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J. Biol. Chem., Vol. 282, Issue 8, 5478-5487, February 23, 2007

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Protease-activating Receptor-4 Induces Full Platelet Spreading on a Fibrinogen Matrix

INVOLVEMENT OF ERK2 AND p38 AND Ca²⁺ MOBILIZATION^*

Alexandra Mazharian¹, Séverine Roger¹, Eliane Berrou, Frédéric Adam², Alexandre Kauskot, Paquita Nurden, Martine Jandrot-Perrus^¶, and Marijke Bryckaert³

From the U689 INSERM, IFR139, Hôpital Lariboisière, 8 rue Guy Patin, 75010 Paris, France, ^¶U698 INSERM, Hôpital Bichat, 75018 Paris, France, and IFR4, Laboratoire d'Hématologie, Hôpital Cardiologique, 33604 Pessac, France

Although the involvement of protease-activating receptor PAR1 and PAR4 is well established in platelet aggregation, their role in platelet adhesion and spreading has yet to be characterized. We investigated platelet adhesion and spreading on a fibrinogen matrix after PAR1 and PAR4 stimulation in correlation with the activation of two MAPKs, ERK2 and p38. Of the two PAR-activating peptides (PAR-APs), PAR1-AP and PAR4-AP, which both induce adhesion, only PAR4-AP induced full platelet spreading. Although both PAR1-AP and PAR4-AP induced ADP secretion, which is required for platelet spreading, only PAR4-AP induced sustained Ca²⁺ mobilization. In these conditions of PAR4 induction, ERK2 and p38 activation were involved in platelet spreading but not in platelet adhesion. p38 phosphorylation was dependent on ADP signaling through P2Y12, its receptor. ERK2 phosphorylation was triggered through integrin IIb3 outside-in signaling and was dependent on the Rho pathway. ERK2 and p38 activation induced phosphorylation of the myosin light chain and actin polymerization, respectively, necessary for cytoskeleton reorganization. These findings provide the first evidence that thrombin requires PAR4 for the full spreading response. ERK2 and p38 and sustained Ca²⁺ mobilization, involved in PAR4-induced platelet spreading, contribute to the stabilization of platelet thrombi at sites of high thrombin production.

Received for publication, October 20, 2006 , and in revised form, December 21, 2006.

^* This work was supported by the Simone and Cino del Duca Foundation and the Agence Nationale de la Recherche and by a Fondation pour la Recherche Médicale fellowship (to A. M.). 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.

¹ Both authors contributed equally to this work.

² Postdoctoral fellow of the Agence Nationale de la Recherche.

³ To whom correspondence should be addressed. Tel.: 33-1-5321-6781; Fax: 33-1-5321-6739; E-mail: marijke.bryckaert{at}larib.inserm.fr.

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