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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1696-1703. Prepublished online as a Blood First Edition Paper on June 10, 2008; DOI 10.1182/blood-2008-02-139733. This Article Full Text (PDF) All Versions of this Article: blood-2008-02-139733v1 112/5/1696    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 Cifuni, S. M Articles by Bergmeier, W. Search for Related Content PubMed PubMed Citation Articles by Cifuni, S. M Articles by Bergmeier, W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 20, 2008 Accepted May 28, 2008 CalDAG-GEFI and protein kinase C (PKC) represent alternative pathways leading to activation of integrin IIb3 in platelets Stephen M Cifuni, Denisa D Wagner, and Wolfgang Bergmeier* Immune Disease Institute, Harvard Medical School, Boston, MA, United States Department of Pathology, Harvard Medical School, Boston, MA, United States Cardeza Foundation and Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United States * Corresponding author; email: wolfgang.bergmeier{at}jefferson.edu. Second messenger-mediated inside-out activation of integrin IIb3 is a key step in platelet aggregation. We recently showed strongly impaired but not absent IIb3-mediated aggregation of CalDAG-GEFI-deficient platelets activated with various agonists. Here we further evaluated the roles of CalDAG-GEFI and protein kinase C (PKC) for IIb3 activation in platelets activated with a PAR4 receptor-specific agonist, GYPGKF (PAR4p). Compared to wild-type controls, platelets treated with the PKC inhibitor Ro31-8220 or CalDAG-GEFI-deficient platelets showed a marked defect in aggregation at low (< 1mM PAR4p) but not high PAR4p concentrations. Blocking of PKC function in CalDAG-GEFI-deficient platelets, however, strongly decreased aggregation at all PAR4p concentrations, demonstrating that CalDAG-GEFI and PKC represent separate, but synergizing, pathways important for IIb3 activation. PAR4p-induced aggregation in the absence of CalDAG-GEFI required co-signaling through the Gi-coupled receptor for ADP, P2Y12. Independent roles for CalDAG-GEFI- and PKC/Gi-signaling were also observed for PAR4p-induced activation of the small GTPase Rap1, with CalDAG-GEFI mediating the rapid but reversible activation of this small GTPase. In summary, our studies identify CalDAG-GEFI and PKC as independent pathways leading to Rap1 and IIb3 activation in mouse platelets activated through the PAR4 receptor. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Stefanini, R. C. Roden, and W. Bergmeier CalDAG-GEFI is at the nexus of calcium-dependent platelet activation Blood, September 17, 2009; 114(12): 2506 - 2514. [Abstract] [Full Text] [PDF] M. Holinstat, A. M. Preininger, S. B. Milne, W. J. Hudson, H. A. Brown, and H. E. Hamm Irreversible Platelet Activation Requires Protease-Activated Receptor 1-Mediated Signaling to Phosphatidylinositol Phosphates Mol. Pharmacol., August 1, 2009; 76(2): 301 - 313. [Abstract] [Full Text] [PDF] S. S. Smyth, D. S. Woulfe, J. I. Weitz, C. Gachet, P. B. Conley, S. G. Goodman, M. T. Roe, A. Kuliopulos, D. J. Moliterno, P. A. French, et al. G-Protein-Coupled Receptors as Signaling Targets for Antiplatelet Therapy Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 449 - 457. [Abstract] [Full Text] [PDF] B. Nagy Jr, K. Bhavaraju, T. Getz, Y. S. Bynagari, S. Kim, and S. P. Kunapuli Impaired activation of platelets lacking protein kinase C-{theta} isoform Blood, March 12, 2009; 113(11): 2557 - 2567. [Abstract] [Full Text] [PDF] R. Evans, I. Patzak, L. Svensson, K. De Filippo, K. Jones, A. McDowall, and N. Hogg Integrins in immunity J. Cell Sci., January 15, 2009; 122(2): 215 - 225. [Abstract] [Full Text] [PDF]

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