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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2601-2609. Prepublished online as a Blood First Edition Paper on December 18, 2003; DOI 10.1182/blood-2003-09-3319. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-09-3319v1 103/7/2601    most recent 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 Marshall, S. J. Articles by Watson, S. P. Search for Related Content PubMed PubMed Citation Articles by Marshall, S. J. Articles by Watson, S. P. Related Collections Signal Transduction Hemostasis, Thrombosis, and Vascular Biology Related Articles in Blood Online Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY GPIb-dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP-dependent kinase Stuart J. Marshall, Yotis A. Senis, Jocelyn M. Auger, Robert Feil, Franz Hofmann, Gary Salmon, J. Thomas Peterson, Frank Burslem, and Steve P. Watson From the Department of Pharmacology, University of Oxford, Oxford United Kingdom; Division of Medical Sciences, The Medical School, University of Birmingham, Edgbaston, Birmingham, United Kingdom; Institut für Pharmakologie und Toxikologie, Technische Universität (TU) München, München, Germany; Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; and Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, MI. Glycoprotein Ib-IX-V (GPIb-IX-V) mediates platelet tethering to von Willebrand factor (VWF), recruiting platelets into the thrombus, and activates integrin IIb3 through a pathway that is dependent on Src kinases. In addition, recent reports indicate that activation of IIb3 by VWF is dependent on protein kinase G (PKG) and mitogen-activated protein (MAP) kinases. The present study compares the importance of these signaling pathways in the activation of IIb3 by GPIb-IX-V. In contrast to a recent report, VWF did not promote an increase in cyclic guanosine monophosphate (cGMP), while agents that elevate cGMP, such as the nitrous oxide (NO) donor glyco–SNAP-1 (N-(-D-glucopyranosyl)-N2-acetyl-S-nitroso-D,L-penicillaminamide) or the type 5 phosphosdiesterase inhibitor, sildenafil, inhibited rather than promoted activation of IIb3 by GPIb-IX-V and blocked aggregate formation on collagen at an intermediate rate of shear (800 s-1). Additionally, sildenafil increased blood flow in a rabbit model of thrombus formation in vivo. A novel inhibitor of the MAP kinase pathway, which is active in plasma, PD184161, had no effect on aggregate formation on collagen under flow conditions, whereas a novel inhibitor of Src kinases, which is also active in plasma, PD173952, blocked this response. These results demonstrate a critical role for Src kinases but not MAP kinases in VWF-dependent platelet activation and demonstrate an inhibitory role for cGMP-elevating agents in regulating this process. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Does cGMP mediate platelet inhibition or stimulation? Wolfgang Siess Blood 2004 103: 2435-2436. [Full Text] [PDF] Potent inhibition of human platelets by cGMP analogs independent of cGMP-dependent protein kinase Stepan Gambaryan, Jörg Geiger, Ulrike R. Schwarz, Elke Butt, Antonija Begonja, Achim Obergfell, and Ulrich Walter Blood 2004 103: 2593-2600. [Abstract] [Full Text] [PDF] Related Letter in Blood Online: On the roles of cGMP and glycoprotein Ib in platelet activation Xiaoping Du, Jasna A. Marjanovic, Zhenyu Li, Yotis Senis, Stuart Marshall, and Steve Watson Blood 2004 103: 4371-4372. [Full Text] [PDF] This article has been cited by other articles: A. Kauskot, F. 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