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.
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Research Article|
June 26 2008
Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary
Sine Godiksen;
Sine Godiksen
*Department of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Joanna Selzer-Plon;
Joanna Selzer-Plon
*Department of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Esben D. K. Pedersen;
Esben D. K. Pedersen
*Department of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Kathrine Abell;
Kathrine Abell
*Department of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Hanne B. Rasmussen;
Hanne B. Rasmussen
†Department of Biomedical Sciences, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
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Roman Szabo;
Roman Szabo
‡Proteases and Tissue Remodeling Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Thomas H. Bugge;
Thomas H. Bugge
‡Proteases and Tissue Remodeling Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Lotte K. Vogel
Lotte K. Vogel
1
*Department of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
1To whom correspondence should be addressed (e-mail vogel@imbg.ku.dk).
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Publisher: Portland Press Ltd
Received:
October 31 2007
Revision Received:
April 07 2008
Accepted:
April 10 2008
Accepted Manuscript online:
April 10 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 413 (2): 251–259.
Article history
Received:
October 31 2007
Revision Received:
April 07 2008
Accepted:
April 10 2008
Accepted Manuscript online:
April 10 2008
Citation
Sine Godiksen, Joanna Selzer-Plon, Esben D. K. Pedersen, Kathrine Abell, Hanne B. Rasmussen, Roman Szabo, Thomas H. Bugge, Lotte K. Vogel; Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary. Biochem J 15 July 2008; 413 (2): 251–259. doi: https://doi.org/10.1042/BJ20071496
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