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Originally published In Press as doi:10.1074/jbc.M006412200 on September 29, 2000

J. Biol. Chem., Vol. 275, Issue 51, 40453-40462, December 22, 2000
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Hepatocyte Growth Factor Activator Inhibitor Type 1 Is a Specific Cell Surface Binding Protein of Hepatocyte Growth Factor Activator (HGFA) and Regulates HGFA Activity in the Pericellular Microenvironment*

Hiroaki KataokaDagger §, Takeshi Shimomura, Toshiya Kawaguchi, Ryouichi HamasunaDagger , Hiroshi ItohDagger , Naomi Kitamura||, Keiji Miyazawa||, and Masashi KoonoDagger

From the Dagger  Second Department of Pathology, Miyazaki Medical College, Kihara, Kiyotake, Miyazaki 889-1692, Japan, the  Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc., Aoba-ku, Yokohama 227-8502, Japan, and the || Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8501, Japan

Hepatocyte growth factor activator (HGFA) is responsible for proteolytic activation of the precursor form of hepatocyte growth factor in injured tissues. To date, two specific inhibitors of HGFA have been identified, namely HGFA inhibitor type 1 (HAI-1) and type 2 (HAI-2)/placental bikunin (PB). Both inhibitors are first synthesized as integral membrane proteins having two Kunitz domains and a transmembrane domain, and are subsequently released from cell surface by shedding. Here we show that an active form of HGFA is specifically complexed with membrane-form HAI-1, but not with HAI-2/PB, on the surface of epithelial cells expressing both inhibitors. This binding required the enzyme activity of HGFA. The selective binding of HGFA to the cell surface HAI-1 was further confirmed in an engineered system using Chinese hamster ovary cells, in which only the cells expressing HAI-1 retained exogenous HGFA. The binding of HGFA to HAI-1 was reversible, and no irreversible modifications affecting the enzyme activity occurred during the binding. Importantly, HAI-1 and the HGFA·HAI-1 complex were quickly released from the cell surface by treatment with phorbol 12-myristate 13-acetate or interleukin 1beta accompanying the generation of 58-kDa fragments of HAI-1, which are less potent against HGFA, as well as significant recovery of HGFA activity in the culture supernatant. This regulated shedding was completely inhibited by BB3103, a synthetic zinc-metalloproteinase inhibitor. We conclude that HAI-1 is not only an inhibitor but also a specific acceptor of active HGFA, acting as a reservoir of this enzyme on the cell surface. The latter property appears to ensure the concentrated pericellular HGFA activity in certain cellular conditions, such as tissue injury and inflammation, via the up-regulated shedding of HGFA·HAI-1 complex. These findings shed light on a novel function of the integral membrane Kunitz-type inhibitor in the regulation of pericellular proteinase activity.

* This work was supported in part by Grant-in-aid for Scientific Research Nos. 11670221 and 12670209 from the Ministry of Education, Science, Sports and Culture of Japan and a grant from Uehara Memorial Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Second Dept. of Pathology, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. Tel.: 81-985-85-2809; Fax: 81-985-85-6003; E-mail: mejina@fc.miyazaki-med.ac.jp.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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