title: HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.
authors.forename: Annika W
authors.initials: AW
authors.lastname: Nonboe
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.
authors.forename: Oliver
authors.initials: O
authors.lastname: Krigslund
authors.affiliation: 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.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Soendergaard
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Skovbjerg
authors.affiliation: 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.
authors.forename: Stine
authors.initials: S
authors.lastname: Friis
authors.affiliation: Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Andersen
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ellis
authors.affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawaguchi
authors.affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen North, Denmark.
authors.forename: Lotte K
authors.initials: LK
authors.lastname: Vogel
mesh_terms: D001692:Biological Transport / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; C109148:SPINT2 protein, human; D012697:Serine Endopeptidases; C485595:matriptase
keywords: HAI-1; HAI-2; SEA domain cleavage; chromogenic activity; matriptase; secretory transport