Abstract
Integrins not only bind adhesive ligands1, they also act as signalling receptors2. Both functions allow the integrin αIIbβ3 to mediate platelet aggregation3. Platelet agonists activate αIIbβ3 (inside-out signalling) to allow the binding of soluble fibrinogen. Subsequent platelet aggregation leads to outside-in αIIbβ3 signalling, which results in calcium mobilization4, tyrosine phosphorylation of numerous proteins5,6 including β3 itself7, increased cytoskeletal reorganisation8 and further activation of αIIbβ3 (ref. 2). 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 αIIbβ3 in which the tyrosines in the integrin cytoplasmic tyrosine motif have been mutated to phenylalanines. These mice are selectively impaired in outside-in αIIbβ3 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 β-integrin signals and a potential target for new therapeutic agents.
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We thank R. Wong for his help with the figures.
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Law, D., DeGuzman, F., Heiser, P. et al. Integrin cytoplasmic tyrosine motif is required for outside-in αIIbβ3 signalling and platelet function. Nature 401, 808–811 (1999). https://doi.org/10.1038/44599
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DOI: https://doi.org/10.1038/44599
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