β3 tyrosine phosphorylation in αIIbβ3 (platelet membrane GP IIb-IIIa) outside-in integrin signaling

The platelet integrin alpha IIb beta3 not only binds fibrinogen and von Willebrand factor to mediate platelet aggregation and adhesion, it also serves as a signaling receptor. Platelet agonists such as ADP, thrombin and collagen induce "inside-out" signaling which activates the receptor function of alpha IIb beta3 for soluble fibrinogen. Subsequent platelet aggregation leads to "outside-in" signaling, inducing platelet aggregate stabilization and triggering a variety of functions important to platelet physiology. This review focuses on the role of beta3 tyrosine phosphorylation in alpha IIb beta3 outside-in signaling. Tyrosine phosphorylation of beta3 in platelets is a dynamic process which is initiated upon platelet aggregation and also by adhesion of platelets to immobilized fibrinogen. Tyrosine phosphorylation occurs on the beta3 integrin cytoplasmic tyrosine (ICY) domain, a conserved motif found in the beta subunits of several integrins. beta 3ICY domain tyrosine phosphorylation induces the recruitment of two proteins to the cytoplasmic domains of alpha IIb beta3: the cytoskeletal protein myosin, important to clot retraction; and the signaling adapter protein Shc, important to platelet stimulation. The critical role of beta3 tyrosine phosphorylation to platelet function was established by the diYF mouse, a novel strain which expresses an alpha IIb beta3 in which the two beta 3ICY domain tyrosines have been mutated to phenylalanine. These mice are selectively impaired in outside-in alpha IIb beta3 signaling, with defective aggregation and clot-retraction responses in vitro, and an in vivo bleeding defect which is characterized by a pronounced tendency to rebleed. Taken together, the data suggest that the beta3 tyrosine phosphorylation signaling mechanism is important to alpha IIb beta3 function and might be applicable to a wide variety of integrin-mediated events.