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Kindlin-3 is essential for integrin activation and platelet aggregation

Abstract

Integrin-mediated platelet adhesion and aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessive platelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke1. To ensure that platelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state and shift to a high-affinity state (in a process known as integrin activation or priming) after contacting a wounded vessel2. The shift is mediated through binding of the cytoskeletal protein Talin to the β subunit cytoplasmic tail3,4,5. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannot activate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind to regions of β-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis.

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Figure 1: Kindlin-3–deficient animals show severe hemorrhages.
Figure 2: Impaired platelet function in Kind3−/− mice.
Figure 3: Biochemical analyses of Kind3−/− platelets.
Figure 4: Defective adhesion and spreading of Kind3−/− platelets.

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Acknowledgements

We thank D. Calderwood (Yale University) and I. Campbell (Oxford University) for recombinant integrin tails and integrin tail expression vectors and help with pull-down assays, G. Wanner for imaging of platelets by scanning electron microscopy, M. Sixt and M. Boesl for mouse manipulation experiments, and R. Zent, A. Pozzi, M. Humphries and M. Schwartz for critical reading of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft and the Max Planck Society.

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M.M. and R.F. designed and supervised research. M.M., B.N. and R.F. wrote the manuscript. M.M., B.N., S.U. and M.P. performed experiments. All authors discussed the results and commented on the manuscript.

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Correspondence to Reinhard Fässler.

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Supplementary Figures 1–3 and Supplementary Table 1 (PDF 303 kb)

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Moser, M., Nieswandt, B., Ussar, S. et al. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 14, 325–330 (2008). https://doi.org/10.1038/nm1722

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