The early stages of α_IIbβ₃outside-in signaling. (A) Following inside-out signaling, the integrin adopts a conformation that enables it to bind ligands such as fibrinogen with high affinity. c-Src can associate with the RGT motif of the β₃-integrin C-terminal tail via its SH3 domain. (B) Integrin clustering supports full c-Src activation, bringing distinct c-Src proteins into proximity for trans-autophosphorylation. For the sake of clarity, all subsequent figures depict nonclustered α_IIbβ₃. (C) Src supports the activation of Syk kinase, which may bind via its SH2 domains to the β₃ C-terminal tail in a manner independent of β₃ tyrosine phosphorylation, or to phosphorylated tyrosines within the ITAM of FcγRIIa. (D) α_IIbβ₃-mediated platelet aggregation leads to SFK-mediated phosphorylation of tyrosine residues within the NxxY motfis of the β₃-integrin C-terminal tail, leading to the recruitment of proteins such as Grb2, Shc, and myosin. Hashed lines represent phosphorylation events, denoted on proteins by a yellow circle.