Proteolysis of platelet receptors in humans and other species.
In the past 5 years, metalloproteinase-mediated ectodomain shedding of platelet receptors has emerged as a new mechanism for modulating platelet function. By regulating surface expression of the platelet-specific receptors, glycoprotein (GP)VI that binds collagen, and GPIbalpha (the major ligand-binding subunit of the GPIb-IX-V complex) that binds von Willebrand factor (VWF) and other procoagulant and proinflammatory ligands, shedding not only irreversibly downregulates GPVI/GPIbalpha function, but generates proteolytic fragments that might be unique biomarkers or modulators in plasma. This is potentially significant because GPVI and GPIbalpha are involved in initiating thrombotic diseases such as heart attack and stroke, as well as autoimmune diseases where anti-platelet antibodies result in thrombocytopenia. Altered expression levels of GPIbalpha/GPVI are associated with both thrombotic propensity and platelet aging, suggesting an additional role in platelet clearance. Although emerging data are elucidating molecular mechanisms underlying GPIbalpha/GPVI shedding, evidence for the functional consequences of shedding in vivo, either clinically or in animal models, is far more limited. Here we consider recent published evidence for GPVI or GPIbalpha shedding in humans, nonhuman primates and mice, and whether conservation of sheddase cleavage sites across species points to a functional role for metalloproteolytic shedding in vivo.
Qiao
Jian L
JL
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
Shen
Yang
Y
Gardiner
Elizabeth E
EE
Andrews
Robert K
RK
D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D006868:Hydrolysis; D008562:Membrane Glycoproteins / Q000097:blood / Q000737:chemistry / Q000502:physiology; D045726:Metalloproteases / Q000378:metabolism*; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000032:analysis / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary
D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; C094990:adhesion receptor; C023592:glycocalicin; C098341:platelet membrane glycoprotein VI; D045726:Metalloproteases; D051722:ADAM Proteins