Beta3 tyrosine phosphorylation in alphaIIbbeta3 (platelet membrane GP IIb-IIIa) outside-in integrin signaling.
The platelet integrin alphaIIbbeta3 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 alphaIIbbeta3 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 alphaIIbbeta3 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. Beta3 ICY domain tyrosine phosphorylation induces the recruitment of two proteins to the cytoplasmic domains of alphaIIbbeta3: 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 alphaIIbbeta3 in which the two beta3 ICY domain tyrosines have been mutated to phenylalanine. These mice are selectively impaired in outside-in alphaIIbbeta3 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 alphaIIbbeta3 function and might be applicable to a wide variety of integrin-mediated events.
Phillips
D R
DR
COR Therapeutics, Inc., South San Francisco, CA 94080, USA. dphillips@corr.com
Nannizzi-Alaimo
L
L
Prasad
K S
KS
D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D039661:Integrin beta3; D010766:Phosphorylation; D015539:Platelet Activation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; D014443:Tyrosine