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 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.

[1]  David R Kaplan,et al.  Neurotrophin signal transduction in the nervous system , 2000, Current Opinion in Neurobiology.

[2]  C. M. Davenport,et al.  Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. , 1999, Science.

[3]  F. Miller,et al.  Ras Regulates Sympathetic Neuron Survival by Suppressing the p53-Mediated Cell Death Pathway , 1999, The Journal of Neuroscience.

[4]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[5]  Dianqing Wu,et al.  Suppression of Glycogen Synthase Kinase Activity Is Not Sufficient for Leukemia Enhancer Factor-1 Activation* , 1999, The Journal of Biological Chemistry.

[6]  P. Cohen,et al.  A GSK3‐binding peptide from FRAT1 selectively inhibits the GSK3‐catalysed phosphorylation of Axin and β‐catenin , 1999, FEBS letters.

[7]  D. Kaplan,et al.  Depolarization and Neurotrophins Converge on the Phosphatidylinositol 3-Kinase–Akt Pathway to Synergistically Regulate Neuronal Survival , 1999, The Journal of cell biology.

[8]  Eugene M. Johnson,et al.  BAX Translocation Is a Critical Event in Neuronal Apoptosis: Regulation by Neuroprotectants, BCL-2, and Caspases , 1999, The Journal of Neuroscience.

[9]  R. Heumann,et al.  Nerve growth factor-induced PKB/Akt activity is sustained by phosphoinositide 3-kinase dependent and independent signals in sympathetic neurons , 1999, Brain Research.

[10]  Z. Xia,et al.  Neuroprotection by Brain-derived Neurotrophic Factor Is Mediated by Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase* , 1999, The Journal of Biological Chemistry.

[11]  J Mao,et al.  Axin and Frat1 interact with Dvl and GSK, bridging Dvl to GSK in Wnt‐mediated regulation of LEF‐1 , 1999, The EMBO journal.

[12]  T. Dale,et al.  Interaction of Axin and Dvl‐2 proteins regulates Dvl‐2‐stimulated TCF‐dependent transcription , 1999, The EMBO journal.

[13]  Susan S. Taylor,et al.  Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. , 1999, Molecular cell.

[14]  Haruo Okado,et al.  Tumor Necrosis Factor Induces Bcl-2 and Bcl-x Expression through NFκB Activation in Primary Hippocampal Neurons* , 1999, The Journal of Biological Chemistry.

[15]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[16]  S. Gerondakis,et al.  Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. , 1999, Genes & development.

[17]  W. Zong,et al.  The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-κB that blocks TNFα-induced apoptosis , 1999 .

[18]  R. Freeman,et al.  Nerve Growth Factor-Dependent Activation of NF-κB Contributes to Survival of Sympathetic Neurons , 1998, The Journal of Neuroscience.

[19]  John Calvin Reed,et al.  Regulation of cell death protease caspase-9 by phosphorylation. , 1998, Science.

[20]  Hans Clevers,et al.  Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis , 1998, Nature.

[21]  Eugene M. Johnson,et al.  Evidence of a Novel Event during Neuronal Death Development of Competence-to-Die in Response to Cytoplasmic Cytochrome c , 1998, Neuron.

[22]  L. Rubin,et al.  Blocking Cytochrome c Activity within Intact Neurons Inhibits Apoptosis , 1998, The Journal of cell biology.

[23]  G. Cooper,et al.  Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway* , 1998, The Journal of Biological Chemistry.

[24]  D. M. Ferkey,et al.  GBP, an Inhibitor of GSK-3, Is Implicated in Xenopus Development and Oncogenesis , 1998, Cell.

[25]  R. Crowder,et al.  Phosphatidylinositol 3-Kinase and Akt Protein Kinase Are Necessary and Sufficient for the Survival of Nerve Growth Factor-Dependent Sympathetic Neurons , 1998, The Journal of Neuroscience.

[26]  L. Rubin,et al.  Role of the Jun Kinase Pathway in the Regulation of c-Jun Expression and Apoptosis in Sympathetic Neurons , 1998, The Journal of Neuroscience.

[27]  T. Deckwerth,et al.  Analysis of the Mechanism of Loss of Trophic Factor Dependence Associated with Neuronal Maturation: A Phenotype Indistinguishable fromBax Deletion , 1997, The Journal of Neuroscience.

[28]  T. Ikeuchi,et al.  Insulin Receptor Substrate (IRS)-1 and IRS-2 Are Tyrosine-phosphorylated and Associated with Phosphatidylinositol 3-Kinase in Response to Brain-derived Neurotrophic Factor in Cultured Cerebral Cortical Neurons* , 1997, The Journal of Biological Chemistry.

[29]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[30]  Virginia M. Y. Lee,et al.  Lithium Reduces Tau Phosphorylation by Inhibition of Glycogen Synthase Kinase-3* , 1997, The Journal of Biological Chemistry.

[31]  E. Krebs,et al.  Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Andrew J. Bannister,et al.  Comparison Between the Timing of JNK activation, c‐Jun Phosphorylation, and Onset of Death Commitment in Sympathetic Neurones , 1997, Journal of neurochemistry.

[33]  S. Bartlett,et al.  In sympathetic but not sensory neurones, phosphoinositide-3 kinase is important for NGF-dependent survival and the retrograde transport of 125I-βNGF , 1997, Brain Research.

[34]  M. Deshmukh,et al.  Programmed cell death in neurons: focus on the pathway of nerve growth factor deprivation-induced death of sympathetic neurons. , 1997, Molecular pharmacology.

[35]  M. Tansey,et al.  Inhibition of Phosphatidylinositol 3-Kinase Activity Blocks Depolarization- and Insulin-like Growth Factor I-mediated Survival of Cerebellar Granule Cells* , 1997, The Journal of Biological Chemistry.

[36]  S. D’Mello,et al.  Insulin-Like Growth Factor and Potassium Depolarization Maintain Neuronal Survival by Distinct Pathways: Possible Involvement of PI 3-Kinase in IGF-1 Signaling , 1997, The Journal of Neuroscience.

[37]  A. Berns,et al.  Activation of a novel proto‐oncogene, Frat1, contributes to progression of mouse T‐cell lymphomas , 1997, The EMBO journal.

[38]  David R. Kaplan,et al.  Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt , 1997, Science.

[39]  M. Birnbaum,et al.  Expression of a Constitutively Active Akt Ser/Thr Kinase in 3T3-L1 Adipocytes Stimulates Glucose Uptake and Glucose Transporter 4 Translocation* , 1996, The Journal of Biological Chemistry.

[40]  James R. Woodgett,et al.  Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells , 1996, Current Biology.

[41]  D. Melton,et al.  A molecular mechanism for the effect of lithium on development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  C. Proud,et al.  GSK3: a SHAGGY frog story. , 1996, Trends in cell biology.

[43]  R. Moon,et al.  The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. , 1996, Genes & development.

[44]  Y. Barde,et al.  Selective Activation of NF-κB by Nerve Growth Factor Through the Neurotrophin Receptor p75 , 1996, Science.

[45]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[46]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[47]  J. Wood.  Regulation of NF-κB activity in rat dorsal root ganglia and PC12 cells by tumour necrosis factor and nerve growth factor , 1995, Neuroscience Letters.

[48]  Harold E. Varmus,et al.  Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos , 1995, Nature.

[49]  Eugene M. Johnson,et al.  Superoxide dismutase delays neuronal apoptosis: A role for reactive oxygen species in programmed neuronal death , 1995, Neuron.

[50]  M. Greenberg,et al.  Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB , 1994, Cell.

[51]  R. Bradshaw,et al.  Activation of phosphatidylinositol 3-kinase by epidermal growth factor, basic fibroblast growth factor, and nerve growth factor in PC12 pheochromocytoma cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[52]  L. Cantley,et al.  Nerve growth factor promotes the activation of phosphatidylinositol 3-kinase and its association with the trk tyrosine kinase. , 1992, The Journal of biological chemistry.

[53]  C. Downes,et al.  Phosphatidylinositol 3-kinase is activated by nerve growth factor and epidermal growth factor in PC12 cells. , 1992, The Journal of biological chemistry.

[54]  M. Hetman,et al.  Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. , 2000, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[55]  M. Andjelkovic,et al.  Nerve growth factor promotes activation of the alpha, beta and gamma isoforms of protein kinase B in PC12 pheochromocytoma cells. , 1998, European journal of biochemistry.