The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online
doi:10.1084/jem.20071827
The Journal of Experimental Medicine, Vol. 204, No. 13, 3113-3118
The Rockefeller University Press, 0022-1007 $30.00
© Nieswandt et al.
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BRIEF DEFINITIVE REPORT

 Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo

Bernhard Nieswandt1,2, Markus Moser3, Irina Pleines1, David Varga-Szabo1, Sue Monkley4, David Critchley4, and Reinhard Fässler3

1 Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, and 2 Institute of Clinical Biochemistry and Pathobiochemisty, University of Würzburg, 97078 Würzburg, Germany
3 Department of Molecular Medicine, Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany
4 Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK

CORRESPONDENCE Reinhard Fässler: Faessler{at}biochem.mpg.de

Platelet adhesion and aggregation at sites of vascular injury are essential for normal hemostasis but may also lead to pathological thrombus formation, causing diseases such as myocardial infarction or stroke. Heterodimeric receptors of the integrin family play a central role in the adhesion and aggregation of platelets. In resting platelets, integrins exhibit a low affinity state for their ligands, and they shift to a high affinity state at sites of vascular injury. It has been proposed that direct binding of the cytoskeletal protein talin1 to the cytoplasmic domain of the integrin β subunits is necessary and sufficient to trigger the activation of integrins to this high affinity state, but direct in vivo evidence in support of this hypothesis is still lacking. Here, we show that platelets from mice lacking talin1 are unable to activate integrins in response to all known major platelet agonists while other cellular functions are still preserved. As a consequence, mice with talin-deficient platelets display a severe hemostatic defect and are completely resistant to arterial thrombosis. Collectively, these experiments demonstrate that talin is required for inside-out activation of platelet integrins in hemostasis and thrombosis.


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