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Differentially regulated GPVI ectodomain shedding by multiple platelet-expressed proteinases
Markus Bender1, Sebastian Hofmann, David Stegner
1Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, Würzburg, Germany.
Blood
|July 21, 2010
Summary
Glycoprotein VI (GPVI) shedding from platelets is crucial for hemostasis and thrombosis. This study reveals that while ADAM10 and ADAM17 can cleave GPVI, a third enzyme mediates antibody-induced shedding, suggesting new therapeutic targets.
Area of Science:
- Biochemistry
- Hematology
- Molecular Biology
Background:
- Glycoprotein VI (GPVI) is vital for platelet activation by collagen during vascular injury, contributing to hemostasis and thrombosis.
- GPVI downregulation via shedding is a potential antithrombotic strategy, with ADAM metalloproteinases implicated but not definitively proven as mediators.
Purpose of the Study:
- To investigate the specific roles of ADAM10 and ADAM17 in Glycoprotein VI (GPVI) ectodomain shedding.
- To identify the enzymes responsible for GPVI shedding in vivo and in vitro, particularly following antibody stimulation.
Main Methods:
- Generated mice with megakaryocyte-specific ADAM10 deficiency and utilized Adam17(ex/ex) mice.
- Performed in vitro and in vivo studies on GPVI shedding using wild-type, ADAM10/ADAM17 deficient platelets, and specific antibodies.
Main Results:
- GPVI shedding in vitro can be mediated by either ADAM10 or ADAM17, depending on the stimulus.
- Antibody-induced GPVI shedding in vivo was not abolished in mice lacking both ADAM10 and ADAM17 in platelets, indicating a distinct cleaving enzyme.
Conclusions:
- GPVI ectodomain shedding is regulated by multiple, differentially expressed platelet proteinases.
- The identification of novel GPVI-cleaving enzymes has significant implications for developing targeted antithrombotic therapies.
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