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Physiological significance of proHB-EGF ectodomain shedding in epideimal development

Research Project

Project/Area Number 14580696
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cell biology
Research InstitutionOsaka University

Principal Investigator

IWAMOTO Ryo  Research Institute For Microbial Diseases, Department of Cell Biology, Assistant Professor, 微生物病研究所, 講師 (10213323)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsHB-EGF / ectodomain shedding / EGF family / ErbB / cardiomyopathy / valvulogenesis / epidermal remodeling / knock-in mice / 増殖因子 / 組織再生
Research Abstract

1)HB-EGF is a member of the EGF family of giowth factors. To examine the role of HB-EGF in viva, we generated HE-EGF-knockout mice HB^<del/del>). HB^<del/del> mice developed severe heart failure with dilated ventricular chambers, similarly to conditional ErbB2 knockout mice. HB^<del/del> mice developed also enlarged cardiac valves, similarly to EGFR knockout mice. Constitulive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HB^<del/del> hearts. These indicated that HB-EGFactivalion of ErbB is essential for normal heartfunclion.
2)HB-EGF is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding fiom proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, xpressing either an uncleavable form (HB^<uc>) or a transmembrane domain-truncated form (HB^<Δtm>) of the molecule. HB^<uc/uc> mice developed severe heart failure and e … More nlarged heart valves, phenotypes similar to those in proHB-EGF-null mice. On the other hand, mice canying HB^<Δtm> exhibited severe hyperplasia in both skin and heart These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in viva, and that this piocess requires strict control.
3)HB^<del/del> mice did not show any abnormalities in developmental piocess of epidermis. Thus, we investigated the role of HE-EGF in re-epithelization. HB-EGF expression in adult epidermis was hardly detected at the steady state, but it was strongly induced after full-thickness wounding and topical treatment with retinoic acid (tRA). The level of hyperprolifemtion of keratinocytes induced by tRA-ireatinent and that of wound healing were estimated among the mutant mice selectively ablated HB-EGF expression in basal keratinocytes (HB^<del/del>-K5-Cre),HB^<uc/uc> mice and normal HB-EGF cDNA knock-in mice (HB^<lox/iox>) as an experimenrtal control. In HB^<del/del>-K5-Cre mice and in HBuc/uc mice, both tRA-induced epidermal hyperproliferation and wound healing activity was reduced compared with HBlox/lox mice. These indicated that the induction of HB-EGF and its ectodomain shedding is an important event in the re-epithelization in vivo. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Shimizu, T., et al.: "Elevated levels of anti-CD9 antibodies in the celebrospinal fluid of patients with subacute sclerosing panencephalitis."J.Infect.Dis.. 185. 1346-1350 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yu, X., et al.: "Ligand-independent dimmer formation of epidermal growth factor receptor (EGFR) is a step separable from ligand-induced EGFR signaling."Mol.Biol.Cell.. 13. 2547-2557 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, R., et al.: "Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function."Proc.Natl.Acad.Sci.USA.. 100. 3221-3226 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamazaki, S., et al.: "Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities."J.Cell Biol.. 163. 469-475 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu, T., et al.: "Elevated levels of anti-CD9 antibodies in the celebrospinal fluid of palients with subacute sclerosing panencephalitis."J.Infect.Dis.. 185. 1346-1350 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yu, X., et al.: "Ligand-independent dimmer formation of epidermal growth factor receptor (EGFR) is a step separable fnm ligand-induced EGFR signaling."Mol.Biol.Cell.. 13. 2547-2557 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iwamoto, R, et al.: "Heparin-binding EGF-like growth factor and ErbB signaling is essential for heartfunction."Pnic.Natl.Acad.Sci.USA.. 100. 3221-3226 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yamazaki, S., et al.: "Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities."J.Cell Biol.. 163. 469-475 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Satoru Yamazaki et al.: "Mice with defects in HB-EGF ectodomain shedding show severe developmental Abnormalities"J.C.B.. 163. 469-475 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ryo Iwamoto et al.: "Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function"Proc.Natl.Acad.Sci.USA. 100. 3221-3226 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Toko Shimizu et al.: "Elevated levels of anti-CD9 antibodies in the cerebrospinal fluid of patients with subacute sclerosing panencephalitis"The Journal of Infectious Diseases. 185. 1346-1350 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Xiaochun Yu et al.: "Ligand-independent dimmer formation of epidermal growth factor receptor (EGFR) is a step separable from ligand-induced EGFR signaling"Molecular Biology of the Cell. 13. 2547-2557 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ryo Iwamoto et al.: "Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function"Proc. Natl. Acad. Sci. USA.. 100. 3221-3226 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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