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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Law, D. A. Articles by Phillips, D. R. Search for Related Content PubMed PubMed Citation Articles by Law, D. A. Articles by Phillips, D. R. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 93 No. 8 (April 15), 1999: pp. 2645-2652 Genetic and Pharmacological Analyses of Syk Function in IIb3 Signaling in Platelets Debbie A. Law, Lisa Nannizzi-Alaimo, Kathleen Ministri, Paul E. Hughes, Jane Forsyth, Martin Turner, Sanford J. Shattil, Mark H. Ginsberg, Victor L.J. Tybulewicz, and David R. Phillips From COR Therapeutics, Inc, South San Francisco, CA; Scripps Research Institute, La Jolla, CA; and National Institute Medical Research, Mill Hill, London, UK. Agonists induce inside-out IIb3 signaling resulting in fibrinogen binding and platelet aggregation. These in turn trigger outside-in signaling resulting in further platelet stimulation. Because the Syk tyrosine kinase is activated during both phases of integrin signaling, we evaluated its role in IIb3 function in murine platelets rendered null for Syk by gene targeting and in human platelets incubated with piceatannol, a tyrosine kinase inhibitor reportedly selective for Syk. Both Syk null murine platelets and piceatannol-treated human platelets exhibited a partial, but statistically significant defect in activation of IIb3 by adenine diphosphate (ADP) ± epinephrine as assessed by fibrinogen binding. Syk null platelets adhered normally to immobilized fibrinogen, and mice with these platelets exhibited normal tail bleeding times. In contrast, piceatannol treatment of human platelets completely inhibited platelet adhesion to immobilized fibrinogen. The discrepancy in extent of integrin dysfunction between murine and human platelet models may be due to lack of specificity of piceatannol, because this compound inhibited the activity of Src and FAK as well as Syk and also reduced tyrosine phosphorylation of multiple platelet proteins. These results provide genetic evidence that Syk plays a role in IIb3 signaling in platelets and pharmacological evidence that, although piceatannol also inhibits IIb3 signaling, it does so by inhibtion of multiple protein tyrosine kinases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. C. Klimowicz, S. A. Bisson, K. Hans, E. M. Long, H. C. Hansen, and S. M. 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Torti Platelet Activation by von Willebrand Factor Requires Coordinated Signaling through Thromboxane A2 and Fcgamma IIA Receptor J. Biol. Chem., July 6, 2001; 276(28): 26022 - 26029. [Abstract] [Full Text] [PDF] T. R. Faruqi, E. J. Weiss, M. J. Shapiro, W. Huang, and S. R. Coughlin Structure-Function Analysis of Protease-activated Receptor 4 Tethered Ligand Peptides. DETERMINANTS OF SPECIFICITY AND UTILITY IN ASSAYS OF RECEPTOR FUNCTION J. Biol. Chem., June 23, 2000; 275(26): 19728 - 19734. [Abstract] [Full Text] [PDF] P. Maschberger, M. Bauer, J. Baumann-Siemons, K. J. Zangl, E. V. Negrescu, A. J. Reininger, and W. Siess Mildly Oxidized Low Density Lipoprotein Rapidly Stimulates via Activation of the Lysophosphatidic Acid Receptor Src Family and Syk Tyrosine Kinases and Ca2+ Influx in Human Platelets J. Biol. Chem., June 16, 2000; 275(25): 19159 - 19166. [Abstract] [Full Text] [PDF] A. Obergfell, K. Eto, A. Mocsai, C. Buensuceso, S. L. Moores, J. S. Brugge, C. A. Lowell, and S. J. 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