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Joint Study on the Tumorigenicity of HGF and c-met Receptor

Research Project

Project/Area Number 05044174
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

MIZUNO Kensaku  Faculty of Science, Kyushu University Associate professor, 理学部, 助教授 (70128396)

Co-Investigator(Kenkyū-buntansha) VANDE Woude  米国国立がん研究所, フレデリックがんセンター(アメリカ合衆国), センター長
NAKAMURA Toshikazu  School of Medicine, Osaka University professor, 医学部, 教授 (00049397)
VANDE WOUDE George f.  Frederick Cancer Research and Development Center, National Cancer Institute Dire
Project Period (FY) 1993 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 1994: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1993: ¥5,000,000 (Direct Cost: ¥5,000,000)
KeywordsHepatocyte Growth Factor / HGF / c-Met / Oncogene / HGF Converting Enzyme / Tyrosine Kinase / LIM Motif / Receptor / 転移 / 人工変異体 / プロテアーゼ阻害剤
Research Abstract

Hepatocyte growth factor (HGF) is a pleiotropic factor, which act as a mitogen, motogen, and morphogen for various epithelial cells. The c-Met protooncogene product was identified as the receptor for HGF.In this study, we analyzed the tumorigenicity of HGF and c-Met receptor. Various sarcoma cell lines were found to express high level of c-Met receptor, indicating that the HGF-Met autocrine signaling contributes to the tumorigenic process of sarcoma.HGF converting enzyme, which converts an inactive single-chain precursor (pro-HGF) to a two-chain active form HGF,was purified and identified as a heterodimer protein composed of a 65-kDa heavy chain and a 32-kDa light chain. A synthetic peptide derivative, Ac-Lys-Gln-Leu-Arg-chloromethylketone, containing the sequence of pro-HGF cleavage site strongly inhibited the converting enzyme activity, and the mitogenic activity of pro-HGF.However, this inhibitor could not block the growth of sarcoma cells, probably because of the instability in the conditioned medium. Using the chicken c-sea tyrosine kinase gene (the gene closely related to c-Met) as a probe, we obtained the cDNAs encoding three novel protein kinases, c-Sea, Sky and LIMK.c-Sea is highly related to the c-Met receptor and seems to be a receptor for a HGF-related growth factor. Sky is a novel receptor tyrosine kinase related to Axl/Ufo/Ark. Identification of the ligands for c-Sea and Sky is the subject of ongoing studies. LIMK is a cytoplasmic serine/threonine kinase containing two repeats of LIM/double zinc finger motif at the N-terminus and a protein kinase domain at the C-terminus. LIMK may be involved in the oncogenic process through interactions with other LIM-containing proteins.

Report

(2 results)
  • 1994 Final Research Report Summary
  • 1993 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] K.Mizuno,et al.: "Hairpin loop and second kringle domain are essential sites for heparin-binding and biological activity of hepatocyte growth factor." J.Biol.Chem.269. 1131-1136 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Ohashi,et al.: "Cloning of the cDNA for a novel receptor tyrosine kinase,Sky,predominantly expressed in brain." Oncogene. 9. 699-705 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Mizuno,et al.: "Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif." Oncogene. 9. 1605-1612 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Ohashi,et al.: "Molecular cloning of a chicken lung cDNA encoding a novel protein kinase with N-terminal two LIM/double zinc finger motif." J.Biochem.116. 636-642 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] T.Harano,et al.: "Phorbol ester-induced activation of a membrane-bound candidate protransforming growth factor-α converting enzyme." J.Biol.Chem.269. 20305-20311 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Ohashi,et al.: "Molecular cloning and in situ localization in the brain of rat Sky receptor tyrosine kinase." J.Biochem.117(in press). (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Mizuno,et al.: "Comprehensive Endocrinology,The Pituitary Gland,2nd.ed." Raven Press, 520 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Mizuno, et al.: "Hairpin loop and second kringle domain are essential sites for heparin-binding and biological activity of hepatocyte growth factor." J.Biol.Chem.269. 1131-1136 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Ohashi, et al.: "Cloning of the cDNA for a novel receptor tyrosine kinase, Sky, predominantly expressed in brain." Oncogene. 9. 699-705 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Mizuno, et al.: "Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif." Oncogene. 9. 1605-1612 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Ohashi, et al.: "Molecular cloning of a chicken lung cDNA encoding a novel protein kinase with N-terminal two LIM/double zinc finger motif." J.Biochem.116. 636-642 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] T.Harano, et al.: "Phorbol ester-induced activation of a membrane-bound candidate protransforming growth factor-a converting enzyme." J.Biol.Chem.269. 20305-20311 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Ohashi, et al.: "Molecular cloning and in situ localization in the brain of rat Sky receptor tyrosine kinase." J.Biochem.117 (in press). (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Mizuno, et al.: Raven Press. Comprehensive Endocrinology, The Pituitary Gland, 2nd.ed., 520 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] K.Mizuno et al.: "Hairpin-loop and second kringle domain are essential for heparin-binding and biological activity of hepatocyte growth factor." J.Biol.Chem.269. 1131-1136 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Ohashi et al.: "Cloning of the cDNA for a novel receptor tyrosine kinase,Sky,predominantly expressed in brain." Oncogene. 9. 699-705 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Mizuno et al.: "Purification and characterization of HGF-converting enzyme:activation of pro-HGF." Biochem.Biophys.Res.Commun.198. 1161-1169 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] M.Lyon et al.: "The interaction of HGF with heparan sulfate.Elucidation of the major heparan sulfate structural determinants." J.Biol.Chem.269(in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Tanoue et al.: "A specific inhibitor for HGF-converting enzyme:synthesis and effects on the mitogenic activity of pro-HGF." Peptide Chemistry. 1993. 201-204 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Mizuno et al.: "Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif." Oncogene. 9(in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Mizuno et al.: "Hepatocyte growth factor-scatter factor and the c-met receptor." Birkhauser Verlag, pp.1-29 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] T.Nakamura et al.: "New Functionality Materials,Volume B:Synthesis and Function Control of Biofunctionality Materials." Elsevier Science Publishers, pp.313-320 (1993)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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