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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-11-3327. This Article Full Text (PDF) All Versions of this Article: 2002-11-3327v1 102/2/541    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 Watanabe, N. Articles by Handa, M. Search for Related Content PubMed PubMed Citation Articles by Watanabe, N. Articles by Handa, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted November 25, 2002 Accepted March 10, 2003 Functional phenotype of phosphoinositide 3-kinase p85 null platelets characterized by an impaired response to GP VI stimulation Naohide Watanabe, Hideaki Nakajima, Hidenori Suzuki, Atsushi Oda, Yumiko Matsubara, Masaaki Moroi, Yasuo Terauchi, Takashi Kadowaki, Harumi Suzuki, Shigeo Koyasu, Yasuo Ikeda, and Makoto Handa* Blood Center, Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan Department of Cardiovascular Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan Laboratory of Environmental Biology, Department of Preventive Medicine, Hokkaido University School of Medicine, Sapporo, Japan Institute of Life Science, Kurume University, Kurume, Japan Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Division of Cellular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan Department of Microbiology and Immunology, Yamaguchi University School of Medicine, Ube, Japan Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan * Corresponding author; email: mhanda{at}sc.itc.keio.ac.jp. Phosphoinositide 3-kinases (PI3Ks), a family of lipid kinases comprising three classes with multiple isoforms, have been shown to participate in different phases of platelet signaling. To investigate the roles that enzyme plays in platelet function in vivo and determine which isoforms are important for particular signaling events, we analyzed platelet function of gene knockout mice deficient in the p85 regulatory subunit of heterodimeric class IA PI3K. The kinase activity of p85 -/- platelets was only 5% of wild-type littermates. Compared with wild-type animals, platelet aggregation induced by ADP, thrombin, U46619, PMA, or botrocetin was not defective in p85 -/- mice. In contrast, collagen- and collagen related peptide (CRP)-induced aggregation was partially but readily impaired in p85 -/- mice. Both P-selectin expression and fibrinogen binding in response to CRP were also decreased to a similar extent in p85 -/- platelets. Platelets from p85a -/- mice appeared to spread poorly over a CRP-coated surface with intact filopodial protrusions. Significant attenuation of CRP-induced tyrosine phosphorylation in known PI3K effectors such as Btk, Tec, PKB/Akt, and phospholipase C2 were observed with p85 -/- platelets, whereas no alteration was noted in upstream molecules of Syk, LAT, and SLP-76. Considered as a whole, these results provide the first genetic evidence that PI3K p85 plays a significant role in platelet function, almost exclusively in the glycoprotein VI/Fc receptor -chain complex-mediated signaling pathway. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Collagen-mediated platelet activation and PI3K Charles S. Abrams Blood 2003 102: 416-417. [Full Text] [PDF] This article has been cited by other articles: K. Gilio, I. C. A. Munnix, P. Mangin, J. M. E. M. Cosemans, M. A. H. Feijge, P. E. J. van der Meijden, S. Olieslagers, M. B. 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