SFKs in integrin αIIbβ3 proximal signaling. (A) The integrin αIIbβ3 is in a low-affinity conformation on the surface of resting platelets. The SFKs Src and Fyn constitutively associate with the cytoplasmic tail of the β3 subunit via their SH3 domains. Src is maintained in an inactive conformation by Csk, which forms a complex with β3 and Src. Inside-out signaling induces the integrin to adopt a high-affinity conformation and fibrinogen binding. Csk subsequently dissociates from the complex and is replaced by the nontransmembrane PTP-1B that dephosphorylates the C-terminal inhibitory tyrosine residue of Src and activates it. The receptor-like PTP CD148 plays a major role in maintaining a pool of activated SFKs at the plasma membrane that contribute to αIIbβ3 signaling. Fibrinogen-mediated clustering of the integrin induces trans-autophosphorylation of the activation loop tyrosine residue of SFKs and maximal activation. (B) The ITIM/immunoreceptor tyrosine-based switch motif (ITSM)–containing inhibitory receptors PECAM-1 and G6b-B are phosphorylated by SFKs downstream of αIIbβ3. The SH2 domain–containing nontransmembrane PTPs Shp1 and Shp2 bind to the tandem phosphorylated ITIM/ITSM. The exact contributions of PECAM-1 and G6b-B to αIIbβ3 signaling remain ambiguous and are denoted by the dashed arrow. SFKs also phosphorylate and activate SH2 domain-containing SHIP-1, which forms a complex with SFKs and the β3 tail. SHIP-1 attenuates integrin signaling by dephosphorylating PI3,4,5P₃ to PI3,4P₂ and disrupting membrane localization of (PLCγ2), which binds to PI3,4,5P₃ via its pleckstrin homology (PH) domain. PLCγ2 must associate with the plasma membrane in order to hydrolyze PI4,5P₂ to the second messenger’s DAG and IP₃ that activate serine/threonine PKC and facilitate Ca²⁺ mobilization, respectively.