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Published 3 March 2003. doi:10.1083/jcb.200208043
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© The Rockefeller University Press, 0021-9525/2003/3/769 $5.00
The Journal of Cell Biology, Volume 160, Number 5, 769-780

Article

Integrin {alpha}2ß1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLC{gamma}2



Osamu Inoue1, Katsue Suzuki-Inoue1, William L. Dean2, Jon Frampton3 and Steve P. Watson1,4

1 Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK
2 Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, KY 40292
3 Division of Infection and Immunity, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
4 Division of Medical Sciences, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

Address correspondence to Osamu Inoue, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK. Tel.: 44-1865-271592. Fax: 44-1865-271853. E-mail: osamu.inoue{at}pharm.ox.ac.uk

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 {alpha}2ß1 and activation through the glycoprotein VI (GPVI)–Fc receptor (FcR) {gamma}-chain complex. The present study extends this model by demonstrating that engagement of {alpha}2ß1 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 {gamma}-chain complex. The same events do not occur in platelet suspensions. {alpha}2ß1 activation of adherent platelets stimulates tyrosine phosphorylation of many of the proteins in the GPVI–FcR {gamma}-chain cascade, including Src, Syk, SLP-76, and PLC{gamma}2 as well as plasma membrane calcium ATPase and focal adhesion kinase. {alpha}2ß1-mediated spreading is dramatically inhibited in the presence of the Src kinase inhibitor PP2 and in PLC{gamma}2-deficient platelets. Spreading is abolished by chelation of intracellular Ca2+. Demonstration that adhesion of platelets to collagen via {alpha}2ß1 generates intracellular signals provides a new insight into the mechanisms that control thrombus formation and may explain the unstable nature of ß1-deficient thrombi and why loss of the GPVI–FcR {gamma}-chain complex has a relatively minor effect on bleeding.

Key Words: integrin {alpha}2ß1; blood platelets; cell spreading; PLC{gamma}2; FAK


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