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J. Biol. Chem., Vol. 282, Issue 10, 7046-7055, March 9, 2007

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Dual Role of Platelet Protein Kinase C in Thrombus Formation

STIMULATION OF PRO-AGGREGATORY AND SUPPRESSION OF PROCOAGULANT ACTIVITY IN PLATELETS^*

Amrei Strehl¹, Imke C. A. Munnix, Marijke J. E. Kuijpers, Paola E. J. van der Meijden, Judith M. E. M. Cosemans, Marion A. H. Feijge, Bernhard Nieswandt², and Johan W. M. Heemskerk³

From the Departments of Biochemistry and Human Biology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6200 MD Maastricht, The Netherlands and Rudolf Virchow Centre for Experimental Biomedicine, University of Würzburg, D97078 Würzburg, Germany

Protein kinase C (PKC) isoforms regulate many platelet responses in a still incompletely understood manner. Here we investigated the roles of PKC in the platelet reactions implicated in thrombus formation as follows: secretion aggregate formation and coagulation-stimulating activity, using inhibitors with proven activity in plasma. In human and mouse platelets, PKC regulated aggregation by mediating secretion and contributing to IIb3 activation. Strikingly, PKC suppressed Ca²⁺ signal generation and Ca²⁺-dependent exposure of procoagulant phosphatidylserine. Furthermore, under coagulant conditions, PKC suppressed the thrombin-generating capacity of platelets. In flowing human and mouse blood, PKC contributed to platelet adhesion and controlled secretion-dependent thrombus formation, whereas it down-regulated Ca²⁺ signaling and procoagulant activity. In murine platelets lacking G_q, where secretion reactions were reduced in comparison with wild type mice, PKC still positively regulated platelet aggregation and down-regulated procoagulant activity. We conclude that platelet PKC isoforms have a dual controlling role in thrombus formation as follows: (i) by mediating secretion and integrin activation required for platelet aggregation under flow, and (ii) by suppressing Ca²⁺-dependent phosphatidylserine exposure, and consequently thrombin generation and coagulation. This platelet signaling protein is the first one identified to balance the pro-aggregatory and procoagulant functions of thrombi.

Received for publication, December 12, 2006

^* This work was supported in part by the Netherlands Heart Foundation Grant 2002-B014 and the Netherlands Organization for Scientific Research Grant 902-16-276. 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 Supported by Marie Curie Fellowship QLK5-CT-2000-60007 from the European Community.

² To whom correspondence may be addressed. E-mail: bernhard.nieswandt{at}virchow.uni-wuerzburg.de. ³ To whom correspondence may be addressed: Dept. of Biochemistry, University of Maastricht, P. O. Box 616, 6200 MD Maastricht, The Netherlands. Tel.: 31-43-3881671; Fax: 31-43-3884159; E-mail: jwm.heemskerk{at}bioch.unimaas.nl.

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