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Papers In Press, published online ahead of print June 17, 2003
INSERM U311, INSERM U311-EFS-Alsace, Strasbourg 67065
Corresponding Author: francois.lanza{at}efs-alsace.fr
Interaction of the platelet GPIb-V-IX complex with surface immobilized von Willebrand factor (vWf) is required for the capture of circulating platelets and their ensuing activation. In previous work, it was found that GPIb/vWf mediated platelet adhesion triggers Ca2+ release from intracellular stores, leading to cytoskeletal reorganization and filopodia extension. Despite the potential functional importance of GPIb-induced cytoskeletal changes, the signaling mechanisms regulating this process have remained ill-defined. The studies presented here demonstrate an important role for phospholipase C (PLC)-dependent phosphoinositide turnover for GPIb-dependent cytoskeletal remodelling. This is supported by the findings that the vWF-GPIb interaction induced a small increase in inositol 1,4,5 triphosphate (IP3) and that treating platelets with the IP3 receptor antagonist APB-2 or the PLC inhibitor U73122 blocked cytosolic Ca2+ flux and platelet shape change. Normal shape change was observed in Galphaq -/- mouse platelets, excluding a role for PLCbeta isoforms in this process. However, decreased shape change and Ca2+ mobilization were observed in mice lacking PLCgamma2, demonstrating that this isotype played an important, albeit incomplete role, in GPIb signaling. The signaling pathways utilized by GPIb involved one or more members of the Src kinase family as platelet shape change and Ca2+ flux were inhibited by the Src kinase inhibitors PP1 and PP2. Strikingly, shape change and Ca2+ release occurred independently of immunoreceptor tyrosine-based activation motif (ITAM) containing receptors, as these platelet responses were normal in human platelets treated with the anti-FcgammaRIIA blocking monoclonal antibody IV.3 and in mouse platelets deficient in the FcR gamma-chain. Taken together, these studies define an important role for PLCgamma2 in GPIb signaling linked to platelet shape change. Moreover, they demonstrate that GPIb-dependent calcium flux and cytoskeletal reorganization involves a signaling pathway distinct from that utilized by ITAM containing receptors.
J. Biol. Chem, 10.1074/jbc.M302333200
Submitted on March 6, 2003
Revised on June 17, 2003
Accepted on June 17, 2003
Signaling role for PLC
2 in platelet glycoprotein Ib
calcium flux and cytoskeletal reorganization involvement of a pathway distinct from FcR -chain and cRIIA
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