Integrin cytoplasmic tyrosine motif is required for outside-in αIIbβ3 signalling and platelet function

Debbie A. Law, Francis R. DeGuzman, Patrick Heiser, Kathleen Ministri-Madrid, Nigel Killeen and David R. Phillips ()
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Debbie A. Law: COR Therapeutics, Inc.
Francis R. DeGuzman: COR Therapeutics, Inc.
Patrick Heiser: COR Therapeutics, Inc.
Kathleen Ministri-Madrid: COR Therapeutics, Inc.
Nigel Killeen: University of California
David R. Phillips: COR Therapeutics, Inc.

Nature, 1999, vol. 401, issue 6755, 808-811

Abstract: 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.

Date: 1999
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DOI: 10.1038/44599

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