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J. Biol. Chem., Vol. 280, Issue 8, 7194-7205, February 25, 2005

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Functional Interaction of Protein Kinase C with the Tyrosine Kinases Syk and Src in Human Platelets^*

Giordano Pula, David Crosby, Julie Baker, and Alastair W. Poole

From the Department of Pharmacology, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom

There is a high degree of cross-talk between tyrosine phosphorylation and the serine/threonine phosphorylation signaling pathways. Here we show a physical and functional interaction between the classical protein kinase C isoform (cPKC), PKC, and two major nonreceptor tyrosine kinases in platelets, Syk and Src. In the presence of the cPKC-selective inhibitor Gö6976, platelet 5-hydroxytryptamine release was abolished in response to co-activation of glycoproteins VI and Ib-IX-V by the snake venom alboaggregin A, whereas platelet aggregation was substantially inhibited. Of the two platelet cPKCs, PKC but not PKC was activated, occurring in an Syk- and phospholipase C-dependent manner. Syk and PKC associate in a stimulation-dependent manner, requiring Syk but not PKC activity. PKC and Syk also co-translocate from the cytosol to the plasma membrane upon platelet activation, in a manner dependent upon the activities of both kinases. Although PKC is phosphorylated on tyrosine downstream of Syk, we provide evidence against phosphorylation of Syk by PKC, consistent with a lack of effect of PKC inhibition on Syk activity. PKC also associates with Src; although in contrast to interaction with Syk, PKC activity is required for the association of these kinases but not the stimulation-induced translocation of Src to the cell membrane. Finally, the activity of Src is negatively regulated by PKC, as shown by potentiation of Src activity in the presence of the PKC inhibitors GF109203X or Gö6976. Therefore, there is a complex interplay between PKC, Syk, and Src involving physical interaction, phosphorylation, translocation within the cell, and functional activity regulation.

Received for publication, August 11, 2004 , and in revised form, November 12, 2004.

^* This work was supported by British Heart Foundation Project Grant PG/2000087 and the Wellcome Trust Project Grants 064785 and 069572. 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.

To whom correspondence should be addressed: Dept. of Pharmacology, School of Medical Sciences, University Walk, Bristol, BS8 1TD, United Kingdom. Tel.: 44-117-928-7635; Fax: 44-117-925-0168; E-mail: a.poole{at}bris.ac.uk.

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