PreprintCited by 4,216Cell death mechanisms and regulationPI3K/AKT/mTOR signaling in cancerNerve injury and regeneration

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Cellular survival: a play in three Akts

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Datta, S. R., Brunet, A., Greenberg, M. E.·1999·Genes & Development

DOI 10.1101/gad.13.22.2905

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Abstract

The programmed cell death that occurs as part of normal mammalian development was first observed nearly a century ago (Collin 1906). It has since been established that approximately half of all neurons in the neuroaxis and >99.9% of the total number of cells generated during the course of a human lifetime go on to die through a process of apoptosis (for review, see Datta and Greenberg 1998; Vaux and Korsmeyer 1999). The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. The purification in the 1950s of the nerve growth factor (NGF), which promotes the survival of sympathetic neurons, set the stage for the discovery that peptide trophic factors promote the survival of a wide variety of cell types in vitro and in vivo (Levi-Montalcini 1987). The profound biological consequences of growth factor (GF) suppression of apoptosis are exemplified by the critical role of target-derived neurotrophins in the survival of neurons and the maintenance of functional neuronal circuits. (Pettmann and Henderson 1998). Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 38-OH kinase (PI3K)/c-Akt kinase cascade. Several targets of the PI3K/c-Akt signaling pathway have been recently identified that may underlie the ability of this regulatory cascade to promote survival. These substrates include two components of the intrinsic cell death machinery, BAD and caspase 9, transcription factors of the forkhead family, and a kinase, IKK, that regulates the NF-kB transcription factor. This article reviews the mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI3K/c-Akt pathway promotes cell survival, and the current spectrum of c-Akt targets and their roles in mediating c-Akt-dependent cell survival.

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Akt activation by growth factors is a multiple-step process: the role of the PH domain
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Impaired B Cell Development and Proliferation in Absence of Phosphoinositide 3-Kinase p85α
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Induction of Vascular Endothelial Growth Factor by Hypoxia Is Modulated by a Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Ha-ras-Transformed Cells Through a Hypoxia Inducible Factor-1 Transcriptional Element
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Akt Protein Kinase Enhances Human Telomerase Activity through Phosphorylation of Telomerase Reverse Transcriptase Subunit
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A Specific Product of Phosphatidylinositol 3-Kinase Directly Activates the Protein Kinase Akt through Its Pleckstrin Homology Domain
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The Drosophila Gene hid Is a Direct Molecular Target of Ras-Dependent Survival Signaling
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Regulation of Insulin-Stimulated Glucose Transporter GLUT4 Translocation and Akt Kinase Activity by Ceramide
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Insulin Stimulates Phosphorylation of the Forkhead Transcription Factor FKHR on Serine 253 through a Wortmannin-sensitive Pathway
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Multiple signals converging on NF-κB
Mercurio, F., & Manning, A. M. (1999) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(99)80030-1 · Cited by 473
Akt, a Pleckstrin Homology Domain Containing Kinase, Is Activated Primarily by Phosphorylation
Kohn, A. D., Takeuchi, F., & Roth, R. A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.36.21920 · Cited by 468
Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease
Nelen, M. R. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.8.1383 · Cited by 465
Phosphorylation and Activation of Heart 6-Phosphofructo-2-kinase by Protein Kinase B and Other Protein Kinases of the Insulin Signaling Cascades
Deprez, J., Vertommen, D., Alessi, D. R., Hue, L., & Rider, M. H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.28.17269 · Cited by 462
Withdrawal of Survival Factors Results in Activation of the JNK Pathway in Neuronal Cells Leading to Fas Ligand Induction and Cell Death
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High Affinity Binding of Inositol Phosphates and Phosphoinositides to the Pleckstrin Homology Domain of RAC/Protein Kinase B and Their Influence on Kinase Activity
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A putative modular domain present in diverse signaling proteins
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PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2
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A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegansPreprint
Paradis, S., Ailion, M., Toker, A., Thomas, J. H., & Ruvkun, G. (1999) · Genes & Development · doi:10.1101/gad.13.11.1438 · Cited by 431
Caspase-dependent Cleavage of Signaling Proteins during Apoptosis
Widmann, C., Gibson, S. B., & Johnson, G. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.12.7141 · Cited by 423
Phosphatidylinositol 3-Kinase Is Required for Integrin-Stimulated AKT and Raf-1/Mitogen-Activated Protein Kinase Pathway Activation
King, W. G., Mattaliano, M. D., Chan, T. O., Tsichlis, P. N., & Brugge, J. S. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.8.4406 · Cited by 422
Transformation of Chicken Cells by the Gene Encoding the Catalytic Subunit of PI 3-Kinase
Chang, H. W., Aoki, M., Fruman, D. A., Auger, K. R., Bellacosa, A., Tsichlis, P. N., Cantley, L. C., Roberts, T. M., & Vogt, P. K. (1997) · Science · doi:10.1126/science.276.5320.1848 · Cited by 412
Phosphatidylinositol 3-Kinase Couples the Interleukin-2 Receptor to the Cell Cycle Regulator E2F
Brennan, P., Babbage, J. W., Burgering, B. M. T., Groner, B., Reif, K., & Cantrell, D. A. (1997) · Immunity · doi:10.1016/s1074-7613(00)80388-x · Cited by 401
Apoptosis in cerebellar granule cells is blocked by high KCl, forskolin, and IGF-1 through distinct mechanisms of action: the involvement of intracellular calcium and RNA synthesis
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Ras Promotes Cell Survival in Drosophila by Downregulating hid Expression
Kurada, P., & White, K. (1998) · Cell · doi:10.1016/s0092-8674(00)81764-x · Cited by 382
Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1
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Rel/NF-κB and IκB proteins: an overview
May, M. J., & Ghosh, S. (1997) · Seminars in Cancer Biology · doi:10.1006/scbi.1997.0057 · Cited by 379
Mitogenic Activation, Phosphorylation, and Nuclear Translocation of Protein Kinase Bβ
Meier, R., Alessi, D. R., Cron, P., Andjelković, M., & Hemmings, B. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.48.30491 · Cited by 378
Essential Role for Protein Kinase B (PKB) in Insulin-induced Glycogen Synthase Kinase 3 Inactivation
van Weeren, P. C., de Bruyn, K. M. T., de Vries-Smits, A. M. M., Lint, J. V., & Burgering, B. M. T. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.21.13150 · Cited by 372
Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis.
Zhan, Q., Fan, S., Bae, I., Guillouf, C., Liebermann, D. A., O'Connor, P. M., & Fornace, A. J. (1994) · PubMed · Cited by 372
A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region
Bellacosa, A., Testa, Staal, S., et al. (1991) · Science · doi:10.1126/science.254.5029.274 · Cited by 365
Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B
Anderson, K. E., Coadwell, J., Stephens, L., & Hawkins, P. T. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70274-x · Cited by 363
Interleukin 3-dependent survival by the Akt protein kinase
Songyang, Z., Baltimore, D., Cantley, L. C., Kaplan, D. R., & Franke, T. F. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.21.11345 · Cited by 361
The Kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136
Blume‐Jensen, P., Janknecht, R., & Hunter, T. R. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70302-1 · Cited by 361
The Product of par-4, a Gene Induced during Apoptosis, Interacts Selectively with the Atypical Isoforms of Protein Kinase C
Díaz-Meco, M. T., Municio, M. M., Frutos, S., Sánchez‐Gómez, P., Lozano, J., Sanz, L., & Moscat, J. (1996) · Cell · doi:10.1016/s0092-8674(00)80152-x · Cited by 361
Identification of a Sequence in the PEPCK Gene That Mediates a Negative Effect of Insulin on Transcription
O’Brien, R. M., Lucas, P. C., Forest, C. D., Magnuson, M. A., & Granner, D. K. (1990) · Science · doi:10.1126/science.2166335 · Cited by 357
Cloning and Characterization of Three Human Forkhead Genes That Comprise an FKHR-like Gene Subfamily
Anderson, M. J., Viars, C. S., Czekay, S., Cavenee, W. K., & Arden, K. C. (1998) · Genomics · doi:10.1006/geno.1997.5122 · Cited by 357
Potential Role of Protein Kinase B in Insulin-induced Glucose Transport, Glycogen Synthesis, and Protein Synthesis
Ueki, K., Yamamoto‐Honda, R., Kaburagi, Y., Yamauchi, T., Tobe, K., Burgering, B. M. T., Coffer, P. J., Komuro, I., Akanuma, Y., Yazaki, Y., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.9.5315 · Cited by 357
Inhibition of Akt Kinase by Cell-permeable Ceramide and Its Implications for Ceramide-induced Apoptosis
Zhou, H., Summers, S. A., Birnbaum, M. J., & Pittman, R. N. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.26.16568 · Cited by 356
SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival
Liu, Q., Sasaki, T., Kozieradzki, I., Wakeham, A., Itie, A., Dumont, D. J., & Penninger, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.7.786 · Cited by 341
Tumor Suppressor PTEN Inhibits Integrin- and Growth Factor–mediated Mitogen-activated Protein (MAP) Kinase Signaling Pathways
Gu, J., Tamura, M., & Yamada, K. M. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.5.1375 · Cited by 337
Constitutive activation of protein kinase B alpha by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells.
Hajduch, E., Alessi, D. R., Hemmings, B. A., & Hundal, H. S. (1998) · Diabetes · doi:10.2337/diabetes.47.7.1006 · Cited by 335 · cited 2×
“…synthase, the translocation of the glucose transporter (GLUT) 4 to the plasma membrane, the induction of GLUT 1 synthesis and the activation of 6-phopshofructo-2-kinase (Kohn et al. 1996b, 1998; Deprez et al. 1997; Tanti et al. 1997; Hajduch et al. 1998; Summers et al. 1998; Wang et al. 1999).”
Background
c-Myc-induced sensitization to apoptosis is mediated through cytochrome c releasePreprint
Juin, P. P., Hueber, A., Littlewood, T. D., & Evan, G. I. (1999) · Genes & Development · doi:10.1101/gad.13.11.1367 · Cited by 333
Activation of Akt/Protein Kinase B by G Protein-coupled Receptors
Murga, C., Laguinge, L. M., Wetzker, R., Cuadrado, A., & Gutkind, J. S. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.30.19080 · Cited by 331
BH3 Domain of BAD Is Required for Heterodimerization with BCL-XL and Pro-apoptotic Activity
Zha, J., Harada, H., Osipov, K. A., Jockel, J., Waksman, G., & Korsmeyer, S. J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.39.24101 · Cited by 309
Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: Involvement of MEK upstream of Bad phosphorylation
Scheid, M. P., & Duronio, V. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7439 · Cited by 305
Construction and Characterization of a Conditionally Active Version of the Serine/Threonine Kinase Akt
Kohn, A. D., Barthel, A., Kovacina, K. S., Boge, A., Wallach, B. J., Summers, S. A., Birnbaum, M. J., Scott, P., Lawrence, J. C., & Roth, R. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.19.11937 · Cited by 304
Akt is more than just a Bad kinase
Khwaja, A. (1999) · Nature · doi:10.1038/43354 · Cited by 302
The Akt kinase: Molecular determinants of oncogenicity
Aoki, M., Batista, O., Bellacosa, A., Tsichlis, P. N., & Vogt, P. K. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14950 · Cited by 294
Activation of protein kinase B β and γ isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B α
Walker, K. S., Deák, M., PATERSON, A., Hudson, K., Cohen, P., & Alessi, D. R. (1998) · Biochemical Journal · doi:10.1042/bj3310299 · Cited by 282
Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma.
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Evidence of a Novel Event during Neuronal Death
Deshmukh, M., & Johnson, E. M. (1998) · Neuron · doi:10.1016/s0896-6273(00)80587-5 · Cited by 281
Akt Is a Direct Target of the Phosphatidylinositol 3-Kinase
Datta, K., Bellacosa, A., Chan, T. O., & Tsichlis, P. N. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.48.30835 · Cited by 281
NF-κB to the rescue: RELs, apoptosis and cellular transformation
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Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.
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Involvement of regulatory and catalytic subunits of phosphoinositide 3-kinase in NF-κB activation
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Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease
Kitamura, Y., Shimohama, S., Kamoshima, W., Ota, T., Matsuoka, Y., Nomura, Y., Smith, M. A., Perry, G. L., Whitehouse, P. J., & Taniguchi, T. (1998) · Brain Research · doi:10.1016/s0006-8993(97)01202-x · Cited by 271
Mechanism of Protein Kinase B Activation by Cyclic AMP-Dependent Protein Kinase
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Potential Role of Protein Kinase B in Glucose Transporter 4 Translocation in Adipocytes
Tanti, J., Grillo, S., Grémeaux, T., Coffer, P. J., OBBERGHEN, E. V., & MARCHAND‐BRUSTEL, Y. L. (1997) · Endocrinology · doi:10.1210/endo.138.5.5136 · Cited by 260
Exposure of rat hippocampal neurons to amyloid β peptide (25–35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3β
Takashima, A., Noguchi, K., Michel, G., Mercken, M., Hoshi, M., Ishiguro, K., & Imahori, K. (1996) · Neuroscience Letters · doi:10.1016/0304-3940(95)12257-5 · Cited by 260
The Activation of p38 and Apoptosis by the Inhibition of Erk Is Antagonized by the Phosphoinositide 3-Kinase/Akt Pathway
Berra, E., Díaz-Meco, M. T., & Moscat, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10792 · Cited by 255
Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid
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Epidermal Growth Factor Protects Epithelial Cells against Fas-induced Apoptosis
Gibson, S. B., Tu, S. S., Oyer, R. J., Anderson, S. M., & Johnson, G. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.25.17612 · Cited by 248
A Role for MAPK/ERK in Sympathetic Neuron Survival: Protection against a p53-Dependent, JNK-Independent Induction of Apoptosis by Cytosine Arabinoside
Anderson, C. N. G., & Tolkovsky, A. M. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-02-00664.1999 · Cited by 246
Akt-Dependent and -Independent Survival Signaling Pathways Utilized by Insulin-Like Growth Factor I
Kulik, G., & Weber, M. J. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.11.6711 · Cited by 244
Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis.
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Activated Phosphatidylinositol 3-Kinase and Akt Kinase Promote Survival of Superior Cervical Neurons
Philpott, K. L., McCarthy, M. J., Klippel, A., & Rubin, L. L. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.139.3.809 · Cited by 241
Rel/NF-κB transcription factors and the control of apoptosis
Sonenshein, G. E. (1997) · Seminars in Cancer Biology · doi:10.1006/scbi.1997.0062 · Cited by 240
Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)
Borkhardt, A., Repp, R., Haas, O. A., Leis, T., Harbott, J., Kreuder, J. G., Hammermann, J., Henn, T., & Lampert, F. H. (1997) · Oncogene · doi:10.1038/sj.onc.1200814 · Cited by 238
The c-Jun N-Terminal Kinase Cascade Plays a Role in Stress-Induced Apoptosis in Jurkat Cells by Up-Regulating Fas Ligand Expression
Faris, M., Kokot, N., Latinis, K. M., Kasibhatla, S., Green, D. R., Koretzky, G. A., & Nel, A. E. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.1.134 · Cited by 231
Further evidence that the inhibition of glycogen synthase kinase‐3β by IGF‐1 is mediated by PDK1/PKB‐induced phosphorylation of Ser‐9 and not by dephosphorylation of Tyr‐216
Shaw, M., Cohen, P., & Alessi, D. R. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01235-0 · Cited by 231
Metabolic and Genetic Analyses of Apoptosis in Potassium/Serum-Deprived Rat Cerebellar Granule Cells
Miller, T. M., & Johnson Jr., E. M. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-23-07487.1996 · Cited by 228
R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways
Marte, B. M., Rodriguez-Viciana, P., Wennström, S., Warne, P. H., & Downward, J. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00028-5 · Cited by 223
Stress signals for apoptosis: ceramide and c-Jun kinase
Basu, S., & Kolesnick, R. (1998) · Oncogene · doi:10.1038/sj.onc.1202570 · Cited by 212
Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stressPreprint
Zundel, W., & Giaccia, A. J. (1998) · Genes & Development · doi:10.1101/gad.12.13.1941 · Cited by 211
The regulation of the human tumor necrosis factor alpha promoter region in macrophage, T cell, and B cell lines.
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AF6q21, a Novel Partner of the MLL Gene in t(6; 11)(q21; q23), Defines a Forkhead Transcriptional Factor Subfamily
Hillion, J., Coniat, M. L., Jonveaux, P., Berger, R., & Bernard, O. (1997) · Blood · doi:10.1182/blood.v90.9.3714 · Cited by 207
A Human Protein Kinase Bγ with Regulatory Phosphorylation Sites in the Activation Loop and in the C-terminal Hydrophobic Domain
Brodbeck, D., Cron, P. D., & Hemmings, B. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.14.9133 · Cited by 204
Molecular Cloning and Characterization of a New Member of the RAC Protein Kinase Family: Association of the Pleckstrin Homology Domain of 3 Types of RAC Protein Kinase with Protein Kinase C Subspecies and βγ Subunits of G Proteins
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Identification of a Human Akt3 (Protein Kinase B γ) Which Contains the Regulatory Serine Phosphorylation Site
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Signal transduction pathways that regulate cell survival and cell death
Dragovich, T., Rudin, C. M., & Thompson, C. B. (1998) · Oncogene · doi:10.1038/sj.onc.1202587 · Cited by 189
ras p21 protein promotes survival and fiber outgrowth of cultured embryonic neurons
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Akt, a Target of Phosphatidylinositol 3-Kinase, Inhibits Apoptosis in a Differentiating Neuronal Cell Line
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Suppression of transforming growth factor-β-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway
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See all 4,216

Authors: Datta, S. R., Brunet, A., & Greenberg, M. E.
Affiliations: Boston Children's Hospital (US)
ORCID: Datta, S. R.
Brunet, A.
Greenberg, M. E.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 1999-11-15
Volume: 13
Issue: 22
Pages: 2905-2927
ISSN: 0890-9369 (ISSN-L)
DOI: 10.1101/gad.13.22.2905
OpenAlex: W2147114673
Cited by: 4,216
References: 233
Citations by year: 2026: 27 · 2025: 36 · 2024: 45 · 2023: 47 · 2022: 60 · 2021: 68 · 2020: 87 · 2019: 86 · 2018: 81 · 2017: 94 · 2016: 90 · 2015: 140 · 2014: 136 · 2013: 149 · 2012: 150
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed (publishedVersion)
Funders: Bentham-Moxon Trust
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Keywords: cell survival, apoptosis, PI3K/Akt signaling, neurotrophins, trophic factors, developmental cell death, Bad, caspase-9, forkhead transcription factor, IκB kinase, NF-kB, neuronal survival, growth factor signaling
MeSH terms: Animals, Carrier Proteins, Cell Survival, Cell Transformation, Neoplastic, Humans, Phosphatidylinositols, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Substrate Specificity, Transcription Factors, Signal Transduction, NF-kappa B, Sequence Alignment, Apoptosis, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Phosphatidylinositol 3-Kinases, Protein Isoforms, Caspases, Glycogen Synthase Kinase 3, bcl-Associated Death Protein, Proto-Oncogene Proteins c-akt, Mice, Rats, I-kappa B Kinase, Caspase 9

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Cellular survival: a play in three Akts

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