Phosphorylation of SLP-76 by p-SYK Recruitment of VAV and BTK to p-SLP-76 Phosphorylation of BTK by p-SYK Phosphorylation of PLCgamma1 by p-BTK/p-SYK Release of p-PLCG1 Phosphorylation of LAT by p-SYK PLCgamma binds to p-5Y-LAT Recruitment of GADS:SLP-76 to p-5Y-LAT Recruitment of GRB2:SOS to p-5Y-LAT SOS mediated nucleotide exchange of RAS (SHC) p85 regulatory unit of PI3K binds p-6Y-SYK PI3K phosphorylates PIP2 to PIP3 Recruitment of SYK to p-DAP12 Phosphorylation of SYK Phosphorylation of DAP12 Activation of RAC1 by VAV2/3 Phosphorylation and activation of VAV2/VAV3 by SYK PathwayStep7022 PathwayStep7023 PathwayStep7024 PathwayStep7025 PathwayStep7026 PathwayStep7027 PathwayStep7028 PathwayStep7029 PathwayStep7035 PathwayStep7036 PathwayStep7033 PathwayStep7034 PathwayStep7037 PathwayStep7038 PathwayStep7031 PathwayStep7032 PathwayStep7030 DAG and IP3 signaling RAF/MAP kinase cascade PIP3 activates AKT signaling DAP12 signaling Authored: Garapati, P V, 2012-05-25 Edited: Garapati, P V, 2012-05-25 In response to receptor ligation, the tyrosine residues in DAP12's immunoreceptor tyrosine-based activation motif (ITAM) are phosphorylated by Src family kinases. These phosphotyrosines form the docking site for the protein tyrosine kinase SYK in myeloid cells and SYK and ZAP70 in NK cells. DAP12-bound SYK autophosphorylates and phosphorylates the scaffolding molecule LAT, recruiting the proximal signaling molecules phosphatidylinositol-3-OH kinase (PI3K), phospholipase-C gamma (PLC-gamma), GADS (GRB2-related adapter downstream of SHC), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), GRB2:SOS (Growth factor receptor-bound protein 2:Son of sevenless homolog 1) and VAV. All of these intermediate signalling molecules result in the recruitment and activation of kinases AKT, CBL (Casitas B-lineage lymphoma) and ERK (extracellular signal-regulated kinase), and rearrangement of the actin cytoskeleton (actin polymerization) finally leading to cellular activation. PLC-gamma generates the secondary messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsP3), leading to activation of protein kinase C (PKC) and calcium mobilization, respectively (Turnbull & Colonna 2007, Klesney-Tait et al. 2006). Pubmed15884055 Pubmed17110943 Pubmed17220916 Reactome Database ID Release 432424491 Reactome, http://www.reactome.org ReactomeREACT_147814 Reviewed: Lanier, Lewis L, 2012-08-09 PathwayStep3897 PathwayStep3857 PathwayStep3841