BioPAX pathway converted from "TIRAP is phosphorylated by BTK" in the Reactome database.LEFT-TO-RIGHT2.7.10MAL is phosphorylated by BTKTIRAP is phosphorylated by BTKUpon activation of TLR2/or 4 signaling pathway TIRAP(MAL), a TIR domain–containing adapter protein, undergoes tyrosine phosphorylation (Piao W et al. 2008; Gray P et al. 2006). Bruton's tyrosine kinase (BTK) was shown to mediate the TIRAP phosphorylation (Jefferies CA et al. 2003; Gray P et al. 2006). BTK-specific inhibitor, LFM-A13, blocked the phosphorylation of TIRAP in human monocytic cell line THP-1 stimulated with LPS or macrophage-activating lipopeptide-2 (MALP-2) (Gray P et al. 2006). LFM-A13 also inhibited activation of NFkappaB in LPS-treated THP-1 (Jefferies CA et al. 2003). Besides BTK kinase TIRAP was shown to associate with other kinases such as protein kinase C delta (PKC delta) suggesting their regulatory role in TIRAP activation (Kubo-Murai M et al. 2007).<p>Tyr-86, Tyr-106 and Tyr-187 were identified as possible phosphorylation sites (Gray P et al. 2006). An additional study has shown that Tyr-86, Tyr-106, and Tyr-159 are important residues, as mutagenesis of these residues impaired TIRAP (MAL) phosphorylation, affected its interaction with BTK and also impaired downstream signaling (Piao W et al. 2008). BTK-mediated phosphorylation of TIRAP leads to recruitment of suppressor of cytokine signaling 1 (SOCS1), which assembles K48-linked polyubiquitin chains resulting in TIRAP's proteosomal degradation, disrupting the TLR complex, and terminating signaling (Mansell A et al. 2006). TIRAP function is also regulated by the cysteine protease caspase-1, which cleaves the protein in a region of the molecule that interacts with MyD88 and TLR4 (Ulrichts P et al. 2010).Authored: Shamovsky, V, 2012-04-19Reviewed: D'Eustachio, P, 2012-05-25Reviewed: Napetschnig, Johanna, 2012-11-16Edited: Shamovsky, V, 2012-11-06ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 113592cytosolGENE ONTOLOGYGO:0005829ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 75113592Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592ReactomeR-ALL-1135924Reactome stable identifier. Use this 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-113592.4Reactomehttp://www.reactome.orgCOMPOUNDC00002additional informationMIMI:03614MAL:PI(4,5)P2:BTK:activated TLR2/4TIRAP:PI(4,5)P2:BTK:activated TLR2/4Reactome DB_ID: 2201331plasma membraneGENE ONTOLOGYGO:0005886MAL:PI(4,5)P2TIRAP:PI(4,5)P2Reactome DB_ID: 2559415PIP2PI(4,5)P21-phosphatidyl-1D-myo-inositol 4,5-bisphosphatePhosphatidylinositol-4,5-bisphosphate1-phosphatidyl-1D-myo-inositol 4,5- bisphosphateReactome DB_ID: 1798561-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348]1-phosphatidyl-1D-myo-inositol 4,5-bisphosphatePIP2ChEBICHEBI:18348Reactome Database ID Release 75179856Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179856ReactomeR-ALL-1798563Reactome stable identifier. Use this 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-179856.3COMPOUNDC046371TIRAPMal Splice Alternative 1Reactome DB_ID: 166141UniProt:P58753 TIRAPTIRAPMALFUNCTION 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.Homo sapiensNCBI Taxonomy9606UniProtP587531EQUAL221EQUALReactome Database ID Release 75166141Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166141ReactomeR-HSA-1661411Reactome stable identifier. Use this 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-166141.11Reactome Database ID Release 752559415Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2559415ReactomeR-HSA-25594152Reactome stable identifier. Use this 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-2559415.22Converted from EntitySet in ReactomeActivated TLR1:2 or TLR 2:6 heterodimers or TLR4 homodimerReactome DB_ID: 181230TLR1:TLR2:TLR1/2 ligand:CD14Reactome DB_ID: 181226TLR1:TLR2 ligand:CD14Reactome DB_ID: 2559462Converted from EntitySet in ReactomeTLR1:TLR2 recognized ligandReactome DB_ID: 168944PorB HomotrimerReactome DB_ID: 180817extracellular regionGENE ONTOLOGYGO:0005576Major outer membrane protein PReactome DB_ID: 180815UniProt:P30690 porBporBNMB2039FUNCTION Serves as a slightly cation selective porin.SUBUNIT Homotrimer.MISCELLANEOUS Present in outer membrane vesicle formulations which are used as vaccines in human.SIMILARITY Belongs to the Gram-negative porin family.Neisseria meningitidis serogroup BNCBI Taxonomy491UniProtP30690Reactome Database ID Release 75180815Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=180815ReactomeR-NME-1808151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-NME-180815.13Reactome Database ID Release 75180817Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=180817ReactomeR-NME-1808171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-NME-180817.1Triacyl lipopeptideReactome DB_ID: 180811triacyl lipopeptide [ChEBI:60192]triacyl lipopeptidetriacylated lipopeptideChEBICHEBI:60192Reactome Database ID Release 75180811Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=180811ReactomeR-ALL-1808112Reactome stable identifier. Use this 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-180811.2PubChem Compound456855Reactome Database ID Release 75168944Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168944ReactomeR-NME-1689441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-NME-168944.11GPI-N345-CD14GPIN-CD14(20-345)GPI-anchored form of CD14Reactome DB_ID: 166033UniProt:P08571 CD14CD14FUNCTION Coreceptor for bacterial lipopolysaccharide (PubMed:1698311, PubMed:23264655). In concert with LBP, binds to monomeric lipopolysaccharide and delivers it to the LY96/TLR4 complex, thereby mediating the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:20133493, PubMed:23264655). Acts via MyD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:8612135). Acts as a coreceptor for TLR2:TLR6 heterodimer in response to diacylated lipopeptides and for TLR2:TLR1 heterodimer in response to triacylated lipopeptides, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187).SUBUNIT Interacts with LPS-bound LPB (PubMed:1698311, PubMed:23264655). Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Interacts with LPAR1 (By similarity). Interacts with the TLR2:TLR6 or TLR2:TLR1 heterodimers; upon interaction with ligands such as diacylated lipopeptides and triacylated lipopeptides, respectively (PubMed:16880211). Interacts with MYO18A (PubMed:25965346).TISSUE SPECIFICITY Detected on macrophages (at protein level) (PubMed:1698311). Expressed strongly on the surface of monocytes and weakly on the surface of granulocytes; also expressed by most tissue macrophages.INDUCTION The expression in monocytes is highly induced by 27-hydroxycholesterol, priming monocytes/macrophages such that LPS-mediated inflammatory reaction is accelerated. Secretion of soluble CD14 is also enhanced.DOMAIN The C-terminal leucine-rich repeat (LRR) region is required for responses to smooth LPS.PTM N- and O- glycosylated. O-glycosylated with a core 1 or possibly core 8 glycan.UniProtP08571345EQUALN-asparaginyl-glycosylphosphatidylinositolethanolamineMODMOD:0016720EQUAL345EQUALReactome Database ID Release 75166033Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166033ReactomeR-HSA-1660331Reactome stable identifier. Use this 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-166033.11Reactome Database ID Release 752559462Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2559462ReactomeR-HSA-25594622Reactome stable identifier. Use this 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-2559462.21TLR1:TLR2Reactome DB_ID: 168946TLR1Toll-like receptor 1TLR1_HUMANReactome DB_ID: 6787702UniProt:Q15399 TLR1TLR1KIAA0012FUNCTION Participates in the innate immune response to microbial agents. Specifically recognizes diacylated and triacylated lipopeptides. Cooperates with TLR2 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852). Forms the activation cluster TLR2:TLR1:CD14 in response to triacylated lipopeptides, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.SUBUNIT Interacts (via extracellular domain) with TLR2. TLR2 seems to exist in heterodimers with either TLR1 or TLR6 before stimulation by the ligand. The heterodimers form bigger oligomers in response to their corresponding ligands as well as further heterotypic associations with other receptors such as CD14 and/or CD36 (PubMed:16880211, PubMed:17889651). The activation cluster TLR2:TLR1:CD14 forms in response to triacylated lipopeptides (PubMed:16880211). Binds MYD88 (via TIR domain). Interacts with CNPY3 (By similarity).TISSUE SPECIFICITY Ubiquitous. Highly expressed in spleen, ovary, peripheral blood leukocytes, thymus and small intestine.DOMAIN The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.POLYMORPHISM Genetic variations in TLR1 may influence susceptibility to or protection against contracting leprosy and define the leprosy susceptibility locus 5 [MIM:613223]. Ser-602 is a common allele in Caucasians. It is associated with impaired cell surface expression and receptor function resulting in protection against leprosy.SIMILARITY Belongs to the Toll-like receptor family.UniProtQ1539925EQUAL786EQUALReactome Database ID Release 756787702Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6787702ReactomeR-HSA-67877021Reactome stable identifier. Use this 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-6787702.11TLR2Toll Like Receptor 2Reactome DB_ID: 167992UniProt:O60603 TLR2TLR2TIL4FUNCTION Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components. Cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852, PubMed:17889651). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. May also activate immune cells and promote apoptosis in response to the lipid moiety of lipoproteins (PubMed:10426995, PubMed:10426996). Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR6 (PubMed:11441107). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via this receptor, but also partially via TLR4 (PubMed:16622205). MAPK activation in response to bacterial peptidoglycan also occurs via this receptor (PubMed:16622205). Acts as a receptor for M.tuberculosis lipoproteins LprA, LprG, LpqH and PstS1, some lipoproteins are dependent on other coreceptors (TLR1, CD14 and/or CD36); the lipoproteins act as agonists to modulate antigen presenting cell functions in response to the pathogen (PubMed:19362712). M.tuberculosis HSP70 (dnaK) but not HSP65 (groEL-2) acts via this protein to stimulate NF-kappa-B expression (PubMed:15809303). Recognizes M.tuberculosis major T-antigen EsxA (ESAT-6) which inhibits downstream MYD88-dependent signaling (shown in mouse) (By similarity). Forms activation clusters composed of several receptors depending on the ligand, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway. Forms the cluster TLR2:TLR6:CD14:CD36 in response to diacylated lipopeptides and TLR2:TLR1:CD14 in response to triacylated lipopeptides (PubMed:16880211). Required for normal uptake of M.tuberculosis, a process that is inhibited by M.tuberculosis LppM (By similarity).SUBUNIT Interacts with LY96, TLR1 and TLR6 (via extracellular domain) (PubMed:17889651). TLR2 seems to exist in heterodimers with either TLR1 or TLR6 before stimulation by the ligand. The heterodimers form bigger oligomers in response to their corresponding ligands as well as further heterotypic associations with other receptors such as CD14 and/or CD36 (PubMed:16880211). Binds MYD88 (via TIR domain). Interacts with TICAM1 (PubMed:12471095). Interacts with CNPY3 (By similarity). Interacts with ATG16L1 (PubMed:23376921). Interacts with PPP1R11 (By similarity). Interacts with TICAM2 (PubMed:25385819).SUBUNIT (Microbial infection) Interacts with M.tuberculosis EsxA.SUBUNIT (Microbial infection) Interacts with M.bovis MPB83.SUBUNIT (Microbial infection) Interacts with Staphylococcus aureus protein SSL5.TISSUE SPECIFICITY Highly expressed in peripheral blood leukocytes, in particular in monocytes, in bone marrow, lymph node and in spleen. Also detected in lung and in fetal liver. Levels are low in other tissues.DOMAIN Ester-bound lipid substrates are bound through a crevice formed between the LRR 11 and LRR 12.DOMAIN The ATG16L1-binding motif mediates interaction with ATG16L1.DOMAIN The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.PTM Glycosylation of Asn-442 is critical for secretion of the N-terminal ectodomain of TLR2.PTM Ubiquitinated at Lys-754 by PPP1R11, leading to its degradation (PubMed:27805901). Deubiquitinated by USP2 (By similarity).POLYMORPHISM Genetic variations in TLR2 are associated with susceptibility to leprosy [MIM:246300]. Leprosy is a chronic disease associated with depressed cellular (but not humoral) immunity, the bacterium requires a lower temperature than 37 degrees Celsius and thrives particularly in peripheral Schwann cells and macrophages. The Trp-677 polymorphism in the intracellular domain of TLR2 has a role in susceptibility to lepromatous leprosy. Wild-type TLR2 mediates CD14-enhanced Mycobacterium leprae-dependent activation of NFKB1, but TLR2 containing the Trp-677 polymorphism did not. The impaired function of the Trp-677 polymorphism provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy.SIMILARITY Belongs to the Toll-like receptor family.UniProtO6060319EQUAL784EQUALReactome Database ID Release 75167992Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167992ReactomeR-HSA-1679921Reactome stable identifier. Use this 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-167992.11Reactome Database ID Release 75168946Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168946ReactomeR-HSA-1689462Reactome stable identifier. Use this 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-168946.21Reactome Database ID Release 75181226Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181226ReactomeR-HSA-1812262Reactome stable identifier. Use this 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-181226.2TLR6:TLR2:ligand:CD14:CD36Reactome DB_ID: 181410TLR6:TLR2Reactome DB_ID: 168949TLR6Toll Like Receptor 6Reactome DB_ID: 168061UniProt:Q9Y2C9 TLR6TLR6FUNCTION Participates in the innate immune response to Gram-positive bacteria and fungi. Specifically recognizes diacylated and, to a lesser extent, triacylated lipopeptides (PubMed:20037584). In response to diacylated lipopeptides, forms the activation cluster TLR2:TLR6:CD14:CD36, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR2 (PubMed:11441107). In complex with TLR4, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion (PubMed:11441107, PubMed:20037584).SUBUNIT Homodimer (via cytoplasmic TIR domain) (PubMed:25088687). Heterodimer with TLR2 via their respective extracellular domains (PubMed:16880211). Binds MYD88 via their respective TIR domains (Probable). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR4. The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4:TLR6 heterodimerization and signal initiation (PubMed:20037584). The heterodimer TLR2:TLR6 interacts with CD14 and CD36 in response to triacylated lipopeptides (PubMed:16880211).TISSUE SPECIFICITY Detected in monocytes, CD11c+ immature dendritic cells, plasmacytoid pre-dendritic cells and dermal microvessel endothelial cells.DOMAIN The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.SIMILARITY Belongs to the Toll-like receptor family.UniProtQ9Y2C932EQUAL796EQUALReactome Database ID Release 75168061Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168061ReactomeR-HSA-1680611Reactome stable identifier. Use this 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-168061.111Reactome Database ID Release 75168949Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168949ReactomeR-HSA-1689491Reactome stable identifier. Use this 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-168949.11TLR6/2 ligand:CD14:CD36Reactome DB_ID: 2559461Converted from EntitySet in ReactomeTLR6:TLR2 recognized ligandReactome DB_ID: 9628992peptidoglycanClostridial peptidoglycanReactome DB_ID: 181161peptidoglycan [ChEBI:8005]peptidoglycanMucopeptidePeptideglycanMureinChEBICHEBI:8005Reactome Database ID Release 75181161Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181161ReactomeR-ALL-1811613Reactome stable identifier. Use this 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-181161.3Diacyl lipopeptideReactome DB_ID: 181403diacyl lipopeptide [ChEBI:46896]diacyl lipopeptidediacylated lipopeptidesdiacyl lipopeptidesdiacylated lipopeptideChEBICHEBI:46896Reactome Database ID Release 75181403Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181403ReactomeR-ALL-1814032Reactome stable identifier. Use this 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-181403.2PubChem Compound456855LTALipoteichoic acidReactome DB_ID: 181015lipoteichoic acid [ChEBI:28640]lipoteichoic acidChEBICHEBI:28640Reactome Database ID Release 75181015Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181015ReactomeR-ALL-1810154Reactome stable identifier. Use this 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-181015.4mipCT_541Reactome DB_ID: 9628834UniProt:P26623 mipmipCT_541FUNCTION PPIases accelerate the folding of proteins.SIMILARITY Belongs to the FKBP-type PPIase family.Chlamydia trachomatisNCBI Taxonomy813UniProtP2662314EQUAL229EQUALReactome Database ID Release 759628834Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9628834ReactomeR-CTR-96288345Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CTR-9628834.5Reactome Database ID Release 759628992Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9628992ReactomeR-CTR-96289921Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CTR-9628992.11GPIV4xPalmC-CD36Platelet glycoprotein IVGPIIIBCD36 antigenPAS IVPAS-4 proteinReactome DB_ID: 51645UniProt:P16671 CD36CD36GP3BGP4FUNCTION Multifunctional glycoprotein that acts as receptor for a broad range of ligands. Ligands can be of proteinaceous nature like thrombospondin, fibronectin, collagen or amyloid-beta as well as of lipidic nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. They are generally multivalent and can therefore engage multiple receptors simultaneously, the resulting formation of CD36 clusters initiates signal transduction and internalization of receptor-ligand complexes. The dependency on coreceptor signaling is strongly ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory response, fatty acid metabolism, taste and dietary fat processing in the intestine (Probable). Binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption (By similarity) (PubMed:18353783, PubMed:21610069). In the small intestine, plays a role in proximal absorption of dietary fatty acid and cholesterol for optimal chylomicron formation, possibly through the activation of MAPK1/3 (ERK1/2) signaling pathway (By similarity) (PubMed:18753675). Involved in oral fat perception and preferences (PubMed:22240721, PubMed:25822988). Detection into the tongue of long-chain fatty acids leads to a rapid and sustained rise in flux and protein content of pancreatobiliary secretions (By similarity). In taste receptor cells, mediates the induction of an increase in intracellular calcium levels by long-chain fatty acids, leading to the activation of the gustatory neurons in the nucleus of the solitary tract (By similarity). Important factor in both ventromedial hypothalamus neuronal sensing of long-chain fatty acid and the regulation of energy and glucose homeostasis (By similarity). Receptor for thombospondins, THBS1 and THBS2, mediating their antiangiogenic effects (By similarity). As a coreceptor for TLR4:TLR6 heterodimer, promotes inflammation in monocytes/macrophages. Upon ligand binding, such as oxLDL or amyloid-beta 42, interacts with the heterodimer TLR4:TLR6, the complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion, through the priming and activation of the NLRP3 inflammasome (By similarity) (PubMed:20037584). Selective and nonredundant sensor of microbial diacylated lipopeptide that signal via TLR2:TLR6 heterodimer, this cluster triggers signaling from the cell surface, leading to the NF-kappa-B-dependent production of TNF, via MYD88 signaling pathway and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (By similarity) (PubMed:16880211).FUNCTION (Microbial infection) Directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and the internalization of particles independently of TLR signaling.SUBUNIT Interacts with THBS1 and THBS2; the interactions mediate the THBS antiangiogenic activity (PubMed:1371676). Upon interaction with a ligand, such as oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42, rapidly forms a complex with TLR4 and TLR6; the complex is internalized and triggers an inflammatory signal. Through its C-terminus, interacts with PTK2, PXN and LYN, but not with SRC. LYN kinase activity is required for facilitating TLR4:TLR6 heterodimerization and signal initiation (PubMed:1371676, PubMed:20037584). Upon interaction with ligands such as diacylated lipopeptides, interacts with the TLR2:TLR6 heterodimer (PubMed:16880211). Interacts with CD9, CD81, FCER1G, ITGB2 and/or ITGB2; forming a membrane heteromeric complex required for the internalization of CD36 and its ligands (By similarity).SUBUNIT (Microbial infection) Binds to Plasmodium falciparum EMP1.PTM N-glycosylated and O-glycosylated with a ratio of 2:1.PTM Ubiquitinated at Lys-469 and Lys-472. Ubiquitination is induced by fatty acids such as oleic acid and leads to degradation by the proteasome (PubMed:21610069, PubMed:18353783). Ubiquitination and degradation are inhibited by insulin which blocks the effect of fatty acids (PubMed:18353783).POLYMORPHISM Genetic variations in CD36 are involved in susceptibility to malaria and influence the severity and outcome of malaria infection [MIM:611162].SIMILARITY Belongs to the CD36 family.UniProtP166713EQUALS-palmitoyl-L-cysteineMODMOD:00115464EQUAL466EQUAL7EQUAL2EQUAL472EQUALReactome Database ID Release 7551645Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=51645ReactomeR-HSA-516451Reactome stable identifier. Use this 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-51645.111Reactome Database ID Release 752559461Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2559461ReactomeR-HSA-25594612Reactome stable identifier. Use this 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-2559461.21Reactome Database ID Release 75181410Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181410ReactomeR-HSA-1814102Reactome stable identifier. Use this 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-181410.2TLR4:LY96:LPS:CD14Reactome DB_ID: 166850Converted from EntitySet in ReactomeCD14Reactome DB_ID: 166029CD14(20-345)Secreted form of CD14Reactome DB_ID: 16602520EQUAL345EQUALReactome Database ID Release 75166025Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166025ReactomeR-HSA-1660251Reactome stable identifier. Use this 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-166025.1Reactome Database ID Release 75166029Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166029ReactomeR-HSA-1660292Reactome stable identifier. Use this 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-166029.21TLR4:LY96Reactome DB_ID: 166050TLR42xN4GlycoAsn-TLR4Reactome DB_ID: 166045UniProt:O00206 TLR4TLR4FUNCTION Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205).SUBUNIT Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain (PubMed:17803912, PubMed:19252480). Interacts with MYD88 and TIRAP via their respective TIR domains (By similarity). Interacts with TICAM2 (PubMed:14519765, PubMed:25736436). Interacts with NOX4 (PubMed:15356101). Interacts with CNPY3 (By similarity). Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling (PubMed:21602844). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6 (PubMed:20037584). The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner (PubMed:25736436). Interacts with WDFY1 in response to LPS (By similarity). Interacts with SMPDL3B (By similarity). Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (By similarity). Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation (PubMed:27022195). Interacts with SCIMP; the interaction occurs in response to lipopolysaccharide stimulation and is enhanced by phosphorylation of SCIMP by LYN (By similarity). This interaction facilitates the phosphorylation of TLR4 by LYN which elicits a selective cytokine response in macrophages (By similarity).SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC.TISSUE SPECIFICITY Highly expressed in placenta, spleen and peripheral blood leukocytes (PubMed:9435236, PubMed:9237759). Detected in monocytes, macrophages, dendritic cells and several types of T-cells (PubMed:9237759, PubMed:27022195).DOMAIN The TIR domain mediates interaction with NOX4.DOMAIN The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity.PTM N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell surface and the LPS-response. Likewise, mutants lacking two or more of the other N-glycosylation sites were deficient in interaction with LPS.PTM Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.POLYMORPHISM Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.MISCELLANEOUS His-456 and His-458 are found in TLR4 of human and several other primate species and may be responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor monomers through specific histidines, triggering the formation of a dimer that structurally resembles that induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4-deficient mice expresses human TLR4 has been proposed.SIMILARITY Belongs to the Toll-like receptor family.UniProtO00206526EQUALN4-glycosyl-L-asparagineMODMOD:00160575EQUAL24EQUAL839EQUALReactome Database ID Release 75166045Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166045ReactomeR-HSA-1660451Reactome stable identifier. Use this 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-166045.11Ly-962xN4GlycoAsn-LY962xN4GlycoAsn-MD2Lymphocyte antigen 96ESOP-1Myeloid differentiation 2Reactome DB_ID: 166047UniProt:Q9Y6Y9 LY96LY96ESOP1MD2FUNCTION Binds bacterial lipopolysaccharide (LPS) (PubMed:17803912, PubMed:17569869). Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria (PubMed:11160242, PubMed:11593030). Enhances TLR4-dependent activation of NF-kappa-B (PubMed:10359581). Cells expressing both LY96 and TLR4, but not TLR4 alone, respond to LPS (PubMed:10359581).SUBUNIT Heterogeneous homopolymer formed from homodimers; disulfide-linked (PubMed:11593030, PubMed:12642668). Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binds to the extracellular domains of TLR2 and TLR4 (PubMed:10359581, PubMed:11593030, PubMed:17803912). Ligand binding induces interaction with TLR4 and oligomerization of the complex.PTM N-glycosylated; high-mannose.UniProtQ9Y6Y926EQUAL114EQUAL19EQUAL160EQUALReactome Database ID Release 75166047Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166047ReactomeR-HSA-1660471Reactome stable identifier. Use this 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-166047.11Reactome Database ID Release 75166050Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166050ReactomeR-HSA-1660501Reactome stable identifier. Use this 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-166050.12LPSGram Negative Bacterial LipopolysaccharidelipopolysaccharideReactome DB_ID: 166005lipopolysaccharide [ChEBI:16412]lipopolysaccharidelipopolysaccharidesLPSChEBICHEBI:16412Reactome Database ID Release 75166005Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166005ReactomeR-ALL-1660054Reactome stable identifier. Use this 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-166005.42Reactome Database ID Release 75166850Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166850ReactomeR-HSA-1668501Reactome stable identifier. Use this 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-166850.1Reactome Database ID Release 75181230Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181230ReactomeR-HSA-1812303Reactome stable identifier. Use this 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-181230.31BTKTyrosine-protein kinase BTKBTK_HUMANReactome DB_ID: 197948UniProt:Q06187 BTKBTKAGMX1ATKBPKFUNCTION 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.UniProtQ061872EQUAL659EQUALReactome Database ID Release 75197948Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=197948ReactomeR-HSA-1979481Reactome stable identifier. Use this 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-197948.12Reactome Database ID Release 752201331Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2201331ReactomeR-HSA-22013313Reactome stable identifier. Use this 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-2201331.3ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 29370ADP(3-) [ChEBI:456216]ADP(3-)ADP5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 7529370Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370ReactomeR-ALL-293704Reactome stable identifier. Use this 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-29370.4COMPOUNDC000084activated TLR2/4:p-4Y-MAL:PI(4,5)P2:BTKactivated TLR2/4:p-4Y-TIRAP:PI(4,5)P2:BTKReactome DB_ID: 2201325p-4Y-TIRAP:PI(4,5)P2Reactome DB_ID: 53658241p-4Y-MALp-4Y-TIRAPp-Y106,Y159,Y187,Y86-TIRAPReactome DB_ID: 220132186EQUALO4'-phospho-L-tyrosineMODMOD:00048106EQUAL159EQUAL187EQUAL1EQUAL221EQUALReactome Database ID Release 752201321Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2201321ReactomeR-HSA-22013211Reactome stable identifier. Use this 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-2201321.11Reactome 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-5365824.1212Reactome 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-2201325.3ACTIVATIONactiveUnit: #Protein13GENE ONTOLOGYGO:0004713gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 752206268Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206268Reactome Database ID Release 752201322Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2201322ReactomeR-HSA-22013222Reactome stable identifier. Use this 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-2201322.216439361Pubmed2006MyD88 adapter-like (Mal) is phosphorylated by Bruton's tyrosine kinase during TLR2 and TLR4 signal transductionGray, PDunne, ABrikos, CJefferies, CADoyle, SLO'Neill, LAJ Biol Chem 281:10489-9517161867Pubmed2007Protein kinase Cdelta binds TIRAP/Mal to participate in TLR signalingKubo-Murai, MihoHazeki, KaoruSukenobu, NaoeYoshikawa, KyokoNigorikawa, KiyomiInoue, KazumiYamamoto, ToshiyoshiMatsumoto, MSeya, TInoue, NHazeki, OsamuMol. Immunol. 44:2257-6420048342Pubmed2010Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction siteUlrichts, PeterBovijn, CeliaLievens, SamBeyaert, RudiTavernier, JanPeelman, FrankJ. Cell. Sci. 123:256-6512724322Pubmed2003Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4Jefferies, CADoyle, SBrunner, CDunne, ABrint, EWietek, CWalch, EWirth, TO'Neill, LAJ Biol Chem 278:26258-6418070880Pubmed2008Tyrosine phosphorylation of MyD88 adapter-like (Mal) is critical for signal transduction and blocked in endotoxin tolerancePiao, WSong, CChen, HWahl, LMFitzgerald, Katherine AO'Neill, LAMedvedev, AEJ Biol Chem 283:3109-1912810683Pubmed2003Bruton's tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha productionHorwood, Nicole JMahon, TaraMcDaid, John PCampbell, JamieMano, HiroyukiBrennan, Fionula MWebster, DavidFoxwell, Brian M JJ. Exp. Med. 197:1603-1116415872Pubmed2006Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradationMansell, AshleySmith, RosealeeDoyle, SLGray, PFenner, Jennifer ECrack, Peter JNicholson, Sandra EHilton, Douglas JO'Neill, Luke A JHertzog, Paul JNat. Immunol. 7:148-55