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> 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: 9854099 1 plasma membrane GO 0005886 TRAF6:hp-IRAK1 [plasma membrane] TRAF6:hp-IRAK1 Reactome DB_ID: 9854042 1 UniProt:P70196 Traf6 Traf6 Traf6 FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2 (PubMed:15322147, PubMed:17633018). Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (By similarity). Leads to the activation of NF-kappa-B and JUN. Seems to also play a role in dendritic cells (DCs) maturation and/or activation (PubMed:14499111). Represses c-Myb-mediated transactivation, in B-lymphocytes (By similarity). Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (PubMed:10421844, PubMed:10215628). Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (PubMed:10421844, PubMed:17092936). Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (PubMed:12881420).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer (By similarity). Homooligomer (By similarity). N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK (By similarity). Associates with NGFR, TNFRSF17, IRAK2, IRAK3, PELI2, PELI3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Binds UBE2V1. Interacts with MAVS/IPS1. Interacts with TAX1BP1 (By similarity). Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ. Interacts with IL1RL1. Interacts with AJUBA (By similarity). Interacts with TRAFD1. Interacts with TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and ARRB2 (By similarity). Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal) (By similarity). Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with RBCK1 (By similarity). Interacts with LIMD1 (via LIM domains). Interacts with RSAD2/viperin. Interacts with IFIT3 (via N-terminus) (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain). Interacts with CARD14 (By similarity). Interacts with CD40 and MAP3K8; the interaction is required for ERK activation. Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (By similarity). Interacts with TANK; this interaction increases in response to DNA damage (By similarity). Interacts with USP10; this interaction increases in response to DNA damage (By similarity). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (By similarity). Interacts with WDFY3 (PubMed:27330028). Interacts with TRIM13 (By similarity). Interacts with GPS2 (PubMed:22424771). Interacts (via C-terminus) with SASH1 (By similarity). Interacts with LRRC19 (By similarity). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (By similarity). Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (By similarity).TISSUE SPECIFICITY Highly expressed in brain, lung, liver, skeletal muscle, and kidney; lower expression in heart, spleen, and testis.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-461 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (By similarity). Polyubiquitinated; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage. LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).DISRUPTION PHENOTYPE Abrogation of IL-1-induced activation of NF-kappa-B, MAPK8/JNK and MAPK14/p38. Animals appear normal at birth but become smaller after one week. Show runting, failure of tooth eruption and die after three weeks. Exhibit severe osteopetrosis, thymic atrophy, lymph node deficiency, splenomegaly, and have alopecia and lack sweat glands.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. Reactome http://www.reactome.org Mus musculus NCBI Taxonomy 10090 UniProt P70196 Chain Coordinates 1 EQUAL 522 EQUAL Reactome DB_ID: 9854097 1 UniProt:Q62406 Irak1 Irak1 Il1rak Irak1 FUNCTION Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3 (By similarity).SUBUNIT Homodimer (By similarity). Forms a complex with TRAF6, PELI1, IRAK4 and MYD88 (PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (By similarity). The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (By similarity). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (By similarity). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (By similarity). Interacts with IL1RL1 (By similarity). Interacts (when polyubiquitinated) with IKBKG/NEMO (By similarity). Interacts with RSAD2/viperin (PubMed:21435586). Interacts with IRAK1BP1 (PubMed:11096118). Interacts with PELI2 (PubMed:12370331). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (PubMed:22037600). Interacts with IRAK4 (By similarity). Interacts with PELI3 (By similarity). Interacts with PELI1 and TRAF6 (By similarity). Interacts with INAVA; the interaction takes place upon PRR stimulation (By similarity). Interacts (via C-terminus) with NFATC4 (via N-terminus) (By similarity).TISSUE SPECIFICITY Highly expressed in liver, followed by kidney and skeletal muscle.DEVELOPMENTAL STAGE Expressed from 11 dpc to 18 dpc.DOMAIN The ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation (By similarity).PTM Following recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity (By similarity).PTM Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through 'Lys-63'. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation (By similarity).DISRUPTION PHENOTYPE Mice show a loss in TLR7- and TLR9-mediated IFN-alpha production in plasmacytoid dendritic cells demonstrating an important role in innate immune response.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. UniProt Q62406 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 Database ID Release 82 9854099 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=9854099 Reactome R-MMU-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-MMU-937036.1 Converted from EntitySet in Reactome Reactome DB_ID: 9850034 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 Q8C669 UniProt Q8BST6 Reactome DB_ID: 9854101 1 TRAF6:hp-IRAK1:Pellino [plasma membrane] TRAF6:hp-IRAK1:Pellino Reactome DB_ID: 9854099 1 Converted from EntitySet in Reactome Reactome DB_ID: 9850034 1 Reactome Database ID Release 82 9854101 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=9854101 Reactome R-MMU-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-MMU-937020.1 Reactome Database ID Release 82 9854106 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=9854106 Reactome R-MMU-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-MMU-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: 9854101 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: 9854101 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9854101 GO 0004672 GO molecular function Reactome Database ID Release 82 9854102 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=9854102 Reactome Database ID Release 82 9854104 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=9854104 Reactome R-MMU-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-MMU-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: 9854101 1 Reactome DB_ID: 9828692 2 K63polyUb [cytosol] K63polyUb Reactome DB_ID: 9828731 1 UBE2N:UBE2V1 [cytosol] UBE2N:UBE2V1 Reactome DB_ID: 9828725 1 UniProt:P61089 Ube2n UniProt P61089 1 EQUAL 152 EQUAL Reactome DB_ID: 9828729 1 UniProt:Q9CZY3 Ube2v1 UniProt Q9CZY3 2 EQUAL 147 EQUAL Reactome Database ID Release 82 9828731 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=9828731 Reactome R-MMU-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-MMU-202463.1 Reactome DB_ID: 9854091 1 K63-linked polyUb p-IRAK1:TRAF6 [cytosol] K63-linked polyUb p-IRAK1:TRAF6 Reactome DB_ID: 9828388 1 1 EQUAL 522 EQUAL Reactome DB_ID: 9850180 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 Database ID Release 82 9854091 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=9854091 Reactome R-MMU-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-MMU-937043.1 Converted from EntitySet in Reactome Reactome DB_ID: 9850034 1 Reactome DB_ID: 9828731 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9854101 GO 0034450 GO molecular function Reactome Database ID Release 82 9854107 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=9854107 Reactome Database ID Release 82 9854109 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=9854109 Reactome R-MMU-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-MMU-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: 9854091 1 Reactome DB_ID: 9835816 1 CHUK:IKBKB:IKBKG [cytosol] CHUK:IKBKB:IKBKG Reactome DB_ID: 9832572 1 UniProt:O88351 UniProt O88351 1 EQUAL 756 EQUAL Reactome DB_ID: 9828515 1 UniProt:O88522 UniProt O88522 1 EQUAL 419 EQUAL Reactome DB_ID: 9833419 1 UniProt:Q60680 UniProt Q60680 1 EQUAL 745 EQUAL Reactome Database ID Release 82 9835816 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=9835816 Reactome R-MMU-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-MMU-168113.1 Reactome DB_ID: 9854093 1 TRAF6:K63-linked polyUb p-IRAK1:IKK complex [cytosol] TRAF6:K63-linked polyUb p-IRAK1:IKK complex Reactome DB_ID: 9854091 1 Reactome DB_ID: 9835816 1 Reactome Database ID Release 82 9854093 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=9854093 Reactome R-MMU-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-MMU-937038.1 Reactome Database ID Release 82 9854095 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=9854095 Reactome R-MMU-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-MMU-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 9927270 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=9927270 Reactome R-MMU-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-MMU-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: 9828388 2 1 EQUAL 522 EQUAL Reactome DB_ID: 9854046 1 TRAF6:p-IRAK2 [plasma membrane] TRAF6:p-IRAK2 Reactome DB_ID: 9854042 1 1 EQUAL 522 EQUAL Reactome DB_ID: 9854044 1 UniProt:Q8CFA1 UniProt Q8CFA1 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 625 EQUAL Reactome Database ID Release 82 9854046 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=9854046 Reactome R-MMU-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-MMU-936961.1 Reactome DB_ID: 9854048 1 p-IRAK2:oligo-TRAF6 [plasma membrane] p-IRAK2:oligo-TRAF6 Reactome DB_ID: 9854046 1 Reactome DB_ID: 9854042 2 1 EQUAL 522 EQUAL Reactome Database ID Release 82 9854048 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=9854048 Reactome R-MMU-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-MMU-936990.1 Reactome Database ID Release 82 9854075 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=9854075 Reactome R-MMU-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-MMU-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: 9816098 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] Ubiquitin (Ubc 6) [cytosol] Ubiquitin (Ubc 3) [cytosol] Ubiquitin (Ubc 2) [cytosol] Ubiquitin (Ubc 4) [cytosol] Ubiquitin related 1 (Ubc r1) [cytosol] Ubiquitin (Ubb 1) [cytosol] Ubiquitin (Pps27a) [cytosol] Ubiquitin (Ubc 1) [cytosol] Ubiquitin (Ubc 5) [cytosol] Ubiquitin (Uba52) [cytosol] Ubiquitin (Ubc 7) [cytosol] Ubiquitin (Ubc 8) [cytosol] UniProt P62983 UniProt P0CG50 UniProt P0CG49 UniProt P62984 Reactome DB_ID: 9854048 1 Reactome DB_ID: 9854053 1 p-IRAK2:K63-linked pUb oligo-TRAF6 [plasma membrane] p-IRAK2:K63-linked pUb oligo-TRAF6 Reactome DB_ID: 9854051 3 ubiquitinylated lysine (K63polyUb [plasma membrane]) at 124 (in Homo sapiens) 124 EQUAL 1 EQUAL 522 EQUAL Reactome DB_ID: 9854044 1 phosphorylated residue at unknown position 1 EQUAL 625 EQUAL Reactome Database ID Release 82 9854053 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=9854053 Reactome R-MMU-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-MMU-936988.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9854048 GO 0004842 GO molecular function Reactome Database ID Release 82 9854054 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=9854054 Reactome Database ID Release 82 9854056 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=9854056 Reactome R-MMU-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-MMU-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: 9816098 1 Reactome DB_ID: 9828692 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9854053 Reactome Database ID Release 82 9854078 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=9854078 Reactome Database ID Release 82 9854080 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=9854080 Reactome R-MMU-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-MMU-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: 9854053 1 Reactome DB_ID: 9849204 3 TAK1 complex [cytosol] TAK1 complex Reactome DB_ID: 9849194 1 UniProt:Q8CF89 Tab1 Tab1 Map3k7ip1 Tab1 FUNCTION May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.SUBUNIT Interacts with XIAP and BIRC7. Interacts with TRAF6 and MAP3K7; during IL-1 signaling. Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (By similarity).PTM Monoubiquitinated.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity. UniProt Q8CF89 1 EQUAL 504 EQUAL Reactome DB_ID: 9849191 1 UniProt:Q62073 Map3k7 Map3k7 Tak1 Map3k7 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR) (PubMed:10748100, PubMed:16157589, PubMed:21183079, PubMed:29291351). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK (PubMed:16157589, PubMed:8533096, PubMed:29291351). MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis (PubMed:10748100). In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity (By similarity). Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (PubMed:28842570).ACTIVITY REGULATION Activated by pro-inflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.SUBUNIT Can form homodimer (By similarity). Binds both upstream activators and downstream substrates in multimolecular complexes (By similarity). Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (By similarity). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (By similarity). Interacts with PPM1L and PPM1B/PP2CB (PubMed:12556533). Interaction with PP2A and PPP6C leads to its repressed activity (By similarity). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (By similarity). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (By similarity). Interacts with DYNC2I2 (via WD domains) (By similarity). Interacts with CYLD and RBCK1 (PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (By similarity). Interacts with MAPK8IP1 and SMAD6 (PubMed:10748100, PubMed:17709393). Interacts with isoform 1 of VRK2 (PubMed:17709393). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (By similarity). Interacts with TRIM5 (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts with PLEKHM1 (via N- and C-terminus) (PubMed:27777970). Interacts with TRIM8 (By similarity). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (PubMed:27084103). Interacts with SASH1 (By similarity). Interacts with RIPK1 (PubMed:31519887).PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Thr-187 by PP2A and PPP6C leads to inactivation (By similarity).PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation (PubMed:16157589). Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (PubMed:25632008). 'Lys-63'-linked polyubiquitination at Lys-158 by TRIM8 does not lead to proteasomal degradation but contributes to autophosphorylation and activation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:17548520, PubMed:29291351).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt Q62073 1 EQUAL 606 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9849202 1 TAB2,TAB3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Tab3 [cytosol] Tab2 [cytosol] UniProt Q571K4 UniProt Q99K90 Reactome Database ID Release 82 9849204 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=9849204 Reactome R-MMU-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-MMU-446878.1 Reactome DB_ID: 9828692 3 Reactome DB_ID: 9854071 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: 9854053 1 Reactome DB_ID: 9849204 3 Reactome DB_ID: 9828692 3 Reactome Database ID Release 82 9854071 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=9854071 Reactome R-MMU-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-MMU-936953.1 Reactome Database ID Release 82 9854073 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=9854073 Reactome R-MMU-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-MMU-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: 9854071 1 Reactome DB_ID: 29370 6 Reactome DB_ID: 9854082 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 Reactome DB_ID: 9849194 3 1 EQUAL 504 EQUAL Reactome DB_ID: 9835825 3 O-phospho-L-threonine at 184 (in Homo sapiens) 184 EQUAL O-phospho-L-threonine at 187 187 EQUAL 1 EQUAL 606 EQUAL Reactome DB_ID: 9854053 1 Converted from EntitySet in Reactome Reactome DB_ID: 9849202 3 Reactome DB_ID: 9828692 3 Reactome Database ID Release 82 9854082 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=9854082 Reactome R-MMU-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-MMU-937008.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9854071 GO 0008349 GO molecular function Reactome Database ID Release 82 9854083 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=9854083 Reactome Database ID Release 82 9854085 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=9854085 Reactome R-MMU-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-MMU-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 9927268 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=9927268 Reactome R-MMU-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-MMU-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: 9828388 1 1 EQUAL 522 EQUAL Reactome DB_ID: 9828385 1 UniProt:P53349 Map3k1 Map3k1 Map3k1 Mekk1 Mekk FUNCTION Component of a protein kinase signal transduction cascade (PubMed:14500727). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:14500727). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:14500727).ACTIVITY REGULATION Activated by autophosphorylation on Thr-1381 and Thr-1393 following oligomerization.SUBUNIT Binds both upstream activators and downstream substrates in multimolecular complexes through its N-terminus. Oligomerizes after binding MAP4K2 or TRAF2. Interacts with AXIN1. Interacts (via the kinase catalytic domain) with STK38 (By similarity). Interacts with GRIPAP1 (By similarity).TISSUE SPECIFICITY Highly expressed in the heart and spleen while a lower level expression is seen in the liver.PTM Autophosphorylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt P53349 2 EQUAL 1512 EQUAL Reactome DB_ID: 9828390 1 MEKK1:activated TRAF6 [cytosol] MEKK1:activated TRAF6 Reactome DB_ID: 9828388 1 1 EQUAL 522 EQUAL Reactome DB_ID: 9828385 1 2 EQUAL 1512 EQUAL Reactome Database ID Release 82 9828390 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=9828390 Reactome R-MMU-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-MMU-166867.1 Reactome Database ID Release 82 9828396 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=9828396 Reactome R-MMU-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-MMU-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 9828397 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=9828397 Reactome DB_ID: 9828394 UniProt:Q9QZH6 Ecsit UniProt Q9QZH6 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: 9832572 1 1 EQUAL 756 EQUAL Reactome DB_ID: 9828515 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9833419 1 1 EQUAL 745 EQUAL Reactome DB_ID: 9835816 1 Reactome Database ID Release 82 9888320 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=9888320 Reactome R-MMU-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-MMU-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: 9816098 3 Reactome DB_ID: 9835818 1 CHUK:p-S177,S181-IKBKB:IKBKG [cytosol] CHUK:p-S177,S181-IKBKB:IKBKG Reactome DB_ID: 9828527 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: 9828515 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9833419 1 1 EQUAL 745 EQUAL Reactome Database ID Release 82 9835818 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=9835818 Reactome R-MMU-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-MMU-202513.1 Reactome DB_ID: 9828731 1 Reactome DB_ID: 9835848 1 CHUK:p-S177,S181-IKBKB:pUb-IKBKG [cytosol] CHUK:p-S177,S181-IKBKB:pUb-IKBKG Reactome DB_ID: 9835846 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: 9828527 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: 9833419 1 1 EQUAL 745 EQUAL Reactome Database ID Release 82 9835848 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=9835848 Reactome R-MMU-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-MMU-202562.1 Reactome DB_ID: 9828731 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9924898 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 9924899 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=9924899 Reactome Database ID Release 82 9924903 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=9924903 Reactome R-MMU-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-MMU-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 9924904 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=9924904 Reactome DB_ID: 9924901 CHUK:IKBKB:IKBKG:USP18 [cytosol] CHUK:IKBKB:IKBKG:USP18 Reactome DB_ID: 9852747 1 UniProt:Q9WTV6 Usp18 UniProt Q9WTV6 1 EQUAL 372 EQUAL Reactome DB_ID: 9835816 1 Reactome Database ID Release 82 9924901 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=9924901 Reactome R-MMU-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-MMU-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> Converted from EntitySet in Reactome Reactome DB_ID: 9828499 1 NFkB inhibitor [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Nfkbib [cytosol] Nfkbia [cytosol] UniProt Q60778 UniProt Q9Z1E3 Reactome DB_ID: 9828489 1 NFKB1(1-433), NFKB2(1-454):RELA [cytosol] NFKB1(1-433), NFKB2(1-454):RELA Converted from EntitySet in Reactome Reactome DB_ID: 9828487 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 P25799 UniProt Q9WTK5 Reactome DB_ID: 9828477 1 UniProt:Q04207 Rela UniProt Q04207 1 EQUAL 551 EQUAL Reactome Database ID Release 82 9828489 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=9828489 Reactome R-MMU-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-MMU-168155.1 Reactome DB_ID: 9828501 1 NFkB inhibitor:NFkB complex [cytosol] NFkB inhibitor:NFkB complex Converted from EntitySet in Reactome Reactome DB_ID: 9828499 1 Reactome DB_ID: 9828489 1 Reactome Database ID Release 82 9828501 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=9828501 Reactome R-MMU-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-MMU-168130.1 Reactome Database ID Release 82 9921303 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=9921303 Reactome R-MMU-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-MMU-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: 9828501 1 Converted from EntitySet in Reactome Reactome DB_ID: 9828511 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-Nfkbia [cytosol] phospho-Nfkbib [cytosol] Reactome DB_ID: 29370 4 Reactome DB_ID: 9828489 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9835818 GO 0004674 GO molecular function Reactome Database ID Release 82 9925084 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=9925084 Reactome Database ID Release 82 9925086 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=9925086 Reactome R-MMU-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-MMU-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 9828543 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=9828543 Converted from EntitySet in Reactome Reactome DB_ID: 9828540 NKIRAS [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NKIRAS2 [cytosol] NKIRAS1 [cytosol] UniProt Q9CR56 UniProt Q8CEC5 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: 9828489 1 Reactome DB_ID: 9828583 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: 9828579 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: 9828581 1 1 EQUAL 551 EQUAL Reactome Database ID Release 82 9828583 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=9828583 Reactome R-MMU-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-MMU-177673.1 Reactome Database ID Release 82 9828609 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=9828609 Reactome R-MMU-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-MMU-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 9828610 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=9828610 Reactome DB_ID: 9828607 AGER ligands:AGER [plasma membrane] AGER ligands:AGER Converted from EntitySet in Reactome Reactome DB_ID: 9828605 1 extracellular region GO 0005576 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(672-711) [extracellular region] HMGB1 [extracellular region] APP(672-713) [extracellular region] UniProt P12023 UniProt P63158 Reactome DB_ID: 9828587 1 UniProt:Q62151 Ager UniProt Q62151 23 EQUAL 404 EQUAL Reactome Database ID Release 82 9828607 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=9828607 Reactome R-MMU-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-MMU-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: 9832572 1 1 EQUAL 756 EQUAL Reactome DB_ID: 9924611 1 UniProt:Q8VC16 Lrrc14 UniProt Q8VC16 1 EQUAL 493 EQUAL Reactome DB_ID: 9833419 1 1 EQUAL 745 EQUAL Reactome DB_ID: 9924613 1 CHUK:IKBKB:LRRC14 [cytosol] CHUK:IKBKB:LRRC14 Reactome DB_ID: 9832572 1 1 EQUAL 756 EQUAL Reactome DB_ID: 9924611 1 1 EQUAL 493 EQUAL Reactome DB_ID: 9833419 1 1 EQUAL 745 EQUAL Reactome Database ID Release 82 9924613 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=9924613 Reactome R-MMU-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-MMU-9749467.1 Reactome Database ID Release 82 9924615 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=9924615 Reactome R-MMU-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-MMU-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 NLRX1 binds CHUK:IKBKB:IKBKG NLRX1 binds CHUK:IKBKB:IKBKG NLRX1 binds activated 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: 9835816 1 Reactome DB_ID: 9924603 1 UniProt:Q3TL44 UniProt Q3TL44 ubiquitinylated lysine (K63polyUb [cytosol]) at unknown position 87 EQUAL 975 EQUAL Reactome DB_ID: 9924605 1 CHUK:IKBKB:IKBKG:K63polyUb-NLRX1 [cytosol] CHUK:IKBKB:IKBKG:K63polyUb-NLRX1 Reactome DB_ID: 9835816 1 Reactome DB_ID: 9924603 1 ubiquitinylated lysine (K63polyUb [cytosol]) at unknown position 87 EQUAL 975 EQUAL Reactome Database ID Release 82 9924605 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=9924605 Reactome R-MMU-9749472 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-MMU-9749472.1 Reactome Database ID Release 82 9924607 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=9924607 Reactome R-MMU-9749471 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-MMU-9749471.1 Nucleotide binding oligomerization domain (NOD)-like receptor (NLR) family member X1 (NLRX1) has been implicated in regulation of the Toll-like receptor (TLR)-mediated nuclear factor kappa-B (NF-kappa-B) signaling pathway. NLRX1 deficiency enhanced phosphorylation of catalytic subunits (CHUK and IKBKB) of the IkB kinase (IKK) complex and NF-kappa-B activation and led to elevated production of inflammatory cytokines in mouse cells in response to bacterial lipopolysaccharide (LPS, a TLR4 ligand) (Allen IC et al. 2011; Xia X et al. 2011; Ma D et al. 2019). NLRX1-knockdown mice showed enhanced susceptibility to LPS-induced septic shock thus further confirming that NLRX1 functions as a negative regulator of TLR signaling in vivo (Xia X et al. 2011). NLRX1 was shown to interact with TRAF6 (Allen et al. 2011; Xia X et al. 2011) and the IKK complex (CHUK:IKBKB:IKBKG) (Xia X et al. 2011) in human and mouse cells. Specifically, in unstimulated cells, NLRX1 was shown to associate with TRAF6 (Xia X et al. 2011). Upon stimulation with LPS, NLRX1 is thought to undergo K63-linked polyubiquitination. Although TRAF6 possesses E3 ubiquitin ligase activity, the TRAF6 deficiency did not affect NLRX1 ubiquitination in mouse embryonic fibroblast (MEF) (Xia X et al. 2011). Further studies are required to identify E3 ubiquitin ligase which is responsible for the ubiquitination of NLRX1. Ubiquitinated NLRX1 then binds to the IKK complex, blocking phosphorylation of the catalytic subunits CHUK (IKBKA) and IKBKB (Xia X et al. 2011). Mutagenesis studies showed that the C-terminal leucine-rich repeat (LRR) domain of NLRX1 binds to the kinase domain of IKBKB (Xia X et al. 2011). <p>The regulatory effects of NLRX1 are highly cell type specific (reviewed in Fekete T et al. 2021). As a regulator of inflammation, NLRX1 has been implicated in the pathology of diverse diseases (reviewed in Pickering RJ & Booty LM 2021).<p>This Reactome event shows interaction between NLRX1 and the IKK complex. 30861394 Pubmed 2019 NLRX1 alleviates lipopolysaccharide-induced apoptosis and inflammation in chondrocytes by suppressing the activation of NF-κB signaling Ma, Ding Zhao, Yangxue She, Jiang Zhu, Yandong Zhao, Y Liu, Liang Zhang, Yingang Int Immunopharmacol 71:7-13 33525671 Pubmed 2021 Focusing on the Cell Type Specific Regulatory Actions of NLRX1 Fekete, Tünde Bencze, Dóra Bíró, Eduárd Benko, Szilvia Pázmándi, Kitti Int J Mol Sci 22: 21703539 Pubmed 2011 NLRX1 negatively regulates TLR-induced NF-κB signaling by targeting TRAF6 and IKK Xia, Xiaojun Cui, Jun Wang, Helen Y Zhu, Liang Matsueda, Satoko Wang, Qinfu Yang, Xiaoang Hong, Jun Songyang, Z Chen, Zhijian J Wang, Rong-Fu Immunity 34:843-53 33314068 Pubmed 2021 NLR in eXile: Emerging roles of NLRX1 in immunity and human disease Pickering, Robert J Booty, Lee M Immunology 162:268-280 21703540 Pubmed 2011 NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways Allen, Irving C Moore, Chris B Schneider, Monika Lei, Yu Davis, Beckley K Scull, Margaret A Gris, Denis Roney, Kelly E Zimmermann, Albert G Bowzard, John B Ranjan, Priya Monroe, Kathryn M Pickles, Raymond J Sambhara, Suryaprakash Ting, Jenny P Y Immunity 34:854-65 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: 9832572 1 1 EQUAL 756 EQUAL Reactome DB_ID: 9833419 1 1 EQUAL 745 EQUAL Reactome DB_ID: 9924653 1 UniProt:C3VPR6 UniProt C3VPR6 1 EQUAL 1866 EQUAL Reactome DB_ID: 9924655 1 endoplasmic reticulum membrane GO 0005789 CHUK:IKBKB:NLRC5 [endoplasmic reticulum membrane] CHUK:IKBKB:NLRC5 Reactome DB_ID: 9832572 1 1 EQUAL 756 EQUAL Reactome DB_ID: 9833419 1 1 EQUAL 745 EQUAL Reactome DB_ID: 9924653 1 1 EQUAL 1866 EQUAL Reactome Database ID Release 82 9924655 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=9924655 Reactome R-MMU-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-MMU-9750228.1 Reactome Database ID Release 82 9924660 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=9924660 Reactome R-MMU-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-MMU-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 INHIBITION Reactome Database ID Release 82 9924661 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=9924661 Reactome DB_ID: 9924658 ubiquitinylated lysine (K63polyUb [cytosol]) at 1178 (in Homo sapiens) 1178 EQUAL 87 EQUAL 975 EQUAL ACTIVATION Reactome Database ID Release 82 9924662 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=9924662 Reactome DB_ID: 9894637 UniProt:Q9JMA1 Usp14 UniProt Q9JMA1 1 EQUAL 494 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> Reactome DB_ID: 9924655 1 Converted from EntitySet in Reactome Reactome DB_ID: 9816098 3 Reactome DB_ID: 9924658 1 ubiquitinylated lysine (K63polyUb [cytosol]) at 1178 (in Homo sapiens) 1178 EQUAL 87 EQUAL 975 EQUAL Reactome DB_ID: 9832572 1 1 EQUAL 756 EQUAL Reactome DB_ID: 9833419 1 1 EQUAL 745 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9911551 TRAF2, TRAF6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Traf6 [cytosol] Traf2 [cytosol] UniProt P39429 Reactome Database ID Release 82 9924687 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=9924687 Reactome Database ID Release 82 9924689 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=9924689 Reactome R-MMU-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-MMU-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: 9924658 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: 9816098 3 Reactome DB_ID: 9924653 1 1 EQUAL 1866 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9894637 1 EQUAL 494 EQUAL GO 0061578 GO molecular function Reactome Database ID Release 82 9924684 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=9924684 Reactome Database ID Release 82 9924686 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=9924686 Reactome R-MMU-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-MMU-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: 9852747 1 1 EQUAL 372 EQUAL Reactome DB_ID: 9835816 1 Reactome DB_ID: 9924901 1 Reactome Database ID Release 82 9925010 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=9925010 Reactome R-MMU-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-MMU-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: 9924878 1 UniProt:Q6A037 N4bp1 UniProt Q6A037 1 EQUAL 896 EQUAL Reactome DB_ID: 9828515 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9924887 1 IKBKG:N4BP1 [cytosol] IKBKG:N4BP1 Reactome DB_ID: 9924878 1 1 EQUAL 896 EQUAL Reactome DB_ID: 9828515 1 1 EQUAL 419 EQUAL Reactome Database ID Release 82 9924887 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=9924887 Reactome R-MMU-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-MMU-9757950.1 Reactome Database ID Release 82 9924889 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=9924889 Reactome R-MMU-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-MMU-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 9924890 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=9924890 Reactome DB_ID: 9824349 active caspase-8 [cytosol] active caspase-8 Reactome DB_ID: 9824347 2 Caspase-8 dimer [cytosol] Caspase-8 dimer Reactome DB_ID: 9824345 1 UniProt:O89110 Casp8 UniProt O89110 385 EQUAL 479 EQUAL Reactome DB_ID: 9824343 1 217 EQUAL 374 EQUAL Reactome Database ID Release 82 9824347 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=9824347 Reactome R-MMU-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-MMU-139950.1 Reactome Database ID Release 82 9824349 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=9824349 Reactome R-MMU-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-MMU-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: 9924878 2 1 EQUAL 896 EQUAL Reactome DB_ID: 9924880 1 1 EQUAL 424 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9824349 GO 0008234 GO molecular function Reactome Database ID Release 82 9924883 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=9924883 Reactome Database ID Release 82 9924885 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=9924885 Reactome R-MMU-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-MMU-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 9928560 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=9928560 Reactome R-MMU-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-MMU-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 9926114 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=9926114 Reactome R-MMU-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-MMU-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: 9849747 1 MAP2K7,MAP2K4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAP2K7 [cytosol] MAP2K4 [cytosol] UniProt Q8CE90 UniProt P47809 Converted from EntitySet in Reactome Reactome DB_ID: 9828570 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-p-S271,T275-MAP2K7 [cytosol] Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9849764 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 9849765 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=9849765 Reactome Database ID Release 82 9849767 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=9849767 Reactome R-MMU-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-MMU-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: 9828549 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] MAPK9 [cytosol] MAPK10 [cytosol] UniProt Q91Y86 UniProt Q9WTU6 UniProt Q61831 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 9828557 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-p-T,Y-MAPK8 [cytosol] phospho-p-T183,Y185-MAPK9 [cytosol] phospho-p-T221,Y223-MAPK10 [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9828570 GO 0008545 GO molecular function Reactome Database ID Release 82 9828571 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=9828571 Reactome Database ID Release 82 9828573 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=9828573 Reactome R-MMU-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-MMU-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: 9828557 1 Converted from EntitySet in Reactome Reactome DB_ID: 9828458 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-p-T183,Y185-MAPK9 [nucleoplasm] phospho-p-T,Y-MAPK8 [nucleoplasm] phospho-p-T221,Y223-MAPK10 [nucleoplasm] Reactome Database ID Release 82 9849777 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=9849777 Reactome R-MMU-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-MMU-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 9926112 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=9926112 Reactome R-MMU-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-MMU-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: 9849773 1 MAP2K3,MAP2K6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAP2K3 [cytosol] MAP2K6 [cytosol] UniProt O09110 UniProt P70236 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 9849720 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-S189,T193-MAP2K3 [cytosol] Phospho MKK6_MOUSE [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9849764 Reactome Database ID Release 82 9849775 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=9849775 Reactome R-MMU-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-MMU-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: 9849720 1 Converted from EntitySet in Reactome Reactome DB_ID: 9849726 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-S189,T193-MAP2K3 [nucleoplasm] phospho-p-S207,T211-MAP2K6 [nucleoplasm] Reactome Database ID Release 82 9849728 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=9849728 Reactome R-MMU-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-MMU-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: 9849738 1 p38 MAPK:MAPKAPK2,3 [nucleoplasm] p38 MAPK:MAPKAPK2,3 Converted from EntitySet in Reactome Reactome DB_ID: 9849683 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 Q3UMW7 UniProt P49138 Converted from EntitySet in Reactome Reactome DB_ID: 9849736 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 MAPK11 [nucleoplasm] MAPK14 [nucleoplasm] UniProt Q9WUI1 UniProt P47811 Reactome Database ID Release 82 9849738 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=9849738 Reactome R-MMU-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-MMU-450269.1 Reactome DB_ID: 29358 2 Reactome DB_ID: 113582 2 Reactome DB_ID: 9849685 1 p-p38 MAPK: MAPKAPK2,3 [nucleoplasm] p-p38 MAPK: MAPKAPK2,3 Converted from EntitySet in Reactome Reactome DB_ID: 9849683 1 Converted from EntitySet in Reactome Reactome DB_ID: 9828442 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 p-T180,Y182-Mapk11 [nucleoplasm] p-T180,Y182-Mapk14 [nucleoplasm] Reactome Database ID Release 82 9849685 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=9849685 Reactome R-MMU-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-MMU-450213.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9849726 GO 0004708 GO molecular function Reactome Database ID Release 82 9849739 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=9849739 Reactome Database ID Release 82 9849741 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=9849741 Reactome R-MMU-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-MMU-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: 9849685 1 Reactome DB_ID: 29358 3 Reactome DB_ID: 113582 3 Reactome DB_ID: 9849693 1 p-p38 MAPK:p-MAPKAPK2/3 [nucleoplasm] p-p38 MAPK:p-MAPKAPK2/3 Converted from EntitySet in Reactome Reactome DB_ID: 9849691 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] Converted from EntitySet in Reactome Reactome DB_ID: 9828442 1 Reactome Database ID Release 82 9849693 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=9849693 Reactome R-MMU-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-MMU-450254.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9849685 Reactome Database ID Release 82 9849694 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=9849694 Reactome Database ID Release 82 9849696 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=9849696 Reactome R-MMU-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-MMU-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: 9849693 1 Reactome DB_ID: 9849698 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: 9831274 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-S,2T-MAPKAPK3 [cytosol] phospho-p-S272,T222,T334-MAPKAPK2 [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 448863 1 phospho-MAPK p38 alpha/beta [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-MAP kinase p38 beta [cytosol] phospho-MAP kinase p38 alpha [cytosol] Reactome Database ID Release 82 9849698 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=9849698 Reactome R-MMU-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-MMU-450241.1 Reactome Database ID Release 82 9849700 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=9849700 Reactome R-MMU-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-MMU-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 9927120 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=9927120 Reactome R-MMU-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-MMU-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: 9843992 1 UniProt:Q07174 UniProt Q07174 1 EQUAL 467 EQUAL Reactome DB_ID: 9850193 1 UniProt:P25799 Nfkb1 1 EQUAL 968 EQUAL Reactome DB_ID: 9850197 1 UniProt:Q99JG7 UniProt Q99JG7 1 EQUAL 429 EQUAL Reactome DB_ID: 9850199 1 NFKB1:MAP3K8:TNIP2 [cytosol] NFKB1:MAP3K8:TNIP2 Reactome DB_ID: 9843992 1 1 EQUAL 467 EQUAL Reactome DB_ID: 9850193 1 1 EQUAL 968 EQUAL Reactome DB_ID: 9850197 1 1 EQUAL 429 EQUAL Reactome Database ID Release 82 9850199 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=9850199 Reactome R-MMU-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-MMU-451638.1 Reactome Database ID Release 82 9850211 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=9850211 Reactome R-MMU-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-MMU-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 9850213 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=9850213 Reactome DB_ID: 9850209 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: 9850204 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: 9850207 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: 9850197 1 1 EQUAL 429 EQUAL Reactome Database ID Release 82 9850209 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=9850209 Reactome R-MMU-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-MMU-5684242.1 INHIBITION Reactome Database ID Release 82 9850212 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=9850212 Reactome DB_ID: 9850204 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 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: 9850199 1 Reactome DB_ID: 9893494 1 NFKB1:p-S400-MAP3K8:TNIP2 [cytosol] NFKB1:p-S400-MAP3K8:TNIP2 Reactome DB_ID: 9843995 1 O-phospho-L-serine at 400 (in Homo sapiens) 400 EQUAL 1 EQUAL 467 EQUAL Reactome DB_ID: 9850193 1 1 EQUAL 968 EQUAL Reactome DB_ID: 9850197 1 1 EQUAL 429 EQUAL Reactome Database ID Release 82 9893494 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=9893494 Reactome R-MMU-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-MMU-5687880.1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9835818 GO 0008384 GO molecular function Reactome Database ID Release 82 9893488 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=9893488 Reactome Database ID Release 82 9893496 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=9893496 Reactome R-MMU-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-MMU-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: 9850199 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9893483 1 NFKB1:p-T290-MAP3K8:TNIP2 [cytosol] NFKB1:p-T290-MAP3K8:TNIP2 Reactome DB_ID: 9850207 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: 9850193 1 1 EQUAL 968 EQUAL Reactome DB_ID: 9850197 1 1 EQUAL 429 EQUAL Reactome Database ID Release 82 9893483 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=9893483 Reactome R-MMU-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-MMU-5684265.1 Reactome Database ID Release 82 9893485 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=9893485 Reactome R-MMU-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-MMU-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: 9850199 1 Reactome DB_ID: 29370 2 Reactome DB_ID: 9893487 1 p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2 [cytosol] p-S927,S932-NFKB1(1-968):MAP3K8:TNIP2 Reactome DB_ID: 9893472 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 DB_ID: 9843992 1 1 EQUAL 467 EQUAL Reactome DB_ID: 9850197 1 1 EQUAL 429 EQUAL Reactome Database ID Release 82 9893487 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=9893487 Reactome R-MMU-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-MMU-5687885.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9835818 Reactome Database ID Release 82 9893490 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=9893490 Reactome R-MMU-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-MMU-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 SCF betaTrCP1,2 binds p-NFkB p105:TPL2:ABIN2 SCF betaTrCP1,2 binds p-NFkB p105:TPL2:ABIN2 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: 9860371 1 CUL1:FBXW11:SKP1 [cytosol] CUL1:FBXW11:SKP1 Reactome DB_ID: 9829595 1 UniProt:Q9WTX5 Skp1 Skp1 Skp1a Skp1 FUNCTION Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5, CEP68 and probably NFKB2. SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2 (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with KDM2B, forming heterodimers (By similarity). The KDM2B-SKP1 heterodimeric complex interacts with the PCGF1-BCORL heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (By similarity). Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit. Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXw2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44. Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC. This complex binds phosphorylated NFKBIA. Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF. Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7. Component of the SCF(FBXW15) complex containing FBXW15 (PubMed:23319590). Interacts with CEP68 (By similarity). Interacts with FBXW15 (PubMed:23319590). Interacts with NOTCH2 (By similarity). The SKP1-KDM2A and SKP1-KDM2B complexes interact with UBB (By similarity).PTM Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.SIMILARITY Belongs to the SKP1 family. UniProt Q9WTX5 2 EQUAL 163 EQUAL Reactome DB_ID: 9829597 1 UniProt:Q9WTX6 Cul1 Cul1 Cul1 FUNCTION Core component of multiple cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. SCF complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins. In the SCF complex, serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and exchange of the substrate recognition component is mediated by TIP120A/CAND1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5 and probably NFKB2. SCF(BTRC) and/or SCF(FBXW11) direct ubiquitination of CEP68. SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO1) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit (PubMed:10097128, PubMed:12140560, PubMed:16880526, PubMed:23452855, PubMed:23452856). Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXW2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44 (By similarity). Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC (PubMed:10097128, PubMed:11735228). This complex binds phosphorylated NFKBIA (PubMed:10097128). Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF (By similarity). Interacts with CCNF (By similarity). Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7. Interacts with CHEK2; mediates CHEK2 ubiquitination and regulates its function. Part of a complex with TIP120A/CAND1 and RBX1. The unneddylated form interacts with TIP120A/CAND1 and the interaction mediates the exchange of the F-box substrate-specific subunit. Can self-associate (By similarity). Interacts with FBXW8 (PubMed:16880526). Interacts with RNF7 (By similarity). Interacts with CUL7; the interaction seems to be mediated by FBXW8 (PubMed:16880526). Interacts with TRIM21 (By similarity). Interacts with COPS2 (PubMed:11967155). Interacts with DCUN1D1 and UBE2M. Interacts with DCUN1D3. Interacts with DCUN1D4 (By similarity). Identified in a complex with RBX1 and GLMN (By similarity). Interacts with CEP68 as part of the SCF(FBXW11) complex; the interaction is probably mediated by FBXW11 and the complex also contains CDK5RAP2 and PCNT. Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1. Interacts with COPS9. Interacts with UBXN1 (By similarity). Interacts with KAT7, probably as part of an SCF complex; the interaction mediates KAT7 ubiquitination (PubMed:23319590). Interacts with NOTCH2 (By similarity). Part of a complex that contains DCUN1D5, CUL1 and RBX1; this interaction is bridged by CUL1 (By similarity). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (By similarity).SUBUNIT (Microbial infection) Interacts with murine cytomegalovirus M48.TISSUE SPECIFICITY Embryo fibroblasts and embryo preadipocytes.PTM Neddylated; which enhances the ubiquitination activity of SCF. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.PTM (Microbial infection) Deneddylated by murine cytomegalovirus M48 leading to a S-phase-like environment that is required for efficient replication of the viral genome.SIMILARITY Belongs to the cullin family. UniProt Q9WTX6 1 EQUAL 776 EQUAL Reactome DB_ID: 5610356 1 UniProt:Q5SRY7 Fbxw11 Fbxw11 Btrcp2 Fbw1b Fbxw11 Fbxw1b FUNCTION Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins. SCF(FBXW11) mediates the ubiquitination of phosphorylated CTNNB1 and participates in Wnt signaling regulation. SCF(FBXW11) mediates the ubiquitination of phosphorylated NFKBIA, which degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. SCF(FBXW11) mediates the ubiquitination of IFNAR1. SCF(FBXW11) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis (By similarity). Involved in the oxidative stress-induced a ubiquitin-mediated decrease in RCAN1. Mediates the degradation of CDC25A induced by ionizing radiation in cells progressing through S phase and thus may function in the intra-S-phase checkpoint. Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and phosphorylated PER2. SCF(FBXW11) mediates the ubiquitination of CYTH1, and probably CYTH2 (By similarity).SUBUNIT Self-associates. Component of the SCF(FBXW11) complex formed of CUL1, SKP1, RBX1 and a FBXW11 dimer. Interacts with BTRC, BST2, PER1, RCAN1 and USP47. Interacts with phosphorylated ubiquitination substrates CTNNB1, NFKBIA, IFNAR1, PER1 and PER2; the interaction requires the phosphorylation of the two serine residues in the substrates' destruction motif D-S-G-X(2,3,4)-S. Interacts with TRIM21. Interacts with PER3. Interacts with phosphorylated ubiquitination substrate CEP68 (By similarity). Interacts with INAVA (By similarity). Interacts with REST (By similarity).INDUCTION Expression is negatively regulated by Wnt/beta-catenin pathway.DOMAIN The N-terminal D domain mediates homodimerization. UniProt Q5SRY7 1 EQUAL 542 EQUAL Reactome Database ID Release 82 9860371 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=9860371 Reactome R-MMU-1168592 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-MMU-1168592.1 Reactome DB_ID: 9893474 1 p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 [cytosol] p-S927,S932-NFKB1(1-968):p-S,T-MAP3K8:TNIP2 Reactome DB_ID: 9893472 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 DB_ID: 9850207 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: 9850197 1 1 EQUAL 429 EQUAL Reactome Database ID Release 82 9893474 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=9893474 Reactome R-MMU-5684268 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-MMU-5684268.1 Reactome DB_ID: 9893476 1 SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2 [cytosol] SCF-beta-TrCP1,2:p-S927,S932-NFKB1:p-S,T-MAP3K8:TNIP2 Reactome DB_ID: 9860371 1 Reactome DB_ID: 9893474 1 Reactome Database ID Release 82 9893476 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=9893476 Reactome R-MMU-5684270 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-MMU-5684270.1 Reactome Database ID Release 82 9893478 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=9893478 Reactome R-MMU-5684248 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-MMU-5684248.1 IKK-mediated NFkB p105 phosphorylation generates a binding site for betaTrCP, the receptor subunit of the SCF-type beta-TrCP ubiquitin E3 ligase complex. 11158290 Pubmed 2001 Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha Heissmeyer, V Krappmann, D Hatada, E N Scheidereit, C Mol. Cell. Biol. 21:1024-35 14673179 Pubmed 2004 Dual effects of IkappaB kinase beta-mediated phosphorylation on p105 Fate: SCF(beta-TrCP)-dependent degradation and SCF(beta-TrCP)-independent processing Cohen, S Achbert-Weiner, H Ciechanover, A Mol Cell Biol 24:475-86 inferred by electronic annotation IEA GO IEA 6.3.2.19 SCF betaTrCP ubiquitinates NFKB p105 within p-S927, S932-NFkB p105:TPL2:ABIN2 SCF betaTrCP ubiquitinates NFKB p105 within p-S927, S932-NFkB p105:TPL2:ABIN2 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: 9893476 1 Converted from EntitySet in Reactome Reactome DB_ID: 9816098 9 Reactome DB_ID: 9850209 1 Reactome DB_ID: 9860371 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9893476 Reactome Database ID Release 82 9893479 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=9893479 Reactome Database ID Release 82 9893481 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=9893481 Reactome R-MMU-5684250 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-MMU-5684250.1 Beta-TrCP ubiquitinates p105 at several lysine residues within the C-terminal region 660-968. The level of ubiquitination is variable; in this reaction p105 is represented with 3 ubiquitinated lysine residues. Removal of all lysines within this region abolishes subsequent p105 degradation. 9535861 Pubmed 1998 Enzymes catalyzing ubiquitination and proteolytic processing of the p105 precursor of nuclear factor kappaB1 Coux, O Goldberg, A L J Biol Chem 273:8820-8 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: 9850209 1 Reactome DB_ID: 9850207 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 Converted from EntitySet in Reactome Reactome DB_ID: 9816098 9 Reactome DB_ID: 9850197 1 1 EQUAL 429 EQUAL Reactome Database ID Release 82 9893492 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=9893492 Reactome R-MMU-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-MMU-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 9927146 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=9927146 Reactome R-MMU-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-MMU-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: 29358 4 Reactome DB_ID: 9833491 1 UniProt:Q8C050 UniProt Q8C050 1 EQUAL 802 EQUAL Reactome DB_ID: 113582 4 Reactome DB_ID: 9833497 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: 9833548 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 9833549 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=9833549 Reactome Database ID Release 82 9833551 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=9833551 Reactome R-MMU-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-MMU-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: 29358 4 Reactome DB_ID: 9833491 1 1 EQUAL 802 EQUAL Reactome DB_ID: 113582 4 Reactome DB_ID: 9833497 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: 9828442 Reactome Database ID Release 82 9833498 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=9833498 Reactome Database ID Release 82 9833500 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=9833500 Reactome R-MMU-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-MMU-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> Converted from EntitySet in Reactome Reactome DB_ID: 9833520 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 Rps6ka3 [nucleoplasm] RPS6KA2 [nucleoplasm] RPS6KA1 [nucleoplasm] UniProt P18654 UniProt Q9WUT3 UniProt P18653 Reactome DB_ID: 29358 6 Reactome DB_ID: 113582 6 Converted from EntitySet in Reactome Reactome DB_ID: 9833537 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,T359,T573-RPS6KA1 [nucleoplasm] phospho-p-4S,T231,T365-RPS6KA3 [nucleoplasm] p-4S,T356,T570-Rps6ka2 [nucleoplasm] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833543 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 9833544 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=9833544 Reactome Database ID Release 82 9833546 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=9833546 Reactome R-MMU-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-MMU-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: 9833543 1 Reactome DB_ID: 113518 1 Converted from EntitySet in Reactome Reactome DB_ID: 9834582 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: 9834586 PP2A-ABdeltaC complex [nucleoplasm] PP2A-ABdeltaC complex Reactome DB_ID: 9834584 1 UniProt:Q7TNL5 Ppp2r5d UniProt Q7TNL5 1 EQUAL 602 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9823741 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 Converted from EntitySet in Reactome Reactome DB_ID: 9823750 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 Database ID Release 82 9834586 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=9834586 Reactome R-MMU-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-MMU-165970.1 GO 0004722 GO molecular function Reactome Database ID Release 82 9834587 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=9834587 Reactome Database ID Release 82 9834589 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=9834589 Reactome R-MMU-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-MMU-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: 9833543 1 Reactome DB_ID: 113518 1 Converted from EntitySet in Reactome Reactome DB_ID: 9834582 1 Reactome DB_ID: 113550 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9836239 ERK-specific DUSP [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity DUSP7 [nucleoplasm] Dusp6 [nucleoplasm] Dusp3 [nucleoplasm] Dusp4 [nucleoplasm] UniProt Q91Z46 UniProt Q9DBB1 UniProt Q9D7X3 UniProt Q8BFV3 GO 0004725 GO molecular function Reactome Database ID Release 82 9836240 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=9836240 Reactome Database ID Release 82 9836248 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=9836248 Reactome R-MMU-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-MMU-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 9836249 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=9836249 Reactome DB_ID: 9836246 VRK3:DUSP3 [nucleoplasm] VRK3:DUSP3 Reactome DB_ID: 9836244 1 UniProt:Q8K3G5 Vrk3 UniProt Q8K3G5 1 EQUAL 474 EQUAL Reactome DB_ID: 9836225 1 UniProt:Q9D7X3 Dusp3 1 EQUAL 185 EQUAL Reactome Database ID Release 82 9836246 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=9836246 Reactome R-MMU-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-MMU-8942511.1 Reactome Database ID Release 82 9926536 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=9926536 Reactome R-MMU-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-MMU-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 9926490 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=9926490 Reactome R-MMU-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-MMU-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: 29358 1 Reactome DB_ID: 9021874 1 UniProt:Q01147 Creb1 Creb1 Creb1 Creb-1 FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. Interacts (phosphorylated form) with TOX3 (By similarity). When phosphorylated on Ser-119, binds CREBBP. Interacts with ARRB1. Binds to HIPK2 (By similarity). Interacts with SGK1 (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (By similarity). Forms a complex with KMT2A and CREBBP (By similarity). Interacts with TOX4; CREB1 is required for full induction of TOX4-dependent activity and the interaction is increased by cAMP and inhibited by insulin (PubMed:34914893).TISSUE SPECIFICITY Ubiquitously expressed.PTM Phosphorylation of Ser-119 allows CREBBP binding. Stimulated by phosphorylation. Phosphorylated Ser-128 can be detected in the suprachiasmatic nucleus (SCN), the amygdala, the cortex, and the hippocampus but not in the striatum nor in the cerebellum. In the SCN, phosphorylation of Ser-128 and Ser-119 are stimulated by light exposure and submitted to circadian oscillations. In the retina, only phosphorylation of Ser-119 can be detected upon light exposure. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CAMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1. Phosphorylation of Ser-271 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP (By similarity). Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion. Phosphorylated by TSSK4 on Ser-119 (By similarity).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization (By similarity).SIMILARITY Belongs to the bZIP family. UniProt Q01147 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 Reactome DB_ID: 2976548 1 O-phospho-L-serine at 133 133 EQUAL 1 EQUAL 341 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9833497 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 9834559 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=9834559 Reactome Database ID Release 82 9834568 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=9834568 Reactome R-MMU-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-MMU-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: 29358 1 Reactome DB_ID: 9834555 1 UniProt:P81269 Atf1 UniProt P81269 1 EQUAL 271 EQUAL Reactome DB_ID: 113582 1 Reactome DB_ID: 9834558 1 O-phospho-L-serine at 63 (in Homo sapiens) 63 EQUAL 1 EQUAL 271 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9833497 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 9834561 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=9834561 Reactome R-MMU-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-MMU-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: 29358 1 Reactome DB_ID: 9021874 1 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 Reactome DB_ID: 2976548 1 O-phospho-L-serine at 133 133 EQUAL 1 EQUAL 341 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833537 Reactome Database ID Release 82 9834549 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=9834549 Reactome Database ID Release 82 9834551 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=9834551 Reactome R-MMU-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-MMU-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: 29358 1 Reactome DB_ID: 9021874 1 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 Reactome DB_ID: 2976548 1 O-phospho-L-serine at 133 133 EQUAL 1 EQUAL 341 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9834563 UniProt:P49138 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 9834564 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=9834564 Reactome Database ID Release 82 9834566 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=9834566 Reactome R-MMU-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-MMU-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 9926534 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=9926534 Reactome R-MMU-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-MMU-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: 9828434 1 UniProt:P16951 Atf2 UniProt P16951 1 EQUAL 505 EQUAL Reactome DB_ID: 29358 2 Reactome DB_ID: 9828438 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 Reactome DB_ID: 113582 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9828462 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 p-T180,Y182-Mapk11 [nucleoplasm] phospho-p-T183,Y185-MAPK9 [nucleoplasm] phospho-p-T,Y-MAPK8 [nucleoplasm] p-T180,Y182-Mapk14 [nucleoplasm] phospho-p-T221,Y223-MAPK10 [nucleoplasm] Reactome Database ID Release 82 9828463 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=9828463 Reactome Database ID Release 82 9828465 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=9828465 Reactome R-MMU-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-MMU-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 Activated JNKs phosphorylate c-JUN Activated JNKs phosphorylate c-JUN 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: 9828468 1 UniProt:P05627 Jun Jun Jun FUNCTION Transcription factor that recognizes and binds to the AP-1 consensus motif 5'-TGA[GC]TCA-3' (PubMed:14707112). Heterodimerizes with proteins of the FOS family to form an AP-1 transcription factor complex, thereby enhancing its DNA binding activity to the AP-1 consensus sequence 5'-TGA[GC]TCA-3' and enhancing its transcriptional activity (PubMed:2498083). Together with FOSB, plays a role in activation-induced cell death of T cells by binding to the AP-1 promoter site of FASLG/CD95L, and inducing its transcription in response to activation of the TCR/CD3 signaling pathway (By similarity). Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation (PubMed:17210646). Involved in activated KRAS-mediated transcriptional activation of USP28 (By similarity). Binds to the USP28 promoter (By similarity).SUBUNIT Heterodimer with either BATF3 or ATF7 (By similarity). Heterodimer with FOS (PubMed:29272704). Heterodimer with FOSB isoform 1 and 2 (PubMed:29272704). Component of an AP-1 transcription factor complex composed of JUN-FOS heterodimers (PubMed:2498083). As part of the AP-1 transcription factor complex, forms heterodimers with FOSB, thereby binding to the AP-1 consensus sequence and stimulating transcription (PubMed:2498083). The ATF7/JUN heterodimer is essential for ATF7 transactivation activity. Interacts with SP1, SPIB and TCF20. Interacts with COPS5; the interaction leads indirectly to its phosphorylation. Component of the SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site. The SMAD3/SMAD4 heterodimer acts synergistically with the JUN/FOS heterodimer to activate transcription in response to TGF-beta (By similarity). Interacts (via its basic DNA binding and leucine zipper domains) with SMAD3 (via an N-terminal domain); the interaction is required for TGF-beta-mediated transactivation of the SMAD3/SMAD4/JUN/FOS/complex (By similarity). Interacts with DSIPI; the interaction inhibits the binding of active AP1 to its target DNA (PubMed:11397794). Interacts with HIVEP3 and MYBBP1A (PubMed:9447996, PubMed:14707112). Interacts with methylated RNF187 (PubMed:20852630). Binds to HIPK3. Interacts (when phosphorylated) with FBXW7 (By similarity). Interacts with PRR7 (PubMed:27458189). Found in a complex with PRR7 and FBXW7 (By similarity). Interacts with PRR7 and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (By similarity). Interacts with RBM39 (PubMed:11704680). Interacts with PAGE4 (By similarity). Interacts with FOSL1 and FOSL2 (PubMed:29272704).PTM Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances the transcriptional activity. Phosphorylated by HIPK3. Phosphorylated by DYRK2 at Ser-246; this primes the protein for subsequent phosphorylation by GSK3B at Thr-242. Phosphorylated at Thr-242, Ser-246 and Ser-252 by GSK3B; phosphorylation reduces its ability to bind DNA. Phosphorylated by PAK2 at Thr-2, Thr-8, Thr-89, Thr-93 and Thr-289 thereby promoting JUN-mediated cell proliferation and transformation. Phosphorylated by PLK3 following hypoxia or UV irradiation, leading to increase DNA-binding activity (By similarity).PTM Ubiquitinated by the SCF(FBXW7), leading to its degradation. Ubiquitination takes place following phosphorylation, that promotes interaction with FBXW7.PTM Acetylated at Lys-271 by EP300.SIMILARITY Belongs to the bZIP family. Jun subfamily. UniProt P05627 1 EQUAL 331 EQUAL Reactome DB_ID: 113582 2 Reactome DB_ID: 9828470 1 O-phospho-L-serine at 63 63 EQUAL O-phospho-L-serine at 73 73 EQUAL 1 EQUAL 331 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9828458 GO 0004705 GO molecular function Reactome Database ID Release 82 9828471 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=9828471 Reactome Database ID Release 82 9828473 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=9828473 Reactome R-MMU-168136 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-MMU-168136.1 JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus. 9561845 Pubmed 1998 Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development Ip, YT Davis, RJ Curr Opin Cell Biol 10:205-19 18793328 Pubmed 2008 c-Jun expression, activation and function in neural cell death, inflammation and repair Raivich, G J Neurochem 107:898-906 10871633 Pubmed 2000 c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity Dennler, S Prunier, C Ferrand, N Gauthier, JM Atfi, A J Biol Chem 275:28858-65 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: 9769935 1 UniProt:P01101 Fos Fos Fos FUNCTION Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor. On TGF-beta activation, forms a multimeric SMAD3/SMAD4/JUN/FOS complex, at the AP1/SMAD-binding site to regulate TGF-beta-mediated signaling (By similarity). Has a critical function in regulating the development of cells destined to form and maintain the skeleton. It is thought to have an important role in signal transduction, cell proliferation and differentiation. In growing cells, activates phospholipid synthesis, possibly by activating CDS1 and PI4K2A. This activity requires Tyr-dephosphorylation and association with the endoplasmic reticulum.SUBUNIT Heterodimer; with JUN (PubMed:29272704). Component of the SMAD3/SMAD4/JUN/FOS complex required for synergistic TGF-beta-mediated transcription at the AP1 promoter site (By similarity). Interacts with SMAD3; the interaction is weak even on TGF-beta activation (By similarity). Interacts with MAFB (By similarity). Interacts with DSIPI; this interaction inhibits the binding of active AP1 to its target DNA (PubMed:11397794). Interacts with CDS1 and PI4K2A, but not with CDIPT, nor PI4K2B (PubMed:22105363). Interacts (via bZIP domain and leucine-zipper region) with the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF) subunits SMARCB1, SMARCC2 and SMARCD1 (PubMed:29272704). Interacts (via bZIP domain and leucine-zipper region) with ARID1A (PubMed:29272704).PTM Phosphorylated in the C-terminal upon stimulation by nerve growth factor (NGF) and epidermal growth factor (EGF). Phosphorylated, in vitro, by MAPK and RSK1. Phosphorylation on both Ser-362 and Ser-374 by MAPK1/2 and RSK1/2 leads to protein stabilization with phosphorylation on Ser-374 being the major site for protein stabilization on NGF stimulation. Phosphorylation on Ser-362 and Ser-374 primes further phosphorylations on Thr-325 and Thr-331 through promoting docking of MAPK to the DEF domain. Phosphorylation on Thr-232, induced by HA-RAS, activates the transcriptional activity and antagonizes sumoylation. Phosphorylation on Ser-362 by RSK2 in osteoblasts contributes to osteoblast transformation (By similarity).PTM Constitutively sumoylated with SUMO1, SUMO2 and SUMO3. Desumoylated by SENP2. Sumoylation requires heterodimerization with JUN and is enhanced by mitogen stimulation. Sumoylation inhibits the AP-1 transcriptional activity and is, itself, inhibited by Ras-activated phosphorylation on Thr-232 (By similarity).PTM In quiescent cells, the small amount of FOS present is phosphorylated at Tyr-10 and Tyr-30 by SRC. This Tyr-phosphorylated form is cytosolic. In growing cells, dephosphorylated by PTPN2. Dephosphorylation leads to the association with endoplasmic reticulum membranes and activation of phospholipid synthesis.SIMILARITY Belongs to the bZIP family. Fos subfamily. UniProt P01101 1 EQUAL 380 EQUAL Reactome DB_ID: 113582 4 Reactome DB_ID: 9849707 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9833548 Reactome Database ID Release 82 9849730 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=9849730 Reactome R-MMU-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-MMU-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 Formation of Activated Protein 1 (AP-1) complex. ATF2/c-JUN heterodimer. Formation of Activated Protein 1 (AP-1) complex. ATF2/c-JUN heterodimer. 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: 9828438 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 Reactome DB_ID: 9828470 1 O-phospho-L-serine at 63 63 EQUAL O-phospho-L-serine at 73 73 EQUAL 1 EQUAL 331 EQUAL Reactome DB_ID: 9828640 1 p-2S-cJUN:p-2T-ATF2 [nucleoplasm] p-2S-cJUN:p-2T-ATF2 Reactome DB_ID: 9828438 1 O-phospho-L-threonine at 71 (in Homo sapiens) 71 EQUAL O-phospho-L-threonine at 69 (in Homo sapiens) 69 EQUAL