BioPAX pathway converted from "Toll-like receptors (TLR) cascades" in the Reactome database. Toll-like receptors (TLR) cascades Toll-like receptors (TLRs) are a group of highly conserved pathogen recognition receptors which initiate and regulate the immune response by controlling cytokine and chemokines expression.<p>Mammalian and avian lineages diverged from the common ancestor approximately 300 millions years ago. Although most of the genes encoding proteins of the chicken TLR cascade molecules have not been cloned and characterized directly, analyses of the chicken genome sequence has defined ten TLRs [Lynn et al. 2003, Temperley ND et al. 2008]. The avian TLR repertoire consists of single orthologs of mammalian TLRs 3, 4, 5 and 7 and distinct new chicken genes TLR15 and TLR21. The TLR2 subfamily is represented by tandemly duplicated avian TLR2 and TLR1 genes and consists of two isoforms of each gene - TLR2 type1 and 2, TLR1 type1 and 2. No functional orthologs of mammalian TLR8, TLR9 and TLR10 have been detected in the chicken genome. However, chicken heterophils and spleen cells are responsive to the broad range of mammalian TLR antagonists including ligands that stimulate mammalian TLR7/8 and TLR9 [Schwarz et al. 2007, He et al. 2006, Kogut et al. 2007].<p>TLR signaling pathways are highly conserved among vertebrates and the chicken proteins involved in the TLR signaling cascade show moderate to high identity with their human counterparts [Yilmaz et al. 2005, Temperley et al. 2008, Cormican et al. 2009]. Thus, a homology-based strategy was used to reconstruct most parts of the chicken TLR pathways in this Reactome module.<p>All TLRs share a similar structure consisting of N-terminus ectodomain with several leucine-rich regions (LRR), one or two trans-membrane domains and an intracellular C-terminus Toll/Interleukin-1 receptor domain (TIR).<p>Activation of TLR pathways occurs upon recognition and interaction with conserved motifs expressed by invading microbes, also known as pathogen-associated molecular patterns (PAMPs). Each TLR recognizes specific PAMPs.</p>Upon PAMP binding TLRs form heterodimers (TLR2 subfamily) or homodimers (all other TLRs). Activated TLRs recruit one or several TIR adaptor proteins myeloid differentiation primary response gene 88 (MyD88), TIR domain containing adaptor protein (TIRAP or MAL), TIR domain-containing adapter protein inducing IFN-beta (TRIF or TIKAM-1), and TRIF related adaptor molecule (TRAM). The fifth known adaptor SARM binds TIR as a negative competitor to TRIF.<p>All TLRs except TLR3 can initiate downstream signaling through MyD88 adaptor protein. In the MyD88-dependent pathway, once the adaptor is bound to TLR, it leads to recruitment of IL1 receptor associated kinase family IRAK, followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 is an ubiquitin E3 ligase, which in turn induces TGF-beta activating kinase 1 (TAK1) autophosphorylation. Once activated, TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides.<p>In contrast to other TLRs, TLR3 functions only through the MyD88-independent signaling cascade, recruiting TRIF, which in turn leads to the interferon regulatory factor 3 or 7 (IRF3/7) activation. Activated IRF3 or 7 mediates innate anti-viral responses through interferon-beta expression.<p> Mammalian TLR4 can ultimately utilize both MyD88-dependent (controlled by the MyD88-TIRAP pair of adaptors) and MyD88-independent (controlled by TRAM-TRIF adaptor proteins) signaling pathways, in contrast, chicken TLR4 signaling is mediated by MyD88-TIRAP exlusively. Authored: Shamovsky, V, 2009-11-11 Reviewed: D'Eustachio, P, 2010-05-23 Edited: Shamovsky, V, 2010-05-24 TLR2 subfamily cascade In chicken, TLR1 and 2 genes are individually duplicated to encode four different proteins of the TLR2 subfamily: <ul><li >chTLR1 type 1 (TLR1-1, or TLR1LA, or TLR16) <li>chTLR1 type 2 (TLR1-2 or TLR1LB)<li> chTLR2 type 1(TLR2A or TLR2-1)<li> chTLR2 type 2 (TLR2B or TLR2-2)</ul>. The TLR1 and TLR2 gene duplication events were estimated to have taken place about 147 and 65 million years ago respectively (Temperley ND et al. 2008).<p>Analyses of chicken genome revealed that all chTLR2 and chTLR1 isoforms are located on Chromosome 4 and are encoded by one exon, like human TLR2 and TLR1. The phylogenetic comparative analysis also showed that chTLR2 isoforms are two distinct genes (not splicing products of the same gene) and TLR2A and B are both orthologs of the single TLR2 of mammals (Temperley ND et al 2008, Cormican et al 2009). Although chicken TLR1 type 1 and 2 genes were reported by Yilmaz et al. (2004) to be highly similar to human TLR1 and TLR6 genes, further analysis revealed that chicken TLR1 and human TLR1/6/10 are not orthologs (Temperley ND et al 2008).<p>The functional profile of chicken TLR2 subfamily proteins is similar to human; members of TLR2 subfamily respond to lipoproteins through heterodimer formation. Authored: Shamovsky, V, 2010-02-20 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 LEFT-TO-RIGHT TLR2-1 :TLR1-1 binds to triacyl lipopeptide Higuchi et al. (2008) and Keestra et al. (2007) demonstrated that chTLR2 subfamily members distinguish between their ligands by combinational events and combined expression of chTLR2 and chTLR1 isoforms is needed for TLR receptor function. Both groups studied the chTLR2 signaling by NF-kB reporter assay using human cells (HEK293 or HeLa 57A) transfected with chTLRs 1 or 2. Keestra et al. (2007) reported that only TLR2 type 2 was able to form functional heterodimer with TLR16 (TLR1 type 1). In contrast, Higuchi et al. (2008) showed on HEK293 cells that both isoforms of chTLR2 form functional TLR2 complexes with chTLR1 type 1 or 2.<p>Based on the data of those studies:<ul><li> chTLR1 type 2 with either chTLR2 type 1 or 2 formed cooperative sensors of peptidoglycan (PGN), diacylated bacterial lypoproteins (BLP), macrophage-activating lipopeptide 2 kDa (Malp-2) and triacylated BLP </li> <li>the combination of chTLR2-1 and chTLR1-1 recognized triacylated BLP and synthetic triacylated lipopeptide - Pam3.</li><li> chTLR2 -2 combined with chTLR1-1(TLR16) cooperatively responded to both diacylated and triacylated bacterial lypoproteins. Authored: Shamovsky, V, 2010-02-20 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 TLR2-1 : TLR1-1 heterodimer Reactome DB_ID: 517847 plasma membrane GENE ONTOLOGY GO:0005886 TLR1 TLR1-1 TLR1LA TLR16 Reactome DB_ID: 517848 UniProt:Q5WA51 TLR1 TLR1 SIMILARITY Contains 1 TIR domain. Gallus gallus NCBI Taxonomy 9031 UniProt Q5WA51 1 EQUAL 818 EQUAL Reactome Database ID Release 83 517848 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517848 Reactome R-GGA-517848 1 Reactome stable identifier. Use this 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-517848.1 Reactome http://www.reactome.org 1 TLR2-1 TLR2 type 1 Reactome DB_ID: 517857 UniProt:Q9DD78 TLR2-1 TLR2-1 FUNCTION Participates in the innate immune response to microbial agents. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity). Does not respond to LPS and responds with less ability than TLR2-2 to mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2).SUBUNIT Binds MYD88 (via TIR domain).TISSUE SPECIFICITY Highly expressed in ovary. Detected at lower levels in heart, lung, gizzard and testis.PTM N-glycosylated. TLR2-1 is more heavily glycosylated than TLR2-2.SIMILARITY Belongs to the Toll-like receptor family.CAUTION In some plant proteins and in human SARM1, the TIR domain has NAD(+) hydrolase (NADase) activity (By similarity). However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (By similarity). Based on this, it is unlikely that Toll-like receptors have NADase activity. UniProt Q9DD78 1 EQUAL 793 EQUAL Reactome Database ID Release 83 517857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517857 Reactome R-GGA-517857 1 Reactome stable identifier. Use this 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-517857.1 1 Reactome Database ID Release 83 517847 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517847 Reactome R-GGA-517847 1 Reactome stable identifier. Use this 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-517847.1 Triacyl lipopeptide Reactome DB_ID: 180811 extracellular region GENE ONTOLOGY GO:0005576 triacyl lipopeptide [ChEBI:60192] triacyl lipopeptide triacylated lipopeptide ChEBI CHEBI:60192 Reactome Database ID Release 83 180811 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=180811 Reactome R-ALL-180811 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-ALL-180811.2 PubChem Compound 456855 additional information MI MI:0361 chicken TLR2-1 : TLR1-1 bound to its ligand Reactome DB_ID: 517853 1 Triacyl lipopeptide Reactome DB_ID: 571346 Reactome Database ID Release 83 571346 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571346 Reactome R-ALL-571346 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-ALL-571346.2 PubChem Compound 456855 1 Reactome Database ID Release 83 517853 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517853 Reactome R-GGA-517853 1 Reactome stable identifier. Use this 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-517853.1 Reactome Database ID Release 83 517846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517846 Reactome R-GGA-517846 1 Reactome stable identifier. Use this 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-517846.1 17513760 Pubmed 2007 The central leucine-rich repeat region of chicken TLR16 dictates unique ligand specificity and species-specific interaction with TLR2 Keestra, AM de Zoete, MR van Aubel, RA van Putten, JP J Immunol 178:7110-9 17614130 Pubmed 2008 Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily Higuchi, M Matsuo, A Shingai, M Shida, K Ishii, A Funami, K Suzuki, Y Oshiumi, H Matsumoto, M Seya, T Dev Comp Immunol 32:147-55 LEFT-TO-RIGHT TLR2-1 : TLR1-2 heterodimer binds to its ligand Higuchi et al. (2008) and Keestra et al. (2007) demonstrated that chTLR2 subfamily members distinguish between their ligands by combinational events and combined expression of chTLR2 and chTLR1 isoforms is needed for TLR receptor function. Both groups studied the chTLR2 signaling by NF-kB reporter assay using human cells (HEK293 or HeLa 57A) transfected with chTLRs 1 or 2. Keestra et al. (2007) reported that only TLR2 type 2 was able to form functional heterodimer with TLR16 (TLR1 type 1). In contrast, Higuchi et al. (2008) showed on HEK293 cells that both isoforms of chTLR2 form functional TLR2 complexes with chTLR1 type 1 or 2.<p>Based on the data of those studies:<ul><li> chTLR1 type 2 with either chTLR2 type 1 or 2 formed cooperative sensors of peptidoglycan (PGN), diacylated bacterial lypoproteins (BLP), macrophage-activating lipopeptide 2 kDa (Malp-2) and triacylated BLP </li> <li>the combination of chTLR2-1 and chTLR1-1 recognized triacylated BLP and synthetic triacylated lipopeptide - Pam3.</li><li> chTLR2 -2 combined with chTLR1-1(TLR16) cooperatively responded to both diacylated and triacylated bacterial lypoproteins. Authored: Shamovsky, V, 2010-02-20 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 TLR2-1 : TLR1-2 heteroodimer Reactome DB_ID: 517845 TLR1-2 TLR2LB chTLR1 type 2 Reactome DB_ID: 517840 UniProt:A5H0S2 TLR1Lb TLR1Lb SIMILARITY Contains 1 TIR domain. UniProt A5H0S2 1 EQUAL 652 EQUAL Reactome Database ID Release 83 517840 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517840 Reactome R-GGA-517840 1 Reactome stable identifier. Use this 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-517840.1 1 1 Reactome Database ID Release 83 517845 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517845 Reactome R-GGA-517845 1 Reactome stable identifier. Use this 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-517845.1 Converted from EntitySet in Reactome Ligand recognized by chicken TLR2-1 : TLR1-2 heterodimer Reactome DB_ID: 517843 Diacyl lipopeptide Reactome DB_ID: 181403 diacyl lipopeptide [ChEBI:46896] diacyl lipopeptide diacylated lipopeptides diacyl lipopeptides diacylated lipopeptide ChEBI CHEBI:46896 Reactome Database ID Release 83 181403 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181403 Reactome R-ALL-181403 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-ALL-181403.2 PubChem Compound 456855 PGN peptidoglycan murein Reactome DB_ID: 517839 peptidoglycan [ChEBI:8005] peptidoglycan Mucopeptide Peptideglycan Murein ChEBI CHEBI:8005 Reactome Database ID Release 83 517839 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517839 Reactome R-ALL-517839 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-ALL-517839.3 ChEBI 8005 Reactome Database ID Release 83 517843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517843 Reactome R-ALL-517843 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-517843.1 chicken TLR2-1 :TLR1-2 bound to its ligand Reactome DB_ID: 517842 1 Converted from EntitySet in Reactome Ligand recognized by chicken TLR2-1 : TLR1-2 heterodimer Reactome DB_ID: 517854 PGN peptidoglycan murein Reactome DB_ID: 517838 Reactome Database ID Release 83 517838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517838 Reactome R-ALL-517838 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-ALL-517838.2 Diacyl lipopeptide Reactome DB_ID: 571253 Reactome Database ID Release 83 571253 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571253 Reactome R-ALL-571253 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-ALL-571253.2 PubChem Compound 456855 Reactome Database ID Release 83 517854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517854 Reactome R-ALL-517854 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-517854.1 1 Reactome Database ID Release 83 517842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517842 Reactome R-GGA-517842 1 Reactome stable identifier. Use this 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-517842.1 Reactome Database ID Release 83 517850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517850 Reactome R-GGA-517850 1 Reactome stable identifier. Use this 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-517850.1 MyD88:TIRAP-dependent cascade initiated on plasma membrane Myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays a crucial role in TLR signaling. All TLRs except TLR3 can initiate downstream signaling through MyD88. In the MyD88-dependent pathway, once the adaptor is bound to TLR it leads to recruitment of proteins of the IL1 receptor associated kinase family - IRAK, followed by activation of tumor necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 is an ubiquitin E3 ligase which in turn induces autophosphorylation of TGF-beta activating kinase 1 (TAK1). Activated TAK1 can ultimately mediate the induction of transcription factor NF-kB or mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides.<p>The chicken MyD88 gene was cloned and its expression was detected in cecum, heart, spleen, liver, kidney, female reproductive tract, thymus and bursa. Over-expression of chicken MyD88 (299aa) significantly stimulated the activation of NF-kB in vitro. Authored: Shamovsky, V, 2010-01-05 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 LEFT-TO-RIGHT Activated TLR homo- or heterodimer recruits adaptors TIRAP(or MAL) and MyD88 Cloning and analysis of full length chicken MyD88 revealed an open reading frame which encodes a predicted protein sequence of 368 amino acids (aa). Two more chicken MyD88 isoforms with 299 and 376 residues are described in the literature [Qiu Y et al 2008, Lynn et al 2003]. The amino acid sequences of the chMyD88 368 and 376 residue isoforms are 99% identical, 97% identical to the 299 aa chMyD88 predicted peptide and 68% identical to human MyD88 (296 aa).<p>Chicken MyD88 is recruited to the activated hetero or homodimer of chTLR that is located either on plasma membrane (TLR4, TLR2/1, TLR5 and TLR15) or endosome membrane (TLR7 and TLR21). Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 TIRAP Reactome DB_ID: 433807 cytosol GENE ONTOLOGY GO:0005829 UniProt:Q4U127 TIRAP TIRAP SIMILARITY Contains 1 TIR domain. UniProt Q4U127 1 EQUAL 221 EQUAL Reactome Database ID Release 83 433807 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433807 Reactome R-GGA-433807 1 Reactome stable identifier. Use this 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-433807.1 2 Converted from EntitySet in Reactome activated TLR2 or 4 bound to ligand Reactome DB_ID: 451517 TLR4:LY96:LPS Reactome DB_ID: 433789 TLR4:LY96 Reactome DB_ID: 434119 MD2 LY96 Reactome DB_ID: 9628168 UniProt:A0A1D5NZX9 LY96 LY96 UniProt A0A1D5NZX9 Reactome Database ID Release 83 9628168 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9628168 Reactome R-GGA-9628168 1 Reactome stable identifier. Use this 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-9628168.1 1 TLR4 Reactome DB_ID: 433970 UniProt:Q7ZTG5 TLR4 TLR4 SIMILARITY Contains 1 TIR domain. UniProt Q7ZTG5 1 EQUAL 843 EQUAL Reactome Database ID Release 83 433970 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433970 Reactome R-GGA-433970 1 Reactome stable identifier. Use this 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-433970.1 1 Reactome Database ID Release 83 434119 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434119 Reactome R-GGA-434119 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-434119.2 2 LPS Gram Negative Bacterial Lipopolysaccharide lipopolysaccharide Reactome DB_ID: 433850 lipopolysaccharide [ChEBI:16412] lipopolysaccharide lipopolysaccharides LPS ChEBI CHEBI:16412 Reactome Database ID Release 83 433850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433850 Reactome R-ALL-433850 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-ALL-433850.3 2 Reactome Database ID Release 83 433789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433789 Reactome R-GGA-433789 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-433789.3 Reactome Database ID Release 83 451517 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451517 Reactome R-GGA-451517 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-451517.3 MyD88 Reactome DB_ID: 433987 UniProt:A5HNF6 MYD88 MYD88 RCJMB04_14h3 FUNCTION Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response.TISSUE SPECIFICITY Expressed in spleen, liver, kidney, bursa of Fabricius, lung and brain (at protein level). Expressed in cecum, heart, spleen, liver, kidney, female reproductive tract, thymus, bursa of Fabricius, muscle and lung.DOMAIN The intermediate domain (ID) is required for the phosphorylation and activation of IRAK. UniProt A5HNF6 1 EQUAL 299 EQUAL Reactome Database ID Release 83 433987 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433987 Reactome R-GGA-433987 1 Reactome stable identifier. Use this 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-433987.1 2 activated TLR hetero- or homodimer : TIRAP : MyD88 complex Reactome DB_ID: 433821 MyD88 Reactome DB_ID: 433900 1 EQUAL 299 EQUAL Reactome Database ID Release 83 433900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433900 Reactome R-GGA-433900 1 Reactome stable identifier. Use this 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-433900.1 2 1 TIRAP Reactome DB_ID: 433857 1 EQUAL 221 EQUAL Reactome Database ID Release 83 433857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433857 Reactome R-GGA-433857 1 Reactome stable identifier. Use this 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-433857.1 2 Reactome Database ID Release 83 433821 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433821 Reactome R-GGA-433821 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-433821.3 Reactome Database ID Release 83 433961 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433961 Reactome R-GGA-433961 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-433961.2 18582498 Pubmed 2008 Molecular cloning and functional characterization of a novel isoform of chicken myeloid differentiation factor 88 (MyD88) Qiu, Y Shen, Y Li, X Ding, C Ma, Z Dev Comp Immunol 32:1522-30 19002681 Pubmed 2009 Differential mRNA expression of the avian-specific toll-like receptor 15 between heterophils from Salmonella-susceptible and -resistant chickens Nerren, JR Swaggerty, CL MacKinnon, KM Genovese, KJ He, H Pevzner, I Kogut, MH Immunogenetics 61:71-7 12447442 Pubmed 2002 The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors Horng, T Barton, GM Flavell, RA Medzhitov, R Nature 420:329-33 19679662 Pubmed 2009 Identification of critical residues of the MyD88 death domain involved in the recruitment of downstream kinases Loiarro, M Gallo, G Fantò, N De Santis, R Carminati, P Ruggiero, V Sette, C J Biol Chem 284:28093-103 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 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 LEFT-TO-RIGHT IRAK4 recruitment to the activated TLR complexed with ligand, TIRAP and MyD88 Mammalian IL-1 receptor-associated kinases IRAK-1, IRAK-2 and IRAK-4 form a multigene family. Those proteins are Ser/Thr protein kinases that are required for TLR mediated pathways leading to NFkB activation. Another IRAK family member IRAK-M has been identified as an inhibitor of TLR signaling.<p>Mammalian IRAK-4 is the homolog of Drosophila melanogaster Pelle. Like Pelle and unlike the other mammalian IRAKs, IRAK-4 is considered to be a central TIR signalling mediator in innate immunity. Mutagenesis analysis showed that any interference with IRAK-4's kinase activity virtually abolished downstream events. This is not the case with other members of the IRAK family.<p>Formation of MyD88:IRAKs multimer relies on homotypic interactions of death domains (DD). It triggers a cascade of phosphorylation reactions that leads to activation of NF-kB/AP-1 and transcription of multiple genes involved in the immune response.<p>The predicted chicken full-length IRAK-4 protein contains 414aa and is 58% identical to human IRAK-4. Chicken IRAK-4 contains a conserved N-terminal death domain and C-terminal protein kinase domain. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 IRAK4 Reactome DB_ID: 433873 UniProt:Q5ZJM6 RCJMB04_17b10 RCJMB04_17b10 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5ZJM6 1 EQUAL 373 EQUAL Reactome Database ID Release 83 433873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433873 Reactome R-GGA-433873 1 Reactome stable identifier. Use this 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-433873.1 2 activated TLR homo- or heterodimer : TIRAP :MyD88 :IRAK4 Reactome DB_ID: 433831 1 IRAK4 Reactome DB_ID: 434129 1 EQUAL 373 EQUAL Reactome Database ID Release 83 434129 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434129 Reactome R-GGA-434129 1 Reactome stable identifier. Use this 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-434129.1 2 Reactome Database ID Release 83 433831 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433831 Reactome R-GGA-433831 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-433831.3 Reactome Database ID Release 83 434073 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434073 Reactome R-GGA-434073 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-434073.2 11923871 Pubmed 2002 Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4 Suzuki, N Suzuki, S Duncan, GS Millar, DG Wada, T Mirtsos, C Takada, H Wakeham, A Itie, A Li, S Penninger, JM Wesche, H Ohashi, PS Mak, TW Yeh, WC Nature 416:750-6 19167362 Pubmed 2009 Contribution of globular death domains and unstructured linkers to MyD88.IRAK-4 heterodimer formation: an explanation for the antagonistic activity of MyD88s Mendoza-Barberá, E Corral-Rodriguez, Maria Ýngeles Soares-Schanoski, A Velarde, M Macieira, S Messerschmidt, A López-Collazo, E Fuentes-Prior, P Biochem Biophys Res Commun 380:183-7 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 12814703 Pubmed 2003 In silico identification of components of the Toll-like receptor (TLR) signaling pathway in clustered chicken expressed sequence tags (ESTs) Lynn, DJ Lloyd, AT O'Farrelly, C Vet Immunol Immunopathol 93:177-84 11960013 Pubmed 2002 IRAK-4: a novel member of the IRAK family with the properties of an Li, S Strelow, A Fontana, EJ Wesche, H Proc Natl Acad Sci U S A 99:5567-72 LEFT-TO-RIGHT 2.7.11.1 Autophosphorylation of chicken IRAK4 Chicken IRAK4 shows 66% amino acid identity to human IRAK4. It is assumed here that chicken IRAK4 is activated by autophosphorylation like its human homologue. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 83 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 2 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 83 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 2 activated TLR : TIRAP : MyD88 ; p-IRAK4 Reactome DB_ID: 434022 activated IRAK4 Reactome DB_ID: 975706 O-phospho-L-serine MOD MOD:00046 O-phospho-L-threonine MOD MOD:00047 1 EQUAL 373 EQUAL Reactome Database ID Release 83 975706 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975706 Reactome R-GGA-975706 1 Reactome stable identifier. Use this 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-975706.1 2 1 Reactome Database ID Release 83 434022 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434022 Reactome R-GGA-434022 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-434022.3 ACTIVATION activeUnit: #Protein11 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 83 433896 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433896 Reactome Database ID Release 83 434018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434018 Reactome R-GGA-434018 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-434018.2 18438411 Pubmed 2008 Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2 Kawagoe, T Sato, S Matsushita, K Kato, H Matsui, Kuniko Kumagai, Y Saitoh, T Kawai, T Takeuchi, O Akira, Shizuo Nat Immunol 9:684-91 14625308 Pubmed 2004 Sequential autophosphorylation steps in the interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling Kollewe, C Mackensen, AC Neumann, D Knop, J Cao, P Li, S Wesche, H Martin, MU J Biol Chem 279:5227-36 LEFT-TO-RIGHT IRAK2 binds to the IRAK4 accociated with the complex of the activated TLR : TIRAP : MyD88 In mammals activated IRAK4 phosphorylates both IRAK1 and IRAK2. Activated IRAK1 and IRAK2 in turn induce NFkB and AP-1 intracellular signaling cascades mediated by TRAF6.<p>Bioinformatic analysis reveals no evidence of IRAK1 in the chicken genome. It is possible that the chicken TLR pathway utilizes only IRAK-2, which shares 47% amino acid sequence identity with human IRAK2. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 IRAK2 Reactome DB_ID: 434068 UniProt:Q5F382 RCJMB04_29d24 RCJMB04_29d24 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5F382 1 EQUAL 691 EQUAL Reactome Database ID Release 83 434068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434068 Reactome R-GGA-434068 1 Reactome stable identifier. Use this 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-434068.1 2 IRAK2 : p-IRAK4 :MyD88 : TIRAP : activated TLR Reactome DB_ID: 434002 1 IRAK2 Reactome DB_ID: 433862 1 EQUAL 691 EQUAL Reactome Database ID Release 83 433862 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433862 Reactome R-GGA-433862 1 Reactome stable identifier. Use this 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-433862.1 2 Reactome Database ID Release 83 434002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434002 Reactome R-GGA-434002 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-434002.3 Reactome Database ID Release 83 433864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433864 Reactome R-GGA-433864 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-433864.2 19224918 Pubmed 2009 Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control Wan, Y Xiao, H Affolter, J Kim, TW Bulek, K Chaudhuri, S Carlson, D Hamilton, T Mazumder, B Stark, GR Thomas, J Li, X J Biol Chem 284:10367-75 LEFT-TO-RIGHT 2.7.11.1 phosphorylation of IRAK2 by activated IRAK4 In mammals activated IRAK4 phosphorylates both IRAK1 and IRAK2. Activated IRAK1 and IRAK2 in turn induce NFkB and AP-1 intracellular signaling cascades mediated by TRAF6.<p>Bioinformatic analysis reveals no evidence of IRAK1 in the chicken genome. It is possible that the chicken TLR pathway utilizes only IRAK-2, which shares 47% amino acid sequence identity with human IRAK2. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 2 2 p-IRAK2 : p-IRAK4 : activated TLR : TIRAP : MyD88 Reactome DB_ID: 433907 phosphorylated IRAK2 Reactome DB_ID: 433788 phosphorylated residue MOD MOD:00696 1 EQUAL 691 EQUAL Reactome Database ID Release 83 433788 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433788 Reactome R-GGA-433788 1 Reactome stable identifier. Use this 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-433788.1 2 1 Reactome Database ID Release 83 433907 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433907 Reactome R-GGA-433907 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-433907.3 ACTIVATION activeUnit: #Protein11 Reactome Database ID Release 83 433985 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433985 Reactome Database ID Release 83 434047 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434047 Reactome R-GGA-434047 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-434047.2 NFkB and MAPK activation mediated by TRAF6 Treatment of chicken heterophiles with either flagellin or lipopolysaccharide induces the expression and secretion of pro-inflammatory cytokines and chemokines (IL-6, IL-18, IL-1 beta, CXCLi2) through activation of transcription factors NFkB and AP-1. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 LEFT-TO-RIGHT TRAF6 binds to p-IRAK2 complexed with activated TLR There is little experimental data about mammalian IRAK2 mediated signaling. It is possible that phosphorylated IRAK2, like IRAK1, dissociates from upstream adapters such as MyD88 but leaves its interaction with the downstream adapter TRAF6 unaffected. Furthermore Keating et al. [2007] showed that IRAK2 can promote TRAF6 ubiquitination. Other studies [Wan et al 2009] detected IRAK2-TRAF6 interaction upon LPS stimulation.<p>In this reaction we assume that chicken IRAK2 behaves like its mammalian homolog IRAK2. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 TRAF6 Reactome DB_ID: 433886 UniProt:E1C626 TRAF6 TRAF6 SIMILARITY: Contains 1 MATH domain. UniProt E1C626 Reactome Database ID Release 83 433886 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433886 Reactome R-GGA-433886 1 Reactome stable identifier. Use this 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-433886.1 2 p-IRAK2 bound to the activated chicken TLR complex Reactome DB_ID: 977243 2 Converted from EntitySet in Reactome ch p-IRAK4 bound to the activated TLR complex Reactome DB_ID: 977236 activated TLR : MyD88 : p-IRAK4 Reactome DB_ID: 977234 2 activated TLR homodimer : MyD88 complex Reactome DB_ID: 977241 2 Converted from EntitySet in Reactome activated TLR5 or 15 bound to ligand Reactome DB_ID: 977246 bacterial flagellin bound to chicken TLR5 homodimer Reactome DB_ID: 451462 Converted from EntitySet in Reactome Flagellin -phase1 and/or 2 Reactome DB_ID: 1063701 Flagellin (phase 2 - flagellin) Reactome DB_ID: 1063704 UniProt:P52616 fljB fljB H2 STM2771 FUNCTION Flagellin is the subunit protein which polymerizes to form the filaments of bacterial flagella.MISCELLANEOUS Individual Salmonella serotypes usually alternate between the production of 2 antigenic forms of flagella, termed phase 1 and phase 2, each specified by separate structural genes.SIMILARITY Belongs to the bacterial flagellin family. Salmonella typhimurium NCBI Taxonomy 90371 UniProt P52616 1 EQUAL 506 EQUAL Reactome Database ID Release 83 1063704 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1063704 Reactome R-STY-1063704 11 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-STY-1063704.11 Flagellin (phase1- flagellin) Reactome DB_ID: 1063703 UniProt:P06179 fliC fliC flaF hag STM1959 FUNCTION Flagellin is the subunit protein which polymerizes to form the filaments of bacterial flagella.INDUCTION Inhibited in nutrient-poor medium (at protein level).MISCELLANEOUS Individual Salmonella serotypes usually alternate between the production of 2 antigenic forms of flagella, termed phase 1 and phase 2, each specified by separate structural genes, fliC and fljB.SIMILARITY Belongs to the bacterial flagellin family. UniProt P06179 1 EQUAL 495 EQUAL Reactome Database ID Release 83 1063703 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1063703 Reactome R-STY-1063703 11 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-STY-1063703.11 Reactome Database ID Release 83 1063701 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1063701 Reactome R-STY-1063701 11 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-STY-1063701.11 1 TLR5:TLR5 homodimer Reactome DB_ID: 451471 TLR5 Reactome DB_ID: 451449 UniProt:Q5GR02 TLR5 TLR5 SIMILARITY Contains 1 TIR domain. UniProt Q5GR02 1 EQUAL 862 EQUAL Reactome Database ID Release 83 451449 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451449 Reactome R-GGA-451449 1 Reactome stable identifier. Use this 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-451449.1 2 Reactome Database ID Release 83 451471 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451471 Reactome R-GGA-451471 1 Reactome stable identifier. Use this 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-451471.1 1 Reactome Database ID Release 83 451462 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451462 Reactome R-GGA-451462 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-451462.2 TLR15 bound to recognized ligand Reactome DB_ID: 451519 TLR15 homodimer Reactome DB_ID: 451488 TLR15 Reactome DB_ID: 451532 UniProt:Q2XQ10 TLR15 TLR15 SIMILARITY Contains 1 TIR domain. UniProt Q2XQ10 1 EQUAL 868 EQUAL Reactome Database ID Release 83 451532 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451532 Reactome R-GGA-451532 1 Reactome stable identifier. Use this 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-451532.1 2 Reactome Database ID Release 83 451488 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451488 Reactome R-GGA-451488 1 Reactome stable identifier. Use this 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-451488.1 1 Ligand recognized by chicken TLR15 Reactome DB_ID: 1063702 Reactome Database ID Release 83 1063702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1063702 Reactome R-ALL-1063702 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-ALL-1063702.2 ChEBI 23367 1 Reactome Database ID Release 83 451519 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451519 Reactome R-GGA-451519 1 Reactome stable identifier. Use this 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-451519.1 Reactome Database ID Release 83 977246 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977246 Reactome R-GGA-977246 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-977246.2 1 Reactome Database ID Release 83 977241 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977241 Reactome R-GGA-977241 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-977241.2 1 Reactome Database ID Release 83 977234 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977234 Reactome R-GGA-977234 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-977234.2 Reactome Database ID Release 83 977236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977236 Reactome R-GGA-977236 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-977236.3 1 Reactome Database ID Release 83 977243 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977243 Reactome R-GGA-977243 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-977243.3 chTRAF6 bound to the activated chicken TLR complex Reactome DB_ID: 977235 2 1 TRAF6 Reactome DB_ID: 975708 Reactome Database ID Release 83 975708 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975708 Reactome R-GGA-975708 1 Reactome stable identifier. Use this 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-975708.1 2 Reactome Database ID Release 83 977235 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977235 Reactome R-GGA-977235 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-977235.2 Reactome Database ID Release 83 434053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434053 Reactome R-GGA-434053 1 Reactome stable identifier. Use this 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-434053.1 17878161 Pubmed 2007 IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination Keating, SE Maloney, GM Moran, EM Bowie, AG J Biol Chem 282:33435-43 18070982 Pubmed 2008 TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB Muroi, M Tanamoto, K J Leukoc Biol 83:702-7 LEFT-TO-RIGHT p-IRAK2- TRAF6 dissociates from the activated chTLR complex There is little experimental data about mammalian IRAK2 mediated signaling. It is possible that phosphorylated IRAK2, like IRAK1, dissociates from upstream adapters such as MyD88 but leaves its interaction with the downstream adapter TRAF6 unaffected. Furthermore Keating et al. [2007] showed that IRAK2 can promote TRAF6 ubiquitination. Other studies [Wan et al 2009] detected IRAK2-TRAF6 interaction upon LPS stimulation.<p>In this reaction we assume that chicken IRAK2 behaves like its mammalian homolog IRAK2. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 TRAF6:p-IRAK2 Reactome DB_ID: 433829 1 1 Reactome Database ID Release 83 433829 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433829 Reactome R-GGA-433829 1 Reactome stable identifier. Use this 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-433829.1 2 Reactome Database ID Release 83 434084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434084 Reactome R-GGA-434084 1 Reactome stable identifier. Use this 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-434084.1 LEFT-TO-RIGHT TRAF6 binding to activated IRAK2 stimulates its oligomerization There is little experimental data about mammalian IRAK2 mediated signaling. It is possible that phosphorylated IRAK2, like IRAK1, dissociates from upstream adapters such as MyD88 but leaves its interaction with the downstream adapter TRAF6 unaffected. Furthermore Keating et al. [2007] showed that IRAK2 can promote TRAF6 ubiquitination. Other studies [Wan et al 2009] detected IRAK2-TRAF6 interaction upon LPS stimulation.<p>In this reaction we assume that chicken IRAK2 behaves like its mammalian homolog IRAK2. Authored: Shamovsky, V, 2010-01-05 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 2 oligo TRAF6 : p-IRAK2 Reactome DB_ID: 451475 2 1 Reactome Database ID Release 83 451475 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451475 Reactome R-GGA-451475 1 Reactome stable identifier. Use this 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-451475.1 Reactome Database ID Release 83 451466 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451466 Reactome R-GGA-451466 1 Reactome stable identifier. Use this 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-451466.1 LEFT-TO-RIGHT 6.3.2.19 Auto ubiquitination of oligo TRAF6 bound to p-IRAK2 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, 2010-01-05 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 Converted from EntitySet in Reactome Ubiquitin Reactome DB_ID: 434147 ubiquitin (RPS27A) Reactome DB_ID: 939879 UniProt:P79781 RPS27A RPS27A UBA80 FUNCTION Ubiquitin Exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in proteotoxic stress response and cell cycle; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity).FUNCTION Ribosomal protein S27a is a component of the 40S subunit of the ribosome.SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P79781 1 EQUAL 76 EQUAL Reactome Database ID Release 83 939879 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939879 Reactome R-GGA-939879 1 Reactome stable identifier. Use this 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-939879.1 ubiquitin (UBA52) Reactome DB_ID: 939891 UniProt:P62985 UBA52 UBA52 UBCEP2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62985 17 EQUAL 1 EQUAL Reactome Database ID Release 83 939891 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939891 Reactome R-GGA-939891 1 Reactome stable identifier. Use this 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-939891.1 ubiquitin (UBB 1) Reactome DB_ID: 939892 UniProt:P0CG62 UBB UBB FUNCTION Ubiquitin Exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in proteotoxic stress response and cell cycle; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG62 1 EQUAL 76 EQUAL Reactome Database ID Release 83 939892 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939892 Reactome R-GGA-939892 1 Reactome stable identifier. Use this 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-939892.1 ubiquitin (UBB 2) Reactome DB_ID: 939878 77 EQUAL 152 EQUAL Reactome Database ID Release 83 939878 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939878 Reactome R-GGA-939878 1 Reactome stable identifier. Use this 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-939878.1 ubiquitin (UBB 3) Reactome DB_ID: 939877 153 EQUAL 228 EQUAL Reactome Database ID Release 83 939877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939877 Reactome R-GGA-939877 1 Reactome stable identifier. Use this 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-939877.1 ubiquitin (UBB 4) Reactome DB_ID: 939898 229 EQUAL 304 EQUAL Reactome Database ID Release 83 939898 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939898 Reactome R-GGA-939898 1 Reactome stable identifier. Use this 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-939898.1 Reactome Database ID Release 83 434147 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434147 Reactome R-GGA-434147 1 Reactome stable identifier. Use this 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-434147.1 9 pUb oligo TRAF6 : p-IRAK2 Reactome DB_ID: 451453 1 K63 linked pUb TRAF6 Reactome DB_ID: 433856 K63-linked Ub TRAF6 Reactome DB_ID: 975686 ubiquitinylated lysine MOD MOD:01148 Reactome Database ID Release 83 975686 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975686 Reactome R-GGA-975686 1 Reactome stable identifier. Use this 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-975686.1 1 K63 polyubiquitin chain Reactome DB_ID: 975690 Reactome Database ID Release 83 975690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975690 Reactome R-GGA-975690 1 Reactome stable identifier. Use this 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-975690.1 1 Reactome Database ID Release 83 433856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433856 Reactome R-GGA-433856 1 Reactome stable identifier. Use this 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-433856.1 3 Reactome Database ID Release 83 451453 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451453 Reactome R-GGA-451453 1 Reactome stable identifier. Use this 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-451453.1 ACTIVATION activeUnit: #Protein31 GENE ONTOLOGY GO:0004842 Reactome Database ID Release 83 451446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451446 TRAM TIKAM2 Reactome DB_ID: 451442 UniProt:Q8AXQ0 TRAM TRAM UniProt Q8AXQ0 1 EQUAL 374 EQUAL Reactome Database ID Release 83 451442 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451442 Reactome R-GGA-451442 1 Reactome stable identifier. Use this 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-451442.1 Reactome Database ID Release 83 451450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451450 Reactome R-GGA-451450 1 Reactome stable identifier. Use this 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-451450.1 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 LEFT-TO-RIGHT 6.3.2.19 Activated chicken TRAF6 synthesizes free K63bound poly_Ub chains within the complex p-IRAK2:pUb_oligo TRAF6 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, 2010-01-05 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 3 free K63_polyubiquitin chain Reactome DB_ID: 451962 Reactome Database ID Release 83 451962 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451962 Reactome R-GGA-451962 1 Reactome stable identifier. Use this 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-451962.1 ACTIVATION activeUnit: #Protein31 Reactome Database ID Release 83 451470 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451470 Reactome R-GGA-451470 1 Reactome stable identifier. Use this 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-451470.1 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 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 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 GENE ONTOLOGY GO:0010994 gene ontology term for cellular process MI MI:0359 LEFT-TO-RIGHT pUb_TRAF6 pIRAK2 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, 2010-01-05 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 TAK1 : TAB1 : TAB2/TAB3 complex Reactome DB_ID: 433839 TAK1 Reactome DB_ID: 433825 ENSEMBL:ENSGALP00000025101 TGF-beta- activated kinase 1 TGF-beta- activated kinase 1 MAP3K7 ENSEMBL ENSGALP00000025101 1 EQUAL 617 EQUAL Reactome Database ID Release 83 433825 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433825 Reactome R-GGA-433825 1 Reactome stable identifier. Use this 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-433825.1 1 Converted from EntitySet in Reactome chicken TAB2/TAB3 Reactome DB_ID: 975711 TAB2 Reactome DB_ID: 434032 ENSEMBL:ENSGALP00000020155 TAB2 TAB2 MAP3K7IP2 (TAB2) ENSEMBL ENSGALP00000020155 1 EQUAL 697 EQUAL Reactome Database ID Release 83 434032 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434032 Reactome R-GGA-434032 1 Reactome stable identifier. Use this 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-434032.1 TAB3 Reactome DB_ID: 442867 ENSEMBL:ENSGALP00000026205 TAB3 TAB3 MAP3K7IP3 ENSEMBL ENSGALP00000026205 Reactome Database ID Release 83 442867 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442867 Reactome R-GGA-442867 1 Reactome stable identifier. Use this 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-442867.1 Reactome Database ID Release 83 975711 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975711 Reactome R-GGA-975711 1 Reactome stable identifier. Use this 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-975711.1 1 TAB1 Reactome DB_ID: 433882 UniProt:Q5ZJW3 RCJMB04_15c17 RCJMB04_15c17 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5ZJW3 1 EQUAL 438 EQUAL Reactome Database ID Release 83 433882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433882 Reactome R-GGA-433882 1 Reactome stable identifier. Use this 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-433882.1 1 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 2 2 p-IRAK2:pUb oligo TRAF6 : TAK1 :TAB1 : TAB2/TAB3 : free K63 pUb chains Reactome DB_ID: 434148 1 TAK1 : TAB1 : TAB2/TAB3 Reactome DB_ID: 975710 TAK1 Reactome DB_ID: 975703 1 EQUAL 617 EQUAL Reactome Database ID Release 83 975703 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975703 Reactome R-GGA-975703 1 Reactome stable identifier. Use this 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-975703.1 1 TAB1 Reactome DB_ID: 975709 1 EQUAL 438 EQUAL Reactome Database ID Release 83 975709 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975709 Reactome R-GGA-975709 1 Reactome stable identifier. Use this 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-975709.1 1 Converted from EntitySet in Reactome chicken TAB2/TAB3 Reactome DB_ID: 975702 TAB2 Reactome DB_ID: 975705 1 EQUAL 697 EQUAL Reactome Database ID Release 83 975705 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975705 Reactome R-GGA-975705 1 Reactome stable identifier. Use this 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-975705.1 TAB3 Reactome DB_ID: 975707 Reactome Database ID Release 83 975707 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975707 Reactome R-GGA-975707 1 Reactome stable identifier. Use this 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-975707.1 Reactome Database ID Release 83 975702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975702 Reactome R-GGA-975702 1 Reactome stable identifier. Use this 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-975702.1 1 Reactome Database ID Release 83 975710 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975710 Reactome R-GGA-975710 1 Reactome stable identifier. Use this 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-975710.1 2 2 Reactome Database ID Release 83 434148 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434148 Reactome R-GGA-434148 1 Reactome stable identifier. Use this 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-434148.1 Reactome Database ID Release 83 451463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451463 Reactome R-GGA-451463 1 Reactome stable identifier. Use this 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-451463.1 LEFT-TO-RIGHT 2.7.11.1 Activation of recruited TAK1 within the complex p-IRAK2: pUb-TRAF6:TAB2/TAB3:TAB1: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, 2010-01-05 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 4 p-IRAK2: pUb_oligo TRAF6 : phospho TAK1 :TAB1 : TAB2/TAB3 : K63linked free pUb chain Reactome DB_ID: 451458 1 phosphorylated TAK1 Reactome DB_ID: 975700 1 EQUAL 617 EQUAL Reactome Database ID Release 83 975700 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975700 Reactome R-GGA-975700 1 Reactome stable identifier. Use this 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-975700.1 2 2 2 2 Reactome Database ID Release 83 451458 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451458 Reactome R-GGA-451458 1 Reactome stable identifier. Use this 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-451458.1 4 ACTIVATION activeUnit: #Protein37 Reactome Database ID Release 83 433969 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433969 Reactome Database ID Release 83 451447 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451447 Reactome R-GGA-451447 1 Reactome stable identifier. Use this 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-451447.1 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 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 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 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 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 LEFT-TO-RIGHT 2.7.11.1 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 IKKs_complex (Inhibitor of kappa B kinases) Reactome DB_ID: 434005 Inhibitor of NF kappa B kinase(IKKA)_subunit alpha Reactome DB_ID: 433915 UniProt:Q5ZJB4 CHUK CHUK IKKA RCJMB04_19h23 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 Database ID Release 83 433915 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433915 Reactome R-GGA-433915 1 Reactome stable identifier. Use this 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-433915.1 1 IKBKB(IKK_beta) Reactome DB_ID: 433865 UniProt:Q5ZI83 RCJMB04_29g15 RCJMB04_29g15 <submittedName> <fullName>Putative uncharacterized protein</fullName> </submittedName> UniProt Q5ZI83 1 EQUAL 739 EQUAL Reactome Database ID Release 83 433865 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433865 Reactome R-GGA-433865 1 Reactome stable identifier. Use this 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-433865.1 1 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 2 2 activated IKKs complex Reactome DB_ID: 433938 phospho IKBKA (IKK alpha)_CHICK Reactome DB_ID: 434000 190 EQUAL 194 EQUAL 1 EQUAL 759 EQUAL Reactome Database ID Release 83 434000 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434000 Reactome R-GGA-434000 1 Reactome stable identifier. Use this 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-434000.1 1 phospho_IKBKB(IKK_beta)_CHICK Reactome DB_ID: 433953 1 EQUAL 739 EQUAL Reactome Database ID Release 83 433953 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433953 Reactome R-GGA-433953 1 Reactome stable identifier. Use this 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-433953.1 1 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 ACTIVATION activeUnit: #Protein48 Converted from EntitySet in Reactome Activated chicken TAK1 complexes Reactome DB_ID: 975491 pUB-TRAF6:TAB2:TAB3:TAB1:free K63-pUb chain:phospho TAK1 Reactome DB_ID: 921146 2 pUb_TRAF6 Reactome DB_ID: 451455 1 K63_polyubiquitin chain Reactome DB_ID: 434061 Reactome Database ID Release 83 434061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434061 Reactome R-GGA-434061 1 Reactome stable identifier. Use this 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-434061.1 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 2 2 2 2 phosphorylated TAK1 Reactome DB_ID: 451473 1 EQUAL 617 EQUAL Reactome Database ID Release 83 451473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451473 Reactome R-GGA-451473 1 Reactome stable identifier. Use this 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-451473.1 2 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 Database ID Release 83 975491 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975491 Reactome R-GGA-975491 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-975491.2 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 phosphorylated TAK1 Reactome DB_ID: 433952 endosome membrane GENE ONTOLOGY GO:0010008 1 EQUAL 617 EQUAL Reactome Database ID Release 83 433952 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433952 Reactome R-GGA-433952 1 Reactome stable identifier. Use this 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-433952.1 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 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 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 LEFT-TO-RIGHT 2.7.11.1 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 2 IkB alpha : NFkB complex Reactome DB_ID: 434019 IkB_alpha Reactome DB_ID: 433811 UniProt:Q91974 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 433811 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433811 Reactome R-GGA-433811 1 Reactome stable identifier. Use this 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-433811.1 1 REL_A Reactome DB_ID: 433980 UniProt:P98152 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 Database ID Release 83 433980 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433980 Reactome R-GGA-433980 1 Reactome stable identifier. Use this 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-433980.1 1 NFkB1_p50 Reactome DB_ID: 433962 UniProt:Q04861 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 Database ID Release 83 433962 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433962 Reactome R-GGA-433962 1 Reactome stable identifier. Use this 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-433962.1 1 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 NFkB complex(p50/p65) Reactome DB_ID: 434125 1 1 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 2 phosphorylated IkB_alpha Reactome DB_ID: 433842 36 EQUAL 40 EQUAL 1 EQUAL 318 EQUAL Reactome Database ID Release 83 433842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433842 Reactome R-GGA-433842 1 Reactome stable identifier. Use this 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-433842.1 ACTIVATION activeUnit: #Protein46 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 LEFT-TO-RIGHT 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 NFkB complex(p50/p65) Reactome DB_ID: 433908 nucleoplasm GENE ONTOLOGY GO:0005654 NFkB1_p50 Reactome DB_ID: 434062 1 EQUAL 984 EQUAL Reactome Database ID Release 83 434062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434062 Reactome R-GGA-434062 1 Reactome stable identifier. Use this 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-434062.1 1 REL_A Reactome DB_ID: 433824 1 EQUAL 558 EQUAL Reactome Database ID Release 83 433824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433824 Reactome R-GGA-433824 1 Reactome stable identifier. Use this 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-433824.1 1 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 15371334 Pubmed 2004 Signaling to NF-kappaB Hayden, MS Ghosh, S Genes Dev 18:2195-224 16056267 Pubmed 2005 Ubiquitin signalling in the NF-kappaB pathway Chen, ZJ Nat Cell Biol 7:758-65 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 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 GENE ONTOLOGY GO:0007250 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 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 LEFT-TO-RIGHT 2.7.11.1 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 MKK4 MAP2K4 SEK1 C-JUN N-terminal kinase kinase 1 Reactome DB_ID: 437642 ENSEMBL:ENSGALP00000001475 MKK4 MKK4 MAP2K4 ENSEMBL ENSGALP00000001475 Reactome Database ID Release 83 437642 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437642 Reactome R-GGA-437642 1 Reactome stable identifier. Use this 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-437642.1 2 2 phosphorylated MKK4 Reactome DB_ID: 437975 Reactome Database ID Release 83 437975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437975 Reactome R-GGA-437975 1 Reactome stable identifier. Use this 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-437975.1 ACTIVATION activeUnit: #Protein48 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 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 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 LEFT-TO-RIGHT 2.7.12.1 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 JNK homologs Reactome DB_ID: 433872 MAPK9_(JNK2) mitogen-activated protein kinase 9 Reactome DB_ID: 434057 UniProt:P79996 MAPK9 MAPK9 JNK2 FUNCTION Responds to activation by environmental stress and pro-inflammatory cytokines by phosphorylating a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity (By similarity). May play a role in the development of the central nervous system during embryogenesis. May play a role in the regulation of the circadian clock (By similarity).ACTIVITY REGULATION Activated by threonine and tyrosine phosphorylation.TISSUE SPECIFICITY Expressed in the neuroepithelium of developing brain at stages 16 to 26.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Dually phosphorylated on Thr-183 and Tyr-185, which activates the enzyme.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt P79996 1 EQUAL 382 EQUAL Reactome Database ID Release 83 434057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434057 Reactome R-GGA-434057 1 Reactome stable identifier. Use this 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-434057.1 MAPK10 Reactome DB_ID: 433946 ENSEMBL:ENSGALP00000018075 MAPK10 MAPK10 ENSEMBL ENSGALP00000018075 Reactome Database ID Release 83 433946 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433946 Reactome R-GGA-433946 1 Reactome stable identifier. Use this 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-433946.1 MAPK8 Reactome DB_ID: 433810 ENSEMBL:ENSGALP00000009848 MAPK8 MAPK8 ENSEMBL ENSGALP00000009848 1 EQUAL 427 EQUAL Reactome Database ID Release 83 433810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433810 Reactome R-GGA-433810 1 Reactome stable identifier. Use this 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-433810.1 Reactome Database ID Release 83 433872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433872 Reactome R-GGA-433872 1 Reactome stable identifier. Use this 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-433872.1 2 Converted from EntitySet in Reactome phosphorylated JNK homologs Reactome DB_ID: 437957 phosphorylated MAPK9_(JNK2) mitogen-activated protein kinase 9 Reactome DB_ID: 438015 183 EQUAL 185 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1 EQUAL 382 EQUAL Reactome Database ID Release 83 438015 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438015 Reactome R-GGA-438015 1 Reactome stable identifier. Use this 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-438015.1 phosphorylated MAPK10 Reactome DB_ID: 437973 Reactome Database ID Release 83 437973 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437973 Reactome R-GGA-437973 1 Reactome stable identifier. Use this 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-437973.1 phosphorylated MAPK8 Reactome DB_ID: 437976 1 EQUAL 427 EQUAL Reactome Database ID Release 83 437976 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437976 Reactome R-GGA-437976 1 Reactome stable identifier. Use this 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-437976.1 Reactome Database ID Release 83 437957 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437957 Reactome R-GGA-437957 1 Reactome stable identifier. Use this 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-437957.1 2 ACTIVATION activeUnit: #Protein56 GENE ONTOLOGY GO:0004712 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 LEFT-TO-RIGHT 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 phosphorylated JNK homologs Reactome DB_ID: 438012 phosphorylated MAPK9_(JNK2) mitogen-activated protein kinase 9 Reactome DB_ID: 437993 1 EQUAL 382 EQUAL Reactome Database ID Release 83 437993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437993 Reactome R-GGA-437993 1 Reactome stable identifier. Use this 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-437993.1 phosphorylated MAPK10 Reactome DB_ID: 437960 Reactome Database ID Release 83 437960 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437960 Reactome R-GGA-437960 1 Reactome stable identifier. Use this 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-437960.1 phosphorylated MAPK8 Reactome DB_ID: 437983 1 EQUAL 427 EQUAL Reactome Database ID Release 83 437983 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437983 Reactome R-GGA-437983 1 Reactome stable identifier. Use this 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-437983.1 Reactome Database ID Release 83 438012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438012 Reactome R-GGA-438012 1 Reactome stable identifier. Use this 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-438012.1 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 LEFT-TO-RIGHT 2.7.11 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 c-JUN Transcription factor AP-1 Reactome DB_ID: 438016 UniProt:P18870 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 Database ID Release 83 438016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438016 Reactome R-GGA-438016 1 Reactome stable identifier. Use this 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-438016.1 2 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 Reactome Database ID Release 83 29358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29358 Reactome R-ALL-29358 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-ALL-29358.3 COMPOUND C00002 4 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 Reactome Database ID Release 83 113582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113582 Reactome R-ALL-113582 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-ALL-113582.3 COMPOUND C00008 4 activated c-JUN dimer Reactome DB_ID: 437991 phosphorylated c-JUN Transcription factor AP-1 Reactome DB_ID: 438013 63 EQUAL 73 EQUAL 1 EQUAL 314 EQUAL Reactome Database ID Release 83 438013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438013 Reactome R-GGA-438013 1 Reactome stable identifier. Use this 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-438013.1 2 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 ACTIVATION activeUnit: #Protein63 activeUnit: #Protein64 activeUnit: #Protein62 GENE ONTOLOGY GO:0004705 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 MAPK phosphatases dual specificity phosphatases Reactome DB_ID: 442886 MKP1 Dual specificity protein phosphatase 1 Reactome DB_ID: 442888 UniProt:O42253 Dual specificity protein phosphatase 1 Dual specificity protein phosphatase 1 MKP1 UniProt O42253 1 EQUAL 353 EQUAL Reactome Database ID Release 83 442888 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442888 Reactome R-GGA-442888 1 Reactome stable identifier. Use this 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-442888.1 MKP2 DUSP4 Reactome DB_ID: 442850 UniProt:Q9PW71 DUSP4 DUSP4 MKP2 FUNCTION Regulates mitogenic signal transduction by dephosphorylating both Thr and Tyr residues on MAP kinases ERK1 and ERK2.SIMILARITY Belongs to the protein-tyrosine phosphatase family. Non-receptor class dual specificity subfamily. UniProt Q9PW71 1 EQUAL 375 EQUAL Reactome Database ID Release 83 442850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442850 Reactome R-GGA-442850 1 Reactome stable identifier. Use this 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-442850.1 MKP3 DUSP6 Reactome DB_ID: 442887 UniProt:Q7T2L9 MKP3 MKP3 dual specificity phosphatase 6 UniProt Q7T2L9 1 EQUAL 382 EQUAL Reactome Database ID Release 83 442887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442887 Reactome R-GGA-442887 1 Reactome stable identifier. Use this 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-442887.1 MKP5 DUSP10 Reactome DB_ID: 442877 UniProt:Q5ZJF8 Dual specificity protein phosphatase 10 Dual specificity protein phosphatase 10 RCJMB04_18i8 UniProt Q5ZJF8 1 EQUAL 478 EQUAL Reactome Database ID Release 83 442877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442877 Reactome R-GGA-442877 1 Reactome stable identifier. Use this 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-442877.1 DUSP16 Reactome DB_ID: 442935 ENSEMBL:ENSGALP00000001453 DUSP16 DUSP16 ENSEMBL ENSGALP00000001453 Reactome Database ID Release 83 442935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442935 Reactome R-GGA-442935 1 Reactome stable identifier. Use this 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-442935.1 DUSP3 dual specificity phosphatase 3 Reactome DB_ID: 442882 ENSEMBL:ENSGALP00000016127 DUSP3 DUSP3 ENSEMBL ENSGALP00000016127 Reactome Database ID Release 83 442882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442882 Reactome R-GGA-442882 1 Reactome stable identifier. Use this 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-442882.1 DUSP5 Reactome DB_ID: 442941 ENSEMBL:ENSGALP00000013956 dual specificity phosphatase 5 dual specificity phosphatase 5 DUSP5 ENSEMBL ENSGALP00000013956 Reactome Database ID Release 83 442941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442941 Reactome R-GGA-442941 1 Reactome stable identifier. Use this 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-442941.1 DUSP8 Reactome DB_ID: 442917 ENSEMBL:ENSGALP00000010737 DUSP8 DUSP8 ENSEMBL ENSGALP00000010737 Reactome Database ID Release 83 442917 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442917 Reactome R-GGA-442917 1 Reactome stable identifier. Use this 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-442917.1 MKP6 DUSP14 Reactome DB_ID: 442874 ENSEMBL:ENSGALP00000008741 DUSP14 DUSP14 dual specificity phosphatase 14 ENSEMBL ENSGALP00000008741 Reactome Database ID Release 83 442874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442874 Reactome R-GGA-442874 1 Reactome stable identifier. Use this 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-442874.1 Reactome Database ID Release 83 442886 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442886 Reactome R-GGA-442886 1 Reactome stable identifier. Use this 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-442886.1 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 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 11057897 Pubmed 2000 Signal transduction by the JNK group of MAP kinases Davis, RJ Cell 103:239-52 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 12471242 Pubmed 2002 Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases Johnson, GL Lapadat, R Science 298:1911-2 GENE ONTOLOGY GO:0007254 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 LEFT-TO-RIGHT 2.7.11.1 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 2 Converted from EntitySet in Reactome MKK3/MKK6 Reactome DB_ID: 437632 MKK3 mitogen-activated protein kinase kinase 3 Reactome DB_ID: 437639 UniProt:Q5ZL06 mitogen-activated protein kinase kinase 3 mitogen-activated protein kinase kinase 3 RCJMB04_8f10 UniProt Q5ZL06 1 EQUAL 258 EQUAL Reactome Database ID Release 83 437639 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437639 Reactome R-GGA-437639 1 Reactome stable identifier. Use this 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-437639.1 MKK6 Mitogen activated protein kinase 6 Reactome DB_ID: 437637 Reactome Database ID Release 83 437637 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437637 Reactome R-GGA-437637 1 Reactome stable identifier. Use this 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-437637.1 Reactome Database ID Release 83 437632 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437632 Reactome R-GGA-437632 1 Reactome stable identifier. Use this 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-437632.1 2 Converted from EntitySet in Reactome phospho MKK3/ phospho MKK6 Reactome DB_ID: 437977 phosphorylated MKK3 Reactome DB_ID: 437990 129 EQUAL 133 EQUAL 1 EQUAL 258 EQUAL Reactome Database ID Release 83 437990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437990 Reactome R-GGA-437990 1 Reactome stable identifier. Use this 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-437990.1 phosphorylated MKK6 Reactome DB_ID: 437965 Reactome Database ID Release 83 437965 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437965 Reactome R-GGA-437965 1 Reactome stable identifier. Use this 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-437965.1 Reactome Database ID Release 83 437977 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437977 Reactome R-GGA-437977 1 Reactome stable identifier. Use this 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-437977.1 ACTIVATION activeUnit: #Protein48 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 LEFT-TO-RIGHT 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 phospho MKK3/ phospho MKK6 Reactome DB_ID: 442940 phosphorylated MKK3 Reactome DB_ID: 571403 1 EQUAL 258 EQUAL Reactome Database ID Release 83 571403 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571403 Reactome R-GGA-571403 1 Reactome stable identifier. Use this 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-571403.1 phosphorylated MKK6 Reactome DB_ID: 571405 Reactome Database ID Release 83 571405 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571405 Reactome R-GGA-571405 1 Reactome stable identifier. Use this 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-571405.1 Reactome Database ID Release 83 442940 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442940 Reactome R-GGA-442940 1 Reactome stable identifier. Use this 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-442940.1 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 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 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 LEFT-TO-RIGHT 2.7.12.1 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 p38 MAPK : MAPKAPK 2 or MAPKAPK3 Reactome DB_ID: 442951 Converted from EntitySet in Reactome MAPKAPK2 and/or MAPKAPK3 Reactome DB_ID: 442936 MAPKAPK2 Reactome DB_ID: 442914 ENSEMBL:ENSGALP00000001295 MAPKAPK2 MAPKAPK2 ENSEMBL ENSGALP00000001295 Reactome Database ID Release 83 442914 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442914 Reactome R-GGA-442914 1 Reactome stable identifier. Use this 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-442914.1 MAPKAPK3 Reactome DB_ID: 442931 ENSEMBL:ENSGALP00000003578 MAPKAPK3 MAPKAPK3 ENSEMBL ENSGALP00000003578 Reactome Database ID Release 83 442931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442931 Reactome R-GGA-442931 1 Reactome stable identifier. Use this 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-442931.1 Reactome Database ID Release 83 442936 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442936 Reactome R-GGA-442936 1 Reactome stable identifier. Use this 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-442936.1 1 Converted from EntitySet in Reactome p38 MAP kinase Reactome DB_ID: 442963 MAPK11 p38 MAP kinase Reactome DB_ID: 442903 UniProt:Q5ZIK8 RCJMB04_25f21 RCJMB04_25f21 CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. UniProt Q5ZIK8 1 EQUAL 361 EQUAL Reactome Database ID Release 83 442903 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442903 Reactome R-GGA-442903 1 Reactome stable identifier. Use this 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-442903.1 MAPK12 p38 MAP kinase Reactome DB_ID: 442937 ENSEMBL:ENSGALP00000014011 MAPK12 MAPK12 ENSEMBL ENSGALP00000014011 Reactome Database ID Release 83 442937 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442937 Reactome R-GGA-442937 1 Reactome stable identifier. Use this 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-442937.1 MAPK13 Reactome DB_ID: 442960 ENSEMBL:ENSGALP00000001204 MAPK13 MAPK13 ENSEMBL ENSGALP00000001204 Reactome Database ID Release 83 442960 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442960 Reactome R-GGA-442960 1 Reactome stable identifier. Use this 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-442960.1 MAPK14 mitogen-activated protein kinase p38 alpha Reactome DB_ID: 442908 ENSEMBL:ENSGALP00000001201 MAPK14 MAPK14 ENSEMBL ENSGALP00000001201 Reactome Database ID Release 83 442908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442908 Reactome R-GGA-442908 1 Reactome stable identifier. Use this 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-442908.1 Reactome Database ID Release 83 442963 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442963 Reactome R-GGA-442963 1 Reactome stable identifier. Use this 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-442963.1 1 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 2 phospho -p38 MAPK : MAPKAPK 2 or MAPKAPK3 Reactome DB_ID: 442905 1 Converted from EntitySet in Reactome phospho_p38 MAP kinase Reactome DB_ID: 442851 phosphorylated MAPK11 Reactome DB_ID: 571401 180 EQUAL 182 EQUAL 1 EQUAL 361 EQUAL Reactome Database ID Release 83 571401 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571401 Reactome R-GGA-571401 1 Reactome stable identifier. Use this 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-571401.1 p38 MAP kinase phosphorylated MAPK12 Reactome DB_ID: 571407 Reactome Database ID Release 83 571407 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571407 Reactome R-GGA-571407 1 Reactome stable identifier. Use this 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-571407.1 phosphorylated MAPK13 Reactome DB_ID: 571406 Reactome Database ID Release 83 571406 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571406 Reactome R-GGA-571406 1 Reactome stable identifier. Use this 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-571406.1 phosphorylated MAPK14 Reactome DB_ID: 571404 Reactome Database ID Release 83 571404 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571404 Reactome R-GGA-571404 1 Reactome stable identifier. Use this 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-571404.1 Reactome Database ID Release 83 442851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442851 Reactome R-GGA-442851 1 Reactome stable identifier. Use this 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-442851.1 1 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 2 ACTIVATION activeUnit: #Protein82 activeUnit: #PhysicalEntity8 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 LEFT-TO-RIGHT 2.7.12.1 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 3 phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho MAPKAPK3 Reactome DB_ID: 442915 Converted from EntitySet in Reactome phospho MAPKAPK2 and/or phospho MAPKAPK3 Reactome DB_ID: 442949 phosphorylated MAPKAPK2 Reactome DB_ID: 442932 Reactome Database ID Release 83 442932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442932 Reactome R-GGA-442932 1 Reactome stable identifier. Use this 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-442932.1 phosphorylated MAPKAPK3 Reactome DB_ID: 442924 Reactome Database ID Release 83 442924 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442924 Reactome R-GGA-442924 1 Reactome stable identifier. Use this 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-442924.1 Reactome Database ID Release 83 442949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442949 Reactome R-GGA-442949 1 Reactome stable identifier. Use this 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-442949.1 1 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 3 ACTIVATION activeUnit: #Protein92 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 15287722 Pubmed 2004 Catalysis and function of the p38 alpha.MK2a signaling complex Lukas, SM Kroe, RR Wildeson, J Peet, GW Frego, L Davidson, W Ingraham, RH Pargellis, CA Labadia, ME Werneburg, BG Biochemistry 43:9950-60 17395714 Pubmed 2007 Molecular basis of MAPK-activated protein kinase 2:p38 assembly White, A Pargellis, CA Studts, JM Werneburg, BG Farmer BT, 2nd Proc Natl Acad Sci U S A 104:6353-8 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 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 LEFT-TO-RIGHT 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 phospho -p38 MAPK : phospho- MAPKAPK 2 or phospho-MAPKAPK3 Reactome DB_ID: 442925 Converted from EntitySet in Reactome phospho_p38 MAP kinase Reactome DB_ID: 437968 phosphorylated MAPK11 Reactome DB_ID: 437962 1 EQUAL 361 EQUAL Reactome Database ID Release 83 437962 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437962 Reactome R-GGA-437962 1 Reactome stable identifier. Use this 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-437962.1 p38 MAP kinase phosphorylated MAPK12 Reactome DB_ID: 438027 Reactome Database ID Release 83 438027 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438027 Reactome R-GGA-438027 1 Reactome stable identifier. Use this 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-438027.1 phosphorylated MAPK13 Reactome DB_ID: 438008 Reactome Database ID Release 83 438008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=438008 Reactome R-GGA-438008 1 Reactome stable identifier. Use this 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-438008.1 phosphorylated MAPK14 Reactome DB_ID: 437963 Reactome Database ID Release 83 437963 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437963 Reactome R-GGA-437963 1 Reactome stable identifier. Use this 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-437963.1 Reactome Database ID Release 83 437968 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=437968 Reactome R-GGA-437968 1 Reactome stable identifier. Use this 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-437968.1 1 Converted from EntitySet in Reactome phospho MAPKAPK2 and/or phospho MAPKAPK3 Reactome DB_ID: 442855 phosphorylated MAPKAPK2 Reactome DB_ID: 442894 Reactome Database ID Release 83 442894 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442894 Reactome R-GGA-442894 1 Reactome stable identifier. Use this 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-442894.1 phosphorylated MAPKAPK3 Reactome DB_ID: 442906 Reactome Database ID Release 83 442906 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442906 Reactome R-GGA-442906 1 Reactome stable identifier. Use this 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-442906.1 Reactome Database ID Release 83 442855 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442855 Reactome R-GGA-442855 1 Reactome stable identifier. Use this 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-442855.1 1 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 15686620 Pubmed 2005 Activation and signaling of the p38 MAP kinase pathway Zarubin, T Han, J Cell Res 15:11-8 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 GENE ONTOLOGY GO:0038066 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 LEFT-TO-RIGHT 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 ERK2(MAPK1) Reactome DB_ID: 433942 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 Database ID Release 83 433942 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433942 Reactome R-GGA-433942 1 Reactome stable identifier. Use this 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-433942.1 phospho MEK2 phospho MAP2K2 phospho MKK2 Reactome DB_ID: 451487 UniProt:Q90891 MAP2K2 MAP2K2 MEK2 MKK2 PRKMK2 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 220 EQUAL 224 EQUAL 1 EQUAL 398 EQUAL Reactome Database ID Release 83 451487 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451487 Reactome R-GGA-451487 1 Reactome stable identifier. Use this 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-451487.1 phospho MEK2 : ERK2 Reactome DB_ID: 451495 1 1 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 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 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 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 LEFT-TO-RIGHT 2.7.11.1 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 2 2 phospho ERK2 : phospho MEK2 Reactome DB_ID: 451480 1 phospho-ERK2 Reactome DB_ID: 451523 193 EQUAL 195 EQUAL 1 EQUAL 368 EQUAL Reactome Database ID Release 83 451523 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451523 Reactome R-GGA-451523 1 Reactome stable identifier. Use this 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-451523.1 1 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 ACTIVATION activeUnit: #Protein109 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 LEFT-TO-RIGHT 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 phospho ERK2 : phospho MEK2 Reactome DB_ID: 451526 1 1 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 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 LEFT-TO-RIGHT 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 2 phospho ERK2 dimer Reactome DB_ID: 451504 2 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 LEFT-TO-RIGHT 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 phospho ERK2 dimer Reactome DB_ID: 451513 phospho-ERK2 Reactome DB_ID: 442961 1 EQUAL 368 EQUAL Reactome Database ID Release 83 442961 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442961 Reactome R-GGA-442961 1 Reactome stable identifier. Use this 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-442961.1 2 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 GENE ONTOLOGY GO:0070371 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 GENE ONTOLOGY GO:0000165 Reactome Database ID Release 83 433822 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433822 Reactome R-GGA-433822 4 Reactome stable identifier. Use this 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-433822.4 GENE ONTOLOGY GO:0038008 Reactome Database ID Release 83 451514 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451514 Reactome R-GGA-451514 1 Reactome stable identifier. Use this 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-451514.1 17981327 Pubmed 2008 Gene expression profiling of chicken lymphoid cells after treatment with Lactobacillus acidophilus cellular components Brisbin, JT Zhou, H Gong, J Sabour, P Akbari, MR Haghighi, HR Yu, H Clarke, A Sarson, AJ Sharif, S Dev Comp Immunol 32:563-74 11044373 Pubmed 2000 Toll-like receptors: lessons from knockout mice Akira, Shizuo Biochem Soc Trans 28:551-6 20053507 Pubmed 2009 Up-regulation of the MyD88-dependent pathway of TLR signaling in spleen and caecum of young chickens infected with Salmonella serovar Pullorum Li, Peng Xia, P Wen, J Zheng, M Chen, J Zhao, J Jiang, R Liu, R Zhao, G Vet Microbiol GENE ONTOLOGY GO:0002755 Reactome Database ID Release 83 517856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=517856 Reactome R-GGA-517856 1 Reactome stable identifier. Use this 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-517856.1 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 15578175 Pubmed 2005 Identification and sequence analysis of chicken Toll-like receptors Yilmaz, A Shen, S Adelson, DL Xavier, S Zhu, JJ Immunogenetics 56:743-53 GENE ONTOLOGY GO:0034134 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 LEFT-TO-RIGHT 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 TLR3 Reactome DB_ID: 433892 UniProt:Q0PQ88 Toll-like receptor 3 Toll-like receptor 3 TLR3 SIMILARITY Contains 1 TIR domain. UniProt Q0PQ88 1 EQUAL 1011 EQUAL Reactome Database ID Release 83 433892 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433892 Reactome R-GGA-433892 1 Reactome stable identifier. Use this 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-433892.1 2 IBV dsRNA intermediate form Reactome DB_ID: 9014378 endosome lumen GENE ONTOLOGY GO:0031904 Reactome Database ID Release 83 9014378 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014378 Reactome R-IBR-9014378 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-IBR-9014378.1 viral dsRNA:TLR3 Reactome DB_ID: 433883 2 1 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 LEFT-TO-RIGHT 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 TRIF TICAM1 TLR_adaptor_molecule1 Reactome DB_ID: 433866 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 433866 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433866 Reactome R-GGA-433866 1 Reactome stable identifier. Use this 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-433866.1 2 viral dsRNA : TLR3 : TICAM1 Reactome DB_ID: 433947 1 TRIF TICAM1 TLR_adaptor_molecule1 Reactome DB_ID: 433979 1 EQUAL 735 EQUAL Reactome Database ID Release 83 433979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433979 Reactome R-GGA-433979 1 Reactome stable identifier. Use this 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-433979.1 2 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 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 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 LEFT-TO-RIGHT 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 TBK1 Reactome DB_ID: 434016 ENSEMBL:ENSGALP00000015982 ch_TBK1 ch_TBK1 TBK1 ENSEMBL ENSGALP00000015982 1 EQUAL 816 EQUAL Reactome Database ID Release 83 434016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434016 Reactome R-GGA-434016 1 Reactome stable identifier. Use this 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-434016.1 2 2 2 ds viral RNA : TLR3 : TICAM1 : TBK1 complex Reactome DB_ID: 433843 TBK1 Reactome DB_ID: 571399 1 EQUAL 816 EQUAL Reactome Database ID Release 83 571399 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=571399 Reactome R-GGA-571399 1 Reactome stable identifier. Use this 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-571399.1 2 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 LEFT-TO-RIGHT 2.7.11.1 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 IRF3 Reactome DB_ID: 433993 UniProt:Q90643 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 Database ID Release 83 433993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433993 Reactome R-GGA-433993 1 Reactome stable identifier. Use this 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-433993.1 3 3 phosphorylated IRF3 Reactome DB_ID: 434100 464 EQUAL 474 EQUAL 1 EQUAL 491 EQUAL Reactome Database ID Release 83 434100 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434100 Reactome R-GGA-434100 1 Reactome stable identifier. Use this 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-434100.1 ACTIVATION activeUnit: #Protein115 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 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 LEFT-TO-RIGHT 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 2 Phosphorylated IRF3 : IRF3 dimer Reactome DB_ID: 433903 2 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 LEFT-TO-RIGHT 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 Phosphorylated IRF3 : IRF3 Reactome DB_ID: 434029 phosphorylated IRF3 Reactome DB_ID: 433971 463 EQUAL 1 EQUAL 491 EQUAL Reactome Database ID Release 83 433971 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433971 Reactome R-GGA-433971 1 Reactome stable identifier. Use this 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-433971.1 2 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 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 LEFT-TO-RIGHT 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 IKBKE IKK epsilon Reactome DB_ID: 434070 ENSEMBL:ENSGALP00000021757 NF kappa B inhibitor kinase epsilon NF kappa B inhibitor kinase epsilon IKBKE IKK epsilon IKK-i ENSEMBL ENSGALP00000021757 Reactome Database ID Release 83 434070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434070 Reactome R-GGA-434070 1 Reactome stable identifier. Use this 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-434070.1 2 2 2 ds viral RNA : TLR3 : TICAM1 : IKK epsilon complex Reactome DB_ID: 434043 2 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 LEFT-TO-RIGHT 2.7.11.1 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 3 3 ACTIVATION activeUnit: #Protein120 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 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 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 LEFT-TO-RIGHT 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 RIP1 ch_RIPK1 Reactome DB_ID: 434046 UniProt:Q7ZZX8 RIP-1 RIP-1 <submittedName> <fullName>Tumor necrosis factor receptor-interacting protein-1</fullName> </submittedName> UniProt Q7ZZX8 1 EQUAL 663 EQUAL Reactome Database ID Release 83 434046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434046 Reactome R-GGA-434046 1 Reactome stable identifier. Use this 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-434046.1 2 viral dsRNA : TLR3 : TICAM1 : RIP1 Reactome DB_ID: 434042 1 RIP1 ch_RIPK1 Reactome DB_ID: 434093 1 EQUAL 663 EQUAL Reactome Database ID Release 83 434093 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434093 Reactome R-GGA-434093 1 Reactome stable identifier. Use this 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-434093.1 2 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 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 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 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 LEFT-TO-RIGHT 2.7.11.1 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 2 2 ACTIVATION activeUnit: #Protein48 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 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 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 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 LEFT-TO-RIGHT 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 2 viral ds RNA : TLR3 : TICAM1 : TRAF6 Reactome DB_ID: 433968 TRAF6 Reactome DB_ID: 433792 Reactome Database ID Release 83 433792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433792 Reactome R-GGA-433792 1 Reactome stable identifier. Use this 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-433792.1 2 1 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 LEFT-TO-RIGHT 6.3.2.19 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 Ubiquitin:UBE2N : UBE2V complex Reactome DB_ID: 446245 1 UBE2V1 Reactome DB_ID: 434105 UniProt:Q90879 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 Reactome Database ID Release 83 434105 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434105 Reactome R-GGA-434105 1 Reactome stable identifier. Use this 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-434105.1 1 UBE2N Ubiquitin carier protein (UBC13 homolog) Reactome DB_ID: 433933 UniProt:Q5F405 RCJMB04_3o20 RCJMB04_3o20 SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt Q5F405 1 EQUAL 152 EQUAL Reactome Database ID Release 83 433933 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433933 Reactome R-GGA-433933 1 Reactome stable identifier. Use this 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-433933.1 1 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 UBE2N : UBE2V complex Reactome DB_ID: 433960 1 1 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 viral ds RNA : TLR3 : TICAM1 : pUb-TRAF6 Reactome DB_ID: 434102 pUb_TRAF6 Reactome DB_ID: 434011 1 K63_polyubiquitin chain Reactome DB_ID: 433989 Reactome Database ID Release 83 433989 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433989 Reactome R-GGA-433989 1 Reactome stable identifier. Use this 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-433989.1 1 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 2 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 ACTIVATION activeUnit: #Protein123 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 LEFT-TO-RIGHT 6.3.2.19 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 3 ACTIVATION activeUnit: #Complex60 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 LEFT-TO-RIGHT 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 2 2 viral dsRNA : TLR3 : TICAM1 : pUb_TRAF6 :TAB2 :TAB3: TAK1 : TAB1: free_pUb_chain Reactome DB_ID: 434146 1 TAK1 : TAB1 : TAB2/TAB3 complex Reactome DB_ID: 433931 TAB1 Reactome DB_ID: 434141 1 EQUAL 438 EQUAL Reactome Database ID Release 83 434141 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434141 Reactome R-GGA-434141 1 Reactome stable identifier. Use this 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-434141.1 1 Converted from EntitySet in Reactome chicken TAB2/TAB3 Reactome DB_ID: 993984 TAB3 Reactome DB_ID: 442975 Reactome Database ID Release 83 442975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442975 Reactome R-GGA-442975 1 Reactome stable identifier. Use this 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-442975.1 TAB2 Reactome DB_ID: 433923 1 EQUAL 697 EQUAL Reactome Database ID Release 83 433923 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433923 Reactome R-GGA-433923 1 Reactome stable identifier. Use this 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-433923.1 Reactome Database ID Release 83 993984 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=993984 Reactome R-GGA-993984 1 Reactome stable identifier. Use this 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-993984.1 1 TAK1 Reactome DB_ID: 433956 1 EQUAL 617 EQUAL Reactome Database ID Release 83 433956 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433956 Reactome R-GGA-433956 1 Reactome stable identifier. Use this 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-433956.1 1 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 2 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 LEFT-TO-RIGHT 2.7.11.1 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 4 4 viral dsRNA : TLR3 : TICAM1 : pUb_TRAF6 :TAB2:TAB3 :phospho TAK1 : TAB1 : free pUb chain Reactome DB_ID: 434152 1 2 2 2 2 2 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 ACTIVATION activeUnit: #Protein130 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 LEFT-TO-RIGHT 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 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 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 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 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 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 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 15733829 Pubmed 2005 Transcriptional signaling by double-stranded RNA: role of TLR3 Sen, GC Sarkar, SN Cytokine Growth Factor Rev 16:1-14 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 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 GENE ONTOLOGY GO:0034138 TLR4 cascade Toll-like Receptor 4 is an evolutionarily conserved microbe associated molecular pattern receptor well known for its sensitivity to bacterial lipopolysaccharides (LPS). LPS is a major cell wall component in all Gram-negative bacteria and a potent activator of the innate immune response in mammals.<p>Chicken TLR4 encodes a 843-amino-acid protein that shows 46% identity to human TLR4. Like its human homologue chicken TLR4 contains a leucine-rich repeat extracellular domain, a short transmembrane domain typical of type I transmembrane proteins, and a Toll-interleukin-1R signaling domain.(Lebeque et al. 2003). Chicken TLR4 was shown to sense LPS of diverse Gram-negative bacteria (Kogut et al. 2005, Leveque et al. 2003). The major difference between mammalian and chicken TLR signaling is the lack of MyD88-independent IFN-beta production in chicken after TLR4 activation (Keestra et al. 2008, Zoete et al. 2009). Unlike its human counterpart activated chicken TLR4 exclusively induces the MyD88/TIRAP-dependent, but not the TRAM/TRIF mediated signaling pathway. At present, inspection of the chicken genome indicated no orthologs for intracellular human adaptor TRAM (Keestra et al. 2008), which acts as a bridge to recruit TRIF to activated TLR4. Authored: Shamovsky, V, 2010-05-18 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 LEFT-TO-RIGHT Association of LBP with bacterial LPS The role of chicken lipopolysaccharide-binding protein (LBP) remains unclear. Inspection of the chicken genome showed no ortholog of human LBP (Keestra et al 2008), and LPS induced the functional activation of heterophils without the presence of LBP. Nevertheless, in the reaction shown here we annotated hypothetical chicken LPB using the data and suggestions reported by Kogut et al. (2005), that LBP and CD14/TLR4 induction is directly involved in LPS-mediated functional activation of chicken heterophils. Authored: Shamovsky, V, 2010-05-18 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 Lipopolysaccharide binding protein Reactome DB_ID: 433876 Reactome Database ID Release 83 433876 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433876 Reactome R-GGA-433876 1 Reactome stable identifier. Use this 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-433876.1 LPS Gram Negative Bacterial Lipopolysaccharide lipopolysaccharide Reactome DB_ID: 166005 Reactome Database ID Release 83 166005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166005 Reactome R-ALL-166005 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-166005.4 LBP : LPS complex Reactome DB_ID: 433795 1 1 Reactome Database ID Release 83 433795 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433795 Reactome R-GGA-433795 1 Reactome stable identifier. Use this 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-433795.1 Reactome Database ID Release 83 433940 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433940 Reactome R-GGA-433940 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-433940.2 16335810 Pubmed 2005 Lipopolysaccharide binding protein/CD14/ TLR4-dependent recognition of salmonella LPS induces the functional activation of chicken heterophils and up-regulation of pro-inflammatory cytokine and chemokine gene expression in these cells Kogut, MH He, H Kaiser, P Anim Biotechnol 16:165-81 2477488 Pubmed 1989 Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles Wright, SD Tobias, PS Ulevitch, RJ Ramos, RA J Exp Med 170:1231-41 18768894 Pubmed 2008 Unique properties of the chicken TLR4/MD-2 complex: selective lipopolysaccharide activation of the MyD88-dependent pathway Keestra, AM van Putten, JP J Immunol 181:4354-62 LEFT-TO-RIGHT LPS binding to CD14 co-receptor Chicken CD14 was reported to be involved in chicken TLR4 activation (Kogut et al 2005). It was cloned from chicken bone marrow cell RNA and is expressed in most lymphoid and non-lymphoid tissues (Wu Z et al 2009). Its cDNA encodes an open reading frame of 465 amino acids, which shares 31-34% identity to mouse, bovine and human CD14 amino acid sequences. Authored: Shamovsky, V, 2009-08-26 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 CD14 co-receptor Reactome DB_ID: 433976 UniProt:B0BL87 Cd14 Cd14 UniProt B0BL87 1 EQUAL 465 EQUAL Reactome Database ID Release 83 433976 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433976 Reactome R-GGA-433976 1 Reactome stable identifier. Use this 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-433976.1 CD14 :LPS complex Reactome DB_ID: 434025 1 1 Reactome Database ID Release 83 434025 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434025 Reactome R-GGA-434025 1 Reactome stable identifier. Use this 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-434025.1 Reactome Database ID Release 83 434003 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434003 Reactome R-GGA-434003 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-434003.2 18761368 Pubmed 2009 Chicken CD14, unlike mammalian CD14, is trans-membrane rather than GPI-anchored Wu, Z Rothwell, L Hu, T Kaiser, P Dev Comp Immunol 33:97-104 LEFT-TO-RIGHT LPS binding to Toll like receptor 4 results in dimerization of the TLR4 associated with LY96 In mammals, LPS stimulation results in the formation of TLR4:LY96 complex (Park et al. 2009). Chicken TLR4:LY96 complex was also shown to mediate responsiveness to LPS (Keestra et al 2008). However, the authors suggested that differences in amino acid composition may results in the species-specific interaction between chTLR4 and chLY96. Authored: Shamovsky, V, 2010-05-18 Reviewed: D'Eustachio, P, 2010-10-15 Edited: Shamovsky, V, 2010-11-05 2 Reactome Database ID Release 83 434058 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434058 Reactome R-GGA-434058 1 Reactome stable identifier. Use this 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-434058.1 19252480 Pubmed 2009 The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex Park, BS Song, DH Kim, HM Choi, BS Lee, Hane Lee, JO Nature 458:1191-5 15373971 Pubmed 2004 Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling Saitoh, S Akashi, S Yamada, T Tanimura, N Matsumoto, F Fukase, K Kusumoto, S Kosugi, A Miyake, K J Endotoxin Res 10:257-60 Reactome Database ID Release 83 433794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433794 Reactome R-GGA-433794 1 Reactome stable identifier. Use this 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-433794.1 12595422 Pubmed 2003 Allelic variation in TLR4 is linked to susceptibility to Salmonella enterica serovar Typhimurium infection in chickens Leveque, G Forgetta, V Morroll, S Smith, AL Bumstead, N Barrow, P Loredo-Osti, JC Morgan, K Malo, D Infect Immun 71:1116-24 GENE ONTOLOGY GO:0034142 TLR5 cascade In mammals, the interaction of flagellin with TLR5 induces a signaling cascade that utilizes MyD88 adaptor, IRAK family members, and downstream signaling mediators such as MAP kinases and NF-kB that regulate pro-inflammatory genes [Smith KD et al 2003].<p>The chicken tlr5 gene was cloned from the chicken NCSU macrophage cell line; It encodes a protein of 861 amino acids. The cloned chTLR5 showed 69% and 68% overall amino acid similarity to human and murine TLR5, respectively (Keestra AM et al, 2008). Chicken TLR5 mRNA is expressed in a broad range of tissues, immune cell subsets and chicken cell lines. The strongest signal was detected in colon, spleen, kidney, lung, heart, and testes (Iqbal M et al, 2005).</p><p>Comparisons of gene structure, genomic location, amino acid composition, and patterns of leucine-rich regions (LRR) consistent with the suggestion that chTLR5 is an orthologue of mammalian TLR5. Like its mammalian counterpart chTLR5 was reported to respond to bacterial flagellin (Iqbal M et al., 2005 and Keestra AM et al.,2008). Authored: Shamovsky, V, 2010-01-05 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 LEFT-TO-RIGHT Bacterial Flagellin binds TLR5 homodimer Like its human counterpart chicken TLR5 recognizes and responds to bacterial flagellin [Keestra AM et al 2008, Iqbal M et al 2005] which stimulates up-regulation of NF-kB and activation of AP-1 family members in chicken cells [Kogut MH et al 2008]. Authored: Shamovsky, V, 2010-01-05 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 Converted from EntitySet in Reactome Flagellin -phase1 and/or 2 Reactome DB_ID: 451464 Flagellin (phase 2 - flagellin) Reactome DB_ID: 451445 1 EQUAL 506 EQUAL Reactome Database ID Release 83 451445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451445 Reactome R-STY-451445 11 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-STY-451445.11 Flagellin (phase1- flagellin) Reactome DB_ID: 451469 1 EQUAL 495 EQUAL Reactome Database ID Release 83 451469 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451469 Reactome R-STY-451469 11 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-STY-451469.11 Reactome Database ID Release 83 451464 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451464 Reactome R-STY-451464 11 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-STY-451464.11 Reactome Database ID Release 83 451474 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451474 Reactome R-GGA-451474 1 Reactome stable identifier. Use this 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-451474.1 17964652 Pubmed 2008 Functional characterization of chicken TLR5 reveals species-specific recognition of flagellin Keestra, AM de Zoete, MR van Aubel, RA van Putten, JP Mol Immunol 45:1298-307 15784580 Pubmed 2005 Identification and functional characterization of chicken toll-like receptor 5 reveals a fundamental role in the biology of infection with Salmonella enterica serovar typhimurium Iqbal, M Philbin, VJ Withanage, GS Wigley, P Beal, RK Goodchild, MJ Barrow, P McConnell, I Maskell, DJ Young, J Bumstead, N Boyd, Y Smith, AL Infect Immun 73:2344-50 14625549 Pubmed 2003 Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility Smith, KD Andersen-Nissen, E Hayashi, F Strobe, K Bergman, MA Barrett, SL Cookson, BT Aderem, A Nat Immunol 4:1247-53 MyD88 cascade initiated on plasma membrane Myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays a crucial role in TLR signaling. All TLRs except TLR3 can initiate downstream signaling through MyD88. In the MyD88-dependent pathway, once the adaptor is bound to TLR it leads to recruitment of proteins of the IL1 receptor associated kinase family - IRAK, followed by activation of tumor necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 is an ubiquitin E3 ligase which in turn induces autophosphorylation of TGF-beta activating kinase 1 (TAK1). Activated TAK1 can ultimately mediate the induction of transcription factor NF-kB or mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides.<p>The chicken MyD88 gene was cloned and its expression was detected in cecum, heart, spleen, liver, kidney, female reproductive tract, thymus and bursa. Over-expression of chicken MyD88 (299aa) significantly stimulated the activation of NF-kB in vitro. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 LEFT-TO-RIGHT Activated TLR5/TLR15 homodimer recruits MyD88 adaptor Cloning and analysis of full length chicken MyD88 revealed an open reading frame which encodes a predicted protein sequence of 368 amino acids (aa). Two more chicken MyD88 isoforms with 299 and 376 residues are described in the literature [Qiu Y et al 2008, Lynn et al 2003]. The amino acid sequences of the chMyD88 368 and 376 residue isoforms are 99% identical, 97% identical to the 299 aa chMyD88 predicted peptide and 68% identical to human MyD88 (296 aa).<p>Chicken MyD88 is recruited to the activated hetero or homodimer of chTLR that is located either on plasma membrane (TLR4, TLR2/1, TLR5 and TLR15) or endosome membrane (TLR7 and TLR21). Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 2 Reactome Database ID Release 83 977238 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977238 Reactome R-GGA-977238 1 Reactome stable identifier. Use this 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-977238.1 LEFT-TO-RIGHT 2.7.11.1 IRAK4 binds to activated TLR5 or 15. Mammalian IL-1 receptor-associated kinases IRAK-1, IRAK-2 and IRAK-4 form a multigene family. Those proteins are Ser/Thr protein kinases that are required for TLR mediated pathways leading to NFkB activation. Another IRAK family member IRAK-M has been identified as an inhibitor of TLR signaling.<p>Mammalian IRAK-4 is the homolog of Drosophila melanogaster Pelle. Like Pelle and unlike the other mammalian IRAKs, IRAK-4 is considered to be a central TIR signalling mediator in innate immunity. Mutagenesis analysis showed that any interference with IRAK-4's kinase activity virtually abolished downstream events. This is not the case with other members of the IRAK family.<p>Formation of MyD88:IRAKs multimer relies on homotypic interactions of death domains (DD). It triggers a cascade of phosphorylation reactions that leads to activation of NF-kB/AP-1 and transcription of multiple genes involved in the immune response.<p>The predicted chicken full-length IRAK-4 protein contains 414aa and is 58% identical to human IRAK-4. Chicken IRAK-4 contains a conserved N-terminal death domain and C-terminal protein kinase domain. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 2 IRAK4 : MyD88 : activated TLR5 or TLR15 Reactome DB_ID: 433838 2 1 Reactome Database ID Release 83 433838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=433838 Reactome R-GGA-433838 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-433838.2 ACTIVATION activeUnit: #Protein11 Reactome Database ID Release 83 977247 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977247 Reactome Database ID Release 83 434130 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=434130 Reactome R-GGA-434130 1 Reactome stable identifier. Use this 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-434130.1 LEFT-TO-RIGHT Autophosphorylation of IRAK4 bound to activated TLR5 or 15 Chicken IRAK4 shows 66% amino acid identity to human IRAK4. It is assumed here that chicken IRAK4 is activated by autophosphorylation like its human homologue. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 2 2 Reactome Database ID Release 83 977250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977250 Reactome R-GGA-977250 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-977250.2 LEFT-TO-RIGHT IRAK2 binds to IRAK4 associated with activated TLR : MyD88 complex In mammals activated IRAK4 phosphorylates both IRAK1 and IRAK2. Activated IRAK1 and IRAK2 in turn induce NFkB and AP-1 intracellular signaling cascades mediated by TRAF6.<p>Bioinformatic analysis reveals no evidence of IRAK1 in the chicken genome. It is possible that the chicken TLR pathway utilizes only IRAK-2, which shares 47% amino acid sequence identity with human IRAK2. Authored: Shamovsky, V, 2010-11-30 Reviewed: D'Eustachio, P, 2010-12-06 Edited: Shamovsky, V, 2011-02-24 2 IRAK2 : p-IRAK4 :MyD88 : activated TLR Reactome DB_ID: 977244 1 2 Reactome Database ID Release 83 977244 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977244 Reactome R-GGA-977244 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-977244.2 Reactome Database ID Release 83 977237 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=977237 Reactome R-GGA-977237 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-977237.2 LEFT-TO-RIGHT