Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signalling and platelet function

Nature. 1999 Oct 21;401(6755):808-11. doi: 10.1038/44599.

Abstract

Integrins not only bind adhesive ligands, they also act as signalling receptors. Both functions allow the integrin alphaIIbbeta3 to mediate platelet aggregation. Platelet agonists activate alphaIIbbeta3 (inside-out signalling) to allow the binding of soluble fibrinogen. Subsequent platelet aggregation leads to outside-in alphaIIbbeta3 signalling, which results in calcium mobilization, tyrosine phosphorylation of numerous proteins including beta3 itself, increased cytoskeletal reorganisation and further activation of alphaIIbbeta3. Thus, outside-in signals enhance aggregation, although the mechanisms and functional consequences of specific signalling events remain unclear. Here we describe a mouse that expresses an alphaIIbbeta3 in which the tyrosines in the integrin cytoplasmic tyrosine motif have been mutated to phenylalanines. These mice are selectively impaired in outside-in alphaIIbbeta3 signalling, with defective aggregation and clot-retraction responses in vitro, and an in vivo bleeding defect which is characterized by a pronounced tendency to rebleed. These data provide evidence for an important role of outside-in signalling in platelet physiology. Furthermore, they identify the integrin cytoplasmic tyrosine motif as a key mediator of beta-integrin signals and a potential target for new therapeutic agents.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Bleeding Time
  • Blood Coagulation
  • Blood Platelets / physiology*
  • Cloning, Molecular
  • Cytoplasm / metabolism
  • Fibrinogen / metabolism
  • In Vitro Techniques
  • Mice
  • Phosphorylation
  • Platelet Aggregation / physiology
  • Platelet Glycoprotein GPIIb-IIIa Complex / genetics
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
  • Point Mutation
  • Signal Transduction*
  • Tyrosine / metabolism*

Substances

  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Tyrosine
  • Fibrinogen