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Molecular mechanisms of signal transduction regulating cell proliferation, cell differentiation and cell cycle

Research Project

Project/Area Number 12219208
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKyoto University

Principal Investigator

NISHIDA Eisuke  Kyoto University, Graduate School of Biostudies, Professor, 大学院生命科学研究科, 教授 (60143369)

Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥443,900,000 (Direct Cost: ¥443,900,000)
Fiscal Year 2004: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2003: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2002: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2001: ¥89,000,000 (Direct Cost: ¥89,000,000)
Fiscal Year 2000: ¥86,400,000 (Direct Cost: ¥86,400,000)
KeywordsMAP kinase / cell cycle / signal transduction / growth factor / cell transformation / 細胞癌化 / ドッキング相互作用 / Tob / シグナル伝達インヒビター / Sprouty / Plk1 / Cdc25C / 核内移行 / サイクリンB1
Research Abstract

MAP kinase is shown to play an important role in regulation of cell proliferation, cell differentiation, and cell transformation. We have analyzed the MAP kinase-mediated docking interaction that could regulate the specificity and efficiency of the MAP kinase signal transduction, and identified a docking groove on the surface of MAP kinase that includes the CD domain and the ED site. ERK MAP kinase functions downstream of receptor tyrosine kinase, and spatiotemporal control of ERK MAP kinase signaling is crucial for cell fate decision. We have shown that Sprouty is a novel type of negative feedback inhibitor that regulates the duration and/or magnitude of ERK activity, and demonstrated that Sef is a spatial regulator that specifically inhibits ERK nuclear translocation without inhibiting ERK activity in the cytoplasm. We have then analyzed that temporal program of ERK-mediated gene expression, and revealed a molecular basis underlying the mechanism by which sustained ERK activation promotes G1 phase progression. Polo-like kinase 1 (Plk1) is an evolutionarily conserved M phase protein kinase that is involved in a wide variety of M phase events. We have demonstrated that Plk1 regulates nuclear import of both cdc2/cyclinB complex, the master engine of M phase entry, and cdc25C, the activator of cdc2/cyclinB complex. In addition, our results have identified the consensus phosphorylation motif by Plk1, and shown that the protein kinase Myt1 is a substrate of Plk1.

Report

(6 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (39 results)

All 2005 2004 2002 2001 2000 Other

All Journal Article (16 results) Publications (23 results)

  • [Journal Article] Resetting of peripheral circadian clock by prostaglandin E2.2005

    • Author(s)
      Tsuchiya, Y.et al.
    • Journal Title

      EMBO Rep. 6

      Pages: 256-261

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ERK activation propagates in epithelial cell sheets and regulates their migration during wound healing.2004

    • Author(s)
      Matsubayashi, Y. et al.
    • Journal Title

      Curr. Biol. 14

      Pages: 731-735

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sef is a spatial regulator for Ras/MAP kinase signaling.2004

    • Author(s)
      Torii, S.
    • Journal Title

      Dev. Cell 7

      Pages: 33-44

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ERK activation propagates in epithelial cell sheets and regulates their migration during wound healing.2004

    • Author(s)
      Matsubayashi, Y., Ebisuya, M., Honjoh, S., Nishida, E.
    • Journal Title

      Curr. Biol. 14

      Pages: 731-735

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sef is a spatial regulator for Ras/MAP kinase tongue2004

    • Author(s)
      Torii, S., Kusakabe, M., Yamamoto, T, Maekawa, M., Nishida, E.
    • Journal Title

      Dev. Cell 7

      Pages: 33-44

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sef is a spatial regulator for Ras/MAP kinase signaling.2004

    • Author(s)
      Torii, S.et al.
    • Journal Title

      Dev.Cell 7

      Pages: 33-44

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The polarity-inducing kinase Par-1 controls Xenopus gastrulation in cooperation with 14-3-3 and aPKC.2004

    • Author(s)
      Kusakabe, M.et al.
    • Journal Title

      EMBO J. 23

      Pages: 4190-4201

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway.2002

    • Author(s)
      Hanafusa, H. et al.
    • Journal Title

      Nature Cell Biol. 4

      Pages: 850-858

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signaling pathway.2002

    • Author(s)
      Hanafusa, H., Torii, S., Yasunaga, T., Nishida, E.
    • Journal Title

      Nature Cell Biol. 4

      Pages: 850-858

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase.2001

    • Author(s)
      Toyoshima-Morimoto, F. et al.
    • Journal Title

      Nature 410

      Pages: 215-220

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1.2001

    • Author(s)
      Harada, T. et al.
    • Journal Title

      Nature Cell Biol. 3

      Pages: 453-459

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase.2001

    • Author(s)
      Toyoshima-Morimoto, F., Taniguchi, E., Shinya, N., Iwamatsu, A., Nishida, E.
    • Journal Title

      Nature 410

      Pages: 215-220

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1.2001

    • Author(s)
      Harada, T., Morooka, T., Ogawa, S., Nishida, E.
    • Journal Title

      Nature Cell Biol. 3

      Pages: 453-459

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A conserved docking motif in MAP kinases common to substrates, activators and regulators.2000

    • Author(s)
      Tanoue, T. et al.
    • Journal Title

      Nature Cell Biol. 2

      Pages: 110-116

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A conserved docking motif in MAP kinases common to substrates, activators and regulators.2000

    • Author(s)
      Tanoue, T., Adachi, M., Moriguchi, T., Nishida, E.
    • Journal Title

      Nature Cell Biol. 2

      Pages: 110-116

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Shp2, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty.

    • Author(s)
      Hanafusa, H.et al.
    • Journal Title

      J.Biol.Chem.

    • Related Report
      2004 Annual Research Report
  • [Publications] Matsubayashi, Y. et al.: "ERK activation propagates in epithelial cell sheets and regulates their migration during wound healing"Curr.Biol.. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Miyata, Y. et al.: "CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone Cdc37."Mol.Cell.Biol.. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Maekawa, M. et al.: "Regulation of subcellular localization of the anti-proliferative protein Tab by its nuclear export signal and bipartite nuclear localization signal sequences."Exp.Cell Res.. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ogawa, S. et al.: "An evolutionarily conserved gene required for proper microtubule architecture in Caenorhabditis elegans."Genes Cells. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakajima, H. et al.: ">:Identification of a consensus motif for Plk (polo-like kinase) phosphorylation reveals Myt1 as a Plk1 substrate."J.Biol.Chem.. 278. 25227-25280 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ookuma, S. et al.: "Identification of a DAF-16 transcriptional target gene scl-1 that regulates longevity and stress resistance in Caenorhabdit is elegans"Current Biology. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Terasawa, K. et al.: "Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway"Genes to Cells. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kawachi, K. et al.: "Essential role of the transcription factor Ets-2 in Xenopus early development"Journal of Biological Chemistry. 278. 5473-5477 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Taniguchi, E. et al.: "Nuclear translocation of Plk1 mediated by its bipartite nuclear localization signal"Journal of Biological Chemistry. 277. 48884-48888 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hanafusa, H. et al.: "Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway"Nature Cell Biology. 4. 850-858 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Maekawa, M. et al.: "Identification of the anti-proliferative protein Tob as a MAP kinase substrate"Journal of Biological Chemistry. 277. 37783-37787 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Toyoshima-Morimoto, F. et al.: "Plk1 promotes nuclear translocation of human Cdc25C during prophase"EMBO Reports. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Bamba, C. et al.: "The GTPase Ran regulates chromosome positioning and nuclear envelope assembly in vivo"Current Biology. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamanaka, H. et al.: "JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates"EMBO Reports. 3. 69-75 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toyoshima-Morimoto, F. et al.: "Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase"Nature. 410. 215-220 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Harada, T. et al.: "ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1"Nature Cell Biology. 3. 453-459 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanoue, T. et al.: "Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions"EMBO Journal. 20. 466-479 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toyoshima-Morimoto,F. et al.: "Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase"Nature. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Harada,T. et al.: "ERK induces p35, the neuron-specific activator of cdk5 essential for neurite outgrowth, through the induction of Egr 1"Nature Cell Biol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanoue,T. et al.: "Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions"EMBO J.. 20巻. 466-479 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hanafuse,H. et al.: "The TGF-b family member derriere is involved in regulation of the establishment of left-right asymmetry"EMBO Reports. 1巻. 32-39 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Akashi,M.and Nishida,E.: "Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock"Genes Dev.. 14巻. 645-649 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanoue,T. et al.: "A conserved docking motif in MAP kinases common to substrates, activators and regulators"Nature Cell Biol.. 2巻. 110-116 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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