beta 3 tyrosine phosphorylation in alpha IIb beta 3 (platelet membrane GP IIb-IIIa) outside-in integrin signaling

The platelet integrin alpha IIb beta3 not only binds fibrinogen and von Wil lebrand factor to mediate platelet aggregation and adhesion, it also serves as a signaling receptor. Platelet agonists such as ADP, thrombin and colla gen induce "inside-out" signaling which activates the receptor function of alpha IIb beta3 for soluble fibrinogen. Subsequent platelet aggregation lea ds to "outside-in" signaling, inducing platelet aggregate stabilization and triggering a variety of functions important to platelet physiology. This r eview focuses on the role of beta3 tyrosine phosphorylation in alpha IIb be ta3 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 ty rosine phosphorylation induces the recruitment of two proteins to the cytop lasmic domains of alpha IIb beta3: the cytoskeletal protein myosin, importa nt to clot retraction; and the signaling adapter protein Shc, important to platelet stimulation. The critical role of beta3 tyrosine phosphorylation t o 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 h ave been mutated to phenylalanine. These mice are selectively impaired in o utside-in alpha IIb beta3 signaling, with defective aggregation and clot-re traction responses in vitro, and an in vivo bleeding defect which is charac terized by a pronounced tendency to rebleed. Taken together, the data sugge st that the beta3 tyrosine phosphorylation signaling mechanism is important to alpha IIb beta3 function and might be applicable to a wide variety of i ntegrin-mediated events.