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J. Biol. Chem., Vol. 282, Issue 44, 31990-31999, November 2, 2007

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Involvement of the Mitogen-activated Protein Kinase c-Jun NH₂-terminal Kinase 1 in Thrombus Formation^*

Alexandre Kauskot¹², Frédéric Adam²³, Alexandra Mazharian, Nadine Ajzenberg^¶||, Eliane Berrou, Arnaud Bonnefoy^**, Jean-Philippe Rosa, Marc F. Hoylaerts, and Marijke Bryckaert⁴

From the Centre de Recherche Cardiovasculaire INSERM Lariboisière, U689-E4, Hôpital Lariboisière, 8 rue Guy Patin, 75010 Paris, France, ^¶U698 INSERM, Hôpital X. Bichat, 75018 Paris, France, ^**U743 INSERM, Montréal, Quebec H2X 1P1, Canada, the Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium, ^||Hématologie et immunologie, Hôpital X. Bichat, AP-HP, 75018 Paris, France, and Université Paris VII Denis Diderot, 75013 Paris, France

The involvement of the mitogen-activated protein kinase c-Jun NH₂-terminal kinase-1 (JNK1) has never been investigated in hemostasis and thrombosis. Using two JNK inhibitors (SP600125 and 6o), we have demonstrated that JNK1 is involved in collagen-induced platelet aggregation dependent on ADP. In these conditions, JNK1 activation requires the coordinated signaling pathways of collagen receptors (21 and glycoprotein (GP)VI) and ADP. In contrast, JNK1 is not required for platelet adhesion on a collagen matrix in static or blood flow conditions (300–1500 s^–1) involving collagen receptors (21 and GPVI). Importantly, at 1500 s^–1, JNK1 acts on thrombus formation on a collagen matrix dependent on GPIb-von Willebrand factor (vWF) interaction but not ADP receptor activation. This is confirmed by the involvement of JNK1 in shear-induced platelet aggregation at 4000 s^–1. We also provide evidence during rolling and adhesion of platelets to vWF that platelet GPIb-vWF interaction triggers IIb3 activation in a JNK1-dependent manner. This was confirmed with a Glanzmann thrombastenic patient lacking IIb3. Finally, in vivo, JNK1 is involved in arterial but not in venular thrombosis in mice. Overall, our in vitro studies define a new role of JNK1 in thrombus formation in flowing blood that is relevant to thrombus development in vivo.

Received for publication, February 23, 2007 , and in revised form, September 4, 2007.

^* This work was supported by l'Institut National de la Santé et de la Recherche Médicale (INSERM) and l'Agence Nationale de la Recherche (ANR). 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 Recipient of a Ph. D. fellowship from the Ministère de l'Enseignement et de la Recherche.

² These authors contributed equally to this work.

³ Frédéric Adam was supported by Agence Nationale de la Recherche (ANR).

⁴ To whom correspondence should be addressed: Hôpital Lariboisière, U689-E4 INSERM, 8 rue Guy Patin, 75010 Paris, France. Tel.: 33-1-53-21-67-81; Fax: 33-1-53-21-67-39; E-mail: marijke.bryckaert{at}larib.inserm.fr.

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