Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway*
- From the Dana-Farber Cancer Institute and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
Abstract
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.
Footnotes
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↵* 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.
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↵‡ On leave from the Dept. of Biology, University Medical School of Pécs, Pécs, Hungary.
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↵§ Present address: Dept. of Biology, Boston University, 5 Cummington St., Boston, MA 02215.
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↵¶ To whom correspondence should be addressed. Tel.: 617-353-8735; Fax: 617-353-8484; E-mail: gmcooper{at}bio.bu.edu.
- Abbreviations:
- PI
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phosphatidylinositol
- GSK-3
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glycogen synthase kinase-3
- DMEM
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Dulbecco’s modified Eagle’s medium
- GFP
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green fluorescent protein
- NGF
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nerve growth factor.
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- Received November 4, 1997.
- Revision received June 1, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
