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Blood, 15 July 2005, Vol. 106, No. 2, pp. 550-557. Prepublished online as a Blood First Edition Paper on April 5, 2005; DOI 10.1182/blood-2004-12-4866. This Article Full Text (PDF) All Versions of this Article: 2004-12-4866v1 106/2/550    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Murugappan, S. Articles by Kunapuli, S. P Search for Related Content PubMed PubMed Citation Articles by Murugappan, S. Articles by Kunapuli, S. P Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 22, 2004 Accepted March 30, 2005 Molecular mechanism and functional implications of thrombin-mediated tyrosine phosphorylation of PKC in platelets Swaminathan Murugappan, Haripriya Shankar, Surya Bhamidipati, Robert T Dorsam, Jianguo Jin, and Satya P Kunapuli* Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA; Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, USA Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, USA Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, USA * Corresponding author; email: spk{at}temple.edu. Thrombin has been known to cause tyrosine phosphorylation of protein kinase (PKC) in platelets, but the molecular mechanisms and function of this tyrosine phosphorylation is not known. In this study, we investigated the signaling pathways utilized by protease-activated receptors (PAR) to cause tyrosine phosphorylation of PKC and the role of this event in platelet function. PKC was tyrosine phosphorylated by either PAR1 or PAR4 in a concentration- and time-dependent manner in human platelets. In particular, only the tyrosine 311 residue was phosphorylated downstream of PAR receptors. Also the tyrosine phosphorylation of PKC did not occur in Gq-deficient mouse platelets and was inhibited in the presence of a phospholipase C (PLC) inhibitor, U73122 and calcium chelator BAPTA suggesting a role for Gq pathways and calcium in this event. Both PAR1 and PAR4 caused a time-dependent activation of Src tyrosine kinase and Src tyrosine kinase inhibitors completely blocked the tyrosine phosphorylation of PKC. Inhibition of tyrosine phosphorylation or the kinase activity of PKC dramatically blocked PAR-mediated thromboxane A2 generation. We conclude that thrombin causes tyrosine phosphorylation of PKC in a calcium- and Src-family kinase dependent manner in platelets, with functional implications in thromboxane A2 generation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z. A. Karim, W. Choi, and S. W. Whiteheart Primary Platelet Signaling Cascades and Integrin-mediated Signaling Control ADP-ribosylation Factor (Arf) 6-GTP Levels during Platelet Activation and Aggregation J. Biol. Chem., May 2, 2008; 283(18): 11995 - 12003. [Abstract] [Full Text] [PDF] M. Valiyaveettil, N. Kar, M. Z. Ashraf, T. V. Byzova, M. Febbraio, and E. A. 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