Collagen stimulates platelet activation through a tyrosine kinase-based pathway downstream of the glycoprotein VI (GPVI)-Fc receptor (FcR) gamma-chain complex. Genetic ablation of FcR gamma-chain results in a complete inhibition of aggregation to collagen. In contrast, a steady increase in light transmission is induced by collagen in phospholipase Cgamma2-deficient (PLCgamma2(-/-)) platelets in a Born aggregometer, indicating a weak level of activation. This increase is inhibited partially in the presence of an alpha(2)beta(1)-blocking antibody or an alpha(IIb)beta(3) antagonist and completely by a combination of the 2 inhibitors. It is also abolished by the Src kinase inhibit or PIP1 and reduced in the presence of the phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. The GPVI-specific agonists convulxin and collagen-related peptide (PRIP) also stimulate weak aggregation in PLCgamma2(-/-) platelets, which is inhibited by wortmannin and PPI. Collagen and CRP stimulate tyrosine phosphorylation of PLCgamma1 at its regulatory site, Tyr 783, in murine but not in human platelets through a Src kinase-dependent pathway. Adhesion of PLCgamma2(-/-) platelets to a collagen monolayer is severely reduced at a shear rate of 800 s(-1), relative to controls, whereas it is abolished in FcR gamma-chain(-/-) platelets. These results provide strong evidence that engagement of GPVI stimulates limited integrin activation in PLCgamma2(-/-) platelets via PLCgamma1 and PI3-kinase. (C) 2003 by The American Society of Hematology.