Physiologic role of c-Cbl Y731 in platelet outside-in signaling. (A) Murine platelets were allowed to adhere to a fibrinogen-coated cover slip. After 3 times washing with PBS, adherent cells were fixed with 3.7% paraformaldehyde and analyzed with DIC imaging. (B) Clot retraction analysis of platelets from c-Cbl KO and c-Cbl^YF/YF animals. (C) Model depicting the signaling events implicated in c-Cbl phosphorylation downstream of αIIbβ3: Fibrinogen binding to αIIbβ3 cause SFKs activation. The active kinases will phosphorylate c-Cbl on Y731 and activate Syk, which in turn, will phosphorylate c-Cbl Y700 and Y774. The phosphorylated tyrosines 700 and 774 will recruit SH2-domain containing proteins that play a role in platelet-spreading, while phosphorylated Y731 recruit molecules important for both platelet-spreading and retraction.