BioPAX pathway converted from "Interaction of DAP12 and TREM2" in the Reactome database.Interaction of DAP12 and TREM2Interaction of DAP12 and TREM2This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 97297311plasma membraneGO0005886UniProt:Q99NH8Trem2Reactomehttp://www.reactome.orgMus musculusNCBI Taxonomy10090UniProtQ99NH8Chain Coordinates19EQUAL230EQUALReactome DB_ID: 23268471Dap12 dimer [plasma membrane]Dap12 dimerReactome DB_ID: 23268252UniProt:O54885 TyrobpTyrobpTyrobpKarapDap12FUNCTION Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors (PubMed:15471863, PubMed:9647200). TYROBP is tyrosine-phosphorylated in the ITAM domain following ligand binding by the associated receptors which leads to activation of additional tyrosine kinases and subsequent cell activation (PubMed:15728241). Also has an inhibitory role in some cells (PubMed:21727189). Non-covalently associates with activating receptors of the CD300 family to mediate cell activation (By similarity). Also mediates cell activation through association with activating receptors of the CD200R family (PubMed:15471863). Required for neutrophil activation mediated by integrin (PubMed:17086186). Required for the activation of myeloid cells mediated by the CLEC5A/MDL1 receptor (By similarity). Associates with natural killer (NK) cell receptors such as the KLRD1/KLRC2 heterodimer to mediate NK cell activation (By similarity). Also associates non-covalently with the NK cell receptors KLRA4/LY49D and KLRA8/LY49H which leads to NK cell activation (PubMed:9647200). Associates with TREM1 to mediate activation of neutrophils and monocytes (By similarity). Associates with TREM2 on monocyte-derived dendritic cells to mediate up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival (By similarity). Association with TREM2 mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages (PubMed:18957693). Stabilizes the TREM2 C-terminal fragment (TREM2-CTF) which is produced by TREM2 ectodomain shedding (By similarity). In microglia, required with TREM2 for phagocytosis of apoptotic neurons (PubMed:15728241). Required with ITGAM/CD11B in microglia to control production of microglial superoxide ions which promote the neuronal apoptosis that occurs during brain development (PubMed:18685038). Promotes proinflammatory responses in microglia following nerve injury which accelerates degeneration of injured neurons (PubMed:25690660). Positively regulates the expression of the IRAK3/IRAK-M kinase and IL10 production by liver dendritic cells and inhibits their T cell allostimulatory ability (PubMed:21257958). Negatively regulates B cell proliferation (PubMed:21727189). Required for CSF1-mediated osteoclast cytoskeletal organization (PubMed:18691974). Positively regulates multinucleation during osteoclast development (PubMed:12569157, PubMed:14969392).SUBUNIT Homodimer; disulfide-linked (By similarity). Homotrimer; disulfide-linked (By similarity). Homotetramer; disulfide-linked (By similarity). Homotrimers and homotetramers form when low levels of partner receptors are available and are competitive with assembly with interacting receptors (By similarity). They may represent alternative oligomerization states or may be intermediates in the receptor assembly process (By similarity). Binding of a metal cation aids in homooligomerization through coordination of the metal ion by the subunits of the oligomer (By similarity). Interacts with TREM1 (By similarity). Interacts with TREM2 (PubMed:29518356). Interacts with TREM3 (PubMed:11754004). Interacts with CLECSF5 (PubMed:10449773). Interacts with CD300LB and CD300C2 (PubMed:12874256, PubMed:12893283, PubMed:17202337, PubMed:17928527). Interacts with CD300E (By similarity). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK mediating neutrophil and macrophage integrin-mediated activation (PubMed:17086186). Interacts (via transmembrane domain) with KLRK1 isoform 2 (via transmembrane domain); the interaction is required for KLRK1 NK cell surface expression and NK cell-mediated cytotoxicity (PubMed:12426564, PubMed:12426565, PubMed:15294961). Interacts with KLRC2 (By similarity). Interacts with CD300H (By similarity). Interacts with KLRD1 (By similarity). Interacts with KLRA4 and KLRA8 (PubMed:9647200).TISSUE SPECIFICITY Expressed on microglia (at protein level) (PubMed:12569157, PubMed:18685038). Expressed on oligodendrocytes (at protein level) (PubMed:12569157). Expressed on macrophages and osteoclasts (PubMed:14969392). Expressed on dendritic cells in liver, spleen, kidney and lung with highest levels in liver dendritic cells (PubMed:21257958).INDUCTION Induced in microglia following nerve injury (at protein level) (PubMed:25690660). Induced in liver dendritic cells by physiological concentrations of lipopolysaccharide (PubMed:21257958).PTM Tyrosine phosphorylated (PubMed:11754004, PubMed:12426565, PubMed:15728241, PubMed:17086186, PubMed:18691974, PubMed:9490415, PubMed:9852069). Following ligand binding by associated receptors, tyrosine phosphorylated in the ITAM domain which leads to activation of additional tyrosine kinases and subsequent cell activation (By similarity).DISRUPTION PHENOTYPE Increased bone mass and failure to generate multinuclear osteoclasts in vitro (PubMed:12569157, PubMed:14969392). Thalamic hypomyelination, synaptic degeneration, reduced startle response and aberrant electrophysiological profiles (PubMed:12569157). Enhanced proliferation of B cells (PubMed:21727189). Reduced number of microglia at sites of nerve injury and high rate of neuronal survival (PubMed:25690660). Impaired macrophage fusion (PubMed:18957693). Defective osteoclast cytoskeletal organization and function (PubMed:18691974).SIMILARITY Belongs to the TYROBP family.UniProtO5488522EQUAL113EQUALReactome Database ID Release 752326847Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2326847ReactomeR-MMU-23268471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-2326847.1Reactome DB_ID: 97297581DAP12 dimer:TREM2 [plasma membrane]DAP12 dimer:TREM2Reactome DB_ID: 9729731119EQUAL230EQUALReactome DB_ID: 23268471Reactome Database ID Release 759729758Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9729758ReactomeR-MMU-2102451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-210245.1Reactome Database ID Release 759729760Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9729760ReactomeR-MMU-2103001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-210300.1TREM2 (triggering receptor expressed on myeloid cells 2 protein) is expressed on the cell membrane of a subset of myeloid cells - namely, immature dendritic cells, osteoclasts, tissue macrophages, and microglia. Like TREM1 the ligand for TREM2 is unknown. TREM2 signals through DAP12, leading to an increase in intracellular calcium and phosphorylation of ERK1/2 (Sharif & Knapp. 2008). It recognises anionic lipopolysacharides in the cell wall of bacteria and triggers the phagocytic uptake of bacteria and the release of reactive oxygen species (Neumann & Daly 2013). TREM2 on immature dendritic cells triggers upregulation of molecules involved in T cell co-stimulation such as CD86, CD40 and MHC class II, as well as up-regulation of the chemokine receptor CCR7 (Bouchon et al. 2001). In macrophages TREM2 is a negative regulator of inflammatory responses (Hamerman et al. 2006, Turnbull et al. 2006). From genome wide association studies, a TREM2 variant (encoding a substitution of arginine by histidine at residue 47 [R47H]) has been reported to be implicated in late-onset Alzheumer's disease (Neumann & Daly 2013). 23151315Pubmed2013Variant TREM2 as risk factor for Alzheimer's diseaseNeumann, HaraldDaly, Mark JN. Engl. J. Med. 368:182-418926286Pubmed2008From expression to signaling: roles of TREM-1 and TREM-2 in innate immunity and bacterial infectionSharif, OKnapp, SImmunobiology 213:701-1316887962Pubmed2006Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12Hamerman, Jessica AJarjoura, Jessica RHumphrey, Mary BethNakamura, Mary CSeaman, William ELanier, Lewis LJ. Immunol. 177:2051-511602640Pubmed2001A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cellsBouchon, AHernández-Munain, CCella, MColonna, MJ. Exp. Med. 194:1111-2216951310Pubmed2006Cutting edge: TREM-2 attenuates macrophage activationTurnbull, Isaiah RGilfillan, SCella, MAoshi, TaikiMiller, MarkPiccio, LauraHernandez, MaristelaColonna, MJ. Immunol. 177:3520-4inferred by electronic annotationIEAGOIEA