Proteolysis of platelet receptors in humans and other species
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Jian L. Qiao
Abstract
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 GPIbα (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/GPIbα function, but generates proteolytic fragments that might be unique biomarkers or modulators in plasma. This is potentially significant because GPVI and GPIbα 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 GPIbα/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 GPIbα/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 GPIbα 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.
©2010 by Walter de Gruyter Berlin New York
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Artikel in diesem Heft
- Guest Editorial
- Highlight: The Biology of Proteolytic Systems
- Highlight: 6th General Meeting of the International Proteolysis Society
- Structure, mechanism and inhibition of γ-secretase and presenilin-like proteases
- Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
- Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
- Proteases in lymphocyte killer function: redundancy, polymorphism and questions remaining
- Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
- Proteolysis of platelet receptors in humans and other species
- Blunting the knife: development of vaccines targeting digestive proteases of blood-feeding helminth parasites
- Impaired turnover of autophagolysosomes in cathepsin L deficiency
- Nuclear cysteine cathepsin variants in thyroid carcinoma cells
- Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer
- Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis
- Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)
- Molecular contortionism – on the physical limits of serpin ‘loop-sheet’ polymers
- The substrate specificity profile of human granzyme A
- Use of granzyme B-based fluorescent protein reporters to monitor granzyme distribution and granule integrity in live cells
