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.
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24 December 2007
Brief Definitive Report|
December 17 2007
Talin is required for integrin-mediated platelet function in hemostasis and thrombosis
Brian G. Petrich,
Brian G. Petrich
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
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Patrizia Marchese,
Patrizia Marchese
2Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
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Zaverio M. Ruggeri,
Zaverio M. Ruggeri
2Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
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Saskia Spiess,
Saskia Spiess
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
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Rachel A.M. Weichert,
Rachel A.M. Weichert
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
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Feng Ye,
Feng Ye
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
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Ralph Tiedt,
Ralph Tiedt
3Department of Experimental Hematology, University Hospital Basel, 4031 Basel, Switzerland
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Radek C. Skoda,
Radek C. Skoda
3Department of Experimental Hematology, University Hospital Basel, 4031 Basel, Switzerland
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Susan J. Monkley,
Susan J. Monkley
4Department of Biochemistry, Henry Wellcome Building, University of Leicester, Leicester LE1 9HN, UK
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David R. Critchley,
David R. Critchley
4Department of Biochemistry, Henry Wellcome Building, University of Leicester, Leicester LE1 9HN, UK
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Mark H. Ginsberg
Mark H. Ginsberg
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
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Brian G. Petrich
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
Patrizia Marchese
2Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
Zaverio M. Ruggeri
2Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
Saskia Spiess
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
Rachel A.M. Weichert
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
Feng Ye
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
Ralph Tiedt
3Department of Experimental Hematology, University Hospital Basel, 4031 Basel, Switzerland
Radek C. Skoda
3Department of Experimental Hematology, University Hospital Basel, 4031 Basel, Switzerland
Susan J. Monkley
4Department of Biochemistry, Henry Wellcome Building, University of Leicester, Leicester LE1 9HN, UK
David R. Critchley
4Department of Biochemistry, Henry Wellcome Building, University of Leicester, Leicester LE1 9HN, UK
Mark H. Ginsberg
1Department of Medicine, University of California, San Diego, La Jolla, CA 92093
CORRESPONDENCE Mark H. Ginsberg: [email protected]
Received:
August 22 2007
Accepted:
November 07 2007
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2007
J Exp Med (2007) 204 (13): 3103–3111.
Article history
Received:
August 22 2007
Accepted:
November 07 2007
Citation
Brian G. Petrich, Patrizia Marchese, Zaverio M. Ruggeri, Saskia Spiess, Rachel A.M. Weichert, Feng Ye, Ralph Tiedt, Radek C. Skoda, Susan J. Monkley, David R. Critchley, Mark H. Ginsberg; Talin is required for integrin-mediated platelet function in hemostasis and thrombosis . J Exp Med 24 December 2007; 204 (13): 3103–3111. doi: https://doi.org/10.1084/jem.20071800
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