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Molecular Mechanisms for injury-dependent activation of c-Met, HGF receptor

Research Project

Project/Area Number 15590272
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionOsaka University

Principal Investigator

MACHIDE Mitsuru  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (90346198)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Toshikazu  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00049397)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordstissue injury / HGF / c-Met / cell-cell contact / tyrosine phosphatase / oxidant stress / aminoacid / HGF(肝細胞増殖因子) / 組織恒常性 / juxtamembrane領域 / protein kinase C / チロシンキナーゼ / ストレス / 発癌
Research Abstract

In this project, we attempted to clarify the molecular mechanisms by which the tissues recognize their injured- or homeostatic states. We especially focused on the physiological changes of activation states of c-Met, the receptor for HGF and obtained the results as descried bellow 1〜4.
1, (1) HGF readily induces cellular proliferation of primary hepatocytes when they are cultured at low cellular density, but in confluent cultures, HGF failed to show the effect. which was thought to mimic the response of parenchymal) hepatocytes in injured liver. In this system, we found that c-Met tyrosine autophosphorylation was down regulated in the confluent cells even after HGF-stimulation. (2) Oxidant stress causes arrest of cellular proliferation, and we found that the stress induced by hydrogen peroxide deprives cells of mitotic response to HGF, which was caused down regulation of c-Met activation through Ser985-phosphorylation on c-Met. (3) Primary hepatocytes could not proliferate in proline-free culture medium even after HGF-stimulation, while the c-Met and the associated signal transducers were readily activated.
2, We successfully identified molecules responsible for 1,(1)〜 (3) as follows. (1) A tyrosine phosphatase LAR, which dephosphorylates c-Met in a cell density dependent way, (2) PKC enhances Ser985 phosphorylation and PP2A which targets phosphorylated Ser985 was suppressed by hydrogen peroxide-treatment, (3) Expression of CDK4 that trigger the cellular proliferation was suppressed under Pro-free medium.
3, We established ES cells for construction of transgenic mouse carrying Ser985 deleted c-Met.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (19 results)

All 2005 2004 2003 Other

All Journal Article (12 results) Book (1 results) Publications (6 results)

  • [Journal Article] Bi-directional regulation of c-met Ser985 phosphorylation via PKC and protein phosphatase 2A involves c-met activation and cellular responsiveness to HGF.2004

    • Author(s)
      Hashigasako A. et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 26445-26452

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Bi-directional regulation of c-met Ser985 phosphorylation via PKC and protein phosphatase 2A involvesc-met activation and cellular responsiveness to HGF2004

    • Author(s)
      Hashigasako A. et al.
    • Journal Title

      J.Biol.Chem. Vol.279

      Pages: 26445-26452

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Bi-directional regulation of c-Met Ser 985 phosphorylation via PKC and protein phosphatase 2A involves c-Met activation and cellular responsiveness to HGF.2004

    • Author(s)
      Hashigasako A.et al.
    • Journal Title

      J.Biol.Chem 279

      Pages: 26445-26452

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Suppression of chronic glomerular injuries and TGF-β1 production by HGF contributes in attenuation of murine diabetic nephropathy.2004

    • Author(s)
      Mizuno S.et al.
    • Journal Title

      Am.J.physiol 286

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Recombinant hepatocyte growth factor accelerates cutaneous wound healing in diabetic mouse model.2004

    • Author(s)
      Yoshida S.et al.
    • Journal Title

      Growth Factors 22

      Pages: 111-119

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions.2004

    • Author(s)
      Ohuchida K.et al.
    • Journal Title

      Cancer Res. 64

      Pages: 3215-3222

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats.2004

    • Author(s)
      Oshima K.et al.
    • Journal Title

      FASEB-J 18

      Pages: 212-214

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Essential role of HGF (hepatocyte growth factor) in blood formation in Xenopus.2004

    • Author(s)
      Koibuchi K.et al.
    • Journal Title

      Blood 103

      Pages: 3320-33257

    • Related Report
      2004 Annual Research Report
  • [Journal Article] -HGFによる肝再生医療の展開-2003

    • Author(s)
      町出 充 他
    • Journal Title

      G.I.Research (Journal of Gastrointestinal Research) 11

      Pages: 69-76

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 増殖因子の臨床応用 -HGFによる再生医療の展開-2003

    • Author(s)
      町出 充 他
    • Journal Title

      現代医療 35

      Pages: 140-148

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regenerative Therapy by HGF for Liver Disease2003

    • Author(s)
      Machide M. et al.
    • Journal Title

      G.I.Research (Journal of Gastrointestinal Research) Vol.11, No.6

      Pages: 69-76

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of Regenerative Medicine by HGF2003

    • Author(s)
      Machide M. et al.
    • Journal Title

      Gendai-Iryou Vol.35,No.7

      Pages: 140-148

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 広範囲 血液・尿化学検査、免疫学的検査(4)形質転換成長因子(TGF)α,β2005

    • Author(s)
      町出 充 et al.(分担執筆)
    • Publisher
      日本臨牀社(In press)
    • Related Report
      2004 Annual Research Report
  • [Publications] Bessho S.et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis"Am.J.Physiol. 284. F1171-F1180 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Qian LW et al.: "Radiation stimulates HGF receptor/c-met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and map kinase activity in pancreatic cancer cells"Intern.J.Cancer. 104. 542-549 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Pai R.et al.: "Prostaglandins promote colon cancer cell invasion ; signaling by cross-talk between two distinct growth factor receptors"FASEB J.. 17. 1640-1647 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 橋ヶ迫 敦子 et al.: "HGFによる難治性肝疾患の再生治療"血液・免疫・腫瘍. 8(1). 44-51 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 町出 充, 中村 敏一: "増殖因子の臨床応用 -HGFによる再生医療の展開-"現代医療. 35(7). 140-148 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 町出 充, 中村 敏一: "HGFによる肝再生医療の展開"G.I.Research. 11(6). 69-76 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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