BioPAX pathway converted from "TRAF6 binds to hp- IRAK1" in the Reactome database.TRAF6 binds to hp- IRAK1TRAF6 binds to hp- IRAK1Hyperphosphorylated IRAK1, still within the receptor complex, binds TRAF6 through multiple regions including the death domain, the undefined domain and the C-terminal C1 domain (Li et al. 2001). The C-terminal region of IRAK-1 contains three potential TRAF6-binding sites; mutation of the amino acids (Glu544, Glu587, Glu706) in these sites to alanine greatly reduces activation of NFkappaB (Ye et al. 2002).Authored: de Bono, B, 2005-08-16 10:54:15Reviewed: Gay, NJ, 2006-04-24 16:48:17Reviewed: Gillespie, ME, 2010-11-30Reviewed: Napetschnig, Johanna, 2012-11-16Edited: Shamovsky, V, 2012-11-06Reactome DB_ID: 1663664cytosolGO0005829UniProt:Q9Y4K3 TRAF6TRAF6TRAF6RNF85FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1. Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (PubMed:28087809). Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1 (PubMed:23776175). Interacts with LRRC19 (PubMed:25026888). Interacts with IL17RA AND TRAF3IP2.TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-453 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (PubMed:19825828). Polyubiquitinated on Lys-124; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappaB signaling upon DNA damage (PubMed:25861989). LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtQ9Y4K3Chain Coordinates1EQUAL522EQUALReactome DB_ID: 1663601plasma membraneGO0005886p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:TIRAP:activated TLR [plasma membrane]p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:TIRAP:activated TLRReactome DB_ID: 9370481p-S,2T-IRAK4:oligo-MyD88:TIRAP:activated TLR receptor [plasma membrane]p-S,2T-IRAK4:oligo-MyD88:TIRAP:activated TLR receptorReactome DB_ID: 9370331oligo-MyD88:TIRAP:BTK:activated TLR [plasma membrane]oligo-MyD88:TIRAP:BTK:activated TLRReactome DB_ID: 22013251activated TLR2/4:p-4Y-TIRAP:PI(4,5)P2:BTK [plasma membrane]activated TLR2/4:p-4Y-TIRAP:PI(4,5)P2:BTKactivated TLR2/4:p-4Y-MAL:PI(4,5)P2:BTKReactome DB_ID: 53658242p-4Y-TIRAP:PI(4,5)P2 [plasma membrane]p-4Y-TIRAP:PI(4,5)P2Reactome DB_ID: 17985611-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348]1-phosphatidyl-1D-myo-inositol 4,5-bisphosphatePIP2ChEBI18348Reactome DB_ID: 22013211UniProt:P58753 TIRAPTIRAPMALTIRAPFUNCTION Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.SUBUNIT Homodimer. Also forms heterodimers with MYD88. May interact with PIK3AP1 (By similarity). Interacts with TLR4 and IRAK2 via their respective TIR domains. Interacts with BMX and TBK1. Interacts with EIF2AK2. Does not interact with IRAK1, nor TLR9.SUBUNIT (Microbial infection) In case of infection, interacts with Brucella protein BtpA.TISSUE SPECIFICITY Highly expressed in liver, kidney, spleen, skeletal muscle and heart. Also detected in peripheral blood leukocytes, lung, placenta, small intestine, thymus, colon and brain.PTM Phosphorylated by IRAK1 and IRAK4. Also phosphorylated by BTK.PTM Polyubiquitinated. Polyubiquitination follows phosphorylation by BTK and leads to TIRAP degradation.POLYMORPHISM Genetic variations in TIRAP may influence susceptibility or resistance to invasive pneumococcal disease, malaria [MIM:611162], and tuberculosis [MIM:607948]. It may define the bacteremia susceptibility locus 1 (BACTS1) [MIM:614382].CAUTION Variant Leu-180 has been reported to reduce TLR2 signal transduction (PubMed:17322885). In contrast, PubMed:19509286 reports that this variant is fully active and has no effect on signal transduction pathways and cytokine production.UniProtP58753O4'-phospho-L-tyrosine at 8686EQUALO4'-phospho-L-tyrosine [MOD:00048]O4'-phospho-L-tyrosine at 106106EQUALO4'-phospho-L-tyrosine at 159159EQUALO4'-phospho-L-tyrosine at 187187EQUAL1EQUAL221EQUALReactome Database ID Release 755365824Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5365824ReactomeR-HSA-53658241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5365824.1Reactome DB_ID: 1979482UniProt:Q06187 BTKBTKAGMX1BTKATKBPKFUNCTION Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.ACTIVITY REGULATION Activated by phosphorylation. In primary B lymphocytes, is almost always non-phosphorylated and is thus catalytically inactive. Stimulation of TLR8 and TLR9 causes BTK activation. As a negative feedback mechanism to fine-tune BCR signaling, activated PRKCB down-modulates BTK function via direct phosphorylation of BTK at Ser-180, resulting in translocation of BTK back to the cytoplasmic fraction. PIN1, SH3BP5, and IBTK were also identified as BTK activity inhibitors. Interaction with CAV1 leads to dramatic down-regulation of the kinase activity of BTK. LFM-13A is a specific inhibitor of BTK. Dasatinib, a cancer drug acting as a tyrosine kinase inhibitor, also blocks BTK activity.SUBUNIT Binds GTF2I through the PH domain. Interacts with SH3BP5 via the SH3 domain. Interacts with IBTK via its PH domain. Interacts with ARID3A, CAV1, FASLG, PIN1, TLR8 and TLR9.TISSUE SPECIFICITY Predominantly expressed in B-lymphocytes.DOMAIN The PH domain mediates the binding to inositol polyphosphate and phosphoinositides, leading to its targeting to the plasma membrane. It is extended in the BTK kinase family by a region designated the TH (Tec homology) domain, which consists of about 80 residues preceding the SH3 domain.PTM Following B-cell receptor (BCR) engagement, translocates to the plasma membrane where it gets phosphorylated at Tyr-551 by LYN and SYK. Phosphorylation at Tyr-551 is followed by autophosphorylation of Tyr-223 which may create a docking site for a SH2 containing protein. Phosphorylation at Ser-180 by PRKCB, leads in translocation of BTK back to the cytoplasmic fraction. Phosphorylation at Ser-21 and Ser-115 creates a binding site for PIN1 at these Ser-Pro motifs, and promotes it's recruitment.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.UniProtQ061872EQUAL659EQUALConverted from EntitySet in ReactomeReactome DB_ID: 1812301Activated TLR1:2 or TLR 2:6 heterodimers or TLR4 homodimer [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 752201325Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2201325ReactomeR-HSA-22013253Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2201325.3Reactome DB_ID: 9370131MyD88 oligomer [plasma membrane]MyD88 oligomerReactome DB_ID: 9370176UniProt:Q99836 MYD88MYD88MYD88FUNCTION Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity).SUBUNIT Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, TLR5, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL18R1. Interacts with BMX, IL1RL1, IKBKE and IRF7. Interacts with LRRFIP1 and LRRFIP2; this interaction positively regulates Toll-like receptor (TLR) signaling in response to agonist. Interacts with FLII. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-binding. Interacts with IRF1. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and TRAF6; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. May interact with PIK3AP1. Interacts (via TIR domain) with DHX9 (via H2A and OB-fold regions); this interaction is direct (PubMed:20696886). Interacts with OTUD4 deubiquitinase; the interaction is direct (PubMed:29395066).SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC; suppressing Toll-like receptor (TLR)-mediated cytokine production.SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.faecalis protein TcpF; suppressing Toll-like receptor (TLR)-mediated cytokine production.TISSUE SPECIFICITY Ubiquitous.DOMAIN The intermediate domain (ID) is required for the phosphorylation and activation of IRAK.PTM Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination. OTUD4 specifically hydrolyzes 'Lys-63'-linked polyubiquitinated MYD88.DISEASE Defects in MYD88 are frequently found in many hematological malignancies, such as activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), Waldenstroem macroglobulinemia, cutaneous diffuse large B cell lymphoma (CBCL) and primary central nervous system lymphoma (PCNSL).UniProtQ998361EQUAL296EQUALReactome Database ID Release 75937013Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=937013ReactomeR-HSA-9370131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-937013.1Reactome Database ID Release 75937033Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=937033ReactomeR-HSA-9370333Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-937033.3Reactome DB_ID: 9369574UniProt:Q9NWZ3 IRAK4IRAK4IRAK4FUNCTION Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.SUBUNIT Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome. Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Interacts with IL1RL1.PTM Phosphorylated.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.UniProtQ9NWZ3O-phospho-L-threonine at 342342EQUALO-phospho-L-threonine [MOD:00047]O-phospho-L-threonine at 345345EQUALO-phospho-L-serine at 346346EQUALO-phospho-L-serine [MOD:00046]1EQUAL460EQUALReactome Database ID Release 75937048Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=937048ReactomeR-HSA-9370483Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-937048.3Reactome DB_ID: 9370114UniProt:P51617 IRAK1IRAK1IRAKIRAK1FUNCTION Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.SUBUNIT Homodimer (By similarity). Forms a complex with TRAF6, PELI1, IRAK4 and MYD88 (PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (PubMed:16951688). The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (PubMed:16951688). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (PubMed:9430229). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (PubMed:10854325). Interacts with IL1RL1 (PubMed:16286016). Interacts with PELI1 and TRAF6 (PubMed:12496252). Interacts (when polyubiquitinated) with IKBKG/NEMO (PubMed:18347055). Interacts with RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity). Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (By similarity). Interacts with IRAK4 (PubMed:11960013). Interacts with PELI3 (PubMed:12874243). Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts (via C-terminus) with NFATC4 (via N-terminus) (PubMed:18691762).SUBUNIT (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.TISSUE SPECIFICITY Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2.DOMAIN The ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation.PTM Following recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity.PTM Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through 'Lys-63'. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.UniProtP51617O-phospho-L-threonine at 387387EQUALO-phospho-L-serine at 376376EQUALO-phospho-L-threonine at 209209EQUALO-phospho-L-serine at unknown positionO-phospho-L-serine at unknown positionO-phospho-L-threonine at unknown position1EQUAL712EQUALReactome Database ID Release 75166360Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166360ReactomeR-HSA-1663603Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166360.3Reactome DB_ID: 9370531TRAF6:hp-IRAK1:p-IRAK4:oligo-MyD88:TIRAP:activated TLR [plasma membrane]TRAF6:hp-IRAK1:p-IRAK4:oligo-MyD88:TIRAP:activated TLRReactome DB_ID: 1663601Reactome DB_ID: 93695541EQUAL522EQUALReactome Database ID Release 75937053Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=937053ReactomeR-HSA-9370533Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-937053.3Reactome Database ID Release 75166363Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166363ReactomeR-HSA-1663631Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-166363.111287640Pubmed2001IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK)Li, XCommane, MJiang, ZStark, GRProc Natl Acad Sci U S A 98:4461-58837778Pubmed1996TRAF6 is a signal transducer for interleukin-1Cao, ZXiong, JTakeuchi, MKurama, TGoeddel, DVNature 383:443-612138165Pubmed2002Identification of threonine 66 as a functionally critical residue of theRoss, KYang, LDower, SVolpe, FGuesdon, FJ Biol Chem 277:37414-2118070982Pubmed2008TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaBMuroi, MTanamoto, KJ Leukoc Biol 83:702-712140561Pubmed2002Distinct molecular mechanism for initiating TRAF6 signallingYe, HArron, JRLamothe, BCirilli, MKobayashi, TShevde, NKSegal, DDzivenu, OKVologodskaia, MYim, MDu, KSingh, SPike, JWDarnay, BGChoi, YWu, HNature 418:443-7