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

Elena Garcia Arias-Salgado, Fawaz Haj, Christophe Dubois, Barry Moran, Ana Kasirer-Friede, Barbara C. Furie, Bruce Furie, Benjamin G. Neel, Sanford J. Shattil

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Outside-in integrin αIIbβ3 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 αIIbβ3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to αIIbβ3 triggers PTP-1B recruitment to the αIIbβ3-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 αIIbβ3, dephosphorylation of c-Src tyrosine 529, and c-Src activation. Furthermore, PTP-1B-deficient platelets are defective in outside-in αIIbβ3 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 αIIbβ3 signaling in platelets.

Original languageEnglish (US)
Pages (from-to)837-845
Number of pages9
JournalJournal of Cell Biology
Volume170
Issue number5
DOIs
StatePublished - Aug 2005
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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    Arias-Salgado, E. G., Haj, F., Dubois, C., Moran, B., Kasirer-Friede, A., Furie, B. C., Furie, B., Neel, B. G., & Shattil, S. J. (2005). PTP-1B is an essential positive regulator of platelet integrin signaling. Journal of Cell Biology, 170(5), 837-845. https://doi.org/10.1083/jcb.200503125