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HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase.
Traffic. 2017 06; 18(6):378-391.T

Abstract

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Nonboe AW
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.
Krigslund O
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.
Soendergaard C
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.
Skovbjerg S
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.
Friis S
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark. Department of Molecular Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen East, Denmark.
Andersen MN
Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Ellis V
School of Biological Sciences, University of East Anglia, Norwich, UK.
Kawaguchi M
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Kataoka H
Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Bugge TH
Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
Vogel LK
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.

MeSH

Biological TransportCell MembraneCells, CulturedEndoplasmic ReticulumHumansMembrane GlycoproteinsProtein DomainsProteolysisSerine Endopeptidases

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28371047

Citation

Nonboe, Annika W., et al. "HAI-2 Stabilizes, Inhibits and Regulates SEA-cleavage-dependent Secretory Transport of Matriptase." Traffic (Copenhagen, Denmark), vol. 18, no. 6, 2017, pp. 378-391.
Nonboe AW, Krigslund O, Soendergaard C, et al. HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase. Traffic. 2017;18(6):378-391.
Nonboe, A. W., Krigslund, O., Soendergaard, C., Skovbjerg, S., Friis, S., Andersen, M. N., Ellis, V., Kawaguchi, M., Kataoka, H., Bugge, T. H., & Vogel, L. K. (2017). HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase. Traffic (Copenhagen, Denmark), 18(6), 378-391. https://doi.org/10.1111/tra.12482
Nonboe AW, et al. HAI-2 Stabilizes, Inhibits and Regulates SEA-cleavage-dependent Secretory Transport of Matriptase. Traffic. 2017;18(6):378-391. PubMed PMID: 28371047.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase. AU - Nonboe,Annika W, AU - Krigslund,Oliver, AU - Soendergaard,Christoffer, AU - Skovbjerg,Signe, AU - Friis,Stine, AU - Andersen,Martin N, AU - Ellis,Vincent, AU - Kawaguchi,Makiko, AU - Kataoka,Hiroaki, AU - Bugge,Thomas H, AU - Vogel,Lotte K, Y1 - 2017/05/02/ PY - 2016/10/05/received PY - 2017/03/24/revised PY - 2017/03/24/accepted PY - 2017/4/4/pubmed PY - 2018/3/3/medline PY - 2017/4/4/entrez KW - HAI-1 KW - HAI-2 KW - SEA domain cleavage KW - chromogenic activity KW - matriptase KW - secretory transport SP - 378 EP - 391 JF - Traffic (Copenhagen, Denmark) JO - Traffic VL - 18 IS - 6 N2 - 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. SN - 1600-0854 UR - https://www.unboundmedicine.com/medline/citation/28371047/HAI_2_stabilizes_inhibits_and_regulates_SEA_cleavage_dependent_secretory_transport_of_matriptase_ L2 - https://doi.org/10.1111/tra.12482 DB - PRIME DP - Unbound Medicine ER -