BioPAX pathway converted from "IKK related kinases bound to dsRNA:TLR3:TICAM1 activate IRF3" in the Reactome database. 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: 434016 2 cytosol GO 0005829 ENSEMBL:ENSGALP00000015982 ch_TBK1 ch_TBK1 TBK1 Reactome http://www.reactome.org Gallus gallus NCBI Taxonomy 9031 ENSEMBL ENSGALP00000015982 Chain Coordinates 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: 433947 1 endosome membrane GO 0010008 viral dsRNA : TLR3 : TICAM1 [endosome membrane] viral dsRNA : TLR3 : TICAM1 Reactome DB_ID: 433883 1 viral dsRNA:TLR3 [endosome membrane] viral dsRNA:TLR3 Reactome DB_ID: 433892 2 UniProt:Q0PQ88 Toll-like receptor 3 Toll-like receptor 3 TLR3 SIMILARITY Contains 1 TIR domain. UniProt Q0PQ88 1 EQUAL 1011 EQUAL Reactome DB_ID: 9014378 1 endosome lumen GO 0031904 IBV dsRNA intermediate form [endosome lumen] IBV dsRNA intermediate form 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 DB_ID: 433979 2 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 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 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: 571399 2 1 EQUAL 816 EQUAL Reactome DB_ID: 433947 1 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 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 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 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 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 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 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 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 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 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 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 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 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: 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: 113592 3 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 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 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 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 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: 113592 2 Reactome DB_ID: 433947 1 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: 433993 1 1 EQUAL 491 EQUAL Reactome DB_ID: 113592 3 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