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Hepatocyte growth factor inhibitor-2 prevents shedding of matritpase

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  • Brian R Larsen, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Simon D Steffensen, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Nis V L Nielsen, Department of Molecular Biology and Genetics - Aarhus University, Denmark
  • Stine Friis, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Sine Godiksen, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Jette Bornholdt, Department of Biology, Faculty of Science, University of Copenhagen, Denmark
  • Christoffer Soendergaard, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Denmark
  • Annika Weile Nonboe, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Denmark
  • Martin N. Andersen, Department of Biomedical Sciences, Faculty of Health Science, University of Copenhagen, Denmark
  • Steen S. Poulsen, Department of Biomedical Sciences, Faculty of Health Science, University of Copenhagen, Denmark
  • Roman Szabo, Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD 20892, USA, United States
  • Thomas H. Bugge, Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD 20892, USA, United States
  • Chen-Yong Lin, Department of Biochemistry and Molecular Biology, Greenebaum Cancer Centre, University of Maryland, Baltimore, MD 21201, USA, United States
  • Hann2 Skovbjerg, Medical Department, Amager Hospital, Copenhagen , Denmark
  • Jan Kristian Jensen
  • Lotte K Vogel, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Denmark
Hepatocyte growth factor activator inhibitor-2 (HAI-2) is an inhibitor of many proteases in vitro, including the membrane-bound serine protease, matriptase. Studies of knock-out mice have shown that HAI-2 is essential for placental development only in mice expressing matriptase, suggesting that HAI-2 is important for regulation of matriptase. Previous studies have shown that recombinant expression of matriptase was unsuccessful unless co-expressed with another HAI, HAI-1. In the present study we show that when human matriptase is recombinantly expressed alone in the canine cell line MDCK, then human matriptase mRNA can be detected and the human matriptase ectodomain is shed to the media, suggesting that matriptase expressed alone is rapidly transported through the secretory pathway and shed. Whereas matriptase expressed together with HAI-1 or HAI-2 accumulates on the plasma membrane where it is activated, as judged by cleavage at Arg614 and increased peptidolytic activity of the cell extracts. Mutagenesis of Kunitz domain 1 but not Kunitz domain 2 abolished this function of HAI-2. HAI-2 seems to carry out its function intracellularly as this is where the vast majority of HAI-2 is located and since HAI-2 could not be detected on the basolateral plasma membrane where matriptase resides. However, minor amounts of HAI-2 not undergoing endocytosis could be detected on the apical plasma membrane. Our results suggest that Kunitz domain 1 of HAI-2 cause matriptase to accumulate in a membrane-bound form on the basolateral plasma membrane.
Original languageEnglish
JournalExperimental Cell Research
Volume319
Issue6
Pages (from-to)918-929
ISSN0014-4827
DOIs
Publication statusPublished - 1 Apr 2013

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