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Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II

Gray, K, Elghadban, S, Thongyoo, P, Owen, KA, Szabo, R, Bugge, TH, Tate, EW, Leatherbarrow, RJ and Ellis, V (2014) Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II. Thrombosis and Haemostasis, 112 (2). pp. 402-411. ISSN 0340-6245

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Open Access URL: https://spiral.imperial.ac.uk:8443/handle/10044/1/... (Accepted version)

Abstract

Matriptase is a type-II transmembrane serine protease involved in epithelial homeostasis in both health and disease, and is implicated in the development and progression of a variety of cancers. Matriptase mediates its biological effects both via as yet undefined substrates and pathways, and also by proteolytic cleavage of a variety of well-defined protein substrates, several of which it shares with the closely-related protease hepsin. Development of targeted therapeutic strategies will require discrimination between these proteases. Here we have investigated cyclic microproteins of the squash Momordica cochinchinensis trypsin-inhibitor family (generated by total chemical synthesis) and found MCoTI-II to be a high-affinity (Ki 9 nM) and highly selective (> 1,000-fold) inhibitor of matriptase. MCoTI-II efficiently inhibited the proteolytic activation of pro-hepatocyte growth factor (HGF) by matriptase but not by hepsin, in both purified and cell-based systems, and inhibited HGF-dependent cell scattering. MCoTI-II also selectively inhibited the invasion of matriptase-expressing prostate cancer cells. Using a model of epithelial cell tight junction assembly, we also found that MCoTI-II could effectively inhibit the re-establishment of tight junctions and epithelial barrier function in MDCK-I cells after disruption, consistent with the role of matriptase in regulating epithelial integrity. Surprisingly, MCoTI-II was unable to inhibit matriptase-dependent proteolytic activation of prostasin, a GPI-anchored serine protease also implicated in epithelial homeostasis. These observations suggest that the unusually high selectivity afforded by MCoTI-II and its biological effectiveness might represent a useful starting point for the development of therapeutic inhibitors, and further highlight the role of matriptase in epithelial maintenance.

Item Type: Article
Additional Information: This article is not an exact copy of the original published article in Thrombosis and Haemostasis. The definitive publisher-authenticated version of "Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II" K. Gray, S. Elghadban, P. Thongyoo, K. A. Owen, R. Szabo, T. H. Bugge, E. W. Tate, R. J. Leatherbarrow, V. Ellis. Vol 112 Issue 2 Pages 402-411 is available online at: https://dx.doi.org/10.1160/TH13-11-0895
Uncontrolled Keywords: 1103 Clinical Sciences, 1102 Cardiovascular Medicine And Haematology
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology
Divisions: Vice-Chancellor's Office
Publisher: Schattauer
Related URLs:
Date Deposited: 26 Jun 2018 11:28
Last Modified: 26 Jun 2018 11:28
DOI or Identification number: 10.1160/TH13-11-0895
URI: http://researchonline.ljmu.ac.uk/id/eprint/8854

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