DAP12 interactions (Homo sapiens)

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36, 46, 47, 61, 6214, 24, 79786740, 737, 5740, 4137, 62, 6610, 18, 684, 27, 5437, 6335, 6932, 47, 55118, 34, 5245, 7458, 703, 2643, 58, 64, 7913, 42, 5162, 72, 7521, 31, 601712, 33385630, 50, 7628, 3923, 473, 222540cytosolB2M(21-119) p-5Y-LAT-2 KLRK1 TREM2 HLA class I histocompatibility antigen, E alpha chain precursor TREM1KLRC2 ATPKIR2DS4 S-Farn-Me PalmS NRAS p-5Y-LAT:PLCG1:GADS:p-3Y-SLP-76:BTK:p-VAVp-4Y-PLCG2 HLA class I histocompatibility antigen, Cw-4 alpha chain precursor SYK KLRC2 PLCG2 CLEC5A S-Farn-Me-PalmS KRAS4A RAC1:GDPp-5Y-LAT-2 VAV3 B2M(21-119) TYROBP TYROBP HLA class I histocompatibility antigen, Cw-3 alpha chain precursor BTKKLRK1 p-Y91,Y102-TYROBP p-Y223,Y551-BTK CD300ETYROBP DAP12:KIR2DS1:HLA-Cw4TREM2 TREM2 p-Y91,Y102-TYROBP SOS1 DAP12 dimer:MDL-1p-Y239,Y240,Y317-SHC1-2 TYROBP GRAP2 ATPp-4Y-PLCG1 KLRK1 p-Y113,128,145-LCP2 GRB2-1 class I MHC B38 NKG2D dimerB2M(21-119) KIR2DS5ADPHLA-CCw4/Cw3:KIR2DS4:DAP12 dimer:KIR2DS4:HLA-C Cw3/Cw4PI(3,4,5)P3 LCK GRB2-1 TYROBP p-Y91,Y102-TYROBP GTP LCP2 TYROBPGRAP2 HLA class I histocompatibility antigen, Cw-3 alpha chain precursor SOS1 ADPp-Y223,Y551-BTK p-5Y-LAT-2 RAC1 KLRK1 PIK3CA SIRPB1:TYROBPHLA class I histocompatibility antigen, E alpha chain precursor p-6Y-SYK TREM2 B2M(21-119) HLA-C1:KIR2DS2:DAP12dimer:KIR2DS2:HLA-C1HLA class I histocompatibility antigen, E alpha chain precursor p-Y173-VAV3 PIK3CA GRB2-1 p-Y113,128,145-LCP2 ATPTYROBP CLEC5APIK3CB p-5Y-LAT:GRB2:SOS:GADS:p-3Y-SLP-76:p-2Y-BTK:VAVTYROBP PI3KHLA class I histocompatibility antigen, E alpha chain precursor DAG and IP3signalingKLRK1 LCK HLA class I histocompatibility antigen, E alpha chain precursor p-5Y-LAT-2 GRAP2 GRB2-1 VAV3 GDP KLRC2 GRB2-1 KLRC2 FYN,LCKTREM2DAP12 dimer:TREM2CLM7:DAP12p-5Y-LAT-2 GADS:SLP76FYN p-Y113,128,145-LCP2 VAV2 ADPFYN TYROBP DAP12receptors:p-Y91,Y102-DAP12 dimerp-5Y-LAT-2 p-5Y-LAT-2p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG:VAV:BTK:PIP3ADPLCK S-Farn-Me PalmS NRAS p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76:PLCGS-Farn-Me-2xPalmS HRAS TREM1 VAV3 DAP12:NKp44p-6Y-SYK GDP GTPGRAP2 VAV3 DAP12receptors:p-DAP12:SYKSIGLEC16 B2M(21-119) p-Y223,Y551-BTK p-Y239,Y240,Y317-SHC1-2 KLRD1 PIP3 activates AKTsignalingKLRC2 LAT-2p-4Y-PLCGB2M(21-119) VAV3 p-Y113,128,145-LCP2 ADPGTP DAP12Receptors:p-DAP12:p-6Y-SYK:PI3KADPSOS1 p21 RAS:GDPPIK3R1 SIGLEC14 KLRK1 CD300LB FYN PLCG1 p-4Y-PLCG2 VAV2 GRB2-1 ATPclass I MHC B38 HLA class I histocompatibility antigen, Cw-3 alpha chain precursor PI(3,4,5)P3 BTK GDPGDPKIR2DS1 oligomer BTK ATPTYROBP KLRD1 PLCG1 NCR2KLRD1 PLCG2 FYN p-Y239,Y240,Y317-SHC1-2 PLCG1 PLCG1 ATPB2M(21-119) TYROBP p-Y113,128,145-LCP2 p-Y172-VAV2 FYN p-5Y-LAT:GRB2:SOS:GADS:p-3Y-SLP-76:p-2Y-BTK:VAV:p-PLCGKIR2DS2 SOS1 GRB2-1 p-5Y-LAT-2 HLA class I histocompatibility antigen, E alpha chain precursor B2M(21-119) DAP12 dimerSIGLEC16 PLCG2 B2M(21-119) LCK SIRPB1KIR2DS5:DAP12dimer:KIR2DS5p-5Y-LAT:p-SHC1:GRB2:SOS1SIGLEC15 HLA-Bw4:KIR3DS1:DAP12 dimer:KIR3DS1:HLA-Bw4PI(3,4,5)P3 p-5Y-LAT-2 CD94:NKG2C:HLA-EGTPPLCG2 p-Y113,128,145-LCP2 PI(3,4,5)P3 GRB2-1 TYROBP p-Y223,Y551-BTK CD300LBKIR2DS1oligomer:HLA-C(Cw4)p-5Y-LAT:GRB2:SOS1:GADS:p-3Y-SLP-76:PLCG:VAV:p-Y223,Y551-BTKLCK VAV2 p-Y239,Y240,Y317-SHC1-2 PLCG2 KIR3DS1 S-Farn-Me KRAS4B SOS1 PIK3R2 PLCG1 S-Farn-Me-2xPalmS HRAS p-Y239,Y240,Y317-SHC1-2 DAP12receptors:DAP12dimerSOS1 p-5Y-LAT-2 TREM2 PLCG1 PI(3,4,5)P3 KLRD1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76GRAP2 KIR2DS4 KIR2DS4:HLA-CCw4/HLA-C Cw3SOS1 B2M(21-119) KLRK1 p-Y239,Y240,Y317-SHC1-2 SOS1 KLRD1 p-Y239,Y240,Y317-SHC1-2 p-Y91,Y102-TYROBP HLA class I histocompatibility antigen, Cw-3 alpha chain precursor SIGLEC14/15/16:DAP12dimerPIK3R2 TYROBP SIGLEC15 p-4Y-PLCG1 PLCG2 PI(3,4,5)P3TYROBP HLA class I histocompatibility antigen, E alpha chain precursor SOS1 B2M(21-119) SYKp-5Y-LAT-2 p-6Y-SYK B2M(21-119) TREM2 KLRD1 SOS1 KIR2DS5 TYROBP KLRK1 VAV2 RAC1:GTPGRAP2 GRAP2 TYROBP NCR2 GRB2-1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCGLCP2 GRB2-1 RAC1 LCK SIRPB1 TREM2 KIR3DS1 LCP2 PLCG1 DAP12Receptors:p-DAP12:p-6Y-SYKSOS1 SIGLEC14/15/16PI(3,4,5)P3p-SHC1:GRB2:SOSB2M(21-119) p-Y91,Y102-TYROBP S-Farn-Me-PalmS KRAS4A HLA class I histocompatibility antigen, Cw-4 alpha chain precursor VAV2 ADPp-Y113,128,145-LCP2 IREM2:DAP12PLCG2 KIR2DS1 oligomer KLRC2 p-Y239,Y240,Y317-SHC1-2 KLRD1 GRAP2 ATPSIGLEC14 HLA class I histocompatibility antigen, Cw-4 alpha chain precursor p-Y239,Y240,Y317-SHC1-2 DAP12:NKG2DKLRC2 S-Farn-Me KRAS4B DAP12 dimer:TREM1PLC gamma1,2VAV2 KIR2DS2 p21 RAS:GTPKIR2DS2:HLA-C1 (Cw3)PI(3,4,5)P3 KIR3DS1:HLA-Bw4PIK3R1 GRAP2 GRAP2 TYROBP PIK3CB HLA class I histocompatibility antigen, E alpha chain precursor p-Y239,Y240,Y317-SHC1-2 ADPKLRC2 HLA class I histocompatibility antigen, Cw-4 alpha chain precursor HLA-E:CD94:NKG2C:DAP12FYN GRB2-1 TYROBP p-SYK/p-BTKCD300E VAV3 PI(4,5)P2p-Y239,Y240,Y317-SHC1-2 VAV2,VAV3B2M(21-119) RAF/MAP kinasecascadeKLRD1 44774477445344444477594477531, 2, 5, 6, 9...


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.


Pathway is converted from Reactome ID: 2172127
Reactome version: 75
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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114756view16:24, 25 January 2021ReactomeTeamReactome version 75
113200view11:26, 2 November 2020ReactomeTeamReactome version 74
112425view15:36, 9 October 2020ReactomeTeamReactome version 73
101329view11:21, 1 November 2018ReactomeTeamreactome version 66
100867view20:54, 31 October 2018ReactomeTeamreactome version 65
100408view19:28, 31 October 2018ReactomeTeamreactome version 64
99956view16:12, 31 October 2018ReactomeTeamreactome version 63
99512view14:45, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94052view13:54, 16 August 2017ReactomeTeamreactome version 61
93680view11:30, 9 August 2017ReactomeTeamreactome version 61
87168view19:21, 18 July 2016MkutmonOntology Term : 'immune response pathway' added !
86804view09:26, 11 July 2016ReactomeTeamreactome version 56
83297view10:40, 18 November 2015ReactomeTeamVersion54
81432view12:57, 21 August 2015ReactomeTeamVersion53
76901view08:17, 17 July 2014ReactomeTeamFixed remaining interactions
76606view11:58, 16 July 2014ReactomeTeamFixed remaining interactions
75937view09:59, 11 June 2014ReactomeTeamRe-fixing comment source
75639view10:52, 10 June 2014ReactomeTeamReactome 48 Update
74994view13:51, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74638view08:41, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
B2M(21-119) ProteinP61769 (Uniprot-TrEMBL)
BTK ProteinQ06187 (Uniprot-TrEMBL)
BTKProteinQ06187 (Uniprot-TrEMBL)
CD300E ProteinQ496F6 (Uniprot-TrEMBL)
CD300EProteinQ496F6 (Uniprot-TrEMBL)
CD300LB ProteinA8K4G0 (Uniprot-TrEMBL)
CD300LBProteinA8K4G0 (Uniprot-TrEMBL)
CD94:NKG2C:HLA-EComplexR-HSA-2326867 (Reactome)
CLEC5A ProteinQ9NY25 (Uniprot-TrEMBL)
CLEC5AProteinQ9NY25 (Uniprot-TrEMBL)
CLM7:DAP12ComplexR-HSA-2426564 (Reactome)
DAG and IP3 signalingPathwayR-HSA-1489509 (Reactome) This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
DAP12 Receptors:p-DAP12:p-6Y-SYK:PI3KComplexR-HSA-2424456 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYKComplexR-HSA-2395411 (Reactome)


ComplexR-HSA-2395430 (Reactome)
DAP12 receptors:p-DAP12:SYKComplexR-HSA-210250 (Reactome)
DAP12 receptors:p-Y91,Y102-DAP12 dimerComplexR-HSA-2395423 (Reactome)
DAP12 dimer:MDL-1ComplexR-HSA-210234 (Reactome)
DAP12 dimer:TREM1ComplexR-HSA-210248 (Reactome)
DAP12 dimer:TREM2ComplexR-HSA-210245 (Reactome)
DAP12 dimerComplexR-HSA-548940 (Reactome)
DAP12:KIR2DS1:HLA-Cw4ComplexR-HSA-2272727 (Reactome)
DAP12:NKG2DComplexR-HSA-210232 (Reactome)
DAP12:NKp44ComplexR-HSA-210241 (Reactome)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYN,LCKComplexR-HSA-2395419 (Reactome)
GADS:SLP76ComplexR-HSA-2424463 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRAP2 ProteinO75791 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HLA class I histocompatibility antigen, Cw-3 alpha chain precursor ProteinP04222 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-4 alpha chain precursor ProteinP30504 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, E alpha chain precursor ProteinP13747 (Uniprot-TrEMBL)
HLA-Bw4:KIR3DS1:DAP12 dimer:KIR3DS1:HLA-Bw4ComplexR-HSA-2272705 (Reactome)
HLA-C Cw4/Cw3:KIR2DS4:DAP12 dimer:KIR2DS4:HLA-C Cw3/Cw4ComplexR-HSA-2272757 (Reactome)
HLA-C1:KIR2DS2:DAP12 dimer:KIR2DS2:HLA-C1ComplexR-HSA-210244 (Reactome)
HLA-E:CD94:NKG2C:DAP12ComplexR-HSA-2326822 (Reactome)
IREM2:DAP12ComplexR-HSA-2426557 (Reactome)


ComplexR-HSA-2272773 (Reactome)
KIR2DS1 oligomer R-HSA-2272704 (Reactome)
KIR2DS2 ProteinP43631 (Uniprot-TrEMBL)
KIR2DS2:HLA-C1 (Cw3)ComplexR-HSA-2272718 (Reactome)
KIR2DS4 ProteinP43632 (Uniprot-TrEMBL)
KIR2DS4:HLA-C Cw4/HLA-C Cw3ComplexR-HSA-2272706 (Reactome)
KIR2DS5 ProteinQ14953 (Uniprot-TrEMBL)
KIR2DS5:DAP12 dimer:KIR2DS5ComplexR-HSA-2272749 (Reactome)
KIR2DS5ProteinQ14953 (Uniprot-TrEMBL)
KIR3DS1 ProteinQ14943 (Uniprot-TrEMBL)
KIR3DS1:HLA-Bw4ComplexR-HSA-2272751 (Reactome)
KLRC2 ProteinP26717 (Uniprot-TrEMBL)
KLRD1 ProteinQ13241 (Uniprot-TrEMBL)
KLRK1 ProteinP26718 (Uniprot-TrEMBL)
LAT-2ProteinO43561-2 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCP2 ProteinQ13094 (Uniprot-TrEMBL)
NCR2 ProteinO95944 (Uniprot-TrEMBL)
NCR2ProteinO95944 (Uniprot-TrEMBL)
NKG2D dimerComplexR-HSA-210233 (Reactome)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3KComplexR-HSA-74693 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) 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.
PLC gamma1,2ComplexR-HSA-1169089 (Reactome)
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG2 ProteinP16885 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-445010 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) 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).
S-Farn-Me KRAS4B ProteinP01116-2 (Uniprot-TrEMBL)
S-Farn-Me PalmS NRAS ProteinP01111 (Uniprot-TrEMBL)
S-Farn-Me-2xPalmS HRAS ProteinP01112 (Uniprot-TrEMBL)
S-Farn-Me-PalmS KRAS4A ProteinP01116-1 (Uniprot-TrEMBL)
SIGLEC14 ProteinQ08ET2 (Uniprot-TrEMBL)
SIGLEC14/15/16:DAP12 dimerComplexR-HSA-2326835 (Reactome)
SIGLEC14/15/16ComplexR-HSA-2326839 (Reactome)
SIGLEC15 ProteinQ6ZMC9 (Uniprot-TrEMBL)
SIGLEC16 ProteinA6NMB1 (Uniprot-TrEMBL)
SIRPB1 ProteinO00241 (Uniprot-TrEMBL)
SIRPB1:TYROBPComplexR-HSA-210222 (Reactome)
SIRPB1ProteinO00241 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SYK ProteinP43405 (Uniprot-TrEMBL)
SYKProteinP43405 (Uniprot-TrEMBL)
TREM1 ProteinQ9NP99 (Uniprot-TrEMBL)
TREM1ProteinQ9NP99 (Uniprot-TrEMBL)
TREM2 ProteinQ9NZC2 (Uniprot-TrEMBL)
TREM2ProteinQ9NZC2 (Uniprot-TrEMBL)
TYROBP ProteinO43914 (Uniprot-TrEMBL)
TYROBPProteinO43914 (Uniprot-TrEMBL)
VAV2 ProteinP52735 (Uniprot-TrEMBL)
VAV2,VAV3ComplexR-HSA-2424458 (Reactome)
VAV3 ProteinQ9UKW4 (Uniprot-TrEMBL)
class I MHC B38 ProteinQ95365 (Uniprot-TrEMBL)
p-4Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-4Y-PLCG2 ProteinP16885 (Uniprot-TrEMBL)
p-4Y-PLCGComplexR-HSA-2685653 (Reactome)
p-5Y-LAT-2 ProteinO43561-2 (Uniprot-TrEMBL)
p-5Y-LAT-2ProteinO43561-2 (Uniprot-TrEMBL)
p-5Y-LAT:GRB2:SOS1:GADS:p-3Y-SLP-76:PLCG:VAV:p-Y223,Y551-BTKComplexR-HSA-2424457 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG:VAV:BTK:PIP3ComplexR-HSA-2424461 (Reactome)
p-5Y-LAT:GRB2:SOS:GADS:p-3Y-SLP-76:p-2Y-BTK:VAV:p-PLCGComplexR-HSA-2424467 (Reactome)
p-5Y-LAT:GRB2:SOS:GADS:p-3Y-SLP-76:p-2Y-BTK:VAVComplexR-HSA-2424459 (Reactome)
p-5Y-LAT:PLCG1:GADS:p-3Y-SLP-76:BTK:p-VAVComplexR-HSA-2424469 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76:PLCGComplexR-HSA-2396571 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76ComplexR-HSA-2424464 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCGComplexR-HSA-2424460 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1ComplexR-HSA-2424468 (Reactome)
p-6Y-SYK ProteinP43405 (Uniprot-TrEMBL)
p-SHC1:GRB2:SOSComplexR-HSA-2685672 (Reactome)
p-SYK/p-BTKComplexR-HSA-2424473 (Reactome)
p-Y113,128,145-LCP2 ProteinQ13094 (Uniprot-TrEMBL)
p-Y172-VAV2 ProteinP52735 (Uniprot-TrEMBL)
p-Y173-VAV3 ProteinQ9UKW4 (Uniprot-TrEMBL)
p-Y223,Y551-BTK ProteinQ06187 (Uniprot-TrEMBL)
p-Y239,Y240,Y317-SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
p-Y91,Y102-TYROBP ProteinO43914 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-2395412 (Reactome)
ADPArrowR-HSA-2395439 (Reactome)
ADPArrowR-HSA-2395801 (Reactome)
ADPArrowR-HSA-2396594 (Reactome)
ADPArrowR-HSA-2424480 (Reactome)
ADPArrowR-HSA-2424484 (Reactome)
ADPArrowR-HSA-2424486 (Reactome)
ADPArrowR-HSA-2424487 (Reactome)
ATPR-HSA-2395412 (Reactome)
ATPR-HSA-2395439 (Reactome)
ATPR-HSA-2395801 (Reactome)
ATPR-HSA-2396594 (Reactome)
ATPR-HSA-2424480 (Reactome)
ATPR-HSA-2424484 (Reactome)
ATPR-HSA-2424486 (Reactome)
ATPR-HSA-2424487 (Reactome)
BTKR-HSA-2424481 (Reactome)
CD300ER-HSA-2426569 (Reactome)
CD300LBR-HSA-2426566 (Reactome)
CD94:NKG2C:HLA-ER-HSA-2172126 (Reactome)
CLEC5AR-HSA-210271 (Reactome)
CLM7:DAP12ArrowR-HSA-2426566 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYK:PI3KArrowR-HSA-2424482 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYK:PI3Kmim-catalysisR-HSA-2424480 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYKArrowR-HSA-2395412 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYKR-HSA-2424482 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYKmim-catalysisR-HSA-2395801 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYKmim-catalysisR-HSA-2396594 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYKmim-catalysisR-HSA-2424484 (Reactome)
DAP12 Receptors:p-DAP12:p-6Y-SYKmim-catalysisR-HSA-2424486 (Reactome)


R-HSA-2395439 (Reactome)
DAP12 receptors:p-DAP12:SYKArrowR-HSA-210289 (Reactome)
DAP12 receptors:p-DAP12:SYKR-HSA-2395412 (Reactome)
DAP12 receptors:p-DAP12:SYKmim-catalysisR-HSA-2395412 (Reactome)
DAP12 receptors:p-Y91,Y102-DAP12 dimerArrowR-HSA-2395439 (Reactome)
DAP12 receptors:p-Y91,Y102-DAP12 dimerR-HSA-210289 (Reactome)
DAP12 dimer:MDL-1ArrowR-HSA-210271 (Reactome)
DAP12 dimer:TREM1ArrowR-HSA-210292 (Reactome)
DAP12 dimer:TREM2ArrowR-HSA-210300 (Reactome)
DAP12 dimerArrowR-HSA-2130151 (Reactome)
DAP12 dimerR-HSA-210271 (Reactome)
DAP12 dimerR-HSA-210273 (Reactome)
DAP12 dimerR-HSA-210292 (Reactome)
DAP12 dimerR-HSA-210295 (Reactome)
DAP12 dimerR-HSA-210298 (Reactome)
DAP12 dimerR-HSA-210300 (Reactome)
DAP12 dimerR-HSA-210309 (Reactome)
DAP12 dimerR-HSA-2172123 (Reactome)
DAP12 dimerR-HSA-2172126 (Reactome)
DAP12 dimerR-HSA-2272668 (Reactome)
DAP12 dimerR-HSA-2272753 (Reactome)
DAP12 dimerR-HSA-2272795 (Reactome)
DAP12 dimerR-HSA-2426566 (Reactome)
DAP12 dimerR-HSA-2426569 (Reactome)
DAP12:KIR2DS1:HLA-Cw4ArrowR-HSA-2272795 (Reactome)
DAP12:NKG2DArrowR-HSA-210295 (Reactome)
DAP12:NKp44ArrowR-HSA-210273 (Reactome)
FYN,LCKR-HSA-2395439 (Reactome)
FYN,LCKmim-catalysisR-HSA-2395439 (Reactome)
GADS:SLP76R-HSA-2396561 (Reactome)
GDPArrowR-HSA-2424476 (Reactome)
GDPArrowR-HSA-2424477 (Reactome)
GTPR-HSA-2424476 (Reactome)
GTPR-HSA-2424477 (Reactome)
HLA-Bw4:KIR3DS1:DAP12 dimer:KIR3DS1:HLA-Bw4ArrowR-HSA-210298 (Reactome)
HLA-C Cw4/Cw3:KIR2DS4:DAP12 dimer:KIR2DS4:HLA-C Cw3/Cw4ArrowR-HSA-2272753 (Reactome)
HLA-C1:KIR2DS2:DAP12 dimer:KIR2DS2:HLA-C1ArrowR-HSA-210309 (Reactome)
HLA-E:CD94:NKG2C:DAP12ArrowR-HSA-2172126 (Reactome)
IREM2:DAP12ArrowR-HSA-2426569 (Reactome)


R-HSA-2272795 (Reactome)
KIR2DS2:HLA-C1 (Cw3)R-HSA-210309 (Reactome)
KIR2DS4:HLA-C Cw4/HLA-C Cw3R-HSA-2272753 (Reactome)
KIR2DS5:DAP12 dimer:KIR2DS5ArrowR-HSA-2272668 (Reactome)
KIR2DS5R-HSA-2272668 (Reactome)
KIR3DS1:HLA-Bw4R-HSA-210298 (Reactome)
LAT-2R-HSA-2395801 (Reactome)
NCR2R-HSA-210273 (Reactome)
NKG2D dimerR-HSA-210295 (Reactome)
PI(3,4,5)P3ArrowR-HSA-2424480 (Reactome)
PI(3,4,5)P3R-HSA-2424481 (Reactome)
PI(4,5)P2R-HSA-2424480 (Reactome)
PI3KR-HSA-2424482 (Reactome)
PLC gamma1,2R-HSA-2396606 (Reactome)
R-HSA-210271 (Reactome) 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).
R-HSA-210273 (Reactome) 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).
R-HSA-210274 (Reactome) 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.
R-HSA-210289 (Reactome) 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).
R-HSA-210292 (Reactome) 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).
R-HSA-210295 (Reactome) 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).
R-HSA-210298 (Reactome) 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).
R-HSA-210300 (Reactome) 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).
R-HSA-210309 (Reactome) 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.
R-HSA-2130151 (Reactome) 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).
R-HSA-2172123 (Reactome) 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).
R-HSA-2172126 (Reactome) 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)
R-HSA-2272668 (Reactome) 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).
R-HSA-2272753 (Reactome) 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.
R-HSA-2272795 (Reactome) 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).
R-HSA-2395412 (Reactome) 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)
R-HSA-2395439 (Reactome) 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).
R-HSA-2395801 (Reactome) 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).
R-HSA-2396561 (Reactome) 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).
R-HSA-2396594 (Reactome) 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).
R-HSA-2396599 (Reactome) 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).
R-HSA-2396606 (Reactome) 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).
R-HSA-2424476 (Reactome) Activated VAV2/3 act as guanine nucleotide exchange factors (GEFs) for RAC-1, catalysing the exchange of bound GDP for GTP.
R-HSA-2424477 (Reactome) 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.
R-HSA-2424480 (Reactome) 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).
R-HSA-2424481 (Reactome) 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).
R-HSA-2424482 (Reactome) 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).
R-HSA-2424484 (Reactome) 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).
R-HSA-2424485 (Reactome) 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
R-HSA-2424486 (Reactome) 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 media