PathwayStep609 PathwayStep608 PathwayStep610 PathwayStep611 PathwayStep612 PathwayStep613 PathwayStep614 PathwayStep615 PathwayStep616 PathwayStep617 PathwayStep619 PathwayStep618 PathwayStep620 PathwayStep628 PathwayStep627 PathwayStep626 PathwayStep625 PathwayStep624 PathwayStep623 PathwayStep622 PathwayStep621 Syk phosphorylates Vav Syk binds Vav VAV2 is a GEF for Rho/Rac family kinases VAV1 is a GEF for Rho/Rac family kinases Syk/Lck phosphorylate LAT VAV3 is a GEF for Rho/Rac family kinases SLP-76 stimulates PLC gamma 2 Syk activation leads to SLP-76 activation PLC gamma 2-mediated PIP2 hydrolysis p-SLP-76 binds VAV GPVI stimulates PI3K beta, gamma PIP2 inhibits Vav PIP3 stimulates Vav PDK1 activates PKC zeta PDK1 binds PKC zeta PIP3 recruits PDK1 and AKT to the membrane PI3K alpha, beta, gamma convert PIP2 to PIP3 Syk is released Syk autophosphorylates Binding of Syk tyrosine kinase Fyn/Lyn-mediated phosphorylation of FcR1 gamma GPVI-mediated activation cascade Edited: Jupe, S, 2009-11-03 Pubmed11943772 Pubmed12649139 Pubmed16102042 Pubmed17127307 Reactome Database ID Release 43114604 Reactome, http://www.reactome.org ReactomeREACT_1695 The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. <br><br>The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76.