Summary
The platelet integrin αIIbβ3 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 αIIbβ3 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 β3 tyrosine phosphorylation in αIIbβ3 outside-in
signaling. Tyrosine phosphorylation of β3 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 β3 integrin cytoplasmic tyrosine
(ICY) domain, a conserved motif found in thesubunits of several integrins. β3 ICY
domain tyrosine phosphorylation induces the recruitment of two proteins to the cytoplasmic
domains of αIIbβ3: the cytoskeletal protein myosin, important to clot retraction;
and the signaling adapter protein Shc, important to platelet stimulation. The critical
role of β3 tyrosine phosphorylation to platelet function was established by the diYF
mouse, a novel strain which expresses an αIIbβ3 in which the two β3 ICY domain tyrosines
have been mutated to phenylalanine. These mice are selectively impaired in outside-in
αIIbβ3 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 β3 tyrosine phosphorylation signaling
mechanism is important to αIIbβ3 function and might be applicable to a wide variety
of integrin-mediated events.
Key words
Platelets - IIb 3 integrin - tyrosine phosphorylation - signaling mechanisms - arterial
thrombosis
