Published online before print April 26, 2007, doi: 10.1161/ATVBAHA.107.141390
© 2007 American Heart Association, Inc.
Brief Reviews |
Platelet Receptor Proteolysis
A Mechanism for Downregulating Platelet Reactivity
From the Departments of Immunology (R.K.A., E.E.G., M.C.B.) and Biochemistry and Molecular Biology (D.K.), Monash University, Melbourne, Australia.
Correspondence to Robert K. Andrews or Michael C. Berndt, Department of Immunology, Monash University, Alfred Medical Research & Education Precinct (AMREP), Melbourne 3004, Australia. E-mail rob.andrews{at}med.monash.edu.au or michael.berndt@med.monash.edu.au
The platelet plasma membrane is literally at the cutting-edge of recent research into proteolytic regulation of the function and surface expression of platelet receptors, revealing new mechanisms for how the thrombotic propensity of platelets is controlled in health and disease. Extracellular proteolysis of receptors irreversibly inactivates receptor-mediated adhesion and signaling, as well as releasing soluble fragments into the plasma where they act as potential markers or modulators. Platelet-surface sheddases, particularly of the metalloproteinase-disintegrin (ADAM) family, can be regulated by many of the same mechanisms that control receptor function, such as calmodulin association or activation of signaling pathways. This provides layers of regulation (proteinase and receptor), and a higher order of control of cellular function. Activation of pathways leading to extracellular shedding is concomitant with activation of intracellular proteinases such as calpain, which may also irreversibly deactivate receptors. In this review, platelet receptor shedding will be discussed in terms of (1) the identity of proteinases involved in receptor proteolysis, (2) key platelet receptors regulated by proteolytic pathways, and (3) how shedding might be regulated in normal physiology or future therapeutics. In particular, a focus on proteolytic regulation of the platelet collagen receptor, glycoprotein (GP)VI, illustrates many of the key biochemical, cellular, and clinical implications of current research in this area.
This review focuses on key proteolytic mechanisms regulating the surface expression, adheso-signaling function and plasma levels of platelet receptors involved in thrombosis, inflammation and other vascular processes, in particular using platelet collagen receptor, glycoprotein (GP)VI, shedding to illustrate the implications for normal physiology or future therapeutics.
Key Words: glycoprotein Ib-IX-V • glycoprotein VI • platelets • thrombosis • shedding
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