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Traffic. 2017 Jun;18(6):378-391. doi: 10.1111/tra.12482. Epub 2017 May 2.

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

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Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.
Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
Department of Molecular Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen East, Denmark.
Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
School of Biological Sciences, University of East Anglia, Norwich, UK.
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.


It has recently been shown that hepatocyte growth factor activator inhibitor-2 (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 this study, we describe 3 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 endoplasmic reticulum (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 and 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.


HAI-1; HAI-2; SEA domain cleavage; chromogenic activity; matriptase; secretory transport

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