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Citation

BibTex format

@article{Gray:2014:10.1160/TH13-11-0895,
author = {Gray, K and Elghadban, S and Thongyoo, P and Owen, KA and Szabo, R and Bugge, TH and Tate, EW and Leatherbarrow, RJ and Ellis, V},
doi = {10.1160/TH13-11-0895},
journal = {Thrombosis and Haemostasis},
pages = {402--411},
title = {Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II},
url = {http://dx.doi.org/10.1160/TH13-11-0895},
volume = {112},
year = {2014}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Gray,K
AU  - Elghadban,S
AU  - Thongyoo,P
AU  - Owen,KA
AU  - Szabo,R
AU  - Bugge,TH
AU  - Tate,EW
AU  - Leatherbarrow,RJ
AU  - Ellis,V
DO  - 10.1160/TH13-11-0895
EP  - 411
PY  - 2014///
SN  - 0340-6245
SP  - 402
TI  - Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II
T2  - Thrombosis and Haemostasis
UR  - http://dx.doi.org/10.1160/TH13-11-0895
UR  - http://hdl.handle.net/10044/1/26836
VL  - 112
ER  -
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Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821