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Blood, 1 May 2004, Vol. 103, No. 9, pp. 3403-3411. Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-10-3664. This Article Full Text (PDF) All Versions of this Article: 2003-10-3664v1 103/9/3403    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 Kasirer-Friede, A. Articles by Shattil, S. J Search for Related Content PubMed PubMed Citation Articles by Kasirer-Friede, A. Articles by Shattil, S. J Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted October 27, 2003 Accepted December 30, 2003 Signaling Through GP Ib-IX-V Activates IIb3 Independently of Other Receptors Ana Kasirer-Friede, Maria R Cozzi, Mario Mazzucato, Luigi De Marco, Zaverio M Ruggeri, and Sanford J Shattil* Cell Biology, The Scripps Research Institute, La Jolla, CA, USA CRO-IRCCS, National Cancer Institute, Aviano, Italy Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA Cell Biology, The Scripps Research Institute, La Jolla, CA, USA; Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA * Corresponding author; email: shattil{at}scripps.edu. Platelet adhesion to von Willebrand factor (VWF) activates IIb3, a prerequisite for thrombus formation. However, it is unclear whether the primary VWF receptor, GP Ib-IX-V, mediates IIb3 activation directly or through other signaling proteins physically associated with it (e.g., FcR -chain), possibly with the contribution of other agonist receptors and of VWF signaling through IIb3. To resolve this question, human and GP Ib transgenic mouse platelets were plated on dimeric VWF A1 domain (dA1VWF), which engages only GP Ib-IX-V, in the presence of inhibitors of other agonist receptors. Platelet adhesion to dA1VWF induced Src kinase-dependent tyrosine phosphorylation of the FcR -chain and the adapter molecule, ADAP, and triggered intracellular Ca2+ oscillations and IIb3 activation. Inhibition of Ca2+ oscillations with BAPTA-AM prevented IIb3 activation but not tyrosine phosphorylation. Pharmacological inhibition of protein kinase C (PKC) or PI 3-kinase prevented IIb3 activation but not Ca2+ oscillations. Inhibition of Src with two distinct compounds blocked all responses downstream of GP Ib-IX-V under static or flow conditions. However, dA1VWF-induced responses were reduced only slightly in GP Ib transgenic platelets lacking FcR -chain. These data establish that GP Ib-IX-V itself can signal to activate IIb3, through sequential actions of Src kinases, Ca2+ oscillations, and PI 3-kinase/PKC. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Platelet GP Ib-IX-V: not just a binding protein Michael C. Berndt Blood 2004 103: 3253. [Full Text] [PDF] This article has been cited by other articles: M. Mazzucato, M. R. Cozzi, M. Battiston, M. Jandrot-Perrus, M. Mongiat, P. Marchese, T. J. Kunicki, Z. M. Ruggeri, and L. De Marco Distinct spatio-temporal Ca2+ signaling elicited by integrin {alpha}2{beta}1 and glycoprotein VI under flow Blood, September 24, 2009; 114(13): 2793 - 2801. [Abstract] [Full Text] [PDF] F. Morello, A. 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