BioPAX pathway converted from "NOD1/2 Signaling Pathway" in the Reactome database. NOD1/2 Signaling Pathway NOD1/2 Signaling Pathway 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> MDP elicits a NOD2 response MDP elicits a NOD2 response 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: 708341 1 cytosol GO 0005829 muramyl dipeptide [ChEBI:59414] muramyl dipeptide Reactome http://www.reactome.org ChEBI 59414 Reactome DB_ID: 10110371 1 UniProt:Q6E804 NOD2 Bos taurus NCBI Taxonomy 9913 UniProt Q6E804 Chain Coordinates 1 EQUAL 1040 EQUAL Reactome DB_ID: 10110373 1 MDP:NOD2 [cytosol] MDP:NOD2 Reactome DB_ID: 708341 1 Reactome DB_ID: 10110371 1 1 EQUAL 1040 EQUAL Reactome Database ID Release 81 10110373 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10110373 Reactome R-BTA-168414 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-BTA-168414.1 Reactome Database ID Release 81 10110385 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10110385 Reactome R-BTA-168412 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-BTA-168412.1 Muramyl dipeptide (MDP) is an essential structural component of bacterial peptidoglycan (PGN) and the minimal elicitor recognized by NOD2. As MDP is present in nearly all bacteria NOD2 is a general sensor of bacteria. NOD2 has additionally been reported to respond to ssRNA (Sabbah et al. 2009) and play a role in T cell activation (Shaw et al. 2011). 12527755 Pubmed 2003 Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection Girardin, SE Boneca, IG Viala, J Chamaillard, M Labigne, A Thomas, G Philpott, DJ Sansonetti, PJ J Biol Chem 278:8869-72 12514169 Pubmed 2003 Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease Inohara, N Ogura, Y Fontalba, A Gutierrez, O Pons, F Crespo, J Fukase, K Inamura, S Kusumoto, S Hashimoto, M Foster, SJ Moran, AP Fernandez-Luna, JL Nunez, G J Biol Chem 278:5509-12 21251876 Pubmed 2011 The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation Shaw, MH Kamada, N Warner, N Kim, YG Nunez, G Trends Immunol 32:73-9 19701189 Pubmed 2009 Activation of innate immune antiviral responses by Nod2 Sabbah, A Chang, TH Harnack, R Frohlich, V Tominaga, K Dube, PH Xiang, Y Bose, S Nat Immunol 10:1073-80 inferred by electronic annotation IEA GO IEA Activated NOD2 oligomerizes Activated NOD2 oligomerizes 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: 10110373 6 Reactome DB_ID: 10110375 1 MDP:NOD2 oligomer [cytosol] MDP:NOD2 oligomer Reactome DB_ID: 10110373 6 Reactome Database ID Release 81 10110375 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10110375 Reactome R-BTA-708350 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-BTA-708350.1 Reactome Database ID Release 81 10133032 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133032 Reactome R-BTA-708349 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-BTA-708349.1 NOD2 is activated by MDP in a LRR domain dependent manner. Based on studies of NOD1 activation and structural data from the NLR-related scaffold Apaf-1, the LRR domain is believed to have a negative influence on NOD2 self-association (Inohara et al. 2000, Riedl & Salvesen 2007); binding of MDP is believed to cause conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on these observations, NOD2 is generally believed to form hexamers or heptamers (Martinon & Tschopp, 2005). NOD2 oliogomerization has been observed in NOD2-transfected HEK293T cells (Zhao et al. 2007). 15967716 Pubmed 2005 NLRs join TLRs as innate sensors of pathogens Martinon, F Tschopp, Jürg Trends Immunol 26:447-54 17377525 Pubmed 2007 The apoptosome: signalling platform of cell death Riedl, SJ Salvesen, Guy S. Nat Rev Mol Cell Biol 8:405-13 17303577 Pubmed 2007 Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells Zhao, L Kwon, MJ Huang, S Lee, JY Fukase, K Inohara, N Hwang, DH J Biol Chem 282:11618-28 10880512 Pubmed 2000 An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways Inohara, N Koseki, T Lin, J del Peso, L Lucas, PC Chen, FF Ogura, Y Nunez, G J Biol Chem 275:27823-31 inferred by electronic annotation IEA GO IEA Activated NOD oligomer recruites RIP2 (RICK) Activated NOD oligomer recruites RIP2 (RICK) 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: 10110375 1 Reactome DB_ID: 10110379 6 UniProt:Q3SZJ2 RIPK2 UniProt Q3SZJ2 1 EQUAL 540 EQUAL Reactome DB_ID: 10110381 1 PAMP:NOD oligomer:RIP2 [cytosol] PAMP:NOD oligomer:RIP2 Reactome DB_ID: 10110375 1 Reactome DB_ID: 10110379 6 1 EQUAL 540 EQUAL Reactome Database ID Release 81 10110381 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10110381 Reactome R-BTA-168409 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-BTA-168409.1 Reactome Database ID Release 81 10110383 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10110383 Reactome R-BTA-168405 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-BTA-168405.1 NOD1 and NOD2 (NOD) interact with the inflammatory kinase RIP2 (RICK) via a homophilic association between CARD domains (Inohara et al. 1999, Ogura et al. 2001). This has the effect of bringing several RIP2 molecules into close proximity, enhancing RIP2-RIP2 interactions (Inohara et al. 2000), a key step in what is termed the 'Induced Proximity Model' for NOD activation of NFkappaB. Note that though the interaction of every NOD with RIP2 is implied here this may not be required for RIP2 activation. RIP2 recruitment leads to subsequent activation of NFkappaB. The kinase activity of RIP2 was initially described as not required (Inohara et al. 2000) but subsequently suggested to be involved in determining signal strength (Windheim et al. 2007) and recently found to be essential for maintaining RIP2 stability and it's role in mediating NOD signaling (Nembrini et al. 2009). 10329646 Pubmed 1999 Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB Inohara, N Koseki, T del Peso, L Hu, Y Yee, C Chen, S Carrio, R Merino, J Liu, D Ni, J Nunez, G J Biol Chem 274:14560-7 19473975 Pubmed 2009 The kinase activity of Rip2 determines its stability and consequently Nod1- and Nod2-mediated immune responses Nembrini, C Kisielow, J Shamshiev, AT Tortola, L Coyle, AJ Kopf, M Marsland, BJ J Biol Chem 284:19183-8 11087742 Pubmed 2001 Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB Ogura, Y Inohara, N Benito, A Chen, FF Yamaoka, S Nunez, G J Biol Chem 276:4812-8 17348859 Pubmed 2007 Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide Windheim, M Lang, C Peggie, M Plater, LA Cohen, P Biochem J 404:179-90 10224040 Pubmed 1999 Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB Bertin, J Nir, WJ Fischer, CM Tayber, OV Errada, PR Grant, JR Keilty, JJ Gosselin, ML Robison, KE Wong, GH Glucksmann, MA DiStefano, PS J Biol Chem 274:12955-8 inferred by electronic annotation IEA GO IEA RIP2 binds NEMO RIP2 binds NEMO 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: 10110273 1 UniProt:Q95KU9 IKBKG UniProt Q95KU9 1 EQUAL 419 EQUAL Reactome DB_ID: 10110381 1 Reactome DB_ID: 10132979 1 PAMP:NOD oligomer:RIP2:NEMO [cytosol] PAMP:NOD oligomer:RIP2:NEMO Reactome DB_ID: 10110273 1 1 EQUAL 419 EQUAL Reactome DB_ID: 10110381 1 Reactome Database ID Release 81 10132979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10132979 Reactome R-BTA-688994 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-BTA-688994.1 Reactome Database ID Release 81 10132981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10132981 Reactome R-BTA-622415 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-BTA-622415.1 An intermediate region located between the CARD and kinase domains mediates the interaction of RIP2 with the IKK complex regulatory subunit NEMO. This interaction is presumed to link NOD1:RIP2 to the IKK complex, ultimately leading to the phosphorylation of IkappaB-alpha and the activation of NF-kappaB (Inohara et al. 2000). Although every NOD molecule in the oligomeric complex is represented as binding RIP2, binding to every member of the complex may not be required for subsequent signaling events. 18079694 Pubmed 2008 A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation Hasegawa, M Fujimoto, Y Lucas, PC Nakano, H Fukase, K Nunez, G Inohara, N EMBO J 27:373-83 inferred by electronic annotation IEA GO IEA CYLD deubiquitinates NEMO CYLD deubiquitinates NEMO 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: 10133079 1 PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO [cytosol] PAMP:NOD oligomer:RIP2:K63-Ub-K285-NEMO Reactome DB_ID: 10110381 1 Reactome DB_ID: 10133077 1 ubiquitinylated lysine (K63polyUb [cytosol]) at 285 (in Homo sapiens) 285 EQUAL ubiquitinylated lysine [MOD:01148] 1 EQUAL 419 EQUAL Reactome Database ID Release 81 10133079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133079 Reactome R-BTA-741389 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-BTA-741389.1 Reactome DB_ID: 10132979 1 Reactome DB_ID: 10110439 1 K63polyUb [cytosol] K63polyUb PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10107151 UniProt:Q1RMU2 CYLD UniProt Q1RMU2 1 EQUAL 956 EQUAL GO 0061578 GO molecular function Reactome Database ID Release 81 10133080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133080 Reactome Database ID Release 81 10133082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133082 Reactome R-BTA-741411 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-BTA-741411.1 RIP2-induced ubiquitination of NEMO and consequent NFkappaB activation can be reversed in a dose-responsive manner by the deubiquitinase CYLD, suggesting that CYLD negatively regulates RIP2-induced NEMO ubiquitinylation. 15620648 Pubmed 2004 The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO Abbott, Derek W Wilkins, A Asara, JM Cantley, Lewis C Curr Biol 14:2217-27 12917691 Pubmed 2003 The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination Kovalenko, A Chable-Bessia, C Cantarella, G Israel, A Wallach, D Courtois, G Nature 424:801-5 inferred by electronic annotation IEA GO IEA RIP2 is K63 polyubiquitinated RIP2 is K63 polyubiquitinated 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: 10132979 1 Reactome DB_ID: 10110439 6 Reactome DB_ID: 10131024 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO [cytosol] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO Reactome DB_ID: 10131022 1 PAMP:NOD oligomer:K63-Ub-RIP2 [cytosol] PAMP:NOD oligomer:K63-Ub-RIP2 Reactome DB_ID: 10131020 6 ubiquitinylated lysine (K63polyUb [cytosol]) at 209 (in Homo sapiens) 209 EQUAL 1 EQUAL 540 EQUAL Reactome DB_ID: 10110375 1 Reactome Database ID Release 81 10131022 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10131022 Reactome R-BTA-706482 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-BTA-706482.1 Reactome DB_ID: 10110273 1 1 EQUAL 419 EQUAL Reactome Database ID Release 81 10131024 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10131024 Reactome R-BTA-706480 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-BTA-706480.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10133015 RIP2 ubiquitin ligases [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ITCH [cytosol] UniProt F1MGQ5 GO 0019787 GO molecular function Reactome Database ID Release 81 10133016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133016 Reactome Database ID Release 81 10133018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133018 Reactome R-BTA-688137 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-BTA-688137.1 The close physical proximity of RIP2 proteins that results from NOD oligomerization triggers the conjugation of lysine (K)-63 linked polyubiquitin chains onto RIP2. Ubiquitination at K209 within the kinase domain was required for subsequent NFkappaB signaling (Hasegawa et al. 2008). The identity of the ubiquitin ligase responsible is an open question, with several candidates capable of RIP2 ubiquitination. TRAF6 has been reported as the ubiquitin ligase responsible (Yang et al. 2007) but subsequent reports suggest it is not responsible (see Tao et al. 2009 and Bertrand et al. 2009). Other candidates include the HECT-domain containing E3 ubiquitin ligase ITCH, which is able to K63 ubiquitinate RIP2 (at an undetermined site that is not K209) and is required for optimal NOD2:RIP2-induced p38 and JNK activation, while inhibiting NOD2:RIP2-induced NFkappaB activation (Tao et al. 2009). The Baculoviral IAP repeat-containing proteins (Birc/cIAP) 2 and 3 have also been shown capable of RIP2 ubiquitination and required for NOD2 signaling (Bertrand et al. 2009). It has been suggested that ITCH and a K209 E3 ligase compete for ubiquitination of RIP2, so that a subset of RIP2 becomes ubiquitinated on K209 to stimulate NEMO ubiquitination and subsequent NFkappaB activation while a second subset of RIP2 is polyubiquitinated by ITCH to activate JNK and p38 signaling (Tao et al. 2009). 19464198 Pubmed 2009 Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2 Bertrand, MJ Doiron, K Labbé, K Korneluk, RG Barker, PA Saleh, M Immunity 30:789-801 17562858 Pubmed 2007 Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains Abbott, Derek W Yang, Y Hutti, JE Madhavarapu, S Kelliher, MA Cantley, Lewis C Mol Cell Biol 27:6012-25 17947236 Pubmed 2007 NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2 Yang, Y Yin, C Pandey, A Abbott, Derek W Sassetti, C Kelliher, MA J Biol Chem 282:36223-9 19592251 Pubmed 2009 ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways Tao, M Scacheri, PC Marinis, JM Harhaj, EW Matesic, LE Abbott, Derek W Curr Biol 19:1255-63 inferred by electronic annotation IEA GO IEA TNFAIP3 (A20) deubiquitinates RIP2 TNFAIP3 (A20) deubiquitinates RIP2 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: 10131024 1 Reactome DB_ID: 10132979 1 Reactome DB_ID: 10110439 6 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10107155 UniProt:A0A3Q1NKI9 TNFAIP3 UniProt A0A3Q1NKI9 1 EQUAL 790 EQUAL Reactome Database ID Release 81 10133007 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133007 Reactome Database ID Release 81 10133009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133009 Reactome R-BTA-688136 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-BTA-688136.1 The deubiquitinase A20 is a negative feedback regulator of inflammatory responses, induced by NFkappaB activation (Krikos et al. 1992) and NOD stimulation (Masumoto et al. 2006). A20 can deubiquitinate RIP2 and restricts NOD2 induced signals (Hitosumatsu et al. 2008). 1381359 Pubmed 1992 Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements Krikos, A Laherty, CD Dixit, VM J Biol Chem 267:17971-6 16418393 Pubmed 2006 Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo Masumoto, J Yang, K Varambally, S Hasegawa, M Tomlins, SA Qiu, S Fujimoto, Y Kawasaki, A Foster, SJ Horie, Y Mak, TW Nunez, G Chinnaiyan, AM Fukase, K Inohara, N J Exp Med 203:203-13 18342009 Pubmed 2008 The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals Hitotsumatsu, O Ahmad, RC Tavares, R Wang, M Philpott, D Turer, EE Lee, BL Shiffin, N Advincula, R Malynn, BA Werts, C Ma, A Immunity 28:381-90 inferred by electronic annotation IEA GO IEA K63 polyubiquitinated RIP2 associates with the TAK1 complex K63 polyubiquitinated RIP2 associates with the 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: 10131024 1 Reactome DB_ID: 10133024 1 plasma membrane GO 0005886 TAK1 complex [plasma membrane] TAK1 complex Converted from EntitySet in Reactome Reactome DB_ID: 10133022 1 TAB2,TAB3 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TAB2 [plasma membrane] TAB3 [plasma membrane] UniProt E1B7Z0 UniProt A0A3Q1M7T8 Reactome DB_ID: 10130474 1 UniProt:A2VDU3 MAP3K7 UniProt A2VDU3 1 EQUAL 606 EQUAL Reactome DB_ID: 10130478 1 UniProt:A0A3Q1LT51 TAB1 UniProt A0A3Q1LT51 1 EQUAL 504 EQUAL Reactome Database ID Release 81 10133024 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133024 Reactome R-BTA-8947970 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-BTA-8947970.1 Reactome DB_ID: 10133026 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex [plasma membrane] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex Reactome DB_ID: 10131024 1 Reactome DB_ID: 10133024 1 Reactome Database ID Release 81 10133026 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133026 Reactome R-BTA-706478 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-BTA-706478.1 Reactome Database ID Release 81 10133028 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133028 Reactome R-BTA-688985 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-BTA-688985.1 K63-polyubiquitinated RIP2 is able to recruit the components of the TAK1 complex, which consists of TAK1, TAB1 and TAB2. inferred by electronic annotation IEA GO IEA TAK1 is activated TAK1 is activated 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: 10133026 1 Reactome DB_ID: 10131026 1 PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex [cytosol] PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex Reactome DB_ID: 10130488 1 TAK1 complex [cytosol] TAK1 complex Reactome DB_ID: 10130474 1 1 EQUAL 606 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10130486 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] Reactome DB_ID: 10130478 1 1 EQUAL 504 EQUAL Reactome Database ID Release 81 10130488 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10130488 Reactome R-BTA-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-BTA-446878.1 Reactome DB_ID: 10131024 1 Reactome Database ID Release 81 10131026 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10131026 Reactome R-BTA-706477 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-BTA-706477.1 Reactome Database ID Release 81 10133030 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133030 Reactome R-BTA-706479 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-BTA-706479.1 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). 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 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 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 inferred by electronic annotation IEA GO IEA 2.7.11.25 TAK1 phosphorylates MKK6 TAK1 phosphorylates 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: 10131041 1 UniProt:Q5E9X2 MAP2K6 UniProt Q5E9X2 1 EQUAL 334 EQUAL Reactome DB_ID: 113592 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 29370 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 10130990 1 O-phospho-L-serine at 207 (in Homo sapiens) 207 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-threonine at 211 (in Homo sapiens) 211 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 334 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10130488 GO 0004709 GO molecular function Reactome Database ID Release 81 10133065 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133065 Reactome Database ID Release 81 10133067 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10133067 Reactome R-BTA-727819 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-BTA-727819.1 Within the TAK1 complex (TAK1 plus TAB1 and TAB2/3) activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways. TAB2 within the TAK1 complex can be linked to polyubiquitinated TRAF6; current models of IL-1 signaling suggest that the TAK1 complex is linked to TRAF6, itself complexed with polyubiquitinated IRAK1 which is linked via NEMO to the IKK complex. The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex (Hasegawa et al. 2008). 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 2.7.12.2 Activation of p38 MAPK Activation of p38 MAPK 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: 10140797 1 p38 MAPK [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 113592 8 Converted from EntitySet in Reactome Reactome DB_ID: 10140803 1 Phospho-p38 MAPK [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 29370 8 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10130990 O-phospho-L-serine at 207 (in Homo sapiens) 207 EQUAL O-phospho-L-threonine at 211 (in Homo sapiens) 211 EQUAL 1 EQUAL 334 EQUAL GO 0004708 GO molecular function Reactome Database ID Release 81 10140804 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10140804 Reactome Database ID Release 81 10140806 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10140806 Reactome R-BTA-1247960 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-BTA-1247960.1 p38 MAPK has 4 representative isoforms in humans, p38 alpha (Han et al. 1993), p38-beta (Jiang et al. 1996), p38-gamma (Lechner et al. 1996) and p38-delta (Hu et al. 1999). All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms (Zarubin & Han, 2005). p38 alpha and gamma are also activated by MKK3. 10066767 Pubmed 1999 Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines Hu, MC Wang, YP Mikhail, A Qiu, WR Tan, TH J Biol Chem 274:7095-102 7693711 Pubmed 1993 Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14 Han, J Lee, JD Tobias, PS Ulevitch, RJ J Biol Chem 268:25009-14 8663524 Pubmed 1996 Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta) Jiang, Y Chen, C Li, Z Guo, W Gegner, JA Lin, S Han, J J Biol Chem 271:17920-6 9430721 Pubmed 1998 Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6 Enslen, H Raingeaud, J Davis, RJ J Biol Chem 273:1741-8 8633070 Pubmed 1996 ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation Lechner, C Zahalka, MA Giot, JF Møller, NP Ullrich, A Proc Natl Acad Sci U S A 93:4355-9 15686620 Pubmed 2005 Activation and signaling of the p38 MAP kinase pathway Zarubin, T Han, J Cell Res 15:11-8 inferred by electronic annotation IEA GO IEA AAMP binds NOD2 AAMP binds NOD2 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: 10199630 1 UniProt:Q3SZK1 AAMP UniProt Q3SZK1 1 EQUAL 434 EQUAL Reactome DB_ID: 10110371 1 1 EQUAL 1040 EQUAL Reactome DB_ID: 10199674 1 AAMP:NOD2 [cytosol] AAMP:NOD2 Reactome DB_ID: 10199630 1 1 EQUAL 434 EQUAL Reactome DB_ID: 10110371 1 1 EQUAL 1040 EQUAL Reactome Database ID Release 81 10199674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10199674 Reactome R-BTA-9676152 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-BTA-9676152.1 Reactome Database ID Release 81 10199676 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10199676 Reactome R-BTA-9676160 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-BTA-9676160.1 AAMP (Angio-associated migratory cell protein) binds the human nucleotide-binding domain, leucine rich repeat containing (NLR) family member NOD2. The interaction involves WD40 domains 2-4 of AAMP. NOD2 is critically involved in innate immune protection against a variety of different bacterial pathogens. AAMP negatively regulates, through an unknown mechanism, NOD2-mediated NF-κB activation in HEK293T cells (Bielig et al. 2009). 19535145 Pubmed 2009 A function for AAMP in Nod2-mediated NF-kappaB activation Bielig, H Zurek, B Kutsch, A Menning, M Philpott, D J Sansonetti, P J Kufer, T A Mol. Immunol. 46:2647-54 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10203005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10203005 Reactome R-BTA-168638 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-BTA-168638.1 GO 0070423 GO biological process NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells (Inohara et al. 2005). NOD1 and NOD2 activation induces transcription of immune response genes, predominantly mediated by the proinflammatory transcriptional factor NFkappaB but also by AP-1 and Elk-1 (Inohara et al. 2005). NFkappaB translocates to the nucleus following release from IkappaB proteins. NOD1 and NOD2 signaling involves an interaction between their caspase-recruitment domain (CARD) and the CARD of the kinase RIPK2 (RIP2/RICK). This leads to the activation of the NFkappaB pathway and MAPK pathways (Windheim et al. 2007).<br>Activated NODs oligomerize via their NACHT domains, inducing physical proximity of RIP2 proteins that is believed to trigger their K63-linked polyubiquitination, facilitating recruitment of the TAK1 complex. RIP2 also recruits NEMO, bringing the TAK1 and IKK complexes into proximity, leading to NF-kappaB activation and activation of MAPK signaling. Recent studies have demonstrated that K63-linked regulatory ubiquitination of RIP2 is essential for the recruitment of TAK1 (Hasegawa et al. 2008, Hitosumatsu et al. 2008). As observed for toll-like receptor (TLR) signaling, ubiquitination can be removed by the deubiquitinating enzyme A20, thereby dampening NOD1/NOD2-induced NF-kappaB activation. NOD1 and NOD2 both induce K63-linked ubiquitination of RIP2, but NOD2-signaling appears to preferentially utilize the E3 ligase TRAF6, while TRAF2 and TRAF5 were shown to be important for NOD1-mediated signaling. In both cases, activation of NF-kappaB results in the upregulated transcription and production of inflammatory mediators. 18414735 Pubmed 2008 Signal transduction pathways used by NLR-type innate immune receptors Kufer, TA Mol Biosyst 4:380-6 18585455 Pubmed 2008 NOD-like receptors (NLRs): bona fide intracellular microbial sensors Shaw, MH Reimer, T Kim, YG Nunez, G Curr Opin Immunol 20:377-82 18928408 Pubmed 2009 NOD-like receptors: role in innate immunity and inflammatory disease Chen, G Shaw, MH Kim, YG Nunez, G Annu Rev Pathol 4:365-98 15952891 Pubmed 2005 NOD-LRR proteins: role in host-microbial interactions and inflammatory disease Inohara, N Chamaillard, M McDonald, C Nunez, G Annu Rev Biochem 74:355-83 inferred by electronic annotation IEA GO IEA