BioPAX pathway converted from "TLR6:TLR2 is recruited to ligand:CD14:CD36" in the Reactome database.LEFT-TO-RIGHTTLR6:TLR2 is recruited to ligand:CD14:CD36TLR2 - in combination with TLR6 - plays a major role in recognizing lipoteichoic acid (LTA) and peptidoglycan wall products from Gram-positive bacteria, as well as Mycobacterial diacylated lipopeptides.Authored: D'Eustachio, P, Gay, NJ, Gale M, Jr, Zwaginga, JJ, 2006-04-19 04:09:58Reviewed: D'Eustachio, P, 2006-07-03 21:35:13Reviewed: Gillespie, ME, 2010-11-30Edited: Shamovsky, V, 2012-11-19TLR6/2 ligand:CD14:CD36Reactome DB_ID: 2559461plasma membraneGENE ONTOLOGYGO:0005886GPIV4xPalmC-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.Homo sapiensNCBI Taxonomy9606UniProtP166713EQUALS-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-51645.1Reactomehttp://www.reactome.org1GPI-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-166033.11Converted from EntitySet in ReactomeTLR6:TLR2 recognized ligandReactome DB_ID: 9628992peptidoglycanClostridial peptidoglycanReactome DB_ID: 181161extracellular regionGENE ONTOLOGYGO:0005576peptidoglycan [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 Compound456855additional informationMIMI:0361LTALipoteichoic 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-9628992.11Reactome 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-2559461.2TLR6: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-168061.11TLR2Toll 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 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-168949.1TLR6:TLR2:ligand:CD14:CD36Reactome DB_ID: 18141011Reactome 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-181410.2Reactome Database ID Release 75168950Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=168950ReactomeR-HSA-1689504Reactome stable identifier. Use this 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-168950.410426996Pubmed1999Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2Aliprantis, AOYang, RBMark, MRSuggett, SDevaux, BRadolf, JDKlimpel, GRGodowski, PZychlinsky, AScience 285:736-914977973Pubmed2004Relationship between structures and biological activities of mycoplasmal diacylated lipopeptides and their recognition by toll-like receptors 2 and 6Okusawa, TFujita, MNakamura, JInto, TYasuda, MYoshimura, AHara, YHasebe, AGolenbock, DTMorita, MKuroki, YOgawa, TShibata, KInfect Immun 72:1657-6511123271Pubmed2001Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulinHajjar, AMO'Mahony, DSOzinsky, AUnderhill, DMAderem, AKlebanoff, SJWilson, CBJ Immunol 166:15-910490993Pubmed1999Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosisMeans, TKWang, SLien, EYoshimura, AGolenbock, DTFenton, MJJ Immunol 163:3920-718178856Pubmed2008The proinflammatory cytokine response to Chlamydia trachomatis elementary bodies in human macrophages is partly mediated by a lipoprotein, the macrophage infectivity potentiator, through TLR2/TLR1/TLR6 and CD14Bas, SylvetteNeff, LaurenceVuillet, MadeleineSpenato, UrsulaSeya, TMatsumoto, MGabay, CemJ. Immunol. 180:1158-6810364168Pubmed1999Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2Schwandner, RDziarski, RWesche, HRothe, MKirschning, CJJ Biol Chem 274:17406-910549626Pubmed1999Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall componentsTakeuchi, OHoshino, KKawai, TSanjo, HTakada, HOgawa, TTakeda, KAkira, ShizuoImmunity 11:443-51