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

Outside-in integrin alpha IIb beta 3 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 IIb beta 3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to alpha IIb beta 3 triggers PTP-1B recruitment to the alpha IIb beta 3-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 IIb beta 3, dephosphorylation of c-Src tyrosine 529, and c-Src activation. Furthermore, PTP-1B-deficient platelets are defective in outside-in alpha IIb beta 3 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 IIb beta 3 signaling in platelets.