BioPAX pathway converted from "Toll Like Receptor 10 (TLR10) Cascade" in the Reactome database. Toll Like Receptor 10 (TLR10) Cascade Toll Like Receptor 10 (TLR10) Cascade This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Ligand binds to TLR10 Ligand binds to TLR10 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 168948 1 extracellular region GO 0005576 Ligand recognized by TLR10 [extracellular region] Ligand recognized by TLR10 Reactome http://www.reactome.org Reactome DB_ID: 10261803 2 plasma membrane GO 0005886 UniProt:I3LPE4 TLR10 Sus scrofa NCBI Taxonomy 9823 UniProt I3LPE4 Chain Coordinates 20 EQUAL 811 EQUAL Reactome DB_ID: 10261807 1 TLR10 homodimer bound to ligand [plasma membrane] TLR10 homodimer bound to ligand Reactome DB_ID: 168948 1 Reactome DB_ID: 10261805 1 TLR10 homodimer [plasma membrane] TLR10 homodimer Reactome DB_ID: 10261803 2 20 EQUAL 811 EQUAL Reactome Database ID Release 82 10261805 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261805 Reactome R-SSC-188112 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-188112.1 Reactome Database ID Release 82 10261807 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261807 Reactome R-SSC-188116 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-188116.1 Reactome Database ID Release 82 10261809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261809 Reactome R-SSC-168947 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168947.1 Microbal stimulation was shown to alter mRNA expression of TLR10 in human granulocytes, monocytes[Zarember KA and Godowski P 2002] and B cells[Bourke ED et al 2003]. However the natural ligand of TLR10 remains unknown. 12689944 Pubmed 2003 The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells Bourke, E Bosisio, D Golay, J Polentarutti, N Mantovani, A Blood 102:956-63 15728506 Pubmed 2005 Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88 Hasan, U Chaffois, C Gaillard, C Saulnier, V Merck, E Tancredi, S Guiet, C Briere, F Vlach, J Lebecque, S Trinchieri, G Bates, EE J Immunol 174:2942-50 11777946 Pubmed 2002 Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines Zarember, KA Godowski, PJ J Immunol 168:554-61 inferred by electronic annotation IEA GO IEA MyD88 cascade initiated on plasma membrane MyD88 cascade initiated on plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> IRAK1 recruits IKK complex IRAK1 recruits IKK complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Pellino binds hp-IRAK1:TRAF6 Pellino binds hp-IRAK1:TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10286146 1 TRAF6:hp-IRAK1 [plasma membrane] TRAF6:hp-IRAK1 Reactome DB_ID: 10286144 1 UniProt:F1RZU1 UniProt F1RZU1 O-phospho-L-threonine at 387 (in Homo sapiens) 387 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 376 (in Homo sapiens) 376 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-threonine at 209 (in Homo sapiens) 209 EQUAL O-phospho-L-serine at unknown position O-phospho-L-serine at unknown position O-phospho-L-threonine at unknown position 1 EQUAL 712 EQUAL Reactome DB_ID: 10286089 1 UniProt:A7XUJ6 TRAF6 UniProt A7XUJ6 1 EQUAL 522 EQUAL Reactome Database ID Release 82 10286146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286146 Reactome R-SSC-937036 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937036.1 Converted from EntitySet in Reactome Reactome DB_ID: 10282312 1 cytosol GO 0005829 p-Pellino-1,2,(3) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-PELI1 [cytosol] phospho-PELI2 [cytosol] UniProt A0A480ULK7 UniProt A0A287B1K0 Reactome DB_ID: 10286148 1 TRAF6:hp-IRAK1:Pellino [plasma membrane] TRAF6:hp-IRAK1:Pellino Reactome DB_ID: 10286146 1 Converted from EntitySet in Reactome Reactome DB_ID: 10282312 1 Reactome Database ID Release 82 10286148 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286148 Reactome R-SSC-937020 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937020.1 Reactome Database ID Release 82 10286153 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286153 Reactome R-SSC-937044 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937044.1 Pellino isoforms -1, 2 and 3 have been shown to interact with IRAK1 and IRAK4 (Jiang et al. 2003, Strellow et al. 2003, Butler et al. 2005, 2007). It has been also reported that Pellino-1 forms a complex with TRAF6, but not TAK1 or IL1R (Jiang et al. 2003), suggesting that Pellino-1 function as intermediate complex with IRAK1 in the propagation of signal from the activated receptor to activation of TAK1. <p>All Pellino isoforms function as E3 ubiquitin ligases in conjunction with several different E2-conjugating enzymes - Ubc13-Uev1a, UbcH4, or UbcH5a/5b.(Schauvliege R et al. 2006, Butler MP et al. 2007, Ordureau A et al. 2008). Their C-terminus contains a RING-like domain which is responsible for IL1-induced Lys63-linked polyubiquitination of IRAK1 in vitro. 17997719 Pubmed 2008 The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1 Ordureau, A Smith, H Windheim, M Peggie, M Carrick, E Morrice, N Cohen, P Biochem J 409:43-52 16884718 Pubmed 2006 Pellino proteins are more than scaffold proteins in TLR/IL-1R signalling: a role as novel RING E3-ubiquitin-ligases Schauvliege, R Janssens, S Beyaert, R FEBS Lett 580:4697-702 12496252 Pubmed 2003 Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex Jiang, Z Johnson, HJ Nie, H Qin, J Bird, TA Li, X J Biol Chem 278:10952-6 17675297 Pubmed 2007 Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases Butler, MP Hanly, JA Moynagh, PN J Biol Chem 282:29729-37 19022706 Pubmed 2009 The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling Moynagh, PN Trends Immunol 30:33-42 15917247 Pubmed 2005 Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-dependent manner Butler, MP Hanly, JA Moynagh, PN J Biol Chem 280:27759-68 12860405 Pubmed 2003 Characterization of Pellino2, a substrate of IRAK1 and IRAK4 Strelow, A Kollewe, C Wesche, H FEBS Lett 547:157-61 18326498 Pubmed 2008 Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation Xiao, H Qian, W Staschke, K Qian, Y Cui, G Deng, L Ehsani, M Wang, X Qian, YW Chen, ZJ Gilmour, R Jiang, Z Li, X J Biol Chem 283:14654-64 inferred by electronic annotation IEA GO IEA IRAK1 phosphorylates Pellino IRAK1 phosphorylates Pellino This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 10286148 1 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 10286148 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10286148 GO 0004672 GO molecular function Reactome Database ID Release 82 10286149 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286149 Reactome Database ID Release 82 10286151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286151 Reactome R-SSC-937034 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937034.1 Both IRAK1 and IRAK4 were shown to phosphorylate Pellino isoforms in vitro. The phosphorylation of Pellino proteins is a necessary step in enhancing of their E3 ubiquitin ligase activity. It remains unclear whether IRAK1(as shown here), IRAK4, or both protein kinases mediate the activation of Pellino isoforms in vivo. 19264966 Pubmed 2009 Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4 Smith, H Peggie, M Campbell, DG Vandermoere, F Carrick, E Cohen, P Proc Natl Acad Sci U S A 106:4584-90 inferred by electronic annotation IEA GO IEA Pellino ubiquitinates hp-IRAK1 Pellino ubiquitinates hp-IRAK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10286148 1 Reactome DB_ID: 10261770 1 UBE2N:UBE2V1 [cytosol] UBE2N:UBE2V1 Reactome DB_ID: 10261764 1 UniProt:A0A5G2QZC6 UBE2N UniProt A0A5G2QZC6 1 EQUAL 152 EQUAL Reactome DB_ID: 10261768 1 UniProt:A0A5G2QIZ7 UBE2V1 UniProt A0A5G2QIZ7 2 EQUAL 147 EQUAL Reactome Database ID Release 82 10261770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261770 Reactome R-SSC-202463 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-202463.1 Reactome DB_ID: 10261731 2 K63polyUb [cytosol] K63polyUb Converted from EntitySet in Reactome Reactome DB_ID: 10282312 1 Reactome DB_ID: 10286138 1 K63-linked polyUb p-IRAK1:TRAF6 [cytosol] K63-linked polyUb p-IRAK1:TRAF6 Reactome DB_ID: 10282440 1 O-phospho-L-threonine at 209 (in Homo sapiens) 209 EQUAL O-phospho-L-serine at 376 (in Homo sapiens) 376 EQUAL O-phospho-L-threonine at 387 (in Homo sapiens) 387 EQUAL O-phospho-L-threonine at unknown position O-phospho-L-serine at unknown position O-phospho-L-serine at unknown position ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 134 (in Homo sapiens) 134 EQUAL ubiquitinylated lysine [MOD:01148] ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 160 (in Homo sapiens) 160 EQUAL 1 EQUAL 712 EQUAL Reactome DB_ID: 10261432 1 1 EQUAL 522 EQUAL Reactome Database ID Release 82 10286138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286138 Reactome R-SSC-937043 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937043.1 Reactome DB_ID: 10261770 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10286148 GO 0034450 GO molecular function Reactome Database ID Release 82 10286154 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286154 Reactome Database ID Release 82 10286156 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286156 Reactome R-SSC-937050 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937050.1 IL1R/TLR induces the Lys48- polyubiquitination and proteosomal degradation of IRAK1. IRAK1 has been shown to undergo Lys63-linked polyubiquitination which induced activation of NFkB (Windheim et al 2008; Conze et al 2008). These two forms of ubiquitination are not mutually exclusive for a protein (Newton K et al 2008). Upon stimulation Lys63-linked ubiquitination may occur first to activate NFkB, but at later time Lys48-linked ubiquitination occurs to target the proteins for proteosomal degradation.<p>IRAK1 is ubiquitinated on Lys134 and Lys180; mutation of these sites impairs IL1R-mediated ubiquitylation of IRAK1 (Conze et al 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al 2008) but this view has been refuted (Windheim et al. 2008; Xiao et al. 2008). There is a stronger agreement that Pellino proteins have a role as IRAK1 E3 ubiquitin ligases. <br>Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al 2008; Butler et al 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and Lys48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UbcH13/Uev1a to catalyze Lys63-linked ubiquitylation (Ordureau et al 2008). 18724939 Pubmed 2008 Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies Newton, Kim Matsumoto, Marissa L Wertz, Ingrid E Kirkpatrick, Donald S Lill, Jennie R Tan, Jenille Dugger, Debra Gordon, Nathaniel Sidhu, SS Fellouse, FA Komuves, Laszlo French, Dorothy M Ferrando, Ronald E Lam, Cynthia Compaan, Deanne Yu, Christine Bosanac, Ivan Hymowitz, Sarah G Kelley, Robert F Dixit, Vishva M Cell 134:668-78 18180283 Pubmed 2008 Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase Windheim, M Stafford, M Peggie, M Cohen, P Mol Cell Biol 28:1783-91 18347055 Pubmed 2008 Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation Conze, DB Wu, CJ Thomas, JA Landstrom, A Ashwell, JD Mol Cell Biol 28:3538-47 inferred by electronic annotation IEA GO IEA NEMO subunit of IKK complex binds to activated IRAK1 NEMO subunit of IKK complex binds to activated IRAK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10286138 1 Reactome DB_ID: 10268316 1 CHUK:IKBKB:IKBKG [cytosol] CHUK:IKBKB:IKBKG Reactome DB_ID: 10261565 1 UniProt:A9QT41 UniProt A9QT41 1 EQUAL 419 EQUAL Reactome DB_ID: 10266304 1 UniProt:F1S8V5 UniProt F1S8V5 1 EQUAL 745 EQUAL Reactome DB_ID: 10265461 1 UniProt:A0A287A5Q1 IKBKB UniProt A0A287A5Q1 1 EQUAL 756 EQUAL Reactome Database ID Release 82 10268316 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10268316 Reactome R-SSC-168113 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168113.1 Reactome DB_ID: 10286140 1 TRAF6:K63-linked polyUb p-IRAK1:IKK complex [cytosol] TRAF6:K63-linked polyUb p-IRAK1:IKK complex Reactome DB_ID: 10268316 1 Reactome DB_ID: 10286138 1 Reactome Database ID Release 82 10286140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286140 Reactome R-SSC-937038 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937038.1 Reactome Database ID Release 82 10286142 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286142 Reactome R-SSC-937032 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937032.1 NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008). 16547522 Pubmed 2006 Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected] Wu, CJ Conze, DB Li, T Srinivasula, SM Ashwell, JD Nat Cell Biol 8:398-406 16603398 Pubmed 2006 Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO Ea, CK Deng, L Xia, ZP Pineda, G Chen, ZJ Mol Cell 22:245-57 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10351418 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10351418 Reactome R-SSC-937039 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937039.1 GO 0043123 GO biological process The role of IRAK1 kinase activity in the activation of NF-kappa-B by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK1 mutants can still activate NF-kappa-B. Furthermore, stimulation of IRAK1-deficient I1A 293 cells with LMP1 (latent membrane protein 1- a known viral activator of NF-kappa-B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK1 enhances p65 Ser536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NF-kappa-B dependent target genes [Liu G et al 2008].<p> IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B. </p><p>Upon IL-1/TLR stimulation IRAK1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003]. 12856330 Pubmed 2003 IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expression Nguyen, H Chatterjee-Kishore, M Jiang, Z Qing, Y Ramana, CV Bayes, J Commane, M Li, X Stark, GR J Interferon Cytokine Res 23:183-92 15767370 Pubmed 2005 Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction Uematsu, S Sato, S Yamamoto, M Hirotani, T Kato, H Takeshita, F Matsuda, M Coban, C Ishii, KJ Kawai, T Takeuchi, O Akira, Shizuo J Exp Med 201:915-23 18276832 Pubmed 2008 Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activity Liu, G Park, YJ Abraham, E FASEB J 22:2285-96 14625308 Pubmed 2004 Sequential autophosphorylation steps in the interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling Kollewe, C Mackensen, AC Neumann, D Knop, J Cao, P Li, S Wesche, H Martin, MU J Biol Chem 279:5227-36 15695821 Pubmed 2005 The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling Schoenemeyer, A Barnes, BJ Mancl, ME Latz, E Goutagny, N Pitha-Rowe, Paula M Fitzgerald, Katherine A Golenbock, DT J Biol Chem 280:17005-12 14661019 Pubmed 2004 Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3 Huang, Q Yang, J Lin, Y Walker, Graham C Cheng, J Liu, ZG Su, B Nat Immunol 5:98-103 16477006 Pubmed 2006 IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activation Song, YJ Jen, KY Soni, V Kieff, E Cahir-McFarland, E Proc Natl Acad Sci U S A 103:2689-94 inferred by electronic annotation IEA GO IEA IRAK2 mediated activation of TAK1 complex IRAK2 mediated activation of TAK1 complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> IRAK2 induces TRAF6 oligomerization IRAK2 induces TRAF6 oligomerization This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10261432 2 1 EQUAL 522 EQUAL Reactome DB_ID: 10286093 1 TRAF6:p-IRAK2 [plasma membrane] TRAF6:p-IRAK2 Reactome DB_ID: 10286091 1 UniProt:A0A287AF06 IRAK2 UniProt A0A287AF06 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 625 EQUAL Reactome DB_ID: 10286089 1 1 EQUAL 522 EQUAL Reactome Database ID Release 82 10286093 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286093 Reactome R-SSC-936961 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936961.1 Reactome DB_ID: 10286095 1 p-IRAK2:oligo-TRAF6 [plasma membrane] p-IRAK2:oligo-TRAF6 Reactome DB_ID: 10286089 2 1 EQUAL 522 EQUAL Reactome DB_ID: 10286093 1 Reactome Database ID Release 82 10286095 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286095 Reactome R-SSC-936990 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936990.1 Reactome Database ID Release 82 10286122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286122 Reactome R-SSC-936963 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936963.1 The mechanism by which IRAK-2 induces TRAF6 E3 ligase activity remains to be deciphered, but one possibility is that IRAK-2 may direct TRAF6 oligomerization. 17878161 Pubmed 2007 IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination Keating, SE Maloney, GM Moran, EM Bowie, AG J Biol Chem 282:33435-43 inferred by electronic annotation IEA GO IEA 6.3.2.19 Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10249581 9 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RPS27A [cytosol] UBC [cytosol] UBA52 [cytosol] UniProt A0A287AZA7 UniProt P0CG68 UniProt P63053 Reactome DB_ID: 10286095 1 Reactome DB_ID: 10286100 1 p-IRAK2:K63-linked pUb oligo-TRAF6 [plasma membrane] p-IRAK2:K63-linked pUb oligo-TRAF6 Reactome DB_ID: 10286098 3 ubiquitinylated lysine (K63polyUb [plasma membrane]) at 124 (in Homo sapiens) 124 EQUAL 1 EQUAL 522 EQUAL Reactome DB_ID: 10286091 1 phosphorylated residue at unknown position 1 EQUAL 625 EQUAL Reactome Database ID Release 82 10286100 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286100 Reactome R-SSC-936988 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936988.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10286095 GO 0004842 GO molecular function Reactome Database ID Release 82 10286101 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286101 Reactome Database ID Release 82 10286103 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286103 Reactome R-SSC-936942 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936942.1 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. 17135271 Pubmed 2007 Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation Lamothe, B Besse, A Campos, AD Webster, WK Wu, H Darnay, BG J Biol Chem 282:4102-12 inferred by electronic annotation IEA GO IEA 6.3.2.19 Activated TRAF6 synthesizes unanchored polyubiquitin chains Activated TRAF6 synthesizes unanchored polyubiquitin chains This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10249581 1 Reactome DB_ID: 10261731 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10286100 Reactome Database ID Release 82 10286125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286125 Reactome Database ID Release 82 10286127 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286127 Reactome R-SSC-936986 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936986.1 Polyubiquitinated TRAF6 (as E3 ubiquitin ligase) generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase. 19675569 Pubmed 2009 Direct activation of protein kinases by unanchored polyubiquitin chains Xia, ZP Sun, L Chen, X Pineda, G Jiang, X Adhikari, A Zeng, W Chen, ZJ Nature inferred by electronic annotation IEA GO IEA Activated TRAF6:p-IRAK2 interacts with TAK1 complex Activated TRAF6:p-IRAK2 interacts with TAK1 complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10281410 3 TAK1 complex [cytosol] TAK1 complex Converted from EntitySet in Reactome Reactome DB_ID: 10281408 1 TAB2,TAB3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TAB2 [cytosol] TAB3 [cytosol] UniProt F1S7S1 UniProt A0A481CGW8 Reactome DB_ID: 10281400 1 UniProt:K7GLB8 TAB1 UniProt K7GLB8 1 EQUAL 504 EQUAL Reactome DB_ID: 10281396 1 UniProt:B0LXP5 UniProt B0LXP5 1 EQUAL 606 EQUAL Reactome Database ID Release 82 10281410 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281410 Reactome R-SSC-446878 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-446878.1 Reactome DB_ID: 10286100 1 Reactome DB_ID: 10261731 3 Reactome DB_ID: 10286118 1 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex [plasma membrane] p-IRAK2:K63-linked pUb oligo-TRAF6:free K63 pUb:TAK1 complex Reactome DB_ID: 10281410 3 Reactome DB_ID: 10286100 1 Reactome DB_ID: 10261731 3 Reactome Database ID Release 82 10286118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286118 Reactome R-SSC-936953 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936953.1 Reactome Database ID Release 82 10286120 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286120 Reactome R-SSC-936960 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936960.1 TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains (Kulathu Y et al 2009). TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.<p>As a de-ubiquitinating/de-ISGylating enzyme, severe acute respiratory syndrome coronavirus type 1 (SARS-CoV-1) 1a-encoded papain-like protease (PLPro or nsp3) antagonizes the host type I interferon (IFN) response by removing Lys63-linked ubiquitin chains of TRAF3 and TRAF6 (Li SW et al. 2016). 19935683 Pubmed 2009 Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain Kulathu, Yogesh Akutsu, Masato Bremm, Anja Hofmann, K Komander, David Nat. Struct. Mol. Biol. 16:1328-30 10882101 Pubmed 2000 TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway Takaesu, G Kishida, S Hiyama, A Yamaguchi, K Shibuya, H Irie, K Ninomiya-Tsuji, J Matsumoto, K Mol Cell 5:649-58 27164085 Pubmed 2016 SARS Coronavirus Papain-Like Protease Inhibits the TLR7 Signaling Pathway through Removing Lys63-Linked Polyubiquitination of TRAF3 and TRAF6 Li, Shih-Wen Wang, Ching-Ying Jou, Yu-Jen Huang, Su-Hua Hsiao, Li-Hsin Wan, Lei Lin, Ying-Ju Kung, Szu-Hao Lin, Cheng-Wen Int J Mol Sci 17: 15327770 Pubmed 2004 TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains Kanayama, A Seth, RB Sun, L Ea, CK Hong, M Shaito, A Chiu, YH Deng, L Chen, ZJ Mol Cell 15:535-48 inferred by electronic annotation IEA GO IEA 2.7.11 Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 6 Reactome DB_ID: 10286118 1 Reactome DB_ID: 29370 6 Reactome DB_ID: 10286129 1 p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex [plasma membrane] p-IRAK2:K63-linked pUb oligo-TRAF6:free K63-linked pUb:p-TAK1complex Converted from EntitySet in Reactome Reactome DB_ID: 10281408 3 Reactome DB_ID: 10286100 1 Reactome DB_ID: 10268328 3 O-phospho-L-threonine at 184 (in Homo sapiens) 184 EQUAL O-phospho-L-threonine at 187 (in Homo sapiens) 187 EQUAL 1 EQUAL 606 EQUAL Reactome DB_ID: 10261731 3 Reactome DB_ID: 10281400 3 1 EQUAL 504 EQUAL Reactome Database ID Release 82 10286129 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286129 Reactome R-SSC-937008 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937008.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10286118 GO 0008349 GO molecular function Reactome Database ID Release 82 10286130 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286130 Reactome Database ID Release 82 10286132 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10286132 Reactome R-SSC-936991 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-936991.1 The TAK1 complex consists of Transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). 14633987 Pubmed 2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling Ishitani, T Takaesu, G Ninomiya-Tsuji, J Shibuya, H Gaynor, RB Matsumoto, K EMBO J 22:6277-88 10702308 Pubmed 2000 TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop Kishimoto, K Matsumoto, K Ninomiya-Tsuji, J J Biol Chem 275:7359-64 10838074 Pubmed 2000 Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1 Sakurai, H Miyoshi, H Mizukami, J Sugita, T FEBS Lett. 474:141-5 16289117 Pubmed 2005 Structural basis for the interaction of TAK1 kinase with its activating protein TAB1 Brown, Kieron Vial, Sarah C M Dedi, Neesha Long, Joanna M Dunster, Nicholas J Cheetham, Graham M T J. Mol. Biol. 354:1013-20 16260493 Pubmed 2005 TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo Shim, JH Xiao, C Paschal, AE Bailey, ST Rao, P Hayden, MS Lee, KY Bussey, C Steckel, M Tanaka, N Yamada, G Akira, Shizuo Matsumoto, K Ghosh, S Genes Dev 19:2668-81 16186825 Pubmed 2005 Essential function for the kinase TAK1 in innate and adaptive immune responses Sato, S Sanjo, H Takeda, K Ninomiya-Tsuji, J Yamamoto, M Kawai, T Matsumoto, K Takeuchi, O Akira, Shizuo Nat Immunol 6:1087-95 8638164 Pubmed 1996 TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction Shibuya, H Yamaguchi, K Shirakabe, K Tonegawa, A Gotoh, Y Ueno, N Irie, K Nishida, E Matsumoto, K Science 272:1179-82 11323434 Pubmed 2001 An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK Ono, K Ohtomo, T Sato, S Sugamata, Y Suzuki, M Hisamoto, N Ninomiya-Tsuji, J Tsuchiya, M Matsumoto, K J. Biol. Chem. 276:24396-400 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10351416 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10351416 Reactome R-SSC-937042 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-937042.1 Although IRAK-1 was originally thought to be a key mediator of TRAF6 activation in the IL1R/TLR signaling (Dong W et al. 2006), recent studies showed that IRAK-2, but not IRAK-1, led to TRAF6 polyubiquitination (Keating SE et al 2007). IRAK-2 loss-of-function mutants, with mutated TRAF6-binding motifs, could no longer activate NF-kB and could no longer stimulate TRAF-6 ubiquitination (Keating SE et al 2007). Furthermore, the proxyvirus protein A52 - an inhibitor of all IL-1R/TLR pathways to NF-kB activation, was found to interact with both IRAK-2 and TRAF6, but not IRAK-1. Further work showed that A52 inhibits IRAK-2 functions, whereas association with TRAF6 results in A52-induced MAPK activation. The strong inhibition effect of A52 was also observed on the TLR3-NFkB axis and this observation led to the discovery that IRAK-2 is recruited to TLR3 to activate NF-kB (Keating SE et al 2007). Thus, A52 possibly inhibits MyD88-independent TLR3 pathways to NF-kB via targeting IRAK-2 as it does for other IL-1R/TLR pathways, although it remains unclear how IRAK-2 is involved in TLR3 signaling.<p>IRAK-2 was shown to have two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002). 21606490 Pubmed 2011 Human interleukin-1 receptor-associated kinase-2 is essential for Toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alpha Flannery, Sinead M Keating, Sinead E Szymak, Joanna Bowie, Andrew G J. Biol. Chem. 286:23688-97 16831874 Pubmed 2006 The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4 Dong, W Liu, Y Peng, J Chen, L Zou, T Xiao, H Liu, Z Li, W Bu, Y Qi, Y J Biol Chem 281:26029-40 12140561 Pubmed 2002 Distinct molecular mechanism for initiating TRAF6 signalling Ye, H Arron, JR Lamothe, B Cirilli, M Kobayashi, T Shevde, NK Segal, D Dzivenu, OK Vologodskaia, M Yim, M Du, K Singh, S Pike, JW Darnay, BG Choi, Y Wu, H Nature 418:443-7 inferred by electronic annotation IEA GO IEA TRAF6 binds MEKK1 TRAF6 binds MEKK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10261432 1 1 EQUAL 522 EQUAL Reactome DB_ID: 10261428 1 UniProt:A0A287ABQ5 UniProt A0A287ABQ5 2 EQUAL 1512 EQUAL Reactome DB_ID: 10261434 1 MEKK1:activated TRAF6 [cytosol] MEKK1:activated TRAF6 Reactome DB_ID: 10261432 1 1 EQUAL 522 EQUAL Reactome DB_ID: 10261428 1 2 EQUAL 1512 EQUAL Reactome Database ID Release 82 10261434 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261434 Reactome R-SSC-166867 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-166867.1 Reactome Database ID Release 82 10261440 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261440 Reactome R-SSC-166869 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-166869.1 TRAF6 binding to MAPK kinase kinase 1 (MEKK1) is mediated by the adapter protein evolutionarily conserved signaling intermediate in Toll pathway or in short ECSIT (Kopp E et al 1999). Induced MEKK1 can activate both IKK alpha and IKK beta thus leading to induction of NF-kappa-B activation. MEKK1 was also shown to induce ERK1/2 and JNK activation [Yujiri T et al 1998].<p>Although TRAF6 interacts with several upstream mediators (IRAK1, IRAK2, TRIF), there is no data showing MEKK1 participating in the interaction with the TRAF6 activators. Therefore this reaction is simplified to include only TRAF6 and MEKK1. 9008162 Pubmed 1997 Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway Lee, FS Hagler, J Chen, ZJ Maniatis, T Cell 88:213-22 10465784 Pubmed 1999 ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway Kopp, E Medzhitov, R Carothers, J Xiao, C Douglas, I Janeway, CA Ghosh, S Genes Dev 13:2059-71 9836645 Pubmed 1998 Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption Yujiri, T Sather, S Fanger, GR Johnson, GL Science 282:1911-4 9689078 Pubmed 1998 MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta Lee, FS Peters, RT Dang, LC Maniatis, T Proc Natl Acad Sci U S A 95:9319-24 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 82 10261441 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261441 Reactome DB_ID: 10261438 UniProt:F1SA17 ECSIT UniProt F1SA17 49 EQUAL 431 EQUAL TAK1-dependent IKK and NF-kappa-B activation TAK1-dependent IKK and NF-kappa-B activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CHUK, IKBKB and IKBKG form IKK complex CHUK, IKBKB and IKBKG form IKK complex IKBKA, IKBKB and IKBKG form IKK complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10261565 1 1 EQUAL 419 EQUAL Reactome DB_ID: 10266304 1 1 EQUAL 745 EQUAL Reactome DB_ID: 10265461 1 1 EQUAL 756 EQUAL Reactome DB_ID: 10268316 1 Reactome Database ID Release 82 10315329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10315329 Reactome R-SSC-5609665 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5609665.1 The multimeric I kappa B kinase (IKK) complex is a key regulator of NF-kappa-B signaling, which is responsible for the phosphorylation of inhibitor kB (IkB). The phosphorylation by IKK triggers K48-linked ubiquitination of IkB leading to proteasomal degradation of IkB, allowing translocation of NFkB factor to the nucleus, where it can activate transcription of a variety of genes participating in the immune and inflammatory response, cell adhesion, growth control, and protection against apoptosis (Alkalay I et al. 1995; Collins T et al. 1995; Kaltschmidt B et al. 2000; Oeckinghaus A and Ghosh S 2009). The IKK complex is composed of the two catalytic subunits, IKKa (IKBKA, IKK1 or CHUK) and IKKb (IKK2 or IKBKB) kinases, and a regulatory subunit, NF-kappa-B essential modulator (NEMO, IKKg or IKBKG). IKBKG (NEMO) associates with the C-termini of unphosphorylated IKKs and promotes the IKK complex activation (Rothwarf DM et al. 1998). The molecular composition and stoichiometry of the IKK complex remains debatable, although the core IKK complex that range from 700 to 900 kDa is thought to consist of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies (DiDonato JA et al. 1997; May J et al. 2002; Tegethoff S et al. 2003; Marienfeld RB et al. 2006; Rushe M et al. 2008). 20066092 Pubmed 2009 The NF-kappaB family of transcription factors and its regulation Oeckinghaus, Andrea Ghosh, Sankar Cold Spring Harb Perspect Biol 1:a000034 7479848 Pubmed 1995 Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway Alkalay, I Yaron, A Hatzubai, A Orian, A Ciechanover, A Ben-Neriah, Y Proc Natl Acad Sci U S A 92:10599-603 9751060 Pubmed 1998 IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex Rothwarf, D M Zandi, E Natoli, G Karin, M Nature 395:297-300 18462684 Pubmed 2008 Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site Rushe, Mia Silvian, Laura Bixler, Sarah Chen, Ling Ling Cheung, Anne Bowes, Scott Cuervo, Hernan Berkowitz, Steven Zheng, Timothy Guckian, Kevin Pellegrini, Maria Lugovskoy, Alexey Structure 16:798-808 17000764 Pubmed 2006 Dimerization of the I kappa B kinase-binding domain of NEMO is required for tumor necrosis factor alpha-induced NF-kappa B activity Marienfeld, Ralf B Palkowitsch, Lysann Ghosh, Sankar Mol. Cell. Biol. 26:9209-19 inferred by electronic annotation IEA GO IEA 6.3.2.19 Ubiquitination of IKBKG by TRAF6 Ubiquitination of IKBKG by TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10249581 3 Reactome DB_ID: 10261770 1 Reactome DB_ID: 10268318 1 CHUK:p-S177,S181-IKBKB:IKBKG [cytosol] CHUK:p-S177,S181-IKBKB:IKBKG Reactome DB_ID: 10261565 1 1 EQUAL 419 EQUAL Reactome DB_ID: 10261577 1 O-phospho-L-serine at 177 (in Homo sapiens) 177 EQUAL O-phospho-L-serine at 181 (in Homo sapiens) 181 EQUAL 1 EQUAL 756 EQUAL Reactome DB_ID: 10266304 1 1 EQUAL 745 EQUAL Reactome Database ID Release 82 10268318 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10268318 Reactome R-SSC-202513 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-202513.1 Reactome DB_ID: 10261770 1 Reactome DB_ID: 10268351 1 CHUK:p-S177,S181-IKBKB:pUb-IKBKG [cytosol] CHUK:p-S177,S181-IKBKB:pUb-IKBKG Reactome DB_ID: 10268349 1 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 321 (in Homo sapiens) 321 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 325 (in Homo sapiens) 325 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 326 (in Homo sapiens) 326 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at unknown position 1 EQUAL 419 EQUAL Reactome DB_ID: 10261577 1 O-phospho-L-serine at 177 (in Homo sapiens) 177 EQUAL O-phospho-L-serine at 181 (in Homo sapiens) 181 EQUAL 1 EQUAL 756 EQUAL Reactome DB_ID: 10266304 1 1 EQUAL 745 EQUAL Reactome Database ID Release 82 10268351 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10268351 Reactome R-SSC-202562 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-202562.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10349095 K63pUb-TRAF6:TAK1 complexes [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 10349096 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349096 Reactome Database ID Release 82 10349100 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349100 Reactome R-SSC-9758604 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9758604.1 During the phosphorylation of the IKK beta (IKBKB), the regulatory subunit NEMO (IKBKG) undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 acts as a E3 ligase and induces this ubiquitination. Studies of different NF-kappa-B signaling pathways revealed several potential ubiquitination sites on IKBKG (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009). 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 17728323 Pubmed 2007 Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti Sebban-Benin, H Pescatore, A Fusco, F Pascuale, V Gautheron, J Yamaoka, S Moncla, A Ursini, MV Courtois, G Hum Mol Genet 127: inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 10349101 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349101 Reactome DB_ID: 10349098 CHUK:IKBKB:IKBKG:USP18 [cytosol] CHUK:IKBKB:IKBKG:USP18 Reactome DB_ID: 10284961 1 UniProt:A0A287B3S1 USP18 UniProt A0A287B3S1 1 EQUAL 372 EQUAL Reactome DB_ID: 10268316 1 Reactome Database ID Release 82 10349098 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349098 Reactome R-SSC-9761338 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9761338.1 NF-kappa-B inhibitor binds NF-kappa-B complex NF-kappa-B inhibitor binds NF-kappa-B complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10261539 1 NFKB1(1-433), NFKB2(1-454):RELA [cytosol] NFKB1(1-433), NFKB2(1-454):RELA Converted from EntitySet in Reactome Reactome DB_ID: 10261537 1 NFKB1(1-433), NFKB2(1-454) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NFKB1 [cytosol] NFKB2 [cytosol] UniProt A0A287AVR3 UniProt F1S861 Reactome DB_ID: 10261527 1 UniProt:F6PVF4 RELA UniProt F6PVF4 1 EQUAL 551 EQUAL Reactome Database ID Release 82 10261539 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261539 Reactome R-SSC-168155 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168155.1 Converted from EntitySet in Reactome Reactome DB_ID: 10261549 1 NFkB inhibitor [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NFKBIA [cytosol] NFKBIB [cytosol] UniProt Q08353 UniProt I3LLS5 Reactome DB_ID: 10261551 1 NFkB inhibitor:NFkB complex [cytosol] NFkB inhibitor:NFkB complex Reactome DB_ID: 10261539 1 Converted from EntitySet in Reactome Reactome DB_ID: 10261549 1 Reactome Database ID Release 82 10261551 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261551 Reactome R-SSC-168130 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168130.1 Reactome Database ID Release 82 10345664 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10345664 Reactome R-SSC-9630923 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9630923.1 NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called NF-kappa-B inhibitors (IkBs, NFKBIA or NFKBIB). IkBs proteins such as NFKBIA, NFKBIB or NFKBIE are characterized by the presence of six to seven ankyrin repeat motifs, which mediate interaction with the Rel homology domain (RHD). RHD mediates DNA binding, dimerization and nuclear localization (Jacobs MD & Harrison SC 1998; Manavalan B et al. 2010). NF-kappa-B inhibitors (IkBs) mask the nuclear localization signal (NLS) of the NF-kappa-B p65 subunit (ReLA, p65) preventing the nuclear translocation of NF-kappa-B (Jacobs MD & Harrison SC 1998; Cervantes CF et al. 2011). A key event in NF-kappa-B activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta) by the IκB kinase (IKK) complex. The phosphorylated NFKBIA is recognized by the E3 ligase complex leading to K48-linked ubiquitination, and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kappa-B dimer p50/p65 (RelA:NFKB1) into the nucleus to turn on target genes (Karin M & Ben-Neriah Y 2000, Kanarek N & Ben-Neriah Y 2012; Hoffmann A et al. 2006). Crystal structures of NF-kappa-B inhibitors:NF-kappaB complexes revealed that an NF-kappa-B dimer binds to one IkB molecule (Jacobs MD & Harrison SC 1998; Ghosh G et 2012). 22435548 Pubmed 2012 Regulation of NF-κB by ubiquitination and degradation of the IκBs Kanarek, Naama Ben-Neriah, Yinon Immunol. Rev. 246:77-94 9865693 Pubmed 1998 Structure of an IkappaBalpha/NF-kappaB complex Jacobs, M D Harrison, S C Cell 95:749-58 17072323 Pubmed 2006 Transcriptional regulation via the NF-kappaB signaling module Hoffmann, A Natoli, G Ghosh, G Oncogene 25:6706-16 10837071 Pubmed 2000 Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity Karin, M Ben-Neriah, Y Annu. Rev. Immunol. 18:621-63 22435546 Pubmed 2012 NF-κB regulation: lessons from structures Ghosh, Gourisankar Wang, Vivien Ya-Fan Huang, De-Bin Fusco, Amanda Immunol. Rev. 246:36-58 15145317 Pubmed 2004 The two NF-kappaB activation pathways and their role in innate and adaptive immunity Bonizzi, G Karin, M Trends Immunol 25:280-8 21203422 Pubmed 2010 Structure-function relationship of cytoplasmic and nuclear IκB proteins: an in silico analysis Manavalan, Balachandran Basith, Shaherin Choi, Yong-Min Lee, Gwang Choi, Sangdun PLoS ONE 5:e15782 21094161 Pubmed 2011 The RelA nuclear localization signal folds upon binding to IκBα Cervantes, Carla F Bergqvist, Simon Kjaergaard, Magnus Kroon, Gerard Sue, Shih-Che Dyson, H Jane Komives, Elizabeth A J. Mol. Biol. 405:754-64 inferred by electronic annotation IEA GO IEA 2.7.11.1 Active IKBKB phosphorylates NF-kappa-B inhibitor Active IKBKB phosphorylates NF-kappa-B inhibitor This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 4 Reactome DB_ID: 10261551 1 Reactome DB_ID: 10261539 1 Reactome DB_ID: 29370 4 Converted from EntitySet in Reactome Reactome DB_ID: 10261561 1 Phospho-NF-kappaB Inhibitor [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-NFKBIB [cytosol] phospho-NFKBIA [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10268318 GO 0004674 GO molecular function Reactome Database ID Release 82 10349298 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349298 Reactome Database ID Release 82 10349300 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349300 Reactome R-SSC-9773803 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9773803.1 In human, IkBs (NFKBIA, NFKBIB or NFKBIE) are inhibitory proteins that sequesters NF-kappa-B in the cytoplasm by masking a nuclear localization signal, located just at the C-terminal end of the RelA (p65) subunit of the RelA:NFKB1 heterodimer.<p>A key event in NF-kappa-B activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kappa-B signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta (IKKb, IKBKB) in an IKK gamma (IKBKG, NEMO)-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta)). Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kappa-B.<br> 19666475 Pubmed 2009 The nemo binding domains of both IKKalpha and IKKbeta regulate IKK complex assembly and classical NFkappaB activation Solt, LA Madge, LA May, MJ J Biol Chem 10723127 Pubmed 2000 Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex Gil, J Alcami, J Esteban, M Oncogene 19:1369-78 27701768 Pubmed 2017 Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κB Yazdi, Samira Naumann, Michael Stein, Matthias Proteins 85:17-29 12221085 Pubmed 2002 IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program Li, X Massa, PE Hanidu, A Peet, GW Aro, P Savitt, A Mische, S Li, J Marcu, KB J Biol Chem 277:45129-40 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 10261593 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261593 Converted from EntitySet in Reactome Reactome DB_ID: 10261590 NKIRAS [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NKIRAS1 [cytosol] NKIRAS2 [cytosol] UniProt I3L911 UniProt F2Z555 NF-kappa-B complex is transported from cytosol to nucleus NF-kappa-B complex is transported from cytosol to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10261539 1 Reactome DB_ID: 10261634 1 nucleoplasm GO 0005654 NFKB1(1-433), NFKB2(1-454):RELA [nucleoplasm] NFKB1(1-433), NFKB2(1-454):RELA Converted from EntitySet in Reactome Reactome DB_ID: 10261630 1 Nuclear factor NF-kappa-B p50 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NFKB2 [nucleoplasm] NFKB1 [nucleoplasm] Reactome DB_ID: 10261632 1 1 EQUAL 551 EQUAL Reactome Database ID Release 82 10261634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261634 Reactome R-SSC-177673 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-177673.1 Reactome Database ID Release 82 10261682 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261682 Reactome R-SSC-168166 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168166.1 NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NF-kappa-B2). All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefore, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.<br> 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 82 10261683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261683 Reactome DB_ID: 10261680 AGER ligands:AGER [plasma membrane] AGER ligands:AGER Reactome DB_ID: 10261638 1 UniProt:F6PXJ4 AGER UniProt F6PXJ4 23 EQUAL 404 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10261678 1 AGER ligands [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity APP [extracellular region] APP(672-711) [extracellular region] APP [extracellular region] APP(672-713) [extracellular region] HMGB1 [extracellular region] UniProt A0A288CFW8 UniProt P79307 UniProt A0A287BEI7 Reactome Database ID Release 82 10261680 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261680 Reactome R-SSC-879365 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-879365.1 Regulation of NF-kappa B signaling Regulation of NF-kappa B signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LRRC14 binds IKBKB and CHUK LRRC14 binds IKBKB and CHUK LRRC14 binds IKBKB and IKBKA This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10266304 1 1 EQUAL 745 EQUAL Reactome DB_ID: 10265461 1 1 EQUAL 756 EQUAL Reactome DB_ID: 10348840 1 UniProt:A0A286ZQY7 LRRC14 UniProt A0A286ZQY7 1 EQUAL 493 EQUAL Reactome DB_ID: 10348842 1 CHUK:IKBKB:LRRC14 [cytosol] CHUK:IKBKB:LRRC14 Reactome DB_ID: 10266304 1 1 EQUAL 745 EQUAL Reactome DB_ID: 10265461 1 1 EQUAL 756 EQUAL Reactome DB_ID: 10348840 1 1 EQUAL 493 EQUAL Reactome Database ID Release 82 10348842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348842 Reactome R-SSC-9749467 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9749467.1 Reactome Database ID Release 82 10348844 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348844 Reactome R-SSC-9749505 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9749505.1 GO 0043124 GO biological process Leucine-rich repeat-containing protein 14 (LRRC14) binds to the helix-loop-helix (HLH) domain of IKBKB (Wu C et al. 2016). This binding blocks IKBKB interaction with IKBKG (NEMO) disrupting IκB kinase (IKK) complex formation and NF-kappa-B activation (Wu C et al. 2016). 27426725 Pubmed 2016 LRRC14 attenuates Toll-like receptor-mediated NF-κB signaling through disruption of IKK complex Wu, Chenglei Yang, Yexin Ou, Jiayu Zhu, Liang Zhao, W Cui, Jun Exp Cell Res 347:65-73 inferred by electronic annotation IEA GO IEA NLRC5 binds IKBKB and CHUK NLRC5 binds IKBKB and CHUK NLRC5 binds IKBKB and IKBKA This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10348873 1 UniProt:A0A286ZS94 NLRC5 UniProt A0A286ZS94 1 EQUAL 1866 EQUAL Reactome DB_ID: 10266304 1 1 EQUAL 745 EQUAL Reactome DB_ID: 10265461 1 1 EQUAL 756 EQUAL Reactome DB_ID: 10348875 1 endoplasmic reticulum membrane GO 0005789 CHUK:IKBKB:NLRC5 [endoplasmic reticulum membrane] CHUK:IKBKB:NLRC5 Reactome DB_ID: 10348873 1 1 EQUAL 1866 EQUAL Reactome DB_ID: 10266304 1 1 EQUAL 745 EQUAL Reactome DB_ID: 10265461 1 1 EQUAL 756 EQUAL Reactome Database ID Release 82 10348875 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348875 Reactome R-SSC-9750228 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9750228.1 Reactome Database ID Release 82 10348880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348880 Reactome R-SSC-9750226 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9750226.1 The I-kappa-B-kinase (IKK) complex, a key regulator of the nuclear factor kappa B (NF-kB) signaling pathway, consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). The IKK complex is responsible for the phosphorylation of inhibitors of NF-kB (IkBs), such as NFKBIA or NFKBIB. Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing the transcription factor NF-kB thereby allowing translocation of NF-kB to the nucleus to regulate gene expression (Oeckinghaus A and Ghosh S 2009). NOD-like receptor C5 (NLRC5), the transcriptional activator of genes coding for MHC-I, has been implicated in the regulation of inflammatory pathways and IFN-dependent antiviral defense (Benko S et al. 2010; Cui J et al. 2010). Overexpression of NLRC5 inhibited NFkB-luciferase reporter activity in human embryonic kidney 293T (HEK293T) cells treated with interleukin (IL)-1β, TNF-α or toll-like receptor (TLR) agonists such as bacterial LPS (TLR4 ligand) or R848 (TLR7/8 ligand) (Cui J et al. 2010). Similar findings were obtained with human monocytic THP-1 cells and murine embryonic fibroblasts (MEFs) (Cui J et al. 2010). Further, NLRC5 deficiency resulted in enhanced phosphorylation of IKBKB, CHUK, and increased expression of NF-kB-responsive cytokines (such as TNF-α and IL-6), in LPS-stimulated THP-1 and mouse macrophage RAW264.7 cells (Cui J et al. 2010). NLRC5 deficiency enhanced NF‐kB activation in mouse cells in response to TLR3, TLR4, TLR7, TLR9 ligands (Tong Y et al. 2012) and TLR2 ligand (Wang M et al. 2019). Knockdown of NLRC5 also enhanced cytokine response and antiviral immunity in vesicular stomatitis virus (VSV)-treated primary human monocytes, primary murine macrophages and RAW264.7 cells. Studies with NLRC5-deficient mice confirmed the regulatory role of NLRC5 in the induction of NF-kB and type I interferon in response to LPS or VSV infection (Tong Y et al. 2012). Moreover, NLRC5 co-immunoprecipitated with IKBKA (CHUK) and IKBKB subunits, but not with IKBKG, upon co-expression of tagged proteins in HEK293T cells (Cui J et al. 2010). Mutagenesis analysis revealed that human NLRC5 targets the amino-terminal kinase domain (KD) of IKBKB. Fractionation of RAW264.7 cells extracts on a size-exclusion column followed by immunoblotting analysis showed that both CHUK:IKBKB:IKBKG and CHUK:IKBKB:NLRC5 complexes co-exist in unstimulated cells suggesting that NLRC5 inhibits the interaction between IKBKG (NEMO) and IKBKB/CHUK (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK upon stimulation is regulated by TRAF2/TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). These data suggest that NLRC5 negatively regulates NF-kappa-B activation via targeting IKBKB and CHUK. 20610642 Pubmed 2010 NLRC5 limits the activation of inflammatory pathways Benko, Szilvia Magalhaes, Joao G Philpott, Dana J Girardin, Stephen E J Immunol 185:1681-91 22473004 Pubmed 2012 Enhanced TLR-induced NF-κB signaling and type I interferon responses in NLRC5 deficient mice Tong, Yanzheng Cui, Jun Li, Qingtian Zou, Jia Wang, Helen Y Wang, Rong-Fu Cell Res 22:822-35 26620909 Pubmed 2015 Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch Meng, Qingcai Cai, Chunmei Sun, Tingzhe Wang, Qianliang Xie, Weihong Wang, Rongfu Cui, Jun J Cell Biol 211:1025-40 20434986 Pubmed 2010 NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways Cui, J Zhu, Lijun Xia, X Wang, HY Legras, X Hong, J Ji, J Shen, P Zheng, S Chen, ZJ Wang, RF Cell 141:483-96 30945291 Pubmed 2019 NLRC5 negatively regulates LTA-induced inflammation via TLR2/NF-κB and participates in TLR2-mediated allergic airway inflammation Wang, Muzi Wang, Lixia Fang, Lei Li, Shuai Liu, Rongyu J Cell Physiol 234:19990-20001 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 82 10348882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348882 Reactome DB_ID: 10321288 UniProt:I3L945 USP14 UniProt I3L945 1 EQUAL 494 EQUAL INHIBITION Reactome Database ID Release 82 10348881 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348881 Reactome DB_ID: 10348878 ubiquitinylated lysine (K63polyUb [cytosol]) at 1178 (in Homo sapiens) 1178 EQUAL 87 EQUAL 975 EQUAL 6.3.2.19 TRAF2,6 ubiquitinates NLRC5 TRAF2,6 ubiquitinates NLRC5 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10249581 3 Reactome DB_ID: 10348875 1 Reactome DB_ID: 10348878 1 ubiquitinylated lysine (K63polyUb [cytosol]) at 1178 (in Homo sapiens) 1178 EQUAL 87 EQUAL 975 EQUAL Reactome DB_ID: 10266304 1 1 EQUAL 745 EQUAL Reactome DB_ID: 10265461 1 1 EQUAL 756 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10336571 TRAF2, TRAF6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TRAF2 [cytosol] TRAF6 [cytosol] UniProt F1RVZ4 Reactome Database ID Release 82 10348907 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348907 Reactome Database ID Release 82 10348909 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348909 Reactome R-SSC-9750946 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9750946.1 NOD-like receptor C5 (NLRC5) functions as negative regulator of the NF-kappa B signaling pathway by targeting the I-kappa-B-kinase (IKK) complex (Cui J et al. 2010). The IKK complex consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). NLRC5 directly binds to CHUK and IKBKB inhibiting their phosphorylation and interaction with IKBKG (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK is regulated by TRAF2 or TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). Active TRAF2/6 catalyzed K63-linked polyubiquitination of NLRC5 at K1178 in human and mouse cells in response to LPS stimulation. The ubiquitinated NLRC5 (K63-polyUb-NLRC5) blocked NLRC5 interaction with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. The TRAF2/TRAF6-mediated ubiquitination of NLRC5 was reversely regulated by USP14 (Meng Q et al. 2015). inferred by electronic annotation IEA GO IEA USP14 deubiquitinates NLRC5 USP14 deubiquitinates NLRC5 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10348878 1 ubiquitinylated lysine (K63polyUb [cytosol]) at 1178 (in Homo sapiens) 1178 EQUAL 87 EQUAL 975 EQUAL Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Converted from EntitySet in Reactome Reactome DB_ID: 10249581 3 Reactome DB_ID: 10348873 1 1 EQUAL 1866 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10321288 1 EQUAL 494 EQUAL GO 0061578 GO molecular function Reactome Database ID Release 82 10348904 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348904 Reactome Database ID Release 82 10348906 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10348906 Reactome R-SSC-9750942 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9750942.1 NLRC5 functions as negative regulator of the NF-kappa B signaling pathway by targeting the I-kappa-B-kinase (IKK) complex (Cui J et al. 2010). The IKK complex consists of two catalytic subunits, IKBKA (KKα or CHUK) and IKBKB (IKKβ), associated with a regulatory subunit IKBKG (NEMO). NLRC5 directly binds to CHUK and IKBKB inhibiting their phosphorylation and interaction with IKBKG (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK is regulated by TRAF2 or TRAF6-dependent K63-linked polyubiquitination of NLRC5 at K1178 (Meng Q et al. 2015). The ubiquitinated NLRC5 (K63-polyUb-NLRC5) showed lower ability to interact with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. Ubiquitin-specific protease 14 (USP14) was found to remove the polyUb chains from NLRC5 and thereby enhanced the NLRC5-mediated inhibition of NF-kB signaling (Meng Q et al. 2015). inferred by electronic annotation IEA GO IEA USP18 binds IKBKG within IKK complex USP18 binds IKBKG within IKK complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10284961 1 1 EQUAL 372 EQUAL Reactome DB_ID: 10268316 1 Reactome DB_ID: 10349098 1 Reactome Database ID Release 82 10349212 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349212 Reactome R-SSC-9761344 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9761344.1 Expression of ubiquitin-specific protease 18 (USP18) is induced by various Toll-like receptor (TLR) ligands in human monocytes and macrophages (Yang Z et al. 2015). A nuclear factor kappa B (NF-kappa-B, NF-κB) luciferase reporter gene assay showed that expression of tagged USP18 negatively regulates TLR-mediated activation of NF-kappa B in human embryonic kidney HEK293T cells. USP18 also inhibited the degradation of endogenous IκBα protein in HEK293T cells (Yang Z et al. 2015). Further, knockdown of USP18 by USP18-specific small interfering RNAs (siRNA) enhanced NF-kappaB activity in LPS- stimulated human monocyte-like THP-1 cells (Yang Z et al. 2015). Co-immunoprecipitation and immunoblot analysis revealed that USP18 targets the regulatory subunit IKBKG (NEMO) of the IKK (CHUK:IKBKB:IKBKG) complex upon co-expression of tagged proteins in HEK293T cells. Mutagenesis analysis using HEK293T cells showed that USP18 directly binds to the UBAN motif of IKBKG inhibiting K63-linked ubiquitination of IKBKG by masking the ubiquitination sites at K325 and K326 (Yang Z et al. 2015). In addition, USP18 targets the TAK1-TAB1 complex and cleaves the K63-linked polyubiquitin chains of TAK1 in a protease-dependent manner (Liu X et al. 2013; Yang Z et al. 2015). These data suggest that USP18 functions as a negative regulator of NF-kappa-B activation.<p>This Reactome events shows USP18 binding to IKBKG within the IKK (CHUK:IKBKB:IKBKG) complex. 23825189 Pubmed 2013 USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex Liu, Xikui Li, Hongxiu Zhong, Bo Blonska, Marzenna Gorjestani, Sara Yan, Ming Tian, Qiang Zhang, Dong-Er Lin, Xin Dong, Chen J. Exp. Med. 210:1575-90 26240016 Pubmed 2015 USP18 negatively regulates NF-κB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms Yang, Zhifen Xian, Huifang Hu, Jiajia Tian, Shuo Qin, Yunfei Wang, Rong-Fu Cui, Jun Sci Rep 5:12738 inferred by electronic annotation IEA GO IEA N4BP1 binds IKBKG N4BP1 binds IKBKG This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10261565 1 1 EQUAL 419 EQUAL Reactome DB_ID: 10349075 1 UniProt:F1REY3 N4BP1 UniProt F1REY3 1 EQUAL 896 EQUAL Reactome DB_ID: 10349084 1 IKBKG:N4BP1 [cytosol] IKBKG:N4BP1 Reactome DB_ID: 10261565 1 1 EQUAL 419 EQUAL Reactome DB_ID: 10349075 1 1 EQUAL 896 EQUAL Reactome Database ID Release 82 10349084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349084 Reactome R-SSC-9757950 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9757950.1 Reactome Database ID Release 82 10349086 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349086 Reactome R-SSC-9757954 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9757954.1 NEDD4-binding protein 1 (N4BP1) negatively regulates Toll-like receptor (TLR)-induced activation of NF-kappaB and cytokine production in human and mouse cells (Shi H et al. 2021; Gitlin AD et al. 2020). N4BP1 was found to target IKBKG (NEMO, IKKg), the regulatory subunit of the IkB kinase (IKK) complex, which is essential for NF-kappa-B activation. N4BP1 co-immunoprecipitated with IKBKG (NEMO) upon co-expression of tagged proteins in human embryonic kidney 293T (HEK293T) cells (Shi H et al. 2021). The interaction between endogenous N4BP1 and IKBKG was also detected in mouse peritoneal macrophages (Shi H et al. 2021). Linear and K63-linked polyubiquitin chains promoted the interaction between N4BP1 and IKBKG. Binding of N4BP1 to IKBKG is thought to block homooligomerization of IKBKG thereby leading to destabilization of the IKK complex (Shi H et al. 2021). In addition, N4BP1 deficiency in mice and mouse cells increased the production of select NF-kappa-B-dependent cytokines via TICAM1 (TRIF)-independent TLR2, TLR7 or TLR9 signaling pathways, but not upon engagement of TLR3 or TLR4 which utilize the adaptor protein TICAM1 (Shi H et al. 2021; Gitlin AD et al. 2020). Similar results were observed in human monocytic THP-1 cells (Shi H et al. 2021). Further, TLR3- or TRL4-induced TICAM1-dependent activation of caspase-8 (CASP8) was found to inactivate N4BP1 via the proteolytic cleavage thus promoting NF-kappa-B activation (Gitlin AD et al. 2020; Shi H et al. 2021). Downregulation of N4BP1 was not observed in TICAM-1-deficient mouse macrophages treated with LPS (Shi H et al. 2021). These data suggest that N4BP1 limits TICAM1-independent TLR-induced NF-kappa-B activation by blocking the function of the IKK complex, while TICAM1-dependent TLR signaling leads to CASP8-mediated inactivation of N4BP1(Shi H et al. 2021; Gitlin AD et al. 2020). 32971525 Pubmed 2020 Integration of innate immune signalling by caspase-8 cleavage of N4BP1 Gitlin, Alexander D Heger, Klaus Schubert, Alexander F Reja, Rohit Yan, Donghong Pham, Victoria C Suto, Eric Zhang, Juan Kwon, Youngsu C Freund, Emily C Kang, Jing Pham, Anna Caothien, Roger Bacarro, Natasha Hinkle, Trent Xu, Min McKenzie, Brent S Haley, Benjamin Lee, Wyne P Lill, Jennie R Roose-Girma, Merone Dohse, Monika Webster, Joshua D Newton, Kim Dixit, Vishva M Nature 587:275-280 33654074 Pubmed 2021 N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization Shi, Hexin Sun, Lei Wang, Ying Liu, Aijie Zhan, Xiaoming Li, Xiaohong Tang, Miao Anderton, Priscilla Hildebrand, Sara Quan, Jiexia Ludwig, Sara Moresco, Eva Marie Y Beutler, B Nat Commun 12:1379 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 10349087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349087 Reactome DB_ID: 10257988 active caspase-8 [cytosol] active caspase-8 Reactome DB_ID: 10257986 2 Caspase-8 dimer [cytosol] Caspase-8 dimer Reactome DB_ID: 10257982 1 UniProt:Q56VC3 CASP8 UniProt Q56VC3 217 EQUAL 374 EQUAL Reactome DB_ID: 10257984 1 385 EQUAL 479 EQUAL Reactome Database ID Release 82 10257986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10257986 Reactome R-SSC-139950 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-139950.1 Reactome Database ID Release 82 10257988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10257988 Reactome R-SSC-2562550 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2562550.1 3.4 CASP8 cleaves N4BP1 at D424, D490 CASP8 cleaves N4BP1 at D424, D490 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10349075 2 1 EQUAL 896 EQUAL Reactome DB_ID: 10349077 1 1 EQUAL 424 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10257988 GO 0008234 GO molecular function Reactome Database ID Release 82 10349080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349080 Reactome Database ID Release 82 10349082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10349082 Reactome R-SSC-9757951 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9757951.1 GO 0043122 GO biological process NEDD4-binding protein 1 (N4BP1) limits the activation of NF-kappaB downstream of TICAM1 (TRIF)-independent Toll-like receptor 2 (TLR2), TLR7 or TLR9 signaling pathways, but not upon engagement of TLR3 or TLR4 which utilize the adaptor protein TICAM1 (Shi H et al. 2021; Gitlin AD et al. 2020). TLR3- or TRL4-induced TICAM1-dependent activation of caspase-8 (CASP8) was found to inactivate N4BP1 via the proteolytic cleavage thus promoting NF-kappa-B activation (Gitlin AD et al. 2020; Shi H et al. 2021). Functional studies of N4BP1 mutants expressed in human embryonic kidney 293T (HEK293T) cells suggest that human N4BP1 is cleaved after D424 and/or D490 (Shi H et al. 2021). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10352666 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10352666 Reactome R-SSC-9758274 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-9758274.1 Nuclear factor kappa B (NF-kappa-B, NF-κB) is activated by a diverse range of stimuli including cytokines, ligands of pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) in myeloid cells, antigen-activated TCR in T-cells and by DNA damage (reviewed in Yu H et al. 2020; Zhang T et al. 2021). NF-kappa-B regulates the transcription of genes that are involved in immune and inflammatory responses, cell cycle, cell proliferation and apoptosis (Bhatt D & Ghosh S 2014; Liu T et al. 2017; Yu H et al. 2020). In unstimulated cells, NF-κB is sequestered in the cytosol through interactions with a class of inhibitor proteins, called NF-κB inhibitors (IkBs, such as NFKBIA or NFKBIB) (Jacobs MD & Harrison SC 1998). IkBs mask the nuclear localization signal (NLS) of NF-κB preventing its nuclear translocation (Cervantes CF et al. 2011). A key event in NF-κB activation involves phosphorylation of IkBs by the IκB kinase (IKK) complex which consists of CHUK, IKBKB and IKBKG subunits (Israël A 2010). The activated NF-κB signaling is tightly controlled at multiple levels (Dorrington MG & Fraser IDC 2019; Prescott JA et al. 2021). Dysregulated NF-κB activity can cause tissue damage associated with inflammatory diseases and is also linked to tumorigenesis (Aggarwal BB & Sung B 2011; Liu T et al.2017; Barnabei L et al. 2021). The regulation of NF-κB is cell-type-, context- , and stimulus-dependent and is crucial for orchestrating specific cellular responses (Mussbacher M et al. 2019).<p>This Reactome module describes several molecular mechanisms that regulate TLR-mediated NF-κB signaling at the level of the IKK signaling complex. <br><br> 34977871 Pubmed 2021 NF-κB signaling in inflammation and cancer Zhang, Tao Ma, Chao Zhang, Zhiqiang Zhang, Huiyuan Hu, Hongbo MedComm (2020) 2:618-653 24611065 Pubmed 2014 Regulation of the NF-κB-Mediated Transcription of Inflammatory Genes Bhatt, Dev Ghosh, Sankar Front Immunol 5:71 22586649 Pubmed 2011 NF-κB in cancer: a matter of life and death Aggarwal, Bharat B Sung, Bokyung Cancer Discov 1:469-71 34269817 Pubmed 2021 Inhibitory feedback control of NF-κB signalling in health and disease Prescott, Jack A Mitchell, Jennifer P Cook, Simon J Biochem J 478:2619-2664 32958760 Pubmed 2020 Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study Yu, Hui Lin, Liangbin Zhang, Zhiqiang Zhang, Huiyuan Hu, Hongbo Signal Transduct Target Ther 5:209 31024544 Pubmed 2019 NF-κB Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration Dorrington, Michael G Fraser, Iain D C Front Immunol 10:705 29158945 Pubmed 2017 NF-κB signaling in inflammation Liu, Ting Zhang, Lingyun Joo, Donghyun Sun, Shao-Cong Signal Transduct Target Ther 2: 34434197 Pubmed 2021 NF-κB: At the Borders of Autoimmunity and Inflammation Barnabei, Laura Laplantine, Emmanuel Mbongo, William Rieux-Laucat, Frederic Weil, Robert Front Immunol 12:716469 30778349 Pubmed 2019 Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis Mussbacher, Marion Salzmann, Manuel Brostjan, Christine Hoesel, Bastian Schoergenhofer, Christian Datler, Hannes Hohensinner, Philipp Basílio, José Petzelbauer, Peter Assinger, Alice Schmid, Johannes A Front Immunol 10:85 20300203 Pubmed 2010 The IKK complex, a central regulator of NF-kappaB activation Israel, A Cold Spring Harb Perspect Biol 2:a000158 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350294 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350294 Reactome R-SSC-445989 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-445989.1 GO 0051092 GO biological process NF-kappa-B is sequestered in the cytoplasm in a complex with inhibitor of NF-kappa-B (IkB). Almost all NF-kappa-B activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappa-B from the complex. This allows translocation of NF-kappa-B to the nucleus where it regulates gene expression. 15837794 Pubmed 2005 Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes Thiefes, A Wolter, S Mushinski, JF Hoffmann, E Dittrich-Breiholz, O Graue, N Dörrie, A Schneider, H Wirth, D Luckow, B Resch, K Kracht, M J Biol Chem 280:27728-41 11460167 Pubmed 2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK Wang, C Deng, L Hong, M Akkaraju, GR Inoue, J Chen, ZJ Nature 412:346-51 inferred by electronic annotation IEA GO IEA MAP kinase activation MAP kinase activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.11.1 Activated TAK1 phosphorylates MKK4/MKK7 Activated TAK1 phosphorylates MKK4/MKK7 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Converted from EntitySet in Reactome Reactome DB_ID: 10282027 1 MAP2K7,MAP2K4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAP2K4 [cytosol] MAP2K7 [cytosol] UniProt A0A5G2QZR5 UniProt F1SA79 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 10261621 1 p-MAP2K4/p-MAP2K7 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S257,T261-MAP2K4 [cytosol] phospho-MAP2K7 [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10282046 Activated TAK complexes [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 10282047 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282047 Reactome Database ID Release 82 10282049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282049 Reactome R-SSC-450337 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450337.1 In human, phosphorylation of MKK4 (MAP2K4) and MKK7 (MAP2K7) by TAK1 occurs at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.<p>Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 and Ser257, Thr261 in MKK4.<p>Cell lines lacking MKK4 exhibit defective activation of JNK and AP-1 dependent transcription activity in response to some cellular stresses; JNK and p38 MAPK activities were decreased by around 80% and 20%, respectively, following deletion of the mkk4 gene. 8533096 Pubmed 1995 Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction Yamaguchi, K Shirakabe, K Shibuya, H Irie, K Oishi, I Ueno, N Taniguchi, T Nishida, E Matsumoto, K Science 270:2008-11 17875933 Pubmed 2007 Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death Wang, X Nadarajah, B Robinson, AC McColl, BW Jin, JW Dajas-Bailador, F Boot-Handford, RP Tournier, C Mol Cell Biol 27:7935-46 inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation of human JNKs by activated MKK4/MKK7 Phosphorylation of human JNKs by activated MKK4/MKK7 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Converted from EntitySet in Reactome Reactome DB_ID: 10261599 1 MAPK8,9,10 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAPK8 [cytosol] MAPK10 [cytosol] MAPK9 [cytosol] UniProt F1SEL1 UniProt K7GP94 UniProt A0A5G2QEQ3 Converted from EntitySet in Reactome Reactome DB_ID: 10261607 1 p-MAPK8,9,10 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-MAPK8 [cytosol] phospho-MAPK10 [cytosol] phospho-MAPK9 [cytosol] Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10261621 GO 0008545 GO molecular function Reactome Database ID Release 82 10261622 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261622 Reactome Database ID Release 82 10261624 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261624 Reactome R-SSC-168162 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168162.1 Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. <p>JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183). 13130464 Pubmed 2003 Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK Sundarrajan, M Boyle, DL Chabaud-Riou, M Hammaker, D Firestein, GS Arthritis Rheum 48:2450-60 11062067 Pubmed 2000 Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7 Fleming, Y Armstrong, CG Morrice, N Paterson, A Goedert, M Cohen, P Biochem J 352:145-54 9162092 Pubmed 1997 Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. Deacon, K Blank, JL J Biol Chem 272:14489-96 18713996 Pubmed 2008 Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases Yoshizawa, T Hammaker, D Sweeney, SE Boyle, DL Firestein, GS J Immunol 181:3252-8 inferred by electronic annotation IEA GO IEA Activated human JNKs migrate to nucleoplasm Activated human JNKs migrate to nucleoplasm This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10261607 1 Converted from EntitySet in Reactome Reactome DB_ID: 10261516 1 p-MAPK8,9,10 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-MAPK10 [nucleoplasm] phospho-MAPK9 [nucleoplasm] phospho-MAPK8 [nucleoplasm] Reactome Database ID Release 82 10282059 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282059 Reactome R-SSC-450348 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450348.1 c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors. 9195981 Pubmed 1997 A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion. Mizukami, Y Yoshioka, K Morimoto, S Yoshida, K J Biol Chem 272:16657-62 12193592 Pubmed 2002 Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low density lipoprotein receptor-related protein (LRP) Lutz, C Nimpf, J Jenny, M Boecklinger, K Enzinger, C Utermann, G Baier-Bitterlich, G Baier, G J Biol Chem 277:43143-51 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350288 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350288 Reactome R-SSC-450321 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450321.1 GO 0007254 GO biological process C-Jun NH2 terminal kinases (JNKs) are an evolutionarily conserved family of serine/threonine protein kinases, that belong to mitogen activated protein kinase family (MAPKs - also known as stress-activated protein kinases, SAPKs). The JNK pathway is activated by heat shock, or inflammatory cytokines, or UV radiation. <p>The JNKs are encoded by at least three genes: JNK1/SAPK-gamma, JNK2/SAPK-alpha and JNK3/ SAPK-beta. The first two are ubiquitously expressed, whereas the JNK3 protein is found mainly in brain and to a lesser extent in heart and testes. As a result of alternative gene splicing all cells express distinct active forms of JNK from 46 to 55 kDa in size. Sequence alignment of these different products shows homologies of >80%. In spite of this similarity, the multiple JNK isoforms differ in their ability to bind and phosphorylate different target proteins, thus leading to the distinctive cellular processes: induction of apoptosis, or enhancment of cell survival, or proliferation.<p>Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7). 9851932 Pubmed 1998 Defective T cell differentiation in the absence of Jnk1 Dong, C Yang, DD Wysk, M Whitmarsh, AJ Davis, RJ Flavell, RA Science 282:2092-5 26988982 Pubmed 2016 IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells Li, Jing-kun Nie, Lin Zhao, Yun-peng Zhang, Yuan-qiang Wang, Xiaoqing Wang, Shuai-shuai Liu, Yi Zhao, Hua Cheng, Lei J Transl Med 14:77 16937364 Pubmed 2006 The isoform-specific functions of the c-Jun N-terminal Kinases (JNKs): differences revealed by gene targeting Bogoyevitch, MA Bioessays 28:923-34 8177321 Pubmed 1994 The stress-activated protein kinase subfamily of c-Jun kinases Kyriakis, JM Banerjee, P Nikolakaki, E Dai, T Rubie, EA Ahmad, MF Avruch, Joseph Woodgett, JR Nature 369:156-60 inferred by electronic annotation IEA GO IEA activated TAK1 mediates p38 MAPK activation activated TAK1 mediates p38 MAPK activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.11.1 activated human TAK1 phosphorylates MKK3/MKK6 activated human TAK1 phosphorylates MKK3/MKK6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Converted from EntitySet in Reactome Reactome DB_ID: 10282055 1 MAP2K3,MAP2K6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAP2K6 [cytosol] MAP2K3 [cytosol] UniProt F1RV28 UniProt A0A286ZTK8 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 10281998 1 p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S207,T211-MAP2K6 [cytosol] phospho-p-S189,T193-MAP2K3 [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10282046 Reactome Database ID Release 82 10282057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282057 Reactome R-SSC-450346 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450346.1 Human MKK3 (MAP2K4) and MKK6 (MAP2K6) are two closely related dual-specificity protein kinases. Both are activated by cellular stress and inflammatory cytokines, and both phosphorylate and activate p38 MAP kinase at its activation site Thr-Gly-Tyr but do not phosphorylate or activate Erk1/2 or SAPK/JNK.<p> Activation of MKK3 and MKK6 occurs through phosphorylation of serine and threonine residues at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loop. Residues involved into these protein kinases activation correspond to human sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6 . 8622669 Pubmed 1996 MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway Raingeaud, J Whitmarsh, AJ Barrett, T Derijard, B Davis, RJ Mol Cell Biol 16:1247-55 inferred by electronic annotation IEA GO IEA Phosphorylated MKK3/MKK6 migrates to nucleus Phosphorylated MKK3/MKK6 migrates to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10281998 1 Converted from EntitySet in Reactome Reactome DB_ID: 10282004 1 p-S189,T193-MAP2K3, p-S207,T211-MAP2K6 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S207,T211-MAP2K6 [nucleoplasm] phospho-p-S189,T193-MAP2K3 [nucleoplasm] Reactome Database ID Release 82 10282006 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282006 Reactome R-SSC-450296 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450296.1 The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. 9768359 Pubmed 1998 Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2 Ben-Levy, R Hooper, S Wilson, R Paterson, HF Marshall, CJ Curr Biol 8:1049-57 7535770 Pubmed 1995 Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine Raingeaud, J Gupta, S Rogers, JS Dickens, M Han, J Ulevitch, RJ Davis, RJ J Biol Chem 270:7420-6 inferred by electronic annotation IEA GO IEA 2.7.12.2 Activated human MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 Activated human MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10282018 1 p38 MAPK:MAPKAPK2,3 [nucleoplasm] p38 MAPK:MAPKAPK2,3 Converted from EntitySet in Reactome Reactome DB_ID: 10282016 1 MAP kinase p38 alpha/beta [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAPK14 [nucleoplasm] MAPK11 [nucleoplasm] UniProt A0A5G2QSG6 UniProt A0A286ZJZ3 Converted from EntitySet in Reactome Reactome DB_ID: 10281959 1 MAPKAP2,3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAPKAPK3 [nucleoplasm] MAPKAPK2 [nucleoplasm] UniProt B8XSJ7 UniProt F1SEZ4 Reactome Database ID Release 82 10282018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282018 Reactome R-SSC-450269 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450269.1 Reactome DB_ID: 29358 2 Reactome DB_ID: 113582 2 Reactome DB_ID: 10281961 1 p-p38 MAPK: MAPKAPK2,3 [nucleoplasm] p-p38 MAPK: MAPKAPK2,3 Converted from EntitySet in Reactome Reactome DB_ID: 10281959 1 Converted from EntitySet in Reactome Reactome DB_ID: 10261498 1 p-p38 MAPK alpha/beta [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T180,Y182-MAPK11 [nucleoplasm] phospho-p-T180,Y182-MAPK14 [nucleoplasm] Reactome Database ID Release 82 10281961 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281961 Reactome R-SSC-450213 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450213.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10282004 GO 0004708 GO molecular function Reactome Database ID Release 82 10282019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282019 Reactome Database ID Release 82 10282021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282021 Reactome R-SSC-450333 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450333.1 The MAPK level components of this cascade are p38MAPK-alpha, -beta, -gamma and -sigma. All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops. inferred by electronic annotation IEA GO IEA 2.7.11.1 Active p38 MAPK phosphorylates MAPKAPK2 or 3 Active p38 MAPK phosphorylates MAPKAPK2 or 3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10281961 1 Reactome DB_ID: 29358 3 Reactome DB_ID: 113582 3 Reactome DB_ID: 10281969 1 p-p38 MAPK:p-MAPKAPK2/3 [nucleoplasm] p-p38 MAPK:p-MAPKAPK2/3 Converted from EntitySet in Reactome Reactome DB_ID: 10261498 1 Converted from EntitySet in Reactome Reactome DB_ID: 10281967 1 Active MAPKAP kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S,2T-MAPKAPK3 [nucleoplasm] phospho-p-T222,S272,T334-MAPKAPK2 [nucleoplasm] Reactome Database ID Release 82 10281969 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281969 Reactome R-SSC-450254 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450254.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10281961 Reactome Database ID Release 82 10281970 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281970 Reactome Database ID Release 82 10281972 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281972 Reactome R-SSC-450222 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450222.1 Human p38 MAPK alpha forms a complex with MK2 even when the signaling pathway is not activated. This heterodimer is found mainly in the nucleus. The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined. The C-terminal regulatory domain of MK2 binds in the docking groove of p38 MAPK alpha, and the ATP-binding sites of both kinases are at the heterodimer interface (ter Haar et al. 2007).<p>Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334 (Ben-Levy et al. 1995). <p>The phosphorylation of MK2 at Thr-334 attenuates the affinity of the binary complex MK2:p38 alpha by an order of magnitude and leads to a large conformational change of an autoinhibitory domain in MK2. This conformational change unmasks not only the MK2 substrate-binding site but also the MK2 nuclear export signal (NES) thus leading to the MK2:p38 alpha translocation from the nucleus to the cytoplasm. Cytoplasmic active MK2 then phosphorylates downstream targets such as the heat-shock protein HSP27 and tristetraprolin (TTP) (Meng et al. 2002, Lukas et al. 2004, White et al. 2007).<p>MAPKAPK (MAPK-activated protein) kinase 3 (MK3, also known as 3pK) has been identified as the second p38 MAPK-activated kinase that is stimulated by different stresses (McLaughlin et al. 1996; Sithanandam et al. 1996; reviewed in Gaestel 2006). MK3 shows 75% sequence identity to MK2 and, like MK2, is activated by p38 MAPK alpha and p38 MAPK beta. MK3 phosphorylates peptide substrates with kinetic constants similar to MK2 and phosphorylates the same serine residues in HSP27 at the same relative rates as MK2 (Clifton et al. 1996) indicating an identical phosphorylation-site consensus sequence. Hence, it is assumed that its substrate spectrum is either identical to or at least overlapping with MK2. 8626550 Pubmed 1996 Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase McLaughlin, M M Kumar, S McDonnell, P C Van Horn, S Lee, J C Livi, G P Young, P R J. Biol. Chem. 271:8488-92 12171911 Pubmed 2002 Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export Meng, W Swenson, LL Fitzgibbon, MJ Hayakawa, K Ter Haar, E Behrens, AE Fulghum, JR Lippke, JA J Biol Chem 277:37401-5 17255097 Pubmed 2007 Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer Ter Haar, E Prabhakar, P Liu, X Lepre, C J Biol Chem 282:9733-9 8622688 Pubmed 1996 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region Sithanandam, G Latif, F Duh, F M Bernal, R Smola, U Li, H Kuzmin, I Wixler, V Geil, L Shrestha, S Mol. Cell. Biol. 16:868-76 8846784 Pubmed 1995 Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2 Ben-Levy, R Leighton, IA Doza, YN Attwood, P Morrice, N Marshall, CJ Cohen, P EMBO J 14:5920-30 15287722 Pubmed 2004 Catalysis and function of the p38 alpha.MK2a signaling complex Lukas, SM Kroe, RR Wildeson, J Peet, GW Frego, L Davidson, W Ingraham, RH Pargellis, CA Labadia, ME Werneburg, BG Biochemistry 43:9950-60 17395714 Pubmed 2007 Molecular basis of MAPK-activated protein kinase 2:p38 assembly White, A Pargellis, CA Studts, JM Werneburg, BG Farmer BT, 2nd Proc Natl Acad Sci U S A 104:6353-8 8774846 Pubmed 1996 A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress Clifton, A D Young, P R Cohen, P FEBS Lett. 392:209-14 inferred by electronic annotation IEA GO IEA Nuclear export of human p38 MAPK mediated by its substrate MAPKAPK2 or 3 Nuclear export of human p38 MAPK mediated by its substrate MAPKAPK2 or 3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10281969 1 Reactome DB_ID: 10281974 1 p-p38 MAPK: p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 [cytosol] p-p38 MAPK: p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 10264231 1 p-p38 MAPK alpha/beta [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-T180,Y182-MAPK11 [cytosol] phospho-p-T180,Y182-MAPK14 [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 10264225 1 p-S272,T222,T334-MAPKAPK2, p-S,2T-MAPKAPK3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S272,T222,T334-MAPKAPK2 [cytosol] phospho-p-S,2T-MAPKAPK3 [cytosol] Reactome Database ID Release 82 10281974 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281974 Reactome R-SSC-450241 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450241.1 Reactome Database ID Release 82 10281976 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10281976 Reactome R-SSC-450257 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450257.1 p38 MAPK alpha does not have a nuclear export signal (NES) and cannot leave the nucleus by itself, but rather needs to be associated with MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2). The NES of MAPKAPK2 facilitates the transport of both kinases from the nucleus to the cytoplasm but only after MK2 has been phosphorylated by p38alpha.<p>p38 MAPK alpha phosphorylates MK2 at Thr222, Ser272, and Thr334. The phosphorylation of Thr334 but not the kinase activity of MK2 has been demonstrated to be critical for the nuclear export of the p38 alpha - MK2 complex. Phosphorylation of Thr334 is believed to induce a conformational change in the complex exposing NES prior to interaction with the leptomycin B-sensitive nuclear export receptor. inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10351270 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10351270 Reactome R-SSC-450302 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450302.1 GO 0038066 GO biological process p38 mitogen-activated protein kinase (MAPK) belongs to a highly conserved family of serine/threonine protein kinases. <p>The p38 MAPK-dependent signaling cascade is activated by pro-inflammatory or stressful stimuli such as ultraviolet radiation, oxidative injury, heat shock, cytokines, and other pro-inflammatory stimuli. p38 MAPK exists as four isoforms (alpha, beta, gamma, and delta). Of these, p38alpha and p38beta are ubiquitously expressed while p38gamma and p38delta are differentially expressed depending on tissue type. Each isoform is activated by upstream kinases including MAP kinase kinases (MKK) 3, 4, and 6, which in turn are phosphorylated by activated TAK1 at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.<p>Once p38 MAPK is phosphorylated it activates numerous downstream substrates, including MAPK-activated protein kinase-2 and 3 (MAPKAPK-2 or 3) and mitogen and stress-activated kinase-1/2 (MSK1/2). MAPKAPK-2/3 and MSK1/2 function to phosphorylate heat shock protein 27 (HSP27) and cAMP-response element binding protein transcriptional factor, respectively. Other transcription factors, including activating transcription factor 2, Elk, CHOP/GADD153, and myocyte enhancer factor 2, are known to be regulated by these kinases. 10878576 Pubmed 2000 p38 MAPK signalling cascades: ancient roles and new functions Martin-Blanco, E Bioessays 22:637-45 inferred by electronic annotation IEA GO IEA MAP3K8 (TPL2)-dependent MAPK1/3 activation MAP3K8 (TPL2)-dependent MAPK1/3 activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NFKB p105, TPL2 (COT) and ABIN2 form a stable complex NFKB p105, TPL2 (COT) and ABIN2 form a stable complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10276235 1 UniProt:K7GKL4 MAP3K8 UniProt K7GKL4 1 EQUAL 467 EQUAL Reactome DB_ID: 10282457 1 UniProt:F1S8Q0 TNIP2 UniProt F1S8Q0 1 EQUAL 429 EQUAL Reactome DB_ID: 10282453 1 UniProt:A0A287AVR3 NFKB1 1 EQUAL 968 EQUAL Reactome DB_ID: 10282459 1 NFKB1:MAP3K8:TNIP2 [cytosol] NFKB1:MAP3K8:TNIP2 Reactome DB_ID: 10276235 1 1 EQUAL 467 EQUAL Reactome DB_ID: 10282457 1 1 EQUAL 429 EQUAL Reactome DB_ID: 10282453 1 1 EQUAL 968 EQUAL Reactome Database ID Release 82 10282459 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282459 Reactome R-SSC-451638 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-451638.1 Reactome Database ID Release 82 10282471 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282471 Reactome R-SSC-451634 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-451634.1 The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with MAP3K8 (TPL2) via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho & Tsichlis 2005). <br><br>A20-binding inhibitor of NFkappaB2 (ABIN-2 ot TNIP2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.<br> 12667451 Pubmed 2003 NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase Waterfield, MR Zhang, M Norman, LP Sun, SC Mol Cell 11:685-94 15699325 Pubmed 2005 Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide Cho, J Tsichlis, PN Proc Natl Acad Sci U S A 102:2350-5 12832462 Pubmed 2003 NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity Beinke, S Deka, J Lang, V Belich, MP Walker, PA Howell, S Smerdon, SJ Gamblin, SJ Ley, SC Mol Cell Biol 23:4739-52 15169888 Pubmed 2004 ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability Lang, V Symons, A Watton, SJ Janzen, J Soneji, Y Beinke, S Howell, S Ley, SC Mol Cell Biol 24:5235-48 9950430 Pubmed 1999 TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105 Belich, MP Salmeron, A Johnston, LH Ley, SC Nature 397:363-8 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 10282472 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282472 Reactome DB_ID: 10282464 O-phospho-L-serine at 927 (in Homo sapiens) 927 EQUAL O-phospho-L-serine at 932 (in Homo sapiens) 932 EQUAL ubiquitinylated lysine (K48polyUb [cytosol]) at unknown position ubiquitinylated lysine (K48polyUb [cytosol]) at unknown position ubiquitinylated lysine (K48polyUb [cytosol]) at unknown position 1 EQUAL 968 EQUAL INHIBITION Reactome Database ID Release 82 10282473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282473 Reactome DB_ID: 10282469 3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 [cytosol] 3xUb, 2xp-S-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 Reactome DB_ID: 10282464 1 O-phospho-L-serine at 927 (in Homo sapiens) 927 EQUAL O-phospho-L-serine at 932 (in Homo sapiens) 932 EQUAL ubiquitinylated lysine (K48polyUb [cytosol]) at unknown position ubiquitinylated lysine (K48polyUb [cytosol]) at unknown position ubiquitinylated lysine (K48polyUb [cytosol]) at unknown position 1 EQUAL 968 EQUAL Reactome DB_ID: 10282457 1 1 EQUAL 429 EQUAL Reactome DB_ID: 10282467 1 O-phospho-L-threonine at 290 (in Homo sapiens) 290 EQUAL O-phospho-L-serine at 400 (in Homo sapiens) 400 EQUAL 1 EQUAL 467 EQUAL Reactome Database ID Release 82 10282469 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282469 Reactome R-SSC-5684242 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5684242.1 2.7.11.10 IKBKB phosphorylates TPL2 (MAP3K8) at Ser400 IKBKB phosphorylates TPL2 (MAP3K8) at Ser400 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 10282459 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 10320363 1 NFKB1:p-S400-MAP3K8:TNIP2 [cytosol] NFKB1:p-S400-MAP3K8:TNIP2 Reactome DB_ID: 10282457 1 1 EQUAL 429 EQUAL Reactome DB_ID: 10276238 1 O-phospho-L-serine at 400 (in Homo sapiens) 400 EQUAL 1 EQUAL 467 EQUAL Reactome DB_ID: 10282453 1 1 EQUAL 968 EQUAL Reactome Database ID Release 82 10320363 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10320363 Reactome R-SSC-5687880 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5687880.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10268318 GO 0008384 GO molecular function Reactome Database ID Release 82 10320357 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10320357 Reactome Database ID Release 82 10320365 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10320365 Reactome R-SSC-5684275 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5684275.1 The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation. MAP3K8 undergoes phosphorylated on S400 in its C-terminal tail to activate MAP2Ks (MEK1/2) following LPS stimulation of macrophages. Different experimental systems have suggested that S400 is either autophosphosphorylated by MAPK3P8 (IL-1?-stimulated IL-1R-293T cells) or transphosphorylated by an unknown kinase (LPS-stimulated RAW264.7 macrophages). 19754427 Pubmed 2009 IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2 Handoyo, Hosea Stafford, Margaret J McManus, Eamon Baltzis, Dionissios Peggie, Mark Cohen, P Biochem. J. 424:109-18 16806191 Pubmed 2006 Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62 Stafford, Margaret J Morrice, Nick A Peggie, Mark W Cohen, P FEBS Lett. 580:4010-4 22988300 Pubmed 2012 I?B kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400 Roget, Karine Ben-Addi, Abduelhakem Mambole-Dema, Agnes Gantke, Thorsten Yang, Huei-Ting Janzen, Julia Morrice, N Abbott, Derek W Ley, Steven C Mol. Cell. Biol. 32:4684-90 inferred by electronic annotation IEA GO IEA MAP3K8 is phosphorylated MAP3K8 is phosphorylated TPL2 (MAP3K8) is phosphorylated at T290 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 10282459 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 10320352 1 NFKB1:p-T290-MAP3K8:TNIP2 [cytosol] NFKB1:p-T290-MAP3K8:TNIP2 Reactome DB_ID: 10282457 1 1 EQUAL 429 EQUAL Reactome DB_ID: 10282467 1 O-phospho-L-threonine at 290 (in Homo sapiens) 290 EQUAL O-phospho-L-serine at 400 (in Homo sapiens) 400 EQUAL 1 EQUAL 467 EQUAL Reactome DB_ID: 10282453 1 1 EQUAL 968 EQUAL Reactome Database ID Release 82 10320352 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10320352 Reactome R-SSC-5684265 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5684265.1 Reactome Database ID Release 82 10320354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10320354 Reactome R-SSC-5684261 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5684261.1 The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation (Gantke T 2011).<p>The catalytic subunit of MAP3K8 (TPL2) was reported to undergo phosphorylation at Thr290 in human embryonic kidney 293 (HEK293) cells transfected with MAP3K8 (Luciano BS et al. 2004; Cho J et al. 2005; Stafford MJ et al. 2006). Mutation of this residue to alanine prevented the LPS-stimulated activation of MAP3K8 in mouse macrophages (Cho J et al. 2005). Experiments with a small-molecule inhibitor of MAP3K8 have suggested that Thr290 is autophosphosphorylated after IL-1 beta stimulation of IL-1R-expressing HEK293T cells (Handoyo H et al. 2009). However, a catalytically inactive mutant of MAP3K8 (Tpl2-K167M) was reported to become phosphorylated at Thr290 in transfected HEK-293 cells, suggesting that Thr290 phosphorylation did not occur as a result of autophosphorylation (Cho J et al. 2005) In addition, the phosphorylation at Thr290 was also reported to be catalysed by IKBKB, based on small interfering RNA(siRNA)-knockdown studies and the use of high concentrations of the IKBKB inhibitor PS1145 (Cho J et al. 2005). However, the other work showed that lower concentrations of PS1145, but nevertheless sufficient to completely inhibit IKBKB, did not affect the IL-1-stimulated phosphorylation of transfected MAP3K8 at Thr290, suggesting that the IL-1 beta stimulated phosphorylation of Thr290 is catalysed by a protein kinase distinct from IKBKB. (Stafford MJ et al. 2006). Thus, phosphorylation at Thr290 is required for the physiological activation of MAP3K8 by external signals, although the mode of the modification remains to be clarified.<p> Activation of MAP3K8 may also occur trough phosphorylation on Ser62 and Ser400 (Stafford MJ et al. 2006; Roget K et al. 2012). 21135874 Pubmed 2011 Regulation and function of TPL-2, an I?B kinase-regulated MAP kinase kinase kinase Gantke, Thorsten Sriskantharajah, Srividya Ley, Steven C Cell Res. 21:131-45 15466476 Pubmed 2004 Phosphorylation of threonine 290 in the activation loop of Tpl2/Cot is necessary but not sufficient for kinase activity Luciano, Brenda S Hsu, Sang Channavajhala, Padma L Lin, Lih-Ling Cuozzo, John W J. Biol. Chem. 279:52117-23 15778223 Pubmed 2005 Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Ikappa-B Kinase-beta-dependent pathway and is required for Tpl2 activation by external signals Cho, Jeonghee Melnick, Michael Solidakis, Georgios P Tsichlis, Philip N J. Biol. Chem. 280:20442-8 inferred by electronic annotation IEA GO IEA 2.7.11.10 IKBKB phosphorylates NFkB p105 within the NFkB p105:TPL2:ABIN2 complex IKBKB phosphorylates NFkB p105 within the NFkB p105:TPL2:ABIN2 complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 10282459 1 Reactome DB_ID: 29370 2 Reactome DB_ID: 10320356 1 p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2 [cytosol] p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2 Reactome DB_ID: 10276235 1 1 EQUAL 467 EQUAL Reactome DB_ID: 10282457 1 1 EQUAL 429 EQUAL Reactome DB_ID: 10320346 1 O-phospho-L-serine at 927 (in Homo sapiens) 927 EQUAL O-phospho-L-serine at 932 (in Homo sapiens) 932 EQUAL 1 EQUAL 968 EQUAL Reactome Database ID Release 82 10320356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10320356 Reactome R-SSC-5687885 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5687885.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10268318 Reactome Database ID Release 82 10320359 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10320359 Reactome R-SSC-5684267 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5684267.1 NFkappaB p105 protein (p105) is a precursor of the NFkappaB p50 subunit and an inhibitor of NFkappaB. The IkappaB kinase (IKK) complex phosphorylates p105 on S927 within the PEST region. TNF-alpha-induced p105 proteolysis additionally requires the phosphorylation of S932. Purified IKK (IKK1) or IKKB (IKK2) can phosphorylate both these regulatory serines in vitro. 12482991 Pubmed 2003 betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932 Lang, V Janzen, J Fischer, GZ Soneji, Y Beinke, S Salmeron, A Allen, H Hay, RT Ben-Neriah, Y Ley, SC Mol Cell Biol 23:402-13 inferred by electronic annotation IEA GO IEA 3xUb,p-S-NFkB p105:TPL2:ABIN2 dissociates due to degradation of p105 3xUb,p-S-NFkB p105:TPL2:ABIN2 dissociates due to degradation of p105 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10282469 1 Converted from EntitySet in Reactome Reactome DB_ID: 10249581 9 Reactome DB_ID: 10282457 1 1 EQUAL 429 EQUAL Reactome DB_ID: 10282467 1 O-phospho-L-threonine at 290 (in Homo sapiens) 290 EQUAL O-phospho-L-serine at 400 (in Homo sapiens) 400 EQUAL 1 EQUAL 467 EQUAL Reactome Database ID Release 82 10320361 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10320361 Reactome R-SSC-5684273 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5684273.1 IKBKB-induced proteolysis of NFkB p105 to p50 releases MAP3K8 (TPL2) from the complex with NFkB p105 and ABIN2. On TLR or IL1beta stimulation, dissociated MAP3K8 with an adequate phosphorylation state activates MAP2K (MKK1/2) and consequently MAPK1/3 (ERK1/2). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10351296 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10351296 Reactome R-SSC-5684264 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5684264.1 Tumor progression locus-2 (TPL2, also known as COT and MAP3K8) functions as a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) in various stress-responsive signaling cascades. MAP3K8 (TPL2) mediates phosphorylation of MAP2Ks (MEK1/2) which in turn phosphorylate MAPK (ERK1/2) (Gantke T et al., 2011).<p>In the absence of extra-cellular signals, cytosolic MAP3K8 (TPL2) is held inactive in the complex with ABIN2 (TNIP2) and NFkB p105 (NFKB1) (Beinke S et al., 2003; Waterfield MR et al., 2003; Lang V et al., 2004). This interaction stabilizes MAP3K8 (TPL2) but also prevents MAP3K8 and NFkB from activating their downstream signaling cascades by inhibiting the kinase activity of MAP3K8 and the proteolysis of NFkB precursor protein p105. Upon activation of MAP3K8 by various stimuli (such as LPS, TNF-alpha, and IL-1 beta), IKBKB phosphorylates NFkB p105 (NFKB1) at Ser927 and Ser932, which trigger p105 proteasomal degradation and releases MAP3K8 from the complex (Beinke S et al., 2003, 2004; Roget K et al., 2012). Simultaneously, MAP3K8 is activated by auto- and/or transphosphorylation (Gantke T et al. 2011; Yang HT et al. 2012). The released active MAP3K8 phosphorylates its substrates, MAP2Ks. The free MAP3K8, however, is also unstable and is targeted for proteasome-mediated degradation, thus restricting prolonged activation of MAP3K8 (TPL2) and its downstream signaling pathways (Waterfield MR et al. 2003; Cho J et al., 2005). Furthermore, partially degraded NFkB p105 (NFKB1) into p50 can dimerize with other NFkB family members to regulate the transcription of target genes.<p>MAP3K8 activity is thought to regulate the dynamics of transcription factors that control an expression of diverse genes involved in growth, differentiation, and inflammation. Suppressing the MAP3K8 kinase activity with selective inhibitors, such as C8-chloronaphthyridine-3-carbonitrile, caused a significant reduction in TNFalpha production in LPS- and IL-1beta-induced both primary human monocytes and human blood (Hall JP et al. 2007). Similar results have been reported for mouse LPS-stimulated RAW264.7 cells (Hirata K et al. 2010). Moreover, LPS-stimulated macrophages derived from Map3k8 knockout mice secreted lower levels of pro-inflammatory cytokines such as TNFalpha, Cox2, Pge2 and CXCL1 (Dumitru CD et al. 2000; Eliopoulos AG et al. 2002). Additionally, bone marrow-derived dendritic cells (BMDCs) and macrophages from Map3k8 knockout mice showed significantly lower expression of IL-1beta in response to LPS, poly IC and LPS/MDP (Mielke et al., 2009). However, several other studies seem to contradict these findings and Map3k8 deficiency in mice has been also reported to enhance pro-inflammatory profiles. Map3k8 deficiency in LPS-stimulated macrophages was associated with an increase in nitric oxide synthase 2 (NOS2) expression (López-Peláez et al., 2011). Similarly, expression of IRAK-M, whose function is to compete with IL-1R-associated kinase (IRAK) family of kinases, was decreased in Map3k8-/- macrophages while levels of TNF and IL6 were elevated (Zacharioudaki et al., 2009). Moreover, significantly higher inflammation level was observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Map3k8-/- mouse skin compared to WT skin (DeCicco-Skinner K. et al., 2011). Additionally, MAP3K8 activity is associated with NFkB inflammatory pathway. High levels of active p65 NFkB were observed in the nucleus of Map3k8 -/- mouse keratinocytes that dramatically increased within 15-30 minutes of TPA treatment. Similarly, increased p65 NFkB was observed in Map3k8-deficient BMDC both basally and after stimulation with LPS when compared to wild type controls (Mielke et al., 2009). The data opposes the findings that Map3k8-deficient mouse embryo fibroblasts and human Jurkat T cells with kinase domain-deficient protein have a reduction in NFkB activation but only when certain stimuli are administered (Lin et al., 1999; Das S et al., 2005). Thus, it is possible that whether MAP3K8 serves more of a pro-inflammatory or anti-inflammatory role may depend on cell- or tissue type and on stimuli (LPS vs. TPA, etc.) (Mielke et al., 2009; DeCicco-Skinner K. et al., 2012).<p>MAP3K8 has been also studied in the context of carcinogenesis, however the physiological role of MAP3K8 in the etiology of human cancers is also convoluted (Vougioukalaki M et al., 2011; DeCicco-Skinner K. et al., 2012). 12234923 Pubmed 2002 Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals Eliopoulos, Aristides G Dumitru, Calin D Wang, Chun-Chi Cho, Jeonghee Tsichlis, Philip N EMBO J. 21:4831-40 19414798 Pubmed 2009 Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expression Zacharioudaki, Vassiliki Androulidaki, Ariadne Arranz, Alicia Vrentzos, George Margioris, Andrew N Tsatsanis, Christos J. Immunol. 182:6444-51 10072079 Pubmed 1999 The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases Lin, X Cunningham, E T Mu, Y Geleziunas, R Greene, W C Immunity 10:271-80 22733995 Pubmed 2012 Coordinate regulation of TPL-2 and NF-?B signaling in macrophages by NF-?B1 p105 Yang, Huei-Ting Papoutsopoulou, Stamatia Belich, Monica Brender, Christine Janzen, Julia Gantke, Thorsten Handley, Matt Ley, Steven C Mol. Cell. Biol. 32:3438-51 978-953-51-0633-3 ISBN 2012 The Role of Tpl2 Protein Kinase in Carcinogenesis and Inflammation DeCicco-Skinner, Kathleen L. Deshpande, Monika Wiest, Jonathan Advances in Protein Kinases (Book) 21377269 Pubmed 2011 Tpl2 kinase signal transduction in inflammation and cancer Vougioukalaki, Maria Kanellis, Dimitris C Gkouskou, Kalliopi Eliopoulos, Aristides G Cancer Lett. 304:80-9 11163183 Pubmed 2000 TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway Dumitru, C D Ceci, J D Tsatsanis, C Kontoyiannis, D Stamatakis, K Lin, J H Patriotis, C Jenkins, N A Copeland, N G Kollias, G Tsichlis, P N Cell 103:1071-83 21469113 Pubmed 2011 Cot/tpl2 activity is required for TLR-induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression López-Peláez, Marta Soria-Castro, Irene Boscá, Lisardo Fernández, Margarita Alemany, Susana Eur. J. Immunol. 41:1733-41 15485931 Pubmed 2004 Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105 Beinke, S Robinson, M J Hugunin, M Ley, S C Mol. Cell. Biol. 24:9658-67 19933865 Pubmed 2009 Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 beta production Mielke, Lisa A Elkins, Karen L Wei, Lai Starr, Robyn Tsichlis, Philip N O'Shea, John J Watford, Wendy T J. Immunol. 183:7984-93 20606319 Pubmed 2010 Inhibition of tumor progression locus 2 protein kinase decreases lipopolysaccharide-induced tumor necrosis factor alpha production due to the inhibition of the tip-associated protein induction in RAW264.7 cells Hirata, Kazuya Miyashiro, Masahiko Ogawa, Hirofumi Taki, Hirofumi Tobe, Kazuyuki Sugita, Takahisa Biol. Pharm. Bull. 33:1233-7 17848581 Pubmed 2007 Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood Hall, J Perry Kurdi, Yahya Hsu, Sang Cuozzo, John Liu, Julie Telliez, Jean-Baptiste Seidl, Katherine J Winkler, Aaron Hu, Yonghan Green, Neal Askew, G Roger Tam, Steve Clark, James D Lin, Lih-Ling J. Biol. Chem. 282:33295-304 inferred by electronic annotation IEA GO IEA MAPK targets/ Nuclear events mediated by MAP kinases MAPK targets/ Nuclear events mediated by MAP kinases This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ERK/MAPK targets ERK/MAPK targets This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.11.1 ERK1/2 phosphorylates MSK1 ERK1/2 phosphorylates MSK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10266324 1 UniProt:I3LQZ5 UniProt I3LQZ5 1 EQUAL 802 EQUAL Reactome DB_ID: 29358 4 Reactome DB_ID: 113582 4 Reactome DB_ID: 10266330 1 O-phospho-L-serine at 376 (in Homo sapiens) 376 EQUAL O-phospho-L-threonine at 581 (in Homo sapiens) 581 EQUAL O-phospho-L-serine at 360 (in Homo sapiens) 360 EQUAL O-phospho-L-serine at 212 (in Homo sapiens) 212 EQUAL 1 EQUAL 802 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10266394 p-T,Y MAPK dimers [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 10266395 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10266395 Reactome Database ID Release 82 10266397 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10266397 Reactome R-SSC-198756 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-198756.1 MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues. 9687510 Pubmed 1998 Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB Deak, M Clifton, AD Lucocq, LM Alessi, DR EMBO J 17:4426-41 inferred by electronic annotation IEA GO IEA 2.7.11.1 p38MAPK phosphorylates MSK1 p38MAPK phosphorylates MSK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10266324 1 1 EQUAL 802 EQUAL Reactome DB_ID: 29358 4 Reactome DB_ID: 113582 4 Reactome DB_ID: 10266330 1 O-phospho-L-serine at 376 (in Homo sapiens) 376 EQUAL O-phospho-L-threonine at 581 (in Homo sapiens) 581 EQUAL O-phospho-L-serine at 360 (in Homo sapiens) 360 EQUAL O-phospho-L-serine at 212 (in Homo sapiens) 212 EQUAL 1 EQUAL 802 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10261498 Reactome Database ID Release 82 10266331 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10266331 Reactome Database ID Release 82 10266333 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10266333 Reactome R-SSC-198669 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-198669.1 MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by p38MAPK through phosphorylation at four key residues.<br> inferred by electronic annotation IEA GO IEA 2.7.11.1 ERK1/2/5 activate RSK1/2/3 ERK1/2/5 activate RSK1/2/3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29358 6 Converted from EntitySet in Reactome Reactome DB_ID: 10266357 1 Ribosomal protein S6 kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RPS6KA1 [nucleoplasm] RPS6KA2 [nucleoplasm] RPS6KA3 [nucleoplasm] UniProt A0A287AJ05 UniProt A0A286ZUB4 UniProt A0A5G2R6S3 Converted from EntitySet in Reactome Reactome DB_ID: 10266383 1 Phospho-Ribosomal protein S6 kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-4S,T356,T570-RPS6KA2 [nucleoplasm] phospho-p-4S,T359,T573-RPS6KA1 [nucleoplasm] phospho-p-4S,T231,T365-RPS6KA3 [nucleoplasm] Reactome DB_ID: 113582 6 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10266389 p-MAPK3/MAPK1/MAPK7 dimers [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 10266390 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10266390 Reactome Database ID Release 82 10266392 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10266392 Reactome R-SSC-198746 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-198746.1 The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK.<br>RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398.<br>Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2. <br> 12832467 Pubmed 2003 Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity Roux, PP Richards, SA Blenis, J Mol Cell Biol 23:4796-804 16626623 Pubmed 2006 The MAP kinase ERK5 binds to and phosphorylates p90 RSK Ranganathan, A Pearson, GW Chrestensen, CA Sturgill, TW Cobb, MH Arch Biochem Biophys 449:8-16 inferred by electronic annotation IEA GO IEA 3.1.3.16 ERKs are inactivated by protein phosphatase 2A ERKs are inactivated by protein phosphatase 2A This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10266389 1 Reactome DB_ID: 113518 1 Converted from EntitySet in Reactome Reactome DB_ID: 10267080 1 MAPK3/MAPK1/MAPK7 dimers [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 113550 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10267084 PP2A-ABdeltaC complex [nucleoplasm] PP2A-ABdeltaC complex Converted from EntitySet in Reactome Reactome DB_ID: 10257402 1 PP2A-subunit A [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10267082 1 UniProt:A0A287BGB1 PPP2R5D UniProt A0A287BGB1 1 EQUAL 602 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10257392 1 PP2A-catalytic subunit C [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 10267084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267084 Reactome R-SSC-165970 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-165970.1 GO 0004722 GO molecular function Reactome Database ID Release 82 10267085 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267085 Reactome Database ID Release 82 10267087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267087 Reactome R-SSC-199959 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-199959.1 ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK.<br>Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown. 16456541 Pubmed 2006 B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK Letourneux, C Rocher, G Porteu, F EMBO J 25:727-38 inferred by electronic annotation IEA GO IEA ERKs are inactivated ERKs are inactivated This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 3.1.3.48 ERKs are inactivated by dual-specific phosphatases (DUSPs) ERKs are inactivated by dual-specific phosphatases (DUSPs) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10266389 1 Reactome DB_ID: 113518 1 Converted from EntitySet in Reactome Reactome DB_ID: 10267080 1 Reactome DB_ID: 113550 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10268761 ERK-specific DUSP [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity DUSP4 [nucleoplasm] DUSP6 [nucleoplasm] DUSP3 [nucleoplasm] UniProt A0A286ZK12 UniProt A0A287AJD2 UniProt A0A480UG54 GO 0004725 GO molecular function Reactome Database ID Release 82 10268762 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10268762 Reactome Database ID Release 82 10268770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10268770 Reactome R-SSC-203797 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-203797.1 Over 10 dual specificity phosphatases (DUSPs) active on MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity. 17322878 Pubmed 2007 A module of negative feedback regulators defines growth factor signaling Amit, I Citri, A Shay, T Lu, Y Katz, M Zhang, F Tarcic, G Siwak, D Lahad, J Jacob-Hirsch, J Amariglio, N Vaisman, N Segal, E Rechavi, G Alon, U Mills, GB Domany, E Yarden, Y Nat Genet 39:503-12 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 82 10268771 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10268771 Reactome DB_ID: 10268768 VRK3:DUSP3 [nucleoplasm] VRK3:DUSP3 Reactome DB_ID: 10268766 1 UniProt:F1RH55 VRK3 UniProt F1RH55 1 EQUAL 474 EQUAL Reactome DB_ID: 10268751 1 UniProt:A0A480UG54 DUSP3 1 EQUAL 185 EQUAL Reactome Database ID Release 82 10268768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10268768 Reactome R-SSC-8942511 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8942511.1 Reactome Database ID Release 82 10350678 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350678 Reactome R-SSC-202670 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-202670.1 MAP Kinases are inactivated by a family of protein named MAP Kinase Phosphatases (MKPs). They act through dephosphorylation of threonine and/or tyrosine residues within the signature sequence -pTXpY- located in the activation loop of MAP kinases (pT=phosphothreonine and pY=phosphotyrosine). MKPs are divided into three major categories depending on their preference for dephosphorylating; tyrosine, serine/threonine and both the tyrosine and threonine (dual specificity phoshatases or DUSPs). The tyrosine-specific MKPs include PTP-SL, STEP and HePTP, serine/threonine-specific MKPs are PP2A and PP2C, and many DUSPs acting on MAPKs are known. Activated MAP kinases trigger activation of transcription of MKP genes. Therefore, MKPs provide a negative feedback regulatory mechanism on MAPK signaling, by inactivating MAPKs via dephosphorylation, in the cytoplasm and the nucleus. Some MKPs are more specific for ERKs, others for JNK or p38MAPK. 15115656 Pubmed 2004 Structure and regulation of MAPK phosphatases Farooq, A Zhou, MM Cell Signal 16:769-79 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350640 Reactome R-SSC-198753 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-198753.1 ERK/MAPK kinases have a number of targets within the nucleus, usually transcription factors or other kinases. The best known targets, ELK1, ETS1, ATF2, MITF, MAPKAPK2, MSK1, RSK1/2/3 and MEF2 are annotated here. inferred by electronic annotation IEA GO IEA CREB phosphorylation CREB phosphorylation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.11.1 MSK1 activates CREB MSK1 activates CREB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10266891 1 UniProt:A0A286ZWB0 CREB1 UniProt A0A286ZWB0 1 EQUAL 341 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 10266894 1 O-phospho-L-serine at 133 (in Homo sapiens) 133 EQUAL 1 EQUAL 341 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10266330 O-phospho-L-serine at 376 (in Homo sapiens) 376 EQUAL O-phospho-L-threonine at 581 (in Homo sapiens) 581 EQUAL O-phospho-L-serine at 360 (in Homo sapiens) 360 EQUAL O-phospho-L-serine at 212 (in Homo sapiens) 212 EQUAL 1 EQUAL 802 EQUAL Reactome Database ID Release 82 10267057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267057 Reactome Database ID Release 82 10267066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267066 Reactome R-SSC-199935 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-199935.1 MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB). inferred by electronic annotation IEA GO IEA 2.7.11.1 MSK1 activates ATF1 MSK1 activates ATF1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10267053 1 UniProt:F1SHC5 ATF1 UniProt F1SHC5 1 EQUAL 271 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 10267056 1 O-phospho-L-serine at 63 (in Homo sapiens) 63 EQUAL 1 EQUAL 271 EQUAL Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10266330 O-phospho-L-serine at 376 (in Homo sapiens) 376 EQUAL O-phospho-L-threonine at 581 (in Homo sapiens) 581 EQUAL O-phospho-L-serine at 360 (in Homo sapiens) 360 EQUAL O-phospho-L-serine at 212 (in Homo sapiens) 212 EQUAL 1 EQUAL 802 EQUAL Reactome Database ID Release 82 10267059 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267059 Reactome R-SSC-199910 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-199910.1 Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it. 12414794 Pubmed 2002 ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expression Gupta, Pankaj Prywes, Ron J. Biol. Chem. 277:50550-6 inferred by electronic annotation IEA GO IEA 2.7.11.1 RSK1/2/3 phosphorylates CREB at Serine 133 RSK1/2/3 phosphorylates CREB at Serine 133 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10266891 1 1 EQUAL 341 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 10266894 1 O-phospho-L-serine at 133 (in Homo sapiens) 133 EQUAL 1 EQUAL 341 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10266383 Reactome Database ID Release 82 10267047 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267047 Reactome Database ID Release 82 10267049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267049 Reactome R-SSC-199895 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-199895.1 CREB is phosphorylated at Serine 133 by RSK1/2/3. 9770464 Pubmed 1998 Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene De Cesare, D Jacquot, S Hanauer, A Sassone-Corsi, P Proc Natl Acad Sci U S A 95:12202-7 inferred by electronic annotation IEA GO IEA 2.7.11.1 MAPKAPK2 phosphorylates CREB at Serine 133 MAPKAPK2 phosphorylates CREB at Serine 133 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10266891 1 1 EQUAL 341 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 10266894 1 O-phospho-L-serine at 133 (in Homo sapiens) 133 EQUAL 1 EQUAL 341 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10267061 UniProt:F1SEZ4 O-phospho-L-threonine at 222 (in Homo sapiens) 222 EQUAL O-phospho-L-serine at 272 (in Homo sapiens) 272 EQUAL 1 EQUAL 400 EQUAL Reactome Database ID Release 82 10267062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267062 Reactome Database ID Release 82 10267064 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10267064 Reactome R-SSC-199917 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-199917.1 p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3. 7551568 Pubmed 1995 Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals Bonni, A Ginty, D D Dudek, H Greenberg, M E Mol. Cell. Neurosci. 6:168-83 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350676 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350676 Reactome R-SSC-199920 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-199920.1 Nerve growth factor (NGF) activates multiple signalling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133. CREB phosphorylation at serine 133 is a crucial event in neurotrophin signalling, being mediated by ERK/RSK, ERK/MSK1 and p38/MAPKAPK2 pathways. Several kinases, such as MSK1, RSK1/2/3 (MAPKAPK1A/B/C), and MAPKAPK2, are able to directly phosphorylate CREB at S133. MSK1 is also able to activate ATF (Cyclic-AMP-dependent transcription factor). However, the NGF-induced CREB phosphorylation appears to correlate better with activation of MSK1 rather than RSK1/2/3, or MAPKAPK2. In retrograde signalling, activation of CREB occurs within 20 minutes after neurotrophin stimulation of distal axons. inferred by electronic annotation IEA GO IEA Activation of the AP-1 family of transcription factors Activation of the AP-1 family of transcription factors This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.11.1 Phosphorylated MAPKs phosphorylate ATF-2 Phosphorylated MAPKs phosphorylate ATF-2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29358 2 Reactome DB_ID: 10261480 1 UniProt:A0A480K1R6 ATF2 UniProt A0A480K1R6 1 EQUAL 505 EQUAL Reactome DB_ID: 113582 2 Reactome DB_ID: 10261484 1 O-phospho-L-threonine at 71 (in Homo sapiens) 71 EQUAL O-phospho-L-threonine at 69 (in Homo sapiens) 69 EQUAL 1 EQUAL 505 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10261520 Activated MAPK kinases ERK1/2, JNK, p38 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-MAPK10 [nucleoplasm] phospho-MAPK9 [nucleoplasm] phospho-p-T180,Y182-MAPK11 [nucleoplasm] phospho-p-T180,Y182-MAPK14 [nucleoplasm] phospho-MAPK8 [nucleoplasm] Reactome Database ID Release 82 10261521 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261521 Reactome Database ID Release 82 10261523 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10261523 Reactome R-SSC-168053 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168053.1 At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'ATF-2' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'ATF-2-P' are present.<br><br> This reaction is mediated by the 'protein kinase activity' of 'MAPK1-P'.<br> inferred by electronic annotation IEA GO IEA 2.7.11.1 c-FOS activation by phospho ERK1/2 c-FOS activation by phospho ERK1/2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29358 4 Reactome DB_ID: 10282008 1 UniProt:A0A5G2RHQ3 FOS UniProt A0A5G2RHQ3 1 EQUAL 380 EQUAL Reactome DB_ID: 10281984 1 O-phospho-L-serine at 362 (in Homo sapiens) 362 EQUAL O-phospho-L-serine at 374 (in Homo sapiens) 374 EQUAL O-phospho-L-threonine at 325 (in Homo sapiens) 325 EQUAL O-phospho-L-threonine at 331 (in Homo sapiens) 331 EQUAL 1 EQUAL 380 EQUAL Reactome DB_ID: 113582 4 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10266394 Reactome Database ID Release 82 10282010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10282010 Reactome R-SSC-450325 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450325.1 The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity. <p>On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.</p><p>Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover. 12134156 Pubmed 2002 Molecular interpretation of ERK signal duration by immediate early gene products Murphy, LO Smith, Stuart Chen, RH Fingar, DC Blenis, J Nat Cell Biol 4:556-64 7588633 Pubmed 1995 The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells Okazaki, K Sagata, N EMBO J 14:5048-59 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350262 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350262 Reactome R-SSC-450341 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450341.1 GO 0051090 GO biological process Activator protein-1 (AP-1) is a collective term referring to a group of transcription factors that bind to promoters of target genes in a sequence-specific manner. AP-1 family consists of hetero- and homodimers of bZIP (basic region leucine zipper) proteins, mainly of Jun-Jun, Jun-Fos or Jun-ATF. <p>AP-1 members are involved in the regulation of a number of cellular processes including cell growth, proliferation, survival, apoptosis, differentiation, cell migration. The ability of a single transcription factor to determine a cell fate critically depends on the relative abundance of AP-1 subunits, the composition of AP-1 dimers, the quality of stimulus, the cell type, the co-factor assembly. </p><p>AP-1 activity is regulated on multiple levels; transcriptional, translational and post-translational control mechanisms contribute to the balanced production of AP-1 proteins and their functions. Briefly, regulation occurs through:<ol><li>effects on jun, fos, atf gene transcription and mRNA turnover.<li> AP-1 protein members turnover. <li>post-translational modifications of AP-1 proteins that modulate their transactivation potential (effect of protein kinases or phosphatases).<li>interactions with other transcription factors that can either induce or interfere with AP-1 activity.</ol> 7622446 Pubmed 1995 The regulation of AP-1 activity by mitogen-activated protein kinases Karin, M J Biol Chem 270:16483-6 19167516 Pubmed 2009 Translational regulation mechanisms of AP-1 proteins Vesely, PW Staber, PB Hoefler, G Kenner, L Mutat Res 682:7-12 15564374 Pubmed 2004 AP-1 subunits: quarrel and harmony among siblings Hess, J Angel, P Schorpp-Kistner, M J Cell Sci 117:5965-73 9069263 Pubmed 1997 AP-1 function and regulation Karin, M Liu, Z Zandi, E Curr Opin Cell Biol 9:240-6 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350264 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350264 Reactome R-SSC-450282 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450282.1 MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity. <p>The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.</p><p>Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).</p><p>JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK. 17158707 Pubmed 2006 Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases Bogoyevitch, MA Kobe, B Microbiol Mol Biol Rev 70:1061-95 16393692 Pubmed 2006 The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions Yoon, S Seger, R Growth Factors 24:21-44 17637696 Pubmed 2007 Coordinating TLR-activated signaling pathways in cells of the immune system Banerjee, A Gerondakis, S Immunol Cell Biol 85:420-4 12471242 Pubmed 2002 Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases Johnson, GL Lapadat, R Science 298:1911-2 19767751 Pubmed 2009 Phosphoproteomics reveals new ERK MAP kinase targets and links ERK to nucleoporin-mediated nuclear transport Kosako, H Yamaguchi, N Aranami, C Ushiyama, M Kose, S Imamoto, N Taniguchi, H Nishida, E Hattori, S Nat Struct Mol Biol 16:1026-35 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350266 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350266 Reactome R-SSC-450294 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-450294.1 GO 0051403 GO biological process The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002). <p>There are three major groups of MAP kinases<ul><li>the extracellular signal-regulated protein kinases ERK1/2, <li>the p38 MAP kinase<li> and the c-Jun NH-terminal kinases JNK.</ul><p>ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).<p>MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.<p>The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.<p>The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear. 11242034 Pubmed 2001 Mammalian MAP kinase signalling cascades Chang, L Karin, M Nature 410:37-40 11861597 Pubmed 2002 MAP kinases in the immune response Dong, C Davis, RJ Flavell, RA Annu Rev Immunol 20:55-72 19196711 Pubmed 2009 Selectivity of docking sites in MAPK kinases Bardwell, AJ Frankson, E Bardwell, L J Biol Chem 284:13165-73 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350240 Reactome R-SSC-975871 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-975871.1 GO 0002755 GO biological process Mammalian myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays crucial role in TLR signaling. All TLRs, with only one exception of TLR3, can initiate downstream signaling trough MyD88. In the MyD88 - dependent pathway, once the adaptor is bound to TLR it leads to recruitment of IL1 receptor associated kinase family IRAK which is followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6) . TRAF6 is an ubiquitin E3 ligase which in turn induces TGF-beta activating kinase 1 (TAK1) auto phosphorylation. Once activated TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides. 10435584 Pubmed 1999 Unresponsiveness of MyD88-deficient mice to endotoxin Kawai, T Adachi, O Ogawa, T Takeda, K Immunity 11:115-22 9430229 Pubmed 1997 MyD88: an adapter that recruits IRAK to the IL-1 receptor complex Wesche, H Henzel, WJ Shillinglaw, W Li, S Cao, Z Immunity 7:837-47 16239509 Pubmed 2005 Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5 Zhang, Z Louboutin, JP Weiner, DJ Goldberg, JB Wilson, JM Infect Immun 73:7151-60 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 82 10350244 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10350244 Reactome R-SSC-168142 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-168142.1 GO 0034166 GO biological process Little is known about TLR10 ligands. It has been established that the receptor homodimerizes upon binding and signals in an MyD88-dependent manner (Hasan U et al 2005; Nyman T et al 2008). It may also heterodimerize with TLRs 1 and 2. It is expressed in a restricted fashion as a highly N-glycosylated protein detectable in B cells and dendritic cells. 18332149 Pubmed 2008 The crystal structure of the human toll-like receptor 10 cytoplasmic domain reveals a putative signaling dimer Nyman, T Stenmark, Pål Flodin, S Johansson, I Hammarström, M Nordlund, Par J Biol Chem 283:11861-5 inferred by electronic annotation IEA GO IEA