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Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway*

  • Marianna Pap
    Footnotes
    Affiliations
    Dana-Farber Cancer Institute and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
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  • Geoffrey M. Cooper
    Correspondence
    To whom correspondence should be addressed. Tel.: 617-353-8735; Fax: 617-353-8484;
    Footnotes
    Affiliations
    Dana-Farber Cancer Institute and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
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  • Author Footnotes
    * This research was supported by National Institutes of Health Grant RO1 CA18689.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
    ‡ On leave from the Dept. of Biology, University Medical School of Pécs, Pécs, Hungary.
    § Present address: Dept. of Biology, Boston University, 5 Cummington St., Boston, MA 02215.
Open AccessPublished:August 07, 1998DOI:https://doi.org/10.1074/jbc.273.32.19929
      Growth factor-dependent survival of a variety of mammalian cells is dependent on the activation of phosphatidylinositol (PI) 3-kinase and its downstream effector, the protein kinase Akt. Glycogen synthase kinase-3 (GSK-3) has been previously identified as a physiological target of Akt, which is inhibited by phosphorylation, so we have investigated the role of GSK-3 in cell survival. Overexpression of catalytically active GSK-3 induced apoptosis of both Rat-1 and PC12 cells, whereas dominant-negative GSK-3 prevented apoptosis following inhibition of PI 3-kinase. GSK-3 thus plays a critical role in regulation of apoptosis and represents a key downstream target of the PI 3-kinase/Akt survival signaling pathway.
      Although many types of mammalian cells are dependent upon growth factors for survival (
      • Raff M.C.
      • Barres B.A.
      • Burne J.F.
      • Coles H.S.
      • Ishizaki Y.
      • Jacobson M.D.
      ), the intracellular signaling pathways that control cell survival by preventing apoptosis have only begun to be elucidated. A role for PI
      The abbreviations used are: PI
      phosphatidylinositol
      GSK-3
      glycogen synthase kinase-3
      DMEM
      Dulbecco's modified Eagle's medium
      GFP
      green fluorescent protein
      NGF
      nerve growth factor.
      1The abbreviations used are: PI
      phosphatidylinositol
      GSK-3
      glycogen synthase kinase-3
      DMEM
      Dulbecco's modified Eagle's medium
      GFP
      green fluorescent protein
      NGF
      nerve growth factor.
      3-kinase in the regulation of cell survival was first indicated by experiments showing that PI 3-kinase was required to prevent apoptosis of PC12 rat pheochromocytoma cells maintained in nerve growth factor (NGF) (
      • Yao R.
      • Cooper G.M.
      ). These findings have been extended by observations demonstrating that PI 3-kinase is required for survival of several other growth factor-dependent cell types, including fibroblasts, epithelial cells, hematopoietic cells, and primary neurons (
      • Yao R.
      • Cooper G.M.
      ,
      • Erhardt P.
      • Cooper G.M.
      ,
      • Dudek H.
      • Datta S.R.
      • Franke T.F.
      • Birnbaum M.J.
      • Yao R.
      • Cooper G.M.
      • Segal R.A.
      • Kaplan D.R.
      • Greenberg M.E.
      ,
      • Khwaja A.
      • Rodriguez-Viciana P.
      • Wennstrom S.
      • Warne P.H.
      • Downward J.
      ,
      • Scheid M.P.
      • Lauener R.W.
      • Duronio V.
      ,
      • Minshall C.
      • Arkins S.
      • Freund G.G.
      • Kelley K.W.
      ,
      • Cai Y.-C.
      • Cefai D.
      • Schneider H.
      • Raab M.
      • Nabavi N.
      • Rudd C.E.
      ,
      • D'Mello S.R.
      • Borodezt K.
      • Soltoff S.P.
      ,
      • Gonzales-Garcia A.
      • Merida I.
      • Martinez-A C.
      • Carrera A.C.
      ,
      • Miller T.M.
      • Tansey M.G.
      • Johnson E.M.J.
      • Creedon D.J.
      ). In addition, the protein kinase Akt has been identified as a key effector of PI 3-kinase in signaling cell survival (
      • Dudek H.
      • Datta S.R.
      • Franke T.F.
      • Birnbaum M.J.
      • Yao R.
      • Cooper G.M.
      • Segal R.A.
      • Kaplan D.R.
      • Greenberg M.E.
      ,
      • Kauffmann-Zeh A.
      • Rodriguez-Viciana P.
      • Ulrich E.
      • Gilbert C.
      • Coffer P.
      • Downward J.
      • Evan G.
      ,
      • Kulik G.
      • Kippel A.
      • Weber M.J.
      ).
      The principal characterized physiological substrate of Akt is glycogen synthase kinase-3 (GSK-3) (
      • Cross D.A.E.
      • Alessi D.R.
      • Cohen P.
      • Andjelkovich M.
      • Hemmings B.A.
      ), which was initially identified as an enzyme that regulates glycogen synthesis in response to insulin (
      • Welsh G.I.
      • Wilson C.
      • Proud C.G.
      ). GSK-3 is a ubiquitously expressed protein-serine/threonine kinase whose activity is inhibited by Akt phosphorylation in response to growth factor stimulation. In addition to glycogen synthase, GSK-3 phosphorylates a broad range of substrates, including several transcription factors and translation initiation factor eIF2B (
      • Welsh G.I.
      • Wilson C.
      • Proud C.G.
      ). GSK-3 has also been implicated in the regulation of cell fate inDictyostelium (
      • Harwood A.J.
      • Plyte S.E.
      • Woodgett J.
      • Strutt H.
      • Kay R.R.
      ) and is a component of the Wnt signaling pathway required for Drosophila and Xenopusdevelopment (
      • Siegfried E.
      • Chou T.-B.
      • Perrimon N.
      ,
      • He X.
      • Saint-Jeannet J.P.
      • Woodgett J.R.
      • Varmus H.E.
      • Dawid I.B.
      ,
      • Pierce S.B.
      • Kimelman D.
      ,
      • Dominguez I.
      • Itoh K.
      • Sokol S.Y.
      ). These studies suggest that GSK-3 is involved in multiple cellular processes, including metabolism, proliferation, and differentiation. Here we show that GSK-3 is also involved in the regulation of apoptosis, identifying it as a critical downstream element of the PI 3-kinase/Akt cell survival pathway.

      ACKNOWLEDGEMENTS

      We are grateful to I. Dominguez for GSK-3 plasmids, to C. E. Rudd for the dominant-negative PI 3-kinase plasmid, and to P. Erhardt for kind help and advice.

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