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Characterization of factors regulating the activity of hepatocyte growth factor which is being developed for a medicine

Research Project

Project/Area Number 10557017
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Pathological medical chemistry
Research InstitutionTokyo Institute of Technology

Principal Investigator

KITAMURA Naomi  Tokyo Institute of Technology, Faculty of Bioscience & Biotechnology, Professor, 生命理工学部, 教授 (80107424)

Co-Investigator(Kenkyū-buntansha) DENDA Kimitoshi  Tokyo Institute of Technology, Faculty of Bioscience & Biotechnology, Research Associate, 生命理工学部, 助手 (50212064)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 1999: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1998: ¥7,200,000 (Direct Cost: ¥7,200,000)
Keywordshepatocyte growth factor (HGF) / liver disease / HGF activator / HGF activator inhibitor / liver injury / protein processing / thrombin / HGFactivator / HGFactivator inhibitor / 血液凝固系
Research Abstract

Hepatocyte growth factor (HGF) is a potent mitogen for hepatocytes, and is being developed for a medicine of liver disease. HGF is activated in the liver by a serine protease, HGF activator (HGFA), following liver injury, and then functions as a liver regeneration factor. In this study, we examined mechanisms for activation and inactivation of HGFA and obtained the following results.
1. Analysis of HGFA and its mRNA after liver injury induced by CClィイD24ィエD2 treatment of rat revealed that amount of HGFA mRNA increased, and HGFA, that circulates in the blood as an inactive precursor at normal state, was activated by thrombin following liver injury. These results indicate that HGFA plays an crucial role in regulating the activity of HGF by increase of its amount and proteolytic activation linked to blood coagulation system following liver injury.
2. Two types of HGFA inhibitor, HAI-1 and HAI-2, were identified as potent inhibitors of HGFA. Using a monoclonal antibody against HAI-1, we identified a transmembrane form of HA1-1 integrated in the plasma membrane of cultured cells. We also identified several soluble forms of HAI-1 in the conditioned medium of the cells, indicating that multiple sites are present in the transmembrane form of HAI-1 at which proteolytic cleavage releases the extracellular domain. At least two proteases, one of which is a metalloprotease, appear to be responsible for the release. Further, the soluble forms of HAI-1 have different inhibitory activity against HGFA. These findings suggest that proteolytic processing plays important roles in regulation of the inhibitory activity of Hal-1.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] L. Qin: "Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 2"FEBS Letters. 436. 111-114 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K, Miyazawa: "Structural organization and chromosomal localization of the human hepatocyte growth factor activator gene : phylogenetic and functional relationship with blood coagulation factor XII, urokinase, and tissue-type plasminogen activator"Eur. J. Biochem.. 258. 355-361 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y. Matsubara: "Hepatocyte growth factor activator ; a possible regulator of morphogenesis during the fetal development of rat gastrointestinal tract"Biochem. Biophys. Res. Commun.. 253. 477-484 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H. Kataoka: "Distribution of hepatocyte growth factor activator inhibitor type 1(HAI-1) in human tissues ; cellular surface localization of HAI-1 in simple columnar epithelium and its modulated expression in injured and regenerative tissues"J. Histochem. Cytochem.. 45. 673-682 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Shimomura: "Multiple sites of proteolytic cleavage to release soluble forms of hepatocyte growth factor activator inhibitor type 1 from a transmembrane form"J. Biochem.. 126. 821-828 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H. Itoh: "Up-regulation of hepatocyte growth factor activtor inhibitor type-1 but not type-2 along with regeneration of intestinal mucosa"Am. J. Physiol.. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] . Qin et al.: "Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 2"FEBS Letters. 436. 111-114 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Miyazawa et al.: "Structural organization and chromosomal localization of the human hepatocyte growth factor activator gene : phylogenetic and functional relationship with blood coagulation factor XII, urokinase, and tissue-type plasminogen activator"Eur. J. Biochem.. 258. 355-361 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y. Matsubara et al.: "Hepatocyte growth factor activator ; a possible regulator of morphogenesis during the fetal development of rat gastrointestinal tract"Biochem. Biophys. Res. Commun.. 253. 477-484 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H. Kataoka et al.: "Distribution of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in human tissues : cellular surface localization of HAI-1 in simple columnar epithelium and its modulated expression in injured and regenerative tissues"J. Histochem. Cytochem.. 45. 673-682 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Shimomura et al.: "Multiple sites of proteolytic cleavage to release soluble forms of hepatocyte growth factor activator inhibitor type 1 from a transmembrane form"J. Biochem.. 126. 821-828 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H. Itoh et al.: "Up-regulation of hepatocyte growth factor activator inhibitor type-1 but not type-2 along with regeneration of intestinal mucosa"Am. J. Physiol.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H.Kataoka: "Distribution of hepatocyte growth factor activator inhibitor type 1(HAI-1) in human tissues: cellular surface localization of HAI-1 in simple columnar epithelium and its modulated expression in injured and regenerative tissues"J.Histochem.Cytochem.. 45. 673-682 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Itoh: "Hepatocyte growth factor activator inhibitor type 2 lacking the first Kunitz-type serine protease inhibitor domain is a predominant product in mouse but not in human"Biochem.Biophys.Res.Commun.. 255. 740-748 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T.Shimomura: "Multiple sites of proteolytic cleavage to release soluble forms of hepatocyte growth factor activator inhibitor type 1 from a transmembrane form"J.Biochem.. 126. 821-828 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Kataoka: "Conserved expression of hepatocyte growth factor activator inhibitor type-2/placental bikunin in human colorectal carcinomas"Cancer Lett.. 148. 127-134 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Itoh: "Up-regulation of hepatocyte growth factor activator inhibitor type-1 but not type-2 along with regeneration of intestinal mucosa"Am.J.Physiol.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Itoh: "Mouse hepatocyte growth factor activator gene: its expression not only in the liver but also in the gastrointestinal tract"Biochim.Biophys.Acta. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] M.Kaibori: "Hepatocyte growth factor stimulates synthesis of lipids and secretion of lipoproteins in rat hepatocytes." Hepatology. 27. 1354-1361 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Kataoka: "Evaluation of hepatocyte growth factor activator inhibitor expression in normal and malignant colonic mucosa." Cancer Letters. 128. 219-227 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] L.Qin: "Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 2." FEBS Letters. 436. 111-114 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Miyazawa: "Structural oganization and chromosomal localization of the human hepatocyte growth factor activator gene:phylogenetic and functional relationship with blood coagulation factor XII,urokinase,and tissue-type plasminogen activator." Eur.J.Biochem.258. 355-361 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Matsubara: "Hepatocyte growth factor activator;a possible regulator of morphogenesis during the fetal development of rat gastrointestinal tract." Biochem.Biophys.Res.Commun.253. 477-484 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Kataoka: "Distribution of hepatocyte growth factor activator inhibitor type1(HAI-1)in human tissues:cellular surface localization of HAI-1in simple columnar epithelium and its modulated expression in injured and regenerative tissues." J.Histochem.Cytochem.(in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Itoh: "Hepatocyte growth factor activator inhibitor type2 lacking the First Kunitz-type serine protease inhibitor domain is a predominant product in mouse but not in human." Biochem.Biophys.Res.Commun.(in press).

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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