β3 Tyrosine Phosphorylation in αIIbβ3 (Platelet Membrane GP IIb-IIIa) Outside-in Integrin Signaling
| Autor: | David Phillips, K. S. Srinivasa Prasad, Lisa Nannizzi-Alaimo |
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| Rok vydání: | 2001 |
| Předmět: | |
| Zdroj: | Thrombosis and Haemostasis. 86:246-258 |
| ISSN: | 2567-689X 0340-6245 |
| DOI: | 10.1055/s-0037-1616222 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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