Glycogen Synthase Kinase-3β Activity Is Critical for Neuronal Death Caused by Inhibiting Phosphatidylinositol 3-Kinase or Akt but Not for Death Caused by Nerve Growth Factor Withdrawal

Numerous studies reveal that phosphatidylinositol (PI) 3-kinase and Akt protein kinase are important mediators of cell survival. However, the survival-promoting mechanisms downstream of these enzymes remain uncharacterized. Glycogen synthase kinase-3β (GSK-3β), which is inhibited upon phosphorylatio...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-11, Vol.275 (44), p.34266-34271
Main Authors: Crowder, Robert J., Freeman, Robert S.
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors
Calcium-Calmodulin-Dependent Protein Kinases - physiology
Cells, Cultured
Glycogen Synthase Kinase 3
Glycogen Synthase Kinases
Nerve Growth Factor - metabolism
Nerve Growth Factor - physiology
Neurons - cytology
Neurons - enzymology
Phosphoinositide-3 Kinase Inhibitors
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins c-akt
Rats
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Summary:Numerous studies reveal that phosphatidylinositol (PI) 3-kinase and Akt protein kinase are important mediators of cell survival. However, the survival-promoting mechanisms downstream of these enzymes remain uncharacterized. Glycogen synthase kinase-3β (GSK-3β), which is inhibited upon phosphorylation by Akt, was recently shown to function during cell death induced by PI 3-kinase inhibitors. In this study, we tested whether GSK-3β is critical for the death of sympathetic neurons caused by the withdrawal of their physiological survival factor, the nerve growth factor (NGF). Stimulation with NGF resulted in PI 3-kinase-dependent phosphorylation of GSK-3β and inhibition of its protein kinase activity, indicating that GSK-3β is targeted by PI 3-kinase/Akt in these neurons. Expression of the GSK-3β inhibitor Frat1, but not a mutant Frat1 protein that does not bind GSK-3β, rescued neurons from death caused by inhibiting PI 3-kinase. Similarly, expression of Frat1 or kinase-deficient GSK-3β reduced death caused by inhibiting Akt. In NGF-maintained neurons, overexpression of GSK-3β caused a small but significant decrease in survival. However, expression of neither Frat1, kinase-deficient GSK-3β, nor GSK-3-binding protein inhibited NGF withdrawal-induced death. Thus, although GSK-3β function is required for death caused by inactivation of PI 3-kinase and Akt, neuronal death caused by NGF withdrawal can proceed through GSK-3β-independent pathways.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M006160200