HAI-2 stabilizes, inhibits, and regulates SEA-cleavage-dependent secretory transport of matriptase

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Nonboe, Annika W., Krigslund, Oliver, Soendergaard, Christoffer, Skovbjerg, Signe, Friis, Stine, Andersen, Martin Nybo, Ellis, Vincent, Kawaguchi, Makiko, Kataoka, Hiroaki, Bugge, Thomas H. and Vogel, Lotte K. (2017) HAI-2 stabilizes, inhibits, and regulates SEA-cleavage-dependent secretory transport of matriptase. Traffic, 18 (6). 378–391. ISSN 1398-9219

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Abstract

It has recently been shown that HAI-2 is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In the present study we describe three mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F, and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the ER. We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation, and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L, C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization, and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway.

Item Type: Article
Uncontrolled Keywords: matriptase,hai-2,hai-1,sea domain cleavage,secretory transport,chromogenic activity
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: Pure Connector
Date Deposited: 07 Apr 2017 05:10
Last Modified: 07 Oct 2023 00:54
URI: https://ueaeprints.uea.ac.uk/id/eprint/63200
DOI: 10.1111/tra.12482

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