1. Integrin α[sub 2]β[sub 1] mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCγ2.
- Author
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Inoue, Osamu, Suzuki-Inoue, Katsue, Dean, William L., Frampton, Jon, and Watson, Steve P.
- Subjects
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COLLAGEN , *BLOOD platelets , *INTEGRINS - Abstract
Collagen plays a critical role in hemostasis by promoting adhesion and activation of platelets at sites of vessel injury. In the present model of platelet-collagen interaction, adhesion is mediated via the inside-out regulation of integrin α[sub 2]β[sub 1] and activation through the glycoprotein VI (GPVI)-Fc receptor (FcR) γ-chain complex. The present study extends this model by demonstrating that engagement of α[sub 2]β[sub 1] by an integrin-specific sequence from within collagen or by collagen itself generates tyrosine kinase-based intracellular signals that lead to formation of filopodia and lamellipodia in the absence of the GPVI-FcR γ-chain complex. The same events do not occur in platelet suspensions, α[sub 2]β[sub 1] activation of adherent platelets stimulates tyrosine phosphorylation of many of the proteins in the GPVI-FcR γ-chain cascade, including Src, Syk, SLP-76, and PLCγ,2 as well as plasma membrane calcium ATPase and focal adhesion kinase, α[sub 2]β[sub 1]-mediated spreading is dramatically inhibited in the presence of the Src kinase inhibitor PP2 and in PLCγ2-deficient platelets. Spreading is abolished by chelation of intracellular Ca[sup 2+]. Demonstration that adhesion of platelets to collagen via α[sub 2]β[sub 1] generates intracellular signals provides a new insight into the mechanisms that control thrombus formation and may explain the unstable nature of β[sub 1]-deficient thrombi and why loss of the GPVI-FcR γ-chain complex has a relatively minor effect on bleeding. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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