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 (FcgammaRIIa) triggers intracellular 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 engagement. An association of Cbl with the p85 subunit of phosphatidylinositol 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 wortmannin led to the blockade of both platelet aggregation and serotonin release mediated by FcgammaRIIa engagement, 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 FcgammaRIIa engagement. Our results suggest that Cbl is involved in platelet signal transduction by the recruitment of PI 3-K to the FcgammaRIIa pathway, possibly by increasing PI 3-K activity.
Saci
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INSERM U428, Faculté de Pharmacie, Université Paris-V, 75270 Paris, France.
Pain
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Rendu
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Bachelot-Loza
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D004789:Enzyme Activation; D006801:Humans; D066298:In Vitro Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015539:Platelet Activation / Q000502:physiology*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D011961:Receptors, Fc / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D011518:Proto-Oncogene Proteins; D011961:Receptors, Fc; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; C067419:CBL protein, human