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2005 Fiscal Year Final Research Report Summary

Activation and functions of the PDK1-Akt pathway in regulation of cell motility

Research Project

Project/Area Number 16370085
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Cell biology
Research InstitutionThe University of Tokyo

Principal Investigator

GOTOH Yukiko  The University of Tokyo, Institute of Molecular and Cellular Biosciences, Professor, 分子細胞生物学研究所, 教授 (70252525)

Project Period (FY) 2004 – 2005
KeywordsAkt / PDK1 / cell motility / actin / Rac / Cdc42 / PAK / Rho
Research Abstract

Growth factors promote cell survival and cell motility, presumably through the activation of Akt and the Rac and Cdc42 GTPases, respectively. Because Akt is dispensable for Rac/Cdc42-regulation of actin reorganization, it has been assumed that Rac and Cdc42 stimulate cell motility independent of Akt in mammalian cells. However, in this study we demonstrate that Akt is essential for Rac/Cdc42-regulated cell motility in mammalian fibroblasts.
A dominant- negative Akt inhibits cell motility stimulated by Rac/Cdc42 or by PDGF treatment, without affecting ruffling membrane-type actin reorganization. We have confirmed a previous report that Akt is activated by expression of Rac and Cdc42, and also observed co-localization of endogenous phosphorylated Akt with Rac and Cdc42 at the leading edge of fibroblasts. Importantly, expression of active Akt, but not the closely related kinase SGK, is sufficient for increasing cell motility. This effect of Akt is cell-autonomous, and not mediated by inhibition of GSK3. Finally, we found that dominant-negative Akt, but not SGK, reverses the increased cell motility phenotype of fibroblasts lacking the PTEN tumor suppressor gene. Taken together, these results suggest that Akt promotes cell motility downstream of Rac/Cdc42 in growth factor-stimulated cells and in invasive PTEN-deficient cells. We then studied the mechanisms by which Akt regulates cell motility. We found that the PDK1-Akt pathway plays an essential role in the positive feedback loop of phosphatidyl inositol 3-phosphate accumulation.
In doing so, antagonistic interaction between the PDK1-Akt pathway and the small G protein Rho appears to be crucial. This mechanism contributes to the establishment of cell polarity, which is essential for the directional movement.

  • Research Products

    (21 results)

All 2005 2004 Other

All Journal Article (21 results)

  • [Journal Article] JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3.2005

    • Author(s)
      Sunayama, J., et al.
    • Journal Title

      J. Cell. Biol. 170

      Pages: 295-304

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Stage-dependent fate determination of neural precursor cells in mouse forebrain.2005

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

      Neurosci. Res. 51

      Pages: 331-336

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Regulation of the cell surface expression of human BCRP/ABCG2 by the phosphorylation state of Akt in polarized cells.2005

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

      Drug Metab. Dispos. 33

      Pages: 905-909

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3.2005

    • Author(s)
      Sunayama, J. et al.
    • Journal Title

      J.Cell.Biol. 170

      Pages: 295-304

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Stage-dependent fate determination of neural precursor cells in mouse forebrain.2005

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

      Neurosci.Res. 51

      Pages: 331-336

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Regulation of the cell surface expression of human BCRP/ABCG2 by the phosphorylation state of Akt in polarized cells.2005

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

      Drug Metab.Dispos. 33

      Pages: 905-909

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Notch promotes survival of neural precursor cells via me chanisms distinct from those regulating neurogenesis.2004

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

      Dev. Biol. 276

      Pages: 172-184

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signaling.2004

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

      Nat. Cell Biol. 6

      Pages: 547-554

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins.2004

    • Author(s)
      Tsuruta, F., et al.
    • Journal Title

      EMBO J. 23

      Pages: 1889-1899

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The Wnt-beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells.2004

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

      Development 131

      Pages: 2791-2801

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The sox-2 regulatory regions display their activities in twodistinct multipotent stem cells.2004

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

      Mol. Cell. Biol. 24

      Pages: 4207-4220

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p322004

    • Author(s)
      Sunayama, J., et al.
    • Journal Title

      Cell Death Differ. 11

      Pages: 771-781

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Adenosine A2A receptor facilitates calcium-dependent protein secretion through the activation of protein kinase A and phosphatidylinositol-3 kinase in PC12 cells2004

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

      Cell Struct. Funct. 29

      Pages: 101-110

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Oxidative stress induces insulin resistance by activating the nuclear factor-B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase2004

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

      Diabetologia 5

      Pages: 794-805

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signaling.2004

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

      Nat.Cell Biol. 6

      Pages: 547-554

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins.2004

    • Author(s)
      Tsuruta, F. et al.
    • Journal Title

      EMBO J. 23

      Pages: 1889-1899

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The Wnt-beta-catenin pathway directs neuronal differentiation of cortical neural pre cursor cells.2004

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

      Development 131

      Pages: 2791-2801

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The sox-2 regulatory regions display their activities in twodistinct multipotent stem cells.2004

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

      Mol.Cell.Biol. 24

      Pages: 4207-4220

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p322004

    • Author(s)
      Sunayama, J. et al.
    • Journal Title

      Cell Death Differ. 11

      Pages: 771-781

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Adenosine A2A receptor facilitates calcium-dependent protein secretion through the activation of protein kinase A and phosphatidylinositol-3 kinase in PC12 cells2004

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

      Cell Struct.Funct. 29

      Pages: 101-110

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Notch promotes survival of neural precursor cells via mechanisms distinct from those regulating neurogenesis.

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

      Dev.Biol. 276

      Pages: 172-184

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2007-12-13  

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