title: Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary.
abstract: HAI-1 [HGF (hepatocyte growth factor) activator inhibitor-1] is a Kunitz-type transmembrane serine protease inhibitor that forms inhibitor complexes with the trypsin-like serine protease, matriptase. HAI-1 is essential for mouse placental development and embryo survival and together with matriptase it is a key regulator of carcinogenesis. HAI-1 is expressed in polarized epithelial cells, which have the plasma membrane divided by tight junctions into an apical and a basolateral domain. In the present study we show that HAI-1 at steady-state is mainly located on the basolateral membrane of both Madin-Darby canine kidney cells and mammary gland epithelial cells. After biosynthesis, HAI-1 is exocytosed mainly to the basolateral plasma membrane from where 15% of the HAI-1 molecules are proteolytically cleaved and released into the basolateral medium. The remaining membrane-associated HAI-1 is endocytosed and then recycles between the basolateral plasma membrane and endosomes for hours until it is transcytosed to the apical plasma membrane. Minor amounts of HAI-1 present at the apical plasma membrane are proteolytically cleaved and released into the apical medium. Full-length membrane-bound HAI-1 has a half-life of 1.5 h and is eventually degraded in the lysosomes, whereas proteolytically released HAI-1 is more stable. HAI-1 is co-localized with its cognate protease, matriptase, at the basolateral plasma membrane. We suggest that HAI-1, in addition to its protease inhibitory function, plays a role in transporting matriptase as a matriptase-HAI-1 complex from the basolateral plama membrane to the apical plasma membrane, as matriptase is known to interact with prostasin, located at the apical plasma membrane.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Sine
authors.initials: S
authors.lastname: Godiksen
authors.forename: Joanna
authors.initials: J
authors.lastname: Selzer-Plon
authors.forename: Esben D K
authors.initials: ED
authors.lastname: Pedersen
authors.forename: Kathrine
authors.initials: K
authors.lastname: Abell
authors.forename: Hanne B
authors.initials: HB
authors.lastname: Rasmussen
authors.forename: Roman
authors.initials: R
authors.lastname: Szabo
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.forename: Lotte K
authors.initials: LK
authors.lastname: Vogel
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D004705:Endocytosis; D005089:Exocytosis; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D021381:Protein Transport; D053491:Proteinase Inhibitory Proteins, Secretory; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; C504591:Spint1 protein, mouse; D012697:Serine Endopeptidases; C485595:matriptase