DNAX activation protein of 12kDa (DAP12) is an immunoreceptor tyrosine-based activation motif (ITAM)-bearing adapter molecule that transduces activating signals in natural killer (NK) and myeloid cells. It mediates signalling for multiple cell-surface receptors expressed by these cells, associating with receptor chains through complementary charged transmembrane amino acids that form a salt-bridge in the context of the hydrophobic lipid bilayer (Lanier et al. 1998). DAP12 homodimers associate with a variety of receptors expressed by macrophages, monocytes and myeloid cells including TREM2, Siglec H and SIRP-beta, as well as activating KIR, LY49 and the NKG2C proteins expressed by NK cells. DAP12 is expressed at the cell surface, with most of the protein lying on the cytoplasmic side of the membrane (Turnbull & Colonna 2007, Tessarz & Cerwenka 2008).
View original pathway at Reactome.
Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMedEurope PMCScholia
Moon KD, Post CB, Durden DL, Zhou Q, De P, Harrison ML, Geahlen RL.; ''Molecular basis for a direct interaction between the Syk protein-tyrosine kinase and phosphoinositide 3-kinase.''; PubMedEurope PMCScholia
Pascal V, Yamada E, Martin MP, Alter G, Altfeld M, Metcalf JA, Baseler MW, Adelsberger JW, Carrington M, Anderson SK, McVicar DW.; ''Detection of KIR3DS1 on the cell surface of peripheral blood NK cells facilitates identification of a novel null allele and assessment of KIR3DS1 expression during HIV-1 infection.''; PubMedEurope PMCScholia
Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMedEurope PMCScholia
Lanier LL, Corliss B, Wu J, Phillips JH.; ''Association of DAP12 with activating CD94/NKG2C NK cell receptors.''; PubMedEurope PMCScholia
Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR.; ''Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Jiang Y, Cheng H.; ''Evidence of LAT as a dual substrate for Lck and Syk in T lymphocytes.''; PubMedEurope PMCScholia
Saulquin X, Gastinel LN, Vivier E.; ''Crystal structure of the human natural killer cell activating receptor KIR2DS2 (CD158j).''; PubMedEurope PMCScholia
Nowak I, Majorczyk E, Wiśniewski A, Pawlik A, Magott-Procelewska M, Passowicz-Muszyńska E, Malejczyk J, Płoski R, Giebel S, Barcz E, Zoń-Giebel A, Malinowski A, Tchórzewski H, Chlebicki A, Łuszczek W, Kurpisz M, Gryboś M, Wilczyński J, Wiland P, Senitzer D, Sun JY, Jankowska R, Klinger M, Kuśnierczyk P.; ''Does the KIR2DS5 gene protect from some human diseases?''; PubMedEurope PMCScholia
Cao H, Lakner U, de Bono B, Traherne JA, Trowsdale J, Barrow AD.; ''SIGLEC16 encodes a DAP12-associated receptor expressed in macrophages that evolved from its inhibitory counterpart SIGLEC11 and has functional and non-functional alleles in humans.''; PubMedEurope PMCScholia
Liu SK, Fang N, Koretzky GA, McGlade CJ.; ''The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors.''; PubMedEurope PMCScholia
McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
Martínez-Barriocanal A, Sayós J.; ''Molecular and functional characterization of CD300b, a new activating immunoglobulin receptor able to transduce signals through two different pathways.''; PubMedEurope PMCScholia
Jevremovic D, Billadeau DD, Schoon RA, Dick CJ, Irvin BJ, Zhang W, Samelson LE, Abraham RT, Leibson PJ.; ''Cutting edge: a role for the adaptor protein LAT in human NK cell-mediated cytotoxicity.''; PubMedEurope PMCScholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
Kim MJ, Kim E, Ryu SH, Suh PG.; ''The mechanism of phospholipase C-gamma1 regulation.''; PubMedEurope PMCScholia
Bakker AB, Baker E, Sutherland GR, Phillips JH, Lanier LL.; ''Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells.''; PubMedEurope PMCScholia
Asada H, Ishii N, Sasaki Y, Endo K, Kasai H, Tanaka N, Takeshita T, Tsuchiya S, Konno T, Sugamura K.; ''Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT.''; PubMedEurope PMCScholia
Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J.; ''The structural basis of the activation of Ras by Sos.''; PubMedEurope PMCScholia
Jiang K, Zhong B, Gilvary DL, Corliss BC, Vivier E, Hong-Geller E, Wei S, Djeu JY.; ''Syk regulation of phosphoinositide 3-kinase-dependent NK cell function.''; PubMedEurope PMCScholia
Carr WH, Rosen DB, Arase H, Nixon DF, Michaelsson J, Lanier LL.; ''Cutting Edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation.''; PubMedEurope PMCScholia
Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMedEurope PMCScholia
Campbell KS, Yusa S, Kikuchi-Maki A, Catina TL.; ''NKp44 triggers NK cell activation through DAP12 association that is not influenced by a putative cytoplasmic inhibitory sequence.''; PubMedEurope PMCScholia
Wang Y, Wang Z.; ''Regulation of EGF-induced phospholipase C-gamma1 translocation and activation by its SH2 and PH domains.''; PubMedEurope PMCScholia
Klesney-Tait J, Turnbull IR, Colonna M.; ''The TREM receptor family and signal integration.''; PubMedEurope PMCScholia
Della Chiesa M, Romeo E, Falco M, Balsamo M, Augugliaro R, Moretta L, Bottino C, Moretta A, Vitale M.; ''Evidence that the KIR2DS5 gene codes for a surface receptor triggering natural killer cell function.''; PubMedEurope PMCScholia
Reeve JL, Zou W, Liu Y, Maltzman JS, Ross FP, Teitelbaum SL.; ''SLP-76 couples Syk to the osteoclast cytoskeleton.''; PubMedEurope PMCScholia
Zeng L, Sachdev P, Yan L, Chan JL, Trenkle T, McClelland M, Welsh J, Wang LH.; ''Vav3 mediates receptor protein tyrosine kinase signaling, regulates GTPase activity, modulates cell morphology, and induces cell transformation.''; PubMedEurope PMCScholia
Turnbull IR, Colonna M.; ''Activating and inhibitory functions of DAP12.''; PubMedEurope PMCScholia
Brumbaugh KM, Binstadt BA, Billadeau DD, Schoon RA, Dick CJ, Ten RM, Leibson PJ.; ''Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity.''; PubMedEurope PMCScholia
Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A.; ''Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product.''; PubMedEurope PMCScholia
Graef T, Moesta AK, Norman PJ, Abi-Rached L, Vago L, Older Aguilar AM, Gleimer M, Hammond JA, Guethlein LA, Bushnell DA, Robinson PJ, Parham P.; ''KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C.''; PubMedEurope PMCScholia
Ormsby T, Schlecker E, Ferdin J, Tessarz AS, Angelisová P, Köprülü AD, Borte M, Warnatz K, Schulze I, Ellmeier W, Horejsí V, Cerwenka A.; ''Btk is a positive regulator in the TREM-1/DAP12 signaling pathway.''; PubMedEurope PMCScholia
Humphries LA, Dangelmaier C, Sommer K, Kipp K, Kato RM, Griffith N, Bakman I, Turk CW, Daniel JL, Rawlings DJ.; ''Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker.''; PubMedEurope PMCScholia
Angata T, Hayakawa T, Yamanaka M, Varki A, Nakamura M.; ''Discovery of Siglec-14, a novel sialic acid receptor undergoing concerted evolution with Siglec-5 in primates.''; PubMedEurope PMCScholia
Peng Q, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB.; ''TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.''; PubMedEurope PMCScholia
Matsuda M, Paterson HF, Rodriguez R, Fensome AC, Ellis MV, Swann K, Katan M.; ''Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor.''; PubMedEurope PMCScholia
Tomasello E, Cant C, Bühring HJ, Vély F, André P, Seiffert M, Ullrich A, Vivier E.; ''Association of signal-regulatory proteins beta with KARAP/DAP-12.''; PubMedEurope PMCScholia
Tomasello E, Vivier E.; ''KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions.''; PubMedEurope PMCScholia
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMedEurope PMCScholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMedEurope PMCScholia
Vitale M, Bottino C, Sivori S, Sanseverino L, Castriconi R, Marcenaro E, Augugliaro R, Moretta L, Moretta A.; ''NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis.''; PubMedEurope PMCScholia
Angata T, Tabuchi Y, Nakamura K, Nakamura M.; ''Siglec-15: an immune system Siglec conserved throughout vertebrate evolution.''; PubMedEurope PMCScholia
Gross BS, Lee JR, Clements JL, Turner M, Tybulewicz VL, Findell PR, Koretzky GA, Watson SP.; ''Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets.''; PubMedEurope PMCScholia
Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG.; ''Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.''; PubMedEurope PMCScholia
Qi Y, Martin MP, Gao X, Jacobson L, Goedert JJ, Buchbinder S, Kirk GD, O'Brien SJ, Trowsdale J, Carrington M.; ''KIR/HLA pleiotropism: protection against both HIV and opportunistic infections.''; PubMedEurope PMCScholia
Cognet C, Farnarier C, Gauthier L, Frassati C, André P, Magérus-Chatinet A, Anfossi N, Rieux-Laucat F, Vivier E, Schleinitz N.; ''Expression of the HLA-C2-specific activating killer-cell Ig-like receptor KIR2DS1 on NK and T cells.''; PubMedEurope PMCScholia
Gumá M, Busch LK, Salazar-Fontana LI, Bellosillo B, Morte C, García P, López-Botet M.; ''The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8+ T cells.''; PubMedEurope PMCScholia
Zhang W, Trible RP, Zhu M, Liu SK, McGlade CJ, Samelson LE.; ''Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling.''; PubMedEurope PMCScholia
Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMedEurope PMCScholia
Todderud G, Wahl MI, Rhee SG, Carpenter G.; ''Stimulation of phospholipase C-gamma 1 membrane association by epidermal growth factor.''; PubMedEurope PMCScholia
Lanier LL.; ''DAP10- and DAP12-associated receptors in innate immunity.''; PubMedEurope PMCScholia
Lanier LL, Corliss BC, Wu J, Leong C, Phillips JH.; ''Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.''; PubMedEurope PMCScholia
McVicar DW, Taylor LS, Gosselin P, Willette-Brown J, Mikhael AI, Geahlen RL, Nakamura MC, Linnemeyer P, Seaman WE, Anderson SK, Ortaldo JR, Mason LH.; ''DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase.''; PubMedEurope PMCScholia
Wen R, Jou ST, Chen Y, Hoffmeyer A, Wang D.; ''Phospholipase C gamma 2 is essential for specific functions of Fc epsilon R and Fc gamma R.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
Zou W, Reeve JL, Liu Y, Teitelbaum SL, Ross FP.; ''DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk.''; PubMedEurope PMCScholia
Aguilar H, Alvarez-Errico D, García-Montero AC, Orfao A, Sayós J, López-Botet M.; ''Molecular characterization of a novel immune receptor restricted to the monocytic lineage.''; PubMedEurope PMCScholia
Paz PE, Wang S, Clarke H, Lu X, Stokoe D, Abo A.; ''Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells.''; PubMedEurope PMCScholia
Abe K, Rossman KL, Liu B, Ritola KD, Chiang D, Campbell SL, Burridge K, Der CJ.; ''Vav2 is an activator of Cdc42, Rac1, and RhoA.''; PubMedEurope PMCScholia
Jabril-Cuenod B, Zhang C, Scharenberg AM, Paolini R, Numerof R, Beaven MA, Kinet JP.; ''Syk-dependent phosphorylation of Shc. A potential link between FcepsilonRI and the Ras/mitogen-activated protein kinase signaling pathway through SOS and Grb2.''; PubMedEurope PMCScholia
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMedEurope PMCScholia
Call ME, Wucherpfennig KW, Chou JJ.; ''The structural basis for intramembrane assembly of an activating immunoreceptor complex.''; PubMedEurope PMCScholia
Cella M, Fujikawa K, Tassi I, Kim S, Latinis K, Nishi S, Yokoyama W, Colonna M, Swat W.; ''Differential requirements for Vav proteins in DAP10- and ITAM-mediated NK cell cytotoxicity.''; PubMedEurope PMCScholia
Dietrich J, Cella M, Seiffert M, Bühring HJ, Colonna M.; ''Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells.''; PubMedEurope PMCScholia
Feng J, Call ME, Wucherpfennig KW.; ''The assembly of diverse immune receptors is focused on a polar membrane-embedded interaction site.''; PubMedEurope PMCScholia
Cantoni C, Bottino C, Vitale M, Pessino A, Augugliaro R, Malaspina A, Parolini S, Moretta L, Moretta A, Biassoni R.; ''NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily.''; PubMedEurope PMCScholia
Dinh M, Grunberger D, Ho H, Tsing SY, Shaw D, Lee S, Barnett J, Hill RJ, Swinney DC, Bradshaw JM.; ''Activation mechanism and steady state kinetics of Bruton's tyrosine kinase.''; PubMedEurope PMCScholia
Bouchon A, Hernández-Munain C, Cella M, Colonna M.; ''A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells.''; PubMedEurope PMCScholia
Yablonski D, Kadlecek T, Weiss A.; ''Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT.''; PubMedEurope PMCScholia
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
Myeloid DAP12-associating lectin (MDL)-1, also designated CLEC5A, is a type II transmembrane protein belonging to the C-type lectin superfamily and expressed exclusively in monocytes and macrophages. MDL-1 contains a charged residue in the transmembrane region and this enables it to pair with DAP12 dimers. MDL-1's natural mammalian ligand is unknown, but MDL-1 is a receptor for Dengue virus CLEC5A is critical for dengue-virus-induced lethal disease (Chen et al 2008). Engagement with DAP12 has been shown to regulate osteoclastogenesis and myeloid cell-associated inflammatory responses (Bakker et al. 1999, Aoki et al. 2009, Inui et al 2009, Joyce-Shaikh et al. 2010, Cheung et al. 2011).
NKp44 is a natural cytotoxicity receptor (NCR) family member selectively expressed by IL-2-activated NK cells. It is a transmembrane receptor involved in recognizing unidentified non-MHC ligands on tumor cells, mediating tumor cell lysis by activated NK cells. NKp44 is coupled to cytoplasmic signal transduction machinery via association with DAP12. Lysine-183 in the transmembrane region of NKp44 may be involved in the association with DAP12. The interaction with DAP12 influences NKp44 surface expression and hence NK cell activation (Campbell et al. 2004, Cantoni et al. 1999, Vitale et al. 1998).
SIRP beta (SIRPB, CD172b) is expressed mainly on myeloid cells and has a very short cytoplasmic region of only six amino acids, lacking the signaling motifs required for association with phosphatases that are found in SIRPA. Instead, SIRPB associates with a dimeric protein TYROBP (DAP12) to transmit activating signals via its ITAM motif. A positively charged amino acid in the transmembrane domain of TYROBP associates with a basic amino acid in the transmembrane region of SIRPB.
Phosphorylated ITAM on DAP12 serves as the docking site for the two SH2 domains of SYK or ZAP70. Binding leads to SYK activation (Lanier et al. 1998, McVicar et al. 1998).
TREM proteins (triggering receptors expressed on myeloid cells) are a family of cell surface receptors involved in innate immune responses. They are expressed in myeloid cells and have both positive and negative functions in regulating myeloid cell activation and differentiation. Humans have two members, TREM1 and TREM2. TREM1 is considered an amplifier of the immune response, while TREM2 is believed to be a negative regulator of inflammatory responses (Sharif & Knaap 2008). TREM proteins consist of a single extracellular V-type Ig-like domain, a transmembrane region and a short cytoplasmic tail lacking any signalling motifs (Kelker et al. 2004). Both receptors associate with DAP12 for signalling. The ligand for TREM1 is unknown. TREM1 associates with DAP12 dimer. This interaction is mediated by aspartic acid and adjacent threonine residues in the DAP12 dimer that interface with lysine residues in the TREM1 transmembrane region. TREM1 engagement triggers the production of inflammatory chemokines and cytokines such as IL-8 and myeloperoxidase (MPO) in neutrophils and IL-8, MCP-1, and TNF in monocytes (Tessarz & Cerwenka 2008, Bouchon et al. 2000).
NKG2D is a member of the NKG2 family of C-type lectin-like surface receptors. It is a homodimeric activating receptor expressed on natural killer (NK) cells, gamma/delta T-cells and CD8+ alpha/beta T-cells. NKG2D can mediate NK activation and cytotoxicity. NKG2D interacts with the stress-induced class I like molecules MICA, MICB and ULBPs expressed on target cells. Interaction of NKG2D and NKG2D ligands leads to NK cell activation (Cosman et al. 2001, Steinle et al. 2001, Long. 2002). In mice there are two alternatively spliced isoforms of NKG2D, designated NKG2D-S and NKG2D-L. DAP12 interacts with NKG2D-S, but not NKG2D-L, whereas the DAP10 adapter associates with both NKG2D-S and NKG2D-L (Gilfillan et al. 2002, Diefenbach et al. 2002). Humans only express an NKG2D-L isoform and exclusively associate with DAP10, and not DAP12 A Structural basis for the association of DAP12 with mouse, but not human, NKG2D (Rosen et al. 2004).
Killer cell immunoglobulin-like three-domain short-tail receptor 1 (KIR3DS1) is a member of the KIR family expressed on peripheral natural killer (NK) cells and implicated in protection against HIV (Carr et al. 2007, Pascal et al. 2007). The physiological ligand for KIR3DS1 is not clearly determined but it has been suggested to bind HLA-B Bw4-80I on HIV-1-infected target cells (Qi et al. 2006). KIR3DS1 associates with DAP12 and this association enhances its cell surface expression. Crosslinking KIR3DS1 with a monoclonal antibody stimulates NK cell-mediated cytolysis and IFN-gamma production (Carr et al. 2007).
TREM2 (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).
Killer cell immunoglobulin-like two-domain short-tail receptor 2 (KIR2DS2) is an activating KIR receptor invariably expressed on the cell surface of NK cells and subsets of T cells. The ligand specificity of KIR2DS2 is unknown; it does not bind the HLA-Cw3 molecules recognised by the inhibitory receptor KIR2DL2, despite 99% extracellular amino acid identity (Saulquin et al. 2003). In the presence of DAP12, cross-linking of KIR2DS2 with monoclonal antibody leads to phosphorylation of JNK and ERK and activation of both cytotoxicity and IFN-production.
DAP12 is expressed as a disulfide-bonded homodimer on NK cells, myeloid cells and a subset of T cells. Cystine-7 in the extracellular domain is involved in the interchain disulphide bond (numbering according to Lanier et al. 1998).
SIGLECs are sialic acid-recognizing receptors of the immunoglobulin (Ig) superfamily expressed on immune cells. SEGLEC14 and SEGLEC15 preferentially recognise ligands containing the glycans N-acetylneuraminic acid (Neu5Ac). SEGLEC14, SEGLEC15 and SEGLEC16 are expressed by myeloid cells and associate with the activating adapter protein DAP12 via the arginine residue in their transmembrane domains (Angata et al. 2006, Angata et al. 2007, Cao et al. 2008).
NKG2C, a C-type lectin-like surface receptor, is a member of the NKG2 family and forms heterodimers with CD94 that is expressed on NK cells and a subset of T cells. The CD94/NKG2C killer lectin-like receptor (KLR) perform an important role in immunosurveillance by binding to HLA-E complexes that present peptides derived from the signal sequences of other HLA class I molecules (A, B, C, G), thereby monitoring MHC class I expression. It has been proposed that the activating receptor CD94/NKG2C may contribute with other NK stimulatory molecules (like NKp46, NKp44 and NKp30 and NKG2D) to trigger effector functions when the control exerted by inhibitory receptors is overcome (Guma et al. 2005). NKG2C/CD94 associates with the ITAM-containing adapter protein DAP12 and this leads to cell activation and cytotoxic function. The charged residues in the transmembrane domains of DAP12 and NKG2C are necessary for this interaction (Lanier et al. 1998). NK cells expressing the CD94/NKG2C receptor are preferentially expanded during cytomegalovirus infection in humans (Lopez-Verges et al. 2011)
Killer cell immunoglobulin-like two-domain short-tail receptor 5 (KIR2DS5) is an activating KIR receptor expressed on natural killer (NK) cells and subpopulations of T lymphocytes (Nowak et al. 2010). KIR2DS5 has two Ig domains of the D1-D2 type, a short cytoplasmic tail and a positive charged transmembrane (TM) portion. No physiological ligand has yet been identified for KIR2DS5 but it is able to associate with DAP12 and induce both cytotoxicity and cytokine release when KIR2DS5 is cross-linked with monoclonal antibody (Della Chiesa et al. 2008).
Killer cell immunoglobulin-like two-domain short-tail receptor 4 (KIR2DS4) is the most prevalent lineage III-activating KIR receptor. It interacts weakly but specifically with HLA-Cw3 and HLA-Cw4 and may also bind to an uncharacterised non-MHC molecule. It can associate with DAP12, activating NK cells.
Killer cell immunoglobulin-like two-domain short-tail receptor 1 (KIR2DS1) is one of the activating KIR receptors expressed on the surface of NK cells. It recognizes and binds to ligand HLA-C2:peptide complexes. KIR2DS1 oligomerizes upon interaction with its HLA-Class I ligands. The interaction between the peptide-HLA and KIR2DS1 oligomers leads to activation of the DAP12 signaling cascade. The engagement of KIR2DS1 with HLA-C2 is not sufficient to drive NK cell cytotoxicity or IFN-gamma production (Stewart et al. 2005). Recognition of HLA-C2 by KIR2DS1 is involved in the anti-leukemic activity of alloreactive NK cells and associated with protection against Hodgkin's lymphoma (Cognet et al. 2010). The presence of the HLA-C2 allele HLA-Cw6 in combination with KIR2DS1 is a major risk factor for psoriasis (Ploski et al. 2006).
The binding of SYK to DAP12 induces conformational changes that result in SYK activation. Around ten autophosporylated tyrosine residues have been identified in SYK, regulating activity and serving as docking sites for other proteins. Sites include Y131 of interdomain A, Y323, Y348, and Y352 of interdomain B, Y525 and Y526 within the activation loop of the kinase domain and Y630 in the C-terminus (Zhang et al. 2002, Lupher et al. 1998, Furlong et al. 1997).
SYK is phosphorylated by Src family kinases and this acts as an initiating trigger by generating a few molecules of activated SYK, which then initiate SYK autophosphorylation (Hillal et al. 1997, Castro et al. 2010)
Crosslinking of receptors associated with DAP12 leads to phosphorylation of tyrosine residues in their cytoplasmic ITAM by SRC family kinases (Turnbull & Colonna 2007). This initiates downstream signaling. FYN and LCK have both been found physically and functionally associated with receptors using DAP12 signaling and have been demonstrated to be involved in DAP12 phosphorylation (Mason et al. 2006).
LAT is palmitoylated and membrane-associated adaptor protein. It rapidly becomes tyrosine-phosphorylated upon receptor engagement. LAT has nine conserved tyrosine residues of which five have been shown to undergo phosphorylation (Y127, Y132, Y171, Y191 and Y226). Src family kinases, SYK and ZAP-70 efficiently phosphorylate LAT on these tyrosine residues (Jiang & Cheng 2007, Paz et al. 2001). Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domain proteins PLC-gamma1, GRB2 and GADS, which indirectly bind SOS, VAV, SLP-76 and ITK (Wange 2000).
Gads/GRAP2 (GRB2-related adapter protein 2) is member of the GRB2 adaptor family with a central SH2 domain and linker region flanked by amino- and carboxy-terminal SH3 domains. SLP-76 associates constitutively via its central 20-amino acid proline-rich domain with the C-terminal SH3 domain of Gads, which recruits it to LAT following receptor stimulation. Upon LAT phosphorylation, Gads:SLP-76 complex principally binds to phosphorylated LAT tyrosine 191, with a reduced amount of binding to phosphorylated tyrosine 171 and no interaction with phosphorylated tyrosines 132 or 226 (Houtman et al. 2004, Zhu et al. 2003). Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways (Liu et al. 1999). The LAT-Gads-SLP-76 complex creates a platform for the recruitment of multiple signaling molecules, including PLCgamma1, GRB2, NCK, Rho GEFs, VAV and the Tec-family kinases ITK and BTK (Liu et al. 1999 & 2001, Asada et al. 1999, Yablonski et al. 2001).
SLP-76 lacks intrinsic catalytic activity and acts as a scaffold, recruiting other proteins for correct localization during molecular signal transduction (Bogin et al. 2007). Activation of DAP12-associated receptors leads to tyrosine phosphorylation of SLP-76 (Gross et al. 1999). SLP-76 has three potential tyrosine phosphorylation sites within its amino terminus region: Y113, Y128, and Y145. Phosphorylation may be mediated by SYK, analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996).
GRB2 is an adapter protein that contains a central SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). Following phosphorylation of LAT, the GRB2:SOS complex binds to the phosphorylated tyrosines and is thereby translocated to the inner face of the plasma membrane where inactive RAS:GDP resides. The three distal tyrosines, Y171, Y191 and Y226 of LAT are responsible for GRB2 association (Balagopalan et al. 2010, Zhang et al. 2000).
The phospholipase PLC-gamma is an important mediator of TCR, FCERI and DAP12 signal transduction. PLC-gamma hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) and in-turn promotes the Ca+2 influx and activation of NFAT. Activation of PLC-gamma1 entails the binding of PLC-gamma1 to both LAT and SLP-76 adapter proteins. The amino-terminal SH2 domain of PLC-gamma1 was shown to preferentially bind phosphorylated LAT Y132 with high affinity and no detectable binding to phosphorylated tyrosines 171, 191, and 226. PLC-gamma1 was also shown to bind the adapter protein SLP-76 indirectly through GADS, which is bound to LAT at Y171 and Y191. SH3 domain of PLC-gamma1 associates with the proline-rich region of SLP-76 (Yablonski et al. 2001). PLC-gamma1 associates with Gads/SLP-76 complex before binding to p-Y132 of LAT (Houtman et al. 2005). PLC-gamma1 association with LAT is stabilized by Gads/SLP-76 bound to LAT (Zhu et al.2003). Association of PLC-gamma to LAT and SLP-76 couples it to the kinases (Syk and Tec family kinase) required for tyrosine phosphorylation and activation of PLC-gamma. Mast cells express both PLC-gamma1 and PLC-gamma2 isoforms, which are phosphorylated by BTK/ITK and/or SYK. FCERI-dependent Ca2+ release requires the recruitment of PLC-gamma by SLP-76 and LAT. In mast cells, increased intracellular calcium triggers rapid release of preformed mediators, through a process of vesicle exocytosis, known as degranulation. Recruitment and activation of phospholipase C gamma (PLC-gamma) is involved in DAP12 signal transduction. Phosphorylation of multiple substrates including PLC-gamma1 has been observed in Ly49D/DAP12 triggered NK cells (McVicar et al. 1998). In myeloid cells, PLC-gamma2 is recruited and then phosphorylated upon activation of TREM2 and DAP12 (Peng et al. 2010).
GRB2-bound SOS promotes the formation of active GTP-bound RAS. This activates the mitogen-activated protein kinase (MAPK) cascade, leading to cell growth and differentiation.
Activated PI3K phosphorylates phosphatidylinositol (PI) 4-phosphate and PI 4,5-bisphosphate (PIP2) to generate PI 3,4-bisphosphate and PI 3,4,5-triphosphate (PIP3) and these second messengers recruit other signaling proteins containing plecstrin homology (PH) domain. Products of PI3K are involved in the regulation of PLC-gamma 1 and VAV activation. The PH domain of PLC-gamma 1 binds to PIP3 and is targeted to the membrane. PIP3 binds to the PH domain of VAV2/VAV3 and increases it activity and PI3K may also strongly stimulate VAV activity by converting an inhibitory regulator VAV to an activator (Toker & Cantley 1997, Fischer et al. 1998, Falasca et al. 1998).
VAV2 and VAV3 are expressed in human NK cells and play a central role in NK cell-mediated cytotoxicity. They are required for DAP12-mediated signaling; their loss profoundly impairs DAP12-induced cytotoxicity (Billadeau et al. 2000, Cella et al. 2004). Phosphorylated SLP-76 tyrosines Y113 and Y128 provide binding sites for the SH2 domains of VAV. The binding of VAV to these phosphotyrosine residues may link SLP-76 to the Jun amino-terminal kinase (JNK) pathway and the actin cytoskeleton. Y145 has been implicated in the binding of SLP-76 to the Tec family kinase BTK (Kettner et al. 2003). BTK is required for secretion of pro-inflammatory cytokines, phosphorylation of ERK1/2 and PLCgamma and Ca2+ mobilization (Ormsby et al. 2011).
Phosphoinositide 3-kinases (PI3Ks) are one of the downstream effectors of activated SYK. The p85 alpha regulatory subunit of PI3K has been shown to interact with SYK phospho-tyrosine Y323. In DAP12 signaling SYK acts via the PI3K-dependent pathway to control NK cell-mediated cytotoxicity. SYK-coupled PI3K is rapidly activated and triggers a sequential activation of VAV2/VA3, RAC1, PAK1, MEK and ERK to mediate NK cell-mediated lysis (Jiang et al. 2002, Moon et al. 2005).
In myeloid cells BTK is phosphorylated on Y551 upon DAP12 activation in a SYK kinase-dependent manner. Y551 is located in the activation loop of BTK, known to be required for activation and kinase activity. Y223 in the SH3 domain of BTK is autophosphorylated, which may also be involved in BTK activation (Ormsby et al. 2010, Rawlings et al. 1996).
Activated PLC-gamma1 disassociates from LAT. Membrane binding is crucial for PLC-gamma 1 activity. The PH-domain of PLC-gamma 1 binds to phosphatidylinositol 3,4,5-trisphosphate [PdtIns(3,4,5)P3], and is targeted to the membrane (Todderud et al. 1990, Wang & Wang. 2003, Kim et al. 2000). Activated PLCG1 then hydrolyses PIP2 to Inositol 1,4,5-triphosphate (IP3) and DAG
VAV exists in an auto-inhibitory state, folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the calponin homology (CH) domain to the C1 region. Activation of VAV may involve three events which relieve this auto-inhibition: phosphorylation of tyrosines in the acidic domain causes them to be displaced from the DH domain; binding of a ligand to the CH domain may cause it to release the C1 domain; binding of the PI3K product PIP3 to the PH domain may alter its conformation (Aghazadeh et al. 2000). VAV2/3 are phosphorylated on Y172/Y173 respectively in the acidic domain. This is mediated by SYK and Src-family tyrosine kinases (Deckert et al. 1996, Schuebel et al. 1998). Once activated, VAV2/VAV3 are involved in the activation of RAC1, PAK1, MEK and ERK.
Three tyrosine residues at positions 771, 783 and 1254 in PLCgamma1 have been identified as the sites of receptor tyrosine kinase phosphorylation. Of these Y783 and Y1254 are required for PLC-gamma1 activation. In myeloid cells phosphorylation of the tyrosine residues of PLC-gamma1 is mediated by SYK and BTK kinases (Ormsby et al. 2010, Kim et al. 1994, Law et al. 1996, Watanabe et al. 2001).
CLM7/TREM5 is a member of the CMRF-35/immune receptor expressed by myeloid cell (IREM) multigene family of immune receptors expressed on myeloid cells. It has a basic residue in its transmembrane domain and a functional tyrosine-based motif in its short cytoplasmic tail. This structural arrangement confers CLM7 the ability to signal through two independent pathways: one through associating with activating adaptor protein DAP12 and the other through the tyrosine motif in its cytoplasmic tail (Martinez-Barriocanal & Sayos 2006).
Immune receptor expressed by myeloid cells 2 (IREM-2), is a member of the Ig-superfamily expressed on myeloid cells. The extracellular region contains a single Ig variable and a positively charged amino acid lysine in its transmembrane region followed by a short cytoplasmic tail. IREM-2 associates with activating adaptor DAP12, through the transmembrane basic amino acid residue. This association induces NFAT transcriptional activity (Aguilar et al. 2004).
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
receptors:DAP12
dimeroligomer:HLA-C
(Cw4)The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
Annotated Interactions
receptors:DAP12
dimeroligomer:HLA-C
(Cw4)The ligand for TREM1 is unknown. TREM1 associates with DAP12 dimer. This interaction is mediated by aspartic acid and adjacent threonine residues in the DAP12 dimer that interface with lysine residues in the TREM1 transmembrane region. TREM1 engagement triggers the production of inflammatory chemokines and cytokines such as IL-8 and myeloperoxidase (MPO) in neutrophils and IL-8, MCP-1, and TNF in monocytes (Tessarz & Cerwenka 2008, Bouchon et al. 2000).
No physiological ligand has yet been identified for KIR2DS5 but it is able to associate with DAP12 and induce both cytotoxicity and cytokine release when KIR2DS5 is cross-linked with monoclonal antibody (Della Chiesa et al. 2008).
SYK is phosphorylated by Src family kinases and this acts as an initiating trigger by generating a few molecules of activated SYK, which then initiate SYK autophosphorylation (Hillal et al. 1997, Castro et al. 2010)
Mast cells express both PLC-gamma1 and PLC-gamma2 isoforms, which are phosphorylated by BTK/ITK and/or SYK. FCERI-dependent Ca2+ release requires the recruitment of PLC-gamma by SLP-76 and LAT. In mast cells, increased intracellular calcium triggers rapid release of preformed mediators, through a process of vesicle exocytosis, known as degranulation.
Recruitment and activation of phospholipase C gamma (PLC-gamma) is involved in DAP12 signal transduction. Phosphorylation of multiple substrates including PLC-gamma1 has been observed in Ly49D/DAP12 triggered NK cells (McVicar et al. 1998). In myeloid cells, PLC-gamma2 is recruited and then phosphorylated upon activation of TREM2 and DAP12 (Peng et al. 2010).
In myeloid cells phosphorylation of the tyrosine residues of PLC-gamma1 is mediated by SYK and BTK kinases (Ormsby et al. 2010, Kim et al. 1994, Law et al. 1996, Watanabe et al. 2001).