BioPAX pathway converted from "TLR3 cascade" in the Reactome database. TLR3 cascade TLR3 cascade Toll-like receptor 3 (TLR3) as was shown for mammals is expressed on myeloid dendritic cells, respiratory epithelium, and macrophages, and appears to play a central role in mediating both the antiviral and inflammatory responses of the innate immunity in combating viral infections.<p>Chicken TLR3 protein shows 61% identity to human TLR3.<p>The chicken ortholog of mammalian TLR3 specifically recognizes poly I:C, a dsRNA analogue, like its mammalian counterpart. In the chicken as in mammals, poly I:C rapidly induces type 1 IFN. Authored: Shamovsky, V, 2009-09-29 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 viral dsRNA binds the toll-like receptor 3 (TLR3) viral dsRNA binds the toll-like receptor 3 (TLR3) Viral dsRNA triggers an antiviral pathway mediated by toll like receptor 3. TLR3 dimerization occurs upon ligand binding to positivly charged residues on the ectodomain termini of TLR3 wich are responsible for the interaction with sugar-phosphate groups of dsRNA. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 9014378 1 endosome lumen GO 0031904 IBV dsRNA intermediate form [endosome lumen] IBV dsRNA intermediate form Reactome http://www.reactome.org Reactome DB_ID: 433892 2 endosome membrane GO 0010008 UniProt:Q0PQ88 Toll-like receptor 3 Toll-like receptor 3 TLR3 SIMILARITY Contains 1 TIR domain. Gallus gallus NCBI Taxonomy 9031 UniProt Q0PQ88 Chain Coordinates 1 EQUAL 1011 EQUAL Reactome DB_ID: 433883 1 viral dsRNA:TLR3 [endosome membrane] viral dsRNA:TLR3 Reactome DB_ID: 9014378 1 Reactome DB_ID: 433892 2 1 EQUAL 1011 EQUAL Reactome Database ID Release 83 433883 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433883 Reactome R-GGA-433883 3 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-GGA-433883.3 Reactome Database ID Release 83 434004 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434004 Reactome R-GGA-434004 3 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-GGA-434004.3 17316136 Pubmed 2007 Chicken toll-like receptor 3 recognizes its cognate ligand when ectopically expressed in human cells Schwarz, H Schneider, K Ohnemus, A Lavric, M Kothlow, S Bauer, S Kaspers, B Staeheli, P J Interferon Cytokine Res 27:97-101 25378498 Pubmed 2015 Activation of the chicken type I interferon response by infectious bronchitis coronavirus Kint, Joeri Fernandez-Gutierrez, Marcela Maier, Helena J Britton, Paul Langereis, Martijn A Koumans, Joseph Wiegertjes, Geert F Forlenza, Maria J. Virol. 89:1156-67 18420935 Pubmed 2008 Structural basis of toll-like receptor 3 signaling with double-stranded RNA Liu, L Botos, I Wang, Y Leonard, JN Shiloach, J Segal, DM Davies, DR Science 320:379-81 viral dsRNA : TRL3 recruits TICAM1 viral dsRNA : TRL3 recruits TICAM1 TICAM1 (or TRIF) is known to be an essential and exclusive adaptor used by TLR3 ; all the poly(I:C)-induced pathways leading to NFkB and IRF3 activation were abolished in TRIF–/– mice (Yamamoto et al. 2003). <p>Human TICAM1 consists of an N-terminal region (1–234), a TIR domain (235–500), and a C-terminal region (501–680).<p> The N-terminal region of TICAM1 harbors TRAF (TNF receptor associated factor) family proteins and forms complexes containing IRF-3 and/or NFkB -activating kinases. <p>The C-terminal region of TICAM1 can recruit receptor-interacting protein-1 (RIP-1), and this event is followed by the activation of IKK complex . Chicken TICAM1 encodes a 735 amino-acid protein that shares 31% sequence identity with its human and mouse orthologs. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 433883 1 Reactome DB_ID: 433866 2 cytosol GO 0005829 UniProt:A0FKC7 Toll/IL-1 recepter (TIR)-domain containing adapter inducing interferon beta Toll/IL-1 recepter (TIR)-domain containing adapter inducing interferon beta TLR adaptor molecule 1(TRIF) <submittedName> <fullName>Toll/IL-1 recepter (TIR)-domain containing adapter inducing interferon beta</fullName> </submittedName> UniProt A0FKC7 1 EQUAL 735 EQUAL Reactome DB_ID: 433947 1 viral dsRNA : TLR3 : TICAM1 [endosome membrane] viral dsRNA : TLR3 : TICAM1 Reactome DB_ID: 433883 1 Reactome DB_ID: 433979 2 1 EQUAL 735 EQUAL Reactome Database ID Release 83 433947 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433947 Reactome R-GGA-433947 2 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-GGA-433947.2 Reactome Database ID Release 83 433815 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433815 Reactome R-GGA-433815 2 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-GGA-433815.2 12539043 Pubmed 2003 TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction Oshiumi, H Matsumoto, M Funami, K Akazawa, T Seya, T Nat Immunol 4:161-7 12855817 Pubmed 2003 Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway Yamamoto, M Sato, S Hemmi, H Hoshino, K Kaisho, T Sanjo, H Takeuchi, O Sugiyama, M Okabe, M Takeda, K Science 301:640-3 17676477 Pubmed 2007 Molecular cloning and expression analysis of chicken MyD88 and TRIF genes Wheaton, S Lambourne, MD Sarson, AJ Brisbin, JT Mayameei, A Sharif, S DNA Seq 18:480-6 IKK related kinases bound to dsRNA:TLR3:TICAM1 activate IRF3 IKK related kinases bound to dsRNA:TLR3:TICAM1 activate IRF3 Cell stimulation with viral ds RNA leads to the activation of two IKK-related serine/threonine kinases, TBK1 and IKK-i which directly phosphorylate IRF3 and IRF7 promoting their dimerization and translocation into the nucleus. Although both kinases show structural and functional similarities, it seems that TBK1 and IKK-i differ in their regulation of downstream signaling events of TLR3.<p>IRF3 activation and IFN-b production by poly(I:C) are decreased in TBK1-deficient mouse fibroblasts, whereas normal activation was observed in the IKK-i-deficient fibroblasts. However, in double-deficient mouse fibroblasts, the activation of IRF3 is completely abolished, suggesting a partially redundant functions of TBK1 and IKK-i (Hemmi et al. 2004).<p>TLR3 recruits and activates PI3 kinase (PI3K), which activates the downstream kinase, Akt, leading to full phosphorylation and activation of IRF-3 [Sarkar SN et al 2004]. When PI3K is not recruited to TLR3 or its activity is blocked, IRF-3 is only partially phosphorylated and fails to bind the promoter of the target gene. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Viral dsRNA:TLR3:TICAM1 Complex Activates TBK1 Viral dsRNA:TLR3:TICAM1 Complex Activates TBK1 TBK1 and IKK epsilon(IKKi) are described as essential regulators of pathogen-triggered IFN gene activation through the direct phosphorylation of IFN regulatory factors.<p>Embryonic fibroblast cells from TBK1-deficient mice show decreased IRF3 activation and IFN induction by poly IC, while IKKi-deficient cells show normal IRF3 activation. However, the activation of IRF3 is totally abolished in TBK1 and IKKi double-deficient cells, indicating that the functions of TBK1 and IKKi are redundant in mouse embryo fibroblast cells.[Hemmi et al 2004].<p>TBK1/IKKi interact with SIKE (Suppressor of IKK epsilon), which was shown to act as an inhibitor of TBK1/IKKi-mediated type I IFN production, but not NF-kB activation signaling[Huang J et al 2005]. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 TBK1 is recruited to the Viral dsRNA:TLR3:TICAM1 complex TBK1 is recruited to the Viral dsRNA:TLR3:TICAM1 complex Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) and inhibitor of ?B kinase epsilon (IKKi) induce type I interferon expression and modulate nuclear factor ?B (NFkB) signaling (Fitzgerald KA et al. 2003; Hemmi H et al. 2004). The structural studies of TBK1 revealed a dimeric assembly which is mediated by several interfaces involving kinase domain (KD), a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 (Larabi A et al. 2013; Tu D et al. 2013). ULD of TBK1 and IKKi was involved in the control of kinase activation, substrate presentation and downstream signaling (Ikeda F et al 2007; Tu D et al. 2013). An intact TBK1 dimer was a subject to K63-linked polyubiquitination on lysines 30 and 401 (Tu D et al. 2013). Activation of TBK1 rearranged the KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al. 2013). The ubiquitination sites and dimer contacts are conserved in the close homolog IKKi (Tu D et al. 2013). The activation of TBK1 and IKKi may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al. 2009). Other studies demonstrated an essential role of TRAF3 in the activation of TBK1 (Hacker et al 2006). TBK1 and IKKi were found to interact with scaffold proteins TANK (TRAF family member associated NFkB activator), NAP1 (NAK-associated protein 1), SINTBAD (similar to NAP1 TBK1 adaptor) which connect TBK1/IKKi to pathogen-activated signaling cascades (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007; Ryzhakov G and Randow F 2007; Goncalves A et al. 2011). Chicken TBK1 protein, confirmed by transcript evidedence, shows 86% amino acid sequence identity to its human ortholog. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 433947 1 Reactome DB_ID: 434016 2 ENSEMBL:ENSGALP00000015982 ch_TBK1 ch_TBK1 TBK1 ENSEMBL ENSGALP00000015982 1 EQUAL 816 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: 433843 1 ds viral RNA : TLR3 : TICAM1 : TBK1 complex [endosome membrane] ds viral RNA : TLR3 : TICAM1 : TBK1 complex Reactome DB_ID: 433947 1 Reactome DB_ID: 571399 2 1 EQUAL 816 EQUAL Reactome Database ID Release 83 433843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433843 Reactome R-GGA-433843 2 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-GGA-433843.2 Reactome Database ID Release 83 434030 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434030 Reactome R-GGA-434030 2 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-GGA-434030.2 21931631 Pubmed 2011 Functional dissection of the TBK1 molecular network Goncalves, Adriana Bürckstümmer, Tilmann Dixit, Evelyn Scheicher, Ruth Górna, Maria W Karayel, Evren Sugar, Cristina Stukalov, Alexey Berg, Tiina Kralovics, Robert Planyavsky, Melanie Bennett, Keiryn L Colinge, Jacques Superti-Furga, Giulio PLoS ONE 6:e23971 10581243 Pubmed 1999 NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase Pomerantz, JL Baltimore, D EMBO J 18:6694-704 17599067 Pubmed 2007 Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes Ikeda, F Hecker, CM Rozenknop, A Nordmeier, RD Rogov, V Hofmann, K Akira, Shizuo Dötsch, V Dikic, I EMBO J 26:3451-62 23453972 Pubmed 2013 Structure and ubiquitination-dependent activation of TANK-binding kinase 1 Tu, Daqi Zhu, Zehua Zhou, Alicia Y Yun, Cai-hong Lee, Kyung-Eun Toms, Angela V Li, Y Dunn, Gavin P Chan, Edmond Thai, Tran Yang, Shenghong Ficarro, Scott B Marto, Jarrod A Jeon, H Hahn, WC Barbie, David A Eck, Michael J Cell Rep 3:747-58 23453971 Pubmed 2013 Crystal structure and mechanism of activation of TANK-binding kinase 1 Larabi, Amede Devos, Juliette M Ng, Sze-Ling Nanao, Max H Round, Adam Maniatis, Tom Panne, Daniel Cell Rep 3:734-46 17823124 Pubmed 2007 Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF Gatot, Jean-Stéphane Gioia, Romain Chau, Tieu-Lan Patrascu, Félicia Warnier, Michael Close, Pierre Chapelle, Jean-Paul Muraille, Eric Brown, Keith Siebenlist, Ulrich Piette, Jacques Dejardin, Emmanuel Chariot, Alain J. Biol. Chem. 282:31131-46 16306937 Pubmed 2006 Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6 Häcker, H Redecke, V Blagoev, B Kratchmarova, I Hsu, LC Wang, GG Kamps, MP Raz, E Wagner, H Häcker, G Mann, M Karin, M Nature 439:204-7 19307177 Pubmed 2009 Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation Clark, K Plater, L Peggie, M Cohen, P J Biol Chem 284:14136-46 12692549 Pubmed 2003 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway Fitzgerald, Katherine A McWhirter, SM Faia, KL Rowe, DC Latz, E Golenbock, DT Coyle, AJ Liao, SM Maniatis, T Nat Immunol 4:491-6 17568778 Pubmed 2007 SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK Ryzhakov, Grigory Randow, Felix EMBO J. 26:3180-90 15210742 Pubmed 2004 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and Hemmi, H Takeuchi, O Sato, S Yamamoto, M Kaisho, T Sanjo, H Kawai, T Hoshino, K Takeda, K J Exp Med 199:1641-50 17327220 Pubmed 2007 Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK Guo, B Cheng, G J Biol Chem 282:11817-26 2.7.11.1 Phosphorylation of IRF3 by TBK1 complexed with activated TLR3 Phosphorylation of IRF3 by TBK1 complexed with activated TLR3 IRF-3 is activated by two step phosphorylation. IKK related kinases TBK1 and/or IKKi mediate the phosphorylation of the residues Ser386 and/or Ser385 (site1) and a cluster of serine/threonine residues between Ser396 and Ser405 (site 2) [Panne et al 2007]. Phosphorylation of residues in site 2 alleviates autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitates phosphorylation at site 1. Phosphorylation at site 1 is required for IRF-3 dimerization.<p> All serine residues mentioned above were empirically defined for human IRF3. Multiple sequence alignment of human, mouse and chicken IRF3 by ClustalW showed similarity in the C-terminal domain and the following chicken residues are predicted to be involved in chicken IRF3 activation:<ul><li>Ser463 and/or Ser464 (site 1, corresponding to human Ser385 and Ser386)<li>Ser474 and Ser476 (site2,corresponding to human Ser396 and Ser398 from the cluster of Ser396-Ser405)</ul> Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 113592 3 Reactome DB_ID: 433993 1 UniProt:Q90643 IRF3 IRF3 IRF3 FUNCTION Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses. Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters. May activate transcription by complex formation with other transcriptional factors, possibly members of the STAT family. Binds specifically to the IFN-stimulated response element (ISRE) but not to the IRF-1 binding site PRD-I.TISSUE SPECIFICITY Widely expressed with higher expression in lung, spleen and intestine.INDUCTION Up-regulated by poly I:C.SIMILARITY Belongs to the IRF family. UniProt Q90643 1 EQUAL 491 EQUAL Reactome DB_ID: 29370 3 Reactome DB_ID: 434100 1 O-phospho-L-serine at 464 464 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 474 474 EQUAL O-phospho-L-serine at unknown position 1 EQUAL 491 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 433843 GO 0004674 GO molecular function Reactome Database ID Release 83 433910 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433910 Reactome Database ID Release 83 433786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433786 Reactome R-GGA-433786 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-GGA-433786.1 14703513 Pubmed 2004 Identification of Ser-386 of interferon regulatory factor 3 as critical Mori, M Yoneyama, M Ito, T Takahashi, K Inagaki, F Fujita, Toshiro J Biol Chem 279:9698-702 17526488 Pubmed 2007 Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch Panne, D McWhirter, SM Maniatis, T Harrison, SC J Biol Chem 282:22816-22 9463386 Pubmed 1998 Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300 Yoneyama, M Suhara, W Fukuhara, Y Fukuda, M Nishida, E Fujita, T EMBO J 17:1087-95 19539094 Pubmed 2009 The avian Toll-Like receptor pathway--subtle differences amidst general conformity Cormican, P Lloyd, AT Downing, T Connell, SJ Bradley, D O'Farrelly, C Dev Comp Immunol 33:967-73 Dimerization of Phospho-IRF3 Dimerization of Phospho-IRF3 Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434100 2 O-phospho-L-serine at 464 464 EQUAL O-phospho-L-serine at 474 474 EQUAL O-phospho-L-serine at unknown position 1 EQUAL 491 EQUAL Reactome DB_ID: 433903 1 Phosphorylated IRF3 : IRF3 dimer [cytosol] Phosphorylated IRF3 : IRF3 dimer Reactome DB_ID: 434100 2 O-phospho-L-serine at 464 464 EQUAL O-phospho-L-serine at 474 474 EQUAL O-phospho-L-serine at unknown position 1 EQUAL 491 EQUAL Reactome Database ID Release 83 433903 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433903 Reactome R-GGA-433903 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-GGA-433903.1 Reactome Database ID Release 83 434027 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434027 Reactome R-GGA-434027 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-GGA-434027.1 14555995 Pubmed 2003 X-ray crystal structure of IRF-3 and its functional implications Takahasi, K Suzuki, NN Horiuchi, M Mori, M Suhara, W Okabe, Y Fukuhara, Y Terasawa, H Akira, Shizuo Fujita, T Inagaki, F Nat Struct Biol 10:922-7 Dimerized Phospho-IRF3 is Transported To The Nucleus Dimerized Phospho-IRF3 is Transported To The Nucleus Phosphorylation and dimerization of IRF3 results in the cytoplasm-to-nucleus translocation of IRF-3, DNA binding, and increased transcriptional activation. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 433903 1 Reactome DB_ID: 434029 1 nucleoplasm GO 0005654 Phosphorylated IRF3 : IRF3 [nucleoplasm] Phosphorylated IRF3 : IRF3 Reactome DB_ID: 433971 2 O-phospho-L-serine at 463 463 EQUAL O-phospho-L-serine at 464 464 EQUAL O-phospho-L-serine at 474 474 EQUAL O-phospho-L-serine at unknown position 1 EQUAL 491 EQUAL Reactome Database ID Release 83 434029 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434029 Reactome R-GGA-434029 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-GGA-434029.1 Reactome Database ID Release 83 433967 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433967 Reactome R-GGA-433967 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-GGA-433967.1 Reactome Database ID Release 83 434136 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434136 Reactome R-GGA-434136 2 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-GGA-434136.2 14679297 Pubmed 2004 IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts McWhirter, SM Fitzgerald, Katherine A Rosains, J Rowe, DC Golenbock, DT Maniatis, T Proc Natl Acad Sci U S A 101:233-8 16281057 Pubmed 2005 SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways Huang, J Liu, T Xu, LG Chen, D Zhai, Z Shu, HB EMBO J 24:4018-28 Viral dsRNA:TLR3:TICAM1 Complex Activates IKBKE_CHICK Viral dsRNA:TLR3:TICAM1 Complex Activates IKBKE_CHICK Embryonic fibroblast cells from TBK1-deficient mice show decreased IRF3 activation and IFN induction by poly IC, while IKKi-deficient cells show normal IRF3 activation. However, residual activation of IRF3 in TBK1-deficient cells is totally abolished in TBK1 and IKKi double-deficient cells, indicating that the functions of TBK1 and IKKi are redundant in fibroblast cells.[Hemmi et al 2004]. <p> It was also reported that IKKi directly phophorylates signal transducer and activator of transcription 1 (STAT1) [Tenoever et al 2007].<p>Chicken IKKi shows 68% and 62% identity to the human IKKi and human TBK1 respectively. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 IKK epsilon is recruited to the Viral dsRNA:TLR3:TICAM1 complex IKK epsilon is recruited to the Viral dsRNA:TLR3:TICAM1 complex Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) and inhibitor of ?B kinase epsilon (IKKi) induce type I interferon expression and modulate nuclear factor ?B (NFkB) signaling (Fitzgerald KA et al. 2003; Hemmi H et al. 2004). The structural studies of TBK1 revealed a dimeric assembly which is mediated by several interfaces involving kinase domain (KD), a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 (Larabi A et al. 2013; Tu D et al. 2013). ULD of TBK1 and IKKi was involved in the control of kinase activation, substrate presentation and downstream signaling (Ikeda F et al 2007; Tu D et al. 2013). An intact TBK1 dimer was a subject to K63-linked polyubiquitination on lysines 30 and 401 (Tu D et al. 2013). Activation of TBK1 rearranged the KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al. 2013). The ubiquitination sites and dimer contacts are conserved in the close homolog IKKi (Tu D et al. 2013). The activation of TBK1 and IKKi may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al. 2009). Other studies demonstrated an essential role of TRAF3 in the activation of TBK1 (Hacker et al 2006). TBK1 and IKKi were found to interact with scaffold proteins TANK (TRAF family member associated NFkB activator), NAP1 (NAK-associated protein 1), SINTBAD (similar to NAP1 TBK1 adaptor) which connect TBK1/IKKi to pathogen-activated signaling cascades (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007; Ryzhakov G and Randow F 2007; Goncalves A et al. 2011). Chicken IKK epsilon protein, confirmed by transcript evidedence, shows 68% amino acid sequence identity to its human ortholog. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434070 2 ENSEMBL:ENSGALP00000021757 NF kappa B inhibitor kinase epsilon NF kappa B inhibitor kinase epsilon IKK-i IKK epsilon IKBKE ENSEMBL ENSGALP00000021757 Reactome DB_ID: 433947 1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 434043 1 ds viral RNA : TLR3 : TICAM1 : IKK epsilon complex [endosome membrane] ds viral RNA : TLR3 : TICAM1 : IKK epsilon complex Reactome DB_ID: 434070 2 Reactome DB_ID: 433947 1 Reactome Database ID Release 83 434043 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434043 Reactome R-GGA-434043 2 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-GGA-434043.2 Reactome Database ID Release 83 433804 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433804 Reactome R-GGA-433804 2 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-GGA-433804.2 2.7.11.1 Phosphorylation of IRF3 by IKK epsilon(IKBKE) complexed with activated TLR3. Phosphorylation of IRF3 by IKK epsilon(IKBKE) complexed with activated TLR3. IRF-3 is activated by two step phosphorylation. IKK related kinases TBK1 and/or IKKi mediate the phosphorylation of the residues Ser386 and/or Ser385 (site1) and a cluster of serine/threonine residues between Ser396 and Ser405 (site 2) [Panne et al 2007]. Phosphorylation of residues in site 2 alleviates autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitates phosphorylation at site 1. Phosphorylation at site 1 is required for IRF-3 dimerization.<p> All serine residues mentioned above were empirically defined for human IRF3. Multiple sequence alignment of human, mouse and chicken IRF3 by ClustalW showed similarity in the C-terminal domain and the following chicken residues are predicted to be involved in chicken IRF3 activation:<ul><li>Ser463 and/or Ser464 (site 1, corresponding to human Ser385 and Ser386)<li>Ser474 and Ser476 (site2,corresponding to human Ser396 and Ser398 from the cluster of Ser396-Ser405)</ul> Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 113592 3 Reactome DB_ID: 433993 1 1 EQUAL 491 EQUAL Reactome DB_ID: 29370 3 Reactome DB_ID: 434100 1 O-phospho-L-serine at 464 464 EQUAL O-phospho-L-serine at 474 474 EQUAL O-phospho-L-serine at unknown position 1 EQUAL 491 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 434043 Reactome Database ID Release 83 434013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434013 Reactome Database ID Release 83 433826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433826 Reactome R-GGA-433826 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-GGA-433826.1 Reactome Database ID Release 83 433819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433819 Reactome R-GGA-433819 2 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-GGA-433819.2 17332413 Pubmed 2007 Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity Tenoever, BR Ng, SL Chua, MA McWhirter, SM Garcia-Sastre, A Maniatis, T Science 315:1274-8 Reactome Database ID Release 83 433835 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433835 Reactome R-GGA-433835 2 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-GGA-433835.2 NFkB activation mediated by RIP1 complexed with activated TLR3 NFkB activation mediated by RIP1 complexed with activated TLR3 Receptor-interacting protein 1 (RIP1) mediates the activation of proinflammatory cytokines via intermediate induction of IKK complex in NFkB pathways [Ea et al. 2006]. Poly(I-C) treatment stimulated the recruitment of RIP1, TRAF6, and TAK1 to the TLR3 receptor complex in human embryonic kidney HEK293 transfected with FLAG-tagged TLR3 [Cusson-Hermance et al. 2005]. RIP1 was shown to be dispensable for TRIF-dependent activation of IRF3, which occurs in a TRIF/TBK1/IKKi-dependent manner [Cusson-Hermance et al. 2005, Sato et al. 2003] Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 viral dsRNA:TRL3:TICAM1 activates RIP1 viral dsRNA:TRL3:TICAM1 activates RIP1 RIP1 is recruited to the activated TLR receptor by binding to TICAM1(TRIF) via its RHIM motif, followed by its polyubiquitination. Polyubiquitination is possibly mediated by TRAF6 that is also recruited to TICAM1 (Cusson-Hermance N et al. 2005). Other E3-ubiquitin ligases - cIAP1 and cIAP2 - have been reported to promote polyubiquitination of RIP proteins (Bertrand MJM et al. 2011).<p> RIP3 was shown to inhibit TRIF-induced NFkB activation in dose-dependent manner when overexpressed in HEK293T cells by competing with TRIF to bind RIP1 (Meylan E et al. 2004). Chicken RIP1 protein, confirmed by transcript evidedence, shows 48% amino acid sequence identity with human RIP1. Authored: Shamovsky, V, 2009-08-31 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434046 2 UniProt:Q7ZZX8 RIP-1 RIP-1 RIP-1 <submittedName> <fullName>Tumor necrosis factor receptor-interacting protein-1</fullName> </submittedName> UniProt Q7ZZX8 1 EQUAL 663 EQUAL Reactome DB_ID: 433947 1 Reactome DB_ID: 434042 1 viral dsRNA : TLR3 : TICAM1 : RIP1 [endosome membrane] viral dsRNA : TLR3 : TICAM1 : RIP1 Reactome DB_ID: 434093 2 1 EQUAL 663 EQUAL Reactome DB_ID: 433947 1 Reactome Database ID Release 83 434042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434042 Reactome R-GGA-434042 2 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-GGA-434042.2 Reactome Database ID Release 83 434097 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434097 Reactome R-GGA-434097 2 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-GGA-434097.2 15814722 Pubmed 2005 Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif Kaiser, WJ Offermann, MK J Immunol 174:4942-52 15064760 Pubmed 2004 RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B Meylan, E Burns, K Hofmann, K Blancheteau, V Martinon, F Kelliher, M Tschopp, Jürg Nat Immunol 5:503-7 21931591 Pubmed 2011 cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4) Bertrand, Mathieu J M Lippens, Saskia Staes, An Gilbert, Barbara Roelandt, Ria De Medts, Jelle Gevaert, Kris Declercq, Wim Vandenabeele, P PLoS ONE 6:e22356 16115877 Pubmed 2005 Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation Cusson-Hermance, N Khurana, S Lee, TH Fitzgerald, Katherine A Kelliher, MA J Biol Chem 280:36560-6 16246838 Pubmed 2005 NF-kappaB protects macrophages from lipopolysaccharide-induced cell death: the role of caspase 8 and receptor-interacting protein Ma, Y Temkin, V Liu, H Pope, RM J Biol Chem 280:41827-34 2.7.11.1 chicken RIP1 facilitates IKKs complex activation chicken RIP1 facilitates IKKs complex activation The IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO[Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta. This basic trimolecular complex is referred to as the IKK complex. <p>Each catalytic IKK subunit has an N-terminus kinase domain, a leucine zipper (LZ) motif, a helix-loop-helix (HLH) and a C-terminus NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.<p>IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 (data for human proteins) and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.<p>Chicken IKK alpha and IKK beta showed 81% and 68% identity to the corresponding human IKK kinases (UniProtKB sequence data using NCBI BLASTP 2.2.20). Multiple sequence alignment of the proteins by ClustalW demonstrated that chicken IKK alpha serine residues 190 and 194 correspond to human Ser176 and Ser180, that are required for the activation. It is unclear what serine residues of chicken IKK beta are involved into the phosphorylation.<p>Chicken IKK gamma or NEMO is considered as avian lost.[Cormican et al 2009]. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434005 1 IKKs_complex (Inhibitor of kappa B kinases) [cytosol] IKKs_complex (Inhibitor of kappa B kinases) Reactome DB_ID: 433915 1 UniProt:Q5ZJB4 CHUK CHUK RCJMB04_19h23 CHUK IKKA FUNCTION Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Phosphorylates 'Ser-10' of histone H3 at NF-kappa-B-regulated promoters during inflammatory responses triggered by cytokines.ACTIVITY REGULATION Activated when phosphorylated and inactivated when dephosphorylated.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. UniProt Q5ZJB4 1 EQUAL 759 EQUAL Reactome DB_ID: 433865 1 UniProt:Q5ZI83 RCJMB04_29g15 RCJMB04_29g15 RCJMB04_29g15 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5ZI83 1 EQUAL 739 EQUAL Reactome Database ID Release 83 434005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434005 Reactome R-GGA-434005 2 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-GGA-434005.2 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 433938 1 activated IKKs complex [cytosol] activated IKKs complex Reactome DB_ID: 434000 1 O-phospho-L-serine at 190 190 EQUAL O-phospho-L-serine at 194 194 EQUAL 1 EQUAL 759 EQUAL Reactome DB_ID: 433953 1 O-phospho-L-serine at unknown position O-phospho-L-serine at unknown position 1 EQUAL 739 EQUAL Reactome Database ID Release 83 433938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433938 Reactome R-GGA-433938 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-GGA-433938.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 975491 Activated chicken 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 83 434076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434076 Reactome Database ID Release 83 433845 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433845 Reactome R-GGA-433845 2 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-GGA-433845.2 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 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 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 ACTIVATION Reactome Database ID Release 83 975685 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975685 Reactome R-GGA-975685 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-GGA-975685.1 Reactome DB_ID: 434042 2.7.11.1 activated IKKs phosphorylates IkB alpha causing the NFkB complex to dissociate from the phospho-IkB activated IKKs phosphorylates IkB alpha causing the NFkB complex to dissociate from the phospho-IkB The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites corresponding to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta), polyubiquitination (at sites corresponding to Lys21 and Lys22 of human IkB-alpha) and subsequent degradation by the 26S proteasome. The K-48 ubiquitination is mediated by the E2 ubiquitin ligases (or SCFs) formed by three subunits: Skp1, Cul A (Cdc53), and one of many F-box proteins.<p>Chicken IkB-alpha shows 71% identity to the human IkB alpha kinase. Multiple sequence alignment of the human and chicken IKB-alpha showed that chicken Ser36 and Ser40 correspond to human Ser32 and Ser 36 mentioned above.<p>There is insufficient data for chicken IkB beta to make a comparison with other species. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434019 1 IkB alpha : NFkB complex [cytosol] IkB alpha : NFkB complex Reactome DB_ID: 433980 1 UniProt:P98152 RELA RELA RELA FUNCTION NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. RELA shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex.SUBUNIT Component of the NF-kappa-B p65-p50 complex. Component of the NF-kappa-B p65-c-Rel complex. Component of the NF-kappa-B p65-p105 complex.TISSUE SPECIFICITY Spleen; lower level in brain.DOMAIN The transcriptional activation domain 1/TA1 and the transcriptional activation domain 2/TA2 have direct transcriptional activation properties (By similarity). The 9aaTAD motif found within the transcriptional activation domain 2 is a conserved motif present in a large number of transcription factors that is required for their transcriptional transactivation activity (By similarity). UniProt P98152 1 EQUAL 558 EQUAL Reactome DB_ID: 433962 1 UniProt:Q04861 NFKB1 NFKB1 NFKB1 FUNCTION P105 is the precursor of the p50 subunit of the nuclear factor NF-kappa-B, which binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. The precursor protein itself does not bind to DNA.SUBUNIT Active NF-kappa-B is a heterodimer of an about 50 kDa DNA-binding subunit and the weak DNA-binding subunit p65. Two heterodimers might form a labile tetramer.DOMAIN The C-terminus of p105 might be involved in cytoplasmic retention, inhibition of DNA-binding by p50 homodimers, and/or transcription activation.PTM While translation occurs, the particular unfolded structure after the GRR repeat promotes the generation of p50 making it an acceptable substrate for the proteasome. This process is known as cotranslational processing. The processed form is active and the unprocessed form acts as an inhibitor (I kappa B-like), being able to form cytosolic complexes with NF-kappa B, trapping it in the cytoplasm. Complete folding of the region downstream of the GRR repeat precludes processing (By similarity).PTM S-nitrosylation of Cys-66 affects DNA binding. UniProt Q04861 1 EQUAL 984 EQUAL Reactome DB_ID: 433811 1 UniProt:Q91974 NFKBIA NFKBIA NFKBIA IKBA FUNCTION Inhibits NF-kappa-B by complexing with and trapping it in the cytoplasm. May be involved in regulation of transcriptional responses to NF-kappa-B, including cell adhesion, immune and pro-inflammatory responses, apoptosis, differentiation and growth. Controlled by sequential serine-phosphorylation, ubiquitination and degradation. Tyrosine-phosphorylation could only lead to dissociation from NF-kappa-B (By similarity).SUBUNIT Interacts with RELA.TISSUE SPECIFICITY Highly expressed in lymph node, thymus followed by liver, brain, muscle, kidney, gastrointestinal and reproductive tract.PTM Ubiquitinated; subsequent to stimulus-dependent phosphorylation on serines, polyubiquitination targets the protein for rapid degradation via the ubiquitin system.SIMILARITY Belongs to the NF-kappa-B inhibitor family. UniProt Q91974 1 EQUAL 318 EQUAL Reactome Database ID Release 83 434019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434019 Reactome R-GGA-434019 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-GGA-434019.1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 434125 1 NFkB complex(p50/p65) [cytosol] NFkB complex(p50/p65) Reactome DB_ID: 433980 1 1 EQUAL 558 EQUAL Reactome DB_ID: 433962 1 1 EQUAL 984 EQUAL Reactome Database ID Release 83 434125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434125 Reactome R-GGA-434125 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-GGA-434125.1 Reactome DB_ID: 433842 1 O-phospho-L-serine at 36 36 EQUAL O-phospho-L-serine at 40 40 EQUAL 1 EQUAL 318 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 433938 Reactome Database ID Release 83 434081 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434081 Reactome Database ID Release 83 433986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433986 Reactome R-GGA-433986 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-GGA-433986.1 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 Released NFkB complex migrates to the nucleus and turns on transcription Released NFkB complex migrates to the nucleus and turns on transcription 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> Chicken NFkB p105 (precursor of p50) subunit and NFkB p65 subunit showed 71% and 51% identity to the corresponding human NFkB subunits (UniProtKB sequence data using NCBI BLASTP 2.2.20). Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434125 1 Reactome DB_ID: 433908 1 NFkB complex(p50/p65) [nucleoplasm] NFkB complex(p50/p65) Reactome DB_ID: 433824 1 1 EQUAL 558 EQUAL Reactome DB_ID: 434062 1 1 EQUAL 984 EQUAL Reactome Database ID Release 83 433908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433908 Reactome R-GGA-433908 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-GGA-433908.1 Reactome Database ID Release 83 433823 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433823 Reactome R-GGA-433823 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-GGA-433823.1 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 15371334 Pubmed 2004 Signaling to NF-kappaB Hayden, MS Ghosh, S Genes Dev 18:2195-224 Reactome Database ID Release 83 434131 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434131 Reactome R-GGA-434131 2 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-GGA-434131.2 1533881 Pubmed 1992 p105, the NF-kappa B p50 precursor protein, is one of the cellular proteins complexed with the v-Rel oncoprotein in transformed chicken spleen cells Capobianco, AJ Chang, D Mosialos, G Gilmore, TD J Virol 66:3758-67 TRAF6 mediated induction of proinflammatory cytokines TRAF6 mediated induction of proinflammatory cytokines Together with ubiquitin-conjugating E2-type enzymes UBC13 and UEV1A (also known as UBE2V1), TRAF6 catalyzes Lys63-linked ubiquitination. It is believed that auto polyubiquitination and oligomerization of TRAF6 is followed by binding the ubiquitin receptors of TAB2 or TAB3 (TAK1 binding protein 2 and 3), which stimulates phosphorylation and activation of TGF beta-activated kinase 1(TAK1).<p>TAK1 phosphorylates IKK alpha and IKK beta, which in turn phosphorylate NF-kB inhibitors - IkB and eventually results in IkB degradation and NF-kB translocation to the nucleus. Also TAK1 mediates JNK and p38 MAP kinases activation by phosphorylating MKK4/7 and MKK3/6 respectively resulting in the activation of many transcription factors. <p>The role of TRAF6 is somewhat controversial and probably cell type specific. TRAF6 autoubiquitination was found to be dispensable for TRAF6 function to activate the TAK1 pathway. These findings are consistent with the new mechanism of TRAF6-mediated NF-kB activation that was suggested by Xia et al. (2009). TRAF6 generates unanchored Lys63-linked polyubiquitin chains that bind to the regulatory subunits of the TAK1 (TAB2 or TAB3) and IKK (NEMO), leading to the activation of the kinases.<p> Xia et al. (2009) demonstrated in vitro that unlike polyubiquitin chains covalently attached to TRAF6 or IRAK, TAB2 and NEMO-associated ubiquitin chains were unanchored and susceptible to N-terminal ubiquitin cleavage. Only K63-linked polyubiquitin chains, but not monomeric ubiquitin, activated TAK1 in a dose-dependent manner. Optimal activation of the IKK complex was achieved using ubiquitin polymers containing both K48 and K63 linkages.<p>Furthermore, the authors proposed that the TAK1 complexes might be brougt in close proximity by binding several TAB2/3 to a single polyubiquitin chain to facilitate TAK1 kinases trans-phosphorylation. Alternatively, the possibility that polyUb binding promotes allosteric activation of TAK1 complex should be considered. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 viral dsRNA: TLR3: TICAM1 recruits TRAF6 viral dsRNA: TLR3: TICAM1 recruits TRAF6 TRAF6 is recruited to the N-terminal domain of TICAM1 and this event is followed by auto polyubiquitination and oligomerization of TRAF6. Chicken TRAF6 protein, confirmed by transcript evidence, shows 76% amino acid sequence identity with human TRAF6. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 433886 2 UniProt:E1C626 TRAF6 TRAF6 TRAF6 SIMILARITY: Contains 1 MATH domain. UniProt E1C626 Reactome DB_ID: 433947 1 Reactome DB_ID: 433968 1 viral ds RNA : TLR3 : TICAM1 : TRAF6 [endosome membrane] viral ds RNA : TLR3 : TICAM1 : TRAF6 Reactome DB_ID: 433947 1 Reactome DB_ID: 433792 2 Reactome Database ID Release 83 433968 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433968 Reactome R-GGA-433968 2 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-GGA-433968.2 Reactome Database ID Release 83 433808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433808 Reactome R-GGA-433808 3 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-GGA-433808.3 6.3.2.19 Auto ubiquitination of the TRAF6 within the complex viral dsRNA:TLR3:TICAM1:TRAF6 Auto ubiquitination of the TRAF6 within the complex viral dsRNA:TLR3:TICAM1:TRAF6 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. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 446245 1 Ubiquitin:UBE2N : UBE2V complex [cytosol] Ubiquitin:UBE2N : UBE2V complex Reactome DB_ID: 434105 1 UniProt:Q90879 UBE2V1 UBE2V1 UBE2V1 FUNCTION Has no ubiquitin ligase activity on its own. The UBE2V1-UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through 'Lys-63'. This type of poly-ubiquitination activates IKK and does not seem to involve protein degradation by the proteasome. Plays a role in the activation of NF-kappa-B. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage (By similarity). Together with RNF135 and UBE2N, may catalyze the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIG-I/DDX58 to activate the downstream signaling pathway that leads to interferon beta production (By similarity).SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt Q90879 1 EQUAL 145 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 434147 1 Ubiquitin [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ubiquitin (UBB 1) [cytosol] ubiquitin (UBB 4) [cytosol] ubiquitin (UBB 2) [cytosol] ubiquitin (UBB 3) [cytosol] ubiquitin (RPS27A) [cytosol] ubiquitin (UBA52) [cytosol] UniProt P0CG62 UniProt P79781 UniProt P62985 Reactome DB_ID: 433933 1 UniProt:Q5F405 RCJMB04_3o20 RCJMB04_3o20 RCJMB04_3o20 SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt Q5F405 1 EQUAL 152 EQUAL Reactome Database ID Release 83 446245 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=446245 Reactome R-GGA-446245 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-GGA-446245.1 Reactome DB_ID: 433968 1 Reactome DB_ID: 434102 1 viral ds RNA : TLR3 : TICAM1 : pUb-TRAF6 [endosome membrane] viral ds RNA : TLR3 : TICAM1 : pUb-TRAF6 Reactome DB_ID: 434011 2 pUb_TRAF6 [endosome membrane] pUb_TRAF6 Reactome DB_ID: 433792 1 Reactome DB_ID: 433989 1 K63_polyubiquitin chain [endosome membrane] K63_polyubiquitin chain Reactome Database ID Release 83 434011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434011 Reactome R-GGA-434011 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-GGA-434011.1 Reactome DB_ID: 433947 1 Reactome Database ID Release 83 434102 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434102 Reactome R-GGA-434102 2 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-GGA-434102.2 Reactome DB_ID: 433960 1 UBE2N : UBE2V complex [cytosol] UBE2N : UBE2V complex Reactome DB_ID: 434105 1 1 EQUAL 145 EQUAL Reactome DB_ID: 433933 1 1 EQUAL 152 EQUAL Reactome Database ID Release 83 433960 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433960 Reactome R-GGA-433960 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-GGA-433960.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 433968 GO 0004842 GO molecular function Reactome Database ID Release 83 434017 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434017 Reactome Database ID Release 83 433981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433981 Reactome R-GGA-433981 3 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-GGA-433981.3 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 6.3.2.19 Activated chicken TRAF6 synthesizes free K63bound poly_Ub chains within the complex dsRNA :TLR3 :TICAM1 Activated chicken TRAF6 synthesizes free K63bound poly_Ub chains within the complex dsRNA :TLR3 :TICAM1 TRAF6 generates unanchored Lys63-linked polyubiquitin chains that bind to the regulatory subunits of the TAK1 (TAB2 or TAB3), leading to the activation of TAK1[Xia et al. 2009]. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Converted from EntitySet in Reactome Reactome DB_ID: 434147 3 Reactome DB_ID: 451962 1 free K63_polyubiquitin chain [cytosol] free K63_polyubiquitin chain PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 434102 Reactome Database ID Release 83 433906 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433906 Reactome Database ID Release 83 433936 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433936 Reactome R-GGA-433936 2 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-GGA-433936.2 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 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 15836773 Pubmed 2005 TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway Kishida, S Sanjo, H Akira, Shizuo Matsumoto, K Ninomiya-Tsuji, J Genes Cells 10:447-54 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 GO 0010994 GO biological process TRAF6 recruits TAK1 kinase complex TRAF6 recruits TAK1 kinase complex Polyubiquitinated TRAF6 activates TAK1 by binding to the ubiquitin receptor TAB2 (also known as MAP3K7IP2). This binding leads to autophosphorylation and activation of TAK1. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2012-05-25 Reactome DB_ID: 434102 1 Reactome DB_ID: 433839 2 TAK1 : TAB1 : TAB2/TAB3 complex [cytosol] TAK1 : TAB1 : TAB2/TAB3 complex Converted from EntitySet in Reactome Reactome DB_ID: 975711 1 chicken TAB2/TAB3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TAB2 [cytosol] TAB3 [cytosol] ENSEMBL ENSGALP00000020155 ENSEMBL ENSGALP00000026205 Reactome DB_ID: 433825 1 ENSEMBL:ENSGALP00000025101 TGF-beta- activated kinase 1 TGF-beta- activated kinase 1 MAP3K7 ENSEMBL ENSGALP00000025101 1 EQUAL 617 EQUAL Reactome DB_ID: 433882 1 UniProt:Q5ZJW3 RCJMB04_15c17 RCJMB04_15c17 RCJMB04_15c17 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5ZJW3 1 EQUAL 438 EQUAL Reactome Database ID Release 83 433839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433839 Reactome R-GGA-433839 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-GGA-433839.1 Reactome DB_ID: 451962 2 Reactome DB_ID: 434146 1 viral dsRNA : TLR3 : TICAM1 : pUb_TRAF6 :TAB2 :TAB3: TAK1 : TAB1: free_pUb_chain [endosome membrane] viral dsRNA : TLR3 : TICAM1 : pUb_TRAF6 :TAB2 :TAB3: TAK1 : TAB1: free_pUb_chain Reactome DB_ID: 434102 1 Reactome DB_ID: 433931 2 TAK1 : TAB1 : TAB2/TAB3 complex [endosome membrane] TAK1 : TAB1 : TAB2/TAB3 complex Reactome DB_ID: 433956 1 1 EQUAL 617 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 993984 1 chicken TAB2/TAB3 [endosome membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TAB2 [endosome membrane] TAB3 [endosome membrane] Reactome DB_ID: 434141 1 1 EQUAL 438 EQUAL Reactome Database ID Release 83 433931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433931 Reactome R-GGA-433931 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-GGA-433931.1 Reactome DB_ID: 451962 2 Reactome Database ID Release 83 434146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434146 Reactome R-GGA-434146 2 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-GGA-434146.2 Reactome Database ID Release 83 433950 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433950 Reactome R-GGA-433950 3 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-GGA-433950.3 2.7.11.1 Activation of recruited TAK1 Activation of recruited TAK1 Polyubiquitinated TRAF6 activates TAK1 by binding to the ubiquitin receptor TAB2 (also known as MAP3K7IP2). This binding leads to autophosphorylation and activation of TAK1. Chicken TAK1 complex proteins TAK1, TAB1, TAB2 and TAB3, confirmed by transcript evidence, show 89%, 88% , 87%, 85% amino acid identity with their human counterparts respectively.<p>Embryonic fibroblasts and B cells derived from TAK1-deficient mice show reduced NF-kappaB, JNK and p38 activation in response to various TLR ligands. Furthermore, ERK1 and ERK2 activation was also reduced in TAK1-deficient mouse B cells [Sato S et al 2005].<p>Although there are no experimental data showing a TAK1 functional role in chicken innate immune response, its kinase activity was demonstrated to be essential for BCR (B cell antigen receptor)-mediated IKK and JNK activation in chicken DT40 B cells [Shinohara H et al 2005]. When BCR-mediated NF-kappaB activation was abolished, JNK phosphorylation was completely abolished, while ERK was activated normally in a TAK1-deficient chicken DT40 B cell line. <p>Thus, TAK1 is believed to activate the IKK complex that leads to NF-kappaB activation. Also TAK1 phosphorylates members of the MAP kinase kinase family, MKK4, MKK3 and MKK6, which subsequently activate JNK and p38. ERK is also activated in response to TLR ligands through the activation of MEK1 and MEK2, although an upstream kinase activating MEK1 and MEK2 in TLR signaling remains unknown. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2012-05-25 Reactome DB_ID: 434146 1 Reactome DB_ID: 113592 4 Reactome DB_ID: 29370 4 Reactome DB_ID: 434152 1 viral dsRNA : TLR3 : TICAM1 : pUb_TRAF6 :TAB2:TAB3 :phospho TAK1 : TAB1 : free pUb chain [endosome membrane] viral dsRNA : TLR3 : TICAM1 : pUb_TRAF6 :TAB2:TAB3 :phospho TAK1 : TAB1 : free pUb chain Reactome DB_ID: 434102 1 Reactome DB_ID: 433923 2 ENSEMBL:ENSGALP00000020155 TAB2 TAB2 MAP3K7IP2 (TAB2) 1 EQUAL 697 EQUAL Reactome DB_ID: 442975 2 ENSEMBL:ENSGALP00000026205 TAB3 TAB3 MAP3K7IP3 Reactome DB_ID: 451962 2 Reactome DB_ID: 433952 2 O-phospho-L-threonine at unknown position O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at unknown position 1 EQUAL 617 EQUAL Reactome DB_ID: 434141 2 1 EQUAL 438 EQUAL Reactome Database ID Release 83 434152 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434152 Reactome R-GGA-434152 2 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-GGA-434152.2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 434146 Reactome Database ID Release 83 434006 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434006 Reactome Database ID Release 83 433957 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433957 Reactome R-GGA-433957 3 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-GGA-433957.3 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 16301747 Pubmed 2005 PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1 Shinohara, H Yasuda, T Aiba, Y Sanjo, H Hamadate, M Watarai, H Sakurai, H Kurosaki, T J Exp Med 202:1423-31 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 Activated chicken TAK1 dissociates from the activated TLR3 complex Activated chicken TAK1 dissociates from the activated TLR3 complex Phosphorylated TAK1 complexed with TRAF6-TAB1-TAB2/TAB3 leaves the activated TLR4 complex and translocates to the cytosol Authored: Shamovsky, V, 2010-08-04 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 Reactome DB_ID: 434152 1 Reactome DB_ID: 921146 1 pUB-TRAF6:TAB2:TAB3:TAB1:free K63-pUb chain:phospho TAK1 [cytosol] pUB-TRAF6:TAB2:TAB3:TAB1:free K63-pUb chain:phospho TAK1 Reactome DB_ID: 434032 2 1 EQUAL 697 EQUAL Reactome DB_ID: 434061 2 K63_polyubiquitin chain [cytosol] K63_polyubiquitin chain Reactome DB_ID: 451473 2 O-phospho-L-threonine at unknown position O-phospho-L-threonine at unknown position 1 EQUAL 617 EQUAL Reactome DB_ID: 451455 2 pUb_TRAF6 [cytosol] pUb_TRAF6 Reactome DB_ID: 433886 1 Reactome DB_ID: 434061 1 Reactome Database ID Release 83 451455 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451455 Reactome R-GGA-451455 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-GGA-451455.1 Reactome DB_ID: 442867 2 Reactome DB_ID: 433882 2 1 EQUAL 438 EQUAL Reactome Database ID Release 83 921146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=921146 Reactome R-GGA-921146 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-GGA-921146.1 Reactome DB_ID: 433947 1 Reactome Database ID Release 83 921145 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=921145 Reactome R-GGA-921145 3 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-GGA-921145.3 12609980 Pubmed 2003 Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR Jiang, Z Zamanian-Daryoush, M Nie, H Silva, AM Williams, BR Li, X J Biol Chem 278:16713-9 TAK1 activates NFkB by phosphorylation and activation of IKKs complex TAK1 activates NFkB by phosphorylation and activation of IKKs complex 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. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 2.7.11.1 Phosphorylation of IKKs complex by activated TAK1 Phosphorylation of IKKs complex by activated TAK1 The IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO[Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta. This basic trimolecular complex is referred to as the IKK complex. <p>Each catalytic IKK subunit has an N-terminus kinase domain, a leucine zipper (LZ) motif, a helix-loop-helix (HLH) and a C-terminus NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.<p>IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 (data for human proteins) and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.<p>Chicken IKK alpha and IKK beta showed 81% and 68% identity to the corresponding human IKK kinases (UniProtKB sequence data using NCBI BLASTP 2.2.20). Multiple sequence alignment of the proteins by ClustalW demonstrated that chicken IKK alpha serine residues 190 and 194 correspond to human Ser176 and Ser180, that are required for the activation. It is unclear what serine residues of chicken IKK beta are involved into the phosphorylation.<p>Chicken IKK gamma or NEMO is considered as avian lost.[Cormican et al 2009]. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 434005 1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 433938 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 975491 Reactome Database ID Release 83 433955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433955 Reactome R-GGA-433955 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-GGA-433955.1 Reactome Database ID Release 83 434001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434001 Reactome R-GGA-434001 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-GGA-434001.1 GO 0007250 GO biological process MAPK activation in TLR cascade MAPK activation in TLR cascade The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002). <p>There are three major groups of MAP kinases<ul><li>the extracellular signal-regulated protein kinases ERK1/2, <li>the p38 MAP kinase<li> and the c-Jun NH-terminal kinases JNK.</ul><p>ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).<p>MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.<p>The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.<p>The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear. Authored: Shamovsky, V, 2010-01-05 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2011-02-17 Activated TAK1 mediates Jun kinases (JNK) phosphorylation and activation Activated TAK1 mediates Jun kinases (JNK) phosphorylation and activation C-Jun NH2 terminal kinases are stress activated MAPKs, also known as SAPKs. The JNK pathway is activated by heat shock, or inflammatory cytokines, or UV radiation. The JNKs are encoded by at least three genes: JNK1/SAPK-gamma, JNK2/SAPK-alpha and JNK3/ SAPK-beta.<p>Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7). Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2011-02-17 2.7.11.1 Phosphorylation of MKK4 by activated TAK1 Phosphorylation of MKK4 by activated TAK1 Phosphorylation of MKK4 and MKK7 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 the deletion of the mkk4 gene.<p>Chicken MKK4 protein as confirmed by mRNA sequence shows 96% identity to human MKK4 (UniProtKB sequence data using NCBI BLASTP 2.2.20). Multiple sequence alignment of the proteins by ClustalW demonstrated that chicken MKK4 serine residue 224 and threonine 228 correspond to human Ser257 and Thr261, that are required for the activation.<p> Since no MKK7 ortholog was identified in the chicken genome, only chicken MKK4 protein is annotated in the chicken JNK pathway as a homolog of the well characterized human MKK4 / MKK7 proteins. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 437642 1 ENSEMBL:ENSGALP00000001475 MKK4 MKK4 MAP2K4 ENSEMBL ENSGALP00000001475 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 437975 1 O-phospho-L-serine at unknown position O-phospho-L-threonine at unknown position PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 975491 Reactome Database ID Release 83 437999 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437999 Reactome R-GGA-437999 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-GGA-437999.1 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 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 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 2.7.12.1 MKK4 phosphorylates JNK MKK4 phosphorylates JNK Activated JNK kinases (MKK4 and MKK7) phosphorylate threonine and tyrosine residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK isoform.<p>Chicken JNK2(MAPK9) shows 98% identity with human JNK2 (UniProtKB sequence data using NCBI BLASTP 2.2.20). Multiple sequence alignment of the human, mouse and chicken JNK2 proteins by ClustalW showed that Thr183 and Tyr185 residues, that are responsible for the JNK activation in human, are identical for all three orthologs.<p>Other chicken JNK isoforms JNK1(MAPK8) and JNK3(MAPK10), whose existence is confirmed at the transcript level, share 99% and 95% amino-acid sequence identity with their human counterparts respectively. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2011-02-17 Converted from EntitySet in Reactome Reactome DB_ID: 433872 1 JNK homologs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAPK9_(JNK2) [cytosol] UniProt P79996 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 437957 1 phosphorylated JNK homologs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPK9_(JNK2) [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 437975 O-phospho-L-serine at unknown position O-phospho-L-threonine at unknown position GO 0004712 GO molecular function Reactome Database ID Release 83 438025 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438025 Reactome Database ID Release 83 438005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438005 Reactome R-GGA-438005 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-GGA-438005.1 Activated JNK migrates to the nucleoplasm Activated JNK migrates to the nucleoplasm Shortly after phosphorylation JNKs are translocated to nucleus where they associate and activate their target transcription factors. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Converted from EntitySet in Reactome Reactome DB_ID: 437957 1 Converted from EntitySet in Reactome Reactome DB_ID: 438012 1 phosphorylated JNK homologs [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPK9_(JNK2) [nucleoplasm] Reactome Database ID Release 83 437995 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437995 Reactome R-GGA-437995 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-GGA-437995.1 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 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 2.7.11 Activation and dimerization of c-JUN in the nucleus Activation and dimerization of c-JUN in the nucleus Shortly after phosphorylation JNKs are translocated to nucleus where they associate and activate their target transcription factors. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 29358 4 Reactome DB_ID: 438016 2 UniProt:P18870 JUN JUN JUN FUNCTION Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'. May be involved in activated KRAS-mediated transcriptional activation of USP28. May bind to the USP28 promoter.SUBUNIT Interacts with FOS to form a dimer. Interacts with Gallid herpesvirus 2 MEQ protein.SIMILARITY Belongs to the bZIP family. Jun subfamily. UniProt P18870 1 EQUAL 314 EQUAL Reactome DB_ID: 113582 4 Reactome DB_ID: 437991 1 activated c-JUN dimer [nucleoplasm] activated c-JUN dimer Reactome DB_ID: 438013 2 O-phospho-L-serine at 63 63 EQUAL O-phospho-L-serine at 73 73 EQUAL 1 EQUAL 314 EQUAL Reactome Database ID Release 83 437991 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437991 Reactome R-GGA-437991 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-GGA-437991.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 438012 GO 0004705 GO molecular function Reactome Database ID Release 83 438001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438001 Reactome Database ID Release 83 438026 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438026 Reactome R-GGA-438026 2 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-GGA-438026.2 18793328 Pubmed 2008 c-Jun expression, activation and function in neural cell death, inflammation and repair Raivich, G J Neurochem 107:898-906 INHIBITION Reactome Database ID Release 83 442857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442857 Reactome R-GGA-442857 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-GGA-442857.1 Converted from EntitySet in Reactome Reactome DB_ID: 442886 MAPK phosphatases [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MKP5 [nucleoplasm] MKP3 [nucleoplasm] MKP2 [nucleoplasm] MKP1 [nucleoplasm] UniProt Q5ZJF8 UniProt Q7T2L9 UniProt Q9PW71 UniProt O42253 Reactome Database ID Release 83 437986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437986 Reactome R-GGA-437986 2 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-GGA-437986.2 12471242 Pubmed 2002 Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases Johnson, GL Lapadat, R Science 298:1911-2 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 7839144 Pubmed 1995 Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms Derijard, B Raingeaud, J Barrett, T Wu, IH Han, J Ulevitch, RJ Davis, RJ Science 267:682-5 11057897 Pubmed 2000 Signal transduction by the JNK group of MAP kinases Davis, RJ Cell 103:239-52 GO 0007254 GO biological process Activated TAK1 mediates p38 MAP kinase phosphorylation Activated TAK1 mediates p38 MAP kinase phosphorylation 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. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2011-02-17 2.7.11.1 Phosphorylation of MKK3/MKK6 by activated TAK1 Phosphorylation of MKK3/MKK6 by activated TAK1 MKK3 and MKK6 are two closely related dual-specificity protein kinases that activate p38 MAP kinase. MKK3 and MKK6 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. MKK3 and MKK6 are both activated by different forms of cellular stress and inflammatory cytokines. 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 in activation of these protein kinases correspond to human sites Ser189 and Thr193 for MKK3 and Ser207 and Thr211 for MKK6.<p>Since there is no data for chicken MKK6, this hypothetical chicken protein is annotated in the chicken p38 pathway as homolog of well characterized human MKK6. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Converted from EntitySet in Reactome Reactome DB_ID: 437632 1 MKK3/MKK6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MKK3 [cytosol] UniProt Q5ZL06 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 437977 1 phospho MKK3/ phospho MKK6 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MKK3 [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 975491 Reactome Database ID Release 83 437984 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437984 Reactome R-GGA-437984 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-GGA-437984.1 activated MAPK3/MAPK6 migrates to nucleus activated MAPK3/MAPK6 migrates to nucleus 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. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Converted from EntitySet in Reactome Reactome DB_ID: 437977 1 Converted from EntitySet in Reactome Reactome DB_ID: 442940 1 phospho MKK3/ phospho MKK6 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MKK3 [nucleoplasm] Reactome Database ID Release 83 442938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442938 Reactome R-GGA-442938 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-GGA-442938.1 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 2.7.12.1 activated chicken MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 activated chicken MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 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. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 442951 1 p38 MAPK : MAPKAPK 2 or MAPKAPK3 [nucleoplasm] p38 MAPK : MAPKAPK 2 or MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 442936 1 MAPKAPK2 and/or MAPKAPK3 [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] ENSEMBL ENSGALP00000003578 ENSEMBL ENSGALP00000001295 Converted from EntitySet in Reactome Reactome DB_ID: 442963 1 p38 MAP kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAPK11 [nucleoplasm] MAPK12 [nucleoplasm] MAPK14 [nucleoplasm] MAPK13 [nucleoplasm] UniProt Q5ZIK8 ENSEMBL ENSGALP00000014011 ENSEMBL ENSGALP00000001201 ENSEMBL ENSGALP00000001204 Reactome Database ID Release 83 442951 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442951 Reactome R-GGA-442951 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-GGA-442951.1 Reactome DB_ID: 29358 2 Reactome DB_ID: 442905 1 phospho -p38 MAPK : MAPKAPK 2 or MAPKAPK3 [nucleoplasm] phospho -p38 MAPK : MAPKAPK 2 or MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 442936 1 Converted from EntitySet in Reactome Reactome DB_ID: 442851 1 phospho_p38 MAP kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPK13 [nucleoplasm] phosphorylated MAPK12 [nucleoplasm] phosphorylated MAPK11 [nucleoplasm] phosphorylated MAPK14 [nucleoplasm] Reactome Database ID Release 83 442905 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442905 Reactome R-GGA-442905 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-GGA-442905.1 Reactome DB_ID: 113582 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 442940 Reactome Database ID Release 83 437955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437955 Reactome Database ID Release 83 438019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438019 Reactome R-GGA-438019 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-GGA-438019.1 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 2.7.12.1 Active p38 MAPK phosphorylates MAPKAPK2 or 3 Active p38 MAPK phosphorylates MAPKAPK2 or 3 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. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 442905 1 Reactome DB_ID: 29358 3 Reactome DB_ID: 442915 1 phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho MAPKAPK3 [nucleoplasm] phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 442949 1 phospho MAPKAPK2 and/or phospho MAPKAPK3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPKAPK2 [nucleoplasm] phosphorylated MAPKAPK3 [nucleoplasm] Converted from EntitySet in Reactome Reactome DB_ID: 442851 1 Reactome Database ID Release 83 442915 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442915 Reactome R-GGA-442915 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-GGA-442915.1 Reactome DB_ID: 113582 3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 442905 Reactome Database ID Release 83 442864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442864 Reactome Database ID Release 83 442913 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442913 Reactome R-GGA-442913 2 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-GGA-442913.2 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 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 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 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 INHIBITION Reactome Database ID Release 83 442897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442897 Reactome R-GGA-442897 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-GGA-442897.1 Converted from EntitySet in Reactome Reactome DB_ID: 442886 Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 Nuclear export of p38 MAPK mediated by its substrate MAPKAPK2 or 3 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. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 442915 1 Reactome DB_ID: 442925 1 phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho-MAPKAPK3 [cytosol] phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho-MAPKAPK3 Converted from EntitySet in Reactome Reactome DB_ID: 437968 1 phospho_p38 MAP kinase [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPK12 [cytosol] phosphorylated MAPK11 [cytosol] phosphorylated MAPK13 [cytosol] phosphorylated MAPK14 [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 442855 1 phospho MAPKAPK2 and/or phospho MAPKAPK3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phosphorylated MAPKAPK2 [cytosol] phosphorylated MAPKAPK3 [cytosol] Reactome Database ID Release 83 442925 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442925 Reactome R-GGA-442925 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-GGA-442925.1 Reactome Database ID Release 83 442862 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442862 Reactome R-GGA-442862 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-GGA-442862.1 Reactome Database ID Release 83 437980 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437980 Reactome R-GGA-437980 2 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-GGA-437980.2 8761479 Pubmed 1996 Tyrosine phosphorylation and activation of a new mitogen-activated protein (MAP)-kinase cascade in human neutrophils stimulated with various agonists Nahas, N Molski, TF Fernandez, GA Sha'afi, RI Biochem J 318:247-53 15686620 Pubmed 2005 Activation and signaling of the p38 MAP kinase pathway Zarubin, T Han, J Cell Res 15:11-8 GO 0038066 GO biological process ERK activation ERK activation Lipopolysaccharide and flagellin were shown to stimulate ERK activation in chicken heterophils.<p>Bioinformatic analysis reveals no evidence of ERK1 in the chicken genome, although chicken orthologs to other mediators of MEK-ERK signaling (MEK1, MEK2, ERK2 etc.) were identified. In this Reactome model we show ERK2 activation and assume that chicken MEK-ERK mediators behave like their human counterparts. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 activated MEK2 binds ERK2 activated MEK2 binds ERK2 Activated mammalian MEK1/2 is a serine/threonine kinase, which phosphorylates and activates ERK1/2. ERK1/2 is then translocates to the nucleus and activates transcription factors.<p> Chicken MEK2 showes 93% amino acid sequence identity to human MEK2. Multiple sequence alignment of human, mouse and chicken MEK2 by ClustalW allows to predict that the following chicken residues are involved in chicken MEK2 activation: Ser220 and Ser224 that are corresponding to human residues Ser222 and Ser226. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 433942 1 UniProt:Q8UWG6 Extracellular signal-regulated kinase 2 Extracellular signal-regulated kinase 2 MAPK1 SIMILARITY Belongs to the protein kinase superfamily. UniProt Q8UWG6 1 EQUAL 368 EQUAL Reactome DB_ID: 451487 1 UniProt:Q90891 MAP2K2 MAP2K2 MKK2 PRKMK2 MAP2K2 MEK2 FUNCTION Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).PTM Activated by phosphorylation on Ser/Thr catalyzed by MAP kinase kinase kinases (RAF).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. UniProt Q90891 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 451495 1 phospho MEK2 : ERK2 [cytosol] phospho MEK2 : ERK2 Reactome DB_ID: 433942 1 1 EQUAL 368 EQUAL Reactome DB_ID: 451487 1 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome Database ID Release 83 451495 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451495 Reactome R-GGA-451495 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-GGA-451495.1 Reactome Database ID Release 83 451482 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451482 Reactome R-GGA-451482 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-GGA-451482.1 17045653 Pubmed 2007 Flagellin and lipopolysaccharide stimulate the MEK-ERK signaling pathway in chicken heterophils through differential activation of the small GTPases, Ras and Rap1 Kogut, MH Genovese, KJ He, H Mol Immunol 44:1729-36 20163623 Pubmed 2009 Extracellular signal-regulated kinase (ERK) activation in chicken heterophils stimulated with phorbol 12-myristate 13-acetate (PMA), formyl-methionylleucyl-phenylalanine (fMLP) and lipopolysaccharide (LPS) Gerilechaogetu, - Hanieh, H Abe, A Kondo, Y Anim Sci J 80:577-84 18669607 Pubmed 2008 Flagellin and lipopolysaccharide up-regulation of IL-6 and CXCLi2 gene expression in chicken heterophils is mediated by ERK1/2-dependent activation of AP-1 and NF-kappaB signaling pathways Kogut, MH Genovese, KJ He, H Kaiser, P Innate Immun 14:213-22 2.7.11.1 activated MEK2 phosphorylates ERK2 activated MEK2 phosphorylates ERK2 Chicken ERK2 shares 99% of amino acid sequence identity with human and mouse ERK2. Multiple sequence alignment of human, mouse and chicken ERK2 by ClustalW allowed to predict that the following chicken residues are involved in chicken ERK2 activation: Thr193 and Tyr195 corresponding to mammalian Thr185 and Tyr187. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451495 1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 451480 1 phospho ERK2 : phospho MEK2 [cytosol] phospho ERK2 : phospho MEK2 Reactome DB_ID: 451487 1 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 451523 1 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 1 EQUAL 368 EQUAL Reactome Database ID Release 83 451480 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451480 Reactome R-GGA-451480 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-GGA-451480.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 451495 Reactome Database ID Release 83 451515 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451515 Reactome Database ID Release 83 451516 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451516 Reactome R-GGA-451516 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-GGA-451516.1 Dissociation of phospho ERK2 :phospho MEK2 complex Dissociation of phospho ERK2 :phospho MEK2 complex MEK-ERK pathways are considered to be highly conserved. Their involvement in up-regulation of the inflammatory response has been demonstrated in mammals and chicken (Johnson GL and Lapadat R 2002; Kogut M et al 2008). <p> In this model we assume that chicken MEK-ERK mediators behave like their human counterparts. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451526 1 phospho ERK2 : phospho MEK2 [cytosol] phospho ERK2 : phospho MEK2 Reactome DB_ID: 451487 1 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 451523 1 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 83 451526 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451526 Reactome R-GGA-451526 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-GGA-451526.1 Reactome DB_ID: 451487 1 O-phospho-L-serine at 220 220 EQUAL O-phospho-L-serine at 224 224 EQUAL 1 EQUAL 398 EQUAL Reactome DB_ID: 451523 1 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 83 451505 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451505 Reactome R-GGA-451505 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-GGA-451505.1 Dimerization of activated ERK2 Dimerization of activated ERK2 MEK-ERK pathways are considered to be highly conserved. Their involvement in up-regulation of the inflammatory response has been demonstrated in mammals and chicken (Johnson GL and Lapadat R 2002; Kogut M et al 2008). <p> In this model we assume that chicken MEK-ERK mediators behave like their human counterparts. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451523 2 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome DB_ID: 451504 1 phospho ERK2 dimer [cytosol] phospho ERK2 dimer Reactome DB_ID: 451523 2 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 83 451504 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451504 Reactome R-GGA-451504 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-GGA-451504.1 Reactome Database ID Release 83 451535 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451535 Reactome R-GGA-451535 2 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-GGA-451535.2 Nuclear translocation of phospho ERK2 dimer Nuclear translocation of phospho ERK2 dimer MEK-ERK pathways are considered to be highly conserved. Their involvement in up-regulation of the inflammatory response has been demonstrated in mammals and chicken (Johnson GL and Lapadat R 2002; Kogut M et al 2008). <p> In this model we assume that chicken MEK-ERK mediators behave like their human counterparts. Authored: Shamovsky, V, 2009-09-22 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-05-04 Reactome DB_ID: 451504 1 Reactome DB_ID: 451513 1 phospho ERK2 dimer [nucleoplasm] phospho ERK2 dimer Reactome DB_ID: 442961 2 O-phospho-L-threonine at 193 193 EQUAL O4'-phospho-L-tyrosine at 195 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 83 451513 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451513 Reactome R-GGA-451513 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-GGA-451513.1 Reactome Database ID Release 83 451508 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451508 Reactome R-GGA-451508 2 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-GGA-451508.2 Reactome Database ID Release 83 451478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451478 Reactome R-GGA-451478 2 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-GGA-451478.2 20954007 Pubmed 2010 Advances in avian immunology--prospects for disease control: a review Kaiser, P Avian Pathol 39:309-24 GO 0070371 GO biological process Reactome Database ID Release 83 451524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451524 Reactome R-GGA-451524 2 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-GGA-451524.2 19196711 Pubmed 2009 Selectivity of docking sites in MAPK kinases Bardwell, AJ Frankson, E Bardwell, L J Biol Chem 284:13165-73 GO 0000165 GO biological process Reactome Database ID Release 83 433871 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433871 Reactome R-GGA-433871 2 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-GGA-433871.2 11057907 Pubmed 2000 Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain Deng, L Wang, C Spencer, E Yang, L Braun, A You, J Slaughter, C Pickart, C Chen, ZJ Cell 103:351-61 19112497 Pubmed 2008 TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL Walsh, MC Kim, GK Maurizio, PL Molnar, EE Choi, Y PLoS One 3:e4064 Reactome Database ID Release 83 434048 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434048 Reactome R-GGA-434048 2 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-GGA-434048.2 19627256 Pubmed 2009 Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins Carpenter, S O'Neill, LA Biochem J 422:1-10 18202435 Pubmed 2008 Sensing of viral infection and activation of innate immunity by toll-like receptor 3 Vercammen, E Staal, J Beyaert, R Clin Microbiol Rev 21:13-25 15733829 Pubmed 2005 Transcriptional signaling by double-stranded RNA: role of TLR3 Sen, GC Sarkar, SN Cytokine Growth Factor Rev 16:1-14 18241342 Pubmed 2008 Evolution of the chicken Toll-like receptor gene family: a story of gene gain and gene loss Temperley, ND Berlin, S Paton, IR Griffin, DK Burt, DW BMC Genomics 9:62 17870162 Pubmed 2008 Activation of the TLR3 pathway regulates IFNbeta production in chickens Karpala, AJ Lowenthal, JW Bean, AG Dev Comp Immunol 32:435-44 GO 0034138 GO biological process