ヘパリン結合性上皮成長因子(EGF)様増殖因子の刺激誘導による活性化機構  [in Japanese] Mechanism for Activation of Heparin-Binding EGF-Like Growth Factor Induced by Stimuli  [in Japanese]

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Author(s)

    • 馬田 敏幸 UMATA Toshiyuki
    • 産業医科大学 産業医学研究支援施設 アイソトープ研究センター Radioisotope Research Center, University of Occupational and Environmental Health

Abstract

ヘパリン結合性EGF様増殖因子(HB-EGF)はEGFファミリーに属する増殖因子で, 創傷治癒や心臓肥大など多くの生理的, 病理的過程に関与している. HB-EGFはEGF同様, 膜蛋白質として産生され細胞表面でプロテアーゼにより切断, 遊離(ectodomain sheddingと呼ばれる. 以下sheddingと略す. )されて増殖活性を有するようになる. HB-EGFのsheddingはG蛋白質共役型受容体(GPCR)のリガンドやストレスあるいは炎症性サイトカインの刺激により誘発される. 刺激によるHB-EGFの活性化は, ホルボールエステル(TPA)ではプロテインキナーゼCが, リゾホスファチジン酸(LPA)では古典的MAPKカスケードと低分子量GTP結合蛋白質Rac1が, またストレスや炎症性サイトカインではP38 MAPKが関与している. 生体内環境に制御されたHB-EGF活性化の分子機構が明らかになりつつある.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), which belongs to the EGF family, is a critical growth factor for a number of physiological and pathological processes, such as wound healing and cardiac hypertrophy. HB-EGF is synthesized as a membrane-anchored form(pro-HB-EGF), and pro-HB-EGF is cleaved at the cell surface to yield soluble HB-EGF by a mechanism called "ectodomain shedding". Soluble HB-EGF has mitogenic activity. Ectodomain shedding of proHB-EGF is induced by stimuli, including 12-O-tetradecanoylphorbol-13-acetate (TPA), a ligand for seven-transmembrane G proteincoupled receptors (GPCR), stress and inflammatory cytokine. Lysophosphatidic acid (LPA), a ligand for GPCR, stimulates the shedding of proHB-EGF, which constitutes a GPCR-mediated transactivation of the EGF receptor. Ras-Raf-MEK signal and the small GTPase Rac are essential for the LPA-induced shedding. On the other hand, protein kinase C and ADAM 9 protease are essential for the TPA-induced shedding. Furthermore, p38 MAPK is essential for the stress- and IL-1β-induced shedding. Finally there is a mechanism for activation of HB-EGF regulated by the environment in the living body.

Journal

  • Journal of UOEH

    Journal of UOEH 26(1), 85-97, 2004

    The University of Occupational and Environmental Health, Japan

Codes

  • NII Article ID (NAID)
    110001259602
  • NII NACSIS-CAT ID (NCID)
    AN0009832X
  • Text Lang
    JPN
  • ISSN
    0387-821X
  • NDL Article ID
    6874639
  • NDL Source Classification
    ZS7(科学技術--医学)
  • NDL Call No.
    Z19-1000
  • Data Source
    NDL  NII-ELS  J-STAGE 
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