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Stphane Bodin, Ccile Viala, Ashraf Ragab, Bernard Payrastre
A critical role of lipid rafts in the organization of a key FcRIIa-mediated signaling pathway in human platelets
The involvement of platelet FcRIIa in heparin-associated thrombocytopenia (HIT) is now well established. However, the precise sequence of molecular events initiated by FcRIIa cross-linking in platelets remains partly characterized. We investigated here the role of lipid rafts in the spatio-temporal organization of the FcRIIa-dependent signaling events. Upon cross-linking, FcRIIa relocated in rafts where the kinase Lyn and the adapter LAT were among the major phosphotyrosyl proteins. Upon stimulation by HIT sera, the second messenger phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulated in rafts in a P2Y12 adenosine diphosphate (ADP) receptor-dependent manner. PtdIns(3,4,5)P3 was then essential to specifically recruit phospholipase C2 (PLC2) to these membrane microdomains. Controlled disruption of rafts by methyl -cyclodextrin reversibly abolished PtdIns(3,4,5)P3 production, PLC activation and platelet responses induced by FcRIIa cross-linking without affecting the tyrosine phosphorylation events. This work demonstrates that platelet rafts are essential for the integration of a key signaling complex leading to the rapid production of PtdIns(3,4,5)P3 and in turn PLC2 activation during HIT.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 89
Pages: 318 - 330