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J. Biol. Chem., Vol. 278, Issue 27, 24533-24541, July 4, 2003

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Physical and Functional Interaction between Protein Kinase C and Fyn Tyrosine Kinase in Human Platelets^*

David Crosby and Alastair W. Poole 

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

An increasing number of tyrosine kinases have been shown to associate with isoforms of the protein kinase C (PKC) family. Here, we show evidence for physical and functional interaction between PKC and the Src family kinase Fyn in human platelets activated by alboaggregin-A, a snake venom capable of activating both GPIb-V-IX and GPVI adhesion receptors. This interaction involves phosphorylation of PKC on tyrosine and is specific in that other isoforms of PKC, PKC and , which also become tyrosine-phosphorylated, do not interact with Fyn. In addition, PKC does not interact with other platelet-expressed tyrosine kinases Syk, Src, or Btk. Stimulation also leads to activation of both Fyn and PKC and to serine phosphorylation of Fyn within a PKC consensus sequence. Alboaggregin-A-dependent activation of Fyn is blocked by bisindolylmaleimide I, suggesting a role for PKC isoforms in regulating Fyn activity. Platelet activation with alboaggregin-A induces translocation of the two kinases from cytoplasm to the plasma membrane of platelets, as observed by confocal immunofluorescence microscopy. Translocation of Fyn and PKC are blocked by PP1 and bisindolylmaleimide I, showing a dependence upon Src and PKC kinase activities. Although PKC activity is required for translocation, it is not required for association between the two kinases, because this was not blocked by bisindolylmaleimide I. Rottlerin, which inhibited PKC activity, did not block translocation of either PKC or Fyn but potentiated platelet aggregation, 5-hydroxytryptamine secretion, and the calcium response induced by alboaggregin-A, indicating that this kinase plays a negative role in the control of these processes.

Received for publication, February 20, 2003 , and in revised form, April 4, 2003.

^* This work was supported by the Medical Research Council (UK) and by project grant support from the Wellcome Trust and the British Heart Foundation. 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. Tel.: 44-1-17-928-7635; Fax: 44-1-17-925-0168; E-mail: a.poole{at}bris.ac.uk.

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