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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-03-0806. This Article Full Text (PDF) All Versions of this Article: 2002-03-0806v1 101/9/3469    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 Wu, Y. Articles by Ozaki, Y. Search for Related Content PubMed PubMed Citation Articles by Wu, Y. Articles by Ozaki, Y. Social Bookmarking                   What's this? Submitted March 15, 2002 Accepted July 25, 2002 Interaction between von Willebrand factor and glycoprotein Ib activates Src kinase in human platelets: role of phosphoinositide 3-kinase Yi Wu, Naoki Asazuma, Kaneo Satoh, Yutaka Yatomi, Toshiro Takafuta, Michael C Berndt, and Yukio Ozaki* Department of Clinical and Laboratory Medicine, Yamanashi Medical University, Yamanashi, Japan Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia * Corresponding author; email: yozaki{at}res.yamanashi-med.ac.jp. The binding of von Willebrand factor (VWF) to glycoprotein (GP) Ib-IX-V stimulates transmembrane signaling events that lead to platelet adhesion and aggregation. Recent studies have implied that activation of Src family kinases is involved in GPIb-mediated platelet activation, although the related signal transduction pathway remains poorly defined. This study presents evidence for an important role of Src and GPIb association. In platelet lysates containing CompleteTM, a broad-spectrum protease inhibitor mixture, Src and Lyn dynamically associated with GPIb upon VWF -botrocetin stimulation. Cytochalasin D, which inhibits translocation of Src kinases to the cytoskeleton, further increased Src and GPIb association. Similar results were obtained with botrocetin and monomeric A1 domain, instead of intact VWF, with induction of both Src activation and association between GP Ib and Src. These findings suggest that ligand binding of GPIb, without receptor clustering, is sufficient to activate Src. Immunoprecipitation studies demonstrated that Src, phosphoinositide 3-kinase (PI 3-kinase) and GPIb form a complex in GPIb-stimulated platelets. When the p85 subunit of PI 3-kinase was immunodepleted, association of Src with GPIb was abrogated. However, wortmannin, a specific PI 3-kinase inhibitor, failed to block complex formation between Src and GPIb. The Src-SH3 domain as a GST-fusion protein co-precipitated the p85 subunit of PI 3-kinase and GPIb. These findings taken together suggest that the p85 subunit of PI 3-kinase mediates GPIb-related activation signals and activates Src independently of the enzymatic activity of PI 3-kinase. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Yin, J. Liu, Z. Li, M. C. Berndt, C. A. Lowell, and X. Du Src family tyrosine kinase Lyn mediates VWF/GPIb-IX-induced platelet activation via the cGMP signaling pathway Blood, August 15, 2008; 112(4): 1139 - 1146. [Abstract] [Full Text] [PDF] F.-T. Mu, R. K. Andrews, J. F. Arthur, A. D. Munday, S. L. Cranmer, S. P. Jackson, F. C. Stomski, A. F. Lopez, and M. C. 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