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Wnt受容体のエンドサイトーシスの多様性と細胞内シグナル伝達機構の選択的制御

Research Project

Project/Area Number 19659079
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field Pathological medical chemistry
Research InstitutionHiroshima University

Principal Investigator

菊池 章  Hiroshima University, 大学院・医歯薬学総合研究科, 教授 (10204827)

Project Period (FY) 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2007: ¥3,300,000 (Direct Cost: ¥3,300,000)
KeywordsWnt / Dkk / LRP6 / 受容体 / クラスリン / カベオリン / β-カテニン
Research Abstract

Dickkopf(Dkk)は分泌蛋白質で、Wntによるβ-カテニンの蓄積を抑制するWntシグナルの阻害因子である。本研究では、その作用機構を明らかにすることを試みた。Dkkを細胞に作用させると、Wnt受容体であるLRP6がインタナリーゼーションされた。このLRP6のインタナリーゼーションはクラスリンRNAiにより抑制された。また、クラスリン依存性の受容体のインタナリーゼーションを阻害することが知られているモノダンシルカダベリンやクロロプロマジンは、やはりDkk依存性のLRP6のインタナリーゼーションを抑制した。さらに、クラスリン依存性のインタナリーゼーションを阻害すると、DkkのWntシグナル阻害作用が消失した。私共は、LRP6がカベオリン依存性にインタナリーゼーションすることが、Wnt依存性のβ-カテニンの安定化に必要であることをすでに明らかにしている。したがって、DkkはWntと異なる経路でLRP6をインタナリーゼーションすることにより、Wntシグナルを抑制すると考えられた。
本来不活性型であるLRP6の細胞質領域(LRP6C)にカベオリンを融合させる(LRP6C-Cav)と、この融合蛋白質はリン酸化され、細胞内で小顆粒状に存在してβ-カテニンを安定化した。また、活性型であることが知られていたLRP6ΔNはリン酸化され、やはり細胞内で小顆粒状に存在し、カベオリンと複合体を形成して、β-カテニンを安定化した。さらに、カベオリンの膜結合領域を融合させるだけで活性型になることも判明した。これらの結果から、LRP6がカベオリンの局在する細胞膜状の領域(脂質ラフト画分)に存在するごとが、Wntによるβ-カテニンの安定化に重要であることが明らかになった。

Report

(1 results)
  • 2007 Annual Research Report
  • Research Products

    (20 results)

All 2008 2007

All Journal Article (15 results) (of which Peer Reviewed: 15 results) Presentation (5 results)

  • [Journal Article] Tumor formation due to abnormalities in the β-catenin-independent pathway of Wnt signaling.2008

    • Author(s)
      Kikuchi, A. and Yamamoto, H.
    • Journal Title

      Cancer Sci. 99

      Pages: 202-208

    • NAID

      10024001624

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GSK-3β regulates proper mitotic spindle formation in cooperation with a component of the γ-tubulinring complex, GCP5.2008

    • Author(s)
      Izumi, N., et. al.
    • Journal Title

      J. Biol. Chem. 283

      Pages: 12981-12991

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] AIP requlates stability of Aurora-A at early mitotic phase coordinately with GSK-3β.2008

    • Author(s)
      Fumoto, K., et. al.
    • Journal Title

      Oncogene (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IFITM1 promotes the invasion at the early stage of head and neck cancer progression.2008

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

      Cli. Cancer Res. (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Wnt3a and Dkkl regulate internalization of LRP6 differently to tune β-catenin pathway.2008

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

      Dev. Cell (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signaling.2007

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

      Biochem. J. 402

      Pages: 515-523

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dvl regulates endo- and exocytotic processes through binding to synaptotaamin.2007

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

      Genes Cells 12

      Pages: 49-61

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a.2007

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

      Genes Cells 12

      Pages: 521-534

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Wnt5a modulates glycogen synthase kinase 3 to induce phospshorylation of receptor tyrosine kinase Ror2.2007

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

      Genes Cells 12

      Pages: 1215-1223

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Increased expression of h-prune is associated with tumor progression and poor survival in gastric cancer.2007

    • Author(s)
      Oue, N., et. al.
    • Journal Title

      Cancer Sci. 98

      Pages: 1198-1205

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sprouty2 and Sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling.2007

    • Author(s)
      Taniguchi, K., et. al.
    • Journal Title

      Biochem. Biophys. Res. Commun. 352

      Pages: 896-902

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multiplicity of the interactions of Wnt proteins and their receptors.2007

    • Author(s)
      Kikuchi, A., et. al.
    • Journal Title

      Cell. Signal. 19

      Pages: 659-671

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of wnt signaling by receptor-mediated endocytosis.2007

    • Author(s)
      Kikuchi, A. and Yamamoto, H.
    • Journal Title

      J. Biochem. 141

      Pages: 443-451

    • NAID

      10020099687

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization.2007

    • Author(s)
      Schwarz-Romond, T., et. al.
    • Journal Title

      Nat. Strut. Mol. Biol. 14

      Pages: 484-492

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Non-covalent binding of SUMO protease to SUMO is necessary for enzymatic activities and cell growth.2007

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

      J. Biol. Chem. 282

      Pages: 16465-16475

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] Aggressiveness of cancer induced by abnormality of Wnt sianaling.2007

    • Author(s)
      Kikuchi, A.
    • Organizer
      The Japan-Korea joint meeting on Wnt sianaling and human diseases.
    • Place of Presentation
      Seoul, Korea
    • Year and Date
      2007-10-26
    • Related Report
      2007 Annual Research Report
  • [Presentation] Spatial and temporal regulation of Glycogen Synthase kinase-3 and Cellular function.2007

    • Author(s)
      Kikuchi, A.
    • Organizer
      2007 Annual meeting of Korean Society of Medical Biochemistry and Molecular Biology.
    • Place of Presentation
      Seoul, Korea
    • Year and Date
      2007-10-25
    • Related Report
      2007 Annual Research Report
  • [Presentation] Wntシグナルによるがんの悪性化2007

    • Author(s)
      菊池章
    • Organizer
      第66回日本癌学会学術総会モーニングレクチャー
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-05
    • Related Report
      2007 Annual Research Report
  • [Presentation] Regulation of Wnt signaling by receptor-mediatedendocytosis.2007

    • Author(s)
      Kikuchi, A.
    • Organizer
      Sympojium of Wnt signaling in development and disease.
    • Place of Presentation
      Berlin, Germany
    • Year and Date
      2007-09-14
    • Related Report
      2007 Annual Research Report
  • [Presentation] Expression of Wnt5a is correlated with aggressiveness of gastric and prostate cancer by stimulating cell migration and invasion.2007

    • Author(s)
      Kikuchi, A. and Yamamoto, H.
    • Organizer
      Traditional Wnt meeting.
    • Place of Presentation
      La Jolla. California, USA
    • Year and Date
      2007-06-22
    • Related Report
      2007 Annual Research Report

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Published: 2007-04-01   Modified: 2016-04-21  

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