Talin is required for integrin-mediated platelet function in hemostasis and thrombosis

Author:

Petrich Brian G.1,Marchese Patrizia2,Ruggeri Zaverio M.2,Spiess Saskia1,Weichert Rachel A.M.1,Ye Feng1,Tiedt Ralph3,Skoda Radek C.3,Monkley Susan J.4,Critchley David R.4,Ginsberg Mark H.1

Affiliation:

1. Department of Medicine, University of California, San Diego, La Jolla, CA 92093

2. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037

3. Department of Experimental Hematology, University Hospital Basel, 4031 Basel, Switzerland

4. Department of Biochemistry, Henry Wellcome Building, University of Leicester, Leicester LE1 9HN, UK

Abstract

Integrins are critical for hemostasis and thrombosis because they mediate both platelet adhesion and aggregation. Talin is an integrin-binding cytoplasmic adaptor that is a central organizer of focal adhesions, and loss of talin phenocopies integrin deletion in Drosophila. Here, we have examined the role of talin in mammalian integrin function in vivo by selectively disrupting the talin1 gene in mouse platelet precursor megakaryocytes. Talin null megakaryocytes produced circulating platelets that exhibited normal morphology yet manifested profoundly impaired hemostatic function. Specifically, platelet-specific deletion of talin1 led to spontaneous hemorrhage and pathological bleeding. Ex vivo and in vitro studies revealed that loss of talin1 resulted in dramatically impaired integrin αIIbβ3-mediated platelet aggregation and β1 integrin–mediated platelet adhesion. Furthermore, loss of talin1 strongly inhibited the activation of platelet β1 and β3 integrins in response to platelet agonists. These data establish that platelet talin plays a crucial role in hemostasis and provide the first proof that talin is required for the activation and function of mammalian α2β1 and αIIbβ3 integrins in vivo.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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