AI Article Synopsis
- - GPVI, a collagen receptor on platelets, is stable in circulation but gets cleaved when platelets are activated, mainly through the action of ADAM10, a type of metalloproteinase.
- - The study assessed the levels of Tissue Inhibitors of Metalloproteinases (TIMPs) on resting and activated platelets, finding variable levels present, particularly TIMP1 and TIMP2.
- - Recombinant TIMP3 effectively inhibited ADAM10 activity, whereas TIMP2 only slightly reduced ligand-dependent cleavage of GPVI, indicating that while some TIMPs can influence ADAM10, they do not strongly regulate GPVI shedding.
Article Abstract
Platelet-specific collagen receptor glycoprotein (GP)VI is stable on the surface of circulating platelets but undergoes ectodomain cleavage on activated platelets. Activation-dependent GPVI metalloproteolysis is primarily mediated by A Disintegrin And Metalloproteinase (ADAM) 10. Regulation of platelet ADAMs activity is not well-defined however Tissue Inhibitors of Metalloproteinases (TIMPs) may play a role. As levels of TIMPs on platelets and the control of ADAMs-mediated shedding by TIMPs has not been evaluated, we quantified the levels of TIMPs on the surface of resting and activated platelets from healthy donors by flow cytometry and multiplex ELISA. Variable levels of all TIMPs could be detected on platelets. Plasma contained significant quantities of TIMP1 and TIMP2, but only trace amounts of TIMP3 and TIMP4. Recombinant TIMP3 strongly ablated resting and activated platelet ADAM10 activity, when monitored using a quenched fluorogenic peptide substrate with ADAM10 specificity. Whilst ADAM10-specific inhibitor GI254023X or ethylenediamine tetraacetic acid (EDTA) could modulate ligand-initiated shedding of GPVI, only recombinant TIMP2 achieved a modest (~20%) inhibition. We conclude that some platelet TIMPs are able to modulate platelet ADAM10 activity but none strongly regulate ligand-dependent shedding of GPVI. Our findings provide new insights into the regulation of platelet receptor sheddase activity.
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| http://dx.doi.org/10.1080/09537104.2023.2288213 | DOI Listing |
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Article Synopsis
- - GPVI, a collagen receptor on platelets, is stable in circulation but gets cleaved when platelets are activated, mainly through the action of ADAM10, a type of metalloproteinase.
- - The study assessed the levels of Tissue Inhibitors of Metalloproteinases (TIMPs) on resting and activated platelets, finding variable levels present, particularly TIMP1 and TIMP2.
- - Recombinant TIMP3 effectively inhibited ADAM10 activity, whereas TIMP2 only slightly reduced ligand-dependent cleavage of GPVI, indicating that while some TIMPs can influence ADAM10, they do not strongly regulate GPVI shedding.
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