Model for αIIbβ3 regulation of Src. (Left) According to current structural models,¹⁴⁰  Src family kinases are membrane associated and maintained in a “clamped,” inactive state through intramolecular interactions between the SH2 domain and a C-terminal phosphotyrosine motif at Tyr529 (Y529), and the SH3 domain and a polyproline motif in the linker region between the SH2 domain and the N-lobe of the catalytic domain. (Middle) In platelets, a pool of c-Src (and several other Src family kinases) is constitutively bound to αIIbβ3 through interaction of the β3 cytoplasmic tail with the SH3 domain. This may maintain Src in a partially unclamped, primed state but not yet fully active, in part because Tyr529 remains phosphorylated by integrin-associated Csk. (Right) Upon αIIbβ3 ligation, Src becomes clustered and Csk dissociates from the integrin complex. The net result is dephosphorylation of Tyr529 by an unidentified tyrosine phosphatase and autophosphorylation of Tyr418 (Y418) in the Src activation loop. Consequently, Src is now unclamped and fully active to phosphorylate downstream effectors. From Arias-Salgado et al⁵¹  and Obergfell et al¹¹²  with permission.