Dominant Role of the Protein-Tyrosine Phosphatase CD 148 in Regulating Platelet Activation Relative to Protein-Tyrosine Phosphatase-1B

Objective-The receptor-like protein-tyrosine phosphatase (PTP) CD 148 and the nontransmembrane PTP1-B have been shown to be net positive regulators of Src family kinases in platelets. In the present study, we compared the relative contributions of these PTPs in platelet activation by the major glycoprotein, glycoprotein VI, alpha(IIb)beta(3), and C-type lectin-like receptor 2 (CLEC-2). Methods and Results-PTP-1B-deficient mouse platelets responded normally to the glycoprotein VI-specific agonist collagen-related peptide and antibody-mediated CLEC-2 activation. However, they exhibited a marginal reduction in alpha(IIb)beta(3)-mediated Src family kinase activation and tyrosine phosphorylation. In contrast, CD 148-deficient platelets exhibited a dramatic reduction in activation by glycoprotein VI and alpha(IIb)beta(3) and a marginal reduction in response to activation by CLEC-2, which was further enhanced in the absence of PTP-1B. These defects were associated with reduced activation of Src family kinase and spleen tyrosine kinase, suggesting a causal relationship. Under arteriolar flow conditions, there was defective aggregate formation in the absence of PTP-1B and, to a greater extent, CD 148 and a severe abrogation of both adhesion and aggregation in the absence of both PTPs. Conclusion-Findings from this study demonstrate that CD 148 plays a dominant role in activating Src family kinases in platelets relative to PTP-1B. Both PTPs are required for optimal platelet activation and aggregate formation under high arterial shear rates. (Arterioscler Thromb Vasc Biol. 2012;32:2956-2965.)