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Published online 22 August 2005. doi:10.1083/jcb.200503125
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 5, 837-845
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Article

PTP-1B is an essential positive regulator of platelet integrin signaling



Elena Garcia Arias-Salgado1, Fawaz Haj2, Christophe Dubois2, Barry Moran1, Ana Kasirer-Friede1, Barbara C. Furie2, Bruce Furie2, Benjamin G. Neel2, and Sanford J. Shattil1

1 Department of Medicine, University of California, San Diego, La Jolla, CA 92093
2 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Correspondence to Sanford J. Shattil: sshattil{at}ucsd.edu

Outside-in integrin {alpha}IIbß3 signaling is required for normal platelet thrombus formation and is triggered by c-Src activation through an unknown mechanism. In this study, we demonstrate an essential role for protein–tyrosine phosphatase (PTP)–1B in this process. In resting platelets, c-Src forms a complex with {alpha}IIbß3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to {alpha}IIbß3 triggers PTP-1B recruitment to the {alpha}IIbß3–c-Src–Csk complex in a manner that is dependent on c-Src and specific tyrosine (tyrosine 152 and 153) and proline (proline 309 and 310) residues in PTP-1B. Studies of PTP-1B–deficient mouse platelets indicate that PTP-1B is required for fibrinogen-dependent Csk dissociation from {alpha}IIbß3, dephosphorylation of c-Src tyrosine 529, and c-Src activation. Furthermore, PTP-1B–deficient platelets are defective in outside-in {alpha}IIbß3 signaling in vitro as manifested by poor spreading on fibrinogen and decreased clot retraction, and they exhibit ineffective Ca2+ signaling and thrombus formation in vivo. Thus, PTP-1B is an essential positive regulator of the initiation of outside-in {alpha}IIbß3 signaling in platelets.

Abbreviation used in this paper: PTP, protein–tyrosine phosphatase.


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