Functional phenotype of phosphoinositide 3-kinase p85α-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, Makoto Handa

研究成果: Article査読

72 被引用数 (Scopus)

抄録

Phosphoinositide 3-kinases (PI3Ks), a family of lipid kinases comprising 3 classes with multiple isoforms, have been shown to participate in different phases of platelet signaling. To investigate the roles that enzymes play 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 p85α regulatory subunit of heterodimeric class IA PI3K. The kinase activity of p85α-/- platelets was only 5% of the activity of platelets from wild-type littermates. Platelet aggregation induced by adenosine diphosphate (ADP), thrombin, U46619, phorbol 12-myristate 13-acetate (PMA), or botrocetin was not defective in p85α-/- mice, compared with wild-type animals. In contrast, aggregation induced by collagen and collagen-related peptide (CRP) was partially but readily impaired in p85α-/- mice. Both P-selectin expression and fibrinogen binding in response to CRP were also decreased to a similar extent in p85α-/- platelets. Platelets from p85α-/- 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 Cγ2 were observed with p85α-/- 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 p85α plays a significant role in platelet function, almost exclusively in the glycoprotein (GP) VI/Fc receptor γ chain complex-mediated signaling pathway.

本文言語English
ページ(範囲)541-548
ページ数8
ジャーナルBlood
102
2
DOI
出版ステータスPublished - 2003 7 15

ASJC Scopus subject areas

  • 生化学
  • 免疫学
  • 血液学
  • 細胞生物学

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