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Published online 8 April 2002. doi:10.1083/jcb.200112113
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© The Rockefeller University Press, 0021-9525/2002/4/265 $5.00
The Journal of Cell Biology, Volume 157, Number 2, April 15, 2002 265-275

Article

Coordinate interactions of Csk, Src, and Syk kinases with {alpha}IIbß3 initiate integrin signaling to the cytoskeleton



Achim Obergfell1, Koji Eto1, Attila Mocsai2, Charito Buensuceso1, Sheri L. Moores3, Joan S. Brugge3, Clifford A. Lowell2 and Sanford J. Shattil1

1 Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
2 Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA 94143
3 Department of Cell Biology, Harvard Medical School, Boston, MA 02115

Address correspondence to Sanford J. Shattil, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., VB-5, La Jolla, CA 92037. Tel.: (858) 784-7148. Fax: (858) 784-7422. E-mail: shattil{at}scripps.edu

Integrins regulate cell adhesion and motility through tyrosine kinases, but initiation of this process is poorly understood. We find here that Src associates constitutively with integrin {alpha}IIbß3 in platelets. Platelet adhesion to fibrinogen caused a rapid increase in {alpha}IIbß3-associated Src activity, and active Src localized to filopodia and cell edges. Csk, which negatively regulates Src by phosphorylating Tyr-529, was also constitutively associated with {alpha}IIbß3. However, fibrinogen binding caused Csk to dissociate from {alpha}IIbß3, concomitant with dephosphorylation of Src Tyr-529 and phosphorylation of Src activation loop Tyr-418. In contrast to the behavior of Src and Csk, Syk was associated with {alpha}IIbß3 only after fibrinogen binding. Platelets multiply deficient in Src, Hck, Fgr, and Lyn, or normal platelets treated with Src kinase inhibitors failed to spread on fibrinogen. Inhibition of Src kinases blocked Syk activation and inhibited phosphorylation of Syk substrates (Vav1, Vav3, SLP-76) implicated in cytoskeletal regulation. Syk-deficient platelets exhibited Src activation upon adhesion to fibrinogen, but no spreading or phosphorylation of Vav1, Vav3, and SLP-76. These studies establish that platelet spreading on fibrinogen requires sequential activation of Src and Syk in proximity to {alpha}IIbß3, thus providing a paradigm for initiation of integrin signaling to the actin cytoskeleton.

Key Words: integrin; signaling; Src; Syk; tyrosine kinase


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