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RAP1-GTPase signaling and platelet function

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Abstract

Platelets are critical for hemostasis, i.e., the body’s ability to prevent blood loss at sites of vascular injury. They patrol the vasculature in a quiescent, non-adhesive state for approximately 10 days, after which they are removed from circulation by phagocytic cells of the reticulo-endothelial system. At sites of vascular injury, they promptly shift to an activated, adhesive state required for the formation of a hemostatic plug. The small GTPase RAP1 is a critical regulator of platelet adhesiveness. Our recent studies demonstrate that the antagonistic balance between the RAP1 regulators, CalDAG-GEFI and RASA3, is critical for the modulation of platelet adhesiveness, both in circulation and at sites of vascular injury. The RAP1 activator CalDAG-GEFI responds to small changes in the cytoplasmic calcium concentration and thus provides sensitivity and speed to the activation response, essential for efficient platelet adhesion under conditions of hemodynamic shear stress. The RAP1 inhibitor RASA3 ensures that circulating platelets remain quiescent by restraining CalDAG-GEFI-dependent RAP1 activation. Upon cellular stimulation, it is turned off by P2Y12 signaling to enable sustained RAP1 activation, required for the formation of a stable hemostatic plug. This review will summarize important studies that elucidated the signaling pathways that control RAP1 activation in platelets.

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Acknowledgments

This work was supported by the American Heart Association (14EIA18910004) and NIH grants R01 HL121650 and P01 HL120846.

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Authors and Affiliations

  1. Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK

    Lucia Stefanini

  2. Department of Biochemistry and Biophysics, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Wolfgang Bergmeier

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  1. Lucia Stefanini
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  2. Wolfgang Bergmeier
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Correspondence to Wolfgang Bergmeier.

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Stefanini, L., Bergmeier, W. RAP1-GTPase signaling and platelet function. J Mol Med 94, 13–19 (2016). https://doi.org/10.1007/s00109-015-1346-3

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  • DOI: https://doi.org/10.1007/s00109-015-1346-3

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