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2004 Fiscal Year Annual Research Report

細胞増殖のシグナリング機構

Research Project

Project/Area Number 12215079
Research InstitutionOsaka University

Principal Investigator

高井 義美  大阪大学, 医学系研究科, 教授 (60093514)

Co-Investigator(Kenkyū-buntansha) 入江 賢児  大阪大学, 医学系研究科, 助教授 (90232628)
匂坂 敏朗  大阪大学, 医学系研究科, 助手 (80359843)
池田 わたる  大阪大学, 医学系研究科, 助手 (90362699)
扇田 久和  大阪大学, 医学系研究科, 助手 (50379236)
Keywords細胞増殖 / 細胞接着 / 細胞運動 / ネクチン / Cdc42 / Rac / Necl-5 / がん
Research Abstract

細胞の運動・増殖・接着のそれぞれのシグナル伝達系の間には密接なクロストークが存在し、細胞の接触阻害の破綻ががんの増殖や浸潤・転移の機構へとつながる。私共は、接着分子ネクチンが、上皮細胞のアドヘレンスジャンクション(AJ)とタイトジャンクション(TJ)の形成を制御すること、低分子量Gタンパク質Cdc42とRacを活性化することを明らかにしている。一方、ネクチン様分子Necl-5が細胞の運動および増殖を制御していることも明らかにしている。本年度の研究では、ネクチンとネクチン様分子を介した細胞の運動・増殖・接着のシグナル系のクロストークに焦点をあてて解析し、以下の成果を得た。
(1)接着分子ネクチンは、アファディンとアクチン細胞骨格を介して、AJとTJの構成因子を接着部位にリクルートしてAJとTJを形成した。また、ネクチンによるCdc42とRacの活性化には、c-Src、低分子量Gタンパク質Rap1、GDP/GTP交換因子FRG、Vav2が関与していた。ネクチンによって活性化されたCdc42とRacはそれぞれフィロポディアとラメリポディアの形成を促進し、細胞間接着の形成の速度を促進した。
(2)ネクチン様分子Necl-5はインテグリンおよび増殖因子受容体と協調的に作用して細胞の運動・増殖を促進した。細胞膜表面のNecl-5は、細胞が接触して他の細胞のネクチンと結合するとダウンレギュレーションされ、その結果細胞の運動・増殖は低下した。細胞ががん化するとNecl-5はアップレギュレーションされ、細胞が接触しても細胞膜表面のNecl-5は減少せず、細胞の運動・増殖は低下しなかった。
以上の結果から、ネクチンとネクチン様分子は、細胞の運動・増殖の接触阻害やがん化によるその破壊の分子機構に関与していることが示唆された。このように、本年度の研究は予想以上に進展し、当初の目的を達成することができた。

  • Research Products

    (30 results)

All 2005 2004 Other

All Journal Article (30 results)

  • [Journal Article] Involvement of the cSrc-Crk-C3G-Rap1 signaling in the nectin-induced activation of Cdc42 and formation of adherens junctions.2005

    • Author(s)
      Fukuyama, T.
    • Journal Title

      J.Biol.Chem. 280・1

      Pages: 815-825

  • [Journal Article] Vav2 as a Rac-GDP/GTP exchange factor responsible for the Nectin-induced, c-Src and Cdc42-mediated activation of Rac.2005

    • Author(s)
      Kawakatsu, T.
    • Journal Title

      J.Biol.Chem. 280・6

      Pages: 4940-4947

  • [Journal Article] Involvement of the annexin II-S100A10 complex in the formation of E-cadherin-based adherens junctions in Madin-Darby Canine Kidney cells.2005

    • Author(s)
      Yamada, A.
    • Journal Title

      J.Biol.Chem. 280・7

      Pages: 6016-6027

  • [Journal Article] Nectin-like molecule-5/Tage4 enhances cell migration in an integrin-dependent, nectin-3-independent manner.2004

    • Author(s)
      Ikeda, W.
    • Journal Title

      J.Biol.Chem. 279・17

      Pages: 18015-18025

  • [Journal Article] Involvement of LMO7 in the association of two cell-cell adhesion molecules, nectin and E-cadherin, through afadin and α-actinin in epithelial cells.2004

    • Author(s)
      Ooshio, T.
    • Journal Title

      J.Biol.Chem. 279・30

      Pages: 31365-31373

  • [Journal Article] Enhancement of serum and platelet-derived growth factor-induced cell proliferation by Necl-5/Tage4/Poliovirus Receptor/CD155 through the Ras-Raf-MEK-ERK signaling.2004

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

      J.Biol.Chem. 279・35

      Pages: 36419-36425

  • [Journal Article] Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release.2004

    • Author(s)
      Takao-Rikitsu, E.
    • Journal Title

      J.Cell Biol. 164・2

      Pages: 301-311

  • [Journal Article] Regulation of SNAREs by tomosyn and ROCK : Implication in extension and retraction of neuritis.2004

    • Author(s)
      Sakisaka, T.
    • Journal Title

      J.Cell Biol. 166・1

      Pages: 17-25

  • [Journal Article] Endocytosis of E-cadherin regulated by Rac and Cdc42 small G proteins through IQGAP1 and actin filaments.2004

    • Author(s)
      Izumi, G.
    • Journal Title

      J.Cell Biol. 166・2

      Pages: 237-248

  • [Journal Article] Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG.2004

    • Author(s)
      Fukuhara, T.
    • Journal Title

      J.Cell Biol. 166・3

      Pages: 393-405

  • [Journal Article] A novel role of nectins in inhibition of the E-cadherin-induced activation of Rac and formation of cell-cell adherens junctions.2004

    • Author(s)
      Hoshino, T.
    • Journal Title

      Mol.Biol.Cell 15・3

      Pages: 1077-1088

  • [Journal Article] Direct binding of the human homologue of the Drosophila disc large tumor suppressor gene to seven-pass transmembrane proteins, tumor endothelial marker 5 (TEM5), and a novel TEM5-like protein.2004

    • Author(s)
      Yamamoto, Y.
    • Journal Title

      Oncogene 23・22

      Pages: 3889-3897

  • [Journal Article] Vmac : A novel protein associated with vimentin-type intermediate filament in podocytes of rat kidney.2004

    • Author(s)
      Yamamoto, Y.
    • Journal Title

      Biochem.Biophys.Res.Commun. 315・4

      Pages: 1120-1125

  • [Journal Article] Afadin and α-actinin-binding protein ADIP directly binds β'-COP, a subunit of the coatomer complex.2004

    • Author(s)
      Asada, M.
    • Journal Title

      Biochem.Biophys.Res.Commun. 321・2

      Pages: 350-354

  • [Journal Article] CAST2 : Identification and characterization of a protein structurally related to the presynaptic cytomatrix protein CAST.2004

    • Author(s)
      Deguchi-Tawarada, M.
    • Journal Title

      Genes Cells 9・1

      Pages: 15-23

  • [Journal Article] Involvement of heterophilic trans-interaction of Necl-5/Tage4/PVR/CD155 with nectin-3 in formation of nectin and cadherin-based adherens junctions.2004

    • Author(s)
      Sato, T.
    • Journal Title

      Genes Cells 9・9

      Pages: 791-799

  • [Journal Article] Requirement of the actin cytoskeleton for the association of nectins with other cell adhesion molecules at adherens and tight junctions in MDCK cells.2004

    • Author(s)
      Yamada, A.
    • Journal Title

      Genes Cells 9・9

      Pages: 843-855

  • [Journal Article] Contacts between the commissural axons and the floor plate cells are mediated by nectins.2004

    • Author(s)
      Okabe, N.
    • Journal Title

      Dev.Biol. 273・2

      Pages: 244-256

  • [Journal Article] Expression patterns of nectins and afadin during epithelial remodeling in the mouse embryo.2004

    • Author(s)
      Okabe, N.
    • Journal Title

      Dev.Dyn. 230・1

      Pages: 174-186

  • [Journal Article] Biology and pathology of nectins and nectin-like molecules.2004

    • Author(s)
      Sakisaka, T.
    • Journal Title

      Curr.Opin.Cell Biol. 16・5

      Pages: 513-521

  • [Journal Article] Roles and modes of action of nectins in cell-cell adhesion.2004

    • Author(s)
      Irie, K.
    • Journal Title

      Seminars in Cell & Dev.Biol. 15・6

      Pages: 643-656

  • [Journal Article] Dual role of DENN/MADD (Rab3GEP) in neurotransmission and neuroprotection.2004

    • Author(s)
      Miyoshi, J.
    • Journal Title

      Trends in Mol.Med. 10・10

      Pages: 476-480

  • [Journal Article] Role of nectins in cell adhesion, migration and polarization.2004

    • Author(s)
      Nakanishi, H.
    • Journal Title

      Biological Chem. 385・10

      Pages: 885-892

  • [Journal Article] Roles of nectins in cell adhesion, signaling and polarization.2004

    • Author(s)
      Irie, K.
    • Journal Title

      Handbook of Experimental Pharmacology 165

      Pages: 343-372

  • [Journal Article] Direct binding of Lgl2 to LGN during mitosis and its requirement for normal cell division.

    • Author(s)
      Yasumi, M.
    • Journal Title

      J.Biol.Chem. (印刷中)

  • [Journal Article] Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway.

    • Author(s)
      Hirota, T.
    • Journal Title

      Oncogene (印刷中)

  • [Journal Article] Nectin-like molecule-1/TSLL1/SynCAM3 : a neural tissue-specific immunoglobulin -like cell-cell adhesion molecule localizing at non-junctional contact sites of presynaptic nerve terminals, axons and glia cell processes.

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

      J.Cell Sci. (印刷中)

  • [Journal Article] Recruitment of E-cadherin associated with α and β-catenins and p120^<ctn> to the nectin-based cell-cell adhesion sites by the action of 12-Ο-tetradecanoylphorbol-13-acetate in MDCK cells.

    • Author(s)
      Okamoto, R
    • Journal Title

      Genes Cells (印刷中)

  • [Journal Article] Roles of cell adhesion molecules nectin-1 and -3 in the ciliary body development.

    • Author(s)
      Inagaki, M.
    • Journal Title

      Development (印刷中)

  • [Journal Article] Molecular perspective on tight-junction assembly and epithelial polarity.

    • Author(s)
      Miyoshi, J.
    • Journal Title

      Delivery Rev. (印刷中)

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Published: 2006-07-12   Modified: 2016-04-21  

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