Fc receptor-mediated platelet activation is dependent on phosphatidylinositol 3-kinase activation and involves p120(cbl)

The platelet receptor for the Fc domain of IgGs (Fc gamma RIIa) triggers in tracellular signaling through protein tyrosine phosphorylations leading to platelet aggregation. In this study, we focused on the adaptor protein p120 (cbl) (Cbl), which became tyrosine-phosphorylated after platelet activation induced by antibodies. Cbl phosphorylation was dependent on Fc receptor en gagement. An association of Cbl with the p85 subunit of phosphatidylinosito l 3-kinase (PI 3-K) occurred in parallel with Cbl tyrosine phosphorylation. We showed by in vitro experiments that Cbl/p85 association was mediated by the Src homology 3 domain of p85/PI 3-K and the proline-rich region of Cbl . Inhibition of PI 3-K activity by wort-mannin led to the blockade of both platelet aggregation and serotonin release mediated by Fc gamma RIIa engage ment, whereas it only partly inhibited those induced by thrombin. Thus, PI 3-K may play a crucial role in the initiation of platelet responses after F c gamma RIIa engagement. Our results suggest that Cbl is involved in platel et signal transduction by the recruitment of PI 3-K to the Fc gamma RIIa pa thway, possibly by increasing PI 3-K activity.