Tissue Inhibitors of Metalloproteinases (TIMPs) modulate platelet ADAM10 activity

Christine Lee, Amandeep Kaur, Samantha J.Montague, Sarah M. Hicks, Robert K.Andrews, Elizabeth Gardiner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 welldefined
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.
Original languageEnglish
Article number2288213
Number of pages10
JournalPlatelets
Volume34
Issue number1
DOIs
Publication statusPublished - 30 Nov 2023
Externally publishedYes

Bibliographical note

Funding
This work was supported by the National Health and Medical Research Council of Australia and the Australian Research Council.

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