A model for the role of the pSPL/RGS/SHP1 complex in platelets. (A) The data indicate that in resting platelets SPL, SHP-1, and RGS proteins exist as a complex in which SPL is phosphorylated on Y398 and Y483. The specificity of subsequent events arises from a requirement for G_q-dependent signaling and/or selective interactions between SPL and the receptors for thrombin and TxA₂. (B) Platelet activation by thrombin or TxA₂ leads to platelet activation and (C) phosphorylation of SHP-1 Y536, activating the phosphatase. (D) SHP-1 activation triggers dephosphorylation of SPL and dissociation of the SPL/RGS/SHP1 complex, releasing RGS proteins that inhibit signaling by G_q. (E) The SPL knockout mimics aspects of the late activation state in platelets, making RGS proteins available prematurely and giving rise to the delayed signaling and loss of function phenotype that we observed. (F) Conversely, blocking SHP-1 activation by substituting Phe for Tyr 536 prevents dephosphorylation and dissociation of the pSPL/RGS/SHP1 complex, sequestering the RGS proteins and producing the observed gain of function.