Coordinate interactions of Csk, Src, and Syk kinases with αIIbβ3 initiate integrin signaling to the cytoskeleton

Achim Obergfell, Koji Eto, Attila Mocsai, Charito Buensuceso, Sheri L. Moores, Joan S. Brugge, Clifford A. Lowell, Sanford J. Shattil

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323 Citations (Scopus)

Abstract

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 αIIbβ3 in platelets. Platelet adhesion to fibrinogen caused a rapid increase in αIIbβ3-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 αIIbβ3. However, fibrinogen binding caused Csk to dissociate from αIIbβ3, 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 αIIbβ3 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 αIIbβ3, thus providing a paradigm for initiation of integrin signaling to the actin cytoskeleton.

Original languageEnglish
Pages (from-to)265-275
Number of pages11
JournalJournal of Cell Biology
Volume157
Issue number2
DOIs
Publication statusPublished - Apr 15 2002

Keywords

  • Integrin
  • Signaling
  • Src
  • Syk
  • Tyrosine kinase

ASJC Scopus subject areas

  • Cell Biology

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    Obergfell, A., Eto, K., Mocsai, A., Buensuceso, C., Moores, S. L., Brugge, J. S., Lowell, C. A., & Shattil, S. J. (2002). Coordinate interactions of Csk, Src, and Syk kinases with αIIbβ3 initiate integrin signaling to the cytoskeleton. Journal of Cell Biology, 157(2), 265-275. https://doi.org/10.1083/jcb.200112113