Beta3 tyrosine phosphorylation in alphaIIbbeta3 (platelet membrane GP IIb-IIIa) outside-in integrin signaling

Thromb Haemost. 2001 Jul;86(1):246-58.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Antigens, CD / chemistry
  • Antigens, CD / metabolism*
  • Antigens, CD / physiology*
  • Humans
  • Integrin beta3
  • Phosphorylation
  • Platelet Activation / physiology
  • Platelet Glycoprotein GPIIb-IIIa Complex / chemistry
  • Platelet Glycoprotein GPIIb-IIIa Complex / physiology*
  • Platelet Membrane Glycoproteins / chemistry
  • Platelet Membrane Glycoproteins / metabolism*
  • Platelet Membrane Glycoproteins / physiology*
  • Protein Structure, Tertiary
  • Signal Transduction*
  • Tyrosine / metabolism

Substances

  • Antigens, CD
  • Integrin beta3
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Platelet Membrane Glycoproteins
  • Tyrosine