Platelet receptor proteolysis: a mechanism for downregulating platelet reactivity.
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.
Andrews
Robert K
RK
Department of Immunology, Monash University, Alfred Medical Research & Education Precinct, Melbourne 3004, Australia. rob.andrews@med.monash.edu.au
Karunakaran
Denuja
D
Gardiner
Elizabeth E
EE
Berndt
Michael C
MC
D001792:Blood Platelets / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D015539:Platelet Activation / Q000502:physiology*; D010973:Platelet Adhesiveness / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction
D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface