketoimine cross link hydroxylysino 5 ketonorleucine (HLKNL). This stable cross-link is formed in tissues where telopeptide residues are predominanly hydroxylated, such as foetal bone and cartilage, accounting for the relative insolubility of collagen from these tissues (Bailey et al. 1998). In bone, telopeptide hydroxyallysines can react with the epsilon-amino group of a helical lysine (Robins & Bailey 1975). The resulting Schiff base undergoes Amadori rearrangement to form lysino-hydroxynorleucine (LHNL). An alternative mechanism of maturation of ketoimine cross-links has been reported in cartilage leading to the formation of arginoline (Eyre et al. 2010). <br><br>These divalent crosslinks greatly diminish as connective tissues mature, due to further spontaneous reactions (Bailey & Shimokomaki 1971, Robins & Bailey 1973) with neighbouring peptides that result in tri- and tetrafunctional cross-links. In mature tissues collagen cross-links are predominantly trivalent. The most common are pyridinoline or 3-hydroxypyridinium cross-links, namely hydroxylysyl-pyridinoline (HL-Pyr) and lysyl-pyridinoline (L-Pyr) cross-links (Eyre 1987, Ogawa et al. 1982, Fujimoto et al. 1978). HL-Pyr is formed from three hydroxylysine residues, HLKNL plus a further hydroxyallysine. It predominates in highly hydroxylated collagens such as type II collagen in cartilage. L-Pyr is formed from two hydroxylysines and a lysine, LKNL plus a further hydroxyallysine, found mostly in calcified tissues (Bailey et al. 1998). Trivalent collagen cross-links can also form as pyrroles, either Lysyl-Pyrrole (L-Pyrrole) or hydroxylysyl-pyrrole (HL-Pyrrole), respectively formed when LKNL or HLKNL react with allysine (Scott et al. 1981, Kuypers et al. 1992). A further three-way crosslink can form when DeH-HLNL reacts with histidine to form histidino-hydroxylysinonorleucine (HHL), found in skin and cornea (Yamauchi et al. 1987, 1996). This can react with an additional lysine to form the tetrafunctional cross-link histidinohydroxymerodesmosine (Reiser et al. 1992, Yamauchi et al. 1996). <br><br>Another mechanism which could be involved in the cross-linking of collagen IV networks is the sulfilimine bond (Vanacore et al. 2009), catalyzed by peroxidasin, an enzyme found in basement membrane (Bhave 2012).<br><br>To improve clarity inter-chain cross-linking is represented here for Collagen type I only. Although the formation of each type of cross-link is represented here as an independent event, the partial and random nature of lysine hydroxylation and subsequent lysyl oxidation means that any combination of these cross-linking events could occur within the same collagen fibril. Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Pubmed11945908 Pubmed1237296 Pubmed1348714 Pubmed1567360 Pubmed17289364 Pubmed17516569 Pubmed18442706 Pubmed19283672 Pubmed19729652 Pubmed20363745 Pubmed22453058 Pubmed22842973 Pubmed3624221 Pubmed3626870 Pubmed3931636 Pubmed4447620 Pubmed4531019 Pubmed4722452 Pubmed5246001 Pubmed5474144 Pubmed5723342 Pubmed7138535 Pubmed728134 Pubmed8604983 Pubmed9065774 Pubmed9883973 Reactome Database ID Release 432243919 Reactome, http://www.reactome.org ReactomeREACT_150206 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Anchoring fibril formation Authored: Jupe, S, 2012-04-30 Collagen VII forms anchoring fibrils, composed of antiparallel dimers that connect the dermis to the epidermis (Bruckner-Tuderman 2009, Has & Kern 2010). During fibrillogenesis, the nascent type VII procollagen molecules dimerize in an antiparallel manner. The C-propeptide is then removed by Bone morphogenetic protein 1 (Rattenholl et al. 2002) and the processed antiparallel dimers laterally aggregate (Villone et al. 2008, Gordon & Hahn 2010). Edited: Jupe, S, 2012-11-12 Pubmed11986329 Pubmed18599485 Pubmed19116634 Pubmed19693541 Pubmed19945617 Pubmed19945621 Reactome Database ID Release 432214320 Reactome, http://www.reactome.org ReactomeREACT_150268 Reviewed: Kalamajski, Sebastian, 2012-10-08 Reviewed: Raleigh, Stewart, 2012-10-08 Reviewed: Ricard-Blum, Sylvie, 2012-11-19 Collagen formation Authored: Jupe, S, 2011-08-05 Collagen is a family of at least 29 structural proteins derived from over 40 human genes (Myllyharju & Kivirikko 2004). It is the main component of connective tissue, and the most abundant protein in mammals making up about 25% to 35% of whole-body protein content. A defining feature of collagens is the formation of trimeric left-handed polyproline II-type helical collagenous regions. The packing within these regions is made possible by the presence of the smallest amino acid, glycine, at every third residue, resulting in a repeating motif Gly-X-Y where X is often proline (Pro) and Y often 4-hydroxyproline (4Hyp). Gly-Pro-Hyp is the most common triplet in collagen (Ramshaw et al. 1998). Collagen peptide chains also have non-collagenous domains, with collagen subclasses having common chain structures. Collagen fibrils are mostly found in fibrous tissues such as tendon, ligament and skin. Other forms of collagen are abundant in cornea, cartilage, bone, blood vessels, the gut, and intervertebral disc. In muscle tissue, collagen is a major component of the endomysium, constituting up to 6% of muscle mass. Gelatin, used in food and industry, is collagen that has been irreversibly hydrolyzed. On the basis of their fibre architecture in tissues, the genetically distinct collagens have been divided into subgroups. Group 1 collagens have uninterrupted triple-helical domains of about 300 nm, forming large extracellular fibrils. They are referred to as the fibril-forming collagens, consisting of collagens types I, II, III, V, XI, XXIV and XXVII. Group 2 collagens are types IV and VII, which have extended triple helices (>350 nm) with imperfections in the Gly-X-Y repeat sequences. Group 3 are the short-chain collagens. These have two subgroups. Group 3A have continuous triple-helical domains (type VI, VIII and X). Group 3B have interrupted triple-helical domains, referred to as the fibril-associated collagens with interrupted triple helices (FACIT collagens, Shaw & Olsen 1991). FACITs include collagen IX, XII, XIV, XVI, XIX, XX, XXI, XXII and XXVI plus the transmembrane collagens (XIII, XVII, XXIII and XXV) and the multiple triple helix domains and interruptions (Multiplexin) collagens XV and XVIII (Myllyharju & Kivirikko 2004). The non-collagenous domains of collagens have regulatory functions; several are biologically active when cleaved from the main peptide chain. Fibrillar collagen peptides all have a large triple helical domain (COL1) bordered by N and C terminal extensions, called the N- and C-propeptides, which are cleaved prior to formation of the collagen fibril. The intact form is referred to as a collagen propeptide, not procollagen, which is used to refer to the trimeric triple-helical precursor of collagen before the propeptides are removed. The C-propeptide, also called the NC1 domain, directs chain association during assembly of the procollagen molecule from its three constituent alpha chains (Hulmes 2002).<br><br>Fibril forming collagens are the most familiar and best studied subgroup. Collagen fibres are aggregates or bundles of collagen fibrils, which are themselves polymers of tropocollagen complexes, each consisting of three polypeptide chains known as alpha chains. Tropocollagens are considered the subunit of larger collagen structures. They are approximately 300 nm long and 1.5 nm in diameter, with a left-handed triple-helical structure, which becomes twisted into a right-handed coiled-coil 'super helix' in the collagen fibril. Tropocollagens in the extracellular space polymerize spontaneously with regularly staggered ends (Hulmes 2002). In fibrillar collagens the molecules are staggered by about 67 nm, a unit known as D that changes depending upon the hydration state. Each D-period contains slightly more than four collagen molecules so that every D-period repeat of the microfibril has a region containing five molecules in cross-section, called the 'overlap', and a region containing only four molecules, called the 'gap'. The triple-helices are arranged in a hexagonal or quasi-hexagonal array in cross-section, in both the gap and overlap regions (Orgel et al. 2006). Collagen molecules cross-link covalently to each other via lysine and hydroxylysine side chains. These cross-links are unusual, occuring only in collagen and elastin, a related protein.<br><br>The macromolecular structures of collagen are diverse. Several group 3 collagens associate with larger collagen fibers, serving as molecular bridges which stabilize the organization of the extracellular matrix. Type IV collagen is arranged in an interlacing network within the dermal-epidermal junction and vascular basement membranes. Type VI collagen forms distinct microfibrils called beaded filaments. Type VII collagen forms anchoring fibrils. Type VIII and X collagens form hexagonal networks. Type XVII collagen is a component of hemidesmosomes where it is complexed wtih alpha6Beta4 integrin, plectin, and laminin-332 (de Pereda et al. 2009). Type XXIX collagen has been recently reported to be a putative epidermal collagen with highest expression in suprabasal layers (Soderhall et al. 2007). Collagen fibrils/aggregates arranged in varying combinations and concentrations in different tissues provide specific tissue properties. In bone, collagen triple helices lie in a parallel, staggered array with 40 nm gaps between the ends of the tropocollagen subunits, which probably serve as nucleation sites for the deposition of crystals of the mineral component, hydroxyapatite (Ca10(PO4)6(OH)2) with some phosphate. Collagen structure affects cell-cell and cell-matrix communication, tissue construction in growth and repair, and is changed in development and disease (Sweeney et al. 2006, Twardowski et al. 2007). A single collagen fibril can be heterogeneous along its axis, with significantly different mechanical properties in the gap and overlap regions, correlating with the different molecular organizations in these regions (Minary-Jolandan & Yu 2009). Edited: Jupe, S, 2012-04-11 Pubmed12064927 Pubmed14698617 Pubmed16751282 Pubmed17850181 Pubmed18220798 Pubmed18487200 Pubmed19242489 Pubmed19693541 Pubmed19694448 Pubmed7574488 Pubmed9724608 Reactome Database ID Release 431474290 Reactome, http://www.reactome.org ReactomeREACT_120729 Reviewed: Canty-Laird, EG, 2012-05-24 Extracellular matrix organization Authored: Jupe, S, 2011-09-09 Edited: Jupe, S, 2012-02-21 GENE ONTOLOGYGO:0030198 ISBN0 19 850268 0 ISBN978-0-12-088562-6 Pubmed11113133 Pubmed12213783 Pubmed12845610 Pubmed17318226 Pubmed1740236 Pubmed18216330 Pubmed19779848 Pubmed19915869 Pubmed19965464 Pubmed21123617 Pubmed21917992 Pubmed2373244 Pubmed7785895 Reactome Database ID Release 431474244 Reactome, http://www.reactome.org ReactomeREACT_118779 Reviewed: D'Eustachio, P, 2012-02-28 The extracellular matrix is a component of all mammalian tissues, a network consisting largely of the fibrous proteins collagen, elastin, fibronectin and laminin embedded in a viscoelastic gel of anionic proteoglycan polymers. It performs many functions in addition to its structural role; as a major component of the cellular microenvironment it influences cell behaviours such as proliferation, adhesion and migration, and regulates cell differentiation and death (Hynes 2009). ECM composition is highly heterogeneous and dynamic, being constantly remodeled (Frantz et al. 2010) and modulated, largely by matrix metalloproteinases (MMPs) and growth factors that bind to the ECM influencing the synthesis, crosslinking and degradation of ECM components (Hynes 2009). ECM remodeling is involved in the regulation of cell differentiation processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. Redundant mechanisms modulate the expression and function of ECM modifying enzymes. Abnormal ECM dynamics can lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Collagen is the most abundant fibrous protein within the ECM constituting up to 30% of total protein in multicellular animals. Collagen provides tensile strength. It associates with elastic fibres, composed of elastin and fibrillins, which give tissues the ability to recover after stretching. Other ECM proteins such as fibronectin, decorin, laminin, and nidogen participate as connectors or linking proteins (Daley et al. 2008). Dermatan sulfate and keratan sulfate proteoglycans are strucural components of cartilage collagen fibrils (Scott 1990), serving to tether the fibril to the surroundng matrix. Decorin belongs to the small leucine-rich repeat proteoglycan family (SLRPs) which also includes biglycan, fibromodulin, lumican and asporin. All appear to be involved in collagen fibril formation and matrix assembly (Ameye & Young 2002). ECM proteins such as osteonectin (SPARC), osteopontin and thrombospondins -1 and -2 appear to modulate cell-matrix interactions. In general they induce de-adhesion, characterized by disruption of focal adhesions and a reorganization of actin stress fibers (Bornstein 2009). Thrombospondin (TS)-1 and -2 bind MMP2. The resulting complex is endocytosed by the low-density lipoprotein receptor-related protein (LRP), clearing MMP2 from the ECM (Yang et al. 2001). Osteopontin interacts with collagen and fibronectin (Mukherjee et al. 1995). It also contains several cell adhesive domains that interact with integrins and CD44. Aggrecan is the predominant ECM proteoglycan form in cartilage (Hardingham & Fosang 1992). Its relatives include versican, neurocan and brevican. In articular cartilage the major non-fibrous macromolecules are aggrecan, hyaluronan and hyaluronan and proteoglycan link protein 1 (HAPLN1). The high negative charge density of these molecules leads to the binding of large amounts of water (Bruckner 2006). Hyaluronan is bound by several large proteoglycans that form extended aggregates. The most significant enzymes in ECM remodeling are the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) families (Cawston & Young 2010). Other notable ECM degrading enzymes include plasmin and cathepsin G. Many ECM proteinases are initially present as precursors, activated by proteolytic processing.MMP precursors include an amino prodomain which masks the catalytic Zn-binding motif (Page-McCawet al. 2007). This can be removed by other proteinases, often other MMPs. ECM proteinases can be inactivated by degradation, or blocked by inhibitors. Some of these inhibitors, including alpha2-macroglobulin, alpha1-proteinase inhibitor, and alpha1-chymotrypsin can inhibit a large variety of proteinases (Woessner & Nagase 2000). Tissue inhibitors of metalloproteinases (TIMPs) are potent MMP inhibitors. Degradation of the extracellular matrix Authored: Jupe, S, 2011-09-09 Edited: Jupe, S, 2012-02-21 GENE ONTOLOGYGO:0022617 Matrix metalloproteinases (MMPs), previously referred to as matrixins because of their role in degradation of the extracellular matrix (ECM), are zinc and calcium dependent proteases belonging to the metzincin family. They contain a characteristic zinc-binding motif HEXXHXXGXXH (Stocker & Bode 1995) and a conserved Methionine which forms a Met-turn. Humans have 24 MMP genes giving rise to 23 MMP proteins, as MMP23 is encoded by two identical genes. All MMPs contain an N-terminal secretory signal peptide and a prodomain with a conserved PRCGXPD motif that in the inactive enzyme is localized with the catalytic site, the cysteine acting as a fourth unpaired ligand for the catalytic zinc atom. Activation involves delocalization of the domain containing this cysteine by a conformational change or proteolytic cleavage, a mechanism referred to as the cysteine-switch (Van Wart & Birkedal-Hansen 1990). Most MMPs are secreted but the membrane type MT-MMPs are membrane anchored and some MMPs may act on intracellular proteins. Various domains determine substrate specificity, cell localization and activation (Hadler-Olsen et al. 2011). MMPs are regulated by transcription, cellular location (most are not activated until secreted), activating proteinases that can be other MMPs, and by metalloproteinase inhibitors such as the tissue inhibitors of metalloproteinases (TIMPs). MMPs are best known for their role in the degradation and removal of ECM molecules. In addition, cleavage of the ECM and other cell surface molecules can release ECM-bound growth factors, and a number of non-ECM proteins are substrates of MMPs (Nagase et al. 2006). MMPs can be divided into subgroups based on domain structure and substrate specificity but it is clear that these are somewhat artificial, many MMPs belong to more than one functional group (Vise & Nagase 2003, Somerville et al. 2003). Pubmed12730128 Pubmed12801404 Pubmed16405877 Pubmed21087458 Pubmed2164689 Pubmed21917992 Pubmed7583637 Reactome Database ID Release 431474228 Reactome, http://www.reactome.org ReactomeREACT_118572 Reviewed: D'Eustachio, P, 2012-02-28 Activation of Matrix Metalloproteinases Authored: Jupe, S, 2011-09-09 Edited: Jupe, S, 2012-02-21 ISBN0 19 850268 0 Pubmed17562450 Pubmed19616423 Pubmed19800373 Pubmed19817485 Reactome Database ID Release 431592389 Reactome, http://www.reactome.org ReactomeREACT_118682 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28 The matrix metalloproteinases (MMPs), previously known as matrixins, are classically known to be involved in the turnover of extracellular matrix (ECM) components. However, recent high throughput proteomics analyses have revealed that ~80% of MMP substrates are non-ECM proteins including cytokines, growth factor binding protiens, and receptors. It is now clear that MMPs regulate ECM turnover not only by cleaving ECM components, but also by the regulation of cell signalling, and that some MMPs are beneficial and may be drug anti-targets. Thus, MMPs have important roles in many processes including embryo development, morphogenesis, tissue homeostasis and remodeling. They are implicated in several diseases such as arthritis, periodontitis, glomerulonephritis, atherosclerosis, tissue ulceration, and cancer cell invasion and metastasis. All MMPs are synthesized as preproenzymes. Alternate splice forms are known, leading to nuclear localization of select MMPs. Most are secreted from the cell, or in the case of membrane type (MT) MMPs become plasma membrane associated, as inactive proenzymes. Their subsequent activation is a key regulatory step, with requirements specific to MMP subtype. Degradation of collagen Authored: Jupe, S, 2011-07-12 Collagen fibril diameter and spatial organisation are dependent on the species, tissue type and stage of development (Parry 1988). The lengths of collagen fibrils in mature tissues are largely unknown but in tendon can be measured in millimetres (Craig et al. 1989). Collagen fibrils isolated from adult bovine corneal stroma had ~350 collagen molecules in transverse section, tapering down to three molecules at the growing tip (Holmes & Kadler 2005). <br><br>The classical view of collagenases is that they actively unwind the triple helical chain, a process termed molecular tectonics (Overall 2002, Bode & Maskos 2003), before preferentially cleaving the alpha2 chain followed by the remaining chains (Chung et al. 2004). More recently it has been suggested that collagen fibrils exist in an equilibrium between protected and vulnerable states (Stultz 2002, Nerenberg & Stultz 2008). The prototypical triple-helical structure of collagen does not fit into the active site of collagenase MMPs. In addition the scissile bonds are not solvent-exposed and are therefore inaccessible to the collagenase active site (Chung et al. 2004, Stultz 2002). It was realized that collagen must locally unfold into non-triple helical regions to allow collagenolysis. Observations using circular dichroism and differential scanning calorimetry confirm that there is considerable heterogeneity along collagen fibres (Makareeva et al. 2008) allowing access for MMPs at physiological temperatures (Salsas-Escat et al. 2010).<br><br>Collagen fibrils with cut chains are unstable and accessible to proteinases that cannot cleave intact collagen strands (Woessner & Nagase 2000, Somerville et al. 2003). Continued degradation leads to the formation of gelatin (Lovejoy et al. 1999). Degradation of collagen types other than I-III is less well characterized but believed to occur in a similar manner. <br><br>Metalloproteinases (MMPs) play a major part in the degradation of several extracellular macromolecules including collagens. MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996), sometimes referred to as collagenases I, II and III respectively, are able to initiate the intrahelical cleavage of the major fibril forming collagens I, II and III at neutral pH, and thus thought to define the rate-limiting step in normal tissue remodeling events. All can cleave additional substrates including other collagen subtypes. Collagenases cut collagen alpha chains at a single conserved Gly-Ile/Leu site approximately 3/4 of the molecule's length from the N-terminus (Fields 1991, Chung et al. 2004). The cleavage site is characterised by the motif G(I/L)(A/L); the G-I/L bond is cleaved. In collagen type I this corresponds to G953-I954 in the Uniprot canonical alpha chain sequences (often given as G775-I776 in literature). It is not clear why only this bond is cleaved, as the motif occurs at several other places in the chain. MMP14, a membrane-associated MMP also known as Membrane-type matrix metalloproteinase 1 (MT-MMP1), is able to cleave collagen types I, II and III (Ohuchi et al. 1997). Edited: Jupe, S, 2012-11-12 GENE ONTOLOGYGO:0030574 ISBN0 19 850268 0 Pubmed10074939 Pubmed11076937 Pubmed12079342 Pubmed12353914 Pubmed12801404 Pubmed12887053 Pubmed15257288 Pubmed15588825 Pubmed1666905 Pubmed18073209 Pubmed18644377 Pubmed20394413 Pubmed21087458 Pubmed2477190 Pubmed3038863 Pubmed3282560 Pubmed6270089 Pubmed8576151 Pubmed8999957 Pubmed9818170 Reactome Database ID Release 431442490 Reactome, http://www.reactome.org ReactomeREACT_150401 Reviewed: Sorsa, Timo, 2012-10-08 Elastic fibre formation Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Elastic fibres (EF) are a major structural constituent of dynamic connective tissues such as large arteries and lung parenchyma, where they provide essential properties of elastic recoil and resilience. EF are composed of a central cross-linked core of elastin, surrounded by a mesh of microfibrils, which are composed largely of fibrillin. In addition to elastin and fibrillin-1, over 30 ancillary proteins are involved in mediating important roles in elastic fibre assembly as well as interactions with the surrounding environment. These include fibulins, elastin microfibril interface located proteins (EMILINs), microfibril-associated glycoproteins (MAGPs) and Latent TGF-beta binding proteins (LTBPs). Fibulin-5 for example, is expressed by vascular smooth muscle cells and plays an essential role in the formation of elastic fibres through mediating interactions between elastin and fibrillin (Yanigasawa et al. 2002, Freeman et al. 2005). In addition, it plays a role in cell adhesion through integrin receptors and has been shown to influence smooth muscle cell proliferation (Yanigasawa et al. 2002, Nakamura et al. 2002). EMILINs are a family of homologous glycoproteins originally identified in extracts of aortas. Found at the elastin-fibrillin interface, early studies showed that antibodies to EMILIN can affect the process of elastic fibre formation (Bressan et al. 1993). EMILIN1 has been shown to bind elastin and fibulin-5 and appears to coordinate their common interaction (Zanetti et al. 2004). MAGPs are found to co-localize with microfibrils. MAGP-1, for example, binds strongly to an N-terminal sequence of fibrillin-1. Other proteins found associated with microfibrils include vitronectin (Dahlback et al. 1990). Fibrillin is most familiar as a component of elastic fibres but microfibrils with no elastin are found in the ciliary zonules of the eye and invertebrate circulatory systems. The addition of elastin to microfibrils is a vertebrate adaptation to high pulsatile pressures in their closed circulatory systems (Faury et al. 2003). Elastin appears to have emerged after the divergence of jawless vertebrates from other vertebrates (Sage 1982). Fibrillin-1 is the major structural component of microfibrils. Fibrillin-2 is expressed earlier in development than fibrillin-1 and may be important for elastic fiber formation (Zhang et al. 1994). Fibrillin-3 arose as a duplication of fibrillin-2 that did not occur in the rodent lineage. It was first isolated from human brain (Corson et al. 2004).<br><br>Fibrillin assembly is not as well defined as elastin assembly. The primary structure of fibrillin is dominated by calcium binding epidermal growth factor like repeats (Kielty et al. 2002). Fibrillin may form dimers or trimers before secretion. However, multimerisation predominantly occurs outside the cell. Formation of fibrils appears to require cell surface structures suggesting an involvement of cell surface receptors. Fibrillin is assembled pericellularly (i.e. on or close to the cell surface) into microfibrillar arrays that undergo time dependent maturation into microfibrils with beaded-string appearance. Transglutaminase forms gamma glutamyl epsilon lysine isopeptide bonds within or between peptide chains. Additionally, intermolecular disulfide bond formation between fibrillins is an important contributor to fibril maturation (Reinhardt et al. 2000).<br><br>Models of fibrillin-1 microfibril structure suggest that the N-terminal half of fibrillin-1 is asymmetrically exposed in outer filaments, while the C-terminal half is buried in the interior (Kuo et al. 2007). Fibrillinopathies include Marfan syndrome, familial ectopia lentis, familial thoracic aneurysm, all due to mutations in the fibrillin-1 gene FBN1, and congenital contractural arachnodactyly which is caused by mutation of FBN2 (Maslen & Glanville 1993, Davis & Summers 2012). In vivo assembly of fibrillin requires the presence of extracellular fibronectin fibres (Sabatier et al. 2009). Fibrillins have Arg-Gly-Asp (RGD) sequences that interact with integrins (Pfaff et al. 1996, Sakamoto et al. 1996, Bax et al., 2003, Jovanovic et al. 2008) and heparin-binding domains that interact with a cell-surface heparan sulfate proteoglycan (Tiedemann et al. 2001) possibly a syndecan (Ritty et al. 2003). Proteoglycans such as versican (Isogai et al. 2002), biglycan, and decorin (Reinboth et al. 2002) can interact with the microfibrils. They confer specific properties including hydration, impact absorption, molecular sieving, regulation of cellular activities, mediation of growth factor association, and release and transport within the extracellular matrix (Buczek-Thomas et al. 2002). In addition, glycosaminoglycans have been shown to interact with tropoelastin through its lysine side chains (Wu et al. 1999), regulating tropoelastin assembly (Tu & Weiss 2008). Elastin is synthesized as a 70kDa monomer called tropoelastin, a highly hydrophobic protein composed largely of two types of domains that alternate along the polypeptide chain. Hydrophobic domains are rich in glycine, proline, alanine, leucine and valine. These amino acids occur in characteristic short (3-9 amino acids) tandem repeats, with a flexible and highly dynamic structure. Unlike collagen, glycine in elastin is not rigorously positioned every 3 residues. However, glycine is distributed frequently throughout all hydrophobic domains of elastin, and displays a strong preference for inter-glycine spacing of 0-3 residues (Rauscher et al. 2006). Elastic fibre formation involves the deposition of tropoelastin onto a template of fibrillin rich microfibrils. Recent results suggest that the first step of elastic fiber formation is the organization of small globules of elastin on the cell surface followed by globule aggregation into microfibres (Kozel et al. 2006). An important contribution to the initial stages assembly is thought to be made by the intrinsic ability of the protein to direct its own polymeric organization in a process termed 'coacervation' (Bressan et al. 1986). This self-assembly process appears to be determined by interactions between hydrophobic domains (Bressan et al. 1986, Vrhovski et al. 1997, Bellingham et al. 2003, Cirulis & Keeley 2010) which result in alignment of the cross-linking domains, allowing the stabilization of elastin through the formation of cross-links generated through the oxidative deamination of lysine residues, catalyzed by members of the lysyl oxidase (LOX) family (Reiser et al. 1992, Mithieux & Weiss 2005). The first step in the cross-linking reaction is the oxidative formation of the delta aldehyde, known as alpha aminoadipic semialdehyde or allysine (Partridge 1963). Subsequent reactions that are probably spontaneous lead to the formation of cross-links through dehydrolysinonorleucine and allysine aldol, a trifunctional cross-link dehydromerodesmosine and two tetrafunctional cross-links desmosine and isodesmosine (Lucero & Kagan 2006), which are unique to elastin. These cross-links confer mechanical integrity and high durability. In addition to their role in self-assembly, hydrophobic domains provide elastin with its elastomeric properties, with initial studies suggesting that the elastomeric propereties of elastin are driven through changes in entropic interactions with surrounding water molecules (Hoeve & Flory 1974). A very specific set of proteases, broadly grouped under the name elastases, is responsible for elastin remodelling (Antonicelli et al. 2007). The matrix metalloproteinases (MMPs) are particularly important in elastin breakdown, with MMP2, 3, 9 and 12 explicitly shown to degrade elastin (Ra & Parks 2007). Nonetheless, elastin typically displays a low turnover rate under normal conditions over a lifetime (Davis 1993). Pubmed10419484 Pubmed10636927 Pubmed11461921 Pubmed11723132 Pubmed11726670 Pubmed11805834 Pubmed11805835 Pubmed12082143 Pubmed12124775 Pubmed12807887 Pubmed12837131 Pubmed1348714 Pubmed14597767 Pubmed14648756 Pubmed14701737 Pubmed14962672 Pubmed15790312 Pubmed15837523 Pubmed16261592 Pubmed1689758 Pubmed16909208 Pubmed17098192 Pubmed17158461 Pubmed17498549 Pubmed17669641 Pubmed18363569 Pubmed18547105 Pubmed19037100 Pubmed20527981 Pubmed22921888 Pubmed3805787 Pubmed4847581 Pubmed7086186 Pubmed8120105 Pubmed8226106 Pubmed8397814 Pubmed8458869 Pubmed8617364 Pubmed8617764 Pubmed9431995 Reactome Database ID Release 431566948 Reactome, http://www.reactome.org ReactomeREACT_150366 Reviewed: Muiznieks, Lisa, 2012-11-02 FGFR1 mutants with enhanced kinase activity Converted from EntitySet in Reactome Reactome DB_ID: 2012030 Reactome Database ID Release 432012030 Reactome, http://www.reactome.org ReactomeREACT_121981 Inactivation of Cdc42 and Rac Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Reactome Database ID Release 43428543 Reactome, http://www.reactome.org ReactomeREACT_19342 Reviewed: Kidd, T, 2009-08-18 Rho family GTPases including Rac, Rho, and Cdc42 are ideal candidates to regulate aspects of cytoskeletal dynamics downstream of axon guidance receptors. Biochemical and genetic studies have revealed an important role for Cdc42 and Rac in Robo repulsion. Robo controls the activity of Rho GTPases by interacting with a family of Slit/Robo specific GAPs (SrGAPs) and Vilse/CrossGAP. SrGAPs inactivate Cdc42 and Vilse/CrossGAP specifically inactivates Rac1. Regulation of Commissural axon pathfinding by Slit and Robo Authored: Garapati, P V, 2008-09-05 06:02:05 Commissural axons project to the floor plate, attracted by the interaction of their DCC receptors with netrin1 produced by floor plate cells. The axons are insensitive to the repulsive action of slit despite expression of repulsive slit receptors (Robo1 and Robo2) because they also express Robo3, a slit receptor that suppresses the activity of Robo1 and Robo2. Once an axon enters the floor plate, however, it must be efficiently expelled on the contralateral side. Based on studies in Xenopus neurons and by yeast two hybrid screens it is observed that the attractive response of the axons to netrins is silenced by activation of Robo. Slit bound Robo binds to DCC, preventing it from transducing an attractive response to netrin. A switch from attraction to repulsion allows commissural axons to enter and then leave the CNS midline. Upon crossing the midline, commissural axons downregulate expression of Robo3 and increases expression of Robo1/Robo2. Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed17029581 Reactome Database ID Release 43428542 Reactome, http://www.reactome.org ReactomeREACT_19376 Reviewed: Kidd, T, 2009-08-18 Signaling by Robo receptor Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed18363568 Reactome Database ID Release 43376176 Reactome, http://www.reactome.org ReactomeREACT_19351 Reviewed: Kidd, T, 2009-08-18 The Roundabout (Robo) family encodes transmembrane receptors that regulate axonal guidance and cell migration. The major function of the Robo receptors is to mediate repulsion of the navigating growth cones. There are four human Robo homologues, Robo1, Robo2, Robo3 and Robo4. Most of the Robos have the similar ectodomain architecture as the cell adhesion molecules, five Ig domains followed by three FN3 repeats except for Robo4, it has 2Ig and 2FN3 repeats. The cytoplasmic domains of Robo receptors are in general poorly conserved. However, there are four short conserved cytoplasmic sequence motifs, named CC0-3, that serve as binding sites for adaptor proteins. The ligands for the human Robo receptors are the three Slit proteins Slit1, Slit2, and Slit3; all of the Slit proteins contain a tandem of four LRR (leucine rich repeat) domains at N terminus, termed D1 D4 followed by six EGF (epidermal growth factor)-like domains, a laminin G like domain (ALPS), three EGF-like domains, and a C-terminal cysteine knot domain. Most Slit proteins are cleaved within the EGF-like region by unknown proteases.<br><br>Slit protein binding modulates Robo interactions with the cytosolic adaptors. The cytoplasmic domain of Robo1 and Robo2 determines the repulsive responses of these receptors. Based on the studies from both invertebrate and vertebrate organisms its been inferred that Robo induces growth cone repulsion by controlling cytoskeletal dynamics via either Abelson kinase (Abl) and Enabled (Ena), or Rac activity.<br> Role of second messengers in netrin-1 signaling Authored: Garapati, P V, 2009-04-27 09:27:02 Edited: Garapati, P V, 2009-04-27 09:27:02 Pubmed15758951 Pubmed15880110 Pubmed18471901 Reactome Database ID Release 43418890 Reactome, http://www.reactome.org ReactomeREACT_22228 Reviewed: Cooper, HM, 2010-02-16 The levels of second messengers such as Ca+2, cAMP and cGMP may regulate the response of the growth cone to a particular cue. Netrin-1 as a guidance molecule depends on intracellular Ca+2 concentration, coactivation of PI3K and PLCgamma, and the type of response depends on the levels of cAMP. Netrin first stimulates its receptor DCC, resulting in the activation of the enzyme phospholipase C. This then produces the messenger molecules, inositol-1,4,5-trisphosphate (IP3) and DAG, which in turn causes the release of Ca+2 from intracellular stores. Ca+2 release from the stores then activates TRPC channels on the cell surface. DAG activates TRPC3 and TRPC6 in a direct, membrane delimited manner, and IP3 may activate TRPC channels by depleting the ER Ca+2 levels. Netrin mediated repulsion signals Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Reactome Database ID Release 43418886 Reactome, http://www.reactome.org ReactomeREACT_22384 Reviewed: Cooper, HM, 2010-02-16 Unc5 netrin receptors mediate repellent responses to netrin. Four Unc5 members have been found in humans: Unc5A, B, C and D. Different studies have suggested that long-range repulsion to netrin requires the cooperation of Unc5 and DCC, but that Unc5 without DCC is sufficient for short-range repulsion. The binding of netrin to Unc5 triggers the phosphorylation of Unc5 in its ZU-5 domain. Several proteins have been proposed to interact with Unc5 family members in mediating a repellent response, including tyrosine phosphatase Shp2, the F-actin anti-capping protein Mena, and ankyrin. DCC mediated attractive signaling Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11239160 Pubmed11817894 Pubmed12149262 Pubmed15494733 Pubmed15557120 Pubmed15960985 Pubmed17254765 Pubmed9950216 Reactome Database ID Release 43418885 Reactome, http://www.reactome.org ReactomeREACT_22351 Reviewed: Cooper, HM, 2010-02-16 The DCC family includes DCC and neogenin in vertebrates. DCC is required for netrin-induced axon attraction. DCC is a transmembrane protein lacking any identifiable catalytic activity. Protein tyrosine kinase 2/FAK and src family kinases bind constitutively to the cytoplasmic domain of DCC and their activation couples to downstream intracellular signaling complex that directs the organization of actin. Netrin-1 signaling Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Netrins are secreted proteins that play a crucial role in neuronal migration and in axon guidance during the development of the nervous system. To date, several Netrins have been described in mouse and humans: Netrin-1, -3/NTL2, -4/h and G-Netrins. Netrin-1 is the most studied member of the family and has been shown to play a crucial role in neuronal navigation during nervous system development mainly through its interaction with its receptors DCC and UNC5. Members of the Deleted in colorectal cancer (DCC) family- which includes DCC and Neogenin in vertebrates- mediate netrin-induced axon attraction, whereas the C. elegans UNC5 receptor and its four vertebrate homologs Unc5a-Unc5d mediate repulsion. Pubmed10499167 Pubmed18269208 Reactome Database ID Release 43373752 Reactome, http://www.reactome.org ReactomeREACT_22237 Reviewed: Cooper, HM, 2010-02-16 Activated STAT1/3 homo and heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1112574 Reactome Database ID Release 431112574 Reactome, http://www.reactome.org ReactomeREACT_27907 NCAM1 interactions Authored: Garapati, P V, 2009-02-24 10:31:41 Edited: Garapati, P V, 2009-02-24 10:31:41 Pubmed15662836 Pubmed18607724 Reactome Database ID Release 43419037 Reactome, http://www.reactome.org ReactomeREACT_18312 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- The neural cell adhesion molecule, NCAM1 is generally considered as a cell adhesion mediator, but it is also considered to be a signal transducing receptor molecule. NCAM1 is involved in multiple cis- and trans-homophilic interactions. It is also involved in several heterophilic interactions with a broad range of other molecules, thereby modulating diverse biological phenomena including cellular adhesion, migration, proliferation, differentiation, survival and synaptic plasticity. NCAM signaling for neurite out-growth Authored: Garapati, P V, 2009-02-24 10:31:41 Edited: Garapati, P V, 2009-02-24 10:31:41 Pubmed12587671 Pubmed12700044 Pubmed15153429 Pubmed15662836 Pubmed17975827 Pubmed18760361 Reactome Database ID Release 43375165 Reactome, http://www.reactome.org ReactomeREACT_18334 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- The neural cell adhesion molecule, NCAM, is a member of the immunoglobulin (Ig) superfamily and is involved in a variety of cellular processes of importance for the formation and maintenance of the nervous system. The role of NCAM in neural differentiation and synaptic plasticity is presumed to depend on the modulation of intracellular signal transduction cascades. NCAM based signaling complexes can initiate downstream intracellular signals by at least two mechanisms: (1) activation of FGFR and (2) formation of intracellular signaling complexes by direct interaction with cytoplasmic interaction partners such as Fyn and FAK. Tyrosine kinases Fyn and FAK interact with NCAM and undergo phosphorylation and this transiently activates the MAPK, ERK 1 and 2, cAMP response element binding protein (CREB) and transcription factors ELK and NFkB. CREB activates transcription of genes which are important for axonal growth, survival, and synaptic plasticity in neurons.<br><br>NCAM1 mediated intracellular signal transduction is represented in the figure below. The Ig domains in NCAM1 are represented in orange ovals and Fn domains in green squares. The tyrosine residues susceptible to phosphorylation are represented in red circles and their positions are numbered. Phosphorylation is represented by red arrows and dephosphorylation by yellow. Ig, Immunoglobulin domain; Fn, Fibronectin domain; Fyn, Proto-oncogene tyrosine-protein kinase Fyn; FAK, focal adhesion kinase; RPTPalpha, Receptor-type tyrosine-protein phosphatase; Grb2, Growth factor receptor-bound protein 2; SOS, Son of sevenless homolog; Raf, RAF proto-oncogene serine/threonine-protein kinase; MEK, MAPK and ERK kinase; ERK, Extracellular signal-regulated kinase; MSK1, Mitogen and stress activated protein kinase 1; CREB, Cyclic AMP-responsive element-binding protein; CRE, cAMP response elements. p(Y701)-STAT1, p(Y705)-STAT3 dimer Reactome DB_ID: 1112590 Reactome Database ID Release 431112590 Reactome, http://www.reactome.org ReactomeREACT_27715 has a Stoichiometric coefficient of 1 Other semaphorin interactions Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:38 Reactome Database ID Release 43416700 Reactome, http://www.reactome.org ReactomeREACT_19200 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 p(Y701)-STAT1 dimer Reactome DB_ID: 1112541 Reactome Database ID Release 431112541 Reactome, http://www.reactome.org ReactomeREACT_27956 has a Stoichiometric coefficient of 2 Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:SHP2 Reactome DB_ID: 1112758 Reactome Database ID Release 431112758 Reactome, http://www.reactome.org ReactomeREACT_27469 has a Stoichiometric coefficient of 1 p(Y705)-STAT3 dimer Reactome DB_ID: 1112525 Reactome Database ID Release 431112525 Reactome, http://www.reactome.org ReactomeREACT_27463 has a Stoichiometric coefficient of 2 Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:SHP2:CBL Reactome DB_ID: 1112744 Reactome Database ID Release 431112744 Reactome, http://www.reactome.org ReactomeREACT_27475 has a Stoichiometric coefficient of 1 PPBSF Reactome DB_ID: 1266704 Reactome Database ID Release 431266704 Reactome, http://www.reactome.org ReactomeREACT_116716 has a Stoichiometric coefficient of 1 pre-pro-B cell growth-stimulating factor IL7RA:JAK1 Reactome DB_ID: 1264843 Reactome Database ID Release 431264843 Reactome, http://www.reactome.org ReactomeREACT_117324 has a Stoichiometric coefficient of 1 IL7:IL7RA:JAK1 Reactome DB_ID: 449983 Reactome Database ID Release 43449983 Reactome, http://www.reactome.org ReactomeREACT_116761 has a Stoichiometric coefficient of 1 IL7:IL7RA:JAK1:IL2RG:JAK3 Reactome DB_ID: 449967 Reactome Database ID Release 43449967 Reactome, http://www.reactome.org ReactomeREACT_116476 has a Stoichiometric coefficient of 1 Neurofascin interactions Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Neurofascin is an L1 family immunoglobulin cell adhesion molecule involved in axon subcellular targeting and synapse formation during neural development. There are a range of different isoforms identified in Neurofascin of which two of them are well studied the 186kDa commonly referred to as neuronal form and is present in node of Ranvier neurons and the 155kDa form known as a glial form present in schwann cells.<br>Neurofascin colocalizes with NrCAM and ankyrinG at the nodes of Ranvier. Neurofascin participates in transheterophilic adhesion with NrCAM and stimulates neurite outgrowth in chicken tectal neurons. The last few amino acids of neurofascin form the PDZ class I binding motif (SLA) and through these last few amino acids it associates with syntenin-1. Pubmed10662501 Pubmed19356150 Reactome Database ID Release 43447043 Reactome, http://www.reactome.org ReactomeREACT_22312 Reviewed: Maness, PF, 2010-02-16 CHL1 interactions Authored: Garapati, P V, 2008-07-30 10:22:58 Close homolog of L1 (CHL1) is a member of the L1 family of cell adhesion molecules expressed by subpopulations of neurons and glia in the central and peripheral nervous system. CHL1 like L1 promotes neuron survival and neurite outgrowth. CHL1 shares the basic structural arrangement of L1 family members yet in contrast to all the members it is not capable of forming homophilic adhesion. The second Ig-like domain of CHL1 contains the integrin interaction motif RGD rather than with in the sixth Ig-like domain as in L1, however the sixth Ig-like domain of CHL1 has another potential integrin binding motif DGEA. CHL1 binds NP-1 via the Ig1 sequence FASNRL to mdediate repulsive axon guidance to Sema3A. CHL1 is the only L1 family member with an altered sequence (FIGAY) in the ankyrin-binding domain, and it lacks the sorting/endocytosis RSLE motif, which is characteristic of other L1 family members. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed10662501 Pubmed19356150 Reactome Database ID Release 43447041 Reactome, http://www.reactome.org ReactomeREACT_22292 Reviewed: Maness, PF, 2010-02-16 Myogenesis Authored: Garapati, P V, 2010-02-16 Edited: Garapati, P V, 2010-02-16 GENE ONTOLOGYGO:0042692 Myogenesis, the formation of muscle tissue, is a complex process involving steps of cell proliferation mediated by growth factor signaling, cell differentiation, reorganization of cells to form myotubes, and cell fusion. Here, one regulatory feature of this process has been annotated, the signaling cascade initiated by CDO (cell-adhesion-molecule-related/downregulated by oncogenes) and associated co-receptors. Reactome Database ID Release 43525793 Reactome, http://www.reactome.org ReactomeREACT_21303 NrCAM interactions Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed10662501 Pubmed16202709 Pubmed19356150 Reactome Database ID Release 43447038 Reactome, http://www.reactome.org ReactomeREACT_22329 Reviewed: Maness, PF, 2010-02-16 The NgCAM-related cell adhesion molecule (NrCAM) is member of the L1 family involved in the eye development and node of Ranvier. Like all the other members of L1 family NrCAM also has the ability to bind to ankyrins. The last C-terminal amino acids of NrCAM form a PDZ-binding motif and can interact with SAP (synapse-associated protein) 102 and SAP97. Member of the GPI-anchored TAG-1/axonin-1 have been shown to interact with NrCAM. NrCAM also binds the Sema3B receptor NP-2 to mediate repulsive axon guidance. Recycling pathway of L1 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 functions in many aspects of neuronal development including axon outgrowth and neuronal migration. These functions require coordination between L1 and the actin cytoskeleton. F-actin continuously moves in a retrograde direction from the P-(peripheral) domain of the growth cone towards the growth cone’s C-(central) domain. L1, attached to the actin cytoskeleton via membrane cytoskeletal linkers (MCKs) such as ankyrins (Ankyrin-G, -B and -R) and members of the ERMs (ezrin, radixin, and moesin) family, link this retrograde F-actin flow with extracellular immobile ligands.<br>Forward translocation of growth cone requires not only the CAM-actin linkage but also a gradient of cell substrate adhesion (strong adhesion at the front and weak adhesion at the rear) so that the cytoskeletal machinery is able to pull the cell forward as attachments at the rear are released. This asymmetry is achieved in part by internalizing L1 molecules as they are moved to the rear of the growth cone coupled to retrograde F-actin flow and recycling them to the leading edge plasma membrane.<br>L1 internalization is mediated by phosphorylation and dephosphorylation. The L1 cytoplasmic domain (L1CD) carries an endocytic or sorting motif, YRSLE, that is recognized by the clathrin associated adaptor protein-2 (AP-2). AP-2 binds the YRSLE motif only when its tyrosine is not phosphorylated and triggers L1 endocytosis. SRC kinase associated with lipid rafts in the P-domain membrane phosphorylates L1 molecules on tyrosine-1176, stabilizing them in the plasma membrane. L1 endocytosis is triggered by the dephosphorylation of Y1176 within the C domain. Some of these internalized L1 molecules are transported in an anterograde direction along microtubules for reuse in the leading edge. Pubmed10804209 Pubmed11717353 Pubmed14709786 Reactome Database ID Release 43437239 Reactome, http://www.reactome.org ReactomeREACT_22365 Reviewed: Maness, PF, 2010-02-16 L1CAM interactions Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed14709786 Pubmed17189949 Pubmed18760361 Pubmed19356150 Pubmed9211984 Reactome Database ID Release 43373760 Reactome, http://www.reactome.org ReactomeREACT_22205 Reviewed: Maness, PF, 2010-02-16 The L1 family of cell adhesion molecules (L1CAMs) are a subfamily of the immunoglobulin superfamily of transmembrane receptors, comprised of four structurally related proteins: L1, Close Homolog of L1 (CHL1), NrCAM, and Neurofascin. These CAMs contain six Ig like domains, five or six fibronectin like repeats, a transmembrane region and a cytoplasmic domain. The L1CAM family has been implicated in processes integral to nervous system development, including neurite outgrowth, neurite fasciculation and inter neuronal adhesion.<br>L1CAM members are predominately expressed by neuronal, as well as some nonneuronal cells, during development. Except CHL1 all the other members of L1 family contain an alternatively spliced 12-nclueotide exon, encoding the amino acid residues RSLE in the neuronal splice forms but missing in the non-neuronal cells. The extracellular regions of L1CAM members are divergent and differ in their abilities to interact with extracellular, heterophilic ligands. The L1 ligands include other Ig-domain CAMs (such as NCAM, TAG-1/axonin and F11), proteoglycans type molecules (neurocan), beta1 integrins, and extra cellular matrix protein laminin, Neuropilin-1, FGF and EGF receptors. Some of these L1-interacting proteins also bind to other L1CAM members. For example TAG-1/axonin interact with L1 and NrCAM; L1, neurofascin and CHL1 binds to contactin family members. The cytoplasmic domains of L1CAM members are most highly conserved. Nevertheless, they have different cytoplasmic binding partners, and even those with similar binding partners may be involved in different signaling complexes and mechanisms. The most conserved feature of L1CAMs is their ability to interact with the actin cytoskeletal adapter protein ankyrin. The cytoplasmic ankyrin-binding domain, exhibits the highest degree of amino acid conservation throughout the L1 family. Signal transduction by L1 Authored: Garapati, P V, 2008-07-30 10:22:58 Besides adhesive roles in cell cell interaction, L1 functions as a signal transducing receptor providing neurons with cues from their environment for axonal growth and guidance. L1 associates with beta1 integrins on the cell surface to induce a signaling pathway involving sequential activation of pp60csrc, Vav2 -GEF, Rac1, PAK1, MEK and ERK1/2. L1 stimulates cell migration and neurite outgrowth through the MAP kinases ERK1/2. CHL1 also associates with integrins and activates a MAPK signaling pathway via pp60c-src, MEK and ERK1/2. <br>L1 also binds the Sema3A receptor neuropilin1 and acts as an obligate coreceptor to mediate Sema3A induced growth cone collapse and axon repulsion. This repulsion can be converted to attraction by homophilic binding of L1 on an apposing cell in trans with L1 complexed with Neuropilin1 (NP1) in the responding neuron.<br>L1 also interacts with FGF receptor and activates PLC gamma and DAG, resulting in the production of arachidonic acid and subsequent opening of voltage-gated channels. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed10608864 Pubmed10818153 Pubmed12721290 Pubmed15597056 Pubmed16597699 Pubmed17189949 Reactome Database ID Release 43445144 Reactome, http://www.reactome.org ReactomeREACT_22272 Reviewed: Maness, PF, 2010-02-16 Interaction between L1 and Ankyrins Ankyrins are a family of adaptor proteins that couple membrane proteins such as voltage gated Na+ channels and the Na+/K+ anion exchanger to the spectrin actin cytoskeleton. Ankyrins are encoded by three genes (ankyrin-G, -B and -R) of which ankyrin-G and -B are the major forms expressed in the developing nervous system. Ankyrins bind to the cytoplasmic domain of L1 CAMs and couple them and ion channel proteins, to the spectrin cytoskeleton. This binding enhances the homophilic adhesive activity of L1 and reduces its mobility within the plasma membrane. L1 interaction with ankyrin mediates branching and synaptogenesis of cortical inhibitory neurons.<br> Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed16904324 Pubmed18839070 Pubmed19356150 Pubmed20156840 Reactome Database ID Release 43445095 Reactome, http://www.reactome.org ReactomeREACT_22266 Reviewed: Maness, PF, 2010-02-16 Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:STAT1/3 Reactome DB_ID: 1112576 Reactome Database ID Release 431112576 Reactome, http://www.reactome.org ReactomeREACT_27946 has a Stoichiometric coefficient of 1 IL6:sIL6R:IL6RB:Activated JAKs Reactome DB_ID: 1112513 Reactome Database ID Release 431112513 Reactome, http://www.reactome.org ReactomeREACT_27811 has a Stoichiometric coefficient of 1 IL6RB:Activated JAKs Reactome DB_ID: 1112556 Reactome Database ID Release 431112556 Reactome, http://www.reactome.org ReactomeREACT_27913 has a Stoichiometric coefficient of 1 Role of Abl in Robo-Slit signaling Abl plays a dual role in the Robo pathway. As a key enzymatic component in the signaling pathway, Abl support repellent signaling (by recruiting the necessary actin binding proteins) and also feed back on the receptor (by down regulating through phosphorylation) to adjust the sensitivity of the pathway.<br>Abl cooperates with multiple effectors, including the actin binding protein Capulet (Capt) and Orbit/MAST/CLASP, suggesting that Abl simultaneously coordinates the dynamics of two major cytoskeletal systems to achieve growth cone repellent guidance. Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed12441051 Pubmed15207230 Pubmed15207236 Reactome Database ID Release 43428890 Reactome, http://www.reactome.org ReactomeREACT_19230 Reviewed: Kidd, T, 2009-08-18 IL6:IL6RA:IL6RB:Activated JAKs Reactome DB_ID: 1112548 Reactome Database ID Release 431112548 Reactome, http://www.reactome.org ReactomeREACT_27794 has a Stoichiometric coefficient of 1 Activation of Rac A low level of Rac activity is essential to maintain axon outgrowth and Robo activation recruits Sos, a dual specificity GEF to the plasma membrane via Dock to activate Rac during midline repulsion. Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Reactome Database ID Release 43428540 Reactome, http://www.reactome.org ReactomeREACT_19226 Reviewed: Kidd, T, 2009-08-18 Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:Tyrosine/serine phosphorylated STAT1/3 Reactome DB_ID: 1112759 Reactome Database ID Release 431112759 Reactome, http://www.reactome.org ReactomeREACT_27789 has a Stoichiometric coefficient of 1 Activated STAT1/3 homo and heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1112537 Reactome Database ID Release 431112537 Reactome, http://www.reactome.org ReactomeREACT_27757 Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:Tyrosine phosphorylated STAT1/3 Reactome DB_ID: 1112524 Reactome Database ID Release 431112524 Reactome, http://www.reactome.org ReactomeREACT_27616 has a Stoichiometric coefficient of 1 Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:SOCS3 Reactome DB_ID: 1112718 Reactome Database ID Release 431112718 Reactome, http://www.reactome.org ReactomeREACT_27461 has a Stoichiometric coefficient of 1 p(Y705)-STAT3 dimer Reactome DB_ID: 1112526 Reactome Database ID Release 431112526 Reactome, http://www.reactome.org ReactomeREACT_27619 has a Stoichiometric coefficient of 2 p(Y701)-STAT1, p(Y705)-STAT3 dimer Reactome DB_ID: 1112555 Reactome Database ID Release 431112555 Reactome, http://www.reactome.org ReactomeREACT_27675 has a Stoichiometric coefficient of 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta Reactome DB_ID: 914180 Reactome Database ID Release 43914180 Reactome, http://www.reactome.org ReactomeREACT_24266 has a Stoichiometric coefficient of 1 IL6RB:JAKs Reactome DB_ID: 1067690 Reactome Database ID Release 431067690 Reactome, http://www.reactome.org ReactomeREACT_27578 has a Stoichiometric coefficient of 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta:p85-containing Class 1A PI3Ks Reactome DB_ID: 914177 Reactome Database ID Release 43914177 Reactome, http://www.reactome.org ReactomeREACT_24243 has a Stoichiometric coefficient of 1 IL6 receptor hexamer:JAKs Reactome DB_ID: 1112588 Reactome Database ID Release 431112588 Reactome, http://www.reactome.org ReactomeREACT_27917 has a Stoichiometric coefficient of 2 IL6 receptor hexamer:Activated JAKs Reactome DB_ID: 1112515 Reactome Database ID Release 431112515 Reactome, http://www.reactome.org ReactomeREACT_27941 has a Stoichiometric coefficient of 2 IL6 receptor trimer:Activated JAKs Converted from EntitySet in Reactome Reactome DB_ID: 1112579 Reactome Database ID Release 431112579 Reactome, http://www.reactome.org ReactomeREACT_27726 IL6:sIL6R:sgp130 Reactome DB_ID: 1067674 Reactome Database ID Release 431067674 Reactome, http://www.reactome.org ReactomeREACT_27719 has a Stoichiometric coefficient of 1 IL6:sIL6R:IL6RB:JAKs Reactome DB_ID: 1067691 Reactome Database ID Release 431067691 Reactome, http://www.reactome.org ReactomeREACT_27679 has a Stoichiometric coefficient of 1 IL6:IL6RA:IL6RB:JAKs Reactome DB_ID: 1067654 Reactome Database ID Release 431067654 Reactome, http://www.reactome.org ReactomeREACT_27957 has a Stoichiometric coefficient of 1 IL6 receptor trimer:JAKs Converted from EntitySet in Reactome Reactome DB_ID: 1112523 Reactome Database ID Release 431112523 Reactome, http://www.reactome.org ReactomeREACT_27696 Sema4D mediated inhibition of cell attachment and migration Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:38 Pubmed14770294 Pubmed16314868 Pubmed18374575 Reactome Database ID Release 43416550 Reactome, http://www.reactome.org ReactomeREACT_19266 Repulsive Sema4D-Plexin-B1 signaling involves four GTPases, Rnd1, R-Ras, Rho and Rac1. Sema4D-Plexin-B1 binding promotes Rnd1-dependent activation of the plexin-B1 GAP domain and transient suppression of R-Ras activity. R-Ras inactivation promotes PI3K and Akt inactivation followed by GSK-3beta activation and CRMP2 inactivation. Plexin-B1 also transiently associates with and activates p190Rho-GAP, triggering a transient decrease in activated Rho. Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema4D in semaphorin signaling Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:38 Pubmed14770294 Pubmed15818466 Pubmed16314868 Reactome Database ID Release 43400685 Reactome, http://www.reactome.org ReactomeREACT_19259 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Semaphorin 4D (Sema 4D/CD100) is an axon guidance molecule with two disulfide-linked 150-kDa subunits. SEMA4D is structurally defined by a conserved 500-amino acid extracellular domain with 16 cysteines (sema domain) and also an Ig-like domain C-terminal to the sema domain. Sema4D is expressed on the cell surface as a homodimer; cysteine 679 within the sema domain is required for this dimerization.<br>The main receptors for Sema4D are plexin-B1 and CD72. The activation of plexins by semaphorins initiates a variety of signaling processes that involve several small GTPases of the Ras and Rho families. Sema4D-Plexin-B1 interaction appears to mediate different and sometimes opposite effects depending on the cellular context. Plexin-B1 activation inhibits integrin-mediated cell attachment and cell migration through the activation of the R-RasGAP activity inherent to plexin-B1 or through the inhibition of RhoA. However, activation of plexin-B1 by Sema4D stimulates the migration of endothelial cells by mediating the activation of RhoA. SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:38 Pubmed16286926 Pubmed16930978 Pubmed18374575 Pubmed18580951 Reactome Database ID Release 43399955 Reactome, http://www.reactome.org ReactomeREACT_19279 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema3A, a prototypical semaphorin, acts as a chemorepellent or a chemoattractant for axons by activating a receptor complex comprising neuropilin-1 as the ligand-binding subunit and plexin-A1 as the signal-transducing subunit. Sema3A inhibits cell migration by inhibiting integrin ligand-binding activity. Sema4D induced cell migration and growth-cone collapse Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:38 Pubmed12220504 Pubmed15210733 Pubmed15818466 Pubmed18374575 Reactome Database ID Release 43416572 Reactome, http://www.reactome.org ReactomeREACT_19277 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema4D-mediated attraction of endothelial cells requires Rho, but not R-Ras, signaling. Sema4D-mediated plexinB1 activation activates Rho and its downstream effector ROCK. ROCK then phosphorylates MLC to induce actomyosin stress fiber contraction and to direct the assembly of focal adhesion complexes and integrin-mediated adhesion. CRMPs in Sema3A signaling Authored: Garapati, P V, 2009-03-23 09:59:28 CRMPs are a small family of plexinA-interacting cytosolic phosphoproteins identified as mediators of Sema3A signaling and neuronal differentiation. After Sema3A activation Plexin-A bound CRMP's undergo phosphorylation by Cdk5, GSK3beta and Fes kinases. Phosphorylation of CRMPs by these kinases blocks the ability of CRMP to bind to tubulin dimers, subsequently induces depolymerization of F-actin, and ultimately leads to growth cone collapse. Edited: Garapati, P V, 2009-03-23 10:00:38 Pubmed17607942 Reactome Database ID Release 43399956 Reactome, http://www.reactome.org ReactomeREACT_19199 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema3A PAK dependent Axon repulsion Activated Rac1 bound to plexin-A might modulate actin dynamics through the sequential phosphorylation and activation of PAK, LIMK1 and cofilin. Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:38 Pubmed11276226 Pubmed11604131 Pubmed12593985 Pubmed18374575 Reactome Database ID Release 43399954 Reactome, http://www.reactome.org ReactomeREACT_19236 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 SHP2:GRB2 Reactome DB_ID: 914028 Reactome Database ID Release 43914028 Reactome, http://www.reactome.org ReactomeREACT_24568 has a Stoichiometric coefficient of 1 IL5 homodimer:IL5RA:p(Y593)-Bc:JAK2 Reactome DB_ID: 914069 Reactome Database ID Release 43914069 Reactome, http://www.reactome.org ReactomeREACT_24124 has a Stoichiometric coefficient of 1 Developmental Biology As a first step towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of three kinds of processes have been annotated. These are aspects of the roles of <b>cell adhesion molecules</b> in axonal guidance and myogenesis, of <b>transcriptional regulation</b> in hematopoiesis (specifically, B lymphopoiesis), pancreatic beta cell and white adipocyte differentiation, and molecular events of <b>"nodal" signaling</b>. Edited: Matthews, L, 2011-05-06 Reactome Database ID Release 431266738 Reactome, http://www.reactome.org ReactomeREACT_111045 Reviewed: Maness, PF, Krauss, RS, Walmod, PS, Jensen, J, 2011-08-22 Molecules associated with elastic fibres Authored: Jupe, S, 2012-04-30 Edited: Jupe, S, 2012-11-12 Proteins found associated with microfibrils include vitronectin (Dahlback et al. 1990), latent transforming growth factor beta-binding proteins (Kielty et al. 2002, Munger & Sheppard 2011), emilin (Bressan et al. 1993, Mongiat et al. 2000), members of the microfibrillar-associated proteins (MFAPs, Gibson et al.1996), and fibulins (Roark et al. 1995, Yanagisawa et al. 2002). The significance of these interactions is not well understood. Proteoglycans such as versican (Isogai et al. 2002), biglycan, and decorin (Reinboth et al. 2002) can interact with the microfibrils. They confer specific properties including hydration, impact absorption, molecular sieving, regulation of cellular activities, mediation of growth factor association, and release and transport within the extracellular matrix (Buczek-Thomas et al. 2002). In addition, glycosaminoglycans have been shown to interact with tropoelastin through its lysine side chains (Wu et al. 1999) regulating tropoelastin assembly (Tu and Weiss, 2008). Pubmed10419484 Pubmed10821830 Pubmed11723132 Pubmed11805834 Pubmed12082143 Pubmed12124775 Pubmed12429738 Pubmed1689758 Pubmed18228265 Pubmed18547105 Pubmed21900405 Pubmed7534784 Pubmed8458869 Pubmed8557636 Reactome Database ID Release 432129379 Reactome, http://www.reactome.org ReactomeREACT_150331 Reviewed: Muiznieks, Lisa, 2012-11-02 Semaphorin interactions Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:38 Pubmed12471249 Pubmed12593985 Pubmed16939971 Pubmed18269210 Pubmed18374575 Reactome Database ID Release 43373755 Reactome, http://www.reactome.org ReactomeREACT_19271 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Semaphorins are a large family of cell surface and secreted guidance molecules divided into eight classes on the basis of their structures. They all have an N-terminal conserved sema domain. Semaphorins signal through multimeric receptor complexes that include other proteins such as plexins and neuropilins. Axon guidance Authored: Garapati, P V, 2009-05-28 19:40:55 Axon guidance / axon pathfinding is the process by which neurons send out axons to reach the correct targets. Growing axons have a highly motile structure at the growing tip called the growth cone, which senses the guidance cues in the environment through guidance cue receptors and responds by undergoing cytoskeletal changes that determine the direction of axon growth. <br>Guidance cues present in the surrounding environment provide the necessary directional information for the trip. These extrinsic cues have been divided into attractive or repulsive signals that tell the growth cone where and where not to grow. <br>Genetic and biochemical studies have led to the identification of highly conserved families of guidance molecules and their receptors that guide axons. These include netrins, Slits, semaphorins, and ephrins, and their cognate receptors, DCC and or uncoordinated-5 (UNC5), roundabouts (Robo), neuropilin and Eph. In addition, many other classes of adhesion molecules are also used by growth cones to navigate properly which include NCAM and L1CAM. Edited: Garapati, P V, 2009-05-28 19:40:55 GENE ONTOLOGYGO:0007411 Reactome Database ID Release 43422475 Reactome, http://www.reactome.org ReactomeREACT_18266 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- High affinity IL-5 receptor complex dimer, inactive JAK2, p(S585)-Common beta chain Reactome DB_ID: 914168 Reactome Database ID Release 43914168 Reactome, http://www.reactome.org ReactomeREACT_24490 has a Stoichiometric coefficient of 2 IL5 homodimer:IL5RA:p(S585)-Common beta chain:JAK2 Reactome DB_ID: 914169 Reactome Database ID Release 43914169 Reactome, http://www.reactome.org ReactomeREACT_24201 has a Stoichiometric coefficient of 1 High affinity GM-CSF receptor complex dimer, inactive JAK2, p(S585)-Bc Reactome DB_ID: 914171 Reactome Database ID Release 43914171 Reactome, http://www.reactome.org ReactomeREACT_24337 has a Stoichiometric coefficient of 2 GM-CSF:GM-CSF receptor alpha subunit:p(S585)-Common beta chain:JAK2 Reactome DB_ID: 914178 Reactome Database ID Release 43914178 Reactome, http://www.reactome.org ReactomeREACT_24432 has a Stoichiometric coefficient of 1 Interleukin-3 receptor IL3:IL3RA:pS585-IL3RB:JAK2 Reactome DB_ID: 914167 Reactome Database ID Release 43914167 Reactome, http://www.reactome.org ReactomeREACT_24128 has a Stoichiometric coefficient of 1 p-S585-IL3RB:JAK2 Reactome DB_ID: 914173 Reactome Database ID Release 43914173 Reactome, http://www.reactome.org ReactomeREACT_24069 has a Stoichiometric coefficient of 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc Converted from EntitySet in Reactome Reactome DB_ID: 914179 Reactome Database ID Release 43914179 Reactome, http://www.reactome.org ReactomeREACT_24222 High affinity IL-3 receptor complex dimer, inactive JAK2 Reactome DB_ID: 914175 Reactome Database ID Release 43914175 Reactome, http://www.reactome.org ReactomeREACT_24344 has a Stoichiometric coefficient of 2 c-src mediated regulation of Cx43 function and closure of gap junctions Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-17 10:03:12 Pubmed10085299 Pubmed11124251 Pubmed12807735 Pubmed14638725 Pubmed15492000 Reactome Database ID Release 43191647 Reactome, http://www.reactome.org ReactomeREACT_11043 The kinases c-Src (Giepmans et al. 2001; Sorgen et al. 2004), PKc (Lin et al. 2003) and MAPK (Mograbi et al. 2003) play an essential role in the phosphorylation of Cx which leads to its degradation. c-Src appears to associate with and phosphorylate Cx43 leading to closure of gap junctions. Evidence suggests that v-src may activate MAPK, which in turn phosphorylates Cx43 on serine sites leading to channel gating (Zhou et al. 1999). DSIF complex binds to RNA Pol II (hypophosphorylated) Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed10757782 Pubmed12653964 Pubmed9450929 Pubmed9857195 Reactome Database ID Release 43167083 Reactome, http://www.reactome.org ReactomeREACT_6250 This HIV-1 event was inferred from the corresponding human RNA Pol II transcription event. DSIF is a heterodimer consisting of hSPT4 (human homolog of yeast Spt4- p14) and hSPT5 (human homolog of yeast Spt5-p160) (Wada et al. 1998). DSIF association with Pol II may be enabled by Spt5 binding to Pol II creating a scaffold for NELF binding. Spt5 subunit of DSIF can be phosphorylated by P-TEFb (Ivanov et al. 2000). Endosomal Sorting Complex Required For Transport (ESCRT) Authored: Gillespie, ME, 2010-08-10 Edited: Gillespie, ME, 2010-08-10 GENE ONTOLOGYGO:0016197 Many plasma membrane proteins are in a constant flux throughout the internal trafficking pathways of the cell. Some receptors are continuously internalized into recycling endosomes and returned to the cell surface. Others are sorted into intralumenal vesicles of morphologically distinctive endosomes that are known as multivesicular bodies (MVBs). These MVBs fuse with lysosomes, resulting in degradation of their cargo by lysosomal acidic hydrolases.<br> Endosomes can be operationally defined as being either early or late, referring to the relative time it takes for endocytosed material to reach either stage. Ultrastructural studies indicate that early endosomes are predominantly tubulovesicular structures, which constitute a major sorting platform in the cell, whereas late endosomes show the characteristics of typical MVBs and are capable of fusing with lysosomes.<br> A well characterized signal for shunting membrane proteins into the degradative MVB pathway is the ubiquitylation of these cargoes. At the center of a vast protein:protein and protein:lipid interaction network that underpins ubiquitin mediated sorting to the lysosome are the endosomal sorting complexes required for transport (ESCRTs), which are conserved throughout all major eukaryotic taxa. Pubmed17450176 Pubmed17988873 Pubmed19345195 Reactome Database ID Release 43917729 Reactome, http://www.reactome.org ReactomeREACT_27258 Reviewed: Rush, MG, 2008-01-11 00:00:00 Formation of DSIF:NELF:HIV-1 early elongation complex Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed10199401 Reactome Database ID Release 43167085 Reactome, http://www.reactome.org ReactomeREACT_6357 This HIV-1 event was inferred from the corresponding human RNA Pol II transcription event. NELF complex is a ~ 300 kDa multiprotein complex composed of 5 peptides (A - E): ~66,61,59,58 and 46 kDa (Yamaguchi et al 1999). All these peptides are required for NELF-mediated inhibition of Pol II elongation. NELF complex has been reported to bind to the pre-formed DSIF:RNA Pol II complex that may act as a scaffold for its binding. NELF-A is suspected to be involved in Wolf-Hirschhorn syndrome. Binding of DSIF:NELF to RNA Pol II CTD results in abortive termination of early elongation steps by the growing transcripts. Formation of annular gap junctions Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Gap junction plaque internalization and the disruption cell communication requires a reorganization of Cx molecular interactions. Proteins including Dab-2, AP-2, Dynamin and Myosin VI associate with gap junction plaques permitting the internalisation of plaques after clathrin association (Piehl et al., 2007). Pubmed11171382 Pubmed15194225 Pubmed15492000 Pubmed16195341 Pubmed17108328 Reactome Database ID Release 43196025 Reactome, http://www.reactome.org ReactomeREACT_11049 Until now, two kinds of annular gap junctions have been described. The first is a small vesicle like structure which permits gap junction plaque renewal without arrest of functionality [Jordan et al., 2001]. The second is a large annular structure, composed primarily of the junctional plaques of two adjacent cells (Jordan et al., 2001; Segretain et al., 2004). Abortive termination of HIV-1 early transcription elongation by DSIF:NELF Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-10-15 23:27:00 In the early elongation phase, shorter transcripts typically of ~30 nt in length are generated due to random termination of elongating nascent transcripts. This abortive cessation of elongation has been observed mainly in the presence of DSIF-NELF bound to Pol II complex. (Reviewed in Conaway et al.,2000; Shilatifard et al., 2003 ). Pubmed10916156 Pubmed12676794 Reactome Database ID Release 43167478 Reactome, http://www.reactome.org ReactomeREACT_6281 Regulation of gap junction activity Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-17 13:54:37 Reactome Database ID Release 43191650 Reactome, http://www.reactome.org ReactomeREACT_11034 Src is believed to suppress gap junction communication by phosphorylating Cx43. Recognition and binding of the HIV-1 mRNA cap by the cap-binding complex Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167089 Reactome, http://www.reactome.org ReactomeREACT_6166 The cap binding complex binds to the methylated GMP cap on the nascent mRNA transcript. Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-12 12:59:16 Pubmed12149451 Pubmed9841901 Reactome Database ID Release 43190840 Reactome, http://www.reactome.org ReactomeREACT_11039 Through videomicroscopy, a saltatory transport of connexon vesicles along curvilinear microtubules from the Golgi to the plasma membrane has been observed (Lauf et al., 2002). Such a transport system has been described for similar secretory vesicles (Toomre et al., 1999). Gap junction degradation Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-03-27 16:29:06 Pubmed17108328 Pubmed7287816 Pubmed8522583 Reactome Database ID Release 43190873 Reactome, http://www.reactome.org ReactomeREACT_11035 The half-life of Cx is very short (1 to 5h) compared to other junctional proteins (Laird et al., 1995 ; Fallon and Goudenough, 1981). Connexins are targeted for degradation by the proteasome and the lysosome. Degradation appears to involve the phosphorylation of Connexins as well as their interactions with other proteins (Piehl et al., 2007). Activation of GT At the beginning of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex' is present. At the end of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex with activated GT' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167133 Reactome, http://www.reactome.org ReactomeREACT_6298 Oligomerization of connexins into connexons Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-26 11:39:00 Pubmed10191254 Pubmed10231375 Pubmed11985493 Pubmed12829738 Pubmed16723732 Pubmed7691412 Pubmed9184217 Reactome Database ID Release 43190704 Reactome, http://www.reactome.org ReactomeREACT_9398 The mechanism of connexin assembly into connexons has been well characterized. Two different types of connexons can be formed. A connexon containing six identical connexin molecules is referred to as an homomeric connexon, while a connexon containing at least two different connexin molecules is referred to as an heteromeric connexon. The connexin molecules making up an heteromeric connexon appear to belong to only one subgroup (alpha or beta); heteromeric connexons containing both alpha and beta subunits have not yet been observed. Indeed, an intrinsic signal in four amino acid positions appears to confer different physicochemical characteristics to certain connexins in the alpha and beta groups (Lagr et al., 2003). These intrinsic signals are Cx specific, however (see Gemel et al., 2006). Therefore, additional yet unknown signals are required to regulate connexin compatibility and hetero-oligomerization. <br>The identification of the subcellular location at which gap junction assembly occurs has proven difficult. One explanation for this difficulty may be that the location of oligomerization for each connexon varies depending upon Cx type or cell type. Oligomerization has been observed after ER membrane insertion (Cx43, Cx32, Cx26) (Falk et al., 1997; Ahmad et al., 1999; Ahmad and Evans, 2002), in the ER-Golgi-intermediate compartment (ERGIC) (Cx32) (Diez et al. 1999) and inside the trans-Goligi network (Cx43) (Musil and Goodenough, 1993). SPT5 subunit of Pol II binds the RNA triphosphatase (RTP) Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167153 Reactome, http://www.reactome.org ReactomeREACT_6295 The capping enzyme interacts with the Spt5 subunit of transcription elongation factor DSIF. This interaction may couple the capping reaction with promoter escape or elongation, thereby acting as a “checkpoint” to assure that capping has occurred before the polymerase proceeds to make the rest of the transcript. Transport of connexons to the plasma membrane Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-04-12 12:57:50 Following connexon oligomerization, the hemichannels must be transported to the plasma membrane. This has been shown to occur in transport vesicles called "cargo containers". Most of post-Golgi cargo containers have a diameter of of 50- 200 nm (Lauf et al., 2002). Recently direct transport of connexins to GJ assembly sides has been described (Shaw et al., 2007). Besides microtuble-dependent trafficking, a microtubule-independent delivery pathway may exist as concluded from studies using the secretory transport inhibitor, Brefeldin A (Musil and Goodenough 1993; De Sousa et al. 1993; Laird et al. 1995). Pubmed12149451 Pubmed17289573 Pubmed7691412 Pubmed8404537 Pubmed8522583 Reactome Database ID Release 43190872 Reactome, http://www.reactome.org ReactomeREACT_11050 Hypophosphorylation of RNA Pol II CTD by FCP1P protein Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 EC Number: 3.1.3.16 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed12370301 Reactome Database ID Release 43167072 Reactome, http://www.reactome.org ReactomeREACT_6206 This HIV-1 event was inferred from the corresponding human RNA Pol II transcription event. FCP1 dephosphorylates RNAP II in ternary elongation complexes as well as in solution and, therefore, is thought to function in the recycling of RNAP II during the transcription cycle. Biochemical experiments suggest that human FCP1 targets CTDs that are phosphorylated at serine 2 (CTD-serine 2) and/or CTD-serine 5. It is also observed to stimulate elongation independent of its catalytic activity. Dephosphorylation of Ser2 - phosphorylated Pol II results in hypophosphorylated form that disengages capping enzymes (CE). Translocation of GLUT4 to the Plasma Membrane Authored: May, B, 2011-07-07 Edited: May, B, 2011-07-07 In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011). In myocytes muscle contraction alone can also cause translocation of GLUT4.<br>Though the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins.<br>Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane. Pubmed18570632 Pubmed19389739 Pubmed20417083 Pubmed21216617 Pubmed21306486 Pubmed21405107 Reactome Database ID Release 431445148 Reactome, http://www.reactome.org ReactomeREACT_147867 Reviewed: Klip, Amira, 2012-08-21 Transport of connexins along the secretory pathway Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Connexins follow the classical secretory transport route from the ER to the plasma membrane: ER -> ERGIC -> Golgi -> TGN (Trans Golgi Network) -> PM (Plasma Membrane). All connexins assemble or oligomerize into hexameric connexons. The site of assembly varies and depends on Cx isoform, or cell type (see Koval et al., 2006).<br>Oligomerization of connexins has been observed during ER membrane insertion (Cx32), just after exit from the ER, in the ER-Golgi-intermediate compartment (Cx26) and inside the Trans-Golgi Network (Cx43) (Falk et al. 1997; Ahmad et al. 1999; Musil and Goodenough 1993; Diez et al. 1999). Edited: Matthews, L, 2007-01-26 11:57:49 Pubmed10191254 Pubmed10231375 Pubmed16490353 Pubmed7691412 Pubmed9184217 Reactome Database ID Release 43190827 Reactome, http://www.reactome.org ReactomeREACT_9392 Hyperphosphorylation (Ser2) of RNA Pol II CTD by the P-TEFb(Cyclin T1:Cdk9) complex Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed10866664 Pubmed7853496 Reactome Database ID Release 43167191 Reactome, http://www.reactome.org ReactomeREACT_6170 The association between Tat, TAR and P-TEFb is believed to bring the catalytic subunit of P-TEFb(Cyclin T1:Cdk9) in close proximity to Pol II where it hyperphosphorylates the CTD of Pol II (Herrmann et al., 1995; Zhou et al. 2000). In the presence of Tat, P-TEFb(Cyclin T1:CDK9) has been shown to phosphorylate serine 5 in addition to serine 2 suggesting that modification of the substrate specificity of CDK9 may play a role in the ability of Tat to promote transcriptional elongation (Zhou et al. 2000). Association of Tat with P-TEFb(Cyclin T1:Cdk9) Pubmed7853496 Pubmed9491887 Pubmed9832504 Pubmed9843510 Reactome Database ID Release 43167234 Reactome, http://www.reactome.org ReactomeREACT_6356 Tat associates with the Cyclin T1 subunit of P-TEFb (Cyclin T1:Cdk9) through a region of cysteine-rich and core sequences referred to as the ARM domain within Tat (Wei et al., 1998; see also Herrmann 1995). This interaction is believed to involve metal ions stabilized by cysteine residues in both proteins (Bieniasz et al., 1998; Garber et al., 1998). Phosphorylation of NEFL by the P-TEFb(Cyclin T1:Cdk9) complex Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Phosphorylation of the RD subunit of NEFL by P-TEFb(Cyclin T1:Cdk9) results in the dissociation of NEFL from TAR as well as the conversion of NEFL to an elongation factor (Fujinaga et al., 2004) Pubmed14701750 Reactome Database ID Release 43170706 Reactome, http://www.reactome.org ReactomeREACT_6311 Downstream TCR signaling Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Changes in gene expression are required for the T cell to gain full proliferative competence and to produce effector cytokines. Three transcription factors in particular have been found to play a key role in TCR-stimulated changes in gene expression, namely NF-kB, NFAT and AP-1. <p>A key step in NF-kB activation is the stimulation and translocation of PKC theta. The critical element that effects PKC theta activation is PI3K. This enzyme complex translocates to the plasma membrane by interacting with phospho-tyrosines on CD28 via its two SH2 domains located in p85 subunit. The p110 subunit of PI3K phosphorylates the inositol ring of PIP2 to generate PIP3 (steps 17-18). PIP3 may also be dephosphorylated by the phosphatase SHIP to generate PI-3,4-P2.<p>PIP3 and PI-3,4-P2 acts as binding sites to the PH domain of PKB/Akt and PDK1 (steps 19, 21 and 22). PKB is activated in response to PI3K stimulation by PDK1 (step 23). PDK1 has an essential role in regulating the activation of PKC theta and recruitment of CBM complex to the immune synapse. PKC theta is a member of novel class (DAG dependent, Ca++ independent) of PKC and the only member known to translocate to this synapse. Prior to TCR stimulation PKC theta exists in an inactive closed conformation. Upon release of DAG, it binds to PKC theta via the C1 domain and undergoes phosphorylation on tyrosine 90 by Lck to attain an open conformation. PKC theta is further phosphorylated by PDK1 on threonine 538. This step is critical for PKC activity (steps 24-26). <p>CARMA1 translocates to the plasma membrane following the interaction of its SH3 domain with the 'PxxP' motif on PDK1. CARMA1 is phosphorylated by PKC-theta on residue S552, leading to the oligomerization of CARMA1. This complex acts as a scaffold, recruiting Bcl10 to the synapse by interacting with their CARD domains. <p>Bcl10 undergoes phosphorylation mediated by the enzyme RIP2. Activated Bcl10 then mediates the ubiquitination of NEMO by recruiting MALT1 and TRAF6. MALT1 binds to Bcl10 with its Ig-like domains and undergoes oligomerization. TRAF6 binds to the oligomerized MALT1 and also undergoes oligomerization. <p>Oligomerized TRAF6 acts as a ubiquitin-protein ligase, catalyzing auto-K63-linked polyubiquitination (steps 27-33). This K-63 ubiquitinated TRAF6 activates TAK1 kinase bound to TAB2 and also ubiquitinates NEMO/IKK-gamma in the IKK complex. TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 kinase phosphorylates IKK-beta on residues S177 and S181 in the activation loop and activates the IKK kinase activity. IKK-beta phosphorylates the IkB-alpha bound to the NF-kB heterodimer, on residues S19 and S23 and directs IkB-beta to 26S proteasome degradation (step 34-38 & 40). <p>The NF-kB heterodimer with a free NTS sequence finally migrates to the nucleus to regulate gene transcription (step 39). Pubmed15084594 Reactome Database ID Release 43202424 Reactome, http://www.reactome.org ReactomeREACT_12555 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Abortive HIV-1 Initiation After Second Transition At the beginning of this reaction, 1 molecule of 'HIV-1 transcription complex containing 4-9 nucleotide long transcript' is present. At the end of this reaction, 1 molecule of 'TFIIH', 1 molecule of 'TFIIE', 1 molecule of 'HIV-1 template DNA:4-9 nucleotide transcript hybrid', and 1 molecule of 'RNA Polymerase II (unphosphorylated):TFIIF complex' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-10-15 23:27:00 Reactome Database ID Release 43167468 Reactome, http://www.reactome.org ReactomeREACT_6265 Costimulation by the CD28 family Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 GENE ONTOLOGYGO:0031295 Optimal activation of T-lymphocytes requires at least two signals. A primary one is delivered by the T-cell receptor (TCR) complex after antigen recognition and additional costimulatory signals are delivered by the engagement of costimulatory receptors such as CD28. The best-characterized costimulatory pathways are mediated by a set of cosignaling molecules belonging to the CD28 superfamily, including CD28, CTLA4, ICOS, PD1 and BTLA receptors. These proteins deliver both positive and negative second signals to T-cells by interacting with B7 family ligands expressed on antigen presenting cells. Different subsets of T-cells have very different requirements for costimulation. CD28 family mediated costimulation is not required for all T-cell responses in vivo, and alternative costimulatory pathways also exist. Different receptors of the CD28 family and their ligands have different regulation of expression. CD28 is constitutively expressed on naive T cells whereas CTLA4 expression is dependent on CD28/B7 engagement and the other receptor members ICOS, PD1 and BTLA are induced after initial T-cell stimulation. <br>The positive signals induced by CD28 and ICOS molecules are counterbalanced by other members of the CD28 family, including cytotoxic T-lymphocyte associated antigen (CTLA)4, programmed cell death (PD)1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. The balance of stimulatory and inhibitory signals is crucial to maximize protective immune responses while maintaining immunological tolerance and preventing autoimmunity. <br>The costimulatory receptors CD28, CTLA4, ICOS and PD1 are composed of single extracellular IgV-like domains, whereas BTLA has one IgC-like domain. Receptors CTLA4, CD28 and ICOS are covalent homodimers, due to an interchain disulphide linkage. The costimulatory ligands B71, B72, B7H2, B7H1 and B7DC, have a membrane proximal IgC-like domain and a membrane distal IgV-like domain that is responsible for receptor binding and dimerization. CD28 and CTLA4 have no known intrinsic enzymatic activity. Instead, engagement by their physiologic ligands B71 and B72 leads to the physical recruitment and activation of downstream T-cell effector molecules. Pubmed10374692 Pubmed11905831 Pubmed14647476 Reactome Database ID Release 43388841 Reactome, http://www.reactome.org ReactomeREACT_19344 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Addition of nucleotides 10 and 11 on the growing HIV-1 transcript: Third Transition Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 EC Number: 2.7.7.6 Edited: Matthews, L, 2005-07-26 23:29:22 Formation of phosphodiester bonds nine and ten creates RNA products, which do not dissociate from the RNA pol II initiation complex. The transcription complex has enter the productive elongation phase. TFIIH and ATP-hydrolysis are required for efficient promoter escape. The open region (“transcription bubble”) expands concomitant with the site of RNA-extension. The region upstream from the transcription start site (-9 to -3) collapses to the double-stranded state. TFIIH remains associated to the RNA pol II initiation complex. Reactome Database ID Release 43167117 Reactome, http://www.reactome.org ReactomeREACT_6208 has a Stoichiometric coefficient of 2 CD28 co-stimulation Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 GENE ONTOLOGYGO:0031295 In naive T cells, CD28 costimulation enhances cell cycle entry, potently stimulates expression of both the mitogenic lymphokine interleukin-2 (IL-2) and its receptor, and stimulates the activation of an antiapoptotic program. CD28 engages with one or both members of the B7 receptor family, B7.1 and B7.2. Upon ligand binding the tyrosines and proline-rich motifs present in the cytoplasmic tail of CD28 are phosphorylated by Lck or Fyn. Upon phosphorylation CD28 recruits and induces phosphorylation and activation of a more restricted set of intracellular signaling components that, together with those mobilized by the TCR, contribute to convert membrane-based biochemical and biophysical changes into gene activation events. Proteins like PI3K, Vav-1, Tec and Itk kinases, AKT, and the Dok-1 adaptor have been identified as elements of the CD28 signaling pathway by biochemical or genetic approaches or both. Pubmed12165654 Pubmed8609386 Pubmed8649453 Reactome Database ID Release 43389356 Reactome, http://www.reactome.org ReactomeREACT_19183 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Abortive HIV-1 Initiation Before Second Transition At the beginning of this reaction, 1 molecule of 'HIV-1 Promoter Escape Complex' is present. At the end of this reaction, 1 molecule of 'TFIIA', 1 molecule of 'TFIIH', 1 molecule of 'HIV-1 template DNA containing promoter with transcript of 2 or 3 nucleotides', 1 molecule of 'TFIIE', 1 molecule of 'TFIID', 1 molecule of 'TFIIB', and 1 molecule of 'RNA Polymerase II (unphosphorylated):TFIIF complex' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-10-15 23:27:00 Reactome Database ID Release 43167474 Reactome, http://www.reactome.org ReactomeREACT_6203 CD28 dependent PI3K/Akt signaling Authored: Garapati, P V, 2008-12-16 11:12:19 Edited: Garapati, P V, 2008-12-16 11:12:19 PI3Ks can be activated by a number of different receptors, including the TcR (T cell receptor), co-stimulatory receptors (CD28), cytokine receptors and chemokine receptors. However, the specific roles of PI3Ks downstream of these receptors vary. CD28 contains the YMNM consensus PI3K-binding motif, and PI3K recruitment by CD28 contributes to or complements TCR-dependent PI3K signaling. Activation of PI3K promotes PIP3 production at the plasma membrane and several potential target molecules for this phospholipid have been implicated in PI3K pathways downstream of the TcR and CD28. Of these targets, at least Vav and Akt have been implicated in CD28 costimulation of T cell activation. AKT/PKB connects PI3K to signaling pathways that promote cytokine transcription, survival, cell-cycle entry and growth. Pubmed12670391 Pubmed15046602 Reactome Database ID Release 43389357 Reactome, http://www.reactome.org ReactomeREACT_19358 Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33 Addition of nucleotides 5 through 9 on the growing HIV-1 transcript Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 EC Number: 2.7.7.6 Edited: Matthews, L, 2005-07-26 23:29:22 Formation of the second phosphodiester bond creates a 3-nt product. This transcript is still loosely associated with the RNA polymerase II initiation complex and can dissociate to yield abortive products, which are not further extended. At this stage pausing by RNA polymerase II may result in repeated slippage and reextension of the nascent RNA. The transcription complex still requires continued ATP-hydrolysis by TFIIH for efficient promoter escape. Basal transcription factor TFIIE dissociates from the initiation complex before position +10. <p>Basal transcription factor TFIIF may reassociate and can stimulate transcription elongation at multiple stages. The open region (“transcription bubble”) expands concomitant with the site of RNA-extension, eventually reaching an open region from -9 to +9. Reactome Database ID Release 43167136 Reactome, http://www.reactome.org ReactomeREACT_6172 has a Stoichiometric coefficient of 5 TCR signaling Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 GENE ONTOLOGYGO:0050852 Pubmed10375551 Pubmed12876557 Pubmed9989491 Reactome Database ID Release 43202403 Reactome, http://www.reactome.org ReactomeREACT_12526 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The TCR is a multisubunit complex that consists of clonotypic alpha/beta chains noncovalently associated with the invariant CD3 delta/epsilon/gamma and TCR zeta chains. T cell activation by antigen presenting cells (APCs) results in the activation of protein tyrosine kinases (PTKs) that associate with CD3 and TCR zeta subunits and the co-receptor CD4. Members of the Src kinases (Lck), Syk kinases (ZAP-70), Tec (Itk) and Csk families of nonreceptor PTKs play a crucial role in T cell activation. Activation of PTKs following TCR engagement results in the recruitment and tyrosine phosphorylation of enzymes such as phospholipase C gamma1 and Vav as well as critical adaptor proteins such as LAT, SLP-76 and Gads. These proximal activation leads to reorganization of the cytoskeleton as well as transcription activation of multiple genes leading to T lymphocyte proliferation, differentiation and/or effector function. Addition of the third nucleotide on the nascent HIV-1 transcript Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 EC Number: 2.7.7.6 Edited: Matthews, L, 2005-07-26 23:29:22 Formation of the second phosphodiester bond creates a 3-nt product. This short transcript is still loosely associated with the RNA polymerase II initiation complex and can dissociate to yield abortive products, which are not further extended. The transcription complex still requires continued ATP-hydrolysis by TFIIH and remains sensitive to single-stranded oligo-nucleotide inhibition.<p>The open region (“transcription bubble”) expands concomitant with the site of RNA-extension. In this case this region spans positions -9 to +3. Reactome Database ID Release 43167121 Reactome, http://www.reactome.org ReactomeREACT_6325 Phosphorylation of CD3 and TCR zeta chains Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Prior to T cell receptor (TCR) stimulation, CD4/CD8 associated Lck remains seperated from the TCR and is maintained in an inactive state by the action of Csk. Csk phosphorylates the negative regulatory tyrosine of Lck and inactivates the Lck kinase domain. <p><br><br>Upon TCR stimulation, CD4/CD8 associated Lck co-localizes with the TCR leading to the phosphorylation of the CD3 and TCR subunit. Lck becomes activated by way of CD45-mediated dephosphorylation of negative regulatory tyrosine residues. The presence to PAG-bound Csk is further reduced via the dephosphorylation of PAG (step 1). <p><br><br>Lck is further activated by trans-autophosphorylation on the tyrosine residue on its activation loop (step 2). Active Lck further phosphorylates the tyrosine residues on CD3 chains. The signal-transducing CD3 delta/epsilon/gamma and TCR zeta chains contain a critical signaling motif known as the immunoreceptor tyrosine-based activation motif (ITAM). The two critical tyrosines of each ITAM motif are phosphorylated by Lck (step 3). Pubmed10375551 Reactome Database ID Release 43202427 Reactome, http://www.reactome.org ReactomeREACT_12582 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Addition of the fourth nucleotide on the nascent HIV-1 transcript: Second Transition Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 EC Number: 2.7.7.6 Edited: Matthews, L, 2005-07-26 23:29:22 Formation of the third phosphodiester bond creates a 4-nt product. This commits the initiation complex to promoter escape. The short 4-nt transcript is still loosely associated with the RNA polymerase II initiation complex and can dissociate to yield abortive products, which are not further extended. Inhibition of ATP-hydrolysis by TFIIH does not lead to collapse of the open region any longer. The transcription complex has lost the sensitivity to single-stranded oligo-nucleotide inhibition. However, ATP-hydrolysis and TFIIH are required for efficient promoter escape. The open region (“transcription bubble”) expands concomitant with the site of RNA-extension. In this case this region spans positions -9 to +4. Reactome Database ID Release 43167113 Reactome, http://www.reactome.org ReactomeREACT_6184 Translocation of ZAP-70 to Immunological synapse Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed10375551 Reactome Database ID Release 43202430 Reactome, http://www.reactome.org ReactomeREACT_12596 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The dual phosphorylated ITAMs recruit Syk kinase ZAP-70 via their tandem SH2 domains (step 4). ZAP-70 subsequently undergoes phosphorylation on multiple tyrosine residues for further activation. ZAP-70 includes both positive and negative regulatory sites. Tyrosine 493 is a conserved regulatory site found within the activation loop of the kinase domain. This site has shown to be a positive regulatory site required for ZAP-70 kinase activity and is phosphorylated by Lck (step 5). This phosphorylation contributes to the active conformation of the catalytic domain. Later ZAP-70 undergoes trans-autophosphorylation at Y315 and Y319 (step 6). These sites appear to be positive regulatory sites. ZAP-70 achieves its full activation after the trans-autophosphorylation. Activated ZAP-70 along with Lck phosphorylates the multiple tyrosine residues in the adaptor protein LAT (step 7). Generation of second messenger molecules Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 In addition to serving as a scaffold via auto-phosphorylation, ZAP-70 also phosphorylates a restricted set of substrates following TCR stimulation - including LAT and SLP-76. These substrates have been recognized to play pivotal role in TCR signaling by releasing second messengers. When phosphorylated, LAT and SLP-76 act as adaptor proteins which serve as nucleation points for the construction of a higher order signalosome: GADS, PLC-gamma1 and GRB2 bind to the LAT on the phosphorylated tyrosine residues (steps 8 and 13). SLP-76 and SOS are then moved to the signalosome by interacting with the SH3 domains of GRB2 and GADS via their proline rich sequences (step 9). Three SLP-76 acidic domain N-term tyrosine residues are phosphorylated by ZAP-70, once SLP-76 binds to GADS (step 10). These phospho-tyrosine residues act as binding sites to the SH2 domains of PLC-gamma1, Vav and Itk (steps 11 and 12). <p>PLC-gamma1 is activated by dual phosphorylation on the tyrosine residues at positions 771, 783 and 1254 by Itk and ZAP-70 (step 14). Phosphorylated PLC-gamma1 subsequently detaches from LAT and SLP-76 and translocates to the plasma membrane by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) via its PH domain (step 15). PLC-gamma1 goes on to hydrolyse PIP2 to second messengers DAG and IP3. These second messengers are involved in PKC and NF-kB activation and calcium mobilization (step 16). Pubmed15084594 Reactome Database ID Release 43202433 Reactome, http://www.reactome.org ReactomeREACT_12623 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 Adaptive Immune System Adaptive immunity refers to antigen-specific immune response efficiently involved in clearing the pathogens. The adaptive immune system is comprised of B and T lymphocytes that express receptors with remarkable diversity tailored to recognize aspects of particular pathogens or antigens. During infection, dendritic cells (DC) which act as sentinels in the peripheral tissues recognize and pick up the pathogen in the form of antigenic determinants and then process these antigens and present them to T cells. These T cells of appropriate specificity respond to the antigen, and either kill the pathogen directly or secrete cytokines that will stimulate B lymphocyte response. B cells provide humoral immunity by secreting antibodies specific for the pathogen or antigen. Authored: de Bono, B, Garapati, P V, Jupe, S, May, B, 2011-05-22 Edited: de Bono, B, Garapati, P V, Jupe, S, May, B, 2011-05-22 Pubmed11861602 Pubmed16551257 Pubmed21682741 Reactome Database ID Release 431280218 Reactome, http://www.reactome.org ReactomeREACT_75774 Reviewed: Trowsdale, J, Bluestone, JA, Elliott, T, Esensten, J, Heemskerk, JW, 2011-05-28 Immune System Authored: de Bono, B, Gillespie, ME, Luo, F, Ouwehand, W.H., 2006-03-30 04:06:59 Humans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first critical hours and days of exposure to a new pathogen, our innate immune system. Immune System signaling Reactome Database ID Release 43168256 Reactome, http://www.reactome.org ReactomeREACT_6900 Reviewed: D'Eustachio, P, Gay, NJ, Gale M, Jr, Zwaginga, JJ, 2006-04-19 04:09:58 Signaling in Immune system RNA Polymerase II CTD (phosphorylated) binds to CE At the beginning of this reaction, 1 molecule of 'mRNA capping enzyme', and 1 molecule of 'HIV-1 transcription complex with (ser5) phosphorylated CTD containing extruded transcript to +30' are present. At the end of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167128 Reactome, http://www.reactome.org ReactomeREACT_6220 Phosphorylation (Ser5) of RNA pol II CTD Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Phosphorylation of serine 5 residue at the CTD of pol II largest subunit is an important step signaling the end of initiation and escape into processive elongation processes. Cdk7 protein subunit of TFIIH phosphorylates RNA Pol II CTD serine 5 residues on its heptad repeats. Reactome Database ID Release 43167098 Reactome, http://www.reactome.org ReactomeREACT_6234 Extrusion of 5'-end of 30 nt long HIV-1 transcript through the pore in Pol II complex At the beginning of this reaction, 1 molecule of 'HIV-1 transcription complex containing transcript to +30' is present. At the end of this reaction, 1 molecule of 'HIV-1 transcription complex containing extruded transcript to +30' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167111 Reactome, http://www.reactome.org ReactomeREACT_6148 Addition of nucleotides between position +11 and +30 on HIV-1 transcript Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 EC Number: 2.7.7.6 Edited: Matthews, L, 2005-07-26 23:29:22 RNA polymerase II transcription complexes are susceptible to transcriptional stalling and arrest, when extending nascent transcripts to 30-nt. This susceptibility depends on presence on down-stream DNA, the particular DNA-sequence of the template and presence of transcription factors. Transcription factor TFIIH remains associated to the RNA pol II elongation complex until position +30. At this stage transcription elongation factor TFIIS can rescue stalled transcription elongation complexes. The transcription bubble varies between 13- and 22-nt in size. Reactome Database ID Release 43167115 Reactome, http://www.reactome.org ReactomeREACT_6240 Regulation of beta-cell development Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 GENE ONTOLOGYGO:0031018 Pubmed11575290 Pubmed12591178 Pubmed15298336 Pubmed18094957 Reactome Database ID Release 43186712 Reactome, http://www.reactome.org ReactomeREACT_13698 Reviewed: Jensen, J, 2008-05-12 21:46:53 The normal development of the pancreas during gestation has been intensively investigated over the past decade especially in the mouse (Servitja and Ferrer 2004; Chakrabarti and Mirmira 2003). Studies of genetic defects associated with maturity onset diabetes of the young (MODY) has provided direct insight into these processes as they take place in humans (Fajans et al. 2001). During embryogenesis, committed epithelial cells from the early pancreatic buds differentiate into mature endocrine and exocrine cells. It is helpful to schematize this process into four consecutive cellular stages, to begin to describe the complex interplay of signal transduction pathways and transcriptional networks. The annotations here are by no means complete - factors in addition to the ones described here must be active, and even for the ones that are described, only key examples of their regulatory effects and interactions have been annotated.<p>It is also important to realize that in the human, unlike the mouse, cells of the different stages can be present simultaneously in the developing pancreas and the linear representation of these developmental events shown here is an over-simplification of the actual developmental process (e.g., Sarkar et al. 2008).<p>The first stage of this process involves the predifferentiated epithelial cells of the two pancreatic anlagen that arise from the definitive endoderm at approximately somite stages 11-15 and undergo budding from somite stages 20-22. This period corresponds to gestational days 8.75-9.5 in the mouse, and 26 in the human.<p>Pancreatic buds subsequently coalesce to form a single primitive gland, while concomitantly a ductal tree lined by highly proliferative epithelial cells is formed. A subset of such epithelial cells is thought to differentiate into either endocrine or acinar exocrine cells. A third cellular stage is defined by the endocrine-committed progenitors that selectively express the basic helix-loop-helix transcription factor NEUROG3. NEUROG3 is known to activate a complex transcriptional network that is essential for the specification of endocrine cells. Many transcription factors that are activated by NEUROG3 are also involved in islet-subtype cellular specification and in subsequent stages of differentiation of endocrine cells. This transient cellular stage thus leads to the generation of all known pancreatic endocrine cells, including insulin-producing beta-cells, and glucagon-producing alpha cells, the final stage of this schematic developmental process.<p>The diagram below summarizes interactions that take place between transcription factors and transcription factor target genes during these cellular stages, and shows cases where there is both functional evidence that a transcription factor is required for the target gene to be expressed, and biochemical evidence that this interaction is direct. We also describe instances where a signaling pathway is known to regulate a transcription factor gene in this process, even if the intervening signaling pathway is not fully understood. Regulation of gene expression in early pancreatic precursor cells Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 GENE ONTOLOGYGO:0031018 Pubmed12591178 Pubmed15298336 Reactome Database ID Release 43210747 Reactome, http://www.reactome.org ReactomeREACT_13778 Reviewed: Jensen, J, 2008-05-12 21:46:53 The properties of transcriptional networks early in the differentiation of human pancreatic cells are inferred from the properties of well-studied networks in mouse models. In mice, the first visible sign of pancreatic development is the appearance of pancreatic buds at about embryonic day 9. The cells in these buds are already committed to differentiate into specialized cells of the exocrine and endocrine pancreas. Expression of transcription factors including Hnf1b, Hnf6, and Pdx1, as well as responsiveness to Fgf10 (fibroblast growth factor 10), up-regulates the expression of factors including Ptf1, Onecut3, Lrh1, and Nkx6.1 (Servitja and Ferrer 2004; Chakrabarti and Mirmira 2003). Association of XRCC4:DNA ligase IV complex with viral DNA ends Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Reactome Database ID Release 43175177 Reactome, http://www.reactome.org ReactomeREACT_9042 Reviewed: Bushman, FD, 2006-10-30 22:19:13 XRCC4 and DNA ligase 4 are recruited to the complex containing viral DNA. CDO in myogenesis Authored: Garapati, P V, 2008-08-11 10:36:48 CDO/Cdon (cell-adhesion-molecule-related/downregulated by oncogenes) is a type I transmembrane multifunctional co-receptor consisting of five immunoglobulin and three fibronectin type III (FNIII) repeats in the extracellular domain, and an intracellular domain with no identifiable motifs. It has been implicated in enhancing muscle differentiation in promyogenic cells. CDO exert its promyogenic effects as a component of multiprotein complexes that include the closely related factor Boc, the Ig superfamily receptor neogenin and its ligand netrin-3, and the adhesion molecules N- and M-cadherin. CDO modulates the Cdc42 and p38 mitogen-activated protein kinase (MAPK) pathways via a direct association with two scaffold-type proteins, JLP and Bnip-2, to regulate activities of myogenic bHLH factors and myogenic differentiation. CDO activates myogenic bHLH factors via enhanced heterodimer formation, most likely by inducing hyper-phosphorylation of E proteins. <br>Myogenic basic helix-loop-helix (bHLH) proteins are master regulatory proteins that activate the transcription of many muscle-specific genes during myogenesis. These myogenic bHLH proteins also referred to as MyoD family includes four members, MyoD, myogenin, myf5 and MRF4. These myogenic factors dimerize with E-proteins such as E12/E47, ITF-2 and HEB to form heterodimeric complexes that bind to a conserved DNA sequence known as the E box, which is present in the promoters and enhancers of most muscle-specific genes. Myocyte enhancer binding factor 2 (MEF2), which is a member of the MADS box family, also plays an important role in muscle differentiation. MEF2 activates transcription by binding to the consensus sequence, called the MEF2-binding site, which is also found in the control regions of numerous muscle-specific genes. MEF2 and myogenic bHLH proteins synergistically activate expression of muscle-specific genes via protein-protein interactions between DNA-binding domains of these heterologous classes of transcription factors. Members of the MyoD and MEF2 family of transcription factors associate combinatorially to control myoblast specification, differentiation and proliferation. Edited: Garapati, P V, 2008-08-11 10:36:48 GENE ONTOLOGYGO:0051149 Pubmed15923648 Reactome Database ID Release 43375170 Reactome, http://www.reactome.org ReactomeREACT_21402 Reviewed: Krauss, RS, 2010-02-09 2-LTR formation due to circularization of viral DNA Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed16291214 Reactome Database ID Release 43175258 Reactome, http://www.reactome.org ReactomeREACT_9073 Reviewed: Bushman, FD, 2006-10-30 22:19:13 Viral DNA that does not become integrated can undergo another fate, which is to have the two viral DNA ends joined together to form a 2-LTR circle. This reaction requires Ku, XRCC4 and ligase 4. has a Stoichiometric coefficient of 2 Regulation of gene expression in beta cells Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 GENE ONTOLOGYGO:0031018 Pubmed12591178 Pubmed15298336 Reactome Database ID Release 43210745 Reactome, http://www.reactome.org ReactomeREACT_13819 Reviewed: Jensen, J, 2008-05-12 21:46:53 Two transcription factors, PDX1 and HNF1A, play key roles in maintaining the gene expression pattern characteristic of mature beta cells in the endocrine pancreas. Targets of these regulatory molecules include genes encoding insulin, the GLUT2 glucose transporter, the liver- (and pancreas) specific form of pyruvate kinase and other transcription factors including HNF4A, HNF4G, and FOXA3. PDX1 expression in turn is controlled by the activities of MAFA, FOXA2, and PAX6, and negatively regulated via AKT (Chakrabarti and Mirmira 2003; Servitja and Ferrer 2004). Suicidal integration leading to inverted circle formation Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Following the integrase-mediated strand transfer reaction of autointegration, the integration complex must be disassembled and the gapped intermediate repaired, just as in normal integration. Pubmed1834863 Pubmed8883604 Reactome Database ID Release 43164845 Reactome, http://www.reactome.org ReactomeREACT_9006 Reviewed: Bushman, FD, 2006-10-30 22:19:13 has a Stoichiometric coefficient of 2 AKT-mediated inactivation of FOXO1A Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 Pubmed12228231 Reactome Database ID Release 43211163 Reactome, http://www.reactome.org ReactomeREACT_13655 Reviewed: Jensen, J, 2008-05-12 21:46:53 The unphosphorylated form of FOXO1A shuttles between the nucleus and cytoplasm, maintaining a substantial concentration of this protein in the nucleoplasm, where it functions as a transcription factor. Phosphorylation of the protein, catalyzed by activated AKT, causes its exclusion from the nucleus (Zhang et al. 2002). Suicidal integration leading to smaller circles of viral DNA Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Following the integrase-mediated strand transfer reaction of autointegration, the integration complex must be disassembled and the gapped intermediate repaired, just as in normal integration. Pubmed1834863 Pubmed8883604 Reactome Database ID Release 43175250 Reactome, http://www.reactome.org ReactomeREACT_9025 Reviewed: Bushman, FD, 2006-10-30 22:19:13 has a Stoichiometric coefficient of 2 Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 GENE ONTOLOGYGO:0031018 Pubmed12591178 Pubmed15298336 Reactome Database ID Release 43210744 Reactome, http://www.reactome.org ReactomeREACT_13673 Reviewed: Jensen, J, 2008-05-12 21:46:53 The properties of transcriptional networks in late stage (branching morphogenesis) pancreatic bud precursor cells are inferred from the properties of well-studied networks in mouse models. In mice, committed but undifferentiated epithelial cells are organized into branching ductal structures. At a molecular level, expression of Pdx1, Nkx2.2, and Nkx6.1 is reduced while Hnf6 expression remains high. Hnf6 mediates the continued expression of Onecut3 and Hnf1 beta and epithelial cell proliferation. As expression of Ngn3 (corresponds to human NEUROG3) rises, endocrine differentiation of the epithelial cells begins (Servitja and Ferrer 2004; Chakrabarti and Mirmira 2003). HIV-1 Promoter Opening: First Transition After assembly of the complete RNA polymerase II-preinitiation complex, the next step is separation of the two DNA strands. This isomerization step is known as the closed-to-open complex transition and occurs prior to the initiation of mRNA synthesis. In the RNA polymerase II system this step requires the hydrolysis of ATP or dATP into Pi and ADP or dADP (in contrast to the other RNA polymerase systems) and is catalyzed by the XPB subunit of TFIIH. The region of the promoter, which becomes single-stranded , spans from –10 to +2 relative to the transcription start site.<p>Negative supercoiling in the promoter region probably induces transient opening events and can alleviate requirement of TFIIE, TFIIH and ATP-hydrolysis for open complex formation. ATP is also used in this step by the cdk7-subunit of TFIIH to phosphorylate the heptad repeats of the C-terminal domain of the largest subunit of RNA polymerase II (RPB1) on serine-2 Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167097 Reactome, http://www.reactome.org ReactomeREACT_6134 Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells Authored: Ferrer, J, Tello-Ruiz, MK, 2008--0-5- Edited: D'Eustachio, P, 2008-05-12 21:43:33 GENE ONTOLOGYGO:0031018 Pubmed12591178 Pubmed15298336 Reactome Database ID Release 43210746 Reactome, http://www.reactome.org ReactomeREACT_13650 Reviewed: Jensen, J, 2008-05-12 21:46:53 Studies in mouse model systems indicate that the transcription factor neurogenin 3 plays a central role in the induction of endocrine differentiation in the developing pancreas (Servitja and Ferrer 2004; Chakrabarti and Mirmira 2003). In both mice and humans critical events in this induction process include the neurogenin 3 (NEUROG3)-dependent transcription of PAX4, NEUROD1, NKX2-2, and INSM1. Transcriptional Regulation of White Adipocyte Differentiation Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes. During this process the preadipocytes cease to proliferate, begin to accumulate lipid droplets and develop morphologic and biochemical characteristics of mature adipocytes such as hormone responsive lipogenenic and lipolytic programs. The most intensively studied model system for adipogenesis is differentiation of the mouse 3T3-L1 preadipocyte cell line by an induction cocktail of containing mitogens (insulin/IGF1), glucocorticoid (dexamethasone), an inducer of cAMP (IBMX), and fetal serum (Cao et al. 1991, reviewed in Farmer 2006). More recently additional cellular models have become available to study adipogenesis that involve almost all stages of development (reviewed in Rosen and MacDougald 2006). In vivo knockout mice lacking putative adipogenic factors have also been extensively studied. Human pathways are traditionally inferred from those discovered in mouse but are now beginning to be validated in cellular models derived from human adipose progenitors (Fischer-Posovszky et al. 2008, Wdziekonski et al. 2011).<br>Adipogenesis is controlled by a cascade of transcription factors (Yeh et al. 1995, reviewed in Farmer 2006, Gesta et al. 2007). One of the first observable events during adipocyte differentiation is a transient increase in expression of the CEBPB (CCAAT/Enhancer Binding Protein Beta, C/EBPB) and CEBPD (C/EBPD) transcription factors (Cao et al. 1991, reviewed in Lane et al. 1999). This occurs prior to the accumulation of lipid droplets. However, it is the subsequent inductions of CEBPA and PPARG that are critical for morphological, biochemical and functional adipocytes.<br>Ectopic expression of CEBPB alone is capable of inducing substantial adipocyte differentiation in fibroblasts while CEBPD has a minimal effect. CEBPB is upregulated in response to intracellular cAMP (possibly via pCREB) and serum mitogens (possibly via Krox20). CEBPD is upregulated in response to glucocorticoids. The exact mechanisms that upregulate the CEBPs are not fully known.<br>CEBPB and CEBPD act directly on the Peroxisome Proliferator-activated Receptor Gamma (PPARG) gene by binding its promoter and activating transcription. CEBPB and CEBPD also directly activate the EBF1 gene (and possibly other EBFs) and KLF5 (Jimenez et al. 2007, Oishi 2005). The EBF1 and KLF5 proteins, in turn bind, and activate the PPARG promoter. Other hormones, such as insulin, affect PPARG expression and other transcription factors, such as ADD1/SREBP1c, bind the PPARG promoter. This is an area of ongoing research.<br>During adipogenesis the PPARG gene is transcribed to yield 2 variants. The adipogenic variant 2 mRNA encodes 30 additional amino acids at the N-terminus compared to the widely expressed variant 1 mRNA.<br>PPARG encodes a type II nuclear hormone receptor (remains in the nucleus in the absence of ligand) that forms a heterodimer with the Retinoid X Receptor Alpha (RXRA). The heterodimer was initially identified as a complex regulating the aP2/FABP4 gene and named ARF6 (Tontonoz et al. 1994).<br>The PPARG:RXRA heterodimer binds a recognition sequence that consists of two hexanucleotide motifs (DR1 motifs) separated by 1 nucleotide. Binding occurs even in the absence of ligands, such as fatty acids, that activate PPARG. In the absence of activating ligands, the PPARG:RXRA complex recruits repressors of transcription such as SMRT/NCoR2, NCoR1, and HDAC3 (Tontonoz and Spiegelman 2008).<br>Each molecule of PPARG can bind 2 molecules of activating ligands. Although, the identity of the endogenous ligands of PPARG is unknown, exogenous activators include fatty acids and the thiazolidinedione class of antidiabetic drugs (reviewed in Berger et al. 2005, Heikkinen et al. 2007, Lemberger et al. 1996). The most potent activators of PPARG in vitro are oxidized derivatives of unsaturated fatty acids.. Upon binding activating ligands PPARG causes a rearrangement of adjacent factors: Corepressors such as SMRT/NCoR2 are lost and coactivators such as TIF2, PRIP, CBP, and p300 are recruited (Tontonoz and Spiegelman). PPARG also binds directly to the TRAP220 subunit of the TRAP/Mediator complex that recruits RNA polymerase II. Thus binding of activating ligand by PPARG causes transcription of PPARG target genes.<br>Targets of PPARG include genes involved in differentiation (PGAR/HFARP, Perilipin, aP2/FABP4, CEBPA), fatty acid transport (LPL, FAT/CD36), carbohydrate metabolism (PEPCK-C, AQP7, GK, GLUT4), and energy homeostasis (LEPTIN and ADIPONECTIN) (Perera et al. 2006).<br>Within 10 days of differentiation CEBPB and CEBPD are no longer located at the PPARG promoter. Instead CEBPA is present. EBF1 and PPARG bind the CEBPA promoter and activate transcription of CEBPA, one of the key transcription factors in adipogenesis. A current hypothesis posits a self-reinforcing loop that maintains PPARG expression and the differentiated state: PPARG activates CEBPA and CEBPA activates PPARG. Additionally EBF1 (and possibly other EBFs) activates CEBPA, CEBPA activates EBF1, and EBF1 activates PPARG. Authored: May, B, 2009-05-15 01:13:47 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 Pubmed10603305 Pubmed15860371 Pubmed16054042 Pubmed16380219 Pubmed17011499 Pubmed17060461 Pubmed17139329 Pubmed17475546 Pubmed17956727 Pubmed1840554 Pubmed18518822 Pubmed20054179 Pubmed21082419 Pubmed7531665 Pubmed7838715 Pubmed8970730 Reactome Database ID Release 43381340 Reactome, http://www.reactome.org ReactomeREACT_27161 Reviewed: D'Eustachio, P, 2009-05-26 22:09:50 Reviewed: Sethi, JK, 2011-02-09 Signaling by NODAL Authored: May, B, 2011-01-23 Edited: May, B, 2011-01-23 Pubmed17287255 Pubmed20066122 Reactome Database ID Release 431181150 Reactome, http://www.reactome.org ReactomeREACT_111057 Reviewed: Peng, C, 2011-08-24 Signaling by NODAL is essential for patterning of the axes of the embryo and formation of mesoderm and endoderm (reviewed in Schier 2009, Shen 2007). The NODAL proprotein is secreted and cleaved extracellularly to yield mature NODAL. Mature NODAL homodimerizes and can also form heterodimers with LEFTY1, LEFTY2, or CERBERUS, which negatively regulate NODAL signaling. NODAL also forms heterodimers with GDF1, which increases NODAL activity. NODAL dimers bind the NODAL receptor comprising a type I Activin receptor (ACVR1B or ACVR1C), a type II Activin receptor (ACVR2A or ACVR2B), and an EGF-CFC coreceptor (CRIPTO or CRYPTIC). After binding NODAL, the type II activin receptor phosphorylates the type I activin receptor which then phosphorylates SMAD2 and SMAD3 (R-SMADs). Phosphorylated SMAD2 and SMAD3 form hetero-oligomeric complexes with SMAD4 (CO-SMAD) and transit from the cytosol to the nucleus. Within the nucleus the SMAD complexes interact with transcription factors such as FOXH1 to activate transcription of target genes. Regulation of Signaling by NODAL Authored: May, B, 2011-07-11 Edited: May, B, 2011-07-11 Mature NODAL can form heterodimers with LEFTY1, LEFTY2, or CERBERUS. The heterodimers do not activate the NODAL receptor. LEFTY1 and LEFTY2 also bind CRIPTO and CRYPTIC coreceptors and prevent them from interacting with other components of the NODAL receptor. By these mechanisms LEFTY1, LEFTY2, and CERBERUS negatively regulate NODAL signaling (reviewed in Shen 2007, Schier 2009). Pubmed17287255 Pubmed20066122 Reactome Database ID Release 431433617 Reactome, http://www.reactome.org ReactomeREACT_111059 Reviewed: May, B, 2011-08-18 NTP binds active site of RNA Polymerase II in HIV-1 open pre-initiation complex At the beginning of this reaction, 1 molecule of 'HIV-1 open pre-initiation complex', and 2 molecules of 'NTP' are present. At the end of this reaction, 1 molecule of 'HIV-1 initiation complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167118 Reactome, http://www.reactome.org ReactomeREACT_6349 has a Stoichiometric coefficient of 2 Fall Back to Closed Pre-initiation Complex At the beginning of this reaction, 1 molecule of 'HIV-1 open pre-initiation complex' is present. At the end of this reaction, 1 molecule of 'HIV-1 closed pre-initiation complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-10-15 23:27:00 Reactome Database ID Release 43167484 Reactome, http://www.reactome.org ReactomeREACT_6211 Newly formed phosphodiester bond stabilized and PPi released At the beginning of this reaction, 1 molecule of 'HIV-1 initiation complex with phosphodiester-PPi intermediate' is present. At the end of this reaction, 1 molecule of 'HIV-1 transcription complex', and 1 molecule of 'pyrophosphate' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167134 Reactome, http://www.reactome.org ReactomeREACT_6333 Nucleophillic attack by 3'-hydroxyl oxygen of nascent HIV-1 transcript on the Alpha phosphate of NTP At the beginning of this reaction, 1 molecule of 'HIV-1 initiation complex' is present. At the end of this reaction, 1 molecule of 'HIV-1 initiation complex with phosphodiester-PPi intermediate' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167130 Reactome, http://www.reactome.org ReactomeREACT_6285 Abortive HIV-1 initiation after formation of the first phosphodiester bond At the beginning of this reaction, 1 molecule of 'HIV-1 transcription complex' is present. At the end of this reaction, 1 molecule of 'TFIIA', 1 molecule of 'TFIIH', 1 molecule of 'TFIIE', 1 molecule of 'TFIID', 1 molecule of 'TFIIB', 1 molecule of 'RNA Polymerase II (unphosphorylated):TFIIF complex', and 1 molecule of 'HIV-1 template DNA with first transcript dinucleotide, opened to +8 position' are present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-10-15 23:27:00 Reactome Database ID Release 43167477 Reactome, http://www.reactome.org ReactomeREACT_6226 Membrane Trafficking GENE ONTOLOGYGO:0016044 Pubmed11031247 Reactome Database ID Release 43199991 Reactome, http://www.reactome.org ReactomeREACT_11123 The secretory membrane system allows a cell to regulate delivery of newly synthesized proteins, carbohydrates, and lipids to the cell surface, a necessity for growth and homeostasis. The system is made up of distinct organelles, including the endoplasmic reticulum (ER), Golgi complex, plasma membrane, and tubulovesicular transport intermediates. These organelles mediate intracellular membrane transport between themselves and the cell surface. Membrane traffic within this system flows along highly organized directional routes. Secretory cargo is synthesized and assembled in the ER and then transported to the Golgi complex for further processing and maturation. Upon arrival at the trans Golgi network (TGN), the cargo is sorted and packaged into post-Golgi carriers that move through the cytoplasm to fuse with the cell surface. This directional membrane flow is balanced by retrieval pathways that bring membrane and selected proteins back to the compartment of origin. Golgi to ER Retrograde Transport Authored: Gillespie, ME, 2007-07-23 15:44:13 GENE ONTOLOGYGO:0006890 Pubmed11031247 Reactome Database ID Release 43199983 Reactome, http://www.reactome.org ReactomeREACT_11208 Reviewed: Rush, MG, 2008-01-11 00:00:00 The anterograde membrane flow from the ER to the Golgi is compensated for by a retrograde pathway. This pathway's functions include the recycling of membrane and proteins to the ER. COPI Mediated Transport Authored: Gillespie, ME, 2007-07-23 15:44:13 GENE ONTOLOGYGO:0048205 Pubmed16956762 Reactome Database ID Release 43199997 Reactome, http://www.reactome.org ReactomeREACT_11096 Reviewed: Rush, MG, 2008-01-11 00:00:00 Secretory transport depends on membrane-bounded carriers to move protein and lipid between intracellular compartments. The COPI coat has a central role in this process, creating a sorting domain on the membrane into which cargo proteins, destined to return to the endoplasmic reticulum (ER), concentrate. The membrane domain deforms into a coated bud, pinches off the membrane as a coated carrier, and then uncoats. Successful operation of the COPI coat system is necessary for selective retrieval of protein and lipid components back to the ER. trans-Golgi Network Vesicle Budding After passing through the Golgi complex, secretory cargo is packaged into post-Golgi transport intermediates (post-Golgi), which translocate plus-end directed along microtubules to the plasma membrane. Authored: Gillespie, ME, 2008-05-21 20:31:41 Edited: Gillespie, ME, 2008-05-21 20:31:41 GENE ONTOLOGYGO:0006892 Pubmed11252894 Reactome Database ID Release 43199992 Reactome, http://www.reactome.org ReactomeREACT_11235 Reviewed: Rush, MG, 2008-01-11 00:00:00 Clathrin derived vesicle budding Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2009-08-14 Reactome Database ID Release 43421837 Reactome, http://www.reactome.org ReactomeREACT_19187 Reviewed: Rush, MG, 2008-01-11 00:00:00 Reviewed: Simpson, JC, 2009-08-27 There at least two classes of clathrin coated vesicles in cells, one predominantly Golgi-associated, involved in budding from the trans-Golgi network and the other at the plasma membrane. Here the clathrin-coated vesicles emerging from the Golgi apparatus are triggered by the heterotetrameric adaptor protein complex, AP-1 at the trans-Golgi network membrane. The cargo can be transmembrane, membrane associated or golgi luminal proteins. Each step in the vesicle sculpting pathway, gathers cargo and clathrin triskeletons, until a complete vesicular sphere is formed. With the scission of the membrane the vesicle is released and eventually losses its clathrin coat. Removal of plus-strand flap and gap closure complete synthesis of linear duplex viral DNA Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 GENE ONTOLOGYGO:0006278 Pubmed15183342 Pubmed7745750 Pubmed9786870 Reactome Database ID Release 43182876 Reactome, http://www.reactome.org ReactomeREACT_9036 Reviewed: Hughes, SH, 2006-10-30 22:00:51 The fate of the discontinuous viral DNA duplex synthesized in the cytosol of an infected cell by HIV-1 reverse transcriptase is not entirely clear. Studies of some viral systems suggest that this discontinuous structure is required for passage of the viral duplex DNA into the nucleus while there are evidence contrary to this observation. Studies in vitro indicate that human nuclear flap endonuclease and DNA ligase can remove the flap and seal the plus-strand discontinuity in HIV-1 DNA (Miller et al. 1995; Rausch and Le Grice 2004; Rumbaugh et al. 1998), although role of flap is not yet clear. Golgi Associated Vesicle Biogenesis Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2009-08-14 Proteins that have been synthesized, processed and sorted eventually reach the final steps of the secretory pathway. This pathway is responsible not only for proteins that are secreted from the cell but also enzymes and other resident proteins in the lumen of the ER, Golgi, and lysosomes as well as integral proteins transported in the vesicle membranes. Reactome Database ID Release 43432722 Reactome, http://www.reactome.org ReactomeREACT_19400 Reviewed: Simpson, JC, 2009-08-27 Formation of Pre-Integration Complex (PIC) Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Concomitant with the completion of reverse transcription, the pre-integration complex is formed by shedding of some viral proteins from the viral core, and binding of cellular proteins, thereby yielding complexes capable of integration. The terminal cleavage reaction takes place in the cytoplasm, where two nucleotides are removed from each viral DNA 3' end. This serves to remove heterogeneous extra bases from the viral DNA ends occasionally added by reverse transcription, thereby yielding a homogeneous substrate for downstream steps, and also serves to stablilize the PIC. The DNA in PICs is considerably compacted relative to its length when fully extended, probably due to binding of proteins in addition to the viral integrase. These proteins are not fully clarified, due to the difficulty of biochemical analysis of small amounts of material, but candidates include the viral NC and MA proteins, and the cellular HMGA, BAF, and PSIP1/LEDGF/p75 proteins. Purified integrase is capable of carrying out the terminal cleavage and initial strand transfer reactions. Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed15308744 Pubmed16175173 Pubmed16291214 Pubmed3032450 Pubmed9038339 Pubmed9188609 Pubmed9465049 Pubmed9860958 Reactome Database ID Release 43173115 Reactome, http://www.reactome.org ReactomeREACT_9010 Reviewed: Bushman, FD, 2006-10-30 22:19:13 Lysosome Vesicle Biogenesis Authored: Gillespie, ME, 2009-08-27 Edited: Gillespie, ME, 2009-08-12 Proteins that have been synthesized, processed and sorted eventually reach the final steps of the secretory pathway. This pathway is responsible not only for proteins that are secreted from the cell but also enzymes and other resident proteins in the lumen of the ER, Golgi, and lysosomes as well as integral proteins transported in the vesicle membranes. Here the proteins in this secretory pathway are ultimately found in lysososmes. Reactome Database ID Release 43432720 Reactome, http://www.reactome.org ReactomeREACT_19287 Reviewed: Simpson, JC, 2009-08-27 Second strand transfer by annealing complementary PBS sequences Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed10723025 Reactome Database ID Release 43164512 Reactome, http://www.reactome.org ReactomeREACT_9056 Reviewed: Hughes, SH, 2006-10-30 22:00:51 With the removal of all viral genomic RNA and tRNA, the PBS sequence at the 3' end of the plus-strand strong-stop DNA (+sssDNA) is free to pair with the complementary PBS sequence at the 3' end of the minus-strand DNA, to generate a circular structure (Telesnitsky and Goff 1997). Gap junction trafficking and regulation Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-26 11:57:49 Gap junctions are clusters of intercellular channels connecting adjacent cells and permitting the direct exchange of ions and small molecules between cells. These channels are composed of two hemichannels, or connexons, one located on each of the two neighboring cells. Each connexon is composed of 6 trans-membrane protein subunits of the connexin (Cx) family. A gap of approximately 3 nm remains between the adjacent cell membranes, but two connexons interact and dock head-to-head in the extra-cellular space forming a tightly sealed, double-membrane intercellular channel (see Segretain and Falk, 2004). The activity of these intercellular channels is regulated, particularly by intramolecular modifications such as phosphorylation which appears to regulate connexin turnover, gap junction assembly and the opening and closure (gating) of gap junction channels. Pubmed11146276 Pubmed11737941 Pubmed15033576 Pubmed15033577 Pubmed15094346 Pubmed17108328 Pubmed8522583 Pubmed8665925 Pubmed9861669 Reactome Database ID Release 43157858 Reactome, http://www.reactome.org ReactomeREACT_9480 Synthesis of full-length duplex viral DNA with a discontinuous plus strand After the second jump, elongation of the plus and minus strands continues. The elongation process requires strand displacement, which RT can mediate, at least in vitro (Huber et al. 1989; Hottiger et al. 1994; Rausch and Le Grice 2004). The final product is a blunt-ended linear duplex DNA with a discontinuity in its "plus" strand at the site of the cPPT sequence motif. Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 2.7.7.7 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed10723025 Pubmed15183342 Pubmed2466838 Pubmed7507115 Reactome Database ID Release 43164505 Reactome, http://www.reactome.org ReactomeREACT_8992 Reviewed: Hughes, SH, 2006-10-30 22:00:51 Gap junction trafficking Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Matthews, L, 2007-01-07 14:51:44 Gap junctions are intercellular communication channels formed from Cx (connexin) protein subunits (see Segretain and Falk 2004 and Evans et al. 2006 for comprehensive reviews). Connexins are transported to the plasma membrane after oligomerizing into hexameric assemblies called hemichannels (CxHcs) or connexons. Connexons dock head-to-head in the extracellular space with opposing hexameric channels located in the plasma membranes of neighbouring cells. The double membrane channel or gap junction generated directly links the cytoplasms of interacting cells and facilitates the integration and co-ordination of cellular signalling, metabolism, secretion and contraction. In addition to their role in intercellular communication, connexon hemichannels coordinate the release of ATP, glutamate, NAD+ and prostaglandin E2 from the cells. CxHcs open in response to various types of external changes, including mechanical, shear, ionic and ischaemic stress.<p>The trafficking of gap junctions involves (1) synthesis of connexin polypeptides at endoplasmic reticulum membranes, (2) oligomerization into homomeric- and heteromeric gap junction connexons (hemi-channels), (3) passage through the Golgi stacks, (4) intracellular storage within Trans Golgi membranes, (5) trafficking along microtubules, (6) insertion of connexons into the plasma membrane, (7) lateral diffusion of connexons in the plasma membrane, (8) aggregation of individual gap junction channels into plaques, (9) stabilization of peripheral microtubule plus-ends by binding to Cx43-based gap junctions, (10) internalization of the channel plaque leading to cytoplasmic annular junctions, and (11) complete degradation via lysosomal and proteasomal pathways (see Segretain and Falk 2004). Aspects of gap assembly are described here. Additional details of assembly, regulation and degradation will be covered in the next release. Pubmed15033576 Pubmed16761954 Pubmed8522583 Reactome Database ID Release 43190828 Reactome, http://www.reactome.org ReactomeREACT_9411 Gap junction assembly Authored: Gilleron, J, Segretain, D, Falk, MM, 2007-01-03 12:23:09 Edited: Joshi-Tope, G, 2004-04-22 09:35:00 Edited: Matthews, L, 2007-01-26 11:41:42 GENE ONTOLOGYGO:0016264 Pubmed15033576 Pubmed8665925 Reactome Database ID Release 43190861 Reactome, http://www.reactome.org ReactomeREACT_9509 The assembly of gap junctions involves (1) synthesis of connexin polypeptides at endoplasmic reticulum membranes, (2) oligomerization into homomeric- and heteromeric gap junction connexons (hemi-channels), (3) passage through the Golgi stacks, (4) intracellular storage within Trans Golgi membranes, (5) trafficking along microtubules, (6) insertion of connexons into the plasma membrane, (7) lateral diffusion of connexons in the plasma membrane, (8) aggregation of individual gap junction channels into plaques, and (9) stabilization of peripheral microtubule plus-ends by binding to Cx43-based gap junctions (see Segretain and Falk, 2004.) Gap repair completes provirus integration Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed16175173 Pubmed16291214 Pubmed1760846 Reactome Database ID Release 43164506 Reactome, http://www.reactome.org ReactomeREACT_9001 Reviewed: Bushman, FD, 2006-10-30 22:19:13 The mechanism by which the integration reaction is completed has not been fully clarified. Unfolding of the integration intermediate resulting from the IN-catalyzed transesterification produces a branched DNA molecule. Denaturation of the host DNA between the points of joining produces DNA gaps at each host-virus DNA junction. How these gaps are repaired is unclear. Well studied host cell gap repair enzymes can carry out this repair step on model virus-host DNA junctions in vitro, providing candidate enzymes. However, efforts to show importance in vivo are complicated by the fact that the functions are either redundant or lethal when mutated.<p>Because the strand transfer complex formed at the completion of integration is quite stable, there may be a requirement for a disassembly step to remove integrase and potentially other proteins to allow access of the gap repair machinery.<br>In order to complete the last stages of integration, the viral proteins must be removed, and the gaps at the host virus DNA junctions repaired. The sequence in which the dissembly of PIC occus is not yet understood. has a Stoichiometric coefficient of 2 Import of PIC to the Host Nucleus Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 GENE ONTOLOGYGO:0051169 HIV can infect non-dividing cells, implying that the PIC must be able to traverse the nuclear membrane. In contrast, simple retroviruses such as MLV can only infect cells once they have passed through mitosis, potentially because they require breakdown of the nucleus to access chromosomal integration sites. The mechanism of nuclear localization is controversial. A variety of proposals have been made for nuclear localization sequences (NLS) in the PIC, but most of those have now been shown to be dispensible for HIV integration. According to a new idea from Yamashita and Emerman, it may be that the PIC is imported into the nucleus by a default pathway, while MLV PICs are retained in the cytoplasm because capsid protein is stably associated with PICs.<br> Pubmed15140964 Pubmed16291214 Pubmed16292356 Pubmed16364740 Pubmed8491198 Reactome Database ID Release 43162590 Reactome, http://www.reactome.org ReactomeREACT_9004 Reviewed: Bushman, FD, 2006-10-30 22:19:13 Terminal (3' end) cleavage of viral DNA Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Prior to integration, two nucleotides are removed from each 3' end of the linear viral DNA, thereby exposing recessed 3' hydroxyls. This reaction may serve to remove heterogenous extra bases from the viral DNA end, and to stabilize the IN-DNA complex. The chemistry of cleavage is a simple hydrolysis by single-step transesterification. Pubmed16482214 Pubmed1760846 Pubmed2539592 Pubmed8041787 Pubmed8883604 Pubmed9188609 Reactome Database ID Release 43164522 Reactome, http://www.reactome.org ReactomeREACT_9069 Reviewed: Bushman, FD, 2006-10-30 22:19:13 Integrase binds viral DNA ends Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed1533044 Pubmed16482214 Pubmed2171144 Pubmed8883604 Reactome Database ID Release 43164514 Reactome, http://www.reactome.org ReactomeREACT_9074 Reviewed: Bushman, FD, 2006-10-30 22:19:13 Upon completion of reverse transcription, the viral integrase protein (IN) becomes bound to the ends of the viral DNA. This is inferred by the fact that this is the site of integrase action, and several biochemical studies have documented integrase interactions with the terminal DNA. Association of Ku heterodimer with viral DNA ends Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed11406603 Reactome Database ID Release 43175174 Reactome, http://www.reactome.org ReactomeREACT_9022 Reviewed: Bushman, FD, 2006-10-30 22:19:13 The Ku protein can be found bound to active PICs in the cytoplasm. However, ligation of the viral DNA ends to form 2-LTR circles takes place in the nucleus. 1-LTR circle formation Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed16175173 Pubmed16291214 Reactome Database ID Release 43175117 Reactome, http://www.reactome.org ReactomeREACT_9045 Reviewed: Bushman, FD, 2006-10-30 22:19:13 The 1-LTR circle can be formed by either of two pathways. The first involves a failure to complete reverse transcription; the second, annotated here, follows the completion of reverse transcription and is mediated by cellular enzymes. In this pathway, the action of host cell homologous recombination enzymes on the long terminal repeat (LTR) termini of the viral DNA results in formation of a single LTR. This reaction probably takes place after partial or complete disassembly of the PIC to expose the viral DNA. Repair of this intermediate as in the late stages of homologous recombination pathways results in formation of the 1-LTR circle. Mutations in the Mre11/Rad50/NBS pathway influence the formation of 1-LTR circles. has a Stoichiometric coefficient of 2 PathwayStep3486 RNase H-mediated digestion of tRNA, 3'PPT and cPPT RNA primers Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 3.1.26.4 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed10723025 Pubmed1370087 Pubmed15183342 RNase H catalyzes the precise cleavage of the bonds linking the primer tRNA attached to the minus-strand DNA, the 3' PPT RNA primer to the plus-strand strong-stop DNA, and the cPPT primer to the stretch of plus-strand DNA whose synthesis it primed. In each case, precise cleavage near the RNA-DNA junction occurs (Pullen et al. 1992). HIV-1 RT is the only reverse transcriptase that cleaves the tRNA:DNA junction so as to leave a ribo A residue from the tRNA at the 5' end of the minus strand.<p>While a single RT heterodimer could in principle catalyze DNA synthesis and primer RNA:DNA bond cleavage, evidence from several in vitro systems suggests that separate RT heterodimers are likely to catalyze these two reactions (Rausch and Le Grice 2004). Reactome Database ID Release 43173769 Reactome, http://www.reactome.org ReactomeREACT_8999 Reviewed: Hughes, SH, 2006-10-30 22:00:51 PathwayStep3487 IL3RB:JAK2 Reactome DB_ID: 879945 Reactome Database ID Release 43879945 Reactome, http://www.reactome.org ReactomeREACT_24165 has a Stoichiometric coefficient of 1 PathwayStep3484 RNase H-mediated degradation of the template strand Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 3.1.26.4 Pubmed10956669 Pubmed11035788 Pubmed15542682 Pubmed1560526 Pubmed1693920 Pubmed7681062 Reactome Database ID Release 43182795 Reactome, http://www.reactome.org ReactomeREACT_9066 Reviewed: Hughes, SH, 2006-10-30 22:00:51 The rate of RNase H cleavage is substantially lower than the rate of DNA synthesis (Kati et al. 1992), so the product of the combined DNA synthesis and RNA degradation events catalyzed by the RT heterodimer mediating minus-strand DNA synthesis is a DNA segment still duplexed with extended viral genomic RNA fragments. Other RT heterodimers bind the remaining RNA:DNA heteroduplexes and their RNase H domains further degrade the viral genomic RNA (Wisniewski et al. 2000a, b). Two PPT (polypurine tract) sequence motifs in the template, one immediately 5' to the U3 sequence and one located within the pol gene in the center of the viral genome, are spared from degradation (Charneau et al. 1992; Julias et al. 2004; Pullen et al. 1993). PathwayStep3485 3' PPT-primed initiation of plus-strand DNA synthesis Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 2.7.7.7 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 HIV-1 genomic RNA contains a centrally located PPT (cPPT) within the pol gene that, like 3'PPT, is spared by RNase H during minus-strand DNA synthesis and persists to prime plus-strand DNA synthesis. This ribonucleotide primes the synthesis of a plus-strand DNA extending through the U3 and R regions of the HIV sequence and terminating in the PBS region (the tRNA primer-binding site). This DNA segment is known as plus-strand strong-stop DNA (+sssDNA) (Telesnitsky and Goff 1997; Pullen et al. 1993; Huber and Richardson 1990). cPPT priming is important for efficient viral replication (Alizon et al. 1992; Rausch and Le Grice 2004). Several features of cPPT priming in vivo remain to be clarified. Pubmed10723025 Pubmed15183342 Pubmed1560526 Pubmed1693920 Pubmed7681062 Reactome Database ID Release 43164513 Reactome, http://www.reactome.org ReactomeREACT_9075 Reviewed: Hughes, SH, 2006-10-30 22:00:51 PathwayStep3482 Minus strand DNA synthesis resumes Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 2.7.7.49 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed10723025 Reactome Database ID Release 43164520 Reactome, http://www.reactome.org ReactomeREACT_9049 Reviewed: Hughes, SH, 2006-10-30 22:00:51 Synthesis of minus-strand DNA proceeds toward the 5' end of the PBS motif of the template HIV genomic RNA. IL3:IL3RA:IL3RB:JAK2 Interleukin-3 receptor Reactome DB_ID: 450064 Reactome Database ID Release 43450064 Reactome, http://www.reactome.org ReactomeREACT_24229 has a Stoichiometric coefficient of 1 PathwayStep3483 RNase H-mediated cleavage of the template strand As the reverse transcriptase activity of the HIV-1 RT heterodimer catalyzes the extension of the minus-strand DNA, the RNaseH activity catalyzes the degradation of the complementary viral genomic RNA sequences. Telesnitsky and Goff (1993) observed that two defective forms of reverse transcriptase can complement to restore retroviral infectivity. The RNase H active site is positioned within the HIV-1 RT heterodimer so as to attack the RNA strand of the RNA:DNA duplex at a point 18 bases behind the site of reverse transcription (Furfine and Reardon 1991; Ghosh et al. 1995; Gopalakrishnan et al. 1992; Wohrl and Moelling 1990). The rate of RNase H cleavage is substantially lower than the rate of DNA synthesis and the level of its activity in vivo is unclear, however (Kati et al. 1992). The product of these combined DNA synthesis and RNA degradation events is a DNA strand still duplexed with extended viral genomic RNA fragments. Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 3.1.26.4 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed10723025 Pubmed1279694 Pubmed1281479 Pubmed15542682 Pubmed1702425 Pubmed1703002 Pubmed7535765 Pubmed7681062 Pubmed7693456 Reactome Database ID Release 43164528 Reactome, http://www.reactome.org ReactomeREACT_9040 Reviewed: Hughes, SH, 2006-10-30 22:00:51 High affinity binding complexes of interleukin receptors using the Common beta chain Converted from EntitySet in Reactome Reactome DB_ID: 913364 Reactome Database ID Release 43913364 Reactome, http://www.reactome.org ReactomeREACT_24474 PathwayStep3480 RNase H-mediated degradation of the RNA strand of the -sssDNA:RNA duplex Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 3.1.26.4 Pubmed10956669 Pubmed11035788 Pubmed1281479 Reactome Database ID Release 43182859 Reactome, http://www.reactome.org ReactomeREACT_9014 Reviewed: Hughes, SH, 2006-10-30 22:00:51 The rate of RNase H cleavage is substantially lower than the rate of DNA synthesis (Kati et al. 1992), so the product of the combined DNA synthesis and RNA degradation events catalyzed by the RT heterodimer mediating minus-strand strong stop DNA (-sssDNA) synthesis is a DNA segment still duplexed with extended viral genomic RNA fragments. In vitro, other RT heterodimers bind the remaining RNA:DNA heteroduplexes and their RNase H domains further degrade the viral genomic RNA (Wisniewski et al. 2000a, b). GM-CSF:GM-CSF receptor alpha subunit:Common beta chain:JAK2 Reactome DB_ID: 913389 Reactome Database ID Release 43913389 Reactome, http://www.reactome.org ReactomeREACT_24858 has a Stoichiometric coefficient of 1 PathwayStep3481 First strand transfer mediated by Repeated (R) sequence Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed10954531 Pubmed10982320 Pubmed7510065 Pubmed7535765 Reactome Database ID Release 43164503 Reactome, http://www.reactome.org ReactomeREACT_9033 Reviewed: Hughes, SH, 2006-10-30 22:00:51 The minus strand strong stop DNA (-sssDNA) is transferred to the 3' end of the HIV-1 genomic RNA, where the 3' end of the -sssDNA anneals to the viral genomic R sequence motif (Ghosh et al. 1995; Klaver and Berkhout 1994; Ohi and Clever 2000; Telesnitsky and Goff 1997). Viral NC (nucleocapsid) protein may play a role in this transfer (Driscoll and Hughes 2000). IL5 homodimer:IL5RA:Common beta chain:JAK2 Reactome DB_ID: 913423 Reactome Database ID Release 43913423 Reactome, http://www.reactome.org ReactomeREACT_24214 has a Stoichiometric coefficient of 1 High affinity GM-CSF receptor complex dimer, inactive JAK2 Reactome DB_ID: 913413 Reactome Database ID Release 43913413 Reactome, http://www.reactome.org ReactomeREACT_24082 has a Stoichiometric coefficient of 2 High affinity IL-5 receptor complex dimer, inactive JAK2 Reactome DB_ID: 913415 Reactome Database ID Release 43913415 Reactome, http://www.reactome.org ReactomeREACT_24530 has a Stoichiometric coefficient of 2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2 Converted from EntitySet in Reactome Reactome DB_ID: 913399 Reactome Database ID Release 43913399 Reactome, http://www.reactome.org ReactomeREACT_24738 High affinity IL-3 receptor complex dimer, inactive JAK2 Reactome DB_ID: 893545 Reactome Database ID Release 43893545 Reactome, http://www.reactome.org ReactomeREACT_24296 has a Stoichiometric coefficient of 2 High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2 Converted from EntitySet in Reactome Reactome DB_ID: 913405 Reactome Database ID Release 43913405 Reactome, http://www.reactome.org ReactomeREACT_24626 RNase H-mediated cleavage of the RNA strand of the -sssDNA:RNA duplex As the reverse transcriptase activity of the HIV-1 RT heterodimer catalyzes the synthesis of minus-strand strong stop DNA (-sssDNA), the RNaseH activity of the same RT heterodimer catalyzes the degradation of the complementary viral genomic RNA sequences. Degradation of this RNA is required for the efficient transfer of the -sssDNA to the 5' end of the viral genomic RNA. The RNase H active site is positioned within the HIV-1 RT heterodimer so as to attack the RNA strand of the RNA:DNA duplex at a point 18 bases behind the site of reverse transcription (Furfine and Reardon 1991; Ghosh et al. 1995; Gopalakrishnan et al. 1992; Wohrl and Moelling 1990). The rate of RNase H cleavage is substantially lower than the rate of DNA synthesis, however (Kati et al. 1992), and may further depend on RT stalling and structural features of the viral genomic RNA template. The product of these combined DNA synthesis and RNA degradation events is a DNA strand still duplexed with extended viral genomic RNA fragments. Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 3.1.26.4 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed10723025 Pubmed1279694 Pubmed1281479 Pubmed1702425 Pubmed1703002 Pubmed7535765 Reactome Database ID Release 43164519 Reactome, http://www.reactome.org ReactomeREACT_9046 Reviewed: Hughes, SH, 2006-10-30 22:00:51 Synthesis of minus strand strong stop DNA (-sssDNA) Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 EC Number: 2.7.7.49 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Pubmed10723025 Pubmed10982320 Pubmed7707372 Reactome Database ID Release 43164504 Reactome, http://www.reactome.org ReactomeREACT_9039 Reviewed: Hughes, SH, 2006-10-30 22:00:51 To catalyze DNA synthesis, retroviral reverse transcriptase requires a primer strand to extend and a template strand to copy. For HIV-1, the primer is the 3'-end of a partially unwound lysine(3) tRNA annealed to the PBS (primer binding site) 179 bases from the 5' end of the retroviral genomic RNA (Isel et al. 1995). Reverse transcription of the viral genomic RNA proceeds from the bound tRNA primer to the 5' end of the viral RNA, yielding a minus-strand strong-stop DNA (-sssDNA) complementary to the R and U5 elements of the HIV-1 viral genome, as shown in the figure below (Telesnitsky and Goff 1997; Jonckheere et al. 2000). The reaction takes place in the host cell cytosol, and is catalyzed by the reverse transcriptase activity of the HIV-1 RT heterodimer.<p>NucleoCapsid (NC) protein prevents self-priming by generating or stabilizing a thermodynamically favored RNA-DNA heteroduplex instead of the kinetically favored TAR hairpin seen in reverse transcription experiments in vitro (Driscoll and Hughes 2000). Annealing of 3'-end of unwound transfer RNA primer with genomic RNA Authored: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 Edited: Gopinathrao, G, D'Eustachio, P, 2006-05-18 20:10:22 GENE ONTOLOGYGO:0006278 Pubmed7511167 Pubmed7540137 Pubmed8497049 Pubmed9343157 Reactome Database ID Release 43164527 Reactome, http://www.reactome.org ReactomeREACT_9015 Retroviruses use cellular tRNAs as primers for reverse transcription of the viral genomic RNA (Mak and Kleiman 1997). The primer tRNA is selectively packaged during assembly of retrovirus particles. In the case of HIV-1, lysine tRNAs are preferentially incorporated during retroviral packaging, and lysine tRNA 3, the specific isoacceptor form that serves as a primer for reverse transcription, anneals to the PBS (primer binding site) within the U5 region of the viral genomic RNA. This association appears to be mediated by the viral reverse transcriptase (RT) protein, possibly its "thumb" and "connection" domains (Jiang et al. 1993; Mak et al. 1994; Mishima and Steitz 1995). Reviewed: Hughes, SH, 2006-10-30 22:00:51 PathwayStep3479 PathwayStep3478 PathwayStep3477 PathwayStep3495 Fusion of viral membrane with host cell membrane Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 GENE ONTOLOGYGO:0019064 Pubmed10504731 Pubmed11038187 Pubmed12773651 Pubmed2846352 Pubmed3629244 Pubmed8076606 Pubmed9094670 Pubmed9166405 Reactome Database ID Release 43164524 Reactome, http://www.reactome.org ReactomeREACT_8032 Reviewed: Reeves, J, 2006-06-12 15:22:40 With the transition of gp41 into the six-helix bundle, fusion of the viral and target cell membranes begins to take place. The specifics of fusion are not completely clear, but it is understood that fusion proceeds after insertion of the gp41 fusion peptide, which results in curvature of viral and target cell membranes. This results in a state of hemi-fusion, where only the outer lipid bilayers of each membrane are fused, whereas membrane leaflets that are distal with respect to the intermembrane gap remain separate at this stage. Hemi-fusion allows the exchange of lipids between the contacting leaflets, whereas the exchange of aqueous content between the virus and the cell remains blocked. The next step in fusion is the merger of the distal leaflets, leading to the formation of a nascent fusion pore, which leads to mixing of viral and cellular contents. Studies of fusion of Influenza virus suggested that multiple hairpin structures may form a narrow fusion pore which subsequently expands to a larger opening. In the case of HIV, this larger opening allows for passage of the Matrix-surrounded viral core out of the virus and into the host cell cytoplasm. PathwayStep3496 Disintegration of matrix layer After fusion of the viral membrane with the target cell membrane, the viral core, which is surrounded by a layer of Matrix (p17) proteins, is exposed to the cytoplasm. Disintegration of the Matrix layer allows for the conical-shaped viral core to be fully released, and allow for viral capsid dissociation and eventually reverse transcription. Dissociation of the Matrix layer is not well characterized, but is believed to occur due to disruption of protein-protein interactions as a result of the conditions of the cytoplasm (including pH), which differ from that of the internal viral structure. Authored: Iordanskiy, S, Bukrinsky, M, 2006-04-03 16:17:37 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Pubmed10881997 Pubmed11264352 Reactome Database ID Release 43173642 Reactome, http://www.reactome.org ReactomeREACT_9044 Reviewed: Aiken, C, 2006-10-30 22:04:39 PathwayStep3497 Disassembly of viral capsid Authored: Iordanskiy, S, Bukrinsky, M, 2006-04-03 16:17:37 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Pubmed10881997 Pubmed11264352 Pubmed11423440 Pubmed16292356 Reactome Database ID Release 43173111 Reactome, http://www.reactome.org ReactomeREACT_9038 Reviewed: Aiken, C, 2006-10-30 22:04:39 The HIV capsid protein (p24) surrounds the viral genome and associated proteins to make up the viral core. Dissolution of the viral capsid allows for release of the viral RNA and other proteins such as Vpr into the cytoplasm, which will subsequently form the Reverse Transcription Complex. Dissolution of capsid proteins may be caused by interaction with cellular proteins, e.g. TRIM5, or may occur in a similar fashion to that of matrix dissolution; as a reaction to a change in pH. Indeed, studies observing capsid assembly and conformation show that this protein-protein interaction is heavily influenced by even small changes in pH (pH7.0 to 6.8). PathwayStep3498 Formation of RTC (Reverse Transcription Complex) Authored: Iordanskiy, S, Bukrinsky, M, 2006-04-03 16:17:37 Edited: Gopinathrao, G, 2006-02-17 18:35:46 GENE ONTOLOGYGO:0019061 Pubmed10881997 Pubmed11264352 Pubmed16409631 Pubmed7687060 Reactome Database ID Release 43173771 Reactome, http://www.reactome.org ReactomeREACT_8994 Reverse transcription complex is a transitory structure where reverse transcription takes place. Initially, it is likely identical to the RNA-protein complex found inside the virion core. Upon maturation, it may shed some HIV proteins (such as MA or Vpr) and incorporate cellular proteins (such as INI1 or PML). Reviewed: Aiken, C, 2006-10-30 22:04:39 PathwayStep3491 Conformational changes in gp120 exposes gp41 Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Pubmed2541505 Pubmed3629244 Pubmed8500173 Pubmed8612573 Reactome Database ID Release 43164500 Reactome, http://www.reactome.org ReactomeREACT_8003 Reviewed: Reeves, J, 2006-06-12 15:22:40 The HIV protein known as gp41 is a transmembrane protein which is considered the major mediator of fusion of extracellular virions to the target cells in the host. HIV gp120 and gp41 proteins form non-covalently linked oligomers on the surface of virions. The gp41 subunit of the oligomer is anchored in the viral membrane and contains a non-polar fusion peptide at its N-terminus. Upon CD4 and receptor binding, gp120 undergoes a second conformation change. The conformation change exposes gp41 which continues to mediate fusion of the viral envelope with the host plasma membrane. Electron microscopy and circular dichroism measurements of the gp41 protein suggest a rod-like conformation with a high alpha-helical content. Although some studies suggest that gp41must dissociate from gp120 in order to cause fusion between HIV envelope and the target cell plasma membrane, evidence on this point is not conclusive. STAT5 dimers Converted from EntitySet in Reactome Reactome DB_ID: 507919 Reactome Database ID Release 43507919 Reactome, http://www.reactome.org ReactomeREACT_24109 PathwayStep3492 Fusogenic activation of gp41 Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Fusion of HIV with target cell plasma membranes is mediated largely by the gp41 glycoprotein. This glycoprotein contains a stretch of strongly hydrophobic amino acids flanked by a series of polar amino acids at its N terminus. Subsequent to the second conformation change in gp120, the N-terminal fusion peptide of gp41 adopts a position which brings it into close proximity with the target cell plasma membrane. As gp41 is found in trimers within the viral membrane, the resulting structure of this conformational change is often referred to as a “prong”, in which three N-terminal peptides extend towards the target cell plasma membrane. The process of fusion begins at this time, with the N-terminus of gp41 inserting itself into the membrane of the target cell. Pubmed2191297 Pubmed7745678 Pubmed8474172 Reactome Database ID Release 43164515 Reactome, http://www.reactome.org ReactomeREACT_8023 Reviewed: Reeves, J, 2006-06-12 15:22:40 gp41 N terminal fusion peptide released from viral membrane STAT5 heterodimer Reactome DB_ID: 507941 Reactome Database ID Release 43507941 Reactome, http://www.reactome.org ReactomeREACT_24819 has a Stoichiometric coefficient of 1 PathwayStep3493 Insertion of gp41 fusion peptide into the target membrane Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Insertion of the N-terminal fusion peptide of the HIV gp41 protein is the first step in the fusion of viral and target cell membranes. Substitutions of polar amino acids at residues 2, 9, 15 and 26 of the N terminus of this peptide completely eliminated its ability to cause fusion, implicating these residues in gp41’s role in insertion and fusion. Studies have also shown that mutations in a stretch of residues from 36-64(568 to 596 of ENV protein) caused gp41 to become partially or completely defective in mediating membrane fusion, suggesting that conformation of the peptide is important for proper insertion and fusion to occur. Pubmed1438243 Pubmed2191297 Pubmed8373393 Pubmed8474172 Reactome Database ID Release 43164521 Reactome, http://www.reactome.org ReactomeREACT_8020 Reviewed: Reeves, J, 2006-06-12 15:22:40 STAT5B homodimer Reactome DB_ID: 507922 Reactome Database ID Release 43507922 Reactome, http://www.reactome.org ReactomeREACT_24191 has a Stoichiometric coefficient of 2 PathwayStep3494 N and C terminal heptad repeat helices of gp41 form six-helix bundle Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Pubmed11591141 Pubmed11926830 Pubmed15504864 Pubmed1629954 Pubmed2364015 Pubmed2788443 Pubmed7538176 Pubmed8612573 Pubmed9108481 Pubmed9546217 Reactome Database ID Release 43164508 Reactome, http://www.reactome.org ReactomeREACT_8010 Reviewed: Reeves, J, 2006-06-12 15:22:40 The gp41 glycoprotein contains N- and C-terminal heptad repeats, which form a stable six-helical bundle. This six-helix bundle represents a fusion-active gp41 core, and its conformation is critical for membrane fusion. Among the interactions necessary for the six helix bundle conformation is the formation of a salt bridge between the Asp632 residue in the C-terminal heptad repeat and the Lys574 terminal in the N-terminal coiled-coil. Disruption of this interaction has been found to lead to destabilization of the six helix bundle formation, with a subsequent severe reduction in viral fusion activity. Also, the N-terminal heptad repeat alone was found to be important in viral fusion, as removal or truncation of this repeat reduced the fusion activity of the peptide even when the adjacent, full length N-terminal fusion peptide was in place. The bundle itself is formed during the fusion process, prior to pore formation but after insertion of the gp41 fusion peptide into the target cell membrane. Upon insertion of the fusion peptide, the three N-terminal helices of gp41 adjacent to the target cell membrane and three C-terminal helices adjacent to the viral membrane undergo a conformational change which brings them into close proximity with one another, creating a six-helix bundle and leading to eventual fusion.<br> STAT5 dimers Converted from EntitySet in Reactome Reactome DB_ID: 508012 Reactome Database ID Release 43508012 Reactome, http://www.reactome.org ReactomeREACT_24289 STAT5 heterodimer Reactome DB_ID: 508014 Reactome Database ID Release 43508014 Reactome, http://www.reactome.org ReactomeREACT_24610 has a Stoichiometric coefficient of 1 STAT5B homodimer Reactome DB_ID: 507998 Reactome Database ID Release 43507998 Reactome, http://www.reactome.org ReactomeREACT_24798 has a Stoichiometric coefficient of 2 IL2:IL2R trimer:p-JAK1:JAK3:SYK Reactome DB_ID: 508449 Reactome Database ID Release 43508449 Reactome, http://www.reactome.org ReactomeREACT_27852 has a Stoichiometric coefficient of 1 PathwayStep3490 IL2:IL2R trimer:p-JAK1:JAK3:p-SYK Reactome DB_ID: 508438 Reactome Database ID Release 43508438 Reactome, http://www.reactome.org ReactomeREACT_27723 has a Stoichiometric coefficient of 1 JAK3:PYK2 Reactome DB_ID: 508512 Reactome Database ID Release 43508512 Reactome, http://www.reactome.org ReactomeREACT_27865 has a Stoichiometric coefficient of 1 JAK3:p-PYK2 Reactome DB_ID: 508510 Reactome Database ID Release 43508510 Reactome, http://www.reactome.org ReactomeREACT_27631 has a Stoichiometric coefficient of 1 CD4:gp120 binds to chemokine co-receptor CCR5/CXCR4 Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 Once the viral gp120 protein has bound to cellular CD4, its bridging sheet region becomes exposed/formed as a result of conformation changes in the V1 and V2 loops as well as a conformational change in the gp120 core domain. Once this region is exposed, it is free to bind the HIV co-receptors CCR5 or CXCR4 (also known as chemokine receptors). Different viruses use different co-receptors (CCR5 or CXCR4) for entry, and many studies investigated the structural determinants of interaction between gp120 and the co-receptor. <br>Studies of CCR5 binding by gp120 revealed that active regions in the second extracellular loop (ECL2), the N-terminal extracellular domain (specifically the NYYTSE motif) and at the junction between the fifth transmembrane domain and third cytoplasmic loop of the receptor are important for viral attachment and subsequent fusion. The N-terminal region likely interacts with the core of gp120 (bridging sheet and adjacent regions) and the base of V3, while ECL2 may be important for interacting with the tip of V3. The transmembrane 5 / cytoplasmic loop 3 junction of CCR5 has been shown to influence the conformation of the receptor which allows for subsequent binding of gp120 (Wang et al.,1999). Deletion of the V3 loop in gp120 abolished Env interaction with co-receptor without affecting the binding of soluble gp120 to CD4, underscoring the importance of this loop in chemokine receptor, but not CD4, binding. Furthermore, the V3 loop is a major determinant of coreceptor specificity, with amino acid at positions 11 and 25 being partly predictive of CCR5 or CXCR4 use. Single amino acid changes in V3 can alter coreceptor use, however sequences outside of V3 can also contribute to coreceptor specificity. <br> Pubmed10497202 Pubmed16284180 Pubmed8649511 Pubmed8658171 Pubmed8674119 Pubmed8906796 Pubmed9311827 Pubmed9499113 Pubmed9632396 Pubmed9641677 Pubmed9721247 Reactome Database ID Release 43164507 Reactome, http://www.reactome.org ReactomeREACT_7962 Reviewed: Reeves, J, 2006-06-12 15:22:40 Conformational change in gp120 of Env oligomer Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 Edited: Gopinathrao, G, 2006-02-17 18:35:46 HIV-1 infection of target cells depends on the sequential interaction of the gp120 glycoprotein with the cellular CD4 receptor as well as members of the chemokine receptor family, such as CCR5. Upon interaction with the cellular CD4 receptor, gp120 undergoes a conformation change which allows interaction with these chemokine receptors to occur. Studies indicate that upon binding to CD4, this conformational change results in a repositioning of V1 and V2 loops of gp120, and exposes or forms the "bridging sheet domain" epitopes, which are then available for co-receptor (chemokine receptor) binding along with other domains of gp120. These epitopes are recognized by 17b, a member of a class of antibodies that recognize CD4-induced (CD4i) epitopes (Kwong et al., 1998, Rizzuto et al., 1998, Zhang et al., 1999). Pubmed10413516 Pubmed2441877 Pubmed3629244 Pubmed7687306 Pubmed9573233 Pubmed9632396 Pubmed9641677 Reactome Database ID Release 43164510 Reactome, http://www.reactome.org ReactomeREACT_7953 Reviewed: Reeves, J, 2006-06-12 15:22:40 PathwayStep3489 PathwayStep3488 PathwayStep3460 Gamma-secretase complex cleaves mNEXT2 Authored: Orlic-Milacic, M, 2012-04-12 By expressing mouse Notch2deltaE recombinant protein, wich mimics the cleavage product of Adam10, NEXT2, in human embryonic kidney cell line HEK293, Saxena et al. determined that activity of the gamma-secretase complex was required for the release of Notch2 intracellular domain, NICD2, and ensuing NICD2-mediated transcriptional response. EC Number: 3.4.23 Edited: D'Eustachio, P, 2012-05-25 Edited: Matthews, L, 2012-05-24 Pubmed11518718 Reactome Database ID Release 432197556 Reactome, http://www.reactome.org ReactomeREACT_121339 Reviewed: Haw, R, 2012-05-25 PathwayStep3461 N-myristoylation of GAG polyprotein by NMT2 Authored: D'Eustachio, P, 2006-07-25 20:21:32 EC Number: 2.3.1.97 Pubmed11527981 Pubmed1548743 Pubmed15613341 Pubmed9506952 Reactome Database ID Release 43184392 Reactome, http://www.reactome.org ReactomeREACT_115774 The amino terminal glycine residue of HIV-1 Gag polyprotein is myristoylated (Henderson et al. 1992). Myristoylation of newly synthesized Gag occurs in the cytosol of the infected host cell, with myristoyl-CoA as the myristate donor and the host cell NMT2 enzyme as the catalyst. Human cells express two isoforms of N-myristoyl transferase (NMT) (Giang and Cravatt 1998). The argumant that the second isoform catalyzes this reaction is indirect, based on the the observations that a stable enzyme:substrate complex forms transiently during the reaction (Farazi et al. 2001), and that Gag polyprotein can be found complexed with NMT2 (but not NMT1) in HIV-1-infected human cells (Hill and Skowronski 2005). Plcg1 phosphorylation by P-ERBB2:P-EGFR Authored: Orlic-Milacic, M, 2011-11-04 EC Number: 2.7.10 Edited: Matthews, L, 2011-11-07 Mouse phospholipase C gamma 1 is phosphorylated by human recombinant ERBB2 exogenously expressed in mouse fibroblasts. Pubmed1672440 Reactome Database ID Release 431251929 Reactome, http://www.reactome.org ReactomeREACT_115779 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 has a Stoichiometric coefficient of 4 Carboxymycobactin binds iron from lactoferrin Authored: Stephan, R, 2011-01-10 Edited: Jassal, B, 2011-02-28 Pubmed22232695 Reactome Database ID Release 431222641 Reactome, http://www.reactome.org ReactomeREACT_121409 Reviewed: Warner, D, 2012-04-30 Since bacterial siderophores bind iron with much greater affinity, they can scavenge iron ions from loaded lactoferrin (Madigan et al. 2012). has a Stoichiometric coefficient of 2 PathwayStep3464 Jaks associate with IL6RB (gp130) Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Mouse JAK1 JAK2 and TYK2 were tyrosine phosphorylated in response to CNTF, mouse JAK1 and JAK2 shown to associate with human gp130 in COS cells Pubmed8272873 Reactome Database ID Release 431067645 Reactome, http://www.reactome.org ReactomeREACT_27148 Reviewed: Rose-John, S, 2011-02-11 PathwayStep3465 ERBB4:Tab2:Ncor1 complex translocates to the nucleus Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Exogenously expressed human ERBB4s80 mediates translocation of cytosolic Tab2:Ncor1 complex to the nucleus. Pubmed17018285 Reactome Database ID Release 431253330 Reactome, http://www.reactome.org ReactomeREACT_116058 Reviewed: Harris, RC, 2011-11-11 Reviewed: Zeng, F, 2011-11-11 PathwayStep3462 Monoubiquitination of N-myristoyl GAG polyprotein Authored: D'Eustachio, P, 2006-07-25 20:21:32 Cytosolic N-myristoyl Gag polyprotein is conjugated with a single molecule of ubiquitin. Conjugation is typically to one of two lysine residues in the p6 domain of Gag but can be to lysine residues in the MA, CA, NC, and SP2 domains of the protein. The specific host cell E2 and E3 proteins that mediate Gag ubiquitination have not been identified. The same studies that first identified the p6 ubiquitination sites in Gag also called the biological significance of Gag ubiquitination into question by demonstrating that Gag proteins in which the p6 ubiquitination sites had been removed by mutagenesis could still assemble efficiently into infectious viral particles (Ott et al. 1998, 2000). More recent work, however, has identified additional ubiquitination sites throughout the carboxyterminal region of the Gag polyprotein, and when all of these sites are removed by mutagenesis, both viral assembly involving the mutant Gag polyprotein and infectivity of the resulting viral particles are sharply reduced (Gottwein et al. 2006). Pubmed11112487 Pubmed16775314 Pubmed9525617 Reactome Database ID Release 43184323 Reactome, http://www.reactome.org ReactomeREACT_115708 PathwayStep3463 Monoubiquitinated N-myristoyl GAG polyprotein associates with an ESCRT-I complex at a late endosomal membrane Authored: D'Eustachio, P, 2006-07-25 20:21:32 Monoubiquitinated N-myristoyl Gag polyprotein associates with the ESCRT-1 complex at an endosomal membrane (Eastman et al. 2005; Martin-Serrano et al. 2003; Stuchell et al. 2004). Pubmed12663786 Pubmed15218037 Pubmed15509564 Reactome Database ID Release 43184269 Reactome, http://www.reactome.org ReactomeREACT_115855 Binding of gp120 of ENV oligomer to the host CD4 Authored: Morrow, MP, Bukrinsky, M, 2006-03-07 21:26:47 CD4, located on the host cell membrane, is the main cellular receptor for the HIV protein gp120, which aids in mediating viral entry into target cells. The initial step in this cascade of events is the binding of viral gp120 protein to its host receptor, CD4. The key binding sites in CD4 for interaction with gp120 are located in the amino-terminal part of the CD4 molecule, distal to the transmembrane domain. The gp120 protein forms an oligomer (trimer) on the viral membrane with each gp120 protein containing variable domains (known as loops) and conservative domains. The V3 loop is also often obscured by gp120 glycosylation. Crystallization studies of CD4 suggest that the molecule has two immunoglobulin like domains important for the CD4/gp120 interaction, with one of the domains (D1) playing a more prominent role. Further studies suggest the Phe 43 and Arg 59 residues of CD4 play a major role in complex formation. Crystallization of gp120 shows that the polypeptide chain is folded into two major domains (an "inner" and "outer" domain with respect to the N and C termini), with the distal end of the “outer” domain containing the V3 loop. Studies of CD4 complexed with gp120 show that CD4 is bound to gp120 in a depression which is formed at the interface between the inner and outer domains. The complex itself is held together through van der Waals forces and hydrogen bonding. Edited: Gopinathrao, G, 2006-02-17 18:35:46 Pubmed2247146 Pubmed2428879 Pubmed3001934 Pubmed6083454 Pubmed6096719 Pubmed9641677 Reactome Database ID Release 43164509 Reactome, http://www.reactome.org ReactomeREACT_8009 Reviewed: Reeves, J, 2006-06-12 15:22:40 PathwayStep3458 PathwayStep3457 PathwayStep3456 PathwayStep3455 Rnf111 ubiquitinates Smad7 Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 Pubmed14657019 Reactome Database ID Release 432186775 Reactome, http://www.reactome.org ReactomeREACT_121045 Recombinant mouse Rnf111 (Arkadia) exogneously expressed in human HEK293 cells polyubiquitinates recombinant mouse Smad7 (Koinuma et al. 2003). Reviewed: Huang, Tao, 2012-05-14 PathwayStep3459 ERKs are inactivated by dual-specific phosphatases (DUSPs) Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 3.1.3.48 Edited: Jassal, B, 2010-11-17 Over 10 dual specificity phosphatases (DUSPs) active an MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity. Pubmed17322878 Reactome Database ID Release 43203797 Reactome, http://www.reactome.org ReactomeREACT_12439 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep3470 MSK1 activates CREB Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB). Pubmed9687510 Reactome Database ID Release 43199935 Reactome, http://www.reactome.org ReactomeREACT_12631 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep3471 MSK1 activates ATF1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it. EC Number: 2.7.11 Reactome Database ID Release 43199910 Reactome, http://www.reactome.org ReactomeREACT_12437 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep3472 RSK1/2/3 phosphorylates CREB at Serine 133 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 CREB is phosphorylated at Serine 133 by RSK1/2/3. EC Number: 2.7.11 Pubmed9770464 Reactome Database ID Release 43199895 Reactome, http://www.reactome.org ReactomeREACT_12622 Reviewed: Greene, LA, 2007-11-08 15:39:37 PathwayStep3473 MAPKAPK2 phosphorylates CREB at Serine 133 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Reactome Database ID Release 43199917 Reactome, http://www.reactome.org ReactomeREACT_12586 Reviewed: Greene, LA, 2007-11-08 15:39:37 p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3. PathwayStep3474 Phosphorylated MAPKs phosphorylate ATF-2 At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'ATF-2' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'ATF-2-P' are present.<br><br> This reaction is mediated by the 'protein kinase activity' of 'MAPK1-P'.<br> Authored: Luo, F, 2005-11-10 11:23:18 EC Number: 2.7.11 Edited: Shamovsky, V, 2009-12-16 Pubmed10878576 Pubmed12110590 Pubmed19647037 Reactome Database ID Release 43168053 Reactome, http://www.reactome.org ReactomeREACT_6719 Reviewed: Gay, NJ, 2006-04-24 16:48:17 has a Stoichiometric coefficient of 2 the Raf–MEK–ERK pathway induces phosphorylation of ATF2 Thr71, whereas subsequent ATF2 Thr69 phosphorylation requires the Ral–RalGDS–Src–p38 pathway. Cooperation between ERK and p38 was found to be essential for ATF2 activation by these mitogens; the activity of p38 and JNK/SAPK in growth factor-stimulated fibroblasts is insufficient to phosphorylate ATF2 Thr71 or Thr69 + 71 significantly by themselves, while ERK cannot dual phosphorylate ATF2 Thr69 + 71 efficiently. PathwayStep3475 Activated JNKs phosphorylate c-JUN Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2009-12-16 JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus. Pubmed10871633 Pubmed18793328 Pubmed9561845 Reactome Database ID Release 43168136 Reactome, http://www.reactome.org ReactomeREACT_6716 Reviewed: Gay, NJ, 2006-04-24 16:48:17 has a Stoichiometric coefficient of 2 PathwayStep3476 c-FOS activation by phospho ERK1/2 Authored: Shamovsky, V, 2009-12-16 EC Number: 2.7.11 Edited: Shamovsky, V, 2010-02-27 Pubmed12134156 Pubmed7588633 Reactome Database ID Release 43450325 Reactome, http://www.reactome.org ReactomeREACT_21251 Reviewed: Gillespie, ME, 2010-02-27 The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity. <p>On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.</p><p>Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover. has a Stoichiometric coefficient of 4 Formation of Activated Protein 1 (AP-1) complex. ATF2/c-JUN heterodimer. At the beginning of this reaction, 1 molecule of 'c-Jun-P', and 1 molecule of 'ATF-2-P' are present. At the end of this reaction, 1 molecule of 'AP-1' is present.<br><br> <br> Authored: Luo, F, 2005-11-16 12:05:41 Edited: Shamovsky, V, 2009-12-16 Pubmed9030721 Reactome Database ID Release 43168440 Reactome, http://www.reactome.org ReactomeREACT_6839 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Formation of Activated Protein 1 (AP-1) complex. cFOS/c-JUN heterodimer. Authored: Luo, F, 2005-11-16 12:05:41 Edited: Shamovsky, V, 2009-12-16 Pubmed7816143 Pubmed9030721 Reactome Database ID Release 43450292 Reactome, http://www.reactome.org ReactomeREACT_21404 Reviewed: Gay, NJ, 2006-04-24 16:48:17 The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995). PathwayStep3467 PathwayStep3466 PathwayStep3469 PathwayStep3468 High affinity IL-5 receptor complex dimer, inactive JAK2, p(Y593)-Bc Reactome DB_ID: 914023 Reactome Database ID Release 43914023 Reactome, http://www.reactome.org ReactomeREACT_24407 has a Stoichiometric coefficient of 2 ERKs are inactivated by protein phosphatase 2A Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK.<br>Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown. Pubmed16456541 Reactome Database ID Release 43199959 Reactome, http://www.reactome.org ReactomeREACT_12539 Reviewed: Greene, LA, 2007-11-08 15:39:37 ERK5 activates the transcription factor MEF2 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Reactome Database ID Release 43199929 Reactome, http://www.reactome.org ReactomeREACT_12413 Reviewed: Greene, LA, 2007-11-08 15:39:37 The MEF2 (Myocyte-specific enhancer factor 2) proteins constitute a family of transcription factors: MEF2A, MEF2B, MEF2C, and MEF2D. MEF2A and MEF2C are known substrates of ERK5, and their transactivating activity can be stimulated by ERK5 via direct phosphorylation. MEF2A and MEF2C are expressed in developing and adult brain including cortex and cerebellum. ERK1/2/5 activate RSK1/2/3 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Pubmed16626623 Reactome Database ID Release 43198746 Reactome, http://www.reactome.org ReactomeREACT_12487 Reviewed: Greene, LA, 2007-11-08 15:39:37 The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK.<br>RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398.<br>Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2. <br> has a Stoichiometric coefficient of 6 p38MAPK phosphorylates MSK1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by p38MAPK through phosphorylation at four key residues.<br> Pubmed9687510 Reactome Database ID Release 43198669 Reactome, http://www.reactome.org ReactomeREACT_12546 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 4 IL3:IL3R active complex, inactive JAK2, p(Y593)-Bc Reactome DB_ID: 914088 Reactome Database ID Release 43914088 Reactome, http://www.reactome.org ReactomeREACT_24173 has a Stoichiometric coefficient of 2 ERK1/2 phosphorylates MSK1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues. Pubmed9687510 Reactome Database ID Release 43198756 Reactome, http://www.reactome.org ReactomeREACT_12576 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 4 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593)-Bc Converted from EntitySet in Reactome Reactome DB_ID: 914054 Reactome Database ID Release 43914054 Reactome, http://www.reactome.org ReactomeREACT_24346 ERK1/2 activates ELK1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 EC Number: 2.7.11 Following translocation to the nucleus, ERK1/2 directly phosphorylates key effectors, including the ubiquitous transcription factors ELK1 (Ets like protein 1). At least five residues in the C terminal domain of ELK1 are phosphorylated upon growth factor stimulation. ELK1 can form a ternary complex with the serum response factor (SRF) and consensus sequences, such as serum response elements (SRE), on DNA, thus stimulating transcription of a set of immediate early genes like c fos. Reactome Database ID Release 43198731 Reactome, http://www.reactome.org ReactomeREACT_12406 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 5 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593)-Bc:SHP1, SHP2 Reactome DB_ID: 914049 Reactome Database ID Release 43914049 Reactome, http://www.reactome.org ReactomeREACT_24560 has a Stoichiometric coefficient of 1 Nuclear translocation of phospho-ERK-2 dimer Authored: Charalambous, M, 2004-04-29 09:21:24 Edited: Schmidt, EE, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0000189 Phospho-ERK-2 dimer is translocated from cytosol to nucleoplasm. Reactome Database ID Release 43109868 Reactome, http://www.reactome.org ReactomeREACT_487 Reviewed: Greene, LA, 2007-11-08 15:39:37 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,p(Y593,628)-Bc:SHP1, SHP2 Reactome DB_ID: 914086 Reactome Database ID Release 43914086 Reactome, http://www.reactome.org ReactomeREACT_24887 has a Stoichiometric coefficient of 1 Dimerisation of phospho-ERK-2 Authored: Charalambous, M, 2005-02-04 06:50:22 Edited: Schmidt, EE, 0000-00-00 00:00:00 Reactome Database ID Release 43109866 Reactome, http://www.reactome.org ReactomeREACT_2196 Reviewed: Greene, LA, 2007-11-08 15:39:37 Two phospho-ERK2 molecules dimerise and enter the nucleus, where they may phosphorylate downstream targets. has a Stoichiometric coefficient of 2 GM-CSF:GM-CSF receptor alpha subunit:p(Y593)-Bc:JAK2 Reactome DB_ID: 914077 Reactome Database ID Release 43914077 Reactome, http://www.reactome.org ReactomeREACT_24845 has a Stoichiometric coefficient of 1 Dissociation of phospho-ERK-2:MEK2 Authored: Charalambous, M, 2005-02-04 06:50:22 Edited: Schmidt, EE, 0000-00-00 00:00:00 MEK2 dissociates from phospho-ERK2, allowing phospho-ERK2 to dimerise with another phospho-ERK2. Reactome Database ID Release 43109864 Reactome, http://www.reactome.org ReactomeREACT_1019 Reviewed: Gillespie, ME, 2010-11-24 High affinity GM-CSF receptor complex dimer, inactive JAK2, p(Y593)- Bc Reactome DB_ID: 914025 Reactome Database ID Release 43914025 Reactome, http://www.reactome.org ReactomeREACT_24200 has a Stoichiometric coefficient of 2 MEK2 phosphorylates ERK-2 Authored: Charalambous, M, 2005-02-04 06:50:22 EC Number: 2.7.11 Edited: Schmidt, EE, 0000-00-00 00:00:00 MEK2 phosphorylates the critical Tyrosine and Threonine on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity. Pubmed8388392 Reactome Database ID Release 43109862 Reactome, http://www.reactome.org ReactomeREACT_2247 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 2 p(Y593)-Bc:JAK2 Reactome DB_ID: 914033 Reactome Database ID Release 43914033 Reactome, http://www.reactome.org ReactomeREACT_24767 has a Stoichiometric coefficient of 1 Interleukin-3 receptor IL3RA:IL3:p(Y593)-IL3RB:JAK2 Reactome DB_ID: 914065 Reactome Database ID Release 43914065 Reactome, http://www.reactome.org ReactomeREACT_24237 has a Stoichiometric coefficient of 1 TEC:VAV1 Reactome DB_ID: 912729 Reactome Database ID Release 43912729 Reactome, http://www.reactome.org ReactomeREACT_24039 has a Stoichiometric coefficient of 1 p(Y700,731,774)-CBL:VAV1 Reactome DB_ID: 912755 Reactome Database ID Release 43912755 Reactome, http://www.reactome.org ReactomeREACT_24764 has a Stoichiometric coefficient of 1 B-cell linker protein:p(Y700,731,774)-CBL Reactome DB_ID: 912760 Reactome Database ID Release 43912760 Reactome, http://www.reactome.org ReactomeREACT_24555 has a Stoichiometric coefficient of 1 Dimerisation of phospho-ERK-1 Authored: Charalambous, M, 2005-02-04 06:50:22 Edited: Schmidt, EE, 0000-00-00 00:00:00 Reactome Database ID Release 43109865 Reactome, http://www.reactome.org ReactomeREACT_1289 Reviewed: Greene, LA, 2007-11-08 15:39:37 Two phospho-ERK1 molecules dimerise and enter the nucleus, where they may phosphorylate downstream targets. has a Stoichiometric coefficient of 2 Dissociation of phospho-ERK-1:MEK1 Authored: Charalambous, M, 2005-02-04 06:50:22 Edited: Schmidt, EE, 0000-00-00 00:00:00 MEK1 dissociates from phospho-ERK1, allowing phospho-ERK1 to dimerise with another phospho-ERK1. Reactome Database ID Release 43109863 Reactome, http://www.reactome.org ReactomeREACT_1740 Reviewed: Gillespie, ME, 2010-11-24 MEK2 binds ERK-2 Authored: Charalambous, M, 2005-02-04 06:50:22 Edited: Schmidt, EE, 0000-00-00 00:00:00 In the cytoplasm activated MEK2 (Serine phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T183) and a critical Tyrosine (Y185). Pubmed8388392 Reactome Database ID Release 43109858 Reactome, http://www.reactome.org ReactomeREACT_495 Reviewed: Greene, LA, 2007-11-08 15:39:37 Nuclear translocation of phospho-ERK-1 dimer Authored: Charalambous, M, 2004-04-29 09:21:24 Edited: Schmidt, EE, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0000189 Phospho-ERK-1 dimer is translocated from cytosol to nucleoplasm. Reactome Database ID Release 43109867 Reactome, http://www.reactome.org ReactomeREACT_1866 Reviewed: Greene, LA, 2007-11-08 15:39:37 Inactivation of MEK1 by p34cdc2 At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'MEK1' are present. At the end of this reaction, 1 molecule of 'phospho_MEK1', and 2 molecules of 'ADP' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'protein serine/threonine kinase activity' of 'phospho-Cdc2 (Thr 161)'.<br> EC Number: 2.7.11 Reactome Database ID Release 43112342 Reactome, http://www.reactome.org ReactomeREACT_1836 has a Stoichiometric coefficient of 2 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:SHC1 Reactome DB_ID: 913387 Reactome Database ID Release 43913387 Reactome, http://www.reactome.org ReactomeREACT_24517 has a Stoichiometric coefficient of 1 Nuclear export of human p38 MAPK mediated by its substrate MAPKAPK2 or 3 Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2010-02-27 Pubmed12171911 Pubmed9768359 Reactome Database ID Release 43450257 Reactome, http://www.reactome.org ReactomeREACT_21358 Reviewed: Gillespie, ME, 2010-02-27 p38 MAPK alpha does not have a nuclear export signal (NES) and cannot leave the nucleus by itself, but rather needs to be associated with MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2). The NES of MAPKAPK2 facilitates the transport of both kinases from the nucleus to the cytoplasm but only after MK2 has been phosphorylated by p38alpha.<p>p38 MAPK alpha phosphorylates MK2 at Thr222, Ser272, and Thr334. The phosphorylation of Thr334 but not the kinase activity of MK2 has been demonstrated to be critical for the nuclear export of the p38 alpha - MK2 complex. Phosphorylation of Thr334 is believed to induce a conformational change in the complex exposing NES prior to interaction with the leptomycin B-sensitive nuclear export receptor. High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:SHC1 Reactome DB_ID: 913433 Reactome Database ID Release 43913433 Reactome, http://www.reactome.org ReactomeREACT_24055 has a Stoichiometric coefficient of 1 MEK1 phosphorylates ERK-1 Authored: Charalambous, M, 2005-02-04 06:50:22 EC Number: 2.7.11 Edited: Schmidt, EE, 0000-00-00 00:00:00 MEK1 phosphorylates the critical Tyrosine and Threonine on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity. Pubmed8388392 Reactome Database ID Release 43109860 Reactome, http://www.reactome.org ReactomeREACT_136 Reviewed: Greene, LA, 2007-11-08 15:39:37 has a Stoichiometric coefficient of 2 FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 912647 Reactome Database ID Release 43912647 Reactome, http://www.reactome.org ReactomeREACT_24228 has a Stoichiometric coefficient of 1 MEK1 binds ERK-1 Authored: Charalambous, M, 2005-02-04 06:50:22 Edited: Schmidt, EE, 0000-00-00 00:00:00 In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y). Pubmed8388392 Reactome Database ID Release 43109857 Reactome, http://www.reactome.org ReactomeREACT_1780 Reviewed: Greene, LA, 2007-11-08 15:39:37 FYN-like kinases:CBL:GRB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 912623 Reactome Database ID Release 43912623 Reactome, http://www.reactome.org ReactomeREACT_24661 has a Stoichiometric coefficient of 1 K48 polyubiquitinated p85-containing Class 1A PI3Ks Reactome DB_ID: 912738 Reactome Database ID Release 43912738 Reactome, http://www.reactome.org ReactomeREACT_24063 has a Stoichiometric coefficient of 1 FYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3Ks Reactome DB_ID: 912799 Reactome Database ID Release 43912799 Reactome, http://www.reactome.org ReactomeREACT_24386 has a Stoichiometric coefficient of 1 Active p38 MAPK phosphorylates MAPKAPK2 or 3 Authored: Shamovsky, V, 2009-12-16 EC Number: 2.7.11 Edited: Shamovsky, V, 2010-02-27 Human p38 MAPK alpha forms a complex with MK2 even when the signaling pathway is not activated. This heterodimer is found mainly in the nucleus. The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined. The C-terminal regulatory domain of MK2 binds in the docking groove of p38 MAPK alpha, and the ATP-binding sites of both kinases are at the heterodimer interface.<p>Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334. <p>The phosphorylation of MK2 at Thr-334 attenuates the affinity of the binary complex MK2:p38 alpha by an order of magnitude and leads to a large conformational change of an autoinhibitory domain in MK2. This conformational change unmasks not only the MK2 substrate-binding site but also the MK2 nuclear export signal (NES) thus leading to the MK2:p38 alpha translocation from the nucleus to the cytoplasm. Cytoplasmic, active MK2 then phosphorylates downstream targets such as the heat-shock protein HSP27 and tristetraprolin (TTP).<p>MAPKAPK (MAPK-activated protein) kinase 3 (MK3, also known as 3pK) has been identified as the second p38 MAPK-activated kinase that is stimulated by different stresses (McLaughlin et al. 1996; Sithanandam et al. 1996; reviewed in Gaestel 2006). MK3 shows 75% sequence identity to MK2 and, like MK2, is activated by p38 MAPK alpha and p38 MAPK beta. MK3 phosphorylates peptide substrates with kinetic constants similar to MK2 and phosphorylates the same serine residues in HSP27 at the same relative rates as MK2 (Clifton et al. 1996) indicating an identical phosphorylation-site consensus sequence. Hence, it is assumed that its substrate spectrum is either identical to or at least overlapping with MK2. Pubmed12171911 Pubmed15287722 Pubmed17255097 Pubmed17395714 Pubmed8846784 Reactome Database ID Release 43450222 Reactome, http://www.reactome.org ReactomeREACT_21375 Reviewed: Gillespie, ME, 2010-02-27 has a Stoichiometric coefficient of 3 p(Y700,731,774)-CBL:CRK:RAPGEF1 Reactome DB_ID: 914209 Reactome Database ID Release 43914209 Reactome, http://www.reactome.org ReactomeREACT_24589 has a Stoichiometric coefficient of 1 activated human MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 Authored: Shamovsky, V, 2009-12-16 EC Number: 2.7.112.1 Edited: Shamovsky, V, 2010-02-27 Pubmed7535770 Pubmed8622669 Reactome Database ID Release 43450333 Reactome, http://www.reactome.org ReactomeREACT_21395 Reviewed: Gillespie, ME, 2010-02-27 The MAPK level components of this cascade are p38MAPK-alpha, -beta, -gamma and -sigma. All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops. has a Stoichiometric coefficient of 2 p(Y700,731,774)-CBL:CRK Reactome DB_ID: 912774 Reactome Database ID Release 43912774 Reactome, http://www.reactome.org ReactomeREACT_24612 has a Stoichiometric coefficient of 1 IL3:IL3R active complex, inactive JAK2, phosphorylated Bc:SHC1 Reactome DB_ID: 913358 Reactome Database ID Release 43913358 Reactome, http://www.reactome.org ReactomeREACT_24305 has a Stoichiometric coefficient of 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-Bc:SHC1 Converted from EntitySet in Reactome Reactome DB_ID: 913458 Reactome Database ID Release 43913458 Reactome, http://www.reactome.org ReactomeREACT_24884 IL3:IL3RA:IL3RB:JAK2 Reactome DB_ID: 879968 Reactome Database ID Release 43879968 Reactome, http://www.reactome.org ReactomeREACT_24678 has a Stoichiometric coefficient of 1 Tyrosine kinases that phosphorylate the Common beta chain Converted from EntitySet in Reactome Reactome DB_ID: 904816 Reactome Database ID Release 43904816 Reactome, http://www.reactome.org ReactomeREACT_24291 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)-Bc Converted from EntitySet in Reactome Reactome DB_ID: 913422 Reactome Database ID Release 43913422 Reactome, http://www.reactome.org ReactomeREACT_24147 High affinity IL-5 receptor complex dimer, activated JAK2:p-STAT5 Reactome DB_ID: 913409 Reactome Database ID Release 43913409 Reactome, http://www.reactome.org ReactomeREACT_24637 has a Stoichiometric coefficient of 1 High affinity GM-CSF receptor complex dimer, activated JAK2:p-STAT5 Reactome DB_ID: 913365 Reactome Database ID Release 43913365 Reactome, http://www.reactome.org ReactomeREACT_24527 has a Stoichiometric coefficient of 1 IL3:IL3R active complex, activated JAK2:p-STAT5 Reactome DB_ID: 912305 Reactome Database ID Release 43912305 Reactome, http://www.reactome.org ReactomeREACT_24780 has a Stoichiometric coefficient of 1 High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2:p-STAT5 Converted from EntitySet in Reactome Reactome DB_ID: 913465 Reactome Database ID Release 43913465 Reactome, http://www.reactome.org ReactomeREACT_24628 High affinity IL-5 receptor complex dimer, activated JAK2:STAT5 Reactome DB_ID: 913407 Reactome Database ID Release 43913407 Reactome, http://www.reactome.org ReactomeREACT_24254 has a Stoichiometric coefficient of 1 PathwayStep3499 High affinity binding complex dimers of cytokine receptors using Bc. activated JAK2:STAT5 Converted from EntitySet in Reactome Reactome DB_ID: 913447 Reactome Database ID Release 43913447 Reactome, http://www.reactome.org ReactomeREACT_24047 IL5 homodimer:IL5RA:Common beta chain:p-JAK2 Reactome DB_ID: 913363 Reactome Database ID Release 43913363 Reactome, http://www.reactome.org ReactomeREACT_24833 has a Stoichiometric coefficient of 1 High affinity GM-CSF receptor complex dimer, activated JAK2:STAT5 Reactome DB_ID: 913386 Reactome Database ID Release 43913386 Reactome, http://www.reactome.org ReactomeREACT_24756 has a Stoichiometric coefficient of 1 IL3:IL3R active complex, activated JAK2:STAT5 Reactome DB_ID: 912301 Reactome Database ID Release 43912301 Reactome, http://www.reactome.org ReactomeREACT_24577 has a Stoichiometric coefficient of 1 High affinity GM-CSF receptor complex dimer, activated JAK2 Reactome DB_ID: 913379 Reactome Database ID Release 43913379 Reactome, http://www.reactome.org ReactomeREACT_24838 has a Stoichiometric coefficient of 2 IL3RB:p-Y1007-JAK2 Reactome DB_ID: 893554 Reactome Database ID Release 43893554 Reactome, http://www.reactome.org ReactomeREACT_24343 has a Stoichiometric coefficient of 1 High affinity IL-5 receptor complex dimer, p-JAK2 Reactome DB_ID: 913457 Reactome Database ID Release 43913457 Reactome, http://www.reactome.org ReactomeREACT_24847 has a Stoichiometric coefficient of 2 GM-CSF:GM-CSF receptor alpha subunit:Common beta chain:p-JAK2 Reactome DB_ID: 913443 Reactome Database ID Release 43913443 Reactome, http://www.reactome.org ReactomeREACT_24375 has a Stoichiometric coefficient of 1 Interleukin-3 receptor IL3:IL3RA:IL3RB:p-Y1007-JAK2 Reactome DB_ID: 893527 Reactome Database ID Release 43893527 Reactome, http://www.reactome.org ReactomeREACT_24282 has a Stoichiometric coefficient of 1 IL3:IL3R active complex, p-Y1007-JAK2 Reactome DB_ID: 893534 Reactome Database ID Release 43893534 Reactome, http://www.reactome.org ReactomeREACT_24682 has a Stoichiometric coefficient of 2 PathwayStep3627 PathwayStep3626 PathwayStep3625 PathwayStep3624 PathwayStep3623 PathwayStep3622 PathwayStep3621 PathwayStep3620 PathwayStep3629 PathwayStep3628 Fibroblast growth factor receptor 2c Converted from EntitySet in Reactome Reactome DB_ID: 192596 Reactome Database ID Release 43192596 Reactome, http://www.reactome.org ReactomeREACT_76141 PathwayStep3630 FGFR2b Converted from EntitySet in Reactome Fibroblast growth factor receptor 2b Reactome DB_ID: 192604 Reactome Database ID Release 43192604 Reactome, http://www.reactome.org ReactomeREACT_76154 PathwayStep3614 PathwayStep3613 PathwayStep3616 PathwayStep3615 PathwayStep3610 PathwayStep3612 PathwayStep3611 PathwayStep3618 PathwayStep3617 PathwayStep3619 Des-acyl Ghrelin Converted from EntitySet in Reactome Reactome DB_ID: 422045 Reactome Database ID Release 43422045 Reactome, http://www.reactome.org ReactomeREACT_19664 Acyl Ghrelin Converted from EntitySet in Reactome Reactome DB_ID: 422096 Reactome Database ID Release 43422096 Reactome, http://www.reactome.org ReactomeREACT_20031 PathwayStep3645 PathwayStep3644 PathwayStep3643 PathwayStep3642 PathwayStep3649 PathwayStep3648 PathwayStep3647 PathwayStep3646 Acyl Ghrelin Converted from EntitySet in Reactome Reactome DB_ID: 422059 Reactome Database ID Release 43422059 Reactome, http://www.reactome.org ReactomeREACT_20017 Interaction of NCAM1 with agrin Agrin, a Heparin Sulfate Proteoglycan (HSPG), plays a role in synaptogenesis and axonal growth. It interacts with NCAM1 both via NCAM's heparin binding domain in the IgII domain and through polysialic acid on the IgV domain. Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 Pubmed8601415 Pubmed8807193 Reactome Database ID Release 43375155 Reactome, http://www.reactome.org ReactomeREACT_18305 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Interaction of NCAM1 with contactin-2 Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 NCAM1 binds with high affinity to the neuronal IgSF receptor, contactin-2/TAG-1/axonin-1. Pubmed8663515 Reactome Database ID Release 43375157 Reactome, http://www.reactome.org ReactomeREACT_18282 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- NCAM1 binds to ATP Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 NCAM1 has been demonstrated to possess (Ca++ or Mg++) dependant ATP hydrolyzing activity. ATP can bind to NCAM directly and that NCAM can act as an ecto-ATPase hydrolyzing around 1000 molecules of ATP/minute. Binding of ATP to NCAM1 inhibits cellular aggregation and neurite outgrowth induced by NCAM1-FGFR binding. The NCAM binding site to ATP overlaps with the site of NCAM-FGFR interaction, and ATP is capable of disrupting NCAM-FGFR binding. Pubmed8262246 Pubmed9398268 Reactome Database ID Release 43375160 Reactome, http://www.reactome.org ReactomeREACT_18264 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Interaction of NCAM1:GFRalpha-1 with GDNF Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 NCAM was identified as an alternative signaling receptor for GDNF family ligands (GFLs). The GFLs is a small group of soluble neurotrophic growth factors involved in neuronal survival, neurite growth and differentiation. Four members are known in the family including GDNF, Neurturin (NTN), Persephin (PSP), and Artemin (ART). NCAM, in collaboration with GFR? receptors, function as a signaling receptor for these GFLs. Signaling downstream of GDNF binding to the NCAM-GFRalpha1 complex activates Fyn-FAK-MAPK signaling pathway and mediates long-range intercellular communication. Pubmed12837245 Reactome Database ID Release 43375144 Reactome, http://www.reactome.org ReactomeREACT_18328 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Interaction of NCAM1 with Neurocan Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 NCAM1 bind all major components of neurocan (N-terminal, central and C-terminal regions as well as CS chains), a brain-specific chondroitin sulfate proteoglycan. This molecule interferes with homophilic NCAM1 interactions and inhibits neuronal adhesion and neurite outgrowth. Pubmed8910306 Reactome Database ID Release 43375148 Reactome, http://www.reactome.org ReactomeREACT_18427 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Interaction of NCAM1 with collagens Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 NCAM1 interacts with several extracellular matrix proteins. NCAM1 has been reported to bind collagens I-IV and IX. Pubmed18607724 Pubmed2809592 Reactome Database ID Release 43375151 Reactome, http://www.reactome.org ReactomeREACT_18390 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Interaction of NCAM1 with Major prion protein (PrP) Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 Prion protein (PrP) is a GPI-anchored protein predominately localized in lipid rafts. NCAM1 is one of the membrane localized proteins that binds PrP. PrP is though to bind NCAM1 at the IgV, F3I and/or F3II domains in an interaction not involving the various carbohydrate moieties of NCAM1. The functional relevance of this interaction is unknown, but may be related to the effects of PrP on activation and proliferation of haemopoietic cells expressing NCAM1. Pubmed11743735 Reactome Database ID Release 43375154 Reactome, http://www.reactome.org ReactomeREACT_18406 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- PathwayStep3651 PathwayStep3652 SOS binds Grb2 bound to pFAK:NCAM1 Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 Guanine nucleotide releasing factor Sos associates with FAK bound Grb2 to activate Ras and initiate Ras-MAPK signaling. This interaction occurs between the carboxy terminal domain of SOS and the Src homology 3 (SH3) domains of GRB2. Pubmed12700044 Pubmed2809592 Reactome Database ID Release 43392053 Reactome, http://www.reactome.org ReactomeREACT_18259 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Acyl Proghrelin Converted from EntitySet in Reactome Reactome DB_ID: 422078 Reactome Database ID Release 43422078 Reactome, http://www.reactome.org ReactomeREACT_20024 NCAM1:pFAK:Grb2:Sos-mediated nucleotide exchange of Ras Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 Pubmed12639709 Pubmed8493579 Reactome Database ID Release 43392054 Reactome, http://www.reactome.org ReactomeREACT_18366 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- The guanine nucleotide exchange factor SOS interacts with GRB2 bound to phosphorylated FAK bound to NCAM. Upon formation of this complex, SOS activates Ras by promoting GDP release and GTP binding. PathwayStep3650 Interaction of NCAM1 with GFRalpha-1 Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 GFRalpha receptors GFRalpha1 and possibly also GFRalpha2 and GFRalpha4 subunit of the GDNF (glial cell line-derived neurotrophic factor) receptor interact in cis with NCAM and functions as a coreceptor for GDNF in the absence of RET. The NCAM1-GFRalpha1 interaction down regulates NCAM1-mediated cell adhesion and promotes GDNF-NCAM1 binding. Pubmed12837245 Reactome Database ID Release 43375149 Reactome, http://www.reactome.org ReactomeREACT_18304 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- PathwayStep3632 PathwayStep3631 PathwayStep3634 PathwayStep3633 PathwayStep3636 PathwayStep3635 PathwayStep3638 PathwayStep3637 PathwayStep3639 Preproghrelin and prepro-des-Gln14-ghrelin Converted from EntitySet in Reactome Reactome DB_ID: 422026 Reactome Database ID Release 43422026 Reactome, http://www.reactome.org ReactomeREACT_19780 DCC interacting NCK-1 Authored: Garapati, P V, 2008-07-16 14:42:16 DCC interacts with the SH3/SH2 adaptor NCK1 in commissural neurons. This interaction is direct and requires the SH3 but not SH2 domains of NCK1. NCK1 can recruit Rac, Cdc42 and their effectors Pak and N-WASP to the activated receptor, thereby providing a direct link between DCC, Rho GTPases and numerous downstream signaling components that regulate the actin cytoskeleton. Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed12149262 Reactome Database ID Release 43373716 Reactome, http://www.reactome.org ReactomeREACT_22309 Reviewed: Cooper, HM, 2010-02-16 Proghrelin and Pro-des-Gln14-ghrelin Converted from EntitySet in Reactome Reactome DB_ID: 422091 Reactome Database ID Release 43422091 Reactome, http://www.reactome.org ReactomeREACT_19492 RhoGTPase GEF's recruited to DCC Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11817894 Pubmed12149262 Pubmed15788770 Pubmed18066058 Pubmed18212043 Reactome Database ID Release 43418858 Reactome, http://www.reactome.org ReactomeREACT_22278 Reviewed: Cooper, HM, 2010-02-16 When Netrin-1 binds to the DCC-NCK1 complex, a conformational change in NCK1 promotes interaction between the SH2 domain proteins, leading to recruitment and activation of RhoGEFs DOCK180 and Trio. These GEFs mediate Netrin-1 signaling in axon outgrowth and guidance through their ability to activate Rac1 and Cdc42. Recruitment of Src and Fyn to DCC:FADK1 Activated (phosphorylated) FADK1 acts as a scaffold and recruits src tyrosine kinases Src and Fyn to DCC. These tyrosine kinases phosphorylate DCC which is critical for Netrin-1 signaling. Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed15494732 Pubmed15494734 Pubmed15557120 Reactome Database ID Release 43418868 Reactome, http://www.reactome.org ReactomeREACT_22199 Reviewed: Cooper, HM, 2010-02-16 Phosphorylation of DCC by Fyn Authored: Garapati, P V, 2008-07-16 14:42:16 EC Number: 2.7.10 Edited: Garapati, P V, 2008-07-30 10:24:23 Netrin-1 stimulates phosphorylation of DCC on serine, threonine, and tyrosine residues. The experimental data suggest that tyrosine phosphorylation of DCC is a prerequisite step for DCC phosphorylation on serine and threonine residues. Fyn initiates the phosphorylation of the tyrosine residue 1420 in the DCC cytoplasmic domain. This phosphorylation of DCC in turn facilitates the DCC-Fyn interaction, forming a positive reinforcement cycle. Pubmed15494734 Pubmed15557120 Pubmed18253061 Reactome Database ID Release 43374701 Reactome, http://www.reactome.org ReactomeREACT_22213 Reviewed: Cooper, HM, 2010-02-16 has a Stoichiometric coefficient of 2 FADK1 interaction with DCC Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed15494734 Reactome Database ID Release 43373720 Reactome, http://www.reactome.org ReactomeREACT_22441 Reviewed: Cooper, HM, 2010-02-16 The carboxy (C) terminal domain of FADK1 interacts with the C-terminal P3 domain of DCC. This FADK1-DCC interaction is required for Netrin-1 to stimulate tyrosine phosphorylation and activation of FADK1. Phosphorylation of FADK1 Authored: Garapati, P V, 2008-07-16 14:42:16 EC Number: 2.7.10 Edited: Garapati, P V, 2008-07-30 10:24:23 FADK1 interacts with the C-terminal P3 domain of DCC complexed with Netrin-1, and undergoes tyrosine phosphorylation and activation. Netrin-1-DCC binding thus leads to the autophosphorylation of tyrosine 393 in FADK1. Pubmed15494733 Reactome Database ID Release 43418872 Reactome, http://www.reactome.org ReactomeREACT_22164 Reviewed: Cooper, HM, 2010-02-16 DCC interaction with Netrin-1 Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-07-30 10:24:23 Edited: Garapati, P V, 2008-09-05 06:02:05 Netrin-1 promotes attraction of the commissural neurons to midline cells. It is secreted in the ventral midline (also known as the floor plate). The transmembrane DCC receptor is a Netrin-1 receptor, involved in the attractive effects of Netrin-1. Contact-dependent mechanisms promote extension of growth cones across the floor plate to the contralateral side, whereupon growth cones acquire sensitivity to the midline repellent Slit and grow away from the midline.<br>Netrin-1 binds directly to the fifth Fibronectin III motif of DCC, thereby inducing DCC clustering through the association between the DCC P3 domains, a process required for an attractive response. Pubmed11239160 Pubmed9950216 Reactome Database ID Release 43373711 Reactome, http://www.reactome.org ReactomeREACT_22153 Reviewed: Cooper, HM, 2010-02-16 Netrin-1 induced DCC clustering Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Netrin binding to DCC causes DCC clustering via its P3 domain in the cytoplasmic region and mediates attractive signaling. Pubmed11239160 Pubmed15494734 Pubmed15960985 Reactome Database ID Release 43373707 Reactome, http://www.reactome.org ReactomeREACT_22142 Reviewed: Cooper, HM, 2010-02-16 PathwayStep3640 Polysialylation of NCAM1 Authored: Garapati, P V, 2009-05-30 17:44:08 EC Number: 2.4.99.8 Edited: Garapati, P V, 2009-05-30 17:44:08 NCAM in the developing brain is highly polysialylated and is referred as the embryonic form of NCAM. Polysialic acid is a developmentally regulated, anti-adhesive glycan with a linear homopolymer of alpha2,8-linked sialic acid units. They are mainly attached to the fifth and sixth N-glycosylation sites of the fifth Ig-like domain of NCAM. Polysialylation of NCAM is catalyzed by two polysialyltransferases, ST8Sia II (STX) and ST8Sia IV (PST), which belong to the family of six genes encoding alpha2,8-sialyltransferases. These enzymes add polysialic acid to NCAM N-glycans until it reaches a certain size (up to 200 sialic acid residues), where neither enzyme can interact with polysialylated N-glycans, and the polymerization of sialic acid is terminated.<br>Due to the structure with its chemical nature, polysialic acid can attenuate the interaction of NCAM with NCAM and other molecules in the same membrane (cis-interaction) or in another cell membrane (trans-interaction). During axonal growth the presence of polysialic acid along axons seems to prevent inappropriate synapse formation. Pubmed12765789 Pubmed16267048 Pubmed18059411 Reactome Database ID Release 43422454 Reactome, http://www.reactome.org ReactomeREACT_18324 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- has a Stoichiometric coefficient of 2 PathwayStep3641 NCAM1 interacts with T- and L-type VDCC Authored: Garapati, P V, 2009-05-30 17:44:08 Edited: Garapati, P V, 2009-05-30 17:44:08 NCAM1 associates with T- and L-type voltage-dependent Ca+2 channels (VDCC) in growthcones at the sites of NCAM1 clustering. This interaction leads to the NCAM-dependent Ca+2 influx to the cell. Reactome Database ID Release 43525833 Reactome, http://www.reactome.org ReactomeREACT_21373 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- PathwayStep3668 PathwayStep3669 PathwayStep3666 PathwayStep3667 PathwayStep3664 PathwayStep3665 PathwayStep3674 PathwayStep3673 PathwayStep3672 PathwayStep3671 PathwayStep3670 PathwayStep3657 PathwayStep3658 PathwayStep3659 PathwayStep3653 PathwayStep3654 PathwayStep3655 PathwayStep3656 PathwayStep3661 PathwayStep3660 PathwayStep3663 PathwayStep3662 PathwayStep3688 PathwayStep3689 PathwayStep3686 PathwayStep3687 PathwayStep3692 PathwayStep3691 PathwayStep3690 PathwayStep3696 PathwayStep3695 PathwayStep3694 PathwayStep3693 PathwayStep3675 PathwayStep3676 PathwayStep3677 PathwayStep3678 PathwayStep3679 PathwayStep3681 PathwayStep3680 PathwayStep3683 PathwayStep3682 PathwayStep3685 PathwayStep3684 L1 binds to AP-2 Clathrin complex Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 in the C-domain membrane is internalized via clathrin mediated endocytosis. The assembly of clathrin coats at the plasma membrane depends on the adaptor complex AP-2 which is composed of two large chains (alpha and beta1 or beta2 adaptin), one medium (mu2) chain, and one small chain (sigma2). When dephosphorylated, the sorting signal/endocytic motif YRSLE sequence enables L1 to directly bind the mu2 subunit of AP-2, and concentrates L1 molecules in clathrin coated areas of the plasma membrane. Pubmed9651214 Reactome Database ID Release 43392748 Reactome, http://www.reactome.org ReactomeREACT_22118 Reviewed: Maness, PF, 2010-02-16 S6K1 signalling Reactome Database ID Release 43165720 Reactome, http://www.reactome.org ReactomeREACT_6772 Formation of clathrin coated vesicle Authored: Garapati, P V, 2008-07-30 10:22:58 Dynamin is a neuronal phosphoprotein and a GTPase enzyme which mediates late stages of endocytosis in both neural and non-neural cells. Dynamin is involved in the membrane fusion event that results in the formation of clathrin-coated vesicles. EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed14709786 Pubmed9651214 Reactome Database ID Release 43555065 Reactome, http://www.reactome.org ReactomeREACT_22359 Reviewed: Maness, PF, 2010-02-16 Release of eIF4E Raptor recruits mTOR to non-phosphorylated 4E-BP1 bound to eIF4E and positively modulates phosphorylation of 4E-BP1 by mTOR. 4E-BP1 is further phosphorylated on multiple sites by other unknown kinases, also contributing to the dissociation of 4E-BP1 from eIF4E. Thus mTORC1 relieves the inhibitory effect of 4E-BP1 on eIF4E dependent translation initiation (PMIDs 15755954, 10872469, 11297505, 12150926 and 15809305). Reactome Database ID Release 43165721 Reactome, http://www.reactome.org ReactomeREACT_6836 Shootin-1 links L1 and retrograde actin flow Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Reactome Database ID Release 43373736 Reactome, http://www.reactome.org ReactomeREACT_22168 Reviewed: Maness, PF, 2010-02-16 Shootin-1 acts as a linker protein, binding L1 to moving actin filaments in axonal growth cones. This interaction mediates the migration of L1 on the plasma membrane from P-domain to the C-domain of the growth cone and enhances neurite elongation. Dephosphorylation of pL1 (Y1176) Authored: Garapati, P V, 2008-07-30 10:22:58 EC Number: 3.1.3.48 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 translocated to the non raft membranes of the C-domain is dephosphorylated. A number of potential candidate phosphatases exist including phosphotyrosine phosphatases. Dephosphorylation of Y1176 allows L1 binding to AP-2, an adaptor required for clathrin mediated internalization of L1. Pubmed12082080 Reactome Database ID Release 43445089 Reactome, http://www.reactome.org ReactomeREACT_22109 Reviewed: Maness, PF, 2010-02-16 has a Stoichiometric coefficient of 2 Interaction of NUMB with L1 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Numb is thought to be a phosphotyrosine binding (PTB) domain containing cargo specific adaptor protein, which links specific cargo to the endocytic machinery. It associates with collapsin response mediator protein-2 (CRMP 2) with its PTB domain and alpha adaptin (a subunit of the AP 2 adaptor complex) through its tripeptide Asp-Pro-Phe (DPF) motif, and is involved in clathrin dependent endocytosis at the plasma membrane. Numb is associated with L1 under physiological conditions and functions in endocytosis of L1 in the C domain membrane of axonal growth cones. Pubmed12942088 Reactome Database ID Release 43443783 Reactome, http://www.reactome.org ReactomeREACT_22358 Reviewed: Maness, PF, 2010-02-16 Recruitment of CAP to Abl Abl associated with Robo1, Slit2, and glypican at the plasma membrane binds CAP and regulate its activity to inhibit net actin assembly. Studies of CAP homologs from yeast, Dictyostelium, mouse, pig, and human suggest that the C terminal actin binding domain acts to sequester monomers to prevent actin polymerization. Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed12441051 Reactome Database ID Release 43428883 Reactome, http://www.reactome.org ReactomeREACT_19260 Reviewed: Kidd, T, 2009-08-18 Signaling by NGF Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0048011 Nerve Growth Factor (NGF) signalling Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: TRK tyrosine kinase receptors (TRKA, TRKB, TRKC), which specifically interact with the different neurotrophins, and p75NTR, which interacts with all neurotrophins. TRK receptors are reported in a variety of tissues in addition to neurons. p75NTRs are also widespread.<br><br><br>Neurotrophins and their receptors are synthesized as several different splice variants, which differ in terms of their biological activities. The nerve growth factor (NGF) was the first growth factor to be identified and has served as a model for studying the mechanisms of action of neurotrophins and growth factors. The mechanisms by which NGF generates diverse cellular responses have been studied extensively in the rat pheochromocytoma cell line PC12. When exposed to NGF, PC12 cells exit the cell cycle and differentiate into sympathetic neuron-like cells. Current data show that signalling by the other neurotrophins is similar to NGF signalling. Reactome Database ID Release 43166520 Reactome, http://www.reactome.org ReactomeREACT_11061 Reviewed: Greene, LA, 2007-11-08 15:39:37 Signalling by NGF Insulin receptor recycling Authored: Bevan, AP, 2003-07-31 08:01:55 Reactome Database ID Release 4377387 Reactome, http://www.reactome.org ReactomeREACT_1109 Triggered by acidification of the endosome, insulin dissociates from the receptor and is degraded. The receptor is dephosphorylated and re-integrated into the plasma membrane, ready to be activated again by the binding of insulin molecules. Signal attenuation Authored: 2003-07-28 10:05:14 Now with the complete receptor-ligand dissociation and subsequent degradation of insulin in the endosomal lumen, the endosomally associated protein tyrosine phosphatases (PTPs) complete the receptor dephosphorylation. So too are all the receptor substrates dephosphorylated leading to the collapse of the signalling complexes and signal attenuation. Reactome Database ID Release 4374749 Reactome, http://www.reactome.org ReactomeREACT_508 SOS-mediated signalling Authored: Charalambous, M, 2004-04-29 09:21:24 Reactome Database ID Release 43112412 Reactome, http://www.reactome.org ReactomeREACT_524 SOS is recruited to the plasma membrane and mediates activation of Ras. Linkage of L1 with treadmilling F-actin Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed12154370 Pubmed14709786 Pubmed18478542 Reactome Database ID Release 43443779 Reactome, http://www.reactome.org ReactomeREACT_22244 Reviewed: Maness, PF, 2010-02-16 The COOH termini of all ERM proteins have sequence motifs that bind directly to F-actin. The L1 molecules on the cell surface are translocated to the C-domain by coupling with the retrograde F-actin. The force generated by linking L1 clusters with retrograde F-actin flow leads to the migration of the growth cone. Activation of PKB Reactome Database ID Release 43165158 Reactome, http://www.reactome.org ReactomeREACT_790 L1 trans-homophilic interaction Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Interaction with ERM may lead to lateral oligomerization of phosphorylated L1 and this enhances the homophilic trans adhesion of L1.<br>L1 mediates cell-cell adhesion by a trans-homophilic binding mechanism. In the nonengaged resting state the L1 N-terminal Ig domains adopt a horseshoe like structure due to an intramolecular binding between domains 1 and 4 or 2 and 3, respectively. When engaged in homophilic binding between adjacent cells, L1 could undergo a conformational change leading to a pairwise antiparallel alignment of Ig domains 1-4 and 2-3.<br> Pubmed17538021 Pubmed19278660 Pubmed2448316 Pubmed7493978 Pubmed9721721 Reactome Database ID Release 43374680 Reactome, http://www.reactome.org ReactomeREACT_22211 Reviewed: Maness, PF, 2010-02-16 Regulation of Rheb GTPase activity by AMPK Activated AMPK phosphorylates TSC2 and activates the TSC complex. TSC2 functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of a small G-protein Rheb. This results in conversion of Rheb-GTP into Rheb-GDP, and in inhibition of the mTOR activation by GTP-bound Rheb. Authored: Katajisto, P, Makela, T, Wu, J, 2008--1-1- Edited: Jassal, B, 2008-11-19 15:14:38 Pubmed17613433 Reactome Database ID Release 43380953 Reactome, http://www.reactome.org ReactomeREACT_21393 Reviewed: Zheng, B, 2009-10-20 L1 binds ERM family members Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Ezrin Radixin Moesin (ERM) are the members of the FERM domain (F for Band 4.1 protein, E for ezrin, R for radixin and M for moesin) containing proteins involved in localizing proteins to the plasma membrane. L1 is coupled to the tread milling actin cytoskeleton through interaction with ERM proteins. The motif KxxKYxV in the juxtamembrane region and the YRSLE sequence in L1CD are important for the ERM binding. This interaction provides a link between L1 and the actin cytoskeleton and plays a critical role in the traction force generation and regulation of neurite branching. Pubmed12070130 Reactome Database ID Release 43374677 Reactome, http://www.reactome.org ReactomeREACT_22428 Reviewed: Maness, PF, 2010-02-16 Regulation of AMPK activity via LKB1 Authored: Katajisto, P, Makela, T, Wu, J, 2008--1-1- Edited: Jassal, B, 2008-11-19 15:14:38 LKB1 forms a complex with STRAD and MO25 thereby attaining a higher activity towards its substrates belonging to the subfamily of AMPK like kinases. LKB1:STRAD:MO25 complex phosphorylates AMPK constantly. This phosphorylation is immediately removed in basal conditions by PP2C, but if the cellular AMP:ATP ratio rises, binding of AMP by AMPK inhibits the dephosphorylation, and the maintained phosphorylation results in activation of the AMPK. Pubmed17712357 Pubmed18022388 Reactome Database ID Release 43380971 Reactome, http://www.reactome.org ReactomeREACT_21285 Reviewed: Zheng, B, 2009-10-20 Phosphorylation of L1 by SRC Authored: Garapati, P V, 2008-07-30 10:22:58 EC Number: 2.7.10 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed12082080 Reactome Database ID Release 43445084 Reactome, http://www.reactome.org ReactomeREACT_22408 Reviewed: Maness, PF, 2010-02-16 The tyrosine based sorting motif (YRSLE) in L1CD is required for clathrin mediated endocytosis. Y1176 of the YRSLE motif is phosphorylated by SRC tyrosine kinase associated with lipid rafts in the P-domain of the growth cone. Phosphorylation of Y1176 prevents L1 binding to AP-2, an adaptor required for clathrin mediated internalization of L1. Energy dependent regulation of mTOR by LKB1-AMPK Authored: Katajisto, P, Makela, T, Wu, J, 2008--1-1- Edited: Jassal, B, 2008-11-19 15:14:38 GENE ONTOLOGYGO:0007050 Pubmed17010524 Pubmed17613433 Pubmed17712357 Reactome Database ID Release 43380972 Reactome, http://www.reactome.org ReactomeREACT_21387 Reviewed: Zheng, B, 2009-10-20 Upon formation of a trimeric LKB1:STRAD:MO25 complex, LKB1 phosphorylates and activates AMPK. If the AMP:ATP ratio rises, this activation is maintained and AMPK activates the TSC complex by phosphorylating TSC2. Active TSC activates the intrinsic GTPase activity of Rheb, resulting in GDP-loaded Rheb and inhibition of mTOR pathway. L1 linked to actin cytoskeleton by ankyrin Ankyrins are bifunctional linker proteins that tether L1 to the membrane associated, spectrin based actin cytoskeleton. Spectrin is a tetramer of two alpha- and two beta-chains. The spectrin alpha chain has 21 and the beta chain has 16 (conventional beta) or 30 (heavy beta) successive triple helix repeats. At the N-terminus of beta spectrin, there is a pair of CH (calponin homology) domains which together form an actin binding domain, while the triple helical repeats 14-15 bind ankyrin. <br>Interaction with spectrin bound F-actin blocks the mobility of L1 and this immobilization mediates adjacent neuron adhesions. Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed11222639 Pubmed16904324 Pubmed17223356 Reactome Database ID Release 43392751 Reactome, http://www.reactome.org ReactomeREACT_22148 Reviewed: Maness, PF, 2010-02-16 Ankyrins link voltage-gated sodium and potassium channels to spectrin and L1 Ankyrins link both L1 and ion channel proteins, coupling them to the spectrin actin cytoskeleton. In the nervous system ankyrins interact with voltage gated channels and cluster them in axon initial segments to generate action potentials. At these points the actin spectrin network is linked via ankyrins to voltage gated sodium channels, L1, and the voltage gated potassium ion channel subunits, KCNQ2 and KCNQ3. Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Reactome Database ID Release 43373739 Reactome, http://www.reactome.org ReactomeREACT_22364 Reviewed: Maness, PF, 2010-02-16 Phosphorylation of Y1229 in L1 Authored: Garapati, P V, 2008-07-30 10:22:58 Binding of ankyrins is dependent on the phosphorylation and dephosphorylation state of the tyrosine in the L1 FIGQY motif. In the dephosphorylated state ankyrins bind to L1 and in the phosphorylated state L1 releases from ankyrins and binds to doublecortin. <br>The specific kinase that is responsible for the phosphorylation of this tyrosine residue is still unknown, but components of the MAP kinase pathway may regulate this event. Tyrosine phosphorylation abolishes ankyrin binding and also increases L1 lateral mobility and neurite growth<br> EC Number: 2.7.10 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed16597699 Reactome Database ID Release 43445076 Reactome, http://www.reactome.org ReactomeREACT_22229 Reviewed: Maness, PF, 2010-02-16 L1 and NCAM1 engaged in cis-interaction Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 and NCAM1 co-expressed on a single cell interact with each other via the fourth Ig domain of NCAM1 and the oligomannose type oligosaccharides carried by L1. This interaction has synergetic effects on L1-mediated cell aggregation and adhesion, a phenomenon referred to as 'assisted homophilic L1-L1 trans-binding'. Pubmed10611478 Pubmed2295682 Pubmed8509458 Reactome Database ID Release 43374681 Reactome, http://www.reactome.org ReactomeREACT_22231 Reviewed: Maness, PF, 2010-02-16 IRS-related events Authored: Bevan, AP, 2003-07-31 08:01:55 IRS is one of the mediators of insulin signalling events. It is activated by phosphorylation and triggers a cascade of events involving PI3K, SOS, RAF and the MAP kinases. The proteins mentioned under IRS are examples of IRS family members acting as indicated. More family members are to be confirmed and added in the future. Reactome Database ID Release 4377389 Reactome, http://www.reactome.org ReactomeREACT_762 mTOR signalling Reactome Database ID Release 43165159 Reactome, http://www.reactome.org ReactomeREACT_6838 PDE3B signalling Reactome Database ID Release 43165160 Reactome, http://www.reactome.org ReactomeREACT_1451 Phosphorylation of L1 by p90rsk Authored: Garapati, P V, 2008-07-30 10:22:58 EC Number: 2.7.11 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed10608864 Pubmed8663493 Reactome Database ID Release 43374696 Reactome, http://www.reactome.org ReactomeREACT_22240 Reviewed: Maness, PF, 2010-02-16 p90rsk associates with the internalized L1 in the endosomes and phosphorylates it at Ser1152. This phosphorylation may regulate the interactions of L1 and intracellular signaling cascades or cytoskeletal elements involved in neurite outgrowth on specific substrates. mTORC1-mediated signalling Reactome Database ID Release 43166208 Reactome, http://www.reactome.org ReactomeREACT_6964 Transport of L1 into endosomes Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Membrane bound L1 is internalized through clathrin coated vesicles and is endocytosed into recycling endosomes. Moreover, L1 promotes co-endocytosis of beta1 integrins with which it is associated into early endosomes. Pubmed10804209 Pubmed16330023 Pubmed9651214 Reactome Database ID Release 43392749 Reactome, http://www.reactome.org ReactomeREACT_22103 Reviewed: Maness, PF, 2010-02-16 Inhibition of TSC complex formation by PKB Phosphorylation of TSC2 by PKB disrupts TSC1/TSC2 heterodimer formation (PMID 15314020). TSC2 function is affected in at least two ways: first, phosphorylation decreases the activity of TSC2; second, phosphorylation destabilizes the TSC2 protein. This destabilization is achieved by disrupting complex formation between TSC1 and TSC2 and inducing ubiquination of the free TSC2 (PMID 12172553). Phosphorylation of complexed TSC2 by PKB induces degradation of both TSC1 and TSC2 through the proteosome pathway (PMID 121676664). Phosphorylation of complexed TSC2 by PKB may therefore result in the dissociation of the TSC1:TSC2 complex (PMID 12423332). Reactome Database ID Release 43165181 Reactome, http://www.reactome.org ReactomeREACT_6743 Transport of L1 from C-domain to P-domain Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Endocytosis is followed by the vesicular transport and recycling of L1 from central (C)-domain into the peripheral (P)-domain of growth cones. <br>Microtubules serve as a rail on which motor proteins convey L1 containing organelles. KIF4 is a plus end motor protein involved in the anterograde transport of L1 containing vesicles along microtubules. Reactome Database ID Release 43445077 Reactome, http://www.reactome.org ReactomeREACT_22136 Reviewed: Maness, PF, 2010-02-16 IRS-mediated signalling Authored: Charalambous, M, 2004-04-29 09:21:24 Reactome Database ID Release 43112399 Reactome, http://www.reactome.org ReactomeREACT_332 Release of phospho-IRS from the insulin receptor triggers a cascade of signalling events via PI3K, SOS, RAF and the MAP kinases. Phosphorylation of L1 by ERK Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 cross linking can activate MAPK cascade components MEK1/2, ERK1/2, as well as Src, Raf-1,and p90rsk. MAP kinase signaling requires endocytosis mediated by Src. ERK2 can phos-phorylate internalized L1 at serine residues 1204 and 1248. This phosphorylation may increase the neurite growth. Pubmed10608864 Pubmed10818153 Pubmed17151951 Reactome Database ID Release 43445079 Reactome, http://www.reactome.org ReactomeREACT_22099 Reviewed: Maness, PF, 2010-02-16 IRS activation Authored: 2003-07-28 10:05:14 Reactome Database ID Release 4374713 Reactome, http://www.reactome.org ReactomeREACT_570 Using receptor mutagenesis studies it is known that IRS1 via its PTB domain binds to the insulin receptor at the juxtamembrane region at tyrosine 972. The interaction is further stabilized by the PH domain of IRS1 which interacts with the phospholipids of the plasma membrane. This allows the receptor to phosphorylate IRS1 on up to 13 of its tyrosine residues. Once phosphorylated the IRS1 falls away from the receptor. (Other IRS family members can also be phosphorylated by the insulin receptor - will be added in the near future.) Now in a tyrosine phosphorylated and hence activated state other proteins can interact with the IRS proteins. L1 dimer binds Ankyrin Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 recruits membrane skeletal component ankyrin to cell to cell contact sites in response to cis interaction with homophilic axonin 1/TAG 1 or trans L1 L1 homophilic interaction although in mammalian cells trans binding interactions are not required. L1 interacts with ankyrin proteins through two highly conserved amino acid sequence motifs, LADY and FIGQY.<br>Ankyrin binding immobilizes L1 molecules in the neuronal plasma membrane. This interaction is required for axon maintenance. L1 also elevates cyclic AMP levels in neurons via ankyrin B and mediates Ca+2 dependent attraction.The L1/ankyrin interaction is a vital determinant of synaptic targeting of retinal axons to the superior colliculus and cooperates with EphrinB/EphB signaling to induce axon branch attraction. Pubmed11222639 Pubmed18171935 Reactome Database ID Release 43374675 Reactome, http://www.reactome.org ReactomeREACT_22141 Reviewed: Maness, PF, 2010-02-16 PKB-mediated events Authored: Scott, J, Tatoud, R, 2005-05-09 06:03:17 PKB and PDK1 are activated via membrane-bound PIP3. Activated PDK1 phosphorylates PKB, which in turn phosphorylates PDE3B. The latter hydrolyses cAMP to 5'AMP, depleting cAMP pools. Reactome Database ID Release 43109703 Reactome, http://www.reactome.org ReactomeREACT_456 Reinsertion of L1 into the plasma membrane Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 transported to the P-domain of growth cones is reinserted into the plasma membrane at the leading edge. Pubmed10747093 Pubmed10804209 Reactome Database ID Release 43445071 Reactome, http://www.reactome.org ReactomeREACT_22298 Reviewed: Maness, PF, 2010-02-16 PI3K Cascade Reactome Database ID Release 43109704 Reactome, http://www.reactome.org ReactomeREACT_976 S6K1-mediated signalling Reactome Database ID Release 43166207 Reactome, http://www.reactome.org ReactomeREACT_6754 Interaction of L1 with Laminin-1 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed9003039 Reactome Database ID Release 43443778 Reactome, http://www.reactome.org ReactomeREACT_22113 Reviewed: Maness, PF, 2010-02-16 While HNK-1 (human natural killer 1) carbohydrate is expressed on several kinds of cell adhesion molecules in the nervous system, L1CAM is the major carrier of HNK-1 carbohydrate. HNK-1 also functions as a ligand for Laminin. L1 binds in a concentration-dependent and saturating manner to Laminin in presence of HNK-1. p75NTR regulates axonogenesis Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0050770 Pubmed17335080 Reactome Database ID Release 43193697 Reactome, http://www.reactome.org ReactomeREACT_13620 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p75NTR modulates axonal growth by regulating the activity of small GTPases like RHOA and RHOB, that control the state of actin polymerization. The best studied is RHOA. In its active, GTP-bound form, RHOA rigidifies the actin cytoskeleton, thereby inhibiting axonal elongation and causing growth cone collapse. Depending on the ligand that binds to it, p75NTR can either promote or inhibit axonal growth, Neurotrophin binding leads to inhibition of RHOA activity and axonal growth. Axonal growth inhibition is caused by myelin molecules named MDGIs (myelin-derived growth inhibitors), such as NOGO, MAG, OMGP. MDGIs bind to a complex made up of p75NTR and the NOGO receptor, causing RHOA activation and axonal growth inhibition. Axonal growth stimulation Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Complex formation between p75NTR and RHOA can leads to inhibition of RHOA activity and axonal growth. Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0050772 Pubmed16215275 Reactome Database ID Release 43209563 Reactome, http://www.reactome.org ReactomeREACT_13779 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Phosphorylation of L1 by CK-II Authored: Garapati, P V, 2008-07-30 10:22:58 CKII phosphorylates L1CAM at serine 1181, just after the AP-2 recognition site (Y1176RSLE motif). CKII-dependent phosphorylation of S1181 has been shown to regulate trafficking of the internalized L1 and subsequent axon growth. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed17253643 Pubmed8592152 Reactome Database ID Release 43392752 Reactome, http://www.reactome.org ReactomeREACT_22378 Reviewed: Maness, PF, 2010-02-16 NF-kB is activated and signals survival Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 Pubmed16187223 Reactome Database ID Release 43209560 Reactome, http://www.reactome.org ReactomeREACT_13696 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Upon activation in response to NGF, NF-kB moves to the nucleus, where it turns on genes that promote survival, and triggers the expression of HES1/5 to modulate dendritic growth. Interaction of L1 with Neurocan Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1CAM binds with high affinity to the proteoglycan neurocan. Neurocan binds to the first Ig domain of L1CAM through its sushi module and a chondroitin sulphate chain. This interaction interferes with the homophilic interaction of L1CAM and inhibits neuronal adhesion and neurite extension mediated by L1CAM. Pubmed10934197 Reactome Database ID Release 43374683 Reactome, http://www.reactome.org ReactomeREACT_22386 Reviewed: Maness, PF, 2010-02-16 Ceramide signalling Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0008624 In certain cell types, ligand binding to p75NTR leads to ceramide production, which can mediate either cell survival (e.g. in noecotical subplate neurons) or apoptosis (e.g. in oligodendrocytes). Low levels of ceramide are also able to stimulate axonal outgrowth in hippocampal neurons. Pubmed12676795 Reactome Database ID Release 43193681 Reactome, http://www.reactome.org ReactomeREACT_13806 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Interaction of PAK1 with Rac1-GTP Authored: Garapati, P V, 2008-07-30 10:22:58 EC Number: 2.7.11 Edited: Garapati, P V, 2008-07-30 10:22:58 In its bound state PAK dimers are arranged in head-to-tail fashion and are maintained in inactive conformation in which the catalytic domain binds the kinase inhibitory (KI) domain. <br>All PAK family members are direct effectors of Rac1. Rac1 binds to a conserved Cdc42/Rac interactive binding (CRIB) domain in PAK1. This binding stimulates serine/threonine kinase activity of PAK1 by a mechanism involving autophosphorylation. Phosphorylation of S-144 and T-423 are required for the activation of PAK1. This phosphorylation disables the KI-domain-kinase interaction and thereby reduces the affinity of the PAK dimers.<br>Its been demonstarted that L1 stimulation propagates through VAV2-Rac1-Pak1 to MEK-ERK. It has been shown that Pak1 is able to phosphoarylate T292 and S298 on MEK, which is essential for the functional association of MEK with Raf. Pubmed15597056 Pubmed9351825 Reactome Database ID Release 43445072 Reactome, http://www.reactome.org ReactomeREACT_22371 Reviewed: Maness, PF, 2010-02-16 has a Stoichiometric coefficient of 2 Activation of TRKA receptors Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0007169 Pubmed16939974 Reactome Database ID Release 43187015 Reactome, http://www.reactome.org ReactomeREACT_11064 Reviewed: Greene, LA, 2007-11-08 15:39:37 Trk receptors can either be activated by neurotrophins or by two G-protein-coupled receptors (GPCRs) although the biological relevance of GPCRs remains to be shown. Activation of Rac1 by VAV2 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed10818153 Pubmed15597056 Reactome Database ID Release 43445064 Reactome, http://www.reactome.org ReactomeREACT_22180 Reviewed: Maness, PF, 2010-02-16 The small GTPase p21Rac1 is one of the important targets of VAV2 GEF activity. On L1 stimulation tyrosine phosphorylated VAV2, catalyses GDP/GTP exchange on Rac1. NGF signalling via TRKA from the plasma membrane Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed10579918 Pubmed10851172 Pubmed11520933 Pubmed12676795 Reactome Database ID Release 43187037 Reactome, http://www.reactome.org ReactomeREACT_12056 Reviewed: Greene, LA, 2007-11-08 15:39:37 Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins. Phosphorylation of VAV2 Authored: Garapati, P V, 2008-07-30 10:22:58 EC Number: 2.7.10 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 crosslinking leads to the tyrosine phosphorylation and activation of VAV2. Tyr-172 in VAV2 binds to the DBL homology region autoinhibiting its GEF-activity. Tyrosine kinase src may phosphorylate this residue and relieve the autoinhibition. Pubmed15597056 Reactome Database ID Release 43445085 Reactome, http://www.reactome.org ReactomeREACT_22236 Reviewed: Maness, PF, 2010-02-16 Regulated proteolysis of p75NTR Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0031293 Pubmed17215246 Pubmed17986144 Reactome Database ID Release 43193692 Reactome, http://www.reactome.org ReactomeREACT_13443 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p75NTR undergoes a process of regulated intramembrane proteolysis (RIP) similar to other transmembrane proteins such as NOTCH, beta-amyloid precursor protein (APP), and ERBB4. Each of these proteins is subjected to two sequential cleavages. The first one occurs in the extracellular part of the protein and is mediated by the metalloproteinase alpha-secretase which causes shedding of the extracellular domain. The second cleavage occurs in the intramembrane region and is mediated by gamma-secretase and causes release of the intracellular domain, ICD, and of a small peptide. The ICD often traffics to the nucleus and, in some instances (e.g. NOTCH), was found to act as transcriptional regulator. Whether the p75NTR ICD does translocate to the nucleus to regulate gene expression in a way similar to the NOTCH receptor remains to be seen. The alpha- and gamma-secretase mediated cleavage of p75 appears to be regulated by neurotrophin (NGF, BDNF) binding to TRKA or TRKB. p75NTR processing also occurs in response to MAG in cerebellar granule neurons. L1 interaction with Integrins Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 can function as a trans-heterophilic ligand for multiple members of the integrin superfamily. It binds multiple integrins including alphavbeta3, alphavbeta1, alpha5beta1, alphaIIbbeta3 and alpha9beta 1. The RGD motif in the sixth Ig domain and the third FnIII repeat of L1 are important for these interactions, which serves to strengthen the adhesion of the neuron to the extracellular matrix.<br>L1 and beta1 integrins association activates a common intracellular signaling pathway. This pathway involves the sequential activation of the tyrosine kinase c-Src, PI3 kinase, Vav2 guanine nucleotide exchange factor, Rac1 GTPase, PAK1, MEK, and the MAP kinases ERK1/2, which is essential for L1 induced neurite outgrowth and cell motility. Pubmed18555990 Pubmed18760361 Pubmed9396761 Reactome Database ID Release 43374686 Reactome, http://www.reactome.org ReactomeREACT_22152 Reviewed: Maness, PF, 2010-02-16 Axonal growth inhibition (RHOA activation) Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0050771 Pubmed12951563 Reactome Database ID Release 43193634 Reactome, http://www.reactome.org ReactomeREACT_13815 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p75NTR can also form a receptor complex with the Nogo receptor (NgR). Such complexes mediates axonal outgrowth inhibitory signals of MDGIs (myelin-derived growth-inhibitors), such as Nogo66, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMGP). L1 binds Neuropilin-1 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 interacts with neuropilin 1 (NP-1) through a conserved sequence (FASNKL) present with in the Ig1 domain of L1 and this association is required as a part of semaphorin 3A (Sema3A) receptor complex for axon guidance responses. <br>L1 interacts with NP-1 in cis to form a receptor complex that induces repulsive turning of the growth cone in response to Sema3A binding, whereas trans interaction of L1 with NP-1 switches Sema3A triggered repulsion to attraction. Pubmed12456642 Reactome Database ID Release 43374669 Reactome, http://www.reactome.org ReactomeREACT_22257 Reviewed: Maness, PF, 2010-02-16 L1-EGFR trans-heterodimerization Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1CAM and EGFR engage in a weak heterophilic trans interaction and this induces EGFR tyrosine kinase activity and its activation. However, this trans interaction alone is not sufficient to induce EGFR autophosphorylation, which requires additional cis type interactions between the two proteins. Pubmed14718570 Reactome Database ID Release 43445069 Reactome, http://www.reactome.org ReactomeREACT_22196 Reviewed: Maness, PF, 2010-02-16 L1-FGFR cis-heterodimerization Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1-L1 trans-homodimers interact with the fibroblast growth factor receptor (FGFR). The CAM homology domain (CHD) in the FGFR, which resides between Ig like domains 1 and 2, interacts with the putative FGFR-CHD binding motif in the Fn3 module 4 of L1. This interaction leads to activation of the tyrosine kinase domain of the FGFR and subsequent activation of PLCgamma. PLCgamma then hydrolyses PIP2 to generate IP3 and DAG which finally leads to an increase in localized Ca+2 influx and activation of Ca+2/Calmodulin kinase II. Pubmed18222703 Reactome Database ID Release 43437230 Reactome, http://www.reactome.org ReactomeREACT_22098 Reviewed: Maness, PF, 2010-02-16 NGF-independant TRKA activation Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0007190 Pubmed16805430 Reactome Database ID Release 43187024 Reactome, http://www.reactome.org ReactomeREACT_11046 TRK receptors can also be activated by at least two G-protein-coupled receptors (GPCR), the adenosine A2a receptor and the PACAP type I receptor, without involvement of neurotrophins. Activity of both receptors is mediated by G proteins that activate adenyl cyclase. How this leads to TRKA activation has not been fully elucidated, although a SRC-family tyrosine kinase and intracellular Ca2+ appear to play a role. TRKA activation through GPCRs occurs with slow kinetics (over 1 hr adenosine or PACAP treatment is required) in an intracellular location (probably the Golgi apparatus), and requires transcriptional and protein synthesis events that may influence the processing and activation of the receptors. GPCR-mediated transactivation of TRK receptors causes the preferential activation of AKT versus ERKs. This leads to a cell survival response. TRKA activation by NGF Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0048011 Neurotrophin functions are mediated by binding of the secreted neurotrophin homodimers to their common neurotrophin receptor p75NTR, and to their cognate tropomyosin related kinase (TRK) receptor. NGF binds to TRKA, BDNF and NT4 bind to TRKB, NT3 binds to TRKC. A tri-molecular signalling complex (NGF-p75NTR-TRKA) might also be possible. Pubmed1315923 Pubmed1844238 Reactome Database ID Release 43187042 Reactome, http://www.reactome.org ReactomeREACT_11060 Reviewed: Greene, LA, 2007-11-08 15:39:37 CHL1 interacts with NP-1 Authored: Garapati, P V, 2008-07-30 10:22:58 CHL1 binds the Sema3A receptor, Neuropilin-1 (NP-1), via a conserved sequence in the Ig1 domain, and acts as obligate coreceptor to mediate Sema3A-induced growth cone collapse and axon repulsion. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed18077678 Reactome Database ID Release 43445083 Reactome, http://www.reactome.org ReactomeREACT_22361 Reviewed: Maness, PF, 2010-02-16 CHL1 interacts with beta1 integrins Authored: Garapati, P V, 2008-07-30 10:22:58 CHL1 interacts with alpha1beta1/alpha2beta1 integrins in cis on the cell surface and promotes intracellular signaling, which stimulates cell migration on extracellular matrix proteins such as collagen-I. The integrin interaction motif, DGEA in the Ig6 domain of CHL1, is necessary to potentiate migration to collagen-I. CHL1 interacts with integrins to mediate radial migration of neural precursors in the development neocortex, and suppresses neuronal branching during migration. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed12721290 Pubmed15504324 Reactome Database ID Release 43445088 Reactome, http://www.reactome.org ReactomeREACT_22369 Reviewed: Maness, PF, 2010-02-16 NGF processing All neurotrophins (NTs) are generated as pre-pro-neurotrophin precursors. The signal peptide is cleaved off as NT is associated with the endoplasmic reticulum (ER). The resulting pro-NT can form a homodimer spontaneously which then transits to the Golgi apparatus and then onto the trans-Golgi network (TGN). Resident protein convertases (PCs) can cleave off the pro-sequence and mature NT is is targeted to constitutively released vesicles. The pro-NT form can also be released to the extracellular region. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0032455 Pubmed12787574 Reactome Database ID Release 43167060 Reactome, http://www.reactome.org ReactomeREACT_11062 Reviewed: Greene, LA, 2007-11-08 15:39:37 p75 NTR receptor-mediated signalling Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Besides signalling through the tyrosine kinase receptors TRK A, B, and C, the mature neurotrophins NGF, BDNF, and NT3/4 signal through their common receptor p75NTR. NGF binding to p75NTR activates a number of downstream signalling events controlling survival, death, proliferation, and axonogenesis, according to the cellular context. p75NTR is devoid of enzymatic activity, and signals by recruiting other proteins to its own intracellular domain. p75 interacting proteins include NRIF, TRAF2, 4, and 6, NRAGE, necdin, SC1, NADE, RhoA, Rac, ARMS, RIP2, FAP and PLAIDD. Here we annotate only the proteins for which a clear involvement in p75NTR signalling was demonstrated.<br>A peculiarity of p75NTR is the ability to bind the pro-neurotrophins proNGF and proBDNF. Proneurotrophins do not associate with TRK receptors, whereas they efficiently signal cell death by apoptosis through p75NTR. The biological action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activating p75NTR, mediating apoptosis, and mature forms activating TRK receptors, to promote survival. Moreover, the two receptors are utilised to differentially modulate neuronal plasticity. For instance, proBDNF-p75NTR signalling facilitates LTD, long term depression, in the hippocampus (Woo NH, et al, 2005), while BDNF-TRKB signalling promotes LTP (long term potentiation). Many biological observations indicate a functional interaction between p75NTR and TRKA signaling pathways. <br> Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0048011 Pubmed12671646 Pubmed16025106 Pubmed16699811 Pubmed16939974 Reactome Database ID Release 43193704 Reactome, http://www.reactome.org ReactomeREACT_13776 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 NFG and proNGF binds to p75NTR Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0048011 Reactome Database ID Release 43205017 Reactome, http://www.reactome.org ReactomeREACT_13724 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 When the co-receptor sortilin is present at the cell surface, proNGF preferentially interacts with a p75NTR:sortilin complex. Thus, proNGF, which does not bind TRKA, discriminates between TRKA and p75NTR, in cells that express both receptors. The same is true for proBDNF. Pro-neurotrophin binding to p75NTR:sortilin activates an apoptotic cascade, which may be involved in cell death after injury, and in neurodegenerative diseases such as Alzheimer's dementia. Phosphorylation of L1 by EPHB2 Authored: Garapati, P V, 2008-07-30 10:22:58 EC Number: 2.7.10 EPH kinase Cek5/EPHB2 phosphorylates tyrosine residue in the cytoplasmic domain of NgCAM/L1. The tyrosine 1229 may be the target site. EphrinB/EphB signaling enhances L1-dependent adhesion to substrates including ALCAM and extracellular matrix proteins. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed18171935 Pubmed9089215 Reactome Database ID Release 43443817 Reactome, http://www.reactome.org ReactomeREACT_22193 Reviewed: Maness, PF, 2010-02-16 NRAGE signals death through JNK Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0006915 Once bound by either NGF or proNGF, p75NTR interacts with NRAGE, thus leading to phosphorylation and activation of JUN Kinase (JNK). JNK controls apoptosis in two ways: it induces transcription of pro-apoptotic genes, and directly activates the cell death machinery. Only NGF-bound p75NTR is shown here. Pubmed12376548 Reactome Database ID Release 43193648 Reactome, http://www.reactome.org ReactomeREACT_13638 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Heat-Stable Antigen binds L1 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Heat-stable antigen (HSA/mouse CD24) is expressed in both haematopoietic and neural cells. HSA binds to L1CAM and mediate cell adhesion and intracellular Ca2+ signals in neurons and B lymphoblasts. Reactome Database ID Release 43437234 Reactome, http://www.reactome.org ReactomeREACT_22333 Reviewed: Maness, PF, 2010-02-16 has a Stoichiometric coefficient of 5 Cell death signalling via NRAGE, NRIF and NADE Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0008624 Pubmed12787561 Reactome Database ID Release 43204998 Reactome, http://www.reactome.org ReactomeREACT_13720 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 p75NTR is a key regulator of neuronal apoptosis, both during development and after injury. Apoptosis is triggered by binding of either mature neurotrophin or proneurotrophin (proNGF, proBDNF). ProNGF is at least 10 times more potent than mature NGF in inducing apoptosis. TRKA signalling protects neurons from apoptosis. The molecular mechanisms involved in p75NTR-apoptosis are not well understood. The death signalling requires activation of c-JUN N-terminal Kinase (JNK), as well as transcriptional events. JNK activation appears to involve the receptor interacting proteins TRAF6, NRAGE, and Rac. The transcription events are thought to be regulated by another p75-interacting protein, NRIF. Two other p75-interacting proteins, NADE and Necdin, have been implicated in apoptosis, but their role is less clear. CHL1 interacts with Hsc70 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 Hsc70 binds to the intracellular domain of CHL1. This interaction is dependent on ADP. CHL1 accumulates in the presynaptic plasma membrane and recruits Hsc70 for clathrin uncoating. Pubmed17178404 Reactome Database ID Release 43445087 Reactome, http://www.reactome.org ReactomeREACT_22427 Reviewed: Maness, PF, 2010-02-16 NADE modulates death signalling Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0006915 NADE protein (p75NTR-associated cell death executor) may induce cell death upon NGF binding, but not BDNF, NT3, or NT4/5 binding, to p75NTR. The NADE-dependent apoptosis is modulated by the 14-3-3-epsilon protein (Kimura MT et al, 2001). Pubmed11278287 Reactome Database ID Release 43205025 Reactome, http://www.reactome.org ReactomeREACT_13526 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 CHL1 interacts with Ankyrin-G Authored: Garapati, P V, 2008-07-30 10:22:58 CHL1 associates with the sub-membranous actin cytoskeleton through a motif for binding the spectrin adaptor protein ankyrin in the cytoplasmic domain (F1181IGAY), which is somewhat different from L1 (F1224IGQY). Edited: Garapati, P V, 2008-07-30 10:22:58 Reactome Database ID Release 43447034 Reactome, http://www.reactome.org ReactomeREACT_22392 Reviewed: Maness, PF, 2010-02-16 NRIF signals cell death from the nucleus Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0006915 NRIF (nuclear receptor-interacting factor) is a DNA binding protein that is essential for p75-mediated apoptosis in retina and sympathetic neurons. Neurotrophin or proneurotrophin binding to p75TR induces nuclear translocation of NRIF, which involves gamma-secretase cleavage of p75NTR ICD (Intra Cellular Domain). Once in the nucleus, NRIF mediates apoptosis, probably by acting as transcription factor. Pubmed15721744 Reactome Database ID Release 43205043 Reactome, http://www.reactome.org ReactomeREACT_13643 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 Cis-heterodimerization of L1 and Contactin-1/F3/F11 Authored: Garapati, P V, 2008-07-30 10:22:58 By analogy to the well-studied chicken system, L1 heterophilically binds to F3/F11/Contactin-1 in cis manner via an L1-binding site resides in the first two immunoglobulin-like domains of Contactin-1. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed7682821 Reactome Database ID Release 43443784 Reactome, http://www.reactome.org ReactomeREACT_22321 Reviewed: Maness, PF, 2010-02-16 p75NTR signals via NF-kB Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0006916 Pubmed16997282 Reactome Database ID Release 43193639 Reactome, http://www.reactome.org ReactomeREACT_13537 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 The NF-kB pathway is an important pro-survival signalling pathway activated by mature NGF, but not BDNF or NT-3, through p75NTR. It is unclear whether TRKA activity also affects NF-kB activation. Cis-heterodimerization of L1 and Axonin-1 Authored: Garapati, P V, 2008-07-30 10:22:58 By analogy to the well-studied chicken system, L1 can be coexpressed with axonin-1 (TAG-1/Contactin-2) on same growth cone membrane and the two proteins form a cis-heterodimer required for neurite growth. Edited: Garapati, P V, 2008-07-30 10:22:58 Reactome Database ID Release 43374672 Reactome, http://www.reactome.org ReactomeREACT_22277 Reviewed: Maness, PF, 2010-02-16 p75NTR negatively regulates cell cycle via SC1 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 GENE ONTOLOGYGO:0045786 Pubmed12371150 Reactome Database ID Release 43193670 Reactome, http://www.reactome.org ReactomeREACT_13695 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 SC1 (Schwann Cell factor 1; also called PR domain zinc finger protein 4, PRDM4) interacts with an NGF:p75NTR complex and signals cell cycle arrest by regulating the levels of cyclin E. L1 binds RanBPM Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 L1 and RanBPM interact with one another and the N-terminus of RanBPM was sufficient for the interaction with L1. RanBPM interacts with RAN, a Ras-like small GTPase that functions as a carrier in nuclear-cytoplasmic exchange. It directly interacts with Sos to activate Ras and induce ERK phosphorylation. RanBPM might function as an adaptor to mediate L1-induced ERK activation. Pubmed16000162 Reactome Database ID Release 43374673 Reactome, http://www.reactome.org ReactomeREACT_22215 Reviewed: Maness, PF, 2010-02-16 Cis-heterodimerization of L1 and DM-GRASP/ALCAM/BEN Authored: Garapati, P V, 2008-07-30 10:22:58 DM GRASP/ALCAM/BEN is one of the heterodimerizing partners for L1/NgCAM. Interation between L1/NgCAM and DM GRASP in the growth cone membrane is involved in L1 stimulated neurite outgrowth. Trans binding of L1 on retinal growth cones to ALCAM on the superior colliculus potentiates adhesion, leading to correct synaptic targeting. Edited: Garapati, P V, 2008-07-30 10:22:58 Pubmed20016077 Pubmed8636239 Reactome Database ID Release 43443780 Reactome, http://www.reactome.org ReactomeREACT_22130 Reviewed: Maness, PF, 2010-02-16 p75NTR recruits signalling complexes Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2008-05-20 12:26:36 NF-kB activation involves recruitment at the cell membrane of several proteins such as RIP2, MYD88, IRAK1, TRAF6, p62 and atypical PKC by the NGF:p75NTR complex. Reactome Database ID Release 43209543 Reactome, http://www.reactome.org ReactomeREACT_13415 Reviewed: Chao, MV, 2008-05-28 09:46:01 Reviewed: Friedman, WJ, 2008-05-20 12:23:46 UNC-5 binds Netrin-1 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed15960985 Reactome Database ID Release 43373751 Reactome, http://www.reactome.org ReactomeREACT_22366 Reviewed: Cooper, HM, 2010-02-16 UNC-5 receptors interact with netrins and mediate the short-range repulsion signal. The extracellular Ig domains of Unc5 bind netrin. Downstream signal transduction Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Pubmed10508235 Pubmed1374684 Pubmed9739761 Reactome Database ID Release 43186763 Reactome, http://www.reactome.org ReactomeREACT_17025 Reviewed: Heldin, CH, 2008-11-23 19:29:34 The role of autophosphorylation sites on PDGF receptors are to provide docking sites for downstream signal transduction molecules which contain SH2 domains. The SH2 domain is a conserved motif of around 100 amino acids that can bind a phosphorylated tyrosine residue. These downstream molecules are activated upon binding to, or phosphorylated by, the receptor kinases intrinsic to PDGF receptors.<br>Some of the dowstream molecules are themselves enzymes, such as phosphatidylinositol 3'-kinase (PI3K), phospholipase C (PLC-gamma), the Src family of tyrosine kinases, the tyrosine phosphatase SHP2, and a GTPase activating protein (GAP) for Ras. Others such as Grb2 are adaptor molecules which link the receptor with downstream catalytic molecules. Recruitment of ABLIM to the plasma membrane Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed12526772 Pubmed15923631 Pubmed15960985 Reactome Database ID Release 43418865 Reactome, http://www.reactome.org ReactomeREACT_22398 Reviewed: Cooper, HM, 2010-02-16 Unc-115/AbLIM is a key regulator of lamellipodia and filopodia in the growth cone during axon pathfinding and acts downstream of Rac GTPase signaling. It acts as a scaffold to recruit other actin-modulating complexes involved in lamellipodia and filopodia. Unc-115/AbLIM is locally recruited to the plasma membrane by activated Rac1 and subsequently dephosphorylated on serine 617. Dephosphorylated Unc-115/AbLIM then might interact with other molecules at the plasma membrane to induce formation of lamellipodia and filopodia by reorganization of the actin cytoskeleton. Signaling by PDGF Authored: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Edited: Garapati, P V, Jassal, B, 2008-11-24 10:14:27 Platelet-derived Growth Factor (PDGF) is a potent stimulator of growth and motility of connective tissue cells such as fibroblasts and smooth muscle cells as well as other cells such as capillary endothelial cells and neurons.The PDGF family of growth factors is composed of four different polypeptide chains encoded by four different genes. The classical PDGF chains, PDGF-A and PDGF-B, and more recently discovered PDGF-C and PDGF-D. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. It is notable that no heterodimers involving PDGF-C and PDGF-D chains have been described. PDGF exerts its effects by binding to, and activating, two protein tyrosine kinase (PTK) receptors, alpha and beta. These receptors dimerize and undergo autophosphorylation. The phosphorylation sites then attract downstream effectors to transduct the signal into the cell. Pubmed10508235 Pubmed15207811 Pubmed9739761 Reactome Database ID Release 43186797 Reactome, http://www.reactome.org ReactomeREACT_16888 Reviewed: Heldin, CH, 2008-11-23 19:29:34 Recruitment and activation of N-WASP by Cdc42 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed10995436 Pubmed15040784 Reactome Database ID Release 43418874 Reactome, http://www.reactome.org ReactomeREACT_22183 Reviewed: Cooper, HM, 2010-02-16 The adaptor protein Nck-1 binds to DCC and recruits Rac-1, Cdc42 and their effectors PAK-1 and N-WASP to the activated receptor. Both Cdc42 and Nck-1 are activators of N-WASP. Cdc42 in its active GTP bound form binds to the CRIB domain of N-WASP and this interaction along with PIP2 results in the activation of N-WASP. Nck-1 activate N-WASP via binding of its SH3 domain to the proline rich domain of N-WASP. Nck-1 also possess an SH2 domain that associates directly with activated tyrosine kinase receptors which can phosphorylate N-WASP. Nuclear Events (kinase and transcription factor activation) An important function of the kinase cascade triggered by neurotrophins is to induce the phosphorylation and activation of transcription factors in the nucleus to initiate new programs of gene expression. Transcription factors directly activated by neurotrophin signalling are responsible for induction of immediate-early genes, many of which are transcription factors. These in turn are involved in the induction of delayed-early genes. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Pubmed8833451 Reactome Database ID Release 43198725 Reactome, http://www.reactome.org ReactomeREACT_12433 Reviewed: Greene, LA, 2007-11-08 15:39:37 Activation of Rac1 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed18066058 Pubmed18212043 Reactome Database ID Release 43418856 Reactome, http://www.reactome.org ReactomeREACT_22200 Reviewed: Cooper, HM, 2010-02-16 Rho GEF's DOCK180 and Trio directly associate with DCC, activate Rac-1 on DCC stimulation and cause cell spreading. Retrograde neurotrophin signalling Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Neurotrophin-TRK complexes can be internalized and enter signalling vesicles, which travel retrogradely over long distances from distal nerve terminals to neuronal cell bodies. Such retrograde signalling by neurotrophin-TRK complexes regulates survival, synaptogenesis and maintenance of proper neural connectivity. The neurotrophin-TRK complex may use three distinct internalization pathways. Although Clathrin-mediated endocytosys appears to be the major internalization route, it is controversial whether it also represents the dominant pathway for retrograde transport and signalling. Pyncher-mediated endocytosis might be more relevant in this regard. Moreover, also caveolin-mediated endocytosis may play a role in NGF-TrkA internalization.<br>Retrograde transport of TRKs is microtubule-dependent: TRKs remain activated and bound to neurotrophins during retrograde transport. The current view is reflected in the signalling endosome model. It is a specialized vesicle containing ligand (NGF, BDNF) bound to its activated TRK receptor, together with activated downstream signalling proteins, transported by motor proteins (dyneins) from nerve terminals to remote cell bodies, where the receptors trigger signalling cascades. Reactome Database ID Release 43177504 Reactome, http://www.reactome.org ReactomeREACT_12435 Reviewed: Greene, LA, 2007-11-08 15:39:37 DCC interaction with ROBO-1 Authored: Garapati, P V, 2008-09-05 06:02:05 DCC and Robo1 heterodimerize via conserved sequence elements in their cytoplasmic domains, namely CC1 (conserved cytoplasmic region1) in Robo1 and P3 in DCC. The formation of this complex is dependent on the previous interaction between Robo and its ligand (Slit). This physical interaction between Robo Slit and DCC silences the attractive effect of Netrin DCC and regulates the midline crossing of axons.<br>From the analysis of multiple double mutant combinations of the Robo Slit and Netrin DCC receptors it was deduced that Robo repulsion on its own is sufficient to prevent commissural axons from recrossing the midline, and that Netrin DCC is not the only source of attraction at the midline.<br> Edited: Garapati, P V, 2008-07-30 10:24:23 Edited: Garapati, P V, 2008-09-05 06:02:05 Reactome Database ID Release 43373715 Reactome, http://www.reactome.org ReactomeREACT_22316 Reviewed: Cooper, HM, 2010-02-16 Signalling to ERK5 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Reactome Database ID Release 43198765 Reactome, http://www.reactome.org ReactomeREACT_12020 Reviewed: Greene, LA, 2007-11-08 15:39:37 The location of neurotrophin stimulation appears to determine the nature of the transcriptional response through differential uses of individual MAP kinases. The ERK5 pathway has a unique function in retrograde signalling; in contrast, ERK1/2, which mediate nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Following neurotrophin stimulation of distal axons, phosphorylated TRK receptors are endocytosed and transported to the cell bodies, where MEK5 phosphorylates ERK5, leading to ERK5 nuclear translocation, phosphorylation of transcription factors, and neuronal survival. In contrast, neurotrophin stimulation of the cell bodies causes concurrent activation and nuclear transport of ERK1/2 as well as ERK5. Several distinctive features of the ERK5 pathway might be important for retrograde signalling. The ERK5 cascade does not depend on activation of the G-protein RAS. Instead, this pathway may use other G-proteins such as RAP that are associated with vesicles, or may not require any G-protein intermediate. Another distinctive feature is that the MEK5 isoform, which is expressed in the nervous system, exhibits a punctate staining pattern, suggesting a vesicular localization. ERK5 itself significantly differs from ERK1/2, and its substrate specificity also differs from ERK1/2. For instance, ERK5 directly activates transcription factors, including MEF2, that are not phosphorylated by ERK1/2. Conversely, ERK1/2, but not ERK5, activate transcription factors such as ELK1 and MITF. Shp2 binds pUnc5C Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11533026 Reactome Database ID Release 43418863 Reactome, http://www.reactome.org ReactomeREACT_22338 Reviewed: Cooper, HM, 2010-02-16 Shp2 is recruited to the phosphorylated Unc5C receptor after netrin stimulation, in a fashion that requires binding of the Shp2 SH2 domains to the Tyr568 phosphorylated motif. The functional significance of the Unc5C-shp2 interaction has not been reported .Shp2 might negatively regulate tyrosine phosphorylation of Unc5C receptor, facilitating resensitization of the receptor to the netrin signal. Signalling to STAT3 Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Neurotrophin-induced increase in Signal transducer and activator of transcription 3 (STAT3; acute-phase response factor) activation appears to underly several downstream functions of neurotrophin signalling, such as transcription of immediate early genes, proliferation arrest, and neurite outgrowth. Reactome Database ID Release 43198745 Reactome, http://www.reactome.org ReactomeREACT_12049 Reviewed: Greene, LA, 2007-11-08 15:39:37 Phosphorylation of Unc5C Authored: Garapati, P V, 2008-07-16 14:42:16 EC Number: 2.7.10 Edited: Garapati, P V, 2008-07-30 10:24:23 Multiple sites on Unc5c are phosphorylated after netrin-1 stimulation. An activated Src tyrosine kinase induces phosphorylation of Unc5c at multiple cytoplasmic tyrosine residues including highly-conserved residues 449, 454, 568, 649 and 667. Phosphorylation of these residues creates potential binding sites for cytoplasmic signaling proteins. Pubmed11533026 Pubmed16371650 Reactome Database ID Release 43418859 Reactome, http://www.reactome.org ReactomeREACT_22174 Reviewed: Cooper, HM, 2010-02-16 DCC heterodimerizes with UNC-5:Netrin-1 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed15960985 Reactome Database ID Release 43373713 Reactome, http://www.reactome.org ReactomeREACT_22173 Reviewed: Cooper, HM, 2010-02-16 UNC-5 uses DCC as a co-receptor and binds to the DCC P1 domain with its DB domain to repel axons at low netrin concentration. It is generally thought that UNC5 receptor alone transduces short range signals whereas DCC-Unc5 complex transduces long range signals important for neuron migration, neurite growth and axon repulsion. PAPP-A2 Converted from EntitySet in Reactome Reactome DB_ID: 381431 Reactome Database ID Release 43381431 Reactome, http://www.reactome.org ReactomeREACT_15600 DCC interaction with SIAH1 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed9858595 Reactome Database ID Release 43374665 Reactome, http://www.reactome.org ReactomeREACT_22137 Reviewed: Cooper, HM, 2010-02-16 Siah-1 binds DCC and promotes its proteolysis via the ubiquitin-proteasome pathway. Siah-1 contains an N-terminal RING domain that is involved in proteolysis function and a C-terminal sequence that is involved in its oligomerization and binding to target proteins, such as DCC. VEGF binds to VEGFR leading to receptor dimerization Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 Pubmed13678960 Pubmed15585754 Pubmed16633338 Pubmed16835467 Reactome Database ID Release 43195399 Reactome, http://www.reactome.org ReactomeREACT_12583 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 The binding of VEGF ligands to VEGFR receptors in the cell membrane induces dimerization and activation of the latter, initiating intracellular signaling cascades that result in proliferation, survival, migration and increased permeability of vascular endothelial cells (Matsumoto and Mugishima, 2006). The receptors predominantly form homodimers but heterodimers between VEGFR-1 and -2 have been observed. Although both VEGFR-1 and -2 are expressed in the vascular endothelium, the angiogenic activities of VEGFs are transduced mainly through VEGFR-2 in vivo. Activation of Cdc42 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed11817894 Pubmed15788770 Reactome Database ID Release 43418850 Reactome, http://www.reactome.org ReactomeREACT_22281 Reviewed: Cooper, HM, 2010-02-16 RhoGEF complexed with Netrin-1-DCC induces guanine nucleotide exchange by Cdc42, activating it. Activated Cdc42 activates N-WASP, which promotes the nucleation of F-actin via the Arp2/3 complex. Netrin-1, via DCC, influences cellular motility by regulating actin-based membrane extension through the activation of Cdc42. Neurophilin interactions with VEGF and VEGFR Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 Pubmed12613545 Reactome Database ID Release 43194306 Reactome, http://www.reactome.org ReactomeREACT_12473 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 The plasma membrane-associated Neuropilin receptors NRP-1 and -2 bind some of the VEGF proteins and associate with VEGF receptor proteins. NRP-1 binds VEGF-A165, -B, and PLGF-2; NRP-2 also binds VEGF-A165 and PLGF-2, as well as VEGF-A145 and -C. The Neurolipin receptors appear to act as cofactors for the VEGF receptors, increasing their affinities for specific VEGF ligands, although the importance of this function in vivo remains unclear (Neufeld et al. 2002). Detailed annotation of NRP interactions with VEGF proteins will be covered in future releases. Signaling by VEGF Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 GENE ONTOLOGYGO:0048010 In normal development vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development during embryogenesis (vasculogenesis) and blood-vessel formation in the adult (angiogenesis). In tumor progression, activation of VEGF pathways promotes tumor vascularization, facilitating tumor growth and metastasis. Abnormal VEGF function is also associated with inflammatory diseases including atherosclerosis, and hyperthyroidism. The members of the VEGF and VEGF-receptor protein families have distinct but overlapping ligand-receptor specificities, cell-type expression, and function. VEGF-receptor activation in turn regulates a network of signaling processes in the body that promote endothelial cell growth, migration and survival (Hicklin and Ellis, 2005; Shibuya and Claesson-Welsh, 2006).<br>Molecular features of the VGF signaling cascades are outlined in the figure below (from Olsson et al. 2006; Nature Publishing Group). Tyrosine residues in the intracellular domains of VEGF receptors 1, 2,and 3 are indicated by dark blue boxes; residues susceptible to phosphorylation are numbered. A circled R indicates that phosphorylation is regulated by cell state (VEGFR2), by ligand binding (VEGFR1), or by heterodimerization (VEGFR3). Specific phosphorylation sites (boxed numbers) bind signaling molecules (dark blue ovals), whose interaction with other cytosolic signaling molecules (light blue ovals) leads to specific cellular (pale blue boxes) and tissue-level (pink boxes) responses in vivo. Signaling cascades whose molecular details are unclear are indicated by dashed arrows. DAG, diacylglycerol; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; FAK, focal adhesion kinase; HPC, hematopoietic progenitor cell; HSP27, heat-shock protein-27; MAPK, mitogen-activated protein kinase; MEK, MAPK and ERK kinase; PI3K, phosphatidylinositol 3' kinase; PKC, protein kinase C; PLCgamma, phospholipase C-gamma; Shb, SH2 and beta-cells; TSAd, T-cell-specific adaptor.<br>In the current release, the first events in these cascades - the interactions between VEGF proteins and their receptors - are annotated. Details of signaling events and their biological outcome, concisely illustrated in the image below, will be available in future versions of this pathway. Pubmed13678960 Pubmed15585754 Pubmed16336962 Pubmed16633338 Pubmed16835467 Reactome Database ID Release 43194138 Reactome, http://www.reactome.org ReactomeREACT_12529 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 Signaling by Vascular Epithelial Growth Factors (VEGF) VEGF ligand-receptor interactions Authored: Krupa, S, Gopinathrao, G, 2007-03-08 22:07:59 Edited: Gopinathrao, G, 2007-04-08 21:14:18 GENE ONTOLOGYGO:0048010 Pubmed12613545 Pubmed13678960 Pubmed15585754 Pubmed16336962 Pubmed16633338 Pubmed16835467 Pubmed17002866 Reactome Database ID Release 43194313 Reactome, http://www.reactome.org ReactomeREACT_12380 Reviewed: Claesson-Welsh, L, 2008-02-28 00:15:17 The VEGF family is encoded by seven genes (VEGF-A, B, C, D, E: PLGF (Placenta Growth Factor)-1, 2). Six isoforms of VEGF-A protein, containing 121, 145, 165, 183, 189, and 206 amino acid residues, and two isoforms of VEGF-B (167 and 186 residues) are specified by alternatively spliced mRNAs. The active form of each of these proteins is a homodimer.<br>The specificities of the three VEGF tyrosine kinase receptors, VEGFR-1, VEGFR-2 and VEGFR-3, for these ligands are shown in the figure (Hicklin and Ellis 2005). All VEGF-A isoforms bind both VEGFR-1 and VEGFR-2; PLGF-1 and -2, and VEGF-B isoforms bind only VEGFR-1; VEGF-E binds VEGFR-2; and VEGF-C and -D bind both VEGFR-2 and -3. VEGF-D undergoes a complex series of post-translational modifications that results in secreted forms with increased activity toward VEGFR-3 and VEGFR-2. <br>Two co-receptor proteins in the cell membrane, neuropilin (NRP)-1 and NRP-2, interact with VEGFR proteins to increase the affinity of the latter for their ligands (Neufeld et al.,2002). They differ from VEGFR proteins in not having intracellular signaling domains. DCC interaction with Ezrin Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Phosphorylated Ezrin can link in microfilaments to the plasma membrane by direct association with transmembrane proteins such as the cytoplasmic domain of DCC. Pubmed12154370 Pubmed16762451 Reactome Database ID Release 43374663 Reactome, http://www.reactome.org ReactomeREACT_22317 Reviewed: Cooper, HM, 2010-02-16 Feedback control in the MAPK signaling module Pubmed17310240 Reactome Database ID Release 43197529 Reactome, http://www.reactome.org ReactomeREACT_22434 The RAF/MEK/ERK network topology underlies ERK dynamics, which is believed to be a major cause of the diversity in cellular response to stimulation of different growth factor receptors. Topological differences exist in such networks, dependent on whether cells are activated with EGF or NGF. On EGF stimulation, the network exhibits negative feedback only whereas a positive feedback is apparent on NGF stimulation. The latter confers stability to ERK activation, thereby governing differentiation (in PC12 cells) upon stimulation with NGF, but not EGF (Santos S.D. et al, 2007). The negative feedback observed on EGF stimulation controls the transient activation of ERK1/2, and is mediated by ERK1/2 down regulation of SOS. The positive feedback observed on NGF stimulation involves PKC, mainly PKC-delta, which acts upstream of the MAPK module, the RAF kinase inhibitory protein RKIP, and ERK, which phosphorylates RAF, increasing its activity. Phosphorylation and activation of Ezrin Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 PIP2 places Ezrin at the membrane in a location to be phosphorylated, and thereby activated, by protein kinase-C theta. Pubmed12154370 Reactome Database ID Release 43374664 Reactome, http://www.reactome.org ReactomeREACT_22301 Reviewed: Cooper, HM, 2010-02-16 Signalling to RAS Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0007265 Pubmed11520933 Reactome Database ID Release 43167044 Reactome, http://www.reactome.org ReactomeREACT_12033 Reviewed: Greene, LA, 2007-11-08 15:39:37 Signalling through Shc adaptor proteins appears to be identical for both NGF and EGF. It leads to a fast, but transient, MAPK/ERK activation, which is insufficient to explain the prolonged activation of MAPK found in NGF-treated cells. Neogenin binds Netrin-1 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Netrin-1 is not only involved as an axon guidance cue during the development of nervous system but is also involved in the morphogenesis of the mammary glands. Netrin-1 acts as a short-range attractant and has an adhesive, rather than a guidance, function during mammary gland morphogenesis. In the developing mammary gland, netrin-1 acts locally through neogenin to maintain close apposition of cap cells and prelumenal cells at the leading edge of the TEB (Terminal end bud). Pubmed12636918 Reactome Database ID Release 43374689 Reactome, http://www.reactome.org ReactomeREACT_22189 Reviewed: Cooper, HM, 2010-02-16 Signalling to p38 via RIT and RIN Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0007264 Pubmed10712923 RIT and RIN are two small guanine nucleotide binding proteins that share more than 50% sequence identity with RAS, including highly conserved core effector domains. Unlike RAS, the C termini of RIT and RIN lack a typical prenylation motif (CAAX, XXCC, or CXC) required for the association of RAS proteins with the plasma membrane. RIT is expressed in all tissues, whereas RIN is neuron-specific. They have similar signalling properties and are activated by NGF through unknown exchange factors. They signal to ERKs and p38 MAP kinase. They mainly lead to p38 activation via the BRAF-MEK kinase cascade. Reactome Database ID Release 43187706 Reactome, http://www.reactome.org ReactomeREACT_12077 Reviewed: Greene, LA, 2007-11-08 15:39:37 Netrin-4 binds DCC/UNC5A Authored: Garapati, P V, 2010-04-13 DCC and UNC5A, are also receptors for Netrin-4. The LNT domain of Netrin-4 is the key domain for this specific binding. Netrin-4 might also mediate attractive action through DCC and repulsive action through UNC5A. Edited: Garapati, P V, 2010-04-13 Pubmed17174565 Reactome Database ID Release 43593685 Reactome, http://www.reactome.org ReactomeREACT_22282 Reviewed: Cooper, HM, 2010-02-16 p38MAPK events Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 NGF induces sustained activation of p38, a member of the MAPK family (Morooka T, Nishida E, 1998). Both p38 and the ERKs appear to be involved in neurite outgrowth and differentiation caused by NGF in PC12 cells. As a matter of fact, PC12 cell differentiation appears to involve activation of both ERK/MAPK and p38. Both ERK/MAPK and p38 pathways contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes (Xing J, 1998). p38 activation by NGF may occur by at least two mechanisms, involving SRC or MEK kinases. Pubmed9297626 Pubmed9528766 Pubmed9733710 Reactome Database ID Release 43171007 Reactome, http://www.reactome.org ReactomeREACT_12065 Reviewed: Greene, LA, 2007-11-08 15:39:37 Myosin-X binds DCC/Neogenin Authored: Garapati, P V, 2010-04-13 Edited: Garapati, P V, 2010-04-13 Myosin-X, an unconventional myosin implicated in cell adhesion and filopodia elongation interacts with DCC and Neogenin and helps in their distribution in neurites. Myosin-X functions to transfer cargo proteins into filopodia and its hypothesized that Myosin-X may deliver DCC to filopodia on Netrin-1 stimulation. Pubmed17237772 Reactome Database ID Release 43593672 Reactome, http://www.reactome.org ReactomeREACT_22102 Reviewed: Cooper, HM, 2010-02-16 Neogenin binds repulsive guidance molecules (RGDs) Among netrin1 receptors neogenin is the only protein to interact with the repulsive guidance molecules (RGM). RGMs are membrane bound proteins involved in axon guidance in the visual system. Neogenin is the dependence receptor and cleaved by activated caspase-3 to trigger apoptotic cell death. RGM binding blocks the cleavage of neogenin so RGM functions as a cell survival factor. Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed15258591 Pubmed15610137 Reactome Database ID Release 43374692 Reactome, http://www.reactome.org ReactomeREACT_22132 Reviewed: Cooper, HM, 2010-02-16 PITPalpha binds DCC Authored: Garapati, P V, 2009-04-27 09:27:02 DCC interacts directly with PITPalpha and this interaction is enhanced in the presence of Netrin-1. The interaction of DCC with PITPalpha requires the carboxy-terminal dmain of both the proteins. PITPalpha signaling pathway is important for netrin-1 mediated axon outgrowth. Netrin-1 activates PITPalpha to regulate local phosphoinositide (PI) synthesis, which is important for PI3K dependent neurite elongation. Edited: Garapati, P V, 2009-04-27 09:27:02 Pubmed16244667 Pubmed16321979 Reactome Database ID Release 43418866 Reactome, http://www.reactome.org ReactomeREACT_22377 Reviewed: Cooper, HM, 2010-02-16 Signalling to ERKs Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Neurotrophins utilize multiple pathways to activate ERKs (ERK1 and ERK2), a subgroup of the large MAP kinase (MAPK) family, from the plasma membrane. The major signalling pathways to ERKs are via RAS, ocurring from caveolae in the plasma membrane or from clathrin-coated vesicles, and via RAP1, taking place in early endosomes. Whereas RAS activation by NGF is transient, RAP1 activation by NGF is sustained for hours. Pubmed10508738 Reactome Database ID Release 43187687 Reactome, http://www.reactome.org ReactomeREACT_12058 Reviewed: Greene, LA, 2007-11-08 15:39:37 PIKE-L interaction with UNC5B Authored: Garapati, P V, 2010-04-13 Edited: Garapati, P V, 2010-04-13 PIKE-L a brain-specific GTPase selectively associates with UNC5B but not with other family members of UNC5. Netrin-1 enhances this interaction and this interaction triggers the activation of PI3K kinase signalling, prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. Pubmed18469807 Reactome Database ID Release 43622357 Reactome, http://www.reactome.org ReactomeREACT_22414 Reviewed: Cooper, HM, 2010-02-16 MMP-1 and MMP-2 Converted from EntitySet in Reactome Reactome DB_ID: 381470 Reactome Database ID Release 43381470 Reactome, http://www.reactome.org ReactomeREACT_15989 PI3K/AKT activation Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 GENE ONTOLOGYGO:0048015 PI3K/AKT signalling is a major regulator of neuron survival. It blocks cell death by both impinging on the cytoplasmic cell death machinery and by regulating the expression of genes involved in cell death and survival. In addition, it may also use metabolic pathways to regulate cell survival.The PI3K/AKT pathway also affects axon diameter and branching (Marcus et al, 2002) and regulates small G proteins like RhoA (Vanhaesebroeck, B and Waterman, MD, 1999), which control the behaviour of the F-actin cytoskeleton. Moreover, through its connection with the TOR pathway, it promotes translation of a subset of mRNAs. Pubmed10579926 Pubmed12123609 Reactome Database ID Release 43198203 Reactome, http://www.reactome.org ReactomeREACT_12464 Reviewed: Greene, LA, 2007-11-08 15:39:37 Prolonged ERK activation events After NGF binding, activated Trk receptors provide multiple docking sites for adaptor proteins and enzymes. Two docking proteins, the Ankyrin-Rich Membrane Spanning protein (ARMS/Kidins220) and Fibroblast growth factor receptor substrate 2 (Frs2), target signaling molecules in response to NGF stimulation and link receptor activation with the MAP kinase (also called the Extracellular signal-Regulated Kinase cascade, ERK) cascade, an essential process for growth factor-induced cell proliferation and differentiation.<br>A feature of NGF signaling is the sustained activation of the MAPK cascade. This is achieved by the small G protein, Rap1 which binds to and activates B-Raf, an activator of the MAPK cascade. Rap1 is a member of the Ras family of G proteins and like all G proteins, Rap1 is in an inactive state when bound to GDP and is active when bound to GTP. A specific GEF (guanine nucleotide exchange factor) called C3G can activate Rap1 by exchanging GDP for GTP. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0000186 Pubmed12765839 Pubmed9069267 Reactome Database ID Release 43169893 Reactome, http://www.reactome.org ReactomeREACT_12005 Reviewed: Greene, LA, 2007-11-08 15:39:37 Frs2-mediated activation Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed9069267 Reactome Database ID Release 43170968 Reactome, http://www.reactome.org ReactomeREACT_12076 Reviewed: Greene, LA, 2007-11-08 15:39:37 The adaptor protein Frs2 (Fibroblast growth factor receptor substrate 2) can mediate the prolonged activation of the MAPK (ERK) cascade. DCC interaction with SIAH2 Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Pubmed9858595 Reactome Database ID Release 43374667 Reactome, http://www.reactome.org ReactomeREACT_22224 Reviewed: Cooper, HM, 2010-02-16 Siah-2 binds to the DCC protein and promote its proteolysis via the ubiquitin-proteasome pathway. ARMS-mediated activation ARMS (Ankyrin-Rich Membrane Spanning/Kidins 220) is a 220kD tetraspanning adaptor protein which becomes rapidly tyrosine phosphorylated by active Trk receptors. ARMS is another adaptor protein which is involved in the activation of Rap1 and the subsequent prolonged activation of the MAPK cascade. Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 Pubmed9069267 Reactome Database ID Release 43170984 Reactome, http://www.reactome.org ReactomeREACT_12002 Reviewed: Greene, LA, 2007-11-08 15:39:37 Translocation of Ezrin to plasma membrane Authored: Garapati, P V, 2008-07-16 14:42:16 Edited: Garapati, P V, 2008-07-30 10:24:23 Ezrin is a member of the ezrin/radixin/moesin (ERM) family that acts as a linker between the plasma membrane and the actin cytoskeleton. Ezrin exists in a dormant, monomeric form in which its FERM/NERMAD and C-ERMAD domains are associated, masking membrane and F-actin binding regions. On production of PIP2, ezrin binds it, is recruited to the plasma membrane, and undergoes conformational changes unmasking the two binding sites. Pubmed12154370 Reactome Database ID Release 43374662 Reactome, http://www.reactome.org ReactomeREACT_22308 Reviewed: Cooper, HM, 2010-02-16 PLC-gamma1 signalling Authored: Nasi, S, Annibali, D, 2006-10-10 09:07:07 Edited: Jassal, B, 2006-10-10 09:20:18 GENE ONTOLOGYGO:0007202 Pubmed10579907 Pubmed12676795 Reactome Database ID Release 43167021 Reactome, http://www.reactome.org ReactomeREACT_12079 Reviewed: Greene, LA, 2007-11-08 15:39:37 The activation of phosphlipase C-gamma (PLC-gamma) and subsequent mobilization of calcium from intracellular stores are essential for neurotrophin secretion. PLC-gamma is activated through the phosphorylation by TrkA receptor kinase and this form hydrolyses PIP2 to generate inositol tris-phosphate (IP3) and diacylglycerol (DAG). IP3 promotes the release of Ca2+ from internal stores and this results in activation of enzymes such as protein kinase C and Ca2+ calmodulin-regulated protein kinases. SrGAP binds Robo1:Slit2 Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed11672528 Reactome Database ID Release 43376145 Reactome, http://www.reactome.org ReactomeREACT_19280 Reviewed: Kidd, T, 2009-08-18 The Robo1 receptor regulates Rho GTPase activity through a ligand-dependent association with members of a novel family of GAPs called srGAPs (slit-robo GAPs). Extracellular interaction between Slit and Robo increases the intracellular interaction between the CC3 motif of Robo1 and the SH3 motif of the SrGAPs. Recruitment of Profilin by Ena/Vasp proteins Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Ena/VASP proteins enhance actin filament elongation via the recruitment of profilin:actin complexes to the tips of spreading lamellipodia. Profilin binds to the central proline rich domain of Ena/VASP protein. Pubmed10892742 Reactome Database ID Release 43428534 Reactome, http://www.reactome.org ReactomeREACT_19293 Reviewed: Kidd, T, 2009-08-18 Ena/VASP binds Robo1:Slit2 complex Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Ena is required in part for Robo's repulsive output. Ena is drawn as an effector downstream of Robo signaling via a direct interaction with Robo. Robo's CC2 (LPPPP) motif is the consensus binding site for the EVH1 domain of Ena.<br>The Ena/VASP family of proteins has a universal role in control of cell motility and actin dynamics. These proteins consist of an N terminal EVH1 domain, a central proline rich region, which acts as a ligand for the actin monomer binding protein Profilin as well as several SH3 domain containing proteins including Abl and a C terminal EVH2 domain involved in oligomerization and F actin binding.<br> Pubmed10892742 Reactome Database ID Release 43376140 Reactome, http://www.reactome.org ReactomeREACT_19132 Reviewed: Kidd, T, 2009-08-18 Robo1 binds Slit2 Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed10102266 Pubmed10102268 Pubmed12508280 Pubmed17553100 Reactome Database ID Release 43204364 Reactome, http://www.reactome.org ReactomeREACT_19272 Reviewed: Kidd, T, 2009-08-18 The Slit family consists of three members that are all expressed in the ventral midline (floor plate) of the neural tube. Slit 1 is predominantly expressed in the nervous system whereas Slit 2 and 3 are also expressed outside the nervous system.<br>Slit proteins are the ligands for the Robo receptors. In humans there are four robo genes: Robo1, 2, 3 and 4. The extracellular domain of Robo comprises five Ig domains and three Fn domains except for Robo4 (2Ig+2Fn). Ig1 and Ig2 domains of Robo are highly conserved and are important for Slit binding. The concave face of slit's second LRR domain accommodates the Robo's Ig1 and 2 domains. Slit binding with Robo4 is controversial as the interaction is weak and its been observed using the in-vitro methods.<br> Glypican-1 binds Slit2 Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed11375980 Pubmed15063764 Reactome Database ID Release 43428518 Reactome, http://www.reactome.org ReactomeREACT_19262 Reviewed: Kidd, T, 2009-08-18 Slit 2 and both its natural cleavage products bind glypican 1, a glycosyl phosphatidyl inositol (GPI) anchored heparan sulfate proteoglycan (HSPG) through its C terminus. Glypican 1 HSPG is important for high affinity binding of Slit to its receptor and for the repulsive activity of Slit. Slit-Robo signaling strictly requires binding to heparan sulfate. HSPGs may also modulate the extracellular distribution or stability of Slit proteins. Robo3 antagonizes Robo1/Robo2 to allow floor plate crossing Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed10102266 Pubmed18466743 Reactome Database ID Release 43428510 Reactome, http://www.reactome.org ReactomeREACT_19205 Reviewed: Kidd, T, 2009-08-18 Robo3 antagonizes Robo1/Robo2 function to prevent their response to slit, thus allowing cells that are expressing Robo1/Robo2 to progress towards and across the floor plate. Exactly how Robo3 interferes with Robo1/Robo2 function is not yet clear. One possibility is that one of the Robo3 isoform Robo3A.1 may sequester Robo1 into inactive receptor complexes. Robo3 in mouse and human have two isoforms, Robo3A.1 and Robo3A.2 with different Slit-binding activities. Both isoforms can form heterodimers with Robo1 and Robo2, but Robo3A.1 heterodimers cannot bind Slit, so this isoform may serve to sequester and inactivate Robo1. Proteolytic processing of Slit Authored: Garapati, P V, 2008-09-05 06:02:05 EC Number: 3.4 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed10102266 Pubmed10102268 Reactome Database ID Release 43376149 Reactome, http://www.reactome.org ReactomeREACT_19284 Reviewed: Kidd, T, 2009-08-18 The full length Slit proteins are membrane bound via the extracellular matrix proteins when not bound to Robo receptors. These full length Slits undergo post translational modification and proteolytic processing to generate an N terminal fragment (Slit2 N) and a corresponding C terminal fragment (Slit2 C). Slit 2 is cleaved within the EGF repeats, between EGF5 and EGF6, by unknown proteases. Cleavage of Slit proteins is evolutionarily conserved, although the molecular biological significance is unknown. The N-terminal fragment of Slit2 stimulates growth and branching of dorsal root ganglia (DRG) axons, and this activity is opposed by un-cleaved Slit. The stimulation of axon branching is mediated by Robo receptors. Additional functional differences between the full-length and N-terminal forms have been discovered in their abilities to repel different populations of axons and dendrites. Finally, Slit can attract migrating muscles in the fly, and also human endothelial cells, both via Robo receptors. PathwayStep3606 PathwayStep3607 PathwayStep3608 PathwayStep3609 PIP2 hydrolysis Authored: Garapati, P V, 2010-04-23 EC Number: 3.1.4.11 Edited: Garapati, P V, 2010-04-23 PIP2 hydrolysis appers to be an important mechanism for netrin-1 mediated neurite elongation. Netrin-1 alone could not elicit hydrolysis of PIP2 but depends on the stimulation of DCC and PLCgamma. Reactome Database ID Release 43622382 Reactome, http://www.reactome.org ReactomeREACT_22318 Reviewed: Cooper, HM, 2010-02-16 Activation of TRPC channels by Netrin-1 Authored: Garapati, P V, 2010-04-23 Edited: Garapati, P V, 2010-04-23 Netrin-1, through its activation of DCC, triggers TRPC channel mediating the Ca+2 influx that is required for the growth cone turning. The effect of netrin-1 on TRP currents in the neurons is studied in Xenopus. In cultured Xenopus spinal neurons, Netrin-1 evoked Ca+2 influx and a depolarizing, TRPC-like current in both soma and growth cones. Inhibition of the Xenopus homologue of mammalian TRPC1 (XTRPC1) prevented Ca+2 influx, TRPC-like current activation and the chemotropic turning of the growth cone in response to a gradient of Netrin-1.<br>Netrin-1 receptor signalling to TRPC channels is mediated via hydrolysis of PIP2 by PLCgamma which then activates TRPC channel activity through IP3 and DAG. Pubmed12857742 Pubmed18471901 Reactome Database ID Release 43622390 Reactome, http://www.reactome.org ReactomeREACT_22181 Reviewed: Cooper, HM, 2010-02-16 PathwayStep3600 PathwayStep3601 Phosphorylation of PLCgamma by Netrin-1 Authored: Garapati, P V, 2010-04-13 Edited: Garapati, P V, 2010-04-13 Netrin-1-DCC mediated signaling rapidly phosphorylates PLCgamma. Netrin-1 mediated PLC activation depends on recruitment of PITPalpha to DCC. Stimulation of PLC signaling and hydrolysis of PIP2 by netrin-1 in neurons is time-dependent, with a maximal activity observed within 15 min of netrin-1 stimulation. Pubmed16321979 Reactome Database ID Release 43593690 Reactome, http://www.reactome.org ReactomeREACT_22216 Reviewed: Cooper, HM, 2010-02-16 PathwayStep3602 PathwayStep3603 PathwayStep3604 PathwayStep3605 Activation of CLASP Authored: Garapati, P V, 2008-09-05 06:02:05 CLASP acts positively downstream of Abl as part of the repellent response initiated by activation of Robo1. CLASP is spatially positioned to interact with Robo receptors. Slit mediated repulsion results in activation of CLASP, presumably through its phosphorylation by the Abl kinase. Activation of CLASP in turn results in inhibition of microtubule polymerization on the side of the growth cone receiving the repulsive signal and consequently the growth cone turns to the opposite side. A direct link between Abl and CLASP, notably the mechanism of CLASP activation, has not been demonstrated, however. Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed12441051 Pubmed15207230 Pubmed15207236 Reactome Database ID Release 43428885 Reactome, http://www.reactome.org ReactomeREACT_19182 Reviewed: Kidd, T, 2009-08-18 Signaling by SCF-KIT Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed15526160 Pubmed16475976 Pubmed16483568 Pubmed17350321 Pubmed19540337 Pubmed2004790 Pubmed7688988 Reactome Database ID Release 431433557 Reactome, http://www.reactome.org ReactomeREACT_111040 Reviewed: Rönnstrand, L, 2011-08-22 Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Rönnstrand 2004, Lennartsson and Rönnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Rönnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Rönnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours. Phosphorylation of Rob1 by Abl kinase Abl kinase phosphorylates the tyrosine residue (1073) of the conserved CC1 motif (PTPYATT) in human Robo1. Authored: Garapati, P V, 2008-09-05 06:02:05 EC Number: 2.7.10 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed10892742 Reactome Database ID Release 43428888 Reactome, http://www.reactome.org ReactomeREACT_19227 Reviewed: Kidd, T, 2009-08-18 Signaling by ERBB2 Authored: Orlic-Milacic, M, 2011-11-04 ERBB2, also known as HER2 or NEU, is a receptor tyrosine kinase (RTK) belonging to the EGFR family. ERBB2 possesses an extracellular domain that does not bind any known ligand, contrary to other EGFR family members, a single transmembrane domain, and an intracellular domain consisting of an active kinase and a C-tail with multiple tyrosine phosphorylation sites. Inactive ERBB2 is associated with a chaperone heat shock protein 90 (HSP90) and its co-chaperone CDC37 (Xu et al. 2001, Citri et al. 2004, Xu et al. 2005). In addition, ERBB2 is associated with ERBB2IP (also known as ERBIN or LAP2), a protein responsible for proper localization of ERBB2. In epithelial cells, ERBB2IP restricts expression of ERBB2 to basolateral plasma membrane regions (Borg et al. 2000).<br><br> ERBB2 becomes activated by forming a heterodimer with another ligand-activated EGFR family member, either EGFR, ERBB3 or ERBB4, which is accompanied by dissociation of chaperoning proteins HSP90 and CDC37 (Citri et al. 2004), as well as ERBB2IP (Borg et al. 2000) from ERBB2. ERBB2 heterodimers function to promote cell proliferation, cell survival and differentiation, depending on the cellular context. ERBB2 can also be activated by homodimerization when it is overexpressed, in cancer for example. <br><br> In cells expressing both ERBB2 and EGFR, EGF stimulation of EGFR leads to formation of both ERBB2:EGFR heterodimers (Wada et al. 1990, Karunagaran et al. 1996) and EGFR homodimers. Heterodimers of ERBB2 and EGFR trans-autophosphorylate on twelve tyrosine residues, six in the C-tail of EGFR and six in the C-tail of ERBB2 - Y1023, Y1139, Y1196, Y1221, Y1222 and Y1248 (Margolis et al. 1989, Hazan et al. 1990,Walton et al. 1990, Helin et al. 1991, Ricci et al. 1995, Pinkas-Kramarski 1996). Phosphorylated tyrosine residues in the C-tail of EGFR and ERBB2 serve as docking sites for downstream signaling molecules. Three key signaling pathways activated by ERBB2:EGFR heterodimers are RAF/MAP kinase cascade, PI3K-induced AKT signaling, and signaling by phospholipase C gamma (PLCG1). Downregulation of EGFR signaling is mediated by ubiquitin ligase CBL, and is shown under Signaling by EGFR.<br><br> In cells expressing ERBB2 and ERBB3, ERBB3 activated by neuregulin NRG1 or NRG2 binding (Tzahar et al. 1994) forms a heterodimer with ERBB2 (Pinkas-Kramarski et al. 1996, Citri et al. 2004). ERBB3 is the only EGFR family member with no kinase activity, and can only function in heterodimers, with ERBB2 being its preferred heterodimerization partner. After heterodimerization, ERBB2 phosphorylates ten tyrosine residues in the C-tail of ERBB3, Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 (Prigent et al. 1994, Pinkas-Kramarski et al. 1996, Vijapurkar et al. 2003, Li et al. 2007) that subsequently serve as docking sites for downstream signaling molecules, resulting in activation of PI3K-induced AKT signaling and RAF/MAP kinase cascade. Signaling by ERBB3 is downregulated by the action of RNF41 ubiquitin ligase, also known as NRDP1. <br><br> In cells expressing ERBB2 and ERBB4, ligand stimulated ERBB4 can either homodimerize or form heterodimers with ERBB2 (Li et al. 2007), resulting in trans-autophosphorylation of ERBB2 and ERBB4 on C-tail tyrosine residues that will subsequently serve as docking sites for downstream signaling molecules, leading to activation of RAF/MAP kinase cascade and, in the case of ERBB4 CYT1 isoforms, PI3K-induced AKT signaling (Hazan et al. 1990, Cohen et al. 1996, Li et al. 2007, Kaushansky et al. 2008). Signaling by ERBB4 is downregulated by the action of WWP1 and ITCH ubiquitin ligases, and is shown under Signaling by ERBB4. Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431227986 Reactome, http://www.reactome.org ReactomeREACT_115755 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Regulation of KIT signaling Authored: Garapati, P V, 2011-07-11 Edited: Garapati, P V, 2011-07-11 Pubmed10582339 Pubmed16483568 Reactome Database ID Release 431433559 Reactome, http://www.reactome.org ReactomeREACT_111225 Reviewed: Rönnstrand, L, 2011-08-22 SCF induced proliferation is negatively regulated by various proteins including SHP1, PKC, CBL, SOCS1, SOCS6 and LNK. Recruitment of Sos to plasma membrane Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed17114045 Pubmed7862111 Reactome Database ID Release 43428515 Reactome, http://www.reactome.org ReactomeREACT_19355 Reviewed: Kidd, T, 2009-08-18 Upon Slit stimulation Sos is recruited into the multiprotein complex consisting of Robo, the SH3-SH2 protein Dock/Nck, and Sos, in which Dock/Nck bridges the physical association between Robo and Sos. GRB2 events in ERBB2 signaling Authored: Orlic-Milacic, M, 2011-11-04 ERBB2:EGFR and ERBB2:ERBB4 can directly recruit GRB2:SOS1 complex through phosphorylated C-tail tyrosines of EGFR (Y1068 and Y1086) and ERBB2 (Y1139) that serve as docking sites for GRB2 (Xie et al. 1995, Sepp-Lorenzino et al. 1996), which, again, results in SOS1-mediated guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinases (Janes et al. 1994, Sepp-Lorenzino et al. 1996). Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431963640 Reactome, http://www.reactome.org ReactomeREACT_115854 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Recruitment of PAK to Nck Authored: Garapati, P V, 2008-09-05 06:02:05 Dock/Nck bound to Robo recruits Pak to specific sites at the growth cone membrane, where Pak, activated by Rac, regulates the recycling and retrograde flow of actin filaments. [In mammals there are six PAK isoforms and PAK binds to the 2nd SH3 domain of Nck with its proline rich PxxP motif.] Edited: Garapati, P V, 2008-09-05 06:02:05 Reactome Database ID Release 43428531 Reactome, http://www.reactome.org ReactomeREACT_19217 Reviewed: Kidd, T, 2009-08-18 SHC1 events in ERBB2 signaling All ERBB2 heterodimers, ERBB2:EGFR, ERBB2:ERBB3 and ERBB2:ERBB4, are able to activate RAF/MAP kinase cascade by recruiting SHC1 (Pinkas-Kramarski et al. 1996, Sepp-Lorenzino et al. 1996) to phosphorylated C-tail tyrosine residues in either EGFR (Y1148 and Y1173), ERBB2 (Y1196, Y1221, Y1222 and Y1248), ERBB3 (Y1328) or ERBB4 (Y1188 and Y1242 in JM-A CYT1 isoform, Y1178 and Y1232 in JM-B CYT1 isoform, Y1172 and Y1226 in JM-A CYT2 isoform). SHC1 recruitment is followed by phosphorylation (Segatto et al. 1993, Soler et al. 1994), and the phosphorylated SHC1 recruits GRB2:SOS1 complex (Xie et al. 1995), which leads to SOS1-mediated guanyl-nucleotide exchange on RAS (Xie et al. 1995) and downstream activation of RAF and MAP kinases. Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431250196 Reactome, http://www.reactome.org ReactomeREACT_115993 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Interaction of Abl with Robo1:Slit2 Abl binds directly, via its SH3 domain, to the CC3 motif in the cytoplasmic domain of human Robo1. Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed10892742 Reactome Database ID Release 43376141 Reactome, http://www.reactome.org ReactomeREACT_19396 Reviewed: Kidd, T, 2009-08-18 PLCG1 events in ERBB2 signaling Activation of PLCG1 signaling is observed only in the presence of ERBB2:EGFR heterodimers, with PLCG1 binding to phosphorylated tyrosine Y992 and Y1173 in the C-tail of EGFR (Chattopadhyay et al. 1999), and potentially Y1023 in the C-tail of ERBB2 (Fazioli et al. 1991, Cohen et al. 1996). Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431251932 Reactome, http://www.reactome.org ReactomeREACT_115720 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Activation of Rac by Sos Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Reactome Database ID Release 43428535 Reactome, http://www.reactome.org ReactomeREACT_19252 Reviewed: Kidd, T, 2009-08-18 Sos bound to Dock/Nck, with its Rac GEF activity activates Rac. Son of sevenless (Sos) is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases. The Ras and Rac-GEF activities of Sos can be uncoupled during Robo-mediated axon repulsion; Sos axon guidance function depends on its Rac-GEF activity, but not its Ras-GEF activity. PI3K events in ERBB2 signaling Authored: Orlic-Milacic, M, 2011-11-04 ERBB2:ERBB3 and ERBB2:ERBB4cyt1 heterodimers activate PI3K signaling by direct binding of PI3K regulatory subunit p85 (Yang et al. 2007, Cohen et al. 1996, Kaushansky et al. 2008) to phosphorylated tyrosine residues in the C-tail of ERBB3 (Y1054, Y1197, Y1222, Y1224, Y1276 and Y1289) and ERBB4 CYT1 isoforms (Y1056 in JM-A CYT1 isoform and Y1046 in JM-B CYT1 isoform). Regulatory subunit p85 subsequently recruits catalytic subunit p110 of PI3K, resulting in the formation of active PI3K, conversion of PIP2 to PIP3, and PIP3-mediated activation of AKT signaling (Junttila et al. 2009, Kainulainen et al. 2000). Heterodimers of ERBB2 and EGFR recruit PI3K indirectly, through GRB2:GAB1 complex (Jackson et al. 2004), which again leads to PIP3-mediated activation of AKT signaling. Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431963642 Reactome, http://www.reactome.org ReactomeREACT_116008 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 IGF1/2 Converted from EntitySet in Reactome Insulin-like Growth Factor Reactome DB_ID: 381451 Reactome Database ID Release 43381451 Reactome, http://www.reactome.org ReactomeREACT_17556 Inactivation of Cdc42 Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed11672528 Pubmed16857672 Reactome Database ID Release 43428533 Reactome, http://www.reactome.org ReactomeREACT_19125 Reviewed: Kidd, T, 2009-08-18 srGAP bound to Robo's cytoplasmic tail increase the intrinsic GTPase activity of Cdc42, which converts the GTP-bound form of Cdc42 into its GDP-bound form, therefore inactivating Cdc42. Inactivation of Cdc42 leads to a reduction in the activation of the Neuronal WiskottAldrich Syndrome protein (NWASP), thus decreasing the level of active Arp2/3 complex. Because active Arp2/3 promotes actin polymerization, the reduction of active Cdc42 eventually decreases actin polymerization. Slit regulates SrGAP interaction with Robo1 and Cdc42, it increases SrGAP interaction with Cdc42. GRB7 events in ERBB2 signaling Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Heterodimers of ERBB2 and ERBB3 are able to bind GRB7 (Fiddes et al. 1998) through phosphorylated tyrosine residues in the C-tail of ERBB3 (Y1199 and Y1262), but the exact downstream signaling of this complex has not been elucidated. Reactome Database ID Release 431306955 Reactome, http://www.reactome.org ReactomeREACT_115896 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 KIAA1688/Vilse binds Robo1:Slit2 Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed15342493 Pubmed15755809 Reactome Database ID Release 43428536 Reactome, http://www.reactome.org ReactomeREACT_19229 Reviewed: Kidd, T, 2009-08-18 Vilse/CrossGAP (CrGAP) a conserved Rac-Specific GAP in Drosophila is involved in Robo mediated repulsion. CrGAP directly binds to Robo both biochemically and genetically. This interaction is mediated by the WW domains in CrGAP and the CC2 motif of Robo. <br>The human homologue of Vilse/CrGAP, KIAA1688, was identified which shares 54.4% sequence similarity with Drosophila CrGAP and is referred as human Vilse/CrGAP protein. Downregulation of ERBB2:ERBB3 signaling Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Level of plasma membrane ERBB3 is regulated by E3 ubiquitin ligase RNF41 (also known as NRDP1), which binds and ubiquitinates both inactive and activated ERBB3, targeting it for degradation (Cao et al. 2007). RNF41 is subject to self-ubiquitination which keeps its levels low when ERBB3 is not stimulated, and preserves ERBB3 expression on the cell surface (Qiu et al. 2002). Self-ubiquitination of RNF41 is reversible, through the action of ubiquitin protease USP8, an enzyme stabilized by AKT-mediated phosphorylation. Therefore, activation of AKT by ERBB2:ERBB3 signaling leads to phosphorylation of USP8 (Cao et al. 2007), which increases level of RNF41 through deubiquitination, and results in degradation of activated ERBB3 (Cao et al. 2007) - a negative feedback loop of ERBB3 signaling. Downregulation of EGFR and ERBB4 signaling is explained in pathways Signaling by EGFR and Signaling by ERBB4. Reactome Database ID Release 431358803 Reactome, http://www.reactome.org ReactomeREACT_115662 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11 Inactivation of Rac1 Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed15342493 Pubmed15755809 Reactome Database ID Release 43428522 Reactome, http://www.reactome.org ReactomeREACT_19359 Reviewed: Kidd, T, 2009-08-18 Vilse and its human homolog bind directly to the intracellular domains of the corresponding Robo receptors and promote the hydrolysis of RacGTP. Signaling by ERBB4 Authored: Orlic-Milacic, M, 2011-11-04 ERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR i.e. HER1), ERBB2 (HER2 i.e. NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains an active tyrosine kinase and a C-tail with multiple phosphorylation sites. At least three and possibly four splicing isoforms of ERBB4 exist that differ in their C-tail and/or the extracellular juxtamembrane regions: ERBB4 JM-A CYT1, ERBB4 JM-A CYT2 and ERBB4 JM-B CYT1 (the existence of ERBB4 JM-B CYT2 has not been confirmed). <br><br>ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation, but their downstream signaling and physiological significance have not been studied. <br><br><br>All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000). <br><br>The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000). <br><br>Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006). <br><br>The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006). Activation of ERBB4 in breast cancer cell lines leads to JNK-dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka-Cook et al. 2006). <br><br>WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009). Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Pubmed10722704 Pubmed10744726 Pubmed10867024 Pubmed11679632 Pubmed12807903 Pubmed12869563 Pubmed15023535 Pubmed15534001 Pubmed16061658 Pubmed16778220 Pubmed16912174 Pubmed16914727 Pubmed16978839 Pubmed17018285 Pubmed1706616 Pubmed17463226 Pubmed17545517 Pubmed18653779 Pubmed18721752 Pubmed19047365 Pubmed19193720 Pubmed7565730 Pubmed7929212 Pubmed8617750 Pubmed8665853 Pubmed9135143 Pubmed9168115 Pubmed9275162 Pubmed9556621 Reactome Database ID Release 431236394 Reactome, http://www.reactome.org ReactomeREACT_115596 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Nck binds Robo1:Slit2 Authored: Garapati, P V, 2008-09-05 06:02:05 Edited: Garapati, P V, 2008-09-05 06:02:05 Pubmed12588847 Pubmed14527437 Reactome Database ID Release 43428511 Reactome, http://www.reactome.org ReactomeREACT_19119 Reviewed: Kidd, T, 2009-08-18 Slit stimulation recruits SH3 SH2 adaptor protein Dreadlocks (Dock) (Nck in vertebrates) to the Robo receptor. Activated TRAF6 synthesizes unanchored polyubiquitin chains upon TLR stimulation Authored: Shamovsky, V, 2009-12-16 EC Number: 6.3.2.19 Edited: Shamovsky, V, 2010-02-27 Polyubiquitinated TRAF6 (as E3 ubiquitin ligase) generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase. Pubmed19675569 Reactome Database ID Release 43450358 Reactome, http://www.reactome.org ReactomeREACT_21364 Reviewed: Gillespie, ME, 2010-03-02 BoNT Light Chain Type C1 cleaves Syntaxin Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 EC Number: 3.4.24 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed8611567 Reactome Database ID Release 43181567 Reactome, http://www.reactome.org ReactomeREACT_11195 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 Syntaxins are involved in the localization (docking) of both synaptic vesicles and calcium channels to the presynaptic active zone. Syntaxin 1A interacts with SNAP-25 in forming t-SNARE part of SNARE complex. BoNT Type C specifically cleaves Syntaxin 1A although a broader target spectrum is suspected. Phospho-IKK Complex phosphorylates IkB within the IkB:NFkB Complex EC Number: 2.7.11 Edited: Shamovsky, V, 2009-12-16 In human, IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits. <p>A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta); Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kB. Pubmed10723127 Pubmed12221085 Pubmed17047224 Pubmed19666475 Reactome Database ID Release 43168140 Reactome, http://www.reactome.org ReactomeREACT_6848 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Napetschnig, Johanna, 2012-11-16 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- has a Stoichiometric coefficient of 4 Activated TAK1 mediates phosphorylation of the IKK Complex Authored: Luo, F, 2005-11-10 11:23:18 EC Number: 2.7.11 Edited: Shamovsky, V, 2009-12-16 In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.<p>This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.<p>IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation. Pubmed11460167 Pubmed12221085 Pubmed17496917 Pubmed19666475 Pubmed9744859 Reactome Database ID Release 43168184 Reactome, http://www.reactome.org ReactomeREACT_6935 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Kufer, TA, 2011-04-28 Reviewed: Napetschnig, Johanna, 2012-11-16 Reviewed: Rittinger, K, 2011-06-06 Reviewed: Wong, Edmond, 2011-06-06 has a Stoichiometric coefficient of 4 Activated TAK1 phosphorylates MKK4/MKK7 Authored: Shamovsky, V, 2009-12-16 EC Number: 2.7.11 Edited: Shamovsky, V, 2010-02-27 In human, phosphorylation of MKK4 and MKK7 by TAK1 occurs at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.<p>Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 and Ser257, Thr261 in MKK4.<p>Cell lines lacking MKK4 exhibit defective activation of JNK and AP-1 dependent transcription activity in response to some cellular stresses; JNK and p38 MAPK activities were decreased by around 80% and 20%, respectively, following deletion of the mkk4 gene. Pubmed15837794 Pubmed16186825 Pubmed17875933 Pubmed8533096 Reactome Database ID Release 43450337 Reactome, http://www.reactome.org ReactomeREACT_21367 Reviewed: Gillespie, ME, 2010-02-27 has a Stoichiometric coefficient of 2 Released NFkB complex is transported to nucleus Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2011-08-12 NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NFkappa-B2), All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefor, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes. Pubmed10723127 Pubmed15145317 Pubmed16056267 Reactome Database ID Release 43168166 Reactome, http://www.reactome.org ReactomeREACT_6906 Reviewed: D'Eustachio, P, 2011-12-07 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Napetschnig, Johanna, 2012-11-16 Reviewed: Upton, JW, Mocarski, ES, 2012--0-2- Activated human JNKs migrate to nucleoplasm Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2010-02-27 Pubmed12193592 Pubmed13130464 Pubmed9195981 Reactome Database ID Release 43450348 Reactome, http://www.reactome.org ReactomeREACT_21385 Reviewed: Gillespie, ME, 2010-02-27 c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors. Phosphorylation of human JNKs by activated MKK4/MKK7 Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. <p>JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183). Authored: Luo, F, 2005-11-10 11:23:18 Edited: Shamovsky, V, 2009-12-16 Pubmed11062067 Pubmed13130464 Pubmed16186825 Pubmed17875933 Pubmed18713996 Pubmed9162092 Reactome Database ID Release 43168162 Reactome, http://www.reactome.org ReactomeREACT_6896 Reviewed: Gay, NJ, 2006-04-24 16:48:17 has a Stoichiometric coefficient of 2 activated human TAK1 phosphorylates MKK3/MKK6 Authored: Shamovsky, V, 2009-12-16 EC Number: 2.7.11 Edited: Shamovsky, V, 2011-08-12 Human MKK3 and MKK6 are two closely related dual-specificity protein kinases. Both are activated by cellular stress and inflammatory cytokines, and both phosphorylate and activate p38 MAP kinase at its activation site Thr-Gly-Tyr but do not phosphorylate or activate Erk1/2 or SAPK/JNK.<p> Activation of MKK3 and MKK6 occurs through phosphorylation of serine and threonine residues at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loop. Residues involved into these protein kinases activation correspond to human sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6 . Pubmed15837794 Pubmed16186825 Pubmed8533096 Pubmed8622669 Reactome Database ID Release 43450346 Reactome, http://www.reactome.org ReactomeREACT_21338 Reviewed: Gillespie, ME, 2010-02-27 has a Stoichiometric coefficient of 2 phosphorylated MKK3/MKK6 migrates to nucleus Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2010-02-27 Pubmed7535770 Pubmed9768359 Reactome Database ID Release 43450296 Reactome, http://www.reactome.org ReactomeREACT_21299 Reviewed: Gillespie, ME, 2010-02-27 The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. Pore or channel formation in endosomal membrane Acidic pH triggers a conformation change in the Heavy chain N-terminal domain leading to its insertion into the lipid bilayer and formation of a trans-membrane channel large enough to accommodate the unfolded Light chain. It has been observed that in the closely related Diptheria toxin, a 10-aa motif is critical for pore formation. Ratts et al. identified this motif in some of the virulent BoNTs (Ratts et al., 2005). Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed16230620 Pubmed2446925 Pubmed8206166 Reactome Database ID Release 43181361 Reactome, http://www.reactome.org ReactomeREACT_11217 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 Conformational change in BoNT induced by pH Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed10212474 Pubmed10518945 Pubmed2424493 Pubmed2446925 Reactome Database ID Release 43168788 Reactome, http://www.reactome.org ReactomeREACT_11131 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 The N-terminal half of the BoNT Heavy Chain undergoes conformational changes effected by endosomal pH resulting in ion channel formation (Blaustein et al., 1987). This process has been demonstrated experimentally for BoNT serotypes A and B, but all serotypes are thought to have this property (Pellizzari et al. 1999). Transcytosis and internalization of BoNT Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Once BoNT molecules are bound to the host cell surface via their HC domains, they undergo transcytosis which include sorting and endocytosis into an acidic vesicular compartment within the cytosol. As a result of endocytosis, the toxin becomes resistant to neutralization by antisera. Endocytosis is temperature and energy-dependent. In the body, endocytosed BoNT molecules remain associated with the neuromuscular junction which they finally reach by transcytosis. Pubmed10212474 Pubmed12417130 Pubmed4273827 Pubmed92475 Reactome Database ID Release 43181536 Reactome, http://www.reactome.org ReactomeREACT_11086 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 BoNT Light Chain Type F cleaves VAMP Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 BoNT Light Chain type F protein cleaves VAMP proteins of human SNARE complex. EC Number: 3.4.24 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed16008342 Pubmed16519520 Pubmed7803399 Pubmed8175689 Reactome Database ID Release 43194808 Reactome, http://www.reactome.org ReactomeREACT_11158 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 BoNT Light Chain Type D cleaves VAMP Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 BoNT Light Chain type D protein cleaves VAMP proteins of human SNARE complex. EC Number: 3.4.24 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed16008342 Pubmed16519520 Pubmed7803399 Pubmed8175689 Reactome Database ID Release 43194809 Reactome, http://www.reactome.org ReactomeREACT_11179 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 BoNT Light Chain Type B cleaves VAMP-2 Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 BoNT Light Chain type B protein cleaves Vamp-2 protein, a member of SNARE complex. EC Number: 3.4.24 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed16008342 Pubmed16519520 Pubmed7803399 Pubmed8175689 Reactome Database ID Release 43194796 Reactome, http://www.reactome.org ReactomeREACT_11165 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 Transportation of BoNT Light chain to cytosol Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed10212474 Pubmed1634516 Pubmed7984234 Reactome Database ID Release 43181365 Reactome, http://www.reactome.org ReactomeREACT_11226 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 The BoNT L chain traverses the H chain channel into the cytosol, refolds, and is released into the cytosol. The complete molecular details of cleavage of the L- H disulfide bond and L chain refolding are not yet known (Pellizzari et al.,1999). The cleavage of host proteins may require the toxins binding to specific recogntion sites as well as cleavage sites (Rossetto et al., 1994). BoNT Light Chain Type E cleaves SNAP-25 Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 BoNT Light Chain type E protein cleaves SNAP-25 protein of human SNARE complex. EC Number: 3.4.24 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed8243676 Pubmed8294407 Pubmed8611567 Pubmed9886085 Reactome Database ID Release 43194800 Reactome, http://www.reactome.org ReactomeREACT_11089 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 BoNT Light Chain Type A cleaves SNAP-25 Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 BoNT Light Chain type A protein cleaves SNAP-25 protein of human SNARE complex. EC Number: 3.4.24 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed8243676 Pubmed8294407 Pubmed8611567 Pubmed9886085 Reactome Database ID Release 43194818 Reactome, http://www.reactome.org ReactomeREACT_11146 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 BoNT Light Chain Type C1 cleaves SNAP-25 Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 BoNT Light Chain type C1 protein cleaves SNAP-25 protein of human SNARE complex. EC Number: 3.4.24 Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed8243676 Pubmed8294407 Pubmed8611567 Pubmed9886085 Reactome Database ID Release 43194793 Reactome, http://www.reactome.org ReactomeREACT_11130 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 Nuclear signaling by ERBB4 Authored: Orlic-Milacic, M, 2011-11-04 Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006). <br><br>The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006). Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431251985 Reactome, http://www.reactome.org ReactomeREACT_116022 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 PI3K events in ERBB4 signaling Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431250342 Reactome, http://www.reactome.org ReactomeREACT_115961 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 The CYT1 isoforms of ERBB4 possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K - PIK3R1 (Kaushansky et al. 2008, Cohen et al. 1996). Binding of PIK3R1 to CYT1 isoforms of ERBB4 is followed by recruitment of the p110 catalytic subunit of PI3K (PIK3CA), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000). Downregulation of ERBB4 signaling Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431253288 Reactome, http://www.reactome.org ReactomeREACT_115828 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009). Prolactin receptor signaling Authored: Jupe, S, 2011-06-13 Edited: Jupe, S, 2011-10-17 Prolactin (PRL) is a hormone secreted mainly by the anterior pituitary gland. It was originally identified by its ability to stimulate the development of the mammary gland and lactation, but is now known to have numerous and varied functions (Bole-Feysot et al. 1998). Despite this, few pathologies have been associated with abnormalities in prolactin receptor (PRLR) signaling, though roles in various forms of cancer and certain autoimmune disorders have been suggested (Goffin et al. 2002). A vast body of literature suggests effects of PRL in immune cells (Matera 1996) but PRLR KO mice have unaltered immune system development and function (Bouchard et al. 1999). In addition to the pituitary, numerous other tissues produce PRL, including the decidua and myometrium, certain cells of the immune system, brain, skin and exocrine glands such as the mammary, sweat and lacrimal glands (Ben-Jonathan et al. 1996). Pituitary PRL secretion is negatively regulated by inhibitory factors originating from the hypothalamus, the most important of which is dopamine, acting through the D2 subclass of dopamine receptors present in lactotrophs (Freeman et al. 2000). PRL-binding sites or receptors have been identified in numerous cells and tissues of adult mammals. Various forms of PRLR, generated by alternative splicing, have been reported in several species including humans (Kelly et al. 1991, Clevenger et al. 2003).<br><br>PRLR is a member of the cytokine receptor superfamily. Like many other members of this family, the first step in receptor activation was generally believed to be ligand-induced dimerization whereby one molecule of PRL bound to two molecules of receptor (Elkins et al. 2000). Recent reports suggest that PRLR pre-assembles at the plasma membrane in the absence of ligand (Gadd & Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in preformed PRLR dimers (Broutin et al. 2010). <br><br>PRLR has no intrinsic kinase activity but associates (Lebrun et al. 1994, 1995) with Janus kinase 2 (JAK2) which is activated following receptor activation (Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009). JAK2-dependent activation of JAK1 has also been reported (Neilson et al. 2007). It is generally accepted that activation of JAK2 occurs by transphosphorylation upon ligand-induced receptor activation, based on JAK activation by chimeric receptors in which various extracellular domains of cytokine or tyrosine kinase receptors were fused to the IL-2 receptor beta chain (see Ihle et al. 1994). This activation step involves the tyrosine phosphorylation of JAK2, which in turn phosphorylates PRLR on specific intracellular tyrosine residues leading to STAT5 recruitment and signaling, considered to be the most important signaling cascade for PRLR. STAT1 and STAT3 activation have also been reported (DaSilva et al. 1996) as have many other signaling pathways; signaling through MAP kinases (Shc/SOS/Grb2/Ras/Raf/MAPK) has been reported as a consequence of PRL stimuilation in many different cellular systems (see Bole-Feysot et al. 1998) though it is not clear how this signal is propagated. Other cascades non exhaustively include Src kinases, Focal adhesion kinase, phospholipase C gamma, PI3 kinase/Akt and Nek3 (Clevenger et al. 2003, Miller et al. 2007). The protein tyrosine phosphatase SHP2 is recruited to the C terminal tyrosine of PRLR and may have a regulatory role (Ali & Ali 2000). PRLR phosphotyrosines can recruit insulin receptor substrates (IRS) and other adaptor proteins to the receptor complex (Bole-Feysot et al. 1998).<br><br>Female homozygous PRLR knockout mice are completely infertile and show a lack of mammary development (Ormandy et al. 1997). Hemizogotes are unable to lactate following their first pregnancy and depending on the genetic background, this phenotype can persist through subsequent pregnancies (Kelly et al. 2001). Pubmed10395643 Pubmed10912517 Pubmed10966654 Pubmed10991949 Pubmed11015620 Pubmed11356125 Pubmed11826263 Pubmed12588805 Pubmed16840534 Pubmed17297458 Pubmed17550976 Pubmed1935820 Pubmed19381268 Pubmed20053995 Pubmed7508935 Pubmed7515493 Pubmed7537736 Pubmed8048164 Pubmed8188682 Pubmed8737372 Pubmed8761011 Pubmed8969972 Pubmed9009200 Pubmed9312112 Pubmed9626554 Reactome Database ID Release 431170546 Reactome, http://www.reactome.org ReactomeREACT_115697 Reviewed: Goffin, V, 2011-11-08 SHC1 events in ERBB4 signaling All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000). Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431250347 Reactome, http://www.reactome.org ReactomeREACT_116005 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 TGF-beta receptor signaling activates SMADs Authored: Orlic-Milacic, M, 2012-04-04 Binding of transforming growth factor beta 1 (TGF beta 1, i.e. TGFB1) to TGF beta receptor type 2 (TGFBR2) activates TGF beta receptor signaling cascade. TGFB1 is posttranslationally processed by furin (Dubois et al. 1995) to form a homodimer and secreted to the extracellular space as part of the large latent complex (LLC). After the LLC disassembles in the extracellular space, dimeric TGFB1 becomes capable of binding to TGFBR2 (Annes et al. 2003, Keski Oja et al. 2004). Formation of TGFB1:TGFBR2 complex creates a binding pocket for TGF-beta receptor type-1 (TGFBR1) and TGFBR1 is recruited to the complex by binding to both TGFB1 and TGFBR2. This results in an active heterotetrameric TGF-beta receptor complex that consists of TGFB1 homodimer bound to two heterodimers of TGFBR1 and TGFBR2 (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). TGF-beta signaling can also occur through a single heterodimer of TGFBR1 and TGFBR2, although with decreased efficiency (Huang et al. 2011). TGFBR1 and TGFBR2 interact through their extracellular domains, which brings their cytoplasmic domains together. Ligand binding to extracellular receptor domains is cooperative, but no conformational change is seen from crystal structures of either TGFB1- or TGFB3-bound heterotetrameric receptor complexes (Groppe et al. 2008, Radaev et al. 2010).<br><br>Activation of TGFBR1 by TGFBR2 in the absence of ligand is prevented by FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase. FKBP1A forms a complex with inactive TGFBR1 and dissociates from it only after TGFBR1 is recruited by TGFB1-bound TGFBR2 (Chen et al. 1997). <br><br>Both TGFBR1 and TGFBR2 are receptor serine/threonine kinases. Formation of the hetero-tetrameric TGF-beta receptor complex (TGFBR) in response to TGFB1 binding induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. TGFBR2 trans-phosphorylates serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of TGFBR1 (Wrana et al. 1994, Souchelnytskyi et al. 1996), activating TGFBR1.<br>In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta stimulation. Sumoylation enhances TGFBR1 kinase activity (Kang et al. 2008). <br><br>The activated TGFBR complex is internalized by clathrin-mediated endocytosis into early endosomes. With the assistance of SARA, an early endosome membrane protein, phosphorylated TGFBR1 within TGFBR complex recruits SMAD2 and/or SMAD3 , i.e. R-SMADs (Tsukazaki et al. 1998). TGFBR1 phosphorylates recruited SMAD2/3 on two C-terminal serine residues (Souchelnytskyi et al. 2001). The phosphorylation changes the conformation of SMAD2/3 MH2 domain, promoting dissociation of SMAD2/3 from SARA and TGFBR1 (Souchelnytskyi et al. 1997, Macias-Silva et al. 1996, Nakao et al. 1997) and formation of SMAD2/3 trimers (Chacko et al. 2004). The phosphorylated C-terminal tail of SMAD2/3 has high affinity for SMAD4 (Co-SMAD), inducing formation of SMAD2/3:SMAD4 heterotrimers, composed of two phosphorylated R-SMADs (SMAD2 and/or SMAD3) and SMAD4 (Co-SMAD). SMAD2/3:SMAD4 heterotrimers are energetically favored over R-SMAD trimers (Nakao et al. 1997, Qin et al. 2001, Kawabata et al. 1998, Chacko et al. 2004). <br>SMAD2/3:SMAD4 heterotrimers translocate to the nucleus where they act as transcriptional regulators. Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0007179 Pubmed11100470 Pubmed11779505 Pubmed12482908 Pubmed1333888 Pubmed15350224 Pubmed15564041 Pubmed18243111 Pubmed20207738 Pubmed21423151 Pubmed7693660 Pubmed7737999 Pubmed8047140 Pubmed8242743 Pubmed8947046 Pubmed8980228 Pubmed9233797 Pubmed9311995 Pubmed9346966 Pubmed9670020 Pubmed9865696 Reactome Database ID Release 432173789 Reactome, http://www.reactome.org ReactomeREACT_120850 Reviewed: Huang, Tao, 2012-05-14 Rho GTPase cycle Authored: Van Aelst, L, 2007-04-28 21:26:24 Edited: Gopinathrao, G, 2007-04-02 21:35:36 GENE ONTOLOGYGO:0051056 Pubmed16212495 Pubmed17222083 Pubmed9308960 Reactome Database ID Release 43194840 Reactome, http://www.reactome.org ReactomeREACT_11051 Reviewed: Bernards, A, 2007-04-28 21:27:12 The cycling of Rho GTPases is tightly controlled by three classes of protein. These are (1) guanine nucleotide dissociation inhibitors or GDIs, which maintain Rho proteins in an inactive state in the cytoplasm, (2) guanine nucleotide exchange factors or GEFs, which destabilize the interaction between Rho proteins and their bound nucleotide, the net result of which is the exchange of bound GDP for the more abundant GTP, and (3) GTPase Activating Proteins or GAPs, which stimulate the low intrinsic GTP hydrolysis activity of Rho family members, thus promoting their inactivation. GDIs, GEFs, and GAPs are themselves subject to tight regulation, and the overall level of Rho activity reflects the balance of their activities.<p>In their active GTP-bound state, Rho family members have the ability to interact with a large variety of so-called effector proteins. By changing the subcellular localization of effectors, by altering their enzymatic properties, or by directing the formation of specific effector complexes, members of the Rho family mediate their various effects.<p>This Rho GTPase cycle is diagrammed in the figure below. External or internal cues promote the release of Rho GTPases from the inhibitory complex (1) which allows them to associate with the plasma membrane (2) where they are activated by GEFs (3) and can signal to effector proteins. Then, GAPs inactivate the GTPases by accelerating the intrinsic GTPase activity, leading to the GDP bound form (4). Once again, the GDI molecules stabilize the inactive GDP bound form in the cytoplasm, waiting for further instructions (5). (Figure and text from Tcherkezian and Lamarche Vane, 2007). Signaling by Rho GTPases Authored: Van Aelst, L, 2007-04-28 21:26:24 Edited: Gopinathrao, G, 2007-04-02 21:35:36 GENE ONTOLOGYGO:0007264 Pubmed10445846 Pubmed12101119 Pubmed12618308 Pubmed14521508 Pubmed15630019 Pubmed16212495 Pubmed16757309 Reactome Database ID Release 43194315 Reactome, http://www.reactome.org ReactomeREACT_11044 Reviewed: Bernards, A, 2007-04-28 21:27:12 The Rho family of small guanine nucleotide binding proteins is one of five generally recognized branches of the Ras superfamily. Like most Ras superfamily members, typical Rho proteins function as binary switches controlling a variety of biological processes. They perform this function by cycling between active GTP-bound and inactive GDP-bound conformations. Mammalian Rho GTPases include RhoA, RhoB and RhoC (Rho proteins), Rac1 3 (Rac proteins), Cdc42, TC10, TCL, Wrch1, Chp/Wrch2, RhoD and RhoG, to name some. The family also includes RhoH and Rnd1-3, which lack GTPase activity and are predicted to exist in a constitutively active state.<p>Members of the Rho family have been identified in all eukaryotes. Including the atypical RHOBTB1-3 and RHOT1-2 proteins, 24 Rho family members have been identified in mammals (Jaffe and Hall, 2005; Bernards, 2005; Ridley, 2006). Among Rho GTPases, RhoA, Rac1 and Cdc42 have been most extensively studied. These proteins are best known for their ability to induce dynamic rearrangements of the plasma membrane-associated actin cytoskeleton (Aspenstrom et al, 2004; Murphy et al, 1999; Govek et al, 2005). Beyond this function, Rho GTPases also regulate actomyosin contractility and microtubule dynamics. Rho mediated effects on transcription and membrane trafficking are believed to be secondary to these functions. At the more macroscopic level, Rho GTPases have been implicated in many important cell biological processes, including cell growth control, cytokinesis, cell motility, cell cell and cell extracellular matrix adhesion, cell transformation and invasion, and development (Govek et al., 2005). The illustration below lists Rho GTPase effectors implicated in actin and microtubule dynamics (courtesy: Govek et al., 2005, Genes and Development, CSHL Press). Detailed annotations of various biological processes regulated by Rho GTPases will be available in future releases. Signaling by TGF-beta Receptor Complex Authored: Heldin, CH, Moustakas, A, Huminiecki, L, Jassal, B, 2006-02-02 Edited: Jassal, B, 2006-04-18 13:31:36 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0007179 Pubmed19648010 Reactome Database ID Release 43170834 Reactome, http://www.reactome.org ReactomeREACT_6844 Reviewed: Heldin, CH, 2006-04-18 14:26:12 Reviewed: Huang, Tao, 2012-05-14 The TGF-beta/BMP pathway incorporates several signaling pathways that share most, but not all, components of a central signal transduction engine. The general signaling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor SMAD (R-SMAD). In the nucleus, the activated R-SMAD promotes transcription in complex with a closely related helper molecule termed Co-SMAD (SMAD4). However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signaling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the R-SMADs, and functionally critical negative feedback loops. The R-SMAD:Co-SMAD complex can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signaling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases.<br>TGF beta (TGFB1) is secreted as a homodimer, and as such it binds to the homodimer of the TGF beta receptor II (TGFBR2) that is preformed on the plasma membrane. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1.<br>The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex. <br>In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner. <br>The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009. Transforming Growth Factor (TGF) beta signaling Signaling by BMP Authored: Huminiecki, L, Moustakas, A, 2007-11-07 10:22:00 GENE ONTOLOGYGO:0030509 Pubmed15621726 Reactome Database ID Release 43201451 Reactome, http://www.reactome.org ReactomeREACT_12034 Reviewed: Heldin, CH, 2007--1-1- The TGF-beta/BMP (bone morphogenetic protein) pathway incorporates several signalling pathways that share most, but not all, components of a central signal transduction engine. The general signalling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor-activated SMAD (r-SMAD). In the nucleus, the activated r-SMAD promotes transcription in a complex with a closely-related helper molecule termed the Co-SMAD. However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signalling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the r-SMAD, and functionally critical negative feedback loops. The r-SMAD/Co-SMAD can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signalling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases. Activated NOTCH1 Transmits Signal to the Nucleus Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Mature NOTCH1 heterodimer on the cell surface is activated by one of its ligands: DLL1 (Cordle et al. 2008, Jarriault et al. 1998), DLL4 (Benedito et al. 2009), JAG1 (Li et al. 1998, Benedito et al. 2009) or JAG2 (Luo et al. 1997, Shimizu et al. 2000), expressed in trans on a neighboring cell. Thus, a ligand-expressing cell is a signal-sending cell, while the NOTCH1 expressing cell is a signal-receiving cell. If NOTCH1 has undergone Fringe modification in the Golgi, it is preferentially activated by Delta ligands (Yang et al. 2005), DLL1 and DLL4. <br><br><br>Upon binding to NOTCH1 on a neighboring cell, NOTCH ligands are ubiquitinated by Mindbomb (MIB1 and MIB2) and/or Neuralized (NEURL and NEURL1B) E3 ubiquitin ligases and endocytosed (Koo et al. 2007, Koo et al. 2005, Itoh et al. 2003, Lai et al. 2001, Koutelou et al. 2008, Song et al. 2006). Endocytosis of ubiquitinated ligands is thought to mechanically stretch the bound NOTCH1 receptor, exposing a cleavage site S2 that is recognized by ADAM10 and/or ADAM17 metalloprotease (van Tetering et al. 2009, Brou et al. 2000, Hartmann et al. 2002, Pan et al. 1997). S2 cleavage of NOTCH1 produces the NEXT1 fragment which is further cleaved at an S3 cleavage site by the gamma-secretase complex, resulting in release of the NOTCH1 intracellular domain (NICD1) into the cytosol (de Strooper et al. 1999, Schroeter et al. 1998, Huppert et al. 2000). NICD1 produced by activation of NOTCH1 in response to in trans presented Delta and Jagged ligands (DLL/JAG) traffics to the nucleus where it acts as a transcription regulator.<br><br><br>NOTCH1 signaling can also be activated by ligands other than DLL1, DLL4, JAG1 and JAG2. CNTN1 (Contactin-1), transiently expressed during central and peripheral nervous system development, activates NOTCH1 and NOTCH2 in trans, promoting oligodendrocyte maturation and myelination (Hu et al. 2003). DNER (Delta and Notch-like epidermal growth factor-related receptor) is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. Activation of NOTCH1 by DNER in trans may play an important role in development of the central nervous system by influencing differentiation of astrocytes (Eiraku et al. 2005). Activation of NOTCH1 by both CNTN1 and DNER is Deltex (DTX)-dependent and results in gamma-secretase mediated release of NICD1. Three members of the Deltex protein family: DTX1, DTX2 and DTX4 possess a domain involved in binding cdc10/ankyrin repeats of NOTCH. DTX proteins are considered as positive regulators of NOTCH signaling, although the exact mechanism has not been elucidated (Matsuno et al. 1998, Kishi et al. 2001).In addition, DTX can mediate downregulation of NOTCH signaling by recruiting non-visual beta-arrestins to NOTCH (Mukherjee et al. 2005), thereby trigerring NOTCH ubiquitination. DTX proteins are negatively regulated by ITCH (AIP4) ubiquitin ligase (Chastagner et al. 2006).<br><br>NOTCH1 signaling in the signal-receiving cell can be turned off in cis by expression of NOTCH ligands DLL/JAG (Cordle et al. 2008, Sprinzak et al. 2010), as well as DLK1 (Baladron et al. 2005, Bray et al. 2008). Formation of NOTCH1:ligand complexes in cis prevents interaction of NOTCH1 with ligands expressed in trans, resulting in the inhibition of NOTCH signaling. In the signal-sending cell, NOTCH signaling can be negatively regulated by the protein NUMB, which is asymmetrically distributed during cell division (Rhyu et al. 1994). NUMB recruits ITCH ubiquitin ligase to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009, Chastagner et al. 2008). Pubmed10206645 Pubmed10879540 Pubmed10882063 Pubmed11006133 Pubmed11226752 Pubmed11740940 Pubmed12354787 Pubmed12530964 Pubmed14567914 Pubmed15574878 Pubmed15652348 Pubmed15824097 Pubmed15965470 Pubmed16284625 Pubmed17003037 Pubmed17028573 Pubmed18043734 Pubmed18077452 Pubmed18237417 Pubmed18296446 Pubmed18628966 Pubmed19524514 Pubmed19567869 Pubmed19726682 Pubmed20418862 Pubmed8313469 Pubmed9244301 Pubmed9315665 Pubmed9462510 Pubmed9590294 Pubmed9620803 Pubmed9819428 Reactome Database ID Release 432122948 Reactome, http://www.reactome.org ReactomeREACT_118614 Reviewed: Haw, R, 2012-02-06 Sema7A binds integrin alpha1beta1 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed12879062 Pubmed17377534 Reactome Database ID Release 43434990 Reactome, http://www.reactome.org ReactomeREACT_19139 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema7A has a RGD-motif in the extracellular region and interacts with alpha1beta1 integrin in both olfactory nerves and monocytes/macrophages. This interaction stimulates cytokine production in monocytes and macrophages, and is critical for the effector phase of the inflammatory immune response. NOTCH1 Intracellular Domain Regulates Transcription Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NICD1 produced by activation of NOTCH1 in response to Delta and Jagged ligands (DLL/JAG) presented in trans, traffics to the nucleus where it acts as a transcription regulator. In the nucleus, NICD1 displaces the NCOR corepressor complex from RBPJ (CSL). When bound to the co-repressor complex that includes NCOR proteins (NCOR1 and NCOR2) and HDAC histone deacetylases, RBPJ (CSL) represses transcription of NOTCH target genes (Kao et al. 1998, Zhou et al. 2000, Perissi et al. 2004, Perissi et al. 2008). Once the co-repressor complex is displaced, NICD1 recruits MAML (mastermind-like) to RBPJ, while MAML recruits histone acetyltransferases EP300 (p300) and PCAF, resulting in formation of the NOTCH coactivator complex that activates transcription from NOTCH regulatory elements. The minimal functional NOTCH coactivator complex that activates transcription from NOTCH regulatory elements is a heterotrimer composed of NICD, MAML and RBPJ (Fryer et al. 2002, Wallberg et al. 2002, Nam et al. 2006). <br><br> <br>NOTCH1 coactivator complex is known to activate transcription of HES1 (Jarriault et al. 1995), HES5 (Arnett et al. 2010), HEY genes (Fischer et al. 2004, Leimeister et al. 2000, Maier et al. 2000, Arnett et al. 2010) and MYC (Palomero et al. 2006) and likely regulates transcription of many other genes (Wang et al. 2011). NOTCH1 coactivator complex on any specific regulatory element may involve additional transcriptional regulatory proteins. HES1 binds TLE proteins, forming an evolutionarily conserved transcriptional corepressor involved in regulation of neurogenesis, segmentation and sex determination (Grbavec et al. 1996, Fisher et al. 1996, Paroush et al. 1994). <br><br>After NOTCH1 coactivator complex is assembled on a NOTCH-responsive promoter, MAML (mastermind-like) recruits CDK8 in complex with cyclin C, triggering phosphorylation of conserved serine residues in TAD and PEST domains of NICD1 by CDK8. Phosphorylated NICD1 is recognized by the E3 ubiquitin ligase FBXW7 which ubiquitinates NICD1, leading to degradation of NICD1 and downregulation of NOTCH1 signaling. FBXW7-mediated ubiquitination and degradation of NOTCH1 depend on C-terminally located PEST domain sequences in NOTCH1 (Fryer et al. 2004, Oberg et al. 2001, Wu et al. 2001). The PEST domain of NOTCH1 and the substrate binding WD40 domain of FBXW7 are frequent targets of mutations in T-cell acute lymphoblastic leukemia - T-ALL (Welcker and Clurman 2008). <br><br> NICD1, which normally has a short half-life, can be stabilized by binding to the hypoxia-inducable factor 1-alpha (HIF1A) which accumulates in the nucleus when oxygen levels are low. This results in HIF1A-induced inhibition of cellular differentiation that is NOTCH-dependent (Gustafsson et al. 2005). Pubmed10713164 Pubmed10964718 Pubmed11044625 Pubmed11461910 Pubmed11585921 Pubmed12050117 Pubmed12391150 Pubmed14980219 Pubmed15107403 Pubmed15546612 Pubmed16256737 Pubmed16530044 Pubmed17114293 Pubmed18094723 Pubmed18374649 Pubmed20972443 Pubmed21737748 Pubmed7566092 Pubmed8001118 Pubmed8649374 Pubmed8687460 Pubmed9694793 Reactome Database ID Release 432122947 Reactome, http://www.reactome.org ReactomeREACT_118780 Reviewed: Haw, R, 2012-02-06 Pre-NOTCH Processing in Golgi Authored: Jassal, B, 2004-12-15 13:08:03 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 NOTCH undergoes final posttranslational processing in the Golgi apparatus (Lardelli et al. 1994, Blaumueller et al. 1997, Weinmaster et al. 1991, Weinmaster et al. 1992, Uyttendaele et al. 1996). Movement of NOTCH precursors from the endoplasmic reticulum to Golgi is controlled by SEL1L protein, a homolog of C. elegans sel-1. SEL1L localizes to the endoplasmic reticulum membrane and prevents translocation of misfolded proteins, therefore serving as a quality control check (Li et al. 2010, Sundaram et al. 1993, Francisco et al. 2010). Similarly, C. elegans sel-9 and its mammalian homolog TMED2 are Golgi membrane proteins that participate in quality control of proteins transported from Golgi to the plasma membrane. Translocation of a mutant C. elegans NOTCH homolog lin-12 from the Golgi to the plasma membrane is negatively regulated by sel-9 (Wen et al. 1999). A GTPase RAB6 positively controls NOTCH trafficking through Golgi (Purcell et al. 1999). <br><br> <br>Processing of mammalian NOTCH precursors in the Golgi typically involves the cleavage by FURIN convertase. Pre-NOTCH is a ~300 kDa protein, and cleavage by FURIN produces two fragments with approximate sizes of 110 kDa and 180 kDa. The 110 kDa fragment contains the transmembrane and intracellular domains of NOTCH and is known as NTM or NTMICD. The 189 kDa fragment contains NOTCH extracellular sequence and is known as NEC or NECD. The NTM and NEC fragments heterodimerize (Blaumueller et al. 1997, Logeat et al. 1998, Chan et al. 1998) and are held together by disulfide bonds and calcium ions (Rand et al. 2000, Gordon et al. 2009). <br> <br> <br>An optional step in Pre-NOTCH processing in the Golgi is modification by fringe enzymes. Fringe enzymes are glycosyl transferases that initiate elongation of O-linked fucose on fucosylated peptides by addition of a beta 1,3 N-acetylglucosaminyl group, resulting in formation of disaccharide chains on NOTCH EGF repeats (GlcNAc-bet1,3-fucitol). Three fringe enzymes are known in mammals: LFNG (lunatic fringe), MFNG (manic fringe) and RFNG (radical fringe). LFNG shows the highest catalytic activity in modifying NOTCH (Bruckner et al. 2000, Moloney et al. 2000). Fringe-created disaccharide chains on NOTCH EGF repeats are further extended by B4GALT1 (beta-1,4-galactosyltransferase 1), which adds galactose to the N-acetylglucosaminyl group, resulting in formation of trisaccharide Gal-beta1,4-GlcNAc-beta1,3-fucitol chains (Moloney et al. 2000, Chen et al. 2001). Formation of trisaccharide chains is the minimum requirement for fringe-mediated modulation of NOTCH signaling, although fringe-modified NOTCH expressed on the cell surface predominantly contains tetrasaccharide chains on EGF repeats. The tetrasaccharide chains are formed by sialyltransferase(s) that add sialic acid to galactose, resulting in formation of Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). Three known Golgi membrane sialyltransferases could be performing this function: ST3GAL3, ST3GAL4 and ST3GAL6 (Harduin-Lepers et al. 2001). The modification of NOTCH by fringe enzymes modulates NOTCH-signaling by increasing the affinity of NOTCH receptors for delta-like ligands, DLL1 and DLL4, while decreasing affinity for jagged ligands, JAG1 and JAG2. Pubmed10366590 Pubmed10459009 Pubmed10669757 Pubmed10935626 Pubmed10935637 Pubmed11135303 Pubmed11707585 Pubmed1295745 Pubmed1764995 Pubmed19701457 Pubmed20170518 Pubmed20197277 Pubmed7918097 Pubmed8293978 Pubmed8681805 Pubmed9187150 Pubmed9244302 Pubmed9653148 Pubmed9727485 Reactome Database ID Release 431912420 Reactome, http://www.reactome.org ReactomeREACT_118798 Reviewed: Haw, R, 2012-02-06 Reviewed: Joutel, A, 2004-12-15 Signaling by NOTCH1 Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 GENE ONTOLOGYGO:0007219 NOTCH1 functions as both a transmembrane receptor presented on the cell surface and as a transcriptional regulator in the nucleus.<br><br>NOTCH1 receptor presented on the plasma membrane is activated by a membrane bound ligand expressed in trans on the surface of a neighboring cell. In trans, ligand binding triggers proteolytic cleavage of NOTCH1 and results in release of the NOTCH1 intracellular domain, NICD1, into the cytosol.<br><br>NICD1 translocates to the nucleus where it associates with RBPJ (also known as CSL or CBF) and mastermind-like (MAML) proteins (MAML1, MAML2, MAML3 or MAMLD1) to form NOTCH1 coactivator complex. NOTCH1 coactivator complex activates transcription of genes that possess RBPJ binding sites in their promoters. <br><br> Pubmed10206645 Pubmed10713164 Pubmed10879540 Pubmed10882063 Pubmed10964718 Pubmed11006133 Pubmed11044625 Pubmed11226752 Pubmed11461910 Pubmed11585921 Pubmed11740940 Pubmed12050117 Pubmed12354787 Pubmed12391150 Pubmed12530964 Pubmed14567914 Pubmed14980219 Pubmed15107403 Pubmed15546612 Pubmed15574878 Pubmed15652348 Pubmed15824097 Pubmed15965470 Pubmed16256737 Pubmed16284625 Pubmed16530044 Pubmed17003037 Pubmed17028573 Pubmed17114293 Pubmed18043734 Pubmed18077452 Pubmed18094723 Pubmed18237417 Pubmed18296446 Pubmed18374649 Pubmed18628966 Pubmed19524514 Pubmed19567869 Pubmed19726682 Pubmed20418862 Pubmed20972443 Pubmed7566092 Pubmed8001118 Pubmed8313469 Pubmed8649374 Pubmed8687460 Pubmed9244301 Pubmed9315665 Pubmed9462510 Pubmed9590294 Pubmed9620803 Pubmed9694793 Pubmed9819428 Reactome Database ID Release 431980143 Reactome, http://www.reactome.org ReactomeREACT_118859 Reviewed: Haw, R, 2012-02-06 Recruitment of FAK to NCAM1:Fyn in lipid rafts Authored: Garapati, P V, 2009-02-24 10:31:15 EC Number: 2.7.10 Edited: Garapati, P V, 2009-02-24 10:58:20 Fyn activation leads to the recruitment and activation of the non-receptor tyrosine kinase FAK. Once recruited to Fyn, FAK undergoes autophosphorylation on tyrosine 397. This tyrosine allows the binding of SH2 domain containing proteins. Pubmed9079653 Reactome Database ID Release 43391865 Reactome, http://www.reactome.org ReactomeREACT_18333 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Downregulation of TGF-beta receptor signaling Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0030512 Pubmed10757800 Pubmed11158580 Pubmed11163210 Pubmed11278251 Pubmed12151385 Pubmed12519765 Pubmed14701756 Pubmed14718519 Pubmed15496141 Pubmed15781469 Pubmed16027725 Pubmed16061177 Pubmed20061380 Pubmed20129061 Pubmed20937913 Pubmed22045334 Pubmed22344298 Pubmed9215638 Pubmed9335507 Reactome Database ID Release 432173788 Reactome, http://www.reactome.org ReactomeREACT_120727 Reviewed: Huang, Tao, 2012-05-14 TGF-beta receptor signaling is downregulated by proteasome and lysosome-mediated degradation of ubiquitinated TGFBR1, SMAD2 and SMAD3, as well as by dephosphorylation of TGFBR1, SMAD2 and SMAD3. <br> <br>In the nucleus, SMAD2/3:SMAD4 complex stimulates transcription of SMAD7, an inhibitory SMAD (I-SMAD). SMAD7 binds phosphorylated TGFBR1 and competes with the binding of SMAD2 and SMAD3 (Hayashi et al. 1997, Nakao et al. 1997). Biding of SMAD7 to TGBR1 can be stabilized by STRAP, a protein that simultanously binds SMAD7 and TGFBR1 (Datta et al. 2000). <br> <br>In addition to competing with SMAD2/3 binding to TGFBR1, SMAD7 recruits protein phosphatase PP1 to phosphorylated TGFBR1, by binding to the PP1 regulatory subunit PPP1R15A (GADD34). PP1 dephosphorylates TGFBR1, preventing the activation of SMAD2/3 and propagation of TGF-beta signal (Shi et al. 2004). <br> <br>SMAD7 associates with several ubiquitin ligases, SMURF1 (Ebisawa et al. 2001, Suzuki et al. 2002, Tajima et al. 2003, Chong et al. 2010), SMURF2 (Kavsak et al. 2000, Ogunjimi et al. 2005), and NEDD4L (Kuratomi et al. 2005), and recruits them to phosphorylated TGFBR1 within TGFBR complex. SMURF1, SMURF2 and NEDD4L ubiquitinate TGFBR1 (and SMAD7), targeting TGFBR complex for proteasome and lysosome-dependent degradation (Ebisawa et al. 2001, Kavsak et al. 2000, Kuratomi et al. 2005). The ubiquitination of TGFBR1 can be reversed by deubiquitinating enzymes, UCHL5 (UCH37) and USP15, which may be recruited to ubiquitinated TGFBR1 by SMAD7 (Wicks et al. 2005, Eichhorn et al. 2012). <br> <br>Basal levels of SMAD2 and SMAD3 are maintained by SMURF2 and STUB1 ubiquitin ligases. SMURF2 is able to bind and ubiquitinate SMAD2, leading to SMAD2 degradation (Zhang et al. 2001), but this has been questioned by a recent study of Smurf2 knockout mice (Tang et al. 2011). STUB1 (CHIP) binds and ubiquitinates SMAD3, leading to SMAD3 degradation (Li et al. 2004, Xin et al. 2005). PMEPA1 can bind and sequester unphosphorylated SMAD2 and SMAD3, preventing their activation in response to TGF-beta signaling. In addition, PMEPA1 can bind and sequester phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimer complexes (Watanabe et al. 2010). A protein phosphatase MTMR4, residing in the membrane of early endosomes, can dephosphorylate activated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 complexes (Yu et al. 2010). <br> Phosphorylation of FAK by Src kinase Authored: Garapati, P V, 2009-02-24 10:31:15 EC Number: 2.7.10 Edited: Garapati, P V, 2009-02-24 10:58:20 Phosphorylation of Tyr397 in FAK triggers the phosphorylation of other tyrosine residues (Tyr407, Tyr576, Tyr577, Tyr861 and Tyr925) in a Src-dependent manner. The initial phosphorylation of FAK at Tyr397 is thought to create a high-affinity binding site for SH2 domains, enabling formation of a signalling complex between FAK and members of the Src-family kinases. Tyr-576 and Tyr-577 are located in the central catalytic domain and their phosphorylation is required for the maximum kinase activity of FAK. The tyrosine phosphorylation of these residues is likely to be mediated by Src (or other members of the src family). Pubmed12387730 Pubmed7529876 Reactome Database ID Release 43391866 Reactome, http://www.reactome.org ReactomeREACT_18385 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- has a Stoichiometric coefficient of 5 TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0007179 In normal cells and in the early stages of cancer development, signaling by TGF-beta plays a tumor suppressive role, as SMAD2/3:SMAD4-mediated transcription inhibits cell division by downregulating MYC oncogene transcription and stimulating transcription of CDKN2B tumor suppressor gene. In advanced cancers however, TGF-beta signaling promotes metastasis by stimulating epithelial to mesenchymal transition (EMT). <br>TGFBR1 is recruited to tight junctions by binding PARD6A, a component of tight junctions. After TGF-beta stimulation, activated TGFBR2 binds TGFBR1 at tight junctions, and phosphorylates both TGFBR1 and PARD6A. Phosphorylated PARD6A recruits SMURF1 to tight junctions. SMURF1 is able to ubiquitinate RHOA, a component of tight junctions needed for tight junction maintenance, leading to disassembly of tight junctions, an important step in EMT (Wang et al. 2003, Ozdamar et al. 2005). Pubmed14657501 Pubmed15761148 Reactome Database ID Release 432173791 Reactome, http://www.reactome.org ReactomeREACT_120726 Reviewed: Huang, Tao, 2012-05-14 Dephosphorylation of NCAM1 bound pFyn Authored: Garapati, P V, 2009-02-24 10:31:15 EC Number: 3.1.3.48 Edited: Garapati, P V, 2009-02-24 10:58:20 Pubmed12743109 Pubmed15623578 Reactome Database ID Release 43391868 Reactome, http://www.reactome.org ReactomeREACT_18389 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- The homophilic NCAM1:NCAM1 interaction redistributes these molecules and leads to the formation of clusters within lipid rafts. Spectrin, an NCAM1 binding cytoskeletal protein, colocalizes with NCAM1 and codistribute to lipid rafts. Spectrin associates with RPTP-alpha, linking it to the cytoplasmic NCAM1 domain and causing its coredistribution to lipid rafts on NCAM1 clustering. The receptor tyrosine phosphatase RPTP-alpha is an activator of all kinases of the Src family, including Fyn kinase.<p>The interaction of RPTP-alpha and the SH2 domain of Fyn induces an interaction of Fyn Tyr531 with the D1 domain of RPTP-alpha. This induces dephosphorylation of Tyr531 and activates Fyn. Autophosphorylation of NCAM1 bound Fyn Authored: Garapati, P V, 2009-02-24 10:31:15 EC Number: 2.7.10 Edited: Garapati, P V, 2009-02-24 10:58:20 Pubmed15623578 Pubmed9079653 Reactome Database ID Release 43391871 Reactome, http://www.reactome.org ReactomeREACT_18343 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- The Tyr420 residue located in the activation loop of Fyn is responsible for its enzymatic activity. Once the Tyr531 in its negative regulatory site is dephosphorylated by RPTPalpha, Fyn undergoes autophosphorylation on Tyr420 for its maximum activity. kainate receptor binds glutamate Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Kainate receptors bind glutamate in the ligand binding domain in the extracellular, N terminal region. Pubmed19342380 Reactome Database ID Release 43451283 Reactome, http://www.reactome.org ReactomeREACT_21269 Reviewed: Tukey, D, 2009-11-17 NCAM1 binds FGFR-1 Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 FGFR is one of the heterophilic interactors of NCAM. The FG loop region of the second Fn3 module of NCAM binds to Ig domains 2 and 3 of FGFR. The FGFR binding site to NCAM overlaps with the site of NCAM-ATP interaction, and ATP is capable of disrupting NCAM-FGFR binding and signaling. <br>The interaction of NCAM activates FGFR and NCAM might merely mimic FGF's in FGFR stimulation, but there is a difference in the activation pattern induced by NCAM and FGF-2. NCAM activated FGFR stimulates neurite outgrowth by stimulating PLCgamma and DAG lipase leading to generation of arachidonic acid. Pubmed12791257 Pubmed16045455 Reactome Database ID Release 43419033 Reactome, http://www.reactome.org ReactomeREACT_18337 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Pre-NOTCH Transcription and Translation Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 Edited: Gillespie, ME, 2012-02-09 Edited: Jupe, S, 2011-09-27 Edited: May, B, 2012-02-09 Edited: Orlic-Milacic, M, 2012-02-10 In humans, the NOTCH protein family has four members: NOTCH1, NOTCH2, NOTCH3 and NOTCH4. NOTCH1 protein was identified first, as the product of a chromosome 9 gene translocated in T-cell acute lymphoblastic leukemia that was homologous to Drosophila Notch (Ellisen et al. 1991). At the same time, rat Notch1 was cloned (Weinmaster et al. 1991), followed by cloning of mouse Notch1, named Motch (Del Amo et al. 1992). NOTCH2 protein is the product of a gene on chromosome 1 (Larsson et al. 1994). NOTCH2 expression is differentially regulated during B-cell development (Bertrand et al. 2000). NOTCH2 mutations are a rare cause of Alagille syndrome (McDaniell et al. 2006). NOTCH3 is the product of a gene on chromosome 19. NOTCH3 mutations are the underlying cause of CADASIL, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (Joutel et al. 1996). NOTCH4, the last NOTCH protein discovered, is the product of a gene on chromosome 6 (Li et al. 1998). <br><br> MicroRNAs play an important negative role in translation and/or stability of NOTCH mRNAs. MicroRNAs miR-34 (miR-34A, miR-34B and mi-R34C), whose transcription is directly induced by the tumor suppressor protein p53 (Chang et al. 2007, Raver-Shapira et al. 2007, He et al. 2007, Corney et al. 2007) bind and negatively regulate translation of NOTCH1 mRNA (Li et al. 2009, Pang et al. 2010, Ji et al. 2009) and NOTCH2 mRNA (Li et al. 2009). NOTCH1 mRNA translation is also negatively regulated by microRNAs miR-200B and miR-200C (Kong et al. 2010), as well as miR-449A, miR-449B and miR-449C (Marcet et al. 2011). Translation of NOTCH3 mRNA is negatively regulated by microRNAs miR-150 (Ghisi et al. 2011) and miR-206 (Song et al. 2009). Translation of NOTCH4 mRNA is negatively regulated by microRNAs miR-181C (Hashimoto et al. 2010) and miR-302A (Costa et al. 2009). <br><br> Nascent NOTCH peptides are co-translationally targeted to the endoplasmic reticulum for further processing, followed by modification in the Golgi apparatus, before trafficking to the plasma membrane. Endoplasmic reticulum calcium ATPases, positively regulate NOTCH trafficking, possibly by contributing to accurate folding of NOTCH precursors (Periz et al. 1999). Pubmed10545110 Pubmed11187898 Pubmed1425352 Pubmed16773578 Pubmed17540598 Pubmed17540599 Pubmed17554337 Pubmed1764995 Pubmed17823410 Pubmed1831692 Pubmed19714243 Pubmed19723635 Pubmed19773441 Pubmed20080834 Pubmed20351093 Pubmed20495621 Pubmed20805998 Pubmed21551231 Pubmed21602795 Pubmed7698746 Pubmed8878478 Pubmed9693032 Reactome Database ID Release 431912408 Reactome, http://www.reactome.org ReactomeREACT_118568 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 Activation of Ca-permeable Kainate receptors Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Kainate receptors that are assembled with subunits GRIK1-5, are Ca2+ permeable if GRIK1 and GRIK2 are not edited at the Q/R or other sites.<br>These channels permit Ca2+ upon activation by glutamate or other agonists. Pubmed8782898 Pubmed9625352 Reactome Database ID Release 43451311 Reactome, http://www.reactome.org ReactomeREACT_21414 Reviewed: Tukey, D, 2009-11-17 Fyn binds NCAM1 Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 Fyn constitutively associates with the 140 kD isoform of NCAM1 in the plasma membrane, probably indirectly. Fyn is attached to the lipid raft membrane compartment via palmitoylation and is inactivated by tyrosine phosphorylation (Y531) within its C-terminal regulatory region. Fyn kinase has two well-known phosphorylation sites which affect its activity in opposite ways. The phosphorylation of Tyr531 located in the C-terminus of the protein inhibits the Fyn kinase activity, due to the binding of this tyrosine residue to the SH2 domain of the protein, which stabilizes its catalytically inactive conformation. Pubmed7962063 Pubmed9079653 Reactome Database ID Release 43391867 Reactome, http://www.reactome.org ReactomeREACT_18353 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Pre-NOTCH Processing in the Endoplasmic Reticulum Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 In the endoplasmic reticulum, glycosyl transferases modify NOTCH precursors by glycosylating conserved serine and threonine residues in EGF repeats of NOTCH. <br><br> O-fucosyl transferase POFUT1 fucosylates NOTCH serine and threonine residues that conform to the consensus sequence C2-X(4-5)-S/T-C3, where C2 and C3 are the second and third cysteine residue within the EGF repeat, and X(4-5) is four to five amino acid residues of any type (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003). <br> <br>O-glucosyl transferase POGLUT1, mammalian homolog of the Drosophila enzyme Rumi, adds a glucosyl group to conserved serine residues within the EGF repeats of NOTCH. The consensus sequence for POGLUT1-mediated glucosylation is C1-X-S-X-P-C2, where C1 and C2 are the first and second cysteine residue in the EGF repeat, respectively, while X represents any amino acid (Acar et al. 2008, Fernandez-Valdivia et al. 2011). Both fucosylation and glucosylation of NOTCH receptor precursors are essential for functionality. Pubmed11524432 Pubmed12486116 Pubmed18243100 Pubmed18347015 Pubmed21464368 Pubmed21490058 Reactome Database ID Release 431912399 Reactome, http://www.reactome.org ReactomeREACT_118722 Reviewed: Haw, R, 2012-02-06 GRIK3 homomer binds glutamate Authored: Mahajan, SS, 2010-01-04 Edited: Gillespie, ME, 2010-02-05 Kainate receptors bind glutamate in the ligand binding domain in the extracellular, N terminal region. Pubmed19342380 Reactome Database ID Release 43500708 Reactome, http://www.reactome.org ReactomeREACT_21255 Reviewed: Tukey, D, 2009-11-17 NCAM1 cis-homophilic interaction Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 NCAM1 located on the cell membrane can participate in parallel cis and antiparallel trans-homophilic interactions. The cis-interaction is mediated by reciprocal IgI-IgII interactions: the IgI domain of one NCAM1 molecule interacts with the IgII domain of a second. Pubmed14527396 Pubmed15353284 Pubmed15662836 Reactome Database ID Release 43391872 Reactome, http://www.reactome.org ReactomeREACT_18267 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- has a Stoichiometric coefficient of 2 Signaling by NOTCH Authored: Jassal, B, 2004-12-15 13:08:03 GENE ONTOLOGYGO:0007219 NOTCH Signaling Pathway Pubmed10221902 Pubmed10889061 Pubmed11112321 Pubmed14986688 Reactome Database ID Release 43157118 Reactome, http://www.reactome.org ReactomeREACT_299 Reviewed: Joutel, A, 2004-12-15 The Notch Signaling Pathway (NSP) is a highly conserved pathway for cell-cell communication. NSP is involved in the regulation of cellular differentiation, proliferation, and specification. For example, it is utilised by continually renewing adult tissues such as blood, skin, and gut epithelium not only to maintain stem cells in a proliferative, pluripotent, and undifferentiated state but also to direct the cellular progeny to adopt different developmental cell fates. Analogously, it is used during embryonic development to create fine-grained patterns of differentiated cells, notably during neurogenesis where the NSP controls patches such as that of the vertebrate inner ear where individual hair cells are surrounded by supporting cells.<br>This process is known as lateral inhibition: a molecular mechanism whereby individual cells within a field are stochastically selected to adopt particular cell fates and the NSP inhibits their direct neighbours from doing the same. The NSP has been adopted by several other biological systems for binary cell fate choice. In addition, the NSP is also used during vertebrate segmentation to divide the growing embryo into regular blocks called somites which eventually form the vertebrae. The core of this process relies on regular pulses of Notch signaling generated from a molecular oscillator in the presomatic mesoderm.<br>The Notch receptor is synthesized in the rough endoplasmic reticulum as a single polypeptide precursor. Newly synthesized Notch receptor is proteolytically cleaved in the trans-golgi network, creating a heterodimeric mature receptor comprising of non-covalently associated extracellular and transmembrane subunits. This assembly travels to the cell surface ready to interact with specific ligands. Following ligand activation and further proteolytic cleavage, an intracellular domain is released and translocates to the nucleus where it regulates gene expression. Activation of GRIK3 homomer Authored: Mahajan, SS, 2010-02-04 Edited: Gillespie, ME, 2010-02-05 Kainate receptor activation activates G protein coupled receptors involving the release of Ca2+ from the intracellular stores. This activity of Kainate receptors is independent of ionic influx and regulates both glutamate release by the pyramidal neurons and gama-aminobutyric acid release by the internuerons. Pubmed20007474 Reactome Database ID Release 43500717 Reactome, http://www.reactome.org ReactomeREACT_21309 Reviewed: Tukey, D, 2009-11-17 NCAM1 trans-homophilic interaction Antiparallel NCAM interactions involve trans-interactions of NCAM molecules on opposed cell membranes. Based on structural and functional studies a 'double zipper' model has been proposed to describe these interactions. The first model - the 'flat zipper'- formed between NCAM1 cis-dimers from one cell surface interacting in trans through IgII-IgIII contacts with NCAM1 cis-dimers from another cell surface. The second model - the 'compact zipper'- is formed between NCAM1 cis-dimers from one cell surface interacting in trans through IgI-IgIII and IgII-IgII contacts with cis-dimers from another cell surface.<p>Abrogation of cis-dimerization inhibits NCAM mediated neurite outgrowth, and cis-dimerization of NCAM1 may be a necessary prerequisite for subsequent trans-interactions. Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 Pubmed14527396 Pubmed15662836 Reactome Database ID Release 43375161 Reactome, http://www.reactome.org ReactomeREACT_18271 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- has a Stoichiometric coefficient of 2 Pre-NOTCH Expression and Processing Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Edited: D'Eustachio, P, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009). <br><br> The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011). <br><br> In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling. Pubmed10669757 Pubmed10935626 Pubmed10935637 Pubmed11524432 Pubmed11707585 Pubmed12486116 Pubmed18243100 Pubmed18347015 Pubmed19701457 Pubmed19714243 Pubmed19723635 Pubmed19773441 Pubmed20080834 Pubmed20351093 Pubmed20495621 Pubmed20805998 Pubmed21464368 Pubmed21490058 Pubmed21551231 Pubmed21602795 Pubmed9187150 Pubmed9207795 Pubmed9244302 Pubmed9653148 Pubmed9727485 Reactome Database ID Release 431912422 Reactome, http://www.reactome.org ReactomeREACT_118744 Reviewed: Haw, R, 2012-02-06 GABAB heterodimeric receptor binds GABA Authored: Jassal, B, 2009-05-13 14:32:46 Edited: Jassal, B, 2009-05-13 14:32:46 Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter in the mammalian central nervous system. GABA exerts its effects through two ligand-gated channels and a the GPCR GABAB (Kaupmann K et al, 1998), which acts through G proteins to regulate potassium and calcium channels. GABAB can only bind GABA once it forms a heterodimer composed of the GABABR1 and GABABR2 receptors (White JH et al, 1998). The effects of this dimer are mediated by coupling to the G protein alpha i subunit, which inhibits adenylyl cyclase. Pubmed9844003 Pubmed9872316 Reactome Database ID Release 43420688 Reactome, http://www.reactome.org ReactomeREACT_18291 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The GABA(A) receptor complex is permeable to Cl- when GABA binds to it Authored: Jassal, B, 2010-09-23 Edited: Jassal, B, 2010-09-23 Pubmed1321750 Pubmed15024690 Pubmed1664410 Pubmed2465923 Pubmed2847710 Pubmed8264558 Pubmed8382267 Pubmed8391122 Pubmed8632757 Pubmed8719414 Pubmed8719416 Reactome Database ID Release 43975340 Reactome, http://www.reactome.org ReactomeREACT_25130 Reviewed: He, L, 2010-11-15 The GABAA receptor (GABA(A)) family belongs to the ligand-gated ion channel superfamily (LGIC). Its endogenous ligand is gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. There are six alpha subunits (Garrett et al, 1988; Schofield et al, 1989; Hadingham et al, 1993; Edenberg et al, 2004; Hadingham et al, 1993; Yang et al, 1995; Wingrove et al, 1992; Hadingham et al, 1996), three beta subunits (Schofield et al, 1989; Hadingham et al, 1993; Wagstaff et al, 1991) and 2 gamma subunits (Khan et al, 1993; Hadingham et al, 1995) characterized. GABA(A) functions as a heteropentamer, the most common structure being 2 alpha subunits, 2 beta subunits and a gamma subunit. Upon binding of GABA, the GABA(A) receptor complex conducts chloride ions through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by reducing the chances of a successful action potential occurring. G alpha-olf:GTP binds to Gi alpha1:GTP:adenylate cyclase complex Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed1658606 Pubmed17230639 Pubmed9865521 Reactome Database ID Release 43170671 Reactome, http://www.reactome.org ReactomeREACT_15435 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The chronic activation of mu-opioid receptors, which, when coupled to pertussis toxin-sensitive Galpha-i/o proteins, inhibit adenylyl cyclase (AC). G alpha (i) inhibits adenylate cyclase Authored: Jupe, S, 2009-02-26 15:48:59 Edited: Jupe, S, 2009-09-09 G-proteins in the Gi class inhibit adenylate cyclase activity, decreasing the production of cAMP from ATP, which has many consequences but classically results in decreased activity of Protein Kinase A (PKA). cAMP also activates the cyclic nucleotide-gated ion channels, a process that is particularly important in olfactory cells. Pubmed8119955 Pubmed8327893 Reactome Database ID Release 43392206 Reactome, http://www.reactome.org ReactomeREACT_19222 Reviewed: Akkerman, JW, 2009-06-03 Adenylate cyclase increases the GTPase activity of Gi alpha Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jassal, B, 2008-11-06 10:17:49 G proteins can deactivate themselves via their intrinsic GTPase activity, which hydrolyzes GTP to GDP. Effectors such as adenylate cyclase can increase the G protein GTPase rate, acting like GTPase-activating proteins (GAPs). Pubmed7937899 Reactome Database ID Release 43170686 Reactome, http://www.reactome.org ReactomeREACT_15495 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Adenylate cyclase increases the GTPase activity of G alpha-olf Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Jassal, B, 2008-11-06 10:17:49 G proteins can deactivate themselves via their intrinsic GTPase activity, which hydrolyzes GTP to GDP. Effectors such as adenylate cyclase can increase the G protein GTPase rate, acting like GTPase-activating proteins (GAPs). Pubmed7937899 Reactome Database ID Release 43170666 Reactome, http://www.reactome.org ReactomeREACT_15335 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Recruitment of Grb2 to pFAK:NCAM1 Authored: Garapati, P V, 2009-02-24 10:31:15 Edited: Garapati, P V, 2009-02-24 10:58:20 Phosphorylated tyrosine 925 in the FAT domain of FADK1 creates a docking site for the SH2 domain of GRB2 and recruits the GRB2/SOS complex. FADK1 may use this mechanism to activate Ras and the MAP kinase pathway. Pubmed12700044 Pubmed2809592 Pubmed7997267 Reactome Database ID Release 43392051 Reactome, http://www.reactome.org ReactomeREACT_18375 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- Chemokine receptors bind chemokines Authored: Jassal, B, 2008-11-07 12:17:32 Chemokine receptors are cytokine receptors found on the surface of certain cells, which interact with a type of cytokine called a chemokine. Following interaction, these receptors trigger a flux of intracellular calcium which leads to chemotaxis. Chemokine receptors are divided into different families, CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors and XC chemokine receptors that correspond to the 4 distinct subfamilies of chemokines they bind. Pubmed10807766 Pubmed11544102 Pubmed15578986 Reactome Database ID Release 43380108 Reactome, http://www.reactome.org ReactomeREACT_15344 Tachykinin receptors bind tachykinins Authored: Jassal, B, 2008-11-24 14:25:55 Edited: Jassal, B, 2008-11-24 14:25:55 Pubmed15224188 Pubmed16918325 Reactome Database ID Release 43380095 Reactome, http://www.reactome.org ReactomeREACT_16963 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Tachykinin peptides are one of the largest family of neuropeptides, so named due to their ability to rapidly induce contraction of gut tissue. Tachykinins excite neurons, elicit behavioural responses, are potent vasodilators and contract many smooth muscles. The tachykinin family is characterized by a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2 (where X can be either an aromatic or an aliphatic amino acid) and are ten to twelve residues long.<br><br>These peptides elicit their effects via the tachykinin receptors, of which there are three types in humans (NK1,2 and 3). There are two human tachykinin peptide genes in humans, TAC1 and TAC3. TAC1 encodes substance P and substance K while TAC3 encodes neurokinin B.<br><br>Antagonists of these receptors are promising candidates for classes of antidepressants, anxiolytics and antipsychotics. Vasopressin-like receptors Authored: Jassal, B, 2008-12-12 10:43:13 Edited: Jassal, B, 2008-12-12 10:43:13 Pubmed11274341 Pubmed8719042 Pubmed8734452 Reactome Database ID Release 43388479 Reactome, http://www.reactome.org ReactomeREACT_17041 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The vasopressins are peptide hormones consisting of nine amino acids (nonapeptides). They include arginine vasopressin (AVP; anti-diuretic hormone, ADH) and oxytocin. They are synthesized in the hypothalamus from a precursor and released from stores in the posterior pituitary into the blood stream. One of the most important roles of vasopressins is the regulation of water retention in the body. Oxytocin is important in uterine contraction during birth. The vasopressins act via AVP and oxytocin receptors. These are connected to G proteins which act as second messengers and convey the signal inside the cell. Sema3E binds plexin-D1 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed15550623 Reactome Database ID Release 43416683 Reactome, http://www.reactome.org ReactomeREACT_19273 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema3E directly binds Plexin-D1. This interaction provides guidance for growing axons and migrating endothelial cells. Sema4A binds Plexin-D1 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed17318185 Pubmed18374575 Reactome Database ID Release 43416690 Reactome, http://www.reactome.org ReactomeREACT_19408 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema4A binds plexinD1 to inhibit angiogenesis. Sema4A–plexinD1 interactions modulate VEGF-mediated endothelial cell migration and proliferation at the intracellular level by suppressing VEGF–VEGFR2-induced activation of Rac1, Akt and integrins. Signaling by NOTCH2 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: Orlic-Milacic, M, 2012-02-10 GENE ONTOLOGYGO:0007219 Reactome Database ID Release 431980145 Reactome, http://www.reactome.org ReactomeREACT_118721 Reviewed: Joutel, A, 2004-12-15 Similar to NOTCH1, NOTCH2 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH2, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH2, NICD2, into the cytosol. NICD2 subsequently traffics to the nucleus where it acts as a transcriptional regulator. Sema5A binds Plexin-B3 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed15218527 Reactome Database ID Release 43416698 Reactome, http://www.reactome.org ReactomeREACT_19322 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema5s have been implicated in invasive growth, vascular patterning and axon guidance. Plexin-B3 is the specific and high-affinity receptor for Sema5A, and their interaction triggers the collapsing response. Signaling by NOTCH3 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: Orlic-Milacic, M, 2012-02-10 GENE ONTOLOGYGO:0007219 Reactome Database ID Release 431980148 Reactome, http://www.reactome.org ReactomeREACT_118862 Reviewed: Joutel, A, 2004-12-15 Similar to NOTCH1, NOTCH3 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH3, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH3, NICD3, into the cytosol. NICD3 subsequently traffics to the nucleus where it acts as a transcriptional regulator. Sema6A binds Plexin-A2 and Plexin-A4 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed17296555 Reactome Database ID Release 43416723 Reactome, http://www.reactome.org ReactomeREACT_19345 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema6A binds plexinA2 and plexinA4 to establish lamina-restricted axon projection in the hippocampus. Signaling by NOTCH4 Authored: Jassal, B, 2004-12-15 13:08:03 Edited: Orlic-Milacic, M, 2012-02-10 GENE ONTOLOGYGO:0007219 Reactome Database ID Release 431980150 Reactome, http://www.reactome.org ReactomeREACT_118636 Reviewed: Joutel, A, 2004-12-15 Similar to NOTCH1, NOTCH4 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH4, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH4, NICD4, into the cytosol. NICD4 subsequently traffics to the nucleus where it acts as a transcriptional regulator. CaMKII enters nucleus Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 Nuclear targeting of CaMKII depends on several factors including the phosphorylation in the regulatory domain of CaMKII and induction of other signal transduction pathways. Pubmed18218981 Reactome Database ID Release 43444792 Reactome, http://www.reactome.org ReactomeREACT_20579 Reviewed: Tukey, D, 2009-11-17 Recruitment and activation of Cdk5 Authored: Garapati, P V, 2009-03-23 09:59:28 Cdk5:p53 complex is recruited to the growth cone by associating with active Fyn. Fyn promotes the kinase activity of Cdk5 by phosphorylating Cdk5 on tyrosine residue 15. Activation of Cdk5 by Fyn via Tyr15 phosphorylation might facilitate suppression of Rac-PAK signaling downstream of PlexinA. <br>Cyclin-dependent kinase 5 (Cdk5), a member of the serine/threonine kinase Cdk family, is complexed with p35 a neuron specific activator of Cdk5. The complex Cdk5:p35 is required for neurite outgrowth and cortical lamination. EC Number: 2.7.10 Edited: Garapati, P V, 2009-03-23 10:00:07 Reactome Database ID Release 43399946 Reactome, http://www.reactome.org ReactomeREACT_19393 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Signaling by GPCR Authored: Jassal, B, 2008-07-02 14:14:59 Edited: D'Eustachio, P, 2008-09-01 11:58:31 G protein-coupled receptors (GPCRs; 7TM receptors; seven transmembrane domain receptors; heptahelical receptors; G protein-linked receptors [GPLR]) are the largest family of transmembrane receptors in humans, accounting for more than 1% of the protein-coding capacity of the human genome. All known GPCRs share a common architecture of seven membrane-spanning helices connected by intra- and extracellular loops. The extracellular loops contain two highly-conserved cysteine residues that form disulphide bonds to stabilize the structure of the receptor. They recognize diverse messengers such as light, odorants, small molecules, hormones and neurotransmitters. Most GPCRs act as guanine nucleotide exchange factors; activated by ligand binding, they promote GDP-GTP exchange on associated heterotrimeric guanine nucleotide-binding (G) proteins. There are two models for GPCR-G Protein interactions: 1) ligand-GPCR binding first, then binding to G Proteins; 2) "Pre-coupling" of GPCRs and G Proteins before ligand binding (review Oldham WM and Hamm HE, 2008). These in turn activate effector enzymes or ion channels. GPCRs are involved in a range of physiological roles which include the visual sense, smell, behavioural regulation, functions of the autonomic nervous system and regulation of the immune system and inflammation.<br>GPCRs are divided into 6 classes based on sequence homology and functional similarity; the main mammalian families are classes A/1-C/3;<br><br>Class A/1 (Rhodopsin-like)<br>Class B/2 (Secretin receptor family)<br>Class C/3 (Metabotropic glutamate/pheromones)<br>Class D/4 (fungal mating pheromone receptors)<br>Class E/5 (cAMP receptors)<br>Class F/6 (Frizzled/Smoothened)<br><br>Here, those Class A/1 (Rhodopsin-like) receptors that bind peptide ligands have been annotated. The binding events mediated by other classes of receptors, as well as the downstream events triggered by receptor-ligand interactions will be annotated in future releases of Reactome. Pubmed10202136 Pubmed16902930 Pubmed18043707 Reactome Database ID Release 43372790 Reactome, http://www.reactome.org ReactomeREACT_14797 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Phosphorylation of CREB by CaMKII Authored: Mahajan, SS, 2009-10-29 CaMKII is an important regulator of neuronal plasticity. CaMKII shows distinct subcellular localization and acts quickly in a spatio-temporal manner. CaMKII shows fast synaptic localization upon synaptic activity and also nuclear localization, where it phosphorylates CREB at serine 133 to activate transcription of set of genes that results in long lasting structural changes at the synapse. EC Number: 2.7.11.17 Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed11013247 Reactome Database ID Release 43443475 Reactome, http://www.reactome.org ReactomeREACT_20576 Reviewed: Tukey, D, 2009-11-17 Phosphorylation of CRMPs by Cdk5 Authored: Garapati, P V, 2009-03-23 09:59:28 Cdk5:p35 complex is associated with Plexin-A through the actived form of Fyn. CRMPs are the downstream substrates for Cdk5. Cdk5 phosphorylates serine 522 of CRMPs. Phosphorylation of CRMPs mediates the Sema3A induced growth cone collapse.<br>Collapsin response mediator proteins (CRMPs) are five homologous cytosolic phosphoproteins (CRMP1–5) involved in neuronal differentiation and axonal guidance. These members oligomerize and exist as tetramers. EC Number: 2.7.11 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed12372285 Pubmed14685275 Pubmed17607942 Reactome Database ID Release 43399944 Reactome, http://www.reactome.org ReactomeREACT_19285 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 has a Stoichiometric coefficient of 4 GPCR ligand binding Authored: Jassal, B, 2010-02-05 Edited: Jupe, S, 2010-02-10 Pubmed12688373 Pubmed12761335 Pubmed15251227 Reactome Database ID Release 43500792 Reactome, http://www.reactome.org ReactomeREACT_21340 Reviewed: D'Eustachio, P, 2009-12-11 There are more than 800 G-protein coupled receptor (GPCRs) in the human genome, making it the largest receptor superfamily. GPCRs are also the largest class of drug targets, involved in virtually all physiological processes (Frederiksson 2003). GPCRs are receptors for a diverse range of ligands from large proteins to photons (Kristiansen et al. 2004) and have an equal diversity of ligand-binding mechanisms (Gether et al. 2002). Classical GPCR signaling involves signal transduction via heterotrimeric G-proteins, however many G-protein independent mechanisms have been reported. Phosphorylation of CRMPs by GSK3beta Authored: Garapati, P V, 2009-03-23 09:59:28 EC Number: 2.7.11 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed15652488 Pubmed15676027 Pubmed17607942 Reactome Database ID Release 43399951 Reactome, http://www.reactome.org ReactomeREACT_19321 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 The phosphorylation of CRMPs at Ser522 allows the subsequent phosphorylation of CRMP1, CRMP2 and CRMP4 at Ser518, Thr509, and Thr514 mediated by serine/threonine kinase GSK3beta. Phosphorylation of CRMP by GSK3beta results in decreased CRMP affinity for beta-tubulin and changes in microtubule dynamics. has a Stoichiometric coefficient of 9 Class A/1 (Rhodopsin-like receptors) Authored: Jassal, B, 2008-07-03 10:57:39 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed12429062 Pubmed16902930 Reactome Database ID Release 43373076 Reactome, http://www.reactome.org ReactomeREACT_14828 Reviewed: Bockaert, J, 2008-09-01 12:04:13 Rhodopsin-like receptors (class A/1) are the largest group of GPCRs and are the best studied group from a functional and structural point of view. They show great diversity at the sequence level and thus, can be subdivided into 19 subfamilies (Subfamily A1-19) based on a phylogenetic analysis (Joost P and Methner A, 2002). They represent members which include hormone, light and neurotransmitter receptors and encompass a wide range of functions including many autocrine, paracrine and endocrine processes. CaMKII enters cytoplasm Authored: Mahajan, SS, 2009-10-29 CaMKII gets activated upon Ca2+ influx through the NMDA receptor and moves from plasma membrane to cytoplasm and then nucleus where it phosphorylates CREB at serine 133. Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed8615909 Reactome Database ID Release 43445367 Reactome, http://www.reactome.org ReactomeREACT_20566 Reviewed: Tukey, D, 2009-11-17 Tyrosine phosphorylation of CRMPs by Fes Authored: Garapati, P V, 2009-03-23 09:59:28 EC Number: 2.7.10 Edited: Garapati, P V, 2009-03-23 10:00:07 Fes bound to Plexin-A is able to phosphorylate all five forms of CRMP, though neither specific sites nor the consequence of tyrosine phosphorylation in CRMP's have yet been investigated directly. Pubmed12093729 Pubmed17607942 Pubmed17607944 Reactome Database ID Release 43399947 Reactome, http://www.reactome.org ReactomeREACT_19161 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 has a Stoichiometric coefficient of 5 Peptide ligand-binding receptors Authored: Jassal, B, 2008-08-21 14:07:16 Edited: D'Eustachio, P, 2008-09-01 11:58:31 Pubmed10977869 Pubmed12432945 Pubmed12895595 Pubmed14507421 Pubmed14576899 Pubmed15734727 Pubmed16612131 Pubmed16847439 Pubmed16918325 Pubmed17293890 Pubmed17604107 Reactome Database ID Release 43375276 Reactome, http://www.reactome.org ReactomeREACT_14819 Reviewed: Bockaert, J, 2008-09-01 12:04:13 These receptors, a subset of the Class A/1 (Rhodopsin-like) family, all bind peptide ligands which include the chemokines, opioids and somatostatins. CaMK IV autophosphorylation Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Autophosphorylation of the N-terminus Ser12-Ser13 is required for full activation after Ca2+/calmodulin binding and phosphorylation of the Ca2+/calmodulin-bound enzyme on Thr200 by a Ca2+/calmodulin-dependent protein kinase kinase. EC Number: 2.7.11.17 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed8702940 Reactome Database ID Release 43111915 Reactome, http://www.reactome.org ReactomeREACT_15320 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 CamKIV enters the nucleus Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Pubmed14701808 Reactome Database ID Release 43112282 Reactome, http://www.reactome.org ReactomeREACT_15332 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 The calmodulin:CaMK IV complex enters the nucleus. Calmodulin binds CaMK IV Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 CaMKIV becomes fully activated after a three-step mechanism: Upon a transient increase in intracellular calcium, calcium-bound calmodulin (Ca2+/CaM) binds to its autoregulatory domain, which relieves intersteric inhibition. An activating protein kinase, calcium/calmodulin-dependent protein kinase kinase (CaMKK), binds to the Ca2+/CaM:CaMKIV complex and phosphorylates CaMKIV on a threonine residue in the activation loop. After full activation by the three-step mechanism mentioned above, the activity of CaMKIV becomes autonomous and no longer requires bound Ca2+/CaM. This activity is required for CaMKIV-mediated transcriptional regulation. The CaMKIV-associated PP2A then dephosphorylates CaMKIV, thereby terminating autonomous activity and CaMKIV-mediated gene transcription. Edited: Jassal, B, 2008-11-06 10:17:49 Reactome Database ID Release 43111913 Reactome, http://www.reactome.org ReactomeREACT_15339 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Activation of CaMKK Authored: Mahajan, SS, 2009-10-29 CaMKK is fully activated upon binding Ca2+/Calmodulin after intracellular Ca2+ levels increase. Once CaMKK binds Ca2+/Calmodulin it autophosphorylates, resulting in activation. CaMKK is negatively regulated by phosphorylation of S74 and T108 by PKA. Once activated CaMKK phosphorylates CaMKIV in a Ca2+/Calmodulin dependent manner. EC Number: 2.7.11.17 Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed15591024 Reactome Database ID Release 43442749 Reactome, http://www.reactome.org ReactomeREACT_20635 Reviewed: Tukey, D, 2009-11-17 Sema7A binds Plexin-C1 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Pubmed10520995 Reactome Database ID Release 43434989 Reactome, http://www.reactome.org ReactomeREACT_19190 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Sema7A signals through two unrelated receptors, an RGD-dependent alpha1beta1-integrin and a member of the plexin family, plexinC1. Sema7A-plexinC1 interactions have been implicated in immune system function and also participate in neuronal network formation. Activation of Edited Kainate receptors Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Pubmed16221857 Reactome Database ID Release 43451310 Reactome, http://www.reactome.org ReactomeREACT_21274 Reviewed: Tukey, D, 2009-11-17 The activation of Kainate receptors by glutamate in the postsynaptic neuron leads to influx of Na+ ions resulting in depolarization of the postsynaptic membrane. Sema6D binds PlexinA1-Trem2-DAP12 Authored: Garapati, P V, 2009-03-23 09:59:28 Edited: Garapati, P V, 2009-03-23 10:00:07 Plexin-A1 is a receptor for the transmembrane semaphorin, Sema6D. Plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12. Pubmed16715077 Reactome Database ID Release 43416725 Reactome, http://www.reactome.org ReactomeREACT_19177 Reviewed: Kumanogoh, A, Kikutani, H, 2009-09-01 Edited Kainate Receptor binds glutamate Authored: Mahajan, SS, 2010-01-15 Edited: Gillespie, ME, 2010-02-05 Kainate receptors bind glutamate in the ligand binding domain in the extracellular, N terminal region. Pubmed19342380 Reactome Database ID Release 43451309 Reactome, http://www.reactome.org ReactomeREACT_21317 Reviewed: Tukey, D, 2009-11-17 Phosphorylation of CREB by CaMKIV Activated CaMKIV phosphorylates CREB at S133 thereby initiating the transcription of CREB regulated set of genes leading to protein synthesis and long lasting changes that underlie synaptic plasticity. Authored: Mahajan, SS, 2009-10-29 EC Number: 2.7.11.17 Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed19001277 Reactome Database ID Release 43443480 Reactome, http://www.reactome.org ReactomeREACT_20666 Reviewed: Tukey, D, 2009-11-17 Serotonin receptors Authored: Jassal, B, 2009-02-12 10:33:32 Edited: Jassal, B, 2009-02-12 10:33:32 Pubmed17897004 Pubmed7938165 Reactome Database ID Release 43390666 Reactome, http://www.reactome.org ReactomeREACT_17064 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role as a modulator of anger, aggression, body temperature, mood, sleep, sexuality, appetite, metabolism, as well as stimulating vomiting. Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics and antimigraine drugs. The activity of 5-HT is modulated by 5-HT receptors, made up of seven families (5-HT1-7). All but 5-HT3 (ligand-gated ion channel) are GPCRs and these receptors bind different G proteins resulting in differing outcomes (Hoyer D et al, 1994; Kitson SL, 2007). Hormone ligand-binding receptors Authored: Jassal, B, 2009-02-23 11:19:01 Edited: Jassal, B, 2009-02-23 11:19:01 Pubmed11750726 Pubmed11861490 Pubmed11917095 Pubmed11943741 Reactome Database ID Release 43375281 Reactome, http://www.reactome.org ReactomeREACT_16942 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The class A (rhodopsin-like) GPCRs that bind to hormone ligands are annotated here. The hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH) and human chorionic gonadotrophin (hCG) are dimeric glycoproteins, sharing an identical alpha subunit and varying beta subunits. Their actions are mediated by the respective GPCRs, influencing reproductive processes and thyroid hormone release. Activation of voltage gated Potassium channels Activation of voltage gated potassium channel is triggered by membrane potential changes that is sensed by the channel assembly. Activation of voltage-gated potassium channel leads to selective outward current of K+ ions. Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Pubmed20393197 Pubmed21231794 Reactome Database ID Release 431296127 Reactome, http://www.reactome.org ReactomeREACT_75857 Reviewed: Jassal, B, 2010-09-23 Dopamine receptors Authored: Jassal, B, 2009-02-10 10:07:58 Dopamine receptors play vital roles in processes such as the control of learning, motivation, fine motor control and modulation of neuroendocrine signaling (Giralt JA and Greengard P, 2004). Abnormalities in dopamine receptor signaling may lead to neuropsychiatric disorders such as Parkinson's disease and schizophrenia. Dopamine receptors are prominent in the CNS and the neurotransmitter dopamine is the primary endogenous ligand for these receptors. In humans, there are five distinct types of dopamine receptor, D1-D5. They are subdivided into two families; D1-like family (D1 and D5) which couple with the G protein alpha-s and are excitatory and D2-like family (D2,D3 and D4) which couple with the G protein alpha-i and are inhibitory (Kebabian JW and Calne DB, 1979). Edited: Jassal, B, 2009-02-10 10:07:58 Pubmed15148138 Pubmed215920 Reactome Database ID Release 43390651 Reactome, http://www.reactome.org ReactomeREACT_16968 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Activation of tandem pore domain in a weak inwardly rectifying K+ channels Activation of TWIK channels results in low outward K+ currents. Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed19959478 Reactome Database ID Release 431299304 Reactome, http://www.reactome.org ReactomeREACT_75806 Reviewed: Jassal, B, 2010-09-23 Histamine receptors Authored: Jassal, B, 2009-02-11 13:39:02 Edited: Jassal, B, 2009-02-11 13:39:02 Histamine is a biogenic amine involved in local immune responses, regulation of gut function and neurotransmission. It exerts its actions by binding to histamine receptors. There are four receptors in humans, H1-H4 (Hill SJ et al, 1997). Pubmed9311023 Reactome Database ID Release 43390650 Reactome, http://www.reactome.org ReactomeREACT_16903 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Activation of TWIK-related K+ channel (TREK) Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Pubmed19536465 Pubmed19840997 Pubmed20133877 Pubmed20410120 Reactome Database ID Release 431296348 Reactome, http://www.reactome.org ReactomeREACT_75846 Reviewed: Jassal, B, 2010-09-23 TREK channels are activated by mechanical stretch, pH temperature and arachidonic acid which leads to efflux of K+ into the extracellular space resulting in membrane hyperpolarization. Muscarinic acetylcholine receptors Authored: Jassal, B, 2009-02-10 10:07:58 Edited: Jassal, B, 2009-02-10 10:07:58 Muscarinic acetylcholine (mAChRs) receptors were so named because they are more sensitive to muscarine than to nicotine (Ishii M and Kurachi Y, 2006). Their counterparts are nicotinic acetylcholine receptors (nAChRs), ion channels receptors that are also important in the autonomic nervous system. Many drugs can manipulate these two distinct receptors by acting as selective agonists or antagonists. mAChRs bind to the bioamine acetylcholine, have a widespread tissue distribution and are involved in the control of numerous central and peripheral physiological responses, particularly voluntary muscle contraction. They are also major targets for drugs in human diseases such as Alzheimer's, Parkinson's and schizophrenia. This family of G-protein coupled receptors consists of five members designated M1-M5 and are sub-divided into two groups based on their primary coupling to G proteins. M2 and M4 receptors couple to Gi/o proteins and M1, M3 and M5 receptors couple to Gq/11 proteins (Caulfield MP and Birdsall NJ, 1998). Pubmed17073660 Pubmed9647869 Reactome Database ID Release 43390648 Reactome, http://www.reactome.org ReactomeREACT_16943 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 Activation of TASK Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed18824070 Reactome Database ID Release 431299318 Reactome, http://www.reactome.org ReactomeREACT_75935 Reviewed: Jassal, B, 2010-09-23 TASK are tandem repeat K+ channels that are sensitive to extracellular pH. Activation of TASK results in efflux of K+ into the extracellular space. Adrenoceptors Authored: Jassal, B, 2009-02-10 10:07:58 Edited: Jassal, B, 2009-02-10 10:07:58 Pubmed7938162 Reactome Database ID Release 43390696 Reactome, http://www.reactome.org ReactomeREACT_16927 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The adrenoceptors (adrenergic receptors) are targets for the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine). These receptors are widespread in the body and binding of catecholamines produces a sympathetic response ('flight-or-fight response') resulting in increased heart rate, pupil dilation and energy mobilization amongst other responses. There are three major types of adrenoceptor, alpha1, alpha2 and beta. Each type is thought to have three subtypes; alpha1 (1A,1B,1D), alpha2 (2A,2B,2C) and beta (1,2,3) (Bylund DB et al, 1994). Relaxin receptors Authored: Jupe, S, 2009-10-26 Edited: Jupe, S, 2010-03-01 Pubmed12826326 Pubmed17293890 Reactome Database ID Release 43444821 Reactome, http://www.reactome.org ReactomeREACT_21314 Relaxins are part of a family of peptide hormones that diverged from insulin in early vertebrate evolution to form the insulin-like peptides and relaxins, now often referred to as the relaxin peptide family. All are heterodimers; both chains are cleaved from a common propeptide and cross-linked by 2 disulphide bonds. Humans have 3 true relaxins encoded by 3 related genes, plus several more distantly related insulin-like peptide genes. Non-primates have 2 relaxin genes. The major circulating form of relaxin in humans is relaxin-2, equivalent to relaxin-1 in non-primates. Relaxin-3 is very highly conserved. Little is known about human relaxin-1; several of the insulin-like peptides have no known receptor or function. <br> There are 4 human G-protein coupled receptors for relaxin family peptides. Relaxin receptor 1 (RXFP1) and relaxin receptor 2 (RXFP2) are also known as LGR7 and LGR8 respectively, members of the LRR-containing G protein-coupled receptors (LGRs). Relaxin-3 receptor 1 (RXFP3) and Relaxin-3 receptor 2 (RXFP4) are unrelated, having more homology with small peptide receptors such as the somatostatin receptors. Reviewed: D'Eustachio, P, 2009-12-11 Amine ligand-binding receptors Authored: Jassal, B, 2008-08-21 14:55:38 Edited: Jassal, B, 2008-08-21 14:55:38 Pubmed11459929 Pubmed15148138 Pubmed17073660 Pubmed17897004 Pubmed7938162 Pubmed9311023 Reactome Database ID Release 43375280 Reactome, http://www.reactome.org ReactomeREACT_16983 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The class A (rhodopsin-like) GPCRs that bind to classical biogenic amine ligands are annotated here. The amines involved (acetylcholine, adrenaline, noradrenaline, dopamine, serotonin and histamine) can all act as neurotransmitters in humans. The so-called 'trace amines', used when referring to p-tyramine, beta-phenylethylamine, tryptamine and octopamine, can also bind to recently-discovered GPCRs. Activation of ATP sensitive Potassium channels in muscle cells Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 In muscle cells such as cardiac, skeletal, vascular and nonvascular smooth muscle, ATP sensitive K+ channels assemble as octamers of four Kir 6.x subunits and four low-affinity sulfonyl urea receptor 2 subunits (SUR2). The human gene encoding SUR2 gives rise to two splice variants, SUR2A and SUR2B. These channels are blocked by excess intracellular levels of ATP. When the ATP is low, ATP dissociates and the channel opens to allow K+ efflux (). Reactome Database ID Release 431369017 Reactome, http://www.reactome.org ReactomeREACT_111144 Reviewed: Jassal, B, 2010-09-23 Orexin and neuropeptides FF and QRFP bind to their respective receptors Authored: Jassal, B, 2009-01-07 14:37:24 Edited: Jassal, B, 2009-01-07 14:37:24 Pubmed12072908 Pubmed12613659 Pubmed16500002 Pubmed17854890 Reactome Database ID Release 43389397 Reactome, http://www.reactome.org ReactomeREACT_16973 Reviewed: D'Eustachio, P, 2009-03-02 09:24:35 The orphan G protein-coupled receptors mentioned here regulate sleep and appetite. Activation of classical Kir channels Activation of classical kir channels results in K+ efflux which contributes to repolarization and resetting of the membrane potential. Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Pubmed18087715 Reactome Database ID Release 431296046 Reactome, http://www.reactome.org ReactomeREACT_75758 Reviewed: Jassal, B, 2010-09-23 Formyl peptide receptors bind formyl peptides and many other ligands Authored: Jupe, S, 2009-10-22 Edited: Jupe, S, 2010-03-01 Pubmed17084101 Reactome Database ID Release 43444473 Reactome, http://www.reactome.org ReactomeREACT_21264 Reviewed: D'Eustachio, P, 2009-12-11 The formyl peptide receptor (FPR) was defined pharmacologically in 1976 as a high affinity binding site on the surface of neutrophils for the peptide N-formyl-methionine-leucine-phenylalanine (fMLF). FPR was cloned in 1990 and the cDNA used as a probe to identify two additional genes, FPRL1 and FPRL2. The three genes for a cluster on 19q13.3. All are coupled to the Gi family of G proteins. <br> All 3 receptors can be activated by formyl peptides but also display affinities for a range of structurally diverse ligands. Activation of TRESK Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed20871611 Reactome Database ID Release 431299338 Reactome, http://www.reactome.org ReactomeREACT_75865 Reviewed: Jassal, B, 2010-09-23 TRESK is expressed in spinal cord and brain and is involved in K+ efflux. TRESK activation may be mediated by calcineurin. Activation of TALK Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed12724142 Reactome Database ID Release 431299359 Reactome, http://www.reactome.org ReactomeREACT_75749 Reviewed: Jassal, B, 2010-09-23 TALK is activated by increase in pH alkalinity in the extracellular fluid. Potassium is pumped out into the extracellular fluid. Binding of BoNT toxins to gut epithelial membrane Authored: Krupa, S, Gopinathrao, G, 2006-06-15 10:36:11 Botulinum neurotoxins (BoNTs) bind to polysialogangliosides, including GT1b, GD1b and GQ1b and synaptotagmin polypeptides on the neuronal plasma membrane (Verderio et al., 2006). In the body, this dual binding may have the effect of targeting BoNTs to specific regions of the neuromuscular junction for endocytosis. Different serotypes are known to bind to different receptors: Bont/A to SV2, Bont/B and G to Syt1 and Syt2 with different affinities. Edited: Gopinathrao, G, 2006-06-15 22:12:29 Pubmed10932256 Pubmed12417130 Pubmed14504267 Pubmed17016457 Pubmed9783260 Reactome Database ID Release 43181359 Reactome, http://www.reactome.org ReactomeREACT_11084 Reviewed: Ichtchenko, K, 2007-08-03 18:17:25 Activation of THIK Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 Pubmed18209473 Reactome Database ID Release 431299297 Reactome, http://www.reactome.org ReactomeREACT_75772 Reviewed: Jassal, B, 2010-09-23 THIK subfamily has 2 members, THIK1 and THIK 2. THIK 1 forms functional homodimers whereas THIK2 function has not been demonstrated. THIK1 channels are inhibited by halothane. THICK1 channels form K+ leak channels and are not regulated by acidity or alkalanity changes. Class B/2 (Secretin family receptors) Authored: Jassal, B, 2008-07-14 12:08:56 Edited: Jassal, B, 2008-07-14 12:08:56 Pubmed11790261 Reactome Database ID Release 43373080 Reactome, http://www.reactome.org ReactomeREACT_18372 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 This family is known as Family B (secretin-receptor family, family 2) G-protein-coupled receptors. Family B GPCRs include secretin, calcitonin, parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide receptors; all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway (Harmar AJ, 2001). Activation of Ca2+ activated Potassium channels with large conductance Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Increase in intracellular concentration of Ca2+ ions and membrane depolarization cooperatively activates BKca, which exhibit large unitary conductance. Ca2+ activated potassium channels. Activation leads to K+ efflux which changes the membrane potential, which leads to inactivation voltage activated Ca2+ channels. BKca are involved in regulation of smooth muscle tone, microbial killing in leukocytes and modulation of neurotransmitter release. Activation of BKca channel with increase in intracellular concentration of Ca2+ leads to efflux of K+ into the extracellular space, which contributes to hyperpolarization of the membrane potential. Pubmed20178789 Pubmed20859064 Reactome Database ID Release 431296037 Reactome, http://www.reactome.org ReactomeREACT_75757 Reviewed: Jassal, B, 2010-09-23 Adenosine P1 receptors Authored: Jassal, B, 2009-04-14 08:47:51 Edited: Jassal, B, 2009-04-14 08:47:51 Pubmed11734617 Reactome Database ID Release 43417973 Reactome, http://www.reactome.org ReactomeREACT_18288 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The adenosine receptors (P1 receptors) are a class of purinergic receptors, G-protein coupled receptors with adenosine as their endogenous ligand.In humans, there are four adenosine receptors. Each is encoded by a separate gene and the four receptors have distinct, though overlapping, functions. For instance, both A1 and A2A receptors play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow. They also have important roles in the brain, regulating the release of other neurotransmitters such as dopamine and glutamate. The A2B and A3 receptors are located peripherally and are involved in processes such as inflammation and immune responses. Fredholm BB et al, 2001). Activation of Ca2+ activated Potassium channels with Intermeidtance conductance Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Intermediate conductance K+ channels are restricted to non neuronal tissues like epithelia, blood cells and are activated by intracellular Ca2+ ion concentration. Activation of Ca2+ activated K+ channels with intermediate conductance leads to K+ efflux in to the extracellular space. Pubmed19074509 Reactome Database ID Release 431296035 Reactome, http://www.reactome.org ReactomeREACT_75793 Reviewed: Jassal, B, 2010-09-23 Lysosphingolipid and LPA receptors Authored: Jassal, B, 2009-04-30 13:38:16 Edited: Jassal, B, 2009-04-30 13:38:16 Pubmed11093753 Pubmed11324705 Pubmed9893266 Reactome Database ID Release 43419408 Reactome, http://www.reactome.org ReactomeREACT_18365 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The Lysophospholipid receptor (LPLR) group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans there are eight LPL receptors, each encoded by a separate gene (these genes also sometimes referred to as "Edg" or endothelial differentiation gene). The ligands for LPLRs are the lysophospholipid extracellular signaling molecules, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The primary effects are inhibition of adenylyl cyclase and release of calcium from the endoplasmic reticulum, as well as secondary effects of preventing apoptosis and increasing cell proliferation (Contos JJ et al, 2000; An S et al, 1998; Fukushima N and Chun J, 2001). Activation of GIRK/Kir3 Channels Authored: Mahajan, SS, 2010-11-11 Binding of G beta gamma activates the GIRK/Kir3 channels that allow the efflux of K+ out of the cell resulting in a hyperpolarized membrane potential. This negative membrane potential prevents the activation of voltage dependent Ca2+ channels. Edited: Mahajan, SS, 2008-11-27 12:40:45 Pubmed17185339 Reactome Database ID Release 431013020 Reactome, http://www.reactome.org ReactomeREACT_25066 Reviewed: Restituito, S, 2008-11-27 12:38:49 Opsins Authored: Jassal, B, 2009-05-07 08:25:16 Edited: Jassal, B, 2009-05-07 08:25:16 Opsins are light-sensitive, 35-55 kDa membrane-bound G protein-coupled receptors of the retinylidene protein family found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical signal, the first step in the visual transduction cascade (Terakita A, 2005; Nickle B and Robinson PR, 2007). Another opsin found in the mammalian retina, melanopsin, is involved in circadian rhythms and pupillary reflex but not in image-forming (Hankins MW et al, 2008; Kumbalasiri T and Provencio I, 2005). Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G protein transducin, encoded by GNAT genes, is one of the transducers of a visual impulse that performs the coupling between rhodopsin and cGMP-phosphodiesterase. Defects in GNAT1 are the cause of congenital stationary night blindness autosomal dominant type 3, also known as congenital stationary night blindness Nougaret type. Congenital stationary night blindness is a non-progressive retinal disorder characterized by impaired night vision (Dryja TP et al, 1996). Defects in GNAT2 are the cause of achromatopsia type 4 (ACHM4). Achromatopsia is an autosomal recessively inherited visual disorder that is present from birth and that features the absence of color discrimination (Kohl S et al, 2002). Pubmed12077706 Pubmed15774036 Pubmed16005867 Pubmed17726575 Pubmed18054803 Pubmed8673138 Reactome Database ID Release 43419771 Reactome, http://www.reactome.org ReactomeREACT_18426 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 The GABA(A)-rho receptor complex is permeable to Cl- when GABA binds to it Authored: Jassal, B, 2010-09-24 Edited: Jassal, B, 2010-09-24 Pubmed10542332 Pubmed1315307 Pubmed17398006 Pubmed1849271 Reactome Database ID Release 43975449 Reactome, http://www.reactome.org ReactomeREACT_25391 Reviewed: He, L, 2010-11-15 The GABA(A)-rho receptor is expressed in many areas of the brain, but in contrast to other GABA(A) receptors, has especially high expression in the retina. It is functional as a homopentamer and is permeable to chloride ions when GABA binds to it (Cutting et al, 1991; Cutting et al, 1992; Bailey et al, 1990). Free fatty acid receptors Authored: Jupe, S, 2009-10-19 Edited: Jupe, S, 2010-03-01 Fatty acids are the ligands for a small family of G-protein-coupled receptors, the Free Fatty Acid receptors, and an unrelated receptor GPR120. <br><br>Free fatty acid receptor 1 (FFAR1/GPR40) is activated by both saturated and unsaturated medium to long-chain fatty acids while FFAR2 (GPR43) and FFAR3 (GPR41) are activated by short-chain fatty acids (carboxylates) with six or fewer carbon molecules. A fourth highly homologous receptor GPR42 is believed to be a pseudogene with intact open reading frame, but could be a functional gene in a significant fraction of the human population. <br><br>GPR120 is activated by long chain (C16-22) fatty acids. Pubmed15684720 Pubmed17052194 Pubmed19630535 Reactome Database ID Release 43444209 Reactome, http://www.reactome.org ReactomeREACT_21268 Reviewed: D'Eustachio, P, 2009-12-11 Prostanoid ligand receptors Authored: Jassal, B, 2009-04-02 10:56:26 Edited: Jassal, B, 2009-04-02 10:56:26 Fatty acid cyclo-oxygenase (COX) converts arachidonic acid to prostaglandin H2 (PGH2) from which the prostanoids PGD2, PGE2, PGF2alpha, PGI2 (prostacyclin) and thromboxane A2 (TXA2) are derived. Based on the agonist potencies, five prostanoid receptors are recognized and correspondingly named DP, EP, FP, IP and TP receptors (Coleman RA et al, 1994). Additionally, EP receptors contains four subtypes, termed EP1, EP2, EP3 and EP4; the DP receptor also has two subtypes, DP1 and DP2 (CRTH2). Pubmed7938166 Reactome Database ID Release 43391908 Reactome, http://www.reactome.org ReactomeREACT_18425 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Dissociation of the Gi alpha:G olf complex Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Edited: Jassal, B, 2008-11-06 10:17:49 Once the intrinsic GTPase hydrolyzes GTP to GDP, Galpha-i dissociates from adenylate cyclase, allowing it to re-associate with G-beta-gamma and starting a new cycle. Pubmed7937899 Reactome Database ID Release 43170674 Reactome, http://www.reactome.org ReactomeREACT_15384 Reviewed: Castagnoli, L, 2008-11-06 12:55:54 Leukotriene receptors Authored: Jassal, B, 2009-03-26 15:30:13 Edited: Jassal, B, 2009-03-26 15:30:13 Leukotriene receptors bind leukotriene ligands. There are four types of receptor in humans; two for leukotriene B4 and two for cysteinyl leukotrienes (Brink C et al, 2003). Pubmed12615958 Reactome Database ID Release 43391906 Reactome, http://www.reactome.org ReactomeREACT_18302 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Nucleotide-like (purinergic) receptors Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 Pubmed16805422 Pubmed19008000 Purinergic receptors (Burnstock G, 2006; Abbracchio MP et al, 2009) are a family of newly characterized plasma membrane molecules involved in several cellular functions such as vascular reactivity, apoptosis and cytokine secretion. The functions of these receptors are as yet only partially characterized. The family includes the GPCR P2Y purinergic receptors and adenosine P1 receptors. A third family member, the P2X receptor, is a ligand-gated ion channel. Reactome Database ID Release 43418038 Reactome, http://www.reactome.org ReactomeREACT_18342 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 P2Y receptors Authored: Jassal, B, 2009-04-14 09:13:21 Edited: Jassal, B, 2009-04-14 09:13:21 P2Y receptors are a family of purinergic receptors, G protein-coupled receptors stimulated by nucleotides such as ATP, ADP, UTP, UDP and UDP-glucose. To date, 12 P2Y receptors have been cloned in humans (Abbracchio MP et al, 2006; Fischer W and Krugel U, 2007). P2Y receptors are present in almost all human tissues where they exert various biological functions based on their G-protein coupling. Purine nucleotides are involved in a large number of intermediate metabolic pathways, taking part as substrates, products or allosteric factors. Pubmed16968944 Pubmed17979698 Reactome Database ID Release 43417957 Reactome, http://www.reactome.org ReactomeREACT_18289 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Eicosanoid ligand-binding receptors Authored: Jassal, B, 2009-02-25 13:56:29 Edited: Jassal, B, 2009-02-25 13:56:29 Eicosanoids, derived from polyunsaturated 20-carbon fatty acids, are paracrine and autocrine regulators of inflammation, smooth muscle contraction, and blood coagulation. The actions of eicosanoids are mediated by eicosanoid receptors, most of which are GPCRs. There are four types of eicosanoid GPCRs in humans; leukotriene, lipoxin (Brink C et al, 2003), prostanoid (Coleman RA et al, 1994) and oxoeicosanoid (Brink C et al, 2004) receptors. Pubmed12615958 Pubmed15001665 Pubmed7938166 Reactome Database ID Release 43391903 Reactome, http://www.reactome.org ReactomeREACT_18352 Reviewed: D'Eustachio, P, 2009-05-29 07:44:22 Activation of ATP sensitive Potassium channels in neuroendocrine cells Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 In neuroendocrine cells such as pancreatic alpha-, beta-, and delta-cells and in the brain, ATP sensitive K+ channels assemble as octamers of four Kir 6.1, 6.2 subunits and four high-affinity sulfonyl urea receptor 1 subunits (SUR1). These channels are blocked by excess intracellular levels of ATP. When the ATP is low, ATP dissociates and the channel opens to allow K+ efflux. Pubmed18258787 Reactome Database ID Release 431296024 Reactome, http://www.reactome.org ReactomeREACT_75911 Reviewed: Jassal, B, 2010-09-23 Activation of Potassium transport channels Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Homotetramers of Kir 1.1 function as inwardly rectifying potassium transport channels. Ki 1.1 are found on the apical side of the cells in the ascending limp of loop of henle and upon activation transport K+ into the extracellular space. Heterotetramers of Kir 4.1 and Ki 5.1 are found on the basolateral side of cells in the distal convoluted tube. Activation of kir 4.1 and 5.1 heterotetramers leads to efflux of K+ into the extracellular space. Pubmed19221509 Reactome Database ID Release 431296045 Reactome, http://www.reactome.org ReactomeREACT_75810 Reviewed: Jassal, B, 2010-09-23 Activation of HCN channels Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 HCN channels are activated upon hyperpolarization of membrane potential and cAMP binding leading to K+ efflux. Pubmed11328811 Reactome Database ID Release 431296043 Reactome, http://www.reactome.org ReactomeREACT_75788 Reviewed: Jassal, B, 2010-09-23 Binding of cAMP to HCN channels Authored: Mahajan, SS, 2011-05-22 Edited: Mahajan, SS, 2011-05-23 HCN channels require cAMP binding and hyperpolarization of membrane potential for channel opening. Pubmed11328811 Reactome Database ID Release 431297444 Reactome, http://www.reactome.org ReactomeREACT_75751 Reviewed: Jassal, B, 2010-09-23 Activation of Ca2+ activated Potassium channels with small conductance Authored: Mahajan, SS, 2011-05-18 Edited: Mahajan, SS, 2011-05-23 Pubmed19074509 Reactome Database ID Release 431296039 Reactome, http://www.reactome.org ReactomeREACT_75830 Reviewed: Jassal, B, 2010-09-23 Small conductance Ca2+ activated potassium channels (SKca) are solely activated by intracellular Ca2+ concentration. SKca channels form functional tetramers. SKca channels control the contractility of uterus, maintian vascular tone, modulate hormone secretion, control cell volume in red blood cells and activation of microglia and lymphocytes. Actiavtion of SKca channels is triggered by increase in the intracellular Ca2+ ion concentration. Activation of Skca channels leads to relatively small K+ ion effluxes. Trafficking of GluR2-containing AMPA receptors to extrasynaptic sites Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2009-05-31 11:49:00 GluR2 containing AMPA receptors are trafficked to the plasmamembrane by the activation of Ca activated PKC that binds PICK.The PICK interaction delivers GluR2 containing AMPA receptors to the Plasmamembrane. This reaction is a part of constitutive recycling of AMPA receptor that delivers the AMPA receptors from the endosome to the plasmamembrane and back to endosome from the plasmamembrane. Pubmed16055064 Reactome Database ID Release 43416639 Reactome, http://www.reactome.org ReactomeREACT_18330 Reviewed: Ziff, EB, 2009-05-15 16:23:37 Growth Hormone: Tyrosine phosphorylated Growth Hormone Receptor-p(Y1007)-JAK2 dimer:SHP2 Reactome DB_ID: 1169227 Reactome Database ID Release 431169227 Reactome, http://www.reactome.org ReactomeREACT_111336 has a Stoichiometric coefficient of 1 Trafficking of GluR2-containing AMPA receptors to synapse Authored: Mahajan, SS, 2008-01-14 16:01:52 Constitutively recycling GluR2 containing AMPA receptors in the plasmamembrane are stabilized by the action of NSF ATPase activity which disassociates PICK from GluR2 thereby retaining AMPA receptors in the plasmamembrane. EC Number: 3.6.1.3 Edited: Mahajan, SS, 2009-05-31 11:49:00 Pubmed16055064 Reactome Database ID Release 43416985 Reactome, http://www.reactome.org ReactomeREACT_18320 Reviewed: Ziff, EB, 2009-05-15 16:23:37 Growth Hormone:p(Y332,487,627)-Growth Hormone Receptor-p(Y1007)-JAK2 dimer:SHP2 Reactome DB_ID: 1169233 Reactome Database ID Release 431169233 Reactome, http://www.reactome.org ReactomeREACT_111750 has a Stoichiometric coefficient of 1 Growth Hormone: Tyrosine phosphorylated Growth Hormone Receptor-p(Y1007)-JAK2 dimer:CIS/SOCS1-3 Reactome DB_ID: 1169217 Reactome Database ID Release 431169217 Reactome, http://www.reactome.org ReactomeREACT_111716 has a Stoichiometric coefficient of 1 Growth Hormone: Tyrosine phosphorylated Growth Hormone Receptor-p(Y1007)-JAK2 dimer:SOCS Reactome DB_ID: 1169198 Reactome Database ID Release 431169198 Reactome, http://www.reactome.org ReactomeREACT_111463 has a Stoichiometric coefficient of 1 Growth Hormone: Activated Growth Hormone Receptor:p(Y1007)-JAK2 dimer:STAT1/STAT3 Reactome DB_ID: 1169146 Reactome Database ID Release 431169146 Reactome, http://www.reactome.org ReactomeREACT_111267 has a Stoichiometric coefficient of 1 Growth Hormone: Activated Growth Hormone Receptor:p(Y1007)-JAK2 dimer:p(Y701)-STAT1/p(Y705)-STAT3 Reactome DB_ID: 1169186 Reactome Database ID Release 431169186 Reactome, http://www.reactome.org ReactomeREACT_111346 has a Stoichiometric coefficient of 1 PathwayStep3581 Activation of highly calcium permeable nicotinic acetylcholine receptors Authored: Mahajan, SS, 2010-04-26 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholine receptors are activated upon ligand binding which opens the acetylcholine channels and permits Ca2+ and Na+ ion influx depending on the subunit composition and stoichiometry of the subunits. The ratio of Ca2+ to Na+ ion influx varies making the receptors either highly Na+ permeable or Ca2+ permeable. Pubmed10945867 Pubmed12810063 Reactome Database ID Release 43622326 Reactome, http://www.reactome.org ReactomeREACT_22354 Reviewed: Cooper, E, 2010-05-24 Growth Hormone:Tyrosine phosphorylated Growth Hormone Receptor-p(Y1007)-JAK2 dimer:p-STAT5 Reactome DB_ID: 1168901 Reactome Database ID Release 431168901 Reactome, http://www.reactome.org ReactomeREACT_111332 has a Stoichiometric coefficient of 1 PathwayStep3582 Binding of acetylcholine to highly sodium permeable acetylcholine receptors Authored: Mahajan, SS, 2010-04-26 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholine receptors bind two molecules of ligand, acetylcholine, in the alpha beta interface in receptors containing heteromeric subunits or in the interface of 2 aplha subunits in receptors containing homomeric subunits. Pubmed19059502 Reactome Database ID Release 43629588 Reactome, http://www.reactome.org ReactomeREACT_22438 Reviewed: Cooper, E, 2010-05-24 Growth Hormone:Growth Hormone Receptor-JAK2 dimer:LYN Reactome DB_ID: 1168921 Reactome Database ID Release 431168921 Reactome, http://www.reactome.org ReactomeREACT_111316 has a Stoichiometric coefficient of 1 Glutamine transport from astrocytes Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Gillespie, ME, 2009-11-19 Glutamine from the astrocytes is exported to the extracellular compartment via the system N amino acid transporter. The system N transporter is Na+ dependant transporter that has substrate specificity to aspargine, glutamine and histidine. Pubmed16516348 Reactome Database ID Release 43212614 Reactome, http://www.reactome.org ReactomeREACT_13773 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Tyrosine phosphorylated Growth Hormone Receptor:p(Y1007)-JAK2 Reactome DB_ID: 1168892 Reactome Database ID Release 431168892 Reactome, http://www.reactome.org ReactomeREACT_111596 has a Stoichiometric coefficient of 1 PathwayStep3580 Binding of acetylcholine to highly calcium permeable acetylcholine receptors Authored: Mahajan, SS, 2010-04-22 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholine receptors bind two molecules of ligand, acetylcholine, in the alpha beta interface in receptors containing heteromeric subunits or in the interface of 2 aplha subunits in receptors containing homomeric subunits. Pubmed19059502 Reactome Database ID Release 43629599 Reactome, http://www.reactome.org ReactomeREACT_22409 Reviewed: Cooper, E, 2010-05-24 Growth Hormone:Tyrosine phosphorylated Growth Hormone Receptor-p(Y1007)-JAK2 dimer:STAT5 Reactome DB_ID: 1168902 Reactome Database ID Release 431168902 Reactome, http://www.reactome.org ReactomeREACT_111581 has a Stoichiometric coefficient of 1 PathwayStep3585 Activation of highly calcium permeable postsynaptic nicotinic acetylcholine receptors Acetylcholine binding activates postsynaptic acetylchloine receptors that show Ca2+ currents which facilitate the process of long term potentiation (LTP). Authored: Mahajan, SS, 2010-04-26 Edited: Gillespie, ME, 2010-05-18 Pubmed10945867 Pubmed12810063 Reactome Database ID Release 43629595 Reactome, http://www.reactome.org ReactomeREACT_22243 Reviewed: Cooper, E, 2010-05-24 PathwayStep3586 Trafficking of GluR1-containing AMPA receptors Authored: Mahajan, SS, 2008-01-14 16:01:52 EC Number: 2.7.11.17 Edited: Mahajan, SS, 2009-05-31 11:49:00 GluR1-containing AMPA receptors are delivered to the synapses in an activity dependent manner. GluR1 trafficking is controlled by protein- protein interactions with 4.1N/G protein, SAP97 and by intricate regulation of phosphorylation of GluR1 at several phosphorylation sites in the C tail. GluR1 has four phosphorylation sites; serine 818 (S818) is phosphorylated by PKC, necessary for LTP, serine 831 (S831) is phosphorylated by CaMKII and increases the delivery of receptors to the synapse and also increases their single channel conductance, Threonine (T840) is implicated in LTP and serine 845 (S845) phosphorylated by PKA regulates open channel probability and also by cGKII, a cyclic GMP activated kinase, that increases the surface expression of GluR1. GluR1 insertion into synapse by CaMKII may induce LTP. CaMKII is a Ca/calmodulin dependent kinase that is activated upon increases in the Ca ion concentration during postsynaptic activity through NMDA receptors. The increase in GluR1-containing AMPA receptor population at the synapse results in enhancement of excitatory post synaptic potential (EPSC) which forms the basis of Long term potentiation (LTP). LTP is one form of synaptic plasticity that is involved in memory and learning. The increase in the GluR1 containing AMPA receptors and their activity leads to rise in intracellular Ca which induces signaling pathways that in turn promote switch in the type of AMPA receptors (Ca impermeable) thereby limiting the Ca increase and preventing cell death. Pubmed18311135 Reactome Database ID Release 43416320 Reactome, http://www.reactome.org ReactomeREACT_18393 Reviewed: Ziff, EB, 2009-05-15 16:23:37 PathwayStep3583 Activation of highly sodium permeable nicotinic acetylcholine receptors Authored: Mahajan, SS, 2010-04-26 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholine receptors containing aplha4(2) beta2 (3) and alpha3(2) beta4(3) are selectively highly Na+ permeable upon activation of these receptors by acetylcholine. Pubmed8987816 Reactome Database ID Release 43622325 Reactome, http://www.reactome.org ReactomeREACT_22390 Reviewed: Cooper, E, 2010-05-24 PathwayStep3584 Binding of acetylcholine to highly calcium permeable postsynaptic nicotinic acetylcholine receptors Authored: Mahajan, SS, 2010-04-26 Edited: Gillespie, ME, 2010-05-18 Nicotinic acetylcholine receptors bind two molecules of ligand, acetylcholine, in the alpha beta interface in receptors containing heteromeric subunits or in the interface of 2 aplha subunits in receptors containing homomeric subunits. Pubmed19059502 Reactome Database ID Release 43629596 Reactome, http://www.reactome.org ReactomeREACT_22116 Reviewed: Cooper, E, 2010-05-24 PathwayStep3579 PathwayStep3578 PathwayStep3577 PathwayStep3576 Reuptake of serotonin from the synapse Authored: Mahajan, SS, 2008-10-17 21:22:50 Edited: Gillespie, ME, 2009-11-19 Pubmed17726476 Reactome Database ID Release 43380620 Reactome, http://www.reactome.org ReactomeREACT_15458 Reviewed: Restituito, S, 2008-11-27 12:38:49 The human gene SLC6A4 encodes the sodium-dependent serotonin transporter 5HTT which mediates the re-uptake of serotonin from the synaptic cleft thus terminating the action of serotonin (Canli T and Lesch KP, 2007). The serotonin taken up in the cytosol from the synaptic cleft may be recycled into synaptic vesicles or metabolized. Growth Hormone: Growth Hormone Receptor-JAK2 dimer Reactome DB_ID: 982813 Reactome Database ID Release 43982813 Reactome, http://www.reactome.org ReactomeREACT_111685 has a Stoichiometric coefficient of 1 5-hydroxyindole acetaldehyde to 5-hydroxyindole acetic acid 5-hydroxyindole acetaldehyde is then catalyzed by aldehyde dehydrogenase to form 5-hydroxyindole acetic acid Authored: Mahajan, SS, 2008-10-17 21:22:14 EC Number: 1.2.1.3 Edited: Gillespie, ME, 2009-11-19 Pubmed17010132 Pubmed8778744 Reactome Database ID Release 43380608 Reactome, http://www.reactome.org ReactomeREACT_15407 Reviewed: Restituito, S, 2008-11-27 12:38:49 Growth Hormone: Tyrosine phosphorylated Growth Hormone Receptor-p(Y1007)-JAK2 dimer Reactome DB_ID: 1168898 Reactome Database ID Release 431168898 Reactome, http://www.reactome.org ReactomeREACT_111649 has a Stoichiometric coefficient of 1 glutamate uptake by astrocytes Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Gillespie, ME, 2009-11-19 Excess L-Glutamate released by the pre-synaptic neuron in the synaptic cleft is cleared by high affinity transporters called the excitatory amino acid transporters (EAATs) to terminate synaptic actions of the neurotransmitter and to recycle these molecules. Five types of EAATs have been identified EAAT1-EAAT5 in the mammalian CNS. EAAT1 and EAAT2 are mainly expressed by astrocytes whereas EAAT3 and EAAT4 are predominantly neuronal. EAAT3 are expressed throughout the CNS however, EAAT4 is predominantly localized to purkinje cells. EAAT5 are expressed rod photoreceptor and bipolar cells of retina. Astrocytic EAATs are expressed in astrocytes in close apposition to the synapses and neuronal EAATs are expressed in the extra-synaptic or peri-synaptic locations on the neurons. Astrocytic EAATs are responsible for majority of the glutamate uptake, neuronal transporters are responsible for glutamate clearance in specialized synapses in cerebellum where the spatial relationship between the glutamate receptors and EAATs is altered and glutamate receptors are expressed in the peri-synaptic region. Pubmed14730707 Reactome Database ID Release 43210439 Reactome, http://www.reactome.org ReactomeREACT_13588 Reviewed: Kavalali, E, 2008-04-24 16:31:34 Tyrosine phosphorylated Growth Hormone Receptor:p(Y1007)-JAK2 dimer Reactome DB_ID: 1168890 Reactome Database ID Release 431168890 Reactome, http://www.reactome.org ReactomeREACT_111657 has a Stoichiometric coefficient of 2 IL7:p(Y449)-IL7RA:JAK1:IL2RG:JAK3:PI3K-regulatory subunits Reactome DB_ID: 1295544 Reactome Database ID Release 431295544 Reactome, http://www.reactome.org ReactomeREACT_116926 has a Stoichiometric coefficient of 1 Growth Hormone Receptor:JAK2 Reactome DB_ID: 982774 Reactome Database ID Release 43982774 Reactome, http://www.reactome.org ReactomeREACT_111660 has a Stoichiometric coefficient of 1 Growth Hormone Receptor-JAK2 dimer Reactome DB_ID: 982764 Reactome Database ID Release 43982764 Reactome, http://www.reactome.org ReactomeREACT_111828 has a Stoichiometric coefficient of 2 GHBP:GHR Reactome DB_ID: 1362481 Reactome Database ID Release 431362481 Reactome, http://www.reactome.org ReactomeREACT_111483 has a Stoichiometric coefficient of 1 PathwayStep3590 PathwayStep3591 Conversion of succinate semialdehyde to succinate Authored: Mahajan, SS, 2010-06-29 EC Number: 1.2.1.24 Edited: Mahajan, SS, 2010-08-03 Pubmed19300440 Reactome Database ID Release 43888548 Reactome, http://www.reactome.org ReactomeREACT_24017 Reviewed: Restituito, S, 2008-11-27 12:38:49 Succinate semialdehyde dehydrogenase (SSADH) converts succinate semialdehyde, in a final step of GABA degradation, into succinate. SSADH uses one water molecule and one molecule of NAD+ per molecule of succinyate semialdehyde. IL7:p(Y449)-IL7RA:JAK1:IL2RG:JAK3 Reactome DB_ID: 1295546 Reactome Database ID Release 431295546 Reactome, http://www.reactome.org ReactomeREACT_117078 has a Stoichiometric coefficient of 1 PathwayStep3592 Noradrenaline clearance from the synaptic cleft Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2008-11-18 00:03:09 Noradrenaline is cleared from the synaptic cleft by Noaradrenaline uptake transporter. This reaction is carried out by neurons as well as astrocytes. Pubmed9260930 Reactome Database ID Release 43374919 Reactome, http://www.reactome.org ReactomeREACT_15341 Reviewed: Restituito, S, 2008-11-27 12:38:49 IL7:p(Y449)-IL7RA:JAK1 Reactome DB_ID: 1295539 Reactome Database ID Release 431295539 Reactome, http://www.reactome.org ReactomeREACT_116947 has a Stoichiometric coefficient of 1 PathwayStep3593 Reuptake of dopamine from the synaptic cleft into neurons Authored: Mahajan, SS, 2008-06-26 19:01:12 Edited: Gillespie, ME, 2009-11-19 Pubmed10889531 Reactome Database ID Release 43379393 Reactome, http://www.reactome.org ReactomeREACT_15468 Reuptake of dopamine from the synaptic celft into neurons Reviewed: Restituito, S, 2008-11-27 12:38:49 The human gene SLC6A3 encodes the sodium-dependent dopamine transporter, DAT which mediates the re-uptake of dopamine from the synaptic cleft (Vandenbergh DJ et al, 2000). Dopamine can then be degraded by either COMT or monoamine oxidase. p(Y449)-IL7RA:JAK1 Reactome DB_ID: 1295512 Reactome Database ID Release 431295512 Reactome, http://www.reactome.org ReactomeREACT_116844 has a Stoichiometric coefficient of 1 PathwayStep3594 methylation of Dopamine to form 3-Methoxytyramine Authored: Mahajan, SS, 2008-06-26 18:29:42 Dopamine in the cytosol is metabolized to 3-methoxytyramine by catecholamine o-methyltransferase (COMT), which uses s-adenosylmethionine as a methyl group donor. EC Number: 2.1.1 Edited: Gillespie, ME, 2009-11-19 Reactome Database ID Release 43379387 Reactome, http://www.reactome.org ReactomeREACT_15531 Reviewed: Restituito, S, 2008-11-27 12:38:49 PathwayStep3595 Oxidation of 3-Methoxytyramine to homovanillic acid 3-methoxytyramine generated by COMT after methylation of dopamine is oxidized into homovanillic acid by monoamine oxidase A Authored: Mahajan, SS, 2008-10-17 21:22:06 EC Number: 1.4.3.21 EC Number: 1.4.3.22 EC Number: 1.4.3.4 Edited: Gillespie, ME, 2009-11-19 Reactome Database ID Release 43379395 Reactome, http://www.reactome.org ReactomeREACT_15434 Reviewed: Restituito, S, 2008-11-27 12:38:49 PathwayStep3596 oxidation of dopamine to 3,4dihydroxyphenylacetic acid (DOPAC) Authored: Mahajan, SS, 2008-06-26 19:01:12 Dopamine is oxidized to 3,4-dihydroxyphenylacetic acid by monoamine oxidase. EC Number: 1.4.3.21 EC Number: 1.4.3.22 EC Number: 1.4.3.4 Edited: Gillespie, ME, 2009-11-19 Reactome Database ID Release 43379382 Reactome, http://www.reactome.org ReactomeREACT_15485 Reviewed: Restituito, S, 2008-11-27 12:38:49 PathwayStep3597 Methylation of 3,4-dihydroxypheylacetic acid to homovanillic acid 3,4-dihydroxyphenylacetic acid, generated after oxidation of dopamine by monoamineoxidase, is methylated by catecholamine o-methyltransferase to homovanillic acid. Authored: Mahajan, SS, 2008-10-17 21:22:06 EC Number: 2.1.1 Edited: Gillespie, ME, 2009-11-19 Reactome Database ID Release 43379464 Reactome, http://www.reactome.org ReactomeREACT_15553 Reviewed: Restituito, S, 2008-11-27 12:38:49 PathwayStep3588 PathwayStep3587 PathwayStep3589 ub-HIF-alpha:VHL:EloB/C:CUL2:RBX1 Reactome DB_ID: 1234103 Reactome Database ID Release 431234103 Reactome, http://www.reactome.org ReactomeREACT_122640 Ubiquitinated HIF-alpha:VHL:EloB/C:CUL2:RBX1 has a Stoichiometric coefficient of 1 ub-HIF-alpha Reactome DB_ID: 1234100 Reactome Database ID Release 431234100 Reactome, http://www.reactome.org ReactomeREACT_124975 Ubiquitinated HIF-alpha has a Stoichiometric coefficient of 1 ub-hydroxyPro-HIF-alpha Reactome DB_ID: 1234113 Reactome Database ID Release 431234113 Reactome, http://www.reactome.org ReactomeREACT_122211 Ubiquitinated HIF-alpha has a Stoichiometric coefficient of 1 UBE2D1,2,3:Ubiquitin E2 Conjugating Enzymes UbcH5a/b/c:Ubiquitin Complex Reactome DB_ID: 1234123 Reactome Database ID Release 431234123 Reactome, http://www.reactome.org ReactomeREACT_124982 UbcH5a/b/c:Ubiquitin has a Stoichiometric coefficient of 1 Phosphorylation of CREB by PKA Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 Protein kinase A has two regulatory subunits and two catalytic subunits which are held together to form the holoenzyme and is activated upon binding of cAMP within the regulatory subunits. Once cAMP binds the regulatory subunits, the catalytic subunits are released to carry out phosphorylation of CREB at serine133. Pubmed17908236 Pubmed19244110 Reactome Database ID Release 43443474 Reactome, http://www.reactome.org ReactomeREACT_20583 Reviewed: Tukey, D, 2009-11-17 FIH1:FIH1 HIF1AN (FIH1) Homodimer Reactome DB_ID: 1235007 Reactome Database ID Release 431235007 Reactome, http://www.reactome.org ReactomeREACT_124556 has a Stoichiometric coefficient of 2 Activation of CaMKII Authored: Mahajan, SS, 2009-10-29 CaMKII is fully activated upon Ca2+/Calmodulin binding. In addition to Ca2+/Calmodulin activation, CaMKII undergoes multiple autophosphorylation events leading Ca2+/Calmodulin independent activity of the enzyme. EC Number: 2.7.11.17 Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed8615909 Reactome Database ID Release 43442725 Reactome, http://www.reactome.org ReactomeREACT_20634 Reviewed: Tukey, D, 2009-11-17 hydroxyPro-HIF-alpha:VHL:EloB/C:CUL2:RBX1 Reactome DB_ID: 1234125 Reactome Database ID Release 431234125 Reactome, http://www.reactome.org ReactomeREACT_121940 has a Stoichiometric coefficient of 1 Phosphorylation of CREB by ribosomal protein S6 kinase Authored: Mahajan, SS, 2009-10-29 CREB is phosphorylated at serine 133 by any of the four isoforms of ribosomal S6 kinase. Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed11160957 Reactome Database ID Release 43442724 Reactome, http://www.reactome.org ReactomeREACT_20503 Reviewed: Tukey, D, 2009-11-17 Activation of Adenylate Cyclase Authored: Mahajan, SS, 2009-10-29 Ca2+ fluxes through NMDA receptors in the post-synaptic neuron facilitate binding of Ca2+/Calmodulin to adenylate cyclase type 1, 3 or 8, resulting in its activation. Once activated, cAMP is produced which further activates PKA. EC Number: 4.6.1.1 Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed8476432 Reactome Database ID Release 43442715 Reactome, http://www.reactome.org ReactomeREACT_20564 Reviewed: Tukey, D, 2009-11-17 Phosphorylation by MAPK/ERK Activated MAPK/ERK activates RSK in its C terminal kinase domain by sequentially phosphorylating T573, S363 and 380. Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed12832467 Reactome Database ID Release 43444253 Reactome, http://www.reactome.org ReactomeREACT_20562 Reviewed: Tukey, D, 2009-11-17 has a Stoichiometric coefficient of 3 hydroxyPro-HIF-alpha:VHL:EloB/C:CUL2:RBX1 Reactome DB_ID: 1234101 Reactome Database ID Release 431234101 Reactome, http://www.reactome.org ReactomeREACT_124934 has a Stoichiometric coefficient of 1 Phophorylation by PDK1 Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 PDK1 activates ribosomal S6 kinase (RSK) by phosphorylating S221. The binding site for PDK1 on RSK is available after RSK phosphorylation by MAPK/ERK. PDK1 is present in the activated form at the plasma membrane where the phosphorylation occurs. The activation of RSK occurs in the cytoplasm, plasma membrane and in the nucleus where it finally activates CREB by phosphorylation. Pubmed10480933 Pubmed12393804 Reactome Database ID Release 43442739 Reactome, http://www.reactome.org ReactomeREACT_20640 Reviewed: Tukey, D, 2009-11-17 ub-hydroxyPro-HIF-alpha:VHL:EloB/C:CUL2:RBX1 Reactome DB_ID: 1234138 Reactome Database ID Release 431234138 Reactome, http://www.reactome.org ReactomeREACT_124595 Ubiquitinated HIF-alpha:VHL:EloB/C:CUL2:RBX1 has a Stoichiometric coefficient of 1 Raf activation Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed12062470 Pubmed17064357 Pubmed17603483 Pubmed19727074 Raf is a downstream effector of ras. Raf is activated upon phosphorylation at S338, oligomerization and membrane localization. Membrane localization is facilitated by ras. Interaction of ras with raf is a necessary step but not sufficient for raf activation. Other unknown protein partner interactions are required for raf activation. Raf further activates MAP kinase. Reactome Database ID Release 43442726 Reactome, http://www.reactome.org ReactomeREACT_20578 Reviewed: Tukey, D, 2009-11-17 VHL:EloB/C:CUL2:RBX1 Reactome DB_ID: 1234141 Reactome Database ID Release 431234141 Reactome, http://www.reactome.org ReactomeREACT_124578 has a Stoichiometric coefficient of 1 Activation of MAPK Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 MAPK/ERK is phosphorylated at threonine 185 and tyrosine 187 by membrane associated activated raf kianse leading to the activation of MAPK/ERK kinase. The activated MAPK/ERK in turn activates ribosomal S6 kinase. Pubmed18022816 Reactome Database ID Release 43442737 Reactome, http://www.reactome.org ReactomeREACT_20631 Reviewed: Tukey, D, 2009-11-17 VBC Complex Reactome DB_ID: 1234128 Reactome Database ID Release 431234128 Reactome, http://www.reactome.org ReactomeREACT_123829 has a Stoichiometric coefficient of 1 Ras activation Authored: Mahajan, SS, 2009-10-29 Binding of RasGRF to Ca2+/Calmodulin in the presence of high Ca2+ leads to the activation of Ras. Activation of Ras involves the exchange of GDP for GTP. Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed14622581 Reactome Database ID Release 43442732 Reactome, http://www.reactome.org ReactomeREACT_20612 Reviewed: Tukey, D, 2009-11-17 Activation of RasGRF Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 Pubmed10373510 RASGRF is activated upon binding of Ca2+/Calmodulin after Ca2+ influx through the NMDA receptor. Reactome Database ID Release 43442760 Reactome, http://www.reactome.org ReactomeREACT_20670 Reviewed: Tukey, D, 2009-11-17 PathwayStep3599 PathwayStep3598 Tyrosine phosphorylated Growth Hormone Receptor-JAK2 dimer Reactome DB_ID: 1169224 Reactome Database ID Release 431169224 Reactome, http://www.reactome.org ReactomeREACT_111465 has a Stoichiometric coefficient of 2 Tyrosine phosphorylated Growth Hormone Receptor:JAK2 Reactome DB_ID: 1169223 Reactome Database ID Release 431169223 Reactome, http://www.reactome.org ReactomeREACT_111379 has a Stoichiometric coefficient of 1 Growth Hormone: Tyrosine phosphorylated Growth Hormone Receptor-p(Y1007)-JAK2 dimer:SHP1 Reactome DB_ID: 1169243 Reactome Database ID Release 431169243 Reactome, http://www.reactome.org ReactomeREACT_111499 has a Stoichiometric coefficient of 1 Growth Hormone: Tyrosine phosphorylated Growth Hormone Receptor-JAK2 dimer:SHP1 Reactome DB_ID: 1169239 Reactome Database ID Release 431169239 Reactome, http://www.reactome.org ReactomeREACT_111822 has a Stoichiometric coefficient of 1 Activation of NMDA Receptor Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 NMDA receptors are activated upon binding of two ligands, glutamate and glycine.<br>The activation leads to Ca2+ influx into the post-synaptic cell. The local rise in the Ca2+ ion concentration further leads to activation of several Ca2+ dependent pathways leading to long term changes in the synapse. Pubmed12815021 Reactome Database ID Release 43432164 Reactome, http://www.reactome.org ReactomeREACT_20499 Reviewed: Tukey, D, 2009-11-17 GHBP:GH Reactome DB_ID: 1362492 Reactome Database ID Release 431362492 Reactome, http://www.reactome.org ReactomeREACT_111655 has a Stoichiometric coefficient of 1 Activation of Ca impermeable AMPA receptors Authored: Mahajan, SS, 2008-01-14 16:01:52 Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecules however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca impermeable AMPA receptors containing GluR2 subunit conduct Na currents upon activation by either glutamate binding or agonist, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. The Na currents mainly lead to depolarization of the membrane leading to activation of voltage gated channels such as NMDA receptors that require both agonist binding and depolarization for their activation. Edited: Mahajan, SS, 2009-05-31 11:49:00 Pubmed17409242 Reactome Database ID Release 43399711 Reactome, http://www.reactome.org ReactomeREACT_18434 Reviewed: Ziff, EB, 2009-05-15 16:23:37 Membrane depolarization upon activation of Ca impermeable AMPA receptors Authored: Mahajan, SS, 2009-09-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 Membrane depolarization occurs due to glutamate dependent activation of Ca-impermeable AMPA receptors, which permit the influx of Na+ ions. The depolarization triggers the removal of Mg2+ from the NMDA receptor pore to facilitate its activation. Therefore activation of AMPA receptors by glutamate precedes activation of NMDA receptors. Pubmed9648857 Reactome Database ID Release 43438037 Reactome, http://www.reactome.org ReactomeREACT_20569 Reviewed: Tukey, D, 2009-11-17 Unblocking of NMDA receptor Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 NMDA receptors are activated in a two step mechanism; first by the removal of the voltage dependent Mg2+ block and then by the ligand dependent activation of the unblocked NMDA receptor. At resting membrane potential NMDA receptors can not be activated by ligand alone due to the presence of Mg2+ ion in the pore of the channel. Due to the activation of other membrane resident channels that allow the influx of Na+ the membrane is depolarized which triggers the removal of Mg2+ form the NMDA receptor pore. Once the Mg2+ is expelled NMDA receptors are ready to be activated by the agonist (glutamate) and the co-agonist (glycine). Pubmed9481670 Reactome Database ID Release 43432162 Reactome, http://www.reactome.org ReactomeREACT_20500 Reviewed: Tukey, D, 2009-11-17 Glutamate binding to NMDA receptor Authored: Mahajan, SS, 2009-10-29 Edited: Gillespie, ME, 2009-06-02 00:56:21 NMDA receptors require binding of two ligands; the agonist, glutamate and co-agonist, glycine. The N terminal extracellular ligand binding domain in NR1 subunits binds co-agonist glycine and the N terminal extracellular ligand binding domain in NR2 binds glutamate. Pubmed8665664 Reactome Database ID Release 43432172 Reactome, http://www.reactome.org ReactomeREACT_20601 Reviewed: Tukey, D, 2009-11-17 Growth Hormone:p(Y332,487,627)-Growth Hormone Receptor-p(Y1007)-JAK2 dimer Reactome DB_ID: 1169232 Reactome Database ID Release 431169232 Reactome, http://www.reactome.org ReactomeREACT_111320 has a Stoichiometric coefficient of 1 Ca permeable AMPA receptor ligand binding AMPA receptors bind glutamate, released in the synaptic cleft by the presynaptic cell, in the ligand binding region in the N terminal domain. Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2009-05-31 11:49:00 Pubmed14567697 Pubmed19144831 Reactome Database ID Release 43420977 Reactome, http://www.reactome.org ReactomeREACT_18296 Reviewed: Ziff, EB, 2009-05-15 16:23:37 p(Y332,487,627)-Growth Hormone Receptor:p(Y1007)-JAK2 dimer Reactome DB_ID: 1169231 Reactome Database ID Release 431169231 Reactome, http://www.reactome.org ReactomeREACT_111726 has a Stoichiometric coefficient of 2 Activation of Ca permeable AMPA receptors Authored: Mahajan, SS, 2008-01-14 16:01:52 Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecule, however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca permeable AMPA receptors containing homomers of GluR1 or heteromers containing GluR1, GluR3 and GluR4 conduct Ca upon glutamate or agonist namely AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. Calcium permeable AMPA receptors conduct Ca and other cations such as Na. The inonic flux leads to Ca or Na currents that leads to either increase in the intracellular Ca concentration leading to further Ca-dependent signaling or increase in depolarization that opens voltage gated channels such as NMDA receptors that require both membrane depolarization and glutamate binding for activation. Edited: Mahajan, SS, 2009-05-31 11:49:00 Pubmed12172541 Reactome Database ID Release 43399712 Reactome, http://www.reactome.org ReactomeREACT_18258 Reviewed: Ziff, EB, 2009-05-15 16:23:37 p(Y332,487,627)-Growth Hormone Receptor:p(Y1007)-JAK2 Reactome DB_ID: 1169228 Reactome Database ID Release 431169228 Reactome, http://www.reactome.org ReactomeREACT_111479 has a Stoichiometric coefficient of 1 Activation of Ca permeable AMPA receptors Authored: Mahajan, SS, 2008-01-14 16:01:52 Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecule, however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca permeable AMPA receptors containing homomers of GluR1 or heteromers containing GluR1, GluR3 and GluR4 conduct Ca upon glutamate or agonist namely AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. Calcium permeable AMPA receptors conduct Ca and other cations such as Na. The inonic flux leads to Ca or Na currents that leads to either increase in the intracellular Ca concentration leading to further Ca-dependent signaling or increase in depolarization that opens voltage gated channels such as NMDA receptors that require both membrane depolarization and glutamate binding for activation. Edited: Mahajan, SS, 2009-05-31 11:49:00 Pubmed19217372 Reactome Database ID Release 43420980 Reactome, http://www.reactome.org ReactomeREACT_18378 Reviewed: Ziff, EB, 2009-05-15 16:23:37 Growth Hormone: Tyrosine phosphorylated Growth Hormone Receptor-JAK2 dimer:SHP2 Reactome DB_ID: 1169221 Reactome Database ID Release 431169221 Reactome, http://www.reactome.org ReactomeREACT_111779 has a Stoichiometric coefficient of 1 Ca impermeable AMPA receptor ligand binding AMPA receptors bind glutamate, released in the synaptic cleft by the presynaptic cell, in the ligand binding region in the N terminal domain. Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2009-05-31 11:49:00 Pubmed14567697 Pubmed19144831 Reactome Database ID Release 43420975 Reactome, http://www.reactome.org ReactomeREACT_18341 Reviewed: Ziff, EB, 2009-05-15 16:23:37 Growth Hormone: Tyrosine phosphorylated Growth Hormone Receptor-JAK2 dimer Reactome DB_ID: 1169225 Reactome Database ID Release 431169225 Reactome, http://www.reactome.org ReactomeREACT_111590 has a Stoichiometric coefficient of 1 Endocytosis of Ca impermeable AMPA receptors Authored: Mahajan, SS, 2008-01-14 16:01:52 Edited: Mahajan, SS, 2009-05-31 11:49:00 GluR2 containing AMPA receptors are constitutively recycled between the endosome membrane and the plasma membrane. GRIP and PICK compete for the binding to the C tail of GluR2. Once the GluR2 containing AMPA receptors are in the plasmamembrane, phosphorylation of GluR2 at S880 by PKC causes disruption of GRIP interaction, but not PICK interaction which facilitates internalization of GluR2 containing AMPA receptors into endosomes. Pubmed16055064 Reactome Database ID Release 43421007 Reactome, http://www.reactome.org ReactomeREACT_18308 Reviewed: Ziff, EB, 2009-05-15 16:23:37 multiubiquitinated Cyclin A associated with MCC:APC/C complex Reactome DB_ID: 174222 Reactome Database ID Release 43174222 Reactome, http://www.reactome.org ReactomeREACT_7710 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Cdc2:Cyclin A:MCC:APC/C complex Reactome DB_ID: 174140 Reactome Database ID Release 43174140 Reactome, http://www.reactome.org ReactomeREACT_7458 has a Stoichiometric coefficient of 1 HIF HIF-alpha:ARNT Hypoxia-inducible Factor Reactome DB_ID: 1234130 Reactome Database ID Release 431234130 Reactome, http://www.reactome.org ReactomeREACT_121564 has a Stoichiometric coefficient of 1 Cyclin A:phospho-Cdc2(Thr 161) complex Reactome DB_ID: 174232 Reactome Database ID Release 43174232 Reactome, http://www.reactome.org ReactomeREACT_7745 has a Stoichiometric coefficient of 1 HIF:CBP:p300 Reactome DB_ID: 1234099 Reactome Database ID Release 431234099 Reactome, http://www.reactome.org ReactomeREACT_125616 has a Stoichiometric coefficient of 1 PathwayStep3796 PathwayStep3797 PathwayStep3798 PathwayStep3799 PathwayStep3795 PathwayStep3794 PathwayStep3793 PathwayStep3792 PathwayStep3791 PathwayStep3790 PathwayStep3789 PathwayStep3787 PathwayStep3788 PathwayStep3785 PathwayStep3786 PathwayStep3782 PathwayStep3781 PathwayStep3784 PathwayStep3783 PathwayStep3780 PathwayStep3778 PathwayStep3779 PathwayStep3774 PathwayStep3775 PathwayStep3776 PathwayStep3777 PathwayStep3772 PathwayStep3773 PathwayStep3770 PathwayStep3771 Rab27A Converted from EntitySet in Reactome Reactome DB_ID: 265190 Reactome Database ID Release 43265190 Reactome, http://www.reactome.org ReactomeREACT_15827 EXOC7 Converted from EntitySet in Reactome Reactome DB_ID: 265012 Reactome Database ID Release 43265012 Reactome, http://www.reactome.org ReactomeREACT_17863 PathwayStep3766 PathwayStep3765 PathwayStep3764 PathwayStep3763 PathwayStep3769 PathwayStep3768 PathwayStep3767 PathwayStep3760 PathwayStep3761 PathwayStep3762 ZnT5 Converted from EntitySet in Reactome Reactome DB_ID: 264944 Reactome Database ID Release 43264944 Reactome, http://www.reactome.org ReactomeREACT_15802 ZnT6 Converted from EntitySet in Reactome Reactome DB_ID: 264920 Reactome Database ID Release 43264920 Reactome, http://www.reactome.org ReactomeREACT_15922 PathwayStep3753 PathwayStep3752 PathwayStep3755 PathwayStep3754 PathwayStep3757 PathwayStep3756 PathwayStep3759 PathwayStep3758 PathwayStep3750 PathwayStep3751 PathwayStep3749 PathwayStep3748 PathwayStep3747 PathwayStep3746 PathwayStep3745 PathwayStep3744 PathwayStep3743 PathwayStep3742 PathwayStep3741 PathwayStep3740 EXOC1 Converted from EntitySet in Reactome Reactome DB_ID: 264910 Reactome Database ID Release 43264910 Reactome, http://www.reactome.org ReactomeREACT_15751 EXOC3 Converted from EntitySet in Reactome Reactome DB_ID: 264907 Reactome Database ID Release 43264907 Reactome, http://www.reactome.org ReactomeREACT_15913 PathwayStep3739 PathwayStep3738 PathwayStep3735 PathwayStep3734 PathwayStep3737 PathwayStep3736 PathwayStep3731 PathwayStep3730 PathwayStep3733 PathwayStep3732 PathwayStep3720 PathwayStep3721 PathwayStep3722 PathwayStep3723 PathwayStep3724 PathwayStep3725 PathwayStep3726 PathwayStep3727 PathwayStep3728 PathwayStep3729 Histone H2A Converted from EntitySet in Reactome Reactome DB_ID: 977558 Reactome Database ID Release 43977558 Reactome, http://www.reactome.org ReactomeREACT_76107 PathwayStep3710 PathwayStep3711 PathwayStep3714 PathwayStep3715 PathwayStep3712 PathwayStep3713 PathwayStep3718 PathwayStep3719 Histone H3 Converted from EntitySet in Reactome Reactome DB_ID: 977586 Reactome Database ID Release 43977586 Reactome, http://www.reactome.org ReactomeREACT_76733 PathwayStep3716 PathwayStep3717 Alpha-synuclein Converted from EntitySet in Reactome Reactome DB_ID: 1247707 Reactome Database ID Release 431247707 Reactome, http://www.reactome.org ReactomeREACT_76570 PathwayStep3701 PathwayStep3702 PathwayStep3703 PathwayStep3704 PathwayStep3700 PathwayStep3709 PathwayStep3705 PathwayStep3706 PathwayStep3707 PathwayStep3708 Histone H2B Converted from EntitySet in Reactome Reactome DB_ID: 977576 Reactome Database ID Release 43977576 Reactome, http://www.reactome.org ReactomeREACT_76382 Protonated Carbamino DeoxyHbA Deoxygenated Protonated Carbamino Hemoglobin A Deoxygenated Protonated Carbamino Hemoglobin alpha:Hemoglobin beta Tetramer Reactome DB_ID: 1237312 Reactome Database ID Release 431237312 Reactome, http://www.reactome.org ReactomeREACT_125222 has a Stoichiometric coefficient of 2 Hemoglobin alpha:ferroheme b:oxygen Reactome DB_ID: 1237036 Reactome Database ID Release 431237036 Reactome, http://www.reactome.org ReactomeREACT_123590 has a Stoichiometric coefficient of 1 Hemoglobin beta:ferroheme b:oxygen Reactome DB_ID: 1237037 Reactome Database ID Release 431237037 Reactome, http://www.reactome.org ReactomeREACT_122810 has a Stoichiometric coefficient of 1 Regulation of Water Balance by Renal Aquaporins Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-11 GENE ONTOLOGYGO:0006833 In the kidney water and solutes are passed out of the bloodstream and into the proximal tubule via the slit-like structure formed by nephrin in the glomerulus. Water is reabsorbed from the filtrate during its transit through the proximal tubule, the descending loop of Henle, the distal convoluted tubule, and the collecting duct.<br>Aquaporin-1 (AQP1) in the proximal tubule and the descending thin limb of Henle is responsible for about 90% of reabsorption (as estimated from mouse knockouts of AQP1). AQP1 is located on both the apical and basolateral surface of epithelial cells and thus transports water through the epithelium and back into the bloodstream.<br>In the collecting duct epithelial cells have AQP2 on their apical surface and AQP3 and AQP4 on their basolateral surface to transport water across the epithelium. The permeability of the epithelium is regulated by vasopressin, which activates the phosphorylation and subsequent translocation of AQP2 from intracellular vesicles to the plasma membrane. Pubmed11773613 Pubmed15924268 Pubmed17222168 Pubmed18566824 Pubmed19096775 Reactome Database ID Release 43432040 Reactome, http://www.reactome.org ReactomeREACT_24023 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Transport of Glycerol from Adipocytes to the Liver by Aquaporins Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 GENE ONTOLOGYGO:0015793 Pubmed16764946 Pubmed19096781 Reactome Database ID Release 43432030 Reactome, http://www.reactome.org ReactomeREACT_23809 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Triglycerides stored in adipocytes are hydrolyzed to yield fatty acids and glycerol. The glycerol is passively transported out of the adipocyte and into the bloodstream by Aquaporin-7 (AQP7) located in the plasma membrane of adipocytes. Glycerol in the bloodstream is passively transported into liver cells by AQP9 located in the plasma membrane of hepatocytes. Once inside the liver cell the glycerol is a substrate for gluconeogenesis. Aquaporin-mediated transport Aquaporins (AQP's) are six-pass transmembrane proteins that form channels in membranes. Each monomer contains a central channel formed in part by two asparagine-proline-alanine motifs (NPA boxes) that confer selectivity for water and/or solutes. The monomers assemble into tetramers. Most aquaporins (i.e. AQP0/MIP, AQP1, AQP2, AQP3, AQP4, AQP5, AQP7, AQP8, AQP9, AQP10) passively transport water into and out of cells according to the osmotic gradient across the membrane. Four aquaporins (the aquaglyceroporins AQP3, AQP7, AQP9, AQP10) conduct glycerol, three aquaporins (AQP7, AQP9, AQP10) conduct urea, and one aquaporin (AQP6) conducts anions, especially nitrate. AQP8 also conducts ammonia in addition to water.<br>AQP11 and AQP12, classified as group III aquaporins, were identified as a result of the genome sequencing project and are characterized by having variations in the first NPA box when compared to more traditional aquaporins. Additionally, a conserved cysteine residue is present about 9 amino acids downstream from the second NPA box and this cysteine is considered indicative of group III aquaporins. Purified AQP11 incorporated into liposomes showed water transport. Knockout mice lacking AQP11 had fatal cyst formation in the proximal tubule of the kidney. Exogenously expressed AQP12 showed intracellular localization. AQP12 is expressed exclusively in pancreatic acinar cells.<br>Aquaporins are important in fluid and solute transport in various tissues. In adipocytes, glycerol generated by triglyceride hydrolysis is exported by AQP7 and is imported by liver cells via AQP9. AQP1 plays a role in forming cerebrospinal fluid and AQP1, AQP4, and AQP9 appear to be important in maintaining fluid balance in the brain. AQP0, AQP1, AQP3, AQP4, AQP8, AQP9, and AQP11 play roles in the physiology of the hepatobiliary tract. In the kidney, water and solutes are passed out of the bloodstream and into the proximal tubule via the slit-like structure formed by nephrin in the glomerulus. Water is reabsorbed from the filtrate during its transit through the proximal tubule, the descending loop of Henle, the distal convoluted tubule, and the collecting duct. Aquaporin-1 (AQP1) in the proximal tubule and the descending thin limb of Henle is responsible for about 90% of reabsorption (as estimated from mouse knockouts of AQP1). AQP1 is located on both the apical and basolateral surface of epithelial cells and thus transports water through the epithelium and back into the bloodstream. In the collecting duct epithelial cells have AQP2 on their apical surfaces and AQP3 and AQP4 on their basolateral surfaces to transport water across the epithelium. The permeability of the epithelium is regulated by vasopressin, which activates a signaling cascade leading to the phosphorylation of AQP2 and its translocation from intracellular vesicles to the apical membrane of collecting duct cells.<br>Here, three views of aquaporin-mediated transport have been annotated: a generic view of transport mediated by the various families of aquaporins independent of tissue type, a view of the role of specific aquaporins in maintenance of renal water balance, and a view of the role of specific aquaporins in glycerol transport from adipocytes to the liver. Authored: May, B, 2009-11-01 Edited: May, B, 2009-11-01 GENE ONTOLOGYGO:0006833 Pubmed11773613 Pubmed15340377 Pubmed15809071 Pubmed15901243 Pubmed15924268 Pubmed16107722 Pubmed16650285 Pubmed17222168 Pubmed17961083 Pubmed19096770 Pubmed19448080 Pubmed20224213 Reactome Database ID Release 43445717 Reactome, http://www.reactome.org ReactomeREACT_23887 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Passive Transport by Aquaporins Aquaporins (AQP's) are six-pass transmembrane proteins that form channels in membranes. Each monomer contains a central channel formed in part by two asparagine-proline-alanine motifs (NPA boxes) that confer selectivity for water and/or solutes. The monomers assemble into tetramers. Most aquaporins (i.e. AQP0/MIP, AQP1, AQP2, AQP3, AQP4, AQP5, AQP7, AQP8, AQP9, AQP10) passively transport water into and out of cells according to the osmotic gradient across the membrane. Four aquaporins (the aquaglyceroporins AQP3, AQP7, AQP9, AQP10) conduct glycerol, three aquaporins (AQP7, AQP9, AQP10) conduct urea, and one aquaporin (AQP6) conducts anions, especially nitrate. AQP8 also conducts ammonia in addition to water.<br>AQP11 and AQP12, classified as group III aquaporins, were identified as a result of the genome sequencing project and are characterized by having variations in the first NPA box when compared to more traditional aquaporins. Additionally, a conserved cysteine residue is present about 9 amino acids downstream from the second NPA box and this cysteine is considered indicative of group III aquaporins. Purified AQP11 incorporated into liposomes showed water transport. Knockout mice lacking AQP11 had fatal cyst formation in the proximal tubule of the kidney. Exogenously expressed AQP12 showed intracellular localization. AQP12 is expressed exclusively in pancreatic acinar cells.<br>Aquaporins are important in fluid and solute transport in various tissues. In adipocytes, glycerol generated by triglyceride hydrolysis is exported by AQP7 and is imported by liver cells via AQP9. AQP1 plays a role in forming cerebrospinal fluid and AQP1, AQP4, and AQP9 appear to be important in maintaining fluid balance in the brain. AQP0, AQP1, AQP3, AQP4, AQP8, AQP9, and AQP11 play roles in the physiology of the hepatobiliary tract. In the kidney, water and solutes are passed out of the bloodstream and into the proximal tubule via the slit-like structure formed by nephrin in the glomerulus. Water is reabsorbed from the filtrate during its transit through the proximal tubule, the descending loop of Henle, the distal convoluted tubule, and the collecting duct. Aquaporin-1 (AQP1) in the proximal tubule and the descending thin limb of Henle is responsible for about 90% of reabsorption (as estimated from mouse knockouts of AQP1). AQP1 is located on both the apical and basolateral surface of epithelial cells and thus transports water through the epithelium and back into the bloodstream. In the collecting duct epithelial cells have AQP2 on their apical surfaces and AQP3 and AQP4 on their basolateral surfaces to transport water across the epithelium. The permeability of the epithelium is regulated by vasopressin, which activates a signaling cascade leading to the phosphorylation of AQP2 and its translocation from intracellular vesicles to the apical membrane of collecting duct cells.<br>Here, three views of aquaporin-mediated transport have been annotated: a generic view of transport mediated by the various families of aquaporins independent of tissue type, a view of the role of specific aquaporins in maintenance of renal water balance, and a view of the role of specific aquaporins in glycerol transport from adipocytes to the liver. Authored: May, B, 2009-08-06 Edited: May, B, 2009-08-06 GENE ONTOLOGYGO:0006833 Pubmed11773613 Pubmed15340377 Pubmed15901243 Pubmed15924268 Pubmed16764946 Pubmed17222168 Pubmed17513417 Pubmed17961083 Pubmed18173545 Pubmed18566824 Pubmed19096770 Pubmed19096775 Pubmed19096781 Pubmed19448080 Reactome Database ID Release 43432047 Reactome, http://www.reactome.org ReactomeREACT_23826 Reviewed: Beitz, E, 2010-06-24 Reviewed: Calamita, G, 2010-07-15 Reviewed: Mathai, JC, MacIver, B, 2010-07-31 Transport of fatty acids Authored: Jassal, B, 2010-05-26 Edited: Jassal, B, 2010-05-26 GENE ONTOLOGYGO:0015909 Long chain fatty acids (LCFAs) are involved in many cellular functions. They can be used as an important source of energy by skeletal muscle and heart tissues. Also, they are used in the production of hormones which can regulate inflammation, blood pressure, the clotting process, blood lipid levels and the immune response. Fatty acid transporter proteins (FATPs) are a family of proteins which mediate fatty acid uptake into cells when overexpressed. FATPs also possess enzymatic activity, the details of which are captured elsewhere. There are 6 human genes of the SLC27A family which encode for FATP1-6 (Stahl A, 2004; Gimeno RE, 2007). To date, only FATP1, 4 and 6 have demonstrable transporter function. Fatty acids with carbon chain lengths of more than 10 are the most likely substrates for these transporters. Pubmed12856180 Pubmed17495600 Reactome Database ID Release 43804914 Reactome, http://www.reactome.org ReactomeREACT_23892 Reviewed: He, L, 2010-07-07 Transport of organic anions Authored: Jassal, B, 2010-06-18 Edited: Jassal, B, 2010-06-18 GENE ONTOLOGYGO:0043252 Organic anion transporting polypeptides (OATPs) are membrane transport proteins that mediate the sodium-independent transport of a wide range of amphipathic organic compounds including bile salts, steroid conjugates, thyroid hormones, anionic oligopeptides and numerous drugs (Hagenbuch B and Meier PJ, 2004). Pubmed14579113 Reactome Database ID Release 43879518 Reactome, http://www.reactome.org ReactomeREACT_23988 Reviewed: He, L, 2010-07-07 Transport of nucleotide sugars Authored: Jassal, B, 2010-05-12 Edited: Jassal, B, 2010-05-12 Nucleotide sugars are used as sugar donors by glycosyltransferases to create the sugar chains for glycoconjugates such as glycoproteins, polysaccharides and glycolipids. Glycosyltransferases reside mainly in the lumen of the Golgi apparatus and endoplasmic reticulum (ER) whereas nucleotide sugars are synthesized in the cytosol. The human solute carrier family SLC35 encode nucleotide sugar transporters (NSTs) which can mediate the antiport of nucleotide sugars in exchange for the corresponding nucleoside monophosphates (eg. UMP for UDP-sugars). Owing to their function, NSTs are primarily located on Golgi and ER membranes (He L et al, 2009; Handford M et al, 2006; Ishida N and Kawakita M, 2004). Pubmed12759756 Pubmed16981043 Pubmed19164095 Reactome Database ID Release 43727802 Reactome, http://www.reactome.org ReactomeREACT_22151 Reviewed: He, L, 2010-05-10 FXN:NFS1:ISD11:ISCU:2Fe-2S Cluster Reactome DB_ID: 1362398 Reactome Database ID Release 431362398 Reactome, http://www.reactome.org ReactomeREACT_151067 has a Stoichiometric coefficient of 2 CA4:Zn2+ Carbonic Anhydrase IV:Zinc Reactome DB_ID: 1237308 Reactome Database ID Release 431237308 Reactome, http://www.reactome.org ReactomeREACT_123990 has a Stoichiometric coefficient of 1 AQP1 tetramer Aquaporin-1 tetramer Reactome DB_ID: 432246 Reactome Database ID Release 43432246 Reactome, http://www.reactome.org ReactomeREACT_24230 has a Stoichiometric coefficient of 4 CA1/CA2 Carbonic Anhydrase I/II Converted from EntitySet in Reactome Erythrocyte Carbonic Anhydrase Reactome DB_ID: 1475437 Reactome Database ID Release 431475437 Reactome, http://www.reactome.org ReactomeREACT_124189 CA1:Zn2+ Carbonic Anhydrase I:Zinc Reactome DB_ID: 1237322 Reactome Database ID Release 431237322 Reactome, http://www.reactome.org ReactomeREACT_122322 has a Stoichiometric coefficient of 1 Ion channel transport Authored: Jassal, B, 2010-11-02 Edited: Jassal, B, 2010-11-02 GENE ONTOLOGYGO:0034220 ISBN0-87893-741-2 Ion channels mediate the flow of ions across the plasma membrane of cells. They are integral membrane proteins, typically a multimer of proteins, which, when arranged in the membrane, create a pore for the flow of ions. There are different types of ion channels. P-type ATPases undergo conformational changes to translocate ions. Ligand-gated ion channels operate like a gate, opened or closed by a chemical signal. Voltage-gated ion channels are activated by changes in electrical potential difference at the membrane (Purves, 2001; Kuhlbrandt, 2004). Pubmed15071553 Reactome Database ID Release 43983712 Reactome, http://www.reactome.org ReactomeREACT_25300 Reviewed: He, L, 2010-11-15 CA2:Zn2+ Carbonic Anhydrase II:Zinc Reactome DB_ID: 1237310 Reactome Database ID Release 431237310 Reactome, http://www.reactome.org ReactomeREACT_124288 has a Stoichiometric coefficient of 1 SLC4A1 dimer Band 3 anion transport protein dimer Reactome DB_ID: 1244330 Reactome Database ID Release 431244330 Reactome, http://www.reactome.org ReactomeREACT_125443 has a Stoichiometric coefficient of 2 Iron uptake and transport Authored: Stephan, R, 2010-06-30 Edited: Jassal, B, 2010-07-30 GENE ONTOLOGYGO:0006879 Pubmed18259769 Pubmed19381358 Pubmed20495089 Reactome Database ID Release 43917937 Reactome, http://www.reactome.org ReactomeREACT_25060 Reviewed: D'Eustachio, P, 2010-11-05 The transport of iron between cells is mediated by transferrin. However, iron can also enter and leave cells not only by itself, but also in the form of heme and siderophores. When entering the cell via the main path (by transferrin endocytosis), its goal is not the (still elusive) chelated iron pool in the cytosol nor the lysosomes but the mitochondria, where heme is synthesized and iron-sulfur clusters are assembled (Kurz et al,2008, Hower et al 2009, Richardson et al 2010). OxyHbA Oxygenated Hemoglobin A Oxygenated Hemoglobin alpha:Hemoglobin beta Tetramer Reactome DB_ID: 1237320 Reactome Database ID Release 431237320 Reactome, http://www.reactome.org ReactomeREACT_123853 has a Stoichiometric coefficient of 2 Transferrin endocytosis and recycling Authored: Stephan, R, 2010-07-11 Edited: Jassal, B, 2010-07-30 Endocytosis of iron loaded transferrin/receptor complex leads, after acidification of the endosome, to the separation of iron and its diffusion out of the vesicle. The endosome is not fused with a lysosome but recycles its content back to the cell surface where soon transferrin dissociates from its receptor (Dautry-Varsat, 1986). GENE ONTOLOGYGO:0033572 Pubmed2874839 Reactome Database ID Release 43917977 Reactome, http://www.reactome.org ReactomeREACT_25283 Reviewed: D'Eustachio, P, 2010-11-05 CA12 Dimer:Zinc Carbonic Anhydrase XII Dimer Reactome DB_ID: 1237535 Reactome Database ID Release 431237535 Reactome, http://www.reactome.org ReactomeREACT_122118 has a Stoichiometric coefficient of 2 CA14:Zinc Carbonic Anhydrase XIV:Zinc Reactome DB_ID: 1237324 Reactome Database ID Release 431237324 Reactome, http://www.reactome.org ReactomeREACT_124027 has a Stoichiometric coefficient of 1 CA9:Zinc Carbonic Anhydrase IX:Zinc Reactome DB_ID: 1237323 Reactome Database ID Release 431237323 Reactome, http://www.reactome.org ReactomeREACT_121734 has a Stoichiometric coefficient of 1 Signaling Pathways Authored: Bevan, AP, Charalambous, M, Gopinathrao, G, Joshi-Tope, G, Rothfels, K, Orlic-Milacic, Marija, 2005--0-5- Pubmed11742412 Pubmed15450248 Pubmed15520807 Pubmed15863030 Pubmed16260143 Pubmed16939974 Pubmed17084981 Pubmed17496910 Pubmed17604717 Pubmed18043707 Pubmed18483217 Pubmed19379690 Pubmed19458711 Pubmed19536106 Pubmed19619488 Pubmed19648010 Pubmed19762341 Pubmed19935667 Pubmed21252999 Pubmed21781017 Reactome Database ID Release 43162582 Reactome, http://www.reactome.org ReactomeREACT_111102 Reviewed: Barroso, I, Stanley, FM, Joutel, A, Rush, MG, 0000-00-00 00:00:00 Signal Transduction Signal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such as hormones and growth factors, or reacting to other types of stimuli, such as light. Stimulation of transmembrane receptors leads to their conformational change which propagates the signal to the intracellular environment by activating downstream signaling cascades. Depending on the cellular context, this may impact cellular proliferation, differentiation, and survival. On the organism level, signal transduction regulates overall growth and behavior. Receptor tyrosine kinases (RTKs) transmit extracellular signals by phosphorylating their protein partners on conserved tyrosine residues. Some of the best studied RTKs are EGFR (reviewed in Avraham and Yarden, 2011), FGFR (reviewed in Eswarakumar et al, 2005), insulin receptor (reviewed in Saltiel and Kahn, 2001), NGF (reviewed in Reichardt, 2006), PDGF (reviewed in Andrae et al, 2008) and VEGF (reviewed in Xie et al, 2004). RTKs frequently activate downstream signaling through RAF/MAP kinases (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT (reviewed in Manning and Cantley, 2007) and PLC- gamma (reviewed in Patterson et al), which ultimately results in changes in gene expression and cellular metabolism. Receptor serine/threonine kinases of the TGF-beta family, such as TGF-beta receptors (reviewed in Kang et al. 2009) and BMP receptors (reviewed in Miyazono et al. 2009), transmit extracellular signals by phosphorylating regulatory SMAD proteins on conserved serine and threonine residues. This leads to formation of complexes of regulatory SMADs and SMAD4, which translocate to the nucleus where they act as transcription factors. WNT receptors transmit their signal through beta-catenin. In the absence of ligand, beta-catenin is constitutively degraded in a ubiquitin-dependent manner. WNT receptor stimulation releases beta-catenin from the destruction complex, allowing it to translocate to the nucleus where it acts as a transcriptional regulator (reviewed in MacDonald et al, 2009 and Angers and Moon, 2009). WNT receptors were originally classified as G-protein coupled receptors (GPCRs). Although they are structurally related, GPCRs primarily transmit their signals through G-proteins, which are trimers of alpha, beta and gamma subunits. When a GPCR is activated, it acts as a guanine nucleotide exchange factor, catalyzing GDP to GTP exchange on the G-alpha subunit of the G protein and its dissociation from the gamma-beta heterodimer. The G-alpha subunit regulates the activity of adenylate cyclase, while the gamma-beta heterodimer can activate AKT and PLC signaling (reviewed in Rosenbaum et al. 2009, Oldham and Hamm 2008, Ritter and Hall 2009). NOTCH receptors are activated by transmembrane ligands expressed on neighboring cells, which results in cleavage of NOTCH receptor and release of its intracellular domain. NOTCH intracellular domain translocates to the nucleus where it acts as a transcription factor (reviewed in Kopan and Ilagan, 2009). Integrins are activated by extracellular matrix components, such as fibronectin and collagen, leading to conformational change and clustering of integrins on the cell surface. This results in activation of integrin-linked kinase and other cytosolic kinases and, in co-operation with RTK signaling, regulates survival, proliferation and cell shape and adhesion (reviewed in Hehlgans et al, 2007) . Besides inducing changes in gene expression and cellular metabolism, extracellular signals that trigger the activation of Rho GTP-ases can trigger changes in the organization of cytoskeleton, thereby regulating cell polarity and cell-cell junctions (reviewed in Citi et al, 2011). Signaling by Insulin receptor Authored: Bevan, AP, 2003-07-31 08:01:55 Edited: Schmidt, EE, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008286 Insulin binding to its receptor results in receptor autophosphorylation on tyrosine residues and the tyrosine phosphorylation of insulin receptor substrates (e.g. IRS and Shc) by the insulin receptor tyrosine kinase. This allows association of IRSs with downstream effectors such as PI-3K via its Src homology 2 (SH2) domains leading to end point events such as Glut4 translocation. Shc when tyrosine phosphorylated associates with Grb2 and can thus activate the Ras/MAPK pathway independent of the IRSs.<p>Signal transduction by the insulin receptor is not limited to its activation at the cell surface. The activated ligand-receptor complex initially at the cell surface, is internalised into endosomes itself a process which is dependent on tyrosine autophosphorylation. Endocytosis of activated receptors has the dual effect of concentrating receptors within endosomes and allows the insulin receptor tyrosine kinase to phosphorylate substrates that are spatially distinct from those accessible at the plasma membrane. Acidification of the endosomal lumen, due to the presence of proton pumps, results in dissociation of insulin from its receptor. (The endosome constitutes the major site of insulin degradation). This loss of the ligand-receptor complex attenuates any further insulin-driven receptor re-phosphorylation events and leads to receptor dephosphorylation by extra-lumenal endosomally-associated protein tyrosine phosphatases (PTPs). The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future. Insulin receptor mediated signaling Reactome Database ID Release 4374752 Reactome, http://www.reactome.org ReactomeREACT_498 Reviewed: Barroso, I, Stanley, FM, 0000-00-00 00:00:00 Insulin receptor signalling cascade Authored: Bevan, AP, 2003-07-31 08:01:55 Autophosphorylation of the insulin receptor triggers a series of signalling events, mediated by SHC or IRS, and resulting in activation of the Ras/RAF and MAP kinase cascades. A second effect of the autophosphorylation of the insulin receptor is its internalisation into an endosome, which downregulates its signalling activity. Pubmed11282018 Pubmed9677303 Reactome Database ID Release 4374751 Reactome, http://www.reactome.org ReactomeREACT_1195 SHC-related events Authored: Bevan, AP, 2003-07-31 08:01:55 Reactome Database ID Release 4377388 Reactome, http://www.reactome.org ReactomeREACT_999 SHC is one of the mediators of insulin signalling events. It is activated by phosphorylation and triggers a cascade of events involving SOS, RAF and the MAP kinases. Ion transport by P-type ATPases Authored: Jassal, B, 2010-08-24 Edited: Jassal, B, 2010-08-24 GENE ONTOLOGYGO:0034220 Pubmed15071553 Reactome Database ID Release 43936837 Reactome, http://www.reactome.org ReactomeREACT_25149 Reviewed: He, L, 2010-11-15 The P-type ATPases (E1-E2 ATPases) are a large group of evolutionarily related ion pumps that are found in bacteria, archaea and eukaryotes. They are referred to as P-type ATPases because they catalyze auto-phosphorylation of a key conserved aspartate residue within the pump. They all appear to interconvert between at least two different conformations, E1 and E2. Most members of this transporter family pump a large variety of cations (Kuhlbrandt W, 2004). Ligand-gated ion channel transport Authored: Jassal, B, 2010-09-23 Edited: Jassal, B, 2010-09-23 GENE ONTOLOGYGO:0034220 ISBN0-87893-741-2 Ligand-gated ion channels (LGICs) are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger (Purves, 2001). Reactome Database ID Release 43975298 Reactome, http://www.reactome.org ReactomeREACT_25387 Reviewed: He, L, 2010-11-15 Meiosis Authored: May, B, 2011-08-19 During meiosis the replicated chromosomes of a single diploid cell are segregated into 4 haploid daughter cells by two successive divisions, meiosis I and meiosis II. In meiosis I, the distinguishing event of meiosis, pairs (bivalents) of homologous chromosomes in the form of sister chromatids are paired, synapsed along their regions of homologous DNA (reviewed in Yang and Wang 2009), and then segregated, resulting in haploid daughters containing sister chromatids paired at their centromeres (reviewed in Cohen et al. 2006, Handel and Schimenti 2010). The sister chromatids are then separated and segregated during meiosis II.<br>Recombination between chromosomal homologues but not between sister chromatids occurs during prophase of meiosis I (reviewed in Inagaki et al. 2010). Though hundreds of recombination events are initiated, most are resolved without crossovers and only tens proceed to become crossovers. In mammals recombination events are required between homologues for normal pairing, synapsis, and segregation. Edited: May, B, 2011-08-19 Pubmed16543383 Pubmed18948708 Pubmed20051984 Pubmed20364103 Reactome Database ID Release 431500620 Reactome, http://www.reactome.org ReactomeREACT_111183 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 Meiotic Recombination Authored: May, B, 2010-07-02 Edited: May, B, 2010-07-02 Meiotic recombination exchanges segments of duplex DNA between chromosomal homologs, generating genetic diversity (reviewed in Handel and Schimenti 2010, Inagaki et al. 2010, Cohen et al. 2006). There are two forms of recombination: non-crossover (NCO) and crossover (CO). In mammals, the former is required for correct pairing and synapsis of homologous chromosomes, while CO intermediates called chiasmata are required for correct segregation of bivalents.<br>Meiotic recombination is initiated by double-strand breaks created by SPO11, which remains covalently attached to the 5' ends after cleavage. SPO11 is removed by cleavage of single DNA strands adjacent to the covalent linkage. The resulting 5' ends are further resected to produce protruding 3' ends. The single-stranded 3' ends are bound by RAD51 and DMC1, homologs of RecA that catalyze a search for homology between the bound single strand and duplex DNA of the chromosomal homolog. RAD51 and DMC1 then catalyze the invasion of the single strand into the homologous duplex and the formation of a D-loop heteroduplex. Approximately 90% of heteroduplexes are resolved without crossovers (NCO), probably by synthesis-dependent strand annealing.<br>The invasive strand is extended along the homolog and ligated back to its original duplex, creating a double Holliday junction. The mismatch repair proteins MSH4, MSH5 participate in this process, possibly by stabilizing the duplexes. The mismatch repair proteins MLH1 and MLH3 are then recruited to the double Holliday structure and an unidentified resolvase (Mus81? Gen1?) cleaves the junctions to yield a crossover. <br>Crossovers are not randomly distributed: The histone methyltransferase PRDM9 recruits the recombination machinery to genetically determined hotspots in the genome and each incipient crossover somehow inhibits formation of crossovers nearby, a phenomenon called crossover interference. Each chromosome bivalent, including the X-Y body in males, has at least one crossover and this is required for meiosis to proceed correctly. Pubmed16543383 Pubmed20051984 Pubmed20364103 Reactome Database ID Release 43912446 Reactome, http://www.reactome.org ReactomeREACT_27271 Reviewed: Bolcun-Filas, E, 2011-02-25 Reviewed: Cohen, PE, 2011-02-04 Reviewed: Holloway, JK, 2011-02-04 Reviewed: Lyndaker, A, 2011-02-25 Reviewed: Schimenti, JC, 2011-02-04 Reviewed: Strong, E, 2011-02-25 ABCG2 dimer Reactome DB_ID: 917863 Reactome Database ID Release 43917863 Reactome, http://www.reactome.org ReactomeREACT_26835 has a Stoichiometric coefficient of 2 CA1/2/3/7/13:Zinc Converted from EntitySet in Reactome Cytosolic Carbonic Anhydrase Reactome DB_ID: 1475034 Reactome Database ID Release 431475034 Reactome, http://www.reactome.org ReactomeREACT_122866 Protonated Carbamino Hemoglobin alpha:ferroheme b Reactome DB_ID: 1237317 Reactome Database ID Release 431237317 Reactome, http://www.reactome.org ReactomeREACT_121441 has a Stoichiometric coefficient of 1 Protonated Carbamino Hemoglobin beta: ferroheme b Reactome DB_ID: 1237318 Reactome Database ID Release 431237318 Reactome, http://www.reactome.org ReactomeREACT_125469 has a Stoichiometric coefficient of 1 CA13:Zinc Carbonic Anhydrase XIII:Zinc Reactome DB_ID: 1237321 Reactome Database ID Release 431237321 Reactome, http://www.reactome.org ReactomeREACT_124770 has a Stoichiometric coefficient of 1 SHC activation Authored: 2003-07-28 10:05:14 Reactome Database ID Release 4374744 Reactome, http://www.reactome.org ReactomeREACT_1661 SHC interacts via its SH2 domain with the carboxyterminal phosphorylated tyrosines of the insulin receptor. As a result, SHC is tyrosine phosphorylated (Tyr317) by the insulin receptor, later falling away from the receptor. The phosphorylation of tyrosine 317 of SHC allows GRB2 to bind to it via its SH2 domain. CA4/9/14/12:Zinc Converted from EntitySet in Reactome Extracellular Carbonic Anhydrase Reactome DB_ID: 1475027 Reactome Database ID Release 431475027 Reactome, http://www.reactome.org ReactomeREACT_123111 SHC-mediated signalling Authored: Charalambous, M, 2004-04-29 09:21:24 Reactome Database ID Release 43112410 Reactome, http://www.reactome.org ReactomeREACT_661 Release of phospho-SHC from the insulin receptor triggers a cascade of signalling events via SOS, RAF and the MAP kinases. CA3:Zinc Carbonic Anhydrase III:Zinc Reactome DB_ID: 1237315 Reactome Database ID Release 431237315 Reactome, http://www.reactome.org ReactomeREACT_125181 has a Stoichiometric coefficient of 1 CA7:Zinc Carbonic Anhydrase VII:Zinc Reactome DB_ID: 1237309 Reactome Database ID Release 431237309 Reactome, http://www.reactome.org ReactomeREACT_122469 has a Stoichiometric coefficient of 1 microsomal GST5 homotrimer Reactome DB_ID: 176040 Reactome Database ID Release 43176040 Reactome, http://www.reactome.org ReactomeREACT_7720 has a Stoichiometric coefficient of 3 Cytosolic GST homodimer Reactome DB_ID: 176046 Reactome Database ID Release 43176046 Reactome, http://www.reactome.org ReactomeREACT_7392 has a Stoichiometric coefficient of 2 FXN:ISD11:NFS1:ISCU Reactome DB_ID: 1362404 Reactome Database ID Release 431362404 Reactome, http://www.reactome.org ReactomeREACT_150577 has a Stoichiometric coefficient of 2 microsomal GST2 homotrimer Reactome DB_ID: 176061 Reactome Database ID Release 43176061 Reactome, http://www.reactome.org ReactomeREACT_7436 has a Stoichiometric coefficient of 3 microsomal GST3 homotrimer Reactome DB_ID: 176047 Reactome Database ID Release 43176047 Reactome, http://www.reactome.org ReactomeREACT_7298 has a Stoichiometric coefficient of 3 microsomal GST4-1 homotrimer Reactome DB_ID: 176064 Reactome Database ID Release 43176064 Reactome, http://www.reactome.org ReactomeREACT_7648 has a Stoichiometric coefficient of 3 microsomal GST4-2 homotrimer Reactome DB_ID: 176055 Reactome Database ID Release 43176055 Reactome, http://www.reactome.org ReactomeREACT_7476 has a Stoichiometric coefficient of 3 gamma-glutamyl-AA Reactome DB_ID: 1247913 Reactome Database ID Release 431247913 Reactome, http://www.reactome.org ReactomeREACT_76051 has a Stoichiometric coefficient of 1 Microsomal GST homotrimer Converted from EntitySet in Reactome Reactome DB_ID: 176042 Reactome Database ID Release 43176042 Reactome, http://www.reactome.org ReactomeREACT_7911 microsomal GST1 homotrimer Reactome DB_ID: 158548 Reactome Database ID Release 43158548 Reactome, http://www.reactome.org ReactomeREACT_7304 has a Stoichiometric coefficient of 3 FDX1L (reduced) Reactome DB_ID: 2395503 Reactome Database ID Release 432395503 Reactome, http://www.reactome.org ReactomeREACT_151527 has a Stoichiometric coefficient of 1 Zinc transporters Authored: Jassal, B, 2009-09-09 Edited: Jassal, B, 2009-09-09 Pubmed16675045 Pubmed17374385 Pubmed18754861 Reactome Database ID Release 43435354 Reactome, http://www.reactome.org ReactomeREACT_20530 Reviewed: He, L, 2009-11-12 Zinc is an essential element for all organisms because it serves as a catalytic or structural cofactor for many different proteins. Cellular zinc homoeostasis is co-ordinated through Zn2+-specific transporters which are members of two distinct gene families. Members of the SLC39 gene family (ZRTL-like import proteins1–14, ZIP1-14) are responsible for Zn2+ import into the cytoplasm, either across the plasma membrane or out of intracellular organelles. In contrast, members of the SLC30 gene family (zinc transporters 1–10, ZnT1-10) export Zn2+ from the cytoplasm, either across the plasma membrane into the extracellular space or into intracellular organelles (Murakami M and Hirano T, 2008; Devirgiliis C et al, 2007; Eide DJ, 2006) Zinc efflux and compartmentalization by the SLC30 family Authored: Jassal, B, 2009-09-09 Edited: Jassal, B, 2009-09-09 Pubmed12748859 Reactome Database ID Release 43435368 Reactome, http://www.reactome.org ReactomeREACT_20582 Reviewed: He, L, 2009-11-12 The human SLC30 gene family of solute carriers is thought to participate in the homeostasis of zinc ions and facilitate zinc transport into specialized compartments of the cell such as endosomes, golgi network and synaptic vesicles. There are 10 members of this family, named ZnT1-10. ZnT4, ZnT9 and ZnT10 have no function determined as of yet (Palmiter RD and Huang L, 2004). Zinc influx into cells by the SLC39 gene family Authored: Jassal, B, 2009-09-25 Edited: Jassal, B, 2009-09-25 Pubmed12659941 Pubmed12748861 Reactome Database ID Release 43442380 Reactome, http://www.reactome.org ReactomeREACT_20603 Reviewed: He, L, 2009-11-12 The SLC39 gene family encode zinc transporters belonging to the ZIP (Zrt-, Irt-like proteins) family of metal ion transporters. All ZIPs transport metal ions into the cytoplasm of cells, be it across cellular membranes or from intracellular compartments. To date, there are 14 human SLC39 genes that encode the zinc transporters hZIP1-14. There are 9 members which belong to a subfamily of the ZIPs called the LZTs (LIV-1 subfamily of ZIP zinc transporters) (Taylor KM and Nicholson RI, 2003). Of these 14 proteins, four (hZIP9, 11, 12 and 13) have no function determined yet (Eide DJ, 2004). Na+/Cl- dependent neurotransmitter transporters Authored: Jassal, B, 2009-09-29 Edited: Jassal, B, 2009-09-29 Pubmed12719981 Reactome Database ID Release 43442660 Reactome, http://www.reactome.org ReactomeREACT_20506 Reviewed: He, L, 2009-11-12 The SLC6 gene family encodes proteins that mediate neurotransmitter uptake thus terminating a synaptic signal. The proteins mediate transport of GABA (gamma-aminobutyric acid), norepinephrine, dopamine, serotonin, glycine, taurine, L-proline, creatine and betaine. These transporters are mainly present in the CNS and PNS (Chen NH et al, 2004). FDX1/1L (reduced) Converted from EntitySet in Reactome Reactome DB_ID: 2408372 Reactome Database ID Release 432408372 Reactome, http://www.reactome.org ReactomeREACT_150657 Reduced Ferredoxin Rhesus glycoproteins mediate ammonium transport. Authored: Jassal, B, 2009-10-23 Edited: Jassal, B, 2009-10-23 Pubmed12920597 Pubmed17106214 Reactome Database ID Release 43444411 Reactome, http://www.reactome.org ReactomeREACT_20508 Reviewed: He, L, 2009-11-12 The Rhesus (Rh) glycoproteins were originally described in human blood cells as potent immunogens. There are three Rh glycoproteins in humans; an erythroid-specific Rh-associated glycoprotein (RhAG) and two non-erythroid Rh glycoproteins, RhBG and RhCG. These proteins are related to ammonium (NH4+) transporters of yeast and bacteria (methylammonium and ammonium permease and ammonium transporter, MEP/Amt) (Nakhoul NL and Hamm LL, 2004; Planelles G, 2007). FDX1 (reduced) Reactome DB_ID: 2395507 Reactome Database ID Release 432395507 Reactome, http://www.reactome.org ReactomeREACT_151370 has a Stoichiometric coefficient of 1 Organic cation/anion/zwitterion transport Authored: Jassal, B, 2010-03-17 Edited: Jassal, B, 2010-03-17 Pubmed12883891 Reactome Database ID Release 43549132 Reactome, http://www.reactome.org ReactomeREACT_22345 Reviewed: He, L, 2010-05-10 The SLC22 gene family of solute carriers function as organic cation transporters (OCTs), cation/zwitterion transporters (OCTNs) and organic anion transporters (OATs). The SLC22 family belongs to the major facilitator superfamily and comprises uniporters, symporters and antiporters.Most of this family are polyspecific transporters. Since many of these transporters are expressed in the liver, kidney and intestine, they play an important role in drug absorption and excretion. Substrates include xenobiotics, drugs, and endogenous amine compounds (Koepsell H and Endou H, 2004). FDX1 (oxidized) Reactome DB_ID: 2395509 Reactome Database ID Release 432395509 Reactome, http://www.reactome.org ReactomeREACT_150777 has a Stoichiometric coefficient of 1 Organic cation transport Authored: Jassal, B, 2010-03-17 Edited: Jassal, B, 2010-03-17 Pubmed12883891 Reactome Database ID Release 43549127 Reactome, http://www.reactome.org ReactomeREACT_22357 Reviewed: He, L, 2010-05-10 The organic cation transporters comprise three SLC22 members, OCT1-3. They can transport a wide range of organic cations including weak bases. All transport by OCTs is electrogenic, sodium-independent and bidirectional. Two further organic cation transporters mediate transport of ergothioneine and carnitine (Koepsell H and Endou H, 2004). FDX1L (oxidized) Reactome DB_ID: 2395505 Reactome Database ID Release 432395505 Reactome, http://www.reactome.org ReactomeREACT_152466 has a Stoichiometric coefficient of 1 Organic anion transport Authored: Jassal, B, 2010-03-25 Edited: Jassal, B, 2010-03-25 Organic anion transporters (OATs) mediate the renal absorption and excretion of a broad range of endogenous substrates and anionic drugs such as diuretics and NSAIDs. Five members belong to these polyspecific transporters (OAT1-4 and URAT1) and are predominantly expressed in the kidney (Koepsell H and Endou H, 2004; Rizwan AN and Burckhardt G, 2007; Ahn SY and Bhatnagar V, 2008). Pubmed12883891 Pubmed17245646 Pubmed18695391 Reactome Database ID Release 43561048 Reactome, http://www.reactome.org ReactomeREACT_22310 Reviewed: He, L, 2010-05-10 FDXR:FADH2 Reactome DB_ID: 2395502 Reactome Database ID Release 432395502 Reactome, http://www.reactome.org ReactomeREACT_150903 has a Stoichiometric coefficient of 1 Transport of vitamins, nucleosides, and related molecules Authored: Jassal, B, 2009-06-04 Edited: Jassal, B, 2009-06-04 Reactome Database ID Release 43425397 Reactome, http://www.reactome.org ReactomeREACT_22285 Reviewed: He, L, 2010-05-10 This pathway groups the processes mediated by SLC transporters, by which vitamins and cofactors, as well as nucleosides, nucleotides, nucleobases, and related molecules cross lipid bilayer membranes. FDX1/1L (oxidized) Converted from EntitySet in Reactome Oxidized Ferredoxin Reactome DB_ID: 2408370 Reactome Database ID Release 432408370 Reactome, http://www.reactome.org ReactomeREACT_151081 Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane Authored: D'Eustachio, P, 2003-12-09 17:40:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Pubmed10455109 Pubmed11032837 Pubmed12110519 Pubmed12527552 Pubmed12838422 Pubmed12856181 Pubmed9124315 Pubmed9435697 Reactome Database ID Release 4383936 Reactome, http://www.reactome.org ReactomeREACT_1206 Reviewed: He, L, 2010-05-10 Two families of transport proteins mediate the movement of nucleosides and free purine and pyrimidine bases across the plasma membrane. Equilibrative nucleoside transporters allow the movement of these molecules along concentration gradients into or out of cells (Baldwin et al. 2003); concentrative nucleoside transporters actively transport nucleosides into cells by coupling their transport to the inward movement of sodium ions (Gray et al. 2003).<P>Of the four human equilibrative nucleoside transporters, two are well characterized. SLC29A1 (solute carrier family 29 (nucleoside transporters), member 1) mediates the transport of nucleosides across the plasma membrane. SLC29A2 (solute carrier family 29 (nucleoside transporters), member 2) mediates the transport of both nucleosides and free bases. Transporter specificities were determined by expressing cloned human genes in Xenopus oocytes or in mammalian cultured cell lines whose own nucleotide transporters had been disrupted by mutation. These studies establish that the transport processes are specific and saturable, and that the multiple nucleotides and bases compete for a single binding site on each transporter. Some features of SLC29A2 specificity are complex. For example, in the Xenopus oocyte system, radiolabeled uracil and adenine are taken up, and an excess of either molecule inhibits uptake of radiolabeled hypoxanthine, while in the cultured mammalian cell system, neither adenine nor uracil can inhibit uptake of radiolabeled uridine. If these results reflect ENT2 function in vivo, they indicate that the net movement of a nucleoside or base across the cell membrane is determined not only by its own concentrations in the extracellular space and the cytosol, but also by the concentrations of the other nucleosides and bases competing for access to the transporter.<P>The human genome encodes three concentrative transporters, SLC28A1, 2, and 3 (solute carrier family 28 (sodium-coupled nucleoside transporter), member 1, 2, and 3). All three genes have been cloned, and expression of the human proteins in Xenopus oocytes has allowed their transport properties to be determined. SLC28A1 mediates the uptake of pyrimidine nucleosides and adenosine (Ritzel et al. 1997); SLC28A2 the uptake of purine nucleosides and uridine (Wang et al. 1997); and SLC28A3 the uptake of purine and pyrimidine nucleosides (Ritzel et al. 2001). Amino acid sequence motifs that determine the specificities of these transporters have been identified in studies of chimeric and mutant proteins (Loewen et al. 1999). SLC28A3 protein co-transports two sodium ions per nucleoside; SLC28A1 and 2 transport one sodium per nucleoside (Ritzel et al. 2001).<P>Physiological roles for nucleoside and base transport include provision of nucleosides to cells with little capacity to synthesize these molecules de novo, and regulation of extracellular levels of adenosine, which is released from muscle during intense exercise and has signaling properties. In kidney and intestinal epithelia, the combination of apically localized CNT transporters and basolaterally localized ENT transporters provides a mechanism for net transport of nucleosides (Mangravite et al. 2003). These transporters also mediate the uptake of nucleoside analogs used clinically as anti-viral and anti-tumor drugs.<P>Orthologs of human concentrative and equilibrative transporter proteins have been identified in many eukaryotes, but functional studies of transporters even from organisms closely related to humans (e.g. rat, Gerstin et al. 2002) have revealed differences in substrate specificities. Prediction of drug uptake and other functions of these molecules by human - model organism orthology is thus risky. 2 Iron:FXN Reactome DB_ID: 1362402 Reactome Database ID Release 431362402 Reactome, http://www.reactome.org ReactomeREACT_152098 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 FDXR:FAD Reactome DB_ID: 2395508 Reactome Database ID Release 432395508 Reactome, http://www.reactome.org ReactomeREACT_151835 has a Stoichiometric coefficient of 1 NFS1:pyridoxal phosphate Reactome DB_ID: 2395497 Reactome Database ID Release 432395497 Reactome, http://www.reactome.org ReactomeREACT_151212 has a Stoichiometric coefficient of 1 2 Iron:FXN:NFS1:ISD11:ISCU Reactome DB_ID: 1362401 Reactome Database ID Release 431362401 Reactome, http://www.reactome.org ReactomeREACT_152530 has a Stoichiometric coefficient of 2 MPG glycosylase:hypoxanthine complex Reactome DB_ID: 110206 Reactome Database ID Release 43110206 Reactome, http://www.reactome.org ReactomeREACT_2392 has a Stoichiometric coefficient of 1 MPG glycosylase:3-methyladenine complex Reactome DB_ID: 110202 Reactome Database ID Release 43110202 Reactome, http://www.reactome.org ReactomeREACT_3532 has a Stoichiometric coefficient of 1 MPG glycosylase:ethenoadenine complex Reactome DB_ID: 110204 Reactome Database ID Release 43110204 Reactome, http://www.reactome.org ReactomeREACT_4629 has a Stoichiometric coefficient of 1 UNG2 glycosylase:uracil complex Reactome DB_ID: 110152 Reactome Database ID Release 43110152 Reactome, http://www.reactome.org ReactomeREACT_2806 has a Stoichiometric coefficient of 1 UNG2 glycosylase:5-hydroxyuracil complex Reactome DB_ID: 110154 Reactome Database ID Release 43110154 Reactome, http://www.reactome.org ReactomeREACT_3795 has a Stoichiometric coefficient of 1 DNA containing an hOGG1-bound apurinic/apyrimidinic site Reactome DB_ID: 110195 Reactome Database ID Release 43110195 Reactome, http://www.reactome.org ReactomeREACT_2850 has a Stoichiometric coefficient of 1 DNA containing an MPG-bound apurinic/apyrimidinic site Reactome DB_ID: 110207 Reactome Database ID Release 43110207 Reactome, http://www.reactome.org ReactomeREACT_2597 has a Stoichiometric coefficient of 1 DNA containing an MYH-bound apurinic/apyrimidinic site Reactome DB_ID: 110200 Reactome Database ID Release 43110200 Reactome, http://www.reactome.org ReactomeREACT_3901 has a Stoichiometric coefficient of 1 hOGG1 glycosylase: formamidopyrimidine complex Reactome DB_ID: 110186 Reactome Database ID Release 43110186 Reactome, http://www.reactome.org ReactomeREACT_5383 has a Stoichiometric coefficient of 1 hOGG1 glycosylase:8-oxo guanine complex Reactome DB_ID: 110185 Reactome Database ID Release 43110185 Reactome, http://www.reactome.org ReactomeREACT_2571 has a Stoichiometric coefficient of 1 MYH glycosylase:adenine complex Reactome DB_ID: 110199 Reactome Database ID Release 43110199 Reactome, http://www.reactome.org ReactomeREACT_2660 has a Stoichiometric coefficient of 1 TDG glycosylase:ethenocytosine complex Reactome DB_ID: 110190 Reactome Database ID Release 43110190 Reactome, http://www.reactome.org ReactomeREACT_2767 has a Stoichiometric coefficient of 1 TDG glycosylase:thymine complex Reactome DB_ID: 110150 Reactome Database ID Release 43110150 Reactome, http://www.reactome.org ReactomeREACT_5014 has a Stoichiometric coefficient of 1 ADP:Calcium Bound Myosin Actin Complex Reactome DB_ID: 445697 Reactome Database ID Release 43445697 Reactome, http://www.reactome.org ReactomeREACT_20931 has a Stoichiometric coefficient of 1 Caldesmon:Calcium Complex Reactome DB_ID: 445808 Reactome Database ID Release 43445808 Reactome, http://www.reactome.org ReactomeREACT_21074 has a Stoichiometric coefficient of 1 Calcium Bound Myosin Actin Complex Reactome DB_ID: 445702 Reactome Database ID Release 43445702 Reactome, http://www.reactome.org ReactomeREACT_21082 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 integrin:cytoskeletal ahesion complex Reactome DB_ID: 445775 Reactome Database ID Release 43445775 Reactome, http://www.reactome.org ReactomeREACT_20932 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 ADP Bound Smooth Muscle Myosin Complex Reactome DB_ID: 445800 Reactome Database ID Release 43445800 Reactome, http://www.reactome.org ReactomeREACT_21152 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 ATP:Calcium Bound Myosin Actin Complex Reactome DB_ID: 445701 Reactome Database ID Release 43445701 Reactome, http://www.reactome.org ReactomeREACT_20759 has a Stoichiometric coefficient of 1 ATP Bound Smooth Muscle Myosin Complex Reactome DB_ID: 445789 Reactome Database ID Release 43445789 Reactome, http://www.reactome.org ReactomeREACT_20923 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 EGF:p-6Y-EGFR Reactome DB_ID: 1248702 Reactome Database ID Release 431248702 Reactome, http://www.reactome.org ReactomeREACT_117771 has a Stoichiometric coefficient of 1 EGF:p-6Y-EGFR:p-7Y-ERBB2 Reactome DB_ID: 1248703 Reactome Database ID Release 431248703 Reactome, http://www.reactome.org ReactomeREACT_117633 has a Stoichiometric coefficient of 1 Phosphorylated ERBB2:EGFR heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 1963587 Reactome Database ID Release 431963587 Reactome, http://www.reactome.org ReactomeREACT_117507 EGF:p-6Y-EGFR:p-6Y-ERBB2 Reactome DB_ID: 1963593 Reactome Database ID Release 431963593 Reactome, http://www.reactome.org ReactomeREACT_116719 has a Stoichiometric coefficient of 1 p-S217,277,376-Gorasp1:PLK1 Reactome DB_ID: 2423779 Reactome Database ID Release 432423779 Reactome, http://www.reactome.org ReactomeREACT_148024 has a Stoichiometric coefficient of 1 Shc1:Phosphorylated ERBB2:EGFR heterodimers Reactome DB_ID: 1985735 Reactome Database ID Release 431985735 Reactome, http://www.reactome.org ReactomeREACT_116349 has a Stoichiometric coefficient of 1 AGER ligands:AGER Reactome DB_ID: 879365 Reactome Database ID Release 43879365 Reactome, http://www.reactome.org ReactomeREACT_24620 has a Stoichiometric coefficient of 1 mNICD1:HIF1A Reactome DB_ID: 2065558 Reactome Database ID Release 432065558 Reactome, http://www.reactome.org ReactomeREACT_119178 has a Stoichiometric coefficient of 1 AGE adducts:Peptide Reactome DB_ID: 879479 Reactome Database ID Release 43879479 Reactome, http://www.reactome.org ReactomeREACT_24245 has a Stoichiometric coefficient of 1 S100A12 dimer Reactome DB_ID: 879439 Reactome Database ID Release 43879439 Reactome, http://www.reactome.org ReactomeREACT_24179 has a Stoichiometric coefficient of 2 S100B homodimer Reactome DB_ID: 879449 Reactome Database ID Release 43879449 Reactome, http://www.reactome.org ReactomeREACT_24848 has a Stoichiometric coefficient of 2 AGER ligands:AGER:Erk Reactome DB_ID: 997399 Reactome Database ID Release 43997399 Reactome, http://www.reactome.org ReactomeREACT_26778 has a Stoichiometric coefficient of 1 IN bound to sticky 3' ends of viral DNA in PIC Reactome DB_ID: 175416 Reactome Database ID Release 43175416 Reactome, http://www.reactome.org ReactomeREACT_7635 has a Stoichiometric coefficient of 1 gamma-secretase complex Reactome DB_ID: 157343 Reactome Database ID Release 43157343 Reactome, http://www.reactome.org ReactomeREACT_5292 has a Stoichiometric coefficient of 1 Presenilin homodimer Reactome DB_ID: 157352 Reactome Database ID Release 43157352 Reactome, http://www.reactome.org ReactomeREACT_4710 has a Stoichiometric coefficient of 2 Inactive Sarcomere Protein Complex Reactome DB_ID: 390590 Reactome Database ID Release 43390590 Reactome, http://www.reactome.org ReactomeREACT_17721 has a Stoichiometric coefficient of 1 pNfasc:Doublecortin Reactome DB_ID: 443663 Reactome Database ID Release 43443663 Reactome, http://www.reactome.org ReactomeREACT_22823 has a Stoichiometric coefficient of 1 CA6:Zinc Carbonic Anhydrase VI:Zinc Reactome DB_ID: 1237316 Reactome Database ID Release 431237316 Reactome, http://www.reactome.org ReactomeREACT_124884 has a Stoichiometric coefficient of 1 CA5B:Zinc Carbonic Anhydrase VB:Zinc Reactome DB_ID: 1237319 Reactome Database ID Release 431237319 Reactome, http://www.reactome.org ReactomeREACT_125354 has a Stoichiometric coefficient of 1 CA5A:Zinc Carbonic Anhydrase VA:Zinc Reactome DB_ID: 1237314 Reactome Database ID Release 431237314 Reactome, http://www.reactome.org ReactomeREACT_124725 has a Stoichiometric coefficient of 1 CA5A/B:Zinc Converted from EntitySet in Reactome Mitochondrial Carbonic Anhydrase Reactome DB_ID: 1475016 Reactome Database ID Release 431475016 Reactome, http://www.reactome.org ReactomeREACT_125046 CA12:Zinc Carbonic Anhydrase XII:Zinc Reactome DB_ID: 1237311 Reactome Database ID Release 431237311 Reactome, http://www.reactome.org ReactomeREACT_122900 has a Stoichiometric coefficient of 1 PathwayStep3699 PathwayStep3698 PathwayStep3697 Thin Filament Reactome DB_ID: 390584 Reactome Database ID Release 43390584 Reactome, http://www.reactome.org ReactomeREACT_17696 has a Stoichiometric coefficient of 1 Troponin Complex Reactome DB_ID: 390583 Reactome Database ID Release 43390583 Reactome, http://www.reactome.org ReactomeREACT_17616 has a Stoichiometric coefficient of 1 Myosin Complex Reactome DB_ID: 390575 Reactome Database ID Release 43390575 Reactome, http://www.reactome.org ReactomeREACT_18044 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 M Disk Complex Reactome DB_ID: 390586 Reactome Database ID Release 43390586 Reactome, http://www.reactome.org ReactomeREACT_17374 has a Stoichiometric coefficient of 1 ATP:Calcium Bound Sarcomere Protein Complex Reactome DB_ID: 390596 Reactome Database ID Release 43390596 Reactome, http://www.reactome.org ReactomeREACT_18068 has a Stoichiometric coefficient of 1 Troponin C:Calcium Complex Reactome DB_ID: 390587 Reactome Database ID Release 43390587 Reactome, http://www.reactome.org ReactomeREACT_17208 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Calcium Bound Sarcomere Protein Complex Reactome DB_ID: 390592 Reactome Database ID Release 43390592 Reactome, http://www.reactome.org ReactomeREACT_17110 has a Stoichiometric coefficient of 1 Z Disk Complex Reactome DB_ID: 390588 Reactome Database ID Release 43390588 Reactome, http://www.reactome.org ReactomeREACT_17890 has a Stoichiometric coefficient of 1 Calcium:Troponin Complex Reactome DB_ID: 390585 Reactome Database ID Release 43390585 Reactome, http://www.reactome.org ReactomeREACT_17267 has a Stoichiometric coefficient of 1 Thin Filament With Troponin Bound Calcium Reactome DB_ID: 390579 Reactome Database ID Release 43390579 Reactome, http://www.reactome.org ReactomeREACT_17139 has a Stoichiometric coefficient of 1 ADP:Calcium Bound Sarcomere Protein Complex Reactome DB_ID: 390591 Reactome Database ID Release 43390591 Reactome, http://www.reactome.org ReactomeREACT_17580 has a Stoichiometric coefficient of 1 ADP Bound Myosin Complex Reactome DB_ID: 390582 Reactome Database ID Release 43390582 Reactome, http://www.reactome.org ReactomeREACT_17958 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 MLCK:Calcium:Calmodulin Reactome DB_ID: 445764 Reactome Database ID Release 43445764 Reactome, http://www.reactome.org ReactomeREACT_20833 has a Stoichiometric coefficient of 1 Inactive Myosin Actin Contractile Complex Reactome DB_ID: 445703 Reactome Database ID Release 43445703 Reactome, http://www.reactome.org ReactomeREACT_20794 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 ATP Bound Myosin Complex Reactome DB_ID: 390580 Reactome Database ID Release 43390580 Reactome, http://www.reactome.org ReactomeREACT_18245 has a Stoichiometric coefficient of 2 has a Stoichiometric coefficient of 4 PathwayStep3899 PathwayStep3895 PathwayStep3896 PathwayStep3897 PathwayStep3898 Beta-amyloid Converted from EntitySet in Reactome Reactome DB_ID: 976800 Reactome Database ID Release 43976800 Reactome, http://www.reactome.org ReactomeREACT_76847 Ligand-responsive p-6Y-EGFR mutants sensitive to non-covalent TKIs Converted from EntitySet in Reactome Reactome DB_ID: 1182977 Reactome Database ID Release 431182977 Reactome, http://www.reactome.org ReactomeREACT_117444 PathwayStep3871 PathwayStep3872 PathwayStep3870 PathwayStep3869 PathwayStep3868 PathwayStep3867 PathwayStep3866 PathwayStep3865 PathwayStep3864 PathwayStep3863 PathwayStep3862 Ligand-responsive p-6Y-EGFR mutants resistant to non-covalent TKIs Converted from EntitySet in Reactome Reactome DB_ID: 1182982 Reactome Database ID Release 431182982 Reactome, http://www.reactome.org ReactomeREACT_116713 PathwayStep3860 PathwayStep3861 PathwayStep3856 PathwayStep3855 PathwayStep3858 PathwayStep3857 PathwayStep3852 PathwayStep3851 PathwayStep3854 PathwayStep3853 PathwayStep3859 PathwayStep3890 PathwayStep3893 PathwayStep3894 PathwayStep3891 PathwayStep3892 PathwayStep3887 PathwayStep3886 PathwayStep3885 PathwayStep3884 PathwayStep3889 PathwayStep3888 Ligand-responsive EGFR mutants resistant to non-covalent TKIs Converted from EntitySet in Reactome Reactome DB_ID: 1182967 Reactome Database ID Release 431182967 Reactome, http://www.reactome.org ReactomeREACT_117285 PathwayStep3880 PathwayStep3881 PathwayStep3882 PathwayStep3883 PathwayStep3874 PathwayStep3873 PathwayStep3876 PathwayStep3875 PathwayStep3878 PathwayStep3877 PathwayStep3879 Ligand-responsive EGFR mutants sensitive to non-covalent TKIs Converted from EntitySet in Reactome Reactome DB_ID: 1176052 Reactome Database ID Release 431176052 Reactome, http://www.reactome.org ReactomeREACT_117387 PathwayStep3826 PathwayStep3827 PathwayStep3828 PathwayStep3829 PathwayStep3822 PathwayStep3823 PathwayStep3824 PathwayStep3825 PathwayStep3820 PathwayStep3821 STAM Converted from EntitySet in Reactome Reactome DB_ID: 182929 Reactome Database ID Release 43182929 Reactome, http://www.reactome.org ReactomeREACT_13299 PathwayStep3819 PathwayStep3817 PathwayStep3818 PathwayStep3815 Adaptor protein complex 2 (AP-2) large adaptins Converted from EntitySet in Reactome Reactome DB_ID: 444999 Reactome Database ID Release 43444999 Reactome, http://www.reactome.org ReactomeREACT_21071 PathwayStep3816 PathwayStep3813 PathwayStep3814 PathwayStep3811 PathwayStep3812 PathwayStep3810 PathwayStep3848 PathwayStep3849 PathwayStep3840 PathwayStep3841 PathwayStep3842 PathwayStep3843 PathwayStep3844 PathwayStep3845 PathwayStep3846 PathwayStep3847 PathwayStep3850 PathwayStep3839 PathwayStep3837 PathwayStep3838 PathwayStep3831 PathwayStep3832 PathwayStep3830 PathwayStep3835 PathwayStep3836 PathwayStep3833 PathwayStep3834 PathwayStep3801 PathwayStep3800 PathwayStep3803 PathwayStep3802 PathwayStep3805 PathwayStep3804 PathwayStep3807 PathwayStep3806 PathwayStep3809 PathwayStep3808 Synthesis of PB1-F2 Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 For most influenza A strains (such as PR8), the PB1 mRNA segment produces a second protein, PB1-F2, from the +1 open reading frame (Chen, 2001). PB1-F2 is a pro-apoptotic, mitochondria-localized protein (Chen, 2001; Gibbs, 2003) that oligomerizes (Bruns, 2007) and sensitizes cells to death in concert with the mitochondrial ANT3 and VDAC proteins (Zamarin, 2005). Pubmed11726970 Pubmed12805420 Pubmed16201016 Pubmed17052982 Reactome Database ID Release 43192704 Reactome, http://www.reactome.org ReactomeREACT_9524 Reviewed: Squires, B, 2007-02-12 19:39:22 vRNA Extension Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 EC Number: 2.7.7.48 Pubmed11252672 Pubmed15298169 Pubmed3243763 Pubmed8709268 Reactome Database ID Release 43192851 Reactome, http://www.reactome.org ReactomeREACT_9438 Reviewed: Squires, B, 2007-02-12 19:39:22 has a Stoichiometric coefficient of 3 vRNA is synthesized from the complementary cRNA strand by the trimeric polymerase complex, and bound by free NP protein (Honda, 1988; Mikulasova, 2000; Neumann, 2004). The PB1 subunit, with PA, catalyzes extension (Nakagawa, 1996). The cRNA is released. Newly synthesized vRNP for export Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed14691253 Pubmed16513387 Pubmed17148142 Pubmed17151603 Pubmed8039508 Pubmed9049350 Pubmed9135141 Reactome Database ID Release 43192677 Reactome, http://www.reactome.org ReactomeREACT_9485 Reviewed: Squires, B, 2007-02-12 19:39:22 The nascent vRNP complexes, one for each gene segment, contain the negative-sense viral RNA and polymerase proteins (PB1, PB2, PA, and NP). In a model using negative-sense viral RNP reconstituted from transfected cells, there are multiple NP complexes and one polymerase complex arranged along a closed vRNA loop (Area et al., 2004). The three-dimensional structure of NP has revealed that three NP molecules form a stable trimer, interacting through beta-sheets b5, b6, and b7 in the C-terminal domain of the protein (Ye, 2006), with the viral RNA wrapping around the outside of the complex. Viral RNA from purified virions is present in an RNase-sensitive complex with NP and PB1, PB2, and PA, consistent with this structural model (Baudin et al, 1994; Ruigrok et al., 1995; Klumpp et al., 1997). It is not clear what controls the fate of vRNP, whether it is destined to become a template for transcription, for replication, or for export into the cytoplasm for packaging into virions at the plasma membrane, nor how distinct sub-nuclear localization and NP distribution at the nuclear matrix might mark, or polarize, a vRNP for export (Elton, 2005; Takizawa et al., 2006). Viral Protein Synthesis Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed16630668 Pubmed17166899 Pubmed2760014 Pubmed7365471 Reactome Database ID Release 43192841 Reactome, http://www.reactome.org ReactomeREACT_9514 Reviewed: Squires, B, 2007-02-12 19:39:22 Spliced and unspliced viral mRNA exported into the cytoplasm are translated by the host cell ribosomal translation machinery (reviewed in Kash, 2006). At least ten viral proteins are synthesized: HA, NA, PB1, PB2, PA, NP, NS1, NEP/NS2 (from spliced NS mRNA), M1, and M2 (from spliced M mRNA). The abundance of each of these proteins is thought to be controlled by differential mRNA abundances and stability (Tekamp, 1980; Hatada, 1989). As the localization of the nascent polypeptides is different between viral proteins with transmembrane domains (HA, NA and M2, which translocate to the ER and are transported through the Golgi to the plasma membrane) and soluble viral proteins (such as NP, the polymerase subunits, and NS1), mechanisms linking the translation of particular viral mRNA with subsequent protein localization rely on signal sequences recognized by the cell. Interleukin receptor complexes with activated SHC1:SHIP1 Reactome DB_ID: 913378 Reactome Database ID Release 43913378 Reactome, http://www.reactome.org ReactomeREACT_24554 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Interleukin receptor complexes with activated SHC1:SHIP1,2 Reactome DB_ID: 913393 Reactome Database ID Release 43913393 Reactome, http://www.reactome.org ReactomeREACT_24093 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 IL2:IL2R trimer p-(Y338,Y392, Y510) beta subunit:p-JAK1:JAK3:p-STAT5 Reactome DB_ID: 507943 Reactome Database ID Release 43507943 Reactome, http://www.reactome.org ReactomeREACT_27707 has a Stoichiometric coefficient of 1 Interleukin receptor complexes with activated SHC1:SHIP:GRB2 Reactome DB_ID: 913411 Reactome Database ID Release 43913411 Reactome, http://www.reactome.org ReactomeREACT_24297 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 926773 Reactome Database ID Release 43926773 Reactome, http://www.reactome.org ReactomeREACT_24089 has a Stoichiometric coefficient of 1 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 926774 Reactome Database ID Release 43926774 Reactome, http://www.reactome.org ReactomeREACT_24277 has a Stoichiometric coefficient of 1 Viral mRNA Splicing (M, NS segments) Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed10920397 Pubmed11421366 Pubmed1710647 Pubmed1824958 Pubmed6246509 Pubmed6945577 Pubmed7541537 Pubmed8895585 Reactome Database ID Release 43192781 Reactome, http://www.reactome.org ReactomeREACT_9402 Reviewed: Squires, B, 2007-02-12 19:39:22 The viral polymerase complex produces positive-sense viral mRNA with host-cell derived 5' methyl caps. Alternately spliced mRNA transcribed from M and NS vRNA segments 7 and 8, producing the spliced mRNA for M2 and NEP/NS2, respectively, are thought to be coupled to the cellular splicing and export mechanisms (Lamb, 1980; Lamb, 1981; Chen, 2000; Li, 2001). As segments 7 and 8 each encode two proteins, splicing must be regulated allowing for alternative mRNAs, with the spliced products in the minority (approximately 10%). M1 splicing may be regulated by the viral polymerase and the cellular SR splicing protein SF2/ASF (Shih, 1995; Shih, 1996); while NS1 splicing appears to be regulated by the viral mRNA intrinsically (Alonso-Caplen, 1991; Valcarel, 1991). Interleukin receptor complexes with activated SHC1:GRB2:SOS1 Reactome DB_ID: 921157 Reactome Database ID Release 43921157 Reactome, http://www.reactome.org ReactomeREACT_24582 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 4 Export of Spliced Viral mRNA Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 In the cases of spliced, polyadenylated mRNA transcribed from M (segment 7) and NS (segment 8) vRNA templates (producing the spliced mRNA for M2 and NS2/NEP, respectively), export may be coupled to aspects of the cellular splicing and export mechanisms (Chen, 2000; Alonso-Caplan et al, 1992; Amorim, 2006). Simultaneously, the export of cellular mRNA appear to be inhibited by the viral NS1 protein, which binds to the cellular cleavage and polyadenylation specificity factor (CPSF), preventing polyadenylation and completion of pre-mRNA processing (Nemerof et al., 1998; Fortes, 1994; Lu, 1994; Li, 2001). Pubmed10920397 Pubmed11421366 Pubmed1531330 Pubmed7958859 Pubmed8313914 Pubmed9651582 Reactome Database ID Release 43192925 Reactome, http://www.reactome.org ReactomeREACT_9528 Reviewed: Squires, B, 2007-02-12 19:39:22 HRAS:GDP Reactome DB_ID: 167214 Reactome Database ID Release 43167214 Reactome, http://www.reactome.org ReactomeREACT_24031 has a Stoichiometric coefficient of 1 Viral mRNA Export Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed10590131 Pubmed10920397 Pubmed15827195 Pubmed16933365 Pubmed17132145 Reactome Database ID Release 43192627 Reactome, http://www.reactome.org ReactomeREACT_9529 Reviewed: Squires, B, 2007-02-12 19:39:22 The viral polymerase complex produces positive-sense viral mRNA with host-cell derived 5' methyl caps. Capped viral mRNAs are selectively exported from the host cell nucleus through a currently unclear mechanism that may rely on components of the host cell mRNA export machinery (Chen, 2000; Engelhardt, 2006). Polyadenylation of viral mRNA appears be required for influenza mRNA export (Poon, 2000). A coupling of viral mRNA export with cellular pre-mRNA processing complexes, recruited by phosphorylation of host RNA polymerase II C-terminal domain which interacts with the viral polymerase (Engelhardt, 2005), has been proposed as controlling the export of a subset (M1, HA, and NS1, but not NP) of viral mRNA from the nucleus (Amorim, 2007). Initiation of cRNA Synthesis Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 EC Number: 2.7.7.48 Pubmed12072510 Pubmed12771209 Pubmed15163719 Pubmed16474140 Pubmed16933365 Pubmed3462695 Pubmed8189550 Pubmed8642663 Reactome Database ID Release 43192832 Reactome, http://www.reactome.org ReactomeREACT_9513 Reviewed: Squires, B, 2007-02-12 19:39:22 Viral vRNA, complexed with NP protein, is bound by the trimeric viral polymerase complex in a stable secondary structure-dependent manner, referred to as a panhandle, fork or cork-screw (Fodor, 1994; Brownlee, 2002; Park, 2003; Crow, 2004). This RNA structure is made of both the 5’ and 3' ends of the vRNA. The polymerase is thought to first bind the 5' end of the vRNA and then the 3' end. Synthesis of cRNA initiates without a host cell methylated RNA cap as a primer (Beaton, 1986; Galarza, 1996; Deng, 2006; Engehardt, 2006). cRNA Extension Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 EC Number: 2.7.7.48 Pubmed15308750 Pubmed17166911 Pubmed8709268 Reactome Database ID Release 43192624 Reactome, http://www.reactome.org ReactomeREACT_9404 Reviewed: Squires, B, 2007-02-12 19:39:22 Virion vRNP is capable of synthesizing cRNA immediately following entry into the cell nucleus (Vreede, 2006). The PB1 subunit principally catalyzes extension (Nakagawa, 1996). However, cRNA does not accumulate until later in the infection process, possiby requiring NP and the trimeric polymerase for stabilization (Vreede, 2004). The vRNA template is released. has a Stoichiometric coefficient of 3 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks Converted from EntitySet in Reactome Reactome DB_ID: 926776 Reactome Database ID Release 43926776 Reactome, http://www.reactome.org ReactomeREACT_24835 Initiation of vRNA Synthesis Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 EC Number: 2.7.7.48 Initiation of synthesis of the viral genomic RNA (vRNA) is thought to require hairpin (or panhandle/corkscrew) RNA loop structures formed by both the 5' and 3' ends of the cRNA (Pritlove, 1995; Crow, 2004; Park, 2003; Deng, 2006). The cRNA promoter has a similar structure to the vRNA promoter, but slight sequence differences are believed to result in a stronger cRNA promoter. As with the vRNA promoter, the polymerase is thought to first bind to the 5' end of the cRNA, then to the 3' end, and subsequently initiate RNA synthesis. Pubmed12771209 Pubmed15163719 Pubmed16474140 Pubmed7561757 Reactome Database ID Release 43192916 Reactome, http://www.reactome.org ReactomeREACT_9487 Reviewed: Squires, B, 2007-02-12 19:39:22 IL3:IL3R active complex, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 912532 Reactome Database ID Release 43912532 Reactome, http://www.reactome.org ReactomeREACT_24531 has a Stoichiometric coefficient of 1 Elongation of viral mRNA Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Catalyzed by the RNA polymerase activity of the viral PB1 subunit, an mRNA complementary to the bound vRNA is synthesized (Plotch, 1977). PA and PB2 move down the growing mRNA in complex with PB1, with PB2 possibly dissociating from the cap (Braam, 1983). However, the 5’ end of the vRNA may remain bound during elongation as the template is threaded through in a 3’ to 5’ direction until a polyadenylation signal is encountered (Poon, 1998; Zheng, 1999). EC Number: 2.7.7.48 GENE ONTOLOGYGO:0019083 Pubmed10233995 Pubmed6616622 Pubmed833924 Pubmed9733864 Reactome Database ID Release 43168334 Reactome, http://www.reactome.org ReactomeREACT_6210 Reviewed: Squires, B, 2007-02-12 19:39:22 Priming and Initiation of Transcription Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 EC Number: 2.7.7.48 GENE ONTOLOGYGO:0019083 Pubmed11296240 Pubmed6261960 Pubmed6269803 Pubmed7301581 Pubmed8107213 Pubmed8879132 Pubmed8955065 Pubmed9755184 Reactome Database ID Release 43168280 Reactome, http://www.reactome.org ReactomeREACT_6239 Reviewed: Squires, B, 2007-02-12 19:39:22 The host cell mRNA bound to viral RNA polymerase PB2 subunit is cleaved by the viral RNA polymerase PB1 subunit's endonuclease activity, and the capped 5' end plus 10-13 nucleotides of the host mRNA remains bound to the polymerase complex (Plotch, 1981; Krug, 1981; Hagen, 1994; Cianci, 1995, Li, 1998; Li, 2001). Viral mRNA may be protected against cap-snatching by the polymerase complex itself, which tightly binds capped viral mRNA (Shih, 1996). A guanine residue, complementary to a cytosine in the vRNA, is added to the host-derived cap, catalyzed by the RNA polymerase activity of the PB1 viral RNA polymerase subunit (Beaton, 1981; Toyoda, 1986). Assembly of an Active Transcription Complex Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 GENE ONTOLOGYGO:0019083 Pubmed10526235 Pubmed12072510 Pubmed15134462 Pubmed15827195 Pubmed283399 Pubmed6261960 Pubmed7769657 Pubmed9755184 Reactome Database ID Release 43168326 Reactome, http://www.reactome.org ReactomeREACT_6142 Reviewed: Squires, B, 2007-02-12 19:39:22 The 5' end of the vRNA associates with a binding site on the PB1 subunit of the viral RNA polymerase, distinct from the 3' vRNA binding site, which is subsequenty bound forming a loop. These binding events set off allosteric conformational changes in the trimeric polymerase complex that induce PB2 binding of the methylated cap on a host pre-mRNA (Plotch, 1981; Cianci, 1995; Li, 1998; Brownlee, 2002; Kolpashchikov, 2004). PB2 amino acids 242-282 and 538-577 are involved in cap binding (Honda, 1999). Direct or indirect interaction with active, transcribing host RNA polymerase II is thought to supply host mRNA for the caps (Bouloy, 1978; Engelhardt, 2005). NP binds vRNA Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed15702989 Pubmed17050598 Pubmed17081640 Pubmed17151603 Pubmed9032315 Pubmed9371635 Reactome Database ID Release 43192912 Reactome, http://www.reactome.org ReactomeREACT_9490 Reviewed: Squires, B, 2007-02-12 19:39:22 Viral genomic RNA (vRNA) and complementary RNA (cRNA) are likely bound by the influenza nucleoprotein (NP) immediately upon synthesis. Although two nuclear localization signals have been mapped in the NP, an unconventional N-terminal NLS and a bipartite NLS within amino acids 198-216 (Wang, 1997; Neumann, 1997; Ozawa, 2007), the crystal structure of the NP suggests that only the unconventional NLS is exposed and can be used as a functional NLS (Ye, 2006). This unconvenetional NLS interacts with importins alpha-1 and -2 (Cros et al., 2005; Wang et al., 1997; Buolo et al., 2006). The three-dimensional structure of NP has revealed that NP molecules associate as a trimer, interacting through beta-sheets b5, b6, and b7 in the C-terminal domain of the protein; the viral RNA likely wraps around the outside of the complex (Ye, 2006). has a Stoichiometric coefficient of 3 IL2:IL2R trimer p(Y338) beta subunit:p-SHC:GRB2:GAB2:p85-containing Class 1A PI3Ks Reactome DB_ID: 508238 Reactome Database ID Release 43508238 Reactome, http://www.reactome.org ReactomeREACT_24492 has a Stoichiometric coefficient of 1 PI3K delta Reactome DB_ID: 508241 Reactome Database ID Release 43508241 Reactome, http://www.reactome.org ReactomeREACT_24632 has a Stoichiometric coefficient of 1 p85-containing Class 1A PI3Ks Converted from EntitySet in Reactome Reactome DB_ID: 508248 Reactome Database ID Release 43508248 Reactome, http://www.reactome.org ReactomeREACT_24162 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2 Reactome DB_ID: 926769 Reactome Database ID Release 43926769 Reactome, http://www.reactome.org ReactomeREACT_24839 has a Stoichiometric coefficient of 1 Polyadenylation and Termination A poly-uridine sequence motif, consisting in most cases of 5-7 U residues, abuts the "panhandle" duplex structure in the vRNA; this sequence is approximately 16 nucleotides from the 5' end of this RNA duplex structure within the vRNA promoter. Encountering this signal, the viral RNA polymerase stutters, leading to the synthesis of a poly-A tail on the viral mRNA (Robertson, 1981; Luo, 1991; Li,1994; Poon, 1998; Zheng et al. 1999). Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 EC Number: 2.7.7.48 GENE ONTOLOGYGO:0019083 Pubmed10233995 Pubmed2033659 Pubmed7241649 Pubmed7507179 Pubmed9733864 Reactome Database ID Release 43168301 Reactome, http://www.reactome.org ReactomeREACT_6264 Reviewed: Squires, B, 2007-02-12 19:39:22 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2 Reactome DB_ID: 926770 Reactome Database ID Release 43926770 Reactome, http://www.reactome.org ReactomeREACT_24852 has a Stoichiometric coefficient of 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2 Converted from EntitySet in Reactome Reactome DB_ID: 926768 Reactome Database ID Release 43926768 Reactome, http://www.reactome.org ReactomeREACT_24317 Recognition of the Nuclear Localization Signal (NLS) by a Karyopherin Alpha Family Protein Authored: Gillespie, ME, 2005-11-14 17:18:07 GENE ONTOLOGYGO:0046796 Pubmed15702989 Pubmed7559393 Reactome Database ID Release 43168297 Reactome, http://www.reactome.org ReactomeREACT_6138 Reviewed: Squires, B, 2006-10-29 16:42:09 The eight influenza virus genome segments never exist as naked RNA but are associated with four viral proteins to form viral ribonucleoprotein complexes (vRNPs). The major viral protein in the RNP complex is the nucleocapsid protein (NP), which coats the RNA. The remaining proteins PB1, PB2 and PA bind to the partially complementary ends of the viral RNA, creating the distinctive panhandle structure. The influenza viral NP behaves like a nuclear localization sequence (NLS) containing protein. The RNP docks at the nuclear envelope only in the presence of the heterodimeric karyopherin alpha and beta complex. Here karyopherin alpha recognizes the RNP. IL3:IL3R active complex, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:p(Y)-GAB2 Reactome DB_ID: 912540 Reactome Database ID Release 43912540 Reactome, http://www.reactome.org ReactomeREACT_24208 has a Stoichiometric coefficient of 1 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:GAB2 Reactome DB_ID: 914047 Reactome Database ID Release 43914047 Reactome, http://www.reactome.org ReactomeREACT_24437 has a Stoichiometric coefficient of 1 IL2:IL2R trimer p(Y338,392,510) beta subunit:p-SHC:GRB2:p(Y)-GAB2 Reactome DB_ID: 912523 Reactome Database ID Release 43912523 Reactome, http://www.reactome.org ReactomeREACT_24333 has a Stoichiometric coefficient of 1 Release of the RNP into the host cell nucleus Authored: Gillespie, ME, 2005-11-14 17:18:07 GENE ONTOLOGYGO:0046796 Once the viral RNP and heterodimeric karyopherin complex has been transported into the nucleus the RNP dissasociates from the heterodimeric karyopherins. Pubmed7559393 Reactome Database ID Release 43168310 Reactome, http://www.reactome.org ReactomeREACT_6164 Reviewed: Squires, B, 2006-10-29 16:42:09 Viral Polymerase Assembly Authored: Bortz, E, Garcia-Sastre, A, 2007-02-12 19:39:05 Pubmed11483758 Pubmed15308710 Pubmed17005651 Pubmed17081640 Pubmed17121807 Pubmed3023071 Pubmed3783823 Pubmed8948635 Reactome Database ID Release 43192830 Reactome, http://www.reactome.org ReactomeREACT_9428 Reviewed: Squires, B, 2007-02-12 19:39:22 The mature ternary influenza viral polymerase complex consists of PB1, PB2, and PA. The N-terminus of PB1 (residues 1-48) interacts with PB2, and amino acids 506-659 in PB1 interact with the PA subunit (Gonzalez, 1996; Perez, 2001). Although monomeric PB1, PB2 and PA, as well as PB1-PB2 and PB1-PA dimers are likely to exist in infected cells, it is believed that most of the polymerase proteins are assembled into the trimeric PB1-PB2-PA complex (Detjen, 1987). Newly synthesized subunits of the polymerase are imported into the nucleus through nuclear localization signals (NLS), which interact with cellular importin family proteins (Jones, 1986; Buolo, 2006). Importin beta-3 (Ran binding protein 5) facilitates nuclear import of PB1 and a PB1-PA dimer (Deng, 2006); coexpression of PA with PB1 was shown to enhance the import of PB1 (Fodor, 2004). A PB1-PB2 dimer has been found to interact with the molecular chaperone heat shock protein 90 (HSP90) to facilitate import (Naito, 2007). The three subunits assembled in the nucleus form a mature ternary polymerase complex that binds viral vRNA or cRNA (Jones, 1986; Buolo, 2006). High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:GAB2 Reactome DB_ID: 914021 Reactome Database ID Release 43914021 Reactome, http://www.reactome.org ReactomeREACT_24487 has a Stoichiometric coefficient of 1 Recruitment of Karyopherin Beta to form a Trimeric Complex Authored: Gillespie, ME, 2005-11-14 17:18:07 GENE ONTOLOGYGO:0046796 Pubmed7559393 Reactome Database ID Release 43168317 Reactome, http://www.reactome.org ReactomeREACT_6322 Reviewed: Squires, B, 2006-10-29 16:42:09 The eight influenza virus genome segments are associated with four viral proteins to form viral ribonucleoprotein complexes (vRNPs). The major viral protein in the RNP complex is the nucleocapsid protein (NP), which coats the RNA. The remaining proteins PB1, PB2 and PA bind to the partially complementary ends of the viral RNA. The influenza viral NP behaves like a nuclear localization sequence (NLS) containing protein. The RNP docks at the nuclear envelope only in the presence of the heterodimeric karyopherin alpha and beta complex. Once the NLS is recognized by karyopherin alpha the karyopherin beta subunit joins the complex. Docking and transport of the RNP:Karyopherin complex through the nuclear pore Authored: Gillespie, ME, 2005-11-14 17:18:07 GENE ONTOLOGYGO:0046796 Pubmed1985200 Reactome Database ID Release 43168337 Reactome, http://www.reactome.org ReactomeREACT_6289 Reviewed: Squires, B, 2006-10-29 16:42:09 These RNPs (10-20nm wide) are too large to passively diffuse into the nucleus and therefore, once released from an incoming particle they must rely on the active import mechanism of the host cell nuclear pore complex (NPC). Once the RNP heterodimeric karyopherin complex docks at the NPC, it is transported into the nucleus. IL2:IL2R trimer p-(Y338,392,510) beta subunit:p-JAK1:JAK3 Reactome DB_ID: 452104 Reactome Database ID Release 43452104 Reactome, http://www.reactome.org ReactomeREACT_24252 has a Stoichiometric coefficient of 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1 Converted from EntitySet in Reactome Reactome DB_ID: 913439 Reactome Database ID Release 43913439 Reactome, http://www.reactome.org ReactomeREACT_24225 IL3:IL3R active complex, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1 Reactome DB_ID: 913412 Reactome Database ID Release 43913412 Reactome, http://www.reactome.org ReactomeREACT_24663 has a Stoichiometric coefficient of 1 IL3:IL3R active complex, JAK2:p-Y593,Y629-IL3RB Reactome DB_ID: 912317 Reactome Database ID Release 43912317 Reactome, http://www.reactome.org ReactomeREACT_24080 has a Stoichiometric coefficient of 2 IL2:IL2R trimer p-(Y338,392,510) beta subunit:p-JAK1:JAK3 Reactome DB_ID: 452119 Reactome Database ID Release 43452119 Reactome, http://www.reactome.org ReactomeREACT_27939 has a Stoichiometric coefficient of 1 IL2:IL2R trimer p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:SHC Reactome DB_ID: 452095 Reactome Database ID Release 43452095 Reactome, http://www.reactome.org ReactomeREACT_27664 has a Stoichiometric coefficient of 1 IL2:IL2R trimer p-(Y338,392,510) beta subunit:p-JAK1:JAK3:STAT5 Reactome DB_ID: 452107 Reactome Database ID Release 43452107 Reactome, http://www.reactome.org ReactomeREACT_27906 has a Stoichiometric coefficient of 1 IL2:IL2R trimer p-(Y338,392,510)-beta subunit:p-JAK1:JAK3:p-SHC Reactome DB_ID: 453099 Reactome Database ID Release 43453099 Reactome, http://www.reactome.org ReactomeREACT_24532 has a Stoichiometric coefficient of 1 IL2RB:p-JAK1 Reactome DB_ID: 451943 Reactome Database ID Release 43451943 Reactome, http://www.reactome.org ReactomeREACT_27380 has a Stoichiometric coefficient of 1 IL2RA:IL2RB:p-JAK1 Interleukin-2 receptor alpha:beta:JAK1 Reactome DB_ID: 451918 Reactome Database ID Release 43451918 Reactome, http://www.reactome.org ReactomeREACT_27412 has a Stoichiometric coefficient of 1 IL2RA:IL2RB:p-JAK1:IL2 Reactome DB_ID: 451939 Reactome Database ID Release 43451939 Reactome, http://www.reactome.org ReactomeREACT_27828 has a Stoichiometric coefficient of 1 IL2:IL2R trimer:JAK1:JAK3 Reactome DB_ID: 450080 Reactome Database ID Release 43450080 Reactome, http://www.reactome.org ReactomeREACT_27501 has a Stoichiometric coefficient of 1 IL2:IL2R trimer:p-JAK1:JAK3 Reactome DB_ID: 451920 Reactome Database ID Release 43451920 Reactome, http://www.reactome.org ReactomeREACT_27786 has a Stoichiometric coefficient of 1 IL2:IL2RA Reactome DB_ID: 538993 Reactome Database ID Release 43538993 Reactome, http://www.reactome.org ReactomeREACT_27750 has a Stoichiometric coefficient of 1 IL2:IL2RA:IL2RB:JAK1 Reactome DB_ID: 450065 Reactome Database ID Release 43450065 Reactome, http://www.reactome.org ReactomeREACT_27637 has a Stoichiometric coefficient of 1 IL2RB:JAK1 Reactome DB_ID: 451905 Reactome Database ID Release 43451905 Reactome, http://www.reactome.org ReactomeREACT_27842 has a Stoichiometric coefficient of 1 IL2RG:JAK3 Reactome DB_ID: 451911 Reactome Database ID Release 43451911 Reactome, http://www.reactome.org ReactomeREACT_24778 has a Stoichiometric coefficient of 1 SCF betaTrCP complex:p-NFKB p105 Reactome DB_ID: 451614 Reactome Database ID Release 43451614 Reactome, http://www.reactome.org ReactomeREACT_22646 has a Stoichiometric coefficient of 1 NFKB p105:TPL2:ABIN2 Reactome DB_ID: 451638 Reactome Database ID Release 43451638 Reactome, http://www.reactome.org ReactomeREACT_22747 has a Stoichiometric coefficient of 1 Poly-K6-Ub-hp-IRAK1:IKK complex Reactome DB_ID: 451560 Reactome Database ID Release 43451560 Reactome, http://www.reactome.org ReactomeREACT_22624 has a Stoichiometric coefficient of 1 IL3:IL3R active complex, phosphorylated Bc:p(Y427,349,350)-SHC1:GRB2:GAB2 Reactome DB_ID: 912538 Reactome Database ID Release 43912538 Reactome, http://www.reactome.org ReactomeREACT_24213 has a Stoichiometric coefficient of 1 IL3:IL3R active complex, phosphorylated Bc:p(Y427,349,350)-SHC1 Reactome DB_ID: 912313 Reactome Database ID Release 43912313 Reactome, http://www.reactome.org ReactomeREACT_24240 has a Stoichiometric coefficient of 1 IL3:IL3R active complex, phosphorylated Bc Converted from EntitySet in Reactome Reactome DB_ID: 912320 Reactome Database ID Release 43912320 Reactome, http://www.reactome.org ReactomeREACT_24127 IL3:IL3R active complex, activated JAK2, phosphorylated Bc Reactome DB_ID: 912314 Reactome Database ID Release 43912314 Reactome, http://www.reactome.org ReactomeREACT_24640 has a Stoichiometric coefficient of 2 Interleukin-3 receptor IL3RA:IL3:p(Y593)-IL3RB:Activated JAK2 Reactome DB_ID: 912319 Reactome Database ID Release 43912319 Reactome, http://www.reactome.org ReactomeREACT_24133 has a Stoichiometric coefficient of 1 p(Y593)-IL3RB:Activated JAK2 Reactome DB_ID: 912306 Reactome Database ID Release 43912306 Reactome, http://www.reactome.org ReactomeREACT_24796 has a Stoichiometric coefficient of 1 IL5 homodimer Reactome DB_ID: 913383 Reactome Database ID Release 43913383 Reactome, http://www.reactome.org ReactomeREACT_24473 has a Stoichiometric coefficient of 2 IL5 homodimer:IL5RA Reactome DB_ID: 450056 Reactome Database ID Release 43450056 Reactome, http://www.reactome.org ReactomeREACT_24270 has a Stoichiometric coefficient of 1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:GAB2 Converted from EntitySet in Reactome Reactome DB_ID: 914052 Reactome Database ID Release 43914052 Reactome, http://www.reactome.org ReactomeREACT_24195 IL2:IL2R trimer p(Y338,392,510) beta subunit:p-SHC:GRB2:GAB2 Reactome DB_ID: 508246 Reactome Database ID Release 43508246 Reactome, http://www.reactome.org ReactomeREACT_24168 has a Stoichiometric coefficient of 1 GM-CSF:GM-CSF receptor alpha subunit:p(Y593, 628)-Bc:JAK2 Reactome DB_ID: 913355 Reactome Database ID Release 43913355 Reactome, http://www.reactome.org ReactomeREACT_24276 has a Stoichiometric coefficient of 1 GM-CSF:GM-CSF receptor alpha subunit Reactome DB_ID: 913362 Reactome Database ID Release 43913362 Reactome, http://www.reactome.org ReactomeREACT_24102 has a Stoichiometric coefficient of 1 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1 Reactome DB_ID: 913428 Reactome Database ID Release 43913428 Reactome, http://www.reactome.org ReactomeREACT_24290 has a Stoichiometric coefficient of 1 High affinity GM-CSF receptor complex dimer, inactive JAK2, p(Y593, 628)- Bc Reactome DB_ID: 913384 Reactome Database ID Release 43913384 Reactome, http://www.reactome.org ReactomeREACT_24154 has a Stoichiometric coefficient of 2 IL5 homodimer:IL5RA:p(Y593, 628)-Bc:JAK2 Reactome DB_ID: 913357 Reactome Database ID Release 43913357 Reactome, http://www.reactome.org ReactomeREACT_24395 has a Stoichiometric coefficient of 1 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bc:p(Y427,349,350)-SHC1 Reactome DB_ID: 913366 Reactome Database ID Release 43913366 Reactome, http://www.reactome.org ReactomeREACT_24540 has a Stoichiometric coefficient of 1 High affinity IL-5 receptor complex dimer, inactive JAK2, p(Y593, 628)-Bc Reactome DB_ID: 913359 Reactome Database ID Release 43913359 Reactome, http://www.reactome.org ReactomeREACT_24205 has a Stoichiometric coefficient of 2 IL3:IL3RA Reactome DB_ID: 450048 Reactome Database ID Release 43450048 Reactome, http://www.reactome.org ReactomeREACT_24866 has a Stoichiometric coefficient of 1 pY593,Y628-IL3RB:JAK2 Reactome DB_ID: 912316 Reactome Database ID Release 43912316 Reactome, http://www.reactome.org ReactomeREACT_24687 has a Stoichiometric coefficient of 1 Interleukin-3 receptor IL3:IL3RA:p-Y593,Y628-IL3RB:JAK2 Reactome DB_ID: 912308 Reactome Database ID Release 43912308 Reactome, http://www.reactome.org ReactomeREACT_24722 has a Stoichiometric coefficient of 1 Recruitment of elongation factors to form HIV-1 elongation complex At the beginning of this reaction, 1 molecule of 'FACT complex', 1 molecule of 'HIV-1 early elongation complex with hyperphosphorylated Pol II CTD', 1 molecule of 'Elongin Complex', 1 molecule of 'TFIIH', 1 molecule of 'RNA polymerase II elongation factor ELL', and 1 molecule of 'TFIIS protein' are present. At the end of this reaction, 1 molecule of 'HIV-1 elongation complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167077 Reactome, http://www.reactome.org ReactomeREACT_6358 Caspase-1 p10/p20 dimer Reactome DB_ID: 448695 Reactome Database ID Release 43448695 Reactome, http://www.reactome.org ReactomeREACT_24131 has a Stoichiometric coefficient of 1 Hyperphosphorylation (Ser2) of RNA Pol II CTD by P-TEFb complex Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed10866664 Pubmed7853496 Reactome Database ID Release 43167084 Reactome, http://www.reactome.org ReactomeREACT_6297 The association between Tat, TAR and P-TEFb is believed to bring the catalytic subunit of P-TEFb(Cyclin T1:Cdk9) in close proximity to Pol II where it hyperphosphorylates the CTD of Pol II (Herrmann et al., 1995; Zhou et al. 2000). In the presence of Tat, P-TEFb(Cyclin T1:CDK9) has been shown to phosphorylate serine 5 in addition to serine 2 suggesting that modification of the substrate specificity of CDK9 may play a role in the ability of Tat to promote transcriptional elongation (Zhou et al. 2000). ISGylated 4EHP:mRNA Reactome DB_ID: 1678836 Reactome Database ID Release 431678836 Reactome, http://www.reactome.org ReactomeREACT_117707 has a Stoichiometric coefficient of 1 EIF4F Reactome DB_ID: 1678832 Reactome Database ID Release 431678832 Reactome, http://www.reactome.org ReactomeREACT_116347 has a Stoichiometric coefficient of 1 eIF4F:mRNA Reactome DB_ID: 72585 Reactome Database ID Release 4372585 Reactome, http://www.reactome.org ReactomeREACT_116627 has a Stoichiometric coefficient of 1 Abortive termination of HIV-1 elongation after arrest (Tat-containing elongation complex) At the beginning of this reaction, 1 molecule of 'HIV-1 Tat-containing arrested processive elongation complex' is present. At the end of this reaction, 1 molecule of 'HIV-1 Tat-containing aborted elongation complex after arrest' is present.<br>This reaction takes place in the 'nucleus'. Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-10-15 23:27:00 Reactome Database ID Release 43167459 Reactome, http://www.reactome.org ReactomeREACT_6269 ISGylated 4EHP Reactome DB_ID: 1678834 Reactome Database ID Release 431678834 Reactome, http://www.reactome.org ReactomeREACT_116416 has a Stoichiometric coefficient of 1 TFIIS-mediated recovery of elongation from arrest Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed12676794 Reactome Database ID Release 43167148 Reactome, http://www.reactome.org ReactomeREACT_6330 TFIIS reactivates arrested RNA Pol II directly interacting with the enzyme resulting in endonucleolytic excision of nascent transcript ~7-14 nucleotides upstream of the 3' end. This reaction is catalyzed by the catalytic site and results in the generation of a new 3'-OH terminus that could be used for re-extension from the correctly base paired site (reviewed by Shilatifard et al., 2003). NS1 homodimer:Importin Reactome DB_ID: 1176067 Reactome Database ID Release 431176067 Reactome, http://www.reactome.org ReactomeREACT_117079 has a Stoichiometric coefficient of 1 Resumption of elongation of HIV-1 transcript after recovery from pausing Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed12676794 Reactome Database ID Release 43167292 Reactome, http://www.reactome.org ReactomeREACT_6155 Recovery from pausing occurs spontaneously after a variable length of time as the enzyme spontaneously slides forward again. This renders the transcript's 3'-OH terminus realigned with the catalytic Mg2+ site of the enzyme. TFIIS is capable of excising the nascent transcript at 2 or 3 nucleotides upstream of the transcript's 3'-end to reinitiate processive elongation (reviewed by Shilatifard et al., 2003). 2-4 nt.backtracking of Pol II complex on the HIV-1 template leading to elongation pausing Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pol II pausing is believed to result from reversible backtracking of the Pol II enzyme complex by ~2 to 4 nucleotides. This leads to misaligned 3'-OH terminus that is unable to be an acceptor for the incoming NTPs in synthesis of next phosphodiester bond (reviewed by Shilatifard et al., 2003). Pubmed12676794 Reactome Database ID Release 43167282 Reactome, http://www.reactome.org ReactomeREACT_6214 Rev molecules assemble onto the RRE RNA sequence through their ARM sequence Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:39 Nuclear export of the unspliced and partially spliced HIV-1 transcripts requires the association of the HIV-1 Rev protein with a cis-acting RNA sequence known as the Rev Response Element (RRE) located within the env gene. The RRE forms a stem loop structure that associates with an arginine-rich RNA binding motif (ARM) within Rev. Pubmed2406030 Pubmed2556643 Reactome Database ID Release 43165027 Reactome, http://www.reactome.org ReactomeREACT_6161 Reviewed: Kumar, A, 2007-01-31 22:47:49 Resumption of elongation of HIV-1 transcript after recovery from pausing Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed12676794 Reactome Database ID Release 43167150 Reactome, http://www.reactome.org ReactomeREACT_6299 Recovery from pausing occurs spontaneously after a variable length of time as the enzyme spontaneously slides forward again. This renders the transcript's 3'-OH terminus realigned with the catalytic Mg2+ site of the enzyme. TFIIS is capable of excising the nascent transcript at 2 or 3 nucleotides upstream of the transcript's 3'-end to reinitiate processive elongation (reviewed by Shilatifard et al., 2003). 2-4 nt.backtracking of Pol II complex on the HIV-1 template leading to elongation pausing Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pol II pausing is believed to result from reversible backtracking of the Pol II enzyme complex by ~2 to 4 nucleotides. This leads to misaligned 3'-OH terminus that is unable to be an acceptor for the incoming NTPs in synthesis of next phosphodiester bond (reviewed by Shilatifard et al., 2003). Pubmed12676794 Reactome Database ID Release 43167076 Reactome, http://www.reactome.org ReactomeREACT_6347 7-14 nt. Backtracking of Pol II complex on the HIV-1 template leading to elongation arrest Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed12676794 RNA Pol II arrest is believed to be a result of irreversible backsliding of the enzyme by ~7-14 nucleotides. It is suggested that, arrest leads to extrusion of displaced transcripts 3'-end through the small pore near the Mg2+ ion. Pol II arrest may lead to abortive termination of elongation due to irreversible trapping of the 3'-end of the displaced transcript in the pore (reviewed by Shilatifard et al., 2003). Reactome Database ID Release 43167090 Reactome, http://www.reactome.org ReactomeREACT_6174 Interleukin 1 receptors:IL1RN Reactome DB_ID: 445751 Reactome Database ID Release 43445751 Reactome, http://www.reactome.org ReactomeREACT_22878 has a Stoichiometric coefficient of 1 Interleukin 1 receptor type 2:interleukin 1 Reactome DB_ID: 446125 Reactome Database ID Release 43446125 Reactome, http://www.reactome.org ReactomeREACT_22786 has a Stoichiometric coefficient of 1 Interleukin-1 receptor type 1:Interleukin-1 Reactome DB_ID: 445755 Reactome Database ID Release 43445755 Reactome, http://www.reactome.org ReactomeREACT_23118 has a Stoichiometric coefficient of 1 Caspase-1 active tetramer Reactome DB_ID: 448691 Reactome Database ID Release 43448691 Reactome, http://www.reactome.org ReactomeREACT_24192 has a Stoichiometric coefficient of 2 ISG15:UBCH8 Reactome DB_ID: 1169385 Reactome Database ID Release 431169385 Reactome, http://www.reactome.org ReactomeREACT_116755 has a Stoichiometric coefficient of 1 ISG15:UBE1L Activated ISG15 Reactome DB_ID: 1169390 Reactome Database ID Release 431169390 Reactome, http://www.reactome.org ReactomeREACT_116548 has a Stoichiometric coefficient of 1 Phosphorylation of DSIF by the P-TEFb(Cyclin T1:Cdk9) complex Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2006-01-10 20:59:19 Phosphorylation of the Spt5 subunit of DSIF by P-TEFb(Cyclin T1:Cdk9) results in the conversion of DSIF to an elongation factor (Ivanov al. 2000). Pubmed10757782 Reactome Database ID Release 43170704 Reactome, http://www.reactome.org ReactomeREACT_6316 ISGylated host proteins Reactome DB_ID: 1169387 Reactome Database ID Release 431169387 Reactome, http://www.reactome.org ReactomeREACT_117075 has a Stoichiometric coefficient of 1 ISG15:UBCH8:ISG15 E3 ligase Reactome DB_ID: 1169383 Reactome Database ID Release 431169383 Reactome, http://www.reactome.org ReactomeREACT_117630 has a Stoichiometric coefficient of 1 Addition of nucleotides leads to HIV-1 transcript elongation Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed11313498 Pubmed11313499 Reactome Database ID Release 43167181 Reactome, http://www.reactome.org ReactomeREACT_6278 This HIV-1 event was inferred from the corresponding human RNA Pol II transcription event. High-resolution structures of free, catalytically active yeast Pol II and of an elongating form reveal that Pol II elongation complex includes features like: <BR> - RNA-DNA hybrid, an unwound template ahead of 3'-OH terminus of growing transcript and an exit groove at the base of the CTD, possibly for dynamic interaction of processing and transcriptional factors.<BR>- a cleft or channel created by Rpb1 and Rpb2 subunits to accommodate DNA template, extending to Mg2+ ion located deep in the enzyme core <BR> -a 50 kDa "clamp" with open confirmation in free polymerase, allowing entry of DNA strands but closed in the processive elongation phase. <BR> The clamp is composed of portions of Rpb1,Rpb2 and Rpb3 , five loops or "switches" that change from unfolded to well-folded structures stabilizing the elongation complex, and a long "bridging helix" that emanates from Rpb1 subunit, crossing near the Mg2+ ion. The bridging helix is thought to "bend" to push on the base pair at the 3'-end of RNA-DNA hybrid like a ratchet, translocating Pol II along the DNA (Cramer et al.,2001; Gnatt et al.,2001).In addition to its dynamic biochemical potential, Pol II possess a repertoire of functions to serve as a critical platform of recruiting and coordinating the actions of a host of additional enzyme and proteins involved in various pathways.<BR> Recruitment of elongation factors to form HIV-1 elongation complex At the beginning of this reaction, 1 molecule of 'FACT complex', 1 molecule of 'Elongin Complex', 1 molecule of 'TFIIH', 1 molecule of 'RNA polymerase II elongation factor ELL', 1 molecule of 'Tat-containing early elongation complex with hyperphosphorylated Pol II CTD ( phospho-NELF phospho DSIF)', and 1 molecule of 'TFIIS protein' are present. At the end of this reaction, 1 molecule of 'HIV-1 elongation complex containing Tat' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167196 Reactome, http://www.reactome.org ReactomeREACT_6275 Separation of elongating HIV-1 transcript from template Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167197 Reactome, http://www.reactome.org ReactomeREACT_6204 This event was inferred from the corresponding human Poll II transcription elongation event. p-STAT1 dimer:PIAS:SUMO1 Reactome DB_ID: 877297 Reactome Database ID Release 43877297 Reactome, http://www.reactome.org ReactomeREACT_25840 has a Stoichiometric coefficient of 1 Pol II elongation complex moves on the HIV-1 template as transcript elongates Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167192 Reactome, http://www.reactome.org ReactomeREACT_6158 This event was inferred from the corresponding human Poll II transcription elongation event. Separation of abortive HIV-1 transcript from template At the beginning of this reaction, 1 molecule of 'DSIF:NELF:early elongation complex after limited nucleotide addition' is present. At the end of this reaction, 1 molecule of 'Early elongation complex with separated aborted transcript' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Reactome Database ID Release 43167147 Reactome, http://www.reactome.org ReactomeREACT_6159 Limited elongation of the HIV-1 transcript Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 In the absence of Tat, transcriptional elongation beyond position +59 does not occur (Kao et al., 1987). Pubmed2825027 Reactome Database ID Release 43167087 Reactome, http://www.reactome.org ReactomeREACT_6192 ISGylated NS1 Reactome DB_ID: 1169392 Reactome Database ID Release 431169392 Reactome, http://www.reactome.org ReactomeREACT_116937 has a Stoichiometric coefficient of 1 Abortive termination of HIV-1 elongation after arrest At the beginning of this reaction, 1 molecule of 'HIV-1 arrested processive elongation complex' is present. At the end of this reaction, 1 molecule of 'HIV-1 aborted elongation complex after arrest' is present.<br><br> This reaction takes place in the 'nucleus'.<br> Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-10-15 23:27:00 Reactome Database ID Release 43167481 Reactome, http://www.reactome.org ReactomeREACT_6352 7-14 nt. Backtracking of Pol II complex on the HIV-1 template leading to elongation arrest Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed12676794 RNA Pol II arrest is believed to be a result of irreversible backsliding of the enzyme by ~7-14 nucleotides. It is suggested that, arrest leads to extrusion of displaced transcripts 3'-end through the small pore near the Mg2+ ion. Pol II arrest may lead to abortive termination of elongation due to irreversible trapping of the 3'-end of the displaced transcript in the pore (reviewed by Shilatifard et al., 2003). Reactome Database ID Release 43167284 Reactome, http://www.reactome.org ReactomeREACT_6254 ISGylated PP2CB Reactome DB_ID: 1169391 Reactome Database ID Release 431169391 Reactome, http://www.reactome.org ReactomeREACT_117694 has a Stoichiometric coefficient of 1 TFIIS-mediated recovery of HIV-1 elongation from arrest Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:29:22 Pubmed12676794 Reactome Database ID Release 43167288 Reactome, http://www.reactome.org ReactomeREACT_6252 TFIIS reactivates arrested RNA Pol II directly interacting with the enzyme resulting in endonucleolytic excision of nascent transcript ~7-14 nucleotides upstream of the 3' end. This reaction is catalyzed by the catalytic site and results in the generation of a new 3'-OH terminus that could be used for re-extension from the correctly base paired site (reviewed by Shilatifard et al., 2003). ISGylated Filamin B Reactome DB_ID: 1169388 Reactome Database ID Release 431169388 Reactome, http://www.reactome.org ReactomeREACT_117791 has a Stoichiometric coefficient of 1 ISG15:NEDD4 Reactome DB_ID: 1169384 Reactome Database ID Release 431169384 Reactome, http://www.reactome.org ReactomeREACT_116438 has a Stoichiometric coefficient of 1 ISGylated E2 conjugating enzymes Reactome DB_ID: 1169382 Reactome Database ID Release 431169382 Reactome, http://www.reactome.org ReactomeREACT_117138 has a Stoichiometric coefficient of 1 Rev:importin beta:B23 recruited to the nuclear pore Authored: Matthews, L, 2006-06-08 06:14:23 Edited: Matthews, L, 2007-01-31 22:42:03 Reactome Database ID Release 43180710 Reactome, http://www.reactome.org ReactomeREACT_9516 Reviewed: Kumar, A, 2007-01-31 22:47:49 The Rev-importin β-B23 complex is recruited to the nuclear pore by an interaction between importin β and nucleoporin. hp-IRAK1:K6-poly-Ub oligo-TRAF6:TAK1 complex Reactome DB_ID: 450185 Reactome Database ID Release 43450185 Reactome, http://www.reactome.org ReactomeREACT_22797 has a Stoichiometric coefficient of 1 Rev associates with B23 Authored: Matthews, L, 2006-06-08 06:14:23 B23 may function as a shuttle for the import of HIV Rev from the cytoplasm into the nucleus or nucleolus permitting additional rounds of export of viral RNAs. Edited: Matthews, L, 2007-01-31 22:42:03 Pubmed2017166 Pubmed9092824 Reactome Database ID Release 43180725 Reactome, http://www.reactome.org ReactomeREACT_9511 Reviewed: Kumar, A, 2007-01-31 22:47:49 hp-IRAK1:oligo-TRAF6 Reactome DB_ID: 450159 Reactome Database ID Release 43450159 Reactome, http://www.reactome.org ReactomeREACT_22793 has a Stoichiometric coefficient of 1 has a Stoichiometric coefficient of 2 Association of multimerized Rev with beta-importin Authored: Matthews, L, 2006-06-08 06:14:23 Edited: Matthews, L, 2007-01-31 22:42:03 Pubmed9405152 Reactome Database ID Release 43180709 Reactome, http://www.reactome.org ReactomeREACT_9394 Reviewed: Kumar, A, 2007-01-31 22:47:49 The association of Rev with importin-beta is mediated by the Rev nuclear localisation signal. hp-IRAK1:TRAF6 Reactome DB_ID: 450121 Reactome Database ID Release 43450121 Reactome, http://www.reactome.org ReactomeREACT_22529 has a Stoichiometric coefficient of 1 Interaction of Vpr with importin alpha Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-05-23 14:55:52 Pubmed15731250 Pubmed9436978 Pubmed9582382 Reactome Database ID Release 43180627 Reactome, http://www.reactome.org ReactomeREACT_8011 Reviewed: Zhao, RY, 2006-07-11 22:08:52 Vpr interacts with importin-alpha through alphaH1 and alphaH2. The interaction via alphaH1 is indispensable for the nuclear entry of Vpr (Kamata et al., 2005) . p62:MEKK3:TRAF6 Reactome DB_ID: 507716 Reactome Database ID Release 43507716 Reactome, http://www.reactome.org ReactomeREACT_23141 has a Stoichiometric coefficient of 1 Vpr binds nucleoporins Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-05-15 07:16:46 Pubmed12228227 Reactome Database ID Release 43180622 Reactome, http://www.reactome.org ReactomeREACT_7952 Reviewed: Zhao, RY, 2006-07-11 22:08:52 hp-IRAK1:p-Pellino, IRAK4:p-Pellino Converted from EntitySet in Reactome Reactome DB_ID: 451425 Reactome Database ID Release 43451425 Reactome, http://www.reactome.org ReactomeREACT_22769 Association of Vpr with ANT1 Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-06-07 20:11:20 Pubmed10620603 Reactome Database ID Release 43180905 Reactome, http://www.reactome.org ReactomeREACT_7958 Reviewed: Zhao, RY, 2006-07-11 22:08:52 Vpr interacts with the PTPC component ANT1. This interaction induces mitochondrial membrane permeabilization and release of cytochrome c and apoptotic factors. IRAK4: Pellino-1,2,3 Reactome DB_ID: 451416 Reactome Database ID Release 43451416 Reactome, http://www.reactome.org ReactomeREACT_22679 has a Stoichiometric coefficient of 1 Translocation of Vpr to the mitochondria Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-06-02 10:55:30 Pubmed10620603 Reactome Database ID Release 43180855 Reactome, http://www.reactome.org ReactomeREACT_7969 Reviewed: Zhao, RY, 2006-07-11 22:08:52 Vpr translocates to the mitochondria. hp-IRAK1: Pellino-1,2,3 Reactome DB_ID: 451420 Reactome Database ID Release 43451420 Reactome, http://www.reactome.org ReactomeREACT_23079 has a Stoichiometric coefficient of 1 Myristoylation of Nef GENE ONTOLOGYGO:0006499 Nef amino terminal myristoylation has been shown to be critical for many of Nef's functions. As expected myristoylated Nef can be identified as co-fractionating with cell membranes and cytoskeletal components. Pubmed15613341 Pubmed7797518 Pubmed8124721 Pubmed8151761 Reactome Database ID Release 43162914 Reactome, http://www.reactome.org ReactomeREACT_116143 hp-IRAK1:Pellino, IRAK4:Pellino Converted from EntitySet in Reactome Reactome DB_ID: 451413 Reactome Database ID Release 43451413 Reactome, http://www.reactome.org ReactomeREACT_23330 IRAK4: p-Pellino-1,2,3 Reactome DB_ID: 451410 Reactome Database ID Release 43451410 Reactome, http://www.reactome.org ReactomeREACT_23142 has a Stoichiometric coefficient of 1 hp-IRAK1: p-Pellino-1,2,(3) Reactome DB_ID: 451411 Reactome Database ID Release 43451411 Reactome, http://www.reactome.org ReactomeREACT_22866 has a Stoichiometric coefficient of 1 Association of Ran-GTP with importin-beta Authored: Matthews, L, 2006-06-08 06:14:23 Edited: Matthews, L, 2007-01-31 22:42:03 Inside the nucleus, Ran-GTP associates with importin-beta. Pubmed9405152 Reactome Database ID Release 43180728 Reactome, http://www.reactome.org ReactomeREACT_9399 Reviewed: Kumar, A, 2007-01-31 22:47:49 Translocation of Rev:importin-beta:B23 to the nucleus Authored: Matthews, L, 2006-06-08 06:14:23 Edited: Matthews, L, 2007-01-31 22:42:03 Following the association of Rev with importin-beta, the Rev:B23:importin-beta complex is imported into the nucleus. Pubmed9092824 Reactome Database ID Release 43180732 Reactome, http://www.reactome.org ReactomeREACT_9521 Reviewed: Kumar, A, 2007-01-31 22:47:49 Rev multimer-bound HIV-1 mRNA:Crm1:Ran:GTP complex associates with the NPC Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2006-07-13 06:31:19 Reactome Database ID Release 43165043 Reactome, http://www.reactome.org ReactomeREACT_6337 Reviewed: Kumar, A, 2007-01-31 22:47:49 The Rev multimer-bound HIV-1 mRNA:Crm1:Ran:GTP complex associates with the NPC. IL1R1:IL1:IL1RAP Reactome DB_ID: 445758 Reactome Database ID Release 43445758 Reactome, http://www.reactome.org ReactomeREACT_22656 has a Stoichiometric coefficient of 1 Rev multimer-bound HIV-1 mRNA:CRM1 complex associates with Ran:GTP Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2006-07-07 14:08:37 Pubmed9837918 RanGTP binds to a preformed Rev-CRM1 complex. Reactome Database ID Release 43165034 Reactome, http://www.reactome.org ReactomeREACT_6140 Reviewed: Kumar, A, 2007-01-31 22:47:49 Association of RanBP1 with Ran-GTP:CRM1:Rev:mRNA complex Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2006-05-23 14:55:52 Reactome Database ID Release 43180739 Reactome, http://www.reactome.org ReactomeREACT_9478 Reviewed: Kumar, A, 2007-01-31 22:47:49 Upon translocation to the cytoplasm, RanBP1 associates with Ran-GTP in the Rev-CRM1-Ran-GTP complex. IL1 receptor complex Reactome DB_ID: 446637 Reactome Database ID Release 43446637 Reactome, http://www.reactome.org ReactomeREACT_23029 has a Stoichiometric coefficient of 1 Translocation of nuclear RNA transport complex to cytoplasm Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Crm1 is a nucleocytoplasmic transport factor that is believed to interact with nucleoporins facilitating docking of the RRE-Rev-CRM1-RanGTP complex to the nuclear pore and the translocation of the complex across the nuclear pore complex (see Cullen 1998) Crm1 has been found in complex with two such nucleoporins, CAN/Nup214 and Nup88 which have been shown to be components of the human nuclear pore complex (Fornerod et al., 1997). Edited: Matthews, L, 2006-07-13 06:31:19 Pubmed11836381 Pubmed7958838 Pubmed9049309 Pubmed9323133 Pubmed9791012 Reactome Database ID Release 43165047 Reactome, http://www.reactome.org ReactomeREACT_6340 Reviewed: Kumar, A, 2007-01-31 22:47:49 IL1:IL1R1:IL1RAP:MYD88 homodimer Reactome DB_ID: 450120 Reactome Database ID Release 43450120 Reactome, http://www.reactome.org ReactomeREACT_23167 has a Stoichiometric coefficient of 1 Multimerization of Rev Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2005-07-26 23:04:06 In order for Rev to function, multiple molecules must bind sequentiallly to the RRE (Malim and Cullen 1991). Pubmed2015625 Reactome Database ID Release 43165033 Reactome, http://www.reactome.org ReactomeREACT_6228 Reviewed: Kumar, A, 2007-01-31 22:47:49 IL1 receptor complex - activated IRAK4:TOLLIP Reactome DB_ID: 446643 Reactome Database ID Release 43446643 Reactome, http://www.reactome.org ReactomeREACT_23002 has a Stoichiometric coefficient of 1 IL1 receptor complex:TOLLIP Reactome DB_ID: 446888 Reactome Database ID Release 43446888 Reactome, http://www.reactome.org ReactomeREACT_23348 has a Stoichiometric coefficient of 1 Conversion of Ran-GDP to Ran-GTP Authored: Matthews, L, 2006-06-08 06:14:23 Edited: Matthews, L, 2007-01-31 22:42:03 Free, nuclear RanGTP is required for export processes out of the nucleus. RCC1 catalyses the conversion of Ran-GDP to Ran-GTP in the nucleus. Pubmed1944575 Pubmed7878053 Reactome Database ID Release 43180687 Reactome, http://www.reactome.org ReactomeREACT_9507 Reviewed: Kumar, A, 2007-01-31 22:47:49 IL1 receptor complex- activated IRAK4:TOLLIP:p-IRAK1 Reactome DB_ID: 446689 Reactome Database ID Release 43446689 Reactome, http://www.reactome.org ReactomeREACT_23087 has a Stoichiometric coefficient of 1 Rev multimer-bound HIV-1 mRNA associates with Crm1 Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 CRM1 associates directly with Rev through the Rev nuclear export signal (NES) domain and acts as the nuclear export receptor for the Rev-RRE ribonucleoprotein complex. Edited: Matthews, L, 2007-01-31 22:42:03 Pubmed9837918 Reactome Database ID Release 43180885 Reactome, http://www.reactome.org ReactomeREACT_9530 Reviewed: Kumar, A, 2007-01-31 22:47:49 IL1 receptor complex-activated IRAK4:TOLLIP:IRAK1 Reactome DB_ID: 446693 Reactome Database ID Release 43446693 Reactome, http://www.reactome.org ReactomeREACT_22771 has a Stoichiometric coefficient of 1 IL1 receptor complex-activated IRAK4:TOLLIP:hp-IRAK:TRAF6 Reactome DB_ID: 446864 Reactome Database ID Release 43446864 Reactome, http://www.reactome.org ReactomeREACT_22757 has a Stoichiometric coefficient of 1 IL1 receptor complex- activated IRAK4:TOLLIP:hp-IRAK1 Reactome DB_ID: 446696 Reactome Database ID Release 43446696 Reactome, http://www.reactome.org ReactomeREACT_23332 has a Stoichiometric coefficient of 1 p62:MEKK3 Reactome DB_ID: 507714 Reactome Database ID Release 43507714 Reactome, http://www.reactome.org ReactomeREACT_23211 has a Stoichiometric coefficient of 1 Hydrolysis of Ran:GTP to Ran:GDP Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 EC Number: 3.6.5.1 EC Number: 3.6.5.2 EC Number: 3.6.5.3 EC Number: 3.6.5.4 Edited: Matthews, L, 2006-07-13 06:31:19 Pubmed7878053 Ran-GAP, a Ran-specific GTPase-activating protein converts Ran-GTP to Ran-GDP, producing a Ran-GTP gradient across the nuclear membrane. Reactome Database ID Release 43165055 Reactome, http://www.reactome.org ReactomeREACT_6171 Reviewed: Kumar, A, 2007-01-31 22:47:49 Release of the HIV-1 mRNA and Crm1 from Rev in the cytoplasm Authored: Matthews, L, Rice, AP, 2005-07-27 00:00:00 Edited: Matthews, L, 2006-07-13 06:31:19 Reactome Database ID Release 43165028 Reactome, http://www.reactome.org ReactomeREACT_6318 Reviewed: Kumar, A, 2007-01-31 22:47:49 The association of RanBp1 with RanGTP:CRM1:Rev promotes disassembly of the complex and release of the Rev:RNA cargo. Synthesis of GAG polyprotein Gag is translated from the unspliced viral RNA on free ribosomes in the cytoplasm. The products of the pro and pol genes are also synthesized from the unspliced viral RNA, but never as parts of an independent polyprotein. They are initially contained within the Gag-Pro or Gag-Pro-Pol fusion protein, the product of translational readthrough ISBN0-87969-571-4 Reactome Database ID Release 43187213 Reactome, http://www.reactome.org ReactomeREACT_115916 Reviewed: Gopinathrao, G, 2006-11-06 22:04:18 Nef Binds and activates the Src-family tyrosine kinase Lck Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed10544125 Pubmed7859737 Reactome Database ID Release 43200954 Reactome, http://www.reactome.org ReactomeREACT_11220 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The Nef protein of the primate lentiviruses, including human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), is a myristylated protein associated with increased viral replication and enhanced pathogenicity. Both the potentiation of T-lymphocyte activation and the enhanced serine-phosphorylation of HIV-1 capsid by Nef correlate with increased viral replication. The Nef proteins from HIV-1 and SIV bind to Lck. The SH3 and SH2 domains of Lck are sufficient for coprecipitation with non-tyrosine-phosphorylated Nef proteins. The conserved core region of HIV-1 Nef is essential for the interaction with Lck and is also important for enhanced HIV-1 replication in T-lymphocytes. The SIV and HIV-1 Nef proteins are differentially tyrosine-phosphorylated. The kinase-active Lck tyrosine-phosphorylates SIVmac239 Nef but does not phosphorylate HIV-1 Nef. Nef Binds and activates the Src-family tyrosine kinase Fyn Authored: Gillespie, ME, 2007-07-25 19:42:36 Nef has been shown to bind specifically to a subset of the Src family of kinases. Nef/Fyn interaction centers on a proline-rich motif (Pro-x-x-Pro), which is implicated in SH3 binding. This domain is partially disordered in the absence of the binding partner; when bound this motif fully adopts a left-handed polyproline type II helix conformation upon complex formation with the Fyn SH3 domain. Within this structure the arginine residue (Arg77) of Nef interacts with Asp 100 of the RT loop within the Fyn SH3 domain, and triggers a hydrogen-bond rearrangement which allows the loop to adapt to complement the Nef surface. The Arg96 residue of the Fyn SH3 domain is specifically accommodated in the same hydrophobic pocket of Nef. The Nef-Fyn complex forms in vivo and may have a crucial role in the T cell perturbating action of Nef by altering T cell receptor signaling. Pubmed7859737 Pubmed9351809 Reactome Database ID Release 43200908 Reactome, http://www.reactome.org ReactomeREACT_11075 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Formation of Nef:Cd28:Clathrin-coated Pit Adapter Protein complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Nef induces accelerated endocytosis of CD28 via clathrin-coated pits. Pubmed11285224 Reactome Database ID Release 43167633 Reactome, http://www.reactome.org ReactomeREACT_11122 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Internalization of Nef:CD28:Clathrin-Coated Pit Adapter Protein Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Once Nef has induced endocytosis of CD28, CD28 containing vesicles are targeted for lysosomal degradation. Pubmed11285224 Reactome Database ID Release 43167637 Reactome, http://www.reactome.org ReactomeREACT_11164 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Nef binds a ternary complex comprising DOCK2 guanine nucleotide exchange factor for small Rho-family GTPase Rac, its cofactor ELMO1, and Rac, and activates Rac through this interaction Pubmed14737186 Reactome Database ID Release 43200952 Reactome, http://www.reactome.org ReactomeREACT_11090 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The infectious cycle of primate lentiviruses is intimately linked to interactions between cells of the immune system. Nef, a potent virulence factor, alters cellular environments to increase lentiviral replication in the host, functioning as an adaptor protein. Nef activates Rac in T cell lines and in primary T cells following infection with HIV-1 in the absence of antigenic stimuli. Nef activates Rac by binding the DOCK2-ELMO1 complex, and this interaction is linked to the abilities of Nef to inhibit chemotaxis and promote T cell activation. Nef targets a critical switch that regulates Rac GTPases downstream of chemokine- and antigen-initiated signaling pathways. This interaction enables Nef to influence multiple aspects of T cell function and thus provides an important mechanism by which Nef impacts pathogenesis by primate lentiviruses. Formation of Nef CD28 cytoplasmic tail complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Down-regulation of CD28 receptors involves a dileucine-based motif in the second disordered loop of Nef, which connects Nef to adaptor protein (AP) complex, which is a part of cellular endocytosis machinery. Pubmed11285224 Reactome Database ID Release 43167630 Reactome, http://www.reactome.org ReactomeREACT_11194 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Transport of MHC I:Nef:AP-1:PACS-1 Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed15569716 Reactome Database ID Release 43182286 Reactome, http://www.reactome.org ReactomeREACT_11229 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The complex of Nef, major histocompatibility complex class I molecules, PACS-1 and AP-1 is transported from the trans-Golgi network to an endosome, where the MHC I complex will be degraded. Degradation of MHC I Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Once the complex of Nef, major histocompatibility complex class I molecules, PACS-1 and AP-1 arrives at the endosome, the MHC I complex is targeted for degradation. Pubmed15569716 Reactome Database ID Release 43182263 Reactome, http://www.reactome.org ReactomeREACT_11147 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Formation of MHC I:Nef Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Nef disrupts the transport of major histocompatibility complex class I molecules by first binding to the the cytoplasmic side of the transmembrane complex. Pubmed15569716 Reactome Database ID Release 43182243 Reactome, http://www.reactome.org ReactomeREACT_11071 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Formation of MHC I:Nef:AP-1:PACS-1 Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed15569716 Reactome Database ID Release 43182279 Reactome, http://www.reactome.org ReactomeREACT_11186 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The complex formed by Nef and the major histocompatibility complex class I molecules creates binding sites for PACS-1 and the AP-1 complex. Disassembly of the Rev-importin beta-B23:Ran-GTP complex Authored: Matthews, L, 2006-06-08 06:14:23 Edited: Matthews, L, 2007-01-31 22:42:03 Pubmed9405152 Reactome Database ID Release 43180736 Reactome, http://www.reactome.org ReactomeREACT_9456 Reviewed: Kumar, A, 2007-01-31 22:47:49 The association of importin-beta with Ran-GTP causes the disassembly of the Rev-importin β-B23 complex releasing the Rev in the nucleus. Nef Binds and activates the Src-family tyrosine kinase Hck Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed7859737 Pubmed8599760 Pubmed9024665 Reactome Database ID Release 43200858 Reactome, http://www.reactome.org ReactomeREACT_11224 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The protein Hck is a member of the Src family of non-receptor tyrosine kinases which is preferentially expressed in haematopoietic cells of the myeloid and B-lymphoid lineages. Src kinases are inhibited by tyrosine-phosphorylation at a carboxy-terminal site. The SH2 domains of these enzymes play an essential role in this regulation by binding to the tyrosine-phosphorylated tail. The SH2 domain of Hck regulates enzymatic activity indirectly; intramolecular interactions between the SH3 and catalytic domains appear to stabilize an inactive form of the kinase. The HIV-1 Nef protein, which is a high-affinity ligand for the Hck SH3 domain, binds to either the downregulated or activated form of Hck causing a large increase in Hck catalytic activity. The intact SH3-binding motif in Nef is crucial for Hck activation. Association of APOBEC3G with Gag APOBEC3G is incorporated into virus particles through its association with components of the viral RNA packaging machinery. It binds to the nucleocapsid portion of Gag (NC), a region of the polyprotein that associates with genomic RNA and functions in RNA encapsidation. Authored: Matthews, L, 2006-06-07 20:09:24 Edited: Matthews, L, 2007-01-30 11:27:41 Pubmed15464836 Pubmed15479846 Reactome Database ID Release 43180630 Reactome, http://www.reactome.org ReactomeREACT_9450 Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 Association of APOBEC3G with single-stranded region of forming HIV-1 minus strand Authored: Matthews, L, 2006-06-07 20:09:24 Edited: Matthews, L, 2007-01-30 11:27:41 In the target cell, HIV-1-associated APOBEC3G binds to the HIV-1 reverse transcript minus strand and catalyzes the deamination of cytidines in a specific dinucleotide context (e.g., dCC). In contrast, APOBEC3F and APOBEC3B display a preference for dTC. Pubmed15098018 Reactome Database ID Release 43180634 Reactome, http://www.reactome.org ReactomeREACT_9444 Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 Deamination of C residues during synthesis of HIV-1 reverse transcript minus-strand Authored: Matthews, L, 2006-06-07 20:09:24 During reverse transcription, APOBEC3G-mediated minus-strand deamination occurs within a CC dinucleotide context over the entire length of the HIV-1 genome (Yu et al., 2004). <br>The polypurine tract is essential for plus strand synthesis and is located at the 3’ end of the retroviral genome. HIV-1 encodes an additional central polypurine tract located in the middle of the genome which also serves as primer for plus strand synthesis.<br>Deamination of the minus strand continues throughout its synthesis with the frequency of deamination events increasing from the 5’ to 3’ regions. A 400bp region downstream of the central polypurine tract seems to be protected from deamination (Wurtzer et al., 2006) EC Number: 3.5.4.13 Edited: Matthews, L, 2007-01-30 11:27:41 Pubmed12808465 Pubmed15098018 Pubmed16537639 Reactome Database ID Release 43180632 Reactome, http://www.reactome.org ReactomeREACT_9435 Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 Association of Vif with APOBEC3G Authored: Matthews, L, 2006-05-15 23:53:25 Edited: Matthews, L, 2007-01-30 11:27:41 Pubmed14528301 Pubmed14978281 Pubmed14999100 Pubmed16501124 Reactome Database ID Release 43180602 Reactome, http://www.reactome.org ReactomeREACT_9445 Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 The HIV-1 Vif protein associates with the DNA editing enzyme APOBEC3G Marin et al) . The binding site has not yet been mapped but emerging evidence suggest that the N-terminal lregion of Vif is essential for APOBEC3G recognition (Tian et al) . <br>Substitution of a single amino acid in the human APOBEC3G (Asp128Lys) abolishes binding and renders it resistant to HIV-1 Vif (Schrofelbauer et al; Bogerd et al.). <br> Association of APOBEC3G:Vif with the Cul5-SCF complex Authored: Matthews, L, 2006-05-15 23:53:25 Edited: Matthews, L, 2007-01-30 11:27:41 Pubmed14564014 Pubmed15574592 Pubmed16530799 Reactome Database ID Release 43180555 Reactome, http://www.reactome.org ReactomeREACT_9469 Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 The interaction between Vif and the E3 ubiquitin ligase complex (Cullin5, Elongin B and Elongin C, and Rbx1) takes place through direct binding of the SOCS box motif in the viral protein Vif to the host protein Elongin C. Moreover, a conserved HCCH motif in Vif allows binding to Cullin 5. Multi-ubiquitination of APOBEC3G APOBEC3G is multi-ubiquitinated by the Vif-Cul5-SCF complex. Authored: Matthews, L, 2006-05-15 23:53:25 EC Number: 6.3.2.19 Edited: Matthews, L, 2007-01-30 11:27:41 Pubmed15781449 Reactome Database ID Release 43180540 Reactome, http://www.reactome.org ReactomeREACT_9471 Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 has a Stoichiometric coefficient of 3 Proteosome-mediated degradation of APOBEC3G Authored: Matthews, L, 2006-05-15 23:53:25 Edited: Matthews, L, 2007-01-30 11:27:41 Following multi-ubiquitination by the Vif-Cul5-SCF complex, APOBEC3G is degraded by the 26S proteasome. Pubmed14528300 Pubmed14564014 Pubmed15781449 Reactome Database ID Release 43180603 Reactome, http://www.reactome.org ReactomeREACT_9466 Reviewed: Mulder, L, 2007-01-30 22:57:00 Reviewed: Simon, V, 2007-01-30 23:07:12 has a Stoichiometric coefficient of 3 Nef mediated activation of the T-cell receptor Authored: Gillespie, ME, 2007-07-25 19:42:36 GENE ONTOLOGYGO:0050690 Nef drives the formation of lipid raft complexes. Pubmed10607567 Pubmed10618429 Pubmed11070003 Pubmed11160719 Pubmed16188976 Pubmed16282498 Pubmed16979207 Reactome Database ID Release 43164943 Reactome, http://www.reactome.org ReactomeREACT_11221 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Binding of the influenza virion to the host cell GENE ONTOLOGYGO:0046718 Influenza viruses bind via their surface HA (hemagglutinin) to sialic acid in alpha 2,3 or alpha 2,6 linkage with galactose on the host cell surface. Sialic acid in 2,6 linkages is characteristic of human cells while 2,3 linkages are characteristic of avian cells. The specificity of influenza HA for sialic acid in alpha 2,6 or alpha 2,3 linkages is a feature restricting the transfer of influenza viruses between avian species and humans. This species barrier can be overcome, however. Notably, passaged viruses adapt to their host through mutation in the receptor binding site of the viral HA gene. Pubmed0 Pubmed10366560 Pubmed12954214 Pubmed7975212 Reactome Database ID Release 43168272 Reactome, http://www.reactome.org ReactomeREACT_6232 Degradation of ubiquitinated CD4 Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-05-15 07:16:46 Pubmed9660940 Reactome Database ID Release 43180573 Reactome, http://www.reactome.org ReactomeREACT_9018 Reviewed: Benarous, R, 2006-09-21 14:25:23 Ubiquitinated CD4 is then subject to proteasome-mediated degradation. has a Stoichiometric coefficient of 3 Ubiquitination of CD4 by Vpu:CD4:beta-TrCP:SKP1 complex Authored: Matthews, L, 2006-05-15 07:16:46 CD4 is ubiquitinated in the CD4:Vpu–h-βTrCP:Skp1 complex. EC Number: 6.3.2.19 Edited: Matthews, L, 2006-05-15 07:16:46 Pubmed9660940 Reactome Database ID Release 43180597 Reactome, http://www.reactome.org ReactomeREACT_9063 Reviewed: Benarous, R, 2006-09-21 14:25:23 has a Stoichiometric coefficient of 3 The Vpu:CD4:beta-TrCP complex recruits SKP1 Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-05-15 07:16:46 Pubmed9660940 Reactome Database ID Release 43180599 Reactome, http://www.reactome.org ReactomeREACT_9071 Reviewed: Benarous, R, 2006-09-21 14:25:23 The SKP1 component of the SCF complex is recruited to the Vpu:beta-TrCP:CD4 complex. SPRY1/2 Converted from EntitySet in Reactome Reactome DB_ID: 182909 Reactome Database ID Release 43182909 Reactome, http://www.reactome.org ReactomeREACT_13348 Sprouty Phospho-Sprouty Converted from EntitySet in Reactome Reactome DB_ID: 182963 Reactome Database ID Release 43182963 Reactome, http://www.reactome.org ReactomeREACT_13129 p-Y53/55-SPRY1/2 Virion-associated M2 protein mediated ion infusion GENE ONTOLOGYGO:0019061 Pubmed563896 Pubmed7688826 Pubmed8841994 Reactome Database ID Release 43168313 Reactome, http://www.reactome.org ReactomeREACT_6315 The uncoating of influenza viruses in endosomes is blocked by changes in pH caused by weak bases (e.g. ammonium chloride and chloroquine) or ionophores (e.g. monensin). Effective uncoating is also dependent on the presence of the viral M2 ion channel protein. Early on it was recognized that amantadine and rimantadine inhibit replication immediately following virus infection. Later it was found that the virus-associated M2 protein allows the influx of H+ ions from the endosome into the virion. This disrupts protein-protein interactions, resulting in the release of viral RNP free of the viral matrix (M1) protein. Amantadine and rimantadine have been shown to block the ion channel activity of the M2 protein and thus uncoating. Ribonucleoprotein release from M1 proteins GENE ONTOLOGYGO:0019061 Pubmed1985199 Reactome Database ID Release 43168299 Reactome, http://www.reactome.org ReactomeREACT_6230 The influx of H+ ions into the virion disrupts protein-protein interactions, resulting in the release of the viral RNP from the viral matrix (M1) protein. The uncoating process is complete with the appearance of free RNP complexes in the cytosol. has a Stoichiometric coefficient of 165 has a Stoichiometric coefficient of 3000 Fusion of the influenza virion HA2 protein transmembrane domain to the host cell endosome membrane GENE ONTOLOGYGO:0019064 Pubmed11208147 Reactome Database ID Release 43168312 Reactome, http://www.reactome.org ReactomeREACT_6180 The fusion peptide of its HA2 subunit interacts with the endosome membrane. The transmembrane domain of the HA2 is inserted into the viral membrane and the fusion peptide is inserted into the endosomal membrane. In the acidic pH structure of HA the two ends of the HA complex are in juxtaposition. Concerted hemagglutinin pore formation GENE ONTOLOGYGO:0019064 Pubmed11208147 Pubmed3663665 Reactome Database ID Release 43168306 Reactome, http://www.reactome.org ReactomeREACT_6176 The concerted structural change of several hemagglutinin molecules opens a pore through which the viral RNP will be able to pass into the host cell cytosol. Clathrin-Mediated Pit Formation And Endocytosis Of The Influenza Virion GENE ONTOLOGYGO:0019065 Pubmed0 Pubmed7328111 Reactome Database ID Release 43168285 Reactome, http://www.reactome.org ReactomeREACT_6262 Virus particles bound to the cell surface can be internalized by four mechanisms. Most internalization appears to be mediated by clathrin-coated pits. Conformation change in hemagglutinin freeing the fusion peptide of HA2 Pubmed11208147 Pubmed3663665 Reactome Database ID Release 43168324 Reactome, http://www.reactome.org ReactomeREACT_6219 The low pH of the endosome causes the viral HA (hemagglutinin) to undergo a structural change which frees the fusion peptide of its HA2 subunit. Nef mediated disruption of CD4:Lck Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Nef disrupts the CD4 Lck complex Pubmed2014052 Reactome Database ID Release 43167566 Reactome, http://www.reactome.org ReactomeREACT_11148 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Internalization of the CD4:Nef:AP-2 Complex:v-ATPase Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed2014052 Reactome Database ID Release 43167597 Reactome, http://www.reactome.org ReactomeREACT_11160 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The Nef:CD4:AP-2 complex is internalized Formation of CD4:Nef:AP-2 Complex:v-ATPase Complex AP-2 is recruited to the newly formed Nef:CD4 complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed2014052 Reactome Database ID Release 43167537 Reactome, http://www.reactome.org ReactomeREACT_11091 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Cool-1 Converted from EntitySet in Reactome Reactome DB_ID: 195011 Reactome Database ID Release 43195011 Reactome, http://www.reactome.org ReactomeREACT_10453 Degradation of CD8 Authored: Gillespie, ME, 2007-07-25 19:42:36 Once the CD8alphabeta receptor has been internalized via endocytosis, the vesicles are targeted for lysosomal degradation. Pubmed16103193 Reactome Database ID Release 43182171 Reactome, http://www.reactome.org ReactomeREACT_11144 Reviewed: Skowronski, J, 2007-08-07 14:33:41 SPRY1/2 Converted from EntitySet in Reactome Reactome DB_ID: 182912 Reactome Database ID Release 43182912 Reactome, http://www.reactome.org ReactomeREACT_13097 Sprouty Association of Vpu with CD4 Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-05-15 07:16:46 Pubmed9660940 Reactome Database ID Release 43180606 Reactome, http://www.reactome.org ReactomeREACT_9024 Reviewed: Benarous, R, 2006-09-21 14:25:23 Vpu is expressed in the ER and associates with a membrane-proximal region in the cytoplasmic tail of CD4. Vpu:CD4 associates with beta-TrCP Authored: Matthews, L, 2006-05-15 07:16:46 Edited: Matthews, L, 2006-05-15 07:16:46 Pubmed9660940 Reactome Database ID Release 43180591 Reactome, http://www.reactome.org ReactomeREACT_9009 Reviewed: Benarous, R, 2006-09-21 14:25:23 Vpu links beta-TrCP to CD4 at the ER membrane through interactions with beta-TrCP and the cytoplasmic tail of CD4. Formation of a Nef:ARF1:CD4 complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed15202998 Reactome Database ID Release 43200879 Reactome, http://www.reactome.org ReactomeREACT_11227 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The HIV Nef protein downregulates CD4 through sequential connection with clathrin-coated pits and the COP1 coatomer, resulting in accelerated endocytosis and lysosomal targeting. The small GTPase ARF1 controls the Nef-induced, COP-mediated late-endosomal targeting of CD4. Nef binds ARF1 directly and can recruit the GTPase onto endosomal membranes, leading to the eventual degradation of CD4 (Faure et al. 2004). Degradation of CD4 Authored: Gillespie, ME, 2007-07-25 19:42:36 CD4 is degraded Pubmed2014052 Reactome Database ID Release 43167601 Reactome, http://www.reactome.org ReactomeREACT_11177 Reviewed: Skowronski, J, 2007-08-07 14:33:41 Formation of CD8:Nef:AP-2 Complex:v-ATPase Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed16103193 Reactome Database ID Release 43182186 Reactome, http://www.reactome.org ReactomeREACT_11125 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The presence of Nef accelerates endocytosis and lysosomal degradation of the transmembrane glycoprotein CD8. Nef facilitates a cascade of protein interactions that ultimately result in the degradation of internalized CD8 protein. The final set of protein interactions that direct Nef to the beta-subunit of the COPI coatomers are at this time unclear.<br>A number of sites within Nef are proposed to be required for CD8 down-regulation, the myristoylation signal and N-terminal anchor regions, the C-terminal flexible loop, and amino acid positions 57 to 58. Consistent with all reported Nef functions, the myristoylation signal was found to be essential for CD8 down-modulation. The flexible loop contains a dileucine-based internalization motif, which is flanked by acidic clusters and is involved in enhanced internalization of the Nef-CD4 complex. Internalization of the CD8:Nef:AP-2 Complex:v-ATPase Complex Authored: Gillespie, ME, 2007-07-25 19:42:36 Pubmed16103193 Reactome Database ID Release 43182198 Reactome, http://www.reactome.org ReactomeREACT_11069 Reviewed: Skowronski, J, 2007-08-07 14:33:41 The CD8alphabeta receptor is internalized via endocytosis. human protein oligomerization YH an oligomerization of a human protein human protein activation an activation of a human protein YH human protein covalent binding YH a covalent binding of human proteins human molecular pathway as part of another pathway a human molecular pathway that is a part (subpathway) of another pathway. YH subpathway of human apoptosis pathway YH a human molecular pathway as part of an apoptosis pathway subpathway of human intrinsic apoptosis pathway a human molecular pathway as part of an intrinsic apoptosis pathway YH