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Originally published In Press as doi:10.1074/jbc.M302333200 on June 17, 2003
J. Biol. Chem., Vol. 278, Issue 35, 32880-32891, August 29, 2003
Signaling Role for Phospholipase C 2 in Platelet Glycoprotein Ib Calcium Flux and Cytoskeletal Reorganization
INVOLVEMENT OF A PATHWAY DISTINCT FROM FcR CHAIN AND FcRIIA*
Pierre Mangin   ¶,
Yuping Yuan ||,
Isaac Goncalves ||,
Anita Eckly ,
Monique Freund ,
Jean-Pierre Cazenave ,
Christian Gachet ,
Shaun P. Jackson || and
François Lanza **
From the
INSERM U.311, Etablissement
Français du Sang-Alsace, 10 rue Spielmann, BP 36, 67065 Strasbourg
cedex, France and the ||Department of Medicine,
Australian Centre for Blood Diseases, Monash University, Victoria 3127,
Australia
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 remodeling. 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 G q–/– mouse
platelets, excluding a role for PLC isoforms in this process. However,
decreased shape change and Ca2+ mobilization were
observed in mice lacking PLC2, 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,
because these platelet responses were normal in human platelets treated with
the anti-FcRIIA blocking monoclonal antibody IV.3 and in mouse
platelets deficient in the FcR chain. Taken together, these studies
define an important role for PLC2 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.
Received for publication, March 6, 2003
, and in revised form, June 12, 2003.
* This work was supported in part by a grant from Association de Recherche et
de Développement en Médecine et Santé Publique and from
the Australia National Health & Medical Research Council and National
Heart Foundation. The costs of publication of this article were defrayed in
part by the payment of page charges. This article must therefore be hereby
marked "advertisement" in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
 Both authors contributed equally to this work.
¶ Supported by the Association de Recherche et de Développement en
Médecine et Santé Publique.
**
To whom correspondence should be addressed. Tel.: 33-388-21-25-25; Fax:
33-388-21-25-21; E-mail:
francois.lanza{at}efs-alsace.fr.
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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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