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J. Biol. Chem., Vol. 281, Issue 40, 30024-30035, October 6, 2006

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Essential Role of Protein Kinase C in Platelet Signaling, _IIb3 Activation, and Thromboxane A₂ Release^*

From the Research Center, Montreal Heart Institute and University of Montreal, Montreal, Quebec H1T 1C8, Canada

The protein kinase C (PKC) family is an essential signaling mediator in platelet activation and aggregation. However, the relative importance of the major platelet PKC isoforms and their downstream effectors in platelet signaling and function remain unclear. Using isolated human platelets, we report that PKC, but not PKC or PKC, is required for collagen-induced phospholipase C-dependent signaling, activation of _IIb3, and platelet aggregation. Analysis of PKC phosphorylation and translocation to the membrane following activation by both collagen and thrombin indicates that it is positively regulated by _IIb3 outside-in signaling. Moreover, PKC triggers activation of the mitogen-activated protein kinase-kinase (MEK)/extracellular-signal regulated kinase (ERK) and the p38 MAPK signaling. This leads to the subsequent release of thromboxane A₂, which is essential for collagen-induced but not thrombin-induced platelet activation and aggregation. This study adds new insight to the role of PKCs in platelet function, where PKC signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A₂.

Received for publication, May 10, 2006 , and in revised form, July 28, 2006.

^* This work was supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. 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 To whom correspondence should be addressed: Laboratory of Experimental Pathology, Research Center, Montreal Heart Institute, 5000 Belanger St., Montreal, PQ H1T 1C8, Canada. Tel.: 514-376-3330 (ext. 3035); Fax: 514-376-1355; E-mail: yahye.merhi{at}icm-mhi.org.

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