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Biological significances of metalloproteases which specific ally bind to membrane-anchored growth factors

Research Project

Project/Area Number 16590680
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionKyoto University

Principal Investigator

NISHI Eiichiro  Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (30362528)

Co-Investigator(Kenkyū-buntansha) 田中 基成  株式会社ロコモジェン, 研究員 (30372593)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsEctodomain Shedding / Growth factors / cytokines / Metalloproteases / ADAM / Nardilysin / HB-EGF / TNF-alpha converting enzyme / 膜蛋白質
Research Abstract

Ectodomain shedding is an irreversible posttranslational modification that releases the extracellular domain of membrane-anchored protein through proteolysis. Abroad spectrum of membrane protein is susceptible to ectodomain shedding, and the process is strictly regulated. Several lines of evidence showed that metalloproteinases, especially those belonging to a disintegrin and metalloproteinase (ADAM) family are directly involved in this process as sheddases. The mechanism of induced shedding, however, remained unclear. Here we show that nardilysin (N-arginine dibasic convertase ; NRDc), a metalloendopeptidase of M16 family, enhances ectodomain shedding of EGF receptor ligands and TNF-alpha When expressed in cells, NRDc enhanced HB-EGF and TNF-α shedding coordinately with TNF-α converting enzyme (TACE, ADAM17). NRDc is hound to TACE and the cnmplex formation in cells is increased by phorhol esters, general activators of ectodomain shedding. Furthermere, NRDc enhanced TACE-induced substrate cleavage in a peptide cleavage assay, indicating that the interaction with NRDc potentiates the catalytic activity of TACE. Importantly, reduction of NEDc expression by RNA interference was accompanied by a decrease in ectodomain shedding. NRDc also induced HB-EGF shedding even in TACE deficient cells and shedding induced by ADAM9 was also enhanced by NRDc. These results indicate the essential role of NEDc in ectodomain shedding and uncover a novel molecular mechanism of how ectodomain shedding is regulated by modulation of sheddase activity.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (9 results)

All 2006 2005 2004

All Journal Article (5 results) Patent(Industrial Property Rights) (4 results)

  • [Journal Article] Visualization of embryonic neural stem cells using Hes promoters in transgenic mice2006

    • Author(s)
      Ohtsuka T, Imayoshi I, Shimojo H, Nishi E, Kageyama R, McConnell SK
    • Journal Title

      Mol Cell Neurosci 31

      Pages: 109-122

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Visualization of embryonic neural stem cells using Hes promoters in transgenic mice.2006

    • Author(s)
      Ohtsuka T, Imayoshi I, Shimojo H, Nishi E, Kageyama R, McConnell SK.
    • Journal Title

      Mol Cell Neurosci. 31

      Pages: 109-122

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) is a Mediator of Multiple Physiological and Pathological Pathways2004

    • Author(s)
      Nishi E, Klagsbrun M.
    • Journal Title

      Growth Factors 22

      Pages: 253-260

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) is a Mediator of Multiple Physiological and Pathological Pathways2004

    • Author(s)
      Nishi E, Klagsbrun M.
    • Journal Title

      Growth Factors. 22

      Pages: 253-260

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Heparin-Binding Epidermal Growth Factor-Like Growth Factor(HB-EGF) is a Mediator of Multiple Physiological and Pathological Pathways.2004

    • Author(s)
      Nishi E, Klagsbrun M.
    • Journal Title

      Growth Factors 22

      Pages: 253-260

    • Related Report
      2004 Annual Research Report
  • [Patent(Industrial Property Rights)] 細胞外ドメインシェディングの異常亢進に起因する疾患の予防及び/又は治療のための医薬2006

    • Inventor(s)
      西 英一郎
    • Industrial Property Rights Holder
      京都大学
    • Filing Date
      2006-02-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Patent(Industrial Property Rights)] 細胞外ドメインシェディングの異常亢進に起因する疾患の予防又は治療のための医薬2006

    • Inventor(s)
      西 英一郎
    • Industrial Property Rights Holder
      京都大学
    • Filing Date
      2006-02-28
    • Related Report
      2005 Annual Research Report
  • [Patent(Industrial Property Rights)] 細胞外ドメインシェディングの異常亢進に起因する疾患の予防及び/又は治療のための医薬2005

    • Inventor(s)
      西 英一郎
    • Industrial Property Rights Holder
      京都大学
    • Industrial Property Number
      2005-055495
    • Filing Date
      2005-03-01
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Patent(Industrial Property Rights)] 細胞外ドメインシェディングの異常亢進に起因する疾患の予防2005

    • Inventor(s)
      西 英一郎
    • Industrial Property Rights Holder
      京都大学
    • Industrial Property Number
      2005-055495
    • Filing Date
      2005-03-01
    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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